1 00:00:06,389 --> 00:00:08,124 >> GOOD AFTERNOON AND WELCOME TO 2 00:00:08,124 --> 00:00:12,194 THE WEDNESDAY AFTERNOON LECTURE 3 00:00:12,194 --> 00:00:15,965 SERIES, I'M MICHELLE ANTWON, THE 4 00:00:15,965 --> 00:00:20,870 ACTING CHIEF ON NIAAA TRIPLE 5 00:00:20,870 --> 00:00:23,873 NEURON CIRCUITS AND IT'S MY 6 00:00:23,873 --> 00:00:27,410 HONOR TO INTRODUCE DR. FENG, 7 00:00:27,410 --> 00:00:33,115 DR. FENG HAS CONTRIBUTED TO HOW 8 00:00:33,115 --> 00:00:36,319 NEUROABNORMALITIES CONTRIBUTE TO 9 00:00:36,319 --> 00:00:37,753 NEURODEVELOPMENTAL DISORDERS, 10 00:00:37,753 --> 00:00:43,125 SUCH AS AUTISM, RHETT'S 11 00:00:43,125 --> 00:00:43,893 SYNDROME, PSYCHIATRIC DISORDERS 12 00:00:43,893 --> 00:00:45,094 LIKE SKITS SKITS. 13 00:00:45,094 --> 00:00:46,996 FOR THOSE REMOTING WATCHING WE 14 00:00:46,996 --> 00:00:48,831 ENCOURAGE TO YOU PARTICIPATE IN 15 00:00:48,831 --> 00:00:51,100 THE Q&A SESSION OF TODAY'S 16 00:00:51,100 --> 00:00:51,434 PRESENTATION. 17 00:00:51,434 --> 00:00:53,869 YOU CAN DO SO BY CLICKING ON THE 18 00:00:53,869 --> 00:00:56,505 BUTTON JUST BELOW YOUR VIDEOCAST 19 00:00:56,505 --> 00:00:58,574 WINDOW THAT SAYS SEND LIVE 20 00:00:58,574 --> 00:00:58,908 FEEDBACK. 21 00:00:58,908 --> 00:01:00,042 CLICK ON THAT TYPE IN YOUR NAME 22 00:01:00,042 --> 00:01:01,844 AND QUESTION AND WE WILL RELAY 23 00:01:01,844 --> 00:01:04,513 THIS TO DR. FENG AT THE END OF 24 00:01:04,513 --> 00:01:05,681 HIS LECTURE. 25 00:01:05,681 --> 00:01:06,949 YOU CAN SUBMIT A QUESTION AT ANY 26 00:01:06,949 --> 00:01:09,185 TIME AND I HOPE YOU DO SO. 27 00:01:09,185 --> 00:01:12,855 SO FOR THOSE OF YOU IN 28 00:01:12,855 --> 00:01:13,522 LIPSETT AMPHITHEATRE TODAY, YOU 29 00:01:13,522 --> 00:01:15,858 CAN USE THE MICs ON THE LEFT 30 00:01:15,858 --> 00:01:18,227 AND RIGHT OF THE ROOM TO ASK 31 00:01:18,227 --> 00:01:18,761 QUESTIONS. 32 00:01:18,761 --> 00:01:20,963 ALSO, WE ARE OFFERING CONTINUING 33 00:01:20,963 --> 00:01:24,400 MEDICAL EDUCATION CREDITS FOR 34 00:01:24,400 --> 00:01:24,834 THIS PRESENTATION. 35 00:01:24,834 --> 00:01:28,237 SO THE CME CODE FOR TODAY IS 36 00:01:28,237 --> 00:01:28,437 57683. 37 00:01:28,437 --> 00:01:31,607 I WILL REPEAT THAT IT'S 57683. 38 00:01:31,607 --> 00:01:36,679 OUR OUR SPEAKER TODAY IS 39 00:01:36,679 --> 00:01:37,413 DR. GUOPING FENG, ASSOCIATE 40 00:01:37,413 --> 00:01:39,849 DIRECTOR OF THE Mc GOVERN 41 00:01:39,849 --> 00:01:41,384 INSTITUTE AT THE MASSACHUSETTS 42 00:01:41,384 --> 00:01:42,785 INSTITUTE OF TECHNOLOGY ALSO THE 43 00:01:42,785 --> 00:01:47,590 JAMES W. AND PATRICIA PROFESSOR 44 00:01:47,590 --> 00:01:48,424 IN BRAIN AND COGNITIVE SCIENCES, 45 00:01:48,424 --> 00:01:52,294 HE IS THE DIRECTOR OF THE HOP E. 46 00:01:52,294 --> 00:01:54,897 TAN AND YANG K. LEE CENTER FOR 47 00:01:54,897 --> 00:01:56,098 AUTISM RESEARCH, HE'S A DIRECTOR 48 00:01:56,098 --> 00:01:59,568 OF MODEL SYSTEMS AND 49 00:01:59,568 --> 00:02:03,139 NEUROBIOLOGY AT THE STEME CENTER 50 00:02:03,139 --> 00:02:07,543 FOR RESEARCH AT THE BROAD 51 00:02:07,543 --> 00:02:08,210 INSTITUTE. 52 00:02:08,210 --> 00:02:11,781 DR. FENG, RECEIVED HIS Ph D AT 53 00:02:11,781 --> 00:02:15,317 BUFFALO UNDER THE THESIS MENTOR 54 00:02:15,317 --> 00:02:19,889 OF OF LINDA HALL, WHERE HE 55 00:02:19,889 --> 00:02:22,658 WORKED ON GPC R50 AND 56 00:02:22,658 --> 00:02:23,259 DROSOPHILA. 57 00:02:23,259 --> 00:02:27,063 HE DID A POST DOC WITH JOSH 58 00:02:27,063 --> 00:02:28,164 RACINs AT WASHINGTON SCHOOL OF 59 00:02:28,164 --> 00:02:29,899 MEDICINE WHERE HE CONTINUED TO 60 00:02:29,899 --> 00:02:33,636 HONE AND DEEPEN HIS KNOWLEDGE 61 00:02:33,636 --> 00:02:35,805 ONIN SYNAPTIC FUNCTION ON 62 00:02:35,805 --> 00:02:36,272 INVERTEBRATES. 63 00:02:36,272 --> 00:02:39,708 IN 2001, HE MOVED TO DUKE 64 00:02:39,708 --> 00:02:41,177 UNIVERSITY WHERE HE BECAME AN 65 00:02:41,177 --> 00:02:42,812 ASSIST APT PROCESSOR IN THE 66 00:02:42,812 --> 00:02:46,348 DEPARTMENT OF NEUROBI 67 00:02:46,348 --> 00:02:47,149 ALGORITHMS. 68 00:02:47,149 --> 00:02:49,018 WHILE THERE HE ESTABLISHED A 69 00:02:49,018 --> 00:02:53,389 POWERFUL BLUEPRINT FOR HOW WE AS 70 00:02:53,389 --> 00:02:59,095 NEUROSCIENTISTS CAN USE GENETIC 71 00:02:59,095 --> 00:03:00,563 MODELS TO REPLICATE COMPLEX 72 00:03:00,563 --> 00:03:02,531 HUMAN DISEASES LIKE OBSESSIVE 73 00:03:02,531 --> 00:03:03,766 COMPULSIVE DISORDER AND HE 74 00:03:03,766 --> 00:03:05,701 DEMONSTRATED THAT TREATMENTS 75 00:03:05,701 --> 00:03:07,937 THAT ARE EFFECTIVE IN HUMANS CAN 76 00:03:07,937 --> 00:03:10,272 BE SIMILARLY APPLIED TO REVERSE 77 00:03:10,272 --> 00:03:11,640 THESE SYMPTOMS MODELED IN MICE. 78 00:03:11,640 --> 00:03:14,643 ALTHOUGH HIS WORK ILLUSTRATED 79 00:03:14,643 --> 00:03:18,781 HOW TO ESTABLISH THE CRITICAL 80 00:03:18,781 --> 00:03:20,583 STEPS IN MODELING DISEASE, HE 81 00:03:20,583 --> 00:03:25,254 ESTABLISHED OUR ABILITY TO 82 00:03:25,254 --> 00:03:26,856 PRODUCE FEASIBILITY, 83 00:03:26,856 --> 00:03:27,890 UNSTRUCTURALLIABILITY AND 84 00:03:27,890 --> 00:03:28,791 UNPREDICTABILITY IN MICE. 85 00:03:28,791 --> 00:03:29,925 HIS FRAMEWORK LAY THE FOUNDATION 86 00:03:29,925 --> 00:03:33,796 OF COURSE FOR THE NEXT ESSENTIAL 87 00:03:33,796 --> 00:03:36,198 STEP WHICH IS CONNECTING THE 88 00:03:36,198 --> 00:03:36,999 SPECIFIC NORMAL BEHAVIORIAL 89 00:03:36,999 --> 00:03:40,769 SYMPTOMS TO THE UNDERLYING GENS 90 00:03:40,769 --> 00:03:42,838 AND SYNAPTIC MECHANISMS AND THAT 91 00:03:42,838 --> 00:03:44,039 GROUND BREAKING WORK WAS 92 00:03:44,039 --> 00:03:46,709 PUBLISHED IN NATURE IN 2007 SO 93 00:03:46,709 --> 00:03:47,543 AS A YOUNG GRADUATE STUDENT AT 94 00:03:47,543 --> 00:03:50,546 THE TIME I WAS DEEPLY INSPIRED 95 00:03:50,546 --> 00:03:52,181 BY DR. FENG'S WORK AND I 96 00:03:52,181 --> 00:03:54,416 CONTINUE TO DO SO TODAY AND IN 97 00:03:54,416 --> 00:03:56,285 FACT MANY OF US IN THIS ROOM 98 00:03:56,285 --> 00:04:00,689 CONTINUE TO APPLY DR. FENG'S 99 00:04:00,689 --> 00:04:03,425 STEAP BY STEP STREAMLINE 100 00:04:03,425 --> 00:04:04,760 APPROACH TO TALK ON SOME OF THE 101 00:04:04,760 --> 00:04:06,662 MOST DIFFICULT AND COMPLEX 102 00:04:06,662 --> 00:04:09,331 BIOLOGICAL QUESTIONS IN OUR OWN 103 00:04:09,331 --> 00:04:13,169 WORK TOWARDS UNDERSTANDING DEC 104 00:04:13,169 --> 00:04:15,304 MECHANISM AND IDENTIFYING NEW 105 00:04:15,304 --> 00:04:15,771 TREATMENTS. 106 00:04:15,771 --> 00:04:18,073 IN 2010 DR. FENG JOINED THE 107 00:04:18,073 --> 00:04:20,009 Mc GOVERN INSTITUTE WHERE HE 108 00:04:20,009 --> 00:04:20,609 REMAINS TODAY. 109 00:04:20,609 --> 00:04:23,479 AND SINCE THEN HE FULLY REFINED 110 00:04:23,479 --> 00:04:25,181 HIS ALREADY RIGOROUS FRAMEWORK 111 00:04:25,181 --> 00:04:33,289 TO EXPLORE THE RULE OF MUTATIONS 112 00:04:33,289 --> 00:04:36,725 IN THIS SHENG 3 GENE AND LINKING 113 00:04:36,725 --> 00:04:38,160 BEHAVIORS LIKE AUTISM IN MOUSE 114 00:04:38,160 --> 00:04:39,662 MODELS, HIS RESEARCH ALSO HELPED 115 00:04:39,662 --> 00:04:42,831 AFFIRM A PROMISE OF GENE THERAPY 116 00:04:42,831 --> 00:04:45,734 AS A TREATMENT STRATEGY FOR 117 00:04:45,734 --> 00:04:47,369 NEURODEVELOPMENTAL DISORDERS. 118 00:04:47,369 --> 00:04:50,839 DR. FENG HAS CONTINUED TO PUSH 119 00:04:50,839 --> 00:04:52,808 THE BOUNDARIES OF NEUROSCIENCE 120 00:04:52,808 --> 00:04:55,077 BY EXTENDING HIS RESEARCH 121 00:04:55,077 --> 00:04:56,245 FRAMEWORK TO NONHUMAN PRIMATE 122 00:04:56,245 --> 00:04:57,813 MODELS AND EXCITING AND 123 00:04:57,813 --> 00:05:00,349 AMBITIOUS THAT YOU HEAR MORE 124 00:05:00,349 --> 00:05:01,183 ABOUT IN HIS TALK. 125 00:05:01,183 --> 00:05:04,920 HIS WORK CONTINUES TO SHAPE HOW 126 00:05:04,920 --> 00:05:07,256 WE UNDERSTAND AND TREAT COMPLEX 127 00:05:07,256 --> 00:05:08,924 HUMAN DISEASES. 128 00:05:08,924 --> 00:05:11,460 DR. FENG HAS RECEIVED NUMEROUS 129 00:05:11,460 --> 00:05:12,795 HIGH PROFILE AWARDS ALONG THE 130 00:05:12,795 --> 00:05:16,131 WAY INCLUDING THE Mc KNIGHT 131 00:05:16,131 --> 00:05:17,766 TECHNOLOGICAL INNOVATIONS IN 132 00:05:17,766 --> 00:05:19,668 NEUROSCIENCE AWARD, THE HEART 133 00:05:19,668 --> 00:05:20,769 WELL INDIVIDUAL BIOMEDICAL 134 00:05:20,769 --> 00:05:21,470 RESEARCH AWARD, HE WAS AFTER THE 135 00:05:21,470 --> 00:05:23,505 ACCIDENT LECTED TO THE NATIONAL 136 00:05:23,505 --> 00:05:26,675 ACADEMY OF MEDICINE IN 2003, THE 137 00:05:26,675 --> 00:05:30,512 AMERICAN ACADEMY OF ARTS AND 138 00:05:30,512 --> 00:05:31,814 SCIENCES IN 2019 AND THE 139 00:05:31,814 --> 00:05:35,451 NATIONAL ACADEMY OF SCIENCES IN 140 00:05:35,451 --> 00:05:36,285 2013, IN 2023. 141 00:05:36,285 --> 00:05:40,089 THE TITLE OF DR. FENG'S TALK 142 00:05:40,089 --> 00:05:40,889 TODAY IS DISSECTING 143 00:05:40,889 --> 00:05:42,324 NEUROBIOLOGICAL MECHANISMS OF 144 00:05:42,324 --> 00:05:44,093 ASD FROM GENES TO CIRCUITS. 145 00:05:44,093 --> 00:05:52,501 PLEASE HELP ME WELCOME 146 00:05:52,501 --> 00:05:52,901 DR. GOUPING FENG. 147 00:05:52,901 --> 00:05:53,202 [ APPLAUSE ] 148 00:05:53,202 --> 00:05:55,638 >> THANK YOU MICHELLE FOR A VERY 149 00:05:55,638 --> 00:05:56,538 GENEROUS INTRODUCTION, IT'S A 150 00:05:56,538 --> 00:06:00,276 REAL HONOR TO BE HERE AND TO BE 151 00:06:00,276 --> 00:06:05,648 IN THIS POWER HOUSE OF RESEARCH 152 00:06:05,648 --> 00:06:07,616 AND SINCE I WAS A GRADUATE 153 00:06:07,616 --> 00:06:11,420 STUDENT HERE IN U.S., I ALWAYS 154 00:06:11,420 --> 00:06:14,657 ADMIRED THE UNBELIEVABLE WORK 155 00:06:14,657 --> 00:06:16,692 DONE HERE AND ACTUALLY AT THE 156 00:06:16,692 --> 00:06:18,661 END OF MY TALK, YOU WILL SEE I 157 00:06:18,661 --> 00:06:20,195 STILL FOLLOW SOME OF THE EARLY 158 00:06:20,195 --> 00:06:22,264 DISCOVERIES AND FROM NIH CAMPUS 159 00:06:22,264 --> 00:06:26,235 BECAUSE I'M ALWAYS VERY GRATEFUL 160 00:06:26,235 --> 00:06:27,636 FOR THE NIH SUPPORTING ALL THE 161 00:06:27,636 --> 00:06:29,371 EXTRAMURAL PROGRAMS THAT WE RELY 162 00:06:29,371 --> 00:06:29,738 ON THIS. 163 00:06:29,738 --> 00:06:32,274 I THINK WE ARE MORE AND MORE 164 00:06:32,274 --> 00:06:34,877 NEED THIS AT THIS TIME TO PUSH 165 00:06:34,877 --> 00:06:39,048 OUR RESEARCH INTO BENEFIT OF 166 00:06:39,048 --> 00:06:39,315 PATIENT. 167 00:06:39,315 --> 00:06:41,517 AND TODAY I WILL TALK ABOUT SOME 168 00:06:41,517 --> 00:06:44,887 OTHER RESEARCH AND THINKING HOW 169 00:06:44,887 --> 00:06:46,121 CAN WE USE AND BUILD OUR 170 00:06:46,121 --> 00:06:48,324 RESEARCH IN THE PAST, MANY, MANY 171 00:06:48,324 --> 00:06:51,994 DECADES AND EVENT CRULLLY CAN 172 00:06:51,994 --> 00:06:54,830 POTENTIALLY HELP -- EVENTUALLY 173 00:06:54,830 --> 00:06:56,465 CAN HELP PATIENTS RESOLVE NIH 174 00:06:56,465 --> 00:06:59,168 RESEARCH AND MANY OF OUR 175 00:06:59,168 --> 00:07:03,706 SCIENTISTS GOALS AND ALSO OUR 176 00:07:03,706 --> 00:07:04,807 NEUROSCIENTISTS GOAL. 177 00:07:04,807 --> 00:07:10,346 SO THIS IS MY DISCLOSURE ALREADY 178 00:07:10,346 --> 00:07:13,882 SHOWED BY MICHELLE'S SLIDES SO, 179 00:07:13,882 --> 00:07:16,552 IN THE PAST YOU KNOW 20 YEARS, 180 00:07:16,552 --> 00:07:20,356 MORE OF THE BIGGEST VANCES IN 181 00:07:20,356 --> 00:07:22,791 YOU KNOW BRAIN SCIENCE, BRAIN 182 00:07:22,791 --> 00:07:25,861 DISSEREDDER RESEARCH IS THE 183 00:07:25,861 --> 00:07:27,096 IDENTIFICATION OF RISK GENES 184 00:07:27,096 --> 00:07:30,466 BECAUSE AS A SCIENTIST FOR BRAIN 185 00:07:30,466 --> 00:07:32,000 RESEARCH UNLIKE CANCER WHICH IS 186 00:07:32,000 --> 00:07:33,235 ALSO VERY DIFFICULT PROBLEM, 187 00:07:33,235 --> 00:07:35,871 IT'S VERY HARD FOR US TO GET 188 00:07:35,871 --> 00:07:37,072 LIVE BRAIN TISSUES, THE WHOLE 189 00:07:37,072 --> 00:07:39,041 BRAIN TO STUDY, SO WE HEAVILY 190 00:07:39,041 --> 00:07:41,477 RELY ON ANIMAL MODELS, RIGHT, SO 191 00:07:41,477 --> 00:07:47,116 BE ABLE TO USE ANIMAL MODELS, WE 192 00:07:47,116 --> 00:07:49,017 NEED, YOU KNOW GENETIC MODELS 193 00:07:49,017 --> 00:07:49,985 AND GENETIC INFORMATION IS 1 OF 194 00:07:49,985 --> 00:07:54,156 THE KEY THINGS WE CAN ACTUALLY 195 00:07:54,156 --> 00:07:58,460 ENGINEER AND PUT A HUMAN 196 00:07:58,460 --> 00:08:00,329 MUTATION INTO GENETIC MODELS. 197 00:08:00,329 --> 00:08:03,132 USING AUTISM RISK GENE AS AN 198 00:08:03,132 --> 00:08:04,166 EXAMPLE, WE ACTUALLY HAVE -- LET 199 00:08:04,166 --> 00:08:13,375 ME SEE, I CAN -- SO IN THE PAST 200 00:08:13,375 --> 00:08:15,677 2 DECADES WE HAVE IDENTIFIED 201 00:08:15,677 --> 00:08:17,212 MANY, MANY GROUPS, NOT IN MY 202 00:08:17,212 --> 00:08:20,115 LAB, BUT MANY OTHER GROUPS AND 203 00:08:20,115 --> 00:08:22,584 IDENTIFIED HUNDREDS OF RISK 204 00:08:22,584 --> 00:08:25,154 GENES AS SOME ARE MONOGENIC 205 00:08:25,154 --> 00:08:28,390 CAUSES OF ASD GENES AND WITH 206 00:08:28,390 --> 00:08:31,693 THIS GENETIC INFORMATION, WE CAN 207 00:08:31,693 --> 00:08:33,662 GENERATE WITH NEW TECHNOLOGY 208 00:08:33,662 --> 00:08:34,963 ESPECIALLY GENOME EDITING 209 00:08:34,963 --> 00:08:36,665 TECHNOLOGY, WE CAN GENERATE MANY 210 00:08:36,665 --> 00:08:39,902 KIND OF GENETIC MODELS INCLUDING 211 00:08:39,902 --> 00:08:41,937 CELL MODELS, RODENT MODELS AND 212 00:08:41,937 --> 00:08:44,840 THE PRIMATE MODELS, AND THEN USE 213 00:08:44,840 --> 00:08:48,977 THIS NEW TECHNOLOGIES LIKE 214 00:08:48,977 --> 00:08:52,347 CRISPR, AND YOU KNOW SEX 215 00:08:52,347 --> 00:08:54,082 MANIPULATION AND ESPECIALLY 216 00:08:54,082 --> 00:08:54,950 SINGLE CELL TRANSCRIPTOMIC 217 00:08:54,950 --> 00:08:57,653 ANALYSIS, WE CAN HELP US 218 00:08:57,653 --> 00:08:58,554 UNDERSTAND THE NEUROBIOLOGICAL 219 00:08:58,554 --> 00:08:59,455 MECHANISMS MPLET THE HOPE IS 220 00:08:59,455 --> 00:09:04,159 WITH THIS KIND OF STUDY WE CAN 221 00:09:04,159 --> 00:09:06,261 EVENTUALLY EXPLORE THERAPEUTIC 222 00:09:06,261 --> 00:09:07,696 STRATEGIES. 