1 00:00:11,444 --> 00:00:13,580 WELCOME TO THE CLINICAL CENTER GRAND ROUNDS, 2 00:00:13,646 --> 00:00:17,384 A WEEKLY SERIES OF EDUCATIONAL LECTURES FOR PHYSICIANS AND 3 00:00:17,450 --> 00:00:20,019 HEALTH CARE PROFESSIONALS BROADCAST FROM THE CLINICAL 4 00:00:20,086 --> 00:00:22,989 CENTER AT THE NATIONAL INSTITUTES OF HEALTH IN 5 00:00:23,056 --> 00:00:24,791 BETHESDA, MD. 6 00:00:24,858 --> 00:00:28,328 THE NIH CLINICAL CENTER IS THE WORLD'S LARGEST HOSPITAL TOTALLY 7 00:00:28,395 --> 00:00:32,031 DEDICATED TO INVESTIGATIONAL RESEARCH AND LEADS THE GLOBAL 8 00:00:32,098 --> 00:00:34,968 EFFORT IN TRAINING TODAY'S INVESTIGATORS AND DISCOVERING 9 00:00:35,034 --> 00:00:37,137 TOMORROW'S CURES. 10 00:00:37,203 --> 00:00:43,410 LEARN MORE BY VISITING US ONLINE AT HTTP://CLINICALCENTER.NIH.GOV 11 00:00:43,476 --> 00:00:45,078 GET STARTED. 12 00:00:45,145 --> 00:00:46,212 ABSOLUTELY DELIGHTED TO THRILLED 13 00:00:46,279 --> 00:00:48,248 TO INTRODUCE OUR SPEAKER TODAY 14 00:00:48,314 --> 00:00:50,583 AND I WANT TOED WELCOME ALL OF 15 00:00:50,650 --> 00:00:53,787 YOU TO THE CLINICAL CENTER GRAND 16 00:00:53,853 --> 00:00:54,854 ROUNDS DISTINGUISHED CLINICAL 17 00:00:54,921 --> 00:00:57,924 RESEARCH SCHOLAR AND EDUCATOR IN 18 00:00:57,991 --> 00:00:58,858 RESIDENCE PRESENTATION. 19 00:00:58,925 --> 00:01:01,628 AND THIS PRESENTATION IS PART OF 20 00:01:01,694 --> 00:01:04,464 THE GREAT TEACHERS SERIES. 21 00:01:04,531 --> 00:01:06,299 THE CONTEMPORARY CLINICAL 22 00:01:06,366 --> 00:01:07,434 MEDICINE GREAT TEACHER GRAND 23 00:01:07,500 --> 00:01:09,269 ROUNDS IS A SPECIAL SERIES 24 00:01:09,335 --> 00:01:10,570 WITHIN THE CLINICAL CENTER GRAND 25 00:01:10,637 --> 00:01:11,171 ROUNDS PROGRAM. 26 00:01:11,237 --> 00:01:15,809 AND THIS WAS FIRST CONCEIVED BY 27 00:01:15,875 --> 00:01:18,678 DR. PAUL PLOTTS WHO WAS A 28 00:01:18,745 --> 00:01:21,114 DISTINGUISHED SCIENTIST OF THE 29 00:01:21,181 --> 00:01:22,782 NIAMS ASK UNFORT MATILY RECENTLY 30 00:01:22,849 --> 00:01:24,517 PASSED AWAY BUT HE WAS THE 1 WHO 31 00:01:24,584 --> 00:01:28,054 REALLY GOT THIS STARTED. 32 00:01:28,121 --> 00:01:31,691 THE PURPOSE OF THIS IS TO INVITE 33 00:01:31,758 --> 00:01:32,992 TO THE CLINICAL CENTER TOP 34 00:01:33,059 --> 00:01:34,027 LEADERS IN MEDICINE AND SCIENCE 35 00:01:34,093 --> 00:01:35,695 TO PRESENT ON TOPICS AND IDEAS 36 00:01:35,762 --> 00:01:39,699 ABOUT WHICH THEY ARE PASSIONATE 37 00:01:39,766 --> 00:01:40,867 TO SHARE THEIR REFLECTIONS WITH 38 00:01:40,934 --> 00:01:42,602 US AND TO INSPIRE YOUNG 39 00:01:42,669 --> 00:01:45,538 INVESTIGATORS IN THE PURSUIT OF 40 00:01:45,605 --> 00:01:48,741 CAREERS IN BIOMEDICAL RESEARCH. 41 00:01:48,808 --> 00:01:52,378 I ALSO WANT TO REMIND ABOUT THE 42 00:01:52,445 --> 00:01:53,046 CME. 43 00:01:53,112 --> 00:01:57,550 SO THOSE OF YOU WHO WANT CME, 44 00:01:57,617 --> 00:01:58,384 THE NUMBER IS 50552. 45 00:01:58,451 --> 00:02:02,922 AND SO, YOU WOULD JUST TEXT 46 00:02:02,989 --> 00:02:05,058 THAT--YEAH, THERE IT IS UP 47 00:02:05,124 --> 00:02:05,258 THERE. 48 00:02:05,325 --> 00:02:06,426 OKAY, GOOD. 49 00:02:06,493 --> 00:02:08,161 AND ALSO, WE INVITE TO YOU 50 00:02:08,228 --> 00:02:09,462 PROVIDE FEEDBACK ON TODAY'S 51 00:02:09,529 --> 00:02:12,532 LECTURE BY SCANNING THE QR CODE, 52 00:02:12,599 --> 00:02:16,169 NOW THESE DAYS IT'S ALL ABOUT QR 53 00:02:16,236 --> 00:02:16,436 CODES. 54 00:02:16,503 --> 00:02:17,737 SO YOU NEED YOUR CELL PHONE IN 55 00:02:17,804 --> 00:02:20,573 ORDER TO DO IT. 56 00:02:20,640 --> 00:02:24,244 FOR APPLYING FOR--FOR THOSE 57 00:02:24,310 --> 00:02:29,682 APPLYING FOR CME, YOU WILL APPLY 58 00:02:29,749 --> 00:02:30,950 VIA SURVEY FEEDBACK AND THE 59 00:02:31,017 --> 00:02:33,786 SURVEY WILL BE USED TO PROVIDE 60 00:02:33,853 --> 00:02:35,321 IMPORTANT INFORMATION ABOUT THIS 61 00:02:35,388 --> 00:02:36,723 PRESENTATION THAT ALLOWS TO YOU 62 00:02:36,789 --> 00:02:38,658 SUBMIT ANY QUESTIONS FOR FUTURE 63 00:02:38,725 --> 00:02:39,292 GRAND ROUND TOPICS. 64 00:02:39,359 --> 00:02:40,727 AND THEN FOLLOWING THE 65 00:02:40,793 --> 00:02:41,461 PRESENTATION, QUESTIONS FOR THE 66 00:02:41,528 --> 00:02:43,029 SPEAKER WILL BE TAKEN FROM THE 67 00:02:43,096 --> 00:02:46,266 MICROPHONES IN THE AISLES OVER 68 00:02:46,332 --> 00:02:48,001 HERE--OOPS SORRY. 69 00:02:48,067 --> 00:02:49,235 AND ADDITIONALLY, THE VIDEOCAST 70 00:02:49,302 --> 00:02:50,503 VIEWERS CAN SUBMIT QUESTIONS AT 71 00:02:50,570 --> 00:02:52,939 ANY TIME DURING THE LECTURE, YOU 72 00:02:53,006 --> 00:02:55,008 HAVE TO DO A SCROLL DOWN AND 73 00:02:55,074 --> 00:02:57,377 CLICK ON THE LIVE FEEDBACK 74 00:02:57,443 --> 00:02:59,913 BUTTON ON THE WEBSITE. 75 00:02:59,979 --> 00:03:03,349 AND THOSE QUESTIONS WILL BE 76 00:03:03,416 --> 00:03:07,053 ANSWERED AT THE END OF THE 77 00:03:07,120 --> 00:03:07,387 PRESENTATION. 78 00:03:07,453 --> 00:03:09,489 SO TODAY, WE ARE ABSOLUTELY 79 00:03:09,556 --> 00:03:17,463 HONORED TO HAVE OUR SPEAKER 80 00:03:17,530 --> 00:03:19,432 DR. DANIEL GERSHWIN AND IS A 81 00:03:19,499 --> 00:03:20,600 PIONEER SCIENTIST RECOGNIZED BY 82 00:03:20,667 --> 00:03:22,936 HIS GROUND BREAKING WORK ON 83 00:03:23,002 --> 00:03:23,603 ACCURACYATISM, GENETICS AND 84 00:03:23,670 --> 00:03:24,938 FUNCTIONAL DENATIONAL LIBRARY OF 85 00:03:25,004 --> 00:03:25,238 MEDICINICS. 86 00:03:25,305 --> 00:03:27,240 HE IS 1 OF THE HIGHEST CITED 87 00:03:27,307 --> 00:03:28,541 NEUROLOGISTS IN THE WORLD. 88 00:03:28,608 --> 00:03:30,076 AND I WILL TELL YOU ON A 89 00:03:30,143 --> 00:03:32,178 PERSONAL NOTE, I WAS TALKING TO 90 00:03:32,245 --> 00:03:36,983 HIM YESTERDAY AND I KNEW HIS 91 00:03:37,050 --> 00:03:40,420 UNCLE NORM GESHWIN, WHO WAS A 92 00:03:40,486 --> 00:03:41,454 WORLD FAMOUS BEHAVIORIAL 93 00:03:41,521 --> 00:03:42,822 NEUROLOGIST AND ALSO HIS COUSIN 94 00:03:42,889 --> 00:03:46,893 WHO IS ALSO A WORLD FAMOUS 95 00:03:46,960 --> 00:03:49,395 NEUROLOGIST AT UCSF, AND 96 00:03:49,462 --> 00:03:51,364 SPECIALIZED IN RAPIDLY 97 00:03:51,431 --> 00:03:52,799 PROGRESSIVE DEMENTIAS AND THEY 98 00:03:52,865 --> 00:03:53,833 HAVE INFLUENCED NEUROLOGY AND 99 00:03:53,900 --> 00:03:56,035 NEUROSCIENCE IN MANY WAYS AND SO 100 00:03:56,102 --> 00:03:57,604 IT IS REALLY A GREAT HONOR TO BE 101 00:03:57,670 --> 00:04:02,976 ABLE TO INTRODUCE YOU. 102 00:04:03,042 --> 00:04:06,479 DR. GESHWIN SERVES AS THE GORDON 103 00:04:06,546 --> 00:04:10,350 AND VIRGINIA MCDONALD PROCESSOR 104 00:04:10,416 --> 00:04:11,784 IN NEUROLOGY, PSYCHIATRY AND 105 00:04:11,851 --> 00:04:12,685 HUMAN GENETICS AT CRUCIATE 106 00:04:12,752 --> 00:04:13,686 LIGAMENT CLA. 107 00:04:13,753 --> 00:04:16,856 IN HIS CAPACITY AS A SENIOR 108 00:04:16,923 --> 00:04:18,424 ASSOCIATE DEAN AND ASSOCIATE 109 00:04:18,491 --> 00:04:20,059 VICE CHANCELLOR FOR PRECISION 110 00:04:20,126 --> 00:04:22,028 HELT, HE LEADS THE INSTITUTE FOR 111 00:04:22,095 --> 00:04:23,696 PRECISION HEALTH AT UCLA. 112 00:04:23,763 --> 00:04:25,898 HE EARNED HIS BACHELOR'S DEBRIS 113 00:04:25,965 --> 00:04:30,069 IN CHEMIST RADIOY AND PSYCHOLOGY 114 00:04:30,136 --> 00:04:33,039 IN DARTMOUTH IN 1982 AND AN 115 00:04:33,106 --> 00:04:35,475 MD-Ph.D. AT YALE SCHOOL OF 116 00:04:35,541 --> 00:04:37,744 MEDICINE IN 1991. 117 00:04:37,810 --> 00:04:39,379 HE COMPLETED INTERNSHIP IN 118 00:04:39,445 --> 00:04:41,214 INTERNAL MEDICINE AND RESIDENCY 119 00:04:41,280 --> 00:04:43,216 INEUROLOGY, AND AS WELL AS POST 120 00:04:43,282 --> 00:04:46,219 DOCTORAL IN GENETICS AT UCLA, 121 00:04:46,285 --> 00:04:49,889 AND HE HAS RISEN UP THROUGH THE 122 00:04:49,956 --> 00:04:53,693 RANKS AT UCLA, AND STARTED THE 123 00:04:53,760 --> 00:04:54,627 NEUROGENETICS PROGRAM WITHIN THE 124 00:04:54,694 --> 00:04:56,362 DEPARTMENT OF NEUROLOGY THERE. 125 00:04:56,429 --> 00:04:58,431 AND HE ALSO CO-FOUNDED THE 126 00:04:58,498 --> 00:04:59,432 CENTER FOR ACCURACYATISM 127 00:04:59,499 --> 00:05:03,436 RESEARCH AND TREATMENT WHICH HE 128 00:05:03,503 --> 00:05:04,671 CONTINUES TO LEAD. 129 00:05:04,737 --> 00:05:07,106 AS A RESEARCHER DR. IMRKS ESHWIN 130 00:05:07,173 --> 00:05:08,941 PILOT PROJECT OR NEARED SYSTEMS 131 00:05:09,008 --> 00:05:11,110 BIOLOGY METHODS IN NEUROLOGIC 132 00:05:11,177 --> 00:05:13,479 AND PSYCHIATRIC DEC WITH A FOCUS 133 00:05:13,546 --> 00:05:16,916 ON AUTISM SPECTRUM DISORDERS AND 134 00:05:16,983 --> 00:05:17,517 NEURODEGENERATIVE CONDITIONS. 135 00:05:17,583 --> 00:05:19,919 HIS LAB HAS MADE PRAIJOR 136 00:05:19,986 --> 00:05:20,953 CONTRIBUTIONS TO ADENTIFYING 137 00:05:21,020 --> 00:05:23,189 GENETIC CAUSINGS OF AUTISM 138 00:05:23,256 --> 00:05:24,590 SPECTRUM DISORDER, DEFINING THE 139 00:05:24,657 --> 00:05:27,960 MOLECULAR PATHOLOGY OF AUTISM 140 00:05:28,027 --> 00:05:34,267 AND ALLIED PSYCHIATRIC DISORDERS 141 00:05:34,333 --> 00:05:41,240 AND WORKED TO INCREASE DEMENTIA 142 00:05:41,307 --> 00:05:43,743 RECOGNITION EMPLOY HE SITS ON 143 00:05:43,810 --> 00:05:45,411 THE EDITORIAL BOARDS OF CELL, 144 00:05:45,478 --> 00:05:48,247 SCIENCE AND NEURON. 145 00:05:48,314 --> 00:05:50,016 HE'S A RECIPIENT OF NUMEROUS 146 00:05:50,083 --> 00:05:53,152 GRANTS FOR HIS RESEARCH AND 147 00:05:53,219 --> 00:05:55,922 RESERVED A CERT ON THE ADVISELY 148 00:05:55,988 --> 00:05:57,990 BOARDS OF THE ALLEN INSTITUTE 149 00:05:58,057 --> 00:05:59,058 AND NIMH. 150 00:05:59,125 --> 00:06:00,693 AS A TEACHER HE MENTORED MORE 151 00:06:00,760 --> 00:06:04,997 THAN A HUNDRED POST DOCTORAL AND 152 00:06:05,064 --> 00:06:06,065 GRADUATE STUDENTS. 153 00:06:06,132 --> 00:06:08,501 IN 2011 HE WAS ELECTED TO THE 154 00:06:08,568 --> 00:06:12,505 NATIONAL ACADEMY OF MEDICINE, 155 00:06:12,572 --> 00:06:17,376 AND IN 2022 HE WAS AWARDED THE 156 00:06:17,443 --> 00:06:18,878 SARNAC PRIZE FOR HIS 157 00:06:18,945 --> 00:06:19,979 CONTRIBUTIONS TO UNDERSTANDING 158 00:06:20,046 --> 00:06:22,982 OF THE GENETICS OF AUTISM NOTING 159 00:06:23,049 --> 00:06:25,184 HE ESTABLISHED THE MODERN ERA OF 160 00:06:25,251 --> 00:06:27,854 RESEARCH IN AUTISM GENETICS. 161 00:06:27,920 --> 00:06:29,655 BY MAKING BIOMEDICALS AND 162 00:06:29,722 --> 00:06:31,324 PHENOTYPE DATA EASILY ACCESSIBLE 163 00:06:31,390 --> 00:06:33,092 TO RESEARCHERS WORLD WIDE, HE'S 164 00:06:33,159 --> 00:06:37,096 OPENED THE FIELD TO COUNTLESS 165 00:06:37,163 --> 00:06:37,897 SCIENTISTS, SPURRING DISCOVERY 166 00:06:37,964 --> 00:06:40,299 AND CREATING NEW PARADIGM FOR 167 00:06:40,366 --> 00:06:41,734 RESEARCH IN PSYCHIATRY GENETICS. 168 00:06:41,801 --> 00:06:44,804 SO PLEASE JOIN ME IN WELCOMING 169 00:06:44,871 --> 00:06:50,042 TODAY'S GRAND ROUNDS SPEAKER 170 00:06:50,109 --> 00:06:54,080 DR. DANIEL GESHWIN WHO WILL 171 00:06:54,147 --> 00:06:57,717 PRESENT HIS TALK ON GENETICS AND 172 00:06:57,784 --> 00:07:00,987 GENOMICS OF NEUROPSYCHIATRIC 173 00:07:01,053 --> 00:07:01,254 DISORDERS. 174 00:07:01,320 --> 00:07:01,554 [ APPLAUSE ] 175 00:07:01,621 --> 00:07:02,855 >> THANK YOU DOCTOR FOR THAT 176 00:07:02,922 --> 00:07:03,456 EXTREMELY OVERLY KIND 177 00:07:03,523 --> 00:07:05,525 INTRODUCTION AND THANK YOU 178 00:07:05,591 --> 00:07:07,426 ALL--THANKS FOR HAVING ME HERE. 179 00:07:07,493 --> 00:07:11,264 IT'S REALLY BEEN A GREAT, YOU 180 00:07:11,330 --> 00:07:13,199 KNOW GREAT NOW DAY AND A HALF, 181 00:07:13,266 --> 00:07:14,767 I'LL CALL IT, FEELS ALMOST LIKE 182 00:07:14,834 --> 00:07:17,303 2 DAYS BUT WE'LL CALL IT 2 DAYS. 183 00:07:17,370 --> 00:07:18,838 IT'S BEEN WONDERFUL TO MEET ALL 184 00:07:18,905 --> 00:07:20,673 THE TRAINEES AND STUDENTS AND 185 00:07:20,740 --> 00:07:23,075 THEN MEET WITH SOME OF MY OLD 186 00:07:23,142 --> 00:07:25,044 COLLEAGUES AND FRIENDS AND SOME 187 00:07:25,111 --> 00:07:26,879 I HABIT MET BEFORE BUT WHOSE 188 00:07:26,946 --> 00:07:28,414 WORK I REALLY ADMIRE. 189 00:07:28,481 --> 00:07:30,049 I WAS TRYING TO FIGURE OUT HOW 190 00:07:30,116 --> 00:07:32,685 TO KIND OF FRAME TODAY AND I 191 00:07:32,752 --> 00:07:33,853 DECIDED THERE WERE A LOT OF 192 00:07:33,920 --> 00:07:43,896 DIFFERENT WAYS I COULD GO. 193 00:07:43,963 --> 00:07:45,464 BEFORE I GET INTO IT AND IT 194 00:07:45,531 --> 00:07:46,966 STARTS ROLLING I WOULD SAY 3 195 00:07:47,033 --> 00:07:52,505 THINGS THEY WOULD LIKE TO GET 196 00:07:52,572 --> 00:07:54,173 ACROSS. 197 00:07:54,240 --> 00:07:56,976 ONE IS THAT THAT DESPITE HAVING 198 00:07:57,043 --> 00:08:00,112 KIND OF NO OVERT PATHOLOGY, 199 00:08:00,179 --> 00:08:01,414 THESE DISORDERS, THESE 200 00:08:01,480 --> 00:08:04,884 PSYCHIATRIC DISORDERS THAT ARE 201 00:08:04,951 --> 00:08:06,485 DIFFERENTIATED FROM NEUROLOGIC 202 00:08:06,552 --> 00:08:08,788 DISORDERS HAVE QUITE 203 00:08:08,855 --> 00:08:09,288 SUBSTANTIALLY MOLECULAR 204 00:08:09,355 --> 00:08:11,257 PATHOLOGY AND THAT CAN BE USED 205 00:08:11,324 --> 00:08:13,626 TO DEMONSTRATE AND DEVELOP 206 00:08:13,693 --> 00:08:13,893 TREATMENT. 207 00:08:13,960 --> 00:08:16,863 I ALSO WANT TO SAY THAT I THINK 208 00:08:16,929 --> 00:08:18,798 IT'S ESSENTIAL, 2 THINGS ARE 209 00:08:18,865 --> 00:08:19,332 ESSENTIAL MOVING FORWARD. 210 00:08:19,398 --> 00:08:23,269 ONE OF THEM IS TO DO DISCOVERY 211 00:08:23,336 --> 00:08:24,503 BASED RESEARCH. 212 00:08:24,570 --> 00:08:26,138 IT'S JUST, WE DON'T HAVE A MODEL 213 00:08:26,205 --> 00:08:27,473 FOR HOW THE BRAIN WORKS, WE 214 00:08:27,540 --> 00:08:29,342 DON'T KNOW HOW IT WORKS AND WE 215 00:08:29,408 --> 00:08:30,610 REALLY HAVE TO PUSH DISCOVERY 216 00:08:30,676 --> 00:08:31,777 FORWARD AND THAT'S ALWAYS HAD A 217 00:08:31,844 --> 00:08:33,813 BAD NAME BUT THAT'S WHAT WE DO, 218 00:08:33,880 --> 00:08:37,884 AND THEN THIRDLY, I THINK WE'RE 219 00:08:37,950 --> 00:08:39,785 ON THE PRECIPICE OR ON THE LIP 220 00:08:39,852 --> 00:08:40,720 OF AMAZING DISCOVERIES BECAUSE 221 00:08:40,786 --> 00:08:42,889 OF ALL THE TECHNOLOGY THAT WE 222 00:08:42,955 --> 00:08:44,857 HAVE AND I REALLY WANT TO MAKE A 223 00:08:44,924 --> 00:08:49,195 PLUG FOR KIND OF HIGH THROUGH 224 00:08:49,262 --> 00:08:49,996 PUT BIOLOGY. 225 00:08:50,062 --> 00:08:52,365 SO RATHER THAN TESTING 226 00:08:52,431 --> 00:08:54,834 HYPOTHESIS 1 AT A TIME TESTING 227 00:08:54,901 --> 00:08:55,301 MANY IN PARALLEL. 228 00:08:55,368 --> 00:08:57,169 SO I HAVE NO DISCLOSURES. 229 00:08:57,236 --> 00:09:01,007 THERE'S MY LEARNING OBJECTIVES 230 00:09:01,073 --> 00:09:02,842 AND I ALSO WANT TO SAY 231 00:09:02,909 --> 00:09:06,812 ESPECIALLY THAT I USE MEDICAL 232 00:09:06,879 --> 00:09:08,848 TERMINOLOGY, EPARTIALLY FOR 233 00:09:08,915 --> 00:09:10,249 SOMETHING AS UNIVERSAL AS 234 00:09:10,316 --> 00:09:12,318 AUTISM, WHERE PEOPLE MIGHT HAVE 235 00:09:12,385 --> 00:09:14,120 A WIDE SUSCEPTIBILITY FOR A VERY 236 00:09:14,186 --> 00:09:16,889 WIDE RAINCHL OF FEATURES BUT I 237 00:09:16,956 --> 00:09:18,758 OFTEN FALL INTO THE USING THE 238 00:09:18,824 --> 00:09:19,692 MEDICAL TERMINOLOGY SUCH AS 239 00:09:19,759 --> 00:09:20,026 RISK. 240 00:09:20,092 --> 00:09:24,830 SO THE THING THAT DRIVES THIS 241 00:09:24,897 --> 00:09:25,698 WORK IN NEUROPSYCHIATRIC 242 00:09:25,765 --> 00:09:27,867 DISORDERS IS THAT HAVING A PATH 243 00:09:27,934 --> 00:09:29,602 OF PHYSIOLOGIC MODEL OF DEC IS A 244 00:09:29,669 --> 00:09:31,737 STARTING POINT FOR TREATMENT TO 245 00:09:31,804 --> 00:09:32,038 DEVELOPMENT. 246 00:09:32,104 --> 00:09:34,640 SO CANCER IS A DISORDER, 247 00:09:34,707 --> 00:09:36,208 PROLIFERATION AND INVASION, 248 00:09:36,275 --> 00:09:37,944 CAUSED BY MANY DIFFERENT THINGS, 249 00:09:38,010 --> 00:09:40,813 ASTHMA IS A DISEASE OF HYPER 250 00:09:40,880 --> 00:09:42,782 REACTIVE WEAR WAVES THAT IS DUE 251 00:09:42,848 --> 00:09:45,151 TO VIERPTAL CHALLENGE DUE TO 252 00:09:45,217 --> 00:09:46,986 GENETIC BACKGROUNDS. 253 00:09:47,053 --> 00:09:50,523 STROKE IS A DISORDER OF ACUTE 254 00:09:50,589 --> 00:09:51,490 BRAIN HYPOOX GENERATEDDATION, I 255 00:09:51,557 --> 00:09:52,992 KNOW THAT SOUNDS LIKE A TWIST 256 00:09:53,059 --> 00:09:54,760 BUT BECAUSE THAT'S ESSENTIALLY 257 00:09:54,827 --> 00:09:55,027 THE BASIS. 258 00:09:55,094 --> 00:09:57,430 IT HAS A NUMBER OF VASCULAR AND 259 00:09:57,496 --> 00:10:00,266 CARDIAC AND OTHER ETIOLOGIES AND 260 00:10:00,333 --> 00:10:02,268 SO THE QUESTION IS, WHAT DEFINES 261 00:10:02,335 --> 00:10:05,538 THE PATH OF PHYSIOLOGY OF 262 00:10:05,604 --> 00:10:06,105 NEUROPSYCHIATRIC DISORDERS, 263 00:10:06,172 --> 00:10:07,473 THAT'S ALWAYS A GREAT STARTING 264 00:10:07,540 --> 00:10:10,476 POINT IN WHICH TO PUT GENETIC 265 00:10:10,543 --> 00:10:11,410 FINDINGS, AND SO ANOTHER POINT 266 00:10:11,477 --> 00:10:14,046 THAT I'M GOING TO MAKE WITH 267 00:10:14,113 --> 00:10:16,916 REGARD TO THIS JUST AS A KIND OF 268 00:10:16,983 --> 00:10:17,984 FOUNDATIONAL POINT JUST TO PAVE, 269 00:10:18,050 --> 00:10:19,752 TO PUT THE PAVEMENT DOWN SO TO 270 00:10:19,819 --> 00:10:22,288 SPEAK FOR THE TALK IS WHAT I 271 00:10:22,355 --> 00:10:25,191 CONSIDER THE FALLACY OF EXPERT 272 00:10:25,257 --> 00:10:26,492 HYPOTHESIS, UNLIKE PHYSICS OR 273 00:10:26,559 --> 00:10:29,295 MATH, BIOLOGY IS STILL HIGHLY 274 00:10:29,362 --> 00:10:30,529 DESCRIPTIVE, PROVING WHAT IS 275 00:10:30,596 --> 00:10:31,364 IMPORTANT IS THEREFORE VERY 276 00:10:31,430 --> 00:10:32,698 HARD, OF COURSE IF I TELL THE 277 00:10:32,765 --> 00:10:34,367 STUDENTS IN MY LAB, IF YOU ARE 278 00:10:34,433 --> 00:10:35,801 WORKING ON SOMEBODY'S DISEASE OR 279 00:10:35,868 --> 00:10:40,039 DISORDER, THAT IS BY ITSELF VERY 280 00:10:40,106 --> 00:10:41,107 IMPORTANT BUT HYPOTHESIS DRIVEN 281 00:10:41,173 --> 00:10:41,974 RESEARCH LED TO DECADES OF 282 00:10:42,041 --> 00:10:43,876 STUDY, THIS IS JUST 1 LITTLE 283 00:10:43,943 --> 00:10:46,779 EXAMPLE FOCUSING ON NEURONS AND 284 00:10:46,846 --> 00:10:47,813 NEURODEGENERATIVE DISEASE AND 285 00:10:47,880 --> 00:10:49,415 CERTAINLY WE LOSE NEURONS AND 286 00:10:49,482 --> 00:10:50,950 THEY'RE IMPORTANT BUT IT IGNORED 287 00:10:51,017 --> 00:10:52,018 HALF THE CELLS IN THE BRAIN AND 288 00:10:52,084 --> 00:10:54,720 I WILL NOT GO INTO THIS IN GORY 289 00:10:54,787 --> 00:10:56,088 DETAIL, BUT THE POINT IS NOW 290 00:10:56,155 --> 00:10:58,290 THAT WE CAN COLLECT RELATIVELY 291 00:10:58,357 --> 00:10:59,859 COMPLETE UNBIASED DATA SETS, WHY 292 00:10:59,925 --> 00:11:01,394 NOT LET THE DATA DRIVE THE 293 00:11:01,460 --> 00:11:05,264 QUESTIONS OR LET THE DATA ORDER 294 00:11:05,331 --> 00:11:06,899 THE HYPOTHESIS FOR US AND PUT 295 00:11:06,966 --> 00:11:10,903 THEM IN AN ORDER FOR US TO TEST 296 00:11:10,970 --> 00:11:11,370 THEM. 297 00:11:11,437 --> 00:11:13,472 GENETIC DATA PROVIDES A CAUSAL 298 00:11:13,539 --> 00:11:13,839 ANCHOR FOR THIS. 299 00:11:13,906 --> 00:11:16,142 SO IF YOU HAVE A GENETIC 300 00:11:16,208 --> 00:11:19,645 MUTATION OR A VARIANT, THE 301 00:11:19,712 --> 00:11:20,813 DISEASE DOESN'T CAUSE THAT IN 302 00:11:20,880 --> 00:11:25,618 THE VAST MAJORITY OF CASES WHERE 303 00:11:25,684 --> 00:11:28,854 YOU CAN GO FROM GENE ALL THE WAY 304 00:11:28,921 --> 00:11:30,623 THROUGH TO FUNCTION. 