1 00:00:05,360 --> 00:00:09,760 I AM WIN ARIAS, SENIOR SCIENTIST 2 00:00:09,760 --> 00:00:11,320 EMERITUS AT THE NATIONAL 3 00:00:11,320 --> 00:00:14,120 INSTITUTES OF HEALTH IN 4 00:00:14,120 --> 00:00:14,880 BETHESDA, MARYLAND. 5 00:00:14,880 --> 00:00:17,520 AND WITH MY COLLEAGUE, DAN 6 00:00:17,520 --> 00:00:19,720 KASTNER, OF THE HUMAN GENOME 7 00:00:19,720 --> 00:00:22,000 RESEARCH INSTITUTE. 8 00:00:22,000 --> 00:00:24,720 WE WELCOME YOU TO THE 16TH 9 00:00:24,720 --> 00:00:27,120 SESSION OF THE 23RD YEAR OF A 10 00:00:27,120 --> 00:00:28,880 COURSE CALLED DEMYSTIFYING 11 00:00:28,880 --> 00:00:31,680 MEDICINE. 12 00:00:31,680 --> 00:00:32,720 THE PURPOSE OF THIS COURSE, 13 00:00:32,720 --> 00:00:36,880 WHICH IS REALLY A COURSE IN 14 00:00:36,880 --> 00:00:37,880 BRIDGE BUILDING, AND IT'S REALLY 15 00:00:37,880 --> 00:00:39,920 TO BRIDGE THE EXCITING 16 00:00:39,920 --> 00:00:42,960 DEVELOPMENTS GOING ON IN BIOLOGY 17 00:00:42,960 --> 00:00:46,800 AND ENGINEERING SCIENCES WITH 18 00:00:46,800 --> 00:00:47,560 MEDICINE. 19 00:00:47,560 --> 00:00:51,520 THE LOGO, SHOWN HERE, IS THE 20 00:00:51,520 --> 00:00:53,040 WORLD FAMOUS BROOKLYN BRIDGE. 21 00:00:53,040 --> 00:00:56,560 AND THE ONLY THING WRONG WITH 22 00:00:56,560 --> 00:00:58,640 THIS PHOTOGRAPH IS THAT FOR 23 00:00:58,640 --> 00:01:00,080 TODAY, THERE SHOULD BE THREE 24 00:01:00,080 --> 00:01:03,120 PEOPLE ON THE CATWALK. 25 00:01:03,120 --> 00:01:06,520 ONE IS A PATIENT, WHO WILL 26 00:01:06,520 --> 00:01:10,120 BRIEFLY DISCUSS HIS ILLNESS. 27 00:01:10,120 --> 00:01:13,800 THE SECOND IS AN ACCOMPLISHED 28 00:01:13,800 --> 00:01:16,360 TRANSLATIONAL ONCOLOGICAL 29 00:01:16,360 --> 00:01:20,000 SURGEON, AND THE THIRD IS A 30 00:01:20,000 --> 00:01:22,160 BASIC SCIENTIST, AND THEY'RE ALL 31 00:01:22,160 --> 00:01:25,000 CONCERNED WITH A MAJOR 32 00:01:25,000 --> 00:01:28,040 BIOLOGICAL AND MEDICAL PROBLEM, 33 00:01:28,040 --> 00:01:30,080 NAMELY, THE METASTASIS OF 34 00:01:30,080 --> 00:01:32,520 MALIGNANCIES. 35 00:01:32,520 --> 00:01:36,080 NOW, CANCER METASTASIS IS IN 36 00:01:36,080 --> 00:01:39,160 SOME RESPECTS A TERRIFYING 37 00:01:39,160 --> 00:01:39,400 SITUATION. 38 00:01:39,400 --> 00:01:42,800 IT IS TRULY A LETHAL CHALLENGE 39 00:01:42,800 --> 00:01:44,480 IN THE SENSE THAT MOST PATIENTS 40 00:01:44,480 --> 00:01:49,240 WHO HAVE CANCER DIE FROM THE 41 00:01:49,240 --> 00:01:50,640 METASTASES, AND NOT FROM THEIR 42 00:01:50,640 --> 00:01:54,560 PRIMARY TUMOR. 43 00:01:54,560 --> 00:01:58,920 FURTHERMORE, DISTRESSINGLY, IF A 44 00:01:58,920 --> 00:02:00,800 METASTASIS IS CLINICALLY 45 00:02:00,800 --> 00:02:04,720 EVIDENT, THE CHANCES OF SURVIVAL 46 00:02:04,720 --> 00:02:12,600 OR CURE ARE EXTREMELY SLIM. 47 00:02:12,600 --> 00:02:14,840 SO WE'VE LEARNED MUCH ABOUT 48 00:02:14,840 --> 00:02:18,080 METASTASIS TEU DUE TO THE 49 00:02:18,080 --> 00:02:19,280 DEVELOPMENT OF NEW TECHNOLOGIES 50 00:02:19,280 --> 00:02:21,280 IN MANY AREAS, AND THE CONSENSUS 51 00:02:21,280 --> 00:02:24,240 IS THAT IT'S A COMPLEX EVOLVING 52 00:02:24,240 --> 00:02:24,960 SYSTEM. 53 00:02:24,960 --> 00:02:26,840 IT'S SORT OF A DISEASE UNTO 54 00:02:26,840 --> 00:02:28,560 ITSELF, AND IT REQUIRES THE 55 00:02:28,560 --> 00:02:31,760 SUCCESSION OF TRAITS OR 56 00:02:31,760 --> 00:02:35,480 CHARACTERISTICS IN ORDER TO 57 00:02:35,480 --> 00:02:37,120 DISSEMINATE, TO ENTER AND LEAVE 58 00:02:37,120 --> 00:02:39,560 THE STATE OF DORMANCY, WHICH LE 59 00:02:39,560 --> 00:02:42,400 WILL HLE -- WHICH WE WILL HEAR , 60 00:02:42,400 --> 00:02:44,120 AND THEN TO COLONIZE DISTANT 61 00:02:44,120 --> 00:02:44,560 SITES. 62 00:02:44,560 --> 00:02:46,760 MANY FACTORS ARE INVOLVED IN 63 00:02:46,760 --> 00:02:48,840 EACH OF THESE STEPS AND IN THE 64 00:02:48,840 --> 00:02:54,120 CONSORTIUM OF THEM ALL TOGETHER. 65 00:02:54,120 --> 00:02:56,000 INCLUDING THE BLOOD SUPPLY, 66 00:02:56,000 --> 00:03:00,400 ANGIOGENESIS AND PERHAPS EVEN 67 00:03:00,400 --> 00:03:00,800 ANTIANGIOGENESIS. 68 00:03:00,800 --> 00:03:02,760 SO ALL OF THESE EVENTS ARE 69 00:03:02,760 --> 00:03:06,200 DRIVEN BY COMPLEX SELECTION AND 70 00:03:06,200 --> 00:03:08,160 A KIND OF DYNAMIC TRANSITION TO 71 00:03:08,160 --> 00:03:11,760 ONE STATE TO THE NEXT. 72 00:03:11,760 --> 00:03:13,520 AND ULTIMATELY THE ABILITY TO 73 00:03:13,520 --> 00:03:15,240 COOPT SYSTEMS OF THE HOST, 74 00:03:15,240 --> 00:03:20,440 PARTICULARLY THE IMMUNE SYSTEM. 75 00:03:20,440 --> 00:03:21,600 EACH OF THESE ARE HIGHLY COMPLEX 76 00:03:21,600 --> 00:03:24,040 AND CHALLENGING, BOTH AT THE 77 00:03:24,040 --> 00:03:27,280 BEDSIDE AND IN THE RESEARCH 78 00:03:27,280 --> 00:03:28,920 LABORATORY. 79 00:03:28,920 --> 00:03:32,520 I CALL YOUR ATTENTION TO AN 80 00:03:32,520 --> 00:03:34,400 EXCELLENT REVIEW IN THE 81 00:03:34,400 --> 00:03:38,440 APRIL 13'S EDITION OF CELL BY 82 00:03:38,440 --> 00:03:40,120 GERSTBERGER AND COLLEAGUES, A 83 00:03:40,120 --> 00:03:41,320 WONDERFUL REVIEW OF THE ENTIRE 84 00:03:41,320 --> 00:03:46,920 FIELD OF CANCER METASTASES. 85 00:03:46,920 --> 00:03:48,680 SO TODAY WE HAVE TWO INDIVIDUALS 86 00:03:48,680 --> 00:03:50,640 WHO ARE HIGHLY ACCOMPLISHED AND 87 00:03:50,640 --> 00:03:53,280 EXPERT AND HAVE DEVOTED ENORMOUS 88 00:03:53,280 --> 00:03:54,880 ENERGY TOWARD THIS BIG PROBLEM 89 00:03:54,880 --> 00:03:57,080 OF TRYING TO UNDERSTAND 90 00:03:57,080 --> 00:03:58,640 METASTASES AND WHAT TO DO WITH 91 00:03:58,640 --> 00:03:58,920 THEM. 92 00:03:58,920 --> 00:04:01,480 SO OUR FIRST SPEAKER IS GOING TO 93 00:04:01,480 --> 00:04:03,960 BE JONATHAN HERNANDEZ, WHO 94 00:04:03,960 --> 00:04:05,520 RECEIVED HIS MEDICAL DEGREE FROM 95 00:04:05,520 --> 00:04:09,120 THE UNIVERSITY OF FLORIDA, HIS 96 00:04:09,120 --> 00:04:10,280 SURGICAL RESIDENCY AT THE 97 00:04:10,280 --> 00:04:11,760 UNIVERSITY OF SOUTH FLORIDA, 98 00:04:11,760 --> 00:04:18,400 WHERE HE ALSO SPENT TIME IN THE 99 00:04:18,400 --> 00:04:20,080 MOFFIT CANCER CENTER AT THE 100 00:04:20,080 --> 00:04:20,600 UNIVERSITY OF CALIFORNIA 101 00:04:20,600 --> 00:04:22,240 SAN FRANCISCO STUDYING THE 102 00:04:22,240 --> 00:04:23,120 MOLECULAR DIAGNOSIS, 103 00:04:23,120 --> 00:04:25,600 PARTICULARLY OF LIVER 104 00:04:25,600 --> 00:04:25,920 METASTASES. 105 00:04:25,920 --> 00:04:28,040 AND THAT WAS FOLLOWED BY A 106 00:04:28,040 --> 00:04:30,040 FELLOWSHIP AT THE MEMORIAL SLOAN 107 00:04:30,040 --> 00:04:33,040 KETTERING CANCER CENTER IN 108 00:04:33,040 --> 00:04:35,360 NEW YORK IN SURGICAL ONCOLOGY 109 00:04:35,360 --> 00:04:40,840 AND PARTICULARLY HE HEPATOBILIAY 110 00:04:40,840 --> 00:04:42,600 SURGERY, SURGERY OF LIVER AND 111 00:04:42,600 --> 00:04:43,120 BILIARY TRACT. 112 00:04:43,120 --> 00:04:44,760 DURING THIS TIME, HE WAS PART OF 113 00:04:44,760 --> 00:04:46,840 THE ESTEEMED CELL BIOLOGY 114 00:04:46,840 --> 00:04:48,720 PROGRAM, WHICH DEALS WITH 115 00:04:48,720 --> 00:04:50,440 RESEARCH ON METASTATIC 116 00:04:50,440 --> 00:04:52,200 COLONIZATION. 117 00:04:52,200 --> 00:04:56,200 HE CAME TO THE NIH IN 2016, AND 118 00:04:56,200 --> 00:04:58,640 IN THE NATIONAL CANCER 119 00:04:58,640 --> 00:05:00,440 INSTITUTE, IS THE HEAD OF THE 120 00:05:00,440 --> 00:05:03,320 METASTASIS BIOLOGY SECTION, AND 121 00:05:03,320 --> 00:05:04,920 CHIEF OF THE SURGICAL ONCOLOGY 122 00:05:04,920 --> 00:05:08,280 BRANCH. 123 00:05:08,280 --> 00:05:10,600 HIS RESEARCH IS FOCUSED ON A 124 00:05:10,600 --> 00:05:13,960 NOVEL EX VIVO CULTURE STUDYING 125 00:05:13,960 --> 00:05:17,120 HUMAN CANCER AND METASTASES, AND 126 00:05:17,120 --> 00:05:18,920 ALSO RESEARCH ON THE POSSIBLE 127 00:05:18,920 --> 00:05:22,160 ROLE OF EXOSOMES. 128 00:05:22,160 --> 00:05:26,480 NOW, OUR SECOND SPEAKER IS 129 00:05:26,480 --> 00:05:29,320 KANDICE TANNER, WHO RECEIVED A 130 00:05:29,320 --> 00:05:32,160 PH.D. IN PHYSICS FROM THE 131 00:05:32,160 --> 00:05:35,520 UNIVERSITY OF ILLINOIS AT 132 00:05:35,520 --> 00:05:37,120 CHAMPAGNE URBANA, DID A 133 00:05:37,120 --> 00:05:39,160 POSTDOCTORAL FELLOWSHIP AT THE 134 00:05:39,160 --> 00:05:39,880 UNIVERSITY OF CALIFORNIA AT 135 00:05:39,880 --> 00:05:42,000 IRVINE, STUDYING THE DYNAMIC 136 00:05:42,000 --> 00:05:45,280 IMAGING OF THICK SECTIONS OF 137 00:05:45,280 --> 00:05:48,760 TUMORS, OF TISSUE, AND THEN 138 00:05:48,760 --> 00:05:51,520 ANOTHER POSTDOCTORAL FELLOW -- 139 00:05:51,520 --> 00:05:55,560 FELLOWSHIP AT THE UNIVERSITY OF 140 00:05:55,560 --> 00:05:56,080 CALIFORNIA, BERKELEY, THE 141 00:05:56,080 --> 00:06:00,880 LAWRENCE NATIONAL LAB OF DR. 142 00:06:00,880 --> 00:06:02,560 DR. BISSELL, WHO HAS DEVELOPED 143 00:06:02,560 --> 00:06:05,600 EXTENSIVELY RESEARCH INTO 144 00:06:05,600 --> 00:06:08,160 EXTRACELLULAR MATRIX. 145 00:06:08,160 --> 00:06:16,440 IN 2012, SHE CAME TO NIH AS AN 146 00:06:16,440 --> 00:06:17,320 NCI STADTMAN TENURE TRACK 147 00:06:17,320 --> 00:06:18,960 INVESTIGATOR, AND IN 2020, SHE 148 00:06:18,960 --> 00:06:20,680 BECAME TENURED AND IS NOW AN NIH 149 00:06:20,680 --> 00:06:23,000 SENIOR INVESTIGATOR IN THE 150 00:06:23,000 --> 00:06:25,840 NATIONAL CANCER INSTITUTES. 151 00:06:25,840 --> 00:06:27,480 SO KANDICE'S RESEARCH HAS BEEN 152 00:06:27,480 --> 00:06:31,400 ON BRIDGING MOLECULAR BIOPHYSICS 153 00:06:31,400 --> 00:06:34,200 WITH CELL BIOLOGY, IN ORDER TO 154 00:06:34,200 --> 00:06:36,680 LEARN HOW CELLS AND TISSUES 155 00:06:36,680 --> 00:06:39,600 SENSE AND RESPOND TO THEIR 156 00:06:39,600 --> 00:06:43,240 PHYSICAL ENVIRONMENT. 157 00:06:43,240 --> 00:06:44,520 HER RESEARCH HAS RESULTED IN 158 00:06:44,520 --> 00:06:47,400 SEVERAL AWARDS, INCLUDING THE 159 00:06:47,400 --> 00:06:49,640 ARTHUR FLEMING AWARD AND THE 160 00:06:49,640 --> 00:06:50,320 NATIONAL CANCER INSTITUTE 161 00:06:50,320 --> 00:06:51,880 DIRECTOR'S AWARD. 162 00:06:51,880 --> 00:06:54,080 SHE'S A FELLOW OF THE AMERICAN 163 00:06:54,080 --> 00:06:55,520 PHYSICAL SOCIETY, WHERE SHE 164 00:06:55,520 --> 00:06:59,160 SERVED ON THE COUNCIL, AND THE 165 00:06:59,160 --> 00:07:00,280 AMERICAN SOCIETY OF CELL 166 00:07:00,280 --> 00:07:01,680 BIOLOGY, AND HAS ALSO BEEN ON 167 00:07:01,680 --> 00:07:03,440 THE COUNCIL OF THE BIOPHYSICAL 168 00:07:03,440 --> 00:07:05,360 SOCIETY. 169 00:07:05,360 --> 00:07:11,600 SO WE WILL BEGIN, JONATHAN, 170 00:07:11,600 --> 00:07:14,800 WOULD YOU PLEASE CARRY ON. 171 00:07:14,800 --> 00:07:15,560 DR. ARIAS, THANK YOU FOR THAT 172 00:07:15,560 --> 00:07:16,360 KIND INTRODUCTION. 173 00:07:16,360 --> 00:07:18,920 WHAT I THOUGHT I'D DO WITH MY 174 00:07:18,920 --> 00:07:21,400 TIME IS SHARE A CLINICIAN'S VIEW 175 00:07:21,400 --> 00:07:25,000 ABOUT HOW WE LOOK AT METASTASIS 176 00:07:25,000 --> 00:07:26,720 BIOLOGY, AND THEN I HAVE A 177 00:07:26,720 --> 00:07:31,360 PATIENT OF MINE WITH ME BEHIND 178 00:07:31,360 --> 00:07:32,280 ME WHO WILL SHARE THE EXPERIENCE 179 00:07:32,280 --> 00:07:33,640 OF A PATIENT AND WHAT THIS LOOKS 180 00:07:33,640 --> 00:07:35,800 LIKE, AND I'LL END WITH SOME 181 00:07:35,800 --> 00:07:36,800 THINGS WE'VE BEEN WORKING ON TO 182 00:07:36,800 --> 00:07:38,560 SORT OF BETTER UNDERSTAND 183 00:07:38,560 --> 00:07:40,520 METASTASIS BIOLOGY FROM A 184 00:07:40,520 --> 00:07:42,400 TRANSLATIONAL PERSPECTIVE. 185 00:07:42,400 --> 00:07:45,960 IF YOU ASKED ME, I WOULD SAY THE 186 00:07:45,960 --> 00:07:47,080 BIOLOGY OF METASTASES, AT LEAST 187 00:07:47,080 --> 00:07:49,920 AS IT RELATES TO SOLID TUMORS, 188 00:07:49,920 --> 00:07:51,160 IS CANCER BIOLOGY. 189 00:07:51,160 --> 00:07:53,840 AS YOU MENTIONED, DR. ARIAS, 190 00:07:53,840 --> 00:07:55,280 PREVIOUSLY, YOU KNOW, THIS IS 191 00:07:55,280 --> 00:07:58,000 WHY PEOPLE DIE FROM CANCER. 192 00:07:58,000 --> 00:08:00,400 MOST PATIENTS WITH A PRIMARY 193 00:08:00,400 --> 00:08:02,280 TUMOR, SOMEBODY LIKE ME CAN 194 00:08:02,280 --> 00:08:03,600 SIMPLY CUT THEM OUT. 195 00:08:03,600 --> 00:08:06,000 THE ISSUE BECOMES, WE CANNOT CUT 196 00:08:06,000 --> 00:08:07,320 OUT WHAT WE CANNOT SEE, AND 197 00:08:07,320 --> 00:08:09,320 THERE ARE DISSEMINATION OF 198 00:08:09,320 --> 00:08:10,720 CELLS, AND SOME OF THESE 199 00:08:10,720 --> 00:08:13,240 EVENTUALLY OUTGROW IN A VERY 200 00:08:13,240 --> 00:08:15,080 COMPLICATED PROCESS CALLED THE 201 00:08:15,080 --> 00:08:16,440 METASTATIC CASCADE. 202 00:08:16,440 --> 00:08:17,720 I'VE HIGHLIGHTED THAT PROCESS 203 00:08:17,720 --> 00:08:18,920 HERE AND I'LL SORT OF WALK YOU 204 00:08:18,920 --> 00:08:20,920 THROUGH IT. 205 00:08:20,920 --> 00:08:22,760 A GIVEN PATIENT WILL HAVE A 206 00:08:22,760 --> 00:08:24,360 PRIMARY TUMOR THAT'S BEEN 207 00:08:24,360 --> 00:08:26,480 IDENTIFIED BECAUSE OF EITHER A 208 00:08:26,480 --> 00:08:28,880 SYMPTOM OR SCREENING, BUT THAT 209 00:08:28,880 --> 00:08:33,440 CAN BE A POTENTIALLY LATE EVENT, 210 00:08:33,440 --> 00:08:34,320 THAT IDENTIFICATION OF THIS. 211 00:08:34,320 --> 00:08:36,720 BUT THIS TUMOR, BEFORE WE EVER 212 00:08:36,720 --> 00:08:39,600 IDENTIFY IT, CAN RELEASE CELLS 213 00:08:39,600 --> 00:08:40,880 INTO THE CIRCULATORY SYSTEM. 214 00:08:40,880 --> 00:08:43,560 THERE ARE A LOT OF STRESSORS ON 215 00:08:43,560 --> 00:08:45,040 THESE CELLS DURING THIS PROCESS, 216 00:08:45,040 --> 00:08:48,440 AND THIS THANKFULLY -- THIS 217 00:08:48,440 --> 00:08:50,640 PROCESS IS INCREDIBLY 218 00:08:50,640 --> 00:08:51,720 INEFFICIENT, BUT FOR SOME 219 00:08:51,720 --> 00:08:52,520 PEOPLE, THIS PROCESS DOES 220 00:08:52,520 --> 00:08:54,040 COMPLETE, AND WHEN THAT HAPPENS, 221 00:08:54,040 --> 00:08:55,920 A PATIENT DEVELOPS STAGE IV 222 00:08:55,920 --> 00:08:57,960 DISEASE, WHICH WE HAD PREVIOUSLY 223 00:08:57,960 --> 00:09:00,680 OUTLINED IS AN EVENT USUALLY 224 00:09:00,680 --> 00:09:01,360 ASSOCIATED WITH ABBREVIATED 225 00:09:01,360 --> 00:09:02,640 SURVIVAL. 226 00:09:02,640 --> 00:09:04,880 NOT ALWAYS, BUT USUALLY 227 00:09:04,880 --> 00:09:06,480 ASSOCIATED WITH AN ABBREVIATED 228 00:09:06,480 --> 00:09:06,800 SURVIVAL. 229 00:09:06,800 --> 00:09:08,840 IN ANY EVENT, THAT PRIMARY TUMOR 230 00:09:08,840 --> 00:09:10,320 WILL RELEASE CELLS INTO THE 231 00:09:10,320 --> 00:09:13,400 CIRCULATORY SYSTEM, WHICH CAN 232 00:09:13,400 --> 00:09:14,360 EXTRAVASATE, THEY WILL LAND 233 00:09:14,360 --> 00:09:15,480 SOMEWHERE IN A FOREIGN 234 00:09:15,480 --> 00:09:17,080 ENVIRONMENT, A NEW ORGAN, A 235 00:09:17,080 --> 00:09:19,840 PLACE THEY ARE NOT SUPPOSED TO 236 00:09:19,840 --> 00:09:20,960 BE. 237 00:09:20,960 --> 00:09:23,200 AND THEY CAN EITHER DIE AT THAT 238 00:09:23,200 --> 00:09:24,520 POINT, KILLED BY THE IMMUNE 239 00:09:24,520 --> 00:09:25,880 SYSTEM, THEY CAN ENTER INTO A 240 00:09:25,880 --> 00:09:29,080 STATE OF KIE ESSENCE OR DORMANCY 241 00:09:29,080 --> 00:09:30,760 WHERE THEY REALLY DON'T MOVE A 242 00:09:30,760 --> 00:09:32,600 WHOLE LOT AND THERE'S THIS BACK 243 00:09:32,600 --> 00:09:33,600 AND FORTH OF STARTING TO GROW 244 00:09:33,600 --> 00:09:38,200 AGAIN OR NOT, AND THIS WOULD BE 245 00:09:38,200 --> 00:09:39,200 TERMED MICROMETASTASIS. 246 00:09:39,200 --> 00:09:40,960 THAT CAN EVENTUALLY OUTGROW 247 00:09:40,960 --> 00:09:44,080 AGAIN, AS I'VE SAID, LEADING TO 248 00:09:44,080 --> 00:09:46,040 WHAT WOULD OSTENSIBLY BE 249 00:09:46,040 --> 00:09:47,640 MOVEMENT OF THIS TUMOR TO A NEW 250 00:09:47,640 --> 00:09:49,280 PLACE, BUT THIS PROCESS IS 251 00:09:49,280 --> 00:09:50,880 INCREDIBLY COMPLICATED AND BEEN 252 00:09:50,880 --> 00:09:54,480 ONGOING FOR SOME TIME. 253 00:09:54,480 --> 00:09:55,920 WE JUST SIMPLY DON'T RECOGNIZE 254 00:09:55,920 --> 00:09:57,360 IT, WE DON'T HAVE A WAY TO TRACK 255 00:09:57,360 --> 00:09:58,560 IT IN ACTUAL PATIENTS, BUT BASED 256 00:09:58,560 --> 00:10:00,200 ON ALL OF OUR MODELING, THIS IS 257 00:10:00,200 --> 00:10:04,400 WHAT THIS PROCESS LOOKS LIKE. 258 00:10:04,400 --> 00:10:05,600 THE QUESTION ALWAYS COMES UP, 259 00:10:05,600 --> 00:10:09,040 WELL, WHEN DOES THIS? 260 00:10:09,040 --> 00:10:10,360 FOR A LONG TIME, THIS WAS THE 261 00:10:10,360 --> 00:10:11,400 MODEL WE THOUGHT WAS HAPPENING. 262 00:10:11,400 --> 00:10:13,400 YOU WOULD GET -- A PATIENT WOULD 263 00:10:13,400 --> 00:10:15,120 HAVE A PRIMARY TUMOR, THAT 264 00:10:15,120 --> 00:10:16,680 PRIMARY TUMOR WOULD GROW AND GET 265 00:10:16,680 --> 00:10:18,760 BIGGER AND EVOLVE, AND IT SHOULD 266 00:10:18,760 --> 00:10:23,040 BE STRESSED THAT THESE PRIMARY 267 00:10:23,040 --> 00:10:24,560 TUMORS AS THEY RELATE TO SOLID 268 00:10:24,560 --> 00:10:25,840 TUMORS ARE NOT ONE BALL OF 269 00:10:25,840 --> 00:10:27,280 CELLS, THEY'RE A COMPLICATED MIX 270 00:10:27,280 --> 00:10:30,160 OF MULTIPLE DIFFERENT CELL TYP 271 00:10:30,160 --> 00:10:32,760 TYPES. 272 00:10:32,760 --> 00:10:34,400 IT WAS THOUGHT THIS WOULD OCCUR 273 00:10:34,400 --> 00:10:35,360 SORT OF LATE IN THE PROCESS. 274 00:10:35,360 --> 00:10:38,320 AND THEN IT BECAME SORT OF THIS 275 00:10:38,320 --> 00:10:39,960 THINKING, ONLY IF WE COULD CUT 276 00:10:39,960 --> 00:10:41,160 THESE THINGS OUT EARLY ENOUGH, 277 00:10:41,160 --> 00:10:43,600 WE COULD SORT OF HELP MORE 278 00:10:43,600 --> 00:10:45,320 PATIENTS. 279 00:10:45,320 --> 00:10:46,400 ON SOME LEVEL, THAT IS TRUE. 280 00:10:46,400 --> 00:10:47,800 THIS IS AN EXAMPLE OF COLON 281 00:10:47,800 --> 00:10:48,160 CANCER. 282 00:10:48,160 --> 00:10:49,600 I'VE SELECTED THIS AS SIMPLY AN 283 00:10:49,600 --> 00:10:53,960 EXAMPLE TO THAT 284 00:10:53,960 --> 00:10:55,480 EARLIER STAGE TUMORS, PATIENTS 285 00:10:55,480 --> 00:10:56,600 DO MUCH BETTER. 286 00:10:56,600 --> 00:10:59,440 AND ON THE Y AXIS HERE, WE HAVE 287 00:10:59,440 --> 00:11:01,240 SURVIVAL, AND HERE IS TIME, AND 288 00:11:01,240 --> 00:11:04,320 OVER TIME WHAT WE REALIZE IS 289 00:11:04,320 --> 00:11:05,640 EVEN PATIENTS WITH EARLY STAGE 290 00:11:05,640 --> 00:11:10,160 COLON CANCER, SOME OF THEM WILL 291 00:11:10,160 --> 00:11:11,240 SUCCUMB TO DISEASE BUT A 292 00:11:11,240 --> 00:11:12,640 MINORITY OF THEM. 293 00:11:12,640 --> 00:11:15,200 MORE AND MORE PATIENTS WILL 294 00:11:15,200 --> 00:11:16,040 ULTIMATELY SUCCUMB TO THIS 295 00:11:16,040 --> 00:11:16,280 DISEASE. 296 00:11:16,280 --> 00:11:18,360 THE REASON, OF COURSE, IS NOT 297 00:11:18,360 --> 00:11:20,560 THAT YOU COULDN'T CUT OUT THE 298 00:11:20,560 --> 00:11:21,840 PRIMARY TUMOR IN THEIR COLON. 299 00:11:21,840 --> 00:11:23,680 AS IT TURNS OUT, YOU DON'T NEED 300 00:11:23,680 --> 00:11:25,880 MUCH OR ANY OF YOUR COLON, WE 301 00:11:25,880 --> 00:11:26,920 COULD CERTAINLY DO THAT. 302 00:11:26,920 --> 00:11:28,000 THE PROBLEM, OF COURSE, IS THAT 303 00:11:28,000 --> 00:11:30,160 THOSE CELLS HAVE DISSEMINATED 304 00:11:30,160 --> 00:11:31,360 AND THOSE PATIENTS HAVE HAD 305 00:11:31,360 --> 00:11:33,760 RECURRENCE OF THAT TUMOR. 306 00:11:33,760 --> 00:11:35,520 THEY'VE HAD COMPLETION OF THE 307 00:11:35,520 --> 00:11:39,720 METASTATIC CASCADE. 308 00:11:39,720 --> 00:11:41,280 THAT EVEN HAPPENS TO PATIENTS 309 00:11:41,280 --> 00:11:42,760 WITH EARLY STAGE DISEASE BUT 310 00:11:42,760 --> 00:11:44,120 IT'S MORE COMMON IN PATIENTS 311 00:11:44,120 --> 00:11:45,600 WITH LATER STAGE DISEASE. 312 00:11:45,600 --> 00:11:46,720 SO BECAUSE IT HAPPENS WITH EARLY 313 00:11:46,720 --> 00:11:47,920 STAGE DISEASE, PROBABLY THE 314 00:11:47,920 --> 00:11:49,640 PARALLEL PROGRESSION MODEL MAY 315 00:11:49,640 --> 00:11:51,400 BE MORE APPLICABLE HERE. 316 00:11:51,400 --> 00:11:53,800 THIS WOULD STATE THAT A PRIMARY 317 00:11:53,800 --> 00:11:55,920 TUMOR DOESN'T NEED TO BE HUGE OR 318 00:11:55,920 --> 00:11:58,640 EVOLVING OVER VERY LONG PERIODS 319 00:11:58,640 --> 00:12:00,040 OF TIME BUT PROBABLY BEGINS TO 320 00:12:00,040 --> 00:12:02,040 SEND OFF THOSE CELLS INTO THE 321 00:12:02,040 --> 00:12:03,880 BLOODSTREAM, INTO THE 322 00:12:03,880 --> 00:12:05,720 CIRCULATORY SYSTEM, PRETTY EARLY 323 00:12:05,720 --> 00:12:07,400 ON. 324 00:12:07,400 --> 00:12:09,640 AND THIS PROCESS AND THE 325 00:12:09,640 --> 00:12:11,400 METASTASES CAN EVOLVE AND THE 326 00:12:11,400 --> 00:12:12,520 PRIMARY TUMORS CAN EVOLVE, AND 327 00:12:12,520 --> 00:12:13,720 THIS CAN ALL BE HAPPENING IN 328 00:12:13,720 --> 00:12:16,360 PARALLEL. 329 00:12:16,360 --> 00:12:17,880 I WOULD SAY SOME OF THE MORE 330 00:12:17,880 --> 00:12:18,760 STRONGER EVIDENCE FOR THINGS 331 00:12:18,760 --> 00:12:22,800 LIKE THIS IS EVEN WHEN A PATIENT 332 00:12:22,800 --> 00:12:24,440 HAS A PRECANCEROUS LESION, AND 333 00:12:24,440 --> 00:12:26,480 I'M SHOWING YOU DATA HERE FROM 334 00:12:26,480 --> 00:12:27,720 THREE CANCEROUS PANCREAS 335 00:12:27,720 --> 00:12:29,680 LESIONS, SOME OF THOSE CELLS ARE 336 00:12:29,680 --> 00:12:32,040 MEASURABLE IN THE BLOODSTREAM. 337 00:12:32,040 --> 00:12:34,400 SO EVEN PATIENTS WITH 338 00:12:34,400 --> 00:12:36,280 PRECANCEROUS LESIONS, SOME OF 339 00:12:36,280 --> 00:12:38,120 THOSE CELLS ESCAPE. 340 00:12:38,120 --> 00:12:41,840 YOU MAY THINK THAT'S INCONGRUOUS 341 00:12:41,840 --> 00:12:43,520 WITH WHAT I'VE SAID SO FAR, BUT 342 00:12:43,520 --> 00:12:45,160 REMEMBER, THE EVENT THAT'S 343 00:12:45,160 --> 00:12:48,520 ASSOCIATED WITH A BAD OUTCOME IS 344 00:12:48,520 --> 00:12:50,160 NOT THE CELLS LEAVING THE TUMOR. 345 00:12:50,160 --> 00:12:52,160 IT'S NOT THE CELLS LANDING IN A 346 00:12:52,160 --> 00:12:55,200 NEW ENVIRONMENT. 347 00:12:55,200 --> 00:12:56,280 IT'S THAT THEY'RE STILL GROWING 348 00:12:56,280 --> 00:12:57,240 IN THAT NEW ENVIRONMENT. 349 00:12:57,240 --> 00:12:59,320 WHAT WE KNOW FROM PRECANCEROUS 350 00:12:59,320 --> 00:13:00,240 LESIONS IS THAT THEY DON'T EVER 351 00:13:00,240 --> 00:13:02,280 DO THAT, THEY'RE NEVER ABLE TO 352 00:13:02,280 --> 00:13:03,840 COMPLETE THE METASTATIC CASCADE, 353 00:13:03,840 --> 00:13:05,480 EVEN THOUGH THIS SHEDDING EVENT 354 00:13:05,480 --> 00:13:07,360 IS HAPPENING CONSTANTLY. 355 00:13:07,360 --> 00:13:09,400 I LIKE TO THINK OF THE PARALLEL 356 00:13:09,400 --> 00:13:10,280 PROGRESSION SORT OF LIKE THIS, 357 00:13:10,280 --> 00:13:12,560 SUCH THAT AS THAT TUMOR GROWS, 358 00:13:12,560 --> 00:13:14,880 IT BEGINS SHEDDING OFF MORE AND 359 00:13:14,880 --> 00:13:17,920 MORE DISSEMINATING CELLS, AND 360 00:13:17,920 --> 00:13:19,480 THESE CELLS, I WOULD SAY, ARE 361 00:13:19,480 --> 00:13:22,640 PROBABLY MOST FIT OR BEST SUITED 362 00:13:22,640 --> 00:13:27,000 TO COLONIZE THAT DISTANT FOREIGN 363 00:13:27,000 --> 00:13:27,560 ORGAN. 364 00:13:27,560 --> 00:13:28,880 SO I LIKE TO THINK OF THE 365 00:13:28,880 --> 00:13:29,520 PROCESS LIKE THIS. 366 00:13:29,520 --> 00:13:31,080 I LIKE THIS VIDEO. 367 00:13:31,080 --> 00:13:33,240 I HAD THIS MADE BECAUSE IT HELPS 368 00:13:33,240 --> 00:13:35,120 CONCEPTUALIZE HOW I SEE THIS. 369 00:13:35,120 --> 00:13:37,280 AND SO THIS IS A PRIMARY TUMOR 370 00:13:37,280 --> 00:13:40,680 IN THE PA PANCREAS OR THE END OF 371 00:13:40,680 --> 00:13:42,400 THE BILE DUCT, AND AS THAT TUMOR 372 00:13:42,400 --> 00:13:44,080 BEGINS TO GROW, IT SHEDS CELLS 373 00:13:44,080 --> 00:13:45,800 ALL OVER THE PLACE. 374 00:13:45,800 --> 00:13:47,880 LIVER, LUNG, THE PERITONEAL 375 00:13:47,880 --> 00:13:48,960 CAVITY, AND THEN AT SOME POINT 376 00:13:48,960 --> 00:13:50,720 IN TIME, THAT PATIENT WILL 377 00:13:50,720 --> 00:13:54,440 DEVELOP METASTASES. 378 00:13:54,440 --> 00:13:55,760 I PIVOTED. 379 00:13:55,760 --> 00:13:57,440 WE LEFT COLON CANCER AND WE WENT 380 00:13:57,440 --> 00:14:00,360 TO MORE AGGRESSIVE TUMORS LIKE 381 00:14:00,360 --> 00:14:03,000 PANCREAS AND BILE DUCT CANCER, 382 00:14:03,000 --> 00:14:08,800 OTHERWISE KNOWN -- THE CHANCES S 383 00:14:08,800 --> 00:14:10,000 METASTATIC CASCADE COMING TO 384 00:14:10,000 --> 00:14:12,640 COMPLETION ARE SIGNIFICANTLY 385 00:14:12,640 --> 00:14:15,560 HIGHER THAN PATIENTS WITH COLON 386 00:14:15,560 --> 00:14:16,080 CANCER. 387 00:14:16,080 --> 00:14:19,840 SO THIS IS A SCAN TO SORT OF 388 00:14:19,840 --> 00:14:21,800 DEMONSTRATE THIS. 389 00:14:21,800 --> 00:14:24,200 BY ALL SORT OF METRICS, A GIVEN 390 00:14:24,200 --> 00:14:26,720 PATIENT WILL HAVE A PRIMARY 391 00:14:26,720 --> 00:14:27,600 TUMOR ONLY. 392 00:14:27,600 --> 00:14:30,120 OUR LIMITS OF DETECTION, WE CAN 393 00:14:30,120 --> 00:14:31,640 NEVER SEE SINGLE CELLS OR EVEN 394 00:14:31,640 --> 00:14:33,280 SMALL CLUSTERS OF CELLS, 395 00:14:33,280 --> 00:14:34,800 CLINICALLY WE CAN NEVER SEE 396 00:14:34,800 --> 00:14:35,360 THIS. 397 00:14:35,360 --> 00:14:36,680 THAT WE'RE LIMITED BY WHAT WE 398 00:14:36,680 --> 00:14:39,320 CAN DO TO LIVING PATIENTS, WE 399 00:14:39,320 --> 00:14:41,800 CAN'T DO ANYTHING SUPER 400 00:14:41,800 --> 00:14:42,040 INVASIVE. 401 00:14:42,040 --> 00:14:45,080 SO BASED ON A PET SCAN OR A CT 402 00:14:45,080 --> 00:14:46,720 SCAN, ALL METRICS WOULD TELL US 403 00:14:46,720 --> 00:14:48,480 THIS PATIENT HAS LOCALIZED 404 00:14:48,480 --> 00:14:50,240 DISEASE BUT THAT METASTATIC 405 00:14:50,240 --> 00:14:51,880 PROCESS HAS BEGUN HAPPENING 406 00:14:51,880 --> 00:14:53,000 ALREADY. 407 00:14:53,000 --> 00:14:54,520 AND THE SCAN I'M GOING TO SHOW 408 00:14:54,520 --> 00:14:56,200 YOU NOW IS THE SCAN OF THE 409 00:14:56,200 --> 00:15:01,440 PATIENT THAT I HAVE BEHIND ME, A 410 00:15:01,440 --> 00:15:02,960 PATIENT OF MINE FROM SEVERAL 411 00:15:02,960 --> 00:15:03,520 YEARS AGO. 412 00:15:03,520 --> 00:15:04,480 THIS IS EXACTLY WHAT HAPPENED TO 413 00:15:04,480 --> 00:15:04,920 KATE. 414 00:15:04,920 --> 00:15:06,920 SHE CAME TO ME AND THIS IS HER 415 00:15:06,920 --> 00:15:07,400 SCAN. 416 00:15:07,400 --> 00:15:09,200 SHE HAD A PRIMARY TUMOR IN THE 417 00:15:09,200 --> 00:15:12,480 END OF HER BILE DUCT, 418 00:15:12,480 --> 00:15:13,120 CHOLANGIOCARCINOMA. 419 00:15:13,120 --> 00:15:14,440 I'LL DRAW YOUR ATTENTION TO IT 420 00:15:14,440 --> 00:15:15,800 IN THIS AREA HERE. 421 00:15:15,800 --> 00:15:17,720 THESE ARE, AGAIN, BAD ACTORS. 422 00:15:17,720 --> 00:15:18,400 KATE WAS SICK. 423 00:15:18,400 --> 00:15:20,120 THE CHANCES OF THIS COMING BACK 424 00:15:20,120 --> 00:15:21,560 FOR KATE WERE QUITE HIGH. 425 00:15:21,560 --> 00:15:24,400 WE HAD DISCUSSIONS ABOUT ALL OF 426 00:15:24,400 --> 00:15:25,520 THESE THINGS, WHAT THIS MEANS, 427 00:15:25,520 --> 00:15:30,080 WHAT SURGERY CAN AND CANNOT DO, 428 00:15:30,080 --> 00:15:31,520 SO THIS IS SORT OF WHAT HAPPENS. 429 00:15:31,520 --> 00:15:32,720 AND THIS IS WHAT HAPPENED TO 430 00:15:32,720 --> 00:15:32,920 KATE. 431 00:15:32,920 --> 00:15:35,480 I REMOVED THE HEAD OF HER 432 00:15:35,480 --> 00:15:37,080 PANCREAS IN AN OPERATION CALLED 433 00:15:37,080 --> 00:15:39,760 A WHIPPLE, A FAIRLY EXTENSIVE 434 00:15:39,760 --> 00:15:40,280 OPERATION. 