1 00:00:05,680 --> 00:00:09,920 I HAVE THE PRIVILEGE OF SERVING 2 00:00:09,920 --> 00:00:11,880 AS THE CHIEF EXECUTIVE OFFICER 3 00:00:11,880 --> 00:00:12,760 OF THE AMERICAN ASSOCIATION FOR 4 00:00:12,760 --> 00:00:14,520 THE ADVANCEMENT OF SCIENCE, OR 5 00:00:14,520 --> 00:00:15,120 AAAS MARTIN AND ROSE WACHTEL 6 00:00:15,120 --> 00:00:15,640 CANCER RESEARCH AWARD AND 7 00:00:15,640 --> 00:00:16,280 LECTURE, AND EXECUTIVE PUBLISHER 8 00:00:16,280 --> 00:00:17,200 OF SCIENCE AND THE SCIENCE 9 00:00:17,200 --> 00:00:18,360 FAMILY OF JOURNALS. 10 00:00:18,360 --> 00:00:26,440 I GET TO WELCOME YOU TO THE 11th 11 00:00:26,440 --> 00:00:27,040 ANNUAL AAAS MARTIN AND ROSE 12 00:00:27,040 --> 00:00:27,640 WACHTEL CANCER RESEARCH AWARD 13 00:00:27,640 --> 00:00:28,440 AND LECTURE. 14 00:00:28,440 --> 00:00:31,240 THIS IS WHERE WE RECOGNIZE EARLY 15 00:00:31,240 --> 00:00:31,960 CAREER RESEARCHERS FOR 16 00:00:31,960 --> 00:00:34,480 OUTSTANDING CONTRIBUTIONS TO THE 17 00:00:34,480 --> 00:00:36,400 FIELD. 18 00:00:36,400 --> 00:00:37,440 TODAY'S AWARD WAS MADE POSSIBLE 19 00:00:37,440 --> 00:00:40,520 BY A BEQUEST BY MARTIN WACHTEL. 20 00:00:40,520 --> 00:00:45,920 HE WISHED TO ESTABLISH AN 21 00:00:45,920 --> 00:00:51,720 ENDOWMENT TO RECOGNIZE A AAAS 22 00:00:51,720 --> 00:00:52,360 WORKER IN SCIENCE. 23 00:00:52,360 --> 00:00:55,280 HE WASN'T A SCIENTIST. 24 00:00:55,280 --> 00:00:57,680 HE PROVIDED ALBINO MICE AND RATS 25 00:00:57,680 --> 00:00:58,840 FOR MEDICAL RESEARCH. 26 00:00:58,840 --> 00:01:00,440 HE WAS A FIRM BELIEVER IN THE 27 00:01:00,440 --> 00:01:03,040 POWER OF SCIENTIFIC RESEARCH TO 28 00:01:03,040 --> 00:01:04,920 BENEFIT HUMANITY AND SOUGHT TO 29 00:01:04,920 --> 00:01:05,920 USE HIS WEALTH TO SUPPORT AND 30 00:01:05,920 --> 00:01:07,720 RECOGNIZE THOSE IN THE MEDICAL 31 00:01:07,720 --> 00:01:09,120 COMMUNITY WHOSE WORK WAS HAVING 32 00:01:09,120 --> 00:01:11,240 THE GREATEST IMPACT. 33 00:01:11,240 --> 00:01:14,400 HE INDICATED HE SELECTED THE 34 00:01:14,400 --> 00:01:16,800 AAAS AS THE PLACE TO ESTABLISH 35 00:01:16,800 --> 00:01:18,960 THIS PRIZE BECAUSE OF ITS LONG 36 00:01:18,960 --> 00:01:19,640 AND DISTINGUISHED HISTORY IN ALL 37 00:01:19,640 --> 00:01:22,320 OF THE SCIENCES. 38 00:01:22,320 --> 00:01:23,640 EARLY RECOGNITION OF 39 00:01:23,640 --> 00:01:25,160 MULTIDISCIPLINARY RESEARCH, THE 40 00:01:25,160 --> 00:01:27,120 FACT THERE IS CONVERGENCE 41 00:01:27,120 --> 00:01:29,880 AMONGST THE SCIENCES AND THEY 42 00:01:29,880 --> 00:01:33,960 LEAD TO EVEN MORE CREATIVE AND 43 00:01:33,960 --> 00:01:35,920 INNOVATIVE SOLUTIONS TO PROPS. 44 00:01:35,920 --> 00:01:37,920 AAAS IS 175 YEARS OLD. 45 00:01:37,920 --> 00:01:41,680 IT WAS FOUNDED IN 1848 BY A 46 00:01:41,680 --> 00:01:46,400 BUNCH OF ENTOMOLOGISTS, MOSTLY 47 00:01:46,400 --> 00:01:47,160 MEN IN PHILADELPHIA. 48 00:01:47,160 --> 00:01:49,280 WHAT IS AMAZING TO ME OVER THAT 49 00:01:49,280 --> 00:01:51,440 TIME IS THERE HAVE BEEN 50 00:01:51,440 --> 00:01:53,560 EVOLUTIONS AND REVOLUTIONS IN 51 00:01:53,560 --> 00:01:55,600 THE SCIENCES THAT HAVE ENABLED 52 00:01:55,600 --> 00:01:57,160 US TO MAKE INCREDIBLE PROGRESS. 53 00:01:57,160 --> 00:01:59,200 SO WHEN I THINK OF THE 54 00:01:59,200 --> 00:02:00,600 CHALLENGES THAT WE FACE TODAY, 55 00:02:00,600 --> 00:02:02,640 YOU KNOW, I THINK THAT THERE'S 56 00:02:02,640 --> 00:02:05,200 DAYS WHEN I'M OPTIMISTIC. 57 00:02:05,200 --> 00:02:07,280 ON MY MOST OPTIMISTIC DAYS I 58 00:02:07,280 --> 00:02:09,640 THINK THAT THE SCIENCES CAN 59 00:02:09,640 --> 00:02:13,280 SERVE AS BRIDGES AND CONNECTORS 60 00:02:13,280 --> 00:02:15,520 AROUND THE WORLD TO CURE 61 00:02:15,520 --> 00:02:19,600 DISEASE, TO FEED THE HUNGRY, TO 62 00:02:19,600 --> 00:02:20,440 PROTECT THE PLANET. 63 00:02:20,440 --> 00:02:23,200 BUT THEN ON MY WORST DAYS I 64 00:02:23,200 --> 00:02:25,120 THINK THAT -- I START TO THINK 65 00:02:25,120 --> 00:02:27,280 THAT WE'RE GOING TO RETREAT TO 66 00:02:27,280 --> 00:02:29,320 OUR CORNERS AND WE'RE GOING TO 67 00:02:29,320 --> 00:02:32,400 DO RESEARCH THAT IS ONLY FOR OUR 68 00:02:32,400 --> 00:02:35,440 TRIBE OR ONLY FOR OUR COUNTRY OR 69 00:02:35,440 --> 00:02:36,400 ONLY FOR DEFENSE. 70 00:02:36,400 --> 00:02:38,560 BOTH OF THOSE FUTURES ARE 71 00:02:38,560 --> 00:02:38,840 POSSIBLE. 72 00:02:38,840 --> 00:02:40,400 BOTH OF THEM ARE POSSIBLE, BUT 73 00:02:40,400 --> 00:02:42,400 NEITHER ONE OF THEM IS 74 00:02:42,400 --> 00:02:43,280 INEVITABLE. 75 00:02:43,280 --> 00:02:45,160 NEITHER ONE IS INEVITABLE. 76 00:02:45,160 --> 00:02:47,600 THE AAAS IS STANDING IN THIS 77 00:02:47,600 --> 00:02:48,920 PLACE WHERE WE ARE TRYING TO 78 00:02:48,920 --> 00:02:51,240 MAKE SURE WE GO FOR A MORE 79 00:02:51,240 --> 00:02:55,560 POSITIVE VERSION OF THAT FUTURE 80 00:02:55,560 --> 00:02:56,800 PART OF THAT IS RECOGNIZING THAT 81 00:02:56,800 --> 00:02:59,360 SCIENCE AND THE CREATIVITY, THE 82 00:02:59,360 --> 00:03:00,760 DISCOVERY AND THE JOYFUL PURSUIT 83 00:03:00,760 --> 00:03:03,040 OF IT, THE PART THAT GETS US ALL 84 00:03:03,040 --> 00:03:05,440 INTO IT IN THE FIRST PLACE CAN 85 00:03:05,440 --> 00:03:06,840 BE MARRIED WITH THE AMAZING 86 00:03:06,840 --> 00:03:09,160 THINGS THAT WE HOPE TO IMPACT IN 87 00:03:09,160 --> 00:03:12,040 PEOPLE'S DAILY LIVES. 88 00:03:12,040 --> 00:03:13,440 WHETHER THAT BE MAKING THEIR 89 00:03:13,440 --> 00:03:16,240 LIVES A LITTLE BETTER THROUGH 90 00:03:16,240 --> 00:03:18,440 TECHNOLOGY, HOPEFULLY NOT SOCIAL 91 00:03:18,440 --> 00:03:19,840 MEDIA, BUT SOMETHING ELSE, OR 92 00:03:19,840 --> 00:03:21,920 WHETHER IT BE CURING DISEASE AND 93 00:03:21,920 --> 00:03:23,120 MAKING LIVES HEALTHIER. 94 00:03:23,120 --> 00:03:28,440 A LOT OF THAT IS DRIVEN BY EARLY 95 00:03:28,440 --> 00:03:29,920 CAREER SCIENTISTS. 96 00:03:29,920 --> 00:03:30,920 EARLY CAREER SCIENTISTS. 97 00:03:30,920 --> 00:03:33,640 IN FACT, IT IS WHAT GIVES ME 98 00:03:33,640 --> 00:03:34,360 HOPE. 99 00:03:34,360 --> 00:03:36,360 WHEN I'M ASKED WHAT IS IT THAT 100 00:03:36,360 --> 00:03:38,560 DRIVES MY OPTIMISM IN THE 101 00:03:38,560 --> 00:03:40,400 SCIENCES IN A TIME OF 102 00:03:40,400 --> 00:03:43,240 MULTIPOLARITY AND PULLING APART 103 00:03:43,240 --> 00:03:43,720 OF THE WORLD? 104 00:03:43,720 --> 00:03:46,280 I SAY WHEN I GO TO ANY CAMPUS, 105 00:03:46,280 --> 00:03:50,640 WHEN I GO TO ANY UNIVERSITY R, 106 00:03:50,640 --> 00:03:52,280 WHEN I GO TO ANY RESEARCH 107 00:03:52,280 --> 00:03:53,600 INSTITUTION AROUND THE WORLD, I 108 00:03:53,600 --> 00:03:57,120 DON'T WANT TO MEET WITH THE 109 00:03:57,120 --> 00:03:58,080 SENIOR LEADERS. 110 00:03:58,080 --> 00:04:00,000 I HAVE GOTTEN TO MEET THEM. 111 00:04:00,000 --> 00:04:01,520 MAN, THEY ARE HARD WORKING. 112 00:04:01,520 --> 00:04:04,320 WHEN I SEE THE CREATIVITY AND 113 00:04:04,320 --> 00:04:06,160 INNOVATION, I SEE IT IN THE 114 00:04:06,160 --> 00:04:07,560 EARLY CAREER SCIENTISTS. 115 00:04:07,560 --> 00:04:10,000 THAT IS WHERE I DERIVE MY HOPE 116 00:04:10,000 --> 00:04:12,000 AND OPTIMISM AND I HOPE YOU ALL 117 00:04:12,000 --> 00:04:12,760 WILL, TOO. 118 00:04:12,760 --> 00:04:15,240 NOW, IN ADDITION TO BEING THIS 119 00:04:15,240 --> 00:04:18,520 MULTIDISCIPLINARY SOCIETY, WE DO 120 00:04:18,520 --> 00:04:19,840 PUBLISH "SCIENCE" AND THE 121 00:04:19,840 --> 00:04:25,680 SCIENCE FAMILY OF JOURNALS, AND 122 00:04:25,680 --> 00:04:27,600 THAT'S IT BY THE WAY. 123 00:04:27,600 --> 00:04:29,520 WE DON'T HAVE A THOUSAND 124 00:04:29,520 --> 00:04:30,440 JOURNALS SITTING BACK THERE WE 125 00:04:30,440 --> 00:04:32,080 THROW THINGS INTO. 126 00:04:32,080 --> 00:04:34,400 WE REALLY BELIEVE THAT IT 127 00:04:34,400 --> 00:04:39,920 MATTERS THAT WE ARE IDENTIFYING 128 00:04:39,920 --> 00:04:46,680 AND CURATING WITH THE COMMENT. 129 00:04:46,680 --> 00:04:48,200 I WANT TO RECOGNIZE THE EDITOR 130 00:04:48,200 --> 00:04:49,760 AND ASSOCIATE EDITORS WHO ARE 131 00:04:49,760 --> 00:04:51,400 HERE FOR OVERSEEING THIS AWARD 132 00:04:51,400 --> 00:04:52,440 AND THE SELECTION PROCESS. 133 00:04:52,440 --> 00:04:54,280 THIS IS NOT EASY. 134 00:04:54,280 --> 00:04:56,440 IT TURNS OUT THERE ARE A LOT OF 135 00:04:56,440 --> 00:04:58,040 WONDERFUL, WONDERFUL EARLY 136 00:04:58,040 --> 00:04:59,240 CAREER SCIENTISTS OUT THERE THAT 137 00:04:59,240 --> 00:05:00,920 COULD HAVE EARNED THIS AWARD. 138 00:05:00,920 --> 00:05:03,760 THAT IS WHY YOU ARE GOING TO SEE 139 00:05:03,760 --> 00:05:05,080 AN EXTRAORDINARY TALK TODAY 140 00:05:05,080 --> 00:05:08,440 BUILT ON AN EXTRAORDINARY ESSAY. 141 00:05:08,440 --> 00:05:10,720 NOW, GIVEN MR. WACHTEL'S HISTORY 142 00:05:10,720 --> 00:05:12,760 OF WORKING WITH NIH RESEARCHERS, 143 00:05:12,760 --> 00:05:13,960 I'M SURE HE WOULD BE 144 00:05:13,960 --> 00:05:15,560 PARTICULARLY PLEASED TO KNOW 145 00:05:15,560 --> 00:05:18,160 THIS IS BEING PRESENTED IN 146 00:05:18,160 --> 00:05:19,280 COLLABORATION WITH THE NATIONAL 147 00:05:19,280 --> 00:05:22,000 CANCER INSTITUTE, THE NCI. 148 00:05:22,000 --> 00:05:25,840 I WANT TO ACKNOWLEDGE JULIA 149 00:05:25,840 --> 00:05:30,040 LAMB, CRYSTAL RIVERA FOR PUTTING 150 00:05:30,040 --> 00:05:30,920 THIS TOGETHER. 151 00:05:30,920 --> 00:05:32,640 AND I WANT TO ACKNOWLEDGE AND 152 00:05:32,640 --> 00:05:37,280 INTRODUCE THE DIRECTOR OF THE 153 00:05:37,280 --> 00:05:40,880 CENTER FOR CANCER RESEARCH DR. 154 00:05:40,880 --> 00:05:43,600 TOM -- TOM HAS BEEN A PARTNER 155 00:05:43,600 --> 00:05:45,120 AND IT IS WONDERFUL TO BE IN THE 156 00:05:45,120 --> 00:05:46,880 SAME ROOM WITH HIM AT THIS TIME. 157 00:05:46,880 --> 00:05:48,440 SO TOM, COME ON UP. 158 00:05:48,440 --> 00:05:53,400 [ APPLAUSE ] 159 00:05:53,400 --> 00:05:54,160 >>THANK YOU. 160 00:05:54,160 --> 00:05:57,120 SO YOU CAN TELL IT IS REALLY 161 00:05:57,120 --> 00:05:58,600 TRUE WHAT WAS JUST SAID. 162 00:05:58,600 --> 00:06:00,880 HE DOESN'T MEET WITH SENIOR 163 00:06:00,880 --> 00:06:04,080 LEADERSHIP BECAUSE WE'VE 164 00:06:04,080 --> 00:06:04,760 ACTUALLY NEVER MET. 165 00:06:04,760 --> 00:06:06,480 SO WELCOME ALL OF YOU TO THIS 166 00:06:06,480 --> 00:06:10,320 YEAR'S WACHTEL AWARD. 167 00:06:10,320 --> 00:06:12,440 AND, OF COURSE, I WANT TO THANK 168 00:06:12,440 --> 00:06:14,920 AAAS AND SCIENCE TRANSLATIONAL 169 00:06:14,920 --> 00:06:16,000 MEDICINE FOR LETTING US BE PART 170 00:06:16,000 --> 00:06:18,040 OF THE WACHTEL AWARD. 171 00:06:18,040 --> 00:06:21,400 THIS HAS BECOME AN ANNUAL EVENT. 172 00:06:21,400 --> 00:06:22,560 FOR SOME REASON WE ALWAYS DO 173 00:06:22,560 --> 00:06:24,360 THIS ON A VERY HOT DAY, AT LEAST 174 00:06:24,360 --> 00:06:28,800 THAT IS HOW I REMEMBER IT. 175 00:06:28,800 --> 00:06:32,400 AND, YOU KNOW, SO THIS IS A 176 00:06:32,400 --> 00:06:36,280 REALLY IMPORTANT AWARD AND 177 00:06:36,280 --> 00:06:36,760 EVENT, ACTUALLY. 178 00:06:36,760 --> 00:06:42,120 SO THE WACHTEL AWARD RECOGNIZES 179 00:06:42,120 --> 00:06:45,840 A TRULY OUTSTANDING EARLY CAREER 180 00:06:45,840 --> 00:06:48,000 INVESTIGATOR AND SO, OF COURSE, 181 00:06:48,000 --> 00:06:49,840 THESE LECTURES, BY DEFINITION, 182 00:06:49,840 --> 00:06:51,360 ARE ALWAYS FANTASTIC. 183 00:06:51,360 --> 00:06:53,200 AND YOU WILL SEE THAT TODAY. 184 00:06:53,200 --> 00:06:55,160 TODAY WILL BE NO EXCEPTION. 185 00:06:55,160 --> 00:06:57,800 BUT I THINK THE AWARD AND THIS 186 00:06:57,800 --> 00:07:00,400 EVENT IS ACTUALLY ALSO REALLY 187 00:07:00,400 --> 00:07:02,520 IMPORTANT TO REALLY HIGHLIGHT 188 00:07:02,520 --> 00:07:04,400 AND RECOGNIZE THE REALLY 189 00:07:04,400 --> 00:07:06,120 IMPORTANT CONTRIBUTIONS THAT 190 00:07:06,120 --> 00:07:08,880 EARLY CAREER INVESTIGATORS MAKE. 191 00:07:08,880 --> 00:07:11,800 I WOULD ARGUE THAT ACTUALLY MANY 192 00:07:11,800 --> 00:07:14,320 FIELDS, IT IS REALLY THE EARLY 193 00:07:14,320 --> 00:07:16,680 INVESTIGATORS WHO DRIVE THE 194 00:07:16,680 --> 00:07:18,160 INNOVATION OF A FIELD, THE 195 00:07:18,160 --> 00:07:19,840 PROGRESS IN A FIELD. 196 00:07:19,840 --> 00:07:21,160 SO THIS IS REALLY IMPORTANT TO 197 00:07:21,160 --> 00:07:22,040 RECOGNIZE THAT. 198 00:07:22,040 --> 00:07:23,920 I ALSO THINK IT IS REALLY 199 00:07:23,920 --> 00:07:26,400 IMPORTANT TO RECOGNIZE THESE 200 00:07:26,400 --> 00:07:28,400 CONTRIBUTIONS RIGHT NOW BECAUSE 201 00:07:28,400 --> 00:07:32,400 I THINK THERE IS A THIRD GENERAL 202 00:07:32,400 --> 00:07:35,000 SENTIMENT THAT A CAREER IN 203 00:07:35,000 --> 00:07:36,400 BIOMEDICAL RESEARCH MIGHT NOT BE 204 00:07:36,400 --> 00:07:38,400 AS ATTRACTIVE AS IT USED TO BE. 205 00:07:38,400 --> 00:07:40,440 AND THAT IS OBVIOUSLY A LITTLE 206 00:07:40,440 --> 00:07:42,480 BIT TROUBLING AND IT IS REALLY A 207 00:07:42,480 --> 00:07:43,120 SHAME. 208 00:07:43,120 --> 00:07:44,240 AND OBVIOUSLY, THERE ARE 209 00:07:44,240 --> 00:07:44,520 CHALLENGES. 210 00:07:44,520 --> 00:07:47,440 THERE ARE CHALLENGES IN 211 00:07:47,440 --> 00:07:48,160 BIOMEDICAL CAREERS. 212 00:07:48,160 --> 00:07:52,160 I THINK WE NEED TO LOOK VERY, 213 00:07:52,160 --> 00:07:53,680 VERY CLOSELY AT, YOU KNOW, 214 00:07:53,680 --> 00:07:56,000 COMPENSATION, PARTICULARLY FOR 215 00:07:56,000 --> 00:07:56,280 TRAINEES. 216 00:07:56,280 --> 00:07:59,080 IT IS OBVIOUSLY STILL VERY, VERY 217 00:07:59,080 --> 00:08:01,280 COMPETITIVE, GRANT FUNDING IS 218 00:08:01,280 --> 00:08:03,440 VERY COMPETITIVE, PAYLINES ARE 219 00:08:03,440 --> 00:08:03,640 LOW. 220 00:08:03,640 --> 00:08:06,320 AND I THINK WE ALSO REALLY NEED 221 00:08:06,320 --> 00:08:07,960 TO MAKE SURE THAT EVERYONE, 222 00:08:07,960 --> 00:08:10,320 REGARDLESS OF THEIR BACKGROUND, 223 00:08:10,320 --> 00:08:12,400 HAS AN EQUAL OPPORTUNITY TO 224 00:08:12,400 --> 00:08:13,800 PROGRESS AND HAVE A SUCCESSFUL 225 00:08:13,800 --> 00:08:15,840 CAREER IN BIOMEDICINE. 226 00:08:15,840 --> 00:08:16,880 AND THESE ARE REAL CHALLENGES 227 00:08:16,880 --> 00:08:19,520 THAT WE'RE FACING AS A 228 00:08:19,520 --> 00:08:19,840 COMMUNITY. 229 00:08:19,840 --> 00:08:21,840 BUT I THINK, YOU KNOW, I THINK 230 00:08:21,840 --> 00:08:24,840 IT WOULD BE A SHAME TO LOSE 231 00:08:24,840 --> 00:08:25,080 TALENT. 232 00:08:25,080 --> 00:08:26,920 I THINK IT WOULD BE A SHAME TO 233 00:08:26,920 --> 00:08:28,720 LOSE A WHOLE GENERATION OF 234 00:08:28,720 --> 00:08:33,680 SCIENTISTS BECAUSE OF THOSE 235 00:08:33,680 --> 00:08:33,960 CHALLENGES. 236 00:08:33,960 --> 00:08:35,480 AND THE REASON WHY I SAY THAT IS 237 00:08:35,480 --> 00:08:37,240 BECAUSE, REALLY, IF YOU LOOK 238 00:08:37,240 --> 00:08:39,560 AROUND, THE OPPORTUNITIES WE 239 00:08:39,560 --> 00:08:40,800 HAVE NOWADAYS IN BIOMEDICAL 240 00:08:40,800 --> 00:08:42,800 RESEARCH ARE JUST AMAZING. 241 00:08:42,800 --> 00:08:44,600 THERE ARE SO MANY EXCITING 242 00:08:44,600 --> 00:08:45,560 OPPORTUNITIES OUT THERE. 243 00:08:45,560 --> 00:08:48,040 I THINK WE AS A COMMUNITY HAVE 244 00:08:48,040 --> 00:08:50,520 ACTUALLY DONE FAIRLY WELL OVER 245 00:08:50,520 --> 00:08:54,240 THE LAST DECADES, I WOULD SAY, 246 00:08:54,240 --> 00:08:59,080 IN IDENTIFYING CELLULAR 247 00:08:59,080 --> 00:09:01,880 MECHANISMS CELLULAR PROCESSES 248 00:09:01,880 --> 00:09:03,520 USED FOR THERAPEUTIC TARGETS. 249 00:09:03,520 --> 00:09:05,680 WE HAVE AMAZING TECHNOLOGIES 250 00:09:05,680 --> 00:09:05,960 AVAILABLE. 251 00:09:05,960 --> 00:09:09,760 AND I ALSO THINK WE ARE GETTING 252 00:09:09,760 --> 00:09:11,560 BETTER AT COLLABORATING ACROSS 253 00:09:11,560 --> 00:09:13,080 DISCIPLINES, WHICH I THINK IS 254 00:09:13,080 --> 00:09:14,800 REALLY, REALLY NEEDED TO 255 00:09:14,800 --> 00:09:17,080 TRANSLATE THE BASIC DISCOVERIES 256 00:09:17,080 --> 00:09:19,080 THAT EVERYONE'S MAKES INTO THE 257 00:09:19,080 --> 00:09:19,320 CLINIC. 