305 00:11:30,689 --> 00:11:31,824 SO ANOTHER KIND OF GUIDING 306 00:11:31,891 --> 00:11:35,494 FRAMEWORK IS THE FOLLOWING: 307 00:11:35,561 --> 00:11:37,630 THAT GENES INTERACT WITH THE 308 00:11:37,696 --> 00:11:38,631 ENVIRONMENT DURING DEVELOPMENT 309 00:11:38,697 --> 00:11:41,700 TO CREATE A STRUCTURE THAT HAS 310 00:11:41,767 --> 00:11:46,639 MANY DIFFERENT LEVELS FROM GLOSS 311 00:11:46,705 --> 00:11:48,074 ANATOMY ALL THE WAY THROUGH 312 00:11:48,140 --> 00:11:48,340 MOLECULAR. 313 00:11:48,407 --> 00:11:50,176 IT'S NOT A STATIC STRUCTURE, 314 00:11:50,242 --> 00:11:51,811 IT'S A VERY DYNAMIC STRUCTURE 315 00:11:51,877 --> 00:11:54,246 AND THAT IS WHAT UNDERLIES 316 00:11:54,313 --> 00:11:55,614 COGNITION AND BEHAVIOR AND OF 317 00:11:55,681 --> 00:11:57,049 COURSE COGNITION AND BEHAVIOR 318 00:11:57,116 --> 00:11:58,584 IMPACTING THE STRUCTURE AND 319 00:11:58,651 --> 00:12:01,153 THE--YOU KNOW WHAT I LOOSELY USE 320 00:12:01,220 --> 00:12:02,054 THE TERM STRUCTURE. 321 00:12:02,121 --> 00:12:03,989 SO EVERYTHING THAT WE ARE DOING 322 00:12:04,056 --> 00:12:06,492 IS KIND OF IN THIS CONTEXT OF 323 00:12:06,559 --> 00:12:10,563 TRYING TO UNDERSTAND HOW GENES 324 00:12:10,629 --> 00:12:12,498 ACT THROUGH DEVELOPMENT, NOW 1 325 00:12:12,565 --> 00:12:14,100 OF THE THINGS ABOUT THE 326 00:12:14,166 --> 00:12:15,234 ENVIRONMENT, IT'S SUPER 327 00:12:15,301 --> 00:12:16,602 IMPORTANT IN BRAIN DEVELOPMENT 328 00:12:16,669 --> 00:12:18,037 BUT GENETIC SYSTEM VERY 329 00:12:18,104 --> 00:12:19,205 CONSTRAINED, EACH THOUGH THE 330 00:12:19,271 --> 00:12:21,407 GENOME IS BIG, IT'S STILL 331 00:12:21,474 --> 00:12:22,942 TRACTABLE, AND SO I VIEW THE 332 00:12:23,008 --> 00:12:25,478 GENETICS AS A TARTING POINT FOR 333 00:12:25,544 --> 00:12:27,313 BEGINNING TO UNDERSTAND EVEN 334 00:12:27,379 --> 00:12:28,347 GENE ENVIRONMENT INTERACTIONS, 335 00:12:28,414 --> 00:12:30,015 SO WE FOCUSED ON GENETICS RATHER 336 00:12:30,082 --> 00:12:31,050 THAN THE ENVIRONMENT FOR THAT 337 00:12:31,117 --> 00:12:34,987 REASON BECAUSE WE THINK IT'S 338 00:12:35,054 --> 00:12:35,488 VERY TRACTABLE. 339 00:12:35,554 --> 00:12:38,791 SO THEN THE QUESTION IS, HOW 340 00:12:38,858 --> 00:12:42,061 MUCH IS THERE GENETIC INFLUENCE 341 00:12:42,128 --> 00:12:42,695 ON NEUROPSYCHIATRIC DISORDERS, 342 00:12:42,761 --> 00:12:43,963 SO THIS IS JUST A REVIEW WE 343 00:12:44,029 --> 00:12:45,965 WROTE A NUMBER OF YEARS AGO, I 344 00:12:46,031 --> 00:12:47,933 SHOW THE PREVALENCE, ON THE 345 00:12:48,000 --> 00:12:49,001 LEFT, FROM ANXIETY DISORDERS ALL 346 00:12:49,068 --> 00:12:51,904 THE WAY DOWN TO TERRETS 347 00:12:51,971 --> 00:12:53,973 SYNDROME, SCHIZOPHRENIA A LITTLE 348 00:12:54,039 --> 00:12:54,974 BIT UNDER 1%. 349 00:12:55,040 --> 00:12:57,176 ACCURACYATISM NOW CLOSE TO 2%, 350 00:12:57,243 --> 00:12:58,477 HIGH HERITABILITY IN A VARIETY 351 00:12:58,544 --> 00:13:03,949 OF STUDIES, YOU LOOK AT 352 00:13:04,016 --> 00:13:05,451 MONOZYGOTIC, VERSUS DIOZYGOTTIC 353 00:13:05,518 --> 00:13:08,554 TWINS, YOU LOOK AT DATA IN 354 00:13:08,621 --> 00:13:11,857 FAMILY HERITABILITY, THERE WAS A 355 00:13:11,924 --> 00:13:13,926 BIG CONFIDENCE BOUND, A LARGE 356 00:13:13,993 --> 00:13:16,862 STUDY RECENTLY IN TWINS SUGGEST 357 00:13:16,929 --> 00:13:17,530 LARGE INHERITABILITY. 358 00:13:17,596 --> 00:13:20,933 IF YOU MEASURE THE SNP, THE 359 00:13:21,000 --> 00:13:21,767 COMMON CONTRIBUTION IT'S USUALLY 360 00:13:21,834 --> 00:13:23,202 LESS THAN THE TOTAL HERITABILITY 361 00:13:23,269 --> 00:13:24,937 FOR A LOT OF REAPS BUT IT'S JUST 362 00:13:25,004 --> 00:13:28,807 ANOTHER WAY OF MEASURING 363 00:13:28,874 --> 00:13:30,743 HERITABILITY, THERE IS 364 00:13:30,809 --> 00:13:32,178 SUBSTANTIAL HERITABILITY ACROSS 365 00:13:32,244 --> 00:13:33,345 THESE DISORDERS THAT VARIES AND 366 00:13:33,412 --> 00:13:35,915 THAT MEANS THAT THERE ARE 367 00:13:35,981 --> 00:13:37,183 GENETIC ARCHITECTURES AS WELL, 368 00:13:37,249 --> 00:13:39,018 THE CONTRIBUTION OF COMMON 369 00:13:39,084 --> 00:13:41,453 VARIANTS IS MORE IN SOME OF THE 370 00:13:41,520 --> 00:13:42,855 ADULT ONSET DISORDERS AND THE 371 00:13:42,922 --> 00:13:46,825 CONTRIBUTION OF RARE PROTEIN 372 00:13:46,892 --> 00:13:48,360 DISRUPTING DISORDERS IS AND DE 373 00:13:48,427 --> 00:13:50,596 NOVO MUTATIONS IS HIGHER IN THE 374 00:13:50,663 --> 00:13:54,333 EARLIER ONSET, LIKE DOWNS 375 00:13:54,400 --> 00:13:55,801 SYNDROME FOR EXAMPLE AND WHAT 376 00:13:55,868 --> 00:13:56,769 THIS LITTLE SIMPLE GRAF SHOWS 377 00:13:56,835 --> 00:13:58,837 HERE IS SOMETHING I THINK IS 378 00:13:58,904 --> 00:14:00,272 KIND OF PROFOUND, THAT THIS IS 379 00:14:00,339 --> 00:14:03,676 THE GENOME WIDE, YOU KNOW AT 380 00:14:03,742 --> 00:14:05,678 THAT TIME IN 2015, AT THE TIME I 381 00:14:05,744 --> 00:14:09,148 WROTE THIS, THIS IS THE NUMBER 382 00:14:09,215 --> 00:14:10,149 OF LOCI IDENTIFIED, 383 00:14:10,216 --> 00:14:10,916 SCHIZOPHRENIA BEING AT THE 384 00:14:10,983 --> 00:14:12,985 BOTTOM AND AS 1 CAN SEE 2 385 00:14:13,052 --> 00:14:13,485 THINGS. 386 00:14:13,552 --> 00:14:15,921 ONE CAN FIND LOCI FOR THESE 387 00:14:15,988 --> 00:14:18,257 DISORDERS THAT ARE NOT DEFINED 388 00:14:18,324 --> 00:14:20,125 BASED ON SOME BIOCHEMICAL 389 00:14:20,192 --> 00:14:21,060 MEASUREMENT, BUT ON OBSERVATION 390 00:14:21,126 --> 00:14:24,129 OF BEHAVIOR AND COGNITION. 391 00:14:24,196 --> 00:14:26,131 SO THERE IS SOME--I DON'T WANT 392 00:14:26,198 --> 00:14:28,534 TO SAY TOTAL, SOME BIOLOGICAL 393 00:14:28,601 --> 00:14:30,603 COHERENCE, BUT AS THE SAMPLE 394 00:14:30,669 --> 00:14:32,571 SIZE INCREASE, 1 IDENTIFIES MORE 395 00:14:32,638 --> 00:14:35,007 AND MORE LOCI, AND THAT'S SHOWN 396 00:14:35,074 --> 00:14:37,042 HERE AGAIN IN A SLIGHTLY LATER 397 00:14:37,109 --> 00:14:38,711 PAPER WITH PAT SULLIVAN, WE JUST 398 00:14:38,777 --> 00:14:41,480 KIND OF LOOK AND YOU CAN SEE 399 00:14:41,547 --> 00:14:43,148 THAT THERE'S ALMOST AN 400 00:14:43,215 --> 00:14:44,516 INFLECTION POINT WHERE ONCE YOU 401 00:14:44,583 --> 00:14:46,852 REACH IN THE 30-50,000, THE 402 00:14:46,919 --> 00:14:48,954 NUMBER OF GENOME WIDE 403 00:14:49,021 --> 00:14:50,956 SIGNIFICANT LOCI GOES UP 404 00:14:51,023 --> 00:14:51,724 EXPONENTIALLY, WHAT'S 405 00:14:51,790 --> 00:14:53,926 INTERESTING THERE IS IN AUTISM 406 00:14:53,993 --> 00:14:55,794 IT REALLY HASN'T HIT THAT YET SO 407 00:14:55,861 --> 00:14:59,932 WE ONLY HAVE A HANDFUL OR SO OF 408 00:14:59,999 --> 00:15:01,767 GENOME WIDE SIGNIFICANT LOCI BUT 409 00:15:01,834 --> 00:15:02,835 STILL GENE DISCOVERY HAS BEEN 410 00:15:02,901 --> 00:15:04,169 VERY ACTIVE AND PRODUCTIVE AS I 411 00:15:04,236 --> 00:15:07,273 WILL TELL YOU IN A 412 00:15:07,339 --> 00:15:07,873 SECURITIZATION. 413 00:15:07,940 --> 00:15:08,907 --IN A SECOND. 414 00:15:08,974 --> 00:15:10,843 ANOTHER THING THAT'S KIND OF 415 00:15:10,909 --> 00:15:13,712 REMARKABLE IS IF YOU TAKE THE 416 00:15:13,779 --> 00:15:16,515 SNP HERITABILITY AND CONTRAST IT 417 00:15:16,582 --> 00:15:18,250 ACROSS THESE DISORDERS THAT 418 00:15:18,317 --> 00:15:19,451 THERE IS SUBSTANTIAL GENETIC 419 00:15:19,518 --> 00:15:20,953 CORRELATION AND THIS EXISTS FOR 420 00:15:21,020 --> 00:15:24,056 MANY REASONS WHICH I WON'T GO 421 00:15:24,123 --> 00:15:26,458 INTO LIKELY BUT BIPOLAR AND SITS 422 00:15:26,525 --> 00:15:28,961 FRENNIA, THE HIGHEST AND EVEN 423 00:15:29,028 --> 00:15:31,196 AUTISM WHICH ARE VASTLY 424 00:15:31,263 --> 00:15:32,264 DIFFERENT TRAJECTORIES AND SIGNS 425 00:15:32,331 --> 00:15:34,133 AND SYMPTOMS HAVE A POINT TO 426 00:15:34,199 --> 00:15:35,534 GENETIC CORRELATION AT THE LEVEL 427 00:15:35,601 --> 00:15:37,503 OF COMMON VARIANCE WHICH IS 428 00:15:37,569 --> 00:15:38,237 QUITE SUBSTANTIAL WHICH IS 429 00:15:38,304 --> 00:15:41,106 TELLING US THAT THERE ARE SHARED 430 00:15:41,173 --> 00:15:44,043 AND DISTINCT COMPONENTS OF RISK. 431 00:15:44,109 --> 00:15:45,944 SO WITH THAT KIND OF AS A 432 00:15:46,011 --> 00:15:47,880 FOUNDATION, I WILL NOW JUMP INTO 433 00:15:47,946 --> 00:15:51,884 AUTISM WHICH I'VE BEEN WORKING 434 00:15:51,950 --> 00:15:56,288 ON SINCE AROUND 1999 OR SO. 435 00:15:56,355 --> 00:16:00,359 SO AUTISM IS NOT DEFINED BY 436 00:16:00,426 --> 00:16:03,529 ANYTHING OTHER THAN COGNITION 437 00:16:03,595 --> 00:16:04,196 AND BEHAVIOR. 438 00:16:04,263 --> 00:16:05,864 IT'S A SYNDROME, NOT A DOZE, IT 439 00:16:05,931 --> 00:16:08,200 OVERLAPS A LOT WITH A LOT OF 440 00:16:08,267 --> 00:16:09,368 DEVELOPMENTAL DISORDERS AND WHAT 441 00:16:09,435 --> 00:16:12,805 MAKES IT AND WHAT STANDS OUT IS 442 00:16:12,871 --> 00:16:13,872 THESE DIFFICULTIES IN SOCIAL 443 00:16:13,939 --> 00:16:15,874 COGNITION AND WHAT I SHORT HAND 444 00:16:15,941 --> 00:16:17,042 AS MENTAL FLEXIBILITY WHICH IS 445 00:16:17,109 --> 00:16:21,747 REALLY, YOU COULD SAY, 446 00:16:21,814 --> 00:16:22,681 REPETITIVE, RESTRICTIVE 447 00:16:22,748 --> 00:16:25,150 BEHAVIORS, ABOUT 30% HAVE 448 00:16:25,217 --> 00:16:26,785 INTELLECTUAL DISABILITY. 449 00:16:26,852 --> 00:16:28,087 INTELLECTUAL DISABILITY DOES 450 00:16:28,153 --> 00:16:29,021 NOT--DOES NOT NECESSARILY TRAVEL 451 00:16:29,088 --> 00:16:31,190 WITH AUTISM ALL THE TIME, IT'S 452 00:16:31,256 --> 00:16:33,392 NOT A CORE COMPONENT, ABOUT 10 453 00:16:33,459 --> 00:16:34,960 OR 15% HAVE DIFFERENT SEIZURES 454 00:16:35,027 --> 00:16:35,661 AT DIFFERENT TIMES. 455 00:16:35,728 --> 00:16:37,229 SO 1 WAY I KIND OF LOOK AT THIS, 456 00:16:37,296 --> 00:16:40,299 AND YOU MIGHT ASK, THERE'S A LOT 457 00:16:40,366 --> 00:16:42,368 OF--THIS SUGGESTS A LOT OF 458 00:16:42,434 --> 00:16:44,103 PLEOTROPY, YOU COULD HAVE 459 00:16:44,169 --> 00:16:45,871 ACCURACYATISM, YOU CAN HAVE 460 00:16:45,938 --> 00:16:47,005 AUTISM WITH INTELLECTUAL 461 00:16:47,072 --> 00:16:48,474 DISABILITY, WITH MOTOR 462 00:16:48,540 --> 00:16:49,041 DYSFUNCTION OR SEIZURES, ET 463 00:16:49,108 --> 00:16:50,476 CETERA AND AS IT TURNS OUT, 1 464 00:16:50,542 --> 00:16:54,046 WAY TO THINK ABOUT THIS IS THIS 465 00:16:54,113 --> 00:16:57,416 NOTION OF WADDING TON'S 466 00:16:57,483 --> 00:16:58,817 EPIGENETIC LANDSCAPE THAT THE 467 00:16:58,884 --> 00:17:01,320 BRAIN DEVELOPMENT IS OCCURRING 468 00:17:01,387 --> 00:17:05,424 IN KIND OF, YOU KNOW, ALONG A 469 00:17:05,491 --> 00:17:07,826 TRACK LET'S SAY AND GENETICS IF 470 00:17:07,893 --> 00:17:09,461 YOU HAVE CERTAIN VARIANTS OR 471 00:17:09,528 --> 00:17:11,096 CERTAIN LARGE EFFECT MUTATIONS 472 00:17:11,163 --> 00:17:14,733 IT KIND OF KNOCKS YOU OFF THAT 473 00:17:14,800 --> 00:17:15,934 TRACK, PREDISPOSING YOU TO THESE 474 00:17:16,001 --> 00:17:18,437 THINGS BUT THERE'S NOT A 1 TO 1 475 00:17:18,504 --> 00:17:19,805 CORRELATION BETWEEN A SPECIFIC 476 00:17:19,872 --> 00:17:21,507 GENE AND A SPECIFIC CLINICAL 477 00:17:21,573 --> 00:17:22,708 SYNDROME REALLY YET THAT WE CAN 478 00:17:22,775 --> 00:17:24,209 POINT TO. 479 00:17:24,276 --> 00:17:25,644 AUTISM AFFECTS ABOUT 1 IN 40 480 00:17:25,711 --> 00:17:27,413 CHILDREN TODAY, THERE'S A 4-1 481 00:17:27,479 --> 00:17:29,148 RATIO OF MALES TO FEMALES. 482 00:17:29,214 --> 00:17:31,383 IT'S MORE COMMON THAN MANY OTHER 483 00:17:31,450 --> 00:17:33,419 CHILDHOOD DISORDERS WHICH MAKES 484 00:17:33,485 --> 00:17:35,287 IT IMPORTANT FROM PUBLIC HEALTH 485 00:17:35,354 --> 00:17:37,256 STANDPOINT, NOT THAT THESE OTHER 486 00:17:37,322 --> 00:17:38,657 DISORDERS AREN'T IMPORTANT, 487 00:17:38,724 --> 00:17:40,859 NORMAL LIFE EXPECTANCY, PRETTY 488 00:17:40,926 --> 00:17:42,227 MUCH, ALTHOUGH AGAIN, DEPENDING 489 00:17:42,294 --> 00:17:43,629 ON HOW COMPLEX IT IS, IF 490 00:17:43,695 --> 00:17:45,397 SOMEBODY HAS, YOU KNOW RECURRENT 491 00:17:45,464 --> 00:17:46,799 SEIZURES AND STUFF LIKE THAT, 492 00:17:46,865 --> 00:17:48,801 THAT'S GOING TO HAVE AN IMPACT 493 00:17:48,867 --> 00:17:51,703 BUT AUTISM SIZE, NORMAL LIFE 494 00:17:51,770 --> 00:17:53,205 EXPECTANCY, ABOUT 10-15% WILL 495 00:17:53,272 --> 00:17:53,839 DEVELOP EPILEPSY. 496 00:17:53,906 --> 00:17:59,077 SO THAT'S KIND OF MY BRIEF 497 00:17:59,144 --> 00:17:59,645 CLINICAL INTRODUCTION. 498 00:17:59,711 --> 00:18:01,180 AND IT'S INTERESTING BECAUSE IF 499 00:18:01,246 --> 00:18:04,049 I HAD BEEN GIVING THIS TALK A 500 00:18:04,116 --> 00:18:11,123 DECADE AGO, IT WOULD BE MENTAL 501 00:18:11,190 --> 00:18:12,624 DYSFUNCTION, AND LANGUAGE 502 00:18:12,691 --> 00:18:13,459 DYSFUNCTION AND COGNITIVE 503 00:18:13,525 --> 00:18:16,061 ABILITY BUT AS PART OF THE 504 00:18:16,128 --> 00:18:17,896 EVOLUTION, THEY TOOK LANGUAGE 505 00:18:17,963 --> 00:18:19,531 OUT OF DISCUSSION WHICH I'M 506 00:18:19,598 --> 00:18:20,265 HAPPY TO DISCUSS. 507 00:18:20,332 --> 00:18:22,401 ABOUT A THIRD WILL HAVE 508 00:18:22,468 --> 00:18:24,470 INLECTUAL DISABILITY, BUT AGAIN, 509 00:18:24,536 --> 00:18:26,438 INLECTUAL DISABILITY IS NOT A 510 00:18:26,505 --> 00:18:28,407 CORE COMPONENT OF AUTISM. 511 00:18:28,474 --> 00:18:30,909 ONE OF THE REASONS WHY IT WAS 512 00:18:30,976 --> 00:18:33,078 FIRST DRIEBED NOT TOO LONG AGO 513 00:18:33,145 --> 00:18:35,981 AND THIS DESCRIPTION BY LEO 514 00:18:36,048 --> 00:18:37,850 CANNER IS UNCANNY IN A LOT OF 515 00:18:37,916 --> 00:18:40,986 WAYS BECAUSE IT NAILED A LOT OF 516 00:18:41,053 --> 00:18:41,353 THINGS. 517 00:18:41,420 --> 00:18:42,387 BUT HE REALLY POINTS TO THE 518 00:18:42,454 --> 00:18:44,156 POINT THAT THESE CHILDREN ARE 519 00:18:44,223 --> 00:18:45,991 BORN LIKE THIS, IT'S INNATE, 520 00:18:46,058 --> 00:18:47,960 DIDN'T SAY IT'S GENETIC BUT 521 00:18:48,026 --> 00:18:51,463 SHOWS THAT THERE'S A FAMILIAL 522 00:18:51,530 --> 00:18:54,299 AGGREGATION OF AUTISM LIKE 523 00:18:54,366 --> 00:18:56,235 FEATURES, BUT THEN YOU KNOW SO 524 00:18:56,301 --> 00:18:57,669 YOU MIGHT ASK WHY DIDN'T THINGS 525 00:18:57,736 --> 00:18:59,271 MOVE AHEAD THAT FAST AND THIS IS 526 00:18:59,338 --> 00:19:01,907 1 OF THE REASONS THIS IS THIS 527 00:19:01,974 --> 00:19:04,877 PSYCHODYNAMIC THEORY THAT AUTISM 528 00:19:04,943 --> 00:19:08,614 WAS PSYCHOGENIC THAT IT WAS 529 00:19:08,680 --> 00:19:10,115 CAUSED BY PARENT, MY COLD 530 00:19:10,182 --> 00:19:11,750 PARENTING AND THE CHILD WAS 531 00:19:11,817 --> 00:19:12,417 PROTECTING THEMSELVES FROM THIS 532 00:19:12,484 --> 00:19:15,654 KIND OF LACK OF EMOTION IN COLD 533 00:19:15,721 --> 00:19:20,826 PARENTING WHICH OF COURSE WAS 534 00:19:20,893 --> 00:19:23,061 WRONG BUT WAS WIDELY ACCEPTED 535 00:19:23,128 --> 00:19:24,663 BECAUSE OF THE KIND OF 536 00:19:24,730 --> 00:19:25,831 PREVALENCE OF ANALYSIS AT THAT 537 00:19:25,898 --> 00:19:28,367 TIME AND THAT'S WEENK REASON WHY 538 00:19:28,433 --> 00:19:29,368 GENETICS HAS BEEN SO IMPORTANT 539 00:19:29,434 --> 00:19:33,405 IS BECAUSE STARTING WITH THE 540 00:19:33,472 --> 00:19:34,172 PAPER BY [INDISCERNIBLE] IT 541 00:19:34,239 --> 00:19:36,108 NAILED THE FACT THAL IS A 542 00:19:36,174 --> 00:19:37,876 GENETIC DISORRER AND IT WAS A 543 00:19:37,943 --> 00:19:39,378 SMALL SAMPLE SIZE AND ALL OF 544 00:19:39,444 --> 00:19:41,480 THAT BUT NOW, YOU KNOW THAT'S 545 00:19:41,547 --> 00:19:44,983 TURNED OUT TO OF COURSE BE TRUE 546 00:19:45,050 --> 00:19:46,952 AND ONCE THAT WAS OF COURSE 547 00:19:47,019 --> 00:19:48,320 PROVEN BEYOND A REASONABLE 548 00:19:48,387 --> 00:19:49,588 DOUBT, WE ALREADY KNEW THAT 549 00:19:49,655 --> 00:19:51,490 THERE WERE MEDICAL GENETIC 550 00:19:51,557 --> 00:19:52,391 DISORDERS ASSOCIATED WITH AUTISM 551 00:19:52,457 --> 00:19:54,326 BUT THIS NAIL THAD IT WAS A 552 00:19:54,393 --> 00:19:56,895 BIOLOGIC DISORDER AND THAT'S WHY 553 00:19:56,962 --> 00:19:57,829 GENETICS HAS BEEN SO IMPORTANT 554 00:19:57,896 --> 00:19:59,965 IN PUSHING THIS FORWARD, SO 555 00:20:00,032 --> 00:20:01,466 INDEED, IF WE LOOK THERE'S A 556 00:20:01,533 --> 00:20:03,201 HUGE GROWTH IN ACCURACYATISM 557 00:20:03,268 --> 00:20:04,269 RISK GENES AND ALMOST ALL OF 558 00:20:04,336 --> 00:20:09,241 THESE THAT ARE LISTED HERE ARE 559 00:20:09,308 --> 00:20:11,543 GENES THAT ARE HAPPEN LO 560 00:20:11,610 --> 00:20:13,045 INSUFFICIENT, THAT MEANS THERE'S 561 00:20:13,111 --> 00:20:15,047 A MUTATION THAT DISRUPTS THE 562 00:20:15,113 --> 00:20:17,883 PROTEIN ON 1 CHROMOSOME, THE 563 00:20:17,950 --> 00:20:20,052 OTHER BEING OKAY. 564 00:20:20,118 --> 00:20:22,554 THESE ARE USUALLY DE NOVO. 565 00:20:22,621 --> 00:20:24,523 OCCASIONALLY INHERITED BUT MOST 566 00:20:24,590 --> 00:20:26,825 OF THESE ARE LIKE DOWNS 567 00:20:26,892 --> 00:20:27,659 SYNDROME, PARENTS DON'T HAVE 568 00:20:27,726 --> 00:20:29,094 THEM, THEY OCCURRED IN THE GERM 569 00:20:29,161 --> 00:20:29,328 LINE. 570 00:20:29,394 --> 00:20:30,929 AND 1 THING THAT'S JUST BEEN 571 00:20:30,996 --> 00:20:33,932 DRIVING THIS IS THE ENDLESS 572 00:20:33,999 --> 00:20:34,900 INNOVATION AND TECHNOLOGY WHICH 573 00:20:34,967 --> 00:20:37,736 HAS ALLOWED US TO GET TO A POINT 574 00:20:37,803 --> 00:20:40,038 WHERE 1 CAN PERFORM WHOLE 575 00:20:40,105 --> 00:20:41,940 EXOHM OR GENOME SEQUENCING IN 576 00:20:42,007 --> 00:20:44,643 10S OF THOUSANDS OF PEOPLE AT 577 00:20:44,710 --> 00:20:46,945 REASONABLE COST IT'S WAY CHEAPER 578 00:20:47,012 --> 00:20:48,447 TO SEQUENCE PEOPLE THAN TO 579 00:20:48,513 --> 00:20:49,748 PHENOTYPE THEM SO THIS HAS LED 580 00:20:49,815 --> 00:20:51,683 TO AN EXPLOSION IN IDENTIFYING 581 00:20:51,750 --> 00:20:54,720 RISK GENES THERE ARE MORE THAN A 582 00:20:54,786 --> 00:20:55,988 HUNDRED SYNDROMIC YEENS, 583 00:20:56,054 --> 00:20:58,657 TOTALLY, YOU COULD SAY 200 HIGH 584 00:20:58,724 --> 00:21:00,826 CONFIDENCE RISK YEENS THAT ARE 585 00:21:00,892 --> 00:21:02,594 YOU ARE IN THE SAN FRANCISCO 586 00:21:02,661 --> 00:21:04,329 PFAFFY DATA BISE BY SIMONS. 