1 00:00:08,273 --> 00:00:14,379 THANKS FOR COMING IN PERSON 2 00:00:14,379 --> 00:00:17,783 AND THE NUMBER IS 7657 AND THERE 3 00:00:17,783 --> 00:00:19,217 WILL BE SLIDE. 4 00:00:19,217 --> 00:00:20,552 MY NAME IS JOHN. 5 00:00:20,552 --> 00:00:22,354 I'M A PROGRAM OFFICER AT NIDA 6 00:00:22,354 --> 00:00:28,093 AND MEMBER OF THE ECONOMIST FOR 7 00:00:28,093 --> 00:00:36,701 THE PROGRAM AND ON BEHALF OF THE 8 00:00:36,701 --> 00:00:39,571 PROGRAM JENNIFER PHILLIPS 9 00:00:39,571 --> 00:00:41,306 CREMINS IS AN ASSOCIATE 10 00:00:41,306 --> 00:00:48,013 PROFESSOR IN GENETICS AT THE 11 00:00:48,013 --> 00:00:51,416 UNIVERSITY OF PENNSYLVANIA AND 12 00:00:51,416 --> 00:00:56,855 SHE OBTAINED AN NIH NEW 13 00:00:56,855 --> 00:01:05,530 INNOVATOR AWARD AND NUCLEOME 14 00:01:05,530 --> 00:01:08,066 AWARD AND THE PRESTIGIOUS NIH 15 00:01:08,066 --> 00:01:11,269 PIONEER AWARD AMONG OTHER 16 00:01:11,269 --> 00:01:11,503 GRANTS. 17 00:01:11,503 --> 00:01:14,072 THAT'S THE EXAMPLE OF HOW NIH 18 00:01:14,072 --> 00:01:19,311 AND THE COMMON FUND CAN SERVE AS 19 00:01:19,311 --> 00:01:21,713 AN INCUBATOR SPATE FOR TALENT. 20 00:01:21,713 --> 00:01:23,648 TODAY SHE'LL TELL US ABOUT THE 21 00:01:23,648 --> 00:01:29,554 SCIENCE OF CONNECTIONS BRIDGING 22 00:01:29,554 --> 00:01:32,724 CHROMATIN FOLDING AND SYNAPTIC 23 00:01:32,724 --> 00:01:33,024 PHYSIOLOGY. 24 00:01:33,024 --> 00:01:37,162 TAKE IT AWAY, JEN. 25 00:01:37,162 --> 00:01:39,097 >> HELLO, EVERYONE. 26 00:01:39,097 --> 00:01:44,135 IT'S A GREAT PRIF LEN -- 27 00:01:44,135 --> 00:01:47,439 PRIVILEGE TO BE HERE AND WANT I 28 00:01:47,439 --> 00:01:49,708 WANT TO THANK FOR THE INVITATION 29 00:01:49,708 --> 00:01:55,580 FOR THE LECTURE. 30 00:01:55,580 --> 00:01:57,582 I'M GOING TO TALK TO ABOUT 31 00:01:57,582 --> 00:01:57,949 MEMORY. 32 00:01:57,949 --> 00:01:59,451 IT'S IMPORTANT TO ALL OF US AND 33 00:01:59,451 --> 00:02:03,121 IT UNDER LIES OUR ABILITY TO 34 00:02:03,121 --> 00:02:07,025 READ, WRITE, ACQUIRE NEW SKILLS, 35 00:02:07,025 --> 00:02:07,993 MAINTAIN RELATIONSHIPS. 36 00:02:07,993 --> 00:02:08,760 IT'S AN IMPORTANT QUESTION 37 00:02:08,760 --> 00:02:13,865 BECAUSE IT'S A UNIFIER OF THE 38 00:02:13,865 --> 00:02:15,100 HUMAN CONDITION. 39 00:02:15,100 --> 00:02:17,502 NO MATTER WHAT BACKGROUND WE 40 00:02:17,502 --> 00:02:19,604 HOLD SPACE WITH US TO CARRY 41 00:02:19,604 --> 00:02:25,844 WONDERFUL MEMORIES AND DIFFICULT 42 00:02:25,844 --> 00:02:29,114 EVENTS LIKE ISOLATION, LOSS OF A 43 00:02:29,114 --> 00:02:29,915 LOVED ONE OR TRAUMA. 44 00:02:29,915 --> 00:02:34,052 LOSS OF A MEMORY UNDER LIES 45 00:02:34,052 --> 00:02:37,155 DISEASES LIKE ALZHEIMER'S AND 46 00:02:37,155 --> 00:02:40,225 EXACERBATION OR RESILIENCE IS 47 00:02:40,225 --> 00:02:42,360 CRITICAL FOR PTSD. 48 00:02:42,360 --> 00:02:44,963 SO WHAT ENCODES MEMORY? 49 00:02:44,963 --> 00:02:47,399 ONE LEADING LINE OF THOUGHT IS 50 00:02:47,399 --> 00:02:49,668 IN THE LIES IN NEURONS AND THE 51 00:02:49,668 --> 00:02:51,102 CONNECTIONS BETWEEN THEM AND 52 00:02:51,102 --> 00:02:53,405 SYNAPSES AND THE MAMMALIAN BRAIN 53 00:02:53,405 --> 00:02:55,607 THERE'S BILLIONS OF NEURONS 54 00:02:55,607 --> 00:02:57,509 CONNECTED BY TRILLIONS OF 55 00:02:57,509 --> 00:02:58,376 SYNAPSES AND WHAT'S SO 56 00:02:58,376 --> 00:03:00,011 INTERESTING IS THEY'RE NOT 57 00:03:00,011 --> 00:03:02,581 STATIC BUT RATHER DYNAMICALLY 58 00:03:02,581 --> 00:03:05,417 ALTERED IN A CONTINUOUS MANNER 59 00:03:05,417 --> 00:03:06,451 ACROSS THE LIFE TIME OF AN 60 00:03:06,451 --> 00:03:07,619 INDIVIDUAL IN RESPONSE TO 61 00:03:07,619 --> 00:03:09,154 EXPERIENCES. 62 00:03:09,154 --> 00:03:11,623 SO I'D LIKE TO SHARE THIS VIDEO 63 00:03:11,623 --> 00:03:14,492 OF DATA FROM JIM McGEE'S LAB 64 00:03:14,492 --> 00:03:18,730 BECAUSE IT HIGHLIGHTS THE 65 00:03:18,730 --> 00:03:21,566 DIFFICULTY AND EXCITEMENT OF THE 66 00:03:21,566 --> 00:03:23,602 PROBLEM SPACE FOR SCIENTISTS 67 00:03:23,602 --> 00:03:25,870 STUDYING MEMORY. 68 00:03:25,870 --> 00:03:29,174 THEY'RE USING CALCIUM CENTER TO 69 00:03:29,174 --> 00:03:29,874 TRACK LONGITUDINALLY POTENTIAL 70 00:03:29,874 --> 00:03:32,310 FIRING IN NEURONS IN THE MOUSE 71 00:03:32,310 --> 00:03:32,544 BRAIN. 72 00:03:32,544 --> 00:03:35,013 THE MOUSE IS IN THE DARK AND 73 00:03:35,013 --> 00:03:37,515 EXPOSED TO A SENSORY STIMULUS. 74 00:03:37,515 --> 00:03:38,817 THIS HIGHLIGHTS HOW DIFFICULT 75 00:03:38,817 --> 00:03:39,884 IT'S GOING TO BE TO UNDERSTAND 76 00:03:39,884 --> 00:03:42,921 WHAT UNDER LIES AND MAINTAINS 77 00:03:42,921 --> 00:03:44,189 MEMORY OVER THE LONG TERM 78 00:03:44,189 --> 00:03:45,590 BECAUSE CLEARLY THE NEURONS ARE 79 00:03:45,590 --> 00:03:47,258 CHANGING OVER TIME AND EVEN THE 80 00:03:47,258 --> 00:03:49,461 SAME NEURON MIGHT BE HAVING 81 00:03:49,461 --> 00:03:51,129 DIFFERENT PATTERNS OF 82 00:03:51,129 --> 00:03:53,565 STIMULATION TEMPORALLY. 83 00:03:53,565 --> 00:03:57,102 SO WE LIKE TO TAKE WHAT I CALL A 84 00:03:57,102 --> 00:03:58,103 MULTI-SCALE APPROACH. 85 00:03:58,103 --> 00:04:00,105 THE IDEA IS THE BRAIN IS 86 00:04:00,105 --> 00:04:03,108 REGULATED AT MANY DIFFERENT 87 00:04:03,108 --> 00:04:04,409 BIOLOGICAL SCALES AND PART OF 88 00:04:04,409 --> 00:04:05,644 THE COMPLICATION IN FINDING 89 00:04:05,644 --> 00:04:08,580 PATTERNS THAT LEAD TO BIOLOGICAL 90 00:04:08,580 --> 00:04:10,081 INSIGHT THROUGH ALL THESE 91 00:04:10,081 --> 00:04:11,182 CHALLENGES IS THE SCALES ALSO 92 00:04:11,182 --> 00:04:14,719 MUST BE INTEGRATED TO UNDERSTAND 93 00:04:14,719 --> 00:04:17,055 HOW NEURAL CIRCUITS WORK. 94 00:04:17,055 --> 00:04:19,157 OF COURSE THERE'S LARGE SCALE 95 00:04:19,157 --> 00:04:21,126 ANATOMY AND PHYSICAL CONNECTIONS 96 00:04:21,126 --> 00:04:23,628 BETWEEN NEURONS AND LABELLING OF 97 00:04:23,628 --> 00:04:27,132 N GRAMS AND PREVIOUS FIRING OF 98 00:04:27,132 --> 00:04:29,401 ACTION POTENTIALS AND 99 00:04:29,401 --> 00:04:32,904 PHYSIOLOGICAL PATTERNS STRUCTURE 100 00:04:32,904 --> 00:04:36,541 AND BIO CHEMICAL AND SYNAPTIC 101 00:04:36,541 --> 00:04:39,110 PLASTICITY AND NUCLEUS WHERE WE 102 00:04:39,110 --> 00:04:41,880 THINK POST TRANSLATIONAL 103 00:04:41,880 --> 00:04:45,116 CHROMATIN AND FIBERS AND 104 00:04:45,116 --> 00:04:48,720 VARIATION IN THE GENETIC 105 00:04:48,720 --> 00:04:50,555 SEQUENCE WHICH MAY CONTRIBUTE TO 106 00:04:50,555 --> 00:04:54,092 DIFFERENCES IN CIRCUITS. 107 00:04:54,092 --> 00:04:55,593 WE AIM TO STUDY TWO OR THREE 108 00:04:55,593 --> 00:04:57,696 MODEL SYSTEMS AND BEGIN TO 109 00:04:57,696 --> 00:04:59,998 GATHER THE INFORMATION IN THE 110 00:04:59,998 --> 00:05:01,099 MODEL SYSTEMS AND INTEGRATE TO 111 00:05:01,099 --> 00:05:01,933 LEAD TO INSIGHT. 112 00:05:01,933 --> 00:05:04,836 THIS IS WHERE WE'RE GOING, GOING 113 00:05:04,836 --> 00:05:05,437 FORWARD. 114 00:05:05,437 --> 00:05:07,605 I HAVE TO SAY OVER THE FIRST 10 115 00:05:07,605 --> 00:05:10,809 YEARS OF THE LAB FOCUSES ON THE 116 00:05:10,809 --> 00:05:11,609 NUCLEUS AND HOW HEADING OUT TO 117 00:05:11,609 --> 00:05:12,410 THE SYNAPSE. 