1 00:00:05,400 --> 00:00:07,000 >> GOOD MORNING. 2 00:00:07,000 --> 00:00:09,600 I'VE SEEN A NUMBER OF SLIDES UP 3 00:00:09,600 --> 00:00:14,200 THAT SAY NIAID BUT THIS IS A 4 00:00:14,200 --> 00:00:17,720 JOINT CONFERENCE WORKSHOP 5 00:00:17,720 --> 00:00:21,560 SPONSORED BY NIAID, NIA, NIDCR. 6 00:00:21,560 --> 00:00:25,920 AS YOU HEARD, I'M THE ACTING 7 00:00:25,920 --> 00:00:27,040 DIRECTOR OF NIAID. 8 00:00:27,040 --> 00:00:28,880 PEOPLE LOOKING FOR THE SUCCESSOR 9 00:00:28,880 --> 00:00:31,640 FOR DR. FAUCI ARE IN THE ROOM, I 10 00:00:31,640 --> 00:00:34,160 APPRECIATE THAT THEY HAVE BEEN 11 00:00:34,160 --> 00:00:35,360 WORKING RAPIDLY. 12 00:00:35,360 --> 00:00:37,320 THANK YOU. 13 00:00:37,320 --> 00:00:45,840 BY WAY OF BACKGROUND, DO WE HAVE 14 00:00:45,840 --> 00:00:47,200 MY SLIDES? 15 00:00:47,200 --> 00:00:48,280 THE WORKSHOP FOCUS ACCORDING TO 16 00:00:48,280 --> 00:00:50,240 THE INFORMATION I RECEIVED BY 17 00:00:50,240 --> 00:00:52,760 E-MAIL, KNOWLEDGE OF IMMUNE 18 00:00:52,760 --> 00:00:54,840 FUNCTION DURING AGING, AND 19 00:00:54,840 --> 00:01:00,560 IMPROVED METHODS TO DEFINE 20 00:01:00,560 --> 00:01:01,880 IMMUNOLOGIC STATES, DOES THAT 21 00:01:01,880 --> 00:01:09,200 COME UP ON MY SCREEN? 22 00:01:09,200 --> 00:01:10,960 THERE WE GO. 23 00:01:10,960 --> 00:01:12,680 SINGLE CELL TECHNOLOGY FOR 24 00:01:12,680 --> 00:01:15,000 INTERROGATION OF IMMUNE CELLS, 25 00:01:15,000 --> 00:01:25,520 AND MECHANISMS OF IMMUNE AGING 26 00:01:26,680 --> 00:01:34,840 AND CHRONIC DISEASE. 27 00:01:34,840 --> 00:01:35,920 SORRY. 28 00:01:35,920 --> 00:01:42,160 NOT RESPONDING. 29 00:01:42,160 --> 00:01:46,000 CAN I GO BACK? 30 00:01:46,000 --> 00:01:47,640 NOW FORWARD ONE. 31 00:01:47,640 --> 00:01:47,920 OKAY. 32 00:01:47,920 --> 00:01:50,680 SO, YES, THIS IS A JOINT 33 00:01:50,680 --> 00:01:53,000 CONFERENCE, IT REFLECTS MANY 34 00:01:53,000 --> 00:01:56,320 YEARS OF COOPERATION BETWEEN OUR 35 00:01:56,320 --> 00:01:58,120 INSTITUTES GOING BACK TO 2009, 36 00:01:58,120 --> 00:02:01,520 WITH AN RFA FOR REJUVENATING THE 37 00:02:01,520 --> 00:02:04,360 AGED IMMUNE SYSTEM BETWEEN NIAID 38 00:02:04,360 --> 00:02:08,280 AND NIA, AND THEN REPEAT IN 2014 39 00:02:08,280 --> 00:02:10,840 AGAIN NIAID AND NIA, IMMUNITY IN 40 00:02:10,840 --> 00:02:13,800 THE ELDERLY, AND THEN WE WERE 41 00:02:13,800 --> 00:02:16,640 JOINED BY NIDCR WITH IMMUNITY IN 42 00:02:16,640 --> 00:02:20,000 THE ELDERLY IN 2019, AND THEN AN 43 00:02:20,000 --> 00:02:22,880 RFA THAT IS GOING TO COME TO 44 00:02:22,880 --> 00:02:24,160 FRUITION IN 2024 BUT 45 00:02:24,160 --> 00:02:25,800 APPLICATIONS HAVE BEEN SUBMITTED 46 00:02:25,800 --> 00:02:34,760 ALREADY, AGAIN INVOLVING THE 47 00:02:34,760 --> 00:02:35,880 THREE INSTITUTES. 48 00:02:35,880 --> 00:02:38,840 THIS IS THE FUNDING FOR AGING 49 00:02:38,840 --> 00:02:43,320 AND IMMUNITY WHICH SHOWS A 50 00:02:43,320 --> 00:02:46,480 PRETTY ROBUST INVESTMENT OF OVER 51 00:02:46,480 --> 00:02:47,840 $100 MILLION BY ESPECIALLY NIA 52 00:02:47,840 --> 00:02:50,880 BUT ALSO NIAID, SO IN TERMS OF 53 00:02:50,880 --> 00:02:52,200 SOLICITED RESEARCH AND AMOUNT OF 54 00:02:52,200 --> 00:02:53,480 MONEY THAT'S BEEN PUT INTO THIS 55 00:02:53,480 --> 00:02:55,480 AREA, I THINK IT IS CLEAR THAT 56 00:02:55,480 --> 00:02:57,520 THERE'S A SERIOUS COMMITMENT ON 57 00:02:57,520 --> 00:03:01,520 THE PART OF NIH TO THIS ISSUE OF 58 00:03:01,520 --> 00:03:06,560 IMMUNITY IN THE AGING 59 00:03:06,560 --> 00:03:07,120 POPULATION. 60 00:03:07,120 --> 00:03:08,520 NEXT SLIDE. 61 00:03:08,520 --> 00:03:09,520 THEN TO HIGHLIGHT WHAT WE'VE 62 00:03:09,520 --> 00:03:12,360 LEARNED IN COVID THE PARTICULAR 63 00:03:12,360 --> 00:03:14,760 PROBLEMS OF AGING, WHERE THE 64 00:03:14,760 --> 00:03:17,640 HIGHEST AT-RISK GROUP WERE THOSE 65 00:03:17,640 --> 00:03:18,480 OVER 65. 66 00:03:18,480 --> 00:03:19,800 WE ALSO ACCORDING TO THIS 67 00:03:19,800 --> 00:03:21,320 ARTICLE THINK WE'VE LEARNED THAT 68 00:03:21,320 --> 00:03:22,520 YOU CAN IDENTIFY MARKERS THAT 69 00:03:22,520 --> 00:03:24,280 SHOW THERE ARE SOME PEOPLE WHO 70 00:03:24,280 --> 00:03:26,680 ARE TRULY AT RISK AS THEY AGE 71 00:03:26,680 --> 00:03:28,640 AND OTHERS WHO SHOW RESILIENCE. 72 00:03:28,640 --> 00:03:30,400 SO THERE'S LOTS TO LEARN ABOUT 73 00:03:30,400 --> 00:03:33,240 WHAT IS HAPPENING IN THE AGING 74 00:03:33,240 --> 00:03:34,480 IMMUNE SYSTEM. 75 00:03:34,480 --> 00:03:37,400 LET ME CONCLUDE, NEXT SLIDE, BY 76 00:03:37,400 --> 00:03:38,720 JUST THANKING THE ORGANIZING 77 00:03:38,720 --> 00:03:41,240 GROUP WHO PUT IN I KNOW A LOT OF 78 00:03:41,240 --> 00:03:45,280 THOUGHT, A LOT OF EFFORT AND 79 00:03:45,280 --> 00:03:47,800 TIME TO MAKE THIS WORKSHOP 80 00:03:47,800 --> 00:03:49,000 POSSIBLE AND IT'S FUN TO BE BACK 81 00:03:49,000 --> 00:03:50,760 IN PERSON. 82 00:03:50,760 --> 00:03:56,240 THANK YOU VERY MUCH. 83 00:03:56,240 --> 00:04:06,680 >> THANK YOU VERY MUCH. 84 00:04:10,880 --> 00:04:16,600 NOW DR. RICHARD HODES WILL GIVE 85 00:04:16,600 --> 00:04:16,840 REMARKS. 86 00:04:16,840 --> 00:04:19,640 >> TRIGGERED BY THE SLIDES HUGH 87 00:04:19,640 --> 00:04:21,360 WAS SHOWING, 2009 THE TITLE OF 88 00:04:21,360 --> 00:04:23,720 THE SLIDES REFLECTS, IF YOU 89 00:04:23,720 --> 00:04:25,240 WILL, THE LIMITED STATUS OF WHAT 90 00:04:25,240 --> 00:04:27,760 WE UNDERSTOOD OR TALKED ABOUT IN 91 00:04:27,760 --> 00:04:30,280 TERMS OF AGING VERSUS THE IMMUNE 92 00:04:30,280 --> 00:04:31,080 SYSTEM. 93 00:04:31,080 --> 00:04:31,680 BOTH DISCIPLINES WERE MOVING 94 00:04:31,680 --> 00:04:33,120 FORWARD BUT WE HAD A MEETING TO 95 00:04:33,120 --> 00:04:37,840 TRY TO FIND OUT WHY, THAT WAS 96 00:04:37,840 --> 00:04:41,120 THE FOCUS FOR OUR DISCIPLINES. 97 00:04:41,120 --> 00:04:43,760 SINCE THEN IT'S REMARKABLE. 98 00:04:43,760 --> 00:04:47,920 IN THE FIELD OF IMMUNOLOGY MORE 99 00:04:47,920 --> 00:04:49,120 SOPHISTICATED MOLECULAR CELLULAR 100 00:04:49,120 --> 00:04:51,840 PROBES, SAME THING HAPPENING IN 101 00:04:51,840 --> 00:04:54,040 AGING RESEARCH AND CONVERGENCE 102 00:04:54,040 --> 00:04:55,040 HAS BEEN SPECTACULAR SO A LOT OF 103 00:04:55,040 --> 00:04:58,320 WHAT GOES ON IN AGING NOW IS 104 00:04:58,320 --> 00:05:00,880 ATTRIBUTING TO INFLAMMATORY 105 00:05:00,880 --> 00:05:04,800 IMMUNE RESPONSES, AMONG THE 106 00:05:04,800 --> 00:05:05,680 HALLMARKS OF AGINGI 107 00:05:05,680 --> 00:05:06,960 IMMUNOSENESCENCE APPEAR TO BE 108 00:05:06,960 --> 00:05:08,640 DRAMATICALLY OCCURRING IN THE 109 00:05:08,640 --> 00:05:09,320 IMMUNE SYSTEM, EVEN FINDINGS 110 00:05:09,320 --> 00:05:10,520 THAT SUGGEST THE WHOLE ANIMAL 111 00:05:10,520 --> 00:05:12,160 THAT MAY BE THE CHANGES 112 00:05:12,160 --> 00:05:15,880 OCCURRING IN THE IMMUNE SYSTEM, 113 00:05:15,880 --> 00:05:17,200 THOSE WRITE SENTINEL AND CENTRAL 114 00:05:17,200 --> 00:05:19,040 TO THINGS IN THE WHOLE BODY, 115 00:05:19,040 --> 00:05:21,920 IT'S AN EXTRAORDINARY AND 116 00:05:21,920 --> 00:05:23,320 EXCITING TIME, THE CONVERGENCE 117 00:05:23,320 --> 00:05:25,840 REFLECTED IN FUNDING WITH GOOD 118 00:05:25,840 --> 00:05:26,840 SCIENCE BEING PROPOSED, I'M 119 00:05:26,840 --> 00:05:28,360 EXCITED TO BE HERE AS PART OF 120 00:05:28,360 --> 00:05:29,560 THIS COLLABORATION ACROSS THE 121 00:05:29,560 --> 00:05:31,240 THREE INSTITUTES AND SHARE WITH 122 00:05:31,240 --> 00:05:33,720 YOU THE NEXT AGE OF EXCITING 123 00:05:33,720 --> 00:05:34,320 SCIENCE. 124 00:05:34,320 --> 00:05:36,600 THAT'S ALL. 125 00:05:36,600 --> 00:05:40,080 LET IT BEGIN. 126 00:05:40,080 --> 00:05:44,440 >> THANK YOU VERY MUCH, DR. 127 00:05:44,440 --> 00:05:44,640 HODES. 128 00:05:44,640 --> 00:05:47,280 NOW PREETHI CHANDER WILL SPEAK 129 00:05:47,280 --> 00:05:53,520 ON BEHALF OF THE DIRECTOR OF 130 00:05:53,520 --> 00:05:56,200 NIDCR, UNABLE TO BE HERE TODAY. 131 00:05:56,200 --> 00:05:58,800 >> YES, GOOD MORNING. 132 00:05:58,800 --> 00:06:00,400 LIKE MERCY SAID, UNFORTUNATELY 133 00:06:00,400 --> 00:06:03,840 ALREADY RENA D'SOUZA COULDN'T 134 00:06:03,840 --> 00:06:06,560 MAKE IT, I'M THE PROGRAM 135 00:06:06,560 --> 00:06:08,920 OFFICER, I MANAGE BIOLOGY AND 136 00:06:08,920 --> 00:06:11,600 IMMUNOLOGY PROGRAM, GLAD TO BE 137 00:06:11,600 --> 00:06:14,880 PARTICIPATING IN THIS GREAT 138 00:06:14,880 --> 00:06:15,280 WORKSHOP. 139 00:06:15,280 --> 00:06:18,480 SO SINCE WE'RE ONE OF THE FEW 140 00:06:18,480 --> 00:06:19,920 ORGAN-SPECIFIC -- IS THERE A WAY 141 00:06:19,920 --> 00:06:24,040 TO GO BACK? 142 00:06:24,040 --> 00:06:27,000 I WANT YOU TO KEEP IN MIND ABOUT 143 00:06:27,000 --> 00:06:28,480 THE PERIPHERAL TISSUES AS YOU 144 00:06:28,480 --> 00:06:29,960 THINK AND PARTICIPATE IN THE 145 00:06:29,960 --> 00:06:32,240 DISCUSSIONS IN THE NEXT FEW 146 00:06:32,240 --> 00:06:32,480 DAYS. 147 00:06:32,480 --> 00:06:35,640 SO, I COME FROM ORAL HEALTH 148 00:06:35,640 --> 00:06:37,280 PERSPECTIVE, I WANTED TO SAY 149 00:06:37,280 --> 00:06:40,360 THAT AS THE AGING POPULATION OF 150 00:06:40,360 --> 00:06:42,760 65 AND OLDER ARE INCREASING 151 00:06:42,760 --> 00:06:44,280 RAPIDLY, THE UNIQUE THING ABOUT 152 00:06:44,280 --> 00:06:46,480 THIS POPULATION IS THEY ARE BY 153 00:06:46,480 --> 00:06:50,560 FAR THE MOST DIVERSE IN TERMS OF 154 00:06:50,560 --> 00:06:51,520 RACE/ETHNICITY, SOCIOECONOMIC 155 00:06:51,520 --> 00:06:52,720 STATUS, HENCE THE HEALTH AND 156 00:06:52,720 --> 00:06:55,720 FUNCTIONAL STATUS THAT WE'RE 157 00:06:55,720 --> 00:07:00,720 GOING TO SEE. 158 00:07:00,720 --> 00:07:05,280 I WANT TO DRAW YOUR ATTENTION 159 00:07:05,280 --> 00:07:10,400 TODAY TO THE ORAL HEALTH IN 160 00:07:10,400 --> 00:07:13,080 AMERICA REPORT RELEASED IN 2021. 161 00:07:13,080 --> 00:07:15,840 IT INCLUDES INPUT FROM MULTIPLE 162 00:07:15,840 --> 00:07:18,240 CONTRIBUTORS, AND EXAMINES OVER 163 00:07:18,240 --> 00:07:19,960 TWO DECADES OF RESEARCH SINCE 164 00:07:19,960 --> 00:07:22,520 THE LAST U.S. SURGEON GENERAL 165 00:07:22,520 --> 00:07:24,800 REPORT FROM 2000. 166 00:07:24,800 --> 00:07:27,880 IT'S ORGANIZED ACROSS THE 167 00:07:27,880 --> 00:07:29,600 LIFESPAN, CHALLENGES, 168 00:07:29,600 --> 00:07:31,400 OPPORTUNITIES, BUT MOST 169 00:07:31,400 --> 00:07:33,080 IMPORTANTLY ARTICULATES FUTURE 170 00:07:33,080 --> 00:07:37,800 PROVISION AND CALL TO ACTION. 171 00:07:37,800 --> 00:07:38,280 THANK YOU. 172 00:07:38,280 --> 00:07:40,840 ONE OF THE SECTIONS IS 173 00:07:40,840 --> 00:07:42,800 SPECIFICALLY DEDICATED TO ORAL 174 00:07:42,800 --> 00:07:46,280 HEALTH IN OLDER ADULTS. 175 00:07:46,280 --> 00:07:48,840 IF YOU HAVE TIME, TAKE A LOOK. 176 00:07:48,840 --> 00:07:49,480 AS THE POPULATION KEEPS 177 00:07:49,480 --> 00:07:51,760 INCREASING AND THERE ARE 178 00:07:51,760 --> 00:07:53,720 INCREASED EXPECTATIONS OF ORAL 179 00:07:53,720 --> 00:07:54,520 HEALTH QUALITY OF RESEARCH, 180 00:07:54,520 --> 00:07:58,440 THERE ARE MORE OLDER ADULTS 181 00:07:58,440 --> 00:08:00,400 SEEKING DENTAL CARE, THAT'S ORAL 182 00:08:00,400 --> 00:08:02,600 HYGIENE AND WITH THAT INCREASE 183 00:08:02,600 --> 00:08:05,640 IN CHRONIC DISEASES IN THIS 184 00:08:05,640 --> 00:08:07,080 PARTICULAR POPULATION THERE'S 185 00:08:07,080 --> 00:08:08,720 INCREASED NEED TO ADDRESS ORAL 186 00:08:08,720 --> 00:08:12,320 HEALTH IN THE DISABLED OR 187 00:08:12,320 --> 00:08:13,200 CARE-GIVING SETTING. 188 00:08:13,200 --> 00:08:15,480 SO, THE KEY CHALLENGES THAT THIS 189 00:08:15,480 --> 00:08:17,800 POPULATION FACES WITH REGARD TO 190 00:08:17,800 --> 00:08:21,840 ORAL HEALTH IS THAT AS WE GET 191 00:08:21,840 --> 00:08:23,480 OLDER THERE'S ALSO A CHALLENGE 192 00:08:23,480 --> 00:08:25,480 WITH ACCESS TO DENTAL CARE IN 193 00:08:25,480 --> 00:08:29,920 TERMS OF INSURANCE AND WITH THAT 194 00:08:29,920 --> 00:08:31,480 AND INCREASING PROPENSITY OF 195 00:08:31,480 --> 00:08:33,680 SYSTEMIC DISEASE AND CHRONIC 196 00:08:33,680 --> 00:08:34,880 INFLAMMATION AND MEDICATIONS 197 00:08:34,880 --> 00:08:37,720 THAT ARE PRESCRIBED TO THIS 198 00:08:37,720 --> 00:08:38,800 POPULATION THERE'S INCREASED 199 00:08:38,800 --> 00:08:42,640 PROBLEM OF DRY MOUTH IN OLDER 200 00:08:42,640 --> 00:08:44,800 ADULTS, ALSO INCREASE IN 201 00:08:44,800 --> 00:08:48,560 DISEASES THAT HAVE ORAL 202 00:08:48,560 --> 00:08:49,160 MANIFESTATION. 203 00:08:49,160 --> 00:08:50,760 I WANT TO LEAVE WITH YOU A 204 00:08:50,760 --> 00:08:53,240 COUPLE ADVANCES TO KEEP IN MIND 205 00:08:53,240 --> 00:08:58,120 THROUGH THE NEXT TWO DAYS. 206 00:08:58,120 --> 00:09:02,200 SO, THIS IS FROM JONATHAN AHM 207 00:09:02,200 --> 00:09:03,840 WHO ASKED THE QUESTION IS IT 208 00:09:03,840 --> 00:09:06,560 POSSIBLE TO TREAT GUM DISEASE BY 209 00:09:06,560 --> 00:09:08,400 TARGETING AGING? 210 00:09:08,400 --> 00:09:13,120 WHAT HE FOUND IS THAT TREATMENT 211 00:09:13,120 --> 00:09:15,560 WITH RAPAMYCIN IN MICE 212 00:09:15,560 --> 00:09:17,720 REJUVENATES THE ORAL MICROBIOME 213 00:09:17,720 --> 00:09:21,800 TO A MORE YOUTHFUL COMPETITION, 214 00:09:21,800 --> 00:09:22,440 ATTENUATES INFLAMMATIONS, 215 00:09:22,440 --> 00:09:22,960 INCREASES REGENERATION. 216 00:09:22,960 --> 00:09:28,240 ON THE RIGHT IS THE BIG STUDY 217 00:09:28,240 --> 00:09:32,280 THE BUFFALO STUDY LOOKING AT 218 00:09:32,280 --> 00:09:35,240 POST-MENOPAUSAL WOMEN, AND 219 00:09:35,240 --> 00:09:37,240 LOOKED AT CORRELATING 220 00:09:37,240 --> 00:09:40,360 ASSOCIATION OF MICROBIOME WITH 221 00:09:40,360 --> 00:09:42,720 ALVEOLAR BONE LOSS AND 222 00:09:42,720 --> 00:09:43,880 PERIODONTITIS. 223 00:09:43,880 --> 00:09:47,080 THEY FOUND YEARS BEFORE 224 00:09:47,080 --> 00:09:48,360 PERIODONTAL BONE LOSS, 225 00:09:48,360 --> 00:09:51,200 MICROBIOME SHOWS CHANGES, ALSO 226 00:09:51,200 --> 00:09:52,000 DIFFERENCE BETWEEN WOMEN WHO 227 00:09:52,000 --> 00:09:55,040 HAVE USED OR ARE CURRENT USERS 228 00:09:55,040 --> 00:09:56,160 OF HORMONAL THERAPY, THESE ARE 229 00:09:56,160 --> 00:09:59,000 CERTAIN THINGS TO KEEP IN MIND 230 00:09:59,000 --> 00:10:00,720 AND THE LAST ONE I WANT TO LEAVE 231 00:10:00,720 --> 00:10:02,480 YOU WITH IS THIS STUDY THAT'S 232 00:10:02,480 --> 00:10:05,200 DONE OUT OF THE U.K. WHERE THEY 233 00:10:05,200 --> 00:10:07,720 LOOKED AT ORAL HEALTH AND HOW 234 00:10:07,720 --> 00:10:10,800 THAT CAN BE ASSOCIATED WITH 235 00:10:10,800 --> 00:10:13,520 REDUCED MUSCLE STRENGTH AND 236 00:10:13,520 --> 00:10:15,080 COULD BE INDICATOR OF FRAILTY 237 00:10:15,080 --> 00:10:18,440 AND LOSS OF PHYSICAL STRENGTH 238 00:10:18,440 --> 00:10:20,840 LATER IN LIFE. 239 00:10:20,840 --> 00:10:24,360 WITH THAT SAID, I THINK ALL THE 240 00:10:24,360 --> 00:10:25,240 AREAS THAT WE COVER IN THIS 241 00:10:25,240 --> 00:10:28,280 CLASS IN THE NEXT TWO DAYS CAN 242 00:10:28,280 --> 00:10:30,360 ONLY BE ADDRESSED BY HAVING 243 00:10:30,360 --> 00:10:31,920 LONG-TERM VISION IN TERMS OF THE 244 00:10:31,920 --> 00:10:32,560 CONTINUUM OF TRANSLATION WHICH 245 00:10:32,560 --> 00:10:34,960 MANY OF YOU MIGHT BE FAMILIAR 246 00:10:34,960 --> 00:10:36,960 WITH AND THEY CAN ONLY BE 247 00:10:36,960 --> 00:10:39,800 ADDRESSED BY ADDRESSING ALL THE 248 00:10:39,800 --> 00:10:41,960 FINDERS ACROSS THE SPECTRUM. 249 00:10:41,960 --> 00:10:45,040 NIDCR IS EXCITED ABOUT THIS 250 00:10:45,040 --> 00:10:46,560 PARTNERSHIP WITH NIAID AND NIA 251 00:10:46,560 --> 00:10:50,280 AND LOOK FORWARD TO TWO DAYS OF 252 00:10:50,280 --> 00:10:50,560 DISCUSSION. 253 00:10:50,560 --> 00:10:59,000 AND THANK YOU VERY MUCH. 254 00:10:59,000 --> 00:11:00,800 >> THANK YOU VERY MUCH. 255 00:11:00,800 --> 00:11:04,040 AT THIS MOMENT WE'LL THEN GO ON 256 00:11:04,040 --> 00:11:06,160 TO OUR KEYNOTE ADDRESS, GIVEN BY 257 00:11:06,160 --> 00:11:07,800 DR. MARK DAVIS, FROM STANFORD. 258 00:11:07,800 --> 00:11:11,480 AND HE WILL BE SPEAKING ON HUMAN 259 00:11:11,480 --> 00:11:14,520 IMMUNE ORGANIZE TO ANALYZE 260 00:11:14,520 --> 00:11:15,560 VACCINE RESPONSES, AUTOIMMUNITY, 261 00:11:15,560 --> 00:11:16,880 AND AGING. 262 00:11:16,880 --> 00:11:23,760 THANK YOU, MARK. 263 00:11:23,760 --> 00:11:26,080 >> GREAT. 264 00:11:26,080 --> 00:11:27,480 THANKS VERY MUCH, MERCY. 265 00:11:27,480 --> 00:11:31,000 IT'S GREAT TO BE BACK HERE AT 266 00:11:31,000 --> 00:11:34,600 NIH IN AN IN-PERSON MEETING, 267 00:11:34,600 --> 00:11:38,240 WHICH IS SO MUCH MORE 268 00:11:38,240 --> 00:11:40,480 INFORMATION TRANSFER MORE 269 00:11:40,480 --> 00:11:40,720 EASILY. 270 00:11:40,720 --> 00:11:43,360 SO, I'M NOT GOING TO TALK 271 00:11:43,360 --> 00:11:44,680 SPECIFICALLY ABOUT AGING. 272 00:11:44,680 --> 00:11:46,320 WE HAVE SOME DATA, SOME 273 00:11:46,320 --> 00:11:52,640 PROMISING DATA, OF COURSE WE'VE 274 00:11:52,640 --> 00:11:56,320 BEEN DOING COHORTS, AGING THE 275 00:11:56,320 --> 00:12:01,080 THE LONGEST-RUNNING AT 15 YEARS, 276 00:12:01,080 --> 00:12:02,520 THE STANFORD COHORT ON AGING, 277 00:12:02,520 --> 00:12:04,680 BUT I'M NOT GOING TO TALK ABOUT 278 00:12:04,680 --> 00:12:06,560 THAT TODAY. 279 00:12:06,560 --> 00:12:08,440 MAYBE DAVID FURMAN WILL. 280 00:12:08,440 --> 00:12:09,280 I'LL TALK ABOUT SOMETHING 281 00:12:09,280 --> 00:12:11,880 HAPPENING THAT I THINK WILL 282 00:12:11,880 --> 00:12:16,080 TOTALLY CHANGE HOW WE DO HUMAN 283 00:12:16,080 --> 00:12:16,440 IMMUNOLOGY. 284 00:12:16,440 --> 00:12:22,160 AND, YOU KNOW, I THINK HUMAN 285 00:12:22,160 --> 00:12:25,120 IMMUNOLOGY HAS STRUGGLED TO MAKE 286 00:12:25,120 --> 00:12:28,520 PROGRESS, SO MANY CHALLENGES IN 287 00:12:28,520 --> 00:12:30,280 TERMS OF TECHNOLOGIES AND SO 288 00:12:30,280 --> 00:12:32,280 FORTH, MOSTLY DESIGNED AROUND 289 00:12:32,280 --> 00:12:33,480 MICE, ALSO THE FIELD OF 290 00:12:33,480 --> 00:12:35,200 IMMUNOLOGY HAS BEEN HEAVILY 291 00:12:35,200 --> 00:12:39,600 DOMINATED BY INBRED MICE AND 292 00:12:39,600 --> 00:12:43,080 PEOPLE WANT TO KEEP DOING THAT 293 00:12:43,080 --> 00:12:53,480 BUT -- HOW DO I MOVE? 294 00:12:56,120 --> 00:12:56,520 HERE? 295 00:12:56,520 --> 00:12:58,760 NOT ALL BUT SOME OF THE MAJOR 296 00:12:58,760 --> 00:13:01,800 PROBLEMS WE FACE BECAUSE IT'S 297 00:13:01,800 --> 00:13:03,880 ONLY BY ELABORATING THAT WE CAN 298 00:13:03,880 --> 00:13:06,760 START TO THINK ABOUT SOLUTIONS, 299 00:13:06,760 --> 00:13:09,120 AND WHAT WE'VE SEEN REPEATEDLY 300 00:13:09,120 --> 00:13:11,120 OVER THE LAST 15 YEARS OF OUR 301 00:13:11,120 --> 00:13:14,080 WORK IS REALLY WE FIND SOMETHING 302 00:13:14,080 --> 00:13:18,680 INTERESTING IN A HUMAN COHORT OR 303 00:13:18,680 --> 00:13:20,040 THIS POPULATION, AND TO GO ANY 304 00:13:20,040 --> 00:13:23,480 FURTHER WE HAVE TO GO TO MICE TO 305 00:13:23,480 --> 00:13:26,440 GET A KNOCKOUT OR SOMETHING, AND 306 00:13:26,440 --> 00:13:28,120 THIS HAS BEEN THE REALITY. 307 00:13:28,120 --> 00:13:32,520 SO IT MEANS WE CAN NEVER STUDY 308 00:13:32,520 --> 00:13:33,600 HUMAN IMMUNE RESPONSES IF THEY 309 00:13:33,600 --> 00:13:34,440 ARE DIFFERENT IN MICE. 310 00:13:34,440 --> 00:13:36,560 AND WE KNOW THEY ARE DIFFERENT. 311 00:13:36,560 --> 00:13:38,520 THERE'S ABUNDANT EVIDENCE THAT 312 00:13:38,520 --> 00:13:40,760 THERE'S LOTS OF DIFFERENCES IN 313 00:13:40,760 --> 00:13:42,360 AERATION, IF NOTHING ELSE, BUT 314 00:13:42,360 --> 00:13:44,200 THERE COULD BE FUNDAMENTAL 315 00:13:44,200 --> 00:13:45,800 PATHWAYS IN HUMAN IMMUNITY THAT 316 00:13:45,800 --> 00:13:47,360 ARE NOT PRESENT IN MICE. 317 00:13:47,360 --> 00:13:52,280 AND THEN YOU CAN'T ACTUALLY DO 318 00:13:52,280 --> 00:13:53,400 ANYTHING ABOUT THAT. 319 00:13:53,400 --> 00:13:57,760 IT DIES ON THE VINE BECAUSE HOW 320 00:13:57,760 --> 00:14:00,920 DO YOU GO FURTHER? 321 00:14:00,920 --> 00:14:02,560 HUMANIZED MICE HAS BEEN A WORK 322 00:14:02,560 --> 00:14:04,200 IN PROGRESS FOR 30-SOME YEARS, 323 00:14:04,200 --> 00:14:05,920 CAN YOU DO SOME THINGS BUT THEY 324 00:14:05,920 --> 00:14:07,000 DON'T DO A LOT OF THINGS WE 325 00:14:07,000 --> 00:14:08,920 WOULD LOOK THEM TO DO AND YOU'RE 326 00:14:08,920 --> 00:14:09,920 FUNDAMENTALLY TRYING TO BALANCE 327 00:14:09,920 --> 00:14:13,520 THE IMMUNE SYSTEM OF ONE SPECIES 328 00:14:13,520 --> 00:14:15,480 IN THE FRAMEWORK OF ANOTHER, AND 329 00:14:15,480 --> 00:14:18,000 THERE'S ALL KINDS OF ISSUES 330 00:14:18,000 --> 00:14:18,320 THERE. 331 00:14:18,320 --> 00:14:20,800 SO, I THOUGHT WE NEEDED AN 332 00:14:20,800 --> 00:14:22,640 ENTIRELY HUMAN SYSTEM THAT CAN 333 00:14:22,640 --> 00:14:25,760 BE MANIPULATED SO THAT WE CAN 334 00:14:25,760 --> 00:14:27,240 ACTUALLY TEST HYPOTHESES IN THAT 335 00:14:27,240 --> 00:14:30,480 SYSTEM AND NOT HAVE TO ALWAYS 336 00:14:30,480 --> 00:14:32,240 RELY ON MICE BECAUSE MICE ARE 337 00:14:32,240 --> 00:14:33,280 GOING TO BE DIFFERENT. 338 00:14:33,280 --> 00:14:34,880 AND THE OTHER THING THAT'S 339 00:14:34,880 --> 00:14:37,720 DRIVEN US INTO THE ORGANOID 340 00:14:37,720 --> 00:14:40,200 BUSINESS IS -- WE HAVE A LOT OF 341 00:14:40,200 --> 00:14:41,040 EXPERIENCE ASSEMBLING AND 342 00:14:41,040 --> 00:14:43,160 WORKING WITH COHORTS OVER THE 343 00:14:43,160 --> 00:14:43,800 LAST 15 YEARS. 344 00:14:43,800 --> 00:14:46,120 THAT'S BEEN GREAT. 345 00:14:46,120 --> 00:14:48,320 WE'VE BEEN AGING COHORTS, TWIN 346 00:14:48,320 --> 00:14:48,560 COHORTS. 347 00:14:48,560 --> 00:14:52,360 IT'S BEEN A REALLY GOOD WAY TO 348 00:14:52,360 --> 00:14:55,440 KIND OF EXPLORE THE IMMUNE 349 00:14:55,440 --> 00:14:56,400 RESPONSES IN BROAD POPULATIONS 350 00:14:56,400 --> 00:14:57,280 OF SPECIFIC TYPES. 351 00:14:57,280 --> 00:15:01,240 BUT IT TAKES A LONG, LONG TIME. 352 00:15:01,240 --> 00:15:04,280 AND JUST IN TERMS OF RECRUITING 353 00:15:04,280 --> 00:15:06,120 YOUNG PEOPLE, YOU KNOW, ONE OF 354 00:15:06,120 --> 00:15:06,800 THE WORST SITUATIONS I CAN 355 00:15:06,800 --> 00:15:09,080 IMAGINE IS THAT YOU HAVE A 356 00:15:09,080 --> 00:15:09,680 REALLY BRIGHT GRADUATE STUDENT 357 00:15:09,680 --> 00:15:12,120 SITTING IN FRONT OF YOU, A GREAT 358 00:15:12,120 --> 00:15:14,760 REALLY, YOU SAY THAT'S JUST A 359 00:15:14,760 --> 00:15:16,680 GREAT IDEA, FANTASTIC, LET'S 360 00:15:16,680 --> 00:15:18,640 WRITE A GRANT, AND SET UP A 361 00:15:18,640 --> 00:15:19,160 COHORT. 362 00:15:19,160 --> 00:15:21,160 AND IN THREE OR FIVE YEARS WE'LL 363 00:15:21,160 --> 00:15:23,920 ACTUALLY BE ABLE TO TEST THAT 364 00:15:23,920 --> 00:15:24,880 IDEA. 365 00:15:24,880 --> 00:15:28,720 AND THE STUDENT WILL SAY BYE! 366 00:15:28,720 --> 00:15:30,680 SHOW ME THE MICE! 367 00:15:30,680 --> 00:15:33,640 YOU KNOW, IT'S A NON-STARTER FOR 368 00:15:33,640 --> 00:15:34,480 A POSTDOCTORAL STUDENT. 369 00:15:34,480 --> 00:15:37,360 THINK ABOUT THAT. 370 00:15:37,360 --> 00:15:44,800 THINK ABOUT HOW YOU CAN LOSE THE 371 00:15:44,800 --> 00:15:48,760 GREATEST TALENT CROSSING OUR 372 00:15:48,760 --> 00:15:49,480 DESK HERE. 373 00:15:49,480 --> 00:15:50,480 THAT'S NOT COOL. 374 00:15:50,480 --> 00:15:52,920 AND NOW I SHOULD HAVE LEARNED 375 00:15:52,920 --> 00:15:57,080 FROM WHAT -- OH, THERE WE GO. 376 00:15:57,080 --> 00:15:57,520 NEXT. 377 00:15:57,520 --> 00:16:07,640 THIS IS AN AWKWARD SYSTEM. 378 00:16:07,640 --> 00:16:07,880 OKAY. 379 00:16:07,880 --> 00:16:09,760 WHY DO WE THINK WE'LL SEE 380 00:16:09,760 --> 00:16:11,800 DIFFERENCES IN HUMANS IN TERMS 381 00:16:11,800 --> 00:16:13,880 OF FUNDAMENTAL DIFFERENCES? 382 00:16:13,880 --> 00:16:17,120 LOOK AT VACCINE RESPONSES. 383 00:16:17,120 --> 00:16:20,680 WE'VE BEEN VERY LUCKY WITH 384 00:16:20,680 --> 00:16:23,320 SARS-COV-2. 385 00:16:23,320 --> 00:16:24,840 THAT JUST FELL OUT ESPECIALLY 386 00:16:24,840 --> 00:16:26,480 WITH RNA VACCINES, HUGELY 387 00:16:26,480 --> 00:16:27,480 SUCCESSFUL, HUGELY FAST. 388 00:16:27,480 --> 00:16:28,800 THAT AIN'T THE CASE WITH A LOT 389 00:16:28,800 --> 00:16:31,000 OF OTHER VACCINE TRIALS. 390 00:16:31,000 --> 00:16:34,000 WE HAVE REPEATED FAILURES. 391 00:16:34,000 --> 00:16:36,680 AND MOSTLY THE INDUSTRY HAS NOT 392 00:16:36,680 --> 00:16:41,600 INNOVATED FOR THE MOST PART. 393 00:16:41,600 --> 00:16:44,320 THAT'S BIONTECH AND MODERNA 394 00:16:44,320 --> 00:16:45,960 COULD BLOW PAST TRADITIONAL 395 00:16:45,960 --> 00:16:48,680 VACCINE MAKERS LIKE NOBODY'S 396 00:16:48,680 --> 00:16:48,960 BUSINESS. 397 00:16:48,960 --> 00:16:52,320 I HEARD ABOUT RNA VACCINES 398 00:16:52,320 --> 00:16:53,320 CONSULTING FOR NOVARTIS TEN 399 00:16:53,320 --> 00:16:54,240 YEARS AGO, PEOPLE SAID THIS WAS 400 00:16:54,240 --> 00:16:56,040 THE FUTURE, THIS IS HOW WE ADAPT 401 00:16:56,040 --> 00:16:58,440 AND MAKE ALL THE VACCINES IN 402 00:16:58,440 --> 00:17:00,760 THIS ONE ROOM. 403 00:17:00,760 --> 00:17:03,480 NOVARTIS SOLD THE WHOLE VACCINE 404 00:17:03,480 --> 00:17:05,080 UNIT BECAUSE THEY COULD MAKE 405 00:17:05,080 --> 00:17:09,840 MORE MONEY WITH CANCER DRUGS 406 00:17:09,840 --> 00:17:10,240 BASICALLY. 407 00:17:10,240 --> 00:17:13,240 WHY MAKE A DRUG FOR $50 WHEN YOU 408 00:17:13,240 --> 00:17:14,760 CAN MAKE ONE FOR $500? 409 00:17:14,760 --> 00:17:18,480 A NO-BRAINER IF YOU'RE A BEAN 410 00:17:18,480 --> 00:17:21,080 COUNTER. 411 00:17:21,080 --> 00:17:30,200 SO, HERE WE GO. 412 00:17:30,200 --> 00:17:31,840 THIS IS AWKWARD. 413 00:17:31,840 --> 00:17:33,480 THERE OUGHT TO BE A BETTER WAY 414 00:17:33,480 --> 00:17:38,960 TO DO THIS. HERE WE GO, OKAY. 415 00:17:38,960 --> 00:17:41,560 NOW OVERLY SUCCESSFUL HERE. 416 00:17:41,560 --> 00:17:41,880 OKAY. 417 00:17:41,880 --> 00:17:44,440 SO, THIS IS A BIG REASON WHY 418 00:17:44,440 --> 00:17:49,000 WHEN WE FOUND OUT THAT THERE WAS 419 00:17:49,000 --> 00:17:50,960 A FAIRLY ABUNDANT SUPPLY OF 420 00:17:50,960 --> 00:17:52,160 TONSILS BEING WHACKED OUT OF 421 00:17:52,160 --> 00:17:54,280 INNOCENT CHILDREN NEXT DOOR IN 422 00:17:54,280 --> 00:17:56,440 THE PEDIATRIC SURGERY, TONSILS 423 00:17:56,440 --> 00:17:57,880 HAD BILLIONS OF LYMPHOCYTES, 424 00:17:57,880 --> 00:17:58,960 EVEN WAY MORE LYMPHOCYTES THAN 425 00:17:58,960 --> 00:18:05,200 WE GET FROM A SMALL CHILD, LISA 426 00:18:05,200 --> 00:18:07,160 WAGAR DEVELOPED A SIMPLE SYSTEM 427 00:18:07,160 --> 00:18:09,240 ASSOCIATING THE CELLS FROM 428 00:18:09,240 --> 00:18:11,200 TONSILS, AND EITHER FREEZING 429 00:18:11,200 --> 00:18:15,600 THEM DOWN OR JUST CULTURING THEM 430 00:18:15,600 --> 00:18:18,080 IN TRANSWELL PLATE, FIVE OR SIX 431 00:18:18,080 --> 00:18:19,840 MILLION CELLS AT A TIME, AND 432 00:18:19,840 --> 00:18:22,280 THIS TURNS OUT TO WORK WELL FOR 433 00:18:22,280 --> 00:18:24,680 AT LEAST SOME VACCINE RESPONSES. 434 00:18:24,680 --> 00:18:27,400 AND, AGAIN, NOW I HAVE TO -- 435 00:18:27,400 --> 00:18:29,720 YEAH, AND WE COULD SEE GERMINAL 436 00:18:29,720 --> 00:18:38,280 CENTERS FORMING IN THE DISH. 437 00:18:38,280 --> 00:18:40,360 WE COULD SEE ANTIBODIES, TREATED 438 00:18:40,360 --> 00:18:43,080 ANTIBODIES WOULD SHOW UP, 7 OR 439 00:18:43,080 --> 00:18:43,400 10 DAYS LATER. 440 00:18:43,400 --> 00:18:44,600 THEY WERE MUTATED, THEY WERE 441 00:18:44,600 --> 00:18:46,040 HIGH AFFINITY. 442 00:18:46,040 --> 00:18:47,640 WE COULD SEE AFFINITY 443 00:18:47,640 --> 00:18:49,640 MATURATION, AND A LOT OF OTHER 444 00:18:49,640 --> 00:18:56,000 STUFF IN THE ORIGINAL PAPER 445 00:18:56,000 --> 00:18:56,200 HERE. 446 00:18:56,200 --> 00:18:59,040 OKAY, GOOD. 447 00:18:59,040 --> 00:18:59,240 GREAT. 448 00:18:59,240 --> 00:19:01,680 AND SO THIS TURNED OUT TO BE A 449 00:19:01,680 --> 00:19:04,920 REALLY ROBUST SYSTEM AND HELPED 450 00:19:04,920 --> 00:19:05,640 US ADDRESS SOME REALLY 451 00:19:05,640 --> 00:19:06,920 INTERESTING THINGS THAT WE HAD 452 00:19:06,920 --> 00:19:10,200 SEEN OVER THE YEARS AND 453 00:19:10,200 --> 00:19:11,760 PARTICULARLY FOR ONE ASPECT OF 454 00:19:11,760 --> 00:19:15,120 THIS IS WE HAD DONE A CELIAC 455 00:19:15,120 --> 00:19:18,760 STUDY IN 2013 WHERE NOT ONLY 456 00:19:18,760 --> 00:19:21,160 WHEN WE INDUCE CELIAC DISEASE IN 457 00:19:21,160 --> 00:19:25,960 VOLUNTEERS ON GLUTEN FREE DIET 458 00:19:25,960 --> 00:19:32,520 BY EATING BREAD WE SAW CD4 CELLS 459 00:19:32,520 --> 00:19:34,840 FOR GLUTEN AND GAMMADELTA CELLS, 460 00:19:34,840 --> 00:19:35,920 SURPRISING, NO ONE EXPECTED 461 00:19:35,920 --> 00:19:37,480 THESE TO BE SHOWING UP. 462 00:19:37,480 --> 00:19:40,720 WHAT WERE THEY AND WHAT ROLE DID 463 00:19:40,720 --> 00:19:44,680 THEY HAVE IN CELIAC DISEASE ? 464 00:19:44,680 --> 00:19:52,560 AND WE MOVED ON TO EAE SYSTEM IN 465 00:19:52,560 --> 00:19:55,560 MICE, AND HERE SALIGRAMA CAME 466 00:19:55,560 --> 00:20:00,400 IN, HAD DONE A THESIS ON EAE, WE 467 00:20:00,400 --> 00:20:01,880 HAVE TO LOOK AT THE BLOOD IN 468 00:20:01,880 --> 00:20:03,440 MICE, THAT'S WHAT WE DID IN 469 00:20:03,440 --> 00:20:04,760 HUMANS, LET'S SEE WHAT HAPPENS. 470 00:20:04,760 --> 00:20:06,560 NO ONE LOOKS AT BLOOD IN MICE, 471 00:20:06,560 --> 00:20:08,000 BUT HE DID. 472 00:20:08,000 --> 00:20:10,080 AND WE SAW BASICALLY THE SAME 473 00:20:10,080 --> 00:20:15,760 THING, THAT DAY 10 AFTER 474 00:20:15,760 --> 00:20:18,600 INDUCTION SAW A SURGE OF CD 4, 475 00:20:18,600 --> 00:20:19,720 CD8, GAMMA CELLS. 476 00:20:19,720 --> 00:20:21,080 A WEEK LATER ANOTHER SURGE IN 477 00:20:21,080 --> 00:20:22,360 THE BLOOD OF THE SAME CELLS, 478 00:20:22,360 --> 00:20:25,520 EVEN A THIRD SURGE. 479 00:20:25,520 --> 00:20:28,440 THIS WAS MIRRORED IN THE NERVOUS 480 00:20:28,440 --> 00:20:30,000 SYSTEM TISSUES OF THESE MICE, 481 00:20:30,000 --> 00:20:31,240 BUT IF YOU LOOK TO THE SPLEEN 482 00:20:31,240 --> 00:20:33,160 AND LYMPH NODES YOU DIDN'T SEE 483 00:20:33,160 --> 00:20:34,400 THIS BECAUSE THERE'S ALSO SO 484 00:20:34,400 --> 00:20:35,040 MUCH ACTIVITY. 485 00:20:35,040 --> 00:20:37,120 SO THE BLOOD EVEN THOUGH WE WERE 486 00:20:37,120 --> 00:20:39,880 CRITICIZED FOR LOOKING AT BLOOD 487 00:20:39,880 --> 00:20:42,360 IN HUMANS, TURNED OUT IF YOU 488 00:20:42,360 --> 00:20:43,560 WANT REALTIME IMMUNE RESPONSES 489 00:20:43,560 --> 00:20:45,520 BLOOD IS ACTUALLY A GREAT PLACE 490 00:20:45,520 --> 00:20:48,720 TO LOOK AT. 491 00:20:48,720 --> 00:20:49,800 THAT'S WHAT'S HAPPENING AT THE 492 00:20:49,800 --> 00:20:50,320 MOMENT. 493 00:20:50,320 --> 00:20:52,400 SPLEEN AND LYMPH NODES THAT 494 00:20:52,400 --> 00:20:53,840 ACCUMULATED WEEKS AND MONTHS AND 495 00:20:53,840 --> 00:20:57,080 YEARS OF PREVIOUS ACTIVITY. 496 00:20:57,080 --> 00:20:58,800 NEXT SLIDE. 497 00:20:58,800 --> 00:21:02,120 AND SO THIS LED TO THE DISCOVERY 498 00:21:02,120 --> 00:21:04,480 OF CD8 REGULATORY T CELLS THAT 499 00:21:04,480 --> 00:21:07,960 WERE BROADLY IMPORTANT, BOTH IN 500 00:21:07,960 --> 00:21:09,600 MICE AND HUMANS, AND THIS IS 501 00:21:09,600 --> 00:21:14,080 WORK THAT CAME OUT LAST YEAR IN 502 00:21:14,080 --> 00:21:15,520 "SCIENCE," JING LI, A POSTDOC IN 503 00:21:15,520 --> 00:21:21,320 THE LAB SHOWED THE EQUIVALENCE 504 00:21:21,320 --> 00:21:22,640 CD8 CELLS, CD4, POSITIVE, 1 OR 505 00:21:22,640 --> 00:21:25,560 2% OF HEALTHY HUMANS IN THE 506 00:21:25,560 --> 00:21:30,760 BLOOD CAN BE 20, 25% IN PEOPLE 507 00:21:30,760 --> 00:21:33,160 WITH ACTIVE LUPUS OR M.S. OR 508 00:21:33,160 --> 00:21:37,360 EVEN CELIAC DISEASE THERE'S 509 00:21:37,360 --> 00:21:38,880 ELEVATION. 510 00:21:38,880 --> 00:21:39,440 NEXT SLIDE. 511 00:21:39,440 --> 00:21:43,280 AND SO RECENTLY WE -- NEXT SLIDE 512 00:21:43,280 --> 00:21:43,720 PLEASE. 513 00:21:43,720 --> 00:21:47,960 RECENTLY WE WANTED TO TEST THIS. 514 00:21:47,960 --> 00:21:52,480 NOW, WE'RE TALKING ABOUT A WHOLE 515 00:21:52,480 --> 00:21:54,000 OTHER AXIS OF TOLERANCE IN THE 516 00:21:54,000 --> 00:21:56,840 IMMUNE SYSTEM DRIVEN BY -- HERE 517 00:21:56,840 --> 00:21:57,280 WE GO. 518 00:21:57,280 --> 00:21:59,040 CD 8 CELLS. 519 00:21:59,040 --> 00:21:59,680 ARE THESE IMPORTANT? 520 00:21:59,680 --> 00:21:59,840 YES. 521 00:21:59,840 --> 00:22:02,560 EVEN IN MICE WE HAVE A 522 00:22:02,560 --> 00:22:03,400 CONDITIONAL KNOCKOUT, TURNED OUT 523 00:22:03,400 --> 00:22:11,640 THAT IF YOU HAVE THIS KNOCKOUT 524 00:22:11,640 --> 00:22:13,480 FOLLOWING INFECTION WITH LCMV 525 00:22:13,480 --> 00:22:15,880 YOU HAVE AUTOIMMUNE SEQUELAE IN 526 00:22:15,880 --> 00:22:16,880 THE MICE, THESE ARE ACTUALLY 527 00:22:16,880 --> 00:22:20,880 ANTIBODY DEPOSITS IN THE KIDNEYS 528 00:22:20,880 --> 00:22:23,320 OF MICE FOLLOWING LCMV 529 00:22:23,320 --> 00:22:25,920 INFECTION, AND THAT WE CAN SEE, 530 00:22:25,920 --> 00:22:33,800 AND THEN IN FLU WE SEE LUNG 531 00:22:33,800 --> 00:22:35,680 INFLAMMATION WHICH WE DON'T SEE 532 00:22:35,680 --> 00:22:41,240 IN MICE, THIS DOESN'T HAPPEN. 533 00:22:41,240 --> 00:22:43,040 THIS SHOWS AUTOIMMUNITY BUT WE 534 00:22:43,040 --> 00:22:47,600 KNOW ABOUT CD 4 TREGS, SO WHAT'S 535 00:22:47,600 --> 00:22:49,080 THE DIVISION OF LABOR? 536 00:22:49,080 --> 00:22:52,080 WELL, WE REPORTED IN THE 537 00:22:52,080 --> 00:22:53,080 "SCIENCE" PAPER, REPORTED IN 538 00:22:53,080 --> 00:22:56,120 COVID WE SEE A LOT OF ACTIVITY 539 00:22:56,120 --> 00:22:59,120 OF CD8 REGULATORY CELLS BUT NOT 540 00:22:59,120 --> 00:23:01,080 CD4 REGULATORY CELLS, WE CAN SEE 541 00:23:01,080 --> 00:23:04,760 DIVISION OF LABOR IN TERMS OF 542 00:23:04,760 --> 00:23:08,320 POSITIVE CD8S BEING MORE 543 00:23:08,320 --> 00:23:09,720 IMPORTANT SUPPRESSING 544 00:23:09,720 --> 00:23:12,240 AUTOIMMUNITY IN INFECTIOUS 545 00:23:12,240 --> 00:23:13,200 DISEASES, WHAT ELSE CAN WE 546 00:23:13,200 --> 00:23:13,840 FIGURE OUT? 547 00:23:13,840 --> 00:23:17,520 THIS IS WHERE WE WENT TO 548 00:23:17,520 --> 00:23:19,480 ORGANOIDS, TONSIL ORGANOIDS. 549 00:23:19,480 --> 00:23:22,880 NEXT SLIDE PLEASE. 550 00:23:22,880 --> 00:23:25,080 SO -- NEXT SLIDE. 551 00:23:25,080 --> 00:23:28,080 AND I THINK THIS IS NOW 552 00:23:28,080 --> 00:23:30,200 TECHNOLOGY THAT'S GOING TO BE 553 00:23:30,200 --> 00:23:31,840 INCREDIBLY POWERFUL IN ORGANIZE 554 00:23:31,840 --> 00:23:33,000 AND FOR HUMAN IMMUNOLOGY 555 00:23:33,000 --> 00:23:37,120 GENERALLY, SPEAKING TO THE IDEA 556 00:23:37,120 --> 00:23:39,320 OF TESTING IN A PURELY HUMAN 557 00:23:39,320 --> 00:23:39,560 SYSTEM. 558 00:23:39,560 --> 00:23:46,760 THIS IS WORK OF A FANTASTIC 559 00:23:46,760 --> 00:23:48,600 GRADUATE STUDENT AND POSTDOC, 560 00:23:48,600 --> 00:23:53,640 WORKING OUT A METHOD FOR DOING 561 00:23:53,640 --> 00:23:54,960 CRISPR KNOCKOUTS IN TONSIL 562 00:23:54,960 --> 00:23:58,160 ORGANOIDS, MAKING USE OF THE 563 00:23:58,160 --> 00:24:00,960 FACT WE GET MULTIPLE ALIQUOTS, 564 00:24:00,960 --> 00:24:05,800 10, 20, 50, FROM THE SAME DONOR, 565 00:24:05,800 --> 00:24:08,280 FREEZE AND THAW WHEN YOU WANT. 566 00:24:08,280 --> 00:24:11,360 TOOK ONE ALIQUOT FROM ONE DONOR, 567 00:24:11,360 --> 00:24:20,360 GOT T CELLS, ELECTROPORATED, 568 00:24:20,360 --> 00:24:23,440 INCUBATED, PUT THEM BACK INTO A 569 00:24:23,440 --> 00:24:31,600 SECOND ALIQUOT DEPLETED T CELLS. 570 00:24:31,600 --> 00:24:33,880 THEN I START THE CULTURE. 571 00:24:33,880 --> 00:24:36,640 AS ADJUVANT PUT IN LIVE 572 00:24:36,640 --> 00:24:38,200 ATTENUATED FLU VACCINE THAT 573 00:24:38,200 --> 00:24:40,040 HELPS EVERYTHING GO BETTER 574 00:24:40,040 --> 00:24:40,680 BASICALLY. 575 00:24:40,680 --> 00:24:42,880 NEXT SLIDE. 576 00:24:42,880 --> 00:24:46,040 AND THESE KNOCKOUTS ARE 577 00:24:46,040 --> 00:24:50,080 EFFICIENT GETTING 90, 95% 578 00:24:50,080 --> 00:24:55,240 DEPLETION, TARGETING THE TWO 579 00:24:55,240 --> 00:24:59,200 PILLARS OF REGULATION HERE, FLOX 580 00:24:59,200 --> 00:25:05,320 B 3 AND GRANZYME B KNOCKS OUT 581 00:25:05,320 --> 00:25:10,400 THE CD 8 FUNCTION. 582 00:25:10,400 --> 00:25:13,840 AND RESULTS ARE COOL. 583 00:25:13,840 --> 00:25:16,920 IF WE STIMULATE CON SILLS 584 00:25:16,920 --> 00:25:18,960 DEPLETED OF FOXP3 AND REGULATORY 585 00:25:18,960 --> 00:25:23,680 T CELLS NOW THE TONSILS WILL 586 00:25:23,680 --> 00:25:25,320 MAKE AUTOANTIBODIES WHICH THEY 587 00:25:25,320 --> 00:25:30,800 WOULDN'T BEFORE, WE USE A 588 00:25:30,800 --> 00:25:33,200 COCKTAIL OF AUTOANTIGENS, 589 00:25:33,200 --> 00:25:34,040 NUCLEAR RNP, HISTONE 590 00:25:34,040 --> 00:25:35,720 DOUBLE-STRANDED DNA, EVERY DAYS 591 00:25:35,720 --> 00:25:37,560 WE'RE GETTING SIGNIFICANT LEVELS 592 00:25:37,560 --> 00:25:40,080 OF A BACKGROUND OF SECRETED 593 00:25:40,080 --> 00:25:42,520 AUTOANTIBODIES. 594 00:25:42,520 --> 00:25:43,800 WE'RE ABLE TO TAKE HEALTHY 595 00:25:43,800 --> 00:25:47,720 TONSIL TISSUE AND CREATE A MODEL 596 00:25:47,720 --> 00:25:48,240 SYSTEM OF AUTOIMMUNITY, 597 00:25:48,240 --> 00:25:50,960 REPRODUCES SOME OF WHAT WE SEE 598 00:25:50,960 --> 00:25:52,880 IN AUTOIMMUNITY, PARTICULARLY 599 00:25:52,880 --> 00:25:55,320 FOXP3 KNOCKOUTS IN MOUSE AND 600 00:25:55,320 --> 00:25:58,000 HUMAN PHENOTYPE IS MASSIVE 601 00:25:58,000 --> 00:26:00,680 AUTOANTIBODY PRODUCTION AND 602 00:26:00,680 --> 00:26:04,920 INFLAMMATION AND EARLY DEATH. 603 00:26:04,920 --> 00:26:07,360 SO IT'S REPRODUCING WHAT WE HAVE 604 00:26:07,360 --> 00:26:07,760 KNOWN. 605 00:26:07,760 --> 00:26:09,520 NEXT SLIDE PLEASE. 606 00:26:09,520 --> 00:26:11,920 AND THEN AS A BONUS, I WAS 607 00:26:11,920 --> 00:26:14,120 IMPRESSED BY THIS PAPER THAT 608 00:26:14,120 --> 00:26:17,200 CAME OUT NOW SEVEN YEARS AGO, 609 00:26:17,200 --> 00:26:23,800 WHICH SHOWED THAT PATIENTS 610 00:26:23,800 --> 00:26:29,760 DEFICIENT IN IN THE AIRE GENE, 611 00:26:29,760 --> 00:26:36,840 IT CONTROLS IN THE THYMUS, 612 00:26:36,840 --> 00:26:38,680 MAKING ANTIBODIES TO SOME 613 00:26:38,680 --> 00:26:39,680 AUTOANTIGEN, INTERFERING WITH T 614 00:26:39,680 --> 00:26:41,880 CELL TOLERANCE COULD RESULT IN 615 00:26:41,880 --> 00:26:43,200 HIGHER AFFINITY ANTIBODIES, 616 00:26:43,200 --> 00:26:44,680 NORMALLY WE SEE NANOMOLAR 617 00:26:44,680 --> 00:26:49,080 AFFINITY ANTIBODIES, PLUS OR 618 00:26:49,080 --> 00:26:53,480 MINUS, TIGHT DISTRIBUTION, FROM 619 00:26:53,480 --> 00:26:56,000 BIOGEN, SO FORTH. 620 00:26:56,000 --> 00:26:57,120 NOT BIOGEN. 621 00:26:57,120 --> 00:27:07,600 WE TOOK A SHOT TO SAY MAYBE 622 00:27:11,680 --> 00:27:14,240 FOXP3, NEXT SLIDE, AND -- NEXT 623 00:27:14,240 --> 00:27:15,200 SLIDE PLEASE. 624 00:27:15,200 --> 00:27:17,120 THERE WE GO. 625 00:27:17,120 --> 00:27:21,080 SURE ENOUGH, LOOKING AT 626 00:27:21,080 --> 00:27:23,000 AFFINITY, THIS IS A STUDY 627 00:27:23,000 --> 00:27:26,160 BASICALLY WE'RE GETTING HIGHER 628 00:27:26,160 --> 00:27:27,840 AFFINITY FLU ANTIBODIES, MUCH 629 00:27:27,840 --> 00:27:29,160 HIGHER THAN NORMALLY SEEN IN 630 00:27:29,160 --> 00:27:33,400 TONSILS, YOU CAN LOOK HERE AT 631 00:27:33,400 --> 00:27:37,800 THE OFF-RATE, WE SEE SOME TONSIL 632 00:27:37,800 --> 00:27:43,800 DONORS MAKING 10 TO 20 TIMES 633 00:27:43,800 --> 00:27:47,440 HIGHER AFFINITY ANTIBODIES, 634 00:27:47,440 --> 00:27:49,920 SLOWER OFF RATE, FOXP3 ARE NOT 635 00:27:49,920 --> 00:27:51,480 ONLY GATE KEEPERS FOR 636 00:27:51,480 --> 00:27:53,320 AUTOANTIGENS BUT ALSO GATE 637 00:27:53,320 --> 00:27:55,920 KEEPERS FOR ANTIBODY AFFINITY IN 638 00:27:55,920 --> 00:27:56,160 GENERAL. 639 00:27:56,160 --> 00:27:57,360 AND PROBABLY BECAUSE HIGHER UP 640 00:27:57,360 --> 00:28:00,320 YOU GO IN AFFINITY, THE MORE 641 00:28:00,320 --> 00:28:01,960 CHANCES OF CROSS-REACTIVITY TO 642 00:28:01,960 --> 00:28:04,720 SOMETHING IMPORTANT THAT YOU'RE 643 00:28:04,720 --> 00:28:05,360 TRYING TO PREVENT. 644 00:28:05,360 --> 00:28:07,640 NEXT SLIDE PLEASE. 645 00:28:07,640 --> 00:28:10,160 BUT THEN WE ALSO -- THE WHOLE 646 00:28:10,160 --> 00:28:12,920 PURPOSE HERE WAS TO LOOK AT THE 647 00:28:12,920 --> 00:28:16,840 RELATIVE ROLE OF THESE DIFFERENT 648 00:28:16,840 --> 00:28:20,360 CD4 AND CD8 CONTROLS OR 649 00:28:20,360 --> 00:28:22,520 CHECKPOINTS, AND SO HERE THE 650 00:28:22,520 --> 00:28:26,640 GRANZYME B KNOCKOUT WHICH KNOCKS 651 00:28:26,640 --> 00:28:28,920 OUT PEER POSITIVE T CELL 652 00:28:28,920 --> 00:28:32,160 FUNCTION, YOU KNOW, WE SEE BOTH 653 00:28:32,160 --> 00:28:35,560 CD4 AND -- SORRY, CD8 AND CD4 654 00:28:35,560 --> 00:28:38,120 AUTOREACTIVE T CELLS THEN COME 655 00:28:38,120 --> 00:28:38,760 UP. 656 00:28:38,760 --> 00:28:43,160 SO NOW WE'RE SIMULATING BOTH 657 00:28:43,160 --> 00:28:44,240 CASES, SIMULATING WITH 658 00:28:44,240 --> 00:28:48,600 AUTOANTIGENS IN IN THE T CELL E 659 00:28:48,600 --> 00:28:52,560 A SELECTION OF CD4 AUTOREACTIVE 660 00:28:52,560 --> 00:28:54,440 THINGS THAT HAVE BEEN DESCRIBED 661 00:28:54,440 --> 00:28:56,840 OR CD 8, THESE ARE RARE CELLS 662 00:28:56,840 --> 00:28:59,680 BUT THEY ARE THERE. 663 00:28:59,680 --> 00:29:01,720 AND THEY ARE JUST BEING 664 00:29:01,720 --> 00:29:03,160 CONTROLLED NORMALLY, BUT SO 665 00:29:03,160 --> 00:29:06,240 WE'RE GETTING A GLIMPSE INTO THE 666 00:29:06,240 --> 00:29:07,320 CONTROL MECHANISM AND SEEING IT 667 00:29:07,320 --> 00:29:12,240 IN A DISH, SO IT'S REALLY 668 00:29:12,240 --> 00:29:14,000 IMPORTANT IN TERMS OF GOING 669 00:29:14,000 --> 00:29:16,640 FURTHER AND LOOKING AT MORE 670 00:29:16,640 --> 00:29:16,960 DETAIL. 671 00:29:16,960 --> 00:29:17,520 NEXT SLIDE PLEASE. 672 00:29:17,520 --> 00:29:21,000 ALL RIGHT. 673 00:29:21,000 --> 00:29:24,200 WHAT ABOUT AGING, MERCY HAS 674 00:29:24,200 --> 00:29:24,400 ASKED? 675 00:29:24,400 --> 00:29:28,800 IN FACT WE'RE IN THE MIDDLE OF 676 00:29:28,800 --> 00:29:30,440 AN INTERESTING PROJECT RUN BY 677 00:29:30,440 --> 00:29:33,080 NATHAN, A POSTDOC IN THE LAB, 678 00:29:33,080 --> 00:29:35,480 AND NOW WE'RE TAKING ADVANTAGE 679 00:29:35,480 --> 00:29:37,720 OF THE LONG TIME SPAN, TONSILS 680 00:29:37,720 --> 00:29:42,480 FROM KIDS AS YOUNG AS 2 YEARS 681 00:29:42,480 --> 00:29:44,200 OLD, AND MORE RECENTLY IT'S NOT 682 00:29:44,200 --> 00:29:49,800 COMMON BUT WE'VE GOT TONSILS 683 00:29:49,800 --> 00:29:51,880 FROM 60 TO 70-YEAR-OLDS, WE WANT 684 00:29:51,880 --> 00:29:52,760 MORE. 685 00:29:52,760 --> 00:29:55,920 A STUDY FIRST STARTING WITH 686 00:29:55,920 --> 00:29:58,560 ANTIBODY TITERS, WE'VE DONE LOTS 687 00:29:58,560 --> 00:30:01,080 OF CONSOLES SIMULATED MOSTLY 688 00:30:01,080 --> 00:30:02,080 WITH LIVE ATTENUATED FLU 689 00:30:02,080 --> 00:30:03,680 VACCINE, GET ANTIBODY RESPONSES 690 00:30:03,680 --> 00:30:05,040 THAT WE MEASURE, PUT THEM 691 00:30:05,040 --> 00:30:11,240 TOGETHER, YOU CAN SEE A CLEAR 692 00:30:11,240 --> 00:30:12,320 CORRELATION WITH AGE. 693 00:30:12,320 --> 00:30:13,520 YOUNGER PEOPLE DOING GREAT, 694 00:30:13,520 --> 00:30:17,720 OLDER PEOPLE DOING LESS AND LESS 695 00:30:17,720 --> 00:30:17,920 GREAT. 696 00:30:17,920 --> 00:30:19,560 SO, THIS MEANS, AGAIN, WE CAN 697 00:30:19,560 --> 00:30:23,000 LOOK AT AGING IN A DISH, TRY TO 698 00:30:23,000 --> 00:30:23,960 FIGURE OUT WHAT'S HAPPENING. 699 00:30:23,960 --> 00:30:26,000 WE'RE STILL IN THE MIDDLE OF 700 00:30:26,000 --> 00:30:27,240 THIS BUT RESULTS ARE ALREADY 701 00:30:27,240 --> 00:30:31,160 STARTING TO BE VERY INTERESTING. 702 00:30:31,160 --> 00:30:32,040 NEXT SLIDE PLEASE. 703 00:30:32,040 --> 00:30:35,760 AND ONE IS JUST LOOKING AT 704 00:30:35,760 --> 00:30:36,320 REPERTOIRE. 705 00:30:36,320 --> 00:30:39,120 AND THIS CORRELATES WITH SOME 706 00:30:39,120 --> 00:30:41,680 THINGS THAT WERE DONE SOME YEARS 707 00:30:41,680 --> 00:30:46,600 BACK, AND WE SEE A DIFFERENCE IN 708 00:30:46,600 --> 00:30:52,400 DIVERSITY OF THE OLDER TONSILS 709 00:30:52,400 --> 00:30:54,480 VERSUS YOUNGER FOLKS, PBMCs, 710 00:30:54,480 --> 00:30:57,080 BRINGING THAT INTO GREATER 711 00:30:57,080 --> 00:31:01,040 RESOLUTION. 712 00:31:01,040 --> 00:31:02,880 MORE IMPORTANTLY, NEXT SLIDE, 713 00:31:02,880 --> 00:31:06,440 GIVES US A PICTURE OF WHAT'S 714 00:31:06,440 --> 00:31:07,720 HAPPENING, WHAT'S DIFFERENT 715 00:31:07,720 --> 00:31:09,800 BETWEEN TONSIL. 716 00:31:09,800 --> 00:31:11,680 TONSIL IS A MUCOSAL ORGAN SO 717 00:31:11,680 --> 00:31:12,880 THERE ARE DIFFERENCES BOTH IN 718 00:31:12,880 --> 00:31:15,280 TERMS OF T CELL SPECIFICITY BUT 719 00:31:15,280 --> 00:31:16,800 ALSO SOME PHENOTYPES. 720 00:31:16,800 --> 00:31:20,640 BUT WHAT'S MOST INTERESTING, 721 00:31:20,640 --> 00:31:24,360 NEXT SLIDE, IS DOING A VOLCANO 722 00:31:24,360 --> 00:31:25,960 PLOT AND JUST SAYING WHAT'S 723 00:31:25,960 --> 00:31:28,320 HEAVILY WEIGHTED IN THE YOUNG 724 00:31:28,320 --> 00:31:33,000 TONSILS VERSUS OLD TONSILS? 725 00:31:33,000 --> 00:31:35,760 AND BASICALLY ASSOCIATED WITH 726 00:31:35,760 --> 00:31:37,920 GERMINAL CENTER FORMATION AND T 727 00:31:37,920 --> 00:31:39,040 CELL -- HELPER T CELL. 728 00:31:39,040 --> 00:31:41,080 THIS IS WHAT'S HAPPENING IN THE 729 00:31:41,080 --> 00:31:43,480 YOUNG TONSILS VERSUS OLD 730 00:31:43,480 --> 00:31:43,880 TONSILS. 731 00:31:43,880 --> 00:31:45,680 SO, THIS MAKES PERFECT SENSE IN 732 00:31:45,680 --> 00:31:50,080 TERMS OF WE KNOW WHAT'S THE 733 00:31:50,080 --> 00:31:51,840 HALLMARK OF AGING FUNCTIONALLY 734 00:31:51,840 --> 00:31:53,920 AND WHAT'S CLINICAL IMPORTANT IS 735 00:31:53,920 --> 00:31:55,200 DECLINE IN ANTIBODY TITER. 736 00:31:55,200 --> 00:31:58,840 SO HERE WE STARTED LOOKING AT 737 00:31:58,840 --> 00:32:01,080 DECLINING ANTIBODY TITERS, AND 738 00:32:01,080 --> 00:32:03,400 NOW WE'RE SEEING A GERMINAL 739 00:32:03,400 --> 00:32:04,840 CENTER T CELL DEFECT, HELPER 740 00:32:04,840 --> 00:32:05,720 CELL DEFECT. 741 00:32:05,720 --> 00:32:08,880 SO THIS MAKES PERFECT SENSE THAT 742 00:32:08,880 --> 00:32:11,280 IF THESE CELLS ARE DEFECTIVE FOR 743 00:32:11,280 --> 00:32:13,080 SOME REASON, WE'LL HAVE TROUBLE 744 00:32:13,080 --> 00:32:14,800 MAKING GOOD ANTIBODY RESPONSES. 745 00:32:14,800 --> 00:32:16,480 SO ANYWAY, WE'RE FOLLOWING THIS 746 00:32:16,480 --> 00:32:18,640 UP AND OF COURSE WE'RE GOING TO 747 00:32:18,640 --> 00:32:21,480 ALSO USE THE CRISPR KNOCKOUT TO 748 00:32:21,480 --> 00:32:24,320 KNOCKOUT SOME OF THE GENES 749 00:32:24,320 --> 00:32:25,400 COMING UP. 750 00:32:25,400 --> 00:32:29,280 WHAT'S ACTUAL OR WHAT'S CAUSAL, 751 00:32:29,280 --> 00:32:32,560 WHAT'S CORRELATION. 752 00:32:32,560 --> 00:32:34,800 NEXT SLIDE. 753 00:32:34,800 --> 00:32:36,680 ANOTHER BIG QUESTION IN 754 00:32:36,680 --> 00:32:39,840 VACCINOLOGY THAT WE'VE BEEN 755 00:32:39,840 --> 00:32:41,520 TACKLING IS SUBTYPE BIAS IN FLU. 756 00:32:41,520 --> 00:32:44,560 SO THIS IS SOMETHING THAT'S BEEN 757 00:32:44,560 --> 00:32:49,080 OBSERVED SINCE THE 1940s IS 758 00:32:49,080 --> 00:32:50,480 THAT PEOPLE HAVE PARTICULAR 759 00:32:50,480 --> 00:32:53,640 PREFERENCES IN TERMS OF WHAT 760 00:32:53,640 --> 00:32:57,080 SUBTYPE OF FLU, SO SUBTYPE IS 761 00:32:57,080 --> 00:32:59,520 ONE TIME H3, B TYPE, MAIN 762 00:32:59,520 --> 00:33:02,320 SUBTYPES THAT GO ON, AND PEOPLE 763 00:33:02,320 --> 00:33:04,160 HAVE A PREFERENCE FOR ONE OR THE 764 00:33:04,160 --> 00:33:07,000 OTHER WHICH MEANS THAT EVEN IF 765 00:33:07,000 --> 00:33:09,800 THEY ARE VACCINATED AS PEOPLE 766 00:33:09,800 --> 00:33:13,720 ARE WITH THE TETRAVALENT FLU 767 00:33:13,720 --> 00:33:15,240 VACCINE, YOU'RE ONLY -- MOSTLY 768 00:33:15,240 --> 00:33:17,320 ONLY GOING TO MAKE A GOOD 769 00:33:17,320 --> 00:33:19,160 RESPONSE AGAINST THE ONE YOU 770 00:33:19,160 --> 00:33:22,040 LIKE, OR THAT YOUR PREFERENCE 771 00:33:22,040 --> 00:33:22,200 IS. 772 00:33:22,200 --> 00:33:23,760 AND SO THAT'S A PROBLEM IF 773 00:33:23,760 --> 00:33:25,880 YOU'RE INFECTED WITH ONE OF THE 774 00:33:25,880 --> 00:33:26,960 OTHER STRAINS. 775 00:33:26,960 --> 00:33:28,600 WE MAKE THIS SELECTION OF 776 00:33:28,600 --> 00:33:30,360 STRAINS BECAUSE THAT'S WHAT'S 777 00:33:30,360 --> 00:33:33,080 CIRCULATING, THAT'S WHAT COULD 778 00:33:33,080 --> 00:33:34,400 INFECT YOU, BUT THIS SUBTYPE 779 00:33:34,400 --> 00:33:39,440 BIAS DEFEATS THE PURPOSE OF 780 00:33:39,440 --> 00:33:40,960 HAVING A MULTI-STRAIN VACCINE. 781 00:33:40,960 --> 00:33:43,600 AND WILL FOR EVERY MULTI-STRAIN. 782 00:33:43,600 --> 00:33:45,280 PNEUMONIA VACCINE IS NOW UP TO 783 00:33:45,280 --> 00:33:46,160 19 STRAINS. 784 00:33:46,160 --> 00:33:48,520 ARE YOU GOING TO BE EQUALLY 785 00:33:48,520 --> 00:33:51,600 PROTECTED AGAINST ALL 19 786 00:33:51,600 --> 00:33:51,960 STRAINS? 787 00:33:51,960 --> 00:33:52,880 ALMOST CERTAINLY NOT BUT THAT'S 788 00:33:52,880 --> 00:33:54,640 WHAT WE KNOW, THAT'S WHAT THE 789 00:33:54,640 --> 00:33:57,080 VACCINE INDUSTRY IS USED TO 790 00:33:57,080 --> 00:33:59,480 DOING, IT'S THE ONLY GAME IN 791 00:33:59,480 --> 00:33:59,680 TOWN. 792 00:33:59,680 --> 00:34:00,560 WE BUY IT. 793 00:34:00,560 --> 00:34:03,200 HAVE TO TAKE YOUR CHANCES. 794 00:34:03,200 --> 00:34:04,840 THAT'S ONE REASON FLU VACCINE 795 00:34:04,840 --> 00:34:06,360 EFFICACY HAS NEVER BEEN THAT 796 00:34:06,360 --> 00:34:09,760 GREAT, NEVER BEEN EVEN CLOSE TO 797 00:34:09,760 --> 00:34:12,160 THE COVID VACCINES WE HAVE NOW. 798 00:34:12,160 --> 00:34:14,160 SO WHAT'S THE BASIS OF IT? 799 00:34:14,160 --> 00:34:17,000 THAT'S WHAT'S INTERESTING IS 800 00:34:17,000 --> 00:34:19,720 THAT SINCE 1960, THE POPULAR 801 00:34:19,720 --> 00:34:22,640 NOTION HAS BEEN THAT IT DEPENDS 802 00:34:22,640 --> 00:34:25,080 ON WHAT FLU STRAIN YOU'RE FIRST 803 00:34:25,080 --> 00:34:27,040 INFECTED WITH OR VACCINATED 804 00:34:27,040 --> 00:34:27,720 WITH. 805 00:34:27,720 --> 00:34:30,160 AND WHAT WAS REALLY BRILLIANT 806 00:34:30,160 --> 00:34:33,200 ABOUT THIS HYPOTHESIS IT WAS 807 00:34:33,200 --> 00:34:35,920 GIVEN THE NAME ORIGINAL ANGENIC, 808 00:34:35,920 --> 00:34:39,120 IF YOU CAN ATTACH THE WORD SIN 809 00:34:39,120 --> 00:34:41,120 TO ANY ANYTHING, YOU'LL 810 00:34:41,120 --> 00:34:43,200 IMMEDIATELY GET A LOT OF 811 00:34:43,200 --> 00:34:45,000 INTEREST AND EXCITEMENT, OF 812 00:34:45,000 --> 00:34:45,480 COURSE. 813 00:34:45,480 --> 00:34:49,280 BUT IS THIS REALLY THE THING? 814 00:34:49,280 --> 00:34:56,880 AND SO THIS IS WORK OF MALIDOSAL 815 00:34:56,880 --> 00:35:00,320 WHO DID FLU AS A Ph.D. AND HAS 816 00:35:00,320 --> 00:35:04,680 DUG IN, IN AMAZING WAY, TAKING 817 00:35:04,680 --> 00:35:06,680 ADVANTAGE OF THE MANY COHORTS. 818 00:35:06,680 --> 00:35:07,880 I CAN'T GO THROUGH EVERYTHING 819 00:35:07,880 --> 00:35:09,880 BUT ONE OF THE MORE RELEVANT 820 00:35:09,880 --> 00:35:16,080 ONES WE HAVE A TWIN COHORT WHERE 821 00:35:16,080 --> 00:35:19,040 WE HAVE SUBSTANTIAL NUMBER OF 78 822 00:35:19,040 --> 00:35:19,920 MONOZYGOTIC TWINS ANALYZED FOR 823 00:35:19,920 --> 00:35:23,840 FLU VACCINE OVER THE YEARS, AND 824 00:35:23,840 --> 00:35:24,960 SO -- NEXT SLIDE. 825 00:35:24,960 --> 00:35:29,760 WE'RE ABLE TO KIND OF LOOK AT 826 00:35:29,760 --> 00:35:33,160 THIS AND -- SORRY, SKIPPING A 827 00:35:33,160 --> 00:35:35,040 SLIDE HERE. 828 00:35:35,040 --> 00:35:36,760 BASICALLY 70-SOME PERCENT OF 829 00:35:36,760 --> 00:35:37,880 MONOZYGOTIC TWINS ARE THE SAME 830 00:35:37,880 --> 00:35:39,280 BIAS, OKAY? 831 00:35:39,280 --> 00:35:40,680 BUT IT DOESN'T CORRELATE WITH 832 00:35:40,680 --> 00:35:41,400 PRIOR EXPOSURE. 833 00:35:41,400 --> 00:35:43,640 THEY HAVE A BIAS THAT THEY SHARE 834 00:35:43,640 --> 00:35:44,640 BUT IT DOESN'T CORRELATE WITH 835 00:35:44,640 --> 00:35:47,040 PRIOR EXPOSURE OR THE YEAR THAT 836 00:35:47,040 --> 00:35:48,360 THEY WERE BORN, BECAUSE THAT'S 837 00:35:48,360 --> 00:35:50,120 BEEN ANOTHER WAY PEOPLE LOOKED 838 00:35:50,120 --> 00:35:51,960 AT THIS. 839 00:35:51,960 --> 00:35:53,800 CERTAIN FLU STRAINS WERE 840 00:35:53,800 --> 00:35:56,000 PREVALENT AT CERTAIN AGE RANGES. 841 00:35:56,000 --> 00:36:00,320 SO POINTED TO A SUBSTANTIAL 842 00:36:00,320 --> 00:36:04,440 COMPONENT OF THIS EFFECT AS 843 00:36:04,440 --> 00:36:06,560 GENETIC, REINFORCED BY OTHER 844 00:36:06,560 --> 00:36:09,720 COLLABORATION WITH MARY STOUT IN 845 00:36:09,720 --> 00:36:10,480 THE IMPRINT COHORT. 846 00:36:10,480 --> 00:36:12,800 THAT'S BEEN GREAT. 847 00:36:12,800 --> 00:36:15,760 SHE HAS JUST A FANTASTIC COHORT 848 00:36:15,760 --> 00:36:17,080 OF YOUNG CHILDREN AND 849 00:36:17,080 --> 00:36:23,560 PARTICULARLY WERE ABLE TO GET 15 850 00:36:23,560 --> 00:36:25,280 SAMPLES FROM 15 KIDS 6 TO 12 851 00:36:25,280 --> 00:36:27,040 MONTHS WHO NEVER HAD A FLU 852 00:36:27,040 --> 00:36:29,440 INFECTION, WE KNOW THIS BECAUSE 853 00:36:29,440 --> 00:36:32,320 IN THIS COHORT EVERY WEEK THE 854 00:36:32,320 --> 00:36:33,560 MOTHER SWABBED THE NOSES OF THE 855 00:36:33,560 --> 00:36:35,600 KIDS AND SENDS IN THE SWABS, AND 856 00:36:35,600 --> 00:36:37,320 THEY ARE ANALYZED FOR FLU 857 00:36:37,320 --> 00:36:37,640 INFECTION. 858 00:36:37,640 --> 00:36:39,280 THIS IS A GROUP OF CHILDREN IN 859 00:36:39,280 --> 00:36:42,800 THIS AGE GROUP WHO NEVER HAD 860 00:36:42,800 --> 00:36:43,320 FLU. 861 00:36:43,320 --> 00:36:47,080 THEY WERE ALL GIVEN A STANDARD 862 00:36:47,080 --> 00:36:50,680 VACCINE, AT 6 MONTHS I BELIEVE. 863 00:36:50,680 --> 00:36:52,520 WE COULD SEE STRAIN BIAS 864 00:36:52,520 --> 00:36:53,120 ALREADY. 865 00:36:53,120 --> 00:36:55,960 SO THIS IS THE FIRST EXPOSURE TO 866 00:36:55,960 --> 00:37:06,200 FLU, AND THEY ARE ALREADY 867 00:37:06,200 --> 00:37:10,160 SHOWING STRAIN BIASES. 868 00:37:10,160 --> 00:37:11,160 869 00:37:11,160 --> 00:37:18,880 OKAY. 870 00:37:18,880 --> 00:37:20,680 MAYBE WE'LL HAVE A MOMENT OF -- 871 00:37:20,680 --> 00:37:24,040 OH. 872 00:37:24,040 --> 00:37:24,360 OKAY. 873 00:37:24,360 --> 00:37:25,680 THANK YOU. 874 00:37:25,680 --> 00:37:30,520 SO ANYWAY, THIS IS FURTHER 875 00:37:30,520 --> 00:37:31,520 EVIDENCE THAT FIRST EXPOSURE IS 876 00:37:31,520 --> 00:37:33,440 NOT THE CAUSE OF STRAIN BIAS OR 877 00:37:33,440 --> 00:37:33,920 ISN'T THE ONLY CAUSE. 878 00:37:33,920 --> 00:37:36,600 I THINK IT IS PART OF THE 879 00:37:36,600 --> 00:37:37,720 EQUATION BUT IT DOESN'T SEEM 880 00:37:37,720 --> 00:37:47,160 LIKE IT'S THE MAIN THING. 881 00:37:47,160 --> 00:37:47,440 NEXT SLIDE. 882 00:37:47,440 --> 00:37:48,240 NEXT SLIDE. 883 00:37:48,240 --> 00:37:50,000 OH. 884 00:37:50,000 --> 00:37:52,200 LET'S SEE IF I CAN DO THIS 885 00:37:52,200 --> 00:37:52,960 MYSELF. 886 00:37:52,960 --> 00:37:54,680 ALL RIGHT. 887 00:37:54,680 --> 00:37:58,120 OKAY, GREAT. 888 00:37:58,120 --> 00:38:01,080 SO, FROM HERE A TERRIFIC LEAP 889 00:38:01,080 --> 00:38:01,920 WAS TAKEN TO WHAT'S REALLY AT 890 00:38:01,920 --> 00:38:08,160 THE HEART OF THIS. 891 00:38:08,160 --> 00:38:10,000 BASICALLY HE COULD SEE A HUGE 892 00:38:10,000 --> 00:38:12,880 GENETIC COMPONENT BUT WHAT WAS 893 00:38:12,880 --> 00:38:13,840 THAT GENETIC COMPONENT? 894 00:38:13,840 --> 00:38:15,120 GENOME IS A BIG THING. WHERE IN 895 00:38:15,120 --> 00:38:17,800 THE GENOME DO YOU LOOK? 896 00:38:17,800 --> 00:38:21,960 AND SO HE LOOKED AT CLASS 2 897 00:38:21,960 --> 00:38:24,720 POLYMORPHISM, HUMANS HAVE A 898 00:38:24,720 --> 00:38:26,800 TERRIFIC AMOUNT OF CLASS II 899 00:38:26,800 --> 00:38:27,240 POLYMORPHISM. 900 00:38:27,240 --> 00:38:31,080 IF YOU USE THE IMMUNE EPITOPE 901 00:38:31,080 --> 00:38:34,120 DATABASE, IN LA JOLLA, YOU CAN 902 00:38:34,120 --> 00:38:37,800 CLEARLY -- YOU FEED IN DIFFERENT 903 00:38:37,800 --> 00:38:40,560 FLU STRAIN SEQUENCES, YOU CAN 904 00:38:40,560 --> 00:38:44,760 SEE A TREMENDOUS HETEROGENEITY 905 00:38:44,760 --> 00:38:50,080 IN HOW CLASS II ALLELES PRESENT 906 00:38:50,080 --> 00:38:52,040 PEPTIDES FOR THOSE STRAINS, 907 00:38:52,040 --> 00:38:54,880 THAT'S WHAT'S SHOWN HERE, FOR 908 00:38:54,880 --> 00:38:58,520 INSTANCE IF YOU HAVE THESE HLA 909 00:38:58,520 --> 00:39:01,040 CLASS II POLYMORPHISMS YOU'LL DO 910 00:39:01,040 --> 00:39:05,080 GREAT WITH H3 STRAINS, DO 911 00:39:05,080 --> 00:39:06,480 TERRIBLE WITH B STRAIN. 912 00:39:06,480 --> 00:39:07,920 SIMILARLY YOU HAVE THESE 913 00:39:07,920 --> 00:39:11,320 ALLELES, YOU'RE GOING TO DO 914 00:39:11,320 --> 00:39:15,000 GREAT WITH THESE STRAINS, 915 00:39:15,000 --> 00:39:16,360 TERRIBLY WITH H3 STRAINS. 916 00:39:16,360 --> 00:39:21,520 THIS EXPLAINS AND IN FACT CAN 917 00:39:21,520 --> 00:39:23,880 PREDICT YOUR STRAIN BIAS. 918 00:39:23,880 --> 00:39:25,320 AND THERE WAS FURTHER WORK, I 919 00:39:25,320 --> 00:39:27,720 DON'T HAVE TIME TO GO OVER IT, 920 00:39:27,720 --> 00:39:29,040 CORRELATING THIS WITH HELPER T 921 00:39:29,040 --> 00:39:29,480 CELLS. 922 00:39:29,480 --> 00:39:31,240 HE MADE PEPTIDES FOR THESE AND 923 00:39:31,240 --> 00:39:33,960 SHOWED THAT YOU GET A 924 00:39:33,960 --> 00:39:36,360 CORRELATION WITH HELPER T CELLS. 925 00:39:36,360 --> 00:39:41,080 WHAT ANY MEANS IS THAT IF YOU 926 00:39:41,080 --> 00:39:46,440 HAVE THESE ALLELES, THEY JUST 927 00:39:46,440 --> 00:39:46,760 DON'T 928 00:39:46,760 --> 00:39:49,480 [AUDIO DISTORTION] 929 00:39:49,480 --> 00:39:58,160 FOR THESE STRAINS. 930 00:39:58,160 --> 00:40:08,200 931 00:40:35,400 --> 00:40:36,880 HELLO? 932 00:40:36,880 --> 00:40:44,520 IT'S WORKING. 933 00:40:44,520 --> 00:40:45,920 WOW! 934 00:40:45,920 --> 00:40:47,440 OKAY. 935 00:40:47,440 --> 00:40:47,600 NOW, 936 00:40:47,600 --> 00:40:57,960 [AUDIO DISTORTION] 937 00:41:05,800 --> 00:41:07,400 THIS IS WHAT ORGANIZE COME IN. 938 00:41:07,400 --> 00:41:09,040 YOU CAN'T DO THIS WITH A MOUSE. 939 00:41:09,040 --> 00:41:15,160 THE MOUSE AS ONE OR TWO ALLELES 940 00:41:15,160 --> 00:41:16,440 CLASS II. 941 00:41:16,440 --> 00:41:25,760 WE REACH FOR OUR SELECTION OF 942 00:41:25,760 --> 00:41:31,440 TONSIL ORGANOIDS. 943 00:41:31,440 --> 00:41:32,560 HE MADE CONSTRUCTING DISPLAYING 944 00:41:32,560 --> 00:41:37,080 SEPARATE MOLECULES FROM EACH FLU 945 00:41:37,080 --> 00:41:40,240 STRAIN, BASICALLY WHAT THE 946 00:41:40,240 --> 00:41:42,920 VACCINE IS, OR HE ALSO MADE 947 00:41:42,920 --> 00:41:47,240 ANOTHER CONSTRUCT WHERE HE MIXED 948 00:41:47,240 --> 00:41:52,320 ALL FOUR FROM DIFFERENT STRAINS. 949 00:41:52,320 --> 00:41:55,600 AND SO THE COCKTAIL, EACH OF THE 950 00:41:55,600 --> 00:41:57,240 CONSTRUCTS WOULD ONLY HIT B 951 00:41:57,240 --> 00:42:01,080 CELLS THAT HAD THESE 952 00:42:01,080 --> 00:42:02,720 SPECIFICITIES ON THEIR 953 00:42:02,720 --> 00:42:05,560 ANTIBODIES, BUT THESE WOULD HIT 954 00:42:05,560 --> 00:42:10,160 ALL THESE CELLS THAT HAD ANY FLU 955 00:42:10,160 --> 00:42:16,600 STRAIN SPECIFICITY AND 956 00:42:16,600 --> 00:42:21,880 FURTHERMORE PRESENT FROM ALL 957 00:42:21,880 --> 00:42:28,200 FOUR OF THE MAJOR STRAINS. 958 00:42:28,200 --> 00:42:29,960 GO BACK ONE SLIDE. 959 00:42:29,960 --> 00:42:34,760 YEAH, SO JUST TO INTRODUCE THIS, 960 00:42:34,760 --> 00:42:42,320 HERE WE HAVE GIVEN INDIVIDUAL 961 00:42:42,320 --> 00:42:45,040 GETTING THE TETRAVALENT AND HAS 962 00:42:45,040 --> 00:42:48,640 A PREFERENCE FOR THREE, YOU CAN 963 00:42:48,640 --> 00:42:51,080 SEE THE NICE ANTIBODY RESPONSE, 964 00:42:51,080 --> 00:42:52,280 CRAPPY RESPONSE TO THE OTHER 965 00:42:52,280 --> 00:42:53,600 THREE STRAINS. 966 00:42:53,600 --> 00:42:56,520 WE USE THE HA COCKTAIL, THAT IS 967 00:42:56,520 --> 00:42:58,200 A SEPARATE CONSTRUCT, BASICALLY 968 00:42:58,200 --> 00:43:01,360 GET THE SAME THING. 969 00:43:01,360 --> 00:43:03,680 GOOD H3 RESPONSE, CRAPPY OTHER. 970 00:43:03,680 --> 00:43:11,120 WE USE CROSS-LINK HA AND WE GIVE 971 00:43:11,120 --> 00:43:16,160 ALL OF THE RESULTS SPECIFIC FOR 972 00:43:16,160 --> 00:43:17,640 ANY STRAIN, FULL COMPLEMENT OF T 973 00:43:17,640 --> 00:43:19,320 CELL HELP, WE KNOW THERE'S A 974 00:43:19,320 --> 00:43:20,520 TREMENDOUS AMOUNT OF T CELLS 975 00:43:20,520 --> 00:43:29,280 SPECIFIC FOR FLU IN TONSILS AND 976 00:43:29,280 --> 00:43:29,960 SPLEENS. 977 00:43:29,960 --> 00:43:30,920 [AUDIO DISTORTION] 978 00:43:30,920 --> 00:43:35,640 STAINED WITH A FLU REAGENT, HA 979 00:43:35,640 --> 00:43:37,800 REAGENT, A LOT OF FLU OVER THE 980 00:43:37,800 --> 00:43:40,640 YEARS, BUILD UP A TREMENDOUS 981 00:43:40,640 --> 00:43:45,680 AMOUNT OF HEALTH. 982 00:43:45,680 --> 00:43:46,680 NEXT SLIDE PLEASE. 983 00:43:46,680 --> 00:43:53,120 THESE ARE INDIVIDUAL RESPONSES 984 00:43:53,120 --> 00:43:54,600 FROM TEN TONSILS. 985 00:43:54,600 --> 00:43:57,840 SOMETHING LIKE SEVEN OF THE TEN 986 00:43:57,840 --> 00:43:58,680 SHOW ANTIBODY RESPONSES BUT 987 00:43:58,680 --> 00:43:59,440 THAT'S GOOD. 988 00:43:59,440 --> 00:44:09,760 SEVEN OUT OF TEN. 989 00:44:14,880 --> 00:44:16,640 I'LL TAKE THAT. 990 00:44:16,640 --> 00:44:17,640 BASICALLY OUGHT THE VACCINES, 991 00:44:17,640 --> 00:44:21,040 COVID VACCINES ARE GOING TO BE 992 00:44:21,040 --> 00:44:22,120 MULTI-STRAIN, MULTI-STRAINS. 993 00:44:22,120 --> 00:44:26,840 ALL THESE OTHER ONES, SO JUST 994 00:44:26,840 --> 00:44:28,360 MIXING TOGETHER, EASY LAZY MAN'S 995 00:44:28,360 --> 00:44:30,280 VACCINE WHERE WE JUST MIX ALL 996 00:44:30,280 --> 00:44:32,760 THE STRAINS TOGETHER, AND HOPING 997 00:44:32,760 --> 00:44:35,800 WE GET GOOD RESPONSE, YOU WILL 998 00:44:35,800 --> 00:44:38,000 GET -- YOU'LL ENCOURAGE MORE 999 00:44:38,000 --> 00:44:43,520 CROSS-REACTIVE RESPONSES, BUT 1000 00:44:43,520 --> 00:44:49,320 YOU WON'T -- GENETICS IS A 1001 00:44:49,320 --> 00:44:52,720 POWERFUL THING. 1002 00:44:52,720 --> 00:44:56,520 I THINK THIS IS HOW WE SHOULD BE 1003 00:44:56,520 --> 00:44:58,600 MAKING MULTI-STRAIN VACCINES. 1004 00:44:58,600 --> 00:45:06,280 THIS RAISES THE PROSPECT OF CAN 1005 00:45:06,280 --> 00:45:10,000 WE HARNESS THIS TREMENDOUS 1006 00:45:10,000 --> 00:45:11,320 (INDISCERNIBLE) FOR FLU-SPECIFIC 1007 00:45:11,320 --> 00:45:13,640 EPITOPES, HARNESS TO MAKE BETTER 1008 00:45:13,640 --> 00:45:15,320 RESPONSES AGAINST OTHER EPITOPES 1009 00:45:15,320 --> 00:45:18,560 LIKE HIV, LIKE BIRD FLU, THINGS 1010 00:45:18,560 --> 00:45:22,480 THAT WE'RE GETTING CRAPPY 1011 00:45:22,480 --> 00:45:24,560 RESPONSES FROM THE GET-GO BUT 1012 00:45:24,560 --> 00:45:28,280 ALL THIS ABUNDANT T CELL HELP WE 1013 00:45:28,280 --> 00:45:30,160 COULD BOOST ANTIBODY RESPONSE. 1014 00:45:30,160 --> 00:45:33,440 THAT'S SOMETHING WE'RE WORKING 1015 00:45:33,440 --> 00:45:35,720 ON. 1016 00:45:35,720 --> 00:45:37,600 NEXT SLIDE PLEASE. 1017 00:45:37,600 --> 00:45:40,880 AND SO THEN WE GET MORE 1018 00:45:40,880 --> 00:45:43,400 AMBITIOUS, AND THOUGHT, WELL, 1019 00:45:43,400 --> 00:45:47,720 MAYBE WE CAN COMBINE THESE 1020 00:45:47,720 --> 00:45:49,520 IMMUNE ORGANOIDS WITH TISSUES 1021 00:45:49,520 --> 00:45:53,560 RELEVANT TO IMMUNE CIRCUITRY, SO 1022 00:45:53,560 --> 00:45:53,760 FORTH. 1023 00:45:53,760 --> 00:45:57,200 ELSA SOLA IS HEAD OF OUR 1024 00:45:57,200 --> 00:46:03,760 ORGANOID EFFORT, AND CHEN WANG 1025 00:46:03,760 --> 00:46:05,240 IS A DERMATOLOGY IS, I ASKED CAN 1026 00:46:05,240 --> 00:46:09,560 YOU GET A PIECE OF SKIN AND 1027 00:46:09,560 --> 00:46:11,240 THROW IN THE TONSIL-RELATED 1028 00:46:11,240 --> 00:46:11,480 DONOR? 1029 00:46:11,480 --> 00:46:12,760 SURE, WHY NOT. 1030 00:46:12,760 --> 00:46:16,280 NEXT SLIDE PLEASE. 1031 00:46:16,280 --> 00:46:18,440 AND WHAT HAPPENED IS TONSIL 1032 00:46:18,440 --> 00:46:23,280 CELLS ATTACKED THE SKIN, SO 1033 00:46:23,280 --> 00:46:26,440 BASICALLY A FOREIGN TISSUE COMES 1034 00:46:26,440 --> 00:46:28,840 INTO VIEW, T CELLS ARE ON IT, B 1035 00:46:28,840 --> 00:46:30,840 CELLS ARE ON IT TOO, IF YOU LOOK 1036 00:46:30,840 --> 00:46:35,400 AT T AND B CELLS, EVEN MORE B 1037 00:46:35,400 --> 00:46:36,720 CELL INFILTRATION THAN T CELL 1038 00:46:36,720 --> 00:46:37,040 INFILTRATION. 1039 00:46:37,040 --> 00:46:38,920 NEXT SLIDE. 1040 00:46:38,920 --> 00:46:42,640 WE GET THIS INFILTRATION AND THE 1041 00:46:42,640 --> 00:46:43,960 TONSILS THEMSELVES START KILLING 1042 00:46:43,960 --> 00:46:44,920 THE SKIN, OF COURSE. 1043 00:46:44,920 --> 00:46:49,680 AS YOU CAN SEE IN THIS ASSAY IN 1044 00:46:49,680 --> 00:46:51,160 RED, ALL EPITHELIAL CELLS ARE 1045 00:46:51,160 --> 00:46:52,920 BUSY DYING. 1046 00:46:52,920 --> 00:46:56,520 WE CAN INHIBIT WITH CYCLOSPORIN 1047 00:46:56,520 --> 00:46:57,840 AND CLASSIC TRANSPLANT REJECTION 1048 00:46:57,840 --> 00:47:01,160 DRUGS, SO WE ARE LOOKING FOR ALL 1049 00:47:01,160 --> 00:47:04,200 INTENTS AND PURPOSES AT 1050 00:47:04,200 --> 00:47:07,480 CLASSICAL SKIN GRAFT REJECTION 1051 00:47:07,480 --> 00:47:09,120 AND OLD-TIME IMMUNOLOGY, I 1052 00:47:09,120 --> 00:47:10,200 ORIGINALLY READ ABOUT THESE 1053 00:47:10,200 --> 00:47:12,000 THINGS HAPPENING IN ANCIENT 1054 00:47:12,000 --> 00:47:16,160 TIMES, BUT NEVER THOUGHT I'D BE 1055 00:47:16,160 --> 00:47:18,760 WORKING ON IT. 1056 00:47:18,760 --> 00:47:22,480 WE WANT TO WORK ON HAPPIER 1057 00:47:22,480 --> 00:47:25,760 THINGS OF SYNERGY BETWEEN SKIN 1058 00:47:25,760 --> 00:47:27,880 AND IMMUNE ORGANOIDS BUT HOW DO 1059 00:47:27,880 --> 00:47:28,920 YOU GET THAT SYSTEM? 1060 00:47:28,920 --> 00:47:31,880 HOW DO YOU WORK THAT OUT? 1061 00:47:31,880 --> 00:47:36,160 SO, THIS FORCED US INTO THE 1062 00:47:36,160 --> 00:47:37,600 ARMS, NEXT SLIDE, OF TRANSPLANT 1063 00:47:37,600 --> 00:47:39,320 COMMUNITY BECAUSE IT TURNS OUT 1064 00:47:39,320 --> 00:47:42,400 THAT WHEN SURGEONS GO TO HARVEST 1065 00:47:42,400 --> 00:47:44,360 ORGANS FROM DONORS, THEY JUST 1066 00:47:44,360 --> 00:47:45,880 SCOOP OUT THE WHOLE INNARDS, 1067 00:47:45,880 --> 00:47:48,160 THROW THEM IN THE ICE BUCKET AND 1068 00:47:48,160 --> 00:47:51,040 HELICOPTER OVER TO WHEREVER THEY 1069 00:47:51,040 --> 00:47:52,800 ARE GOING. 1070 00:47:52,800 --> 00:47:55,360 AND THE SPLEENS ARE IN THE MIX. 1071 00:47:55,360 --> 00:47:57,920 BUT AT THE END OF THE DAY WHEN 1072 00:47:57,920 --> 00:48:02,320 THEY ARE PUTTING ORGANS INTO -- 1073 00:48:02,320 --> 00:48:03,080 VALUABLE ORGANS INTO RECIPIENTS 1074 00:48:03,080 --> 00:48:06,240 THEY THROW AWAY THE SPLEEN. 1075 00:48:06,240 --> 00:48:08,640 NOBODY WANTS TO TRANSPLANT 1076 00:48:08,640 --> 00:48:09,520 SPLEENS. 1077 00:48:09,520 --> 00:48:12,600 YOU PROBABLY GET THE WORST 1078 00:48:12,600 --> 00:48:14,200 GvHD, YOU THROW THEM AWAY, ONE 1079 00:48:14,200 --> 00:48:20,440 SURGEON TOLD ME YOU MAKE DNA, I 1080 00:48:20,440 --> 00:48:22,760 WAS THINKING, TENS OF BILLIONS 1081 00:48:22,760 --> 00:48:23,960 OF LYMPHOCYTES THAT TELL THE 1082 00:48:23,960 --> 00:48:26,040 IMMUNE HISTORY OF THAT 1083 00:48:26,040 --> 00:48:27,680 PARTICULAR PERSON, AND WE CAN DO 1084 00:48:27,680 --> 00:48:32,160 NOW ALL THESE THINGS WITH. 1085 00:48:32,160 --> 00:48:32,840 SO LET'S TALK. 1086 00:48:32,840 --> 00:48:33,920 SEND THEM TO US. 1087 00:48:33,920 --> 00:48:36,640 SO OVER THE PAST YEAR WE'VE 1088 00:48:36,640 --> 00:48:38,280 GOTTEN OVER 30 SPLEENS, EVERY 1089 00:48:38,280 --> 00:48:40,160 OTHER WEEK WE GET A SPLEEN. 1090 00:48:40,160 --> 00:48:42,680 THEY ARE HUGE. 1091 00:48:42,680 --> 00:48:44,120 WE GET UP TO 50 ALIQUOTS OF 1092 00:48:44,120 --> 00:48:45,400 MATERIAL WE CAN FREEZE DOWN, YOU 1093 00:48:45,400 --> 00:48:47,400 CAN GO BACK TO THE SAME DONOR 1094 00:48:47,400 --> 00:48:48,640 OVER AND OVER AGAIN, BUT THE 1095 00:48:48,640 --> 00:48:50,320 OTHER GOOD THING IS THE SPLEENS 1096 00:48:50,320 --> 00:48:52,840 ARE MUCH MORE DIVERSE THAN 1097 00:48:52,840 --> 00:48:54,480 TONSILS. 1098 00:48:54,480 --> 00:48:56,480 TONSILS ARE MOSTLY B AND T 1099 00:48:56,480 --> 00:48:59,440 CELLS, 99%, BUT SPLEENS ARE 60% 1100 00:48:59,440 --> 00:49:06,960 B AND T, LOTS OF DENDRITIC AND 1101 00:49:06,960 --> 00:49:10,160 NK CELLS, MORE DIVERSE ORGAN, 1102 00:49:10,160 --> 00:49:11,480 BIGGER, MORE ATTRACTIVE. 1103 00:49:11,480 --> 00:49:12,680 NEXT SLIDE PLEASE. 1104 00:49:12,680 --> 00:49:16,160 AND WE GET BETTER ANTIBODY 1105 00:49:16,160 --> 00:49:20,400 RESPONSES, IT'S A QUIETER 1106 00:49:20,400 --> 00:49:20,640 ORGAN. 1107 00:49:20,640 --> 00:49:22,280 TONSILS ARE FRONT LINE, LOTS OF 1108 00:49:22,280 --> 00:49:23,840 STUFF COMING INTO THE MOUTH, 1109 00:49:23,840 --> 00:49:26,320 KNOWS YOU'RE TRYING TO MAKE A 1110 00:49:26,320 --> 00:49:26,720 RESPONSE. 1111 00:49:26,720 --> 00:49:27,560 NEXT SLIDE. 1112 00:49:27,560 --> 00:49:30,520 AND ALSO THEY ARE CLEANER. 1113 00:49:30,520 --> 00:49:31,600 LOWER BACKGROUND. 1114 00:49:31,600 --> 00:49:34,520 AND WE GET BIGGER ANTIBODY 1115 00:49:34,520 --> 00:49:36,720 RESPONSES IN SPLEENS VERSUS 1116 00:49:36,720 --> 00:49:37,120 TONSILS. 1117 00:49:37,120 --> 00:49:39,920 SO THAT'S ALL COOL. 1118 00:49:39,920 --> 00:49:41,640 AND BUT WHAT'S REALLY IMPORTANT, 1119 00:49:41,640 --> 00:49:43,600 THE REASON WE WENT TO THIS TO 1120 00:49:43,600 --> 00:49:46,120 GET SKIN AND LUNG AND OTHER BODY 1121 00:49:46,120 --> 00:49:48,720 PARTS FROM THE SAME DONOR AS 1122 00:49:48,720 --> 00:49:55,560 WHAT WE'RE MAKING IN THE IMMUNE 1123 00:49:55,560 --> 00:50:01,960 JOGGER -- JOGGER -- ORGANOID. 1124 00:50:01,960 --> 00:50:04,200 WE HAVE SOLVED A NUMBER OF 1125 00:50:04,200 --> 00:50:05,520 PROBLEMS THAT WERE BUGGING US. 1126 00:50:05,520 --> 00:50:08,040 ONE IS WE COULD NEVER GET A 1127 00:50:08,040 --> 00:50:09,760 YELLOW FEVER VACCINE RESPONSE IN 1128 00:50:09,760 --> 00:50:11,200 THE TONSILS. 1129 00:50:11,200 --> 00:50:15,040 PROBABLY BECAUSE THERE ARE TOO 1130 00:50:15,040 --> 00:50:16,320 FEW DENDRITIC CELLS. 1131 00:50:16,320 --> 00:50:19,520 NOW WITH SPLEENS ARE ABLE TO GET 1132 00:50:19,520 --> 00:50:22,360 YELLOW FEVER ANTIBODY RESPONSE, 1133 00:50:22,360 --> 00:50:24,640 SO FAR JUST IgM BUT THEY ARE 1134 00:50:24,640 --> 00:50:25,320 CHARACTERISTIC OF YELLOW FEVER 1135 00:50:25,320 --> 00:50:27,200 AND WE HAVE THE PUSH TO CELLS 1136 00:50:27,200 --> 00:50:30,120 LONGER TO GET INTO SOME IgG 1137 00:50:30,120 --> 00:50:30,400 TERRITORY. 1138 00:50:30,400 --> 00:50:32,000 WE NEVER COULD GET RNA VACCINES 1139 00:50:32,000 --> 00:50:34,840 TO WORK IN THE TONSILS. 1140 00:50:34,840 --> 00:50:40,480 BUT NOW THEY DO WORK IN SPLEENS, 1141 00:50:40,480 --> 00:50:41,760 AGAIN PROBABLY CELL DRIVEN. 1142 00:50:41,760 --> 00:50:45,480 IF WE DIDN'T GET A RESPONSE, WE 1143 00:50:45,480 --> 00:50:47,760 ISOLATED DENDRITIC CELLS FROM 1144 00:50:47,760 --> 00:50:49,320 THE SPLEEN, ONE ALIQUOT OF 1145 00:50:49,320 --> 00:50:51,360 SPLEEN, HIT THAT DIRECTLY WITH 1146 00:50:51,360 --> 00:50:53,560 RNA VACCINE, AND THEN PUT THAT 1147 00:50:53,560 --> 00:50:55,200 WITH A SECOND ALIQUOT FROM THE 1148 00:50:55,200 --> 00:50:56,320 SAME DONOR. 