258 00:09:19,320 --> 00:09:22,640 SO I THINK THERE ARE REMARKABLE 259 00:09:22,640 --> 00:09:23,320 OPPORTUNITIES OUT THERE. 260 00:09:23,320 --> 00:09:25,560 AND WE REALLY WANT TO CAPITALIZE 261 00:09:25,560 --> 00:09:26,080 ON THOSE. 262 00:09:26,080 --> 00:09:28,440 AND SO WE NEED THE EARLY CAREER 263 00:09:28,440 --> 00:09:29,520 INVESTIGATORS. 264 00:09:29,520 --> 00:09:32,280 AGAIN, AS I SAID, YOU KNOW, 265 00:09:32,280 --> 00:09:33,720 EARLY CAREER INVESTIGATORS 266 00:09:33,720 --> 00:09:35,920 REALLY HAVE MADE MANY OF THESE 267 00:09:35,920 --> 00:09:36,600 OPPORTUNITIES ACTUALLY POSSIBLE 268 00:09:36,600 --> 00:09:38,920 AND HAVE CONTRIBUTED TO THESE. 269 00:09:38,920 --> 00:09:40,400 SO, AND AGAIN, I THINK THAT IS 270 00:09:40,400 --> 00:09:42,560 THE SPIRIT OF THE WACHTEL AWARD, 271 00:09:42,560 --> 00:09:43,960 TO RECOGNIZE THAT AND TO 272 00:09:43,960 --> 00:09:45,400 HIGHLIGHT THOSE CONTRIBUTIONS. 273 00:09:45,400 --> 00:09:49,160 SO REALLY IN THAT SPIRIT, AGAIN, 274 00:09:49,160 --> 00:09:50,200 THANK YOU VERY MUCH AND ON 275 00:09:50,200 --> 00:09:55,280 BEHALF OF THE NCI, I WANT TO 276 00:09:55,280 --> 00:09:58,160 CONGRATULATE HUMSA FOR THE 277 00:09:58,160 --> 00:09:58,920 AWARD, OBVIOUSLY. 278 00:09:58,920 --> 00:10:01,760 I'M NOW GOING TO HAND IT OVER TO 279 00:10:01,760 --> 00:10:05,680 ORLA SMITH AND ORLA IS THE 280 00:10:05,680 --> 00:10:09,200 EDITOR OF "SCIENCE TRANSLATIONAL 281 00:10:09,200 --> 00:10:09,480 MEDICINE." 282 00:10:09,480 --> 00:10:11,040 THANK YOU VERY MUCH. 283 00:10:11,040 --> 00:10:11,320 [ APPLAUSE ] 284 00:10:11,320 --> 00:10:13,280 >>THANKS, TOM, AND GOOD 285 00:10:13,280 --> 00:10:14,880 AFTERNOON TO EVERYONE. 286 00:10:14,880 --> 00:10:16,920 AND THANK YOU FOR JOINING US 287 00:10:16,920 --> 00:10:17,280 TODAY. 288 00:10:17,280 --> 00:10:19,080 THE MISSION OF SCIENCE 289 00:10:19,080 --> 00:10:20,800 TRANSLATIONAL MEDICINE IS TO 290 00:10:20,800 --> 00:10:22,920 PROMOTE HUMAN HEALTH BY 291 00:10:22,920 --> 00:10:24,560 PROVIDING AN INTERDISCIPLINARY 292 00:10:24,560 --> 00:10:26,800 FORUM FOR BIOMEDICAL RESEARCHERS 293 00:10:26,800 --> 00:10:29,280 ACROSS SCIENCE, MEDICINE AND 294 00:10:29,280 --> 00:10:29,600 ENGINEERS. 295 00:10:29,600 --> 00:10:31,280 SCIENCE TRANSLATIONAL MEDICINE 296 00:10:31,280 --> 00:10:33,480 IS FLIGHTED TO BE COORDINATING 297 00:10:33,480 --> 00:10:37,080 THE 11th ANNUAL WACHTEL AWARD ON 298 00:10:37,080 --> 00:10:39,840 BEHALF OF AAAS, RECOGNIZING A 299 00:10:39,840 --> 00:10:41,080 LEADING EARLY CAREER SCIENTIST 300 00:10:41,080 --> 00:10:43,280 IN THE FIELD OF CANCER RESEARCH. 301 00:10:43,280 --> 00:10:46,000 WE ARE DELIGHTED TO BE 302 00:10:46,000 --> 00:10:47,760 PARTNERING WITH TOM AND THE 303 00:10:47,760 --> 00:10:49,720 CENTER FOR CANCER RESEARCH AT 304 00:10:49,720 --> 00:10:52,400 THE NATIONAL CANCER INSTITUTE ON 305 00:10:52,400 --> 00:10:54,560 THIS PRESTIGIOUS AWARD. 306 00:10:54,560 --> 00:10:59,640 I WOULD LIKE TO THANK OUR 307 00:10:59,640 --> 00:11:01,280 DISTINGUISHED JUDGING PANEL, 308 00:11:01,280 --> 00:11:06,040 HEINZ LOVELY, LAUREN BIAS, AND 309 00:11:06,040 --> 00:11:08,240 MARK DORSON. 310 00:11:08,240 --> 00:11:10,400 AND NOW WITHOUT FURTHER ADO, I 311 00:11:10,400 --> 00:11:16,360 WOULD LIKE TO HAND OVER TO 312 00:11:16,360 --> 00:11:19,360 ASSOCIATE EDITOR COURT MALO WHO 313 00:11:19,360 --> 00:11:20,720 IS GOING TO INTRODUCE THIS 314 00:11:20,720 --> 00:11:23,520 YEAR'S PRIZE WINNER. 315 00:11:23,520 --> 00:11:23,760 COURTNEY. 316 00:11:23,760 --> 00:11:24,360 [ APPLAUSE ] 317 00:11:24,360 --> 00:11:25,560 >>ALL RIGHT. 318 00:11:25,560 --> 00:11:25,760 HELLO. 319 00:11:25,760 --> 00:11:28,000 I AM COURTNEY MALO AND IT IS 320 00:11:28,000 --> 00:11:29,800 WITH GREAT PLEASURE I AM ABLE TO 321 00:11:29,800 --> 00:11:33,200 INTRODUCE THE WINNER OF THE 11th 322 00:11:33,200 --> 00:11:35,240 ANNUAL WACHTEL CANCER RESEARCH 323 00:11:35,240 --> 00:11:35,560 AWARD. 324 00:11:35,560 --> 00:11:39,760 THIS YEAR'S WINNER IS DR. HUMSA 325 00:11:39,760 --> 00:11:41,800 VENKATESH, A GROUP LEADER AT 326 00:11:41,800 --> 00:11:42,480 BRIGHAM AND WOMEN'S HOSPITAL AT 327 00:11:42,480 --> 00:11:42,960 HARVARD MEDICAL SCHOOL. 328 00:11:42,960 --> 00:11:46,680 SHE IS RECOGNIZED FOR HER WORK 329 00:11:46,680 --> 00:11:48,480 ON RECIPROCAL INTERACTIONS ON 330 00:11:48,480 --> 00:11:52,120 NERVOUS SYSTEM AND CANCERS HOW 331 00:11:52,120 --> 00:11:54,160 NEURAL ACTIVITY CAN PROMOTE 332 00:11:54,160 --> 00:11:54,600 TUMOR PROGRESSION. 333 00:11:54,600 --> 00:11:58,360 SHE IS HER TO TELL US MORE ABOUT 334 00:11:58,360 --> 00:12:02,320 HER GROUNDBREAKING WORK. 335 00:12:02,320 --> 00:12:04,600 DR. VENKATESH, PLEASE JOIN ME. 336 00:12:04,600 --> 00:12:06,280 [ APPLAUSE ] 337 00:12:06,280 --> 00:12:09,120 >>AS A RECIPIENT OF THE AAAS 338 00:12:09,120 --> 00:12:10,720 WACHTEL PRIZE PLEASE ACCEPT THE 339 00:12:10,720 --> 00:12:11,200 PLAQUE. 340 00:12:11,200 --> 00:12:13,320 IT SAYS AAAS MARTIN AND ROSE 341 00:12:13,320 --> 00:12:15,280 WACHTEL CANCER RESEARCH AWARD 342 00:12:15,280 --> 00:12:16,480 PRESENTED TO HUMSA VENKATESH FOR 343 00:12:16,480 --> 00:12:18,280 OUTSTANDING WORK IN THE FIELD OF 344 00:12:18,280 --> 00:12:20,040 CANCER RESEARCH BY AN EARLY 345 00:12:20,040 --> 00:12:20,480 CAREER INVESTIGATOR. 346 00:12:20,480 --> 00:12:26,120 [ APPLAUSE ] 347 00:12:26,120 --> 00:12:28,280 WE WOULD LIKE TO PRESENT YOU 348 00:12:28,280 --> 00:12:31,120 WITH THIS $25,000 CHECK. 349 00:12:31,120 --> 00:12:31,640 >>THANK YOU VERY MUCH. 350 00:12:31,640 --> 00:12:34,000 >>IN ADDITION HUMSA'S ESSAY 351 00:12:34,000 --> 00:12:35,680 DESCRIBING HER GROUNDBREAKING 352 00:12:35,680 --> 00:12:37,320 WORK ON CANCER NEUROSCIENCE HAS 353 00:12:37,320 --> 00:12:38,800 BEEN PUBLISHED THIS WEEK IN 354 00:12:38,800 --> 00:12:39,960 SCIENCE TRANSLATIONAL MEDICINE. 355 00:12:39,960 --> 00:12:42,920 THERE ARE COPIES OF HER ESSAY 356 00:12:42,920 --> 00:12:43,320 OUTSIDE. 357 00:12:43,320 --> 00:12:45,160 PLEASE TAKE ONE. 358 00:12:45,160 --> 00:12:46,600 TODAY'S WEBINAR IS BEING 359 00:12:46,600 --> 00:12:48,080 RECORDED AND AFTER THE 360 00:12:48,080 --> 00:12:49,560 COMPLETION OF DR. VENKATESH'S 361 00:12:49,560 --> 00:12:51,120 PRESENTATION THERE WILL BE 15 362 00:12:51,120 --> 00:12:52,480 MINUTES AVAILABLE FOR QUESTIONS 363 00:12:52,480 --> 00:12:53,200 AND ANSWERS. 364 00:12:53,200 --> 00:12:57,520 WITHOUT FURTHER ADO, I WILL 365 00:12:57,520 --> 00:12:59,240 INVITE DR. VENKATESH TO PRESENT 366 00:12:59,240 --> 00:13:01,960 HER AWARD LECTURE. 367 00:13:01,960 --> 00:13:02,520 >>ALL RIGHT. 368 00:13:02,520 --> 00:13:04,000 I WOULD JUST LIKE TO START BY 369 00:13:04,000 --> 00:13:06,480 TELLING YOU ALL WHAT A SINCERE 370 00:13:06,480 --> 00:13:09,360 HONOR IT SO TO BE HERE TODAY. 371 00:13:09,360 --> 00:13:12,440 THE AAAS STM AND THE NCI 372 00:13:12,440 --> 00:13:13,960 TOGETHER HAVE CREATED A 373 00:13:13,960 --> 00:13:15,640 WONDERFUL OPPORTUNITY FOR 374 00:13:15,640 --> 00:13:16,440 SPECIFICALLY EARLY INVESTIGATORS 375 00:13:16,440 --> 00:13:18,080 AND HIGHLIGHTING WORK THAT IS 376 00:13:18,080 --> 00:13:19,840 BEING DONE IN THE FIELD I THINK 377 00:13:19,840 --> 00:13:21,400 IS REALLY IMPORTANT FOR EARLY 378 00:13:21,400 --> 00:13:24,080 INVESTIGATORS LIKE ME AS WE GET 379 00:13:24,080 --> 00:13:26,920 THE PLATFORM TO LAUNCH OUR 380 00:13:26,920 --> 00:13:27,240 CAREERS. 381 00:13:27,240 --> 00:13:29,240 I'M THANKFUL AND HONORED TO BE 382 00:13:29,240 --> 00:13:29,440 HERE. 383 00:13:29,440 --> 00:13:30,480 SPECIFICALLY TO MARTIN WACHTEL 384 00:13:30,480 --> 00:13:32,080 AND HIS FAMILY FOR ENDOWING THIS 385 00:13:32,080 --> 00:13:32,280 PRIZE. 386 00:13:32,280 --> 00:13:34,000 I THINK IT IS REALLY SOMETHING 387 00:13:34,000 --> 00:13:34,800 SPECIAL AND UNIQUE. 388 00:13:34,800 --> 00:13:38,640 THERE IS NOT A LOT OF 389 00:13:38,640 --> 00:13:40,120 OPPORTUNITIES FOR EARLY 390 00:13:40,120 --> 00:13:41,000 INVESTIGATORS. 391 00:13:41,000 --> 00:13:42,760 FUNDING PAYLINES IS DIFFICULT. 392 00:13:42,760 --> 00:13:50,640 IT IS NICE TO SEE THE AAAS HOW 393 00:13:50,640 --> 00:13:51,840 EARLY RESEARCHERS CAN 394 00:13:51,840 --> 00:13:52,160 CONTRIBUTE. 395 00:13:52,160 --> 00:13:54,080 I THINK THERE IS LOTS OF 396 00:13:54,080 --> 00:13:55,920 EXCITING THINGS TO COME THERE 397 00:13:55,920 --> 00:13:59,000 THE REALM OF CANCER RESEARCH. 398 00:13:59,000 --> 00:14:01,720 HOPEFULLY MY TALK WILL BE 399 00:14:01,720 --> 00:14:06,160 INSPIRING IN POTENTIAL FUTURE 400 00:14:06,160 --> 00:14:07,320 MODULATIONS AND HOW TO TREAT 401 00:14:07,320 --> 00:14:09,440 THESE DEVASTATING DISEASES. 402 00:14:09,440 --> 00:14:10,840 WITH THAT, I WILL BE TALKING 403 00:14:10,840 --> 00:14:13,960 ABOUT PAST WORK AND THE ONGOING 404 00:14:13,960 --> 00:14:20,920 WORK IN MY LAB, TARGETING 405 00:14:20,920 --> 00:14:22,440 ELECTRICAL TRANSMISSION BETWEEN 406 00:14:22,440 --> 00:14:25,400 NEURONS AND CANCER CELLS. 407 00:14:25,400 --> 00:14:28,080 MY EARLY WORK WAS UH 408 00:14:28,080 --> 00:14:29,080 UNDERSTANDING BRAIN CANCER OR 409 00:14:29,080 --> 00:14:32,240 HIGH GRADE GLIOMAS. 410 00:14:32,240 --> 00:14:33,800 AN EXTREMELY DEVASTATING 411 00:14:33,800 --> 00:14:34,800 DISEASE. 412 00:14:34,800 --> 00:14:36,240 DESPITE REALLY UNDERSTANDING 413 00:14:36,240 --> 00:14:39,120 ABOUT THE MOLECULAR LANDSCAPE OF 414 00:14:39,120 --> 00:14:41,560 THESE TUMORS, WHAT IS PROMINENT 415 00:14:41,560 --> 00:14:44,000 IS IT IS TRANSLATED TO VERY 416 00:14:44,000 --> 00:14:45,040 LIMITED APPLICABILITY IN THE 417 00:14:45,040 --> 00:14:45,320 CLINIC. 418 00:14:45,320 --> 00:14:48,480 THAT TELLS US PERHAPS WE NEED TO 419 00:14:48,480 --> 00:14:50,720 STUDY THIS DISEASE MORE 420 00:14:50,720 --> 00:14:51,200 COMPREHENSIVELY. 421 00:14:51,200 --> 00:14:52,480 WHEN I STARTED MY GRADUATE 422 00:14:52,480 --> 00:14:54,280 TRAINING I WANTED TO THINK ABOUT 423 00:14:54,280 --> 00:14:56,640 THIS WHOLISTICALLY AND HOW WE 424 00:14:56,640 --> 00:14:58,360 MIGHT WANT TO STUDY THIS DISEASE 425 00:14:58,360 --> 00:15:03,160 IN A WAY THAT TOOK INTO ACCOUNT 426 00:15:03,160 --> 00:15:04,760 CELL MECHANIC 234I678S THAT MAY 427 00:15:04,760 --> 00:15:08,840 CONTRIBUTE TO MALIGNANT 428 00:15:08,840 --> 00:15:11,240 TRANSFORMATION BUT EXTRINSIC 429 00:15:11,240 --> 00:15:15,240 FACTORS THAT MAY INSTRUCT TUMOR 430 00:15:15,240 --> 00:15:15,640 GROWTH. 431 00:15:15,640 --> 00:15:16,240 HOLISTICALLY THINKING ABOUT 432 00:15:16,240 --> 00:15:17,880 CANCER AS A DISEASE. 433 00:15:17,880 --> 00:15:19,800 IN BRAIN CANCERS THAT INVOLVES A 434 00:15:19,800 --> 00:15:22,080 NUMBER OF DIFFERENT CELL TYPES, 435 00:15:22,080 --> 00:15:28,080 IMMUNE CELLS, VASCULAR CELLS, 436 00:15:28,080 --> 00:15:29,280 BRAIN CELLS. 437 00:15:29,280 --> 00:15:31,520 WHAT IS OBVIOUS AND LARGELY 438 00:15:31,520 --> 00:15:34,080 UNRECOGNIZED AND LEFT OUT OF THE 439 00:15:34,080 --> 00:15:35,440 UNDERSTANDING OF THE MICROVIMPLT 440 00:15:35,440 --> 00:15:37,120 IS THE NEURONS AND NERVOUS 441 00:15:37,120 --> 00:15:37,360 SYSTEM. 442 00:15:37,360 --> 00:15:39,200 WHAT WE WANTED TO UNDERSTAND IS 443 00:15:39,200 --> 00:15:41,600 HOW DO NERVES AND NEURAL 444 00:15:41,600 --> 00:15:44,080 ACTIVITY CONTRIBUTE TO MALIGNANT 445 00:15:44,080 --> 00:15:45,400 DISEASE PROGRESSION. 446 00:15:45,400 --> 00:15:47,200 THIS IS A PRIMARY PATIENT SAMPLE 447 00:15:47,200 --> 00:15:48,360 TAKEN FROM THE BRAIN. 448 00:15:48,360 --> 00:15:50,520 AND WHAT WE DID WAS CLEAR THIS 449 00:15:50,520 --> 00:15:52,080 TISSUE SAMPLE AND STAIN IT FOR 450 00:15:52,080 --> 00:15:53,400 THESE NERVE FIBERS. 451 00:15:53,400 --> 00:15:54,760 YOU CAN SEE EVEN WITHIN THE CORE 452 00:15:54,760 --> 00:15:57,600 OF THIS TUMOR THERE IS A DENSE 453 00:15:57,600 --> 00:16:00,600 NETWORK OF THESE NERVE FIBERS 454 00:16:00,600 --> 00:16:02,120 AND BUNDLES SUGGESTING THESE 455 00:16:02,120 --> 00:16:04,000 NERVES MAY PLAY A CRITICAL ROLE 456 00:16:04,000 --> 00:16:07,800 IN THE CONTEXT OF THE TUMOR 457 00:16:07,800 --> 00:16:08,200 MICROENVIRONMENT. 458 00:16:08,200 --> 00:16:09,560 I LIKE TO CREATE THIS ANALOGY, 459 00:16:09,560 --> 00:16:11,200 SIMILAR TO THE IDEA OF A CANCER 460 00:16:11,200 --> 00:16:14,800 TRYING TO KILL A TREE OR A WEED. 461 00:16:14,800 --> 00:16:16,880 PERHAPS ONE STRATEGY MIGHT BE TO 462 00:16:16,880 --> 00:16:18,400 PLUCK OFF THESE INDIVIDUAL 463 00:16:18,400 --> 00:16:21,600 LEAVES OF THIS WEED OR TREE, BUT 464 00:16:21,600 --> 00:16:23,040 ANOTHER WAY OF GOING ABOUT THIS 465 00:16:23,040 --> 00:16:26,160 IS TO PULL OUT THOSE ROOTS AND 466 00:16:26,160 --> 00:16:28,080 PREVENT THIS WEED FROM TAKING UP 467 00:16:28,080 --> 00:16:31,080 THE NUTRIENTS FROM THE SOIL. 468 00:16:31,080 --> 00:16:33,560 SIMILARLY, THE MICROENVIRONMENT, 469 00:16:33,560 --> 00:16:35,600 WE CAN THINK ABOUT AS NUTRIENT 470 00:16:35,600 --> 00:16:37,320 DENSE SOIL. 471 00:16:37,320 --> 00:16:39,400 WE STUDIED THE SICKLATORY SYSTEM 472 00:16:39,400 --> 00:16:42,000 AND THE BLOOD VESSELS THAT 473 00:16:42,000 --> 00:16:43,000 PROVIDE NUTRIENTS. 474 00:16:43,000 --> 00:16:44,320 THE IMMUNE SYSTEM HAS BEEN 475 00:16:44,320 --> 00:16:46,080 STUDIED FOR DECADES. 476 00:16:46,080 --> 00:16:48,440 WE HAVE MADE HUGE STRIDES IN 477 00:16:48,440 --> 00:16:51,200 HARNESSES THE IMMUNE SYSTEM. 478 00:16:51,200 --> 00:16:54,440 THE NERVOUS SYSTEM IS THE LAST 479 00:16:54,440 --> 00:16:57,800 STONE UNTURNED HOUT THESE TUMORS 480 00:16:57,800 --> 00:17:01,000 DERIVE CUES FROM THESE NEURONS. 481 00:17:01,000 --> 00:17:03,200 WHETHER OR NOT NEURONAL ACTIVITY 482 00:17:03,200 --> 00:17:04,680 CAN PROMOTE TUMOR GROWTH HAS NOT 483 00:17:04,680 --> 00:17:07,920 BEEN PROBED, BUT IT PLAYING A 484 00:17:07,920 --> 00:17:10,080 ROLE HAS BEEN APPRECIATED. 485 00:17:10,080 --> 00:17:16,080 IN THE 1930s, THIS TUMOR CELLS 486 00:17:16,080 --> 00:17:18,360 ARE CLUSTERING AROUND NEURONAL 487 00:17:18,360 --> 00:17:19,960 CELL BODIES WAS DEFINED. 488 00:17:19,960 --> 00:17:25,160 IT IS A HISTOPATHOLOGICAL 489 00:17:25,160 --> 00:17:25,920 FRAMEWORK. 490 00:17:25,920 --> 00:17:28,040 THIS SUGGESTS THAT PERHAPS IN 491 00:17:28,040 --> 00:17:30,040 ADDITION TO A STRUCTURAL 492 00:17:30,040 --> 00:17:31,760 RELATIONSHIP THERE MAY BE A 493 00:17:31,760 --> 00:17:32,960 FUNCTIONAL RELATIONSHIP BETWEEN 494 00:17:32,960 --> 00:17:34,440 TWO DIFFERENT CELL TYPES. 495 00:17:34,440 --> 00:17:37,920 TO ASK THIS QUESTION, DOES 496 00:17:37,920 --> 00:17:39,800 NEURONAL ACTIVITY PROMOTE TUMOR 497 00:17:39,800 --> 00:17:42,280 GROWTH, THAT VERY BASIC 498 00:17:42,280 --> 00:17:43,200 QUESTION, IS SOMETHING THAT 499 00:17:43,200 --> 00:17:44,880 COULDN'T DIRECTLY BE ADDRESSED 500 00:17:44,880 --> 00:17:46,160 UNTIL A LOT OF NOVEL 501 00:17:46,160 --> 00:17:49,880 TECHNOLOGIES WERE DEVELOPED. 502 00:17:49,880 --> 00:17:54,880 WE USE OPTOGENETICS. 503 00:17:54,880 --> 00:17:57,280 A TOOL THAT ALLOWS PRECISE 504 00:17:57,280 --> 00:17:59,240 CONTROL AND FIRING OF NEURONS 505 00:17:59,240 --> 00:18:00,880 WITHIN A VERY SPECIFIC CIRCUIT. 506 00:18:00,880 --> 00:18:02,920 YOU CAN SEE HERE WHEN WE TURN 507 00:18:02,920 --> 00:18:05,640 THE LIGHT ON AND EXPRESS THESE 508 00:18:05,640 --> 00:18:08,280 BLUE LIGHT SENSITIVES IN A 509 00:18:08,280 --> 00:18:10,480 CIRCUIT, WE CAN ATTACH THIS BLUE 510 00:18:10,480 --> 00:18:14,920 LIGHT ON TO THIS MOUSE AND WE 511 00:18:14,920 --> 00:18:22,760 GET A COMPLEX PHISIOMEMETIC SIR 512 00:18:22,760 --> 00:18:22,920 CAT. 513 00:18:22,920 --> 00:18:25,800 WE CAN QUERY HOW DO THE TUMOR 514 00:18:25,800 --> 00:18:29,440 CELLS RESPOND TO THIS ELEVATED 515 00:18:29,440 --> 00:18:30,680 NEURONAL ACTIVITY. 