118 00:05:12,410 --> 00:05:15,513 WHERE WE FOCUSSED IS ON 119 00:05:15,513 --> 00:05:17,749 UNDERSTANDING SO-CALLED 120 00:05:17,749 --> 00:05:26,958 EPIGENETIC OR CHROMATIN 121 00:05:26,958 --> 00:05:31,730 MECHANISMS TO DNA OR HISTONES 122 00:05:31,730 --> 00:05:33,798 DYNAMICALLY ALTERED THROUGH THE 123 00:05:33,798 --> 00:05:35,266 LIFE TIME OF A CIRCUIT. 124 00:05:35,266 --> 00:05:39,104 THE CLASSICAL APPROACH OF WHAT 125 00:05:39,104 --> 00:05:40,572 CHROMATIN MARKS IS FUNCTIONAL IS 126 00:05:40,572 --> 00:05:45,110 TO DO A TYPE OF GENOME EDITING 127 00:05:45,110 --> 00:05:47,612 AND LOOK AT HOW THE LOSS OF 128 00:05:47,612 --> 00:05:49,447 FUNCTION MUTATION AFFECT 129 00:05:49,447 --> 00:05:50,915 EXPRESSION OF A NEARBY GENE. 130 00:05:50,915 --> 00:05:52,917 WE'VE TAKEN WHAT I CALLED A 131 00:05:52,917 --> 00:05:55,620 STRUCTURED APPROACH IN WHICH WE 132 00:05:55,620 --> 00:05:58,389 HAVE MAPPED THE HIGHER ORDER 133 00:05:58,389 --> 00:06:01,726 FOLDING WITHIN THE NUCLEUS AND 134 00:06:01,726 --> 00:06:02,427 COMPUTATIONALLY IDENTIFIED THE 135 00:06:02,427 --> 00:06:04,496 SPATIAL OR PHYSICAL TOUCH DOWN 136 00:06:04,496 --> 00:06:06,297 POINTS BETWEEN DISTAL DNA 137 00:06:06,297 --> 00:06:08,867 FRAGMENTS AND STUDIED HOW GENES 138 00:06:08,867 --> 00:06:11,603 ARE REGULATED FROM LONG RANGE 139 00:06:11,603 --> 00:06:14,806 MECHANISMS. 140 00:06:14,806 --> 00:06:16,241 SO, WHEN I STARTED IN THE FIELD 141 00:06:16,241 --> 00:06:20,111 AS A POSTDOC BACK IN 2008 OR SO, 142 00:06:20,111 --> 00:06:20,845 THIS WAS THE TECHNOLOGY AND 143 00:06:20,845 --> 00:06:21,446 WHERE THE FIELD WAS AT THAT 144 00:06:21,446 --> 00:06:23,615 TIME. 145 00:06:23,615 --> 00:06:29,754 WE COULD USE A VERSION OF DNA 146 00:06:29,754 --> 00:06:32,524 PHISH TO DETERMINE THERE WAS 147 00:06:32,524 --> 00:06:33,591 INDEPENDENT LOCATIONS IN THE 148 00:06:33,591 --> 00:06:33,825 NUCLEUS. 149 00:06:33,825 --> 00:06:36,561 AT THE OTHER END OF THE SPECTRUM 150 00:06:36,561 --> 00:06:39,097 USE DNA PHISH AND PAIR-WISE 151 00:06:39,097 --> 00:06:40,899 PROBES TO LOOK AT FOCAL DOTS IN 152 00:06:40,899 --> 00:06:43,635 THE NUCLEUS AND BEGIN TO MAKE 153 00:06:43,635 --> 00:06:46,337 INFERENCE OF THE OVERLAP OF THE 154 00:06:46,337 --> 00:06:49,707 DOTS AND IT WOULD REPRESENT A 155 00:06:49,707 --> 00:06:50,375 LONG-RANGE INTERACTION BETWEEN 156 00:06:50,375 --> 00:06:52,377 TWO DISTAL FRAGMENTS. 157 00:06:52,377 --> 00:06:54,312 EVERYTHING ELSE IN BETWEEN WAS 158 00:06:54,312 --> 00:06:56,247 THEORETICAL OR ABSTRACTION OF 159 00:06:56,247 --> 00:06:58,049 POSSIBLE FOLDING PATTERNS. 160 00:06:58,049 --> 00:06:59,117 AND SO WHAT I THINK I'D LIKE TO 161 00:06:59,117 --> 00:07:00,752 SAY HERE IS THAT OVER THE LAST 162 00:07:00,752 --> 00:07:03,588 10 YEARS OR SO IT'S BEEN A WILD 163 00:07:03,588 --> 00:07:09,127 RIDE I THINK FROM ALL COLLEAGUES 164 00:07:09,127 --> 00:07:15,300 IN THE 40 NUCLEOME AND HAVE 165 00:07:15,300 --> 00:07:17,902 FILLED IN THE GAPS CONFIRMING 166 00:07:17,902 --> 00:07:20,638 TERRITORIES AND ALSO FINDING AB 167 00:07:20,638 --> 00:07:23,041 COMPARTMENTS, SUBCOMPARTS AND 168 00:07:23,041 --> 00:07:25,610 NANO COMPARTMENTS TOP LOGICALLY 169 00:07:25,610 --> 00:07:27,879 ASSOCIATED DOMAINS AND TAGS 170 00:07:27,879 --> 00:07:30,415 WITHIN TAGS AND EVEN NANO TAGS 171 00:07:30,415 --> 00:07:32,083 AND LONG-RANGE LOOPING 172 00:07:32,083 --> 00:07:32,417 INTERACTIONS. 173 00:07:32,417 --> 00:07:34,686 SO FOR THOSE THAT ARE IN A 174 00:07:34,686 --> 00:07:37,388 BROADER AUDIENCE I WANTED TO 175 00:07:37,388 --> 00:07:39,591 SHOW THE TYPE OF DATA THAT'S 176 00:07:39,591 --> 00:07:41,392 BEEN ABLE TO DRIVE DISCOVERIES 177 00:07:41,392 --> 00:07:42,994 IN THE FIELD OVER THE LAST 10 178 00:07:42,994 --> 00:07:43,394 YEARS. 179 00:07:43,394 --> 00:07:47,866 THIS IS A SO-CALLED CHROMOSOME 180 00:07:47,866 --> 00:07:50,935 CONFIRMATION CAPTURE MAP THROUGH 181 00:07:50,935 --> 00:07:57,041 PRINCIPLES OF PROXIMAL LOCATION 182 00:07:57,041 --> 00:07:58,843 ORIGINALLY BACK AROUND 2002. 183 00:07:58,843 --> 00:08:01,279 THE IDEA IS IF YOU POST THE 184 00:08:01,279 --> 00:08:02,714 GENOME FRAGMENT OF INTEREST ON 185 00:08:02,714 --> 00:08:06,417 BOTH THE X AND THE Y AXIS, ONE 186 00:08:06,417 --> 00:08:08,887 CAN LOOK AT THE PIXEL 187 00:08:08,887 --> 00:08:10,321 INTERSECTING THE PARTICULAR 188 00:08:10,321 --> 00:08:12,123 GENOMIC LOCI AND LOOK AT THE 189 00:08:12,123 --> 00:08:14,425 READS IN THE PIXEL. 190 00:08:14,425 --> 00:08:15,994 THAT REPRESENT THE NUMBER OF 191 00:08:15,994 --> 00:08:19,597 TIMES THOSE TWO PARTICULAR 192 00:08:19,597 --> 00:08:23,768 FRAGMENTS WERE DETECTS AS 193 00:08:23,768 --> 00:08:27,005 ARTIFICIALLY 194 00:08:27,005 --> 00:08:28,106 >>Y GLUED TOGETHER IN 195 00:08:28,106 --> 00:08:29,874 THE PHYSICAL OR NUCLEAR SPACE. 196 00:08:29,874 --> 00:08:32,110 WHAT ONE CAN SEE IMMEDIATELY IS 197 00:08:32,110 --> 00:08:34,279 THERE'S EXCITING AND ALSO VERY 198 00:08:34,279 --> 00:08:36,014 DIFFICULT TO UNDERSTAND FOLDING 199 00:08:36,014 --> 00:08:37,949 PATTERNS THAT THESE MAPS 200 00:08:37,949 --> 00:08:38,216 REVEALED. 201 00:08:38,216 --> 00:08:40,251 AND ONE I WANT TO HIGHLIGHT HAVE 202 00:08:40,251 --> 00:08:46,090 THE SO-CALLED FOCAL DOTS. 203 00:08:46,090 --> 00:08:49,894 THEY HAVE BEEN VERY DIFFICULT 204 00:08:49,894 --> 00:08:52,230 WORK TO DETECT AND ANALYZE AND 205 00:08:52,230 --> 00:08:55,600 NOW WE HAVE THE ABILITY TO 206 00:08:55,600 --> 00:08:59,037 DETECT THEM GENOME WIDE AND THEY 207 00:08:59,037 --> 00:09:01,839 ARE REPRESENT BIO LOGICALLY IS 208 00:09:01,839 --> 00:09:09,647 AN INTERACTION WHERE THE TWO 209 00:09:09,647 --> 00:09:15,820 DISTAL FRAGMENTS CONTACT EACH 210 00:09:15,820 --> 00:09:19,590 OTHER AND THROUGH LOOP EXTRUSION 211 00:09:19,590 --> 00:09:25,596 WHERE AN ATP DEPENDENT MANNER 212 00:09:25,596 --> 00:09:27,098 MEDIATEDS THE BOUNDARIES. 213 00:09:27,098 --> 00:09:29,133 WHEN YOU SEE FOCAL DOTS OF THIS 214 00:09:29,133 --> 00:09:31,602 NATURE THEY'RE IMPORTANT BECAUSE 215 00:09:31,602 --> 00:09:33,438 THEY REPRESENT A SO-CALLED LONG 216 00:09:33,438 --> 00:09:34,706 RANGE LOOPING INTERACTION. 217 00:09:34,706 --> 00:09:37,675 WHEN MY LAP STARTED WE COULD SEE 218 00:09:37,675 --> 00:09:41,112 THE TECHNOLOGY WAS ADVANCING 219 00:09:41,112 --> 00:09:42,480 RAPIDLY AND KNEW REFERENCE MAPS 220 00:09:42,480 --> 00:09:44,115 WERE BEGINNING TO BE CREATED A 221 00:09:44,115 --> 00:09:45,116 WIDE RANGE OF CELL TYPES. 222 00:09:45,116 --> 00:09:47,585 THE QUESTION WE HAD IS WHAT IF 223 00:09:47,585 --> 00:09:49,587 WE SORT OF MOVED TO THE NEXT 224 00:09:49,587 --> 00:09:51,122 THING THAT WAS GOING TO BE 225 00:09:51,122 --> 00:09:53,825 DIFFICULT AND THAT IS IF WE KNOW 226 00:09:53,825 --> 00:09:56,160 THE GENOME FOLDS INTO MANY 227 00:09:56,160 --> 00:09:58,696 COMPLICATED STRUCTURES HOW DO WE 228 00:09:58,696 --> 00:10:00,264 FIGURE OUT WHAT ASPECTS OF 229 00:10:00,264 --> 00:10:01,332 STRUCTURE ARE FUNCTIONAL AND 230 00:10:01,332 --> 00:10:03,134 GIVE INSIGHT TO WHAT THE GENOME 231 00:10:03,134 --> 00:10:04,669 IS DOING? 