1 00:00:05,080 --> 00:00:08,920 >>WELCOME TO A COMBINED 2 00:00:08,920 --> 00:00:11,120 WEDNESDAY AFTERNOON LECTURE 3 00:00:11,120 --> 00:00:15,000 SERIES AND DEMYSTIFYING MEDICINE 4 00:00:15,000 --> 00:00:20,160 LECTURE TODAY. 5 00:00:20,160 --> 00:00:22,480 THIS IS THE 12TH DEMYSTIFYING 6 00:00:22,480 --> 00:00:23,480 MEDICINE TOPIC OF THE YEAR, AND 7 00:00:23,480 --> 00:00:24,760 WE'RE IN OUR 21ST YEAR. 8 00:00:24,760 --> 00:00:29,360 SO THE GOAL OF BOTH OF THESE 9 00:00:29,360 --> 00:00:31,080 ACTIVITIES, THE WALS AND THE 10 00:00:31,080 --> 00:00:31,880 DEMYSTIFYING MEDICINE, IS TO 11 00:00:31,880 --> 00:00:34,440 BRIDGE AND EXCITE YOU WITH 12 00:00:34,440 --> 00:00:35,920 DEVELOPMENTS IN BIOLOGY, AND 13 00:00:35,920 --> 00:00:37,440 TODAY, THE TOPIC IS ENGINEERING, 14 00:00:37,440 --> 00:00:39,960 EXCITING BRIDGING THIS WITH 15 00:00:39,960 --> 00:00:40,320 MEDICINE. 16 00:00:40,320 --> 00:00:43,000 THIS IS THE LOGO, THE BROOKLYN 17 00:00:43,000 --> 00:00:43,560 BRIDGE. 18 00:00:43,560 --> 00:00:46,160 WE AS ALWAYS ARE LIKE THE 19 00:00:46,160 --> 00:00:48,720 INDIVIDUALS ON THE CATWALK, AND 20 00:00:48,720 --> 00:00:51,520 TODAY, WE'RE GOING TO HEAR FROM 21 00:00:51,520 --> 00:00:55,440 A LEADING BIOENGINEER, AND WE'RE 22 00:00:55,440 --> 00:00:59,520 INTERESTED IN ITS RELATIONSHIP 23 00:00:59,520 --> 00:01:01,360 OF HER WORK TO MEDICINE, AND 24 00:01:01,360 --> 00:01:02,240 THAT'S THE TOPIC. 25 00:01:02,240 --> 00:01:03,920 THIS IS A COURSE IN BRIDGE 26 00:01:03,920 --> 00:01:04,560 BUILDING. 27 00:01:04,560 --> 00:01:05,760 NEXT SLIDE. 28 00:01:05,760 --> 00:01:07,720 ANOTHER WAY OF EXPRESSING THE 29 00:01:07,720 --> 00:01:13,720 SAME IDEA WAS BY PROFESSOR 30 00:01:13,720 --> 00:01:16,720 KOLLATH, A EUROPEAN BIOCHEMIST 31 00:01:16,720 --> 00:01:19,560 IN THE EARLY 20TH CENTURY WHO 32 00:01:19,560 --> 00:01:20,160 SAID, TRANSLATED: MUCH IS 33 00:01:20,160 --> 00:01:21,240 KNOWN, BUT UNFORTUNATELY IN 34 00:01:21,240 --> 00:01:22,760 DIFFERENT HEADS. 35 00:01:22,760 --> 00:01:24,520 SO ONE OF THE PURPOSES OF 36 00:01:24,520 --> 00:01:28,160 DEMYSTIFYING MEDICINE IS TO 37 00:01:28,160 --> 00:01:30,120 EXCHANGE INFORMATION AND BRING 38 00:01:30,120 --> 00:01:31,120 TOGETHER KNOWLEDGE INTO AREAS 39 00:01:31,120 --> 00:01:37,440 THAT OTHERWISE WE WOULDN'T KNOW. 40 00:01:37,440 --> 00:01:39,840 TODAY WE ARE FORTUNATE TO HAVE 41 00:01:39,840 --> 00:01:45,720 WITH US SANGEETA BHATIA, WHO IS 42 00:01:45,720 --> 00:01:51,240 TREUL LIE AN IS 43 00:01:51,240 --> 00:01:55,920 A EXTRAORDINARY BRIDGE BUILDER. 44 00:01:55,920 --> 00:01:57,520 HER RESEARCH GOAL HAS BEEN TO 45 00:01:57,520 --> 00:01:59,000 ENGINEER MICRO AND 46 00:01:59,000 --> 00:02:00,120 NANOTECHNOLOGIES TO ADDRESS 47 00:02:00,120 --> 00:02:01,080 COMPLEX CHALLENGES IN HUMAN 48 00:02:01,080 --> 00:02:02,600 HEALTH INCLUDING CANCER, LIVER 49 00:02:02,600 --> 00:02:05,480 DISEASE, AND ACQUIRED 50 00:02:05,480 --> 00:02:06,120 INFECTIONS. 51 00:02:06,120 --> 00:02:07,800 THE NEXT SLIDE. 52 00:02:07,800 --> 00:02:09,880 SOMETHING ABOUT SANGEETA, SHE IS 53 00:02:09,880 --> 00:02:13,720 A PERSON OF EXTRAORDINARY 54 00:02:13,720 --> 00:02:14,080 ACCOMPLISHMENT. 55 00:02:14,080 --> 00:02:16,520 I THINK OF HER SOMETIMES AS A 56 00:02:16,520 --> 00:02:16,880 COLLECTOR. 57 00:02:16,880 --> 00:02:19,920 FOR EXAMPLE, SHE HAS 58 00:02:19,920 --> 00:02:20,760 COLLECTED DEGREES LISTED ON THE 59 00:02:20,760 --> 00:02:23,640 TOP OF THE SLIDE. 60 00:02:23,640 --> 00:02:26,080 AND HAS A PH.D. IN BIOMEDICAL 61 00:02:26,080 --> 00:02:27,120 ENGINEERING FROM THE HEALTH 62 00:02:27,120 --> 00:02:36,040 SCIENCE TECHNOLOGY PROGRAM. 63 00:02:36,040 --> 00:02:38,120 TENURED AT UCSD, THEN RETURNED 64 00:02:38,120 --> 00:02:40,400 TO MIT, WHERE SHE IS THE WILSON 65 00:02:40,400 --> 00:02:42,680 PROFESSOR OF HEALTH SCIENCE AND 66 00:02:42,680 --> 00:02:47,360 TECHNOLOGY, THE DIRECTOR OF THE 67 00:02:47,360 --> 00:02:48,920 MARBLE CENTER FOR CANCER STUDIES 68 00:02:48,920 --> 00:02:50,440 WITH NANOMEDICINE. 69 00:02:50,440 --> 00:02:51,520 SHE'S A HOWARD HUGHES 70 00:02:51,520 --> 00:02:52,640 INVESTIGATOR, AND A MEMBER OF 71 00:02:52,640 --> 00:02:54,400 THE BROAD AND THE WYSS 72 00:02:54,400 --> 00:02:56,600 INSTITUTES. 73 00:02:56,600 --> 00:02:58,120 SANGEETA HAS RECEIVED 74 00:02:58,120 --> 00:03:01,720 EXTRAORDINARY RECOGNITION. 75 00:03:01,720 --> 00:03:02,920 I'LL JUST MENTION A FEW. 76 00:03:02,920 --> 00:03:06,800 SHE RECEIVED THE LEMELSON-MIT 77 00:03:06,800 --> 00:03:08,360 AWARD REFERRED TO AS THE OSCAR 78 00:03:08,360 --> 00:03:13,080 FOR INVENTORS, AND THE HEINZ 79 00:03:13,080 --> 00:03:15,400 AWARD FOR INVENTIONS IN 80 00:03:15,400 --> 00:03:16,280 ADVOCACY. 81 00:03:16,280 --> 00:03:20,640 SANGEETA IS A POWERFUL ADVOCATE 82 00:03:20,640 --> 00:03:22,880 FOR WOMEN, FOR DIVERSITY AND FOR 83 00:03:22,880 --> 00:03:24,000 HIGH STANDARDS IN ALL OF OUR 84 00:03:24,000 --> 00:03:26,480 ACTIVITIES. 85 00:03:26,480 --> 00:03:27,320 EXTRAORDINARILY ENOUGH, SHE'S 86 00:03:27,320 --> 00:03:29,280 THE ONLY PERSON I KNOW WHO'S 87 00:03:29,280 --> 00:03:32,120 BEEN ELECTED TO ALL FIVE 88 00:03:32,120 --> 00:03:34,320 NATIONAL ACADEMIES: OF SCIENCE, 89 00:03:34,320 --> 00:03:37,040 ENGINEERING, MEDICINE, ARTS AND 90 00:03:37,040 --> 00:03:41,120 SCIENCE, AND INVENTORS. 91 00:03:41,120 --> 00:03:43,920 IN ADDITION, SHE HAS CRITICAL 92 00:03:43,920 --> 00:03:45,360 BOARD MEMBERSHIPS, ADVISORY 93 00:03:45,360 --> 00:03:46,520 COMMITTEES AND CONSULTING, AND 94 00:03:46,520 --> 00:03:48,880 WE ARE REALLY MOST PLEASED AND 95 00:03:48,880 --> 00:03:50,520 DELIGHTED TO HAVE YOU WITH US 96 00:03:50,520 --> 00:03:52,280 TODAY, SANGEETA, AND SHE WILL 97 00:03:52,280 --> 00:03:55,320 SPEAK TO US ABOUT TINY 98 00:03:55,320 --> 00:03:57,400 TECHNOLOGIES AND MEDICINE: FROM 99 00:03:57,400 --> 00:03:59,880 HEPATIC TISSUE ENGINEERING TO 100 00:03:59,880 --> 00:04:02,560 CANCER NANOTECHNOLOGY. 101 00:04:02,560 --> 00:04:04,360 SANGEETA? 102 00:04:04,360 --> 00:04:07,960 >> THANK YOU, WIN. 103 00:04:07,960 --> 00:04:09,360 I JUST WANTED TO THANK WIN 104 00:04:09,360 --> 00:04:12,200 AND THE ORGANIZERS FOR THIS 105 00:04:12,200 --> 00:04:13,720 DOUBLEHEADER TODAY, DOING BOTH 106 00:04:13,720 --> 00:04:16,120 WALS AND DEMYSTIFYING MEDICINE. 107 00:04:16,120 --> 00:04:18,000 IT'S A REAL TREAT TO SHARE MY 108 00:04:18,000 --> 00:04:20,640 PERSPECTIVES AND TO SEE YOU ALL 109 00:04:20,640 --> 00:04:21,320 VIRTUALLY, AND I'M LOOKING 110 00:04:21,320 --> 00:04:23,040 FORWARD TO THE DAY WHEN WE CAN 111 00:04:23,040 --> 00:04:25,440 ALL MEET IN PERSON. 112 00:04:25,440 --> 00:04:26,880 BUT TECHNOLOGY HAS SOME 113 00:04:26,880 --> 00:04:27,920 ADVANTAGES, WHICH IS THAT WE GET 114 00:04:27,920 --> 00:04:30,320 TO REACH A WIDER AUDIENCE. 115 00:04:30,320 --> 00:04:32,320 SO THE STORY I'LL BE TELLING YOU 116 00:04:32,320 --> 00:04:35,280 TODAY IS, AS WIN DESCRIBED, A 117 00:04:35,280 --> 00:04:38,000 STORY ABOUT USING ENGINEERING 118 00:04:38,000 --> 00:04:40,320 TOOLS TO TACKLE PROBLEMS IN 119 00:04:40,320 --> 00:04:43,160 BIOMEDICAL RESEARCH, AS WELL AS 120 00:04:43,160 --> 00:04:45,800 NEW POTENTIAL INVENTIONS TO 121 00:04:45,800 --> 00:04:47,200 ADDRESS UNMET MEDICAL NEEDS. 122 00:04:47,200 --> 00:04:48,520 AND I'LL BE TELLING YOU ABOUT 123 00:04:48,520 --> 00:04:50,440 OUR WORK IN LIVER TISSUE 124 00:04:50,440 --> 00:04:52,080 ENGINEERING AND CANCER 125 00:04:52,080 --> 00:04:55,840 NANOTECHNOLOGY. 126 00:04:55,840 --> 00:04:57,480 THESE ARE MY REQUIRED 127 00:04:57,480 --> 00:04:57,800 DISCLOSURES. 128 00:04:57,800 --> 00:05:00,280 I DO WANT TO HIGHLIGHT THAT I'LL 129 00:05:00,280 --> 00:05:05,320 BE SHOWING DATA FROM TWO 130 00:05:05,320 --> 00:05:09,480 STARTUPS: GLYMPSE AND SAT LIE 131 00:05:09,480 --> 00:05:11,040 BIOTHAT RELATE TO MY WORK AND I 132 00:05:11,040 --> 00:05:12,440 AM AN EQUITY HOLDER IN THOSE 133 00:05:12,440 --> 00:05:14,320 ESTABLISHMENTS. 134 00:05:14,320 --> 00:05:14,720 OKAY. 135 00:05:14,720 --> 00:05:18,200 SO MY KIND OF PLAY SAND BOX HAS 136 00:05:18,200 --> 00:05:19,560 BEEN THE WORLD OF TINY 137 00:05:19,560 --> 00:05:19,920 TECHNOLOGIES. 138 00:05:19,920 --> 00:05:22,400 AND JUST TO SORT OF GET US ALL 139 00:05:22,400 --> 00:05:23,920 ON THE SAME PAGE ABOUT WHAT THAT 140 00:05:23,920 --> 00:05:26,880 MEANS, WHAT I'M REFERRING TO ARE 141 00:05:26,880 --> 00:05:29,040 THE TECHNOLOGIES OF MICRO AND 142 00:05:29,040 --> 00:05:30,680 NANOTECHNOLOGY THAT REALLY GREW 143 00:05:30,680 --> 00:05:33,240 OUT OF THE SEMICONDUCTOR 144 00:05:33,240 --> 00:05:34,120 INDUSTRY. 145 00:05:34,120 --> 00:05:37,240 SO HERE YOU CAN SEE ONE MARBLE 146 00:05:37,240 --> 00:05:39,680 THAT THIS HAS GIVEN US, AND THAT 147 00:05:39,680 --> 00:05:40,960 IS THAT ONE TRANSISTOR USED TO 148 00:05:40,960 --> 00:05:42,920 BE THE SIZE THAT YOU SEE ON THE 149 00:05:42,920 --> 00:05:43,360 LEFT. 150 00:05:43,360 --> 00:05:46,000 AND WE CAN NOW FIT A BILLION OF 151 00:05:46,000 --> 00:05:47,880 THOSE ON THE SAME FOOTPRINT. 152 00:05:47,880 --> 00:05:50,920 AND THAT'S THROUGH AGGRESSIVE 153 00:05:50,920 --> 00:05:52,400 MINIATURIZATION OF SEMICONDUCTOR 154 00:05:52,400 --> 00:05:54,040 TECHNOLOGY. 155 00:05:54,040 --> 00:05:56,480 THAT HAS, OF COURSE, 156 00:05:56,480 --> 00:05:57,040 MINIATURIZED COMPUTATION AND 157 00:05:57,040 --> 00:05:59,920 CHANGE TO ALL OF OUR LIVES, 158 00:05:59,920 --> 00:06:00,160 REALLY. 159 00:06:00,160 --> 00:06:01,280 SO IF WE LOOK BACK AND THINK 160 00:06:01,280 --> 00:06:03,320 ABOUT HOW THAT HAPPENED, YOU 161 00:06:03,320 --> 00:06:05,120 KNOW, BEGINNING IN THE 1960s 162 00:06:05,120 --> 00:06:10,240 UP TO THE 2000s, THE CIRCUITS 163 00:06:10,240 --> 00:06:12,880 THAT ARE WRITTEN ON SILICON 164 00:06:12,880 --> 00:06:13,640 SEMICONDUCTOR CHIPS WITH LIGHT 165 00:06:13,640 --> 00:06:16,360 HAVE GOTTEN SMALLER AND SMALLER. 166 00:06:16,360 --> 00:06:20,640 AND STARTING IN THE YEAR 2000, 167 00:06:20,640 --> 00:06:22,400 WE STARTED TO BE ABLE TO MAKE 168 00:06:22,400 --> 00:06:23,600 FEATURES ON THESE CHIPS THAT 169 00:06:23,600 --> 00:06:26,000 WERE SMALLER THAN 100 170 00:06:26,000 --> 00:06:26,960 NANOMETERS. 171 00:06:26,960 --> 00:06:29,520 AND ACTUALLY IN 2020, IN THE 172 00:06:29,520 --> 00:06:32,240 LATEST SMARTPHONE, THEY'RE 173 00:06:32,240 --> 00:06:34,400 SMALLER THAN 5 NANOMETERS. 174 00:06:34,400 --> 00:06:36,400 SO WE CAN DRAW INCREDIBLY TINY 175 00:06:36,400 --> 00:06:39,560 FEATURES IN WHAT'S CALLED 176 00:06:39,560 --> 00:06:41,080 TOP-DOWN FABRICATION. 177 00:06:41,080 --> 00:06:43,160 START WITH A BIG THING AND YOU 178 00:06:43,160 --> 00:06:45,920 WRITE SMALL THINGS ON IT. 179 00:06:45,920 --> 00:06:47,720 NOW THIS ADVANCE HAS BEEN 180 00:06:47,720 --> 00:06:50,120 COUPLED BY ANOTHER ADVANCE ON 181 00:06:50,120 --> 00:06:52,360 THE RIGHT HERE, WHICH COMES FROM 182 00:06:52,360 --> 00:06:54,600 THE WORLD OF -- REALLY FROM 183 00:06:54,600 --> 00:06:56,760 CHEMISTRY AND MACROMOLECULAR 184 00:06:56,760 --> 00:06:57,120 CHEMISTRY. 185 00:06:57,120 --> 00:06:58,440 AND HERE, THERE'S A GROUP OF 186 00:06:58,440 --> 00:07:00,080 INVESTIGATORS THAT HAVE BEEN 187 00:07:00,080 --> 00:07:01,800 ASSEMBLING MOLECULES AND COAXING 188 00:07:01,800 --> 00:07:04,520 THEM INTO MAKING NANOMATERIALS. 189 00:07:04,520 --> 00:07:06,520 YOU SEE A VARIETY OF THEM ON THE 190 00:07:06,520 --> 00:07:08,120 SIDE HERE, INCLUDING, FOR 191 00:07:08,120 --> 00:07:10,440 EXAMPLE, LIPID NANOMATERIALS 192 00:07:10,440 --> 00:07:13,360 WHICH ARE, OF COURSE, HOW COVID 193 00:07:13,360 --> 00:07:15,200 MRNA VACCINES ARE DELIVERED, AS 194 00:07:15,200 --> 00:07:17,440 WELL AS SOME OTHER VERY FAMOUS 195 00:07:17,440 --> 00:07:20,280 ONES, FOR EXAMPLE, BUT KEY 196 00:07:20,280 --> 00:07:25,320 BALLS. BUCKY BALLS. 197 00:07:25,320 --> 00:07:27,160 SO WE HAVE TWO DIFFERENT SETS OF 198 00:07:27,160 --> 00:07:30,560 TECHNOLOGY THAT HAVE CONVERGED 199 00:07:30,560 --> 00:07:33,320 OND A SCALE, WE THINK OF HUMAN 200 00:07:33,320 --> 00:07:42,280 HARRAH'S ABOUT 100 MICRONS, AND. AS 201 00:07:42,280 --> 00:07:44,400 INVENTORS INTERESTED IN HUMAN 202 00:07:44,400 --> 00:07:47,920 HEALTH, IF YOU KIND OF SPLAY 203 00:07:47,920 --> 00:07:49,040 THESE TECHNIQUES ACROSS A RULER, 204 00:07:49,040 --> 00:07:50,840 THIS INDUSTRY HAS GIVEN US TOOLS 205 00:07:50,840 --> 00:07:53,800 THAT ARROW US TO MA MANIPULATE 206 00:07:53,800 --> 00:07:55,440 EVERYTHING FROM THE LINK SCALE 207 00:07:55,440 --> 00:07:56,840 OF A RECEPTOR UP TO GROUPS OF 208 00:07:56,840 --> 00:07:58,600 CELLS WHICH REALLY FORM 209 00:07:58,600 --> 00:08:00,800 FUNCTIONAL UNITS IN OUR TISSUES 210 00:08:00,800 --> 00:08:02,120 AROUND SORT OF HUNDREDS OF 211 00:08:02,120 --> 00:08:02,760 MICRONS. 212 00:08:02,760 --> 00:08:04,280 SO WHAT I'D LIKE TO TELL YOU 213 00:08:04,280 --> 00:08:08,040 TODAY IS ABOUT TWO TISSUE MICRO 214 00:08:08,040 --> 00:08:09,880 ENVIRONMENTS, THE LIVER 215 00:08:09,880 --> 00:08:12,160 MICROENVIRONMENT AND TUMOR MICRO 216 00:08:12,160 --> 00:08:12,520 ENVIRONMENTS. 217 00:08:12,520 --> 00:08:16,160 AND HOW WE CAN CREATE TOOLS THAT 218 00:08:16,160 --> 00:08:17,920 ALLOW US TO DISSECT THESE 219 00:08:17,920 --> 00:08:19,760 MICROENVIRONMENT OR ASSEMBLE 220 00:08:19,760 --> 00:08:21,920 THEM FOR THERAPEUTIC PURPOSES. 221 00:08:21,920 --> 00:08:23,560 I'LL TELL YOU TWO STORIES ABOUT 222 00:08:23,560 --> 00:08:26,360 THE LIVER, IN HONOR OF WIN, AND 223 00:08:26,360 --> 00:08:28,080 ONE STORY ABOUT TEU TUMORS. 224 00:08:28,080 --> 00:08:30,720 SO STARTING WITH HEPATIC MICRO 225 00:08:30,720 --> 00:08:34,880 ENVIRONMENTS, THEN, JUST A 226 00:08:34,880 --> 00:08:36,360 LITTLE ORIENTATION ON THE LIVER. 227 00:08:36,360 --> 00:08:39,120 THIS IS AN IMAGE FROM A FAMOUS 228 00:08:39,120 --> 00:08:39,600 ANATOMIST OF THE LIVER. 229 00:08:39,600 --> 00:08:41,560 YOU CAN SEE IT HAS THIS GORGEOUS 230 00:08:41,560 --> 00:08:44,840 MICRO ARCHITECTURE WITH MANY 231 00:08:44,840 --> 00:08:47,520 INTERACTING CELL TYPES, AND THIS 232 00:08:47,520 --> 00:08:49,120 GIVES RISE TO SOME 500 233 00:08:49,120 --> 00:08:49,400 FUNCTIONS. 234 00:08:49,400 --> 00:08:54,280 THE THE LIVER IS VITAL FOR LIFE. 235 00:08:54,280 --> 00:08:57,680 PABLO NARUTA DESCRIBED IT AS THE 236 00:08:57,680 --> 00:08:59,320 MODEST ORGANIZED UNDERGROUND 237 00:08:59,320 --> 00:09:02,800 WORKER OF OUR BODY. 238 00:09:02,800 --> 00:09:03,720 IT'S UNDERAPPRECIATED. 239 00:09:03,720 --> 00:09:05,960 IT CAN DO REMARKABLE THINGS. 240 00:09:05,960 --> 00:09:10,800 IT'S UNFORTUNATELY -- ITS 241 00:09:10,800 --> 00:09:11,440 DYSFUNCTION TOUCHES 500 MILLION 242 00:09:11,440 --> 00:09:13,120 PATIENTS WORLDWIDE, AND IT HAS 243 00:09:13,120 --> 00:09:14,720 REMARKABLE CAPABILITIES WHERE IT 244 00:09:14,720 --> 00:09:16,520 CAN REGENERATE UNDER CERTAIN 245 00:09:16,520 --> 00:09:16,840 CIRCUMSTANCES. 246 00:09:16,840 --> 00:09:18,280 SO IT'S JUST A FASCINATING 247 00:09:18,280 --> 00:09:18,560 ORGAN. 248 00:09:18,560 --> 00:09:19,920 I'VE STUDIED IT MOST OF MY 249 00:09:19,920 --> 00:09:21,640 CAREER AND I KNOW WIN HAS 250 00:09:21,640 --> 00:09:22,720 STUDIED IT MUCH LONGER THAN ME. 251 00:09:22,720 --> 00:09:24,280 SO YOU THINK ABOUT WHAT CAN YOU 252 00:09:24,280 --> 00:09:26,720 STUDY ABOUT THIS ARCHITECTURE OF 253 00:09:26,720 --> 00:09:28,680 THIS ORGAN WITH THESE TOOLS. 