1 00:00:07,273 --> 00:00:08,374 >> OKAY, THANKS FOR COMING. 2 00:00:08,374 --> 00:00:11,677 LET'S GET STARTED. 3 00:00:11,677 --> 00:00:13,546 I AM MIA SUN. 4 00:00:13,546 --> 00:00:14,880 IT'S MY PLEASURE TO INTRODUCED 5 00:00:14,880 --> 00:00:17,550 TO'S SPEAKER. 6 00:00:17,550 --> 00:00:20,719 BUT BEFORE I FORGET, TODAY'S 7 00:00:20,719 --> 00:00:23,856 CME CODE IS 5016. 8 00:00:23,856 --> 00:00:25,991 -- 50116. 9 00:00:25,991 --> 00:00:28,093 AND THE PEOPLE WATCHING THE 10 00:00:28,093 --> 00:00:31,730 TALK ON VIDEOCAST CAN SUBMIT 11 00:00:31,730 --> 00:00:33,532 YOUR QUESTIONS ON THE BUTTON 12 00:00:33,532 --> 00:00:34,767 SEND LIVE FEEDBACK. 13 00:00:34,767 --> 00:00:35,668 YOU CAN ASK THE SPEAKER 14 00:00:35,668 --> 00:00:38,804 QUESTIONS THAT WAY. 15 00:00:38,804 --> 00:00:41,640 OKAY, SO LET ME TRY TO GIVE A 16 00:00:41,640 --> 00:00:43,576 GOOD INTRODUCTION. 17 00:00:43,576 --> 00:00:50,349 BECAUSE IT'S REALLY NOT AN EASY 18 00:00:50,349 --> 00:00:52,718 JOB TO CONDENSE WENDELL LIM'S 19 00:00:52,718 --> 00:00:53,419 ACCOMPLISHMENT INTO A SHORT 20 00:00:53,419 --> 00:00:54,186 INTRODUCTION BUT I WILL DO MY 21 00:00:54,186 --> 00:00:56,455 BEST. 22 00:00:56,455 --> 00:00:59,992 SO WENDELL LIM, DR. WENDELL LIM 23 00:00:59,992 --> 00:01:01,860 IS BUYER'S DISTINGUISHED 24 00:01:01,860 --> 00:01:06,165 PROFESSOR AT U.C. SAN 25 00:01:06,165 --> 00:01:08,968 FRANCISCO, SCIENTIST OF 26 00:01:08,968 --> 00:01:12,237 MOLECULAR, HE GOT BACHELOR'S 27 00:01:12,237 --> 00:01:14,006 HARVARD IN CHEMISTRY. 28 00:01:14,006 --> 00:01:16,141 POSTDOC AT YALE. 29 00:01:16,141 --> 00:01:17,610 ALSO IN BIO PHYSICS AND 30 00:01:17,610 --> 00:01:19,578 BIOCHEMISTRY. 31 00:01:19,578 --> 00:01:21,246 HE JOINED U.C. SAN FRANCISCO IN 32 00:01:21,246 --> 00:01:22,848 1996. 33 00:01:22,848 --> 00:01:24,717 SINCE THEN HE HAS TAKEN 34 00:01:24,717 --> 00:01:27,119 NUMEROUS LEADERSHIP POSITIONS 35 00:01:27,119 --> 00:01:28,754 INCLUDING THE DIRECTOR OF U.C. 36 00:01:28,754 --> 00:01:30,389 SAN FRANCISCO CENTER FOR 37 00:01:30,389 --> 00:01:32,491 SYSTEMS AND SYNTHETIC BIOLOGY, 38 00:01:32,491 --> 00:01:34,660 ONE OF THE NIH CENTERS IN 39 00:01:34,660 --> 00:01:37,396 SYSTEMS BIOLOGY UNTIL 2019. 40 00:01:37,396 --> 00:01:40,165 SINCE 2020 HE HAS BEEN THE 41 00:01:40,165 --> 00:01:41,600 DIRECTOR OF CELL DESIGN 42 00:01:41,600 --> 00:01:44,370 INSTITUTE, AND ALSO DIRECTOR OF 43 00:01:44,370 --> 00:01:45,504 CENTER FOR SYNTHETIC 44 00:01:45,504 --> 00:01:46,105 IMMUNOLOGY, BOTH AT U.C. SAN 45 00:01:46,105 --> 00:01:48,107 FRANCISCO. 46 00:01:48,107 --> 00:01:49,742 AND BEYOND U.C. SAN FRANCISCO 47 00:01:49,742 --> 00:01:54,113 HE HAS BEEN REALLY SERVING THE 48 00:01:54,113 --> 00:01:56,715 ENTIRE COMMUNITY OF PEOPLE WHO 49 00:01:56,715 --> 00:01:58,350 ARE DOING QUANTITATIVE SYSTEMS 50 00:01:58,350 --> 00:02:00,719 BIOLOGY AND SYNTHETIC BIOLOGY 51 00:02:00,719 --> 00:02:03,389 IN THIS ANNUAL CONCERT SERIES 52 00:02:03,389 --> 00:02:06,158 WE CALL WINTER Q BIO. 53 00:02:06,158 --> 00:02:07,359 A LONG TIME CO-ORGANIZER IN 54 00:02:07,359 --> 00:02:09,728 THAT CONFERENCE SERIES. 55 00:02:09,728 --> 00:02:11,964 WENDELL IS REALLY A PIONEER IN 56 00:02:11,964 --> 00:02:13,599 SYNTHETIC BIOLOGY APPROACHES 57 00:02:13,599 --> 00:02:16,902 AND HE HAS OPENED MANY MULTIPLE 58 00:02:16,902 --> 00:02:18,303 DIFFERENT RESEARCH AVENUES. 59 00:02:18,303 --> 00:02:19,605 SO I WILL JUST TRY TO COVER A 60 00:02:19,605 --> 00:02:24,910 LITTLE BIT HERE. 61 00:02:24,910 --> 00:02:26,345 SO HIS APPROACHES TO 62 00:02:26,345 --> 00:02:27,279 ENGINEERING CELLS IS REALLY 63 00:02:27,279 --> 00:02:34,253 COOL IN THE SENSE YOU BASICALLY 64 00:02:34,253 --> 00:02:35,220 TELL LYMPHOCYTES TO TELL 65 00:02:35,220 --> 00:02:37,556 INSTRUCTIONS LIKE IF YOU SEE A 66 00:02:37,556 --> 00:02:39,458 AND B, DO, C AND D. 67 00:02:39,458 --> 00:02:41,527 SUCH AS KILLING THE TARGET 68 00:02:41,527 --> 00:02:44,096 CELLS OR ACTIVATE SOME GENES. 69 00:02:44,096 --> 00:02:46,665 SO THESE ARE REALLY HIGH 70 00:02:46,665 --> 00:02:47,766 PRECISION THERAPEUTIC 71 00:02:47,766 --> 00:02:50,836 APPROACHES HE HAS PIONEERED. 72 00:02:50,836 --> 00:02:53,639 AND IN 2016 HE PUBLISHED NOT 73 00:02:53,639 --> 00:02:57,376 ONE, BUT THREE CELL PAPERS THAT 74 00:02:57,376 --> 00:02:58,744 REALLY DEMONSTRATE THAT THIS 75 00:02:58,744 --> 00:03:02,548 WORKS WITH THE SYSTEM THAT HE 76 00:03:02,548 --> 00:03:04,383 TERMS SYNTHETIC NOTCH 77 00:03:04,383 --> 00:03:05,117 RECEPTORS, ALSO CALLED SYN 78 00:03:05,117 --> 00:03:08,687 NOTCH SYSTEMS. 79 00:03:08,687 --> 00:03:11,223 AND IN 2022 HE PUBLISHED TWO 80 00:03:11,223 --> 00:03:19,164 PAPERS IN SCIENCE. 81 00:03:19,164 --> 00:03:22,401 ABOUT HOW CAR T-CELL PHENOTYPES 82 00:03:22,401 --> 00:03:24,536 CAN BE MANIPULATED BY MIXING 83 00:03:24,536 --> 00:03:25,471 AND MATCHING OF DIFFERENT 84 00:03:25,471 --> 00:03:26,672 MOTIFS OR DOMAINS. 85 00:03:26,672 --> 00:03:28,507 REALLY BEAUTIFUL WORK. 86 00:03:28,507 --> 00:03:32,177 HE SO FAR PUBLISHED MORE THAN 87 00:03:32,177 --> 00:03:34,179 150 PEER-REVIEWED PAPERS IN HIS 88 00:03:34,179 --> 00:03:36,215 OVER 60 PATENTS. 89 00:03:36,215 --> 00:03:39,184 AND I WAS CURIOUS TO SEE WHAT 90 00:03:39,184 --> 00:03:40,219 IS THE TOP-SIDED PAPER OUT OF 91 00:03:40,219 --> 00:03:42,721 ALL OF THIS. 92 00:03:42,721 --> 00:03:46,291 SO I FOUND IT'S ACTUALLY THIS 93 00:03:46,291 --> 00:03:53,799 CELL PAPER PUBLISHED IN 2013. 94 00:03:53,799 --> 00:03:56,301 TOGETHER WITH ACTUALLY ANOTHER 95 00:03:56,301 --> 00:04:00,239 WALS SPEAKER NEXT MONTH, 96 00:04:00,239 --> 00:04:01,173 JENNIFER DOUDNA, SHOWING CRISPR 97 00:04:01,173 --> 00:04:05,210 CAN BE MADE TO BE REVERSIBLE. 98 00:04:05,210 --> 00:04:06,345 HE DEVELOPED THIS CRISPR EYE 99 00:04:06,345 --> 00:04:09,081 METHOD IN THE PAPER. 100 00:04:09,081 --> 00:04:12,217 FOR ALL HIS ACCOMPLISHMENTS HE 101 00:04:12,217 --> 00:04:16,722 HAS RECEIVED NUMEROUS HONORS 102 00:04:16,722 --> 00:04:17,356 AND AWARDS, MANY DISTINGUISHED 103 00:04:17,356 --> 00:04:19,291 LECTURES. 104 00:04:19,291 --> 00:04:21,593 HE HAS BEEN EDITORIAL BOARD OF 105 00:04:21,593 --> 00:04:23,195 CELL AND SCIENCE. 106 00:04:23,195 --> 00:04:23,829 HOWARD HUGHES MEDICAL INSTITUTE 107 00:04:23,829 --> 00:04:26,265 INVESTIGATOR. 108 00:04:26,265 --> 00:04:30,169 AND EVEN BACK IN 2012, HE WAS 109 00:04:30,169 --> 00:04:32,805 NAMED ONE OF THE 50 PEOPLE WHO 110 00:04:32,805 --> 00:04:35,107 WILL CHANGE THE WORLD BY U.K. 111 00:04:35,107 --> 00:04:37,709 MAGAZINE WIRED. 112 00:04:37,709 --> 00:04:39,845 AND TODAY'S LECTURE, WE WILL 113 00:04:39,845 --> 00:04:42,815 SEE HOW HE CONTINUES TO REALLY 114 00:04:42,815 --> 00:04:45,050 PUSH THE BOUNDARIES, BOTH 115 00:04:45,050 --> 00:04:45,851 TECHNOLOGICALLY AND 116 00:04:45,851 --> 00:04:47,286 CONCEPTUALLY AT THE FOREFRONT 117 00:04:47,286 --> 00:04:48,754 OF SYNTHETIC BIOLOGY. 118 00:04:48,754 --> 00:04:49,988 THANK YOU SO MUCH FOR VISITING 119 00:04:49,988 --> 00:04:51,723 NIH. 120 00:04:51,723 --> 00:04:52,658 WENDELL, I WOULD LIKE TO 121 00:04:52,658 --> 00:04:53,192 WELCOME YOU. 122 00:04:53,192 --> 00:04:55,928 [ APPLAUSE ] 123 00:04:55,928 --> 00:04:57,696 >> WENDELL LIM: THANK YOU. 124 00:04:57,696 --> 00:04:59,231 CAN EVERYONE HEAR ME OKAY? 125 00:04:59,231 --> 00:05:01,767 SO THANK YOU VERY MUCH, MIA, 126 00:05:01,767 --> 00:05:03,035 FOR THAT KIND INTRODUCTION AND 127 00:05:03,035 --> 00:05:04,369 FOR INVITING ME. 128 00:05:04,369 --> 00:05:05,871 AND HELLO TO EVERYONE BOTH HERE 129 00:05:05,871 --> 00:05:09,007 IN PERSON AND ONLINE. 130 00:05:09,007 --> 00:05:11,743 SO WHAT I WOULD LIKE TO TALK 131 00:05:11,743 --> 00:05:13,846 ABOUT IS OUR EFFORTS OVER THE 132 00:05:13,846 --> 00:05:15,948 LAST SEVERAL YEARS TO TRY TO 133 00:05:15,948 --> 00:05:17,816 ASK WHETHER WE CAN ACTUALLY 134 00:05:17,816 --> 00:05:18,984 CREATE NEW BIOLOGY. 135 00:05:18,984 --> 00:05:21,954 WHAT DOES IT TAKE TO ACTUALLY 136 00:05:21,954 --> 00:05:24,556 LEARN HOW TO PROGRAM CELLS AND 137 00:05:24,556 --> 00:05:27,125 CELLS IN THEIR FUNCTION AND HOW 138 00:05:27,125 --> 00:05:29,895 CAN WE APPLY THIS TO VARIOUS 139 00:05:29,895 --> 00:05:31,330 IMPORTANT THERAPEUTIC PROBLEMS. 140 00:05:31,330 --> 00:05:32,731 HERE ARE MY DISCLOSURES. 141 00:05:32,731 --> 00:05:34,132 AND THEN WHAT I WOULD LIKE TO 142 00:05:34,132 --> 00:05:36,034 DO IS START BY TALKING ABOUT 143 00:05:36,034 --> 00:05:37,870 THIS GENERAL FIELD OF SYNTHETIC 144 00:05:37,870 --> 00:05:39,805 BIOLOGY AND HOW I THINK ABOUT 145 00:05:39,805 --> 00:05:39,972 IT. 146 00:05:39,972 --> 00:05:41,273 AND IT'S REALLY THIS IDEA OF 147 00:05:41,273 --> 00:05:43,041 LEARNING BY BUILDING. 148 00:05:43,041 --> 00:05:46,311 I THINK THAT OVER THE LAST MANY 149 00:05:46,311 --> 00:05:48,413 DECADES WITH THE ADVENT OF 150 00:05:48,413 --> 00:05:49,581 MOLECULAR BIOLOGY AND 151 00:05:49,581 --> 00:05:51,250 UNDERSTANDING THE GENE, WE HAVE 152 00:05:51,250 --> 00:05:53,285 COME TO REALIZE THAT BIOLOGY IN 153 00:05:53,285 --> 00:05:59,591 THE HIGH-LEVEL FUNCTIONS WE SEE 154 00:05:59,591 --> 00:06:03,061 IN VARIOUS ORGANISMS ARE THE 155 00:06:03,061 --> 00:06:08,734 RESULT OF A HIERARCHY OF LEVELS 156 00:06:08,734 --> 00:06:10,836 WHERE GENETIC PROGRAMS LEAD TO 157 00:06:10,836 --> 00:06:12,471 ENCODE MOLECULAR NETWORKS LEAD 158 00:06:12,471 --> 00:06:14,373 TO CELLULAR NETWORKS AND IT'S 159 00:06:14,373 --> 00:06:18,343 REALLY THE ENSEMBLE OF THESE 160 00:06:18,343 --> 00:06:20,646 THAT LEAD TO THE FUNCTIONS WE 161 00:06:20,646 --> 00:06:22,614 ARE SOEN NAM ORED OF THAT WE 162 00:06:22,614 --> 00:06:24,316 SEE IN LIVING SYSTEMS. 163 00:06:24,316 --> 00:06:25,851 RIGHT NOW IN GENERAL, THE WAY 164 00:06:25,851 --> 00:06:27,519 WE LOOK AT THESE SORTS OF 165 00:06:27,519 --> 00:06:28,687 SYSTEMS WE ARE INTERESTED IN 166 00:06:28,687 --> 00:06:30,322 PARTICULAR FUNCTION AT A HIGH 167 00:06:30,322 --> 00:06:34,559 LEVEL AND WE TEND TO TRY TO 168 00:06:34,559 --> 00:06:35,761 DECONSTRUCT AND MAP OUT THE 169 00:06:35,761 --> 00:06:37,162 GENES AND HOW DO THEY INTERACT 170 00:06:37,162 --> 00:06:38,363 WITH ONE ANOTHER. 171 00:06:38,363 --> 00:06:41,400 THIS IS FOCUSED ON TAKING THOSE 172 00:06:41,400 --> 00:06:42,567 BIOLOGICAL BEHAVIORS THAT EXIST 173 00:06:42,567 --> 00:06:44,736 AND TRYING TO UNDERSTAND THEM. 174 00:06:44,736 --> 00:06:47,606 IN A WAY, WHAT WE ARE 175 00:06:47,606 --> 00:06:48,440 INTERESTED IN SYNTHETIC 176 00:06:48,440 --> 00:06:49,708 BIOLOGY, WE ARE INTERESTED IN 177 00:06:49,708 --> 00:06:51,276 THAT PROBLEM BUT REALLY IN A 178 00:06:51,276 --> 00:06:53,679 BIGGER CONTEXT. 179 00:06:53,679 --> 00:06:54,579 MAYBE ANOTHER WAY OF PHRASING 180 00:06:54,579 --> 00:06:55,747 WHAT ARE POSSIBLE. 181 00:06:55,747 --> 00:06:57,649 WHAT ARE THINGS YOU COULD BUILD 182 00:06:57,649 --> 00:07:00,052 WITH BIOLOGICAL SYSTEMS? 183 00:07:00,052 --> 00:07:01,753 AND THAT IS IMPORTANT FROM 184 00:07:01,753 --> 00:07:05,057 SEVERAL DIFFERENT PERSPECTIVES. 185 00:07:05,057 --> 00:07:06,658 ONE IS THAT REALLY, YOU KNOW, 186 00:07:06,658 --> 00:07:09,461 IF YOU LOOK AT A BROADER SET OF 187 00:07:09,461 --> 00:07:11,363 SYSTEMS AND UNDERSTAND WHAT CAN 188 00:07:11,363 --> 00:07:17,769 ACHIEVE A CERTAIN FUNCTION, 189 00:07:17,769 --> 00:07:19,471 WHAT ARE THE GENERACIES, 190 00:07:19,471 --> 00:07:22,507 PAERNTS, YOU CAN GET A BETTER 191 00:07:22,507 --> 00:07:24,343 UNDERSTANDING OF THE RULES THAT 192 00:07:24,343 --> 00:07:26,211 GOVERN THE BEHAVIOR. 193 00:07:26,211 --> 00:07:29,548 IF YOU EXPLORE THIS SPACE OF 194 00:07:29,548 --> 00:07:31,383 USING BIOLOGIC COMPONENTS TO 195 00:07:31,383 --> 00:07:32,951 CREATE NEW SYSTEMS PROBABLY 196 00:07:32,951 --> 00:07:33,952 THERE ARE INTERESTING NEW 197 00:07:33,952 --> 00:07:36,388 BEHAVIOR S OUT THERE SOME WHICH 198 00:07:36,388 --> 00:07:37,956 COULD BE THERAPEUTICALLY USEFUL. 199 00:07:37,956 --> 00:07:40,025 WE ARE INTERESTED IN BOTH 200 00:07:40,025 --> 00:07:41,226 QUESTIONS AND EXPLORING THEM 201 00:07:41,226 --> 00:07:42,160 REALLY IN CONJUNCTION. 202 00:07:42,160 --> 00:07:44,730 ONE WAY OF THINKING ABOUT THAT, 203 00:07:44,730 --> 00:07:46,665 THE TRADITIONAL WAY, PERHAPS 204 00:07:46,665 --> 00:07:48,266 THINKING ABOUT PROBLEMS IN 205 00:07:48,266 --> 00:07:49,001 IMMUNOLOGY OR DEVELOPMENT, 206 00:07:49,001 --> 00:07:51,303 THESE ARE BOTH CASES WHERE 207 00:07:51,303 --> 00:07:53,572 SYSTEMS OF CELLS DO AMAZINGLY 208 00:07:53,572 --> 00:07:56,208 COMPLEX AND PRECISE ACTIONS. 