232 00:10:04,669 --> 00:10:06,971 I WANTED TO SHARE THIS CAME OUT 233 00:10:06,971 --> 00:10:09,107 IN THE MEETING WITH THE STUDENTS 234 00:10:09,107 --> 00:10:11,376 AND POSTDOCS OVER LUNCH, HOW 235 00:10:11,376 --> 00:10:12,643 DOES ONE PICK A BIOLOGICAL 236 00:10:12,643 --> 00:10:14,545 PROBLEM AND FOR US WHAT WE TRIED 237 00:10:14,545 --> 00:10:15,847 TO DO IS FIND A QUESTION 238 00:10:15,847 --> 00:10:18,783 TIMELESS AND SO I'D LIKE TO USE 239 00:10:18,783 --> 00:10:21,119 THIS EXAMPLE OF THE EARLIEST 240 00:10:21,119 --> 00:10:23,921 POSSIBLE REFERENCE I COULD FIND 241 00:10:23,921 --> 00:10:27,325 FROM THOMAS HUNT MORGAN BACK 242 00:10:27,325 --> 00:10:29,994 WHEN NATURE PAPERS WERE SINGLE 243 00:10:29,994 --> 00:10:31,629 PAGE AND ONE LAND DRAWN FIGURE. 244 00:10:31,629 --> 00:10:34,565 THERE WAS NO SOCIAL MEDIA BUT 245 00:10:34,565 --> 00:10:39,137 CLEARLY NO ABSENCE OF SNARK AND 246 00:10:39,137 --> 00:10:41,439 THERE WAS AN ARRANGEMENT OF 247 00:10:41,439 --> 00:10:44,409 LINKED GENES IN THREE DIMENSIONS 248 00:10:44,409 --> 00:10:45,309 BASED ON THE ASSUMPTION THE 249 00:10:45,309 --> 00:10:47,512 DISTANCE BETWEEN TWO LOCI IS 250 00:10:47,512 --> 00:10:50,748 PROPORTIONAL TO THE OBSERVED 251 00:10:50,748 --> 00:10:52,617 CROSS OVER VALUE AND BELIEVES 252 00:10:52,617 --> 00:10:54,152 THERE'S A BETTER AGREEMENT 253 00:10:54,152 --> 00:10:55,453 BETWEEN OBSERVATION AND 254 00:10:55,453 --> 00:10:56,988 EXPECTATION THAN THE HYPOTHESIS 255 00:10:56,988 --> 00:10:58,923 OF A STRICTLY LINEAR ARRANGEMENT 256 00:10:58,923 --> 00:11:00,158 WE HAVE DEVELOPED. 257 00:11:00,158 --> 00:11:02,593 SO I THINK PROBABLY JOHN CAN 258 00:11:02,593 --> 00:11:03,594 SPEAK TO THIS AS WELL AS MANY IN 259 00:11:03,594 --> 00:11:07,298 THE 3-D GENOME FIELD I SEE PEDRO 260 00:11:07,298 --> 00:11:09,100 HERE, THESE TYPES OF DEBATES ARE 261 00:11:09,100 --> 00:11:11,436 STILL ONGOING AT THIS EXACT TIME 262 00:11:11,436 --> 00:11:13,671 ADVANCING ALL THE WAY TO 2024 263 00:11:13,671 --> 00:11:15,540 AND WILL CERTAINLY BE HAPPENING 264 00:11:15,540 --> 00:11:24,916 AT THE CLOSING MEETING OF THE 40 265 00:11:24,916 --> 00:11:26,384 NUCELEOME PHASE 2 AND THERE'S SO 266 00:11:26,384 --> 00:11:28,319 MUCH FOR THE NEXT WAVE OF 267 00:11:28,319 --> 00:11:29,087 SCIENTISTS AFTER US. 268 00:11:29,087 --> 00:11:30,455 AFTER THE YEARS WE'VE CONDUCTED 269 00:11:30,455 --> 00:11:32,023 A VARIETY OF STUDIES. 270 00:11:32,023 --> 00:11:34,258 FIRST IN MODELS OF NEURONS 271 00:11:34,258 --> 00:11:35,226 THROUGH NEURAL DIFFERENTIATION 272 00:11:35,226 --> 00:11:39,597 AND REPROGRAMMING AND MORE 273 00:11:39,597 --> 00:11:40,765 RECENTLY NEURAL CIRCUIT 274 00:11:40,765 --> 00:11:42,400 STIMULATION IN VITRO AND IN 275 00:11:42,400 --> 00:11:42,600 VIVO. 276 00:11:42,600 --> 00:11:44,335 INDEED LOOPS ARE HIGHLY DYNAMIC 277 00:11:44,335 --> 00:11:46,971 ACROSS ALL THE SYSTEMS. 278 00:11:46,971 --> 00:11:48,539 MOST IMPORTANTLY CHANGING ON 279 00:11:48,539 --> 00:11:50,041 FAST TIME SCALES DURING 280 00:11:50,041 --> 00:11:52,844 ACTIVATION OF NEURAL CIRCUITS 281 00:11:52,844 --> 00:11:54,979 AND ALSO NECESSARY AND ESSENTIAL 282 00:11:54,979 --> 00:12:01,119 FOR THE ACTIVATION OF CRITICAL 283 00:12:01,119 --> 00:12:03,221 SYNAPTIC, IMMEDIATE, EARLY AND 284 00:12:03,221 --> 00:12:07,358 DELAYED RESPONSE GENES IN VIVO 285 00:12:07,358 --> 00:12:10,628 AND IN VITRO AND PROTEINS TO GET 286 00:12:10,628 --> 00:12:12,597 AT THE GENOME STRUCTURE 287 00:12:12,597 --> 00:12:14,198 RELATIONSHIP RAND THIS IS AN 288 00:12:14,198 --> 00:12:15,933 EXAMPLE WHERE WE CREATED 289 00:12:15,933 --> 00:12:17,768 SOMETHING CALLED LIGHT ACTIVATED 290 00:12:17,768 --> 00:12:19,604 DYNAMIC LOOPING TO FORM LOOPS ON 291 00:12:19,604 --> 00:12:22,206 DEMAND AND ASK IF THEY WERE 292 00:12:22,206 --> 00:12:26,878 SUFFICIENT FOR EN LANCER 293 00:12:26,878 --> 00:12:32,350 PROMOTER AND -- ENHANCER AND 294 00:12:32,350 --> 00:12:37,955 GENE EXPRESSION AND WE WORKED 295 00:12:37,955 --> 00:12:39,790 WITH THE GILBERT LAB TO 296 00:12:39,790 --> 00:12:45,129 UNDERSTAND COHESIVE MEDIATED 297 00:12:45,129 --> 00:12:48,699 LOOP EXTRUSION WAS NEEDED FOR 298 00:12:48,699 --> 00:12:53,204 LOCATIONS IN THE GENOME IN EARLY 299 00:12:53,204 --> 00:12:54,005 S PHASE. 300 00:12:54,005 --> 00:12:56,774 THESE ARE ALL ALUMNI WHO WORKED 301 00:12:56,774 --> 00:12:59,110 ON THE EARLY STAGES AND THEY NOW 302 00:12:59,110 --> 00:13:02,146 HAVE HIGH FLYING CAREERS IN 303 00:13:02,146 --> 00:13:03,748 START-UP COMPANIES IN ARTIFICIAL 304 00:13:03,748 --> 00:13:05,316 INTELLIGENCE AS WELL AS IN THE 305 00:13:05,316 --> 00:13:07,585 DEVELOPMENT OF THERAPEUTICS. 306 00:13:07,585 --> 00:13:10,454 GOOD KIM AND REGE BOTH MY FIRST 307 00:13:10,454 --> 00:13:11,822 POSTDOCS IN THE LAB AND NOW EACH 308 00:13:11,822 --> 00:13:16,427 RUN LABORATORIES IN SOUTH KOREA 309 00:13:16,427 --> 00:13:19,230 AS WELL AS IN MUMBAI AND IN THE 310 00:13:19,230 --> 00:13:20,565 REPLICATION STUDY DR. EMMERSON 311 00:13:20,565 --> 00:13:27,605 IS A POSTDOC AND DR. COOK AT THE 312 00:13:27,605 --> 00:13:31,742 FDA AND OTHERS ARE IN THE JOB 313 00:13:31,742 --> 00:13:33,144 MARKET AND FABULOUS 314 00:13:33,144 --> 00:13:35,580 COMPUTATIONAL BIOLOGISTS. 315 00:13:35,580 --> 00:13:37,682 ANOTHER THING WE'VE DONE IN THE 316 00:13:37,682 --> 00:13:41,619 RECENT FUTURE IS THINK OF 317 00:13:41,619 --> 00:13:44,989 DISEASE AS NATURE'S PERTURBATION 318 00:13:44,989 --> 00:13:47,024 AND WONDER WHEN WE BROKE THE 3-D 319 00:13:47,024 --> 00:13:49,126 GENOME WHAT WOULD HAPPEN TO THE 320 00:13:49,126 --> 00:13:50,962 GENE EXPRESSION IN A PATH LOGIC 321 00:13:50,962 --> 00:13:51,762 SITUATION. 322 00:13:51,762 --> 00:13:56,133 WE CHOSE WHAT WE THOUGHT WAS A 323 00:13:56,133 --> 00:13:57,134 DISORDER KNOWN IN THE TEXTBOOKS 324 00:13:57,134 --> 00:14:00,171 TO BE DRIVEN BY A SINGLE 325 00:14:00,171 --> 00:14:02,707 MUTATION RAY SHORT REPEAT TRACK 326 00:14:02,707 --> 00:14:06,143 IN THE FML1 GENE IN THE UTR. 327 00:14:06,143 --> 00:14:08,045 FOR REASONS THAT ARE STILL 328 00:14:08,045 --> 00:14:09,614 POORLY UNDERSTAND, THIS SEQUENCE 329 00:14:09,614 --> 00:14:10,715 GROWS OUT OF CONTROL. 330 00:14:10,715 --> 00:14:14,752 IT REACHES A LENGTH OF 200CGGs 331 00:14:14,752 --> 00:14:16,854 AND THEN BECOMES FULL MUTATION 332 00:14:16,854 --> 00:14:20,458 AND AT THAT TIME THERE IS 333 00:14:20,458 --> 00:14:23,160 SO-CALLED EPIGENETIC SILENCING 334 00:14:23,160 --> 00:14:25,563 OF THE FMR1 GENE AND QUITE 335 00:14:25,563 --> 00:14:27,131 SEVERE DISEASE. 336 00:14:27,131 --> 00:14:29,433 THE TEAM FOUND IN THE SYNDROME 337 00:14:29,433 --> 00:14:33,371 THERE'S ISN'T JUST A LOCAL 338 00:14:33,371 --> 00:14:37,108 SILENCING OF THE FMR1 BUT IN THE 339 00:14:37,108 --> 00:14:45,049 PCs AND NEURONS THAT HAVE THIS 340 00:14:45,049 --> 00:14:47,318 FRAGILE DOMAINS AMONG AUTOSOME. 341 00:14:47,318 --> 00:14:49,153 THEY COME TOGETHER TO PHYSICALLY 342 00:14:49,153 --> 00:14:50,488 CONTACT EACH OTHER AND THE GENES 343 00:14:50,488 --> 00:14:53,991 UNDER THE LOCATIONS ARE LARGELY 344 00:14:53,991 --> 00:14:56,627 SYNAPTIC GENES SILENCED AND 345 00:14:56,627 --> 00:15:02,233 LINKED TO FRAGILE X AND AUTISM. 