1149 00:50:56,320 --> 00:51:00,360 NOW WE GET A GOOD ANTIBODY 1150 00:51:00,360 --> 00:51:01,000 RESPONSE. 1151 00:51:01,000 --> 00:51:03,520 SO THESE ARGUMENTS, 20, 30 YEARS 1152 00:51:03,520 --> 00:51:06,400 AGO, HEATED ARGUMENTS WITH MY 1153 00:51:06,400 --> 00:51:08,440 PROFESSIONAL APC IS MORE 1154 00:51:08,440 --> 00:51:09,240 PROFESSIONAL THAN YOURS. 1155 00:51:09,240 --> 00:51:10,160 ALL RIGHT, FINE. 1156 00:51:10,160 --> 00:51:11,480 DIDN'T HAVE ANYTHING TO DO WITH 1157 00:51:11,480 --> 00:51:13,920 ME SO I JUST IGNORED IT BUT NOW 1158 00:51:13,920 --> 00:51:15,280 I'M STARTING TO APPRECIATE IT. 1159 00:51:15,280 --> 00:51:17,080 THERE WAS SOMETHING TO WHAT 1160 00:51:17,080 --> 00:51:17,680 PEOPLE SAID. 1161 00:51:17,680 --> 00:51:20,160 OF COURSE EVERYBODY WAS RIGHT. 1162 00:51:20,160 --> 00:51:22,600 I THINK THE FLU EXPERIMENT SHOWS 1163 00:51:22,600 --> 00:51:30,000 TARGETING B CELLS IS USEFUL FOR 1164 00:51:30,000 --> 00:51:31,680 T-CELL RESPONSES. 1165 00:51:31,680 --> 00:51:34,320 AND DENDRITIC CELLS ARE REALLY 1166 00:51:34,320 --> 00:51:36,920 IMPORTANT FOR SOME FORMS OF 1167 00:51:36,920 --> 00:51:37,280 IMMUNITY. 1168 00:51:37,280 --> 00:51:39,440 EVERYONE IS RIGHT SO THAT'S 1169 00:51:39,440 --> 00:51:39,640 GOOD. 1170 00:51:39,640 --> 00:51:40,520 NEXT SLIDE. 1171 00:51:40,520 --> 00:51:41,960 I THINK WE'RE ALMOST AT THE END. 1172 00:51:41,960 --> 00:51:45,800 SO WE'RE JUST STARTING TO DO 1173 00:51:45,800 --> 00:51:46,680 EXPERIMENTS WHERE WE HAVE SKIN 1174 00:51:46,680 --> 00:51:48,080 AND SPLEEN FROM THE SAME DONOR 1175 00:51:48,080 --> 00:51:50,320 AND WE'RE ABLE TO VACCINATE THE 1176 00:51:50,320 --> 00:51:54,040 SKIN AND SEE A RESPONSE IN THE 1177 00:51:54,040 --> 00:51:54,400 SPLEEN. 1178 00:51:54,400 --> 00:51:55,880 AGAIN YOU DON'T NEED PLUMBING. 1179 00:51:55,880 --> 00:51:57,520 YOU CALL IN THE BIOENGINEERS, 1180 00:51:57,520 --> 00:52:01,160 THEY ARE GOING TO BUILD A 1181 00:52:01,160 --> 00:52:02,680 TREMENDOUSLY BEAUTIFUL 1182 00:52:02,680 --> 00:52:04,000 MICROFLUIDIC DEVICE AND ORGANS 1183 00:52:04,000 --> 00:52:06,320 ON CHIP, SO FORTH. 1184 00:52:06,320 --> 00:52:09,600 WE PUT THINGS IN THE SAME WELL, 1185 00:52:09,600 --> 00:52:11,760 AND THEY TALK. 1186 00:52:11,760 --> 00:52:15,400 IMMUNE CELLS ARE PRETTY FLEXIBLE 1187 00:52:15,400 --> 00:52:17,480 THAT WAY. 1188 00:52:17,480 --> 00:52:19,520 WE'RE JUST GETTING A LUNG, 1189 00:52:19,520 --> 00:52:20,960 SPECIFICALLY USED FOR TRANSPLANT 1190 00:52:20,960 --> 00:52:22,920 SO WE DON'T GET LUNG ALL THE 1191 00:52:22,920 --> 00:52:24,480 TIME, BUT WE DO GET LUNG SOME OF 1192 00:52:24,480 --> 00:52:25,000 THE TIME. 1193 00:52:25,000 --> 00:52:28,920 HERE IN THE NEXT SLIDE WE'VE 1194 00:52:28,920 --> 00:52:31,680 BEEN WORKING WITH CALVIN QUO WHO 1195 00:52:31,680 --> 00:52:33,640 HAS A LUNG ORGANOID SYSTEM, IT'S 1196 00:52:33,640 --> 00:52:36,280 A MORE STANDARD TYPE OF ORGANOID 1197 00:52:36,280 --> 00:52:38,240 DRIVEN BY STEM CELLS THAN WHAT 1198 00:52:38,240 --> 00:52:39,600 WE'RE DRIVEN WITH IMMUNE CELLS, 1199 00:52:39,600 --> 00:52:42,000 BUT ANYWAY IT WORKS. 1200 00:52:42,000 --> 00:52:47,120 HE'S ALREADY SHOWN THAT HE CAN 1201 00:52:47,120 --> 00:52:51,160 GET SARS-COV-2 IN LUNG AND IN 1202 00:52:51,160 --> 00:52:57,320 THIS LATEST PAPER YOU CAN SEE 1203 00:52:57,320 --> 00:53:02,520 USING OUR TECHNOLOGY, CAN SEE 1204 00:53:02,520 --> 00:53:03,440 SARS-COV-2 SPECIFIC T CELLS IN 1205 00:53:03,440 --> 00:53:05,080 THE LUNG, THIS TYPE OF LUNG 1206 00:53:05,080 --> 00:53:07,960 ORGANOID HAS SOME OF THE 1207 00:53:07,960 --> 00:53:10,800 ENDOGENOUS LYMPHOCYTES IN IT. 1208 00:53:10,800 --> 00:53:13,520 WE'RE COUPLING THIS TYPE OF LUNG 1209 00:53:13,520 --> 00:53:16,160 ORGANOID WITH A SPLEEN ORGANOID 1210 00:53:16,160 --> 00:53:18,080 FROM THE SAME INDIVIDUAL AND 1211 00:53:18,080 --> 00:53:19,840 HOPEFULLY WE CAN TEST VACCINES 1212 00:53:19,840 --> 00:53:28,480 IN AN ENTIRELY DIFFERENT WAY 1213 00:53:28,480 --> 00:53:29,680 NOW, VACCINATE THE SPLEEN, DOES 1214 00:53:29,680 --> 00:53:33,080 IT PROTECT FROM THIS OR THAT 1215 00:53:33,080 --> 00:53:34,000 VIRUS. 1216 00:53:34,000 --> 00:53:36,280 SO NO MICE WILL BE HARMED IN 1217 00:53:36,280 --> 00:53:37,560 THESE EXPERIMENTS, I WANT TO 1218 00:53:37,560 --> 00:53:40,000 ASSURE PEOPLE OF THAT. 1219 00:53:40,000 --> 00:53:41,080 NEXT SLIDE. 1220 00:53:41,080 --> 00:53:47,680 OH, OF COURSE WE'RE ALSO VERY 1221 00:53:47,680 --> 00:53:49,240 KEENLY INTERESTED, DEVELOPING 1222 00:53:49,240 --> 00:53:51,400 THE CASE THAT THERE ARE 1223 00:53:51,400 --> 00:53:52,240 HUMAN-SPECIFIC SYSTEMS IN 1224 00:53:52,240 --> 00:53:53,800 IMMUNITY, HAVE BEEN PART OF 1225 00:53:53,800 --> 00:53:55,640 WHAT'S HOLDING US UP IN THE 1226 00:53:55,640 --> 00:53:57,280 VACCINE BUSINESS. 1227 00:53:57,280 --> 00:54:01,880 SO, WE BROKE DOWN AND MADE NOW A 1228 00:54:01,880 --> 00:54:04,320 MOUSE SPLEEN ORGANOID, AND 1229 00:54:04,320 --> 00:54:07,360 STIMULATED WITH ATTENUATED FLU 1230 00:54:07,360 --> 00:54:13,080 VACCINE, GET STIMULATION, 1231 00:54:13,080 --> 00:54:13,640 ANTIBODIES. 1232 00:54:13,640 --> 00:54:17,000 WE'LL BE ABLE TO RUN HUMAN 1233 00:54:17,000 --> 00:54:18,760 SPLEENS AND MOUSE SPLEENS SIDE 1234 00:54:18,760 --> 00:54:22,920 BY SIDE WITH THE SAME VACCINE, 1235 00:54:22,920 --> 00:54:25,440 AND DO SINGLE CELL EVERYTHING TO 1236 00:54:25,440 --> 00:54:28,000 SEE ARE THERE DIFFERENT 1237 00:54:28,000 --> 00:54:32,040 PATHWAYS, CAN WE IDENTIFY WHOLE 1238 00:54:32,040 --> 00:54:34,000 NEW WAYS IN WHICH HUMANS ARE 1239 00:54:34,000 --> 00:54:35,280 RESPONDING OR DIFFERENT HUMANS 1240 00:54:35,280 --> 00:54:36,280 ARE RESPONDING BECAUSE THAT'S 1241 00:54:36,280 --> 00:54:37,920 THE OTHER ADVANTAGE OF AN 1242 00:54:37,920 --> 00:54:40,680 ORGANOID, WE'RE SEEING HUMAN 1243 00:54:40,680 --> 00:54:41,960 DIVERSITY WHICH MICE ARE 1244 00:54:41,960 --> 00:54:44,600 DESIGNED NOT TO HAVE ANY 1245 00:54:44,600 --> 00:54:45,960 DIVERSITY, BUT HUMANS, WE'RE 1246 00:54:45,960 --> 00:54:52,040 STUCK WITH HUMAN DIVERSITY. 1247 00:54:52,040 --> 00:54:52,840 DIFFERENT PHENOTYPES, DIFFERENT 1248 00:54:52,840 --> 00:54:53,800 DRUG AND VACCINE RESPONSES. 1249 00:54:53,800 --> 00:54:55,600 HOW DO WE GET AT THAT? 1250 00:54:55,600 --> 00:54:57,760 THERE ARE OTHER SYSTEMS PEOPLE 1251 00:54:57,760 --> 00:55:00,720 HAVE ADVOCATED BUT I WOULD SAY 1252 00:55:00,720 --> 00:55:03,800 THIS IS -- GET THOSE SPLEENS, WE 1253 00:55:03,800 --> 00:55:06,880 HAVE NOW 33 SPLEENS AND WE'LL 1254 00:55:06,880 --> 00:55:10,040 HAVE 100 BY NEXT YEAR. 1255 00:55:10,040 --> 00:55:10,720 IT'S A COHORT. 1256 00:55:10,720 --> 00:55:12,560 AND YOU'RE GOING TO BE ABLE TO 1257 00:55:12,560 --> 00:55:14,520 DO THE SAME ASSAYS, SAME VACCINE 1258 00:55:14,520 --> 00:55:15,720 ACROSS SEVERAL COHORTS AND LOOK 1259 00:55:15,720 --> 00:55:18,920 AT THIS VARIATION AND TRY TO GET 1260 00:55:18,920 --> 00:55:20,560 AT WHAT IS CAUSAL, WHAT IS 1261 00:55:20,560 --> 00:55:23,400 ACTUALLY HAPPENING HERE, WHY ARE 1262 00:55:23,400 --> 00:55:24,800 PEOPLE LIKE THIS? 1263 00:55:24,800 --> 00:55:27,680 I THINK IT'S A WHOLE, YOU KNOW, 1264 00:55:27,680 --> 00:55:30,200 NEW ERA OF HUMAN IMMUNOLOGY AND 1265 00:55:30,200 --> 00:55:33,440 WE'RE GOING TO LEARN A 1266 00:55:33,440 --> 00:55:34,320 TREMENDOUS AMOUNT OVER THE 1267 00:55:34,320 --> 00:55:41,560 NEXT -- AT THE END HERE. 1268 00:55:41,560 --> 00:55:44,200 NEXT SLIDE PLEASE. 1269 00:55:44,200 --> 00:55:46,080 COULD CONCLUDE WE'RE FINDING OUT 1270 00:55:46,080 --> 00:55:53,080 ABOUT RELATIVE ROLES OF CD4 1271 00:55:53,080 --> 00:55:54,600 VERSUS CD8 REGULATORY CELLS, 1272 00:55:54,600 --> 00:55:57,160 ABLE TO ADDRESS SOME 1273 00:55:57,160 --> 00:55:59,200 LONGSTANDING ISSUES IN HUMAN 1274 00:55:59,200 --> 00:56:02,400 IMMUNOLOGY LIKE AGING, LIKE 1275 00:56:02,400 --> 00:56:03,840 STRAIN PREFERENCES IN FLU. 1276 00:56:03,840 --> 00:56:06,680 AND JUST THE ABILITY TO 1277 00:56:06,680 --> 00:56:09,240 MANIPULATE CELL POPULATIONS AND 1278 00:56:09,240 --> 00:56:10,480 GENE EDITING MEANS REALLY FOR 1279 00:56:10,480 --> 00:56:14,880 THE FIRST TIME WE CAN TEST 1280 00:56:14,880 --> 00:56:16,400 HYPOTHESES AND FIND MECHANISMS 1281 00:56:16,400 --> 00:56:17,200 IN ENTIRELY HUMAN SYSTEMS AND 1282 00:56:17,200 --> 00:56:21,160 THAT WILL BE THE BASIS OF A NEW 1283 00:56:21,160 --> 00:56:22,400 IMMUNOLOGY THAT NOW WE'RE GOING 1284 00:56:22,400 --> 00:56:25,160 TO FIND OUT A LOT OF WHAT WE'VE 1285 00:56:25,160 --> 00:56:27,360 BEEN MISSING. 1286 00:56:27,360 --> 00:56:30,320 AND THEN ALSO RECAPITULATING 1287 00:56:30,320 --> 00:56:31,200 IMMUNE NETWORKS, SKIN, THE 1288 00:56:31,200 --> 00:56:33,720 TRIPLE PLAY YOU HAVE SKIN AND 1289 00:56:33,720 --> 00:56:35,880 SPLEEN AND LUNG FROM THE SAME 1290 00:56:35,880 --> 00:56:38,000 DONOR, AND YOU VACCINATE THE 1291 00:56:38,000 --> 00:56:40,040 SKIN TO TRIGGER A RESPONSE IN 1292 00:56:40,040 --> 00:56:43,440 THE SPLEEN THAT HOPEFULLY IS 1293 00:56:43,440 --> 00:56:44,880 THEN PROTECTIVE AGAINST 1294 00:56:44,880 --> 00:56:48,080 INFECTION IN THE LUNG. 1295 00:56:48,080 --> 00:56:50,360 ALL IN THE SAME. 1296 00:56:50,360 --> 00:56:52,120 AND OF COURSE WE'RE ALSO TRAINED 1297 00:56:52,120 --> 00:56:55,520 MORE DIRECTLY TO COMPARE HUMAN 1298 00:56:55,520 --> 00:56:58,160 AND MICE USING ALL THE FANTASTIC 1299 00:56:58,160 --> 00:57:00,080 TECHNOLOGY THAT'S AVAILABLE. 1300 00:57:00,080 --> 00:57:00,440 LAST SLIDE. 1301 00:57:00,440 --> 00:57:03,800 OF COURSE NONE OF THIS WOULD BE 1302 00:57:03,800 --> 00:57:05,240 POSSIBLE WITHOUT SOME REALLY 1303 00:57:05,240 --> 00:57:14,640 TALENTED PEOPLE IN THE GROUP AND 1304 00:57:14,640 --> 00:57:25,160 COLLABORATORS, I MENTIONED CD 1305 00:57:28,920 --> 00:57:30,880 SUPPRESSION KNOCKOUT 1306 00:57:30,880 --> 00:57:33,600 EXPERIMENTS, GREAT 1307 00:57:33,600 --> 00:57:35,200 COLLABORATORS, MARY, CALVIN, 1308 00:57:35,200 --> 00:57:39,200 SCOTT. 1309 00:57:39,200 --> 00:57:39,680 LOTS OF PATIENT-FUNDING 1310 00:57:39,680 --> 00:57:44,880 AGENCIES, NATIONAL INSTITUTE OF 1311 00:57:44,880 --> 00:57:47,840 AGING, NIA, SO THANK YOU. 1312 00:57:47,840 --> 00:57:53,840 1313 00:57:53,840 --> 00:57:55,040 1314 00:57:55,040 --> 00:57:56,360 >> THANKS FOR A GREAT TALK. 1315 00:57:56,360 --> 00:57:58,120 WE HAVE TIME FOR QUESTIONS. 1316 00:57:58,120 --> 00:58:00,320 PLEASE RAISE YOUR HAND. 1317 00:58:00,320 --> 00:58:02,040 SPEAK INTO THE MICROPHONE AND 1318 00:58:02,040 --> 00:58:07,760 INTRODUCE YOURSELF AND WHICH 1319 00:58:07,760 --> 00:58:08,840 INSTITUTION YOU'RE FROM. 1320 00:58:08,840 --> 00:58:14,200 >> MICHELLE, CAMBRIDGE U.K. 1321 00:58:14,200 --> 00:58:17,040 I THOUGHT THE FOXP3 KNOCKOUT WAS 1322 00:58:17,040 --> 00:58:26,040 COOL AND DATA ON AGING ANTIBODY 1323 00:58:26,040 --> 00:58:28,080 AND AFFINITY 1324 00:58:28,080 --> 00:58:29,720 [AUDIO DISTORTION] 1325 00:58:29,720 --> 00:58:40,240 CURIOUS WHETHER YOU HAVE MORE 1326 00:58:41,400 --> 00:58:42,960 CENTERS -- 1327 00:58:42,960 --> 00:58:53,280 [AUDIO DISTORTION] 1328 00:58:59,680 --> 00:59:03,920 >> YEAH. 1329 00:59:03,920 --> 00:59:05,120 IT'S INTERESTING. 1330 00:59:05,120 --> 00:59:08,040 ONE OF THE TECHNICAL ISSUES WITH 1331 00:59:08,040 --> 00:59:11,200 ORGANOIDS IS THEY ARE VERY 1332 00:59:11,200 --> 00:59:14,400 SLOPPY, THEY ARE NOT AS WELL 1333 00:59:14,400 --> 00:59:17,680 FORMED, OTHER ORGANOIDS ARE 1334 00:59:17,680 --> 00:59:19,800 BIOPSIES THAT YOU THEN ARE 1335 00:59:19,800 --> 00:59:21,080 CULTURING, DON'T HAVE A LOT OF 1336 00:59:21,080 --> 00:59:24,360 STRUCTURE AROUND FALL APART 1337 00:59:24,360 --> 00:59:24,600 EASILY. 1338 00:59:24,600 --> 00:59:26,640 IT'S A CHALLENGE TO EVEN GET 1339 00:59:26,640 --> 00:59:29,640 GERMINAL CENTER PICTURES, WE'RE 1340 00:59:29,640 --> 00:59:33,200 LOOKING FOR BETTER WAYS. 1341 00:59:33,200 --> 00:59:33,840 MAYBE MULTI-PHOTON MICROSCOPY, 1342 00:59:33,840 --> 00:59:35,240 IT WILL BE REALLY GOOD. 1343 00:59:35,240 --> 00:59:39,280 SOMEDAY WE HOPE TO HAVE MOVIES 1344 00:59:39,280 --> 00:59:41,880 OF GERMINAL CENTERS FORMING AND 1345 00:59:41,880 --> 00:59:43,440 CELLS RUNNING RUN. 1346 00:59:43,440 --> 00:59:45,280 WE'RE NOT THERE YET. 1347 00:59:45,280 --> 00:59:47,800 >> I WAS CURIOUS BECAUSE YOU 1348 00:59:47,800 --> 00:59:51,000 DON'T HAVE THE NETWORK THAT 1349 00:59:51,000 --> 00:59:51,840 UNDERPINS THE -- 1350 00:59:51,840 --> 00:59:52,600 >>WE DO. 1351 00:59:52,600 --> 00:59:54,520 >> WITH THE SPLEEN ORGANOIDS 1352 00:59:54,520 --> 00:59:56,480 YOU GET THE STROMAL CELLS? 1353 00:59:56,480 --> 00:59:58,880 >> YEAH, YEAH. 1354 00:59:58,880 --> 01:00:01,200 >> DOES IT FORM THE NORMAL 1355 01:00:01,200 --> 01:00:02,720 ZONAL STRUCTURES? 1356 01:00:02,720 --> 01:00:06,000 AGAIN WE NEED BETTER MICROSCOPY, 1357 01:00:06,000 --> 01:00:08,640 TRYING TO WORK THAT OUT. 1358 01:00:08,640 --> 01:00:10,080 IT'S A FRONTIER. 1359 01:00:10,080 --> 01:00:20,600 IT'S SOMETHING WE WANT TO GET 1360 01:00:22,040 --> 01:00:22,520 TO. 1361 01:00:22,520 --> 01:00:23,080 [AUDIO DISTORTION] 1362 01:00:23,080 --> 01:00:25,360 >> ONE THING WE CAN DO PARTLY 1363 01:00:25,360 --> 01:00:28,560 BECAUSE IT IS A DIFFUSE TYPE OF 1364 01:00:28,560 --> 01:00:30,520 ORGANOID CAN MANIPULATE CELL 1365 01:00:30,520 --> 01:00:33,560 POPULATIONS, AND THAT'S ALMOST 1366 01:00:33,560 --> 01:00:36,280 THE EASIEST THING. 1367 01:00:36,280 --> 01:00:38,280 SO WE JUST NOTICED IN THE 1368 01:00:38,280 --> 01:00:39,360 ORIGINAL PROTOCOL FOR SPLEENS, 1369 01:00:39,360 --> 01:00:42,080 WE DID NOT GET STROMAL CELLS, 1370 01:00:42,080 --> 01:00:44,920 BUT THEN ONE OF MY STUDENTS 1371 01:00:44,920 --> 01:00:46,920 FIGURED THIS OUT AND DEVELOPED A 1372 01:00:46,920 --> 01:00:50,200 NEW PROTOCOL SO WE'RE JUST IN 1373 01:00:50,200 --> 01:00:55,880 THAT MIX RIGHT NOW. 1374 01:00:55,880 --> 01:01:00,160 STAY TUNED. 1375 01:01:00,160 --> 01:01:00,320 YES? 1376 01:01:00,320 --> 01:01:01,480 >> LIZ KOVAZ, UNIVERSITY OF 1377 01:01:01,480 --> 01:01:04,760 COLORADO, INTRIGUED BY THE 1378 01:01:04,760 --> 01:01:09,640 CONCEPT OF BEING ABLE TO TAKE 1379 01:01:09,640 --> 01:01:11,760 TISSUE FROM YOUNGER AND OLDER 1380 01:01:11,760 --> 01:01:16,800 SUBJECTS AND BEING ABLE TO 1381 01:01:16,800 --> 01:01:18,120 COMPARE BECAUSE HOW ELSE -- 1382 01:01:18,120 --> 01:01:20,520 [AUDIO DISTORTION] 1383 01:01:20,520 --> 01:01:21,720 BUT I'M CONCERNED WHEN TONSILS 1384 01:01:21,720 --> 01:01:31,320 ARE TAKEN OUT OF LITTLE KIDS, 1385 01:01:31,320 --> 01:01:36,040 BECAUSE OF INFECTION. 1386 01:01:36,040 --> 01:01:40,080 >> THEY ARE ACTUALLY -- KIDS, 1387 01:01:40,080 --> 01:01:41,400 LITTLE THROATS. 1388 01:01:41,400 --> 01:01:44,480 WE TRY TO USE TONSILS FROM 1389 01:01:44,480 --> 01:01:46,880 TONSILLITIS, THEY WERE A MESS, 1390 01:01:46,880 --> 01:01:47,680 INFLAMED, YOU COULDN'T REALLY DO 1391 01:01:47,680 --> 01:01:51,120 ANY OF THE THINGS WE DO, SO WE 1392 01:01:51,120 --> 01:01:53,760 ONLY NOW GET THEM FROM SLEEP 1393 01:01:53,760 --> 01:01:55,520 APNEA FOR CHILDREN AND ALL THE 1394 01:01:55,520 --> 01:01:56,400 WAY UP. 1395 01:01:56,400 --> 01:01:59,240 SO THE WHOLE AGE SPAN IS 1396 01:01:59,240 --> 01:02:00,360 AVAILABLE. 1397 01:02:00,360 --> 01:02:01,360 THERE'S ANOTHER PROJECT WE'RE 1398 01:02:01,360 --> 01:02:03,320 STILL KNOCK QUITE READY FOR 1399 01:02:03,320 --> 01:02:06,200 PRIME TIME WHICH IS LOOKING AT 1400 01:02:06,200 --> 01:02:07,120 IMMUNE RESPONSES, WHAT'S 1401 01:02:07,120 --> 01:02:07,560 DIFFERENT? 1402 01:02:07,560 --> 01:02:09,400 I MEAN WE KNOW HISTORICALLY THAT 1403 01:02:09,400 --> 01:02:13,160 KIDS UNDER 5 ARE TREMENDOUSLY 1404 01:02:13,160 --> 01:02:14,600 SUSCEPTIBLE TO INFECTIOUS 1405 01:02:14,600 --> 01:02:16,000 DISEASE, THERE'S HUGE INFANT 1406 01:02:16,000 --> 01:02:17,200 MORTALITY FOR THAT REASON BUT 1407 01:02:17,200 --> 01:02:19,160 NOW IT'S GONE AWAY BECAUSE OF 1408 01:02:19,160 --> 01:02:22,160 VACCINES BUT THAT MEANS THERE'S 1409 01:02:22,160 --> 01:02:24,960 A WHOLE MYSTERY THERE JUST 1410 01:02:24,960 --> 01:02:27,360 WHAT'S DEFICIENT IN EARLY 1411 01:02:27,360 --> 01:02:28,800 CHILDHOOD FROM THE IMMUNE SYSTEM 1412 01:02:28,800 --> 01:02:32,520 THAT MAKES THEM SO VULNERABLE. 1413 01:02:32,520 --> 01:02:36,680 ONE ANSWER IS T INDEPENDENT 1414 01:02:36,680 --> 01:02:37,040 RESPONSES. 1415 01:02:37,040 --> 01:02:38,240 IN THE NATURE MEDICINE PAPER WE 1416 01:02:38,240 --> 01:02:42,280 HAVE NICE DATA TO SAY CHILDREN 1417 01:02:42,280 --> 01:02:45,000 UNDER 5 COULD NOT, IF YOU 1418 01:02:45,000 --> 01:02:46,440 DELETED T CELLS, COULD NOT MAKE 1419 01:02:46,440 --> 01:02:49,040 AN ANTIBODY RESPONSE TO FLU BUT 1420 01:02:49,040 --> 01:02:50,040 OVER 5 COULD. 1421 01:02:50,040 --> 01:02:54,960 AND SO IT'S ABOUT T 1422 01:02:54,960 --> 01:02:58,040 INDEPENDENTS, SOMEHOW T CELL 1423 01:02:58,040 --> 01:02:58,600 INDEPENDENT RESPONSES ONLY 1424 01:02:58,600 --> 01:03:02,520 HAPPEN AFTER 5 OR SO YEARS, SO 1425 01:03:02,520 --> 01:03:04,720 ANYWAY THERE'S A HUGE AMOUNT TO 1426 01:03:04,720 --> 01:03:09,960 DO AND TONSILS ARE A REALLY 1427 01:03:09,960 --> 01:03:11,720 PROMISING WAY TO TAKE APART 1428 01:03:11,720 --> 01:03:13,800 WHAT'S GOING ON AND MAKE BETTER 1429 01:03:13,800 --> 01:03:15,200 VACCINES THOUGH WE ALREADY MAKE 1430 01:03:15,200 --> 01:03:16,000 VACCINES FOR KIDS LIKE 1431 01:03:16,000 --> 01:03:18,080 PNEUMONIA, THEY HAVE TO HAVE A 1432 01:03:18,080 --> 01:03:20,600 PROTEIN COMPONENT OR THEY DON'T 1433 01:03:20,600 --> 01:03:21,120 WORK. 1434 01:03:21,120 --> 01:03:25,440 SO, AGAIN, BECAUSE T INDEPENDENT 1435 01:03:25,440 --> 01:03:26,640 IS OFTEN CARBOHYDRATE SPECIFIC, 1436 01:03:26,640 --> 01:03:28,280 AND LIPID. 1437 01:03:28,280 --> 01:03:30,880 THERE'S A TREMENDOUS AMOUNT WE 1438 01:03:30,880 --> 01:03:33,640 CAN LEARN FROM ORGANOIDS. 1439 01:03:33,640 --> 01:03:35,120 YEAH, THEY ARE NOT -- THEY MAY 1440 01:03:35,120 --> 01:03:36,040 NOT BE NORMAL. 1441 01:03:36,040 --> 01:03:37,680 WE GOT THIS CRITICISM ALL THE 1442 01:03:37,680 --> 01:03:39,400 TIME IN OUR EARLY GRANTS. 1443 01:03:39,400 --> 01:03:43,160 WELL, THEY ARE NOT NORMAL. 1444 01:03:43,160 --> 01:03:45,320 YEAH, WELL, PROBABLY NOT. 1445 01:03:45,320 --> 01:03:46,120 BUT THEY WORK. 1446 01:03:46,120 --> 01:03:49,360 SO WE'RE GOING WITH IT. 1447 01:03:49,360 --> 01:03:54,200 THERE'S SOME THINGS YOU JUST 1448 01:03:54,200 --> 01:03:55,040 HAVE TO IGNORE. 1449 01:03:55,040 --> 01:03:59,000 I'M SURE NO ONE ELSE HAS THIS. 1450 01:03:59,000 --> 01:04:02,000 >> I'LL ASK OTHER QUESTIONS. 1451 01:04:02,000 --> 01:04:08,120 BAYLOR COLLEGE OF MEDICINE. 1452 01:04:08,120 --> 01:04:10,400 CAN YOU COMMENT ON LOGISTICAL 1453 01:04:10,400 --> 01:04:12,800 ISSUES WITH HAVING TISSUES FROM 1454 01:04:12,800 --> 01:04:17,840 VARIOUS ACROSS THE BODY AND 1455 01:04:17,840 --> 01:04:21,360 IMMUNE CELLS, MATRIGEL, SO ON, 1456 01:04:21,360 --> 01:04:23,120 COMMENT ON LOGISTICS TO THINK 1457 01:04:23,120 --> 01:04:23,320 ABOUT. 1458 01:04:23,320 --> 01:04:26,080 >> THIS IS A HUGE CHALLENGE FOR 1459 01:04:26,080 --> 01:04:26,720 ACADEMIC LABS. 1460 01:04:26,720 --> 01:04:30,000 IF I WAS IN A COMPANY YOU WOULD 1461 01:04:30,000 --> 01:04:31,560 SET UP A WHOLE FACILITY TO DO 1462 01:04:31,560 --> 01:04:32,000 THIS. 1463 01:04:32,000 --> 01:04:34,720 THAT'S WHAT I'VE DONE IN THE 1464 01:04:34,720 --> 01:04:34,880 LAB. 1465 01:04:34,880 --> 01:04:39,320 I HAVE SENIOR POSTDOC AND TWO 1466 01:04:39,320 --> 01:04:41,520 TECHNICIANS WHO ARE BRINGING IN 1467 01:04:41,520 --> 01:04:46,440 TONSILS, PEDIATRIC TONSILS, 1468 01:04:46,440 --> 01:04:49,160 ADULT TONSILS FROM ADULT 1469 01:04:49,160 --> 01:04:51,240 SURGEONS, NOW WE HAVE THREE 1470 01:04:51,240 --> 01:04:53,880 DIFFERENT SCREENS OF TISSUE. 1471 01:04:53,880 --> 01:04:56,640 AND OF COURSE IT'S NOT SOMETHING 1472 01:04:56,640 --> 01:05:00,680 MOST LABS WANT TO HANDLE BUT IT 1473 01:05:00,680 --> 01:05:01,440 WORKS. 1474 01:05:01,440 --> 01:05:04,640 AND WE'RE BANKING BASICALLY 1475 01:05:04,640 --> 01:05:06,280 PROCESSING, YOU KNOW, MAKING 1476 01:05:06,280 --> 01:05:07,360 SINGLE CELL SUSPENSIONS OF 1477 01:05:07,360 --> 01:05:10,160 EVERYTHING WHICH TAKES HOURS FOR 1478 01:05:10,160 --> 01:05:11,320 EACH EVENT. 1479 01:05:11,320 --> 01:05:13,040 AND SO WE'VE GOT A LOT OF WORK 1480 01:05:13,040 --> 01:05:13,240 TO DO. 1481 01:05:13,240 --> 01:05:17,120 AT THE END OF THE DAY NOW WE 1482 01:05:17,120 --> 01:05:19,520 HAVE OVER 400 ALIQUOTS FROM 1483 01:05:19,520 --> 01:05:20,200 SPLEENS ALONE. 1484 01:05:20,200 --> 01:05:25,000 WE HAVE A FEW HUNDRED FROM 1485 01:05:25,000 --> 01:05:25,200 TONSILS. 1486 01:05:25,200 --> 01:05:28,080 IT MAKES AVAILABLE TO EVERYONE 1487 01:05:28,080 --> 01:05:30,560 IN THE LAB, THEY CAN GET A 1488 01:05:30,560 --> 01:05:32,320 FROZEN FILE AND DO AN 1489 01:05:32,320 --> 01:05:32,720 EXPERIMENT. 1490 01:05:32,720 --> 01:05:34,920 SO I'D LIKE TO SEE THIS IN THE 1491 01:05:34,920 --> 01:05:36,800 NATIONAL LEVEL, IN CASE ANYONE 1492 01:05:36,800 --> 01:05:39,080 IS LISTENING ON THAT SIDE. 1493 01:05:39,080 --> 01:05:43,880 THIS IS -- YOU KNOW, THESE 1494 01:05:43,880 --> 01:05:46,960 SPLEENS ARE THIRTY OR FORTY 1495 01:05:46,960 --> 01:05:48,520 THOUSAND TRANSPLANTS EVERY YEAR 1496 01:05:48,520 --> 01:05:53,440 IN THE U.S., 30,000 OR 40, 40,00 1497 01:05:53,440 --> 01:05:54,880 SPLEENS NO ONE WANTS, COULD BE 1498 01:05:54,880 --> 01:05:58,200 PART OF A NATIONAL FACILITY THAT 1499 01:05:58,200 --> 01:05:59,600 WOULD LOWER ACTIVATION ENERGY 1500 01:05:59,600 --> 01:06:01,640 FOR ANYONE THAT WANTS TO DO 1501 01:06:01,640 --> 01:06:02,840 HUMAN IMMUNOLOGY BUT IT'S 1502 01:06:02,840 --> 01:06:06,360 UNCOMFORTABLE BEING TOO FAR FROM 1503 01:06:06,360 --> 01:06:07,360 THE MOUSE ROUTE. 1504 01:06:07,360 --> 01:06:13,600 JUST A THOUGHT. 1505 01:06:13,600 --> 01:06:15,880 >>ORGANOID CHIP MODELS. 1506 01:06:15,880 --> 01:06:17,680 >> THAT'S OUR BIG RIVAL. 1507 01:06:17,680 --> 01:06:18,120 >> YEAH. 1508 01:06:18,120 --> 01:06:19,520 >> SORT OF. 1509 01:06:19,520 --> 01:06:22,920 WE'RE SLIGHTLY AHEAD OF THEM. 1510 01:06:22,920 --> 01:06:26,600 I THINK FLOW IS GOOD. 1511 01:06:26,600 --> 01:06:28,040 FLOWING MEDIA DEFINITELY IS A 1512 01:06:28,040 --> 01:06:29,440 WAY TO KEEP CELLS HEALTHIER BUT 1513 01:06:29,440 --> 01:06:32,840 WE SEEM TO BE DOING OKAY WITH 1514 01:06:32,840 --> 01:06:35,680 THE TRANSWELL SYSTEM WHERE YOU 1515 01:06:35,680 --> 01:06:38,440 BASICALLY HAVE A MEDIA THAT'S 1516 01:06:38,440 --> 01:06:39,320 SUPPORTING 12 WELLS WITH 1517 01:06:39,320 --> 01:06:40,040 PERMEABLE MEMBRANES. 1518 01:06:40,040 --> 01:06:42,040 WE DO CHANGE THE MEDIA. 1519 01:06:42,040 --> 01:06:44,880 WE DO FEED THE MEDIA. 1520 01:06:44,880 --> 01:06:46,400 THESE ARE NOT SUPER LONG TERM, 1521 01:06:46,400 --> 01:06:48,480 TWO WEEKS, TWO WEEKS TO FOUR 1522 01:06:48,480 --> 01:06:51,120 WEEKS IS THE LIFETIME OF A 1523 01:06:51,120 --> 01:06:53,040 CONSOLE OR SPLEEN ORGANOID. 1524 01:06:53,040 --> 01:06:56,280 SO, SO FAR WE HAVEN'T SEEN THE 1525 01:06:56,280 --> 01:06:56,480 NEED. 1526 01:06:56,480 --> 01:06:59,000 WE HAVE BEEN OF COURSE LOOKING 1527 01:06:59,000 --> 01:07:00,760 AT THE LITERATURE FOR ORGAN ON A 1528 01:07:00,760 --> 01:07:03,040 CHIP AND I DO THINK FLOW IS 1529 01:07:03,040 --> 01:07:06,120 ALWAYS A GOOD THING, IF YOU CAN 1530 01:07:06,120 --> 01:07:13,200 WORK IT IN, DISRUPTION. 1531 01:07:13,200 --> 01:07:17,080 >> ONE MORE QUESTION. 1532 01:07:17,080 --> 01:07:27,240 >> RICHARD HODES, NIA, 1533 01:07:27,240 --> 01:07:30,680 DIFFERENCE BETWEEN EPITOPE AND 1534 01:07:30,680 --> 01:07:32,080 CROSS-LINKING, TAKE US THROUGH 1535 01:07:32,080 --> 01:07:34,160 WHAT ULTIMATELY GIVES THAT 1536 01:07:34,160 --> 01:07:34,440 DIFFERENCE. 1537 01:07:34,440 --> 01:07:34,920 >> RIGHT. 1538 01:07:34,920 --> 01:07:38,760 SO, THE WAY WE THINK IT'S 1539 01:07:38,760 --> 01:07:40,960 HAPPENING IS YOU HAVE THIS 1540 01:07:40,960 --> 01:07:42,600 CONSTRUCT THAT HAS FOUR 1541 01:07:42,600 --> 01:07:45,760 DIFFERENT HA STRAINS ON IT, AND 1542 01:07:45,760 --> 01:07:49,040 SO ANY B CELL THAT HAS 1543 01:07:49,040 --> 01:07:50,360 ANTIBODIES SPECIFIC FOR ANY OF 1544 01:07:50,360 --> 01:07:52,760 THOSE STRAINS AS WELL AS 1545 01:07:52,760 --> 01:07:55,280 CROSS-REACTIVE ONES WILL PULL IN 1546 01:07:55,280 --> 01:07:58,040 THE WHOLE SELECTION AND PROCESS 1547 01:07:58,040 --> 01:08:04,040 AND PRESENT ALL THAT IT CAN, 1548 01:08:04,040 --> 01:08:06,120 GIVEN ITS MAKEUP IS. 1549 01:08:06,120 --> 01:08:09,040 SO THAT'S A LOT OF HELP. 1550 01:08:09,040 --> 01:08:11,480 YOU KNOW, AND I'M ALSO -- WE 1551 01:08:11,480 --> 01:08:12,800 DON'T HAVE EXACT NUMBERS BUT 1552 01:08:12,800 --> 01:08:18,240 KNOW A TREMENDOUS NUMBER OF B 1553 01:08:18,240 --> 01:08:20,120 CELLS ALREADY SPECIFIC FOR FLU, 1554 01:08:20,120 --> 01:08:22,520 WE IMAGINE T CELLS AS WELL, SO 1555 01:08:22,520 --> 01:08:27,560 BEING ABLE TO MOBILIZE ALL OF 1556 01:08:27,560 --> 01:08:28,680 THAT HELP THAT'S THERE SITTING 1557 01:08:28,680 --> 01:08:30,200 WAITING SEEMS TO BE ABLE TO 1558 01:08:30,200 --> 01:08:33,920 BOOST UP THE OTHER ANTIBODY 1559 01:08:33,920 --> 01:08:36,760 RESPONSES TO THE DISFAVORITE 1560 01:08:36,760 --> 01:08:37,000 STRAIN. 1561 01:08:37,000 --> 01:08:42,560 >> SO THE EFFICIENCY OF CELLS, 1562 01:08:42,560 --> 01:08:44,440 ULTIMATELY ANTIBODY RESPONSE -- 1563 01:08:44,440 --> 01:08:44,840 [AUDIO DISTORTION] 1564 01:08:44,840 --> 01:08:47,480 >> ABSOLUTELY. 1565 01:08:47,480 --> 01:08:49,600 BUT THERE HAVE BEEN -- THE ONE 1566 01:08:49,600 --> 01:08:53,080 THEY SHOWED ME, OTHER PAPERS IN 1567 01:08:53,080 --> 01:08:54,920 THE FIELD HAVE DONE EXPERIMENTS 1568 01:08:54,920 --> 01:08:59,760 TO SHOW THAT HELP IS LIMITING, 1569 01:08:59,760 --> 01:09:01,240 SPECIFICALLY HELP IS LIMITING 1570 01:09:01,240 --> 01:09:03,160 FOR ANY PARTICULAR B CELL 1571 01:09:03,160 --> 01:09:04,360 RESPONSE SO BY MOBILIZING MORE T 1572 01:09:04,360 --> 01:09:05,480 CELL HELP WE'LL PUSH TO THE 1573 01:09:05,480 --> 01:09:06,120 LIMIT. 1574 01:09:06,120 --> 01:09:07,440 WHAT THAT LIMIT IS, I DON'T 1575 01:09:07,440 --> 01:09:09,600 KNOW, WE HAVEN'T HIT IT YET. 1576 01:09:09,600 --> 01:09:12,720 WE'VE REALLY HIT IT WITH SOME OF 1577 01:09:12,720 --> 01:09:15,560 THESE EXPERIMENTS WE'RE PLANNING 1578 01:09:15,560 --> 01:09:17,880 WITH HIV OR BIRD FLU, IT'S GOING 1579 01:09:17,880 --> 01:09:19,880 TO DEPEND HOW MANY B CELLS ARE 1580 01:09:19,880 --> 01:09:23,560 THERE WITH SPECIFICITY TO WORK 1581 01:09:23,560 --> 01:09:24,360 WITH, AND HOW MUCH, YOU KNOW, 1582 01:09:24,360 --> 01:09:30,240 GOING TO BE SOME PLATEAU VALUE. 1583 01:09:30,240 --> 01:09:32,480 SO INDEPENDENT ON THE FREQUENCY 1584 01:09:32,480 --> 01:09:37,480 OF B CELLS WITH BIGGER 1585 01:09:37,480 --> 01:09:40,000 SPECIFICITY BUT IT WORKED REALLY 1586 01:09:40,000 --> 01:09:40,200 WELL. 1587 01:09:40,200 --> 01:09:41,880 >>BASED ON EFFICIENCY PRIMING T 1588 01:09:41,880 --> 01:09:43,320 CELLS NOT HAVING MORE B CELLS. 1589 01:09:43,320 --> 01:09:44,080 >> RIGHT. 1590 01:09:44,080 --> 01:09:48,640 >> WHICH EVER IS LIMITING IN A 1591 01:09:48,640 --> 01:09:53,680 GIVEN CIRCUMSTANCE 1592 01:09:53,680 --> 01:09:55,160 EFFICIENCY OF THAT APPROACH. 1593 01:09:55,160 --> 01:09:55,520 >> ABSOLUTELY. 1594 01:09:55,520 --> 01:09:56,120 >> ANY QUESTIONS ONLINE? 1595 01:09:56,120 --> 01:10:04,760 THANK YOU SO MUCH. 1596 01:10:04,760 --> 01:10:12,000 1597 01:10:12,000 --> 01:10:13,960 >> WE'RE GOING TO TAKE SHORT 1598 01:10:13,960 --> 01:10:16,360 BREAK BEFORE THE NEXT SESSION, 1599 01:10:16,360 --> 01:10:17,920 SO MAYBE 10 OR 12 MINUTES. 1600 01:10:17,920 --> 01:10:19,080 MARK, THANK YOU. 1601 01:10:19,080 --> 01:10:28,840 THANK YOU FOR B CELL HELP. 1602 01:10:28,840 --> 01:10:29,480 WE'LL BE BACK. 1603 01:10:29,480 --> 01:10:32,800 >> WE'LL COME BACK AT 10:20. 1604 01:10:32,800 --> 01:10:36,280 THE AV PERSON WILL MAKE SOME 1605 01:10:36,280 --> 01:10:36,640 ADJUSTMENTS. 1606 01:10:36,640 --> 01:10:37,920 AND GRACE HAS AN ANNOUNCEMENT 1607 01:10:37,920 --> 01:11:30,840 FOR EVERYBODY AS WELL. 1608 01:11:30,840 --> 01:11:34,560 INADEQUATE STEM CELL BIOLOGY, 1609 01:11:34,560 --> 01:11:36,680 WORKING WITH MOUSE MODEL, GOOD 1610 01:11:36,680 --> 01:11:39,840 SURROGATE TO UNDERSTAND BIOLOGY 1611 01:11:39,840 --> 01:11:42,520 OF THE BLOOD SYSTEM. 1612 01:11:42,520 --> 01:11:47,920 WITH AGE, WE HAVE AN EXPANSION 1613 01:11:47,920 --> 01:11:51,560 OF HEMATOPOIETIC STEM CELL IN 1614 01:11:51,560 --> 01:12:02,040 BLACK 57 MICE, OKAY IN OTHERS, 1615 01:12:04,960 --> 01:12:06,520 PROGRESSIVELY EXPONENTIAL. 1616 01:12:06,520 --> 01:12:09,920 IN THE BEST CHARACTERISTIC IN 1617 01:12:09,920 --> 01:12:15,080 TERMS OF DEFICIENCY IS LACK OF 1618 01:12:15,080 --> 01:12:17,040 POTENTIAL, YOUNG MICE FAIL TO 1619 01:12:17,040 --> 01:12:19,560 RECONSTITUTE TO THE EXTENT TO 1620 01:12:19,560 --> 01:12:26,800 YOUNG STEM CELL DO, AND OUTPUT 1621 01:12:26,800 --> 01:12:30,840 IS EXTREMELY BIASED, FAIL TO 1622 01:12:30,840 --> 01:12:31,320 MAKE. 1623 01:12:31,320 --> 01:12:38,200 THE UNDERLYING BASIS OF A LOT OF 1624 01:12:38,200 --> 01:12:40,160 AGE-RELATED BLOOD DEFECT, 1625 01:12:40,160 --> 01:12:41,840 ACCUMULATION OF HEMATOPOIETIC 1626 01:12:41,840 --> 01:12:43,480 STEM CELL IMPAIR REGENERATION 1627 01:12:43,480 --> 01:12:46,080 POTENTIAL WHICH PRODUCE A LOT 1628 01:12:46,080 --> 01:12:49,120 MORE MYELOID AND PLATELET IN 1629 01:12:49,120 --> 01:12:59,600 MICE AND MUCH LESS RED BLOOD 1630 01:13:00,240 --> 01:13:01,200 CELL ASSOCIATED WITH DISORDER 1631 01:13:01,200 --> 01:13:04,240 I'M NOT GOING TO TALK ABOUT. 1632 01:13:04,240 --> 01:13:07,640 LIKE IN EVERY AGING CELL, WE 1633 01:13:07,640 --> 01:13:13,040 HAVE THIS BALANCE BETWEEN ALL 1634 01:13:13,040 --> 01:13:19,680 RANGE OF REGULATION IN THE CASE 1635 01:13:19,680 --> 01:13:21,320 OF THE BONE MARROW NICHE. 1636 01:13:21,320 --> 01:13:26,440 I FORGET TO PUT THE SLIDE TO 1637 01:13:26,440 --> 01:13:27,080 HIGHLIGHT THIS QUESTION, IF 1638 01:13:27,080 --> 01:13:29,080 THERE IS ONE THING I WOULD LIKE 1639 01:13:29,080 --> 01:13:30,960 TO SAY THE PROBLEM WE ARE FACING 1640 01:13:30,960 --> 01:13:39,800 AT THIS POINT WE HAVE A LOT OF 1641 01:13:39,800 --> 01:13:41,440 INDICATION OF INDIVIDUAL 1642 01:13:41,440 --> 01:13:42,800 REGULATION, BUT VERY LITTLE 1643 01:13:42,800 --> 01:13:50,320 UNDERSTANDING OF HOW THEY FIT 1644 01:13:50,320 --> 01:13:52,720 TOGETHER WHAT I WANT TO TELL YOU 1645 01:13:52,720 --> 01:13:55,120 IS A TALE OF CHRONIC 1646 01:13:55,120 --> 01:13:58,760 INFLAMMATION, CHANGE IN THE 1647 01:13:58,760 --> 01:13:59,400 STROMA DRIVING AGE-RELATED 1648 01:13:59,400 --> 01:14:04,800 INFLAMMATION HAS IMPACT ON THE 1649 01:14:04,800 --> 01:14:06,000 BLOOD SYSTEM AND ITS FUNCTION. 1650 01:14:06,000 --> 01:14:09,200 I WANT TO START WITH WORK I'VE 1651 01:14:09,200 --> 01:14:13,560 DONE WHEN I WAS AT UCSF TO SHOW 1652 01:14:13,560 --> 01:14:17,480 IN THE CONTEXT OF BLACK THE GOAL 1653 01:14:17,480 --> 01:14:18,720 OF AGING BIOLOGY HEMATOPOIETIC 1654 01:14:18,720 --> 01:14:25,480 STEM CELL FUNCTION, CLASSICAL 1655 01:14:25,480 --> 01:14:26,080 SYSTEMIC BLOOD-BORNE 1656 01:14:26,080 --> 01:14:27,560 INTERVENTION WHICH HAS SHOWN TO 1657 01:14:27,560 --> 01:14:30,520 WORK IN MANY OTHER ORGANS DO NOT 1658 01:14:30,520 --> 01:14:31,200 WORK WITH HEMATOPOIETIC STEM 1659 01:14:31,200 --> 01:14:35,280 CELL AND YOU HAVE AN EXAMPLE OF 1660 01:14:35,280 --> 01:14:45,680 THIS APPROACH, THERE'S 1661 01:14:50,520 --> 01:14:52,520 ABSOLUTELY NO CHANGE, PLASMA 1662 01:14:52,520 --> 01:14:54,480 TRANSFER TO OLD MICE DOESN'T 1663 01:14:54,480 --> 01:14:57,680 CHANGE ABILITY OF STEM CELL OR 1664 01:14:57,680 --> 01:15:00,520 LOOKING AT CROSSOVER AND THE 1665 01:15:00,520 --> 01:15:03,160 LODGING OF OLD CELL CROSSING TO 1666 01:15:03,160 --> 01:15:07,200 YOUNG EXPOSED TO YOUNG BONE 1667 01:15:07,200 --> 01:15:12,760 MARROW NICHE DOES HAVE EFFECT, 1668 01:15:12,760 --> 01:15:18,480 SHOWN IN GRADIENT OF ONE MONTH 1669 01:15:18,480 --> 01:15:24,640 AFTER, FOUR MONTHS AFTER 1670 01:15:24,640 --> 01:15:25,480 SEPARATION, LACKS REGENERATIVE 1671 01:15:25,480 --> 01:15:33,280 POTENTIAL EXTENDED TO OTHER TYPE 1672 01:15:33,280 --> 01:15:33,640 OF INTERVENTION. 1673 01:15:33,640 --> 01:15:42,000 AND WE DO NOT SEE AN EFFECT ON 1674 01:15:42,000 --> 01:15:50,560 REGENERATIVE HEMATOPOIETIC STEM 1675 01:15:50,560 --> 01:15:52,000 CELL, REGENERATION POTENTIAL. 1676 01:15:52,000 --> 01:15:54,920 BASICALLY WHAT WE NOTICED, NONE 1677 01:15:54,920 --> 01:15:56,040 OF THE SYSTEMIC APPROACH WERE 1678 01:15:56,040 --> 01:16:05,000 ABLE TO CHANGE THE LEVEL OF BONE 1679 01:16:05,000 --> 01:16:05,560 MARROW INFLAMMATION. 1680 01:16:05,560 --> 01:16:09,680 ANOTHER STORY, CAN I GO BACK ONE 1681 01:16:09,680 --> 01:16:10,480 SLIDE? 1682 01:16:10,480 --> 01:16:12,440 OKAY. 1683 01:16:12,440 --> 01:16:15,080 ANOTHER STORY WE DID, AND WE 1684 01:16:15,080 --> 01:16:18,440 LOOK AT THE GRADATION OF THE 1685 01:16:18,440 --> 01:16:20,640 BONE NARROW NICHE, YOU CAN SEE 1686 01:16:20,640 --> 01:16:31,160 IN THE RNAseq ANALYSIS OF THE 1687 01:16:31,480 --> 01:16:35,080 YOUNG STROMA, A LOT OF DIVERSITY 1688 01:16:35,080 --> 01:16:39,920 HERE, BIG POPULATION OF 1689 01:16:39,920 --> 01:16:44,600 ENDOTHELIAL CELL, AND SMALL 1690 01:16:44,600 --> 01:16:46,120 POPULATION OF MESENCHYMAL CELL, 1691 01:16:46,120 --> 01:16:49,480 WHICH EXPRESS A PARTICULAR 1692 01:16:49,480 --> 01:16:51,280 MARKER, LEPTIN RECEPTOR, A 1693 01:16:51,280 --> 01:16:53,360 SITUATION IN YOUNG MICE, 1694 01:16:53,360 --> 01:16:54,240 ABSOLUTELY NO CHRONIC 1695 01:16:54,240 --> 01:16:56,560 INFLAMMATION IN THE YOUNG NICHE. 1696 01:16:56,560 --> 01:17:04,040 IN CONTRAST IN OLD NICHE WE SEE 1697 01:17:04,040 --> 01:17:06,480 WE HAVE MASSIVE DEGRADATION, 1698 01:17:06,480 --> 01:17:09,080 THEY DIE FROM THE PROCESS AND 1699 01:17:09,080 --> 01:17:15,320 THIS MASSIVE EXPANSION OF 1700 01:17:15,320 --> 01:17:18,640 INFLAMMATORY POPULATION MSC-L, 1701 01:17:18,640 --> 01:17:20,720 ESTABLISH CROSS-TALK BETWEEN 1702 01:17:20,720 --> 01:17:24,640 DYSFUNCTION DRIVING PRODUCTION 1703 01:17:24,640 --> 01:17:28,040 OF THE INFLAMMATORY FACTOR, ACT 1704 01:17:28,040 --> 01:17:30,120 ON THE MARROW, LEPTIN RECEPTOR, 1705 01:17:30,120 --> 01:17:32,200 BUT MORE IMPORTANTLY THERE'S A 1706 01:17:32,200 --> 01:17:34,400 CROSSOVER BETWEEN THE 1707 01:17:34,400 --> 01:17:35,680 DYSFUNCTIONAL NICHE AND 1708 01:17:35,680 --> 01:17:36,680 DYSFUNCTIONAL AGED BLOOD SYSTEM 1709 01:17:36,680 --> 01:17:43,080 WHERE IN RESPONSE TO CHRONIC 1710 01:17:43,080 --> 01:17:47,520 INFLAMMATION WE HAVE ACTIVATION, 1711 01:17:47,520 --> 01:17:58,040 THE NOTION, ACTIVATION OF STEM 1712 01:17:58,280 --> 01:18:02,880 CELLS TO PRODUCE MORE 1713 01:18:02,880 --> 01:18:03,200 PROGENITOR. 1714 01:18:03,200 --> 01:18:06,480 AWAY IN NORMAL DISTRIBUTION OF 1715 01:18:06,480 --> 01:18:07,600 BLOOD CELL, TOWARD 1716 01:18:07,600 --> 01:18:08,320 OVEREXPRESSION OF MYELOID CELL 1717 01:18:08,320 --> 01:18:17,280 AND I DON'T KNOW IF IT'S BECAUSE 1718 01:18:17,280 --> 01:18:18,040 (INDISCERNIBLE). 1719 01:18:18,040 --> 01:18:27,600 BASICALLY WHAT WE FOUND AS WELL 1720 01:18:27,600 --> 01:18:37,920 IS THAT WE CAN -- 1721 01:19:11,560 --> 01:19:15,440 >>ROOM 160 IS MUTED. 1722 01:19:15,440 --> 01:19:21,440 1723 01:19:21,440 --> 01:19:28,480 1724 01:19:28,480 --> 01:19:31,600 ROOM 160 IS MUTED. 1725 01:19:31,600 --> 01:19:39,080 1726 01:19:39,080 --> 01:19:49,120 1727 01:19:52,600 --> 01:19:53,400 1728 01:19:53,400 --> 01:19:54,600 WE BLOCK SIGNALING CAUSING STEM 1729 01:19:54,600 --> 01:19:55,680 CELL TO ACTIVATE AND PRODUCE 1730 01:19:55,680 --> 01:19:57,680 BLOOD CELL. 1731 01:19:57,680 --> 01:20:02,040 YOU CAN SEE RESULTS HERE IN 1732 01:20:02,040 --> 01:20:05,880 YOUNG MICE, TREATMENT WITH 1733 01:20:05,880 --> 01:20:10,120 ANAKINRA NO NEGATIVE EFFECT, IN 1734 01:20:10,120 --> 01:20:16,480 OLD MICE VERY NASTY MARROW 1735 01:20:16,480 --> 01:20:19,560 CONTENT WHEN YOU INDUCE 5FU 1736 01:20:19,560 --> 01:20:23,080 CHALLENGE, REGENERATE THE BLOOD 1737 01:20:23,080 --> 01:20:26,120 SYSTEM IN SITU, USUALLY IMPROVED 1738 01:20:26,120 --> 01:20:28,240 WHEN WE BLOCK SIGNALING. 1739 01:20:28,240 --> 01:20:30,840 FOR THE MICE WE USE INTERLEUKIN 1740 01:20:30,840 --> 01:20:34,240 1 DEFICIENT MICE AND CAN SEE IN 1741 01:20:34,240 --> 01:20:40,560 THE CONTEXT WE ARE VERY MUCH 1742 01:20:40,560 --> 01:20:45,160 RECUING INFLAMMATORY NATURE, AGE 1743 01:20:45,160 --> 01:20:51,720 BONE MARROW NICHE, NOT RESCUING 1744 01:20:51,720 --> 01:20:56,840 THE CHANGING BUT DAMPENING THE 1745 01:20:56,840 --> 01:21:01,000 BLUE, THEY ARE BACK TO THIS 1746 01:21:01,000 --> 01:21:03,440 ORANGE MSCL 2 SUBSET 1747 01:21:03,440 --> 01:21:05,480 NON-INFLAMMATORY GOOD GUY. 1748 01:21:05,480 --> 01:21:07,080 AS A CONSEQUENCE, WHEN 1749 01:21:07,080 --> 01:21:11,960 TRANSPLANTED COMPARED TO OLD 1750 01:21:11,960 --> 01:21:18,440 STEM CELL, OLD STEM CELL FROM 1751 01:21:18,440 --> 01:21:20,680 INTERLEUKIN 1 REMAINS IN 1752 01:21:20,680 --> 01:21:22,800 ORIGINAL STATE POTENTIAL MUCH 1753 01:21:22,800 --> 01:21:26,520 LESS AGING FEATURE IN THE MICE 1754 01:21:26,520 --> 01:21:27,960 WHICH LACK INTERLEUKIN 1 1755 01:21:27,960 --> 01:21:29,240 SIGNALING OVER THE LIFESPAN. 1756 01:21:29,240 --> 01:21:31,880 SO THIS IS KIND OF LIKE THE 1757 01:21:31,880 --> 01:21:35,200 MESSAGE OF THE PAPER, REALLY THE 1758 01:21:35,200 --> 01:21:37,600 CROSS-TALK BETWEEN AN INFLAMED 1759 01:21:37,600 --> 01:21:43,160 NICHE AND REGULATION OF BLOOD 1760 01:21:43,160 --> 01:21:46,760 PRODUCTION, ALL WE CAN RESCUE 1761 01:21:46,760 --> 01:21:49,600 SOME ASPECT OF AGING, BALANCING 1762 01:21:49,600 --> 01:21:53,960 OF BLOOD PRODUCTION BY BLOCKING 1763 01:21:53,960 --> 01:21:54,520 INTERLEUKIN 1 SIGNALING. 1764 01:21:54,520 --> 01:21:57,760 WHAT I WANT TO TELL YOU NOW IS 1765 01:21:57,760 --> 01:22:02,080 THAT YOU CANNOT WELL PLATE ON 1766 01:22:02,080 --> 01:22:02,840 AGE-RELATED CHRONIC 1767 01:22:02,840 --> 01:22:05,360 INFLAMMATION, AND HAVE DIRECT 1768 01:22:05,360 --> 01:22:08,680 EFFECT, ON SOME PROPERTIES WHICH 1769 01:22:08,680 --> 01:22:16,200 ARE THE DEREGULATED IN 1770 01:22:16,200 --> 01:22:20,720 HEMATOPOIETIC STEM CELL AND 1771 01:22:20,720 --> 01:22:22,000 BRING BACK AUTOPHAGY, IN 1772 01:22:22,000 --> 01:22:24,200 PARTICULAR USED IN YOUNG STEM 1773 01:22:24,200 --> 01:22:29,880 CELL AS KEY STRESS RESPONSE 1774 01:22:29,880 --> 01:22:31,000 MECHANISM WHICH PARTICULARLY 1775 01:22:31,000 --> 01:22:31,600 QUIESCENCE, A FUNDAMENTAL 1776 01:22:31,600 --> 01:22:35,440 PROPERTY FOR STEM CELLS TO BE 1777 01:22:35,440 --> 01:22:40,240 ABLE TO ENGRAFT IN TRANSPLANTED 1778 01:22:40,240 --> 01:22:46,880 MICE. 1779 01:22:46,880 --> 01:22:54,960 AUTOPHAGY, WITH SIGNAL FROM 1780 01:22:54,960 --> 01:22:55,920 MITOCHONDRIA, GLYCOLYTIC, THE 1781 01:22:55,920 --> 01:22:59,960 BASIS OF YOUNG STEM CELL 1782 01:22:59,960 --> 01:23:00,400 REGENERATIVE ACTIVITY. 1783 01:23:00,400 --> 01:23:07,400 WHAT WE SEE WITH AGE IN THIS 1784 01:23:07,400 --> 01:23:08,440 EXPANDED POPULATION, ACTIVATION 1785 01:23:08,440 --> 01:23:18,920 OF AUTOPHAGY IN A SUBSET, AND 1786 01:23:21,200 --> 01:23:22,240 THESE WHEN TRANSPLANTED ENGRAFT 1787 01:23:22,240 --> 01:23:28,440 MUCH BETTER, WITH ALL THE 1788 01:23:28,440 --> 01:23:28,840 HALLMARKS. 1789 01:23:28,840 --> 01:23:31,160 SO WE WERE VERY INTERESTED TO 1790 01:23:31,160 --> 01:23:34,360 UNDERSTAND THE MECHANISM BEHIND 1791 01:23:34,360 --> 01:23:36,560 THAT AND CONNECTION TO CHRONIC 1792 01:23:36,560 --> 01:23:37,160 INFLAMMATION. 1793 01:23:37,160 --> 01:23:42,120 THIS IS JUST THE MODEL WE USE, 1794 01:23:42,120 --> 01:23:45,720 YOUNG AND OLD, AUTOPHAGY 1795 01:23:45,720 --> 01:23:47,200 REPORTER MICE, CAN SEPARATE 1796 01:23:47,200 --> 01:23:52,640 BASED ON INTENSITY OF THE GFP 1797 01:23:52,640 --> 01:23:56,320 SIGNAL WHEN YOU DOWNREGULATE 1798 01:23:56,320 --> 01:24:02,040 GPF-LC 3 INTENSITY AND CAN 1799 01:24:02,040 --> 01:24:03,080 REGULATE FROM AUTOPHAGY 1800 01:24:03,080 --> 01:24:04,200 INACTIVATED OLD STEM CELL 1801 01:24:04,200 --> 01:24:06,320 DIFFERENT FROM YOUNG, WHERE WE 1802 01:24:06,320 --> 01:24:09,360 TAKE ANYTHING ALONG THE CURVE, 1803 01:24:09,360 --> 01:24:17,440 EXACTLY THE SAME FUNCTION, VERY 1804 01:24:17,440 --> 01:24:17,720 DIFFERENT. 1805 01:24:17,720 --> 01:24:22,160 SO THE ANALYSIS, WE DID 1806 01:24:22,160 --> 01:24:23,280 ATAC-SEQ, RNAseq, SINGLE CELL 1807 01:24:23,280 --> 01:24:23,800 RNAseq. 1808 01:24:23,800 --> 01:24:24,800 I'M NOT GOING TO SHOW ALL OF 1809 01:24:24,800 --> 01:24:25,080 THAT. 1810 01:24:25,080 --> 01:24:30,800 I WANT TO SHOW YOU THE RESULTS, 1811 01:24:30,800 --> 01:24:33,240 DIFFERENCE IN TRANSCRIPTIONAL 1812 01:24:33,240 --> 01:24:36,160 NATURE OF AUTOPHAGY ACTIVATED 1813 01:24:36,160 --> 01:24:38,160 NON-ACTIVATED OLD STEM CELL AND 1814 01:24:38,160 --> 01:24:41,640 WHAT WAS TRACKING WAS STRONG 1815 01:24:41,640 --> 01:24:43,280 PROMINENCE FOR INFLAMMATORY 1816 01:24:43,280 --> 01:24:44,800 SIGNATURE IN ASSOCIATE WITH 1817 01:24:44,800 --> 01:24:47,000 AUTOPHAGY ENGAGEMENT IN THE 1818 01:24:47,000 --> 01:24:50,280 QUIESCENT OLD STEM CELL SUBSET. 1819 01:24:50,280 --> 01:24:52,800 THAT LED US TO INFLAMMATION AS 1820 01:24:52,800 --> 01:24:58,400 AN INDUCER OF AUTOPHAGY, EXPOSED 1821 01:24:58,400 --> 01:25:02,240 YOUNG MICE TO ONE INJECTION OF 1822 01:25:02,240 --> 01:25:04,520 INTERFERON GAMMA WE HAVE THE 1823 01:25:04,520 --> 01:25:08,720 SAME RESULT WITH TNF ALPHA, IN 1824 01:25:08,720 --> 01:25:10,000 INTERFERON GAMMA PARTICULARLY 1825 01:25:10,000 --> 01:25:13,600 YOU SEE REPRESSION OF AUTOPHAGY 1826 01:25:13,600 --> 01:25:15,840 SIGNAL INTENSITY, THAT WHEN THE 1827 01:25:15,840 --> 01:25:19,200 CELL ENTERS THE CELL CYCLE 1828 01:25:19,200 --> 01:25:21,840 THERE'S MUCH LESS QUIESCENCE, 1829 01:25:21,840 --> 01:25:26,200 MUCH MORE CELL IN G1 PHASE, AND 1830 01:25:26,200 --> 01:25:28,160 BY 48 HOUR FOLLOWING ONE 1831 01:25:28,160 --> 01:25:31,080 CHALLENGE WHEN THE CELL ARE THE 1832 01:25:31,080 --> 01:25:33,720 MAX OF THEIR ACTIVATION AND NEED 1833 01:25:33,720 --> 01:25:35,840 TO RETURN TO QUIESCENCE, THIS IS 1834 01:25:35,840 --> 01:25:40,640 WHEN WE SEE THE DOWN-SHIFT 1835 01:25:40,640 --> 01:25:42,160 ENGAGEMENT OF AUTOPHAGY, USING 1836 01:25:42,160 --> 01:25:44,360 DEFICIENT MICE WE CAN SHOW WHEN 1837 01:25:44,360 --> 01:25:48,600 WE SUPPRESS THIS ABILITY TO 1838 01:25:48,600 --> 01:25:50,040 ENGAGE AUTOPHAGY TO REENTER 1839 01:25:50,040 --> 01:25:52,360 QUIESCENCE WE KILLED THE STEM 1840 01:25:52,360 --> 01:25:53,760 CELL, WHICH WAS AT IN VIVO BY 1841 01:25:53,760 --> 01:25:56,280 THE LOSS OF THE STEM CELL 1842 01:25:56,280 --> 01:25:59,040 COMPARTMENT, IN VITRO BY 1843 01:25:59,040 --> 01:26:02,080 PARTICULARLY LOSS OF EXPANSION 1844 01:26:02,080 --> 01:26:06,800 ACTIVITY AND AUTOPHAGY. 1845 01:26:06,800 --> 01:26:08,760 IN YOUNG MICE WITH REPEATED 1846 01:26:08,760 --> 01:26:10,320 INJECTION OF IL-1, A PERFECT 1847 01:26:10,320 --> 01:26:16,080 MODEL TO MIMIC AGING IN A YOUNG 1848 01:26:16,080 --> 01:26:18,040 BACKGROUND, 20 DAYS OF DAILY 1849 01:26:18,040 --> 01:26:21,600 INJECTION OF IL-1, WE SEE AGAIN 1850 01:26:21,600 --> 01:26:27,680 WITH DOWN SHIFT OF GFPL, 1851 01:26:27,680 --> 01:26:29,320 PARTICULARLY WHEN WE TEST 1852 01:26:29,320 --> 01:26:30,840 TRANSPLANTABILITY WE SEE EXACTLY 1853 01:26:30,840 --> 01:26:35,480 WHAT WE'VE SEEN WITH OLD AGE 1854 01:26:35,480 --> 01:26:38,840 WHICH IS AUTOPHAGY ENGAGED CELL 1855 01:26:38,840 --> 01:26:42,920 ENGRAFT ALMOST LIKE UNCHALLENGED 1856 01:26:42,920 --> 01:26:44,520 CELL, OKAY, VERSUS NON-ENGAGED, 1857 01:26:44,520 --> 01:26:46,400 ABSOLUTELY DEFECTIVE IN THE 1858 01:26:46,400 --> 01:26:47,080 REGENERATION POTENTIAL. 1859 01:26:47,080 --> 01:26:52,640 I NEED TO SPEED UP. 1860 01:26:52,640 --> 01:26:54,800 THE MECHANISM IS COMPLICATED, 1861 01:26:54,800 --> 01:27:00,560 INTERPLAY BETWEEN INFLAMMATION, 1862 01:27:00,560 --> 01:27:02,640 NUTRIENT SENSING PATHWAY, 1863 01:27:02,640 --> 01:27:08,200 KINASE, SIGNALING, MANAGEMENT OF 1864 01:27:08,200 --> 01:27:11,000 BLEW GLUCOSE. 1865 01:27:11,000 --> 01:27:13,040 WE SHOW SOC 3 IS DIFFERENTIALLY 1866 01:27:13,040 --> 01:27:18,600 EXPRESSED BETWEEN YOUNG AND OLD 1867 01:27:18,600 --> 01:27:21,160 STEM CELL, REPRESS PATHWAY, 1868 01:27:21,160 --> 01:27:23,640 TRANSPORTER, GLUCOSE RECEPTOR TO 1869 01:27:23,640 --> 01:27:28,800 THE SURFACE, EXPRESSION OF 1870 01:27:28,800 --> 01:27:31,400 GLUT1, NO CHANGE IN LOSS BETWEEN 1871 01:27:31,400 --> 01:27:35,680 YOUNG AND OLD, JUST EXPRESSION 1872 01:27:35,680 --> 01:27:37,840 ON THE SURFACE AND UPTAKE, 1873 01:27:37,840 --> 01:27:45,080 SUPPRESS IN THOSE CELLS, OLD 1874 01:27:45,080 --> 01:27:48,480 CELL, SUPPRESS KINASE, REALLY 1875 01:27:48,480 --> 01:27:51,560 LACK OF CORRELATION WHICH 1876 01:27:51,560 --> 01:27:54,520 INDICATE CELL WITH HIGHER LEVEL 1877 01:27:54,520 --> 01:27:59,200 OF INFLAMMATORY SIGNALING HAS NO 1878 01:27:59,200 --> 01:28:00,960 PHOSPHORYLATED FOXO, AND WHEN 1879 01:28:00,960 --> 01:28:05,360 THEY DO THAT THEY UNDERGO 1880 01:28:05,360 --> 01:28:06,760 METABOLIC ADAPTATION, I'M NOT 1881 01:28:06,760 --> 01:28:09,240 SHOWING DATA BUT PARTICULARLY 1882 01:28:09,240 --> 01:28:11,800 SHIFT TO LIPID METABOLISM, 1883 01:28:11,800 --> 01:28:13,760 BETTER OXIDATION, WHICH IS 1884 01:28:13,760 --> 01:28:21,920 ALTERNATIVE WAY TO BE MAINTAINED 1885 01:28:21,920 --> 01:28:27,760 IN THIS INFLAMMATORY NICHE, 1886 01:28:27,760 --> 01:28:29,400 SURVIVE THE INFLAMMATORY 1887 01:28:29,400 --> 01:28:30,480 CHALLENGE. 1888 01:28:30,480 --> 01:28:31,560 CAN WE MANIPULATE THIS 1889 01:28:31,560 --> 01:28:34,400 INFORMATION TO OLD STEM CELL 1890 01:28:34,400 --> 01:28:35,280 FUNCTION AND IMPROVE 1891 01:28:35,280 --> 01:28:36,240 REGENERATION POTENTIAL? 1892 01:28:36,240 --> 01:28:43,960 YES, WE WENT BACK TO THE LITTER, 1893 01:28:43,960 --> 01:28:47,000 REFEEDING, WHEN WE DO RECEIPT IN 1894 01:28:47,000 --> 01:28:50,280 SHORT STEM, 24 HOUR FASTING, 24 1895 01:28:50,280 --> 01:28:52,720 HOUR REFEEDING WITH FASTING, WE 1896 01:28:52,720 --> 01:28:54,360 SEE INDUCTION OF AUTOPHAGY IN 1897 01:28:54,360 --> 01:29:04,840 YOUNG MICE AND IN OLD MICE. 1898 01:29:05,480 --> 01:29:07,160 WE SEE NOW REVISION BRINGS BACK 1899 01:29:07,160 --> 01:29:09,360 TO THE LEVEL WHAT WE EXPECT IN 1900 01:29:09,360 --> 01:29:10,640 YOUNG MICE. 1901 01:29:10,640 --> 01:29:11,120 BINGO. 1902 01:29:11,120 --> 01:29:16,040 WHEN WE TEST ENGRAFTABILITY OF 1903 01:29:16,040 --> 01:29:19,840 OLD CELL WE SEE ALMOST NORMAL 1904 01:29:19,840 --> 01:29:22,560 REGENERATIVE POTENTIAL, WHICH IS 1905 01:29:22,560 --> 01:29:25,520 ABSOLUTELY NOT OBSERVED WHEN WE 1906 01:29:25,520 --> 01:29:29,600 JUST FAST AND ACTUALLY HAVE SOME 1907 01:29:29,600 --> 01:29:31,120 REBALANCING OF BLOOD 1908 01:29:31,120 --> 01:29:32,440 DISTRIBUTION IN THESE 1909 01:29:32,440 --> 01:29:35,720 TRANSPLANTED MICE WITH 1910 01:29:35,720 --> 01:29:37,800 REAPPEARANCE OF SOME BETTER 1911 01:29:37,800 --> 01:29:38,240 OUTPUT. 1912 01:29:38,240 --> 01:29:42,760 SO WE KNOW IT'S NOT JUST 1913 01:29:42,760 --> 01:29:44,400 AUTOPHAGY ENGAGEMENT BECAUSE WE 1914 01:29:44,400 --> 01:29:45,680 DON'T SEE THIS RESCUE. 1915 01:29:45,680 --> 01:29:48,320 AND PARTICULARLY WHAT WE'RE 1916 01:29:48,320 --> 01:29:53,440 DOING IS WE'RE RESTORING GLUCOSE 1917 01:29:53,440 --> 01:29:55,800 METABOLISM EXPRESSION OF GLUT1 1918 01:29:55,800 --> 01:29:57,080 AND GLYCOLYTIC METABOLICS, THAT 1919 01:29:57,080 --> 01:29:58,640 PARTICULARLY THE MODEL THAT 1920 01:29:58,640 --> 01:29:59,400 WE'RE PROPOSING AND HOPEFULLY 1921 01:29:59,400 --> 01:30:04,440 YOU WILL BE ABLE TO READ ABOUT 1922 01:30:04,440 --> 01:30:06,920 SOON IN THE LITERATURE, AND 1923 01:30:06,920 --> 01:30:09,560 PARTICULARLY IT JUST TELL US BY 1924 01:30:09,560 --> 01:30:11,760 UNDERSTANDING THE CROSSOVER 1925 01:30:11,760 --> 01:30:14,040 BETWEEN NICHE AND DEREGULATION 1926 01:30:14,040 --> 01:30:19,760 WE CAN REALLY DESIGN THE 1927 01:30:19,760 --> 01:30:20,680 TARGETED INTERVENTION, 1928 01:30:20,680 --> 01:30:22,480 HEMATOPOIETIC STEM CELL, BASED 1929 01:30:22,480 --> 01:30:23,800 ON WHAT THE CELL ARE 1930 01:30:23,800 --> 01:30:29,160 EXPERIENCING IN THEIR OWN NICHE 1931 01:30:29,160 --> 01:30:30,800 AND NOT WHAT'S TRENDING WITH 1932 01:30:30,800 --> 01:30:31,680 OTHER ORGAN DAMAGE. 1933 01:30:31,680 --> 01:30:35,400 I THANK MY LAB, ALL THE PEOPLE 1934 01:30:35,400 --> 01:30:40,320 WORKENING ON THIS PROJECT HAVE 1935 01:30:40,320 --> 01:30:41,320 BEEN HIGHLIGHTED, AND CARL 1936 01:30:41,320 --> 01:30:43,280 MITCHELL IS HERE AND WILL 1937 01:30:43,280 --> 01:30:45,240 PRESENT A POSTER TOMORROW IN THE 1938 01:30:45,240 --> 01:30:46,160 POSTER SESSION. 1939 01:30:46,160 --> 01:30:51,400 IF ANYONE IS INTERESTED WE HAVE 1940 01:30:51,400 --> 01:30:53,000 SOME LITERATURE RELATED TO THIS 1941 01:30:53,000 --> 01:30:53,440 QUESTION. 1942 01:30:53,440 --> 01:30:53,760 THANK YOU. 1943 01:30:53,760 --> 01:30:57,280 >> THANK YOU. 1944 01:30:57,280 --> 01:30:57,560 EXCELLENT. 1945 01:30:57,560 --> 01:31:01,240 WE MAY HAVE TIME FOR ONE 1946 01:31:01,240 --> 01:31:07,120 QUESTION SO WE CAN STAY ON TIME 1947 01:31:07,120 --> 01:31:10,080 BUT THIS WAS -- YOUR CONNECTION 1948 01:31:10,080 --> 01:31:11,840 BETWEEN ALL OF THE METABOLISM 1949 01:31:11,840 --> 01:31:16,960 AND EVERYTHING THAT YOU'VE BEEN 1950 01:31:16,960 --> 01:31:17,320 DOING. 1951 01:31:17,320 --> 01:31:26,160 IN THE BACK, SAY YOUR NAME. 1952 01:31:26,160 --> 01:31:29,600 >> FRED HUTCH. 1953 01:31:29,600 --> 01:31:33,640 INTRODUCED IN THE MESENCHYMAL 1954 01:31:33,640 --> 01:31:40,080 CELLS, ARE THEY DYING, 1955 01:31:40,080 --> 01:31:41,040 UNDERGOING APOPTOSIS? 1956 01:31:41,040 --> 01:31:43,080 >> ONE SOURCE OF IL-1, OTHER 1957 01:31:43,080 --> 01:31:45,440 SOURCES HAVE BEEN ISOLATED BY 1958 01:31:45,440 --> 01:31:48,960 OTHER PEOPLE, NO, WE DIDN'T SEE 1959 01:31:48,960 --> 01:31:52,680 MACROPHAGE BEING THE MAIN SOURCE 1960 01:31:52,680 --> 01:31:55,000 OF IL-1. 1961 01:31:55,000 --> 01:31:57,520 WE SAW OSTEOPROGENITOR, ONE 1962 01:31:57,520 --> 01:31:59,400 POPULATION SHRINKING WITH AGE, 1963 01:31:59,400 --> 01:32:02,120 THIS CELL BECOME EVEN MORE 1964 01:32:02,120 --> 01:32:03,240 DYSFUNCTION, ACTIVATED, WE SEE A 1965 01:32:03,240 --> 01:32:05,200 LOT OF PRODUCTION OF IL-1 FROM 1966 01:32:05,200 --> 01:32:05,600 THIS CELL. 1967 01:32:05,600 --> 01:32:08,240 >> ARE THEY DYING OUT? 1968 01:32:08,240 --> 01:32:10,240 >>WELL, THE POPULATION IS 1969 01:32:10,240 --> 01:32:13,840 COLLAPSING SO I THINK THEY ARE 1970 01:32:13,840 --> 01:32:15,080 PROGRESSIVELY DYING, AND IN 1971 01:32:15,080 --> 01:32:19,600 DYING CREATING A LOT OF IL-1. 1972 01:32:19,600 --> 01:32:25,640 BUT THEY DO NOT HAVE MARKER OF 1973 01:32:25,640 --> 01:32:31,640 THAT, WE CAN CULTIVATE, DO 1974 01:32:31,640 --> 01:32:33,600 CULTURE WITH OLD, SO THEY WILL 1975 01:32:33,600 --> 01:32:35,920 EVENTUALLY DIE BUT BEFORE THAT 1976 01:32:35,920 --> 01:32:39,240 THEY ARE PRODUCING A LOT OF 1977 01:32:39,240 --> 01:32:39,440 IL-1. 1978 01:32:39,440 --> 01:32:40,840 >> THANK YOU SO MUCH. 1979 01:32:40,840 --> 01:32:46,520 WE'LL GO TO THE NEXT SPEAKER, 1980 01:32:46,520 --> 01:32:49,240 EMILY GOLDBERG FROM UCSF, 1981 01:32:49,240 --> 01:32:51,320 TALKING ABOUT INNATE LYMPHOID 1982 01:32:51,320 --> 01:32:55,080 CELLS IN AN AGED 1983 01:32:55,080 --> 01:32:57,440 MICROENVIRONMENT. 1984 01:32:57,440 --> 01:33:04,480 1985 01:33:04,480 --> 01:33:08,760 >> HERE WE GO. 1986 01:33:08,760 --> 01:33:11,440 I DON'T KNOW IF I'LL BE 1987 01:33:11,440 --> 01:33:12,360 CONTROLLING THIS. 1988 01:33:12,360 --> 01:33:14,760 EMILY GOLDBERG. 1989 01:33:14,760 --> 01:33:16,200 THANKS FOR THE INTRODUCTION. 1990 01:33:16,200 --> 01:33:18,880 WHAT I HAVE TODAY IS NOT THE 1991 01:33:18,880 --> 01:33:26,480 COMPLETE STORY, BEAUTIFUL STORY 1992 01:33:26,480 --> 01:33:27,200 EMANUELLE JUST SHOWED YOU, THIS 1993 01:33:27,200 --> 01:33:29,080 IS A LOOK AT WHERE WE'RE GOING. 1994 01:33:29,080 --> 01:33:30,600 LET'S SEE IF I CAN MAKE THIS -- 1995 01:33:30,600 --> 01:33:31,960 I DON'T KNOW WHAT I'M GOING TO 1996 01:33:31,960 --> 01:33:34,440 MAKE IT MOVE BUT IT'S GOING. 1997 01:33:34,440 --> 01:33:36,760 EVERYONE IN THIS ROOM KNOWS THAT 1998 01:33:36,760 --> 01:33:39,040 AGING IS ASSOCIATED WITH A 1999 01:33:39,040 --> 01:33:41,240 CHRONIC LOW GRADE INFLAMMATION, 2000 01:33:41,240 --> 01:33:42,800 ASSOCIATED WITH MANY AGE-RELATED 2001 01:33:42,800 --> 01:33:43,240 DISEASES. 2002 01:33:43,240 --> 01:33:44,840 BUT I THINK WHAT IS REALLY 2003 01:33:44,840 --> 01:33:47,400 IMPORTANT TO THINK ABOUT IS THAT 2004 01:33:47,400 --> 01:33:48,480 THIS AFFECTS BASICALLY EVERY 2005 01:33:48,480 --> 01:33:51,000 ORGAN SYSTEM IN THE BODY, RIGHT? 2006 01:33:51,000 --> 01:33:54,400 EVERY ORGAN IS SUSCEPTIBLE TO 2007 01:33:54,400 --> 01:33:56,040 AGE-RELATED DISEASE, AGE-RELATED 2008 01:33:56,040 --> 01:33:56,680 FUNCTIONAL DECLINE, ILLUSTRATED 2009 01:33:56,680 --> 01:33:59,640 IN THE PIECHART ON THE BOTTOM 2010 01:33:59,640 --> 01:34:01,840 RIGHT, WHERE WE LOOKED AT DATA 2011 01:34:01,840 --> 01:34:03,480 THAT WAS EXPLAINING THE CAUSE OF 2012 01:34:03,480 --> 01:34:05,120 DEATH IN ELDERLY AND YOU CAN SEE 2013 01:34:05,120 --> 01:34:07,640 IT'S IN EVERY ORGAN. 2014 01:34:07,640 --> 01:34:08,600 WE HAVE CARDIOVASCULAR DISEASES, 2015 01:34:08,600 --> 01:34:11,920 LEADING CAUSE OF DEATH. 2016 01:34:11,920 --> 01:34:13,200 CANCERS, METABOLIC DISORDERS, 2017 01:34:13,200 --> 01:34:20,000 NEUROLOGICAL DISORDERS, 2018 01:34:20,000 --> 01:34:21,000 MUSCULOSKELETAL, A COMPLEX 2019 01:34:21,000 --> 01:34:22,080 PROBLEM RATHER THAN TREATING 2020 01:34:22,080 --> 01:34:23,640 INDIVIDUAL SYMPTOMS OF 2021 01:34:23,640 --> 01:34:25,360 INDIVIDUAL DISEASES, IF WE COULD 2022 01:34:25,360 --> 01:34:26,000 INSTEAD UNDERSTAND MECHANISMS 2023 01:34:26,000 --> 01:34:27,640 THAT ARE ALLOWING FOR THAT 2024 01:34:27,640 --> 01:34:29,200 INFLAMMATION TO ARISE IN THE 2025 01:34:29,200 --> 01:34:32,040 FIRST PLACE PERHAPS WE COULD 2026 01:34:32,040 --> 01:34:34,560 PREVENT DISEASE, WE COULD A 2027 01:34:34,560 --> 01:34:37,600 ALLEVIATE MULTIPLE SYMPTOMS OR 2028 01:34:37,600 --> 01:34:41,200 DISEASES SIMULTANEOUSLY. 2029 01:34:41,200 --> 01:34:42,800 AND I REALLY LIKE THIS CARTOON 2030 01:34:42,800 --> 01:34:45,920 BECAUSE THIS IS SUPPOSED TO 2031 01:34:45,920 --> 01:34:47,080 EMPHASIZE THAT EXCESSIVE 2032 01:34:47,080 --> 01:34:48,440 ADIPOSITY IS ALSO ASSOCIATED 2033 01:34:48,440 --> 01:34:50,320 WITH CHRONIC DISEASES AND 2034 01:34:50,320 --> 01:34:50,640 INFLAMMATION. 2035 01:34:50,640 --> 01:34:52,440 THIS IS ILLUSTRATED IN THE 2036 01:34:52,440 --> 01:34:53,640 CONTEXT OF OBESITY BUT WHAT I 2037 01:34:53,640 --> 01:34:55,360 HOPE YOU CAN APPRECIATE IS THAT 2038 01:34:55,360 --> 01:34:56,680 ALL THESE DISEASES HERE ARE 2039 01:34:56,680 --> 01:34:58,440 BASICALLY ON THE PREVIOUS SLIDE, 2040 01:34:58,440 --> 01:35:00,280 RIGHT? 2041 01:35:00,280 --> 01:35:06,640 THESE ARE IMMUNE SENESCENCE 2042 01:35:06,640 --> 01:35:07,200 DISEASES, INFECTION 2043 01:35:07,200 --> 01:35:08,080 SUSCEPTIBILITY, CANCERS, ALL 2044 01:35:08,080 --> 01:35:08,520 DISEASES OF AGING. 2045 01:35:08,520 --> 01:35:10,040 THERE ARE PEOPLE IN THIS ROOM 2046 01:35:10,040 --> 01:35:11,680 TALKING ABOUT THIS FOR A LONG 2047 01:35:11,680 --> 01:35:13,320 TIME TOO BUT WE THINK THAT 2048 01:35:13,320 --> 01:35:16,240 ADIPOSE TISSUE CAN BE A VERY 2049 01:35:16,240 --> 01:35:17,800 IMPORTANT DRIVER OF INFLAMMATION 2050 01:35:17,800 --> 01:35:20,320 IN AGING, SOME OF THIS MIGHT 2051 01:35:20,320 --> 01:35:21,200 MODEL -- MIGHT BE SIMILAR TO 2052 01:35:21,200 --> 01:35:26,120 WHAT WE SEE IN OBESITY, SOME 2053 01:35:26,120 --> 01:35:26,680 MIGHT BE AGE-SPECIFIC 2054 01:35:26,680 --> 01:35:30,600 MECHANISMS. 2055 01:35:30,600 --> 01:35:33,080 AND SO WE ARE IMMUNOLOGISTS, 2056 01:35:33,080 --> 01:35:35,440 INTERESTED IN STUDYING HOW THE 2057 01:35:35,440 --> 01:35:40,240 IMMUNE SYSTEM CAN HELP CONTROL 2058 01:35:40,240 --> 01:35:40,800 INFLAMMATION AND ORGAN 2059 01:35:40,800 --> 01:35:42,560 PHYSIOLOGY, AND SO BECAUSE WE'RE 2060 01:35:42,560 --> 01:35:44,600 INTERESTED IN ADIPOSE TISSUE WE 2061 01:35:44,600 --> 01:35:48,120 WANTED TO STUDY THIS IN THE 2062 01:35:48,120 --> 01:35:49,000 ADIPOSE-RESIDENT IMMUNE 2063 01:35:49,000 --> 01:35:49,520 COMPARTMENT. 2064 01:35:49,520 --> 01:35:56,440 THE WAY WE STUDY THIS IS WE CAN 2065 01:35:56,440 --> 01:35:58,240 GIVE AN IV INJECTION OF AN 2066 01:35:58,240 --> 01:36:00,280 ANTIBODY THAT WILL BIND ALL 2067 01:36:00,280 --> 01:36:01,400 MATURE IMMUNE CELLS IN THE 2068 01:36:01,400 --> 01:36:02,480 BLOOD, IT DOESN'T GET A CHANCE 2069 01:36:02,480 --> 01:36:03,680 TO GO INTO THE TISSUE. 2070 01:36:03,680 --> 01:36:07,400 WE CAN USE THIS TO BASICALLY BE 2071 01:36:07,400 --> 01:36:10,800 ABLE TO SEGREGATE CELLS THAT ARE 2072 01:36:10,800 --> 01:36:12,240 CIRCULATING IN THE TISSUE OR 2073 01:36:12,240 --> 01:36:13,520 NON-CIRCULATING AT THE TIME OF 2074 01:36:13,520 --> 01:36:14,440 TISSUE COLLAPSING. 2075 01:36:14,440 --> 01:36:16,800 THERE'S A REPRESENTATIVE IMAGE 2076 01:36:16,800 --> 01:36:18,360 HERE OF A MOUSE, ALL THE IMMUNE 2077 01:36:18,360 --> 01:36:20,880 CELLS IN GREEN, YOU CAN SEE THEY 2078 01:36:20,880 --> 01:36:26,000 ARE RESTRICTED IN VAST VASCULAN 2079 01:36:26,000 --> 01:36:27,880 RED, ONE TINY PIECE OF FAT FROM 2080 01:36:27,880 --> 01:36:28,640 THE ANIMAL. 2081 01:36:28,640 --> 01:36:31,040 YOU CAN APPRECIATE IN DENSELY 2082 01:36:31,040 --> 01:36:32,000 VASCULARIZED TISSUE LIKE THE 2083 01:36:32,000 --> 01:36:34,240 FAT, FOR INSTANCE, HOW MANY 2084 01:36:34,240 --> 01:36:36,440 IMMUNE CELLS ARE ACTUALLY IN 2085 01:36:36,440 --> 01:36:37,080 CIRCULATION AND PASSIVELY MOVING 2086 01:36:37,080 --> 01:36:38,280 THROUGH THE TISSUE AT THE TIME 2087 01:36:38,280 --> 01:36:41,880 OF TISSUE COLLECTION BUT HAVE NO 2088 01:36:41,880 --> 01:36:44,880 INTEREST OR BEARING ON THE 2089 01:36:44,880 --> 01:36:45,760 BIOLOGY OF THAT ORGAN. 2090 01:36:45,760 --> 01:36:51,080 WE USE THIS APPROACH TO DO 2091 01:36:51,080 --> 01:36:54,160 SINGLE CELL RNA-SEQ TO HAVE AN 2092 01:36:54,160 --> 01:36:55,080 UNBIASED AND BROAD VIEW OF WHAT 2093 01:36:55,080 --> 01:36:56,320 IMMUNE CELLS ARE THAT ARE IN THE 2094 01:36:56,320 --> 01:37:03,040 FAT AND HOW THEY ARE CHANGING 2095 01:37:03,040 --> 01:37:07,680 DURING AGING. 2096 01:37:07,680 --> 01:37:11,000 WE DID THESE IN THE LAB AND WE 2097 01:37:11,000 --> 01:37:12,680 KNEW THERE'S A TON OF IMMUNE 2098 01:37:12,680 --> 01:37:13,560 CELLS IN THE FAT. 2099 01:37:13,560 --> 01:37:15,600 IF YOU DON'T KNOW ALREADY, 2100 01:37:15,600 --> 01:37:16,600 ESSENTIALLY ANY IMMUNE CELLS IN 2101 01:37:16,600 --> 01:37:18,480 THE PERIPHERY, YOU CAN FIND IN 2102 01:37:18,480 --> 01:37:20,760 SOME FLAVOR IN YOUR FAT TISSUE, 2103 01:37:20,760 --> 01:37:23,520 HAS A HUGE IMMUNE COMPARTMENT, 2104 01:37:23,520 --> 01:37:25,560 DISPLAYS VERY LARGE CHANGES WITH 2105 01:37:25,560 --> 01:37:26,000 AGE. 2106 01:37:26,000 --> 01:37:26,560 BASICALLY EVERY IMMUNE CELL 2107 01:37:26,560 --> 01:37:28,120 THAT'S PRESENT IN THE FAT IS 2108 01:37:28,120 --> 01:37:30,000 CHANGING IN SOME WAY IN AGING, 2109 01:37:30,000 --> 01:37:32,560 SOME ARE GOING UP, SOME GOING 2110 01:37:32,560 --> 01:37:32,760 DOWN. 2111 01:37:32,760 --> 01:37:38,600 WHAT I HAVE TODAY IS A VERY 2112 01:37:38,600 --> 01:37:40,120 BRIEF RECAP ON THE -- 2113 01:37:40,120 --> 01:37:45,680 ESSENTIALLY COMPLETE LOSS OF 2114 01:37:45,680 --> 01:37:46,800 IMMUNE CELL SUBSET. 2115 01:37:46,800 --> 01:37:47,800 WE PUBLISHED THIS ALREADY BUT 2116 01:37:47,800 --> 01:37:50,880 I'M GOING TO USE THIS AS SORT OF 2117 01:37:50,880 --> 01:37:53,080 OUR SEGUE TO EXPLAIN HOW WE ARE 2118 01:37:53,080 --> 01:37:54,520 CHOOSING WHAT DIRECTIONS WE MOVE 2119 01:37:54,520 --> 01:37:59,280 FORWARD IN. 2120 01:37:59,280 --> 01:38:00,960 AND SO, YOU KNOW, TO EXPLAIN WHY 2121 01:38:00,960 --> 01:38:02,920 WE'RE INTERESTED IN FOLLOWING UP 2122 01:38:02,920 --> 01:38:06,840 ON THIS LOSS OF ILC 2 OF AGING, 2123 01:38:06,840 --> 01:38:08,960 IT'S BECAUSE WE'VE BEEN GIVEN A 2124 01:38:08,960 --> 01:38:10,400 CENTRAL ROLE IN ADIPOSE TISSUE 2125 01:38:10,400 --> 01:38:11,360 BIOLOGY, AND SO THEY ARE THOUGHT 2126 01:38:11,360 --> 01:38:15,040 TO BE ABLE TO CONTROL ADIPOSE 2127 01:38:15,040 --> 01:38:16,080 TISSUE INFLAMMATION WITH 2128 01:38:16,080 --> 01:38:17,880 IMPORTANT SEQUENCES ON GLUCOSE 2129 01:38:17,880 --> 01:38:18,600 TOLERANCE, INSULIN SENSITIVITY, 2130 01:38:18,600 --> 01:38:22,680 BUT CAN ALSO BE IMPORTANT IN 2131 01:38:22,680 --> 01:38:28,280 HELPING TO INDICATE ADIPOSE 2132 01:38:28,280 --> 01:38:28,960 TISSUE THERMOGENESIS, IN 2133 01:38:28,960 --> 01:38:33,840 RESPONSE TO COLD. 2134 01:38:33,840 --> 01:38:38,000 IN AGING, BOTH OF THESE PROGRAMS 2135 01:38:38,000 --> 01:38:40,000 GET LOST AND DEREGULATED IN 2136 01:38:40,000 --> 01:38:40,640 AGING. 2137 01:38:40,640 --> 01:38:43,840 SO THIS WAS SHEATHING -- 2138 01:38:43,840 --> 01:38:45,040 SATISFYING TO SEE A CELL TYPE 2139 01:38:45,040 --> 01:38:47,000 THAT CAN CONTROL BOTH IS LOSTING 2140 01:38:47,000 --> 01:38:49,080 IN AGING, PERHAPS A VERY SIMPLE 2141 01:38:49,080 --> 01:38:50,840 EXPLANATION FOR WHY YOU LOSE 2142 01:38:50,840 --> 01:38:55,720 THESE FUNCTIONS OF YOUR ADIPOSE 2143 01:38:55,720 --> 01:38:56,200 TISSUE. 2144 01:38:56,200 --> 01:38:59,920 SO WE ASKED THE FIRST QUESTION, 2145 01:38:59,920 --> 01:39:01,880 COULD WE RESTORE THESE CELLS? 2146 01:39:01,880 --> 01:39:04,520 CURE AGING WITH IMMUNE 2147 01:39:04,520 --> 01:39:04,840 REJUVENATION. 2148 01:39:04,840 --> 01:39:07,560 AND WE CAN DO THAT. 2149 01:39:07,560 --> 01:39:11,720 WE GIVE MICE IP INJECTION OF 2150 01:39:11,720 --> 01:39:13,920 ILC2 GROWTH FACTOR, IL-33, A 2151 01:39:13,920 --> 01:39:16,120 CYTOKINE IN THE IL-1 FAMILY. 2152 01:39:16,120 --> 01:39:16,960 THERE WE ARE. 2153 01:39:16,960 --> 01:39:19,920 AND WHAT YOU CAN SEE IS IN OLD 2154 01:39:19,920 --> 01:39:26,280 MICE GIVEN IL-33 WE CAN EXPAND 2155 01:39:26,280 --> 01:39:29,240 ILC2 ROBUSTLY, WHICH WE THOUGHT 2156 01:39:29,240 --> 01:39:31,320 WAS PROMISING. 2157 01:39:31,320 --> 01:39:34,600 AND WE'VE LOOKED AT LEAST THREE 2158 01:39:34,600 --> 01:39:41,800 MONTHS AFTER WE DO INJECTIONS, 2159 01:39:41,800 --> 01:39:43,800 ILC2s ARE RETAINED IN THE FAT, 2160 01:39:43,800 --> 01:39:45,040 A NICE THERAPEUTIC WINDOW TO 2161 01:39:45,040 --> 01:39:48,240 TEST AND ASK THE QUESTION COULD 2162 01:39:48,240 --> 01:39:50,040 WE RESTORE THE DYSFUNCTION THAT 2163 01:39:50,040 --> 01:39:53,720 SEEMS TO ARISE IN AGED FAT. 2164 01:39:53,720 --> 01:39:54,200 OKAY. 2165 01:39:54,200 --> 01:39:59,080 SO WE ASKED THIS QUESTION, CAN 2166 01:39:59,080 --> 01:40:01,640 WE INCREASE ILC 2 TO RECOVER 2167 01:40:01,640 --> 01:40:03,200 LOSS OF FUNCTIONALITY WITH 2168 01:40:03,200 --> 01:40:05,120 BENEFITS TO THE ORGANISM AS A 2169 01:40:05,120 --> 01:40:05,640 RESULT? 2170 01:40:05,640 --> 01:40:07,080 AND SO WHAT I'LL DO FOR THE SAKE 2171 01:40:07,080 --> 01:40:08,960 OF TIME IS SKIP EVERYTHING WE 2172 01:40:08,960 --> 01:40:11,600 LOOKED AT FOR METABOLIC HEALTH, 2173 01:40:11,600 --> 01:40:15,800 NO IMPACT ON GLUCOSE 2174 01:40:15,800 --> 01:40:16,640 HOMEOSTASIS, ADIPOSE TISSUE 2175 01:40:16,640 --> 01:40:17,960 INFLAMMATION, NOTHING. 2176 01:40:17,960 --> 01:40:20,360 INSTEAD WHAT HAPPENS WITH 2177 01:40:20,360 --> 01:40:21,680 THERMOGENESIS, CORE BODY 2178 01:40:21,680 --> 01:40:23,240 TEMPERATURE, WHAT YOU NEED, ALL 2179 01:40:23,240 --> 01:40:26,080 YOU NEED TO KNOW IS THAT ILC 2180 01:40:26,080 --> 01:40:27,840 2s HAVE A FEW DIFFERENT WAYS 2181 01:40:27,840 --> 01:40:33,760 THAT IT CAN -- THEY CAN INDUCE 2182 01:40:33,760 --> 01:40:34,880 THERMOGENESIS EITHER INDIRECTLY, 2183 01:40:34,880 --> 01:40:39,680 STIMULATE MACROPHAGE OR 2184 01:40:39,680 --> 01:40:42,640 EOSINOPHILS, CAN DO THIS 2185 01:40:42,640 --> 01:40:43,760 DIRECTLY THROUGH RELEASE OF 2186 01:40:43,760 --> 01:40:47,360 PEPTIDE, ALL OF THIS LEADS TO 2187 01:40:47,360 --> 01:40:49,760 THE ACTIVATION OF A PROGRAM 2188 01:40:49,760 --> 01:40:53,040 WHERE THEY INCREASE EXPRESSION 2189 01:40:53,040 --> 01:40:54,560 OF THIS PROTEIN UCP1, WHAT THIS 2190 01:40:54,560 --> 01:40:56,240 DOES IS WHEN YOU'RE BURNING FAT 2191 01:40:56,240 --> 01:40:59,280 FOR ENERGY INSTEAD OF GENERATING 2192 01:40:59,280 --> 01:41:02,680 ATP YOU GENERATE HEAT, OKAY? 2193 01:41:02,680 --> 01:41:04,400 AND WHAT WE WERE SURPRISED TO 2194 01:41:04,400 --> 01:41:09,000 FIND IS OLD MICE THAT WERE GIVEN 2195 01:41:09,000 --> 01:41:14,480 IL-33 AND EXPANDED ILC2s, HAVE 2196 01:41:14,480 --> 01:41:17,120 INCREASED SUSCEPTIBILITY TO COLD 2197 01:41:17,120 --> 01:41:19,280 CHALLENGE, FAILING TO UPREGULATE 2198 01:41:19,280 --> 01:41:21,480 UCP 1 IN ADIPOSE TISSUE, 2199 01:41:21,480 --> 01:41:22,920 SUCCUMBING TO THE COLD 2200 01:41:22,920 --> 01:41:23,240 CHALLENGE. 2201 01:41:23,240 --> 01:41:26,760 THIS IS WEIRD BECAUSE THE ILC 2 2202 01:41:26,760 --> 01:41:28,480 SHOULD NOT BE DOING THIS, SHOULD 2203 01:41:28,480 --> 01:41:29,640 HAVE OPPOSITE EFFECT. 2204 01:41:29,640 --> 01:41:32,320 WE THOUGHT THIS MEANT SOMETHING 2205 01:41:32,320 --> 01:41:33,520 IS WRONG WITH ILC2s PRESENT IN 2206 01:41:33,520 --> 01:41:35,520 OLD MICE. 2207 01:41:35,520 --> 01:41:38,280 WE DID ADOPTIVE TRANSFER 2208 01:41:38,280 --> 01:41:38,680 EXPERIMENT. 2209 01:41:38,680 --> 01:41:45,280 WE GOT MICE THAT EXPRESS THE RED 2210 01:41:45,280 --> 01:41:45,880 FLUORESCENT PROTEIN, ILC2s ARE 2211 01:41:45,880 --> 01:41:48,120 THE ONLY CELLS IN THE FAT 2212 01:41:48,120 --> 01:41:51,960 EXPRESSING IL-5 SO WE CAN EXPAND 2213 01:41:51,960 --> 01:41:55,120 IN VIVO, WE CAN SORT WITH FLOW 2214 01:41:55,120 --> 01:41:59,080 CYTOMETRY AND TRANSFER INTO OLD 2215 01:41:59,080 --> 01:42:00,480 MICE, THAT GOT ADULT ILC2s, 2216 01:42:00,480 --> 01:42:04,640 NOW PROTECTED FROM THE COLD 2217 01:42:04,640 --> 01:42:05,440 CHALLENGE. 2218 01:42:05,440 --> 01:42:07,160 INTRODUCTION OF ADULT ILC2 INTO 2219 01:42:07,160 --> 01:42:08,360 OLD HOST IS SUFFICIENT TO 2220 01:42:08,360 --> 01:42:10,240 PROTECT AGAINST THE COLD 2221 01:42:10,240 --> 01:42:11,200 CHALLENGE THAT'S OTHERWISE 2222 01:42:11,200 --> 01:42:14,480 LETHAL IN THE OLD MICE. 2223 01:42:14,480 --> 01:42:16,600 AND SO WE WANTED TO FIGURE OUT 2224 01:42:16,600 --> 01:42:18,680 WHAT IS THE DIFFERENCE IN ILC 2225 01:42:18,680 --> 01:42:20,640 2s IN AGING THAT MIGHT BE 2226 01:42:20,640 --> 01:42:22,520 UNDERLYING THE SORT OF -- THIS 2227 01:42:22,520 --> 01:42:25,240 PROBLEM WHETHER THE OLD ILC2s 2228 01:42:25,240 --> 01:42:25,840 ARE HEIGHTENING SUSCEPTIBILITY 2229 01:42:25,840 --> 01:42:28,080 TO COLD AND SO WE DID BOTH 2230 01:42:28,080 --> 01:42:30,840 RNAseq ON ADULT AND OLD 2231 01:42:30,840 --> 01:42:32,600 ILC2s FROM ADIPOSE TISSUE TO 2232 01:42:32,600 --> 01:42:34,000 UNDERSTAND THIS, AND AS EXPECTED 2233 01:42:34,000 --> 01:42:35,760 WE SAW A LOT OF CHANGES. 2234 01:42:35,760 --> 01:42:40,680 WHAT I WANT TO EMPHASIZE IS THE 2235 01:42:40,680 --> 01:42:42,960 GENE SIGNATURES BEING ENRICHED 2236 01:42:42,960 --> 01:42:50,440 IN THE OLD CELLS ARE ALL SORT OF 2237 01:42:50,440 --> 01:42:52,160 DOWNSTREAM ACTIVATION SIGNALS, 2238 01:42:52,160 --> 01:42:53,320 LIKE CYTOKINE SIGNALING 2239 01:42:53,320 --> 01:42:55,280 PATHWAYS, REFLECTIVE THAT THE 2240 01:42:55,280 --> 01:42:58,200 OLD ENVIRONMENT IS STILL 2241 01:42:58,200 --> 01:42:59,160 INFORMING AND IMPACTING THESE 2242 01:42:59,160 --> 01:43:01,280 CELLS, RIGHT? 2243 01:43:01,280 --> 01:43:03,400 SORT OF OUTSIDE-IN SIGNALING 2244 01:43:03,400 --> 01:43:04,240 BECOMING DYSREGULATED. 2245 01:43:04,240 --> 01:43:07,400 WE HAVE AN IMMUNE CELL INTRINSIC 2246 01:43:07,400 --> 01:43:09,160 DEFECT IN OLD ILC2s WE THOUGHT 2247 01:43:09,160 --> 01:43:11,880 THIS WAS STILL BEING -- 2248 01:43:11,880 --> 01:43:14,640 REFLECTIVE STILL OF EXTERNAL 2249 01:43:14,640 --> 01:43:16,280 SIGNALS THAT ARE HAVING A 2250 01:43:16,280 --> 01:43:17,560 CONSEQUENCE ON THESE CELLS. 2251 01:43:17,560 --> 01:43:19,320 AND SO THAT HAS SHAPED A LOT 2252 01:43:19,320 --> 01:43:21,280 ABOUT HOW WE'RE THINKING ABOUT 2253 01:43:21,280 --> 01:43:22,720 THIS PROBLEM MOVING FORWARD. 2254 01:43:22,720 --> 01:43:25,320 WHERE WE STEP BACK AND THINK HOW 2255 01:43:25,320 --> 01:43:29,080 DOES AN IMMUNE CELL IN ADIPOSE 2256 01:43:29,080 --> 01:43:30,880 TISSUE BECOME DYSREGULATED OVER 2257 01:43:30,880 --> 01:43:32,120 THE LIFESPAN? 2258 01:43:32,120 --> 01:43:34,520 THEY ARE LONG LIVED, SEATED 2259 01:43:34,520 --> 01:43:35,960 EARLY, MAINTAINED THROUGH THE 2260 01:43:35,960 --> 01:43:36,720 LIFESPAN. 2261 01:43:36,720 --> 01:43:42,040 WE THINK THAT MAKES THEM 2262 01:43:42,040 --> 01:43:42,840 SUSCEPTIBLE TO DYSFUNCTIONAL 2263 01:43:42,840 --> 01:43:43,960 DYSREGULATION, THREE WAYS COULD 2264 01:43:43,960 --> 01:43:45,560 YOU HAVE APPARENT DYSREGULATION 2265 01:43:45,560 --> 01:43:46,880 OF THE RESIDENT IMMUNE 2266 01:43:46,880 --> 01:43:47,240 COMPARTMENT. 2267 01:43:47,240 --> 01:43:50,720 WE KNOW CELLS FROM THE PERIPHERY 2268 01:43:50,720 --> 01:43:52,480 ARE INFILTRATING OVER THE 2269 01:43:52,480 --> 01:43:54,240 LIFESPAN AND BECOME RESIDENT IN 2270 01:43:54,240 --> 01:43:56,760 THE FAT AND EVERY ORGAN, SO THAT 2271 01:43:56,760 --> 01:43:58,600 WOULD EFFECTIVELY MAKE THE 2272 01:43:58,600 --> 01:43:59,400 RESIDENT COMPARTMENT LOOK 2273 01:43:59,400 --> 01:44:02,640 DIFFERENT BECAUSE NEW CELLS ARE 2274 01:44:02,640 --> 01:44:05,400 COMING IN, THROUGH UNKNOWN 2275 01:44:05,400 --> 01:44:05,760 MECHANISMS. 