209 00:07:56,208 --> 00:07:57,342 PERHAPS TRYING TO REPHRASE THIS 210 00:07:57,342 --> 00:07:59,011 IN A MORE GENERATIVE WAY IN 211 00:07:59,011 --> 00:08:01,113 TERMS OF HOW YOU CREATE 212 00:08:01,113 --> 00:08:02,514 FUNCTION FROM THE BOTTOM UP. 213 00:08:02,514 --> 00:08:05,584 WE COULD ASK IF WE UNDERSTAND 214 00:08:05,584 --> 00:08:07,919 THE DESIGN LOGIC OF THESE 215 00:08:07,919 --> 00:08:12,290 SYSTEMS HOW MIGHT WE BE ABLE TO 216 00:08:12,290 --> 00:08:14,359 FOR INSTANCE IN IMMUNOLOGY 217 00:08:14,359 --> 00:08:17,629 CREATE IMMUNE CELLS THAT KILL 218 00:08:17,629 --> 00:08:18,230 FOREIGN CELLS THAT NATURALLY 219 00:08:18,230 --> 00:08:19,965 INVADE. 220 00:08:19,965 --> 00:08:21,833 OR SYNTHETIC DEVELOPMENT HOW 221 00:08:21,833 --> 00:08:24,603 CAN WE PROGRAM CELLS SO THEY 222 00:08:24,603 --> 00:08:26,405 SELF ORGANIZE IN CUSTOM TISSUES 223 00:08:26,405 --> 00:08:27,939 FOR REGENERATION OR REPAIR. 224 00:08:27,939 --> 00:08:30,742 BY TAKING ON THESE SORTS OF 225 00:08:30,742 --> 00:08:32,144 PROBLEMS WE ARE TRYING TO DO 226 00:08:32,144 --> 00:08:33,979 THING THAT'S ARE USEFUL AND 227 00:08:33,979 --> 00:08:37,015 ONLY CELLS COULD DO BUT ALSO 228 00:08:37,015 --> 00:08:39,351 COULD HELP US GIVE US BIGGER 229 00:08:39,351 --> 00:08:40,519 CONTEXT FOR UNDERSTANDING THE 230 00:08:40,519 --> 00:08:42,554 PRINCIPLES AND RULES AND LOGIC 231 00:08:42,554 --> 00:08:44,256 OF BIOLOGICAL REGULATION. 232 00:08:44,256 --> 00:08:46,124 THE OTHER THING IS RIGHT NOW WE 233 00:08:46,124 --> 00:08:47,993 ARE VERY FOCUSED ON THE NOTION 234 00:08:47,993 --> 00:08:49,161 OF TRYING TO CHANGE CELLULAR 235 00:08:49,161 --> 00:08:50,595 CONVERSATIONS. 236 00:08:50,595 --> 00:08:51,696 HOW CELLS INTERACT WITH ONE 237 00:08:51,696 --> 00:08:54,599 ANOTHER AS NETWORKS. 238 00:08:54,599 --> 00:08:55,934 OF COURSE BIOLOGY OCCURS AT 239 00:08:55,934 --> 00:08:57,235 MANY DIFFERENT LEVELS. 240 00:08:57,235 --> 00:09:00,005 ONE OF THE POINTS I WANT TO 241 00:09:00,005 --> 00:09:02,374 MAKE, WE HAVE MADE AMAZING 242 00:09:02,374 --> 00:09:05,143 ADVANCES AT THE ATOMIC AND 243 00:09:05,143 --> 00:09:06,778 MOLECULAR SCALE UNDERSTANDING 244 00:09:06,778 --> 00:09:07,312 THE INTERACTIONS BETWEEN 245 00:09:07,312 --> 00:09:08,313 DIFFERENT MODULES. 246 00:09:08,313 --> 00:09:09,581 FOR EXAMPLE, THE FIELD OF 247 00:09:09,581 --> 00:09:11,616 CHEMISTRY USED TO BE ABOUT 248 00:09:11,616 --> 00:09:13,218 STUDYING INDIVIDUAL MOLECULES. 249 00:09:13,218 --> 00:09:15,887 BUT REALLY NOW WE HAVE THIS 250 00:09:15,887 --> 00:09:16,588 GREAT FUNDAMENTAL UNDERSTANDING 251 00:09:16,588 --> 00:09:18,690 HOW ORBITALS AND BONDS WORK. 252 00:09:18,690 --> 00:09:21,059 AND REALLY CHEMISTRY IS MUCH 253 00:09:21,059 --> 00:09:23,962 MORE BASED ON PRINCIPLES AND 254 00:09:23,962 --> 00:09:26,031 NOT ABOUT WHAT MOLECULES DON'T 255 00:09:26,031 --> 00:09:28,834 AND DO EXIST BUT WHAT CAN EXIST. 256 00:09:28,834 --> 00:09:29,801 LIKE THAT WE UNDERSTAND 257 00:09:29,801 --> 00:09:30,969 MOLECULES AT A BETTER LEVEL. 258 00:09:30,969 --> 00:09:36,074 BUT I THINK A LOT OF BIOLOGY WE 259 00:09:36,074 --> 00:09:39,144 LOOK AT THE HIGHER LEVEL BOILS 260 00:09:39,144 --> 00:09:40,545 DOWN TO MOLECULES ENGAGING AT 261 00:09:40,545 --> 00:09:41,780 THE CELLULAR LEVEL. 262 00:09:41,780 --> 00:09:42,514 WE ARE INTERESTED IN TRYING TO 263 00:09:42,514 --> 00:09:44,015 FOCUS ON THAT. 264 00:09:44,015 --> 00:09:45,317 WHAT WE WOULD LIKE TO BE ABLE 265 00:09:45,317 --> 00:09:47,452 TO DO IS TO DEVELOP THE FIELD 266 00:09:47,452 --> 00:09:49,988 OF CELL ENGINEERING AND CELL 267 00:09:49,988 --> 00:09:52,190 DESIGN TO BE AS FACILE WHAT WE 268 00:09:52,190 --> 00:09:58,363 CAN DO WITH TODAY'S SYNTHETIC 269 00:09:58,363 --> 00:09:58,830 CHEMISTRY OR PROTEIN 270 00:09:58,830 --> 00:10:00,765 ENGINEERING. 271 00:10:00,765 --> 00:10:02,834 THEY HAVE AMAZING CAPABILITIES 272 00:10:02,834 --> 00:10:06,505 I THINK MOLECULES BY THEMSELVES 273 00:10:06,505 --> 00:10:08,240 CAN'T HAVE, WHETHER SMALL 274 00:10:08,240 --> 00:10:13,745 MOLECULES OR BIOLOGICS. 275 00:10:13,745 --> 00:10:18,049 MOLECULES COULD HAVE PRECISE 276 00:10:18,049 --> 00:10:18,717 SPECIFICITY. 277 00:10:18,717 --> 00:10:19,885 BECAUSE THESE ARE MOLECULES 278 00:10:19,885 --> 00:10:21,286 THEY WILL GO EVERYWHERE, AND 279 00:10:21,286 --> 00:10:22,954 THE SAME GENES ARE EXPRESSED IN 280 00:10:22,954 --> 00:10:24,856 DIFFERENT CELLS YOU WILL HAVE 281 00:10:24,856 --> 00:10:26,091 SYSTEMIC CROSS REACTIONS AND 282 00:10:26,091 --> 00:10:27,659 TOXICITIES. 283 00:10:27,659 --> 00:10:29,494 CELLS, HOWEVER, THIS HAPPENS OF 284 00:10:29,494 --> 00:10:30,662 COURSE NATURALLY IN THE BODY, 285 00:10:30,662 --> 00:10:33,498 CELLS HAVE THE ABILITY TO SENSE 286 00:10:33,498 --> 00:10:34,900 AND INTEGRATE ENVIRONMENTAL 287 00:10:34,900 --> 00:10:36,067 INFORMATION TO CONTROL WHERE 288 00:10:36,067 --> 00:10:38,069 THEY GO AND WHEN THEY EXECUTE 289 00:10:38,069 --> 00:10:38,870 CERTAIN FUNCTIONS. 290 00:10:38,870 --> 00:10:41,239 CELLS CAN MIGRATE. 291 00:10:41,239 --> 00:10:42,841 THEY CAN ADHERE OR BE RETAINED 292 00:10:42,841 --> 00:10:47,112 IN CERTAIN PLACES. 293 00:10:47,112 --> 00:10:51,349 INTERACT SPECIFICALLY AND 294 00:10:51,349 --> 00:10:52,250 LOCALLY INDUCE ACTIVITIES, 295 00:10:52,250 --> 00:10:53,018 PROLIFERATION, PAYLOADS OR 296 00:10:53,018 --> 00:10:55,787 COMMUNICATION WITH OTHER CELLS. 297 00:10:55,787 --> 00:10:57,622 I WOULD ARGUE MANIPULATING 298 00:10:57,622 --> 00:10:59,324 CELLULAR AGENTS MAY BE A FAR 299 00:10:59,324 --> 00:11:01,626 MORE POWERFUL WAY TO INTERACT 300 00:11:01,626 --> 00:11:03,295 WITH DISEASES SPECIFICALLY 301 00:11:03,295 --> 00:11:06,097 COMPLEX DISEASES THAT INVOLVE 302 00:11:06,097 --> 00:11:07,532 CELLULAR ECOSYSTEMS LIKE 303 00:11:07,532 --> 00:11:08,166 CANCER, AUTOIMMUNE ORFEI BREAUX 304 00:11:08,166 --> 00:11:08,466 SIS. 305 00:11:08,466 --> 00:11:11,236 WHAT I WOULD LIKE TO TALK ABOUT 306 00:11:11,236 --> 00:11:12,304 TODAY QUICKLY IS THREE THINGS. 307 00:11:12,304 --> 00:11:14,039 ONE I WANT TO GIVE YOU AN 308 00:11:14,039 --> 00:11:17,542 INTRODUCTION TO THE TYPE OF 309 00:11:17,542 --> 00:11:18,143 SYNTHETIC BIOLOGY TOOLKIT TO 310 00:11:18,143 --> 00:11:19,878 REWIRE CELLS. 311 00:11:19,878 --> 00:11:20,912 WHAT ARE THE FUNDAMENTAL UNITS 312 00:11:20,912 --> 00:11:22,914 IF YOU WERE GOING TO ENGINEER 313 00:11:22,914 --> 00:11:24,082 CELLS WHAT ARE THE MODULES YOU 314 00:11:24,082 --> 00:11:25,483 NEED THAT WOULD GIVE YOU THE 315 00:11:25,483 --> 00:11:27,085 MOST CAPABILITIES. 316 00:11:27,085 --> 00:11:28,520 I WILL TELL YOU ABOUT SOME 317 00:11:28,520 --> 00:11:30,822 THINGS WE HAVE BEEN WORKING ON 318 00:11:30,822 --> 00:11:32,457 AND REWIRE HOW CELLS INTERACT 319 00:11:32,457 --> 00:11:32,991 WITH THEMSELVES AND THEIR 320 00:11:32,991 --> 00:11:33,658 ENVIRONMENT. 321 00:11:33,658 --> 00:11:35,994 AND THEN I WANT TO TALK ABOUT 322 00:11:35,994 --> 00:11:38,563 HOW WE CAN THEN APPLY THIS 323 00:11:38,563 --> 00:11:39,097 TOOLKIT TO TWO DIFFERENT 324 00:11:39,097 --> 00:11:39,965 PROBLEMS. 325 00:11:39,965 --> 00:11:42,767 MOSTLY I WILL TALK ABOUT 326 00:11:42,767 --> 00:11:45,070 DEVELOPING NEXT GENERATION 327 00:11:45,070 --> 00:11:47,839 IMMUNE CELL THERAPIES FOR SOLID 328 00:11:47,839 --> 00:11:49,941 TUMORS BUT BEYOND CANCER, 329 00:11:49,941 --> 00:11:51,576 INCREASED RECOGNITION, THIS 330 00:11:51,576 --> 00:11:53,245 DEVELOPMENT OF A TISSUE GPS 331 00:11:53,245 --> 00:11:54,846 SYSTEM THAT ALLOWS US TO TELL 332 00:11:54,846 --> 00:11:58,116 CELLS TO GO TO AND ONLY ACT IN 333 00:11:58,116 --> 00:12:00,685 A CERTAIN ANATOMIC ISSUE AND 334 00:12:00,685 --> 00:12:02,287 PROGRAMMING CELLS TO TREAT 335 00:12:02,287 --> 00:12:04,389 DISEASES LIKE CANCER LIKE 336 00:12:04,389 --> 00:12:04,756 AUTOIMMUNITY OR 337 00:12:04,756 --> 00:12:05,790 NEUROINFORMATION. 338 00:12:05,790 --> 00:12:07,926 AND A SHORTER PART TO TALK 339 00:12:07,926 --> 00:12:10,228 ABOUT EFFORT TO APPLY SAME TOOL 340 00:12:10,228 --> 00:12:11,863 WITH DIFFERENT PROBLEM THAT OF 341 00:12:11,863 --> 00:12:12,797 DEVELOPMENT TRYING TO 342 00:12:12,797 --> 00:12:15,333 UNDERSTAND HOW WE CAN WIRE 343 00:12:15,333 --> 00:12:17,669 CELLS TO SELF-ORGANIZE AND SELF 344 00:12:17,669 --> 00:12:18,370 PATTERN INTO VARIOUS 345 00:12:18,370 --> 00:12:19,537 ARCHITECTURES AND HOW THIS 346 00:12:19,537 --> 00:12:22,874 MIGHT BE USED TO HELP GUIDE 347 00:12:22,874 --> 00:12:25,076 STEM CELLS TO DEVELOP INTO 348 00:12:25,076 --> 00:12:27,078 SPECIFIC TISSUES OR SHAPES. 349 00:12:27,078 --> 00:12:31,750 SO LET ME FIRST TALK ABOUT THIS 350 00:12:31,750 --> 00:12:32,350 TOOLKIT FOR REWIRING CELLULAR 351 00:12:32,350 --> 00:12:32,951 NETWORKS. 352 00:12:32,951 --> 00:12:36,187 LET'S SAY WE HAVE A PROBLEM OF 353 00:12:36,187 --> 00:12:39,024 A CAR-T CELL AND WE WANT TO 354 00:12:39,024 --> 00:12:40,425 ENGINEER TO TREAT A SOLID TUMOR. 355 00:12:40,425 --> 00:12:42,527 WE NEED IT TO BE ABLE TO TALK 356 00:12:42,527 --> 00:12:44,229 TO THE TUMOR, RECOGNIZE IT, 357 00:12:44,229 --> 00:12:46,264 HAVE A CONVERSATION, TALK TO 358 00:12:46,264 --> 00:12:48,566 THE STROMA, AS WELL AS OTHER 359 00:12:48,566 --> 00:12:51,136 IMMUNE CELLS IN THE ENDOGENOUS 360 00:12:51,136 --> 00:12:53,271 IMMUNE SYSTEM BUT ALSO AMONGST 361 00:12:53,271 --> 00:12:54,072 THEMSELVES IN AUTOCRATIC SORT 362 00:12:54,072 --> 00:12:54,906 OF WAYS. 363 00:12:54,906 --> 00:12:56,775 IF WE WANT TO DO THAT WHAT ARE 364 00:12:56,775 --> 00:12:59,110 THE WORDS WE NEED TO WRITE NEW 365 00:12:59,110 --> 00:13:01,680 CELLULAR PROGRAMS TO CHANGE THE 366 00:13:01,680 --> 00:13:03,081 RELATIONSHIPS AND CONVERSATIONS 367 00:13:03,081 --> 00:13:04,249 THESE CELLS HAVE, IDEALLY WE 368 00:13:04,249 --> 00:13:07,052 WOULD LIKE TO, LIKE WITH THIS 369 00:13:07,052 --> 00:13:08,520 DRY ERASE MARKER PENCIL IN NEW 370 00:13:08,520 --> 00:13:09,854 THINGS AND ASK HOW DOES THAT 371 00:13:09,854 --> 00:13:10,655 CHANGE THE BEHAVIOR OF THE NEW 372 00:13:10,655 --> 00:13:11,956 SYSTEM. 373 00:13:11,956 --> 00:13:13,625 WE WANT TO BE ABLE TO DO THAT 374 00:13:13,625 --> 00:13:17,829 AND WE WANT TO HAVE GENETICALLY 375 00:13:17,829 --> 00:13:21,132 ENCODED COMMANDS THAT COULD 376 00:13:21,132 --> 00:13:21,599 PROGRAM NEW CELLULAR 377 00:13:21,599 --> 00:13:23,735 INPUT/OUTPUT RELATIONSHIPS. 378 00:13:23,735 --> 00:13:25,170 THIS IS STILL DIFFICULT BUT 379 00:13:25,170 --> 00:13:26,538 FINITE QUESTION, WE WOULD LIKE 380 00:13:26,538 --> 00:13:28,640 A CELLULAR NODE TO ENGINEER TO 381 00:13:28,640 --> 00:13:31,643 DETECT A NEW INPUT LIKE XYZ, 382 00:13:31,643 --> 00:13:32,344 SOMETHING OUTSIDE ITS 383 00:13:32,344 --> 00:13:35,880 ENVIRONMENT, HAVE THAT TURN ON 384 00:13:35,880 --> 00:13:38,683 A NUMBER OF CANONICAL 385 00:13:38,683 --> 00:13:39,851 RESPONSES, PRODUCING SECRETED 386 00:13:39,851 --> 00:13:41,953 SIGNAL OR RECEPTOR TO SEND 387 00:13:41,953 --> 00:13:43,054 SOMETHING OR CHANGE SHAPE OR 388 00:13:43,054 --> 00:13:44,522 DIVIDE AND GROW. 389 00:13:44,522 --> 00:13:45,457 CLASSICAL RESPONSES WE WOULD 390 00:13:45,457 --> 00:13:46,891 LIKE TO BE ABLE TO HAVE AS 391 00:13:46,891 --> 00:13:49,127 OUTPUTS. 392 00:13:49,127 --> 00:13:50,495 SO WHAT ARE SOME OF THESE 393 00:13:50,495 --> 00:13:52,097 GENETIC COMMANDS? 394 00:13:52,097 --> 00:14:01,406 MANY OF YOU ARE PROBABLY 395 00:14:01,406 --> 00:14:04,442 FAMILIAR WITH CHIMERIC -- CAR. 396 00:14:04,442 --> 00:14:07,846 BASICALLY IT TAKES THE 397 00:14:07,846 --> 00:14:10,882 INTRACELLULAR PARTS OF THE TCR 398 00:14:10,882 --> 00:14:11,516 COMBINED WITH SIGNATORY 399 00:14:11,516 --> 00:14:13,918 RECEPTORS BUT PUTS ON THE 400 00:14:13,918 --> 00:14:16,287 OUTSIDE NEW ANTIBODY FOR A 401 00:14:16,287 --> 00:14:18,390 PARTICULAR ANTIGEN. 402 00:14:18,390 --> 00:14:20,024 THAT ALLOWS US TO REDIRECT TO A 403 00:14:20,024 --> 00:14:22,093 CELL THAT HAS THIS NEW ANTIGEN. 404 00:14:22,093 --> 00:14:25,830 SO IT SHOWS HOW YOU CAN 405 00:14:25,830 --> 00:14:28,266 REPROGRAM THAT OUTPUT TO LINK 406 00:14:28,266 --> 00:14:30,301 IT TO ENDOGENOUS OUTPUT. 407 00:14:30,301 --> 00:14:31,703 HERE ARE THINGS WE HAVE 408 00:14:31,703 --> 00:14:32,904 DEVELOPED AND ARE WORKING ON, 409 00:14:32,904 --> 00:14:35,707 ONE I WILL GO INTO MORE DETAIL, 410 00:14:35,707 --> 00:14:38,309 SYNTHETIC NOTCH SYSTEM. 411 00:14:38,309 --> 00:14:40,145 THAT'S THE WAY WE COULD CHANGE 412 00:14:40,145 --> 00:14:45,650 THE OUTSIDE WITH SINGLE CHAIN 413 00:14:45,650 --> 00:14:50,021 ANTIBODY, WHAT IT DOES, IT 414 00:14:50,021 --> 00:14:50,989 RELEASES TRANSCRIPTION ALDO 415 00:14:50,989 --> 00:14:56,594 MAIN THAT GOES INTO THE NUCLEAL 416 00:14:56,594 --> 00:14:57,462 DOMAIN. 417 00:14:57,462 --> 00:15:01,132 SO IT'S A NEW WAY TO PUT A NEW 418 00:15:01,132 --> 00:15:02,567 INPUT BUT HAVE ALMOST ANYTHING 419 00:15:02,567 --> 00:15:04,302 AS AN OUTPUT THAT WE CAN ENCODE 420 00:15:04,302 --> 00:15:05,870 GENETICALLY. 421 00:15:05,870 --> 00:15:08,373 IT'S VERY, VERY FLEXIBLE AS AN 422 00:15:08,373 --> 00:15:08,907 INFORMATION TRANSMISSION 423 00:15:08,907 --> 00:15:10,408 MODALITY. 