254 00:09:28,680 --> 00:09:30,520 SO I'M GOING TO START WITH AN 255 00:09:30,520 --> 00:09:32,920 EXAMPLE OF WHAT ONE CAN STUDY BY 256 00:09:32,920 --> 00:09:35,120 CREATING AN ARTIFICIAL HUMAN 257 00:09:35,120 --> 00:09:36,200 MICROENVIRONMENT IN TWO 258 00:09:36,200 --> 00:09:36,520 DIMENSIONS. 259 00:09:36,520 --> 00:09:39,680 SO ON A FLAT SURFACE. 260 00:09:39,680 --> 00:09:41,360 AND HERE WHAT WE DO IS WE 261 00:09:41,360 --> 00:09:44,000 PATTERN SURFACES WITH LIGHT FROM 262 00:09:44,000 --> 00:09:46,080 THE SEMICONDUCTOR TOOL INDUSTRY, 263 00:09:46,080 --> 00:09:48,480 AND WE PATTERN BIOMOLECULES ON 264 00:09:48,480 --> 00:09:50,200 THOSE SURFACES THAT WILL CONFER 265 00:09:50,200 --> 00:09:54,360 THE ADHESION OF CELLS. 266 00:09:54,360 --> 00:09:55,880 SO HERE YOU CAN SEE WORK FROM MY 267 00:09:55,880 --> 00:09:57,560 COLLEAGUES WHERE YOU CAN PATTERN 268 00:09:57,560 --> 00:10:03,520 A SINGLE CELL ON AN ISLAND OF 269 00:10:03,520 --> 00:10:04,320 FIBRANECTIN OR A BOW TIE OF TWO 270 00:10:04,320 --> 00:10:08,640 CELLS OR AN ASYMMETRIC 271 00:10:08,640 --> 00:10:09,160 MULTICELLULAR ISLAND. 272 00:10:09,160 --> 00:10:11,040 SO THESE TOOLS ARE VERY GENERIC, 273 00:10:11,040 --> 00:10:12,560 WE CAN ESSENTIALLY PRECISELY 274 00:10:12,560 --> 00:10:17,600 PLACE SELLS KRELS ON CELLS ON A SURFACE 275 00:10:17,600 --> 00:10:18,600 AND STUDY THE ARCHITECTURE OF 276 00:10:18,600 --> 00:10:19,360 THAT COMMUNITY. 277 00:10:19,360 --> 00:10:21,240 JUST TO GIVE YOU A SENSE OF HOW 278 00:10:21,240 --> 00:10:23,840 GENERIC THIS TOOL IS, THIS IS AN 279 00:10:23,840 --> 00:10:25,840 IMAGE OF A SURFACE THAT HAD BEEN 280 00:10:25,840 --> 00:10:28,680 PATTERNED WITH COLLAGEN TYPE 281 00:10:28,680 --> 00:10:30,680 1 BY A FORMER POSTDOC OF MINE. 282 00:10:30,680 --> 00:10:32,560 THIS IS ACTUALLY PART OF A 283 00:10:32,560 --> 00:10:33,600 TRAVELING ART EXHIBIT AND WIN 284 00:10:33,600 --> 00:10:35,320 HAS A COPY OF THIS ON HIS WALL 285 00:10:35,320 --> 00:10:37,200 ACTUALLY. 286 00:10:37,200 --> 00:10:40,320 THESE ARE RAD HEPATOCYTES 287 00:10:40,320 --> 00:10:41,320 PATTERNED IN COLLABORATION WITH 288 00:10:41,320 --> 00:10:42,320 AN ARTIST. 289 00:10:42,320 --> 00:10:44,320 IF YOU ZOOM IN ON THESE, YOU CAN 290 00:10:44,320 --> 00:10:47,000 SEE THESE STRUCTURES WHICH ARE 291 00:10:47,000 --> 00:10:50,520 SPECIFIED BY LIGHT-BASED PA 292 00:10:50,520 --> 00:10:52,320 PATTERNING OF COLLAGEN ARE 293 00:10:52,320 --> 00:10:53,320 INCREDIBLY PRECISE AND REALLY 294 00:10:53,320 --> 00:10:56,520 WHAT'S COMPOSED OF THEM IS RAD 295 00:10:56,520 --> 00:10:57,360 HEPATOCYTES SPREAD ON THAT 296 00:10:57,360 --> 00:10:57,600 SURFACE. 297 00:10:57,600 --> 00:10:59,680 SO THESE ARE VERY GENERIC TOOLS. 298 00:10:59,680 --> 00:11:01,160 SO I'D LIKE TO TELL YOU NOW WHAT 299 00:11:01,160 --> 00:11:03,280 ONE COULD STUDY IN A 300 00:11:03,280 --> 00:11:04,120 TWO-DIMENSIONAL SYSTEM LIKE 301 00:11:04,120 --> 00:11:04,320 THIS. 302 00:11:04,320 --> 00:11:06,120 IT MAY SURPRISE YOU THAT THIS 303 00:11:06,120 --> 00:11:09,600 VIGNETTE IS GOING TO BE ACTUALLY 304 00:11:09,600 --> 00:11:11,120 ABOUT A HUMAN PATHOGEN THAT WE 305 00:11:11,120 --> 00:11:13,880 THINK OF AS A DISEASE OF THE 306 00:11:13,880 --> 00:11:15,320 BLOOD. 307 00:11:15,320 --> 00:11:18,120 THAT'S PLASMODIUM VIVAX. 308 00:11:18,120 --> 00:11:19,480 AS I'LL SHOW YOU IN A MOMENT, 309 00:11:19,480 --> 00:11:21,000 THIS ORGANISM HAS AN OBLIGATE 310 00:11:21,000 --> 00:11:23,720 STAGE OF ITS LIFE CYCLE IN THE 311 00:11:23,720 --> 00:11:24,720 LIVER, WHICH UNTIL VERY 312 00:11:24,720 --> 00:11:28,200 RECENTLY, WE HAVE NOT KNOWN MUCH 313 00:11:28,200 --> 00:11:31,680 ABOUT. 314 00:11:31,680 --> 00:11:33,680 SO PLASMODIUM VIVAX REALLY 315 00:11:33,680 --> 00:11:35,440 AFFECTS MANY PEOPLE GLOBALLY, 316 00:11:35,440 --> 00:11:38,360 AND UNLIKE ITS COUSIN, IT TURNS 317 00:11:38,360 --> 00:11:41,320 OUT TO BE A RELAPSING FORM OF 318 00:11:41,320 --> 00:11:43,520 MALARIA, AND BECAUSE OF THAT, 319 00:11:43,520 --> 00:11:45,320 IT'S QUITE DIFFICULT TO 320 00:11:45,320 --> 00:11:45,800 ERADICATE. 321 00:11:45,800 --> 00:11:46,880 SO LET ME SHOW YOU A LITTLE BIT 322 00:11:46,880 --> 00:11:50,920 MORE ABOUT ITS LIFE CYCLE. 323 00:11:50,920 --> 00:11:52,760 AND WHY THE LIVER PART OF IT IS 324 00:11:52,760 --> 00:11:53,320 SO INTERESTING. 325 00:11:53,320 --> 00:11:57,280 SO HERE IS A SPORE ZOITE COMING 326 00:11:57,280 --> 00:11:59,600 FROM AN INFECTED MOSQUITO. 327 00:11:59,600 --> 00:12:00,720 THAT WILL TRAVEL TO THE LIVER, 328 00:12:00,720 --> 00:12:04,000 WHERE IT INFECTS HEPATOCYTES, 329 00:12:04,000 --> 00:12:04,440 UNIQUELY. 330 00:12:04,440 --> 00:12:06,680 IT WILL MULTIPLY OVER SEVEN TO 331 00:12:06,680 --> 00:12:09,680 10 DAYS. 332 00:12:09,680 --> 00:12:10,800 AND THEN BURST OUT OF THE LIVER, 333 00:12:10,800 --> 00:12:12,640 WHERE IT WILL INFECT YOUNG RED 334 00:12:12,640 --> 00:12:15,360 BLOOD CELLS, RETICULOCYTES, AND 335 00:12:15,360 --> 00:12:18,520 THEN START THE PATTERN OF CYCLIC 336 00:12:18,520 --> 00:12:20,840 FEVER THAT WE ASSOCIATE WITH 337 00:12:20,840 --> 00:12:22,040 MALARIA. 338 00:12:22,040 --> 00:12:24,000 NOW WHAT'S INTERESTING AND 339 00:12:24,000 --> 00:12:25,960 SPECIAL ABOUT THE LIVER STAGE OF 340 00:12:25,960 --> 00:12:29,560 THIS ORGANISM IS THAT THIS IS A 341 00:12:29,560 --> 00:12:30,720 BOTTLENECK IN THE LIFE CYCLE, IF 342 00:12:30,720 --> 00:12:31,880 YOU WILL. 343 00:12:31,880 --> 00:12:33,920 SO WHEN YOU START OUT WITH 344 00:12:33,920 --> 00:12:35,360 RELATIVELY FEW SPORE ZOITES AND 345 00:12:35,360 --> 00:12:37,440 THE ORGANISM MULTIPLIES. 346 00:12:37,440 --> 00:12:39,000 SO FROM A THERAPEUTIC 347 00:12:39,000 --> 00:12:40,440 PERSPECTIVE, IF YOU COULD TARGET 348 00:12:40,440 --> 00:12:42,520 IT IN THE LIVER, YOU WOULD 349 00:12:42,520 --> 00:12:44,000 PREVENT SYMPTOMS, YOU WOULD 350 00:12:44,000 --> 00:12:45,000 PREVENT TRANSMISSION, WHICH WILL 351 00:12:45,000 --> 00:12:48,080 HAPPEN LATER IN THE BLOOD STAGE, 352 00:12:48,080 --> 00:12:50,040 AND YOU WOULD PREVENT THIS 353 00:12:50,040 --> 00:12:50,800 AMPLIFICATION OF BIOMASS OF THE 354 00:12:50,800 --> 00:12:51,120 ORGANISM. 355 00:12:51,120 --> 00:12:52,600 SO THERE'S BEEN A LOT OF 356 00:12:52,600 --> 00:12:54,320 INTEREST IN TARGETING AT THIS 357 00:12:54,320 --> 00:12:55,760 STAGE, AND THERE'S ONLY ONE DRUG 358 00:12:55,760 --> 00:12:57,320 SO FAR THAT'S ABLE TO DO IT, AND 359 00:12:57,320 --> 00:13:03,000 THAT'S A VERY OLD DRUG CALLED 360 00:13:03,000 --> 00:13:04,720 PRIMOQUINN. 361 00:13:04,720 --> 00:13:06,520 THE REASON THIS CAN RELAPSE EVEN 362 00:13:06,520 --> 00:13:07,520 AFTER IT'S CLEARED IS BECAUSE OF 363 00:13:07,520 --> 00:13:08,120 THIS GUY HERE. 364 00:13:08,120 --> 00:13:14,520 THIS IS CALLED THE HYPNOZOITE 365 00:13:14,520 --> 00:13:15,920 FOR HYPNOTIZE. 366 00:13:15,920 --> 00:13:20,480 IT CAN STAY IN THE LIVER AS A 367 00:13:20,480 --> 00:13:21,480 DORMANT -- IT STARTS TO MULTIPLY 368 00:13:21,480 --> 00:13:23,680 AND IT CAN START THE WHOLE LIFE 369 00:13:23,680 --> 00:13:24,040 CYCLE AGAIN. 370 00:13:24,040 --> 00:13:27,000 SO THERE HAVE BEEN MANY GAPS IN 371 00:13:27,000 --> 00:13:30,520 OUR UNDERSTANDING OF THIS LITTLE 372 00:13:30,520 --> 00:13:30,840 ORGANISM. 373 00:13:30,840 --> 00:13:32,360 WE DON'T KNOW ITS INCIDENCE 374 00:13:32,360 --> 00:13:34,240 BECAUSE THERE ARE NO CLINICAL 375 00:13:34,240 --> 00:13:35,000 BIOMARKER, WE DON'T KNOW ABOUT 376 00:13:35,000 --> 00:13:37,320 HOW LONG IT CAN SURVIVE IN VIVO, 377 00:13:37,320 --> 00:13:39,280 WE DON'T KNOW ABOUT THE 378 00:13:39,280 --> 00:13:40,240 PERSISTENCE, WE DON'T KNOW WHAT 379 00:13:40,240 --> 00:13:41,520 THE REACTIVATION QUEUES ARE, WE 380 00:13:41,520 --> 00:13:43,600 DON'T KNOW WHAT DRUG TARGETS IT 381 00:13:43,600 --> 00:13:44,920 EXPRESSES AND WHAT DRUGS IT 382 00:13:44,920 --> 00:13:47,320 MIGHT BE SENSITIVE TO. 383 00:13:47,320 --> 00:13:49,200 SO WE SET OUT TO DEVELOP AN IN 384 00:13:49,200 --> 00:13:50,520 VITRO MODEL OF THIS ORGANISM IN 385 00:13:50,520 --> 00:13:52,120 OUR TWO-DIMENSIONAL LIVERS THAT 386 00:13:52,120 --> 00:13:55,640 I SHOWED YOU EARLIER. 387 00:13:55,640 --> 00:13:57,280 SO THE MODEL SYSTEM THAT WE 388 00:13:57,280 --> 00:14:00,120 DEVELOPED USING HUMAN 389 00:14:00,120 --> 00:14:01,200 HEPATOCYTES LOOKS A LOT LIKE THE 390 00:14:01,200 --> 00:14:02,640 PICTURE I SHOWED YOU EARLIER BUT 391 00:14:02,640 --> 00:14:04,520 IT HAS ONE ADDITIONAL CELL TYPE. 392 00:14:04,520 --> 00:14:07,120 AND SO HERE WHAT WE'VE DONE IS 393 00:14:07,120 --> 00:14:08,960 PATTERN HUMAN HEPATOCYTES FROM 394 00:14:08,960 --> 00:14:11,840 ORGAN DONORS ON COLLAGEN TYPE 1, 395 00:14:11,840 --> 00:14:13,120 AND NOW WE SURROUND THEM WITH 396 00:14:13,120 --> 00:14:15,000 FEEDER CELLS, WITH FIBROBLASTS 397 00:14:15,000 --> 00:14:17,280 THAT SUPPORT THEIR PHENOTYPE. 398 00:14:17,280 --> 00:14:19,560 AND USING THIS MANIPULATION, 399 00:14:19,560 --> 00:14:23,880 WE'RE ABLE TO MAINTAIN THE HUMAN 400 00:14:23,880 --> 00:14:26,360 HEPATOCYTE PHENOTYPE IN A 401 00:14:26,360 --> 00:14:27,560 TWO-DIMENSIONAL CONSTRUCT IN THE 402 00:14:27,560 --> 00:14:29,400 BOTTOM OF A WELL FOR ABOUT FOUR 403 00:14:29,400 --> 00:14:30,720 TO SIX WEEKS. 404 00:14:30,720 --> 00:14:34,680 DEPENDING ON THE DONOR. 405 00:14:34,680 --> 00:14:35,760 AND WHAT'S INTERESTING AND WHAT 406 00:14:35,760 --> 00:14:37,880 WIN AND I SPENT A LOT OF TIME 407 00:14:37,880 --> 00:14:39,160 TALKING ABOUT OVER THE YEARS IS 408 00:14:39,160 --> 00:14:40,920 THESE CELLS ACTUALLY POLARIZE IN 409 00:14:40,920 --> 00:14:41,880 THIS CONFIGURATION. 410 00:14:41,880 --> 00:14:43,720 EVEN THOUGH THEY'RE IN A 411 00:14:43,720 --> 00:14:44,640 TWO-DIMENSIONAL MONO LAYER. 412 00:14:44,640 --> 00:14:46,720 SO FOR EXAMPLE, IF YOU ADD A 413 00:14:46,720 --> 00:14:48,000 FLOOR SEEN DAIS TATE INTO THIS 414 00:14:48,000 --> 00:14:50,120 CULTURE, YOU CAN SEE THAT IT'S 415 00:14:50,120 --> 00:14:53,600 TAKEN UP AND PUT OUT INTO THE 416 00:14:53,600 --> 00:14:59,160 BIOCANULICULI JUST LIKE THEY DO 417 00:14:59,160 --> 00:15:00,200 IN VIVO. 418 00:15:00,200 --> 00:15:01,520 THEY ALSO EXPRESS DRUG 419 00:15:01,520 --> 00:15:02,120 METABOLIZING ENZYMES AND THEY 420 00:15:02,120 --> 00:15:04,000 HAVE LOTS OF UTILITY FOR MANY 421 00:15:04,000 --> 00:15:04,920 APPLICATIONS IN ADDITION TO 422 00:15:04,920 --> 00:15:06,800 STUDYING THE LIVER STAGE OF 423 00:15:06,800 --> 00:15:07,080 PATHOGENS. 424 00:15:07,080 --> 00:15:08,200 SO IN ORDER TO MAKE THIS USEFUL 425 00:15:08,200 --> 00:15:11,520 TO THE BIOMEDICAL RESEARCH 426 00:15:11,520 --> 00:15:13,800 COMMUNITY, WE MINIATURIZE THESE 427 00:15:13,800 --> 00:15:17,320 MICRO PATTERNED CO-CULTURES IN A 428 00:15:17,320 --> 00:15:19,920 WAY THAT WE COULD PUT THEM 429 00:15:19,920 --> 00:15:24,760 INSIDE OF MULTIPLE PLATES. 430 00:15:24,760 --> 00:15:26,080 SO WE'RE NO LONGER USING THE 431 00:15:26,080 --> 00:15:27,760 EXACT TECHNIQUES OF THE 432 00:15:27,760 --> 00:15:28,480 SEMICONDUCTOR INDUSTRY WHERE YOU 433 00:15:28,480 --> 00:15:30,280 PATTERN A SURFACE WITH LIGHT. 434 00:15:30,280 --> 00:15:31,440 INSTEAD HERE WE'RE BASICALLY 435 00:15:31,440 --> 00:15:32,920 MAKING STAMPS AND THEN WE'RE 436 00:15:32,920 --> 00:15:34,840 STAMPING INTO MULTI-WELL PLATES. 437 00:15:34,840 --> 00:15:36,560 AND THAT'S ALLOWED US TO MAKE 438 00:15:36,560 --> 00:15:39,640 DIFFERENT FORMATS OF THIS TOOL. 439 00:15:39,640 --> 00:15:43,240 A 24-WELL VERSION, A 96-WELL 440 00:15:43,240 --> 00:15:44,880 VERSION, AND A 384-WELL VERSION. 441 00:15:44,880 --> 00:15:47,160 SO YOU CAN DO LOTS OF BIOLOGY 442 00:15:47,160 --> 00:15:49,120 WITH VERY FEW HUMAN HEPATOCYTES. 443 00:15:49,120 --> 00:15:49,440 OKAY. 444 00:15:49,440 --> 00:15:50,680 SO NOW I WANTED TO DO THE 445 00:15:50,680 --> 00:15:52,680 EXPERIMENT WITH VIVAX, AND I HAD 446 00:15:52,680 --> 00:15:56,000 A VERY ADVENTUROUS GRADUATE 447 00:15:56,000 --> 00:15:57,520 STUDENT AND THIS IS HOW HER 448 00:15:57,520 --> 00:15:57,920 THESIS WENT. 449 00:15:57,920 --> 00:16:01,120 SHE WOULD PATTERN THESE PLATES 450 00:16:01,120 --> 00:16:03,080 IN BOSTON, WAIT FOR THE RAINY 451 00:16:03,080 --> 00:16:05,600 SEASON IN THAILAND, WHERE VIVAX 452 00:16:05,600 --> 00:16:08,680 IS ENDEMIC, FLY WITH THE CELLS 453 00:16:08,680 --> 00:16:10,640 FROZEN AND THE PLATES TO OUR 454 00:16:10,640 --> 00:16:16,120 COLLABORATOR LAB IN THAILAND, 455 00:16:16,120 --> 00:16:18,080 WHERE THE LAB HAD COLLECTED 456 00:16:18,080 --> 00:16:20,240 BLOOD FROM INFECTED VIVAX 457 00:16:20,240 --> 00:16:22,200 PATIENTS IN THE FIELD AND FED 458 00:16:22,200 --> 00:16:25,280 THOSE TO MOSQUITOES AND THEN 459 00:16:25,280 --> 00:16:28,320 ISOLATED SPORE ZOITES FROM THOSE 460 00:16:28,320 --> 00:16:29,240 MOSQUITOES THAT WE COULD PUT 461 00:16:29,240 --> 00:16:30,000 INTO THE CULTURE. 462 00:16:30,000 --> 00:16:32,840 SO WE WOULD THEN PUT THESE INTO 463 00:16:32,840 --> 00:16:34,480 OUR MOO CROW PATTERN COCULTURES, 464 00:16:34,480 --> 00:16:36,120 DO THE EXPERIMENT, TYPICALLY IT 465 00:16:36,120 --> 00:16:37,320 LASTED 21 DAYS, TAKE SOME OF THE 466 00:16:37,320 --> 00:16:39,840 PLATES AND FIX THEM, BRING THEM 467 00:16:39,840 --> 00:16:42,040 BACK TO BOSTON TO THE BROAD 468 00:16:42,040 --> 00:16:43,200 INSTITUTE, WHERE WE WOULD USE 469 00:16:43,200 --> 00:16:45,520 MACHINE ALGORITHMS TO STUDY THE 470 00:16:45,520 --> 00:16:46,720 PARASITES OVER THE COURSE OF 471 00:16:46,720 --> 00:16:50,880 THEIR LIFE CYCLE, AND WITH THE 472 00:16:50,880 --> 00:16:55,800 OTHER PLATE, WE WORKED WITH ALEX 473 00:16:55,800 --> 00:16:57,600 SHALAK TO DO SINGLE CELL 474 00:16:57,600 --> 00:16:59,600 SEQUENCING OF THE INFECTED 475 00:16:59,600 --> 00:16:59,920 HEPATOSITES. 476 00:16:59,920 --> 00:17:02,280 SO 477 00:17:02,280 --> 00:17:02,600 HEPATOCYTES. 478 00:17:02,600 --> 00:17:04,680 SO WE WOULD DISPERSE THOSE 479 00:17:04,680 --> 00:17:07,000 CULTURES AND PUT THEM INTO A 480 00:17:07,000 --> 00:17:12,360 FORMAT THAT ALEX HAS INVENTED 481 00:17:12,360 --> 00:17:17,680 CALLED SEQ-WELL WHERE EVERY -- 482 00:17:17,680 --> 00:17:20,520 YOU CAN BARCODE THE RNA ON A 483 00:17:20,520 --> 00:17:21,120 PER-WELL BASIS. 484 00:17:21,120 --> 00:17:28,320 IF IT CONTAINED A HEPATOCYTE -- 485 00:17:28,320 --> 00:17:30,480 IF IT HAD BOTH THE HEPATOCYTE 486 00:17:30,480 --> 00:17:31,800 AND A PATHOGEN, IT COULD CARRY 487 00:17:31,800 --> 00:17:33,000 BOTH OF THEM ON THE SAME 488 00:17:33,000 --> 00:17:33,440 BARCODE. 489 00:17:33,440 --> 00:17:34,520 SO WHAT DID WE LEARN? 490 00:17:34,520 --> 00:17:35,400 LET ME JUST SHOW YOU SOME 491 00:17:35,400 --> 00:17:37,160 PICTURES OF THIS KIND OF ELUSIVE 492 00:17:37,160 --> 00:17:37,920 PARASITE BECAUSE WE WERE SO 493 00:17:37,920 --> 00:17:39,320 HAPPY TO HAVE GROWN IT AFTER 10 494 00:17:39,320 --> 00:17:42,000 YEARS OF WORK ON WORKING ON IT. 495 00:17:42,000 --> 00:17:43,720 SO WHAT YOU'RE LOOKING AT NOW IS 496 00:17:43,720 --> 00:17:45,120 A CULTURE, AND THIS IS A 497 00:17:45,120 --> 00:17:46,760 HISTOGRAM OF THE PARASITES 498 00:17:46,760 --> 00:17:48,520 INSIDE THAT CULTURE. 499 00:17:48,520 --> 00:17:52,840 AND HERE WE'RE STAINING THE 500 00:17:52,840 --> 00:17:54,720 VACUOLE, SO THIS IS A MEMBRANE 501 00:17:54,720 --> 00:17:56,920 THAT SURROUNDS A PARASITE INSIDE 502 00:17:56,920 --> 00:17:58,240 THE HEPATOCYTE. 