346 00:15:02,233 --> 00:15:04,135 WHEN WE LOOK AT THE BASE OF 347 00:15:04,135 --> 00:15:06,470 THOSE PARTICULAR GENOMIC 348 00:15:06,470 --> 00:15:08,939 COORDINATES WE FOUND GENOME 349 00:15:08,939 --> 00:15:11,609 INSTABILITY WE DIDN'T EXPECT IN 350 00:15:11,609 --> 00:15:12,877 A MONOGENIC DISORDER AND CALL 351 00:15:12,877 --> 00:15:15,579 THEM BEACONS OF REPEAT EXPANSION 352 00:15:15,579 --> 00:15:25,990 BY CONTACTING HETEROCROW 353 00:15:25,990 --> 00:15:29,327 PLAT -- HOTERO CHROMATIN AND A 354 00:15:29,327 --> 00:15:32,997 GROUP IN A RARE FORM OF 355 00:15:32,997 --> 00:15:35,199 PEDIATRIC BRAIN CANCER FOUND A 356 00:15:35,199 --> 00:15:37,068 SIMILAR PATTERN THEY ARE CALL 357 00:15:37,068 --> 00:15:39,003 TULIPS. 358 00:15:39,003 --> 00:15:43,607 THE SAME IDEA THERE'S LARGE 359 00:15:43,607 --> 00:15:48,312 SCALE HETEROCHROMATINS AND THINK 360 00:15:48,312 --> 00:15:50,748 IT WILL CAN MEAN WE HAVE NEW 361 00:15:50,748 --> 00:15:53,217 IDEAS FOR DRUGGABLE TARGETS IN 362 00:15:53,217 --> 00:15:55,186 THUS FAR INTRACTABLE 363 00:15:55,186 --> 00:15:55,686 NEUROLOGICAL DISORDERS. 364 00:15:55,686 --> 00:16:00,057 THIS WORK WAS LED BY A TEAM OF 365 00:16:00,057 --> 00:16:05,363 WONDERFUL PEOPLE WHO ARE STILL 366 00:16:05,363 --> 00:16:10,334 IN THE LAB. 367 00:16:10,334 --> 00:16:17,108 AND DURING THE PANDEMIC I THINK 368 00:16:17,108 --> 00:16:20,711 WE ALL WENT THROUGH SOME FORM OF 369 00:16:20,711 --> 00:16:25,616 EXISTENTIAL CRISIS AND I STARTED 370 00:16:25,616 --> 00:16:27,284 TO THINK ABOUT THE QUESTIONS THE 371 00:16:27,284 --> 00:16:29,687 LAB WANTS TO THINK IF GOING 372 00:16:29,687 --> 00:16:31,589 FORWARD ONCE WE'RE ALL ABLE TO 373 00:16:31,589 --> 00:16:34,458 GO BACK TOGETHER AND I WAS 374 00:16:34,458 --> 00:16:38,329 IMPACTED BY THE BOOK WRITTEN BY 375 00:16:38,329 --> 00:16:44,402 ERIC KANDEL AND TEACHES PEOPLE 376 00:16:44,402 --> 00:16:45,569 THE SEQUENCE OF EVENTS OR 377 00:16:45,569 --> 00:16:47,505 HISTORICAL EVENTS OF MANY OF THE 378 00:16:47,505 --> 00:16:48,839 CORE DISCOVERIES. 379 00:16:48,839 --> 00:16:51,008 AND HAD US THINKING ABOUT THE 380 00:16:51,008 --> 00:16:55,613 CONCEPT OF MEMORY AND CERTAINLY 381 00:16:55,613 --> 00:17:01,519 THE FOCUS HERE WAS A LOT OF ON 382 00:17:01,519 --> 00:17:03,154 SYNAPTIC PLASTICITY AND THOUGHT 383 00:17:03,154 --> 00:17:07,591 THERE'D BE IMPORTANT WAYS WHERE 384 00:17:07,591 --> 00:17:12,062 CRHROMATIN CAN PLAY A ROLE AND 385 00:17:12,062 --> 00:17:13,998 THEY'RE SCORED ON TIME SCALES OF 386 00:17:13,998 --> 00:17:16,233 DECADES AND BIO MOLECULES, RNA 387 00:17:16,233 --> 00:17:18,002 PROTEINS, ETCETERA, HAVE HALF 388 00:17:18,002 --> 00:17:19,203 LIVES ON THE MANNER OF HOURS UP 389 00:17:19,203 --> 00:17:23,874 TO A FEW DAYS. 390 00:17:23,874 --> 00:17:27,144 SO THERE HAS TO BE A CONNECTING 391 00:17:27,144 --> 00:17:28,779 POINT THAT MAINTAINS THINGS IN 392 00:17:28,779 --> 00:17:29,313 THE LONG TERM. 393 00:17:29,313 --> 00:17:32,249 ONE THING I WANTED TO SHARE IS 394 00:17:32,249 --> 00:17:35,519 OFTEN TIMES THE CLASSIC STUDIES 395 00:17:35,519 --> 00:17:38,823 OF NEURAL PHYSIOLOGY AND 396 00:17:38,823 --> 00:17:42,760 SYNAPTIC PLASTICITY MAY OVERLAP 397 00:17:42,760 --> 00:17:48,299 THE CONTRIBUTION OF CRHROMATIN 398 00:17:48,299 --> 00:17:49,700 AND IF WE CONNECT THE TIME 399 00:17:49,700 --> 00:17:53,704 SCALES WE CAN STUDY HOW THE 400 00:17:53,704 --> 00:17:59,109 NUCLEUS AND SYNAPSE INTERPLAY TO 401 00:17:59,109 --> 00:18:00,444 KEEP THINGS GOING IN THE LONG 402 00:18:00,444 --> 00:18:01,479 TERM. 403 00:18:01,479 --> 00:18:03,280 THERE'S CRITICAL DATA THROUGHOUT 404 00:18:03,280 --> 00:18:04,482 THE FIELD THAT FORM THE 405 00:18:04,482 --> 00:18:07,051 FOUNDATION FOR THIS IDEA. 406 00:18:07,051 --> 00:18:08,786 THERE'S A CLASSIC EM STUDY 407 00:18:08,786 --> 00:18:12,323 LOOKING AT A SINGLE NUCLEUS FROM 408 00:18:12,323 --> 00:18:18,863 A MAMMALIAN NEURON AND WE SEE 409 00:18:18,863 --> 00:18:26,036 MARK RESTRUCTURING OF CRHROMATI 410 00:18:26,036 --> 00:18:29,039 AND WE SEE RECOVERY AS ONE MIGHT 411 00:18:29,039 --> 00:18:31,041 EXPECT BUT THERE ARE POCKETS 412 00:18:31,041 --> 00:18:33,077 THAT REMAIN THAT OF COURSE WE 413 00:18:33,077 --> 00:18:36,380 DON'T KNOW FROM THIS IMAGE WHAT 414 00:18:36,380 --> 00:18:38,148 THAT GENETIC SEQUENCE IS BUT 415 00:18:38,148 --> 00:18:39,116 WE'RE EXCITED TO FIGURE THIS 416 00:18:39,116 --> 00:18:39,583 OUT. 417 00:18:39,583 --> 00:18:41,619 THE OTHER FOUNDATIONAL DATA IS 418 00:18:41,619 --> 00:18:42,720 THERE'S LESSER KNOWN STUDIES 419 00:18:42,720 --> 00:18:46,290 THAT HAVE LOOKED MULTIPLE YEARS 420 00:18:46,290 --> 00:18:51,362 AGO NOW ALMOST 10 YEARS OF CDC 421 00:18:51,362 --> 00:18:54,031 KNOCKOUT MICE AND ANIMALS AND 422 00:18:54,031 --> 00:18:57,801 KNOW THEY ARE HAVE DEFECTS IN 423 00:18:57,801 --> 00:18:59,603 GENOME WIDE FOLDING AND THEY 424 00:18:59,603 --> 00:19:00,804 DEMONSTRATED THERE WAS SEVERE 425 00:19:00,804 --> 00:19:02,673 LEARNING DEFECTS BOTH INABILITY 426 00:19:02,673 --> 00:19:07,511 OF ANIMALS TO LEARN THE WATER 427 00:19:07,511 --> 00:19:10,414 AND FEAR CONDITIONING. 428 00:19:10,414 --> 00:19:14,518 AT THE NEURAL PHYSIOLOGICAL 429 00:19:14,518 --> 00:19:16,320 LEVEL THERE WERE LONG-TERM 430 00:19:16,320 --> 00:19:18,355 DEFECTS IN POTENTIATION AND AT 431 00:19:18,355 --> 00:19:22,126 THE CELLULAR LEVEL THE KNOCKOUT 432 00:19:22,126 --> 00:19:25,729 LEADS TO DECREASED IN DENDRITIC 433 00:19:25,729 --> 00:19:27,231 AND SPINE SIZE AND THE DEFECTS 434 00:19:27,231 --> 00:19:28,999 ARE ACROSS SCALES AND WE THINK 435 00:19:28,999 --> 00:19:30,935 THERE'S A FOUNDATIONAL BASIS FOR 436 00:19:30,935 --> 00:19:31,135 THIS. 437 00:19:31,135 --> 00:19:34,905 THE OTHER IMPORTANT POINT IS 438 00:19:34,905 --> 00:19:36,840 JUST THAT IN THE CLASSIC 439 00:19:36,840 --> 00:19:39,543 LITERATURE AND SUMMARIZED BY 440 00:19:39,543 --> 00:19:41,812 KANDEL NOT ONLY DOES ANY FORM OF 441 00:19:41,812 --> 00:19:44,248 ACTION POTENTIAL LEAD TO CHANGES 442 00:19:44,248 --> 00:19:47,251 AT THE SYNAPSE BUT RAPID CHANGES 443 00:19:47,251 --> 00:19:51,589 IN THE NUCLEUS AT THE PRESYNAPSE 444 00:19:51,589 --> 00:19:54,825 THERE'S RAY RELEASE OF NEURAL 445 00:19:54,825 --> 00:19:57,127 TRANSMITTERS SUCH AS DOPAMINE OR 446 00:19:57,127 --> 00:20:01,365 GLUTAMATE AND LEADING TO 447 00:20:01,365 --> 00:20:02,900 STRENGTHENING OF SPECIFIC 448 00:20:02,900 --> 00:20:09,139 SYNAPSES OR SPINES AND INFLUX OF 449 00:20:09,139 --> 00:20:12,910 CALCIUM GOING RAPIDLY TO THE 450 00:20:12,910 --> 00:20:16,847 NUCLEUS TO FIRE AND SECONDARY 451 00:20:16,847 --> 00:20:21,719 RESPONSE GENES FOLLOW SHORTLY 452 00:20:21,719 --> 00:20:22,019 THEREAFTER. 453 00:20:22,019 --> 00:20:26,290 ONE EXCITING THOUGHT IN THE 454 00:20:26,290 --> 00:20:28,826 FIELD IS OF SYNAPTIC TAGGING AND 455 00:20:28,826 --> 00:20:29,293 CAPTURE. 456 00:20:29,293 --> 00:20:31,462 THE IDEA IS DURING THE LEARNING 457 00:20:31,462 --> 00:20:36,867 THERE'S THE EVER ELUSIVE BIO 458 00:20:36,867 --> 00:20:40,971 CHEMICAL SYNAPSE AND MARKS THE 459 00:20:40,971 --> 00:20:43,607 SPINES AND TRANSCRIPTIONAL 460 00:20:43,607 --> 00:20:46,010 PROGRAMS OR CERTAIN RNAs GO BACK 461 00:20:46,010 --> 00:20:49,246 TO THE SPINE AND LEAD TO THE BIO 462 00:20:49,246 --> 00:20:50,881 CHEMICAL MECHANISMS THAT 463 00:20:50,881 --> 00:20:52,549 PROPAGATE THE TAGS OVER THE LONG 464 00:20:52,549 --> 00:20:53,183 TERM. 465 00:20:53,183 --> 00:20:54,018 WE'RE EXCITED TO WORK ON THIS 466 00:20:54,018 --> 00:20:56,353 PROBLEM AND FIGURE OUT SOME 467 00:20:56,353 --> 00:20:57,621 DETAILS AMONG OTHER COLLEAGUES 468 00:20:57,621 --> 00:20:59,556 ALREADY INVESTED AND WORKING ON 469 00:20:59,556 --> 00:20:59,857 THE PROBLEM. 