424 00:15:10,408 --> 00:15:11,576 AND THEN SOME OTHER THINGS, 425 00:15:11,576 --> 00:15:19,851 WHAT I WILL CALL SYNTHETIC CELL 426 00:15:19,851 --> 00:15:22,253 ADHESION MOLECULES, SYNCAMS. 427 00:15:22,253 --> 00:15:26,524 WHAT KIND OF INTERFACE BY 428 00:15:26,524 --> 00:15:30,762 CHANGING THE INTRACELLULAR 429 00:15:30,762 --> 00:15:31,262 DOMAINS AND CHANGE THE 430 00:15:31,262 --> 00:15:37,502 CYTOSKELETON. 431 00:15:37,502 --> 00:15:41,573 ENGINEERED CHEMOKINE SYSTEM. 432 00:15:41,573 --> 00:15:42,974 GIVE YOU LONG-TERM MEMORY AND 433 00:15:42,974 --> 00:15:44,142 FATE BIFURCATION. 434 00:15:44,142 --> 00:15:46,744 I WON'T TALK ABOUT TODAY. 435 00:15:46,744 --> 00:15:47,779 LET'S GO OVER THE SYN NOTCH 436 00:15:47,779 --> 00:15:52,951 SYSTEM. 437 00:15:52,951 --> 00:15:56,020 THE NATURAL NOTCH RECEPTOR 438 00:15:56,020 --> 00:15:58,590 DETECTS SIGNAL DELTA ON A 439 00:15:58,590 --> 00:16:00,291 NEIGHBORING CELL, THIS 440 00:16:00,291 --> 00:16:02,627 MECHANICAL FORCE LEADS TO 441 00:16:02,627 --> 00:16:05,563 CLEAVAGE AND INTRACELLULAR KETS 442 00:16:05,563 --> 00:16:09,033 CUT OFF AND REGULATES 443 00:16:09,033 --> 00:16:13,137 TRANSCRIPTION OF VARIOUS GENES. 444 00:16:13,137 --> 00:16:15,273 WE COULD RECOGNIZE ARBITRARY 445 00:16:15,273 --> 00:16:18,309 MOLECULE X ON THE OUTSIDE WORLD. 446 00:16:18,309 --> 00:16:19,244 PUT TRANSCRIPTION FACTOR ON THE 447 00:16:19,244 --> 00:16:20,411 INSIDE. 448 00:16:20,411 --> 00:16:22,514 THIS COULD TURN ON WHATEVER 449 00:16:22,514 --> 00:16:24,182 GENES, WHY WE PUT BEYOND THAT 450 00:16:24,182 --> 00:16:25,517 RESPONSIVE PROMOTER. 451 00:16:25,517 --> 00:16:26,751 SO THIS ALLOWS US TO CHANGE 452 00:16:26,751 --> 00:16:28,620 WHAT WE DETECT IN THE 453 00:16:28,620 --> 00:16:29,754 ENVIRONMENT AND CONTROL ALSO 454 00:16:29,754 --> 00:16:32,390 WHAT THE CELLULAR RESPONSE IS. 455 00:16:32,390 --> 00:16:34,993 MOREOVER, WE HAVE SHOWN THAT WE 456 00:16:34,993 --> 00:16:36,828 CAN CHANGE THE OUTSIDES, HAVE 457 00:16:36,828 --> 00:16:37,996 DIFFERENT KIND OF RECOGNITION 458 00:16:37,996 --> 00:16:40,064 HEADS AND BY THE SAME TOKEN WE 459 00:16:40,064 --> 00:16:41,699 CAN ALSO CHANGE THE 460 00:16:41,699 --> 00:16:43,801 INTRACELLULAR PART AND PUT ON 461 00:16:43,801 --> 00:16:45,937 DIFFERENT TRAN DESCRIPTION ALDO 462 00:16:45,937 --> 00:16:46,838 MAIN THAT'S RECOGNIZE DIFFERENT 463 00:16:46,838 --> 00:16:51,342 PROMOTERS SO WE COULD HAVE A 464 00:16:51,342 --> 00:16:51,943 WHOLE SET, ORTHOGONAL TO EACH 465 00:16:51,943 --> 00:16:52,977 OTHER. 466 00:16:52,977 --> 00:16:54,178 THESE CAN ALL FUNCTION IN THE 467 00:16:54,178 --> 00:16:56,047 SAME CELL. 468 00:16:56,047 --> 00:16:57,682 THAT'S AN INCREDIBLY FLEXIBLE 469 00:16:57,682 --> 00:17:00,285 WAY TO CHANGE RELATIONSHIPS 470 00:17:00,285 --> 00:17:00,885 BETWEEN CELLS AND INDUCE NEW 471 00:17:00,885 --> 00:17:03,588 RESPONSES. 472 00:17:03,588 --> 00:17:10,028 VERY QUICKLY ABOUT SYNTHETIC 473 00:17:10,028 --> 00:17:10,929 ADHESION MOLECULES. 474 00:17:10,929 --> 00:17:12,564 THEY HAVE THIS, THEY HAVE TO 475 00:17:12,564 --> 00:17:15,567 BIND TO EACH OTHER TO FORM 476 00:17:15,567 --> 00:17:17,435 TISSUE, TO THE EXTRA CELLULAR 477 00:17:17,435 --> 00:17:20,438 MATRIX AND TO MIGRATE OR 478 00:17:20,438 --> 00:17:22,674 TRANSMIGRATE THROUGH THE 479 00:17:22,674 --> 00:17:26,911 ENDOTHELIUM AND IMPORTANT FOR T 480 00:17:26,911 --> 00:17:27,445 CELL SYNAPSE OR NEURONAL 481 00:17:27,445 --> 00:17:27,845 SYNAPSES. 482 00:17:27,845 --> 00:17:34,052 THERE ARE A LOT OF COMPLEX 483 00:17:34,052 --> 00:17:35,119 ADHESION MOL KEWELLS. 484 00:17:35,119 --> 00:17:37,689 WE COULD ENGINEER SYNTHETIC WE 485 00:17:37,689 --> 00:17:40,625 REPLACE THESE EXTRA CELLULAR 486 00:17:40,625 --> 00:17:43,061 DOMAINS WITH ANTIGEN 487 00:17:43,061 --> 00:17:43,995 INTERACTIONS OR GFP BUT 488 00:17:43,995 --> 00:17:46,164 DEPENDING ON WHAT KIND OF 489 00:17:46,164 --> 00:17:47,332 INTRACELLULAR DOMAIN WE PUT ON 490 00:17:47,332 --> 00:17:53,304 THE INSIDE AND HOW IT ENGAGES 491 00:17:53,304 --> 00:17:54,439 THE INTRACELLULAR, CYTOSKELETON 492 00:17:54,439 --> 00:17:56,908 WE COULD GET DIFFERENT STRENGTH 493 00:17:56,908 --> 00:17:57,976 AND MORPHOLOGICAL DEPEN DEN SY. 494 00:17:57,976 --> 00:18:00,778 WHAT IS SHOWN HERE IS AN 495 00:18:00,778 --> 00:18:02,180 EXAMPLE, IF WE TAKE GFP 496 00:18:02,180 --> 00:18:05,249 INTERACTION BUT HAVE IT TIED TO 497 00:18:05,249 --> 00:18:08,286 THE INTRACELLULAR, WE GET 498 00:18:08,286 --> 00:18:11,956 SOMETHING THAT REPLICATES BROAD 499 00:18:11,956 --> 00:18:14,025 AND TIGHT INTERFACE WITH 500 00:18:14,025 --> 00:18:15,026 CADHERIN. 501 00:18:15,026 --> 00:18:18,062 THIS ALLOWS US TO TUNE STRENGTH 502 00:18:18,062 --> 00:18:18,863 AND SYNAPSE PROPERTIES FOR 503 00:18:18,863 --> 00:18:20,131 SORTING AND ASSEMBLY. 504 00:18:20,131 --> 00:18:22,266 I WILL SHOW YOU MOVIES THESE 505 00:18:22,266 --> 00:18:24,335 ARE THINGS WE ENGINEERED THE 506 00:18:24,335 --> 00:18:26,671 BLUE CELLS WITH DIFFERENT 507 00:18:26,671 --> 00:18:28,306 ADHESIONS THEY COULD EITHER 508 00:18:28,306 --> 00:18:30,642 FORM A NODE OR FORM THIS SHELL 509 00:18:30,642 --> 00:18:33,244 AROUND THE CLUSTER SO WE COULD 510 00:18:33,244 --> 00:18:33,945 START PROGRAMMING THOSE 511 00:18:33,945 --> 00:18:35,113 BEHAVIORS AND WE HAVE USED THAT 512 00:18:35,113 --> 00:18:37,015 IN A LOT OF DIFFERENT WAYS. 513 00:18:37,015 --> 00:18:39,417 LET ME GO TO THE MAIN PART OF 514 00:18:39,417 --> 00:18:43,187 THE TALK HOW WE CAN APPLY THIS 515 00:18:43,187 --> 00:18:45,456 TO NEXT GEN CELL THERAPIES. 516 00:18:45,456 --> 00:18:46,958 EVERYONE KNOWS ABOUT CAR T 517 00:18:46,958 --> 00:18:50,194 THERAPIES ONE OF THE FIRST CELL 518 00:18:50,194 --> 00:18:53,331 THERAPIES FDA A PROVED, THANKS 519 00:18:53,331 --> 00:18:55,466 TO PIONEERING WORK BY JIM -- 520 00:18:55,466 --> 00:18:58,503 WE KNOW WE CAN MAKE THESE 521 00:18:58,503 --> 00:18:59,470 ARTIFICIAL RECEPTORS THAT 522 00:18:59,470 --> 00:19:00,438 RECOGNIZE ANTIGENS ON CANCER 523 00:19:00,438 --> 00:19:06,911 AND KILL THEM AND THIS HAS BEEN 524 00:19:06,911 --> 00:19:07,412 REMARKABLE ADVANCE FOR 525 00:19:07,412 --> 00:19:08,546 HEMOPOETIC CANCERS. 526 00:19:08,546 --> 00:19:11,349 WE HAVEN'T HAD AS MUCH SUCCESS 527 00:19:11,349 --> 00:19:12,583 IN TARGETING SOLID TUMORS WITH 528 00:19:12,583 --> 00:19:13,751 CAR T'S. 529 00:19:13,751 --> 00:19:15,820 BECAUSE IT'S NOT REALLY THAT 530 00:19:15,820 --> 00:19:16,621 SIMPLE AS RECOGNIZING THE 531 00:19:16,621 --> 00:19:20,892 CANCER CELLS. 532 00:19:20,892 --> 00:19:23,494 RECOGNIZING CD 19 KILLS ALL T 533 00:19:23,494 --> 00:19:24,996 CELLS IS TOLERABLE AND THAT'S 534 00:19:24,996 --> 00:19:26,097 HOW IT CAN WORK. 535 00:19:26,097 --> 00:19:27,465 WE NEED A CELL THAT CAN 536 00:19:27,465 --> 00:19:28,066 RECOGNIZE THE ANTIGENS ON THE 537 00:19:28,066 --> 00:19:30,968 CANCER. 538 00:19:30,968 --> 00:19:32,637 BUT EQUALLY IMPORTANT, MANY 539 00:19:32,637 --> 00:19:34,539 ANTIGENS ESPECIALLY FOR SOLID 540 00:19:34,539 --> 00:19:35,540 TUMOR ARE ALSO EXPRESSED ON 541 00:19:35,540 --> 00:19:36,641 NORMAL TISSUE. 542 00:19:36,641 --> 00:19:40,311 WE HAVE TO FIND WAYS TO AVOID 543 00:19:40,311 --> 00:19:42,880 TOXIC CROSS REACTION. 544 00:19:42,880 --> 00:19:45,683 IN ADDITION MANY TUMOR SPECIFIC 545 00:19:45,683 --> 00:19:51,355 ARE ALSO HETEROGENEOUS. 546 00:19:51,355 --> 00:19:53,224 CERTAIN CELLS CAN ESCAPE. 547 00:19:53,224 --> 00:19:55,593 IF YOU GET TOO SPECIFIC YOU 548 00:19:55,593 --> 00:19:56,494 HAVE PROBLEM OF MORE CELLS 549 00:19:56,494 --> 00:19:58,863 MIGHT ESCAPE. 550 00:19:58,863 --> 00:20:00,932 ALSO SOLID TUMORS TEND TO BE 551 00:20:00,932 --> 00:20:03,735 SUPPRESSIVE, SO YOU HAVE TO 552 00:20:03,735 --> 00:20:04,569 OVERCOME THE SUPPRESSIVE TUMOR 553 00:20:04,569 --> 00:20:06,070 MICRO ENVIRONMENT. 554 00:20:06,070 --> 00:20:07,972 THERE ARE MULTIPLE CHALLENGE 555 00:20:07,972 --> 00:20:10,508 THAT'S HAVE TO BE SOLVED IN 556 00:20:10,508 --> 00:20:11,909 CONCERT TO GET THIS THERAPY. 557 00:20:11,909 --> 00:20:14,746 PART OF OUR GOAL IS DEPLOY SOME 558 00:20:14,746 --> 00:20:16,147 OF THE DIFFERENT MODULAR TOOLS 559 00:20:16,147 --> 00:20:17,782 WE HAVE TO IMPROVE EACH OF 560 00:20:17,782 --> 00:20:18,950 THESE DIFFERENT ISSUES AND TRY 561 00:20:18,950 --> 00:20:20,852 TO DO IT IN CONCERT. 562 00:20:20,852 --> 00:20:21,819 LET ME TELL YOU ABOUT ONE 563 00:20:21,819 --> 00:20:23,187 SOLUTION WE HAVE BEEN WORKING 564 00:20:23,187 --> 00:20:25,890 ON FOR QUITE SOME TIME. 565 00:20:25,890 --> 00:20:28,559 FIRST FOCUSED ON INCREASING 566 00:20:28,559 --> 00:20:30,194 RECOGNITION SPECIFICITY OF SAY 567 00:20:30,194 --> 00:20:32,296 SOLID TUMORS BUT HAS OTHER 568 00:20:32,296 --> 00:20:32,864 IMPLICATIONS ON SOME OTHER 569 00:20:32,864 --> 00:20:34,165 PROBLEMS. 570 00:20:34,165 --> 00:20:36,968 CAN WE PROGRAM FOR EXAMPLE A T 571 00:20:36,968 --> 00:20:38,369 CELL TO RECOGNIZE A 572 00:20:38,369 --> 00:20:40,204 MULTI-ANTIGEN SIGNATURE USING A 573 00:20:40,204 --> 00:20:45,743 TWO RECEPTOR CIRCUIT WHERE WE 574 00:20:45,743 --> 00:20:47,645 COMBINE SYN NOTCH AND A CAR 575 00:20:47,645 --> 00:20:49,213 INTO A KIR SET. 576 00:20:49,213 --> 00:20:53,151 KIR SET. 577 00:20:53,151 --> 00:20:55,019 -- CIRCUIT. 578 00:20:55,019 --> 00:20:56,654 IN NORMAL TISSUES COULD YOU GET 579 00:20:56,654 --> 00:20:57,889 THIS CROSS REACTION THAT COULD 580 00:20:57,889 --> 00:20:58,756 BE TOXIC. 581 00:20:58,756 --> 00:21:01,125 THIS IS WHAT I WAS TALKING 582 00:21:01,125 --> 00:21:04,829 ABOUT, WE COULD MAKE A CELL 583 00:21:04,829 --> 00:21:08,332 THAT HAS A SYN NOTCH RECEPTOR 584 00:21:08,332 --> 00:21:09,066 THAT WOULD RECOGNIZE ANTIGEN A 585 00:21:09,066 --> 00:21:11,135 THAT WOULD BE IN THE TUMOR. 586 00:21:11,135 --> 00:21:13,204 IT WOULD BE LINKED TO THE 587 00:21:13,204 --> 00:21:14,605 EXPRESSION OF A CAR GENE, SO 588 00:21:14,605 --> 00:21:18,843 THAT CAR IS NOT GOING TO BE 589 00:21:18,843 --> 00:21:20,244 EXPRESS BUD ONLY -- EXPRESSED. 590 00:21:20,244 --> 00:21:26,517 IF WE MAKE THIS TWO RECEPTOR 591 00:21:26,517 --> 00:21:28,352 CIRCUIT, BASICALLY IT'S OFF SO 592 00:21:28,352 --> 00:21:31,155 IT WOULD SPARE THAT HAD AND 593 00:21:31,155 --> 00:21:33,491 GENT B BUT TISSUE THAT HAS 594 00:21:33,491 --> 00:21:35,827 ANTIGEN A ON A CANCER CELL OR 595 00:21:35,827 --> 00:21:37,028 PART OF THE CANCER MICRO 596 00:21:37,028 --> 00:21:39,630 ENVIRONMENT IT WOULD TURN ON 597 00:21:39,630 --> 00:21:41,432 THE SYN NOTCH AND THIS WOULD 598 00:21:41,432 --> 00:21:43,100 TURN ON THE CAR, AND THE CAR 599 00:21:43,100 --> 00:21:44,735 WOULD BE ABLE TO INDUCE 600 00:21:44,735 --> 00:21:46,537 EXPRESSION OF THE CAR AND KILL 601 00:21:46,537 --> 00:21:48,139 THE CELLS THAT HAD ANTIGEN B. 602 00:21:48,139 --> 00:21:51,042 BUT ONLY IN THE CASE WHERE THE 603 00:21:51,042 --> 00:21:52,977 A AND B WERE TOGETHER LOCALLY 604 00:21:52,977 --> 00:21:55,446 IN SPACE, OKAY. 605 00:21:55,446 --> 00:21:57,582 AND WHAT IS SHOWN HERE IS AN 606 00:21:57,582 --> 00:21:58,282 ANIMATION OF WHAT WE HOPED 607 00:21:58,282 --> 00:21:59,650 WOULD HAPPEN. 608 00:21:59,650 --> 00:22:03,821 AS WE TAKE THESE SORT OF CAR 609 00:22:03,821 --> 00:22:05,990 SYN NOTCH T-CELLS AND PUT THEM 610 00:22:05,990 --> 00:22:15,600 IN A MOUSE WITH TWO TUMORS, ONE 611 00:22:15,600 --> 00:22:17,435 WITH THE KILLING ANTIGEN, THEY 612 00:22:17,435 --> 00:22:19,303 WOULDN'T BE ACTIVATED AND BE 613 00:22:19,303 --> 00:22:20,938 NEUTRAL BUT WITH THE PRIMARY 614 00:22:20,938 --> 00:22:23,241 ANTIGEN IN GREEN THEY WOULD GET 615 00:22:23,241 --> 00:22:25,443 TURNED ON AND KILL THAT IN THAT 616 00:22:25,443 --> 00:22:27,411 CASE ON THAT SIDE. 617 00:22:27,411 --> 00:22:29,080 WE SHOW WE TAKE MODEL TUMORS 618 00:22:29,080 --> 00:22:31,182 PUT IN ONE THAT HAS THE 619 00:22:31,182 --> 00:22:32,583 KILLING, KILLING AND PRIMING, 620 00:22:32,583 --> 00:22:34,218 WE SEE THIS AMAZING DIFFERENCE 621 00:22:34,218 --> 00:22:37,955 IN THE SAME ANIMAL WHERE THE 622 00:22:37,955 --> 00:22:39,123 SYN CAR T CELLS ONLY KILL THAT 623 00:22:39,123 --> 00:22:40,124 ONE SIDE. 624 00:22:40,124 --> 00:22:42,360 THIS SHOWS THESE ARE THE 625 00:22:42,360 --> 00:22:43,761 CONTROL T-CELLS AREN'T KILLED 626 00:22:43,761 --> 00:22:46,097 IF YOU PUT IN THE NORMAL CAR T 627 00:22:46,097 --> 00:22:49,867 CELLS IT WILL KILL BOTH TUMORS 628 00:22:49,867 --> 00:22:52,003 BUT THE SYN NOTCH CAN DETERMINE 629 00:22:52,003 --> 00:22:52,570 BETWEEN THE SINGLE AND DUAL 630 00:22:52,570 --> 00:22:54,138 ANTIGEN. 631 00:22:54,138 --> 00:22:57,174 SO WE HAVE NOW MOVED FROM THE 632 00:22:57,174 --> 00:22:58,476 SIMPLE MODEL ENGINEERED TUMORS 633 00:22:58,476 --> 00:23:00,211 TO SEVERAL DIFFERENT THINGS. 