503 00:17:58,240 --> 00:18:00,400 THIS IS THE HEPATOCYTE NUCLEI 504 00:18:00,400 --> 00:18:02,720 WITH UIS4, AND WE'RE MARKING ITS 505 00:18:02,720 --> 00:18:07,840 GENOME WITH THIS HISTONE 506 00:18:07,840 --> 00:18:08,600 ACETYLATION MARKER. 507 00:18:08,600 --> 00:18:10,360 YOU CAN SEE IN THE BEGINNING ALL 508 00:18:10,360 --> 00:18:12,680 THE PARASITES ARE QUITE SMALL. 509 00:18:12,680 --> 00:18:15,000 AS WE LET THESE GROW, LOOKING AT 510 00:18:15,000 --> 00:18:16,240 DAY 8, WE SEE SOME OF THE SMALL 511 00:18:16,240 --> 00:18:17,800 FORMS AND WE SEE SOME THAT HAVE 512 00:18:17,800 --> 00:18:19,320 BEEN HIGHLY MULTINUCLEATED. 513 00:18:19,320 --> 00:18:22,160 SO THESE HAVE REPLICATED. 514 00:18:22,160 --> 00:18:23,920 IN PATIENT BIOPSIES, THE BIGGEST 515 00:18:23,920 --> 00:18:27,120 ONE OF THESE THAT HAD BEEN NOTED 516 00:18:27,120 --> 00:18:29,360 PREVIOUSLY WAS ABOUT 40 MICRONS. 517 00:18:29,360 --> 00:18:32,040 IN OUR CULTURES, WE SEE THEM TO 518 00:18:32,040 --> 00:18:33,560 BE UP TO 130 MICRONS. 519 00:18:33,560 --> 00:18:36,520 YOU CAN SEE THEY JUST TAKE UP 520 00:18:36,520 --> 00:18:42,320 THE WHOLE HEPATOCYTE CYTOPLASM. 521 00:18:42,320 --> 00:18:44,160 THEN IF YOU WAIT A LITTLE 522 00:18:44,160 --> 00:18:45,320 LONGER, ON DAY 10, THIS IS THE 523 00:18:45,320 --> 00:18:46,760 FIRST TIME WE BELIEVE ANYONE HAD 524 00:18:46,760 --> 00:18:50,320 EVER SEEN THIS IN VITRO, YOU CAN 525 00:18:50,320 --> 00:18:54,440 SEE THE STRUCTURE BURSTING OUT, 526 00:18:54,440 --> 00:18:57,520 AND THESE MARAZOITES COMING OUT 527 00:18:57,520 --> 00:18:59,360 OF THE HEPATOCYTES, STREAMING 528 00:18:59,360 --> 00:19:00,120 OUT 529 00:19:00,120 --> 00:19:01,320 >>, AND THIS IS WHEN THEY WOULD 530 00:19:01,320 --> 00:19:03,040 ENTER INTO THE BLOOD STAGE IN 531 00:19:03,040 --> 00:19:03,520 THE BODY. 532 00:19:03,520 --> 00:19:06,920 THIS IMAGE, I SHOULD SAY NEIL 533 00:19:06,920 --> 00:19:08,760 WAS SO HAPPY TO SEE THIS, SHE 534 00:19:08,760 --> 00:19:10,720 TOOK THIS IMAGE THROUGH THE 535 00:19:10,720 --> 00:19:12,400 MICROSCOPE OBJECTIVE WITH HER 536 00:19:12,400 --> 00:19:14,200 IPHONE BECAUSE WE HAVE NO VIDEO 537 00:19:14,200 --> 00:19:15,080 MY 538 00:19:15,080 --> 00:19:15,360 MICROSCOPY. 539 00:19:15,360 --> 00:19:18,920 SO IF WE OVERLAY RETICULOCYTES, 540 00:19:18,920 --> 00:19:20,280 YOUNG RED BLOOD CELLS ON TOP OF 541 00:19:20,280 --> 00:19:21,520 THESE CULTURES, IN FACT, THEY 542 00:19:21,520 --> 00:19:23,120 CAN COMPLETE THEIR FULL LIFE 543 00:19:23,120 --> 00:19:24,640 CYCLE AND INFECT THE RED BLOOD 544 00:19:24,640 --> 00:19:25,040 CELLS. 545 00:19:25,040 --> 00:19:26,760 AND THEN IF WE LOOK AT WHAT'S 546 00:19:26,760 --> 00:19:29,120 LEFT IN THE CULTURE AFTER 547 00:19:29,120 --> 00:19:30,960 21 DAYS, ALL WE SEE ARE THESE 548 00:19:30,960 --> 00:19:36,800 SMALL PERSISTENT FORMS, WHICH WE 549 00:19:36,800 --> 00:19:39,200 THINK ARE HYPNOZOITES. 550 00:19:39,200 --> 00:19:41,800 THERE ARE NO BIOMARKERS 551 00:19:41,800 --> 00:19:43,120 DEFINITIVE FOR THEM, SO WE 552 00:19:43,120 --> 00:19:44,720 WANTED TO SEE IF THEY REALLY 553 00:19:44,720 --> 00:19:46,000 MIGHT CARRY ALL OF THE HALL 554 00:19:46,000 --> 00:19:47,960 MARKS THAT ARE KNOWN CLINICALLY 555 00:19:47,960 --> 00:19:49,720 TO DESCRIBE HYPNOZOITES, AND 556 00:19:49,720 --> 00:19:50,920 THERE ARE FOUR OF THEM. 557 00:19:50,920 --> 00:19:53,520 SO THE FIRST IS THAT THEY ARE 558 00:19:53,520 --> 00:19:56,320 SMALL, QUIESCENT, MONO NUCLEATE, 559 00:19:56,320 --> 00:19:57,240 AND PERSISTING. 560 00:19:57,240 --> 00:19:59,720 WHICH WE FOUND. 561 00:19:59,720 --> 00:20:03,880 THE SECOND IS THAT WHILE THEY DO 562 00:20:03,880 --> 00:20:05,640 EXPRESS MARKERS LIKE UIS4, THEY 563 00:20:05,640 --> 00:20:08,480 SHOULD NOT EXPRESS MATURE 564 00:20:08,480 --> 00:20:11,520 MARKERS LIKE MARAZOITE SURFACE 565 00:20:11,520 --> 00:20:13,280 PROTEIN, WHICH IS ON THE SURFACE 566 00:20:13,280 --> 00:20:14,280 OF THESE REPLICATING FORMS THAT 567 00:20:14,280 --> 00:20:15,720 ARE ABOUT TO COME OUT INTO THE 568 00:20:15,720 --> 00:20:19,520 BLOOD, AND YOU SEE THEY ARE MSP1 NEGATIVE. 569 00:20:19,520 --> 00:20:20,720 THE THIRD, AND THIS IS VERY 570 00:20:20,720 --> 00:20:23,120 IMPORTANT, WE LEARNED THIS FROM 571 00:20:23,120 --> 00:20:24,440 PATIENTS, IS THAT THESE 572 00:20:24,440 --> 00:20:26,240 ORGANISMS SHOULD BE 573 00:20:26,240 --> 00:20:27,520 DIFFERENTIALLY DRUG-SENSITIVE. 574 00:20:27,520 --> 00:20:29,000 THAT IS THAT THEY SHOULD BE 575 00:20:29,000 --> 00:20:34,160 SENSITIVE TO A DRUG LIKE 576 00:20:34,160 --> 00:20:35,240 PRIAQUINE, AND YOU SEE THEY ARE, 577 00:20:35,240 --> 00:20:36,560 BUT THEY SHOULD BE INSENSITIVE 578 00:20:36,560 --> 00:20:38,640 TO A DRUG THAT ONLY KILLS 579 00:20:38,640 --> 00:20:47,720 REPLICATING FORMS LIKE 580 00:20:47,720 --> 00:20:49,720 ATOVAKWAN. 581 00:20:49,720 --> 00:20:50,560 THE SMALL FORMS PERSIST. 582 00:20:50,560 --> 00:20:54,360 THIS IS THE THIRD HALLMARK. 583 00:20:54,360 --> 00:20:55,320 THE FOURTH HALLMARK SHOULD BE 584 00:20:55,320 --> 00:20:56,880 THAT THE DORMANT FORMS ARE 585 00:20:56,880 --> 00:20:58,400 CAPABLE OF REACTIVATING. 586 00:20:58,400 --> 00:21:00,360 HERE WE GOT LUCKY, SOMETIMES IN 587 00:21:00,360 --> 00:21:02,760 SCIENCE YOU GET LUCKY, WHICH IS 588 00:21:02,760 --> 00:21:04,760 THAT IN SOME OF THE CULTURES, WE 589 00:21:04,760 --> 00:21:06,720 WAITED, AND AFTER THEY WERE 590 00:21:06,720 --> 00:21:07,800 CLEARED COMPLETELY OF THOSE 591 00:21:07,800 --> 00:21:09,480 LARGE FORMS THAT BURST OUT ON 592 00:21:09,480 --> 00:21:14,560 DAY 10, WE CAME BACK A WEEK OR 593 00:21:14,560 --> 00:21:16,880 TWO LATER AND SAW THE DORMANT 594 00:21:16,880 --> 00:21:18,320 NUMBER HAD DECREASED AND WE NOW 595 00:21:18,320 --> 00:21:19,840 FOUND THESE LARGE REACTIVATED 596 00:21:19,840 --> 00:21:21,240 FORMS. 597 00:21:21,240 --> 00:21:24,640 SO WE HAVE ESSENTIALLY ALL FOUR 598 00:21:24,640 --> 00:21:26,680 HALLMARKS OF HYPNOZOITES IN 599 00:21:26,680 --> 00:21:28,000 VITRO THAT WE BELIEVE TO BE 600 00:21:28,000 --> 00:21:29,240 CONSISTENT WITH CLINICAL DATA, 601 00:21:29,240 --> 00:21:31,320 SO WE WERE BRAVE ENOUGH TO CALL 602 00:21:31,320 --> 00:21:34,240 THIS A HYPNOZOITE WHEN WE 603 00:21:34,240 --> 00:21:37,440 PUBLISHED OUR PAPER IN 2018. 604 00:21:37,440 --> 00:21:39,200 NOW WE'VE SEEN IT MANY, MANY 605 00:21:39,200 --> 00:21:40,320 TIMES, THERE'S LOTS TO STUDY 606 00:21:40,320 --> 00:21:42,160 ABOUT IT, AND FOR THOSE OF YOU 607 00:21:42,160 --> 00:21:43,480 WHO ARE INTERESTED IN NEW 608 00:21:43,480 --> 00:21:44,520 EXCITING RESEARCH PROJECTS, 609 00:21:44,520 --> 00:21:45,440 THESE ARE JUST SOME OF THE 610 00:21:45,440 --> 00:21:47,040 THINGS THAT WE'VE BEEN DOING 611 00:21:47,040 --> 00:21:48,640 WITH THIS MODEL SYSTEM AND 612 00:21:48,640 --> 00:21:50,360 SHARING IT WITH THE COMMUNITY. 613 00:21:50,360 --> 00:21:52,080 YOU CAN DO THE TRANSCRIPTIONAL 614 00:21:52,080 --> 00:21:53,520 PROFILE OF THIS ORGANISM AND 615 00:21:53,520 --> 00:21:55,360 I'LL SHOW YOU SOME OF THAT IN A 616 00:21:55,360 --> 00:21:57,000 SECOND, YOU CAN STUDY THE 617 00:21:57,000 --> 00:22:00,160 MECHANISMS OF DORMANCY AND 618 00:22:00,160 --> 00:22:00,800 REACTIVATION, SEXUAL COMMITMENT 619 00:22:00,800 --> 00:22:04,680 IN THE ORGANIZE ORGANISM, WHICH IS 620 00:22:04,680 --> 00:22:06,640 THOUGHT TO HAPPEN IN THE BLOOD 621 00:22:06,640 --> 00:22:06,920 STAGE. 622 00:22:06,920 --> 00:22:08,240 NOW THAT WE HAVE THIS TOOL TO 623 00:22:08,240 --> 00:22:10,680 STUDY THIS FORM IN VITRO, 624 00:22:10,680 --> 00:22:12,120 THERE'S LOTS TO DO. 625 00:22:12,120 --> 00:22:13,680 SO LET ME TELL YOU ONE OF THE 626 00:22:13,680 --> 00:22:17,120 NEWER STORIES QUICKLY ABOUT THIS 627 00:22:17,120 --> 00:22:19,320 ORGANISM THAT'S ABOUT TO BE 628 00:22:19,320 --> 00:22:20,920 PUBLISHED THAT HAS TO DO WITH 629 00:22:20,920 --> 00:22:22,120 THIS DUAL SEQUENCING. 630 00:22:22,120 --> 00:22:23,800 SO I DESCRIBED THIS TO YOU 631 00:22:23,800 --> 00:22:27,720 EARLIER, WHERE WE DISPERSED THE 632 00:22:27,720 --> 00:22:29,120 CULTURE INTO SINGLE WELLS AND 633 00:22:29,120 --> 00:22:31,120 EVERY WELL IS BARCODED. 634 00:22:31,120 --> 00:22:33,920 AND WHAT WE DID WHEN WE DID THIS 635 00:22:33,920 --> 00:22:36,560 EXPERIMENT WAS WE FOUND 1400 636 00:22:36,560 --> 00:22:40,840 PARASITE GENOMES AND 33,000 637 00:22:40,840 --> 00:22:41,120 HEPATOCYTES. 638 00:22:41,120 --> 00:22:44,480 SOME WERE INFECTED, SOME WERE 639 00:22:44,480 --> 00:22:45,520 UNINFECTED. 640 00:22:45,520 --> 00:22:49,280 WE COULD TELL WHICH WERE 641 00:22:49,280 --> 00:22:50,120 UNINFECTED BECAUSE THEY HAD THE 642 00:22:50,120 --> 00:22:50,800 SAME BARCODE. 643 00:22:50,800 --> 00:22:51,640 THESE ARE SOME OF THE THINGS 644 00:22:51,640 --> 00:22:52,880 THAT WE'VE LEARNED IN THIS 645 00:22:52,880 --> 00:22:54,080 STUDY. 646 00:22:54,080 --> 00:22:57,000 SO ONE OF THEM IS THAT WE COULD 647 00:22:57,000 --> 00:22:59,200 SEE THE PARASITE MATURING OVER 648 00:22:59,200 --> 00:23:00,920 THE FIRST TWO WEEKS OF LIFE. 649 00:23:00,920 --> 00:23:04,120 SO WHAT WE DID WAS WE TOOK THE 650 00:23:04,120 --> 00:23:06,080 TRANSCRIPTOME THAT WE PREVIOUSLY 651 00:23:06,080 --> 00:23:08,280 HAD DONE IN THE INITIAL 652 00:23:08,280 --> 00:23:11,520 EXPERIMENT AND CREATED A 10-GENE 653 00:23:11,520 --> 00:23:13,520 SIGNATURE FOR THE HYPNOZOITE, 654 00:23:13,520 --> 00:23:15,440 THE DORMANT FORM, BASED OFF OF 655 00:23:15,440 --> 00:23:16,520 THE ORIGINAL DATA. 656 00:23:16,520 --> 00:23:18,280 AND THEN WE APPLIED IT TO THE 657 00:23:18,280 --> 00:23:19,000 SINGLE CELL DATA. 658 00:23:19,000 --> 00:23:20,000 AND THERE'S SOME VERY 659 00:23:20,000 --> 00:23:20,880 INTERESTING GENES HERE. 660 00:23:20,880 --> 00:23:23,120 ONE OF THEM IS A TRANSLATIONAL 661 00:23:23,120 --> 00:23:25,800 REPRE SER, WHICH SEEMS TO BE 662 00:23:25,800 --> 00:23:26,920 IMPORTANT FOR QUIESCENCE. 663 00:23:26,920 --> 00:23:28,520 TWO OF THEM ARE ACTUALLY 664 00:23:28,520 --> 00:23:30,720 PROTEASES, AND THERE'S SOME 665 00:23:30,720 --> 00:23:33,560 SUGGESTION THAT PROTEOLYSIS OF 666 00:23:33,560 --> 00:23:34,480 HOST PROTEINS IS IMPORTANT FOR 667 00:23:34,480 --> 00:23:35,760 THE PARASITE TO PERSIST. 668 00:23:35,760 --> 00:23:38,920 AND THEN ONE OF THEM IS ACTUALLY 669 00:23:38,920 --> 00:23:40,480 MDR2, WHICH MAKES ONE WONDER 670 00:23:40,480 --> 00:23:42,880 ABOUT RESISTANCE TO DRUGS. 671 00:23:42,880 --> 00:23:45,960 SO THIS IS A SIGNATURE FOR THE 672 00:23:45,960 --> 00:23:46,720 HYPNOZOITE. 673 00:23:46,720 --> 00:23:51,280 AND NOW, WHEN YOU FOLLOW THE 674 00:23:51,280 --> 00:23:52,600 PARASITE AROUND ITS LIFE CYCLE 675 00:23:52,600 --> 00:23:53,800 OVER TIME IN THE LIVER, YOU SEE 676 00:23:53,800 --> 00:23:56,320 THAT THE DAY ONE FORMS CLUSTER 677 00:23:56,320 --> 00:23:56,680 TOGETHER. 678 00:23:56,680 --> 00:23:57,920 THESE ARE THOSE SPORE ZOITES 679 00:23:57,920 --> 00:23:59,600 THAT CAME OUT OF THE MOSQUITO 680 00:23:59,600 --> 00:24:02,440 INTO THE LIVER. 681 00:24:02,440 --> 00:24:04,480 THE MIDDLE FORMS HAVE TWO 682 00:24:04,480 --> 00:24:06,240 CLUSTERS, AND THIS CLUSTER HERE 683 00:24:06,240 --> 00:24:09,840 CARRIES ALL THOSE HYPNOZOITE 684 00:24:09,840 --> 00:24:10,720 GENES, AND AS THEY MATURE, 685 00:24:10,720 --> 00:24:15,680 THERE'S A FORM THAT'S STILL IN 686 00:24:15,680 --> 00:24:17,840 HEPATOCYTES HERE AND THIS THAT'S 687 00:24:17,840 --> 00:24:18,400 BURST OUT. 688 00:24:18,400 --> 00:24:20,120 SO YOU CAN ANNOTATE THESE AS WE 689 00:24:20,120 --> 00:24:20,560 GO. 690 00:24:20,560 --> 00:24:21,680 WHAT'S REALLY INTERESTING ABOUT 691 00:24:21,680 --> 00:24:23,520 THIS, AND I'LL SHOW YOU AT THE 692 00:24:23,520 --> 00:24:24,720 END, IS THAT YOU CAN EVEN ASK 693 00:24:24,720 --> 00:24:28,320 WHETHER ANY OF THESE HAVE 694 00:24:28,320 --> 00:24:30,320 COMMITTED ALONG THE SEXUAL 695 00:24:30,320 --> 00:24:31,080 DIFFERENTIATION PATH, WHICH 696 00:24:31,080 --> 00:24:32,240 AGAIN WAS THOUGHT TO OCCUR ONLY 697 00:24:32,240 --> 00:24:34,000 IN THE BLOOD STAGE. 698 00:24:34,000 --> 00:24:35,400 SO WE'RE STARTING TO GET A SENSE 699 00:24:35,400 --> 00:24:36,760 FOR THE LIFE CYCLE OF THIS 700 00:24:36,760 --> 00:24:38,080 ORGANISM, AND THIS IS JUST THE 701 00:24:38,080 --> 00:24:38,520 PARASITE. 702 00:24:38,520 --> 00:24:41,120 THEN YOU MIGHT ASK, HOW IS THE 703 00:24:41,120 --> 00:24:44,640 HEPATOCYTE RESPONDING TO THIS 704 00:24:44,640 --> 00:24:47,120 INFECTION? 705 00:24:47,120 --> 00:24:50,240 SO HERE NOW, THESE ARE THE 706 00:24:50,240 --> 00:24:50,680 33,000 HEPATOCYTES. 707 00:24:50,680 --> 00:24:52,480 YOU CAN SEE HOW THEY CLUSTER 708 00:24:52,480 --> 00:24:53,120 LARGELY TOGETHER. 709 00:24:53,120 --> 00:24:54,440 WE HAVE EIGHT DIFFERENT SUBTYPES 710 00:24:54,440 --> 00:24:55,640 IN THIS SAMPLE. 711 00:24:55,640 --> 00:24:56,600 WHAT'S INTERESTING TO ASK HERE 712 00:24:56,600 --> 00:24:59,400 IS, WHICH CELLS ARE INFECTED? 713 00:24:59,400 --> 00:25:01,400 SO IF YOU LOOK IN THESE EIGHT 714 00:25:01,400 --> 00:25:03,400 DIFFERENT CLUSTERS, WHICH ARE 715 00:25:03,400 --> 00:25:04,920 INFECTED, YOU SEE ACTUALLY ALL 716 00:25:04,920 --> 00:25:07,320 THE CLUSTERS CARRY INFECTION. 717 00:25:07,320 --> 00:25:11,120 SO THERE'S NO PREDOMINANT 718 00:25:11,120 --> 00:25:13,000 HEPATOCELLULAR PHENOTYPE THAT'S 719 00:25:13,000 --> 00:25:14,440 MORE PERMISSIVE. 720 00:25:14,440 --> 00:25:19,920 THE ONLY THING THAT ABOUT 60% OF 721 00:25:19,920 --> 00:25:25,920 THESE SHARES SOLD HAD IN COMMON WAS 722 00:25:25,920 --> 00:25:27,320 SRD1, AND WE CONFIRMED THAT IN 723 00:25:27,320 --> 00:25:28,960 OUR DATA AND VALIDATED THAT 724 00:25:28,960 --> 00:25:29,200 RESULT. 725 00:25:29,200 --> 00:25:31,280 SO THE ONE THING THAT CAME UP IN 726 00:25:31,280 --> 00:25:34,200 IN MANY OF THE CULTURES WERE 727 00:25:34,200 --> 00:25:36,080 INTERFERON PATHWAY-RELATED 728 00:25:36,080 --> 00:25:38,520 GENES, OR SO CALLED ISG OR 729 00:25:38,520 --> 00:25:39,160 INTERFERON STRESS GENES. 730 00:25:39,160 --> 00:25:43,400 SO HERE YOU CAN SEE TWO OF THEM, 731 00:25:43,400 --> 00:25:45,600 IFI6 AND IFI-T1, AND THEY'RE 732 00:25:45,600 --> 00:25:49,560 SORT OF SCATTERED AMONG THE 733 00:25:49,560 --> 00:25:51,360 NAIVE HEPATOCYTES AND THOSE THAT 734 00:25:51,360 --> 00:25:54,120 HAVE JUST BEEN EXPOSED WITH 735 00:25:54,120 --> 00:25:56,080 MALARIA SALIVARY GLAND MATERIAL. 736 00:25:56,080 --> 00:25:57,520 THAT'S CALLED A MOCK EXPOSURE. 737 00:25:57,520 --> 00:25:59,800 YOU CAN SEE WHEN YOU EXPOSE A 738 00:25:59,800 --> 00:26:02,520 CULTURE TO VIVAX ITSELF, THAT 739 00:26:02,520 --> 00:26:05,520 MANY OF THE HEPATOCYTES LIGHT UP 740 00:26:05,520 --> 00:26:06,920 WITH THESE ISGs. 741 00:26:06,920 --> 00:26:08,960 NOT JUST THE INFECTED 742 00:26:08,960 --> 00:26:10,720 HEPATOCYTES, AND, IN FACT, THE 743 00:26:10,720 --> 00:26:13,120 INFECTED HEPATOCYTES, THE 744 00:26:13,120 --> 00:26:14,320 PARASITE SEEMS TO SUPPRESS THE 745 00:26:14,320 --> 00:26:17,160 RESPONSE TO INFECTION, BUT THE 746 00:26:17,160 --> 00:26:19,400 BYSTANDER HEPATOCYTES ACTUALLY 747 00:26:19,400 --> 00:26:21,880 UPREGULATE ALL OF THESE 748 00:26:21,880 --> 00:26:24,760 INTERFERON RESPONSES. 