470 00:20:59,857 --> 00:21:01,291 AND WE BOILED IT DOWN TO THREE 471 00:21:01,291 --> 00:21:05,829 THINGS WE FIRST HAVE TO PROVE TO 472 00:21:05,829 --> 00:21:06,563 OURSELVES. 473 00:21:06,563 --> 00:21:10,868 FIRST IS FIND SOMETHING IN THE 474 00:21:10,868 --> 00:21:11,602 CHROMATIN THAT'S CONSISTENT AND 475 00:21:11,602 --> 00:21:14,605 REMAIN FOR A LONG TIME UPWARDS 476 00:21:14,605 --> 00:21:16,874 OF MONTHS OR MAYBE EVEN YEARS. 477 00:21:16,874 --> 00:21:19,143 THE SECOND IS WHATEVER THE 478 00:21:19,143 --> 00:21:20,611 PERSISTENT THING IT HAS TO GIVE 479 00:21:20,611 --> 00:21:28,018 A FLASHLIGHT OR BEACON TO WHAT 480 00:21:28,018 --> 00:21:32,890 RNAs MAY BE CHANGING AND QUAN WE 481 00:21:32,890 --> 00:21:35,359 FIND THE ONES BACK IT OUR 482 00:21:35,359 --> 00:21:37,061 SYNAPSE AND WE'D HAVE TO 483 00:21:37,061 --> 00:21:38,262 COLLABORATE WHAT IS GOING ON FOR 484 00:21:38,262 --> 00:21:40,964 THE PROPAGATION OF THE TAG BUT 485 00:21:40,964 --> 00:21:43,600 THINK WE HAVE TO FIND BOTH 486 00:21:43,600 --> 00:21:48,038 THINGS AND DISRUPTED TO SOME 487 00:21:48,038 --> 00:21:48,806 DEGREE IN A DISORDER WHERE 488 00:21:48,806 --> 00:21:52,342 THERE'S LOSS OR GAIN OF MEMORY. 489 00:21:52,342 --> 00:21:54,845 THE LAB IS DIVIDED AMONG FOUR 490 00:21:54,845 --> 00:21:55,045 AREAS. 491 00:21:55,045 --> 00:22:04,755 WE'RE STUDYING HOW CRHROMATIN I 492 00:22:04,755 --> 00:22:09,126 CHANGED IN IN VIVO AND LEARNING 493 00:22:09,126 --> 00:22:13,831 IN IN VITRO WE'RE BUILDING 494 00:22:13,831 --> 00:22:15,132 IMAGING TECHNOLOGIES TO CREATE 495 00:22:15,132 --> 00:22:17,634 OVER MANY YEARS SYNAPSE 496 00:22:17,634 --> 00:22:20,771 RESOLUTION ACTIVITY DEPENDENT 497 00:22:20,771 --> 00:22:23,507 NEURAL CONNECTOME MAPS AND OTHER 498 00:22:23,507 --> 00:22:24,708 CONNECTIVITY PROBLEM AND STUDY 499 00:22:24,708 --> 00:22:26,243 NUCLEUS TO SYNAPSE. 500 00:22:26,243 --> 00:22:28,712 USING OUR TECHNOLOGIES TO 501 00:22:28,712 --> 00:22:34,952 UNDERSTAND WHICH RNAs HAD BACK 502 00:22:34,952 --> 00:22:37,454 OUT FROM NUCLEUS TO THE FINE AND 503 00:22:37,454 --> 00:22:38,455 ARE THEY ARE FUNCTIONING FOR 504 00:22:38,455 --> 00:22:43,060 BEHAVIOR AND IS THE GENOME 505 00:22:43,060 --> 00:22:47,598 STRUCTURE MISWIRED IN 506 00:22:47,598 --> 00:22:52,002 NEUROLOGICAL DISORDERS. 507 00:22:52,002 --> 00:22:54,338 ONE WORK IS HIGHLIGHTING THINGS 508 00:22:54,338 --> 00:22:55,639 WE PUBLISHED IN THE AREA OF 509 00:22:55,639 --> 00:22:57,241 NEURAL STIMULATION. 510 00:22:57,241 --> 00:23:01,345 AND SHOW YOU NEW SINGLE CELL 511 00:23:01,345 --> 00:23:03,113 WORK FROM MY GROUP. 512 00:23:03,113 --> 00:23:06,316 AND ALSO SUMMARIZE AN ANY STORY 513 00:23:06,316 --> 00:23:12,523 OF LOSS OF MEMORY IN THE DISEASE 514 00:23:12,523 --> 00:23:15,692 OF ALZHEIMER'S. 515 00:23:15,692 --> 00:23:17,828 SO THE OTHER UNTIL WORK IN MY 516 00:23:17,828 --> 00:23:19,596 LAB IN NEURAL STIMULATION WAS 517 00:23:19,596 --> 00:23:22,933 LED BY JOHN BEACON AND UPON 518 00:23:22,933 --> 00:23:25,235 CALCIUM INFLUX WHEN ACTION 519 00:23:25,235 --> 00:23:27,137 POTENTIAL FIRED THERE'S THE 520 00:23:27,137 --> 00:23:29,540 EARLY GENES AND SECONDARY 521 00:23:29,540 --> 00:23:31,475 RESPONSE GENES. 522 00:23:31,475 --> 00:23:32,609 FOR CHROMATIN STRUCTURE PEOPLE 523 00:23:32,609 --> 00:23:35,078 IT'S EXCITING BECAUSE THINGS 524 00:23:35,078 --> 00:23:38,582 HAPPEN SO FAST. 525 00:23:38,582 --> 00:23:39,416 SYNAPTIC PLASTICITY IN TIME 526 00:23:39,416 --> 00:23:43,587 SCALES OF MILLISECONDS AND 527 00:23:43,587 --> 00:23:44,354 SECONDARY RESPONSE AGAINST ON 528 00:23:44,354 --> 00:23:47,057 HOURS TO A DAY. 529 00:23:47,057 --> 00:23:49,493 THIS HELPS GET FASTER Ph.D.s 530 00:23:49,493 --> 00:23:50,127 BECAUSE THE STUDENTS AREN'T 531 00:23:50,127 --> 00:23:52,596 WAITING TO ARE A YEAR TO PROCESS 532 00:23:52,596 --> 00:23:55,499 A SAMPLE AND LAD NO PROBLEM TO 533 00:23:55,499 --> 00:23:56,600 RECRUITING TO THIS PARTICULAR 534 00:23:56,600 --> 00:23:56,834 PROJECT. 535 00:23:56,834 --> 00:24:04,808 THIS IS ONE EXAMPLE OF DATA 536 00:24:04,808 --> 00:24:08,879 JOHN CREATED AND INDUCERS AS 537 00:24:08,879 --> 00:24:15,152 FUNCTIONALLY REPRODUCED BY MANY 538 00:24:15,152 --> 00:24:17,855 NEUROSCIENT SCIENSCIENTISTS IN D 539 00:24:17,855 --> 00:24:19,990 IT STAYS UP TO 60 MONTHS AND 540 00:24:19,990 --> 00:24:21,158 THEN BEGINS TO DISSIPATE AS THE 541 00:24:21,158 --> 00:24:23,627 GENE IS TURNED OFF. 542 00:24:23,627 --> 00:24:24,895 I WANTED TO SHOW THIS TIME 543 00:24:24,895 --> 00:24:26,330 COURSE BECAUSE IN THE EARLY DAYS 544 00:24:26,330 --> 00:24:36,874 WE REALLY HAD NO IDEA IF LOOPS 545 00:24:37,941 --> 00:24:40,644 MATTERED FOR LOOP EXPRESSION AND 546 00:24:40,644 --> 00:24:42,179 WAITED UP AGAINST THE GENE 547 00:24:42,179 --> 00:24:47,384 EXPRESSION AND LOOPS FORM 548 00:24:47,384 --> 00:24:49,786 QUICKER THAN mRNA LEVELS AND 549 00:24:49,786 --> 00:24:51,455 NEVER WENT BACK TO LOOK EVEN 550 00:24:51,455 --> 00:24:52,556 EARLIER. 551 00:24:52,556 --> 00:24:55,259 SO WE KNOW THEY FORM FAST AND 552 00:24:55,259 --> 00:24:57,160 THEY'RE ACTIVITY DEPENDENT. 553 00:24:57,160 --> 00:24:58,996 I'M REDUCING PERHAPS FOUR YEARS 554 00:24:58,996 --> 00:25:05,235 TO A SINGLE SLIDE BUT ALSO SAW 555 00:25:05,235 --> 00:25:10,841 PATTERNS OF GENE EXPRESSION AND 556 00:25:10,841 --> 00:25:13,410 ACTIVATED SUPER FAST AND TURNED 557 00:25:13,410 --> 00:25:14,978 OFF JUST AS FAST. 558 00:25:14,978 --> 00:25:17,881 BY CONTRAST THE SECONDARY 559 00:25:17,881 --> 00:25:20,550 RESPONSE TEAM FORMS A COMPLEX 560 00:25:20,550 --> 00:25:23,353 NETWORK OF MULTIPLE LOOPING 561 00:25:23,353 --> 00:25:25,155 INTERACTIONS AND THINK IT MIGHT 562 00:25:25,155 --> 00:25:25,923 CONTRIBUTE TO THE FURTHER 563 00:25:25,923 --> 00:25:27,090 DELAYED GENE EXPRESSION. 564 00:25:27,090 --> 00:25:29,092 AND SO MORE LOOPS, LONGER LOOPS 565 00:25:29,092 --> 00:25:33,130 AND MORE ENHANCERS AT LEAST IN A 566 00:25:33,130 --> 00:25:37,200 NEURAL ACTIVATION PARADIGM OFTEN 567 00:25:37,200 --> 00:25:40,370 LEADS TO DELAYED DYNAMIC LOOP 568 00:25:40,370 --> 00:25:41,705 EXPRESSION. 569 00:25:41,705 --> 00:25:43,373 ANOTHER QUESTION IS DO LOOPS 570 00:25:43,373 --> 00:25:45,142 MATTER FOR GENE EXPRESSION AND 571 00:25:45,142 --> 00:25:51,148 THIS IS CRITICAL WORK KICKED OFF 572 00:25:51,148 --> 00:25:52,783 BY AIDAN AND LIDS COLLEAGUES AND 573 00:25:52,783 --> 00:25:54,618 OTHERS GOING UP TO EIGHT YEARS 574 00:25:54,618 --> 00:25:55,052 AGO. 575 00:25:55,052 --> 00:26:02,392 IN THIS STUDY THERE WAS A DEGRON 576 00:26:02,392 --> 00:26:07,297 USED IN CANCER CELL LINES. 