516 00:18:30,680 --> 00:18:32,880 WHAT WE FIND IS SPECIFICALLY 517 00:18:32,880 --> 00:18:35,240 WITHIN THAT ACTIVE MOTOR CIRCUIT 518 00:18:35,240 --> 00:18:36,640 WE SEE A CLEAR INCREASE IN THE 519 00:18:36,640 --> 00:18:41,680 NUMBER OF PROLIFERATING CELLS, 520 00:18:41,680 --> 00:18:47,320 MEASURED BY KR67 AND EDU, 521 00:18:47,320 --> 00:18:49,080 INCORPORATES INTO NEWLY 522 00:18:49,080 --> 00:18:49,680 SYNTHESIZED DNA. 523 00:18:49,680 --> 00:18:51,720 THIS WAS VERY SPECIFIC TO THE 524 00:18:51,720 --> 00:18:52,080 ACTIVE CIRCUIT. 525 00:18:52,080 --> 00:18:53,600 WHEN WE START LOOKING OUTSIDE OF 526 00:18:53,600 --> 00:18:55,920 THE CIRCUIT, WE NO LONGER SEE 527 00:18:55,920 --> 00:18:58,560 THE INCREASE IN PROLIFERATION. 528 00:18:58,560 --> 00:19:00,280 TO UNDERSTAND MECHANICISTICALLY 529 00:19:00,280 --> 00:19:04,080 WHAT WAS GOING ON, WE DEVELOPED 530 00:19:04,080 --> 00:19:10,360 THIS TOOL WHERE WE TOOK THESE 531 00:19:10,360 --> 00:19:13,160 SLICES OPTOGENETICALLY 532 00:19:13,160 --> 00:19:16,320 STIMULATED THEM AND PLACE THE 533 00:19:16,320 --> 00:19:19,200 MEDIUM ON HIGH GRADE CULTURES IN 534 00:19:19,200 --> 00:19:21,440 VETO. 535 00:19:21,440 --> 00:19:23,920 IN THIS DOSE DEPENDENT WAY WE 536 00:19:23,920 --> 00:19:26,440 SEE INCREASE IN PROLIFERATION OF 537 00:19:26,440 --> 00:19:27,880 OUFR CELLS IN RESPONSE TO 538 00:19:27,880 --> 00:19:28,560 CONDITION MEDIUM. 539 00:19:28,560 --> 00:19:33,600 THAT IS SPECIFICALLY ACTIVITY 540 00:19:33,600 --> 00:19:34,080 DEPENDENT. 541 00:19:34,080 --> 00:19:37,480 WHEN WE ADD THE TOX IS, WE CAN 542 00:19:37,480 --> 00:19:41,720 ABROGATE THIS EFFECT THERE IS A 543 00:19:41,720 --> 00:19:42,960 SECRETED SPONSOR THAT IS 544 00:19:42,960 --> 00:19:44,560 INDUCING THIS INCREASE IN 545 00:19:44,560 --> 00:19:46,680 PROLIFERATION IN OUR TUMOR 546 00:19:46,680 --> 00:19:47,200 CELLS. 547 00:19:47,200 --> 00:19:51,080 NOW WE FOUND THIS WAS TRUE IN 548 00:19:51,080 --> 00:19:55,040 NOT ONLY THIS INITIAL PAID 549 00:19:55,040 --> 00:20:05,480 RATTIC COURT KOL GLEE -- 550 00:20:07,760 --> 00:20:08,880 CORTICOGLIOBLASTOMA THAT IS IT 551 00:20:08,880 --> 00:20:13,960 IS A BROAD PHENOMENON. 552 00:20:13,960 --> 00:20:20,360 WE FOUND IT WAS USE TO GEL 553 00:20:20,360 --> 00:20:23,200 ELECTROPHORESIS TO IDENTITY THE 554 00:20:23,200 --> 00:20:25,320 PROTEINS DIFFERENTIALLY 555 00:20:25,320 --> 00:20:26,800 REGULATED AS A RESULT OF THIS 556 00:20:26,800 --> 00:20:27,920 NEURONAL ACTIVITY. 557 00:20:27,920 --> 00:20:30,640 THAT GAVE US A CANDIDATE LIST OF 558 00:20:30,640 --> 00:20:30,920 PROTEINS. 559 00:20:30,920 --> 00:20:33,280 SOME TO BE EXPECTED. 560 00:20:33,280 --> 00:20:37,000 PRIMARILY BDNF, AN ACTIVITY 561 00:20:37,000 --> 00:20:42,600 DEPENDENT SECRETED PROTEIN AND 562 00:20:42,600 --> 00:20:53,160 IMPLICATED IN GLIO PROGRESSION. 563 00:20:53,600 --> 00:20:56,040 NEUROLIGAN3 IS A MOLECULE THAT 564 00:20:56,040 --> 00:20:59,680 TYPICALLY FUNCTIONS AT POST SIN 565 00:20:59,680 --> 00:21:03,200 NAS TO STABILIZE PREAND POST 566 00:21:03,200 --> 00:21:04,720 SYNAPTIC CELL TYPES. 567 00:21:04,720 --> 00:21:09,560 IT HAS NOT KNOWN TO BE A 568 00:21:09,560 --> 00:21:09,760 MITOGEN. 569 00:21:09,760 --> 00:21:12,200 IT WAS A SURPRISING FINDING. 570 00:21:12,200 --> 00:21:15,920 NOT ONLY WAS NLGN3 SUFFICIENT TO 571 00:21:15,920 --> 00:21:19,240 PROMOTE THIS GROWTH, A RECOME BY 572 00:21:19,240 --> 00:21:27,200 NANT VERSION OF THIS PROTEIN WAS 573 00:21:27,200 --> 00:21:29,280 NECESSARY IN ORDER TO SEE THIS 574 00:21:29,280 --> 00:21:31,480 ACTIVITY DEPENDENT PROLIFERATIVE 575 00:21:31,480 --> 00:21:31,720 EFFECT. 576 00:21:31,720 --> 00:21:34,080 WHEN WE CREATED OUR ACTIVE 577 00:21:34,080 --> 00:21:44,800 CONDITION MEDIA USING A THIS N 578 00:22:47,760 --> 00:22:53,240 DISTINT -- TO INVESTIGATE THE 579 00:22:53,240 --> 00:22:55,160 CLINICAL RELEVANCE, WE TURNED TO 580 00:22:55,160 --> 00:22:57,520 THE TCGA DATA BASE AND WE FOUND 581 00:22:57,520 --> 00:23:01,080 LOOKING AT JUST A SINGLE STUDY 582 00:23:01,080 --> 00:23:03,960 WHERE THEY LOOKED AT OVER 500 583 00:23:03,960 --> 00:23:05,800 ADULT GBM PATIENTS THAT THE 584 00:23:05,800 --> 00:23:09,360 LEVEL OF NEUROLIGIN THREE 585 00:23:09,360 --> 00:23:10,600 INVERSELY CORRELATED WITH 586 00:23:10,600 --> 00:23:11,000 SURVIVAL. 587 00:23:11,000 --> 00:23:12,880 WE WANTED TO UNDERSTAND HOW 588 00:23:12,880 --> 00:23:15,120 MIGHT WE POTENTIALLY CLINICALLY 589 00:23:15,120 --> 00:23:17,800 TARGET THIS PROTEIN AND THIS 590 00:23:17,800 --> 00:23:18,160 INTERACTION? 591 00:23:18,160 --> 00:23:21,600 SO TO THAT END WE FOUND AS I 592 00:23:21,600 --> 00:23:23,160 MENTIONED WE IDENTIFIED THIS 593 00:23:23,160 --> 00:23:25,840 PROTEIN BECAUSE WE SAW IT WAS 594 00:23:25,840 --> 00:23:27,240 SECRETED IN OUR CONDITION MEDIA. 595 00:23:27,240 --> 00:23:29,520 IT IS CLEARLY ACTIVITY DEPENDENT 596 00:23:29,520 --> 00:23:29,760 MANNER. 597 00:23:29,760 --> 00:23:32,640 WHEN WE WENT BACK TO LOOK AT THE 598 00:23:32,640 --> 00:23:34,960 PEPTIDES IN OUR CONDITIONED 599 00:23:34,960 --> 00:23:36,440 MEDIA, WE NOTICED THEY HAPPENED 600 00:23:36,440 --> 00:23:39,920 TO BE IN THE EXTRA CELLULAR 601 00:23:39,920 --> 00:23:42,480 REGION AND TRANSMEMBRANE AND 602 00:23:42,480 --> 00:23:44,200 INTRASELL YOU LAR DIDN'T SEEM TO 603 00:23:44,200 --> 00:23:46,120 BE PRESENT IN THAT CONDITION 604 00:23:46,120 --> 00:23:46,360 MEDIUM. 605 00:23:46,360 --> 00:23:49,680 THIS IS LIKELY CLEAVED IN THIS 606 00:23:49,680 --> 00:23:52,320 VERY SPECIFIC AND TARGETED 607 00:23:52,320 --> 00:23:53,680 ACTIVITY DEPENDENT MANNER. 608 00:23:53,680 --> 00:23:55,360 WE SOUGHT TO IDENTIFY THE 609 00:23:55,360 --> 00:23:57,160 MECHANISM OF THAT AK TVTY 610 00:23:57,160 --> 00:23:58,560 DEPENDENT CLEAVAGE OF THIS 611 00:23:58,560 --> 00:23:58,800 PROTEIN. 612 00:23:58,800 --> 00:24:00,680 I WILL SPARE YOU THE DETAILS 613 00:24:00,680 --> 00:24:02,400 HERE, BUT THIS WAS SEVERAL 614 00:24:02,400 --> 00:24:03,720 MONTHS OF MY LIFE USING A 615 00:24:03,720 --> 00:24:07,000 COMBINATION OF GENETIC AND 616 00:24:07,000 --> 00:24:08,440 PHARMACOLOGICAL INHIBITION 617 00:24:08,440 --> 00:24:10,920 TECHNIQUES WE FOUND THAT ATOM 618 00:24:10,920 --> 00:24:17,440 10, A COMMON PROTEASE HIGHLY UP 619 00:24:17,440 --> 00:24:18,920 GRADED IN THE TUMOR 620 00:24:18,920 --> 00:24:20,440 MICROENVIRONMENT WAS RESPONSIBLE 621 00:24:20,440 --> 00:24:23,240 FOR THE SECRETION OF THIS 622 00:24:23,240 --> 00:24:28,320 PROTEIN NEUROLIGIN3. 623 00:24:28,320 --> 00:24:31,320 LUCKILY FOR US, ADAM 10 624 00:24:31,320 --> 00:24:33,400 INHIBITORS HAVE BEEN CREATED IN 625 00:24:33,400 --> 00:24:36,000 OTHER NEURODEGENERATIVE 626 00:24:36,000 --> 00:24:36,280 DISEASES. 627 00:24:36,280 --> 00:24:37,520 THEY WEREN'T ACTIVELY BEING USED 628 00:24:37,520 --> 00:24:39,240 IN THE CLINIC. 629 00:24:39,240 --> 00:24:41,640 WE HYPOTHESIZED IF WE COULD 630 00:24:41,640 --> 00:24:44,680 CONVINCE A PHARMACEUTICAL 631 00:24:44,680 --> 00:24:47,280 COMPANY TO LET US USE THEIR 632 00:24:47,280 --> 00:24:51,640 COMPOUND WE COULD TREAT 633 00:24:51,640 --> 00:24:55,120 XENOGRAFTED MICE TO PREVENT 634 00:24:55,120 --> 00:24:58,400 NEUROLIGIN3 SHEDDING AND LIMIT 635 00:24:58,400 --> 00:24:58,760 TUMOR GROWTH. 636 00:24:58,760 --> 00:25:01,400 THIS ADAM 10 INHIBITOR HAD NO 637 00:25:01,400 --> 00:25:05,840 EFFECT ON THESE GLIOMA CELLS IN 638 00:25:05,840 --> 00:25:06,240 VITRO. 639 00:25:06,240 --> 00:25:10,000 THIS WAS NOT A CELL INTRINSIC 640 00:25:10,000 --> 00:25:10,280 PHENOMENON. 641 00:25:10,280 --> 00:25:12,520 ANYTHING IN VEEFO IS WE WERE 642 00:25:12,520 --> 00:25:16,120 HAVING AN EFFECT REMODELING THE 643 00:25:16,120 --> 00:25:17,240 MICROENVIRONMENT AND 644 00:25:17,240 --> 00:25:18,520 INTRACELLULAR REACTIONS. 645 00:25:18,520 --> 00:25:21,160 IN MULTIPLE MODELS OF FWLEE 646 00:25:21,160 --> 00:25:22,760 OHMA, TREATMENT WITH ADAM 10 HIN 647 00:25:22,760 --> 00:25:26,480 HIB TOR IN GLIOMA BEARING MICE 648 00:25:26,480 --> 00:25:28,960 SHOWED THESE TUMORS ACTUALLY 649 00:25:28,960 --> 00:25:30,560 STARTED -- SHOWED REDUCTION IN 650 00:25:30,560 --> 00:25:32,640 THE AMOUNT OF GROWTH, BOTH, 651 00:25:32,640 --> 00:25:37,000 AGAIN, VIA HISTOLOGICAL ANALYSIS 652 00:25:37,000 --> 00:25:47,400 AND VIA JUST OVERALL 653 00:25:48,760 --> 00:25:49,640 BIOLUMINESCEN TROIM. 654 00:25:49,640 --> 00:25:51,480 THIS IS TREATMENT ONBEING WITH 655 00:25:51,480 --> 00:25:54,680 PAID RATTIC GLIOMA WITH AN ADULT 656 00:25:54,680 --> 00:25:56,240 IS STUDY TO BE LAUNCHED LATER 657 00:25:56,240 --> 00:25:57,040 THIS FALL. 658 00:25:57,040 --> 00:25:59,400 WE ARE EXCITED ABOUT THAT. 659 00:25:59,400 --> 00:26:00,840 TAKEN TOGETHER THESE EARLY 660 00:26:00,840 --> 00:26:03,600 STUDIES PLACED THESE ACTIVE 661 00:26:03,600 --> 00:26:04,920 NEURONS IN THE TUMOR 662 00:26:04,920 --> 00:26:05,400 MICROENVIRONMENT. 663 00:26:05,400 --> 00:26:09,480 PLAYING A KEY ROLE IN PROMOTING 664 00:26:09,480 --> 00:26:10,960 GLIOMA GROWTH THROUGH THIS 665 00:26:10,960 --> 00:26:12,800 SIGNALLING MECHANISM, ACTIVITY 666 00:26:12,800 --> 00:26:16,480 DEPENDENT WAY PROTEINS SUCH AS 667 00:26:16,480 --> 00:26:17,720 NEUROLIGIN3, AND OTHER PROTEINS 668 00:26:17,720 --> 00:26:19,920 ARE ACTING ON THESE TUMOR CELLS 669 00:26:19,920 --> 00:26:21,120 TO PROMOTE GROWTH. 670 00:26:21,120 --> 00:26:22,920 HOWEVER, I REALLY WANTED TO COME 671 00:26:22,920 --> 00:26:25,040 BACK IN THE NEXT PART OF MY 672 00:26:25,040 --> 00:26:26,840 STORY DRAWS UPON THIS REALLY 673 00:26:26,840 --> 00:26:28,360 STARK FINDING THAT I SHOWED YOU 674 00:26:28,360 --> 00:26:31,960 IN THESE NEUROLIGIN3 KNOCKOUT 675 00:26:31,960 --> 00:26:32,200 MODELS. 676 00:26:32,200 --> 00:26:34,120 FOR THOSE OF US WHO WORK IN 677 00:26:34,120 --> 00:26:35,800 CANCER RESEARCH YOU CAN 678 00:26:35,800 --> 00:26:37,280 APPRECIATE THE PRESENCE OR 679 00:26:37,280 --> 00:26:41,320 ABSENCE OF A SINGLE MITOGEN 680 00:26:41,320 --> 00:26:43,200 RARELY HAS SUCH AN EFFECT. 681 00:26:43,200 --> 00:26:45,960 PERHAPS NEUROLIGIN3 SECRETION 682 00:26:45,960 --> 00:26:49,360 AND ACTING AS A MITOGEN MAY 683 00:26:49,360 --> 00:26:52,080 REPRESENT ACTIVITY TO DRIVE 684 00:26:52,080 --> 00:26:53,160 TUMOR GROWTH BUT NOT SUFFICIENT 685 00:26:53,160 --> 00:26:54,960 TO EXPLAIN THE MAGNITUDE OF THIS 686 00:26:54,960 --> 00:26:56,080 EFFECT WE ARE SEEING. 687 00:26:56,080 --> 00:26:58,840 WE WANTED TO DIG DEEPER AND 688 00:26:58,840 --> 00:27:00,640 LOOKING AT THE TRANSCRIPTIONAL 689 00:27:00,640 --> 00:27:04,200 LEVEL WE FOUND EXPOSURE TO EXTRA 690 00:27:04,200 --> 00:27:08,320 CELLULAR NEUROLIGIN3 UPREL 691 00:27:08,320 --> 00:27:10,240 REGULATED SYNAPSE RELATED GENES 692 00:27:10,240 --> 00:27:13,400 IN THE TUMOR THEMSELVES. 693 00:27:13,400 --> 00:27:22,280 NEUROLIGIN3 IS A POST SYNAPTIC 694 00:27:22,280 --> 00:27:23,120 ADHESION PROGRAM. 695 00:27:23,120 --> 00:27:25,720 IT IS -- SYNAPTIC STRUCTURAL 696 00:27:25,720 --> 00:27:26,920 PROTEINS AND A LOT OF 697 00:27:26,920 --> 00:27:29,640 INTERESTING RECEPTORS AND 698 00:27:29,640 --> 00:27:30,640 STRUCTURAL PROTEINS SUGGESTED 699 00:27:30,640 --> 00:27:32,720 THERE MIGHT BE A WAY IN WHICH 700 00:27:32,720 --> 00:27:35,280 THESE TUMOR CELLS ARE DRIVING 701 00:27:35,280 --> 00:27:38,080 DIRECT ELECTRICAL CUES FROM 702 00:27:38,080 --> 00:27:39,120 NEURONS FROM DIRECT SYNAPTIC 703 00:27:39,120 --> 00:27:44,400 NEUROTRANSMISSION. 704 00:27:44,400 --> 00:27:46,200 IN COLLABORATION WITH HARVARD, 705 00:27:46,200 --> 00:27:50,040 WE LOOKED AT BIOPSIES OF PATIENT 706 00:27:50,040 --> 00:27:53,080 SAMPLES, PEDIATRIC AND ADULT IDH 707 00:27:53,080 --> 00:27:53,320 MUTANT. 708 00:27:53,320 --> 00:27:56,520 A SUBSET OF CELLS WITHIN ANY 709 00:27:56,520 --> 00:28:00,760 GIVEN TUMOR DO SEEM TO BE 710 00:28:00,760 --> 00:28:03,000 ENRICHED FOR THESE SAME SYNAPSE 711 00:28:03,000 --> 00:28:05,560 RELATED GENES AND STRUG CHURL 712 00:28:05,560 --> 00:28:06,080 SYNAPTIC PROTEINS. 713 00:28:06,080 --> 00:28:09,040 WHEN PLOTTED AS THIS LINEAGE 714 00:28:09,040 --> 00:28:11,080 HIERARCHY THAT TAKES INTO 715 00:28:11,080 --> 00:28:13,520 ACCOUNT FEEN OTIPPIC CELLULAR 716 00:28:13,520 --> 00:28:15,240 STATES WE FIND SUB POPULATION 717 00:28:15,240 --> 00:28:18,120 CELLS HIGHLY ENRICHED FOR 718 00:28:18,120 --> 00:28:20,480 SYNAPSE CELLS, GENE EXPRESSION 719 00:28:20,480 --> 00:28:26,320 PROGRAMS ARE THE SAME CELLS THAT 720 00:28:26,320 --> 00:28:30,000 MOST CLOSELY LOOK LIKE THESE 721 00:28:30,000 --> 00:28:30,360 CELLS. 722 00:28:30,360 --> 00:28:31,960 WHAT IS INTERESTING ABOUT THIS 723 00:28:31,960 --> 00:28:34,600 IS A LOT OF THESE HIGH GRADE 724 00:28:34,600 --> 00:28:36,760 GLIOMAS ARE THOUGHT TO ARISE 725 00:28:36,760 --> 00:28:39,440 FROM CELLS WHO FALL IN THIS 726 00:28:39,440 --> 00:28:40,800 LINEAGE, BUT VERY IMPORTANTLY, 727 00:28:40,800 --> 00:28:43,120 IN ADDITION TO THE NORMAL NEURON 728 00:28:43,120 --> 00:28:45,680 TO NEURON SYNAPSE WE ARE VERY 729 00:28:45,680 --> 00:28:49,720 FAMILIAR WITH, THE AXON DEBRISO 730 00:28:49,720 --> 00:28:53,080 SYNAPSE IS ONE OF THE ONLY OTHER 731 00:28:53,080 --> 00:28:54,400 SYNAPTIC INTERACTIONS DEFINED IN 732 00:28:54,400 --> 00:28:55,440 THE ADULT BRAIN. 733 00:28:55,440 --> 00:28:58,040 SO WE HYPOTHESIZED COULD IT BE 734 00:28:58,040 --> 00:29:01,400 POSSIBLE THAT THESE MALIGNANT 735 00:29:01,400 --> 00:29:03,560 TUMOR CELLS WERE FORMING DIRECT 736 00:29:03,560 --> 00:29:05,200 SYNAPSES WITH HEALTHY NEURONS IN 737 00:29:05,200 --> 00:29:07,480 THEIR TUMOR MICROENVIRONMENT. 738 00:29:07,480 --> 00:29:12,400 WHEN WE EXAMINED THESE PATIENT 739 00:29:12,400 --> 00:29:17,040 DERIVED XENOGRAFT MODELS WE 740 00:29:17,040 --> 00:29:19,360 FOUND THESE AND LABEL THESE POST 741 00:29:19,360 --> 00:29:21,520 SYNAPTIC CELL AND FOUND THEY 742 00:29:21,520 --> 00:29:24,480 WERE UNAMBIGUOUSLY IDENTIFIED AS 743 00:29:24,480 --> 00:29:26,320 THESE TUMOR CELLS. 744 00:29:26,320 --> 00:29:29,520 YOU CAN SEE THE CLEAR SYNAPTIC 745 00:29:29,520 --> 00:29:31,360 CLEFT AND VESICLES THAT 746 00:29:31,360 --> 00:29:33,600 SUGGESTED THIS WAS A DIRECT SIN 747 00:29:33,600 --> 00:29:35,640 NAPPIC INTERACTION OCCURRING 748 00:29:35,640 --> 00:29:35,840 HERE. 749 00:29:35,840 --> 00:29:38,200 WE NEWS NEURON GLIOMA 750 00:29:38,200 --> 00:29:41,760 CO-CULTURING TO MORE PRECISELY 751 00:29:41,760 --> 00:29:44,760 VISUALIZE AND QUANTITY FIZ THESE 752 00:29:44,760 --> 00:29:49,880 SYNAPSES BASED ON THE MARKERS. 753 00:29:49,880 --> 00:29:53,960 WE SAW A NUMBER OF THE 754 00:29:53,960 --> 00:29:55,520 CO-LOCALIZATIONS IN THE CONTEXT 755 00:29:55,520 --> 00:29:58,720 AND IN THE ABSENCE OF 756 00:29:58,720 --> 00:29:59,880 NEUROLIGIN3, WE ACTUALLY SEE 757 00:29:59,880 --> 00:30:02,240 THERE IS MARKED REDUCTION IN THE 758 00:30:02,240 --> 00:30:03,560 NUMBER OF THESE SYNAPSES. 759 00:30:03,560 --> 00:30:05,480 THAT TELLS US PERHAPS IN 760 00:30:05,480 --> 00:30:10,840 ADDITION TO FUNCTIONING AS A 761 00:30:10,840 --> 00:30:14,880 MITOGEN, PERHAPS NEUROLIGIN3 WAS 762 00:30:14,880 --> 00:30:17,320 REGULATED THE FORMATION OF BONA 763 00:30:17,320 --> 00:30:20,440 FIDE NEURON TO GLIOMA SYNAPSES. 764 00:30:20,440 --> 00:30:26,600 WERE THEY TRULY EK TRO 765 00:30:26,600 --> 00:30:28,440 PHYSIOLOGICAL FUNCTIONAL OR FROM 766 00:30:28,440 --> 00:30:31,200 THE CELLS WHICH THESE DEBRIS 767 00:30:31,200 --> 00:30:32,600 OHMAS EMERGE. 