435 00:15:40,280 --> 00:15:41,240 MOST OF THE TIME AFTER THIS, 436 00:15:41,240 --> 00:15:43,560 PATIENTS ARE GIVEN SOME SORT OF 437 00:15:43,560 --> 00:15:45,280 THERAPY, AND THAT THERAPY, THE 438 00:15:45,280 --> 00:15:46,520 INTENT OF THAT THERAPY IS TO 439 00:15:46,520 --> 00:15:49,240 KILL WHAT WE CANNOT SEE, TO STOP 440 00:15:49,240 --> 00:15:50,880 WHAT WE CANNOT SEE, AND WE 441 00:15:50,880 --> 00:15:52,200 REALLY DON'T UNDERSTAND THIS 442 00:15:52,200 --> 00:15:55,560 PROCESS VERY WELL. 443 00:15:55,560 --> 00:15:57,280 IN PATIENTS ARE THESE CELLS AND 444 00:15:57,280 --> 00:15:59,280 CLUSTERS OF CELLS, ARE THEY 445 00:15:59,280 --> 00:16:00,720 GROWING AND DYING, WHAT DO THEY 446 00:16:00,720 --> 00:16:01,280 LOOK LIKE IN PATIENTS? 447 00:16:01,280 --> 00:16:03,320 THIS IS, AGAIN, REALLY HARD TO 448 00:16:03,320 --> 00:16:05,320 KNOW IN PATIENTS. 449 00:16:05,320 --> 00:16:08,080 IT'S HARD TO KNOW IN MOUSE 450 00:16:08,080 --> 00:16:09,480 MODELS, BUT IT'S REALLY HARD TO 451 00:16:09,480 --> 00:16:11,120 KNOW IN PATIENTS. 452 00:16:11,120 --> 00:16:12,960 BUT MY ANGLES ARE MOSTLY 453 00:16:12,960 --> 00:16:14,040 TRANSLATIONAL, SO I ALWAYS ASK 454 00:16:14,040 --> 00:16:15,920 THE QUESTION, WHAT CAN WE DO 455 00:16:15,920 --> 00:16:17,440 ABOUT THIS? 456 00:16:17,440 --> 00:16:20,600 WELL, YOU WOULD INTUITIVELY 457 00:16:20,600 --> 00:16:23,880 THINK THAT ONCE THAT 458 00:16:23,880 --> 00:16:25,280 QUINTESSENTIAL PRIMARY TUMOR IS 459 00:16:25,280 --> 00:16:26,280 REMOVED, ALL THAT IS LEFT IN 460 00:16:26,280 --> 00:16:27,440 THAT PATIENT, AS FAR AS DISEASE 461 00:16:27,440 --> 00:16:29,040 IS CONCERNED, IS THE STUFF WE 462 00:16:29,040 --> 00:16:30,360 CANNOT SEE. 463 00:16:30,360 --> 00:16:33,760 THE SOURCE IS REMOVED, SO THE 464 00:16:33,760 --> 00:16:35,200 DISSEMINATED CELLS HAVE 465 00:16:35,200 --> 00:16:36,920 DISSEMINATED, THEY ARE EITHER IN 466 00:16:36,920 --> 00:16:38,320 TARGET ORGANS OR THEY'RE NOT. 467 00:16:38,320 --> 00:16:39,720 IF THEY'RE NOT, THE PATIENT IS 468 00:16:39,720 --> 00:16:42,040 NOT GOING TO HAVE RECURRENCE OF 469 00:16:42,040 --> 00:16:44,000 THAT PROBLEM. 470 00:16:44,000 --> 00:16:45,120 BUT FOR MOST PATIENTS, 471 00:16:45,120 --> 00:16:46,560 ESPECIALLY WITH CERTAIN KINDS OF 472 00:16:46,560 --> 00:16:47,880 TUMORS, THE LIKELIHOOD OF THAT 473 00:16:47,880 --> 00:16:49,400 PROBLEM IS REALLY HIGH. 474 00:16:49,400 --> 00:16:51,240 THE LIKELIHOOD OF HAVING 475 00:16:51,240 --> 00:16:52,880 DISSEMINATED TUMOR CELLS IN 476 00:16:52,880 --> 00:16:54,200 VARIOUS PARTS OF THEIR BODY IS 477 00:16:54,200 --> 00:16:55,640 REALLY HIGH, AND SO WE COULD 478 00:16:55,640 --> 00:16:57,680 THINK OF THIS AS, WELL, IT'S NOT 479 00:16:57,680 --> 00:17:00,440 A HUGE TUMOR, THERE'S NOT A HUGE 480 00:17:00,440 --> 00:17:01,080 MICROENVIRONMENT, THERE ISN'T -- 481 00:17:01,080 --> 00:17:02,840 MAYBE THIS IS A TIME WHERE THOSE 482 00:17:02,840 --> 00:17:05,840 CELLS WOULD BE MOST SUSCEPTIBLE 483 00:17:05,840 --> 00:17:07,200 TO CHEMOTHERAPY, AND THAT'S WHAT 484 00:17:07,200 --> 00:17:08,400 WE THOUGHT FOR A LONG TIME. 485 00:17:08,400 --> 00:17:10,080 AND SO WHAT I'M SHOWING YOU HERE 486 00:17:10,080 --> 00:17:12,920 IS, I'M USING COLON CANCER AS AN 487 00:17:12,920 --> 00:17:14,240 EXAMPLE AGAIN, COLON CANCER 488 00:17:14,240 --> 00:17:16,480 WOULD PROBABLY BE THE G.I. 489 00:17:16,480 --> 00:17:17,720 CANCER THAT HAS THE MOST 490 00:17:17,720 --> 00:17:19,520 CHEMOTHERAPY OPTIONS AVAILABLE 491 00:17:19,520 --> 00:17:22,840 TO PATIENTS WITH THIS DISEASE. 492 00:17:22,840 --> 00:17:24,000 BUT WHAT YOU SEE HERE ON THE 493 00:17:24,000 --> 00:17:25,680 LEFT IS THE RECURRENCE-FREE 494 00:17:25,680 --> 00:17:27,200 SURVIVAL, ON THE RIGHT IS THE 495 00:17:27,200 --> 00:17:28,480 OVERALL SURVIVAL, AND WHAT WE'VE 496 00:17:28,480 --> 00:17:30,200 BEEN ABLE TO DO -- AND THIS IS 497 00:17:30,200 --> 00:17:31,360 DATA I WANT TO CALL YOUR 498 00:17:31,360 --> 00:17:33,240 ATTENTION FROM 1990, WITH THE 499 00:17:33,240 --> 00:17:38,480 DRUG CA, WE'VE BEEN ABLE TO 500 00:17:38,480 --> 00:17:40,880 DECREASE THE CHANCES OF THESE 501 00:17:40,880 --> 00:17:49,760 MICRO ME TAS MICRO M METASTASIZE 502 00:17:49,760 --> 00:17:53,480 CERTAINLY HAVEN'T FICKED ALL THE 503 00:17:53,480 --> 00:17:54,680 PROBLEM, WE'VE BEEN ABLE TO HELP 504 00:17:54,680 --> 00:17:56,120 SOME PEOPLE BUT THERE'S A LOT OF 505 00:17:56,120 --> 00:17:56,840 PROBLEMS WITH THIS. 506 00:17:56,840 --> 00:17:57,960 I'LL DRAW YOUR ATTENTION TO THE 507 00:17:57,960 --> 00:18:00,360 BOTTOM HERE. 508 00:18:00,360 --> 00:18:01,600 MOST PATIENTS ARE NOT GOING TO 509 00:18:01,600 --> 00:18:06,040 HAVE THIS EVENT, SO WE ARE 510 00:18:06,040 --> 00:18:07,320 POTENTIALLY SUBJECTING A LOT OF 511 00:18:07,320 --> 00:18:08,720 PATIENTS TO THERAPY THEY MAY NOT 512 00:18:08,720 --> 00:18:11,920 EVEN NEED. 513 00:18:11,920 --> 00:18:14,080 WE JUST DON'T HAVE A WAY TO 514 00:18:14,080 --> 00:18:16,400 DECIPHER WHO IS WHO. 515 00:18:16,400 --> 00:18:17,400 MOREOVER, THERE'S A SMALL 516 00:18:17,400 --> 00:18:19,160 IMPROVEMENT BUT IT'S NOT A LOT. 517 00:18:19,160 --> 00:18:20,880 THIS IS 1990. 518 00:18:20,880 --> 00:18:22,640 CLEARLY 2023 WOULD BE DIFFERENT. 519 00:18:22,640 --> 00:18:24,560 LET ME SHOW YOU. 520 00:18:24,560 --> 00:18:26,480 SO LET'S GO -- LET'S FAST 521 00:18:26,480 --> 00:18:26,720 FORWARD. 522 00:18:26,720 --> 00:18:28,520 THIS IS 2004. 523 00:18:28,520 --> 00:18:33,800 FOR 14 YEARS, ALL WE HAD YAS 524 00:18:33,800 --> 00:18:37,000 ADJUNCT 5FU. 525 00:18:37,000 --> 00:18:43,200 WE CAN ADD NEWER DRUGS, 526 00:18:43,200 --> 00:18:44,360 OXALIPLATIN. 527 00:18:44,360 --> 00:18:46,280 WE SEE A SMALL IMPROVEMENT IN 528 00:18:46,280 --> 00:18:47,280 RECURRENCE-FREE SURVIVAL AND WE 529 00:18:47,280 --> 00:18:49,640 SEE A SMALL IMPROVEMENT IN 530 00:18:49,640 --> 00:18:50,440 OVERALL SURVIVAL, BUT AGAIN, AND 531 00:18:50,440 --> 00:18:52,600 THIS IS THE HIGHEST RISK GROUP, 532 00:18:52,600 --> 00:18:53,800 THESE PATIENTS, MOSTLY DIDN'T 533 00:18:53,800 --> 00:18:57,320 NEED THIS, AND THERE'S STILL A 534 00:18:57,320 --> 00:18:58,280 SUBSTANTIAL PORTION OF PATIENTS 535 00:18:58,280 --> 00:18:59,600 DYING OF THEIR DISEASE. 536 00:18:59,600 --> 00:19:00,920 AGAIN, THIS IS 2004. 537 00:19:00,920 --> 00:19:03,560 LET'S FAST FORWARD TO 2023. 538 00:19:03,560 --> 00:19:05,800 WE DON'T HAVE ANYTHING MORE, BUT 539 00:19:05,800 --> 00:19:07,720 THOSE SIMPLE DRUG COMBINATIONS 540 00:19:07,720 --> 00:19:13,480 OF 5FU AND OXOLIPLATIN, HOW CAN 541 00:19:13,480 --> 00:19:14,240 THAT BE? 542 00:19:14,240 --> 00:19:15,880 IT BECOMES REALLY COMPLICATED TO 543 00:19:15,880 --> 00:19:16,600 SORT OF TARGET SOMETHING YOU 544 00:19:16,600 --> 00:19:17,760 CAN'T REALLY SEE, YOU DON'T 545 00:19:17,760 --> 00:19:18,960 REALLY KNOW ABOUT, AND THE ONLY 546 00:19:18,960 --> 00:19:20,520 WAY TO KNOW IS TO GIVE TO PEOPLE 547 00:19:20,520 --> 00:19:23,560 AND YOU CAN'T EVEN MEASURE 548 00:19:23,560 --> 00:19:25,520 ANYTHING. 549 00:19:25,520 --> 00:19:27,400 AS LEAST WE COULDN'T FOR A VERY 550 00:19:27,400 --> 00:19:28,080 LONG PERIOD OF TIME. 551 00:19:28,080 --> 00:19:29,600 SO HERE WE ARE AS CANCER 552 00:19:29,600 --> 00:19:30,960 SURGEONS, WE'RE REMOVING TUMORS, 553 00:19:30,960 --> 00:19:32,280 SOME OF THESE ARE POTENTIALLY 554 00:19:32,280 --> 00:19:37,400 HUGE OPERATIONS. 555 00:19:37,400 --> 00:19:38,440 BUT ONLY TO HAVE SOME OF THE 556 00:19:38,440 --> 00:19:39,760 PATIENTS COME BACK WITH 557 00:19:39,760 --> 00:19:40,880 RECURRENCES, AGAIN, THIS WOULD 558 00:19:40,880 --> 00:19:43,840 BE STAGE IV, THEY HAVE COMPLETED 559 00:19:43,840 --> 00:19:45,600 THEIR METASTATIC CASCADE, SOME 560 00:19:45,600 --> 00:19:46,880 OF THOSE CELLS HAVE COMPLETED 561 00:19:46,880 --> 00:19:48,680 THE METASTATIC CASCADE AND WE 562 00:19:48,680 --> 00:19:49,840 DON'T REALLY HAVE A VERY GOOD 563 00:19:49,840 --> 00:19:51,600 WAY OF INTERRUPTING THEM. 564 00:19:51,600 --> 00:19:54,120 THIS KEEPS ME UP AT NIGHT. 565 00:19:54,120 --> 00:19:55,520 THIS IS A HUGE PROBLEM IN SOLID 566 00:19:55,520 --> 00:19:57,480 TUMOR ONCOLOGY. 567 00:19:57,480 --> 00:20:05,160 AND SO I LIKE THIS SLIDE, IT'S 568 00:20:05,160 --> 00:20:06,440 OLD, IT'S FROM A MOUSE MODEL, 569 00:20:06,440 --> 00:20:07,720 BUT I THINK IT HIGHLIGHTS THE 570 00:20:07,720 --> 00:20:08,200 POINT. 571 00:20:08,200 --> 00:20:09,840 AND THIS IS FROM DR. WEINBERG A 572 00:20:09,840 --> 00:20:11,520 NUMBER OF YEARS AGO. 573 00:20:11,520 --> 00:20:12,960 AND WHAT HE BASICALLY SHOWED IN 574 00:20:12,960 --> 00:20:14,120 THIS MOUSE MODEL IS WHEN THESE 575 00:20:14,120 --> 00:20:17,040 CELLS ARE DISSEMINATED AND 576 00:20:17,040 --> 00:20:18,840 THEY'RE KIE HE SENT OR DORMANT, 577 00:20:18,840 --> 00:20:20,840 THEY WERE GIVING THESE MICE 578 00:20:20,840 --> 00:20:21,680 CHEMOTHERAPY TO KILL THE TUMORS 579 00:20:21,680 --> 00:20:23,280 THEY COULD SEE WHICH WAS DOING A 580 00:20:23,280 --> 00:20:24,560 GOOD JOB BUT IT DID NOT DO 581 00:20:24,560 --> 00:20:26,120 ANYTHING TO THESE DORMANT CELLS. 582 00:20:26,120 --> 00:20:27,800 THIS SORT OF HOLDS TRUE. 583 00:20:27,800 --> 00:20:31,520 WHEN YOU LOOK AT WHAT 5FU AND 584 00:20:31,520 --> 00:20:32,600 OXALIPLATIN DOES TO TUMORS THAT 585 00:20:32,600 --> 00:20:33,920 WE CAN SEE, THE RESPONSE RATES 586 00:20:33,920 --> 00:20:37,640 ARE REALLY GREAT. 587 00:20:37,640 --> 00:20:39,160 BUT WHEN YOU TRY AND GET RID OF 588 00:20:39,160 --> 00:20:40,280 STUFF YOU CANNOT SEE, IT'S A 589 00:20:40,280 --> 00:20:41,720 LITTLE BIT BETTER, IT IS BETTER, 590 00:20:41,720 --> 00:20:43,200 BUT YOU DON'T GET A LOT OF BANG 591 00:20:43,200 --> 00:20:45,840 FOR YOUR BUCK, SO TO SPEAK. 592 00:20:45,840 --> 00:20:47,200 AND I THINK THIS HIGHLIGHTS THE 593 00:20:47,200 --> 00:20:49,120 FACT THAT WE HAVE FUNDAMENTAL 594 00:20:49,120 --> 00:20:54,480 LACK OF UNDERSTANDING ABOUT WHAT 595 00:20:54,480 --> 00:20:56,840 THESE DISSEMINATED TUMOR CELLS 596 00:20:56,840 --> 00:20:59,560 AND MICRO METASTASES ARE, WHAT 597 00:20:59,560 --> 00:21:01,280 THEY'RE DEPENDENT ON, WHAT WE 598 00:21:01,280 --> 00:21:02,920 CAN USE TO EXPLOIT THEM AND KILL 599 00:21:02,920 --> 00:21:04,360 THEM OR AT LEAST STOP THEM FROM 600 00:21:04,360 --> 00:21:04,800 GROWING. 601 00:21:04,800 --> 00:21:06,320 I'M GOING TO STOP THERE AND I 602 00:21:06,320 --> 00:21:08,120 WANT KATE TO COME UP AND SHARE 603 00:21:08,120 --> 00:21:10,560 HER STORY WITH US AS A PATIENT 604 00:21:10,560 --> 00:21:14,800 WHO HAD ONE OF THESE HIGH RISK 605 00:21:14,800 --> 00:21:15,600 TUMORS. 606 00:21:15,600 --> 00:21:18,200 AND SHE CAME TO ME AS SOMEBODY 607 00:21:18,200 --> 00:21:20,400 WHO HAD A VERY HIGH RISK TUMOR, 608 00:21:20,400 --> 00:21:24,000 WE HAD AN EXTENSIVE DISCUSSION 609 00:21:24,000 --> 00:21:25,240 ABOUT WHAT SHE -- YOU KNOW, 610 00:21:25,240 --> 00:21:26,520 SURGERY WOULD ONLY DO SO MUCH. 611 00:21:26,520 --> 00:21:28,040 AGAIN, IT ONLY REMOVES WHAT WE 612 00:21:28,040 --> 00:21:28,480 CAN SEE. 613 00:21:28,480 --> 00:21:29,600 IS THERE ANYTHING ELSE WE COULD 614 00:21:29,600 --> 00:21:31,680 DO TO SORT OF PUT THE ODDS MORE 615 00:21:31,680 --> 00:21:34,280 IN HER FAVOR. 616 00:21:34,280 --> 00:21:35,640 ULTIMATELY I ENROLLED KATE ON A 617 00:21:35,640 --> 00:21:38,880 STUDY WHERE SHE GOT A MONOCLONAL 618 00:21:38,880 --> 00:21:39,760 ANTIBODY THAT SOUGHT TO KILL 619 00:21:39,760 --> 00:21:41,960 THOSE DISSEMINATED TUMOR CELLS. 620 00:21:41,960 --> 00:21:43,160 I ULTIMATELY HAD TO STOP THE 621 00:21:43,160 --> 00:21:44,360 TRIAL BECAUSE WE SAW SOME 622 00:21:44,360 --> 00:21:46,240 TOXICITY AND I THOUGHT IT WAS 623 00:21:46,240 --> 00:21:47,760 UNFAIR FOR PATIENTS TO CONTINUE 624 00:21:47,760 --> 00:21:50,480 ENROLLMENT, BUT KATE DID 625 00:21:50,480 --> 00:21:51,360 EXCEPTIONALLY WELL. 626 00:21:51,360 --> 00:21:53,120 THIS HAS BEEN SOMEWHAT AROUND 627 00:21:53,120 --> 00:21:53,720 TWO YEARS -- 628 00:21:53,720 --> 00:21:54,160 >> THREE. 629 00:21:54,160 --> 00:21:56,040 >> THREE YEARS. 630 00:21:56,040 --> 00:21:56,720 TIME GOES BY. 631 00:21:56,720 --> 00:22:00,000 SO IT'S BEEN THREE YEARS, AND 632 00:22:00,000 --> 00:22:02,280 KATE HAS BECOME AN ADVOCATE, I 633 00:22:02,280 --> 00:22:05,560 WOULD SAY, SHE HAD A DISEASE 634 00:22:05,560 --> 00:22:06,280 CALLED CHOLANGIOCARCINOMA. 635 00:22:06,280 --> 00:22:09,400 YOU GO TO THE CHOLANGIOCARCINOMA 636 00:22:09,400 --> 00:22:10,920 FOUNDATION, KATE IS FRONT AND 637 00:22:10,920 --> 00:22:12,120 CENTER, MENTORING PEOPLE AND 638 00:22:12,120 --> 00:22:13,920 SHE'S BECOME VERY INVOLVED. 639 00:22:13,920 --> 00:22:15,400 AND SO WHAT I'D LIKE TO DO IS 640 00:22:15,400 --> 00:22:19,080 HAVE KATE SHARE HER EXPERIENCE, 641 00:22:19,080 --> 00:22:20,960 SO I THINK PEOPLE CAN UNDERSTAND 642 00:22:20,960 --> 00:22:23,080 HOW REAL THIS PROBLEM IS FOR ALL 643 00:22:23,080 --> 00:22:25,280 PATIENTS WITH SOLID TUMORS. 644 00:22:25,280 --> 00:22:27,120 SO KATE, I'D LIKE YOU TO SIT 645 00:22:27,120 --> 00:22:27,880 HERE, IF YOU WOULD. 646 00:22:27,880 --> 00:22:34,760 >> THANK YOU. 647 00:22:34,760 --> 00:22:36,320 JONATHAN, AND TO NIH FOR 648 00:22:36,320 --> 00:22:39,520 INCLUDING ME TODAY. 649 00:22:39,520 --> 00:22:43,200 I CAN'T SAY ENOUGH ABOUT MY 650 00:22:43,200 --> 00:22:44,600 TREATMENT HERE, THE 651 00:22:44,600 --> 00:22:46,400 ORGANIZATION, EACH AND EVERY 652 00:22:46,400 --> 00:22:49,000 PERSON WHO'S EVER INTERACTED 653 00:22:49,000 --> 00:22:52,200 WITH ME IN THE LAST THREE YEARS. 654 00:22:52,200 --> 00:22:53,440 NIH HAS SAVED MY LIFE. 655 00:22:53,440 --> 00:22:56,600 SO I WANT TO BEGIN WITH THAT. 656 00:22:56,600 --> 00:22:59,920 WHAT I WANT TO DO TODAY IS TO 657 00:22:59,920 --> 00:23:02,240 TRY TO NOT ONLY TELL MY STORY, 658 00:23:02,240 --> 00:23:03,560 BUT TO INCLUDE THE STORIES OF 659 00:23:03,560 --> 00:23:06,600 ALL THE OTHER PEOPLE THAT I'VE 660 00:23:06,600 --> 00:23:10,720 BEEN FORTUNATE TO TALK TO, WHOG 661 00:23:10,720 --> 00:23:11,560 SUFFER WITH CHOLANGIOCARCINOMA, 662 00:23:11,560 --> 00:23:13,400 SOME PEOPLE WITH PANCREATIC 663 00:23:13,400 --> 00:23:14,480 CANCER, I HAD A LONG 664 00:23:14,480 --> 00:23:16,120 CONVERSATION WITH SOMEONE I'M 665 00:23:16,120 --> 00:23:17,640 MENTORING WHO IS DEALING WITH A 666 00:23:17,640 --> 00:23:19,600 RECURRENCE OF COLON CANCER JUST 667 00:23:19,600 --> 00:23:22,000 RECENTLY, SO THE COLON CANCER 668 00:23:22,000 --> 00:23:25,520 SLIDES WERE FASCINATING FOR ME. 669 00:23:25,520 --> 00:23:26,520 BECAUSE WHAT I'VE THOUGHT A LOT 670 00:23:26,520 --> 00:23:31,880 ABOUT IS HOW TO HELP PATIENTS 671 00:23:31,880 --> 00:23:33,640 LEARN MORE AND PROCESS WHAT 672 00:23:33,640 --> 00:23:35,080 THEY'RE GOING THROUGH AS A 673 00:23:35,080 --> 00:23:37,000 MENTOR OF PATIENTS. 674 00:23:37,000 --> 00:23:38,680 I'M GOING TO TRY TO INCLUDE 675 00:23:38,680 --> 00:23:41,520 THEIR PERSPECTIVES IN WHAT I 676 00:23:41,520 --> 00:23:42,440 SAW. 677 00:23:42,440 --> 00:23:46,440 MY STORY IS VERY SIMPLE, QUITE 678 00:23:46,440 --> 00:23:46,960 DRAMATIC. 679 00:23:46,960 --> 00:23:48,160 I HAD A TRIFECTA DIAGNOSIS IN 680 00:23:48,160 --> 00:23:51,480 THE SENSE I WAS DIAGNOSED WITH 681 00:23:51,480 --> 00:23:52,840 CHOLANGIOCARCINOMA BY BECOMING 682 00:23:52,840 --> 00:23:54,120 VERY SICK WHEN MY TUMOR 683 00:23:54,120 --> 00:23:55,640 COMPLETELY BLOCKED MY BILE DUCT, 684 00:23:55,640 --> 00:23:59,120 AND I TURNED YELLOW, I WAS 685 00:23:59,120 --> 00:24:00,400 HORRIBLY ILL, VERY SUDDENLY, BUT 686 00:24:00,400 --> 00:24:01,920 IT WAS AT THE HEIGHT OF COVID. 687 00:24:01,920 --> 00:24:04,880 IT WAS MEMORIAL DAY 2020, IF YOU 688 00:24:04,880 --> 00:24:07,080 WELL REMEMBER MEMORIAL DAY 2020. 689 00:24:07,080 --> 00:24:09,600 AND WE WERE ONE WEEK AWAY FROM 690 00:24:09,600 --> 00:24:10,960 SETTLING AND MOVING OUT OF OUR 691 00:24:10,960 --> 00:24:14,320 HOUSE OF 35 YEARS. 692 00:24:14,320 --> 00:24:20,200 SO I HAD A -- A STUNNING WEEK OF 693 00:24:20,200 --> 00:24:23,040 PACKING BOXES AND BEING SICK 694 00:24:23,040 --> 00:24:24,840 AND, MEANWHILE, ACCESSING 695 00:24:24,840 --> 00:24:27,080 DOCTORS AND TRYING TO DO 696 00:24:27,080 --> 00:24:30,400 EVERYTHING OVER THE PHONE, 697 00:24:30,400 --> 00:24:31,400 FINDING SURGICAL SITES, MY 698 00:24:31,400 --> 00:24:32,520 DOCTORS HAD TO FIND SURGICAL 699 00:24:32,520 --> 00:24:33,640 SITES WHERE THEY WOULD LET THEM 700 00:24:33,640 --> 00:24:36,000 DO THE TESTS, BUT WHAT GOT ME 701 00:24:36,000 --> 00:24:37,760 THROUGH THAT PERIOD WAS THAT I 702 00:24:37,760 --> 00:24:42,000 WAS FORTUNATE TO HAVE EXCELLENT 703 00:24:42,000 --> 00:24:44,720 DOCTORS ALREADY AT MY SIDE 704 00:24:44,720 --> 00:24:45,080 INVOLVED. 705 00:24:45,080 --> 00:24:46,920 AND ONE OF THE THINGS I WANT TO 706 00:24:46,920 --> 00:24:49,000 POINT OUT IS THAT I'VE LEARNED 707 00:24:49,000 --> 00:24:50,880 OVER THE PAST YEAR HOW RARE THAT 708 00:24:50,880 --> 00:24:52,320 IS, HOW MANY PEOPLE THROUGHOUT 709 00:24:52,320 --> 00:24:53,360 OUR COUNTRY, THROUGHOUT THE 710 00:24:53,360 --> 00:24:56,000 WORLD COULD HAVE BEEN IN EXACTLY 711 00:24:56,000 --> 00:24:57,800 MY SITUATION BUT DID NOT HAVE 712 00:24:57,800 --> 00:24:59,600 ACCESS TO EXCELLENT MEDICAL CARE 713 00:24:59,600 --> 00:25:01,680 AND ADVICE. 714 00:25:01,680 --> 00:25:03,640 WERE NOT ABLE TO GET HOSPITAL 715 00:25:03,640 --> 00:25:05,560 OUTPATIENT SURGERY CENTERS OPEN 716 00:25:05,560 --> 00:25:09,680 FOR ERCPs, ET CETERA. 717 00:25:09,680 --> 00:25:12,400 I ALSO HAD THE REMARKABLE GOOD 718 00:25:12,400 --> 00:25:14,480 FORTUNE OF A VERY CLOSE FRIEND 719 00:25:14,480 --> 00:25:17,560 NAMED DR. CYNTHIA TIFT, WHO 720 00:25:17,560 --> 00:25:19,160 HAPPENS TO BE HERE AT THE NIH. 721 00:25:19,160 --> 00:25:24,000 SO AFTER I HAD WORKED THROUGH MY 722 00:25:24,000 --> 00:25:25,880 G.I. AND MY PRIMARY CARE DOCTOR 723 00:25:25,880 --> 00:25:28,560 AND THEIR CONNECTIONS AND SOME 724 00:25:28,560 --> 00:25:30,200 DOCTORS AT TWO FINE HOSPITALS, 725 00:25:30,200 --> 00:25:32,840 ONE OF THEM HOPKINS IN 726 00:25:32,840 --> 00:25:37,480 BALTIMORE, AND WAS LINED UP FOR 727 00:25:37,480 --> 00:25:41,840 CARE, I ALSO WAS ABLE TO COME TO 728 00:25:41,840 --> 00:25:45,680 NIH THROUGH MY FRIEND. 729 00:25:45,680 --> 00:25:47,080 AND WITH DR. HERNANDEZ. 730 00:25:47,080 --> 00:25:49,360 HE OPENED UP THIS TOPIC THAT 731 00:25:49,360 --> 00:25:53,080 HE'S TALKING ABOUT TODAY OF 732 00:25:53,080 --> 00:25:54,200 MICROMETASTASES AT THAT POINT, 733 00:25:54,200 --> 00:25:55,160 AND IT WAS SOMETHING THAT I HAD 734 00:25:55,160 --> 00:25:57,880 NOT HEARD BEFORE. 735 00:25:57,880 --> 00:26:00,640 I'D HAD WONDERFUL SESSIONS WITH 736 00:26:00,640 --> 00:26:04,680 TWO FINE WHIPPLE SURGEONS IN 737 00:26:04,680 --> 00:26:07,200 BALTIMORE ABOUT SURGERY. 738 00:26:07,200 --> 00:26:10,600 I THINK THROUGH THE FOG OF MY 739 00:26:10,600 --> 00:26:13,440 ILLNESS, I REMEMBER THAT MAYBE 740 00:26:13,440 --> 00:26:16,400 ONE OF THEM MENTIONED ADJUVANT 741 00:26:16,400 --> 00:26:17,360 CHEMO SOMEWHERE DOWN THE LINE, 742 00:26:17,360 --> 00:26:19,560 MONTHS LATER, TO PREVENT 743 00:26:19,560 --> 00:26:19,880 RECURRENCE. 744 00:26:19,880 --> 00:26:21,440 BUT THAT'S ABOUT ALL ANYONE 745 00:26:21,440 --> 00:26:22,440 SAID. 746 00:26:22,440 --> 00:26:24,560 I WAS TOO SICK AT THAT POINT TO 747 00:26:24,560 --> 00:26:26,040 DO ANY RESEARCH MYSELF. 748 00:26:26,040 --> 00:26:29,760 I WAS JUST PACKING BOXES. 749 00:26:29,760 --> 00:26:31,360 AND FRANKLY, I WAS TOO SICK TO 750 00:26:31,360 --> 00:26:33,000 BE VERY AFRAID. 751 00:26:33,000 --> 00:26:34,880 MY FRIENDS AND FAMILY WERE 752 00:26:34,880 --> 00:26:36,400 TERRIFIED BECAUSE THEY WENT 753 00:26:36,400 --> 00:26:38,920 ONLINE AND READ THE STATISTICS. 754 00:26:38,920 --> 00:26:43,000 BUT I WAS LOOKING FOR SOMEONE 755 00:26:43,000 --> 00:26:47,240 WHO WOULD MAKE ME FEEL THAT I 756 00:26:47,240 --> 00:26:51,360 COULD TRUST THAT DOCTOR TO MOVE 757 00:26:51,360 --> 00:26:54,320 ME FORWARD WHEN I COULD NOT 758 00:26:54,320 --> 00:26:55,480 UNDERSTAND ENOUGH MYSELF. 759 00:26:55,480 --> 00:26:57,320 AT THIS POINT, I WANT TO SHIFT 760 00:26:57,320 --> 00:27:00,080 GEARS AND TALK ABOUT THE COMMON 761 00:27:00,080 --> 00:27:01,120 EXPERIENCE OF PATIENTS WHO HAVE 762 00:27:01,120 --> 00:27:03,120 JUST HEARD THE WORD "CANCER." 763 00:27:03,120 --> 00:27:04,760 I THINK WHAT I'VE LEARNED OVER 764 00:27:04,760 --> 00:27:08,400 THE LAST THREE YEARS IS THAT THE 765 00:27:08,400 --> 00:27:10,160 FIRST QUESTION IN VIRTUALLY 766 00:27:10,160 --> 00:27:12,000 EVERYONE'S MIND IS, CAN YOU TAKE 767 00:27:12,000 --> 00:27:15,360 IT OUT? 768 00:27:15,360 --> 00:27:17,040 THAT'S THE QUESTION, AND THAT'S 769 00:27:17,040 --> 00:27:19,320 THE WAY SOMEONE WHO HAS NOT GONE 770 00:27:19,320 --> 00:27:21,360 THROUGH THIS EXPERIENCE AND 771 00:27:21,360 --> 00:27:23,240 LEARNED SEES IT. 772 00:27:23,240 --> 00:27:24,560 THERE'S A THING IN MY BODY THAT 773 00:27:24,560 --> 00:27:25,760 SHOULDN'T BE THERE, AND I WANT 774 00:27:25,760 --> 00:27:27,160 SOMEONE TO TAKE IT OUT. 775 00:27:27,160 --> 00:27:32,200 IF THEY ARE TOLD, AS I WAS, YOU 776 00:27:32,200 --> 00:27:33,840 HAVE A MALIGNANT TUMOR AND 777 00:27:33,840 --> 00:27:35,160 YOU'LL HAVE A WHIPPLE SURGERY 778 00:27:35,160 --> 00:27:36,560 AND IT'S POTENTIALLY CURATIVE, 779 00:27:36,560 --> 00:27:39,840 THEY'RE GOING TO HEAR 780 00:27:39,840 --> 00:27:41,160 POTENTIALLY CURATIVE SURGERY, 781 00:27:41,160 --> 00:27:43,920 WHICH WILL TAKE IT OUT, AND THEN 782 00:27:43,920 --> 00:27:47,600 WITHOUT KNOWING TH, WITHOUT 783 00:27:47,600 --> 00:27:48,360 UNDERSTANDING, THEY'RE EXACTLY 784 00:27:48,360 --> 00:27:49,600 IN THE POSITION THAT JONATHAN 785 00:27:49,600 --> 00:27:53,640 WAS EXPLAINING, OF BEING AT RISK 786 00:27:53,640 --> 00:27:55,760 IN WAYS THAT THE PATIENT MIND 787 00:27:55,760 --> 00:27:57,920 DOESN'T UNDERSTAND. 788 00:27:57,920 --> 00:27:59,680 EVEN IF IT'S EXPLAINED, EVEN IF 789 00:27:59,680 --> 00:28:04,040 THEY THINK THEY UNDERSTAND. 790 00:28:04,040 --> 00:28:06,480 THAT PHRASE, "CAN YOU CUT IT 791 00:28:06,480 --> 00:28:10,720 OUT," IS, I THINK, CENTRAL TO 792 00:28:10,720 --> 00:28:13,360 THE PATIENT PSYCHE. 793 00:28:13,360 --> 00:28:17,600 ONLY LATER IN THE PROCESS, AFTER 794 00:28:17,600 --> 00:28:21,080 SURGERY, AND THEN SPEAKING TO 795 00:28:21,080 --> 00:28:21,760 PATIENTS FORTUNATE ENOUGH TO 796 00:28:21,760 --> 00:28:23,280 HAVE SURGERY OFFERED, ONLY LATER 797 00:28:23,280 --> 00:28:25,600 DOES THE IDEA OF RECURRENCE 798 00:28:25,600 --> 00:28:28,640 BEGIN TO REALLY HAVE MEANING, I 799 00:28:28,640 --> 00:28:32,360 THINK, FOR CANCER PATIENTS IN 800 00:28:32,360 --> 00:28:33,800 THIS SITUATION. 801 00:28:33,800 --> 00:28:36,520 AND AS JONATHAN WAS EXPLAINING, 802 00:28:36,520 --> 00:28:40,240 THAT LATER CAN BE, IN MANY 803 00:28:40,240 --> 00:28:41,000 CASES, TOO LATE. 804 00:28:41,000 --> 00:28:42,320 WELL, THIS IS WHAT HE EXPLAINED 805 00:28:42,320 --> 00:28:43,760 TO ME WHEN I CAME IN TO MEET 806 00:28:43,760 --> 00:28:46,160 WITH HIM. 807 00:28:46,160 --> 00:28:47,360 THREE YEARS AGO. 808 00:28:47,360 --> 00:28:51,320 IN A BILIRUBIN FOG WHERE I COULD 809 00:28:51,320 --> 00:28:54,400 ONLY BARELY FOLLOW, BUT WITH THE 810 00:28:54,400 --> 00:28:56,520 BACKUP OF MY DOCTOR FRIEND WHO 811 00:28:56,520 --> 00:28:58,920 COULD ACTUALLY LEAD THE PROTOCOL 812 00:28:58,920 --> 00:29:02,880 HE PROPOSED, WHEN HE GAVE ME A 813 00:29:02,880 --> 00:29:05,400 SHORTER, SIMPLER VERSION OF WHAT 814 00:29:05,400 --> 00:29:08,800 HE WAS EXPLAINING TO YOU ABOUT 815 00:29:08,800 --> 00:29:12,200 HIS FRUSTRATION WITH DOING A 816 00:29:12,200 --> 00:29:14,360 BRILLIANT SURGERY TO BE FOLLOWED 817 00:29:14,360 --> 00:29:18,760 BY RECURRENCE WITHIN A FEW 818 00:29:18,760 --> 00:29:19,640 MONTHS. 819 00:29:19,640 --> 00:29:23,440 WHAT I THINK IS IMPORTANT TO 820 00:29:23,440 --> 00:29:26,200 SHARE IS THAT MY RESPONSE AT 821 00:29:26,200 --> 00:29:27,840 THAT POINT WAS ENTIRELY 822 00:29:27,840 --> 00:29:28,480 POSITIVE. 823 00:29:28,480 --> 00:29:32,120 I REMEMBER THAT MY IMMEDIATE 824 00:29:32,120 --> 00:29:34,240 INSTINCT WAS, THIS MAKES SENSE, 825 00:29:34,240 --> 00:29:36,560 AND I HAPPEN TO BE A PRETTY 826 00:29:36,560 --> 00:29:37,680 PROACTIVE PLANNER, SO THE IDEA 827 00:29:37,680 --> 00:29:40,600 OF INTRODUCING THE IDEA OF 828 00:29:40,600 --> 00:29:43,360 GETTING AHEAD OF THE PROCESS 829 00:29:43,360 --> 00:29:46,720 MADE SENSE TO ME. 830 00:29:46,720 --> 00:29:47,720 FOR OTHER PATIENTS, OF COURSE, 831 00:29:47,720 --> 00:29:49,040 IT WOULD HAVE JUST ADDED MORE 832 00:29:49,040 --> 00:29:50,720 FEAR, AND I'M WELL AWARE OF 833 00:29:50,720 --> 00:29:51,160 THAT. 834 00:29:51,160 --> 00:29:57,280 BUT I THINK THAT IT'S IMPORTANT 835 00:29:57,280 --> 00:29:59,640 TO STRESS AGAIN THAT FOR MOST 836 00:29:59,640 --> 00:30:01,080 PATIENTS, THIS IDEA OF A MIDDLE 837 00:30:01,080 --> 00:30:03,360 GROUND, THIS MIDDLE PERIOD 838 00:30:03,360 --> 00:30:06,560 BETWEEN TUMOR AND METASTASIS IS 839 00:30:06,560 --> 00:30:07,800 NOT SOMETHING THAT THEY ARE 840 00:30:07,800 --> 00:30:09,280 GOING TO BE ABLE TO THINK ABOUT 841 00:30:09,280 --> 00:30:11,920 NATURALLY. 842 00:30:11,920 --> 00:30:13,080 AND THEY DON'T WANT TO THINK 843 00:30:13,080 --> 00:30:16,080 ABOUT IT. 844 00:30:16,080 --> 00:30:17,920 GOING BACK TO MY STORY, I ENDED 845 00:30:17,920 --> 00:30:20,880 UP HAVING A CHOICE BETWEEN THREE 846 00:30:20,880 --> 00:30:22,080 WONDERFUL SURGEONS, AND I CHOSE 847 00:30:22,080 --> 00:30:24,560 TO COME TO NIH PRECISELY SO THAT 848 00:30:24,560 --> 00:30:28,840 I COULD TAKE PART IN THIS 849 00:30:28,840 --> 00:30:30,440 EXPERIMENTAL PROGRAM THAT 850 00:30:30,440 --> 00:30:33,640 OFFERED ME ATTENTION TO THAT 851 00:30:33,640 --> 00:30:35,760 MIDDLE GROUND. 852 00:30:35,760 --> 00:30:37,760 AND FROM THE BEGINNING, AFTER MY 853 00:30:37,760 --> 00:30:39,440 FRIEND CINDY TOLD ME THAT SHE 854 00:30:39,440 --> 00:30:40,560 WOULD LET ME GO THROUGH WITH 855 00:30:40,560 --> 00:30:42,840 THIS AFTER SHE WROTE THE 856 00:30:42,840 --> 00:30:47,880 PROTOCOL, I FELT EXCITED. 857 00:30:47,880 --> 00:30:49,240 SO THERE WERE SEVERAL THINGS 858 00:30:49,240 --> 00:30:51,120 THAT I FELT IN RESPONSE TO THE 859 00:30:51,120 --> 00:30:54,440 IDEA OF TACKLING THESE 860 00:30:54,440 --> 00:30:56,760 MICROMETASTASES THROUGH AN 861 00:30:56,760 --> 00:30:58,560 EXPERIMENTAL STUDY DRUG. 862 00:30:58,560 --> 00:31:00,360 THE FIRST WAS THAT IT MADE 863 00:31:00,360 --> 00:31:01,320 SENSE. 864 00:31:01,320 --> 00:31:03,520 THE SECOND WAS PURELY PERSONAL, 865 00:31:03,520 --> 00:31:05,960 WHERE I INTENDED TO DO ANYTHING 866 00:31:05,960 --> 00:31:10,800 AND EVERYTHING THAT I COULD DO, 867 00:31:10,800 --> 00:31:13,040 AND WASN'T AS OVERWHELMED BY 868 00:31:13,040 --> 00:31:14,560 FEAR AS A LOT PATIENTS ARE AT 869 00:31:14,560 --> 00:31:15,240 THAT POINT. 