587 00:21:04,396 --> 00:21:07,532 IF YOU KIND OF BROADEN IT TO SAY 588 00:21:07,599 --> 00:21:09,501 IT COULD CAUSE AUTISM OR 589 00:21:09,568 --> 00:21:10,869 DEVELOPMENTAL DISABILITY SO YOU 590 00:21:10,936 --> 00:21:12,638 COULD GET MORE POWER IN LARGE 591 00:21:12,704 --> 00:21:14,406 SAMPLES, THERE ARE MORE GENES 592 00:21:14,473 --> 00:21:15,374 AFFILIATED WITH AUTISM, YOU 593 00:21:15,440 --> 00:21:17,843 COULD SAY, AND ALL THIS GENETICS 594 00:21:17,909 --> 00:21:19,778 HAS SHOWN EVIDENT FOR A FEMALE 595 00:21:19,845 --> 00:21:20,746 PROTECTIVE EFFECT, THAT IS 596 00:21:20,812 --> 00:21:22,748 FEMALES HAVE TO HAVE A GENETIC 597 00:21:22,814 --> 00:21:24,316 LOAD TO HAVE AUTISM, THAT'S WHAT 598 00:21:24,383 --> 00:21:26,451 IT LOOKS LIKE AT THIS POINT AND 599 00:21:26,518 --> 00:21:28,286 IN TERMS OF DE NOVO EVENTS, 600 00:21:28,353 --> 00:21:29,588 THEY'RE MORE LIKELY TO OCCUR IN 601 00:21:29,655 --> 00:21:33,592 SPERM THAN IN THE EGG, SO OLDER 602 00:21:33,659 --> 00:21:36,795 DATS ARE ASSOCIATED WITH MORE DE 603 00:21:36,862 --> 00:21:39,464 NOVO CNVs ALTHOUGH AGE IS NOT 604 00:21:39,531 --> 00:21:40,165 TOTALLY ACCOUNTING FOR WHAT'S 605 00:21:40,232 --> 00:21:44,569 GOING ON IN AUTISM. 606 00:21:44,636 --> 00:21:46,805 SO ALL IN ALL, IF I WILL 607 00:21:46,872 --> 00:21:47,773 SUMMARIZE THE GENETIC 608 00:21:47,839 --> 00:21:49,074 DISCOVERIES, MANY FORMS OF 609 00:21:49,141 --> 00:21:51,476 GENETIC VARIATION AND MOTES OF 610 00:21:51,543 --> 00:21:52,177 INHERITANCE AND THIS HAS SHOWN 611 00:21:52,244 --> 00:21:54,513 HERE WHAT WE SAW IN 2016 AND THE 612 00:21:54,579 --> 00:21:55,947 WAY WE SUMMARIZE IT STANDS TRUE 613 00:21:56,014 --> 00:21:57,215 TODAY, THAT THERE ARE MORE AND 614 00:21:57,282 --> 00:21:59,217 MORE OF THESE RARE CONDITIONS, 615 00:21:59,284 --> 00:22:00,619 NONE OF WHICH ACCOUNT FOR MORE 616 00:22:00,686 --> 00:22:03,288 THAN 1% OF AUTISM, EITHER SINGLE 617 00:22:03,355 --> 00:22:05,490 YEEN MUTATIONS OR TRUCTURAL 618 00:22:05,557 --> 00:22:06,224 CHROMOSOMAL VARIATION, THAT IS 619 00:22:06,291 --> 00:22:09,795 GAIN OR LOSS OF A COPY OF A 620 00:22:09,861 --> 00:22:11,163 CHROMOSOME THAT INVOLVES USUALLY 621 00:22:11,229 --> 00:22:13,031 MORE THAN 1 GENE AND THESE ARE 622 00:22:13,098 --> 00:22:14,900 SHOWN HERE, AND THEN THE 623 00:22:14,966 --> 00:22:16,601 SYNDROMIC FORMS LIKE FRAGILE X, 624 00:22:16,668 --> 00:22:18,370 ET CETERA. 625 00:22:18,437 --> 00:22:20,305 BUT IN 2016 IF WOE COLLAPSE THIS 626 00:22:20,372 --> 00:22:22,274 IT ACCOUNTED FOR ABOUT 10% OF 627 00:22:22,340 --> 00:22:23,542 THE PATIENTS, WE COULD PREDICT 628 00:22:23,608 --> 00:22:25,510 THAT THE DE NOVO SINGLE GENE 629 00:22:25,577 --> 00:22:26,912 MUTATIONS WOULD ACCOUNT FOR 630 00:22:26,978 --> 00:22:30,248 ABOUT 15% OR SO, AND THAT'S BORN 631 00:22:30,315 --> 00:22:30,982 OUT. 632 00:22:31,049 --> 00:22:34,519 BUT THERE'S PREDICTED COMMON 633 00:22:34,586 --> 00:22:36,588 INHERENT, INHERITED IT IS ABOUT 634 00:22:36,655 --> 00:22:39,925 49% AND THERE'S ABOUT 40% 635 00:22:39,991 --> 00:22:42,728 UNACCOUNTED FOR WHICH IS LIKELY 636 00:22:42,794 --> 00:22:44,129 UNINHERITTED FORMS OF VARIATION 637 00:22:44,196 --> 00:22:46,465 AND OTHER FORMS OF VARIATION 638 00:22:46,531 --> 00:22:48,166 THAT HAVEN'T BEEN PICKED UP YET. 639 00:22:48,233 --> 00:22:49,935 SO THERE'S STILL A LOT OF GENE 640 00:22:50,001 --> 00:22:51,470 DISCOVERIES TO HAPPEN BECAUSE 641 00:22:51,536 --> 00:22:52,337 WHAT'S BEEN IDENTIFIED ARE 642 00:22:52,404 --> 00:22:56,007 MUTATIONS IN THE HIGHLY 643 00:22:56,074 --> 00:22:56,908 CONSTRAINED DEVELOPMENTAL JEEPS, 644 00:22:56,975 --> 00:22:58,577 THEY'RE REALLY BIG EFFECT ON 645 00:22:58,643 --> 00:22:59,644 MUTATIONS THAT KNOCK OUT YEENS 646 00:22:59,711 --> 00:23:01,680 OR IN A COPY NUMBER VARIANT 647 00:23:01,747 --> 00:23:06,752 KNOCK OUT 22 YEENS OR 3 GENES 648 00:23:06,818 --> 00:23:09,121 AND SO THERE'S AN ENORM AUSNEED 649 00:23:09,187 --> 00:23:10,522 TO IDENTIFY THE COMMON GENETIC 650 00:23:10,589 --> 00:23:11,923 VARIATION AND AS I MENTIONED 651 00:23:11,990 --> 00:23:14,292 THERE ARE ONLY ABOUT 5 OR MAYBE 652 00:23:14,359 --> 00:23:15,827 NOW 12 UNPUBLISHED LOCI, SO WE 653 00:23:15,894 --> 00:23:17,796 MEDE TO, YOU KNOW REALLY MOVE 654 00:23:17,863 --> 00:23:21,099 FORWARD AND PART OF THIS HAS TO 655 00:23:21,166 --> 00:23:23,702 DO, I WILL MAKE A QUICK 656 00:23:23,769 --> 00:23:25,570 DEVIATION IN A WAY, WITH THE 657 00:23:25,637 --> 00:23:29,341 FACT THAT THE WAY FAMILIES AND 658 00:23:29,407 --> 00:23:30,876 AUTISTIC PRO BANDS, THE WAY 659 00:23:30,942 --> 00:23:31,743 PATIENTS ARE RECRUITED AFFECTS 660 00:23:31,810 --> 00:23:33,478 WHAT YOU WILL FIND AND THERE 661 00:23:33,545 --> 00:23:34,846 HAVEN'T BEEN ENOUGH LARGE FAMILY 662 00:23:34,913 --> 00:23:37,149 STUDIES BUT THE CURRENT YIELD IN 663 00:23:37,215 --> 00:23:38,216 CLINICAL TESTING IS SOMEWHERE 664 00:23:38,283 --> 00:23:42,053 BETWEEN 10 AND 15%, YOU DO A 665 00:23:42,120 --> 00:23:44,222 CLINAL MICROARRAY, IF IT'S A 666 00:23:44,289 --> 00:23:48,627 WHOLE YOU DO WHOLE PRAJ ILLEGALS 667 00:23:48,693 --> 00:23:50,595 X SEQUENCING AND IF NOT YOU DO 668 00:23:50,662 --> 00:23:52,564 WHOLE IME NOAM CHROMOSOME 669 00:23:52,631 --> 00:23:55,233 SEQUENCING AND THERE'S TONS OF 670 00:23:55,300 --> 00:23:56,034 PLEOTROPY. 671 00:23:56,101 --> 00:23:57,335 SO AGAIN, I COULD SPEND THE 672 00:23:57,402 --> 00:23:59,304 WHOLE TALK JUST TALKING ABOUT 673 00:23:59,371 --> 00:24:00,672 THE RELATIONSHIP, THE PHENOTYPES 674 00:24:00,739 --> 00:24:02,107 TO GENO TYPES AND ALL OF THAT 675 00:24:02,174 --> 00:24:03,208 AND I DON'T WANT TO DO THAT BUT 676 00:24:03,275 --> 00:24:06,178 I DO WANT TO JUST MAKE 1 POINT, 677 00:24:06,244 --> 00:24:09,014 THAT JUST LIKE ALMOST EVERY 678 00:24:09,080 --> 00:24:11,783 OTHER HUMAN CONDITION, IT 679 00:24:11,850 --> 00:24:13,518 FOLLOWS A COMPLEX GENETIC MODEL 680 00:24:13,585 --> 00:24:17,589 THAT I WILL CALL LIABILITY 681 00:24:17,656 --> 00:24:19,457 THRESHOLD MODEL DEVELOPED BY 682 00:24:19,524 --> 00:24:21,226 FALCONER AND BEHAVIORIAL 683 00:24:21,293 --> 00:24:22,894 GENETICS LIKE 70 YEARS AGO. 684 00:24:22,961 --> 00:24:25,463 BUT IF YOU KIND OF THINK OF 685 00:24:25,530 --> 00:24:27,332 THESE REPETITIVE RESTRICTIVE 686 00:24:27,399 --> 00:24:27,933 BEHAVIORS, SOCIAL BEHAVIORS, 687 00:24:27,999 --> 00:24:29,134 LANGUAGE WHICH I DO BELIEVE IS 688 00:24:29,201 --> 00:24:30,902 PART OF AUTISM, THERE'S A 689 00:24:30,969 --> 00:24:33,738 CONTOUR, A FUNCTION AND 690 00:24:33,805 --> 00:24:35,373 DYSFUNCTION AND THE GENETICS 691 00:24:35,440 --> 00:24:37,576 JUST PULLS YOU OVER ON 1 SIDE, 692 00:24:37,642 --> 00:24:40,645 AND IT COULD BE A BUNCH OF LARGE 693 00:24:40,712 --> 00:24:42,614 EFFECT 1 SINGLE LARGE EFFECT 694 00:24:42,681 --> 00:24:45,717 MUTATION OR IT COULD BE A BUNCH 695 00:24:45,784 --> 00:24:46,651 OF ADAATIVE POLYGENIC RISK WHICH 696 00:24:46,718 --> 00:24:48,153 WE KNOW LESS ABOUT AND I WILL 697 00:24:48,220 --> 00:24:51,156 SHOW YOU 2 GRAPHS THAT MAKE THAT 698 00:24:51,223 --> 00:24:51,423 POINT. 699 00:24:51,489 --> 00:24:54,326 THIS IS FROM OUR OWN WORK IN 700 00:24:54,392 --> 00:24:55,827 INHERITED AND FAMILIES WITH 2 OR 701 00:24:55,894 --> 00:24:57,796 MORE CHILDREN, AND WHAT WE 702 00:24:57,863 --> 00:25:00,632 FOUND, WE FOUND REALLY THE FIRST 703 00:25:00,699 --> 00:25:02,167 STRONG STATISTICAL EVIDENT, THAT 704 00:25:02,234 --> 00:25:04,002 THERE ARE RARE INHERITED 705 00:25:04,069 --> 00:25:04,936 VARIANTS THAT COME PRACTICES 706 00:25:05,003 --> 00:25:07,339 PARENTS TO CHILDREN, THE 707 00:25:07,405 --> 00:25:08,940 REQUESTY IS, WHY ISN'T THE 708 00:25:09,007 --> 00:25:10,809 PARENT AFFECTED IF THIS RARE 709 00:25:10,876 --> 00:25:11,943 INHERITED VARIANT. 710 00:25:12,010 --> 00:25:16,414 WELL, IT'S NOT SUFFICIENT TO 711 00:25:16,481 --> 00:25:17,015 CAUSE THE AUTISM. 712 00:25:17,082 --> 00:25:18,316 WHAT HAPPENS IS THE KIELD IS 713 00:25:18,383 --> 00:25:20,886 GETTING THE RARE INHERITED 714 00:25:20,952 --> 00:25:22,187 VARIANT PLUS POLYGENIC RISK AND 715 00:25:22,254 --> 00:25:23,955 THAT'S WHAT'S SHOWN ON THE 716 00:25:24,022 --> 00:25:27,259 Y-AXIS IS THE POLYGENIC RISK AND 717 00:25:27,325 --> 00:25:30,195 SO, THIS PERSON WHO HAS--IS 718 00:25:30,262 --> 00:25:32,497 ASHINGED, WHO'S CARRYING A RARE 719 00:25:32,564 --> 00:25:34,199 INHERITED VARIANT IN THE BLUE, 720 00:25:34,266 --> 00:25:34,900 THEY HAVE INCREASED TRANSMISSION 721 00:25:34,966 --> 00:25:36,668 FROM THE PARENTS OFPOLOGYY GENIC 722 00:25:36,735 --> 00:25:39,004 RISK, SO IT'S A MIX OF RARE 723 00:25:39,070 --> 00:25:42,507 VARIANT AND POLYGENIC RISK. 724 00:25:42,574 --> 00:25:43,842 AND THAT'S ALSO BEEN SEEN IN 725 00:25:43,909 --> 00:25:48,246 OTHER STUDIES, THIS IS 1 FROM 726 00:25:48,313 --> 00:25:48,980 JONATHAN'S [INDISCERNIBLE] LAB 727 00:25:49,047 --> 00:25:53,451 WHICH IS NOT A FAMILIARIAL STUDY 728 00:25:53,518 --> 00:25:56,755 BUT THOSE WHO HAVE DAMAGING DE 729 00:25:56,821 --> 00:25:59,424 NOVO MUTATIONS ARE NOT GETTING 730 00:25:59,491 --> 00:26:00,725 THE TRANSMISSION OF POLYGENIC 731 00:26:00,792 --> 00:26:04,462 RISK AGAIN ON THE Y-AXIS. 732 00:26:04,529 --> 00:26:06,998 AND WHAT WE SHOW IS THAT THOSE 733 00:26:07,065 --> 00:26:08,066 WITHOUT IT ARE GETTING THAT. 734 00:26:08,133 --> 00:26:11,770 SO IF YOU HAVE A LARGE DAMAGING 735 00:26:11,836 --> 00:26:14,306 MUTATION, YOU DON'T NEED TO 736 00:26:14,372 --> 00:26:15,173 INHERIT POLYGENIC RISK. 737 00:26:15,240 --> 00:26:18,109 YOU MIGHT BUT YOU DON'T NEED TO 738 00:26:18,176 --> 00:26:21,746 BUT IF YOU HAVE A RARE INHERITED 739 00:26:21,813 --> 00:26:23,481 VARIANT FROM THE PARENT IT'S 740 00:26:23,548 --> 00:26:25,150 LIKELY TO BE LESS BECAUSE OF THE 741 00:26:25,216 --> 00:26:26,785 PARENT SO YOU NEED A COMBINATION 742 00:26:26,851 --> 00:26:27,852 OF FACTORS. 743 00:26:27,919 --> 00:26:29,587 SO THIS GIVES YOU 1 LITTLE WAY 744 00:26:29,654 --> 00:26:31,022 THAT 1 CAN BEGIN TO PARSE OUT 745 00:26:31,089 --> 00:26:33,725 AND PEOPLE HAVE STARTED TO DO 746 00:26:33,792 --> 00:26:35,961 THIS, THE GENO TYPE, PHENOTYPE 747 00:26:36,027 --> 00:26:37,329 RELATIONSHIPS AND THAT'S A VERY 748 00:26:37,395 --> 00:26:39,331 INTERESTING AREA OF AUTISM BUT I 749 00:26:39,397 --> 00:26:40,799 WILL FOCUS ON MORE ON THE 750 00:26:40,865 --> 00:26:41,967 THERAPEUTIC DEVELOPMENT AND 751 00:26:42,033 --> 00:26:45,203 MOVING TO MECHANISTIC 752 00:26:45,270 --> 00:26:47,305 UNDERSTANDING EMPLOY SO GENETICS 753 00:26:47,372 --> 00:26:49,641 HAS BEEN AMAZINGLY SUCCESSFUL IN 754 00:26:49,708 --> 00:26:56,147 IDENTIFYING CAUSES OF AUTISM. 755 00:26:56,214 --> 00:26:59,818 SO MANY, AND ACROSS 756 00:26:59,884 --> 00:27:00,485 NEUROPSYCHIATRIC DISORDERS, 757 00:27:00,552 --> 00:27:01,486 ESPECIALLY SCHIZOPHRENIA AS 758 00:27:01,553 --> 00:27:03,922 WELL, AND THESE GENES PROVIDE 759 00:27:03,989 --> 00:27:05,090 TARGETS FOR UNDERSTANDING 760 00:27:05,156 --> 00:27:14,265 THERAPEUTIC DEVELOPMENT BUT THEY 761 00:27:14,332 --> 00:27:15,400 HIGHLIGHT EXTREME HETEROGENETIC 762 00:27:15,467 --> 00:27:17,002 DISORDERS, AND WE CAN SEE THAT 763 00:27:17,068 --> 00:27:18,269 IN 10-15% OF CASES AND THE 764 00:27:18,336 --> 00:27:19,671 QUESTION IS DO WE HAVE TO 765 00:27:19,738 --> 00:27:21,873 DEVELOP A TREATMENT FOR EACH 766 00:27:21,940 --> 00:27:23,875 DISORDER WILL WILL THERE BE 1 767 00:27:23,942 --> 00:27:25,377 VERGE ENSEL IN SPECIFIC 768 00:27:25,443 --> 00:27:26,678 BIOLOGICAL PATHWAYS, DEVELOPMENT 769 00:27:26,745 --> 00:27:29,614 STAGES, PROCESSES OR BRAIN 770 00:27:29,681 --> 00:27:32,017 CIRCUITRY THAT WE CAN THEN 771 00:27:32,083 --> 00:27:32,384 CAPITALIZE ON. 772 00:27:32,450 --> 00:27:34,152 AND I THOUGHT ABOUT THIS FOR 773 00:27:34,219 --> 00:27:36,087 ALMOST 20 YEARS AS A VERY HARD 774 00:27:36,154 --> 00:27:38,156 PROBLEM AND IT'S GOING TO 775 00:27:38,223 --> 00:27:40,458 REQUIRE US ASKING AT WHAT LEVEL 776 00:27:40,525 --> 00:27:42,527 IS THEIR CONVERGENCE, OBVIOUSLY 777 00:27:42,594 --> 00:27:43,828 THERE'S CONVERGENCE AT SOME 778 00:27:43,895 --> 00:27:45,130 LEVEL IN THE PHENOTYPES AGAIN 779 00:27:45,196 --> 00:27:48,566 BUT IS THERE MOLECULAR 780 00:27:48,633 --> 00:27:50,502 CONVERGENCE, AND THIS WILL 781 00:27:50,568 --> 00:27:52,670 REQUIRE REALLY INTEGRATING DATA 782 00:27:52,737 --> 00:27:53,638 ACROSS MANY LEVELS, SO 1 OF THE 783 00:27:53,705 --> 00:27:55,507 QUESTIONS IS HOW DO YOU TAKE 784 00:27:55,573 --> 00:28:00,145 DATA THAT HAS MANY DIFFERENT 785 00:28:00,211 --> 00:28:01,780 KINDS OF MEASUREMENTS RIGHT IF 786 00:28:01,846 --> 00:28:03,014 YOU'RE MEASURING GENE EXPRESSION 787 00:28:03,081 --> 00:28:05,450 VERSUS SOME OTHER QUANTITATIVE 788 00:28:05,517 --> 00:28:06,184 PHENOTYPE OR EPIGENETIC DATA HOW 789 00:28:06,251 --> 00:28:07,485 DO YOU PUT ALL THAT TOGETHER, 790 00:28:07,552 --> 00:28:10,055 AND THE WAY THAT WE'VE 791 00:28:10,121 --> 00:28:12,023 CONCEPTUALIZED IT IS THAT NO 792 00:28:12,090 --> 00:28:13,658 SINGLE YEEN ORANTITY IS ACTING 793 00:28:13,725 --> 00:28:15,427 ALONE, JUST LIKE WE DON'T ACT 794 00:28:15,493 --> 00:28:16,795 ALONE, WE'RE PART OF SOCIAL 795 00:28:16,861 --> 00:28:18,463 NETWORKS AND OTHER TYPES OF 796 00:28:18,530 --> 00:28:20,432 NETWORKS, YEENS ARE PART OF 797 00:28:20,498 --> 00:28:22,867 NETWORKS, AND SO WE SPENT A LOT 798 00:28:22,934 --> 00:28:24,669 OF TIME IDENTIFYING WHO ARE THE 799 00:28:24,736 --> 00:28:26,938 NETWORKS OF GENES AND SO YOU CAN 800 00:28:27,005 --> 00:28:27,872 THINK HERE, WE HAVE EXPRESSION 801 00:28:27,939 --> 00:28:30,041 LEVEL, THIS IS JUST A CARTOON 802 00:28:30,108 --> 00:28:32,811 OVER A BUNCH OF DIFFERENT BRAIN 803 00:28:32,877 --> 00:28:33,411 SAMPLES. 804 00:28:33,478 --> 00:28:36,681 AND THE GENES NATURALLY BECAUSE 805 00:28:36,748 --> 00:28:38,216 OF THE WAY THEY'RE REGULATED 806 00:28:38,283 --> 00:28:41,252 WILL BE GROUPED INTO DIFFERENT 807 00:28:41,319 --> 00:28:42,020 FUNCTIONAL CATEGORIES. 808 00:28:42,087 --> 00:28:48,093 SO, THE YEENS --GENES IN GROUP P 809 00:28:48,159 --> 00:28:50,762 AND DOWN, I AM NOLL TELLING YOU 810 00:28:50,829 --> 00:28:51,796 WHAT THE SAMPLES, ARE, IT 811 00:28:51,863 --> 00:28:53,198 DOESN'T MATTER AND THEN THERE'S 812 00:28:53,264 --> 00:28:54,132 GROUP B AND C. 813 00:28:54,199 --> 00:28:56,201 ET CETERA. 814 00:28:56,267 --> 00:28:58,403 SO WE CAN IDENTIFY THE NATURAL 815 00:28:58,470 --> 00:29:01,573 CO VARIANTS THAT'S GOING ON THAT 816 00:29:01,639 --> 00:29:04,609 WE THINK IS RELATED TO THE 817 00:29:04,676 --> 00:29:05,076 UNDERLYING REGULATORY 818 00:29:05,143 --> 00:29:09,647 ARCHITECTURE OF TURNING YEENS ON 819 00:29:09,714 --> 00:29:10,815 AND--GENES ON AND OFF. 820 00:29:10,882 --> 00:29:12,584 EACH OF THESE GROUPS YOU CAN 821 00:29:12,650 --> 00:29:16,621 CALL THEM CLUSTERS, WE CALL THEM 822 00:29:16,688 --> 00:29:16,988 NETWORK MODULES. 823 00:29:17,055 --> 00:29:18,356 THEY'RE CONNECTED IN SUCH A WAY 824 00:29:18,423 --> 00:29:20,758 THAT THE NETWORK IS MORE LIKE AN 825 00:29:20,825 --> 00:29:22,293 AIRLINE MAP NOT LIKE A HUB MAT, 826 00:29:22,360 --> 00:29:24,295 SO THERE ARE HUBS AND SPOKES SO 827 00:29:24,362 --> 00:29:26,264 THE HUBS ARE PARTICULARLY 828 00:29:26,331 --> 00:29:26,965 VULNERABLE TO DISRUPTION OF THE 829 00:29:27,031 --> 00:29:28,600 NETWORK AND THEN YOU CAN 830 00:29:28,666 --> 00:29:30,435 DECOMPOSE LEAVES OR LEAVE A LOT 831 00:29:30,502 --> 00:29:32,203 OF DIFFERENT WAYS TO UNDERSTAND 832 00:29:32,270 --> 00:29:34,906 WHAT MODULTIMATELYS MEAN SO THEY 833 00:29:34,973 --> 00:29:38,109 ALMOST ALWAYS CORRESPOND TO SOME 834 00:29:38,176 --> 00:29:38,743 ELEMENTAL BIOLOGICAL FUNCTION 835 00:29:38,810 --> 00:29:41,246 EMPLOY SO IF WE PROFILES A 836 00:29:41,312 --> 00:29:42,847 HUNDRED DIFFERENT PIECES OF 837 00:29:42,914 --> 00:29:44,249 CEREBRAL CORTEX FROM A HUNDRED 838 00:29:44,315 --> 00:29:45,650 DIFFERENT INDIVIDUALS, THE MAIN 839 00:29:45,717 --> 00:29:48,486 SOURCE OF VARIANCE WELL IS THE 840 00:29:48,553 --> 00:29:50,221 CELL TYPE COMPOSITION AND SO 841 00:29:50,288 --> 00:29:54,225 WHAT WE END UP PULLING OUT IS 842 00:29:54,292 --> 00:29:55,326 MODULES RELATED TO DIFFERENT 843 00:29:55,393 --> 00:29:57,562 CELL TYPES KIND OF A 844 00:29:57,629 --> 00:29:59,764 DISCIPLINARY SILIC O DISSECTION 845 00:29:59,831 --> 00:30:00,365 SO TO SPEAK. 846 00:30:00,431 --> 00:30:02,534 AND WHEN WE DO THAT WITH BULK 847 00:30:02,600 --> 00:30:04,035 TISSUE WE PULL OUT 848 00:30:04,102 --> 00:30:04,669 TRANSCRIPTIONAL PATTERNS THAT 849 00:30:04,736 --> 00:30:05,703 RELATE TO EACH OF THE INDIVIDUAL 850 00:30:05,770 --> 00:30:08,706 CELL TYPES TO SOME EXTENT IF YOU 851 00:30:08,773 --> 00:30:12,944 HAVE ENOUGH SAMPLES. 