2276 01:44:05,760 --> 01:44:11,320 THESE ARE CELLS ARE MAINTAINED 2277 01:44:11,320 --> 01:44:13,280 THROUGH SELF-RENEWAL, THIS COULD 2278 01:44:13,280 --> 01:44:15,480 PREDISPOSE TO THE POSSIBILITY OF 2279 01:44:15,480 --> 01:44:17,360 ACCUMULATING DEFECTS OVER TIME. 2280 01:44:17,360 --> 01:44:19,080 AND THEN BECAUSE THEY LIVE IN 2281 01:44:19,080 --> 01:44:21,400 THE TISSUE AND NEVER LEAVE, THEY 2282 01:44:21,400 --> 01:44:24,120 ARE GOING TO BE SUSCEPTIBLE TO 2283 01:44:24,120 --> 01:44:25,520 AGE-RELATED CHANGES THAT ARISE 2284 01:44:25,520 --> 01:44:26,720 IN THE TISSUE. 2285 01:44:26,720 --> 01:44:28,080 SO THAT'S GOING TO TELL YOU ONE 2286 01:44:28,080 --> 01:44:31,240 OF THE AREAS WE'RE INVESTIGATING 2287 01:44:31,240 --> 01:44:34,200 IS HOW WE CAN IDENTIFY SECRETED 2288 01:44:34,200 --> 01:44:36,320 FACTORS SPECIFICALLY IN AGED 2289 01:44:36,320 --> 01:44:37,080 ENVIRONMENT INFLUENCING IMMUNE 2290 01:44:37,080 --> 01:44:39,920 CELLS, NOT ONLY IN THAT TISSUE 2291 01:44:39,920 --> 01:44:40,680 BUT PERHAPS SYSTEMICALLY. 2292 01:44:40,680 --> 01:44:42,760 WE HAVE A PROBLEM HERE. 2293 01:44:42,760 --> 01:44:44,600 WE'RE INTERESTED IN HOW 2294 01:44:44,600 --> 01:44:47,880 DIFFERENT CELL TYPES IN FAT ARE 2295 01:44:47,880 --> 01:44:48,480 INFLUENCING RESIDENT IMMUNE 2296 01:44:48,480 --> 01:44:50,720 CELLS, BUT HOW DO WE DO THAT? 2297 01:44:50,720 --> 01:44:55,680 HOW DO WE TAKE BE A OLD ANIMAL, 2298 01:44:55,680 --> 01:44:58,720 OLD ORGANISM, WE KNOW A PROTEIN 2299 01:44:58,720 --> 01:45:00,800 CAME FROM FAT, IMPORTANT FOR 2300 01:45:00,800 --> 01:45:01,480 DOWNSTREAM PHYSIOLOGY WE'RE 2301 01:45:01,480 --> 01:45:02,480 INTERESTED IN STUDYING. 2302 01:45:02,480 --> 01:45:04,000 WE'VE BEEN THINKING ABOUT THAT 2303 01:45:04,000 --> 01:45:07,280 AND SAW A TALK BY MY COLLEAGUE 2304 01:45:07,280 --> 01:45:09,360 JOHN LONG AT STANFORD WHERE HE 2305 01:45:09,360 --> 01:45:14,480 HAD A BRILLIANT IDEA TO USE 2306 01:45:14,480 --> 01:45:18,000 ADENO-ASSOCIATE VIRUSES AS GENE 2307 01:45:18,000 --> 01:45:24,800 DELIVERY TOOLS TO EXPRESS 2308 01:45:24,800 --> 01:45:25,840 PROMISCUOUS LIGASE, EXPRESSING 2309 01:45:25,840 --> 01:45:29,280 THIS NOW SPECIFICALLY IN FAT 2310 01:45:29,280 --> 01:45:34,720 TISSUE AND CAN NOW MEASURE 2311 01:45:34,720 --> 01:45:36,560 SECRETED PROTEINS FROM FAT IN 2312 01:45:36,560 --> 01:45:36,760 VIVO. 2313 01:45:36,760 --> 01:45:41,520 THE WAY THIS WORKS IS IF WE HAVE 2314 01:45:41,520 --> 01:45:46,200 ADIPOCYTE HERE, USING THE VIRUS 2315 01:45:46,200 --> 01:45:47,520 TO EXPRESS ON MEMBRANE, WHAT 2316 01:45:47,520 --> 01:45:49,080 HAPPENS IS WE KNOW THERE'S A LOT 2317 01:45:49,080 --> 01:45:50,920 OF PROTEINS IN THE BLOOD. 2318 01:45:50,920 --> 01:45:58,920 WE'VE ALL MEASURED CYTOKINES IN 2319 01:45:58,920 --> 01:46:05,400 THE BLOOD. 2320 01:46:05,400 --> 01:46:07,880 NOW IT GETS BIOTINYLATED, WE CAN 2321 01:46:07,880 --> 01:46:10,600 ACTIVE PROTEINS THAT CAME FROM 2322 01:46:10,600 --> 01:46:12,720 ADIPOCYTES AND IDENTIFY AND ASK 2323 01:46:12,720 --> 01:46:15,320 WHAT'S GOING, IN AGING OR STRESS 2324 01:46:15,320 --> 01:46:15,880 CONDITIONS. 2325 01:46:15,880 --> 01:46:19,560 THE VIRUS HAS A V5 TAG WHICH 2326 01:46:19,560 --> 01:46:29,560 WE'RE USING TO CHECK TISSUE 2327 01:46:29,560 --> 01:46:30,000 SPECIFICITY. 2328 01:46:30,000 --> 01:46:33,520 LIVER LOVES AAVs, IT'S A 2329 01:46:33,520 --> 01:46:34,480 MASSIVE PROTEIN SECRETION ORGAN 2330 01:46:34,480 --> 01:46:36,880 SO WE MAKE SURE THERE'S 2331 01:46:36,880 --> 01:46:38,320 SPECIFICITY AND WE'RE NOT 2332 01:46:38,320 --> 01:46:40,640 INTEGRATING INTO THE LIVER, THAT 2333 01:46:40,640 --> 01:46:44,760 WOULD SWAMP OUT FAT SECRETION 2334 01:46:44,760 --> 01:46:45,240 BASICALLY. 2335 01:46:45,240 --> 01:46:50,920 AND THIS WAS WHAT THIS LOOKS 2336 01:46:50,920 --> 01:46:53,000 LIKE. 2337 01:46:53,000 --> 01:46:56,520 THIS IS -- PROTEINS ARE 2338 01:46:56,520 --> 01:46:58,160 BIOTYNLATED, THIS IS THE SILVER 2339 01:46:58,160 --> 01:47:01,440 STAIN GEL OF ADULT AND OLD MICE 2340 01:47:01,440 --> 01:47:03,040 THAT UNDERWENT THIS TREATMENT. 2341 01:47:03,040 --> 01:47:06,120 IF THEY DON'T GET THE AAV, IT'S 2342 01:47:06,120 --> 01:47:09,440 A CLEAN SYSTEM, YOU HAVE NO 2343 01:47:09,440 --> 01:47:10,640 BIOTYNLATED PROTEINS IN PLASMA, 2344 01:47:10,640 --> 01:47:11,280 IT'S REALLY NICE. 2345 01:47:11,280 --> 01:47:11,920 THANK YOU. 2346 01:47:11,920 --> 01:47:15,400 NOW WE CAN USE THESE SAMPLES AND 2347 01:47:15,400 --> 01:47:18,160 SUBMIT THEM FOR MASS SPEC, 2348 01:47:18,160 --> 01:47:19,400 IDENTIFY PROTEINS SECRETED. 2349 01:47:19,400 --> 01:47:20,720 WHERE ARE WE NOW, THE BIG 2350 01:47:20,720 --> 01:47:24,000 QUESTIONS WE THINK WE CAN HELP 2351 01:47:24,000 --> 01:47:26,760 ADDRESS IN THESE EXPERIMENTS? 2352 01:47:26,760 --> 01:47:30,200 WE CAN ASK HOW DIFFERENT TISSUES 2353 01:47:30,200 --> 01:47:32,760 ARE -- WHAT THEY ARE SECRETING, 2354 01:47:32,760 --> 01:47:34,400 HOW IT MIGHT CHANGE WITH AGE, IN 2355 01:47:34,400 --> 01:47:36,560 RESPONSE TO STRESS LIKE 2356 01:47:36,560 --> 01:47:38,960 INFECTION OR DIETARY 2357 01:47:38,960 --> 01:47:40,280 MANIPULATION, ASK HOW THESE 2358 01:47:40,280 --> 01:47:42,440 SECRETED PROTEINS MIGHT BE 2359 01:47:42,440 --> 01:47:44,880 INFLUENCING LOCAL IMMUNE CELLS, 2360 01:47:44,880 --> 01:47:45,880 SYSTEMIC IMMUNE RESPONSES, 2361 01:47:45,880 --> 01:47:47,080 VACCINATION OR SOMETHING LIKE 2362 01:47:47,080 --> 01:47:49,120 THAT, AND WE CAN ASK HOW AGED 2363 01:47:49,120 --> 01:47:51,760 FAT IS CONTRIBUTING TO OTHER 2364 01:47:51,760 --> 01:47:53,160 INFLAMMATORY DISEASES, HAVE ANY 2365 01:47:53,160 --> 01:47:55,600 MODEL OF DISEASE, YOU CAN INDUCE 2366 01:47:55,600 --> 01:47:57,680 IN MICE, WE CAN NOW USE THESE 2367 01:47:57,680 --> 01:47:59,440 STRATEGIES AND DO THIS IN LOTS 2368 01:47:59,440 --> 01:48:02,360 OF TISSUES, I'M SHOWING FAT BUT 2369 01:48:02,360 --> 01:48:05,800 WE HAVE TOOLS FOR LOTS OF 2370 01:48:05,800 --> 01:48:06,000 ORGANS. 2371 01:48:06,000 --> 01:48:08,200 I'LL END WITH ACKNOWLEDGMENTS. 2372 01:48:08,200 --> 01:48:12,440 THE IDEAS STARTED DURING MY 2373 01:48:12,440 --> 01:48:15,080 POSTDOC'S LAB, AND WE DID 2374 01:48:15,080 --> 01:48:18,160 SEQUENCING WITH MAX AND IRINA, 2375 01:48:18,160 --> 01:48:25,160 CONTINUING IN MY LAB ARE 2376 01:48:25,160 --> 01:48:26,400 PROTEOMICS, HAPPY TO TAKE 2377 01:48:26,400 --> 01:48:28,560 QUESTIONS. 2378 01:48:28,560 --> 01:48:28,920 2379 01:48:28,920 --> 01:48:33,160 >> GREAT. 2380 01:48:33,160 --> 01:48:39,400 JUST GREAT. 2381 01:48:39,400 --> 01:48:40,120 HERE'S A QUESTION. 2382 01:48:40,120 --> 01:48:41,800 >> BAYLOR COLLEGE OF MEDICINE. 2383 01:48:41,800 --> 01:48:46,240 TERRIFIC TALK, EMILY. 2384 01:48:46,240 --> 01:48:48,720 I NOTICED IN YOUR TRANSCRIPTOMIC 2385 01:48:48,720 --> 01:48:50,240 ANALYSIS YOUNG VERSUS OLD YOU 2386 01:48:50,240 --> 01:48:55,080 SAW INVOLVEMENT OF RIBOSOMES IN 2387 01:48:55,080 --> 01:49:00,320 YOUNG NOT IN OLD. 2388 01:49:00,320 --> 01:49:01,840 YOU DISCUSSED EXTRINSIC BUT AS 2389 01:49:01,840 --> 01:49:05,360 CELLS ARE AGING MAYBE THEY ARE 2390 01:49:05,360 --> 01:49:07,080 LOSING TRANSLATIONAL CAPACITY? 2391 01:49:07,080 --> 01:49:08,200 2392 01:49:08,200 --> 01:49:12,000 >> YES, WE HAVE AN NIH-FRIENDLY 2393 01:49:12,000 --> 01:49:14,240 HYPOTHESIS THAT BOTH CELL 2394 01:49:14,240 --> 01:49:19,960 INTRINSIC AN EXTRINSIC ARE AT 2395 01:49:19,960 --> 01:49:20,480 PLAY. 2396 01:49:20,480 --> 01:49:22,160 I FOCUSED ON ONE, FUN AND OF 2397 01:49:22,160 --> 01:49:23,880 INTEREST TO THE COMMUNITY. 2398 01:49:23,880 --> 01:49:25,120 WE THINK THERE'S INTRINSIC AS 2399 01:49:25,120 --> 01:49:25,320 WELL. 2400 01:49:25,320 --> 01:49:27,080 THESE ARE SUPPOSED TO BE MAJOR 2401 01:49:27,080 --> 01:49:28,160 CYTOKINE PRODUCERS AND STUFF 2402 01:49:28,160 --> 01:49:31,040 LIKE THAT SO WE EXPECT TO SEE 2403 01:49:31,040 --> 01:49:32,360 SIGNATURES IN HEALTHY CELLS. 2404 01:49:32,360 --> 01:49:37,560 >> AND FOLLOWING UP DO YOU SEE 2405 01:49:37,560 --> 01:49:38,320 REDUCED IL-33 SECRETION? 2406 01:49:38,320 --> 01:49:39,360 >> IL-33 DOESN'T COME FROM 2407 01:49:39,360 --> 01:49:41,840 THESE CELLS BUT FROM STROMAL 2408 01:49:41,840 --> 01:49:43,280 CELLS IN THE FAT, NOT SO MUCH 2409 01:49:43,280 --> 01:49:46,000 THERE'S LESS BUT WE THINK 2410 01:49:46,000 --> 01:49:47,040 BIOAVAILABILITY, YEAH. 2411 01:49:47,040 --> 01:49:50,480 >> AND WE HAVE ANOTHER 2412 01:49:50,480 --> 01:49:50,840 QUESTION. 2413 01:49:50,840 --> 01:49:51,240 >> NORTHWESTERN. 2414 01:49:51,240 --> 01:49:53,320 THANKS FOR A GREAT TALK. 2415 01:49:53,320 --> 01:49:54,440 QUICK QUESTION. 2416 01:49:54,440 --> 01:49:58,040 IF YOU SEE AGE RELATED CHANGES 2417 01:49:58,040 --> 01:50:00,880 IN ILCs IN THE FAT, CALORIC 2418 01:50:00,880 --> 01:50:04,040 RESTRICTION, ANTI-AGING 2419 01:50:04,040 --> 01:50:06,160 INTERVENTION OR RAPAMYCIN OR GLP 2420 01:50:06,160 --> 01:50:06,400 AGONIST? 2421 01:50:06,400 --> 01:50:10,160 >>WE HAVEN'T DONE ANYTHING 2422 01:50:10,160 --> 01:50:11,360 MODERN. 2423 01:50:11,360 --> 01:50:12,360 WE'VE DONE CALORIC RESTRICTION. 2424 01:50:12,360 --> 01:50:16,080 AS A PIECE OF THE PIE THE ILC2S 2425 01:50:16,080 --> 01:50:17,600 ARE RETAINED IN CALORICALLY 2426 01:50:17,600 --> 01:50:20,680 RESTRICTED ANIMALS BUT THESE 2427 01:50:20,680 --> 01:50:21,480 MICE ARE LYMPHOPENIC, DEPENDS 2428 01:50:21,480 --> 01:50:22,320 WHAT'S IMPORTANT, DO YOU NEED 2429 01:50:22,320 --> 01:50:24,280 MORE CELLS OR TO BE A BIGGER 2430 01:50:24,280 --> 01:50:24,640 REPRESENTATION? 2431 01:50:24,640 --> 01:50:26,920 THEY SEEM LIKE THEY ARE 2432 01:50:26,920 --> 01:50:27,920 PRESERVED BUT THAT'S AS MUCH 2433 01:50:27,920 --> 01:50:29,800 CHARACTERIZATION AS WE DID. 2434 01:50:29,800 --> 01:50:32,280 YEAH, THANK YOU. 2435 01:50:32,280 --> 01:50:37,120 2436 01:50:37,120 --> 01:50:43,080 >> ONE LAST QUESTION. 2437 01:50:43,080 --> 01:50:45,560 >>UCSF. 2438 01:50:45,560 --> 01:50:48,280 SYMPATHETIC NERVOUS SYSTEM THAT 2439 01:50:48,280 --> 01:50:50,000 TISSUE IS INNOVATIVE, I WAS 2440 01:50:50,000 --> 01:50:52,960 WONDERING ABOUT LOCAL INFLUENCE. 2441 01:50:52,960 --> 01:50:53,840 >> YEAH, SO THERE'S BEEN A 2442 01:50:53,840 --> 01:50:56,160 LITTLE BIT OF WORK DONE ON THAT 2443 01:50:56,160 --> 01:51:00,640 WITH THESE CELLS IN PARTICULAR, 2444 01:51:00,640 --> 01:51:05,800 DAVID ARTIS' LAB LOOKED AT 2445 01:51:05,800 --> 01:51:08,840 NEUROIMMUNE INTERACTION, ALL THE 2446 01:51:08,840 --> 01:51:11,920 IMMUNE CELLS IN THE FAT ARE 2447 01:51:11,920 --> 01:51:13,440 ARRANGED NEAR THE VASCULATURE 2448 01:51:13,440 --> 01:51:15,840 WHICH TENDS TO CO-LOCALIZE WITH 2449 01:51:15,840 --> 01:51:16,960 THE SYMPATHETIC NERVOUS SYSTEM 2450 01:51:16,960 --> 01:51:18,400 SO THERE'S SOMETHING GOING ON 2451 01:51:18,400 --> 01:51:20,880 THERE BUT I DON'T KNOW THAT'S 2452 01:51:20,880 --> 01:51:24,040 BEEN LOOKED AT CAREFULLY AND WE 2453 01:51:24,040 --> 01:51:25,040 DIDN'T REALLY INVESTIGATE IT 2454 01:51:25,040 --> 01:51:26,360 DEEPLY IN THIS PROJECT. 2455 01:51:26,360 --> 01:51:28,360 I CAN'T REALLY ANSWER. 2456 01:51:28,360 --> 01:51:28,680 YEAH, THANKS. 2457 01:51:28,680 --> 01:51:30,840 >> MAYBE WE'LL BRING IT UP AT 2458 01:51:30,840 --> 01:51:36,000 THE END DURING GAPS OR 2459 01:51:36,000 --> 01:51:43,440 SOMETHING. 2460 01:51:43,440 --> 01:51:45,560 NEXT SPEAKER IS BERENICE 2461 01:51:45,560 --> 01:51:47,400 BENAYOUN, SO SORRY IF I 2462 01:51:47,400 --> 01:51:51,040 MISPRONOUNCE THESE BEAUTIFUL 2463 01:51:51,040 --> 01:51:55,000 NAMES. 2464 01:51:55,000 --> 01:51:58,080 SHE'S TALK FROM USC, TALKING 2465 01:51:58,080 --> 01:52:00,400 ABOUT NEUTROPHIL AGING 2466 01:52:00,400 --> 01:52:07,040 MECHANISMS, TISSUE PATHOLOGY AND 2467 01:52:07,040 --> 01:52:07,600 SEXUAL DIMORPHISM. 2468 01:52:07,600 --> 01:52:09,120 >> TODAY I'M GOING TO TELL YOU 2469 01:52:09,120 --> 01:52:17,320 ABOUT THE WORK WE'RE DOING ON 2470 01:52:17,320 --> 01:52:27,640 NEUTROPHILS WITH AGING. 2471 01:52:27,640 --> 01:52:29,920 THIS IS GOING TO BE PAINFUL. 2472 01:52:29,920 --> 01:52:36,280 MANY PEOPLE IN THE AGING FIELD 2473 01:52:36,280 --> 01:52:37,080 KNOW THERE'S BEEN A 2474 01:52:37,080 --> 01:52:38,400 DISPROPORTIONATE AMOUNT OF WORK 2475 01:52:38,400 --> 01:52:39,240 IN MALE ANIMALS SPECIFICALLY. 2476 01:52:39,240 --> 01:52:41,320 WHEN YOU TALK TO PEOPLE AND ASK 2477 01:52:41,320 --> 01:52:43,080 WHAT PUSHED THEM TO FOCUS ON 2478 01:52:43,080 --> 01:52:46,480 MALES YOU GET A LOT OF 2479 01:52:46,480 --> 01:52:48,320 EXPLANATION LIKE TOO EXPENSIVE 2480 01:52:48,320 --> 01:52:51,520 TO DO BOTH SEXES, FEMALE DATA IS 2481 01:52:51,520 --> 01:52:56,640 TOO NOISY. 2482 01:52:56,640 --> 01:53:00,040 AND MY FAVORITE 2483 01:53:00,040 --> 01:53:00,800 [AUDIO DISTORTION] 2484 01:53:00,800 --> 01:53:05,960 THAT MEANS WE HAVE A VERY, VERY 2485 01:53:05,960 --> 01:53:07,360 LIMITED SORT OF SITUATION, 2486 01:53:07,360 --> 01:53:08,680 DIFFERENCE BETWEEN FEMALES AND 2487 01:53:08,680 --> 01:53:10,640 MALES IN AGING. 2488 01:53:10,640 --> 01:53:11,040 NEXT. 2489 01:53:11,040 --> 01:53:12,280 REALLY IMPORTANT BECAUSE IF WE 2490 01:53:12,280 --> 01:53:14,800 LOOK AT THE FANTASTIC WORK DONE 2491 01:53:14,800 --> 01:53:16,880 BY THE NIH INTERVENTION TESTING 2492 01:53:16,880 --> 01:53:22,320 PROGRAM WHAT WE KNOW IS THAT 2493 01:53:22,320 --> 01:53:23,880 APPARENTLY -- APPARENTLY PEOPLE 2494 01:53:23,880 --> 01:53:25,400 AREN'T HEARING ME? 2495 01:53:25,400 --> 01:53:27,800 WHAT WE KNOW IS OF ALL OF THE 2496 01:53:27,800 --> 01:53:29,920 INTERVENTIONS THAT HAVE BEEN 2497 01:53:29,920 --> 01:53:33,400 SHOWN TO WORK TO IMPROVE HEALTH 2498 01:53:33,400 --> 01:53:34,800 AND LIFESPAN IN MICE BASICALLY 2499 01:53:34,800 --> 01:53:35,920 THERE'S NOT A SINGLE 2500 01:53:35,920 --> 01:53:37,440 INTERVENTION THAT WORKS THE SAME 2501 01:53:37,440 --> 01:53:39,400 IN FEMALES AND MALES, BUT 2502 01:53:39,400 --> 01:53:42,360 MAJORITY EITHER WORK IN ONLY ONE 2503 01:53:42,360 --> 01:53:43,360 SEX OR WORKING MUCH BETTER IN 2504 01:53:43,360 --> 01:53:45,960 ONE SEX THAN THE OTHER. 2505 01:53:45,960 --> 01:53:46,320 NEXT. 2506 01:53:46,320 --> 01:53:49,920 AND WE ALSO KNOW IN HUMANS JUST 2507 01:53:49,920 --> 01:53:52,320 FROM OBSERVATIONAL DATA THAT 2508 01:53:52,320 --> 01:53:54,440 AGE-RELATED DISEASES SKYROCKET 2509 01:53:54,440 --> 01:53:54,960 AFTER MENOPAUSE, REALLY 2510 01:53:54,960 --> 01:53:56,600 SUGGESTING THAT SEX IS SOMETHING 2511 01:53:56,600 --> 01:53:58,280 WE NEED TO TAKE INTO ACCOUNT FOR 2512 01:53:58,280 --> 01:54:00,640 THE STUDY OF AGING. 2513 01:54:00,640 --> 01:54:00,840 NEXT. 2514 01:54:00,840 --> 01:54:02,720 WHEN WE THINK OF LEVEL OF GENE 2515 01:54:02,720 --> 01:54:07,760 REGULATION THIS IS ALL THE MORE 2516 01:54:07,760 --> 01:54:08,360 IMPORTANT. 2517 01:54:08,360 --> 01:54:11,280 LARGE CONSORTIUM EFFORTS LIKE 2518 01:54:11,280 --> 01:54:12,920 NIH ROADMAP SHOW GENE REGULATION 2519 01:54:12,920 --> 01:54:13,920 PATTERNS ARE EXTREMELY DIFFERENT 2520 01:54:13,920 --> 01:54:18,400 IN MALE AND FEMALE CELLS AND 2521 01:54:18,400 --> 01:54:18,640 TISSUE. 2522 01:54:18,640 --> 01:54:18,960 NEXT. 2523 01:54:18,960 --> 01:54:20,680 AND IN THE IMMUNE COMPARTMENT 2524 01:54:20,680 --> 01:54:23,560 ITSELF THIS IS A 2525 01:54:23,560 --> 01:54:27,680 WELL-ESTABLISHED FACT THAT 2526 01:54:27,680 --> 01:54:29,680 AUTOIMMUNE DISEASE ARE MORE 2527 01:54:29,680 --> 01:54:32,520 FREQUENT IN WOMEN, SEPSIS MUCH 2528 01:54:32,520 --> 01:54:34,280 WORSE IN MEN, SUGGESTING A HUGE 2529 01:54:34,280 --> 01:54:37,000 GAP AND HUGE OPPORTUNITY TO 2530 01:54:37,000 --> 01:54:38,400 UNDERSTAND IMPORTANT THINGS 2531 01:54:38,400 --> 01:54:39,200 THERE. 2532 01:54:39,200 --> 01:54:39,400 NEXT. 2533 01:54:39,400 --> 01:54:41,920 AND SO I'M GOING TO SHOW WORK OF 2534 01:54:41,920 --> 01:54:43,800 SOME FANTASTIC PEOPLE IN MY LAB, 2535 01:54:43,800 --> 01:54:48,000 I'LL INTRODUCE THEM. 2536 01:54:48,000 --> 01:54:49,560 RYAN LU, GRAD OPPORTUNITY ON 2537 01:54:49,560 --> 01:54:54,840 MIGHT ROW FILLS WITH HELP OF MIN 2538 01:54:54,840 --> 01:54:55,920 HOO KIM AND CLAYTON BAKER JOINED 2539 01:54:55,920 --> 01:54:59,080 THE LAB TO HELP DO THE WORK. 2540 01:54:59,080 --> 01:55:00,280 IN THIS AUDIENCE I'M SURE I 2541 01:55:00,280 --> 01:55:02,280 DON'T NEED TO EXPLAIN WHY 2542 01:55:02,280 --> 01:55:03,200 NEUTROPHILS ARE SUPER COOL BUT 2543 01:55:03,200 --> 01:55:04,040 I'M STILL GOING TO DO IT A 2544 01:55:04,040 --> 01:55:04,920 LITTLE BIT. 2545 01:55:04,920 --> 01:55:08,160 THEY ARE THE MOST ABUNDANT WHITE 2546 01:55:08,160 --> 01:55:10,480 BLOOD CELL IN HUMANS, 50 TO 70% 2547 01:55:10,480 --> 01:55:13,440 OF CIRCULATING WHITE BLOOD 2548 01:55:13,440 --> 01:55:15,160 CELLS, SHORT-LIVED. 2549 01:55:15,160 --> 01:55:15,800 NEXT. 2550 01:55:15,800 --> 01:55:17,600 WITH THE MAJORITY OF THEM HAVING 2551 01:55:17,600 --> 01:55:21,520 ABOUT 12 HOURS AFTER TERMINAL 2552 01:55:21,520 --> 01:55:22,160 DIFFERENTIATION, ALTHOUGH SOME 2553 01:55:22,160 --> 01:55:23,600 CAN SURVIVE LONGER IN TISSUES. 2554 01:55:23,600 --> 01:55:25,320 AND THEY ARE REALLY IMPORTANT AS 2555 01:55:25,320 --> 01:55:29,240 A FIRST LINE OF DEFENSE FOR 2556 01:55:29,240 --> 01:55:30,320 INFECTION. 2557 01:55:30,320 --> 01:55:33,000 NEXT. 2558 01:55:33,000 --> 01:55:36,600 NOTABLY THROUGH A MECHANISM 2559 01:55:36,600 --> 01:55:40,760 WHERE THEY CAN EXPEL TO TRAP 2560 01:55:40,760 --> 01:55:42,760 PATHOGENS BASICALLY AND HELP 2561 01:55:42,760 --> 01:55:44,600 KICK START IMMUNE RESPONSE. 2562 01:55:44,600 --> 01:55:47,400 THE PROBLEM IS THOSE 2563 01:55:47,400 --> 01:55:48,640 EXTRACELLULAR TRAPS, IF THERE 2564 01:55:48,640 --> 01:55:50,720 ARE TOO MANY OR IF THEY ARE FOR 2565 01:55:50,720 --> 01:55:53,600 NO GOOD REASON CAN FUEL 2566 01:55:53,600 --> 01:55:55,640 INFLAMMATORY DISEASE, A LOT OF 2567 01:55:55,640 --> 01:55:57,840 REASONS TO BELIEVE NEUTROPHILS 2568 01:55:57,840 --> 01:55:59,720 WILL HAVE IMPORTANT IMPLICATION 2569 01:55:59,720 --> 01:56:02,560 IN AGE-RELATED INFLAMMATION. 2570 01:56:02,560 --> 01:56:03,000 NEXT. 2571 01:56:03,000 --> 01:56:06,080 BECAUSE OF THAT WE DECIDED TO 2572 01:56:06,080 --> 01:56:07,080 SEE, OKAY, THERE'S NOT MUCH 2573 01:56:07,080 --> 01:56:10,240 KNOWN AS A MATTER OF SEX AND AGE 2574 01:56:10,240 --> 01:56:11,120 IN NEUTROPHILS, SO WE'RE GOING 2575 01:56:11,120 --> 01:56:15,640 TO TAKE ADVANTAGE OF THE 2576 01:56:15,640 --> 01:56:19,000 FANTASTIC RESOURCES AND TRY TO 2577 01:56:19,000 --> 01:56:21,840 UNDERSTAND WHAT'S GOING ON BY 2578 01:56:21,840 --> 01:56:23,600 USING MULTIOMIC APPROACH. 2579 01:56:23,600 --> 01:56:25,240 SO WE'RE USING OBVIOUSLY FEMALE 2580 01:56:25,240 --> 01:56:27,640 AND MALES, AND WE'RE LOOKING AT 2581 01:56:27,640 --> 01:56:29,200 YOUNG MICE, USING HORMONES 2582 01:56:29,200 --> 01:56:31,400 BECAUSE THAT'S WHEN A STRESS 2583 01:56:31,400 --> 01:56:33,120 CYCLE IS STABILIZED, THIS 2584 01:56:33,120 --> 01:56:39,120 CORRESPONDS TO REAL LIKE 2585 01:56:39,120 --> 01:56:46,120 REPRODUCTIVE STABLE ADULTS, AND 2586 01:56:46,120 --> 01:56:49,320 20 MONTH OLD ANIMALS, BECAUSE 2587 01:56:49,320 --> 01:56:54,280 THERE'S AN EXPLOSION OF 24 2588 01:56:54,280 --> 01:56:55,560 MONTHS, MODELING HORMONE DEFECT 2589 01:56:55,560 --> 01:56:56,160 SIGNALING. 2590 01:56:56,160 --> 01:56:57,120 THERE'S NOT MUCH BLOOD IN THE 2591 01:56:57,120 --> 01:56:57,440 MOUSE. 2592 01:56:57,440 --> 01:57:00,240 WENT TO THE MOST ABUNDANT SOURCE 2593 01:57:00,240 --> 01:57:03,840 OF NEUTROPHILS IN THE BONE 2594 01:57:03,840 --> 01:57:04,240 MARROW. 2595 01:57:04,240 --> 01:57:05,040 NEXT. 2596 01:57:05,040 --> 01:57:09,160 PERFORMED A THREE PRONGED 2597 01:57:09,160 --> 01:57:15,200 PROFILING USING TRANSCRIPTOMICS, 2598 01:57:15,200 --> 01:57:16,280 METABOLOMICS, LIPIDOMICS. 2599 01:57:16,280 --> 01:57:19,640 WE DIDN'T KNOW WHAT TO EXPECT. 2600 01:57:19,640 --> 01:57:24,360 BUT WE WERE REALLY IMPRESSED 2601 01:57:24,360 --> 01:57:25,640 SEEING -- THAT RESONATES WITH 2602 01:57:25,640 --> 01:57:28,760 WHAT I TOLD YOU, BUT THE BIGGEST 2603 01:57:28,760 --> 01:57:31,200 SOURCE OF SEPARATION BETWEEN ANY 2604 01:57:31,200 --> 01:57:33,840 SAMPLES, THIS IS HERE IN 2605 01:57:33,840 --> 01:57:34,720 MULTI-DIMENSIONAL SCALING SPACE, 2606 01:57:34,720 --> 01:57:37,440 WAS BETWEEN FEMALES AND MALES 2607 01:57:37,440 --> 01:57:40,440 AND NOT REALLY YOUNG AND OLD 2608 01:57:40,440 --> 01:57:40,760 SAMPLES. 2609 01:57:40,760 --> 01:57:43,480 THIS IS TRANSCRIPTOMIC LEVEL. 2610 01:57:43,480 --> 01:57:43,680 NEXT. 2611 01:57:43,680 --> 01:57:44,880 AND NEXT ACTUALLY. 2612 01:57:44,880 --> 01:57:49,840 BUT WE ALSO SAW A HUGE 2613 01:57:49,840 --> 01:57:51,120 SEPARATION BY METABOLOMICS AND 2614 01:57:51,120 --> 01:57:54,880 LIPIDOMIC LEVEL, NOT EVEN A 2615 01:57:54,880 --> 01:57:57,400 SECONDARY SEPARATION BY AGE 2616 01:57:57,400 --> 01:57:58,280 THERE. 2617 01:57:58,280 --> 01:58:03,160 NEXT THREE TIMES. 2618 01:58:03,160 --> 01:58:04,560 WE CONSISTENTLY SAW GENES AND 2619 01:58:04,560 --> 01:58:06,240 GENES REGULATED AS A FUNCTION OF 2620 01:58:06,240 --> 01:58:09,280 AGING AND SEX WITH AGE. 2621 01:58:09,280 --> 01:58:10,440 IN RNAseq. 2622 01:58:10,440 --> 01:58:14,440 BUT ONLY METABOLITES AND LIPIDS 2623 01:58:14,440 --> 01:58:16,440 REGULATED AS A FUNCTION. 2624 01:58:16,440 --> 01:58:18,840 FOR INTEREST OF TIME I'LL FOCUS 2625 01:58:18,840 --> 01:58:22,200 ON THE AGE AND SEX RELATIONSHIP 2626 01:58:22,200 --> 01:58:23,200 AND TRANSCRIPTOME. 2627 01:58:23,200 --> 01:58:23,520 NEXT. 2628 01:58:23,520 --> 01:58:25,320 SO ONE THING I WANT TO SAY 2629 01:58:25,320 --> 01:58:27,120 BECAUSE, AGAIN, I KNOW WHEN I'M 2630 01:58:27,120 --> 01:58:30,760 TALKING TO IMMUNOLOGISTS THE 2631 01:58:30,760 --> 01:58:31,400 ISSUE IS UNDERLYING 2632 01:58:31,400 --> 01:58:32,960 HETEROGENEITY, ONE THING WE'VE 2633 01:58:32,960 --> 01:58:35,760 BEEN DOING IS OPTIMIZING RNA 2634 01:58:35,760 --> 01:58:37,200 SINGLE CELL Seq ON 2635 01:58:37,200 --> 01:58:39,720 NEUTROPHILS, A PAIN TO WORK ON 2636 01:58:39,720 --> 01:58:42,160 FOR THIS SPECIFIC THING, WE HAD 2637 01:58:42,160 --> 01:58:43,240 TO OPTIMIZE PROTOCOL. 2638 01:58:43,240 --> 01:58:45,240 BUT THE NICE THING, NEXT AND 2639 01:58:45,240 --> 01:58:48,720 NEXT, WE WERE ABLE TO -- THESE 2640 01:58:48,720 --> 01:58:52,480 ARE YOUNG ANIMALS, ABLE TO DO 2641 01:58:52,480 --> 01:58:56,160 SINGLE CELL RNAseq, IDENTIFY 2642 01:58:56,160 --> 01:59:01,000 PRE-DETERMINED SORT OF DEFINED 2643 01:59:01,000 --> 01:59:01,760 DIFFERENTIATION IN OUR 2644 01:59:01,760 --> 01:59:06,920 POPULATION, RECOMMENDED BY 2645 01:59:06,920 --> 01:59:15,440 PROBING, SEEING SEX DIFFERENCE. 2646 01:59:15,440 --> 01:59:17,720 WHEN YOU SIGH BIG DIFFERENCES IN 2647 01:59:17,720 --> 01:59:19,200 THE BASAL STATE, THE QUESTION 2648 01:59:19,200 --> 01:59:20,720 IS, WELL, ARE THEY STILL GOING 2649 01:59:20,720 --> 01:59:23,480 TO AGE THE SAME OR ALSO GOING TO 2650 01:59:23,480 --> 01:59:24,520 AGE DIFFERENTLY? 2651 01:59:24,520 --> 01:59:26,960 AND SO HERE ON THE X-AXIS I'M 2652 01:59:26,960 --> 01:59:29,120 SHOWING TO YOU THE RATE OF 2653 01:59:29,120 --> 01:59:31,560 CHANGE IN GENE EXPRESSION IN 2654 01:59:31,560 --> 01:59:32,640 FEMALE NEUTROPHILS, ON THE 2655 01:59:32,640 --> 01:59:34,640 Y-AXIS IN THE MALE NEUTROPHILS. 2656 01:59:34,640 --> 01:59:36,360 AND OBVIOUSLY THE CORRELATION IS 2657 01:59:36,360 --> 01:59:38,240 NOT PERFECT BUT IT'S PRETTY 2658 01:59:38,240 --> 01:59:38,440 GOOD. 2659 01:59:38,440 --> 01:59:40,200 SO GOOD THAT THE COMPUTER CAN'T 2660 01:59:40,200 --> 01:59:42,760 GIVE US AN ACTUAL P-VALUE 2661 01:59:42,760 --> 01:59:45,360 SUGGESTING THAT THERE'S A PRETTY 2662 01:59:45,360 --> 01:59:46,960 GOOD CORRELATION BETWEEN THE 2663 01:59:46,960 --> 01:59:50,480 TRAJECTORIES OF AGING IN THE 2664 01:59:50,480 --> 01:59:53,240 FEMALES, NEXT PLEASE, AND 2665 01:59:53,240 --> 01:59:54,680 FEMALES AND MALE NEUTROPHILS. 2666 01:59:54,680 --> 01:59:56,280 THAT BEING SAID, IF WE THEN 2667 01:59:56,280 --> 01:59:57,640 FOCUS ON THINGS THAT ARE 2668 01:59:57,640 --> 01:59:58,920 SIGNIFICANT WITH AGE IN ONE SEX 2669 01:59:58,920 --> 02:00:01,240 AND NOT THE OTHER WE SEE HERE IN 2670 02:00:01,240 --> 02:00:02,520 THIS SPECIFIC CASE IT'S 2671 02:00:02,520 --> 02:00:03,960 DIFFERENT IN OTHER CELL TYPES 2672 02:00:03,960 --> 02:00:05,400 WE'VE LOOKED AT. 2673 02:00:05,400 --> 02:00:06,720 A LOT MORE AGE-RELATED CHANGES 2674 02:00:06,720 --> 02:00:08,520 IN THE MALES THAN THE FEMALES. 2675 02:00:08,520 --> 02:00:10,320 BUT IF YOU LOOK AT THEM, IT'S 2676 02:00:10,320 --> 02:00:12,960 MORE LIKE THIS SLOPE HAS BEEN 2677 02:00:12,960 --> 02:00:15,160 INCREASED SUGGESTING MAYBE AN 2678 02:00:15,160 --> 02:00:20,720 ACCELERATION AT TRANSCRIPTIONAL 2679 02:00:20,720 --> 02:00:21,000 LEVEL. 2680 02:00:21,000 --> 02:00:24,080 AT THAT POINT WE WONDERED WHAT 2681 02:00:24,080 --> 02:00:26,960 FUNCTIONS WERE REGULATED AS A 2682 02:00:26,960 --> 02:00:31,680 FUNCTION OF AGE AND SEX IN 2683 02:00:31,680 --> 02:00:36,480 NEUTROPHILS OMIC LANDSCAPES. 2684 02:00:36,480 --> 02:00:40,720 WE PERFORMED -- THERE'S A LOT OF 2685 02:00:40,720 --> 02:00:41,520 ANIMATION. 2686 02:00:41,520 --> 02:00:46,240 AND SO THESE ARE THE TOP TEN 2687 02:00:46,240 --> 02:00:47,000 PATHWAYS UPREGULATED AND 2688 02:00:47,000 --> 02:00:48,640 DOWNREGULATED IN THIS CASE WITH 2689 02:00:48,640 --> 02:00:50,600 AGE BECAUSE WE HAD A GOOD 2690 02:00:50,600 --> 02:00:52,160 CORRELATION BETWEEN SEXES, WE 2691 02:00:52,160 --> 02:00:54,120 CAN REGRESS OUT EFFECTS OF SEX 2692 02:00:54,120 --> 02:00:55,000 IN THIS CASE. 2693 02:00:55,000 --> 02:00:56,600 AND SO THERE'S SOME THINGS 2694 02:00:56,600 --> 02:00:58,840 HAPPENING ON THE UPREGULATION 2695 02:00:58,840 --> 02:01:00,960 SIDE, NOTHING TOO EXCITING, BUT, 2696 02:01:00,960 --> 02:01:03,560 NEXT, WE THOUGHT WHAT WAS REALLY 2697 02:01:03,560 --> 02:01:05,760 INTERESTING IS THE PREPONDERANCE 2698 02:01:05,760 --> 02:01:07,840 OF CELL CYCLE AND CHROMATIN 2699 02:01:07,840 --> 02:01:08,640 RELATED TERMS IN DOWNREGULATED 2700 02:01:08,640 --> 02:01:09,920 SIDE OF THINGS. 2701 02:01:09,920 --> 02:01:12,960 FOR THOSE WONDERING, WE HAVE 2702 02:01:12,960 --> 02:01:13,720 CHECKED NEUTROPHILS, NOT 2703 02:01:13,720 --> 02:01:15,520 PROLIFERATING, WE THINK THIS HAS 2704 02:01:15,520 --> 02:01:18,000 TO DO WITH ACTUALLY MITOSIS 2705 02:01:18,000 --> 02:01:19,360 REGULATION SHOWN TO CAUSE A LOT 2706 02:01:19,360 --> 02:01:22,080 OF CELL CYCLE MACHINERY. 2707 02:01:22,080 --> 02:01:22,360 NEXT. 2708 02:01:22,360 --> 02:01:23,920 WE DO THE SAME ANALYSIS LOOKING 2709 02:01:23,920 --> 02:01:26,440 AT WHAT'S GOING ON WITH SEX. 2710 02:01:26,440 --> 02:01:27,400 NEXT. 2711 02:01:27,400 --> 02:01:29,400 AND YOU CAN SEE ON THE FEMALE 2712 02:01:29,400 --> 02:01:32,800 SIDE OF THINGS THERE'S, AGAIN, 2713 02:01:32,800 --> 02:01:34,280 ENRICHMENTS, NOTHING TOO 2714 02:01:34,280 --> 02:01:34,840 EXCITING. 2715 02:01:34,840 --> 02:01:35,720 MIGHT BE INTERFERON GAMMA 2716 02:01:35,720 --> 02:01:37,160 SIGNALING WHICH WE HAVE IDEAS 2717 02:01:37,160 --> 02:01:37,840 THAT IS. 2718 02:01:37,840 --> 02:01:41,880 BUT ON THE MALE SIDE OF THINGS 2719 02:01:41,880 --> 02:01:44,600 WE HAVE THIS ENRICHMENT. 2720 02:01:44,600 --> 02:01:45,080 NEXT. 2721 02:01:45,080 --> 02:01:48,080 FOR CELL CYCLE, AND 2722 02:01:48,080 --> 02:01:49,000 CHROMATIN-RELATED GENES. 2723 02:01:49,000 --> 02:01:52,160 AND SO AT THIS POINT, NEXT, 2724 02:01:52,160 --> 02:01:53,560 NEXT, WE WONDERED WHETHER THOSE 2725 02:01:53,560 --> 02:01:55,560 CHANGES WE HAVE SEEN WOULD HAVE 2726 02:01:55,560 --> 02:01:57,640 FUNCTIONAL IMPACT. 2727 02:01:57,640 --> 02:02:05,720 BECAUSE WE SAW UNIQUE ROLE OF 2728 02:02:05,720 --> 02:02:10,120 CHROMATIN AND NEUTROPHILS MIGHT 2729 02:02:10,120 --> 02:02:14,280 BE RELATED TO MITOSIS, 2730 02:02:14,280 --> 02:02:16,120 UPREGULATED PROTOCOL TO MEASURE. 2731 02:02:16,120 --> 02:02:20,920 AND SO THIS IS A CAUTIONARY TALE 2732 02:02:20,920 --> 02:02:22,720 BASED ON OMICS, BECAUSE EVEN 2733 02:02:22,720 --> 02:02:24,560 THOUGH AT THE TRANSCRIPTIONAL 2734 02:02:24,560 --> 02:02:28,360 LEVEL THINGS SEEM TO BE 2735 02:02:28,360 --> 02:02:30,800 INTERACTING LINEARLY, WHAT WE 2736 02:02:30,800 --> 02:02:35,040 OBSERVED WAS CLEAR INCREASE IN 2737 02:02:35,040 --> 02:02:36,480 NETosis CAPACITY OF FEMALES 2738 02:02:36,480 --> 02:02:39,400 WITH AGE BUT IN MALE NEUTROPHILS 2739 02:02:39,400 --> 02:02:42,400 THERE'S NOT REALLY MUCH GOING ON 2740 02:02:42,400 --> 02:02:42,600 THERE. 2741 02:02:42,600 --> 02:02:46,080 BUT THAT SHOWS WE HAVE SOME 2742 02:02:46,080 --> 02:02:49,200 POTENTIAL IMPACT HERE OF 2743 02:02:49,200 --> 02:02:51,800 INTERACTION, EFFECT AND AGE. 2744 02:02:51,800 --> 02:02:53,320 NEXT. 2745 02:02:53,320 --> 02:02:55,920 AND SO ANYTIME YOU SEE SEX 2746 02:02:55,920 --> 02:02:57,040 DIFFERENCES, MY LAB IS 2747 02:02:57,040 --> 02:02:58,920 INTERESTED IN GENERAL, YOU 2748 02:02:58,920 --> 02:03:01,600 WONDER WHAT DRIVES DIFFERENCES. 2749 02:03:01,600 --> 02:03:01,800 NEXT. 2750 02:03:01,800 --> 02:03:04,160 AND IF I TAKE YOU BACK TO VERY 2751 02:03:04,160 --> 02:03:05,680 LONG TIME AGO IN YOUR BIOLOGY 2752 02:03:05,680 --> 02:03:07,320 CLASSES THERE CAN BE TWO THINGS 2753 02:03:07,320 --> 02:03:10,040 BASICALLY THAT ARE RELATED TO 2754 02:03:10,040 --> 02:03:12,160 SEX DIFFERENCES. 2755 02:03:12,160 --> 02:03:16,520 ONE OF THEM, NEXT, BEING GONADAL 2756 02:03:16,520 --> 02:03:20,880 HORMONES, FEMALES ARE HIGHER 2757 02:03:20,880 --> 02:03:24,200 LEVELS OF ESTROGEN, MALES HIGHER 2758 02:03:24,200 --> 02:03:26,480 LEVELS OF ANDROGEN, THOSE ARE 2759 02:03:26,480 --> 02:03:29,120 NORMALLY RELATED, FEMALES ARE 2760 02:03:29,120 --> 02:03:30,840 GENETICALLY XX, AND MALES ARE 2761 02:03:30,840 --> 02:03:31,160 XY. 2762 02:03:31,160 --> 02:03:36,560 ALL OF THOSE CAN LEAD TO, NEXT, 2763 02:03:36,560 --> 02:03:38,720 REGULATORY DIFFERENCES BECAUSE 2764 02:03:38,720 --> 02:03:40,720 SEX HORMONE RECEPTORS, NEXT, CAN 2765 02:03:40,720 --> 02:03:42,240 ACT AS TRANSCRIPTION FACTORS AND 2766 02:03:42,240 --> 02:03:44,680 HAVE HUGE IMPACT EVEN IN SOMATIC 2767 02:03:44,680 --> 02:03:45,200 CELLS. 2768 02:03:45,200 --> 02:03:47,720 AND THERE ARE A NUMBER OF REALLY 2769 02:03:47,720 --> 02:03:49,600 IMPORTANT CHROMATIN REGULATORS 2770 02:03:49,600 --> 02:03:51,880 AND RNA PROCESSING PROTEINS 2771 02:03:51,880 --> 02:03:53,680 ENCODED ON X AND Y, AND THAT ARE 2772 02:03:53,680 --> 02:03:56,680 NOT EXPRESSED AT THE SAME DOSES 2773 02:03:56,680 --> 02:04:01,320 IN FEMALE AND MALE CELLS. 2774 02:04:01,320 --> 02:04:01,520 NEXT. 2775 02:04:01,520 --> 02:04:03,720 THE REALLY -- BACK. 2776 02:04:03,720 --> 02:04:04,480 THE REALLY INTERESTING THING A 2777 02:04:04,480 --> 02:04:07,960 LOT OF PEOPLE DON'T KNOW IS THAT 2778 02:04:07,960 --> 02:04:10,480 SEX HORMONES HAVE TWO WINDOWS OF 2779 02:04:10,480 --> 02:04:10,800 ACTION. 2780 02:04:10,800 --> 02:04:13,200 ONE IS IN UTERO DURING 2781 02:04:13,200 --> 02:04:16,600 DEVELOPMENT, ONE IS AFTER 2782 02:04:16,600 --> 02:04:17,440 PUBERTY. 2783 02:04:17,440 --> 02:04:20,240 THOSE ARE CALLEDOAL VERSUS 2784 02:04:20,240 --> 02:04:22,040 ACTIVATIONAL EFFECT HORMONES AND 2785 02:04:22,040 --> 02:04:24,280 CAN HAVE COMPLETELY OPPOSITE 2786 02:04:24,280 --> 02:04:27,320 EFFECTS ON BIOLOGY, EXAMPLE 2787 02:04:27,320 --> 02:04:29,200 BEING ESTROGENS IN ALZHEIMER'S, 2788 02:04:29,200 --> 02:04:38,600 IN UTERO EXPOSURE INCREASES 2789 02:04:38,600 --> 02:04:39,920 LIFETIME RISK VERSUS POST 2790 02:04:39,920 --> 02:04:40,160 PUBERTY. 2791 02:04:40,160 --> 02:04:43,760 I WAS FAMILIAR WITH A MODEL THAT 2792 02:04:43,760 --> 02:04:44,960 COULD BE LEVERAGED, I'M NOT 2793 02:04:44,960 --> 02:04:46,800 GOING TO GIVE ALL OF THE REASONS 2794 02:04:46,800 --> 02:04:55,040 WHY IT WORKS BUT THERE'S A GENE 2795 02:04:55,040 --> 02:04:56,320 FOXL2, MASTER DETERMINATOR OF 2796 02:04:56,320 --> 02:04:57,280 OVARIAN FATE. 2797 02:04:57,280 --> 02:04:59,160 IN 2009 THEY SHOWED IF YOU LET 2798 02:04:59,160 --> 02:05:02,440 THE MICE DEVELOP NORMALLY, DO 2799 02:05:02,440 --> 02:05:08,040 THEIR THING, LET THEM BECOME 2800 02:05:08,040 --> 02:05:10,560 SEXUALLY MATURE, NEXT, INTUITION 2801 02:05:10,560 --> 02:05:12,840 FOXL2, EVERYONE IS NORMALLY 2802 02:05:12,840 --> 02:05:18,200 EXCEPT THE MICE, THE FEMALE MICE 2803 02:05:18,200 --> 02:05:20,520 THAT LOSE FOXL2 WITHIN TWO 2804 02:05:20,520 --> 02:05:21,160 WEEKS, GIVING ACTIVATIONAL 2805 02:05:21,160 --> 02:05:27,440 EFFECT, YOU GET A COMPLETE 2806 02:05:27,440 --> 02:05:28,240 REORGANIZATION OF OVARIAN 2807 02:05:28,240 --> 02:05:28,480 TISSUE. 2808 02:05:28,480 --> 02:05:32,680 WILD TYPE IS WHAT YOU EXPECT FOR 2809 02:05:32,680 --> 02:05:35,680 A YOUNG HEALTHY TWO TO THREE 2810 02:05:35,680 --> 02:05:40,720 MONTH OLD MICE, INDUCED KNOCKOUT 2811 02:05:40,720 --> 02:05:46,760 EMERGENCE OF TUBULARRIZED 2812 02:05:46,760 --> 02:05:47,760 STRUCTURES, YOU HAVE LEVELS OF 2813 02:05:47,760 --> 02:05:50,240 TESTOSTERONE IN MICE AND THIS IS 2814 02:05:50,240 --> 02:05:52,760 TWO WEEKS AFTER INDUCTION THAT 2815 02:05:52,760 --> 02:05:54,240 ARE NOW BASICALLY ALMOST 2816 02:05:54,240 --> 02:05:57,240 IDENTICAL TO THOSE OF THE MALE 2817 02:05:57,240 --> 02:05:57,560 LITTERMATES. 2818 02:05:57,560 --> 02:05:59,000 THE PROBLEM IS THAT THE LAST 2819 02:05:59,000 --> 02:06:02,360 AUTHOR ON THE PAPER WOULD NOT 2820 02:06:02,360 --> 02:06:03,040 SHARE THE MOUSE. 2821 02:06:03,040 --> 02:06:04,480 DON'T BE LIKE HIM WHEN YOU GROW 2822 02:06:04,480 --> 02:06:05,040 UP. 2823 02:06:05,040 --> 02:06:14,200 WE HAD TO REGENERATE THEM FROM 2824 02:06:14,200 --> 02:06:18,920 SCRATCH. 2825 02:06:18,920 --> 02:06:20,560 NEXT. 2826 02:06:20,560 --> 02:06:21,880 OKAY. 2827 02:06:21,880 --> 02:06:23,400 NEXT, NEXT. 2828 02:06:23,400 --> 02:06:30,760 BASICALLY WE'RE ABLE TO 2829 02:06:30,760 --> 02:06:31,840 RECAPITULATE HISTOLOGY, CAN SEE 2830 02:06:31,840 --> 02:06:36,320 GONAD AL MARKERS, WE SEE 2831 02:06:36,320 --> 02:06:36,640 TESTOSTERONE. 2832 02:06:36,640 --> 02:06:37,000 NEXT. 2833 02:06:37,000 --> 02:06:39,840 AND WE GOT NEUTROPHILS, JUST A 2834 02:06:39,840 --> 02:06:40,680 YOUNG COHORT. 2835 02:06:40,680 --> 02:06:43,880 IT TAKES TWO YEARS TO GET A 2836 02:06:43,880 --> 02:06:44,640 2-YEAR-OLD MOUSE. 2837 02:06:44,640 --> 02:06:44,840 NEXT. 2838 02:06:44,840 --> 02:06:47,520 WHEN WE DO RNAseq THE FIRST 2839 02:06:47,520 --> 02:06:49,760 THING WE SEE, WE CAN REPRODUCE 2840 02:06:49,760 --> 02:06:53,080 OUR OWN RESULTS, FEMALE AND MALE 2841 02:06:53,080 --> 02:06:55,600 NEUTROPHILS SEPARATE NICELY BUT 2842 02:06:55,600 --> 02:06:57,600 NOW THE NEUTROPHILS ISOLATED 2843 02:06:57,600 --> 02:06:59,840 FROM SEX REVERSE MICE ARE IN 2844 02:06:59,840 --> 02:07:00,640 PURPLE, BASICALLY OVERLAPPING 2845 02:07:00,640 --> 02:07:02,800 WITH THE MALE ONES. 2846 02:07:02,800 --> 02:07:03,200 NEXT. 2847 02:07:03,200 --> 02:07:05,560 AND IF WE COMPARE AGAIN LIKE THE 2848 02:07:05,560 --> 02:07:08,840 CHANGE IN GENE EXPRESSION AND 2849 02:07:08,840 --> 02:07:12,680 CONTROLS XY VERSUS XX COMPARED 2850 02:07:12,680 --> 02:07:14,080 TO KNOCKOUTS VERSUS CONTROLS 2851 02:07:14,080 --> 02:07:17,480 THERE'S A NICE CORRELATION. 2852 02:07:17,480 --> 02:07:17,720 NEXT. 2853 02:07:17,720 --> 02:07:22,840 AND NEXT. 2854 02:07:22,840 --> 02:07:30,400 WHEN WE PERFORMED DSC WE CAN SE 2855 02:07:30,400 --> 02:07:30,760 UPREGULATION. 2856 02:07:30,760 --> 02:07:32,480 SKIP THE NEXT SLIDE BECAUSE OF 2857 02:07:32,480 --> 02:07:32,800 TIME. 2858 02:07:32,800 --> 02:07:36,960 STARTING TO DO SINGLE CELL ON 2859 02:07:36,960 --> 02:07:37,400 THIS. 2860 02:07:37,400 --> 02:07:40,440 BASICALLY WE SEE THAT NEUTROPHIL 2861 02:07:40,440 --> 02:07:42,440 BIOLOGY IS SEX DIMORPHIC, SHOW 2862 02:07:42,440 --> 02:07:43,880 THE ENTIRE SLIDE. 2863 02:07:43,880 --> 02:07:45,600 IF YOU'RE INTERESTED ABOUT WHAT 2864 02:07:45,600 --> 02:07:47,760 WE'VE ALREADY DONE ON JUST AGING 2865 02:07:47,760 --> 02:07:49,760 AND SEX, THIS IS PUBLISHED, 2866 02:07:49,760 --> 02:07:51,640 WE'RE INTERESTED IN THOSE 2867 02:07:51,640 --> 02:07:53,280 HORMONAL VERSUS GENETIC DRIVERS 2868 02:07:53,280 --> 02:07:54,920 OF SEX DIFFERENCES. 2869 02:07:54,920 --> 02:07:55,160 NEXT. 2870 02:07:55,160 --> 02:07:57,560 AND SO REALLY THAT'S ONE OF THE 2871 02:07:57,560 --> 02:07:58,760 BIG CHALLENGES HERE IS 2872 02:07:58,760 --> 02:08:01,480 UNDERSTANDING SEX IS NOT JUST AN 2873 02:08:01,480 --> 02:08:02,560 ANNOYING CONFOUND, YOU NEED TO 2874 02:08:02,560 --> 02:08:05,080 DEAL WITH, BECAUSE NIH ASKED YOU 2875 02:08:05,080 --> 02:08:06,600 TO BUT IT'S BIOLOGICALLY 2876 02:08:06,600 --> 02:08:08,920 RELEVANT AND IMPORTANT AND WITH 2877 02:08:08,920 --> 02:08:11,080 TRANSLATIONAL POTENTIAL WHEN 2878 02:08:11,080 --> 02:08:12,840 WE'RE TALKING ABOUT, YOU KNOW, 2879 02:08:12,840 --> 02:08:14,400 PERSONALIZED MEDICINE AND THINGS 2880 02:08:14,400 --> 02:08:14,680 LIKE THIS. 2881 02:08:14,680 --> 02:08:20,320 SO CAN YOU SKIP TO MY 2882 02:08:20,320 --> 02:08:21,000 ACKNOWLEDGMENT SLIDE PLEASE. 2883 02:08:21,000 --> 02:08:23,840 I WANT TO THANK THE PEOPLE WHO 2884 02:08:23,840 --> 02:08:31,040 HAVE DONE THE WORK, FANTASTIC 2885 02:08:31,040 --> 02:08:31,360 COLLABORATORS. 2886 02:08:31,360 --> 02:08:33,440 AND OBVIOUSLY THE SOURCES OF 2887 02:08:33,440 --> 02:08:35,080 FUNDING WITHOUT WHOM WE WOULDN'T 2888 02:08:35,080 --> 02:08:35,960 DO THIS WORK. 2889 02:08:35,960 --> 02:08:36,760 >> THANK YOU. 2890 02:08:36,760 --> 02:08:39,920 THAT WAS JUST GREAT. 2891 02:08:39,920 --> 02:08:42,960 USC HAS A REALLY GOOD PERSON IN 2892 02:08:42,960 --> 02:08:44,720 YOU. 2893 02:08:44,720 --> 02:08:49,080 WE HAVE A COUPLE MINUTES FOR 2894 02:08:49,080 --> 02:08:51,480 QUESTIONS. 2895 02:08:51,480 --> 02:08:53,560 THERE'S A QUESTION ONLINE. 2896 02:08:53,560 --> 02:08:55,200 TO WHAT EXTENT DAWES SEXUAL 2897 02:08:55,200 --> 02:08:59,320 DIMORPH NICHE IN RODENTS MIRROR 2898 02:08:59,320 --> 02:09:04,200 SEXUAL DIMORPHISM IN HUMANS. 2899 02:09:04,200 --> 02:09:06,520 >> CLOSE MOLECULARLY BECAUSE 2900 02:09:06,520 --> 02:09:09,360 BROAD EXPRESSION OF SEX HORMONE 2901 02:09:09,360 --> 02:09:12,080 RECEPTORS IS RECAPITULATED 2902 02:09:12,080 --> 02:09:13,640 PERFECTLY. 2903 02:09:13,640 --> 02:09:15,240 AND ALTHOUGH THE EXTENT OF 2904 02:09:15,240 --> 02:09:16,720 CHROMATIN INACTIVATION IS NOT 2905 02:09:16,720 --> 02:09:19,200 EXACTLY THE SAME A LOT OF 2906 02:09:19,200 --> 02:09:19,840 FUNDAMENTAL MECHANISMS ARE GOING 2907 02:09:19,840 --> 02:09:23,640 TO BE CONSERVED. 2908 02:09:23,640 --> 02:09:25,640 IT'S NOT AS IF PEOPLE ARE 2909 02:09:25,640 --> 02:09:27,840 RUSHING TO UNDERSTAND SEX 2910 02:09:27,840 --> 02:09:29,240 DIFFERENCES IN HUMANS, WE HAVE 2911 02:09:29,240 --> 02:09:34,040 TO START SOMEWHERE. 2912 02:09:34,040 --> 02:09:36,320 THAT'S WHERE WE'RE GOING. 2913 02:09:36,320 --> 02:09:39,640 >> DO AGED FEMALE MICE 2914 02:09:39,640 --> 02:09:41,120 DEMONSTRATE ANESTRUS? 2915 02:09:41,120 --> 02:09:45,200 >>YEAH, BASICALLY FEMALE MICE 2916 02:09:45,200 --> 02:09:47,760 WILL BECOME ACYCLIC 12 TO 13 2917 02:09:47,760 --> 02:09:50,440 MONTHS, THEY DON'T GET 2918 02:09:50,440 --> 02:09:50,880 MENOPAUSE. 2919 02:09:50,880 --> 02:09:51,880 SEPARATE DIRECTION OF RESEARCH 2920 02:09:51,880 --> 02:09:54,280 IN MY LAB, WE'RE DEVELOPING 2921 02:09:54,280 --> 02:09:56,680 MODELS OF MENOPAUSE IN MICE SO 2922 02:09:56,680 --> 02:09:58,240 WE CAN MODEL THIS PROPERLY. 2923 02:09:58,240 --> 02:09:59,880 BUT AGAIN YOU HAVE TO START 2924 02:09:59,880 --> 02:10:02,160 SOMEWHERE. 2925 02:10:02,160 --> 02:10:06,880 2926 02:10:06,880 --> 02:10:09,160 >> GO AHEAD, MARK. 2927 02:10:09,160 --> 02:10:09,440 >> OKAY. 2928 02:10:09,440 --> 02:10:11,560 IT'S WORKING, GOOD. 2929 02:10:11,560 --> 02:10:14,760 THAT'S REALLY INTERESTING. 2930 02:10:14,760 --> 02:10:19,360 I WANT TO MENTION THAT IN OUR 2931 02:10:19,360 --> 02:10:24,840 KNOCKOUT EXPERIMENTS WITH TONSIL 2932 02:10:24,840 --> 02:10:29,640 ORGANOIDS, ESPECIALLY WITH FOXP3 2933 02:10:29,640 --> 02:10:31,080 KNOCKOUT, THE TONSILS FROM WOMEN 2934 02:10:31,080 --> 02:10:34,480 TEND TO MAKE MUCH HIGHER LEVELS 2935 02:10:34,480 --> 02:10:37,200 OF AUTOANTIBODIES, AND ALSO EVEN 2936 02:10:37,200 --> 02:10:40,280 IN UNMANIPULATED TONSILS WE SEE 2937 02:10:40,280 --> 02:10:43,120 SOME WOMEN HAVE DETECTABLE 2938 02:10:43,120 --> 02:10:47,160 LEVELS OF B CELLS SPECIFIC FOR 2939 02:10:47,160 --> 02:10:48,040 CLASSICAL AUTOANTIGEN LIKE 2940 02:10:48,040 --> 02:10:49,160 DOUBLE-STRANDED DNA AND SO FORTH 2941 02:10:49,160 --> 02:10:51,040 AND I WOULD PUT UP LIKE FOR 2942 02:10:51,040 --> 02:10:54,720 ORGANOIDS IN TERMS OF SPLEEN 2943 02:10:54,720 --> 02:10:56,360 ORGANOIDS PRESERVE SOME 2944 02:10:56,360 --> 02:10:57,520 NEUTROPHILS, MOST PBMCs OF 2945 02:10:57,520 --> 02:11:00,640 COURSE DO NOT, AND SO DOING 2946 02:11:00,640 --> 02:11:01,720 THINGS LIKE HORMONAL TREATMENTS 2947 02:11:01,720 --> 02:11:04,440 WOULD BE SUPER EASY IN A DISH OF 2948 02:11:04,440 --> 02:11:06,880 THE MOUSE. 2949 02:11:06,880 --> 02:11:12,880 2950 02:11:12,880 --> 02:11:13,640 2951 02:11:13,640 --> 02:11:17,280 >> TERRIFIC. 2952 02:11:17,280 --> 02:11:25,160 I WAS WONDERING, I'M WONDERING 2953 02:11:25,160 --> 02:11:29,320 IF SEX DIFFERENCES CHANGE WITH 2954 02:11:29,320 --> 02:11:29,480 AGE. 2955 02:11:29,480 --> 02:11:31,040 >> YEAH, I DIDN'T WANT TO GO 2956 02:11:31,040 --> 02:11:33,680 INTO IT, AGE DECLINE IS OBSERVED 2957 02:11:33,680 --> 02:11:37,200 WHEN YOU PRIME NEUTROPHILS WITH 2958 02:11:37,200 --> 02:11:38,720 TNF ALPHA IN VITRO, 2959 02:11:38,720 --> 02:11:39,840 RECAPITULATED IN OUR PAPER BUT 2960 02:11:39,840 --> 02:11:41,680 IF YOU DON'T PRIME THEM IN VITRO 2961 02:11:41,680 --> 02:11:44,520 BECAUSE THEY ARE TECHNICALLY 2962 02:11:44,520 --> 02:11:46,080 ALREADY PRIMED IN VIVO WITH AGE 2963 02:11:46,080 --> 02:11:49,600 THERE'S AN INCREASE. 2964 02:11:49,600 --> 02:11:52,440 YEAH, THAT'S YOU -- YOU GO INTO 2965 02:11:52,440 --> 02:11:53,840 THE MATERIAL METHODS, PRIMED IN 2966 02:11:53,840 --> 02:11:56,600 VITRO, CELLS ARE ALREADY EXPOSED 2967 02:11:56,600 --> 02:11:58,600 TO MORE TNF ALPHA IN VIVO THAT 2968 02:11:58,600 --> 02:12:00,320 WOULD CREATE ISSUES THERE BUT 2969 02:12:00,320 --> 02:12:02,960 THERE'S AN INCREASE WHICH MAKES 2970 02:12:02,960 --> 02:12:04,520 SENSE WITH INCREASED AGE-RELATED 2971 02:12:04,520 --> 02:12:12,800 INFLAMMATION ACTUALLY. 2972 02:12:12,800 --> 02:12:15,280 >> EXCELLENT. 2973 02:12:15,280 --> 02:12:21,440 IN MICE, THE CYCLE IS SHORT, AND 2974 02:12:21,440 --> 02:12:24,720 THESE ARE SHORT-LIVED CELLS. 2975 02:12:24,720 --> 02:12:26,480 DO YOU SEE CHANGES THAT ARE 2976 02:12:26,480 --> 02:12:31,600 HORMONAL DEPENDENT IN SPECIES 2977 02:12:31,600 --> 02:12:33,920 WITH A LONG NEUTROPHIL LIFE 2978 02:12:33,920 --> 02:12:35,800 BACKED BY HORMONAL CHANGE? 2979 02:12:35,800 --> 02:12:37,440 >>FROM REANALYZING PUBLICLY 2980 02:12:37,440 --> 02:12:38,960 AVAILABLE TRANSCRIPTOMIC DATA 2981 02:12:38,960 --> 02:12:45,880 THERE ARE HUGE DIFFERENCES IN 2982 02:12:45,880 --> 02:12:46,480 TRANSCRIPTOMES, ADULT 2983 02:12:46,480 --> 02:12:49,040 NEUTROPHILS FEMALE AND MALE 2984 02:12:49,040 --> 02:12:49,600 HUMANS. 2985 02:12:49,600 --> 02:12:51,320 THAT'S DEFINITELY THE CASE. 2986 02:12:51,320 --> 02:12:54,920 AND JUST EVEN WERE SUPER SHORT 2987 02:12:54,920 --> 02:12:59,120 NEUTROPHILS WE HAVE WORK ON 2988 02:12:59,120 --> 02:12:59,960 MACROPHAGE, PHENOTYPES CHANGE 2989 02:12:59,960 --> 02:13:03,240 QUITE A LOT BASED ON HORMONAL 2990 02:13:03,240 --> 02:13:03,480 STATUS. 2991 02:13:03,480 --> 02:13:06,120 IT LOOKS LIKE RESPONSE OF THE 2992 02:13:06,120 --> 02:13:08,200 CELLS CAN BE SUPER DYNAMIC, 2993 02:13:08,200 --> 02:13:11,040 DOESN'T NEED TO LAST 28 DAYS. 2994 02:13:11,040 --> 02:13:12,440 >> THANK YOU VERY MUCH. 2995 02:13:12,440 --> 02:13:14,960 WE'VE HAD A GREAT SESSION. 2996 02:13:14,960 --> 02:13:17,600 IT'S TIME FOR A SHORT BREAK. 2997 02:13:17,600 --> 02:13:20,800 AND SO IF WE CAN COME BACK IN 15 2998 02:13:20,800 --> 02:13:21,160 MINUTES. 2999 02:13:21,160 --> 02:14:36,040 THANK YOU. 3000 02:14:36,040 --> 02:14:44,160 HIS REAL TITLE IS IMMUNE AGING 3001 02:14:44,160 --> 02:14:46,560 AT SINGLE-CELL RESOLUTION, 3002 02:14:46,560 --> 02:14:46,760 PBMCs. 3003 02:14:46,760 --> 02:14:47,120 ALL RIGHT. 3004 02:14:47,120 --> 02:14:53,360 >> AM I GOING TO HAVE TO SAY 3005 02:14:53,360 --> 02:14:56,320 THE WORD "NEXT" MORE IN THIS 3006 02:14:56,320 --> 02:15:02,680 CONFERENCE? 3007 02:15:02,680 --> 02:15:04,120 OKAY. 3008 02:15:04,120 --> 02:15:05,600 [LAUGHTER] 3009 02:15:05,600 --> 02:15:06,920 AT LEAST HALF THE AUDIENCE 3010 02:15:06,920 --> 02:15:08,800 IMMUNE SYSTEMS SHOULD BE IN THE 3011 02:15:08,800 --> 02:15:09,920 CENTER OF THE AGING PHENOTYPE 3012 02:15:09,920 --> 02:15:14,280 PERHAPS, FOR MANY PEOPLE BEFORE 3013 02:15:14,280 --> 02:15:17,760 US, AND FOR ME THE BIGGEST 3014 02:15:17,760 --> 02:15:21,920 CONVINCING ARGUMENT IS ON THE 3015 02:15:21,920 --> 02:15:24,640 NEXT SLIDE, THAT SHOWS THE 3016 02:15:24,640 --> 02:15:27,520 EXTENSION OF THE LIFE FOR 3017 02:15:27,520 --> 02:15:31,200 LONGEVITY HAPPENS DUE TO 3018 02:15:31,200 --> 02:15:33,160 DRAMATIC IMPROVEMENTS IN IMMUNE 3019 02:15:33,160 --> 02:15:33,440 SCIENCES. 3020 02:15:33,440 --> 02:15:39,000 AND SO IF YOU GO NEXT NOW, THREE 3021 02:15:39,000 --> 02:15:42,480 SLIDES, YOU'LL SEE THAT THERE 3022 02:15:42,480 --> 02:15:47,640 ARE CURRENT CANCER IMMUNOLOGY, 3023 02:15:47,640 --> 02:15:48,480 NEURODEGENERATION, I WILL 3024 02:15:48,480 --> 02:15:51,000 SPECULATE IMMUNE AGING IS THE 3025 02:15:51,000 --> 02:15:52,440 ULTIMATE FRONTIER THAT COMES 3026 02:15:52,440 --> 02:15:52,880 NEXT TO IT. 3027 02:15:52,880 --> 02:15:55,360 AS MUCH AS IT IS FUNDAMENTAL, 3028 02:15:55,360 --> 02:15:57,320 NEXT SLIDE, YOU'LL SEE ALSO IN 3029 02:15:57,320 --> 02:16:01,320 THE NEXT, IT'S FOR ALL OF US, A 3030 02:16:01,320 --> 02:16:06,400 PERSONAL PROBLEM AS WELL. 3031 02:16:06,400 --> 02:16:09,600 SURPRISINGLY ACCURATE PICTURE OF 3032 02:16:09,600 --> 02:16:11,360 PREDICTION, MIXTURE OF MY MOM 3033 02:16:11,360 --> 02:16:14,440 AND DAD'S IMAGES. 3034 02:16:14,440 --> 02:16:16,720 GOING TO SCIENCE, NEXT, WHEN YOU 3035 02:16:16,720 --> 02:16:17,960 THINK ABOUT CHARACTERIZING 3036 02:16:17,960 --> 02:16:19,240 AGING, BIGGEST ISSUE THAT SOME 3037 02:16:19,240 --> 02:16:24,400 OF THE SPEAKERS BEFORE ME TALKED 3038 02:16:24,400 --> 02:16:27,680 ABOUT, CHANGES ASSOCIATED WITH 3039 02:16:27,680 --> 02:16:29,800 AGING, DUE TO THE LIMITATIONS OF 3040 02:16:29,800 --> 02:16:33,160 TECHNOLOGY MOST OF THE -- A LOT 3041 02:16:33,160 --> 02:16:38,640 OF STUDIES USED BLOOD TISSUE, 3042 02:16:38,640 --> 02:16:39,600 BLOOD PROFILING, NOT INFORMATIVE 3043 02:16:39,600 --> 02:16:40,600 ABOUT BIOLOGY INSIDE THE CELLS 3044 02:16:40,600 --> 02:16:48,600 OR WITH THE CELL SYSTEMS. 3045 02:16:48,600 --> 02:16:51,960 GOING NEXT, NEXT, NEXT, GO TO 3046 02:16:51,960 --> 02:16:53,040 SINGLE-CELL RESOLUTION OR 3047 02:16:53,040 --> 02:16:57,320 PROFILING TO ISOLATE AND PURIFY 3048 02:16:57,320 --> 02:17:07,000 SINGLE POPULATION SUCH AS 3049 02:17:07,000 --> 02:17:07,520 BERENICE. 3050 02:17:07,520 --> 02:17:12,480 ONE ABOUT THE POSTER THAT'S 3051 02:17:12,480 --> 02:17:14,640 UNPUBLISHED, NEXT SLIDE, IRINA 3052 02:17:14,640 --> 02:17:16,840 WHO HELPED EMILY AND SHE WILL 3053 02:17:16,840 --> 02:17:19,200 PRESENT A POSTER, LONGED AT THE 3054 02:17:19,200 --> 02:17:21,000 ISOLATED MONOCYTES BETWEEN YOUNG 3055 02:17:21,000 --> 02:17:24,920 AND OLD INDIVIDUALS, AND 3056 02:17:24,920 --> 02:17:26,040 COMPREHENSIVELY CHARACTERIZED 3057 02:17:26,040 --> 02:17:28,240 DIFFERENCE, MULTIPLE MULTIOMICS 3058 02:17:28,240 --> 02:17:28,600 LEVELS. 3059 02:17:28,600 --> 02:17:31,080 WHAT IS INTERESTING THEY DO LOOK 3060 02:17:31,080 --> 02:17:34,480 VERY IDENTICAL IF YOU TAKE TRULY 3061 02:17:34,480 --> 02:17:35,680 HEALTHY OLD INDIVIDUALS, IT WILL 3062 02:17:35,680 --> 02:17:39,600 NOT BE EASY BUT MONOCYTES ARE NO 3063 02:17:39,600 --> 02:17:42,560 DIFFERENT EXCEPT, NEXT SLIDE, 3064 02:17:42,560 --> 02:17:46,520 EXCEPT FOR THE DNA METHYLATION 3065 02:17:46,520 --> 02:17:46,760 PROFILE. 3066 02:17:46,760 --> 02:17:48,040 SOMETHING IS HAPPENING IN 3067 02:17:48,040 --> 02:17:53,040 PURIFIED POPULATION NOT ON 3068 02:17:53,040 --> 02:17:54,160 TRANSCRIPTION LEVEL OR CHROMATIN 3069 02:17:54,160 --> 02:17:58,960 LEVEL BUT CHANGES IN DNA 3070 02:17:58,960 --> 02:17:59,240 METHYLATION. 3071 02:17:59,240 --> 02:17:59,520 NEXT. 3072 02:17:59,520 --> 02:18:01,280 THIS PAPER CHARACTERIZES 3073 02:18:01,280 --> 02:18:03,680 PREVIOUS SLIDE THE DNA 3074 02:18:03,680 --> 02:18:06,440 METHYLATION LOCATIONS, NOT THE 3075 02:18:06,440 --> 02:18:07,960 INDIVIDUAL CpGs BUT 3076 02:18:07,960 --> 02:18:09,920 STRETCHES IN PROMOTERS OR 3077 02:18:09,920 --> 02:18:11,320 ENHANCER REGIONS WHICH ARE 3078 02:18:11,320 --> 02:18:13,920 CHANGING AND PERHAPS HAVE TO DO 3079 02:18:13,920 --> 02:18:16,480 WITH THE CHANGING OF THE 3080 02:18:16,480 --> 02:18:17,160 HEMATOPOIETIC STEM CELL, 3081 02:18:17,160 --> 02:18:19,880 SOMETHING THAT WE TALKED ABOUT. 3082 02:18:19,880 --> 02:18:24,360 SWITCHING GEARS TO THE NEXT 3083 02:18:24,360 --> 02:18:26,440 SLIDE, THEN LOOKING AT MONOCYTES 3084 02:18:26,440 --> 02:18:28,640 THOUGHT WE'LL USE COMPLEMENTARY 3085 02:18:28,640 --> 02:18:29,720 APPROACH, SINGLE CELL TECHNIQUES 3086 02:18:29,720 --> 02:18:31,880 TO LOOK AT ALL IMMUNE CELLS THAT 3087 02:18:31,880 --> 02:18:34,240 ARE POSSIBLE, IT OF COURSE AS 3088 02:18:34,240 --> 02:18:37,440 SOMEBODY WAS SAYING IT'S EASY TO 3089 02:18:37,440 --> 02:18:40,680 LOOK AT TISSUES OF MICE, HARD IN 3090 02:18:40,680 --> 02:18:45,880 HUMANS, MUCH EASIER IN BLOOD. 3091 02:18:45,880 --> 02:18:46,960 NEXT SLIDE. 3092 02:18:46,960 --> 02:18:56,680 LOOKED AT THE MICE, SEVERAL 3093 02:18:56,680 --> 02:18:59,800 ORGANS IN MICE, NEXT SLIDE. 3094 02:18:59,800 --> 02:19:05,920 WHAT HE FOUND SHORT SUMMARY, 3095 02:19:05,920 --> 02:19:08,040 PARTICULAR SUBPOPULATION OF 3096 02:19:08,040 --> 02:19:12,640 GRANZYME POSITIVE CELLS STRONG 3097 02:19:12,640 --> 02:19:19,280 LINEAGE, POPULATION HIGH IN 3098 02:19:19,280 --> 02:19:20,320 TYPICAL MARKERS. 3099 02:19:20,320 --> 02:19:22,000 IN LIVER, MAJORITY OF CELLS WITH 3100 02:19:22,000 --> 02:19:24,960 AGE, SAME TRUE FOR OTHER ORGANS. 3101 02:19:24,960 --> 02:19:27,360 WHAT IS INTERESTING, NEXT, IS 3102 02:19:27,360 --> 02:19:29,120 THAT THESE ARE THE, IN MICE, THE 3103 02:19:29,120 --> 02:19:39,640 CELLS THAT ARE RESPONSIBLE FOR 3104 02:19:45,160 --> 02:19:45,440 THE INCREASE. 3105 02:19:45,440 --> 02:19:47,400 THE QUESTION, WE CAN CURE THE 3106 02:19:47,400 --> 02:19:49,480 MICE AM PRETTY MUCH ANY DISEASE, 3107 02:19:49,480 --> 02:19:52,880 WHAT ABOUT HUMANS? 3108 02:19:52,880 --> 02:19:59,640 TRANSLATING TO HUMANS, LET'S SEE 3109 02:19:59,640 --> 02:19:59,960 THE GRANZYME. 3110 02:19:59,960 --> 02:20:02,600 HE SET UP THE PANEL TO LOOK INTO 3111 02:20:02,600 --> 02:20:05,880 GRANZYME B, AND WHAT YOU SEE 3112 02:20:05,880 --> 02:20:07,600 HERE IS GRANZYME K POSITIVE 3113 02:20:07,600 --> 02:20:10,240 CELLS ARE INCREASING WITH AGE 3114 02:20:10,240 --> 02:20:11,800 WHILE GRANZYME B POSITIVE ARE 3115 02:20:11,800 --> 02:20:12,640 TRENDING BUT NOT REALLY 3116 02:20:12,640 --> 02:20:14,720 INCREASING WITH AGE IN THIS 3117 02:20:14,720 --> 02:20:14,960 COHORT. 3118 02:20:14,960 --> 02:20:20,680 SO YOU CAN SEE ALSO IN THE RIGHT 3119 02:20:20,680 --> 02:20:23,720 THESE ARE TWO SUBPOPULATIONS, 3120 02:20:23,720 --> 02:20:31,720 GRANZYME K OR GRANZYME B 3121 02:20:31,720 --> 02:20:32,360 POSITIVE CELLS. 3122 02:20:32,360 --> 02:20:34,880 IF YOU LOOK AT DATA, YOUNG 3123 02:20:34,880 --> 02:20:36,280 VERSUS OLD, THEN YOU'LL SEE 3124 02:20:36,280 --> 02:20:39,800 THERE ARE FIVE MAJOR POPULATIONS 3125 02:20:39,800 --> 02:20:44,280 IN CD8 T CELLS, NAIVE AND THREE 3126 02:20:44,280 --> 02:20:46,240 MEMORY AND POPULATIONS DEFINED 3127 02:20:46,240 --> 02:20:49,760 BY SINGLE CELL RNA SEQUENCINGS, 3128 02:20:49,760 --> 02:20:52,160 CENTRAL MEMORY, TWO CLUSTERS 3129 02:20:52,160 --> 02:21:02,600 GRANZYME K AND GRANZYME B 3130 02:21:13,680 --> 02:21:15,240 POSITIVE, CENTRAL MEMORY ALSO 3131 02:21:15,240 --> 02:21:19,840 ACCUMULATING WITH AGE. 3132 02:21:19,840 --> 02:21:20,360 AND NEXT. 3133 02:21:20,360 --> 02:21:22,120 SO THE QUESTION FOR HUMANS 3134 02:21:22,120 --> 02:21:27,280 TYPICALLY YOU WANT MANY MORE, 3135 02:21:27,280 --> 02:21:29,040 WOULD HAVE TO COVER, INURE WE 3136 02:21:29,040 --> 02:21:32,520 WANTED FIRST TO SCALE USING 3137 02:21:32,520 --> 02:21:36,240 CYTOMETRY, THIS IS THE BROAD 3138 02:21:36,240 --> 02:21:38,560 CYTOMETRY STUDY THAT INCLUDED 3139 02:21:38,560 --> 02:21:42,720 GRANZYME K AND GRANZYME B AS ONE 3140 02:21:42,720 --> 02:21:44,000 OF IMPORTANT PROTEINS. 3141 02:21:44,000 --> 02:21:45,360 SO THERE'S ALSO IN THE PAPER A 3142 02:21:45,360 --> 02:21:47,320 LITTLE BIT ABOUT COVID. 3143 02:21:47,320 --> 02:21:49,040 ONCE WE COLLECTED DATA COVID 3144 02:21:49,040 --> 02:21:52,040 HIT, TO CONTINUE THE WORK WE HAD 3145 02:21:52,040 --> 02:21:59,360 TO INCLUDE SOME OF THE POPULAR 3146 02:21:59,360 --> 02:22:07,720 DISEASE AT THE TIME. 3147 02:22:07,720 --> 02:22:08,640 WE GOT DATA. 3148 02:22:08,640 --> 02:22:10,960 HERE IS THE MAP SHOWING 3149 02:22:10,960 --> 02:22:13,240 POPULATIONS, YOU CAN SEE 3150 02:22:13,240 --> 02:22:16,840 SUBPOPULATION POSITIVE IN 3151 02:22:16,840 --> 02:22:18,800 GRANZYME K AND MORE OF THE 3152 02:22:18,800 --> 02:22:25,000 GRANZYME B, THEY ARE ASSOCIATED 3153 02:22:25,000 --> 02:22:28,280 WITH TRANSCRIPTION FACTOR T-BET, 3154 02:22:28,280 --> 02:22:29,680 SUGGESTING EPIGENETIC AND 3155 02:22:29,680 --> 02:22:30,680 TRANSCRIPTIONALLY DISTINCT 3156 02:22:30,680 --> 02:22:31,000 POPULATION. 3157 02:22:31,000 --> 02:22:32,280 SLOWLY CLICK THROUGH THE NEXT 3158 02:22:32,280 --> 02:22:37,000 FOUR SLIDES YOU CAN SEE HOW 3159 02:22:37,000 --> 02:22:38,960 AGING DENSITY FLOW CHANGES OVER 3160 02:22:38,960 --> 02:22:42,160 HERE, SO YOU CAN SEE 3161 02:22:42,160 --> 02:22:43,000 ACCUMULATION, ONE MORE, THAT 3162 02:22:43,000 --> 02:22:46,320 BASICALLY THESE ARE THE THREE 3163 02:22:46,320 --> 02:22:49,400 SUBPOPULATIONS THAT ARE REALLY 3164 02:22:49,400 --> 02:22:50,800 HEAVILY ACCUMULATED. 3165 02:22:50,800 --> 02:22:51,560 NEXT SLIDE. 3166 02:22:51,560 --> 02:22:53,160 COVID IS SCREWING UP EVERYTHING, 3167 02:22:53,160 --> 02:22:54,960 YES, WE ARE HERE. 3168 02:22:54,960 --> 02:22:56,360 YOU CAN SEE STATISTICALLY IF YOU 3169 02:22:56,360 --> 02:22:59,960 LOOK AT NOT JUST VISUALLY BUT 3170 02:22:59,960 --> 02:23:07,520 WITH PROPER DISTANCE YOU CAN SEE 3171 02:23:07,520 --> 02:23:08,960 STATISTICALLY GRANZYME K 3172 02:23:08,960 --> 02:23:10,520 POSITIVE ARE ACCUMULATING, SAME 3173 02:23:10,520 --> 02:23:17,160 TRUE FOR CENTRAL MEMORIES, NAIVE 3174 02:23:17,160 --> 02:23:18,360 GOING DOWN, EMRA NOT 3175 02:23:18,360 --> 02:23:21,640 STATISTICALLY GOING UP. 3176 02:23:21,640 --> 02:23:21,840 NEXT. 3177 02:23:21,840 --> 02:23:28,440 AND WE COVER A LOT OF GROUND, 3178 02:23:28,440 --> 02:23:30,200 YOU CAN LOOK IT UP. 3179 02:23:30,200 --> 02:23:30,800 NEXT. 3180 02:23:30,800 --> 02:23:32,920 THIS IS THE PART OF THE 3181 02:23:32,920 --> 02:23:35,320 UNPUBLISHED STORY THAT I'M GOING 3182 02:23:35,320 --> 02:23:37,440 TO TELL YOU, AND MARINA HERE, 3183 02:23:37,440 --> 02:23:42,480 YOU CAN SEE HER PICTURE, SHE'S 3184 02:23:42,480 --> 02:23:43,440 PRESENTING THE POSTER, PLEASE GO 3185 02:23:43,440 --> 02:23:46,080 BY AND TALK TO HER ABOUT THE 3186 02:23:46,080 --> 02:23:46,320 DETAILS. 3187 02:23:46,320 --> 02:23:48,960 AND HAVING SEEN THESE CHANGES IN 3188 02:23:48,960 --> 02:23:54,080 OUR DATA WE WERE WONDERING CAN 3189 02:23:54,080 --> 02:23:57,680 WE TAKE A LOOK AND IDENTIFY 3190 02:23:57,680 --> 02:23:58,800 CHANGES IN BROADER SPEAKING. 3191 02:23:58,800 --> 02:24:02,480 AT THIS POINT THERE HAVE BEEN A 3192 02:24:02,480 --> 02:24:04,440 LOT IN THE COMMUNITY OF THE 3193 02:24:04,440 --> 02:24:05,880 STANDARDIZED DATASET OF THE 3194 02:24:05,880 --> 02:24:08,400 HUMAN SINGLE CELL RNA SEQUENCING 3195 02:24:08,400 --> 02:24:10,680 ACROSS HEALTHY AGING, WE BELIEVE 3196 02:24:10,680 --> 02:24:15,120 WE WILL FILL THIS GAP, WHAT WE 3197 02:24:15,120 --> 02:24:16,720 HAVE DONE COLLECTED 166 DONORS 3198 02:24:16,720 --> 02:24:23,200 ACROSS 25 TO 85 YEARS OLD, 3199 02:24:23,200 --> 02:24:24,680 HEALTHY AGERS, SOME PROFILED 3200 02:24:24,680 --> 02:24:24,960 TWICE. 3201 02:24:24,960 --> 02:24:27,880 ONE YEAR AFTER FOLLOW-UP, TWO 3202 02:24:27,880 --> 02:24:30,840 YEARS FOLLOW-UP. 3203 02:24:30,840 --> 02:24:31,800 PERFORMED SINGLE-CELL RNA 3204 02:24:31,800 --> 02:24:36,440 SEQUENCING AND SOME OF THE 3205 02:24:36,440 --> 02:24:37,520 FINDINGS VALIDATED USING 3206 02:24:37,520 --> 02:24:37,840 CYTOMETRY. 3207 02:24:37,840 --> 02:24:38,760 NEXT SLIDE. 3208 02:24:38,760 --> 02:24:42,320 ONE OF THE QUESTIONS AND ONE OF 3209 02:24:42,320 --> 02:24:44,000 THE VERY -- NEXT SLIDE PLEASE. 3210 02:24:44,000 --> 02:24:45,200 ONE OF THE IMPORTANT QUESTIONS 3211 02:24:45,200 --> 02:24:48,680 IS SELECTION OF THE COHORTS, 3212 02:24:48,680 --> 02:24:51,320 VERY DIFFICULT AS SOME PEOPLE 3213 02:24:51,320 --> 02:24:54,120 HAVE BEEN MENTIONING, VERY HARD 3214 02:24:54,120 --> 02:24:56,120 TO MAINTAIN OR RECRUIT PEOPLE TO 3215 02:24:56,120 --> 02:24:58,840 DO THAT BECAUSE COLLECT COHORT 3216 02:24:58,840 --> 02:25:00,480 FOR THREE YEARS AND THEN ANOTHER 3217 02:25:00,480 --> 02:25:02,600 FOUR YEARS WOULD BE DOING 3218 02:25:02,600 --> 02:25:03,680 SCIENCE, BUT IMPORTANT QUESTION 3219 02:25:03,680 --> 02:25:07,240 IS WHAT IS THE CRITICAL PART OF 3220 02:25:07,240 --> 02:25:09,360 THE LOOKING HUMAN AGING TO HAVE 3221 02:25:09,360 --> 02:25:11,240 THE HEALTHY AGING, NOTE SOMEBODY 3222 02:25:11,240 --> 02:25:15,040 WHO IS SICK WITH ARTHRITIS, 3223 02:25:15,040 --> 02:25:17,640 INFLAMED MONOCYTES, HERE IS THE 3224 02:25:17,640 --> 02:25:28,160 BLOOD OF BIOCHEMICAL PROFILES, 3225 02:25:28,800 --> 02:25:31,560 TYPICAL AGING, TESTOSTERONE 3226 02:25:31,560 --> 02:25:35,680 GOING DOWN, TSH GOING UP, CRP 3227 02:25:35,680 --> 02:25:37,240 AND OTHER TRIGLYCERIDES AND SO 3228 02:25:37,240 --> 02:25:41,320 ON ARE IDENTICAL BETWEEN THESE 3229 02:25:41,320 --> 02:25:42,640 AGES, EXCLUSIVELY VERY HEALTHY 3230 02:25:42,640 --> 02:25:45,680 COHORT, SOME PEOPLE TAKING HEART 3231 02:25:45,680 --> 02:25:48,280 MEDICATION, NOT ABSOLUTELY 3232 02:25:48,280 --> 02:25:49,720 HEALTHY PEOPLE. 3233 02:25:49,720 --> 02:25:52,320 NEXT. 3234 02:25:52,320 --> 02:25:57,320 WE'VE COLLECTED AND PROFILED 300 3235 02:25:57,320 --> 02:25:59,240 SAMPLES, ABOUT 2 MILLION 3236 02:25:59,240 --> 02:26:00,240 PBMCs, THE BIGGEST DATASET OUT 3237 02:26:00,240 --> 02:26:07,120 THERE, ONE OF THE BIGGEST 3238 02:26:07,120 --> 02:26:08,560 CHALLENGES APPROPRIATE 3239 02:26:08,560 --> 02:26:09,840 BIOLOGICALLY RELEVANT IN 3240 02:26:09,840 --> 02:26:11,720 SUBPOPULATION, CD4 AND CD8 3241 02:26:11,720 --> 02:26:14,200 SUBPOPULATIONS, YOU CAN SEE HOW 3242 02:26:14,200 --> 02:26:15,920 THESE ARE CHANGING WITH AGE, AND 3243 02:26:15,920 --> 02:26:19,920 WHAT I'M GOING TO DO IS GIVE A 3244 02:26:19,920 --> 02:26:21,480 LITTLE PRIMER FOR THOSE WHO ARE 3245 02:26:21,480 --> 02:26:24,760 INTERESTED TO COME TO MARINA'S 3246 02:26:24,760 --> 02:26:31,000 POSTER, NEXT SLIDE, AND TO SAY 3247 02:26:31,000 --> 02:26:34,360 THAT WE RECAPITULATE RATIO, 3248 02:26:34,360 --> 02:26:39,440 TYPICAL HALLMARKS OF AGING PBMC. 3249 02:26:39,440 --> 02:26:39,640 NEXT. 3250 02:26:39,640 --> 02:26:50,240 AND THEN CD 4 T CELLS, 3251 02:26:50,240 --> 02:26:53,240 ACCUMULATION OF MEMORY CELLS. 3252 02:26:53,240 --> 02:26:57,160 AND THIS WAS PARALLEL, NEXT, BY 3253 02:26:57,160 --> 02:26:58,360 VERY NICE ACCUMULATION OF 3254 02:26:58,360 --> 02:27:00,280 CENTRAL MEMORY THAT WE DISCUSSED 3255 02:27:00,280 --> 02:27:01,640 BUT TWO SUBSETS. 3256 02:27:01,640 --> 02:27:06,480 YOU CAN SEE ON SINGLE CELL 3257 02:27:06,480 --> 02:27:08,160 RNAseq TWO SUBSETS OF CD4 3258 02:27:08,160 --> 02:27:16,120 POSITIVE AND NEGATIVE CELLS. 3259 02:27:16,120 --> 02:27:17,120 MOST INTRIGUING WAS AMAZING 3260 02:27:17,120 --> 02:27:18,960 POPULATION OF CELLS GOING DOWN 3261 02:27:18,960 --> 02:27:20,960 WITH AGE. 3262 02:27:20,960 --> 02:27:22,240 THIS IS EXTREMELY 3263 02:27:22,240 --> 02:27:22,800 COUNTERINTUITIVE. 3264 02:27:22,800 --> 02:27:27,520 AND FIRST I DID NOT BELIEVE, I 3265 02:27:27,520 --> 02:27:30,040 HARASSED MARINA, SAYING IT'S A 3266 02:27:30,040 --> 02:27:32,680 DUPLICATE, MANY AN ARTIFACT, SO 3267 02:27:32,680 --> 02:27:35,920 ON, BUT SHE PERSISTED, LOOKED AT 3268 02:27:35,920 --> 02:27:38,680 THE OTHER DATA AND SAME 3269 02:27:38,680 --> 02:27:41,320 POPULATION EXISTS, NOBODY LOOKED 3270 02:27:41,320 --> 02:27:42,640 AT AGE. 3271 02:27:42,640 --> 02:27:44,800 PEOPLE JUST IGNORED IT, ALSO 3272 02:27:44,800 --> 02:27:47,120 PROBABLY LIKE ME THINKING THIS 3273 02:27:47,120 --> 02:27:48,760 IS JUST SOME KIND OF ARTIFACT 3274 02:27:48,760 --> 02:27:51,320 BUT AGE BEHAVIOR AND COMPLIANCE 3275 02:27:51,320 --> 02:27:54,240 BETWEEN THE DATASETS SERVED 3276 02:27:54,240 --> 02:27:56,880 THESE ARE REAL DISTINCT 3277 02:27:56,880 --> 02:27:59,920 TRANSCRIPTIONAL SUBPOPULATIONS. 3278 02:27:59,920 --> 02:28:03,760 THE REASON WHY I THINK 3279 02:28:03,760 --> 02:28:05,760 SEPARATION WITH CELLS IS THEY 3280 02:28:05,760 --> 02:28:09,040 ACCUMULATE WITH DIFFERENT PLACE 3281 02:28:09,040 --> 02:28:10,320 BUT MOST IMPORTANTLY TCR 3282 02:28:10,320 --> 02:28:14,520 POSITIVE CELLS BEAR STRONG 3283 02:28:14,520 --> 02:28:16,680 SIGNATURES OF IL-4 AND IL-13 3284 02:28:16,680 --> 02:28:17,560 SIGNALING, AND OVERALL 3285 02:28:17,560 --> 02:28:19,600 SIGNATURES FOR A MOMENT, PLUG 3286 02:28:19,600 --> 02:28:21,360 THEM INTO CD8 CELLS THEY WOULD 3287 02:28:21,360 --> 02:28:28,040 BE ENRICHED IN THE TCR4 3288 02:28:28,040 --> 02:28:29,840 POPULATION. 3289 02:28:29,840 --> 02:28:34,840 ACROSS THE DATASET THEY 3290 02:28:34,840 --> 02:28:36,720 ACCUMULATE Th2 AND POSITIVE 3291 02:28:36,720 --> 02:28:38,800 CD8 CELLS, TO US THERE IS SOME 3292 02:28:38,800 --> 02:28:42,200 SORT OF HEALTHY AGING 3293 02:28:42,200 --> 02:28:44,360 ACCUMULATION OF Th2 TYPE 2 3294 02:28:44,360 --> 02:28:47,000 MEMORY AXIS, NO TYPE 1, NO TYPE 3295 02:28:47,000 --> 02:28:49,960 17, SPECIFICALLY TYPE 2 MEMORY 3296 02:28:49,960 --> 02:28:50,320 AXIS. 3297 02:28:50,320 --> 02:28:50,560 NEXT. 3298 02:28:50,560 --> 02:28:52,960 SO THIS IS A LITTLE BIT OF A 3299 02:28:52,960 --> 02:28:55,440 SUMMARY IF YOU LOOK AT THE 3300 02:28:55,440 --> 02:28:57,760 DATASETS YOU CAN DEFINE 3301 02:28:57,760 --> 02:29:00,680 BIOLOGICALLY MATCHING TO THE 3302 02:29:00,680 --> 02:29:06,200 PUBLISHED DATA TRANSCRIPTIONAL 3303 02:29:06,200 --> 02:29:10,120 SIGNATURE, 53 SUBPOPULATION, 10 3304 02:29:10,120 --> 02:29:10,680 STATISTICALLY SIGNIFICANT 3305 02:29:10,680 --> 02:29:12,960 INCLUDING GAMMADELTA 1 T CELLS, 3306 02:29:12,960 --> 02:29:15,280 AND IF YOU CAN ADVANCE BY 3307 02:29:15,280 --> 02:29:19,320 IMPORTANCE YOU CAN SEE ON THE 3308 02:29:19,320 --> 02:29:21,520 VOLCANO PLOT ON THE LEFT THE 3309 02:29:21,520 --> 02:29:30,760 CELLS ARE AMONG THE STRONGEST 3310 02:29:30,760 --> 02:29:31,600 DECREASING ONES, AND MEMORY 3311 02:29:31,600 --> 02:29:37,040 CELLS ARE THE STRONGEST AND MOST 3312 02:29:37,040 --> 02:29:38,840 DISTINCT, GRANZYME K CELLS AS 3313 02:29:38,840 --> 02:29:42,240 WELL AMONG THE STRONGEST 3314 02:29:42,240 --> 02:29:43,760 ACCUMULATING CELLS. 3315 02:29:43,760 --> 02:29:44,280 NEXT. 3316 02:29:44,280 --> 02:29:47,240 I WANT TO THANK THREE GROUPS OF 3317 02:29:47,240 --> 02:29:48,920 PEOPLE, THIS IS NOT THE WHOLE 3318 02:29:48,920 --> 02:29:50,960 LAB PICTURE. 3319 02:29:50,960 --> 02:29:54,560 I THANK MANY PEOPLE WHO DID THIS 3320 02:29:54,560 --> 02:29:56,200 PROCESS, WE HAVE OUR OWN FAMILY 3321 02:29:56,200 --> 02:29:57,960 INTERNAL CONTROL FOR ALL OF THE 3322 02:29:57,960 --> 02:30:00,480 OPTIMIZATION, THERE'S MY DAD AND 3323 02:30:00,480 --> 02:30:02,440 ME GIVING BLOOD FOR MY LAB TO 3324 02:30:02,440 --> 02:30:09,560 PLAY WITH IT, AND OF COURSE THE 3325 02:30:09,560 --> 02:30:11,400 COLLEAGUES WHO ARE FUN BUT I 3326 02:30:11,400 --> 02:30:12,400 LEARNED THIS MORNING THIS 3327 02:30:12,400 --> 02:30:22,880 ALCOHOL IS NOT GOOD FOR YOU. 3328 02:30:24,440 --> 02:30:27,320 THANK YOU. 3329 02:30:27,320 --> 02:30:28,600 [LAUGHTER] 3330 02:30:28,600 --> 02:30:30,360 WHAT I WANTED TO POINT OUT WHEN 3331 02:30:30,360 --> 02:30:36,000 YOU LOOK AT SINGLE CELL RNAseq 3332 02:30:36,000 --> 02:30:41,320 DATASET WHICH WE'VE DON AD 3333 02:30:41,320 --> 02:30:44,720 NAUSEAM, YOU FIND MANY IF NOT 3334 02:30:44,720 --> 02:30:45,360 ALL INCLUDING HUMAN 3335 02:30:45,360 --> 02:30:47,880 IMMUNOLOGISTS USE IS NOT WORKING 3336 02:30:47,880 --> 02:30:49,640 FOR CD8 T CELLS, SO THIS IS THE 3337 02:30:49,640 --> 02:30:51,720 BIG QUESTION AND NOW THAT WE 3338 02:30:51,720 --> 02:30:53,040 HAVE SINGLE CELL RNA SEQUENCING 3339 02:30:53,040 --> 02:30:55,000 DATA WE NEED TO FIGURE OUT HOW 3340 02:30:55,000 --> 02:30:56,200 TO DO IT PROPERLY. 3341 02:30:56,200 --> 02:30:58,720 I THINK IT'S ONE OF THE BIGGEST 3342 02:30:58,720 --> 02:31:00,560 QUESTIONS BECAUSE ONCE WE TALK 3343 02:31:00,560 --> 02:31:01,560 ABOUT SUBPOPULATIONS WE NEED TO 3344 02:31:01,560 --> 02:31:04,320 KNOW HOW WE DO IT THE RIGHT WAY 3345 02:31:04,320 --> 02:31:13,600 WHICH FOR ME IS SINGLE CELL 3346 02:31:13,600 --> 02:31:14,400 RNAseq WAY OR (INDISCERNIBLE). 3347 02:31:14,400 --> 02:31:15,880 >> THANK YOU. 3348 02:31:15,880 --> 02:31:21,880 WE HAVE TIME FOR -- YEAH. 3349 02:31:21,880 --> 02:31:22,280 >> THANK YOU. 3350 02:31:22,280 --> 02:31:25,720 I HAVE A QUESTION ON TYPE 2 3351 02:31:25,720 --> 02:31:28,280 EXPANDING IN AGING, ARE THEY 3352 02:31:28,280 --> 02:31:33,400 CONTRIBUTING TO INFLAME AGING OR 3353 02:31:33,400 --> 02:31:34,160 EXPANDING TO INFLAMMATORY? 3354 02:31:34,160 --> 02:31:37,120 >>YEAH, THESE ARE THE 3355 02:31:37,120 --> 02:31:40,320 HOMEOSTATIC WHAT WE BELIEVE 3356 02:31:40,320 --> 02:31:43,800 INDIVIDUALS, THE INFLAME AGING 3357 02:31:43,800 --> 02:31:46,560 IN HUMANS, FOR THAT WE NEED TO 3358 02:31:46,560 --> 02:31:50,360 TAKE HEALTHY TISSUES, ESTABLISH 3359 02:31:50,360 --> 02:31:52,880 INFLAMMATION IN HUMANS, WHICH IS 3360 02:31:52,880 --> 02:31:55,400 DIFFERENT COMPARED TO THE IDEA 3361 02:31:55,400 --> 02:31:58,320 THAT WITH AGE AT THE RATE OF 3362 02:31:58,320 --> 02:32:00,680 RHEUMATOID ARTHRITIS, FOR 3363 02:32:00,680 --> 02:32:01,760 EXAMPLE, IS INCREASING, SO IN 3364 02:32:01,760 --> 02:32:03,080 MICE IT'S VERY EASY TO DO. 3365 02:32:03,080 --> 02:32:05,120 IN HUMANS I DON'T THINK THERE 3366 02:32:05,120 --> 02:32:06,800 HAVE BEEN CONVINCING STUDIES 3367 02:32:06,800 --> 02:32:09,960 STATISTICALLY ON A LOT OF 3368 02:32:09,960 --> 02:32:12,680 HEALTHY OLD TISSUES FROM HEALTHY 3369 02:32:12,680 --> 02:32:14,320 NON-INFLAMED INDIVIDUALS. 3370 02:32:14,320 --> 02:32:16,400 BUT TO ANSWER YOUR QUESTION WITH 3371 02:32:16,400 --> 02:32:19,080 RESPECT TO ACTIVATION THESE ARE 3372 02:32:19,080 --> 02:32:23,840 NOT ACTIVATING CELLS, DO NOT 3373 02:32:23,840 --> 02:32:27,360 PRODUCE BIOACTIVELY BUT EVEN IN 3374 02:32:27,360 --> 02:32:30,440 YOUNG INDIVIDUALS 5% ALWAYS NICE 3375 02:32:30,440 --> 02:32:30,720 PROPORTION. 3376 02:32:30,720 --> 02:32:33,720 HOWEVER STUDIES IN GERMANY, FOR 3377 02:32:33,720 --> 02:32:35,720 EXAMPLE, AND FINLAND 3378 02:32:35,720 --> 02:32:42,280 EPIDEMIOLOGICAL STUDIES WITH AGE 3379 02:32:42,280 --> 02:32:44,920 INCREASED WHAT CALLED ATYPICAL 3380 02:32:44,920 --> 02:32:45,240 ASTHMA. 3381 02:32:45,240 --> 02:32:47,640 WHEN YOU'RE YOUNG IT'S POLLEN, 3382 02:32:47,640 --> 02:32:48,840 THIS OR THAT. 3383 02:32:48,840 --> 02:32:50,800 PERHAPS THE CONNECTION THERE 3384 02:32:50,800 --> 02:32:53,120 COULD BE THESE CELLS ARE 3385 02:32:53,120 --> 02:32:56,040 PREDISPOSING, NOT NECESSARILY 3386 02:32:56,040 --> 02:32:58,040 CONTRIBUTING TO THE ONGOING, BUT 3387 02:32:58,040 --> 02:32:59,680 PREDISPOSING TO EASIER 3388 02:32:59,680 --> 02:33:10,200 DEVELOPMENT OF TYPE 2 IMMUNE. 3389 02:33:14,160 --> 02:33:17,760 >> UNIVERSITY OF VIRGINIA. 3390 02:33:17,760 --> 02:33:25,400 WONDERING IF YOU HAD IDEAS ON, 3391 02:33:25,400 --> 02:33:26,960 FIRST, WHAT ARE POTENTIAL SIGNAL 3392 02:33:26,960 --> 02:33:28,240 PATHWAYS OR MECHANISMS FOR 3393 02:33:28,240 --> 02:33:30,880 DESCRIBING THESE CHANGES OVER 3394 02:33:30,880 --> 02:33:33,000 AGING, HAVE YOU TRANSCRIPTIONAL. 3395 02:33:33,000 --> 02:33:35,480 AND MORE BIG PICTURE, HEALTHY 3396 02:33:35,480 --> 02:33:37,320 AGING POPULATION, DO YOU SEE 3397 02:33:37,320 --> 02:33:39,640 THESE PATHWAYS THAT YOU'D FIND 3398 02:33:39,640 --> 02:33:42,920 AT BENEFICIAL OR DETRIMENTAL TO 3399 02:33:42,920 --> 02:33:43,280 HUMAN HEALTH? 3400 02:33:43,280 --> 02:33:46,880 >>OH, YES, THIS IS GREAT 3401 02:33:46,880 --> 02:33:47,320 QUESTIONS. 