223 00:09:07,696 --> 00:09:11,767 AND SO FOR ASD FOR EXAMPLE, MANY 224 00:09:11,767 --> 00:09:14,303 OF THE GENES ARE ACTUALLY RISK 225 00:09:14,303 --> 00:09:16,171 GENES AFFECT THE SYNAPSE, PLAY 226 00:09:16,171 --> 00:09:19,208 AN IMPORTANT ROLE IN SYNAPSE 227 00:09:19,208 --> 00:09:20,342 ENVIRONMENTAL FUNCTION AND 228 00:09:20,342 --> 00:09:20,642 PLASTICITY. 229 00:09:20,642 --> 00:09:25,047 THIS IS A SLIDE I BORROWED FROM 230 00:09:25,047 --> 00:09:29,218 THOMAS' REVIEW, AND YOU CAN SEE 231 00:09:29,218 --> 00:09:31,753 FROM THESE EXCITED SYNAPSE, 232 00:09:31,753 --> 00:09:34,122 INHIBITOR SYNAPSE, BROWN ARE THE 233 00:09:34,122 --> 00:09:36,291 PROTEINS AND IMPORTANT FOR 234 00:09:36,291 --> 00:09:37,025 SYNAPTIC FUNCTIONING AND 235 00:09:37,025 --> 00:09:40,863 ENVIRONMENT BUT ALSO RISK GENES 236 00:09:40,863 --> 00:09:42,231 FOR AUTISM. 237 00:09:42,231 --> 00:09:45,667 AND SO MY LAB LIKE MANY LABS ARE 238 00:09:45,667 --> 00:09:46,835 VERY INTERESTED IN THE 239 00:09:46,835 --> 00:09:47,736 ENVIRONMENT, FUNCTION AND 240 00:09:47,736 --> 00:09:52,207 DYSFUNCTION OF THE EXCITED 241 00:09:52,207 --> 00:09:54,676 SYNAPSE ESPECIALLY IN THE 242 00:09:54,676 --> 00:09:56,111 POSTSYNAPTIC SITE, SO IN THE 243 00:09:56,111 --> 00:09:57,379 PAST 3 DECADES HAVE CONTRIBUTED 244 00:09:57,379 --> 00:10:00,449 TO THE UNDERSTANDING OF OUR 245 00:10:00,449 --> 00:10:03,151 MOLECULAR ARCHITECTURE OF 246 00:10:03,151 --> 00:10:04,786 POSTSYNAPTIC DENSITY INCLUDING 247 00:10:04,786 --> 00:10:08,991 MARY KENNEDY, MORGON SHENG, AND 248 00:10:08,991 --> 00:10:10,659 DAVID BREDT, AND MANY OTHER 249 00:10:10,659 --> 00:10:12,361 LABS, I GIST LIST A FEW OF THEM. 250 00:10:12,361 --> 00:10:17,399 SO IN THIS VERY SMALL STRUCTURE, 251 00:10:17,399 --> 00:10:18,667 POSTSYNAPTIC DENSITY, WHICH IS 252 00:10:18,667 --> 00:10:22,871 ABOUT 2 MICRONS AND THE 253 00:10:22,871 --> 00:10:26,174 THICKNESS IS 2-NANOMETERS WE 254 00:10:26,174 --> 00:10:27,142 ACTUALLY IDENTIFIED 1500 TYPE OF 255 00:10:27,142 --> 00:10:28,911 PROTEINS AND THAT'S THE IMPACT, 256 00:10:28,911 --> 00:10:31,613 THAT'S WHY I CALL IT 257 00:10:31,613 --> 00:10:32,714 POSTSYNAPTIC DENSITY, CAN YOU 258 00:10:32,714 --> 00:10:35,117 SEE IT HERE WITHOUT ANY STAINING 259 00:10:35,117 --> 00:10:39,588 AND HOW THESE -- SUCH A 260 00:10:39,588 --> 00:10:41,323 MACROMOLECULAR STRUCTURE IS 261 00:10:41,323 --> 00:10:43,325 ASSEMBLED AND DYNAMICALLY 262 00:10:43,325 --> 00:10:44,459 REGULATED IS ALWAYS AN 263 00:10:44,459 --> 00:10:47,796 INTERESTING PHENOMENA TO MANY OF 264 00:10:47,796 --> 00:10:51,767 US AND ESPECIALLY FOR FULL STUDY 265 00:10:51,767 --> 00:10:52,301 SYNAPSES. 266 00:10:52,301 --> 00:10:54,469 SO FOR THIS ASSEMBLY IS CALLED A 267 00:10:54,469 --> 00:10:55,537 SCAFFOLDING PROTEIN, SO THEY ARE 268 00:10:55,537 --> 00:11:00,609 MORE OF THE SCAFFOLD IS A PS95 269 00:11:00,609 --> 00:11:03,912 SHANK, A SCAFFOLDING, EACH OF 270 00:11:03,912 --> 00:11:04,947 THESE PROTEINS HAVE 271 00:11:04,947 --> 00:11:07,583 PROTEIN-PROTEIN DOMAINS AND WITH 272 00:11:07,583 --> 00:11:08,650 THE PS95 INTERACTING WITH THE 273 00:11:08,650 --> 00:11:10,485 PROTEINS WITH THE MEMBRANE 274 00:11:10,485 --> 00:11:13,055 PROTEINS ON THE POSTSYNAPTIC 275 00:11:13,055 --> 00:11:14,990 SIDE INCLUDING THE AMP O AMD 276 00:11:14,990 --> 00:11:18,293 RECEPTORS AND ION CHANEMS AND 277 00:11:18,293 --> 00:11:19,695 MOLECULES, ON THE OTHER HAND YOU 278 00:11:19,695 --> 00:11:22,230 CAN BRING MANY, MANY SIGNALING 279 00:11:22,230 --> 00:11:24,900 MOLECULES TO THE POSTSYNAPTIC 280 00:11:24,900 --> 00:11:27,536 SITE VERY DYNAMICALLY AND OTHER 281 00:11:27,536 --> 00:11:29,571 WITH SHEK, NOT ONLY BRING THE 282 00:11:29,571 --> 00:11:31,073 SIGNALING MOLECULE TO IT BUT 283 00:11:31,073 --> 00:11:35,911 ALSO IT CAN INTERACT WITH YOU 284 00:11:35,911 --> 00:11:36,845 KNOW CYTOSKELETON INTERACTING 285 00:11:36,845 --> 00:11:37,079 PROTEIN. 286 00:11:37,079 --> 00:11:39,414 SO IT PLAY A ROLE IN NOT ONLY 287 00:11:39,414 --> 00:11:40,816 FUNCTION BUT PLASTICITY BOTH IN 288 00:11:40,816 --> 00:11:42,784 THE SIGNALING AND THE FUNCTIONAL 289 00:11:42,784 --> 00:11:46,088 PLASTICITY BUT ALSO STRUCTURAL 290 00:11:46,088 --> 00:11:46,388 PLASTICITY. 291 00:11:46,388 --> 00:11:48,223 AND SO 1 OF THE PROTEINS, WE ARE 292 00:11:48,223 --> 00:11:50,292 REALLY INTERESTED IN MANY OTHERS 293 00:11:50,292 --> 00:11:55,297 AND ALSO IS THE SHENG, FAMILY OF 294 00:11:55,297 --> 00:11:58,867 PROTEINS, THE SHANK IS A ON THE 295 00:11:58,867 --> 00:12:01,436 POSTSYNAPTIC SITE, THE GLUTEA 296 00:12:01,436 --> 00:12:03,271 MITTERGIC SYNAPSES BUT THE SHANK 297 00:12:03,271 --> 00:12:04,506 MORE IMPORTANTLY SHANK 3 AND THE 298 00:12:04,506 --> 00:12:07,209 MUTATION OF SHANK 3 IS 299 00:12:07,209 --> 00:12:10,012 MONOCLONAL, AND CAUSES SEVERE 300 00:12:10,012 --> 00:12:10,679 AUTISM WITH INTELLECTUAL 301 00:12:10,679 --> 00:12:14,316 DISABILITY AND THIS IS THE MAIN 302 00:12:14,316 --> 00:12:19,488 GENE IN THE DERMA SYNDROME WHICH 303 00:12:19,488 --> 00:12:23,558 IS IDENTIFIED BY DR. FEELIN AND 304 00:12:23,558 --> 00:12:25,861 DR. Mc DERM, AND IT IS 22 Q13, 305 00:12:25,861 --> 00:12:30,232 THIS IS VERY SEVERE, THEY HAVE 306 00:12:30,232 --> 00:12:31,967 HYPOTONIA, DEVELOPMENTAL DELAY, 307 00:12:31,967 --> 00:12:32,934 SEVERE INLECTUAL DISABILITY, 308 00:12:32,934 --> 00:12:39,107 MOST IF NOT ALL PATIENT CANNOT 309 00:12:39,107 --> 00:12:40,776 LIVE INDEPENDENTLY AND THEY ALSO 310 00:12:40,776 --> 00:12:42,477 HAVE IMPAIRED LANGUAGE 311 00:12:42,477 --> 00:12:43,612 DEVELOPMENT AND AUTISM SPECTRUM 312 00:12:43,612 --> 00:12:46,248 FEATURES AND THEY ALSO HAVE MANY 313 00:12:46,248 --> 00:12:52,387 OR CO-MORBIDITY ISSUES INCLUDING 314 00:12:52,387 --> 00:12:54,923 SLEEP DISORDERS AND SEIZURE 315 00:12:54,923 --> 00:12:56,725 ANDOR OIJINALLY BECAUSE THIS WAS 316 00:12:56,725 --> 00:12:57,826 MONOGENIC WE COULD MAKE MODELS 317 00:12:57,826 --> 00:13:00,862 AND THEN TRY TO UNDERSTAND WHAT 318 00:13:00,862 --> 00:13:03,765 IS THE MOLECULAR CHANGE THAT YOU 319 00:13:03,765 --> 00:13:06,201 KNOW WE CAN IDENTIFY THEN WE CAN 320 00:13:06,201 --> 00:13:07,502 DEVELOP A THERAPEUTICS, DRUGS TO 321 00:13:07,502 --> 00:13:10,072 TREAT THIS CONDITION BECAUSE 322 00:13:10,072 --> 00:13:11,006 IT'S SO SEVERE. 323 00:13:11,006 --> 00:13:13,642 SO WE -- 1 OF THE FEATURES OF 324 00:13:13,642 --> 00:13:15,143 THIS GENE IS IT'S HIGHLY 325 00:13:15,143 --> 00:13:17,746 EXPRESSED IN THE TRIT UMKC. 326 00:13:17,746 --> 00:13:19,781 THERE ARE 3 SHANKS AND ONLY 3 327 00:13:19,781 --> 00:13:30,025 SHANKS ARE EXPRESSED IN THE 328 00:13:30,025 --> 00:13:30,392 STRIATUM. 329 00:13:30,392 --> 00:13:31,927 THE DYSFUNCTION HAS BEEN 330 00:13:31,927 --> 00:13:36,498 STRONGLY SMLICATED LIAISON -- 331 00:13:36,498 --> 00:13:37,799 IMPLICATED IN AUTISM AND OTHER 332 00:13:37,799 --> 00:13:39,768 NAWR O LOGIC DISORDERS, I WILL 333 00:13:39,768 --> 00:13:42,070 GO QUICKLY AND SO WE MADE A 334 00:13:42,070 --> 00:13:45,474 KNOCK OUT OF THE SHANK PROTEIN, 335 00:13:45,474 --> 00:13:47,309 YOU KNOCK OUT SHANK 3 AND YOU 336 00:13:47,309 --> 00:13:49,144 LOSE OTHER SYNAPTIC PROTEINS IN 337 00:13:49,144 --> 00:13:51,880 THE SIDE CLUING AS A SCAFFOLDING 338 00:13:51,880 --> 00:13:53,715 PROTEIN AND THE AMPORECEPTORS 339 00:13:53,715 --> 00:13:56,218 AND ALSO AFFECT FUNCTION AND 340 00:13:56,218 --> 00:13:58,153 REDUCE SYNAPTIC TRANSMISSION AND 341 00:13:58,153 --> 00:14:01,490 MOST OF THE MINUTE FREQUENCY AND 342 00:14:01,490 --> 00:14:02,424 BUT ALSO AMPLITUDE. 343 00:14:02,424 --> 00:14:08,263 THEY ALSO AFFECTED A NUMBER OF 344 00:14:08,263 --> 00:14:11,900 SYNAPSES IN THE -- OUT OF THE 345 00:14:11,900 --> 00:14:14,770 SPINE 1S SO WE FOCUS ON THE 346 00:14:14,770 --> 00:14:16,538 SYNAPSES AND THE SPINE IN THE 347 00:14:16,538 --> 00:14:18,740 MEDIAN AND SPINE NEURONS IN THE 348 00:14:18,740 --> 00:14:19,241 STRIATUM. 349 00:14:19,241 --> 00:14:24,146 SO THIS ANIMAL ALSO HAVE MANY 350 00:14:24,146 --> 00:14:25,981 BEHAVIOR IN HOMOZYGOUS KNOCK 351 00:14:25,981 --> 00:14:28,817 OUT, IN PATIENTS ALL 352 00:14:28,817 --> 00:14:30,252 HETEROZYGOUS, BUT IN MICE THEY 353 00:14:30,252 --> 00:14:32,454 HAVE VERY LITTLE PHENOTYPE, WE 354 00:14:32,454 --> 00:14:34,523 USE HOMOZYGOUS TO STUDY THE 355 00:14:34,523 --> 00:14:36,124 FUNCTION OF SHANK 3, THEY ALSO 356 00:14:36,124 --> 00:14:38,493 HAVE VERY ANIMAL BEHAVIOR, 357 00:14:38,493 --> 00:14:39,461 REPETITIVE, COMPULSIVE, THEY ARE 358 00:14:39,461 --> 00:14:41,530 GROOMING THEIR HAIR OFF AND SKIN 359 00:14:41,530 --> 00:14:47,869 OFF AND THEY ALSO HAVE CHAMBER 360 00:14:47,869 --> 00:14:49,871 ASSAYS, AND THEY DEVELOPED THIS 361 00:14:49,871 --> 00:14:54,943 HERE AT NIMH AND ALSO HAVE 362 00:14:54,943 --> 00:14:56,945 SOCIAL INTERACTION DEFICIT, 363 00:14:56,945 --> 00:14:58,213 SENSORY OVERSENSITIVITY, 364 00:14:58,213 --> 00:14:59,114 ANXIETY, REDUCED LOCOMOTION, 365 00:14:59,114 --> 00:15:01,049 IMPAIR THE MOTOR LEARNING, THIS 366 00:15:01,049 --> 00:15:03,985 IS RELATIVE TO AUTISM DISORDER 367 00:15:03,985 --> 00:15:08,757 ANDS COMORBID CONDITIONS SO WE 368 00:15:08,757 --> 00:15:09,891 CAN IDENTIFY CONVERGING 369 00:15:09,891 --> 00:15:11,059 MECHANISMS THAT ALLOW US TO 370 00:15:11,059 --> 00:15:11,760 DEVELOP A DRUG. 371 00:15:11,760 --> 00:15:13,361 SO WE LOOK AT MOLECULAR AND 372 00:15:13,361 --> 00:15:16,398 CELLULAR DEFECT IN THE ANIMALS, 373 00:15:16,398 --> 00:15:17,999 I'M NOT GOING THROUGH ALL THE 374 00:15:17,999 --> 00:15:20,235 STUDIES, I JUST SUMMARIZE WITH 375 00:15:20,235 --> 00:15:20,468 YOU 1. 376 00:15:20,468 --> 00:15:23,538 WHAT WE FOUND IS FOR EACH 377 00:15:23,538 --> 00:15:24,806 PHENOTYPE, THE THERE IS A 378 00:15:24,806 --> 00:15:26,908 DIFFERENT CELL TYPE INVOLVED AND 379 00:15:26,908 --> 00:15:28,310 DIFFERENT DEFECT INVOLVED, SO 380 00:15:28,310 --> 00:15:30,378 FOR EXAMPLE, THE COMPULSIVE 381 00:15:30,378 --> 00:15:33,014 BEHAVIOR, WE FINALLY REDUCE THE 382 00:15:33,014 --> 00:15:34,516 NEURONAL ACTIVITY INTERACTIVE 383 00:15:34,516 --> 00:15:39,454 PATHWAY, AND SPINE NEURON WHICH 384 00:15:39,454 --> 00:15:39,821 IS THE STRIATUM. 385 00:15:39,821 --> 00:15:44,226 IF YOU CORRECT THE DEFECT IN THE 386 00:15:44,226 --> 00:15:46,895 SPINE, YOU CAN CORRECT THE 387 00:15:46,895 --> 00:15:47,996 REPETITIVE GROOMING BEHAVIOR, 388 00:15:47,996 --> 00:15:49,798 AND FOR SOCIAL INTERACTION, MANY 389 00:15:49,798 --> 00:15:52,334 LAB STUDY AND MY LAB STUDIED 390 00:15:52,334 --> 00:15:55,437 WITH A FORMER POST DOC AND FOUND 391 00:15:55,437 --> 00:15:59,474 THAT THE MAIN STUDY REDUCED THE 392 00:15:59,474 --> 00:16:01,710 EXCITED NEURONS IN THE ACC, IT 393 00:16:01,710 --> 00:16:03,478 IS THE CAUSE AT LEAST 1 OF THE 394 00:16:03,478 --> 00:16:05,614 CAUSE OF THE SOCIAL INTERACTION 395 00:16:05,614 --> 00:16:06,948 DEFICIT. 396 00:16:06,948 --> 00:16:10,118 IF YOU INCREASE ACTIVITY OR 397 00:16:10,118 --> 00:16:13,388 KNOCK OUT SHANK 3 ONLY IN THESE 398 00:16:13,388 --> 00:16:14,322 NEURONS YOU CAN PROVIDE DIRECT 399 00:16:14,322 --> 00:16:15,724 EVIDENCE THAT THIS GROUP OF 400 00:16:15,724 --> 00:16:21,463 NEURONS AT LEAST IS INVOLVED IN 401 00:16:21,463 --> 00:16:24,032 THIS SOCIAL INTERACTION DEFICIT. 402 00:16:24,032 --> 00:16:26,468 WE ALSO SAW SENSORY 403 00:16:26,468 --> 00:16:27,402 OVERSENSITIVITY, IN 404 00:16:27,402 --> 00:16:29,204 COLLABORATION WITH CHRIS AT THE 405 00:16:29,204 --> 00:16:31,606 UNIVERSITY, SHOWED THAT 406 00:16:31,606 --> 00:16:32,340 INHIBITING INTERNEURONS IN THE 407 00:16:32,340 --> 00:16:34,142 SOPHISTICATED MAT O SENSORY 408 00:16:34,142 --> 00:16:36,411 TORTEX IS RESPONSIBLE FOR THE 409 00:16:36,411 --> 00:16:37,479 SENSORY OVERSENSITIVITY. 410 00:16:37,479 --> 00:16:41,683 SO PUT THEM ALTOGETHER, THIS IS 411 00:16:41,683 --> 00:16:46,421 A SINGLE MONOGENIC CAUSE, RIGHT? 412 00:16:46,421 --> 00:16:48,924 EVEN FOR MONOGENIC CAUSE, YOU 413 00:16:48,924 --> 00:16:49,891 HAVE DIFFERENT CIRCUITS, 414 00:16:49,891 --> 00:16:51,526 DIFFERENT CELL TYPES IN 415 00:16:51,526 --> 00:16:53,828 DIFFERENT BRAIN REGIONS FOR 416 00:16:53,828 --> 00:16:55,897 DIFFERENT PHENOTYPES AND IMAGINE 417 00:16:55,897 --> 00:16:57,499 THIS IS POLYGENIC AND WE DON'T 418 00:16:57,499 --> 00:16:59,301 KNOW HOW TO MODEL THEM SO IT 419 00:16:59,301 --> 00:17:01,503 SEEMED LIKE IT'S REALLY 420 00:17:01,503 --> 00:17:03,104 DIFFICULT TO IDENTIFY A 421 00:17:03,104 --> 00:17:06,908 CONVERGING MECHANISM FROM MUCH 422 00:17:06,908 --> 00:17:09,544 OF A MODELS OF AUTISM TO FIND A 423 00:17:09,544 --> 00:17:10,478 THERAPEUTIC TARGET. 