749 00:26:24,760 --> 00:26:26,800 SO THIS IS A LOT OF DATA, IT'S 750 00:26:26,800 --> 00:26:27,520 ABOUT TO COME OUT. 751 00:26:27,520 --> 00:26:30,600 I JUST WANTED TO GIVE YOU A 752 00:26:30,600 --> 00:26:31,880 SNIPPET AND TO SUMMARIZE THE TWO 753 00:26:31,880 --> 00:26:34,000 THINS THAT WE'RE LEARNING AND 754 00:26:34,000 --> 00:26:34,560 THE CONVERSATION BETWEEN THE 755 00:26:34,560 --> 00:26:36,520 HOST AND THE PARASITE THAT THIS 756 00:26:36,520 --> 00:26:38,720 SYSTEM, I HOPE, WILL ALLOW US TO 757 00:26:38,720 --> 00:26:39,120 UNWIND. 758 00:26:39,120 --> 00:26:44,120 AS ON THE HEPATOCYTE SIDE, THE 759 00:26:44,120 --> 00:26:45,120 INFECTED HEPATOSIDE DOWN 760 00:26:45,120 --> 00:26:47,000 REGULATES THE INTERFERON 761 00:26:47,000 --> 00:26:47,280 RESPONSE. 762 00:26:47,280 --> 00:26:52,320 AND THE BYSTANDER HEPATOCYTES 763 00:26:52,320 --> 00:26:54,600 UPREGULATE THE RESPONSE. 764 00:26:54,600 --> 00:26:58,320 BASED ON SOME OTHER DATA THAT 765 00:26:58,320 --> 00:26:59,720 HEPATOCYTES ACTUALLY MEDIATED BY 766 00:26:59,720 --> 00:27:00,400 GAP JUNCTIONS. 767 00:27:00,400 --> 00:27:01,720 THIS IS SOMETHING SIMILAR THAT 768 00:27:01,720 --> 00:27:02,800 CHARLIE RICE AND I SAW WHEN 769 00:27:02,800 --> 00:27:04,520 LOOKING AT HEPATITIS C, SO 770 00:27:04,520 --> 00:27:05,200 THERE'S SOMETHING VERY 771 00:27:05,200 --> 00:27:06,280 INTERESTING HAPPENING HERE JUST 772 00:27:06,280 --> 00:27:08,920 ON THE HOST RESPONSE SIDE. 773 00:27:08,920 --> 00:27:11,680 IF YOU ADD INTERFERON GAMMA INTO 774 00:27:11,680 --> 00:27:13,120 THIS CULTURE, YOU ACTUALLY CAN 775 00:27:13,120 --> 00:27:18,000 USE TO CLEAR HYPNOZOITES. 776 00:27:18,000 --> 00:27:20,160 ON THE PARASITE SIDE, I 777 00:27:20,160 --> 00:27:21,320 MENTIONED TO YOU THAT THERE ARE 778 00:27:21,320 --> 00:27:24,000 THESE VARIOUS SUBSTRUCTURES IN 779 00:27:24,000 --> 00:27:25,160 THE DATA, ZOITES ARE HERE. 780 00:27:25,160 --> 00:27:27,120 IF YOU ACTUALLY LOOK, WE'VE 781 00:27:27,120 --> 00:27:29,520 FOUND A MASTER REGULATOR SEXUAL 782 00:27:29,520 --> 00:27:32,600 DIFFERENTIATION CALLED AP2G, 783 00:27:32,600 --> 00:27:34,200 THOUGHT TO ONLY BE UPREGULATED 784 00:27:34,200 --> 00:27:36,200 IN THE BLOOD STATE YOUR NAME. 785 00:27:36,200 --> 00:27:38,320 WE STAGE. 786 00:27:38,320 --> 00:27:39,360 WE FOUND IT HERE IN THE LIVER 787 00:27:39,360 --> 00:27:42,000 FROM THE VERY BEGINNING, FROM 788 00:27:42,000 --> 00:27:42,320 DAY ONE. 789 00:27:42,320 --> 00:27:44,720 WE SEE THAT SOME OF THE 790 00:27:44,720 --> 00:27:46,120 HYPNOZOITES ACTUALLY CARRY THIS 791 00:27:46,120 --> 00:27:47,560 AND SOME OF THE REPLICATED 792 00:27:47,560 --> 00:27:48,200 FORMS. 793 00:27:48,200 --> 00:27:50,640 AND THIS IS ACTUALLY REALLY 794 00:27:50,640 --> 00:27:52,040 INTARIQING BECAUSE THERE ARE 795 00:27:52,040 --> 00:27:54,160 SOME DATA IN THE MALARIA 796 00:27:54,160 --> 00:27:55,720 COMMUNITY IN CHALLENGE 797 00:27:55,720 --> 00:27:56,720 EXPERIMENTS WHERE PATIENTS HAVE 798 00:27:56,720 --> 00:28:00,760 SHOWN THE ABILITY TO BE 799 00:28:00,760 --> 00:28:02,520 TRANSMISSIBLE AT DAY 9 AFTER 800 00:28:02,520 --> 00:28:03,320 INFECTION. 801 00:28:03,320 --> 00:28:04,480 WHICH EVERYONE ALWAYS THOUGHT 802 00:28:04,480 --> 00:28:06,320 WAS WAY TOO EARLY, BECAUSE 803 00:28:06,320 --> 00:28:07,280 THEY'RE SUPPOSED TO COME OUT OF 804 00:28:07,280 --> 00:28:08,720 THE LIVER AT DAY 10 AND THEN GO 805 00:28:08,720 --> 00:28:10,920 INTO THE BLOOD STAGE AND THEN 806 00:28:10,920 --> 00:28:12,160 UNDERGO SEXUAL DIFFERENTIATION 807 00:28:12,160 --> 00:28:14,680 BEFORE YOU COULD BE TRANS 808 00:28:14,680 --> 00:28:17,080 MISSABLE. 809 00:28:17,080 --> 00:28:20,720 THESE DATA SUGGEST IT'S 810 00:28:20,720 --> 00:28:23,320 DEVIATING SEXUALLY EVEN IN THE 811 00:28:23,320 --> 00:28:23,640 LIVER STAGE. 812 00:28:23,640 --> 00:28:25,160 SO FROM A TRANSLATIONAL 813 00:28:25,160 --> 00:28:26,480 PERSPECTIVE, IT MAY SUGGEST THAT 814 00:28:26,480 --> 00:28:28,760 SOME OF THE DRUGS THAT ARE BEING 815 00:28:28,760 --> 00:28:30,000 DEVELOPED AGAINST THE SEXUAL 816 00:28:30,000 --> 00:28:32,920 STAGES OF THE ORGANISM MIGHT 817 00:28:32,920 --> 00:28:34,360 ACTUALLY BE USEFUL FOR TARGETING 818 00:28:34,360 --> 00:28:36,920 THE LIVER STAGE. 819 00:28:36,920 --> 00:28:37,320 OKAY. 820 00:28:37,320 --> 00:28:39,080 SO THIS IS MY FIRST VIGNETTE. 821 00:28:39,080 --> 00:28:42,320 IT'S AN EXAMPLE OF WHAT A 2D 822 00:28:42,320 --> 00:28:45,320 MICROENVIRONMENT OF HUMAN 823 00:28:45,320 --> 00:28:46,840 HEPATOCYTES IN VITRO MIGHT ALLOW 824 00:28:46,840 --> 00:28:49,000 YOU TO DO FOR INFECTIOUS 825 00:28:49,000 --> 00:28:50,000 DISEASE. 826 00:28:50,000 --> 00:28:51,200 THE LAST THING I'D LIKE TO 827 00:28:51,200 --> 00:28:53,720 MENTION FROM A TOOL PERSPECTIVE 828 00:28:53,720 --> 00:28:56,440 IS THAT THE DEVELOPMENT OF TOOLS 829 00:28:56,440 --> 00:28:57,960 CAN REALLY OPEN UP NEW DOORS. 830 00:28:57,960 --> 00:29:00,920 SO WE STARTED THIS IN 2008, AND 831 00:29:00,920 --> 00:29:02,920 IN THE BEGINNING, WE WORKED ON 832 00:29:02,920 --> 00:29:06,160 HEPATITIS C AND HEPATITIS B WITH 833 00:29:06,160 --> 00:29:09,120 CHARLIE RICE. 834 00:29:09,120 --> 00:29:13,160 AND THEN VALCIPRIN AND VIVAX, 835 00:29:13,160 --> 00:29:14,800 AND THIS TOOL HAS BEEN USINGED 836 00:29:14,800 --> 00:29:16,840 BY A VARIETY OF LABS REALLY 837 00:29:16,840 --> 00:29:18,040 AROUND THE WORLD, AS I MENTIONED 838 00:29:18,040 --> 00:29:19,920 TO STUDY MANY, MANY TOPICS, 839 00:29:19,920 --> 00:29:22,120 INCLUDING VACCINES, AND WE'RE 840 00:29:22,120 --> 00:29:26,520 NOW JUST GETTING TO THE NOVEL 841 00:29:26,520 --> 00:29:28,160 THERAPEUTIC ACTIVITY, THINGS 842 00:29:28,160 --> 00:29:30,480 LIKE RNA INTERFERENCE AND 843 00:29:30,480 --> 00:29:32,640 CRISPR, AND GENE DELIVERY. 844 00:29:32,640 --> 00:29:35,120 SO THIS VERY SIMPLE TOOL, I 845 00:29:35,120 --> 00:29:36,240 THINK ACTUALLY HAS A LOT TO 846 00:29:36,240 --> 00:29:38,120 OFFER. 847 00:29:38,120 --> 00:29:40,160 SO THAT'S MY FIRST VIGNETTE. 848 00:29:40,160 --> 00:29:41,360 THE SECOND ONE I'D LIKE TO 849 00:29:41,360 --> 00:29:44,880 MENTION IS ABOUT 850 00:29:44,880 --> 00:29:46,320 THREE-DIMENSIONAL HEPATIC MICRO 851 00:29:46,320 --> 00:29:46,640 ENVIRONMENTS. 852 00:29:46,640 --> 00:29:48,480 SO I SHOWED YOU BEFORE THAT 853 00:29:48,480 --> 00:29:49,680 SEMICONDUCTOR TOOLS ALLOWED US 854 00:29:49,680 --> 00:29:54,120 TO WRITE ON SURFACES. 855 00:29:54,120 --> 00:29:55,760 THOSE SAME TOOLS CAN BE USED TO 856 00:29:55,760 --> 00:29:58,720 MOLD AND TEMPLATE AND PRINT 857 00:29:58,720 --> 00:30:00,040 THREE-DIMENSIONAL MATERIALS. 858 00:30:00,040 --> 00:30:03,680 SO WHAT YOU SEE HERE ARE SOME 859 00:30:03,680 --> 00:30:06,160 IMAGES OF A VARIETY OF DIFFERENT 860 00:30:06,160 --> 00:30:07,600 STRUCTURES MADE USING MICRO 861 00:30:07,600 --> 00:30:09,360 FABRICATION TOOLS BUT IN THREE 862 00:30:09,360 --> 00:30:09,760 DIMENSIONAL FORMS. 863 00:30:09,760 --> 00:30:12,120 FOR EXAMPLE, THIS IS A MICRO 864 00:30:12,120 --> 00:30:14,400 FLUIDIC STRUCTURE THAT'S MAKING 865 00:30:14,400 --> 00:30:16,360 LITTLE HEPATIC 3D MICRO TISSUES. 866 00:30:16,360 --> 00:30:17,880 SO WHAT I'D LIKE TO DO IS TELL 867 00:30:17,880 --> 00:30:19,960 YOU A STORY ABOUT 3D MICRO 868 00:30:19,960 --> 00:30:22,000 ENVIRONMENTS IN THE CONTEXT OF 869 00:30:22,000 --> 00:30:26,520 ANOTHER REALLY FASCINATING 870 00:30:26,520 --> 00:30:28,160 MEDICAL CHALLENGE, WHICH IS 871 00:30:28,160 --> 00:30:32,000 LIVER REGENERATION. 872 00:30:32,000 --> 00:30:33,360 SO JUST TO KIND OF ORIENT YOU 873 00:30:33,360 --> 00:30:34,560 HERE, THIS IS A STORY WHICH AS 874 00:30:34,560 --> 00:30:39,640 FAR AS I KNOW START IN 1930s, 875 00:30:39,640 --> 00:30:41,160 ALTHOUGH WIN MAY KNOW AN OLDER 876 00:30:41,160 --> 00:30:46,880 STORY, WHERE ONE CAN DO A 877 00:30:46,880 --> 00:30:51,320 PARTIAL HEPATECTOMY IN WHICH THE 878 00:30:51,320 --> 00:30:52,760 LIVER REGENERATES WITHIN WEEKS. 879 00:30:52,760 --> 00:30:54,320 THERE'S MANY FASCINATING THINGS 880 00:30:54,320 --> 00:30:56,760 ABOUT THIS, BUT ONE THAT'S 881 00:30:56,760 --> 00:30:57,680 ALWAYS FASCINATED OUR WORK HAS 882 00:30:57,680 --> 00:31:00,840 BEEN THE WORK OF NANCY BOOKER, 883 00:31:00,840 --> 00:31:04,840 WHICH DATES BACK TO THE 1950s. 884 00:31:04,840 --> 00:31:06,480 A PARABIOSIS EXPERIMENT, WHERE 885 00:31:06,480 --> 00:31:08,840 THE CIRCULATION OF TWO ANIMALS 886 00:31:08,840 --> 00:31:11,320 WAS CONNECTED AND A PARTIAL HELP 887 00:31:11,320 --> 00:31:12,640 TECT MEE WAS DONE IN THE ONE AND 888 00:31:12,640 --> 00:31:13,800 THE OTHER LIVER COULD ACTUALLY 889 00:31:13,800 --> 00:31:17,560 RESPOND TO THAT INJURY. 890 00:31:17,560 --> 00:31:18,880 THAT SUGGESTED IN PART THAT THE 891 00:31:18,880 --> 00:31:20,840 SIGNALS INVOLVED WITH HEPATIC 892 00:31:20,840 --> 00:31:26,480 REGENERATION MUST BE BLOODBORNE 893 00:31:26,480 --> 00:31:28,560 OVER THE YEARS, GEORGE AND MANY 894 00:31:28,560 --> 00:31:29,880 OTHERS HAVE DUG INTO THIS, AND 895 00:31:29,880 --> 00:31:33,920 WHAT THEY'VE FOUND IS THAT IN 896 00:31:33,920 --> 00:31:35,520 PART, THE QUEUES IN HEPATIC 897 00:31:35,520 --> 00:31:36,960 REGENERATION ARE A CONVERSATION 898 00:31:36,960 --> 00:31:40,480 BETWEEN HEPATOCYTES IN THE LIVER 899 00:31:40,480 --> 00:31:45,200 AND THEIR NEIGHBORING CELLS, THE 900 00:31:45,200 --> 00:31:47,040 SINUSOIDAL AND EPITHELIAL CELLS. 901 00:31:47,040 --> 00:31:49,120 I'M KIND OF BLOWN UP WHERE YOU 902 00:31:49,120 --> 00:31:51,400 SEE THAT CONVERSATION HERE WHERE 903 00:31:51,400 --> 00:31:56,120 YOU SEE EPITHELIAL CELLS AND 904 00:31:56,120 --> 00:31:57,520 HEPATOCYTES, PART RESPOND TO 905 00:31:57,520 --> 00:32:00,360 INJURY, PART RESPOND TO FLUID 906 00:32:00,360 --> 00:32:01,560 FLOW, THESE CELLS START 907 00:32:01,560 --> 00:32:03,640 PRODUCING PARAFFIN FACTORS, SO 908 00:32:03,640 --> 00:32:07,120 FOR COMPACT, ENDOTHELIAL CELLS 909 00:32:07,120 --> 00:32:09,000 MAKE THINGS, AND THE HEPATOCYTES 910 00:32:09,000 --> 00:32:12,400 IN TURN MAKE GROWTH FACTORS. 911 00:32:12,400 --> 00:32:14,360 AND THAT ALLOWS THE HEPATOCYTES 912 00:32:14,360 --> 00:32:19,280 AND THE ENT THEEL YELL CELLS TO 913 00:32:19,280 --> 00:32:21,480 COORDINATE THEIR REPLICATION AS 914 00:32:21,480 --> 00:32:22,320 THE LIVER REGROWS. 915 00:32:22,320 --> 00:32:25,160 SO WE WANTED TO STUDY THE HUMAN 916 00:32:25,160 --> 00:32:26,120 ANALOG OF THIS. 917 00:32:26,120 --> 00:32:29,680 IT HAD BEEN REALLY WELL STUDIED 918 00:32:29,680 --> 00:32:32,840 IN RODENTS AND NOT WELL STUDIED 919 00:32:32,840 --> 00:32:35,320 IN HUMANS, SO WE WANTED TO SEE 920 00:32:35,320 --> 00:32:39,520 IF WE COULD MAKE A PATTERN OF 921 00:32:39,520 --> 00:32:41,120 INTERACTIONS AS THEY RELATE TO 922 00:32:41,120 --> 00:32:43,400 REGENERATION USING SOME OF THESE 923 00:32:43,400 --> 00:32:43,680 PD TOOLS. 924 00:32:43,680 --> 00:32:45,520 SO THIS IS HOW WE DID IT. 925 00:32:45,520 --> 00:32:48,120 THE FIRST STEP WAS TO TAKE HUMAN 926 00:32:48,120 --> 00:32:49,480 HEPATOCYTES AND MAKE SPHEROIDS 927 00:32:49,480 --> 00:32:50,400 OUT OF THEM. 928 00:32:50,400 --> 00:32:54,120 WE DO THIS USING A MICRO FABL 929 00:32:54,120 --> 00:32:55,640 KATEED MOLDS, THEY FORM THESE 930 00:32:55,640 --> 00:32:57,680 AGGREGATES OF ABOUT 150 MICRONS 931 00:32:57,680 --> 00:32:58,800 IN DIAMETER. 932 00:32:58,800 --> 00:33:01,120 IN THIS STRUCTURE, THEY'RE 933 00:33:01,120 --> 00:33:03,960 STABLE IN CULTURE FOR WEEKS. 934 00:33:03,960 --> 00:33:04,840 THE FULL PHENOTYPE THAT I 935 00:33:04,840 --> 00:33:06,880 DESCRIBED. 936 00:33:06,880 --> 00:33:10,720 AND THEN WE WANTED TO PUT THEM 937 00:33:10,720 --> 00:33:12,240 CLOSE IN TRACKS WITH ENDOTHELIAL 938 00:33:12,240 --> 00:33:13,440 CELLS, AND IN ORDER TO DO THIS 939 00:33:13,440 --> 00:33:15,400 WORK, WE WORKED WITH MY 940 00:33:15,400 --> 00:33:17,800 COLLEAGUE, CHRIS CHEN AND BOSTON 941 00:33:17,800 --> 00:33:19,920 UNIVERSITY, WHO'S AN EXPERT IN 942 00:33:19,920 --> 00:33:20,960 VASCULAR BIOENGINEERING. 943 00:33:20,960 --> 00:33:22,600 WHAT CHRIS AND HIS LAB HAD DONE, 944 00:33:22,600 --> 00:33:26,520 AND AS YOU SEE HERE, IS TAKEN 945 00:33:26,520 --> 00:33:28,720 ENDOTHELIAL CELLS, HUMAN VEIN 946 00:33:28,720 --> 00:33:30,000 ENDOTHELIAL CELLS, SO THEY'RE 947 00:33:30,000 --> 00:33:32,840 NOT SIGN SOY DAL ENDOTHELIAL 948 00:33:32,840 --> 00:33:34,520 CELLS BUT THEY ARE HUMAN CELLS, 949 00:33:34,520 --> 00:33:38,760 AND PUT THEM IN A CHANNEL, MICRO 950 00:33:38,760 --> 00:33:40,520 FABRICATED CHANNEL INSIDE A 951 00:33:40,520 --> 00:33:40,760 HYDROGEL. 952 00:33:40,760 --> 00:33:44,120 SO THIS IS A FIBRIN HYDROGEL. 953 00:33:44,120 --> 00:33:45,760 YOU CAN SEE THEY FORM THESE 954 00:33:45,760 --> 00:33:46,880 LOVELY JUNCTIONS THAT YOU COULD 955 00:33:46,880 --> 00:33:48,840 PUT FLOW THROUGH THIS CHANNEL, 956 00:33:48,840 --> 00:33:51,600 AND KRILS AND HIS LAB HAVE USED 957 00:33:51,600 --> 00:33:54,360 THIS TO STUDY ANGIOGENIC 958 00:33:54,360 --> 00:33:56,120 SPROUTING AND ANY NUMBER OF 959 00:33:56,120 --> 00:33:56,760 VASCULAR QUESTIONS. 960 00:33:56,760 --> 00:33:58,480 SO WE WANTED TO PUT THESE TWO 961 00:33:58,480 --> 00:33:59,840 SYSTEMS TOGETHER AND GET THE 962 00:33:59,840 --> 00:34:02,120 HEPATOCYTES TO TALK TO THE 963 00:34:02,120 --> 00:34:03,640 ENDOTHELIAL CELLS AND SEE IF WE 964 00:34:03,640 --> 00:34:08,320 COULD STUDY LIVER REGENERATION. 965 00:34:08,320 --> 00:34:10,960 SO WE MADE A LITTLE CHIP, WE 966 00:34:10,960 --> 00:34:12,600 CALLED IT SHEER, WHERE THERE'S A 967 00:34:12,600 --> 00:34:16,160 PANEL IN THE MIDDLE THAT HAS THE 968 00:34:16,160 --> 00:34:20,360 HUMAN ENDOTHELIAL CELLS AND THE 969 00:34:20,360 --> 00:34:22,120 SPHEROIDS AROUND THEM AND ASK 970 00:34:22,120 --> 00:34:23,680 HOW THEY RESPONDED TO VARIOUS 971 00:34:23,680 --> 00:34:24,640 STIMULI. 972 00:34:24,640 --> 00:34:25,640 AND TO TAKE THIS CONVERSATION 973 00:34:25,640 --> 00:34:26,840 THAT WE WERE INTERROGATING 974 00:34:26,840 --> 00:34:28,040 BEFORE AND SEE WHETHER WE COULD 975 00:34:28,040 --> 00:34:29,520 LEARN ANYTHING NEW ABOUT IT IN A 976 00:34:29,520 --> 00:34:31,320 HUMAN CONTEXT. 977 00:34:31,320 --> 00:34:33,080 SO WE DID THESE EXPERIMENTS, WE 978 00:34:33,080 --> 00:34:35,920 CAN ADD THINGS LIKE FLOW, YOU 979 00:34:35,920 --> 00:34:38,520 CAN SEE THAT THE CELLS THEN WILL 980 00:34:38,520 --> 00:34:41,120 PRODUCE A VARIETY OF DIFFERENT 981 00:34:41,120 --> 00:34:43,120 FACTORS IN THE PRESENCE OF FLOW 982 00:34:43,120 --> 00:34:45,200 BECAUSE THE ENDOTHELIAL CELLS 983 00:34:45,200 --> 00:34:47,120 ARE TOO SENSITIVE TO SHARE, THEN 984 00:34:47,120 --> 00:34:48,800 WE COULD ADD INFLAMMATORY 985 00:34:48,800 --> 00:34:50,000 CYTOKINES LIKE THOSE THAT YOU 986 00:34:50,000 --> 00:34:52,360 MIGHT SEE IN INJURY, LIKE IL-1 987 00:34:52,360 --> 00:34:52,920 BETA. 988 00:34:52,920 --> 00:34:56,880 NOW YOU SEE A WHOLE BUNCH OF 989 00:34:56,880 --> 00:34:58,200 FACTORS COMING UP IN THE MEDIA, 990 00:34:58,200 --> 00:34:59,920 AND ONE THING THAT WE WERE 991 00:34:59,920 --> 00:35:02,320 REALLY INTRIGUED BY WAS THIS 992 00:35:02,320 --> 00:35:04,720 ONE, PROSTAGLANDIN E2. 993 00:35:04,720 --> 00:35:05,720 OUR COLLEAGUE HAD PREVIOUSLY 994 00:35:05,720 --> 00:35:08,240 REPORTED THAT THIS WAS INVOLVED 995 00:35:08,240 --> 00:35:10,240 ACTUALLY IN ZEBRAFISH LIVER 996 00:35:10,240 --> 00:35:10,560 REGENERATION. 