3402 02:33:47,320 --> 02:33:50,040 SO I'M NOT SURE WHAT ARE 3403 02:33:50,040 --> 02:33:52,640 SPECIFIC MECHANISMS, AND I'M NOT 3404 02:33:52,640 --> 02:33:54,200 EVEN SURE HOW TO EXACTLY 3405 02:33:54,200 --> 02:33:56,960 ESTABLISH THEM BECAUSE IT'S 3406 02:33:56,960 --> 02:33:58,480 PROBABLY CONNECTION BETWEEN 3407 02:33:58,480 --> 02:34:02,760 EVOLUTION AND PERIPHERAL TISSUE 3408 02:34:02,760 --> 02:34:04,240 CHANGE IN HOMEOSTATIC, SO MY 3409 02:34:04,240 --> 02:34:07,120 FEELING IS THAT THESE ARE WHAT 3410 02:34:07,120 --> 02:34:10,880 WE'VE SEE IN BLOOD AND THIS IS 3411 02:34:10,880 --> 02:34:12,480 REFLECTION OF PERIPHERAL TISSUE 3412 02:34:12,480 --> 02:34:14,680 OR PROCESSES. 3413 02:34:14,680 --> 02:34:17,520 NOW, SECOND PART BASICALLY 3414 02:34:17,520 --> 02:34:19,400 DETRIMENTAL OR PROTECTIVE, I 3415 02:34:19,400 --> 02:34:23,760 GUESS WITH IMMUNE SYSTEM IT'S 3416 02:34:23,760 --> 02:34:24,160 PROBABLY BOTH. 3417 02:34:24,160 --> 02:34:26,320 IT'S ONE MECHANISM THAT'S 3418 02:34:26,320 --> 02:34:28,960 REUTILIZED FOR OTHER PURPOSES, 3419 02:34:28,960 --> 02:34:30,600 AND IT TRIES TO BASICALLY WHEN 3420 02:34:30,600 --> 02:34:36,480 YOU STOP INFLAKS OF THE MAIN 3421 02:34:36,480 --> 02:34:37,640 -- STOP INFLUX, 3422 02:34:37,640 --> 02:34:41,360 TRIES TO REBALANCE BUT CREATES 3423 02:34:41,360 --> 02:34:41,880 OTHER ISSUES, MORE 3424 02:34:41,880 --> 02:34:49,960 PHILOSOPHICAL. 3425 02:34:49,960 --> 02:34:54,880 3426 02:34:54,880 --> 02:34:57,000 >> WONDERFUL TALK, AS ALWAYS. 3427 02:34:57,000 --> 02:34:59,560 DID YOU LOOK AT SEX DIFFERENCES? 3428 02:34:59,560 --> 02:35:03,880 >>I MEANT TO SAY WE DID. 3429 02:35:03,880 --> 02:35:06,120 NO DIFFERENCE, SORRY. 3430 02:35:06,120 --> 02:35:07,280 WE WERE HOPING. 3431 02:35:07,280 --> 02:35:09,160 IN INITIAL PLAN OF PAPER BEFORE 3432 02:35:09,160 --> 02:35:16,080 WE HAD EVEN DATA I RESERVED 3433 02:35:16,080 --> 02:35:19,440 DIFFERENCES, LIKE, OH, IT'S VERY 3434 02:35:19,440 --> 02:35:19,680 COMMON. 3435 02:35:19,680 --> 02:35:22,280 BUT I THINK WE'RE NOT TALKING 3436 02:35:22,280 --> 02:35:24,440 ABOUT THE FACT THAT PBMC 3437 02:35:24,440 --> 02:35:25,680 POPULATION NOT REALLY MUCH OF 3438 02:35:25,680 --> 02:35:27,400 THE SEX DIFFERENCE WITH AGE, A 3439 02:35:27,400 --> 02:35:29,960 NUMBER OF OTHER PAPERS TALK 3440 02:35:29,960 --> 02:35:34,000 ABOUT IT. 3441 02:35:34,000 --> 02:35:36,000 ONE PAPER -- 3442 02:35:36,000 --> 02:35:38,600 >>SORRY. 3443 02:35:38,600 --> 02:35:45,000 QUICKLY, YOUR QUESTION. 3444 02:35:45,000 --> 02:35:45,920 YOU'RE NEXT. 3445 02:35:45,920 --> 02:35:47,680 >> IF YOU LOOK AT THE 3446 02:35:47,680 --> 02:35:52,920 DISTRIBUTION OF USUAL HEALTHY 3447 02:35:52,920 --> 02:35:54,680 AGERS, DO YOU HAVE ENOUGH 3448 02:35:54,680 --> 02:35:57,120 CLINICAL DATA TO ASK ABOUT 3449 02:35:57,120 --> 02:35:57,440 DIFFERENCE? 3450 02:35:57,440 --> 02:36:01,520 >>THIS IS THE NEXT STEP 3451 02:36:01,520 --> 02:36:05,360 PERHAPS, TO TRANSLATE, IF I 3452 02:36:05,360 --> 02:36:09,200 UNDERSTAND CORRECTLY, TRANSLATE 3453 02:36:09,200 --> 02:36:12,440 THE QUESTION, SOME OF THE OLDER 3454 02:36:12,440 --> 02:36:14,120 PEOPLE LOOK YOUNGER, MORE LIKE 3455 02:36:14,120 --> 02:36:15,560 SOME YOUNGER PEOPLE BASED ON 3456 02:36:15,560 --> 02:36:17,520 PROPORTIONS OF THE CELLS. 3457 02:36:17,520 --> 02:36:27,960 SO SINCE WE HAVE A LOT OF 3458 02:36:29,840 --> 02:36:30,520 BIOCHEMISTRY, AND OFTENTIMES 3459 02:36:30,520 --> 02:36:35,240 WITH THIS HAPPENING YOU CAN LOOK 3460 02:36:35,240 --> 02:36:38,600 YOUNGER IN CD8, SLIGHTLY OLDER 3461 02:36:38,600 --> 02:36:43,440 OR THE DIFFERENCE IN CD4 3462 02:36:43,440 --> 02:36:46,200 PROPORTION, SO CONNECTION LIKE 3463 02:36:46,200 --> 02:36:47,680 WAS PUBLISHED WITH CONNECTION 3464 02:36:47,680 --> 02:36:50,120 BETWEEN FATTY ACID AND 3465 02:36:50,120 --> 02:37:00,560 MONOCYTES, SO ON, SO WE'RE 3466 02:37:02,320 --> 02:37:03,600 HOPEFUL. 3467 02:37:03,600 --> 02:37:04,320 >> THANK YOU. 3468 02:37:04,320 --> 02:37:09,160 >> NEXT IS SCOTT BOYD, ANTIBODY 3469 02:37:09,160 --> 02:37:09,960 REPERTOIRE ACROSS THE LIFESPAN. 3470 02:37:09,960 --> 02:37:13,160 >> THANKS FOR THE OPPORTUNITY 3471 02:37:13,160 --> 02:37:17,440 TO TALK TODAY. 3472 02:37:17,440 --> 02:37:18,800 3473 02:37:18,800 --> 02:37:19,640 OKAY. 3474 02:37:19,640 --> 02:37:20,760 SO I'M HIGHLIGHTING SOME OF THE 3475 02:37:20,760 --> 02:37:22,640 LAB MEMBERS THAT HAVE DONE THE 3476 02:37:22,640 --> 02:37:24,240 WORK I'M GOING TO TALK ABOUT, 3477 02:37:24,240 --> 02:37:26,240 I'LL MENTION THEM AS WE GO 3478 02:37:26,240 --> 02:37:28,840 ALONG, BEGINNING WITH A BIT OF 3479 02:37:28,840 --> 02:37:29,120 BACKGROUND. 3480 02:37:29,120 --> 02:37:32,040 WE'VE BEEN LOOKING HARD AT 3481 02:37:32,040 --> 02:37:36,840 DIFFERENT IMMUNOLOGIC 3482 02:37:36,840 --> 02:37:39,520 CONDITIONS, SEEING HOW THEY 3483 02:37:39,520 --> 02:37:40,760 CHANGE, WHICH ARE MOST IMPORTANT 3484 02:37:40,760 --> 02:37:42,320 FOR FUNCTIONAL RESPONSES. 3485 02:37:42,320 --> 02:37:44,000 WE THINK THIS IS AN INFORMATIVE 3486 02:37:44,000 --> 02:37:46,760 WAY TO LOOK AT THE B CELL 3487 02:37:46,760 --> 02:37:48,520 POPULATIONS BECAUSE THE HUGE 3488 02:37:48,520 --> 02:37:49,400 DIVERSITY OF RECEPTORS GIVES US 3489 02:37:49,400 --> 02:37:52,000 THE CHANCE TO RESPOND TO ALL 3490 02:37:52,000 --> 02:37:54,200 KINDS OF ANTIGENS. 3491 02:37:54,200 --> 02:37:55,520 THE SIGNAL OF CLONAL EXPANSIONS 3492 02:37:55,520 --> 02:37:57,720 WHEN YOU GET A SPECIFIC RESPONSE 3493 02:37:57,720 --> 02:37:59,560 IS A LARGE SIGNAL IN BIOLOGICAL 3494 02:37:59,560 --> 02:38:01,760 DATA, IF YOU SEQUENCE RECEPTORS. 3495 02:38:01,760 --> 02:38:03,920 YOU CAN TRACK FUNCTIONAL ASPECTS 3496 02:38:03,920 --> 02:38:06,040 LIKE AFFINITY MATURATION OF 3497 02:38:06,040 --> 02:38:07,280 ACCUMULATION OF SOMATIC MUTATION 3498 02:38:07,280 --> 02:38:09,880 THAT LEADS TO INCREASING BINDING 3499 02:38:09,880 --> 02:38:17,120 OF ANTIBODIES. 3500 02:38:17,120 --> 02:38:20,360 REVIEWING THINGS WITH REGARD TO 3501 02:38:20,360 --> 02:38:23,000 SEROLOGICAL RESPONSES, IT'S BEEN 3502 02:38:23,000 --> 02:38:25,080 WELL REPORTED IN COHORTS AND 3503 02:38:25,080 --> 02:38:26,480 STUDIES THAT OLDER INDIVIDUALS 3504 02:38:26,480 --> 02:38:28,560 ARE MORE SUSCEPTIBLE TO 3505 02:38:28,560 --> 02:38:33,040 DIFFERENT INFECTIOUS DISEASES, 3506 02:38:33,040 --> 02:38:34,600 OFTEN HAVE POORER SEROLOGICAL 3507 02:38:34,600 --> 02:38:36,680 RESPONSES. 3508 02:38:36,680 --> 02:38:39,400 ON THE LEFT PANEL ELDERLY GIVE 3509 02:38:39,400 --> 02:38:40,320 LOWER RESPONSE TO INFLUENZA 3510 02:38:40,320 --> 02:38:41,400 VACCINE COMPARED TO YOUNG 3511 02:38:41,400 --> 02:38:41,760 PEOPLE. 3512 02:38:41,760 --> 02:38:43,360 BUT THE PICTURE IS NOT QUITE AS 3513 02:38:43,360 --> 02:38:45,000 SIMPLE AS THAT BECAUSE THERE ARE 3514 02:38:45,000 --> 02:38:47,200 OTHER FACTORS THAT CAN AFFECT A 3515 02:38:47,200 --> 02:38:47,960 SEROLOGICAL RESPONSE, FOR 3516 02:38:47,960 --> 02:38:49,960 EXAMPLE WHAT DEGREE OF 3517 02:38:49,960 --> 02:38:51,840 PREEXISTING ANTIBODIES YOU HAD 3518 02:38:51,840 --> 02:38:53,440 THAT RECOGNIZED ANTIGENS OR 3519 02:38:53,440 --> 02:38:55,520 THOSE SIMILAR IS PARTLY BEHIND 3520 02:38:55,520 --> 02:38:58,880 WHAT MAY ACCOUNT FOR ELDERLY 3521 02:38:58,880 --> 02:38:59,480 VERSUS YOUNG DIFFERENCES, NOT 3522 02:38:59,480 --> 02:39:03,600 THE WHOLE STORY BUT PART OF IT. 3523 02:39:03,600 --> 02:39:07,320 LONGITUDINAL DATA GOING BACK TO 3524 02:39:07,320 --> 02:39:17,400 EARLIER FLU VACCINE STUDIES, IF 3525 02:39:17,400 --> 02:39:20,560 YOU IMMUNIZE REPEATEDLY THE GAP 3526 02:39:20,560 --> 02:39:21,520 DECREASES OVER TIME, THE ELDERLY 3527 02:39:21,520 --> 02:39:23,640 JUST NEED A HIGHER DOSE OR MORE 3528 02:39:23,640 --> 02:39:25,160 ROUNDS OF BOOSTING. 3529 02:39:25,160 --> 02:39:27,400 WHICH IS A GOOD THING AND CAN BE 3530 02:39:27,400 --> 02:39:30,080 HELPFUL FOR INTERVENTIONS OF 3531 02:39:30,080 --> 02:39:30,480 COURSE. 3532 02:39:30,480 --> 02:39:32,960 IT'S REALLY IMPORTANT TO KEEP 3533 02:39:32,960 --> 02:39:35,160 TRACK OF THOSE POTENTIAL 3534 02:39:35,160 --> 02:39:37,560 CONFOUNDERS OF RESPONSES. 3535 02:39:37,560 --> 02:39:38,960 SO, WHEN SARS-COV-2 CAME ALONG 3536 02:39:38,960 --> 02:39:40,640 THIS GAVE A GREAT OPPORTUNITY TO 3537 02:39:40,640 --> 02:39:46,440 STUDY YOUNG AND OLD RESPONSES TO 3538 02:39:46,440 --> 02:39:48,640 ANTIGENS WE HADN'T ENCOUNTERED, 3539 02:39:48,640 --> 02:39:49,600 THERE'S SOME CROSS-REACTIVITY, 3540 02:39:49,600 --> 02:39:51,240 CORONAVIRUS SPIKES AND SO ON, 3541 02:39:51,240 --> 02:39:52,120 BUT NOT STRONG ONES. 3542 02:39:52,120 --> 02:39:53,920 AND WE ALSO HAD THE OPPORTUNITY 3543 02:39:53,920 --> 02:39:56,280 TO LOOK AT RNA VACCINE RESPONSES 3544 02:39:56,280 --> 02:39:58,160 IN MUCH BIGGER COHORTS THAN EVER 3545 02:39:58,160 --> 02:39:59,560 TESTED BEFORE. 3546 02:39:59,560 --> 02:40:03,600 SO THE RESULTS WERE PRETTY 3547 02:40:03,600 --> 02:40:05,160 INTRIGUES, FOR EXAMPLE, THE RED 3548 02:40:05,160 --> 02:40:08,760 BOX IF YOU LOOKED A RESPONSE TO 3549 02:40:08,760 --> 02:40:10,040 SARS-COV-2 SPIKE FROM YOUNGER OR 3550 02:40:10,040 --> 02:40:13,720 OLDER INDIVIDUALS WHO GOT THE 3551 02:40:13,720 --> 02:40:15,200 REGULAR RNA VACCINE, THERE'S 3552 02:40:15,200 --> 02:40:16,400 SOME DECREASE TITER RESPONSE IN 3553 02:40:16,400 --> 02:40:19,560 OLDER INDIVIDUALS BUT NOT A HUGE 3554 02:40:19,560 --> 02:40:20,600 DIFFERENCE, RELATIVELY MODESTER. 3555 02:40:20,600 --> 02:40:22,760 AND THIS IS SOMETHING THAT WOULD 3556 02:40:22,760 --> 02:40:24,840 ELIMINATE THE DIFFERENCE OF 3557 02:40:24,840 --> 02:40:25,920 PREVIOUS EXPOSURE THAT WE HAVE 3558 02:40:25,920 --> 02:40:28,040 IN INFLUENZA STUDIES FOR 3559 02:40:28,040 --> 02:40:28,320 EXAMPLE. 3560 02:40:28,320 --> 02:40:29,760 SOME OTHER ANALYSIS DONE BY A 3561 02:40:29,760 --> 02:40:30,640 DIFFERENT GROUP ON RIGHT-HAND 3562 02:40:30,640 --> 02:40:32,960 PANEL SHOWS IF YOU LOOK AT VERY 3563 02:40:32,960 --> 02:40:35,560 ELDERLY OVER 80 YEARS OLD YOU 3564 02:40:35,560 --> 02:40:36,880 SEE BIGGER DIFFERENCE IN RNA 3565 02:40:36,880 --> 02:40:39,720 VACCINE RESPONSE BUT IT'S STILL 3566 02:40:39,720 --> 02:40:41,160 NOT LIKE ELDERLY DON'T RESPOND 3567 02:40:41,160 --> 02:40:41,400 AT ALL. 3568 02:40:41,400 --> 02:40:43,640 THAT WAS A GOOD OPPORTUNITY TO 3569 02:40:43,640 --> 02:40:45,640 SAY THERE'S CERTAINLY SOME 3570 02:40:45,640 --> 02:40:48,680 IMPAIRMENTS BUT NOT AS SEVERE AS 3571 02:40:48,680 --> 02:40:51,240 SOME OF THE LITERATURE MIGHT 3572 02:40:51,240 --> 02:40:52,320 SUGGEST. 3573 02:40:52,320 --> 02:40:54,920 OTHER THINGS WE LOOKED AT, IF WE 3574 02:40:54,920 --> 02:40:58,560 LOOK AT TIME SERIES OF INFECTION 3575 02:40:58,560 --> 02:40:59,520 LIKE SARS-COV-2 INFECTION 3576 02:40:59,520 --> 02:41:01,280 SEROLOGICAL RESPONSES THESE ARE 3577 02:41:01,280 --> 02:41:03,480 PEOPLE THAT HAD COVID, COVID-19, 3578 02:41:03,480 --> 02:41:07,760 LOOK AT OLDER INDIVIDUALS AND 3579 02:41:07,760 --> 02:41:11,920 YOUNGER ONES, THE SETS THERE, 3580 02:41:11,920 --> 02:41:14,760 RESPONSE OF IgG, OF VARIANTS 3581 02:41:14,760 --> 02:41:17,080 LISTED OVER A TIME SOURCE HOW 3582 02:41:17,080 --> 02:41:17,960 LONG AFTER ONSET, THERE ISN'T 3583 02:41:17,960 --> 02:41:20,240 MUCH OF A DIFFERENCE BETWEEN THE 3584 02:41:20,240 --> 02:41:21,800 YOUNG AND OLD. 3585 02:41:21,800 --> 02:41:23,640 HOWEVER, THAT'S A DIFFERENT 3586 02:41:23,640 --> 02:41:25,680 CONFOUNDER, WHICH IS THAT VERY 3587 02:41:25,680 --> 02:41:27,800 OFTEN OLDER INDIVIDUALS HAD MORE 3588 02:41:27,800 --> 02:41:29,320 SEVERE SARS-COV-2 AND SEVERITY 3589 02:41:29,320 --> 02:41:32,160 OF ILLNESS IS ASSOCIATED WITH 3590 02:41:32,160 --> 02:41:33,880 HIGHER ANTIBODY RESPONSE. 3591 02:41:33,880 --> 02:41:36,400 SO THESE WERE THINGS THEY ARE 3592 02:41:36,400 --> 02:41:37,320 ALL DIFFERENT, SHIFTING ASPECTS, 3593 02:41:37,320 --> 02:41:39,040 YOU CAN'T ALWAYS FULLY CONTROL 3594 02:41:39,040 --> 02:41:42,000 FOR IN STUDIES BUT IMPORTANT FOR 3595 02:41:42,000 --> 02:41:43,320 UNDERSTANDING WHAT'S HAPPENING. 3596 02:41:43,320 --> 02:41:44,920 SO, IN THINKING WHAT'S CHANGING 3597 02:41:44,920 --> 02:41:47,080 IN THE B CELL REPERTOIRES AND 3598 02:41:47,080 --> 02:41:48,800 RESPONSES OVER TIME THERE ARE A 3599 02:41:48,800 --> 02:41:51,760 FEW THINGS CLEAR IF YOU SEQUENCE 3600 02:41:51,760 --> 02:41:52,840 RECEPTOR REPERTOIRES IN PEOPLE 3601 02:41:52,840 --> 02:41:57,480 OF DIFFERENT AGES, HEALTHY 3602 02:41:57,480 --> 02:41:59,880 INDIVIDUALS ABLE TO PARTICIPATE 3603 02:41:59,880 --> 02:42:01,280 IN STUDY, ONGOING ACCUMULATION 3604 02:42:01,280 --> 02:42:02,920 OF SOMATIC MUTATION OVER TIME 3605 02:42:02,920 --> 02:42:04,720 BEGINNING FROM FIRST MONTHS OF 3606 02:42:04,720 --> 02:42:07,520 LIFE THROUGH TO WELL INTO THE 3607 02:42:07,520 --> 02:42:09,880 PEOPLE'S 80s, IF YOU LOOK AT 3608 02:42:09,880 --> 02:42:11,960 THE TOP ROW IgG SOMATIC 3609 02:42:11,960 --> 02:42:13,240 MUTATION CONTINUES TO INCREASE, 3610 02:42:13,240 --> 02:42:14,960 MAY PLATEAU IN YOUR 80s OR 3611 02:42:14,960 --> 02:42:16,000 90s BUT PEOPLE STILL SEEM TO 3612 02:42:16,000 --> 02:42:19,920 BE ABLE TO HAVE INCREASED 3613 02:42:19,920 --> 02:42:21,160 ANTIGENIC STIMULATION OF NEW 3614 02:42:21,160 --> 02:42:22,880 MUTATIONS THAT ACCUMULATE OVER 3615 02:42:22,880 --> 02:42:23,440 TIME. 3616 02:42:23,440 --> 02:42:27,600 THAT'S TRUE FOR IgA. 3617 02:42:27,600 --> 02:42:29,280 PEOPLE WITH COVID-19 THE LEVEL 3618 02:42:29,280 --> 02:42:31,080 OF MUTATION AND CLONES HAS 3619 02:42:31,080 --> 02:42:32,040 SHIFTED DOWNWARD, BECAUSE YOU 3620 02:42:32,040 --> 02:42:35,080 HAVE A MIXTURE OF NEW RECENTLY 3621 02:42:35,080 --> 02:42:36,280 STIMULATED CLONES WHICH HAVE 3622 02:42:36,280 --> 02:42:38,680 VERY LITTLE MUTATION MIXED INTO 3623 02:42:38,680 --> 02:42:41,160 THE REPERTOIRE. 3624 02:42:41,160 --> 02:42:43,760 THIS SHIFTS EVERYTHING DOWN BUT 3625 02:42:43,760 --> 02:42:45,000 DOESN'T REALLY CHANGE THE 3626 02:42:45,000 --> 02:42:46,880 OVERALL TREND OF MUTATION WITH 3627 02:42:46,880 --> 02:42:47,320 AGE. 3628 02:42:47,320 --> 02:42:52,360 SO IT'S A BIT HARD TO GET YOUR 3629 02:42:52,360 --> 02:42:54,320 HEAD AROUND REPERTOIRES AND 3630 02:42:54,320 --> 02:42:55,720 STUDYING IN THE SCALE OF 3631 02:42:55,720 --> 02:42:57,440 CLINICAL STUDIES, GROUPS OF 3632 02:42:57,440 --> 02:42:57,760 INDIVIDUALS. 3633 02:42:57,760 --> 02:43:01,840 SO THIS IS A SORT OF BIG PICTURE 3634 02:43:01,840 --> 02:43:03,400 OVERVIEW OF ONE OF THE 3635 02:43:03,400 --> 02:43:05,040 LONGITUDINAL COHORTS THAT WAS 3636 02:43:05,040 --> 02:43:07,880 STARTED BY MARK'S GROUP AND 3637 02:43:07,880 --> 02:43:08,840 CONTINUED IN COLLABORATION WITH 3638 02:43:08,840 --> 02:43:12,360 HIS LAB AND MINE OF STUDYING 3639 02:43:12,360 --> 02:43:13,680 VACCINE RESPONSES IN ELDERLY 3640 02:43:13,680 --> 02:43:16,520 INDIVIDUALS VERSUS YOUNG ADULTS. 3641 02:43:16,520 --> 02:43:18,800 EACH OF THOSE BOXES IS THE 3642 02:43:18,800 --> 02:43:23,760 RESULTS OF SEQUENCING THE 3643 02:43:23,760 --> 02:43:24,720 ANTIBODY HEAVY CHAIN REPERTOIRE, 3644 02:43:24,720 --> 02:43:26,680 EACH WAS A PERSON TRACKED 3645 02:43:26,680 --> 02:43:28,040 LONGITUDINALLY OVER TIME, EACH 3646 02:43:28,040 --> 02:43:30,440 ROW IS A TIME POINT IN THE 3647 02:43:30,440 --> 02:43:32,080 MANY-YEAR ANALYSIS, WE HAVE 3648 02:43:32,080 --> 02:43:34,920 MULTIPLE YEARS WITH DAY ZERO, 3649 02:43:34,920 --> 02:43:36,800 DAY 7, DAY 28 AFTER VACCINATION. 3650 02:43:36,800 --> 02:43:40,720 CLONES SEEN THERE ARE DEPICTED 3651 02:43:40,720 --> 02:43:48,720 WHERE THE HEAVY CHAIN IS X-AXIS, 3652 02:43:48,720 --> 02:43:52,120 CDR 3 IS THE Y-AXIS. 3653 02:43:52,120 --> 02:43:53,520 IF YOU FOLLOW INDIVIDUALS THERE 3654 02:43:53,520 --> 02:43:56,400 ARE SEVERAL KINDS OF CLONES YOU 3655 02:43:56,400 --> 02:43:58,480 CAN PICK OUT, SOME PERSISTENT, 3656 02:43:58,480 --> 02:44:00,320 DETECTED AT EVERY TIME POINT, 3657 02:44:00,320 --> 02:44:01,600 THERE ARE OTHERS RELATED TO THE 3658 02:44:01,600 --> 02:44:03,480 VACCINE RESPONSE SO YOU DON'T 3659 02:44:03,480 --> 02:44:06,560 SEE THEM CLONALLY EXPANDED AT 3660 02:44:06,560 --> 02:44:09,120 SOMEDAY ZERO BUT SEE THEM AT DAY 3661 02:44:09,120 --> 02:44:10,680 7 OR 28 AND OTHERS AT MULTIPLE 3662 02:44:10,680 --> 02:44:12,680 YEARS IN RESPONSE TO 3663 02:44:12,680 --> 02:44:13,680 VACCINE,OTHERS YOU SEE ONCE AND 3664 02:44:13,680 --> 02:44:14,320 NEVER AGAIN. 3665 02:44:14,320 --> 02:44:16,080 IF WE LOOK AT THE PERSISTENT 3666 02:44:16,080 --> 02:44:17,280 ONES THIS IS SOMETHING WE'RE 3667 02:44:17,280 --> 02:44:19,560 USED TO READING ABOUT IN 3668 02:44:19,560 --> 02:44:20,760 LITERATURE ABOUT ELDERLY, THEY 3669 02:44:20,760 --> 02:44:24,960 WOULD HAVE LARGE EXPANDED CLONES 3670 02:44:24,960 --> 02:44:27,400 OF LYMPHOCYTES. 3671 02:44:27,400 --> 02:44:28,920 WE SEE THAT, IN THE OLDER 3672 02:44:28,920 --> 02:44:29,720 INDIVIDUALS IN THE STUDY. 3673 02:44:29,720 --> 02:44:31,880 FOR EXAMPLE THIS IS RANKED IN 3674 02:44:31,880 --> 02:44:33,400 ORDER OF AGE, OLDEST INDIVIDUAL 3675 02:44:33,400 --> 02:44:36,240 WAS IN THEIR 90s. 3676 02:44:36,240 --> 02:44:38,440 YOUNG ADULTS IN THEIR 20s AND 3677 02:44:38,440 --> 02:44:39,400 30s. 3678 02:44:39,400 --> 02:44:41,720 IF YOU LOOK CLOSELY, YOUNG 3679 02:44:41,720 --> 02:44:43,400 INDIVIDUALS ALSO HAVE PERSISTENT 3680 02:44:43,400 --> 02:44:45,680 CLONES YOU CAN DETECT EVERY TIME 3681 02:44:45,680 --> 02:44:52,000 YOU SEQUENCE THEM, NOT SOLELY 3682 02:44:52,000 --> 02:44:52,840 AGE RELATED. 3683 02:44:52,840 --> 02:44:53,480 CHARACTERISTICS CHANGE. 3684 02:44:53,480 --> 02:44:57,080 THIS IS SHOWING AMOUNT OF 3685 02:44:57,080 --> 02:44:59,680 MUTATION IN THE CLONES, PURPLE 3686 02:44:59,680 --> 02:45:01,880 MORE HEAVILY MUTATED. 3687 02:45:01,880 --> 02:45:04,040 YOUNGER ADULTS PERSIST OVER LONG 3688 02:45:04,040 --> 02:45:06,240 TIMES, WE SEE THEM, BUT THEY ARE 3689 02:45:06,240 --> 02:45:07,440 NOT HEAVILY MUTATED LIKE THEY 3690 02:45:07,440 --> 02:45:08,760 HAVE HAD MULTIPLE ROUNDS EVER 3691 02:45:08,760 --> 02:45:10,400 ANTIGEN EXPERIENCE. 3692 02:45:10,400 --> 02:45:12,600 IN ELDERLY THEY ARE QUITE 3693 02:45:12,600 --> 02:45:12,960 MUTATED USUALLY. 3694 02:45:12,960 --> 02:45:16,440 IF WE LOOK AT VACCINE-STIMULATED 3695 02:45:16,440 --> 02:45:18,400 CLONES, DAY 7 TIME POINTS, EACH 3696 02:45:18,400 --> 02:45:20,560 ROW WITH MORE DOTS IN THEM, YOU 3697 02:45:20,560 --> 02:45:22,520 CAN SEE BOTH ELDERLY AND YOUNG 3698 02:45:22,520 --> 02:45:24,840 ADULTS ARE HAVING PRETTY 3699 02:45:24,840 --> 02:45:25,360 VIGOROUS RESPONSES TO THE 3700 02:45:25,360 --> 02:45:28,000 VACCINATION, MOST OF THE PEOPLE 3701 02:45:28,000 --> 02:45:32,040 IN THE STUDY BEGAN TO BE FLU 3702 02:45:32,040 --> 02:45:33,040 VACCINATED IN 2008, REVACCINATED 3703 02:45:33,040 --> 02:45:34,560 EVERY YEAR. 3704 02:45:34,560 --> 02:45:35,680 LATER YEARS REPEAT VACCINATIONS 3705 02:45:35,680 --> 02:45:37,200 GETTING REDUCES RESPONSES IN 3706 02:45:37,200 --> 02:45:39,200 MANY INDIVIDUALS REGARDLESS OF 3707 02:45:39,200 --> 02:45:45,040 AGE. 3708 02:45:45,040 --> 02:45:46,920 THIS UNDERSCORES NOT A HUGE 3709 02:45:46,920 --> 02:45:48,120 IMPAIRMENT OF RESPONSE, RESPOND 3710 02:45:48,120 --> 02:45:50,320 WITH LOTS OF CLONES, NOT ALL THE 3711 02:45:50,320 --> 02:45:51,440 CLONAL PROCESS, BUT THAT'S 3712 02:45:51,440 --> 02:45:53,280 SOMETHING THEY SHARE WITH 3713 02:45:53,280 --> 02:45:53,640 YOUNGER ADULTS. 3714 02:45:53,640 --> 02:45:55,040 SOMETHING THAT DOES SEEM TO BE 3715 02:45:55,040 --> 02:45:59,160 TRUE THEY ARE HAVING A POOR 3716 02:45:59,160 --> 02:46:00,360 ABILITY TO GENERATE 3717 02:46:00,360 --> 02:46:01,720 PLASMABLASTS, OVERALL GETTING 3718 02:46:01,720 --> 02:46:03,560 LOWER TITERS BECAUSE THEY HAVE 3719 02:46:03,560 --> 02:46:04,760 FEWER CELLS BUT PER CELL 3720 02:46:04,760 --> 02:46:10,600 ANTIBODY PROSECUTION IS NOT THAT 3721 02:46:10,600 --> 02:46:10,920 DIFFERENT. 3722 02:46:10,920 --> 02:46:20,080 SO WHEN WE LOOK AT PUNITIVE 3723 02:46:20,080 --> 02:46:20,240 -- 3724 02:46:20,240 --> 02:46:25,120 PUTATIVE, IN BOTH YOUNG AND 3725 02:46:25,120 --> 02:46:27,760 ELDERLY. 3726 02:46:27,760 --> 02:46:29,520 EVERY WITH FLU VACCINES RESPONDS 3727 02:46:29,520 --> 02:46:33,560 TO THE CLONES, SOMETHING THE 3728 02:46:33,560 --> 02:46:37,280 LITERATURE HAS NOT CAPTURED IN 3729 02:46:37,280 --> 02:46:38,080 SENSE OF TECHNOLOGY, SOMETHING 3730 02:46:38,080 --> 02:46:39,240 WE'RE TRYING TO ADDRESS. 3731 02:46:39,240 --> 02:46:43,520 A FEW OTHER POINTS IF YOU LOOK 3732 02:46:43,520 --> 02:46:44,800 FOR RECURRENT VACCINE-STIMULATED 3733 02:46:44,800 --> 02:46:47,440 CLONES, THERE'S NOT THAT BIG A 3734 02:46:47,440 --> 02:46:47,760 DIFFERENCE. 3735 02:46:47,760 --> 02:46:49,360 I WENT INTO THIS WITH 3736 02:46:49,360 --> 02:46:50,720 PRE-CONCEPTION MAYBE OLDER 3737 02:46:50,720 --> 02:46:51,960 PEOPLE REUSE THE SAME CLONES 3738 02:46:51,960 --> 02:46:54,280 OVER AND OVER BUT WE SEE THAT IN 3739 02:46:54,280 --> 02:46:55,880 YOUNG PEOPLE AS WELL. 3740 02:46:55,880 --> 02:47:00,400 MANY CLONES FOR EXAMPLE 3741 02:47:00,400 --> 02:47:04,880 RESPONSIVE TO H1, H-A OR H3, 3742 02:47:04,880 --> 02:47:07,120 YOU'LL SEE THEM REPEATEDLY, IT'S 3743 02:47:07,120 --> 02:47:08,280 NOT BLACK AND WHITE DIFFERENCE 3744 02:47:08,280 --> 02:47:10,000 BETWEEN, YOU KNOW, AND OLD. 3745 02:47:10,000 --> 02:47:12,320 WAYS THAT WE AND OTHERS HAVE 3746 02:47:12,320 --> 02:47:14,520 BEEN TRYING EXTRACT MAXIMUM 3747 02:47:14,520 --> 02:47:16,040 INFORMATION FROM THESE 3748 02:47:16,040 --> 02:47:18,000 REPERTOIRES, BY LOOKING FOR 3749 02:47:18,000 --> 02:47:20,080 ANTIBODIES WITH HIGHLY SIMILAR 3750 02:47:20,080 --> 02:47:20,960 SEQUENCES, BINDING ACTIVITY YOU 3751 02:47:20,960 --> 02:47:24,040 KNOW FOR SURE IS A WAY TO 3752 02:47:24,040 --> 02:47:25,320 GENERALIZE IF YOU IDENTIFY A 3753 02:47:25,320 --> 02:47:30,160 SPECIFIC ANTIBODY AND FIND 3754 02:47:30,160 --> 02:47:31,480 OTHERS HIGH OR SIMILAR, WE 3755 02:47:31,480 --> 02:47:33,760 LOOKED AT THAT IN THIS PAPER 3756 02:47:33,760 --> 02:47:38,000 PUBLISHED A COUPLE YEARS AGO, IN 3757 02:47:38,000 --> 02:47:41,760 "SCIENCE" LOOKING FOR 3758 02:47:41,760 --> 02:47:43,080 CONVERGENCE OF HEAVY CHAINS. 3759 02:47:43,080 --> 02:47:44,720 LOOKING AT YOUNG PEOPLE, 3760 02:47:44,720 --> 02:47:46,360 CHILDREN IN EARLY YEARS, CLONAL 3761 02:47:46,360 --> 02:47:48,120 EXPANSIONS ARE BIGGER WITH A 3762 02:47:48,120 --> 02:47:50,760 MORE PUBLIC REPERTOIRE RESPONSE 3763 02:47:50,760 --> 02:47:54,560 TO COMMON EXPOSURE LIKE 3764 02:47:54,560 --> 02:48:01,800 CHILDHOOD VACCINES, INFLUENZA. 3765 02:48:01,800 --> 02:48:04,760 IN OLDER PEOPLE SEE COMMON 3766 02:48:04,760 --> 02:48:06,360 THINGS LIKE INFLUENZA. 3767 02:48:06,360 --> 02:48:10,520 THE LOWER PANEL SHOWS DIFFERENT 3768 02:48:10,520 --> 02:48:18,200 AGES, PUBLIC CLONOTYPES FOR FLU 3769 02:48:18,200 --> 02:48:19,760 OVER AGE RANGE FREQUENCIES DON'T 3770 02:48:19,760 --> 02:48:21,280 DIFFER MUCH, A PUBLIC 3771 02:48:21,280 --> 02:48:22,800 REPERTOIRE, BUT UNLESS YOU'RE 3772 02:48:22,800 --> 02:48:24,400 RECENTLY EXPOSED AS THE CHILDREN 3773 02:48:24,400 --> 02:48:32,600 HAD BEEN TO OTHER VACCINES AND 3774 02:48:32,600 --> 02:48:34,040 ANTIGENS, NOT TERRIBLY HIGH, 3775 02:48:34,040 --> 02:48:37,080 ONLY REPEATED EXPOSURES. 3776 02:48:37,080 --> 02:48:40,800 I WANTED TO HIGHLIGHT SOME 3777 02:48:40,800 --> 02:48:42,960 CHALLENGES IN HUMAN B CELL 3778 02:48:42,960 --> 02:48:45,720 STUDIES, WE'VE HAD LOWER ABILITY 3779 02:48:45,720 --> 02:48:46,840 TO ANALYZE ANTIGEN SPECIFIC B 3780 02:48:46,840 --> 02:48:48,000 CELLS BECAUSE IT'S QUITE 3781 02:48:48,000 --> 02:48:48,840 EXPENSIVE TO CHARACTERIZE IN THE 3782 02:48:48,840 --> 02:48:51,520 WAY WE'VE DONE UP TO NOW, SORT 3783 02:48:51,520 --> 02:48:54,920 ANTIGEN BINDING B CELLS OR 3784 02:48:54,920 --> 02:48:55,920 PLASMABLASTS, MAKING MONOCLONAL 3785 02:48:55,920 --> 02:48:56,600 ANTIBODIES, CHARACTERIZE THEM, 3786 02:48:56,600 --> 02:48:57,880 AND THAT LIMITS THE NUMBER OF 3787 02:48:57,880 --> 02:48:59,520 PEOPLE YOU CAN STUDY, NUMBER OF 3788 02:48:59,520 --> 02:49:02,320 CELLS PER PERSON, AND RESULTED 3789 02:49:02,320 --> 02:49:03,240 IN MANY PAPERS BASED ON 3790 02:49:03,240 --> 02:49:05,080 INDIVIDUALS THAT MAY NOT BE 3791 02:49:05,080 --> 02:49:06,440 REPRESENTATIVE FOR ASKING 3792 02:49:06,440 --> 02:49:08,040 QUESTIONS THAT WOULD TACKLE TRUE 3793 02:49:08,040 --> 02:49:10,920 HUMAN DIVERSITY WE HAVE IN 3794 02:49:10,920 --> 02:49:11,360 POPULATIONS. 3795 02:49:11,360 --> 02:49:14,960 AND ALSO FOR EACH CELL YOU WANT 3796 02:49:14,960 --> 02:49:16,520 TO KNOW BREADTH OF BINDING, 3797 02:49:16,520 --> 02:49:17,360 PARTICULARLY IMPORTANT DURING 3798 02:49:17,360 --> 02:49:20,000 COVID, ALSO FOR FLU AND OTHER 3799 02:49:20,000 --> 02:49:22,880 TOPICS IT'S REALLY IMPORTANT. 3800 02:49:22,880 --> 02:49:25,800 AND TO UNDERSTAND IMMUNOLOGIC 3801 02:49:25,800 --> 02:49:26,360 IMPRINTING, EVOLUTION OF 3802 02:49:26,360 --> 02:49:27,680 RESPONSES OVER TIME AS PEOPLE 3803 02:49:27,680 --> 02:49:29,960 ARE EXPOSED TO VARIANTS OF 3804 02:49:29,960 --> 02:49:31,280 ANTIGENS WHICH CLONES ARE 3805 02:49:31,280 --> 02:49:33,880 RETAINED, WHICH GO INTO MEMORY 3806 02:49:33,880 --> 02:49:35,320 COMPARTMENT OR BECOME PLASMA 3807 02:49:35,320 --> 02:49:36,840 CELLS IS KEY. 3808 02:49:36,840 --> 02:49:40,040 SECOND THING IS IT WOULD BE 3809 02:49:40,040 --> 02:49:42,640 IDEAL TO EXTRACT FOR FUNCTIONAL 3810 02:49:42,640 --> 02:49:43,960 INFORMATION, WE HAVE SOME 3811 02:49:43,960 --> 02:49:45,280 APPROACHES TO THAT. 3812 02:49:45,280 --> 02:49:47,120 AS MARK HIGHLIGHTED SO NICELY, 3813 02:49:47,120 --> 02:49:48,760 WE NEED TO STUDY OTHER TISSUES 3814 02:49:48,760 --> 02:49:54,040 IN THE HUMANS MORE TO UNDERSTAND 3815 02:49:54,040 --> 02:49:56,640 WHAT'S OUTSIDE THE BLOOD TO GET 3816 02:49:56,640 --> 02:49:58,600 A SENSE OF MEMORY, MARROW, 3817 02:49:58,600 --> 02:50:00,680 PLASMA CELLS AND SO ON. 3818 02:50:00,680 --> 02:50:04,960 A COUPLE APPROACHES TO ADDRESS 3819 02:50:04,960 --> 02:50:06,280 SOME ISSUES, AREA OF SARS-COV-2, 3820 02:50:06,280 --> 02:50:14,200 A GREAT OPPORTUNITY TO STUDY 3821 02:50:14,200 --> 02:50:15,280 PEOPLE'S RESPONSES TO VARIANTS. 3822 02:50:15,280 --> 02:50:17,840 THIS IS THE APPROACH WE'VE BEEN 3823 02:50:17,840 --> 02:50:19,360 USING, HELPFUL GOING FORWARD. 3824 02:50:19,360 --> 02:50:21,840 AND IT'S THE FOLLOWING. 3825 02:50:21,840 --> 02:50:23,920 SO, PEOPLE HAVE BEEN SORTING 3826 02:50:23,920 --> 02:50:27,000 ANTIGEN SPECIFIC B CELLS BY 3827 02:50:27,000 --> 02:50:27,920 MAKING FLUORESCENTLY LABELED 3828 02:50:27,920 --> 02:50:28,640 COMPLEXES, RIGHT? 3829 02:50:28,640 --> 02:50:30,480 WITH THE SIMPLE ADDITION OF 3830 02:50:30,480 --> 02:50:35,760 HAVING A DNA TAG ATTACHED TO 3831 02:50:35,760 --> 02:50:37,520 THE, FOR EXAMPLE, ANTIGEN, THAT 3832 02:50:37,520 --> 02:50:39,880 ALLOWS MUCH BIGGER PANELS OF 3833 02:50:39,880 --> 02:50:40,960 ANTIGENS THAT YOU CAN ALL 3834 02:50:40,960 --> 02:50:44,960 DISTINGUISH IF DO YOU SICKLE 3835 02:50:44,960 --> 02:50:45,840 CELL TRANSCRIPTOME SEQUENCING, 3836 02:50:45,840 --> 02:50:47,320 THE EXPERIMENTAL DESIGN IS LAID 3837 02:50:47,320 --> 02:50:53,200 OUT HERE, A PANEL OF ANTIGENS, 3838 02:50:53,200 --> 02:50:58,040 SARS-COV-2 SPIKE, F2 DOMAIN, F2, 3839 02:50:58,040 --> 02:51:00,120 RBD, YOU CAN MAKE COMPLEXES WITH 3840 02:51:00,120 --> 02:51:01,840 DIFFERENT DNA TAGS ON EACH ONE 3841 02:51:01,840 --> 02:51:06,560 AND MIX THEM TOGETHER WITH CELL 3842 02:51:06,560 --> 02:51:10,240 THAT CONTAINS B CELLS, ANTIGENS 3843 02:51:10,240 --> 02:51:11,680 WILL BIND, IF THE B CELL HAS 3844 02:51:11,680 --> 02:51:14,640 REACTIVITY IT WILL BIND TO ALL. 3845 02:51:14,640 --> 02:51:15,640 SINGLE CELL TRANSCRIPTOME 3846 02:51:15,640 --> 02:51:17,160 SEQUENCING YOU CAN READ GENE 3847 02:51:17,160 --> 02:51:20,120 EXPRESSION OF EACH B CELL, 3848 02:51:20,120 --> 02:51:22,440 CHAINS, AND TAGS ON ANY OF THE 3849 02:51:22,440 --> 02:51:24,480 ANTIGENS OF THE CELL BOUND SO 3850 02:51:24,480 --> 02:51:27,360 YOU CAN HAVE A BIG PANEL AND 3851 02:51:27,360 --> 02:51:36,120 READ OUT SPECIFICITY AND 3852 02:51:36,120 --> 02:51:36,560 BREADTH. 3853 02:51:36,560 --> 02:51:39,440 WE'VE APPLIED THAT TO 3854 02:51:39,440 --> 02:51:40,000 SARS-COV-2. 3855 02:51:40,000 --> 02:51:42,480 12 ANTIGENS, ANOTHER WITH 26, 3856 02:51:42,480 --> 02:51:45,760 ENABLING A SCALING OF ANALYZING 3857 02:51:45,760 --> 02:51:48,520 A SPECIFIC CELL, YOU CAN FOLLOW 3858 02:51:48,520 --> 02:51:50,800 THE TIME COURSE OF RESPONSE TO 3859 02:51:50,800 --> 02:51:52,760 INFECTION OR VACCINATION, AND 3860 02:51:52,760 --> 02:51:53,640 SEE DIFFERENT PHENOTYPES. 3861 02:51:53,640 --> 02:51:55,400 FOR EXAMPLE IN INFECTION A 3862 02:51:55,400 --> 02:51:57,240 SUBSET OF MEMORY TYPE B CELLS 3863 02:51:57,240 --> 02:51:58,120 WITH ACTIVATION MARKERS YOU 3864 02:51:58,120 --> 02:52:00,440 DON'T SEE IN VACCINATED PEOPLE 3865 02:52:00,440 --> 02:52:01,520 WITH RNA VACCINES. 3866 02:52:01,520 --> 02:52:04,480 HERE IS WHERE WE SEE SPECIFICS. 3867 02:52:04,480 --> 02:52:08,520 IN THE UPPER PANEL ON THE UMAP 3868 02:52:08,520 --> 02:52:11,040 PLOD, WHICH ANTIGENS THEY BIND, 3869 02:52:11,040 --> 02:52:14,560 WHAT PHENOTYPES ARE ON THE UMAP, 3870 02:52:14,560 --> 02:52:17,400 FOR EXAMPLE, AND THIS ALLOWS US 3871 02:52:17,400 --> 02:52:19,360 TO DO THINGS EQUIVALENT TO 3872 02:52:19,360 --> 02:52:21,000 EPISODE MAPPING OR IDENTIFYING 3873 02:52:21,000 --> 02:52:23,240 WHAT AMOUNT OF BREADTH OR 3874 02:52:23,240 --> 02:52:25,680 CROSS-REACTIVITY B CELLS HAVE. 3875 02:52:25,680 --> 02:52:30,400 IF YOU LOOK AT B CELLS THAT BIND 3876 02:52:30,400 --> 02:52:32,880 TO RBD WUHAN VERSUS VARIANTS, 3877 02:52:32,880 --> 02:52:35,080 FOR INDIVIDUAL B CELLS SOME 3878 02:52:35,080 --> 02:52:38,520 VIRUSES ESCAPE BINDING MORE THAN 3879 02:52:38,520 --> 02:52:42,600 OTHERS, FOR EXAMPLE BETA HAS 3880 02:52:42,600 --> 02:52:46,720 POOR BINDING, OTHERWISE WOULD BE 3881 02:52:46,720 --> 02:52:47,800 THE RBD WUHAN, GENERALIZED 3882 02:52:47,800 --> 02:52:49,680 ACROSS BIG DATA SETS, THIS SHOWS 3883 02:52:49,680 --> 02:52:50,760 FROM INFECTED AND VACCINATED 3884 02:52:50,760 --> 02:52:52,000 PEOPLE RESULTS FROM OVER A 3885 02:52:52,000 --> 02:52:55,560 THOUSAND B CELLS FROM JUST A 3886 02:52:55,560 --> 02:52:57,320 COUPLE EXPERIMENTS, WHERE EACH 3887 02:52:57,320 --> 02:53:03,040 ROW IS A CELL, EACH COLUMN IS 3888 02:53:03,040 --> 02:53:09,160 ANTIGEN, SPIKE BINDERS, RBD 3889 02:53:09,160 --> 02:53:10,400 VARIANTS, YOU GET A READOUT. 3890 02:53:10,400 --> 02:53:11,680 SO THAT'S SOMETHING THAT'S GOING 3891 02:53:11,680 --> 02:53:13,840 TO BE USEFUL FOR ANALYZING 3892 02:53:13,840 --> 02:53:17,560 DIFFERENCES AND OF IN 3893 02:53:17,560 --> 02:53:18,880 REPERTOIRES, HOW PEOPLE RESPOND, 3894 02:53:18,880 --> 02:53:20,560 EXPOSURES OVER TIME. 3895 02:53:20,560 --> 02:53:22,080 AND WE'VE ALSO VALIDATED THE 3896 02:53:22,080 --> 02:53:23,960 METHOD BY ALSO MAKING 3897 02:53:23,960 --> 02:53:26,440 MONOCLONALS SHOWING BINDING IS 3898 02:53:26,440 --> 02:53:28,760 RECAPITULATED WHEN YOU DO 3899 02:53:28,760 --> 02:53:29,640 STANDARD EXPRESSIONS. 3900 02:53:29,640 --> 02:53:30,480 THAT'S ONE THING. 3901 02:53:30,480 --> 02:53:33,120 A SECOND ONE I'LL TOUCH ON 3902 02:53:33,120 --> 02:53:35,000 BRIEFLY IS USING MACHINE 3903 02:53:35,000 --> 02:53:39,040 LEARNING METHODS TO ANALYZE 3904 02:53:39,040 --> 02:53:40,280 IMMUNOGLOBULIN SEQUENCES TO 3905 02:53:40,280 --> 02:53:42,320 IDENTIFY ONES SIMILAR BUT NOT 3906 02:53:42,320 --> 02:53:48,320 NECESSARILY AT LEVEL OF SEQUENCE 3907 02:53:48,320 --> 02:53:49,360 IDENTITY. 3908 02:53:49,360 --> 02:53:52,760 BY LOOKING AT SOMEBODY'S OVERALL 3909 02:53:52,760 --> 02:53:54,040 REPERTOIRE COMPOSITION, MUTATION 3910 02:53:54,040 --> 02:53:56,240 LEVELS YOU HAVE, WHAT SEQUENCE 3911 02:53:56,240 --> 02:53:59,200 IDENTITY CLUSTERS WITHIN THE 3912 02:53:59,200 --> 02:54:02,880 REPERTOIRE COMPARED TO OTHERS, 3913 02:54:02,880 --> 02:54:04,440 USING PROTEIN LANGUAGE MODEL TO 3914 02:54:04,440 --> 02:54:05,520 EXTRACT, WE CAN IDENTIFY PEOPLE 3915 02:54:05,520 --> 02:54:08,240 IN TERMS OF WHAT INFECTIONS THEY 3916 02:54:08,240 --> 02:54:09,040 HAVE HAD OR WHAT EXPOSURES AND 3917 02:54:09,040 --> 02:54:12,080 WE THINK THIS WILL BE USEFUL FOR 3918 02:54:12,080 --> 02:54:13,160 TRACKING IMMUNOLOGICAL 3919 02:54:13,160 --> 02:54:15,120 DEFICIENCY ASSOCIATED WITH AGE. 3920 02:54:15,120 --> 02:54:22,800 JUST BRIEFLY IF YOU LOOK AT 3921 02:54:22,800 --> 02:54:23,680 DIFFERENT IMMUNOLOGIC DISORDERS 3922 02:54:23,680 --> 02:54:26,400 YOU CAN PICK THEM OUT BASED ON 3923 02:54:26,400 --> 02:54:27,840 HEAVY CHAIN SEQUENCING ALONE IN 3924 02:54:27,840 --> 02:54:29,720 THIS ANALYSIS. 3925 02:54:29,720 --> 02:54:32,200 I'LL LEAVE OFF THERE. 3926 02:54:32,200 --> 02:54:34,520 AND SAY WE THINK THESE WILL HELP 3927 02:54:34,520 --> 02:54:38,000 US GET A BETTER GRIP ON HUMAN 3928 02:54:38,000 --> 02:54:41,200 IMMUNE REPERTOIRES AND T CELLS 3929 02:54:41,200 --> 02:54:42,480 BY EXTENSION AND UNDERSTAND 3930 02:54:42,480 --> 02:54:44,600 DIFFERENCES WITH AGING CLOSING 3931 02:54:44,600 --> 02:54:47,480 GAPS IN LITERATURE BASED ON TOO 3932 02:54:47,480 --> 02:54:48,080 FEW PEOPLE. 3933 02:54:48,080 --> 02:54:50,120 THANK YOU VERY MUCH. 3934 02:54:50,120 --> 02:54:51,480 THESE ARE THE GRAD STUDENTS AND 3935 02:54:51,480 --> 02:54:53,760 POSTDOCS WHO DID THIS WORK I'VE 3936 02:54:53,760 --> 02:54:57,360 HIGHLIGHTED AS WE WENT ALONG, 3937 02:54:57,360 --> 02:54:59,680 SPECIFIC BINDING STUFF, KATRINA, 3938 02:54:59,680 --> 02:55:05,360 ONEL VEER, 3939 02:55:05,360 --> 02:55:06,800 ON -- OLIVER AND BRANDON, AND 3940 02:55:06,800 --> 02:55:12,680 MAXIM. 3941 02:55:12,680 --> 02:55:13,760 THANKS FOR YOUR ATTENTION. 3942 02:55:13,760 --> 02:55:15,840 >> SOME WILL CARRY TO THE 3943 02:55:15,840 --> 02:55:20,880 DISCUSSION AT THE END. 3944 02:55:20,880 --> 02:55:21,520 GO AHEAD. 3945 02:55:21,520 --> 02:55:21,760 >> HI. 3946 02:55:21,760 --> 02:55:25,480 SO DID YOU SEE ANY DIFFERENCES 3947 02:55:25,480 --> 02:55:27,440 IN THE REPERTOIRES BETWEEN OLDER 3948 02:55:27,440 --> 02:55:30,760 AND YOUNGER PEOPLE IN YOUR COVID 3949 02:55:30,760 --> 02:55:31,000 DATASETS? 3950 02:55:31,000 --> 02:55:33,040 >> YEAH, SO I WOULD SAY SO FAR 3951 02:55:33,040 --> 02:55:35,360 IN THE COVID ONES WE HAD WE 3952 02:55:35,360 --> 02:55:37,320 HAVEN'T SEEN ANYTHING THAT WAS 3953 02:55:37,320 --> 02:55:38,520 ABSOLUTELY SYSTEMATIC, DIFFERENT 3954 02:55:38,520 --> 02:55:39,200 BETWEEN OLDER AND YOUNG 3955 02:55:39,200 --> 02:55:39,600 IRINDIVIDUALS. 3956 02:55:39,600 --> 02:55:41,800 WE DID SEE FEWER CLONES OR FEWER 3957 02:55:41,800 --> 02:55:44,760 SPECIFIC CELLS IN THE MOST 3958 02:55:44,760 --> 02:55:52,560 ELDERLY WE LOOKED AT BUT OVERALL 3959 02:55:52,560 --> 02:55:56,800 MORE SIMILARITIES THAN 3960 02:55:56,800 --> 02:55:57,280 DIFFERENCES. 3961 02:55:57,280 --> 02:55:59,320 IT'S PROBABLY BECAUSE MOST 3962 02:55:59,320 --> 02:56:01,640 PEOPLE START WITH A CLEAN SLATE, 3963 02:56:01,640 --> 02:56:03,360 THERE AREN'T THAT MANY 3964 02:56:03,360 --> 02:56:05,440 CROSS-REACTIVE TO VIRUSES WE'VE 3965 02:56:05,440 --> 02:56:07,520 BEEN EXPOSED TO, T CELL MAY BE 3966 02:56:07,520 --> 02:56:17,480 MORE, B CELLS IT'S A SMALL 3967 02:56:17,480 --> 02:56:17,920 FRACTION THAT BIND. 3968 02:56:17,920 --> 02:56:22,200 >> THANKS. 3969 02:56:22,200 --> 02:56:22,840 >> IN THE BACK. 3970 02:56:22,840 --> 02:56:26,000 >> I WAS WONDERING IF IN ANY OF 3971 02:56:26,000 --> 02:56:27,760 YOUR MACHINE LEARNING MODELS YOU 3972 02:56:27,760 --> 02:56:30,240 HAVE HAD THE OPPORTUNITY YET TO 3973 02:56:30,240 --> 02:56:35,440 ASK THE QUESTION IF YOU CAN 3974 02:56:35,440 --> 02:56:37,400 PREDICT SOMEONE'S RESPONSE BASED 3975 02:56:37,400 --> 02:56:39,520 OFF THEIR REPERTOIRE BEFORE 3976 02:56:39,520 --> 02:56:39,800 VACCINATION? 3977 02:56:39,800 --> 02:56:41,000 >> YEAH, SO WE HAVEN'T DONE 3978 02:56:41,000 --> 02:56:42,360 THAT YET. 3979 02:56:42,360 --> 02:56:43,520 I THINK THERE'S PROSPECT ONE 3980 02:56:43,520 --> 02:56:45,200 COULD DO SO BUT IN TERMS OF 3981 02:56:45,200 --> 02:56:46,920 FREQUENCY OF MEMORY CELLS THAT 3982 02:56:46,920 --> 02:56:50,000 SHOULD RESPOND TO THAT 3983 02:56:50,000 --> 02:56:51,800 PARTICULAR ANTIGEN, IT'S 3984 02:56:51,800 --> 02:56:55,240 SOMETHING WE'RE HEADED TOWARDS. 3985 02:56:55,240 --> 02:56:58,440 IT'S PROBABLY -- YOU KNOW, WILL 3986 02:56:58,440 --> 02:57:00,840 WORK MORE COMBINED WITH OTHER 3987 02:57:00,840 --> 02:57:04,120 INFORMATION FROM THE PERSON'S 3988 02:57:04,120 --> 02:57:04,520 REPERTOIRE. 3989 02:57:04,520 --> 02:57:07,120 I SHOWED BCR DATA, ALSO APPLYING 3990 02:57:07,120 --> 02:57:08,080 TO TCRs FROM THE SAME 3991 02:57:08,080 --> 02:57:10,360 INDIVIDUALS. 3992 02:57:10,360 --> 02:57:15,800 3993 02:57:15,800 --> 02:57:17,480 >> EXCELLENT. 3994 02:57:17,480 --> 02:57:19,640 WONDERING IF IT'S POSSIBLE TO 3995 02:57:19,640 --> 02:57:22,840 IDENTIFY THE B CELL CLONES 3996 02:57:22,840 --> 02:57:25,040 PRODUCING AUTOANTIBODIES FOR 3997 02:57:25,040 --> 02:57:27,440 INTERFERON AGAINST THE -- IN 3998 02:57:27,440 --> 02:57:29,960 COVID, ARE THOSE THE POTENTIAL 3999 02:57:29,960 --> 02:57:31,920 DRIVERS OF CHANGES IN THE 4000 02:57:31,920 --> 02:57:32,160 ELDERLY? 4001 02:57:32,160 --> 02:57:35,000 >> YEAH, I THINK THAT'S A GREAT 4002 02:57:35,000 --> 02:57:36,560 EXPERIMENT, USING THOSE AS 4003 02:57:36,560 --> 02:57:39,040 SORTING BUT WE HAVEN'T DONE THAT 4004 02:57:39,040 --> 02:57:39,200 YET. 4005 02:57:39,200 --> 02:57:41,320 I THINK THE FREQUENCY OF SUCH B 4006 02:57:41,320 --> 02:57:43,560 CELLS IS PROBABLY NOT TERRIBLY 4007 02:57:43,560 --> 02:57:45,360 HIGH, YOU KNOW, SOME OF THE 4008 02:57:45,360 --> 02:57:47,440 STUDIES THAT REPORT THEY ARE 4009 02:57:47,440 --> 02:57:50,000 PRESENT IN 30 OR 50% OF 4010 02:57:50,000 --> 02:57:51,520 INDIVIDUALS MAYBE USING VERY 4011 02:57:51,520 --> 02:57:53,600 SENSITIVE ASSAYS, BUT I THINK 4012 02:57:53,600 --> 02:57:54,920 THAT'S A VERY FOCUSED TOPIC TO 4013 02:57:54,920 --> 02:57:56,880 LOOK AT IN THE ELDERLY, AND WE 4014 02:57:56,880 --> 02:58:00,480 EXPECT TO SEE A DIFFERENCE. 4015 02:58:00,480 --> 02:58:02,440 >> I THINK WE CAN GO ON IF 4016 02:58:02,440 --> 02:58:05,400 THERE ARE NO OTHER QUESTIONS. 4017 02:58:05,400 --> 02:58:14,840 KEEP THOSE QUESTIONS FOR THE 4018 02:58:14,840 --> 02:58:18,360 NEXT DISCUSSION. 4019 02:58:18,360 --> 02:58:22,280 NEXT SPEAKER IS JARROD DUDAKOV. 4020 02:58:22,280 --> 02:58:26,200 AND HE'S GOING TO SPEAK ABOUT 4021 02:58:26,200 --> 02:58:28,200 AGE-RELATED T CELL FUNCTIONAL 4022 02:58:28,200 --> 02:58:28,520 CHANGES. 4023 02:58:28,520 --> 02:58:30,720 AND WE'LL HAVE AN ANNOUNCEMENT 4024 02:58:30,720 --> 02:58:36,000 ABOUT A PROGRAM AFTER HIS TALK 4025 02:58:36,000 --> 02:58:37,680 RELATED TO THIS. 4026 02:58:37,680 --> 02:58:39,120 >> THANK YOU. 4027 02:58:39,120 --> 02:58:43,840 I'M TRYING SOMETHING DIFFERENT 4028 02:58:43,840 --> 02:58:44,160 HERE. 4029 02:58:44,160 --> 02:58:47,120 I'M NOT GOING TO TALK MUCH ABOUT 4030 02:58:47,120 --> 02:58:48,520 T CELLS BUT WHERE THEY COME FROM 4031 02:58:48,520 --> 02:58:50,400 AND HOW THAT CHANGES WITH AGE 4032 02:58:50,400 --> 02:58:51,960 AND IMPACT T CELL FUNCTION IN 4033 02:58:51,960 --> 02:58:53,480 THE PERIPHERY. 4034 02:58:53,480 --> 02:58:55,960 THE TITLE IS REALLY TALKING 4035 02:58:55,960 --> 02:58:58,800 ABOUT NEW STORY TOTALLY 4036 02:58:58,800 --> 02:59:02,800 UNPUBLISHED, NOW OUT AS 4037 02:59:02,800 --> 02:59:05,160 PRE-PRINT, WE'LL TRYING TO 4038 02:59:05,160 --> 02:59:11,400 IDENTIFY THE ATYPICAL EPITHELIAL 4039 02:59:11,400 --> 02:59:17,760 POPULATION, T CELL DEVELOPMENT 4040 02:59:17,760 --> 02:59:22,800 AND REPAIR AS WELL. 4041 02:59:22,800 --> 02:59:24,800 AS MARK SAID EARLIER, WE'RE 4042 02:59:24,800 --> 02:59:26,400 INTERESTED BECAUSE OF THE BROAD 4043 02:59:26,400 --> 02:59:28,000 REPERTOIRE OF CELLS THAT THEY 4044 02:59:28,000 --> 02:59:33,280 CAN PRODUCE THAT CAN RECOGNIZE 4045 02:59:33,280 --> 02:59:33,920 UNKNOWN ANTIGENS, NEOANTIGENS, 4046 02:59:33,920 --> 02:59:37,360 PATHOGENS, THINGS LIKE THAT. 4047 02:59:37,360 --> 02:59:39,240 NOW, THERE'S ENORMOUSLY DIVERSE 4048 02:59:39,240 --> 02:59:41,200 REPERTOIRE POTENTIAL OF T CELLS, 4049 02:59:41,200 --> 02:59:43,040 MOST AUTOREACTIVE, TAKEN CARE OF 4050 02:59:43,040 --> 02:59:45,320 IN THE THYMUS THROUGH TOLERANCE 4051 02:59:45,320 --> 02:59:47,000 MECHANISMS BUT REALLY THE RESULT 4052 02:59:47,000 --> 02:59:49,280 IS THAT THERE'S THE REQUIREMENT 4053 02:59:49,280 --> 02:59:50,800 THAT IS SPECIALIZED ORGAN TO 4054 02:59:50,800 --> 02:59:52,680 MAKE THIS HAPPEN SO UNLIKE 4055 02:59:52,680 --> 02:59:54,840 PRETTY MUCH EVERY OTHER 4056 02:59:54,840 --> 02:59:56,360 HEMATOPOIETIC CELL INCLUDING B 4057 02:59:56,360 --> 02:59:59,560 CELLS THAT REQUIRE SPRINKLING OF 4058 02:59:59,560 --> 03:00:02,640 CYTOKINES IN BONE MARROW T CELLS 4059 03:00:02,640 --> 03:00:04,400 REQUIRE THIS SPECIALIZED ROLE. 4060 03:00:04,400 --> 03:00:06,120 THE REASON IS BECAUSE OF THE 4061 03:00:06,120 --> 03:00:08,000 STROMAL MARKER ENVIRONMENT THAT 4062 03:00:08,000 --> 03:00:10,640 SUPPORTS THAT T CELL 4063 03:00:10,640 --> 03:00:10,920 DEVELOPMENT. 4064 03:00:10,920 --> 03:00:15,440 THIS IS COMPRISED OF THYMIC 4065 03:00:15,440 --> 03:00:17,480 EPITHELIAL CELLS, THESE ARE THE 4066 03:00:17,480 --> 03:00:28,000 CELLS THAT SUPPORT ALL ASPECTS 4067 03:00:29,720 --> 03:00:31,520 OF T CELL DEVELOPMENT, REALLY 4068 03:00:31,520 --> 03:00:33,640 CRITICALLY ALSO NEGATIVE 4069 03:00:33,640 --> 03:00:37,640 SELECTION STUDIES, EDUCATING T 4070 03:00:37,640 --> 03:00:39,400 CELLS AGAINST ANTIGENS. 4071 03:00:39,400 --> 03:00:47,720 THIS IS A COMPLICATED SLIDE, 4072 03:00:47,720 --> 03:00:52,080 HIGHLIGHTING STROMAL CELL 4073 03:00:52,080 --> 03:00:54,160 POPULATIONS, FIBROBLASTS, 4074 03:00:54,160 --> 03:00:56,000 ENDOTHELIAL, HEMATOPOIETIC, 4075 03:00:56,000 --> 03:00:57,680 DENDRITIC, MACROPHAGES, THINGS 4076 03:00:57,680 --> 03:00:58,440 LIKE THAT. 4077 03:00:58,440 --> 03:01:01,080 THYMIC FUNCTION IS NOT A STATIC 4078 03:01:01,080 --> 03:01:03,920 PROCESS, ONE OF THE EARLIEST 4079 03:01:03,920 --> 03:01:05,560 ORGANS TO SHOW SIGNS OF AGE. 4080 03:01:05,560 --> 03:01:10,160 YOU CAN SEE THIS IS IN THE HUMAN 4081 03:01:10,160 --> 03:01:13,360 TISSUE WHERE EVEN AS EARLY AS 4082 03:01:13,360 --> 03:01:15,960 PEDIATRIC PATIENTS YOU START TO 4083 03:01:15,960 --> 03:01:18,960 SEE PERIVASCULAR SPACES FORMING, 4084 03:01:18,960 --> 03:01:25,360 FATTY ISSUE ACCUMULATING, PAST 4085 03:01:25,360 --> 03:01:27,080 50 YOU'VE GOT VERY LITTLE 4086 03:01:27,080 --> 03:01:28,520 FUNCTIONAL TISSUE LEFT, SOME BUT 4087 03:01:28,520 --> 03:01:29,720 VERY LITTLE FUNCTIONAL TISSUE 4088 03:01:29,720 --> 03:01:31,360 LEFT, MOST IS JUST FAT, AT LEAST 4089 03:01:31,360 --> 03:01:32,120 IN HUMAN. 4090 03:01:32,120 --> 03:01:35,200 IN THE MOUSE IF IT SHRINKS IN 4091 03:01:35,200 --> 03:01:38,040 SIZE YOU HAVE LESS FATTY TISSUE 4092 03:01:38,040 --> 03:01:39,480 ITSELF. 4093 03:01:39,480 --> 03:01:41,880 THIS RESULTS IN A LOSS OF EXPORT 4094 03:01:41,880 --> 03:01:45,800 OF NEW NAIVE T CELLS OUT OF THE 4095 03:01:45,800 --> 03:01:46,880 PERIPHERY. 4096 03:01:46,880 --> 03:01:49,640 THESE ARE A MARKER OF THE T-CELL 4097 03:01:49,640 --> 03:01:54,040 RECEPTOR RECOMBINATION EVENTS IN 4098 03:01:54,040 --> 03:02:02,080 THE THYMUS, TRECs, CELLS WITH 4099 03:02:02,080 --> 03:02:03,680 A REMNANT RECENTLY COMING OUT OF 4100 03:02:03,680 --> 03:02:04,320 THE THYMUS. 4101 03:02:04,320 --> 03:02:05,920 WHAT DOES THIS MEAN WHEN YOU 4102 03:02:05,920 --> 03:02:09,000 TALK ABOUT A NORMAL HEALTHY 4103 03:02:09,000 --> 03:02:09,360 INDIVIDUAL? 4104 03:02:09,360 --> 03:02:11,880 IN A NORMAL YOUNG PERSON YOU GET 4105 03:02:11,880 --> 03:02:14,480 A ROBUST EXPORT OF NEW NAIVE 4106 03:02:14,480 --> 03:02:15,720 CELLS COMING OUT, ROBUST 4107 03:02:15,720 --> 03:02:17,640 REPERTOIRE OF T CELLS. 4108 03:02:17,640 --> 03:02:19,600 IN AN AGED INDIVIDUAL, OLD 4109 03:02:19,600 --> 03:02:23,000 INDIVIDUAL, FEWER T CELLS COMING 4110 03:02:23,000 --> 03:02:24,560 OUT, HOMEOSTATIC EXPANSION OF 4111 03:02:24,560 --> 03:02:29,040 MEMORY CELLS, SAME NUMBER BUT 4112 03:02:29,040 --> 03:02:32,320 RATIO OF NAIVE TO MEMORY CELLS 4113 03:02:32,320 --> 03:02:35,480 IS RADICALLY REDUCED, MAXIM 4114 03:02:35,480 --> 03:02:37,880 INDICATED THAT EARLIER AS WELL. 4115 03:02:37,880 --> 03:02:41,280 HOW CAN THIS IMPACT OUR CLINICAL 4116 03:02:41,280 --> 03:02:41,560 PATHOLOGY? 4117 03:02:41,560 --> 03:02:43,480 TWO ASPECTS HERE, MARK INDICATED 4118 03:02:43,480 --> 03:02:47,080 THIS EARLIER, RESPONSES TO FLU 4119 03:02:47,080 --> 03:02:48,040 VACCINE, AND OTHER VACCINES 4120 03:02:48,040 --> 03:02:49,920 REDUCED WITH AGE. 4121 03:02:49,920 --> 03:02:54,400 SOME IS GOING TO BE DEPENDS ON T 4122 03:02:54,400 --> 03:02:56,680 CELLS, SOME IS T CELL DEPENDENT. 4123 03:02:56,680 --> 03:02:59,000 AND SO THIS REDUCED EXPORT OF 4124 03:02:59,000 --> 03:03:02,400 NAIVE T CELLS CAN IMPACT ON 4125 03:03:02,400 --> 03:03:02,600 THAT. 4126 03:03:02,600 --> 03:03:04,880 AND SOMETHING WE'RE INTERESTED 4127 03:03:04,880 --> 03:03:06,320 IN AT THE MOMENT, LESS DIRECT 4128 03:03:06,320 --> 03:03:09,680 EVIDENCE BUT A GOOD RATIONALE, 4129 03:03:09,680 --> 03:03:12,120 THERE'S A STRONG CORRELATION 4130 03:03:12,120 --> 03:03:13,760 BETWEEN RESPONSES TO CHECKPOINT 4131 03:03:13,760 --> 03:03:14,480 IMMUNOTHERAPY AND MUTATIONAL 4132 03:03:14,480 --> 03:03:16,600 BURDEN OF THE TUMOR ITSELF. 4133 03:03:16,600 --> 03:03:18,880 NOW, WHAT THIS SAYS TO ME IS 4134 03:03:18,880 --> 03:03:25,040 THAT THERE IS THIS KIND OF STASH 4135 03:03:25,040 --> 03:03:26,440 OF ABILITY TO RESPOND, 4136 03:03:26,440 --> 03:03:29,000 MUTATIONAL BURDEN IS ONE ASPECT, 4137 03:03:29,000 --> 03:03:30,440 BREADTH OF T-CELL RECEPTOR IS 4138 03:03:30,440 --> 03:03:32,600 ANOTHER BECAUSE IF YOU -- BOTH 4139 03:03:32,600 --> 03:03:33,760 THERAPIES ARE PREDICATED ON THE 4140 03:03:33,760 --> 03:03:38,480 FACT THERE'S A T CELL THERE THAT 4141 03:03:38,480 --> 03:03:39,760 CAN RECOGNIZE THAT ANTIGEN OR 4142 03:03:39,760 --> 03:03:41,560 PATHOGEN OR WHATEVER IT IS. 4143 03:03:41,560 --> 03:03:43,640 IF YOU'VE GOT REDUCED NAIVE T 4144 03:03:43,640 --> 03:03:44,720 CELLS COMING OUT THE POSSIBILITY 4145 03:03:44,720 --> 03:03:48,240 OF HAVING THAT CLONE IS GOING TO 4146 03:03:48,240 --> 03:03:50,960 DECLINE AND DECLINE AND DECLINE. 4147 03:03:50,960 --> 03:03:54,040 NOW, THE OTHER PROBLEM, IF IT 4148 03:03:54,040 --> 03:03:57,640 WANTS TO ADVANCE, IS THE THYMUS 4149 03:03:57,640 --> 03:03:59,520 IS EXTREMELY SENSITIVE TO 4150 03:03:59,520 --> 03:04:00,720 NEGATIVE STIMULUS, SO ACUTE 4151 03:04:00,720 --> 03:04:01,240 DAMAGE. 4152 03:04:01,240 --> 03:04:03,640 THERE ARE THREE FORMS OF DAMAGE 4153 03:04:03,640 --> 03:04:13,400 HERE THAT I'M HIGHLIGHTING, 4154 03:04:13,400 --> 03:04:13,880 IONIZING RADIATION, 4155 03:04:13,880 --> 03:04:19,920 CYCLOPHOSPHAMIDE, AND 4156 03:04:19,920 --> 03:04:20,840 DEXAMETHASONE GOING DOWN OVER 4157 03:04:20,840 --> 03:04:24,680 THE FIRST COUPLE DAYS AFTER THE 4158 03:04:24,680 --> 03:04:25,160 INJURY. 4159 03:04:25,160 --> 03:04:27,600 THE THING IS THERE'S A 4160 03:04:27,600 --> 03:04:29,160 REMARKABLE CAPACITY TO REPAIR 4161 03:04:29,160 --> 03:04:29,560 ITSELF. 4162 03:04:29,560 --> 03:04:31,880 IF YOU FOLLOW THAT KINETIC 4163 03:04:31,880 --> 03:04:34,080 ANALYSIS YOU SEE UPSTREAM IN THE 4164 03:04:34,080 --> 03:04:44,040 ABILITY TO REPAIR AND GET ROBUST 4165 03:04:44,040 --> 03:04:48,920 CELLULARITY GAIN. 4166 03:04:48,920 --> 03:04:50,800 IN THE CORTICOSTEROID MODEL YOU 4167 03:04:50,800 --> 03:04:52,600 GET THIS IN THE TISSUE. 4168 03:04:52,600 --> 03:04:54,960 WHERE THIS COMES REALLY INTO THE 4169 03:04:54,960 --> 03:04:59,720 FORE IS IN LET'S SAY BONE MARROW 4170 03:04:59,720 --> 03:05:00,400 TRANSPLANT PARTICULARLY 4171 03:05:00,400 --> 03:05:01,400 ALLOGENEIC, YOU CAN TAKE YEARS 4172 03:05:01,400 --> 03:05:03,520 TO RECOVER T CELLS AFTER THERAPY 4173 03:05:03,520 --> 03:05:06,000 BECAUSE THE WHY YOU GIVE A 4174 03:05:06,000 --> 03:05:08,440 TRANSPLANT, YOU WIPE OUT THE 4175 03:05:08,440 --> 03:05:10,520 ENTIRE HEMATOPOIETIC SYSTEM AND 4176 03:05:10,520 --> 03:05:11,720 REPLACE WITH SOMEBODY ELSE'S, IT 4177 03:05:11,720 --> 03:05:13,680 CAN TAKE A LONG TIME TO COME 4178 03:05:13,680 --> 03:05:15,440 BACK. 4179 03:05:15,440 --> 03:05:17,640 THIS CAN HAVE PROFOUND IMPACT IN 4180 03:05:17,640 --> 03:05:18,200 CLINICAL OUTCOMES. 4181 03:05:18,200 --> 03:05:21,920 ON THE LEFT IS LOOKING AT T CELL 4182 03:05:21,920 --> 03:05:26,080 RECONSTITUTION AFTER BONE MARROW 4183 03:05:26,080 --> 03:05:27,280 TRANSPLANT, ALLOGENEIC 4184 03:05:27,280 --> 03:05:35,160 TRANSPLANT, DAY 100 CD4 T CELL 4185 03:05:35,160 --> 03:05:40,960 RECONSTITUTION, IF YOU STRATIFY, 4186 03:05:40,960 --> 03:05:42,680 YOU SEE PROFOUND BETWEEN THE 4187 03:05:42,680 --> 03:05:43,440 GROUPS, OVERALL SURVIVAL, 4188 03:05:43,440 --> 03:05:45,440 ANYTHING THAT MIGHT BE GOING 4189 03:05:45,440 --> 03:05:46,000 WITH THOSE PATIENTS. 4190 03:05:46,000 --> 03:05:47,920 ON THE RIGHT THERE'S A FLIP 4191 03:05:47,920 --> 03:05:48,160 SLIDE. 4192 03:05:48,160 --> 03:05:50,240 THIS IS LOOKING AT THYMIC 4193 03:05:50,240 --> 03:05:53,960 FUNCTION AT THE TIME OF 4194 03:05:53,960 --> 03:05:55,200 TRANSPLANT, THE NUMBER OF 4195 03:05:55,200 --> 03:05:57,240 TRECs BEFORE THE TRANSPLANT 4196 03:05:57,240 --> 03:05:58,800 ITSELF, AND AGAIN IF YOU HAVE 4197 03:05:58,800 --> 03:06:01,200 PATIENTS WITH HIGH TREC LEVELS, 4198 03:06:01,200 --> 03:06:03,840 YOU HAVE A BETTER CLINICAL 4199 03:06:03,840 --> 03:06:05,160 OUTCOME THAN LOW TREC LEVELS. 4200 03:06:05,160 --> 03:06:08,640 WHAT BOTH SAY IS HAVING THYMUS, 4201 03:06:08,640 --> 03:06:09,640 THYMIC FUNCTION, ROBUST THYMIC 4202 03:06:09,640 --> 03:06:11,960 FUNCTION, IS GOING TO BE OF 4203 03:06:11,960 --> 03:06:15,440 BENEFIT TO OUR TRANSPLANT 4204 03:06:15,440 --> 03:06:15,760 OUTCOMES. 4205 03:06:15,760 --> 03:06:18,400 PART OF WHY THIS IS IS THAT EVEN 4206 03:06:18,400 --> 03:06:21,120 THOUGH IT HAS A REMARKABLE 4207 03:06:21,120 --> 03:06:22,440 CAPACITY TO REPAIR ITSELF THAT 4208 03:06:22,440 --> 03:06:24,080 DECLINE WITH AGE. 4209 03:06:24,080 --> 03:06:26,480 YOU CAN SEE IN THE MODEL ON THE 4210 03:06:26,480 --> 03:06:27,800 LEFT IN MOUSE, IT TAKES A LITTLE 4211 03:06:27,800 --> 03:06:30,520 BIT LONGER TO COME BACK. 4212 03:06:30,520 --> 03:06:32,160 THE RIGHT IS CLINICAL DATA GOING 4213 03:06:32,160 --> 03:06:36,320 QUITE A FEW YEARS BACK FROM 4214 03:06:36,320 --> 03:06:40,480 CRYSTAL McCALL SHOWING THE 4215 03:06:40,480 --> 03:06:40,800 PERIPHERY. 4216 03:06:40,800 --> 03:06:42,360 YOU CAN SEE EVEN AFTER ALMOST 4217 03:06:42,360 --> 03:06:45,000 TWO YEARS THEY STILL HAVE NOT 4218 03:06:45,000 --> 03:06:47,600 RECOVERED THEIR CD4 COUNTS. 4219 03:06:47,600 --> 03:06:49,280 TO GO TO SCOTT'S POINT BEFORE, 4220 03:06:49,280 --> 03:06:53,240 THIS IS A 23-YEAR-OLD. 4221 03:06:53,240 --> 03:06:54,440 THESE EFFECTS, BEFORE ANYONE IS 4222 03:06:54,440 --> 03:06:56,480 SAYING YOU WOULD NOT CALL THIS 4223 03:06:56,480 --> 03:06:58,640 PERSON AND OLD PERSON, BUT 4224 03:06:58,640 --> 03:06:59,240 IMMUNOLOGICALLY THEY ARE 4225 03:06:59,240 --> 03:07:00,640 STARTING TO BECOME AN OLD 4226 03:07:00,640 --> 03:07:02,600 PERSON, AT LEAST IN SOME SENSE 4227 03:07:02,600 --> 03:07:02,840 ANYWAY. 4228 03:07:02,840 --> 03:07:07,720 AND WHEN YOU PUT THIS INTO THE 4229 03:07:07,720 --> 03:07:11,040 TRANSPLANT CONTEXT, LOOK AT AGE, 4230 03:07:11,040 --> 03:07:15,600 THIS COMES TOGETHER, OLDER 4231 03:07:15,600 --> 03:07:18,120 PATIENTS DO PERFORM WORSE 4232 03:07:18,120 --> 03:07:20,880 OVERALL AFTER TRANSPLANT. 4233 03:07:20,880 --> 03:07:22,520 WE'RE INTERESTED OVER THE LAST 4234 03:07:22,520 --> 03:07:25,360 COUPLE YEARS UNDERSTANDING WHY 4235 03:07:25,360 --> 03:07:30,480 IS IT THAT REGENERATIVE CAPACIY 4236 03:07:30,480 --> 03:07:31,280 IS LIMITED WITH AGE, STARTING TO 4237 03:07:31,280 --> 03:07:32,120 UNDERSTAND THAT. 4238 03:07:32,120 --> 03:07:34,880 WHAT DO YOU DO WHEN YOU DON'T 4239 03:07:34,880 --> 03:07:36,880 KNOW WHERE TO START? 4240 03:07:36,880 --> 03:07:38,400 GO INTO SINGLE CELL SEQUENCING. 4241 03:07:38,400 --> 03:07:39,760 THAT'S WHAT WE DID. 4242 03:07:39,760 --> 03:07:43,960 WE WANTED TO FOCUS ON 4243 03:07:43,960 --> 03:07:46,560 NON-HEMATOPOIETIC STROMAL CELL 4244 03:07:46,560 --> 03:07:47,760 TAKING CD45 NEGATIVE CELLS, 4245 03:07:47,760 --> 03:07:50,080 SINGLE CELL SEQUENCING IN YOUNG 4246 03:07:50,080 --> 03:07:52,760 AND AGED MICE, AND ALSO ADDING A 4247 03:07:52,760 --> 03:07:54,360 DAMAGED STIMULI AS WELL. 4248 03:07:54,360 --> 03:07:59,280 WE'VE GOT TOTAL BODY IRRADIATION 4249 03:07:59,280 --> 03:08:02,440 LOOKING AT DAY 0, 1, 4, 7. 4250 03:08:02,440 --> 03:08:07,280 YOU CAN SEE THIS IS A DOWN 4251 03:08:07,280 --> 03:08:08,800 SWING, SIMILARITY, STARTING TO 4252 03:08:08,800 --> 03:08:10,680 COME BACK BUT HASN'T PROGRESSED 4253 03:08:10,680 --> 03:08:11,240 TOO MUCH. 4254 03:08:11,240 --> 03:08:15,160 WHEN WE DO THIS WE GET A BUNCH 4255 03:08:15,160 --> 03:08:18,160 OF CELL POPULATIONS. 4256 03:08:18,160 --> 03:08:27,320 THREE BIG ONES WE'RE 4257 03:08:27,320 --> 03:08:28,120 CONCENTRATING ON ENDOTHELIAL, WE 4258 03:08:28,120 --> 03:08:31,040 CAN BREAK DOWN, GET SUBSETS, 4259 03:08:31,040 --> 03:08:32,640 FIBROBLAST SUBSETS, I WON'T GO 4260 03:08:32,640 --> 03:08:34,120 INTO THOSE TODAY, IN THE 4261 03:08:34,120 --> 03:08:35,440 INTEREST OF TIME. 4262 03:08:35,440 --> 03:08:38,080 SOMETHING THAT STOOD OUT IS WHEN 4263 03:08:38,080 --> 03:08:40,560 WE WERE LOOKING AT EPITHELIAL 4264 03:08:40,560 --> 03:08:42,000 CELLS, IN ADDITION TO 4265 03:08:42,000 --> 03:08:42,680 HETEROGENEITY THAT'S BEEN 4266 03:08:42,680 --> 03:08:45,080 IDENTIFIED OVER THE LAST FEW 4267 03:08:45,080 --> 03:08:48,760 YEARS IN THYMIC EPITHELIAL 4268 03:08:48,760 --> 03:08:52,840 CELLS, WHAT WE FOUND WERE TWO 4269 03:08:52,840 --> 03:08:53,800 ATYPICAL POPULATIONS OF THYMIC 4270 03:08:53,800 --> 03:08:55,120 EPITHELIAL CELLS THAT ONLY SEEM 4271 03:08:55,120 --> 03:08:57,640 TO BE THERE IN OLD MICE AND NOT 4272 03:08:57,640 --> 03:08:59,520 YOUNG MICE. 4273 03:08:59,520 --> 03:09:03,360 THAT'S THESE TWO POPULATIONS 4274 03:09:03,360 --> 03:09:06,840 OVER HERE, REFERRED TO AS AATEC 4275 03:09:06,840 --> 03:09:08,240 1 AND IT. 4276 03:09:08,240 --> 03:09:11,000 THEY ONLY START TO EMERGE WITH 4277 03:09:11,000 --> 03:09:11,240 AGE. 4278 03:09:11,240 --> 03:09:13,400 IF WE LOOK AT WHAT THEY ARE 4279 03:09:13,400 --> 03:09:18,440 EXPRESSING, THEY ARE QUITE 4280 03:09:18,440 --> 03:09:18,720 ATYPICAL. 4281 03:09:18,720 --> 03:09:25,320 THE Y DO NOT EXPRESS MARKERS, 4282 03:09:25,320 --> 03:09:27,200 THEY LOSE A LOT OF MARKERS. 4283 03:09:27,200 --> 03:09:34,000 IN FACT, IF YOU LOOK AT STANDARD 4284 03:09:34,000 --> 03:09:38,160 FLOW CYTOMETRY, THESE ARE 4285 03:09:38,160 --> 03:09:42,440 MARKERS, WHAT WE'VE NOTICED, 4286 03:09:42,440 --> 03:09:45,400 DISMISSED AS ARTIFACTUAL IS WE 4287 03:09:45,400 --> 03:09:51,520 SEE THIS EMERGENCE OF DOUBLE 4288 03:09:51,520 --> 03:09:53,800 NEGATIVE POPULATION, WE THINK 4289 03:09:53,800 --> 03:09:54,920 THIS IS AATEC 1. 4290 03:09:54,920 --> 03:09:59,280 WHEN YOU TALK ABOUT AATEC 2, 4291 03:09:59,280 --> 03:10:01,160 EVEN WEIRDER, QUINTESSENTIAL 4292 03:10:01,160 --> 03:10:05,840 MARKER OF EPITHELIAL CELLS, DO 4293 03:10:05,840 --> 03:10:11,960 NOT SEEM TO EXPRESS. 4294 03:10:11,960 --> 03:10:19,280 IF WE RUN GSEA ANALYSIS WE LOSE 4295 03:10:19,280 --> 03:10:21,080 ANTIGEN PROCESSING, CORRELATES 4296 03:10:21,080 --> 03:10:23,240 WITH THEM LOSING TYPICAL 4297 03:10:23,240 --> 03:10:25,320 EPITHELIAL CELL FUNCTION AND 4298 03:10:25,320 --> 03:10:28,720 PRESENTATION IS A MAJOR ROLE OF 4299 03:10:28,720 --> 03:10:33,520 CELLS, IN THE AATEC 2s THE 4300 03:10:33,520 --> 03:10:36,480 HIGHEST ENRICHED PATHWAY WAS 4301 03:10:36,480 --> 03:10:37,360 THIS EMT SIGNATURE. 4302 03:10:37,360 --> 03:10:41,400 IF WE LOOK AT THAT MORE CLOSELY 4303 03:10:41,400 --> 03:10:45,400 AND GAUGE ON THESE -- THIS IS A 4304 03:10:45,400 --> 03:10:49,920 LIST OF 9,000 EMT-RELATED GENES, 4305 03:10:49,920 --> 03:10:51,480 WE RANK THEM ACCORDING TO 4306 03:10:51,480 --> 03:10:53,960 EXPRESSION ACROSS THE CELL 4307 03:10:53,960 --> 03:10:58,920 SUBSETS AND FIND THE AATEC 2s 4308 03:10:58,920 --> 03:11:02,080 ARE IN THE MIDDLE HERE, 4309 03:11:02,080 --> 03:11:05,480 SOMEWHERE IN THE MIDDLE. 4310 03:11:05,480 --> 03:11:11,920 IN THE SCATTER PLOT CAN LOOK AT 4311 03:11:11,920 --> 03:11:15,720 MARKERS, WE THINK AATEC 2s ARE 4312 03:11:15,720 --> 03:11:18,680 AT LEAST PARTIALLY DOWN THE 4313 03:11:18,680 --> 03:11:18,960 PHENOTYPE. 4314 03:11:18,960 --> 03:11:20,440 WE DON'T THINK THEY HAVE GONE 4315 03:11:20,440 --> 03:11:22,080 THE FULL WAY BUT SITTING IN THE 4316 03:11:22,080 --> 03:11:24,280 MIDDLE SECTION. 4317 03:11:24,280 --> 03:11:25,520 ARE THESE EPITHELIAL CELLS? 4318 03:11:25,520 --> 03:11:27,920 WE DID A LINEAGE TRACING 4319 03:11:27,920 --> 03:11:28,880 EXPERIMENT WITH OUR 4320 03:11:28,880 --> 03:11:32,320 COLLABORATORS AT UNIVERSITY OF 4321 03:11:32,320 --> 03:11:35,480 GEORGIA WHO THEY HAD GENERATED A 4322 03:11:35,480 --> 03:11:41,920 REPORTER MOUSE UNDER THE CONTROL 4323 03:11:41,920 --> 03:11:48,800 OF FOXM 1 PROMOTER, THIS IS 4324 03:11:48,800 --> 03:11:49,360 EXPRESSED. 4325 03:11:49,360 --> 03:11:50,800 WHEN WE OVERLAY THAT DATASET ON 4326 03:11:50,800 --> 03:11:52,840 TOP OF THE LARGER DATASET, IT'S 4327 03:11:52,840 --> 03:11:56,440 ONLY A FEW NUMBER OF CELLS AWAY, 4328 03:11:56,440 --> 03:11:59,000 A THOUSAND VERSUS 20,000 LARGE 4329 03:11:59,000 --> 03:12:03,360 DATASET, YOU CAN SEE WHEN YOU 4330 03:12:03,360 --> 03:12:04,720 LOOK AT EXPRESSION, IT'S PRETTY 4331 03:12:04,720 --> 03:12:09,640 MUCH ALL OVER OUR DIFFERENT 4332 03:12:09,640 --> 03:12:12,120 EPITHELIAL CELLS, INCLUDING 4333 03:12:12,120 --> 03:12:17,680 AATEC 2 AND A SMATTERING OF 4334 03:12:17,680 --> 03:12:19,360 1s, COMING FROM A POPULATION 4335 03:12:19,360 --> 03:12:20,000 BEFOREHAND. 4336 03:12:20,000 --> 03:12:22,600 WE TOOK A SIMILAR APPROACH, 4337 03:12:22,600 --> 03:12:24,040 COLLABORATORS DOING A SIMILAR 4338 03:12:24,040 --> 03:12:26,800 STUDY, THIS TIME INSTEAD OF 4339 03:12:26,800 --> 03:12:35,640 STRAIGHT TD TOMATO REPORTER, IN 4340 03:12:35,640 --> 03:12:41,040 THIS MOUSE IT IS EXPRESSED, THEY 4341 03:12:41,040 --> 03:12:44,840 SWITCH TO GFP. 4342 03:12:44,840 --> 03:12:46,720 YOU CAN SEE NEGATIVE POPULATION 4343 03:12:46,720 --> 03:12:53,920 GFP POSITIVE CELLS AS WELL AS 4344 03:12:53,920 --> 03:12:55,560 POSITIVE POPULATION AND DOUBLE 4345 03:12:55,560 --> 03:12:57,200 NEGATIVE AATAC 1 POPULATION. 4346 03:12:57,200 --> 03:13:05,200 WE CAN CONFIRM TWO POPULATIONS, 4347 03:13:05,200 --> 03:13:08,160 BOTH COME FROM FOXM 1 PRECURSOR. 4348 03:13:08,160 --> 03:13:10,560 THE BEAUTY, IT REALLY ALLOWS FOR 4349 03:13:10,560 --> 03:13:13,200 HIGH RESOLUTION IMAGING. 4350 03:13:13,200 --> 03:13:17,320 THE REASON IS THE CONSTRUCT 4351 03:13:17,320 --> 03:13:18,560 LEADS TO NUCLEAR LOCALIZATION. 4352 03:13:18,560 --> 03:13:21,720 NOW YOU CAN GET HIGH DIMENSIONAL 4353 03:13:21,720 --> 03:13:23,160 HIGH RESOLUTION IMAGING OF 4354 03:13:23,160 --> 03:13:26,880 THYMUS AND LOOK AT THINGS 4355 03:13:26,880 --> 03:13:29,840 LIKE -- WE CAN LOOK AT THE 4356 03:13:29,840 --> 03:13:30,600 CENTRAL MEDULLA REGION, YOU'LL 4357 03:13:30,600 --> 03:13:33,880 SEE THIS IN TWO SECONDS HERE 4358 03:13:33,880 --> 03:13:35,760 WHERE THE CENTRAL MEDULLA IS 4359 03:13:35,760 --> 03:13:38,160 ALMOST ALL CONNECTED, ALL 4360 03:13:38,160 --> 03:13:38,920 CONNECTED THROUGHOUT THE 4361 03:13:38,920 --> 03:13:39,240 MEDULLA. 4362 03:13:39,240 --> 03:13:42,640 A BIT OF A SURPRISE. 4363 03:13:42,640 --> 03:13:48,680 LOOK AT AGING MOUSE, FIRSTLY YOU 4364 03:13:48,680 --> 03:13:59,200 LOSE THAT AREA, SEE SPINDLES OF 4365 03:13:59,800 --> 03:13:59,960 BLUE. 4366 03:13:59,960 --> 03:14:02,240 BLUE AREAS ARE HIGH DENSITY 4367 03:14:02,240 --> 03:14:03,400 AREAS OF EPITHELIAL CELLS, 4368 03:14:03,400 --> 03:14:09,880 CURIOUS BECAUSE YOU DO NOT SEE 4369 03:14:09,880 --> 03:14:14,960 THESE IN YOUNG MICE. 4370 03:14:14,960 --> 03:14:19,320 LOOKING AT CONFOCAL IMAGES, BLUE 4371 03:14:19,320 --> 03:14:21,400 HERE IS GFPs, EPITHELIAL CELLS 4372 03:14:21,400 --> 03:14:25,120 THROUGHOUT, DOTS AS YOU DO IN 4373 03:14:25,120 --> 03:14:26,640 MEDULLARY AREAS, BUT IN 4374 03:14:26,640 --> 03:14:29,040 PERIMEDULLARY SPACE YOU SEE HIGH 4375 03:14:29,040 --> 03:14:31,800 DENSITY REGIONS OF EPITHELIAL 4376 03:14:31,800 --> 03:14:32,000 CELLS. 4377 03:14:32,000 --> 03:14:34,000 AND YOU DON'T SEE THEM IN YOUNG 4378 03:14:34,000 --> 03:14:35,600 AT ALL. 4379 03:14:35,600 --> 03:14:39,320 WE DO THINK THESE ARE AATECs, 4380 03:14:39,320 --> 03:14:43,760 DON'T EXPRESS THE SAME MARKERS. 4381 03:14:43,760 --> 03:14:48,480 THEY DON'T SEEM TO EXPRESS THE 4382 03:14:48,480 --> 03:14:50,520 SAME THINGS. 4383 03:14:50,520 --> 03:14:51,520 INTERESTINGLY, THEY ARE 4384 03:14:51,520 --> 03:14:52,960 THYMOCYTE DESERTS, WHEN WE LOOK 4385 03:14:52,960 --> 03:14:56,480 AT THESE YOU CANNOT SEE ANY TD 4386 03:14:56,480 --> 03:15:01,600 TOMATO CELLS IN THE HIGH DENSITY 4387 03:15:01,600 --> 03:15:03,400 REGIONS, AATEC REGIONS. 4388 03:15:03,400 --> 03:15:04,920 I'LL SKIP OVER THAT. 4389 03:15:04,920 --> 03:15:07,360 SO HOW COULD THIS BE IMPACTING 4390 03:15:07,360 --> 03:15:09,960 ON THE RESPONSE TO DAMAGE? 4391 03:15:09,960 --> 03:15:11,520 THESE POPULATIONS SEEM TO EMERGE 4392 03:15:11,520 --> 03:15:14,240 WITH AGE, SEEM TO BE 4393 03:15:14,240 --> 03:15:15,640 NON-PRODUCTIVE, TAKING AWAY 4394 03:15:15,640 --> 03:15:17,280 FUNCTIONAL TISSUE REPLACING WITH 4395 03:15:17,280 --> 03:15:18,680 NON-FUNCTIONAL TISSUE, HOW DOES 4396 03:15:18,680 --> 03:15:19,880 THIS IMPACT ON RESPONSE TO 4397 03:15:19,880 --> 03:15:20,240 DAMAGE? 4398 03:15:20,240 --> 03:15:22,440 FIRST OF ALL WHEN WE LOOK AT THE 4399 03:15:22,440 --> 03:15:24,000 DAMAGE RESPONSE THEY DO 4400 03:15:24,000 --> 03:15:26,120 DISAPPEAR AFTER RADIATION. 4401 03:15:26,120 --> 03:15:29,120 WE DO KNOW THEY COME BACK. 4402 03:15:29,120 --> 03:15:31,440 THIS IS IN DAY 42, YOU CAN SEE 4403 03:15:31,440 --> 03:15:39,360 ALL THESE AGER, DAY ZERO, AND 4404 03:15:39,360 --> 03:15:40,000 THEY COME BACK. 4405 03:15:40,000 --> 03:15:43,000 IF YOU LOOK AT IMAGING THEY COME 4406 03:15:43,000 --> 03:15:45,960 BACK IN A MAJOR WAY, THERE'S A 4407 03:15:45,960 --> 03:15:47,800 MUCH GREATER PROPORTION OF THE 4408 03:15:47,800 --> 03:15:56,680 THYMUS NOW TAKEN OUT BY THIS 4409 03:15:56,680 --> 03:15:58,840 AGE-AASSOCIATED AATEC REASON. 4410 03:15:58,840 --> 03:16:07,040 WE HAVE PATHWAYS THAT UNDERLINE 4411 03:16:07,040 --> 03:16:10,560 ENDOGENOUS REGENERATION, KGF, 4412 03:16:10,560 --> 03:16:11,880 FGF 7, IL-22, BNP 4. 4413 03:16:11,880 --> 03:16:14,040 ONE THING THAT HAPPENS WITH AGE, 4414 03:16:14,040 --> 03:16:20,200 NOW SWINGING TOWARDS TOWARDS THE 4415 03:16:20,200 --> 03:16:21,440 SUPPORT OF FIBROBLASTS AND 4416 03:16:21,440 --> 03:16:27,880 EPITHELIAL CELLS AS WE LOSE THE 4417 03:16:27,880 --> 03:16:30,080 ENDOGENOUS RESPONSE, PRIMARILY 4418 03:16:30,080 --> 03:16:31,840 IN FIBROBLASTS, ENDOTHELIAL 4419 03:16:31,840 --> 03:16:36,960 CELLS AS WELL, YOU LOSE THAT 4420 03:16:36,960 --> 03:16:37,960 INDUCTION OF REGENERATIVE 4421 03:16:37,960 --> 03:16:39,360 PROGRAM AFTER DAMAGE. 4422 03:16:39,360 --> 03:16:41,360 WHAT PROGRAM THERE IS THERE IS 4423 03:16:41,360 --> 03:16:45,200 ACTUALLY STOLEN BY THE 4424 03:16:45,200 --> 03:16:45,760 AGE-ASSOCIATED TECs, 4425 03:16:45,760 --> 03:16:49,880 INTERACTION MAP LOOKING AT 4426 03:16:49,880 --> 03:16:53,480 INTERACTION BETWEEN FIBROBLASTS, 4427 03:16:53,480 --> 03:16:54,360 EPITHELIAL CELLS, AGE-ASSOCIATED 4428 03:16:54,360 --> 03:16:59,840 TECs ARE HERE, NO SIGNAL IN 4429 03:16:59,840 --> 03:17:04,960 YOUNG BUT IN AGED FGS SIGNALING, 4430 03:17:04,960 --> 03:17:09,560 BNP SIGNALING GOING TOWARDS AGE 4431 03:17:09,560 --> 03:17:12,320 ASSOCIATED, ROARING AWAY FROM 4432 03:17:12,320 --> 03:17:17,040 NORMAL TECs, REPLACING THEIR 4433 03:17:17,040 --> 03:17:17,760 FUNCTION. 4434 03:17:17,760 --> 03:17:18,560 WHAT TO NOW? 4435 03:17:18,560 --> 03:17:20,000 I THINK THE PROBLEM WE HAVE AT 4436 03:17:20,000 --> 03:17:22,600 THE MOMENT IS BEING ABLE TO 4437 03:17:22,600 --> 03:17:27,520 TARGET THE CELLS, YET TO COME UP 4438 03:17:27,520 --> 03:17:29,160 WITH A GREAT MARKER, BUT WORKING 4439 03:17:29,160 --> 03:17:32,000 ON WAYS TO TARGET PARTICULARLY 4440 03:17:32,000 --> 03:17:33,280 AFTER RADIATION. 4441 03:17:33,280 --> 03:17:34,840 AND I'VE NOT MENTIONED BUT ONE 4442 03:17:34,840 --> 03:17:37,800 OF THE THINGS THAT DRIVES THEIR 4443 03:17:37,800 --> 03:17:39,680 EMERGENCE IS SENESCENCE, 4444 03:17:39,680 --> 03:17:40,880 FORMATION OF SENESCENT 4445 03:17:40,880 --> 03:17:44,600 FIBROBLASTS THAT START TO TURN 4446 03:17:44,600 --> 03:17:45,760 ON INFLAME AGING, YOU KNOW, 4447 03:17:45,760 --> 03:17:47,760 PHENOTYPE AND THAT SEEMS TO 4448 03:17:47,760 --> 03:17:48,360 DRIVE THE DRIVER. 4449 03:17:48,360 --> 03:17:51,280 THAT'S WHAT WE THINK IS GOING 4450 03:17:51,280 --> 03:17:51,800 ON. 4451 03:17:51,800 --> 03:17:52,800 WE'RE STARTING TO WORK ON 4452 03:17:52,800 --> 03:18:00,000 WHETHER WE CAN TARGET FOR 4453 03:18:00,000 --> 03:18:00,240 REPAIR. 4454 03:18:00,240 --> 03:18:06,400 THIS IS A LARGE COLLABORATIVE 4455 03:18:06,400 --> 03:18:08,880 EFFORT, PARTICULARLY BETWEEN 4456 03:18:08,880 --> 03:18:13,680 MELBOURNE, AND MY GROUP AND 4457 03:18:13,680 --> 03:18:14,480 MARCEL AND MEMORIAL 4458 03:18:14,480 --> 03:18:14,920 SLOAN-KETTERING. 4459 03:18:14,920 --> 03:18:16,720 WITH THAT I'LL TAKE ANY 4460 03:18:16,720 --> 03:18:19,040 QUESTIONS. 4461 03:18:19,040 --> 03:18:19,720 THANK YOU. 4462 03:18:19,720 --> 03:18:20,280 >> GREAT. 4463 03:18:20,280 --> 03:18:23,560 I COMMEND YOU AND ALL THE OTHER 4464 03:18:23,560 --> 03:18:24,520 SPEAKERS PUTTING THE GAP IN THE 4465 03:18:24,520 --> 03:18:26,800 FIELD IN YOUR LAST SLIDE SO 4466 03:18:26,800 --> 03:18:28,920 WE'LL HAVE A GREAT DISCUSSION 4467 03:18:28,920 --> 03:18:31,840 AFTER WE HAVE SOME QUESTIONS 4468 03:18:31,840 --> 03:18:33,160 FROM PEOPLE HERE. 4469 03:18:33,160 --> 03:18:42,120 YES, PLEASE, GO RIGHT AHEAD. 4470 03:18:42,120 --> 03:18:48,160 4471 03:18:48,160 --> 03:18:49,800 >> DID YOU SEE SENESCENT 4472 03:18:49,800 --> 03:18:50,560 PROFILING IN THE POPULATION OR 4473 03:18:50,560 --> 03:18:54,520 DID YOU NOT? 4474 03:18:54,520 --> 03:18:55,160 IT'S HARD TO DETECT. 4475 03:18:55,160 --> 03:18:56,720 >> WE'VE TRIED A LITTLE BIT BUT 4476 03:18:56,720 --> 03:18:59,640 NOT ABLE TO STATE THE OBVIOUS AT 4477 03:18:59,640 --> 03:19:00,640 THE MOMENT. 4478 03:19:00,640 --> 03:19:03,960 THEY DO SEEM TO -- WHEN WE LOOK 4479 03:19:03,960 --> 03:19:04,920 PATHWAY ANALYSIS THEY UPREGULATE 4480 03:19:04,920 --> 03:19:06,560 A LOT OF PATHWAYS THAT YOU 4481 03:19:06,560 --> 03:19:10,240 ASSOCIATE WITH INFLAME AGING BUT 4482 03:19:10,240 --> 03:19:14,440 NOT P16 OR ANY MARKERS, FIND ANY 4483 03:19:14,440 --> 03:19:19,360 ROBUST, THAT'S DEFINITELY THE 4484 03:19:19,360 --> 03:19:19,680 THING, YEAH 4485 03:19:19,680 --> 03:19:20,240 >>AWESOME. 4486 03:19:20,240 --> 03:19:27,600 IT'S GREAT TO SEE THESE DATA, IN 4487 03:19:27,600 --> 03:19:32,080 2008 USING CRE OR MODEL YOU CAN 4488 03:19:32,080 --> 03:19:33,200 TRANSITION TO PHENOTYPE BUT THE 4489 03:19:33,200 --> 03:19:39,200 POINT I WAS TRYING TO UNDERSTAND 4490 03:19:39,200 --> 03:19:47,640 WAS ATYPICAL TECs THAT EMERGE 4491 03:19:47,640 --> 03:19:49,920 DO THEY EXPRESS CANONICAL 4492 03:19:49,920 --> 03:19:50,360 MESENCHYMAL MARKERS? 4493 03:19:50,360 --> 03:19:52,000 >> THEY ARE STARTING TO. 4494 03:19:52,000 --> 03:19:55,160 THEY ARE MORE OF A PARTIAL, 4495 03:19:55,160 --> 03:19:57,480 DON'T TEAM TO HAVE GONE THE FULL 4496 03:19:57,480 --> 03:19:57,680 WAY. 4497 03:19:57,680 --> 03:19:59,200 I WONDER IN THE HUMAN WHETHER 4498 03:19:59,200 --> 03:20:00,640 THEY DO, IN THE MOUSE THEY 4499 03:20:00,640 --> 03:20:00,840 DON'T. 4500 03:20:00,840 --> 03:20:07,840 I'M NOT SURE BUT THEY DON'T -- 4501 03:20:07,840 --> 03:20:12,800 THEY DO START TO UPREGULATE. 4502 03:20:12,800 --> 03:20:13,160 >> (INAUDIBLE). 4503 03:20:13,160 --> 03:20:13,520 >> I'M SORRY? 4504 03:20:13,520 --> 03:20:13,920 >> (INAUDIBLE). 4505 03:20:13,920 --> 03:20:17,600 >> WE'VE NOT DONE THE FULL LIFE 4506 03:20:17,600 --> 03:20:20,560 COURSE ANALYSIS, LET'S SAY AGING 4507 03:20:20,560 --> 03:20:25,080 VERSUS TWO MONTH OLD, BUT WE DID 4508 03:20:25,080 --> 03:20:29,360 NOTICE -- IT'S HARD TO 4509 03:20:29,360 --> 03:20:29,640 OSCILLATE. 4510 03:20:29,640 --> 03:20:34,440 >> ALL DATA, IF YOU TAKE THEM 4511 03:20:34,440 --> 03:20:36,960 OUT FROM STROMAL, THAT 4512 03:20:36,960 --> 03:20:39,200 DETECTS -- NO LONGER DETECTS IN 4513 03:20:39,200 --> 03:20:43,320 THE THYMUS, WHEN WE DO SINGLE 4514 03:20:43,320 --> 03:20:45,200 CELL ANALYSIS HOW REAL ARE THESE 4515 03:20:45,200 --> 03:20:49,440 CELLS AND HAVE WE DONE 4516 03:20:49,440 --> 03:20:51,640 ORTHOGONAL VALIDATION? 4517 03:20:51,640 --> 03:20:53,200 >> THAT'S WHERE THE IMAGING IS 4518 03:20:53,200 --> 03:20:56,800 SO POWERFUL, WHOLE TISSUE 4519 03:20:56,800 --> 03:20:57,560 IMAGING APPROACH. 4520 03:20:57,560 --> 03:20:59,800 DAN WAS DOING HIS IMAGING, WE 4521 03:20:59,800 --> 03:21:01,520 WERE TALKING ABOUT THE SAME 4522 03:21:01,520 --> 03:21:03,800 THING, WE STARTED TO FOLLOW THAT 4523 03:21:03,800 --> 03:21:03,960 UP. 4524 03:21:03,960 --> 03:21:07,320 SO I THINK THERE ARE PROBLEMS 4525 03:21:07,320 --> 03:21:08,720 WITH SINGLE CELL DIGESTION 4526 03:21:08,720 --> 03:21:10,760 THAT'S GOING TO HAVE AN IMPACT 4527 03:21:10,760 --> 03:21:13,200 ON THE TRANSCRIPTOME, BUT I DO 4528 03:21:13,200 --> 03:21:17,680 THINK WE'RE ABLE TO VALIDATE IN 4529 03:21:17,680 --> 03:21:19,120 SOME OTHER DAYS. 4530 03:21:19,120 --> 03:21:20,120 >> ONE MORE QUESTION. 