634 00:23:00,211 --> 00:23:02,380 WE AND OUR COLLEAGUES HAVE 635 00:23:02,380 --> 00:23:12,890 WORKED ON DEPLOYING THIS IN 636 00:23:16,694 --> 00:23:20,998 GLIOBLASTOMA. 637 00:23:20,998 --> 00:23:22,233 THEY ONLY KILL WHERE THEY ARE 638 00:23:22,233 --> 00:23:24,035 IN PROXIMITY. 639 00:23:24,035 --> 00:23:25,937 CAR EXPRESSION SHUTS OFF ONCE 640 00:23:25,937 --> 00:23:27,538 THE CELLS LEAVE THE REGION OF 641 00:23:27,538 --> 00:23:28,773 PRIMING WITH A HALF-LIFE OF A 642 00:23:28,773 --> 00:23:29,907 FEW HOURS. 643 00:23:29,907 --> 00:23:35,012 SO THEY DON'T HAVE TIME TO 644 00:23:35,012 --> 00:23:35,846 MOUNT THIS MULTI-DAY RESPONSE 645 00:23:35,846 --> 00:23:37,982 YOU NEED TO CLEAR A TUMOR. 646 00:23:37,982 --> 00:23:39,717 IN ADDITION, IT'S IMPORTANT TO 647 00:23:39,717 --> 00:23:41,185 NOTE THAT THE PRIMING ANTIGEN 648 00:23:41,185 --> 00:23:42,787 IS NOW ONLY USED FOR 649 00:23:42,787 --> 00:23:44,455 RECOGNITION AND NOT FOR KILLING. 650 00:23:44,455 --> 00:23:47,425 SO IT'S REALLY JUST AN 651 00:23:47,425 --> 00:23:48,592 INFORMATIONAL MOLECULE THAT 652 00:23:48,592 --> 00:23:49,160 LOCALIZES WHERE THE KILLING 653 00:23:49,160 --> 00:23:50,227 WILL TAKE PLACE. 654 00:23:50,227 --> 00:23:54,665 IT DOESN'T NEED TO BE 655 00:23:54,665 --> 00:23:59,103 HOMOGENOUS. 656 00:23:59,103 --> 00:24:00,738 IT CREATES BLAST RADIUS THE 657 00:24:00,738 --> 00:24:02,340 CELLS PRIMED CAN NOW KILL ANY 658 00:24:02,340 --> 00:24:04,408 CELL THAT HAS THE KILLING 659 00:24:04,408 --> 00:24:12,550 ANTIGEN OVER A BLAST RADIUS. 660 00:24:12,550 --> 00:24:16,053 WE CAN HARNESS NEOANTIGENS THAT 661 00:24:16,053 --> 00:24:20,124 ARE SPECIFIC BUT HOMOGENOUS. 662 00:24:20,124 --> 00:24:21,692 THE KILLING ANTIGEN NEED NOT BE 663 00:24:21,692 --> 00:24:23,794 PERFECTLY SPECIFIC AS LONG AS 664 00:24:23,794 --> 00:24:24,729 DUAL ANTIGEN COMBINATION IS 665 00:24:24,729 --> 00:24:26,397 ONLY FOUND ON THE TUMOR. 666 00:24:26,397 --> 00:24:28,232 THAT'S IMPORTANT, IF WE PRIME 667 00:24:28,232 --> 00:24:29,867 AT A VERY LOCALIZED WAY WE 668 00:24:29,867 --> 00:24:31,502 COULD START KILLING BASED ON 669 00:24:31,502 --> 00:24:32,436 BROADER SET OF ANTIGENS 670 00:24:32,436 --> 00:24:34,538 INCLUDING ONE THAT'S MIGHT HAVE 671 00:24:34,538 --> 00:24:35,706 CROSS REACTION IN OTHER 672 00:24:35,706 --> 00:24:37,341 TISSUES, AS LONG AS THOSE DON'T 673 00:24:37,341 --> 00:24:41,879 OCCUR WITH THE PRIMING ANTIGEN. 674 00:24:41,879 --> 00:24:43,547 AND THEN IMPORTANTLY, 675 00:24:43,547 --> 00:24:46,884 CONDITIONAL INDUCTION OF THE 676 00:24:46,884 --> 00:24:49,186 CAR, GREATLY DECREASES THE 677 00:24:49,186 --> 00:24:52,690 DEGREE OF CAR T CELL EXHAUSTION. 678 00:24:52,690 --> 00:24:54,091 MANY CIRCUIT ARE MUCH BETTER 679 00:24:54,091 --> 00:24:56,961 CLEARING THE TUMORS IN THE 680 00:24:56,961 --> 00:24:57,795 CIRCUIT CONTEXT RATHER THAN 681 00:24:57,795 --> 00:24:59,930 CONSTITUENT OF CAR. 682 00:24:59,930 --> 00:25:01,332 ALSO IMPORTANTLY, I WON'T TALK 683 00:25:01,332 --> 00:25:03,868 ABOUT THIS BUT VERY IMPORTANT 684 00:25:03,868 --> 00:25:07,405 PART, SYN NOTCH COULD BE USED 685 00:25:07,405 --> 00:25:08,339 TO INDUCE INFLAMMATORY PAYLOADS 686 00:25:08,339 --> 00:25:11,609 WE HAVE DONE THIS WITH IL2 AND 687 00:25:11,609 --> 00:25:15,212 HAS POWERFUL EFFECT OVERCOMING 688 00:25:15,212 --> 00:25:17,648 THE MICRO ENVIRONMENT IN 689 00:25:17,648 --> 00:25:19,817 PANCREATIC AND MELANOMA TUMORS 690 00:25:19,817 --> 00:25:24,188 AND MORE EFFECTIVE THAN ARMORED 691 00:25:24,188 --> 00:25:30,361 FORMS OF CAR THAT ARE 692 00:25:30,361 --> 00:25:31,295 CONSTITUTIVE. 693 00:25:31,295 --> 00:25:33,431 I WANT TO TALK B WE HAVE DONE A 694 00:25:33,431 --> 00:25:35,733 LOT OF THIS WORK IN 695 00:25:35,733 --> 00:25:39,003 COLLABORATION WITH MY COLLEAGUE 696 00:25:39,003 --> 00:25:40,704 IN NEUROSURGERY AN EXPERT IN 697 00:25:40,704 --> 00:25:44,308 GLIOBLASTOMA, THERE ARE TWO WE 698 00:25:44,308 --> 00:25:45,776 HAVE BEEN DEVELOPING, ONE 699 00:25:45,776 --> 00:25:46,010 E-SYNC. 700 00:25:46,010 --> 00:25:51,782 A CIRCUIT THAT PRIMES WITH A 701 00:25:51,782 --> 00:25:54,985 TUMOR NEOANTIGEN, EGFRVIII. 702 00:25:54,985 --> 00:25:56,720 SPLICE VARIANT PART OF THE 703 00:25:56,720 --> 00:25:58,189 EXTRA CELLULAR DOMAIN. 704 00:25:58,189 --> 00:25:59,423 THIS IS TUMOR SPECIFIC. 705 00:25:59,423 --> 00:26:01,792 BUT WHEN THEY DID A TRIAL USING 706 00:26:01,792 --> 00:26:03,861 A CAR OF RECOGNIZING IT, IT 707 00:26:03,861 --> 00:26:08,666 WENT TO THE TUMOR AND KILLED 708 00:26:08,666 --> 00:26:11,435 THE EGFRVIII CELLS BUT IT 709 00:26:11,435 --> 00:26:12,703 ESCAPED AND SURVIVED WITH 710 00:26:12,703 --> 00:26:14,705 EDITING OF THAT ANTIGEN. 711 00:26:14,705 --> 00:26:16,874 SO IT'S VERY POWERFUL BUT WE 712 00:26:16,874 --> 00:26:20,411 WANT TO USE IT FOR KILLING IN A 713 00:26:20,411 --> 00:26:21,846 SELECTIVE WAY BUT INFORMATION 714 00:26:21,846 --> 00:26:23,914 PRIMING ANTIGEN, WE HAVE USED 715 00:26:23,914 --> 00:26:27,351 IT AS A SYN NOTCH RECEPTOR TO 716 00:26:27,351 --> 00:26:30,254 PRIME EXPRESSION OF A 717 00:26:30,254 --> 00:26:32,323 TWO-HEADED CAR. 718 00:26:32,323 --> 00:26:35,326 THESE ARE MORE HOMOGENOUS BUT 719 00:26:35,326 --> 00:26:36,293 IMPERFECTLY SPECIFIC BUT BY 720 00:26:36,293 --> 00:26:37,695 COMBINING IN THIS PARTICULAR 721 00:26:37,695 --> 00:26:39,597 WAY, ONE GIVES MORE COMPLETE 722 00:26:39,597 --> 00:26:42,900 KILLING AND ONE GIVES MORE 723 00:26:42,900 --> 00:26:43,534 LOCALIZED SPECIFICITY IT WORKS 724 00:26:43,534 --> 00:26:44,301 QUITE WELL. 725 00:26:44,301 --> 00:26:47,338 THIS HAS BEEN PUBLISHED. 726 00:26:47,338 --> 00:26:50,541 WE HAVE A 90-YEAR APPROVAL AND 727 00:26:50,541 --> 00:26:51,976 IN PHASE TWO OF CLINICAL TRIAL, 728 00:26:51,976 --> 00:26:55,679 WE ARE EXCITED ABOUT THAT. 729 00:26:55,679 --> 00:26:58,349 THIS OTHER ONE B-SYNC PRIME 730 00:26:58,349 --> 00:26:58,916 ONCOA NORMAL BRAIN-SPECIFIC 731 00:26:58,916 --> 00:27:00,384 ANTIGEN. 732 00:27:00,384 --> 00:27:02,520 BCAN ONLY FOUND IN THE BRAIN. 733 00:27:02,520 --> 00:27:05,523 WE COULD MAKE A SYN NOTCH THAT 734 00:27:05,523 --> 00:27:08,092 RECOGNIZE THAT'S MOLECULE IN 735 00:27:08,092 --> 00:27:09,927 THE BRAIN AND INDUCES THIS 736 00:27:09,927 --> 00:27:13,297 TWO-HEADED CAR, THE SAME ONE. 737 00:27:13,297 --> 00:27:14,765 AND THESE ANTIGENS ARE NOT 738 00:27:14,765 --> 00:27:16,567 EXPRESSED IN THE NORMAL BRAIN. 739 00:27:16,567 --> 00:27:18,202 IT ENDS UP BEING REALLY VERY 740 00:27:18,202 --> 00:27:19,470 SPECIFIC AND WE ARE VERY 741 00:27:19,470 --> 00:27:20,437 EXCITED ABOUT IT AND I WILL 742 00:27:20,437 --> 00:27:22,439 TELL YOU ABOUT THAT. 743 00:27:22,439 --> 00:27:23,841 ONE OF THE KEY CONCEPTS HERE IS 744 00:27:23,841 --> 00:27:25,709 THAT WE WOULD LIKE TO ACTUALLY 745 00:27:25,709 --> 00:27:28,045 BE ABLE TO RESTRICT A 746 00:27:28,045 --> 00:27:29,446 THERAPEUTIC, NOT TO JUST 747 00:27:29,446 --> 00:27:31,081 RECOGNIZE IT'S MOLECULAR TARGET 748 00:27:31,081 --> 00:27:32,283 BUT RESTRICT ANATOMICALLY IN A 749 00:27:32,283 --> 00:27:33,651 TISSUE WHERE IT ACTS. 750 00:27:33,651 --> 00:27:35,486 IT'S HARD TO DO THAT WITH A 751 00:27:35,486 --> 00:27:38,422 MOLECULAR DRUG. 752 00:27:38,422 --> 00:27:39,590 OFTEN BIND WITH MULTIPLE 753 00:27:39,590 --> 00:27:41,725 TISSUES BECAUSE OF THE SAME OR 754 00:27:41,725 --> 00:27:42,927 RELATED TARGETS ARE IN 755 00:27:42,927 --> 00:27:44,228 DIFFERENT TISSUES. 756 00:27:44,228 --> 00:27:45,462 LET'S SAY WE WANTED TO HAVE 757 00:27:45,462 --> 00:27:46,330 THIS ATTACK SOMETHING IN THE 758 00:27:46,330 --> 00:27:47,765 BRAIN. 759 00:27:47,765 --> 00:27:49,633 THEN ONE IT MIGHT HAVE TROUBLE 760 00:27:49,633 --> 00:27:51,735 GETTING INTO THE BRAIN BUT ALSO 761 00:27:51,735 --> 00:27:53,871 CROSS REACT WITH OTHER CITES. 762 00:27:53,871 --> 00:27:55,739 -- SITES. 763 00:27:55,739 --> 00:27:57,074 IF WE COULD INSTRUCT THE DRUG 764 00:27:57,074 --> 00:27:58,542 TO ONLY GO TO THE BRAIN IT 765 00:27:58,542 --> 00:28:00,444 WOULD SOLVE A LOT OF PROBLEMS, 766 00:28:00,444 --> 00:28:01,579 IT MIGHT BE MORE EFFECTIVE IN 767 00:28:01,579 --> 00:28:03,247 THE BRAIN WHERE THE DISEASE IS. 768 00:28:03,247 --> 00:28:05,349 BUT ALSO WE WOULD DROP OUT ALL 769 00:28:05,349 --> 00:28:06,617 THE CROSS REACTION THAT 770 00:28:06,617 --> 00:28:07,918 OCCURRED OUTSIDE THAT TISSUE. 771 00:28:07,918 --> 00:28:09,520 OF COURSE THIS IS HOW A LOT OF 772 00:28:09,520 --> 00:28:10,788 BIOLOGY WORKS. 773 00:28:10,788 --> 00:28:13,090 THINGS GO AND OCCUR IN THE 774 00:28:13,090 --> 00:28:14,959 SPECIFIC TISSUES AND THAT'S WHY 775 00:28:14,959 --> 00:28:16,627 THE SAME MOLECULES COULD BE 776 00:28:16,627 --> 00:28:18,229 USED IN DIFFERENT CONTEXT. 777 00:28:18,229 --> 00:28:21,232 HOW MIGHT WE DESIGN A CELL TO 778 00:28:21,232 --> 00:28:22,866 RESTRICT ITS ACTIVITY TO A 779 00:28:22,866 --> 00:28:24,535 SPECIFIC TISSUE LIKE THE BRAIN? 780 00:28:24,535 --> 00:28:29,206 WE HAVE TRIED TO IDENTIFY BRAIN 781 00:28:29,206 --> 00:28:31,976 OR CNS SPECIFIC EXTRA CELLULAR 782 00:28:31,976 --> 00:28:34,345 ANTIGEN AND DESIGN SYN NOTCH TO 783 00:28:34,345 --> 00:28:36,480 RECOGNIZE THESE, AND USE TO 784 00:28:36,480 --> 00:28:37,881 INDUCE EXPRESSION OF A 785 00:28:37,881 --> 00:28:38,749 THERAPEUTIC PAYLOAD. 786 00:28:38,749 --> 00:28:42,219 IN THE CASE OF A CANCER LIKE 787 00:28:42,219 --> 00:28:43,153 GLIOBLASTOMA WE COULD INDUCE 788 00:28:43,153 --> 00:28:44,888 EXPRESSION OF A CAR, ONLY KILL 789 00:28:44,888 --> 00:28:45,990 WITHIN THOSE ANTIGENS IN THE 790 00:28:45,990 --> 00:28:46,890 BRAIN CONTEXT. 791 00:28:46,890 --> 00:28:50,160 BUT AS I WILL TELL YOU LATER WE 792 00:28:50,160 --> 00:28:52,463 ARE ALSO INTERESTED IN 793 00:28:52,463 --> 00:28:55,266 EXPRESSING OTHER PAYLOADS FOR 794 00:28:55,266 --> 00:28:55,866 NEUROINFLAMMATION COULD BE 795 00:28:55,866 --> 00:28:59,837 EXPRESSED SUPPRESSIVE PAYLOADS. 796 00:28:59,837 --> 00:29:07,544 SO WE DID WITH MILOS SIMIC LAB 797 00:29:07,544 --> 00:29:08,245 RESEARCH, THERE ARE CERTAIN 798 00:29:08,245 --> 00:29:10,080 MOLECULES IN THE BRAIN THAT ARE 799 00:29:10,080 --> 00:29:12,650 EXTRA CELLULAR THAT ARE QUITE 800 00:29:12,650 --> 00:29:14,518 SPECIFIC THAT INCLUDES CERTAIN 801 00:29:14,518 --> 00:29:25,062 SURFACE MOLECULES ON NEURONS OR 802 00:29:29,166 --> 00:29:33,304 ON OLIGO DEN SITES. 803 00:29:33,304 --> 00:29:41,412 EXTRA CELLULAR NETWORK, IT HAS 804 00:29:41,412 --> 00:29:43,681 HYLAURONIC, BUT THEN BCAN. 805 00:29:43,681 --> 00:29:47,084 WE RAISE ANTIBODIES AGAINST 806 00:29:47,084 --> 00:29:49,753 THIS AND MADE ELEVATED BCAN SYN 807 00:29:49,753 --> 00:30:00,030 NOTCH RECEPTORS. 808 00:30:02,900 --> 00:30:05,169 AS IT INTERACTS WITH THE P 809 00:30:05,169 --> 00:30:13,911 REGION AROUND THE ASTROCYTE IN 810 00:30:13,911 --> 00:30:14,378 GREEN. 811 00:30:14,378 --> 00:30:17,247 HOW DO WE APPLY THIS TO 812 00:30:17,247 --> 00:30:18,582 SOMETHING LIKE GLIOBLASTOMA, I 813 00:30:18,582 --> 00:30:20,684 WANT TO REVIEW, THE ANTIGENS WE 814 00:30:20,684 --> 00:30:24,221 CHOOSE TO USE FOR KILLING, WELL 815 00:30:24,221 --> 00:30:26,123 KNOWN GLIOBLASTOMA. 816 00:30:26,123 --> 00:30:30,361 BOTH OF THESE ARE WELL 817 00:30:30,361 --> 00:30:31,929 EXPRESSED ON MOST GLIOBLASTOMAS. 818 00:30:31,929 --> 00:30:34,031 BUT ONE OF THE PROBLEMS IS THAT 819 00:30:34,031 --> 00:30:36,166 THESE ARE ALSO EXPRESSED IN 820 00:30:36,166 --> 00:30:36,834 OTHER NORMAL TISSUES BUT NOT IN 821 00:30:36,834 --> 00:30:38,035 THE BRAIN. 822 00:30:38,035 --> 00:30:40,237 NOT IN THE NORMAL BRAIN. 823 00:30:40,237 --> 00:30:45,042 SO WHAT WE DECIDED TO DO, FROM 824 00:30:45,042 --> 00:30:46,944 MILOS SIMIC LEADING THIS WORK, 825 00:30:46,944 --> 00:30:49,513 TO MAKE A SYN NOTCH AGAINST 826 00:30:49,513 --> 00:30:51,382 BCAN AND HAVE THAT SO IF WE 827 00:30:51,382 --> 00:30:52,316 DETECT THE BRAIN, THAT WILL 828 00:30:52,316 --> 00:30:57,621 TURN ON THE CAR THAT WILL KILL 829 00:30:57,621 --> 00:30:58,322 THESE GLIOMA ASSOCIATED 830 00:30:58,322 --> 00:30:59,723 ANTIGENS EVEN THOUGH THEY 831 00:30:59,723 --> 00:31:00,491 AREN'T ABSOLUTELY SPECIFIC BUT 832 00:31:00,491 --> 00:31:02,326 THE ONLY ONES IN THE BRAIN, SO 833 00:31:02,326 --> 00:31:08,632 THE IDEA IS THE INTERSECTION OF 834 00:31:08,632 --> 00:31:10,300 THESE TWO VENN DIAGRAMS WOULD 835 00:31:10,300 --> 00:31:12,803 BE THE GLIOBLASTOMA. 836 00:31:12,803 --> 00:31:15,606 SO THEIR LAB MADE THESE CELLS, 837 00:31:15,606 --> 00:31:18,842 TESTED IN VITRO AND NOW INVIVO 838 00:31:18,842 --> 00:31:22,613 WITH A GBM TEW MORE, PBK MODEL 839 00:31:22,613 --> 00:31:24,615 IMPLANTED IN THE BRAIN. 840 00:31:24,615 --> 00:31:27,151 THIS ROBUSTLY CLEARED THESE 841 00:31:27,151 --> 00:31:28,352 TUMORS FROM THESE, INCREASED 842 00:31:28,352 --> 00:31:29,920 SURVIVAL, NEARLY ALL THE MICE 843 00:31:29,920 --> 00:31:30,454 SURVIVED. 