424 00:17:10,478 --> 00:17:12,013 SO IT'S NOT SURPRISING BECAUSE 425 00:17:12,013 --> 00:17:14,683 FOR SHANK 3 AND MANY OTHERS IT'S 426 00:17:14,683 --> 00:17:17,319 A TRANSLATIONAL REGULATOR THAT 427 00:17:17,319 --> 00:17:20,221 AFFECTS THE GENES BY BOB 428 00:17:20,221 --> 00:17:22,724 DARNEL'S LAB AT THE UNIVERSITY, 429 00:17:22,724 --> 00:17:25,493 AND IDENTIFY X, AND SHOW AT 430 00:17:25,493 --> 00:17:28,964 LEAST 300 GENES ARE AFFECTED BY 431 00:17:28,964 --> 00:17:29,331 TRANSCRIPTION. 432 00:17:29,331 --> 00:17:31,733 SO FOR SHANK 3 IT'S A SCAF OLDER 433 00:17:31,733 --> 00:17:32,334 PEOPLING PROTEIN INTERACTING 434 00:17:32,334 --> 00:17:34,469 WITH MANY DIFFERENT PROTEINS AND 435 00:17:34,469 --> 00:17:36,338 SO IT'S NOT SURPRISING THAT CAN 436 00:17:36,338 --> 00:17:38,974 YOU IMAGINE IN DIFFERENT CELL 437 00:17:38,974 --> 00:17:40,208 TYPES AND DURING DIFFERENT 438 00:17:40,208 --> 00:17:41,710 ENVIRONMENT TIME IT WOULD 439 00:17:41,710 --> 00:17:42,944 REQUIRE DIFFERENT SIGNALING MECH 440 00:17:42,944 --> 00:17:45,914 NIMS, 441 00:17:45,914 --> 00:17:47,182 NIMS -- MECHANISMS, SO IT WILL 442 00:17:47,182 --> 00:17:48,883 BE DIFFICULT TO FIND CONVERGING 443 00:17:48,883 --> 00:17:51,086 MECHANISMS IN MY VIEW, MY LAB 444 00:17:51,086 --> 00:17:53,154 STUDY, MANY OTHER LABS STUDIED 445 00:17:53,154 --> 00:17:54,556 SHOWED THAT THERE ARE MANY 446 00:17:54,556 --> 00:17:55,890 PATHWAYS HAVE BEEN DISRUPTED, SO 447 00:17:55,890 --> 00:18:00,495 THEN THE QUESTION IS, IF IT'S SO 448 00:18:00,495 --> 00:18:04,366 COMPLEX HOW CAN YOU FIND A CELL 449 00:18:04,366 --> 00:18:07,135 TO TARGET THAT WOULD BENEFIT 450 00:18:07,135 --> 00:18:08,336 MANY AUTISTIC KIDS. 451 00:18:08,336 --> 00:18:10,505 SO HOW CAN YOU TREAT ALL 452 00:18:10,505 --> 00:18:12,907 DIFFERENT SYMPTOMS CAUSED BY 453 00:18:12,907 --> 00:18:13,375 DIFFERENT MECHANISMS? 454 00:18:13,375 --> 00:18:15,343 SO THAT MADE US TO THINK ABOUT 455 00:18:15,343 --> 00:18:17,379 THE CHANGE THE STRATEGY AND WE 456 00:18:17,379 --> 00:18:19,647 THINK THAT MANY OF US INCLUDING 457 00:18:19,647 --> 00:18:22,384 MYSELF THINK THERE MAY BE WE USE 458 00:18:22,384 --> 00:18:24,853 DIFFERENT STRATEGIES, FOR THE 459 00:18:24,853 --> 00:18:25,787 MONOGENIC CAUSE, MAYBE GENE 460 00:18:25,787 --> 00:18:27,756 THERAPY WAS THE NEW TECHNOLOGY 461 00:18:27,756 --> 00:18:28,857 ENVIRONMENT, MAYBE THE BEST WAY 462 00:18:28,857 --> 00:18:31,693 OR AT LEAST 1 OF THE BEST WAYS 463 00:18:31,693 --> 00:18:34,429 TO DIRECTLY CORRECT THE GENETIC 464 00:18:34,429 --> 00:18:35,997 DETHAT ACCOUNT BE POTENTIALLY A 465 00:18:35,997 --> 00:18:38,833 CURE FOR THE MONOGENIC 466 00:18:38,833 --> 00:18:40,735 DISORDERS, ON THE OTHER HAND 467 00:18:40,735 --> 00:18:42,470 MOST AUTISM OR MOST ARE NOT 468 00:18:42,470 --> 00:18:44,139 MONOGENIC, THAT ARE NOT 469 00:18:44,139 --> 00:18:46,975 MONOGENIC, THEY ARE CALLED BY 470 00:18:46,975 --> 00:18:48,610 POLYGENIC FACTORS PLUS OTHER 471 00:18:48,610 --> 00:18:49,411 FACTORS INCLUDING ENVIRONMENTAL, 472 00:18:49,411 --> 00:18:52,914 AND MANY RPGHT FACTORS AND 473 00:18:52,914 --> 00:18:53,782 ENVIRONMENTAL, ALL THIS COULD 474 00:18:53,782 --> 00:18:54,582 CONTRIBUTE TO IT. 475 00:18:54,582 --> 00:18:56,684 FOR THIS WE THINK THAT 1 476 00:18:56,684 --> 00:18:59,454 APPROACH COULD BE BY 477 00:18:59,454 --> 00:19:01,890 UNDERSTANDING NEUROSUBSET OF 478 00:19:01,890 --> 00:19:04,092 CAUSE A MOST PARTICULAR 479 00:19:04,092 --> 00:19:04,993 DEBILITATING SYMPTOM AND BY 480 00:19:04,993 --> 00:19:07,195 CORRECTING THAT WE MIGHT BE ABLE 481 00:19:07,195 --> 00:19:09,431 TO DRAMATICALLY IMPROVE THE 482 00:19:09,431 --> 00:19:10,732 BRAIN FUNCTION, BEHAVIOR AND THE 483 00:19:10,732 --> 00:19:11,266 PATIENT'S LIFE. 484 00:19:11,266 --> 00:19:14,402 SO I WILL USE 2 EXAMPLES, I WILL 485 00:19:14,402 --> 00:19:16,204 USE SHANK 3 AS AN EXAMPLE TO 486 00:19:16,204 --> 00:19:18,640 ILLUSTRATE HOW WE MIGHT BE ABLE 487 00:19:18,640 --> 00:19:24,245 TO MAKE A PROGRESS IN THESE 2 488 00:19:24,245 --> 00:19:25,613 FRONTS. 489 00:19:25,613 --> 00:19:26,714 SO NEURAL DEVELOPMENT DISORDER 490 00:19:26,714 --> 00:19:32,620 SUCH AS AUTISM, THEY ARE MAYBE 491 00:19:32,620 --> 00:19:33,254 ENVIRONMENTAL, MAYBE REVERSIBLE, 492 00:19:33,254 --> 00:19:35,557 SO SOME OF THE EARLY WORK, YOU 493 00:19:35,557 --> 00:19:37,592 KNOW LANDMARK WORK BY ANDRIEA 494 00:19:37,592 --> 00:19:40,995 BURG SHOWED THAT IF YOU KNOCK -- 495 00:19:40,995 --> 00:19:43,231 IF YOU PROVIDE THE GENE LATER 496 00:19:43,231 --> 00:19:45,834 ON, IT CAN REVERSE EVERYTHING. 497 00:19:45,834 --> 00:19:47,969 SO I THINK EACH GENE IS 498 00:19:47,969 --> 00:19:48,970 DIFFERENT, DEPENDS WHERE THEY 499 00:19:48,970 --> 00:19:50,038 ARE EXPRESSED AND WHEN THEY ARE 500 00:19:50,038 --> 00:19:51,272 EXPRESSED SO I THINK FOR EACH 501 00:19:51,272 --> 00:19:54,042 GENE WE HAVE TO TEST THEM SO WE 502 00:19:54,042 --> 00:19:56,077 TEST THEM WITH SHANK 3, WE MADE 503 00:19:56,077 --> 00:20:04,052 A MOUSE MODEL THAT USED DOUBLE 504 00:20:04,052 --> 00:20:04,886 FLOX, INCLUDING CODING THE 505 00:20:04,886 --> 00:20:07,355 DOMAIN HAD IS A KEY FUNCTIONAL 506 00:20:07,355 --> 00:20:09,457 DOMAIN IN THE SHAIRCHG 3 PROTEIN 507 00:20:09,457 --> 00:20:12,227 AND SO THESE MICE GREW UP LIKE 508 00:20:12,227 --> 00:20:13,661 KNOCK OUT, THEY HAVE BASICALLY 509 00:20:13,661 --> 00:20:19,868 ALL THE PHENOTYPES I DESCRIBED 510 00:20:19,868 --> 00:20:20,235 BEFORE. 511 00:20:20,235 --> 00:20:27,008 BECAUSE FLOX IS CREE DEPENDENT 512 00:20:27,008 --> 00:20:30,979 YOU CAN USE TAMOXIFEN-CREE CROSS 513 00:20:30,979 --> 00:20:33,882 AND AT WHICH TIME POINT YOU 514 00:20:33,882 --> 00:20:37,385 PROVIDE A FULL SHANK 3 GENE CAN 515 00:20:37,385 --> 00:20:38,119 RESCUE THIS PHENOTYPE. 516 00:20:38,119 --> 00:20:40,588 SO WHAT WE FOUND IS THAT IN 517 00:20:40,588 --> 00:20:42,457 ADDITION, IF YOU TURN UP SHANK 3 518 00:20:42,457 --> 00:20:46,494 GENE BACK ON IN ADULT, YOU CAN 519 00:20:46,494 --> 00:20:51,332 ACTUALLY CORRECT SOME OF THE 520 00:20:51,332 --> 00:20:54,802 DEFECT, SO FOR EXAMPLE, 521 00:20:54,802 --> 00:20:57,005 GROOMING, BEFORE THE TAMOXIFEN, 522 00:20:57,005 --> 00:21:00,775 YOU SKIN OFF, AFTER THE 523 00:21:00,775 --> 00:21:01,809 TAMOXIFEN FEEDING, THE LESION 524 00:21:01,809 --> 00:21:03,344 HEALED THE ONLY DIFFERENCE THE 525 00:21:03,344 --> 00:21:05,713 AIR GROWS BACK WHITE, WE THINK 526 00:21:05,713 --> 00:21:06,948 IT'S RELATED TO TAMOXIFEN, IT'S 527 00:21:06,948 --> 00:21:07,916 A BREAST CANCER DRUG, CAN YOU 528 00:21:07,916 --> 00:21:10,051 SEE SOME OF THE PATIENTS ONLINE, 529 00:21:10,051 --> 00:21:11,819 SOME PATIENTS, OH WHY MY HAIR 530 00:21:11,819 --> 00:21:12,287 BECOME WHITE? 531 00:21:12,287 --> 00:21:16,090 SO YOU CAN SEE THAT THIS CAN BE 532 00:21:16,090 --> 00:21:16,357 REVERSED. 533 00:21:16,357 --> 00:21:18,960 WE ALSO FOUND SURPRISING SOCIAL 534 00:21:18,960 --> 00:21:20,595 INTERACTION ALSO CAN BE 535 00:21:20,595 --> 00:21:22,964 REVERSED, HOWEVER, MANY THINGS 536 00:21:22,964 --> 00:21:25,667 WE CANNOT REVERSE, ANXIETY LIKE 537 00:21:25,667 --> 00:21:27,168 BEHAVIOR, SENSORY 538 00:21:27,168 --> 00:21:30,438 OVERSENSITIVITY, MOTOR DEFECT, 539 00:21:30,438 --> 00:21:32,774 NONE OF THEM WE CAN REVERSE IN 540 00:21:32,774 --> 00:21:33,074 ADULT. 541 00:21:33,074 --> 00:21:36,444 HOW IF YOU TURN ON SHANK 3 GENE, 542 00:21:36,444 --> 00:21:38,446 3 WEEKS POSTNATAL P21 OR 2 WEEKS 543 00:21:38,446 --> 00:21:40,481 YOU CAN REVERSE ALMOST 544 00:21:40,481 --> 00:21:41,683 EVERYTHING, SO THAT -- THERE 545 00:21:41,683 --> 00:21:43,418 MIGHT BE I -- THIS IS CONSISTENT 546 00:21:43,418 --> 00:21:47,422 WITH ALL THE GREATER WORK DONE 547 00:21:47,422 --> 00:21:49,390 BY VIDEO SYSTEM, WHEN DO YOU 548 00:21:49,390 --> 00:21:51,559 CRASS THE CRITICAL PERIOD, 549 00:21:51,559 --> 00:21:52,193 WHETHER IT'S CRITICAL LANGUAGE 550 00:21:52,193 --> 00:21:53,595 OR OTHER THINGS ARE HARDER TO 551 00:21:53,595 --> 00:21:55,196 MODIFY, BUT AT LEAST THIS TELLS, 552 00:21:55,196 --> 00:21:57,665 THERE MIGHT BE A POSTNATAL 553 00:21:57,665 --> 00:22:00,301 WINDOW FOR GENE THERAPY IF YOU 554 00:22:00,301 --> 00:22:02,036 CAN TURN OFF THE GENE WITHIN A 555 00:22:02,036 --> 00:22:03,871 CERTAIN PERIOD OF TIME 556 00:22:03,871 --> 00:22:04,739 POSTINATEALLY, YOU MIGHT BE 557 00:22:04,739 --> 00:22:07,141 CORRECT MOST OF THE THINGS, SO 558 00:22:07,141 --> 00:22:08,910 OF COURSE, FOR HUMAN PATIENT WE 559 00:22:08,910 --> 00:22:10,812 CANNOT USE THIS GENETIC 560 00:22:10,812 --> 00:22:12,714 APPROACH, BUT WE CAN TRY GENE 561 00:22:12,714 --> 00:22:13,014 THERAPY. 562 00:22:13,014 --> 00:22:16,918 SO WE DECIDE TO USE JOON 563 00:22:16,918 --> 00:22:18,286 REPLACEMENT GENE THERAPY, THE 564 00:22:18,286 --> 00:22:23,291 REASON IS MOST PATIENT, AT LEAST 565 00:22:23,291 --> 00:22:24,826 MANY, MANY PATIENT RIGHT NOW 566 00:22:24,826 --> 00:22:26,227 WITH THE GENOME TECHNOLOGY WHICH 567 00:22:26,227 --> 00:22:27,795 HAVE GREAT PROMISES FOR MEDICINE 568 00:22:27,795 --> 00:22:30,531 CANNOT DO THIS EASILY. 569 00:22:30,531 --> 00:22:31,566 AND ALSO, EVEN THE POINT OF 570 00:22:31,566 --> 00:22:34,068 MUTATIONS OVER THE GENE, LIKE 571 00:22:34,068 --> 00:22:35,637 ISSUE MUTATION, THERE'S NOT A 572 00:22:35,637 --> 00:22:36,938 SINGLE MEDIAN ACCOUNT FOR MANY 573 00:22:36,938 --> 00:22:39,040 PATIENTS OR MOST PATIENTS, SO WE 574 00:22:39,040 --> 00:22:40,642 DECIDE WE WANT A SYSTEM THAT 575 00:22:40,642 --> 00:22:43,978 CAN, YOU KNOW TREAT FOR, YOU 576 00:22:43,978 --> 00:22:45,079 KNOW VAST MAJORITY OF THE 577 00:22:45,079 --> 00:22:49,450 PATIENT, AND SO, WE DECIDE TO 578 00:22:49,450 --> 00:22:50,351 USE GENE REPLACEMENT 579 00:22:50,351 --> 00:22:51,619 POSTINATEALLY, BUT RIGHT NOW, 580 00:22:51,619 --> 00:22:55,890 THE MAIN WAY TO DELIVER INTO 581 00:22:55,890 --> 00:22:59,060 GENES INTO THE BRAIN IS USE AAV, 582 00:22:59,060 --> 00:23:01,362 BUT AAV HAS A PACKAGING LIMIT SO 583 00:23:01,362 --> 00:23:04,365 SHANK 3 IS TOO BIG, WAY TOO BIG 584 00:23:04,365 --> 00:23:07,035 FOR AAV SO WE DECIDE TO MAKE A 585 00:23:07,035 --> 00:23:09,270 MINISHAIRCHG 3 WHICH CONTAINS 586 00:23:09,270 --> 00:23:12,874 SOME OF THE MOST IMPORTANT 587 00:23:12,874 --> 00:23:14,709 DOMAINS AND STILL FUNCTIONAL. 588 00:23:14,709 --> 00:23:18,246 SO WE TESTED INVITRO, WE TEST IT 589 00:23:18,246 --> 00:23:21,049 IN VIVO USING PHYSIOLOGY AND 590 00:23:21,049 --> 00:23:22,350 COLOCALIZATION SHOW IT'S STILL 591 00:23:22,350 --> 00:23:25,086 FUNCTIONAL AND THE USE OF BI ONY 592 00:23:25,086 --> 00:23:26,921 CHEMISTRY TO SHOW IT GOES TO 593 00:23:26,921 --> 00:23:27,288 PSD. 594 00:23:27,288 --> 00:23:31,159 SO WITH THIS APPROACH, WE 595 00:23:31,159 --> 00:23:33,394 ACTUALLY USE THE AAV CAPSID THAT 596 00:23:33,394 --> 00:23:37,465 IT CAN PASS BBB, SO CAN YOU DO 597 00:23:37,465 --> 00:23:40,101 IV INJECTION DEVELOPED BY VIVIAN 598 00:23:40,101 --> 00:23:41,803 GRANAD O OUT OF CALTECH, AND 599 00:23:41,803 --> 00:23:44,539 BAND IS NOW AT THE BROAD 600 00:23:44,539 --> 00:23:45,406 INSWORKING WITH COLLEAGUES NOW, 601 00:23:45,406 --> 00:23:48,476 SO WE CAN USE THIS BECAUSE OF 602 00:23:48,476 --> 00:23:51,346 GENE THERAPY WE CAN INJECT AT 603 00:23:51,346 --> 00:23:53,815 DIFFERENT TIME POINT. 604 00:23:53,815 --> 00:23:55,350 POSTINATEAAL 0, P47, P28, AND 605 00:23:55,350 --> 00:23:57,485 THEN YOU WAIT FOR 2 MONTHS AND 606 00:23:57,485 --> 00:23:59,220 YOU DO BIOCHEMICAL TESTS, CAN 607 00:23:59,220 --> 00:24:00,021 YOU DO ELECTROPHYSIOLOGY TESTS 608 00:24:00,021 --> 00:24:01,823 AND YOU CAN DO BEHAVIOR TEST TO 609 00:24:01,823 --> 00:24:04,158 SEE, AT WHICH TIME POINT CAN YOU 610 00:24:04,158 --> 00:24:04,959 RESCUE THEM, SECOND AT WHICH 611 00:24:04,959 --> 00:24:06,661 TIME POINT YOU RESCUE THEM, WHAT 612 00:24:06,661 --> 00:24:09,864 WE FOUND IN ALL THESE TIME 613 00:24:09,864 --> 00:24:12,967 POINT, YOU CAN ALMOST RESCUE, 614 00:24:12,967 --> 00:24:15,870 ALMOST ALL THE PHENOTYPES, VERY 615 00:24:15,870 --> 00:24:16,170 CLEARLY. 616 00:24:16,170 --> 00:24:20,475 SO THIS IS EXAMPLE, SO CORTICALE 617 00:24:20,475 --> 00:24:22,176 SYNAPTIC FUNCTION, THIS IS A 618 00:24:22,176 --> 00:24:25,113 FIELD RECORDING, BLACK IS THE 619 00:24:25,113 --> 00:24:29,350 WILD-TYPE, RED IS THE SHANK 3 620 00:24:29,350 --> 00:24:30,618 INJECTED CAN AAVG, AND THEN THE 621 00:24:30,618 --> 00:24:33,187 BLUE IS THE INJECTED WITH,A,A V 622 00:24:33,187 --> 00:24:39,894 MINISHANK SO CAN YOU SEE THAT 623 00:24:39,894 --> 00:24:41,729 CORTICALE STRATEGIC PLANS ON HAS 624 00:24:41,729 --> 00:24:42,764 FUNCTION, THERE'S NO PREFERENCE 625 00:24:42,764 --> 00:24:46,100 FOR SOCIAL COMPARED TO THE 626 00:24:46,100 --> 00:24:51,539 OBJECT, BUT THE GENE THERAPY 627 00:24:51,539 --> 00:24:52,640 RESCUED THE BEHAVIOR, SO THAT 628 00:24:52,640 --> 00:24:54,242 GAVE US SOME HOPE THAT MAYBE 629 00:24:54,242 --> 00:24:55,777 THIS GENE THERAPY WILL WORK, THE 630 00:24:55,777 --> 00:24:59,714 ISSUE FOR US AT THIS TIME IS TO 631 00:24:59,714 --> 00:25:03,718 MOVE THIS TO HUMANS IS A REAL 632 00:25:03,718 --> 00:25:05,520 CHALLENGE BECAUSE GENE THERAPY 633 00:25:05,520 --> 00:25:06,154 UNLIKE DRUG TESTING. 