997 00:35:10,560 --> 00:35:11,560 SO WE'RE VERY INTERESTED TO SEE 998 00:35:11,560 --> 00:35:12,800 IT HERE. 999 00:35:12,800 --> 00:35:14,880 SO THE QUESTION BECAME FOR US, 1000 00:35:14,880 --> 00:35:18,120 WHO IS MAKING THE PGE2 IN THIS 1001 00:35:18,120 --> 00:35:19,560 SYSTEM, AND HOW IS IT WORKING IN 1002 00:35:19,560 --> 00:35:21,920 THIS SORT OF CONVERSATION 1003 00:35:21,920 --> 00:35:23,520 BETWEEN HEPATOCYTES AND 1004 00:35:23,520 --> 00:35:26,520 ENDOTHELIAL CELLS? 1005 00:35:26,520 --> 00:35:30,920 SO RE WE PUT A CELL CYCLE REPORTER 1006 00:35:30,920 --> 00:35:32,800 AND LOOKED AT CYCLING 1007 00:35:32,800 --> 00:35:33,920 HEPATOCYTES IN RESPONSE TO THESE 1008 00:35:33,920 --> 00:35:35,120 SIGNALS, AND WE COULD SEE THAT 1009 00:35:35,120 --> 00:35:38,840 IN THE PRESENCE OF IL-1 BETA, WE 1010 00:35:38,840 --> 00:35:40,280 SAW THEM ENTERING THE CELL 1011 00:35:40,280 --> 00:35:44,880 CYCLE, AND IN THE PRESENCE OF 1012 00:35:44,880 --> 00:35:45,760 ENTERING THE CYCLE. 1013 00:35:45,760 --> 00:35:48,280 SO THE QUESTION WE HAD WAS, 1014 00:35:48,280 --> 00:35:50,000 WHETHER THIS PROSTAGLANDIN E IT 1015 00:35:50,000 --> 00:35:52,120 WAS 1016 00:35:52,120 --> 00:35:53,920 E2 WAS BEING PRODUCED BY THE 1017 00:35:53,920 --> 00:35:55,120 ENDOTHELIAL CELLS AND ACTUALLY 1018 00:35:55,120 --> 00:35:56,080 MEDIATING THIS ENTRY INTO THE 1019 00:35:56,080 --> 00:35:56,600 CELL CYCLE. 1020 00:35:56,600 --> 00:35:58,480 SO BECAUSE WE'RE IN AN IN VITRO 1021 00:35:58,480 --> 00:35:59,920 SYSTEM, WE CAN JUST MANIPULATE 1022 00:35:59,920 --> 00:36:01,440 THE CELLS GENETICALLY 1023 00:36:01,440 --> 00:36:02,400 INDIVIDUALLY, SO WE DID THAT. 1024 00:36:02,400 --> 00:36:06,080 WE TOOK THE ENDOTHELIAL CELLS, 1025 00:36:06,080 --> 00:36:09,160 WE USED CRISPR, WE MAPPED OUT 1026 00:36:09,160 --> 00:36:11,600 PGE SYNTHASE WHICH ALLOWS US TO 1027 00:36:11,600 --> 00:36:13,880 PRODUCE PGE2 IN THE ENDOTHELIAL 1028 00:36:13,880 --> 00:36:14,680 CELLS AND DID THE SAME 1029 00:36:14,680 --> 00:36:16,080 EXPERIMENT AND ASKED WHAT 1030 00:36:16,080 --> 00:36:17,400 HAPPENS, AND SO WHAT YOU SEE IS, 1031 00:36:17,400 --> 00:36:19,120 HERE'S A CONTROL EXPERIMENT, SO 1032 00:36:19,120 --> 00:36:21,440 NOW IN THE PRESENCE OF IL-1 1033 00:36:21,440 --> 00:36:23,400 BETA, THE CELLS ARE CYCLING. 1034 00:36:23,400 --> 00:36:25,760 AND NOW IN THE PRESENCE OF IL-1 1035 00:36:25,760 --> 00:36:29,520 BETA, WITH THE ABSENCE OF PGE IN 1036 00:36:29,520 --> 00:36:30,840 ENDOTHELIAL CELLS, THE CELLS NO 1037 00:36:30,840 --> 00:36:32,280 LONGER CYCLE. 1038 00:36:32,280 --> 00:36:35,520 SO ALL OF THE IL-1 BETA INDUCED 1039 00:36:35,520 --> 00:36:37,920 CYCLING IN THIS SYSTEM SEEM TO 1040 00:36:37,920 --> 00:36:40,560 BE DEPENDENT ON PGE2 FROM THE 1041 00:36:40,560 --> 00:36:41,320 ENDOTHELIAL CELLS. 1042 00:36:41,320 --> 00:36:43,440 SO THIS ALLOWS US NOW TO HAVE A 1043 00:36:43,440 --> 00:36:44,280 WORKING MODEL WHERE WE THINK 1044 00:36:44,280 --> 00:36:46,040 THAT THE ENDOTHELIAL CELLS IN 1045 00:36:46,040 --> 00:36:48,280 HUMAN LIVER REGENERATION ARE 1046 00:36:48,280 --> 00:36:50,720 MAKING PGE2 AND CONTRIBUTING TO 1047 00:36:50,720 --> 00:36:53,720 HEPATOCYTE CELL CYCLE ENTRY. 1048 00:36:53,720 --> 00:36:55,120 THE TRANSLATIONAL IMPLICATIONS 1049 00:36:55,120 --> 00:36:56,520 ARE VERY INTERESTING BECAUSE OF 1050 00:36:56,520 --> 00:36:59,000 COURSE THE PROSTAGLANDINS HAVE A 1051 00:36:59,000 --> 00:37:05,520 SET OF GPCR RESPEP RECEPTORS AND 1052 00:37:05,520 --> 00:37:08,080 TARGETING THEM COULD ACTUALLY 1053 00:37:08,080 --> 00:37:10,800 PRODUCE HEPATOCYTE PROLIFERATION 1054 00:37:10,800 --> 00:37:11,680 THERAPEUTICALLY, SO THAT'S THE 1055 00:37:11,680 --> 00:37:13,120 IMPLICATION OF THIS WORK. 1056 00:37:13,120 --> 00:37:15,920 SO THAT WAS IN VITRO EXPERIMENT. 1057 00:37:15,920 --> 00:37:17,520 WE WANTED TO GO BACK THEN AND 1058 00:37:17,520 --> 00:37:19,000 ASK HOW THIS WORKS RELATES TO 1059 00:37:19,000 --> 00:37:20,520 WHAT NANCY BOOKER SAW IN VIVO. 1060 00:37:20,520 --> 00:37:22,320 SO HOW WOULD THESE TYPES OF 1061 00:37:22,320 --> 00:37:25,040 CONSTRUCTS REACT TO A REAL IN 1062 00:37:25,040 --> 00:37:26,560 VIVO LIVER INJURY. 1063 00:37:26,560 --> 00:37:28,440 AND IN ORDER TO DO THAT, WE MADE 1064 00:37:28,440 --> 00:37:29,640 AN IMPLANTABLE VERSION OF THESE 1065 00:37:29,640 --> 00:37:30,480 CHIPS. 1066 00:37:30,480 --> 00:37:32,920 SO NOW WE HAVE A MULTICHANNEL 1067 00:37:32,920 --> 00:37:34,520 SYSTEM, AND WE SURROUND THOSE 1068 00:37:34,520 --> 00:37:37,600 MULTIPLE CHANNELS WITH THE 1069 00:37:37,600 --> 00:37:39,240 HEPATOCYTE SPHEROIDS, AND WE 1070 00:37:39,240 --> 00:37:41,440 EMBED THE WHOLE THING IN FIBRIN, 1071 00:37:41,440 --> 00:37:45,560 WHICH IS A HYDROGEL, AND WE CAN 1072 00:37:45,560 --> 00:37:46,720 MAKE IMPLANTABLE STRUCTURES THAT 1073 00:37:46,720 --> 00:37:48,120 LOOK LIKE THIS IN THE MICROSCOPE 1074 00:37:48,120 --> 00:37:49,400 AND LOOK LIKE THIS ON THE TIP OF 1075 00:37:49,400 --> 00:37:49,840 YOUR GLOVE. 1076 00:37:49,840 --> 00:37:53,120 SO THIS IS ABOUT A 1 CENTIMETER 1077 00:37:53,120 --> 00:37:53,520 IMPLANT. 1078 00:37:53,520 --> 00:37:58,000 AND WE PUT THEM IN THE 1079 00:37:58,000 --> 00:37:58,760 INTRAPERITONEAL SPACE OF A 1080 00:37:58,760 --> 00:38:00,840 MOUSE, WHERE WE CAN MANIPULATE 1081 00:38:00,840 --> 00:38:03,120 THE LIVER AND ASK HOW THESE 1082 00:38:03,120 --> 00:38:06,320 GRAPHS RESPOND. 1083 00:38:06,320 --> 00:38:08,080 SO HERE YOU CAN SEE THE 1084 00:38:08,080 --> 00:38:08,400 EXPERIMENT. 1085 00:38:08,400 --> 00:38:10,560 THESE GRAPHS NOW CARRY A 1086 00:38:10,560 --> 00:38:12,480 REPORTER FOR HEPATOCYTE HEALTH, 1087 00:38:12,480 --> 00:38:15,520 SO THIS IS DRIVEN BY THE ALBUMEN 1088 00:38:15,520 --> 00:38:18,320 GENE, AND IT'S LUCIFERASE. 1089 00:38:18,320 --> 00:38:20,720 SO ESSENTIALLY WHAT YOU SEE IS 1090 00:38:20,720 --> 00:38:24,200 THAT THE GRAPHS WILL ENGRAFT IN 1091 00:38:24,200 --> 00:38:26,560 THE PERITONEAL SPACE BY 1092 00:38:26,560 --> 00:38:27,880 RECRUITING VASCULATURE, AND THAT 1093 00:38:27,880 --> 00:38:29,160 RECRUITMENT OF VASCULATURE IS 1094 00:38:29,160 --> 00:38:30,520 REALLY DEPENDENT ON THE 1095 00:38:30,520 --> 00:38:31,560 ENDOTHELIAL CELLS IN OUR 1096 00:38:31,560 --> 00:38:31,920 CONSTRUCT. 1097 00:38:31,920 --> 00:38:34,720 AND THEY PERSIST FOR ABOUT 90 1098 00:38:34,720 --> 00:38:36,080 DAYS IN THESE ANIMALS, WHICH IS 1099 00:38:36,080 --> 00:38:38,560 PLENTY OF TIME TO DO SORT OF A 1100 00:38:38,560 --> 00:38:40,440 SURGICAL OR CHEMICAL INJURY TO 1101 00:38:40,440 --> 00:38:41,960 THE LIVER. 1102 00:38:41,960 --> 00:38:43,600 SO WHEN WE DO THAT SAME 1103 00:38:43,600 --> 00:38:45,480 EXPERIMENT, THE PARTIAL 1104 00:38:45,480 --> 00:38:47,440 HEPATECTOMY TO THE MOUSE LIVER 1105 00:38:47,440 --> 00:38:50,360 AND ASK WHAT HAPPENS TO THIS 1106 00:38:50,360 --> 00:38:51,920 GRAFT IN THE PERITONEAL SPACE, 1107 00:38:51,920 --> 00:38:55,120 WHAT WE SEE IS THAT THE 1108 00:38:55,120 --> 00:38:56,840 HEPATOCYTES, A FEW PERCENT OF 1109 00:38:56,840 --> 00:38:58,920 THEM, ABOUT 5% OF THEM, ENTER 1110 00:38:58,920 --> 00:39:00,760 INTO CELL CYCLE. 1111 00:39:00,760 --> 00:39:03,920 WE SEE THAT BY USING AN ANALOG 1112 00:39:03,920 --> 00:39:08,280 WE GIVE THE ANIMALS, AND YOU CAN 1113 00:39:08,280 --> 00:39:10,520 SEE THIS IN THE HEPATOCYTES. 1114 00:39:10,520 --> 00:39:11,720 SO THIS IS VERY INTERESTING, BUT 1115 00:39:11,720 --> 00:39:13,040 IT WAS A TRANSIENT EFFECT, 1116 00:39:13,040 --> 00:39:15,440 BECAUSE WHEN THE MOUSE LIVER 1117 00:39:15,440 --> 00:39:16,640 REGROWS, THE REGENERATIVE 1118 00:39:16,640 --> 00:39:17,320 STIMULUS WENT AWAY. 1119 00:39:17,320 --> 00:39:19,800 SO WE WANTED TO ASK WHETHER WE 1120 00:39:19,800 --> 00:39:21,240 COULD GET THESE ECTOPIC LIVERS, 1121 00:39:21,240 --> 00:39:23,640 IF YOU WILL, TO PROLIFERATE EVEN 1122 00:39:23,640 --> 00:39:26,480 FURTHER BY CREATING A SUSTAINED 1123 00:39:26,480 --> 00:39:29,960 INJURY SIGNAL IP IN VIVO. 1124 00:39:29,960 --> 00:39:32,160 WE DID THAT USING THE SO CALLED 1125 00:39:32,160 --> 00:39:33,280 FAH MOUSE, WHICH IS A MOUSE 1126 00:39:33,280 --> 00:39:36,720 MODEL OF A HUMAN DISEASE. 1127 00:39:36,720 --> 00:39:40,040 IT'S A TYROSINEMIA. 1128 00:39:40,040 --> 00:39:45,400 THIS HAS BEEN POPULARIZED BY THE 1129 00:39:45,400 --> 00:39:46,000 GROUP. 1130 00:39:46,000 --> 00:39:47,520 AND IF YOU FEED THE MOUSE A 1131 00:39:47,520 --> 00:39:51,120 PROTECTIVE DRUG, NTBC, THE 1132 00:39:51,120 --> 00:39:51,800 ANIMALS ARE FINE. 1133 00:39:51,800 --> 00:39:53,240 IF YOU TAKE THEM OFF THE DRUG, 1134 00:39:53,240 --> 00:39:55,120 THEY DEVELOP TOXIC LEVELS OF 1135 00:39:55,120 --> 00:39:57,280 TYROSINE, WHICH IS A LIVER 1136 00:39:57,280 --> 00:40:00,200 INJURY, AND YOU CAN CONTINUE 1137 00:40:00,200 --> 00:40:01,320 THAT PROCESS WHICH WILL MAINTAIN 1138 00:40:01,320 --> 00:40:04,360 A STEADY STATE OF LIVER INJURY. 1139 00:40:04,360 --> 00:40:05,920 SO WE ASK WHAT WOULD THE 1140 00:40:05,920 --> 00:40:08,960 RESPONSE OF OUR HUMAN GRAFTS TO 1141 00:40:08,960 --> 00:40:11,080 THIS CHRONIC LIVER INJURY BE, 1142 00:40:11,080 --> 00:40:14,120 AND WHAT YOU SEE HERE IS YOU 1143 00:40:14,120 --> 00:40:15,640 ESSENTIALLY EXPAND PRETTY 1144 00:40:15,640 --> 00:40:17,480 DRAMATICALLY, SO ABOUT 50 FOLD. 1145 00:40:17,480 --> 00:40:18,720 SO HERE ON THE LEFT, YOU'RE 1146 00:40:18,720 --> 00:40:20,840 LOOKING AT HEPATOCYTES STAINED 1147 00:40:20,840 --> 00:40:30,320 FOR ARNLG ARGENASE, YOU CAN SEE THE 1148 00:40:30,320 --> 00:40:32,480 HEPATOCYTES HAVE EXPANDED. 1149 00:40:32,480 --> 00:40:33,480 INTERESTINGLY, REORGANIZED. 1150 00:40:33,480 --> 00:40:37,080 IF YOU LOOK NE BLOOD OF THOSE 1151 00:40:37,080 --> 00:40:39,360 ANIMALS, YOU CAN TRACK HUMAN 1152 00:40:39,360 --> 00:40:40,480 ALBUMIN AT ABOUT A 50 FOLD 1153 00:40:40,480 --> 00:40:40,840 INCREASE. 1154 00:40:40,840 --> 00:40:42,120 SO WE'VE BEEN REALLY INTERESTED 1155 00:40:42,120 --> 00:40:53,320 IN THIS SORT OF CONCEPT NA A CONCEPT -- WE 'VE 1156 00:40:53,320 --> 00:40:54,720 STARTED TO THINK ABOUT WHETHER 1157 00:40:54,720 --> 00:40:59,200 THIS MIGHT BE THERAPEUTICALLY 1158 00:40:59,200 --> 00:41:00,080 USEFUL. 1159 00:41:00,080 --> 00:41:01,360 SO JUST TO SORT OF WALK YOU 1160 00:41:01,360 --> 00:41:02,360 THROUGH OUR THINKING, ESPECIALLY 1161 00:41:02,360 --> 00:41:04,120 FOR DISEASES, FOR EXAMPLE, 1162 00:41:04,120 --> 00:41:06,440 SINGLE GENE DEFECTS THAT DON'T 1163 00:41:06,440 --> 00:41:10,080 REQUIRE MUCH ENZYME TO BE 1164 00:41:10,080 --> 00:41:10,720 THERAPEUTICALLY IMPORTANT, EVEN 1165 00:41:10,720 --> 00:41:14,520 TODAY WHAT WE DO IS WHOLE ORGAN 1166 00:41:14,520 --> 00:41:14,920 TRANSPLANTATION. 1167 00:41:14,920 --> 00:41:18,680 SO YOU TAKE THE UREA CYCLE 1168 00:41:18,680 --> 00:41:19,440 DISORDERS, THOSE PEDIATRIC 1169 00:41:19,440 --> 00:41:21,400 PATIENTS ARE TRANSPLANTED WITH 1170 00:41:21,400 --> 00:41:21,880 LIVERS. 1171 00:41:21,880 --> 00:41:23,800 SO IT'S REALLY A WHOLE 1172 00:41:23,800 --> 00:41:25,560 REPLACEMENT APPROACH. 1173 00:41:25,560 --> 00:41:26,760 SO THE FIELD HAS BEEN INTERESTED 1174 00:41:26,760 --> 00:41:30,600 IN A LONG TIME WHETHER WE COULD 1175 00:41:30,600 --> 00:41:36,160 ACTUALLY JUST INFUSE HEPATOCYTES 1176 00:41:36,160 --> 00:41:37,920 THEMSELVES WITHOUT REMOVING THE 1177 00:41:37,920 --> 00:41:38,880 LIVER AND REPLACING IT 1178 00:41:38,880 --> 00:41:41,120 COMPLETELY, AND THESE 1179 00:41:41,120 --> 00:41:43,240 EXPERIMENTS, THERE'VE BEEN ABOUT 1180 00:41:43,240 --> 00:41:44,320 100 CASE STUDIES IN PATIENTS 1181 00:41:44,320 --> 00:41:45,880 THAT HAVE LARGELY BEEN 1182 00:41:45,880 --> 00:41:46,440 DISAPPOINTING, THAT WE'VE 1183 00:41:46,440 --> 00:41:47,960 LEARNED A LOT FROM THIS FIELD, 1184 00:41:47,960 --> 00:41:50,880 BUT INJECTING CELLS INTO THE 1185 00:41:50,880 --> 00:41:52,200 LIVER HAS A VARIETY OF 1186 00:41:52,200 --> 00:41:52,520 CHALLENGES. 1187 00:41:52,520 --> 00:41:54,640 ONE OF THEM IS THAT THEY DON'T 1188 00:41:54,640 --> 00:41:55,640 ENGRAFT EFFICIENTLY. 1189 00:41:55,640 --> 00:41:58,480 SO WE LOSE 90-PLUS PERCENTAGE OF 1190 00:41:58,480 --> 00:42:02,840 THOSE HEPATOCYTES ALONG THE WAY. 1191 00:42:02,840 --> 00:42:04,160 SO OUR THINKING HAS BEEN TO 1192 00:42:04,160 --> 00:42:05,720 BUILD OFF OF OUR PRE-CLINICAL 1193 00:42:05,720 --> 00:42:06,040 DATA. 1194 00:42:06,040 --> 00:42:07,200 PERHAPS WE CAN JUST LEAVE THE 1195 00:42:07,200 --> 00:42:09,920 LIVER IN PLACE AND ADD A 1196 00:42:09,920 --> 00:42:12,040 PERITONEAL GRAFT OF HUMAN 1197 00:42:12,040 --> 00:42:13,120 HEPATOCYTES THAT HAVE BEEN ENG 1198 00:42:13,120 --> 00:42:16,840 FEARED TO BE IMPLANTED AND 1199 00:42:16,840 --> 00:42:18,040 RECRUIT VASCULATURE AND SUPPORT 1200 00:42:18,040 --> 00:42:19,240 THE PATIENT, KIND OF LIKE A 1201 00:42:19,240 --> 00:42:20,320 BOOSTER. 1202 00:42:20,320 --> 00:42:24,920 SO WE ARE ACTUALLY -- WE HAVE A 1203 00:42:24,920 --> 00:42:26,240 STARTUP COMMITTEE I MENTIONED 1204 00:42:26,240 --> 00:42:27,520 EARLIER THAT IS ATTEMPTING TO DO 1205 00:42:27,520 --> 00:42:32,040 THAT, WHICH WE'LL BE FILING AN 1206 00:42:32,040 --> 00:42:32,800 IND FOR FIRST PATIENT TRIALS, WE 1207 00:42:32,800 --> 00:42:36,920 HOPE IN ABOUT A YEAR. 1208 00:42:36,920 --> 00:42:39,560 SO WHAT I'VE TOLD YOU ABOUT THE 1209 00:42:39,560 --> 00:42:41,280 LIVER IS THAT WE CAN STUDY IT IN 1210 00:42:41,280 --> 00:42:42,640 TWO DIMENSIONS, AND THAT CAN 1211 00:42:42,640 --> 00:42:44,800 ENABLE THE INVESTIGATION OF 1212 00:42:44,800 --> 00:42:46,920 HUMAN PATHOGENS LIKE P. VIVAX. 1213 00:42:46,920 --> 00:42:49,120 WE CAN STUDY IT IN THREE 1214 00:42:49,120 --> 00:42:50,760 DIMENSIONS, FOR EXAMPLE, WE CAN 1215 00:42:50,760 --> 00:42:53,440 STUDY REGENERATION THAT'S 1216 00:42:53,440 --> 00:42:54,600 PATHWAYS THAT ARE SPECIFIC TO 1217 00:42:54,600 --> 00:42:55,840 THE HUMAN. 1218 00:42:55,840 --> 00:42:57,040 AND THAT WE ARE STARTING TO 1219 00:42:57,040 --> 00:42:58,720 THINK ABOUT WAYS TO TRANSLATE 1220 00:42:58,720 --> 00:42:59,760 SOME OF THESE THINGS TO 1221 00:42:59,760 --> 00:43:01,200 PATIENTS, AND THIS IS JUST AN 1222 00:43:01,200 --> 00:43:04,160 IMAGE OF A GRAFT THAT WE'RE 1223 00:43:04,160 --> 00:43:05,160 WORKING ON THE MANUFACTURING OF 1224 00:43:05,160 --> 00:43:09,920 THESE TO SCALE THEM UP. 1225 00:43:09,920 --> 00:43:11,400 SO MY LAST VIGNETTE, I WANT TO 1226 00:43:11,400 --> 00:43:17,120 TELL YOU A LITTLE BIT ABOUT 1227 00:43:17,120 --> 00:43:18,320 DISREGULATED TISSUE ENVIRONMENT 1228 00:43:18,320 --> 00:43:19,520 LIKE THE TUMOR MICROENVIRONMENT. 1229 00:43:19,520 --> 00:43:20,840 AND NOT REALLY BUILDING IT UP SO 1230 00:43:20,840 --> 00:43:23,360 MUCH WITH TOOLS LIKE ON A 1231 00:43:23,360 --> 00:43:25,000 TWO-DIMENSIONAL PATTERN OR 1232 00:43:25,000 --> 00:43:26,000 THREE-DIMENSIONAL PATTERN, BUT 1233 00:43:26,000 --> 00:43:27,400 INSTEAD MAKING MATERIALS THAT 1234 00:43:27,400 --> 00:43:29,640 ARE SO SMALL THAT THEY CAN 1235 00:43:29,640 --> 00:43:32,800 ACTUALLY ENTER INTO THAT TISSUE 1236 00:43:32,800 --> 00:43:36,720 MICROENVIRONMENT AND MAKE 1237 00:43:36,720 --> 00:43:37,480 MEASUREMENTS THAT WOULD INFORM 1238 00:43:37,480 --> 00:43:38,680 US SCIENTISTS. 