844 00:31:30,454 --> 00:31:31,655 THIS SOMEONE OF THE STRONGEST 845 00:31:31,655 --> 00:31:33,657 RESPONSES WE HAVE SEEN OF ALL 846 00:31:33,657 --> 00:31:35,626 OUR GLIOBLASTOMA THERAPIES. 847 00:31:35,626 --> 00:31:38,028 IT WAS ACTING VERY EFFECTIVELY 848 00:31:38,028 --> 00:31:40,264 AND WE ARE GETTING A LOT OF 849 00:31:40,264 --> 00:31:40,497 PRIMING. 850 00:31:40,497 --> 00:31:41,598 WE TAKE THE TISSUE EARLY MID 851 00:31:41,598 --> 00:31:46,036 TREATMENT AND WE LOOK AT THE 852 00:31:46,036 --> 00:31:48,639 CD3 T CELLS THERE'S ONLY 853 00:31:48,639 --> 00:31:49,573 SIGNIFICANT ACTIVATION OF THE 854 00:31:49,573 --> 00:31:53,210 SYN NOTCH IN THE BRAIN SAMPLE. 855 00:31:53,210 --> 00:31:54,845 SO WE ARE VERY EXCITED ABOUT 856 00:31:54,845 --> 00:31:56,847 THAT, SEEMS TO BE VERY STRONG 857 00:31:56,847 --> 00:31:58,348 AND BRAIN SPECIFIC INDUCTION OF 858 00:31:58,348 --> 00:31:59,283 THE SYN NOTCH. 859 00:31:59,283 --> 00:32:01,952 ONE OF THE THINGS WE ARE MOST 860 00:32:01,952 --> 00:32:04,721 EXCITED IS THIS COULD BE A PAN 861 00:32:04,721 --> 00:32:06,957 GBM THERAPY, IT'S NOT THAT WE 862 00:32:06,957 --> 00:32:09,059 HAVE TO FIND PATIENTS THAT HAVE 863 00:32:09,059 --> 00:32:10,594 THAT SPECIFICKING THIS SHOULD 864 00:32:10,594 --> 00:32:12,129 WORK FOR ALL PATIENTS, THAT'S A 865 00:32:12,129 --> 00:32:13,764 BIG DEAL THINKING ABOUT HOW TO 866 00:32:13,764 --> 00:32:15,666 SCREEN AND HOW HARD IT IS FOR 867 00:32:15,666 --> 00:32:17,501 FINDING THE RIGHT PATIENTS. 868 00:32:17,501 --> 00:32:19,870 WHAT ABOUT OUTSIDE OF THE BRAIN? 869 00:32:19,870 --> 00:32:22,706 WHAT WE DID IS TOOK THE SAME 870 00:32:22,706 --> 00:32:23,707 TUMOR CELLS AND PLANTED ONE IN 871 00:32:23,707 --> 00:32:25,542 THE BRAIN AND ONE IN THE FLANK. 872 00:32:25,542 --> 00:32:29,313 NECESSITY -- THEY BOTH HAVE 873 00:32:29,313 --> 00:32:33,417 THE KILLING ANTIGEN BUT ONLY 874 00:32:33,417 --> 00:32:35,385 THE ONE IN THE BRAIN. 875 00:32:35,385 --> 00:32:37,287 IN THE SAME MICE, BRAIN TUMORS 876 00:32:37,287 --> 00:32:39,690 ARE CLEARED BUT THE FLANK 877 00:32:39,690 --> 00:32:40,858 IMPLANTED TUMORS ARE NOT 878 00:32:40,858 --> 00:32:42,526 CLEARED IN THE SAME ANIMALS. 879 00:32:42,526 --> 00:32:45,229 IT REALLY INDICATES THAT THIS 880 00:32:45,229 --> 00:32:48,398 IS BRAIN RESTRICTED ACTIVITY. 881 00:32:48,398 --> 00:32:50,033 OKAY, SO WE NOW ACTUALLY ARE 882 00:32:50,033 --> 00:32:52,369 REALLY EXCITED THAT WE HAVE 883 00:32:52,369 --> 00:32:54,004 THIS KIND OF GPS SYSTEM THAT 884 00:32:54,004 --> 00:32:54,671 CELLS COULD KNOW THEY ARE IN 885 00:32:54,671 --> 00:32:56,540 THE BRAIN. 886 00:32:56,540 --> 00:32:57,741 WE HAVE INTERESTED RESULTS 887 00:32:57,741 --> 00:32:59,343 ABOUT THINGS IN LUNG AND 888 00:32:59,343 --> 00:33:04,147 PANCREAS ALSO. 889 00:33:04,147 --> 00:33:07,417 BUT WHAT WE REALIZE THIS COULD 890 00:33:07,417 --> 00:33:08,619 BE USED FOR OTHER DISEASES TO 891 00:33:08,619 --> 00:33:09,753 DELIVER TO THE BRAIN. 892 00:33:09,753 --> 00:33:11,388 THERE'S BEEN A LOT OF WORK IN 893 00:33:11,388 --> 00:33:13,924 THE PAST PEOPLE TRYING TO FIND 894 00:33:13,924 --> 00:33:15,359 DIFFERENT CYTOKINES OR FACTOR 895 00:33:15,359 --> 00:33:19,930 THAT'S COULD HAVE DIFFERENT 896 00:33:19,930 --> 00:33:21,098 IMPACT ON NEUROINFLAMMATION, EA 897 00:33:21,098 --> 00:33:24,101 MODELS, SOME WORK WAS SHOWN TEN 898 00:33:24,101 --> 00:33:26,403 YEARS AGO, SOMETHING LIKE 899 00:33:26,403 --> 00:33:27,137 IL-10, SUPPRESSIVE CYTOKINE 900 00:33:27,137 --> 00:33:29,806 WHEN EXPRESSED IN THE BRAIN, 901 00:33:29,806 --> 00:33:31,742 WHEN YOU INJECT AAV IN THE 902 00:33:31,742 --> 00:33:33,810 BRAIN, THE HIGH LEVEL 903 00:33:33,810 --> 00:33:36,647 EXPRESSION CAN BLOCK EAE BUT 904 00:33:36,647 --> 00:33:38,982 SYSTEMICALLY INJECTED IL 10 IS 905 00:33:38,982 --> 00:33:39,716 INEFFECTIVE, EITHER NOT ABLE TO 906 00:33:39,716 --> 00:33:42,119 GET TO THE BRAIN OR HIGH ENOUGH 907 00:33:42,119 --> 00:33:43,921 LEVEL. 908 00:33:43,921 --> 00:33:46,290 MILOS WORKING WITH COLLEAGUES, 909 00:33:46,290 --> 00:33:48,425 INCLUDING SCOTT ZANVILLE IN THE 910 00:33:48,425 --> 00:33:50,961 NEUROLOGY DEPARTMENT ASKED CAN 911 00:33:50,961 --> 00:33:55,132 WE MAKE A T-CELL WITH SYN NOTCH 912 00:33:55,132 --> 00:33:58,335 DELIVER IL 10 AND HOW WOULD 913 00:33:58,335 --> 00:34:00,904 THIS WORK WITH MULTIPLE 914 00:34:00,904 --> 00:34:01,171 SCLEROSIS. 915 00:34:01,171 --> 00:34:06,710 LET ME TELL YOU ABOUT THE 916 00:34:06,710 --> 00:34:09,880 ANIMALS, MOG, ANTIGEN FROM 917 00:34:09,880 --> 00:34:12,215 MYELIN SHEATH CELLS. 918 00:34:12,215 --> 00:34:13,984 TH 17 AND ADOPTIVELY TRANSFER 919 00:34:13,984 --> 00:34:17,087 THAT INTO A MOUSE AND THAT 920 00:34:17,087 --> 00:34:18,455 MOUSE WILL DEVELOP 921 00:34:18,455 --> 00:34:18,922 NEURODEGENERATION AND 922 00:34:18,922 --> 00:34:19,389 NEUROINFLAMMATION. 923 00:34:19,389 --> 00:34:23,694 IN THIS CASE WE WOULD ASK COULD 924 00:34:23,694 --> 00:34:25,829 WE TRANSFER THE SYN NOTCH, 925 00:34:25,829 --> 00:34:26,763 THERAPEUTIC CELLS INTO THOSE 926 00:34:26,763 --> 00:34:28,732 CELLS AND WOULD THOSE HAVE 927 00:34:28,732 --> 00:34:31,201 EFFECTS ON THE EAE? 928 00:34:31,201 --> 00:34:34,004 WE LOOK AT DIFFERENT EFFECTS, 929 00:34:34,004 --> 00:34:34,671 NEUROLOGICAL SCORES, PARALYSIS, 930 00:34:34,671 --> 00:34:36,573 ET CETERA, WHAT WE SEE IN FACT 931 00:34:36,573 --> 00:34:38,442 WHEN WE GIVE THESE CELLS WE 932 00:34:38,442 --> 00:34:48,385 COULD SEE SIGNIFICANT 933 00:34:48,385 --> 00:34:52,255 AMELIORATION. 934 00:34:52,255 --> 00:34:55,525 BY DAY 12 THEY ADOPTED EAE BUT 935 00:34:55,525 --> 00:34:59,763 THE MICE TREATED WITH THOSE 936 00:34:59,763 --> 00:35:00,364 SUPPRESSORS CELLS MAINTAINED 937 00:35:00,364 --> 00:35:01,164 GOOD MOBILITY. 938 00:35:01,164 --> 00:35:03,934 WE ARE ABLE TO SEE AN EFFECT. 939 00:35:03,934 --> 00:35:05,636 WE ARE EXCITED THESE ARE EARLY 940 00:35:05,636 --> 00:35:08,138 DAYS BUT IDEA WE CAN TARGET 941 00:35:08,138 --> 00:35:11,508 CELLS TO TISSUE. 942 00:35:11,508 --> 00:35:14,544 WE ENGINEERED T-CELLS THAT USE 943 00:35:14,544 --> 00:35:18,048 MULTI-RECEPTOR CIRCUIT, 944 00:35:18,048 --> 00:35:18,615 MULTIPLE COMPONENTS LINKED 945 00:35:18,615 --> 00:35:23,286 TOGETHER. 946 00:35:23,286 --> 00:35:24,187 TO MAKE PRECISE 947 00:35:24,187 --> 00:35:24,821 DISEASE-SPECIFIC DECISIONS AS 948 00:35:24,821 --> 00:35:26,323 AN EXAMPLE IN THE CASE OF 949 00:35:26,323 --> 00:35:29,359 GLIOBLASTOMA WE ARE ABLE TO 950 00:35:29,359 --> 00:35:31,261 ENGINEER PRECISE BRAIN CANCER 951 00:35:31,261 --> 00:35:32,629 CELL THERAPIES BY PROGRAM CELLS 952 00:35:32,629 --> 00:35:34,731 THAT ONE CAN SENSE THEY ARE IN 953 00:35:34,731 --> 00:35:35,532 THE BRAIN AND INDUCE EXPRESSION 954 00:35:35,532 --> 00:35:36,433 OF A CAR. 955 00:35:36,433 --> 00:35:39,703 THIS IS AN EXAMPLE OF A 956 00:35:39,703 --> 00:35:41,104 POWERFUL EXPRESSION OF 957 00:35:41,104 --> 00:35:41,972 ANATOMICAL AND MOLECULAR 958 00:35:41,972 --> 00:35:43,440 SPECIFICITIES THAT REALLY ONLY 959 00:35:43,440 --> 00:35:47,144 A CELL CAN DO EFFECTIVELY. 960 00:35:47,144 --> 00:35:48,812 WE ARE EXCITED THAT WE HAVE 961 00:35:48,812 --> 00:35:50,914 DEVELOPED A WAY TO HAVE BRAIN 962 00:35:50,914 --> 00:35:53,250 SENSING CELLS THAT COULD BE 963 00:35:53,250 --> 00:35:55,385 USED IN A DISEASE-AGNOSTIC 964 00:35:55,385 --> 00:36:02,959 MANNER TO DELIVER EITHER IMMUNE 965 00:36:02,959 --> 00:36:03,894 SUPPRESSIVE BUT ALSO 966 00:36:03,894 --> 00:36:06,663 REGENERATIVE PIE LOADS OR ONES 967 00:36:06,663 --> 00:36:08,331 FOR NEODEGENERATION. 968 00:36:08,331 --> 00:36:13,503 WE ARE TRYING TO IMPROVE CELL 969 00:36:13,503 --> 00:36:14,071 MIGRATION, TRANSMIGRATION 970 00:36:14,071 --> 00:36:16,073 ACROSS THE BBB BUT ALSO IT'S 971 00:36:16,073 --> 00:36:18,608 POSSIBLE WE COULD TARGET OTHER 972 00:36:18,608 --> 00:36:22,479 TISSUES IN AN ANALOGOUS KIND OF 973 00:36:22,479 --> 00:36:24,081 GPS, CELL GPS MECHANISM. 974 00:36:24,081 --> 00:36:26,183 I WANT TO REMIND EVERYONE WE 975 00:36:26,183 --> 00:36:30,187 ARE REALLY EXCITED WE ARE 976 00:36:30,187 --> 00:36:32,622 STARTING THIS EGRB3 WITH THIS 977 00:36:32,622 --> 00:36:35,092 TEAM AT UCSF AS WELL AS MID 978 00:36:35,092 --> 00:36:37,828 STREAM IN TERMS OF PREPARING 979 00:36:37,828 --> 00:36:39,930 OUR IND FOR THE BRAIN-PRIMED 980 00:36:39,930 --> 00:36:41,331 BCAN ONE, HOPEFULLY WE WILL BE 981 00:36:41,331 --> 00:36:43,200 ABLE TO REPORT ON THAT SOON. 982 00:36:43,200 --> 00:36:45,068 SO THE LAST PART OF MY TALK, I 983 00:36:45,068 --> 00:36:47,838 WANT TO TALK ABOUT TRYING TO 984 00:36:47,838 --> 00:36:49,473 APPLY THESE SAME FUNDAMENTAL 985 00:36:49,473 --> 00:36:50,741 TOOLS TO A DIFFERENT PROBLEMS 986 00:36:50,741 --> 00:36:52,476 FACED IN BIOLOGY. 987 00:36:52,476 --> 00:36:53,910 BUT ONE THAT STILL REQUIRES 988 00:36:53,910 --> 00:36:56,213 CELLS TO TALK TO EACH OTHER IN 989 00:36:56,213 --> 00:36:57,547 VERY PRECISE PROGRAMS IN THE 990 00:36:57,547 --> 00:36:59,516 CASE OF DEVELOPMENT. 991 00:36:59,516 --> 00:37:02,319 HOW CELLS INTERACT WITH ONE 992 00:37:02,319 --> 00:37:03,120 ANOTHER TO CHANGE AND ORGANIZE 993 00:37:03,120 --> 00:37:05,088 IN SPACE. 994 00:37:05,088 --> 00:37:06,957 THAT COMPLEX BEHAVIOR COULD BE 995 00:37:06,957 --> 00:37:07,657 PRE-PROGRAMMED INTO A SET OF 996 00:37:07,657 --> 00:37:09,292 DNA. 997 00:37:09,292 --> 00:37:11,862 SO THIS, I WILL SHOW YOU IN 998 00:37:11,862 --> 00:37:16,967 THIS MOVIE, ACTUALLY SOME 999 00:37:16,967 --> 00:37:18,368 SIMPLE CASES WE TOOK, GOT THEM 1000 00:37:18,368 --> 00:37:19,536 TO ORGANIZE IN DIFFERENT THINGS. 1001 00:37:19,536 --> 00:37:24,207 SPONTANEOUS WAY. 1002 00:37:24,207 --> 00:37:28,411 SO WHY GENE DEVELOPMENT, WE ARE 1003 00:37:28,411 --> 00:37:28,979 INTERESTED FROM A BOTTOM-UP 1004 00:37:28,979 --> 00:37:31,681 VIEW. 1005 00:37:31,681 --> 00:37:33,784 ARE THEY UTILIZED IN DIFFERENT 1006 00:37:33,784 --> 00:37:34,718 DEVELOPMENTAL PROGRAMS AND HOW 1007 00:37:34,718 --> 00:37:37,187 THEY ARE PUT TOGETHER TO 1008 00:37:37,187 --> 00:37:38,255 CONSTRUCT THE DIFFERENT 1009 00:37:38,255 --> 00:37:46,363 MORPHOLOGIES WE SEE IN METZOANS. 1010 00:37:46,363 --> 00:37:49,699 FOR TRANSPLANT, MIGHT IT BE 1011 00:37:49,699 --> 00:37:50,634 BETTER TO HAVE CERTAIN 1012 00:37:50,634 --> 00:37:52,536 PROPERTIES UNIQUE TO THAT. 1013 00:37:52,536 --> 00:37:53,336 THE FUNDAMENTAL QUESTION, PART 1014 00:37:53,336 --> 00:37:55,639 OF WHAT WE ARE TRYING TO DO AT 1015 00:37:55,639 --> 00:37:57,507 A MORE BASIC LEVEL IS, TO ASK, 1016 00:37:57,507 --> 00:37:59,643 CAN WE USE THE SAME SORT OF 1017 00:37:59,643 --> 00:38:01,878 TOOLKIT WE HAVE BEEN USING FOR 1018 00:38:01,878 --> 00:38:02,813 ENGINEERING THE T-CELLS TO ALSO 1019 00:38:02,813 --> 00:38:05,115 ENGINEER DEVELOPMENT? 1020 00:38:05,115 --> 00:38:06,550 ARE THOSE REALLY THE 1021 00:38:06,550 --> 00:38:07,717 FUNDAMENTAL RELATIONSHIPS THAT 1022 00:38:07,717 --> 00:38:09,419 ARE POWERFUL FOR CREATING THESE 1023 00:38:09,419 --> 00:38:12,455 NEW PROGRAMS? 1024 00:38:12,455 --> 00:38:19,229 AND SO SEVERAL YEARS AGO, TODA 1025 00:38:19,229 --> 00:38:21,097 AND MARSUIT WHEN POST DOCS THEY 1026 00:38:21,097 --> 00:38:23,867 ASKED CAN WE TAKE CELL LINES 1027 00:38:23,867 --> 00:38:26,369 LIKE IL 19 OR LESS THAT DON'T 1028 00:38:26,369 --> 00:38:28,171 SELF ORGANIZATION AND PUT IN 1029 00:38:28,171 --> 00:38:29,673 PROGRAMS THAT WOULD. 1030 00:38:29,673 --> 00:38:33,210 WHAT IS THE BASIC LOGIC OF 1031 00:38:33,210 --> 00:38:36,213 DEVELOPMENTAL PROGRAMS, ONE 1032 00:38:36,213 --> 00:38:37,113 HYPOTHESIS, MOST PATHWAYS IN 1033 00:38:37,113 --> 00:38:38,048 DEVELOPMENT HAVE CELL THAT'S 1034 00:38:38,048 --> 00:38:41,685 TALK TO ONE ANOTHER AND THOSE 1035 00:38:41,685 --> 00:38:42,986 INDUCE SELECTIVE CHANGES IN 1036 00:38:42,986 --> 00:38:46,289 MORPH FOLG. 1037 00:38:46,289 --> 00:38:48,625 SO CAN WE USE SYN NOTCH TO 1038 00:38:48,625 --> 00:38:49,426 ENGINEER TO RECOGNIZE EACH 1039 00:38:49,426 --> 00:38:53,296 OTHER BUT LINK THOSE TO THE 1040 00:38:53,296 --> 00:38:55,165 INDUCTION OF VARIOUS 1041 00:38:55,165 --> 00:38:57,200 MORPHOLOGICAL, THINGS LIKE 1042 00:38:57,200 --> 00:39:00,370 ADHESION, COULD WE INDUCE 1043 00:39:00,370 --> 00:39:01,638 ADHESION MOLECULES THAT CHANGE 1044 00:39:01,638 --> 00:39:04,207 HOW THE CELLS SORT, AS STANDARD 1045 00:39:04,207 --> 00:39:06,309 FOR DIFFERENTIATION, COULD WE 1046 00:39:06,309 --> 00:39:07,944 INTRODUCE FLUORESCENT PROTEINS 1047 00:39:07,944 --> 00:39:10,714 BUT ALSO INTRODUCE NEW SIGNALS 1048 00:39:10,714 --> 00:39:12,816 LIKE SYN NOTCH LIGANDS THAT 1049 00:39:12,816 --> 00:39:13,283 WOULD CARRY ON THIS 1050 00:39:13,283 --> 00:39:14,517 CONVERSATION FURTHER. 