634 00:25:06,154 --> 00:25:08,022 IF YOU TAKE A DRUG, IT HAS A 635 00:25:08,022 --> 00:25:09,524 SIDE EFFECT, A SEVERE SIDE 636 00:25:09,524 --> 00:25:11,292 EFFECT OR NOT EFFECTIVE, YOU CAN 637 00:25:11,292 --> 00:25:13,361 TOP IT WITH AAV, YOU INJECT IT, 638 00:25:13,361 --> 00:25:18,433 YOU CAN NEVER TAKE IT OUT, SO WE 639 00:25:18,433 --> 00:25:20,968 PROBABLY NEED BETTER MODEL OR AT 640 00:25:20,968 --> 00:25:22,437 LEAST ANOTHER MODEL CLOSER TO 641 00:25:22,437 --> 00:25:24,105 HUMAN TO TEST THEM. 642 00:25:24,105 --> 00:25:26,574 SO WE ALL KNOW MICE ARE GREAT 643 00:25:26,574 --> 00:25:28,142 MODELS FOR BIOMEDICAL RESEARCH, 644 00:25:28,142 --> 00:25:31,145 IT'S EVOLUTIONAL FOR THE PAST 645 00:25:31,145 --> 00:25:33,481 MANY, MANY DECADES BUT THERE ARE 646 00:25:33,481 --> 00:25:34,949 ALSO SIGNIFICANT 647 00:25:34,949 --> 00:25:36,551 DIFFERENCESENTIOUS SPECIALLY NOW 648 00:25:36,551 --> 00:25:40,188 WITH, YOU KNOW, ANATOMICAL 649 00:25:40,188 --> 00:25:40,888 STUDIES, CONNECTIVITY STUDIES 650 00:25:40,888 --> 00:25:42,957 AND A SINGLE CELL STUDIES AND 651 00:25:42,957 --> 00:25:44,926 CELL TYPE OF STUDIES THERE ARE 652 00:25:44,926 --> 00:25:45,793 STILL MANY DIFFERENCES, SO IT 653 00:25:45,793 --> 00:25:48,196 WOULD BE REALLY GOOD FOR US, 654 00:25:48,196 --> 00:25:49,564 ESPECIALLY TO STUDY SOCIAL 655 00:25:49,564 --> 00:25:52,366 COGNITION OR OTHER HIGH 656 00:25:52,366 --> 00:25:53,768 FUNCTIONING, WE HAVE NONHUMAN 657 00:25:53,768 --> 00:25:56,437 PRIMATE MODEL SO THAT TIME WAS 658 00:25:56,437 --> 00:25:57,705 MANY, MANY DONORS AND NOW MORE 659 00:25:57,705 --> 00:25:59,407 RECENTLY WITH THE BRAIN 660 00:25:59,407 --> 00:26:00,875 INITIATIVE AND WE ARE REALLY, 661 00:26:00,875 --> 00:26:03,911 REALLY GRATEFUL FOR THE BRAIN 662 00:26:03,911 --> 00:26:06,614 INITIATIVE ESPECIALENTIALLY AND 663 00:26:06,614 --> 00:26:08,483 WE GENERATE MARMOSET MODEL. 664 00:26:08,483 --> 00:26:10,017 IT'S ANOTHER SMALL NONHUMAN 665 00:26:10,017 --> 00:26:11,152 PRIMATE, A LITTLE MONKEY, 666 00:26:11,152 --> 00:26:18,593 THEY'RE NOT AS CLOSE AS MACAQUES 667 00:26:18,593 --> 00:26:21,195 TO THE HUMANS BUT THEY'RE VERY 668 00:26:21,195 --> 00:26:22,830 SMALL, THEIR REPRODUCTION IS 669 00:26:22,830 --> 00:26:23,764 MUCH FASTER, IT'S ACTUALLY 670 00:26:23,764 --> 00:26:25,433 MATURE IN A ABOUT A YEAR AND A 671 00:26:25,433 --> 00:26:28,202 HELPFUL AND THEY GIVE BIRTH 672 00:26:28,202 --> 00:26:30,204 TWICE A YEAR, THEY EACH GIVE 673 00:26:30,204 --> 00:26:32,406 BIRTH TO TWIN OR TRIPLET, SO IF 674 00:26:32,406 --> 00:26:34,642 YOU WANT A ANIMAL, YOU WANT TO 675 00:26:34,642 --> 00:26:36,410 BREED FAST SO YOU DON'T HAVE TO 676 00:26:36,410 --> 00:26:38,045 WEIGHT FOR 20 YEARS, HAVE YOU A 677 00:26:38,045 --> 00:26:40,448 COLONY YOU CAN STUDY THEM. 678 00:26:40,448 --> 00:26:43,651 SO OUR FIRST MODEL WAS ACTUALLY 679 00:26:43,651 --> 00:26:46,854 SHANK 3 WE MADE A SMALL 680 00:26:46,854 --> 00:26:49,257 CONDITION, HUMAN CONDITION EXON 681 00:26:49,257 --> 00:26:51,759 21 AND WE MADE A SINGLE JEAN 682 00:26:51,759 --> 00:26:55,796 INSERTION WHICH IS COMMONLY 683 00:26:55,796 --> 00:26:57,231 FOUND IN SEVERAL ASD PATIENTS 684 00:26:57,231 --> 00:26:59,901 NOW, THIS IS MOST COMMON IN 685 00:26:59,901 --> 00:27:02,303 SEARCHING FOR SHANK 3 MUTATION 686 00:27:02,303 --> 00:27:03,037 IN PATIENT. 687 00:27:03,037 --> 00:27:06,741 AND SO NOW WE HAVE A SIGNIFICANT 688 00:27:06,741 --> 00:27:10,778 NUMBER OF F1s, THE PURE 689 00:27:10,778 --> 00:27:16,350 HETEROZYGOUS, SO IN MARMOSET WE 690 00:27:16,350 --> 00:27:21,322 STUDY CONDITION, SO THEN THE 691 00:27:21,322 --> 00:27:22,423 OTHER ADVANTAGE IS MARMOSET IS 692 00:27:22,423 --> 00:27:23,724 VERY SMALL ISSUES THE KAINL IS 693 00:27:23,724 --> 00:27:25,793 VERY BIG COMPARED TO BODY SIZE 694 00:27:25,793 --> 00:27:27,962 AND THEY LIVE WITH FAMILY AND 695 00:27:27,962 --> 00:27:30,197 YOU CAN SEE WE DEVELOP A MACHINE 696 00:27:30,197 --> 00:27:31,399 BASED BEHAVIOR TRACKING AND WE 697 00:27:31,399 --> 00:27:32,667 CAN TRACK THEM REALLY WELL, NOW 698 00:27:32,667 --> 00:27:36,404 YOU CAN JUST PUT A CAMERA ON, 699 00:27:36,404 --> 00:27:37,939 YOU CAN TRACK THEM FOR DAYS OR 700 00:27:37,939 --> 00:27:40,408 WEEKS OR MONTH BECAUSE IT'S 701 00:27:40,408 --> 00:27:40,942 AUTOMATED BEHAVIOR 702 00:27:40,942 --> 00:27:41,642 QUANTIFICATION, YOU DON'T HAVE 703 00:27:41,642 --> 00:27:42,910 TO SPEND A LOT OF TIME DOING ALL 704 00:27:42,910 --> 00:27:44,312 THE WORK FOR YOU, RIGHT? 705 00:27:44,312 --> 00:27:47,582 SO I WON'T JUST GIVE A COUPLE 706 00:27:47,582 --> 00:27:48,849 EXAMPLES HOW WE STUDY THEM AND 707 00:27:48,849 --> 00:27:51,519 WHAT DO THEY LOOK LIKE, SO WITH 708 00:27:51,519 --> 00:27:53,187 THIS KIND OF PROGRAM, CAN YOU 709 00:27:53,187 --> 00:27:55,122 TRACK THEIR BEHAVIOR, SO AGAIN, 710 00:27:55,122 --> 00:27:57,425 THERE ARE 2 MARMOSET IN THE HOME 711 00:27:57,425 --> 00:28:00,394 CAGE, ALL THESE STUDIES ARE IN 712 00:28:00,394 --> 00:28:00,962 HOME CAGE. 713 00:28:00,962 --> 00:28:03,130 YOU CAN LOOK AT IT, THEY ARE 714 00:28:03,130 --> 00:28:04,565 FRACTION OF TIME, THEY STAY 715 00:28:04,565 --> 00:28:07,068 TOGETHER, WHICH IS SOCIAL, THEY 716 00:28:07,068 --> 00:28:08,502 GROMEACH OTHER, THEY AT A AND 717 00:28:08,502 --> 00:28:12,740 LOOKING TOGETHER, YOU KNOW LIKE 718 00:28:12,740 --> 00:28:13,341 COORDINATED LOOKING AND JUST 719 00:28:13,341 --> 00:28:14,742 SITTING THERE TO BE FED. 720 00:28:14,742 --> 00:28:16,577 AND ALSO FRACTION TIME THEY ARE 721 00:28:16,577 --> 00:28:20,247 APART FROM EACH OTHER, THEY ARE 722 00:28:20,247 --> 00:28:21,882 RUNNING AROUND, DOING THEIR OWN 723 00:28:21,882 --> 00:28:22,316 TYPE. 724 00:28:22,316 --> 00:28:24,285 AND KIELD TYPE, IF THE 2 ARE 725 00:28:24,285 --> 00:28:26,921 WILD-TYPE, WHETHER IT'S YOUNG 726 00:28:26,921 --> 00:28:29,657 ANIMAL OR ADULT ANIMAL THEY ALSO 727 00:28:29,657 --> 00:28:31,192 HAVE 2 PEAKS, NEAR FROM EACH 728 00:28:31,192 --> 00:28:32,693 OTHER, APART FROM EACH OTHER, 729 00:28:32,693 --> 00:28:34,829 BUT IF IT WAS WITH THE SHANK 3, 730 00:28:34,829 --> 00:28:37,798 WE SEE IS NEAR EACH OTHER, PEAK 731 00:28:37,798 --> 00:28:38,332 IS GONE. 732 00:28:38,332 --> 00:28:39,533 IT'S ALMOST LIKE YOU GO TO A 733 00:28:39,533 --> 00:28:41,802 BAR, YOU WANT TO MEET SOMEONE, 734 00:28:41,802 --> 00:28:43,104 YOU GOTTA DRINK, YOU SIT DOWN 735 00:28:43,104 --> 00:28:46,140 WITH SOMEONE, YOU START TO 736 00:28:46,140 --> 00:28:47,174 TALKING, SOCIAL, IF THAT PERSON 737 00:28:47,174 --> 00:28:48,609 NEVER RESPOND TO YOU, YOU WILL 738 00:28:48,609 --> 00:28:50,177 NOT STAY THERE VERY LONG, YOU 739 00:28:50,177 --> 00:28:52,146 WILL FIND SOMEWHERE ELSE SO IT'S 740 00:28:52,146 --> 00:28:53,047 AN INTERESTING PHENOMENA, YOU 741 00:28:53,047 --> 00:28:55,149 CAN SEE FROM THIS AUTOMATED 742 00:28:55,149 --> 00:28:56,150 BEHAVIOR TRACKING, THERE ARE 743 00:28:56,150 --> 00:28:59,754 MANY OTHER THINGS CAN YOU DO FOR 744 00:28:59,754 --> 00:29:01,222 EXAMPLE, MARMOSET LOVE iPAD, 745 00:29:01,222 --> 00:29:03,324 BUT THEY LOVE iPAD, BUT THEY 746 00:29:03,324 --> 00:29:06,260 LOVE TOUCH PAD, SO THEY ALL GO 747 00:29:06,260 --> 00:29:06,994 IN FRONT. 748 00:29:06,994 --> 00:29:08,496 AND YOU TEACH THEM LEARN, TOUCH 749 00:29:08,496 --> 00:29:11,632 A PARTICULAR SPOT, YOU GET A 750 00:29:11,632 --> 00:29:12,566 REWARD, THEY LOVE MARSHMALLOW, 751 00:29:12,566 --> 00:29:15,803 SO WE GIVE THEM A LITTLE TINY 752 00:29:15,803 --> 00:29:17,038 TINY MARSHMALLOW, AND LET THEM 753 00:29:17,038 --> 00:29:17,938 GO AND TOUCH IT AGAIN. 754 00:29:17,938 --> 00:29:20,341 SO CAN YOU SEE WHEN WE HAVE A 755 00:29:20,341 --> 00:29:22,243 TOUCH PAD IS THE BLUE SQUARE, 756 00:29:22,243 --> 00:29:24,845 THEY ALL STAY IN FRONT WHETHER 757 00:29:24,845 --> 00:29:27,148 IT'S WILD-TYPE OR SHANK 3. 758 00:29:27,148 --> 00:29:29,917 IF YOU CHANGE THIS BLUE SQUARE 759 00:29:29,917 --> 00:29:33,254 TO A MARMOSET IMAGING WILD-TYPE 760 00:29:33,254 --> 00:29:35,056 DOESN'T CARE, MUTANT THEY STAY 761 00:29:35,056 --> 00:29:36,691 BACK MORE, AND THEY STILL WILL 762 00:29:36,691 --> 00:29:37,491 GO GET REWARD BUT THEY DON'T 763 00:29:37,491 --> 00:29:39,026 WANT TO AT A THERE ALL THE TIME 764 00:29:39,026 --> 00:29:41,729 THEY JUST GO THERE SO IT'S A 765 00:29:41,729 --> 00:29:42,296 REALLY INTERESTING PHENOMENA 766 00:29:42,296 --> 00:29:44,632 EVEN THE FACE OF MARMOSET, THEY 767 00:29:44,632 --> 00:29:45,833 DON'T LIKE TO STAY THERE ALL THE 768 00:29:45,833 --> 00:29:46,400 TIME. 769 00:29:46,400 --> 00:29:48,369 AND YOU CAN ALSO TEST IT WITH 770 00:29:48,369 --> 00:29:49,503 ANIMAL, RIGHT? 771 00:29:49,503 --> 00:29:51,772 SO THIS IS SMALL CAGE, PUT IT 772 00:29:51,772 --> 00:29:53,708 INSIDE THE CAGE BECAUSE THEY 773 00:29:53,708 --> 00:29:57,144 CANNOT COME OUT, BUT OH, THE 774 00:29:57,144 --> 00:29:59,213 WILD-TYPE, YOU SEE WILD-TYPE, OH 775 00:29:59,213 --> 00:30:00,848 COME TO LOOK, WHO IS THE NEW 776 00:30:00,848 --> 00:30:02,850 KIDOT BLOCK JUST LIKE HUMAN 777 00:30:02,850 --> 00:30:04,785 BEHAVIOR, AND YOU WANT TO 778 00:30:04,785 --> 00:30:06,454 INVESTIGATE, BUT IF IT'S A 779 00:30:06,454 --> 00:30:09,156 MUTANT MARMOSET, THEY ARE 780 00:30:09,156 --> 00:30:10,891 ACTUALLY REALLY SCARED OF 781 00:30:10,891 --> 00:30:12,493 STRANGER MARMOSETS THEY WILL 782 00:30:12,493 --> 00:30:14,662 SCREAM AND CLIMB ON TOP OF THE 783 00:30:14,662 --> 00:30:14,995 CAGE. 784 00:30:14,995 --> 00:30:17,398 THAT'S USUALLY THEIR SAFE PLACE, 785 00:30:17,398 --> 00:30:21,035 UNLIKE TREES, SO YOU SEE THERE 786 00:30:21,035 --> 00:30:22,703 IS A SIGNIFICANT RESPONSE TO NEW 787 00:30:22,703 --> 00:30:25,139 THINGS INCLUDING NEW NARMA SET. 788 00:30:25,139 --> 00:30:27,575 SO THIS KIND OF ASSAY WE CAN DO 789 00:30:27,575 --> 00:30:29,009 A LOT THIJS, THE RISK OF 790 00:30:29,009 --> 00:30:29,577 BEHOUSTON AND RICE FOOTBALLS 791 00:30:29,577 --> 00:30:31,645 BECAUSE THEY'RE IN THE HOME 792 00:30:31,645 --> 00:30:34,181 CAGE, YOU CAN DO iPAD, 793 00:30:34,181 --> 00:30:35,483 MOTIVATION, SOCIAL, AND YOU CAN 794 00:30:35,483 --> 00:30:37,017 DO A LOT OF THINGS. 795 00:30:37,017 --> 00:30:38,319 AND THEN YOU CAN INDUCE THE 796 00:30:38,319 --> 00:30:40,354 BEHAVIOR, BECAUSE THE MARMOSET 797 00:30:40,354 --> 00:30:41,822 ARE VERY HETEROGENEOUS, THEY ARE 798 00:30:41,822 --> 00:30:46,761 NOT INBRED, THEY ARE COMPLETELY 799 00:30:46,761 --> 00:30:47,661 OUTBRED, WE DO EVERYTHING TO 800 00:30:47,661 --> 00:30:49,430 MAKE SURE THEY ARE NOT INBRED, 801 00:30:49,430 --> 00:30:51,832 SO THE BEHAVIOR IS VERY VARIABLE 802 00:30:51,832 --> 00:30:54,435 JUST LIKE HUMANS BUT WE FOUND 803 00:30:54,435 --> 00:30:56,570 THAT IF YOU DO COMPARE BEFORE 804 00:30:56,570 --> 00:30:58,305 AND AFTER STIMULI, THAT'S THE 805 00:30:58,305 --> 00:30:59,306 MOST ROBUST PHENOTYPE YOU CAN 806 00:30:59,306 --> 00:31:00,674 FIND SO THIS IS ACTUALLY 1 OF 807 00:31:00,674 --> 00:31:03,410 THE MOST IMPORTANT ASSAYS WE DO, 808 00:31:03,410 --> 00:31:06,981 AND YOU CAN DO BASIC FUNCTION 809 00:31:06,981 --> 00:31:08,349 WHETHER IT'S FEEDING, GAIT OR 810 00:31:08,349 --> 00:31:09,483 SLEEPING TIME ALL THE THINGS CAN 811 00:31:09,483 --> 00:31:11,585 YOU DO SO WITH THIS KIND OF 812 00:31:11,585 --> 00:31:15,322 ASSAY, NOW WE CAN TEST WILL YOUR 813 00:31:15,322 --> 00:31:16,490 GENE THERAPY IMPROVE ANY OF 814 00:31:16,490 --> 00:31:17,324 THESE ISSUES. 815 00:31:17,324 --> 00:31:17,758 RIGHT? 816 00:31:17,758 --> 00:31:20,361 SO WE DID THE 2 GROUP GENE 817 00:31:20,361 --> 00:31:20,628 THERAPY. 818 00:31:20,628 --> 00:31:23,097 WE HAVE A LARGE WILD-TYPE 819 00:31:23,097 --> 00:31:24,732 CONTROL WE TRACK THEM FOR LONG, 820 00:31:24,732 --> 00:31:26,333 LONG TIME, SO WE KNOW THE BASE 821 00:31:26,333 --> 00:31:30,504 LINE, AND THEN WE HAVE A GROUP 822 00:31:30,504 --> 00:31:34,141 OF SHANK 3, WITHOUT GENE THERAPY 823 00:31:34,141 --> 00:31:37,411 AND 1 GROUP OF SHANK 3 STARTED 824 00:31:37,411 --> 00:31:39,814 WITH 9 MONTHS, 9 MONTH SYSTEM 825 00:31:39,814 --> 00:31:40,915 ABOUT 10-12 YEAR-OLD KIDS IN 826 00:31:40,915 --> 00:31:42,416 DEVELOPMENT AND THEN WE HAVE 827 00:31:42,416 --> 00:31:45,052 ANOTHER GROUP STARTED WITH 3 828 00:31:45,052 --> 00:31:48,556 MONTHS OLDER, BABY, SO 3 MONTHS 829 00:31:48,556 --> 00:31:50,658 OLDER, ABOUT 3-4 YEARS OLD HUMAN 830 00:31:50,658 --> 00:31:50,858 BABY. 831 00:31:50,858 --> 00:31:52,493 AND THEN WE WAIT FOR 3 MONTHS, 832 00:31:52,493 --> 00:31:54,662 THIS IS THE IV INJECTION, WE 833 00:31:54,662 --> 00:31:56,897 FOUND THAT WITH THE SEPARATE 834 00:31:56,897 --> 00:31:59,400 MARMOSET, WITH IV INJECTION WITH 835 00:31:59,400 --> 00:32:03,003 THIS PARTICULAR CAPSID DEVELOPER 836 00:32:03,003 --> 00:32:04,271 IN COLLABORATION, MOSTLY BY LAB 837 00:32:04,271 --> 00:32:06,140 AT BROAD RIGHT NOW, THIS IS 838 00:32:06,140 --> 00:32:07,541 SPECIFIC TO MARMOSET 839 00:32:07,541 --> 00:32:09,476 UNFORTUNATELY, IT DOESN'T GO 840 00:32:09,476 --> 00:32:10,377 THROUGH EVEN MACAQUES, SO I 841 00:32:10,377 --> 00:32:11,946 DON'T THINK IT WILL WORK WITH 842 00:32:11,946 --> 00:32:13,714 HUMANS BUT IT WORKS REALLY WELL 843 00:32:13,714 --> 00:32:16,617 WITH MARMOSET AND YOU CAN IN 844 00:32:16,617 --> 00:32:20,421 FACT USE THE PROMOTER, AND 845 00:32:20,421 --> 00:32:21,522 AFFECT ABOUT 15-20% NEURONS IN 846 00:32:21,522 --> 00:32:23,924 THE BRAIN WITH IV INJECTION. 