4531 03:21:20,120 --> 03:21:30,680 YOU HAD YOUR HAND UP. 4532 03:21:30,680 --> 03:21:32,840 >> JESSICA, MAYO CLINIC. 4533 03:21:32,840 --> 03:21:37,320 DOES LYMPHOTOXIN CHANGE WITH 4534 03:21:37,320 --> 03:21:37,520 AGING? 4535 03:21:37,520 --> 03:21:40,920 >> RANK GOES DOWN, IT MIGHT BE 4536 03:21:40,920 --> 03:21:42,680 MORE RANK THAN LYMPHOTOXIN, I 4537 03:21:42,680 --> 03:21:44,160 THINK, BUT THAT'S SPECULATIVE AT 4538 03:21:44,160 --> 03:21:44,560 THE MOMENT. 4539 03:21:44,560 --> 03:21:47,240 I DON'T KNOW ABOUT LEVELS. 4540 03:21:47,240 --> 03:21:49,680 WE'VE NOT LOOKED AT CELLS IN 4541 03:21:49,680 --> 03:21:52,880 EITHER OF THE TWO FACTORS 4542 03:21:52,880 --> 03:21:53,200 THEMSELVES. 4543 03:21:53,200 --> 03:21:57,440 >> I THOUGHT IT WAS INTERESTING 4544 03:21:57,440 --> 03:22:03,640 BECAUSE YOUR AATEC 2 AS BCL-2 1. 4545 03:22:03,640 --> 03:22:05,600 >> ONE QUESTION ONLINE. 4546 03:22:05,600 --> 03:22:08,200 HERE WE GO. 4547 03:22:08,200 --> 03:22:12,360 4548 03:22:12,360 --> 03:22:15,000 >> M1/M2, OH, I HAVE NO IDEA. 4549 03:22:15,000 --> 03:22:20,560 I MEAN, WE'RE STARTING A 4550 03:22:20,560 --> 03:22:22,120 MACROPHAGE PROJECT, IMMUNE CELLS 4551 03:22:22,120 --> 03:22:25,040 ARE DIFFERENT IN THE THYMUS, 4552 03:22:25,040 --> 03:22:25,840 THERE ARE DIFFERENT MACROPHAGES. 4553 03:22:25,840 --> 03:22:27,080 >> WOULD ALL THE SPEAKERS 4554 03:22:27,080 --> 03:22:28,800 PLEASE COME TO THE TABLE. 4555 03:22:28,800 --> 03:22:31,440 WE'RE GOING TO HAVE OUR GAPS IN 4556 03:22:31,440 --> 03:22:34,160 THE FIELD DISCUSSION. 4557 03:22:34,160 --> 03:22:40,160 4558 03:22:40,160 --> 03:22:44,120 4559 03:22:44,120 --> 03:22:54,160 4560 03:22:58,240 --> 03:23:04,760 WE HAVE ANOTHER QUESTION, WE PUT 4561 03:23:04,760 --> 03:23:06,800 IN THE GAPS. 4562 03:23:06,800 --> 03:23:14,800 >> WE HAVE -- THIS QUESTION 4563 03:23:14,800 --> 03:23:16,680 CAME IN, ADVOCACY GROUP, 4564 03:23:16,680 --> 03:23:18,960 REPRESENTATIVE WOULD LIKE TO 4565 03:23:18,960 --> 03:23:20,720 KNOW IF PATIENTS WITH HERPES 4566 03:23:20,720 --> 03:23:22,560 WERE CONSIDERED AS A 4567 03:23:22,560 --> 03:23:25,880 SUBPOPULATION FOR THE RESEARCH, 4568 03:23:25,880 --> 03:23:28,400 ALSO IF THE HYPOTHESIS 4569 03:23:28,400 --> 03:23:30,000 CONSIDERED CHRONIC NEUROPATHIC 4570 03:23:30,000 --> 03:23:30,960 HERPES INFECTION WOULD BE 4571 03:23:30,960 --> 03:23:32,400 CONTRIBUTED TO SOME OF THIS? 4572 03:23:32,400 --> 03:23:37,240 >> IT MIGHT BE THAT SOME OF THE 4573 03:23:37,240 --> 03:23:41,240 SECTION WOULD BE CONTRIBUTING TO 4574 03:23:41,240 --> 03:23:43,720 WHAT IS SUBPOPULATION, EDD AND 4575 03:23:43,720 --> 03:23:48,520 HERPES, NONE OF THESE PEOPLE HAD 4576 03:23:48,520 --> 03:23:49,160 ACTIVE HERPES MANIFESTATIONS, 4577 03:23:49,160 --> 03:23:52,280 BUT OVERALL HEALTH WAS A BIT ON 4578 03:23:52,280 --> 03:23:56,120 THE KIND OF THEIR OWN SELF 4579 03:23:56,120 --> 03:23:59,520 ASSESSMENT, SOMETIMES THERE WAS 4580 03:23:59,520 --> 03:24:03,120 PEOPLE DID NOT -- THEY WERE 4581 03:24:03,120 --> 03:24:06,000 REQUIRED -- THE BENEFIT OF 4582 03:24:06,000 --> 03:24:08,280 METABOLIC PROFILING, REQUIRED TO 4583 03:24:08,280 --> 03:24:10,640 FAST, COLLECT METABOLIC DATA BUT 4584 03:24:10,640 --> 03:24:13,200 FOR SOME PEOPLE WE COULD SEE 4585 03:24:13,200 --> 03:24:15,640 SPIKES, YOU HAD A DOUGHNUT IN 4586 03:24:15,640 --> 03:24:16,080 THE MORNING. 4587 03:24:16,080 --> 03:24:19,240 THE SAME DAY A COUPLE PEOPLE 4588 03:24:19,240 --> 03:24:22,600 WITH HIGH CYTOKINE, WE KNEW THEY 4589 03:24:22,600 --> 03:24:25,840 WERE LYING ABOUT SOMETHING, OR 4590 03:24:25,840 --> 03:24:29,160 JUST RECOVERING, BUT MIGHT HAVE 4591 03:24:29,160 --> 03:24:33,200 BEEN HERPES BUT WE'VE NOT 4592 03:24:33,200 --> 03:24:35,320 (INDISCERNIBLE) THIS LATENT 4593 03:24:35,320 --> 03:24:35,600 INFECTION. 4594 03:24:35,600 --> 03:24:37,280 >> THIS IS A GAPS IN THE FIELD 4595 03:24:37,280 --> 03:24:37,600 DISCUSSION. 4596 03:24:37,600 --> 03:24:41,240 WE HAVE A LOT OF GOOD SPEAKERS 4597 03:24:41,240 --> 03:24:42,640 WHO HAVE INTRODUCED SOME OF THE 4598 03:24:42,640 --> 03:24:44,400 THINGS THAT THEY THOUGHT WERE 4599 03:24:44,400 --> 03:24:45,480 GAPS IN THE FIELD. 4600 03:24:45,480 --> 03:24:48,240 WE PROBABLY COULD HAVE A WHOLE 4601 03:24:48,240 --> 03:24:51,480 OTHER SESSION ON THIS, BUT WE 4602 03:24:51,480 --> 03:24:54,440 ONLY HAVE ENOUGH TIME FOR ABOUT 4603 03:24:54,440 --> 03:24:58,080 MAYBE TWO MINUTES PER PERSON, 4604 03:24:58,080 --> 03:25:00,080 BASICALLY BOTTOM LINE WHAT YOU 4605 03:25:00,080 --> 03:25:02,280 THINK WOULD BE A GAP THAT YOU 4606 03:25:02,280 --> 03:25:04,200 ARE INTERESTED IN OR YOU THINK 4607 03:25:04,200 --> 03:25:07,600 WE SHOULD BE INTERESTED IN, IN 4608 03:25:07,600 --> 03:25:09,440 THE FIELD, WITH REGARD TO WHAT 4609 03:25:09,440 --> 03:25:10,480 YOU'VE ALREADY SAID OR SOMETHING 4610 03:25:10,480 --> 03:25:12,280 THAT YOU WANT TO SAY NEWLY. 4611 03:25:12,280 --> 03:25:14,680 IS THERE ANYBODY ELSE THAT HAS 4612 03:25:14,680 --> 03:25:18,880 ANY OTHER POINT THEY WOULD LIKE 4613 03:25:18,880 --> 03:25:19,960 TO BRING UP THAT, YOU KNOW, 4614 03:25:19,960 --> 03:25:21,280 WE'RE GOING TO DISCUSS GAPS IN 4615 03:25:21,280 --> 03:25:22,600 THE FIELD, HOPEFULLY THAT WILL 4616 03:25:22,600 --> 03:25:25,400 GO ON OVER LUNCH, YOU CAN 4617 03:25:25,400 --> 03:25:28,000 DISCUSS OTHER GAPS THAT YOU WANT 4618 03:25:28,000 --> 03:25:30,760 TO DISCUSS WITH THE SPEAKERS OR 4619 03:25:30,760 --> 03:25:32,000 EACH OTHER. 4620 03:25:32,000 --> 03:25:34,280 I GUESS WE'LL START AT THE FIRST 4621 03:25:34,280 --> 03:25:41,400 SPEAKER AT THE OTHER END PLEASE. 4622 03:25:41,400 --> 03:25:42,000 THANK YOU. 4623 03:25:42,000 --> 03:25:43,200 >> CHALLENGING QUESTION. 4624 03:25:43,200 --> 03:25:43,960 THANK YOU. 4625 03:25:43,960 --> 03:25:54,480 SO ONE GAP FOR ME IS THIS AGING 4626 03:25:57,560 --> 03:25:59,920 FEMALE, THE DOMINANCE OF THE 4627 03:25:59,920 --> 03:26:03,400 SENESCENT CELL, FITTING THE 4628 03:26:03,400 --> 03:26:09,560 STROMA, WE DIDN'T SEE THE 4629 03:26:09,560 --> 03:26:10,880 FEATURE. 4630 03:26:10,880 --> 03:26:19,240 WE HAVE STILL SECRETED CYTOKINE, 4631 03:26:19,240 --> 03:26:22,840 SO BROADER MINDSET UNDERSTANDING 4632 03:26:22,840 --> 03:26:27,480 INFLAMMATION TO CONFER RESPONSE, 4633 03:26:27,480 --> 03:26:28,520 BEING PRODUCED, BEING AMBIGUATED 4634 03:26:28,520 --> 03:26:39,000 IN BIOLOGY AND AGING IN THE 4635 03:26:41,280 --> 03:26:41,440 CONTEXT. 4636 03:26:41,440 --> 03:26:44,320 >> I TOUCHED ON THIS. 4637 03:26:44,320 --> 03:26:47,040 THERE'S A FOCUS, AREAS GOING 4638 03:26:47,040 --> 03:26:48,800 FORWARD, RARE CELLS ARE 4639 03:26:48,800 --> 03:26:49,800 IMPORTANT LIKE ANTIGEN SPECIFIC 4640 03:26:49,800 --> 03:26:51,880 B OR T CELLS, THERE'S NO REASON 4641 03:26:51,880 --> 03:26:54,040 THAT STUDIES COULDN'T BE DONE ON 4642 03:26:54,040 --> 03:26:56,400 BIGGER COHORTS LOOKING AT THOSE, 4643 03:26:56,400 --> 03:26:57,440 SOME CURRENT METHODS, LIKE A 4644 03:26:57,440 --> 03:26:58,360 THOUSAND PEOPLE OR SOMETHING 4645 03:26:58,360 --> 03:27:01,600 LIKE THAT THAT WOULD BE THE 4646 03:27:01,600 --> 03:27:05,120 WITHIN THE SCALE OF THINGS YOU 4647 03:27:05,120 --> 03:27:07,000 COULD LOOK AT, THAT'S A 4648 03:27:07,000 --> 03:27:09,400 DIRECTION THAT WOULD BE GOOD, IT 4649 03:27:09,400 --> 03:27:11,960 MEANS THERE WOULD HAVE TO BE 4650 03:27:11,960 --> 03:27:12,920 COHORTS AND GOOD QUALITY 4651 03:27:12,920 --> 03:27:14,080 BIOSPECIMENS AND THINGS LIKE 4652 03:27:14,080 --> 03:27:15,320 THAT, SOMETHING THAT WOULD BE 4653 03:27:15,320 --> 03:27:17,360 VALUABLE AND COULD GIVE MORE 4654 03:27:17,360 --> 03:27:19,360 INSIGHT INTO WHAT REALLY CHANGES 4655 03:27:19,360 --> 03:27:21,080 IN IMMUNE MEMORY ARE AGE TO THE 4656 03:27:21,080 --> 03:27:26,040 VERY EXTREMES OF AGE RANGE AND 4657 03:27:26,040 --> 03:27:29,640 ARE DIFFERENT COMORBIDITIES TO 4658 03:27:29,640 --> 03:27:31,720 UNDERSTAND WHY SOME PEOPLE HAVE 4659 03:27:31,720 --> 03:27:33,000 WORSE IMMUNE RESPONSES TO 4660 03:27:33,000 --> 03:27:34,040 SCENARIOS LIKE VACCINATION OR 4661 03:27:34,040 --> 03:27:35,120 INFECTIONS THAT MIGHT BE 4662 03:27:35,120 --> 03:27:39,160 NECESSARY TO UNDERSTAND WHAT'S 4663 03:27:39,160 --> 03:27:42,000 HAPPENING IN PEOPLE. 4664 03:27:42,000 --> 03:27:44,200 ONE TOPIC AREA MAYBE. 4665 03:27:44,200 --> 03:27:44,880 >> GO AHEAD. 4666 03:27:44,880 --> 03:27:49,320 >> TO THE SURPRISE OF NO ONE 4667 03:27:49,320 --> 03:27:49,920 SEX DIFFERENCES NEED TO BE 4668 03:27:49,920 --> 03:27:51,760 STUDIED MORE AND THEY ARE 4669 03:27:51,760 --> 03:27:52,200 IGNORED. 4670 03:27:52,200 --> 03:27:54,600 SOME PEOPLE DON'T KNOW ABOUT 4671 03:27:54,600 --> 03:27:56,000 LIKE 80% OF PHASE 1 CLINICAL 4672 03:27:56,000 --> 03:27:57,840 TRIALS ARE DONE SPECIFICALLY IN 4673 03:27:57,840 --> 03:27:58,040 MALES. 4674 03:27:58,040 --> 03:27:59,920 AND THEN ONCE THE DRUG HITS THE 4675 03:27:59,920 --> 03:28:01,680 MARKET 2/3 OF SEVERE SIDE 4676 03:28:01,680 --> 03:28:03,440 EFFECTS ARE REPORTED IN WOMEN. 4677 03:28:03,440 --> 03:28:05,640 AND SO I THINK IF WE HAD A 4678 03:28:05,640 --> 03:28:06,960 CHANGE IN MENTALITY AND INSTEAD 4679 03:28:06,960 --> 03:28:10,000 OF CONSIDERING THAT, YOU KNOW, 4680 03:28:10,000 --> 03:28:14,080 OH, THIS HORMONAL CYCLE MAKES 4681 03:28:14,080 --> 03:28:16,560 THINGS COMPLICATED WE SHOULD SEX 4682 03:28:16,560 --> 03:28:17,920 DIFFERENCES AS AN OPPORTUNITY TO 4683 03:28:17,920 --> 03:28:18,880 UNDERSTAND BIOLOGY AND CHEAPLY 4684 03:28:18,880 --> 03:28:20,200 AND EASILY BE ABLE TO 4685 03:28:20,200 --> 03:28:24,800 PERSONALIZE MEDICINE AND 4686 03:28:24,800 --> 03:28:26,760 RESEARCH TO UNDERSTAND 4687 03:28:26,760 --> 03:28:27,680 DIFFERENCES IN HETEROGENEITY. 4688 03:28:27,680 --> 03:28:29,520 >> I THINK NIH AND THE REST OF 4689 03:28:29,520 --> 03:28:38,360 US AGREE WITH YOU. 4690 03:28:38,360 --> 03:28:38,680 THANK YOU. 4691 03:28:38,680 --> 03:28:40,040 >> I THINK UNDERSTANDING SOME 4692 03:28:40,040 --> 03:28:42,640 OF THE ENVIRONMENTAL CHANGES IN 4693 03:28:42,640 --> 03:28:44,280 AGING AND CLEARLY DEFINING WHAT 4694 03:28:44,280 --> 03:28:47,040 THOSE ARE IS REALLY IMPORTANT 4695 03:28:47,040 --> 03:28:50,400 AND MISSING. 4696 03:28:50,400 --> 03:28:51,600 WE'RE LOOKING FROM SECRETED 4697 03:28:51,600 --> 03:28:53,480 PROTEIN PERSPECTIVE BUT BORROWED 4698 03:28:53,480 --> 03:28:55,560 IDEAS FROM TUMOR IMMUNOLOGY, HOW 4699 03:28:55,560 --> 03:28:57,080 METABOLIC ENVIRONMENT IS 4700 03:28:57,080 --> 03:28:57,960 CONTROLLING ACCESS TO NUTRIENTS 4701 03:28:57,960 --> 03:28:59,720 FOR IMMUNE CELLS AND HOW THIS IS 4702 03:28:59,720 --> 03:29:01,560 CONTROLLING THEIR ABILITY TO 4703 03:29:01,560 --> 03:29:02,320 RESPOND OR PERFORM FUNCTIONS, 4704 03:29:02,320 --> 03:29:05,200 AND THAT'S GOING TO BE TRUE FOR 4705 03:29:05,200 --> 03:29:07,800 EVERY CELL IN EVERY ORGAN ALL 4706 03:29:07,800 --> 03:29:10,520 THESE THINGS ARE CHANGING AND WE 4707 03:29:10,520 --> 03:29:12,000 DON'T REPLACING HAVE GRANULAR 4708 03:29:12,000 --> 03:29:15,480 VIEW HOW THIS IS HAPPENING OWNED 4709 03:29:15,480 --> 03:29:18,200 OVER THE -- OVER THE COURSE OF 4710 03:29:18,200 --> 03:29:19,080 THE LIFESPAN. 4711 03:29:19,080 --> 03:29:21,720 IT'S AN IMPORTANT PART OF 4712 03:29:21,720 --> 03:29:24,520 TARGETING DISEASE MECHANISMS. 4713 03:29:24,520 --> 03:29:27,600 4714 03:29:27,600 --> 03:29:29,480 >> ABOUT THE SEX STUFF, 4715 03:29:29,480 --> 03:29:31,000 ABSOLUTELY RIGHT. 4716 03:29:31,000 --> 03:29:33,680 I PRESENTED EVERYTHING TODAY IN 4717 03:29:33,680 --> 03:29:37,120 FEMALES, WE'VE DONE A BUNCH IN 4718 03:29:37,120 --> 03:29:40,840 MALE, GENERALLY WORSE IN AGING. 4719 03:29:40,840 --> 03:29:45,800 IN TERMS OF GAPS, I'M A HAMMER 4720 03:29:45,800 --> 03:29:50,680 SO I'LL TALK ABOUT A NAIL. 4721 03:29:50,680 --> 03:29:56,400 STROMAL CELLS ARE IGNORED. 4722 03:29:56,400 --> 03:29:57,600 WE'RE THINKING THYMIC STROMAL 4723 03:29:57,600 --> 03:30:00,880 CELLS ARE IMPACTED BY AGE, MAYBE 4724 03:30:00,880 --> 03:30:06,160 HARD OR BARRIER TO OVERCOME 4725 03:30:06,160 --> 03:30:11,720 MIGHT BE HARDER, I WAS GOING TO 4726 03:30:11,720 --> 03:30:13,800 ASK ABOUT MARK'S TALK, STROMAL 4727 03:30:13,800 --> 03:30:20,880 CELLS TOO OFTEN IGNORED. 4728 03:30:20,880 --> 03:30:23,760 NOT ALWAYS INTRINSIC TO T CELLS, 4729 03:30:23,760 --> 03:30:26,280 THAT SEEMS IMPORTANT TOO. 4730 03:30:26,280 --> 03:30:28,360 >> MARK WAS GIVING HIS FINGER 4731 03:30:28,360 --> 03:30:30,320 UP AND SO I'D LIKE TO SAY AFTER 4732 03:30:30,320 --> 03:30:33,760 WE HAVE YOU SPEAK IF OTHER 4733 03:30:33,760 --> 03:30:36,000 PEOPLE WOULD LIKE TO CHIME IN 4734 03:30:36,000 --> 03:30:38,800 ABOUT A GAP, YES, RAISE YOUR 4735 03:30:38,800 --> 03:30:39,120 HAND. 4736 03:30:39,120 --> 03:30:39,840 JUST A SECOND. 4737 03:30:39,840 --> 03:30:41,240 GO AHEAD. 4738 03:30:41,240 --> 03:30:41,520 ONE MORE. 4739 03:30:41,520 --> 03:30:44,880 >> I WANT TO TAKE THE 4740 03:30:44,880 --> 03:30:46,320 OPPORTUNITY TO BE PROVOCATIVE, 4741 03:30:46,320 --> 03:30:47,400 ON THREE TOPICS. 4742 03:30:47,400 --> 03:30:49,560 ONE WITH THE MOUSE, AGING 4743 03:30:49,560 --> 03:30:52,760 MODELS, MUCH THAT WE SEE IS FROM 4744 03:30:52,760 --> 03:30:55,280 THE OBESITY, VERSUS AGE. 4745 03:30:55,280 --> 03:30:59,640 IL-1 EFFECTS IN AGING MOUSE 4746 03:30:59,640 --> 03:31:01,720 BECAUSE IT'S OBESE OR AGED? 4747 03:31:01,720 --> 03:31:02,960 THAT'S ONE. 4748 03:31:02,960 --> 03:31:08,640 THE OTHER IS SENESCENCE. 4749 03:31:08,640 --> 03:31:12,880 WHEN PEOPLE REPORT 4750 03:31:12,880 --> 03:31:13,400 ANTI-SENESCENT TREATMENT 4751 03:31:13,400 --> 03:31:15,000 INHIBITOR OF PCR SIGNALING HOW 4752 03:31:15,000 --> 03:31:17,160 MUCH IS SENESCENCE VERSUS IMMUNE 4753 03:31:17,160 --> 03:31:22,520 EFFECT FOR ONE, OR ANY OTHER 4754 03:31:22,520 --> 03:31:24,920 EFFECT. 4755 03:31:24,920 --> 03:31:28,000 AND DISCORDANCE BETWEEN SICKLE 4756 03:31:28,000 --> 03:31:30,080 CELL RNA SEQUENCING AND EXISTING 4757 03:31:30,080 --> 03:31:32,480 SINCE 1999, GREAT AT THAT TIME 4758 03:31:32,480 --> 03:31:34,240 BUT THERE WAS NO SINGLE CELL 4759 03:31:34,240 --> 03:31:37,520 RNA-SEQ DATA SO WE NEED TO DO 4760 03:31:37,520 --> 03:31:38,240 SOMETHING ABOUT IT. 4761 03:31:38,240 --> 03:31:39,800 >> I CAN ADD SOMETHING? 4762 03:31:39,800 --> 03:31:41,120 THE MOUSE THING IS REALLY 4763 03:31:41,120 --> 03:31:43,080 IMPORTANT BECAUSE ONE THING I'VE 4764 03:31:43,080 --> 03:31:45,280 BEEN GRAPPLING WITH, WITH AGED 4765 03:31:45,280 --> 03:31:46,720 MICE, PARTICULARLY WITH REGARDS 4766 03:31:46,720 --> 03:31:50,080 TO T CELL FUNCTION, THEY ARE NOT 4767 03:31:50,080 --> 03:31:53,040 NORMAL, HAVE NOT SEEN ANYTHING, 4768 03:31:53,040 --> 03:31:54,360 SPF, DEPENDING ON ANIMAL HOUSE 4769 03:31:54,360 --> 03:31:55,800 AND HOW CLEAN IT IS, BUT I THINK 4770 03:31:55,800 --> 03:31:58,400 THAT'S GOING TO BE A REAL 4771 03:31:58,400 --> 03:31:59,400 PROBLEM FOR US. 4772 03:31:59,400 --> 03:32:00,840 THE WORK ABOUT WILD MICE IS 4773 03:32:00,840 --> 03:32:02,360 FANTASTIC BUT HAS ITS OWN 4774 03:32:02,360 --> 03:32:04,000 LIMITATIONS HOW YOU CAN DO 4775 03:32:04,000 --> 03:32:05,280 EXPERIMENTS BUT I THINK THIS IS 4776 03:32:05,280 --> 03:32:06,960 A REAL PROBLEM THAT WE NEED TO 4777 03:32:06,960 --> 03:32:10,440 ADDRESS THESE SORT OF THINGS. 4778 03:32:10,440 --> 03:32:13,080 >> I'D LIKE TO OPEN TO THE 4779 03:32:13,080 --> 03:32:13,360 AUDIENCE. 4780 03:32:13,360 --> 03:32:14,280 AND REMEMBER THIS IS NOT GOING 4781 03:32:14,280 --> 03:32:19,320 TO BE THE ONLY GAPS IN THE FIELD 4782 03:32:19,320 --> 03:32:19,600 DISCUSSION. 4783 03:32:19,600 --> 03:32:22,200 SO DON'T WORRY, I THINK -- WHO 4784 03:32:22,200 --> 03:32:29,040 WAS THE FIRST PERSON? 4785 03:32:29,040 --> 03:32:29,240 OKAY. 4786 03:32:29,240 --> 03:32:31,680 >> BONE MARROW, THYMUS, 4787 03:32:31,680 --> 03:32:32,480 PERIPHERAL, LYMPH NODE 4788 03:32:32,480 --> 03:32:34,000 STRUCTURES, ALL HAVE ISSUES WITH 4789 03:32:34,000 --> 03:32:34,240 STROMA. 4790 03:32:34,240 --> 03:32:35,920 AND I THINK WE'RE WAKING UP TO 4791 03:32:35,920 --> 03:32:37,680 THAT PART. 4792 03:32:37,680 --> 03:32:43,160 I COULDN'T AGREE MORE WITH THE 4793 03:32:43,160 --> 03:32:46,160 LIMITATIONS MAX WAS MAKING, AND 4794 03:32:46,160 --> 03:32:46,360 JARROD. 4795 03:32:46,360 --> 03:32:55,000 MICROBIOME IS GOING TO BE HUGELY 4796 03:32:55,000 --> 03:32:56,120 IMPORTANT, DIFFERENCES WERE 4797 03:32:56,120 --> 03:32:59,480 AMPLIFIED WHEN IT COMES TO 4798 03:32:59,480 --> 03:33:01,240 THYMUS VERSUS PERIPHERAL, 4799 03:33:01,240 --> 03:33:05,840 MAINTENANCE OF AT LEAST HUGELY 4800 03:33:05,840 --> 03:33:07,800 IMPACTED BY MICROBIOME, SO IN 4801 03:33:07,800 --> 03:33:11,640 DIRTY MICE OR IN CO-HOUSED MICE 4802 03:33:11,640 --> 03:33:13,840 THYMUS INVOLUTES AS EARLY AS IN 4803 03:33:13,840 --> 03:33:14,160 HUMAN. 4804 03:33:14,160 --> 03:33:16,720 SO THEN YOU'VE GOT A DIFFERENT 4805 03:33:16,720 --> 03:33:17,920 SHIFT IN PERIPHERAL MAINTENANCE 4806 03:33:17,920 --> 03:33:22,040 THAT IS AGAIN A LOT MORE 4807 03:33:22,040 --> 03:33:23,440 HUMAN-LIKE BUT IN APPROXIMATING 4808 03:33:23,440 --> 03:33:25,040 HUMANS WITH MICE AND STUDYING 4809 03:33:25,040 --> 03:33:26,760 THESE THINGS THAT WE HEARD ABOUT 4810 03:33:26,760 --> 03:33:30,680 I THINK PUSH THE ENVELOPE IN 4811 03:33:30,680 --> 03:33:31,600 HUMANS IS PHENOMENAL. 4812 03:33:31,600 --> 03:33:33,960 MAX, WHAT WOULD BE THE BEST WAY 4813 03:33:33,960 --> 03:33:38,640 TO FIGURE OUT THE GATING ON 4814 03:33:38,640 --> 03:33:39,880 SINGLE CELL, THAT'S ONE OF THE 4815 03:33:39,880 --> 03:33:42,400 THINGS THAT I FIND CHALLENGING 4816 03:33:42,400 --> 03:33:44,880 AND OF COURSE I DON'T KNOW THAT 4817 03:33:44,880 --> 03:33:45,040 -- 4818 03:33:45,040 --> 03:33:47,640 >>YOU'RE GOING TO HATE ME FOR 4819 03:33:47,640 --> 03:33:47,960 THAT. 4820 03:33:47,960 --> 03:33:49,520 ONE PERSON IN THE ROOM, SHE 4821 03:33:49,520 --> 03:33:53,120 MIGHT HAVE AN ANSWER FOR YOU. 4822 03:33:53,120 --> 03:33:54,760 WE CAN TALK AFTERWARDS. 4823 03:33:54,760 --> 03:34:02,120 BUT THE WAY -- PRACTICALLY THE 4824 03:34:02,120 --> 03:34:03,400 WAY IS TAKE CLUSTERS, LOOK 4825 03:34:03,400 --> 03:34:04,400 THROUGH MANY MARKERS AND SEE 4826 03:34:04,400 --> 03:34:06,360 THEM ONCE YOU HAVE THE ANSWER, 4827 03:34:06,360 --> 03:34:09,960 THEN PULL THEM DOWN AND DO THE 4828 03:34:09,960 --> 03:34:17,080 SINGLE CELL SUBPOPULATION AND 4829 03:34:17,080 --> 03:34:23,680 SEE IF IT MATCHES. 4830 03:34:23,680 --> 03:34:23,960 >> THANKS. 4831 03:34:23,960 --> 03:34:26,000 >> I WANT TO DIRECTLY COMMENT 4832 03:34:26,000 --> 03:34:27,320 ON A COUPLE POINTS. 4833 03:34:27,320 --> 03:34:29,080 I WORK ON AGING AND VACCINE 4834 03:34:29,080 --> 03:34:31,480 RESPONSES, MY LAB DOES WORK IN 4835 03:34:31,480 --> 03:34:34,760 PARALLEL IN HUMAN AND MICE, TO 4836 03:34:34,760 --> 03:34:40,040 WHAT EXTENT WE CAN USE MICE AS A 4837 03:34:40,040 --> 03:34:40,400 MODEL. 4838 03:34:40,400 --> 03:34:43,640 WE DID AN EXPERIMENT WITH THE 4839 03:34:43,640 --> 03:34:46,040 ASTRAZENECA VACCINE JUST BEFORE 4840 03:34:46,040 --> 03:34:46,680 THEY WERE RUNNING THE CLINICAL 4841 03:34:46,680 --> 03:34:48,880 TRIALS, WE RAN IT IN OUR AGED 4842 03:34:48,880 --> 03:34:50,960 MICE, ABOUT 22 MONTHS OLD. 4843 03:34:50,960 --> 03:34:52,520 AND I WAS REALLY IMPRESSED AT 4844 03:34:52,520 --> 03:34:54,440 LEAST FROM ALL OF THE PARAMETERS 4845 03:34:54,440 --> 03:34:55,600 THAT WERE MEASURED. 4846 03:34:55,600 --> 03:35:02,760 AGED MICE DID A GOOD JOB 4847 03:35:02,760 --> 03:35:04,240 MIMICKING IN HUMANS, FAIRLY 4848 03:35:04,240 --> 03:35:05,320 REASONABLE PRE-CLINICAL MODEL. 4849 03:35:05,320 --> 03:35:06,720 OBVIOUSLY HUMANS ARE NOT MICE. 4850 03:35:06,720 --> 03:35:08,360 IT'S ABOUT UNDERSTANDING THE 4851 03:35:08,360 --> 03:35:11,000 STRENGTHS AND WEAKNESSES OF ALL 4852 03:35:11,000 --> 03:35:13,840 OF OUR MODELS AND JUST DOING THE 4853 03:35:13,840 --> 03:35:15,840 COMPARATIVE ANALYSES. 4854 03:35:15,840 --> 03:35:17,240 WE ALSO DID THE EXPERIMENT 4855 03:35:17,240 --> 03:35:19,240 STARTED WEIGHING EVERY ONE OF 4856 03:35:19,240 --> 03:35:21,720 OUR AGED MICE, BEFORE WE DO ANY 4857 03:35:21,720 --> 03:35:24,760 EXPERIMENTS BECAUSE MANY OF YOU 4858 03:35:24,760 --> 03:35:27,800 WILL KNOW THERE CAN BE A 30-GRAM 4859 03:35:27,800 --> 03:35:28,960 DISPARITY DEPENDING ON THE 4860 03:35:28,960 --> 03:35:29,400 STRAIN. 4861 03:35:29,400 --> 03:35:33,560 WE SAW NO EFFECT OF WEIGHT ON 4862 03:35:33,560 --> 03:35:34,560 VACCINE RESPONSE. 4863 03:35:34,560 --> 03:35:38,040 NO CORRELATION, IF YOU JUST DID 4864 03:35:38,040 --> 03:35:39,600 A CLASSIC LINEAR, WHICH I WASN'T 4865 03:35:39,600 --> 03:35:40,920 EXPECTING BUT THAT WAS WHAT THE 4866 03:35:40,920 --> 03:35:44,960 DATA SAID. 4867 03:35:44,960 --> 03:35:47,760 >> WAIT, WAIT, WAIT. 4868 03:35:47,760 --> 03:35:51,040 >> I WANT TO SAY REASONABLE 4869 03:35:51,040 --> 03:35:54,560 KNOWN IN THE COMMUNITY AS FAR AS 4870 03:35:54,560 --> 03:36:04,960 B CELL RESPONSE MICE ARE GOOD 4871 03:36:04,960 --> 03:36:05,880 MODELS. 4872 03:36:05,880 --> 03:36:06,000 >> 4873 03:36:06,000 --> 03:36:06,320 [CROSSTALK] 4874 03:36:06,320 --> 03:36:06,840 >>MARK, HOLD ON. 4875 03:36:06,840 --> 03:36:14,280 PLEASE GIVE YOUR NAME AND WHERE 4876 03:36:14,280 --> 03:36:14,600 YOU'RE FROM. 4877 03:36:14,600 --> 03:36:16,360 >> HELLO, INDIANA SCHOOL OF 4878 03:36:16,360 --> 03:36:18,320 DENTISTRY, A COMMENT ABOUT THE 4879 03:36:18,320 --> 03:36:21,480 SEX DIFFERENCES, I AGREE IT'S 4880 03:36:21,480 --> 03:36:23,760 REALLY IMPORTANT TOPIC NOW, SO 4881 03:36:23,760 --> 03:36:27,960 ABOUT DENTISTY, THERE IS A CLEAR 4882 03:36:27,960 --> 03:36:30,280 EVIDENCE PERIODONTITIS IS MORE 4883 03:36:30,280 --> 03:36:31,800 RELEVANT IN MALES, AND RECENTLY 4884 03:36:31,800 --> 03:36:34,880 IT MAY NOT BE TRUE BECAUSE WOMEN 4885 03:36:34,880 --> 03:36:36,320 MAY NOT HAVE ENOUGH TIME TO GO 4886 03:36:36,320 --> 03:36:39,240 TO DENTIST BECAUSE THEY ARE BUSY 4887 03:36:39,240 --> 03:36:41,400 WITH OTHER THINGS. 4888 03:36:41,400 --> 03:36:42,400 >> OKAY. 4889 03:36:42,400 --> 03:36:45,240 MARK, YOU'RE NEXT. 4890 03:36:45,240 --> 03:36:45,800 THANK YOU. 4891 03:36:45,800 --> 03:36:50,400 >> YEAH, WE HAVE TO REMIND 4892 03:36:50,400 --> 03:36:55,960 OURSELVES THAT MICE, BLACK OF 4893 03:36:55,960 --> 03:37:00,280 MICE, IS AN ARTIFICIAL ORGANISM 4894 03:37:00,280 --> 03:37:03,520 IN AN ARTIFICIAL ENVIRONMENT. 4895 03:37:03,520 --> 03:37:05,600 MICE LIVE UNDER HEPA FILTERS, 4896 03:37:05,600 --> 03:37:07,760 INBREEDING IS BAD IN TERMS OF 4897 03:37:07,760 --> 03:37:09,960 FITNESS. 4898 03:37:09,960 --> 03:37:15,240 THERE'S A BIG ADVANTAGE TO 4899 03:37:15,240 --> 03:37:16,200 ZYGOSITY, LOOKING AT 4900 03:37:16,200 --> 03:37:18,960 HETEROZYGOSITY, IMMUNE SYSTEM IS 4901 03:37:18,960 --> 03:37:20,400 BIG. 4902 03:37:20,400 --> 03:37:23,120 AND I THINK ALSO SOMETHING MORE 4903 03:37:23,120 --> 03:37:24,120 RECENTLY THAT THERE'S THOUSANDS 4904 03:37:24,120 --> 03:37:26,920 OF GENES INVOLVED IN THE IMMUNE 4905 03:37:26,920 --> 03:37:29,440 SYSTEM THAT THERE'S A HUGE 4906 03:37:29,440 --> 03:37:31,640 PROPORTION OF GENOME DEVOTED TO 4907 03:37:31,640 --> 03:37:35,680 YOUR IMMUNE SYSTEM WORKING WELL, 4908 03:37:35,680 --> 03:37:38,560 THERE'S A HUGE GENETIC LOAD ON 4909 03:37:38,560 --> 03:37:40,040 IMMUNE SYSTEM WHICH MEANS THAT 4910 03:37:40,040 --> 03:37:43,440 INDIVIDUALS ARE GOING TO BE 4911 03:37:43,440 --> 03:37:45,920 DEFECTIVE IN MAYBE ALL SORTS OF 4912 03:37:45,920 --> 03:37:48,320 GENES, AFFECT THE IMMUNE SYSTEM, 4913 03:37:48,320 --> 03:37:50,160 SO THAT COULD EXPLAIN A LOT OF 4914 03:37:50,160 --> 03:37:53,240 HETEROGENEITY THAT WE SEE IN 4915 03:37:53,240 --> 03:37:55,280 TERMS OF DRUG TREATMENT FOR 4916 03:37:55,280 --> 03:37:57,800 CANCER AND AUTOIMMUNITY, FOR 4917 03:37:57,800 --> 03:37:58,120 EXAMPLE. 4918 03:37:58,120 --> 03:37:59,840 THIS IS REALLY WHAT YOU DON'T 4919 03:37:59,840 --> 03:38:03,080 SEE IN MICE, IT'S INDICATING 4920 03:38:03,080 --> 03:38:05,160 THAT PROBABLY PEOPLE HAVE 4921 03:38:05,160 --> 03:38:08,680 DIFFERENT IMMUNE SYSTEMS. 4922 03:38:08,680 --> 03:38:10,280 AND THAT BY STUDYING HUMANS, NOT 4923 03:38:10,280 --> 03:38:13,560 JUST BLOOD BUT ALSO ORGANOIDS, 4924 03:38:13,560 --> 03:38:17,160 WE'LL GET A SENSE OF THAT, THAT 4925 03:38:17,160 --> 03:38:20,160 WE'RE GETTING NO SENSE OF, IN 4926 03:38:20,160 --> 03:38:22,360 INBRED MICE AS POWERFUL AS THEY 4927 03:38:22,360 --> 03:38:23,120 ARE. 4928 03:38:23,120 --> 03:38:26,240 WE KNOW HOW POWERFUL THIS SYSTEM 4929 03:38:26,240 --> 03:38:28,160 IS AND ILLUSTRATED ALL THE 4930 03:38:28,160 --> 03:38:29,800 THINGS YOU CAN DO WITH THAT, BUT 4931 03:38:29,800 --> 03:38:32,520 HUMANS ARE GOING TO BE THE NEXT 4932 03:38:32,520 --> 03:38:35,680 LEVEL IN TERMS OF THAT VARIATION 4933 03:38:35,680 --> 03:38:39,440 AND PROBABLY WE'LL SEE A LOT 4934 03:38:39,440 --> 03:38:44,800 MORE SEX VARIATIONS AND 4935 03:38:44,800 --> 03:38:46,440 GEOGRAPHIC, RACIAL, ETHNIC 4936 03:38:46,440 --> 03:38:47,040 POPULATIONS DOING DIFFERENT 4937 03:38:47,040 --> 03:38:48,280 THINGS JUST BECAUSE SOME PART OF 4938 03:38:48,280 --> 03:38:50,120 THE IMMUNE SYSTEM IS NOT WORKING 4939 03:38:50,120 --> 03:38:57,720 WELL SO YOU GO TO THE BACKUP 4940 03:38:57,720 --> 03:38:58,360 PLAN B, ET CETERA. 4941 03:38:58,360 --> 03:39:01,840 >> I THINK WE ALL KNOW THAT YOU 4942 03:39:01,840 --> 03:39:03,040 STARTED IN MICE. 4943 03:39:03,040 --> 03:39:04,480 WE ALL APPRECIATE THAT HUMANS 4944 03:39:04,480 --> 03:39:10,920 AND MICE ARE VERY IMPORTANT TO 4945 03:39:10,920 --> 03:39:11,800 THE BEGINNING, MIDDLE, END. 4946 03:39:11,800 --> 03:39:14,680 YOU'RE PREACHING TO THE CHOIR. 4947 03:39:14,680 --> 03:39:19,240 THERE WAS ANOTHER QUESTION. 4948 03:39:19,240 --> 03:39:20,320 YES, ONLINE FROM BEFORE. 4949 03:39:20,320 --> 03:39:24,520 >> IT WAS MAX'S QUESTION, MAX'S 4950 03:39:24,520 --> 03:39:27,960 COMMENT ON DISENANGLING OBESITY 4951 03:39:27,960 --> 03:39:34,960 FROM AGING, HARD TO DO. 4952 03:39:34,960 --> 03:39:36,960 >> OKAY. 4953 03:39:36,960 --> 03:39:39,800 WE HAVE ONE MORE COMMENT ABOUT 4954 03:39:39,800 --> 03:39:42,320 AN OPPORTUNITY I THINK. 4955 03:39:42,320 --> 03:39:42,760 >> HELLO. 4956 03:39:42,760 --> 03:39:46,600 I AM FROM THE RADIATION MEASURES 4957 03:39:46,600 --> 03:39:47,800 PROGRAM AT NIAID, AND I WANTED 4958 03:39:47,800 --> 03:39:49,880 TO BRING UP A LITTLE BIT OF 4959 03:39:49,880 --> 03:39:51,600 MAYBE SOMETIMES WE COME EMPTY 4960 03:39:51,600 --> 03:39:52,920 HANDED BUT I HAVE SOMETHING TO 4961 03:39:52,920 --> 03:39:55,000 SHARE WITH YOU ALL. 4962 03:39:55,000 --> 03:39:56,120 THIS IS A SEX DIFFERENCES 4963 03:39:56,120 --> 03:39:56,400 OPPORTUNITY. 4964 03:39:56,400 --> 03:40:00,600 I KEEP HEARING ABOUT THIS. 4965 03:40:00,600 --> 03:40:02,680 AND I ACTUALLY PUBLISHED A 4966 03:40:02,680 --> 03:40:04,080 REQUEST FOR INFORMATION LAST 4967 03:40:04,080 --> 03:40:06,520 YEAR ON UNDERSTANDING THE SEX 4968 03:40:06,520 --> 03:40:07,200 DIFFERENCES IN RADIATION 4969 03:40:07,200 --> 03:40:10,240 EXPOSURES SO WE ARE A PROGRAM 4970 03:40:10,240 --> 03:40:13,640 THAT WAS ESTABLISHED IN 2004, 4971 03:40:13,640 --> 03:40:14,640 CONGRESSIONALLY MANDATED, THREE 4972 03:40:14,640 --> 03:40:17,440 PILLARS. 4973 03:40:17,440 --> 03:40:19,440 ONE IS TO IDENTIFY AND DEVELOP 4974 03:40:19,440 --> 03:40:20,200 MEDICAL COUNTERMEASURES FOR 4975 03:40:20,200 --> 03:40:22,600 RADIATION EXPOSURE IN A MASS 4976 03:40:22,600 --> 03:40:24,560 CASUALTY SITUATION, DEVELOP 4977 03:40:24,560 --> 03:40:33,640 DIAGNOSTICS AS WELL AS 4978 03:40:33,640 --> 03:40:34,800 RADIONUCLEID MEASURES. 4979 03:40:34,800 --> 03:40:39,120 WE GIANT A -- GAINED A LOT OF 4980 03:40:39,120 --> 03:40:39,880 INFORMATION. 4981 03:40:39,880 --> 03:40:41,000 THIS IS WHAT'S REALLY IMPORTANT. 4982 03:40:41,000 --> 03:40:44,040 FROM THAT WE WERE ABLE TO PUT 4983 03:40:44,040 --> 03:40:45,600 TOGETHER A REQUEST FOR 4984 03:40:45,600 --> 03:40:48,000 APPLICATION, WHICH IS ACTUALLY 4985 03:40:48,000 --> 03:40:50,520 ALREADY PUBLIC, IT'S THREE-YEAR 4986 03:40:50,520 --> 03:40:52,240 OPPORTUNITY FOR A YEAR 1 4987 03:40:52,240 --> 03:40:53,040 COOPERATIVE AGREEMENT AND THEY 4988 03:40:53,040 --> 03:40:58,720 ARE GOING TO POST IT UP ON THE 4989 03:40:58,720 --> 03:41:00,040 BOARD DURING THE BREAK. 4990 03:41:00,040 --> 03:41:04,520 AND SO THIS IS A THREE-YEAR 4991 03:41:04,520 --> 03:41:06,920 PROGRAM FOR DIRECT COSTS UP TO 4992 03:41:06,920 --> 03:41:09,960 $350,000, COME IN AS A 4993 03:41:09,960 --> 03:41:11,640 CONSORTIUM, REALLY GREAT TO HEAR 4994 03:41:11,640 --> 03:41:13,200 JARROD, JARROD IS PART OF OUR 4995 03:41:13,200 --> 03:41:17,080 PORTFOLIO NOW, HE HAS A UO1 IN 4996 03:41:17,080 --> 03:41:17,880 IMMUNE DYSFUNCTION, A LOT OF 4997 03:41:17,880 --> 03:41:19,120 GREAT THINGS I HEARD TOGETHER 4998 03:41:19,120 --> 03:41:25,320 AND PROGRAM THAT I WANTED TO 4999 03:41:25,320 --> 03:41:27,440 HEAR, A MEDICAL COUNTERMEASURE 5000 03:41:27,440 --> 03:41:28,480 THAT IMPROVED BLOOD FUNCTION, WE 5001 03:41:28,480 --> 03:41:30,040 WANT TO SEE THESE PRODUCTS, 5002 03:41:30,040 --> 03:41:31,760 REALLY IMPORTANT IN RADIATION 5003 03:41:31,760 --> 03:41:32,760 EXPOSURE. 5004 03:41:32,760 --> 03:41:33,960 I HEARD ABOUT COVID-19, AND 5005 03:41:33,960 --> 03:41:36,080 THERE ARE A LOT OF SIMILARITIES 5006 03:41:36,080 --> 03:41:37,480 BETWEEN COVID-19 AND RADIATION 5007 03:41:37,480 --> 03:41:40,000 EXPOSURE. 5008 03:41:40,000 --> 03:41:43,400 THERE'S A PUBLICATION OUR GROUP 5009 03:41:43,400 --> 03:41:44,600 PUBLISHED, BY CARMEN RIOS. 5010 03:41:44,600 --> 03:41:49,520 LASTLY I HEARD ABOUT 5011 03:41:49,520 --> 03:41:51,840 INFLAMMATORY PATHWAYS, A LOT OF 5012 03:41:51,840 --> 03:41:53,840 GAPS, ONE IS SEX DIFFERENCES, TO 5013 03:41:53,840 --> 03:41:58,200 MAKE SURE THERE ARE EQUAL 5014 03:41:58,200 --> 03:41:59,400 REPRESENTATION OF MALE VERSUS 5015 03:41:59,400 --> 03:42:00,920 FEMALE ANIMAL MODELS AS WELL AS 5016 03:42:00,920 --> 03:42:02,880 CELL LINES, ET CETERA. 5017 03:42:02,880 --> 03:42:04,320 SO PLEASE APPLY, IF YOU HAVE 5018 03:42:04,320 --> 03:42:06,400 QUESTIONS PLEASE LOOK UP THE 5019 03:42:06,400 --> 03:42:08,040 RADIATION AND NUCLEAR 5020 03:42:08,040 --> 03:42:09,520 COUNTERMEASURES PROGRAM OR LOOK 5021 03:42:09,520 --> 03:42:10,880 AT THE RFA. 5022 03:42:10,880 --> 03:42:14,160 OR SEE ME. 5023 03:42:14,160 --> 03:42:14,480 THANK YOU. 5024 03:42:14,480 --> 03:42:18,120 >> THANK YOU. 5025 03:42:18,120 --> 03:42:20,800 WE'RE GOING TO LUNCH. 5026 03:42:20,800 --> 03:42:21,560 5027 03:42:21,560 --> 03:42:23,800 >> ONE QUICK COMMENT. 5028 03:42:23,800 --> 03:42:26,200 THERE'S NOBODY TALKING ABOUT 5029 03:42:26,200 --> 03:42:28,040 AGING IN CANCER, THAT MAY BE 5030 03:42:28,040 --> 03:42:30,440 BECAUSE NCI IS NOT A 5031 03:42:30,440 --> 03:42:31,240 CO-ORGANIZER. 5032 03:42:31,240 --> 03:42:34,080 THERE'S A HUGE GAP IN THE FIELD, 5033 03:42:34,080 --> 03:42:38,320 IT'S LIKE -- 5034 03:42:38,320 --> 03:42:40,520 >>SOME OF US ARE WORKING ON 5035 03:42:40,520 --> 03:42:40,960 THAT. 5036 03:42:40,960 --> 03:42:43,360 YOU CAN SPEAK UP. 5037 03:42:43,360 --> 03:42:45,320 OR GO TO LUNCH AND WE'LL HIT IT 5038 03:42:45,320 --> 03:42:46,760 AT THE NEXT BREAK. 5039 03:42:46,760 --> 03:42:47,160 OR THE NEXT ONE. 5040 03:42:47,160 --> 03:42:49,840 THANK YOU SO MUCH. 5041 03:42:49,840 --> 03:42:52,720 I APPRECIATE THAT. 5042 03:42:52,720 --> 03:42:53,200 WHERE ARE WE GOING? 5043 03:42:53,200 --> 03:42:56,760 >> THANK YOU VERY MUCH. 5044 03:42:56,760 --> 03:42:56,920 5045 03:42:56,920 --> 03:43:00,280 >> YOU CAN FOLLOW ME OUTSIDE. 5046 03:43:00,280 --> 03:43:02,960 I CAN SHOW YOU WHERE THE CAFE IS 5047 03:43:02,960 --> 03:43:04,960 OR GO IN ONE GROUP AFTER THE 5048 03:43:04,960 --> 03:43:06,840 OTHER SO ONE GROUP CAN PUT YOUR 5049 03:43:06,840 --> 03:43:09,440 ORDER IN, THEN THE SECOND GROUP 5050 03:43:09,440 --> 03:43:10,280 COMES. 5051 03:43:10,280 --> 03:43:14,720 YOU CAN COME TOGETHER OR COME IN 5052 03:43:14,720 --> 03:43:15,440 DIFFERENT GROUPS. 5053 03:43:15,440 --> 03:43:16,680 I WILL TAKE YOU THERE. 5054 03:43:16,680 --> 03:43:18,520 I WILL GUIDE YOU THERE. 5055 03:43:18,520 --> 03:43:19,440 JUST FOLLOW ME. 5056 03:43:19,440 --> 03:43:23,160 THANK YOU. 5057 03:43:23,160 --> 03:43:24,480 ALL RIGHT, EVERYONE, I THINK 5058 03:43:24,480 --> 03:43:25,680 WE'RE ABOUT READY. 5059 03:43:25,680 --> 03:43:26,600 EVERYONE LOOKS LIKE THEY'VE COME 5060 03:43:26,600 --> 03:43:27,360 IN. 5061 03:43:27,360 --> 03:43:29,240 SO I'M HAPPY TO BE CHAIRING THE 5062 03:43:29,240 --> 03:43:30,960 SECOND SESSION ON ORGAN-IMMUNE 5063 03:43:30,960 --> 03:43:35,480 SYSTEM CROSSTALK. 5064 03:43:35,480 --> 03:43:36,040 THANK YOU. 5065 03:43:36,040 --> 03:43:40,200 I'M HAPPY TO INTRODUCE OUR FIRST 5066 03:43:40,200 --> 03:43:50,760 SPEAKER, GEORGE HAJISHENGALLIS. 5067 03:44:12,480 --> 03:44:13,000 HELLO. 5068 03:44:13,000 --> 03:44:16,040 CAN YOU HEAR ME? 5069 03:44:16,040 --> 03:44:18,640 >>YOU CAN START YOUR SLIDES. 5070 03:44:18,640 --> 03:44:20,120 >>I WILL SHARE MY SCREEN. 5071 03:44:20,120 --> 03:44:20,720 JUST A SECOND. 5072 03:44:20,720 --> 03:44:31,040 >>YES, THAT TOO. 5073 03:44:35,520 --> 03:44:38,640 CAN YOU SEE MY SCREEN? 5074 03:44:38,640 --> 03:44:39,520 YES, WE GOT IT. 5075 03:44:39,520 --> 03:44:39,840 IT THANK YOU. 5076 03:44:39,840 --> 03:44:41,520 >>I'M STARTING. 5077 03:44:41,520 --> 03:44:43,200 WELL, I WOULD LIKE TO THANK THE 5078 03:44:43,200 --> 03:44:45,400 ORGANIZERS FOR THIS INVITATION 5079 03:44:45,400 --> 03:44:47,560 AND TO TALK ABOUT OUR WORK ON 5080 03:44:47,560 --> 03:44:49,840 THE CHRONIC INFLAMMATORY 5081 03:44:49,840 --> 03:44:50,120 DISEASE. 5082 03:44:50,120 --> 03:44:57,480 I WILL START WITH PER PERIODONTL 5083 03:44:57,480 --> 03:44:57,760 DISEASE -- 5084 03:44:57,760 --> 03:45:00,800 >>CAN YOU SPEAK LOUDER OR 5085 03:45:00,800 --> 03:45:02,400 CLOSER TO YOUR MICROPHONE, 5086 03:45:02,400 --> 03:45:02,760 PLEASE? 5087 03:45:02,760 --> 03:45:04,800 >>IS THAT BETTER? 5088 03:45:04,800 --> 03:45:08,200 >>NOT REALLY. 5089 03:45:08,200 --> 03:45:18,640 LET ME SEE WHEN I CAN DO. 5090 03:45:20,560 --> 03:45:24,000 UNLESS THE AV PEOPLE CAN MAKE IT 5091 03:45:24,000 --> 03:45:29,640 LOUDER FOR US IN THE ROOM. 5092 03:45:29,640 --> 03:45:30,720 IS 245 BETTER NOW. 5093 03:45:30,720 --> 03:45:31,800 MUCH BETTER. 5094 03:45:31,800 --> 03:45:33,800 >>I HAVE SOMETHING APPEARS THAT 5095 03:45:33,800 --> 03:45:37,000 IT HAS WORKED. 5096 03:45:37,000 --> 03:45:39,440 SO, PERIODONTAL DISEASE IS AN 5097 03:45:39,440 --> 03:45:40,520 ORAL INFLAM ARY DISEASE THAT 5098 03:45:40,520 --> 03:45:42,200 LEADS TO THE TISSUE THAT 5099 03:45:42,200 --> 03:45:43,720 SURROUNDING AND SUPPORT THE 5100 03:45:43,720 --> 03:45:45,240 TEETH AND QUITE PREVALENT 5101 03:45:45,240 --> 03:45:47,720 DISEASE EVEN IF IT MEANS SEVERE 5102 03:45:47,720 --> 03:45:52,960 FORSEVEREFORM IT HAS THE POPULAD 5103 03:45:52,960 --> 03:45:55,080 INVOLVES A TREMENDOUS 5104 03:45:55,080 --> 03:45:56,320 EXPENDITURE AND VERY IMPORTANTLY 5105 03:45:56,320 --> 03:46:00,160 THE INCREASES THE RISK OF 5106 03:46:00,160 --> 03:46:01,720 SYSTEMIC INFLAMMATORY DISEASE. 5107 03:46:01,720 --> 03:46:04,280 THERE'S AN UP MET NEED FOR 5108 03:46:04,280 --> 03:46:05,560 THERAPY IN THIS DISEASE WHICH IS 5109 03:46:05,560 --> 03:46:07,520 TREATED THE SAME WAY IT WAS 5110 03:46:07,520 --> 03:46:09,640 TREATED 100 YEARS AGO AND IN 5111 03:46:09,640 --> 03:46:12,800 THAT REGARD AND WITH THE HELP OF 5112 03:46:12,800 --> 03:46:14,600 NIDCR FUNDING MORE THAN 10 YEARS 5113 03:46:14,600 --> 03:46:25,160 AND STARTING ORIGINALLY WE HAVE 5114 03:46:26,160 --> 03:46:28,720 SHOWN THERE'S TARGET FOR PERRY 5115 03:46:28,720 --> 03:46:30,560 RODENTAL DISEASE AND IN OUR WORK 5116 03:46:30,560 --> 03:46:33,080 A CLINICAL TRIAL WE HAVE SHOWN 5117 03:46:33,080 --> 03:46:35,680 THAT LOCAL TREATMENT OF HUMAN 5118 03:46:35,680 --> 03:46:39,400 PATIENTS WITH INHIBITOR CALLED 5119 03:46:39,400 --> 03:46:43,640 ME101 SIGNIFICANTLY INHIBITS 5120 03:46:43,640 --> 03:46:48,120 PERRY RODENTAL INFLAMMATION AND 5121 03:46:48,120 --> 03:46:51,640 PERIODONTAL INFLAMMATION AND OUR 5122 03:46:51,640 --> 03:46:54,400 NEXT STEP IS PHASE 3 CRYO AND 5123 03:46:54,400 --> 03:46:58,480 HOPING WE CAN BRING AND FOR THE 5124 03:46:58,480 --> 03:47:02,400 BENEFIT OF THE HUMAN PERRY 5125 03:47:02,400 --> 03:47:06,120 ADOPERIODONTALPATIENT. 5126 03:47:06,120 --> 03:47:10,960 WHAT OTHER DISEASES HAVE BEEN 5127 03:47:10,960 --> 03:47:21,480 INFLAMMATION AND THE -- TISSUE 5128 03:47:36,120 --> 03:47:37,480 MICROENVIRONMENT AND THE VARIOUS 5129 03:47:37,480 --> 03:47:40,320 TISSUE AND THE MICROBIOME ALL 5130 03:47:40,320 --> 03:47:42,240 CONTRIBUTE TO THE INFLAMMATION. 5131 03:47:42,240 --> 03:47:44,840 IN SOME OF OUR REGIONAL WORK, WE 5132 03:47:44,840 --> 03:47:48,600 FOCUSED ON THE TISSUE 5133 03:47:48,600 --> 03:47:51,880 MICROENVIRONMENT AND WE HAVE 5134 03:47:51,880 --> 03:47:54,680 DESCRIBED PROTEINS CALLED 5135 03:47:54,680 --> 03:47:57,640 PRODUCED BY TISSUE RESIDENT 5136 03:47:57,640 --> 03:48:03,080 CELLS IN SOME OF THE TISSUES 5137 03:48:03,080 --> 03:48:04,600 BECAUSE TISSUE PATTERN 5138 03:48:04,600 --> 03:48:08,160 EXPRESSION THAT IS NOT HOMO 5139 03:48:08,160 --> 03:48:10,760 GENIOUS AND IN THE WE HAVE SHOWN 5140 03:48:10,760 --> 03:48:13,800 THAT THE EXPRESSION OF DEL-1 AND 5141 03:48:13,800 --> 03:48:17,760 THIS IS WORK FROM MICE BUT OTHER 5142 03:48:17,760 --> 03:48:18,760 INDEPENDENT GROUPS IN EUROPE 5143 03:48:18,760 --> 03:48:20,760 HAVE SHOWN THE SAME THING IS 5144 03:48:20,760 --> 03:48:22,240 SEEN IN HUMAN PATIENTS AND 5145 03:48:22,240 --> 03:48:23,120 ANYWAY. 5146 03:48:23,120 --> 03:48:24,600 WE HAD A VERY INTERESTING 5147 03:48:24,600 --> 03:48:25,800 CORRELATION IN OUR FIRST STUDIES 5148 03:48:25,800 --> 03:48:28,840 WE SHOWED THAT THE OLD MICE WHO 5149 03:48:28,840 --> 03:48:32,040 HAD VERY LITTLE EXPRESSION OF 5150 03:48:32,040 --> 03:48:33,560 DEL-1 THIS DECLINE EXPRESSION 5151 03:48:33,560 --> 03:48:35,480 WAS CORRELATED WITH INCREASING 5152 03:48:35,480 --> 03:48:38,320 INFLAMMATION AND INCREASE INFILL 5153 03:48:38,320 --> 03:48:39,480 STATION AND MORE BONE LOSS. 5154 03:48:39,480 --> 03:48:42,400 AND OVER THE YEARS, IN 5155 03:48:42,400 --> 03:48:43,320 SUBSEQUENT STUDIES WE WERE ABLE 5156 03:48:43,320 --> 03:48:45,640 TO FULLY UNDERSTAND THE 5157 03:48:45,640 --> 03:48:48,760 MECHANISTIC BASIS OF THESE. 5158 03:48:48,760 --> 03:48:52,960 ORIGINALLY WE KNEW THAT DEL-1 5159 03:48:52,960 --> 03:48:55,560 BLOCKS THE INTERACTION BETWEEN 5160 03:48:55,560 --> 03:48:59,600 THE NEUTROPHILS AND IN THE CELLS 5161 03:48:59,600 --> 03:49:03,920 AND THIS IS PREREQUISITE FOR 5162 03:49:03,920 --> 03:49:06,560 NEUTROPHIL OF DEL-1 IS 5163 03:49:06,560 --> 03:49:09,520 REGULATING THIS STEP AND 5164 03:49:09,520 --> 03:49:11,720 INFLAMMATION. 5165 03:49:11,720 --> 03:49:14,760 WE'VE SHOWED THAT DEL-1 PROMOTES 5166 03:49:14,760 --> 03:49:19,880 A WASTE DISPOSAL TO GET RID OF 5167 03:49:19,880 --> 03:49:25,400 DEAD NUT TREE FILLS AND IT'S FOR 5168 03:49:25,400 --> 03:49:28,240 THIS FUNCTION AT LEAST IN 5169 03:49:28,240 --> 03:49:29,400 CERTAIN TISSUE AND WE HAVE ALSO 5170 03:49:29,400 --> 03:49:32,600 SHOWN THAT DEL-1 REGULATES CELLS 5171 03:49:32,600 --> 03:49:35,320 THAT PROMOTES THE STABILITY AND 5172 03:49:35,320 --> 03:49:38,440 SUPPRESSIVE ACTIVITY AND IN 5173 03:49:38,440 --> 03:49:41,280 RELEVANT WITH BONE LOSS AND 5174 03:49:41,280 --> 03:49:46,280 DISORDERS SUCH AS DEL-1 PROMOTES 5175 03:49:46,280 --> 03:49:48,280 DIFFERENTIATION BUT SUB CRISIS 5176 03:49:48,280 --> 03:49:52,600 OF ACTIVITY SO, IT'S OF USE THAT 5177 03:49:52,600 --> 03:49:55,000 SEEMS DEL-1 IS IMPORTANT FROM 5178 03:49:55,000 --> 03:49:58,120 YOUR STATIC FUNCTIONS IT'S 5179 03:49:58,120 --> 03:49:59,880 DECLINED IN OLD AGE IN BOTH MICE 5180 03:49:59,880 --> 03:50:02,120 AND HUMANS IS GOING TO HAVE 5181 03:50:02,120 --> 03:50:02,760 REPERCUSSIONS AND WE HAVE SHOWN 5182 03:50:02,760 --> 03:50:05,800 BY THE WAYS THIS CONCEPT NOT 5183 03:50:05,800 --> 03:50:08,160 ONLY IN PRECLINICAL MODELS OF 5184 03:50:08,160 --> 03:50:14,240 PERRY ADPERRYADOPTAL IN MULTIPL. 5185 03:50:14,240 --> 03:50:16,120 I DIDN'T HAVE TIME TO SHOW YOU 5186 03:50:16,120 --> 03:50:21,520 TODAY IS THAT WE COULD REVERSE 5187 03:50:21,520 --> 03:50:23,880 THIS CONDITIONS BY SUPPLYING 5188 03:50:23,880 --> 03:50:24,080 DEL-1. 5189 03:50:24,080 --> 03:50:26,880 HOWEVER IN OLD AGE, IT MAY BE 5190 03:50:26,880 --> 03:50:28,440 MORE PRACTICAL NOT TO REPLENISH 5191 03:50:28,440 --> 03:50:30,920 THE MISSING DEL-1 LEVELS BUT TO 5192 03:50:30,920 --> 03:50:33,160 FIND A WAY TO STIMULATE DELL 1 5193 03:50:33,160 --> 03:50:42,440 EXPRESSION IN OLD AGE. 5194 03:50:42,440 --> 03:50:45,120 WE HAVE A HORMONE AT LOW LEVELS 5195 03:50:45,120 --> 03:50:49,320 IN OLD AGE AND WE HAVE SHOWN 5196 03:50:49,320 --> 03:50:50,960 THAT IN DEL-1 EXPRESSION OLD AGE 5197 03:50:50,960 --> 03:50:53,480 BUT MORE RECENTLY, THIS IS VERY 5198 03:50:53,480 --> 03:50:58,240 MORE INTERESTING, THE 5199 03:50:58,240 --> 03:50:59,280 ANTIBIOTICS PROMOTES GOOD 5200 03:50:59,280 --> 03:51:02,080 EXPRESSION OF DEL-1 IN OLD MICE 5201 03:51:02,080 --> 03:51:03,880 AND IN FACT THERE ARE MICRO 5202 03:51:03,880 --> 03:51:06,200 LIGHTS THAT DO NOT HAVE ACTIVITY 5203 03:51:06,200 --> 03:51:08,200 AND THEY'RE GOOD REGULATING 5204 03:51:08,200 --> 03:51:09,800 DEL-1 IN OLD AGE IN OLD MICE BUT 5205 03:51:09,800 --> 03:51:12,600 THIS IS SOMETHING THAT CAN BE 5206 03:51:12,600 --> 03:51:15,880 EASILY TESTED IN HUMANS. 5207 03:51:15,880 --> 03:51:19,600 SO, I WOULD LIKE NOW TO FOCUS ON 5208 03:51:19,600 --> 03:51:25,080 THE POET HE POETIC SYSTEM AND S 5209 03:51:25,080 --> 03:51:27,520 SYSTEM CAN IMPACT FROM PERRY OWE 5210 03:51:27,520 --> 03:51:32,840 TONIGHTAL DISEASE AND OTHER 5211 03:51:32,840 --> 03:51:40,960 CO-MORBIDITIES. 5212 03:51:40,960 --> 03:51:43,160 THEY HAVE THE IMMUNE SYSTEM TO 5213 03:51:43,160 --> 03:51:46,480 FORM A MEMORY AND BASED ON THAT, 5214 03:51:46,480 --> 03:51:48,600 TO ILLICIT NEW RESPONSES TO 5215 03:51:48,600 --> 03:51:49,680 SECONDARY CHALLENGES. 5216 03:51:49,680 --> 03:51:52,360 SO THIS IS HOW LET'S SAY A MACRO 5217 03:51:52,360 --> 03:51:55,200 PAGE WILL RESPOND BUT IF YOU 5218 03:51:55,200 --> 03:51:56,360 ACQUIRE THIS EXPERIENCE WITH A 5219 03:51:56,360 --> 03:51:57,960 PREVIOUS INFECTION IT CAN 5220 03:51:57,960 --> 03:51:59,760 RESPOND MUCH FASTER AND STRONGER 5221 03:51:59,760 --> 03:52:03,280 TO A SECONDARY INSPECTION WHICH 5222 03:52:03,280 --> 03:52:04,960 IS NOT THE SAME AS THE ORIGINAL 5223 03:52:04,960 --> 03:52:05,320 ONE. 5224 03:52:05,320 --> 03:52:07,480 THIS IS THE CLASSICAL MEMORY 5225 03:52:07,480 --> 03:52:10,320 WHICH IS SPECIFIC. 5226 03:52:10,320 --> 03:52:13,400 SO, THIS IMMUNITY IS SUPPOSED TO 5227 03:52:13,400 --> 03:52:16,800 BE PROTECTIVE AND SELECTED 5228 03:52:16,800 --> 03:52:18,080 PROTECTING US AGAINST INFECTION 5229 03:52:18,080 --> 03:52:20,400 AND THERE ARE STUDIES THAT SHOW 5230 03:52:20,400 --> 03:52:24,240 IT PROTECTS AGAINST TUMORS BUT 5231 03:52:24,240 --> 03:52:26,040 LIKE EVERYTHING, NOTHING CAN BE 5232 03:52:26,040 --> 03:52:29,240 100% PROTECTIVE AND SO HAVING 5233 03:52:29,240 --> 03:52:31,880 'EM UNITY IT MAY BE EXCESSIVE 5234 03:52:31,880 --> 03:52:33,600 AND INFLAMMATION IN THAT CASE WE 5235 03:52:33,600 --> 03:52:35,280 WOULD CALL IT MALL ADAPTIVE 5236 03:52:35,280 --> 03:52:40,680 TRAINED IMMUNITY. 5237 03:52:40,680 --> 03:52:43,080 SO RECENTLY MY LAB AND 5238 03:52:43,080 --> 03:52:48,520 COLLABORATORS HAVE SHOWN THAT IS 5239 03:52:48,520 --> 03:52:51,520 THE MACKNESS TICK BASIS THAT CAN 5240 03:52:51,520 --> 03:52:53,760 EXPLAIN THE CO MORBID CONNECTION 5241 03:52:53,760 --> 03:52:56,600 BETWEEN PERIODONTAL DISEASE. 5242 03:52:56,600 --> 03:53:02,560 THE SYSTEMIC INNA MISSION IN 5243 03:53:02,560 --> 03:53:06,280 MICE AND HUMANS, THE 5244 03:53:06,280 --> 03:53:08,080 INFLAMMATION IS SENT TO THE BONE 5245 03:53:08,080 --> 03:53:10,800 MARROW BY THE PROGENITORSES AND 5246 03:53:10,800 --> 03:53:13,200 THEY UNDERGO GENETIC ALTERATIONS 5247 03:53:13,200 --> 03:53:15,480 AND THEY BECOME TRAINED AND 5248 03:53:15,480 --> 03:53:18,560 MYELOID BIAS THAT MEANS THEY 5249 03:53:18,560 --> 03:53:20,240 PRODUCE A LOT OF MYELOID CELLS 5250 03:53:20,240 --> 03:53:22,520 AND MONOCYTES WHICH THEMSELVES 5251 03:53:22,520 --> 03:53:24,680 ARE TRAINED THAT IS HYPER 5252 03:53:24,680 --> 03:53:25,680 INFLAMMATORY OF COURSE THEY WILL 5253 03:53:25,680 --> 03:53:28,400 NOT STAY IN THE BONE MARROW, 5254 03:53:28,400 --> 03:53:29,760 THEY CIRCULATE AND THEY CAN BE 5255 03:53:29,760 --> 03:53:31,240 RECRUITED IN TISSUE WHERE 5256 03:53:31,240 --> 03:53:35,520 THERE'S AN I AM FEX AND INFECTID 5257 03:53:35,520 --> 03:53:36,640 INFLAMMATION AND THEY GO BACK 5258 03:53:36,640 --> 03:53:40,840 BUT THEY CAN ALSO BE RECRUITED 5259 03:53:40,840 --> 03:53:43,840 IN LET'S SEE IN THE JOINTS AND 5260 03:53:43,840 --> 03:53:48,520 WE HAVE SHOWN THAT THESE ALSO 5261 03:53:48,520 --> 03:53:51,440 EXACERBATES ARTHRITIS. 5262 03:53:51,440 --> 03:53:53,080 SO, THESE ARE HUMAN RELEVANCE 5263 03:53:53,080 --> 03:53:54,040 FOR THAT. 5264 03:53:54,040 --> 03:53:58,840 WELL, GOING BACK TO IN HUMANS, 5265 03:53:58,840 --> 03:54:01,800 WE SEE THAT WHEN PEOPLE WERE 5266 03:54:01,800 --> 03:54:07,360 GETTING PERIPHERAL BLOOD 5267 03:54:07,360 --> 03:54:10,160 MONOCYTES THESE CELLS WHEN 5268 03:54:10,160 --> 03:54:13,480 STIMULATED, HAD BACTERIA OR LPS 5269 03:54:13,480 --> 03:54:15,280 THEY WERE PRODUCING HIGH LEVELS 5270 03:54:15,280 --> 03:54:18,840 OF INFLAMMATORY CYTOKINES THEN 5271 03:54:18,840 --> 03:54:20,240 CELLS FROM NORMAL CONTROLS. 5272 03:54:20,240 --> 03:54:22,360 ALSO THIS IS VERY IMPORTANT AND 5273 03:54:22,360 --> 03:54:23,480 AT THAT TIME THEY COULD NOT 5274 03:54:23,480 --> 03:54:26,280 EXPLAIN THIS OBSERVATION. 5275 03:54:26,280 --> 03:54:29,160 EVEN THE BLOOD WAS TAKEN FROM 5276 03:54:29,160 --> 03:54:31,280 PATIENTS, THAT WERE TREATED 5277 03:54:31,280 --> 03:54:32,440 SUCCESSFULLY AND THEY HAD NO 5278 03:54:32,440 --> 03:54:40,040 SIGNS OF PER OWE ADOPTAL PER PEE 5279 03:54:40,040 --> 03:54:43,600 ONLY EXPLANATION FOR THAT IS 5280 03:54:43,600 --> 03:54:45,280 INFLAMMATORY MEMORY AND EVEN A 5281 03:54:45,280 --> 03:54:47,240 GROUP IN BOSTON WITH A CLINICAL 5282 03:54:47,240 --> 03:54:49,640 IMAGING STUDY HAVE SHOWN THAT 5283 03:54:49,640 --> 03:54:52,560 VERY NICE CORRELATION BETWEEN 5284 03:54:52,560 --> 03:54:54,200 PERIODONTAL INFLAMMATION AND 5285 03:54:54,200 --> 03:54:55,800 TISSUE ACTIVITY WHICH IMPLIES 5286 03:54:55,800 --> 03:55:03,360 THAT THERE IS AN INFLAMMATORY 5287 03:55:03,360 --> 03:55:04,920 AND WHAT WE HAVE DESCRIBED IN 5288 03:55:04,920 --> 03:55:07,920 OUR PUBLICATION ABOUT THE MOUSE 5289 03:55:07,920 --> 03:55:10,640 MODEL. 5290 03:55:10,640 --> 03:55:12,880 NOW, TRADE IMMUNITY CAN PERSIST 5291 03:55:12,880 --> 03:55:13,960 FOR SEVERAL MONTHS IN MICE. 5292 03:55:13,960 --> 03:55:15,720 THERE'S SOME PAPERS IN HUMAN 5293 03:55:15,720 --> 03:55:18,120 STATING THIS CAN GO MORE THAN A 5294 03:55:18,120 --> 03:55:21,880 YEAR FOR 14 OR 15 MONTHS SO IT'S 5295 03:55:21,880 --> 03:55:23,800 QUITE SUSTAINED BUT 5296 03:55:23,800 --> 03:55:27,320 NEVERTHELESS, IT'S A REVERSIBLE 5297 03:55:27,320 --> 03:55:29,640 STATE OF WEARING SO IS THERE ANY 5298 03:55:29,640 --> 03:55:30,960 PATHOLOGICAL CONDITION WHICH IS 5299 03:55:30,960 --> 03:55:34,640 ASSOCIATED WITH THE FIX STATE OF 5300 03:55:34,640 --> 03:55:35,600 A LOT TERRATIONS SO THIS IS THE 5301 03:55:35,600 --> 03:55:38,200 LAST PART OF MY TALK AND IN DEED 5302 03:55:38,200 --> 03:55:42,600 IT APPEARS THE DETERMINE SHAPE 5303 03:55:42,600 --> 03:55:45,840 IS SUCH A CONDITION AND LET ME 5304 03:55:45,840 --> 03:55:48,440 EXPLAIN WHAT SO AS WE BECOME 5305 03:55:48,440 --> 03:55:54,160 OLDER, THERE'S A ACCUMULATION OF 5306 03:55:54,160 --> 03:55:57,960 CELLS AND OF THESE MUTATIONS ARE 5307 03:55:57,960 --> 03:56:00,960 CONFER TO THE AFFECTED CELL AS 5308 03:56:00,960 --> 03:56:02,560 SELF-RENEWAL OR PROLIFERATION 5309 03:56:02,560 --> 03:56:09,680 ADVANTAGE AND THIS LEADS THE 5310 03:56:09,680 --> 03:56:15,080 MUTANT CELLS PRODUCE AND A LARGE 5311 03:56:15,080 --> 03:56:17,680 FRACTION OF MUTANT CELLS IN THE 5312 03:56:17,680 --> 03:56:21,840 BLOOD AND NOT ONLY THAT BUT 5313 03:56:21,840 --> 03:56:26,320 THESE MUTANT CELLS MYELOID CELLS 5314 03:56:26,320 --> 03:56:30,120 LIKE ET CETERA, THEY'RE HYPER 5315 03:56:30,120 --> 03:56:32,040 INFLAMMATORY AND THE GENES THAT 5316 03:56:32,040 --> 03:56:37,480 ARE MORE COMMONLY EFFECTED IS 5317 03:56:37,480 --> 03:56:46,960 THESE ARE EPIGENETIC ENZYMES BUT 5318 03:56:46,960 --> 03:56:56,680 IT'S A THIRD ASXL1. 5319 03:56:56,680 --> 03:56:58,920 AND IT'S PREF LEAPT OF CHIP AND 5320 03:56:58,920 --> 03:57:01,160 EFFECTS 10% THAT ARE OLDER THAN 5321 03:57:01,160 --> 03:57:04,600 65 YEARS OF AGE. 5322 03:57:04,600 --> 03:57:06,160 VERY EPIDEMIOLOGICAL EVIDENCE 5323 03:57:06,160 --> 03:57:09,000 WHICH IS CONCLUSIVE THAT CHIP 5324 03:57:09,000 --> 03:57:11,520 PROMOTES OR EXACERBATES 5325 03:57:11,520 --> 03:57:13,200 CARDIOVASCULAR DISEASE AND THIS 5326 03:57:13,200 --> 03:57:15,040 IS EPIDEMIOLOGICAL LEVEL THERE'S 5327 03:57:15,040 --> 03:57:16,560 BEEN SEVERAL STUDIES WHICH IS 5328 03:57:16,560 --> 03:57:19,800 THE FIRST ONE OR THERE WERE 1 AT 5329 03:57:19,800 --> 03:57:26,040 THE SAME TIME BUT THIS IS 5330 03:57:26,040 --> 03:57:29,280 SHOWING THAT IN MICE ACCELERATED 5331 03:57:29,280 --> 03:57:30,720 THROUGH CELLO SIS IN THAT MODEL 5332 03:57:30,720 --> 03:57:33,240 SO THE QUESTION WE ASKED IS THAT 5333 03:57:33,240 --> 03:57:35,280 WHETHER KEEP THESE ASSOCIATED 5334 03:57:35,280 --> 03:57:36,920 WITH CARDIOVASCULAR DISEASE OR 5335 03:57:36,920 --> 03:57:41,160 WHETHER IT CAN PROMOTE TERRY OWE 5336 03:57:41,160 --> 03:57:45,480 TONIGHTAL DISEASE IN OLD AGE. 5337 03:57:45,480 --> 03:57:50,600 WE STARTED ASKING ASKING THIS 5338 03:57:50,600 --> 03:57:52,360 QUESTION AT EPIDEMIOLOGICAL 5339 03:57:52,360 --> 03:57:53,600 LEVEL AND WE'VE BEEN 5340 03:57:53,600 --> 03:57:57,040 COLLABORATING WITH AN ONGOING 5341 03:57:57,040 --> 03:57:58,800 STUDY AND HUMAN DEVICES FROM THE 5342 03:57:58,800 --> 03:58:00,520 UNIVERSITY OF NORTH CAROLINA AND 5343 03:58:00,520 --> 03:58:02,080 THESE ARE SOME OF OUR INITIAL 5344 03:58:02,080 --> 03:58:03,720 DATA THAT I'M REPORTING BRIEFLY 5345 03:58:03,720 --> 03:58:05,880 HERE SO WE ANALYZED THE 5346 03:58:05,880 --> 03:58:07,760 PARTICIPANTS OF DENTAL STUDY AND 5347 03:58:07,760 --> 03:58:10,600 IN THIS STUDY THERE'S NOT ONLY 5348 03:58:10,600 --> 03:58:12,000 INFORMATION ABOUT THE STUDIES OF 5349 03:58:12,000 --> 03:58:15,080 THESE PATIENTS BUT THERE IS FULL 5350 03:58:15,080 --> 03:58:16,560 GENETIC INFORMATION AND THIS 5351 03:58:16,560 --> 03:58:18,640 ANALYSIS HAS SHOWN THAT 5352 03:58:18,640 --> 03:58:19,720 INDIVIDUALS IN PARTICULARLY 5353 03:58:19,720 --> 03:58:23,200 THOSE WITH MUTATIONS IN THE FREE 5354 03:58:23,200 --> 03:58:27,040 AGING HAD INCREASES PERIODONTAL 5355 03:58:27,040 --> 03:58:29,200 DISEASE AND INFLAMMATION AND 5356 03:58:29,200 --> 03:58:31,040 THES ASSOCIATION ASK CORRELATIVE 5357 03:58:31,040 --> 03:58:32,360 AND THAT'S WHY WE HAVE THE 5358 03:58:32,360 --> 03:58:36,000 CLINICAL MODELS AND HERE I WOULD 5359 03:58:36,000 --> 03:58:40,680 LIKE TO SAY THAT THE MOST 5360 03:58:40,680 --> 03:58:43,800 MUTATION IN HUMAN THE HOTSPOT 5361 03:58:43,800 --> 03:58:46,920 MUTATION IS THE R82H AND THE 5362 03:58:46,920 --> 03:58:51,360 EQUIVALENT MUTATION IN MICE IS 5363 03:58:51,360 --> 03:58:52,560 R878H WE HAVE THESE MICE AND WE 5364 03:58:52,560 --> 03:58:54,160 HAVE THIS MODEL IF MY LAB RIGHT 5365 03:58:54,160 --> 03:58:55,560 NOW AND WE'RE USE PARTICULAR TO 5366 03:58:55,560 --> 03:58:59,320 ANSWER THESE QUESTIONS. 5367 03:58:59,320 --> 03:59:02,640 THE MICE WOULD HAVE 100% MUTANT 5368 03:59:02,640 --> 03:59:04,800 CLONES AND IN HUMANS THIS IS NOT 5369 03:59:04,800 --> 03:59:08,280 OF COURSE 100% BUT THE CLINICAL 5370 03:59:08,280 --> 03:59:11,680 RELEVANCE OF VAF IS 10% OR 5371 03:59:11,680 --> 03:59:15,960 AROUND THERE AND SO WE ARE USING 5372 03:59:15,960 --> 03:59:18,200 THIS MICE AND TO BONE MARROW 5373 03:59:18,200 --> 03:59:21,080 TRANSPLANTATION WE TRANSPLANT A 5374 03:59:21,080 --> 03:59:21,760 CLINICAL IRRELEVANT FACTION LIKE 5375 03:59:21,760 --> 03:59:25,640 10% TO RECEIVE IN MICE AND WE 5376 03:59:25,640 --> 03:59:28,000 FOLLOW WHETHER WE HAVE EXPANSION 5377 03:59:28,000 --> 03:59:28,920 OF THE MUTANT CLONES AND WHAT 5378 03:59:28,920 --> 03:59:31,440 HAPPENS OF COURSE IN CONTROLS. 5379 03:59:31,440 --> 03:59:37,480 AND WE DID THIS A STUDY AND IT'S 5380 03:59:37,480 --> 03:59:41,640 UNPUBLISHED DATA RIGHT NOW SO 5381 03:59:41,640 --> 03:59:42,520 THE MUTANT CLONES WE'RE 5382 03:59:42,520 --> 03:59:45,760 EXPANDING WITH TIME LIKE THE 5383 03:59:45,760 --> 03:59:47,200 WHITE TYPE CLONES IN THESE 5384 03:59:47,200 --> 03:59:48,840 RECIPIENTS HERE THAT THE 5385 03:59:48,840 --> 03:59:50,760 FREQUENCY IN THE PERIPHERAL 5386 03:59:50,760 --> 03:59:53,160 BLOOD WAS PRETTY MUCH CONSTANT 5387 03:59:53,160 --> 03:59:57,240 AND OF COURSE, THE CASE WE'RE 5388 03:59:57,240 --> 04:00:01,400 ALSO EXPANDING IF THE BONE 5389 04:00:01,400 --> 04:00:03,400 MARROW AND VERY INTERESTINGLY 5390 04:00:03,400 --> 04:00:04,800 AND THIS IS WITHOUT ANY 5391 04:00:04,800 --> 04:00:07,960 CONVENTION NOW, THIS IS NOT ANY 5392 04:00:07,960 --> 04:00:11,520 MODEL, WE NOTICED THIS MICE THAT 5393 04:00:11,520 --> 04:00:13,560 RECEIVED THE 10% MUTANT CLONES, 5394 04:00:13,560 --> 04:00:16,160 DEVELOPED MORE NATURALLY BONE 5395 04:00:16,160 --> 04:00:18,760 LOSS, NATURAL BONE LOSS THAN THE 5396 04:00:18,760 --> 04:00:21,080 CONTROLLERS AND NOT ONLY THAT, 5397 04:00:21,080 --> 04:00:26,240 WHEN THE TISSUE WAS ANALYZED FOR 5398 04:00:26,240 --> 04:00:33,200 FOR FOR IN FROM MISSION AND IT S 5399 04:00:33,200 --> 04:00:35,360 CYTOKINES AND IN MICE AND HUMANS 5400 04:00:35,360 --> 04:00:39,560 AND ALSO I OBJECT CREASED 5401 04:00:39,560 --> 04:00:42,040 ACTIVITY. 5402 04:00:42,040 --> 04:00:44,200 WE HAVE ALSO SUBJECTED THE MICE 5403 04:00:44,200 --> 04:00:48,440 THAT WE SEE THE MUTANT CLONES TO 5404 04:00:48,440 --> 04:00:52,280 ANTIBODY INDUCED ARTHRITIS AND 5405 04:00:52,280 --> 04:00:58,160 THE CONTROLS AND -- HELLO? 5406 04:00:58,160 --> 04:01:00,360 AND THE MICE THAT RECEIVED THE 5407 04:01:00,360 --> 04:01:03,960 CLONES HAD INCREASED A ALSO 5408 04:01:03,960 --> 04:01:05,640 INCREASED AND THIS IS THIS 5409 04:01:05,640 --> 04:01:09,760 CORRELATED WITH INCREASES 5410 04:01:09,760 --> 04:01:12,240 FILTRATION OF MUTANT MYELOID 5411 04:01:12,240 --> 04:01:12,800 CELLS. 5412 04:01:12,800 --> 04:01:16,720 VERY VICIOUS CYCLE HERE IN THE 5413 04:01:16,720 --> 04:01:21,480 CONTEXT OF I SAID BEFORE, 5414 04:01:21,480 --> 04:01:24,880 INCREASES FROM MISSION AND 5415 04:01:24,880 --> 04:01:26,320 EXACERBATES AND FROM THIS 5416 04:01:26,320 --> 04:01:36,640 CHRONIC DISEASES. 5417 04:02:02,920 --> 04:02:04,440 ANOTHER QUESTION OF CLINICAL 5418 04:02:04,440 --> 04:02:06,120 SIGNIFICANCE IS WHETHER WE CAN 5419 04:02:06,120 --> 04:02:07,400 SCREEN FOR IDENTIFY INDIVIDUALS 5420 04:02:07,400 --> 04:02:10,320 WITH INCREASE RISK FOR CLONE INA 5421 04:02:10,320 --> 04:02:11,960 FLAM TORI DISEASES AND IF THAT 5422 04:02:11,960 --> 04:02:16,000 IS POSSIBLE, CAN WE INTERVENE 5423 04:02:16,000 --> 04:02:17,680 WITH PREVENTATIVE TREATMENTS 5424 04:02:17,680 --> 04:02:19,120 WHEN WE HAVE IN MINDS IS WHETHER 5425 04:02:19,120 --> 04:02:23,640 WE CAN BLOCK THE EXPANSION OF 5426 04:02:23,640 --> 04:02:26,840 CLONES AND BLOCK THEM TO HAVE 5427 04:02:26,840 --> 04:02:31,320 IMPACT ON CO MORBID CONDITIONS 5428 04:02:31,320 --> 04:02:32,560 AND WE'LL GIVE AN EXAMPLE. 5429 04:02:32,560 --> 04:02:35,360 THIS IS FROM OUR RECENT STUDY 5430 04:02:35,360 --> 04:02:39,760 WHICH WE IMPLICATED IMMUNITY AS 5431 04:02:39,760 --> 04:02:43,400 MECHANISTIC BASIS BETWEEN THEM 5432 04:02:43,400 --> 04:02:44,840 AND WE HAVE SHOWN WE DIDN'T HAVE 5433 04:02:44,840 --> 04:02:46,600 TIME TO SHOW YOU DATA BUT FOR 5434 04:02:46,600 --> 04:02:47,640 ANYONE INTERESTED IN THE PAPER 5435 04:02:47,640 --> 04:02:49,800 AND SEE IT BUT WE HAVE 5436 04:02:49,800 --> 04:02:53,000 IDENTIFIED THAT BETA WAS THE 5437 04:02:53,000 --> 04:02:56,920 RESPONSIBLE FOR THE MALL 5438 04:02:56,920 --> 04:02:58,640 ADAPTIVE FOR THE OTHER 5439 04:02:58,640 --> 04:03:00,840 ALTERATIONS AND ALSO, THIS IS 5440 04:03:00,840 --> 04:03:03,560 FROM A DIFFERENT GROUP. 5441 04:03:03,560 --> 04:03:04,480 WORKING WITH CHEAP AND 5442 04:03:04,480 --> 04:03:06,760 SPECIFICALLY FOR THE TWO DRIVEN 5443 04:03:06,760 --> 04:03:08,760 THEY HAVE SHOWN ANYONE BETTER 5444 04:03:08,760 --> 04:03:10,760 WILL CYTOKINE THAT WAS DRIVING 5445 04:03:10,760 --> 04:03:14,800 THIS FORM OF INHIB (INAUDIBLE). 5446 04:03:14,800 --> 04:03:18,560 SO, CAN WE USE L1 BLOCKADES FOR 5447 04:03:18,560 --> 04:03:21,640 HOLISTIC TREATMENT OF 5448 04:03:21,640 --> 04:03:22,240 INFLAMMATORY CO-MORBIDITY. 5449 04:03:22,240 --> 04:03:23,760 WE DON'T KNOW THE ANSWER. 5450 04:03:23,760 --> 04:03:25,200 NO ONE HAS DONE THIS STUDY YET 5451 04:03:25,200 --> 04:03:27,000 BUT WE CAN GET AND FINISH WITH 5452 04:03:27,000 --> 04:03:29,200 THAT I THINK WE CAN GET SOME 5453 04:03:29,200 --> 04:03:38,360 INSIGHTS FROM THE TRIAL THAT WAS 5454 04:03:38,360 --> 04:03:40,000 I SAID IT'S A HUGE TRIAL BECAUSE 5455 04:03:40,000 --> 04:03:45,040 YOU CAN WORK MORE THAN 10,000 5456 04:03:45,040 --> 04:03:46,800 PATIENTS AND MIO CARDIAL 5457 04:03:46,800 --> 04:03:48,600 INFECTION SO THESE PEOPLE SHOWED 5458 04:03:48,600 --> 04:03:50,640 WHAT THESE INVESTIGATORS SHOWED 5459 04:03:50,640 --> 04:03:52,560 IS THAT THE TREATMENT RESULTED 5460 04:03:52,560 --> 04:03:55,760 IN A USE INCIDENTS OF MAJOR 5461 04:03:55,760 --> 04:03:57,280 CARDIOVASCULAR EVENTS BUT 5462 04:03:57,280 --> 04:03:58,400 SURPRISINGLY, NOT SURPRISINGLY 5463 04:03:58,400 --> 04:04:01,320 BASED ON WHAT WE KNOW NOW, IT 5464 04:04:01,320 --> 04:04:03,600 HAS ALSO EXACTED IN THE REDUCE 5465 04:04:03,600 --> 04:04:07,440 INCIDENTS OF CO MORBID 5466 04:04:07,440 --> 04:04:08,240 CONDITIONS LIKE ARTHRITIS, GATE 5467 04:04:08,240 --> 04:04:11,280 AND OSTEOARTHRITIS SO I'M 5468 04:04:11,280 --> 04:04:12,160 TEMPTED TO SUGGEST THIS 5469 04:04:12,160 --> 04:04:14,280 SUCCESSFUL APPLICATION THE 5470 04:04:14,280 --> 04:04:16,160 BLOCKADE IN THE TRIAD COULD IN 5471 04:04:16,160 --> 04:04:19,720 PART HAVE RESULTED FROM TRAINED 5472 04:04:19,720 --> 04:04:21,120 IMMUNE IN BONE MARROW AND THIS 5473 04:04:21,120 --> 04:04:25,600 IS ALSO FROM A RECENT STUDY, 5474 04:04:25,600 --> 04:04:29,320 THEY HAVE SHOWN IN THAT STUDY IN 5475 04:04:29,320 --> 04:04:31,120 THE TRIAL WAS MORE EFFECTIVE IN 5476 04:04:31,120 --> 04:04:35,160 THOSE PATIENTS WHO HAD ALSO 5477 04:04:35,160 --> 04:04:36,600 MUTATIONS AND THEY'RE SPECIFIC 5478 04:04:36,600 --> 04:04:38,680 REFERRING TO THE TED 2 MUTATIONS 5479 04:04:38,680 --> 04:04:41,200 SUGGESTING THAT THE MAJOR 5480 04:04:41,200 --> 04:04:43,160 EFFECTOR OF CARDIOVASCULAR 5481 04:04:43,160 --> 04:04:44,600 DISEASE TO WITH THAT I WOULD 5482 04:04:44,600 --> 04:04:46,520 LIKE TO THANK THE PEOPLE IN MY 5483 04:04:46,520 --> 04:04:49,800 LIFE THAT CONTRIBUTED TO THESE 5484 04:04:49,800 --> 04:04:54,000 STUDIES AND MORE SPECIFICALLY 5485 04:04:54,000 --> 04:04:57,160 WHO PERFORMED MOST OF THE 5486 04:04:57,160 --> 04:04:59,280 EXPERIMENTS IN THE STUDIES THAT 5487 04:04:59,280 --> 04:04:59,640 I MENTIONED. 5488 04:04:59,640 --> 04:05:01,160 OF COURSE WE WOULD NOT BE ABLE 5489 04:05:01,160 --> 04:05:03,800 TO DO ALL THE STUDIES WITHOUT 5490 04:05:03,800 --> 04:05:05,440 THIS SIGNIFICANCE CONTRIBUTION 5491 04:05:05,440 --> 04:05:07,800 FROM OUR COLLABORATORS AND WE 5492 04:05:07,800 --> 04:05:09,280 HAVE MANY COLLABORATORS BUT FOR 5493 04:05:09,280 --> 04:05:11,440 THE WORK I PRESENTED TODAY I 5494 04:05:11,440 --> 04:05:13,680 WOULD LIKE TO THANK THEM AND THE 5495 04:05:13,680 --> 04:05:15,960 GROUP FOR THE UNIVERSITY WHO 5496 04:05:15,960 --> 04:05:16,480 PARTICIPATED IN ALMOST 5497 04:05:16,480 --> 04:05:18,920 EVERYTHING I SAID TODAY BECAUSE 5498 04:05:18,920 --> 04:05:20,280 WE'RE COLLABORATING FOR MANY 5499 04:05:20,280 --> 04:05:21,320 YEARS IN THE WORK WE WANT 5500 04:05:21,320 --> 04:05:26,760 BETWEEN IMMUNITY AND FOR OUR 5501 04:05:26,760 --> 04:05:29,520 COLLABORATION AND THE PERSON WHO 5502 04:05:29,520 --> 04:05:32,480 PROMOTED THIS CONCEPT OF TRAINED 5503 04:05:32,480 --> 04:05:34,000 IMMUNITY AND OF COURSE FOR THE 5504 04:05:34,000 --> 04:05:36,040 HEMATOLOGICAL STUDY TO THANK THE 5505 04:05:36,040 --> 04:05:38,200 VERY MUCH HUMAN DEVICE OF 5506 04:05:38,200 --> 04:05:40,720 UNIVERSITY OF NORTH CAROLINA AND 5507 04:05:40,720 --> 04:05:43,520 THE COLLABORATORS FOR THE WEEK 5508 04:05:43,520 --> 04:05:47,480 WE'VE DONE FOR MANY YEARS AND 5509 04:05:47,480 --> 04:05:48,720 MEN FORWARD TO OF THE INHIBITOR 5510 04:05:48,720 --> 04:05:51,200 THAT WAS USED IN THE CLINICAL 5511 04:05:51,200 --> 04:05:54,080 TRIAL AND WAS THE P.I. AT 5512 04:05:54,080 --> 04:05:55,120 FORESIGHT WHO CONDUCTED THE 5513 04:05:55,120 --> 04:05:57,480 CLINICAL STUDY THE PHASE 2 TRIAL 5514 04:05:57,480 --> 04:05:59,080 CLINICAL STUDY AND OF COURSE, WE 5515 04:05:59,080 --> 04:06:00,120 WOULD NOT BE ABLE TO DO ANYTHING 5516 04:06:00,120 --> 04:06:03,120 OF WHAT I PRESENTED TODAY 5517 04:06:03,120 --> 04:06:03,800 WITHOUT THE GENEROUS SUPPORT 5518 04:06:03,800 --> 04:06:05,560 FROM THE NIH AND PARTICULARLY 5519 04:06:05,560 --> 04:06:09,800 FROM THE NIDCI SO THANK YOU VERY 5520 04:06:09,800 --> 04:06:20,240 MUCH FOR YOUR ATTENTION. 5521 04:06:24,920 --> 04:06:27,640 >>WE'LL TAKE A QUESTION AND 5522 04:06:27,640 --> 04:06:29,720 WE'RE GOING TO KEEP MOVING. 5523 04:06:29,720 --> 04:06:32,240 >>CAN THEY BE EXAMINED TO SEE 5524 04:06:32,240 --> 04:06:36,120 IF THEY'RE RESIST ANTS TO 5525 04:06:36,120 --> 04:06:36,520 MUTATION IN DNA 3. 5526 04:06:36,520 --> 04:06:39,080 >>CAN YOU REPEAT THE QUESTION, 5527 04:06:39,080 --> 04:06:39,360 PLEASE? 5528 04:06:39,360 --> 04:06:43,640 >>CAN CENTENARIANS BE EXAMINED 5529 04:06:43,640 --> 04:06:47,080 TO SEE IF APPROXIMATE THEY'RE 5530 04:06:47,080 --> 04:06:47,360 RESISTANT. 5531 04:06:47,360 --> 04:06:48,680 >>THAT'S A GOOD QUESTION. 5532 04:06:48,680 --> 04:06:49,560 I DON'T KNOW THE ANSWER. 5533 04:06:49,560 --> 04:06:51,000 I DON'T KNOW IF THEY HAVE BEEN 5534 04:06:51,000 --> 04:06:54,840 CHECKED AND FOUND TO HAVE LESS 5535 04:06:54,840 --> 04:06:55,920 PREVIOUS LENS. 5536 04:06:55,920 --> 04:07:00,000 HOWEVER I HAVE TO SAY HERE THAT 5537 04:07:00,000 --> 04:07:01,880 BY HAVING CHIP IT DOES NOT MEAN 5538 04:07:01,880 --> 04:07:02,720 THESE WILL BE SO HE IS A TIVE 5539 04:07:02,720 --> 04:07:05,840 WITH SOME FOREIGN DISEASE LIKE 5540 04:07:05,840 --> 04:07:08,600 MALIGNANCY OR SOME OTHER 5541 04:07:08,600 --> 04:07:09,800 INFLAMMATORY DISEASE AND THE 5542 04:07:09,800 --> 04:07:12,640 THING IS IF YOU HAVE CHIP YOUR 5543 04:07:12,640 --> 04:07:14,760 CHANCES FOR THESE DISEASES IS 5544 04:07:14,760 --> 04:07:16,800 INCREASING BUT THIS IS A GREAT 5545 04:07:16,800 --> 04:07:18,560 QUESTION AND I WILL LOOK AT 5546 04:07:18,560 --> 04:07:20,080 LITERATURE AND FIND OUT WHETHER. 5547 04:07:20,080 --> 04:07:22,120 BUT IF IT'S NOT BEEN SO FAR IT'S 5548 04:07:22,120 --> 04:07:26,720 A GREAT QUESTION TO FOLLOW. 5549 04:07:26,720 --> 04:07:27,000 THANK YOU. 5550 04:07:27,000 --> 04:07:28,960 >>THANK YOU, GEORGE. 5551 04:07:28,960 --> 04:07:37,640 WE'LL MOVE ON TO OUR SECOND 5552 04:07:37,640 --> 04:07:48,040 SPEAKER, SCOTT BUDINGER. 5553 04:07:49,560 --> 04:07:50,920 >>AM I DOING THIS OR ARE YOU? 5554 04:07:50,920 --> 04:07:52,560 >>I CAN? 5555 04:07:52,560 --> 04:08:00,400 WHICH WAY DO I CONTROL IT? 5556 04:08:00,400 --> 04:08:04,640 PUSHING WE WENT TOO FAR. 5557 04:08:04,640 --> 04:08:04,840 OKAY. 5558 04:08:04,840 --> 04:08:07,280 ALL RIGHT, SO OUR GROUP IS 5559 04:08:07,280 --> 04:08:09,440 UNDERSTANDING WHY AGE IS THE 5560 04:08:09,440 --> 04:08:10,840 BIGGEST RISK FACT OR FOR 5561 04:08:10,840 --> 04:08:12,600 MORBIDITY AND MORTALITY RELATE 5562 04:08:12,600 --> 04:08:14,640 TO PNEUMONIA AND AS EVERYONE IN 5563 04:08:14,640 --> 04:08:16,560 THIS ROOM KNOWS, PNEUMONIA IS 5564 04:08:16,560 --> 04:08:18,680 THE NUMBER ONE CAUSE OF 5565 04:08:18,680 --> 04:08:20,360 INFECTIOUS DISEASE BEFORE THE 5566 04:08:20,360 --> 04:08:23,000 PANDEMIC AND THIS AGE RELATED 5567 04:08:23,000 --> 04:08:25,160 SUSCEPTIBLE TO PNEUMONIA 5568 04:08:25,160 --> 04:08:26,920 SEVERITY WAS EVIDENT DURING THE 5569 04:08:26,920 --> 04:08:29,040 FIRST WAVES OF THE PANDEMIC AND 5570 04:08:29,040 --> 04:08:31,080 THE SPAIN SHOWING THAT OLDER 5571 04:08:31,080 --> 04:08:32,680 INDIVIDUALS IN TERMS OF MOR 5572 04:08:32,680 --> 04:08:35,080 TATTI AND OLDER MEN IN 5573 04:08:35,080 --> 04:08:35,840 PARTICULAR. 5574 04:08:35,840 --> 04:08:39,160 AND SO, I LEAD A PROGRAMME 5575 04:08:39,160 --> 04:08:39,680 PROJECT GROUP GRANT FROM A 5576 04:08:39,680 --> 04:08:41,080 NUMBER OF VERY TALENTED 5577 04:08:41,080 --> 04:08:42,640 INVESTIGATORS THAT ARE ASKING 5578 04:08:42,640 --> 04:08:44,080 QUESTIONS WHY ARE OLDER 5579 04:08:44,080 --> 04:08:46,480 INDIVIDUALS MORE SUSCEPTIBLE TO 5580 04:08:46,480 --> 04:08:47,840 DEVELOPING DEATH FROM PNEUMONIA 5581 04:08:47,840 --> 04:08:50,760 AND WHY ARE THEY MORE 5582 04:08:50,760 --> 04:08:52,160 SUSCEPTIBLE TO THE WELL 5583 04:08:52,160 --> 04:08:53,640 ESTABLISHED BEFORE THE PANDEMIC 5584 04:08:53,640 --> 04:08:58,040 ACUTE OR POST SA QUELL A MA 5585 04:08:58,040 --> 04:08:59,600 KNOWNIA AND SKELETAL MUSCLE 5586 04:08:59,600 --> 04:09:01,200 DYSFUNCTION AND TODAY I WILL 5587 04:09:01,200 --> 04:09:04,400 TALK ABOUT TWO OF THOSE STORIES 5588 04:09:04,400 --> 04:09:05,640 BRIEF LEASE AND THE EFFECT 5589 04:09:05,640 --> 04:09:08,120 ABILITY OF PNEUMONIA AND SOME OF 5590 04:09:08,120 --> 04:09:10,360 THE HYPOTHESIS THAT WE HAVE 5591 04:09:10,360 --> 04:09:13,640 ABOUT MECHANISMS WE HAVE. 5592 04:09:13,640 --> 04:09:15,440 I'LL TELL YOU THE STORY FROM A 5593 04:09:15,440 --> 04:09:20,720 SINGLE SELL POPULATION IN THE 5594 04:09:20,720 --> 04:09:21,600 TISSUE RESIDENTS AND THIS IS 5595 04:09:21,600 --> 04:09:23,360 STARTING HERE WITH MOUSE DATA 5596 04:09:23,360 --> 04:09:25,160 AND THIS IS A SUMMARY FROM A 5597 04:09:25,160 --> 04:09:27,360 REVIEW ARTICLE IN 2020 AND I'M 5598 04:09:27,360 --> 04:09:33,920 MAKING A LOT OF WORK ABOUT THE 5599 04:09:33,920 --> 04:09:37,640 FUNCTION OF MACRO PAGES AND 5600 04:09:37,640 --> 04:09:43,320 THEY'RE DERIVED FROM THE FETAL 5601 04:09:43,320 --> 04:09:43,840 YOKE SACK OR LIVER. 5602 04:09:43,840 --> 04:09:46,400 I WANT TO SHOW YOU DATA TODAY 5603 04:09:46,400 --> 04:09:49,040 BUT THEY'RE NOT REPLACED BY BONE 5604 04:09:49,040 --> 04:09:50,800 MARROW CELLS AND EACH OF THEM IS 5605 04:09:50,800 --> 04:09:53,120 CAPABLE OF SELF-RENEWAL SO 5606 04:09:53,120 --> 04:09:54,680 THEY'RE OWN STEM CELL AND 5607 04:09:54,680 --> 04:09:57,080 IMPORTANT FOR HOMO OWE STATIC 5608 04:09:57,080 --> 04:09:57,840 FUNCTION. 5609 04:09:57,840 --> 04:10:01,360 EVERYTHING CHANGES DURING 5610 04:10:01,360 --> 04:10:02,920 INJURY. 5611 04:10:02,920 --> 04:10:05,200 THEY AIR DATE INTO CELLS AND WE 5612 04:10:05,200 --> 04:10:08,960 MONETIZE THE MACROPHAGES AT THE 5613 04:10:08,960 --> 04:10:10,160 LEVEL OF FOE, THEY ARE VERY 5614 04:10:10,160 --> 04:10:11,840 SIMILAR TO TISSUE IN MAKO PAGES 5615 04:10:11,840 --> 04:10:14,360 AND IT'S VERY HARD TO 5616 04:10:14,360 --> 04:10:15,480 DISTINGUISH THEM BY SURFACE 5617 04:10:15,480 --> 04:10:17,760 MARKERS ALONE BUT THEY'RE 5618 04:10:17,760 --> 04:10:19,160 FUNCTIONALLY DISTINCT AND 5619 04:10:19,160 --> 04:10:19,880 THEY'RE FUNCTIONALLY DISTINCT 5620 04:10:19,880 --> 04:10:22,160 BECAUSE YOU USE GENETIC TRAITS 5621 04:10:22,160 --> 04:10:23,040 SPECIFICALLY DELETE THOSE 5622 04:10:23,040 --> 04:10:25,280 THEY'LL BE IN A MACROPHAGES 5623 04:10:25,280 --> 04:10:27,360 LEAVING THE TISSUE CELLS IN FACT 5624 04:10:27,360 --> 04:10:34,400 YOU ARE A RATE OF SEVERITY LIKE 5625 04:10:34,400 --> 04:10:39,080 FIBROSIS AND THEY 5626 04:10:39,080 --> 04:10:42,000 HAVE UNDERGO POP TOE SIS AND 5627 04:10:42,000 --> 04:10:43,800 REPOPULATION IN THIS HAPPENS 5628 04:10:43,800 --> 04:10:46,440 BOTH BY PROLIFERATION OF TISSUE 5629 04:10:46,440 --> 04:10:47,280 RESIDENTS THERE BEFORE THE 5630 04:10:47,280 --> 04:10:49,360 INJURY AND SOME OF THESE 5631 04:10:49,360 --> 04:10:51,400 MONOCYTE DRIVES PERSIST IN THE 5632 04:10:51,400 --> 04:10:54,920 LUNG WHERE THEY'RE SLOWLY SHAPED 5633 04:10:54,920 --> 04:10:56,480 INTO CELLS THAT BECOME 5634 04:10:56,480 --> 04:10:58,040 FUNCTIONALLY AND 5635 04:10:58,040 --> 04:10:59,160 TRANSCRIPTIONALLY INDISTINGUISH 5636 04:10:59,160 --> 04:11:01,200 ABLE FROM THEIR TISSUE RESIDENT 5637 04:11:01,200 --> 04:11:04,480 COUNTERPARTS AND WHICH KNOW THAT 5638 04:11:04,480 --> 04:11:05,520 FROM VIN YANG THAT I'LL TALK 5639 04:11:05,520 --> 04:11:06,600 ABOUT LATER. 