1051 00:39:14,517 --> 00:39:16,653 SO THEY DID THAT, THIS JUST 1052 00:39:16,653 --> 00:39:18,021 SHOWS SOME OF THE THINGS THEY 1053 00:39:18,021 --> 00:39:20,357 WERE ABLE TO DO, THIS WAS A 1054 00:39:20,357 --> 00:39:21,524 CELL POPULATION ABLE TO 1055 00:39:21,524 --> 00:39:23,159 INTERACT WITH ONE ANOTHER AND 1056 00:39:23,159 --> 00:39:25,028 YOU GET THIS DIFFERENTIATION 1057 00:39:25,028 --> 00:39:26,696 INTO GREEN AND RED POPULATION, 1058 00:39:26,696 --> 00:39:28,965 IN THIS CASE, THEY ORGANIZE IN 1059 00:39:28,965 --> 00:39:30,667 THIS POLARIZED FASHION. 1060 00:39:30,667 --> 00:39:33,203 THE NEXT EXAMPLE IS ONE WHERE 1061 00:39:33,203 --> 00:39:35,572 WE HAVE SIMILAR SET OF CELLS WE 1062 00:39:35,572 --> 00:39:36,506 PUT TOGETHER, THEY START 1063 00:39:36,506 --> 00:39:39,109 INTERACTING, WHAT YOU WILL SEE 1064 00:39:39,109 --> 00:39:40,744 IS FORMATION OF A GREEN-COLORED 1065 00:39:40,744 --> 00:39:42,846 CORE AND THAT LEADS TO 1066 00:39:42,846 --> 00:39:48,752 FORMATION OF AN INTERMEDIATE 1067 00:39:48,752 --> 00:39:49,352 RED OR M-CHERRY INTERMEDIATE 1068 00:39:49,352 --> 00:39:50,186 SHELL. 1069 00:39:50,186 --> 00:39:52,489 JUST TO EXPLAIN HOW THIS WORKS, 1070 00:39:52,489 --> 00:39:56,893 IN THIS LAST CASE THIS IS 1071 00:39:56,893 --> 00:39:58,061 RECIPROCAL CONVERSATION BETWEEN 1072 00:39:58,061 --> 00:39:59,696 TWO CELLS. 1073 00:39:59,696 --> 00:40:00,897 TWO CELLS, A AND B SHOWN AT THE 1074 00:40:00,897 --> 00:40:03,233 TOP. 1075 00:40:03,233 --> 00:40:06,002 THE A CELL HAS A SIGNAL THAT 1076 00:40:06,002 --> 00:40:09,005 WILL TURN ON A SYN NOTCH AND B 1077 00:40:09,005 --> 00:40:14,911 WILL TURN ON GFP AND HIGH LEVEL 1078 00:40:14,911 --> 00:40:16,746 OF KADHERON. 1079 00:40:16,746 --> 00:40:20,550 TURNS OUT THAT WAS AN EXTRA 1080 00:40:20,550 --> 00:40:23,620 CELLULAR, THAT TURNS ON M 1081 00:40:23,620 --> 00:40:26,623 SHARING AND INTERMEDIATE LEVEL. 1082 00:40:26,623 --> 00:40:27,757 THOSE CELLS TURN RED AND FORM 1083 00:40:27,757 --> 00:40:29,159 THIS SHELL. 1084 00:40:29,159 --> 00:40:32,429 THIS HAPPENS IN A VERY 1085 00:40:32,429 --> 00:40:33,063 SPONTANEOUS AND STEREOTYPED WAY 1086 00:40:33,063 --> 00:40:34,297 CONSISTENTLY. 1087 00:40:34,297 --> 00:40:36,766 WE CAN CUT THEM AND THEY WILL 1088 00:40:36,766 --> 00:40:37,233 STILL REGENERATE THAT 1089 00:40:37,233 --> 00:40:39,936 STRUCTURE, ET CETERA. 1090 00:40:39,936 --> 00:40:40,470 WE COULD GET SIMPLE SELF 1091 00:40:40,470 --> 00:40:41,338 ORGANIZATION. 1092 00:40:41,338 --> 00:40:43,406 THIS IS ANOTHER EXAMPLE OF A 1093 00:40:43,406 --> 00:40:46,343 LOT OF DEVELOPMENT HAS LARGER 1094 00:40:46,343 --> 00:40:47,911 SCALE INGREDIENTS THAT LEAD TO 1095 00:40:47,911 --> 00:40:50,046 PATTERNING. 1096 00:40:50,046 --> 00:40:56,052 TODA SHOWED HE COULD MAKE A SYN 1097 00:40:56,052 --> 00:40:58,555 NOTCH, BY MAKING SECRETOR CELLS 1098 00:40:58,555 --> 00:40:59,956 THAT WOULD PRODUCE A GFP IN 1099 00:40:59,956 --> 00:41:03,293 THIS CASE, WHAT WE CALL A BODY, 1100 00:41:03,293 --> 00:41:05,362 BOTH ANCHOR CELLS THAT WOULD 1101 00:41:05,362 --> 00:41:07,731 TRAP THE GFP AND THEN COULD 1102 00:41:07,731 --> 00:41:15,705 ALLOW IT TO BE DETECTED BY A 1103 00:41:15,705 --> 00:41:18,508 TELL WITH AN ANTIGFP SYN NOTCH. 1104 00:41:18,508 --> 00:41:20,944 SENDERS AND BODY OF CELLS, FOUR 1105 00:41:20,944 --> 00:41:21,511 MILLILITER SO FAIRLY LARGE 1106 00:41:21,511 --> 00:41:24,047 SCALE. 1107 00:41:24,047 --> 00:41:26,683 WHAT WE SEE WE ARE ABLE TO 1108 00:41:26,683 --> 00:41:28,118 GENERATE A GRADIENT OF RESPONSE 1109 00:41:28,118 --> 00:41:29,519 THAT EMANATES FROM THAT SOURCE. 1110 00:41:29,519 --> 00:41:32,555 AND IF WE NOW ELABORATE THAT 1111 00:41:32,555 --> 00:41:34,190 WITH VARIOUS POSITIVE AND 1112 00:41:34,190 --> 00:41:35,125 NEGATIVE FEEDBACK LOOPS THAT 1113 00:41:35,125 --> 00:41:37,227 OCCUR IN THE BODY, THIS 1114 00:41:37,227 --> 00:41:38,628 ARTIFICIAL BODY OF CELLS WE ARE 1115 00:41:38,628 --> 00:41:40,597 ABLE TO GET THE SAME BODY TO 1116 00:41:40,597 --> 00:41:41,965 RESPOND IN DIFFERENT WAYS TO 1117 00:41:41,965 --> 00:41:44,034 THE GRADIENTS AND WE GET 1118 00:41:44,034 --> 00:41:44,734 DIFFERENT KINDS OF PATTERNS 1119 00:41:44,734 --> 00:41:46,836 LIKE SHOWN ON THE RIGHT SIDE. 1120 00:41:46,836 --> 00:41:48,471 A FRENCH FLAG PATTERN, THE 1121 00:41:48,471 --> 00:41:51,941 CLASSIC RESPONSES THAT HAVE 1122 00:41:51,941 --> 00:41:52,575 BEEN THEORIZED IN DEVELOPMENTAL 1123 00:41:52,575 --> 00:41:54,044 BIOLOGY. 1124 00:41:54,044 --> 00:41:55,678 I WON'T TALK, MUCH OF THAT HAS 1125 00:41:55,678 --> 00:41:56,880 BEEN PUBLISHED AND THERE'S A 1126 00:41:56,880 --> 00:41:58,481 LOT OF INTERESTING STUFF THERE. 1127 00:41:58,481 --> 00:42:01,351 BUT THAT'S KIND OF TAKING CELLS 1128 00:42:01,351 --> 00:42:03,053 THAT DON'T DEVELOP AND TRY TO 1129 00:42:03,053 --> 00:42:10,460 MAKE SIMPLE THINGS FROM SCRATCH. 1130 00:42:10,460 --> 00:42:13,596 WHAT ABOUT TRYING TO GUIDE LIKE 1131 00:42:13,596 --> 00:42:13,897 STEM CELLS. 1132 00:42:13,897 --> 00:42:15,799 ONE THING WE HAVE BEEN 1133 00:42:15,799 --> 00:42:17,200 INTERESTED IN MORE RECENTLY, 1134 00:42:17,200 --> 00:42:20,203 ASKING IF WE CAN TAKE ES CELLS 1135 00:42:20,203 --> 00:42:23,073 AND ENGINEER CELLS THAT WILL 1136 00:42:23,073 --> 00:42:24,307 TALK TO THEM AND SPATIALLY 1137 00:42:24,307 --> 00:42:25,742 DEFINED WAYS. 1138 00:42:25,742 --> 00:42:27,944 THESE ARE WHAT WE ARE CALLING 1139 00:42:27,944 --> 00:42:30,447 SYNTHETIC ORGANIZER CELLS THAT 1140 00:42:30,447 --> 00:42:33,583 COULD PROVIDE MORPH GENIC 1141 00:42:33,583 --> 00:42:33,883 INSTRUCTION. 1142 00:42:33,883 --> 00:42:34,517 WE CAN GET PRETTY INTERESTING 1143 00:42:34,517 --> 00:42:36,319 THINGS TO COME OUT OF THAT. 1144 00:42:36,319 --> 00:42:38,455 YOU KNOW, THE IDEA IS WHEN WE 1145 00:42:38,455 --> 00:42:41,224 LOOK AT DEVELOPMENT AND TRY TO 1146 00:42:41,224 --> 00:42:41,958 DRIVE DIFFERENTIATION IN VITRO, 1147 00:42:41,958 --> 00:42:46,196 MOST OF THE TIME WE ARE TAKING 1148 00:42:46,196 --> 00:42:48,998 ES CELLS AND ADDING MORPHOGENS, 1149 00:42:48,998 --> 00:42:50,433 MAYBE CHANGING THE TIME AND 1150 00:42:50,433 --> 00:42:52,035 DOSE BUT DOING THIS IN THIS 1151 00:42:52,035 --> 00:42:53,670 ISOTROPIC WAY. 1152 00:42:53,670 --> 00:42:55,505 VERY DIFFERENT FROM WHAT 1153 00:42:55,505 --> 00:42:58,174 HAPPENS IN VIVO, THERE ARE 1154 00:42:58,174 --> 00:43:01,911 CELLS IN SPECIFIC LOCATIONS 1155 00:43:01,911 --> 00:43:05,448 PRODUCING SPECIFIC MORPHOGENS. 1156 00:43:05,448 --> 00:43:06,850 SOME EXCITING WORK ON EMBRYOS 1157 00:43:06,850 --> 00:43:09,619 WORK FROM VARIOUS LAB THAT'S 1158 00:43:09,619 --> 00:43:14,657 SHOW EXTRA EMBRYONIC CELLS CAN 1159 00:43:14,657 --> 00:43:16,559 SELF ORGANIZE AROUND ES CELLS 1160 00:43:16,559 --> 00:43:19,729 THAT LEAD TO QUITE ADVANCED IN 1161 00:43:19,729 --> 00:43:22,265 VITRO EMBRYO GENESIS. 1162 00:43:22,265 --> 00:43:26,102 CAN WE TRY TO RECAPITULATE THAT. 1163 00:43:26,102 --> 00:43:26,836 REENGINEER SYNTHETIC CELL 1164 00:43:26,836 --> 00:43:28,438 THAT'S WOULD ORGANIZE IN SPACE 1165 00:43:28,438 --> 00:43:31,007 AROUND THE ES CELLS AND BE NOW 1166 00:43:31,007 --> 00:43:36,846 THE SOURCES OF THESE MORPHOGENS. 1167 00:43:36,846 --> 00:43:38,615 WE NEED TO PROGRAM SPATIAL CELL 1168 00:43:38,615 --> 00:43:41,284 ASSEMBLY. 1169 00:43:41,284 --> 00:43:42,685 NATURAL ADHESION AND ENGINEERED 1170 00:43:42,685 --> 00:43:45,488 ONES WE COULD PROGRAM WITH 1171 00:43:45,488 --> 00:43:47,557 SYNTHETIC ADHESION MOLECULES. 1172 00:43:47,557 --> 00:43:51,761 AS I SHOWED BEFORE THESE MOVIES 1173 00:43:51,761 --> 00:43:52,929 ARE FIBROBLAST CELL LINES 1174 00:43:52,929 --> 00:43:54,364 ENGINEERED, THE SAME ONES BUT 1175 00:43:54,364 --> 00:43:56,633 ENGINEERED IN DIFFERENT WAYS TO 1176 00:43:56,633 --> 00:43:58,034 ORGANIZE AROUND THESE RED ES 1177 00:43:58,034 --> 00:43:59,536 CELLS IN EITHER FORMING A NODE 1178 00:43:59,536 --> 00:44:01,070 OR A SHELL. 1179 00:44:01,070 --> 00:44:03,439 WHAT WE CAN DO WITH THESE IS 1180 00:44:03,439 --> 00:44:08,044 NOW COMBINE IN DIFFERENT WAYS 1181 00:44:08,044 --> 00:44:10,380 AND GET DIFFERENT 1182 00:44:10,380 --> 00:44:11,347 ARCHITECTURES, SINGLE NODE, 1183 00:44:11,347 --> 00:44:12,982 SHELLS COMBINED TO GET 1184 00:44:12,982 --> 00:44:16,519 DIFFERENT PATTERNS AND TRY TO 1185 00:44:16,519 --> 00:44:17,820 EXPRESS MORPHOGENS FROM THESE 1186 00:44:17,820 --> 00:44:19,789 ANISOTROPIC WAYS. 1187 00:44:19,789 --> 00:44:23,059 THE FIRST THING, THIS IS WORK 1188 00:44:23,059 --> 00:44:25,395 FROM TOSHI, POST DOC IN THE 1189 00:44:25,395 --> 00:44:28,665 LAB, IS TO ASK CAN WE DELIVER 1190 00:44:28,665 --> 00:44:31,434 THIS KEY EARLY EMBRYONIC 1191 00:44:31,434 --> 00:44:33,937 MORPHOGEN WITH 3A FROM SPECIFIC 1192 00:44:33,937 --> 00:44:35,805 ORGANIZER CELLS AND WHAT WE 1193 00:44:35,805 --> 00:44:38,208 FIND IS WE CAN GENERATE VERY 1194 00:44:38,208 --> 00:44:38,708 TUNABLE AND DIRECTIONAL 1195 00:44:38,708 --> 00:44:41,177 GRADIENTS. 1196 00:44:41,177 --> 00:44:46,816 THESE ARE ES CELLS WITH PTCF 1197 00:44:46,816 --> 00:44:47,483 MCHERRY, THAT'S WHY IT WILL 1198 00:44:47,483 --> 00:44:49,919 TURN ON. 1199 00:44:49,919 --> 00:44:52,722 IF WE GIVE A WNT AGONIST, IT 1200 00:44:52,722 --> 00:44:54,824 TURNS ON, IN THE MEDIA IT TURNS 1201 00:44:54,824 --> 00:44:56,960 EVERYTHING ON IN THIS ISOTROPIC 1202 00:44:56,960 --> 00:44:59,262 SPHERICAL WAY. 1203 00:44:59,262 --> 00:45:01,331 IF WE PROVIDE WNT EXPRESS FROM 1204 00:45:01,331 --> 00:45:01,965 SHELL, WE SEE SOMETHING VERY 1205 00:45:01,965 --> 00:45:04,133 SIMILAR. 1206 00:45:04,133 --> 00:45:07,370 BUT IF WE EXPRESS WNT FROM THIS 1207 00:45:07,370 --> 00:45:08,538 NODE WE SEE POLARIZED 1208 00:45:08,538 --> 00:45:10,873 ACTIVATION, GRADIENT THAT GOES 1209 00:45:10,873 --> 00:45:12,542 ACROSS THAT AND ELON GAIGS OF 1210 00:45:12,542 --> 00:45:15,578 THE BODY ALONG WHAT LOOKS LIKE 1211 00:45:15,578 --> 00:45:17,380 A PRIMITIVE ANTERIOR, POS 1212 00:45:17,380 --> 00:45:18,381 STEEROR AXIS. 1213 00:45:18,381 --> 00:45:22,352 IF WE MAKE A SECOND NODE AND 1214 00:45:22,352 --> 00:45:29,359 PUT IT 180° AWAY AND MAKE A WNT 1215 00:45:29,359 --> 00:45:33,630 INHIBITOR DKK1 WE CAN GET 1216 00:45:33,630 --> 00:45:35,231 STEEPER, ACROSS THE SPAN OF 1217 00:45:35,231 --> 00:45:37,300 THAT BODY, IF YOU WILL. 1218 00:45:37,300 --> 00:45:39,736 SO WHAT HAPPENS AS WE TUNE 1219 00:45:39,736 --> 00:45:42,071 THESE GRADIENTS? WHAT HAPPENS 1220 00:45:42,071 --> 00:45:43,940 TO THE MORPHOLOGICAL OUTPUTS? 1221 00:45:43,940 --> 00:45:45,008 WHAT IS SHOWN HERE AFTER EIGHT 1222 00:45:45,008 --> 00:45:46,409 DAYS SOME OF THE THINGS WE SEE. 1223 00:45:46,409 --> 00:45:47,443 I WANT TO START WITH THE MIDDLE 1224 00:45:47,443 --> 00:45:48,511 ONE. 1225 00:45:48,511 --> 00:45:51,781 WHICH IS WHERE WE HAVE BOTH THE 1226 00:45:51,781 --> 00:45:54,617 WNT AND DKK NODES, THE 1227 00:45:54,617 --> 00:45:57,620 INHIBITOR, THIS LEADS TO STEEP 1228 00:45:57,620 --> 00:45:59,289 GRADIENT WITH HIGH DYNAMIC 1229 00:45:59,289 --> 00:46:01,824 RANGE ACROSS THE WHOLE BODY. 1230 00:46:01,824 --> 00:46:02,792 WE SEE SPECIFIC TISSUES 1231 00:46:02,792 --> 00:46:05,828 ARRANGED IN MORE OR LESS THE 1232 00:46:05,828 --> 00:46:06,429 CORRECT ANTERIOR, POS STEEROR 1233 00:46:06,429 --> 00:46:09,299 ARRANGEMENT. 1234 00:46:09,299 --> 00:46:12,335 WE SEE THINGS LIKE OTX2 NEURAL 1235 00:46:12,335 --> 00:46:14,671 MARKERS AROUND THE DKK1 NODE 1236 00:46:14,671 --> 00:46:17,006 AND THEN VARIOUS MARKERS FOR 1237 00:46:17,006 --> 00:46:18,341 EXAMPLE, THIS IS CARDIAC 1238 00:46:18,341 --> 00:46:19,042 TISSUE, VERY LOCALIZED IN THE 1239 00:46:19,042 --> 00:46:20,076 MIDDLE. 1240 00:46:20,076 --> 00:46:22,612 WE THINK THIS IS THE ANTERIOR 1241 00:46:22,612 --> 00:46:24,614 AND POS STEEROR IN THIS DUAL 1242 00:46:24,614 --> 00:46:27,050 NODE STRUCTURE. 1243 00:46:27,050 --> 00:46:30,320 INTERESTINGLY THOUGH, IF WE USE 1244 00:46:30,320 --> 00:46:37,860 SINGLE NODE WITH DKK1 WE GET 1245 00:46:37,860 --> 00:46:43,232 ALMOST ALL NEURAL FATES. 1246 00:46:43,232 --> 00:46:45,134 WE SEE POSTERIOR AND THE 1247 00:46:45,134 --> 00:46:46,469 CARDIAC TISSUE AT THE MOST 1248 00:46:46,469 --> 00:46:49,272 ANTERIOR THERE. 1249 00:46:49,272 --> 00:46:52,542 AND SO WHAT WE SEE, WE CAN SEE 1250 00:46:52,542 --> 00:46:53,910 SPECIFIC LINEAGES ARISING AND 1251 00:46:53,910 --> 00:46:58,414 ORGANIZED IN THE APPROPRIATE 1252 00:46:58,414 --> 00:46:59,549 ANTERIOR POSTERIOR TOPOLOGY BUT 1253 00:46:59,549 --> 00:47:02,118 THE RANGE AND SHAPE AND 1254 00:47:02,118 --> 00:47:04,454 STEEPNESS DETERMINE THE 1255 00:47:04,454 --> 00:47:06,723 SPECTRUM OF LINEAGES WE 1256 00:47:06,723 --> 00:47:08,891 OBSERVED IN THE RESULTING 1257 00:47:08,891 --> 00:47:11,160 EMBRYOID. 1258 00:47:11,160 --> 00:47:14,097 DUAL HEAD WITH THE MOST RANGE 1259 00:47:14,097 --> 00:47:14,364 OF FATES. 