847 00:32:23,924 --> 00:32:26,694 SO WE WAITED IF ARE 3 MONTHS AND 848 00:32:26,694 --> 00:32:28,863 THEN EVERY 3 MONTHS WE TESTED 849 00:32:28,863 --> 00:32:30,865 THEIR BEHAVIOR AND WHAT WE FOUND 850 00:32:30,865 --> 00:32:32,800 IS, WE FOUND HOW DO YOU -- 851 00:32:32,800 --> 00:32:35,502 BECAUSE YOU CANNOT USE 20 -- 852 00:32:35,502 --> 00:32:39,974 LIKE MICE, 20 MONKEYS FOR 853 00:32:39,974 --> 00:32:40,641 WILD-TYPE, 20 MONKEYS ARE FOR 854 00:32:40,641 --> 00:32:43,277 GENE THERAPY, SO WE ONLY HAVE 8 855 00:32:43,277 --> 00:32:46,947 MONKEYS, RIGHT, FOR THE GENE 856 00:32:46,947 --> 00:32:48,515 THERAPY, 4 FROM 3 MONTHS, 4 FROM 857 00:32:48,515 --> 00:32:50,084 9 MONTHS, SO WE FOUND THE MOST 858 00:32:50,084 --> 00:32:54,788 ROBUST WAY IS TO COMPARE THEIR 859 00:32:54,788 --> 00:32:56,757 BEHAVIOR TO THEIR CAGE MATE, 860 00:32:56,757 --> 00:32:58,058 WILD-TYPE CAGE MATE BECAUSE 861 00:32:58,058 --> 00:32:59,426 MONKEYS LIVING IN DIFFERENT 862 00:32:59,426 --> 00:33:01,662 ROOMS, DIFFERENT CAGES, IF 1 863 00:33:01,662 --> 00:33:03,230 CAGE MATE IS VERY HYPER AFFECT, 864 00:33:03,230 --> 00:33:04,765 IT WILL AFFECT THE OTHERS, THEY 865 00:33:04,765 --> 00:33:06,901 WILL GET MORE ACTIVE. 866 00:33:06,901 --> 00:33:09,069 AND THEN, IF SOMEONE COME TO 867 00:33:09,069 --> 00:33:10,771 CHANGE THE CAGE, MAKE A NOTICES, 868 00:33:10,771 --> 00:33:12,539 THE WHOLE ROOM WILL BE AFFECTED. 869 00:33:12,539 --> 00:33:14,808 BUT OTHER ROOM WILL NOT BE 870 00:33:14,808 --> 00:33:15,409 AFFECTED. 871 00:33:15,409 --> 00:33:18,078 SO WE FOUND IT'S MOST ROBUST WAY 872 00:33:18,078 --> 00:33:21,582 IS TO SEE THE MONKEY'S BEHAVIOR, 873 00:33:21,582 --> 00:33:23,450 HOW CORRELATED WAS THE WILD-TYPE 874 00:33:23,450 --> 00:33:24,652 CONTROL IN THE SAME CAGE. 875 00:33:24,652 --> 00:33:27,221 SO THESE 2 IN THE SAME CAGE FYOU 876 00:33:27,221 --> 00:33:28,923 LOOK AT BEHAVIOR, VERY LITTLE 877 00:33:28,923 --> 00:33:29,623 DIFFERENCE, WILD-TYPE. 878 00:33:29,623 --> 00:33:31,725 BUT IN THE SAME CAGE IF 1 IS 879 00:33:31,725 --> 00:33:33,093 WILD-TYPE AND 1 IS SHANK 3, CAN 880 00:33:33,093 --> 00:33:34,361 YOU SEE, THEY'RE VERY DIFFERENT, 881 00:33:34,361 --> 00:33:37,531 SO NOW YOU CAN SEE, CAN YOU 882 00:33:37,531 --> 00:33:39,466 REVERSE THIS INTO BECOME LIKE 883 00:33:39,466 --> 00:33:40,000 THIS, RIGHT? 884 00:33:40,000 --> 00:33:42,937 SO WE DID A LOT OF ASSAYS, 885 00:33:42,937 --> 00:33:45,940 TRACKING MANY, MANY HOURS, THIS 886 00:33:45,940 --> 00:33:52,680 IS 5 SOLID SESSIONS ALMOST LIKE 887 00:33:52,680 --> 00:33:54,014 200 QUESTIONS OR NUMBER OF 888 00:33:54,014 --> 00:33:56,483 QUESTIONS AND YOU CLICK ALL THE 889 00:33:56,483 --> 00:33:58,752 THINGS, WHAT WE FOUND IS THIS IS 890 00:33:58,752 --> 00:34:00,587 WILD-TYPE, RIGHT, THEY HAVE 891 00:34:00,587 --> 00:34:01,488 COORDINATION, THEY HAVE 892 00:34:01,488 --> 00:34:03,524 CORRELATION WITH THE WILD-TYPE 893 00:34:03,524 --> 00:34:06,727 CAGE MATE THIS, IS SHANK 3, WAY 894 00:34:06,727 --> 00:34:08,062 LESS CORRELATED BEHAVIOR WITH 895 00:34:08,062 --> 00:34:09,897 THE WILD-TYPE AND GENE THERAPY 896 00:34:09,897 --> 00:34:11,065 AND ACTIVITIES AND PROJECTS 897 00:34:11,065 --> 00:34:12,800 OVERALL YOU CAN IT CORRECTED TO 898 00:34:12,800 --> 00:34:13,233 THE WILD-TYPE LEVEL. 899 00:34:13,233 --> 00:34:14,601 THEN YOU GO AND LOOK AT EACH 900 00:34:14,601 --> 00:34:15,469 INDIVIDUAL BEHAVIOR, WHICH IS 901 00:34:15,469 --> 00:34:16,603 CORRECTED WHICH IS NOT 902 00:34:16,603 --> 00:34:17,805 CORRECTED, SO FROM BEHAVIOR 903 00:34:17,805 --> 00:34:21,642 POINT OF VIEW, YOU CAN SEE FOR 904 00:34:21,642 --> 00:34:23,610 WILD-TYPE, THEY ARE WIDER 905 00:34:23,610 --> 00:34:24,712 SPREAD, FOR MONKEYS WIDER 906 00:34:24,712 --> 00:34:27,281 SPREAD, BUT YOU CAN SEE AVERAGE 907 00:34:27,281 --> 00:34:28,282 ANIMAL THIS, IS TOUCH SCREEN, 908 00:34:28,282 --> 00:34:30,417 RIGHT IN AND THEY ARE LESS 909 00:34:30,417 --> 00:34:31,819 CORRELATE WIDE COMPARED TO 910 00:34:31,819 --> 00:34:34,188 WILD-TYPE, GENE THR 'Y CAN 911 00:34:34,188 --> 00:34:35,589 RESTORE TO WILD-TYPE LEVEL, THIS 912 00:34:35,589 --> 00:34:37,591 IS MA REMEMBERRA SET FACE, SAME 913 00:34:37,591 --> 00:34:38,792 THING GENE THERAPY CAN CORRECT 914 00:34:38,792 --> 00:34:41,328 ON AVERAGE AND THIS IS FOR NOVEL 915 00:34:41,328 --> 00:34:44,365 TOY THIS, IS FOR STRANGER 916 00:34:44,365 --> 00:34:45,699 MARMOSET, YOU SEE THEY CAN ALL 917 00:34:45,699 --> 00:34:46,333 CORRECT THROUGH WILD-TYPE LEVEL 918 00:34:46,333 --> 00:34:49,036 EMPLOY NOW WITH THIS, WE CAN -- 919 00:34:49,036 --> 00:34:51,205 IN MICE WE TRY VERY HARD AND 920 00:34:51,205 --> 00:34:52,473 MANY OTHER LEVELS, MANY OTHER 921 00:34:52,473 --> 00:34:56,777 LAB TRIED TO SEE -- WHETHER YOU 922 00:34:56,777 --> 00:34:57,945 SEE A LEARNING DEFECT IN 923 00:34:57,945 --> 00:35:00,314 MARMOSET, IT WAS HARD TO FIND. 924 00:35:00,314 --> 00:35:01,815 IN OUR ORIGINAL PUBLICATION, WE 925 00:35:01,815 --> 00:35:03,984 SAID OTHER THINGS WE DIDN'T SEE 926 00:35:03,984 --> 00:35:05,552 HOMOZYGOUS, WE DID NOT SEE 927 00:35:05,552 --> 00:35:08,288 LEARNING DEFECT, THAT WAS 928 00:35:08,288 --> 00:35:11,558 PUBLISHED IN OUR PAPER, AND BUT 929 00:35:11,558 --> 00:35:13,594 IN MARMOSET, IT'S HETEROGENEOUS 930 00:35:13,594 --> 00:35:16,930 OR O ZYGOUS, IN HUMANS VERY 931 00:35:16,930 --> 00:35:18,232 SEVERE PROBLEM, THEIR AVERAGE IQ 932 00:35:18,232 --> 00:35:20,634 IS HARD TO MEASURE, 80 OR 90% 933 00:35:20,634 --> 00:35:23,670 PEOPLE YOU CAN'T, BUT THE 1S YOU 934 00:35:23,670 --> 00:35:25,539 CAN MEASURE, THE AVERAGE IQ IS 935 00:35:25,539 --> 00:35:26,040 ABOUT 30 OR 40. 936 00:35:26,040 --> 00:35:27,741 SO IT'S VERY LOW. 937 00:35:27,741 --> 00:35:28,976 SO FOR MARMOSET, WE CAN TEST 938 00:35:28,976 --> 00:35:30,911 WHETHER WE SEE A LEARNING 939 00:35:30,911 --> 00:35:33,547 DEFECT, SO WHAT WE FOUND IS THAT 940 00:35:33,547 --> 00:35:35,115 YOU CAN USE MANY COGNITIVE 941 00:35:35,115 --> 00:35:36,383 TESTING YOU CAN DO LEARNING 942 00:35:36,383 --> 00:35:38,819 DEFECT, SO THIS IS A VERY 943 00:35:38,819 --> 00:35:42,322 SIMPLE, RIGHT? 944 00:35:42,322 --> 00:35:43,457 BASICALLY, YOU KNOW 2-POINT 945 00:35:43,457 --> 00:35:45,292 CHOICE, SO BASICALLY YOU TOUCH 946 00:35:45,292 --> 00:35:46,960 RIGHT PLACE, YOU GET NEW 1, YOU 947 00:35:46,960 --> 00:35:50,998 CAN SEE VERY QUICKLY, WILD-TYPE 948 00:35:50,998 --> 00:35:53,634 MAKE VERY FEW MISTAKES BUT FOR 949 00:35:53,634 --> 00:35:55,636 SHANK 3 WE FOUND 2 PHENOMENA. 950 00:35:55,636 --> 00:35:57,237 ONE IS THEY INSIST TO TOUCH 1 951 00:35:57,237 --> 00:35:58,806 SPOT, LIKE THE MARMOSET WILL 952 00:35:58,806 --> 00:36:01,642 JUST GO THERE AND TOUCH 1 SPOT. 953 00:36:01,642 --> 00:36:04,344 AND SO THEY HAVE -- YOU KNOW 954 00:36:04,344 --> 00:36:06,080 THIS IS JUST 1 -- SO THEN WE 955 00:36:06,080 --> 00:36:07,514 FORCE THEM TO TOUCH MORE, LIKE 956 00:36:07,514 --> 00:36:09,650 IF YOU KEEP THEM SAME PLACE, YOU 957 00:36:09,650 --> 00:36:12,219 DON'T GET REWARD, SO EVEN WITH 958 00:36:12,219 --> 00:36:14,955 THAT, YOU STILL HAVE PREFERENCE 959 00:36:14,955 --> 00:36:15,989 AND LIKE WILD-TYPE, AND THEY 960 00:36:15,989 --> 00:36:19,126 ALSO MAKE A LOT OF MISTAKES, SO 961 00:36:19,126 --> 00:36:21,595 THEY'RE MUCH SLOWER AND ALONG 962 00:36:21,595 --> 00:36:22,996 THE WAY THEY MAKE MISTAKES. 963 00:36:22,996 --> 00:36:25,165 SO CAN YOU VISUALIZE THIS, 964 00:36:25,165 --> 00:36:26,767 BASICALLY THIS IS TOUCH PAD, 965 00:36:26,767 --> 00:36:31,205 THEY HAVE TO TOUCH THIS SPOT TO 966 00:36:31,205 --> 00:36:32,973 GET THE REWARD, WILD-TYPE DO 967 00:36:32,973 --> 00:36:34,608 REALLY WELL, EVERYTHING IN THE 968 00:36:34,608 --> 00:36:36,310 MIDDLE AND THEY TOUCH MANY, MANY 969 00:36:36,310 --> 00:36:36,777 TIMES. 970 00:36:36,777 --> 00:36:37,845 SHANK 3, THEY KNOW THEY NEED TO 971 00:36:37,845 --> 00:36:39,847 TOUCH BUT THEY TOUCH THE SCREEN, 972 00:36:39,847 --> 00:36:41,715 THEY DON'T UNDERSTAND YOU HAVE 973 00:36:41,715 --> 00:36:43,016 TO TOUCH IT HERE AND YOU HAVE TO 974 00:36:43,016 --> 00:36:45,052 TOUCH IT LESS TIMES SO LESS 975 00:36:45,052 --> 00:36:47,121 TRIALS BUT WITH GENE THERAPY, 976 00:36:47,121 --> 00:36:48,655 YOU MOVE ALMOST MOST OF THIS 977 00:36:48,655 --> 00:36:50,691 INTO THE MITSD SO THAT YOU CAN 978 00:36:50,691 --> 00:36:52,926 CORRECT THIS KIND OF DEFECT, SO 979 00:36:52,926 --> 00:36:56,363 TO US, EVEN MORE INTERESTING TO 980 00:36:56,363 --> 00:36:58,565 LOOK AT SEX LEVEL CHANGES 981 00:36:58,565 --> 00:37:06,640 BECAUSE IF YOU CAN PERMEATE THE 982 00:37:06,640 --> 00:37:10,177 SECTION, YOU CAN REDICT THE 983 00:37:10,177 --> 00:37:12,713 REWARD, THIS IS RESTING STATE 984 00:37:12,713 --> 00:37:17,651 FUNCTIONAL MRI, SO IF YOU 985 00:37:17,651 --> 00:37:19,319 COMPARE THE LOCAL FUNCTIONAL 986 00:37:19,319 --> 00:37:21,355 CONNECTIVITY AND YOU CAN SEE 987 00:37:21,355 --> 00:37:25,692 THIS IS SUBTRACTION, WILD-TYPE 988 00:37:25,692 --> 00:37:28,462 FROM THE SHANK 3, RED MEANS 989 00:37:28,462 --> 00:37:30,097 HIGHER, BLUE MEANS MUTANT IS 990 00:37:30,097 --> 00:37:33,200 HIGHER, SO IN GENERAL WE HAVE 991 00:37:33,200 --> 00:37:36,170 FEELING FRONT CORTEX ACTIVITY IN 992 00:37:36,170 --> 00:37:39,239 THE SHANK 3 MARMOSET IS LOWER IN 993 00:37:39,239 --> 00:37:41,008 SHANK 3 BUT THE OTHER PART IS 994 00:37:41,008 --> 00:37:45,879 HIGHER IN SHANK 3, BUT IF YOU DO 995 00:37:45,879 --> 00:37:47,814 STATISTICAL ANALYSIS, THE STEADY 996 00:37:47,814 --> 00:37:49,249 SIGNIFICANCE IS PART OF THE 997 00:37:49,249 --> 00:37:50,817 REDUCED ACTIVITY AND REDUCED 998 00:37:50,817 --> 00:37:52,186 FUNCTIONAL ACTIVITY IS VERY 999 00:37:52,186 --> 00:37:53,587 SIGNIFICANT, AND SO YOU CAN USE 1000 00:37:53,587 --> 00:37:57,024 DIFFERENT VIEWS AND THIS WAS 1001 00:37:57,024 --> 00:37:59,159 INCOLLABORATION WITH FRED AND 1002 00:37:59,159 --> 00:38:00,994 BOB'S LAB, AND WITH THE GENE 1003 00:38:00,994 --> 00:38:03,931 THERAPY, YOU CAN SEE, THIS IS -- 1004 00:38:03,931 --> 00:38:06,833 I JUST SHOW YOU IF YOU COMPARE 1005 00:38:06,833 --> 00:38:08,235 WILD-TYPE WITH GENE THERAPY, 1006 00:38:08,235 --> 00:38:09,436 SHANK 3 GENE THERAPY, YOU SEE 1007 00:38:09,436 --> 00:38:10,137 THE DIFFERENCE IS GONE. 1008 00:38:10,137 --> 00:38:12,573 SO CAN YOU SEE THAT NOT ONLY IT 1009 00:38:12,573 --> 00:38:14,007 CAN CHANGE THE CORRECTED 1010 00:38:14,007 --> 00:38:16,577 BEHAVIOR, BUT IT CAN ALSO 1011 00:38:16,577 --> 00:38:18,679 CORRECT THE RESTING STATE 1012 00:38:18,679 --> 00:38:20,047 FUNCTIONAL CONNECTIVITY IN THIS 1013 00:38:20,047 --> 00:38:22,282 ANNUAL, WHETHER IT'S LOCAL 1014 00:38:22,282 --> 00:38:24,017 FUNCTIONAL CONNECTIVITY OR 1015 00:38:24,017 --> 00:38:24,651 GLOBAL FUNCTIONAL CONNECTIVITY. 1016 00:38:24,651 --> 00:38:27,688 SO YOU CAN SEE, SO WE'RE REALLY 1017 00:38:27,688 --> 00:38:29,489 EXCITED ABOUT THIS KIND -- SO 1018 00:38:29,489 --> 00:38:31,058 WITH THIS POST MOUSE AND THE 1019 00:38:31,058 --> 00:38:32,459 MONKEY STUDY, THIS THING IS NOT 1020 00:38:32,459 --> 00:38:34,861 IN CLINICAL TRIAL, ACTUALLY, 1021 00:38:34,861 --> 00:38:36,897 THEY JUST DOSED FIRST PATIENT IN 1022 00:38:36,897 --> 00:38:38,232 FEBRUARY, SO WE DON'T KNOW 1023 00:38:38,232 --> 00:38:40,033 RESULT AND THE HOPE IS THIS WILL 1024 00:38:40,033 --> 00:38:41,401 REALLY HELP PATIENT IN THE LONG 1025 00:38:41,401 --> 00:38:42,769 RUN. 1026 00:38:42,769 --> 00:38:45,439 THIS IS THE FIRST TRY OF THE 1027 00:38:45,439 --> 00:38:48,375 GENE THERAPY FOR THE SHANK 3 AND 1028 00:38:48,375 --> 00:38:50,877 WE'RE HOPING WITH THE CLINICAL 1029 00:38:50,877 --> 00:38:52,179 FEEDBACK, IT IS EFFECTIVE OR 1030 00:38:52,179 --> 00:38:54,781 HAVE SOME EFFECT AND THEN WE CAN 1031 00:38:54,781 --> 00:38:56,450 CONTINUE TO IMPROVE THIS TYPE 1032 00:38:56,450 --> 00:38:58,685 BECAUSE THESE PATIENTS ARE VERY 1033 00:38:58,685 --> 00:39:00,187 SEVERELY DISABLED, NONE OF THEM 1034 00:39:00,187 --> 00:39:02,856 CAN REALLY LIVE INDEPENDENTLY. 1035 00:39:02,856 --> 00:39:05,559 SO, IN MY VIEW, MANY OF THESE 1036 00:39:05,559 --> 00:39:07,261 MONOGENIC DISORDERS, WE CAN 1037 00:39:07,261 --> 00:39:08,195 DEVELOP DIFFERENT GENE THERAPY 1038 00:39:08,195 --> 00:39:11,932 APPROACHES IN THE FUTURE AND THE 1039 00:39:11,932 --> 00:39:14,768 MOST DIFFICULT PART IS HOW TO 1040 00:39:14,768 --> 00:39:20,474 GET A NEW VECTOR THAT YOU CAN IV 1041 00:39:20,474 --> 00:39:21,775 INJECTION AND GOOD BRAIN 1042 00:39:21,775 --> 00:39:23,910 COVERAGE WHICH NOW SEVERAL LABS 1043 00:39:23,910 --> 00:39:25,812 AND COMPANY MADE PROGRESS. 1044 00:39:25,812 --> 00:39:30,984 THE OTHER IS THIS IS RARE 1045 00:39:30,984 --> 00:39:32,352 GENETIC DISORDERS, MOST PHARMA 1046 00:39:32,352 --> 00:39:35,122 WOULD -- HOW TO GET SOCIETY TO 1047 00:39:35,122 --> 00:39:36,123 INVEST IN THIS RARE GENERATEDET 1048 00:39:36,123 --> 00:39:36,857 INCREASE IN BODY DISORDER 1049 00:39:36,857 --> 00:39:38,292 BECAUSE THIS IS 1 OF THE FEW 1050 00:39:38,292 --> 00:39:41,261 CASES WE CAN REALLY MAKE 1051 00:39:41,261 --> 00:39:41,528 PROGRESS. 