852 00:30:13,011 --> 00:30:15,246 AND WE AND MANY OTHER PEOPLE 853 00:30:15,313 --> 00:30:17,248 HAVE SHOWN THIS IS ROBUST AND 854 00:30:17,315 --> 00:30:17,582 REPRODUCIBLE. 855 00:30:17,649 --> 00:30:19,117 IF YOU TAKE A HUNDRED HUMANS AND 856 00:30:19,184 --> 00:30:21,019 GET A PIECE OF CORTEX YOU GET A 857 00:30:21,085 --> 00:30:21,953 ROBUST NETWORK AND YOU CAN USE 858 00:30:22,020 --> 00:30:24,155 THAT FOR A LOT OF DIFFERENT 859 00:30:24,222 --> 00:30:27,091 THINGS, THE NETWORK IS ALSO 860 00:30:27,158 --> 00:30:28,193 BIOLODGEICALLY MEANINGFUL, IF 861 00:30:28,259 --> 00:30:30,295 YOU'RE A HUB VERSUS PERIPHERAL 862 00:30:30,361 --> 00:30:31,629 IN THAT NETWORK OR MODULE. 863 00:30:31,696 --> 00:30:34,732 BUT THE STRUCTURE SERVES AS A 864 00:30:34,799 --> 00:30:35,900 CRITICAL BASIS, THE TRANSCRIPT 865 00:30:35,967 --> 00:30:37,769 OHM HAS AN ORGANIZATION AND YOU 866 00:30:37,835 --> 00:30:39,671 CAN ASK ARE THE MODULES CHANGING 867 00:30:39,737 --> 00:30:41,139 IN DISEASE, IS THE GENE 868 00:30:41,206 --> 00:30:43,107 CONNECTIVITY WHERE IT IS IN THE 869 00:30:43,174 --> 00:30:44,108 MODULE CHANGING OR IF I DON'T 870 00:30:44,175 --> 00:30:48,079 KNOW WHAT A GENE DOES, IF IT 871 00:30:48,146 --> 00:30:51,683 SITS IN A RIBOSOMAL MODULE, IT'S 872 00:30:51,749 --> 00:30:52,283 DOING THAT FUNCTION. 873 00:30:52,350 --> 00:30:54,986 SO IT CAN HELP WITH FUNCTIONAL 874 00:30:55,053 --> 00:30:56,187 ANNOTATION FOR THINGS THAT 875 00:30:56,254 --> 00:30:57,088 AREN'T WELL KNOWN. 876 00:30:57,155 --> 00:30:59,090 SO, IF WE TAKE THIS KIND OF 877 00:30:59,157 --> 00:31:01,960 MODEL AND BEGIN TO THINK ABOUT 878 00:31:02,026 --> 00:31:03,361 THE CONSEQUENCES OF GENETIC 879 00:31:03,428 --> 00:31:04,562 VARIATION IN THE BRAIN MOVING 880 00:31:04,629 --> 00:31:07,432 FROM DNA ALL THE WAY UP TO 881 00:31:07,498 --> 00:31:08,933 BEHAVIOR, WE'RE LOOKING AT AN 882 00:31:09,000 --> 00:31:12,503 INTERMEDIATE PENE O TYPE, MRNA, 883 00:31:12,570 --> 00:31:16,407 NOT BECAUSE IT'S THE MOST 884 00:31:16,474 --> 00:31:17,842 MEANINGFUL PHENOTYPE, IT IS BUT 885 00:31:17,909 --> 00:31:18,343 IT'S TRACTABLE. 886 00:31:18,409 --> 00:31:21,079 WE CAN LOOK AT HIGH RESOLUTION 887 00:31:21,145 --> 00:31:23,281 AT VERY HIGH DYNAMIC RANGE. 888 00:31:23,348 --> 00:31:25,450 WE CAN MEASURE HUNDREDS OR 889 00:31:25,516 --> 00:31:28,753 THOUSANDS OF SAMPLES AND 890 00:31:28,820 --> 00:31:30,288 THEREFORE, WE CAN GET DATA THAT 891 00:31:30,355 --> 00:31:31,656 ALLOWS US TO MAKE INFERENCES 892 00:31:31,723 --> 00:31:32,757 ABOUT THESE OTHER THINGS IN 893 00:31:32,824 --> 00:31:36,060 THESE OTHER LEVELS AND CONNECT 894 00:31:36,127 --> 00:31:36,461 TO THEM. 895 00:31:36,527 --> 00:31:38,596 SO FIRST I'M GOING TO TALK ABOUT 896 00:31:38,663 --> 00:31:41,566 WORK THAT WE'VE DONE TO ASK 897 00:31:41,633 --> 00:31:45,003 QUESTIONS IN THE BRAIN, 898 00:31:45,069 --> 00:31:49,173 POSTMORTEM BRAIN, USING MRNA 899 00:31:49,240 --> 00:31:49,641 MEASUREMENTS. 900 00:31:49,707 --> 00:31:50,808 SO NEUROLOGIC DISORDERS, I 901 00:31:50,875 --> 00:31:53,144 MENTIONED THIS AT THE BEGINNING, 902 00:31:53,211 --> 00:31:56,047 I MENTIONED THIS LIKE 903 00:31:56,114 --> 00:32:03,588 PARKINSON'S AND, ALS, I HAVE 904 00:32:03,655 --> 00:32:04,555 NEUROPATHOLOGY BUT PSYCHIATRIC 905 00:32:04,622 --> 00:32:05,356 DISORDERS ARE CONSIDERED 906 00:32:05,423 --> 00:32:07,025 DIFFERENTLY BECAUSE OF THEIR 907 00:32:07,091 --> 00:32:08,393 LACK OF DEFINING PATHOLOGY. 908 00:32:08,459 --> 00:32:10,161 SO WE LOOKED AT THIS YEARS AGO 909 00:32:10,228 --> 00:32:12,730 WHEN MICRO,A RAYS WERE BECOMING 910 00:32:12,797 --> 00:32:15,066 ACCESSIBLE THAT WE COULD LOOK 911 00:32:15,133 --> 00:32:16,567 BEYOND MICROSCOPIC EVOLUTION TO 912 00:32:16,634 --> 00:32:18,870 IDENTIFY AND FIND MOLECULAR 913 00:32:18,936 --> 00:32:20,505 PATHOLOGY AND ACROSS 914 00:32:20,571 --> 00:32:21,339 NEUROPSYCHIATRIC DISORDERS BUT 915 00:32:21,406 --> 00:32:23,408 FIRST IN AUTISM, AGAIN IT'S LIKE 916 00:32:23,474 --> 00:32:25,543 THE METAPHOR IS, BEFORE WE HAD 917 00:32:25,610 --> 00:32:28,179 THE MICROSCOPE, WE COULD NEVER 918 00:32:28,246 --> 00:32:29,881 SEE AMYLOID OR NUCLEAN BEFORE WE 919 00:32:29,947 --> 00:32:31,149 HAD ANTIBODIES AND OTHER THINGS 920 00:32:31,215 --> 00:32:32,750 SO AS OUR RESOLUTION GETS BETTER 921 00:32:32,817 --> 00:32:34,285 AND BETTER WE GET A DIFFERENT 922 00:32:34,352 --> 00:32:42,193 VIEW OF THESE DISORDERS AND WHAT 923 00:32:42,260 --> 00:32:44,595 REALLY DEFERENTIATES THE 924 00:32:44,662 --> 00:32:46,631 PSYCHIATRIC DISORRERS FROM 925 00:32:46,698 --> 00:32:49,867 NEUROLOGIC DISORRERS IS THE LACK 926 00:32:49,934 --> 00:32:50,535 OF PHYSICAL PATHOLOGY. 927 00:32:50,601 --> 00:32:51,969 SO FIRST STUDY WAS DONE IN 928 00:32:52,036 --> 00:32:53,571 AROUND 20 CASES AND CONTROLS, 929 00:32:53,638 --> 00:32:57,008 LED BY A POST DOCTORAL FELLOW AT 930 00:32:57,075 --> 00:33:00,511 THE TIME [INDISCERNIBLE] WHO 931 00:33:00,578 --> 00:33:02,613 RUNS A VERY SUCCESSFUL LAB IN 932 00:33:02,680 --> 00:33:04,682 SYDNEY OFF THE RAILIA, AND 933 00:33:04,749 --> 00:33:06,517 BASICALLY WITH THE SMALL SAMPLE 934 00:33:06,584 --> 00:33:08,286 SIZE, SHE FOUND IN ABOUT 2/3RDS 935 00:33:08,353 --> 00:33:11,489 OF PATIENTS THERE WAS A 936 00:33:11,556 --> 00:33:11,989 REPRODOUSIBLE PATHOLOGY 937 00:33:12,056 --> 00:33:13,624 INVOLVING DOWN REGULATION OF A 938 00:33:13,691 --> 00:33:16,260 BUNCH OF GENES INVOLVED IN 939 00:33:16,327 --> 00:33:17,495 NEURAL TRANSMISSION AND SYNAPSE 940 00:33:17,562 --> 00:33:19,797 FUNCTION AND AN UPREGULATION OF 941 00:33:19,864 --> 00:33:24,802 YEENS EXPRESSED IN ASTRO CITES 942 00:33:24,869 --> 00:33:25,269 AND MICROGLIA. 943 00:33:25,336 --> 00:33:26,804 AND SO WHAT WAS INTERESTING IS 944 00:33:26,871 --> 00:33:28,639 NOW, REMEMBER, THIS IS A 945 00:33:28,706 --> 00:33:30,441 PHENOTYPE, EVEN THOUGH IT'S 946 00:33:30,508 --> 00:33:32,577 MOLECULAR, IT'S JUST SOMETHING 947 00:33:32,643 --> 00:33:33,578 WE'RE VISUALIZING, WE'RE SEEING 948 00:33:33,644 --> 00:33:33,745 IT. 949 00:33:33,811 --> 00:33:36,147 WE DON'T KNOW IF IT'S A CAUSE OR 950 00:33:36,214 --> 00:33:37,615 CONSEQUENCE OF HAVING THE DISORD 951 00:33:37,682 --> 00:33:39,717 BUT 1 THING WE CAN DO IS WE ASK 952 00:33:39,784 --> 00:33:42,120 ASK TO THE EXTENT THAT WE 953 00:33:42,186 --> 00:33:44,756 UNDERSTAND OR CAN MEASURE 954 00:33:44,822 --> 00:33:46,491 GENETIC VARIATION, RARE OR 955 00:33:46,557 --> 00:33:47,658 COMMON GENETIC VARIATION THAT 956 00:33:47,725 --> 00:33:48,826 CONTRIBUTES TO AUTISM, WHERE 957 00:33:48,893 --> 00:33:51,095 DOES THAT SIT WITHIN THESE 958 00:33:51,162 --> 00:33:55,299 MODULES AND IT SAT 100 PERCENT 959 00:33:55,366 --> 00:33:58,236 IN M12 THE SINATTIC NEURONAL 960 00:33:58,302 --> 00:34:01,038 YEENS SO OUR CAUSAL MODEL IS 961 00:34:01,105 --> 00:34:03,007 THAT THE GENETIC VARIATION IS 962 00:34:03,074 --> 00:34:05,209 SITTING THERE, SOMEHOW CAUSING 963 00:34:05,276 --> 00:34:07,578 DYSFUNCTION IN NEURONS AND WELL 964 00:34:07,645 --> 00:34:10,681 IS A CHANGE IN MICROGLIA AND 965 00:34:10,748 --> 00:34:13,117 ASTRO SIGHTS THAT'S CALLED 966 00:34:13,184 --> 00:34:14,018 NEUROINFLAMMATORY EMPLOY NOW 967 00:34:14,085 --> 00:34:15,720 SINCE THEM WE MASSIVELY 968 00:34:15,787 --> 00:34:17,355 INCREASED THE SAMPLE SIZE, THIS 969 00:34:17,422 --> 00:34:20,391 IS LED BY AN MD-Ph.D. STUDENTS 970 00:34:20,458 --> 00:34:24,695 WHO WERE 2 POST DOCS, 971 00:34:24,762 --> 00:34:25,763 [INDISCERNIBLE], AND HERE 972 00:34:25,830 --> 00:34:27,865 INSTEAD OF HAVING 2 MODULES WE 973 00:34:27,932 --> 00:34:29,700 NOW IDENTIFY BECAUSE WE HAVE 974 00:34:29,767 --> 00:34:31,669 MORE SAMPLES WE GET MORE REFINED 975 00:34:31,736 --> 00:34:35,640 VIEW OF CO EXPRESSION, WE CAN 976 00:34:35,706 --> 00:34:36,541 DISENTANGLE THE 977 00:34:36,607 --> 00:34:37,608 NEUROINFLAMMATORY AND THE 978 00:34:37,675 --> 00:34:40,711 NEURONAL PIECE, THERE WERE 3 979 00:34:40,778 --> 00:34:41,679 DOWN REGULATED MODULES SHOWN 980 00:34:41,746 --> 00:34:43,848 THERE, AND THEY CONTAIN 981 00:34:43,915 --> 00:34:45,716 DIFFERENT ASPECTS OF SYNAPTIC 982 00:34:45,783 --> 00:34:47,585 AND MIEWRONAL FUNCTION, AND THEN 983 00:34:47,652 --> 00:34:49,787 THERE ARE 2 UPREGULATED, 1 OF 984 00:34:49,854 --> 00:34:51,622 THEM IS AN ASTRO SIGHT MODULE 985 00:34:51,689 --> 00:34:54,225 AND THE OTHER CONTAINS MICROGLIA 986 00:34:54,292 --> 00:34:55,626 MARKERS, IN OTHER WORDS, THE 987 00:34:55,693 --> 00:34:57,295 HUBS ARE KNOWN MARKERS OF THOSE 988 00:34:57,361 --> 00:34:59,764 CELLS, SO AS WE GO ALONG, WE'RE 989 00:34:59,831 --> 00:35:02,300 REFINING THIS PATTERN MORE AND 990 00:35:02,366 --> 00:35:04,135 MORE AND REPLICATING IS QUITE 991 00:35:04,202 --> 00:35:06,204 SURPRISINGLY, THIS IS IN 113 992 00:35:06,270 --> 00:35:08,606 SAMPLES, WE ALSO HAD SAIT 993 00:35:08,673 --> 00:35:09,807 SAMPLES OF PATIENTS WITH 994 00:35:09,874 --> 00:35:12,376 DUPLICATIONS WHICH IS THE 995 00:35:12,443 --> 00:35:13,211 MONOGENIC FORMS OF WHICH 90% OF 996 00:35:13,277 --> 00:35:15,279 THE PATIENTS HAVE AUTISM AND 997 00:35:15,346 --> 00:35:17,014 THAT PATTERN WAS MORE HOMOGENIUS 998 00:35:17,081 --> 00:35:19,350 AND A LITTLE BIT STRONGER BUT 999 00:35:19,417 --> 00:35:21,419 MATCHED THIS AUTISM PATTERN, 1000 00:35:21,486 --> 00:35:25,723 IDIO PATHIC AUTISM EXACTLY. 1001 00:35:25,790 --> 00:35:28,159 SO OVER THE YEARS IN A NUMBER OF 1002 00:35:28,226 --> 00:35:29,327 STUDIES, WE AND OTHER PEOPLE 1003 00:35:29,393 --> 00:35:31,329 HAVE NOW SHOWN THERE WERE KIND 1004 00:35:31,395 --> 00:35:34,632 OF 3 MAJOR FEATURES OF THE 1005 00:35:34,699 --> 00:35:35,266 CONVERGENT MOLECULAR PATHOLOGY, 1006 00:35:35,333 --> 00:35:36,767 IMEAN THIS IS JUST A STARTING 1007 00:35:36,834 --> 00:35:37,001 POINT. 1008 00:35:37,068 --> 00:35:40,204 THIS IS NOT A REFINED CELLS FIN. 1009 00:35:40,271 --> 00:35:41,839 ONE THING WOE SAW IN ALL OF OUR 1010 00:35:41,906 --> 00:35:43,574 STUDIES WAS THAT IF YOU LOOK AT 1011 00:35:43,641 --> 00:35:47,078 THE DIFFERENCE BETWEEN TEMPORAL 1012 00:35:47,144 --> 00:35:48,813 LOBE AND FRONTAL LOBE YOU SAW A 1013 00:35:48,880 --> 00:35:51,382 LOT OF GENES AND CONTROLS AND 1014 00:35:51,449 --> 00:35:54,485 THAT PATTERN WAS ATTENUATE IN 1015 00:35:54,552 --> 00:35:55,219 AUTISM. 1016 00:35:55,286 --> 00:35:58,356 SO THERE WAS AN ATTENUATE 1017 00:35:58,422 --> 00:35:59,056 CORTICALE PATTERNING EMPLOY AND 1018 00:35:59,123 --> 00:36:01,058 ANOTHER THING WE SAW IS THAT 1019 00:36:01,125 --> 00:36:02,793 CEREBELLUM DOESN'T REALLY HAVE 1020 00:36:02,860 --> 00:36:04,061 MUCH MOLECULAR PATHOLOGY AT ALL. 1021 00:36:04,128 --> 00:36:06,063 THERE WERE NO DIFFERENTIALLY 1022 00:36:06,130 --> 00:36:08,466 EXPRESSED YEENS IN CEREBELLUM. 1023 00:36:08,533 --> 00:36:11,802 AND WE SEE THIS CHARACTERISTIC 1024 00:36:11,869 --> 00:36:12,303 MOLECULAR DISREGULATION 1025 00:36:12,370 --> 00:36:14,739 INVOLVING INCREASE IN THE NEURAL 1026 00:36:14,805 --> 00:36:16,574 IMMUNE INFLAMMATORY AND 1027 00:36:16,641 --> 00:36:17,241 DECREASED SYNAPTIC YEEN 1028 00:36:17,308 --> 00:36:19,176 EXPRESSION AND IT'S SHARED BY 1029 00:36:19,243 --> 00:36:22,013 THE 15 KEY DUPLICATION. 1030 00:36:22,079 --> 00:36:24,382 SO NOW, IF WE GO BACK TO THIS 1031 00:36:24,448 --> 00:36:24,949 MODEL CITIZEN LEAKULAR 1032 00:36:25,016 --> 00:36:26,350 NEUROPATHOLOGY IN A CAUSAL 1033 00:36:26,417 --> 00:36:27,885 MODEL, THIS IS VERY HAND WAVING, 1034 00:36:27,952 --> 00:36:29,554 BUT WE HAVE TO START THINKING 1035 00:36:29,620 --> 00:36:32,690 THIS WAY, WE HAVE CAUSAL GENETIC 1036 00:36:32,757 --> 00:36:35,126 VARIATION THAT'S SOMEHOW LEADING 1037 00:36:35,192 --> 00:36:36,661 TO ALTERED DEVELOPMENT, NEURONAL 1038 00:36:36,727 --> 00:36:39,397 GENE EXPRESSION, ET CETERA, 1039 00:36:39,463 --> 00:36:41,365 SYNAPTIC DYSFUNCTION AND THEN 1040 00:36:41,432 --> 00:36:42,400 THERE'S ASTROCYTE, MICROTBLIA 1041 00:36:42,466 --> 00:36:44,435 AND INFLAMMA ARE TOY. 1042 00:36:44,502 --> 00:36:45,002 IS IT ADAPTIVE? 1043 00:36:45,069 --> 00:36:45,970 IS IT MALTAXER DATA 1044 00:36:46,037 --> 00:36:46,337 PROTECTIONIVE? 1045 00:36:46,404 --> 00:36:47,939 WE DO NOT KNOW. 1046 00:36:48,005 --> 00:36:50,408 MY GUT FEELING IS THAT IT CAN BE 1047 00:36:50,474 --> 00:36:51,642 THAT ARK DATA PROTECTIONIVE. 1048 00:36:51,709 --> 00:36:54,612 SO EVEN THOUGH IT'S NOT CAUSAL, 1049 00:36:54,679 --> 00:36:55,813 THAT MICRODPLIA ASTRO SIGHT 1050 00:36:55,880 --> 00:36:58,549 PICTURE STILL MIGHT BE A 1051 00:36:58,616 --> 00:37:00,718 THERAPEUTIC TARGET, SO I'M NOT 1052 00:37:00,785 --> 00:37:01,786 SAYING YOU CAN ONLY TARGET BUT 1053 00:37:01,852 --> 00:37:02,954 YOU HAVE TO UNDERSTAND WHERE 1054 00:37:03,020 --> 00:37:04,155 THINGS BEGENERATED AND HOW THEY 1055 00:37:04,221 --> 00:37:07,358 PROGRESS TO BEGIN TO UNDERSTAND 1056 00:37:07,425 --> 00:37:07,692 WHERE WE ARE. 1057 00:37:07,758 --> 00:37:10,127 AND SO, THIS IS A KIND OF MODEL, 1058 00:37:10,194 --> 00:37:12,830 RIGHT IN AND OBVIOUSLY THERE'S A 1059 00:37:12,897 --> 00:37:14,899 TON MORE WORK BUT IF YOU THINK 1060 00:37:14,966 --> 00:37:16,701 BACK TO 75 YEARS AGO, LOOKING AT 1061 00:37:16,767 --> 00:37:17,868 CANCER TISSUE OR A HUNDRED YEARS 1062 00:37:17,935 --> 00:37:19,537 OKAY WHEN YOU COULD SAY, CANCER 1063 00:37:19,604 --> 00:37:21,839 IS A DISORDER OF PROLIFERATION 1064 00:37:21,906 --> 00:37:22,807 AND INVASION, WE'RE AT LEAST 1065 00:37:22,873 --> 00:37:24,208 TARTING TO HIT WHAT THE 1066 00:37:24,275 --> 00:37:25,409 POTENTIAL CELL TYPES MIGHT BE 1067 00:37:25,476 --> 00:37:28,713 THAT ARE INVOLVED IN WHAT'S 1068 00:37:28,779 --> 00:37:29,113 GOING ON. 1069 00:37:29,180 --> 00:37:30,381 SO 1 OF THE MAJOR QUESTIONS THAT 1070 00:37:30,448 --> 00:37:34,485 WAS ANYTHING --GOING ON IN OUR T 1071 00:37:34,552 --> 00:37:35,686 MIKE ASKED WHEN HE WAS A POST 1072 00:37:35,753 --> 00:37:37,755 DOC IN THE LAB, HE WAS A 1073 00:37:37,822 --> 00:37:39,824 RESIDENT IN PSYCHIATRY WHEN HE 1074 00:37:39,890 --> 00:37:41,759 DID THIS WORK BEFORE BECOMING A 1075 00:37:41,826 --> 00:37:45,196 POST DOC WITH AN UNDERGRADUATE 1076 00:37:45,262 --> 00:37:47,431 STUDENT JILL HANEY WHO BECAME A 1077 00:37:47,498 --> 00:37:47,999 GRADUATE STUDENT LATER. 1078 00:37:48,065 --> 00:37:50,401 SO HERE'S THE THING, HAVE YOU 1079 00:37:50,468 --> 00:37:51,469 ALL THE GENETIC ETIOLOGY, YOU 1080 00:37:51,535 --> 00:37:54,639 HAVE ALL THESE THINGS YOU COULD 1081 00:37:54,705 --> 00:37:56,807 MEASURE, EEGs, IMAGING, WE'RE 1082 00:37:56,874 --> 00:37:59,310 MEASURING ALTERED GENE BRAIN 1083 00:37:59,377 --> 00:38:01,245 EXPRESSION POSTMORTEM ACROSS 1084 00:38:01,312 --> 00:38:01,612 THESE DISORDERS. 1085 00:38:01,679 --> 00:38:05,650 WHAT MIKE DID IS HE BASICALLY, 1086 00:38:05,716 --> 00:38:06,951 WE REASONED--WE WENT LOOKING ON 1087 00:38:07,018 --> 00:38:09,387 THE WEB FOR AS MANY DATA SETS AS 1088 00:38:09,453 --> 00:38:11,756 WE COULD FIND ASK IT WAS MOSTLY 1089 00:38:11,822 --> 00:38:13,491 MICROARRAY DATA SETS AT THE TIME 1090 00:38:13,557 --> 00:38:15,359 SO THERE WAS ALMOST 900 1091 00:38:15,426 --> 00:38:16,427 DIFFERENT MICROARRAYS FROM 1092 00:38:16,494 --> 00:38:17,495 DOZENS OF DIFFERENT TODAYS, IT 1093 00:38:17,561 --> 00:38:19,730 WAS A HUGE TASK, TOOK MORE THAN 1094 00:38:19,797 --> 00:38:21,899 AIER TO INTEGRATE THEM AND 1095 00:38:21,966 --> 00:38:22,733 NORMALIZE THEM TOGETHER, AND 1096 00:38:22,800 --> 00:38:25,036 WHAT WE COULD SEE ACROSS ALL OF 1097 00:38:25,102 --> 00:38:28,039 THESE STUDIES WAS THAT THERE WAS 1098 00:38:28,105 --> 00:38:29,840 A TRANSCRIPTOMICY RELATIONSHIP 1099 00:38:29,907 --> 00:38:31,242 BETWEEN THEM, THAT 1100 00:38:31,308 --> 00:38:33,177 IS--DEPRESSION WAS CORRELATE 1101 00:38:33,244 --> 00:38:35,279 WIDE BIPOLAR AND SCHIZOPHRENIA 1102 00:38:35,346 --> 00:38:36,614 ABOUT THE SAME. 1103 00:38:36,681 --> 00:38:37,815 BIPOLAR AND SCHIZOPHRENIA WAS 1104 00:38:37,882 --> 00:38:39,617 HIGHLY CORRELATE WIDE EACH 1105 00:38:39,684 --> 00:38:41,952 OTHER, AS WELL AS AUTISM MORE SO 1106 00:38:42,019 --> 00:38:46,057 AND THEN THERE WAS THIS 1107 00:38:46,123 --> 00:38:46,857 CORRELATION WITH INFLAMMATORY 1108 00:38:46,924 --> 00:38:49,060 BOWEL DISEASE THAT WAS VEXING, 1109 00:38:49,126 --> 00:38:50,561 BECAUSE IT TURNS OUT THAT'S A 1110 00:38:50,628 --> 00:38:54,098 SMALL PART OF THE 1111 00:38:54,165 --> 00:38:54,999 NEUROINFLAMMATORY CYTOKINE 1112 00:38:55,066 --> 00:38:55,433 UPREGULATION. 1113 00:38:55,499 --> 00:38:57,168 ANOTHER BRAIN DISORDER LIKE 1114 00:38:57,234 --> 00:38:58,002 ALCOHOLISM WASN'T CONNECTED TO 1115 00:38:58,069 --> 00:39:00,971 ANY OF THESE, IT REALLY DIDN'T 1116 00:39:01,038 --> 00:39:05,409 SHOW ANY, ANY FEATURES THAT 1117 00:39:05,476 --> 00:39:07,812 REALLY CONNECTED IT. 1118 00:39:07,878 --> 00:39:09,914 SO I WAS WONDERING THIS LOOKED A 1119 00:39:09,980 --> 00:39:12,450 LOT LIKE THE RISK OF POLYGENIC 1120 00:39:12,516 --> 00:39:14,552 RISK SCORES I SHOW YOU IN THE 1121 00:39:14,618 --> 00:39:15,720 BEGINNING SO WE ASK THE 1122 00:39:15,786 --> 00:39:18,355 QUESTION, SO THE FIRST THING WE 1123 00:39:18,422 --> 00:39:23,761 ASKED IS, WHAT CELLS ARE BEING 1124 00:39:23,828 --> 00:39:24,095 IMPACTED? 1125 00:39:24,161 --> 00:39:25,496 ARE THESE DISORDERS THE SAME? 1126 00:39:25,563 --> 00:39:28,132 AND WE COULD SEE MUCH MORE 1127 00:39:28,199 --> 00:39:29,166 PROPOUND SYNAPTIC REGULATION IN 1128 00:39:29,233 --> 00:39:31,836 AWSHATISM BUT IT WAS PARTIALLY 1129 00:39:31,902 --> 00:39:34,371 SHARED BY SCHIZOPHRENIA, WE SAW 1130 00:39:34,438 --> 00:39:35,673 INCREASED ASTRO CITE 1131 00:39:35,740 --> 00:39:36,607 UPREGULATION ACROSS THESE 1132 00:39:36,674 --> 00:39:38,008 DISORDERS BUT THE MICROGLIA 1133 00:39:38,075 --> 00:39:40,277 ACTIVATION WAS SPECIFIC TO 1134 00:39:40,344 --> 00:39:40,745 AUTISM. 