1239 00:43:38,680 --> 00:43:41,560 SO HERE WHAT WE'VE DONE IS MAKE 1240 00:43:41,560 --> 00:43:42,280 NANOMATERIALS THAT CAN ENTER 1241 00:43:42,280 --> 00:43:44,240 INTO THE TUMOR MICROENVIRONMENT 1242 00:43:44,240 --> 00:43:46,320 TO QUERY IT. 1243 00:43:46,320 --> 00:43:48,240 SO TO SORT OF SET THE STAGE FOR 1244 00:43:48,240 --> 00:43:50,120 THIS WORK, AND I KNOW I'M 1245 00:43:50,120 --> 00:43:52,160 RUNNING SHORT ON TIME SO I WON'T 1246 00:43:52,160 --> 00:43:53,600 BE AS LONG WITH THIS EXAMPLE, 1247 00:43:53,600 --> 00:43:56,680 WE'VE BEEN REALLY INTERESTED IN 1248 00:43:56,680 --> 00:43:59,680 OFFERING PHYSICIANS TOOLS TO 1249 00:43:59,680 --> 00:44:00,520 MAKE INFORMED DECISIONS ABOUT 1250 00:44:00,520 --> 00:44:01,960 PATIENT CARE. 1251 00:44:01,960 --> 00:44:02,960 SO IF YOU JUST SORT OF THINK 1252 00:44:02,960 --> 00:44:05,880 ABOUT THE LANDSCAPE OF CANCER 1253 00:44:05,880 --> 00:44:08,880 CARE, YOU NEED TO ASSESS RISK, 1254 00:44:08,880 --> 00:44:11,720 DETECT EARLY, MAKE A DIAGNOSIS, 1255 00:44:11,720 --> 00:44:12,920 ASSESS TREATMENT RESPONSE, AND 1256 00:44:12,920 --> 00:44:15,880 THEN MONITOR FOR SURVEILLANCE. 1257 00:44:15,880 --> 00:44:17,520 SO THERE'S OBVIOUSLY MANY, MANY 1258 00:44:17,520 --> 00:44:18,600 POINTS ALONG A PATIENT JOURNEY 1259 00:44:18,600 --> 00:44:21,400 THAT WE NEED BETTER INFORMATION. 1260 00:44:21,400 --> 00:44:22,720 AND IN PARTICULAR, WITH REGARD 1261 00:44:22,720 --> 00:44:25,520 TO OUTCOMES, WE KNOW THAT EARLY 1262 00:44:25,520 --> 00:44:26,440 DETECTION ACROSS A WIDE VARIETY 1263 00:44:26,440 --> 00:44:28,320 OF TUMORS LEADS TO BETTER 1264 00:44:28,320 --> 00:44:30,480 OUTCOMES, SO THIS HAS BEEN A 1265 00:44:30,480 --> 00:44:33,720 REAL AREA OF INTEREST FOR THE 1266 00:44:33,720 --> 00:44:35,520 FIELD. 1267 00:44:35,520 --> 00:44:36,800 HISTORICALLY WE HAVE SCREENED 1268 00:44:36,800 --> 00:44:40,720 THINGS LIKE MAMMOGRAMS AND 1269 00:44:40,720 --> 00:44:41,840 COLONOSCOPY, PRETTY HIGH 1270 00:44:41,840 --> 00:44:44,120 INFRASTRUCTURE APPROACHES. 1271 00:44:44,120 --> 00:44:45,480 SO THERE'S A FIELD EMERGING THAT 1272 00:44:45,480 --> 00:44:46,920 YOU MAY WELL KNOW ABOUT, WHICH 1273 00:44:46,920 --> 00:44:48,560 IS CALLED LIQUID BIOPSY, AND IN 1274 00:44:48,560 --> 00:44:50,080 THIS FIELD, WHAT'S BEEN 1275 00:44:50,080 --> 00:44:52,640 INTERESTING HAS BEEN TO TAKE A 1276 00:44:52,640 --> 00:44:55,600 BLOOD SAMPLE AND TO TRY AND 1277 00:44:55,600 --> 00:44:57,120 ESSENTIALLY -- TO LOOK AT SHED 1278 00:44:57,120 --> 00:45:00,320 PRODUCTS OF CANCER IN THE 1279 00:45:00,320 --> 00:45:01,520 CIRCULATION, FOR EXAMPLE, 1280 00:45:01,520 --> 00:45:02,720 CELL-FREE NUCLEIC ACIDS. 1281 00:45:02,720 --> 00:45:03,920 WHILE THIS IS A VERY EXCITING 1282 00:45:03,920 --> 00:45:05,560 FIELD, IT HAS MANY LIMITATIONS 1283 00:45:05,560 --> 00:45:07,440 SO FAR AND IN PARTICULAR, IT'S 1284 00:45:07,440 --> 00:45:15,520 VERY HARD TO DETECT TO DETECT 1285 00:45:15,520 --> 00:45:17,040 TUMORS EARLY, WHEN THEY'RE 1286 00:45:17,040 --> 00:45:17,520 SMALL. 1287 00:45:17,520 --> 00:45:19,120 SO WE CAN AMPLIFY THOSE SIGNALS 1288 00:45:19,120 --> 00:45:20,920 BY USING SOME OF THESE 1289 00:45:20,920 --> 00:45:21,400 NANOMATERIAL APPROACHES. 1290 00:45:21,400 --> 00:45:23,160 SO I'LL SHOW YOU WHAT I MEAN. 1291 00:45:23,160 --> 00:45:24,000 IN PARTICULAR, WE'RE INTERESTED 1292 00:45:24,000 --> 00:45:27,880 IN USING A CLASS OF ENZYMES THAT 1293 00:45:27,880 --> 00:45:30,720 ARE KNOWN TO BE CANCER 1294 00:45:30,720 --> 00:45:31,480 DISREGULATED AND THOSE ARE 1295 00:45:31,480 --> 00:45:32,560 CALLED THE PROTEASES. 1296 00:45:32,560 --> 00:45:33,960 SO THERE'S ABOUT 500 OF THEM IN 1297 00:45:33,960 --> 00:45:36,280 THE HUMAN GENOME AND THERE ARE 1298 00:45:36,280 --> 00:45:37,920 FIVE MAJOR CLASSES, AND THESE 1299 00:45:37,920 --> 00:45:38,920 HAVE BEEN ASSOCIATED WITH REALLY 1300 00:45:38,920 --> 00:45:41,000 ALL THE CANCER HALLMARKS. 1301 00:45:41,000 --> 00:45:44,840 SO THEY'RE KNOWN TO BE 1302 00:45:44,840 --> 00:45:46,680 DISREGULATED WITH CANCER TUMOR 1303 00:45:46,680 --> 00:45:48,640 INITIATION, SURVIVAL, 1304 00:45:48,640 --> 00:45:49,720 ANGIOGENESIS INNOVATION AND THE 1305 00:45:49,720 --> 00:45:50,200 IMMUNE SYSTEM. 1306 00:45:50,200 --> 00:45:52,000 AND REALLY MOST FAMOUSLY, I 1307 00:45:52,000 --> 00:45:57,280 THINK, MMP9 IS THE POSTER CHILD 1308 00:45:57,280 --> 00:46:03,280 FOR THIS FIELD AS ONE THAT IS 1309 00:46:03,280 --> 00:46:04,480 INVOLVED WITH THIS ANGIOGENIC 1310 00:46:04,480 --> 00:46:05,200 SWITCH. 1311 00:46:05,200 --> 00:46:06,520 SO DESPITE THEIR INVOLVEMENT 1312 00:46:06,520 --> 00:46:07,720 WITH TUMOR PATHOGENESIS, THEY'VE 1313 00:46:07,720 --> 00:46:09,320 BEEN REALLY DIFFICULT TO STUDY. 1314 00:46:09,320 --> 00:46:10,720 THEY'RE EXPRESSED IN PRO FORMS, 1315 00:46:10,720 --> 00:46:12,240 THEY'RE TYPICALLY ACTIVE 1316 00:46:12,240 --> 00:46:13,760 LOCALLY, AND THEY ACTUALLY CAN 1317 00:46:13,760 --> 00:46:15,520 EXIST WITH LOCAL INHIBITORS. 1318 00:46:15,520 --> 00:46:16,720 SO WE'RE REALLY INTERESTED TO 1319 00:46:16,720 --> 00:46:19,240 SEE WHETHER WE COULD MAKE SOME 1320 00:46:19,240 --> 00:46:23,280 SORT OF MULTIPLEX TOOL TO 1321 00:46:23,280 --> 00:46:24,200 PROFILE THEIR ACTIVITY IN TUMORS 1322 00:46:24,200 --> 00:46:25,600 IN A WAY THAT COULD BE AMPLIFIED 1323 00:46:25,600 --> 00:46:27,440 AND GIVE US A WINDOW INTO TUMOR 1324 00:46:27,440 --> 00:46:27,800 BIOLOGY. 1325 00:46:27,800 --> 00:46:29,840 SO WE DID THAT BY INVENTING A 1326 00:46:29,840 --> 00:46:33,680 CLASS OF MATERIALS THAT ARE WHAT 1327 00:46:33,680 --> 00:46:35,440 WE CALL ACTIVITY-BASED SENSORS. 1328 00:46:35,440 --> 00:46:36,560 SO HERE WHAT YOU'RE LOOKING AT 1329 00:46:36,560 --> 00:46:38,080 IS A SOLID TUMOR SURROUNDING A 1330 00:46:38,080 --> 00:46:40,480 BLOOD VESSEL. 1331 00:46:40,480 --> 00:46:42,280 IN THIS BLOOD VESSEL, WE'RE 1332 00:46:42,280 --> 00:46:42,880 DELIVERING NANOMATERIALS THAT 1333 00:46:42,880 --> 00:46:45,080 ARE ABOUT 100 NANOMETERS IN 1334 00:46:45,080 --> 00:46:47,360 SIZE, AND THEY ARE EXTRAVASATING 1335 00:46:47,360 --> 00:46:48,680 FROM THE VESSEL, SO THEY'RE 1336 00:46:48,680 --> 00:46:51,720 LEAKING OUT OF THAT VESSEL. 1337 00:46:51,720 --> 00:46:54,960 AND THEY ARE DESIGNED TO BE 1338 00:46:54,960 --> 00:46:56,240 ACTIVATED BY PROTEASES THAT ARE 1339 00:46:56,240 --> 00:46:58,560 IN THE TUMOR MICROENVIRONMENT. 1340 00:46:58,560 --> 00:47:04,720 SO FOR EXAMPLE, MMP9, WHICH IS A 1341 00:47:04,720 --> 00:47:07,040 PROTEASE WHICH CAN CATALYZE THE 1342 00:47:07,040 --> 00:47:08,240 CLEAVAGE OF A PEPTIDE. 1343 00:47:08,240 --> 00:47:09,800 SO ONE COPY OF THE PROTEASE 1344 00:47:09,800 --> 00:47:11,000 COULD LIBERATE MANY, MANY 1345 00:47:11,000 --> 00:47:13,920 PEPTIDES FROM A NANOMATERIAL. 1346 00:47:13,920 --> 00:47:15,960 AND WE DESIGN THESE PEPTIDES SO 1347 00:47:15,960 --> 00:47:17,760 THAT THEY ARE RESISTANT TO 1348 00:47:17,760 --> 00:47:19,520 DEGRADATION IN THE BLOODSTREAM, 1349 00:47:19,520 --> 00:47:22,320 WE DO THAT BY MAKING THEM OUT OF 1350 00:47:22,320 --> 00:47:24,760 D AMINO ACIDS, AND THEN WE 1351 00:47:24,760 --> 00:47:27,640 DESIGN THEM SO THAT THEY CAN BE 1352 00:47:27,640 --> 00:47:30,560 CONCENTRATED BY THE KIDNEY INTO 1353 00:47:30,560 --> 00:47:33,520 THE URINE AFTER ABOUT ONE HOUR. 1354 00:47:33,520 --> 00:47:35,520 SO WHAT YOU FIND IS THAT ONE 1355 00:47:35,520 --> 00:47:38,920 COULD ADMINISTER THIS MATERIAL, 1356 00:47:38,920 --> 00:47:40,360 COLLECT THE URINE IN AN HOUR, 1357 00:47:40,360 --> 00:47:42,000 AND ONE WOULD HAVE THE CLEAVAGE 1358 00:47:42,000 --> 00:47:44,680 PRODUCTS ASSOCIATED WITH -- IN 1359 00:47:44,680 --> 00:47:45,800 THE TUMOR INSTEAD NOW IN THE 1360 00:47:45,800 --> 00:47:47,760 URINE SAMPLE. 1361 00:47:47,760 --> 00:47:51,920 SO SORT OF NONINVASIVE WINDOW TO 1362 00:47:51,920 --> 00:47:53,880 THE TUMOR MICROENVIRONMENT. 1363 00:47:53,880 --> 00:47:57,320 SO WE INVENTED THIS TOOL AND 1364 00:47:57,320 --> 00:47:58,560 FIRST IN VITRO, HERE'S FOR 1365 00:47:58,560 --> 00:48:00,440 EXAMPLE ONE OF THESE SENSORS 1366 00:48:00,440 --> 00:48:04,120 SENSITIVE TO THROMBIN. 1367 00:48:04,120 --> 00:48:06,640 WE THEN STARTED TO MAKE A WHOLE 1368 00:48:06,640 --> 00:48:08,200 LIBRARY OF THESE MATERIALS SO WE 1369 00:48:08,200 --> 00:48:09,920 COULD QUERY PROTEASES ACROSS 1370 00:48:09,920 --> 00:48:11,720 MANY OF THE DIFFERENT CLASSES, 1371 00:48:11,720 --> 00:48:14,200 WHEN I 1372 00:48:14,200 --> 00:48:14,920 WHAT I MENTIONED. 1373 00:48:14,920 --> 00:48:17,720 WHEN I PUT THEM IN VIVO, THEY 1374 00:48:17,720 --> 00:48:18,800 WORKED AS I DESCRIBED. 1375 00:48:18,800 --> 00:48:20,120 FOR EXAMPLE, THIS IS A MATERIAL 1376 00:48:20,120 --> 00:48:23,520 THAT'S SENSITIVE TO MMP2, AND IN 1377 00:48:23,520 --> 00:48:25,840 A MOUSE MODEL OF LIVER FIBROSIS. 1378 00:48:25,840 --> 00:48:28,240 SO THESE MATERIALS HAVE BEEN 1379 00:48:28,240 --> 00:48:29,880 ADMINISTERED INTRAVENOUSLY IN 1380 00:48:29,880 --> 00:48:31,720 OUR LIVER TARGETED, AND IN THIS 1381 00:48:31,720 --> 00:48:33,880 MOUSE MODEL OF FIBROSIS, WHERE 1382 00:48:33,880 --> 00:48:37,640 THERE'S MMP2, THE MATERIALS ARE 1383 00:48:37,640 --> 00:48:38,040 ACTIVATED. 1384 00:48:38,040 --> 00:48:39,480 YOU CAN SEE IN AN HOUR THAT THE 1385 00:48:39,480 --> 00:48:42,640 BLAH DIDDER IS LIGHTING 1386 00:48:42,640 --> 00:48:44,760 BLADDER IS LIGHTING UP AS I 1387 00:48:44,760 --> 00:48:47,800 SHOWED YOU IN THE VIDEO. 1388 00:48:47,800 --> 00:48:50,120 SO THAT'S ONE THING. 1389 00:48:50,120 --> 00:48:54,720 YOU CAN MAKE A HIGHLY SPECIFIC 1390 00:48:54,720 --> 00:48:55,920 AND SENSITIVE TEST SO WE 1391 00:48:55,920 --> 00:48:58,520 BARCODED THE SENSORS USING MASS 1392 00:48:58,520 --> 00:48:59,080 SPECTROMETRY. 1393 00:48:59,080 --> 00:49:00,720 WE MAKE DIFFERENT MATERIALS WITH 1394 00:49:00,720 --> 00:49:02,000 DIFFERENT TETHERS, AND EACH OF 1395 00:49:02,000 --> 00:49:03,920 THE TETHERS, WHEN CLEAVED, WILL 1396 00:49:03,920 --> 00:49:05,200 RELEASE A DIFFERENT BARCODE. 1397 00:49:05,200 --> 00:49:06,800 SO YOU COLLECT THE URINE, AND 1398 00:49:06,800 --> 00:49:08,920 THEN YOU CAN MASS SPEC THE URINE 1399 00:49:08,920 --> 00:49:12,760 AND THAT GLIF YOU GIVE YOU A QUANTITATIVE 1400 00:49:12,760 --> 00:49:14,960 READOUT OF EACH DIFFERENT SENSOR 1401 00:49:14,960 --> 00:49:16,600 IN VIVO. 1402 00:49:16,600 --> 00:49:16,800 OKAY. 1403 00:49:16,800 --> 00:49:17,720 THAT'S A LOT TO DIGEST, BUT THIS 1404 00:49:17,720 --> 00:49:19,000 IS BASICALLY HOW IT WORKS. 1405 00:49:19,000 --> 00:49:20,520 YOU GIVE AN ENSEMBLE OF 1406 00:49:20,520 --> 00:49:22,200 MATERIALS, THEY GO TO THE 1407 00:49:22,200 --> 00:49:23,720 MICROENVIRONMENT OF INTEREST, 1408 00:49:23,720 --> 00:49:26,760 THEY'RE ACTIVATED BY RESIDENT 1409 00:49:26,760 --> 00:49:28,840 PROTEASES, AND THE FRAGMENTS, 1410 00:49:28,840 --> 00:49:30,720 THE BARCODES, COME OUT AN HOUR 1411 00:49:30,720 --> 00:49:31,400 LATER IN THE URINE. 1412 00:49:31,400 --> 00:49:33,000 AND YOU CAN USE THIS POTENTIALLY 1413 00:49:33,000 --> 00:49:36,000 AS A WINDOW INTO BIOLOGY IN THE 1414 00:49:36,000 --> 00:49:37,520 BODY THAT WOULD BE DIFFICULT TO 1415 00:49:37,520 --> 00:49:40,800 ACCESS OTHERWISE, AND BECAUSE OF 1416 00:49:40,800 --> 00:49:43,120 THE AMPLIFICATION, WE'RE HOPEFUL 1417 00:49:43,120 --> 00:49:44,640 THIS WILL ALLOW US EARLIER 1418 00:49:44,640 --> 00:49:45,640 DETECTION OF THE DISEASE. 1419 00:49:45,640 --> 00:49:47,120 SO I'M GOING TO SKIP THE DETAILS 1420 00:49:47,120 --> 00:49:49,240 ON THIS EXAMPLE WHERE WE'VE DONE 1421 00:49:49,240 --> 00:49:51,720 IT FOR LUNG CANCER, BECAUSE I'M 1422 00:49:51,720 --> 00:49:53,480 RUNNING SHORT ON TIME. 1423 00:49:53,480 --> 00:49:56,160 AND JUST SORT OF SUMMARIZE THAT 1424 00:49:56,160 --> 00:49:58,480 THIS IS A PRETTY LARGE BODY OF 1425 00:49:58,480 --> 00:49:59,920 WORK THAT WE'VE NOW PUBLISHED, 1426 00:49:59,920 --> 00:50:01,440 AND WHAT WE'VE LEARNED IS THAT 1427 00:50:01,440 --> 00:50:03,720 THIS IS A HIGHLY SENSITIVE TOOL 1428 00:50:03,720 --> 00:50:05,040 SO FAR IN MOUSE MODELS. 1429 00:50:05,040 --> 00:50:06,560 SO IN MICE, WE CAN DETECT 1430 00:50:06,560 --> 00:50:09,840 LESIONS THAT ARE ABOUT 1431 00:50:09,840 --> 00:50:10,480 THREE CUBIC MILLIMETERS, AND SO 1432 00:50:10,480 --> 00:50:12,120 FAR THIS IS QUITE A BIT MORE 1433 00:50:12,120 --> 00:50:14,280 SENSITIVE THAN BOTH PROTEIN AND 1434 00:50:14,280 --> 00:50:17,040 CIRCULATING DNA. 1435 00:50:17,040 --> 00:50:18,040 IT'S HIGHLY SPECIFIC. 1436 00:50:18,040 --> 00:50:21,080 NOW OF COURSE ANIMALS ARE 1437 00:50:21,080 --> 00:50:23,400 VERY -- WHEN WE GET INTO HUMAN 1438 00:50:23,400 --> 00:50:24,520 POPULATIONS, WE HAVE TO SEE HOW 1439 00:50:24,520 --> 00:50:25,920 MANY PROBES WE NEED REALLY TO 1440 00:50:25,920 --> 00:50:27,480 MAKE THIS BOTH SENSITIVE AND 1441 00:50:27,480 --> 00:50:29,760 SPECIFIC, BUT SO FAR WE CAN 1442 00:50:29,760 --> 00:50:31,400 MULTIPLEX TO 19 PROBES AND WE'VE 1443 00:50:31,400 --> 00:50:32,720 BEEN ABLE TO CLASSIFY THINGS 1444 00:50:32,720 --> 00:50:37,560 VERY READILY. 1445 00:50:37,560 --> 00:50:38,760 THEN WE'VE MADE A BUNCH OF 1446 00:50:38,760 --> 00:50:40,000 DIFFERENT VERSIONS OF THESE SO 1447 00:50:40,000 --> 00:50:41,840 YOU CAN HAVE NOT JUST A MASS 1448 00:50:41,840 --> 00:50:42,800 SPEC-BASED TEST BUT AS I'LL SHOW 1449 00:50:42,800 --> 00:50:43,920 YOU IN A MINUTE, YOU CAN DO THE 1450 00:50:43,920 --> 00:50:48,360 READ YOWLT ON PAPER OR OUT ON PAPER OR BY 1451 00:50:48,360 --> 00:50:49,240 BREATHALYZER, WHICH WE THINK 1452 00:50:49,240 --> 00:50:50,320 MIGHT HAVE CLINICAL UTILITY. 1453 00:50:50,320 --> 00:50:52,920 AS BEFORE, THIS WORK IS BEING 1454 00:50:52,920 --> 00:50:56,520 TAKEN FORWARD BY A STARTUP, 1455 00:50:56,520 --> 00:50:58,640 WHICH JUST FINISHED ITS PHASE 1456 00:50:58,640 --> 00:50:59,600 1 CLINICAL TRIAL OVER THE 1457 00:50:59,600 --> 00:51:00,920 PANDEMIC AND IS POISED TO MOVE 1458 00:51:00,920 --> 00:51:03,520 FORWARD TO ACTUALLY TRY AND 1459 00:51:03,520 --> 00:51:04,520 REPLACE LIVER BIOPSY OR A 1460 00:51:04,520 --> 00:51:07,680 DISEASE CALLED NASH, 1461 00:51:07,680 --> 00:51:09,560 NON-ALCOHOLIC SEATTLE HEPATITIS. 1462 00:51:09,560 --> 00:51:11,400 SO I KNOW I WENT QUICKLY THROUGH 1463 00:51:11,400 --> 00:51:11,960 THAT EXAMPLE. 1464 00:51:11,960 --> 00:51:13,280 I JUST WANT TO TALK TO YOU A 1465 00:51:13,280 --> 00:51:15,240 LITTLE BIT ABOUT HOW ONE MIGHT 1466 00:51:15,240 --> 00:51:19,720 THINK ABOUT BUILDING ON THIS AND 1467 00:51:19,720 --> 00:51:21,360 INTERFACING WITH CLINICIANS. 1468 00:51:21,360 --> 00:51:22,560 SO IT'S POSSIBLE THAT URINE IS 1469 00:51:22,560 --> 00:51:25,320 SUCH AN AMAZING BIOFLUID THAT WE 1470 00:51:25,320 --> 00:51:26,840 COULD ENVISION MAKING A PAPER 1471 00:51:26,840 --> 00:51:28,240 DIAGNOSTIC IN THE WAY YOU'VE ALL 1472 00:51:28,240 --> 00:51:29,560 SEEN COVID DIAGNOSTICS. 1473 00:51:29,560 --> 00:51:31,120 SO IN FACT, WE HAVE THE FOURPLEX 1474 00:51:31,120 --> 00:51:32,120 VERSION OF THIS THAT WE'VE PUT 1475 00:51:32,120 --> 00:51:33,920 ON PAPER. 1476 00:51:33,920 --> 00:51:35,120 THAT WE ENVISION COULD BE USED 1477 00:51:35,120 --> 00:51:36,320 AT THE POINT OF CARE. 1478 00:51:36,320 --> 00:51:39,600 IT STILL TAKES ABOUT AN HOUR TO 1479 00:51:39,600 --> 00:51:39,840 DEVELOP. 