1052 00:39:41,528 --> 00:39:46,500 SO WE LEARN A LOT FROM THIS 1053 00:39:46,500 --> 00:39:48,368 MARMOSET SHANK 3 MODEL SO WE 1054 00:39:48,368 --> 00:39:50,003 STARTED THINKING WHAT ELSE WE 1055 00:39:50,003 --> 00:39:52,673 CAN DO TO HELP THE RESEARCH 1056 00:39:52,673 --> 00:39:54,608 COMMUNITY AND THE BIOTECH 1057 00:39:54,608 --> 00:39:55,876 COMMUNITY TO GENERATE OTHER 1058 00:39:55,876 --> 00:39:58,512 MODELS THAT HELP US TEST THE 1059 00:39:58,512 --> 00:40:00,347 THERAPEUTICS IN THESE MODELS. 1060 00:40:00,347 --> 00:40:04,084 SO NOW WE GENERATED MECP2 MODELS 1061 00:40:04,084 --> 00:40:08,255 WHICH IS THE HUMAN R-GENINE, 1062 00:40:08,255 --> 00:40:10,691 STOP PROGRAM, THIS IS ALSO A 1063 00:40:10,691 --> 00:40:12,259 TERRIBLE DISORDER AFFECT ALMOST 1064 00:40:12,259 --> 00:40:13,694 EXCLUSIVELY GIRLS BECAUSE I 1065 00:40:13,694 --> 00:40:15,762 THINK BOYS CANNOT SURVIVE, AND 1066 00:40:15,762 --> 00:40:21,601 SO, THERE ARE MANY GENE 1067 00:40:21,601 --> 00:40:23,337 THERAPIES, FOR RETT SYNDROME, SO 1068 00:40:23,337 --> 00:40:25,072 HOPEFULLY WE GENERATE THIS MODEL 1069 00:40:25,072 --> 00:40:27,140 TO BE USEFUL IN THE FUTURE. 1070 00:40:27,140 --> 00:40:32,512 WE ALSO GENERATED A VERY ONSET 1071 00:40:32,512 --> 00:40:36,083 MUSEUM TAITIONZ, P117S AND P117 1072 00:40:36,083 --> 00:40:39,686 L MUTATION, THIS PATIENT BECOME 1073 00:40:39,686 --> 00:40:41,388 VERY SEVERE AT 30 YEARS OLD AND 1074 00:40:41,388 --> 00:40:43,724 SO 30 YEARS, OR ABOUT 4 YEARS 1075 00:40:43,724 --> 00:40:46,093 OLD MARNLA SET, SO YOU DON'T 1076 00:40:46,093 --> 00:40:47,694 HAVE TO WAIT 20 YEARS TO STUDY 1077 00:40:47,694 --> 00:40:47,961 THIS. 1078 00:40:47,961 --> 00:40:55,102 SO WE'RE HOPING THIS WILL GIVE 1079 00:40:55,102 --> 00:40:56,069 US SOME INSIGHT. 1080 00:40:56,069 --> 00:40:57,337 -- WAS HERE BUT ALSO AT 1081 00:40:57,337 --> 00:40:59,706 PITTSBURGH ALSO MADE DIFFERENT 1082 00:40:59,706 --> 00:41:01,308 MUTATIONS WHICH IS LATER ONSET, 1083 00:41:01,308 --> 00:41:03,744 I THINK IS ALREADY SHOWED THERE 1084 00:41:03,744 --> 00:41:08,715 ARE PLAQUES IN THIS MARMOSET, SO 1085 00:41:08,715 --> 00:41:09,549 USUALLY KNOCKIN OPPOSING 1086 00:41:09,549 --> 00:41:11,151 MUTATION IN MICE SO YOU DON'T 1087 00:41:11,151 --> 00:41:12,986 SEE THESE PLAQUE CHANGES. 1088 00:41:12,986 --> 00:41:15,288 SO WE ARE HOPEFUL. 1089 00:41:15,288 --> 00:41:18,125 WITH THE STANLEY CONSORTIUM OF 1090 00:41:18,125 --> 00:41:20,660 THE GLOBAL CONSORTIUM OF THE 1091 00:41:20,660 --> 00:41:23,263 SCHIZOPHRENIA WHOLE EXOHM 1092 00:41:23,263 --> 00:41:26,166 SEQUENCING THIS IS THE FIRST 1093 00:41:26,166 --> 00:41:27,434 PUBLICATION FROM STANLEY CENTER 1094 00:41:27,434 --> 00:41:30,871 FROM THE GLOBAL CONSORTIUM 1095 00:41:30,871 --> 00:41:33,273 IDENTIFY DEN HIGH PENETRANT RARE 1096 00:41:33,273 --> 00:41:34,374 GENETIC MUTATIONS CONTRIBUTED TO 1097 00:41:34,374 --> 00:41:40,447 SKITS SKITS 1098 00:41:40,447 --> 00:41:42,482 SCHIZOPHRENIA AND WE TESTED 1099 00:41:42,482 --> 00:41:46,186 INITIALLY GENERATED A FEW MOUSE 1100 00:41:46,186 --> 00:41:47,387 MODELS TO TEST HETEROZYGOUS, YOU 1101 00:41:47,387 --> 00:41:48,688 SEE SOME OF THE FINE O TYPES, 1102 00:41:48,688 --> 00:41:50,390 SOME OF THE INTERESTING 1103 00:41:50,390 --> 00:41:53,260 PHENOTYPES, SO NOW WE GENERATE 1104 00:41:53,260 --> 00:41:54,628 FIRST MARMOSET MODEL, HOPEFULLY 1105 00:41:54,628 --> 00:41:56,530 THIS WILL BE USEFUL, ALL THE 1106 00:41:56,530 --> 00:41:58,031 GERONTOLOGYSTS MEMORY CLONE AND 1107 00:41:58,031 --> 00:41:58,632 ENGINEERING TECHNOLOGY WHETHER 1108 00:41:58,632 --> 00:42:02,068 IT'S A PRIME EDITING, GENOME 1109 00:42:02,068 --> 00:42:03,670 EDITING, SMALL KNOCKINGS OUT, WE 1110 00:42:03,670 --> 00:42:07,908 MADE IT VERY EFFECTIVE IN 1111 00:42:07,908 --> 00:42:09,309 MARMOSET THANKS TO THE BRAIN 1112 00:42:09,309 --> 00:42:11,445 INITIATIVE AND THE NIH SUPPORT 1113 00:42:11,445 --> 00:42:18,418 FOR GENOME ENGINEERING IN 1114 00:42:18,418 --> 00:42:19,186 NONHUMAN PRIMATE PROGRAM. 1115 00:42:19,186 --> 00:42:22,355 I SAID MOST OF THE DISORDERS IN 1116 00:42:22,355 --> 00:42:24,758 MENTAL HEALTH INCLUDING 1117 00:42:24,758 --> 00:42:25,425 SCHIZOPHRENIA, DEPRESSION, 1118 00:42:25,425 --> 00:42:28,562 AUTISM, THEY'RE NOT MONOGENIC SO 1119 00:42:28,562 --> 00:42:33,133 CAN WE USE A SUCH DYSFUNCTION AS 1120 00:42:33,133 --> 00:42:33,967 A BIOMARKER AND THERAPEUTIC 1121 00:42:33,967 --> 00:42:38,338 TESTING THAT CO POTENTIALLY 1122 00:42:38,338 --> 00:42:39,506 TRANSLATE INTO HELP FOR HUMANS. 1123 00:42:39,506 --> 00:42:42,342 SO WE ARE IDENTIFYING ON HOW DO 1124 00:42:42,342 --> 00:42:44,744 WE IDENTIFY CIRC YOUS THAT 1125 00:42:44,744 --> 00:42:46,012 BEHAVIOR TRIGGERED DEFECT, I 1126 00:42:46,012 --> 00:42:48,348 SHOWED IT IN MARMOSET AND PEOPLE 1127 00:42:48,348 --> 00:42:50,517 ALREADY PUBLISH IN MOUSE SHANK 3 1128 00:42:50,517 --> 00:42:53,153 MODELS, YOU CAN DO RESTING 1129 00:42:53,153 --> 00:42:56,022 ESTATE WHICH IS ANESTHETIZED 1130 00:42:56,022 --> 00:42:59,059 ANIMAL BUT IS THIS SAME OR 1131 00:42:59,059 --> 00:43:02,863 DIFFERENT FROM A BEHAVIOR WE'RE 1132 00:43:02,863 --> 00:43:03,864 WEAK TRIGGER? 1133 00:43:03,864 --> 00:43:06,299 BECAUSE MOST TRIGGER AUTISM IS 1134 00:43:06,299 --> 00:43:07,701 IN SOCIAL ENVIRONMENT OR 1135 00:43:07,701 --> 00:43:09,736 SOMETHING IRRITATED THEM SO CAN 1136 00:43:09,736 --> 00:43:13,673 WE TEST BEHAVIOR TRIGGERED 1137 00:43:13,673 --> 00:43:14,474 CIRCUITS ACTIVITY WHETHER THEY 1138 00:43:14,474 --> 00:43:16,343 HAVE A DIFFERENCE? 1139 00:43:16,343 --> 00:43:17,811 SO MY LAB ALWAYS FOCUSED ON 1140 00:43:17,811 --> 00:43:20,113 THYME O CORTICAL CIRCUITS AND 1141 00:43:20,113 --> 00:43:21,781 BECAUSE OF CONSERVATION BUT ALSO 1142 00:43:21,781 --> 00:43:23,316 BECAUSE IT'S IMPLICATED IN MANY 1143 00:43:23,316 --> 00:43:26,019 DISORDERS, SO WE IN THE LAST FEW 1144 00:43:26,019 --> 00:43:28,922 YEARS, WE ARE -- WE ARE STILL 1145 00:43:28,922 --> 00:43:30,090 DOING FUNCTIONAL MRI WITH ANIMAL 1146 00:43:30,090 --> 00:43:30,824 BUT WE ARE MORE INTERESTED 1147 00:43:30,824 --> 00:43:32,459 NONAPOPTOTIC YOU IN USING THIS 1148 00:43:32,459 --> 00:43:35,128 RELATIVELY NEW TECHNOLOGY CALLED 1149 00:43:35,128 --> 00:43:36,196 FUNCTIONAL ULTRASOUND IMAGING 1150 00:43:36,196 --> 00:43:41,368 BECAUSE IT HAS A HIGHER 1151 00:43:41,368 --> 00:43:43,670 RESOLUTION BUT IT ALSO CAN DO 1152 00:43:43,670 --> 00:43:45,705 WEAK ANIMAL, SOMETIMES CAN YOU 1153 00:43:45,705 --> 00:43:47,073 DO BEHAVING ANIMALS BECAUSE IT'S 1154 00:43:47,073 --> 00:43:50,010 A PROBE ON THE HEAD. 1155 00:43:50,010 --> 00:43:53,113 SO THIS IS BASICALLY SIMILAR -- 1156 00:43:53,113 --> 00:43:56,349 IT'S BASICALLY BLOOD FLOW TOPLER 1157 00:43:56,349 --> 00:43:57,384 IMAGING, SIMILAR TO FUNCTIONAL 1158 00:43:57,384 --> 00:44:00,554 MRI, YOU LOOK AT BLOOD FLOW 1159 00:44:00,554 --> 00:44:02,289 REPRESENTATIVE OF THE COLORED 1160 00:44:02,289 --> 00:44:03,490 WITH THE NEURAL ACTIVITY. 1161 00:44:03,490 --> 00:44:07,027 SO WE TESTED THIS INITIALLY AN 1162 00:44:07,027 --> 00:44:09,095 ESTIMATE THADITIZEED RESTING 1163 00:44:09,095 --> 00:44:13,700 STATE BECAUSE RESTING STATE FMRI 1164 00:44:13,700 --> 00:44:16,903 HAS BEEN DONE MULTITELETIMES IN 1165 00:44:16,903 --> 00:44:18,305 SHANK 3 ANIMAL AND WE KNOW IT 1166 00:44:18,305 --> 00:44:21,441 WAS REPORTED WITH REDUCED 1167 00:44:21,441 --> 00:44:23,143 FUNCTIONAL CONNECTIVITY IN THE 1168 00:44:23,143 --> 00:44:24,778 FUNCTIONAL CORTEX IN THE 1169 00:44:24,778 --> 00:44:25,879 STRIATUM, AND WE SHOWED THAT IN 1170 00:44:25,879 --> 00:44:28,982 THE CORTEX OF THE MARMOSET, TOO. 1171 00:44:28,982 --> 00:44:30,083 SO WE SHOWED SHANK 3. 1172 00:44:30,083 --> 00:44:32,352 SO WE TEST IS FIND A SIMILAR 1173 00:44:32,352 --> 00:44:34,588 PHENOMENA IN THE SHANK 3 MICE, 1174 00:44:34,588 --> 00:44:36,990 THIS IS OUR 10 ANIMALS FOR EACH, 1175 00:44:36,990 --> 00:44:38,692 CAN YOU SEE WILD-TYPE, AND YOU 1176 00:44:38,692 --> 00:44:40,894 CAN SEE THAT IT'S A RELATIVE 1177 00:44:40,894 --> 00:44:43,430 ACTIVITY, RIGHT? 1178 00:44:43,430 --> 00:44:48,435 YOU CAN SEE KNOCK OUT WITH 1179 00:44:48,435 --> 00:44:50,904 FRONTAL CORTEXT AND STRIATUM SO 1180 00:44:50,904 --> 00:44:52,772 YOU CAN CONFIRM THIS NEW 1181 00:44:52,772 --> 00:44:55,508 APPROACH, NEW TECHNOLOGY CAN BE 1182 00:44:55,508 --> 00:44:59,512 USED TOY DID TECT CIRCUITS 1183 00:44:59,512 --> 00:45:00,880 ACTIVITY CHANGE AND MOUSE 1184 00:45:00,880 --> 00:45:02,349 MODELS. 1185 00:45:02,349 --> 00:45:04,250 SO THEN WE DESIGN EXPERIMENT TO 1186 00:45:04,250 --> 00:45:05,318 LOOK AT BEHAVIOR TRADING SO 1187 00:45:05,318 --> 00:45:08,188 BASICALLY WHAT WE DID WAS TO 1188 00:45:08,188 --> 00:45:09,522 MAKE THE EFFECTS OF THIS TESTING 1189 00:45:09,522 --> 00:45:11,291 ANIMAL THEN WE HAVE A PROBE 1190 00:45:11,291 --> 00:45:13,526 ANIMAL, YOU HAVE A LOOP OF TUBE, 1191 00:45:13,526 --> 00:45:15,662 SO THE ANIMAL CAN GO OVER SOCIAL 1192 00:45:15,662 --> 00:45:16,062 AND GO AWAY. 1193 00:45:16,062 --> 00:45:18,898 SO HAVE YOU WINDOWS SOCIAL, 1194 00:45:18,898 --> 00:45:19,666 NONSOCIAL, SOCIAL, NONSOCIAL SO 1195 00:45:19,666 --> 00:45:21,368 CAN YOU SEE WHEN THEY ARE 1196 00:45:21,368 --> 00:45:24,504 SOCIAL, THIS BOX ARE SOCIAL, YOU 1197 00:45:24,504 --> 00:45:25,505 SEE THE ACTIVITY INCREASE FROM 1198 00:45:25,505 --> 00:45:28,375 THE CORTEX AND IN THE STRIATUM. 1199 00:45:28,375 --> 00:45:30,210 SO THEN YOU SEE THE SAME THING 1200 00:45:30,210 --> 00:45:33,079 WITH IMK OUT ANIMAL. 1201 00:45:33,079 --> 00:45:35,315 TO OUR SURPRISE IN A WEAK 1202 00:45:35,315 --> 00:45:36,783 CONDITION, EVERY TIME THERE'S 1203 00:45:36,783 --> 00:45:38,918 SOCIAL ACTIVITY, THE FRONT 1204 00:45:38,918 --> 00:45:40,987 CORTEX AND STRIATAL ACTIVITY 1205 00:45:40,987 --> 00:45:41,521 DRAMATICALLY INCREASE, SO 1206 00:45:41,521 --> 00:45:44,658 PREVIOUSLY WE WERE THINKING 1207 00:45:44,658 --> 00:45:46,693 BASED ON ELECTROPHYSIOLOGY IN 1208 00:45:46,693 --> 00:45:48,695 SLICE, BASED ON FMRI RESTING 1209 00:45:48,695 --> 00:45:50,597 STATE WE NEED TO BOOST THE 1210 00:45:50,597 --> 00:45:51,931 CORTICALE SYNAPSE, NOT WITH 1211 00:45:51,931 --> 00:45:54,267 THIS, BUT WHAT WE NEED ACTUALLY 1212 00:45:54,267 --> 00:45:57,904 IS TO CALM DOWN THE CORTICALE 1213 00:45:57,904 --> 00:45:59,873 STRIATAL FUNCTION SO THIS IS NOT 1214 00:45:59,873 --> 00:46:02,175 A 1 IMAGING, THIS IS THE AVERAGE 1215 00:46:02,175 --> 00:46:04,344 IMAGING FROM ABOUT 10 ANIMALS, 1216 00:46:04,344 --> 00:46:07,647 CAN YOU SEE THE SIGNIFICANT 1217 00:46:07,647 --> 00:46:09,949 ESPECIALLY IN THE FRONTAL CORTEX 1218 00:46:09,949 --> 00:46:11,885 AND STRIATUM, SO THIS HAS BECOME 1219 00:46:11,885 --> 00:46:13,520 A NEW KIND OF ANGLE TO NOT ONLY 1220 00:46:13,520 --> 00:46:16,823 LOOK AT THE CIRCUIT BUT ALSO TO 1221 00:46:16,823 --> 00:46:19,159 LOOK AT THE WHAT KIND OF CELL 1222 00:46:19,159 --> 00:46:20,193 TYPE CHANGED BUT MORE IMPORTANT 1223 00:46:20,193 --> 00:46:22,262 TO US, CAN WE FIND THE TARGET 1224 00:46:22,262 --> 00:46:26,499 CALM DOWN THE CIRCUITS OF THIS 1225 00:46:26,499 --> 00:46:28,334 BEHAVIOR TRIGGERED CIRCUITS 1226 00:46:28,334 --> 00:46:29,369 NEURONAL HYPER-ACTIVITY, IF WE 1227 00:46:29,369 --> 00:46:32,906 CAN CORRECT THAT, MAYBE WE WILL 1228 00:46:32,906 --> 00:46:35,075 ELIMINATE IT FOR MOST OF THIS 1229 00:46:35,075 --> 00:46:35,975 BEHAVIOR DEFECT. 1230 00:46:35,975 --> 00:46:39,045 SO WE FOUND THE TARGET AND WE 1231 00:46:39,045 --> 00:46:40,814 FOUND THE MODULATE BECAUSE THE 1232 00:46:40,814 --> 00:46:43,683 EXPRESSION PATTERNS AND THEY ARE 1233 00:46:43,683 --> 00:46:45,118 FUNCTIONING IN GABBAERGIC 1234 00:46:45,118 --> 00:46:46,286 NEURONS ACTUALLY SO WHAT WE 1235 00:46:46,286 --> 00:46:48,221 FOUND IS THAT WILD-TYPE, RIGHT, 1236 00:46:48,221 --> 00:46:50,790 SO CAN YOU SEE THERE'S BEFORE 1237 00:46:50,790 --> 00:46:52,792 DRUG KNOCK OUT BEFORE DRUG, YOU 1238 00:46:52,792 --> 00:46:55,462 HAVE HYPER ACTIVE. 1239 00:46:55,462 --> 00:47:00,366 THESE ARE SOCIAL TRIGGERED 1240 00:47:00,366 --> 00:47:00,767 NEUROSUBACTIVITY. 1241 00:47:00,767 --> 00:47:05,371 WE GIVE 1 DOSE, 1 INJECTION, 2 1242 00:47:05,371 --> 00:47:08,374 HOURS LATER WILD-TYPE HAVE 1243 00:47:08,374 --> 00:47:11,244 LITTLE BIT ACTIVITY, BUT NORMAL 1244 00:47:11,244 --> 00:47:13,847 ALMOST KNOCK OUT, 2 DOSE, 7 DAYS 1245 00:47:13,847 --> 00:47:15,248 LATER IT STILL HAS EFFECT. 1246 00:47:15,248 --> 00:47:16,850 IT START TO CREEP BACK BUT IT 1247 00:47:16,850 --> 00:47:23,356 STILL HAS IT, IT'S VERY SIMILAR 1248 00:47:23,356 --> 00:47:27,660 TO KETA MEAN -- IT'S A LONG 1249 00:47:27,660 --> 00:47:29,529 LASTING MODULATOR ACTIVITY, AND 1250 00:47:29,529 --> 00:47:31,464 SO THE PREDICTION, IF YOU CAN 1251 00:47:31,464 --> 00:47:35,468 CORRECT THIS SO WELL AT A LEVEL, 1252 00:47:35,468 --> 00:47:37,570 YOU SHOULD BE ABLE TO PREDICT 1253 00:47:37,570 --> 00:47:39,105 THE BEHAVIOR WOULD CHANGE, THIS 1254 00:47:39,105 --> 00:47:40,373 IS TRIGGERED BY SOCIAL 1255 00:47:40,373 --> 00:47:42,175 INTERACTION SO WE DID TEST THEM 1256 00:47:42,175 --> 00:47:44,844 USING THE SAME SOCIAL ASSAY. 1257 00:47:44,844 --> 00:47:46,780 ONE DOSE, THEN YOU TEST 24 HOURS 1258 00:47:46,780 --> 00:47:48,448 LATER AND 21 DAYS LATER. 