870 00:31:15,240 --> 00:31:16,240 THE THIRD WAS THAT I WAS TOO 871 00:31:16,240 --> 00:31:17,480 SICK TO READ OR RESEARCH 872 00:31:17,480 --> 00:31:19,600 ANYTHING ON MY OWN, AND I NEEDED 873 00:31:19,600 --> 00:31:21,560 TO FIND SOMEONE TO TRUST. 874 00:31:21,560 --> 00:31:23,960 AND I FELT INTUITIVELY THAT I 875 00:31:23,960 --> 00:31:27,560 COULD TRUST DR. HERNANDEZ. 876 00:31:27,560 --> 00:31:28,480 AND THE FOURTH WAS IMMEDIATE. 877 00:31:28,480 --> 00:31:30,120 IT WAS A SENSE OF SATISFACTION 878 00:31:30,120 --> 00:31:31,920 OF BEING PART OF SCIENTIFIC 879 00:31:31,920 --> 00:31:32,840 RESEARCH. 880 00:31:32,840 --> 00:31:37,760 I IMMEDIATELY FELT PART OF THIS 881 00:31:37,760 --> 00:31:38,200 COMMUNITY. 882 00:31:38,200 --> 00:31:40,480 AND THROUGHOUT MY ILLNESS, WHICH 883 00:31:40,480 --> 00:31:44,320 INCLUDED OVER A MONTH IN THE 884 00:31:44,320 --> 00:31:47,360 HOSPITAL, FOUR MONTHS OF 885 00:31:47,360 --> 00:31:48,680 RECOVERY AT HOME BEFORE I COULD 886 00:31:48,680 --> 00:31:51,200 DO MUCH OF ANYTHING AND A SECOND 887 00:31:51,200 --> 00:31:54,280 SURGERY MONTHS LATER, IT WAS 888 00:31:54,280 --> 00:31:55,680 CRUCIAL TO ME THAT I FELT LIKE 889 00:31:55,680 --> 00:31:59,400 PART OF AN ONGOING COMMUNITY. 890 00:31:59,400 --> 00:32:01,040 AND THAT, FOR ME, HAS TURNED 891 00:32:01,040 --> 00:32:03,160 INTO WORKING AS A VOLUNTEER FOR 892 00:32:03,160 --> 00:32:05,760 THE CHOLANGIOCARCINOMA 893 00:32:05,760 --> 00:32:06,520 FOUNDATION. 894 00:32:06,520 --> 00:32:08,680 TO FINISH UP BY GOING BACK TO 895 00:32:08,680 --> 00:32:11,320 OTHER PATIENTS, I THINK WHAT 896 00:32:11,320 --> 00:32:12,760 I'VE LEARNED IN THE LAST THREE 897 00:32:12,760 --> 00:32:20,960 YEARS IS THAT WHEN ANYONE HEARS 898 00:32:20,960 --> 00:32:22,480 THE WORD CANCER, AND I JUST 899 00:32:22,480 --> 00:32:24,880 HEARD YESTERDAY FROM A FRIEND 900 00:32:24,880 --> 00:32:27,960 WHO WAS JUST DIAGNOSED WITH 901 00:32:27,960 --> 00:32:30,920 PANCREATIC CANCER, WHEN SOMEONE 902 00:32:30,920 --> 00:32:33,880 HEARS THAT WORD, CANCER, FOR THE 903 00:32:33,880 --> 00:32:37,040 FIRST TIME, NOT AS A POSSIBILITY 904 00:32:37,040 --> 00:32:38,560 BUT AS A CERTAINTY, THE 905 00:32:38,560 --> 00:32:41,520 IMMEDIATE YEARNING IS FOR 906 00:32:41,520 --> 00:32:42,160 SECURITY. 907 00:32:42,160 --> 00:32:48,280 I THINK OF A WOUNDED ANIMAL. 908 00:32:48,280 --> 00:32:50,240 I'VE HAD NUMEROUS CONVERSATIONS 909 00:32:50,240 --> 00:32:54,000 WITH FELLOW SURVIVORS OF 910 00:32:54,000 --> 00:32:55,840 CHOLANGIOCARCINOMA AND 911 00:32:55,840 --> 00:32:57,480 PANCREATIC CANCER, ABOUT THE 912 00:32:57,480 --> 00:32:59,880 FACT THAT WHEN FIRST DIAGNOSED, 913 00:32:59,880 --> 00:33:01,640 THEY DIDN'T WANT TO GO ANYWHERE 914 00:33:01,640 --> 00:33:02,080 ELSE. 915 00:33:02,080 --> 00:33:05,040 THEY DIDN'T WANT TO READ, THEY 916 00:33:05,040 --> 00:33:06,120 DIDN'T WANT TO RESEARCH. 917 00:33:06,120 --> 00:33:07,920 I KNOW SOME PEOPLE DO 918 00:33:07,920 --> 00:33:08,320 IMMEDIATELY. 919 00:33:08,320 --> 00:33:11,080 BUT I THINK THE VAST MAJORITY OF 920 00:33:11,080 --> 00:33:14,240 PATIENTS TURN TO FAMILY, TURN TO 921 00:33:14,240 --> 00:33:15,120 THEIR PRIMARY CARE DOCTOR, TURN 922 00:33:15,120 --> 00:33:17,960 TO THE LOCAL ONCOLOGIST, THE 923 00:33:17,960 --> 00:33:18,760 FAMILIAR HOSPITAL. 924 00:33:18,760 --> 00:33:22,520 THEY WANT SOMEONE TO SIMPLIFY 925 00:33:22,520 --> 00:33:24,000 THINGS FOR THEM, NOT COMPLICATE 926 00:33:24,000 --> 00:33:25,480 THINGS FOR THEM. 927 00:33:25,480 --> 00:33:27,880 AND THEY WANT TO BE SOMEPLACE 928 00:33:27,880 --> 00:33:30,720 THEY FEEL FAMILIAR, WHERE THEY 929 00:33:30,720 --> 00:33:32,800 FEEL THEY CAN RELAX AS MUCH AS 930 00:33:32,800 --> 00:33:36,520 POSSIBLE. 931 00:33:36,520 --> 00:33:39,560 THE IDEA OF MICROMETASTASES 932 00:33:39,560 --> 00:33:43,880 DOESN'T FIT INTO THAT NATURALLY. 933 00:33:43,880 --> 00:33:48,680 SO THAT BECOMES A CHALLENGE, IN 934 00:33:48,680 --> 00:33:49,600 MEETING PATIENTS WHERE THEY ARE, 935 00:33:49,600 --> 00:33:52,480 HOW TO ADD ANOTHER LEVEL BEHIND 936 00:33:52,480 --> 00:33:54,480 CAN YOU CUT IT OUT, OR HOW CAN 937 00:33:54,480 --> 00:33:56,440 WE PREVENT IT FROM RECURRING? 938 00:33:56,440 --> 00:33:57,440 BUT ON THE OTHER HAND, THE LAST 939 00:33:57,440 --> 00:34:05,880 THING I'LL SAY IS THAT NA IN THE 940 00:34:05,880 --> 00:34:07,440 LAST THREE YEARS, WHENEVER I 941 00:34:07,440 --> 00:34:08,800 TALK WITH PATIENTS AND I'M ABLE 942 00:34:08,800 --> 00:34:10,800 TO TELL MY STORY AND TELL THEM 943 00:34:10,800 --> 00:34:12,560 THE STORY THAT NOBODY'S EVER 944 00:34:12,560 --> 00:34:16,480 HEARD OF, THEY'RE THRILLED. 945 00:34:16,480 --> 00:34:17,480 THEY'RE FASCINATED. 946 00:34:17,480 --> 00:34:18,600 THEY'RE EXCITED. 947 00:34:18,600 --> 00:34:20,000 PEOPLE WHO WENT NO FURTHER THAN 948 00:34:20,000 --> 00:34:21,400 THE DOCTOR AT THE CORNER WITH 949 00:34:21,400 --> 00:34:24,360 THEIR OWN DIAGNOSIS ARE SUDDENLY 950 00:34:24,360 --> 00:34:28,600 ASKING QUESTIONS, WANTING TO 951 00:34:28,600 --> 00:34:30,920 KNOW WHAT THEY CAN READ, AND 952 00:34:30,920 --> 00:34:31,400 WISHING THEY HAD THAT 953 00:34:31,400 --> 00:34:34,240 OPPORTUNITY. 954 00:34:34,240 --> 00:34:36,520 SO I THINK THAT'S WHERE THE 955 00:34:36,520 --> 00:34:38,240 CHALLENGE GOING FORWARD FOR 956 00:34:38,240 --> 00:34:40,440 CLINICIANS LIES, TO THE DEGREE 957 00:34:40,440 --> 00:34:42,960 THAT THEY CAN WORK WITH THE 958 00:34:42,960 --> 00:34:47,680 SCIENCE TO ADDRESS THAT MIDDLE 959 00:34:47,680 --> 00:34:51,880 GROUND, IS IN FINDING WAYS TO 960 00:34:51,880 --> 00:34:54,680 DRAW PATIENT ATTENTION AND 961 00:34:54,680 --> 00:34:57,200 PATIENT CURIOSITY AND PATIENT 962 00:34:57,200 --> 00:34:59,680 TRUST ALONG WITH THEM. 963 00:34:59,680 --> 00:35:01,000 I'M GOING TO FINISH BY SAYING 964 00:35:01,000 --> 00:35:04,280 THAT THE IRONY OF ALL OF THIS IS 965 00:35:04,280 --> 00:35:07,120 THAT I'VE SPENT THE LAST YEAR OR 966 00:35:07,120 --> 00:35:08,680 TWO TALKING WITH -- WHEN I SEE 967 00:35:08,680 --> 00:35:12,200 JONATHAN, ABOUT MY CASE AND WHY 968 00:35:12,200 --> 00:35:18,080 I'M WELL AND -- WHY I'M WELL AT 969 00:35:18,080 --> 00:35:19,160 THIS POINT, THREE YEARS LATER, 970 00:35:19,160 --> 00:35:22,320 AS FAR AS WE KNOW, AND HE ALWAYS 971 00:35:22,320 --> 00:35:29,440 EXPLAINS IT AS GOOD FORTUNE, OR 972 00:35:29,440 --> 00:35:33,080 LUCK OR MYSTERY OR THE FACT THAT 973 00:35:33,080 --> 00:35:36,320 IT WAS EARLY OR THAT IT'S A RARE 974 00:35:36,320 --> 00:35:37,680 OUTCOME. 975 00:35:37,680 --> 00:35:42,040 I SEE IT AS A COMBINATION OF 976 00:35:42,040 --> 00:35:45,080 BRILLIANT SURGERY AND AN 977 00:35:45,080 --> 00:35:48,720 EXPERIMENTAL TRIAL PRODUCED BY 978 00:35:48,720 --> 00:35:50,320 LEADING SCIENTISTS AT NIH. 979 00:35:50,320 --> 00:35:52,760 AND THAT'S WHAT I TELL PEOPLE, 980 00:35:52,760 --> 00:35:55,120 AND THAT'S WHAT I -- HOW I 981 00:35:55,120 --> 00:35:56,560 INTEND TO CONTINUE TO TELL MY 982 00:35:56,560 --> 00:35:57,640 STORY GOING FORWARD. 983 00:35:57,640 --> 00:36:02,160 SO THANK YOU. 984 00:36:02,160 --> 00:36:10,960 >> THANK YOU, KATE. 985 00:36:10,960 --> 00:36:16,320 >>I ALWAYS SAY 986 00:36:16,320 --> 00:36:18,160 THERE'S ACES IN EVERY DECK, AND 987 00:36:18,160 --> 00:36:19,520 I TOLD YOU FROM THE BEGINNING I 988 00:36:19,520 --> 00:36:21,080 THOUGHT YOU WERE AND I WAS RIGHT 989 00:36:21,080 --> 00:36:24,360 ABOUT YOU, AND SOMETIMES I'M 990 00:36:24,360 --> 00:36:25,320 RIGHT FOR OTHER REASONS AND I 991 00:36:25,320 --> 00:36:26,520 DON'T LIKE IT AND I KNOW THERE 992 00:36:26,520 --> 00:36:32,720 ARE PEOPLE WITH ISSUES, AND THIS 993 00:36:32,720 --> 00:36:33,800 IS WHY WE COME TO WORK EVERY 994 00:36:33,800 --> 00:36:34,040 DAY. 995 00:36:34,040 --> 00:36:35,640 WITH THE TIME I HAVE LEFT, WHAT 996 00:36:35,640 --> 00:36:37,240 I'D LIKE TO DO IS, I'M 997 00:36:37,240 --> 00:36:38,000 FRUSTRATED BY THE PROBLEM AND BY 998 00:36:38,000 --> 00:36:39,000 THE LACK OF THERAPEUTIC 999 00:36:39,000 --> 00:36:40,040 OPPORTUNITIES, SO I WANT TO SHOW 1000 00:36:40,040 --> 00:36:40,280 YOU WHAT I'M DOING WITH IT, 1001 00:36:40,280 --> 00:36:41,160 DOING ABOUT IT. 1002 00:36:41,160 --> 00:36:42,480 SO WHAT I SORT OF CAME UP WITH, 1003 00:36:42,480 --> 00:36:44,120 AND I DO OPERATE ON PATIENTS 1004 00:36:44,120 --> 00:36:45,800 WITH METASTASES QUITE 1005 00:36:45,800 --> 00:36:49,200 FREQUENTLY, AND I'LL DO LIVER 1006 00:36:49,200 --> 00:36:50,320 OPERATIONS, INSTEAD OF GIVING 1007 00:36:50,320 --> 00:36:51,840 THIS SPECIMEN TO PATHOLOGY, WHAT 1008 00:36:51,840 --> 00:36:54,880 I'VE COME UP WITH IS, WHAT IF WE 1009 00:36:54,880 --> 00:36:56,040 INSTEAD TOOK IT DOWN THE HALL TO 1010 00:36:56,040 --> 00:36:59,280 THE LAB AND CREATED A PERFUSION 1011 00:36:59,280 --> 00:37:02,480 MACHINE SUCH THAT WE COULD KEEP 1012 00:37:02,480 --> 00:37:05,440 THIS PIECE OF TISSUE WITH A 1013 00:37:05,440 --> 00:37:08,040 MACRO METASTASES AS WELL AS A 1014 00:37:08,040 --> 00:37:09,240 MICRO -- ALL OF THE -- ALL OF 1015 00:37:09,240 --> 00:37:11,080 THE MICRO METASTASES PRESENT 1016 00:37:11,080 --> 00:37:15,640 OUTSIDE OF A GIVEN PATIENT, WE 1017 00:37:15,640 --> 00:37:16,960 KNOW THOSE CELLS ARE GOING TO BE 1018 00:37:16,960 --> 00:37:18,600 THERE, ALREADY SOME HAVE BEGUN 1019 00:37:18,600 --> 00:37:20,480 TO OUTGROW, WE CAN PUT IN SOME 1020 00:37:20,480 --> 00:37:21,800 ANTIBODIES TO HELP IDENTIFY 1021 00:37:21,800 --> 00:37:23,480 THEM, AND THEN WE COULD BEGIN TO 1022 00:37:23,480 --> 00:37:24,880 UNDERSTAND WHAT THESE MICRO 1023 00:37:24,880 --> 00:37:26,240 METASTASES OR DISSEMINATED TUMOR 1024 00:37:26,240 --> 00:37:27,400 CELLS ARE ACTUALLY LIKE. 1025 00:37:27,400 --> 00:37:29,240 ARE THERE ANY THERAPEUTIC 1026 00:37:29,240 --> 00:37:31,880 VULNERABILITIES WE COULD USE TO 1027 00:37:31,880 --> 00:37:32,240 EXPLOIT. 1028 00:37:32,240 --> 00:37:33,480 AND THIS WAS A CONCEPT THAT I 1029 00:37:33,480 --> 00:37:35,480 SORT OF THOUGHT OF SHORTLY AFTER 1030 00:37:35,480 --> 00:37:39,480 ARRIVING ABOUT SIX YEARS AGO. 1031 00:37:39,480 --> 00:37:41,440 WE FINALLY MADE THIS HAPPEN 1032 00:37:41,440 --> 00:37:42,680 AFTER A LOT OF MONEY AND A LOT 1033 00:37:42,680 --> 00:37:44,960 OF TIME, AND THIS IS SORT OF 1034 00:37:44,960 --> 00:37:45,600 WHAT IT LOOKS LIKE. 1035 00:37:45,600 --> 00:37:51,320 WE SA CALL THIS THE TUMOR BEARIG 1036 00:37:51,320 --> 00:37:52,840 ORGAN MACHINE, PRIMARILY USED 1037 00:37:52,840 --> 00:37:54,720 FOR LIVER BUT WE CAN USE OTHER 1038 00:37:54,720 --> 00:37:55,040 ORGANS. 1039 00:37:55,040 --> 00:37:56,720 WE HAD TO REBUILD THE PATIENT'S 1040 00:37:56,720 --> 00:37:58,080 BODY AROUND THIS. 1041 00:37:58,080 --> 00:38:00,000 YOU COULDN'T JUST BUY A PUMP AND 1042 00:38:00,000 --> 00:38:00,840 AN OXYGENATOR. 1043 00:38:00,840 --> 00:38:02,200 WE TRIED THAT, IT WOULD HAVE 1044 00:38:02,200 --> 00:38:03,720 BEEN WAY SIMPLER BUT IT DIDN'T 1045 00:38:03,720 --> 00:38:04,040 WORK. 1046 00:38:04,040 --> 00:38:05,680 I'M GOING TO TAKE A FEW MOMENTS 1047 00:38:05,680 --> 00:38:07,320 TO SHOW YOU HOW WE DO THIS. 1048 00:38:07,320 --> 00:38:09,480 WE CREATED A HEART AND A PUMP, 1049 00:38:09,480 --> 00:38:12,440 AND FOR THE LIVER, THE LIVER HAS 1050 00:38:12,440 --> 00:38:13,920 TWO OUTFLOW SYSTEMS, WE USED 1051 00:38:13,920 --> 00:38:15,120 BOTH OF THOSE. 1052 00:38:15,120 --> 00:38:17,120 OF COURSE THERE'S LUNGS, WE USE 1053 00:38:17,120 --> 00:38:24,880 OXYGOXYGENATORS, WE LEARNED ALLF 1054 00:38:24,880 --> 00:38:25,440 THESE THINGS THE HARD WAY. 1055 00:38:25,440 --> 00:38:27,760 OF COURSE THERE WILL BE A 1056 00:38:27,760 --> 00:38:29,040 KIDNEY, SO YOU HAVE TO HAVE 1057 00:38:29,040 --> 00:38:29,800 FILTRATION, AND WE SORT OF 1058 00:38:29,800 --> 00:38:36,920 RIGGED THIS UP WITH VARIOUS PAIS 1059 00:38:36,920 --> 00:38:39,480 PUMPS, WE ALSO REMAKE THE 1060 00:38:39,480 --> 00:38:43,400 PANCREAS INSOFAR AS INSULIN AND 1061 00:38:43,400 --> 00:38:45,800 GLUCAGON, WE CAN TELL ABOUT THE 1062 00:38:45,800 --> 00:38:49,000 GLUCOSE UTILIZATION. 1063 00:38:49,000 --> 00:38:50,720 WE HAVE VASOPRESSOR SUBSTANCES 1064 00:38:50,720 --> 00:38:52,760 AVAILABLE TO USE, SIMULATING THE 1065 00:38:52,760 --> 00:38:56,000 ADRENAL GLANDS, AND THEN WE ALSO 1066 00:38:56,000 --> 00:38:58,520 HAVE THE G.I. TRACTS, WE HAVE 1067 00:38:58,520 --> 00:39:04,840 TPN AND VI BILE SALTS, AND THISS 1068 00:39:04,840 --> 00:39:05,640 INTEGRATED INTO A VERY 1069 00:39:05,640 --> 00:39:07,160 COMPLICATED COMPUTER SYSTEM THAT 1070 00:39:07,160 --> 00:39:08,480 WE WROTE THAT'S SEMI AUTOMATED 1071 00:39:08,480 --> 00:39:10,160 SO WE CAN UTILIZE THIS IN A WAY 1072 00:39:10,160 --> 00:39:10,920 THAT SOMEBODY DOESN'T HAVE TO 1073 00:39:10,920 --> 00:39:14,400 SLEEP NEXT TO IT ALL THE TIME. 1074 00:39:14,400 --> 00:39:15,480 ADMITTEDLY THEY DO AND THAT'S 1075 00:39:15,480 --> 00:39:16,800 WHAT THE SURGERY RESIDENTS DO 1076 00:39:16,800 --> 00:39:18,480 FOR U BUT IT'S A WORTHWHILE 1077 00:39:18,480 --> 00:39:19,920 CAUSE AND THEY'RE COMMITTED AND 1078 00:39:19,920 --> 00:39:21,640 SO AM I. 1079 00:39:21,640 --> 00:39:25,600 AND SO THIS IS SOMEBODY WITH A 1080 00:39:25,600 --> 00:39:26,280 METASTATIC NEUROENDOCRINE TUMOR. 1081 00:39:26,280 --> 00:39:27,800 I HAD TO CUT OUT HALF OF HER 1082 00:39:27,800 --> 00:39:29,440 LIVER IN ORDER TO GET THIS TUMOR 1083 00:39:29,440 --> 00:39:30,760 OUT, AND INSTEAD OF GIVING IT 1084 00:39:30,760 --> 00:39:32,320 STRAIGHT TO PATHOLOGY, WE GOT IT 1085 00:39:32,320 --> 00:39:33,840 ON THE BACK TABLE, WALKED TO THE 1086 00:39:33,840 --> 00:39:34,480 LAB. 1087 00:39:34,480 --> 00:39:36,360 WITHIN 10 MINUTES, IT WAS ON OUR 1088 00:39:36,360 --> 00:39:37,560 PERFUSION MACHINE, AND WE WERE 1089 00:39:37,560 --> 00:39:40,800 ABLE TO PERFUSE THIS ORGAN. 1090 00:39:40,800 --> 00:39:42,200 POSTOPERATIVE DAY NUMBER 5, I 1091 00:39:42,200 --> 00:39:43,360 WALKED THAT PATIENT BACK DOWN TO 1092 00:39:43,360 --> 00:39:45,800 THE LAB AND HER LIVER WITH HER 1093 00:39:45,800 --> 00:39:47,760 TUMOR IN IT AND ALL OF THOSE 1094 00:39:47,760 --> 00:39:49,200 MICRO METASTASES IS BEING 1095 00:39:49,200 --> 00:39:50,040 PERFUSED BEHIND HER. 1096 00:39:50,040 --> 00:39:51,880 AND SO I THINK THIS IS THE FIRST 1097 00:39:51,880 --> 00:39:53,320 WAY IN HUMANS WE COULD EVER 1098 00:39:53,320 --> 00:39:56,040 REALLY LOOK AT THIS. 1099 00:39:56,040 --> 00:39:58,360 AT LEAST IN ANY REAL WAY. 1100 00:39:58,360 --> 00:40:00,320 SO THIS IS HER LIVER 1101 00:40:00,320 --> 00:40:00,760 ENVIRONMENT. 1102 00:40:00,760 --> 00:40:03,320 I'M NOT SHOWING YOU ANY MICRO 1103 00:40:03,320 --> 00:40:04,080 METASTASES IN THIS PICTURE, BUT 1104 00:40:04,080 --> 00:40:06,040 THIS IS THE OSTENSIBLY NORMAL 1105 00:40:06,040 --> 00:40:07,400 LIVER THAT WE KNOW IS GOING TO 1106 00:40:07,400 --> 00:40:08,920 HAVE MICRO METASTASES IN IT. 1107 00:40:08,920 --> 00:40:10,320 THIS IS HER TUMOR AFTER ABOUT A 1108 00:40:10,320 --> 00:40:11,760 WEEK, AND IT LOOKS PRETTY 1109 00:40:11,760 --> 00:40:12,080 NORMAL. 1110 00:40:12,080 --> 00:40:13,520 AND SO NOW WE HAVE THE ABILITY 1111 00:40:13,520 --> 00:40:15,360 TO UNDERSTAND THE TUMOR 1112 00:40:15,360 --> 00:40:18,800 VULNERABILITIES, MATT CROW THE O 1113 00:40:18,800 --> 00:40:19,880 METASTASES AND THE POTENTIAL TO 1114 00:40:19,880 --> 00:40:21,560 FIND THOSE MACRO METASTASES. 1115 00:40:21,560 --> 00:40:23,280 WE'VE MADE THE HAYSTACK MUCH 1116 00:40:23,280 --> 00:40:24,440 SMALLER AND WE'RE ACTIVELY 1117 00:40:24,440 --> 00:40:26,920 LOOKING FOR THERAPEUTIC 1118 00:40:26,920 --> 00:40:28,040 VULNERABILITY SO I CAN COME UP 1119 00:40:28,040 --> 00:40:29,920 WITH NEW THERAPIES TO OFFER 1120 00:40:29,920 --> 00:40:30,720 PATIENTS LIKE KATE. 1121 00:40:30,720 --> 00:40:32,200 THAT'S ALL I WANT TO SHARE WITH 1122 00:40:32,200 --> 00:40:33,960 YOU, AND I SLIGHTLY WENT OVER 1123 00:40:33,960 --> 00:40:36,280 TIME AND I APOLOGIZE, BUT I 1124 00:40:36,280 --> 00:40:38,040 APPRECIATE THE OPPORTUNITY TO 1125 00:40:38,040 --> 00:40:43,200 SPEAK. 1126 00:40:43,200 --> 00:40:44,480 >> THANK YOU VERY MUCH, 1127 00:40:44,480 --> 00:40:45,080 JONATHAN. 1128 00:40:45,080 --> 00:40:45,800 THAT'S VERY EXCITING. 1129 00:40:45,800 --> 00:40:47,320 NOW WE'RE GOING TO GO ON TO 1130 00:40:47,320 --> 00:40:50,040 KANDICE TANNER. 1131 00:40:50,040 --> 00:40:52,840 KANDICE? 1132 00:40:52,840 --> 00:40:54,080 >> SO THANK YOU SO MUCH FOR THE 1133 00:40:54,080 --> 00:40:56,280 OPPORTUNITY TO SHARE OUR, I 1134 00:40:56,280 --> 00:40:57,480 GUESS, PERSPECTIVE IN TERMS OF 1135 00:40:57,480 --> 00:41:00,080 HOW WE APPROACH METASTASIS. 1136 00:41:00,080 --> 00:41:02,080 AND WE'VE ALREADY HAD SOME 1137 00:41:02,080 --> 00:41:03,960 EXCELLENT INTRODUCTIONS INTO THE 1138 00:41:03,960 --> 00:41:05,240 TOPIC, BUT WE'RE GOING TO PURSUE 1139 00:41:05,240 --> 00:41:07,560 IT FROM A DIFFERENT ANGLE IN 1140 00:41:07,560 --> 00:41:12,360 TERMS OF HOW MICROENVIRONMENTAL 1141 00:41:12,360 --> 00:41:14,360 FACTORS REGULATE THIS VERY 1142 00:41:14,360 --> 00:41:15,880 IMPORTANT PROCESS AND 1143 00:41:15,880 --> 00:41:17,240 UNFORTUNATELY LETHAL PROCESS OF 1144 00:41:17,240 --> 00:41:18,360 CANCER, AND WE'RE GOING TO 1145 00:41:18,360 --> 00:41:19,960 INTRODUCE CONCEPTS THAT PHYSICAL 1146 00:41:19,960 --> 00:41:22,040 PROPERTY, PHYSICAL 1147 00:41:22,040 --> 00:41:23,880 CHARACTERISTICS OF THESE TISSUES 1148 00:41:23,880 --> 00:41:25,840 AND MATRIX COMPONENTS WITHIN 1149 00:41:25,840 --> 00:41:28,160 THIS MICROENVIRONMENT ARE 1150 00:41:28,160 --> 00:41:29,480 IMPORTANT. 1151 00:41:29,480 --> 00:41:32,880 SO YOU MAY BE SURPRISED THAT 1152 00:41:32,880 --> 00:41:35,720 PHYSICS CAN PLAY A ROLE IN TERMS 1153 00:41:35,720 --> 00:41:41,080 OF CANCER BIOLOGY, SO LET'S 1154 00:41:41,080 --> 00:41:42,200 FIRST INTRODUCE THIS. 1155 00:41:42,200 --> 00:41:45,000 FIRST MY DISCLOSURES, AS WELL AS 1156 00:41:45,000 --> 00:41:47,000 THE OBJECTIVES OF TODAY. 1157 00:41:47,000 --> 00:41:48,320 SO IN TERMS OF ORIENTATION, 1158 00:41:48,320 --> 00:41:50,040 WE'RE LOOKING AT A 1159 00:41:50,040 --> 00:41:51,040 HISTOPATHOLOGY SLIDE HERE, AND 1160 00:41:51,040 --> 00:41:52,400 IT'S SHOWING A PROGRESSION, SO 1161 00:41:52,400 --> 00:41:54,240 THIS IS FROM A TISSUE BIOPSY 1162 00:41:54,240 --> 00:41:57,280 WHERE WE HAVE NORMAL EPITHELIUM, 1163 00:41:57,280 --> 00:41:59,080 THAT'S SEPARATE BID CONNECTIVE 1164 00:41:59,080 --> 00:42:01,720 TISSUE BY THIS SPECIALIZED 1165 00:42:01,720 --> 00:42:03,480 BASEMENT MEMBRANE, AND AS A 1166 00:42:03,480 --> 00:42:05,240 FUNCTION OF MALIGNANCY, SO FROM 1167 00:42:05,240 --> 00:42:07,040 LEFT TO RIGHT, WE'RE MOVING FROM 1168 00:42:07,040 --> 00:42:11,160 NORMAL TO FULL TUMORS, INDICATED 1169 00:42:11,160 --> 00:42:15,440 BY THESE SIMPLY MARCATIONS. 1170 00:42:15,440 --> 00:42:17,200 THERE ARE TWO OBVIOUS PHYSICAL 1171 00:42:17,200 --> 00:42:18,520 CHARACTERISTICS THAT YOU CAN 1172 00:42:18,520 --> 00:42:23,440 APPRECIATE FROM THESE BIOPSIES. 1173 00:42:23,440 --> 00:42:25,000 ONE IS THE SIZE OF THE CELLS IN 1174 00:42:25,000 --> 00:42:26,760 TERMS OF THESE NORMAL 1175 00:42:26,760 --> 00:42:28,840 COMPARTMENTS, AS WELL AS IN THE 1176 00:42:28,840 --> 00:42:31,480 STROMAL OR CONNECTIVE TISSUE ARE 1177 00:42:31,480 --> 00:42:31,680 ALTERED. 1178 00:42:31,680 --> 00:42:33,320 THE SECOND THING IS THAT THE 1179 00:42:33,320 --> 00:42:35,080 ARCHITECTURES IN TERMS OF HOW WE 1180 00:42:35,080 --> 00:42:36,440 DEFINE THESE TISSUE BOUNDARIES 1181 00:42:36,440 --> 00:42:39,600 ARE ALSO ALTERED AS A FUNCTION 1182 00:42:39,600 --> 00:42:40,920 OF MALIGNANCY. 1183 00:42:40,920 --> 00:42:42,720 AND AS A THIRD PROPERTY THAT WE 1184 00:42:42,720 --> 00:42:45,560 AND OTHERS HAVE SHOWN, THAT IT 1185 00:42:45,560 --> 00:42:47,760 IS ALSO ALTERED AS A FUNCTION OF 1186 00:42:47,760 --> 00:42:49,920 THIS TRANSITION FROM NORMAL TO 1187 00:42:49,920 --> 00:42:50,360 MALIGNANCY. 1188 00:42:50,360 --> 00:42:52,480 AND THAT IS IN THE SENSE THAT 1189 00:42:52,480 --> 00:42:54,640 MECHANICAL PROPERTIES OF THESE 1190 00:42:54,640 --> 00:42:57,200 TISSUES ALSO CHANGE DURING THIS 1191 00:42:57,200 --> 00:42:58,920 PROGRESSION. 1192 00:42:58,920 --> 00:43:00,680 SO THE IDEA THAT MECHANICAL 1193 00:43:00,680 --> 00:43:03,520 PROPERTIES IN ITSELF CAN BE USED 1194 00:43:03,520 --> 00:43:05,200 TO DELINEATE NORMAL TISSUES FROM 1195 00:43:05,200 --> 00:43:08,040 THAT OF CANCERS HAS BEEN KNOWN 1196 00:43:08,040 --> 00:43:09,880 SINCE ANTIQUITY. 1197 00:43:09,880 --> 00:43:15,320 IN EARLY EGYPTIAN PERIODS, IT 1198 00:43:15,320 --> 00:43:18,360 WAS SHOWN IN PAPYRUS SORT OF 1199 00:43:18,360 --> 00:43:22,040 MARKINGS THAT IF ONE USES SIMPLE 1200 00:43:22,040 --> 00:43:22,920 TOUCH, ONE CAN DIFFERENTIATE 1201 00:43:22,920 --> 00:43:25,600 THAT A CANCER MASS HAS A 1202 00:43:25,600 --> 00:43:26,760 DIFFERENT PHYSICAL OR MECHANICAL 1203 00:43:26,760 --> 00:43:27,880 PROPERTY COMPARED TO NORMAL 1204 00:43:27,880 --> 00:43:29,920 TISSUES. 1205 00:43:29,920 --> 00:43:32,680 BUT HOW DO WE THEN RECONCILE 1206 00:43:32,680 --> 00:43:34,880 THESE SORT OF ANECDOTAL, SORT OF 1207 00:43:34,880 --> 00:43:37,080 GROSS TYPES OF DATA AND 1208 00:43:37,080 --> 00:43:39,600 RE-CREATE IT IN A LAB? 1209 00:43:39,600 --> 00:43:42,320 SO YOU MAY HAVE HEARD OF THREE 1210 00:43:42,320 --> 00:43:45,680 DIMENSIONAL CULTURE SYSTEMS OR 1211 00:43:45,680 --> 00:43:48,600 ORGANORGANOID SIM TELLS, WITH TE 1212 00:43:48,600 --> 00:43:52,160 ABILITY TO RE-CREATE TISSUES 1213 00:43:52,160 --> 00:43:53,440 USING THESE HYDROGEL MODELS. 1214 00:43:53,440 --> 00:43:56,040 ON THE LEFT WE'RE LOOKING AT THE 1215 00:43:56,040 --> 00:44:02,200 RECREATION OF MAMMARY EPITHELIAL 1216 00:44:02,200 --> 00:44:03,560 ASSAY, WE CAN SEE THE EVOLUTION 1217 00:44:03,560 --> 00:44:06,360 AND DIFFERENT TYPES OF MOTILITY, 1218 00:44:06,360 --> 00:44:07,640 BUT MORE IMPORTANTLY, WE COULD 1219 00:44:07,640 --> 00:44:09,040 USE THESE AS SCREENS TO 1220 00:44:09,040 --> 00:44:10,880 RE-CREATE THESE TUMOR TISSUES 1221 00:44:10,880 --> 00:44:13,560 THAT JONATHAN JUST SPOKE ABOUT. 1222 00:44:13,560 --> 00:44:14,280 BUT ONE OF THE THINGS THAT 1223 00:44:14,280 --> 00:44:15,960 ALLOWS US TO DO IS TO BE ABLE TO 1224 00:44:15,960 --> 00:44:17,400 USE OPTICAL TECHNIQUES THAT ARE 1225 00:44:17,400 --> 00:44:18,600 SHOWN BELOW. 1226 00:44:18,600 --> 00:44:20,280 I'M GOING TO TALK BRIEFLY ABOUT 1227 00:44:20,280 --> 00:44:21,600 THEM LATER ON. 1228 00:44:21,600 --> 00:44:24,360 BUT JUST AS AN EXAMPLE, BY USING 1229 00:44:24,360 --> 00:44:26,320 THESE ORGANOID SYSTEMS AS WELL 1230 00:44:26,320 --> 00:44:31,800 AS OPTICAL BASED SYSTEMS, WE AND 1231 00:44:31,800 --> 00:44:33,160 OTHERS HAVE BEEN ABLE TO 1232 00:44:33,160 --> 00:44:34,320 IDENTIFY THESE MECHANICAL 1233 00:44:34,320 --> 00:44:37,040 CHANGES THAT OCCUR AS A FUNCTION 1234 00:44:37,040 --> 00:44:40,840 OF MALIGNANCY. 1235 00:44:40,840 --> 00:44:45,960 THE QUESTION IS -- WHAT EXCITED 1236 00:44:45,960 --> 00:44:47,080 ME, THIS CAN ALSO BE DONE IN THE 1237 00:44:47,080 --> 00:44:49,720 CLINIC RIGHT NOW, ALBEIT 1238 00:44:49,720 --> 00:44:51,560 DIFFERENT LENGTH SCALES, NOT 1239 00:44:51,560 --> 00:44:53,520 QUITE AT THE MICRO SCALE WE DO 1240 00:44:53,520 --> 00:44:55,640 IN TISSUES BUT IN MILLIMETER 1241 00:44:55,640 --> 00:44:56,800 SCALES IN TERMS OF IN VIVO. 1242 00:44:56,800 --> 00:44:58,880 AND ONE OF MY COLLEAGUES AND 1243 00:44:58,880 --> 00:45:00,760 COLLABORATORS USES ANOTHER 1244 00:45:00,760 --> 00:45:03,840 OPTICAL BASED TECHNIQUE KNOWN AS 1245 00:45:03,840 --> 00:45:09,600 MAGNETIC RESONANCE ELASTOGRAPHY 1246 00:45:09,600 --> 00:45:11,440 WHERE YOU CAN PROBE THE ABILITY 1247 00:45:11,440 --> 00:45:13,040 IF THESE TUMORS HAVE DIFFERENT 1248 00:45:13,040 --> 00:45:14,040 PHYSICAL OR MECHANICAL 1249 00:45:14,040 --> 00:45:15,400 PROPERTIES COMPARED TO NORMAL 1250 00:45:15,400 --> 00:45:17,080 TISSUE COUNTERPARTS. 1251 00:45:17,080 --> 00:45:18,800 SO I'VE SHOWN YOU THAT WE COULD 1252 00:45:18,800 --> 00:45:20,560 DO THESE MEASUREMENTS IN CULTURE 1253 00:45:20,560 --> 00:45:21,040 MODELS. 1254 00:45:21,040 --> 00:45:22,560 WE COULD DO THESE MEASUREMENTS 1255 00:45:22,560 --> 00:45:24,520 IN HUMANS. 1256 00:45:24,520 --> 00:45:26,160 BUT WHY YET IS THIS NOT BEING 1257 00:45:26,160 --> 00:45:29,040 USED ACTIVELY AS A DIAGNOSTIC 1258 00:45:29,040 --> 00:45:29,600 MODEL? 1259 00:45:29,600 --> 00:45:30,680 AND ONE OF THE REASONS BEING IS 1260 00:45:30,680 --> 00:45:34,080 THAT WE STILL CANNOT UNDERSTAND 1261 00:45:34,080 --> 00:45:36,160 THE BIOLOGY THAT DRIVES THESE 1262 00:45:36,160 --> 00:45:37,720 CHANGES IN A PREDICTABLE MANNER. 1263 00:45:37,720 --> 00:45:39,400 SO THIS IS ONE OF THE 1264 00:45:39,400 --> 00:45:40,680 OUTSTANDING QUESTIONS IN WHAT WE 1265 00:45:40,680 --> 00:45:44,560 WOULD CALL A FIELD OF CANCER 1266 00:45:44,560 --> 00:45:44,920 MECHANOBIOLOGY. 1267 00:45:44,920 --> 00:45:47,280 SO I'VE SPOKEN TO YOU ABOUT THE 1268 00:45:47,280 --> 00:45:50,560 ABILITY TO SEE THESE PHYSICAL 1269 00:45:50,560 --> 00:45:51,480 PROPERTIES, HOW THEY'RE USED 1270 00:45:51,480 --> 00:45:53,000 RIGHT NOW IN TERMS OF THEIR 1271 00:45:53,000 --> 00:45:54,880 STANDARD TECHNIQUES, BUT I 1272 00:45:54,880 --> 00:45:56,440 HAVEN'T SPOKEN TO YOU ABOUT 1273 00:45:56,440 --> 00:45:57,640 METASTASIS AND WHAT ROLE IT MAY 1274 00:45:57,640 --> 00:46:02,280 PLAY IN DRIVING THIS PROCESS. 1275 00:46:02,280 --> 00:46:03,320 SO WE'VE ALREADY HAD THIS 1276 00:46:03,320 --> 00:46:04,560 INTRODUCTION SO I'M GOING TO 1277 00:46:04,560 --> 00:46:05,280 RE-INTRODUCE THE CONCEPT FOR YOU 1278 00:46:05,280 --> 00:46:06,840 SO THAT YOU CAN LOOK AT IT FROM 1279 00:46:06,840 --> 00:46:09,480 A DYNAMIC PERSPECTIVE. 1280 00:46:09,480 --> 00:46:10,800 THIS IS A VERY CRUDE SCHEMATIC 1281 00:46:10,800 --> 00:46:14,200 OF A TUMOR, TUMOR CELLS ARE 1282 00:46:14,200 --> 00:46:16,000 SHOWN IN PURPLE. 1283 00:46:16,000 --> 00:46:17,200 TO ORIENT YOU, THIS IS SOME 1284 00:46:17,200 --> 00:46:19,360 EXAMPLE OF, IN THIS CASE, A 1285 00:46:19,360 --> 00:46:20,640 CONDUIT, A BLOOD VESSEL, AND 1286 00:46:20,640 --> 00:46:21,920 THESE ARE BLOOD CELLS, AND ONE 1287 00:46:21,920 --> 00:46:25,000 THING THAT YOU COULD APPRECIATE 1288 00:46:25,000 --> 00:46:26,880 THAT YES, METASTASIS DESCRIBES 1289 00:46:26,880 --> 00:46:28,200 THE DISSEMINATION FROM A PRIMARY 1290 00:46:28,200 --> 00:46:29,840 SITE WITHIN SOME CONDUIT, SO IN 1291 00:46:29,840 --> 00:46:32,120 SOME CASES, EVEN ALONG NERVES 1292 00:46:32,120 --> 00:46:33,720 AND SO FORTH, TO BE ABLE TO 1293 00:46:33,720 --> 00:46:35,440 SURVIVE AT A DISTANT SITE. 1294 00:46:35,440 --> 00:46:37,760 AS THIS MOVIE LOOPS, I WANT YOU 1295 00:46:37,760 --> 00:46:39,840 TO APPRECIATE THAT IT'S A 1296 00:46:39,840 --> 00:46:41,160 DYNAMIC PROCESS, THAT THESE 1297 00:46:41,160 --> 00:46:42,560 CELLS UNDERGO DIFFERENT CHANGES 1298 00:46:42,560 --> 00:46:45,200 IN TERMS OF THEIR CELL SHAPE. 