1480 00:51:39,840 --> 00:51:41,120 SO THE OTHER THING THAT WE WERE 1481 00:51:41,120 --> 00:51:42,560 CHALLENGED TO DO BY ONE OF OUR 1482 00:51:42,560 --> 00:51:44,440 CLINICAL COLLABORATORS WAS MAKE 1483 00:51:44,440 --> 00:51:46,160 A BREATHALYZER FOR THE LUNG 1484 00:51:46,160 --> 00:51:47,520 CANCER APPLICATION. 1485 00:51:47,520 --> 00:51:49,560 SO WE'VE DONE THAT AND PUBLISHED 1486 00:51:49,560 --> 00:51:51,840 THAT A COUPLE YEARS AGO NOW, AND 1487 00:51:51,840 --> 00:51:53,520 WE'RE WORKING WITH A COMPANY IN 1488 00:51:53,520 --> 00:51:56,160 THE U.K. CALLED ALSTONE. 1489 00:51:56,160 --> 00:51:58,120 IN THIS USE CASE, WHAT'S DONE IS 1490 00:51:58,120 --> 00:52:00,040 YOU INHALE THE SENSORS, AND WHEN 1491 00:52:00,040 --> 00:52:02,000 THEY'RE ACTIVATED, INSTEAD OF 1492 00:52:02,000 --> 00:52:05,920 TURNING FOO A URINE INTO A URINE READOUT, 1493 00:52:05,920 --> 00:52:07,760 YOU EXHALE A VOLATILE, AND THE 1494 00:52:07,760 --> 00:52:09,840 VOLATILE HAS ZERO BACKGROUND 1495 00:52:09,840 --> 00:52:10,840 BECAUSE IT'S COMPLETELY 1496 00:52:10,840 --> 00:52:11,120 SYNTHETIC. 1497 00:52:11,120 --> 00:52:12,920 SO IT'S VERY SENSITIVE AND THE 1498 00:52:12,920 --> 00:52:14,200 PEAKS COME UP AT ABOUT 10 1499 00:52:14,200 --> 00:52:15,640 MINUTES, SO IT'S A 10-MINUTE 1500 00:52:15,640 --> 00:52:16,200 TEST. 1501 00:52:16,200 --> 00:52:17,720 AGAIN, WE'RE JUST GETTING 1502 00:52:17,720 --> 00:52:19,200 STARTED, BUT WE ENVISION THAT 1503 00:52:19,200 --> 00:52:20,960 THIS MIGHT BE A WAY FORWARD FOR 1504 00:52:20,960 --> 00:52:25,720 SORT OF CHANGING DIAGNOSTICS. 1505 00:52:25,720 --> 00:52:27,240 THEN THE LAST EXAMPLE I'LL GIVE 1506 00:52:27,240 --> 00:52:29,000 IS, IF ONE, IN FACT, IDENTIFIES 1507 00:52:29,000 --> 00:52:33,760 CANCER EARLY IN A PATIENT'S 1508 00:52:33,760 --> 00:52:34,600 JOURNEY, THE VERY NEXT QUESTION 1509 00:52:34,600 --> 00:52:36,240 AS A CLINICIAN, OR ONE NEXT 1510 00:52:36,240 --> 00:52:38,160 QUESTION WOULD BE TO IDENTIFY 1511 00:52:38,160 --> 00:52:39,400 WHERE THE LESIONS ARE. 1512 00:52:39,400 --> 00:52:41,560 SO WHAT'S THE TISSUE OF ORIGIN 1513 00:52:41,560 --> 00:52:44,760 AND HAS THE TUMOR SPREAD. 1514 00:52:44,760 --> 00:52:46,160 SO IN RECOGNITION OF THAT, WE 1515 00:52:46,160 --> 00:52:47,920 MADE A VERSION OF THE SENSOR 1516 00:52:47,920 --> 00:52:51,000 THAT NOT ONLY ALLOWS LONGITUDAL 1517 00:52:51,000 --> 00:52:53,560 URINARY MONITORING, BUT WHEN THE 1518 00:52:53,560 --> 00:52:55,080 URINE SIGNAL TURNS POSITIVE, YOU 1519 00:52:55,080 --> 00:52:57,520 COULD LOAD THIS MATERIAL WITH A 1520 00:52:57,520 --> 00:53:00,120 PET PROBE, SO THIS IS COPPER 64. 1521 00:53:00,120 --> 00:53:01,720 AND IN THIS CASE, THEN, YOU CAN 1522 00:53:01,720 --> 00:53:05,320 SEE THAT YOU CAN, IN THIS CASE 1523 00:53:05,320 --> 00:53:06,640 IDENTIFY LIVER METASTASES WITH 1524 00:53:06,640 --> 00:53:10,240 THE VERY SAME PROBE AFTER THE 1525 00:53:10,240 --> 00:53:10,720 URINE TEST. 1526 00:53:10,720 --> 00:53:12,680 SO THE IDEA HERE IS THAT 1527 00:53:12,680 --> 00:53:13,880 MULTIMODAL AGENTS MAY BE HELPFUL 1528 00:53:13,880 --> 00:53:15,200 TO CLINICIANS THAT ARE TRYING TO 1529 00:53:15,200 --> 00:53:21,000 MAKE DECISIONS FOR PATIENTS. 1530 00:53:21,000 --> 00:53:22,400 SO ON THE NANOSIDE, I'M SHOWING 1531 00:53:22,400 --> 00:53:26,120 YOU THAT I THINK ENSEMBLES OF 1532 00:53:26,120 --> 00:53:27,320 NANOSENSORS COULD BE USEFUL FOR 1533 00:53:27,320 --> 00:53:27,760 MONITORING DISEASE. 1534 00:53:27,760 --> 00:53:29,920 I SHOWED YOU A CASE STUDY IN 1535 00:53:29,920 --> 00:53:31,160 LUNG CANCER, AND SOME PRODUCT 1536 00:53:31,160 --> 00:53:33,560 CONCEPTS THAT WE'RE TRYING TO 1537 00:53:33,560 --> 00:53:34,680 TAKE FORWARD TO MAKE THIS USEFUL 1538 00:53:34,680 --> 00:53:39,560 FOR OUR CLINICAL COLLEAGUES. 1539 00:53:39,560 --> 00:53:41,440 I'D LIKE TO JUST CLOSE UP WITH 1540 00:53:41,440 --> 00:53:44,920 SOME THOUGHTS ABOUT HOW TOOLS 1541 00:53:44,920 --> 00:53:47,600 COULD BE USEFUL MORE BROADLY TO 1542 00:53:47,600 --> 00:53:49,320 THE FIELD, AND JUST SORT OF 1543 00:53:49,320 --> 00:53:50,520 OBSERVE THE MOMENT THAT WE'RE AT 1544 00:53:50,520 --> 00:53:52,560 IN TIME. 1545 00:53:52,560 --> 00:53:54,120 SO IN ORDER FOR THE TOOLS REALLY 1546 00:53:54,120 --> 00:53:56,280 TO MAKE AN IMPACT ON MODERN 1547 00:53:56,280 --> 00:53:56,920 MEDICINE, WE NEED DIFFERENT 1548 00:53:56,920 --> 00:53:58,120 FIELDS TO COME TOGETHER. 1549 00:53:58,120 --> 00:54:00,800 YOU NEED TO CROSS THAT BRIDGE 1550 00:54:00,800 --> 00:54:02,840 THAT WIN WAS ALLUDING TO. 1551 00:54:02,840 --> 00:54:04,280 AND IN THE EXAMPLE I'VE GIVEN 1552 00:54:04,280 --> 00:54:07,240 YOU, THE MINIATURIZATION 1553 00:54:07,240 --> 00:54:09,960 REVOLUTION AND NUCLEIC ACID 1554 00:54:09,960 --> 00:54:11,520 THERAPEUTICS AND MANY DIFFERENT 1555 00:54:11,520 --> 00:54:13,480 STRANDS OF BIOLOGY HAVE COME 1556 00:54:13,480 --> 00:54:14,840 TOGETHER, AND REALLY WE'RE 1557 00:54:14,840 --> 00:54:16,440 POISED NOW, I THINK, IN THIS 1558 00:54:16,440 --> 00:54:17,720 DECADE TO TACKLE SOME OF THE 1559 00:54:17,720 --> 00:54:19,360 HARDEST PROBLEMS IN CANCER 1560 00:54:19,360 --> 00:54:19,880 RESEARCH. 1561 00:54:19,880 --> 00:54:24,080 EARLY DETECTION, RECALCITRANT 1562 00:54:24,080 --> 00:54:24,920 TUMOR THERAPY, METASTATIC 1563 00:54:24,920 --> 00:54:25,920 DISEASE, EVEN THINKING ABOUT 1564 00:54:25,920 --> 00:54:26,920 GLOBAL ONCOLOGY. 1565 00:54:26,920 --> 00:54:30,720 SO IT A REALLY EXCITING TIME TO 1566 00:54:30,720 --> 00:54:32,520 THINK ABOUT BRIDGE BUILDING AND 1567 00:54:32,520 --> 00:54:33,240 BRINGING THINGS TOGETHER TO 1568 00:54:33,240 --> 00:54:36,160 TACKLE SOME OF THESE GRAND 1569 00:54:36,160 --> 00:54:36,480 CHALLENGES. 1570 00:54:36,480 --> 00:54:37,840 MYSELF AND MY COLLEAGUES AT MIT 1571 00:54:37,840 --> 00:54:39,280 WELCOME YOU TO COME VISIT US. 1572 00:54:39,280 --> 00:54:40,280 WE THINK ABOUT THIS ALL THE 1573 00:54:40,280 --> 00:54:40,680 TIME. 1574 00:54:40,680 --> 00:54:43,440 WE HAVE ABOUT 200 TRAINEES IN 1575 00:54:43,440 --> 00:54:45,160 OUR CENTER FOR NANOMEDICINE, 1576 00:54:45,160 --> 00:54:46,920 THINKING ABOUT THIS SORT OF 1577 00:54:46,920 --> 00:54:49,240 CONVERGENCE OF IDEAS. 1578 00:54:49,240 --> 00:54:50,960 AND THE LAST IMPORTANT 1579 00:54:50,960 --> 00:54:53,000 INGREDIENT, I THINK, FOR MAKING 1580 00:54:53,000 --> 00:54:55,120 AN IMPACT IS HAVING ALL THE 1581 00:54:55,120 --> 00:54:56,640 RIGHT PEOPLE AT THE TABLE. 1582 00:54:56,640 --> 00:54:57,800 SO THAT'S SOMETHING THAT I'VE 1583 00:54:57,800 --> 00:55:00,440 REALLY WORKED ON OVER MY CAREER, 1584 00:55:00,440 --> 00:55:03,400 AND I'LL JUST SHOW YOU SOME 1585 00:55:03,400 --> 00:55:04,600 PICTURES IN THIS LAST MINUTE OR 1586 00:55:04,600 --> 00:55:05,840 SO TO SHARE SOME OF THE THINGS 1587 00:55:05,840 --> 00:55:07,760 THAT WE DO AT MIT ALONG THESE 1588 00:55:07,760 --> 00:55:07,960 LINES. 1589 00:55:07,960 --> 00:55:09,920 SO THIS IS AN OUTREACH WORKSHOP 1590 00:55:09,920 --> 00:55:12,240 RUN BY THE SOCIETY OF WOMEN 1591 00:55:12,240 --> 00:55:13,560 ENGINEERS FOR MIDDLE SCHOOL 1592 00:55:13,560 --> 00:55:15,200 GIRLS TO BRING THEM TO MIT. 1593 00:55:15,200 --> 00:55:16,800 THESE ARE ACTUALLY MY TWO 1594 00:55:16,800 --> 00:55:17,160 DAUGHTERS. 1595 00:55:17,160 --> 00:55:19,040 THEY'RE A LITTLE BIT OLDER NOW, 1596 00:55:19,040 --> 00:55:21,440 ONE OF THEM IS IN COLLEGE. 1597 00:55:21,440 --> 00:55:23,520 THIS IS A SOCIAL MEDIA CAMPAIGN 1598 00:55:23,520 --> 00:55:25,920 WITH TWO DEPARTMENT HEADS AT 1599 00:55:25,920 --> 00:55:27,520 MIT. 1600 00:55:27,520 --> 00:55:29,400 #I LOOK LIKE AN ENGINEER, TO 1601 00:55:29,400 --> 00:55:30,520 CHANGE PERCEPTIONS OF 1602 00:55:30,520 --> 00:55:32,320 ENGINEERING. 1603 00:55:32,320 --> 00:55:34,320 THIS IS A POSTDOC PROGRAM TO 1604 00:55:34,320 --> 00:55:36,520 DEVELOP LEADERS IN OUR POSTDOC 1605 00:55:36,520 --> 00:55:38,800 COMMUNITY THAT WE RUN AND WE 1606 00:55:38,800 --> 00:55:41,920 CALL IT THE CONVERGENCE SCHOLAR 1607 00:55:41,920 --> 00:55:42,240 PROGRAM. 1608 00:55:42,240 --> 00:55:44,080 AND I'VE BEEN MOST RECENTLY 1609 00:55:44,080 --> 00:55:45,600 WORKING ON WOMEN 1610 00:55:45,600 --> 00:55:47,240 ENTREPRENEURSHIP, WOMEN FACULTY 1611 00:55:47,240 --> 00:55:48,520 ENTREPRENEURSHIP AFTER HAVING 1612 00:55:48,520 --> 00:55:50,760 COLLABORATED WITH SUSAN HOTFIELD 1613 00:55:50,760 --> 00:55:53,240 AND NANCY HOPKINS AT MIT TO NOTE 1614 00:55:53,240 --> 00:55:58,480 THAT WOMEN ARE UNDERFOUNDING 1615 00:55:58,480 --> 00:55:59,840 COMPANIES IN THE LIFE SCIENCES. 1616 00:55:59,840 --> 00:56:01,720 IF WE JUST LOOK AT MIT IN THE 1617 00:56:01,720 --> 00:56:03,000 LAST 18 YEARS, THERE COULD HAVE 1618 00:56:03,000 --> 00:56:04,840 BEEN 40 MORE COMPANIES FROM 1619 00:56:04,840 --> 00:56:06,840 WOMEN FACULTY LABS. 1620 00:56:06,840 --> 00:56:09,960 SO THIS IS AN OBSERVATION THAT 1621 00:56:09,960 --> 00:56:11,520 WE'RE SHARING, AND WE HAVE LOTS 1622 00:56:11,520 --> 00:56:13,840 OF IDEAS ABOUT HOW TO IMPROVE 1623 00:56:13,840 --> 00:56:16,720 THAT, INCLUDING SOMETHING THAT 1624 00:56:16,720 --> 00:56:18,120 I'M VERY PROUD OF THAT'S ONGOING 1625 00:56:18,120 --> 00:56:20,080 NOW CALLED THE MIT FUTURE 1626 00:56:20,080 --> 00:56:21,040 FOUNDER PRIZE COMPETITION. 1627 00:56:21,040 --> 00:56:22,920 THEY HAVE THESE NINE AMAZING 1628 00:56:22,920 --> 00:56:24,520 WOMEN PARTICIPATING. 1629 00:56:24,520 --> 00:56:25,960 AND WE'LL BE STREAMING A 1630 00:56:25,960 --> 00:56:28,560 SHOWCASE WITH THEIR PITCHES 1631 00:56:28,560 --> 00:56:31,400 ONLINE ON MAY 5TH AS THEY START 1632 00:56:31,400 --> 00:56:32,720 TO THINK ABOUT HOW TO BRING 1633 00:56:32,720 --> 00:56:35,280 THEIR IDEAS FORWARD TO PATIENTS. 1634 00:56:35,280 --> 00:56:37,440 SO WITH THAT, THANK YOU VERY 1635 00:56:37,440 --> 00:56:39,160 MUCH FOR YOUR ATTENTION. 1636 00:56:39,160 --> 00:56:39,840 HOPEFULLY I'VE CONVINCED YOU 1637 00:56:39,840 --> 00:56:42,560 THAT MAKING NEW TOOLS IS AN 1638 00:56:42,560 --> 00:56:44,200 IMPORTANT PART OF FUTURE, AND I 1639 00:56:44,200 --> 00:56:45,640 REALLY COULDN'T THANK MY LAB AND 1640 00:56:45,640 --> 00:56:47,520 MY ALUMNI AND MY COLLABORATORS 1641 00:56:47,520 --> 00:56:49,000 AND OUR FUNDING SOURCES ENOUGH. 1642 00:56:49,000 --> 00:56:52,880 THANK YOU. 1643 00:56:52,880 --> 00:56:54,000 >> SANGEETA, ON BEHALF OF 1644 00:56:54,000 --> 00:56:59,120 EVERYONE, REALLY, THANK YOU FOR 1645 00:56:59,120 --> 00:57:01,320 INTRODUCING MOST OF US TO THIS 1646 00:57:01,320 --> 00:57:04,960 EXCITING NEW WORLD OF ENORMOUS 1647 00:57:04,960 --> 00:57:07,760 POTENTIAL, GREAT EXCITEMENT AND 1648 00:57:07,760 --> 00:57:09,720 GREAT OPPORTUNITY FOR BRIGHT 1649 00:57:09,720 --> 00:57:13,480 YOUNG PEOPLE TO CONTINUE AND 1650 00:57:13,480 --> 00:57:15,080 EXPAND THIS. 1651 00:57:15,080 --> 00:57:16,960 WE HAVE SEVERAL QUESTIONS THAT 1652 00:57:16,960 --> 00:57:21,040 HAVE COME UP. 1653 00:57:21,040 --> 00:57:24,960 ARE THERE SPECIFIC PROTEASES 1654 00:57:24,960 --> 00:57:26,480 ASSOCIATED WITH SPECIFIC KINDS 1655 00:57:26,480 --> 00:57:30,640 OF TUMORS, SO THAT THE ANALYSIS 1656 00:57:30,640 --> 00:57:32,920 GIVES SOME CLUE AS TO THE 1657 00:57:32,920 --> 00:57:35,040 IDENTITY OF THE TUMOR? 1658 00:57:35,040 --> 00:57:36,200 >> YES, THIS IS A GREAT 1659 00:57:36,200 --> 00:57:37,000 QUESTION. 1660 00:57:37,000 --> 00:57:38,920 AND ONE THAT I GLOSSED OVER OUR 1661 00:57:38,920 --> 00:57:40,920 KIND OF PIPELINE. 1662 00:57:40,920 --> 00:57:43,640 SO THERE ARE TUMOR-SPECIFIC -- 1663 00:57:43,640 --> 00:57:45,280 THERE ARE BOTH TUMOR-SPECIFIC 1664 00:57:45,280 --> 00:57:46,040 PROTEASES AND THERE ARE ALSO 1665 00:57:46,040 --> 00:57:49,000 SORT OF PANCANCER PROTEASES. 1666 00:57:49,000 --> 00:57:51,480 THE WAY WE FIND THE 1667 00:57:51,480 --> 00:57:52,400 TUMOR-SPECIFIC ONES TYPICALLY IS 1668 00:57:52,400 --> 00:57:54,200 TO START WITH THE CANCER GENOME 1669 00:57:54,200 --> 00:57:56,160 ATLAS, WHICH IS A GREAT 1670 00:57:56,160 --> 00:57:57,040 RESOURCE. 1671 00:57:57,040 --> 00:57:59,320 AND JUST CLASSIFY THOSE 550. 1672 00:57:59,320 --> 00:58:00,680 SO FAR EXAMPLE, IN THE LUNG 1673 00:58:00,680 --> 00:58:02,080 CANCER MODEL THAT I SHOWED YOU, 1674 00:58:02,080 --> 00:58:04,600 WE PICKED THE TOP 20 1675 00:58:04,600 --> 00:58:08,600 DISREGULATED CANCERS, PROTEASES, 1676 00:58:08,600 --> 00:58:10,080 AND THEN ANOTHER FILTER THAT WE 1677 00:58:10,080 --> 00:58:12,920 NEEDED TO ADD WAS ACTUALLY 1678 00:58:12,920 --> 00:58:15,680 COMMON COMORBIDITIES THAT LUNG 1679 00:58:15,680 --> 00:58:16,800 CANCER PATIENTS MAY HAVE, FOR 1680 00:58:16,800 --> 00:58:18,920 EXAMPLE, IF THEY'RE SMOKERS OR 1681 00:58:18,920 --> 00:58:22,040 THEY HAVE COPD, THOSE ALSO HAVE 1682 00:58:22,040 --> 00:58:23,440 PROTEASES ASSOCIATED WITH THEM, 1683 00:58:23,440 --> 00:58:24,560 SO WE DELETE THOSE FROM THE 1684 00:58:24,560 --> 00:58:26,120 SIGNATURE SO THAT THEY'RE SORT 1685 00:58:26,120 --> 00:58:27,960 OF SPECIFIC TO, IN THIS CASE, 1686 00:58:27,960 --> 00:58:30,600 NON-SMALL CELL LUNG CANCER. 1687 00:58:30,600 --> 00:58:37,320 >> ANOTHER INTERESTING QUESTION 1688 00:58:37,320 --> 00:58:39,000 IS, CAN YOU VISUALIZE PERHAPS 1689 00:58:39,000 --> 00:58:42,520 THAT NANOSENSORS BE DEVELOPED TO 1690 00:58:42,520 --> 00:58:48,080 HELP MONITOR THE PROGRESSION OF 1691 00:58:48,080 --> 00:58:48,800 TISSUE REGENERATION? 1692 00:58:48,800 --> 00:58:53,520 FOR EXAMPLE, I'M SURE YOU KNOW 1693 00:58:53,520 --> 00:58:54,520 THAT ONE OF THE BIG PROBLEMS IN 1694 00:58:54,520 --> 00:58:57,800 LIVER INJURY IS TO DECIDE 1695 00:58:57,800 --> 00:59:00,680 WHETHER A PATIENT NEEDS AN 1696 00:59:00,680 --> 00:59:02,120 EMERGENCY TRANSPLANT OR WHETHER 1697 00:59:02,120 --> 00:59:06,680 THE LIVER IS REALLY BEGINNING TO 1698 00:59:06,680 --> 00:59:07,000 REGENERATE. 1699 00:59:07,000 --> 00:59:09,080 THIS IS STILL A VERY DIFFICULT 1700 00:59:09,080 --> 00:59:11,720 QUESTION TO ANSWER. 1701 00:59:11,720 --> 00:59:14,240 DO YOU THINK THERE IS SOME 1702 00:59:14,240 --> 00:59:16,720 POSSIBLE ROLE OF NANOSENSORS IN 1703 00:59:16,720 --> 00:59:21,240 A SITUATION LIKE THAT? 1704 00:59:21,240 --> 00:59:23,080 >> I HAVEN'T THOUGHT EXACTLY 1705 00:59:23,080 --> 00:59:23,920 ABOUT THAT USE CASE. 1706 00:59:23,920 --> 00:59:25,480 SO IT WOULD BE FUN TO TALK MORE 1707 00:59:25,480 --> 00:59:26,320 ABOUT IT, WIN. 1708 00:59:26,320 --> 00:59:30,160 BUT I THINK WHAT WE'VE SEEN, FOR 1709 00:59:30,160 --> 00:59:32,120 EXAMPLE, IN JUST REJECTION, FOR 1710 00:59:32,120 --> 00:59:35,200 EXAMPLE, WHICH IS T-CELL 1711 00:59:35,200 --> 00:59:40,520 MEDIATED, BUT T-CELLS KILL BY 1712 00:59:40,520 --> 00:59:42,120 GRANZYME, AND GRANZYME ACTUALLY 1713 00:59:42,120 --> 00:59:43,280 IS A PROTEASE. 1714 00:59:43,280 --> 00:59:46,280 SO MY FORMER POSTDOC PUBLISHED A 1715 00:59:46,280 --> 00:59:47,920 VERY NICE PAPER COLLEAGUES AT 1716 00:59:47,920 --> 00:59:52,320 EMORY SHOWING THEY COULD DETECT 1717 00:59:52,320 --> 00:59:53,680 REJECTION EARLY USING A PROTEASE 1718 00:59:53,680 --> 00:59:53,920 SENSOR. 1719 00:59:53,920 --> 00:59:55,840 SO I DO THINK WITH 550 TO CHOOSE 1720 00:59:55,840 --> 00:59:57,480 FROM, IT OFTEN THE CASE THAT WE 1721 00:59:57,480 --> 01:00:02,040 CAN POINT IT AT A DISEASE. 