1259 00:47:48,448 --> 00:47:49,182 WE ALSO TESTED 7. 1260 00:47:49,182 --> 00:47:52,752 SO CAN YOU SEE THAT IT VERY 1261 00:47:52,752 --> 00:47:54,220 CLEARLY TO CHANGE THE BEHAVIOR 1262 00:47:54,220 --> 00:47:57,090 THAT YOU CAN RESTORE THE SOCIAL 1263 00:47:57,090 --> 00:48:00,593 INTERACTION VERY CLEAR, THIS IS 1264 00:48:00,593 --> 00:48:02,028 BLACK WILD-TYPE WITH VEHICLE, 1265 00:48:02,028 --> 00:48:03,429 CAN DRUG MUTANT WITH VEHICLE, 1266 00:48:03,429 --> 00:48:07,667 WITH DRUG, YOU CAN SEE VERY 1267 00:48:07,667 --> 00:48:09,536 CLEARLY, IT CAN LAST VERY LONG, 1268 00:48:09,536 --> 00:48:12,739 21 DAYS LATER STILL HAS EFFECT, 1269 00:48:12,739 --> 00:48:15,175 SIMILARLY FOR GROOMING BEHAVIOR, 1270 00:48:15,175 --> 00:48:17,610 1 DOSE, TOP LINE, OPEN CIRCLE IS 1271 00:48:17,610 --> 00:48:20,246 KNOCK OUT, WITH VEHICLE. 1272 00:48:20,246 --> 00:48:23,583 THE BLACK OPEN CIRCLE IS THE 1273 00:48:23,583 --> 00:48:26,119 WILD-TYPE WITH VEHICLE. 1274 00:48:26,119 --> 00:48:28,354 THE FILLED CIRCLE IS THE KNOCK 1275 00:48:28,354 --> 00:48:33,126 OUT WITH THE NR2 B ANTAG NAST 1276 00:48:33,126 --> 00:48:34,661 AND THE WHITE CIRC CELL 1277 00:48:34,661 --> 00:48:36,162 WILD-TYPE WITH DRUG, SO YOU CAN 1278 00:48:36,162 --> 00:48:38,698 SEE IT LASTS ALMOST 4 WEEKS SO 1279 00:48:38,698 --> 00:48:39,966 WE'RE REALLY EXCITED ABOUT THIS 1280 00:48:39,966 --> 00:48:40,967 LONG LASTING EFFECT AND WE TRY 1281 00:48:40,967 --> 00:48:44,003 TO FIGURE OUT WHAT IS THE 1282 00:48:44,003 --> 00:48:46,039 MECHANISM, ALTHOUGH A DRUG IS A 1283 00:48:46,039 --> 00:48:49,642 DRUG, NO COMPOUND IS A HUNDRED 1284 00:48:49,642 --> 00:48:50,510 PERCENT, YOU KNOW SPECIFIC. 1285 00:48:50,510 --> 00:48:53,313 SO WE WANT TO SEE, IS THIS 1286 00:48:53,313 --> 00:48:57,784 REALLY NR2 B, SO WE MAY USE 1287 00:48:57,784 --> 00:48:59,886 CRISPR, WE MADE A KNOCK OUT, 1288 00:48:59,886 --> 00:49:01,187 JUST ADULT KNOCK OUT IN THE 1289 00:49:01,187 --> 00:49:03,990 SHANK 3 AND IN THE ANIMAL 1290 00:49:03,990 --> 00:49:04,524 DIRECTLY. 1291 00:49:04,524 --> 00:49:07,594 SO THIS IS CONTROL WITH THE 1292 00:49:07,594 --> 00:49:09,095 CONTROL GUIDE RNA, SCRAMLE RNA 1293 00:49:09,095 --> 00:49:11,231 AS A KNOCK OUT, YOU CAN SEE WITH 1294 00:49:11,231 --> 00:49:13,633 THE SOCIAL INTERACTION, THE 1295 00:49:13,633 --> 00:49:14,567 TRIGGERS HYPER-ACTIVITY IN THE 1296 00:49:14,567 --> 00:49:17,036 FRONT CORTEX IN THE TRIAT UMKC, 1297 00:49:17,036 --> 00:49:19,806 AND WHEN YOU KNOCK OUT OF SHANK 1298 00:49:19,806 --> 00:49:21,441 3 AND R2 B, YOU DON'T SEE THIS 1299 00:49:21,441 --> 00:49:22,508 TYPE OF ACTIVITY. 1300 00:49:22,508 --> 00:49:25,278 SO WE CONFIRM THE NR2 B IS 1301 00:49:25,278 --> 00:49:29,515 REALLY THE TARGET, SO NOW, YOU 1302 00:49:29,515 --> 00:49:31,251 ALL KNOW BLOCK NMD RECEPTOR IS 1303 00:49:31,251 --> 00:49:33,419 PROBABLY NOT BEST THING TO DO 1304 00:49:33,419 --> 00:49:34,888 FOR KIDS AND ADULT, FIRST OF ALL 1305 00:49:34,888 --> 00:49:37,690 THEY ARE CLINICAL STUDIES THAT 1306 00:49:37,690 --> 00:49:39,359 SHOW THEY DISASSOCIATED FACT, 1307 00:49:39,359 --> 00:49:40,360 WITH PROBLEMS, HYPER-ACTIVITY IN 1308 00:49:40,360 --> 00:49:43,763 ANIMALS AT LEAST N. HUMANS IT 1309 00:49:43,763 --> 00:49:44,564 AWZ DISASSOCIATION EFFECT. 1310 00:49:44,564 --> 00:49:46,933 SO WE'RE NOW VERY INTERESTED IN, 1311 00:49:46,933 --> 00:49:48,167 CAN WE FIND THE DOWN STREAM 1312 00:49:48,167 --> 00:49:50,436 SIGNAL AS A NEW DRUG OF TARGETS 1313 00:49:50,436 --> 00:49:53,873 THAT COULD COME DOWN, AND THESE 1314 00:49:53,873 --> 00:49:54,874 HYPER-ACTIVITY BEHAVIOR 1315 00:49:54,874 --> 00:49:55,775 TRIGGERED TO HYPER-ACTIVITY, 1316 00:49:55,775 --> 00:49:57,644 WE'RE ALSO REALLY INTERESTED, 1317 00:49:57,644 --> 00:49:59,712 HOW THIS THING CAN WORK SO LONG 1318 00:49:59,712 --> 00:50:02,715 FROM A DRUG IS GONE WITHIN 24 1319 00:50:02,715 --> 00:50:05,652 HOURS, SO WHY DOES THE EFFECT 1320 00:50:05,652 --> 00:50:07,287 LAST SO LONG? 1321 00:50:07,287 --> 00:50:08,087 IS IT ALTP? 1322 00:50:08,087 --> 00:50:09,722 OR SOMETHING ELSE? 1323 00:50:09,722 --> 00:50:11,357 WE WANT TO KNOW, WE DON'T KNOW 1324 00:50:11,357 --> 00:50:13,293 YET, WE HAVE A HINT BUT WE DON'T 1325 00:50:13,293 --> 00:50:13,626 KNOW YET. 1326 00:50:13,626 --> 00:50:15,595 SO OUR HOPE IS THAT IN NEXT 1327 00:50:15,595 --> 00:50:16,696 COUPLE YEARS WE COULD FIGURE OUT 1328 00:50:16,696 --> 00:50:18,031 A TARGET AND THIS COULD BE MOVE 1329 00:50:18,031 --> 00:50:20,133 ON TO TESTING AND THE MONKEYS 1330 00:50:20,133 --> 00:50:21,134 AND HUMANS IN THE FUTURE. 1331 00:50:21,134 --> 00:50:22,936 SO I THINK I WILL STOP HERE, I 1332 00:50:22,936 --> 00:50:25,305 WANT TO ACKNOWLEDGE MANY PEOPLE, 1333 00:50:25,305 --> 00:50:28,775 ESPECIALLY OUR MARMOSET TEAM. 1334 00:50:28,775 --> 00:50:31,477 THIS IS NOT MY LAB'S PROGRAM FOR 1335 00:50:31,477 --> 00:50:33,146 MARMOSET, IT'S IMPOSSIBLE TO DO, 1336 00:50:33,146 --> 00:50:35,415 WE HAVE MANY, MANY COLLABORATORS 1337 00:50:35,415 --> 00:50:38,351 ISSUES IT'S A WHOLE COMMUNITY 1338 00:50:38,351 --> 00:50:42,221 EFFORT ESPECIALLY BOB, AND FENG, 1339 00:50:42,221 --> 00:50:47,260 AND STEVE, AND FENNA, SHE WAS A 1340 00:50:47,260 --> 00:50:50,596 POST DOC WITH STEVE Mc CARROLL 1341 00:50:50,596 --> 00:50:54,200 ASSISTANT PROFESSOR AT PRINCETON 1342 00:50:54,200 --> 00:50:55,368 UNIVERSITY, AND HARVARD, AND 1343 00:50:55,368 --> 00:50:58,271 THEN SPECIALLY BROAD AND MIT 1344 00:50:58,271 --> 00:50:58,638 ANIMAL FACILITY. 1345 00:50:58,638 --> 00:51:00,206 THEY TAKE CARE OF THESE ANIMALS 1346 00:51:00,206 --> 00:51:04,110 SO WELL, AND EVERY SURGERY YOU 1347 00:51:04,110 --> 00:51:08,348 NEED ANESTHESIOLOGIST OR MRI 1348 00:51:08,348 --> 00:51:10,216 SCANNING, ANESTHESIOLOGIST, 1349 00:51:10,216 --> 00:51:12,018 SURGEON, SURGEON ASSISTANT, IT'S 1350 00:51:12,018 --> 00:51:14,187 BETTER ARRANGED THAN YOU GO TO 1351 00:51:14,187 --> 00:51:16,656 HOSPITAL SURGERY, I HAD SEVERAL 1352 00:51:16,656 --> 00:51:17,957 SURGERY IN THE HOSPITAL REALLY 1353 00:51:17,957 --> 00:51:20,126 WELL DO AND THEY DO PHENOMENAL 1354 00:51:20,126 --> 00:51:21,527 WORK TO TAKE CARE OF THESE 1355 00:51:21,527 --> 00:51:25,198 ANIMALS AND WE HAVE COLLABORATE 1356 00:51:25,198 --> 00:51:28,468 WITH JIM PICTEL, HERE AND 1357 00:51:28,468 --> 00:51:29,469 AFONSO, SILVA USED TO BE HERE 1358 00:51:29,469 --> 00:51:35,441 AND WE HAVE OUR COLLABORATOR IN 1359 00:51:35,441 --> 00:51:39,078 JAPAN, PROFESSOR OKANO AND 1360 00:51:39,078 --> 00:51:40,513 SASAKI, THEY ARE MARMOSET FOR 1361 00:51:40,513 --> 00:51:42,582 ALMOST 50 YEARS, AND I ASK THEM 1362 00:51:42,582 --> 00:51:44,550 WHY 50 YEARS AGO THEY THINK 1363 00:51:44,550 --> 00:51:47,186 MARMOSET WAS GOOD AND ASK THE 1364 00:51:47,186 --> 00:51:47,820 PRESIDENT OF CIEA. 1365 00:51:47,820 --> 00:51:50,623 SO THEY TAUGHT US A LOT. 1366 00:51:50,623 --> 00:51:52,892 WE HAVE 3 OR 4 PEOPLE THERE THAT 1367 00:51:52,892 --> 00:51:54,127 ARE THE LEARNING GROUP 1368 00:51:54,127 --> 00:51:55,795 BIOLOGISTS AND THEY ARE OUR 1369 00:51:55,795 --> 00:51:57,030 LONG-TERM COLLABORATORS AND ALSO 1370 00:51:57,030 --> 00:52:00,099 WE HAVE COLLABORATORS IN CHINA 1371 00:52:00,099 --> 00:52:02,502 SOME OF THEM MY FORMER GRADUATE 1372 00:52:02,502 --> 00:52:04,704 STUDENT AND THEY WORK ON MACAQUE 1373 00:52:04,704 --> 00:52:06,706 MONKEYS AND WE ALSO LEARNED A 1374 00:52:06,706 --> 00:52:08,674 LOT OF BIOLOGY OF MACAQUE 1375 00:52:08,674 --> 00:52:11,344 MONKEYS TO HELP US ESTABLISH 1376 00:52:11,344 --> 00:52:13,946 GENETIC ENGINEERING AND PLATFORM 1377 00:52:13,946 --> 00:52:15,014 AT MIT. 1378 00:52:15,014 --> 00:52:17,116 AND MOST IMPORTANTLY, I REALLY 1379 00:52:17,116 --> 00:52:19,218 WANT TO THANK THE MANY, MANY 1380 00:52:19,218 --> 00:52:21,487 TALENTED AND DEDICATED ANIMAL 1381 00:52:21,487 --> 00:52:22,655 CARES, EACH MARMOSET AND LIKE 1382 00:52:22,655 --> 00:52:25,158 MICE, YOU NEED A LOT OF CARE, 1383 00:52:25,158 --> 00:52:29,929 ALL THE TIME AND WE CHECK THEIR 1384 00:52:29,929 --> 00:52:31,764 BUS ON THE CELL PHONE, WHETHER 1385 00:52:31,764 --> 00:52:33,900 IT'S MITTED OF THE NIGHT OR 1386 00:52:33,900 --> 00:52:35,601 MORNING, WE WILL GO THERE TO 1387 00:52:35,601 --> 00:52:38,004 MAKE SURE THE BABIES ARE IN GOOD 1388 00:52:38,004 --> 00:52:39,839 SHAPE SO THESE ARE VERY, VERY 1389 00:52:39,839 --> 00:52:43,009 DEDICATED PEOPLE AND OF COURSE 1390 00:52:43,009 --> 00:52:43,643 WITHOUT FINANCIAL SUPPORT NONE 1391 00:52:43,643 --> 00:52:45,711 OF THIS IS POSSIBLE AND REALLY I 1392 00:52:45,711 --> 00:52:50,550 WANT TO EMPHASIZE HOW THE NIH 1393 00:52:50,550 --> 00:52:52,351 BRAIN INITIATIVE MONOPOLY US AND 1394 00:52:52,351 --> 00:52:53,186 HELP MANY OTHERS IN NEUROSCIENCE 1395 00:52:53,186 --> 00:52:55,254 IN THE FIELD IN THE PAST DECADE, 1396 00:52:55,254 --> 00:52:56,823 THIS IS INCREDIBLE TECHNOLOGY 1397 00:52:56,823 --> 00:52:57,824 DEVELOPMENT AND A MODEL 1398 00:52:57,824 --> 00:53:00,760 DEVELOPMENT AND WE ARE REALLY 1399 00:53:00,760 --> 00:53:04,163 GRATEFUL TO THE SUPPORT FOR NIH 1400 00:53:04,163 --> 00:53:09,702 AND ALSO AGREE FOR MANY DONORS, 1401 00:53:09,702 --> 00:53:12,371 ESPECIALLY THE BROAD TEXT 10 FOR 1402 00:53:12,371 --> 00:53:15,908 RESEARCH AND ALSO MASSACHUSETTS 1403 00:53:15,908 --> 00:53:19,445 LIFE SCIENCE CENTER AND POITRAS 1404 00:53:19,445 --> 00:53:21,681 CENTER FOR PSYCHIATRIC RESEARCH 1405 00:53:21,681 --> 00:53:23,716 AND MANY OTHER NIMH, COMMON 1406 00:53:23,716 --> 00:53:27,820 FUND, ALSO NINDS AND ALSO BROAD 1407 00:53:27,820 --> 00:53:30,056 INSTITUTE, AND ALSO THE BRAIN 1408 00:53:30,056 --> 00:53:32,358 RESEARCH FOUNDATION ACTUALLY WAS 1409 00:53:32,358 --> 00:53:33,426 THE FIRST SMALL FOUNDATION GIVE 1410 00:53:33,426 --> 00:53:40,199 US MONEY TO GET US STARTED FOR 1411 00:53:40,199 --> 00:53:42,735 SHANK 3 MARMOSET AND MANY OTHER 1412 00:53:42,735 --> 00:53:53,146 DONORS, TOO, THANK YOU. 1413 00:53:53,412 --> 00:53:53,646 [ APPLAUSE ] 1414 00:53:53,646 --> 00:53:55,348 NOKAY, THANK YOU THAT WAS AN 1415 00:53:55,348 --> 00:54:00,353 AMAZING TALK LIKE WE ALL 1416 00:54:00,353 --> 00:54:01,487 EXPECTED, QUESTIONS, YES. 1417 00:54:01,487 --> 00:54:04,724 >> THANKS FOR AN INCREDIBLE 1418 00:54:04,724 --> 00:54:05,658 WORK, INSPIRING TALK THE FIRST 1419 00:54:05,658 --> 00:54:09,228 HAS TO DO WITH GENETIC MARMOSET 1420 00:54:09,228 --> 00:54:10,096 IN THE MULTIVIEW 1421 00:54:10,096 --> 00:54:11,130 CHARACTERIZATION OF THEIR 1422 00:54:11,130 --> 00:54:12,965 BEHAVIOR, DID YOU FIND THAT SOME 1423 00:54:12,965 --> 00:54:13,566 OF THE BEHAVIORIAL DEFICITS 1424 00:54:13,566 --> 00:54:19,906 ASSOCIATED WITH THE DELETION 1425 00:54:19,906 --> 00:54:22,875 WERE MORE RESISTANT TO OTHERS 1426 00:54:22,875 --> 00:54:24,177 AND THE OTHER IS A SORT OF 1427 00:54:24,177 --> 00:54:26,379 BROADER QUESTION, HOW DO YOU 1428 00:54:26,379 --> 00:54:28,981 THINK ABOUT THE PROSPECT FOR 1429 00:54:28,981 --> 00:54:30,249 INDIVIDUAL VARIATION AND IN 1430 00:54:30,249 --> 00:54:34,687 GENETICS AND ENVIRONMENT 1431 00:54:34,687 --> 00:54:36,289 INCLUESING HETEROGENEITY AND A 1432 00:54:36,289 --> 00:54:37,590 VARIABLE PEN TRANCE OF THE MIN 1433 00:54:37,590 --> 00:54:38,791 EPIGENETICCULATION WHEN YOU PUT 1434 00:54:38,791 --> 00:54:43,196 IT INTO A REAL COMMUNITY? 1435 00:54:43,196 --> 00:54:44,063 >> THOSE ARE VERY GOOD 1436 00:54:44,063 --> 00:54:44,330 QUESTIONS. 1437 00:54:44,330 --> 00:54:45,865 THE FIRST QUESTION IS THERE'S A 1438 00:54:45,865 --> 00:54:48,034 LOT OF VARIATION, NOT EVERY 1439 00:54:48,034 --> 00:54:49,502 ANIMAL IS RISK AT SAME LEVEL, SO 1440 00:54:49,502 --> 00:54:56,475 WE ARE AS A GROUP, BUT VERY 1441 00:54:56,475 --> 00:54:58,844 OBVIOUSLY, VERY DIFFICULT 1442 00:54:58,844 --> 00:55:00,146 COGNITIVE TESTING WE CANNOT 1443 00:55:00,146 --> 00:55:01,013 RESCUE, THERE'S ONLY A CHANCE 1444 00:55:01,013 --> 00:55:03,182 AND WE DON'T KNOW THAT BECAUSE 1445 00:55:03,182 --> 00:55:04,550 IF IT'S ENVIRONMENTAL OR YOU 1446 00:55:04,550 --> 00:55:07,153 NEED EARLIER OR WE DON'T KNOW 1447 00:55:07,153 --> 00:55:10,990 WHETHER WE HAVE NOT ENOUGH 1448 00:55:10,990 --> 00:55:12,325 NEURONS BECAUSE HIGH COGNITIVE 1449 00:55:12,325 --> 00:55:13,826 FUNCTION IS YOUR BRAIN COMPUTING 1450 00:55:13,826 --> 00:55:14,360 POWER. 1451 00:55:14,360 --> 00:55:17,630 WE ONLY GOT INTO 15, 20% OF 1452 00:55:17,630 --> 00:55:20,800 NEURONS YOU MAY NEED MUCH MORE 1453 00:55:20,800 --> 00:55:22,001 WOODER SPREAD, SO WE DON'T KNOW 1454 00:55:22,001 --> 00:55:27,306 BUT THERE ARE THINGS MOSTLY IS 1455 00:55:27,306 --> 00:55:30,710 THE COGNITIVE FUNCTION, WE 1456 00:55:30,710 --> 00:55:33,379 CANNOT COMPLETELY RESCUE, SIMPLE 1457 00:55:33,379 --> 00:55:34,347 COGNITIVE FUNCTION WE CAN 1458 00:55:34,347 --> 00:55:36,949 RESCUE, BUT MORE DIFFICULT 1S WE 1459 00:55:36,949 --> 00:55:37,817 CANNOT RESCUE COMPLETELY. 1460 00:55:37,817 --> 00:55:39,218 AND THE SECOND QUESTION IS ALSO 1461 00:55:39,218 --> 00:55:43,456 REALLY GOOD QUESTION, ALTHOUGH 1462 00:55:43,456 --> 00:55:47,526 WE EXACTLY GENETIC MUTATION, SO 1463 00:55:47,526 --> 00:55:49,262 IT'S A PHENOMENA THAT'S REALLY 1464 00:55:49,262 --> 00:55:50,963 INTERESTING, THEY ALL HAVE 1465 00:55:50,963 --> 00:55:52,131 DEFECT, BUT THEY HAVE DIFFERENT 1466 00:55:52,131 --> 00:55:53,199 DEFECT AND TO DIFFERENT DEGREE, 1467 00:55:53,199 --> 00:55:56,535 SO IF YOU CLUSTER, USE COMPUTER, 1468 00:55:56,535 --> 00:55:57,937 THE CLUSTER WILD-TYPE, MUTANT. 