1299 00:46:45,200 --> 00:46:46,800 THEY ENCOUNTER DIFFERENT CELL 1300 00:46:46,800 --> 00:46:47,360 TYPES. 1301 00:46:47,360 --> 00:46:50,000 AND HENCE THEY WILL BE EXPOSED 1302 00:46:50,000 --> 00:46:50,440 TO DIFFERENT PHYSICAL 1303 00:46:50,440 --> 00:46:52,720 ENVIRONMENTAL PRESSURES THAT MAY 1304 00:46:52,720 --> 00:46:56,240 INFLUENCE THE CELL'S ABILITY TO 1305 00:46:56,240 --> 00:46:59,480 SURVIVE OR GET -- ACQUIRE TRAITS 1306 00:46:59,480 --> 00:47:01,160 THAT MAY ENHANCE SURVIVABILITY 1307 00:47:01,160 --> 00:47:03,720 AT THEIR DISTANT SITES. 1308 00:47:03,720 --> 00:47:05,280 WE'VE ALREADY INTRODUCED THIS 1309 00:47:05,280 --> 00:47:12,160 CONCEPT THAT METASTASIS REMAI 1310 00:47:12,160 --> 00:47:14,320 REMAINS -- A MAIN CAUSE OF -- 1311 00:47:14,320 --> 00:47:16,960 WHERE 90% OF PATIENTS WITH 1312 00:47:16,960 --> 00:47:18,400 METASTATIC DISEASE WILL SUCCUMB 1313 00:47:18,400 --> 00:47:18,840 WITHIN FIVE YEARS. 1314 00:47:18,840 --> 00:47:20,040 SO FOR US, THE QUESTION THEN, 1315 00:47:20,040 --> 00:47:24,040 HOW CAN WE THEN BRING THIS IDEA 1316 00:47:24,040 --> 00:47:26,640 OF RE-CREATING THIS DYNAMIC 1317 00:47:26,640 --> 00:47:29,600 PROCESS INTO SOME OF THE MODEL 1318 00:47:29,600 --> 00:47:32,280 SYSTEMS THAT WE INTRODUCED 1319 00:47:32,280 --> 00:47:32,840 EARLIER. 1320 00:47:32,840 --> 00:47:34,080 SO THERE'S ONE MORE THING I NEED 1321 00:47:34,080 --> 00:47:36,240 TO TELL YOU ABOUT METASTASIS. 1322 00:47:36,240 --> 00:47:38,440 NOT ONLY IS IT DYNAMIC, NOT ONLY 1323 00:47:38,440 --> 00:47:39,960 DO THESE CELLS ENCOUNTER 1324 00:47:39,960 --> 00:47:41,520 DIFFERENT CELL TYPES AS THEY GO 1325 00:47:41,520 --> 00:47:44,760 ABOUT THEIR JOURNEY. 1326 00:47:44,760 --> 00:47:46,560 IS THAT HOW THEN DO WE RE-CREATE 1327 00:47:46,560 --> 00:47:49,560 THIS PROCESS? 1328 00:47:49,560 --> 00:47:50,440 IN TERMS OF BEING ABLE TO GET 1329 00:47:50,440 --> 00:47:51,000 THAT. 1330 00:47:51,000 --> 00:47:52,880 SO I'VE INTRODUCED THIS ORGANOID 1331 00:47:52,880 --> 00:47:54,800 MODEL. 1332 00:47:54,800 --> 00:47:56,240 I'VE INTRODUCED THE CONCEPT NOW 1333 00:47:56,240 --> 00:47:58,080 THAT I'M GOING TO INTRODUCE TO 1334 00:47:58,080 --> 00:48:00,120 YOU ANIMAL MODELS, IN THIS CASE, 1335 00:48:00,120 --> 00:48:03,240 WE USED ZEBRAFISH, AND HOW COULD 1336 00:48:03,240 --> 00:48:06,240 WE THEN BUILD IN THE COMPLEXITY 1337 00:48:06,240 --> 00:48:08,320 OF THESE DYNAMIC PROCESSES THAT 1338 00:48:08,320 --> 00:48:10,120 I JUST SHOWED YOU IN THE 1339 00:48:10,120 --> 00:48:10,840 SCHEMATIC. 1340 00:48:10,840 --> 00:48:13,600 SO AS A REMINDER, THESE ARE 1341 00:48:13,600 --> 00:48:14,720 THREE DIMENSIONAL HYDROGELS. 1342 00:48:14,720 --> 00:48:18,360 WHAT IS NOT SPE SEEN IN BLACK SS 1343 00:48:18,360 --> 00:48:19,560 HERE IS THAT THIS IS A MATRIX 1344 00:48:19,560 --> 00:48:20,880 THAT USUALLY REPRESENTS THE 1345 00:48:20,880 --> 00:48:22,360 CHEMISTRY AND BIOPHYSICAL 1346 00:48:22,360 --> 00:48:23,560 PROPERTIES THAT THESE CELLS 1347 00:48:23,560 --> 00:48:25,160 WOULD SEE IN AN ORGAN-SPECIFIC 1348 00:48:25,160 --> 00:48:25,520 MANNER. 1349 00:48:25,520 --> 00:48:27,920 AND I AS I PLAY THIS MOVIE HERE, 1350 00:48:27,920 --> 00:48:29,400 NOW, TO BE ABLE TO BUILD IN 1351 00:48:29,400 --> 00:48:31,560 THESE CONDUITS WHERE THESE 1352 00:48:31,560 --> 00:48:32,760 PHYSIOLOGICAL FORCES SUCH AS 1353 00:48:32,760 --> 00:48:35,760 BLOOD FLOW OR LYMPHATIC FLOW CAN 1354 00:48:35,760 --> 00:48:37,200 INFLUENCE AND IMPART FORCES ON 1355 00:48:37,200 --> 00:48:40,880 TO THESE CELLS, WE'RE USING A 1356 00:48:40,880 --> 00:48:41,480 LARVAL ZEBRAFISH. 1357 00:48:41,480 --> 00:48:43,360 SO TO ORIENT YOU, THIS IS NOW 1358 00:48:43,360 --> 00:48:45,120 THE HEAD OF THE FISH, THIS IS 1359 00:48:45,120 --> 00:48:48,160 ITS EYE, BLOOD VESSELS ARE IN 1360 00:48:48,160 --> 00:48:50,880 RED -- ARE IN GREEN, AND WHAT 1361 00:48:50,880 --> 00:48:53,560 YOU SEE IN HERE ARE HUMAN BREAST 1362 00:48:53,560 --> 00:48:55,160 CANCER CELLS THAT WERE 1363 00:48:55,160 --> 00:48:56,240 INTRODUCED INTO CIRCULATION AND 1364 00:48:56,240 --> 00:48:57,880 WE'RE ABLE TO FOLLOW THESE CELLS 1365 00:48:57,880 --> 00:48:59,600 WITH SINGLE CELL RESOLUTIONS AS 1366 00:48:59,600 --> 00:49:01,000 THEY TRAVERSE WITHIN THESE 1367 00:49:01,000 --> 00:49:04,040 CONDUITS, AND THEN WHAT YOU'RE 1368 00:49:04,040 --> 00:49:05,480 LOOKING AT IS THE ABILITY TO 1369 00:49:05,480 --> 00:49:07,280 FOLLOW VERY EARLY STAGES OF 1370 00:49:07,280 --> 00:49:08,480 EXTRAVASATION, NAMELY WHEN THESE 1371 00:49:08,480 --> 00:49:11,240 CELLS HAVE LEFT THESE BLOOD 1372 00:49:11,240 --> 00:49:12,840 VESSELS, IN THIS CASE, AND ENTER 1373 00:49:12,840 --> 00:49:15,760 INTO THE HEAD OF THE FISH. 1374 00:49:15,760 --> 00:49:19,760 SO THESE ARE NO MODELS THAT MO E 1375 00:49:19,760 --> 00:49:21,640 NOW MODELS THAT ALLOW US TO GET 1376 00:49:21,640 --> 00:49:23,360 TO EARLY STAGES THAT AS JONATHAN 1377 00:49:23,360 --> 00:49:25,080 POINTED OUT ARE NOT OPTICALLY 1378 00:49:25,080 --> 00:49:26,400 ACCESSIBLE RIGHT NOW IN HUMANS. 1379 00:49:26,400 --> 00:49:28,240 OF COURSE WE'D LIKE TO GET TO 1380 00:49:28,240 --> 00:49:29,480 THIS STAGE, BUT THIS IS WHERE 1381 00:49:29,480 --> 00:49:30,040 WE'RE AT TODAY. 1382 00:49:30,040 --> 00:49:31,440 BUT THERE'S ONE MORE THING I 1383 00:49:31,440 --> 00:49:39,960 NEED TO TELL BUT ME ABOUT META, 1384 00:49:39,960 --> 00:49:42,560 HERE I'M SHOWING YOU FOUR 1385 00:49:42,560 --> 00:49:43,880 DIFFERENT EXAMPLES, AND BASED ON 1386 00:49:43,880 --> 00:49:45,280 WHERE THESE TUMORS ORIGINATED, 1387 00:49:45,280 --> 00:49:47,520 IF WE FOCUS ON PROSTATE CANCER, 1388 00:49:47,520 --> 00:49:49,840 SOME MOLECULAR SUBTYPES OF 1389 00:49:49,840 --> 00:49:53,600 PROSTATE CANCER, PREFS LENGSLY 1390 00:49:53,600 --> 00:49:55,320 GO TO BONE, WHEREAS LUNG AND 1391 00:49:55,320 --> 00:49:58,320 BREAST CANCERS ARE FAIRLY 1392 00:49:58,320 --> 00:49:59,760 PROMISCUOUS IN THAT THEY CAN 1393 00:49:59,760 --> 00:50:01,080 COLONIZE MANY SITES SUCH AS THE 1394 00:50:01,080 --> 00:50:03,480 BONE, LIVER, LUNG AND BRAIN, 1395 00:50:03,480 --> 00:50:06,080 ALBEIT WITH DIFFERENT LATENCIES 1396 00:50:06,080 --> 00:50:07,840 AND ALSO TO SOME EXTENT BASED ON 1397 00:50:07,840 --> 00:50:11,320 THE MOLECULAR SUBTYPE. 1398 00:50:11,320 --> 00:50:14,720 SO THIS IDEA THAT THERE'S SOME 1399 00:50:14,720 --> 00:50:16,480 TROPISM IN THAT CELLS CAN ONLY 1400 00:50:16,480 --> 00:50:20,280 COLONIZE AND SURVIVE IN DISTANT 1401 00:50:20,280 --> 00:50:22,520 ORGANS HAVE ALREADY BEEN 1402 00:50:22,520 --> 00:50:24,400 DESCRIBED IN THAT HE COULD 1403 00:50:24,400 --> 00:50:26,040 FOLLOW THE OBSERVATION THAT 1404 00:50:26,040 --> 00:50:28,200 TUMOR CELLS, IF ONE CAN 1405 00:50:28,200 --> 00:50:31,800 APPROXIMATE THEM AS IF THEY WERE 1406 00:50:31,800 --> 00:50:33,960 SEEDS, WITH SOME GIVEN INTRINSIC 1407 00:50:33,960 --> 00:50:36,160 PROPERTIES, ONLY BEFELL ON 1408 00:50:36,160 --> 00:50:37,360 CONGENIAL SOIL, WHICH WOULD NOW 1409 00:50:37,360 --> 00:50:41,160 BE TH THE DISTANT SITES AND THAT 1410 00:50:41,160 --> 00:50:43,080 WHICH DRIVE ACROSS 1411 00:50:43,080 --> 00:50:44,080 COMPASSIBILITY, THAT ONLY THEN, 1412 00:50:44,080 --> 00:50:46,440 A SUCCESSFUL LESION EMERGES. 1413 00:50:46,440 --> 00:50:48,480 SO SINCE THAT EARLY OBSERVATION 1414 00:50:48,480 --> 00:50:50,880 IN 19TH CENTURY, YOU KNOW, THERE 1415 00:50:50,880 --> 00:50:53,800 ARE MANY SORT OF LIKE, I WOULD 1416 00:50:53,800 --> 00:50:59,320 SAY, SEMINAL WORKS BUILT ON THIS 1417 00:50:59,320 --> 00:51:01,120 FROM THE ORIGINAL FINDINGS IN 1418 00:51:01,120 --> 00:51:02,560 BREAST CANCERS TO OTHER TYPES OF 1419 00:51:02,560 --> 00:51:06,080 CANCERS, IN THAT FIGURING OUT 1420 00:51:06,080 --> 00:51:07,640 ONE OF THOSE TWO MAIN INTRINSIC 1421 00:51:07,640 --> 00:51:09,480 OR SEED PROPERTIES, VERSUS ONE 1422 00:51:09,480 --> 00:51:12,240 OF THOSE PROPERTIES THAT ARE 1423 00:51:12,240 --> 00:51:13,800 COMPATIBLE OR NEED TO BE 1424 00:51:13,800 --> 00:51:17,080 COMPATIBLE IN SOIL FOR THE ORGAN 1425 00:51:17,080 --> 00:51:21,720 OF THE SECONDARY OUTGROWTH. 1426 00:51:21,720 --> 00:51:24,680 SO THEY'VE SHOWN THERE'S SOME 1427 00:51:24,680 --> 00:51:25,520 GENE SIGNATURE THAT REGULATES 1428 00:51:25,520 --> 00:51:27,320 THIS PROCESS AND IN TERMS OF THE 1429 00:51:27,320 --> 00:51:28,440 CELL'S AVAILABILITY TO TALK TO 1430 00:51:28,440 --> 00:51:34,320 THE MICRO VIERPT, THIS ALSO, MIE 1431 00:51:34,320 --> 00:51:36,040 WITH CHEMOKINES OR THAT WE 1432 00:51:36,040 --> 00:51:37,080 RECEIVE FROM THE SOIL OR 1433 00:51:37,080 --> 00:51:40,680 SECONDARY SITE CAN THEN DIRECT 1434 00:51:40,680 --> 00:51:44,800 THIS COMPATIBILITY. 1435 00:51:44,800 --> 00:51:46,600 MORE RECENTLY, THE IDEA THAT 1436 00:51:46,600 --> 00:51:48,160 TUMOR CELLS SECRETE THESE 1437 00:51:48,160 --> 00:51:49,600 PACKETS OF EXOSOMES AND THAT 1438 00:51:49,600 --> 00:51:52,520 WHEN THEY GET TO THESE SECONDARY 1439 00:51:52,520 --> 00:51:57,280 SITES, MAKE THE ORGAN MORE 1440 00:51:57,280 --> 00:51:58,600 ACCESSIBLE FOR A SUCCESSFUL 1441 00:51:58,600 --> 00:52:01,360 OUTGROWTH OF TUMOR CELLS ONCE IT 1442 00:52:01,360 --> 00:52:06,400 GETS THERE, KNOWN AS THE 1443 00:52:06,400 --> 00:52:07,160 PREMETASTATIC NICHE. 1444 00:52:07,160 --> 00:52:08,560 SO THESE ARE SOME OF THE FACTORS 1445 00:52:08,560 --> 00:52:09,920 THAT HAVE SINCE BEEN DETERMINED 1446 00:52:09,920 --> 00:52:11,760 BUT WE'RE STILL NOT GETTING THAT 1447 00:52:11,760 --> 00:52:13,440 PREDICTABILITY IN TERMS OF COULD 1448 00:52:13,440 --> 00:52:17,280 WE REALLY PREDICT IF, ONE, A 1449 00:52:17,280 --> 00:52:19,160 TUMOR WOULD METASTASIZE IN A 1450 00:52:19,160 --> 00:52:20,680 GIVEN PATIENT, AND, MORE 1451 00:52:20,680 --> 00:52:22,320 IMPORTANTLY, WHERE WOULD IT 1452 00:52:22,320 --> 00:52:23,200 METASTASIZE TO. 1453 00:52:23,200 --> 00:52:25,240 SO WE PUT FORWARD THE HYPOTHESIS 1454 00:52:25,240 --> 00:52:31,040 THAT BECAUSE CELLS CAN UNDERGO 1455 00:52:31,040 --> 00:52:32,560 DIFFERENT FORCES AND DIFFERENT 1456 00:52:32,560 --> 00:52:36,600 PHYSICAL PROPERTIES CAN DIRECTLY 1457 00:52:36,600 --> 00:52:38,200 CHANGE GENE EXPRESSES, THAT THIS 1458 00:52:38,200 --> 00:52:40,360 MIGHT BE ONE OF THE MISSING 1459 00:52:40,360 --> 00:52:41,440 DETERMINANTS THAT CAN PLAY A 1460 00:52:41,440 --> 00:52:45,560 ROLE IN THIS NON-RANDOM 1461 00:52:45,560 --> 00:52:49,800 SELECTION DURING METASTASIS. 1462 00:52:49,800 --> 00:52:51,800 SO I'VE TOLD YOU THAT WE CAN USE 1463 00:52:51,800 --> 00:52:53,640 ZEBRAFISH AS A MODEL TO 1464 00:52:53,640 --> 00:52:56,080 RE-CREATE SOME OF THE 1465 00:52:56,080 --> 00:52:57,440 PHYSIOLOGICAL PRESSURES, BUT THE 1466 00:52:57,440 --> 00:52:59,240 IDEA IS THAT A MODEL NEEDS ALSO 1467 00:52:59,240 --> 00:53:03,040 TO BE RELEVANT FOR 1468 00:53:03,040 --> 00:53:03,600 HUMAN-SPECIFIC DISEASE. 1469 00:53:03,600 --> 00:53:05,040 SO I'M GOING TO INTRODUCE A FEW 1470 00:53:05,040 --> 00:53:06,320 CONCEPTS WHERE WE THINK THAT 1471 00:53:06,320 --> 00:53:08,280 SOME ASPECTS OF HUMAN RELEVANT 1472 00:53:08,280 --> 00:53:11,400 DISEASE CAN BE RECAPITULATED, 1473 00:53:11,400 --> 00:53:13,120 ESPECIALLY GIVEN THIS 1474 00:53:13,120 --> 00:53:17,160 ORGAN-SPECIFIC COLONIZATION. 1475 00:53:17,160 --> 00:53:19,360 SO IN THIS SCHEMATIC, WE'RE 1476 00:53:19,360 --> 00:53:20,440 LOOKING AT TWO DIFFERENT CLONES 1477 00:53:20,440 --> 00:53:21,960 OF A BREAST CANCER CELL LINE 1478 00:53:21,960 --> 00:53:24,080 THAT REPRESENTS A SUBTYPE KNOWN 1479 00:53:24,080 --> 00:53:25,600 AS TRIPLE NEGATIVE BREAST 1480 00:53:25,600 --> 00:53:26,920 CANCERS. 1481 00:53:26,920 --> 00:53:31,240 AND THEY EXIST SUCH THAT IF YOU 1482 00:53:31,240 --> 00:53:33,080 INTRODUCE THEM INTO MICE, A 1483 00:53:33,080 --> 00:53:34,840 BRAIN TARGETING CLONE GOES TO 1484 00:53:34,840 --> 00:53:38,480 THE BRAIN WHEREAS IF YOU 1485 00:53:38,480 --> 00:53:40,120 INTRODUCE BONE MARROW -- IT GOES 1486 00:53:40,120 --> 00:53:43,280 TO THE BONE MARROW. 1487 00:53:43,280 --> 00:53:45,040 SO IF WE CAN RE-CREATE THIS 1488 00:53:45,040 --> 00:53:47,040 ASPECT IN TERMS OF ORGAN 1489 00:53:47,040 --> 00:53:48,200 SPECIFIC COLONIZATION, WE SIMPLY 1490 00:53:48,200 --> 00:53:49,600 ASK THE QUESTION, IF WE 1491 00:53:49,600 --> 00:53:50,880 INTRODUCE THESE CLONES DIRECTLY 1492 00:53:50,880 --> 00:53:54,440 INTO THE FISH, DO WE THEN SEE 1493 00:53:54,440 --> 00:53:58,160 THE SAME PATTERN OF COLONIZATION 1494 00:53:58,160 --> 00:53:59,600 WHERE BRAIN TARGETING GOES TO 1495 00:53:59,600 --> 00:54:01,320 THE BRAIN AND BONE MARROW 1496 00:54:01,320 --> 00:54:04,480 TARGETING GOES TO THIS BO BONE 1497 00:54:04,480 --> 00:54:05,000 MARROW NICHE. 1498 00:54:05,000 --> 00:54:06,080 SO WHAT DID WE FIND? 1499 00:54:06,080 --> 00:54:07,800 HERE WE'RE LOOKING AT 1500 00:54:07,800 --> 00:54:08,160 MICROGRAPHS. 1501 00:54:08,160 --> 00:54:11,760 LET ME ORIENT YOU. 1502 00:54:11,760 --> 00:54:12,640 HERE'S THE HEAD OF THE FISH, 1503 00:54:12,640 --> 00:54:15,120 HERE IS ITS EYE. 1504 00:54:15,120 --> 00:54:17,960 AND WHAT WE OBSERVED IS THAT 1505 00:54:17,960 --> 00:54:20,560 FIVE DAYS AFTER INJECTION, WE 1506 00:54:20,560 --> 00:54:24,200 SEE THAT BRAIN TARGETING CELL 1507 00:54:24,200 --> 00:54:26,280 SHOWS MULTIPLE SITES OF 1508 00:54:26,280 --> 00:54:27,960 EXTRAVASATION AND GROWTH IN THE 1509 00:54:27,960 --> 00:54:29,760 HEAD OF THE FISH. 1510 00:54:29,760 --> 00:54:32,640 WHEREAS THE CLONE THAT'S HOME TO 1511 00:54:32,640 --> 00:54:38,360 THE BO BONE MARROW, THEY'RE DEVD 1512 00:54:38,360 --> 00:54:38,920 OF ANY CELLS. 1513 00:54:38,920 --> 00:54:41,120 TO BE SURE THIS IS REALLY A 1514 00:54:41,120 --> 00:54:42,600 NON-RANDOM SELECTION, WE NEED TO 1515 00:54:42,600 --> 00:54:44,000 QUANTIFY IN THE SAME FISH IF 1516 00:54:44,000 --> 00:54:45,200 THESE CELLS ARE REDIRECTED TO 1517 00:54:45,200 --> 00:54:47,880 THE OTHER ORGANS. 1518 00:54:47,880 --> 00:54:50,440 SO WHEN WE CHECK WITH BRAIN 1519 00:54:50,440 --> 00:54:52,000 TARGETING CELLS FOR OUR BONE 1520 00:54:52,000 --> 00:54:54,320 MARROW NICHE OF THE FISH, WE DO 1521 00:54:54,320 --> 00:54:56,000 SEE SOME BLUE CELLS PRESENT BUT 1522 00:54:56,000 --> 00:54:57,200 THEY'RE LARGELY DEAD OR DYING. 1523 00:54:57,200 --> 00:55:07,000 THEY HAVE MI MIXED TRAF SATED -- 1524 00:55:07,000 --> 00:55:09,640 HAVE INDEED WENT INTO THE BONE 1525 00:55:09,640 --> 00:55:10,720 MARROW NICHE AND ARE ACTIVELY 1526 00:55:10,720 --> 00:55:11,240 GROWING THERE. 1527 00:55:11,240 --> 00:55:14,280 SO I'M SHOWING YOU FOR -- BUT 1528 00:55:14,280 --> 00:55:18,240 WHAT IS COMING FOR BASIC SCIENCE 1529 00:55:18,240 --> 00:55:19,080 APPLICATIONS WE HAVE TO PROVE 1530 00:55:19,080 --> 00:55:20,320 THIS FOR MULTIPLE CLONES AND 1531 00:55:20,320 --> 00:55:21,520 THIS IS INDEED THE CASE. 1532 00:55:21,520 --> 00:55:23,080 BUT MOVING FORWARD, I'M JUST 1533 00:55:23,080 --> 00:55:24,520 GOING TO SHOW YOU SOME OF THESE 1534 00:55:24,520 --> 00:55:25,600 DATA. 1535 00:55:25,600 --> 00:55:27,920 SO ONE OF THE THINGS THAT WE 1536 00:55:27,920 --> 00:55:31,880 THINK IS THAT TUMOR CELLS NEED 1537 00:55:31,880 --> 00:55:34,160 TO GET STUCK. 1538 00:55:34,160 --> 00:55:36,240 SO THESE ARE NOW WHEN THESE 1539 00:55:36,240 --> 00:55:38,960 BLOOD VESSELS, ALL LYMPHATIC 1540 00:55:38,960 --> 00:55:41,080 VESSELS SOUGHT TO GET INTO THESE 1541 00:55:41,080 --> 00:55:43,400 VERY NARROW SPACES, WHERE THE 1542 00:55:43,400 --> 00:55:45,840 CELL DIAMETER IS COMPARABLE 1543 00:55:45,840 --> 00:55:48,040 INSIDE TO THE WIDTH OF THE 1544 00:55:48,040 --> 00:55:48,240 VESSELS. 1545 00:55:48,240 --> 00:55:50,040 AND WHEN WE FIRST FOCUSED HERE 1546 00:55:50,040 --> 00:55:50,960 JUST IN THE INTEREST BECAUSE 1547 00:55:50,960 --> 00:55:53,760 THIS IS SUPPORTED TO BE AN 1548 00:55:53,760 --> 00:55:56,160 OVERVIEW, WE'VE NOTICED THAT IF 1549 00:55:56,160 --> 00:55:57,800 WE UNDERSTAND HOW THESE CELLS 1550 00:55:57,800 --> 00:56:02,280 INTERACT WITH THESE ENT THEEL EL 1551 00:56:02,280 --> 00:56:10,200 CELLS AT THIS INTERFACE -- HOW 1552 00:56:10,200 --> 00:56:13,280 DO WE FINE THAT LESS DEFINED -- 1553 00:56:13,280 --> 00:56:15,040 CONCEPTS HOW IN ADDITION TO 1554 00:56:15,040 --> 00:56:16,800 GENETIC MODULATION, THAT 1555 00:56:16,800 --> 00:56:17,840 BIOPHYSICAL PROPERTIES MAY PLAY 1556 00:56:17,840 --> 00:56:21,080 A ROLE. 1557 00:56:21,080 --> 00:56:22,480 SO LET'S START WITH THE 1558 00:56:22,480 --> 00:56:23,120 FOLLOWING SCHEMATIC. 1559 00:56:23,120 --> 00:56:24,520 ON YOUR LEFT, I'M SHOWING YOU 1560 00:56:24,520 --> 00:56:28,320 NOW WWHEN A CELL GETS STUCK IN A 1561 00:56:28,320 --> 00:56:30,080 BLOOD VESSEL THAT'S COMPARABLE 1562 00:56:30,080 --> 00:56:32,560 IN SIZE, AND THE CELL ITSELF CAN 1563 00:56:32,560 --> 00:56:34,920 BE FINE AS IF IT HAS MATERIAL 1564 00:56:34,920 --> 00:56:36,960 PROPERTIES JUST AS IF YOU WERE 1565 00:56:36,960 --> 00:56:39,960 PICKING UP THIS BOTTLE THAT HAS 1566 00:56:39,960 --> 00:56:42,360 SOME GIVEN SOFTNESS OR STIFFNESS 1567 00:56:42,360 --> 00:56:44,200 VERSUS JUST LIKE -- A CELL HAS 1568 00:56:44,200 --> 00:56:45,480 THAT DIFFERENT TYPE OF MATERIAL, 1569 00:56:45,480 --> 00:56:46,800 WHICH I'M GOING TO INTRODUCE 1570 00:56:46,800 --> 00:56:49,080 WHAT WE MEAN BY THAT LATER. 1571 00:56:49,080 --> 00:56:51,840 BUT BY UNDERSTANDING CELLS' 1572 00:56:51,840 --> 00:56:54,360 MECHANICAL PROPERTY IN ASSIGNING 1573 00:56:54,360 --> 00:56:56,880 THAT MECHANICAL SIGNATURE, THESE 1574 00:56:56,880 --> 00:56:59,440 CELLS, IN ORDER TO MAINTAIN CELL 1575 00:56:59,440 --> 00:57:01,160 SHAPE, OR THE ABILITY TO BE ABLE 1576 00:57:01,160 --> 00:57:03,040 TO GET OUT, THEY ALSO WOULD BE 1577 00:57:03,040 --> 00:57:05,720 INFLUENCED BY THE MECHANICAL 1578 00:57:05,720 --> 00:57:07,320 PROPERTIES OF THESE BLOOD 1579 00:57:07,320 --> 00:57:08,200 VESSELS THAT THEY'RE STUCK IN. 1580 00:57:08,200 --> 00:57:09,720 SO I WANT YOU TO THINK ABOUT IF 1581 00:57:09,720 --> 00:57:12,920 A CELL IS IN A TUBE AND IS 1582 00:57:12,920 --> 00:57:15,760 TRYING TO GET OUT, WHEN THE 1583 00:57:15,760 --> 00:57:17,200 FORCES THAT ARE IMPARTING ON 1584 00:57:17,200 --> 00:57:19,080 THESE CELLS AT THAT TUBE IS 1585 00:57:19,080 --> 00:57:20,640 GOING TO INFLUENCE THE CELLS' 1586 00:57:20,640 --> 00:57:23,080 ABILITY TO MAINTAIN ITS SHAPE OR 1587 00:57:23,080 --> 00:57:28,040 THE ABILITY TO OVERCOME TO GET 1588 00:57:28,040 --> 00:57:33,840 OUT SO ONE OF THE LIMITING STEPS 1589 00:57:33,840 --> 00:57:34,880 IN MOVING THIS FORWARD IS THAT 1590 00:57:34,880 --> 00:57:37,040 WHAT DO WE MEAN AND HOW DO WE 1591 00:57:37,040 --> 00:57:38,560 MEASURE WHAT CELLS SENSE ONCE 1592 00:57:38,560 --> 00:57:44,240 THEY GET INTO THESE IN VIVO-LIKE 1593 00:57:44,240 --> 00:57:49,160 SITUATIONS. 1594 00:57:49,160 --> 00:57:51,840 , OPTICAL TWEEZERS HAD BEEN 1595 00:57:51,840 --> 00:57:54,360 USED, IN FACT THE NOBEL PRIZE IN 1596 00:57:54,360 --> 00:57:56,400 PHYSICS HAD BEEN OPTICAL 1597 00:57:56,400 --> 00:57:57,520 TWEEZERS HAS BEEN GIVEN A FEW 1598 00:57:57,520 --> 00:58:01,880 YEARS AGO NOW,, AND WE'RE GOING 1599 00:58:01,880 --> 00:58:04,480 TO INTRODUCE THIS CONCEPT IN 1600 00:58:04,480 --> 00:58:05,480 THESE VERY COMPLEX MECHANICAL 1601 00:58:05,480 --> 00:58:08,600 PROPERTIES KNOWN AS A SHARED MOD 1602 00:58:08,600 --> 00:58:08,840 MODULUS. 1603 00:58:08,840 --> 00:58:10,160 BY DOING THIS, WE COULD THEN 1604 00:58:10,160 --> 00:58:12,760 UNDERSTAND THIS RELATIVE BALANCE 1605 00:58:12,760 --> 00:58:14,320 BETWEEN THE CELLS' ABILITY TO 1606 00:58:14,320 --> 00:58:16,840 MAINTAIN CELL SHAPE AND TO GET 1607 00:58:16,840 --> 00:58:18,080 OUT. 1608 00:58:18,080 --> 00:58:19,960 A SECOND PHYSICAL PROPERTY THAT 1609 00:58:19,960 --> 00:58:21,480 THESE CELLS ENCOUNTER ONCE 1610 00:58:21,480 --> 00:58:24,080 THEY'RE IN THESE SORT OF 1611 00:58:24,080 --> 00:58:26,160 CAPILLARY BEDS IS THAT THE 1612 00:58:26,160 --> 00:58:28,280 ABILITY TO BIND IN TERMS OF 1613 00:58:28,280 --> 00:58:32,680 RECEIVING QUEUES EITHER BY -- BY 1614 00:58:32,680 --> 00:58:36,840 RECEPTOR LIGAND PARENTS, 1615 00:58:36,840 --> 00:58:38,080 PHYSICAL OR -- PROPERTIES, ALSO 1616 00:58:38,080 --> 00:58:39,880 REGULATED BY THE MEMBRANE 1617 00:58:39,880 --> 00:58:43,480 PROPERTIES. 1618 00:58:43,480 --> 00:58:45,760 SO SO IF THE CELL IS IN THESE 1619 00:58:45,760 --> 00:58:47,480 CURVED TYPES OF BEHAVIORS AND 1620 00:58:47,480 --> 00:58:48,560 THE MEMBRANES WOULD THEN BE 1621 00:58:48,560 --> 00:58:49,960 INFLUENCED BY THAT CURVATURE AND 1622 00:58:49,960 --> 00:58:52,520 IT COULD INFLUENCE HOW THESE 1623 00:58:52,520 --> 00:58:54,320 DIFFERENT RECEPTORS CLUSTER AT 1624 00:58:54,320 --> 00:58:58,320 THE CELL SURFACE THAT THEN DRIVE 1625 00:58:58,320 --> 00:59:00,800 DOWNSTREAM SIGNALING EFFECTS. 1626 00:59:00,800 --> 00:59:03,600 IN ADDITION, NOT ONLY DOES IT 1627 00:59:03,600 --> 00:59:04,640 INFLUENCE THE MEMBRANE 1628 00:59:04,640 --> 00:59:05,720 STRUCTURES IN TERMS OF 1629 00:59:05,720 --> 00:59:07,480 CLUSTERING, IT MAY ALSO DRIVE A 1630 00:59:07,480 --> 00:59:08,960 PREFERENCE FOR ONE TYPE OF 1631 00:59:08,960 --> 00:59:10,480 RECEPTOR VERSUS THE OTHER, 1632 00:59:10,480 --> 00:59:12,280 BECAUSE THESE HAVE BEEN SHOWN TO 1633 00:59:12,280 --> 00:59:13,880 BE ALSO SENSITIVE TO DIFFERENT 1634 00:59:13,880 --> 00:59:17,280 PHYSICAL PROPERTIES. 1635 00:59:17,280 --> 00:59:18,880 SO WHAT WE CAN THEN DO BECAUSE 1636 00:59:18,880 --> 00:59:20,920 WE HAVE THE SINGLE CELL 1637 00:59:20,920 --> 00:59:22,840 RESOLUTION IS DEFINE THESE 1638 00:59:22,840 --> 00:59:24,360 ARCHITECTURAL CHANGES, AND THEN 1639 00:59:24,360 --> 00:59:25,960 MOVE FORWARD IN TERMS OF HOW DO 1640 00:59:25,960 --> 00:59:28,280 THEY THEN INFLUENCE CELLS' 1641 00:59:28,280 --> 00:59:30,200 ABILITY TO SENSE AND RESPOND TO 1642 00:59:30,200 --> 00:59:33,400 THESE QUEUES AND IF THESE ARE, 1643 00:59:33,400 --> 00:59:35,760 INDEED FACTORS IN DRIVING THE 1644 00:59:35,760 --> 00:59:38,360 NON-RANDOM SELECTION THAT WE 1645 00:59:38,360 --> 00:59:39,840 OBSERVED. 1646 00:59:39,840 --> 00:59:41,880 SO I INTRODUCED MECHANICAL 1647 00:59:41,880 --> 00:59:42,680 PROPERTIES BUT I DIDN'T REALLY 1648 00:59:42,680 --> 00:59:44,880 GET INTO WHAT DOES IT MEAN, THE 1649 00:59:44,880 --> 00:59:47,880 COMPLEXITY OF IT, AND HOW COULD 1650 00:59:47,880 --> 00:59:49,080 WE POSSIBLY DEFINE THEM SO THAT 1651 00:59:49,080 --> 00:59:50,720 IN THE EVENT WE COULD USE IT AS 1652 00:59:50,720 --> 00:59:54,320 A POTENTIAL BIOMARKER. 1653 00:59:54,320 --> 00:59:56,600 SO TISSUES ARE NEITHER JUST 1654 00:59:56,600 --> 00:59:58,720 SIMPLY ELASTIC OR SIMPLY SOLID. 1655 00:59:58,720 --> 01:00:00,120 THEY SHOW A COMBINATION OF THE 1656 01:00:00,120 --> 01:00:03,480 TWO, WHICH IS KNOWN AS 1657 01:00:03,480 --> 01:00:04,280 VISCOELASTICITY. 1658 01:00:04,280 --> 01:00:07,120 SO AS I PLAY THIS MOVIE, THIS IS 1659 01:00:07,120 --> 01:00:09,680 A FLUID REPRESENTATIVE OF WHAT A 1660 01:00:09,680 --> 01:00:10,520 VISCOELASTIC MATERIAL BEHAVES 1661 01:00:10,520 --> 01:00:12,280 LIKE, AND YOU SEE AS A FUNCTION 1662 01:00:12,280 --> 01:00:16,320 OF HOW IN THIS CASE A FINGER 1663 01:00:16,320 --> 01:00:17,080 INTERROGATES THIS MATERIAL, ON 1664 01:00:17,080 --> 01:00:20,680 YOUR LEFT YOU SEE THAT AT HIGH 1665 01:00:20,680 --> 01:00:22,440 FREQUENCIES, SO VERY FAST 1666 01:00:22,440 --> 01:00:24,040 TAPPING, THE MATERIAL BEHAVES AS 1667 01:00:24,040 --> 01:00:26,000 IF IT HAS MORE SOLID-LIKE 1668 01:00:26,000 --> 01:00:26,880 PROPERTIES. 1669 01:00:26,880 --> 01:00:30,320 WHEREAS, IF YOU THEN LOOK AT THE 1670 01:00:30,320 --> 01:00:32,560 SAME MATERIAL WHERE YOU PROBE AT 1671 01:00:32,560 --> 01:00:34,360 LOWER FREQUENCIES, SO LONGER 1672 01:00:34,360 --> 01:00:36,760 TIME SCALES, THIS MATERIAL 1673 01:00:36,760 --> 01:00:39,400 BEHAVES MORE LIQUID-LIKE. 1674 01:00:39,400 --> 01:00:42,120 SO THE IDEA NOW THAT DEFINING 1675 01:00:42,120 --> 01:00:43,200 THESE TWO PROPERTIES CAN BE 1676 01:00:43,200 --> 01:00:47,640 SHOWN IN THIS FORMULA BELOW, 1677 01:00:47,640 --> 01:00:49,720 WHERE THE RELATIVE CONTRIBUTIONS 1678 01:00:49,720 --> 01:00:52,680 ARE GIVEN BY THE STORAGE, AND 1679 01:00:52,680 --> 01:00:55,160 IMAGINARY -- THAT GOES THROUGH 1680 01:00:55,160 --> 01:00:57,920 THIS LOSS MODULUS. 1681 01:00:57,920 --> 01:00:58,920 BY UNDERSTANDING THESE THINGS, 1682 01:00:58,920 --> 01:01:00,480 NOT ONLY CAN WE DEFINE EITHER 1683 01:01:00,480 --> 01:01:01,720 THE MECHANICAL PROPERTIES OF 1684 01:01:01,720 --> 01:01:03,440 THESE CELLS, THE IDEA IS ONCE WE 1685 01:01:03,440 --> 01:01:06,280 MEASURE THEM, AND LINK THAT TO 1686 01:01:06,280 --> 01:01:09,520 BIOLOGICAL SIGNATURE, THEN MAYBE 1687 01:01:09,520 --> 01:01:13,240 THEY MAY GIVE A HINT IN TERMS OF 1688 01:01:13,240 --> 01:01:13,920 BIOMARKERS FOR THERAPY. 1689 01:01:13,920 --> 01:01:15,040 SO GOING BACK TO THE 1690 01:01:15,040 --> 01:01:19,240 DEMONSTRATION OF IF THE LARVAL 1691 01:01:19,240 --> 01:01:20,080 ZEBRAFISH CAN RECAPITULATE SOME 1692 01:01:20,080 --> 01:01:22,320 ASPECTS OF HUMAN DISEASE, ONE OF 1693 01:01:22,320 --> 01:01:24,320 THE THINGS WE ASK SIMPLY IS AS A 1694 01:01:24,320 --> 01:01:26,000 FUNCTION OF WHERE THESE CELLS 1695 01:01:26,000 --> 01:01:27,760 HOME TO, WHETHER THEY WENT TO 1696 01:01:27,760 --> 01:01:29,000 BRAIN VERSUS A BONE MARROW, 1697 01:01:29,000 --> 01:01:30,280 COULD WE USE THAT AS OUR METRIC 1698 01:01:30,280 --> 01:01:34,440 IN ITSELF, JUST LIKE SOME GENE 1699 01:01:34,440 --> 01:01:36,160 SIGNATURE, TO BE ABLE TO 1700 01:01:36,160 --> 01:01:37,360 DETERMINE OR MATCH A MECHANICAL 1701 01:01:37,360 --> 01:01:41,840 SIGNATURE TO THAT PROCESS. 1702 01:01:41,840 --> 01:01:46,600 SO ON THE Y AXIS WE SIMPLY SHOW 1703 01:01:46,600 --> 01:01:51,240 YOU THE -- ON THE X AXIS ARE 1704 01:01:51,240 --> 01:01:52,520 FREQUENCIES, AND WHAT I WANT YOU 1705 01:01:52,520 --> 01:01:56,240 TO TAKE AWAY TB FROM THIS, WE CN 1706 01:01:56,240 --> 01:01:57,680 DEFINE A FACTOR HERE THAT THEN 1707 01:01:57,680 --> 01:02:00,680 ALLOWS US TO THEN USE THIS AS A 1708 01:02:00,680 --> 01:02:02,400 METRIC TO DEFINE A MECHANICAL 1709 01:02:02,400 --> 01:02:03,080 PHENOTYPE. 1710 01:02:03,080 --> 01:02:04,720 SO THIS CROSSOVER FREQUENCY 1711 01:02:04,720 --> 01:02:08,080 SIMPLY TELLS ME WHEN A MATERIAL 1712 01:02:08,080 --> 01:02:10,120 BECOMES MORE SOLID-LIKE VERSUS 1713 01:02:10,120 --> 01:02:10,960 LIQUID-LIKE. 1714 01:02:10,960 --> 01:02:12,520 AS IT SHIFTS FROM LEFT TO RIGHT, 1715 01:02:12,520 --> 01:02:13,960 IF IT GOES TO THE LEFT THAT, 1716 01:02:13,960 --> 01:02:15,600 MEANS MATERIAL HAS MORE 1717 01:02:15,600 --> 01:02:16,560 LIQUID-LIKE PROPERTIES. 