768 00:30:32,600 --> 00:30:36,720 WE USE WHOLESALE PATCH 769 00:30:36,720 --> 00:30:37,120 ELECTROPHYSIOLOGY. 770 00:30:37,120 --> 00:30:40,000 WE GRAFTED THE CELLS INTO THE 771 00:30:40,000 --> 00:30:40,400 HIPPOCAMPUS. 772 00:30:40,400 --> 00:30:43,600 THE BRAIN IS A VERY COMPLICATED 773 00:30:43,600 --> 00:30:44,080 ORGAN. 774 00:30:44,080 --> 00:30:46,720 THE HIPPOCAMPUS IS A FEW PLACE 775 00:30:46,720 --> 00:30:49,080 WHERE THERE IS A WELL MAPPED 776 00:30:49,080 --> 00:30:50,080 CIRCUITRY. 777 00:30:50,080 --> 00:30:51,640 WE COULD STIMULATE THESE AXONS 778 00:30:51,640 --> 00:30:55,200 AND WE KNOW THAT THESE AXONS 779 00:30:55,200 --> 00:30:57,280 SPECIFICALLY SIGNAL SYNAPTIC 780 00:30:57,280 --> 00:30:59,600 INPUT DIRECTLY INTO THE REGION 781 00:30:59,600 --> 00:31:02,120 WHERE WE CAN GRAFT OUR TUMOR 782 00:31:02,120 --> 00:31:02,600 KRELS. 783 00:31:02,600 --> 00:31:05,400 WE GRAFTED THESE IN THE CAI 784 00:31:05,400 --> 00:31:08,760 REGION AND USING WHOLESALE 785 00:31:08,760 --> 00:31:09,880 ELECTROPHYSIOLOGY MEASURE THE 786 00:31:09,880 --> 00:31:12,360 RESPONSES OF THOSE TUMOR CELLS. 787 00:31:12,360 --> 00:31:15,560 WE FOUND, INDEED, IN DIFFERENT 788 00:31:15,560 --> 00:31:17,280 GLIOMA TUMOR TYPES THERE IS A 789 00:31:17,280 --> 00:31:20,280 SUB POPULATION OF TUMOR CELLS 790 00:31:20,280 --> 00:31:25,080 THAT RESPOND TO THESE EXCITED 791 00:31:25,080 --> 00:31:27,680 POST SYNAPTIC IN RESPONSE TO 792 00:31:27,680 --> 00:31:28,680 THIS NEURONAL ACTIVITY. 793 00:31:28,680 --> 00:31:32,040 THIS IS ACTIVITY DEPEND AND CAN 794 00:31:32,040 --> 00:31:33,720 BEING A ROW GAITED WITH THE 795 00:31:33,720 --> 00:31:35,920 TOXIN THAT WLOKS THE ABROGATION 796 00:31:35,920 --> 00:31:37,440 OF THE POTENTIALS. 797 00:31:37,440 --> 00:31:39,040 NOT GOING TOO MUCH INTO THE 798 00:31:39,040 --> 00:31:44,400 WEEDS BUT THE PRESENCE OF THIS 799 00:31:44,400 --> 00:31:48,040 PARA PULSE STIMULATION SUGGESTS 800 00:31:48,040 --> 00:31:51,360 THAT THESE CELLS THAT WAS THIS 801 00:31:51,360 --> 00:31:55,040 WAS DIRECT SYNAPTIC 802 00:31:55,040 --> 00:31:55,440 NEUROTRANSMISSION. 803 00:31:55,440 --> 00:31:59,480 THE ELECTROPHYSIOLOGY SUGGESTED 804 00:31:59,480 --> 00:32:10,000 THEY MAY BE MEDIATED BY AMPER 805 00:32:10,480 --> 00:32:10,720 RESENTTORS. 806 00:32:10,720 --> 00:32:14,120 A CALCIUM RESENT TOR SEEMED TO 807 00:32:14,120 --> 00:32:15,800 BE MEDIATING THESE CURRENTS IN 808 00:32:15,800 --> 00:32:16,840 THE TUMOR CELLS. 809 00:32:16,840 --> 00:32:21,080 THAT IS REALLY IMPORTANT BECAUSE 810 00:32:21,080 --> 00:32:23,600 CALCIUM PERMEABLE RECEPTORS ARE 811 00:32:23,600 --> 00:32:25,480 EXPRESSED IN THE BRAIN IN 812 00:32:25,480 --> 00:32:27,600 PRECURSOR CELLS, BUT TYPICALLY 813 00:32:27,600 --> 00:32:31,640 NOT AS PROMINENT IN THE MA CHUF 814 00:32:31,640 --> 00:32:32,800 HEALTHY ADULT BRAIN THAN IN THE 815 00:32:32,800 --> 00:32:33,520 TUMOR CELLS. 816 00:32:33,520 --> 00:32:37,000 THIS MIGHT BE A WAY TO 817 00:32:37,000 --> 00:32:39,720 SPECIFICALLY TARGET TUMOR CELLS 818 00:32:39,720 --> 00:32:43,680 COMPARED TO OTHER NEURONAL TYPES 819 00:32:43,680 --> 00:32:45,320 IN THE BRAIN. 820 00:32:45,320 --> 00:32:47,960 FRANK WINKLER'S GROUP FOUND THE 821 00:32:47,960 --> 00:32:49,680 EXACT SAME PHENOMENON IN ADULT 822 00:32:49,680 --> 00:32:54,800 THREE OH-- GLIOMAS. 823 00:32:54,800 --> 00:32:57,280 THAT WAS REASSURING. 824 00:32:57,280 --> 00:32:58,920 THE IDEA THAT SOMEONE ELSE 825 00:32:58,920 --> 00:33:00,080 INDEPENDENTLY FOUND THIS WAS 826 00:33:00,080 --> 00:33:01,840 QUITE NICE AND LED TO A 827 00:33:01,840 --> 00:33:03,160 WONDERFUL COLLABORATION BETWEEN 828 00:33:03,160 --> 00:33:04,240 THE TWO LABS. 829 00:33:04,240 --> 00:33:07,480 WE CO-SUBMITTED AND THEY ARE 830 00:33:07,480 --> 00:33:09,160 WONDERFUL COLLEAGUES AND 831 00:33:09,160 --> 00:33:09,480 COLLABORATORS. 832 00:33:09,480 --> 00:33:11,880 WITH THIS DEPOT LARIZATION, WE 833 00:33:11,880 --> 00:33:14,080 WANTED TO SEE IF WE COULD 834 00:33:14,080 --> 00:33:15,160 VISUALIZE THESE CURRENTS. 835 00:33:15,160 --> 00:33:18,920 WHAT WE DID WAS EXPRESS 836 00:33:18,920 --> 00:33:21,360 GENETICALLY ENCODED IN OUR TUMOR 837 00:33:21,360 --> 00:33:21,560 CELL. 838 00:33:21,560 --> 00:33:24,640 WE GRAFTED THOSE IN THE 839 00:33:24,640 --> 00:33:26,360 HIPPOCAMPUS AND SHAPED THE 840 00:33:26,360 --> 00:33:26,600 AXSONS. 841 00:33:26,600 --> 00:33:28,200 IN RESPONSE TO THAT STIMULATION 842 00:33:28,200 --> 00:33:30,800 YOU SEE VERY CLEAR EVOKED 843 00:33:30,800 --> 00:33:32,360 CALCIUM TRANSIENTS IN SUB 844 00:33:32,360 --> 00:33:35,840 POPULATION OF THESE TUMOR CELLS. 845 00:33:35,840 --> 00:33:37,320 ABROGATED WITH THE ADDITION OF 846 00:33:37,320 --> 00:33:40,480 THE TOXnd TELLS US THIS IS AN 847 00:33:40,480 --> 00:33:41,480 ACTIVITY DEPENDENT EFFECT. 848 00:33:41,480 --> 00:33:43,680 OF COURSE, IN THE BRAIN, WE 849 00:33:43,680 --> 00:33:44,880 DON'T NECESSARILY NEED TO 850 00:33:44,880 --> 00:33:46,120 STIMULATE ACTIVITY. 851 00:33:46,120 --> 00:33:48,800 THERE IS A PARTICULARLY ACTIVE 852 00:33:48,800 --> 00:33:50,280 REGION OF A XENOGRAFT. 853 00:33:50,280 --> 00:33:52,520 I WANTED TO PUT THIS UP HERE TO 854 00:33:52,520 --> 00:33:54,960 ILLUSTRATE TO YOU ALL THE THE 855 00:33:54,960 --> 00:33:58,000 GREEN SIGNAL YOU ARE SEEING IS 856 00:33:58,000 --> 00:34:02,600 ION FLEX OCCURRING THROUGHOUT 857 00:34:02,600 --> 00:34:04,000 THESE MALIGNANT TUMOR CELL 858 00:34:04,000 --> 00:34:05,560 NETWORKS. 859 00:34:05,560 --> 00:34:09,400 THESE CANCERS ARE ELECTRICALLY 860 00:34:09,400 --> 00:34:11,440 ACTIVE TISSUES. 861 00:34:11,440 --> 00:34:13,000 THIS IS LIKELY GOING TO BE VERY 862 00:34:13,000 --> 00:34:14,280 IMPORTANT MOVING FORWARD. 863 00:34:14,280 --> 00:34:15,840 AS YOU CAN SEE HERE IN THE 864 00:34:15,840 --> 00:34:18,080 STILLS FROM THIS VIDEO, THESE 865 00:34:18,080 --> 00:34:20,640 CALCIUM TRANSIENTS SEEM TO BE 866 00:34:20,640 --> 00:34:22,000 PROPAGATED THROUGHOUT THESE 867 00:34:22,000 --> 00:34:23,120 INTERCONNECTED TUMOR CELL 868 00:34:23,120 --> 00:34:23,440 NETWORKS. 869 00:34:23,440 --> 00:34:27,840 SO AGAIN, THINKING BACK TO FRANK 870 00:34:27,840 --> 00:34:30,160 WINKLER'S GROUP WHO IDENTIFIED 871 00:34:30,160 --> 00:34:31,960 THESE GAP JUNCTION CONNECTED 872 00:34:31,960 --> 00:34:34,200 TUMOR CELL NETWORKS BETWEEN 873 00:34:34,200 --> 00:34:37,200 VARIOUS MALIGNANT CELLS PERHAPS 874 00:34:37,200 --> 00:34:38,240 THIS GAP JUNCTION WAS 875 00:34:38,240 --> 00:34:39,840 FUNCTIONING TO AMPLIFY THESE 876 00:34:39,840 --> 00:34:40,840 ELECTRIC CURRENTS. 877 00:34:40,840 --> 00:34:43,880 WE SEE A LOT OF SYNCHRONIZED 878 00:34:43,880 --> 00:34:45,880 CELLS, NEIGHBORING CELLS THAT 879 00:34:45,880 --> 00:34:48,000 ARE KIND OF EVOKING THESE 880 00:34:48,000 --> 00:34:56,120 CALCIUM TRANSSENTS IN SYNCHRONY. 881 00:34:56,120 --> 00:34:58,680 IT BLOCKED THE PROPAGATION, BUT 882 00:34:58,680 --> 00:35:01,120 IN ANY GIVEN CELL IT VERY 883 00:35:01,120 --> 00:35:02,720 CLEARLY DIMINISHED THE AMOUNT OF 884 00:35:02,720 --> 00:35:04,480 CURRENT SENSED BY ANY INDIVIDUAL 885 00:35:04,480 --> 00:35:05,840 CELL. 886 00:35:05,840 --> 00:35:08,120 THAT TELLS US THE TUMOR NETWORKS 887 00:35:08,120 --> 00:35:11,720 MAY BE FUNCTIONING TO AMPLIFY 888 00:35:11,720 --> 00:35:13,640 ELECTRICAL CUES SENSED BY THE 889 00:35:13,640 --> 00:35:15,600 TUMOR CELLS IN THE 890 00:35:15,600 --> 00:35:16,000 MICROENVIRONMENT. 891 00:35:16,000 --> 00:35:17,440 NOW TO UNDERSTAND WHAT IS THE 892 00:35:17,440 --> 00:35:19,440 RELEVANCE OF ANY OF THIS DEPOT 893 00:35:19,440 --> 00:35:22,000 LARIZATION TO THESE TUMORS, TO 894 00:35:22,000 --> 00:35:23,440 MALIGNANT NETWORKS I WANTED TO 895 00:35:23,440 --> 00:35:25,080 UNDERSTAND IF THERE IS RELEVANCE 896 00:35:25,080 --> 00:35:26,320 TO DEPOT LARIZATION. 897 00:35:26,320 --> 00:35:29,920 TO THAT END WE BLOCKED THIS 898 00:35:29,920 --> 00:35:31,520 NEUROTRANSMISSION BY EXPRESSING 899 00:35:31,520 --> 00:35:34,520 A DOMINANT NEGATIVE VERSION OF 900 00:35:34,520 --> 00:35:37,120 THESE CONCEPTS, MEDIATES THESE 901 00:35:37,120 --> 00:35:37,400 CONNECTIONS. 902 00:35:37,400 --> 00:35:39,400 YOU CAN SEE HERE THAT WITH THE 903 00:35:39,400 --> 00:35:41,520 EXPRESSION OF THIS DOMINANT 904 00:35:41,520 --> 00:35:43,080 NEGATIVE CONSTRUCT REALLY 905 00:35:43,080 --> 00:35:44,720 CLEARLY STARKLY STAGNATES 906 00:35:44,720 --> 00:35:46,760 GROWTH, SIMILAR TO WHAT WE SAW 907 00:35:46,760 --> 00:35:50,080 IN THE NEUROLIGIN3 KNOCKOUT 908 00:35:50,080 --> 00:35:50,320 MODELS. 909 00:35:50,320 --> 00:35:52,040 IF WE OVEREXPRESS THE WILD TYPE 910 00:35:52,040 --> 00:35:54,760 VERSION OF THIS CONSTRUCT, WE 911 00:35:54,760 --> 00:35:56,480 CAN ACCELERATE GROWTH AND 912 00:35:56,480 --> 00:35:57,320 DECREASE MOUSE SURVIVAL. 913 00:35:57,320 --> 00:36:01,160 THE EXPRESSION OF THE DOMINANT 914 00:36:01,160 --> 00:36:02,120 EXTENDED MOUSE SURVIVAL. 915 00:36:02,120 --> 00:36:04,080 IMPORTANTLY IN THE TUMORS OF THE 916 00:36:04,080 --> 00:36:06,960 MICE THAT DID SUCCUMB TO THEIR 917 00:36:06,960 --> 00:36:09,040 TUMORS WE FOUND THESE TUMORS AT 918 00:36:09,040 --> 00:36:10,960 THE TIME OF LETHALITY WERE 919 00:36:10,960 --> 00:36:12,760 COMPRISED OF CELLS THAT TURNED 920 00:36:12,760 --> 00:36:14,240 OFF THE CONSTRUCT OR DIDN'T 921 00:36:14,240 --> 00:36:16,800 EXPRESS IT TO BEGIN WITH THIS 922 00:36:16,800 --> 00:36:19,280 TELLS US THERE IS PERHAPS 923 00:36:19,280 --> 00:36:21,000 EVOLUTIONARY SELECTION OF CELLS 924 00:36:21,000 --> 00:36:22,520 THAT WERE ABLE TO PARTICIPATE IN 925 00:36:22,520 --> 00:36:25,480 THIS SYNAPTIC NEUROTRANSMISSION. 926 00:36:25,480 --> 00:36:27,840 NOW, SO FAR I HAVE TALKED TO YOU 927 00:36:27,840 --> 00:36:30,280 ABOUT HOW NEURONS CAN INFLUENCE 928 00:36:30,280 --> 00:36:32,240 TUMOR CELL GROWTH, BUT IT HAS 929 00:36:32,240 --> 00:36:35,200 BEEN KNOWN FOR QUITE SOME TIME 930 00:36:35,200 --> 00:36:36,560 FWLEE OHMAS CAN REMODEL 931 00:36:36,560 --> 00:36:38,080 MICROENVIRONMENT AND HAVE A 932 00:36:38,080 --> 00:36:39,720 HEFTY INFLUENCE ON NEURONS 933 00:36:39,720 --> 00:36:40,120 THEMSELVES. 934 00:36:40,120 --> 00:36:42,880 IT HAS BEEN THOUGHT TO BE 935 00:36:42,880 --> 00:36:44,360 THROUGH GLUTAMATE SE CESSION AND 936 00:36:44,360 --> 00:36:49,400 A NUMBER OF DIFFERENT 937 00:36:49,400 --> 00:36:52,200 SYNAPSEGENESIS FACTORS BUT WE 938 00:36:52,200 --> 00:36:54,360 HAVE SEEN THAT IN CLINICAL MO 939 00:36:54,360 --> 00:36:56,560 MODELS OF ADULT GLIOMA. 940 00:36:56,560 --> 00:36:59,480 WE FIND A SIMILAR FINDING IN 941 00:36:59,480 --> 00:37:01,840 PEDIATRIC GLEO BLAST OHMA. 942 00:37:01,840 --> 00:37:04,480 WE WERE INTERESTED IN THIS IF 943 00:37:04,480 --> 00:37:06,520 THIS WAS RELEVANT TO PATIENTS. 944 00:37:06,520 --> 00:37:09,160 TO THAT END WE COLLABORATED WITH 945 00:37:09,160 --> 00:37:12,880 A PHENOMENAL NEUROSURGEON AT 946 00:37:12,880 --> 00:37:15,480 UCSF TO PERFORM INTRAOPERATIVE 947 00:37:15,480 --> 00:37:18,360 IN ADULT GBM PATIENTS PRIOR TO 948 00:37:18,360 --> 00:37:18,600 RESECTION. 949 00:37:18,600 --> 00:37:20,480 WHAT WE FOUND IS THAT EVEN 950 00:37:20,480 --> 00:37:22,840 COMPARED TO HEALTHY APPEARING 951 00:37:22,840 --> 00:37:24,920 TISSUE, THIS TUMOR INFILTRATED 952 00:37:24,920 --> 00:37:26,440 REGIONS OF THE BRAIN EXHIBITED 953 00:37:26,440 --> 00:37:27,840 THIS CLEAR INCREASE IN HIGH 954 00:37:27,840 --> 00:37:29,760 GAMMA BAND POWER WHICH 955 00:37:29,760 --> 00:37:31,240 CORRELATES WITH INCREASED 956 00:37:31,240 --> 00:37:33,040 NEURONAL ACTIVITY. 957 00:37:33,040 --> 00:37:35,280 IT TELLS US THESE GLIOMAS ARE 958 00:37:35,280 --> 00:37:38,680 CAPABLE OF REMODELING THEIR 959 00:37:38,680 --> 00:37:39,680 MICROENVIRONMENT SUCH THEY 960 00:37:39,680 --> 00:37:41,840 INCREASE NEURONAL ACTIVITY AND 961 00:37:41,840 --> 00:37:44,320 CREATE FEEDBACK MECHANISM WHERE 962 00:37:44,320 --> 00:37:46,760 MULTIPLE MECHANISMS ACTIVITY 963 00:37:46,760 --> 00:37:48,600 DEPENDENT GROWTH ARE POE TEN 964 00:37:48,600 --> 00:37:48,840 SHATED. 965 00:37:48,840 --> 00:37:51,560 IT IS AN EXCITING TIME TO START 966 00:37:51,560 --> 00:37:54,280 THINKING ABOUT CLEAR RECIPROCAL 967 00:37:54,280 --> 00:37:56,600 INTERACTIONS BETWEEN NEURONS AND 968 00:37:56,600 --> 00:37:57,680 MALIGNANT TUMOR CELLS. 969 00:37:57,680 --> 00:37:59,440 WHAT IS CLEAR NOW IS ATTACKING 970 00:37:59,440 --> 00:38:04,240 THIS NEW ANGLE OF DISEASE 971 00:38:04,240 --> 00:38:04,920 PROGRESSION IS GOING TO BE 972 00:38:04,920 --> 00:38:07,840 CRUCIAL TO THINKING OF NOVEL 973 00:38:07,840 --> 00:38:08,200 THERAPIES. 974 00:38:08,200 --> 00:38:10,040 MULTIPLE GROUPS ARE THINKING 975 00:38:10,040 --> 00:38:12,600 ABOUT WAYS TO TARGET THESE 976 00:38:12,600 --> 00:38:12,920 INTERACTIONS. 977 00:38:12,920 --> 00:38:16,120 NEURON TO TUMOR SYNAPTIC 978 00:38:16,120 --> 00:38:20,640 INTERACTIONS, NEURONAL 979 00:38:20,640 --> 00:38:22,600 HYPEREXCITABILITY AND WAYS WE 980 00:38:22,600 --> 00:38:24,680 CAN FOCUS ON ACTIVITY MECHANISMS 981 00:38:24,680 --> 00:38:26,240 OF GLIOMA GROWTH. 982 00:38:26,240 --> 00:38:28,840 WE'VE ALREADY FOUND A NUMBER OF 983 00:38:28,840 --> 00:38:32,960 DIFFERENT ALREADY EXISTINGS 984 00:38:32,960 --> 00:38:34,440 NEUROMODULATORY AGENTS -- TO 985 00:38:34,440 --> 00:38:36,840 BEGIN WITH, THAT SEEM TO 986 00:38:36,840 --> 00:38:38,640 STAGNATE FWLEE OHMA GROWTH IN 987 00:38:38,640 --> 00:38:40,720 PRECLINICAL MODELS AND SOME OF 988 00:38:40,720 --> 00:38:42,680 WHICH ARE MOVING INTO CLINICAL 989 00:38:42,680 --> 00:38:44,320 TRIALS, BUT THERE IS A LOT OF 990 00:38:44,320 --> 00:38:46,440 WORK ONGOING IN THE FIELD VERY 991 00:38:46,440 --> 00:38:48,040 BROADLY SPEAKING THAT IS REALLY 992 00:38:48,040 --> 00:38:49,480 THINKING ABOUT THE BROAD 993 00:38:49,480 --> 00:38:50,320 APOLITICABILITY OF THESE 994 00:38:50,320 --> 00:38:52,000 DRUGGINGS ACROSS MODELS AND THE 995 00:38:52,000 --> 00:38:54,160 POSSIBILITY OF REPURPOSING THESE 996 00:38:54,160 --> 00:38:56,440 ALREADY EXISTING CLINICALLY 997 00:38:56,440 --> 00:39:00,840 AVAILABLE AGENTS THAT ARE USED, 998 00:39:00,840 --> 00:39:02,800 ANTI-EPILEPTIC, ANTIDEPRESSANTS 999 00:39:02,800 --> 00:39:04,560 WE COULD REPURPOSE TO TREAT THIS 1000 00:39:04,560 --> 00:39:04,840 DISEASE. 1001 00:39:04,840 --> 00:39:07,400 WHAT IS CLEAR IS NEURONAL 1002 00:39:07,400 --> 00:39:11,440 ACTIVITY DRIVES TUMOR GROWTH. 1003 00:39:11,440 --> 00:39:13,960 THROUGH REPAIR MECHANISMS AS 1004 00:39:13,960 --> 00:39:15,720 WELL AS POTENTIALLY DIRECT 1005 00:39:15,720 --> 00:39:18,400 ELECTRIC RO CHEMICAL SYNAPTIC 1006 00:39:18,400 --> 00:39:18,800 NEUROTRANSMISSION. 1007 00:39:18,800 --> 00:39:21,760 WE SEE FUNDAMENTAL PROPERTY OF 1008 00:39:21,760 --> 00:39:24,600 CANCER IS ELECTRICAL PROPERTY IS 1009 00:39:24,600 --> 00:39:26,120 CRITICAL TO OVERALL PROGRESSION. 1010 00:39:26,120 --> 00:39:28,720 THIS IS A REALLY EXCITING TIME 1011 00:39:28,720 --> 00:39:31,600 TO REFRAME OUR UNDERSTANDING OF 1012 00:39:31,600 --> 00:39:32,960 MALIGNANT TISSUE. 