1469 00:55:57,937 --> 00:56:01,440 THEN YOU BRING NEW BATCHES, SAY 1470 00:56:01,440 --> 00:56:02,808 WILD-TYPE, WHERE'S CLUSTER, ALL 1471 00:56:02,808 --> 00:56:04,910 WILD-TYPE CLUSTER WERE 1472 00:56:04,910 --> 00:56:06,312 WILD-TYPE. 1473 00:56:06,312 --> 00:56:08,814 THE NEW BATCH MUTANT, BECAUSE 1474 00:56:08,814 --> 00:56:10,316 MUTANT IS EVERY MUTANT IS 1475 00:56:10,316 --> 00:56:12,018 DIFFERENT FROM WILD-TYPE BUT 1476 00:56:12,018 --> 00:56:13,753 EVERY MUTANT IS DIFFERENT FROM 1477 00:56:13,753 --> 00:56:15,354 EACH OTHER, SO YOU CAN USE THE 1478 00:56:15,354 --> 00:56:17,890 TRAINING TO HAVE A CLUSTER BUT 1479 00:56:17,890 --> 00:56:19,825 THE NEW 1 MAY NOT CLUSTER INTO, 1480 00:56:19,825 --> 00:56:22,194 SO THAT MEANS, SO FOR EXAMPLE, 1481 00:56:22,194 --> 00:56:26,198 SOME ARE VERY SOCIAL DEFICIT, 1482 00:56:26,198 --> 00:56:27,800 SOME ARE NOT -- SOCIAL OKAY, BUT 1483 00:56:27,800 --> 00:56:29,235 OTHER I THINK THISS ARE, BUT 1484 00:56:29,235 --> 00:56:32,338 IT'S A SPECTRUM OF THINGS AND 1485 00:56:32,338 --> 00:56:34,674 KIND OF SIMILAR TO HUMAN 1486 00:56:34,674 --> 00:56:36,175 CONDITIONS, THEY ARE NOT 1487 00:56:36,175 --> 00:56:38,611 IDENTICAL, EVEN IF THEY HAVE 1488 00:56:38,611 --> 00:56:40,313 IDENTICAL MUTATIONS, THEY ARE 1489 00:56:40,313 --> 00:56:41,147 JUST GENETIC BACKGROUND AND 1490 00:56:41,147 --> 00:56:42,882 AFFECT THEM A LOT, ACTUALLY, SO 1491 00:56:42,882 --> 00:56:44,917 THAT'S WHY I THINK -- THAT'S WHY 1492 00:56:44,917 --> 00:56:46,052 I MENTIONED COMPARE BEFORE AND 1493 00:56:46,052 --> 00:56:50,856 AFTER IS OUR MOST ROBUST 1494 00:56:50,856 --> 00:56:51,290 RESULTS. 1495 00:56:51,290 --> 00:56:53,159 >> HI, SO, DID I UNDERSTAND 1496 00:56:53,159 --> 00:56:56,662 CORRECTLY WHEN YOU SAID THAT BY 1497 00:56:56,662 --> 00:56:59,298 FUNCTIONAL ULTRASOUND, YOU FIND 1498 00:56:59,298 --> 00:57:00,633 INCREASED PREFRONTAL ACTIVITY IN 1499 00:57:00,633 --> 00:57:02,501 THE SHANK MUTANT WHEREAS ALL THE 1500 00:57:02,501 --> 00:57:04,870 OLD LIKE PHYSIOLOGY SLICES, AND 1501 00:57:04,870 --> 00:57:07,840 SO FORTH TOLD YOU SHOULD BE 1502 00:57:07,840 --> 00:57:09,241 EXPECTING THE OPPOSITE? 1503 00:57:09,241 --> 00:57:11,210 >> YEAH, SO, YES OR NO. 1504 00:57:11,210 --> 00:57:14,513 SO IN THE RESTING STATE AND IN 1505 00:57:14,513 --> 00:57:17,650 SLICE, YOU FIND REDUCE THE 1506 00:57:17,650 --> 00:57:18,517 SYNAPTIC FUNCTIONAL 1507 00:57:18,517 --> 00:57:18,851 CONNECTIVITY. 1508 00:57:18,851 --> 00:57:22,988 IN SLICE YOU FIND REDUCED 1509 00:57:22,988 --> 00:57:23,956 CORTICALE STRIATAL, BUT YEAH, 1510 00:57:23,956 --> 00:57:25,925 THAT'S TRUE, BUT IN FUNCTIONAL 1511 00:57:25,925 --> 00:57:29,095 ULTRASOUND, IF YOU DO RESTING 1512 00:57:29,095 --> 00:57:31,764 STATE, YOU ALSO FIND IT REDUCED, 1513 00:57:31,764 --> 00:57:33,199 IT'S ONLY BEHAVIOR TRIGGERED 1514 00:57:33,199 --> 00:57:33,833 ACTIVITY IS DIFFERENT. 1515 00:57:33,833 --> 00:57:35,801 >> I SEE AND YOU COULDN'T ASK 1516 00:57:35,801 --> 00:57:38,904 ABOUT THE BEHAVIORED TRIGGER TD 1517 00:57:38,904 --> 00:57:40,206 ACTIVITY, BECAUSE THE QUESTION 1518 00:57:40,206 --> 00:57:41,006 OBVIOUSLY IS HOW THIS AFFECTS 1519 00:57:41,006 --> 00:57:42,675 HOW WE THINK ABOUT A HUGE AMOUNT 1520 00:57:42,675 --> 00:57:45,144 OF EXISTING DATA THAT IS SORT OF 1521 00:57:45,144 --> 00:57:47,346 UNDERLYING YOUR WHOLE PICTURE OF 1522 00:57:47,346 --> 00:57:50,383 THE DISEASE ETIOLOGY, RIGHT? 1523 00:57:50,383 --> 00:57:52,118 >> WE ALSO DID 2-PHOTON IMAGING 1524 00:57:52,118 --> 00:57:55,187 IN MICE, IF YOU USE WHISKER 1525 00:57:55,187 --> 00:57:57,656 TRIGGERING THEY ARE ALSO HYPER 1526 00:57:57,656 --> 00:57:58,891 ACTIVE, IF YOU ANONSPECIFIC SIDE 1527 00:57:58,891 --> 00:58:00,926 EFFECTSITIZE MICE, THE PICTURE 1528 00:58:00,926 --> 00:58:01,360 MAY BE DIFFERENT. 1529 00:58:01,360 --> 00:58:05,097 >> OKAY. 1530 00:58:05,097 --> 00:58:05,765 THANK YOU. 1531 00:58:05,765 --> 00:58:08,200 >> OKAY 1 QUESTION FROM ONLINE, 1532 00:58:08,200 --> 00:58:12,004 THIS IS FROM SUE YING LEE, CAN 1533 00:58:12,004 --> 00:58:16,242 YOU TELL US GENE THERAPY 3 1534 00:58:16,242 --> 00:58:18,144 MONTHS VERSUS LATER, DO YOU SEE 1535 00:58:18,144 --> 00:58:18,911 DIFFERENCES IN RECOVERY? 1536 00:58:18,911 --> 00:58:21,547 >> THAT'S VERY GOOD QUESTION. 1537 00:58:21,547 --> 00:58:25,317 SO 3 MONTHS SINCE WE STARTED 1538 00:58:25,317 --> 00:58:27,186 VERY YOUNG IT'S A QUESTION, A 1539 00:58:27,186 --> 00:58:29,889 LITTLE DIFFICULT TO ANSWER 1540 00:58:29,889 --> 00:58:33,292 BECAUSE THE MARMOSET BEHAVIOR 1541 00:58:33,292 --> 00:58:35,060 CHANGES WHEN THEY GROW, SO IT'S 1542 00:58:35,060 --> 00:58:38,998 HARD TO SAY WHETHER IMPROVEMENT 1543 00:58:38,998 --> 00:58:41,066 IS 9 MONTHS IS BETTER THAN 3 1544 00:58:41,066 --> 00:58:43,803 MONTHS BECAUSE WE CANNOT MEASURE 1545 00:58:43,803 --> 00:58:45,971 EXACTLY SAME LEVEL, LIKE 3 1546 00:58:45,971 --> 00:58:48,340 MONTHS THEIR SOCIAL LEVEL MAY BE 1547 00:58:48,340 --> 00:58:49,975 DIFFERENT FROM 9 MONTHS, MAYBE 1548 00:58:49,975 --> 00:58:50,976 EVEN WILD-TYPE SO IT'S HARD TO 1549 00:58:50,976 --> 00:58:52,411 SAY SO WE DON'T HAVE ENOUGH DATA 1550 00:58:52,411 --> 00:58:54,513 TO ANSWER THAT QUESTION, BUT AT 1551 00:58:54,513 --> 00:58:56,749 3 MONTHS AFTER GENE THERAPY WE 1552 00:58:56,749 --> 00:58:58,017 ALREADY SEE VERY SIGNIFICANTLY, 1553 00:58:58,017 --> 00:59:01,320 SO AT THE END WE PUT A 3, 6, 9 1554 00:59:01,320 --> 00:59:03,122 MONTHS TESTING ALTOGETHER SO WE 1555 00:59:03,122 --> 00:59:04,657 DON'T SEE CLEAR SEPARATION, WE 1556 00:59:04,657 --> 00:59:06,992 ALSO DON'T SEE CLEAR SEPARATION 1557 00:59:06,992 --> 00:59:09,094 MALE AND FEMALE, WE ALSO DON'T 1558 00:59:09,094 --> 00:59:11,730 SEE CLEAR SEPARATION BECAUSE OF 1559 00:59:11,730 --> 00:59:13,499 THE SMALL NUMBER WHETHER 3 1560 00:59:13,499 --> 00:59:15,701 MONTHS INJECTION OR 9 MONTHS 1561 00:59:15,701 --> 00:59:17,236 INJECTION OR BETTER BECAUSE YOU 1562 00:59:17,236 --> 00:59:18,838 CAN COMPARE WHEN IT'S 12 MONTHS 1563 00:59:18,838 --> 00:59:21,907 WE DID NOT SEE, FOR THE 1564 00:59:21,907 --> 00:59:23,476 FUNCTIONAL MRI IT WAS WAY OVER 1 1565 00:59:23,476 --> 00:59:26,479 YEAR SO A LONG LASTING EFFECT. 1566 00:59:26,479 --> 00:59:28,113 >> OKAY, 1 THING I'M SUPPOSED TO 1567 00:59:28,113 --> 00:59:31,150 REPEAT THE CME CODE, SORRY FOR 1568 00:59:31,150 --> 00:59:34,019 THE INTERRUPTION, IT'S 57683, 1569 00:59:34,019 --> 00:59:34,987 THAT'S 57683. 1570 00:59:34,987 --> 00:59:38,891 SO YEAH, WE HAVE 1 MORE QUESTION 1571 00:59:38,891 --> 00:59:40,025 AND THIS QUESTION, I THINK A LOT 1572 00:59:40,025 --> 00:59:42,294 OF US HAVE THIS QUESTION, WHAT 1573 00:59:42,294 --> 00:59:44,330 IS THE THRESHOLD MIN NUM NUMBER 1574 00:59:44,330 --> 00:59:47,399 OF NEURONS TRANSDUCED BY THE AAV 1575 00:59:47,399 --> 00:59:48,901 VECTOR NEEDED FOR EFFECTIVE 1576 00:59:48,901 --> 00:59:49,134 RESCUE. 1577 00:59:49,134 --> 00:59:50,102 >> THAT'S A VERY GOOD QUESTION. 1578 00:59:50,102 --> 00:59:52,771 >> AND ALSO LIKE THE CELL TYPES. 1579 00:59:52,771 --> 00:59:54,640 >> YEAH, SO THAT'S A VERY GOOD 1580 00:59:54,640 --> 00:59:58,377 QUESTION, VERY TOUGH TO ANSWER, 1581 00:59:58,377 --> 01:00:00,279 WE -- MANY OTHER VS DONE 1582 01:00:00,279 --> 01:00:02,248 DIFFERENT STUDIES, WE DID OTHER 1583 01:00:02,248 --> 01:00:06,018 STUDIES, I THINK MY FEELING IS 1584 01:00:06,018 --> 01:00:07,353 IF THIS IS 15-20%. 1585 01:00:07,353 --> 01:00:09,922 I THINK IF YOU HAVE 5% OF 1586 01:00:09,922 --> 01:00:13,559 NEURONS, BRAIN WIDE, YOU WILL 1587 01:00:13,559 --> 01:00:15,427 SEE A SIGNIFICANT DIFFERENCE AND 1588 01:00:15,427 --> 01:00:17,296 10% DEFINITELY, WE HAVE LOCAL 1589 01:00:17,296 --> 01:00:20,366 INJECTIONS OF 10%, WE CAN SEE 1590 01:00:20,366 --> 01:00:22,434 VERY SIGNIFICANT CHANGE AND SO, 1591 01:00:22,434 --> 01:00:27,506 IT DEPENDS ON THE GENES. 1592 01:00:27,506 --> 01:00:29,174 FOR THE SHANK 3 FOR YOUNG 1593 01:00:29,174 --> 01:00:32,745 NEURONS ARE VERY PLASTIC, THEY 1594 01:00:32,745 --> 01:00:33,946 KNOW, THEY WILL SHIFT THEIR 1595 01:00:33,946 --> 01:00:37,816 WEIGHT TO THE FUNCTIONAL NEURONS 1596 01:00:37,816 --> 01:00:41,520 INSTEAD OF AVERAGE, SO THIS WAS 1597 01:00:41,520 --> 01:00:44,323 WITH THE SYNAPSE CAN WORK REALLY 1598 01:00:44,323 --> 01:00:45,791 WELL, SO 5-10% WILL PROBABLY 1599 01:00:45,791 --> 01:00:46,492 MAKE A DIFFERENCE? 1600 01:00:46,492 --> 01:00:48,327 YOUR OTHER QUESTION? 1601 01:00:48,327 --> 01:00:48,594 I FORGOT. 1602 01:00:48,594 --> 01:00:51,797 >> OKAY, SO HAVE YOU LOOKED AT 1603 01:00:51,797 --> 01:00:53,399 SLEEP DISORREREDDERS AND THEIR 1604 01:00:53,399 --> 01:00:55,801 RESCUE IN TRANSGENIC -- 1605 01:00:55,801 --> 01:00:57,603 >> NEURON TYPE, SHANK 3 EXPRESS 1606 01:00:57,603 --> 01:00:59,939 IN EXCITED NEURONS AND INHIBITED 1607 01:00:59,939 --> 01:01:01,373 NEURONS BECAUSE THEY BOTH HAVE 1608 01:01:01,373 --> 01:01:03,042 EXCITE O SYNAPSE AND THESE 1609 01:01:03,042 --> 01:01:05,411 SYNAPSE BOTH NEED SO WE USE THE 1610 01:01:05,411 --> 01:01:06,779 SYNAPSE SIN PROMOTER SO IT GOES 1611 01:01:06,779 --> 01:01:09,415 TO BOTH TYPES AND THEY MATCH, 1612 01:01:09,415 --> 01:01:10,482 THE PERCENTAGE MATCHED 1613 01:01:10,482 --> 01:01:14,954 ENDOGENOUS AND WE TEST THIS. 1614 01:01:14,954 --> 01:01:15,154 SORRY. 1615 01:01:15,154 --> 01:01:16,422 >> OH, HI, WOBDERFUL TALK, 1616 01:01:16,422 --> 01:01:20,359 REALLY SHOWS THE VALUE OF 1617 01:01:20,359 --> 01:01:21,193 CONSTRUCT VALIDITY, YOU KNOW AND 1618 01:01:21,193 --> 01:01:23,095 YOU TALKED ABOUT SOME OF THE 1619 01:01:23,095 --> 01:01:24,830 RARE MUTATIONS THAT ARE 1620 01:01:24,830 --> 01:01:25,864 ASSOCIATED WITH SCHIZOPHRENIA, 1621 01:01:25,864 --> 01:01:27,766 AND I'M WONDERING IF YOU GUYS 1622 01:01:27,766 --> 01:01:30,302 ARE THINKING ABOUT WAYS TO MODEL 1623 01:01:30,302 --> 01:01:31,270 COPY NUMBER VARIANCE. 1624 01:01:31,270 --> 01:01:35,341 NYEAH, SO VERY GOOD QUESTION. 1625 01:01:35,341 --> 01:01:37,242 SO WHEN JOSH GARDENER WAS HERE 1626 01:01:37,242 --> 01:01:40,079 HE WAS VERY INTERESTED IN THE 22 1627 01:01:40,079 --> 01:01:43,882 Q DELETION, YOU CAN CAN MODEL 1628 01:01:43,882 --> 01:01:44,083 THEM. 1629 01:01:44,083 --> 01:01:46,652 WE CAN DO LARGE DELETION NO 1630 01:01:46,652 --> 01:01:48,754 PROBLEM, DUPLICATION IS MORE 1631 01:01:48,754 --> 01:01:51,857 DIFFICULT SO WE TESTED THAT FOR 1632 01:01:51,857 --> 01:01:56,462 I THINK 6 KB, 6 MEGABASE, 1633 01:01:56,462 --> 01:01:58,030 SMALLER EDITION, IT WORKS WELL 1634 01:01:58,030 --> 01:02:00,332 IN EMBRYOS BUT WE END UP WITH 1635 01:02:00,332 --> 01:02:02,768 NOT REACHING THE MARMOSET MODEL 1636 01:02:02,768 --> 01:02:05,037 BECAUSE IT ALSO HAVE CARDIAC 1637 01:02:05,037 --> 01:02:05,404 ISSUE. 1638 01:02:05,404 --> 01:02:06,772 AND WE'RE WORRIED THAT THE 1639 01:02:06,772 --> 01:02:08,340 MONKEY WILL NOT SURVIVE SO WE 1640 01:02:08,340 --> 01:02:10,209 DID NOT. 1641 01:02:10,209 --> 01:02:12,044 SO TECHNOLOGICALLY, YES WE CAN 1642 01:02:12,044 --> 01:02:13,946 DO CMEs. 1643 01:02:13,946 --> 01:02:16,682 >> OKAY, SO 1 ONLINE QUESTION 1644 01:02:16,682 --> 01:02:18,384 ABOUT SLEEP DISSEREDDER 1645 01:02:18,384 --> 01:02:18,851 PHENOTYPES. 1646 01:02:18,851 --> 01:02:20,319 >> YEAH, OH, THAT'S -- SO WE DID 1647 01:02:20,319 --> 01:02:23,255 A TEST AND WE DID NOT SEE 1648 01:02:23,255 --> 01:02:25,290 BECAUSE WE HAVE THESE VIDEOED WE 1649 01:02:25,290 --> 01:02:27,226 DID NOT SEE ANY SIGNIFICANT 1650 01:02:27,226 --> 01:02:28,460 DEFECT IN SLEEP, WE DON'T KNOW 1651 01:02:28,460 --> 01:02:33,032 WHETHER IT'S MONKEYS ARE 1652 01:02:33,032 --> 01:02:34,933 DIFFERENT FROM HUMAN, WE DON'T 1653 01:02:34,933 --> 01:02:36,802 KNOW IF IT'S IN THE HOUSING 1654 01:02:36,802 --> 01:02:39,672 CONDITION THEY DON'T HAVE 1655 01:02:39,672 --> 01:02:40,539 NATURALISTIC SLEEP, HAVE YOU 1656 01:02:40,539 --> 01:02:42,074 TURN ON AND TURN OFF, SO WE 1657 01:02:42,074 --> 01:02:43,442 DON'T KNOW WHICH IS THE CAUSE, 1658 01:02:43,442 --> 01:02:45,110 WHETHER IT'S BECAUSE OF HUMAN 1659 01:02:45,110 --> 01:02:46,545 MONKEY DIFFERENCE OR WHETHER 1660 01:02:46,545 --> 01:02:48,414 IT'S BECAUSE THE HOUSING 1661 01:02:48,414 --> 01:02:49,348 CONDITION DIFFERENCE, WE DON'T 1662 01:02:49,348 --> 01:02:52,685 KNOW ABOUT YOU WE DID TEST IT, 1663 01:02:52,685 --> 01:02:55,954 WE DID NOTICE SLEEP DIFFERENCE. 1664 01:02:55,954 --> 01:02:59,391 LAST QUESTION FROM YU GU, ARE 1665 01:02:59,391 --> 01:03:01,527 ALL SHANK 3 MUTATIONS FOR AUTISM 1666 01:03:01,527 --> 01:03:02,594 LOSS OF FUNCTION? 1667 01:03:02,594 --> 01:03:04,663 >> SO FAR, YES, MOST OF THEM ON 1668 01:03:04,663 --> 01:03:05,631 LE LESIONS ACTUALLY. 1669 01:03:05,631 --> 01:03:06,231 YEAH. 1670 01:03:06,231 --> 01:03:06,799 >> OKAY, THAT'S IT. 1671 01:03:06,799 --> 01:03:09,935 THANK YOU EVERYONE FOR YOUR TIME 1672 01:03:09,935 --> 01:03:10,302 AND COMING. 1673 01:03:10,302 --> 01:03:20,512 [ APPLAUSE ]