1718 01:02:16,560 --> 01:02:19,000 IF IT GOES TO THE RIGHT, IT 1719 01:02:19,000 --> 01:02:21,400 ALLOWS US TO TELL US IT'S MORE 1720 01:02:21,400 --> 01:02:22,720 SOLID-LIKE BUT MORE IMPORTANTLY, 1721 01:02:22,720 --> 01:02:24,320 IT GIVES US A QUANTITATIVE 1722 01:02:24,320 --> 01:02:26,440 PARAMETER THAT ASSIGNS A 1723 01:02:26,440 --> 01:02:28,040 MECHANICAL PHENOTYPE. 1724 01:02:28,040 --> 01:02:29,240 SIMPLY LIKE IF YOU ARE TRYING TO 1725 01:02:29,240 --> 01:02:33,040 ASSIGN A GENE EXPRESSION, THIS 1726 01:02:33,040 --> 01:02:35,480 GIVES US THE SAME MECHANICAL 1727 01:02:35,480 --> 01:02:36,280 SIGNATURE. 1728 01:02:36,280 --> 01:02:38,480 SO JUST AS A REMINDER WHAT SOLID 1729 01:02:38,480 --> 01:02:40,880 LIKE AND LIQUID LIKE MEAN, WHAT 1730 01:02:40,880 --> 01:02:42,320 WE COMPARE, THIS IS NOW THE 1731 01:02:42,320 --> 01:02:43,800 PARENTAL CLONE FROM WHICH EACH 1732 01:02:43,800 --> 01:02:46,760 OF THESE CLONES WERE DERIVED, WE 1733 01:02:46,760 --> 01:02:54,280 SEE NOW THAT THE CLONE TO THE 1734 01:02:54,280 --> 01:02:57,080 BONE MARROW, MORE LIQUID-LIKE, 1735 01:02:57,080 --> 01:02:58,280 VERSUS THE CLONE THAT WENT MORE 1736 01:02:58,280 --> 01:02:59,280 TO THE BRAIN. 1737 01:02:59,280 --> 01:03:00,840 SO WE CAN SEE IN ADDITION TO 1738 01:03:00,840 --> 01:03:01,640 GENE EXPRESSION CHANGES THAT I 1739 01:03:01,640 --> 01:03:04,040 DIDN'T SHOW YOU EARLIER BUT WE 1740 01:03:04,040 --> 01:03:04,920 KNOW EXIST BETWEEN CLONES, THAT 1741 01:03:04,920 --> 01:03:06,920 THERE'S A MECHANICAL SIGNATURE 1742 01:03:06,920 --> 01:03:09,040 THAT CAN BE PULLED OUT AND THIS 1743 01:03:09,040 --> 01:03:10,360 IS QUITE EXCITING FROM THE 1744 01:03:10,360 --> 01:03:13,440 PRIMARY TUMOR. 1745 01:03:13,440 --> 01:03:15,240 BUT NOW WE WANT TO GET BACK TO 1746 01:03:15,240 --> 01:03:18,160 THIS IDEA OF IS THIS THEN 1747 01:03:18,160 --> 01:03:19,920 INDICATIVE OR AN ADVANTAGE IN 1748 01:03:19,920 --> 01:03:22,080 TERMS OF BEING ABLE TO GET OUT 1749 01:03:22,080 --> 01:03:23,840 INTO THESE SECONDARY SITES. 1750 01:03:23,840 --> 01:03:26,320 SO CAN WE GO BACK TO OUR FORCE 1751 01:03:26,320 --> 01:03:28,360 BALANCE TO UNDERSTAND WHAT TYPES 1752 01:03:28,360 --> 01:03:31,320 OF PRESSURE OR I WOULD SAY 1753 01:03:31,320 --> 01:03:33,720 RESISTANCE THESE ENDOTHELIAL 1754 01:03:33,720 --> 01:03:35,040 BARRIERS HAVE AT THESE SECONDARY 1755 01:03:35,040 --> 01:03:36,640 SITES. 1756 01:03:36,640 --> 01:03:38,080 AND WHILE I'M SHOWING YOU DATA 1757 01:03:38,080 --> 01:03:39,720 IN A DIFFERENT FORM WHERE NOW WE 1758 01:03:39,720 --> 01:03:41,560 HAVE THIS MAGNITUDE OF THE 1759 01:03:41,560 --> 01:03:47,120 COMPLEX MODULUS, THE CROSSOVER 1760 01:03:47,120 --> 01:03:49,040 FREQUENCY -- ONE CAN APPRECIATE 1761 01:03:49,040 --> 01:03:51,320 THAT THERE ARE NO DIFFERENCES AS 1762 01:03:51,320 --> 01:03:53,640 A FUNCTION OF WHERE THESE 1763 01:03:53,640 --> 01:03:54,360 ENDOTHELIAL CELLS -- THE 1764 01:03:54,360 --> 01:03:55,480 MECHANICAL PROPERTIES OF THE 1765 01:03:55,480 --> 01:03:56,920 ENDOTHELIAL CELLS. 1766 01:03:56,920 --> 01:03:58,600 SO AT LEAST WE COULD SAY AT THE 1767 01:03:58,600 --> 01:04:02,360 AGES AT WHICH WE SEE THESE 1768 01:04:02,360 --> 01:04:03,680 EXTRAVASATION EVENTS ARE 1769 01:04:03,680 --> 01:04:04,680 NON-RANDOM, AT LEAST THAT 1770 01:04:04,680 --> 01:04:05,760 MECHANICAL PROPERTY WAS 1771 01:04:05,760 --> 01:04:06,480 CONSTANT. 1772 01:04:06,480 --> 01:04:08,560 INSTEAD NOW, LET'S INVESTIGATE 1773 01:04:08,560 --> 01:04:11,160 THE SECOND ASPECT OF THE CELLS' 1774 01:04:11,160 --> 01:04:14,120 ABILITY TO RESPOND TO THESE 1775 01:04:14,120 --> 01:04:15,720 QUEUES VIA THE INFLUENCE ON 1776 01:04:15,720 --> 01:04:16,480 MEMBRANE DYNAMICS. 1777 01:04:16,480 --> 01:04:18,800 AND WHAT WE DID IS THAT IF WE 1778 01:04:18,800 --> 01:04:21,400 QUANTIFIED IN TERMS OF THE 1779 01:04:21,400 --> 01:04:25,120 CURVATURE THAT THESE CELLS SAW, 1780 01:04:25,120 --> 01:04:28,840 IS THAT THE BONE MARROW NICHE -- 1781 01:04:28,840 --> 01:04:30,680 PLEXUS IS MUCH MORE HIGHLY 1782 01:04:30,680 --> 01:04:32,520 CURVED COMPARED TO THAT OF THE 1783 01:04:32,520 --> 01:04:35,160 BRAIN, AND WE USE THESE 1784 01:04:35,160 --> 01:04:36,280 INTERSEGMENTAL VESSELS AS A 1785 01:04:36,280 --> 01:04:37,080 CONTROL. 1786 01:04:37,080 --> 01:04:39,000 AND WITH THAT, WE SIMPLY ASK 1787 01:04:39,000 --> 01:04:41,360 THEN, COULD THAT BE ONE OF THE 1788 01:04:41,360 --> 01:04:44,000 REASONS WHERE MOST OF THE BRAIN 1789 01:04:44,000 --> 01:04:45,160 TARGETED CELLS PREFER TO GET 1790 01:04:45,160 --> 01:04:48,000 STUCK IN THE BRAIN ENVIRONMENT 1791 01:04:48,000 --> 01:04:50,080 VERSUS THE VASCULAR PLEXUS. 1792 01:04:50,080 --> 01:04:52,160 AND TO OUR SURPRISE, WHAT WE 1793 01:04:52,160 --> 01:04:54,240 FOUND IS THAT INDEPENDENTLY OF 1794 01:04:54,240 --> 01:04:56,600 THE CELL TYPE, SO LET ME TALK 1795 01:04:56,600 --> 01:04:59,360 YOU THROUGH THIS VERY BUSY 1796 01:04:59,360 --> 01:05:01,160 CURVE, IS THAT WE'RE NOW 1797 01:05:01,160 --> 01:05:02,160 QUANTIFYING VERY EARLY STAGES. 1798 01:05:02,160 --> 01:05:04,120 SO THIS IS THE FIRST 12 HOURS 1799 01:05:04,120 --> 01:05:07,600 AFTER WE DIRECTLY INTRODUCE THE 1800 01:05:07,600 --> 01:05:09,080 LESIONS INTO THE CIRCULATORY 1801 01:05:09,080 --> 01:05:09,320 SYSTEM. 1802 01:05:09,320 --> 01:05:11,440 WHAT WE OBSERVED IS THAT 1803 01:05:11,440 --> 01:05:12,200 INDEPENDENTLY OF CELL TYPE, SO 1804 01:05:12,200 --> 01:05:14,840 HERE ARE TWO DIFFERENT CLONES, 1805 01:05:14,840 --> 01:05:16,440 AND 10-MICRON DIAMETER BEADS 1806 01:05:16,440 --> 01:05:19,800 THAT SHOULD NOT HAVE A RECEPTOR 1807 01:05:19,800 --> 01:05:21,320 THAT'S BIASED FOR ONE ORGAN 1808 01:05:21,320 --> 01:05:22,280 VERSUS ANOTHER, THAT MOST OF 1809 01:05:22,280 --> 01:05:24,600 THEM GET STUCK, INDICATING THAT 1810 01:05:24,600 --> 01:05:29,040 THE ARC 10 TOUR ARCHITECTURE THE 1811 01:05:29,040 --> 01:05:30,440 CHAOTIC ACTUALLY ACTS AS A FIRST 1812 01:05:30,440 --> 01:05:32,200 PASS TO GET THESE CELLS 1813 01:05:32,200 --> 01:05:33,680 PREFERENTIALLY STUCK IN ONE 1814 01:05:33,680 --> 01:05:35,720 ORGAN VERSUS THE OTHER. 1815 01:05:35,720 --> 01:05:39,280 BUT WHY, THEN, DO WE OBSERVE 1816 01:05:39,280 --> 01:05:41,680 THAT BRAIN TARGETING CELL 1817 01:05:41,680 --> 01:05:43,200 PREFERS TO GO TO THE BRAIN IN 1818 01:05:43,200 --> 01:05:45,680 TERMS OF EXTRAVASATION, AND THE 1819 01:05:45,680 --> 01:05:48,640 BONE MARROW TARGETING CELL THEN 1820 01:05:48,640 --> 01:05:50,200 PREFERS TO EXTRAVASATE, WHEREAS 1821 01:05:50,200 --> 01:05:52,160 THIS INITIAL STEP TELLS US THAT 1822 01:05:52,160 --> 01:05:54,880 THEY TEND TO GET STUCK IN THIS 1823 01:05:54,880 --> 01:05:57,360 HIGH HIGHLY CURVED AREA, AND ITS 1824 01:05:57,360 --> 01:06:00,320 BACK TO, ONE, THE ASSUMPTION 1825 01:06:00,320 --> 01:06:02,840 THAT THESE SECTORS THAT ARE 1826 01:06:02,840 --> 01:06:03,760 PRESENT ON THESE CELLS TO BE 1827 01:06:03,760 --> 01:06:06,400 ABLE TO RESPOND TO THIS QUEUE, 1828 01:06:06,400 --> 01:06:07,920 ARE THEY EVEN CONSTANT, AND 1829 01:06:07,920 --> 01:06:09,360 WOULD THEY BE EXPRESSED IN THE 1830 01:06:09,360 --> 01:06:11,000 SAME WAY, AND WOULD THEY RESPOND 1831 01:06:11,000 --> 01:06:12,400 TO THESE QUEUES IN A DIFFERENT 1832 01:06:12,400 --> 01:06:12,840 WAY? 1833 01:06:12,840 --> 01:06:17,320 SO FOR THAT, WE PERFORMED 1834 01:06:17,320 --> 01:06:18,760 PROTEOMIC ANALYSIS THAT THEN 1835 01:06:18,760 --> 01:06:20,920 IDENTIFIED THAT THERE IS INDEED 1836 01:06:20,920 --> 01:06:22,760 A DIFFERENCE IN DIFFERENT 1837 01:06:22,760 --> 01:06:24,400 RECEPTORS THAT ALLOW CELLS TO 1838 01:06:24,400 --> 01:06:26,120 RESPOND TO DIFFERENT QUEUES, AND 1839 01:06:26,120 --> 01:06:28,240 NAMELY ONE OF THEM IS INTERGRIN 1840 01:06:28,240 --> 01:06:30,600 BETA 1, WHICH IS UPREGULATED IN 1841 01:06:30,600 --> 01:06:32,120 THE BONE MARROW HOMING CELLS 1842 01:06:32,120 --> 01:06:35,440 COMPARED TO BRAIN TARGETING 1843 01:06:35,440 --> 01:06:37,480 CELLS, AND THE LAST IS 1844 01:06:37,480 --> 01:06:39,760 UNCONVENTIONAL MYOSIN 1B 1845 01:06:39,760 --> 01:06:42,560 TARGETING BRAIN CELLS VERSUS THE 1846 01:06:42,560 --> 01:06:43,280 BONE MARROW TARGETING CELLS. 1847 01:06:43,280 --> 01:06:44,480 IN THE INTEREST OF TIME I'M JUST 1848 01:06:44,480 --> 01:06:45,760 GOING TO SHOW YOU SOME SNAPSHOTS 1849 01:06:45,760 --> 01:06:52,400 OF THIS UNCONVENTIONAL MYOSIN 1850 01:06:52,400 --> 01:06:52,680 1B. 1851 01:06:52,680 --> 01:06:54,440 WE INDEED CONFIRM THIS HAD IS 1852 01:06:54,440 --> 01:06:55,760 LOCALIZED IN BRAIN TARGETING 1853 01:06:55,760 --> 01:06:57,680 CELLS LARGELY DEVOID IN BONE 1854 01:06:57,680 --> 01:06:58,800 MARROW CELLS AND AS YOU CAN SEE, 1855 01:06:58,800 --> 01:07:00,440 THERE'S A DIFFERENCE IN THIS 1856 01:07:00,440 --> 01:07:01,520 MEMBRANE DYNAMICS GOING BACK TO 1857 01:07:01,520 --> 01:07:03,360 THIS CONCEPT OF HOW THESE 1858 01:07:03,360 --> 01:07:04,840 ARCHITECTURES CAN REGULATE 1859 01:07:04,840 --> 01:07:05,760 MEMBRANES AND, THEREFORE, THE 1860 01:07:05,760 --> 01:07:11,440 ABILITY TO BIND. 1861 01:07:11,440 --> 01:07:14,040 WHEN WE SILENCE, WE FIND THESE 1862 01:07:14,040 --> 01:07:15,920 CELLS ARE NO LONGER ABLE TO 1863 01:07:15,920 --> 01:07:19,560 COLONIZE THE BRAIN, INSTEAD -- 1864 01:07:19,560 --> 01:07:21,600 SO JUST BY TUNING THESE CELLS' 1865 01:07:21,600 --> 01:07:23,080 ABILITY TO SENSE THESE QUEUES BY 1866 01:07:23,080 --> 01:07:24,680 THESE RECEPTORS, WE COULD THEN 1867 01:07:24,680 --> 01:07:26,920 CHANGE THEM. 1868 01:07:26,920 --> 01:07:31,400 WE WANT TO MAKE SURE THIS ISN'T 1869 01:07:31,400 --> 01:07:32,840 ZEBRA CELL SPECIFIC, SO WE TOOK 1870 01:07:32,840 --> 01:07:34,320 PARENTAL CELLS AND DID THE SAME 1871 01:07:34,320 --> 01:07:35,280 SILENCING AND WHAT WE OBSERVED 1872 01:07:35,280 --> 01:07:37,400 IS THAT THERE'S A DISTINCTION 1873 01:07:37,400 --> 01:07:38,960 BETWEEN A REDUCTION IN CELLS' 1874 01:07:38,960 --> 01:07:40,400 ABILITY TO COLONIZE THE BRAIN 1875 01:07:40,400 --> 01:07:43,280 COMPARED TO THE CONTROL. 1876 01:07:43,280 --> 01:07:45,160 SO WHAT I THINK I'D LIKE TO 1877 01:07:45,160 --> 01:07:46,800 INTRODUCE IS THAT YOU MAY HAVE 1878 01:07:46,800 --> 01:07:48,160 HEARD OF MOUSE MODELS, YOU MAY 1879 01:07:48,160 --> 01:07:51,440 HAVE HEARD OF 3D ORGANOID MODEL, 1880 01:07:51,440 --> 01:07:53,160 BUT THERE ARE OTHER PRE-CLINICAL 1881 01:07:53,160 --> 01:07:55,360 MODELS OUT THERE THAT CAN 1882 01:07:55,360 --> 01:07:56,200 RECAPITULATE SOME ASPECTS OF 1883 01:07:56,200 --> 01:07:57,080 HUMAN DISEASE. 1884 01:07:57,080 --> 01:08:00,160 AND IN THIS CASE BY USING CELLS 1885 01:08:00,160 --> 01:08:02,000 THAT RECAPITULATED THIS 1886 01:08:02,000 --> 01:08:04,640 NON-RANDOM TROPISM, WE CAN 1887 01:08:04,640 --> 01:08:06,160 IDENTIFY THAT IN ADDITION TO 1888 01:08:06,160 --> 01:08:08,440 GENE EXPRESSION CHANGES, THAT A 1889 01:08:08,440 --> 01:08:10,200 MECHANICAL SIGNATURE MAY INDEED 1890 01:08:10,200 --> 01:08:13,600 BE PROMISING IN TERMS OF 1891 01:08:13,600 --> 01:08:16,440 DEFINING THESE CELL TYPES 1892 01:08:16,440 --> 01:08:17,760 A PRIORI. 1893 01:08:17,760 --> 01:08:21,240 WE ALSO INTRODUCE A CONCEPT THAT 1894 01:08:21,240 --> 01:08:23,760 THIS SELECTION CAN OCCUR AT 1895 01:08:23,760 --> 01:08:25,480 ENDOTHELIAL INTERFACES AND BY 1896 01:08:25,480 --> 01:08:26,240 UNDERSTANDING HOW CELLS GET IN 1897 01:08:26,240 --> 01:08:28,600 AND OUT OF THESE DIFFERENT 1898 01:08:28,600 --> 01:08:30,600 ARCHITECTURAL COMPLEXITIES MAY 1899 01:08:30,600 --> 01:08:33,320 ALSO DRIVE WHY METASTASIS, ONE, 1900 01:08:33,320 --> 01:08:34,840 IS AN INEFFICIENT PROCESS, BUT 1901 01:08:34,840 --> 01:08:36,240 WHEN IT DOES WORK, WHY IT 1902 01:08:36,240 --> 01:08:39,440 ACTUALLY DOES WORK. 1903 01:08:39,440 --> 01:08:41,200 NOW, THERE ARE A FEW CAVEATS. 1904 01:08:41,200 --> 01:08:43,040 REMEMBER WE'RE TRYING TO 1905 01:08:43,040 --> 01:08:44,000 RECAPITULATE SOME ASPECTS OF 1906 01:08:44,000 --> 01:08:49,120 HUMAN DISEASE. 1907 01:08:49,120 --> 01:08:51,560 WHEN WE PLACE HUMAN BREAST 1908 01:08:51,560 --> 01:08:53,160 CANCER CELLS IN ZEBRAFISH THERE 1909 01:08:53,160 --> 01:08:55,040 ARE THINGS WE NEED TO TAKE INTO 1910 01:08:55,040 --> 01:08:55,360 CONSIDERATION. 1911 01:08:55,360 --> 01:08:58,400 WHILE WE COULD RECAPITULATE THE 1912 01:08:58,400 --> 01:08:59,840 PHYSIOLOGICAL FORCES SUCH AS 1913 01:08:59,840 --> 01:09:01,920 BLOOD FLOW AND BLOOD VESSELS, WE 1914 01:09:01,920 --> 01:09:08,600 DON'T HAVE TO WORRY ABOUT STOKES 1915 01:09:08,600 --> 01:09:10,640 CONSERVED IN MAY MAILIAN BRAIN, 1916 01:09:10,640 --> 01:09:12,400 FISH IS ACTIVELY GROWING. 1917 01:09:12,400 --> 01:09:13,880 AND WHILE THERE'S A PRESENCE OF 1918 01:09:13,880 --> 01:09:15,480 THE INNATE IMMUNE SYSTEM, THE 1919 01:09:15,480 --> 01:09:17,280 REASON WHY WE CAN GET HUMAN 1920 01:09:17,280 --> 01:09:18,640 CANCER CELLS TO SURVIVE AT THESE 1921 01:09:18,640 --> 01:09:20,920 STAGES IS THAT THE ADAPTIVE 1922 01:09:20,920 --> 01:09:23,720 IMMUNITY IS NOT PRESENT YET AND 1923 01:09:23,720 --> 01:09:24,840 ONLY MATURES LATER ON. 1924 01:09:24,840 --> 01:09:26,480 SO THERE'S THIS WINDOW THAT 1925 01:09:26,480 --> 01:09:28,960 ALLOWS US TO LOOK AT THESE SORT 1926 01:09:28,960 --> 01:09:31,480 OF EXTRAVASATION PROCESSES. 1927 01:09:31,480 --> 01:09:32,800 LIMITATIONS ARE THAT WE CAN'T 1928 01:09:32,800 --> 01:09:36,600 LOOK AT THESE BIG METASTASES, 1929 01:09:36,600 --> 01:09:37,960 ONLY THESE EXTRAVASATION EVENTS 1930 01:09:37,960 --> 01:09:39,440 AND THE IDEA IS THAT HOW CAN WE 1931 01:09:39,440 --> 01:09:43,200 THEN FOLLOW THIS PROCESS FROM 1932 01:09:43,200 --> 01:09:45,120 THE BEAUTY OF THE FISH WHICH IS 1933 01:09:45,120 --> 01:09:46,320 SINGLE CELL DISSEMINATION AND 1934 01:09:46,320 --> 01:09:48,880 STILL MAINTAIN THE ABILITY TO 1935 01:09:48,880 --> 01:09:50,920 HAVE THIS VISUALIZATION AND 1936 01:09:50,920 --> 01:09:52,000 MANIPULATION THAT I MENTIONED, 1937 01:09:52,000 --> 01:09:55,400 BUT MORE IMPORTANTLY, FOLLOW TO 1938 01:09:55,400 --> 01:09:56,360 FRANK LESIONS. 1939 01:09:56,360 --> 01:10:00,400 HOW DO WE GET FROM HERE TO HERE? 1940 01:10:00,400 --> 01:10:02,280 SO THIS IS NOW THE ADULT FISH ON 1941 01:10:02,280 --> 01:10:04,240 YOUR RIGHT AND HERE WE'RE 1942 01:10:04,240 --> 01:10:05,560 SLIGHTLY -- WE'RE CHANGING 1943 01:10:05,560 --> 01:10:07,200 MODELS HERE, AND THAT WAY WE'RE 1944 01:10:07,200 --> 01:10:11,000 USING A HUMAN RELEVANT MELANOMA 1945 01:10:11,000 --> 01:10:13,280 MODEL DRIVEN BY THE SAME GENETIC 1946 01:10:13,280 --> 01:10:15,920 DRIVERS THAT ARE FOUND IN 1947 01:10:15,920 --> 01:10:19,000 ZEBRA -- IN HUMAN MELANOMAS, IN 1948 01:10:19,000 --> 01:10:20,440 FACT, ONE OF THE FIRST ANIMAL 1949 01:10:20,440 --> 01:10:25,560 MODELS OF ME MELANOMA WAS DONE N 1950 01:10:25,560 --> 01:10:26,760 FISH AND WE'RE ABLE TO BRING 1951 01:10:26,760 --> 01:10:30,680 THIS SORT OF RESOLUTION TO HERE, 1952 01:10:30,680 --> 01:10:32,240 WHERE YOU SEE THE -- HEAD AND 1953 01:10:32,240 --> 01:10:33,160 THE TAIL OF THE FISH. 1954 01:10:33,160 --> 01:10:35,160 SO FOR THAT, WE HAD TO BE A BIT 1955 01:10:35,160 --> 01:10:35,520 CREATIVE. 1956 01:10:35,520 --> 01:10:38,320 SO WHAT WE DESIGNED IN 1957 01:10:38,320 --> 01:10:41,600 COLLABORATION IS THAT THE 1958 01:10:41,600 --> 01:10:44,360 ABILITY TO SOLVE ONE OF THE 1959 01:10:44,360 --> 01:10:47,040 ISSUES THAT EXISTED IN THE 1960 01:10:47,040 --> 01:10:48,160 ZEBRAFISH FIELD IS HOW DO WE 1961 01:10:48,160 --> 01:10:52,080 KEEP THIS FISH ALIVE AND MORE 1962 01:10:52,080 --> 01:10:53,600 IMPORTANTLY, ALIVE LONG ENOUGH 1963 01:10:53,600 --> 01:10:56,480 SO THAT WE COULD MAINTAIN THIS 1964 01:10:56,480 --> 01:10:57,120 SINGLE CELL RESOLUTION THAT I 1965 01:10:57,120 --> 01:11:01,320 SHOWED YOU EARLIER. 1966 01:11:01,320 --> 01:11:03,320 JUST TO ORIENT YOU HOW THIS IS 1967 01:11:03,320 --> 01:11:06,840 DONE, IT'S A MICRO FLUID DEVICE 1968 01:11:06,840 --> 01:11:10,440 WHERE WE HAVE AN ORAL LAVAGE 1969 01:11:10,440 --> 01:11:11,400 INTO THE FISH. 1970 01:11:11,400 --> 01:11:12,640 THIS FISH DOESN'T HAVE STRIPES, 1971 01:11:12,640 --> 01:11:14,200 THIS IS A MUTANT FISH, AND MORE 1972 01:11:14,200 --> 01:11:15,800 IMPORTANTLY, WE CAN GET LONG 1973 01:11:15,800 --> 01:11:18,000 TERM SURVIVAL, THE FISH STAYS 1974 01:11:18,000 --> 01:11:19,720 ALIVE AND WE CAN DO LONGITUDINAL 1975 01:11:19,720 --> 01:11:25,840 FOR SEVERAL DAYS. 1976 01:11:25,840 --> 01:11:27,520 SO WITH THIS IN MIND, ONE OF THE 1977 01:11:27,520 --> 01:11:28,480 TECHNIQUES I SHOWED YOU BEFORE, 1978 01:11:28,480 --> 01:11:30,800 WE CAN BRING THIS INTO THE ADULT 1979 01:11:30,800 --> 01:11:33,160 FISH AND MORE IMPORTANTLY, INTO 1980 01:11:33,160 --> 01:11:36,120 METASTATIC LESIONS THAT WERE NOT 1981 01:11:36,120 --> 01:11:36,440 POSSIBLE. 1982 01:11:36,440 --> 01:11:37,960 SO JUST AS A REMINDER, WE STILL 1983 01:11:37,960 --> 01:11:42,400 HAVE THE ABILITY TO DO 1984 01:11:42,400 --> 01:11:43,120 MECHANICAL PROPERTIES, WE STILL 1985 01:11:43,120 --> 01:11:44,320 HAVE THE ABILITY TO THEN LOOK AT 1986 01:11:44,320 --> 01:11:46,400 WHAT MAY BE RELEVANT IN THE 1987 01:11:46,400 --> 01:11:50,160 HUMAN DISEASE. 1988 01:11:50,160 --> 01:11:51,560 SO I'D LIKE TO KIND OF INTRODUCE 1989 01:11:51,560 --> 01:11:53,040 A FEW CONCEPTS HERE QUICKLY TO 1990 01:11:53,040 --> 01:11:57,040 WRAP UP. 1991 01:11:57,040 --> 01:12:02,360 YOI SHOWED YOU MECHANICAL CHANGS 1992 01:12:02,360 --> 01:12:03,880 CAN PLAY A ROLE BUT ULTIMATELY 1993 01:12:03,880 --> 01:12:05,720 IF THIS WERE INDEED GOING TO BE 1994 01:12:05,720 --> 01:12:07,240 USED AS A BIOMARKER, WE STILL 1995 01:12:07,240 --> 01:12:12,400 NEED TO UNDERSTAND WHAT DOES IT 1996 01:12:12,400 --> 01:12:14,240 MEAN -- RELATIVELY SOLID VERSUS 1997 01:12:14,240 --> 01:12:15,440 LIQUID LIKE, IS THAT INDICATIVE 1998 01:12:15,440 --> 01:12:17,160 OF A BIOLOGICAL PROCESS? 1999 01:12:17,160 --> 01:12:19,040 AND HERE I'M SHOWING YOU NOW 2000 01:12:19,040 --> 01:12:21,080 THAT WHAT WE THINK MAY BE AN 2001 01:12:21,080 --> 01:12:23,520 IMPORTANT ROLE IS THAT CELLS -- 2002 01:12:23,520 --> 01:12:25,320 THAT MECHANICAL SIGNATURE MAY BE 2003 01:12:25,320 --> 01:12:27,240 A FUNCTION OF THE METABOLIC 2004 01:12:27,240 --> 01:12:30,280 STATE OF THE CELL. 2005 01:12:30,280 --> 01:12:32,040 SO HERE ON THE Y AXIS, THIS GOES 2006 01:12:32,040 --> 01:12:33,760 BACK TO DEFINING HOW SOFT OR 2007 01:12:33,760 --> 01:12:39,680 STIFF A MATERIAL IS, AND EACH OF 2008 01:12:39,680 --> 01:12:40,320 THESE INDIVIDUALS CURVES ARE 2009 01:12:40,320 --> 01:12:43,320 SHOWN ON THE RIGHT HERE, GIVEN 2010 01:12:43,320 --> 01:12:44,640 PH KNOWN TO GIVE A DIFFERENT 2011 01:12:44,640 --> 01:12:46,280 METABOLIC TYPE OF STATE, MEANING 2012 01:12:46,280 --> 01:12:50,280 HOW THESE CELLS METABOLIZE 2013 01:12:50,280 --> 01:12:50,720 ENSOMETIMES. 2014 01:12:50,720 --> 01:12:52,800 AND BY USING THIS, WE SEE THAT 2015 01:12:52,800 --> 01:12:55,440 AS A FUNCTION OF CHANGE IN THE 2016 01:12:55,440 --> 01:12:57,480 PH IN A SENSE, WE ALSO MODULATE 2017 01:12:57,480 --> 01:12:58,360 MECHANICAL PROPERTY AS SHOWN 2018 01:12:58,360 --> 01:13:02,960 HERE WHERE THE MOST ACIDIC PH IS 2019 01:13:02,960 --> 01:13:06,560 STIFFER THAN THAT OF THE MOST 2020 01:13:06,560 --> 01:13:10,360 BASIC IN OUR DYNAMIC RANGE. 2021 01:13:10,360 --> 01:13:13,120 SO I HYPOTHESIZED THAT MAYBE, 2022 01:13:13,120 --> 01:13:14,840 GOING BACK TO TRY TO LINK THESE 2023 01:13:14,840 --> 01:13:18,120 PHYSICAL PROPERTIES, THAT THEY 2024 01:13:18,120 --> 01:13:19,640 ARE INDEED INDICATIVE OR MAY BE 2025 01:13:19,640 --> 01:13:22,280 INDICATIVE OF BIOMARKER OF THIS 2026 01:13:22,280 --> 01:13:25,120 METABOLISM AND CAN BE USED IN 2027 01:13:25,120 --> 01:13:27,200 CONCERT IN TERMS OF TESTING THIS 2028 01:13:27,200 --> 01:13:29,480 RULE OF DRIVING ORGAN-SPECIFIC 2029 01:13:29,480 --> 01:13:32,520 METASTASIS. 2030 01:13:32,520 --> 01:13:34,480 SO THESE ARE THE TWO QUESTIONS 2031 01:13:34,480 --> 01:13:36,360 WE'RE TRYING TO ADDRESS RIGHT 2032 01:13:36,360 --> 01:13:37,440 NOW AND QUITE FRANKLY I'M 2033 01:13:37,440 --> 01:13:38,880 PUTTING IT OUT THERE IN TERMS OF 2034 01:13:38,880 --> 01:13:39,640 DIRECTIONS OF THE LAB AND I 2035 01:13:39,640 --> 01:13:41,280 THINK TO SOME EXTENT THE FIELD 2036 01:13:41,280 --> 01:13:42,480 WILL START TO GET INVOLVED IN 2037 01:13:42,480 --> 01:13:45,120 THESE TYPES OF MEASUREMENTS. 2038 01:13:45,120 --> 01:13:47,960 BUT THE IDEA IS THAT HOW CAN WE 2039 01:13:47,960 --> 01:13:49,560 THEN LINK, WE HAVE A LOT OF 2040 01:13:49,560 --> 01:13:50,640 MICRO SCALE TECHNIQUES THAT WE 2041 01:13:50,640 --> 01:13:54,920 AND OTHERS HAVE DEVELOPED, MY 2042 01:13:54,920 --> 01:13:56,120 COLLEAGUE IN GERMANY HAS THE 2043 01:13:56,120 --> 01:13:57,640 ABILITY TO MEASURE THESE THINGS 2044 01:13:57,640 --> 01:13:58,840 DIRECTLY, HOW CAN WE THEN REALLY 2045 01:13:58,840 --> 01:14:00,720 TRY TO BRIDGE THESE GAPS. 2046 01:14:00,720 --> 01:14:03,000 SO IN MY LAB, WE HAVE BEGUN 2047 01:14:03,000 --> 01:14:05,000 TESTING THESE MECHANICAL 2048 01:14:05,000 --> 01:14:06,960 PROPERTIES OF THESE TISSUES AND 2049 01:14:06,960 --> 01:14:09,680 THESE LESIONS THAT I SHOWED YOU 2050 01:14:09,680 --> 01:14:11,960 EARLIER ON, WE ALREADY FOUND 2051 01:14:11,960 --> 01:14:14,720 SOME LINKS BETWEEN MECHANICAL 2052 01:14:14,720 --> 01:14:16,480 PROPERTIES AND BY USING A 2053 01:14:16,480 --> 01:14:21,360 PROCESS KNOWN AS FLUORESCENT 2054 01:14:21,360 --> 01:14:22,720 LIFETIME -- METABOLIC STATE, AND 2055 01:14:22,720 --> 01:14:24,800 MY COLLEAGUE IN COLLABORATION, 2056 01:14:24,800 --> 01:14:26,080 WE'LL TRY TO DO THESE 2057 01:14:26,080 --> 01:14:27,280 MEASUREMENTS WHERE WE COULD MAP 2058 01:14:27,280 --> 01:14:29,080 THESE MECHANICAL MEASUREMENTS 2059 01:14:29,080 --> 01:14:32,600 DONE WITH MAGNETIC RESONANCE EE 2060 01:14:32,600 --> 01:14:34,960 LAS TOGRAPHY WITH PET IMAGING 2061 01:14:34,960 --> 01:14:36,600 THAT ALSO GIVES US A READOUT OF 2062 01:14:36,600 --> 01:14:38,240 THE METABOLIC STATES OF THESE 2063 01:14:38,240 --> 01:14:41,640 TUMORS. 2064 01:14:41,640 --> 01:14:43,040 SO JUST TO KIND OF BUILD IN TO 2065 01:14:43,040 --> 01:14:44,800 WHAT WE'VE DONE IN TERMS OF THIS 2066 01:14:44,800 --> 01:14:46,680 IN VITRO MODEL, SORRY THIS IN 2067 01:14:46,680 --> 01:14:48,280 VIVO MODEL, THE ZEBRAFISH 2068 01:14:48,280 --> 01:14:49,080 SYSTEM, AND WE'VE SEEN THAT 2069 01:14:49,080 --> 01:14:51,600 THERE'S A CORRELATION BETWEEN 2070 01:14:51,600 --> 01:14:53,720 THE CELLS, TUMOR CELLS IN TERMS 2071 01:14:53,720 --> 01:14:58,320 OF THEIR BRAIN -- THEIR ORGAN 2072 01:14:58,320 --> 01:15:01,680 LOCATION, BRAIN METASTASES, 2073 01:15:01,680 --> 01:15:04,600 SKELETAL METASTASES, THAT IS 2074 01:15:04,600 --> 01:15:06,320 ALSO CORRELATED WHERE WE SEE A 2075 01:15:06,320 --> 01:15:08,240 HIGHER RATE OF GLYCOLYSIS IN THE 2076 01:15:08,240 --> 01:15:11,200 BRAIN METASTASES VERSUS A HIGHER 2077 01:15:11,200 --> 01:15:13,600 OXIDATIVE -- IN SKELETAL 2078 01:15:13,600 --> 01:15:15,680 METASTASES, SO THIS IS EXCITING 2079 01:15:15,680 --> 01:15:16,520 BECAUSE IT AGAIN STARTS TO 2080 01:15:16,520 --> 01:15:17,520 BRIDGE THESE CONCEPTS OF WHAT 2081 01:15:17,520 --> 01:15:19,080 DOES IT MEAN TO HAVE A 2082 01:15:19,080 --> 01:15:19,920 MECHANICAL PROPERTY AND HOW CAN 2083 01:15:19,920 --> 01:15:22,320 WE THEN CORRELATE THAT TO SOME 2084 01:15:22,320 --> 01:15:23,400 BIOLOGY. 2085 01:15:23,400 --> 01:15:26,920 AND I'D LIKE TO JUST LEAVE WITH 2086 01:15:26,920 --> 01:15:28,760 A LAST TWO CAVEATS. 2087 01:15:28,760 --> 01:15:32,520 WE STARTED OFF BY BEING ABLE TO 2088 01:15:32,520 --> 01:15:34,000 VISUALIZE THE CELLS' ABILITY TO 2089 01:15:34,000 --> 01:15:36,640 INTERACT WITH ITS 2090 01:15:36,640 --> 01:15:37,400 MICROENVIRONMENT. 2091 01:15:37,400 --> 01:15:38,960 SO WHILE THESE QUANTITATIVE 2092 01:15:38,960 --> 01:15:40,280 MULTIPLEX MEASUREMENTS ARE 2093 01:15:40,280 --> 01:15:42,880 INDEED INDICATIVE, ULTIMATELY, 2094 01:15:42,880 --> 01:15:44,960 THERE'S SO MUCH POWER IN SEEING 2095 01:15:44,960 --> 01:15:47,720 THINGS THAT WE CANNOT SEE AT THE 2096 01:15:47,720 --> 01:15:50,000 SINGLE CELL RESOLUTION AND 2097 01:15:50,000 --> 01:15:51,960 LESIONS IN VIVO IN THE HUMAN. 2098 01:15:51,960 --> 01:15:53,960 SO THE ZEBRAFISH IS POWERFUL IN 2099 01:15:53,960 --> 01:15:58,520 THAT THE IMMUNE SYSTEM IS 2100 01:15:58,520 --> 01:16:00,160 CONSERVED WITH THE HUMAN SYSTEM 2101 01:16:00,160 --> 01:16:01,360 FOR MANY ASPECTS, MAINLY, IN 2102 01:16:01,360 --> 01:16:02,720 THIS CASE YOU'RE LOOKING AT 2103 01:16:02,720 --> 01:16:03,400 T-CELLS. 2104 01:16:03,400 --> 01:16:05,120 AND ONE OF THE THINGS YOU CAN 2105 01:16:05,120 --> 01:16:05,880 APPRECIATE IN THE T-CELLS I 2106 01:16:05,880 --> 01:16:07,520 FOUND IN THESE DIFFERENT 2107 01:16:07,520 --> 01:16:09,800 METASTATIC LOCATIONS IS THAT 2108 01:16:09,800 --> 01:16:10,760 THERE'S A DIFFERENCE IN THE WAY 2109 01:16:10,760 --> 01:16:12,640 THAT THEY MOVE, THERE'S A 2110 01:16:12,640 --> 01:16:14,600 DIFFERENCE IN THEIR MORPHOLOGY. 2111 01:16:14,600 --> 01:16:18,600 DO YOU SEE THESE TYPES OF -- 2112 01:16:18,600 --> 01:16:20,520 THAT WE OBSERVE THEM, AND MORE 2113 01:16:20,520 --> 01:16:23,040 IMPORTANTLY, WHEN WE TRY TO MAP 2114 01:16:23,040 --> 01:16:24,880 THIS SINGLE CELL SEQUENCING, WE 2115 01:16:24,880 --> 01:16:26,320 OBSERVE THAT THERE ARE DIFFERENT 2116 01:16:26,320 --> 01:16:28,960 FLAVORS OF THE IMMUNE 2117 01:16:28,960 --> 01:16:29,400 INFILTRATES. 2118 01:16:29,400 --> 01:16:31,600 AND WHILE THIS IS POWERFUL IN 2119 01:16:31,600 --> 01:16:32,760 TERMS OF GENE EXPRESSIONS THAT 2120 01:16:32,760 --> 01:16:34,320 MAY BE DISTINCT OR 2121 01:16:34,320 --> 01:16:35,760 DIFFERENTIALLY EXPRESSED, RIGHT 2122 01:16:35,760 --> 01:16:37,520 AWAY, YOU COULD SEE THAT EVEN IN 2123 01:16:37,520 --> 01:16:39,360 THESE TUMORS, THERE'S A 2124 01:16:39,360 --> 01:16:41,640 HETEROGENEITY IN TERMS OF THEIR 2125 01:16:41,640 --> 01:16:43,280 MOTILITY, HETEROGENEITY IN TERMS 2126 01:16:43,280 --> 01:16:44,600 OF A MORPHOLOGY, SO IT BRINGS 2127 01:16:44,600 --> 01:16:47,120 BACK THIS CONCEPT OF WHEN WE GET 2128 01:16:47,120 --> 01:16:49,760 THESE TYPES OF DATA, HOW MUCH 2129 01:16:49,760 --> 01:16:51,840 HAD THEY REALLY -- ARE THEY 2130 01:16:51,840 --> 01:16:53,480 INDICATIVE OF WHAT'S GOING ON IN 2131 01:16:53,480 --> 01:16:55,080 THE TUMOR AND HOW THIS MAY 2132 01:16:55,080 --> 01:16:57,000 IMPACT ANY OF OUR THERAPEUTIC 2133 01:16:57,000 --> 01:16:59,000 TARGETS. 