1722 01:00:02,040 --> 01:00:04,160 >> THERE WAS ALSO A QUESTION 1723 01:00:04,160 --> 01:00:06,120 ABOUT IN STUDIES FROM THE PAST 1724 01:00:06,120 --> 01:00:08,800 WHERE PEOPLE HAVE PUT 1725 01:00:08,800 --> 01:00:17,280 HEPATOCYTES IN DIFFERENT MEDIA, 1726 01:00:17,280 --> 01:00:19,800 COLLAGEN AND WHATNOT AND PLANTED 1727 01:00:19,800 --> 01:00:23,120 THEM IN THE PERITONEUM, THAT 1728 01:00:23,120 --> 01:00:26,760 WITHIN A SHORT PERIOD OF TIME, 1729 01:00:26,760 --> 01:00:28,120 GUY PRO CYST OCCURS AND THE 1730 01:00:28,120 --> 01:00:29,720 BLOOD SUPPLY IS CHOKED OFF AND 1731 01:00:29,720 --> 01:00:33,520 THEY DON'T LIVE VERY LONG, AND I 1732 01:00:33,520 --> 01:00:38,920 GUESS THE OTHER PART OF IT IS, 1733 01:00:38,920 --> 01:00:41,840 THEY'RE SECRETING A DETERGENT 1734 01:00:41,840 --> 01:00:42,520 PRESUMABLY OF BIOACID, WHICH 1735 01:00:42,520 --> 01:00:45,800 ISN'T SO HEALTHY TO HAVE JUST 1736 01:00:45,800 --> 01:00:46,240 FLOATING AROUND. 1737 01:00:46,240 --> 01:00:52,880 SO WHAT IS THERE ABOUT YOUR 1738 01:00:52,880 --> 01:00:54,160 PREPARATIONS THAT APPARENTLY 1739 01:00:54,160 --> 01:00:55,720 THOSE EVENTS DON'T HAPPEN? 1740 01:00:55,720 --> 01:00:56,560 WHY NOT? 1741 01:00:56,560 --> 01:00:57,000 >> YEAH. 1742 01:00:57,000 --> 01:00:58,560 THAT'S A GREAT QUESTION AND 1743 01:00:58,560 --> 01:01:00,320 ACTUALLY THE -- I THINK YOU 1744 01:01:00,320 --> 01:01:01,320 KNOW, THE BILE DUCT QUESTION 1745 01:01:01,320 --> 01:01:04,720 HAUNTED ME EARLIER IN MY CAREER. 1746 01:01:04,720 --> 01:01:06,320 WE ARE TRYING TO BUILD A BILE 1747 01:01:06,320 --> 01:01:08,840 DUCT BUT I THOUGHT WE HAD TO DO 1748 01:01:08,840 --> 01:01:10,640 THAT FIRST UNTIL JIM BOIL AT 1749 01:01:10,640 --> 01:01:13,360 YALE POINTED OUT TO ME THE 1750 01:01:13,360 --> 01:01:14,480 HEPATOCYTES THAT PERSIST IN THE 1751 01:01:14,480 --> 01:01:16,080 SPLEEN WHEN WE DO THOSE 1752 01:01:16,080 --> 01:01:16,960 INJECTIONS ACTUALLY DON'T HAVE A 1753 01:01:16,960 --> 01:01:19,120 BILE DUCT EITHER AND THEY DON'T 1754 01:01:19,120 --> 01:01:21,040 BECOME CHOLESTATIC. 1755 01:01:21,040 --> 01:01:21,920 THAT GAVE ME HOPE. 1756 01:01:21,920 --> 01:01:25,520 SO ACTUALLY OUR INTRAPERITONEAL 1757 01:01:25,520 --> 01:01:26,800 HEPATOCYTES ARE DOWNREGULATING 1758 01:01:26,800 --> 01:01:29,000 THE BIOACID PRODUCTION AXIS, AND 1759 01:01:29,000 --> 01:01:31,040 THE TRANSCRIPTIONAL DATA KIND OF 1760 01:01:31,040 --> 01:01:32,160 SUPPORTS THAT, SO I THINK THAT'S 1761 01:01:32,160 --> 01:01:35,120 WHY THEY'RE NOT TOX GUYING 1762 01:01:35,120 --> 01:01:37,080 THEMSELVES WITH DETERGENT. 1763 01:01:37,080 --> 01:01:39,520 THE REASON I THINK THEY'RE NOT 1764 01:01:39,520 --> 01:01:40,560 FIBROSING IS BECAUSE OUR 1765 01:01:40,560 --> 01:01:42,200 MATERIAL IS A DEGRADABLE 1766 01:01:42,200 --> 01:01:44,920 MATERIAL, SO ONCE THE 1767 01:01:44,920 --> 01:01:46,280 HEPATOCYTES GET VASCULARIZED, 1768 01:01:46,280 --> 01:01:47,480 THE MATERIAL DEGRADES OVER THE 1769 01:01:47,480 --> 01:01:49,320 COURSE OF A COUPLE OF WEEKS. 1770 01:01:49,320 --> 01:01:52,800 THERE'S NO FOREIGN BODY 1771 01:01:52,800 --> 01:01:54,280 REACTION. 1772 01:01:54,280 --> 01:01:57,600 >> THAT'S VERY INTERESTING. 1773 01:01:57,600 --> 01:01:59,440 WE HAVE SOME QUESTIONS ABOUT THE 1774 01:01:59,440 --> 01:02:03,360 MALARIA PROJECT. 1775 01:02:03,360 --> 01:02:07,640 IS THE HYPNOZOITE IN A SPECIAL 1776 01:02:07,640 --> 01:02:09,400 COMPARTMENT, A MEMBRANE-LIMITED 1777 01:02:09,400 --> 01:02:10,280 COMPARTMENT OR SOMETHING, AND 1778 01:02:10,280 --> 01:02:15,720 WHAT MAKES IT DIFFERENT FROM THE 1779 01:02:15,720 --> 01:02:16,960 OTHER SORT OF VACUOLES OR 1780 01:02:16,960 --> 01:02:20,240 WHATEVER YOU CALL THEM, WHERE 1781 01:02:20,240 --> 01:02:24,280 THE VIVAX IS THAT'S ACTUALLY 1782 01:02:24,280 --> 01:02:25,800 BECOME ACTIVE? 1783 01:02:25,800 --> 01:02:27,400 IS THERE SOMETHING SPECIAL ABOUT 1784 01:02:27,400 --> 01:02:30,280 THE CELL BIOLOGY OF THE HIP 1785 01:02:30,280 --> 01:02:31,680 ZOITE? 1786 01:02:31,680 --> 01:02:33,120 >> THAT'S A GREAT QUESTION. 1787 01:02:33,120 --> 01:02:35,120 SO FAR WE'VE STAINED ONLY FOR A 1788 01:02:35,120 --> 01:02:39,720 COUPLE OF MARKERS OF THE VACUOLE 1789 01:02:39,720 --> 01:02:43,560 AND SEEN NO DIFFERENCES IN THE 1790 01:02:43,560 --> 01:02:45,720 MEMBRANE AROUND THE HYPNOZOITE 1791 01:02:45,720 --> 01:02:47,440 VERSUS THE REPLICATING FORM. 1792 01:02:47,440 --> 01:02:48,840 BUT AS I SORT OF BRIEFLY ALLUDED 1793 01:02:48,840 --> 01:02:50,920 TO, IT DOES SEEM THAT THE 1794 01:02:50,920 --> 01:02:56,880 HYPNOZOITE IS MAKING PROTEASES 1795 01:02:56,880 --> 01:02:59,400 CALLED VIVOPANES. 1796 01:02:59,400 --> 01:03:01,680 THEY SEEM IMPORTANT IN DIGESTING 1797 01:03:01,680 --> 01:03:03,040 HOST PROTEINS AND MAINTAINING 1798 01:03:03,040 --> 01:03:03,360 QUIESCENCE. 1799 01:03:03,360 --> 01:03:06,920 IF YOU INHIBIT THOSE, ACTUALLY 1800 01:03:06,920 --> 01:03:08,600 THE PARASITE DIES, SO IT'S NOT 1801 01:03:08,600 --> 01:03:10,560 CLEAR TO ME IF THAT SAME PROCESS 1802 01:03:10,560 --> 01:03:12,680 IS LAPPING IN THE REPLICATING 1803 01:03:12,680 --> 01:03:14,960 FORMS. 1804 01:03:14,960 --> 01:03:15,840 >> VERY INTERESTING. 1805 01:03:15,840 --> 01:03:17,480 I SEEM TO REMEMBER BUT I MAY BE 1806 01:03:17,480 --> 01:03:19,440 WRONG ABOUT THIS, THAT THERE 1807 01:03:19,440 --> 01:03:24,240 WERE PEOPLE INFECTED WITH VIVAX 1808 01:03:24,240 --> 01:03:26,000 WHO RECOVERED FROM SEVERAL 1809 01:03:26,000 --> 01:03:29,160 EPISODES AND THEN SEEM TO BE 1810 01:03:29,160 --> 01:03:31,120 PERFECTLY NORMAL AND THEN MAYBE 1811 01:03:31,120 --> 01:03:34,200 AS LONG AS FIVE YEARS, 10 YEARS 1812 01:03:34,200 --> 01:03:35,840 LATER, FOR ONE REASON OR 1813 01:03:35,840 --> 01:03:38,520 ANOTHER, THEY WERE GIVEN A 1814 01:03:38,520 --> 01:03:41,720 CORTICOSTEROID FOR SOME -- 1815 01:03:41,720 --> 01:03:44,040 DISEASE AND BINGO, THE VIVAX 1816 01:03:44,040 --> 01:03:49,600 RETURNED IN ITS VARYING FORM. 1817 01:03:49,600 --> 01:03:50,840 IS THERE SOME RELATIONSHIP 1818 01:03:50,840 --> 01:03:52,680 BETWEEN THAT CLINICAL EVENT AND 1819 01:03:52,680 --> 01:03:53,920 WHAT YOU'RE DESCRIBING IN THE 1820 01:03:53,920 --> 01:03:54,720 CULTURED CELLS? 1821 01:03:54,720 --> 01:03:55,920 >> YEAH, I THINK THESE ARE THE 1822 01:03:55,920 --> 01:03:57,960 QUESTIONS WE CAN NOW ASK. 1823 01:03:57,960 --> 01:03:58,960 THE OTHER ONE I'VE BEEN -- THE 1824 01:03:58,960 --> 01:04:01,720 OTHER DATASET THAT'S REALLY 1825 01:04:01,720 --> 01:04:02,680 FASCINATING IS THAT FROM OLD 1826 01:04:02,680 --> 01:04:05,400 SORT OF MILITARY MOVEMENTS THAT 1827 01:04:05,400 --> 01:04:09,760 VIVAX CLEARED SOLDIERS WHO WERE 1828 01:04:09,760 --> 01:04:15,360 INFECTED WITH VALCIFIRIM, WOULD 1829 01:04:15,360 --> 01:04:17,440 HAVE THEIR VIVAX FLARE. 1830 01:04:17,440 --> 01:04:19,720 SO THERE'S A LOT OF INTERESTING 1831 01:04:19,720 --> 01:04:21,160 HYPOTHESES I THINK WE COULD NOW 1832 01:04:21,160 --> 01:04:24,080 TEST. 1833 01:04:24,080 --> 01:04:24,760 >> WELL, THAT'S VERY 1834 01:04:24,760 --> 01:04:26,320 INTERESTING. 1835 01:04:26,320 --> 01:04:32,440 WHY DID YOU PICK VIVAX AND NOT 1836 01:04:32,440 --> 01:04:34,960 VALCIPIR MI OR ANY OF THE 1837 01:04:34,960 --> 01:04:35,200 OTHERS? 1838 01:04:35,200 --> 01:04:36,600 IS THERE SOME REASON? 1839 01:04:36,600 --> 01:04:38,120 >> WE WANTED TO DO ANY OF THE 1840 01:04:38,120 --> 01:04:41,520 HUMAN MALARIAS, SO ACTUALLY WE 1841 01:04:41,520 --> 01:04:45,000 ACHIEVED VALCIPIRIM FIRST, BUT 1842 01:04:45,000 --> 01:04:47,080 WE WANTED TO DO -- WE ALWAYS ARE 1843 01:04:47,080 --> 01:04:49,160 TRYING TO DO SOMETHING WITH OUR 1844 01:04:49,160 --> 01:04:52,800 TOOLS THAT HAD NEVER BEEN DONE, 1845 01:04:52,800 --> 01:04:53,720 THAT NO OTHER TECHNIQUE COULD 1846 01:04:53,720 --> 01:04:54,240 APPROACH. 1847 01:04:54,240 --> 01:04:56,920 SO WE DID THAT AND OTHERS HAD 1848 01:04:56,920 --> 01:04:58,520 DONE IT ACTUALLY PREVIOUSLY AND 1849 01:04:58,520 --> 01:05:00,840 WE SORT OF MADE IT HIGH 1850 01:05:00,840 --> 01:05:02,480 THROUGHPUT, BUT NOBODY HAD EVER 1851 01:05:02,480 --> 01:05:02,760 DONE VIVAX. 1852 01:05:02,760 --> 01:05:04,320 I HAVE TO SAY, IT WAS INCREDIBLY 1853 01:05:04,320 --> 01:05:04,600 DIFFICULT. 1854 01:05:04,600 --> 01:05:05,640 IT TOOK US 10 YEARS. 1855 01:05:05,640 --> 01:05:07,720 BUT THAT'S WHY WE CLOSE TO DO IT 1856 01:05:07,720 --> 01:05:09,040 BECAUSE WE FELT LIKE WE REALLY 1857 01:05:09,040 --> 01:05:11,000 COULD OPEN SOME NEW BIOLOGY 1858 01:05:11,000 --> 01:05:12,280 DOORS THERE. 1859 01:05:12,280 --> 01:05:14,080 >> HOW DOES -- ANOTHER QUESTION, 1860 01:05:14,080 --> 01:05:19,080 HOW DOES THE PARASITE GET FROM 1861 01:05:19,080 --> 01:05:23,960 THE BLOOD THROUGH THE SIGH SINUSOIDAL 1862 01:05:23,960 --> 01:05:26,400 IF HENESS TRAL BARRIER TO THE 1863 01:05:26,400 --> 01:05:26,720 HEPATOCYTE? 1864 01:05:26,720 --> 01:05:33,280 >> SO THE SPORE ZOITE TRAVERSES 1865 01:05:33,280 --> 01:05:35,280 ALONG FREU THE FENESTRATED 1866 01:05:35,280 --> 01:05:37,560 EPITHELIUM AND IT GLIDES, THIS 1867 01:05:37,560 --> 01:05:40,880 HAS BEEN STUDIED BY MARIA MODA 1868 01:05:40,880 --> 01:05:41,600 AND OTHERS. 1869 01:05:41,600 --> 01:05:42,920 IT ACTUALLY CAN BREAK THROUGH 1870 01:05:42,920 --> 01:05:44,040 SEVERAL HEPATOCYTES BEFORE IT 1871 01:05:44,040 --> 01:05:45,120 SETS UP SHOP IN ONE. 1872 01:05:45,120 --> 01:05:47,080 SO IT HAS A GLIDING MECHANISM. 1873 01:05:47,080 --> 01:05:49,480 YOU CAN ACTUALLY SEE IT IN CULL 1874 01:05:49,480 --> 01:05:53,280 FEWER IF YOU PUT 1875 01:05:53,280 --> 01:05:54,480 CULTURE, IF YOU PUT A SPORE SEW 1876 01:05:54,480 --> 01:05:57,440 IETD ON A GLASS SLIDE, IT WILL 1877 01:05:57,440 --> 01:05:59,120 LEAVE THESE LITTLE SPIRALS. 1878 01:05:59,120 --> 01:06:01,720 >> BUT ISN'T IT TOO BIG TO GO 1879 01:06:01,720 --> 01:06:02,320 THROUGH THE -- 1880 01:06:02,320 --> 01:06:05,000 >> IT IS, IT IS BIG. 1881 01:06:05,000 --> 01:06:08,720 >> LIKE 100-NANOMETERS AT BEST. 1882 01:06:08,720 --> 01:06:09,960 >> THAT'S A GOOD QUESTION. 1883 01:06:09,960 --> 01:06:11,480 SO FOR A WHILE, THERE WAS A 1884 01:06:11,480 --> 01:06:16,080 THEORY THAT THEY WERE ACTUALLY 1885 01:06:16,080 --> 01:06:18,480 FIRST INVADING KUFER CELLS AND 1886 01:06:18,480 --> 01:06:20,760 THEY WERE SHEPPARDING ACROSS THE 1887 01:06:20,760 --> 01:06:21,120 SINUSOID. 1888 01:06:21,120 --> 01:06:22,520 I THINK THERE'S DATA ON BOTH 1889 01:06:22,520 --> 01:06:23,920 SIDES OF THAT, AND ONLY IN 1890 01:06:23,920 --> 01:06:25,240 RODENTS, SO I'M NOT SURE ANYONE 1891 01:06:25,240 --> 01:06:29,840 IS CONVINCED THAT THE KUFER 1892 01:06:29,840 --> 01:06:30,560 CELLS ARE REQUIRED. 1893 01:06:30,560 --> 01:06:34,640 >> DO YOU HAVE KUFER CELLS IN 1894 01:06:34,640 --> 01:06:35,240 YOUR OPERATION? 1895 01:06:35,240 --> 01:06:35,800 >> I DON'T. 1896 01:06:35,800 --> 01:06:36,920 BUT I WILL SAY THAT OUR 1897 01:06:36,920 --> 01:06:38,120 INFECTION RATES ARE VERY LOW 1898 01:06:38,120 --> 01:06:39,760 COMPARED TO WHAT YOU EXPECT. 1899 01:06:39,760 --> 01:06:42,080 WE KNOW THAT VERY FEW -- I MEAN, 1900 01:06:42,080 --> 01:06:43,720 ONE PARASITE CAN CAUSE A 1901 01:06:43,720 --> 01:06:44,920 PRODUCTIVE INFECTION, AND IN 1902 01:06:44,920 --> 01:06:48,000 OURS, WE PUT THOUSANDS OF 1903 01:06:48,000 --> 01:06:49,440 PARASITES IN SO THE EFFICIENCY 1904 01:06:49,440 --> 01:06:54,560 IS MUCH LOWER. 1905 01:06:54,560 --> 01:06:57,160 >> SO HERE'S A PROVOCATIVE 1906 01:06:57,160 --> 01:07:03,080 QUESTION FOR YOU. 1907 01:07:03,080 --> 01:07:05,120 WHAT DO YOU THINK THE NEXT 1908 01:07:05,120 --> 01:07:06,680 DEVELOPMENT IN SEMICONDUCTORS IS 1909 01:07:06,680 --> 01:07:14,520 GOING TO BE THAT'S GOING TO 1910 01:07:14,520 --> 01:07:15,520 INFLUENCE WORK SUCH AS WHAT 1911 01:07:15,520 --> 01:07:17,560 YOU'RE DOING. 1912 01:07:17,560 --> 01:07:19,760 WHERE DO YOU THINK THAT WHOLE 1913 01:07:19,760 --> 01:07:21,120 FIELD -- I MEAN, WE'VE GOTTEN 1914 01:07:21,120 --> 01:07:26,560 DOWN TO THE POINT NOW OF 1915 01:07:26,560 --> 01:07:34,920 NANOMETERS, MY KNEE CHIPS. 1916 01:07:34,920 --> 01:07:35,360 MINI CHIPS. 1917 01:07:35,360 --> 01:07:37,520 WHAT DO YOU SEE HAPPENING NEXT 1918 01:07:37,520 --> 01:07:38,520 HAPPENING IN THAT FIELD THAT 1919 01:07:38,520 --> 01:07:40,520 SEEMS TO BE DRAMATICALLY MOVING 1920 01:07:40,520 --> 01:07:41,040 ALL OVER THE WORLD? 1921 01:07:41,040 --> 01:07:42,160 >> THAT'S A GOOD QUESTION. 1922 01:07:42,160 --> 01:07:43,520 I MEAN, I THINK WHAT'S 1923 01:07:43,520 --> 01:07:45,600 INTERESTING NOW IS NOT JUST THE 1924 01:07:45,600 --> 01:07:48,280 ADVANCEMENTS THAT WILL HELP IN 1925 01:07:48,280 --> 01:07:52,240 HARDWARE, AND SO THE MAIN WAYS 1926 01:07:52,240 --> 01:07:53,560 THE FIELD IS THINKING ABOUT IT 1927 01:07:53,560 --> 01:07:55,320 IS TO MAKE THREE-DIMENSIONAL 1928 01:07:55,320 --> 01:07:57,520 COMPUTERS, SO INSTEAD OF 2D, 3D, 1929 01:07:57,520 --> 01:07:59,560 AND THEN ALSO QUANTUM COMPUTING, 1930 01:07:59,560 --> 01:08:00,680 WHICH IS A COMPLETELY DIFFERENT 1931 01:08:00,680 --> 01:08:03,840 WAY OF DOING COMPUTATION. 1932 01:08:03,840 --> 01:08:05,000 BUT THE OTHER REALLY INTERESTING 1933 01:08:05,000 --> 01:08:06,480 THING NOW IS THAT IT'S NOT JUST 1934 01:08:06,480 --> 01:08:09,400 HARDWARE, IT'S ALSO WHAT 1935 01:08:09,400 --> 01:08:10,600 COMPUTATION ENABLES US IN 1936 01:08:10,600 --> 01:08:11,840 BIOLOGY. 1937 01:08:11,840 --> 01:08:13,520 AND SO THAT -- I MEAN, JUST FOR 1938 01:08:13,520 --> 01:08:14,960 EXAMPLE THE SINGLE CELL DATA, WE 1939 01:08:14,960 --> 01:08:18,800 COULDN'T HAVE DONE THAT KIND OF 1940 01:08:18,800 --> 01:08:19,920 ANALYSIS 10 YEARS AGO, JUST 1941 01:08:19,920 --> 01:08:21,200 BECAUSE OF THE SHEER VOLUME OF 1942 01:08:21,200 --> 01:08:22,840 THE DATA OR THE MACHINE LEARNING 1943 01:08:22,840 --> 01:08:24,720 IN OUR DIAGNOSTIC SIGNATURES. 1944 01:08:24,720 --> 01:08:28,120 SO I THINK WHAT'S COMING NOW IN 1945 01:08:28,120 --> 01:08:30,600 THIS CHAPTER IS MACHINE LEARNING 1946 01:08:30,600 --> 01:08:32,040 AND ARTIFICIAL INTELLIGENCE ARE 1947 01:08:32,040 --> 01:08:36,600 REALLY CHANGING THE WAY WE HAS 1948 01:08:36,600 --> 01:08:37,840 HANDLE DATA AS BIOLOGISTS 1949 01:08:37,840 --> 01:08:39,120 BECAUSE THERE'S MORE DATA THAN 1950 01:08:39,120 --> 01:08:40,440 WE CAN COMPREHEND SO WE NEED 1951 01:08:40,440 --> 01:08:42,720 THOSE TOOLS. 1952 01:08:42,720 --> 01:08:43,720 >> WELL, IT WOULD BE VERY 1953 01:08:43,720 --> 01:08:46,560 EXCITING TO SEE WHAT'S GOING TO 1954 01:08:46,560 --> 01:08:49,960 HAPPEN IN THE NEXT YEARS TO PUSH 1955 01:08:49,960 --> 01:08:51,280 THIS FURTHER. 1956 01:08:51,280 --> 01:08:52,360 LISTEN, ON BEHALF OF EVERYBODY, 1957 01:08:52,360 --> 01:08:55,000 WE WANT TO REALLY THANK YOU 1958 01:08:55,000 --> 01:08:56,640 ENORMOUSLY, AND LOOK FORWARD TO 1959 01:08:56,640 --> 01:08:59,280 SEEING YOU IN THE NEAR FUTURE. 1960 01:08:59,280 --> 01:09:00,040 >> THANK YOU. 1961 01:09:00,040 --> 01:09:02,200 >> SO THANKS AGAIN, AND WE 1962 01:09:02,200 --> 01:09:03,080 GREATLY APPRECIATE YOU SPENDING 1963 01:09:03,080 --> 01:09:06,920 YOUR TIME GIVING THIS COMBINED 1964 01:09:06,920 --> 01:09:08,520 WALS DEMYSTIFYING SESSION. 1965 01:09:08,520 --> 01:09:09,880 IT WAS SUPERB. 1966 01:09:09,880 --> 01:09:10,480 >> THANK YOU. 1967 01:09:10,480 --> 01:09:11,480 IT WAS GREAT TO SPEND THE 1968 01:09:11,480 --> 01:09:12,920 AFTERNOON WITH YOU. 1969 01:09:12,920 --> 01:09:14,720 AS ALWAYS. 1970 01:09:14,720 --> 00:00:00,000 >> YES, THANK YOU, EVERYONE.