577 00:26:07,297 --> 00:26:11,001 COHESIN WAS TAKEN AND ALL THE 578 00:26:11,001 --> 00:26:12,002 LOOPS WERE GONE. 579 00:26:12,002 --> 00:26:13,337 WHAT SHOCKED THE FIELD AND LED 580 00:26:13,337 --> 00:26:18,108 TO DISMAY IS LOOKING AT THE GENE 581 00:26:18,108 --> 00:26:19,876 EXPRESSION THERE WAS ESSENTIALLY 582 00:26:19,876 --> 00:26:21,011 NO CHANGE WHETHER THE CANCER 583 00:26:21,011 --> 00:26:24,881 CELL LINE LAD LOOPS OR NOT. 584 00:26:24,881 --> 00:26:28,685 SO LOOPS DON'T METER FOR GREEN 585 00:26:28,685 --> 00:26:30,187 EXPRESSION MAINTENANCE AT LEAST 586 00:26:30,187 --> 00:26:31,254 IN THIS SYSTEM. 587 00:26:31,254 --> 00:26:36,693 ONE IDEA WE MHAD IS WE HAD TO 588 00:26:36,693 --> 00:26:38,095 THINK OF THE ESTABLISHMENT OF 589 00:26:38,095 --> 00:26:40,364 NEW GENE EXPRESSION PATTERNS. 590 00:26:40,364 --> 00:26:50,907 WE TEAMED UP WITH MATHIAS AND WE 591 00:26:53,577 --> 00:26:55,445 ACTIVATED THE NEURONS AND 592 00:26:55,445 --> 00:26:58,215 ASSESSED DO THEY ARE HAVE THE 593 00:26:58,215 --> 00:26:59,683 ABILITY TO ACTIVATE THE 594 00:26:59,683 --> 00:27:02,853 IMMEDIATE EARLY GENES AND SECOND 595 00:27:02,853 --> 00:27:06,189 RESPONSE GENES AND I'M SUMMARIZE 596 00:27:06,189 --> 00:27:08,191 AND THE IMMEDIATE EARLY GENES 597 00:27:08,191 --> 00:27:11,294 TURNED ON JUST FINE EVEN WHEN 598 00:27:11,294 --> 00:27:14,364 LOOPS WERE GONE, HOWEVER A LARGE 599 00:27:14,364 --> 00:27:15,532 RANGE OF PLASTICITY AND RESPONSE 600 00:27:15,532 --> 00:27:18,235 GENES HAD NO ABILITY TO TURN ON 601 00:27:18,235 --> 00:27:22,339 ONCE WE ASKED THE NEURONS TO DO 602 00:27:22,339 --> 00:27:23,840 SOMETHING NEW. 603 00:27:23,840 --> 00:27:25,308 MAYBE THEY'RE JUST NOT NEEDED TO 604 00:27:25,308 --> 00:27:27,577 MAIN TRAIN WHAT YOU HAVE BUT 605 00:27:27,577 --> 00:27:30,814 NEED TO GO SOMEWHERE NEW AS A 606 00:27:30,814 --> 00:27:32,215 CELL YOU NEED NEW LOOPING 607 00:27:32,215 --> 00:27:33,183 INTERACTIONS TO GET TO WHERE YOU 608 00:27:33,183 --> 00:27:34,484 WANT TO GO NEXT. 609 00:27:34,484 --> 00:27:38,855 SO WHERE ARE WE GOING NOW? 610 00:27:38,855 --> 00:27:45,962 WE'RE WORKING AS LAB WITH TWO 611 00:27:45,962 --> 00:27:53,537 AMAZING NEURO BIOLOGISTS AND 612 00:27:53,537 --> 00:27:54,638 SCIENTISTS. 613 00:27:54,638 --> 00:27:57,841 WE WANTED TO GO IN VIVO AND USE 614 00:27:57,841 --> 00:27:59,509 CONTEXTUAL FEAR CONDITIONING AND 615 00:27:59,509 --> 00:28:01,278 THE IDEA IS EXPOSE THE MOUSE TO 616 00:28:01,278 --> 00:28:04,748 A NEUTRAL AND AVERSIVE STIMULUS 617 00:28:04,748 --> 00:28:09,186 IN THIS CASE SHOCK AND LOOK FOR 618 00:28:09,186 --> 00:28:15,025 CHROMATIN PERSISTENCE AND HAVE A 619 00:28:15,025 --> 00:28:17,594 SPAN OF DAYS TO A MONTH RAND 620 00:28:17,594 --> 00:28:25,268 HAVE RECALL TO EXPOSE THE MOUSE 621 00:28:25,268 --> 00:28:29,439 TO A MONTH IN AND RAY ONE-SHOT 622 00:28:29,439 --> 00:28:31,441 BEHAVIORAL DEAL AND HAVE 623 00:28:31,441 --> 00:28:33,176 ISOLATION IN VARIOUS PARTS OF 624 00:28:33,176 --> 00:28:36,279 THE BRAIN RELEVANT FOR ENCODING, 625 00:28:36,279 --> 00:28:38,882 CONSOLIDATION OR RECALL OF FIELD 626 00:28:38,882 --> 00:28:39,182 MEMORY. 627 00:28:39,182 --> 00:28:41,017 HOW DO WE GET ALL THE 628 00:28:41,017 --> 00:28:43,587 COMPLICATED PRAT EARNS AND GET 629 00:28:43,587 --> 00:28:45,589 THE NEURONS AT THE EXACT RIGHT 630 00:28:45,589 --> 00:28:47,324 PERIOD OF TIME? 631 00:28:47,324 --> 00:28:49,860 WE USED AN EXCITING AND ELEGANT 632 00:28:49,860 --> 00:28:53,630 MOUSE MODEL CALLED THE TRAP 2 633 00:28:53,630 --> 00:28:53,830 MOUSE. 634 00:28:53,830 --> 00:28:57,400 WHAT THIS MOUSE DOES IN BRIEF IS 635 00:28:57,400 --> 00:29:01,171 USES AN ACTIVITY-DRIVEN CRAY TO 636 00:29:01,171 --> 00:29:03,173 GENETICALLY MARK IN A PERMANENT 637 00:29:03,173 --> 00:29:04,508 MANNER THE NEURONS FIRED ONLY 638 00:29:04,508 --> 00:29:08,245 DURING THE EXACT WINDOW OF THE 639 00:29:08,245 --> 00:29:11,581 BEHAVIOR DURING THE INJECTION. 640 00:29:11,581 --> 00:29:13,583 THEN SUBSEQUENTLY WE CAN WAIT 641 00:29:13,583 --> 00:29:15,519 LONG PERIOD OF TIME AND SORT OUT 642 00:29:15,519 --> 00:29:17,754 THE NUCLEAR ALMOST A MONTH LATER 643 00:29:17,754 --> 00:29:18,755 BECAUSE THEY ARE WERE ACTIVE 644 00:29:18,755 --> 00:29:21,158 ONLY TO OUR KNOWLEDGE BACK AT 645 00:29:21,158 --> 00:29:24,094 THE ORIGINAL ENCODING. 646 00:29:24,094 --> 00:29:31,701 WE USED A NEW MULTIMODAL 647 00:29:31,701 --> 00:29:36,940 TECHNOLOGY CALLED SINGLE NUCLEUS 648 00:29:36,940 --> 00:29:43,180 3C SEQ AND WHAT WE CAN DO IS NOW 649 00:29:43,180 --> 00:29:43,613 CLU 650 00:29:43,613 --> 00:29:44,714 CLUSTER THE CELLS AND GRAB ALL 651 00:29:44,714 --> 00:29:49,019 THE NEURONS THAT LOOK EXACTLY 652 00:29:49,019 --> 00:29:52,789 LIKE THEY HAVE THE SAME 653 00:29:52,789 --> 00:29:59,596 METHYLATION PROFILE AND MATCHED 654 00:29:59,596 --> 00:30:05,068 THE CELL TYPE AND CREATE ONE 655 00:30:05,068 --> 00:30:08,338 LESS SPARSE AND NOW THERE'S A 656 00:30:08,338 --> 00:30:15,378 PROXY PAUSE IT'S A PSEUDO BULK 657 00:30:15,378 --> 00:30:17,180 DATA AND THIS IS HOT OFF THE 658 00:30:17,180 --> 00:30:20,884 PRESS OF TWO YEARS OF EFFORT. 659 00:30:20,884 --> 00:30:24,654 THIS IS AROUND THE MMD RAF 660 00:30:24,654 --> 00:30:28,358 RECEPTOR GENE AND THERE'S NO 661 00:30:28,358 --> 00:30:31,595 LOOP FORM IN THE NEURONS IN THE 662 00:30:31,595 --> 00:30:33,163 CONTROL AND SEE IT FORMED IN THE 663 00:30:33,163 --> 00:30:35,165 TRAPPED NEURONS. 664 00:30:35,165 --> 00:30:36,866 IT REMAINS AT THREE DAYS AND 665 00:30:36,866 --> 00:30:37,667 THROUGH DAY 28. 666 00:30:37,667 --> 00:30:39,803 THIS IS JUST ONE EXAMPLE JUST IN 667 00:30:39,803 --> 00:30:42,572 THE LAST FEW DAYS WHERE WE THINK 668 00:30:42,572 --> 00:30:44,641 IS A LAB WE ARE GOING TO BE ABLE 669 00:30:44,641 --> 00:30:51,181 TO HAVE THE POTENTIAL TO SEARCH 670 00:30:51,181 --> 00:30:53,550 FOR PERSISTENT LOOPING 671 00:30:53,550 --> 00:30:55,318 INTERACTIONS AND THE HYPOTHESIS 672 00:30:55,318 --> 00:30:57,020 WE'RE CHASING OR TRYING TO DID 673 00:30:57,020 --> 00:30:59,089 PROF IS DURING MEMORY ENCODING 674 00:30:59,089 --> 00:31:01,091 THERE'S DEPENDENT LOOPS THAT 675 00:31:01,091 --> 00:31:03,193 STAY STUCK AND PERSISTENT AND 676 00:31:03,193 --> 00:31:04,527 REMAIN OVER LONG PERIOD OF TIME 677 00:31:04,527 --> 00:31:05,862 EVEN IF THE GENE EXPRESSION 678 00:31:05,862 --> 00:31:06,696 COMES BACK DOWN. 679 00:31:06,696 --> 00:31:17,240 AND WHEN THAT NEURON IS CALLED 680 00:31:18,174 --> 00:31:20,343 PON UPON THERE'S A FASTER 681 00:31:20,343 --> 00:31:22,746 RESPONSE AND HAVE TO FIGURE OUT 682 00:31:22,746 --> 00:31:25,048 THE FUNCTIONALITY OF HOW THAT 683 00:31:25,048 --> 00:31:25,682 ENABLES THIS EXPRESSION DURING 684 00:31:25,682 --> 00:31:28,551 RECALL. 685 00:31:28,551 --> 00:31:30,487 JUST TO SUMMARIZE THIS PART 686 00:31:30,487 --> 00:31:31,588 BEFORE GOING TO THE LAST SESSION 687 00:31:31,588 --> 00:31:34,758 WE FIND IN NEURONS MANY LOOPS 688 00:31:34,758 --> 00:31:41,064 CONNECT IN ACTIVITY OF GENES 689 00:31:41,064 --> 00:31:49,039 DURING STIMULATION AND EN 690 00:31:49,039 --> 00:31:54,544 HANCERS AND SEE THEIR COHESIN 691 00:31:54,544 --> 00:31:56,513 INDEPENDENT AND FIND A COMPLEX 692 00:31:56,513 --> 00:31:58,381 NETWORK OF LONG DISTANCE LOOPS 693 00:31:58,381 --> 00:32:02,686 THAT CONNECT ON LATER TIME 694 00:32:02,686 --> 00:32:07,390 SCALES AND COHESIN DEPENDENT 695 00:32:07,390 --> 00:32:12,028 LOOPS NEEDED FOR MATURATION AND 696 00:32:12,028 --> 00:32:13,697 ACTIVITY DEPENDENT SECONDARY 697 00:32:13,697 --> 00:32:15,131 RESPONSE IN VITRO. 