5640 04:11:06,600 --> 04:11:09,600 I'LL START IF THE ACUTE PART IN 5641 04:11:09,600 --> 04:11:11,200 THE PNEUMONIA AND TALK ABOUT OUR 5642 04:11:11,200 --> 04:11:13,000 WORK IN COVID-19. 5643 04:11:13,000 --> 04:11:14,800 AND THIS IS GOING TO BE DATA 5644 04:11:14,800 --> 04:11:17,440 THAT'S PRIMARILY DERIVED FROM 5645 04:11:17,440 --> 04:11:18,600 HUMAN. 5646 04:11:18,600 --> 04:11:21,280 SO, WE HAD BEEN INTERESTED IN 5647 04:11:21,280 --> 04:11:23,480 THESE MONOCYTE DRIVE AND TISSUE 5648 04:11:23,480 --> 04:11:25,520 RESIDENT MACROPHAGES IN MOUSE 5649 04:11:25,520 --> 04:11:27,640 MODELS PRIOR TO THE INCIDENT AND 5650 04:11:27,640 --> 04:11:29,560 WE HAVE DEVELOPED A PROGRAMME IN 5651 04:11:29,560 --> 04:11:32,520 OUR INTENSIVE CARE UNIT WITH OUR 5652 04:11:32,520 --> 04:11:33,400 ICU DIRECTOR CALLED THE 5653 04:11:33,400 --> 04:11:35,160 SUCCESSFUL CLINICAL RESPONSE OF 5654 04:11:35,160 --> 04:11:37,320 PNEUMONIA THERAPY SYSTEMS 5655 04:11:37,320 --> 04:11:38,960 BIOLOGY CENTRE. 5656 04:11:38,960 --> 04:11:40,480 THIS PROGRAMME LEVERAGES THE 5657 04:11:40,480 --> 04:11:42,400 FACT IN CLINICIANS IN OUR 5658 04:11:42,400 --> 04:11:43,600 INTENSIVE CARE UNIT THEY HAVE 5659 04:11:43,600 --> 04:11:46,120 THE PRIMARY SIDE OF INFECTION OF 5660 04:11:46,120 --> 04:11:47,880 PNEUMONIA OVER THE COURSE OF THE 5661 04:11:47,880 --> 04:11:49,760 PATIENT ILLNESS IF THEY'RE INNU 5662 04:11:49,760 --> 04:11:53,360 BATED AND ON A VENT A LATER TO 5663 04:11:53,360 --> 04:11:53,560 GUIDE. 5664 04:11:53,560 --> 04:11:54,240 >> Donald Berwick: THAT THERAPY 5665 04:11:54,240 --> 04:11:55,440 FOR THOSE NON CLINICIANS IN THE 5666 04:11:55,440 --> 04:11:57,600 ROOM, WHAT THIS IS AWE TAKE A 5667 04:11:57,600 --> 04:11:58,920 SMALL SCOPE AND PUT IT THROUGH 5668 04:11:58,920 --> 04:12:02,760 THE END OF THE TUBE AND WAGE IT 5669 04:12:02,760 --> 04:12:03,960 INTO AIRWAVES AND BACKOUT AND 5670 04:12:03,960 --> 04:12:06,120 MOST THAT HAVE IS IN AND GOES TO 5671 04:12:06,120 --> 04:12:11,120 THE MICROBIOLOGY LACK WHERE IT'S 5672 04:12:11,120 --> 04:12:13,920 CULTURE AND WE GET PATIENTS THAT 5673 04:12:13,920 --> 04:12:15,760 COME TO THE RESEARCH LAB AND 5674 04:12:15,760 --> 04:12:17,120 THIS IS THE PROCEDURE THAT WE'RE 5675 04:12:17,120 --> 04:12:20,880 DOING ON THE LEFT SIDE. 5676 04:12:20,880 --> 04:12:22,560 YOU CAN SEE A PATIENT WITH 5677 04:12:22,560 --> 04:12:24,000 COVID-19 WHO HAS GROWN IN OUR 5678 04:12:24,000 --> 04:12:26,120 INFENCE I HAVE CARE UNITS AND 5679 04:12:26,120 --> 04:12:27,680 ALL THE OF THE SAMPLES ARE 5680 04:12:27,680 --> 04:12:29,440 SUBJECTED AND WE HAVE A VARIETY 5681 04:12:29,440 --> 04:12:31,280 OF DIFFERENT ANALYSIS WE CAN 5682 04:12:31,280 --> 04:12:32,960 APPLY FOR THE CELLS AND FLUID 5683 04:12:32,960 --> 04:12:34,640 THAT WE OBTAINED "OUR EDMONTON" 5684 04:12:34,640 --> 04:12:36,040 WORKFORCE TECHNOLOGY IS SIMPLE 5685 04:12:36,040 --> 04:12:40,640 AND WE COMBINE THOSE DATA WITH 5686 04:12:40,640 --> 04:12:42,160 WE ATTAINED FROM THE DATA 5687 04:12:42,160 --> 04:12:43,800 WAREHOUSE TO DEVELOP MODELS OF 5688 04:12:43,800 --> 04:12:45,840 MA KNOWNIA PATHOGENESIS AND THIS 5689 04:12:45,840 --> 04:12:49,040 IS A RICH RESOURCE WE HAVE 710 5690 04:12:49,040 --> 04:12:52,280 PATIENTS AND A LITTLE OVER 200 5691 04:12:52,280 --> 04:12:54,240 WERE CHOSEN AND WE HAD 1500 5692 04:12:54,240 --> 04:12:55,720 PATIENTS AND IT CONTINUES TO 5693 04:12:55,720 --> 04:12:57,680 RECRUIT AT TWO PATIENTS A WEEK. 5694 04:12:57,680 --> 04:13:00,520 SO BECAUSE WE HAVE COLLECTED 5695 04:13:00,520 --> 04:13:02,400 DATA FROM 200 PATIENTS PRIOR TO 5696 04:13:02,400 --> 04:13:04,280 THE PANDEMIC WE WERE POISE TO 5697 04:13:04,280 --> 04:13:06,240 ASK QUESTIONS WHAT DIS TINGE 5698 04:13:06,240 --> 04:13:09,720 WISH AS FAR AS A WHAT PNEUMONIA 5699 04:13:09,720 --> 04:13:10,440 PATHOGEN. 5700 04:13:10,440 --> 04:13:12,320 SO FIRST WE LOOKED AT THE 5701 04:13:12,320 --> 04:13:14,240 CLINICAL DIFFERENCES BETWEEN 5702 04:13:14,240 --> 04:13:15,800 PATIENTS WITH SARS-CoV-2 5703 04:13:15,800 --> 04:13:18,960 COMPARED TO OTHER PNEUMONIA AND 5704 04:13:18,960 --> 04:13:21,600 THE RED IS GOING TO BE YOUR 5705 04:13:21,600 --> 04:13:23,200 SARS-CoV-2 AND THE GREEN BARS 5706 04:13:23,200 --> 04:13:27,120 ARE PATIENTS INTUBATE REQUESTED 5707 04:13:27,120 --> 04:13:28,400 OTHER KINDS OF PNEUMONIA AND 5708 04:13:28,400 --> 04:13:31,400 THOSE WITH BACTERIAL PATHOGENS 5709 04:13:31,400 --> 04:13:34,400 AND THE BLUE ON 9 LEFT WE 5710 04:13:34,400 --> 04:13:36,640 THOUGHT THEY HAD MA MOANIA FROM 5711 04:13:36,640 --> 04:13:37,120 ANOTHER CONSTRUCT. 5712 04:13:37,120 --> 04:13:38,840 YOU WITH SEE THIS IS ALL THE 5713 04:13:38,840 --> 04:13:40,480 AIMS ARE SIMILAR AND OLD. 5714 04:13:40,480 --> 04:13:42,480 AS WE TALKED ABOUT IN THE FIRST 5715 04:13:42,480 --> 04:13:44,160 SLIDES. 5716 04:13:44,160 --> 04:13:46,320 THESE PATIENTS ARE SIMILE 5717 04:13:46,320 --> 04:13:47,200 ACUTELY ILL. 5718 04:13:47,200 --> 04:13:48,520 THERE ARE SEVERAL OTHERS THAT 5719 04:13:48,520 --> 04:13:51,760 ARE SIMILAR AND MORTALITY IS 5720 04:13:51,760 --> 04:13:52,560 SIMILAR IN THE PATIENTS WITH 5721 04:13:52,560 --> 04:13:53,520 SARS-CoV-2. 5722 04:13:53,520 --> 04:13:54,840 WHAT IS DIFFERENT AND WHAT IS 5723 04:13:54,840 --> 04:13:59,680 REALLY DIFFERENT LENGTH OF STAY. 5724 04:13:59,680 --> 04:14:02,760 PATIENTS HAVE DOUBLE THE LENGTH 5725 04:14:02,760 --> 04:14:09,040 OF STAY AND TRIPLE VIRAL VI PNEA 5726 04:14:09,040 --> 04:14:10,960 THAT'S WHY SARS-CoV-2 IS 5727 04:14:10,960 --> 04:14:12,520 DEVASTATING TO THE HEALTH SYSTEM 5728 04:14:12,520 --> 04:14:15,640 AND PATIENTS IN THE ICU AND ONE 5729 04:14:15,640 --> 04:14:18,720 SHICU BED FOR ONE MONTH. 5730 04:14:18,720 --> 04:14:21,160 WE DID MOLECULAR ANALYSIS THAT I 5731 04:14:21,160 --> 04:14:22,600 WON'T HAVE TIME TO GO THROUGH 5732 04:14:22,600 --> 04:14:23,320 WITH YOU. 5733 04:14:23,320 --> 04:14:27,720 IT'S PUBLISHED INCLUDING 5734 04:14:27,720 --> 04:14:29,000 SEQUENCING AND FLOATS AND 5735 04:14:29,000 --> 04:14:31,280 LOOKING THE HOST RESPONSE AND 5736 04:14:31,280 --> 04:14:33,400 LOOKING FOR PACKAGED AS WELL AS 5737 04:14:33,400 --> 04:14:34,800 SINGLE CELL WITH CONFIRMATION 5738 04:14:34,800 --> 04:14:37,640 WITH SINGLE MOLECULE FISH AND WE 5739 04:14:37,640 --> 04:14:40,920 USE THAT TO DEVELOP A MODEL OF 5740 04:14:40,920 --> 04:14:41,960 SARS-CoV-2 MA MOANIA AND HOW 5741 04:14:41,960 --> 04:14:44,360 IT MIGHT BE DIFFERENT. 5742 04:14:44,360 --> 04:14:46,400 ON THE LEFT WE HAVE A SIMPLIFIED 5743 04:14:46,400 --> 04:14:47,040 VERSION. 5744 04:14:47,040 --> 04:14:50,200 WE HAVE THE TYPE 2 CELL AND WE 5745 04:14:50,200 --> 04:14:52,520 HAVE THE SMALL CELLS FOR CORNERS 5746 04:14:52,520 --> 04:14:55,000 OF THE SPACE AND YOU HAVE THESE 5747 04:14:55,000 --> 04:14:57,480 BIG FLAT CELLS WHERE THE GAS 5748 04:14:57,480 --> 04:14:59,360 EXCHANGE RAPS AND YOU HAVE A 5749 04:14:59,360 --> 04:15:02,160 TISSUE MACROPHAGE SITTING THERE 5750 04:15:02,160 --> 04:15:04,440 IN THE SCHEMATIC AND 5751 04:15:04,440 --> 04:15:05,760 IMPORTANTLY, THE TYPE 2 CELLS 5752 04:15:05,760 --> 04:15:08,360 ARE THOSE THAT EXPRESS THE H2 5753 04:15:08,360 --> 04:15:10,040 RECEPTORS THAT'S IS RECEPTORS 5754 04:15:10,040 --> 04:15:11,800 FOR SARS-CoV-2 AND PAULSLY SO 5755 04:15:11,800 --> 04:15:17,440 IN THE HUMAN HUNG CELL LESS THAN 5756 04:15:17,440 --> 04:15:18,760 1% CHROME TWO AND NO AGING ONE 5757 04:15:18,760 --> 04:15:25,600 AND MACROPHAGES DO NOT AS WELL. 5758 04:15:25,600 --> 04:15:28,240 WE'RE A PRODUCTIVELY AND ACE TO 5759 04:15:28,240 --> 04:15:29,440 EXPRESS TYPE TWO CELLS AND 5760 04:15:29,440 --> 04:15:40,000 INCREASING THE CONCENTRATION AND 5761 04:15:54,360 --> 04:15:57,400 AND IT'S IN BOTH SOUTH END AND 5762 04:15:57,400 --> 04:16:01,320 GAMMA INDUCES THE APOPTOSIS AND 5763 04:16:01,320 --> 04:16:04,000 MONO TYPE DRIVE MACROPHAGES AND 5764 04:16:04,000 --> 04:16:05,800 THE MACROPHAGES ARE SUSCEPTIBLE 5765 04:16:05,800 --> 04:16:07,480 TO SARS-CoV-2 INFECTION SO 5766 04:16:07,480 --> 04:16:08,720 AMPLIFIED THAT SIGNALING MOVE 5767 04:16:08,720 --> 04:16:13,000 AND MORE IMPORTANTLY DURING THE 5768 04:16:13,000 --> 04:16:16,520 PANDEMIC SHOWED THOSE 5769 04:16:16,520 --> 04:16:24,800 MACROPHAGES AND CREATING THAT 5770 04:16:24,800 --> 04:16:27,520 LONG PROLONGED INFLAMMATORY TIME 5771 04:16:27,520 --> 04:16:29,680 FORCE AND WE ARE ACTUALLY VERY 5772 04:16:29,680 --> 04:16:31,120 FORTUNATE DURING THE PANDEMIC TO 5773 04:16:31,120 --> 04:16:41,600 BE ABLE TO TEST THIS MODEL AND 5774 04:16:49,320 --> 04:16:52,080 WITH T CELLS AND MACRO PAGES SO 5775 04:16:52,080 --> 04:16:55,040 WE DID A PKPD STUDY WITH A 5776 04:16:55,040 --> 04:16:56,840 CLINICAL TRIAL OF A CROSS 5777 04:16:56,840 --> 04:16:58,600 CHANNEL INHIBITOR WITH A GROUP 5778 04:16:58,600 --> 04:17:01,440 AND THIS WAS USING AGAIN THOSE 5779 04:17:01,440 --> 04:17:04,160 SAME ANALYSIS OF LOOKING FOUR 5780 04:17:04,160 --> 04:17:07,680 AND A HALF TREATMENT WITH THE 5781 04:17:07,680 --> 04:17:09,320 DRUGS AND IN TERMS OF THE 5782 04:17:09,320 --> 04:17:11,960 TRANSRIPTOME OF MONOCYTE DRIVE 5783 04:17:11,960 --> 04:17:14,280 AND T CELLS REMEMBER THIS IS 5784 04:17:14,280 --> 04:17:16,080 DATA FOR THE T CELLS BUT THEY 5785 04:17:16,080 --> 04:17:17,840 HAVE A RESPONDING AND SO ON THE 5786 04:17:17,840 --> 04:17:24,400 LEFT YOU SEE THE CHANGE WE SEE 5787 04:17:24,400 --> 04:17:25,320 BETWEEN DAY ONE AND DAY THREE 5788 04:17:25,320 --> 04:17:26,880 AND THE TREATED RESPONSE OF THE 5789 04:17:26,880 --> 04:17:27,720 PATIENTS AND WE WERE PLEASE 5790 04:17:27,720 --> 04:17:30,480 TODAY SEE THE MULTI CENTRED HAD 5791 04:17:30,480 --> 04:17:32,240 PROMISING PHASE 2 TRIALS 5792 04:17:32,240 --> 04:17:40,960 FINDINGS WITH A 56% REDUCTION IN 5793 04:17:40,960 --> 04:17:44,600 THE COHORT. 5794 04:17:44,600 --> 04:17:47,240 SO, THAT WAS THE AND I'M GOING 5795 04:17:47,240 --> 04:17:51,600 TO MOVE TO THE CHRONIC DISEASE 5796 04:17:51,600 --> 04:17:52,920 AND WE TURNED AGAIN TO MICE 5797 04:17:52,920 --> 04:17:53,600 BECAUSE THE QUESTION WE WERE 5798 04:17:53,600 --> 04:17:56,160 ASKING IS WHAT IS WRONG WITH OLD 5799 04:17:56,160 --> 04:17:57,840 MACK PAGES AND I SHOWED YOU HALL 5800 04:17:57,840 --> 04:17:59,960 OF OUR HUMAN DATA AND OUR SICK 5801 04:17:59,960 --> 04:18:01,600 PATIENTS ARE ALL OLD PATIENTS 5802 04:18:01,600 --> 04:18:03,840 RIGHT SO WE DON'T HAVE YOUNG 5803 04:18:03,840 --> 04:18:08,000 PATIENTS AND ANY POWER AND WE 5804 04:18:08,000 --> 04:18:09,240 HAD SEVERAL HIGH BOTH SIS ABOUT 5805 04:18:09,240 --> 04:18:13,400 WHY IT MIGHT BE TRUE. 5806 04:18:13,400 --> 04:18:16,760 ONE HAD CHIMER THAT DEVELOPS 5807 04:18:16,760 --> 04:18:20,120 WITH AGING THAT IS LONG MAKE ROW 5808 04:18:20,120 --> 04:18:21,840 FAGE POPULATIONS ARE REPLACED BY 5809 04:18:21,840 --> 04:18:24,880 CELLS OVER THE LIFESPAN REMEMBER 5810 04:18:24,880 --> 04:18:27,360 THEY WERE ONCE INFLAME TORI 5811 04:18:27,360 --> 04:18:29,160 MONOCYTE WAS DIFFERENT TO ACCEPT 5812 04:18:29,160 --> 04:18:30,520 STIMULI AND ANOTHER POSSIBILITY 5813 04:18:30,520 --> 04:18:32,480 WE HAD DIFFERENCES IN 5814 04:18:32,480 --> 04:18:34,640 CIRCULATING CELLS OR CIRCULATING 5815 04:18:34,640 --> 04:18:38,480 BONE NARROW AND THAT WAS ANOTHER 5816 04:18:38,480 --> 04:18:39,680 POSSIBILITY AND STILL ONE WITH 5817 04:18:39,680 --> 04:18:40,720 CHANGES IN THE ENVIRONMENT THAT 5818 04:18:40,720 --> 04:18:41,440 WERE DRIVING. 5819 04:18:41,440 --> 04:18:43,600 WE NEED TO TRANSCRIPTOMIC 5820 04:18:43,600 --> 04:18:45,520 APPROACH TO DO AND WE LOOKED AND 5821 04:18:45,520 --> 04:18:48,120 FOUND A REPRODUCE ABLE TRANCE 5822 04:18:48,120 --> 04:18:50,480 PERFORM I CAN SIGNATURE THAT HAD 5823 04:18:50,480 --> 04:18:52,360 INFLUENZA INFECTION AND THE DOWN 5824 04:18:52,360 --> 04:18:53,920 REGULATION OF CELL CYCLE GENES 5825 04:18:53,920 --> 04:18:56,200 THAT IS IMPORTANT IN THE A 5826 04:18:56,200 --> 04:18:58,120 COUPLE AND SOME HAVE A LOT OF IT 5827 04:18:58,120 --> 04:18:59,200 QUICKLY HERE AND THE ANSWER IS 5828 04:18:59,200 --> 04:19:02,960 NO, NO, NO, ALL THESE QUESTIONS. 5829 04:19:02,960 --> 04:19:03,400 IT'S NOT. 5830 04:19:03,400 --> 04:19:05,760 SO WE DID A COMPLICATED SECOND 5831 04:19:05,760 --> 04:19:07,240 HIT EXPERIMENT WHICH IS NO 5832 04:19:07,240 --> 04:19:09,120 DIFFERENT AND IT'S NOT CELL 5833 04:19:09,120 --> 04:19:11,200 AUTONOMOUS AND EVERYTHING 5834 04:19:11,200 --> 04:19:12,120 REVERTS TO THE AGE OF THE HOST 5835 04:19:12,120 --> 04:19:19,320 AND IT'S DRIVEN BY MODELS 5836 04:19:19,320 --> 04:19:22,520 ITSELF. 5837 04:19:22,520 --> 04:19:24,760 IT WAS CHANGING THE PHENOTYPE OF 5838 04:19:24,760 --> 04:19:35,200 THESE OLD MACROPHAGES AND 5839 04:19:37,920 --> 04:19:39,960 FIBROSIS AND HUMAN STUDIES USING 5840 04:19:39,960 --> 04:19:42,000 LONG EX PLANTS FROM PATIENTS AND 5841 04:19:42,000 --> 04:19:45,480 INCLUDING PATIENTS WITH 5842 04:19:45,480 --> 04:19:47,160 COVID-19. 5843 04:19:47,160 --> 04:19:49,280 WE HAVE THE AT1 CELL LIKE I 5844 04:19:49,280 --> 04:19:50,600 SHOWED YOU BEFORE AND WE HAVE 5845 04:19:50,600 --> 04:19:52,840 INJURY LIKE SARS-CoV-2 THAT 5846 04:19:52,840 --> 04:19:53,560 DAMAGES THAT TYPE 2 CELL AND WE 5847 04:19:53,560 --> 04:19:55,560 HAVE THE MONEY SIGHT DRIVER 5848 04:19:55,560 --> 04:20:00,040 COMING IN AND INTERACTING WITH 5849 04:20:00,040 --> 04:20:02,960 AND CEILING OF THE JOINT AND WE 5850 04:20:02,960 --> 04:20:05,360 HAVE WHAT WE FOUND IN THE SINGLE 5851 04:20:05,360 --> 04:20:08,120 CELL RNA SEQUENCING DATA IT'S 5852 04:20:08,120 --> 04:20:10,240 TYPE TWO CELL AND DIVIDES TO 5853 04:20:10,240 --> 04:20:13,240 REPLACE THE TYPE 1 CELL AND CELL 5854 04:20:13,240 --> 04:20:14,640 POPULATIONS FORMED AND THESE ARE 5855 04:20:14,640 --> 04:20:15,840 THE MAIN THINGS. 5856 04:20:15,840 --> 04:20:18,040 I'LL JUST CALL THEM A TRANSITION 5857 04:20:18,040 --> 04:20:19,560 CELL SO SHARE FEATURES WITH THE 5858 04:20:19,560 --> 04:20:21,960 TYPE ONE AND THE TYPE 2 CELL AND 5859 04:20:21,960 --> 04:20:26,360 THEY'RE FOUND IN DISEASE IN MICE 5860 04:20:26,360 --> 04:20:28,720 AND HUMANS YOU DON'T FIND THEM 5861 04:20:28,720 --> 04:20:30,480 AT ALL IN NORMAL LUNG. 5862 04:20:30,480 --> 04:20:32,600 AND WE FOUND THESE CELLS WERE 5863 04:20:32,600 --> 04:20:34,280 ACTUALLY PRESENT IN PATIENTS 5864 04:20:34,280 --> 04:20:36,160 WITH SARS-CoV-2 AND USING DATA 5865 04:20:36,160 --> 04:20:37,440 FROM OUR LUNG TRANSPLANT 5866 04:20:37,440 --> 04:20:41,520 PROGRAMME IN PART OF 19 EX 5867 04:20:41,520 --> 04:20:52,280 PLANTS AND IT AT THE EXPRESS P16 5868 04:20:52,280 --> 04:20:55,200 AND OTHER MARKERS BUT DEFINITIVE 5869 04:20:55,200 --> 04:21:00,120 ORGANOID STUDIES AND SHOWS THESE 5870 04:21:00,120 --> 04:21:00,720 THEY WILL DURING THE 5871 04:21:00,720 --> 04:21:04,360 DIFFERENTIATION OF THE TYPE 2 5872 04:21:04,360 --> 04:21:07,120 CELL INTO A TYPE ONE CELL AND 5873 04:21:07,120 --> 04:21:08,800 MARKERS AND ONE OF OUR POSTDOCS 5874 04:21:08,800 --> 04:21:11,440 NOTED THERE WAS AN ACTIVATION OF 5875 04:21:11,440 --> 04:21:12,520 THE EXPRESS RESPONSE THAT 5876 04:21:12,520 --> 04:21:15,360 HAPPENED IN THESE CELLS PRIOR TO 5877 04:21:15,360 --> 04:21:17,920 THEIR DIFFERENTIATION AND SO HE 5878 04:21:17,920 --> 04:21:20,840 GAVE A SMALL INHIBITOR AT UCSF 5879 04:21:20,840 --> 04:21:22,040 SO HE SHOWED THAT WAS ABLE TO 5880 04:21:22,040 --> 04:21:30,680 DECREASE THE SEVERITY FIBROSIS 5881 04:21:30,680 --> 04:21:41,200 AND HE PUT A PINE AND EACH TYPE 5882 04:21:49,640 --> 04:21:52,640 CELLS AND THE DECREASE AND THIS 5883 04:21:52,640 --> 04:21:56,600 TRANSITIONAL POPULATION AND 5884 04:21:56,600 --> 04:21:58,960 SUGGESTING THAT THE ACCELERATED 5885 04:21:58,960 --> 04:22:00,680 THESE TYPE TWO CELLS AND TYPE 5886 04:22:00,680 --> 04:22:02,080 ONE CELLS AND WHAT WAS REALLY 5887 04:22:02,080 --> 04:22:03,280 INTERESTING WITH WHAT HAPPENED 5888 04:22:03,280 --> 04:22:06,120 WITH THE MACROPHAGE POPULATION 5889 04:22:06,120 --> 04:22:07,920 SO YOU HAVE LYNN YANG SYSTEM AND 5890 04:22:07,920 --> 04:22:09,080 SHOWED THERE WAS DECREASE 5891 04:22:09,080 --> 04:22:10,920 RECRUITMENT OF MONO TYPE FOR 5892 04:22:10,920 --> 04:22:12,680 MACROPHAGES IN THIS MODEL AND IF 5893 04:22:12,680 --> 04:22:14,280 WE LOOKED AT THE GENE EXPRESSION 5894 04:22:14,280 --> 04:22:16,400 PATTERN WE SAW THOSE MACROPHAGES 5895 04:22:16,400 --> 04:22:20,920 WERE MORE MATURE AND EXPRESSING 5896 04:22:20,920 --> 04:22:22,160 LESS IMMATURE GENES. 5897 04:22:22,160 --> 04:22:24,360 THEY WERE GETTING SIGNALS THEY 5898 04:22:24,360 --> 04:22:28,000 NEEDED FROM THE EPITHELIAL TO BE 5899 04:22:28,000 --> 04:22:30,480 A MATURE MACROPHAGES SO THIS IS 5900 04:22:30,480 --> 04:22:34,760 BOTH A SUMMARY AND DATA SO WHAT 5901 04:22:34,760 --> 04:22:38,520 WE'RE THINKING RIGHT NOW IS 5902 04:22:38,520 --> 04:22:40,560 WE'RE THINKING THAT DURING THESE 5903 04:22:40,560 --> 04:22:42,920 TYPE 2 CELLS AND TYPE 1 CELLS 5904 04:22:42,920 --> 04:22:45,560 AND THEY'RE A BIG BLANKETS THAT 5905 04:22:45,560 --> 04:22:47,240 FITS OVER THREE, IT'S A BIG 5906 04:22:47,240 --> 04:22:47,440 CELL. 5907 04:22:47,440 --> 04:22:48,760 YOU HAVE TO MAKE A LOT OF 5908 04:22:48,760 --> 04:22:52,440 PROTEIN AND A LOT OF LIPIDS AND 5909 04:22:52,440 --> 04:22:55,160 THERE'S DURING AGING, OR IN 5910 04:22:55,160 --> 04:22:58,280 CERTAIN GENETIC CONDITIONS THAT 5911 04:22:58,280 --> 04:23:01,160 ISR IS PATHOLOGICAL ALLOWING 5912 04:23:01,160 --> 04:23:02,960 ACCUMULATION OF THESE CELLS AND 5913 04:23:02,960 --> 04:23:04,480 UNDERSTANDING WHY THAT IS A BIG 5914 04:23:04,480 --> 04:23:06,280 GAP AND THE SECOND QUESTION IS 5915 04:23:06,280 --> 04:23:08,280 WHY DO YOU HAVE THIS RECRUITMENT 5916 04:23:08,280 --> 04:23:10,880 OF THESE MONOCYTE MACROPHAGES 5917 04:23:10,880 --> 04:23:13,640 WHEN YOU DON'T HAVE THE FULL 5918 04:23:13,640 --> 04:23:16,000 DIFFERENTIATION AND JUST ONE 5919 04:23:16,000 --> 04:23:20,280 LAST SLIDE SHOWS THAT THIS, 5920 04:23:20,280 --> 04:23:21,360 THESE MACROPHAGES IS A SIGNAL 5921 04:23:21,360 --> 04:23:24,280 FOR DYSFUNCTIONAL PAIR AND I 5922 04:23:24,280 --> 04:23:26,080 WILL SHOW YOU A BRIEF SUMMARY OF 5923 04:23:26,080 --> 04:23:28,480 WORK WE'VE DONE IN PATIENTS WITH 5924 04:23:28,480 --> 04:23:31,200 POST ACUTE SEE QUELL' SO THESE 5925 04:23:31,200 --> 04:23:34,400 ARE SYMPTOMS AND 180 DAYS OR 5926 04:23:34,400 --> 04:23:36,160 MORE AFTER THEIR COVID INFECTION 5927 04:23:36,160 --> 04:23:38,280 YOU CAN SEE THEY HAVE 5928 04:23:38,280 --> 04:23:40,080 ABNORMALITIES ON THE LIFE 5929 04:23:40,080 --> 04:23:41,640 CHARACTERIZED WHEN WE DO SINGLE 5930 04:23:41,640 --> 04:23:43,880 CELL ARMY SEQUENCING ON SAMPLES 5931 04:23:43,880 --> 04:23:46,240 FROM THE PATIENTS WE DETECT 5932 04:23:46,240 --> 04:23:47,920 THOSE MACROPHAGES WHICH ARE 5933 04:23:47,920 --> 04:23:50,400 CORRELATED WITH THE SEVERITY OF 5934 04:23:50,400 --> 04:23:51,360 FIBROSIS. 5935 04:23:51,360 --> 04:23:52,680 SO, I WANTED TO THANK ALL THE 5936 04:23:52,680 --> 04:23:54,800 PEOPLE THAT DID IT WORK AND IT 5937 04:23:54,800 --> 04:23:56,120 TAKES A VILLAGE. 5938 04:23:56,120 --> 04:23:57,200 THERE'S A LOT OF PEOPLE 5939 04:23:57,200 --> 04:23:59,720 ACKNOWLEDGED HERE AND I TRY TO 5940 04:23:59,720 --> 04:24:00,440 ACKNOWLEDGE PEOPLE DURING THE 5941 04:24:00,440 --> 04:24:02,160 TALK AND I WANT TO ADDRESS AND 5942 04:24:02,160 --> 04:24:04,440 THANK OUR FUNDERS AND THE NIA 5943 04:24:04,440 --> 04:24:08,480 AND NIAAD AND THIS WOULDN'T BE 5944 04:24:08,480 --> 04:24:11,680 SO POSSIBLE WITHOUT THE 5945 04:24:11,680 --> 04:24:13,360 PHILANTHROPY FROM THE INSTITUTE 5946 04:24:13,360 --> 04:24:15,920 FOR TRANSLATIONAL TIME. 5947 04:24:15,920 --> 04:24:16,520 YOU THANK YOU. 5948 04:24:31,760 --> 04:24:34,120 >>REALLY FANTASTIC WORK. 5949 04:24:34,120 --> 04:24:37,000 SO WHEN YOU COLLECT THE LAVAGES 5950 04:24:37,000 --> 04:24:39,240 DO YOU SEE A LOT OF SHED OF 5951 04:24:39,240 --> 04:24:39,440 CELLS. 5952 04:24:39,440 --> 04:24:40,920 >>YES, WE SEE SOME. 5953 04:24:40,920 --> 04:24:41,640 NOT A LOT. 5954 04:24:41,640 --> 04:24:43,480 SO WE DO HAVE SOME TYPE, I 5955 04:24:43,480 --> 04:24:47,720 DIDN'T SHOW YOU BUT WE SEE 5956 04:24:47,720 --> 04:24:50,000 THE -- WE CAN'T MAKE MUCH OF 5957 04:24:50,000 --> 04:24:51,920 THEIR TRANSCRIPT SEEM BECAUSE 5958 04:24:51,920 --> 04:24:52,920 THEY'RE DYING AND WE SEE 5959 04:24:52,920 --> 04:24:53,920 SARS-CoV-2 IN THERE. 5960 04:24:53,920 --> 04:24:56,400 >>BECAUSE I'M THINKING WITH ALL 5961 04:24:56,400 --> 04:24:57,800 INCREASED INFLAMMATION AND 5962 04:24:57,800 --> 04:25:00,160 INABILITY TO REPAIR THEMSELVES 5963 04:25:00,160 --> 04:25:01,960 THE CELLS ARE CHOOSING TO DIE? 5964 04:25:01,960 --> 04:25:04,000 >>YES, WE DON'T HAVE CONTROL 5965 04:25:04,000 --> 04:25:06,920 FOR THAT SO WE DON'T HAVE 5966 04:25:06,920 --> 04:25:07,280 ANYBODY. 5967 04:25:07,280 --> 04:25:09,000 WE HAVE A HEAVY BIAS TOWARDS 5968 04:25:09,000 --> 04:25:09,760 PEOPLE THAT ARE SICK. 5969 04:25:09,760 --> 04:25:13,120 >>YES. 5970 04:25:13,120 --> 04:25:18,520 >>SO, THE HOTSPOT FOR COVID-19 5971 04:25:18,520 --> 04:25:22,280 BY MULTIPLE DEVICES IS AN CHROME 5972 04:25:22,280 --> 04:25:24,720 OWE SOME 3B21. 5973 04:25:24,720 --> 04:25:27,800 THE MORPHISM IS SUPPOSED TO BE 5974 04:25:27,800 --> 04:25:29,120 INVOLVING DYSFUNCTION SO HOW DO 5975 04:25:29,120 --> 04:25:32,000 YOU RECONCILE THAT WORK WITH 5976 04:25:32,000 --> 04:25:33,080 YOUR INITIAL ONE? 5977 04:25:33,080 --> 04:25:34,960 >>WELL IT GETS BACK TO THE 5978 04:25:34,960 --> 04:25:36,880 FIRST QUESTION WE'RE NOT 5979 04:25:36,880 --> 04:25:37,600 SAMPLING IT. 5980 04:25:37,600 --> 04:25:40,320 AND THERE'S WHAT IT LOOKS LIKE 5981 04:25:40,320 --> 04:25:41,840 IS IF WE LOOK AMOUNT STUDIES 5982 04:25:41,840 --> 04:25:43,400 THEY'RE LOOKING AT SEVERE 5983 04:25:43,400 --> 04:25:45,040 DISEASE AND WE'RE AT POST APP 5984 04:25:45,040 --> 04:25:46,560 RIGHT, WE'RE LOOK AT PEOPLE THAT 5985 04:25:46,560 --> 04:25:49,920 HAVE SEVERE DISEASE AND IF YOU 5986 04:25:49,920 --> 04:25:52,560 HOOK FOR EXAMPLE THE LOSS OF 5987 04:25:52,560 --> 04:25:54,600 INTERFERON TYPE ONE AT THE TIME 5988 04:25:54,600 --> 04:25:57,720 ARE AT THAT TIME WE'RE SAMPLING 5989 04:25:57,720 --> 04:25:59,640 THESE, WE SEE DON'T DETECT HIGH 5990 04:25:59,640 --> 04:26:01,040 FORM INTERFERENCE ANYMORE WE'RE 5991 04:26:01,040 --> 04:26:02,240 PAST THAT POINT SO THEY HAVE 5992 04:26:02,240 --> 04:26:03,680 GOTTEN TO THE POINT WHERE THEY 5993 04:26:03,680 --> 04:26:05,440 HAVE SEVERE DISEASES INVOLVING 5994 04:26:05,440 --> 04:26:07,800 THE SO I THINK YOU HAVE TO JUST 5995 04:26:07,800 --> 04:26:10,880 HAVE A LOT OF THOSE GENETIC 5996 04:26:10,880 --> 04:26:11,720 STUDIES BY DEFINITION BECAUSE 5997 04:26:11,720 --> 04:26:13,240 THEY'RE LOOKING AT THE WHOLE 5998 04:26:13,240 --> 04:26:14,800 POPULATION TO IDENTIFY RISK 5999 04:26:14,800 --> 04:26:16,840 FACTORS FOR GETTING TO OUR ICU 6000 04:26:16,840 --> 04:26:19,480 AND WHAT ARE THE RISK FACTORS 6001 04:26:19,480 --> 04:26:23,720 FOR THEM DYING WHEN WHEN YOU ARE 6002 04:26:23,720 --> 04:26:24,800 IN INTENSIVE CARE UNIT. 6003 04:26:24,800 --> 04:26:28,800 HOW DO WE INTERRUPT THAT. 6004 04:26:28,800 --> 04:26:32,120 >>THANK YOU, SCOTT. 6005 04:26:32,120 --> 04:26:42,200 NEXT UP IS DAN YAM TYRRELL. 6006 04:26:42,200 --> 04:26:45,800 >>THANK YOU FOR THE 6007 04:26:45,800 --> 04:26:49,320 INTRODUCTION. 6008 04:26:49,320 --> 04:26:51,880 MY TALK IS GOING TO BE ON AIMING 6009 04:26:51,880 --> 04:26:54,280 AND MOSTLY T CELLS AND ALTHOUGH 6010 04:26:54,280 --> 04:26:59,480 I TALKED ABOUT THE AGENT LER OWE 6011 04:26:59,480 --> 04:27:03,080 CIRRHOSIS AND MOSTLY USING MY ON 6012 04:27:03,080 --> 04:27:13,680 HUMAN DATA SPRINKLED INFUL DRIVY 6013 04:27:25,560 --> 04:27:27,720 HIGH LEVELS OF LDL CHOLESTEROL 6014 04:27:27,720 --> 04:27:34,880 AND IF YOU DON'T RESOLVE THE 6015 04:27:34,880 --> 04:27:45,360 CHOLESTEROL, WITH HEARD ATTACK 6016 04:27:50,960 --> 04:27:51,640 HEART ATTACK AND STROKE. 6017 04:27:51,640 --> 04:27:54,000 I WILL TALK ABOUT VASCULAR 6018 04:27:54,000 --> 04:27:57,280 PATHWAYS AND THAT WE'VE FOUND 6019 04:27:57,280 --> 04:27:59,000 OUR ACTIVATED WITH AGING. 6020 04:27:59,000 --> 04:28:00,720 FOR THIS STUDY WE WERE LOOKING 6021 04:28:00,720 --> 04:28:04,160 AT THE VASCULAR IN DISEASE FREE 6022 04:28:04,160 --> 04:28:05,720 OLD AND YOUNG MICE. 6023 04:28:05,720 --> 04:28:08,880 SO WHAT WE DID WITH IS WE JUST 6024 04:28:08,880 --> 04:28:11,400 TOOK THE ATE AORTA FROM YOUNG 6025 04:28:11,400 --> 04:28:14,080 AND AGED MICE AND YOUNG IS Y AND 6026 04:28:14,080 --> 04:28:19,000 AGED IS A AND LOW FAT DIET AND 6027 04:28:19,000 --> 04:28:20,360 DISEASE FREE AND YOUNG AND OLD 6028 04:28:20,360 --> 04:28:21,960 MICE AND THREE MONTHS AND 18 6029 04:28:21,960 --> 04:28:23,440 MONTHS OF AGE AND LOOKED FOR 6030 04:28:23,440 --> 04:28:25,920 SOME OF THESE INFLAMMATORY 6031 04:28:25,920 --> 04:28:29,840 PROTEINS THAT WE THINK COULD BE 6032 04:28:29,840 --> 04:28:32,240 ACTIVATED BY HIGH DOUGH CON 6033 04:28:32,240 --> 04:28:34,440 TREAL DNA AND DYSFUNCTION IN THE 6034 04:28:34,440 --> 04:28:38,080 AGING EIGHT OR THE A SO WE SEE 6035 04:28:38,080 --> 04:28:40,320 TLR9 MIGHT BE THE EIGHTH AND IL6 6036 04:28:40,320 --> 04:28:44,520 ARE ELEVATED WITH AGING. 6037 04:28:44,520 --> 04:28:47,160 SO THE NEXT THING THAT WE WERE 6038 04:28:47,160 --> 04:28:48,200 CORE COWS ABOUT IS AND I DIDN'T 6039 04:28:48,200 --> 04:28:50,760 PUT AN INTRODUCTION TO THIS 6040 04:28:50,760 --> 04:28:52,360 PROTEIN BUT THIS EXPRESSION SO 6041 04:28:52,360 --> 04:28:54,240 WE SEE THAT EXPRESSION GOES UP 6042 04:28:54,240 --> 04:28:58,240 WITH AGE AND THE EIGHT ORDER AND 6043 04:28:58,240 --> 04:29:08,800 THIS IS PROTEINS THAT -- THERE'S 6044 04:29:41,920 --> 04:29:42,640 SOMETHING CIRCULATE TAG CAN 6045 04:29:42,640 --> 04:29:44,200 UPDATE THE CAUSE AND WE FOLLOWED 6046 04:29:44,200 --> 04:29:45,840 UP WITH A LITTLE BIT CLEANER OF 6047 04:29:45,840 --> 04:29:56,360 AN EXPERIMENT WHERE WE JUST ADD 6048 04:29:59,680 --> 04:30:00,200 IL6. 6049 04:30:00,200 --> 04:30:06,800 WE HAD ACCESS TO SOME BIOBANK 6050 04:30:06,800 --> 04:30:11,800 HUMAN HAIR AND SOME WERE 6051 04:30:11,800 --> 04:30:12,040 HEALTHY. 6052 04:30:12,040 --> 04:30:15,800 AND SO WE DID A APPROACH JUST TO 6053 04:30:15,800 --> 04:30:23,080 LOOK AT AN UNBIASED WAY PROTEINS 6054 04:30:23,080 --> 04:30:25,400 AND HOPING THAT IDENTIFY 6055 04:30:25,400 --> 04:30:26,600 PATHWAYS WE FOUND. 6056 04:30:26,600 --> 04:30:31,120 WE DID A PATHWAY ANALYSIS AND 6057 04:30:31,120 --> 04:30:32,960 THESE ARE ANALYSIS PATHWAYS WE 6058 04:30:32,960 --> 04:30:35,840 FOUND AND THOSE ARE PUBLISHED 6059 04:30:35,840 --> 04:30:37,640 THAT THESE ARE SOME THAT RELATED 6060 04:30:37,640 --> 04:30:46,280 THAT WE FOUND TO IN MICE. 6061 04:30:46,280 --> 04:30:48,520 SOME OF THE POTH WAYS OF AGING 6062 04:30:48,520 --> 04:30:51,680 AND DIFFERENT INFLAMMATORY 6063 04:30:51,680 --> 04:31:01,000 RESPONSES AND RESPONSIVE TO THEY 6064 04:31:01,000 --> 04:31:02,760 WERE ALL STATISTICALLY 6065 04:31:02,760 --> 04:31:06,880 SIGNIFICANT TO VALIDATING WHAT 6066 04:31:06,880 --> 04:31:17,120 WE LOOKED AT. 6067 04:31:17,400 --> 04:31:19,000 WE HAD AN IDEA SOMETHING WAS 6068 04:31:19,000 --> 04:31:23,280 GOING ON IN THE IMMUNE 6069 04:31:23,280 --> 04:31:26,000 DEPARTMENT SO I WANT TO TALK 6070 04:31:26,000 --> 04:31:29,560 ABOUT OUR MODEL. 6071 04:31:29,560 --> 04:31:34,680 THIS IS A MODEL AND THIS IS 6072 04:31:34,680 --> 04:31:36,120 POTENTIALLY YOU HAVE TO DO 6073 04:31:36,120 --> 04:31:38,560 SOMETHING AND IN MICE AND MICE 6074 04:31:38,560 --> 04:31:40,960 NORMALLY HAVE HIGH HDL LEVELS 6075 04:31:40,960 --> 04:31:43,160 AND LOW LDL LEVELS SO YOU CAN 6076 04:31:43,160 --> 04:31:45,880 SEE A WILD TYPE AS HIGH FAT DIET 6077 04:31:45,880 --> 04:31:49,680 AS YOU CAN THINK AND IT WON'T 6078 04:31:49,680 --> 04:31:52,880 DEVELOP AGENTER OWE CELLO SIS 6079 04:31:52,880 --> 04:31:58,280 AND WHEN YOU DO THAT, THE 6080 04:31:58,280 --> 04:31:58,800 DOUBLED. 6081 04:31:58,800 --> 04:32:01,120 IF YOU AGE THE MICE THEY DEVELOP 6082 04:32:01,120 --> 04:32:04,880 OVER THE COURSE OF 12 MONTHS 6083 04:32:04,880 --> 04:32:07,720 EVEN ON A LOW FAT DIET. 6084 04:32:07,720 --> 04:32:12,280 THIS WAS PUBLISHED IN 2016 AND 6085 04:32:12,280 --> 04:32:17,240 UP REGULATE AND THAT LDL 6086 04:32:17,240 --> 04:32:20,040 RECEPTORS TO BE DEGRADED SO WE 6087 04:32:20,040 --> 04:32:22,320 DO THE INJECTIONS AND SEE THE 6088 04:32:22,320 --> 04:32:24,200 HIGH FAT DIET SO THE YOUNG MICE 6089 04:32:24,200 --> 04:32:27,400 AND THE OLD MICE AND HAVE THE 6090 04:32:27,400 --> 04:32:36,680 SAME LDL. 6091 04:32:36,680 --> 04:32:39,280 ONE DATA WE HAD WHEN WE DID THAT 6092 04:32:39,280 --> 04:32:44,880 BACK IN 2016 OR 217, THIS WERE 6093 04:32:44,880 --> 04:32:49,160 MORE T CELLS IN THE PLAQUE OF 6094 04:32:49,160 --> 04:32:50,880 THE OLD MICE. 6095 04:32:50,880 --> 04:32:53,000 THEY WILL BE OUTLINED AND 6096 04:32:53,000 --> 04:32:53,800 THEY'RE HARD INFORM SEE AND 6097 04:32:53,800 --> 04:33:02,600 THERE'S NOT A LOT OF THEM SO THE 6098 04:33:02,600 --> 04:33:05,320 NEXT THING O DO WAS DELETE THE 6099 04:33:05,320 --> 04:33:05,680 CELLS. 6100 04:33:05,680 --> 04:33:06,960 WE DID THE SAME APPROACH. 6101 04:33:06,960 --> 04:33:09,000 WE DID THE INJECTION AND USED 6102 04:33:09,000 --> 04:33:10,560 THE WESTERN DIET AND WE TREATED 6103 04:33:10,560 --> 04:33:15,800 THE MICE WITH AN ANTI CD8 6104 04:33:15,800 --> 04:33:18,040 ANTIBODY WHICH DOWN REGULATES 6105 04:33:18,040 --> 04:33:20,240 THE NUMBER OF CIRCULATING T 6106 04:33:20,240 --> 04:33:24,160 CELLS OVER THE COURSE OF THE 10 6107 04:33:24,160 --> 04:33:34,640 WEEKS AND WE GET 30 PER MOUSE 6108 04:33:39,120 --> 04:33:41,440 AND THAT'S QUANTIFIED HERE. 6109 04:33:41,440 --> 04:33:43,480 WE DON'T SEE A DIFFERENCE IN A 6110 04:33:43,480 --> 04:33:45,000 CHRONIC BUT IN THE OLD MICE WE 6111 04:33:45,000 --> 04:33:49,920 SEE A SIGNIFICANT REDUCTION AND 6112 04:33:49,920 --> 04:33:51,360 IN THE AREA. 6113 04:33:51,360 --> 04:33:53,360 THAT GOT ME WONDERING WHAT WAS 6114 04:33:53,360 --> 04:33:54,560 GOING ON. 6115 04:33:54,560 --> 04:33:57,080 WHY DID THIS WORK FOR OLD MICE 6116 04:33:57,080 --> 04:33:58,240 BUT NOT YOUNG MICE. 6117 04:33:58,240 --> 04:34:05,120 AND SO THIS NEXT EXPERIMENT WE 6118 04:34:05,120 --> 04:34:08,040 ISOLATED THREE-MONTH-OLD OR 6119 04:34:08,040 --> 04:34:10,240 18-MONTH-OLD WILD TYPE DONORS 6120 04:34:10,240 --> 04:34:12,520 AND TRANSLATED THEM INTO CDA 6121 04:34:12,520 --> 04:34:18,680 KNOCK OUT MICE AND THEY HAVE 6122 04:34:18,680 --> 04:34:20,120 CD8T-CELLS AND WE GAVE THEM ONE 6123 04:34:20,120 --> 04:34:23,160 MONTH TO RECOVER AND WE DID THE 6124 04:34:23,160 --> 04:34:27,240 SAME EXPERIMENT AND WE PULLED 6125 04:34:27,240 --> 04:34:28,040 ALL THE SPLEENS AND THE YOUNG 6126 04:34:28,040 --> 04:34:31,480 AND OLD DONORS AND THE YOUNG WAS 6127 04:34:31,480 --> 04:34:34,440 YOUNG AND OLD WAS OLD. 6128 04:34:34,440 --> 04:34:37,040 T CELLS FROM THE YOUNG DONORS 6129 04:34:37,040 --> 04:34:42,000 RECEIVED ABOUT 75% CD8T CELLS 6130 04:34:42,000 --> 04:34:44,760 VERSUS THE MIGHT WHO RECEIVED 6131 04:34:44,760 --> 04:34:48,080 CD8s FROM THE OLD DONORS AND A 6132 04:34:48,080 --> 04:34:49,440 LOT MORE CENTRAL MEMORY AND 6133 04:34:49,440 --> 04:34:51,400 EFFECTIVE MEMORY CELLS AND A LOT 6134 04:34:51,400 --> 04:34:54,760 OF THESE WERE PD1 POSITIVE SO 6135 04:34:54,760 --> 04:34:57,240 LIKELY EXHAUSTED. 6136 04:34:57,240 --> 04:34:58,920 AND WHEN WE DO THIS EXPERIMENT 6137 04:34:58,920 --> 04:35:03,960 WE SEE THE MICE, THE YOUNG MICE, 6138 04:35:03,960 --> 04:35:07,400 THAT RECEIVED CD8T CELLS FROM 6139 04:35:07,400 --> 04:35:09,240 OLD DONORS HAD TOTAL PLAQUE SIZE 6140 04:35:09,240 --> 04:35:10,600 COMPARED TO THE MICE THAT 6141 04:35:10,600 --> 04:35:14,640 RECEIVED NO T CELLS OR NO CD8T 6142 04:35:14,640 --> 04:35:23,320 CELLS OR THE YOUNG CD8T CELLS. 6143 04:35:23,320 --> 04:35:27,680 SO WE DID LIKE MOST PEOPLE, 6144 04:35:27,680 --> 04:35:36,640 SINGLE CELL AND THE PLAQUE AND 6145 04:35:36,640 --> 04:35:39,640 ENRICHED FOR CD3 IT WILL CELLS 6146 04:35:39,640 --> 04:35:41,000 AND MOST OF THE CELLS WE HAVE 6147 04:35:41,000 --> 04:35:43,040 ARE T CELLS AND THERE ARE SOME 6148 04:35:43,040 --> 04:35:45,960 OTHER CELLS IN THERE AND WHEN 6149 04:35:45,960 --> 04:35:49,560 YOU LOOK AT JUST THE CD8 T-CELL 6150 04:35:49,560 --> 04:35:51,040 CLUSTERS ONE THING THAT POPPED 6151 04:35:51,040 --> 04:35:52,680 OUT WAS THIS GREEN CLUSTER WHICH 6152 04:35:52,680 --> 04:35:56,240 YOU REMEMBER FROM THE TALK 6153 04:35:56,240 --> 04:36:00,720 EARLIER ARE THESE PD8C CELLS 6154 04:36:00,720 --> 04:36:03,000 EFFECTIVE MEMORY CAN AND HIGH 6155 04:36:03,000 --> 04:36:09,640 EXPRESSION AND IT'S THE MOST 6156 04:36:09,640 --> 04:36:11,840 SPECIFIC GENE FOR THIS CLUSTER 6157 04:36:11,840 --> 04:36:13,400 AND WHEN WE LOOKED AT THE 6158 04:36:13,400 --> 04:36:15,640 COMPETITION OF CELLS YOU SEE THE 6159 04:36:15,640 --> 04:36:17,160 SAME PREPORTIONS YOU MIGHT 6160 04:36:17,160 --> 04:36:27,560 EXPECT BUT THE CELLS WE 6161 04:36:28,040 --> 04:36:31,520 IDENTIFIED WAS THIS EFFECTER 6162 04:36:31,520 --> 04:36:33,400 MEMORY AND IT WAS IN THE PAPER 6163 04:36:33,400 --> 04:36:35,600 AND I DON'T KNOWN IT WAS IN THE 6164 04:36:35,600 --> 04:36:37,560 PAPER MEMORY CELLS WHEN WE SAW 6165 04:36:37,560 --> 04:36:40,680 THESE CELLS IN OUR DATA AND 6166 04:36:40,680 --> 04:36:42,640 LOOKING AND LUCKILY WE PUBLISHED 6167 04:36:42,640 --> 04:36:44,800 THIS PAPER BEFORE WE STARTED 6168 04:36:44,800 --> 04:36:47,400 LOOKING AND IT WAS A VERY GOOD 6169 04:36:47,400 --> 04:36:49,440 RESOURCE SHOUT AND SO WE STARTED 6170 04:36:49,440 --> 04:36:52,160 LOOKING AT THE INTENSELY AND ONE 6171 04:36:52,160 --> 04:36:54,240 THING THAT WE DID THAT WE 6172 04:36:54,240 --> 04:36:55,680 CALCULATED THIS COURSE FOR 6173 04:36:55,680 --> 04:36:59,160 EXHAUSTION AND THE GENES WE USED 6174 04:36:59,160 --> 04:37:03,080 AND BELOW TODAY AND IN ESSENCE 6175 04:37:03,080 --> 04:37:07,560 AND THEN SPEND THIS PAPER CAME 6176 04:37:07,560 --> 04:37:09,000 OUT IN THE FALL OF LAST YEAR 6177 04:37:09,000 --> 04:37:12,480 WITH A SET OF 120 GENES AND 6178 04:37:12,480 --> 04:37:14,560 WHICH WE HAVE 112 IN OUR DATASET 6179 04:37:14,560 --> 04:37:16,960 AND WE LEFT IT FROM MAYO CORE 6180 04:37:16,960 --> 04:37:21,720 AND INTERESTINGLY THE CLUSTER 6181 04:37:21,720 --> 04:37:23,480 CELLS AND THE GROUP THEY CAME 6182 04:37:23,480 --> 04:37:26,840 FROM WITH THE PRY AND BOTH OF 6183 04:37:26,840 --> 04:37:29,440 THESE MARKERS WAS FROM THE AGE 6184 04:37:29,440 --> 04:37:34,360 EIGHT OWE A OR PLAQUE AND IT WAS 6185 04:37:34,360 --> 04:37:38,480 THE YOUNG BLACK CELLS AND I 6186 04:37:38,480 --> 04:37:43,760 DON'T KNOW THAT THESE ARE BASED 6187 04:37:43,760 --> 04:37:46,640 ON THE TRANSCRIPT LEVEL DATA 6188 04:37:46,640 --> 04:37:49,760 THAT IS SO SOMETHING IS GOING ON 6189 04:37:49,760 --> 04:37:52,440 I THINK AND WE NEED TO LOOK MORE 6190 04:37:52,440 --> 04:37:54,280 INTO THAT SO WE HAVE CONCLUSIONS 6191 04:37:54,280 --> 04:37:56,280 AND THE GAP I CAME UP WITH 6192 04:37:56,280 --> 04:38:03,600 ACHI --CONTRIBUTES TO DISEASES D 6193 04:38:03,600 --> 04:38:07,480 AGING FREQUENCIES FUNCTION AND 6194 04:38:07,480 --> 04:38:10,440 IN DATA FROM MY AND MOST DISEASE 6195 04:38:10,440 --> 04:38:12,320 OCCURRING IN AGING AND IT'S 6196 04:38:12,320 --> 04:38:15,360 IMPORTANT LESS FOR THIS AUDIENCE 6197 04:38:15,360 --> 04:38:17,680 AND IT'S LESS CONVINCING AND I 6198 04:38:17,680 --> 04:38:19,120 THINK THAT LEADS INTO THE GAP 6199 04:38:19,120 --> 04:38:20,560 AND OPPORTUNITIES SO WE'RE DOING 6200 04:38:20,560 --> 04:38:24,720 DISEASE RELATED EXPERIMENTS AND 6201 04:38:24,720 --> 04:38:28,680 RESEARCH IN THE CONTEXT OF AGING 6202 04:38:28,680 --> 04:38:30,600 AND IF WE HAD ONE WHAT MOST 6203 04:38:30,600 --> 04:38:33,680 MOUSE STUDIES DID WE WOULD USE 6204 04:38:33,680 --> 04:38:35,840 YOUNG MICE AND WE WOULD NEVER 6205 04:38:35,840 --> 04:38:38,240 FOUND THESE MECHANISMS RELATE TO 6206 04:38:38,240 --> 04:38:41,720 T ELSE AND SO I THINK THAT THE 6207 04:38:41,720 --> 04:38:42,560 OPPORTUNITIES ARE IF YOU ARE 6208 04:38:42,560 --> 04:38:45,160 DOING A MODEL AND YOU CAN GET 6209 04:38:45,160 --> 04:38:46,920 ACCESS TO STAGE MICE THEN THOSE 6210 04:38:46,920 --> 04:38:49,440 ARE USEFUL AND I THINK 6211 04:38:49,440 --> 04:38:50,480 EXPERIENCE OF YOUR OWN FROM THE 6212 04:38:50,480 --> 04:38:54,840 NIH TO GET THOSE COMPLETION AND 6213 04:38:54,840 --> 04:38:56,840 SHARES TISSUE AND ON THE PEOPLE 6214 04:38:56,840 --> 04:39:01,160 CAN TAKE ADVANTAGE OF. 6215 04:39:01,160 --> 04:39:03,880 IF ANYONE HAS ANY IDEAS, WHEN WE 6216 04:39:03,880 --> 04:39:08,120 LOOK AT THE STYLES WE DID THE 6217 04:39:08,120 --> 04:39:09,160 DEPRESSION AND THEY'RE NOT VERY 6218 04:39:09,160 --> 04:39:10,720 MANY PEOPLE IN THE POCKET CELL 6219 04:39:10,720 --> 04:39:15,120 SO WE THINK THERE'S SOMETHING 6220 04:39:15,120 --> 04:39:17,840 AND LIVE NODES OR OTHER TYPES OF 6221 04:39:17,840 --> 04:39:22,240 IF THEY HAVE ANY IDEA I'M ALL 6222 04:39:22,240 --> 04:39:25,760 YEARS. 6223 04:39:25,760 --> 04:39:32,400 I TAUNT TO THANK THEM AND IT WAS 6224 04:39:32,400 --> 04:39:34,520 UNDER TO PRESENT THIS TALK AND 6225 04:39:34,520 --> 04:39:36,320 WOULDN'T FOR PERSONAL REASONS 6226 04:39:36,320 --> 04:39:37,760 AND I THANK YOU FOR SUGGESTING 6227 04:39:37,760 --> 04:39:40,800 ME FOR THIS AND I'M HAPPY TO 6228 04:39:40,800 --> 04:39:44,760 TAKE THIS RESPONSE. 6229 04:39:44,760 --> 04:39:52,520 MORGUE APP. 6230 04:39:52,520 --> 04:39:57,360 >>DO YOU GET ANY SORT OF 6231 04:39:57,360 --> 04:39:59,400 (INAUDIBLE) AROUND THE. 6232 04:39:59,400 --> 04:40:02,400 LIKE AGRI GETS OF T AND VASSEL. 6233 04:40:02,400 --> 04:40:04,560 >>ONLY IN A VERY MINOR NUMBER 6234 04:40:04,560 --> 04:40:05,880 OF CASES. 6235 04:40:05,880 --> 04:40:08,400 YOU DON'T KNOW WHAT THE CELLS 6236 04:40:08,400 --> 04:40:09,440 ARE BUT I HAVEN'T TRIED TO 6237 04:40:09,440 --> 04:40:13,000 FIGURE IT OUT BUT WE'VE DONE 6238 04:40:13,000 --> 04:40:15,160 ANOTHER THEY'RE NOT T CELLS BUT 6239 04:40:15,160 --> 04:40:18,200 IT ONLY OCCURS WHEN IT'S REALLY 6240 04:40:18,200 --> 04:40:19,600 A LESS THAN 1% OF MICE. 6241 04:40:19,600 --> 04:40:22,680 >>THANK YOU. 6242 04:40:22,680 --> 04:40:24,080 >>SUPER COOL TALK. 6243 04:40:24,080 --> 04:40:30,080 I HAVE A QUESTION ABOUT LIKE TH. 6244 04:40:30,080 --> 04:40:32,680 IF YOU COULD SUB SORT THOSE OLD 6245 04:40:32,680 --> 04:40:34,960 O T CELLS AND TOOK JUST THE 6246 04:40:34,960 --> 04:40:38,080 NAIVE ONCE, DO YOU THINK THAT 6247 04:40:38,080 --> 04:40:42,080 THEY WOULD LEAD TO NORMAL, THE 6248 04:40:42,080 --> 04:40:42,840 YOUNG PLAQUE FORMATION OR DO YOU 6249 04:40:42,840 --> 04:40:45,080 THINK IT'S THE COMPOSITION OR 6250 04:40:45,080 --> 04:40:46,480 THERE'S SOMETHING INTRINSICALLY 6251 04:40:46,480 --> 04:40:47,560 WRONG WITH THE CELLS? 6252 04:40:47,560 --> 04:40:50,520 >>YEAH, I DON'T KNOW ANYBODY 6253 04:40:50,520 --> 04:40:51,720 KNOWS THAT AND MOST PEOPLE 6254 04:40:51,720 --> 04:40:54,840 LOOKING AT THESE MAP, DON'T LOOK 6255 04:40:54,840 --> 04:40:57,840 AT AGING SO, YOU COULD PROBABLY 6256 04:40:57,840 --> 04:40:59,840 SORT CELLS, I DON'T THINK THAT 6257 04:40:59,840 --> 04:41:01,640 THE PROBLEM WITH THE INEXTRA 6258 04:41:01,640 --> 04:41:04,280 CELLULAR MARKERS YOU COULD SORT 6259 04:41:04,280 --> 04:41:05,640 CELLS FROM YOUNG MICE AND DO THE 6260 04:41:05,640 --> 04:41:07,840 SAME THING FROM OLD MICE AND 6261 04:41:07,840 --> 04:41:11,720 COMPARE HEAD-TO-HEAD WITH THE 6262 04:41:11,720 --> 04:41:13,760 MICE AND THEY HAVE TO COME FROM 6263 04:41:13,760 --> 04:41:15,840 THE SPLEEN BECAUSE WE 6264 04:41:15,840 --> 04:41:16,640 TRANSFERRED 10 MILLION CELLS BUT 6265 04:41:16,640 --> 04:41:17,480 IT'S POSSIBLE. 6266 04:41:17,480 --> 04:41:19,400 I THINK, I DON'T HAVE DATA TO 6267 04:41:19,400 --> 04:41:21,640 SUPPORT THIS BUT THE CELLS MAY 6268 04:41:21,640 --> 04:41:24,120 BE PROTECTIVE WHERE THE MEMORY 6269 04:41:24,120 --> 04:41:28,160 CELLS, IT'S IN THE AGED MICE, 6270 04:41:28,160 --> 04:41:29,480 MAYBE MORE PRO (INAUDIBLE) WHEN 6271 04:41:29,480 --> 04:41:32,480 YOU COMPARE THEM NAIVE YOUNG 6272 04:41:32,480 --> 04:41:35,920 VERSUS NAIVE AGE CELLS THERE ARE 6273 04:41:35,920 --> 04:41:40,000 DIFFERENCES BUT NOTHING THAT'S A 6274 04:41:40,000 --> 04:41:44,240 SMOKING GUN THAT WOULD BE THE 6275 04:41:44,240 --> 04:41:44,520 ANSWER. 6276 04:41:44,520 --> 04:41:46,480 >>WONDERFUL TALK. 6277 04:41:46,480 --> 04:41:48,800 YOU COULD GIVE US ANOTHER TALK 6278 04:41:48,800 --> 04:41:51,280 ABOUT YOUR CANINE TO NINE ROO 6279 04:41:51,280 --> 04:41:52,120 PATHWAY TO PEOPLE. 6280 04:41:52,120 --> 04:41:53,640 YOU MENTIONED ABOUT THE 6281 04:41:53,640 --> 04:41:54,840 CIRCULATING FACTORS, RIGHT. 6282 04:41:54,840 --> 04:41:56,440 DO YOU THINK AS THESE CELLS ARE 6283 04:41:56,440 --> 04:41:58,040 GOING ARE THEY RESPONDING TO 6284 04:41:58,040 --> 04:42:02,200 SIGNALS FROM THE TISSUES OR IS 6285 04:42:02,200 --> 04:42:05,120 IT JUST A GRADIENT THING IN THE 6286 04:42:05,120 --> 04:42:07,160 PERIPHERY WHERE DO YOU THINK THE 6287 04:42:07,160 --> 04:42:08,560 SIGNALS AND ORGAN COMMUNICATION 6288 04:42:08,560 --> 04:42:09,320 ARE COMING FROM IF. 6289 04:42:09,320 --> 04:42:12,120 >>THAT'S A GOOD QUESTION. 6290 04:42:12,120 --> 04:42:13,200 I'VE BEEN THINKING A LOT ABOUT 6291 04:42:13,200 --> 04:42:14,960 THAT AND THERE'S A STUDY WHERE 6292 04:42:14,960 --> 04:42:17,720 THEY DID THE SAME DEPRESSION IN 6293 04:42:17,720 --> 04:42:19,640 MICE AND THEY SEE THAT IS 6294 04:42:19,640 --> 04:42:23,000 BENEFICIAL AND IT REDUCES PLAQUE 6295 04:42:23,000 --> 04:42:24,600 SIZE AND CHANGES CIRCULATING MAN 6296 04:42:24,600 --> 04:42:26,320 OWE FACE OF IT AND MOST OF IT IN 6297 04:42:26,320 --> 04:42:30,240 THE PLATFORM ARE MACROPHAGES AND 6298 04:42:30,240 --> 04:42:35,160 THE COMPARED OF THE YOUNG LDL IN 6299 04:42:35,160 --> 04:42:38,080 MICE AND THEY HAVE DIFFERENT 6300 04:42:38,080 --> 04:42:39,160 T-CELL SUBSETS AND THAT MOST 6301 04:42:39,160 --> 04:42:44,040 YOUNG LDL MICE HAVE NOT A LOT OF 6302 04:42:44,040 --> 04:42:46,120 CENTRAL CELLS AND WE HAVE TO DO 6303 04:42:46,120 --> 04:42:48,200 ANOTHER EXPERIMENT TO FIND OUT, 6304 04:42:48,200 --> 04:42:48,560 I GUESS. 6305 04:42:48,560 --> 04:42:49,040 >>THANK YOU. 6306 04:42:49,040 --> 04:42:56,080 >>THANK YOU. 6307 04:42:56,080 --> 04:43:03,840 >>OUR NEXT SPEAKER IS CONNIE 6308 04:43:03,840 --> 04:43:04,600 WEYAND. 6309 04:43:04,600 --> 04:43:05,880 I'M NOT GOING TO TRY TO TELL 6310 04:43:05,880 --> 04:43:07,560 WHAT SHE'S GOING TO TELL US 6311 04:43:07,560 --> 04:43:10,640 ABOUT BUT SOMETHING FUN. 6312 04:43:10,640 --> 04:43:12,880 >>YOU'LL GET THIS. 6313 04:43:12,880 --> 04:43:15,440 >>HE WAS RIGHT. 6314 04:43:15,440 --> 04:43:17,200 >>YES, THAT'S WHAT WE ARE GOING 6315 04:43:17,200 --> 04:43:22,360 TO TALK ABOUT. 6316 04:43:22,360 --> 04:43:25,360 ACTUALLY, THIS IS OUR DISEASE 6317 04:43:25,360 --> 04:43:25,840 MODEL. 6318 04:43:25,840 --> 04:43:29,640 WE ARE INTERESTED IN AUTOIMMUNE 6319 04:43:29,640 --> 04:43:30,800 DISEASE AND THIS IS A PROTO TIP 6320 04:43:30,800 --> 04:43:36,080 I CAN AUTOIMMUNE DISEASE AND A 6321 04:43:36,080 --> 04:43:39,280 CLASS 2HLA CLASS II ASSOCIATED 6322 04:43:39,280 --> 04:43:41,680 DISEASE SO IT'S THE STRONGESTEN 6323 04:43:41,680 --> 04:43:44,280 GET I CAN RISK FACTORS AND THESE 6324 04:43:44,280 --> 04:43:45,520 PATIENTS ARE CENTERING ENOUGH 6325 04:43:45,520 --> 04:43:49,280 THEY BUILD THEM AGAIN RANGE OF 6326 04:43:49,280 --> 04:43:50,840 TRANSCRIPTION BE MODIFIED 6327 04:43:50,840 --> 04:43:55,760 PROTEIN AND IF YOU GO INTO THIS 6328 04:43:55,760 --> 04:43:57,520 LESION FOR THESE PATIENTS THEIR 6329 04:43:57,520 --> 04:44:00,360 JOINTS ARE UNDER FIRE. 6330 04:44:00,360 --> 04:44:02,400 YOU WILL FIND MICRO LANGUAGE' 6331 04:44:02,400 --> 04:44:06,600 AND T CELLS AND OF COURSE FORMER 6332 04:44:06,600 --> 04:44:07,160 CELLS. 6333 04:44:07,160 --> 04:44:09,040 WE'RE NOT GOING TO TRY TO SEE IF 6334 04:44:09,040 --> 04:44:13,080 IT'S A DISEASE OF OLD 6335 04:44:13,080 --> 04:44:13,680 INDIVIDUALS, HIGHEST INCIDENTS 6336 04:44:13,680 --> 04:44:16,120 IN VICTIMS OVER 07 BUT MUCH MORE 6337 04:44:16,120 --> 04:44:17,800 IMPORTANTLY, IF YOU GO INTO 6338 04:44:17,800 --> 04:44:20,320 YOUNGER PATIENTS, AND THIS IS AN 6339 04:44:20,320 --> 04:44:22,240 OBSERVATION WE MADE A COUPLE OF 6340 04:44:22,240 --> 04:44:25,600 YEARS BACK, YOU SEE THAT THESE 6341 04:44:25,600 --> 04:44:29,880 PATIENTS AND WHAT WE CALL 6342 04:44:29,880 --> 04:44:34,160 PREMATURE AGING, WE MEASURED THE 6343 04:44:34,160 --> 04:44:38,240 LINK AND WE MEASURED THE 6344 04:44:38,240 --> 04:44:39,720 TELOMERE LENGTH BECAUSE THIS IS 6345 04:44:39,720 --> 04:44:42,600 A CLASS ASSOCIATED THE C AND WE 6346 04:44:42,600 --> 04:44:46,880 MEASURED THE TELOMERE CELLS THAT 6347 04:44:46,880 --> 04:44:49,480 HAVE A NAIVE PHENOTYPE AND YOU 6348 04:44:49,480 --> 04:44:54,800 SEE THE PATIENT AT THE AGE OF 30 6349 04:44:54,800 --> 04:44:58,520 LOOKED ABOUT 50 SO THERE AN 6350 04:44:58,520 --> 04:45:02,560 INTERESTING SHIFT THAT THEY 6351 04:45:02,560 --> 04:45:03,440 PREMATURELY AGED AND THE COULD 6352 04:45:03,440 --> 04:45:04,560 SURFS BETWEEN US AND ORANGE AND 6353 04:45:04,560 --> 04:45:08,000 THE PATIENTS AND BLUE THAT'S 6354 04:45:08,000 --> 04:45:09,200 ANOTHER INTERESTING PHENOMENON 6355 04:45:09,200 --> 04:45:16,440 MANY AND IT NEEDS EXPLANATION. 6356 04:45:16,440 --> 04:45:19,040 ED QUESTION IS WHY DO THESE T 6357 04:45:19,040 --> 04:45:20,920 CELLS AGE AND PREMATURELY AGE. 6358 04:45:20,920 --> 04:45:22,480 WELL WE HEARD TODAY IT'S NOT 6359 04:45:22,480 --> 04:45:24,040 ONLY IMPORTANT WHAT HAPPENED IN 6360 04:45:24,040 --> 04:45:25,640 THE CELLS IT'S IMPORTANT WHAT 6361 04:45:25,640 --> 04:45:30,200 HAPPENS AROUND THE CELLS. 6362 04:45:30,200 --> 04:45:31,600 SO, WE HAVE REALLY GIVEN 6363 04:45:31,600 --> 04:45:33,440 ATTENTION TO WHAT HAPPENS AROUND 6364 04:45:33,440 --> 04:45:37,160 THE CELLS AND WE HAVE MEASURES 6365 04:45:37,160 --> 04:45:39,600 IN THE MICROENVIRONMENT WHAT 6366 04:45:39,600 --> 04:45:42,720 KIND OF NUTRIENTS THE CELLS 6367 04:45:42,720 --> 04:45:43,920 ENCOUNTER THERE AND I'LL SHOW 6368 04:45:43,920 --> 04:45:47,360 YOU THE DATA HERE FOR GLUCOSE 6369 04:45:47,360 --> 04:45:49,280 BECAUSE EVERYBODY OF COURSE WAS 6370 04:45:49,280 --> 04:45:50,680 PREDICTING THE INFLAMMATORY 6371 04:45:50,680 --> 04:45:55,680 CELLS WILL BE EATING GLUCOSE AND 6372 04:45:55,680 --> 04:45:57,440 WHILE THEY MIGHT EAT GLUCOSE IF 6373 04:45:57,440 --> 04:46:00,800 THEY COULD, I CAN TELL YOU THEY 6374 04:46:00,800 --> 04:46:01,240 CAN'T. 6375 04:46:01,240 --> 04:46:02,960 BECAUSE THERE IS NO GLUCOSE. 6376 04:46:02,960 --> 04:46:04,560 AT LEAST NOT MUCH. 6377 04:46:04,560 --> 04:46:08,840 SO, THE GLUCOSE LEVELS IN THESE 6378 04:46:08,840 --> 04:46:09,800 SIN OAF Y'ALL TISSUE AND THESE 6379 04:46:09,800 --> 04:46:17,600 WERE COLLECTED OUT OF THE DONOR 6380 04:46:17,600 --> 04:46:28,080 INDIVIDUAL -- SO MORE TISSUE 6381 04:46:29,160 --> 04:46:30,720 HERE DO HAVE LOWER LEVELS BUT 6382 04:46:30,720 --> 04:46:34,720 YOU SEE THAT THE UNINFLAMED 6383 04:46:34,720 --> 04:46:36,800 TISSUE WHICH WERE SELECTED FROM 6384 04:46:36,800 --> 04:46:38,240 PATIENTS WITH SPORTS INJURIES 6385 04:46:38,240 --> 04:46:40,520 THAT THESE NOT PATHS ARE VERY 6386 04:46:40,520 --> 04:46:43,240 LOW GLUCOSE LEVELS AS WELL SO 6387 04:46:43,240 --> 04:46:45,960 HOW DO T-CELLS AIMING IN THESE 6388 04:46:45,960 --> 04:46:47,480 PATIENTS AND WHAT DO THEY LIVE 6389 04:46:47,480 --> 04:46:47,960 OFF? 6390 04:46:47,960 --> 04:46:50,400 THEY SAY REALLY DON'T HAVE A 6391 04:46:50,400 --> 04:46:53,400 CHANCE TO EAT GLUCOSE IN THE 6392 04:46:53,400 --> 04:46:57,440 SYNOVIAL ENVIRONMENT. 6393 04:46:57,440 --> 04:47:01,680 WELL, MANY LEADS TO THIS 6394 04:47:01,680 --> 04:47:02,720 ORGANIZE INHE WILL AND I'LL GIVE 6395 04:47:02,720 --> 04:47:04,640 YOU AN OVERVIEW ABOUT WHAT WE 6396 04:47:04,640 --> 04:47:07,520 HAVE FOUND OVER THE YEARS. 6397 04:47:07,520 --> 04:47:11,360 SO, OF A REAL PROBLEM IS THAT 6398 04:47:11,360 --> 04:47:12,720 THE MIGHT OWE CON DEGREE AN THE 6399 04:47:12,720 --> 04:47:15,680 T CELLS HAVE A PROBLEM WITH DNA 6400 04:47:15,680 --> 04:47:19,320 PREPARE AND THEY'RE GETTING A 6401 04:47:19,320 --> 04:47:21,080 NUKELY ACE WHICH LEADS TO DNA 6402 04:47:21,080 --> 04:47:24,720 LEAKAGE TO INFLAM TOMORROW 6403 04:47:24,720 --> 04:47:28,040 ACTIVATION AND SO THE TWO PLANS 6404 04:47:28,040 --> 04:47:33,240 UNDERGO WHEN THEY REACH SYNOVIAL 6405 04:47:33,240 --> 04:47:37,960 TISSUE AND THE CELLS REVERT BY 6406 04:47:37,960 --> 04:47:40,680 SHUTTING DOWN AND THIS LEADS TO 6407 04:47:40,680 --> 04:47:47,440 AN INCREASE SIGH TRADE AND AND 6408 04:47:47,440 --> 04:47:50,040 HYPER ESCALATION WHICH MAKES THE 6409 04:47:50,040 --> 04:47:52,360 CELL VERY MIGRATORY. 6410 04:47:52,360 --> 04:47:57,000 THE CELLS DO NOT PRODUCE ENOUGH 6411 04:47:57,000 --> 04:47:58,880 ASPERTAME IN THE MITOCHONDRIA 6412 04:47:58,880 --> 04:48:01,720 AND THIS IS A CRITICAL 6413 04:48:01,720 --> 04:48:02,240 DEFICIENCY. 6414 04:48:02,240 --> 04:48:06,960 THIS DISRUPTS ADPD OF VIP AND 6415 04:48:06,960 --> 04:48:10,080 LEADS TO THE EXPANSION OF ER 6416 04:48:10,080 --> 04:48:14,960 MEMBRANE AND TO INCREASE 6417 04:48:14,960 --> 04:48:16,840 PROLIFERATION TRANSPORTATION AND 6418 04:48:16,840 --> 04:48:18,880 BIOGEN SIS WHILE YOU MAY ALL 6419 04:48:18,880 --> 04:48:21,840 KNOW THAT IN RHUMATOID ARTHRITIS 6420 04:48:21,840 --> 04:48:29,120 CNF IS TH TH THE CYTOKINE WHICHT 6421 04:48:29,120 --> 04:48:32,000 SO IT'S POSSIBLE FOR THE OVER 6422 04:48:32,000 --> 04:48:34,640 PRODUCTION AND THE SHAFTION 6423 04:48:34,640 --> 04:48:37,640 GLUCOSE AWAY FROM THE 6424 04:48:37,640 --> 04:48:39,480 MITOCHONDRIA INTO THE FOSS EIGHT 6425 04:48:39,480 --> 04:48:43,680 AND IT INCREASES IN A NIDPH 6426 04:48:43,680 --> 04:48:47,200 LEVEL AND INCREASE FINAL GENESIS 6427 04:48:47,200 --> 04:48:50,840 LEADS TO LIPID DROPLET FORMATION 6428 04:48:50,840 --> 04:48:51,600 I AM VASE I HAVE MEMBRANE 6429 04:48:51,600 --> 04:48:53,360 FORMATION AND TISSUE 6430 04:48:53,360 --> 04:48:55,320 INVASIVENESS AND THEY HAVE SAFE 6431 04:48:55,320 --> 04:48:56,960 FUNCTION AM TRANSPORT CHAIN 6432 04:48:56,960 --> 04:48:58,600 WHICH DECREASES THE PRODUCTION 6433 04:48:58,600 --> 04:49:02,600 OF A IT TP AND THIS ACTUALLY IN 6434 04:49:02,600 --> 04:49:06,760 OUR HANDS CONNECTS DIRECTLY TO 6435 04:49:06,760 --> 04:49:10,640 THE -- AND OPPOSED UPON 6436 04:49:10,640 --> 04:49:11,480 ACTIVATION. 6437 04:49:11,480 --> 04:49:14,280 SO THIS IS THE NATURAL SUMMARY 6438 04:49:14,280 --> 04:49:16,280 AND I'LL JUST SHOW YOU HAVE 6439 04:49:16,280 --> 04:49:19,640 WHERE THE MAJOR MOLECULAR 6440 04:49:19,640 --> 04:49:21,120 TARGETS ARE BECAUSE WE'RE HERE 6441 04:49:21,120 --> 04:49:23,640 TODAY TO TALK ABOUT THE FUTURE. 6442 04:49:23,640 --> 04:49:24,920 WHERE WE COULD GO? 6443 04:49:24,920 --> 04:49:26,800 HOW CAN WE TAKE IT KNOWLEDGE AND 6444 04:49:26,800 --> 04:49:28,240 BRING IT TO THE PATIENT AND 6445 04:49:28,240 --> 04:49:29,560 ACTUALLY MAKE THEM BETTER. 6446 04:49:29,560 --> 04:49:32,480 SO IF YOU MISH ATP PRODUCTION IN 6447 04:49:32,480 --> 04:49:35,600 THE CD4 CELLS OF PATIENTS TO SEE 6448 04:49:35,600 --> 04:49:39,840 THAT APP IS SLOWS AND AMP IS 6449 04:49:39,840 --> 04:49:41,640 HIGH, BUT YOU ALSO SEE THAT 6450 04:49:41,640 --> 04:49:44,240 THERE'S A RANGE OF ATP 6451 04:49:44,240 --> 04:49:48,040 PRODUCTION AND SOME CELLS ARE 6452 04:49:48,040 --> 04:49:52,240 SLOW AND SOME CELLS ARE AS HIGH 6453 04:49:52,240 --> 04:49:52,720 AS 7. 6454 04:49:52,720 --> 04:49:54,000 DOES THAT MATTER? 6455 04:49:54,000 --> 04:49:56,360 IS THAT IMPORTANT? 6456 04:49:56,360 --> 04:49:57,800 HOW MUCH THEY MAKE? 6457 04:49:57,800 --> 04:50:00,400 IF YOU RECRUITED A QUICK WORD OF 6458 04:50:00,400 --> 04:50:02,840 THAT PATIENTS WE STARTED WITH 6459 04:50:02,840 --> 04:50:05,360 MEASURING ATP CELLS AND YOU SEE 6460 04:50:05,360 --> 04:50:08,840 THAT THERE'S THAT RANGE IF WE 6461 04:50:08,840 --> 04:50:11,960 ACTUALLY CLASSIFY THEM INTO AN 6462 04:50:11,960 --> 04:50:15,640 ATPEL SUBJECT AND INTO AN ATP 6463 04:50:15,640 --> 04:50:18,720 SUBSET BECAUSE THE ATP NEVER AS 6464 04:50:18,720 --> 04:50:20,680 HIGH AS THEFT IN THE YELLOW 6465 04:50:20,680 --> 04:50:24,200 CONTROLS AND THEN YOU SEE THAT 6466 04:50:24,200 --> 04:50:28,160 WE HAVE ABOUT ATP LOCATIONS AND 6467 04:50:28,160 --> 04:50:30,240 ATP IN IMMEDIATE PATIENTS AND 6468 04:50:30,240 --> 04:50:32,960 WELL IF YOU MEASURE COMPLEX 6469 04:50:32,960 --> 04:50:35,280 ACTIVITY OF THE MITOCHONDRIA WE 6470 04:50:35,280 --> 04:50:40,040 SEE THAT ATP PRODUCTION AND IS 6471 04:50:40,040 --> 04:50:46,080 EXPECTED CORRELATES VERY WELL 6472 04:50:46,080 --> 04:50:47,840 WITH -- THIS IS OUR MODERN 6473 04:50:47,840 --> 04:50:50,920 SYSTEM WHERE YOU CRASH AND HUMAN 6474 04:50:50,920 --> 04:50:52,760 SYNOVIAL TISSUE INTO A MOUSE 6475 04:50:52,760 --> 04:50:55,960 THAT WE HAVE MODIFIED AND WE 6476 04:50:55,960 --> 04:50:58,800 ADOPTED THE TRANSFER INTO THAT 6477 04:50:58,800 --> 04:51:03,760 NSG MOUSE THE PATIENT AND THEN 6478 04:51:03,760 --> 04:51:08,280 WE EXPLAINED THE TISSUE AND DO 6479 04:51:08,280 --> 04:51:08,880 TISSUE TRANCE CHROME I CAN AND 6480 04:51:08,880 --> 04:51:11,680 DO CLOSE OR WHATEVER YOUR HEART 6481 04:51:11,680 --> 04:51:12,680 DESIRES. 6482 04:51:12,680 --> 04:51:17,680 SO, IF WE TAKE THE PRODUCES THE 6483 04:51:17,680 --> 04:51:20,120 LOWER A-A-T-P OR IN THE 6484 04:51:20,120 --> 04:51:21,920 IMMEDIATE AMOUNT OF ATP THAT HAS 6485 04:51:21,920 --> 04:51:27,000 A MAJOR IMPACT ON THE INTENSITY 6486 04:51:27,000 --> 04:51:37,520 OF THE NIAGARA FALLS THE CELLS 6487 04:51:52,960 --> 04:51:57,720 OF THE LOW PATIENT THERE'S LOW 6488 04:51:57,720 --> 04:51:59,040 MITOCHONDRIAL TO TEN SHALL WHERE 6489 04:51:59,040 --> 04:52:00,600 THE PATIENTS HAVE A POPULATION 6490 04:52:00,600 --> 04:52:11,080 OF CELLS THAT STILL HAVE OF 6491 04:52:22,320 --> 04:52:25,000 THESE ARE THE TISSUE TRANSCRIPT 6492 04:52:25,000 --> 04:52:26,800 OWN AND WITH WHEN THE CELLS A 6493 04:52:26,800 --> 04:52:29,320 ARRIVE INTO THE TISSUE, THEY 6494 04:52:29,320 --> 04:52:32,160 INDUCE AN INFLAMMATION THAT UP 6495 04:52:32,160 --> 04:52:41,200 REGULATE CD163FAP AND IN THE GAM 6496 04:52:41,200 --> 04:52:43,040 AND IL6. 6497 04:52:43,040 --> 04:52:44,680 WE ARE GO AND LOOK WHICH CELLS 6498 04:52:44,680 --> 04:52:47,760 THAT ARE AND BEFORE I SHOW YOU 6499 04:52:47,760 --> 04:52:49,800 THAT, I SHOULD EXPLAIN THAT WE 6500 04:52:49,800 --> 04:52:52,880 DID ONE EXPERIMENT AND WE TOOK A 6501 04:52:52,880 --> 04:52:54,640 HEALTHY T-CELL AND WE INHIBITED 6502 04:52:54,640 --> 04:52:58,840 THE COMPLEX 5, THIS WAS WE 6503 04:52:58,840 --> 04:53:04,680 TRANSFERRED IT INTO THE MICE AND 6504 04:53:04,680 --> 04:53:08,920 WE WONDERED IT'S EFFICIENT TO 6505 04:53:08,920 --> 04:53:10,680 INDUCE IT THIS TYPE OF TISSUE 6506 04:53:10,680 --> 04:53:12,360 INFORMATION AND THE ANSWER IS 6507 04:53:12,360 --> 04:53:16,120 YES, SO IN THE UPPER BLUE YOU 6508 04:53:16,120 --> 04:53:20,760 SEE THE CD4 CELLS THAT HAVE A 6509 04:53:20,760 --> 04:53:22,360 FUNCTIONAL COMPLEX HIGH AND IN 6510 04:53:22,360 --> 04:53:24,480 THE LOWER RED, YOU SEE THE 6511 04:53:24,480 --> 04:53:26,960 RESULT FOR THE T CELLS THAT HAVE 6512 04:53:26,960 --> 04:53:30,840 AN INHIBITED COMPLEX AND YOU SEE 6513 04:53:30,840 --> 04:53:33,120 HERE THAT THE DENSITY OF T CELLS 6514 04:53:33,120 --> 04:53:38,720 IN THE TISSUE IS HIGHER IN THE T 6515 04:53:38,720 --> 04:53:41,720 CELLS AND THAT THE PRODUCTION OF 6516 04:53:41,720 --> 04:53:44,440 IL6 AND THE PLAN IS POSITIVE 6517 04:53:44,440 --> 04:53:50,720 THAT ARE HYPO GLASS AND IT'S 6518 04:53:50,720 --> 04:53:52,960 MUCH HIGHER AND THE PRODUCTION 6519 04:53:52,960 --> 04:53:55,960 IN MICROFAGES IS MUCH HIGHER AND 6520 04:53:55,960 --> 04:53:58,560 THAT THE PRODUCTION OF IL6 IN 6521 04:53:58,560 --> 04:54:01,320 THE MICRO IS MUCH HIGHER IF ALL 6522 04:54:01,320 --> 04:54:05,320 OF WHAT WE DID IS TO BLOCK THE 6523 04:54:05,320 --> 04:54:09,400 COMPLEX PIE IN THE CD4 CELLS. 6524 04:54:09,400 --> 04:54:12,000 SO, HOW DO WE REPAIR THIS? 6525 04:54:12,000 --> 04:54:14,480 HOW DO WE MAKE THIS BETTER? 6526 04:54:14,480 --> 04:54:19,000 WELL WE HAVE TO GO TO THE ROOT 6527 04:54:19,000 --> 04:54:19,720 MOLECULE. 6528 04:54:19,720 --> 04:54:21,400 HERE IS ONE OF THE ROOT 6529 04:54:21,400 --> 04:54:21,840 MOLECULES. 6530 04:54:21,840 --> 04:54:24,800 WE STARRED WITH THE ANALYSIS OF 6531 04:54:24,800 --> 04:54:26,720 CD4 CELLS OF BOTH NAIVE AND AS 6532 04:54:26,720 --> 04:54:29,600 WELL AS MEMORY CD4 CELLS COMING 6533 04:54:29,600 --> 04:54:32,560 OUT OF OUR ROTATION IN CONTROLS 6534 04:54:32,560 --> 04:54:38,040 AND THE PATIENTS ARE IN REST AND 6535 04:54:38,040 --> 04:54:43,480 WE ARE IN PURPLE AND ONE OF THE 6536 04:54:43,480 --> 04:54:48,360 MOLECULES THAT FELL OUT WAS 6537 04:54:48,360 --> 04:54:48,960 MRE11A. 6538 04:54:48,960 --> 04:54:51,480 IT DECLINED IN T CELLS WITH H 6539 04:54:51,480 --> 04:54:54,480 AND IT IS MUCH MORE PRONOUNCED 6540 04:54:54,480 --> 04:54:58,840 IN THE PATIENTS AND MEMORY C 6541 04:54:58,840 --> 04:55:03,400 CELLS AND MRE11 IS A ' LACE THAT 6542 04:55:03,400 --> 04:55:06,640 FORMS WITH NUCLEASES ATPA 6543 04:55:06,640 --> 04:55:10,200 NUCLEAR PLAN AND IT REPAIRS THE 6544 04:55:10,200 --> 04:55:11,880 MA DOUBLE TREND AND WE WEPT 6545 04:55:11,880 --> 04:55:16,200 LOOKING FOR MRE11 AND SAW THAT 6546 04:55:16,200 --> 04:55:20,560 MRE11 IN HEALTHY CELLS IS IN THE 6547 04:55:20,560 --> 04:55:24,280 AND IN THE MIO CON DEGREE A AND 6548 04:55:24,280 --> 04:55:33,640 OF COURSE THERE'S MRE11 AND IT'S 6549 04:55:33,640 --> 04:55:37,560 A NUKELY ACE AND YOU SEE THE RA 6550 04:55:37,560 --> 04:55:48,120 CELLS DO LESS MRE22 BOTH IN THE 6551 04:56:07,440 --> 04:56:08,760 WHEN YOU COMPARE CONTROLS. 6552 04:56:08,760 --> 04:56:15,480 NOT ONLY DOES MITOCHONDRIAL MIGN 6553 04:56:15,480 --> 04:56:17,200 DEGREE CONSUMPTION GO DOWN THEY 6554 04:56:17,200 --> 04:56:19,520 LEAD MITOCHONDRIAL OUTSIDE OF 6555 04:56:19,520 --> 04:56:23,600 THE CELLS AND SO THIS SHOWS 6556 04:56:23,600 --> 04:56:26,560 INCLUDES WHAT A HAPPENED WHEN 6557 04:56:26,560 --> 04:56:29,280 MRE11 IS KNOCKED DOWN OR WHEN WE 6558 04:56:29,280 --> 04:56:31,720 PHARMACOLOGICALLY INHIBIT THIS 6559 04:56:31,720 --> 04:56:35,360 OR SPONTANEOUSLY IN THE PATIENT 6560 04:56:35,360 --> 04:56:37,720 AND SO WE DO KNOW THAT HAPPENS 6561 04:56:37,720 --> 04:56:41,600 IN VIVO HERE WE ARE IN THE LYMPH 6562 04:56:41,600 --> 04:56:41,920 NODE. 6563 04:56:41,920 --> 04:56:49,280 WE DO KNOW THAT ACTIVATES CHEST 6564 04:56:49,280 --> 04:56:51,560 PACE ONE AND ACTUALLY FROM 6565 04:56:51,560 --> 04:56:55,440 ACTIVATION AS PART OF THE 6566 04:56:55,440 --> 04:57:05,880 PROCESS AND EDITED IN THE 6567 04:57:09,600 --> 04:57:10,120 POSITIVE CONTROL. 6568 04:57:10,120 --> 04:57:12,400 THIS HAPPENS IN THE LIVE NODE OF 6569 04:57:12,400 --> 04:57:17,760 THE PATIENTS AND IT IS A RESULT 6570 04:57:17,760 --> 04:57:28,560 OF THOF YOU SEE IT'S PLACED IN E 6571 04:57:42,200 --> 04:57:43,800 CD3 POSITIVE CELL. 6572 04:57:43,800 --> 04:57:47,880 WE DO KNOW THAT THE RA T-CELL 6573 04:57:47,880 --> 04:57:56,800 UTILIZES THESE CYTO PLASTIC AND 6574 04:57:56,800 --> 04:58:05,080 AS A RESOURCE TO MIGRATE INTO 6575 04:58:05,080 --> 04:58:15,640 THE THE AMOUNT OF MY PROTEIN IS 6576 04:58:44,680 --> 04:58:47,520 LOWER IN THE CELLS AND WHAT THIS 6577 04:58:47,520 --> 04:58:52,240 LEADS TO IS THEY FAILED TO AMPK 6578 04:58:52,240 --> 04:58:55,480 AND YOU ALL KNOW THAT AMPK IS 6579 04:58:55,480 --> 04:58:57,960 THE ONE KINASE THAT MAINTAINS 6580 04:58:57,960 --> 04:59:04,080 HEALTH OF THE MIGHT OWE CON MIGA 6581 04:59:04,080 --> 04:59:06,840 AND YOU SEE HERE THAT IN THE 6582 04:59:06,840 --> 04:59:11,600 PATIENT, THE AMPK MOLECULES 6583 04:59:11,600 --> 04:59:12,800 PROTEIN IS NOT. 6584 04:59:12,800 --> 04:59:15,200 WHAT THIS LEADS TO IS THAT WHEN 6585 04:59:15,200 --> 04:59:18,880 YOU GO TO THE LIPOSOME WHERE IT 6586 04:59:18,880 --> 04:59:29,360 IT HAS TO TRAVEL TO, THE AMK 6587 04:59:32,160 --> 04:59:35,600 AMOUNT IS LOWER AND YOU SEE THAT 6588 04:59:35,600 --> 04:59:39,720 ON THE SURFACE M.T.O. R IS STILL 6589 04:59:39,720 --> 04:59:42,360 MAINTAINED BECAUSE M.T.O. R AND 6590 04:59:42,360 --> 04:59:48,720 MEET ON THE SURFACE OF THE LICE 6591 04:59:48,720 --> 04:59:58,240 OWE SEEM WE HAVE CON SPAIN YUS 6592 04:59:58,240 --> 05:00:02,520 AND UNIMPOSED ACTIVATION. 6593 05:00:02,520 --> 05:00:07,640 OR WHAT HAPPENS IN A HEALTHY 6594 05:00:07,640 --> 05:00:11,840 CELL, THE MODIFICATION OF AMPK 6595 05:00:11,840 --> 05:00:15,440 TARGETS AMPK TO THE SURFACE 6596 05:00:15,440 --> 05:00:18,880 WHERE THERE IT ROSS REGULATES 6597 05:00:18,880 --> 05:00:21,560 AND THIS PATHWAY IS DISRUPTED IN 6598 05:00:21,560 --> 05:00:25,960 THE RAC4 T-CELL AND AMPK IS NO 6599 05:00:25,960 --> 05:00:28,600 LONGER AND IT FAILS TO TRAVEL TO 6600 05:00:28,600 --> 05:00:32,720 THE LICE OSEM AND IMPORT ONE 6601 05:00:32,720 --> 05:00:37,600 REMAINS UNOPPOSED EX AMPK NEEDS 6602 05:00:37,600 --> 05:00:42,600 TO BE PROTECTIVE SO IF THE AMPK 6603 05:00:42,600 --> 05:00:45,720 ACTIVATION WE CAN AND REDUCE 6604 05:00:45,720 --> 05:00:48,800 TISSUE AND INFLAMMATION. 6605 05:00:48,800 --> 05:00:52,320 I'LL BRIEFLY SHOW YOU HOW THE 6606 05:00:52,320 --> 05:00:54,120 MITOCHONDRIA TALK TO THE ER HAD 6607 05:00:54,120 --> 05:00:58,280 WE STARTED LOOKING AT SIZE OF ER 6608 05:00:58,280 --> 05:01:01,960 IN THE RA T CELLS WE SAW THAT 6609 05:01:01,960 --> 05:01:05,400 THE RA TELL CELL HAS EXPANSION 6610 05:01:05,400 --> 05:01:07,560 OF THE ER AND THE EXPANSION OF 6611 05:01:07,560 --> 05:01:12,520 THE ER IS INVERSELY RELATED TO 6612 05:01:12,520 --> 05:01:15,640 THE ACTIVITY OF THE MITOCHONDRIA 6613 05:01:15,640 --> 05:01:18,000 AND BY PLUCKING MITOCHONDRIA 6614 05:01:18,000 --> 05:01:22,960 ACTIVITY WE CAN PAN THE E.R. 6615 05:01:22,960 --> 05:01:24,880 MEMBRANE AND IT'S MOSTLY AN 6616 05:01:24,880 --> 05:01:26,640 EXPANSION OF THE ROUGH ER AS YOU 6617 05:01:26,640 --> 05:01:29,240 SEE HERE WHEN WE PRUNE DOWN THE 6618 05:01:29,240 --> 05:01:32,480 E.R. IT'S THE ROUGH E.R. THAT IS 6619 05:01:32,480 --> 05:01:32,880 EXPANDED. 6620 05:01:32,880 --> 05:01:37,200 WHY IS THE ROUGH E.R. EXPANDED? 6621 05:01:37,200 --> 05:01:40,520 THE MITOCHONDRIA IS NOT 6622 05:01:40,520 --> 05:01:43,160 PRODUCING ENOUGH AND ENOUGH 6623 05:01:43,160 --> 05:01:45,560 ASPER TATE SO IF YOU GO INTO THE 6624 05:01:45,560 --> 05:01:49,200 RA T-CELL YOU SEE THAT ASPER 6625 05:01:49,200 --> 05:01:54,840 TATE LEVELS ARE REDUCED TO ABOUT 6626 05:01:54,840 --> 05:02:01,920 50% AND THIS LEADS TO THE CUTEL 6627 05:02:01,920 --> 05:02:09,320 AND TO RESTORE THE NADP POOL AND 6628 05:02:09,320 --> 05:02:10,880 IT'S THAT TRUE IS THAT 6629 05:02:10,880 --> 05:02:11,800 IMPORTANT? 6630 05:02:11,800 --> 05:02:14,440 BECAUSE IF WE GO INTO THE MOUSE 6631 05:02:14,440 --> 05:02:17,240 AND THREE THE MOUSE WITH ASPER 6632 05:02:17,240 --> 05:02:21,000 TATE YOU SEE THAT WE HAVE A VERY 6633 05:02:21,000 --> 05:02:23,480 NICE ANTIINFLAMMATORY EFFECT. 6634 05:02:23,480 --> 05:02:24,200 WHY? 6635 05:02:24,200 --> 05:02:28,480 BECAUSE THE E.R. ON THE SURFACE 6636 05:02:28,480 --> 05:02:29,680 HINDS RYAN OWE TOMES AND DEMANDS 6637 05:02:29,680 --> 05:02:31,720 THESE BE BROUGHT AND THERE'S 6638 05:02:31,720 --> 05:02:34,800 ENRICH. 6639 05:02:34,800 --> 05:02:45,200 FOR THE SO WHEN THE E.R. 6640 05:02:48,400 --> 05:02:52,000 MEMBRANE EXPANDS, THERE IS MORE 6641 05:02:52,000 --> 05:02:59,160 PRODUCED AND THAT IS SHOWN HERE 6642 05:02:59,160 --> 05:03:00,840 AND TD14. 6643 05:03:00,840 --> 05:03:03,840 SO, IN A NUTSHELL, MITOCHONDRIA 6644 05:03:03,840 --> 05:03:08,960 AND THE ROUGH ER AND THE 6645 05:03:08,960 --> 05:03:18,360 LYSOZOME ARE THESE PATIENTS HAVE 6646 05:03:18,360 --> 05:03:28,720 BEEN A VERY NICE MODEL AND HOW 6647 05:03:28,720 --> 05:03:30,000 IT CAUSES A SCENE. 6648 05:03:30,000 --> 05:03:32,320 I THINK I WILL STOP HERE AND 6649 05:03:32,320 --> 05:03:39,280 GIVE ME A MINUTE. 6650 05:03:39,280 --> 05:03:42,280 I'M ALREADY OVER TIME. 6651 05:03:42,280 --> 05:03:48,040 SO LET ME SHOW YOU WHO IS DOING 6652 05:03:48,040 --> 05:03:57,960 THE WORK. 6653 05:03:57,960 --> 05:03:59,600 THEY HELPED US FIND THESE 6654 05:03:59,600 --> 05:04:00,800 PATIENTS AND BECAUSE WE DO NOT 6655 05:04:00,800 --> 05:04:03,800 HAVE DONE IT AND IN THE TODAY 6656 05:04:03,800 --> 05:04:11,240 IT'S REALLY THREE NIH INSTITUTES 6657 05:04:11,240 --> 05:04:17,160 THAT CONTRIBUTE TODAY THIS WORK. 6658 05:04:17,160 --> 05:04:27,560 >>THANK YOU, VERY MUCH. 6659 05:04:32,560 --> 05:04:34,480 YOU HAVE THE AGE CELLS OR AIM 6660 05:04:34,480 --> 05:04:36,360 MISSING SOMETHING? 6661 05:04:36,360 --> 05:04:41,960 >>WELL, WE SEE THIS H PHONE OWE 6662 05:04:41,960 --> 05:04:45,440 TYPE IN A AND A E CELL AND WE 6663 05:04:45,440 --> 05:04:49,440 SEE APPROXIMATE PRONOUNCED 6664 05:04:49,440 --> 05:04:50,600 DIFFERENT BETWEEN THE NAIVE 6665 05:04:50,600 --> 05:04:53,720 YOUNG AND THE NAIVE OLD AND THE 6666 05:04:53,720 --> 05:04:57,160 NAIVE RA CELL AND WITH THE OLD 6667 05:04:57,160 --> 05:05:01,640 AND NAIVE AND THE OLD RA BEING 6668 05:05:01,640 --> 05:05:05,000 PRETTY SIMILAR TO EACH OTHER. 6669 05:05:05,000 --> 05:05:06,200 >>THEY ARE EVEN UNIFIED. 6670 05:05:06,200 --> 05:05:06,640 >>YES. 6671 05:05:06,640 --> 05:05:08,480 >>BECAUSE WHEN YOU ACTIVATE 6672 05:05:08,480 --> 05:05:10,400 THEY DON'T LOSE RA PLUS RIGHT 6673 05:05:10,400 --> 05:05:11,880 AWAY. 6674 05:05:11,880 --> 05:05:14,240 SO, THEY ARE NOT EYE THIEF AND 6675 05:05:14,240 --> 05:05:15,080 THE NEUROLOGICAL SENSE. 6676 05:05:15,080 --> 05:05:16,920 >>THAT'S TRUE. 6677 05:05:16,920 --> 05:05:17,480 >>THANK YOU. 6678 05:05:17,480 --> 05:05:20,320 >>SO IS THE OLD NAIVE CELLS. 6679 05:05:20,320 --> 05:05:30,880 IT'S NO LONGER AS NAIVE, RIGHT. 6680 05:05:36,400 --> 05:05:38,600 WE CANNOT SEE THAT IN THE 6681 05:05:38,600 --> 05:05:39,000 TRANSCRIPT. 6682 05:05:39,000 --> 05:05:41,840 YOU HAVE TO LOOK UNDER MEMBRANE 6683 05:05:41,840 --> 05:05:42,520 OF THE E.R. 6684 05:05:42,520 --> 05:05:45,920 >>THANK YOU. 6685 05:05:45,920 --> 05:05:56,440 >>OUR LAST SPEAKER IS DAVID. 6686 05:06:11,040 --> 05:06:13,120 >>GOOD AFTERNOON, EVERYBODY, 6687 05:06:13,120 --> 05:06:16,920 AND I HOPE YOU STICK AROUND AND 6688 05:06:16,920 --> 05:06:18,960 ARE STILL AWAKE. 6689 05:06:18,960 --> 05:06:21,320 IT'S BEEN A LONG AFTERNOON. 6690 05:06:21,320 --> 05:06:23,520 I'M REALLY PLEASED TO BE HERE 6691 05:06:23,520 --> 05:06:25,560 BACK AT THE NIAD AND THANK YOU 6692 05:06:25,560 --> 05:06:27,000 FOR PUTTING TOGETHER THIS 6693 05:06:27,000 --> 05:06:30,760 AMAZING WORKSHOP AND REALLY 6694 05:06:30,760 --> 05:06:33,240 STELLAR AND THEY SEE SO MANY 6695 05:06:33,240 --> 05:06:35,320 BASIS EX IT'S GO AHEAD TO BE 6696 05:06:35,320 --> 05:06:38,320 BACK AND I'M GOING TO TALK ABOUT 6697 05:06:38,320 --> 05:06:43,160 CLINICAL RELEVANCE OF THE CLOCKS 6698 05:06:43,160 --> 05:06:44,760 THAT WE'RE BUILDING USING FOR 6699 05:06:44,760 --> 05:06:47,360 THE MOST PART HUMAN BEINGS. 6700 05:06:47,360 --> 05:06:48,680 SOME OF THE DISCLOSURES ARE 6701 05:06:48,680 --> 05:06:51,240 THERE AND I'M GOING TO 6702 05:06:51,240 --> 05:06:54,640 SCHOLARSHIP THROUGH THIS TO 6703 05:06:54,640 --> 05:06:56,640 COVER THIS SESSION. 6704 05:06:56,640 --> 05:07:00,400 24 WAS PUBLISHED IN MARK AND IN 6705 05:07:00,400 --> 05:07:02,200 20717 AND PUTTING TOGETHER THE 6706 05:07:02,200 --> 05:07:03,640 IDEA THAT IMMUNE LOGICAL HEALTH 6707 05:07:03,640 --> 05:07:07,280 IS IMPORTANT FOR OTHER ASPECTS 6708 05:07:07,280 --> 05:07:11,840 OF AGING AND NOT JUST UM UNION 6709 05:07:11,840 --> 05:07:15,800 AND AGING BUT OTHERS AND ONE 6710 05:07:15,800 --> 05:07:19,280 ASPECT OF AGING, THAT IS 6711 05:07:19,280 --> 05:07:21,520 PARTICULARLY TO A IMMUNE SIS TO 6712 05:07:21,520 --> 05:07:26,000 IS THE AGING AND MANY OF YOU 6713 05:07:26,000 --> 05:07:27,640 HAVE SEEN TALKS RELATED TO 6714 05:07:27,640 --> 05:07:28,720 CHRONIC INFORMATION AND IT'S 6715 05:07:28,720 --> 05:07:30,040 IMPORTANT TO NOTICE THAT THIS 6716 05:07:30,040 --> 05:07:31,400 VERY DIFFERENT FROM ACUTE 6717 05:07:31,400 --> 05:07:35,480 INFORMATION AND I THINK THAT 6718 05:07:35,480 --> 05:07:38,680 THERE'S NO GOOD CONSENSUS AS TO 6719 05:07:38,680 --> 05:07:42,440 WHAT REALLY THIS TYPE OF 6720 05:07:42,440 --> 05:07:45,120 INFLAMMATORY RESPONSES SO AS 6721 05:07:45,120 --> 05:07:48,240 PART OF THE PROJECT THAT WE 6722 05:07:48,240 --> 05:07:50,160 STARTED IN 2007, IN WHICH WE 6723 05:07:50,160 --> 05:07:54,160 COLLECTED SIM POLLS FROM A 6724 05:07:54,160 --> 05:07:57,400 THOUSAND PEOPLE, A FRACTION WERE 6725 05:07:57,400 --> 05:07:58,800 PROVIDED BOTH FOR 13 YEARS NOW 6726 05:07:58,800 --> 05:08:02,640 AND SECURE THE FUNDING AND NO 6727 05:08:02,640 --> 05:08:04,280 NIH AND AND TO CONTINUE THIS 6728 05:08:04,280 --> 05:08:06,160 STUDY FOR THE NEXT FIVE YEARS 6729 05:08:06,160 --> 05:08:10,840 AND RECENTLY AND WE FOCUS ON 6730 05:08:10,840 --> 05:08:12,360 SYSTEMIC INFORMATION BUT REALLY 6731 05:08:12,360 --> 05:08:16,320 WE LOOK AT MANY DIFFERENT 6732 05:08:16,320 --> 05:08:23,920 ASPECTS OF IMMUNITY AND WE'RE 6733 05:08:23,920 --> 05:08:29,520 LOOKING AT A THOUSAND AND THE 6734 05:08:29,520 --> 05:08:31,520 THE FIRST STORY WE SUCCESSFULLY 6735 05:08:31,520 --> 05:08:35,040 PUT TOGETHER WAS IDENTIFIED 6736 05:08:35,040 --> 05:08:39,440 INFLAM OZONE WHICH IS KNOWN FOR 6737 05:08:39,440 --> 05:08:44,520 RECOGNIZING BACTERIAL FROM 6738 05:08:44,520 --> 05:08:47,240 GELLEN FOUND IN INDIVIDUALS THAT 6739 05:08:47,240 --> 05:08:48,120 ARE INFLAMED AND THEY SUFFER 6740 05:08:48,120 --> 05:08:51,400 FROM A NUMBER OF CARDIOVASCULAR 6741 05:08:51,400 --> 05:08:54,320 CONDITIONS AND THOSE DEATH AND 6742 05:08:54,320 --> 05:08:57,040 IN THE FOLLOW-UP LONGITUDINAL 6743 05:08:57,040 --> 05:08:58,680 STUDY THAT WE DID IN THAT 6744 05:08:58,680 --> 05:09:00,560 FRACTION OF INDIVIDUALS. 