1135 00:39:40,811 --> 00:39:41,679 NOW I'M NOT SAYING THAT THAT 1136 00:39:41,746 --> 00:39:45,716 MEANS THAT IT IS, BUT AT LEAST, 1137 00:39:45,783 --> 00:39:48,319 WITH ALL THESE DATA THAT'S WHAT 1138 00:39:48,385 --> 00:39:48,552 WE SAW. 1139 00:39:48,619 --> 00:39:52,123 YOU CAN ALSO SEE THERE'S NO 1140 00:39:52,189 --> 00:39:53,157 OLIGIO DENDRITIC CELLROCYTE, 1141 00:39:53,224 --> 00:39:57,995 PATHOLOGY, AGAIN, THIS IS BULK 1142 00:39:58,062 --> 00:39:59,029 TISSUE PROFILING. 1143 00:39:59,096 --> 00:40:04,602 SO I HAD THIS IDEA THAT HOW ARE 1144 00:40:04,668 --> 00:40:06,237 THESE TRANSCRIPT OM CORRELATIONS 1145 00:40:06,303 --> 00:40:08,305 RELATED TO THE GENETIC OVERLAM 1146 00:40:08,372 --> 00:40:10,708 AND WHAT REALLY STRUCK US AND 1147 00:40:10,775 --> 00:40:12,209 THIS IS SURPRISING, I HAVE TO 1148 00:40:12,276 --> 00:40:16,280 ADMIT THAT ALMOST 50% OF THE 1149 00:40:16,347 --> 00:40:17,815 VARIANTS IN TRANSCRIPT OHM OVER 1150 00:40:17,882 --> 00:40:20,217 LAP IN RELATED TO VARIATIONS SO 1151 00:40:20,284 --> 00:40:23,320 IF WE PLOT TRANSCRIPT OHM AND 1152 00:40:23,387 --> 00:40:25,489 GENETIC SNP CORRELATION, THE ROW 1153 00:40:25,556 --> 00:40:27,558 WAS .7. 1154 00:40:27,625 --> 00:40:30,361 AND THE GREEN STUFF IS PART OF 1155 00:40:30,427 --> 00:40:32,029 RNA SEQ TO REPLICATE THIS USING 1156 00:40:32,096 --> 00:40:32,997 A DIFFERENT MODEL AND METHOD. 1157 00:40:33,063 --> 00:40:34,632 SO THIS WAS KIND OF STRIKING. 1158 00:40:34,698 --> 00:40:37,535 IT DOESN'T MEAN THAT THE GENETIC 1159 00:40:37,601 --> 00:40:38,335 SYSTEM DIRECTLY INFLUENCING 1160 00:40:38,402 --> 00:40:40,471 THESE BUT THERE'S SOME 1161 00:40:40,538 --> 00:40:41,205 RELATIONSHIP WITH THIS 1162 00:40:41,272 --> 00:40:43,140 TRANSCRIPT OHM PATTERN IT TO THE 1163 00:40:43,207 --> 00:40:44,141 KIND OF EPPED STATE THAT WE'RE 1164 00:40:44,208 --> 00:40:47,478 SEEING IN THE BRAIN THAT'S 1165 00:40:47,545 --> 00:40:50,748 REPRESENTED BY THE 1166 00:40:50,815 --> 00:40:51,816 TRANSCRIPTOME, SO ON THE BACK OF 1167 00:40:51,882 --> 00:40:54,051 THIS, ALL THIS WORK AT THE SAME 1168 00:40:54,118 --> 00:40:58,022 TIME WE WERE PART OF A 1169 00:40:58,088 --> 00:41:00,057 CONSORTIUM CALLED THE PSYCHE END 1170 00:41:00,124 --> 00:41:02,693 CONSORTIUM WHICH HAS BEEN 1171 00:41:02,760 --> 00:41:04,528 IMPORTANT AND INFLUENTIAL IN THE 1172 00:41:04,595 --> 00:41:06,564 FIELD BECAUSE WE'RE WORKING 1173 00:41:06,630 --> 00:41:08,299 TOGETHER AS A CONSORTIUM, WE 1174 00:41:08,365 --> 00:41:09,867 WERE ABLE TO HAVE ENORM 1175 00:41:09,934 --> 00:41:11,402 AUSNUMBER OF SAMPLES EMPLOY SO I 1176 00:41:11,468 --> 00:41:14,705 WENT FROM 113 TO 936 CONTROLS. 1177 00:41:14,772 --> 00:41:18,709 AND AGAIN, ALL THE DATA WAS 1178 00:41:18,776 --> 00:41:20,110 PROCESSED BY DATA CORE MARKER 1179 00:41:20,177 --> 00:41:23,881 AND GP WANG WHO WERE PART OF 1180 00:41:23,948 --> 00:41:26,016 ENCODE AND NORMALIZED AND THIS 1181 00:41:26,083 --> 00:41:27,651 GAVE US EVEN A WAY MORE REFINED 1182 00:41:27,718 --> 00:41:31,155 VIEW OF WHAT MIGHT BE GOING ON 1183 00:41:31,222 --> 00:41:35,125 WITH USING BULK TISSUE, 1184 00:41:35,192 --> 00:41:35,826 MASSIVELY PRIME NETWORK WHICH I 1185 00:41:35,893 --> 00:41:39,430 WILL SHOW IN A SEC. 1186 00:41:39,496 --> 00:41:42,766 NEXT THING WE SAW WAS ISOFORMS, 1187 00:41:42,833 --> 00:41:43,934 YEENS ARE SPLICED AND DIFFERENT 1188 00:41:44,001 --> 00:41:46,136 FORMS OF THEM AND THE BIGGEST 1189 00:41:46,203 --> 00:41:48,405 SIGNAL IN TERMS OF CELL TYPE 1190 00:41:48,472 --> 00:41:51,742 SPECIFICITY AND DEC WAS ISOFORM 1191 00:41:51,809 --> 00:41:52,309 DISREGULATION. 1192 00:41:52,376 --> 00:41:54,278 WE SAW VERY SPECIFIC MUCH MORE 1193 00:41:54,345 --> 00:41:57,147 REFINED NEURAL IMMUNE PATHWAY 1194 00:41:57,214 --> 00:41:58,649 ANDS TRAJECTORIES AND I WILL PUT 1195 00:41:58,716 --> 00:42:00,818 THIS UP HERE FOR THOSE WHO 1196 00:42:00,885 --> 00:42:02,453 HAVEN'T SEEN THE PAPER, THESE 1197 00:42:02,519 --> 00:42:03,854 ARE ALL THE MODULES THAT ARE 1198 00:42:03,921 --> 00:42:05,956 ASSOCIATE WIDE DEC THAT WE 1199 00:42:06,023 --> 00:42:06,991 IDENTIFIED THERE WERE NIX OF 1200 00:42:07,057 --> 00:42:07,458 THEM. 1201 00:42:07,524 --> 00:42:08,659 SOME OF THEM WERE GENE WHICH 1202 00:42:08,726 --> 00:42:10,828 MEAN ITS WAS A TRANSCRIPT AND 1203 00:42:10,895 --> 00:42:12,029 OTHERS OF THE ISOFORM MODULES 1204 00:42:12,096 --> 00:42:13,998 AND THE NICE THING IS THAT THE 1205 00:42:14,064 --> 00:42:15,199 ISOFORM AND YEEN CLUSTERED 1206 00:42:15,266 --> 00:42:15,466 TOGETHER. 1207 00:42:15,532 --> 00:42:19,803 AND WE LOOK HERE AT THEIR DEC 1208 00:42:19,870 --> 00:42:23,107 ASSOCIATION THE CELL TYPE THAT 1209 00:42:23,173 --> 00:42:24,608 THEY'RE LIKELY REPRESENTING WITH 1210 00:42:24,675 --> 00:42:26,310 COMMON GENETIC VARIATION AND HAD 1211 00:42:26,377 --> 00:42:29,546 IS JUST A SMALL PEAK AT SOME OF 1212 00:42:29,613 --> 00:42:31,849 THE DEC ASSOCIATED MODULES, BLUE 1213 00:42:31,916 --> 00:42:34,285 BEING GENES THAT ARE DOWN 1214 00:42:34,351 --> 00:42:37,121 REGULATED, RED UPREGULATED AND 1215 00:42:37,187 --> 00:42:39,857 YOU THE COLOR, THE MORE DARK IT 1216 00:42:39,924 --> 00:42:40,925 IS THE MORE PROFOUND IT IS AND 1217 00:42:40,991 --> 00:42:42,326 WE CAN SEE THERE ARE THINGS THAT 1218 00:42:42,393 --> 00:42:44,061 ARE MORE SEVERE IN AUTISM, 1219 00:42:44,128 --> 00:42:46,163 THINGS MORE SEVERE IN 1220 00:42:46,230 --> 00:42:47,464 SCHIZOPHRENIA AND BIPOLAR, ET 1221 00:42:47,531 --> 00:42:49,667 CETERA, IT BASICALLY PARALLELS 1222 00:42:49,733 --> 00:42:51,368 THE MAJOR FINDINGS WE HAD BEFORE 1223 00:42:51,435 --> 00:42:52,770 BUT IT REFINE TODAY 1224 00:42:52,836 --> 00:42:54,638 EXTRAORDINARILY INTO VERY 1225 00:42:54,705 --> 00:42:56,473 SPECIFIC PATHWAYS, VESICLE 1226 00:42:56,540 --> 00:42:57,675 RECYCLING AND SYNAPTIC SIGNALING 1227 00:42:57,741 --> 00:43:01,078 ALSO GAVE US A HINT THAT THE 1228 00:43:01,145 --> 00:43:02,379 BLOOD BRAIN BANIER AND THE EPPED 1229 00:43:02,446 --> 00:43:05,683 O THELLIAL CELLS AND THE 1230 00:43:05,749 --> 00:43:08,652 INFLAMMATORY RESPONSE WENT 1231 00:43:08,719 --> 00:43:09,119 BEYOND GLIAL CELLS. 1232 00:43:09,186 --> 00:43:10,421 I WILL GIVE YOU A SENSE OF THIS 1233 00:43:10,487 --> 00:43:13,223 SO WE WERE ABLE TO HAVE INSTEAD 1234 00:43:13,290 --> 00:43:18,429 OF AN ASTRO CITE AND MODULE, WE 1235 00:43:18,495 --> 00:43:20,297 NOW HAVE ASTRO GLIAL MODEL, 1236 00:43:20,364 --> 00:43:22,599 EXPRESSED THERE, WE HAVE AN NF 1237 00:43:22,666 --> 00:43:25,869 CAPPA B MODULE AND THE ISHT 1238 00:43:25,936 --> 00:43:27,604 FERON RESPONSE MODULE CONTAINED 1239 00:43:27,671 --> 00:43:29,773 59 OF 63 KNOWN RESPONSE 1240 00:43:29,840 --> 00:43:30,207 INTERFERENCE YEENS. 1241 00:43:30,274 --> 00:43:33,177 SO THESE ARE VERY, VERY TIGHT 1242 00:43:33,243 --> 00:43:34,678 BIOLOGICAL PROCESSES THAT WE'RE 1243 00:43:34,745 --> 00:43:38,549 IDENTIFYING AND NOW THAT WE'RE 1244 00:43:38,615 --> 00:43:40,551 IRS DENTIFYING THE 2011 STUDY, 1245 00:43:40,617 --> 00:43:43,153 AND THE 2016 ASTRO CITE 1246 00:43:43,220 --> 00:43:44,922 MICROGLIA TO PULLING THESE APART 1247 00:43:44,989 --> 00:43:46,590 AND SHOWING THERE IS DIFFERENCE 1248 00:43:46,657 --> 00:43:49,526 HERE AND AGAIN THE MICROGLIA 1249 00:43:49,593 --> 00:43:50,828 BEING UPREGULATED IN AUTISM AND 1250 00:43:50,894 --> 00:43:52,463 NOT THE OTHER DISORDERS AS WELL 1251 00:43:52,529 --> 00:43:54,598 AS A VERY, VERY STRIKING 1252 00:43:54,665 --> 00:43:57,067 INTERFERON RESPONSE WHICH AGAIN 1253 00:43:57,134 --> 00:43:58,102 IS QUITE INTERESTING. 1254 00:43:58,168 --> 00:44:00,170 AND AGAIN, 1 CAN LOOK AT THE 1255 00:44:00,237 --> 00:44:01,805 TRAJECTORY AS WELL, NOW OF 1256 00:44:01,872 --> 00:44:04,041 COURSE, THE PATIENTS WITH 1257 00:44:04,108 --> 00:44:04,708 SCHIZOPHRENIA AND BIPOLAR, WE 1258 00:44:04,775 --> 00:44:07,277 ONLY HAVE A FEW FOLKS IN THEIR 1259 00:44:07,344 --> 00:44:10,047 TEENS OR SO, BUT 1 CAN SEE 1260 00:44:10,114 --> 00:44:11,982 REALLY MASSIVELY DIFFERENT 1261 00:44:12,049 --> 00:44:14,318 TRAJECTORIES, 1 IS THAT 1262 00:44:14,385 --> 00:44:15,352 SCHIZOPHRENIA AND BIPOLAR LOOK 1263 00:44:15,419 --> 00:44:16,854 SIMILAR AND THEY LOOK DIFFERENT 1264 00:44:16,920 --> 00:44:19,056 IN AUTISM AND AGAIN THIS FFCAPA 1265 00:44:19,123 --> 00:44:20,224 B MODULE WAS INTERESTING TO ME 1266 00:44:20,290 --> 00:44:21,959 BECAUSE IT'S GOING DOWN IN 1267 00:44:22,026 --> 00:44:25,429 AUTISM, BUT IT'S STAYING UP IN 1268 00:44:25,496 --> 00:44:26,363 SCHIZOPHRENIA AND BIPOLAR 1269 00:44:26,430 --> 00:44:28,132 DISORDER SO AGAIN, THEY'RE 1270 00:44:28,198 --> 00:44:31,035 UNIQUE SIGNALING PATHWAYS GOING 1271 00:44:31,101 --> 00:44:33,804 ON AND SO IN THE NEXT ITERATION 1272 00:44:33,871 --> 00:44:36,240 OF PSYCHE ENCODE WE BESTARTED TO 1273 00:44:36,306 --> 00:44:38,809 BEGIN TO PULL THIS APART USING 1274 00:44:38,876 --> 00:44:39,877 SINGLE CELL WORK WHICH I WILL 1275 00:44:39,943 --> 00:44:42,179 GET TO IN A SECOND, HOPEFULLY. 1276 00:44:42,246 --> 00:44:44,081 SO 1 OF THE QUESTIONS WE ALSO 1277 00:44:44,148 --> 00:44:46,717 ASKED AND WE'RE ASKING HOW WIDE 1278 00:44:46,784 --> 00:44:46,950 SPREAD. 1279 00:44:47,017 --> 00:44:49,019 THE STUDIES I'VE SHOWN YOU SO 1280 00:44:49,086 --> 00:44:51,822 FAR USE FRONTAL LOBE OR FRONTAL 1281 00:44:51,889 --> 00:44:53,791 TEMPORAL LOBE OR COMPARE THEM TO 1282 00:44:53,857 --> 00:44:54,091 CEREBELLUM. 1283 00:44:54,158 --> 00:44:56,927 WE WERE INTERESTED AND MY 1284 00:44:56,994 --> 00:44:58,796 HYPOTHESIS WAS AUTISM INVOLVES 1285 00:44:58,862 --> 00:45:00,164 SOCIAL COGNITION AND MENTAL 1286 00:45:00,230 --> 00:45:02,466 FLEXIBILITY SO IT'S A FRONTAL 1287 00:45:02,533 --> 00:45:07,471 LOBE AND ANTERIOR TEMPORAL LOBE, 1288 00:45:07,538 --> 00:45:08,739 MAYBE POSTERIOR TEMPORAL 1289 00:45:08,806 --> 00:45:11,041 DISORDER SO WE PROFILES ALL 1290 00:45:11,108 --> 00:45:13,043 THESE REGIONS ACROSS A LOT OF 1291 00:45:13,110 --> 00:45:14,678 SUBJECTS, THIS TOOK YEARS JUST 1292 00:45:14,745 --> 00:45:16,747 TO DO THE DISSECTIONS SO THE 1293 00:45:16,814 --> 00:45:27,291 ANALYSIS WAS LED BY MIKE AND 1294 00:45:36,667 --> 00:45:39,002 JILL AND MIKE, BUT--I'M SHOWING 1295 00:45:39,069 --> 00:45:39,837 DIFFERENTIAL GENE EXPRESSION UP 1296 00:45:39,903 --> 00:45:42,840 AND DOWN OVER THE REGIONS AND SO 1297 00:45:42,906 --> 00:45:47,845 IF YOU AVERAGE THE WHOLE CORTEXT 1298 00:45:47,911 --> 00:45:49,113 EFFECT HA'SOT X-AXIS AND THE 1299 00:45:49,179 --> 00:45:51,815 REGIONAL EFFECT IS ON THE Y, SO 1300 00:45:51,882 --> 00:45:53,083 A STEEP, STEEPER SLOPE THAN 1 IS 1301 00:45:53,150 --> 00:45:56,787 SHOWING THAT THAT AREA'S MORE 1302 00:45:56,854 --> 00:45:57,054 AFFECTED. 1303 00:45:57,121 --> 00:46:00,724 AND YOU CAN SEE MANAGE REALLY 1304 00:46:00,791 --> 00:46:02,926 STANDS OUT, BA 7 AND 17, BUT BA 1305 00:46:02,993 --> 00:46:04,661 17 IS PRIMARY VISUAL CORTEX, IT 1306 00:46:04,728 --> 00:46:08,332 SHOWED BY FAR THE MOST PROFOUND 1307 00:46:08,398 --> 00:46:08,699 DISREGULATION. 1308 00:46:08,765 --> 00:46:10,434 AND IT WASN'T DUE TO A CHANGE IN 1309 00:46:10,501 --> 00:46:12,069 CELL TYPE OR ANYTHING LIKE THAT, 1310 00:46:12,136 --> 00:46:14,271 WE DID SINGLE CELL ANALYSIS, SO 1311 00:46:14,338 --> 00:46:17,774 THIS WAS REALLY QUITE SHOCKING. 1312 00:46:17,841 --> 00:46:19,409 AND WE WERE ALSO ABLE TO SHOW 1313 00:46:19,476 --> 00:46:21,044 AGAIN, I WANT TO EMPHASIZE THIS, 1314 00:46:21,111 --> 00:46:23,347 THAT WHEN WE LOOKED FOR 1315 00:46:23,413 --> 00:46:24,948 ENRICHMENT HAD COMMON GENETIC 1316 00:46:25,015 --> 00:46:27,084 VARIATION AND RARE GENETIC 1317 00:46:27,151 --> 00:46:28,218 VARIATION, REMEMBER THIS IS 1318 00:46:28,285 --> 00:46:30,454 2022, SO SINCE THE INITIAL 2011 1319 00:46:30,521 --> 00:46:33,223 PAPER, THERE'S BEEN A TON OF 1320 00:46:33,290 --> 00:46:34,258 GENE DISCOVERY AND WHAT WE'RE 1321 00:46:34,324 --> 00:46:37,127 ABLE TO SHOW IS THAT THERE'S 1322 00:46:37,194 --> 00:46:39,163 THIS MODULE AGAIN, MOST 1323 00:46:39,229 --> 00:46:40,831 PROMINENT POSTERIORLY IN THE 1324 00:46:40,898 --> 00:46:42,566 BRAIN, IN OCCIPITAL LOBE AND 1325 00:46:42,633 --> 00:46:45,435 TEMPORAL LOBE AND SUPERIOR 1326 00:46:45,502 --> 00:46:48,038 PARIETAL LOBE, BUT THAT IS 1327 00:46:48,105 --> 00:46:49,239 DISREGULATED ACROSS THE WHOLE 1328 00:46:49,306 --> 00:46:51,742 BRAIN THAT INVOLVES CHEMICAL 1329 00:46:51,808 --> 00:46:55,546 SYNAPTIC TRAN MISSION, SYNAPSE, 1330 00:46:55,612 --> 00:46:56,947 COGNITION AND SOME OF THE MOST 1331 00:46:57,014 --> 00:46:57,915 HIGHLY CONNECTED YEEN NASAA.COM 1332 00:46:57,981 --> 00:47:03,620 THAT SHOWN HERE. 1333 00:47:03,687 --> 00:47:05,255 SO AGAIN, THIS--1 OF THE THREADS 1334 00:47:05,322 --> 00:47:07,124 GOING THROUGH HERE IS THAT 1335 00:47:07,191 --> 00:47:08,425 GENETIC VARIATION IS SITTING AND 1336 00:47:08,492 --> 00:47:09,993 RISK ASSESSMENTS RUPTING 1337 00:47:10,060 --> 00:47:11,795 SOMETHING ABOUT NEURONAL 1338 00:47:11,862 --> 00:47:13,530 DYSFUNCTION, SO NOW OF COURSE WE 1339 00:47:13,597 --> 00:47:16,800 CAN DO SINGLE CELL ANALYSIS. 1340 00:47:16,867 --> 00:47:18,468 SO WE STARTED THIS LITERALLY 6 1341 00:47:18,535 --> 00:47:20,837 OR 7 YEARS -ING AND WE VERY, 1342 00:47:20,904 --> 00:47:22,773 VERY PAIN STAKING AND CAREFULLY, 1343 00:47:22,839 --> 00:47:25,909 THIS IS LED BY A POST DOC CANNED 1344 00:47:25,976 --> 00:47:30,347 WHAT, AND WE HAD A ABOUT 30,000 1345 00:47:30,414 --> 00:47:32,216 CEILS, WE DO THE USUAL QUALITY 1346 00:47:32,282 --> 00:47:34,451 CONTROL, WE DO 2 WAYS OF 1347 00:47:34,518 --> 00:47:35,953 IDENTIFYING CELL TYPES, 1 OF 1348 00:47:36,019 --> 00:47:41,325 THEM USING REFERENCE ATLAS LIKE 1349 00:47:41,391 --> 00:47:43,060 ASMA, AND THE OTHER WITH THE 1350 00:47:43,126 --> 00:47:44,962 ATLAS WAS IN MOTOR CORTEX, SO IT 1351 00:47:45,028 --> 00:47:46,196 DOESN'T HAVE ALL THE CELLS AND 1352 00:47:46,263 --> 00:47:49,566 NUMBER 2 IT DOESN'T HAVE DISEASE 1353 00:47:49,633 --> 00:47:50,400 INFLAMMATORY AND MICRO DPLIA AND 1354 00:47:50,467 --> 00:47:52,970 ALL THAT AND WE COULD SO THAT 1355 00:47:53,036 --> 00:47:54,037 OUR ANNOTATIONS PRETTY MUCH 1356 00:47:54,104 --> 00:47:55,339 CORRESPONDED WITH THE KNOWN 1357 00:47:55,405 --> 00:47:56,373 ANNOTATIONS AND WHETHER WE DID 1358 00:47:56,440 --> 00:47:58,709 IT IN A SUPER VIED OR UNSUPER 1359 00:47:58,775 --> 00:48:00,544 VISED WAY AND I'M JUST GOING 1360 00:48:00,611 --> 00:48:02,379 TO--IT IS UP ON BIOARCHIVE AND 1361 00:48:02,446 --> 00:48:03,447 SLEEP APNEA AND OBESITY KNOW TO 1362 00:48:03,513 --> 00:48:04,581 BE PUBLISHED AND I WANT TO 1363 00:48:04,648 --> 00:48:06,116 HIGHLIGHT A FEW THINGS ABOUT 1364 00:48:06,183 --> 00:48:08,986 SINGLE CELL ANALYSIS THAT WERE 1365 00:48:09,052 --> 00:48:09,419 QUITE REMARKABLE. 1366 00:48:09,486 --> 00:48:12,256 SO 1 THING THAT WE SEE, IS THAT 1367 00:48:12,322 --> 00:48:14,591 THERE'S DOWN REGULATION IN LAYER 1368 00:48:14,658 --> 00:48:19,963 2, 3, AND LAYER 5, CLOSESALLY 1369 00:48:20,030 --> 00:48:21,598 PROYECTING EXCITATORY NEURONS 1370 00:48:21,665 --> 00:48:23,467 AND SOMATIC STATIC NEURONS. 1371 00:48:23,533 --> 00:48:26,336 IT'S NOT ALL EXCITATORY NEURONS, 1372 00:48:26,403 --> 00:48:27,571 IT'S MOSTLY BIGGEST CHANGES ARE 1373 00:48:27,638 --> 00:48:28,805 IN LAYER TO 3. 1374 00:48:28,872 --> 00:48:29,740 IT'S INTERESTING TO US BECAUSE 1375 00:48:29,806 --> 00:48:33,443 THESE ARE THE REGIONS THAT ARE 1376 00:48:33,510 --> 00:48:35,379 CONNECKING DIFFERENT HEMISPHERES 1377 00:48:35,445 --> 00:48:36,480 AND LONG RANGE CONNECTIONS IN 1378 00:48:36,546 --> 00:48:40,150 THE CORTEX BUT WE ALSO SEE A 1379 00:48:40,217 --> 00:48:41,652 PROFOUND DISREGULATION IN OLIGO 1380 00:48:41,718 --> 00:48:42,452 DENDRITIC CELLROCYTES WHICH WE 1381 00:48:42,519 --> 00:48:47,257 HAVEN'T BEEN ABLE TO SEE IN THE 1382 00:48:47,324 --> 00:48:47,624 TISSUE. 1383 00:48:47,691 --> 00:48:49,459 IT WAS MASKED BY THE CHANGING IN 1384 00:48:49,526 --> 00:48:50,661 THE ASTRO FLI COLSISSA AND THAT 1385 00:48:50,727 --> 00:48:51,695 WAS INTERESTING AS WELL. 1386 00:48:51,762 --> 00:48:54,931 AND IF WE LOOK FOR ENRICHMENT IN 1387 00:48:54,998 --> 00:48:57,601 THE ASD ENRICHED YEENS IT'S ALL 1388 00:48:57,668 --> 00:49:00,804 IN THE DOWN REGULATED YEENS, 1389 00:49:00,871 --> 00:49:02,839 COLOSESLY PROECTOMYOSIN ARED SO 1390 00:49:02,906 --> 00:49:04,441 NOT CORTICALE NEURONS BUT 1391 00:49:04,508 --> 00:49:06,510 NEURONS THAT PROJECTING ACROSS 1392 00:49:06,576 --> 00:49:07,878 THE CORPUS COLOSES ORDER OF 1393 00:49:07,944 --> 00:49:08,211 MICRONS. 1394 00:49:08,278 --> 00:49:10,781 SO WE SEE THESE REACTIVE STATES, 1395 00:49:10,847 --> 00:49:13,383 NOT JUST IN MICROTBLIA BUT NOW 1396 00:49:13,450 --> 00:49:14,618 IN OLIGO DENDRITIC CELLROCYTES. 1397 00:49:14,685 --> 00:49:16,853 SO IT'S GIVING US AGAIN A MORE 1398 00:49:16,920 --> 00:49:20,490 REFINED PICTURE, WE ALSO DID 1399 00:49:20,557 --> 00:49:21,224 SPATIAL TRANSCRIPTOMICS WHICH I 1400 00:49:21,291 --> 00:49:23,860 DON'T HAVE TIME TO SHOW YOU 1401 00:49:23,927 --> 00:49:26,396 WHICH SHOWED THAT THE MICROGLIA 1402 00:49:26,463 --> 00:49:28,565 AND ASTRO CITE REGULATION 1403 00:49:28,632 --> 00:49:29,733 EXTENDED THROUGHOUT THE GRAY 1404 00:49:29,800 --> 00:49:30,801 MATTER BUT AGAIN WAS MOST 1405 00:49:30,867 --> 00:49:35,305 PROFOUND IN THE UPPER LAYERS. 