698 00:32:15,131 --> 00:32:21,104 SO FOR THE QUESTION OF DO LOOPS 699 00:32:21,104 --> 00:32:23,606 MATTER IN POST MITOTIC 700 00:32:23,606 --> 00:32:25,775 EXPRESSION THEY ARE DO AND WE 701 00:32:25,775 --> 00:32:27,077 ALSO FIND THROUGH NEW 702 00:32:27,077 --> 00:32:29,279 PRELIMINARY DATA I'VE SHOWN 703 00:32:29,279 --> 00:32:30,513 PERSISTENT LOOPS AND N GRAMS 704 00:32:30,513 --> 00:32:32,449 PLAY EXIST AND WE'RE CONTINUING 705 00:32:32,449 --> 00:32:35,585 TO PURSUE THAT THROUGH THE FINAL 706 00:32:35,585 --> 00:32:46,129 YEAR OF THE 4D NUCLEOME AND NOW 707 00:32:47,664 --> 00:32:48,965 THINKING ABOUT WHAT ABOUT IN A 708 00:32:48,965 --> 00:32:51,201 DISEASE WHERE THERE'S LOSS OF 709 00:32:51,201 --> 00:32:51,568 MEMORY? 710 00:32:51,568 --> 00:32:55,138 FOR THAT WE TURN TO ALZHEIMER'S 711 00:32:55,138 --> 00:32:56,973 DISEASE THERE'S MANY EXPERTS AT 712 00:32:56,973 --> 00:33:02,345 THE NIH I HAD THE GREAT FORTUNE 713 00:33:02,345 --> 00:33:03,580 OF DISCUSSING THIS EARLIER THIS 714 00:33:03,580 --> 00:33:06,883 MORNING AND THE MOST COMMON FORM 715 00:33:06,883 --> 00:33:12,655 OF DEMENTIA AND PLAYS OUT 716 00:33:12,655 --> 00:33:14,557 THROUGH COMPLEX 717 00:33:14,557 --> 00:33:15,191 NEURODEGENERATION. 718 00:33:15,191 --> 00:33:25,735 THE LARGE MAJORITY AND DRIVEN BY 719 00:33:29,839 --> 00:33:30,640 RARE MUTATIONS. 720 00:33:30,640 --> 00:33:33,510 THE COMMONALITY IS THEY ARE 721 00:33:33,510 --> 00:33:35,378 OFTEN HAVE SIMILARITY IN BIO 722 00:33:35,378 --> 00:33:38,782 CHEMICAL HALLMARKS OF AGGREGATES 723 00:33:38,782 --> 00:33:40,483 OF AMYLOID OR 724 00:33:40,483 --> 00:33:41,418 HYPERPHOSPHORYLATION OF TAU. 725 00:33:41,418 --> 00:33:47,123 SO SOMETHING LESS APPRECIATED IS 726 00:33:47,123 --> 00:33:48,124 THAT MULTIPLE CELLS TYPES ALSO 727 00:33:48,124 --> 00:33:50,026 HAVE SEVERE TRANSCRIPTIONAL 728 00:33:50,026 --> 00:33:53,062 DEFECTS AND IT'S LATELY COME 729 00:33:53,062 --> 00:33:57,100 INTO FASHION BECAUSE OF STUDIES 730 00:33:57,100 --> 00:34:07,343 IN POSTMORTEM BRAIN TISSUE AND 731 00:34:07,343 --> 00:34:10,980 WHAT FORMS THE DYSREGULATION? 732 00:34:10,980 --> 00:34:13,650 WHERE IS THERE'S LESS INSIGHT? 733 00:34:13,650 --> 00:34:18,755 MANY STUDIES AND RIGHTFULLY SO 734 00:34:18,755 --> 00:34:22,392 ARE FOCUSED ON POST MORTEM BRAIN 735 00:34:22,392 --> 00:34:25,061 TISSUE SO IT'S DIFFICULT TO GET 736 00:34:25,061 --> 00:34:26,296 BACK TO THE EARLY EVENTS. 737 00:34:26,296 --> 00:34:28,331 MOLECULAR AND CELLULAR DEFECTS 738 00:34:28,331 --> 00:34:30,733 THAT OCCUR DECADES BEFORE THE 739 00:34:30,733 --> 00:34:32,135 CLINICAL PRESENTATIONS WILL BE 740 00:34:32,135 --> 00:34:35,171 MISSED BY FOCUSSING ON THE LATE 741 00:34:35,171 --> 00:34:35,371 STAGE. 742 00:34:35,371 --> 00:34:37,440 LATE STAGE AGAIN MISSES EARLY 743 00:34:37,440 --> 00:34:39,409 DRIVERS OF THE DISEASE AND FOR 744 00:34:39,409 --> 00:34:42,479 SPORADIC ALZHEIMER'S, IPS 745 00:34:42,479 --> 00:34:43,880 STUDIES ARE DIFFICULT BECAUSE 746 00:34:43,880 --> 00:34:46,249 THE DEGENERATION IS LATE ONSET 747 00:34:46,249 --> 00:34:51,187 AND MORE SPORADIC AND VARIABLE 748 00:34:51,187 --> 00:34:52,322 ACROSS INDIVIDUALS. 749 00:34:52,322 --> 00:34:52,989 VERY TECHNICALLY CHALLENGING TO 750 00:34:52,989 --> 00:34:55,191 COVER THE DETAILS IN A 751 00:34:55,191 --> 00:34:56,025 REPRODUCIBLE WAY THAT ARE 752 00:34:56,025 --> 00:34:59,529 REPRESENTING A FETAL STAGE. 753 00:34:59,529 --> 00:35:03,199 OUR GOAL IS TO SEE IF THERE'S 754 00:35:03,199 --> 00:35:11,708 CHROMATIN DYSREGULATION DURING 755 00:35:11,708 --> 00:35:15,411 EARLY ONSET AND BEFORE OBVIOUS 756 00:35:15,411 --> 00:35:18,414 PRESENCE OF AMYLOID PLAQUE OR 757 00:35:18,414 --> 00:35:22,218 TAU TANGLES. 758 00:35:22,218 --> 00:35:31,594 THIS WAS WORK WAS BY AN AMAZING 759 00:35:31,594 --> 00:35:38,134 COMPUTATIONAL BIOLOGIST AND THE 760 00:35:38,134 --> 00:35:43,907 TEAM AND TO DO THIS WORK WE 761 00:35:43,907 --> 00:35:45,208 CREATED IPS LINES OF ALZHEIMER'S 762 00:35:45,208 --> 00:35:48,478 AND WANTED TO FOCUS ON FAMILIAL 763 00:35:48,478 --> 00:35:49,846 ONSET TO GET THE EARLY 764 00:35:49,846 --> 00:35:50,847 MECHANISM. 765 00:35:50,847 --> 00:35:53,116 AND SHE CREATED THE STABLE LINES 766 00:35:53,116 --> 00:35:54,717 IN WHICH THERE'S ISOGEN 767 00:35:54,717 --> 00:36:02,759 BASICALLY MATCHED FOR THE 768 00:36:02,759 --> 00:36:09,832 BACKGROUND IN BOTH ALLELES SO 769 00:36:09,832 --> 00:36:11,301 HOMOZYGOUS AND USED A 2-D 770 00:36:11,301 --> 00:36:16,673 PROTOCOL DOMINICK AND HIS TEAM 771 00:36:16,673 --> 00:36:18,575 OPTIMIZED TO GET A PURE 772 00:36:18,575 --> 00:36:20,109 POPULATION OF EXCITATORY 773 00:36:20,109 --> 00:36:20,343 NEURONS. 774 00:36:20,343 --> 00:36:24,147 IN PARALLEL WE CREATED BRAIN 775 00:36:24,147 --> 00:36:26,482 ORGANOIDS THROUGH THE PROTOCOL 776 00:36:26,482 --> 00:36:29,118 TO LOOK AT 2-D AND 3-D MODELS. 777 00:36:29,118 --> 00:36:29,886 WHAT WAS IMPORTANT WITH THE 778 00:36:29,886 --> 00:36:31,287 LINES AND WHAT WE WERE EXCITED 779 00:36:31,287 --> 00:36:33,489 TO SEE IS WHEN WE TAKE THE 780 00:36:33,489 --> 00:36:35,992 ORGANOIDS CREATE FROM THE IPS 781 00:36:35,992 --> 00:36:39,195 CELLS TO DAY 200 IN VITRO, WE'RE 782 00:36:39,195 --> 00:36:43,600 ABLE TO SEE THE BIO CHEMICAL 783 00:36:43,600 --> 00:36:50,139 HALLMARKS OF EARLY FORMULATION 784 00:36:50,139 --> 00:36:51,774 AND WITH THE SAME BACKGROUND IN 785 00:36:51,774 --> 00:36:54,143 2-D MONOLAYER AND CULTURE THEM 786 00:36:54,143 --> 00:36:56,179 UP TO DAY 65 WE DON'T SEE THE 787 00:36:56,179 --> 00:36:59,582 PRESENCE OF THE HALL MARKS AND 788 00:36:59,582 --> 00:37:03,186 THIS MEANT WE COULD SEE A PURE 789 00:37:03,186 --> 00:37:13,363 POPULATION BEFORE THE OBVIOUS 790 00:37:13,363 --> 00:37:13,630 HALLMARKS. 791 00:37:13,630 --> 00:37:18,368 SO FIRST AND FOREMOST WE DID 792 00:37:18,368 --> 00:37:19,602 GENE EXPRESSION AND LOOKED AT 793 00:37:19,602 --> 00:37:21,104 RNA SEQ ACROSS THE TIME COURSE 794 00:37:21,104 --> 00:37:23,606 OF DIFFERENTIATION OF EARLY AND 795 00:37:23,606 --> 00:37:30,913 LATE NPCs AND CORTICONEURONS AND 796 00:37:30,913 --> 00:37:32,782 WITH THE MUTATION WE SAW 797 00:37:32,782 --> 00:37:34,183 WIDESPREAD GENE EXPRESSION 798 00:37:34,183 --> 00:37:38,287 DYSREGULATION WITH A FOUR FOLD 799 00:37:38,287 --> 00:37:40,023 MORE DECREASE IN GENE 800 00:37:40,023 --> 00:37:40,390 EXPRESSION. 801 00:37:40,390 --> 00:37:42,925 THE RESULT IS REPRODUCEABLE 802 00:37:42,925 --> 00:37:44,560 ACROSS MUTATIONS. 803 00:37:44,560 --> 00:37:51,200 THE SAME GENES DOWN AND UP IN 804 00:37:51,200 --> 00:37:54,337 LARGE PART WERE DISRUPTED AND WE 805 00:37:54,337 --> 00:38:01,744 SAW A SIMILAR PATTERNS IN THE 806 00:38:01,744 --> 00:38:03,680 ORGANOID AND CHANGED AT DAY 200. 807 00:38:03,680 --> 00:38:13,589 WE WANTED TO LOOK AT CRHROMATIN 808 00:38:13,589 --> 00:38:13,923 ACCESSIBILITY. 