1013 00:39:32,960 --> 00:39:34,440 PRIMARY BRAIN CANCERS THERE ARE 1014 00:39:34,440 --> 00:39:36,000 A NUMBER OF FOLLOW UP QUESTIONS 1015 00:39:36,000 --> 00:39:38,080 TO BE ADDRESSED, LOTS OF PEOPLE 1016 00:39:38,080 --> 00:39:40,040 REALLY WORKING ON UNDERSTANDING 1017 00:39:40,040 --> 00:39:41,800 THESE RESIP ROW CALL 1018 00:39:41,800 --> 00:39:43,200 INTERACTIONS BETWEEN THE TWO AND 1019 00:39:43,200 --> 00:39:45,360 HOW WE MIGHT TARGET THEM, BUT 1020 00:39:45,360 --> 00:39:47,040 MOVING FORWARD WHAT REALLY 1021 00:39:47,040 --> 00:39:48,960 PIQUED MY INTEREST AND HAS BEEN 1022 00:39:48,960 --> 00:39:53,080 A FOCUS OF MY LAB IS REALLY 1023 00:39:53,080 --> 00:39:57,080 UNDERSTANDING HOW NONGLIAL 1024 00:39:57,080 --> 00:39:58,120 DERIVED MALIGNANCIES MAY HIJACK 1025 00:39:58,120 --> 00:39:59,720 THESE NEURONAL CUES. 1026 00:39:59,720 --> 00:40:04,760 OFTENTIMES WHEN I PRESENTED TO 1027 00:40:04,760 --> 00:40:05,960 NEUROSCIENTISTS, CANCER 1028 00:40:05,960 --> 00:40:08,240 BIOLOGISTS THOUGHT THIS IS 1029 00:40:08,240 --> 00:40:09,720 GREAT, ELECTRICAL PROPERTIES. 1030 00:40:09,720 --> 00:40:11,760 WHEN I PRESENTED TO 1031 00:40:11,760 --> 00:40:12,800 NEUROSCIENTISTS THEY WERE LIKE, 1032 00:40:12,800 --> 00:40:14,440 WELL, THESE ARE CELLS THAT 1033 00:40:14,440 --> 00:40:16,160 ORIGINATE FROM THE BRAIN. 1034 00:40:16,160 --> 00:40:18,840 IT MAKES SENSE THEY ARE 1035 00:40:18,840 --> 00:40:19,680 ELECTRICALLY ACTIVE. 1036 00:40:19,680 --> 00:40:21,560 WHAT WAS INTERESTING IS THINKING 1037 00:40:21,560 --> 00:40:28,080 ABOUT NONGLIAL DERIVED CANCERS, 1038 00:40:28,080 --> 00:40:31,240 THAT END UP IN THE BRAIN, CAN 1039 00:40:31,240 --> 00:40:33,560 THEY DERIVE THIS NEURONAL INPUT 1040 00:40:33,560 --> 00:40:36,280 TO FACILITATE THEIR OWN GROWTH. 1041 00:40:36,280 --> 00:40:38,720 AND SO THOUGH I LARGELY FOCUS ON 1042 00:40:38,720 --> 00:40:40,040 PRIMARY BRAIN CANCERS, OUR LAB 1043 00:40:40,040 --> 00:40:46,120 HAS TURNED TO THINKING ABOUT 1044 00:40:46,120 --> 00:40:47,840 METASTISES AS WELL AS ANOTHER 1045 00:40:47,840 --> 00:40:51,600 PROJECT WE ARE THINKING ABOUT IN 1046 00:40:51,600 --> 00:40:53,520 PRIMARY LUNG CANCER IN REF RAL 1047 00:40:53,520 --> 00:40:55,840 NERVE INNOVATION. 1048 00:40:55,840 --> 00:41:01,520 TO COME BACK TO METASTICES 1049 00:41:01,520 --> 00:41:05,000 OUTNUMBER ALL BRAIN CANCERS 10 1050 00:41:05,000 --> 00:41:05,280 FOLD. 1051 00:41:05,280 --> 00:41:13,880 THEY ARE THE CRITICAL CAUSE OF 1052 00:41:13,880 --> 00:41:15,320 LETHALITY AND WE HAVE SOME DRUGS 1053 00:41:15,320 --> 00:41:18,520 THAT ARE EFFECTIVE IN TREATING 1054 00:41:18,520 --> 00:41:19,600 EXTRA CRANIAL DISEASE. 1055 00:41:19,600 --> 00:41:23,440 WHEN IT GETS TO METASTASES WE 1056 00:41:23,440 --> 00:41:25,120 HAVE LIMITED TREATMENT OPTIONS. 1057 00:41:25,120 --> 00:41:25,440 SORRY. 1058 00:41:25,440 --> 00:41:28,480 I DID WANT TO MENTION THIS IDEA 1059 00:41:28,480 --> 00:41:30,360 OF NEURAL ACTIVITY IN THE 1060 00:41:30,360 --> 00:41:37,200 CONTEXT OF BRAIN METASTASES HAS 1061 00:41:37,200 --> 00:41:40,600 BEEN THOUGHT ABOUT. 1062 00:41:40,600 --> 00:41:46,600 BREAST CANCER BRAIN METASTASES 1063 00:41:46,600 --> 00:41:48,800 SHOWED THEY SIT NEXT TO THESE 1064 00:41:48,800 --> 00:41:51,400 NEURONS TO USURP GLUTAMATE AND 1065 00:41:51,400 --> 00:41:54,600 DERIVE THAT GLUTAMATE TO PROMOTE 1066 00:41:54,600 --> 00:41:57,600 THEIR OWN GROWTH VIA MDAR 1067 00:41:57,600 --> 00:41:59,080 RECEPTOR SIGNALS. 1068 00:41:59,080 --> 00:42:00,360 THINKING ABOUT OTHER CANCERS 1069 00:42:00,360 --> 00:42:02,200 THAT MAY BENEFIT FROM THIS 1070 00:42:02,200 --> 00:42:05,080 NEURONAL INPUT, OUR LAB HAS BEEN 1071 00:42:05,080 --> 00:42:07,080 THINKING ABOUT SMALL CELL LUNG 1072 00:42:07,080 --> 00:42:10,040 CANCER ACCOUNTS FOR 15% OF ALL 1073 00:42:10,040 --> 00:42:10,800 LUNG CANCERS. 1074 00:42:10,800 --> 00:42:12,440 THE REASON WE CHOSE TO STUDY 1075 00:42:12,440 --> 00:42:15,000 THIS CANCER IS IT HAS AN 1076 00:42:15,000 --> 00:42:17,840 EXTREMELY HIGH PROPENSITY TO END 1077 00:42:17,840 --> 00:42:20,480 UP IN THE BRAIN AND THESE SMALL 1078 00:42:20,480 --> 00:42:22,440 CELL LUNG CANCERS ARE THOUGHT TO 1079 00:42:22,440 --> 00:42:25,200 BE DERIVED FROM PULMONARY CELLS 1080 00:42:25,200 --> 00:42:28,000 IN THE LUNG. 1081 00:42:28,000 --> 00:42:33,480 THEY HAVE A NEURAL PHENOTYPE SO 1082 00:42:33,480 --> 00:42:35,440 NEURONS ARE PLAYING A ROLE IN 1083 00:42:35,440 --> 00:42:37,200 THIS CONTEXT AS WELL. 1084 00:42:37,200 --> 00:42:39,880 WE USED MULTIPLE DIFFERENT 1085 00:42:39,880 --> 00:42:40,120 MODELS. 1086 00:42:40,120 --> 00:42:42,520 I WILL TELL YOU ABOUT THE 1087 00:42:42,520 --> 00:42:45,960 GENETIC MODEL OF SMALL CELL LUNG 1088 00:42:45,960 --> 00:42:48,120 CANCER DEVELOPED AT STANFORD, A 1089 00:42:48,120 --> 00:42:50,760 CLOSE COLLABORATORS AND PRIMARY 1090 00:42:50,760 --> 00:42:54,840 LUNG METASTA SIZES TO THE LIVE 1091 00:42:54,840 --> 00:42:55,880 AND SPLEEN. 1092 00:42:55,880 --> 00:43:04,000 THERE ARE NO GREAT MODELS FOR 1093 00:43:04,000 --> 00:43:05,200 METASTASES TO THE BRAIN. 1094 00:43:05,200 --> 00:43:08,200 I WANT TO EMPHASIZE THIS WAS AN 1095 00:43:08,200 --> 00:43:10,240 UNDERSTANDING OF HOW NEURONAL 1096 00:43:10,240 --> 00:43:12,520 ACTIVITY CAN AFFECT GROWTH ONCE 1097 00:43:12,520 --> 00:43:23,080 THE METS A -- METASTASES. 1098 00:43:25,880 --> 00:43:32,960 THESE EXPREX OF THESE PROGRAMS 1099 00:43:32,960 --> 00:43:34,680 CORRELATES WITH MORE METASTATIC 1100 00:43:34,680 --> 00:43:36,200 DISEASE AND LOWER SURVIVAL 1101 00:43:36,200 --> 00:43:36,520 RATES. 1102 00:43:36,520 --> 00:43:40,000 YOU CAN SEE AT HIGH RESOLUTION 1103 00:43:40,000 --> 00:43:43,160 THEY LOOK NEURONAL WITH AXON 1104 00:43:43,160 --> 00:43:45,880 PROTRUSIONS THAT ALMOST LIKE 1105 00:43:45,880 --> 00:43:49,160 LIKE DENDITIC SPINES. 1106 00:43:49,160 --> 00:43:52,520 USING STAINING IN THESE ANIMAL 1107 00:43:52,520 --> 00:43:54,520 MODELS AND PRIMARY PATIENT BRAIN 1108 00:43:54,520 --> 00:43:56,360 TISSUE WE CAN SEE THERE IS VERY 1109 00:43:56,360 --> 00:43:58,920 CLEAR INTERACTIONS BETWEEN 1110 00:43:58,920 --> 00:44:00,920 NEURONS LABELED HERE IN WHITE 1111 00:44:00,920 --> 00:44:03,440 AND TUMOR CELL PROCESSES 1112 00:44:03,440 --> 00:44:08,240 SUGGESTING THAT SIMILAR TO DPLEE 1113 00:44:08,240 --> 00:44:11,600 OHMAE -- GLIOMAS THERE MIGHT BEA 1114 00:44:11,600 --> 00:44:13,640 FUNCTIONAL RELATIONSHIP. 1115 00:44:13,640 --> 00:44:20,800 JUST USING HNE STAINING, WE 1116 00:44:20,800 --> 00:44:22,920 THINK OF THESE METS GROWING AT, 1117 00:44:22,920 --> 00:44:25,640 WE SEE A LOT OF AREAS WHERE WE 1118 00:44:25,640 --> 00:44:27,760 SEE EXTENSIVE NEURONAL 1119 00:44:27,760 --> 00:44:28,120 INFILTRATION. 1120 00:44:28,120 --> 00:44:31,160 IF WE LOOK AT THE CELLS IN THE 1121 00:44:31,160 --> 00:44:33,720 REGION OPPOSED TO 'ONES AWAY 1122 00:44:33,720 --> 00:44:35,840 FROM THE NEURONS WE SEE HIGHER 1123 00:44:35,840 --> 00:44:37,760 LEVEL OF PROLIFERATION IN THE 1124 00:44:37,760 --> 00:44:40,440 CELLS CLOSER TO THE AXON FIBERS. 1125 00:44:40,440 --> 00:44:42,040 AND SO THINKING FUNCTIONALLY 1126 00:44:42,040 --> 00:44:43,920 ABOUT THE RELEVANCE OF THESE 1127 00:44:43,920 --> 00:44:45,800 INTERACTIONS WE DECIDED TO APPLY 1128 00:44:45,800 --> 00:44:47,680 PAST TECHNOLOGIES TO UNDERSTAND 1129 00:44:47,680 --> 00:44:49,160 HOW THESE NEURONS MAY PLAY A 1130 00:44:49,160 --> 00:44:52,760 ROLE IN THE CONTEXT OF SMALL 1131 00:44:52,760 --> 00:44:54,920 CELL LUNG CANCER GROWTH. 1132 00:44:54,920 --> 00:44:58,440 IN OUR IN VITRO MODELS, WE 1133 00:44:58,440 --> 00:45:02,960 ISOLATED THESE CORTICAL NEURONS 1134 00:45:02,960 --> 00:45:06,920 FROM MICE AND CULTURED THEM WITH 1135 00:45:06,920 --> 00:45:09,040 SMALL CELL LUNG CANCER CELL. 1136 00:45:09,040 --> 00:45:10,960 AND WE SEE CLEAR PROLIFERATION. 1137 00:45:10,960 --> 00:45:13,360 AN ACTIVITY DEPENDENT EFFECT. 1138 00:45:13,360 --> 00:45:15,520 THIS WAS SPEFGLY IN A SMALL CELL 1139 00:45:15,520 --> 00:45:17,920 LUNG CANCER TYPE A, A VERY 1140 00:45:17,920 --> 00:45:20,240 SPECIFIC SUBTYPE OF LUNG CANCER, 1141 00:45:20,240 --> 00:45:22,680 BUT EVEN IN A SEPARATE SUBTYPE 1142 00:45:22,680 --> 00:45:25,640 OF SMALL CELL LUNG CANCER WE SEE 1143 00:45:25,640 --> 00:45:28,360 A SIMILAR PHENOMENA. 1144 00:45:28,360 --> 00:45:29,600 INNOVATION MAY PLAY A ROLE COULD 1145 00:45:29,600 --> 00:45:31,560 BE A BROADLY APPLICABLE 1146 00:45:31,560 --> 00:45:33,600 PHENOMENON THAT RELATES TO 1147 00:45:33,600 --> 00:45:36,200 MULTIPLE CELLULAR STATES WITHIN 1148 00:45:36,200 --> 00:45:38,240 SMALL CELL LUNG CANCERS. 1149 00:45:38,240 --> 00:45:40,160 REALLY, DESPITE THE FACT THAT WE 1150 00:45:40,160 --> 00:45:43,200 KNOW NEURONS MAY PLAY RA ROLE OF 1151 00:45:43,200 --> 00:45:45,360 THE TUMOR MICROENVIRONMENT, WE 1152 00:45:45,360 --> 00:45:47,240 WANTED TO UNDERSTAND WHAT DID 1153 00:45:47,240 --> 00:45:50,800 THAT MEAN IN VEEFO SETTING. 1154 00:45:50,800 --> 00:45:54,320 USING THE SAME TOOLS AS THE 1155 00:45:54,320 --> 00:45:54,960 GLIOMAS, WE USED A MODEL HERE 1156 00:45:54,960 --> 00:46:00,240 THAT ALLOWED FOR BOTH THE 1157 00:46:00,240 --> 00:46:01,480 ALAGRAFTING WITH TUMOR CELLS 1158 00:46:01,480 --> 00:46:02,640 WITH THIS STIMULATION. 1159 00:46:02,640 --> 00:46:07,200 WE FOUND IN RESPONSE TO THIS 1160 00:46:07,200 --> 00:46:09,160 ELEVATION OF NEURONAL ACTIVITY 1161 00:46:09,160 --> 00:46:11,400 WE SEE INCREASE IN SMALL CELL 1162 00:46:11,400 --> 00:46:13,200 LUNG CANCER GROWTH AND 1163 00:46:13,200 --> 00:46:13,960 PROLIFERATION. 1164 00:46:13,960 --> 00:46:16,440 COMING BACK TO THIS IDEA OF 1165 00:46:16,440 --> 00:46:18,080 METASTATIC ABILITY AND INVASION, 1166 00:46:18,080 --> 00:46:20,880 WE SEE TUMORS OF THE MICE THAT 1167 00:46:20,880 --> 00:46:23,520 ARE STIMULATED LOOK MORE DIFFUSE 1168 00:46:23,520 --> 00:46:24,880 THAN CONTROL COUNTERPARTS. 1169 00:46:24,880 --> 00:46:26,240 WHEN QUANTIFIED YOU CAN SEE 1170 00:46:26,240 --> 00:46:28,840 THERE IS A CLEAR INCREASE IN THE 1171 00:46:28,840 --> 00:46:30,680 SPREAD OF THESE TUMORS IN 1172 00:46:30,680 --> 00:46:34,520 RESPONSE TO ELEVATED NEURONAL 1173 00:46:34,520 --> 00:46:36,760 ACTIVITY, SUGGESTING THERE IS A 1174 00:46:36,760 --> 00:46:39,920 FUNCTIONAL IMPACT OF NEURONS IN 1175 00:46:39,920 --> 00:46:41,440 INTRACRANIAL SMALL CELL LUNG 1176 00:46:41,440 --> 00:46:43,640 CANCER PROGRESSION. 1177 00:46:43,640 --> 00:46:45,600 NOW WE HAVE SEEN THIS FUNCTIONAL 1178 00:46:45,600 --> 00:46:46,800 RELEVANCE OF ACTIVE NEURONS IN 1179 00:46:46,800 --> 00:46:48,360 THE CONTEXT OF THE 1180 00:46:48,360 --> 00:46:50,160 MICROENVIRONMENT WE CAME BACK TO 1181 00:46:50,160 --> 00:46:52,160 UNDERSTANDING THIS STRUCTURAL 1182 00:46:52,160 --> 00:46:53,880 INTEGRATION OF THESE TUMOR CELLS 1183 00:46:53,880 --> 00:46:56,280 INTO THE NEURONS AND THE HEALTHY 1184 00:46:56,280 --> 00:46:57,720 MICROENVIRONMENT AND WHAT WE SEE 1185 00:46:57,720 --> 00:47:00,280 IS WE DO FIND EVIDENCE OF DIRECT 1186 00:47:00,280 --> 00:47:02,560 SYNAPTIC INTERACTIONS, I 1187 00:47:02,560 --> 00:47:04,400 DESCRIBED TO YOU WITH THE 1188 00:47:04,400 --> 00:47:04,640 GLIOMAS. 1189 00:47:04,640 --> 00:47:07,160 WE SEE A NUMBER OF CELLS THAT 1190 00:47:07,160 --> 00:47:08,920 SIT SIMILARLY AS THE BREAST 1191 00:47:08,920 --> 00:47:14,320 CANCER CELLS, PERISYNAPTICALLY. 1192 00:47:14,320 --> 00:47:17,040 THERE ARE DIFFERENT CELLULAR SUB 1193 00:47:17,040 --> 00:47:18,160 POPULATIONS THAT BEHAVE VERY 1194 00:47:18,160 --> 00:47:18,480 DIFFERENTLY. 1195 00:47:18,480 --> 00:47:20,800 WHAT IS CLEAR IS THERE IS SOME 1196 00:47:20,800 --> 00:47:23,160 CROSSTALK AND SOME INTEGRATION 1197 00:47:23,160 --> 00:47:24,720 WITH THESE SMALL CELL LUNG 1198 00:47:24,720 --> 00:47:25,960 CANCER CELLS AND NEURONS IN THE 1199 00:47:25,960 --> 00:47:28,040 BRAIN AND PERHAPS MIGHT BE A 1200 00:47:28,040 --> 00:47:30,040 REASON THEY ARE SO WELL EQUIPPED 1201 00:47:30,040 --> 00:47:32,640 TO THRIVE IN THAT BRAIN 1202 00:47:32,640 --> 00:47:33,040 MICROENVIRONMENT. 1203 00:47:33,040 --> 00:47:34,280 TO UNDERSTAND AGAIN 1204 00:47:34,280 --> 00:47:35,200 MECHANICISTICALLY WHAT IS GOING 1205 00:47:35,200 --> 00:47:38,040 ON HERE, WE TOOK OUR SMALL CELL 1206 00:47:38,040 --> 00:47:40,440 LUNG CANCER CELLS CO-CULTURED 1207 00:47:40,440 --> 00:47:43,440 WITH OUR NEURONSES AND SEE 1208 00:47:43,440 --> 00:47:45,360 YENSED THEM WITH THE CELLS THAT 1209 00:47:45,360 --> 00:47:46,760 WERE CULTURED ALONE. 1210 00:47:46,760 --> 00:47:49,040 THEY DO UPREGULATE A NUMBER OF 1211 00:47:49,040 --> 00:47:50,760 DIFFERENT I ONCHANNEL RECEPTORS 1212 00:47:50,760 --> 00:47:59,240 THAT INCLUDED GLUTAMATERGIC 1213 00:47:59,240 --> 00:48:03,960 RECEPTORS AND A UP TAKE OF GABBA 1214 00:48:03,960 --> 00:48:06,680 RESENTTORS SO AN ADDITIONAL 1215 00:48:06,680 --> 00:48:09,440 NEURAL SET POPULATION COULD BE 1216 00:48:09,440 --> 00:48:09,680 INVOLVED. 1217 00:48:09,680 --> 00:48:11,880 WE PROBE THE FUNCTIONAL 1218 00:48:11,880 --> 00:48:12,680 INTERACTIONS AND DEPOT 1219 00:48:12,680 --> 00:48:14,320 LARIZATION THAT IS OSECURING IN 1220 00:48:14,320 --> 00:48:18,920 THESE CELLS TO QUERY THE SBE 1221 00:48:18,920 --> 00:48:20,960 SBRAGS OF CELLS. 1222 00:48:20,960 --> 00:48:22,560 WE COLLABORATED WITH ANOTHER LAB 1223 00:48:22,560 --> 00:48:24,720 AND FOUND IN RESPONSE TO 1224 00:48:24,720 --> 00:48:26,200 NEURONAL ACTIVITY WE SEE 1225 00:48:26,200 --> 00:48:28,400 EVIDENCE OF EVOKED CURRENTS AND 1226 00:48:28,400 --> 00:48:30,120 RESPONSE TO THE NEURONAL 1227 00:48:30,120 --> 00:48:32,680 STIMULATION BUT WHAT LOOK LIKE 1228 00:48:32,680 --> 00:48:38,640 SPONTANEOUS GLUTAMETERGIC IN 1229 00:48:38,640 --> 00:48:41,120 MALIGNANT SMALL CELL LUNG CANCER 1230 00:48:41,120 --> 00:48:42,240 CELLS. 1231 00:48:42,240 --> 00:48:43,640 EXCITEDLY, THIS IS VERY NEW. 1232 00:48:43,640 --> 00:48:45,160 THIS SLIDE IS THROWN TOGETHER. 1233 00:48:45,160 --> 00:48:48,400 WHAT WE ALSO SEE IS WE HAPPEN TO 1234 00:48:48,400 --> 00:48:51,000 SEE A HIGH PROPORTION OF CELLS 1235 00:48:51,000 --> 00:48:57,840 THAT EXHIBIT THESE GABBA IN OUR 1236 00:48:57,840 --> 00:48:59,120 TUMOR CELLS. 1237 00:48:59,120 --> 00:49:01,600 WE THINK ABOUT GLUTAMATE IN THE 1238 00:49:01,600 --> 00:49:03,640 NORMAL BRAIN DEPOT LARIZING 1239 00:49:03,640 --> 00:49:08,600 TRANSMITTER AND GABBA AS AN 1240 00:49:08,600 --> 00:49:11,040 INHIBITORY NEUROTRANSMITTER. 1241 00:49:11,040 --> 00:49:13,400 HERE WE WERE SEEING THESE GABBA 1242 00:49:13,400 --> 00:49:15,440 CURRENTS SO THINKING HOW THAT 1243 00:49:15,440 --> 00:49:17,680 MIGHT MAKE SENSE GABBA IN THIS 1244 00:49:17,680 --> 00:49:26,960 CONTEXT WAS DEPOLARIZING LIKE 1245 00:49:26,960 --> 00:49:31,120 FLUTE -- GLUTAMATE. 1246 00:49:31,120 --> 00:49:32,960 GABBA INDUCED THIS OUTWARD 1247 00:49:32,960 --> 00:49:34,760 CURRENT SAYING THAT GABBA WAS 1248 00:49:34,760 --> 00:49:40,560 DEPOT -- DEPOLARIZING. 1249 00:49:40,560 --> 00:49:43,160 BOTH GLUTAMATE AND GABBA 1250 00:49:43,160 --> 00:49:44,760 NEUROTRANSMITTERS WERE ACTING ON 1251 00:49:44,760 --> 00:49:51,600 THESE TUMOR CELLS TO INDUCE 1252 00:49:51,600 --> 00:49:53,120 DEPOLARIZING EFFECT. 1253 00:49:53,120 --> 00:49:59,320 WE SPECIFICALLY ISOLATED 1254 00:49:59,320 --> 00:50:01,600 GABBAURGIC NEURONS WERE HAVING A 1255 00:50:01,600 --> 00:50:04,600 STRONG PROLIFERATIVE EFFECT ON 1256 00:50:04,600 --> 00:50:06,400 THE SMALL CELL LUNG CANCER 1257 00:50:06,400 --> 00:50:07,200 CELLS. 1258 00:50:07,200 --> 00:50:09,000 WE SPECIFICALLY NOW EXPRESSED 1259 00:50:09,000 --> 00:50:12,840 THESE OPSINS IN INTRANEURON 1260 00:50:12,840 --> 00:50:14,440 POPULATION AND FOUND THERE WAS A 1261 00:50:14,440 --> 00:50:17,320 VERY ROBUST INCREASE IN SMALL 1262 00:50:17,320 --> 00:50:22,080 CELL LUNG CANCER GROWTH UPON 1263 00:50:22,080 --> 00:50:25,160 ACTIVATION OF INTER NEURONS. 1264 00:50:25,160 --> 00:50:30,760 SUB POPULATIONS WERE DRIVING 1265 00:50:30,760 --> 00:50:35,600 POPULATIONS IN NONGLIAL TUMORS. 