1406 00:49:35,372 --> 00:49:37,240 BUT 1 THING CAN YOU DO THAT YOU 1407 00:49:37,307 --> 00:49:39,710 CANNOT DO WITH BULK TISSUE IS 1408 00:49:39,776 --> 00:49:42,312 IDENTIFY THE REGULATORY DRIVERS 1409 00:49:42,379 --> 00:49:44,414 WITH I THINK HIGH ACCURACY AND 1410 00:49:44,481 --> 00:49:46,249 PRECISION EMPLOY SO YOU CREATE 1411 00:49:46,316 --> 00:49:48,018 SINGLE CELL CO EXPRESSION 1412 00:49:48,085 --> 00:49:49,653 NETWORKS, WE USED A PROGRAM 1413 00:49:49,720 --> 00:49:51,621 CALLED SCENIC HERE, IT'S BEEN 1414 00:49:51,688 --> 00:49:53,824 REVISED TO BE SCENIC +, WE FOUND 1415 00:49:53,890 --> 00:49:56,593 THAT IT'S PREDICTIONS ARE QUITE 1416 00:49:56,660 --> 00:49:57,160 ACCURATE WHEN YOU--WHEN THE 1417 00:49:57,227 --> 00:49:59,162 DAILY BASIS THEA IS GOOD. 1418 00:49:59,229 --> 00:50:03,834 IT PRINTS THE DATA INTO REGUE 1419 00:50:03,900 --> 00:50:05,035 LONS, AND THE YEEPS THAT HAVE 1420 00:50:05,102 --> 00:50:09,339 THE BINDING SITES IN THE 5 PRIME 1421 00:50:09,406 --> 00:50:10,774 REGION AND AUTOCO REGULATED 1422 00:50:10,841 --> 00:50:12,075 WITH, SO THE NOTION THAT IT'S 1423 00:50:12,142 --> 00:50:14,511 COMBINED THERE AND IN YOUR DAT 1424 00:50:14,578 --> 00:50:16,046 IT'S CO REGULATED. 1425 00:50:16,113 --> 00:50:17,114 WE CORE THEM, AND RANK THEM. 1426 00:50:17,180 --> 00:50:19,516 SO 1 OF THE QUESTIONS WAS, IF WE 1427 00:50:19,583 --> 00:50:21,051 COULD IDENTIFY REGULATORY 1428 00:50:21,118 --> 00:50:22,586 DRIVERS WHICH WE COULD DO, AND 1429 00:50:22,652 --> 00:50:24,254 THIS WAS LED BY LUCY A POST DOC 1430 00:50:24,321 --> 00:50:25,989 IN THE LAB, HOW MUCH ARE THE 1431 00:50:26,056 --> 00:50:27,858 EXPRESSION DID IT ACCOUNT FOR 1432 00:50:27,924 --> 00:50:29,693 AND ACCOUNTED FOR ENORMOUS 1433 00:50:29,760 --> 00:50:30,360 AMOUNT. 1434 00:50:30,427 --> 00:50:34,598 JUST THE YEENS DOWN STREM WAS 6 1435 00:50:34,664 --> 00:50:35,332 TRANSCRIPTION FACTORS ACCOUNTED 1436 00:50:35,399 --> 00:50:37,501 FOR MORE THAN HALF OF THE 1437 00:50:37,567 --> 00:50:38,034 TRANSCRIPTION ALGORITHMS 1438 00:50:38,101 --> 00:50:39,536 DISREGGULES, AT LEAST PREDICTED 1439 00:50:39,603 --> 00:50:40,337 TO ACCOUNT FOR THEM. 1440 00:50:40,404 --> 00:50:46,176 SO THIS IS A BIOINFORMATIC 1441 00:50:46,243 --> 00:50:46,510 PREDICTION. 1442 00:50:46,576 --> 00:50:50,380 IT'S REALLY REMARKABLE. 1443 00:50:50,447 --> 00:50:54,651 NOW YOU MAY NOTICE IF YOU'RE A 1444 00:50:54,718 --> 00:50:57,921 OFFICKIANAD O, THESE DRIVERS, 1445 00:50:57,988 --> 00:50:59,990 HALF THE YEENS HERE ARE KNOWN 1446 00:51:00,056 --> 00:51:03,059 AUTISM RISK YEERNS IN WHICH MEAS 1447 00:51:03,126 --> 00:51:07,164 MONOGENIC DE NOVO MUTATIONS 1448 00:51:07,230 --> 00:51:07,431 MUTATIONS 1449 00:51:07,497 --> 00:51:09,166 OCCUR, SO THAT WAS PRETTY 1450 00:51:09,232 --> 00:51:09,533 INTERESTING. 1451 00:51:09,599 --> 00:51:11,401 SO WE ASKED IF WE LOOK AT WHAT 1452 00:51:11,468 --> 00:51:13,236 WAS CHANGE NOTHING AUTISM, WAS 1453 00:51:13,303 --> 00:51:16,072 IT ENRICH INDEED ACCURACYATISM 1454 00:51:16,139 --> 00:51:18,308 RISK YEENS SO 72 OF THE 1S 1455 00:51:18,375 --> 00:51:21,211 IDENTIFIED ARE ASD SAFARI HIGH 1456 00:51:21,278 --> 00:51:24,114 CONFIDENCE GENES ADENTIFIED NOW. 1457 00:51:24,181 --> 00:51:24,981 A REMARKABLE ENRICHMENT. 1458 00:51:25,048 --> 00:51:25,882 SO THIS PATTERN THAT'S 1459 00:51:25,949 --> 00:51:27,050 CONSIDERING AT A CELL TYPE 1460 00:51:27,117 --> 00:51:29,352 LEVEL, AT SOME LEVEL, IS BEING 1461 00:51:29,419 --> 00:51:31,555 DRIVEN BY RISK GENES AT LEAST, 1462 00:51:31,621 --> 00:51:34,090 THAT'S THE MODEL AND WHETHER 1463 00:51:34,157 --> 00:51:37,260 THAT'S A DEVELOPMENTAL 1464 00:51:37,327 --> 00:51:39,596 PHENOMENON THAT'S PERSISTING OR 1465 00:51:39,663 --> 00:51:40,263 AN UNGOING DENATIONAL LIBRARY OF 1466 00:51:40,330 --> 00:51:41,998 MEDICINE NONE IS CLEAR, SO YOU 1467 00:51:42,065 --> 00:51:43,834 MAY SAY HOW DO YOU KNOW THIS? 1468 00:51:43,900 --> 00:51:45,569 SO WE WENT FURTHER AND TRIED TO 1469 00:51:45,635 --> 00:51:46,436 VALIDATE THIS. 1470 00:51:46,503 --> 00:51:48,872 SO THE EXPERIMENTAL VALIDATION 1471 00:51:48,939 --> 00:51:50,607 USING PUBLICLY AVAILABLE DATA, 1472 00:51:50,674 --> 00:51:52,976 THE CONNECTIVITY MAP WHERE 1473 00:51:53,043 --> 00:51:56,079 PEOPLE AT ON BROAD AND 1474 00:51:56,146 --> 00:51:57,714 COLLABORATORS HAVE NOT JUST 1475 00:51:57,781 --> 00:51:59,015 GIVEN, THEY'VE GIVEN THOUSANDS 1476 00:51:59,082 --> 00:52:02,018 OF FDA DRUGS TO CELLS AND 1477 00:52:02,085 --> 00:52:02,619 MEASURED THE TRANSCRIPTIONAL 1478 00:52:02,686 --> 00:52:04,554 PATTERN BUT THEY ALSO KNOCKED 1479 00:52:04,621 --> 00:52:07,190 OUT ABOUT 10,000 YEENS AND 1480 00:52:07,257 --> 00:52:08,024 MEASURED THE TRANSCRIPTIONAL 1481 00:52:08,091 --> 00:52:11,328 PATTERN SO WE CAN ASK, IF YOU 1482 00:52:11,394 --> 00:52:12,729 KNOCK OUT THESE TRANSCRIPTION 1483 00:52:12,796 --> 00:52:13,997 FACTORS THAT THEY'VE KNOCKED 1484 00:52:14,064 --> 00:52:15,932 OUT, DOES IT CAUSE THE GENE 1485 00:52:15,999 --> 00:52:18,068 EXPRESSION CHANGES THAT WE 1486 00:52:18,134 --> 00:52:22,105 PREDICT OCCUR AND THE ANSWER IS 1487 00:52:22,172 --> 00:52:22,706 A RESOUNDING YES. 1488 00:52:22,772 --> 00:52:26,610 SO IF WE TAKE ALL REGUE LON 1489 00:52:26,676 --> 00:52:27,978 TRANSCRIPTION FACTORS IT'S NOT 1490 00:52:28,044 --> 00:52:28,812 REALLY SIGNIFICANT BUT IF WE 1491 00:52:28,879 --> 00:52:32,082 TAKE THOSE THAT ARE IN CNS CELL 1492 00:52:32,148 --> 00:52:34,551 TYPES FROM CNS DATA IT'S HIGHLY 1493 00:52:34,618 --> 00:52:35,519 SIGNIFICANT, WE'RE ONLY ABLE TO 1494 00:52:35,585 --> 00:52:42,259 ELECTRIC AT 31 OUT OF THE 70, IF 1495 00:52:42,325 --> 00:52:44,461 THEY DID CRSPR OF ALL CELL TYPES 1496 00:52:44,528 --> 00:52:46,897 THAT'S STRONGER AND THAT'S ALSO 1497 00:52:46,963 --> 00:52:50,300 SIGNIFICANT AND SO BOTH SH KNOCK 1498 00:52:50,367 --> 00:52:53,169 OUT AND CRSPR KNOCK OUT SHOWS 1499 00:52:53,236 --> 00:52:55,438 REALLY PROFOUND OVERLAP OF THE 1500 00:52:55,505 --> 00:52:57,507 YEEPS THAT WE WOULD--OF THE 1501 00:52:57,574 --> 00:52:58,975 REGUE LONS THAT WE IDENTIFIED SO 1502 00:52:59,042 --> 00:53:02,178 WE THINK THIS IS A NICE WAY TO 1503 00:53:02,245 --> 00:53:03,146 USE EXTERNAL DATA SO WE 1504 00:53:03,213 --> 00:53:07,017 DEPARTMENT HAVE TO DO THE CRSPR 1505 00:53:07,083 --> 00:53:08,618 EXPERIMENTS IN OUR LAB, SOMEONE 1506 00:53:08,685 --> 00:53:10,186 HAD ALREADY DONE THEM AND IT'S A 1507 00:53:10,253 --> 00:53:12,322 GREAT EXAMPLE OF THE UTILITY OF 1508 00:53:12,389 --> 00:53:14,024 PUBLIC DATA AND THESE KINDS OF 1509 00:53:14,090 --> 00:53:16,092 RESOURCES SO OUR MODEL FOR 1510 00:53:16,159 --> 00:53:18,061 WHAT'S GOING ON POSTMORTEM BRAIN 1511 00:53:18,128 --> 00:53:21,398 IS THAT THE CORTEX IS IMPACTED 1512 00:53:21,464 --> 00:53:23,366 BY A GENETICALLY DRIVEN NEURONAL 1513 00:53:23,433 --> 00:53:26,336 FUNCTION AND SHIFTED TO A MORE 1514 00:53:26,403 --> 00:53:29,406 REACTIVE HOMEOSTASIS BROADLY BUT 1515 00:53:29,472 --> 00:53:30,574 MORE STRONGLY CONVERGES ON 1516 00:53:30,640 --> 00:53:32,108 LAYERS OF THE CORTEX. 1517 00:53:32,175 --> 00:53:34,044 SO NOW THE BIG DEAL IS TO 1518 00:53:34,110 --> 00:53:35,145 UNDERSTAND HOW DID THIS ARRIVE 1519 00:53:35,211 --> 00:53:36,680 IN MOW DID IT HAPPEN IN WE KNOW 1520 00:53:36,746 --> 00:53:38,148 THAT IS THE STATE OF THE BRAIN 1521 00:53:38,214 --> 00:53:40,584 WHEN THESE PEOPLE DIED BUT 1522 00:53:40,650 --> 00:53:43,119 LIKELY RELATED TO THEIR 1523 00:53:43,186 --> 00:53:44,020 UNDERLYING DISORDER BECAUSE IT'S 1524 00:53:44,087 --> 00:53:47,624 SEEN OVER AND OVER AND OVER 1525 00:53:47,691 --> 00:53:50,727 AGAIN EMPLOY BUT HOW DOES IT 1526 00:53:50,794 --> 00:53:50,961 OCCUR? 1527 00:53:51,027 --> 00:53:52,829 SO IF WE GO BACK TO THE MODEL 1528 00:53:52,896 --> 00:53:55,298 AGAIN, WE COULD ALSO ASK IN A 1529 00:53:55,365 --> 00:53:56,666 FORWARD GENETIC WAY, WE'VE BEEN 1530 00:53:56,733 --> 00:53:57,934 KIND OF GOING IN A VERMEN 1531 00:53:58,001 --> 00:53:59,903 INFECTED VERSE GENETIC WAY, HOW 1532 00:53:59,970 --> 00:54:01,938 DOES KNOWN AUTISM RISK IMPACT 1533 00:54:02,005 --> 00:54:04,574 THESE MODEL CITIZEN LICKULAR 1534 00:54:04,641 --> 00:54:06,743 PHENOTYPES GOING FORWARD IN THAT 1535 00:54:06,810 --> 00:54:08,345 DIRECTION AND OF COURSE WE CAN'T 1536 00:54:08,411 --> 00:54:11,014 DO THAT IN ADULT HUMAN BRAIN BUT 1537 00:54:11,081 --> 00:54:12,148 THERE ARE--ARE WAYS TO LOOK AT 1538 00:54:12,215 --> 00:54:12,349 THAT. 1539 00:54:12,415 --> 00:54:16,953 ONE OF THE WAYS WE DID EARLY ON 1540 00:54:17,020 --> 00:54:22,325 IN 2013, WITH NEIL WIDE WHO WAS 1541 00:54:22,392 --> 00:54:25,328 A MD-PHEAR D IN THE LAB, IS WE 1542 00:54:25,395 --> 00:54:28,398 TOOK THAT DATA AND BASICALLY HAD 1543 00:54:28,465 --> 00:54:31,368 FETAL CORTEX ALL THE WAY THROUGH 1544 00:54:31,434 --> 00:54:35,271 ADULTHOOD, WE WENT FROM 8 WEEKS 1545 00:54:35,338 --> 00:54:38,241 GUESTATION TO 3 YEARS BECAUSE 1546 00:54:38,308 --> 00:54:40,777 AUTISM IS DIAGNOSED BEFORE 3 1547 00:54:40,844 --> 00:54:44,814 YEARS, OR STARTS OFTEN NOT 1548 00:54:44,881 --> 00:54:45,548 DIAGNOSED UNFORTUNATELY. 1549 00:54:45,615 --> 00:54:47,150 AND ASKED IF WE CRETE 1550 00:54:47,217 --> 00:54:48,118 MODULTIMATELYS THAT CORRESPOND 1551 00:54:48,184 --> 00:54:50,053 TO BASIC ASPECTS OF DEVELOPMENT 1552 00:54:50,120 --> 00:54:52,689 AND WE SHOW CELL BIRTH, 1553 00:54:52,756 --> 00:54:53,757 MIGRATION, OUTBIRTH, ALL THIS 1554 00:54:53,823 --> 00:54:55,258 HAPPENING WAS THERE ANY 1555 00:54:55,325 --> 00:54:56,226 CONVERGENCE AND WHAT WE FOUND 1556 00:54:56,292 --> 00:54:58,528 AND THIS HAS BEEN PUBLISHED SO 1557 00:54:58,595 --> 00:55:00,563 I'M SUMMARIZING IT IS THAT 1558 00:55:00,630 --> 00:55:03,333 INDEED THE AUTISM RISK GENES WE 1559 00:55:03,400 --> 00:55:05,201 KNEW THIS 2012 ARE HIGH 1560 00:55:05,268 --> 00:55:06,703 LIKELIHOOD CONVERGED DURING 1561 00:55:06,770 --> 00:55:07,671 FETAL DEVELOPMENT AND THEY 1562 00:55:07,737 --> 00:55:09,606 CONVERGED IN KIND OF 2 MAIN 1563 00:55:09,673 --> 00:55:12,042 PATTERNS, 1 WAS GENES THAT 1564 00:55:12,108 --> 00:55:14,010 DISRUPT CHROMATIN AND 1565 00:55:14,077 --> 00:55:14,844 TRANSCRIPTIONAL REGULATION THAT 1566 00:55:14,911 --> 00:55:16,379 WAS ENRICH INDEED THESE DE NOVO 1567 00:55:16,446 --> 00:55:18,348 MUSEUM THAIGZS AND THEN LOWER 1568 00:55:18,415 --> 00:55:20,650 IMPACT VARIANTS THAT IMPACTED 1569 00:55:20,717 --> 00:55:22,585 SYNAPTIC DEVELOPMENT BUT ALL 1570 00:55:22,652 --> 00:55:26,089 EXPRESSED KIND OF MIDGUESTATION 1571 00:55:26,156 --> 00:55:26,690 IN FEEDAL BRAIN. 1572 00:55:26,756 --> 00:55:29,759 AND WE LOOK TO SEE WHERE 1573 00:55:29,826 --> 00:55:34,964 THESE--WE HAD A MACAQUE ATLAS AT 1574 00:55:35,031 --> 00:55:37,400 THE TIME ASK WE COULD SEE THEY 1575 00:55:37,467 --> 00:55:39,235 WERE IN SUPERFICIAL LAYERS. 1576 00:55:39,302 --> 00:55:41,004 THIS IS A PREMONITION OF WHAT WE 1577 00:55:41,071 --> 00:55:42,739 FOUND 10 YEARS LATER IN THE 1578 00:55:42,806 --> 00:55:44,808 CORTEX THAT THE SUPERFICIAL 1579 00:55:44,874 --> 00:55:46,810 LAYERS ARE MORE IMPACTED SO THIS 1580 00:55:46,876 --> 00:55:48,578 REALLY BEGAN TO TELL US THAT WE 1581 00:55:48,645 --> 00:55:51,347 NEEDED, WE HAVE HIGH IMPACT 1582 00:55:51,414 --> 00:55:52,515 GENES AFFECTING TRANSCRIPTIONAL 1583 00:55:52,582 --> 00:55:55,151 REGULATION AND THE KIND OF LOWER 1584 00:55:55,218 --> 00:55:56,553 IMPACT AFFECTING SYNAPTIC 1585 00:55:56,619 --> 00:55:57,187 DEVELOPMENT NEURONAL FUNCTION 1586 00:55:57,253 --> 00:55:59,656 AND FIT WITH THE MODEL THAT 1587 00:55:59,723 --> 00:56:03,259 ENCODES HAD KIND OF PUT OUT 1588 00:56:03,326 --> 00:56:05,361 THERE FOR KIND OF 1589 00:56:05,428 --> 00:56:06,262 TRANSCRIPTIONAL REGULATION. 1590 00:56:06,329 --> 00:56:07,897 THAT THE GENETIC ARCHITECTURE 1591 00:56:07,964 --> 00:56:09,999 WE'RE SEEING, THAT THESE DE NOVO 1592 00:56:10,066 --> 00:56:11,601 LARGE MUTATIONS ARE OCCUR 1593 00:56:11,668 --> 00:56:13,436 NOTHING IN TRANSCRIPTIONAL 1594 00:56:13,503 --> 00:56:14,871 REGULATION, THIS TOP TIER 1595 00:56:14,938 --> 00:56:16,706 REGULATORS THAT WE REALLY NEED 1596 00:56:16,773 --> 00:56:17,774 TO UNDERSTAND NEURODEVELOPMENT 1597 00:56:17,841 --> 00:56:18,975 MUCH BETTER AND HIGHLIGHT THE 1598 00:56:19,042 --> 00:56:20,844 NEED FOR REFINED UNDERSTANDING 1599 00:56:20,910 --> 00:56:22,846 OF REGULATORY NETWORKS AND MOST 1600 00:56:22,912 --> 00:56:24,514 REGULATORY NETWORKS, MOST OF THE 1601 00:56:24,581 --> 00:56:26,583 REGULATORY ELEMENTS IN THE HUMAN 1602 00:56:26,649 --> 00:56:28,818 GENOME ARE IN NONCODING REGIONS 1603 00:56:28,885 --> 00:56:30,653 AND IT LED US TO SPENDING YEARS 1604 00:56:30,720 --> 00:56:32,889 WHICH WE STILL ARE DOING TO MAKE 1605 00:56:32,956 --> 00:56:34,190 MAPS OF THESE NONCODING REGIONS 1606 00:56:34,257 --> 00:56:37,193 AND WHAT THEY DO, SO YOU NEED TO 1607 00:56:37,260 --> 00:56:38,795 UNDERSTAND ARE THEY ACTIVE 1608 00:56:38,862 --> 00:56:44,868 REGIONS OR OPEN IN THAT TISSUES 1609 00:56:44,934 --> 00:56:47,570 AND 1 CAN DO THAT BY LOOKING AT 1610 00:56:47,637 --> 00:56:51,040 THE HISTONE MODIIVES, DNA 1611 00:56:51,107 --> 00:56:51,875 METHYLATION, TRANSCRIPTION 1612 00:56:51,941 --> 00:56:52,308 FACTOR BINDING. 1613 00:56:52,375 --> 00:56:54,511 THE KEY IS THAT THIS OCCURS IN A 1614 00:56:54,577 --> 00:56:55,712 CELL TYPE AND TISSUE DEVELOPMENT 1615 00:56:55,779 --> 00:56:57,547 IN A SPECIFIC WAY SO YOU NEED TO 1616 00:56:57,614 --> 00:56:59,415 MAKE MAPS FOR ALMOST EVERY 1617 00:56:59,482 --> 00:57:01,050 TISSUE IN CELL TYPE THAT YOU'RE 1618 00:57:01,117 --> 00:57:02,152 INTERESTED IN LOOKING AT TO 1619 00:57:02,218 --> 00:57:02,652 REALLY UNDERSTAND THAT. 1620 00:57:02,719 --> 00:57:05,054 SO WE WERE INTERESTED IN BRAIN 1621 00:57:05,121 --> 00:57:07,323 DEVELOPMENT AND WE HAD SEEN THAT 1622 00:57:07,390 --> 00:57:08,725 AUTISM GENETIC RISK IS SUPER 1623 00:57:08,792 --> 00:57:10,260 RICH IN FETAL BRAIN DEVELOPMENT 1624 00:57:10,326 --> 00:57:12,495 SO WE SPENT YEARS MAKING MAPS, 1625 00:57:12,562 --> 00:57:16,466 BUILDING REFERENCE MAPS OF YEEN 1626 00:57:16,533 --> 00:57:18,635 REGULATION AND CO EXPRESSION 1627 00:57:18,701 --> 00:57:20,637 BOTH USING ININATE NUR 2016 1628 00:57:20,703 --> 00:57:22,806 WHICH CONNECTED ENHANCERS TO 1629 00:57:22,872 --> 00:57:24,507 YEENS, LOOKING AT OPEN CHROMATIN 1630 00:57:24,574 --> 00:57:26,309 AND CONNECT THAGOREAN TO THE 1631 00:57:26,376 --> 00:57:29,512 HIGH C, CANNED WHAT, A NUMBER OF 1632 00:57:29,579 --> 00:57:31,948 THE PSYCHE ENCODE PAPERS MAKING 1633 00:57:32,015 --> 00:57:34,184 A FETAL SINGLE CELL MAP OF HUMAN 1634 00:57:34,250 --> 00:57:36,219 BRAIN, MAKING A EQTL MAP OF 1635 00:57:36,286 --> 00:57:38,354 HUMAN BRAIN, ET CETERA. 1636 00:57:38,421 --> 00:57:39,656 SO ONCE WE HAVE THESE MAPS 1637 00:57:39,722 --> 00:57:42,292 THERE'S A LOT WE CAN WITH IT 1638 00:57:42,358 --> 00:57:44,627 NOW, WE CAN ANNOTATE NONCODING 1639 00:57:44,694 --> 00:57:45,595 VARIATION AND THERE'S A LOT WE 1640 00:57:45,662 --> 00:57:47,130 HAVE DONE THERE AND I WILL SHOW 1641 00:57:47,197 --> 00:57:48,631 YOU 1 SLIDE TO GIVE YOU AN IDEA, 1642 00:57:48,698 --> 00:57:52,669 SO THIS WAS WORK THAT 1643 00:57:52,735 --> 00:57:53,736 [INDISCERNIBLE] DID IN THE LAB 1644 00:57:53,803 --> 00:57:55,138 AND WE MADE OUR FIRST GENERATION 1645 00:57:55,205 --> 00:57:58,608 MAPS AND SO THERE WAS AN AUTISM 1646 00:57:58,675 --> 00:58:04,447 GWAS, COMMON GENETIC VARIATION. 1647 00:58:04,514 --> 00:58:06,115 NINETY-FIVE% OF THE YEEPS SAT 1648 00:58:06,182 --> 00:58:07,083 IN THE NONENCODING REGION. 1649 00:58:07,150 --> 00:58:08,284 WE COULD USE THE MAPS TO 1650 00:58:08,351 --> 00:58:09,352 UNDERSTAND THAT AND AGAIN IT 1651 00:58:09,419 --> 00:58:11,187 SHOWED THAT NOT JUST RARE 1652 00:58:11,254 --> 00:58:13,056 GENETIC VARIATION BUT COMMON 1653 00:58:13,122 --> 00:58:13,890 GENETIC VARIATION WAS 1654 00:58:13,957 --> 00:58:16,326 PARTITIONED INTO THIS VERY, VERY 1655 00:58:16,392 --> 00:58:17,026 EARLY FETAL DEVELOPMENTAL 1656 00:58:17,093 --> 00:58:17,327 TRAJECTORY. 1657 00:58:17,393 --> 00:58:20,263 AND WHEN WE LOOKED ACROSS BRAIN 1658 00:58:20,330 --> 00:58:21,898 REGIONS WE ALSO SAW AGAIN IT WAS 1659 00:58:21,965 --> 00:58:25,435 FETAL MORE EXPRESSED IN ADULT 1660 00:58:25,501 --> 00:58:27,570 BUT CORMORE IN OTHERS ESPECIALLY 1661 00:58:27,637 --> 00:58:28,738 DURING FETAL SO AGAIN WEB 1662 00:58:28,805 --> 00:58:29,806 CONNECTED REPLICATED THIS AND 1663 00:58:29,873 --> 00:58:31,107 VALIDATED IT BUT THISSIVE GOES 1664 00:58:31,174 --> 00:58:32,442 YOU 1 IDEA FOR HOW THESE MAPS 1665 00:58:32,508 --> 00:58:34,210 WITH BE USED AND I WILL SHOW YOU 1666 00:58:34,277 --> 00:58:34,444 ANOTHER. 1667 00:58:34,510 --> 00:58:36,212 I KNOW I'M RUNNING SHORT SO I'M 1668 00:58:36,279 --> 00:58:42,518 GOING TO SKIP THIS AND JUST SAY 1669 00:58:42,585 --> 00:58:44,821 THAT IF WE LOOK AT GWAS, NOT 1670 00:58:44,888 --> 00:58:46,122 JUST FOR AUTISM OR SCETS FRENNIA 1671 00:58:46,189 --> 00:58:51,261 BUT IF YOU HAVE ANY 1 OF 6 1672 00:58:51,327 --> 00:58:51,995 DEFINED PSYCHIATRIC DISORDERS 1673 00:58:52,061 --> 00:58:54,063 AND CALL YOU AFFECTED AND IF YOU 1674 00:58:54,130 --> 00:58:55,565 DON'T HAVE 1 YOU'RE UNINFECTED 1675 00:58:55,632 --> 00:58:58,001 SO THIS IS EYE SIGHT WITH THOMAS 1676 00:58:58,067 --> 00:58:59,535 AND ANDREW, WE IDENTIFIED 1677 00:58:59,602 --> 00:59:01,938 MULTIPLE LOKREBS CYCLE I, GENOME 1678 00:59:02,005 --> 00:59:03,439 WIDE SIGNIFICANT THAT GIVE RISK 1679 00:59:03,506 --> 00:59:06,409 FOR ALL THESE DISORDERS IN THE 1680 00:59:06,476 --> 00:59:08,244 SAME KIND OF DIRECTION AND WHEN 1681 00:59:08,311 --> 00:59:11,347 WE AGAIN MAP THOSE AND FOLLOW UP 1682 00:59:11,414 --> 00:59:13,449 WITH THE PGC GROUP AND A MUCH 1683 00:59:13,516 --> 00:59:17,954 LARGER SAMPLE, WE MAP THEM AND 1684 00:59:18,021 --> 00:59:19,722 THEY'RE IMPACTING RISK, AND 1685 00:59:19,789 --> 00:59:20,890 REGISTER DURING FETAL BRAIN 1686 00:59:20,957 --> 00:59:21,824 DEVELOPMENT AND IT'S NOT 1687 00:59:21,891 --> 00:59:23,893 EXCLUSIVE AND THE SAME THING 1688 00:59:23,960 --> 00:59:24,394 WITH AUTISM. 