2134 01:16:59,000 --> 01:17:00,720 SO I JUST WANT TO WRAP UP IN 2135 01:17:00,720 --> 01:17:01,800 SAYING THAT SOME OF THE GOALS 2136 01:17:01,800 --> 01:17:05,880 THAT WE HAVE, BECAUSE OF THE 2137 01:17:05,880 --> 01:17:07,160 FACT METASTATIC DISEASE IS STILL 2138 01:17:07,160 --> 01:17:10,280 OF CLINICAL RELEVANCE, IS CAN WE 2139 01:17:10,280 --> 01:17:12,440 THEN USE SOME PRE-CLINICAL 2140 01:17:12,440 --> 01:17:14,400 MODELS TO REALLY RE-CREATE SOME 2141 01:17:14,400 --> 01:17:16,560 ASPECTS OF THIS HUMAN DISEASE, 2142 01:17:16,560 --> 01:17:18,720 BE REALISTIC IN TERMS OF WHAT WE 2143 01:17:18,720 --> 01:17:21,720 CAN RE-CREATE AND BE TRANSPARENT 2144 01:17:21,720 --> 01:17:23,760 ON WHAT WE'RE NOT RE-CREATING, 2145 01:17:23,760 --> 01:17:25,680 AND THEN MOVE TOWARDS JUST 2146 01:17:25,680 --> 01:17:29,200 DEFINING THESE MECHANICAL 2147 01:17:29,200 --> 01:17:30,400 PROPERTIES, IN THE REALM OF 2148 01:17:30,400 --> 01:17:32,680 BASIC BIOLOGY IN TERMS OF 2149 01:17:32,680 --> 01:17:33,560 MECHANOBIOLOGY, BUT TRYING TO 2150 01:17:33,560 --> 01:17:35,160 UNDERSTAND THEN, HOW COULD WE 2151 01:17:35,160 --> 01:17:40,120 THEN LINK THIS SORT OF SIGNATURE 2152 01:17:40,120 --> 01:17:41,880 INTO WHAT'S CLINICAL BIOMARKERS. 2153 01:17:41,880 --> 01:17:44,320 JUST TO RECAP, CAN WE USE IT 2154 01:17:44,320 --> 01:17:46,280 RELIABLY TO DIFFERENTIATE NORMAL 2155 01:17:46,280 --> 01:17:47,240 TISSUES FROM CANCERS? 2156 01:17:47,240 --> 01:17:48,680 WE COULD DO THAT, BUT HOW COULD 2157 01:17:48,680 --> 01:17:49,960 WE DO IT FUNCTIONALLY? 2158 01:17:49,960 --> 01:17:52,960 CAN WE THEN USE THIS TO 2159 01:17:52,960 --> 01:17:54,960 UNDERSTAND WHAT HAPPENS IN THE 2160 01:17:54,960 --> 01:17:55,840 SELECTION OF SITES OF 2161 01:17:55,840 --> 01:17:56,280 METASTASIS? 2162 01:17:56,280 --> 01:17:57,920 AND THEN I WOULD SAY THIS IS MY 2163 01:17:57,920 --> 01:18:00,320 PIE IN THE SKY GOAL, WOULD IT BE 2164 01:18:00,320 --> 01:18:02,400 USEFUL IN TERMS OF UNDERSTANDING 2165 01:18:02,400 --> 01:18:05,440 WHAT REGULATES THERAPY 2166 01:18:05,440 --> 01:18:06,560 EFFECTIVENESS? 2167 01:18:06,560 --> 01:18:08,400 SO OBVIOUSLY I DON'T DO THIS 2168 01:18:08,400 --> 01:18:09,400 WORK ALONE. 2169 01:18:09,400 --> 01:18:10,320 I'M REALLY FORTUNATE TO BE HERE 2170 01:18:10,320 --> 01:18:12,320 IN THE INTRAMURAL PROGRAM. 2171 01:18:12,320 --> 01:18:14,320 OF COURSE I LIKE TO THANK MY 2172 01:18:14,320 --> 01:18:16,080 FUNDING SOURCES, MY ALUMNI, AS 2173 01:18:16,080 --> 01:18:17,720 WELL AS THE PEOPLE WHO CURRENTLY 2174 01:18:17,720 --> 01:18:18,240 WORK IN THE LAB. 2175 01:18:18,240 --> 01:18:19,880 AND WITH THAT, I'M HAPPY TO TAKE 2176 01:18:19,880 --> 01:18:21,160 ANY QUESTIONS, AND THANKS AGAIN 2177 01:18:21,160 --> 01:18:24,720 FOR THE OPPORTUNITY. 2178 01:18:24,720 --> 01:18:29,200 >> WELL, THANK YOU BOTH FOR VERY 2179 01:18:29,200 --> 01:18:33,080 STIMULATING TALKS COVERING VERY 2180 01:18:33,080 --> 01:18:35,040 DIFFERENT ASPECTS OF THIS 2181 01:18:35,040 --> 01:18:36,920 COMPLICATED PROBLEM. 2182 01:18:36,920 --> 01:18:39,880 WE'VE GOT ENOUGH QUESTIONS TO 2183 01:18:39,880 --> 01:18:41,240 KEEP THIS GOING FOR ANOTHER 2184 01:18:41,240 --> 01:18:43,720 COUPLE OF HOURS, SO I'M GOING TO 2185 01:18:43,720 --> 01:18:47,320 TRY AND CONDENSE SOME OF THEM 2186 01:18:47,320 --> 01:18:48,320 INTO CERTAIN AREAS. 2187 01:18:48,320 --> 01:18:51,920 SO THERE ARE A WHOLE SERIES OF 2188 01:18:51,920 --> 01:18:54,120 QUESTIONS ABOUT THE IDEA OF 2189 01:18:54,120 --> 01:19:01,760 DORMANCY, OF DORMANT CELLS, AND 2190 01:19:01,760 --> 01:19:03,600 I SEEM TO RECALL THAT IT KIND OF 2191 01:19:03,600 --> 01:19:07,320 CAME TO LIGHT WHEN PATIENTS WHO 2192 01:19:07,320 --> 01:19:10,600 WERE SUCCESSFULLY SUPPOSED 2193 01:19:10,600 --> 01:19:12,000 LIQUEURED OF CERTAIN CANCERS, I 2194 01:19:12,000 --> 01:19:13,680 THINK IT WAS BREAST CANCER, IN 2195 01:19:13,680 --> 01:19:17,600 LATER YEARS, DONATED A KIDNEY 2196 01:19:17,600 --> 01:19:19,760 FOR A SIBLING OR SOMEONE WHO WAS 2197 01:19:19,760 --> 01:19:21,320 MATCHED, AND THEN LO AND BEHOLD, 2198 01:19:21,320 --> 01:19:23,480 IT TURNED OUT THAT THE KIDNEY, 2199 01:19:23,480 --> 01:19:26,920 WHICH HAD NOT BEEN KNOWN TO HAVE 2200 01:19:26,920 --> 01:19:30,960 ANY UNUSUAL CELLS IN IT, WAS THE 2201 01:19:30,960 --> 01:19:33,480 SOURCE OF A VERY ACTIVE BREAST 2202 01:19:33,480 --> 01:19:33,800 CANCER. 2203 01:19:33,800 --> 01:19:37,000 NOW, I THINK I'VE GOT THAT RIG 2204 01:19:37,000 --> 01:19:38,400 RIGHT. 2205 01:19:38,400 --> 01:19:41,240 BUT THE CONCEPT OF DORMANCY, 2206 01:19:41,240 --> 01:19:42,960 MAYBE YOU'D EACH LIKE TO BRIEFLY 2207 01:19:42,960 --> 01:19:43,720 COMMENT ABOUT IT. 2208 01:19:43,720 --> 01:19:44,600 THE SPECIFIC QUESTIONS PEOPLE 2209 01:19:44,600 --> 01:19:46,320 HAVE ASKED, WHAT DO WE KNOW 2210 01:19:46,320 --> 01:19:49,320 ABOUT THE GENETICS, ABOUT THE 2211 01:19:49,320 --> 01:19:50,640 METABOLISM? 2212 01:19:50,640 --> 01:19:52,160 IS THERE ANY WAY WE COULD 2213 01:19:52,160 --> 01:19:55,560 IDENTIFY DORMANT CELLS BY ANY 2214 01:19:55,560 --> 01:19:59,760 IMAGING TECHNIQUE, AND DORMANT 2215 01:19:59,760 --> 01:20:03,880 CELLS IN THE IN VITRO MODELS OR 2216 01:20:03,880 --> 01:20:06,840 IN THE ORGANOIDS BEING CREATED 2217 01:20:06,840 --> 01:20:07,800 AND FOLLOWED? 2218 01:20:07,800 --> 01:20:09,640 CAN YOU BRIEFLY -- I'M SURE WE 2219 01:20:09,640 --> 01:20:12,280 CAN HAVE A WHOLE SESSION ON 2220 01:20:12,280 --> 01:20:13,720 DORMANCY, BUT IT WOULD BE, I 2221 01:20:13,720 --> 01:20:17,120 THINK, OF GREAT INTEREST TO HEAR 2222 01:20:17,120 --> 01:20:18,200 YOUR VIEWS ABOUT THIS. 2223 01:20:18,200 --> 01:20:20,080 SO JONATHAN, YOU WANT TO GO 2224 01:20:20,080 --> 01:20:22,640 FIRST? 2225 01:20:22,640 --> 01:20:25,680 >> SURE, THAT'S A VERY BIG 2226 01:20:25,680 --> 01:20:27,400 QUESTION. 2227 01:20:27,400 --> 01:20:31,320 THIS PROCESS IS INVALUABLE IN 2228 01:20:31,320 --> 01:20:31,920 MOUSE MODELS. 2229 01:20:31,920 --> 01:20:33,520 WHEN I SHOWED UP HERE, I SORT OF 2230 01:20:33,520 --> 01:20:38,760 HAD THIS IDEA THAT I WOULD SEW 2231 01:20:38,760 --> 01:20:40,280 WINDOWS ON THE MOUSE LIVER AND 2232 01:20:40,280 --> 01:20:41,280 GLUE THE LIVER UP AND WE COULD 2233 01:20:41,280 --> 01:20:43,160 DO ALL SORTS OF MANIPULATION 2234 01:20:43,160 --> 01:20:44,240 INCLUDING INJECTING VARIOUS CELL 2235 01:20:44,240 --> 01:20:45,760 LINES. 2236 01:20:45,760 --> 01:20:48,520 I ULTIMATELY SETTLE OED ON THE T 2237 01:20:48,520 --> 01:20:51,000 THAT IF YOUR ANGLE IS HEAVILY 2238 01:20:51,000 --> 01:20:52,200 TRANSLATIONAL, THEN I'M JUST NOT 2239 01:20:52,200 --> 01:20:54,920 SURE THAT THIS WOULD ACCURATELY 2240 01:20:54,920 --> 01:20:56,280 PREDICT ANYTHING IN PEOPLE SUCH 2241 01:20:56,280 --> 01:20:59,200 THAT IT WOULD BE SOMETHING WE 2242 01:20:59,200 --> 01:20:59,840 SHOULD FOLLOW PHARMACOLOGICALLY 2243 01:20:59,840 --> 01:21:01,520 AND TRY AND MANIPULATE. 2244 01:21:01,520 --> 01:21:03,120 SO THE LONG AND SHORT OF THIS 2245 01:21:03,120 --> 01:21:08,400 IS, IT'S VERY HARD TO IDENTIFY, 2246 01:21:08,400 --> 01:21:11,120 I'LL CALL THEM DORMANT 2247 01:21:11,120 --> 01:21:12,120 DISSEMINATED TUMOR CELLS IN 2248 01:21:12,120 --> 01:21:13,760 PEOPLE. 2249 01:21:13,760 --> 01:21:16,280 IT HAS BEEN DONE BY DOING BONE 2250 01:21:16,280 --> 01:21:18,360 MARROW ASPIRATES AND IDENTIFYING 2251 01:21:18,360 --> 01:21:21,520 SMALL NUMBERS OF CELLS, THIS IS 2252 01:21:21,520 --> 01:21:22,520 IN BREAST CANCER, BUT IT'S 2253 01:21:22,520 --> 01:21:23,840 REALLY HARD, AND THEN I THINK 2254 01:21:23,840 --> 01:21:25,360 THE QUESTION REALLY RELATES TO, 2255 01:21:25,360 --> 01:21:27,520 WHAT CAN WE LEARN ABOUT THEM? 2256 01:21:27,520 --> 01:21:29,280 I THINK YOU CAN GARNISH SOME 2257 01:21:29,280 --> 01:21:31,080 INFORMATION ABOUT THE GENETICS 2258 01:21:31,080 --> 01:21:33,680 OF MACRO METASTASES AND YOU 2259 01:21:33,680 --> 01:21:35,760 KNOW, IT'S UNLIKELY THAT IF YOU 2260 01:21:35,760 --> 01:21:38,960 WERE TO SINGLE CELL SEQUENCE AN 2261 01:21:38,960 --> 01:21:40,880 ENTIRE MICRO METASTASES, YOU 2262 01:21:40,880 --> 01:21:43,280 MUST PICK UP THE HE GENETICS OF 2263 01:21:43,280 --> 01:21:45,920 A MICRO METASTASIS AT SOME 2264 01:21:45,920 --> 01:21:46,120 POINT. 2265 01:21:46,120 --> 01:21:47,560 I DON'T THINK GENETICS IS GOING 2266 01:21:47,560 --> 01:21:48,800 TO CAPTURE THE PROBLEM. 2267 01:21:48,800 --> 01:21:52,160 THIS IS A PLASTIC STATE. 2268 01:21:52,160 --> 01:21:54,640 CLEARLY, THE DORMANCY PART, YOU 2269 01:21:54,640 --> 01:21:56,880 LEAVE A PRIMARY TUMOR WHERE 2270 01:21:56,880 --> 01:21:58,080 YOU'RE LIKELY TO BE GROWING AT 2271 01:21:58,080 --> 01:21:59,680 LEAST AT SOME POINT, YOU WERE 2272 01:21:59,680 --> 01:22:02,360 DIVIDING, AND YOU END UP IN THIS 2273 01:22:02,360 --> 01:22:04,760 PLACE, AND YOU STOP. 2274 01:22:04,760 --> 01:22:06,160 YOU DIDN'T CHANGE YOUR GENETICS 2275 01:22:06,160 --> 01:22:06,960 IMMEDIATELY. 2276 01:22:06,960 --> 01:22:09,360 YOU PROBABLY WENT THROUGH AN 2277 01:22:09,360 --> 01:22:10,240 EPIGENETIC REPROGRAMMING EVENT 2278 01:22:10,240 --> 01:22:12,560 WHERE YOU WERE SORT OF NOT DOING 2279 01:22:12,560 --> 01:22:14,800 ANYTHING OR YOU WERE SORT OF IN 2280 01:22:14,800 --> 01:22:16,200 AN ENVIRONMENT THAT WASN'T QUITE 2281 01:22:16,200 --> 01:22:17,560 FAVORABLE FOR YOU AND SO YOU 2282 01:22:17,560 --> 01:22:18,760 DECIDED NOT TO DO ANYTHING. 2283 01:22:18,760 --> 01:22:20,360 THIS DOESN'T REALLY MEAN CHANGES 2284 01:22:20,360 --> 01:22:21,000 IN GENETICS. 2285 01:22:21,000 --> 01:22:21,840 SO THE SECOND PART OF THE 2286 01:22:21,840 --> 01:22:22,960 QUESTION WAS DOES IT MEAN 2287 01:22:22,960 --> 01:22:23,920 CHANGES IN METABOLISM. 2288 01:22:23,920 --> 01:22:25,800 I WOULD SAY THE ANSWER IS YEAH, 2289 01:22:25,800 --> 01:22:27,520 I WOULD SAY THE ANSWER IS HIGHLY 2290 01:22:27,520 --> 01:22:29,600 LIKELY TO BE YES, YOU DEFINITELY 2291 01:22:29,600 --> 01:22:32,560 HAVE CHANGE IN METABOLISM, 2292 01:22:32,560 --> 01:22:37,320 AGAIN, CAPTURING THAT INTO -- 2293 01:22:37,320 --> 01:22:38,360 WAYS IS REALLY HARD. 2294 01:22:38,360 --> 01:22:39,680 IT'S GOING TO BE REALLY HARD TO 2295 01:22:39,680 --> 01:22:41,680 DO IN A PERSON, ALTHOUGH I 2296 01:22:41,680 --> 01:22:45,600 CERTAINLY WOULD BE AB LOVE TO BE 2297 01:22:45,600 --> 01:22:47,160 ABLE TO DO THAT ZEBRAFISH STUFF 2298 01:22:47,160 --> 01:22:47,880 IN A PERSON. 2299 01:22:47,880 --> 01:22:49,600 THAT'S GOING TO BE TOUGH, BUT 2300 01:22:49,600 --> 01:22:51,600 WHAT IF WE SEPARATE THE ORGAN 2301 01:22:51,600 --> 01:22:53,400 THAT HAS A LOT OF METASTASES 2302 01:22:53,400 --> 01:22:54,920 FROM THE PERSON SUCH THAT WE CAN 2303 01:22:54,920 --> 01:22:57,080 DO A LOT OF ME NIP LATING. 2304 01:22:57,080 --> 01:22:58,960 BUT EVEN THEN, STILL A BIG PIECE 2305 01:22:58,960 --> 01:23:00,840 OF TISSUE IS NOT SEE-THROUGH, 2306 01:23:00,840 --> 01:23:01,920 IT'S JUST VERY DIFFICULT, BUT 2307 01:23:01,920 --> 01:23:03,040 THAT'S SORT OF WHERE WE ARE IN 2308 01:23:03,040 --> 01:23:03,560 WORKING WITH THIS. 2309 01:23:03,560 --> 01:23:07,080 SO I WOULD SAY DO WE HAVE ANY 2310 01:23:07,080 --> 01:23:09,160 IDEA OF WHAT DORMANT 2311 01:23:09,160 --> 01:23:11,680 DISSEMINATED TUMORS ARE LIKE 2312 01:23:11,680 --> 01:23:12,320 METABOLICALLY? 2313 01:23:12,320 --> 01:23:13,600 NO, I DON'T FEEL LIKE I KNOW THE 2314 01:23:13,600 --> 01:23:14,920 ANSWER TO THAT QUESTION. 2315 01:23:14,920 --> 01:23:16,000 GENETICALLY I THINK YOU CAN 2316 01:23:16,000 --> 01:23:18,320 INFER THIS, BUT I DON'T THINK 2317 01:23:18,320 --> 01:23:25,120 GENETICS IS GOING TO ANSWER THE 2318 01:23:25,120 --> 01:23:25,360 QUESTION. 2319 01:23:25,360 --> 01:23:26,960 >> KANDICE, WHAT IS YOUR VIEW? 2320 01:23:26,960 --> 01:23:28,560 >> DORMANCY IN ITSELF IS THAT 2321 01:23:28,560 --> 01:23:31,440 YOU HAVE SINGLE QUIESCENT CELLS 2322 01:23:31,440 --> 01:23:34,560 THAT HAVE SUCCESSFULLY 2323 01:23:34,560 --> 01:23:36,480 EXTRAVASATED, AND THAT THEY'RE 2324 01:23:36,480 --> 01:23:40,680 ABLE TO, QUOTE-UNQUOTE, BE -- 2325 01:23:40,680 --> 01:23:43,600 RESIDE AND RESIST ANY SORT OF 2326 01:23:43,600 --> 01:23:45,240 IMMUNE SURVEILLANCE, RIGHT? 2327 01:23:45,240 --> 01:23:47,320 SECOND ASPECT IS THAT YOU COULD 2328 01:23:47,320 --> 01:23:49,680 HAVE THESE CELLS THAT CAN DIVIDE 2329 01:23:49,680 --> 01:23:53,560 TO SOME EXTENT, BUT THEN THEY 2330 01:23:53,560 --> 01:23:56,400 MANAGE, EITHER BY SOME BALANCE 2331 01:23:56,400 --> 01:23:59,200 BETWEEN DEATH AND SURVIVABILITY, 2332 01:23:59,200 --> 01:24:00,600 THAT KEEPS IT BELOW SOME 2333 01:24:00,600 --> 01:24:02,240 CRITICAL MASK. 2334 01:24:02,240 --> 01:24:04,400 SO I THINK THAT GOING BACK TO 2335 01:24:04,400 --> 01:24:06,280 WHAT HAS BEEN SHOWN IN 2336 01:24:06,280 --> 01:24:07,240 PRE-CLINICAL MODELS, AND THESE 2337 01:24:07,240 --> 01:24:11,160 ARE MOUSE MODELS, AND SOME OF 2338 01:24:11,160 --> 01:24:12,520 THE WORK WE WANT TO ILLUSTRATE 2339 01:24:12,520 --> 01:24:13,880 STARTS WITH ANNE CHAMBERS, WHO 2340 01:24:13,880 --> 01:24:15,280 WAS AT UNIVERSITY OF TORONTO, 2341 01:24:15,280 --> 01:24:17,000 WHO LOOKED AT SOME OF THESE 2342 01:24:17,000 --> 01:24:19,120 FACTORS THAT COULD EITHER BE 2343 01:24:19,120 --> 01:24:21,880 CELLULAR BASED VERSUS THAT OF 2344 01:24:21,880 --> 01:24:23,640 THE MICROENVIRONMENT. 2345 01:24:23,640 --> 01:24:28,960 JEFF BREEN HEJEFF GREEN HERE ATI 2346 01:24:28,960 --> 01:24:31,080 BEFORE HE RETIRED LOOKED AT WHAT 2347 01:24:31,080 --> 01:24:33,160 COULD WEAKEN THESE CELLS, THEY 2348 01:24:33,160 --> 01:24:34,760 WERE MICROENVIRONMENT TALL 2349 01:24:34,760 --> 01:24:37,000 FACTORS, AND THEN MORE RECENTLY, 2350 01:24:37,000 --> 01:24:42,120 A COLLEAGUE OF MINE HAS REALLY 2351 01:24:42,120 --> 01:24:43,920 EXTENSIVELY LOOKED AT THESE 2352 01:24:43,920 --> 01:24:46,200 GENETIC FACTORS IN AN 2353 01:24:46,200 --> 01:24:47,320 ORGAN-SPECIFIC FACTOR, MEANING 2354 01:24:47,320 --> 01:24:49,280 ORGAN CELLS THAT ARE RESIDENT IN 2355 01:24:49,280 --> 01:24:50,560 ONE ORGAN MAY HAVE SOME GENETIC 2356 01:24:50,560 --> 01:24:51,760 SIGNATURE THAT'S DISTINCT FROM 2357 01:24:51,760 --> 01:24:52,160 ANOTHER ORGAN. 2358 01:24:52,160 --> 01:24:54,280 SO I DO THINK IT'S POSSIBLE IF 2359 01:24:54,280 --> 01:24:56,480 WE RELY ON WHAT HAS BEEN SHOWN 2360 01:24:56,480 --> 01:24:58,320 IN THE PRE-CLINICAL MODEL 2361 01:24:58,320 --> 01:24:58,640 SYSTEMS. 2362 01:24:58,640 --> 01:25:02,240 NOW IN TERMS OF WHAT MAY DEFINE 2363 01:25:02,240 --> 01:25:04,360 THESE ESCAPE MECHANISMS, THAT 2364 01:25:04,360 --> 01:25:07,160 WOULD I PREDICT IF THEY REMAIN 2365 01:25:07,160 --> 01:25:09,600 DODORMANT OR SO FORTH, I THINK E 2366 01:25:09,600 --> 01:25:12,640 EVIDENCE IS THERE THAT SOMETHING 2367 01:25:12,640 --> 01:25:14,080 THAT -- STROMAL CHANGES IN THE 2368 01:25:14,080 --> 01:25:15,400 MICROENVIRONMENT CAN THEN 2369 01:25:15,400 --> 01:25:16,600 REACTIVATE THESE DOOR MALL 2370 01:25:16,600 --> 01:25:16,800 CELLS. 2371 01:25:16,800 --> 01:25:20,880 ONE OF THESE -- I WOULD SAY TGF 2372 01:25:20,880 --> 01:25:22,200 BETA HAS BEEN IMPLICATED IN 2373 01:25:22,200 --> 01:25:23,800 TERMS OF THESE CELLS BEING ABLE 2374 01:25:23,800 --> 01:25:27,920 TO WEAKEN FROM THESE DORMANT 2375 01:25:27,920 --> 01:25:29,640 CELLS AND THE HE ABILITY TO 2376 01:25:29,640 --> 01:25:32,400 REMODEL AND CREATE -- SECRETE 2377 01:25:32,400 --> 01:25:35,760 DIFFERENT TYPES OF PROTEINS LIKE 2378 01:25:35,760 --> 01:25:37,520 FIBROME CAN TIN. 2379 01:25:37,520 --> 01:25:40,040 AT LEAST FROM THE PRE-CLINICAL 2380 01:25:40,040 --> 01:25:41,160 SIDE, OF COURSE JONATHAN IS A 2381 01:25:41,160 --> 01:25:42,800 SURGEON, I'M JUST A PHYSICIST, 2382 01:25:42,800 --> 01:25:44,320 THERE IS EVIDENCE THAT YOU CAN 2383 01:25:44,320 --> 01:25:47,160 AT LEAST DELINEATE SOME OF THESE 2384 01:25:47,160 --> 01:25:49,240 PORE TANT DETERMINANTS, NOW 2385 01:25:49,240 --> 01:25:51,440 TRYING TO TRANSLATE THAT INTO 2386 01:25:51,440 --> 01:25:53,880 THE HUMAN STUDIES, GOES BACK TO 2387 01:25:53,880 --> 01:25:55,880 THE LIMITATIONS OF HOW DO WE 2388 01:25:55,880 --> 01:26:00,920 THEN IMAGE THESE THINGS TO THEN 2389 01:26:00,920 --> 01:26:03,200 REALIZE, THE ASSUMPTION IS CELLS 2390 01:26:03,200 --> 01:26:04,640 HAVE DISSEMINATED ONCE A PRIMARY 2391 01:26:04,640 --> 01:26:05,520 TUMOR IS PRESENT AND THE 2392 01:26:05,520 --> 01:26:07,040 QUESTION BECOMES THEN HOW DO WE 2393 01:26:07,040 --> 01:26:08,360 ISOLATE THEM OR AT LEAST KNOW 2394 01:26:08,360 --> 01:26:09,240 THAT THEY'RE PRESENT TO BACK UP 2395 01:26:09,240 --> 01:26:10,800 SOME OF THESE PRE CLINICAL 2396 01:26:10,800 --> 01:26:11,320 STUDIES. 2397 01:26:11,320 --> 01:26:15,560 SO I THINK THAT THE ANSWER IS 2398 01:26:15,560 --> 01:26:17,360 STILL OPEN-ENDED. 2399 01:26:17,360 --> 01:26:18,760 OBVIOUSLY AT THE PRE-CLINICAL 2400 01:26:18,760 --> 01:26:20,040 MODEL, WE STILL HAVE TO SHOW THE 2401 01:26:20,040 --> 01:26:22,440 RELEVANCE BUT THE EVIDENCE IS 2402 01:26:22,440 --> 01:26:23,480 MOUNTING THAT THERE IS GOING TO 2403 01:26:23,480 --> 01:26:24,920 BE A SIGNATURE THAT ALLOWS US 2404 01:26:24,920 --> 01:26:28,400 THEN TO TEST THESE IN CLINICAL 2405 01:26:28,400 --> 01:26:31,400 TRIALS. 2406 01:26:31,400 --> 01:26:34,360 >> SOUNDS TO ME IT'S A LITTLE 2407 01:26:34,360 --> 01:26:35,680 BIT LIKE STAR TREK, WHEN THE 2408 01:26:35,680 --> 01:26:38,520 SHIELDS ARE UP, NOTHING MUCH IS 2409 01:26:38,520 --> 01:26:39,640 HAPPENING, BUT THERE'S 2410 01:26:39,640 --> 01:26:40,800 RESISTANCE, AND WHEN THE SHIELDS 2411 01:26:40,800 --> 01:26:43,440 ARE DOWN, YOU CAN MOVE, YOU CAN 2412 01:26:43,440 --> 01:26:45,760 SPREAD, BUT YOU'RE ALSO 2413 01:26:45,760 --> 01:26:49,280 VULNERABLE. 2414 01:26:49,280 --> 01:26:51,440 >> I DON'T KNOW, THAT'S JUST MY 2415 01:26:51,440 --> 01:26:51,920 NAIVE INTERPRETATION. 2416 01:26:51,920 --> 01:26:53,800 I THINK THAT WE STILL -- WELL, 2417 01:26:53,800 --> 01:26:55,040 LET ME SPEAK FOR MYSELF, I THINK 2418 01:26:55,040 --> 01:26:57,720 THAT I DON'T UNDERSTAND HOW DO 2419 01:26:57,720 --> 01:27:00,760 CELLS EVEN RESPOND TO DIFFERENT 2420 01:27:00,760 --> 01:27:01,800 CELLS IN THEIR OWN ENVIRONMENT, 2421 01:27:01,800 --> 01:27:03,760 SO MUCH LESS FOR WHAT HAPPENS 2422 01:27:03,760 --> 01:27:05,400 UNDER PERTURBATIONS. 2423 01:27:05,400 --> 01:27:08,720 I THINK THESE ARE VERY COMPLEX 2424 01:27:08,720 --> 01:27:09,720 QUESTIONS AND WE'RE JUST 2425 01:27:09,720 --> 01:27:10,720 SCRAPING THE SURFACE OF THEM 2426 01:27:10,720 --> 01:27:12,560 QUITE FRANKLY. 2427 01:27:12,560 --> 01:27:16,480 >> SO ANOTHER QUESTION THAT POPS 2428 01:27:16,480 --> 01:27:19,360 UP DEALS WITH METABOLIC 2429 01:27:19,360 --> 01:27:23,040 DIFFERENCES. 2430 01:27:23,040 --> 01:27:25,160 GENERALLY SPEAKING, CANCERS ARE 2431 01:27:25,160 --> 01:27:28,000 SAID TO ANABOLIC. 2432 01:27:28,000 --> 01:27:31,400 WHAT ABOUT METASTASES OR THE 2433 01:27:31,400 --> 01:27:33,600 CIRCULATING CELLS IN THE BODY, 2434 01:27:33,600 --> 01:27:35,880 OR, AS YOU MENTIONED, THIS 2435 01:27:35,880 --> 01:27:38,960 FASCINATING PH RELATIONSHIP 2436 01:27:38,960 --> 01:27:41,560 WHICH USUALLY IMPLIES THAT THERE 2437 01:27:41,560 --> 01:27:43,760 ARE PATHWAYS AND METABOLIC 2438 01:27:43,760 --> 01:27:46,280 MECHANISMS THAT ARE AT WORK, 2439 01:27:46,280 --> 01:27:47,520 CREATING THAT. 2440 01:27:47,520 --> 01:27:51,320 SO IN BRIEF, WHAT DO WE -- DO WE 2441 01:27:51,320 --> 01:27:53,760 KNOW MUCH ABOUT THE DIFFERENT 2442 01:27:53,760 --> 01:27:57,240 METABOLISM THAT'S OCCURRING IN A 2443 01:27:57,240 --> 01:27:59,440 METASTATIC CELL IN A FULL BLOWN 2444 01:27:59,440 --> 01:28:02,640 METASTASES AS COMPARED, SAY, TO 2445 01:28:02,640 --> 01:28:05,040 THE PRIMARY TUMOR? 2446 01:28:05,040 --> 01:28:07,480 IS THIS A RELEVANT QUESTION? 2447 01:28:07,480 --> 01:28:08,880 WE'VE BEEN ASKED THIS SEVERAL 2448 01:28:08,880 --> 01:28:14,080 TIMES HERE. 2449 01:28:14,080 --> 01:28:15,600 >> I THINK IT'S A VERY RELEVANT 2450 01:28:15,600 --> 01:28:15,880 QUESTION. 2451 01:28:15,880 --> 01:28:17,200 I'LL ANSWER WITH SOME WORK WE'VE 2452 01:28:17,200 --> 01:28:18,600 BEEN DOING WITH MOUSE MODELS IN 2453 01:28:18,600 --> 01:28:20,840 THE LAB WITH PANCREAS CANCER. 2454 01:28:20,840 --> 01:28:23,480 THAT IS, IF YOU SIMULATE A 2455 01:28:23,480 --> 01:28:25,560 METASTASIS MODEL IN THE LIVER, 2456 01:28:25,560 --> 01:28:29,600 WHAT A CELL HAS TO DO WHEN IT'S 2457 01:28:29,600 --> 01:28:32,120 LEFT A PRIMARY TUMOR IS IT HAS 2458 01:28:32,120 --> 01:28:32,880 TO COPE WITH THINGS. 2459 01:28:32,880 --> 01:28:34,120 ONE THE NUTRIENT ENVIRONMENT IS 2460 01:28:34,120 --> 01:28:35,360 GOING TO BE DIFFERENT, AND TWO 2461 01:28:35,360 --> 01:28:37,280 IS THE OXIDATIVE STRESS IS GOING 2462 01:28:37,280 --> 01:28:39,880 TO BE DIFFERENT. 2463 01:28:39,880 --> 01:28:41,200 THE THIRD PART OF THIS IS YOU 2464 01:28:41,200 --> 01:28:42,960 HAVE TO EVADE THE IMMUNE SYSTEM. 2465 01:28:42,960 --> 01:28:45,240 ONCE YOU LEAVE A PRIMARY TUMOR 2466 01:28:45,240 --> 01:28:46,640 AND YOU END UP IN A FOREIGN 2467 01:28:46,640 --> 01:28:48,240 LAND, I USED TO SAY IF YOU 2468 01:28:48,240 --> 01:28:49,640 DROPPED ME IN RURAL CHINA, I 2469 01:28:49,640 --> 01:28:50,960 DON'T SPEAK THE LANGUAGE, I'VE 2470 01:28:50,960 --> 01:28:52,960 GOT TO HELP -- GET THE LOCAL 2471 01:28:52,960 --> 01:28:54,280 PEOPLE, I'VE GOT TO LEARN HOW TO 2472 01:28:54,280 --> 01:28:55,560 GET FOOD, I HAVE TO SPEAK THE 2473 01:28:55,560 --> 01:28:56,640 LANGUAGE, I HAVE TO INTERACT 2474 01:28:56,640 --> 01:28:58,240 WITH PEOPLE. 2475 01:28:58,240 --> 01:29:00,080 ALL OF THOSE THINGS THAT 2476 01:29:00,080 --> 01:29:01,040 METASTATIC TUMOR CELL HAS TO DO 2477 01:29:01,040 --> 01:29:01,600 AS WELL. 2478 01:29:01,600 --> 01:29:03,400 AND SO THERE ARE GENE 2479 01:29:03,400 --> 01:29:04,320 SIGNATURES, EPIGENETIC CHANGES 2480 01:29:04,320 --> 01:29:05,640 THAT OCCUR THAT ALLOW THAT CELL 2481 01:29:05,640 --> 01:29:08,240 TO INTAKE NUTRIENTS, TO HAVE TO 2482 01:29:08,240 --> 01:29:10,240 DEAL WITH NEW OXIDATIVE STRESS. 2483 01:29:10,240 --> 01:29:12,880 PRIMARY TUMORS ARE VERY HYPOXIC. 2484 01:29:12,880 --> 01:29:14,080 THEY DON'T HAVE A LOT OF BLOOD 2485 01:29:14,080 --> 01:29:14,400 VESSELS. 2486 01:29:14,400 --> 01:29:17,680 IF YOU LOOK AT THEM UNDER A 2487 01:29:17,680 --> 01:29:18,680 MICROSCOPE, YOU ALMOST WONDER 2488 01:29:18,680 --> 01:29:19,680 HOW THE THING DOESN'T DIE. 2489 01:29:19,680 --> 01:29:20,960 THERE'S NOT A LOT OF BLOOD 2490 01:29:20,960 --> 01:29:21,240 VESSELS. 2491 01:29:21,240 --> 01:29:23,080 BUT WHEN YOU GO INTO THAT 2492 01:29:23,080 --> 01:29:24,640 CIRCULATION, YOU'RE IN A LOT 2493 01:29:24,640 --> 01:29:25,800 MORE OXYGEN INTENSIVE, YOU HAVE 2494 01:29:25,800 --> 01:29:27,120 TO SORT OF DEAL WITH THAT TOO, 2495 01:29:27,120 --> 01:29:28,200 THEN YOU END UP IN A PLACE LIKE 2496 01:29:28,200 --> 01:29:29,560 THE LIVER OR LUNG WHERE THE 2497 01:29:29,560 --> 01:29:30,440 OXYGEN IS MUCH HIGHER. 2498 01:29:30,440 --> 01:29:32,280 YOU HAVE TO DEAL WITH ALL OF 2499 01:29:32,280 --> 01:29:33,560 THESE THINGS SIMULTANEOUSLY OR 2500 01:29:33,560 --> 01:29:34,840 YOU DIE IF YOU'RE THAT TUMOR 2501 01:29:34,840 --> 01:29:36,680 CELL. 2502 01:29:36,680 --> 01:29:41,640 SO WE HAVE IDENTIFIED A CERTAIN 2503 01:29:41,640 --> 01:29:43,080 STRESS RESPONSE THAT THESE 2504 01:29:43,080 --> 01:29:44,160 DISSEMINATED TUMOR CELLS ARE 2505 01:29:44,160 --> 01:29:45,120 LIKELY TO EMPLOY IN ORDER TO 2506 01:29:45,120 --> 01:29:48,000 DEAL WITH ALL THESE THINGS 2507 01:29:48,000 --> 01:29:49,080 SIMULTANEOUSLY. 2508 01:29:49,080 --> 01:29:52,080 THE TARGETTABILITY OF THIS IS 2509 01:29:52,080 --> 01:29:53,160 UNCLEAR TO ME AT PRESENT, BUT 2510 01:29:53,160 --> 01:29:55,440 THESE ARE THINGS THAT HAVE TO 2511 01:29:55,440 --> 01:29:56,520 BE -- YOU HAVE TO DO THIS IF 2512 01:29:56,520 --> 01:29:58,920 YOU'RE GOING TO SURVIVE. 2513 01:29:58,920 --> 01:30:00,040 AND TO I GUESS I'LL ANSWER THE 2514 01:30:00,040 --> 01:30:03,000 QUESTION THAT WAY. 2515 01:30:03,000 --> 01:30:07,600 >> SO I GUESS IT MUST BE OVER 40 2516 01:30:07,600 --> 01:30:12,080 YEARS AGO, A MAJOR ISSUE 2517 01:30:12,080 --> 01:30:13,840 INVOLVED IN CANCER ITSELF AS 2518 01:30:13,840 --> 01:30:18,360 WELL AS METASTASIS WAS THE ROLE 2519 01:30:18,360 --> 01:30:23,400 OF ANGIOGENESIS, AND THE 2520 01:30:23,400 --> 01:30:27,720 POTENTIAL CLINICAL THERAPEUTIC 2521 01:30:27,720 --> 01:30:28,880 EFFECT OF ANTIANGIOGENIC 2522 01:30:28,880 --> 01:30:29,520 COMPOUNDS. 2523 01:30:29,520 --> 01:30:31,120 THINGS AS I RECALL, THINGS 2524 01:30:31,120 --> 01:30:32,960 CALLED ENDO STATIN AND 2525 01:30:32,960 --> 01:30:34,720 ONCOSTATIN AND SO FORTH. 2526 01:30:34,720 --> 01:30:38,120 THAT SEEMS TO HAVE DISAPPEARED 2527 01:30:38,120 --> 01:30:41,840 ENTIRELY FROM DISCUSSIONS OF ME 2528 01:30:41,840 --> 01:30:45,400 TAS CYST AND TUMOR. 2529 01:30:45,400 --> 01:30:46,400 METASTASIS AND TUMOR. 2530 01:30:46,400 --> 01:30:48,280 DO YOU WANT TO COMMENT AS TO WHY 2531 01:30:48,280 --> 01:30:49,920 IS THERE NO ROLE OF -- IS IT 2532 01:30:49,920 --> 01:30:52,640 WRONG THAT THE TUMORS AND 2533 01:30:52,640 --> 01:30:56,680 METASTASES ARE DEPENDENT UPON 2534 01:30:56,680 --> 01:30:58,240 THEIR BLOOD SUPPLY, AND IF YOU 2535 01:30:58,240 --> 01:30:58,880 COULD INTERFERE WITH IT, THAT 2536 01:30:58,880 --> 01:31:00,440 YOU WOULD BE INHIBITING THEIR 2537 01:31:00,440 --> 01:31:02,400 GROWTH? 2538 01:31:02,400 --> 01:31:04,040 WHY IS THAT SORT OF NO LONGER 2539 01:31:04,040 --> 01:31:08,040 CONSIDERED? 2540 01:31:08,040 --> 01:31:13,600 >> SO THIS ALL STARTED WITH 2541 01:31:13,600 --> 01:31:16,080 FOLKMAN, WHO COINED THIS TERM 2542 01:31:16,080 --> 01:31:16,760 ANGIOGENESIS AND OTHERS HAVE 2543 01:31:16,760 --> 01:31:18,040 BUILT ON THESE FINDINGS, AND 2544 01:31:18,040 --> 01:31:19,640 QUITE FRANKLY, I THINK THAT 2545 01:31:19,640 --> 01:31:24,560 THERE IS SORT OF A -- FROM MY 2546 01:31:24,560 --> 01:31:27,040 UNDERSTANDING, IT'S A MIXED BAG 2547 01:31:27,040 --> 01:31:29,080 IN TERMS OF USING 2548 01:31:29,080 --> 01:31:30,320 ANTIANGIOGENIC, I WILL SAY -- 2549 01:31:30,320 --> 01:31:32,880 WELL, INHIBITORS OF 2550 01:31:32,880 --> 01:31:34,840 ANGIOGENESIS, IN THE SENSE THAT 2551 01:31:34,840 --> 01:31:36,440 DEPENDING ON THE SIZE OF THE 2552 01:31:36,440 --> 01:31:37,240 TUMOR, DEPENDING ON HOW 2553 01:31:37,240 --> 01:31:41,200 PROGRESSIVE IT IS, IT MAY BE 2554 01:31:41,200 --> 01:31:42,520 PORE TANT CERTAIN STAGES OF 2555 01:31:42,520 --> 01:31:45,920 TUMOR GROWTH AND MAY BE LESS 2556 01:31:45,920 --> 01:31:48,920 EFFECTIVE IN THE METASTATIC 2557 01:31:48,920 --> 01:31:49,280 SETTING. 