1266 00:50:35,600 --> 00:50:39,360 WE WERE ABLE TO SEE NOT ONLY THE 1267 00:50:39,360 --> 00:50:41,240 SPONTANEOUS CALCIUM TRANSIENTS 1268 00:50:41,240 --> 00:50:43,960 BUT CLEAR ELICITED CALCIUM 1269 00:50:43,960 --> 00:50:46,360 TRANSIENTS IN RESPONSE TO 1270 00:50:46,360 --> 00:50:48,480 NEURONAL ACTIVITY THAT WERE 1271 00:50:48,480 --> 00:50:50,520 DIMINISHED UPON ABROGATION OF 1272 00:50:50,520 --> 00:50:51,440 ACTION POTENTIALS. 1273 00:50:51,440 --> 00:50:54,680 THIS REALLY FOR THE FIRST TIME 1274 00:50:54,680 --> 00:50:56,880 TELLS US DESPITE NOT ORIGINATING 1275 00:50:56,880 --> 00:50:58,920 FROM CELLS IN THE BRAIN, SMALL 1276 00:50:58,920 --> 00:51:01,800 CELL LUNG CANCER CELLS HAVE 1277 00:51:01,800 --> 00:51:02,880 CAPACITY TO INTERPRET IN 1278 00:51:02,880 --> 00:51:03,760 NEURONAL INPUT. 1279 00:51:03,760 --> 00:51:05,760 TO FUNCTIONALLY UNDERSTAND THE 1280 00:51:05,760 --> 00:51:08,480 ROLE OF DEPOLARIZATION, WE 1281 00:51:08,480 --> 00:51:10,240 WANTED TO UNDERSTAND HOW MEM 1282 00:51:10,240 --> 00:51:15,840 DRAIN DEPOLARIZATION MAY BE 1283 00:51:15,840 --> 00:51:16,520 FUNCTIONING. 1284 00:51:16,520 --> 00:51:19,800 TO EXPRESS THE OPSINS IN THE 1285 00:51:19,800 --> 00:51:24,920 NEURON MICROENVIRONMENT, WE 1286 00:51:24,920 --> 00:51:26,480 EXPRESSED THEM IN THE TUMOR 1287 00:51:26,480 --> 00:51:27,000 CELLS. 1288 00:51:27,000 --> 00:51:29,040 IMPLANTED INTO THE MICE AND 1289 00:51:29,040 --> 00:51:32,640 CHRONICALLY DEPOLARIZED IN VEEFO 1290 00:51:32,640 --> 00:51:34,520 USING BLUE LIGHT WHERE WE 1291 00:51:34,520 --> 00:51:37,320 DIRECTLY DEPOLARIZE THE TUMOR 1292 00:51:37,320 --> 00:51:40,520 CELLS AND THAT PROMOTED GROWTH. 1293 00:51:40,520 --> 00:51:44,240 MEMBRANE DEPOLARIZATION ON ITS 1294 00:51:44,240 --> 00:51:46,760 OWN INDUCES GROWTH SIGNALLING 1295 00:51:46,760 --> 00:51:49,440 CASCADE IN THESE TUMOR CELLS AND 1296 00:51:49,440 --> 00:51:51,960 ACTIVELY WORKING ON 1297 00:51:51,960 --> 00:51:56,440 UNDERSTANDING WHAT THOSE VOLTAGE 1298 00:51:56,440 --> 00:51:57,800 PATHWAYS THAT MEDIATE THIS 1299 00:51:57,800 --> 00:51:58,680 GROWTH WILL BE. 1300 00:51:58,680 --> 00:52:00,360 MORE TO COME ON THAT NEXT TIME. 1301 00:52:00,360 --> 00:52:02,320 I ALSO WANTED TO MENTION THAT AS 1302 00:52:02,320 --> 00:52:04,480 I MENTIONED THIS WAS A VERY 1303 00:52:04,480 --> 00:52:07,200 SPECIFIC SUB POPULATION OF CELLS 1304 00:52:07,200 --> 00:52:12,520 THAT WAS INTEGRATED THESE CUES. 1305 00:52:12,520 --> 00:52:13,920 THERE WAS A VERY SPECIFIC SUB 1306 00:52:13,920 --> 00:52:23,360 POPULATION OF CELLS THAT SHIFTED 1307 00:52:23,360 --> 00:52:23,640 MORPHOLOGY. 1308 00:52:23,640 --> 00:52:25,880 THEY SEEM TO BE CONNECTED VIA 1309 00:52:25,880 --> 00:52:27,920 GAP JUNCTIONS AND THEY 1310 00:52:27,920 --> 00:52:31,760 ASSOCIATED ALSO WITH THIS 1311 00:52:31,760 --> 00:52:39,640 UPREGULATION OF ASTROCYTIC GENE 1312 00:52:39,640 --> 00:52:39,880 STRUCTURE. 1313 00:52:39,880 --> 00:52:46,720 THIS SYNAPTIC ASTROCYTIC. 1314 00:52:46,720 --> 00:52:57,240 WE KNOW AS ASTROCYTES MAY BE 1315 00:52:58,080 --> 00:53:01,800 RECIPROCAL SIMILAR TO WHAT WE 1316 00:53:01,800 --> 00:53:05,320 THOUGHT IN THE GLIOMAS. 1317 00:53:05,320 --> 00:53:07,000 USING THESE ARRAYS AND WE HAVE 1318 00:53:07,000 --> 00:53:10,280 MOVED TO SETTING THIS IN VEEFO 1319 00:53:10,280 --> 00:53:11,880 USING FIELD POTENTIAL RECORDINGS 1320 00:53:11,880 --> 00:53:13,680 FROM IN VEEFO SLICES WE SEE THE 1321 00:53:13,680 --> 00:53:16,080 NEURONS AND THE PRESENCE OF 1322 00:53:16,080 --> 00:53:19,880 THESE SMALL CELL LUNG CANCER 1323 00:53:19,880 --> 00:53:22,160 CELLS PRESENT HYPEREXSIBLT WITH 1324 00:53:22,160 --> 00:53:23,360 INCREASED SPIKED NUMBER AS WELL 1325 00:53:23,360 --> 00:53:26,960 AS INCREASED SPIKE AMPLITUDE. 1326 00:53:26,960 --> 00:53:28,880 AGAIN, TELLING US THESE 1327 00:53:28,880 --> 00:53:31,360 RECIPROCAL INTERACTIONS ARE 1328 00:53:31,360 --> 00:53:32,400 IMPORTANT TO TARGET MOVING 1329 00:53:32,400 --> 00:53:32,640 FORWARD. 1330 00:53:32,640 --> 00:53:35,200 THIS IS ASSOCIATED WITH AN 1331 00:53:35,200 --> 00:53:38,240 INCREASE IN THE SYNAPSE NUMBER 1332 00:53:38,240 --> 00:53:41,680 IN THE NEURONS SURROUNDING THE 1333 00:53:41,680 --> 00:53:44,120 SMALL CELL LUNG CANCER CELLS. 1334 00:53:44,120 --> 00:53:47,320 SO IN SUMMARY WHAT WE NOW KNOW 1335 00:53:47,320 --> 00:53:50,560 IS WE SEE NEURONAL INFILTRATION 1336 00:53:50,560 --> 00:53:52,240 OF SMALL CELL LUNG CANCER IN THE 1337 00:53:52,240 --> 00:53:52,440 BRAIN. 1338 00:53:52,440 --> 00:53:56,800 THIS NEURONAL ACTIVITY SEEMS TO 1339 00:53:56,800 --> 00:53:59,000 PROMOTE INTRACRANIAL CANCER 1340 00:53:59,000 --> 00:54:01,200 GROWTH AND INVOKE CANCER 1341 00:54:01,200 --> 00:54:02,600 TRANSIENTS IN THE CELLS AND 1342 00:54:02,600 --> 00:54:05,240 THESE CELLS CAN PROMOTE 1343 00:54:05,240 --> 00:54:07,640 HYPEREXCITABILITY IN THEIR TUMOR 1344 00:54:07,640 --> 00:54:08,040 MICROENVIRONMENT. 1345 00:54:08,040 --> 00:54:09,960 THERE ARE A LOT OF REMAINING 1346 00:54:09,960 --> 00:54:12,840 QUESTIONS WITH THOSE MECHANISMS 1347 00:54:12,840 --> 00:54:16,080 THAT MEDIATE THE GROWTH 1348 00:54:16,080 --> 00:54:18,120 PROMOTING SIBLING PATHWAYS AFTER 1349 00:54:18,120 --> 00:54:22,160 MEMBRANE DEPOLARIZATION. 1350 00:54:22,160 --> 00:54:24,680 MIGHT THESE SYNAPTIC PATHWAYS 1351 00:54:24,680 --> 00:54:26,680 EXIST. 1352 00:54:26,680 --> 00:54:31,360 WE ARE ACTIVELY WORKING ON THESE 1353 00:54:31,360 --> 00:54:31,600 QUESTIONS. 1354 00:54:31,600 --> 00:54:32,960 I WANT TO TELL YOU A DIFFERENT 1355 00:54:32,960 --> 00:54:34,520 STORY THAT FOCUSES ON 1356 00:54:34,520 --> 00:54:36,400 UNDERSTANDING THE ROLE OF 1357 00:54:36,400 --> 00:54:44,360 PERIPHERAL NERVOUS SYSTEM INN 1358 00:54:44,360 --> 00:54:44,640 INNERVATION. 1359 00:54:44,640 --> 00:54:45,960 IT IS IMPORTANT IN A NUMBER OF 1360 00:54:45,960 --> 00:54:47,800 DIFFERENT ORGANS OUTSIDE OF THE 1361 00:54:47,800 --> 00:54:50,840 CONTEXT OF THE BRAIN, 1362 00:54:50,840 --> 00:54:52,800 NEUROTROPHIC FACTORS. 1363 00:54:52,800 --> 00:54:54,400 ADDITIONAL, IN A NUMBER OF 1364 00:54:54,400 --> 00:54:55,720 DIFFERENT CANCERS, BREAST 1365 00:54:55,720 --> 00:54:57,480 CANCERS AND SKIN CANCERS AND 1366 00:54:57,480 --> 00:55:03,160 GASTRIC CANCERS AND PROSTRATE 1367 00:55:03,160 --> 00:55:06,880 CANCERS, INNERVATION HAS PLAYED 1368 00:55:06,880 --> 00:55:07,400 A ROLE. 1369 00:55:07,400 --> 00:55:09,560 AFTER DEMONSTRATING THAT IT WAS 1370 00:55:09,560 --> 00:55:12,400 SO IMPORTANT TO INTRACRANIAL 1371 00:55:12,400 --> 00:55:15,200 SMALL CELL LUNG CANCER GROWTH WE 1372 00:55:15,200 --> 00:55:16,960 HYPOTHESIZED PERHAPS THIS IDEA 1373 00:55:16,960 --> 00:55:21,560 OF INNERVATION IN THE LUNG MIGHT 1374 00:55:21,560 --> 00:55:22,880 BE AN IMPORTANT QUESTION TO TRY 1375 00:55:22,880 --> 00:55:24,040 TO ADDRESS. 1376 00:55:24,040 --> 00:55:26,280 AND SO TO THAT END, WE LOOKED AT 1377 00:55:26,280 --> 00:55:28,720 A NUMBER OF PRIMARY PATIENT 1378 00:55:28,720 --> 00:55:31,120 SAMPLES FOUND THAT THEY HIGHLY 1379 00:55:31,120 --> 00:55:33,680 EXPRESS A NUMBER OF THESE SAME 1380 00:55:33,680 --> 00:55:36,680 ION CHANNEL RECEPTORS SYNAPSE 1381 00:55:36,680 --> 00:55:37,480 RELATED GENES. 1382 00:55:37,480 --> 00:55:39,880 IF WE LOOK AT THE TUMORS 1383 00:55:39,880 --> 00:55:42,360 THEMSELVES, THEY SEEM TO BE 1384 00:55:42,360 --> 00:55:45,800 CLEARLY INNERVATED WITH SENSORY 1385 00:55:45,800 --> 00:55:47,680 NERVE FIBERS IN THE CONTEXT OF 1386 00:55:47,680 --> 00:55:48,520 THE LUNG. 1387 00:55:48,520 --> 00:55:49,960 AND SO TO UNDERSTAND HOW 1388 00:55:49,960 --> 00:55:55,520 IMPORTANT THE ROLE OF INN 1389 00:55:55,520 --> 00:55:58,760 INNERVATION WAS, WE CAME BACK TO 1390 00:55:58,760 --> 00:56:00,280 SPONTANEOUS SMALL CELL LUNG 1391 00:56:00,280 --> 00:56:02,520 CANCER MODEL WHEREBY THEY FORM 1392 00:56:02,520 --> 00:56:05,760 AFTER INHALATION OF THIS VIRUS 1393 00:56:05,760 --> 00:56:08,760 THEY CLEARLY FORM PRIMARY LUNG 1394 00:56:08,760 --> 00:56:15,440 TUMORS, THIS IS VERY CLEAR TUMOR 1395 00:56:15,440 --> 00:56:15,760 EVOLUTION. 1396 00:56:15,760 --> 00:56:17,960 WE WANTED TO TRACK THESE MICE 1397 00:56:17,960 --> 00:56:20,520 OVER TIME TO SEE HOW IT AFFECTED 1398 00:56:20,520 --> 00:56:21,640 OVERALL TUMOR GROWTH. 1399 00:56:21,640 --> 00:56:26,000 WHAT WE SAW AFTER 10 WEEKS POTE 1400 00:56:26,000 --> 00:56:28,320 VAGOTOMY WE SAW CLEAR 1401 00:56:28,320 --> 00:56:29,840 DISTINCTION AND DIFFERENCE 1402 00:56:29,840 --> 00:56:32,160 BETWEEN THE TUMOR SIZE IN THE 1403 00:56:32,160 --> 00:56:34,000 PRIMARY LUNG OF THESE MICE THAT 1404 00:56:34,000 --> 00:56:38,320 HAD UNDERGONE VAGOTOMY VERSUS 1405 00:56:38,320 --> 00:56:44,600 MICE SHAM MA LIPLAT -- MANIPULA. 1406 00:56:44,600 --> 00:56:48,120 WE CAN SEE THERE IS A PRIMARY 1407 00:56:48,120 --> 00:56:51,720 EFFECT IN THE PRIMARY TUMOR 1408 00:56:51,720 --> 00:56:52,000 BURDEN. 1409 00:56:52,000 --> 00:56:54,760 THE SHAM SURGERY WERE ENTIRE PLI 1410 00:56:54,760 --> 00:56:56,320 ENCAPSULATED THE TUMORS. 1411 00:56:56,320 --> 00:56:59,320 THE SHAM MANIPULATED MICE HAD 1412 00:56:59,320 --> 00:57:01,080 LITTLE TUMOR BURDEN IF ANY AT 1413 00:57:01,080 --> 00:57:01,280 ALL. 1414 00:57:01,280 --> 00:57:04,240 THAT WAS A STARK FINDING. 1415 00:57:04,240 --> 00:57:07,920 AND WITH THIS DIMINISHING OF THE 1416 00:57:07,920 --> 00:57:09,920 PRIMARY TUMOR BURDEN WHAT IS 1417 00:57:09,920 --> 00:57:13,080 VERY CLEAR IS THAT THE 1418 00:57:13,080 --> 00:57:14,400 METASTASES TO THE LIVER WAS 1419 00:57:14,400 --> 00:57:14,960 COMPLETELY GONE. 1420 00:57:14,960 --> 00:57:17,880 YOU CAN SEE HERE IN THE CONTROL 1421 00:57:17,880 --> 00:57:22,000 MICE YOU SEE THESE VERY CLEAR 1422 00:57:22,000 --> 00:57:25,640 LIVER MICE DISTINCT SIX-MONTH 1423 00:57:25,640 --> 00:57:26,480 TIMELINE. 1424 00:57:26,480 --> 00:57:28,680 EVERY MICE THAT UNDERWENT 1425 00:57:28,680 --> 00:57:38,120 VAGOTOMY WAS CLEAN, NO 1426 00:57:38,120 --> 00:57:39,480 METASTASES AND SURVIVAL. 1427 00:57:39,480 --> 00:57:44,080 THIS VAGAL INTEGRATION IS 1428 00:57:44,080 --> 00:57:45,880 CRITICAL TO SMALL CELL LUNG 1429 00:57:45,880 --> 00:57:46,920 CANCER PROGRESSION. 1430 00:57:46,920 --> 00:57:48,360 THERE IS A REAL POTENTIAL TO 1431 00:57:48,360 --> 00:57:51,160 HARNESS THE POWER OF THE NERVOUS 1432 00:57:51,160 --> 00:57:52,360 SYSTEM AND NEURAL INTERACTIONS 1433 00:57:52,360 --> 00:57:57,680 IN THE CONTEXT OF NOPT ON-- NOT 1434 00:57:57,680 --> 00:58:00,160 ONLY PRIMARY BUT SECONDARY TUMOR 1435 00:58:00,160 --> 00:58:00,560 GROWTH. 1436 00:58:00,560 --> 00:58:02,600 GOING FORWARD THAT IS NOT ONLY 1437 00:58:02,600 --> 00:58:04,240 THE BRAIN, BUT OTHER CANCERS 1438 00:58:04,240 --> 00:58:06,240 OUTSIDE OF THE CNS AS WELL. 1439 00:58:06,240 --> 00:58:07,480 MOVING FORWARD MY LAB IS 1440 00:58:07,480 --> 00:58:10,880 THINKING ABOUT UNDERSTANDING THE 1441 00:58:10,880 --> 00:58:13,080 MECHANISMS THAT DRIVE ACTIVITY 1442 00:58:13,080 --> 00:58:17,120 MEDIATED GROWTH IN BRAIN 1443 00:58:17,120 --> 00:58:18,560 METASTASES AND INTEGRATION AT 1444 00:58:18,560 --> 00:58:20,840 THE PRIMARY SITE AND PERIPHERAL 1445 00:58:20,840 --> 00:58:22,800 NERVOUS SYSTEM ROLE IN THE 1446 00:58:22,800 --> 00:58:24,560 DIRECT ACTION OF THE TUMOR AND 1447 00:58:24,560 --> 00:58:25,640 REMODELING THE MICROENVIRONMENT 1448 00:58:25,640 --> 00:58:29,600 AS A WHOLE AND HOW THE NERVOUS 1449 00:58:29,600 --> 00:58:31,400 SYSTEM MAY IMPACT THE IMMUNE 1450 00:58:31,400 --> 00:58:37,040 SYSTEM TO CREATE AND PRIME A 1451 00:58:37,040 --> 00:58:39,600 SPECIFIC ORGAN FROM MALIGNANT 1452 00:58:39,600 --> 00:58:39,840 OUTGROWTH. 1453 00:58:39,840 --> 00:58:45,320 WE HAVE STARTED STUDIES THINKING 1454 00:58:45,320 --> 00:58:47,000 ABOUT TUMORS SYSTEMICALLY. 1455 00:58:47,000 --> 00:58:51,160 WHAT HAS BEEN VERY CLEAR IS THAT 1456 00:58:51,160 --> 00:58:53,920 THINKING ABOUT THIS DISEASE AS A 1457 00:58:53,920 --> 00:58:57,800 HOLISTIC PERSPECTIVE AND 1458 00:58:57,800 --> 00:58:59,200 BIOLOGICAL SYSTEMS COMMUNICATE 1459 00:58:59,200 --> 00:59:00,600 WITH ONE ANOTHER IS VERY 1460 00:59:00,600 --> 00:59:02,160 IMPORTANT MOVING FORWARD. 1461 00:59:02,160 --> 00:59:04,600 I WILL END BY A PLUG FOR CANCER 1462 00:59:04,600 --> 00:59:05,960 NEUROSCIENCE AS A WHOLE. 1463 00:59:05,960 --> 00:59:07,800 THIS IS A VERY EXCITING NEW 1464 00:59:07,800 --> 00:59:08,000 FIELD. 1465 00:59:08,000 --> 00:59:10,680 THIS IS TAKEN FROM A REVIEW WE 1466 00:59:10,680 --> 00:59:13,640 JUST WROTE ILLUSTRATING A LOT OF 1467 00:59:13,640 --> 00:59:15,120 MECHANISMS THROUGH WHICH THE 1468 00:59:15,120 --> 00:59:16,920 NERVOUS SYSTEM HAS THE 1469 00:59:16,920 --> 00:59:21,560 CAPABILITY OF MODULATING 1470 00:59:21,560 --> 00:59:22,800 MALIGNANT GROWTH, DIRECT 1471 00:59:22,800 --> 00:59:25,720 INTERACTIONS I TALKED ABOUT 1472 00:59:25,720 --> 00:59:27,800 TODAY, AND SIGNALLING MECHANISMS 1473 00:59:27,800 --> 00:59:30,920 BETWEEN NERVES, TUMOR CELLS AND 1474 00:59:30,920 --> 00:59:33,280 OTHER CELLS IN THE TUMOR 1475 00:59:33,280 --> 00:59:33,680 MICROENVIRONMENT. 1476 00:59:33,680 --> 00:59:38,040 THE SYSTEMIC INTERACTIONS TO THE 1477 00:59:38,040 --> 00:59:39,360 WHOLE ACCESS OF NEURAL IMMUNE 1478 00:59:39,360 --> 00:59:40,600 INTERACTIONS THAT I THINK IS 1479 00:59:40,600 --> 00:59:43,720 GOING TO BE HUGE IN THE CONTEXT 1480 00:59:43,720 --> 00:59:47,680 OF NEURAL IMMUNOONCOLOGY. 1481 00:59:47,680 --> 00:59:49,640 WE CAN SEE THE ROLE THE NERVES 1482 00:59:49,640 --> 00:59:53,880 ARE PLAYING IN THIS ENVIRONMENT. 1483 00:59:53,880 --> 00:59:57,600 CANCER CELL INTRINSIC 1484 00:59:57,600 --> 00:59:58,680 ENVIRONMENT SHOW NEUROBIOLOGICAL 1485 00:59:58,680 --> 01:00:00,920 PROPERTIES THAT NEED TO BE 1486 01:00:00,920 --> 01:00:01,240 APPRECIATED. 1487 01:00:01,240 --> 01:00:03,640 I DIDN'T EVEN GET TO THIS LAST 1488 01:00:03,640 --> 01:00:05,360 PANEL THINKING ABOUT HOW CANCER 1489 01:00:05,360 --> 01:00:06,800 THERAPY AFFECTS THE NERVOUS 1490 01:00:06,800 --> 01:00:08,000 SYSTEM AS A WHOLE. 1491 01:00:08,000 --> 01:00:10,800 WE ARE FINDING THESE THERAPIES 1492 01:00:10,800 --> 01:00:14,320 CAN HAVE DEBILITATING EFFECTS ON 1493 01:00:14,320 --> 01:00:16,200 THE NERVOUS SYSTEM WITH 1494 01:00:16,200 --> 01:00:17,880 COGNITIVE DEFICITS AND THAT 1495 01:00:17,880 --> 01:00:19,840 PERHAPS MIGHT BE A WAY IN WHICH 1496 01:00:19,840 --> 01:00:22,560 THEY ARE INDIRECTLY AFFECTING 1497 01:00:22,560 --> 01:00:23,960 TUMOR GROWTH ESSENTIALLY 1498 01:00:23,960 --> 01:00:25,360 DEGRADING THE NERVOUS SYSTEM AS 1499 01:00:25,360 --> 01:00:26,280 A WHOLE. 1500 01:00:26,280 --> 01:00:31,200 LOOKING INTO THOSE MECHANISMS IS 1501 01:00:31,200 --> 01:00:32,480 IMPORTANT MOVING FORWARD 1502 01:00:32,480 --> 01:00:34,160 THINKING ABOUT THERAPIES AND 1503 01:00:34,160 --> 01:00:37,640 QUALITY OF LIFE FOR PATIENTS 1504 01:00:37,640 --> 01:00:39,600 GETTING TREATED WITH A NUMBER OF 1505 01:00:39,600 --> 01:00:40,560 DIFFERENT THERAPIES. 1506 01:00:40,560 --> 01:00:42,400 I WOULD LIKE TO END 1507 01:00:42,400 --> 01:00:43,400 ACKNOWLEDGING BY WONDERFUL LAB. 1508 01:00:43,400 --> 01:00:45,240 IT IS A TESTAMENT TO THESE 1509 01:00:45,240 --> 01:00:47,360 STUDENTS WHO HAVE TAKEN A CHANCE 1510 01:00:47,360 --> 01:00:50,160 ON A NEW PI. 1511 01:00:50,160 --> 01:00:53,240 MY COLLABORATORS. 