1260 00:47:14,364 --> 00:47:17,767 ONE THING I HOPE YOU CAN SEE IN 1261 00:47:17,767 --> 00:47:19,869 THE MOVIE, THE BEATING CARDIAC 1262 00:47:19,869 --> 00:47:23,139 TISSUE, IT'S LOCALIZED. 1263 00:47:23,139 --> 00:47:25,007 THESE ARE SELF ORGANIZING 1264 00:47:25,007 --> 00:47:27,910 ORGANIZED SUB TISSUES IN THIS 1265 00:47:27,910 --> 00:47:30,613 ANTERIOR, POSTERIOR AXIS. 1266 00:47:30,613 --> 00:47:32,248 IF WE LOOK MORE CAREFULLY IN 1267 00:47:32,248 --> 00:47:35,985 THE CASE IF WE HAVE SINGLE WNT 1268 00:47:35,985 --> 00:47:37,420 NODE, THAT HAPPENS THERE, THIS 1269 00:47:37,420 --> 00:47:39,055 GRADIENT IS LESS STEEP AND YOU 1270 00:47:39,055 --> 00:47:41,357 DON'T GET ALL THE TISSUES BUT 1271 00:47:41,357 --> 00:47:45,528 IT'S SHALLOWER, WE FIND WE 1272 00:47:45,528 --> 00:47:48,097 ACTUALLY GET INTERESTING 1273 00:47:48,097 --> 00:47:49,966 MORPHOLOGY SUGGESTING HIGHER 1274 00:47:49,966 --> 00:47:50,433 RESOLUTION SPATIAL OR 1275 00:47:50,433 --> 00:47:51,567 MORPHOLOGICAL INFORMATION. 1276 00:47:51,567 --> 00:47:56,305 ONE THING WE SEE PROBABLY ABOUT 1277 00:47:56,305 --> 00:47:58,875 15% OF THOSE EMBRYOIDS. 1278 00:47:58,875 --> 00:48:02,645 WE SEE A CAVITY, AND HEART BY 1279 00:48:02,645 --> 00:48:04,380 IMAGING HAS A REGULAR BEAT, 1280 00:48:04,380 --> 00:48:05,915 WHICH IS QUITE UNEXPECTED AND 1281 00:48:05,915 --> 00:48:08,718 REALLY DIFFICULT TO SEE IN A 1282 00:48:08,718 --> 00:48:09,385 SPONTANEOUS SELF ORGANIZING 1283 00:48:09,385 --> 00:48:12,488 WAY, THIS KIND OF STRUCTURE. 1284 00:48:12,488 --> 00:48:14,357 MOST OTHER EFFORTS AT 1285 00:48:14,357 --> 00:48:16,626 RECONSTRUCTING HEARTS HAVE 1286 00:48:16,626 --> 00:48:18,227 INVOLVED TAKING MULTIPLE 1287 00:48:18,227 --> 00:48:19,228 LINEAGES AND COMBINING THEM. 1288 00:48:19,228 --> 00:48:21,063 NOT ONLY TO WE SEE THIS 1289 00:48:21,063 --> 00:48:24,200 HEART-LIKE CAVITY. 1290 00:48:24,200 --> 00:48:31,974 IT HAS MARKERS LIKE CARDIAC TRA 1291 00:48:31,974 --> 00:48:33,576 CONE IN, OR TX2K5 LOCALIZED 1292 00:48:33,576 --> 00:48:37,847 AROUND THE REGION, BUT WE SEE 1293 00:48:37,847 --> 00:48:39,215 BY STAINING FOR ENDOTHELIAL 1294 00:48:39,215 --> 00:48:41,818 MARKERS, IT LOOKS IT'S LINKED 1295 00:48:41,818 --> 00:48:42,919 TO THE EXTENDED VASCULAR 1296 00:48:42,919 --> 00:48:51,227 NETWORK MARKED IN GREEN. 1297 00:48:51,227 --> 00:48:52,929 (NKX2.5) REALLY THIS IS AN 1298 00:48:52,929 --> 00:48:55,231 AMAZING CASE OF SELF 1299 00:48:55,231 --> 00:48:56,866 ORGANIZATION OF A MULTI-CELL 1300 00:48:56,866 --> 00:49:01,103 TYPE HEART-LIKE STRUCTURE IN A 1301 00:49:01,103 --> 00:49:01,471 SPONTANEOUS WAY. 1302 00:49:01,471 --> 00:49:03,406 SO ONE OF THE THINGS WE ARE 1303 00:49:03,406 --> 00:49:04,841 THINKING, THERE ARE KIND OF 1304 00:49:04,841 --> 00:49:07,410 DIFFERENT WAYS OF LOOKING HOW 1305 00:49:07,410 --> 00:49:09,145 TO DRIVE DEVELOPMENT IN VITRO 1306 00:49:09,145 --> 00:49:11,147 OR RECONSTITUTING. 1307 00:49:11,147 --> 00:49:13,716 SOME WORK IN THE PAST HAS BEEN 1308 00:49:13,716 --> 00:49:16,285 TAKING ES CELLS AND USING 1309 00:49:16,285 --> 00:49:19,255 COMBINATIONS OF PROTOCOLS OF 1310 00:49:19,255 --> 00:49:20,656 DIFFERENTIATION FACTORS TO 1311 00:49:20,656 --> 00:49:23,292 DRIVE DIFFERENTIATION OF 1312 00:49:23,292 --> 00:49:24,494 SPECIFIC LINEAGES AND MAYBE YOU 1313 00:49:24,494 --> 00:49:25,795 COMBINE THOSE IF YOU ARE 1314 00:49:25,795 --> 00:49:29,198 INTERESTED IN TISSUES. 1315 00:49:29,198 --> 00:49:35,137 ON THE SYNTHETIC EMBRYO SIDE 1316 00:49:35,137 --> 00:49:36,906 USING FAIRLY NATURAL CELLS, CAN 1317 00:49:36,906 --> 00:49:38,508 YOU PUSH ALL THE LINEAGES AND 1318 00:49:38,508 --> 00:49:39,308 GET SELF ORGANIZATION OF THE 1319 00:49:39,308 --> 00:49:41,310 WHOLE BODY. 1320 00:49:41,310 --> 00:49:42,945 WE THINK WITH SOME SYNTHETIC 1321 00:49:42,945 --> 00:49:44,347 ORGANIZERS WE CAN TUNE 1322 00:49:44,347 --> 00:49:46,015 SOMEWHERE BETWEEN THAT TO DRIVE 1323 00:49:46,015 --> 00:49:49,318 CERTAIN REGIONS OR RANGES OF 1324 00:49:49,318 --> 00:49:50,953 LINEAGES AND STILL GET SOME 1325 00:49:50,953 --> 00:49:53,055 SELF ORGANIZATION OR DRIVE 1326 00:49:53,055 --> 00:49:55,658 THINGS TO NON NATURAL NON 1327 00:49:55,658 --> 00:49:56,792 NATIVE FATES IN SOME CONTROLLED 1328 00:49:56,792 --> 00:49:57,994 WAYS. 1329 00:49:57,994 --> 00:49:59,562 THIS IS EARLY DAYS BUT WE ARE 1330 00:49:59,562 --> 00:50:01,063 VERY EXCITED ABOUT THAT. 1331 00:50:01,063 --> 00:50:03,165 WHAT WE HAVE SHOWN WITH THE 1332 00:50:03,165 --> 00:50:05,568 SYNTHETIC DEVELOPMENT WORK, WE 1333 00:50:05,568 --> 00:50:09,272 CAN COMBINE COMPONENTS THAT 1334 00:50:09,272 --> 00:50:11,140 CONTROL CELL-CELL SIGNALING, 1335 00:50:11,140 --> 00:50:14,610 DIFFERENTIATING CELL ADHESION 1336 00:50:14,610 --> 00:50:16,712 AND MORPHOLOGICAL PRODUCTION 1337 00:50:16,712 --> 00:50:27,256 FOR EXTRA CELLULAR MORPHOLOGIES. 1338 00:50:29,125 --> 00:50:31,627 THEY CAN PROVIDE PROGRAMABLE 1339 00:50:31,627 --> 00:50:32,995 CELLS WITH INFORMATION RICH 1340 00:50:32,995 --> 00:50:38,868 SPATIAL THAT CAN GENERATE 1341 00:50:38,868 --> 00:50:40,036 DISTINCT TISSUE, ASSOCIATED 1342 00:50:40,036 --> 00:50:41,904 VASCULAR NETWORK, WE CAN CUSTOM 1343 00:50:41,904 --> 00:50:43,506 TUNE THE GRADIENT RANGE AND 1344 00:50:43,506 --> 00:50:44,907 STEEPNESS TO ALTER THE RANGE 1345 00:50:44,907 --> 00:50:46,609 AND RESOLUTION OF THE 1346 00:50:46,609 --> 00:50:48,177 MORPHOLOGICAL OUTCOMES. 1347 00:50:48,177 --> 00:50:49,579 AND THIS APPROACH, WE THINK 1348 00:50:49,579 --> 00:50:53,015 COULD BE APPLIED TO MANY 1349 00:50:53,015 --> 00:50:58,454 DIFFERENT TYPES OF MORPHOGENS 1350 00:50:58,454 --> 00:51:00,122 AS PROGENITOR CELLS. 1351 00:51:00,122 --> 00:51:05,394 COULD WE USE THIS APPROACH IN 1352 00:51:05,394 --> 00:51:08,230 VIVO TO GENERATE OR RECONSTRUCT 1353 00:51:08,230 --> 00:51:13,469 AROUND SITES OF INJURY TO DRIVE 1354 00:51:13,469 --> 00:51:15,237 REGENERATION IN SITU. 1355 00:51:15,237 --> 00:51:17,006 A LONG WAYS AWAY BUT REALLY 1356 00:51:17,006 --> 00:51:18,040 EXCITING. 1357 00:51:18,040 --> 00:51:19,241 TO CONCLUDE THE WHOLE TALK I 1358 00:51:19,241 --> 00:51:21,110 HOPE I HAVE BEEN ABLE TO SHOW 1359 00:51:21,110 --> 00:51:23,713 YOU LIVING CELLS ARE THESE 1360 00:51:23,713 --> 00:51:25,114 AMAZING MACHINES UNLIKE OTHER 1361 00:51:25,114 --> 00:51:27,216 SCALES LIKE MOLECULES HAVE THIS 1362 00:51:27,216 --> 00:51:29,552 MUCH HIGHER LEVEL TO INTEGRATE 1363 00:51:29,552 --> 00:51:32,321 INFORMATION OVER A HIERARCHY OF 1364 00:51:32,321 --> 00:51:34,256 SCALES, ANATOMICAL OR 1365 00:51:34,256 --> 00:51:35,658 MOLECULAR, AND THEY CAN 1366 00:51:35,658 --> 00:51:38,461 SPATIALLY COORDINATE BY SENSING 1367 00:51:38,461 --> 00:51:39,495 AND INTERACTING WITH THEIR 1368 00:51:39,495 --> 00:51:40,062 ENVIRONMENT OR NEIGHBORING 1369 00:51:40,062 --> 00:51:40,563 CELLS. 1370 00:51:40,563 --> 00:51:42,198 IF WE TAKE ADVANTAGE OF THIS, 1371 00:51:42,198 --> 00:51:44,800 THERE ARE MANY THINGS WE CAN DO 1372 00:51:44,800 --> 00:51:46,636 AND BUILD TOOLS AND SENSORS 1373 00:51:46,636 --> 00:51:49,071 THAT ALLOW US TO PRECISELY 1374 00:51:49,071 --> 00:51:51,407 CONTROL AND CHANGE THE CELLULAR 1375 00:51:51,407 --> 00:51:53,275 INTERACTIONS AND BUILD 1376 00:51:53,275 --> 00:51:55,711 DIFFERENT CELLULAR PROGRAMS AND 1377 00:51:55,711 --> 00:51:58,080 CIRCUIT, INCLUDING USING THESE 1378 00:51:58,080 --> 00:51:59,715 TWO OPERATING, MANY DIFFERENT 1379 00:51:59,715 --> 00:52:01,150 CELLS INCLUDING IMMUNE CELLS 1380 00:52:01,150 --> 00:52:05,087 THAT COULD SEARCH FOR CANCER OR 1381 00:52:05,087 --> 00:52:06,288 TARGET TISSUE FOR SUPPRESSING 1382 00:52:06,288 --> 00:52:08,391 INFLAMMATION OR PUTTING IN CELL 1383 00:52:08,391 --> 00:52:09,759 THAT'S COULD PROVIDE SPATIAL 1384 00:52:09,759 --> 00:52:10,359 INSTRUCTION THAT COULD GUIDE 1385 00:52:10,359 --> 00:52:12,094 DEVELOPMENT. 1386 00:52:12,094 --> 00:52:14,196 AND JUST WANT TO LEAVE YOU WITH 1387 00:52:14,196 --> 00:52:16,532 THE THOUGHT THAT UNDERSTANDING 1388 00:52:16,532 --> 00:52:21,170 HOW TO MANIPULATE THE LOGIC 1389 00:52:21,170 --> 00:52:22,605 WILL ANSWER I THINK MANY 1390 00:52:22,605 --> 00:52:23,205 QUESTIONS IN BIOLOGY WE DON'T 1391 00:52:23,205 --> 00:52:24,006 UNDERSTAND. 1392 00:52:24,006 --> 00:52:28,878 WE KNOW A LOT ABOUT THE 1393 00:52:28,878 --> 00:52:32,648 COMPONENTS OF BIOLOGY, WE KNOW 1394 00:52:32,648 --> 00:52:33,649 LESS HOW THEY ARE PUT TOGETHER, 1395 00:52:33,649 --> 00:52:35,685 THE LOGIC. 1396 00:52:35,685 --> 00:52:38,220 POWERFUL WAYS TO GENERATE NEW 1397 00:52:38,220 --> 00:52:39,388 THERAPEUTIC PLATFORM THAT'S 1398 00:52:39,388 --> 00:52:41,257 COULD INTERFACE WITH COMPLEX 1399 00:52:41,257 --> 00:52:46,729 DISEASES LIKE CANCER OR 1400 00:52:46,729 --> 00:52:49,498 FIBROSIS OR AUTOIMMUNITY. 1401 00:52:49,498 --> 00:52:50,833 WE CAN DIRECT THE CONVERSATIONS 1402 00:52:50,833 --> 00:52:53,169 THAT HAPPEN IN THESE ECOSYSTEMS. 1403 00:52:53,169 --> 00:52:54,804 WITH THAT LET ME THANK ALL THE 1404 00:52:54,804 --> 00:52:55,771 PEOPLE IN MY LAB AND 1405 00:52:55,771 --> 00:52:56,706 COLLABORATORS. 1406 00:52:56,706 --> 00:53:04,647 I WANT TO FOCUS, MILO SIMIC THE 1407 00:53:04,647 --> 00:53:08,551 FELLOW LEADING THAT, WATCHMAKER. 1408 00:53:08,551 --> 00:53:12,855 SCOTT ZAMVIL. 1409 00:53:12,855 --> 00:53:21,163 ALSO BIO INFORMATICS DONE WITH 1410 00:53:21,163 --> 00:53:22,932 MY COLLEAGUE AT PRINCETON. 1411 00:53:22,932 --> 00:53:25,968 THE SYNTHETIC ORGANIZE ERICCA 1412 00:53:25,968 --> 00:53:30,906 ALSTEAD WORK DONE BY SOSHI 1413 00:53:30,906 --> 00:53:32,742 YAMADA IN COLLABORATION WITH 1414 00:53:32,742 --> 00:53:34,043 OPHIR KLEIN. 1415 00:53:34,043 --> 00:53:35,411 SO THANK YOU VERY MUCH. 1416 00:53:35,411 --> 00:53:37,313 [ APPLAUSE ] 1417 00:53:37,313 --> 00:53:39,014 >> ANYONE WITH QUESTIONS PLEASE 1418 00:53:39,014 --> 00:53:40,082 USE THE MICKS. 1419 00:53:40,082 --> 00:53:41,517 WE HAD A QUESTION THAT CAME IN, 1420 00:53:41,517 --> 00:53:42,685 IF YOU ARE READY FOR IT. 1421 00:53:42,685 --> 00:53:44,754 >> OKAY. 1422 00:53:44,754 --> 00:53:48,891 >> SO HOW DO BRAIN TARGETED CAR 1423 00:53:48,891 --> 00:53:53,429 T CELLS PENETRATE THE 1424 00:53:53,429 --> 00:53:54,730 BLOOD-BRAIN BARRIER? 1425 00:53:54,730 --> 00:53:57,533 >> WE KNOW THERE IS ALWAYS, I 1426 00:53:57,533 --> 00:53:59,401 MEAN T-CELLS CAN GET IN THE 1427 00:53:59,401 --> 00:54:01,003 BRAIN, THEY END UP CAUSING 1428 00:54:01,003 --> 00:54:06,475 M.S., THEY CAN GET IN EARLY GBM 1429 00:54:06,475 --> 00:54:07,977 TRIALS THAT EGFR CAR THEY DID 1430 00:54:07,977 --> 00:54:09,779 GET INTO THE BRAIN. 1431 00:54:09,779 --> 00:54:12,348 IT'S PRETTY CLEAR IN DISEASES 1432 00:54:12,348 --> 00:54:13,916 LIKE BRAIN TUMORS AND M.S., 1433 00:54:13,916 --> 00:54:17,386 THERE ARE SOME ALSO SOME DAMAGE 1434 00:54:17,386 --> 00:54:19,955 TO THE BBB THAT ALLOWS CELLS TO 1435 00:54:19,955 --> 00:54:20,422 GET IN EARLIER, MORE 1436 00:54:20,422 --> 00:54:22,958 EFFECTIVELY. 1437 00:54:22,958 --> 00:54:24,627 SO IT'S UNCLEAR, OUR CELLS ARE 1438 00:54:24,627 --> 00:54:26,595 GETTING IN THERE, WE DO SEE 1439 00:54:26,595 --> 00:54:28,864 THEM, THEY ARE PROLIFERATING. 1440 00:54:28,864 --> 00:54:31,200 SO THEY DO GET IN. 1441 00:54:31,200 --> 00:54:33,769 TO SOME DEGREE, WE THINK IT'S 1442 00:54:33,769 --> 00:54:35,404 AMPLIFIED IN THESE PARTICULAR 1443 00:54:35,404 --> 00:54:37,273 DISEASE CASES BUT WE ARE 1444 00:54:37,273 --> 00:54:38,707 WORKING ON TRYING TO IMPROVE 1445 00:54:38,707 --> 00:54:40,476 WAYS TO GET THEM THROUGH THE 1446 00:54:40,476 --> 00:54:42,711 BBB. 1447 00:54:42,711 --> 00:54:44,313 >> VERY BRILLIANT, AS USUAL. 1448 00:54:44,313 --> 00:54:47,616 MY QUESTION IS ABOUT THE 1449 00:54:47,616 --> 00:54:48,517 SPECIFICITY OF YOUR GBM 1450 00:54:48,517 --> 00:54:49,985 TARGETING T-CELLS. 1451 00:54:49,985 --> 00:54:50,853 YOU SHOWED BACKGROUND 1452 00:54:50,853 --> 00:54:52,521 INFORMATION IN THE SPLEEN. 1453 00:54:52,521 --> 00:54:54,890 DO YOU UNDERSTAND IT, IS THERE 1454 00:54:54,890 --> 00:54:58,027 ENOUGH LIGANDS IN THE SPLEEN? 1455 00:54:58,027 --> 00:54:59,628 WHAT IS HAPPENING THERE? 1456 00:54:59,628 --> 00:55:01,063 IS THERE LEAKINESS. 1457 00:55:01,063 --> 00:55:02,498 >> YOU ARE SEEING THE GLASS 1458 00:55:02,498 --> 00:55:07,503 HALF EMPTY. 1459 00:55:07,503 --> 00:55:08,003 >> VERY CONCERNED ABOUT 1460 00:55:08,003 --> 00:55:09,138 BACKGROUND. 1461 00:55:09,138 --> 00:55:10,806 >> IT'S MUCH, MUCH LOWER. 1462 00:55:10,806 --> 00:55:16,645 THERE'S A LITTLE BIT, I WOULD 1463 00:55:16,645 --> 00:55:22,284 SAY, WE, I GUESS, WE HAVE DONE 1464 00:55:22,284 --> 00:55:22,985 EXTENSIVE NON-BRAIN TUMOR 1465 00:55:22,985 --> 00:55:23,686 KILLING AND WE DON'T SEE 1466 00:55:23,686 --> 00:55:26,288 ANYTHING THERE. 