6745 05:09:00,560 --> 05:09:04,160 MORE UNBIASED, WE BUILD A DEEP 6746 05:09:04,160 --> 05:09:06,360 NEURO NETWORK TO CREATE WHAT WE 6747 05:09:06,360 --> 05:09:08,200 CALL INFLAMMATORY AGE USING A 6748 05:09:08,200 --> 05:09:11,840 THOUSAND INDIVIDUALS IN THE 6749 05:09:11,840 --> 05:09:13,480 STUDY AND THE TYPE OF APPROACH 6750 05:09:13,480 --> 05:09:17,400 WE DID IS NOT JUST A TYPICAL 6751 05:09:17,400 --> 05:09:19,400 DEEP LEARNING APPROACH, IN THIS 6752 05:09:19,400 --> 05:09:22,600 CASE WE'RE TRYING TO PREDICT 6753 05:09:22,600 --> 05:09:23,960 CHRONOLOGICAL AGE AND AT THE 6754 05:09:23,960 --> 05:09:27,480 TIME, IN PARALLEL, 6755 05:09:27,480 --> 05:09:28,680 RECONSTRUCTION THE SITE OWE KEEN 6756 05:09:28,680 --> 05:09:30,640 DATA AND IT'S CLOSEST TO 6757 05:09:30,640 --> 05:09:33,120 INFLAMMATORY AGE AND YOU CAN SEE 6758 05:09:33,120 --> 05:09:36,160 THE LOSS FUNCTION THERE AND SO 6759 05:09:36,160 --> 05:09:38,120 WHEN WE BUILD A EDGE FLAM TORI 6760 05:09:38,120 --> 05:09:40,640 AGE CLOCK WE START LOOKING AT 6761 05:09:40,640 --> 05:09:43,240 DIFFERENT MORBIDITIES AND THINGS 6762 05:09:43,240 --> 05:09:48,800 LIKE THAT AND IT DID CORRELATEEL 6763 05:09:48,800 --> 05:09:49,880 SIGNIFICANTLY WITH MULTI 6764 05:09:49,880 --> 05:09:51,640 MORBIDITY AS SHOWN IN THIS FIRST 6765 05:09:51,640 --> 05:09:51,840 BLOCK. 6766 05:09:51,840 --> 05:09:54,600 WE COULD PREDICT QUALITY IN 6767 05:09:54,600 --> 05:10:01,840 INDIVIDUALS OVER 75 YEARS OF AGE 6768 05:10:01,840 --> 05:10:12,360 AND THEIR PROTECTS INTERESTED 6769 05:10:26,400 --> 05:10:27,720 THIS TYPE OF INFLAMMATORY 6770 05:10:27,720 --> 05:10:29,800 RESPONSE AND THIS SHOW HERE, 6771 05:10:29,800 --> 05:10:31,520 THIS I'M POINTING WITH MY CURSOR 6772 05:10:31,520 --> 05:10:35,960 THAT OVER ALL, INDIVIDUALS WITH 6773 05:10:35,960 --> 05:10:37,760 HIGH INFLAMMATORY AGE HAS LOW 6774 05:10:37,760 --> 05:10:40,000 RESPONSES TO MULTI EX VIVO SO 6775 05:10:40,000 --> 05:10:43,880 THE IMMUNE HEALTH OF THOSE IS 6776 05:10:43,880 --> 05:10:45,800 COMPROMISED AND WE DO GENE 6777 05:10:45,800 --> 05:10:47,560 EXPRESSION OF INFLAMMATORY AGE 6778 05:10:47,560 --> 05:10:49,440 TO GO TO THE PUBLIC DOMAIN AND 6779 05:10:49,440 --> 05:10:51,640 ASKED THE QUESTION IS THIS A 6780 05:10:51,640 --> 05:10:53,840 CLINICAL OR RELEVANCE IN OTHER 6781 05:10:53,840 --> 05:10:56,520 TYPES OF COHORTS AND YES WE CAN 6782 05:10:56,520 --> 05:11:00,640 PREDICT MORTALITY IN THE 6783 05:11:00,640 --> 05:11:03,760 FRAMING. 6784 05:11:03,760 --> 05:11:06,840 SO GOING FORWARD WE WANTED TO 6785 05:11:06,840 --> 05:11:11,600 DEVELOP INTERVENTIONS FOR IN 6786 05:11:11,600 --> 05:11:13,840 FLAM TORI AGE WE BUILT AN ATLAS 6787 05:11:13,840 --> 05:11:17,120 FOR IN FLAM TORI MODULATORS AND 6788 05:11:17,120 --> 05:11:18,440 WE TUFTED SOME OF THESE THINGS 6789 05:11:18,440 --> 05:11:23,560 WITH A CORPORATE PARTNER IN WE 6790 05:11:23,560 --> 05:11:25,840 SHOWED IN THE EXPERIMENTAL GROUP 6791 05:11:25,840 --> 05:11:27,480 WE INCREASE INFLAMMATORY AGE AS 6792 05:11:27,480 --> 05:11:33,080 WELL AS PROTEIN TAX AND IT'S 6793 05:11:33,080 --> 05:11:41,360 TYPICALLY KNOWN AS ASSOCIATED 6794 05:11:41,360 --> 05:11:43,280 WITH DRAINAGE SO WE'RE NOW 6795 05:11:43,280 --> 05:11:45,400 ANALYZING THE DATA FROM A MUCH 6796 05:11:45,400 --> 05:11:50,160 LARGER STUDY ALSO DOUBLE BLINDED 6797 05:11:50,160 --> 05:11:50,960 PRACTICE TEAGUE OWE CONTROL IN A 6798 05:11:50,960 --> 05:11:54,320 THOUSAND PEOPLE AS PART OF THIS 6799 05:11:54,320 --> 05:11:54,720 EFFORTS. 6800 05:11:54,720 --> 05:11:56,800 I WANTED TO POINT OUT IT'S 6801 05:11:56,800 --> 05:11:59,040 REALLY IMPORTANT SO THIS PAPER 6802 05:11:59,040 --> 05:12:01,520 WILL PUBLISH WITH MARK DAVIS AS 6803 05:12:01,520 --> 05:12:05,640 WELL AND IN 2019 AND SHOWS THAT 6804 05:12:05,640 --> 05:12:14,960 INDIVIDUAL VARIATIONS IF WE WERE 6805 05:12:14,960 --> 05:12:16,560 NOT TO SEPARATE INDIVIDUALS 6806 05:12:16,560 --> 05:12:18,560 BASED ON THEIR PROJECTORY SO 6807 05:12:18,560 --> 05:12:20,240 THERE'S A POPULATION BASE EFFECT 6808 05:12:20,240 --> 05:12:22,040 OF AGING THAT WE HAVE OUTLIERS 6809 05:12:22,040 --> 05:12:23,600 THAT HAVE DIFFERENT RATES OF 6810 05:12:23,600 --> 05:12:25,280 AGING AND THOSE RATES OF EDGING 6811 05:12:25,280 --> 05:12:29,120 ARE LARGELY DUE TO THE IMMUNE 6812 05:12:29,120 --> 05:12:30,160 SYSTEM BEHAVES AND THIS SECOND 6813 05:12:30,160 --> 05:12:35,000 PAPER I'M SHOWING YOU HERE, WE 6814 05:12:35,000 --> 05:12:35,720 BUILD CLOCKS. 6815 05:12:35,720 --> 05:12:41,520 WE DO LIKE FOR A LIVING. 6816 05:12:41,520 --> 05:12:44,560 AND, I'M SHOWING YOU A NEW CLUB 6817 05:12:44,560 --> 05:12:46,120 EXTRUDING AND YOU SEE THE 6818 05:12:46,120 --> 05:12:48,320 POPULATION TREND AND THE 6819 05:12:48,320 --> 05:12:51,600 INDIVIDUAL RATES THAT SHALL 6820 05:12:51,600 --> 05:12:52,440 REMARKABLY DIFFERENT AND 6821 05:12:52,440 --> 05:12:53,960 DIFFERENT INDIVIDUALS AND THAT 6822 05:12:53,960 --> 05:12:58,400 ACTUALLY PREDICTS THE HEART 6823 05:12:58,400 --> 05:13:00,400 FAILURE AND AND INJECTION 6824 05:13:00,400 --> 05:13:02,000 PROTECTION IN THIS STUDY AND IT 6825 05:13:02,000 --> 05:13:05,280 DOES HAVE A CLINICAL IMPORTANCE 6826 05:13:05,280 --> 05:13:13,240 AND NOT YET ANOTHER CLOCK AND WE 6827 05:13:13,240 --> 05:13:16,200 PUBLISHED LAST YEAR AND 6828 05:13:16,200 --> 05:13:17,640 INTERESTING BECAUSE BRAIN AGING 6829 05:13:17,640 --> 05:13:20,840 DOES NOT MOSTLY RELATED WITH 6830 05:13:20,840 --> 05:13:24,760 AGING AND BUT WE LOOKED AT THE 6831 05:13:24,760 --> 05:13:26,400 PARTICULAR WAY THAT CYTOKINE IN 6832 05:13:26,400 --> 05:13:28,200 BLOOD BECAUSE IT'S A COMPLETELY 6833 05:13:28,200 --> 05:13:31,520 SEPARATE STUDY WE DID IN 6834 05:13:31,520 --> 05:13:32,800 COLLABORATION WITH JOEL KRAMER 6835 05:13:32,800 --> 05:13:34,640 AT UCSF AND THE AGE EFFECT IS 6836 05:13:34,640 --> 05:13:37,920 SHOWN HERE, NOTHING NOVEL HERE, 6837 05:13:37,920 --> 05:13:39,360 IT WAS REALLY INTERESTING 6838 05:13:39,360 --> 05:13:41,280 BECAUSE WOMEN TEND TO HAVE A 6839 05:13:41,280 --> 05:13:44,880 BETTER EXECUTIVE FUNCTION SO 6840 05:13:44,880 --> 05:13:48,560 THIS IS SOMETHING I THINK REALLY 6841 05:13:48,560 --> 05:13:50,120 NOVEL AND IT WAS START TO BE 6842 05:13:50,120 --> 05:13:52,120 PRETTY SIMILAR IN MULTIPLE 6843 05:13:52,120 --> 05:13:56,440 STUDIES NOW WE'RE SHOWING THAT 6844 05:13:56,440 --> 05:13:57,520 WOMEN ARE DOING BETTER AND IT 6845 05:13:57,520 --> 05:14:00,960 HAS AN EFFECT ON A NETWORK OF 6846 05:14:00,960 --> 05:14:03,920 BRAIN FUNCTION WHICH IS RELATED 6847 05:14:03,920 --> 05:14:05,800 HOW WE GRASP THINGS WE REACH 6848 05:14:05,800 --> 05:14:10,360 THINGS WHICH IS THE DEFAULT MODE 6849 05:14:10,360 --> 05:14:11,600 NETWORK AND WE THINK OURSELVES 6850 05:14:11,600 --> 05:14:13,440 IN THE PAST OR THE FUTURE WE'RE 6851 05:14:13,440 --> 05:14:16,040 USING THAT NETWORK AND THAT'S 6852 05:14:16,040 --> 05:14:20,040 ASSOCIATED WITH INCREASING 6853 05:14:20,040 --> 05:14:21,240 INDIKE LOW SO WE HAVE LOON BEING 6854 05:14:21,240 --> 05:14:25,800 LIKE AT AGING IN MICE WE'RE 6855 05:14:25,800 --> 05:14:27,760 BUILDING CLOCKS FOR TISSUE AND 6856 05:14:27,760 --> 05:14:29,280 BONE, BRAIN, FAT, LUNG AND I 6857 05:14:29,280 --> 05:14:31,520 KNOW ALL THIS IS IN MICE AND WE 6858 05:14:31,520 --> 05:14:34,040 WERE INTERESTED IN THE BRAIN AND 6859 05:14:34,040 --> 05:14:38,280 YOU SEE IN THE SLIDES IS THE 6860 05:14:38,280 --> 05:14:41,720 TRANSCRIPT DOME I CAN AGE OF THE 6861 05:14:41,720 --> 05:14:45,000 BRAIN AND CORRELATED WITH 6862 05:14:45,000 --> 05:14:47,240 CHRONOLOGICAL AGE AND IN THE 6863 05:14:47,240 --> 05:14:48,280 RIGHT-HAND SIDE OF THE SLIDE, 6864 05:14:48,280 --> 05:14:53,200 YOU CAN SEE THE MICE THESE ARE 6865 05:14:53,200 --> 05:14:56,360 MUTATIONS THAT IS A MODEL FOR. 6866 05:14:56,360 --> 05:15:00,200 >>Al: DISEASE WITH AMYLOID 6867 05:15:00,200 --> 05:15:01,600 ALTERATIONS OR PLAQUES AND YOU 6868 05:15:01,600 --> 05:15:06,440 CAN SEE THAT THE MICE HAVE A 6869 05:15:06,440 --> 05:15:09,760 MASSIVE OF THE CLOTHE AS 6870 05:15:09,760 --> 05:15:15,160 COMPARED TO THE NORMAL MICE AND 6871 05:15:15,160 --> 05:15:16,840 WHAT YOU SEE ON THE LEFT-HAND 6872 05:15:16,840 --> 05:15:18,840 SIDE IS A CORRELATION WITH AGING 6873 05:15:18,840 --> 05:15:21,120 HUMANS AND THE Y IS CORRELATION 6874 05:15:21,120 --> 05:15:24,840 WITH AGE IN MICE AND IN THE X 6875 05:15:24,840 --> 05:15:26,080 AXIS OF THE MOST SIGNIFICANT 6876 05:15:26,080 --> 05:15:28,600 GENES THAT ARE PART OF THIS 6877 05:15:28,600 --> 05:15:32,920 BRAIN AGING PLOT AND THEY WERE 6878 05:15:32,920 --> 05:15:36,560 TWO MAJOR CONTRIBUTORS TO THIS 6879 05:15:36,560 --> 05:15:40,880 CLOCK AND THEY'RE ALL ELEVATED 6880 05:15:40,880 --> 05:15:45,200 IN ALL DIFFERENT WITH NORMAL 6881 05:15:45,200 --> 05:15:46,840 AGING AND HUMANS. 6882 05:15:46,840 --> 05:15:49,400 SO WE THEN WEPT AHEAD AND DID 6883 05:15:49,400 --> 05:15:50,720 SOMETHING SIMILAR TO WHAT WE'VE 6884 05:15:50,720 --> 05:15:57,520 DONE BEFORE FOR TH THAT CAN REVE 6885 05:15:57,520 --> 05:16:02,680 THE SIGNATURES FOR TESTING THEM 6886 05:16:02,680 --> 05:16:04,160 IN ORGANIZE AN SYSTEMS. 6887 05:16:04,160 --> 05:16:05,440 I'M GOING TO SWITCH GEARS AND 6888 05:16:05,440 --> 05:16:06,680 TELL YOU ABOUT A RELATIONSHIP I 6889 05:16:06,680 --> 05:16:10,400 HAVE THAT WITH SUZANNE. 6890 05:16:10,400 --> 05:16:13,040 SHE USED TO BE AT NASA IN THE 6891 05:16:13,040 --> 05:16:16,440 RUMINA AN RESOURCE PROGRAMME IN 6892 05:16:16,440 --> 05:16:18,520 HOUSTON AND SHE REACHED OUT TO 6893 05:16:18,520 --> 05:16:20,280 ME TWO AND A HALF YEARS AGO AND 6894 05:16:20,280 --> 05:16:21,440 SAID YOU ARE RESEARCH IS 6895 05:16:21,440 --> 05:16:22,880 IMPORTANT FOR US BECAUSE WE'RE 6896 05:16:22,880 --> 05:16:24,440 TRYING TO DEVELOP COUNTER 6897 05:16:24,440 --> 05:16:26,000 MEASURES FOR THE STATES RELATED 6898 05:16:26,000 --> 05:16:27,200 RISK WHICH SEEMS TO BE 6899 05:16:27,200 --> 05:16:29,880 ASSOCIATED WITH AGING. 6900 05:16:29,880 --> 05:16:31,800 WE HAVE THIS ACCELERATED AGING 6901 05:16:31,800 --> 05:16:34,160 IN ASTRONAUTS AND IT'S 6902 05:16:34,160 --> 05:16:35,520 INFLAMMATION OR AGING AND SO 6903 05:16:35,520 --> 05:16:37,520 THAT'S STARTED A WHOLE 6904 05:16:37,520 --> 05:16:40,120 CONVERSATION WITH SUZIE AND I 6905 05:16:40,120 --> 05:16:41,600 REALISED SHE WAS REALLY PASSING 6906 05:16:41,600 --> 05:16:45,800 THE TORCH SAYS SHE HAD TERMINAL 6907 05:16:45,800 --> 05:16:47,480 CANCER AND I GOT TO KNOW HER 6908 05:16:47,480 --> 05:16:49,600 FAMILY AND WE WERE BECAME GOOD 6909 05:16:49,600 --> 05:16:51,160 FRIENDS AND SHE PASSED AWAY IN 6910 05:16:51,160 --> 05:16:52,840 DECEMBER OF LAST YEAR BUT WE 6911 05:16:52,840 --> 05:16:54,280 WERE ASKING THIS QUESTION MANY, 6912 05:16:54,280 --> 05:16:57,440 MANY TIMES AS TO THE SAME 6913 05:16:57,440 --> 05:16:59,760 QUESTION THAT WAS POSED IN 6914 05:16:59,760 --> 05:17:04,800 PRINCETON IN 1969 TO HIS 6915 05:17:04,800 --> 05:17:05,240 STUDENTS. 6916 05:17:05,240 --> 05:17:07,440 HE ASKED THE QUESTION, IS THE 6917 05:17:07,440 --> 05:17:08,960 PLANETARY SURFACE THE RIGHT 6918 05:17:08,960 --> 05:17:12,880 PLACE FOR EXPANDING 6919 05:17:12,880 --> 05:17:13,240 CIVILIZATION? 6920 05:17:13,240 --> 05:17:14,880 AND OBVIOUSLY THE ANSWER IS NO. 6921 05:17:14,880 --> 05:17:16,560 WE CREATED AS PART OF THIS 6922 05:17:16,560 --> 05:17:17,960 EFFORT THE CONSORTIUM FOR SPACE 6923 05:17:17,960 --> 05:17:20,000 HEATHER AND HUMAN LONGEVITY 6924 05:17:20,000 --> 05:17:21,960 WHICH INTENDS TO FUND RESEARCH 6925 05:17:21,960 --> 05:17:25,200 IN THAT INTERSECTION. 6926 05:17:25,200 --> 05:17:30,680 JUST TO GIVE YOU A ACCELERATED 6927 05:17:30,680 --> 05:17:33,320 AGING YOU CAN SEE DIFFERENT 6928 05:17:33,320 --> 05:17:35,000 PHYSIOLOGICAL MEASUREMENTS AND 6929 05:17:35,000 --> 05:17:36,280 COGNITIVE FUNCTION, MUSCLE SIZE 6930 05:17:36,280 --> 05:17:38,480 AND MASS AND CARDIOVASCULAR 6931 05:17:38,480 --> 05:17:41,440 HEALTH THEY'RE ALL ACCELERATED 6932 05:17:41,440 --> 05:17:44,160 IN SPACE AND ON AVERAGE, THERE'S 6933 05:17:44,160 --> 05:17:45,520 AN EXCEL RACE OF 34. 6934 05:17:45,520 --> 05:17:48,560 FOR EVERY YEAR, SOMEONE SPENT 6935 05:17:48,560 --> 05:17:51,280 YOU WOULD AGE SIMILARLY TO A 30 6936 05:17:51,280 --> 05:17:54,000 YEARS ON THE GROUND AND THINGS 6937 05:17:54,000 --> 05:17:55,520 CAN REVERSE WHEN THEY COME BACK 6938 05:17:55,520 --> 05:17:58,720 TO EARTH AND THEY RETURN. 6939 05:17:58,720 --> 05:18:01,120 BUT IT'S A PARTICULAR RELEVANCE 6940 05:18:01,120 --> 05:18:03,880 THAT WE SEE THIS IMMUNE 6941 05:18:03,880 --> 05:18:05,520 DYSFUNCTION SO THERE ARE 6942 05:18:05,520 --> 05:18:07,960 REACTIVATION OF VIRUSES AND WE 6943 05:18:07,960 --> 05:18:12,200 DO SPACE LIFE AND THERE'S AN 6944 05:18:12,200 --> 05:18:14,000 ENHANCED IMPAIRED FUNCTION AND 6945 05:18:14,000 --> 05:18:19,840 THERE'S A SHIFT FROM TH1 TO TH2 6946 05:18:19,840 --> 05:18:21,960 AND ELEVATED AGING SO WE CREATED 6947 05:18:21,960 --> 05:18:26,080 THIS PIPELINE WHERE WE HAVE A 6948 05:18:26,080 --> 05:18:28,320 SYSTEM TO MEASURE MICRO GRAVITY 6949 05:18:28,320 --> 05:18:31,160 VERSUS SIMULATE MICRO GRAVITY ON 6950 05:18:31,160 --> 05:18:33,480 THE GROUPED AND THAT IS A 6951 05:18:33,480 --> 05:18:35,040 ROTATING VESSEL DESIGNED BY NASA 6952 05:18:35,040 --> 05:18:37,960 AND WE HAVE A SYSTEM IN WHICH WE 6953 05:18:37,960 --> 05:18:42,720 AGE AND IMMUNE ORGANOIDS IN THE 6954 05:18:42,720 --> 05:18:44,640 ROTATING WALL VESSEL AND THIS 6955 05:18:44,640 --> 05:18:46,760 SIMULATED GRAVITY AND YOU CAN 6956 05:18:46,760 --> 05:18:48,800 SEE THAT WITH THIS DISCOLORATION 6957 05:18:48,800 --> 05:18:52,000 AND MARK DATA HERE AS WELL IN 6958 05:18:52,000 --> 05:18:54,640 THE IMMUNE ORGANOIDS WE HAVE 6959 05:18:54,640 --> 05:18:56,160 ORGANOIDS AND THEY'RE BEATING 6960 05:18:56,160 --> 05:18:58,000 AND THEY'RE LARGELY EFFECTED BY 6961 05:18:58,000 --> 05:19:01,600 MICRO GRAVITY AND WE KNOW KNOW 6962 05:19:01,600 --> 05:19:05,360 THAT THE CELLS ARE PLAYING A BIG 6963 05:19:05,360 --> 05:19:08,040 ROLE IN WE CAN TEST THE NEURO 6964 05:19:08,040 --> 05:19:10,320 ORGANOIDS BY LOOKING AT ELECTRO 6965 05:19:10,320 --> 05:19:11,960 PHYSIOLOGY AND HOW IT EFFECTED 6966 05:19:11,960 --> 05:19:16,320 BY MICRO GRAVITY AND WE ALSO 6967 05:19:16,320 --> 05:19:18,000 TEST DIFFERENT SEQUENCING 6968 05:19:18,000 --> 05:19:20,960 METHODS AND WE USED SEQUENCING 6969 05:19:20,960 --> 05:19:23,640 METHODS TO DO OTHER ASSESSMENTS 6970 05:19:23,640 --> 05:19:25,520 AND MOLECULAR ASSESSMENTS AND 6971 05:19:25,520 --> 05:19:27,160 WHERE YOU CAN SEE HERE IS AN 6972 05:19:27,160 --> 05:19:30,840 INCREASE IN INFLAMMATORY AGE AND 6973 05:19:30,840 --> 05:19:34,400 24 HOURS OF SIMULATED MICRO 6974 05:19:34,400 --> 05:19:36,480 GRAVITY INCREASES BY 50% SO 6975 05:19:36,480 --> 05:19:37,360 WE'RE AGING THESE THINGS AND 6976 05:19:37,360 --> 05:19:39,080 WE'RE ADDING COMPOUNDS TO THOSE 6977 05:19:39,080 --> 05:19:41,560 CULTURES TO SEE IF WE CAN 6978 05:19:41,560 --> 05:19:42,840 REVERSE THOSE. 6979 05:19:42,840 --> 05:19:46,960 AND THESE ARE PARTICULARLY 6980 05:19:46,960 --> 05:19:48,880 REALLY STRONG EVIDENCE IN 6981 05:19:48,880 --> 05:19:49,440 MONOCYTES. 6982 05:19:49,440 --> 05:19:59,960 WE USE ALSO SPACE DATA AND MORE 6983 05:20:02,280 --> 05:20:04,360 DATA TO SHOW YOU WE SEE 6984 05:20:04,360 --> 05:20:07,560 REACTIVATION OF VIRUS AND IN 6985 05:20:07,560 --> 05:20:09,800 VITRO AND WE SEE CELLULAR 6986 05:20:09,800 --> 05:20:11,600 SENESCENCE AND THIS IS THE MAYO 6987 05:20:11,600 --> 05:20:14,000 SCORE AND INCREASE IN MIKE GROW 6988 05:20:14,000 --> 05:20:15,840 GRAVITY AND INCREASE IN THE 6989 05:20:15,840 --> 05:20:18,160 CLOTHE AND PREDICTED PACE OF 6990 05:20:18,160 --> 05:20:19,840 AGING AND A DECREASING NEW 6991 05:20:19,840 --> 05:20:26,560 RESPONSE WHEN WE STIMULATE CELLS 6992 05:20:26,560 --> 05:20:37,040 AND WE HAVE A REALLY AMAZING 6993 05:20:43,600 --> 05:20:46,160 EVIDENCE FROM FE WU WHO IS 6994 05:20:46,160 --> 05:20:48,440 SPEARHEADING THIS PROJECT AND HE 6995 05:20:48,440 --> 05:20:50,560 CAN REDUCE THE EFFECT OF MICRO 6996 05:20:50,560 --> 05:20:53,240 GRAVITY SIGNIFICANTLY AFTER 6997 05:20:53,240 --> 05:20:56,480 TREATING THE CELLS WITH THESE 6998 05:20:56,480 --> 05:20:56,920 COMPOUNDS. 6999 05:20:56,920 --> 05:20:59,280 SO WITH THAT I WOULD LIKE TO 7000 05:20:59,280 --> 05:21:00,920 THANK MY MANY COLLABORATORS 7001 05:21:00,920 --> 05:21:07,280 AROUND THE U.S. AND FUNDING. 7002 05:21:07,280 --> 05:21:08,840 WE DO OTHER THINGS RATHER THAN 7003 05:21:08,840 --> 05:21:10,960 SCIENCE AND WE GO SURFING AND 7004 05:21:10,960 --> 05:21:12,520 PARTY AND WE GROW WATERMELON. 7005 05:21:12,520 --> 05:21:18,720 THANK YOU SO MUCH. 7006 05:21:18,720 --> 05:21:19,800 >>THANK YOU, DAVID. 7007 05:21:19,800 --> 05:21:22,000 MAYBE I CAN ASK A GENERAL 7008 05:21:22,000 --> 05:21:22,400 QUESTION. 7009 05:21:22,400 --> 05:21:24,200 I MEAN, THERE ARE SO MANY CLOCKS 7010 05:21:24,200 --> 05:21:28,240 IN THE FIELD AS YOU KNOW, AIMING 7011 05:21:28,240 --> 05:21:30,000 FIELDS AND EVERYBODY PREDICTS 7012 05:21:30,000 --> 05:21:31,800 MORTALITY AND BIOLOGICAL AGE SO 7013 05:21:31,800 --> 05:21:34,600 IT'S GREAT TO SEE IT'S A CLOCK 7014 05:21:34,600 --> 05:21:35,960 YOU HAVE BASED ON BIOLOGY AND 7015 05:21:35,960 --> 05:21:39,840 HOW MUCH OF THIS CORRELATES WITH 7016 05:21:39,840 --> 05:21:41,320 THE NEGATIVE OUTCOMES THAT 7017 05:21:41,320 --> 05:21:44,240 PEOPLE ARE TALKING ABOUT IN 7018 05:21:44,240 --> 05:21:48,200 TERMS OF AGE REVERSAL AND DO YOU 7019 05:21:48,200 --> 05:21:51,920 SEE THE THINGS THAT YOU HAVE 7020 05:21:51,920 --> 05:21:56,520 DESCRIBED IN THE IMMUNAL CLOCK. 7021 05:21:56,520 --> 05:21:58,160 DO OTHER INTERVENTIONS IN MOUSE 7022 05:21:58,160 --> 05:22:00,760 WHICH INCREASES LIFESPAN ARE 7023 05:22:00,760 --> 05:22:04,720 THEY IMPACTED BY THAT? 7024 05:22:04,720 --> 05:22:07,200 >> 7025 05:22:07,200 --> 05:22:08,680 >>THAT'S A LOADED QUESTION. 7026 05:22:08,680 --> 05:22:12,280 I COULD STAY THAT WE DO SEE 7027 05:22:12,280 --> 05:22:15,480 EARLY SIGNS INTERVENTION WHEN 7028 05:22:15,480 --> 05:22:19,040 YOU TREAT A GROUP OF INDIVIDUALS 7029 05:22:19,040 --> 05:22:22,000 IN THE IH WE ALSO SEE 7030 05:22:22,000 --> 05:22:23,800 MODIFICATIONS AT THE PROTEIN 7031 05:22:23,800 --> 05:22:25,600 LEVEL AND WHETHER OR NOT THAT 7032 05:22:25,600 --> 05:22:28,800 TRANSLATES INTO IMPROVEMENT OF 7033 05:22:28,800 --> 05:22:31,040 OUTCOMES, WE HAVE YET TO ANALYZE 7034 05:22:31,040 --> 05:22:32,840 THE DATA FROM THE 1,000 7035 05:22:32,840 --> 05:22:34,160 INDIVIDUALS THAT WE'RE RUNNING 7036 05:22:34,160 --> 05:22:35,480 AND THAT STUDY. 7037 05:22:35,480 --> 05:22:39,280 WE HAVEN'T DONE ANY MOUSE 7038 05:22:39,280 --> 05:22:40,000 EXPERIMENTS TO TWEAK 7039 05:22:40,000 --> 05:22:43,360 INFLAMMATORY AGE OF THIS OTHER 7040 05:22:43,360 --> 05:22:44,920 CLOCKS. 7041 05:22:44,920 --> 05:22:49,160 BUT THEY'RE ALL GOOD THING. 7042 05:22:49,160 --> 05:22:51,080 >>I WAS GOING TO ASK A QUESTION 7043 05:22:51,080 --> 05:22:53,360 THAT JUST POPPED UP ON THE CHAT. 7044 05:22:53,360 --> 05:22:55,000 WHICH FOR SPACE TRAVEL, WHAT 7045 05:22:55,000 --> 05:22:57,240 DOES RADIATION DO TO THIS AND DO 7046 05:22:57,240 --> 05:23:02,320 YOU HAVE A RADIATION COMPONENT 7047 05:23:02,320 --> 05:23:05,200 IN YOUR ORGANOID CENTRE FUGE IN 7048 05:23:05,200 --> 05:23:06,440 CALIFORNIA OR WHERE IT IS? 7049 05:23:06,440 --> 05:23:11,120 >>YEAH, SO, IF YOU STAY WITHIN 7050 05:23:11,120 --> 05:23:13,000 THE LOWER ORBIT, RADIATION IS 7051 05:23:13,000 --> 05:23:15,120 NOT A BIG DEAL. 7052 05:23:15,120 --> 05:23:16,200 WE'RE VERY MUCH PARTICULAR. 7053 05:23:16,200 --> 05:23:17,720 IF YOU GO ABOVE AND BEYOND TO 7054 05:23:17,720 --> 05:23:21,360 THE MOON AND MARS, THERE ARE 7055 05:23:21,360 --> 05:23:25,400 HEAVY PARTICLES, SHOWERS OF 7056 05:23:25,400 --> 05:23:27,800 PARTICLES THAT WILL BE AFTER AND 7057 05:23:27,800 --> 05:23:31,120 SO ON AND WE HAVE WITH NASA AND 7058 05:23:31,120 --> 05:23:34,280 WHERE WE'RE SPENDING ORGANOIDS 7059 05:23:34,280 --> 05:23:36,520 THROUGH THE NATIONAL LAB TO 7060 05:23:36,520 --> 05:23:37,960 SIMULATE THE RADIATION SO WE 7061 05:23:37,960 --> 05:23:40,240 HAVE THAT COMPONENT AND IT'S 7062 05:23:40,240 --> 05:23:41,920 JUST STARTING. 7063 05:23:41,920 --> 05:23:43,840 THE MAIN FOCUS AT THE MOMENT IS 7064 05:23:43,840 --> 05:23:45,720 MICRO GRAVITY. 7065 05:23:45,720 --> 05:23:47,760 >>IS THERE A DAMAGE RESPONSE A 7066 05:23:47,760 --> 05:23:48,320 IMPORTANT PART OF THAT. 7067 05:23:48,320 --> 05:23:50,240 >>IT'S EVERYTHING, RIGHT. 7068 05:23:50,240 --> 05:23:51,840 AND YOU HAVE DAMAGE RESPONSE. 7069 05:23:51,840 --> 05:23:54,200 WE'RE NOW TRYING TO FIND 7070 05:23:54,200 --> 05:23:55,960 PREDICTORS OF THE DAMAGE SO WE 7071 05:23:55,960 --> 05:23:59,080 HAVE ALL THE BASELINE DATA AND 7072 05:23:59,080 --> 05:24:01,360 THEN THE ASSAY WHICH TELLS YOU 7073 05:24:01,360 --> 05:24:03,080 WHO RESPONDED WELL AND YOU FIND 7074 05:24:03,080 --> 05:24:06,400 PREDICTORS AND TRY TO FIND 7075 05:24:06,400 --> 05:24:08,760 MIMICKERS TO BOOST THE DEALINGS 7076 05:24:08,760 --> 05:24:09,280 AND RESPONSE. 7077 05:24:09,280 --> 05:24:10,320 >>THANK YOU. 7078 05:24:10,320 --> 05:24:13,040 DON'T GO ANYWHERE BECAUSE LET'S 7079 05:24:13,040 --> 05:24:15,080 GO MY COLLEAGUE WILL TAKE OVER 7080 05:24:15,080 --> 05:24:16,960 AND MODERATE GAPS AND THE 7081 05:24:16,960 --> 05:24:17,680 DISCUSSION SESSION. 7082 05:24:17,680 --> 05:24:21,600 THANK YOU FOR YOUR TIME. 7083 05:24:21,600 --> 05:24:31,840 >>THANK YOU. 7084 05:24:40,080 --> 05:24:42,680 >>THIS WAS A WONDERFUL AND 7085 05:24:42,680 --> 05:24:43,440 ENTERTAINING ORGAN SYSTEM 7086 05:24:43,440 --> 05:24:44,040 DISCUSSION. 7087 05:24:44,040 --> 05:24:47,880 YOU CAN SIT WHERE YOU WANT. 7088 05:24:47,880 --> 05:24:49,080 WITHIN REASON. 7089 05:24:49,080 --> 05:24:51,440 AND JUST LIKE BONNIE DID IN HER 7090 05:24:51,440 --> 05:24:53,360 SESSION, I'D LIKE TO GO THROUGH 7091 05:24:53,360 --> 05:24:55,520 EACH PERSON GIVING THEM TWO 7092 05:24:55,520 --> 05:24:56,920 MINUTES OR SO AND WE WILL START 7093 05:24:56,920 --> 05:24:58,800 WITH OUR ON-LINE SPEAKER BECAUSE 7094 05:24:58,800 --> 05:25:01,760 I HAVE HIM STARING AT ME, 7095 05:25:01,760 --> 05:25:02,960 THROUGH THE COMPUTER SCREEN. 7096 05:25:02,960 --> 05:25:04,560 YOU CAN'T SEE. 7097 05:25:04,560 --> 05:25:05,640 BUT MAYBE YOU WILL GET TO AT 7098 05:25:05,640 --> 05:25:08,080 SOME POINT. 7099 05:25:08,080 --> 05:25:10,840 SO, GO AHEAD, TWO MINUTES, OF 7100 05:25:10,840 --> 05:25:14,800 WHAT YOU THINK ARE THE GAP. 7101 05:25:14,800 --> 05:25:18,880 >>YOU ARE MUTED. 7102 05:25:18,880 --> 05:25:19,400 HE IS HERE. 7103 05:25:19,400 --> 05:25:24,960 HE IS RIGHT THERE. 7104 05:25:24,960 --> 05:25:27,720 THERE HE IS. 7105 05:25:27,720 --> 05:25:38,000 CAN'T HEAR YOU. 7106 05:25:41,600 --> 05:25:44,520 >>WELL, WITH REGARD TO THE WORK 7107 05:25:44,520 --> 05:25:48,760 THAT I PRESENTED, LIKE I 7108 05:25:48,760 --> 05:25:54,040 SUGGESTED, WE THINK IT IS GOOD 7109 05:25:54,040 --> 05:25:57,600 TO TRY TO PREVENT INFLAMMATORY 7110 05:25:57,600 --> 05:25:59,800 DISEASES, NOT ONE BY ONE, NOT 7111 05:25:59,800 --> 05:26:02,320 EACH ONE DIFFERENTLY, BUT SINCE 7112 05:26:02,320 --> 05:26:09,520 THERE ARE SYSTEMIC MECHANISM 7113 05:26:09,520 --> 05:26:11,640 THAT CAN PRECIPITATION THE 7114 05:26:11,640 --> 05:26:15,400 UNRELATED SYSTEMIC DISEASES LIKE 7115 05:26:15,400 --> 05:26:19,800 TRAINED IMMUNITY OR (INAUDIBLE) 7116 05:26:19,800 --> 05:26:22,840 POTENTIAL I THINK THAT THE 7117 05:26:22,840 --> 05:26:26,840 KNOWLEDGE IS TO IDENTIFY FACTORS 7118 05:26:26,840 --> 05:26:30,520 THAT CAN BE COMMON IN THE 7119 05:26:30,520 --> 05:26:32,080 PROMOTION OR EXACERBATION OF 7120 05:26:32,080 --> 05:26:34,320 THESE DISEASES AND I GAVE SOME 7121 05:26:34,320 --> 05:26:38,400 PRELIMINARY EXAMPLES BASED ON 7122 05:26:38,400 --> 05:26:40,440 SOME EVIDENCE FROM IN VIVO MODEL 7123 05:26:40,440 --> 05:26:44,920 OR FROM HUMAN STUDIES AND ONE 7124 05:26:44,920 --> 05:26:47,000 EXAMPLE IS L1 BETA. 7125 05:26:47,000 --> 05:26:49,720 WHICH APPEARS TO HAVE SOMETHING 7126 05:26:49,720 --> 05:26:53,560 TO DO WITH INDUCTION OF TRAINED 7127 05:26:53,560 --> 05:26:54,720 IMMUNITY. 7128 05:26:54,720 --> 05:26:55,600 THERE'S PARTICULAR EVIDENCE AND 7129 05:26:55,600 --> 05:26:57,320 THERE'S SOME SUGGESTION THAT 7130 05:26:57,320 --> 05:27:01,680 HUMAN STUDIES AND IT'S ALSO 7131 05:27:01,680 --> 05:27:04,560 CRITICAL CYTOKINE THAT DRIVES AT 7132 05:27:04,560 --> 05:27:09,160 LEAST SOME FORMS OF DRIVEN CHIP 7133 05:27:09,160 --> 05:27:12,840 SO BY BLOCKING L1 BETA IN PEOPLE 7134 05:27:12,840 --> 05:27:14,240 THAT WE ARE IDENTIFIED THAT THEY 7135 05:27:14,240 --> 05:27:16,560 WILL BENEFIT, YOU CAN HELP THEM 7136 05:27:16,560 --> 05:27:23,200 NOT ONLY TO TREAT THE AGENTER 7137 05:27:23,200 --> 05:27:25,080 CIRRHOSIS BUT LINK DISEASE AND 7138 05:27:25,080 --> 05:27:26,880 SO ON SO THERE ARE A LOT OF 7139 05:27:26,880 --> 05:27:30,080 OTHER THINGS THAT I WOULD SAY AT 7140 05:27:30,080 --> 05:27:32,240 THE MORE BASIC LEVEL BUT I THINK 7141 05:27:32,240 --> 05:27:34,720 THAT WITH ALL THIS METHODS OF 7142 05:27:34,720 --> 05:27:37,880 INVESTIGATE YEAR AFTER YEAR IT'S 7143 05:27:37,880 --> 05:27:39,640 TIME NOW TO PROVIDE SOMETHING 7144 05:27:39,640 --> 05:27:40,880 FOR THE PATIENT AND I SAY THIS 7145 05:27:40,880 --> 05:27:42,720 IS ESPECIALLY FROM MY POINT OF 7146 05:27:42,720 --> 05:27:45,640 VIEW, WORKING THE RESEARCH 7147 05:27:45,640 --> 05:27:50,520 FIELD, THE PER PER PERRY OWE DOT 7148 05:27:50,520 --> 05:27:53,400 HAVE BEEN DOING THIS FOR THE 7149 05:27:53,400 --> 05:27:56,360 PAST 100 YEARS THAT'S WHY WE'RE 7150 05:27:56,360 --> 05:27:58,280 TRYING TO BRING A TREATMENT, AT 7151 05:27:58,280 --> 05:27:59,960 LEAST A LOCAL TREATMENT BASED ON 7152 05:27:59,960 --> 05:28:01,880 THE COMPLIMENT SYSTEM IN THE 7153 05:28:01,880 --> 05:28:04,320 CLINIC LIKE I SAID, WE'RE AT 7154 05:28:04,320 --> 05:28:06,280 PHASE 2A AND WE HOPE TOP GO TO 7155 05:28:06,280 --> 05:28:08,040 PHASE 3 BEFORE I RETIRE TO SEE 7156 05:28:08,040 --> 05:28:11,280 AT LEAST THE HOST WITH 7157 05:28:11,280 --> 05:28:12,840 RECOLLECTION TREATMENT FOR THE 7158 05:28:12,840 --> 05:28:14,240 PERIODONTAL PATIENT OTHER THAN 7159 05:28:14,240 --> 05:28:16,280 THE MECHANICAL TREATMENT THAT IS 7160 05:28:16,280 --> 05:28:17,160 DONE. 7161 05:28:17,160 --> 05:28:18,720 THE MECHANICAL DEPARTMENT. 7162 05:28:18,720 --> 05:28:20,200 THAT'S ALL I HAVE TO SAY. 7163 05:28:20,200 --> 05:28:21,360 >>TERRIFIC. 7164 05:28:21,360 --> 05:28:26,120 WE'LL MOVE ON TO OUR NEXT. 7165 05:28:26,120 --> 05:28:31,520 WE'LL TALK DOWN THE LINE THERE. 7166 05:28:31,520 --> 05:28:37,600 >>SO, I THINK I AGREE 7167 05:28:37,600 --> 05:28:39,040 COMPLETELY THAT THE NEXT STEP WE 7168 05:28:39,040 --> 05:28:40,800 HAVE TO STAKE TO BRING THIS TO 7169 05:28:40,800 --> 05:28:42,920 THE PATIENT AND THE QUESTION IS 7170 05:28:42,920 --> 05:28:44,480 HOW CAN WE BRING IT TO THE 7171 05:28:44,480 --> 05:28:46,040 PATIENT AND THE PATIENT IN THAT 7172 05:28:46,040 --> 05:28:48,320 SENSE ALL OF US. 7173 05:28:48,320 --> 05:28:51,200 BECAUSE WE HAVE TO BRING IT TO 7174 05:28:51,200 --> 05:28:56,160 THE AGING PROSPER SAY. 7175 05:28:56,160 --> 05:29:00,840 WE CAN OF COURSE LEARN FROM 7176 05:29:00,840 --> 05:29:04,000 OTHERS THAT HAVE ONE IMMUNO 7177 05:29:04,000 --> 05:29:06,360 MODULATORY THERAPY AND THAT IS 7178 05:29:06,360 --> 05:29:08,440 PARTICULARLY IN CANCER 7179 05:29:08,440 --> 05:29:11,120 IMMUNOLOGY AND THE BIG BREAK 7180 05:29:11,120 --> 05:29:13,520 THROUGH CAME WHEN THE CANCER 7181 05:29:13,520 --> 05:29:15,800 IMMUNOLOGISTS BEGAN TO MAKE THE 7182 05:29:15,800 --> 05:29:17,640 IMMUNE SYSTEM STRONGER AND NOT 7183 05:29:17,640 --> 05:29:18,240 WEAKER. 7184 05:29:18,240 --> 05:29:20,120 SO WHEN THEY ARE NOT 7185 05:29:20,120 --> 05:29:22,440 IMMUNOSUPPRESSED BUT IMMUNO 7186 05:29:22,440 --> 05:29:24,360 ENHANCED AND I THINK WE NEED TO 7187 05:29:24,360 --> 05:29:27,840 BE VERY THANKFUL TO THEM THAT 7188 05:29:27,840 --> 05:29:29,360 THEY SHOWED US THAT THE NEGATIVE 7189 05:29:29,360 --> 05:29:32,200 SIGNALS IN THE IMMUNE SYSTEM ARE 7190 05:29:32,200 --> 05:29:35,520 PROBABLY MORE IMPORTANT THAN THE 7191 05:29:35,520 --> 05:29:37,000 POSITIVE SIGNALS. 7192 05:29:37,000 --> 05:29:39,360 BECAUSE THEY CAN'T STOP NEGATIVE 7193 05:29:39,360 --> 05:29:40,880 SIGNALS AND UNLEASH THE IMMUNE 7194 05:29:40,880 --> 05:29:41,640 SYSTEM. 7195 05:29:41,640 --> 05:29:48,160 SO I THINK THAT IS A DIMENSION 7196 05:29:48,160 --> 05:29:50,200 AM STEP THAT WE HAVE ALL TAKEN 7197 05:29:50,200 --> 05:29:53,160 AND THAT WE HAVE TO BRING TO THE 7198 05:29:53,160 --> 05:29:55,760 THERAPY OF OUR PATIENTS. 7199 05:29:55,760 --> 05:29:58,240 WE CAN ACTUALLY INDUCE 7200 05:29:58,240 --> 05:30:01,360 AUTOIMMUNE DISEASE IN PATIENTS 7201 05:30:01,360 --> 05:30:03,400 BY CHECKPOINT INHIBITOR AND WE 7202 05:30:03,400 --> 05:30:07,480 DO IT EVERYDAY AND THERE WILL BE 7203 05:30:07,480 --> 05:30:11,880 MORE AUTOIMMUNE DIS SIS THAN 7204 05:30:11,880 --> 05:30:13,440 SPONTANEOUS DISEASE VERY SOON. 7205 05:30:13,440 --> 05:30:24,000 IN TERMS OF MECHANIC AND WE ALSO 7206 05:30:27,120 --> 05:30:29,840 HAPPEN TO COME FROM THE MOTHER 7207 05:30:29,840 --> 05:30:34,520 SIDE SO THAT MAKES IT VERY 7208 05:30:34,520 --> 05:30:45,040 VALUABLE AND I THINK WE COULD BE 7209 05:30:48,680 --> 05:30:50,640 VERY MUCH MAKE PROGRESS AND IN 7210 05:30:50,640 --> 05:30:52,840 TERMS OF BASIC MECHANISMS I 7211 05:30:52,840 --> 05:30:58,360 THINK THE NEXT FRONTIER LIES AND 7212 05:30:58,360 --> 05:31:02,360 DNA PREPARE AND WE CAN REPAIR 7213 05:31:02,360 --> 05:31:04,120 THE DNA. 7214 05:31:04,120 --> 05:31:04,360 TERRIFIC. 7215 05:31:04,360 --> 05:31:07,080 >>NEXT, SCOTT. 7216 05:31:07,080 --> 05:31:09,680 I'LL FOCUS ON MONO TYPE. 7217 05:31:09,680 --> 05:31:11,160 AND THERE I THINK ACTUALLY WE 7218 05:31:11,160 --> 05:31:13,000 WENT INTO THIS WITH A STRONG 7219 05:31:13,000 --> 05:31:15,240 BIAS THAT WE WERE GOING TO SEE 7220 05:31:15,240 --> 05:31:16,640 ECONOMIST CHANGES AND WHAT THEY 7221 05:31:16,640 --> 05:31:18,440 HAVE SEEN RIGHT IN MONO TIGHT 7222 05:31:18,440 --> 05:31:21,000 AND MICROFAGES WE SAW I SHOWED 7223 05:31:21,000 --> 05:31:22,200 YOU SOME OF THE DATA AND WE ALSO 7224 05:31:22,200 --> 05:31:24,120 FOUND IN THE MICROGLIA THAT YOU 7225 05:31:24,120 --> 05:31:27,160 HAVE THE VERY REPRODUCE ABLE 7226 05:31:27,160 --> 05:31:29,400 MICRO DEAL AT YOU COMPLETE AND 7227 05:31:29,400 --> 05:31:31,520 IT COMES BACK WITH EX SEE THE 7228 05:31:31,520 --> 05:31:32,640 SAME SIGNATURE RIGHT AWAY AND WE 7229 05:31:32,640 --> 05:31:33,920 SEE THAT WE HAVE THESE NON SELL 7230 05:31:33,920 --> 05:31:37,920 OUT A CON US IN CHANGES INDUCED 7231 05:31:37,920 --> 05:31:39,200 BY ININFLUENZA INFECTION WHERE 7232 05:31:39,200 --> 05:31:39,800 WE DON'T HAVE INFLUENZA LIKE 7233 05:31:39,800 --> 05:31:40,880 SARS-CoV-2 WE DON'T HAVE 7234 05:31:40,880 --> 05:31:42,600 DIRECT INFECTION BUT WE SEE 7235 05:31:42,600 --> 05:31:43,720 THESE REPRODUCE ABLE CHANGES 7236 05:31:43,720 --> 05:31:45,760 THAT ARE REFERRING IN THE 7237 05:31:45,760 --> 05:31:47,400 MICROGLIA SO UNDERSTANDING HOW 7238 05:31:47,400 --> 05:31:48,880 THOSE CELLS, WHAT THOSE CELLS 7239 05:31:48,880 --> 05:31:51,200 ARE RESPOND TO GO IN THE MICRO 7240 05:31:51,200 --> 05:31:51,960 ENVIRONMENT THAT IS DRIVING THAT 7241 05:31:51,960 --> 05:31:54,920 AND HOW CAN WE SORT OF GO BACK 7242 05:31:54,920 --> 05:31:56,680 DOWN THE CHAIN OF CAUSALITY AND 7243 05:31:56,680 --> 05:31:57,760 TRYING TO FIGURE OUT WHAT IT IS 7244 05:31:57,760 --> 05:31:59,840 IN THE MICROENVIRONMENT INDUCING 7245 05:31:59,840 --> 05:32:01,520 THOSE CHANGES AND I THINK IT'S 7246 05:32:01,520 --> 05:32:05,480 REALLY GOING TO BE A BIG 7247 05:32:05,480 --> 05:32:11,880 CHALLENGE. 7248 05:32:11,880 --> 05:32:16,480 >>I THINK PIGGYBACKING ON WHAT 7249 05:32:16,480 --> 05:32:18,520 WAS SAID EARLIER WE'VE LEARNED A 7250 05:32:18,520 --> 05:32:20,760 LOT FROM T-CELL BIOLOGY FROM 7251 05:32:20,760 --> 05:32:22,280 CANCER AND I THINK WE CAN APPLY 7252 05:32:22,280 --> 05:32:23,920 A LOT THAT HAVE BUT I KEEP 7253 05:32:23,920 --> 05:32:26,840 COMING UP AGAINST THIS UNKNOWN 7254 05:32:26,840 --> 05:32:29,320 WHERE WE'RE SITTING AT CHRONIC 7255 05:32:29,320 --> 05:32:34,000 DISEASE THAT'S INFLAMMATION IN 7256 05:32:34,000 --> 05:32:37,920 THE MICE AND SFF FREE CONDITIONS 7257 05:32:37,920 --> 05:32:40,520 WE SEE THIS PCR EXPANSION AND 7258 05:32:40,520 --> 05:32:44,160 SUBSET AND WE SEE EXHAUSTED IN 7259 05:32:44,160 --> 05:32:46,000 DISEASE TYPE BUT WE DON'T REALLY 7260 05:32:46,000 --> 05:32:48,400 KNOW WHAT THE ANTIGEN IS AND 7261 05:32:48,400 --> 05:32:50,960 IT'S NOT CLEAR WHETHER THERE IS 7262 05:32:50,960 --> 05:32:57,400 A FUNCTIONAL ANTIGEN BUT IT 7263 05:32:57,400 --> 05:33:02,000 FEELS LIKE WE'RE AT THIS POINT 7264 05:33:02,000 --> 05:33:08,120 AND WE'RE THINKING BEYOND 7265 05:33:08,120 --> 05:33:09,440 FOLLOWING THESE INFECTIOUS 7266 05:33:09,440 --> 05:33:11,200 DISEASE MODELS AND CANCER MODEL 7267 05:33:11,200 --> 05:33:13,120 WHERE WE CAN ADAPT IT TO A 7268 05:33:13,120 --> 05:33:15,280 SPECIFIC DISEASE AND IT'S TAKING 7269 05:33:15,280 --> 05:33:18,360 THINGS FROM THE PERSPECTIVE OF 7270 05:33:18,360 --> 05:33:20,400 TREATING ALL AGING AND YOU CAN 7271 05:33:20,400 --> 05:33:24,240 TREAT ALL THE BUT KEEPING IN 7272 05:33:24,240 --> 05:33:25,720 MIND THAT MICROENVIRONMENT AND 7273 05:33:25,720 --> 05:33:27,720 THERE'S DIFFERENCES AND THE WAY 7274 05:33:27,720 --> 05:33:31,440 CELL FUNCTION AND SO, YEAH I 7275 05:33:31,440 --> 05:33:32,800 DON'T HAVE ANY CLEAR ANSWERS BUT 7276 05:33:32,800 --> 05:33:39,320 LOTS OF QUESTIONS. 7277 05:33:39,320 --> 05:33:41,680 >>I SOMEWHAT DISAGREE BUT WORE 7278 05:33:41,680 --> 05:33:43,080 READING FOR PRIME TIME AND 7279 05:33:43,080 --> 05:33:43,640 TREAT. 7280 05:33:43,640 --> 05:33:47,680 THE MORE I LEARN THE MORE 7281 05:33:47,680 --> 05:33:50,440 PUZZLED I AM AND THE REASON IS 7282 05:33:50,440 --> 05:33:51,920 THERE'S SO MUCH VARIABILITY, 7283 05:33:51,920 --> 05:33:52,360 RIGHT. 7284 05:33:52,360 --> 05:33:55,200 WHEN WE USE A COHORT HERE, AND 7285 05:33:55,200 --> 05:33:57,600 CONTINUE A PLAN FORM WE LEARN 7286 05:33:57,600 --> 05:33:59,160 SOMETHING AND IT'S AN ASPECT OF 7287 05:33:59,160 --> 05:34:00,600 AGING AND YOU DO SOMETHING 7288 05:34:00,600 --> 05:34:03,200 DIFFERENT, AND A DIFFERENT 7289 05:34:03,200 --> 05:34:04,760 COHORT AND A DIFFERENT DEM A 7290 05:34:04,760 --> 05:34:05,920 GREAT I HAVE AND A DIFFERENT 7291 05:34:05,920 --> 05:34:07,320 PLATFORM YOU HAVE A DIFFERENT 7292 05:34:07,320 --> 05:34:08,400 ASPECT THAT YOU ARE OPTION IN 7293 05:34:08,400 --> 05:34:13,000 THERE AND MAYBE OPPOSING RESULTS 7294 05:34:13,000 --> 05:34:17,400 SO I THINK THERE'S A MEAN TO 7295 05:34:17,400 --> 05:34:19,160 COORDINATE THE EFFORTS AND HAVE 7296 05:34:19,160 --> 05:34:23,320 A MUCH LARGER STUDY SO WE NEED 7297 05:34:23,320 --> 05:34:23,960 MORE MONEY. 7298 05:34:23,960 --> 05:34:27,120 I THINK THAT'S WHAT WE NEED. 7299 05:34:27,120 --> 05:34:29,600 MAYBE PEOPLE THAT WE COULD 7300 05:34:29,600 --> 05:34:31,200 FOLLOW BECAUSE VARIABILITY AGAIN 7301 05:34:31,200 --> 05:34:32,960 IS SO LARGE THAT YOU ARE JUST 7302 05:34:32,960 --> 05:34:35,960 CAPTURING A FEW ASPECTS OF THE 7303 05:34:35,960 --> 05:34:39,800 AGING PROCESS IN THIS SENSE. 7304 05:34:39,800 --> 05:34:42,440 THE OTHER IMPORTANT ASPECT THAT 7305 05:34:42,440 --> 05:34:45,520 I THINK IT'S PRETTY TOUGH TO 7306 05:34:45,520 --> 05:34:51,200 DISCUSS IS THAT WHEN WE DEVELOP 7307 05:34:51,200 --> 05:34:53,680 BIOMARKERS OF DERIVE BIOMARKERS 7308 05:34:53,680 --> 05:34:58,320 CLOCKS THEY OFTEN DISAGREE AND 7309 05:34:58,320 --> 05:34:59,720 THERE'S NOT A UNIFIED VERSION OF 7310 05:34:59,720 --> 05:35:01,680 IT AND I THINK THE REASON ALSO 7311 05:35:01,680 --> 05:35:07,560 COMES DOWN TO THERE ARE FACTSORS 7312 05:35:07,560 --> 05:35:09,600 THAT PROMOTE AGING AND FACTORS 7313 05:35:09,600 --> 05:35:11,600 THAT ARE BENEFICIAL THAT 7314 05:35:11,600 --> 05:35:13,880 INCREASE OR CHANGE WITH AGE AND 7315 05:35:13,880 --> 05:35:15,040 WE DON'T KNOW WHAT IS WHAT. 7316 05:35:15,040 --> 05:35:17,560 SO THERE'S THE BODY FIGHTING 7317 05:35:17,560 --> 05:35:19,240 AGING, RIGHT, AND THEN YOU HAVE 7318 05:35:19,240 --> 05:35:21,040 BIOMARKERS OF AGING AND THERE'S 7319 05:35:21,040 --> 05:35:30,840 THE AGING PROSPER SAY AND. 7320 05:35:30,840 --> 05:35:32,440 >>BEFORE I OPEN IT UP TO 7321 05:35:32,440 --> 05:35:35,720 QUESTIONS OR COMMENTS FROM THE 7322 05:35:35,720 --> 05:35:36,600 AUDIENCE, ONE THING I'D LIKE TO 7323 05:35:36,600 --> 05:35:37,880 BRING UP IS THE TITLE OF THIS 7324 05:35:37,880 --> 05:35:40,880 SESSION HAS THE WORD CROSSTALK 7325 05:35:40,880 --> 05:35:44,440 AND MULTI OR I GUESS IT'S ORGAN 7326 05:35:44,440 --> 05:35:46,240 IMMUNE SO I THINK THINKING ABOUT 7327 05:35:46,240 --> 05:35:48,640 WHAT IS GOING ON AGING WISE IN 7328 05:35:48,640 --> 05:35:50,360 ONE ORGAN AND HOW IT MIGHT 7329 05:35:50,360 --> 05:35:52,000 AFFECT ANOTHER ORGAN I THINK IS 7330 05:35:52,000 --> 05:35:53,440 A CRITICAL ELEMENT THAT WE NEED 7331 05:35:53,440 --> 05:35:55,080 TO CONTINUE TO EXPLORE AND FOR 7332 05:35:55,080 --> 05:35:58,720 THOSE OF YOU WHO ARE DOING 7333 05:35:58,720 --> 05:36:00,160 ANIMAL BASED STUDIES, THINK 7334 05:36:00,160 --> 05:36:01,360 ABOUT COLLECTING EVERY POSSIBLE 7335 05:36:01,360 --> 05:36:03,400 ORGAN YOU CAN THINK OF PUTTING 7336 05:36:03,400 --> 05:36:05,520 IT IN A FREEZER AND FINDING A 7337 05:36:05,520 --> 05:36:07,160 COLLABORATOR WHO WANTS TO PURSUE 7338 05:36:07,160 --> 05:36:09,880 THAT ORGAN BECAUSE IT REALLY 7339 05:36:09,880 --> 05:36:11,760 ACCELERATES THE OPPORTUNITY TO 7340 05:36:11,760 --> 05:36:13,400 BE ABLE TO SEE IF YOU SEE THE 7341 05:36:13,400 --> 05:36:16,400 SAME THING IN DIFFERENT ORGANS. 7342 05:36:16,400 --> 05:36:19,800 SCOTT MENTIONED MACROPHAGES AND 7343 05:36:19,800 --> 05:36:21,600 LUNG MACROPHAGES SUBSETS AND 7344 05:36:21,600 --> 05:36:23,760 MICROGLIA. 7345 05:36:23,760 --> 05:36:25,280 LOOKING AT THE GUT-BRAIN 7346 05:36:25,280 --> 05:36:28,240 CROSSTALK AND GUT-LUNG BRAIN AND 7347 05:36:28,240 --> 05:36:29,880 ANY OF THE OTHER THE HEART IS 7348 05:36:29,880 --> 05:36:31,880 IMPORTANT SOMEHOW TOO. 7349 05:36:31,880 --> 05:36:33,560 THINKING ABOUT HOW ALL THESE 7350 05:36:33,560 --> 05:36:35,280 ORGANS INTERACT BECAUSE WE ARE 7351 05:36:35,280 --> 05:36:36,680 ALL AT LEAST PHYSICALLY 7352 05:36:36,680 --> 05:36:39,560 CONNECTED WITH OURSELVES AND TO 7353 05:36:39,560 --> 05:36:41,320 CONTINUE ALONG THAT CONCEPT. 7354 05:36:41,320 --> 05:36:42,320 ALSO, ANOTHER THING THAT WAS 7355 05:36:42,320 --> 05:36:45,000 BROUGHT UP BY DANIEL IS TO THINK 7356 05:36:45,000 --> 05:36:46,080 ABOUT PEOPLE WHO ARE DOING SOME 7357 05:36:46,080 --> 05:36:47,760 OF THESE MODELS IN YOUNG MICE 7358 05:36:47,760 --> 05:36:48,960 THAT ARE NOT PARTICULARLY 7359 05:36:48,960 --> 05:36:51,920 RELEVANT TO AGING. 7360 05:36:51,920 --> 05:36:54,240 LOOKING AT AGENTER OWE SCLEROSIS 7361 05:36:54,240 --> 05:36:55,920 IN A 12-YEAR-OLD IS HAPPENING IN 7362 05:36:55,920 --> 05:36:57,440 AMERICA BECAUSE OF OUR DIET BUT 7363 05:36:57,440 --> 05:37:00,040 IT MAY NOT BE AS POTENT OR THE 7364 05:37:00,040 --> 05:37:05,840 SAME AS THE AGENTER OWE 7365 05:37:05,840 --> 05:37:07,080 SCLEROSIS OF A SUBJECT. 7366 05:37:07,080 --> 05:37:09,600 >>THIS IS AN EXCELLENT POINT 7367 05:37:09,600 --> 05:37:11,880 AND IN DATE THE COMMUNICATION 7368 05:37:11,880 --> 05:37:13,640 BETWEEN DIFFERENT ORGANS, 7369 05:37:13,640 --> 05:37:17,240 BETWEEN LET'S SAY THE BONE 7370 05:37:17,240 --> 05:37:19,160 NARROW AND THE TESTING THESE ARE 7371 05:37:19,160 --> 05:37:21,040 CRITICAL THINGS AND THIS IS A 7372 05:37:21,040 --> 05:37:22,480 RELEVANT WITH THE ESSENTIAL 7373 05:37:22,480 --> 05:37:23,440 REDUCTION OF IMMUNE RESPONSE 7374 05:37:23,440 --> 05:37:25,600 WITH HOW WE RESPOND TO INFECTION 7375 05:37:25,600 --> 05:37:27,520 AND WITH ALL DUE RESPECT TO THE 7376 05:37:27,520 --> 05:37:30,040 IN VITRO MODELS WHICH ARE 7377 05:37:30,040 --> 05:37:31,760 SOPHISTICATED LIKE THE 7378 05:37:31,760 --> 05:37:33,320 ORGANOIDS, HOW DO YOU ADDRESS 7379 05:37:33,320 --> 05:37:34,240 COMMUNICATION BETWEEN DIFFERENT 7380 05:37:34,240 --> 05:37:36,040 ORGANS WHEN YOU USE ORGANOIDS? 7381 05:37:36,040 --> 05:37:38,400 BY PUTTING THEM SIDE BY SIDE? 7382 05:37:38,400 --> 05:37:40,200 THIS DOES NOT HAPPEN. 7383 05:37:40,200 --> 05:37:42,120 THE CLINICAL SAID YEAH, IF 7384 05:37:42,120 --> 05:37:45,640 THEY'RE USED CORRECTLY. 7385 05:37:45,640 --> 05:37:47,360 THEY'RE NEEDED 100 IN BIOMEDICAL 7386 05:37:47,360 --> 05:37:48,480 RESEARCH AND THE POINT IS IT TO 7387 05:37:48,480 --> 05:37:53,360 FIND THE RELEVANT MODELS TO USE 7388 05:37:53,360 --> 05:37:55,440 AND REFRESH NO MODEL CAN 7389 05:37:55,440 --> 05:37:56,800 CAPITULATE THE HUMAN DISEASE AND 7390 05:37:56,800 --> 05:37:59,080 IT CAN BE USED TORR SPECIFIC 7391 05:37:59,080 --> 05:38:01,800 HYPOTHESIS AND IF THEY'RE USED 7392 05:38:01,800 --> 05:38:02,360 WISELY THEY'RE USED FOR US. 7393 05:38:02,360 --> 05:38:04,080 >>THAT'S AN EXCELLENT POINT. 7394 05:38:04,080 --> 05:38:05,600 WE HAVE THREE MORE MINUTES. 7395 05:38:05,600 --> 05:38:07,120 AND ANYBODY FROM THE AUDIENCE 7396 05:38:07,120 --> 05:38:08,320 WANT TO SAY ANYTHING? 7397 05:38:08,320 --> 05:38:08,520 YES,. 7398 05:38:08,520 --> 05:38:11,440 >>I WANTED TO COMMAND ON THE 7399 05:38:11,440 --> 05:38:12,200 TIME SCALE OF THE EXAMINATION 7400 05:38:12,200 --> 05:38:14,840 AND I THINK THAT IT'S VERY 7401 05:38:14,840 --> 05:38:16,080 IMPORTANT. 7402 05:38:16,080 --> 05:38:17,920 THE MAJOR BREAK THROUGH IN ALL 7403 05:38:17,920 --> 05:38:20,200 AUTOIMMUNE DISEASES HAS BEEN THE 7404 05:38:20,200 --> 05:38:21,760 RECOGNITION THAT BY THE TIME THE 7405 05:38:21,760 --> 05:38:25,440 PATIENT COMES TO US, THEY HAVE 7406 05:38:25,440 --> 05:38:30,320 BEEN QUOTE SICK FOR 30 OR 40 7407 05:38:30,320 --> 05:38:31,600 YEARS. 7408 05:38:31,600 --> 05:38:33,000 I THINK THAT IS VERY IMPORTANT. 7409 05:38:33,000 --> 05:38:37,640 WE NEED TO START STUDYING AGING 7410 05:38:37,640 --> 05:38:39,320 IN THE YOUNG. 7411 05:38:39,320 --> 05:38:41,680 >>THANK YOU. 7412 05:38:41,680 --> 05:38:42,400 VERY INTERESTING. 7413 05:38:42,400 --> 05:38:45,280 I THINK THERE'S A BASIC THING 7414 05:38:45,280 --> 05:38:46,480 THAT I DON'T THINK ANYONE HAS 7415 05:38:46,480 --> 05:38:51,200 TOUCHED ON WHICH IS THINGS CAN 7416 05:38:51,200 --> 05:38:54,160 FALL APART IN SO MANY DIFFERENT 7417 05:38:54,160 --> 05:38:57,000 WAYS AND FROM WHAT EXTENT IS 7418 05:38:57,000 --> 05:39:01,480 THERE OVER ALL AGING PROGRESSION 7419 05:39:01,480 --> 05:39:02,680 DRIVEN BY WHAT? 7420 05:39:02,680 --> 05:39:03,880 AND WHAT EXTENT ARE JUST 7421 05:39:03,880 --> 05:39:07,640 DIFFERENT ORGAN SYSTEMS BREAKING 7422 05:39:07,640 --> 05:39:09,800 DOWN MAYBE BECAUSE OF THE 7423 05:39:09,800 --> 05:39:10,280 MUTATIONS? 7424 05:39:10,280 --> 05:39:14,400 I THINK IT'S A MIXTURE BUT I 7425 05:39:14,400 --> 05:39:18,200 DON'T KNOW AND I THINK YOU HAVE 7426 05:39:18,200 --> 05:39:21,400 TO LOOK ALMOST LOOK AT THIS IN 7427 05:39:21,400 --> 05:39:25,320 CROSS MICE NOT BLACK SIX MICE 7428 05:39:25,320 --> 05:39:26,600 BECAUSE BLACK MICE YOU LOOK AT 7429 05:39:26,600 --> 05:39:28,120 ONE GENOTYPE. 7430 05:39:28,120 --> 05:39:30,080 HUMANS AND OF COURSE ALSO WORK. 7431 05:39:30,080 --> 05:39:31,640 AND THEY AGE IN DIFFERENT WAYS 7432 05:39:31,640 --> 05:39:34,480 AND THEY AGE IN DIFFERENT RATES 7433 05:39:34,480 --> 05:39:36,360 CLEARLY AND SO THERE'S A LOT OF 7434 05:39:36,360 --> 05:39:38,800 CLUES THERE AND I THINK THAT A 7435 05:39:38,800 --> 05:39:40,360 LOT OF QUESTIONS THAT ARE 7436 05:39:40,360 --> 05:39:42,200 DIFFICULT TO ANSWER BUT I THINK 7437 05:39:42,200 --> 05:39:43,800 PEOPLE SHOULD GET AND THINK 7438 05:39:43,800 --> 05:39:44,080 ABOUT THEM. 7439 05:39:44,080 --> 05:39:46,080 >>I THINK THAT COMES DOWN TO 7440 05:39:46,080 --> 05:39:46,680 COLLABORATION. 7441 05:39:46,680 --> 05:39:49,840 WE HAVE A COUPLE MORE QUESTIONS. 7442 05:39:49,840 --> 05:39:52,840 >>SO I WAS JUST GOING TO ADD TO 7443 05:39:52,840 --> 05:39:56,000 WHAT DAVID MENTIONED ABOUT THE 7444 05:39:56,000 --> 05:39:57,760 NEED FOR -- I MEAN ALWAYS MORE 7445 05:39:57,760 --> 05:40:00,360 FUNDING BUT DIFFERENT FUNDING. 7446 05:40:00,360 --> 05:40:02,600 ONE OF THE THINGS THAT WE 7447 05:40:02,600 --> 05:40:06,560 PROBABLY CANNOT DO IS MASSIVE 7448 05:40:06,560 --> 05:40:06,920 CLINICAL TRIALS. 7449 05:40:06,920 --> 05:40:10,520 WE CAN DO SMALL PRAGMATIC WITH A 7450 05:40:10,520 --> 05:40:13,200 WHOLE BUNCH OF THINGS THAT AS 7451 05:40:13,200 --> 05:40:15,240 LONG AS THEY'RE SAFE AND WE 7452 05:40:15,240 --> 05:40:18,320 STUDIED THEM IN DEPTH WITH 7453 05:40:18,320 --> 05:40:19,640 EVERYTHING ELSE SO WE SHOULD BE 7454 05:40:19,640 --> 05:40:22,720 ABLE TO LEARN A LOT ABOUT THE 7455 05:40:22,720 --> 05:40:23,960 VARIABILITY AND WHAT IS NOISE 7456 05:40:23,960 --> 05:40:27,080 AND WHAT IS SIGNAL. 7457 05:40:27,080 --> 05:40:28,720 >>VERY IMPORTANT. 7458 05:40:28,720 --> 05:40:30,520 LAST QUESTION. 7459 05:40:30,520 --> 05:40:35,720 >>YES, I WANT TO FORMATION ON 7460 05:40:35,720 --> 05:40:39,480 ORGAN AND COMMUNICATION NIA HAS 7461 05:40:39,480 --> 05:40:43,240 WRITTEN ON THIS RESEARCH AND WE 7462 05:40:43,240 --> 05:40:49,440 SEE A GREAT GAP ON THAT AREA AND 7463 05:40:49,440 --> 05:40:52,040 WE PUT AN RECENTLY AND SOME OF 7464 05:40:52,040 --> 05:40:54,120 YOU MAY HAVE SEEN THAT AND RFA 7465 05:40:54,120 --> 05:40:58,160 ON THE UO1 ON ENTERSER ORGAN 7466 05:40:58,160 --> 05:40:59,280 COMMUNICATION DURING AGING AND 7467 05:40:59,280 --> 05:41:02,040 WE COULD BE CLOSING BY 7468 05:41:02,040 --> 05:41:02,360 JUNE 3rd AND. 7469 05:41:02,360 --> 05:41:04,920 >>SO HURRY UP AND WRITE YOUR 7470 05:41:04,920 --> 05:41:05,920 APPLICATION. 7471 05:41:05,920 --> 05:41:06,520 >>OKAY. 7472 05:41:06,520 --> 05:41:07,280 THAT LAST THING. 7473 05:41:07,280 --> 05:41:09,240 >>I JUST WANT TO ECHO SOME OF 7474 05:41:09,240 --> 05:41:09,680 THE COMMENTS BEFORE. 7475 05:41:09,680 --> 05:41:13,760 I MEAN, ONE OF THE THINGS THAT I 7476 05:41:13,760 --> 05:41:15,760 THINK IS IMPORTANT THAT WE USE 7477 05:41:15,760 --> 05:41:16,440 THE RESOURCES WE HAVE A LITTLE 7478 05:41:16,440 --> 05:41:18,240 BIT BETTER AND WE HAVE 7479 05:41:18,240 --> 05:41:19,080 ELECTRONIC HEALTH RECORDS NOW IN 7480 05:41:19,080 --> 05:41:21,360 ALL OF OUR FEDERAL CENTRES. 7481 05:41:21,360 --> 05:41:22,680 THE DATA COMING OUT OF THEM ARE 7482 05:41:22,680 --> 05:41:24,840 A MESS AND THEY'RE DIFFICULT TO 7483 05:41:24,840 --> 05:41:27,160 USE AND I THINK ORGANIZATION 7484 05:41:27,160 --> 05:41:29,040 WE'LL HAVE A BIG EXPERIMENT 7485 05:41:29,040 --> 05:41:30,920 WHERE WE PUT PEOPLE AND WE'LL 7486 05:41:30,920 --> 05:41:31,520 LOOSE A LOT OF WEIGHT AND SEE 7487 05:41:31,520 --> 05:41:32,880 WHAT HAPPENS AND WE'RE GOING TO 7488 05:41:32,880 --> 05:41:34,080 MISS IT BECAUSE WE'LL HAVE NO 7489 05:41:34,080 --> 05:41:36,920 WAY TO LOOK AT THOSE MEDICAL 7490 05:41:36,920 --> 05:41:38,680 RECORDS AND TO SEE WHAT IS GOING 7491 05:41:38,680 --> 05:41:39,920 ON AND ALSO MAKES IT DIFFICULT 7492 05:41:39,920 --> 05:41:42,480 TO DO WHAT WE'RE DOING WHICH IS 7493 05:41:42,480 --> 05:41:45,480 TAKING SAMPLES GENERATED IN 7494 05:41:45,480 --> 05:41:46,760 CLINICAL CARE AND INTEGRATING 7495 05:41:46,760 --> 05:41:49,600 THEM WITH PATIENTS IS REALLY 7496 05:41:49,600 --> 05:41:51,600 IMPORTANT TO UNDERSTAND THE 7497 05:41:51,600 --> 05:41:53,160 GENEITY AND THE NIH TO MAKE 7498 05:41:53,160 --> 05:41:54,800 COMMENTS AND MAKING ELECTRONIC 7499 05:41:54,800 --> 05:41:57,800 HEALTH RECORDS MORE ACCESSIBLE. 7500 05:41:57,800 --> 05:41:58,960 >>THAT'S TERRIFIC. 7501 05:41:58,960 --> 05:42:00,400 I WILL CLOSE THIS DISCUSSION. 7502 05:42:00,400 --> 05:42:02,160 THANK YOU EVERYBODY FOR WHO 7503 05:42:02,160 --> 05:42:03,000 SPOKE. 7504 05:42:03,000 --> 05:42:04,840 LONG DISTANCE AND LOCALLY. 7505 05:42:04,840 --> 05:42:07,280 AS WELL AS QUESTIONS. 7506 05:42:07,280 --> 05:42:08,440 ALSO, WE HAVE, WE NEED TO BE 7507 05:42:08,440 --> 05:42:17,960 BACK HERE AT 4:40. 7508 05:42:17,960 --> 05:42:22,640 SO IT'S TIME FOR THE LAST 7509 05:42:22,640 --> 05:42:26,360 SESSION OF THE DAY AND CHRISTINA 7510 05:42:26,360 --> 05:42:27,320 CAMEL FROM THE UNIVERSITY OF 7511 05:42:27,320 --> 05:42:28,680 MINNESOTA AND I WILL CO-CHAIR. 7512 05:42:28,680 --> 05:42:32,120 MY NAME IS MAYA MAREK AND I'M A 7513 05:42:32,120 --> 05:42:33,520 PROGRAMME OFFICER AT THE 7514 05:42:33,520 --> 05:42:38,720 DIVISION OF NEUROSCIENCE AT NIH. 7515 05:42:38,720 --> 05:42:39,960 SO APPROPRIATELY AS OUR BRAINS 7516 05:42:39,960 --> 05:42:43,480 ARE SHUTTING DOWN THIS LATE, THE 7517 05:42:43,480 --> 05:42:44,880 THIRD SESSION WILL BE ABOUT 7518 05:42:44,880 --> 05:42:50,200 NEURO IMMUNE PASS WAYS AND 7519 05:42:50,200 --> 05:42:51,720 NEURODEGENERATIVE DISEASES AND I 7520 05:42:51,720 --> 05:42:55,040 ALSO WANT TO REMIND THE 7521 05:42:55,040 --> 05:42:56,400 PRESENTERS 15 MINUTES. 7522 05:42:56,400 --> 05:43:01,640 I WILL TRY TO KEEP YOU IN LINE 7523 05:43:01,640 --> 05:43:03,440 WITH SOUND REMINDERS. 7524 05:43:03,440 --> 05:43:06,160 13 MINUTES AND THEN TWO MINUTE 7525 05:43:06,160 --> 05:43:09,040 AT THE END. 7526 05:43:09,040 --> 05:43:12,400 SO CHRISTINA -- 7527 05:43:12,400 --> 05:43:14,360 >>LET ME GO AHEAD AND INTRODUCE 7528 05:43:14,360 --> 05:43:16,080 OUR FIRST SPEAKER IT'S GOING TO 7529 05:43:16,080 --> 05:43:19,120 BE SAUL VILLEDA FROM UNIVERSITY 7530 05:43:19,120 --> 05:43:20,560 OF CALIFORNIA OF SAN FRANCISCO 7531 05:43:20,560 --> 05:43:22,120 WHO WILL TALK TO US ABOUT 7532 05:43:22,120 --> 05:43:26,440 SYSTEMIC MECHANISMS OF BRAIN 7533 05:43:26,440 --> 05:43:26,800 REJUVENATION. 7534 05:43:26,800 --> 05:43:27,440 >>GREAT. 7535 05:43:27,440 --> 05:43:28,840 GOOD AFTERNOON, EVERYONE, FIRST 7536 05:43:28,840 --> 05:43:30,160 OF ALL THANK YOU FOR THIS 7537 05:43:30,160 --> 05:43:30,480 MEETING. 7538 05:43:30,480 --> 05:43:32,640 I'VE LEARNED A LOT. 7539 05:43:32,640 --> 05:43:35,000 FULL DISCLOSURE I'M A 7540 05:43:35,000 --> 05:43:36,080 NEUROSCIENTIST BY TRAINING AND 7541 05:43:36,080 --> 05:43:37,920 ONE SPEAKER SAID EVERYTHING 7542 05:43:37,920 --> 05:43:40,680 AGING LEADS TO IMMUNOLOGY AND 7543 05:43:40,680 --> 05:43:43,480 HERE I AM AT THIS WORKSHOP. 7544 05:43:43,480 --> 05:43:48,360 I GOT WITH OH NO, HERE IS THIS. 7545 05:43:48,360 --> 05:43:49,160 OKAY, MAYBE. 7546 05:43:49,160 --> 05:43:51,520 WELL, BIG PICTURE AND IF NOT I 7547 05:43:51,520 --> 05:43:55,560 WILL JUST SAY NEXT 400 TIMES, 7548 05:43:55,560 --> 05:43:56,640 WHAT WE ARE INTERESTED LONG TERM 7549 05:43:56,640 --> 05:43:58,600 VISION OF THIS IDEA OF REVERSE 7550 05:43:58,600 --> 05:44:00,920 ABILITY AND SO NOT JUST HALTING 7551 05:44:00,920 --> 05:44:02,680 AGING BUT WAYS WE CAN TAKE AN 7552 05:44:02,680 --> 05:44:04,240 ALREADY OLD BRAIN AND SOMEHOW 7553 05:44:04,240 --> 05:44:05,880 BRING IT BACK TO YOUTH AND FOR 7554 05:44:05,880 --> 05:44:08,320 MY PERSPECTIVE THAT'S ABOUT 7555 05:44:08,320 --> 05:44:10,640 FUNCTION. 7556 05:44:10,640 --> 05:44:21,040 SO I FOCUS ON -- IT'S OKAY. 7557 05:44:21,040 --> 05:44:22,960 LEFT SIDE. 7558 05:44:22,960 --> 05:44:23,280 HERE. 7559 05:44:23,280 --> 05:44:25,800 THERE WE GO. 7560 05:44:25,800 --> 05:44:26,800 OKAY. 7561 05:44:26,800 --> 05:44:27,600 FUNCTIONS. 7562 05:44:27,600 --> 05:44:29,880 SO, THE WAY WE DEFINE 7563 05:44:29,880 --> 05:44:32,400 REJUVENATION IN IN LAB IS CAN WE 7564 05:44:32,400 --> 05:44:34,360 REVERSE THAT COGNITIVE DECLINE 7565 05:44:34,360 --> 05:44:36,240 WHETHER IT'S BY ENGAGEMENT 7566 05:44:36,240 --> 05:44:38,720 MECHANISMS CHANGE IN AGING OR BY 7567 05:44:38,720 --> 05:44:40,320 ENGAGING PARALLEL MECHANISMS 7568 05:44:40,320 --> 05:44:42,480 WHERE THE END RESULT IS ROSS 7569 05:44:42,480 --> 05:44:43,480 TORRATION OF COGNITION. 7570 05:44:43,480 --> 05:44:44,320 WE THINK THIS IS IMPORTANT IS 7571 05:44:44,320 --> 05:44:46,320 YOU KNOW, AS WE GET OLDER AND 7572 05:44:46,320 --> 05:44:48,840 USUALLY THE TOPPINGS AREN'T 7573 05:44:48,840 --> 05:44:49,920 RETIREMENT AGE YOU SEE SOME 7574 05:44:49,920 --> 05:44:52,080 SIGNS OF COGNITIVE DECLINE. 7575 05:44:52,080 --> 05:44:56,160 AND THAT TRAINING IS ASSOCIATED 7576 05:44:56,160 --> 05:44:58,920 WELL WITH INCREASE THE RISK OR 7577 05:44:58,920 --> 05:45:00,120 NEURODEGENERATIVE DISEASES WHAT 7578 05:45:00,120 --> 05:45:01,400 WE THINK ABOUT IS ALZHEIMER'S 7579 05:45:01,400 --> 05:45:02,840 AND NOW THE IDEA IS THERE ARE 7580 05:45:02,840 --> 05:45:04,240 NORMAL MECHANISMS FOR EXAMPLE 7581 05:45:04,240 --> 05:45:06,400 SOMEONE THAT IS 20 DOES NOT HAVE 7582 05:45:06,400 --> 05:45:07,720 OVERT PATHOLOGY OF ALZHEIMER'S. 7583 05:45:07,720 --> 05:45:10,000 EVEN WITH GENETIC 7584 05:45:10,000 --> 05:45:11,120 PREDISPOSITIONS WHICH MEANS WE 7585 05:45:11,120 --> 05:45:12,960 CAN LEVERAGE BIOLOGY OF AGING TO 7586 05:45:12,960 --> 05:45:14,360 UNDERSTAND WHAT ARE MECHANISMS 7587 05:45:14,360 --> 05:45:19,920 THEN THAT CAN MAINTAIN FUNCTION 7588 05:45:19,920 --> 05:45:20,440 OR EPIDEMIOLOGY RESTORE 7589 05:45:20,440 --> 05:45:23,440 FUNCTIONS. 7590 05:45:23,440 --> 05:45:25,120 WHETHER THEY ARE SYSTEMIC OR 7591 05:45:25,120 --> 05:45:26,640 BLOOD BASED INTERVENTIONS AND 7592 05:45:26,640 --> 05:45:28,840 THE WHOLE IDEA IS BY LEVERAGING 7593 05:45:28,840 --> 05:45:31,120 THOSE MECHANISMS WE CAN BRING 7594 05:45:31,120 --> 05:45:32,800 BACK THE STATE THAT WE HAVE 7595 05:45:32,800 --> 05:45:34,960 EARLIER ON THAT NATURALLY WAS 7596 05:45:34,960 --> 05:45:35,640 ABLE TO STAVE OFF THIS DISEASE 7597 05:45:35,640 --> 05:45:37,160 AND THAT'S WHAT WE FOCUS ON IN 7598 05:45:37,160 --> 05:45:37,920 THE LAB. 7599 05:45:37,920 --> 05:45:40,240 WHAT DO I MEAN BY COGNITIVE 7600 05:45:40,240 --> 05:45:40,560 DECLINE. 7601 05:45:40,560 --> 05:45:42,080 I LOVE THIS EXAMPLE JUST BECAUSE 7602 05:45:42,080 --> 05:45:44,320 IT'S A PARKING LOT AND AT LEAST 7603 05:45:44,320 --> 05:45:45,800 IN CALIFORNIA WE ALL DRIVE. 7604 05:45:45,800 --> 05:45:48,320 I'M TAKING TRAINING HERE AND SO 7605 05:45:48,320 --> 05:45:50,480 LET'S PRETEND WE'RE DRIVING AN 7606 05:45:50,480 --> 05:45:51,920 ELECTRIC CAR AND YOU COME IN IN 7607 05:45:51,920 --> 05:45:53,360 THE MORNING AND YOUR JUST 7608 05:45:53,360 --> 05:45:55,240 NATURALLY GOING TO LOOK AT 7609 05:45:55,240 --> 05:45:55,880 COMPUTERS IF APPROXIMATE YOU 7610 05:45:55,880 --> 05:45:58,320 HAVE THE GOLDEN GATE BRIDGE YOU 7611 05:45:58,320 --> 05:45:59,760 CAN GET THE END OF THE DAY NO 7612 05:45:59,760 --> 05:46:01,120 PROBLEM YOUR BRAIN IS LIKE YOU 7613 05:46:01,120 --> 05:46:02,920 LIKE THAT VIEW SO GO FIND YOUR 7614 05:46:02,920 --> 05:46:03,880 CAR NEAR THAT. 7615 05:46:03,880 --> 05:46:05,560 AS YOU GET OLDER YOU CAN'T DO 7616 05:46:05,560 --> 05:46:06,760 THIS SO WELL ANYMORE. 7617 05:46:06,760 --> 05:46:08,400 THAT'S BASICALLY ONE TYPE OF 7618 05:46:08,400 --> 05:46:09,760 COGNITIVE DECLINE. 7619 05:46:09,760 --> 05:46:10,960 SPACIAL LEARNING AND MEMORY 7620 05:46:10,960 --> 05:46:13,240 BECOMES IMPAIRED. 7621 05:46:13,240 --> 05:46:14,800 NOT ALL COGNITIVE DECLINED BUT A 7622 05:46:14,800 --> 05:46:16,560 VAST MAJORITY OF THEM DO. 7623 05:46:16,560 --> 05:46:18,360 WHAT WE DO IS WE THEN USE THIS 7624 05:46:18,360 --> 05:46:20,200 BECAUSE IT'S THE SAME TYPE OF I 7625 05:46:20,200 --> 05:46:21,160 REMEMBER AMOUNT. 7626 05:46:21,160 --> 05:46:23,080 AS ACROSS SPECIES AND WE FOCUS 7627 05:46:23,080 --> 05:46:33,560 ON THE MOUSE PODAL AND THEY'RE 7628 05:46:42,760 --> 05:46:43,920 GOING IN DIFFERENT DIRECTIONS SO 7629 05:46:43,920 --> 05:46:45,560 THEY'RE MAKING ERRORS AND THEY 7630 05:46:45,560 --> 05:46:47,360 FIND LIKE AN ELDERLY PERSON WILL 7631 05:46:47,360 --> 05:46:50,040 FIND THEIR CAR AND BEHAVIOURAL 7632 05:46:50,040 --> 05:46:51,840 TASK TO ASK WHAT'S PROMOTING 7633 05:46:51,840 --> 05:46:53,400 DECLINE OR ALREADY OLD ANIMAL 7634 05:46:53,400 --> 05:46:56,000 WITH REMOTING RECOVERY OR 7635 05:46:56,000 --> 05:46:56,600 IMPROVEMENT. 7636 05:46:56,600 --> 05:46:57,680 WE'VE HEARD THIS ON ONE PART OF 7637 05:46:57,680 --> 05:46:58,480 THE BRAIN. 7638 05:46:58,480 --> 05:47:00,000 A REGULATE OR OF LEARNING IN 7639 05:47:00,000 --> 05:47:04,120 MEMORY AND HERE IT'S JUST 7640 05:47:04,120 --> 05:47:05,920 HIPPOCAMPUS NOW WHAT IS 7641 05:47:05,920 --> 05:47:07,120 INTERESTING IT'S ONE OF THE 7642 05:47:07,120 --> 05:47:08,320 FIRST PARTS OF THE BRAIN 7643 05:47:08,320 --> 05:47:10,480 IMPACTED BY AGING SO IT'S A 7644 05:47:10,480 --> 05:47:12,160 REGION AND THERE'S A SERIES OF 7645 05:47:12,160 --> 05:47:13,120 CELLULAR HALLMARKS THAT WE 7646 05:47:13,120 --> 05:47:14,920 UNDERSTAND TO CONTRIBUTE TOWARDS 7647 05:47:14,920 --> 05:47:16,200 THAT COGNITIVE DECLINE. 7648 05:47:16,200 --> 05:47:18,400 FOR EXAMPLE, THINGS LIKE 7649 05:47:18,400 --> 05:47:19,480 REGENERATION, STEM CELL FUNCTION 7650 05:47:19,480 --> 05:47:21,960 GOES AWAY AND WE KNOW THAT THE 7651 05:47:21,960 --> 05:47:23,960 COMMUNICATION BETWEEN THE 7652 05:47:23,960 --> 05:47:26,280 NEURONS AND THE DECLINES AND ONE 7653 05:47:26,280 --> 05:47:28,320 IS REALLY EMERGING A LOT IS THE 7654 05:47:28,320 --> 05:47:29,960 IDEA OF NEUROINFLAMMATION BOTH 7655 05:47:29,960 --> 05:47:33,520 WITHIN THE BRAIN AND IT'S GLEIA 7656 05:47:33,520 --> 05:47:36,040 OR MICROGLIA AS WELL AS ALSO 7657 05:47:36,040 --> 05:47:37,120 INFILTRATING CELLS IN THE 7658 05:47:37,120 --> 05:47:38,680 CONFLICT OF DISEASE AND THE 7659 05:47:38,680 --> 05:47:39,960 OTHER ONE THAT THERE'S MORE AND 7660 05:47:39,960 --> 05:47:41,880 MORE EVIDENCE NOW FOR A REAL KEY 7661 05:47:41,880 --> 05:47:43,760 ROLE WOULD BE THE VASCULAR WHERE 7662 05:47:43,760 --> 05:47:45,920 WE'LL HEAR ABOUT IN TERMS OF 7663 05:47:45,920 --> 05:47:47,200 BLOOD BRAIN BARRIER AS WELL. 7664 05:47:47,200 --> 05:47:49,480 TODAY MY LAB LOOKS AT ALL OF 7665 05:47:49,480 --> 05:47:50,920 THESE DIFFERENT HALLMARKS AND 7666 05:47:50,920 --> 05:47:53,400 TODAY I WANT TO SHARE ON THE 7667 05:47:53,400 --> 05:47:54,400 NEUROINFLAMMATION COMMENT WITHIN 7668 05:47:54,400 --> 05:47:56,640 THE HIPPOCAMPUS AND THE INTRA 7669 05:47:56,640 --> 05:47:57,440 PLAY. 7670 05:47:57,440 --> 05:48:00,160 SO I WAS DOING SO WELL FOR SO 7671 05:48:00,160 --> 05:48:00,520 LONG. 7672 05:48:00,520 --> 05:48:03,280 SO I MENTIONED, IN MY LAB WE 7673 05:48:03,280 --> 05:48:05,080 FOCUS ON INTERVENTIONS WHEN WE 7674 05:48:05,080 --> 05:48:07,640 FIRST BEGAN IN THE LAB WE 7675 05:48:07,640 --> 05:48:09,040 FOCUSED ON CONNECT THE YOUNG AND 7676 05:48:09,040 --> 05:48:11,920 OLD ANIMAL AND WE SHOWED THAT 7677 05:48:11,920 --> 05:48:13,440 THERE'S AGING FACTORS A LOT OF 7678 05:48:13,440 --> 05:48:15,720 IMMUNE FACTORS PROMOTING AIMING 7679 05:48:15,720 --> 05:48:18,360 SO WE SAW SAW THE CONVERSE 7680 05:48:18,360 --> 05:48:20,160 THERE'S SOMETHING IN YOUNG BLOOD 7681 05:48:20,160 --> 05:48:21,000 THAT RESTORES FUNCTION AND WE 7682 05:48:21,000 --> 05:48:24,360 SHARED IT IN NEURONS AND ON 7683 05:48:24,360 --> 05:48:25,160 REGENERATION ALTHOUGH UP UNTIL 7684 05:48:25,160 --> 05:48:29,440 THIS POINT WE DID NOT LOOK INTO 7685 05:48:29,440 --> 05:48:39,960 NEURO AND OUGHT WRACK WE'VE BEEN 7686 05:48:48,760 --> 05:48:50,440 DOING SO THIS IS NOW ALMOST A 7687 05:48:50,440 --> 05:48:55,000 DECADE AGO THAT WE SHARED YOU 7688 05:48:55,000 --> 05:48:56,080 REQUEST CORRECT THE PLASMA AND 7689 05:48:56,080 --> 05:48:57,600 IT'S MOSTLY DESTROYED OF CELLS 7690 05:48:57,600 --> 05:48:59,200 AS WE DISCOVERED NOT COMPLETELY 7691 05:48:59,200 --> 05:49:05,120 DESTROYED OF CELLS AND YOU DO 7692 05:49:05,120 --> 05:49:07,000 THE BEHAVIOUR AND WHEN YOU COME 7693 05:49:07,000 --> 05:49:09,000 BACK A MONTH LATER AFTER THESE 7694 05:49:09,000 --> 05:49:10,680 TREATMENTS IN GRAY YOU SEE A 7695 05:49:10,680 --> 05:49:12,440 NORMAL OLD ANIMAL RECEIVING OLD 7696 05:49:12,440 --> 05:49:13,520 PLASMA THEY'RE ABOUT 7697 05:49:13,520 --> 05:49:14,800 TWO-YEARS-OLD AND EQUIVALENT TO 7698 05:49:14,800 --> 05:49:16,600 SOMEONE IN THEIR 70s AND WHEN 7699 05:49:16,600 --> 05:49:19,320 YOU GIVE THIS OLDER AND LITTER 7700 05:49:19,320 --> 05:49:21,440 MATES THIS CASE, OLD ANIMALS AND 7701 05:49:21,440 --> 05:49:23,600 YOU GIVE THEM IN RED IT'S A HUGE 7702 05:49:23,600 --> 05:49:27,520 SEPARATION WHERE THE ANIMALS ARE 7703 05:49:27,520 --> 05:49:28,200 MAKING LESSER OR. 7704 05:49:28,200 --> 05:49:29,800 THEY'RE GUIDED DIRECTLY TOWARDS 7705 05:49:29,800 --> 05:49:30,880 THAT POPCORN. 7706 05:49:30,880 --> 05:49:32,000 SO WE KNOW THAT THERE'S 7707 05:49:32,000 --> 05:49:33,040 REVERSION ABILITY AND WE THOUGH 7708 05:49:33,040 --> 05:49:34,240 THERE'S SOMETHING IN YOUNG 7709 05:49:34,240 --> 05:49:35,440 BLOOD. 7710 05:49:35,440 --> 05:49:37,560 AND WE HAVE NOW SPENT A LONG 7711 05:49:37,560 --> 05:49:39,360 TIME TRYING TO FIGURE OUT THE 7712 05:49:39,360 --> 05:49:41,040 CELLULAR MECHANISMS THAT ARE 7713 05:49:41,040 --> 05:49:43,280 PROMOTING THAT RECOVERY THAT 7714 05:49:43,280 --> 05:49:44,360 REJUVENATION AND WE HAVE TO GIVE 7715 05:49:44,360 --> 05:49:46,640 CREDIT TO A VERY TALENTED 7716 05:49:46,640 --> 05:49:48,680 POSTDOC WHO IS REALLY 7717 05:49:48,680 --> 05:49:49,640 SPEARHEADED THE RESEARCH THAT 7718 05:49:49,640 --> 05:49:51,160 I'M ABOUT TO SHEAR WITH YOU. 7719 05:49:51,160 --> 05:49:52,840 SO FIRST THING WE DID IS WENT 7720 05:49:52,840 --> 05:49:54,960 BACK AND JUST FOCUSED ON THAT 7721 05:49:54,960 --> 05:49:56,640 SORT OF YOUNG AND AGED PLASMA. 7722 05:49:56,640 --> 05:49:58,680 THIS IS ABOUT 20 TO 22 MONTHS 7723 05:49:58,680 --> 05:50:01,520 OLD VERSUS ABOUT THREE TO FOUR 7724 05:50:01,520 --> 05:50:04,400 MONTHS AND WE DIDN'T ASK THIS IS 7725 05:50:04,400 --> 05:50:06,520 UNI BELIEVED AND WE ASKED WHAT 7726 05:50:06,520 --> 05:50:07,840 BIOLOGICAL PROCESS ARE CHANGING 7727 05:50:07,840 --> 05:50:10,440 BASED ON THE CHANGES WE SEE IN 7728 05:50:10,440 --> 05:50:12,080 THE SOL YOU ABLE FACTORS IN THE 7729 05:50:12,080 --> 05:50:17,800 TOP IT WAS CHANGES IN PLATELETS 7730 05:50:17,800 --> 05:50:19,200 AND WE WENT BACK AND THE FIELD 7731 05:50:19,200 --> 05:50:23,160 USE AND WE WERE AMONG THE FIRST 7732 05:50:23,160 --> 05:50:33,720 THAT DID THIS WE ENDED UPTAKING 7733 05:50:47,840 --> 05:50:58,080 PLATE LATE AND OF THE CONTROL, 7734 05:50:58,080 --> 05:51:00,240 THE YOUNG PLASMA AS WELL AS THE 7735 05:51:00,240 --> 05:51:02,440 AN MEALS RECEIVING THAT AND WE 7736 05:51:02,440 --> 05:51:04,600 PHOTOGRAPHIC YOU USED ON THE 7737 05:51:04,600 --> 05:51:05,400 QUEEN'S THAT WERE CONSERVED 7738 05:51:05,400 --> 05:51:07,680 BETWEEN BOTH AND THERE WERE 7739 05:51:07,680 --> 05:51:09,560 ABOUT 200 OUT OF 600 IN CASE 7740 05:51:09,560 --> 05:51:12,160 CASE AND WE LOOKED AT THE LIE 7741 05:51:12,160 --> 05:51:13,360 LOGICAL PROCESSES ASSOCIATED 7742 05:51:13,360 --> 05:51:15,440 WITH THAT WE SAW CENTRAL NERVOUS 7743 05:51:15,440 --> 05:51:16,800 SYSTEM DEVELOPMENT INDICATIVE OF 7744 05:51:16,800 --> 05:51:18,960 THAT PLASTICITY OR REGENERATION 7745 05:51:18,960 --> 05:51:21,520 WHICH WE SHOWN TO BE IMPACTED BY 7746 05:51:21,520 --> 05:51:24,120 AND WE SAW THINGS LIKE A LOT OF 7747 05:51:24,120 --> 05:51:26,320 CHEMO SIGN 123458ING POP UP AND 7748 05:51:26,320 --> 05:51:28,680 WE HAD NOT YET LOOKED INTO 7749 05:51:28,680 --> 05:51:30,840 NEUROINFLAMMATION SO IT COULD BE 7750 05:51:30,840 --> 05:51:32,960 IT'S YOUNG PLASMA COULD EXTEND 7751 05:51:32,960 --> 05:51:35,080 TO THE NEUROINFLAMMATION 7752 05:51:35,080 --> 05:51:37,760 HALLMARKS OF AGING SO WE THOUGHT 7753 05:51:37,760 --> 05:51:39,640 NEXT WORK AND AGAIN BROADLY JUST 7754 05:51:39,640 --> 05:51:41,200 YOUNG PLASMA AS WELL AS THAT 7755 05:51:41,200 --> 05:51:42,800 YOUNG FRACTION FIRST WE JUST 7756 05:51:42,800 --> 05:51:44,400 LOOKED AT SOME MARKERS THAT 7757 05:51:44,400 --> 05:51:49,120 CHANGES AGE AND IT'S TMS AND 7758 05:51:49,120 --> 05:51:51,040 TD11B AND SAW A REDUCTION 7759 05:51:51,040 --> 05:51:56,080 COMPARED TO THAT OLD ANIMAL AND 7760 05:51:56,080 --> 05:51:58,240 AND REDISCUSSION WE RESIDENT AND 7761 05:51:58,240 --> 05:52:03,240 MAKE OWE PAGES AND MIKE GLIA 7762 05:52:03,240 --> 05:52:06,080 WHICH IS WHEN THESE PEOPLE ON 7763 05:52:06,080 --> 05:52:08,360 THE WILL SAY ACTIVATED AND I'M 7764 05:52:08,360 --> 05:52:09,560 JUST GOING TO RESPONSE WITH BUT 7765 05:52:09,560 --> 05:52:12,000 WITH AGING WE KNOW THERE'S ANNA 7766 05:52:12,000 --> 05:52:15,000 ACCUMULATION OF CDC CA HAD WE 7767 05:52:15,000 --> 05:52:18,360 TREAT THESE ANIMALS WITH YOUNG 7768 05:52:18,360 --> 05:52:19,280 PLASMA OR PLATELET FRACTION SO 7769 05:52:19,280 --> 05:52:21,560 WE GOT EXCITED WITH THAT AND MY 7770 05:52:21,560 --> 05:52:23,720 LAB WE'D LIKE TO TAKE A 7771 05:52:23,720 --> 05:52:25,120 REDUCTION APPROACH AND GO FROM 7772 05:52:25,120 --> 05:52:26,840 BIGGER TO SMALLER SO WE FOUND 7773 05:52:26,840 --> 05:52:28,880 COMPARE BIAS TO PLASMA AND 7774 05:52:28,880 --> 05:52:35,040 PLASMA TO INFRACTION WHAT IS 7775 05:52:35,040 --> 05:52:36,560 LEADING TOWARDS THESE 7776 05:52:36,560 --> 05:52:38,360 ATTENUATION AND MICRO GLEE OWE 7777 05:52:38,360 --> 05:52:40,720 MARKERS AND SO WHAT WE ENDED UP 7778 05:52:40,720 --> 05:52:42,440 DOING HERE IS TAKING APPROACH 7779 05:52:42,440 --> 05:52:46,600 AND WE DID ADDITIONAL PROTEOMIC 7780 05:52:46,600 --> 05:52:49,640 AND WE SAW THE PLATELET FRACTION 7781 05:52:49,640 --> 05:52:51,800 WHAT IS HAPPENING BETWEEN THAT 7782 05:52:51,800 --> 05:52:53,080 PLATELET FRACTION IN THE END AND 7783 05:52:53,080 --> 05:52:55,120 THE TECHNICAL REASONS AND 7784 05:52:55,120 --> 05:52:56,920 LIMITATIONS AND IT'S REALLY WE 7785 05:52:56,920 --> 05:52:58,680 PULLED A LOT OF ANIMALS INTO ONE 7786 05:52:58,680 --> 05:53:01,000 GROUP AND SO I'M ONLY LISTING 7787 05:53:01,000 --> 05:53:02,080 ONE FACTORS BUT THIS IS JUST 7788 05:53:02,080 --> 05:53:03,400 PULLING A LOT INTO ONE WHERE WE 7789 05:53:03,400 --> 05:53:07,120 HAD ONE CHANCE AT IT BASICALLY. 7790 05:53:07,120 --> 05:53:07,720 WE SURVEYED THE FACTORIES THAT 7791 05:53:07,720 --> 05:53:09,040 WE HAD AND WHAT WAS REALLY 7792 05:53:09,040 --> 05:53:10,320 INTERESTING IS THAT THERE'S ONE 7793 05:53:10,320 --> 05:53:11,760 FACTOR THAT HAD APPEARED AND 7794 05:53:11,760 --> 05:53:14,400 BEEN ASSOCIATED WITH ADDITIONAL 7795 05:53:14,400 --> 05:53:15,480 INTERCEPTIONS BUT NO ONE LOOKED 7796 05:53:15,480 --> 05:53:18,440 AT IT FUNCTIONALLY AND BOTH 7797 05:53:18,440 --> 05:53:22,840 EXERCISING IN YOUNG ANIMALS AND 7798 05:53:22,840 --> 05:53:25,080 CXCL4 IT'S ELEVATED IN YOUNG 7799 05:53:25,080 --> 05:53:27,000 ANIMALS AND ASSOCIATED WITH 7800 05:53:27,000 --> 05:53:28,280 INCREASE NEURO GENESIS IN THE 7801 05:53:28,280 --> 05:53:30,560 BRAIN WHEN YOU ACTUALLY REPLACE 7802 05:53:30,560 --> 05:53:35,920 450RE 50 OFBLOOD WITH OLD ANIMAE 7803 05:53:35,920 --> 05:53:38,280 AN INCREASE IN ASSOCIATED WITH 7804 05:53:38,280 --> 05:53:39,560 SOME OF THE IMPROVEMENT THAT'S 7805 05:53:39,560 --> 05:53:41,720 THEY SAW ON THAT MODEL SO WE 7806 05:53:41,720 --> 05:53:42,760 THOUGHT THIS WAS INTERESTING 7807 05:53:42,760 --> 05:53:45,280 IT'S ONE FACTOR THAT APPEARS 7808 05:53:45,280 --> 05:53:46,720 ACROSS DIFFERENT INTERVENTIONS 7809 05:53:46,720 --> 05:53:47,560 AND WE ARE PERSUADE IT 7810 05:53:47,560 --> 05:53:47,920 FUNCTIONALLY. 7811 05:53:47,920 --> 05:53:50,640 THE FIRST WE DID IS JUST LET 7812 05:53:50,640 --> 05:53:51,680 THAT PLATELET FRACTION AS WELL 7813 05:53:51,680 --> 05:53:52,760 AS THE PROBLEM ITSELF AND YOU 7814 05:53:52,760 --> 05:53:56,400 CAN SEE THERE'S A DECREASE ON 7815 05:53:56,400 --> 05:53:59,800 THE VARIABLE WITH AN AGE RELATED 7816 05:53:59,800 --> 05:54:02,160 DECREASE IN OUR PREPARATIONS AND 7817 05:54:02,160 --> 05:54:04,600 WE HAVE ACCESS TO HUMAN SAMPLES 7818 05:54:04,600 --> 05:54:07,800 SO WE RECRUITED AROUND 20 YOUNG 7819 05:54:07,800 --> 05:54:10,080 INDIVIDUALS BETWEEN 22 TO 34 AND 7820 05:54:10,080 --> 05:54:13,520 THEN ABOUT 20 OLDER INDIVIDUALS. 7821 05:54:13,520 --> 05:54:14,240 ACTUALLY 16 IS THE ACTUAL 7822 05:54:14,240 --> 05:54:15,160 NUMBER. 