1512 01:00:53,240 --> 01:00:54,600 I WOULD LIKE TO HIGHLIGHT A 1513 01:00:54,600 --> 01:00:56,600 MEDICAL STUDENT THAT DID A LOT 1514 01:00:56,600 --> 01:00:57,720 OF THIS MEDICAL WORK. 1515 01:00:57,720 --> 01:01:01,120 LE MICHELLE WHO IS A WONDERFUL 1516 01:01:01,120 --> 01:01:02,120 MENTOR AND COLLABORATOR 1517 01:01:02,120 --> 01:01:04,840 COLLEAGUE AND THE PATIENTS AND 1518 01:01:04,840 --> 01:01:06,320 FAMILIES WHOSE DONATIONS OF 1519 01:01:06,320 --> 01:01:08,000 WHICH I COULD NOT HAVE DONE ANY 1520 01:01:08,000 --> 01:01:09,000 OF THIS. 1521 01:01:09,000 --> 01:01:11,000 LAST BUT NOT LEAST THE MARTIN 1522 01:01:11,000 --> 01:01:13,960 WACHTEL FAMILY AND STM, AAAS AND 1523 01:01:13,960 --> 01:01:16,600 THE NCI TO ALLOW ME TO SHARE MY 1524 01:01:16,600 --> 01:01:18,800 WORK AND HIGHLIGHT THIS FIELD AS 1525 01:01:18,800 --> 01:01:19,640 A WHOLE. 1526 01:01:19,640 --> 01:01:21,840 I THINK IT IS GOING TO BE REALLY 1527 01:01:21,840 --> 01:01:23,520 IMPORTANT FOR MANY OF US MOVING 1528 01:01:23,520 --> 01:01:27,320 FORWARD SO THANK YOU SO MUCH. 1529 01:01:27,320 --> 01:01:37,480 [ APPLAUSE ] 1530 01:01:37,480 --> 01:01:39,320 >>SO THANK YOU AGAIN, DR. 1531 01:01:39,320 --> 01:01:41,040 VENKATESH, FOR SUCH AN AMAZING 1532 01:01:41,040 --> 01:01:41,760 TALK. 1533 01:01:41,760 --> 01:01:44,440 REALLY INTERESTING WORK AND JUST 1534 01:01:44,440 --> 01:01:46,160 FASCINATING NEW AND UPCOMING 1535 01:01:46,160 --> 01:01:46,560 FIELD. 1536 01:01:46,560 --> 01:01:48,680 SO WE HAVE ABOUT 15 MINUTES FOR 1537 01:01:48,680 --> 01:01:49,800 QUESTIONS THAT WE CAN TAKE. 1538 01:01:49,800 --> 01:01:50,680 >>HI. 1539 01:01:50,680 --> 01:01:51,640 BEAUTIFUL TALK. 1540 01:01:51,640 --> 01:01:52,120 >>THANK YOU. 1541 01:01:52,120 --> 01:01:54,800 >>YOU ALLUDED TO THIS IN YOUR 1542 01:01:54,800 --> 01:01:58,280 VERY LAST SLIDE, BUT I WANTED TO 1543 01:01:58,280 --> 01:02:00,520 ASK, IT IS WELL KNOWN OR HAS 1544 01:02:00,520 --> 01:02:01,400 BECOME RECENTLY KNOWN THERE ARE 1545 01:02:01,400 --> 01:02:03,240 A LOT OF INTERACTIONS BETWEEN 1546 01:02:03,240 --> 01:02:04,840 THE NERVOUS SYSTEM AND THE 1547 01:02:04,840 --> 01:02:05,600 IMMUNE SYSTEM. 1548 01:02:05,600 --> 01:02:06,640 >>ABSOLUTELY. 1549 01:02:06,640 --> 01:02:08,480 >>I WAS WONDERING HOW MUCH OF 1550 01:02:08,480 --> 01:02:10,680 WHAT YOU DESCRIBED IS DEPENDENT 1551 01:02:10,680 --> 01:02:12,960 ON EFFECTS ON THE IMMUNE SYSTEM 1552 01:02:12,960 --> 01:02:16,120 AS WELL AS SOME OF THE DIRECT 1553 01:02:16,120 --> 01:02:19,680 EFFECTS YOU SHOWED BY SYNAPSES 1554 01:02:19,680 --> 01:02:21,360 BETWEEN NERVES AND CANCER CELLS. 1555 01:02:21,360 --> 01:02:23,400 >>THAT IS A GREAT QUESTION, ONE 1556 01:02:23,400 --> 01:02:25,160 I THINK WE ARE ALL STILL TRYING 1557 01:02:25,160 --> 01:02:25,880 TO UNDERSTAND. 1558 01:02:25,880 --> 01:02:27,440 I THINK THE REALITY OF THE 1559 01:02:27,440 --> 01:02:29,320 SITUATION IS IT IS GOING TO BE 1560 01:02:29,320 --> 01:02:32,120 VERY TUMOR DEPENDENT AND VERY 1561 01:02:32,120 --> 01:02:33,640 PATIENT SPECIFIC PERHAPS. 1562 01:02:33,640 --> 01:02:36,760 WHAT WE KNOW NOW IS THE BROAD 1563 01:02:36,760 --> 01:02:38,880 OVERVIEW IS THIS IDEA THAT THE 1564 01:02:38,880 --> 01:02:39,920 NERVOUS SYSTEM CERTAINLY SHOULD 1565 01:02:39,920 --> 01:02:42,360 BE LOOKED AT AND THOUGHT ABOUT 1566 01:02:42,360 --> 01:02:44,240 IN THE TUMOR MICROENVIRONMENT, 1567 01:02:44,240 --> 01:02:45,640 NOT ONLY FOR DIRECT INTERACTIONS 1568 01:02:45,640 --> 01:02:49,360 WITH TUMOR CELLS, BUT THE REMOLD 1569 01:02:49,360 --> 01:02:51,080 ELS OF THE IMMUNE SYSTEM THAT 1570 01:02:51,080 --> 01:02:53,600 ARE IN THAT SPACE. 1571 01:02:53,600 --> 01:02:55,200 THERE HAVE BEEN BEAUTIFUL PAPERS 1572 01:02:55,200 --> 01:02:56,640 RECENTLY ILLUSTRATED THAT 1573 01:02:56,640 --> 01:02:59,200 SENSORY NEURONS PLAY A HUGE ROLE 1574 01:02:59,200 --> 01:03:02,800 IN CREATING THIS 1575 01:03:02,800 --> 01:03:03,920 IMMUNOSUPPRESSIVE 1576 01:03:03,920 --> 01:03:04,840 MICROENVIRONMENT SO ONCE YOUING 1577 01:03:04,840 --> 01:03:07,280 A ROW GAIT THE SENSORY NEURONS 1578 01:03:07,280 --> 01:03:15,520 YOU CAN REACTIVATE THE IMMUNE 1579 01:03:15,520 --> 01:03:15,720 SYSTEM. 1580 01:03:15,720 --> 01:03:17,960 HOW IMPORTANT THESE DIFFERENT 1581 01:03:17,960 --> 01:03:20,520 AXES ARE GOING TO BE IS VERY 1582 01:03:20,520 --> 01:03:23,440 HIGHLY DEPENDENT ON THE TISSUE 1583 01:03:23,440 --> 01:03:25,880 TYPE, THE GENETIC ABERRATIONS 1584 01:03:25,880 --> 01:03:26,920 SPECIFIC TO THAT TUMOR. 1585 01:03:26,920 --> 01:03:29,960 SUB POPULATIONS THERE IS SO MUCH 1586 01:03:29,960 --> 01:03:32,400 CELL LOU LAR PLASTICITY. 1587 01:03:32,400 --> 01:03:36,720 THERE MIGHT BE DIFFERENT AXES 1588 01:03:36,720 --> 01:03:38,960 TAKING THE REINS AND PRIMARY 1589 01:03:38,960 --> 01:03:39,160 FOCUS. 1590 01:03:39,160 --> 01:03:40,840 THERE IS A LOT TO BE UNDERSTOOD, 1591 01:03:40,840 --> 01:03:43,800 BUT I THINK ALL WE CAN SAY IS 1592 01:03:43,800 --> 01:03:45,760 ALL OF THESE DIFFERENT AXES NEED 1593 01:03:45,760 --> 01:03:47,120 TO BE STUDIED. 1594 01:03:47,120 --> 01:03:48,720 AS WE MOVE FORWARD WE MIGHT HAVE 1595 01:03:48,720 --> 01:03:50,360 A BETTER UNDERSTANDING OF WHEN 1596 01:03:50,360 --> 01:03:52,880 AND WHERE AND HOW WE COULD 1597 01:03:52,880 --> 01:03:54,520 TARGET THESE DIFFERENT 1598 01:03:54,520 --> 01:03:56,280 INTERACTIONS, NEURAL SUB 1599 01:03:56,280 --> 01:03:58,360 POPULATIONS AND AXES BASED ON 1600 01:03:58,360 --> 01:04:00,600 TUMOR TIME, STAGE, PROGRESSION, 1601 01:04:00,600 --> 01:04:02,280 TISSUE TYPE, PATIENT AND ALL OF 1602 01:04:02,280 --> 01:04:03,120 THAT. 1603 01:04:03,120 --> 01:04:03,920 >>OKAY. 1604 01:04:03,920 --> 01:04:06,680 ONE VERY SIMPLE WAY IS TO 1605 01:04:06,680 --> 01:04:08,720 COMPARE SOME OF YOUR XENOGRAFT 1606 01:04:08,720 --> 01:04:10,920 MODELS WHERE THERE IS NO IMMUNE 1607 01:04:10,920 --> 01:04:11,160 SYSTEM. 1608 01:04:11,160 --> 01:04:13,840 >>WE ARE DOING THAT RIGHT NOW. 1609 01:04:13,840 --> 01:04:15,200 >>WITH THE -- WHAT HAPPENS IN 1610 01:04:15,200 --> 01:04:16,080 THE INTACT MOUSE. 1611 01:04:16,080 --> 01:04:18,720 >>ABSOLUTELY. 1612 01:04:18,720 --> 01:04:18,960 ONGOING. 1613 01:04:18,960 --> 01:04:20,920 I WILL SOON HAVE DATA FOR YOU ON 1614 01:04:20,920 --> 01:04:21,760 THAT. 1615 01:04:21,760 --> 01:04:25,320 BUT, YEAH, I THINK ESPECIALLY 1616 01:04:25,320 --> 01:04:28,160 THE EFFECT IN THE PERIPHERY, WE 1617 01:04:28,160 --> 01:04:30,600 SEE IT IN SMALL CELL LUNG 1618 01:04:30,600 --> 01:04:30,840 CANCER. 1619 01:04:30,840 --> 01:04:34,360 OTHER PEOPLE HAVE SHOWN IT IN 1620 01:04:34,360 --> 01:04:36,000 GASTRIC CANCERS IS CERTAINLY 1621 01:04:36,000 --> 01:04:37,560 ALMOST GOING TO HAVE SOME IMMUNE 1622 01:04:37,560 --> 01:04:38,800 COMPONENT TO IT. 1623 01:04:38,800 --> 01:04:41,600 I BELIEVE THESE ELECTRICAL, 1624 01:04:41,600 --> 01:04:42,880 DIRECT ELECTRICAL COMMUNICATION 1625 01:04:42,880 --> 01:04:44,440 IS PLAYING SOME IMPORTANT ROLE, 1626 01:04:44,440 --> 01:04:46,200 WHETHER THAT IS NOT DIRECTLY 1627 01:04:46,200 --> 01:04:47,200 GROWTH PROMOTING OR WHETHER OR 1628 01:04:47,200 --> 01:04:48,440 NOT THAT IS TRANSITIONING IN 1629 01:04:48,440 --> 01:04:51,040 TERMS OF HELPING AS WE DISCUSSED 1630 01:04:51,040 --> 01:04:53,680 EARLIER, WHETHER THAT IS PERHAPS 1631 01:04:53,680 --> 01:04:56,240 SIGNALLING TO THE TUMOR CELLS TO 1632 01:04:56,240 --> 01:04:59,200 SHIFT AND MOVING THEM INTO A 1633 01:04:59,200 --> 01:05:01,880 DIFFERENT CELLULAR STATE TO 1634 01:05:01,880 --> 01:05:03,760 EVADE SPECIFIC THERAPIES WE ARE 1635 01:05:03,760 --> 01:05:04,840 NOT YET SURE BUT IMPORTANT TO 1636 01:05:04,840 --> 01:05:05,360 THINK ABOUT. 1637 01:05:05,360 --> 01:05:06,640 >>SURE. 1638 01:05:06,640 --> 01:05:07,200 >>THANK YOU. 1639 01:05:07,200 --> 01:05:08,800 >>REALLY AMAZING WORK. 1640 01:05:08,800 --> 01:05:10,760 I HAVE ONE QUESTION. 1641 01:05:10,760 --> 01:05:14,600 DO YOU THINK YOUR WORK INDICATE 1642 01:05:14,600 --> 01:05:16,560 THAT PEOPLE WHO GOT DEPRESSED 1643 01:05:16,560 --> 01:05:17,800 HAVE A HIGHER RISK OF GETTING 1644 01:05:17,800 --> 01:05:20,480 CANCER? 1645 01:05:20,480 --> 01:05:22,560 >>NO. 1646 01:05:22,560 --> 01:05:24,440 I THINK THAT -- I THINK THERE IS 1647 01:05:24,440 --> 01:05:25,920 NOT -- WE CAN'T SAY ENOUGH ABOUT 1648 01:05:25,920 --> 01:05:27,080 IT JUST YET, I THINK. 1649 01:05:27,080 --> 01:05:29,400 WE HAVE TO REALLY UNDERSTAND THE 1650 01:05:29,400 --> 01:05:30,480 MECHANISMS THROUGH WHICH ALL OF 1651 01:05:30,480 --> 01:05:31,840 THIS IS HAPPENING. 1652 01:05:31,840 --> 01:05:34,520 I DON'T THINK IT IS AS CLEAR AS 1653 01:05:34,520 --> 01:05:36,920 THERE HAVE BEEN EPIDEMIOLOGICAL 1654 01:05:36,920 --> 01:05:38,160 STUDIES TO UNDERSTAND WHETHER OR 1655 01:05:38,160 --> 01:05:42,840 NOT WE CAN DRAW SOME CORRELATION 1656 01:05:42,840 --> 01:05:44,280 BETWEEN DIFFERENT 1657 01:05:44,280 --> 01:05:46,280 NEURODEGENERATIVE DISEASES, 1658 01:05:46,280 --> 01:05:48,400 DIFFERENT BRAIN CANCER 1659 01:05:48,400 --> 01:05:49,040 MALIGNANCIES TO SEE WHETHER OR 1660 01:05:49,040 --> 01:05:51,120 NOT THE STATE OF THE BRAIN CAN 1661 01:05:51,120 --> 01:05:53,440 BE KIND OF -- INDICATE WHETHER 1662 01:05:53,440 --> 01:05:55,520 YOU ARE MORE SUSCEPTIBLE TO ONE 1663 01:05:55,520 --> 01:05:57,440 OR THE OTHER. 1664 01:05:57,440 --> 01:05:59,120 RETROSPECTIVE STUDIES THAT ARE 1665 01:05:59,120 --> 01:06:00,760 NOT THE CLEANEST OF DATA SETS. 1666 01:06:00,760 --> 01:06:02,440 I THINK THERE ARE SOME VERY 1667 01:06:02,440 --> 01:06:04,120 INTERESTING STUDIES COMING OUT 1668 01:06:04,120 --> 01:06:06,800 THAT SUGGEST IF YOU ARE PRONE TO 1669 01:06:06,800 --> 01:06:10,200 SOME TYPE OF NEURODEGENERATIVE 1670 01:06:10,200 --> 01:06:12,120 DISEASES CAN BE PROTECTIVE 1671 01:06:12,120 --> 01:06:12,680 AGAINST CANCERS. 1672 01:06:12,680 --> 01:06:14,560 WE HAVE TO UNDERSTAND THE 1673 01:06:14,560 --> 01:06:15,720 DISTINCT MECHANISMS TO 1674 01:06:15,720 --> 01:06:16,760 UNDERSTAND IF THAT IS GOING TO 1675 01:06:16,760 --> 01:06:18,520 BE TRUE AND ALSO REALLY 1676 01:06:18,520 --> 01:06:20,000 SPECIFICALLY THINK ABOUT, AGAIN, 1677 01:06:20,000 --> 01:06:22,160 THIS IS GOING TO BE CONTEXT 1678 01:06:22,160 --> 01:06:26,440 SPECIFIC TO SPECIFIC N F1 TUMORS 1679 01:06:26,440 --> 01:06:28,800 OR P # 50 TUMORS. 1680 01:06:28,800 --> 01:06:30,480 ELECTRICAL ABERRATIONS WILL PLAY 1681 01:06:30,480 --> 01:06:32,400 A CRITICAL ROLE IN THIS 1682 01:06:32,400 --> 01:06:33,200 UNDERSTANDING AS WELL. 1683 01:06:33,200 --> 01:06:36,720 >>IT WAS SUCH AN EXCITING TALK. 1684 01:06:36,720 --> 01:06:39,640 I HAD A SIMILAR QUESTION GIVEN 1685 01:06:39,640 --> 01:06:44,200 NONNEURONAL CELLS CAN EXPRESS 1686 01:06:44,200 --> 01:06:45,960 AMPA RECEPTORS. 1687 01:06:45,960 --> 01:06:48,040 MY SECOND QUESTION WAS THAT YOU 1688 01:06:48,040 --> 01:06:51,200 MENTIONED THAT THE SMALL CELL 1689 01:06:51,200 --> 01:06:55,200 LUNG CANCER MIGHT HAVE A NEURAL 1690 01:06:55,200 --> 01:06:55,640 ENDOCRINE BACKGROUND. 1691 01:06:55,640 --> 01:06:59,400 I WONDER IF THERE WAS EVIDENCE 1692 01:06:59,400 --> 01:07:06,080 PERIPHERAL TUMORS MORE LILY 1693 01:07:06,080 --> 01:07:07,960 INNERVATED HAD SELECTIVE 1694 01:07:07,960 --> 01:07:13,840 ADVANTAGE FOR BRAIN METATASES. 1695 01:07:13,840 --> 01:07:15,360 >>THAT IS ONGOING. 1696 01:07:15,360 --> 01:07:16,560 IT DOESN'T LOOK LIKE THEY ARE 1697 01:07:16,560 --> 01:07:18,240 SPECIFIC TO THE BRAIN, BUT THERE 1698 01:07:18,240 --> 01:07:20,160 ARE SPECIFIC SUB POPULATIONS OF 1699 01:07:20,160 --> 01:07:23,200 THESE TUMORS RELYING UPON NEURAL 1700 01:07:23,200 --> 01:07:24,240 INPUT. 1701 01:07:24,240 --> 01:07:25,720 THE BRAIN HAS A VERY SPECIFIC 1702 01:07:25,720 --> 01:07:28,000 POPULATION OF NEURONS. 1703 01:07:28,000 --> 01:07:29,640 MY HYPOTHESIS WOULD BE MELANOMAS 1704 01:07:29,640 --> 01:07:32,000 AND LUNG CANCERS AND BREAST 1705 01:07:32,000 --> 01:07:37,320 CANCERS SEEM TO DERIVE THESE 1706 01:07:37,320 --> 01:07:38,600 INPUTS AND THEREFORE ALLOW 1707 01:07:38,600 --> 01:07:39,880 THEMSELVES TO THRIVE IN THE 1708 01:07:39,880 --> 01:07:40,480 BRAIN. 1709 01:07:40,480 --> 01:07:42,920 THINGS LIKE THE PANCREATIC 1710 01:07:42,920 --> 01:07:45,360 CANCER AND PROSTATE CANCERS MAY 1711 01:07:45,360 --> 01:07:50,920 BE MORE RELIANT UPON ADONERGI 1712 01:07:50,920 --> 01:07:56,520 KRRK SIGNALLING AND TEND TO -- A 1713 01:07:56,520 --> 01:07:58,600 LOT OF THIS IS NEURAL POPULATION 1714 01:07:58,600 --> 01:08:00,600 SPECIFIC AND TISSUE SPECIFIC. 1715 01:08:00,600 --> 01:08:01,640 TEASING THOSE APART ARE GOING TO 1716 01:08:01,640 --> 01:08:03,240 BE VERY, VERY DIFFICULT, BUT 1717 01:08:03,240 --> 01:08:04,840 VERY FASCINATING AND I THINK WE 1718 01:08:04,840 --> 01:08:07,200 ARE ON OUR WAY TO DOING THAT. 1719 01:08:07,200 --> 01:08:10,360 WE HAVE GENETIC MODELS TO PROBE 1720 01:08:10,360 --> 01:08:11,480 DIFFERENT SUB POPULATIONS. 1721 01:08:11,480 --> 01:08:14,320 WE ARE ACTIVELY DOING A LOT OF 1722 01:08:14,320 --> 01:08:16,040 SYNAPTIC TRACING TO UNDERSTAND 1723 01:08:16,040 --> 01:08:19,880 WHAT SUB POPULATIONS ARE 1724 01:08:19,880 --> 01:08:20,120 IMPORTANT. 1725 01:08:20,120 --> 01:08:22,080 THAT SHOULD GIVE US A MORE CLEAR 1726 01:08:22,080 --> 01:08:23,840 UNDERSTANDING OF WHICH 1727 01:08:23,840 --> 01:08:25,240 POPULATIONS TO TARGET, BUT THAT 1728 01:08:25,240 --> 01:08:26,760 TAKES ME TO YOUR FIRST QUESTION, 1729 01:08:26,760 --> 01:08:30,680 AS I MENTIONED, I THINK WE 1730 01:08:30,680 --> 01:08:31,600 HAVEN'T APPRECIATED THE NERVOUS 1731 01:08:31,600 --> 01:08:33,880 SYSTEM NOT ONLY IN THE CONTEXT 1732 01:08:33,880 --> 01:08:36,720 OF MALIGNANT CANCERS BUT A LOT 1733 01:08:36,720 --> 01:08:39,360 OF NONNEURONAL CELL TYPES. 1734 01:08:39,360 --> 01:08:40,920 THIS NEURAL ACCESS IS A HOT 1735 01:08:40,920 --> 01:08:43,280 TOPIC AND A LOT OF NOT ONLY 1736 01:08:43,280 --> 01:08:45,080 DISEASE PATHOLOGIES BUT IN 1737 01:08:45,080 --> 01:08:46,200 NORMAL DEVELOPMENT AND 1738 01:08:46,200 --> 01:08:47,440 UNDERSTANDING HOW DO THESE 1739 01:08:47,440 --> 01:08:52,560 IMMUNE CELLS, FINE RO BLASTS, 1740 01:08:52,560 --> 01:08:54,720 MACROFAGES, HOW ARE THEY 1741 01:08:54,720 --> 01:08:57,000 RESPONDING TO THESE 1742 01:08:57,000 --> 01:08:57,600 NEUROTRANSMITTERS? 1743 01:08:57,600 --> 01:08:59,040 THEY ARE INDEED RESPONDING. 1744 01:08:59,040 --> 01:09:00,320 UNDERSTANDING HOW THAT SHAPING 1745 01:09:00,320 --> 01:09:01,720 THE MICROENVIRONMENT IS GOING TO 1746 01:09:01,720 --> 01:09:03,400 BE VERY INTERESTING AND THAT IS 1747 01:09:03,400 --> 01:09:06,640 ANOTHER REASON WHY QUESTION NEED 1748 01:09:06,640 --> 01:09:10,760 TO RECIPROCALLY UNDERSTAND THE 1749 01:09:10,760 --> 01:09:11,120 ACTIVITY. 1750 01:09:11,120 --> 01:09:13,360 IT SEEMS THE NEURONAL ACTIVITY 1751 01:09:13,360 --> 01:09:14,600 IS CHANGES. 1752 01:09:14,600 --> 01:09:17,280 IS THE MAKEUP OF THE NEURONS 1753 01:09:17,280 --> 01:09:17,560 DIFFERENT? 1754 01:09:17,560 --> 01:09:19,400 ARE THEY BEING ACTIVATED IN A 1755 01:09:19,400 --> 01:09:20,960 DIFFERENT WAY? 1756 01:09:20,960 --> 01:09:22,760 ARE THEIR FREQUENCY PATTERNS 1757 01:09:22,760 --> 01:09:23,040 DIFFERENT? 1758 01:09:23,040 --> 01:09:24,960 THAT IS UNKNOWN SO THAT IS 1759 01:09:24,960 --> 01:09:26,200 EXCITING TO THINK ABOUT MOVING 1760 01:09:26,200 --> 01:09:26,600 FORWARD. 1761 01:09:26,600 --> 01:09:28,560 >>IT IS REALLY EXCITING. 1762 01:09:28,560 --> 01:09:29,680 THANK YOU. 1763 01:09:29,680 --> 01:09:31,120 >>THANK YOU. 1764 01:09:31,120 --> 01:09:32,160 >>FASCINATING TALK. 1765 01:09:32,160 --> 01:09:35,040 I HAVE A QUESTION ABOUT THE GAP 1766 01:09:35,040 --> 01:09:36,080 JUNCTION DATA YOU SHOWED. 1767 01:09:36,080 --> 01:09:37,000 >>SURE. 1768 01:09:37,000 --> 01:09:38,520 >>IT IS VERY STRIKING. 