2558 01:31:49,280 --> 01:31:50,800 AND IT GOES BACK TO THE FACTORS, 2559 01:31:50,800 --> 01:31:54,080 IF YOU TARGET VEGF, VEGF IN 2560 01:31:54,080 --> 01:31:56,440 ITSELF IS ALSO REGULATED BY 2561 01:31:56,440 --> 01:31:58,240 TUMOR SECRETE VEGF AND THERE'S 2562 01:31:58,240 --> 01:31:59,760 ALSO VEGF FROM THE ENDOTHELIAL 2563 01:31:59,760 --> 01:32:00,000 CELLS. 2564 01:32:00,000 --> 01:32:02,040 SO I THINK THE REASON WHY 2565 01:32:02,040 --> 01:32:04,320 THEY'RE, I GUESS IN MY NAIVE 2566 01:32:04,320 --> 01:32:04,960 INTERPRETATION OF THE DATA, IS 2567 01:32:04,960 --> 01:32:06,360 THAT THE REASON WHY THERE ARE 2568 01:32:06,360 --> 01:32:07,800 DIFFERENCES IN TERMS OF THE 2569 01:32:07,800 --> 01:32:09,920 EFFICACY, IS THAT ONE NEEDS TO 2570 01:32:09,920 --> 01:32:11,000 UNDERSTAND THESE RELATIVE 2571 01:32:11,000 --> 01:32:12,720 BALANCES OF HOW MUCH OF IT IS 2572 01:32:12,720 --> 01:32:15,080 TUMOR DERIVED, WHICH IS STROMAL 2573 01:32:15,080 --> 01:32:17,360 DERIVED, AND THAT'S WHY IN SOME 2574 01:32:17,360 --> 01:32:18,520 WAYS, THESE -- I WOULDN'T SAY 2575 01:32:18,520 --> 01:32:23,440 THAT THEY WOULD NOT -- WERE NOT 2576 01:32:23,440 --> 01:32:24,840 EFFECTIVE, IT'S JUST THAT THE 2577 01:32:24,840 --> 01:32:26,160 EFFECTS ARE NOT COMPLETELY 2578 01:32:26,160 --> 01:32:27,400 UNDERSTOOD. 2579 01:32:27,400 --> 01:32:29,360 AND ARE STILL BEING FLESHED OUT, 2580 01:32:29,360 --> 01:32:31,840 ESPECIALLY GIVEN THAT THERE ARE 2581 01:32:31,840 --> 01:32:33,520 ORGAN-SPECIFIC REACTIONS WHEN WE 2582 01:32:33,520 --> 01:32:34,160 TARGET DIFFERENT ENDOTHELIAL 2583 01:32:34,160 --> 01:32:37,480 CELLS. 2584 01:32:37,480 --> 01:32:39,320 >> SO WHAT DO YOU THINK, 2585 01:32:39,320 --> 01:32:40,600 JONATHAN, IN YOUR REMARKABLE 2586 01:32:40,600 --> 01:32:45,600 SETUP THAT YOU DESCRIBE, IS THIS 2587 01:32:45,600 --> 01:32:47,160 SOMETHING THAT YOU'RE 2588 01:32:47,160 --> 01:32:50,080 INVESTIGATING OR IS WORTHWHILE 2589 01:32:50,080 --> 01:32:50,440 INVESTIGATING? 2590 01:32:50,440 --> 01:32:52,000 >> I THINK THERE'S A COUPLE OF 2591 01:32:52,000 --> 01:32:54,400 PIECES OF DATA THAT SHOULD BE 2592 01:32:54,400 --> 01:32:56,480 STATED ABOUT WHY. 2593 01:32:56,480 --> 01:32:57,880 I DON'T THINK THIS SORT OF -- IF 2594 01:32:57,880 --> 01:33:03,400 YOU'RE GOING TO TRY AND PROHIBIT 2595 01:33:03,400 --> 01:33:06,040 MICRO METASTASIS, WE DON'T 2596 01:33:06,040 --> 01:33:07,240 REQUIRE THIS BLOOD SUPPLY, WE 2597 01:33:07,240 --> 01:33:08,560 DON'T NEED IT, WE DON'T DEPEND 2598 01:33:08,560 --> 01:33:10,320 ON IT, SO IT'S NOT NECESSARY. 2599 01:33:10,320 --> 01:33:12,960 WE HAVE SOME DATA, PRE-CLINICAL 2600 01:33:12,960 --> 01:33:13,960 DATA THAT WOULD SUGGEST THAT 2601 01:33:13,960 --> 01:33:14,840 WHEN CELLS GET INTO THE LIVER, 2602 01:33:14,840 --> 01:33:16,720 THEY PROBABLY STAY RIGHT AROUND 2603 01:33:16,720 --> 01:33:17,840 THE PERIVASCULATURE, THEY 2604 01:33:17,840 --> 01:33:19,120 PROBABLY GET PLENTY OF OXYGEN. 2605 01:33:19,120 --> 01:33:21,200 THEY DON'T REQUIRE NEW BLOOD 2606 01:33:21,200 --> 01:33:22,560 VESSELS UNTIL THEY'VE REACHED A 2607 01:33:22,560 --> 01:33:24,600 CERTAIN CELL MASS. 2608 01:33:24,600 --> 01:33:26,920 NOW, WE SHOULD TALK ABOUT 2609 01:33:26,920 --> 01:33:31,400 THERE'S A DRUG CALLED BEV SIZ 2610 01:33:31,400 --> 01:33:33,240 BEVACIZUMAB, SO IT FINDS THE 2611 01:33:33,240 --> 01:33:33,640 ACTUAL FACTOR. 2612 01:33:33,640 --> 01:33:37,600 THIS IS A VERY POTENT MEDICA 2613 01:33:37,600 --> 01:33:38,240 MEDICATION. 2614 01:33:38,240 --> 01:33:39,840 IT'S BEEN USED IN COLON CANCER, 2615 01:33:39,840 --> 01:33:41,240 IT'S USED IN COMBINATION WITH 2616 01:33:41,240 --> 01:33:43,240 OTHER AGENTS FOR STAGE IV 2617 01:33:43,240 --> 01:33:45,040 DISEASE, IT'S BEEN TRIED IN 2618 01:33:45,040 --> 01:33:47,080 MULTIPLE SCENARIOS TO TRY AND 2619 01:33:47,080 --> 01:33:49,560 PREVENT MIC MICRO METASTASES. 2620 01:33:49,560 --> 01:33:51,000 WHAT YOU SEE IS THE CURVE 2621 01:33:51,000 --> 01:33:53,200 SHIFTS, YOU CAN DELAY THAT 2622 01:33:53,200 --> 01:33:54,680 OUTGROWTH, SUGGESTING THAT THOSE 2623 01:33:54,680 --> 01:33:56,320 CELLS DO EVENTUALLY REQUIRE 2624 01:33:56,320 --> 01:33:57,760 THAT. 2625 01:33:57,760 --> 01:33:59,160 BUT THOSE CELLS CIRCUMVENT IT 2626 01:33:59,160 --> 01:34:00,160 SUCH THAT EVERYBODY WHO WAS 2627 01:34:00,160 --> 01:34:01,920 GOING TO RECUR, RECURRED, SUCH 2628 01:34:01,920 --> 01:34:05,080 THAT THE RECURRENCE RATE OR 2629 01:34:05,080 --> 01:34:06,280 EQUIVALENT, SURVIVAL OR 2630 01:34:06,280 --> 01:34:08,480 EQUIVALENT IS NOT USED IN A 2631 01:34:08,480 --> 01:34:10,240 SETTING TO USE MICRO METASTASES 2632 01:34:10,240 --> 01:34:12,120 BECAUSE THERE'S PROBABLY 2633 01:34:12,120 --> 01:34:13,040 WORK-AROUND CIRCUITS, NUMBER 2634 01:34:13,040 --> 01:34:13,200 ONE. 2635 01:34:13,200 --> 01:34:14,360 NUMBER TWO, EARLY ON THEY 2636 01:34:14,360 --> 01:34:15,520 PROBABLY DON'T NEED NEW 2637 01:34:15,520 --> 01:34:16,200 VASCULATURE TO GROW. 2638 01:34:16,200 --> 01:34:18,640 AND SO THIS SORT OF CONCEPT HAS 2639 01:34:18,640 --> 01:34:19,480 FALLEN OUT OF FAVOR BECAUSE IT 2640 01:34:19,480 --> 01:34:24,120 DOESN'T WORK. 2641 01:34:24,120 --> 01:34:26,160 >> HERE'S AN INTERESTING 2642 01:34:26,160 --> 01:34:27,120 QUESTION. 2643 01:34:27,120 --> 01:34:29,480 ARE M METASTASES USUALLY DRUG 2644 01:34:29,480 --> 01:34:31,920 RESISTANT EVEN IF THE PRIMARY IS 2645 01:34:31,920 --> 01:34:33,440 NOT? 2646 01:34:33,440 --> 01:34:35,240 >> YES. 2647 01:34:35,240 --> 01:34:37,720 YES. 2648 01:34:37,720 --> 01:34:40,360 >> THEY ARE INVARIABLY DRUG 2649 01:34:40,360 --> 01:34:41,240 RESISTANT? 2650 01:34:41,240 --> 01:34:44,120 I MEAN, YOU KNOW, MOST LIKELY, 2651 01:34:44,120 --> 01:34:44,440 SOMETHING? 2652 01:34:44,440 --> 01:34:46,760 >> SO YOU KNOW, IT'S FUNNY, YOU 2653 01:34:46,760 --> 01:34:48,880 KNOW, BECAUSE YOU TAKE A 2654 01:34:48,880 --> 01:34:49,520 PATIENT, LET'S TAKE A GIVEN 2655 01:34:49,520 --> 01:34:51,000 PATIENT AND THEY MAY HAVE 10 2656 01:34:51,000 --> 01:34:52,240 METASTASES AND WE GIVE THEM 2657 01:34:52,240 --> 01:34:55,880 DRUGS AND THEY RESPOND. 2658 01:34:55,880 --> 01:34:56,520 OKAY. 2659 01:34:56,520 --> 01:34:58,720 10 TUMORS SHRINK A LITTLE BIT. 2660 01:34:58,720 --> 01:35:00,040 LET'S SAY YOU GIVE THAT PATIENT 2661 01:35:00,040 --> 01:35:02,480 NO TUMORS BUT GIVE THEM MICRO 2662 01:35:02,480 --> 01:35:03,480 KRO METASTASES EVERYWHERE. 2663 01:35:03,480 --> 01:35:05,560 IF THE DRUG KILLS 99 OUT OF 100 2664 01:35:05,560 --> 01:35:07,600 OF THOSE MICRO METASTASES BUT 2665 01:35:07,600 --> 01:35:08,840 ONE GROWS FOR WHATEVER REASON, 2666 01:35:08,840 --> 01:35:10,800 WE WOULD SAY SAID DRUG DOESN'T 2667 01:35:10,800 --> 01:35:11,600 WORK. 2668 01:35:11,600 --> 01:35:14,640 WE DON'T HAVE A WAY TO SORT OF 2669 01:35:14,640 --> 01:35:16,440 GAUGE, YOU KNOW, THE DEGREE OF 2670 01:35:16,440 --> 01:35:17,200 WORKING OR NOT. 2671 01:35:17,200 --> 01:35:18,600 WE SORT OF HAVE A BLACK AND 2672 01:35:18,600 --> 01:35:21,120 WHITE READOUT IN THE END AS DID 2673 01:35:21,120 --> 01:35:23,080 THEY RECUR, DID THEY DEVELOP A 2674 01:35:23,080 --> 01:35:23,800 MICRO METASTASES? 2675 01:35:23,800 --> 01:35:25,800 SO I THINK IT'S POSSIBLE THAT 2676 01:35:25,800 --> 01:35:27,560 SOME OF THE STUFF HAS BEEN 2677 01:35:27,560 --> 01:35:28,920 DISMISSED AS NOT WORKING WHEN, 2678 01:35:28,920 --> 01:35:32,720 IN FACT, MAYBE IT DID REDUCE BY 2679 01:35:32,720 --> 01:35:35,760 A LARGE PERCENTAGE THE AMOUNT OF 2680 01:35:35,760 --> 01:35:36,640 DISSEMINATED TUMOR CELLS BUT 2681 01:35:36,640 --> 01:35:38,320 JUST DIDN'T GET RID OF ALL OF 2682 01:35:38,320 --> 01:35:39,800 THEM SUCH THAT SOME OF THEM WERE 2683 01:35:39,800 --> 01:35:40,480 TO OUTGROW. 2684 01:35:40,480 --> 01:35:41,800 THE PROBLEM IS REALLY QUITE 2685 01:35:41,800 --> 01:35:43,000 COMPLICATED AND I THINK HAS TO 2686 01:35:43,000 --> 01:35:44,200 BE -- IF YOU'RE GOING TO LOOK AT 2687 01:35:44,200 --> 01:35:45,920 THIS FROM A TARGETABLE 2688 01:35:45,920 --> 01:35:48,160 PERSPECTIVE, YOU REALLY HAVE TO 2689 01:35:48,160 --> 01:35:49,440 UNDERSTAND THE COMPLEXITY OF THE 2690 01:35:49,440 --> 01:35:51,920 MICRO ME TAS SEES, DISSEMINATED 2691 01:35:51,920 --> 01:35:54,480 TUMOR CELLS THAT MAY NOT ALL BE 2692 01:35:54,480 --> 01:35:55,160 ONE THING. 2693 01:35:55,160 --> 01:35:57,240 I LIKE TO NOT SAY BECAUSE IT 2694 01:35:57,240 --> 01:35:58,880 CREATES AN ALMOST UNSOLVABLE 2695 01:35:58,880 --> 01:35:59,880 PROBLEM BUT IT COULD VERY WELL 2696 01:35:59,880 --> 01:36:00,320 BE THE CASE. 2697 01:36:00,320 --> 01:36:04,520 >> MAY I ADD, SO I THINK THAT IT 2698 01:36:04,520 --> 01:36:06,960 MAY NOT BE THAT IS RESISTANCE, 2699 01:36:06,960 --> 01:36:09,360 PER SE, BUT IN THAT 2700 01:36:09,360 --> 01:36:10,720 MICROENVIRONMENT, HOW THE CELLS 2701 01:36:10,720 --> 01:36:13,520 SIGNAL AND RECEIVE QUEUES ARE 2702 01:36:13,520 --> 01:36:16,000 DISTINCT FROM WHAT THE PRIMARY 2703 01:36:16,000 --> 01:36:18,160 TUMOR ENVIRONMENT IS IN TERMS OF 2704 01:36:18,160 --> 01:36:21,000 REGULATED CELL SIGNALING EVENTS, 2705 01:36:21,000 --> 01:36:23,040 AND THESE MICROENVIRONMENT TALL 2706 01:36:23,040 --> 01:36:27,280 FACTORS MAY RENDER THESE DRUGS 2707 01:36:27,280 --> 01:36:28,160 INEFFECTIVE, AND IT HAS NOTHING 2708 01:36:28,160 --> 01:36:29,880 TO DO WITH THE SIGNALING THAT'S 2709 01:36:29,880 --> 01:36:31,360 BEING TARGETED, IT'S SIMPLY THAT 2710 01:36:31,360 --> 01:36:32,360 IT'S BEING BLUNTED BY THE 2711 01:36:32,360 --> 01:36:34,080 EFFECTS OF WHAT MICROENVIRONMENT 2712 01:36:34,080 --> 01:36:35,000 THAT THESE CELLS SEE. 2713 01:36:35,000 --> 01:36:38,080 SO I THINK UNTIL WE UNDERSTAND 2714 01:36:38,080 --> 01:36:40,720 HOW DRUGS -- I WOULD SAY HOW 2715 01:36:40,720 --> 01:36:42,040 CELLS RESPOND TO DRUGS IN 2716 01:36:42,040 --> 01:36:42,920 DIFFERENT MICRO ENVIRONMENTS, 2717 01:36:42,920 --> 01:36:47,200 AND THIS COULD BE DONE IN SORT 2718 01:36:47,200 --> 01:36:48,840 OF -- SETTINGS, ONLY THEN CAN WE 2719 01:36:48,840 --> 01:36:50,040 TRULY ASSESS IF THERE'S 2720 01:36:50,040 --> 01:36:51,520 RESISTANCE OR SIMPLY JUST SIMPLY 2721 01:36:51,520 --> 01:36:54,360 NOT EFFECTIVE BECAUSE OF OTHER 2722 01:36:54,360 --> 01:36:59,520 FACTORS. 2723 01:36:59,520 --> 01:37:00,960 >> WE HAVE ANOTHER QUESTION 2724 01:37:00,960 --> 01:37:06,880 THAT'S SORT OF TIMELY, IT SEEMS. 2725 01:37:06,880 --> 01:37:07,560 DO WE HAVE INFORMATION ABOUT THE 2726 01:37:07,560 --> 01:37:09,200 ROLE OF THE MICROBIOME IN THE 2727 01:37:09,200 --> 01:37:11,520 ROLE OF THE MICROENVIRONMENT? 2728 01:37:11,520 --> 01:37:11,760 >> RIGHT. 2729 01:37:11,760 --> 01:37:22,120 SO I THINK THAT IS GREGORIA 2730 01:37:22,120 --> 01:37:25,680 CHINCURRI'S WORK, HOW THE 2731 01:37:25,680 --> 01:37:28,320 MICROBIOME CAN PLAY A ROLE. 2732 01:37:28,320 --> 01:37:34,800 AS FAR AS I KNOW, THEY ARE 2733 01:37:34,800 --> 01:37:37,520 RELATED EXPERTS, IN CHAIN CAL 2734 01:37:37,520 --> 01:37:38,600 TRIAL BUT THAT'S THE EXTENT THAT 2735 01:37:38,600 --> 01:37:39,000 I KNOW. 2736 01:37:39,000 --> 01:37:40,400 I DON'T KNOW IF JONATHAN KNOWS 2737 01:37:40,400 --> 01:37:41,120 MORE THAN I DO. 2738 01:37:41,120 --> 01:37:42,520 >> I DON'T HAVE A COMMENT HERE 2739 01:37:42,520 --> 01:37:45,720 OTHER THAN TO SAY I THINK IT'S 2740 01:37:45,720 --> 01:37:48,120 INTERESTING, I THINK IT'S BEING 2741 01:37:48,120 --> 01:37:52,320 LOOKED AT BUT I'M NOT SURE 2742 01:37:52,320 --> 01:37:53,600 WHAT'S GOING TO COME OF IT. 2743 01:37:53,600 --> 01:37:56,800 WHAT I KNOW IS THAT THIS IN MICE 2744 01:37:56,800 --> 01:37:57,880 LOOKS VERY DIFFERENT THAN IT 2745 01:37:57,880 --> 01:37:59,480 DOES IN PEOPLE. 2746 01:37:59,480 --> 01:38:03,640 I'VE JUST SEEN SOME DATA IN MICE 2747 01:38:03,640 --> 01:38:05,040 DONE IN A NUMBER OF PEOPLE, IT 2748 01:38:05,040 --> 01:38:06,480 DOESN'T SEEM TO WORK THAT WAY. 2749 01:38:06,480 --> 01:38:07,880 I THINK IT'S SUPER INTERESTING, 2750 01:38:07,880 --> 01:38:10,360 I THINK THERE ARE SOME TRIALS 2751 01:38:10,360 --> 01:38:11,680 HAPPENING. 2752 01:38:11,680 --> 01:38:14,360 BUT AS FAR AS IMPACT UPON MICRO 2753 01:38:14,360 --> 01:38:16,320 METASTASES AND DISSEMINATED 2754 01:38:16,320 --> 01:38:17,520 TUMOR CELLS AND DORMANCY, I 2755 01:38:17,520 --> 01:38:20,000 THINK IT'S VERY HARD TO KNOW. 2756 01:38:20,000 --> 01:38:21,800 >> SO I'LL JUST SAY MAYBE TO 2757 01:38:21,800 --> 01:38:23,920 DIRECT THAT PERSON, THERE IS 2758 01:38:23,920 --> 01:38:27,400 WORK BEING DONE AND THE EXPERTS 2759 01:38:27,400 --> 01:38:31,040 ARE HERE AT THE NCI, IN MY 2760 01:38:31,040 --> 01:38:32,040 BUILDING ON THE THIRD FLOOR, SO 2761 01:38:32,040 --> 01:38:33,400 MAYBE THAT WOULD BE A GOOD WAY 2762 01:38:33,400 --> 01:38:36,440 FOR THEM TO FOLLOW UP. 2763 01:38:36,440 --> 01:38:37,880 BECAUSE WHAT I'VE SEEN WAS 2764 01:38:37,880 --> 01:38:39,080 EXCITING, BUT THEY WERE DONE IN 2765 01:38:39,080 --> 01:38:41,280 MOUSE MODELS. 2766 01:38:41,280 --> 01:38:43,560 >> SO WE HAVE A SERIES OF 2767 01:38:43,560 --> 01:38:49,880 QUESTIONS ABOUT CIRCULATING 2768 01:38:49,880 --> 01:38:51,720 TUMOR DNA AND CIRCULATING CANCER 2769 01:38:51,720 --> 01:38:55,000 CELLS. 2770 01:38:55,000 --> 01:38:57,360 DO YOU THINK -- IS THIS -- ARE 2771 01:38:57,360 --> 01:38:59,560 THESE PREDICTIVE? 2772 01:38:59,560 --> 01:39:01,600 OR IF YOU CARRY OUT SOME 2773 01:39:01,600 --> 01:39:04,720 PROCEDURE, LET'S SAY A SURGICAL 2774 01:39:04,720 --> 01:39:06,600 PROCEDURE, AND YOU FOLLOW A 2775 01:39:06,600 --> 01:39:10,080 PATIENT, ARE THEY INDICATIVE OF 2776 01:39:10,080 --> 01:39:14,600 RECURRENCE? 2777 01:39:14,600 --> 01:39:16,320 PEOPLE HAVE ALSO ASKED DO ALL 2778 01:39:16,320 --> 01:39:18,320 SOLID CANCERS HAVE TUMOR DNA IN 2779 01:39:18,320 --> 01:39:19,080 THE BLOOD? 2780 01:39:19,080 --> 01:39:22,800 AND IF SO, DOES THAT INDICATE 2781 01:39:22,800 --> 01:39:23,680 METASTASES? 2782 01:39:23,680 --> 01:39:26,360 I REALIZE THESE ARE SORT OF 2783 01:39:26,360 --> 01:39:28,160 GLOBAL ISSUES, BUT I THINK 2784 01:39:28,160 --> 01:39:29,240 EVERYONE WOULD BE INTERESTED IN 2785 01:39:29,240 --> 01:39:31,200 YOUR VIEWS ABOUT IT. 2786 01:39:31,200 --> 01:39:32,600 JONATHAN, DO YOU WANT TO GO 2787 01:39:32,600 --> 01:39:32,800 FIRST? 2788 01:39:32,800 --> 01:39:34,600 >> WELL, I HAD A FEELING THIS 2789 01:39:34,600 --> 01:39:36,840 QUESTION WAS GOING TO COME UP. 2790 01:39:36,840 --> 01:39:39,600 I THINK THE DATA IS SUPER 2791 01:39:39,600 --> 01:39:40,880 INTERESTING ABOUT CIRCULATING 2792 01:39:40,880 --> 01:39:45,440 TUMOR DNA BEING ABLE TO TELL US 2793 01:39:45,440 --> 01:39:46,520 ABOUT WHETHER SOMEBODY MIGHT 2794 01:39:46,520 --> 01:39:50,360 RECUR OR NOT. 2795 01:39:50,360 --> 01:39:51,680 I THINK THIS IS GOING TO COME 2796 01:39:51,680 --> 01:39:53,080 INTO PLAY, AND THERE ARE TRIALS 2797 01:39:53,080 --> 01:39:54,120 ONGOING ABOUT THIS, WHERE 2798 01:39:54,120 --> 01:39:56,960 SOMEBODY LIKE ME WOULD REMOVE A 2799 01:39:56,960 --> 01:39:58,000 PRIMARY TUMOR, AND THIS WOULD BE 2800 01:39:58,000 --> 01:39:59,680 A SITUATION WHERE IT WASN'T 2801 01:39:59,680 --> 01:40:01,520 REALLY CLEAR THAT CHEMOTHERAPY 2802 01:40:01,520 --> 01:40:02,600 OR ADJUVANT THERAPY WAS GOING TO 2803 01:40:02,600 --> 01:40:04,240 BE OF GREAT BENEFIT, AND WOULD 2804 01:40:04,240 --> 01:40:07,800 YOU THEN USE THAT MEASUREMENT OF 2805 01:40:07,800 --> 01:40:10,040 CIRCULATING TUMOR DNA AFTER THE 2806 01:40:10,040 --> 01:40:12,240 TUMOR WAS OUT AND IF THAT WAS 2807 01:40:12,240 --> 01:40:14,240 PRESENT, THAT WOULD BE 2808 01:40:14,240 --> 01:40:15,240 INDICATIVE THAT THE PATIENT 2809 01:40:15,240 --> 01:40:17,240 SHOULD, IN FACT, RECEIVE 2810 01:40:17,240 --> 01:40:18,960 TREATMENT BECAUSE THEY'RE LIKELY 2811 01:40:18,960 --> 01:40:21,120 TO HAVE DISSEMINATED TUMOR CELL. 2812 01:40:21,120 --> 01:40:23,520 AGAIN, WE REMOVE THE SOURCE, YET 2813 01:40:23,520 --> 01:40:25,800 THEY STILL HAVE THIS CIRCULATING 2814 01:40:25,800 --> 01:40:27,840 TUMOR DNA PRESENT. 2815 01:40:27,840 --> 01:40:30,560 DOES THAT MEAN THEY HAVE 2816 01:40:30,560 --> 01:40:31,440 METASTASES? 2817 01:40:31,440 --> 01:40:32,960 I THINK IT'S LIKELY THAT MEANS 2818 01:40:32,960 --> 01:40:36,280 THEY HAVE DISSEMINATED TUMOR 2819 01:40:36,280 --> 01:40:38,840 CELLS AND THEY'RE MOVING AROUND. 2820 01:40:38,840 --> 01:40:42,840 AGAIN, THE DIFFICULT PART IS, 2821 01:40:42,840 --> 01:40:45,200 IT'S NOT THE DISSEMINATION THAT 2822 01:40:45,200 --> 01:40:46,400 MATTERS, IT'S WHEN THE CELLS 2823 01:40:46,400 --> 01:40:47,840 BEGIN TO GROW AND COLONIZE, 2824 01:40:47,840 --> 01:40:52,680 THAT'S THE EVENT WE DON'T WANT. 2825 01:40:52,680 --> 01:40:55,320 SO I THINK DISSEMINATED TUMOR 2826 01:40:55,320 --> 01:40:58,480 DARN, I'M GOING TO USE THIS 2827 01:40:58,480 --> 01:41:00,520 SYNONYMOUSLY, MOSTLY THE FIELD 2828 01:41:00,520 --> 01:41:02,360 HAS TURNED TO DISSEMINATED TUMOR 2829 01:41:02,360 --> 01:41:04,040 DNA, I THINK IT'S GOING TO BE A 2830 01:41:04,040 --> 01:41:04,400 PREDICTION TOOL. 2831 01:41:04,400 --> 01:41:05,720 THE DATA LOOKS REALLY GOOD, I'D 2832 01:41:05,720 --> 01:41:07,560 LIKE TO SEE IT REPLICATED, BUT 2833 01:41:07,560 --> 01:41:10,040 THE PUBLICATION FROM JAPAN LOOKS 2834 01:41:10,040 --> 01:41:11,960 AMAZINGLY GOOD IN A VERY LARGE 2835 01:41:11,960 --> 01:41:12,720 NUMBER OF PATIENTS. 2836 01:41:12,720 --> 01:41:14,120 BUT I THINK IT'S GOING TO BE A 2837 01:41:14,120 --> 01:41:14,720 STRATIFICATION TOOL. 2838 01:41:14,720 --> 01:41:17,280 AND I THINK IT MAY HELP PEOPLE 2839 01:41:17,280 --> 01:41:19,560 AVOID CHEMOTHERAPY WHO PROBABLY 2840 01:41:19,560 --> 01:41:23,880 DO NOT NEED IT. 2841 01:41:23,880 --> 01:41:24,880 BUT ON THE OTHER SIDE OF THAT 2842 01:41:24,880 --> 01:41:26,400 TOKEN, LET'S SAY YOU FOUND 2843 01:41:26,400 --> 01:41:27,680 SOMEONE YOU THINK SHOULD HAVE 2844 01:41:27,680 --> 01:41:29,080 IT, WE HAVE VERY LIMITED TOOLS 2845 01:41:29,080 --> 01:41:29,640 TO TREAT THIS DISEASE. 2846 01:41:29,640 --> 01:41:31,160 IN TREATING DISEASE YOU CANNOT 2847 01:41:31,160 --> 01:41:32,680 SEE, YOU KNOW, IT'S TOUGH. 2848 01:41:32,680 --> 01:41:33,960 AND WE DON'T HAVE A LOT OF 2849 01:41:33,960 --> 01:41:34,320 TOOLS. 2850 01:41:34,320 --> 01:41:36,120 SO I THINK THE BIGGEST BANG FOR 2851 01:41:36,120 --> 01:41:37,600 THE BUCK IN THIS SORT OF FIELD 2852 01:41:37,600 --> 01:41:41,880 IS GOING TO BE CAN WE UTILIZE 2853 01:41:41,880 --> 01:41:44,520 THIS DATA TO AVOID TREATING 2854 01:41:44,520 --> 01:41:45,360 PEOPLE -- REMEMBER I SHOWED YOU 2855 01:41:45,360 --> 01:41:47,120 THAT CIRCLE UNDER THE CURVE 2856 01:41:47,120 --> 01:41:47,760 WHERE A LOT OF THE PEOPLE ARE 2857 01:41:47,760 --> 01:41:49,720 NOT GOING TO RECUR. 2858 01:41:49,720 --> 01:41:51,560 YOU CERTAINLY WOULDN'T WANT 2859 01:41:51,560 --> 01:41:52,200 CHEMOTHERAPY IF YOU DIDN'T NEED 2860 01:41:52,200 --> 01:41:52,400 IT. 2861 01:41:52,400 --> 01:41:53,880 I THINK WE CAN USE IT IN THAT 2862 01:41:53,880 --> 01:41:55,200 WAY, AND THAT'S ULTIMATELY HOW I 2863 01:41:55,200 --> 01:41:58,040 SEE THIS PLAYING OUT, WHERE WE 2864 01:41:58,040 --> 01:41:59,960 WILL USE THAT TO SORT OF AVOID 2865 01:41:59,960 --> 01:42:00,880 TREATING PEOPLE WHO DON'T NEED 2866 01:42:00,880 --> 01:42:01,720 IT. 2867 01:42:01,720 --> 01:42:03,960 SUBJECTING THEM TO ALL OF THE 2868 01:42:03,960 --> 01:42:06,120 RISKS BUT THEY HAVE NO REAL WAY 2869 01:42:06,120 --> 01:42:07,800 OF BENEFITING FROM IT BECAUSE 2870 01:42:07,800 --> 01:42:08,680 THEY DON'T NEED IT. 2871 01:42:08,680 --> 01:42:12,720 >> SO I THINK THAT IF YOU WANT 2872 01:42:12,720 --> 01:42:13,960 TO GO BACK TO SOME OF THE 2873 01:42:13,960 --> 01:42:15,720 EARLIER WORK LIKE FIDDLER WHO 2874 01:42:15,720 --> 01:42:17,040 WAS AT THE NCI WHO STUDIED THAT 2875 01:42:17,040 --> 01:42:18,600 FOR EVERY GRAM OF TUMOR, THERE'S 2876 01:42:18,600 --> 01:42:21,200 A MILLION CELLS THAT IS 2877 01:42:21,200 --> 01:42:23,720 DISSEMINATED AND ABOUT 0.01% OF 2878 01:42:23,720 --> 01:42:24,920 THESE CELLS CAN FORM TUMORS. 2879 01:42:24,920 --> 01:42:26,400 SO IT'S AN INEFFICIENT PROCESS. 2880 01:42:26,400 --> 01:42:30,200 SO INSTEAD, I THINK -- THE 2881 01:42:30,200 --> 01:42:32,920 DIRECTION THE FIELD IS GOING, MY 2882 01:42:32,920 --> 01:42:33,840 COLLEAGUE, SEE MORE AGARWAL, 2883 01:42:33,840 --> 01:42:35,480 WHAT SHE'S DOING, YOU DO HAVE 2884 01:42:35,480 --> 01:42:37,560 ACCESS TO BLOOD SAMPLES AND YOU 2885 01:42:37,560 --> 01:42:40,080 CAN SERIALLY OR LONGITUDINALLY 2886 01:42:40,080 --> 01:42:42,640 SAMPLE BLOOD, IT'S EASY TO GET 2887 01:42:42,640 --> 01:42:44,720 BLOOD FROM PATIENTS, AS OPPOSED 2888 01:42:44,720 --> 01:42:46,040 TO HAVING TO GO DO TUMOR 2889 01:42:46,040 --> 01:42:46,520 BIOPSIES. 2890 01:42:46,520 --> 01:42:48,160 THE QUESTION THEN IS HOW DO YOU 2891 01:42:48,160 --> 01:42:50,120 EXPAND AND KEEP THESE 2892 01:42:50,120 --> 01:42:51,120 CIRCULATING TUMOR CELLS IN 2893 01:42:51,120 --> 01:42:52,880 CULTURE LONG ENOUGH AND COULD 2894 01:42:52,880 --> 01:42:57,160 YOU THEN USE THESE TO SORT OF DO 2895 01:42:57,160 --> 01:43:00,000 DRUG SCREENS AND SHE HAS 2896 01:43:00,000 --> 01:43:02,360 SUCCESSFULLY DONE THESE 2897 01:43:02,360 --> 01:43:03,600 XENOGRAPH MODELS FROM THESE 2898 01:43:03,600 --> 01:43:04,320 CIRCULATING TUMOR CELLS AND THEN 2899 01:43:04,320 --> 01:43:06,200 CAN BE USED TO BE ABLE TO SEE 2900 01:43:06,200 --> 01:43:11,960 WHICH OF THESE DRUGS ARE 2901 01:43:11,960 --> 01:43:12,920 EFFECTIVE, GOING BACK TO USING 2902 01:43:12,920 --> 01:43:14,520 THAT AS SCREENING PROCESS. 2903 01:43:14,520 --> 01:43:16,160 SO FROM THE BASIC CLINICAL SIDE, 2904 01:43:16,160 --> 01:43:17,760 THIS IS WHERE PEOPLE ARE GOING, 2905 01:43:17,760 --> 01:43:20,000 AND THE FACT THAT YOU COULD GET 2906 01:43:20,000 --> 01:43:22,240 THESE CELLS EXPANDED AND SURVIVE 2907 01:43:22,240 --> 01:43:24,560 AND IN CULTURE WITHOUT CHANGING 2908 01:43:24,560 --> 01:43:26,000 ANY PHENOTYPES FROM THE ORIGINAL 2909 01:43:26,000 --> 01:43:28,440 STRUCTURES, I THINK IS 2910 01:43:28,440 --> 01:43:34,360 PROMISING. 2911 01:43:34,360 --> 01:43:36,600 >> WE ALSO HAD SOME INQUIRY, OF 2912 01:43:36,600 --> 01:43:39,040 COURSE I HAD MENTIONED IT IN THE 2913 01:43:39,040 --> 01:43:41,520 BEGINNING, JONATHAN, ABOUT YOUR 2914 01:43:41,520 --> 01:43:44,320 WORK WITH EXTRACELLULAR 2915 01:43:44,320 --> 01:43:46,280 VESICLES. 2916 01:43:46,280 --> 01:43:47,680 THIS IS ANOTHER SORT OF 2917 01:43:47,680 --> 01:43:52,680 EXPANDING AREA OF GREAT INTEREST 2918 01:43:52,680 --> 01:43:53,560 FROM MANY DIFFERENT 2919 01:43:53,560 --> 01:43:54,360 PERSPECTIVES, BUT FROM THE 2920 01:43:54,360 --> 01:43:58,200 STANDPOINT OF CAN SE YOU WANT TU 2921 01:43:58,200 --> 01:44:03,040 WANT TO TELL US, ARE THE 2922 01:44:03,040 --> 01:44:04,720 EXTRACELLULAR VESICLES CREATED 2923 01:44:04,720 --> 01:44:06,360 BY CANCER CELLS, DO THEY HAVE 2924 01:44:06,360 --> 01:44:11,360 DIAGNOSTIC OR PROGNOSTIC VALUE? 2925 01:44:11,360 --> 01:44:14,680 WHAT'S THE STATE OF THAT FIELD? 2926 01:44:14,680 --> 01:44:18,280 >> YOU KNOW, BEFORE I CAME TO 2927 01:44:18,280 --> 01:44:21,360 THE NCI, I WORKED WITH DAVID 2928 01:44:21,360 --> 01:44:23,240 LYDON IN NEW YORK EXTENSIVELY, 2929 01:44:23,240 --> 01:44:24,800 AND DAVID AND HIS GROUP, WE 2930 01:44:24,800 --> 01:44:25,960 WORKED TOGETHER ON A LARGE 2931 01:44:25,960 --> 01:44:30,360 NUMBER OF PAPERS ABOUT HOW 2932 01:44:30,360 --> 01:44:32,560 PREMETASTATIC -- EDUCATION AND 2933 01:44:32,560 --> 01:44:34,760 HOW YOU CAN USE EXTRACELLULAR 2934 01:44:34,760 --> 01:44:36,640 VESICLES REFERRED TO AS EXOSOMES 2935 01:44:36,640 --> 01:44:40,600 TO SORT OF -- THESE WOULD 2936 01:44:40,600 --> 01:44:42,960 DICTATE WHERE THE SEED IN SOIL 2937 01:44:42,960 --> 01:44:45,040 TYPE THING WAS HAPPENING. 2938 01:44:45,040 --> 01:44:48,560 I THINK THE ISOLATION OF 2939 01:44:48,560 --> 01:44:50,080 EXOSOMES IS NOT -- IT TAKES SOME 2940 01:44:50,080 --> 01:44:51,760 TIME AND EFFORT AND I THINK IF 2941 01:44:51,760 --> 01:44:53,280 YOU'RE LOOKING AT IT FROM A 2942 01:44:53,280 --> 01:44:57,520 PREDICTION PERSPECTIVE ALONE, I 2943 01:44:57,520 --> 01:44:58,480 THINK THE CIRCULATING TUMOR DNA 2944 01:44:58,480 --> 01:44:59,800 FIELD, JUST BECAUSE OF THE EASE 2945 01:44:59,800 --> 01:45:02,120 OF A BLOOD DRAW AND NOT 2946 01:45:02,120 --> 01:45:04,240 REQUIRING HAVING TO ISOLATE 2947 01:45:04,240 --> 01:45:05,000 EXTRACELLULAR PARTICLES WILL 2948 01:45:05,000 --> 01:45:07,400 PROBABLY TAKE THE LEAD INSOFAR 2949 01:45:07,400 --> 01:45:10,360 AS PREDICTION AS FAR AS A 2950 01:45:10,360 --> 01:45:11,400 CLINICALLY RELEVANT TEST. 2951 01:45:11,400 --> 01:45:14,360 I DO THINK EXTRACELLULAR 2952 01:45:14,360 --> 01:45:16,240 VESICLES AND EXOSOMES ARE SUPER 2953 01:45:16,240 --> 01:45:17,040 INTERESTING, BECAUSE THEY HAVE 2954 01:45:17,040 --> 01:45:18,600 THE ABILITY AND DATA HAS SHOWN 2955 01:45:18,600 --> 01:45:20,320 THIS, WE'VE SHOWN IT ON MULTIPLE 2956 01:45:20,320 --> 01:45:22,600 LEVELS, TO ALTER THE PHENOTYPE 2957 01:45:22,600 --> 01:45:24,320 OF RECIPIENT CELLS, AND THAT'S 2958 01:45:24,320 --> 01:45:25,760 WHY INTRODUCTION OF PROTEINS 2959 01:45:25,760 --> 01:45:27,280 THROUGH THOSE EXOSOMES AND OTHER 2960 01:45:27,280 --> 01:45:27,520 THINGS. 2961 01:45:27,520 --> 01:45:30,640 SO I THINK THE FIELD ABOUT 2962 01:45:30,640 --> 01:45:31,800 UNDERSTANDING CANCER BIOLOGY IS 2963 01:45:31,800 --> 01:45:33,960 CERTAINLY GOING TO LIE WITH THE 2964 01:45:33,960 --> 01:45:35,280 EXTRACELLULAR VESICLES AND 2965 01:45:35,280 --> 01:45:36,160 PARTICLES, BUT IF YOU ASK ME, I 2966 01:45:36,160 --> 01:45:38,000 THINK THE PREDICTION ABOUT WHO'S 2967 01:45:38,000 --> 01:45:40,520 GOING TO RECUR ON A CLINICALLY 2968 01:45:40,520 --> 01:45:43,880 VALUABLE TEST AND YOU THINK 2969 01:45:43,880 --> 01:45:45,200 ABOUT A TEST HAS TO BE DONE IN 2970 01:45:45,200 --> 01:45:46,680 SO MANY PATIENTS, IT HAS TO BE 2971 01:45:46,680 --> 01:45:48,040 EASY, IT HAS TO BE DONE IN 2972 01:45:48,040 --> 01:45:48,560 MULTIPLE LABORATORIES. 2973 01:45:48,560 --> 01:45:50,440 I THINK THE CIRCULATING TUMOR 2974 01:45:50,440 --> 01:45:52,720 DNA FIELD IS GOING TO SORT OF 2975 01:45:52,720 --> 01:45:55,640 LIVE IN THAT SPACE. 2976 01:45:55,640 --> 01:45:57,680 BUT THE EXOSOMES ARE REALLY 2977 01:45:57,680 --> 01:45:59,000 INTERESTING AS FAR AS CANCER 2978 01:45:59,000 --> 01:46:02,120 BIOLOGY GOES, EDUCATING ON 2979 01:46:02,120 --> 01:46:04,880 PREMETASTATIC NICHE, THESE 2980 01:46:04,880 --> 01:46:07,920 AREAS, AND CHANGING BIOLOGY OF 2981 01:46:07,920 --> 01:46:09,120 NEIGHBORING CELLS, THESE THINGS 2982 01:46:09,120 --> 01:46:10,400 ARE POSSIBLE WITH EXOSOMES. 