1689 00:59:24,460 --> 00:59:26,663 SO THE QUESTION IS WHAT'S NEXT, 1690 00:59:26,729 --> 00:59:29,098 HOW DO THESE MOLECULAR CHANGES 1691 00:59:29,165 --> 00:59:31,901 OCCUR OVERTIME AND HOW DO 1692 00:59:31,968 --> 00:59:33,069 GENETICS IMPACT DEVELOPMENT. 1693 00:59:33,136 --> 00:59:34,704 SO HOW DO WE CONNECT THESE TO 1694 00:59:34,771 --> 00:59:36,773 THE PATTERNS IN THE BRAIN, SO 1695 00:59:36,839 --> 00:59:38,675 WE'VE BEEN USING INVITRO IPSC 1696 00:59:38,741 --> 00:59:41,077 MODELS TO UNDERSTAND HOW GENETIC 1697 00:59:41,144 --> 00:59:43,279 RISK KIND OF PERCOLATES TO LEAD 1698 00:59:43,346 --> 00:59:44,347 TO DEVELOPMENT TO THESE PATTERNS 1699 00:59:44,414 --> 00:59:46,282 AND THE QUESTION IS HOW DO WE 1700 00:59:46,349 --> 00:59:47,317 USE THESE TO DEVELOP TREATMENT. 1701 00:59:47,383 --> 00:59:49,118 SO AGAIN I WILL TRY TO ZIP 1702 00:59:49,185 --> 00:59:52,322 THROUGH THIS IN 5 MINUTES, IF 1703 00:59:52,388 --> 00:59:53,790 YOU'LL STICK WITH ME BECAUSE I 1704 00:59:53,856 --> 00:59:55,591 THINK THIS IS--I REALLY WANTED 1705 00:59:55,658 --> 00:59:58,795 TO SHOW SOME NEW THINGS WE'VE 1706 00:59:58,861 --> 00:59:59,629 BEEN DOING. 1707 00:59:59,696 --> 01:00:01,097 INITIALLY THE FIRST QUESTION IS 1708 01:00:01,164 --> 01:00:03,933 HOW WELL DO THESE IPSC MODELS, 1709 01:00:04,000 --> 01:00:05,201 MODEL DEVELOPMENT AND WHICH 1710 01:00:05,268 --> 01:00:06,602 PARTS OF HUMAN CORTICALE 1711 01:00:06,669 --> 01:00:07,670 DEVELOPMENT DO THEY MODEL. 1712 01:00:07,737 --> 01:00:13,009 SO WE DEVELOPED A TRANSCRIPTOMIC 1713 01:00:13,076 --> 01:00:15,244 FRAMEWORK TO EVALUATE MODELS OF 1714 01:00:15,311 --> 01:00:16,045 NEUR-AL DEVELOPMENT BY STEM 1715 01:00:16,112 --> 01:00:19,115 CELLS. THIS IS JASON STEIN AND 1716 01:00:19,182 --> 01:00:20,917 LUIS WHEN THEY WERE POST DOCS IN 1717 01:00:20,984 --> 01:00:21,484 THE LAB. 1718 01:00:21,551 --> 01:00:22,986 SO WE DEVELOP A NUMBER OF TOOLS 1719 01:00:23,052 --> 01:00:32,729 TO ASK WHAT DO I HAVE IN MY 1720 01:00:32,795 --> 01:00:32,929 DISH? 1721 01:00:32,996 --> 01:00:34,397 AND THEN WE ASK, IF WE TAKE 1722 01:00:34,464 --> 01:00:37,500 THESE YEENS IN THE M2 CHROMATIN 1723 01:00:37,567 --> 01:00:39,168 MODIFIER IS IT PRESERVED AND 1724 01:00:39,235 --> 01:00:42,338 EXPRESSED, IT IS INVITRO, EVEN 1725 01:00:42,405 --> 01:00:44,374 FOR PRIMARY IN 2 D IN A DISH, 1726 01:00:44,440 --> 01:00:45,575 GOING FORWARD WITH WORK WITH THE 1727 01:00:45,641 --> 01:00:46,743 LAB, WE'VE BEEN ABLE TO SHOW 1728 01:00:46,809 --> 01:00:48,878 THAT IF YOU GROW THESE IN 3D 1729 01:00:48,945 --> 01:00:51,481 INSTEAD OF 2 D, AT 2 D, THEY 1730 01:00:51,547 --> 01:00:57,553 KIND OF STOP AT 26 WEEKS, YOU 1731 01:00:57,620 --> 01:01:00,556 NEVER GET THAT WELL 1732 01:01:00,623 --> 01:01:00,890 DEFERENTIATED. 1733 01:01:00,957 --> 01:01:02,658 BUT THEY GROW THESE AND WE'VE 1734 01:01:02,725 --> 01:01:03,626 BEEN GROWING THEM FOR 2ER YOAN 1735 01:01:03,693 --> 01:01:06,162 MONCADAS IN THE LAB NOW AND AT 1736 01:01:06,229 --> 01:01:07,663 THIS POINT SURGEIO HAD IT HAS 1737 01:01:07,730 --> 01:01:10,867 WELL, AND YOU CAN SEE THAT THE 1738 01:01:10,933 --> 01:01:12,635 OCCURS IN VIVO, MATCH WHAT'S 1739 01:01:12,702 --> 01:01:14,137 HAPPENING IN VIVO EACH PAST 1740 01:01:14,203 --> 01:01:14,971 POSTNATAL BIRTH. 1741 01:01:15,038 --> 01:01:18,674 THIS IS WITH THE TRANSCRIPT OHM, 1742 01:01:18,741 --> 01:01:19,709 WE SHOWED THIS 1743 01:01:19,776 --> 01:01:20,743 ELECTROPHYSIOLOGICALLY, WE SHOW 1744 01:01:20,810 --> 01:01:21,944 IT WITH HISTONE MARKS AND OTHER 1745 01:01:22,011 --> 01:01:24,113 TOOLS AS WELL, SO WE THINK WE 1746 01:01:24,180 --> 01:01:26,682 HAVE A GOOD TOOL FOR ESPECIALLY 1747 01:01:26,749 --> 01:01:28,985 MODELING EARLY DEVELOPMENT IN A 1748 01:01:29,052 --> 01:01:29,185 DISH. 1749 01:01:29,252 --> 01:01:30,053 HOW ABOUT TREATMENT DEVELOPMENT 1750 01:01:30,119 --> 01:01:32,221 IN SO WE'RE USING THESE TO 1751 01:01:32,288 --> 01:01:33,189 UNDERSTAND THE IMPACT OF 1752 01:01:33,256 --> 01:01:34,123 SPECIFIC YEENS BUT THERE ARE 2 1753 01:01:34,190 --> 01:01:37,360 WAYS TO THINK ABOUT THIS. 1754 01:01:37,427 --> 01:01:38,995 TARGETING RARE FORMS OF AUTISM 1 1755 01:01:39,062 --> 01:01:42,231 GENE AT A TIME OR TARGETING 1756 01:01:42,298 --> 01:01:43,533 CONVERGE EPT PATHWAYS, THESE BIG 1757 01:01:43,599 --> 01:01:45,268 NETWORKS THAT I'VE BEEN TALKING 1758 01:01:45,334 --> 01:01:47,703 ABOUT, SO HOW CAN WE DO THAT, 1759 01:01:47,770 --> 01:01:48,538 WELL, THE AUTISM RISK JEERNS 1760 01:01:48,604 --> 01:01:50,406 THAT I TOLD YOU ABOUT, VAST 1761 01:01:50,473 --> 01:01:54,310 MAJORITY OF THEM ACT BY HAPLO 1762 01:01:54,377 --> 01:01:56,946 INSUFFICIENCY, THERE'S A DE NOVO 1763 01:01:57,013 --> 01:01:58,848 MUTATION THAT KNOCKS OUT 1 COPY 1764 01:01:58,915 --> 01:02:00,183 AND THAT'S SHOWN HERE. 1765 01:02:00,249 --> 01:02:02,485 SO YOU ONLY GET AN EXPRESSION 1766 01:02:02,552 --> 01:02:04,587 OFF 1 ALLELE AND THERE'S A 1767 01:02:04,654 --> 01:02:06,722 MUTATION, A LOT OF DIFFERENT 1768 01:02:06,789 --> 01:02:09,926 REGIONS, STOPS THE EXPRESSION, 1769 01:02:09,992 --> 01:02:11,494 USUALLY MEDIATED TO K, AND IT 1770 01:02:11,561 --> 01:02:14,130 TURNS OUT THAT THESE HAPLO 1771 01:02:14,197 --> 01:02:15,198 DEFICIENT GENES HAVE MUCH LOWER 1772 01:02:15,264 --> 01:02:17,600 EXPRESSION AND PART OF THAT IS 1773 01:02:17,667 --> 01:02:19,202 BECAUSE THEY'RE DOSE SENSITIVE 1774 01:02:19,268 --> 01:02:21,537 GENES, THEY'RE NOT JUST 1775 01:02:21,604 --> 01:02:23,372 SENSITIVE TO THESE 1776 01:02:23,439 --> 01:02:24,006 INSUFFICIENCIES, THEY ACTUALLY 1777 01:02:24,073 --> 01:02:26,008 OVER EXPRESSION OF THESE YEENS 1778 01:02:26,075 --> 01:02:27,743 AND QUITE DETRIMENTAL SO HOW DO 1779 01:02:27,810 --> 01:02:29,612 WE RESCUE THESE, LIKE IF--HOW DO 1780 01:02:29,679 --> 01:02:32,815 YOU GET THE RIGHT LEVEL OF 1781 01:02:32,882 --> 01:02:33,416 EXPRESSION, KIND OF--YOU KNOW 1782 01:02:33,483 --> 01:02:34,550 YOU HAVE TO BE CONCERNED ABOUT 1783 01:02:34,617 --> 01:02:36,652 THAT SO WE REASONED WITH ALL OF 1784 01:02:36,719 --> 01:02:38,421 OUR ENHANCER MAPS IF WE HIT THE 1785 01:02:38,488 --> 01:02:39,956 RIGHT ENHANCERS WE COULD GET 1786 01:02:40,022 --> 01:02:41,891 SMALL AMOUNTS OF INCREASED 1787 01:02:41,958 --> 01:02:43,092 EXPRESSION, THAT WOULDN'T BE 1788 01:02:43,159 --> 01:02:47,396 TOXIC, WE WOULD BE HITTING THE 1789 01:02:47,463 --> 01:02:48,030 ENDOGENOUS REGULATORY ELEMENTS. 1790 01:02:48,097 --> 01:02:50,700 AND SO THIS IS WORK LED BY 1791 01:02:50,766 --> 01:02:52,435 GEORGE 10, A POST DOC IN THE 1792 01:02:52,502 --> 01:02:55,538 LAB, SO THE IDEA WE USE CRSPR, 1793 01:02:55,605 --> 01:02:59,742 TO BASIC LYE TARGET THE 1794 01:02:59,809 --> 01:03:01,911 REMAINING NONMUTANT ALLELE TO 1795 01:03:01,978 --> 01:03:05,414 TURN JEEP EXPRESSION BACK UP. 1796 01:03:05,481 --> 01:03:06,949 AND THERE'S A LOT OF WORK 1797 01:03:07,016 --> 01:03:07,683 INVOLVED IN THAT, 1 OF THE 1798 01:03:07,750 --> 01:03:09,318 THINGS YOU HAVE TO DO IS YOU 1799 01:03:09,385 --> 01:03:11,354 HAVE TO IDENTIFY ENHANCERS AND 1800 01:03:11,420 --> 01:03:12,755 TEST THEM AND MAKE SURE THEY 1801 01:03:12,822 --> 01:03:14,624 WORK SO AGAIN WE TOOK ALL THOSE 1802 01:03:14,690 --> 01:03:16,359 MAPS THAT WE AND OTHER PEOPLE 1803 01:03:16,425 --> 01:03:18,394 HAD MADE EMPLOY COMBINED THEM, 1804 01:03:18,461 --> 01:03:22,231 DESIGNED MULTIPLE GUIDES TO EACH 1805 01:03:22,298 --> 01:03:24,133 ENHANCER, HAD 3 OR 4 OR 5 1806 01:03:24,200 --> 01:03:25,968 ENHANCERS PER YEEN AND WE 1807 01:03:26,035 --> 01:03:27,537 TARGETED THEM IN CELL CULTURE 1808 01:03:27,603 --> 01:03:30,072 AND WE IDENTIFIED A HANDFUL OF 1809 01:03:30,139 --> 01:03:31,140 GUIDE RNAs THAT WORKED AND WE 1810 01:03:31,207 --> 01:03:33,709 HAVE A WHOLE FLOW WHERE WE DO IT 1811 01:03:33,776 --> 01:03:35,511 FIRST IN PRIMARY NEURAL 1812 01:03:35,578 --> 01:03:36,145 PROGENITORS AND NEURAL 1813 01:03:36,212 --> 01:03:37,280 DEMENTIONS WHICH IS AN EASIER 1814 01:03:37,346 --> 01:03:42,318 THING AND THEN ALSO IN HUMAN, 3 1815 01:03:42,385 --> 01:03:43,853 DIMENSIONAL ORGANOIDS BI PSC 1816 01:03:43,920 --> 01:03:45,588 ORGANOIDS AND THIS IS SHOWING 1817 01:03:45,655 --> 01:03:51,827 FOR 2 MUTATIONS WE GOT FROM 1818 01:03:51,894 --> 01:03:52,995 [INDISCERNIBLE] LAB, THAT 1819 01:03:53,062 --> 01:03:55,631 INDEED, THEY'RE KNOCKED OUT AND 1820 01:03:55,698 --> 01:03:57,600 WHEN WE CRSPR A THEM WE CAN 1821 01:03:57,667 --> 01:04:00,469 RESCUE THE LEVELS BUT THE KEY IS 1822 01:04:00,536 --> 01:04:01,537 PHENOTYPE RESCUE. 1823 01:04:01,604 --> 01:04:03,139 THE REASON WE CHOSE THESE 2 IS 1824 01:04:03,206 --> 01:04:04,707 BECAUSE THEY HAVE WELL 1825 01:04:04,774 --> 01:04:05,741 CHARACTERIZED PHENOTYPES BY 1826 01:04:05,808 --> 01:04:06,142 OTHER PEOPLE. 1827 01:04:06,209 --> 01:04:08,411 ONE MUCH THEM IS DECREASED 1828 01:04:08,477 --> 01:04:10,213 FIRING RATE IN SCN 2 A, AND 1829 01:04:10,279 --> 01:04:14,850 THAT'S WHAT IT LOOKS LIKE 1830 01:04:14,917 --> 01:04:15,851 COMPARED TO CONTROL. 1831 01:04:15,918 --> 01:04:19,388 WHEN WE CHRIS RSPR A AND 1832 01:04:19,455 --> 01:04:23,859 CONTROL, WE'RE ABLE TO RESCUE 1833 01:04:23,926 --> 01:04:25,795 THE YEEN. 1834 01:04:25,861 --> 01:04:26,395 SO THERE'S PROLIFERATION 1835 01:04:26,462 --> 01:04:28,664 PHENOTYPE AND A CELL FEIGNEE 1836 01:04:28,731 --> 01:04:39,275 TYPE SO WE LOOKED AT THOSE WE'RE 1837 01:04:40,309 --> 01:04:41,844 ALSO ABLE TO MEASURE GENE 1838 01:04:41,911 --> 01:04:44,013 EXPRESSION AND SAY ARE WE 1839 01:04:44,080 --> 01:04:45,181 PUSSING GENE EXPRESSION BACK 1840 01:04:45,248 --> 01:04:46,115 TOWARDS WILD-TYPE AND YOU CAN 1841 01:04:46,182 --> 01:04:48,284 SEE THERE THE MUTANT IS ON TOP 1842 01:04:48,351 --> 01:04:55,858 IN YELLOW AND THE CRSPRA AND 1843 01:04:55,925 --> 01:04:57,026 WILD-TYPE ARE TOGETHER. 1844 01:04:57,093 --> 01:04:58,961 MAYBE NOT SURPRISING BAH WE'RE 1845 01:04:59,028 --> 01:05:02,164 ONLY GETTING A 30% INCREASE IN 1846 01:05:02,231 --> 01:05:05,668 THE CHDA ISSUE BUT WE ARE ABLE 1847 01:05:05,735 --> 01:05:07,003 TO RESCUE THE SIZE AND 1848 01:05:07,069 --> 01:05:07,303 PHENOTYPE. 1849 01:05:07,370 --> 01:05:11,407 SO THERE ARE A LOT OF HURDLES A 1850 01:05:11,474 --> 01:05:13,709 LOT OF OBSTACLES FOR IN VIVO 1851 01:05:13,776 --> 01:05:14,543 HUMAN USE AND ET CETERA BUT WE 1852 01:05:14,610 --> 01:05:18,147 THINK THIS IS A PROMISING WAY TO 1853 01:05:18,214 --> 01:05:19,048 THINK ABOUT IT. 1854 01:05:19,115 --> 01:05:22,318 THELING THING WAS TO TALK ABOUT 1855 01:05:22,385 --> 01:05:23,419 AND I APOLOGIZE FOR GOING OVER 1856 01:05:23,486 --> 01:05:25,855 BUT I WAS TOO EXCITED IS HOW 1857 01:05:25,921 --> 01:05:27,323 ABOUT TARGETING THESE CONVERGENT 1858 01:05:27,390 --> 01:05:28,658 PATHWAYS AND A LOT OF THIS HAS 1859 01:05:28,724 --> 01:05:31,227 TO DO WITH FOLKS I SPOKE WITH 1860 01:05:31,294 --> 01:05:33,195 YESTERDAY, PUTTING THIS IN REAR, 1861 01:05:33,262 --> 01:05:34,997 THOSE WITH POLYGENIC RISK OR 1862 01:05:35,064 --> 01:05:36,299 COPY NUMBER VALID AND RELIABLE 1863 01:05:36,365 --> 01:05:37,900 YABTS THAT AFFECT MANY YEENS SO 1864 01:05:37,967 --> 01:05:39,435 WITH SURGERY WE'VE BEEN DOING 1865 01:05:39,502 --> 01:05:41,203 THIS MASSIVE STUDY THAT WAS JUST 1866 01:05:41,270 --> 01:05:43,372 PUT UP ON BIOARCHIVE WITH ALL 1867 01:05:43,439 --> 01:05:45,675 THESE DIFFERENT MONO, KIND OF 1868 01:05:45,741 --> 01:05:47,076 LARGE GENE MOSTLY COPY NUMBER 1869 01:05:47,143 --> 01:05:48,244 VARIANT FORMS OF ACCURACYATISM 1870 01:05:48,311 --> 01:05:50,646 AND ABOUT 10 CASES OF IDIO 1871 01:05:50,713 --> 01:05:53,182 PATHIC AUTISM AND CONTROLS AND 1872 01:05:53,249 --> 01:05:55,384 WE DIFFERENTIATE THEM AT 25, 50, 1873 01:05:55,451 --> 01:05:58,354 75 AND A HUNDRED DAYS, MEASURE 1874 01:05:58,421 --> 01:05:59,288 THEIR TRANSCRIPT OHM, SHOWN ON 1875 01:05:59,355 --> 01:06:02,591 THE LEFT IS EXTREMELY HIGH 1876 01:06:02,658 --> 01:06:03,292 REPRODUCIBILITY, BETWEEN 1877 01:06:03,359 --> 01:06:03,993 DIFFERENT LINEUPS AND DIFFERENT 1878 01:06:04,060 --> 01:06:11,434 INDIVIDUALS WITH THE SAME 1879 01:06:11,500 --> 01:06:12,435 MUTATION, ET CETERA. 1880 01:06:12,501 --> 01:06:15,838 SO WE FOUND SOMETHING 1881 01:06:15,905 --> 01:06:16,138 FASCINATING. 1882 01:06:16,205 --> 01:06:18,107 AT DAY 25 THERE IS EXPRESSION 1883 01:06:18,174 --> 01:06:19,742 BETWEEN MUTANTS AND THERE'S 1884 01:06:19,809 --> 01:06:20,810 CORRELATION BETWEEN MANY OF THEM 1885 01:06:20,876 --> 01:06:22,778 BUT IT'S NOT MASSIVE, BUT AT DAY 1886 01:06:22,845 --> 01:06:23,946 100 THIS IS LAWEDDER DALE IT 1887 01:06:24,013 --> 01:06:24,680 LOOKS LIKE. 1888 01:06:24,747 --> 01:06:29,919 THERE'S KIND OF A MASSIVE--WE 1889 01:06:29,985 --> 01:06:32,088 CALL IT CONVERGENT OR WHAT'S 1890 01:06:32,154 --> 01:06:33,489 OCCURRED SO DEEPT KNOW WHY IT'S 1891 01:06:33,556 --> 01:06:35,024 OCCURRED SO WE STARTED TO ASK 1892 01:06:35,091 --> 01:06:36,425 COULD THERE BE SOMETHING DRIVING 1893 01:06:36,492 --> 01:06:37,226 THIS. 1894 01:06:37,293 --> 01:06:38,861 SO WE LOOKED UPSTREAM OF ALL 1895 01:06:38,928 --> 01:06:40,963 THESE GENES, WE DID A GENE CO 1896 01:06:41,030 --> 01:06:42,598 EXPRESSION ANALYSIS AND WE 1897 01:06:42,665 --> 01:06:43,799 IDENTIFIED A BUNCH OF MODULES 1898 01:06:43,866 --> 01:06:47,103 THAT ARE CHANGING AND WE FOUND 1 1899 01:06:47,169 --> 01:06:48,804 CALLED M5 THAT WAS ENRICHED IN 1900 01:06:48,871 --> 01:06:49,739 TRANSCRIPTION FACTORS AND IN 1901 01:06:49,805 --> 01:06:51,941 FACT THE BINDING SITES OF THOSE 1902 01:06:52,007 --> 01:06:52,675 TRANSCRIPTION FACTORS WERE 1903 01:06:52,742 --> 01:06:55,411 ENRICHED IN THE OTHER MODULES. 1904 01:06:55,478 --> 01:06:58,781 SO WE REASONED THAT MAYBE THIS 1905 01:06:58,848 --> 01:07:00,549 MODULE IS DRIVING THE OTHERS AND 1906 01:07:00,616 --> 01:07:06,889 SO, AGAIN THIS WORK WAS DONE BY 1907 01:07:06,956 --> 01:07:09,892 AARON GORDON AND SE-GIN YOON AND 1908 01:07:09,959 --> 01:07:11,193 LUCY AND THIS IS FASCINATING 1909 01:07:11,260 --> 01:07:13,796 THIS IS SHOWING THE M5 MODULE AT 1910 01:07:13,863 --> 01:07:14,997 THE BEGINNING, I'M SORRY IN THE 1911 01:07:15,064 --> 01:07:16,866 MITTED AND THE OTHERS ARE ON THE 1912 01:07:16,932 --> 01:07:19,602 OUTSIDE, THESE ARE ALL 1913 01:07:19,668 --> 01:07:20,436 ACCURACYATISM RISK GENES, BEING 1914 01:07:20,503 --> 01:07:23,205 DRIVEN BY THE M5 SET OF 1915 01:07:23,272 --> 01:07:24,407 TRANSCRIPTIONAL REG IEWLGTORS, 1916 01:07:24,473 --> 01:07:28,144 MASSIVELY AGAIN ENRICHED AND 1917 01:07:28,210 --> 01:07:28,778 AUTISM RISK GENES. 1918 01:07:28,844 --> 01:07:29,979 AND IN FACT IF YOU THINK ABOUT 1919 01:07:30,045 --> 01:07:32,648 IT FOR THIS TO BE THE DRIVER IT 1920 01:07:32,715 --> 01:07:33,783 WOULD HAVE TO BE EXPRESSED 1921 01:07:33,849 --> 01:07:34,950 EARLIER THAN THE OTHERS AND 1922 01:07:35,017 --> 01:07:38,687 THAT'S WHAT WE SEE, WE SEE THAT 1923 01:07:38,754 --> 01:07:40,923 M5 IS IF YOU LOOK AT THE LIGHT 1924 01:07:40,990 --> 01:07:42,391 BLUE, THAT'S SHOWING EXPRESSION 1925 01:07:42,458 --> 01:07:46,262 AT DWIF AT AS, SO M5 IS A VERY 1926 01:07:46,328 --> 01:07:47,263 EARLY EXPRESSED MODULE. 1927 01:07:47,329 --> 01:07:48,130 MOST YEENS EXPRESSED EARLIER 1928 01:07:48,197 --> 01:07:49,865 THAN THE YEENS IN THE OTHER 1929 01:07:49,932 --> 01:07:52,635 MODULE, SO THIS BECOMES 1930 01:07:52,701 --> 01:07:53,702 PLAUSIBLE THAT BIO-INFORMATICS 1931 01:07:53,769 --> 01:07:56,238 IS TELLING US THAT HE'S MIGHT BE 1932 01:07:56,305 --> 01:07:57,406 REGULATING THOSE YEENS SO WE 1933 01:07:57,473 --> 01:08:02,878 AGAIN, HERE WE HAD TO DO THE 1934 01:08:02,945 --> 01:08:07,216 CRISPR EXPERIMENT IN OUR LAB. 1935 01:08:07,283 --> 01:08:08,584 WE TOO NEUROPROGENITTORS AND 1936 01:08:08,651 --> 01:08:16,559 THIS WAS LED BY JACQUELINE 1937 01:08:16,625 --> 01:08:23,566 MARTIN AND LUCY BICKS, SO WE CUT 1938 01:08:23,632 --> 01:08:24,600 THE GENES AND APPROXIMATELY THEM 1939 01:08:24,667 --> 01:08:26,035 TO THE DIFFERENT GENES, IT WAS 1940 01:08:26,101 --> 01:08:27,436 26 OF THEM AND YOU DO THE 1941 01:08:27,503 --> 01:08:29,205 EXPERIMENT ONCE AND THEN YOU DO 1942 01:08:29,271 --> 01:08:30,706 SINGLE SECURITIES LAWQUENCING 1943 01:08:30,773 --> 01:08:32,208 AND YOU IDENTIFY WHICH CELLS 1944 01:08:32,274 --> 01:08:34,176 HAVE WHICH GUIDE AND WHAT THEIR 1945 01:08:34,243 --> 01:08:34,743 GENE EXPRESSION IS. 1946 01:08:34,810 --> 01:08:36,846 AND 1 THING WE CAN SEE IS THIS 1947 01:08:36,912 --> 01:08:38,781 IS THE EXTENT OF DOWN 1948 01:08:38,848 --> 01:08:39,181 REGULATION. 1949 01:08:39,248 --> 01:08:43,185 WE'RE ABLE TO KNOCK DOWN 80% OF 1950 01:08:43,252 --> 01:08:45,087 THE GENES, AT LEAST 50%, BUT NOT 1951 01:08:45,154 --> 01:08:48,157 ALL OF THEM, SOME OF THEM WERE 1952 01:08:48,224 --> 01:08:49,692 KNOCKED DOWN ABOUT PIRT MORES 1953 01:08:49,758 --> 01:08:51,327 BUT 80% HAD REALLY STRIKING 1954 01:08:51,393 --> 01:08:53,329 KNOCK DOWN SO THIS WORKED, 1955 01:08:53,395 --> 01:08:55,531 THERE'S A WIDE VARIATION IN THE 1956 01:08:55,598 --> 01:08:56,565 AMOUNT OF DOWN STREAM GENES FROM 1957 01:08:56,632 --> 01:08:58,767 EACH OF THESE, SOME OF THESE 1958 01:08:58,834 --> 01:09:00,402 HAVE MINOR EFFECTS, OTHERS HAVE 1959 01:09:00,469 --> 01:09:01,370 HUGE EFFECTS BUT WHAT WE COULD 1960 01:09:01,437 --> 01:09:03,572 SEE WHEN WE ASKED IF THERE WAS 1961 01:09:03,639 --> 01:09:05,407 AN ENRICHMENT IN THE PREDICTED 1962 01:09:05,474 --> 01:09:08,577 TARGET YEENS IN THIS VERY SIMPLE 1963 01:09:08,644 --> 01:09:12,081 NEURONAL SYSTEM, WE GOT VERY 1964 01:09:12,147 --> 01:09:13,916 SIGNIFICANT ENRICHMENT IN 11 OF 1965 01:09:13,983 --> 01:09:14,416 THE 26. 