7823 05:54:15,160 --> 05:54:17,640 AND AGAIN THIS IS A CASE WE 7824 05:54:17,640 --> 05:54:19,080 LOOKED AT PLATELET RICH PLASMA 7825 05:54:19,080 --> 05:54:21,480 AND WE SORT OF SAW THIS DECREASE 7826 05:54:21,480 --> 05:54:24,800 WITHIN AGAIN THIS PLATELET RICH 7827 05:54:24,800 --> 05:54:25,760 PREPARATION THAT WE HAD. 7828 05:54:25,760 --> 05:54:28,600 SO FROM THERE WE WANTED GO INTO 7829 05:54:28,600 --> 05:54:29,440 THE ONE MARK. 7830 05:54:29,440 --> 05:54:31,600 WHAT IS IT WE CAN DO JUST HERE. 7831 05:54:31,600 --> 05:54:35,120 WHEN WE SORT OF SYSTEMICALLY 7832 05:54:35,120 --> 05:54:37,400 ADMINISTERED IT BEFORE THE INTRA 7833 05:54:37,400 --> 05:54:38,760 VENUS INJECTIONS WE LOOK AT THE 7834 05:54:38,760 --> 05:54:42,400 READ OUT AND AGAIN SIMILAR TO 7835 05:54:42,400 --> 05:54:44,280 PLASMA AND PLATELET FRACTION WE 7836 05:54:44,280 --> 05:54:47,920 SEE IT IN TNF AND WE LOOKED AT 7837 05:54:47,920 --> 05:54:50,000 IL AND BETA AND AGAIN WE LOOKED 7838 05:54:50,000 --> 05:54:52,760 AT THAT CD68 AS A MARKER AT A 7839 05:54:52,760 --> 05:54:54,640 SEM YOU LAR LEVEL AND WE SAW 7840 05:54:54,640 --> 05:54:57,160 REJECTION SO IT'S JUST INJECTION 7841 05:54:57,160 --> 05:54:59,800 THAT IN INNU EIGHTING THEIR I AM 7842 05:54:59,800 --> 05:55:01,680 FLEW INDICATION AND WE ISOLATED 7843 05:55:01,680 --> 05:55:04,160 THE MICROGLIA FROM ANIMALS THAT 7844 05:55:04,160 --> 05:55:06,160 WERE ADMINISTERED AND WE DID RNA 7845 05:55:06,160 --> 05:55:07,680 SEQUENCING AND WE LOOKED AT THE 7846 05:55:07,680 --> 05:55:10,080 QUEEN'S THAT WERE DECREASED, 7847 05:55:10,080 --> 05:55:11,040 FOLLOWING ADMINISTRATION, WE SAW 7848 05:55:11,040 --> 05:55:14,000 A LOT OF TNF MEDIATED SIGNALING 7849 05:55:14,000 --> 05:55:15,280 PATHWAYS THAT WERE DECREASING 7850 05:55:15,280 --> 05:55:17,000 AND IT SEEMED TO BE TARGETING 7851 05:55:17,000 --> 05:55:18,520 SOME OF THESE SIGNALING WITHIN 7852 05:55:18,520 --> 05:55:20,440 THE MICROGLIA. 7853 05:55:20,440 --> 05:55:21,960 THE NEXT QUESTION WHEN YOU THINK 7854 05:55:21,960 --> 05:55:23,760 ABOUT THE BRAIN BECAUSE WE HAVE 7855 05:55:23,760 --> 05:55:25,320 BLOOD BRAIN BARRIER YOU ARE 7856 05:55:25,320 --> 05:55:26,880 GETTING IN FROM THE BLOOD OR 7857 05:55:26,880 --> 05:55:28,760 IT'S IMPACTING THE PERIPHERY AND 7858 05:55:28,760 --> 05:55:30,520 THE PERIPHERY HAS AN IMPACT ON 7859 05:55:30,520 --> 05:55:32,280 THE BRAIN AND WE WANTED TO 7860 05:55:32,280 --> 05:55:33,440 PURSUE THAT PARTICULAR IDEA. 7861 05:55:33,440 --> 05:55:36,320 SO WE MADE A FORM OF THAT WE 7862 05:55:36,320 --> 05:55:38,080 COULD OVER PRESS INTO THE RIVER 7863 05:55:38,080 --> 05:55:40,720 THAT HAS A HYBRID TAG THAT WHEN 7864 05:55:40,720 --> 05:55:44,840 EXPRESSED, THEY HAVE THE HUMAN 7865 05:55:44,840 --> 05:55:55,360 INNES ENTRY ACTION AND WHEN OF 7866 05:56:08,200 --> 05:56:11,880 COURSE THEN YOU HAVE TO GO WHAT 7867 05:56:11,880 --> 05:56:19,120 IS IT WE WENT AND ASKED WHAT 7868 05:56:19,120 --> 05:56:20,680 CHANGING AND WHEN WE LOOKED AT 7869 05:56:20,680 --> 05:56:23,480 THE SORT OF FACTORS IN BLOOD 7870 05:56:23,480 --> 05:56:26,280 THAT WERE BEING LOWER IN THE PF4 7871 05:56:26,280 --> 05:56:28,360 TREAT AND THE CONTROL, WE SAW A 7872 05:56:28,360 --> 05:56:29,640 LOT OF THINGS THAT WERE INVOLVED 7873 05:56:29,640 --> 05:56:33,120 IN SORT OF INFLAMMATORY 7874 05:56:33,120 --> 05:56:34,520 RESPONSES AND WE WERE SEEING A 7875 05:56:34,520 --> 05:56:35,800 DECREASE IN FACTORS ASSOCIATED 7876 05:56:35,800 --> 05:56:37,360 WITH INFLAMMATION. 7877 05:56:37,360 --> 05:56:39,440 SO THAT PROMPTED US TO GET A 7878 05:56:39,440 --> 05:56:42,320 LITTLE BIT MORE OF A PERSPECTIVE 7879 05:56:42,320 --> 05:56:43,640 ON WHAT IS HAPPENING TO THE 7880 05:56:43,640 --> 05:56:47,560 IMMUNE SYSTEM IN THESE ANIMALS 7881 05:56:47,560 --> 05:56:49,920 FOLLOWING PM4 ADMINISTRATION WE 7882 05:56:49,920 --> 05:56:53,640 DID RNA SEQUENCING WHERE YOU 7883 05:56:53,640 --> 05:56:55,440 HAVE CON GRA JAYED WITH NUCLI 7884 05:56:55,440 --> 05:56:57,440 OWE TIED SO YOU CAN GET 7885 05:56:57,440 --> 05:56:58,400 TRANSCRIPTIONAL CHANGES WITHIN 7886 05:56:58,400 --> 05:57:00,600 THE CELL AND DETECT THE SURFACE 7887 05:57:00,600 --> 05:57:02,560 INVESTIGATION ON THE SURFACE AS 7888 05:57:02,560 --> 05:57:04,360 A NEUROSCIENTIST COMING INTO THE 7889 05:57:04,360 --> 05:57:09,280 IMMUNOLOGY RNA AND DO NOT LIKE 7890 05:57:09,280 --> 05:57:10,120 MATCH IN THIS PARTICULAR PART OF 7891 05:57:10,120 --> 05:57:14,720 THE BODY SO WE JUST HAD TO TAKE 7892 05:57:14,720 --> 05:57:17,800 THIS APPROACH. 7893 05:57:17,800 --> 05:57:23,240 I IT GIVE YOU HIGHLIGHT WE 7894 05:57:23,240 --> 05:57:24,600 LOOKED AT THE EXPRESS IN AND YOU 7895 05:57:24,600 --> 05:57:26,600 WILL NOTICE THERE'S THIS AGE 7896 05:57:26,600 --> 05:57:27,440 RELATED TRANSPORTATION PROFILE 7897 05:57:27,440 --> 05:57:29,880 THAT EMERGING THAT IS IN PART 7898 05:57:29,880 --> 05:57:31,520 REVERSE IN THESE TREATED ANIMALS 7899 05:57:31,520 --> 05:57:33,360 AND WHEN WE LOOKED AT THE 7900 05:57:33,360 --> 05:57:35,520 RELATIVE POPULATIONS AND TO 7901 05:57:35,520 --> 05:57:39,120 MACROPHAGES YOU HAVE TWO MINUTES 7902 05:57:39,120 --> 05:57:40,280 LEFT? 7903 05:57:40,280 --> 05:57:42,760 WE LOOKED AT THE MACROPHAGES YOU 7904 05:57:42,760 --> 05:57:44,480 WILL SEE THAT IF YOU LOOK AT THE 7905 05:57:44,480 --> 05:57:47,400 LINE ZERO IT IS YOUTHFUL LEVELS 7906 05:57:47,400 --> 05:57:50,080 AND INCREASE IN THE MACROPHAGE 7907 05:57:50,080 --> 05:57:51,400 POPULATION THAT IS BROUGHT DOWN 7908 05:57:51,400 --> 05:57:53,200 CLOSER TO YOUNGER LEVELS AND IF 7909 05:57:53,200 --> 05:57:55,840 WE LOOK ALTERNATIVELY, AT T 7910 05:57:55,840 --> 05:57:57,600 CELLS WHICH IS WHAT I'M 7911 05:57:57,600 --> 05:57:58,720 HIGHLIGHTING HERE YOU HAVE THIS 7912 05:57:58,720 --> 05:58:00,840 AGE RELATED TRANSCRIPTIONAL 7913 05:58:00,840 --> 05:58:07,200 CHANGES YOU SEE IN PART REVERSE 7914 05:58:07,200 --> 05:58:08,960 I WILL HIGHLIGHT THE AGE 7915 05:58:08,960 --> 05:58:10,960 ASSOCIATED AND THE POSITIVE AND 7916 05:58:10,960 --> 05:58:12,720 THEN A HIGH INCREASE JUST LIKE 7917 05:58:12,720 --> 05:58:14,160 WE HEARD ABOUT IN A COUPLE OF 7918 05:58:14,160 --> 05:58:15,960 TALKS BEFORE AND THOSE LEVELS 7919 05:58:15,960 --> 05:58:16,760 ARE BROUGHT DOWN FOR EXAMPLE IF 7920 05:58:16,760 --> 05:58:20,200 YOU LOOKED AT NAIVE DETAILS 7921 05:58:20,200 --> 05:58:22,200 THOSE ARE A DECREASE AND THAT 7922 05:58:22,200 --> 05:58:23,400 DECREASE IS IN PART AND 7923 05:58:23,400 --> 05:58:24,440 FOLLOWING THIS ADMINISTRATION 7924 05:58:24,440 --> 05:58:26,000 AND AGAIN SUGGESTING THAT WE'RE 7925 05:58:26,000 --> 05:58:30,600 GETTING CLOSER TO A YOUNGER 7926 05:58:30,600 --> 05:58:31,600 COMPETITION AND THEY'RE LOOKING 7927 05:58:31,600 --> 05:58:33,680 AT REFLECTIVE OF A YOUNGER 7928 05:58:33,680 --> 05:58:34,080 CONTINUE AS WELL. 7929 05:58:34,080 --> 05:58:35,320 SO JUST BIG PICTURE. 7930 05:58:35,320 --> 05:58:38,560 YOU KNOW, A LOT OF WORK THAT HAS 7931 05:58:38,560 --> 05:58:40,600 DONE FOR RECONSTITUTION IS THE 7932 05:58:40,600 --> 05:58:42,840 OLD AND YOUNG HAVE SHOWN THAT 7933 05:58:42,840 --> 05:58:44,280 THE PERIPHERAL IMMUNE SYSTEM CAN 7934 05:58:44,280 --> 05:58:46,640 IMPACT COGNITION AND BEAUTIFUL 7935 05:58:46,640 --> 05:58:49,720 WORK THAT YOU WILL HEAR ABOUT 7936 05:58:49,720 --> 05:58:51,120 MORE TOMORROW AND SHOWED 7937 05:58:51,120 --> 05:58:52,920 TARGETING METABOLISM WITHIN THE 7938 05:58:52,920 --> 05:58:55,760 AGE CAN IMPROVE COGNITION AND WE 7939 05:58:55,760 --> 05:58:56,920 THOUGHT WE HAVE AN INTERVENTION 7940 05:58:56,920 --> 05:58:59,320 HERE THAT IS CHANGING 7941 05:58:59,320 --> 05:59:02,360 NEUROINFLAMMATION IN THE BRAIN 7942 05:59:02,360 --> 05:59:02,880 AND CHANGING I OBJECT FROM 7943 05:59:02,880 --> 05:59:04,040 MISSION COULD IT BE THAT 7944 05:59:04,040 --> 05:59:05,720 FUNCTIONING IS REFLECTIVE IN 7945 05:59:05,720 --> 05:59:09,120 IMPROVED COGNITION. 7946 05:59:09,120 --> 05:59:10,680 WE WENT BACK I HAVE TO SPEND 7947 05:59:10,680 --> 05:59:13,040 WITH BEHAVIOUR BECAUSE I AM A 7948 05:59:13,040 --> 05:59:14,360 NEUROSCIENTIST AND IN BLACK IT'S 7949 05:59:14,360 --> 05:59:17,600 AN OLD ANIMAL CREATED WITH 7950 05:59:17,600 --> 05:59:19,840 CONTROL AND IN BLUE OLD ANIMAL 7951 05:59:19,840 --> 05:59:20,960 TREATED SYSTEMICALLY AND YOU CAN 7952 05:59:20,960 --> 05:59:24,000 SEE THE NUMBER OF ERRORS BY THE 7953 05:59:24,000 --> 05:59:28,360 NUMBER OF TESTING IS IMPROVED SO 7954 05:59:28,360 --> 05:59:29,600 AGAIN, WE KNOW INTERESTED 7955 05:59:29,600 --> 05:59:31,000 ADDITIVE MECHANISMS AND IT DOES 7956 05:59:31,000 --> 05:59:32,800 NOT ACCOUNT FOR THE BLOOD BUT WE 7957 05:59:32,800 --> 05:59:34,480 THINK IT'S ONE QUITE POTENT 7958 05:59:34,480 --> 05:59:39,920 FACTOR THAT WE'VE IDENTIFIED. 7959 05:59:39,920 --> 05:59:41,240 WITH THAT, WE FOUND AN 7960 05:59:41,240 --> 05:59:42,520 INTERESTING ROLE FOR LATE LET'S 7961 05:59:42,520 --> 05:59:44,920 AND DIFFERENT INTERVENTIONS AND 7962 05:59:44,920 --> 05:59:46,680 EXERCISES DELIVER FACTORS SO 7963 05:59:46,680 --> 05:59:49,960 THEY'RE ALL THERE AND SORT OF 7964 05:59:49,960 --> 05:59:51,280 BIG QUESTION WHAT ARE THINGS 7965 05:59:51,280 --> 05:59:53,520 THAT ARE A GAP I HOPE THE 7966 05:59:53,520 --> 05:59:54,840 INTERACT AND COMMUNICATION 7967 05:59:54,840 --> 05:59:56,520 BETWEEN NEUROSCIENCE AND 7968 05:59:56,520 --> 05:59:57,480 IMMUNOLOGIST GETS BETTER BECAUSE 7969 05:59:57,480 --> 05:59:59,520 WE'RE THINKING A LOT ABOUT 7970 05:59:59,520 --> 06:00:01,400 MICROGLIA, GLIA, INFILTRATION, 7971 06:00:01,400 --> 06:00:03,080 NOT SO MUCH NECESSARILY ABOUT 7972 06:00:03,080 --> 06:00:05,240 HOW IS THE PERIPHERAL IMMUNE 7973 06:00:05,240 --> 06:00:07,760 SYSTEM HAVING HUGE IMPACTS ON 7974 06:00:07,760 --> 06:00:08,680 FUNCTION WITH WITHOUT 7975 06:00:08,680 --> 06:00:10,040 NECESSARILY THOSE FACTORS 7976 06:00:10,040 --> 06:00:11,600 GETTING IN AND THERE MUST BE 7977 06:00:11,600 --> 06:00:13,760 THAT WAY AND WE'RE STILL TO 7978 06:00:13,760 --> 06:00:14,600 FIGURE THOSE OUT. 7979 06:00:14,600 --> 06:00:17,880 WITH THAT I'LL TAKE THAT. 7980 06:00:17,880 --> 06:00:19,680 >>ALL THE ACKNOWLEDGMENTS 7981 06:00:19,680 --> 06:00:30,120 FUNDING AND THANK YOU NIH. 7982 06:00:33,640 --> 06:00:36,200 >>THANK YOU. 7983 06:00:36,200 --> 06:00:44,480 >>SO THE CORRECTED AND WHEN YOU 7984 06:00:44,480 --> 06:00:47,040 SUBSTITUTE BLOOD AND TF4 GOES UP 7985 06:00:47,040 --> 06:00:48,120 DID YOU THAT THAT? 7986 06:00:48,120 --> 06:00:50,120 >>YOU ARE IN A CONVOY AT 7987 06:00:50,120 --> 06:00:52,400 BERKELEY AND THE INTERVENTION 7988 06:00:52,400 --> 06:00:54,680 SHE'S DONE AS WELL AND THEY DID 7989 06:00:54,680 --> 06:00:56,000 PROTEOMIC THEY DID SEE A LOT OF 7990 06:00:56,000 --> 06:00:57,760 THINGS GO DOWN AND THINGS 7991 06:00:57,760 --> 06:01:00,360 STEPPED UP OF WHICH IT'S ONE OF 7992 06:01:00,360 --> 06:01:00,760 AND EXERCISE. 7993 06:01:00,760 --> 06:01:04,760 >>HOW DO YOU IMAGINE. 7994 06:01:04,760 --> 06:01:06,920 >>THESE ARE INVOLVED IN WOUND 7995 06:01:06,920 --> 06:01:10,480 HEALING IT'S LIKE A WOUND 7996 06:01:10,480 --> 06:01:19,040 HEALING RESPONSE AN ANDED WE ARE 7997 06:01:19,040 --> 06:01:19,560 ENGAGING THOSE MECHANISMS. 7998 06:01:19,560 --> 06:01:21,400 >>IN THE LAST SLIDE YOU SHOWED 7999 06:01:21,400 --> 06:01:23,560 WHICH YOU SHOWED PREVIOUSLY, WAS 8000 06:01:23,560 --> 06:01:25,120 THE 99 DAYS AND HOW LONG TUESDAY 8001 06:01:25,120 --> 06:01:29,680 THAT LAST AND IF YOU ADD MORE 8002 06:01:29,680 --> 06:01:31,320 PLAS THAT CAN YOU GO LONGER OR 8003 06:01:31,320 --> 06:01:33,600 GIVE MORE DETAIL? 8004 06:01:33,600 --> 06:01:35,360 >>PEOPLE HAVE DONE IT AND WE'VE 8005 06:01:35,360 --> 06:01:37,440 DONE SOME OF IT AND IF YOU 8006 06:01:37,440 --> 06:01:38,840 SEPARATE THEM IN TISSUE LIKE 8007 06:01:38,840 --> 06:01:40,200 MUSCLE YOU CAN ASSOCIATE SIX 8008 06:01:40,200 --> 06:01:43,080 MONTHS LATER AND WE'VE DONE 8009 06:01:43,080 --> 06:01:44,200 COGNITION BY THREE MONTHS AND 8010 06:01:44,200 --> 06:01:45,360 THERE'S STILL KIND OF A TREND 8011 06:01:45,360 --> 06:01:52,120 BUT THE VARIABILITIES IS MUCH 8012 06:01:52,120 --> 06:01:53,920 HIGHER IT DOES DECAY. 8013 06:01:53,920 --> 06:01:56,320 I DON'T THINK WE'VE BOOSTED THE 8014 06:01:56,320 --> 06:01:57,880 FACT BEFORE AND WE'VE DONE IT 8015 06:01:57,880 --> 06:01:59,760 WITH LIVER ENZYMES TA WE FOUND 8016 06:01:59,760 --> 06:02:01,720 IN EXERCISE AND THAT WE CAN 8017 06:02:01,720 --> 06:02:03,360 BOOST OR MAINTAIN THE EFFECT FOR 8018 06:02:03,360 --> 06:02:04,120 LONGER. 8019 06:02:04,120 --> 06:02:09,880 BUT IT DOES WAIN. 8020 06:02:09,880 --> 06:02:11,040 >>THAT WAS GREAT. 8021 06:02:11,040 --> 06:02:12,480 I JUST WANTED TO SAY THERE'S 8022 06:02:12,480 --> 06:02:15,120 THIS OLD DATA THAT SUGGESTS THAT 8023 06:02:15,120 --> 06:02:17,000 IT'S ACTUALLY INCREASE IN THE 8024 06:02:17,000 --> 06:02:20,440 CONTEXT OF AGE AND SO IS THIS A 8025 06:02:20,440 --> 06:02:22,680 MATTER OF A DIFFERENT 8026 06:02:22,680 --> 06:02:23,720 PREPARATION OF PLATELETS OR. 8027 06:02:23,720 --> 06:02:25,120 >>THAT'S A GREAT QUESTION. 8028 06:02:25,120 --> 06:02:27,640 SO IN A LOT OF, I GET THESE 8029 06:02:27,640 --> 06:02:28,840 BECAUSE ACTIVATION AND THERE'S 8030 06:02:28,840 --> 06:02:35,360 AN INCREASE NUMBER OF ABOUT WE 8031 06:02:35,360 --> 06:02:36,080 LOOKED. 8032 06:02:36,080 --> 06:02:37,120 ALL OF THESE INDIVIDUALS THAT WE 8033 06:02:37,120 --> 06:02:39,360 GOT ARE HEALTHY SO THEY'RE 8034 06:02:39,360 --> 06:02:47,320 EXCLUDEDDED ANYTHING AND THE 8035 06:02:47,320 --> 06:02:48,520 WHAT IS IT IN THE PREPARATION 8036 06:02:48,520 --> 06:02:50,160 AND WE TRY AND FIGURE OUT WHAT 8037 06:02:50,160 --> 06:02:51,800 IS IT AND WHAT ARE WE PUTTING 8038 06:02:51,800 --> 06:02:52,880 THAT INTO IT THAT MIGHT HAVE AN 8039 06:02:52,880 --> 06:02:56,920 EFFECT AND WHEN WE MEASURED IT 8040 06:02:56,920 --> 06:02:58,920 HOWEVER IN WE DID SEE A DECLINE 8041 06:02:58,920 --> 06:03:01,440 IN SORT OF THAT PRP LEVELS AS 8042 06:03:01,440 --> 06:03:02,160 WELL. 8043 06:03:02,160 --> 06:03:03,440 THERE'S EVIDENCE THAT IS SHOWN 8044 06:03:03,440 --> 06:03:05,080 THAT IF YOU INCREASE AT LEAST A 8045 06:03:05,080 --> 06:03:07,920 CERTAIN LEVELS, WHEN IT'S A 8046 06:03:07,920 --> 06:03:09,720 MONEY MER VERSUS A DIMER IT CAN 8047 06:03:09,720 --> 06:03:11,160 HAVE NEGATIVE AND POSITIVE 8048 06:03:11,160 --> 06:03:13,560 EFFECTS AND THE CREASE IS THE 8049 06:03:13,560 --> 06:03:14,680 LOWER LEVEL WHICH HAS BEEN 8050 06:03:14,680 --> 06:03:17,040 SHOWING THE LITERATURE TO IMPACT 8051 06:03:17,040 --> 06:03:18,920 THINGS LIKE T CELLS AND PREVENT 8052 06:03:18,920 --> 06:03:19,760 THAT ACTIVATION O IT'S 8053 06:03:19,760 --> 06:03:20,400 CONSISTENT. 8054 06:03:20,400 --> 06:03:23,400 I DIDN'T SHOW RECEPTORS STUFF 8055 06:03:23,400 --> 06:03:24,720 WEAN DONE ON T-CELL THAT MEDIATE 8056 06:03:24,720 --> 06:03:31,880 PART OF IT FOR KINE BUT THAT'S 8057 06:03:31,880 --> 06:03:40,280 HOW WE SEE IT. 8058 06:03:40,280 --> 06:03:42,880 >>YOU ARE ASKING HOW WE LOOKED 8059 06:03:42,880 --> 06:03:44,680 AT CONDITIONS IN WHICH LEVELS 8060 06:03:44,680 --> 06:03:45,840 ABOUT DOWN AND WHAT WOULD BE THE 8061 06:03:45,840 --> 06:03:46,440 IMPACT OF THAT. 8062 06:03:46,440 --> 06:03:48,360 WE'VE DONE THE PLATELET BEFORE 8063 06:03:48,360 --> 06:03:49,720 KNOCK OUTS SO WHEN YOU DO THE 8064 06:03:49,720 --> 06:03:52,320 KNOCK OUT AT YOUNG AGES, 8065 06:03:52,320 --> 06:04:00,000 NOTHING, THERE'S THEY'RE FINE IT 8066 06:04:00,000 --> 06:04:01,280 SEEMS LIKE IT'S INVOLVED IN 8067 06:04:01,280 --> 06:04:03,280 RESILIENCE OR PROTECTION RATHER 8068 06:04:03,280 --> 06:04:05,440 THAN HOMEOSTATIC CONTINUE AND IT 8069 06:04:05,440 --> 06:04:07,080 WILL PLAY A ROLE IN THE HUMAN 8070 06:04:07,080 --> 06:04:08,960 CONTINUE IF YOU ARE UNDER 8071 06:04:08,960 --> 06:04:12,760 HOMEOSTATIC VERSUS WHAT THE 8072 06:04:12,760 --> 06:04:16,120 CONDITION. 8073 06:04:16,120 --> 06:04:17,760 >>HAVE YOU LOOKED AT PHENOTYPES 8074 06:04:17,760 --> 06:04:21,200 DO YOU SEE REDUCED ASSOCIATED 8075 06:04:21,200 --> 06:04:25,360 MICROGLIA WITH AGING AND THERE'S 8076 06:04:25,360 --> 06:04:27,200 AN IMPLICATION IN AGING YOU CAN 8077 06:04:27,200 --> 06:04:28,600 SEE WITH THAT GAIN OR LOSS 8078 06:04:28,600 --> 06:04:29,080 FUNCTION? 8079 06:04:29,080 --> 06:04:30,240 >>GOOD QUESTION. 8080 06:04:30,240 --> 06:04:32,320 LET ME START FIRST WITH T-CELL 8081 06:04:32,320 --> 06:04:33,680 BECAUSE IT'S INTERESTING. 8082 06:04:33,680 --> 06:04:35,440 WHEN WE LOOKED AT LET'S SAY 8083 06:04:35,440 --> 06:04:36,440 INFILTRATION, WE'VE SEEN IT A 8084 06:04:36,440 --> 06:04:40,280 LOT ON THE VENTRICLES WHERE 8085 06:04:40,280 --> 06:04:44,960 THERE'S CSF SORT OF DEPRESSION 8086 06:04:44,960 --> 06:04:47,120 AND YOU COMPLETE THEM AND YOU 8087 06:04:47,120 --> 06:04:49,280 START GETTING DOWN TO THE HIM A 8088 06:04:49,280 --> 06:04:52,800 CAMPUS WE DON'T SEE THAT THEY'RE 8089 06:04:52,800 --> 06:04:54,560 REDUCING IT SO THEY'RE 8090 06:04:54,560 --> 06:04:56,160 MAINTAINING IT AND WHEN YOU LOOK 8091 06:04:56,160 --> 06:04:58,480 AT THE SEVEN ON THERE LIKE GANG 8092 06:04:58,480 --> 06:04:59,960 BUSTERS EVERYWHERE SO THE 8093 06:04:59,960 --> 06:05:01,840 MECHANISMS WHICH INFILTRATING IN 8094 06:05:01,840 --> 06:05:05,240 AN AREA LIKE THE VENTRICLES 8095 06:05:05,240 --> 06:05:06,640 VERSUS A DEEP AREA LIKE THE TIP 8096 06:05:06,640 --> 06:05:17,040 A CAMPUS IS DIFFERENT. 8097 06:05:17,280 --> 06:05:25,880 WE JUST DID BOTH WITH THESE. 8098 06:05:25,880 --> 06:05:29,800 THANK YOU VERY MUCH FOR THAT 8099 06:05:29,800 --> 06:05:32,160 PRESENTATION. 8100 06:05:32,160 --> 06:05:34,000 I WOULD LIKE TO INTRODUCE THE 8101 06:05:34,000 --> 06:05:37,400 NEXT SPEAKER FROM BAYLOR COLLEGE 8102 06:05:37,400 --> 06:05:42,240 OF MEDICINE AND WE'LL TAKE ABOUT 8103 06:05:42,240 --> 06:05:44,760 THE BRAIN BLOOD BARRIER AND 8104 06:05:44,760 --> 06:05:55,520 VASCULAR BETT BEAR YEAR FUNCTIO. 8105 06:05:58,720 --> 06:05:59,360 ALL RIGHT. 8106 06:05:59,360 --> 06:06:03,440 I WILL CONTINUE WITH THE NEW 8107 06:06:03,440 --> 06:06:04,640 THING TO TALK ABOUT THE AGING 8108 06:06:04,640 --> 06:06:07,600 AND THE DISEASES OF THE CENTRAL 8109 06:06:07,600 --> 06:06:10,200 NERVOUS SYSTEM AND I 8110 06:06:10,200 --> 06:06:12,080 SPECIFICALLY RELATED TO THE 8111 06:06:12,080 --> 06:06:18,200 COMPLIMENT SIGNALING IN THE 8112 06:06:18,200 --> 06:06:24,920 AGING AND ALL THE THEM AND SO, 8113 06:06:24,920 --> 06:06:29,600 ALL THE IS THE MOST COMMON FORM 8114 06:06:29,600 --> 06:06:33,000 OF THE AIMING RELATED WITH TWO 8115 06:06:33,000 --> 06:06:34,920 PATHOLOGICAL PAUL MARK ONE IS 8116 06:06:34,920 --> 06:06:41,200 THE EXTRA CELLULAR AND INTRA AND 8117 06:06:41,200 --> 06:06:43,040 SINGLE AND DECIDE THOSE 8118 06:06:43,040 --> 06:06:44,960 PATHOLOGICAL HALLMARKS, IT'S 8119 06:06:44,960 --> 06:06:46,960 KNOWN THAT THE DISEASE IS THE 8120 06:06:46,960 --> 06:06:49,240 ACCOMPANIED BY THE HYPER 8121 06:06:49,240 --> 06:06:51,240 ACTIVATION ON THE THREE OF THOSE 8122 06:06:51,240 --> 06:06:52,840 AND IN PARTICULAR THE EXERCISE 8123 06:06:52,840 --> 06:06:56,280 AND THE MICROGLIA THAT IS MARKED 8124 06:06:56,280 --> 06:07:00,400 BY THIS GFAP AND RESPECTIVELY 8125 06:07:00,400 --> 06:07:08,320 YOU CAN COMPARE TO THE NORMAL 8126 06:07:08,320 --> 06:07:13,400 THOSE ASSOCIATED WITH THIS IS 8127 06:07:13,400 --> 06:07:16,360 ASSOCIATED WITH INCREASE 8128 06:07:16,360 --> 06:07:19,680 PRODUCTION OF OUR CYTOKINES AND 8129 06:07:19,680 --> 06:07:24,280 THE RECENT ASSOCIATED STUDY THAT 8130 06:07:24,280 --> 06:07:25,240 DEMONSTRATED A IMAGINE ON COP 8131 06:07:25,240 --> 06:07:26,800 CONTRIBUTING ROLE OF THOSE 8132 06:07:26,800 --> 06:07:29,240 IMMUNE SYSTEMS AND ALSO LOOKING 8133 06:07:29,240 --> 06:07:32,280 AT METABOLIC PATHWAYS IN THE 8134 06:07:32,280 --> 06:07:33,960 LATE ONSET OF ALZHEIMER'S 8135 06:07:33,960 --> 06:07:34,920 DISEASE. 8136 06:07:34,920 --> 06:07:41,600 AND FOR EXAMPLE, THE FOR ALLELE 8137 06:07:41,600 --> 06:07:45,920 IS A RISK FACTOR FOR DISEASES 8138 06:07:45,920 --> 06:07:49,240 AND IT'S EXPRESSED IN EXERCISE 8139 06:07:49,240 --> 06:07:52,760 AND IT LIPID AND CHOLESTEROL 8140 06:07:52,760 --> 06:07:54,120 METABOLISM. 8141 06:07:54,120 --> 06:07:55,560 AND IT'S ANOTHER RESPOND RISK 8142 06:07:55,560 --> 06:07:57,240 FACTORS FOR ALZHEIMER'S DISEASE 8143 06:07:57,240 --> 06:07:59,440 AND IT IS EXCLUSIVELY EXPRESSED 8144 06:07:59,440 --> 06:08:04,040 IN THE MICROGLIA OF THE BRAIN. 8145 06:08:04,040 --> 06:08:08,120 AND SO IN ADDITION THE COMPANY 8146 06:08:08,120 --> 06:08:09,720 PATHWAY ARE ALSO SEVERAL 8147 06:08:09,720 --> 06:08:14,040 COMPANIES HAVE MOLECULES AND 8148 06:08:14,040 --> 06:08:16,560 ALSO GENETIC MODIFIERS OF 8149 06:08:16,560 --> 06:08:21,520 ALZHEIMER'S DISEASE SUCH AS CR1 8150 06:08:21,520 --> 06:08:25,520 AND THE BLUE SO IN PART OF THE 8151 06:08:25,520 --> 06:08:26,600 COMPLIMENT IN THE (INAUDIBLE) 8152 06:08:26,600 --> 06:08:30,600 THIS AFTERNOON, IT IS IMPORTANT 8153 06:08:30,600 --> 06:08:35,800 OF UNITY SYSTEM AND RESPONSIBLE 8154 06:08:35,800 --> 06:08:37,800 FOR RECRUITMENT AND CYTO SIS AND 8155 06:08:37,800 --> 06:08:45,120 CYTOKINE REGULATION AND THE COL 8156 06:08:45,120 --> 06:08:47,960 OOPS ARE EXPRESSED AND 8157 06:08:47,960 --> 06:08:50,160 ASSOCIATED WELCOME BACK 8158 06:08:50,160 --> 06:08:51,200 ALZHEIMER'S DISEASE AND THE 8159 06:08:51,200 --> 06:08:52,760 COMPLIMENT HALFWAY CAN BE 8160 06:08:52,760 --> 06:08:58,000 ACTIVATED BY ONE OF THE THREE 8161 06:08:58,000 --> 06:08:58,600 TRIGGERS. 8162 06:08:58,600 --> 06:09:03,760 AND ON THE COMPLIMENT FACTORS 8163 06:09:03,760 --> 06:09:06,680 WHICH UNDERGOES A CASCADE OF 8164 06:09:06,680 --> 06:09:09,880 REACTION LEADING TO THE REGION 8165 06:09:09,880 --> 06:09:15,080 OF TAX SO TODAY, I'LL BE 8166 06:09:15,080 --> 06:09:16,480 FOCUSING ON THE THROUGH AID 8167 06:09:16,480 --> 06:09:23,400 BINDING TO THE RECEPTORS AND THE 8168 06:09:23,400 --> 06:09:28,280 AMYLOID FOLLOWED BY ATP THAT WE 8169 06:09:28,280 --> 06:09:33,200 CAPITULATE THE PATHOLOGY AND THE 8170 06:09:33,200 --> 06:09:37,920 OTHER IS THE IN AGING. 8171 06:09:37,920 --> 06:09:40,240 SO, WORK IN MY LAB IN THE PAST 8172 06:09:40,240 --> 06:09:47,520 THREE YEARS ALSO, MAPPED OUT IN 8173 06:09:47,520 --> 06:09:50,200 PRO ACTION PATHWAY AND THAT IS 8174 06:09:50,200 --> 06:09:54,800 THE C3 IS EXPRESSING EXERCISE ON 8175 06:09:54,800 --> 06:09:57,080 WHERE THE RECEPTORS IS EXPRESSED 8176 06:09:57,080 --> 06:10:01,840 IN MICROGLIA FORMING A C3 8177 06:10:01,840 --> 06:10:05,240 RECEPTORS MEDIATED EXERCISE 8178 06:10:05,240 --> 06:10:08,720 MICROGLIA THIS IS ACTIVATED IN 8179 06:10:08,720 --> 06:10:11,440 THE SMALL DOSE AND THAT IS 8180 06:10:11,440 --> 06:10:15,920 ASSOCIATED WITH THE GFAP 8181 06:10:15,920 --> 06:10:19,400 POSITIVE EXERCISE AND THE 8182 06:10:19,400 --> 06:10:19,960 MICROGLIA. 8183 06:10:19,960 --> 06:10:22,720 AND LATER ON IT IT HAS SHOWN 8184 06:10:22,720 --> 06:10:24,880 THIS NORMALLY HAPPENS IN MOUSE 8185 06:10:24,880 --> 06:10:26,720 MODELS BUT IT ALSO HAPPENS IN 8186 06:10:26,720 --> 06:10:37,240 HUMANS AND DISEASES AND IT IT 8187 06:10:45,040 --> 06:10:46,440 SUCH AS ALZHEIMER'S AND 8188 06:10:46,440 --> 06:10:49,000 PARKINSON'S DISEASE. 8189 06:10:49,000 --> 06:10:53,600 AND KNOWING THE THREE 8190 06:10:53,600 --> 06:10:55,720 EXPRESSIONS MY STUDENTS DECIDED 8191 06:10:55,720 --> 06:11:00,320 TO TAKE A CLOSER LOOK OF ITS 8192 06:11:00,320 --> 06:11:05,560 CRIMES BETWEEN ACCEPT AND SO 8193 06:11:05,560 --> 06:11:10,680 USING THE HUMAN I SAW MOUSE 8194 06:11:10,680 --> 06:11:14,840 MODELS AND HERE MICROGLIA IS 8195 06:11:14,840 --> 06:11:18,240 MARKED AND BETWEEN REIS SCEPTER 8196 06:11:18,240 --> 06:11:21,640 IT'S MARG MARKED BY PURPLE HERD 8197 06:11:21,640 --> 06:11:25,280 IT'S SHOWN IN WHITE AND WHAT SHE 8198 06:11:25,280 --> 06:11:28,480 FOUND IS THAT THE RECEPTORS IS 8199 06:11:28,480 --> 06:11:31,440 ACTUALLY EXPRESSED QUITE HETERO 8200 06:11:31,440 --> 06:11:35,280 GENIOUSLY AND IT'S IN THE AREA 8201 06:11:35,280 --> 06:11:37,040 SURROUNDING THE AMYLOID WERE IN 8202 06:11:37,040 --> 06:11:41,880 THE MICROGLIA THIS IS THE PLUS 8203 06:11:41,880 --> 06:11:43,400 MUCH LOWER WITH THE AR 8204 06:11:43,400 --> 06:11:51,680 EXPRESSION O SHE DECIDED TO LOOK 8205 06:11:51,680 --> 06:11:54,880 THAT AND SHE USED RIGHT 8206 06:11:54,880 --> 06:11:58,280 SCEPTER AND WHICH THE RECEPTORS 8207 06:11:58,280 --> 06:12:02,200 IS MATCHED BY THE WHEN SHE DID 8208 06:12:02,200 --> 06:12:05,920 THIS CLOSE AND WHAT SHE FOUND IS 8209 06:12:05,920 --> 06:12:08,320 THAT IN THE WILD TYPE CONDITION 8210 06:12:08,320 --> 06:12:10,400 THE POPULATION OF THE C3AR LOW 8211 06:12:10,400 --> 06:12:14,520 AND THE MID AND IN THE A IT TC 8212 06:12:14,520 --> 06:12:18,160 MICE THIS POPULATION IS SHIFTED 8213 06:12:18,160 --> 06:12:21,200 TO C3R HIGH CONSISTENT WITH THE 8214 06:12:21,200 --> 06:12:26,360 EXPRESSION IN THE MICROGLIA 8215 06:12:26,360 --> 06:12:28,880 SURROUNDING AMYLOID AND SHE 8216 06:12:28,880 --> 06:12:30,440 WANTED TO UNDERSTAND WHAT 8217 06:12:30,440 --> 06:12:33,960 MOLECULES THAT ARE ASSOCIATED 8218 06:12:33,960 --> 06:12:36,680 WITH THIS C3 HIGH POP NATION SHE 8219 06:12:36,680 --> 06:12:40,520 SORTED THE MICROGLIA AND THIS 8220 06:12:40,520 --> 06:12:43,360 SEQUENCING AND WHAT SHE FOUND 8221 06:12:43,360 --> 06:12:45,720 THAT IT HAS PATHWAYS THAT 8222 06:12:45,720 --> 06:12:48,760 SPECULATED ASSOCIATED WITH A 8223 06:12:48,760 --> 06:12:51,400 HIGH STATE AND IN PARTICULAR IT 8224 06:12:51,400 --> 06:12:56,040 WAS ONE PATHWAY AND ALSO THE 8225 06:12:56,040 --> 06:12:59,280 LIPID AND IN ALSO SHOWN HERE IN 8226 06:12:59,280 --> 06:13:01,800 THE STIGMA AND WE'RE INTERESTED 8227 06:13:01,800 --> 06:13:12,320 IN THE PATHWAY BECAUSE AND THAT 8228 06:13:38,760 --> 06:13:41,440 PERSISTENT IT'S ASSOCIATED WITH 8229 06:13:41,440 --> 06:13:46,920 AND CELLULAR METABOLISM AND 8230 06:13:46,920 --> 06:13:50,360 LOWER AND SO THEY WANTED TO 8231 06:13:50,360 --> 06:13:54,000 FURTHER GET INTO THE MAG NISM IN 8232 06:13:54,000 --> 06:13:57,480 WHICH THE ISOLATED MICROGLIATURE 8233 06:13:57,480 --> 06:14:01,640 FROM THE WILD TYPE AND THE MOUSE 8234 06:14:01,640 --> 06:14:04,960 OF MICROGLIA AND THE PERFORMANCE 8235 06:14:04,960 --> 06:14:08,200 OF HIS ONE EXPRESSION. 8236 06:14:08,200 --> 06:14:12,680 JUST LIKE THE I EXPRESSION 8237 06:14:12,680 --> 06:14:16,000 ASSOCIATED WITH EXPRESSION AND 8238 06:14:16,000 --> 06:14:19,920 NOW IS LEAST TO THE LOWER ONE 8239 06:14:19,920 --> 06:14:21,800 EXPRESSION AND THE ASSOCIATED 8240 06:14:21,800 --> 06:14:26,040 WITH HIGHER ATP PRODUCTION AND 8241 06:14:26,040 --> 06:14:30,480 THE PUT THOSE CELLS INTO THE AND 8242 06:14:30,480 --> 06:14:33,680 THE CONDITIONS IN THE WILD TYPE 8243 06:14:33,680 --> 06:14:37,080 MICROGLIA IS ASSOCIATED WITH 8244 06:14:37,080 --> 06:14:40,760 INTEREST IF EXPRESSION AND 8245 06:14:40,760 --> 06:14:43,400 INTERESTINGLY BETWEEN IT'S 8246 06:14:43,400 --> 06:14:45,480 RESIST APARTMENT TO HYPOXIA 8247 06:14:45,480 --> 06:14:49,720 INDUCED IN ONE EXPRESSION. 8248 06:14:49,720 --> 06:14:51,960 THIS IS REFLECTED IN EXPRESSION 8249 06:14:51,960 --> 06:14:55,720 IT'S ALSO CAN BE CAPTURED BY ITS 8250 06:14:55,720 --> 06:14:59,560 FUNCTION AND USING THE CORE IN 8251 06:14:59,560 --> 06:15:04,000 WHICH THE INDUCED HYPOXIA USING 8252 06:15:04,000 --> 06:15:10,040 THE SUPPORT AND THE PERFORM THIS 8253 06:15:10,040 --> 06:15:11,040 EXPRESSION AND THE RECEIPT 8254 06:15:11,040 --> 06:15:14,040 FORATION OF THE MAXIMUM OF THE 8255 06:15:14,040 --> 06:15:17,560 CR AND ITS PRODUCTION AND UNDER 8256 06:15:17,560 --> 06:15:21,160 ALL THIS CONDITIONS, THE HYPOXY 8257 06:15:21,160 --> 06:15:26,360 IS TO REDUCE OCR PRODUCTION AND 8258 06:15:26,360 --> 06:15:30,920 HOWEVER IN THE THE MICROGLIA IS 8259 06:15:30,920 --> 06:15:34,760 RESISTANT TO THIS OCAR REDUCTION 8260 06:15:34,760 --> 06:15:37,960 AND FORMATIONS THAT THE IT'S 8261 06:15:37,960 --> 06:15:40,400 HIGH, MICK ROW GLIA IS THE 8262 06:15:40,400 --> 06:15:42,080 ASSOCIATED WITH HIGH 8263 06:15:42,080 --> 06:15:43,840 PRODUCTIVITY AND IT'S ONE 8264 06:15:43,840 --> 06:15:46,240 PATHWAY AND ALSO THE METABOLISM 8265 06:15:46,240 --> 06:15:50,400 SO TO DETECT WHETHER THIS AR HAS 8266 06:15:50,400 --> 06:15:53,640 ONE ACCESS ALSO REGULATES THE 8267 06:15:53,640 --> 06:15:56,720 LIPID METABOLISM MEANT THE 8268 06:15:56,720 --> 06:16:01,560 EXAMINED THE LIPID JOBLESS 8269 06:16:01,560 --> 06:16:04,040 FORMATION USING THE HIGH POX IS 8270 06:16:04,040 --> 06:16:07,480 TREATMENT WHICH LEADS TO THE 8271 06:16:07,480 --> 06:16:11,520 LIPID ACCUMULATION IN THE WILD 8272 06:16:11,520 --> 06:16:17,120 TYPE CULTURE BUT AGAIN, THE IS 8273 06:16:17,120 --> 06:16:23,240 RESIST APARTMENT AND AND ONE 8274 06:16:23,240 --> 06:16:24,160 REGULATION. 8275 06:16:24,160 --> 06:16:27,040 WHILE IN VIVO, WHAT WE FOUND IS 8276 06:16:27,040 --> 06:16:32,000 THAT JUST LIKE WHAT WE SAW IN IN 8277 06:16:32,000 --> 06:16:34,520 VIVO IT'S NOW CROSSING THE ON TO 8278 06:16:34,520 --> 06:16:39,120 THE ATP ON WHAT SHE FOUND THAT 8279 06:16:39,120 --> 06:16:43,000 IN THIS ASSOCIATED THAT THE DO 8280 06:16:43,000 --> 06:16:46,000 IT'S OUR EXPRESSION IN THE 8281 06:16:46,000 --> 06:16:52,320 MICROGLIA AND THAT NEEDS TO THE 8282 06:16:52,320 --> 06:16:54,040 (INAUDIBLE) OF THIS MICROGLIA 8283 06:16:54,040 --> 06:16:59,480 SURROUNDING THE BEAT AN AM LLOYD 8284 06:16:59,480 --> 06:17:03,120 AND FORMATION AND ALSO THE 8285 06:17:03,120 --> 06:17:06,200 HIGHER CYTO SIS OF THE MICRO 8286 06:17:06,200 --> 06:17:08,240 GLEE TO THE BETA AM LLOYD SHOWN 8287 06:17:08,240 --> 06:17:11,240 BY INCREASE AND SIX TO EIGHT AND 8288 06:17:11,240 --> 06:17:13,720 IT MEANS IN HERE WE USE 8289 06:17:13,720 --> 06:17:17,040 MICROGLIA FITTING MARKER AND THE 8290 06:17:17,040 --> 06:17:21,160 DATA THAT IS BY THE MICROGLIA 8291 06:17:21,160 --> 06:17:24,000 AND OVER ALL, THIS INTEREST 8292 06:17:24,000 --> 06:17:27,800 UPDATE LEADS TO THE REDUCED BETA 8293 06:17:27,800 --> 06:17:32,280 PATHOLOGY AS THE HERE YOU SEE 8294 06:17:32,280 --> 06:17:35,000 USING THAT THE ACT AND THE 8295 06:17:35,000 --> 06:17:36,720 PROPOFOL SPEAKER TALKS ABOUT THE 8296 06:17:36,720 --> 06:17:38,760 BEHAVIOUR AND HERE WE USE THIS 8297 06:17:38,760 --> 06:17:41,520 NOVEL OBJECT AND RECOGNITION AND 8298 06:17:41,520 --> 06:17:46,120 THAT IS WE LET THE MOUSE TO 8299 06:17:46,120 --> 06:17:50,240 RECOGNIZE THIS TWO OBJECTS AND 8300 06:17:50,240 --> 06:17:52,400 WHICH THE ONE OBJECT WITH A 8301 06:17:52,400 --> 06:17:56,640 DIFFERENT OBJECT AND THE MOUSE 8302 06:17:56,640 --> 06:17:59,120 REMEMBERS, THIS OBJECT THEN IT 8303 06:17:59,120 --> 06:18:00,560 WILL NATURALLY SPEND MORE TIME 8304 06:18:00,560 --> 06:18:06,480 ON THIS NOVEL OBJECT AND THE 8305 06:18:06,480 --> 06:18:09,360 MICE THIS IS REDUCED TO THE 8306 06:18:09,360 --> 06:18:13,520 LEVEL 50 PERSON HOWEVER IT'S THE 8307 06:18:13,520 --> 06:18:15,920 AMOUNT OF MY SHOW ALMOST CLOSE 8308 06:18:15,920 --> 06:18:19,600 TO WILD TYPE AND RESPONSE IN 8309 06:18:19,600 --> 06:18:23,840 THIS WORKING MEMORY PET SO ALL 8310 06:18:23,840 --> 06:18:25,160 AND ALL WE ARE COMING UP WITH 8311 06:18:25,160 --> 06:18:32,200 THIS MODEL AND THAT IS THE POPPY 8312 06:18:32,200 --> 06:18:35,640 AND IN RESPONSE TO THE AMYLOID 8313 06:18:35,640 --> 06:18:37,800 PATHOLOGY AND THE HEIGHTENED GTR 8314 06:18:37,800 --> 06:18:48,360 LEADS TO THE OPERATING THOSE ARE 8315 06:18:55,480 --> 06:18:57,920 REVERSED LEADING TO THE BETTER 8316 06:18:57,920 --> 06:19:02,840 MICRO GLOW A PATH STREAM AND 8317 06:19:02,840 --> 06:19:07,720 REDUCE APP MALL PATHOLOGY AND 8318 06:19:07,720 --> 06:19:09,680 BEHAVIOUR AND THIS ALZHEIMER'S 8319 06:19:09,680 --> 06:19:11,560 MODEL ANOTHER STUDENT NICK 8320 06:19:11,560 --> 06:19:13,880 THOMPSON WAS INTERESTED IN 8321 06:19:13,880 --> 06:19:16,320 UNDERSTANDING THIS PATHWAY IN 8322 06:19:16,320 --> 06:19:20,520 DOING AGING AND SO WHAT NICK 8323 06:19:20,520 --> 06:19:24,280 FOUND WAS THAT IT'S NOT ONLY UP 8324 06:19:24,280 --> 06:19:26,680 REGULATED IN THE CONDITION IT'S 8325 06:19:26,680 --> 06:19:31,280 ACTUALLY UP REMEMBER LATED IN 8326 06:19:31,280 --> 06:19:33,840 AGING AND EVEN A AGE OF ABOUT 12 8327 06:19:33,840 --> 06:19:41,160 MONTHS THERE'S A CLEAR UP 8328 06:19:41,160 --> 06:19:42,680 REGULATION OF THESE THREE AND 8329 06:19:42,680 --> 06:19:47,560 THAT IS ASSOCIATED WITH VASCULAR 8330 06:19:47,560 --> 06:19:49,360 INFLAMMATION MARKED BY LOCALIZE 8331 06:19:49,360 --> 06:19:55,960 WITH THE 31 POSITIVE AND THIS 8332 06:19:55,960 --> 06:19:58,320 INCREASE IS BECAUSE WHEN WE LOOK 8333 06:19:58,320 --> 06:20:04,920 AT THIS IT BECOMES ON THE 8334 06:20:04,920 --> 06:20:10,640 BACKGROUND AND IT IS SO TO EXAM 8335 06:20:10,640 --> 06:20:15,560 WHETHER IT'S ASSOCIATED WITH THE 8336 06:20:15,560 --> 06:20:18,120 BLOOD BARRIER CHANGES NICK 8337 06:20:18,120 --> 06:20:20,760 PROSECUTE FORMED THIS FLOW 8338 06:20:20,760 --> 06:20:23,520 CYTOMETRY AND EXAMINED THE 8339 06:20:23,520 --> 06:20:24,520 POPULATION OF THOSE CELLS 8340 06:20:24,520 --> 06:20:29,760 INCLUDING THE MICROGLIA AND THE 8341 06:20:29,760 --> 06:20:32,960 TAKING THE MONOCYTES AND IT'S 8342 06:20:32,960 --> 06:20:34,760 DIFFERENT AGES AND THE WORK KEEP 8343 06:20:34,760 --> 06:20:38,400 IS THAT THERE'S EIGHT RELATED 8344 06:20:38,400 --> 06:20:41,600 INCREASE OF THE EIGHT POSITIVE 8345 06:20:41,600 --> 06:20:46,760 HEALING FOR SIDE AND BUT NOT THE 8346 06:20:46,760 --> 06:20:53,640 MONOCYTE AND AGAIN THIS INCREASE 8347 06:20:53,640 --> 06:21:01,680 IS BECAUSE WHEN YOU LOOK AT THIS 8348 06:21:01,680 --> 06:21:04,080 POPULATION THIS INCREASE IS NO 8349 06:21:04,080 --> 06:21:05,160 LONGER HAPPENING. 8350 06:21:05,160 --> 06:21:07,760 SO THEN HE CHECKED ON THE 8351 06:21:07,760 --> 06:21:13,680 VASCULAR MORPHOLOGY USING THIS 8352 06:21:13,680 --> 06:21:15,480 OF THE AND THE DIFFERENT AGES 8353 06:21:15,480 --> 06:21:17,960 AND WHAT HE FOUND IS THAT THERE 8354 06:21:17,960 --> 06:21:26,320 IS SOME VASCULAR CHANGES HELPS 8355 06:21:26,320 --> 06:21:28,440 AT MID AGE AND IT GOATS WORSE 8356 06:21:28,440 --> 06:21:31,600 AMONG AGES AND THIS CHANGES CAN 8357 06:21:31,600 --> 06:21:35,760 BE RESCUED BY USING THE C3R 8358 06:21:35,760 --> 06:21:38,560 ANTAGONIST AND ALSO BY GENETIC 8359 06:21:38,560 --> 06:21:42,560 KNOCK OFF OF C3R SO THEN NEXT 8360 06:21:42,560 --> 06:21:45,520 NICK ASKED WHETHER THIS MORPH 8361 06:21:45,520 --> 06:21:49,920 LOGICAL CHANGES WOULD LEAD TO 8362 06:21:49,920 --> 06:21:52,200 THE REGION OF THE INTEGRITY SO 8363 06:21:52,200 --> 06:21:55,800 TO DO THAT, HE USED IT IN VITRO 8364 06:21:55,800 --> 06:21:57,880 AS SAY AND IMAGE HE CULTURE AND 8365 06:21:57,880 --> 06:22:01,480 THE PRIMARY HUMOUR VES KULAR 8366 06:22:01,480 --> 06:22:04,320 CELLS WITH A EXERCISE AND THE 8367 06:22:04,320 --> 06:22:06,320 MEASURED THIS SPIRAL 8368 06:22:06,320 --> 06:22:09,360 INTERPRETATION USING THIS CORE 8369 06:22:09,360 --> 06:22:11,120 AS SAY AND IT'S A PEER VALUE AND 8370 06:22:11,120 --> 06:22:21,640 WE KNOW THAT THIS PEER POSITIVE 8371 06:22:23,720 --> 06:22:26,760 CONTROL WITH BARRIER AS EXPECTED 8372 06:22:26,760 --> 06:22:30,400 AND SIMILAR, WHEN HE TREATED 8373 06:22:30,400 --> 06:22:33,680 THIS VARIOUS SYSTEM THAT ALSO 8374 06:22:33,680 --> 06:22:37,960 NEEDS TO DISRUPT THE BARRIER AND 8375 06:22:37,960 --> 06:22:40,880 THIS AREA OF DISRUPTION CAN BE 8376 06:22:40,880 --> 06:22:45,800 BLOCKED BY TREATING THE CULTURES 8377 06:22:45,800 --> 06:22:50,800 WITH THE C3R RECEPTORS AND ALSO 8378 06:22:50,800 --> 06:22:54,960 USING THIS SHOWING THAT THE 8379 06:22:54,960 --> 06:22:59,400 INTRA CELLULAR IS DOWN STREAM 8380 06:22:59,400 --> 06:23:04,320 MEDIATOR OF THE C3A BARRIER 8381 06:23:04,320 --> 06:23:05,880 IMPAIRMENT AND THEN THE FURTHER 8382 06:23:05,880 --> 06:23:09,120 PAST THE HYPOTHESIS HE PERFORMED 8383 06:23:09,120 --> 06:23:13,560 THIS ON THE USES OF LIGHTS WHICH 8384 06:23:13,560 --> 06:23:21,520 IS A CAUSE OF INDEPENDENT AND 8385 06:23:21,520 --> 06:23:26,040 THAT REGULATES THE DO YOU THE 8386 06:23:26,040 --> 06:23:36,400 VASCULAR DISRUPTION. 8387 06:23:53,080 --> 06:23:55,400 THIS CAN BE BLOCKED BY SEEKING 8388 06:23:55,400 --> 06:23:58,840 THE CELLS WITH RECEPTION AND 8389 06:23:58,840 --> 06:24:01,200 HAPPINESS FOR BY WHEN HE LOOKED 8390 06:24:01,200 --> 06:24:04,000 AT THOSE THE SAME TREATMENT AS 8391 06:24:04,000 --> 06:24:10,800 24 HOURS AND IT'S AND HOWEVER AT 8392 06:24:10,800 --> 06:24:21,320 THIS STAGE, AND OUR SIMPLE AND I 8393 06:24:23,120 --> 06:24:25,760 MOTIONED ABOUT THE IN MICROGLIA 8394 06:24:25,760 --> 06:24:27,120 AND OKAY, OKAY AND I'M ALMOST 8395 06:24:27,120 --> 06:24:32,320 DONE SO THE QUESTION IS THIS 8396 06:24:32,320 --> 06:24:36,800 AUTONOMOUS OR THIS SO I USED IT 8397 06:24:36,800 --> 06:24:39,160 INTO A CONDITIONAL A LEGAL AND 8398 06:24:39,160 --> 06:24:44,120 THE SPECIFIC DELETED THE CTR IN 8399 06:24:44,120 --> 06:24:46,400 THE CSL AND BASICALLY SO SIMILAR 8400 06:24:46,400 --> 06:24:56,800 EFFECT AND SO WITH THAT, 8401 06:25:12,200 --> 06:25:13,440 MODELING AND THAT AMOUNTERS THE 8402 06:25:13,440 --> 06:25:20,000 FUNCTION LEAD TO GO THE CDHT 8403 06:25:20,000 --> 06:25:30,120 CELLS. 8404 06:25:51,680 --> 06:25:54,120 IN ALL THE AND IN AGING AND THE 8405 06:25:54,120 --> 06:25:56,960 IN FACT THERE'S A PROPOSAL FOR 8406 06:25:56,960 --> 06:26:01,480 OF A COMPLIMENT OF POSITIVE 8407 06:26:01,480 --> 06:26:06,920 RECEIVE AND THIS IS SUPPORT THE 8408 06:26:06,920 --> 06:26:17,440 PREMISE AND AND I WILL I'LL TALK 8409 06:26:19,400 --> 06:26:22,000 ABOUT THAT TOMORROW AND I THINK 8410 06:26:22,000 --> 06:26:24,720 THERE'S A GAP IN OPPORTUNITIES 8411 06:26:24,720 --> 06:26:26,520 DISCUSSION AND I WILL END BY OF 8412 06:26:26,520 --> 06:26:28,520 AK KNOWLEDGING THE PEOPLE AND I 8413 06:26:28,520 --> 06:26:32,760 WILL LIKE TO GIVE A SPECIAL 8414 06:26:32,760 --> 06:26:37,160 SHOUT OUT TO A THAT FOLLOW ME. 8415 06:26:37,160 --> 06:26:47,360 THANK YOU. 8416 06:26:51,320 --> 06:26:56,320 >>IT'S A COMPLIMENT C3 IS 8417 06:26:56,320 --> 06:26:58,120 REALLY COOL AND IT POPS UP 8418 06:26:58,120 --> 06:27:00,840 EVERYWHERE IN AGING IN MULTIPLE 8419 06:27:00,840 --> 06:27:02,720 PLACES IT GOES UP AND I RECALL 8420 06:27:02,720 --> 06:27:04,520 WE HAVE SEEN SEVERAL YEARS AGO 8421 06:27:04,520 --> 06:27:06,520 IN GOING UP AND JUST A REGULAR 8422 06:27:06,520 --> 06:27:08,360 AGE DATA APART FROM ALZHEIMER'S 8423 06:27:08,360 --> 06:27:14,800 MODELS AND IT'S REALLY STRONG 8424 06:27:14,800 --> 06:27:19,240 MOLECULES AND HAVE YOU SEEN THE 8425 06:27:19,240 --> 06:27:21,400 INHIB TANTS HAVE ANY IMPACT ON 8426 06:27:21,400 --> 06:27:27,360 AGING ASSOCIATED DECLINE? 8427 06:27:27,360 --> 06:27:37,760 JUST THE C3 INHIBITORS? 8428 06:27:44,120 --> 06:27:54,480 ACTUALLY, C3 IS APPROVED. 8429 06:27:55,240 --> 06:27:57,440 I DIDN'T KNOW IF IT WAS A BLOOD 8430 06:27:57,440 --> 06:27:57,880 BARRIER. 8431 06:27:57,880 --> 06:28:01,480 SO ACTUALLY, I'M CONCERNED ABOUT 8432 06:28:01,480 --> 06:28:07,760 THE FACT AND I THINK IT'S 8433 06:28:07,760 --> 06:28:10,560 PROBABLY USEFUL TO TREAT 8434 06:28:10,560 --> 06:28:21,320 PROPERTY PIECES AND FOR WHEN YOT 8435 06:28:21,320 --> 06:28:24,280 ROLE IN THE UNITY AND INFECTION 8436 06:28:24,280 --> 06:28:26,800 SO I DON'T KNOW IF YOU JUST 8437 06:28:26,800 --> 06:28:31,320 BLOCK THE C3 AND WHETHER IT WILL 8438 06:28:31,320 --> 06:28:33,000 FIGHT FOR THE OVER ALL IMMUNE 8439 06:28:33,000 --> 06:28:40,080 AND WHETHER IT WILL FIGHT IT'S A 8440 06:28:40,080 --> 06:28:41,400 CONCERN AND HERE IT'S THE SAME 8441 06:28:41,400 --> 06:28:44,440 THING WITH THE SITUATED AND 8442 06:28:44,440 --> 06:28:47,160 ANTAGONIST AND THE ANTAGONIST IS 8443 06:28:47,160 --> 06:28:51,880 NOT APPROVED BECAUSE IT'S HAVING 8444 06:28:51,880 --> 06:28:58,040 ISSUES WITH THE PENETRATION AND 8445 06:28:58,040 --> 06:29:01,920 AND AND PROBABLY NOT AND AND 8446 06:29:01,920 --> 06:29:07,120 IT'S MINUS AND ANOTHER ANIMAL 8447 06:29:07,120 --> 06:29:14,080 AND ANY SORT OF MAINTENANCE AND 8448 06:29:14,080 --> 06:29:19,120 AND THAT'S NOT AGE ASSOCIATED 8449 06:29:19,120 --> 06:29:24,760 DEGENERATION. 8450 06:29:24,760 --> 06:29:28,080 >>WITH LESS FUNCTION OF DECLINE 8451 06:29:28,080 --> 06:29:29,600 ANDED WE HAVE BEHAVIOUR AND THE 8452 06:29:29,600 --> 06:29:32,320 WAY WE DIDN'T SEE A DEGREE OF 8453 06:29:32,320 --> 06:29:35,600 CHANGE BUT WE HAVEN'T HAD VERY 8454 06:29:35,600 --> 06:29:39,680 MUCH DETAIL HOWEVER, THEY HAVE 8455 06:29:39,680 --> 06:29:41,240 LOOKED AT THE SHOW THAT IS 8456 06:29:41,240 --> 06:29:44,200 ACTUALLY RESIST APARTMENT TO AGE 8457 06:29:44,200 --> 06:29:45,680 RELATED FUNCTION AND DECLINE. 8458 06:29:45,680 --> 06:29:55,960 >>THANK YOU. 8459 06:29:57,120 --> 06:30:02,400 >>WE'LL PULL UP THE NEXT 8460 06:30:02,400 --> 06:30:03,120 SPEAKER'S SLIDE. 8461 06:30:03,120 --> 06:30:03,680 >>THANK YOU. 8462 06:30:03,680 --> 06:30:05,200 ALL RIGHT, SO OUR LAST SPEAKER 8463 06:30:05,200 --> 06:30:06,600 FOR THE DAY AND THEN WE'LL 8464 06:30:06,600 --> 06:30:08,600 ADJOURN FOR THE DAY PICKING UP 8465 06:30:08,600 --> 06:30:10,320 THE REMAINDER OF THIS SESSION 8466 06:30:10,320 --> 06:30:11,960 TOMORROW. 8467 06:30:11,960 --> 06:30:16,320 IT'S GOING TO BE SARAH KNOX FROM 8468 06:30:16,320 --> 06:30:20,280 UCSF REVERSING ORGAN AGING IN 8469 06:30:20,280 --> 06:30:22,400 THE SALIVARY GLAND. 8470 06:30:22,400 --> 06:30:25,280 THANK YOU. 8471 06:30:25,280 --> 06:30:30,920 >>LOOK AT THAT. 8472 06:30:30,920 --> 06:30:31,360 AMAZING. 8473 06:30:31,360 --> 06:30:32,920 RIGHT UP THERE WITH YOU. 8474 06:30:32,920 --> 06:30:34,200 SO, IT'S THE AFTERNOON PEOPLE 8475 06:30:34,200 --> 06:30:37,720 IT'S GOING ONTO THE EVENING I 8476 06:30:37,720 --> 06:30:39,520 FEEL LIKE MY TASTE BUDS ARE 8477 06:30:39,520 --> 06:30:40,920 DOING THINGS I DON'T FIND 8478 06:30:40,920 --> 06:30:43,040 APPROPRIATE RIGHT NOW BECAUSE MY 8479 06:30:43,040 --> 06:30:43,640 SALIVARY GLANDS ARE STILL 8480 06:30:43,640 --> 06:30:44,040 WORKING. 8481 06:30:44,040 --> 06:30:46,760 I MIGHT HAVE DRY MOUTH BUT MY 8482 06:30:46,760 --> 06:30:49,480 SALIVA IS RIGHT THERE AND I HOPE 8483 06:30:49,480 --> 06:30:50,080 YOU APPRECIATE YOUR GLANDS 8484 06:30:50,080 --> 06:30:51,640 BECAUSE IT'S ONE OF THE MOST 8485 06:30:51,640 --> 06:30:53,400 UNDERSTAND STUDIED ORGANS IN 8486 06:30:53,400 --> 06:30:54,960 YOUR BODY. 8487 06:30:54,960 --> 06:30:55,960 MOST PEOPLE DON'T CARE ABOUT IT 8488 06:30:55,960 --> 06:30:57,160 UNTIL THEY LOSE THEM AND THEY 8489 06:30:57,160 --> 06:30:57,880 CALL ME. 8490 06:30:57,880 --> 06:30:59,320 HOW ABOUT THAT. 8491 06:30:59,320 --> 06:31:01,360 I'M NOT EVEN A CLINICIAN BUT 8492 06:31:01,360 --> 06:31:02,400 THERE'S NOTHING TO DO AND A 8493 06:31:02,400 --> 06:31:05,440 FRIEND OF MINE HAS LOSS OF 8494 06:31:05,440 --> 06:31:06,560 SALARY GLANDS CANCER AND HE 8495 06:31:06,560 --> 06:31:08,200 CARRIES AROUND A BOTTLE OF MILK. 8496 06:31:08,200 --> 06:31:10,320 IF I GIVE YOU A BOTHEL OF MILK 8497 06:31:10,320 --> 06:31:12,000 AND SAY THAT'S IT, GOOD LUCK, 8498 06:31:12,000 --> 06:31:13,800 YOU WOULD BE LIKE NOT HAPPY WITH 8499 06:31:13,800 --> 06:31:16,880 ME SO LET'S EXPLORE THAT AND 8500 06:31:16,880 --> 06:31:19,600 WE'RE GOING TO GO INTO THE ROLE 8501 06:31:19,600 --> 06:31:20,320 OF AGING HERE. 8502 06:31:20,320 --> 06:31:22,680 WE'RE NOT TALKING ABOUT THE 8503 06:31:22,680 --> 06:31:23,760 BRAIN PEOPLE, WE'RE OUT OF THE 8504 06:31:23,760 --> 06:31:26,120 BRAIN GOING INTO THE NERVOUS 8505 06:31:26,120 --> 06:31:26,960 SYSTEM. 8506 06:31:26,960 --> 06:31:28,400 SO I STUDY NERVES AND 8507 06:31:28,400 --> 06:31:29,040 DEVELOPMENT. 8508 06:31:29,040 --> 06:31:31,200 SO WE'VE LEARNED A LOT THERE AND 8509 06:31:31,200 --> 06:31:32,440 NERVES AND REGENERATION IT 8510 06:31:32,440 --> 06:31:36,480 SOMETHING EXTREMELY VITAL AND OF 8511 06:31:36,480 --> 06:31:38,120 COURSE NERVES AND AGING, THAT'S 8512 06:31:38,120 --> 06:31:39,800 THE REASON WHY I GOT INTO IT BUT 8513 06:31:39,800 --> 06:31:41,600 I DON'T KNOW MUCH ABOUT IT 8514 06:31:41,600 --> 06:31:43,880 COMPARED TO YOU GUYS I'M SURE. 8515 06:31:43,880 --> 06:31:47,800 I'M NOT GOING TO TALK ABOUT THE 8516 06:31:47,800 --> 06:31:49,360 SYSTEM YOU CAN TELL ME WHAT YOUR 8517 06:31:49,360 --> 06:31:56,680 THOUGHTS ON THE IMMUNE CELLS. 8518 06:31:56,680 --> 06:31:59,240 WE WERE TALKING ABOUT SALIVARY 8519 06:31:59,240 --> 06:32:02,360 GLANDS AND THESE ARE DEVELOPING 8520 06:32:02,360 --> 06:32:03,200 SALIVARY GLANDS THIS IS ALL DONE 8521 06:32:03,200 --> 06:32:04,960 BECAUSE WE WANT TO LOOK AT THE 8522 06:32:04,960 --> 06:32:08,280 NERVES AND SEE A NERVE AND THIS 8523 06:32:08,280 --> 06:32:10,800 IS A GANG GLEE ON WRAPPED AROUND 8524 06:32:10,800 --> 06:32:13,040 THAT GLAND EARLY IN ITS 8525 06:32:13,040 --> 06:32:15,320 DEVELOPMENT SO YOU KEEP THE NOSE 8526 06:32:15,320 --> 06:32:19,800 ON THAT GRAND AND UNDERGO AND IT 8527 06:32:19,800 --> 06:32:23,000 FORMS A BUD LIKE STRUCTURES AND 8528 06:32:23,000 --> 06:32:25,600 WE MADE CHANGES AND POSITIVE POS 8529 06:32:25,600 --> 06:32:28,280 LAKE OF STEM CELLS IF YOU LOSE 8530 06:32:28,280 --> 06:32:29,400 THOSE NERVES, GUESS WHAT, YOU 8531 06:32:29,400 --> 06:32:31,520 GET A MOR PHYSICAL AND VEMMENT 8532 06:32:31,520 --> 06:32:35,080 AND DEVELOPMENT OF CELL AND LOSS 8533 06:32:35,080 --> 06:32:37,600 OF THESE STEM CELLS IF YOU 8534 06:32:37,600 --> 06:32:41,000 SIMPLY AND I JUST WANT YOU TO 8535 06:32:41,000 --> 06:32:45,960 LOOK AT THE SIMPLY ADD BACK SETS 8536 06:32:45,960 --> 06:32:47,440 OF THIS IS COLOURFUL YOU ARE 8537 06:32:47,440 --> 06:32:49,600 GOING THROUGH TO RETURN THOSE 8538 06:32:49,600 --> 06:32:50,520 CELLS. 8539 06:32:50,520 --> 06:32:52,600 NOT ALL THE WAY. 8540 06:32:52,600 --> 06:32:55,920 BUT LET'S NOT BE TOO HASTY ABOUT 8541 06:32:55,920 --> 06:33:06,160 THAT AND WE'RE 8542 06:33:49,000 --> 06:33:50,560 >>THIS IS REALLY GOOD AT COMING 8543 06:33:50,560 --> 06:33:58,000 BACK TOGETHER AND HEALING. 8544 06:33:58,000 --> 06:34:00,080 WHEN THEY HEAL YOU SEE A LARGE 8545 06:34:00,080 --> 06:34:04,880 INCREASE AND GUESS WHAT YOUR 8546 06:34:04,880 --> 06:34:06,920 COME BACK AND DO WE HAVE ANY 8547 06:34:06,920 --> 06:34:07,240 ANYONE ELSE. 8548 06:34:07,240 --> 06:34:08,880 I WANTED TO TELL YOU THAT YOU 8549 06:34:08,880 --> 06:34:11,320 CAN DO THIS OUTSIDE THE BODY AND 8550 06:34:11,320 --> 06:34:19,000 YOU ARE ONLY GOING TO ON THE 8551 06:34:19,000 --> 06:34:21,360 LEFT IS SENSE OF SELLING ON THE 8552 06:34:21,360 --> 06:34:22,560 RIGHT-HAND AND IT'S AGO NIST AND 8553 06:34:22,560 --> 06:34:24,760 YOU CAN SEE EXTENSIVE 8554 06:34:24,760 --> 06:34:25,920 REPOPULATION OF THAT ISSUE SO 8555 06:34:25,920 --> 06:34:27,720 THAT'S SIMPLE. 8556 06:34:27,720 --> 06:34:30,040 WE ONLY HAVE ONE FACTOR. 8557 06:34:30,040 --> 06:34:31,480 THE LAST THING I WILL TELL YOU 8558 06:34:31,480 --> 06:34:33,400 ABOUT BEFORE WE GET INTO AGING 8559 06:34:33,400 --> 06:34:34,960 IS THIS IMPORTANT PIECE. 8560 06:34:34,960 --> 06:34:37,080 SO, IT'S ALL ABOUT GAMMA 8561 06:34:37,080 --> 06:34:41,240 RADIATION AND WE TALKED ABOUT 8562 06:34:41,240 --> 06:34:43,160 RADIATION TODAY AND YOU HAVE 8563 06:34:43,160 --> 06:34:46,880 RADIATION AND THE OPPORTUNITY TO 8564 06:34:46,880 --> 06:34:49,400 GET IS HIGH AND WHAT WE DID WAS 8565 06:34:49,400 --> 06:34:50,640 ASKED WHETHER WE COULD MAINTAIN 8566 06:34:50,640 --> 06:34:55,560 OR REGENERATE THE DELIVERY OF A 8567 06:34:55,560 --> 06:34:58,600 OF (INAUDIBLE) AND SO THIS 8568 06:34:58,600 --> 06:35:00,480 EXPERIMENT, RADIATION AND AMONG 8569 06:35:00,480 --> 06:35:01,600 PLACE WE'RE GOING TO START 8570 06:35:01,600 --> 06:35:02,640 TREATMENT AND THIS IS A VERY 8571 06:35:02,640 --> 06:35:04,080 LONG TIME BY THE WAY. 8572 06:35:04,080 --> 06:35:14,560 HUMANS IS A VERY LONG TIME. 8573 06:35:19,040 --> 06:35:21,440 NOW ON THE LEFT-HAND SIDE IS THE 8574 06:35:21,440 --> 06:35:23,120 RED, THE RADIATED YOU CAN SEE A 8575 06:35:23,120 --> 06:35:25,000 LOT OF RED THERE AND THAT IS 8576 06:35:25,000 --> 06:35:27,120 BECAUSE THERE'S NOT MANY CELLS 8577 06:35:27,120 --> 06:35:30,960 THERE AND WE TREAT GUESS WHAT WE 8578 06:35:30,960 --> 06:35:33,560 GET THE CELLS ARE THERE AND 8579 06:35:33,560 --> 06:35:35,160 GLORIOUS FORM AND THEY'RE HIGHLY 8580 06:35:35,160 --> 06:35:36,720 FUNCTIONSAL SO THIS IS A GREAT 8581 06:35:36,720 --> 06:35:38,200 FUNCTIONS IS ESSENTIAL FOR AWFUL 8582 06:35:38,200 --> 06:35:41,600 YOUR ORGANS SO THINK ABOUT THAT 8583 06:35:41,600 --> 06:35:43,160 THIS IS ONE TREATMENT RESULT IN 8584 06:35:43,160 --> 06:35:46,960 COMPLETE REGENERATION OF 8585 06:35:46,960 --> 06:35:50,680 FUNCTION. 8586 06:35:50,680 --> 06:35:52,680 AGING, OKAY, AGING GREAT. 8587 06:35:52,680 --> 06:35:56,920 BUT WHAT HAPPENS WITH HUMAN 8588 06:35:56,920 --> 06:35:57,600 GLANDS AT THE TIME NONE OF US 8589 06:35:57,600 --> 06:35:59,840 HERE TODAY AND HERE IS THE 8590 06:35:59,840 --> 06:36:00,480 MIDDLE. 8591 06:36:00,480 --> 06:36:02,960 THE MID LIFE SOME OF US HERE. 8592 06:36:02,960 --> 06:36:04,360 I'M GOING TO SAY ANYBODY OVER 8593 06:36:04,360 --> 06:36:05,160 THERE. 8594 06:36:05,160 --> 06:36:06,520 MOSTLY WE'RE GOING TO BE AROUND 8595 06:36:06,520 --> 06:36:08,280 THE MIDDLE I WOULD SAY. 8596 06:36:08,280 --> 06:36:10,400 SO THIS TELLS YOU THAT YOU ARE 8597 06:36:10,400 --> 06:36:11,800 LOSING THESE CELLS AND YOU ARE 8598 06:36:11,800 --> 06:36:15,040 GETTING AN INCREASE IN FAT SO 8599 06:36:15,040 --> 06:36:17,560 YOU KNOW, EMILY CAN YOU HELP ME 8600 06:36:17,560 --> 06:36:19,400 WITH THAT IS SO WE DON'T KNOW 8601 06:36:19,400 --> 06:36:22,880 WHAT THE FAT IS DOING BUT MICE 8602 06:36:22,880 --> 06:36:25,320 DON'T GET FAT IN THEIR ORGANS 8603 06:36:25,320 --> 06:36:26,680 BUT SOMETHING WE HAVE TO 8604 06:36:26,680 --> 06:36:27,400 CONSIDER. 8605 06:36:27,400 --> 06:36:31,400 SO WHEN WE LOOK AT POPULATIONS, 8606 06:36:31,400 --> 06:36:32,760 LET'S DO SOME WE DID THAT AND 8607 06:36:32,760 --> 06:36:35,520 YOU CAN SEE FROM THE ANALYSIS 8608 06:36:35,520 --> 06:36:37,440 IT'S VERY SEPARATE IF YOU LOOK 8609 06:36:37,440 --> 06:36:40,160 ACROSS TIME IT'S SEPARATE AND 8610 06:36:40,160 --> 06:36:42,280 YOU LOOK ACROSS TIME AND YOU 8611 06:36:42,280 --> 06:36:44,400 LOOK AT THE POPULATIONS YOU CAN 8612 06:36:44,400 --> 06:36:46,480 SAY THIS DECREASES AT A TIME SO 8613 06:36:46,480 --> 06:36:48,160 THAT GOES ALONG WITH THAT DATA. 8614 06:36:48,160 --> 06:36:52,040 SO IF WE LOOK AT ONE OF THE MOST 8615 06:36:52,040 --> 06:36:53,960 IT IS GOING DOWN AND GUESS WHAT, 8616 06:36:53,960 --> 06:36:56,680 WE ALSO LOOK AT HUMAN TISSUE AND 8617 06:36:56,680 --> 06:36:58,080 THIS GOES DOWN THERE TOO WITH 8618 06:36:58,080 --> 06:36:59,960 AGE SO WE LOOKED AT PEOPLE LESS 8619 06:36:59,960 --> 06:37:01,240 THAN 45 YEARS AND OTHER PEOPLE 8620 06:37:01,240 --> 06:37:11,520 WHO ARE OVER 65. 8621 06:37:22,800 --> 06:37:25,960 IT GOES OFF A CLIFF AND DRAMATIC 8622 06:37:25,960 --> 06:37:28,880 REDUCTION AND OBVIOUSLY 8623 06:37:28,880 --> 06:37:30,240 PROLIFERATING THESE GILLS IS 8624 06:37:30,240 --> 06:37:31,080 GREATLY DIMINISHED. 8625 06:37:31,080 --> 06:37:33,080 THE NERVOUS SYSTEM, OKAY, THE 8626 06:37:33,080 --> 06:37:33,800 NERVES. 8627 06:37:33,800 --> 06:37:34,800 WHAT ARE THE NERVES DOING AT A 8628 06:37:34,800 --> 06:37:35,200 TIME. 8629 06:37:35,200 --> 06:37:36,880 SO WHEN THEY LOOKED AT TWO 8630 06:37:36,880 --> 06:37:38,880 MONTHS AND VERSUS 189 MONTHS WE 8631 06:37:38,880 --> 06:37:42,400 SAW A GREAT REDUCTION IN 8632 06:37:42,400 --> 06:37:44,960 INNOVATION AND HERE SO WE'RE 8633 06:37:44,960 --> 06:37:46,560 LIKE OKAY, WE DIDN'T SEE A 8634 06:37:46,560 --> 06:37:48,840 DECREASE AT NINE MONTHS OR 12 8635 06:37:48,840 --> 06:37:50,640 MONTHS OKAY SO THE NERVES ARE 8636 06:37:50,640 --> 06:37:52,800 STILL PRESENT AND WHAT ARE YOU 8637 06:37:52,800 --> 06:37:53,160 ASKING? 8638 06:37:53,160 --> 06:37:54,360 YOU ASK ABOUT FUNCTION. 8639 06:37:54,360 --> 06:37:56,240 WE ASK ABOUT FUNCTION BY GUESS 8640 06:37:56,240 --> 06:37:58,040 WHAT DOING A TWO PCR. 8641 06:37:58,040 --> 06:37:59,480 THANK YOU SO MUCH. 8642 06:37:59,480 --> 06:38:05,680 WE DID THAT BUT IT'S DOWN AND 8643 06:38:05,680 --> 06:38:07,480 IT'S DOWN BY NINE MONTHS AND YOU 8644 06:38:07,480 --> 06:38:09,920 STILL HAVE IT PRESENT AND 8645 06:38:09,920 --> 06:38:13,840 REDUCING YOUR NEURON FUNCTION. 8646 06:38:13,840 --> 06:38:15,720 SO REPLENISHMENT AND TELLING YOU 8647 06:38:15,720 --> 06:38:18,560 BY NINE MONTHS OF AGE THE 8648 06:38:18,560 --> 06:38:22,480 SUBSTITUTE CELLS ARE RIGHT AT 8649 06:38:22,480 --> 06:38:24,040 NOT SO GOOD AT NINE MONTHS YOU 8650 06:38:24,040 --> 06:38:26,000 SEE A MASSIVE REDUCTION IN 8651 06:38:26,000 --> 06:38:26,920 REPLACEMENT OF THESE CELLS SO 8652 06:38:26,920 --> 06:38:30,240 THIS IS THE AGING. 8653 06:38:30,240 --> 06:38:31,400 IT WORLD IT'S A THAT DECREASE 8654 06:38:31,400 --> 06:38:35,280 FUNCTIONAL INNOVATION SO THESE 8655 06:38:35,280 --> 06:38:39,480 TWO THINGS CAN IT WORK TOGETHER. 8656 06:38:39,480 --> 06:38:40,880 SO WE'RE JUST GOING TO USE THIS 8657 06:38:40,880 --> 06:38:42,720 SAME THING THAT WE TALKED ABOUT 8658 06:38:42,720 --> 06:38:43,400 BEFORE, RIGHT. 8659 06:38:43,400 --> 06:38:46,840 WE'RE GOING TO ASK IF THE 8660 06:38:46,840 --> 06:38:48,840 ACTIVITY TALKING RECEPTORS 8661 06:38:48,840 --> 06:38:50,160 ACTIVATION CAN DO SOMETHING 8662 06:38:50,160 --> 06:38:51,760 POSITIVE TO THIS AGING 8663 06:38:51,760 --> 06:38:55,680 EXPERIENCE OF ALL COMING FROM SO 8664 06:38:55,680 --> 06:38:58,000 THIS IS EXPERIMENTS WE DID AND 8665 06:38:58,000 --> 06:39:01,520 WE ASKED OKAY CAN WE GET TWO 8666 06:39:01,520 --> 06:39:03,960 CELLS BACK BY OVER TIME AND WE 8667 06:39:03,960 --> 06:39:05,840 LOOK AT YOUR ON YOUR LEFT AND 8668 06:39:05,840 --> 06:39:10,480 YOUR RIGHT AND YOU CAN SAY YES, 8669 06:39:10,480 --> 06:39:15,360 CLEARLY THESE CELLS BRING CELLS 8670 06:39:15,360 --> 06:39:16,680 ARE EXAMINING BACK SO WHAT THEY 8671 06:39:16,680 --> 06:39:20,760 NOTE HERE WE'RE USING LPO IS A 8672 06:39:20,760 --> 06:39:24,240 MARKER ACTIVITY AND STEM CELL 8673 06:39:24,240 --> 06:39:25,640 POPULATION AND IT'S NOT BRIGHT 8674 06:39:25,640 --> 06:39:28,160 IN THE UNTREATED LOOK IT'S 8675 06:39:28,160 --> 06:39:29,800 TWO-MONTH-OLD AND 11 TO OLD YOU 8676 06:39:29,800 --> 06:39:34,200 CAN SAY THAT AS REDUCTION IN THE 8677 06:39:34,200 --> 06:39:36,240 LPO AND YOU GET A REDUCTION 8678 06:39:36,240 --> 06:39:39,360 HOWEVER IF YOU COMPLETE WITH AGO 8679 06:39:39,360 --> 06:39:42,600 NISM OF 11 ANIMALS AND FOR 30 8680 06:39:42,600 --> 06:39:45,760 DAYS, GUESS WHAT, YOU ARE 8681 06:39:45,760 --> 06:39:46,960 ACTIVATING AND GETTING YOUR 8682 06:39:46,960 --> 06:39:49,120 CELLS BACK SO THAT'S PRETTY 8683 06:39:49,120 --> 06:39:50,160 SCHOOL ISN'T IT AND SO OF 8684 06:39:50,160 --> 06:39:54,000 COURSE, I JUST WANTED TO POINT 8685 06:39:54,000 --> 06:39:55,000 OUT I KNOW WE'RE TALKING ABOUT 8686 06:39:55,000 --> 06:40:01,360 IT TODAY I FEEL -- IT'S 8687 06:40:01,360 --> 06:40:02,600 11-MONTH-OLD AND WE'RE GOING TO 8688 06:40:02,600 --> 06:40:08,160 DO WITH FEMALE IN THE MALE AND 8689 06:40:08,160 --> 06:40:11,640 WE'RE GOING TO TREAT THIS FOR 30 8690 06:40:11,640 --> 06:40:15,360 DAYS AND WHAT HAPPENS IS THAT 8691 06:40:15,360 --> 06:40:16,920 YOU USE THE EX AT THE PRESENT 8692 06:40:16,920 --> 06:40:19,280 TIME OF REPLACEMENT AND YOU HAVE 8693 06:40:19,280 --> 06:40:20,360 TREATMENT AND GUESS WHAT THIS IS 8694 06:40:20,360 --> 06:40:23,680 THE MALES. 8695 06:40:23,680 --> 06:40:24,720 THE MALES AND FEMALES DO WELL. 8696 06:40:24,720 --> 06:40:25,920 THE MALES DO BETTER. 8697 06:40:25,920 --> 06:40:29,120 I HATE IT SAY IT LADIES BUT THAT 8698 06:40:29,120 --> 06:40:30,400 IS WHAT WE'RE THINKING. 8699 06:40:30,400 --> 06:40:37,160 SOME DAYS THEY'RE 18-MONTH-OLD 8700 06:40:37,160 --> 06:40:40,800 AND SO THE OTHER PIECES OF THIS 8701 06:40:40,800 --> 06:40:43,240 IS WE FEEL IT'S CELL IDENTITY 8702 06:40:43,240 --> 06:40:44,640 AND YOU NOTICE DOWN HERE THERE'S 8703 06:40:44,640 --> 06:40:47,040 A PROBLEM, MISSED ONE IS A 8704 06:40:47,040 --> 06:40:49,280 MARKER CREATIVE FUNCTION IT'S 8705 06:40:49,280 --> 06:40:50,680 DEREGULATED THAT YOU MUST HAVE 8706 06:40:50,680 --> 06:40:52,360 IT SO YOU CAN SEE IT'S ON THE 8707 06:40:52,360 --> 06:40:54,640 LEFT AND YOU CAN SEE WAY MORE ON 8708 06:40:54,640 --> 06:40:58,720 THE RIGHT AND WE'RE ALSO SEEING 8709 06:40:58,720 --> 06:41:00,280 THESE PLEASURE WE THINK IT COULD 8710 06:41:00,280 --> 06:41:05,240 BE THIS AND THEY CERTAINLY NOT 8711 06:41:05,240 --> 06:41:08,960 (INAUDIBLE) OKAY, SO WE ARE 8712 06:41:08,960 --> 06:41:10,560 RISKING THE DISEASE STATE AND 8713 06:41:10,560 --> 06:41:13,200 THE IDENTITY OR MAYBE A OF 8714 06:41:13,200 --> 06:41:15,200 DEGREE SET. 8715 06:41:15,200 --> 06:41:17,240 SO, THE LAST BIT ARE ABOUT 8716 06:41:17,240 --> 06:41:18,760 REGENERATION OF AGED PEOPLE. 8717 06:41:18,760 --> 06:41:20,000 YOU SHOULD ALL BE INTERESTED IN 8718 06:41:20,000 --> 06:41:20,560 THIS. 8719 06:41:20,560 --> 06:41:22,240 SOME OF YOU ARE. 8720 06:41:22,240 --> 06:41:24,240 I'M INTERESTED. 8721 06:41:24,240 --> 06:41:25,200 AND WHAT WAS INTERESTING TO US 8722 06:41:25,200 --> 06:41:27,280 BECAUSE WE STUDY REGENERATION 8723 06:41:27,280 --> 06:41:32,200 AFTER RADIATION, YOUNG LAND HERE 8724 06:41:32,200 --> 06:41:33,880 ON THE LEFT RADIATION OF THE 8725 06:41:33,880 --> 06:41:37,080 YOUNG AND THE MIDDLE, AND THE 8726 06:41:37,080 --> 06:41:39,800 RADIATION AGE ON THE RIGHT OKAY, 8727 06:41:39,800 --> 06:41:43,360 THE YOUNG AND RAID IS SIMILAR 8728 06:41:43,360 --> 06:41:45,560 AND MAYBE THE NO RADIATION AGE 8729 06:41:45,560 --> 06:41:48,000 IS GOING BETTER AND BUT THIS IS 8730 06:41:48,000 --> 06:41:49,800 THE STATE OF THINGS AND IF YOU 8731 06:41:49,800 --> 06:41:51,280 COME IN AND YOU HAVE RADIATION 8732 06:41:51,280 --> 06:41:53,200 AND YOU ARE OVER THE AGE OF 65 8733 06:41:53,200 --> 06:41:56,680 WHICH IS BASICALLY A LOT OF 8734 06:41:56,680 --> 06:41:57,480 PATIENTS IT COULD BE A PROBLEM 8735 06:41:57,480 --> 06:42:00,200 FOR YOU WITH REGENERATION. 8736 06:42:00,200 --> 06:42:02,160 I MEAN, THE TISSUE IS GOING TO 8737 06:42:02,160 --> 06:42:03,920 BE GENERATION OVER TIME BUT YOU 8738 06:42:03,920 --> 06:42:05,120 MIGHT HAVE A WORK. 8739 06:42:05,120 --> 06:42:07,600 WHAT WE'RE GOING TO DO HERE IS 8740 06:42:07,600 --> 06:42:10,680 WE'RE GOING TO TREAT THESE NOT 8741 06:42:10,680 --> 06:42:11,160 EGGS. 8742 06:42:11,160 --> 06:42:15,040 THIS IS 11-MONTH-OLD MICE AND 8743 06:42:15,040 --> 06:42:17,800 DAY 30 WE'RE GOING TO TREAT THEM 8744 06:42:17,800 --> 06:42:19,600 WITH FOR ANOTHER TWO MONTHS. 8745 06:42:19,600 --> 06:42:22,280 SO THAT 14 MONTH DAY LOOK AT 8746 06:42:22,280 --> 06:42:23,840 THEM AND RADIATION HERE ON YOUR 8747 06:42:23,840 --> 06:42:28,000 LEFT AND LOTS OF THE BEAUTIFUL 8748 06:42:28,000 --> 06:42:29,920 LOOKING MARK 10 AND IN THE 8749 06:42:29,920 --> 06:42:34,480 MIDDLE YOU SEE RADIATION AND 8750 06:42:34,480 --> 06:42:37,480 SALINE AND A LOT AND WHEN YOU 8751 06:42:37,480 --> 06:42:39,280 SEE IT'S DAMAGE RADIATED ALL 8752 06:42:39,280 --> 06:42:41,400 ANIMALS YOU ARE GETTING A RESCUE 8753 06:42:41,400 --> 06:42:43,200 OF THE TISSUE AND WHAT YOU ARE 8754 06:42:43,200 --> 06:42:49,040 SEEING OVER ON THE FAR-RIGHT, IS 8755 06:42:49,040 --> 06:42:51,760 THE NERVES INDUCED SALIVA OUTPUT 8756 06:42:51,760 --> 06:42:54,200 SO YOU WANT TO COMPARE THE BLUE 8757 06:42:54,200 --> 06:42:56,040 BAR WITH THE RED BAR AND YOU 8758 06:42:56,040 --> 06:42:57,440 WILL NOTICE IT KEEPS GOING UP 8759 06:42:57,440 --> 06:43:00,520 AND IT'S TRUE AND THIS IS A 8760 06:43:00,520 --> 06:43:01,840 SIGNIFICANT RISK YOU ARE SAYING 8761 06:43:01,840 --> 06:43:05,360 IT OTHER IS COMPLETELY SIMILAR 8762 06:43:05,360 --> 06:43:08,280 TO THE SO I HOPE THAT YOU CAN 8763 06:43:08,280 --> 06:43:09,520 THINK ABOUT IMMUNE CELLS IN 8764 06:43:09,520 --> 06:43:09,960 THERE. 8765 06:43:09,960 --> 06:43:12,520 I CAN TELL YOU RIGHT NOW THAT WE 8766 06:43:12,520 --> 06:43:14,000 ACTUALLY SAY AND I'M HAPPY TO BE 8767 06:43:14,000 --> 06:43:16,080 TALKING ABOUT IT OVER DINNER, AN 8768 06:43:16,080 --> 06:43:20,280 INCREASE IN IMMUNE RELATED GENES 8769 06:43:20,280 --> 06:43:21,320 BUT SINCE I DON'T KNOW ABOUT IT 8770 06:43:21,320 --> 06:43:22,600 I'M ASKING YOU TO HELP ME WHEN 8771 06:43:22,600 --> 06:43:24,400 YOU SEE THAT DATA. 8772 06:43:24,400 --> 06:43:25,600 SO, THERE ARE A NUMBER OF 8773 06:43:25,600 --> 06:43:31,240 QUESTIONS AND YOU ALL ASKING -- 8774 06:43:31,240 --> 06:43:33,840 I'M GOING TO TURN INTO ROLL BACK 8775 06:43:33,840 --> 06:43:36,040 BECAUSE THEY'RE AMAZING LIVING 8776 06:43:36,040 --> 06:43:36,520 FOREVER. 8777 06:43:36,520 --> 06:43:38,280 I'M NOT BECAUSE IT LOOKS LIKE 8778 06:43:38,280 --> 06:43:39,000 THAT. 8779 06:43:39,000 --> 06:43:46,600 SO, YOU PROBABLY ARE THINKING 8780 06:43:46,600 --> 06:43:47,400 CHOLINERGIC NERVES AND WOULD 8781 06:43:47,400 --> 06:43:49,760 THEY BE INVOLVED IN A PROCESS 8782 06:43:49,760 --> 06:43:50,840 LIKE THIS. 8783 06:43:50,840 --> 06:43:52,640 CAN IT BE MAINTAINED LONG-TERM? 8784 06:43:52,640 --> 06:43:54,320 WE'RE WORKING ON THIS RIGHT NOW. 8785 06:43:54,320 --> 06:43:56,200 I CAN TELL YOU WHEN YOU TURN OFF 8786 06:43:56,200 --> 06:43:59,440 THE DELIVERY OF AGO NISM IT 8787 06:43:59,440 --> 06:44:01,480 HOLDS IT AND NOW HOW LONG CAN IT 8788 06:44:01,480 --> 06:44:04,640 HOLD IT WE'VE LOOKED AT TWO 8789 06:44:04,640 --> 06:44:06,240 MONTHS, THREE MONTHS, IT LOOKS 8790 06:44:06,240 --> 06:44:07,640 GOOD. 8791 06:44:07,640 --> 06:44:09,280 WHETHER IT'S GOING TO BE IT I 8792 06:44:09,280 --> 06:44:11,160 DOUBT IT BUT WITH GOING INTO 8793 06:44:11,160 --> 06:44:13,000 THAT BUT REALLY WHAT ARE WE 8794 06:44:13,000 --> 06:44:18,320 GOING TO DO IN HUMANS? 8795 06:44:18,320 --> 06:44:20,440 PLEASE COME AND COLLABORATE WITH 8796 06:44:20,440 --> 06:44:23,800 THEM AND CONSERVE AND I'M 8797 06:44:23,800 --> 06:44:26,280 INTERESTED IN IT YOU SHOULD BE 8798 06:44:26,280 --> 06:44:27,160 INTERESTED AND IS IT ONLY 8799 06:44:27,160 --> 06:44:28,520 ENOUGH. 8800 06:44:28,520 --> 06:44:30,120 MAYBE THEY WITH WRITE ABOUT IT 8801 06:44:30,120 --> 06:44:33,000 MAYBE IT'S GOING ON NERVE 8802 06:44:33,000 --> 06:44:34,000 COMMUNICATION. 8803 06:44:34,000 --> 06:44:34,600 THAT'S IT. 8804 06:44:34,600 --> 06:44:41,640 I'M THREE MINUTES OVER. 8805 06:44:41,640 --> 06:44:43,440 I HOPE I DIDN'T SPEAK TOO 8806 06:44:43,440 --> 06:44:45,400 QUICKLY WITH MY AUSTRALIAN 8807 06:44:45,400 --> 06:44:46,720 ACCENT. 8808 06:44:46,720 --> 06:44:49,520 AND THERE'S ANOTHER STRAIN. 8809 06:44:49,520 --> 06:44:53,720 >>REALLY FASCINATING. 8810 06:44:53,720 --> 06:44:55,520 I WAS ROCKED BY HOW SIMILAR IN 8811 06:44:55,520 --> 06:44:59,040 MANY DIFFERENT WAYS AND THE 8812 06:44:59,040 --> 06:45:00,720 TISSUE AND I HAVE MANY 8813 06:45:00,720 --> 06:45:05,560 QUESTIONS, ONE INVOLVING KGF TO 8814 06:45:05,560 --> 06:45:06,960 TREAT AND DID YOU HAVE A ROLE IN 8815 06:45:06,960 --> 06:45:09,080 THE SALIVARY GLANDS AS WELL BUT 8816 06:45:09,080 --> 06:45:15,240 I WAS MORE CURIOUS WHAT TO GET 8817 06:45:15,240 --> 06:45:15,480 REGULAR. 8818 06:45:15,480 --> 06:45:18,480 >>IF THE SALIVARY GLANDS IF. 8819 06:45:18,480 --> 06:45:20,680 >>SO, OVER TIME OR JUST 8820 06:45:20,680 --> 06:45:21,280 NATURALLY? 8821 06:45:21,280 --> 06:45:22,200 >>JUST NATURALLY. 8822 06:45:22,200 --> 06:45:26,960 >>YOU HAVE A BUNCH OF 8823 06:45:26,960 --> 06:45:28,400 MACROPHAGES MAKES SENSE AND OVER 8824 06:45:28,400 --> 06:45:32,440 TIME YOU GET BOTH WE TALKED 8825 06:45:32,440 --> 06:45:36,880 ABOUT THAT AND SO THIS IS MAYBE 8826 06:45:36,880 --> 06:45:38,120 12 MONTHS AND ON AND THERE'S 8827 06:45:38,120 --> 06:45:39,560 MORE AND MORE ACCUMULATION 8828 06:45:39,560 --> 06:45:40,120 THERE. 8829 06:45:40,120 --> 06:45:41,920 EARLY ON, YOU KNOW, WE THINK 8830 06:45:41,920 --> 06:45:45,880 THAT THERE'S GOING TO BE SOME 8831 06:45:45,880 --> 06:45:47,440 LEVEL OF INLOUD AND IT'S VERY 8832 06:45:47,440 --> 06:45:49,240 KNOWN AND IT'S BEEN KNOWN FOR 8833 06:45:49,240 --> 06:45:51,000 LIKE I DON'T KNOW 50 PLUS YEARS 8834 06:45:51,000 --> 06:45:54,120 AND DO WE KNOW WHAT THEY DO THE 8835 06:45:54,120 --> 06:45:56,360 ANSWER IS NO. 8836 06:45:56,360 --> 06:45:57,320 UNLESS YOU DO. 8837 06:45:57,320 --> 06:46:00,320 BUT YEAH, THERE'S AN ASSORTMENT 8838 06:46:00,320 --> 06:46:04,160 OF I MEAN, HOW THEY ACT IN AGING 8839 06:46:04,160 --> 06:46:06,920 PROCESS AND HOW THEY ACT IN 8840 06:46:06,920 --> 06:46:09,240 REGENERATIVE PROCESS, RIGHT. 8841 06:46:09,240 --> 06:46:12,600 AND WHETHER YOU CAN ACTIVATE IN 8842 06:46:12,600 --> 06:46:14,800 AGE AGING PROCESS WHETHER 8843 06:46:14,800 --> 06:46:15,640 THEY'RE AGING OR WHETHER THEY'RE 8844 06:46:15,640 --> 06:46:17,680 INVOLVED IN THE REVERSAL OF 8845 06:46:17,680 --> 06:46:18,200 AGING. 8846 06:46:18,200 --> 06:46:21,640 >>VERY GOOD. 8847 06:46:21,640 --> 06:46:30,120 >>THE NERVE HEALING EXPERIMENT 8848 06:46:30,120 --> 06:46:32,600 THAT YOU DID WAS IN YOUNG MICE. 8849 06:46:32,600 --> 06:46:35,520 DO OLD MICE FEEL THE NERVES? 8850 06:46:35,520 --> 06:46:36,200 >>THAT'S A GREAT QUESTION. 8851 06:46:36,200 --> 06:46:37,680 WE HAVEN'T DONE IT AND WE 8852 06:46:37,680 --> 06:46:38,800 SHOULD. 8853 06:46:38,800 --> 06:46:40,320 IT'S ONE OF THE HARDEST 8854 06:46:40,320 --> 06:46:41,680 EXPERIMENTS YOU CAN DO AND THE 8855 06:46:41,680 --> 06:46:43,400 LIKELIHOOD OF KILLING THE MICE 8856 06:46:43,400 --> 06:46:48,320 IS HIGH SO IT WILL BE BETTER. 8857 06:46:51,400 --> 06:46:52,400 ON-LINE QUESTIONS? 8858 06:46:52,400 --> 06:46:57,760 WHAT ABOUT INCREASING 8859 06:46:57,760 --> 06:47:08,280 AVAILABILITY AND YEAH, SO, OKAY, 8860 06:47:08,280 --> 06:47:11,360 YOU WANT TO INCREASE A INSCEPTER 8861 06:47:11,360 --> 06:47:12,480 ANTAGONIST. 8862 06:47:12,480 --> 06:47:12,880 IT'S VEIL ABILITY. 8863 06:47:12,880 --> 06:47:14,960 >>YOU THINK SO OKAY, THE 8864 06:47:14,960 --> 06:47:18,240 QUESTION IS ABOUT AVAILABILITY. 8865 06:47:18,240 --> 06:47:19,440 IT COULD BE A PROBLEM TOO, 8866 06:47:19,440 --> 06:47:19,920 RIGHT. 8867 06:47:19,920 --> 06:47:23,920 SO I JUST THINK ABOUT OKAY, THE 8868 06:47:23,920 --> 06:47:25,240 MAJORITY OF THE ORGANS ARE GOING 8869 06:47:25,240 --> 06:47:29,200 TO BE WRAPPED INTENSELY BY THESE 8870 06:47:29,200 --> 06:47:33,120 NERVES, RIGHT AND YOU GOT THEM 8871 06:47:33,120 --> 06:47:36,240 COVERED AS WELL WHICH WE DON'T 8872 06:47:36,240 --> 06:47:38,120 KNOW ABOUT AND IT'S RIGHT AROUND 8873 06:47:38,120 --> 06:47:39,120 THAT TISSUE SO IS IT THAT YOU 8874 06:47:39,120 --> 06:47:44,320 ARE NOT HAVING CONNECTIONS WITH 8875 06:47:44,320 --> 06:47:45,640 THOSE CELLS AND SO THOSE ARE THE 8876 06:47:45,640 --> 06:47:46,720 THINGS THAT I THINK ABOUT ALL 8877 06:47:46,720 --> 06:47:48,240 THE TIME BECAUSE YOU HAVE TO 8878 06:47:48,240 --> 06:47:50,840 HAVE THOSE IN ORDER TO RECEIVE 8879 06:47:50,840 --> 06:47:56,000 IT AS IT GETS TAKEN AWAY WITH IN 8880 06:47:56,000 --> 06:47:56,560 SECONDS AND MILLEY SECONDS 8881 06:47:56,560 --> 06:47:58,240 WHATEVER YOU WANT TO CALL IT SO, 8882 06:47:58,240 --> 06:48:01,400 YOU KNOW, YES, THE PRODUCTION 8883 06:48:01,400 --> 06:48:03,280 AND THE INTERACTION WITH THE 8884 06:48:03,280 --> 06:48:05,600 CELLS, RIGHT, BUT THE THEY ALL 8885 06:48:05,600 --> 06:48:07,800 HAVE IT OTHERWISE WE CANNOT SEE 8886 06:48:07,800 --> 06:48:09,880 CRATE AND THIS IS INVOLVED 8887 06:48:09,880 --> 06:48:11,800 THOUGH IN PROLIFERATION AS WELL 8888 06:48:11,800 --> 06:48:14,880 AS REPLENISHMENT, RIGHT. 8889 06:48:14,880 --> 06:48:17,120 SO, YES, IT'S A GREAT POINT AND 8890 06:48:17,120 --> 06:48:18,320 I THINK THAT MOST OF US THINK 8891 06:48:18,320 --> 06:48:20,720 ABOUT THE SIN AS TICK 8892 06:48:20,720 --> 06:48:21,880 CONNECTIONS WITH YOU THINK ABOUT 8893 06:48:21,880 --> 06:48:24,680 YOUR ORGANS AND THE NEO FILLS 8894 06:48:24,680 --> 06:48:26,000 COME IN THERE TOO SO THEY TRAVEL 8895 06:48:26,000 --> 06:48:30,600 ON THE NERVOUS SYSTEM YEAST. 8896 06:48:30,600 --> 06:48:32,200 CANCER DOES TOO, REALLY BAD. 8897 06:48:32,200 --> 06:48:33,240 I STUDIED THAT AS WELL. 8898 06:48:33,240 --> 06:48:34,360 ANYTHING ELSE. 8899 06:48:34,360 --> 06:48:35,440 >>ONE MORE QUESTION. 8900 06:48:35,440 --> 06:48:38,680 >>ANY DATA TO VERIFY THE 8901 06:48:38,680 --> 06:48:40,480 AGONIST YOU THINK ANTAGONIST IN 8902 06:48:40,480 --> 06:48:41,680 PRO CLINICAL MODELS? 8903 06:48:41,680 --> 06:48:45,920 >>YEAH, SO, CLINICAL MODEL. 8904 06:48:45,920 --> 06:48:47,240 I SUPPOSE IT'S BECAUSE WE DID 8905 06:48:47,240 --> 06:48:49,680 ALL OF OUR STUDIES WHERE WE CAN 8906 06:48:49,680 --> 06:48:52,880 JUST ADD THE AGO NIST OUTSIDE OF 8907 06:48:52,880 --> 06:48:56,360 THE BODIES AND SO WE TAKE BLOOD, 8908 06:48:56,360 --> 06:48:58,000 TISSUE AND WE CAN TRACE THEM. 8909 06:48:58,000 --> 06:48:59,080 NOW THE QUESTION COULD BE IF YOU 8910 06:48:59,080 --> 06:49:02,160 TAKE THAT TISSUE AND YOU PLACE 8911 06:49:02,160 --> 06:49:05,200 IT IN VIVO AND YOU PUT IT AGO 8912 06:49:05,200 --> 06:49:07,640 NIST IF THERE DOES IT CAUSE IT 8913 06:49:07,640 --> 06:49:09,440 TO PROLIFERATE AND THE ANSWER IS 8914 06:49:09,440 --> 06:49:10,720 YES. 8915 06:49:10,720 --> 06:49:12,080 SO, IT'S WHETHER YOU CAN BLOCK 8916 06:49:12,080 --> 06:49:12,880 IT. 8917 06:49:12,880 --> 06:49:13,720 WE HAVEN'T DONE THAT. 8918 06:49:13,720 --> 06:49:15,040 IT'S VERY DIFFICULT TO DO IT 8919 06:49:15,040 --> 06:49:17,960 BECAUSE YOU NEED YOUR NERVOUS 8920 06:49:17,960 --> 06:49:20,400 SYSTEM AND IT'S NOT REALLY A 8921 06:49:20,400 --> 06:49:23,320 WHAT SPECIFICALLY DEACTIVATE, 8922 06:49:23,320 --> 06:49:23,760 RIGHT. 8923 06:49:23,760 --> 06:49:29,280 YOU HAVE TO DEACT EVERYTHING. 8924 06:49:29,280 --> 06:49:30,800 DON'T DO THAT BECAUSE IT WON'T 8925 06:49:30,800 --> 06:49:31,280 GOOD. 8926 06:49:31,280 --> 06:49:32,760 BUT THERE'S A PROBLEM THERE WITH 8927 06:49:32,760 --> 06:49:35,800 THAT ASK JUST THE FOOL. 8928 06:49:35,800 --> 06:49:37,360 I THINK IT'S THE CENTRAL NERVOUS 8929 06:49:37,360 --> 06:49:39,480 SYSTEM BY THE WAY BECAUSE GUESS 8930 06:49:39,480 --> 00:00:00,000 WHAT THERE'S NO FALL.