2983 01:46:10,400 --> 01:46:13,000 SO I LOOK AT THIS IN SORT OF 2984 01:46:13,000 --> 01:46:15,520 THAT WAY. 2985 01:46:15,520 --> 01:46:21,040 >> SO KANDICE, GRANTED YOU'RE YR 2986 01:46:21,040 --> 01:46:23,040 REALLY EXCITING, BRILLIANT WORK 2987 01:46:23,040 --> 01:46:28,400 WITH ZEBRAFISH AND BIOPHYSICAL 2988 01:46:28,400 --> 01:46:30,400 PLESHMENTS ASSOCIATED WITH THE 2989 01:46:30,400 --> 01:46:39,800 MOVEMENT OF TUMOR CELLS AN. 2990 01:46:39,800 --> 01:46:45,600 IF THE HYPOTHESIS THAT THE ANG 2991 01:46:45,600 --> 01:46:54,080 LAAANGULARITY AND ASSOCIATED 2992 01:46:54,080 --> 01:46:56,920 FACTORS IS IMPORTANT IN WHERE 2993 01:46:56,920 --> 01:47:01,480 TUMORS GO, IT'S ALL RATHER 2994 01:47:01,480 --> 01:47:03,560 MYSTERIOUS TO ME WHY METASTATIC 2995 01:47:03,560 --> 01:47:05,440 TUMORS VERY RARELY GO TO THE 2996 01:47:05,440 --> 01:47:07,520 KIDNEY, FOR EXAMPLE. 2997 01:47:07,520 --> 01:47:09,320 WHICH HAS AN ENORMOUS BLOOD 2998 01:47:09,320 --> 01:47:12,520 SUPPLY AND MANY CURVED AND 2999 01:47:12,520 --> 01:47:15,280 BRANCHED AND IT'S A WHOLE -- THE 3000 01:47:15,280 --> 01:47:19,640 WHOLE NETWORK, GRANTED, YOU 3001 01:47:19,640 --> 01:47:21,080 KNOW, YOU'RE WORKING WITH A 3002 01:47:21,080 --> 01:47:23,600 MODEL AND THE MODEL IS 3003 01:47:23,600 --> 01:47:27,000 EXCEPTIONAL FOR UNDERSTANDING 3004 01:47:27,000 --> 01:47:29,800 BASIC MECHANISMS, BUT IT IS A 3005 01:47:29,800 --> 01:47:30,800 CURIOUS PHENOMENA, AND I THINK 3006 01:47:30,800 --> 01:47:34,320 THAT'S CORRECT, AM I WRONG, 3007 01:47:34,320 --> 01:47:35,760 JONATHAN, THAT RARELY METASTASES 3008 01:47:35,760 --> 01:47:36,680 GO TO THE KIDNEY? 3009 01:47:36,680 --> 01:47:39,960 >> YOU KNOW, I THINK THE EXAMPLE 3010 01:47:39,960 --> 01:47:43,120 YOU CITED SUCH THAT THE TUMOR 3011 01:47:43,120 --> 01:47:45,120 CELLS ARE IN THE KIDNEY BUT WHEN 3012 01:47:45,120 --> 01:47:49,120 THE ORGAN GETS TRANSLATED TO 3013 01:47:49,120 --> 01:47:49,720 IMMUNOSUPPRESSED PATIENT THEN 3014 01:47:49,720 --> 01:47:50,640 YOU GET OUTGROWTH. 3015 01:47:50,640 --> 01:47:52,200 THAT WAS ONE OF THE EARLIEST 3016 01:47:52,200 --> 01:47:53,800 EXAMPLES OF THESE DISSEMINATED 3017 01:47:53,800 --> 01:47:55,440 CELLS BEING DORMANT FOR VERY 3018 01:47:55,440 --> 01:47:56,440 LONG PERIODS OF TIME. 3019 01:47:56,440 --> 01:47:57,520 IT'S A VERY CURIOUS THING, WHY 3020 01:47:57,520 --> 01:47:58,800 DOESN'T THE KIDNEY GET 3021 01:47:58,800 --> 01:47:59,080 METASTASES? 3022 01:47:59,080 --> 01:48:00,520 I TALK ABOUT THIS ALL THE TIME. 3023 01:48:00,520 --> 01:48:02,400 OH, THAT'S NOT A METASTASIS. 3024 01:48:02,400 --> 01:48:03,080 THAT'S JUST A CYST. 3025 01:48:03,080 --> 01:48:05,640 WE NEVER SEE KIDNEY METASTASES, 3026 01:48:05,640 --> 01:48:06,840 AT LEAST WITH THE CANCERS I SEE. 3027 01:48:06,840 --> 01:48:10,720 I DON'T THINK THAT MEANS THE 3028 01:48:10,720 --> 01:48:11,920 CELLS DON'T GET THERE, THE CELLS 3029 01:48:11,920 --> 01:48:12,880 DON'T PERSIST, PERHAPS. 3030 01:48:12,880 --> 01:48:14,720 I THINK IT MEANS THEY CAN'T 3031 01:48:14,720 --> 01:48:15,800 OUTGROW WHICH GETS TO THE WHOLE 3032 01:48:15,800 --> 01:48:16,920 POINT THAT THE COLONIZATION PART 3033 01:48:16,920 --> 01:48:17,960 OF THIS IS THE REALLY IMPORTANT 3034 01:48:17,960 --> 01:48:18,320 PART. 3035 01:48:18,320 --> 01:48:19,720 IF THEY GET THERE AND THEY NEVER 3036 01:48:19,720 --> 01:48:20,920 DO ANYTHING AND THEY JUST 3037 01:48:20,920 --> 01:48:22,440 PERSIST FOREVER, THE PATIENT HAS 3038 01:48:22,440 --> 01:48:24,240 NO PROBLEMS, THEY GO ON TO LIVE 3039 01:48:24,240 --> 01:48:25,240 THEIR NATURAL LIFE. 3040 01:48:25,240 --> 01:48:26,560 THE ISSUES BECOME WHEN THEY CAN 3041 01:48:26,560 --> 01:48:28,080 START TO GROW AND TAKE OVER AN 3042 01:48:28,080 --> 01:48:28,600 ORGAN. 3043 01:48:28,600 --> 01:48:29,680 I DON'T THINK THEY CAN DO THAT 3044 01:48:29,680 --> 01:48:30,760 IN THE KIDNEY. 3045 01:48:30,760 --> 01:48:31,600 BY AND LARGE. 3046 01:48:31,600 --> 01:48:33,280 WHY THAT IS, SUPER INTERESTING 3047 01:48:33,280 --> 01:48:34,480 QUESTION. 3048 01:48:34,480 --> 01:48:44,920 I DO NOT HAVE THE ANSWER. 3049 01:48:46,320 --> 01:48:50,320 >> SO APROPOS, KANDICE, OF YOUR 3050 01:48:50,320 --> 01:48:55,400 STUDIES INVOLVING BONE MARROW 3051 01:48:55,400 --> 01:48:58,760 CELLS GOING - TO THE BONE MARRO, 3052 01:48:58,760 --> 01:49:00,280 AMONGST THE BIOMARKERS THAT ARE 3053 01:49:00,280 --> 01:49:04,320 CURRENTLY WRITTEN ABOUT, SORT OF 3054 01:49:04,320 --> 01:49:06,400 LIQUID BIOPSIES LOOKING AT 3055 01:49:06,400 --> 01:49:11,040 CIRCULATING DNA AND TUMOR DNA, 3056 01:49:11,040 --> 01:49:15,680 AND THEN APPARENTLY AS AN EARLY 3057 01:49:15,680 --> 01:49:17,400 INDICATION, I GATHER FOLKS ARE 3058 01:49:17,400 --> 01:49:19,680 DOING BONE MARROW BIOPSIES OR 3059 01:49:19,680 --> 01:49:22,280 ASPIRATIONS IN PATIENTS WITH 3060 01:49:22,280 --> 01:49:24,480 BREAST CANCER, AS PART OF THE 3061 01:49:24,480 --> 01:49:28,440 INITIAL SCREENING LOOKING FOR 3062 01:49:28,440 --> 01:49:29,560 METASTASIS. 3063 01:49:29,560 --> 01:49:33,360 AND I WAS THINKING OF YOUR 3064 01:49:33,360 --> 01:49:35,800 PRESENTATION, DO YOU SEE ANY 3065 01:49:35,800 --> 01:49:38,360 RELATIONSHIP BETWEEN THAT, WHY 3066 01:49:38,360 --> 01:49:40,640 WOULD BREAST CANCER CELLS 3067 01:49:40,640 --> 01:49:41,880 PARTICULARLY GO TO THE BONE 3068 01:49:41,880 --> 01:49:44,840 MARROW? 3069 01:49:44,840 --> 01:49:47,880 >> WELL, I FEEL LIKE THE 3070 01:49:47,880 --> 01:49:49,360 CROSSTALK BETWEEN WHAT DIFFERENT 3071 01:49:49,360 --> 01:49:51,000 RECEPTORS ARE FOUND IN BREAST 3072 01:49:51,000 --> 01:49:53,760 CANCER CELLS AND THOSE FOUND 3073 01:49:53,760 --> 01:49:55,920 EITHER -- THE LIGANDS SECRETED 3074 01:49:55,920 --> 01:49:57,920 BY THE OSTEOCLASTS PRESENT IN 3075 01:49:57,920 --> 01:49:58,760 THE BONE MARROW NICHE, THERE'S 3076 01:49:58,760 --> 01:50:02,560 SOME EVIDENCE IN TERMS OF THESE 3077 01:50:02,560 --> 01:50:04,880 RECEPTOR COMPATIBILITY. 3078 01:50:04,880 --> 01:50:07,800 NOW, ONE OF THE PROVOCATIVE 3079 01:50:07,800 --> 01:50:09,200 IDEAS IS THAT THE BONE MARROW 3080 01:50:09,200 --> 01:50:13,800 NICHE IS ALSO SORT OF LIKE A 3081 01:50:13,800 --> 01:50:14,560 RESIDENT FOR IMMUNE CELLS AND 3082 01:50:14,560 --> 01:50:16,840 MAYBE IN THAT CASE, THEY COULD 3083 01:50:16,840 --> 01:50:18,800 ALSO RECRUIT THESE IMMUNE CELLS 3084 01:50:18,800 --> 01:50:22,280 TO SORT OF ACTIVATE THE CELLS' 3085 01:50:22,280 --> 01:50:25,280 ABILITY TO FORM LESIONS THERE. 3086 01:50:25,280 --> 01:50:27,080 NOW GOING BACK TO OUR SYSTEM, WE 3087 01:50:27,080 --> 01:50:28,800 HAVE TO BE VERY CLEAR ABOUT WHAT 3088 01:50:28,800 --> 01:50:31,080 WE'RE ABLE TO RECAPITULATE. 3089 01:50:31,080 --> 01:50:33,480 WE'RE LOOKING AT THE ENDOTHELIAL 3090 01:50:33,480 --> 01:50:35,760 INTERFACE, BUT THERE IS NO 3091 01:50:35,760 --> 01:50:36,960 SKELETAL BONE THAT'S PRESENT AT 3092 01:50:36,960 --> 01:50:38,680 THE TIME THAT WE'RE LOOKING AT. 3093 01:50:38,680 --> 01:50:40,880 INSTEAD, WE'RE LOOKING AT 3094 01:50:40,880 --> 01:50:42,840 COMPONENTS THAT ARE REMINISCENT 3095 01:50:42,840 --> 01:50:47,400 OF THE FACTORS THAT CONTRIBUTE 3096 01:50:47,400 --> 01:50:49,800 TO THE MYELOID LINEAGE 3097 01:50:49,800 --> 01:50:50,800 DERIVATIONS, SO THIS SYSTEM 3098 01:50:50,800 --> 01:50:52,440 ALLOWS YOU TO TEASE OUT THOSE 3099 01:50:52,440 --> 01:50:52,800 CONTRIBUTIONS. 3100 01:50:52,800 --> 01:50:55,520 BUT IF ONE WERE TO SAY THAT IS 3101 01:50:55,520 --> 01:50:57,480 REMINISCENT OF WHAT YOU WOULD 3102 01:50:57,480 --> 01:50:59,720 SEE IN A -- WHERE YOU HAVE THE 3103 01:50:59,720 --> 01:51:04,240 SKELETAL TISSUE AS WELL AS THESE 3104 01:51:04,240 --> 01:51:05,480 MYELOID DERIVED CELLS OR I WOULD 3105 01:51:05,480 --> 01:51:07,160 SAY EMBRYONIC LINEAGES, THEN 3106 01:51:07,160 --> 01:51:08,720 THAT IS NOT THE CASE. 3107 01:51:08,720 --> 01:51:10,160 SO TO ANSWER THE QUESTION THAT 3108 01:51:10,160 --> 01:51:14,200 YOU JUST PROPOSED, INSTEAD WE 3109 01:51:14,200 --> 01:51:15,840 WOULD HAVE TO LOOK AT THE ADULT 3110 01:51:15,840 --> 01:51:19,280 FISH IN THAT SKELETAL METASTASIS 3111 01:51:19,280 --> 01:51:20,640 MODEL WHERE WE HAVE ALL OF THE 3112 01:51:20,640 --> 01:51:22,240 POPULATIONS OF THE CELLS THAT 3113 01:51:22,240 --> 01:51:23,280 RECAPITULATE A BONE NICHE AND 3114 01:51:23,280 --> 01:51:26,360 ONLY THEN COULD I GIVE YOU AN 3115 01:51:26,360 --> 01:51:26,920 ANSWER. 3116 01:51:26,920 --> 01:51:28,240 >> SO HERE'S AN INTERESTING 3117 01:51:28,240 --> 01:51:30,320 QUESTION THAT CAME IN. 3118 01:51:30,320 --> 01:51:33,240 OUR METASTASES ALWAYS DERIVED 3119 01:51:33,240 --> 01:51:38,440 FROM THE PRIMARY TUMOR. 3120 01:51:38,440 --> 01:51:40,520 DOES METASTASIS GIVE RISE TO A 3121 01:51:40,520 --> 01:51:44,240 SECOND METASTASIS? 3122 01:51:44,240 --> 01:51:47,480 >> THIS IS A FUN QUESTION. 3123 01:51:47,480 --> 01:51:49,840 I LIKE THINKING ABOUT THIS 3124 01:51:49,840 --> 01:51:50,560 QUESTION, AND WE'VE TOSSED THIS 3125 01:51:50,560 --> 01:51:51,200 AROUND A LOT. 3126 01:51:51,200 --> 01:51:56,120 I THINK IT WOULD BE ALMOST 3127 01:51:56,120 --> 01:51:58,560 NONSENSICAL TO THINK THAT A CELL 3128 01:51:58,560 --> 01:52:00,440 THAT WAS ABLE TO ESCAPE TO A NEW 3129 01:52:00,440 --> 01:52:01,880 SITE COULD NOT THEN DO IT AGAIN. 3130 01:52:01,880 --> 01:52:03,600 DO WE HAVE GOOD EVIDENCE THAT 3131 01:52:03,600 --> 01:52:04,480 THIS HAPPENS? 3132 01:52:04,480 --> 01:52:07,640 NOT TO MY KNOWLEDGE. 3133 01:52:07,640 --> 01:52:08,840 IT'S CERTAINLY A QUESTION I 3134 01:52:08,840 --> 01:52:10,280 THINK ABOUT, AND THE OTHER 3135 01:52:10,280 --> 01:52:12,640 QUESTION I THINK ABOUT IS, COULD 3136 01:52:12,640 --> 01:52:14,600 A PRIMARY TUMOR SEND OFF NEW 3137 01:52:14,600 --> 01:52:17,160 METASTASES AND DO THEY END UP 3138 01:52:17,160 --> 01:52:19,920 GUGOING TO METASTATIC SITES SUCH 3139 01:52:19,920 --> 01:52:20,560 THAT THAT WOULD CONTRIBUTE TO 3140 01:52:20,560 --> 01:52:21,680 THE HETEROGENEITY AS WELL? 3141 01:52:21,680 --> 01:52:24,080 I USE THE ANALOGY, YOU WALK INTO 3142 01:52:24,080 --> 01:52:25,360 A BAR AND YOU DON'T KNOW ANYBODY 3143 01:52:25,360 --> 01:52:26,200 AND YOU SEE A TABLE OF YOUR 3144 01:52:26,200 --> 01:52:27,520 FRIENDS, YOU'RE PROBABLY GOING 3145 01:52:27,520 --> 01:52:29,920 TO GO SIT NEXT TO YOUR FRIENDS. 3146 01:52:29,920 --> 01:52:31,000 THERE'S THE SAME SORT OF THING 3147 01:52:31,000 --> 01:52:31,440 THAT CONTRIBUTES. 3148 01:52:31,440 --> 01:52:33,320 I THINK THERE'S A WHOLE DYNAMIC 3149 01:52:33,320 --> 01:52:35,800 HAPPENING BELOW THE LEVEL OF 3150 01:52:35,800 --> 01:52:38,720 VISIBILITY THAT'S SUPER 3151 01:52:38,720 --> 01:52:39,720 FASCINATING THAT I DON'T THINK I 3152 01:52:39,720 --> 01:52:42,680 HAVE ANY REAL UNDERSTANDING OF, 3153 01:52:42,680 --> 01:52:43,920 BUT IT IS A VERY BIG QUESTION. 3154 01:52:43,920 --> 01:52:45,560 I WOULD SAY IT WOULD BE 3155 01:52:45,560 --> 01:52:47,080 NONSENSICAL TO THINK THAT A 3156 01:52:47,080 --> 01:52:49,840 METASTASES COULD NOT IN TURN 3157 01:52:49,840 --> 01:52:52,080 METASTASIZE, BUT DO I HAVE PROOF 3158 01:52:52,080 --> 01:52:53,080 THAT THAT HAPPENS? 3159 01:52:53,080 --> 01:52:53,560 I DO NOT. 3160 01:52:53,560 --> 01:52:55,720 >> GOING BACK TO THE 3161 01:52:55,720 --> 01:52:57,680 PRE-CLINICAL MODELS, THERE ARE 3162 01:52:57,680 --> 01:52:59,720 SOME -- THERE IS SOME DATA THAT 3163 01:52:59,720 --> 01:53:00,920 SUGGESTS IN A MOUSE MODEL THAT 3164 01:53:00,920 --> 01:53:02,640 THERE ARE SOME SITES OF 3165 01:53:02,640 --> 01:53:03,280 METASTASES THAT SEED OTHER 3166 01:53:03,280 --> 01:53:03,720 SITES. 3167 01:53:03,720 --> 01:53:06,760 AND THIS IS ONLY IN VERY 3168 01:53:06,760 --> 01:53:07,880 AGGRESSIVE ADVANCED STAGES OF 3169 01:53:07,880 --> 01:53:09,480 CANCERS, AND PEOPLE HAVE DERIVED 3170 01:53:09,480 --> 01:53:11,920 THIS BY LOOKING AT LINEAGES 3171 01:53:11,920 --> 01:53:13,760 BEING ABLE TO SEE WHERE THESE 3172 01:53:13,760 --> 01:53:15,160 CELLS ORIGINATED FROM AND IF 3173 01:53:15,160 --> 01:53:17,240 THEY CAME FROM YOUR PRIMARY 3174 01:53:17,240 --> 01:53:19,120 TUMOR OR IF THEY CAME FROM 3175 01:53:19,120 --> 01:53:20,360 ANOTHER METASTATIC LESION. 3176 01:53:20,360 --> 01:53:21,560 AGAIN THESE ARE MOUSE MODEL, AND 3177 01:53:21,560 --> 01:53:23,280 I DON'T KNOW IF ANYONE HAS DONE 3178 01:53:23,280 --> 01:53:25,720 THIS IN HUMAN STUDIES, BUT I 3179 01:53:25,720 --> 01:53:27,240 ARGUE IF IT HAPPENS IN A MOUSE, 3180 01:53:27,240 --> 01:53:29,520 IT COULD HAPPEN IN A HUMAN. 3181 01:53:29,520 --> 01:53:31,280 BUT AGAIN, YOU'RE TALKING TO A 3182 01:53:31,280 --> 01:53:34,240 VERY NAIVE BASIC SCIENTIST HERE. 3183 01:53:34,240 --> 01:53:36,080 >> WE'RE ALL NAIVE. 3184 01:53:36,080 --> 01:53:38,040 >> I WOULD AGREE WHOLEHEARTEDLY 3185 01:53:38,040 --> 01:53:39,080 WITH THAT. 3186 01:53:39,080 --> 01:53:40,880 >> WE'VE GOT TIME FOR A FEW MORE 3187 01:53:40,880 --> 01:53:41,360 HERE. 3188 01:53:41,360 --> 01:53:46,080 HERE'S ANOTHER ONE. 3189 01:53:46,080 --> 01:53:48,040 IN A SERIES OF ARTICLES OVER THE 3190 01:53:48,040 --> 01:53:52,320 PAST I DON'T KNOW COUPLE YEARS 3191 01:53:52,320 --> 01:53:55,880 ABOUT INTRACANCER BACTERIA, AND 3192 01:53:55,880 --> 01:53:58,600 THOSE WHO HAVE WRITTEN THESE 3193 01:53:58,600 --> 01:54:00,560 ARTICLES ASCRIBE SOME MEANING TO 3194 01:54:00,560 --> 01:54:01,800 IT, THEY DON'T KNOW EXACTLY WHAT 3195 01:54:01,800 --> 01:54:04,880 ALL THE MEANING IS, BUT EVEN ONE 3196 01:54:04,880 --> 01:54:07,280 HAS SUGGESTED AS A ROLE IN 3197 01:54:07,280 --> 01:54:07,720 METASTASIS. 3198 01:54:07,720 --> 01:54:10,200 DO YOU HAVE ANY EXPERIENCE OR 3199 01:54:10,200 --> 01:54:14,960 WHAT'S YOUR OPINION ABOUT THAT? 3200 01:54:14,960 --> 01:54:16,720 THE ROLE OF INTRACELLULAR 3201 01:54:16,720 --> 01:54:19,480 BACTERIA IN CANCER. 3202 01:54:19,480 --> 01:54:20,960 >> I WOULD SAY WE DO HAVE 3203 01:54:20,960 --> 01:54:22,280 EXPERIENCE IN THIS. 3204 01:54:22,280 --> 01:54:25,120 THIS SORT OF CAME ABOUT IN A WAY 3205 01:54:25,120 --> 01:54:26,640 WHERE WE WERE KEEPING THESE 3206 01:54:26,640 --> 01:54:28,000 TISSUES VIABLE OUTSIDE OF 3207 01:54:28,000 --> 01:54:29,200 PATIENTS AND THIS CAN BE DONE IN 3208 01:54:29,200 --> 01:54:30,760 A COUPLE OF WAYS. 3209 01:54:30,760 --> 01:54:32,960 I'VE SHOWED YOU ONE, BUT ONE 3210 01:54:32,960 --> 01:54:35,560 CONCERN WE HAD WAS ABOUT 3211 01:54:35,560 --> 01:54:37,600 CONTAMINATION, WOULD WE GET 3212 01:54:37,600 --> 01:54:38,720 INFECTION, SO -- AND THIS CAME 3213 01:54:38,720 --> 01:54:40,600 ABOUT BECAUSE WE DID A BUNCH OF 3214 01:54:40,600 --> 01:54:42,280 SEQUENCING ON SOME OF THESE 3215 01:54:42,280 --> 01:54:44,360 TUMORS, AND THEN THERE WOULD BE 3216 01:54:44,360 --> 01:54:45,960 BACTERIAL SEQUENCE OF PART OF 3217 01:54:45,960 --> 01:54:48,920 THE TUMOR SEQUENCING. 3218 01:54:48,920 --> 01:54:50,560 WE LOOKED AT IT -- YOU KNOW, I 3219 01:54:50,560 --> 01:54:52,240 GOT VERY CONCERNED THAT WE 3220 01:54:52,240 --> 01:54:53,520 POTENTIALLY HAD INFECTION WHICH 3221 01:54:53,520 --> 01:54:56,000 COULD BE SKEWING RESULTS IN 3222 01:54:56,000 --> 01:54:58,200 THESE SORT OF THINGS AND THEN 3223 01:54:58,200 --> 01:55:00,480 YOU SORT OF REALIZE THERE ARE 3224 01:55:00,480 --> 01:55:01,560 BACTERIA PRESENT INSIDE TUMOR 3225 01:55:01,560 --> 01:55:02,400 CELLS. 3226 01:55:02,400 --> 01:55:04,360 THERE ARE IDENTIFIABLE AND THERE 3227 01:55:04,360 --> 01:55:08,080 ARE BACTERIA THAT -- THERE'S 3228 01:55:08,080 --> 01:55:10,400 SORT OF THIS RELATIONSHIP THAT 3229 01:55:10,400 --> 01:55:10,920 EXISTS. 3230 01:55:10,920 --> 01:55:12,600 THE MORE INTERESTING QUESTION, I 3231 01:55:12,600 --> 01:55:14,040 THINK, IS WHAT'S THE NATURE OF 3232 01:55:14,040 --> 01:55:17,800 THE RELATIONSHIP AND WHAT IF YOU 3233 01:55:17,800 --> 01:55:18,520 PERTURBED IT, WHAT WOULD IT 3234 01:55:18,520 --> 01:55:18,800 MEAN? 3235 01:55:18,800 --> 01:55:20,240 I DON'T KNOW THE ANSWER TO THAT. 3236 01:55:20,240 --> 01:55:21,600 IT'S SUPER INTERESTING TO THINK 3237 01:55:21,600 --> 01:55:25,560 ABOUT, PARTICULARLY THE INTRA -- 3238 01:55:25,560 --> 01:55:27,240 BACTERIA INSIDE THESE TUMOR 3239 01:55:27,240 --> 01:55:28,880 CELLS. 3240 01:55:28,880 --> 01:55:31,160 MITOCHONDRIA CAME FROM A FOREIGN 3241 01:55:31,160 --> 01:55:34,080 BACTERIA MANY EE YONS AGO, BUT 3242 01:55:34,080 --> 01:55:36,720 IS THIS A RELATIONSHIP WE COULD 3243 01:55:36,720 --> 01:55:38,360 BE LEVERAGING FOR THERAPEUTIC 3244 01:55:38,360 --> 01:55:39,000 GAIN? 3245 01:55:39,000 --> 01:55:40,600 IT'S FASCINATING, I DON'T HAVE 3246 01:55:40,600 --> 01:55:42,400 AN ANSWER. 3247 01:55:42,400 --> 01:55:44,200 >> WELL, WE HAVE A WHOLE BUNCH 3248 01:55:44,200 --> 01:55:46,560 OF OTHER QUESTIONS, BUT I THINK 3249 01:55:46,560 --> 01:55:52,080 WHAT THEY ALL INDICATE IS THAT 3250 01:55:52,080 --> 01:55:59,280 THIS IS AN EXTREMELY CHALLENGING 3251 01:55:59,280 --> 01:56:03,160 COMPLEX AREA OF SCIENCE FROM ALL 3252 01:56:03,160 --> 01:56:07,480 DIFFERENT DISCIPLINES. 3253 01:56:07,480 --> 01:56:09,960 AND PERHAPS OUT OF BRIDGING MANY 3254 01:56:09,960 --> 01:56:13,200 OF THESE DISCIPLINES, NEW IDEAS 3255 01:56:13,200 --> 01:56:18,000 AND CONCEPTS WILL EMERGE. 3256 01:56:18,000 --> 01:56:22,960 BECAUSE METASTASIS IS WHAT KILLS 3257 01:56:22,960 --> 01:56:25,760 PEOPLE, AND WE HAVE A WAYS TO 3258 01:56:25,760 --> 01:56:26,000 GO. 3259 01:56:26,000 --> 01:56:28,760 SO THE LAST QUESTION IS ONE I'D 3260 01:56:28,760 --> 01:56:32,200 LIKE TO ASK BOTH OF YOU, IF YOU 3261 01:56:32,200 --> 01:56:36,040 WOULD BRIEFLY DARE TO GIVE A FEW 3262 01:56:36,040 --> 01:56:37,560 PREDICTIONS. 3263 01:56:37,560 --> 01:56:40,320 WHAT DO YOU THINK IS THE AREA OR 3264 01:56:40,320 --> 01:56:45,600 THE AREAS OF ONGOING AND FUTURE 3265 01:56:45,600 --> 01:56:48,600 RESEARCH THAT SEEM TO YOU TO BE 3266 01:56:48,600 --> 01:56:52,040 MOST EXCITING AND POTENTIAL IN 3267 01:56:52,040 --> 01:56:54,680 TERMS OF ACHIEVING THEIR 3268 01:56:54,680 --> 01:56:55,440 OBJECTIVE? 3269 01:56:55,440 --> 01:56:57,000 JONATHAN, YOU WANT TO GO FIRST? 3270 01:56:57,000 --> 01:56:59,920 >> SURE. 3271 01:56:59,920 --> 01:57:02,960 SO I WOULD SAY THE OPPORTUNITY 3272 01:57:02,960 --> 01:57:06,320 TO KEEP DISSEMINATED TUMOR CELLS 3273 01:57:06,320 --> 01:57:07,640 QUIESCENT OR DORMANT WOULD 3274 01:57:07,640 --> 01:57:09,480 CREATE WHAT WOULD OTHERWISE BE 3275 01:57:09,480 --> 01:57:10,240 CONSIDERED A CHRONIC CONDITION 3276 01:57:10,240 --> 01:57:12,520 FOR CANCER. 3277 01:57:12,520 --> 01:57:14,080 YOU NE, I USE THE ANALOGY ALL 3278 01:57:14,080 --> 01:57:17,960 THE TIME, I CANNOT STOP TAKING A 3279 01:57:17,960 --> 01:57:19,640 PROTON PUMP INHIBITOR BECAUSE I 3280 01:57:19,640 --> 01:57:20,760 HAVE ACID REFLUX. 3281 01:57:20,760 --> 01:57:22,000 I'M FINE AS LONG AS I TAKE THE 3282 01:57:22,000 --> 01:57:23,640 REFLUX MEDICINE BUT IF MY REFLUX 3283 01:57:23,640 --> 01:57:25,920 DOESN'T GO AWAY, IT'S JUST 3284 01:57:25,920 --> 01:57:27,000 CONTROLLED BY THE ACID 3285 01:57:27,000 --> 01:57:27,400 MEDICATION. 3286 01:57:27,400 --> 01:57:28,320 THE SAME THING WE SAID OF BLOOD 3287 01:57:28,320 --> 01:57:28,760 PRESSURE. 3288 01:57:28,760 --> 01:57:30,440 PEOPLE WHO TAKE BLOOD PRESSURE 3289 01:57:30,440 --> 01:57:31,480 MEDICINE, THEIR BLOOD PRESSURE 3290 01:57:31,480 --> 01:57:32,360 IS STILL HIGH. 3291 01:57:32,360 --> 01:57:33,160 THEY JUST TAKE A MEDICINE TO 3292 01:57:33,160 --> 01:57:34,680 TREAT IT. 3293 01:57:34,680 --> 01:57:37,080 IF YOU CAN TURN CANCER INTO THIS 3294 01:57:37,080 --> 01:57:39,480 SAME THING BY KEEPING THOSE 3295 01:57:39,480 --> 01:57:41,200 QUIESCENT, THOSE DORMANT CELLS 3296 01:57:41,200 --> 01:57:42,360 QUIET, AND SOMEONE LIKE ME COULD 3297 01:57:42,360 --> 01:57:44,120 COME ALONG AND CHOP OUT ALL YOUR 3298 01:57:44,120 --> 01:57:45,640 TUMOR AND THEN YOU WOULD SIMPLY 3299 01:57:45,640 --> 01:57:46,840 HAVE THIS MAINTENANCE SORT OF 3300 01:57:46,840 --> 01:57:48,040 THING WHERE YOU KEPT EVERYTHING 3301 01:57:48,040 --> 01:57:49,760 AT BAY AND YOU COULD GO ON WITH 3302 01:57:49,760 --> 01:57:52,600 YOUR NORMAL LIFE, THAT, I THINK 3303 01:57:52,600 --> 01:57:54,040 IS HOW THIS IS GOING TO PLAY 3304 01:57:54,040 --> 01:57:54,400 OUT. 3305 01:57:54,400 --> 01:57:56,200 I THINK THAT'S THE BEST CASE 3306 01:57:56,200 --> 01:57:59,000 SCENARIO HOW THIS PLAYS OUT. 3307 01:57:59,000 --> 01:58:00,000 I AGREE WITH EVERYTHING YOU SAID 3308 01:58:00,000 --> 01:58:02,000 ABOUT THIS BEING INCREDIBLY 3309 01:58:02,000 --> 01:58:03,520 COMPLEX, LOTS OF FIELDS HAVE TO 3310 01:58:03,520 --> 01:58:06,280 BE INVOLVED, BUT I THINK THE 3311 01:58:06,280 --> 01:58:08,560 QUINTESSENTIAL THING IS, CAN WE 3312 01:58:08,560 --> 01:58:11,280 KEEP THOSE DORMANT OR QUIESCENT 3313 01:58:11,280 --> 01:58:12,880 OR MICRO METASTATIC CELLS FROM 3314 01:58:12,880 --> 01:58:13,200 OUTGROWING. 3315 01:58:13,200 --> 01:58:14,440 IF THAT'S TRUE, I THINK YOU CAN 3316 01:58:14,440 --> 01:58:17,480 CHANGE THE FIELD. 3317 01:58:17,480 --> 01:58:21,160 >> KANDICE? 3318 01:58:21,160 --> 01:58:22,480 >> SO I'LL SAY THERE ARE THREE 3319 01:58:22,480 --> 01:58:24,040 FACTORS I THINK ARE GOING TO BE 3320 01:58:24,040 --> 01:58:24,760 REVOLUTIONARY. 3321 01:58:24,760 --> 01:58:26,320 ONE IS THAT FOCUSING ON THE IDEA 3322 01:58:26,320 --> 01:58:29,080 THAT THE INCLUSION OF PATIENTS 3323 01:58:29,080 --> 01:58:30,600 WITH METASTATIC DISEASE IN 3324 01:58:30,600 --> 01:58:32,520 CLINICAL TRIALS IS GOING TO BE 3325 01:58:32,520 --> 01:58:33,960 GAME CHANGING. 3326 01:58:33,960 --> 01:58:36,120 IN TERMS OF BEING ABLE TO 3327 01:58:36,120 --> 01:58:37,600 UNDERSTAND HOW DRUGS WORK IN A 3328 01:58:37,600 --> 01:58:38,720 MORE ADVANCED DISEASE SETTING 3329 01:58:38,720 --> 01:58:39,960 VERSUS THOSE THAT MAY PRESENT 3330 01:58:39,960 --> 01:58:43,000 WITH EARLIER STAGES OF CANCER. 3331 01:58:43,000 --> 01:58:45,160 AND I THINK THAT REVOLUTION 3332 01:58:45,160 --> 01:58:46,280 WOULD THEN REALLY DELINEATE WHAT 3333 01:58:46,280 --> 01:58:49,680 DRUGS REALLY WORK AT EARLIER 3334 01:58:49,680 --> 01:58:51,000 STAGES THAN WE CURRENTLY KNOW. 3335 01:58:51,000 --> 01:58:52,160 THE SECOND IS THE BRIDGING OF 3336 01:58:52,160 --> 01:58:55,040 THESE PRE-CLINICAL MODELS WHICH 3337 01:58:55,040 --> 01:58:58,000 BEING MORE REALISTIC IN TERMS 3338 01:58:58,000 --> 01:58:59,880 OF -- I WOULD SAY EMBRACING THE 3339 01:58:59,880 --> 01:59:00,680 COMPLEXITY INSTEAD OF TRYING TO 3340 01:59:00,680 --> 01:59:02,960 HAVE THESE MORE SIMPLIFIED 3341 01:59:02,960 --> 01:59:04,360 SYSTEMS BECAUSE THEY SIMPLY ARE 3342 01:59:04,360 --> 01:59:06,840 NOT BEING PREDICTIVE IN TERMS OF 3343 01:59:06,840 --> 01:59:09,840 HOW DRUGS ARE TESTED IN THE 3344 01:59:09,840 --> 01:59:11,120 PRE-CLINICAL SETTING AND WHY 3345 01:59:11,120 --> 01:59:12,320 THEY FAIL IN THE CLINICAL 3346 01:59:12,320 --> 01:59:13,000 SETTING. 3347 01:59:13,000 --> 01:59:14,200 AND LARGE LEGAL THIS EMERGENCE 3348 01:59:14,200 --> 01:59:18,080 OF TECHNOLOGIES THAT IF WE COULD 3349 01:59:18,080 --> 01:59:19,640 GO WITH IMAGE BASED APPROACHES 3350 01:59:19,640 --> 01:59:22,720 BECAUSE ULTIMATELY, WHAT A 3351 01:59:22,720 --> 01:59:24,120 SURGEON OR ONCOLOGIST HAS 3352 01:59:24,120 --> 01:59:25,200 INFORMATION ABOUT IS WHAT THEY 3353 01:59:25,200 --> 01:59:27,400 CAN SEE, WITH THE CURRENT 3354 01:59:27,400 --> 01:59:29,560 IMAGING MODALITIES, AND THEN 3355 01:59:29,560 --> 01:59:30,560 TRYING TO UNDERSTAND WHAT OF 3356 01:59:30,560 --> 01:59:33,600 THESE ASPECTS IS PREDICTABLE OF 3357 01:59:33,600 --> 01:59:35,480 HOW THIS DISEASE MAY EMERGE, AND 3358 01:59:35,480 --> 01:59:38,360 I THINK ARTIFICIAL INTELLIGENCE 3359 01:59:38,360 --> 01:59:40,200 IS INDEED GOING TO PLAY A ROLE 3360 01:59:40,200 --> 01:59:42,120 AT LEAST FROM THE EXISTING 3361 01:59:42,120 --> 01:59:42,560 METHODOLOGIES. 3362 01:59:42,560 --> 01:59:44,280 NOW FROM THE BASIC SCIENCE 3363 01:59:44,280 --> 01:59:46,760 PERSPECTIVE, AS MUCH AS WE CLOSE 3364 01:59:46,760 --> 01:59:49,760 THE GAP BETWEEN WHAT OUR MODEL 3365 01:59:49,760 --> 01:59:50,960 SYSTEMS ARE DOING VERSUS WHAT 3366 01:59:50,960 --> 01:59:53,280 WE'RE SEEING IN THE HUMAN 3367 01:59:53,280 --> 01:59:54,560 RELEVANT DISEASES, I THINK THAT 3368 01:59:54,560 --> 01:59:58,680 ALSO WOULD GO A LONG WAY, 3369 01:59:58,680 --> 02:00:00,000 ESPECIALLY WITH THESE AI-BASED 3370 02:00:00,000 --> 02:00:02,320 TECHNIQUES IN TERMS OF BEING 3371 02:00:02,320 --> 02:00:03,520 MUCH MORE PREDICTIVE WITH THE 3372 02:00:03,520 --> 02:00:07,880 INFORMATION AT HAND. 3373 02:00:07,880 --> 02:00:10,840 SO THOSE ARE MY BIASED FEELINGS. 3374 02:00:10,840 --> 02:00:15,200 >> YOU WOULDN'T HELP BUT BELIEVE 3375 02:00:15,200 --> 02:00:16,840 IN READING SOME OF THE 3376 02:00:16,840 --> 02:00:17,480 LITERATURE, PARTICULARLY THE 3377 02:00:17,480 --> 02:00:20,440 REVIEW THAT I MENTIONED, THAT 3378 02:00:20,440 --> 02:00:25,280 THIS IS REALLY A BRAVE NEW WORLD 3379 02:00:25,280 --> 02:00:26,960 AND MANY EXCITING THINGS ARE 3380 02:00:26,960 --> 02:00:28,600 GOING TO HAPPEN WHICH AT THE 3381 02:00:28,600 --> 02:00:32,520 MOMENT WE CAN'T FULLY PREDICT 3382 02:00:32,520 --> 02:00:35,600 BUT WE CAN HOPE FOR. 3383 02:00:35,600 --> 02:00:39,640 SO I WANT TO THANK YOU VERY MUCH 3384 02:00:39,640 --> 02:00:43,280 SHARING HER PERSONAL EXPERIENCE. 3385 02:00:43,280 --> 02:00:44,800 MOST OF THE PEOPLE WATCHING THIS 3386 02:00:44,800 --> 02:00:51,040 AROUND THE WORLD ARE NOT 3387 02:00:51,040 --> 02:00:51,880 PHYSICIANS. 3388 02:00:51,880 --> 02:00:54,280 THEY'RE YOUNG STUDENTS, GRADUATE 3389 02:00:54,280 --> 02:00:56,680 STUDENTS, PH.D.s AND SO FORTH. 3390 02:00:56,680 --> 02:01:01,720 AND SO THEY DON'T HAVE THAT 3391 02:01:01,720 --> 02:01:02,920 CONTACT WITH PATIENTS AND THE 3392 02:01:02,920 --> 02:01:08,080 HUMAN EXPERIENCE IS REALLY 3393 02:01:08,080 --> 02:01:09,600 DIRECTED TO. 3394 02:01:09,600 --> 02:01:10,760 SO HAVING SHARE YOUR EXPERIENCE 3395 02:01:10,760 --> 02:01:13,600 WITH US IS EXTREMELY VALUABLE, 3396 02:01:13,600 --> 02:01:16,800 AND WE APPRECIATE IT VERY MUCH. 3397 02:01:16,800 --> 02:01:18,000 SO LAST THING I MENTIONED IS 3398 02:01:18,000 --> 02:01:19,400 JUST TO MENTION THAT NEXT WEEK, 3399 02:01:19,400 --> 02:01:21,480 WE HAVE ANOTHER CHALLENGING 3400 02:01:21,480 --> 02:01:24,040 SESSION, AND THAT'S ON MESSENGER 3401 02:01:24,040 --> 02:01:25,640 RNA, WILL IT DELIVER US FROM 3402 02:01:25,640 --> 02:01:27,960 ILLNESS? 3403 02:01:27,960 --> 02:01:33,080 THE CME CREDIT 45392, THE 3404 02:01:33,080 --> 02:01:37,640 TELEPHONE NUMBER 443-541-5052. 3405 02:01:37,640 --> 02:01:40,040 SO THANK YOU ALL VERY MUCH, 3406 02:01:40,040 --> 02:01:41,720 AGAIN, AND WE'RE ALL GRATEFULLY 3407 02:01:41,720 --> 02:01:42,360 APPRECIATIVE. 3408 02:01:42,360 --> 00:00:00,000 THANK YOU.