1769 01:09:38,520 --> 01:09:42,640 I AM WONDERING IF I REMEMBER 1770 01:09:42,640 --> 01:09:44,640 CORRECTLY, GENETICALLY YOU 1771 01:09:44,640 --> 01:09:47,120 BLOCKED A GAP JUNCTION ACTIVITY. 1772 01:09:47,120 --> 01:09:53,680 I'M WONDERING IF PHARMACOLOGY 1773 01:09:53,680 --> 01:09:54,600 GET NEW DROP? 1774 01:09:54,600 --> 01:09:56,160 >>YEAH. 1775 01:09:56,160 --> 01:10:03,280 WE USED METHROPHENATE AND CBX 1776 01:10:03,280 --> 01:10:05,240 WHICH ARE INHIBITORS. 1777 01:10:05,240 --> 01:10:07,000 A LOT OF THE GAP JUNCTION 1778 01:10:07,000 --> 01:10:08,360 INHIBITORS IS THEY ARE VERY 1779 01:10:08,360 --> 01:10:08,640 DIRTY. 1780 01:10:08,640 --> 01:10:10,800 WE HAVE USED THOSE AND SEE A 1781 01:10:10,800 --> 01:10:11,800 STARK EFFECT. 1782 01:10:11,800 --> 01:10:14,880 SO I THINK THEY ARE AND I THINK 1783 01:10:14,880 --> 01:10:18,240 IN GERMANY, THEY HAVE A TRIAL 1784 01:10:18,240 --> 01:10:20,480 TRYING TO COMBINE THE DRUG WITH 1785 01:10:20,480 --> 01:10:23,080 OTHER NEUROMODULATED AGENTS TO 1786 01:10:23,080 --> 01:10:24,680 TREAT GLIOMAS FOR THIS REASON. 1787 01:10:24,680 --> 01:10:26,880 THAT WILL BE EXCITING DATA TO 1788 01:10:26,880 --> 01:10:28,080 SEE HOW THAT COMES OUT. 1789 01:10:28,080 --> 01:10:29,880 WHAT WE KNOW IS THE GAP 1790 01:10:29,880 --> 01:10:31,560 JUNCTIONS ARE CLEARLY PLAYING A 1791 01:10:31,560 --> 01:10:33,280 ROLE, HOW TO TARGET THEM I THINK 1792 01:10:33,280 --> 01:10:34,520 IS UP FOR DEBATE BECAUSE THERE 1793 01:10:34,520 --> 01:10:35,840 IS A LOT OF CONTROVERSY AS TO 1794 01:10:35,840 --> 01:10:38,120 THE SPECIFICITY OF THE CURRENTLY 1795 01:10:38,120 --> 01:10:39,760 AVAILABLE INHIBITORS. 1796 01:10:39,760 --> 01:10:40,480 >>THANK YOU. 1797 01:10:40,480 --> 01:10:41,280 >>OVER HERE. 1798 01:10:41,280 --> 01:10:44,080 >>THANKS FOR A GREAT TALK. 1799 01:10:44,080 --> 01:10:46,000 I HAVE A VERY BASIC BIOLOGY 1800 01:10:46,000 --> 01:10:46,600 QUESTION. 1801 01:10:46,600 --> 01:10:47,880 IS THERE ANY ASSOCIATION BETWEEN 1802 01:10:47,880 --> 01:10:50,000 ANY OF YOUR MEASUREMENTS AND 1803 01:10:50,000 --> 01:10:53,760 WHERE THE MICE ARE IN THEIR 1804 01:10:53,760 --> 01:10:55,200 SLEEP/WAKE CYCLE? 1805 01:10:55,200 --> 01:10:56,880 >>AWESOME QUESTION. 1806 01:10:56,880 --> 01:10:58,520 BECAUSE LUCKILY FOR ME WHEN I 1807 01:10:58,520 --> 01:11:02,080 WAS DOING THIS A POSTDOC WAS 1808 01:11:02,080 --> 01:11:07,800 INTERESTED IN CIRCADIAN CYCLE. 1809 01:11:07,800 --> 01:11:09,960 I CAN'T TELL YOU IF THERE IS 1810 01:11:09,960 --> 01:11:10,200 DIFFERENT. 1811 01:11:10,200 --> 01:11:13,240 WE HAVE TIMED OUR EXPERIMENTS TO 1812 01:11:13,240 --> 01:11:14,640 BE MORNING EXPERIMENTS. 1813 01:11:14,640 --> 01:11:16,600 WE CONTROLLED FOR IT. 1814 01:11:16,600 --> 01:11:17,600 I'M NOT SURE. 1815 01:11:17,600 --> 01:11:27,040 AS YOU KNOW, THIS IDEA OF TIMING 1816 01:11:27,040 --> 01:11:28,120 CHEMOTHERAPIES IS BECOMING A 1817 01:11:28,120 --> 01:11:29,280 VERY HOT TOPIC. 1818 01:11:29,280 --> 01:11:30,800 I ENVISION THIS MIGHT BE 1819 01:11:30,800 --> 01:11:31,080 IMPORTANT. 1820 01:11:31,080 --> 01:11:34,920 MY COLLEAGUE IS ACTUALLY, YOU 1821 01:11:34,920 --> 01:11:36,880 KNOW, HAS FOUND HER LAB ON HER 1822 01:11:36,880 --> 01:11:38,960 OWN AND FOUND THESE PRECURSOR 1823 01:11:38,960 --> 01:11:41,800 CELLS THEMSELVES HAVE A VERY -- 1824 01:11:41,800 --> 01:11:44,160 RESPOND VERY ROBUSTLY TO 1825 01:11:44,160 --> 01:11:46,000 NEURONAL INPUT BASED UPON THE 1826 01:11:46,000 --> 01:11:47,240 TIME OF DAY. 1827 01:11:47,240 --> 01:11:49,960 AND SO GLIOMA CELLS THINKING 1828 01:11:49,960 --> 01:11:51,720 ABOUT NORMAL DEVELOPMENT IT IS A 1829 01:11:51,720 --> 01:11:53,800 HIGH POSSIBILITY THEY SIMILARLY 1830 01:11:53,800 --> 01:11:55,760 RESPOND BASED ON THE TIME OF 1831 01:11:55,760 --> 01:11:55,920 DAY. 1832 01:11:55,920 --> 01:11:57,720 WE HAVE NOT TESTED THE 1833 01:11:57,720 --> 01:11:58,040 HYPOTHESIS. 1834 01:11:58,040 --> 01:11:59,600 >>WHAT WOULD BE THE 1835 01:11:59,600 --> 01:12:00,800 IMPLICATIONS FOR SCHEDULING 1836 01:12:00,800 --> 01:12:01,040 TREATMENT? 1837 01:12:01,040 --> 01:12:02,920 >>I COULDN'T TELL YOU UNTIL I 1838 01:12:02,920 --> 01:12:05,000 FOUND OUT EXACTLY AT WHICH POINT 1839 01:12:05,000 --> 01:12:08,320 IN TIME I FELT THE NEURAL 1840 01:12:08,320 --> 01:12:09,720 ACTIVITY WAS PLAYING AN 1841 01:12:09,720 --> 01:12:10,480 IMPORTANT ROLE. 1842 01:12:10,480 --> 01:12:12,520 AT WHICH POINT WAS IT HAVING ITS 1843 01:12:12,520 --> 01:12:13,640 BIGGEST EFFECT. 1844 01:12:13,640 --> 01:12:14,920 WE HAVE DONE OUR EXPERIMENTS 1845 01:12:14,920 --> 01:12:15,880 LARGELY IN THE MORNING TO 1846 01:12:15,880 --> 01:12:17,680 CONTROL FOR THAT, BUT WE DON'T 1847 01:12:17,680 --> 01:12:20,360 KNOW, WOULD IT BE A MORE DRASTIC 1848 01:12:20,360 --> 01:12:22,840 EFFECT OR LESS DRASTIC EFFECT AT 1849 01:12:22,840 --> 01:12:24,960 A DIFFERENT PHASE IN THE MOUSE 1850 01:12:24,960 --> 01:12:25,240 CYCLE. 1851 01:12:25,240 --> 01:12:26,800 WHETHER OR NOT THAT CORRELATES 1852 01:12:26,800 --> 01:12:28,720 TO THE HUMAN CYCLE IS A WHOLE 1853 01:12:28,720 --> 01:12:29,840 OTHER QUESTION SO WE HAVE A LOT 1854 01:12:29,840 --> 01:12:31,480 OF TESTING TO DO. 1855 01:12:31,480 --> 01:12:34,800 THAT COULD BE VERY EASILY TO DO 1856 01:12:34,800 --> 01:12:37,080 ON EEGs IN PATIENTS. 1857 01:12:37,080 --> 01:12:38,840 IT IS A TESTABLE HYPOTHESIS. 1858 01:12:38,840 --> 01:12:40,280 >>AND WE'LL TAKE THE LAST 1859 01:12:40,280 --> 01:12:40,720 QUESTION HERE. 1860 01:12:40,720 --> 01:12:41,920 >>GREAT TALK. 1861 01:12:41,920 --> 01:12:44,040 SO MY QUESTION IS MORE 1862 01:12:44,040 --> 01:12:46,480 CLINICALLY BASED AND ONE OF THE 1863 01:12:46,480 --> 01:12:48,720 CHARACTERISTICS OF MALIGNANT 1864 01:12:48,720 --> 01:12:50,320 GLIOMA IS THEY DON'T SPREAD 1865 01:12:50,320 --> 01:12:50,640 SYSTEMICALLY. 1866 01:12:50,640 --> 01:12:51,240 >>MM-HMM. 1867 01:12:51,240 --> 01:12:55,080 >>BASED ON YOUR DATA, VERY 1868 01:12:55,080 --> 01:12:57,400 COMPELLING THAT THEY SEEM TO 1869 01:12:57,400 --> 01:13:00,480 THRIVE IN BRAIN AND NERVOUS 1870 01:13:00,480 --> 01:13:00,720 TISSUE. 1871 01:13:00,720 --> 01:13:04,560 WHAT HAPPENS OR WHAT WOULD YOU 1872 01:13:04,560 --> 01:13:07,080 SPECULATE WOULD HAPPEN IF YOU DO 1873 01:13:07,080 --> 01:13:09,680 MODULATE THAT AND YOU DO -- I 1874 01:13:09,680 --> 01:13:11,680 MEAN, YOU DON'T CURE THE ANIMALS 1875 01:13:11,680 --> 01:13:13,400 BUT PROLONG SURVIVAL AND WHAT 1876 01:13:13,400 --> 01:13:16,440 ARISES SEEMS TO BE GLIOMA CELLS 1877 01:13:16,440 --> 01:13:19,520 THAT DON'T REQUIRE THE NEURONAL 1878 01:13:19,520 --> 01:13:19,720 INPUT. 1879 01:13:19,720 --> 01:13:24,560 ARE YOU CHANGING THE CANCER 1880 01:13:24,560 --> 01:13:24,800 BIOLOGY? 1881 01:13:24,800 --> 01:13:28,200 WOULD YOU SAY THAT SYSTEMIC 1882 01:13:28,200 --> 01:13:30,160 METATASES WOULD OCCUR? 1883 01:13:30,160 --> 01:13:33,000 WE KNOW GLIOMA CELLS GET INTO 1884 01:13:33,000 --> 01:13:33,600 CIRCULATION. 1885 01:13:33,600 --> 01:13:35,240 THEY ARE HARD TO FIND, BUT THEY 1886 01:13:35,240 --> 01:13:35,920 ARE THERE. 1887 01:13:35,920 --> 01:13:37,440 THEY JUST CAN'T FIND THE RIGHT 1888 01:13:37,440 --> 01:13:37,640 SOIL. 1889 01:13:37,640 --> 01:13:38,240 >>RIGHT. 1890 01:13:38,240 --> 01:13:40,000 >>ANY THOUGHTS ABOUT THAT 1891 01:13:40,000 --> 01:13:42,920 MECHANISM OF RESISTANCE AND WHAT 1892 01:13:42,920 --> 01:13:45,240 IT WOULD IMPLY AS WE MOVE 1893 01:13:45,240 --> 01:13:48,280 FORWARD INTO CLINICAL TESTING. 1894 01:13:48,280 --> 01:13:49,720 >>IT IS AN INTERESTING 1895 01:13:49,720 --> 01:13:50,600 QUESTION. 1896 01:13:50,600 --> 01:13:52,920 SO I THINK THAT, YOU KNOW, THE 1897 01:13:52,920 --> 01:13:54,400 BRAIN, THE ONLY WAY FOR ME TO 1898 01:13:54,400 --> 01:13:56,040 ANSWER THAT QUESTION IS THE 1899 01:13:56,040 --> 01:13:57,840 BRAIN MICROENVIRONMENT IS 1900 01:13:57,840 --> 01:13:59,160 OBVIOUSLY VERY, VERY SPECIFIC. 1901 01:13:59,160 --> 01:14:01,200 IT HAS ONE LARGE COMPONENT OF IT 1902 01:14:01,200 --> 01:14:04,600 IS THESE NEURONS AND NEURONAL 1903 01:14:04,600 --> 01:14:06,400 INPUTS THAT ARE IMPORTANT TO 1904 01:14:06,400 --> 01:14:06,760 DISEASE BIOLOGY. 1905 01:14:06,760 --> 01:14:09,240 BUT THERE IS ALSO SO MANY MORE 1906 01:14:09,240 --> 01:14:10,640 VERY BRAIN SPECIFIC CELLS THAT 1907 01:14:10,640 --> 01:14:12,080 ARE HIGHLY SUPPORTIVE AND I 1908 01:14:12,080 --> 01:14:16,600 THINK THAT CREATES THIS NICHE 1909 01:14:16,600 --> 01:14:19,920 THAT ALLOWS THESE TUMOR CELLS TO 1910 01:14:19,920 --> 01:14:20,400 THRIVE. 1911 01:14:20,400 --> 01:14:23,640 UNDERSTANDING A BETTER WAY TO 1912 01:14:23,640 --> 01:14:25,920 UNDERSTAND THIS QUESTION OF 1913 01:14:25,920 --> 01:14:27,360 RELIANCE UPON SEED VERSUS SOIL 1914 01:14:27,360 --> 01:14:29,000 IS ACTUALLY PROBABLY THINKING 1915 01:14:29,000 --> 01:14:30,360 ABOUT THE OTHER CELL TYPES FROM 1916 01:14:30,360 --> 01:14:32,160 THE PERIPHERY THAT CAN GET INTO 1917 01:14:32,160 --> 01:14:33,120 THE BRAIN. 1918 01:14:33,120 --> 01:14:35,800 TO REALLY UNDERSTAND HOW, WHAT 1919 01:14:35,800 --> 01:14:38,120 MIGHT BE HAPPENING THERE. 1920 01:14:38,120 --> 01:14:40,800 THERE ARE U87, DIFFERENT MODELS 1921 01:14:40,800 --> 01:14:43,760 OF GLIOMAS OUT THERE PERPETUATED 1922 01:14:43,760 --> 01:14:45,320 FOR YEARS AND YEARS AND YEARS 1923 01:14:45,320 --> 01:14:48,200 THAT HAVE DEVELOPED SO MANY 1924 01:14:48,200 --> 01:14:50,080 MUTATIONS YOU CAN INJECT IN A 1925 01:14:50,080 --> 01:14:51,640 MOUSE THEY WILL GROW. 1926 01:14:51,640 --> 01:14:53,120 I DON'T THINK THOSE CELLS ARE 1927 01:14:53,120 --> 01:14:55,240 ANY LONGER RELIANT UPON THIS 1928 01:14:55,240 --> 01:14:56,240 NEURONAL INPUT. 1929 01:14:56,240 --> 01:14:58,040 THEY HAVE ENOUGH MUTATIONS TO 1930 01:14:58,040 --> 01:14:59,920 SURVIVE ON THEIR OWN AND 1931 01:14:59,920 --> 01:15:02,400 OVERRIDE ANY OF THESE EXTERNAL 1932 01:15:02,400 --> 01:15:02,680 CUES. 1933 01:15:02,680 --> 01:15:06,600 I THINK, YOU KNOW, UNDERSTANDING 1934 01:15:06,600 --> 01:15:08,800 EXACTLY THE DIFFERENT CELLULAR 1935 01:15:08,800 --> 01:15:10,720 POPULATIONS AND INPUTS FROM 1936 01:15:10,720 --> 01:15:12,760 OTHER CELL, OTHER MALIGNANCIES 1937 01:15:12,760 --> 01:15:14,680 IN THE BODY THAT ALLOW THEM TO 1938 01:15:14,680 --> 01:15:16,200 THRIVE WITHIN THE BRAIN MAY GIVE 1939 01:15:16,200 --> 01:15:19,200 US INSIGHT INTO THE CELLULAR SUB 1940 01:15:19,200 --> 01:15:20,960 POPULATIONS AND UP REGULATION OF 1941 01:15:20,960 --> 01:15:26,880 SPECIFIC RECEPTORS THAT DO ALLOW 1942 01:15:26,880 --> 01:15:27,200 METASTASES. 1943 01:15:27,200 --> 01:15:29,120 HOW DO WE STOP THE SPREAD OF THE 1944 01:15:29,120 --> 01:15:30,720 DISEASE BECAUSE THAT IS WHAT 1945 01:15:30,720 --> 01:15:32,560 ULTIMATELY KILLS THESE PATIENTS. 1946 01:15:32,560 --> 01:15:35,240 THIS IS A SEED-AND-SOIL QUESTION 1947 01:15:35,240 --> 01:15:37,880 AND PREVENT THESE CELLS FROM 1948 01:15:37,880 --> 01:15:39,120 KIND OF GAINING THE ABILITY TO 1949 01:15:39,120 --> 01:15:43,040 THRIVE IN A COMPLETELY DIFFERENT 1950 01:15:43,040 --> 01:15:45,600 ORGAN WILL BASEBALL TO STOP THAT 1951 01:15:45,600 --> 01:15:46,000 SUSCEPTIBILITY. 1952 01:15:46,000 --> 01:15:47,600 THE NERVOUS SYSTEM IS LIKELY ONE 1953 01:15:47,600 --> 01:15:48,880 COMPONENT OF THAT. 1954 01:15:48,880 --> 01:15:51,040 THERE ARE OTHER TISSUE SPECIFIC 1955 01:15:51,040 --> 01:15:52,840 INTERACTIONS WE LIKELY NEED TO 1956 01:15:52,840 --> 01:15:53,720 TARGET AND THINK ABOUT. 1957 01:15:53,720 --> 01:15:56,080 IT COMES BACK TO THINKING ABOUT 1958 01:15:56,080 --> 01:15:58,880 THESE CANCERS VERY HOLISTICALLY. 1959 01:15:58,880 --> 01:16:00,000 I DON'T KNOW IF THAT ANSWERS 1960 01:16:00,000 --> 01:16:00,400 YOUR QUESTION? 1961 01:16:00,400 --> 01:16:02,560 >>AS A CLINICAL INVESTIGATOR, 1962 01:16:02,560 --> 01:16:04,520 WE ARE ALWAYS CONCERNED AND 1963 01:16:04,520 --> 01:16:05,600 THERE IS A NATURAL EXPERIMENT 1964 01:16:05,600 --> 01:16:07,200 THAT HAS GONE ON FOR DECADES 1965 01:16:07,200 --> 01:16:16,120 WHICH IS WHEN PATIENTS WITH 1966 01:16:16,120 --> 01:16:21,120 GLIOMA DEVELOP HYDROCEPHALIS AND 1967 01:16:21,120 --> 01:16:22,240 SHUNTING CELL. 1968 01:16:22,240 --> 01:16:24,680 AT AUTOPSY YOU DON'T FIND TUMOR 1969 01:16:24,680 --> 01:16:24,920 MASSES. 1970 01:16:24,920 --> 01:16:27,200 YOU FIND TINY NODULES OF CANCER. 1971 01:16:27,200 --> 01:16:28,080 THEY JUST CAN'T THRIVE. 1972 01:16:28,080 --> 01:16:28,960 >>RIGHT. 1973 01:16:28,960 --> 01:16:32,080 >>I WONDER HOW MUCH OF THAT IS 1974 01:16:32,080 --> 01:16:33,960 THE SOIL AND WHETHER CHANGING IT 1975 01:16:33,960 --> 01:16:37,960 MAKES THEM MORE ADAPTABLE, BUT 1976 01:16:37,960 --> 01:16:38,720 WE'LL KNOW. 1977 01:16:38,720 --> 01:16:40,240 IT WOULD BE INTERESTING TO SEE 1978 01:16:40,240 --> 01:16:47,200 WHEN WE START DOING THE CLINICAL 1979 01:16:47,200 --> 01:16:49,880 WORK, WHEN PATIENTS GET THESE 1980 01:16:49,880 --> 01:16:52,080 THERAPIES WHAT THEIR TUMOR LOOKS 1981 01:16:52,080 --> 01:16:53,520 LIKE AND HOW THEY HAVE CHANGED. 1982 01:16:53,520 --> 01:16:54,800 >>YEAH. 1983 01:16:54,800 --> 01:16:55,200 ABSOLUTELY. 1984 01:16:55,200 --> 01:16:56,640 THE ONE THING THAT IS VERY 1985 01:16:56,640 --> 01:16:58,560 CLEAR, IF YOU TAKE ANY 1986 01:16:58,560 --> 01:17:00,400 SEQUENCING FROM PATIENTS THAT 1987 01:17:00,400 --> 01:17:04,480 HAVE DEVELOPED BRAIN METS THERE 1988 01:17:04,480 --> 01:17:06,840 ASTASES AND COMPARE TO PRIMARY 1989 01:17:06,840 --> 01:17:08,800 TISSUE, ACROSS THE BOARD THEY 1990 01:17:08,800 --> 01:17:12,120 SEEM TO UP REGULATE ION CHANNEL 1991 01:17:12,120 --> 01:17:13,320 RECEPTORS THAT ALLOW THEM TO 1992 01:17:13,320 --> 01:17:14,160 THRIVE IN THE BRAIN. 1993 01:17:14,160 --> 01:17:16,040 WE PROBED FOR THE 1994 01:17:16,040 --> 01:17:18,400 NEUROTRANSMITTER RECEPTORS BUT 1995 01:17:18,400 --> 01:17:23,960 IN TERMS OF SPECIFIC MICROGLIAL 1996 01:17:23,960 --> 01:17:25,120 CUES OR OTHER CELLS. 1997 01:17:25,120 --> 01:17:27,600 THEY ARE PLASTIC CELLS AND 1998 01:17:27,600 --> 01:17:29,040 ADAPTS IN AN IMPORTANT WAY AND 1999 01:17:29,040 --> 01:17:30,000 THINKING ABOUT THAT IS VERY 2000 01:17:30,000 --> 01:17:30,400 IMPORTANT. 2001 01:17:30,400 --> 01:17:31,560 THAT IS A GREAT QUESTION. 2002 01:17:31,560 --> 01:17:32,560 >>THANK YOU. 2003 01:17:32,560 --> 01:17:33,840 >>THANK YOU, DR. VENKATESH. 2004 01:17:33,840 --> 01:17:34,400 >>YEAH. 2005 01:17:34,400 --> 01:17:34,840 THANK YOU. 2006 01:17:34,840 --> 01:17:36,720 >>CONGRATULATIONS. 2007 01:17:36,720 --> 01:17:38,520 >>THANK YOU SO MUCH TO 2008 01:17:38,520 --> 01:17:39,840 EVERYBODY AND THANK YOU FOR YOUR 2009 01:17:39,840 --> 01:17:40,640 TIME AND ATTENTION. 2010 01:17:40,640 --> 01:17:43,080 >>I WANT TO SAY A BIG THANK YOU 2011 01:17:43,080 --> 01:17:45,400 TO EVERYONE WHO CAME TODAY. 2012 01:17:45,400 --> 01:17:48,960 PLEASE DO SPREAD THE WORD ABOUT 2013 01:17:48,960 --> 01:17:49,920 THIS AWARD. 2014 01:17:49,920 --> 01:17:51,360 NEW INVESTIGATORS CAN APPLY FOR 2015 01:17:51,360 --> 01:17:55,200 THE 2024 WACHTEL AWARD. 2016 01:17:55,200 --> 01:17:57,800 I BELIEVE APPLICATION IS OPEN 2017 01:17:57,800 --> 01:17:58,600 MID SEPTEMBER. 2018 01:17:58,600 --> 01:18:00,240 AND THEN FOR EVERYONE IN PERSON, 2019 01:18:00,240 --> 01:18:03,040 PLEASE DO JOIN US FOR LUNCH IN 2020 01:18:03,040 --> 01:18:04,680 THE FAES TERRACE. 2021 01:18:04,680 --> 01:18:08,880 AND THERE ARE COPIES OF DR. 2022 01:18:08,880 --> 01:18:11,080 VENKATESH'S ESSAY OUT FRONT, I 2023 01:18:11,080 --> 01:18:11,520 BELIEVE. 2024 01:18:11,520 --> 01:18:11,720 YEAH. 2025 01:18:11,720 --> 01:18:20,920 SO PLEASE TAKE ONE.