1966 01:09:14,483 --> 01:09:16,418 THIS IS A SIMPLE VALIDATION IN A 1967 01:09:16,485 --> 01:09:18,053 SIMPLE SYSTEM THAT THE 1968 01:09:18,120 --> 01:09:20,122 PREDICTIONS WE'RE MAKING ABOUT 1969 01:09:20,189 --> 01:09:21,056 TRANSCRIPTIONAL REGULATION ARE 1970 01:09:21,123 --> 01:09:25,127 LIKELY TO BE ACTUALLY TRUE. 1971 01:09:25,194 --> 01:09:31,634 SO NOW WE HAVE A NETWORK OF 1972 01:09:31,700 --> 01:09:33,335 GENES THAT ARE DIFFERENT AND SO 1973 01:09:33,402 --> 01:09:35,204 HOW DO WE TARGET IT. 1974 01:09:35,271 --> 01:09:36,505 THIS IS WHERE I WILL END. 1975 01:09:36,572 --> 01:09:39,174 ONE OF THE WAYS TO MATCH THE 1976 01:09:39,241 --> 01:09:40,709 TARGET, IS MATCHING THE GENE 1977 01:09:40,776 --> 01:09:43,445 COMEGZ TO THE CONNECTIVITY MAP, 1978 01:09:43,512 --> 01:09:44,914 THEY HAVE THOUSANDS OF PROFILES 1979 01:09:44,980 --> 01:09:47,683 OF F, DIDA APPROVED DRUGS, SO 1980 01:09:47,750 --> 01:09:49,652 YOU LOOK AT GENE COMEGZ FROM 1981 01:09:49,718 --> 01:09:53,989 YOUR DISEASE MODEL AND YOU MATCH 1982 01:09:54,056 --> 01:09:58,227 IT TO LINETWORK CSCLOUD, AND YOU 1983 01:09:58,294 --> 01:09:59,295 MODIFY THE PATTERN, AND I GET A 1984 01:09:59,361 --> 01:10:01,864 LOT OF PUSH BACK FROM IT BUT I 1985 01:10:01,931 --> 01:10:03,299 THINK IT'S AN INCREDIBLE 1986 01:10:03,365 --> 01:10:04,900 LOAMACYY POWERFUL METHOD. 1987 01:10:04,967 --> 01:10:07,603 YOU IDENTIFY GENE MODULE, YOU 1988 01:10:07,670 --> 01:10:09,505 SCREEN CLUE AND THEN YOU RESCUE 1989 01:10:09,572 --> 01:10:10,372 THE PHENOTYPE. 1990 01:10:10,439 --> 01:10:13,409 WE'VE DONE IN THIS CNS 1991 01:10:13,475 --> 01:10:15,144 REGENERATION WITH CLIFFORD 1992 01:10:15,210 --> 01:10:18,614 WOLF'S LAB IN HARVARD, WE'VE 1993 01:10:18,681 --> 01:10:23,452 DONE IN THIS MOUSE AND INVITRO 1994 01:10:23,519 --> 01:10:24,853 IN NEURODEGENERATIVE TAU-OP A 1995 01:10:24,920 --> 01:10:26,922 THY MODELS AND WE'VE DONE THIS 1996 01:10:26,989 --> 01:10:29,158 MORE RECENTLY TO MODULATE 1997 01:10:29,224 --> 01:10:32,895 MICRODPLIA FUNCTION ASK WE CAN 1998 01:10:32,962 --> 01:10:36,298 MODULATE PHAGOCYTOSIS AS 1999 01:10:36,365 --> 01:10:40,903 PREDICTED BY THE TRANSCRIPT OHM 2000 01:10:40,970 --> 01:10:44,473 NETWORK, DECREASING FATOSTATIN 2001 01:10:44,540 --> 01:10:46,008 INCREASING SO THE KEY HERE IS 2002 01:10:46,075 --> 01:10:48,344 YOU CHARACTERIZE THE NETWORK 2003 01:10:48,410 --> 01:10:48,978 MODULES. 2004 01:10:49,044 --> 01:10:50,212 YOU IDENTIFY DRUGS OR GENES 2005 01:10:50,279 --> 01:10:51,347 PREDICTED TO CHANGE EXPRESSION. 2006 01:10:51,413 --> 01:10:54,950 YOU TEST IF THE PERTURBED 2007 01:10:55,017 --> 01:10:56,085 PROTURBATION DRIVES THE CHANGES 2008 01:10:56,151 --> 01:11:00,923 AND HERE'S THE PROBLEM, IN THE 2009 01:11:00,990 --> 01:11:04,627 TEST IT HAS THE DESIRED 2010 01:11:04,693 --> 01:11:06,462 PHENOTYPE EFFECT, IN 2011 01:11:06,528 --> 01:11:07,730 NEURODEGENERATION, DECREASE 2012 01:11:07,796 --> 01:11:08,697 INFLAMMATION IN CNS 2013 01:11:08,764 --> 01:11:10,232 DEGENERATION, I WANT THEAXON TO 2014 01:11:10,299 --> 01:11:12,768 GROW LONGER AND IN THE 2015 01:11:12,835 --> 01:11:13,335 NEUROPSYCHIATRIC DISEASES, I 2016 01:11:13,402 --> 01:11:14,803 DON'T KNOW WHAT THE PHENOTYPES 2017 01:11:14,870 --> 01:11:19,041 ARE SO THERE'S A HUGE NEED TO DO 2018 01:11:19,108 --> 01:11:20,676 INVITRO TYPE DISCOVERY WHICH WE 2019 01:11:20,743 --> 01:11:21,977 AND OTHER PEOPLE ARE INVOLVED IN 2020 01:11:22,044 --> 01:11:25,414 BUT THAT'S THE MISSING LINK IN 2021 01:11:25,481 --> 01:11:27,449 NEUROPSYCHIATRIC DISORDERS NOW. 2022 01:11:27,516 --> 01:11:30,119 SO HIGH THROUGH PUT METHODS, THE 2023 01:11:30,185 --> 01:11:32,154 BIOLOGY CENTER, STEM CELLS 2024 01:11:32,221 --> 01:11:33,122 MAKING OVER 200 LINES AND WE 2025 01:11:33,188 --> 01:11:35,858 WILL TEST THEM USING HIGH 2026 01:11:35,924 --> 01:11:40,763 THROUGH PUT PHYSIOLOGY DEVELOPED 2027 01:11:40,829 --> 01:11:45,134 BY MY COLLEAGUES AND HIGH 2028 01:11:45,200 --> 01:11:46,035 THROUGH PUT NEUROPHYSIOLOGY AND 2029 01:11:46,101 --> 01:11:49,705 WE THINK WE WILL BE ABLE TO 2030 01:11:49,772 --> 01:11:50,372 IDENTIFY REPRODUCIBLE PHENOTYPES 2031 01:11:50,439 --> 01:11:53,442 THAT COULD BE USED FOR DRUG 2032 01:11:53,509 --> 01:11:54,009 SCREENING. 2033 01:11:54,076 --> 01:11:59,248 SO IN SUMMARY, GENOMIC AND GENE 2034 01:11:59,314 --> 01:12:00,282 NETWORK APPROACHES FOR DEFINING 2035 01:12:00,349 --> 01:12:03,886 POINTS IN THE BRAIN, THEY DEFINE 2036 01:12:03,952 --> 01:12:05,521 BIOLODGE CONVERGENCE, I TOLD YOU 2037 01:12:05,587 --> 01:12:07,056 WHERE THAT CONVERGENCE OCCURS IN 2038 01:12:07,122 --> 01:12:09,491 AUTISM AND THIS OVERLAPS IN THE 2039 01:12:09,558 --> 01:12:12,127 DRIVERS OF THE CHANGES AS WELL 2040 01:12:12,194 --> 01:12:13,462 IN TERMS OF THE GENETIC DRIVERS 2041 01:12:13,529 --> 01:12:15,798 AND I THINK THIS PROVIOLATIONS A 2042 01:12:15,864 --> 01:12:17,332 STARTING POINT, IT'S A BASIC 2043 01:12:17,399 --> 01:12:19,168 FOUNDATION FOR UNDERSTANDING HOW 2044 01:12:19,234 --> 01:12:21,437 GENETIC RISK PROPAGATES ACROSS 2045 01:12:21,503 --> 01:12:22,838 DEVELOPMENT AS WELL AS FOR 2046 01:12:22,905 --> 01:12:24,206 DISEASE MODEL ANDS THERAPEUTIC 2047 01:12:24,273 --> 01:12:24,506 DEVELOPMENT. 2048 01:12:24,573 --> 01:12:26,709 SO I HAVE TO THANK A HUGE LAB. 2049 01:12:26,775 --> 01:12:27,710 I MENTIONED PRETTY MUCH 2050 01:12:27,776 --> 01:12:29,411 EVERYBODY INVOLVED IN THIS. 2051 01:12:29,478 --> 01:12:30,946 PEOPLE WITH THE STARS HAVE GONE 2052 01:12:31,013 --> 01:12:35,951 ON TO SET UP THEIR OWN LABS OR 2053 01:12:36,018 --> 01:12:36,652 NEXT THING. 2054 01:12:36,719 --> 01:12:42,124 AND I HAVE LONG-TERM 2055 01:12:42,191 --> 01:12:45,194 COLLABORATIONS WITH SURGE ROW P 2056 01:12:45,260 --> 01:12:49,098 A SCA'S LAB IN TAN FORD, THOMAS 2057 01:12:49,164 --> 01:12:51,400 WERGE AND HICOLLEAGUES AT 2058 01:12:51,467 --> 01:12:53,135 iPSYCHE IN DENMARK, CLIFFORD 2059 01:12:53,202 --> 01:12:55,771 WOOLF, AND ALL OF THIS, KIND OF 2060 01:12:55,838 --> 01:12:57,406 KREENS WORK IN NEUROAL REPAIR. 2061 01:12:57,473 --> 01:12:58,807 SO AGAIN, AND OUR FUNDING 2062 01:12:58,874 --> 01:13:00,709 SOURCES ARE LISTED THERE, THANKS 2063 01:13:00,776 --> 01:13:01,877 FOR YOUR ATTENTION. 2064 01:13:01,944 --> 01:13:05,547 I REALIZE I'VE GONE QUITE OVER, 2065 01:13:05,614 --> 01:13:05,881 I APOLOGIZE. 2066 01:13:05,948 --> 01:13:16,158 [ APPLAUSE ] 2067 01:13:18,127 --> 01:13:20,095 I GUESS THERE ISN'T TIME FOR ANY 2068 01:13:20,162 --> 01:13:23,332 QUESTIONS 2069 01:13:23,398 --> 01:13:25,200 QUESTIONS BUT I'M HAPPY TO TAKE 2070 01:13:25,267 --> 01:13:25,400 SOME. 2071 01:13:25,467 --> 01:13:27,736 I DON'T WANT ANY DIFFICULT 2072 01:13:27,803 --> 01:13:28,003 QUESTIONS. 2073 01:13:28,070 --> 01:13:28,370 >> THANK YOU. 2074 01:13:28,437 --> 01:13:29,037 ONE QUICK QUESTION. 2075 01:13:29,104 --> 01:13:30,939 I WAS STRUCK BY THE FACT THAT 2076 01:13:31,006 --> 01:13:33,108 THE PRIMARY VISUAL CON'RE CORTEX 2077 01:13:33,175 --> 01:13:35,310 HAD THAT HIGHER CORRELATION SO I 2078 01:13:35,377 --> 01:13:36,745 WAS CURIOUS, DO YOU SEE SIMILAR 2079 01:13:36,812 --> 01:13:38,714 THING FIST YOU LOOK IN DIFFERENT 2080 01:13:38,781 --> 01:13:40,682 CORTICALE REGIONS AND OTHER 2081 01:13:40,749 --> 01:13:42,084 DISEASES, LIKE SCHIZOPHRENIA 2082 01:13:42,151 --> 01:13:42,785 WHICH IS PREDOMINANTLY THOUGHT 2083 01:13:42,851 --> 01:13:45,687 TO BE A FRONTAL LOBE ISSUE, AND 2084 01:13:45,754 --> 01:13:47,656 THEN, TOO, IN THE SCIENCE PAPER, 2085 01:13:47,723 --> 01:13:48,957 MAYBE YOU MENTIONED AND I MISSED 2086 01:13:49,024 --> 01:13:50,926 IT BUT DID YOU COLLECT TISSUE 2087 01:13:50,993 --> 01:13:53,095 FROM THE PRIMARY VISUAL CORTEX 2088 01:13:53,162 --> 01:13:54,897 THERE, AND WAS IT--DO YOU SEE 2089 01:13:54,963 --> 01:13:55,931 THAT SIMILAR EFFECT OR 2090 01:13:55,998 --> 01:13:57,766 CONSISTENT EFFECT WHERE IT HAD 2091 01:13:57,833 --> 01:14:00,102 THE STRONGEST DIFFERENCE IN GENE 2092 01:14:00,169 --> 01:14:00,402 REGULATION. 2093 01:14:00,469 --> 01:14:02,371 >> YEAH, I MEAN I WOULD LO OF TO 2094 01:14:02,437 --> 01:14:03,172 DO THAT STUDY. 2095 01:14:03,238 --> 01:14:05,073 WE'RE NOT FUNDED TO DO THE 2096 01:14:05,140 --> 01:14:06,141 SINGLE CELL ANALYSIS BEYOND WHAT 2097 01:14:06,208 --> 01:14:08,210 WE LOOKED AT IN EVERY STUDY, 2098 01:14:08,277 --> 01:14:10,946 EVEN THE NEW PSYCHE ENCODE 2099 01:14:11,013 --> 01:14:11,980 PACKAGE IS FOCUSING ON 2100 01:14:12,047 --> 01:14:12,748 PREFRONTAL CORTEX. 2101 01:14:12,815 --> 01:14:16,451 THAT'S BEEN THE FOCUS. 2102 01:14:16,518 --> 01:14:21,089 WE'VE LOOKED IN SOME 2103 01:14:21,156 --> 01:14:24,359 NEURODEGENERATIVE DISEASE, PSP, 2104 01:14:24,426 --> 01:14:26,528 PROGRESSIVE SUPERIOR NUCLEAR 2105 01:14:26,595 --> 01:14:28,597 POLICY, ALZHEIMERS AND TEMPORAL 2106 01:14:28,664 --> 01:14:29,998 FRONTAL DEMENTIA, THERE WE SEE 2107 01:14:30,065 --> 01:14:32,434 VISUAL CORTEX EVEN THOUGH 2108 01:14:32,501 --> 01:14:33,468 THERE'S NO TAU PATHOLOGY. 2109 01:14:33,535 --> 01:14:35,637 SO IT IS INTERESTING HOW THESE 2110 01:14:35,704 --> 01:14:38,207 CHANGES ARE PROPAGATING THROUGH 2111 01:14:38,273 --> 01:14:39,875 THE CORTEX ASK WHAT THEY 2112 01:14:39,942 --> 01:14:41,410 ACTUALLY MEAN, THEY'RE GIVING US 2113 01:14:41,476 --> 01:14:42,477 A MA LECULAR PICTURE OF THE 2114 01:14:42,544 --> 01:14:43,779 STATE OF THE TISSUE AND WHY IT'S 2115 01:14:43,846 --> 01:14:47,983 IN THAT STATE, STILL, I THINK IS 2116 01:14:48,050 --> 01:14:48,584 HARD TO UNDERSTAND. 2117 01:14:48,650 --> 01:14:51,987 BUT WE ARE DOING SPATIAL 2118 01:14:52,054 --> 01:14:54,623 TRANSCRIPTOMICS NOW LOOKING AT 2119 01:14:54,690 --> 01:14:56,158 AREA 17-18 BECAUSE THERE ARE A 2120 01:14:56,225 --> 01:14:58,227 LOT OF HYPOTHESIS HAS TO WHY IT 2121 01:14:58,293 --> 01:15:02,464 BEING BE THE EXPANSION OF AREA 4 2122 01:15:02,531 --> 01:15:04,967 OR 3-4 IN PRIMARY VISUAL CORTEX, 2123 01:15:05,033 --> 01:15:08,103 SO WE'RE LOOKING AT 17, 18, 2124 01:15:08,170 --> 01:15:09,304 THALAMUS, VISUAL THALAMUS, WE'RE 2125 01:15:09,371 --> 01:15:11,073 LOOKING AT OTHER SENSORY REGIONS 2126 01:15:11,139 --> 01:15:14,843 TO SEE IF WHAT'S HAPPENING IS 2127 01:15:14,910 --> 01:15:15,878 PRIMARY SENSORY DYSFUNCTION 2128 01:15:15,944 --> 01:15:18,180 WHICH OF COURSE SENSORY MOTOR 2129 01:15:18,247 --> 01:15:19,715 DYSFUNCTION HAS BEEN VERY 2130 01:15:19,781 --> 01:15:21,550 RECOGNIZED BY PATIENTS AND 2131 01:15:21,617 --> 01:15:22,951 FAMILIES BUT VERY 2132 01:15:23,018 --> 01:15:24,353 UNDERRECOGNIZED IN THE 2133 01:15:24,419 --> 01:15:26,121 DIAGNOSTIC RUBRIC RELATED TO 2134 01:15:26,188 --> 01:15:26,555 AUTISM. 2135 01:15:26,622 --> 01:15:32,194 SO THERE ARE A BUNCH OF 2136 01:15:32,261 --> 01:15:32,628 POSSIBILITIES THERE. 2137 01:15:32,694 --> 01:15:34,096 YEAH BUT WE PROFILED VISUAL 2138 01:15:34,162 --> 01:15:35,597 CORTEX BECAUSE WE THOUGHT IT 2139 01:15:35,664 --> 01:15:39,268 WOULD BE UNAFFECTED SO NOT TRUE. 2140 01:15:39,334 --> 01:15:44,273 >> JUST A TERRIFIC TALK. 2141 01:15:44,339 --> 01:15:44,940 REALLY ENJOYED IT. 2142 01:15:45,007 --> 01:15:46,875 SO VOWRSLY THIS IS A 2143 01:15:46,942 --> 01:15:47,676 NEUROLOGICAL DISORDER WHEN YOU 2144 01:15:47,743 --> 01:15:48,777 ARE LOOKING AT THE BRAIN, YOU 2145 01:15:48,844 --> 01:15:50,779 KNOW A LOT OF THESE YEENS ARE 2146 01:15:50,846 --> 01:15:52,314 EXPRESSED ELSEWHERE AT THE SAME 2147 01:15:52,381 --> 01:15:54,049 TIME SO I WAS WONDERING WHETHER 2148 01:15:54,116 --> 01:15:56,518 THERE'S BEEN ANY ATTEMPT TO LOCK 2149 01:15:56,585 --> 01:15:59,054 AT SAY PERIPHERAL BLOOD, 2150 01:15:59,121 --> 01:15:59,888 LEUKOCYTES OR SPINAL FLUID TO 2151 01:15:59,955 --> 01:16:05,093 SEE IF THERE ARE SIMILAR GENE 2152 01:16:05,160 --> 01:16:05,928 DISREGULATIONS OR TRANSCRIPTS 2153 01:16:05,994 --> 01:16:09,665 THAT CAN BE DISEASE SPECIFIC? 2154 01:16:09,731 --> 01:16:13,702 >> YEAH, WE'VE DONE BLOOD. 2155 01:16:13,769 --> 01:16:16,238 I DON'T--AND THE STUDENT IN MY 2156 01:16:16,305 --> 01:16:18,740 LAB WAS HIGHER BY AMAZON TO DO 2157 01:16:18,807 --> 01:16:20,542 MACHINE LEARNING SO WE NEVER 2158 01:16:20,609 --> 01:16:22,477 ENDED UP PUB LIRIM HAJRULLAHUING 2159 01:16:22,544 --> 01:16:24,112 THE PAPER BUT WE'VE DONE 2160 01:16:24,179 --> 01:16:26,782 HUNDREDS OF BLOOD SAMPLES FROM 2161 01:16:26,848 --> 01:16:29,117 SIBLINGS, MATCH SIBLINGS THERE'S 2162 01:16:29,184 --> 01:16:29,885 REALLY NO SUBSTANTIAL SIGNATURE 2163 01:16:29,952 --> 01:16:32,087 THERE, WHAT WE'RE SEEING IS A 2164 01:16:32,154 --> 01:16:33,488 REALLY A MOLECULAR PATHOLOGY. 2165 01:16:33,555 --> 01:16:36,024 IT'S NOT CAUSAL SO IF WE LOOK IN 2166 01:16:36,091 --> 01:16:40,128 BLOOD AT 16 P DELETION OR ANY OF 2167 01:16:40,195 --> 01:16:42,331 THESE CMDs, WE CAN SEE 2168 01:16:42,397 --> 01:16:44,599 UPEAGULATION OF THE CMV IN 2169 01:16:44,666 --> 01:16:46,301 ALMOST ANY TISSUE SO WE CAN 2170 01:16:46,368 --> 01:16:47,936 CAPTURE THAT, THE PRIMARY 2171 01:16:48,003 --> 01:16:50,572 GENETIC LESION, LET'S CALL IT, 2172 01:16:50,639 --> 01:16:53,442 BUT YOU DON'T CAPTURE THE LATER 2173 01:16:53,508 --> 01:16:54,943 KIND OF PATHOPHYSIOLOGY IN THE 2174 01:16:55,010 --> 01:16:56,878 BLOOD YET, WE CERTAINLY HAVEN'T 2175 01:16:56,945 --> 01:16:58,180 SEEN IT WITH TRANSCRIPTOMICS AND 2176 01:16:58,246 --> 01:16:59,915 WE'VE DONE A LOT AND WE SHOULD 2177 01:16:59,982 --> 01:17:01,350 PROBABLY PUT IT SOMEWHERE AT 2178 01:17:01,416 --> 01:17:02,050 SOME POINT. 2179 01:17:02,117 --> 01:17:06,188 IT'S PRETTY OLD NOW. 2180 01:17:06,254 --> 01:17:08,790 BUT WE REALLY DIDN'T FIND 2181 01:17:08,857 --> 01:17:10,759 ANYTHING OF ANY INTEREST, WHAT 2182 01:17:10,826 --> 01:17:14,162 WE DO FIND IS WHEN YOU LOOK AT 2183 01:17:14,229 --> 01:17:15,664 MONOGENIC DISORDERS THAT HAVE 2184 01:17:15,731 --> 01:17:17,265 VERY BIG IMPACTS CAN YOU BEGIN 2185 01:17:17,332 --> 01:17:20,635 TO SEE SOME OF IT PLAYING OUT IN 2186 01:17:20,702 --> 01:17:21,536 THE PERIPHERAL BLOOD. 2187 01:17:21,603 --> 01:17:24,940 >> WHAT ABOUT SPINAL FLUID? 2188 01:17:25,007 --> 01:17:25,540 >> NEVER LOOKED. 2189 01:17:25,607 --> 01:17:29,044 IT'S HARD ENOUGH TO GET CONSENT 2190 01:17:29,111 --> 01:17:31,713 TO TAKE BLOOD OR EVEN SALIVA 2191 01:17:31,780 --> 01:17:35,150 FROM AN AUTISTIC CHILD OR 2192 01:17:35,217 --> 01:17:38,787 ADOLESCENT, AND THE PARENTS AND 2193 01:17:38,854 --> 01:17:42,090 GETTING SPINAL FLUID WOULD BE 2194 01:17:42,157 --> 01:17:42,324 HARD. 2195 01:17:42,391 --> 01:17:45,227 IF IT'S NOT IN THE 2196 01:17:45,293 --> 01:17:47,362 COURSE--ESPECIALLY WITH--RIBs 2197 01:17:47,429 --> 01:17:50,966 AND STUFF, IF THEY'RE IN REGULAR 2198 01:17:51,033 --> 01:17:51,733 CLINICAL CARE. 2199 01:17:51,800 --> 01:17:53,835 IT WOULD CERTAINLY BE 2200 01:17:53,902 --> 01:17:54,403 INTERESTING. 2201 01:17:54,469 --> 01:17:55,404 NOBODY'S LOOKED AT EXOSTUDIES OF 2202 01:17:55,470 --> 01:17:56,038 MULTIPLE ENDOCRINES, THERE ARE A 2203 01:17:56,104 --> 01:17:56,838 LOT OF INTERESTING THINGS 1 2204 01:17:56,905 --> 01:17:57,539 COULD DO. 2205 01:17:57,606 --> 01:17:59,141 I THINK LOOKING AT PROTEOMICS 2206 01:17:59,207 --> 01:18:05,614 MIGHT BE MORE INTERESTING THAN 2207 01:18:05,680 --> 01:18:07,549 THE TRANSCRIPT OHM. 2208 01:18:07,616 --> 01:18:08,450 YEAH? 2209 01:18:08,517 --> 01:18:10,085 >> QUICK QUESTION REGARDING BY O 2210 01:18:10,152 --> 01:18:11,420 INFORMATICS PIPELINE. 2211 01:18:11,486 --> 01:18:13,088 SO THE MODULES YOU'RE REFERRING 2212 01:18:13,155 --> 01:18:17,459 TO THEY'RE DERIVE FRIDAY BULK 2213 01:18:17,526 --> 01:18:19,528 TRANSCRIPTOMIC DATA OR WELL IS A 2214 01:18:19,594 --> 01:18:20,829 SINGLE CELL IMPLEMENTATION FOR 2215 01:18:20,896 --> 01:18:21,963 THAT AS WELL? 2216 01:18:22,030 --> 01:18:25,467 >> YEAH, SO WHAT I'VE SHOWED 2217 01:18:25,534 --> 01:18:28,737 HERE IS VAST MAJORITY OF BULK 2218 01:18:28,804 --> 01:18:31,740 WGCNA, BUT THE HGWGCNA CAN ALSO 2219 01:18:31,807 --> 01:18:33,542 BE AMRIED TO THE SINGLE CELL 2220 01:18:33,608 --> 01:18:36,244 DATA AS WELL. 2221 01:18:36,311 --> 01:18:36,578 YEAH. 2222 01:18:36,645 --> 01:18:42,684 YEAH, SO IT'S ALL JUST--IT'S 2223 01:18:42,751 --> 01:18:43,785 ROBUST RWGCNA. 2224 01:18:43,852 --> 01:18:44,586 >> THANKS. 2225 01:18:44,653 --> 01:18:45,854 NI WANT TO SAY THANK YOU VERY 2226 01:18:45,921 --> 01:18:48,490 MUCH FOR GIVING THE DISTIN 2227 01:18:48,557 --> 01:18:49,558 WISHED SCHOLARRED LEDGE'RE 2228 01:18:49,624 --> 01:18:50,525 LECTOR PREC, WE HAVE SOMETHING 2229 01:18:50,592 --> 01:18:54,696 WE WOULD LIKE TO PRESENT TO YOU 2230 01:18:54,763 --> 01:18:56,631 SO DR. [INDISCERNIBLE] FOR THE 2231 01:18:56,698 --> 01:18:58,233 GREAT TEACHERS,. 2232 01:18:58,300 --> 01:19:02,804 >> OH GREAT. 2233 01:19:02,871 --> 01:19:05,774 >> SO. 2234 01:19:05,841 --> 01:19:07,075 >> SOMETHING ELSE FOR YOU TO 2235 01:19:07,142 --> 01:19:09,945 TAKE HOME, RIGHT IN [LAUGHTER] 2236 01:19:10,011 --> 01:19:12,814 NAS THE NIH MEDICAL EXAMINER 2237 01:19:12,881 --> 01:19:14,516 COMMITTEE CHAIR, I HAVE THE 2238 01:19:14,583 --> 01:19:16,518 HONOR AMONGST ALL THE CLINICAL 2239 01:19:16,585 --> 01:19:18,120 DIRECTORS YOU MET DURING YOUR 2240 01:19:18,186 --> 01:19:20,355 VISIT TO PRESENT YOU WITH THIS, 2241 01:19:20,422 --> 01:19:21,756 THIS IS THE 2024 DISTINGUISHED 2242 01:19:21,823 --> 01:19:24,192 CLINICAL SCHOLAR ASK EDUCATOR IN 2243 01:19:24,259 --> 01:19:24,893 RESIDENCE SO CONGRATULATIONS AND 2244 01:19:24,960 --> 01:19:26,795 THANK YOU FOR YOUR VISITING AND 2245 01:19:26,862 --> 01:19:28,897 IT THANK YOU FOR A WONDERFUL 2246 01:19:28,964 --> 01:19:29,097 TALK. 2247 01:19:29,164 --> 01:19:30,031 NTHANK YOU VERY MUCH. 2248 01:19:30,098 --> 01:19:31,533 IT'S BEAUTIFUL. 2249 01:19:31,600 --> 01:19:31,833 THANK YOU. 2250 01:19:31,900 [ APPLAUSE ]