1467 00:55:26,288 --> 00:55:27,122 WE DON'T SEE PROLIFERATION OF 1468 00:55:27,122 --> 00:55:28,157 CELLS THERE. 1469 00:55:28,157 --> 00:55:30,059 WE THINK WE ARE BELOW THE 1470 00:55:30,059 --> 00:55:33,562 THRESHOLD FOR ANY SORT OF 1471 00:55:33,562 --> 00:55:33,796 EFFECTS. 1472 00:55:33,796 --> 00:55:35,197 >> I GUESS MORE GENERAL 1473 00:55:35,197 --> 00:55:36,866 QUESTION, MOVING FROM THE MOUSE 1474 00:55:36,866 --> 00:55:38,734 MODEL TO PATIENT, DO YOU HAVE A 1475 00:55:38,734 --> 00:55:40,669 WAY TO TEST THE DIFFERENT 1476 00:55:40,669 --> 00:55:45,674 TISSUES TO SEE -- 1477 00:55:45,674 --> 00:55:49,278 >> WELL, I MEAN, WE'VE GONE 1478 00:55:49,278 --> 00:55:50,846 THROUGH THE R&D PROCESS ON THIS 1479 00:55:50,846 --> 00:55:53,916 AND WE ARE USING MOUSE CROSS 1480 00:55:53,916 --> 00:55:54,550 REACTIVE ANTIBODIES. 1481 00:55:54,550 --> 00:55:59,188 WE ARE DOING TOX IN THE MOUSE. 1482 00:55:59,188 --> 00:56:01,090 ALSO RECHECKING EVERYTHING 1483 00:56:01,090 --> 00:56:02,458 AGAINST HUMAN TISSUE LIBRARIES 1484 00:56:02,458 --> 00:56:03,325 AND SO FAR THAT'S ALL CHECKED 1485 00:56:03,325 --> 00:56:05,294 OUT. 1486 00:56:05,294 --> 00:56:09,932 YOU KNOW, THIS IS WHAT A DOSE 1487 00:56:09,932 --> 00:56:11,233 ESCALATION IS FOR. 1488 00:56:11,233 --> 00:56:15,871 I WOULD SAY, A LOT OF THESE, 1489 00:56:15,871 --> 00:56:18,007 THE EGFR 3, THAT CAR HAS BEEN 1490 00:56:18,007 --> 00:56:19,041 IN TRIALS AND THERE WASN'T A 1491 00:56:19,041 --> 00:56:21,677 PROBLEM. 1492 00:56:21,677 --> 00:56:22,811 SO YOU KNOW, COMBINATION OF 1493 00:56:22,811 --> 00:56:25,781 THINGS. 1494 00:56:25,781 --> 00:56:26,482 BUT THERE ARE UNKNOWNS. 1495 00:56:26,482 --> 00:56:27,883 YES? 1496 00:56:27,883 --> 00:56:31,186 >> WHEN YOU WERE SHOWING US THE 1497 00:56:31,186 --> 00:56:33,923 EXPRESSION OF THE WNT, AND YOU 1498 00:56:33,923 --> 00:56:36,725 SHOWED US THE GRADIENT WHEN YOU 1499 00:56:36,725 --> 00:56:39,328 INDUCED THE NODES AND 1500 00:56:39,328 --> 00:56:40,362 INHIBITORS WHAT WERE YOU USING 1501 00:56:40,362 --> 00:56:41,797 TO DIRECT THE NODES AND 1502 00:56:41,797 --> 00:56:43,065 INHIBITORS? 1503 00:56:43,065 --> 00:56:43,799 >> TO THE SECOND NODE? 1504 00:56:43,799 --> 00:56:45,334 >> YES. 1505 00:56:45,334 --> 00:56:47,303 >> THE SECOND NODE HAS MORE -- 1506 00:56:47,303 --> 00:56:49,171 ELEMENT TO IT AND WE ARE 1507 00:56:49,171 --> 00:56:50,472 TRYING TO IMPROVE THAT. 1508 00:56:50,472 --> 00:56:56,712 >> OKAY, AND THE ON THE CARDIAC 1509 00:56:56,712 --> 00:56:58,113 EXPRESSING CELLS, WHAT WERE 1510 00:56:58,113 --> 00:57:00,683 THEY, SO THEY INDUCED THE 1511 00:57:00,683 --> 00:57:01,583 VESSEL EXPRESSION IN THE NEARBY 1512 00:57:01,583 --> 00:57:03,986 CELLS. 1513 00:57:03,986 --> 00:57:06,555 DID THOSE VESSEL, WHAT DID 1514 00:57:06,555 --> 00:57:07,589 THOSE VESSEL EXPRESSING DO TO 1515 00:57:07,589 --> 00:57:10,726 THE NEIGHBORING CELLS? 1516 00:57:10,726 --> 00:57:12,861 >> WENDELL LIM: YEAH, WE ARE 1517 00:57:12,861 --> 00:57:14,029 JUST KICK-STARTING THE EVENT. 1518 00:57:14,029 --> 00:57:15,597 THIS IS ONE SIGNAL. 1519 00:57:15,597 --> 00:57:20,469 AND CLEARLY, THERE'S A LOT OF 1520 00:57:20,469 --> 00:57:22,204 WNT PNB4, A LOT OF THINGS THAT 1521 00:57:22,204 --> 00:57:24,006 GO ON IN REGIONS THERE. 1522 00:57:24,006 --> 00:57:32,281 SO WE ARE TRYING TO TRACK BY 1523 00:57:32,281 --> 00:57:33,916 SCOPE AND OTHER THINGS WHAT ARE 1524 00:57:33,916 --> 00:57:34,950 THE SEQUEL LA OF EVENT THAT'S 1525 00:57:34,950 --> 00:57:36,018 HAPPEN. 1526 00:57:36,018 --> 00:57:39,455 THIS IS THE TRICKY THING. 1527 00:57:39,455 --> 00:57:40,322 ONE TRIGGERING THE NEXT THING 1528 00:57:40,322 --> 00:57:41,523 AND SO FORTH. 1529 00:57:41,523 --> 00:57:42,758 SO THAT'S ALL TO BE WORKED OUT. 1530 00:57:42,758 --> 00:57:47,162 >> THANK YOU. 1531 00:57:47,162 --> 00:57:48,430 >> GREAT TALK. 1532 00:57:48,430 --> 00:57:52,468 I HAVE A QUESTION ABOUT YOUR 1533 00:57:52,468 --> 00:57:54,703 BRAIN-SPECIFIC SYN NOTCH CAR. 1534 00:57:54,703 --> 00:57:58,240 AND YOU ARE USING TANDEM CAR? 1535 00:57:58,240 --> 00:57:59,641 AND I'M WONDERING IF THERE'S 1536 00:57:59,641 --> 00:58:01,744 ANY DIFFERENCE WHEN YOU HAVE 1537 00:58:01,744 --> 00:58:04,313 ONLY SINGLE TARGET VERSUS TWO 1538 00:58:04,313 --> 00:58:05,514 TARGETS, ANY RATIONALE BETWEEN 1539 00:58:05,514 --> 00:58:07,082 USING TANDEM CAR? 1540 00:58:07,082 --> 00:58:11,487 >> WENDELL LIM: YEAH, THE 1541 00:58:11,487 --> 00:58:12,421 RATIONALE BEHIND USING THE 1542 00:58:12,421 --> 00:58:14,523 TANDEM CAR HAS TO DO WITH THE 1543 00:58:14,523 --> 00:58:15,691 FACT THAT EVERY PATIENT IS 1544 00:58:15,691 --> 00:58:19,028 DIFFERENT, BUT THE NUMBER OF 1545 00:58:19,028 --> 00:58:29,438 PATIENTS THAT HAVE HIGH 1546 00:58:30,372 --> 00:58:32,541 RELATIVELY HOMOGENOUS 1547 00:58:32,541 --> 00:58:32,841 EXPRESSION. 1548 00:58:32,841 --> 00:58:36,245 IF YOU ARE LOOKING AT TANDEM, 1549 00:58:36,245 --> 00:58:38,013 THAT'S AN ORGATE, KILLING 1550 00:58:38,013 --> 00:58:39,081 ACROSS BOTH CIRCLES, RIGHT? 1551 00:58:39,081 --> 00:58:41,617 WE WANT TO MAKE THE DECISION 1552 00:58:41,617 --> 00:58:43,085 SWITCH OF SPECIFICITY TO BE 1553 00:58:43,085 --> 00:58:44,920 VERY SPECIFIC AND WE WANT THE 1554 00:58:44,920 --> 00:58:48,357 KILLING TO BE BROADER. 1555 00:58:48,357 --> 00:58:50,492 >> ALL RIGHT, THANKS. 1556 00:58:50,492 --> 00:58:53,095 >> I WANT TO BUILD OFF THE 1557 00:58:53,095 --> 00:58:54,029 QUESTION ON THE SYNTHETIC 1558 00:58:54,029 --> 00:58:57,299 ORGANIZER CELLS IN THE ASSEMBLY. 1559 00:58:57,299 --> 00:58:59,334 IT'S INCREDIBLE YOU COULD SEE 1560 00:58:59,334 --> 00:59:01,236 THE DEVELOPMENT OF THE CARDIAC 1561 00:59:01,236 --> 00:59:03,338 TISSUE, BUT COULD YOU COMBINE 1562 00:59:03,338 --> 00:59:09,178 THAT WITH YOUR SYN NOTCH TO 1563 00:59:09,178 --> 00:59:09,812 FURTHER DEVELOP -- 1564 00:59:09,812 --> 00:59:11,613 >> WENDELL LIM: THAT WAS REALLY 1565 00:59:11,613 --> 00:59:13,382 OUR INTENT AT FIRST. 1566 00:59:13,382 --> 00:59:14,483 THEN WE REALIZED WE HAVE TO DO 1567 00:59:14,483 --> 00:59:16,652 FIRST THINGS FIRST. 1568 00:59:16,652 --> 00:59:17,719 EVEN JUST LOCALIZING THEM WOULD 1569 00:59:17,719 --> 00:59:19,655 BE VERY IMPORTANT. 1570 00:59:19,655 --> 00:59:21,757 BUT YES, WE HAVE NOW THE 1571 00:59:21,757 --> 00:59:23,625 ABILITY TO KILL NODES AND 1572 00:59:23,625 --> 00:59:26,395 REPLACE THEM WITH NEW NODES AND 1573 00:59:26,395 --> 00:59:27,830 WHAT WOULD BE REALLY POWERFUL, 1574 00:59:27,830 --> 00:59:29,932 WHEN YOU TRY TO STRING TOGETHER 1575 00:59:29,932 --> 00:59:31,600 THESE DIFFERENT EVENTS, AS IN 1576 00:59:31,600 --> 00:59:33,435 DEVELOPMENT, IS TO BE ABLE TO 1577 00:59:33,435 --> 00:59:35,404 NOW HAVE AN ORGANIZER THAT 1578 00:59:35,404 --> 00:59:37,172 WOULD DETECT A MARKER OF THE 1579 00:59:37,172 --> 00:59:38,674 NEXT STAGE OF DEVELOPMENT IN A 1580 00:59:38,674 --> 00:59:40,476 LOCALIZED WAY. 1581 00:59:40,476 --> 00:59:41,610 WE ARE TOTALLY INTO THAT. 1582 00:59:41,610 --> 00:59:45,080 >> THANK YOU. 1583 00:59:45,080 --> 00:59:46,181 >> HI, PROFESSOR, REALLY 1584 00:59:46,181 --> 00:59:47,416 FANTASTIC WORK. 1585 00:59:47,416 --> 00:59:51,520 I HAVE A KIND OF NAIVE QUESTION. 1586 00:59:51,520 --> 00:59:55,657 THE OTHER LAB GOING TO USE SYN 1587 00:59:55,657 --> 00:59:56,225 NOTCH FOR CUSTOMIZED INVIVO 1588 00:59:56,225 --> 00:59:57,526 EXPERIENCE. 1589 00:59:57,526 --> 01:00:01,296 HOW COULD WE UTILIZE THAT? 1590 01:00:01,296 --> 01:00:03,632 ARE THOSE SYN NOTCH BUNCH OF 1591 01:00:03,632 --> 01:00:05,901 PLASMA WITH MULTI-CODING OR ARE 1592 01:00:05,901 --> 01:00:07,769 THERE COMPANIES WE CAN WORK 1593 01:00:07,769 --> 01:00:08,737 TOGETHER OR PAY FOR SERVICE? 1594 01:00:08,737 --> 01:00:09,972 >> WENDELL LIM: THAT'S A GREAT 1595 01:00:09,972 --> 01:00:10,839 QUESTION. 1596 01:00:10,839 --> 01:00:13,909 I WOULD SAY THERE ARE NOW 1597 01:00:13,909 --> 01:00:15,310 SEVERAL VERSIONS OF SYN NOTCH 1598 01:00:15,310 --> 01:00:18,814 AND WHEN WE TAKE A NEW 1599 01:00:18,814 --> 01:00:20,215 ANTIBODY, AN ANTIGEN THERE'S 1600 01:00:20,215 --> 01:00:21,183 SOME DEGREE OF OPTIMIZATION WE 1601 01:00:21,183 --> 01:00:23,218 NEED TO DO. 1602 01:00:23,218 --> 01:00:26,054 IT ALSO DEPENDS ON SOME 1603 01:00:26,054 --> 01:00:27,689 VERSIONS PRODUCE MORE PAYLOAD 1604 01:00:27,689 --> 01:00:29,791 BUT MORE LEAKAGE, SOME ARE 1605 01:00:29,791 --> 01:00:31,827 TIGHTER BUT HAVE LESS AND ALSO 1606 01:00:31,827 --> 01:00:32,861 CELL-TYPE SPECIFIC THINGS. 1607 01:00:32,861 --> 01:00:35,697 WE ARE TRYING TO COME UP, TO 1608 01:00:35,697 --> 01:00:37,966 MAKE OUR LIVES EASIER BUT 1609 01:00:37,966 --> 01:00:39,034 EVERYONE'S LIFE EASIER IS COME 1610 01:00:39,034 --> 01:00:41,236 UP WITH A SMALL LIBRARY OF 1611 01:00:41,236 --> 01:00:43,605 DIFFERENT TEMPLATES WHERE ONE 1612 01:00:43,605 --> 01:00:49,912 COULD POP IN YOUR ANTIBODY, 1613 01:00:49,912 --> 01:00:51,780 SCSV OF INTEREST, AND GUIDE 1614 01:00:51,780 --> 01:00:53,882 THOSE INTO THINKING WHAT THE 1615 01:00:53,882 --> 01:00:54,816 APPLICATION IS AND WHAT 1616 01:00:54,816 --> 01:00:56,785 BEHAVIORS WOULD BE THE BEST. 1617 01:00:56,785 --> 01:01:00,022 >> SO IF THIS IS LIKE A MINI 1618 01:01:00,022 --> 01:01:00,622 LIBRARY AVAILABLE -- 1619 01:01:00,622 --> 01:01:02,024 >> WENDELL LIM: NOT YET. 1620 01:01:02,024 --> 01:01:05,827 A LOT OF THESE THINGS ARE 1621 01:01:05,827 --> 01:01:08,130 AVAILABLE ON ADD GENE, BUT WE 1622 01:01:08,130 --> 01:01:10,699 ARE CHANGING HEIGHTS OF EXTRA 1623 01:01:10,699 --> 01:01:11,833 CELLULAR DOMAIN AND DIFFERENT 1624 01:01:11,833 --> 01:01:13,268 SCAFFOLDS FOR THE RECEPTOR. 1625 01:01:13,268 --> 01:01:14,369 WE ARE EXPANDING THAT FOR OUR 1626 01:01:14,369 --> 01:01:15,370 OWN CASE. 1627 01:01:15,370 --> 01:01:17,272 BUT WE WILL MAKE THAT AVAILABLE. 1628 01:01:17,272 --> 01:01:18,006 >> OKAY, THANK YOU. 1629 01:01:18,006 --> 01:01:19,841 >> ONE MORE? 1630 01:01:19,841 --> 01:01:21,944 >> THANK YOU FOR THE TALK. 1631 01:01:21,944 --> 01:01:24,980 I HAVE A VERY GENERAL QUESTION. 1632 01:01:24,980 --> 01:01:27,783 I'M THINKING WHETHER THERE ARE 1633 01:01:27,783 --> 01:01:28,617 ANY EMERGING PHENOMENA IN THE 1634 01:01:28,617 --> 01:01:31,720 WORK YOU PRESENTED. 1635 01:01:31,720 --> 01:01:33,055 UNEXPECTED CELL STATE OR 1636 01:01:33,055 --> 01:01:33,855 UNEXPECTED CELL FUNCTIONS? 1637 01:01:33,855 --> 01:01:36,758 >> WENDELL LIM: IN THE T-CELLS 1638 01:01:36,758 --> 01:01:37,326 OR DEVELOPMENTAL SYSTEMS? 1639 01:01:37,326 --> 01:01:38,493 >> IN BOTH. 1640 01:01:38,493 --> 01:01:40,862 >> WENDELL LIM: YEAH. 1641 01:01:40,862 --> 01:01:44,666 WELL, THAT RAISES OBVIOUSLY A 1642 01:01:44,666 --> 01:01:46,268 GREAT QUESTION OF ARE THERE 1643 01:01:46,268 --> 01:01:50,239 POSSIBLE CELL STATES THAT YOU 1644 01:01:50,239 --> 01:01:52,574 COULD DRIVE CELLS INTO, BE THEY 1645 01:01:52,574 --> 01:01:55,911 IMMUNE CELLS OR STEM CELLS 1646 01:01:55,911 --> 01:01:56,378 ALONG SOME TRAJECTORY. 1647 01:01:56,378 --> 01:01:57,446 AND I SUSPECT THAT THERE ARE. 1648 01:01:57,446 --> 01:01:58,780 I THINK IT'S A VERY FUNDAMENTAL 1649 01:01:58,780 --> 01:02:00,716 QUESTION. 1650 01:02:00,716 --> 01:02:03,952 YOU SEE A CERTAIN REALM OF 1651 01:02:03,952 --> 01:02:04,519 SIMULATIONS DURING LIFE AND 1652 01:02:04,519 --> 01:02:07,623 EVOLUTION. 1653 01:02:07,623 --> 01:02:10,659 AND ARE THE CELL FATES OF THE 1654 01:02:10,659 --> 01:02:17,132 T-CELLS AND STEM CELLS SO 1655 01:02:17,132 --> 01:02:18,467 CANONIZED THEY STAY ON TRACK. 1656 01:02:18,467 --> 01:02:20,068 THEY COULD GO OFF SOME. 1657 01:02:20,068 --> 01:02:20,869 THERE ARE CELL THAT'S ARE HARD 1658 01:02:20,869 --> 01:02:22,437 TO CLASSIFY. 1659 01:02:22,437 --> 01:02:24,473 TO WHAT DEGREE, I DON'T KNOW. 1660 01:02:24,473 --> 01:02:26,775 BUT THAT'S A VERY, SORT OF 1661 01:02:26,775 --> 01:02:27,309 IMPORTANT AND FUNDAMENTAL 1662 01:02:27,309 --> 01:02:27,576 QUESTION. 1663 01:02:27,576 --> 01:02:29,711 >> THANK YOU. 1664 01:02:29,711 --> 01:02:32,247 >> OKAY, THANK YOU VERY MUCH, 1665 01:02:32,247 --> 01:02:33,482 EVERYONE, FOR COMING TO THE 1666 01:02:33,482 --> 01:02:34,349 LECTURE. 1667 01:02:34,349 --> 01:02:38,420 AND THIS HAS BEEN A REALLY, YOU 1668 01:02:38,420 --> 01:02:38,987 KNOW, LIVELY QUESTIONS AND 1669 01:02:38,987 --> 01:02:41,390 ANSWERS. 1670 01:02:41,390 --> 01:02:42,591 BUT YOU CAN CONTINUE CHATTING 1671 01:02:42,591 --> 01:02:45,093 WITH THE SPEAKER IF YOU WANT. 1672 01:02:45,093 --> 01:02:46,628 WE HAVE A RECEPTION JUST 1673 01:02:46,628 --> 01:02:48,397 OUTSIDE THE AUDITORIUM. 1674 01:02:48,397 --> 01:02:49,097 AND WITH THIS, THIS WRAPS UP 1675 01:02:49,097 --> 01:02:49,398 THE LECTURE. 1676 01:02:49,398 --> 01:02:50,265 THANK YOU. 1677 01:02:50,265 --> 01:02:51,600 [ APPLAUSE ] 1678 01:02:51,600 --> 01:03:02,044 >> WENDELL LIM: THANK YOU.