809 00:38:13,923 --> 00:38:15,725 THE GENES THAT SHOWED 810 00:38:15,725 --> 00:38:16,592 DYSREGULATION AND LOOKING AT THE 811 00:38:16,592 --> 00:38:18,161 PROMOTERS, 99% OF THE TIME IT 812 00:38:18,161 --> 00:38:24,567 DID NOT CHANGE AT ALL. 813 00:38:24,567 --> 00:38:26,169 THOUGH THE GENES WERE 814 00:38:26,169 --> 00:38:29,038 DRAMATICALLY CHANGING IN. 815 00:38:29,038 --> 00:38:31,708 LOOKING AT DISTAL NON-CODING IS 816 00:38:31,708 --> 00:38:33,843 WHERE THE ACCESSIBILITY CHANGED 817 00:38:33,843 --> 00:38:36,179 BUT IN WAYS NOT THAT PREDICTABLE 818 00:38:36,179 --> 00:38:37,980 WITH THE GENE EXPRESSION. 819 00:38:37,980 --> 00:38:40,249 AND SO FOR A LAB FOCUSSED 820 00:38:40,249 --> 00:38:43,086 INITIALLY ON THE 3-D GENOME IT 821 00:38:43,086 --> 00:38:45,955 GAVE INSIGHT WE NEEDED THE LOOPS 822 00:38:45,955 --> 00:38:48,491 TO FIGURE OUT THE PROBLEMS. 823 00:38:48,491 --> 00:38:51,961 HERE'S THE POST-MITOTIC NEURONS 824 00:38:51,961 --> 00:38:53,229 IN WILD TYPE AND GENOTYPE AND 825 00:38:53,229 --> 00:38:55,364 JUST TO GIVE AN EXAMPLE TO SEE 826 00:38:55,364 --> 00:38:57,200 THE DOTS AROUND THE GENE AND HOW 827 00:38:57,200 --> 00:38:59,135 THEY'RE DRAMATICALLY DISRUPTED 828 00:38:59,135 --> 00:39:02,605 IN POST-MITOTIC NEURONS. 829 00:39:02,605 --> 00:39:04,774 AND WE CALLED THESE WITH METHODS 830 00:39:04,774 --> 00:39:09,345 DEVELOPED WITHIN OUR LARGER 831 00:39:09,345 --> 00:39:12,482 COMMUNITY OVER THE YEARS WE 832 00:39:12,482 --> 00:39:22,425 FOUND THE RARE MUTATION 30,000 833 00:39:22,425 --> 00:39:28,564 UNCHANGED AND SOME WITH THE APP 834 00:39:28,564 --> 00:39:31,567 MUTATION. 835 00:39:48,785 --> 00:39:52,155 6:WE SAW THEM DUE TO THE RARE 836 00:39:52,155 --> 00:39:54,557 MUTATION AND GRABBED THE LOOPS 837 00:39:54,557 --> 00:39:55,992 GAINED DUE TO THE RARE MUTATION 838 00:39:55,992 --> 00:39:59,428 AND FOUND THE LOOPS UNCHANGING 839 00:39:59,428 --> 00:40:00,730 AND ALSO GROUPED UP GENES NOT 840 00:40:00,730 --> 00:40:03,966 FORMING ANY STRUCTURE AT ALL AND 841 00:40:03,966 --> 00:40:06,636 WANTED TO ASK SO NOW WHAT 842 00:40:06,636 --> 00:40:09,005 HAPPENS IN GENE EXPRESSION IN 843 00:40:09,005 --> 00:40:12,208 THE UNDIVIDING POST-MITOTIC GENE 844 00:40:12,208 --> 00:40:13,009 EXPRESSION. 845 00:40:13,009 --> 00:40:14,710 THIS ONE YOU WILL NOT BE 846 00:40:14,710 --> 00:40:16,279 SURPRISED ABOUT. 847 00:40:16,279 --> 00:40:18,681 WHEN YOU SEE A GENE THAT LOSES 848 00:40:18,681 --> 00:40:23,586 ONE LOOP IN POST-MITOTIC NEURON 849 00:40:23,586 --> 00:40:26,088 THERE'S NO POWER AND YOU CAN 850 00:40:26,088 --> 00:40:28,991 HAVE EQUAL PROBABILITY OF 851 00:40:28,991 --> 00:40:31,594 UNCHANGED, INCREASING OR 852 00:40:31,594 --> 00:40:32,328 DECREASING EXPRESSION 853 00:40:32,328 --> 00:40:32,995 REPRESENTATIVE OF THE 854 00:40:32,995 --> 00:40:35,298 EXPERIMENTAL RESULTS 855 00:40:35,298 --> 00:40:39,135 DEMONSTRATED IN OUR FIELD. 856 00:40:39,135 --> 00:40:41,604 WHEN WE BEGIN TO STRATIFY BY 857 00:40:41,604 --> 00:40:43,573 NUMBER OF ENHANCER LOOPS THE 858 00:40:43,573 --> 00:40:47,577 MORE LOOPS YOU LOSE, THE MORE 859 00:40:47,577 --> 00:40:51,447 IT'S PREDICTIVE OF THE 860 00:40:51,447 --> 00:40:54,050 DIRECTIONALITY AND EFFECT SIZE 861 00:40:54,050 --> 00:40:57,053 OF THE GENE EXPRESSION. 862 00:40:57,053 --> 00:40:59,288 THE MORE LOOPS A GENE GAINS THE 863 00:40:59,288 --> 00:41:04,193 MORE IT'S PREDICTIVE OF AN UP 864 00:41:04,193 --> 00:41:07,563 REGULATED GENE EXPRESSION 865 00:41:07,563 --> 00:41:08,231 PATTERN. 866 00:41:08,231 --> 00:41:10,666 THERE'S NO PREDICTIVE POWER OVER 867 00:41:10,666 --> 00:41:11,500 GENE EXPRESSION AND GENES THAT 868 00:41:11,500 --> 00:41:13,769 DON'T LOOP AT ALL THERE'S ALSO 869 00:41:13,769 --> 00:41:14,437 NO PREDICTIVE POWER. 870 00:41:14,437 --> 00:41:20,443 SO AS WE LIKE TO SAY IN THE LAB, 871 00:41:20,443 --> 00:41:21,277 MORE LOOPS, MORE PROBLEMS. 872 00:41:21,277 --> 00:41:24,847 WHAT'S AT THE BASE OF ALL THE 873 00:41:24,847 --> 00:41:25,481 LOOPS CHANGING? 874 00:41:25,481 --> 00:41:27,583 I'LL SPARE YOU ALL THE DEFEATS 875 00:41:27,583 --> 00:41:29,619 AND SAY AMONG THE ARCHITECTURE 876 00:41:29,619 --> 00:41:30,920 PROTEINS IN THE OBVIOUS 877 00:41:30,920 --> 00:41:31,854 CANDIDATES, WE LOOKED AT THE 878 00:41:31,854 --> 00:41:33,923 BASE OF THE LOOPS AND CLASSIFIED 879 00:41:33,923 --> 00:41:35,424 THEM IN ALL SORTS OF WAYS AND 880 00:41:35,424 --> 00:41:37,326 THE BOTTOM LINE IS THAT ALL 881 00:41:37,326 --> 00:41:43,566 THESE LOOPS THAT ARE LOST AND 882 00:41:43,566 --> 00:41:48,070 GAINED IN POST-MITOTIC IS 883 00:41:48,070 --> 00:41:49,071 UNCHANGING. 884 00:41:49,071 --> 00:41:50,506 THERE'S SOMETHING ELSE LEADING 885 00:41:50,506 --> 00:41:53,075 TO THESE LOOP DYSREGULATIONS. 886 00:41:53,075 --> 00:41:54,510 AND THE ONE MAIN SIGNAL WE'VE 887 00:41:54,510 --> 00:41:56,245 BEEN ABLE TO FIND OVER THE YEARS 888 00:41:56,245 --> 00:42:00,249 IS THAT AT THE BASE OF THE LOOPS 889 00:42:00,249 --> 00:42:02,385 LOST AND GAINED IN THE 890 00:42:02,385 --> 00:42:03,386 ALZHEIMER'S MUTATION GENETIC 891 00:42:03,386 --> 00:42:08,457 BACKGROUND THEY HAVE STRONG 892 00:42:08,457 --> 00:42:18,601 PRESENCE OF RNA POLL II WE CAN 893 00:42:18,601 --> 00:42:23,372 LOOK UNDER THE BAY AND LOOK AT 894 00:42:23,372 --> 00:42:26,309 THE MOTIFS AND LOOKED AT THE 895 00:42:26,309 --> 00:42:28,778 LOST AND GAINED LOOPS IN THE 896 00:42:28,778 --> 00:42:29,011 NEURONS. 897 00:42:29,011 --> 00:42:32,281 USUALLY WITH MOTIF ENRICHMENT 898 00:42:32,281 --> 00:42:33,215 FLALS YOU CAN FIND ANY NUMBER OF 899 00:42:33,215 --> 00:42:35,184 HITS WITH THIS TYPE OF WORK BUT 900 00:42:35,184 --> 00:42:39,588 IN THIS CASE WE KEPT GETTING ONE 901 00:42:39,588 --> 00:42:41,490 SINGULAR HIT. 902 00:42:41,490 --> 00:42:45,094 RAY IF THE LOOPS ARE LOST UNDER 903 00:42:45,094 --> 00:42:47,797 THOSE DYNAMIC SITES IT'S 904 00:42:47,797 --> 00:42:49,432 PRESENTS IN AN ARRAY IF THEY'RE 905 00:42:49,432 --> 00:42:50,433 GAINED IT'S PRESENT TYPICALLY 906 00:42:50,433 --> 00:42:53,769 ONLY OWN ONE KWOPY. 907 00:42:53,769 --> 00:42:55,404 -- COPY. 908 00:42:55,404 --> 00:42:58,908 THE RESULT YOU GET IS FAIRLY 909 00:42:58,908 --> 00:42:59,508 DISTURBING. 910 00:42:59,508 --> 00:43:01,911 THESE ARE TRANSCRIPTION FACTORS 911 00:43:01,911 --> 00:43:03,379 THAT IS HIGHLY REDUNDANT AND 912 00:43:03,379 --> 00:43:05,481 WOULD BE DIFFICULT TO DO A 913 00:43:05,481 --> 00:43:10,753 SINGULAR LOSS OF GENE EXPERIMENT 914 00:43:10,753 --> 00:43:12,221 BUT SOME STOOD OUT AND WE 915 00:43:12,221 --> 00:43:13,923 SEARCHED OUR GENE EXPRESSION 916 00:43:13,923 --> 00:43:14,156 RESULTS. 917 00:43:14,156 --> 00:43:18,661 AND HERE'S WHERE I THINK WE GOT 918 00:43:18,661 --> 00:43:19,128 LUCKY. 919 00:43:19,128 --> 00:43:23,599 WE SAW THAT FOR EXAMPLE THE 920 00:43:23,599 --> 00:43:28,971 DIFFERENTIATION TIME POINTS THE 921 00:43:28,971 --> 00:43:31,507 mRNA PLUMMET AND TURNED OFF BUT 922 00:43:31,507 --> 00:43:33,376 HIGH IN WILD TYPE. 923 00:43:33,376 --> 00:43:36,879 SIMILARLY BUT OPT SIT, DLX5 AND 924 00:43:36,879 --> 00:43:42,818 6 ARE NOT PRESENT IN WILD TYPE 925 00:43:42,818 --> 00:43:44,420 BUT EXPRESS UP REGULATED DUE TO 926 00:43:44,420 --> 00:43:45,955 THE MUTATION AND SO FOR THAT 927 00:43:45,955 --> 00:43:47,890 REASON IT GIVES CANDIDATES WE 928 00:43:47,890 --> 00:43:49,925 CAN BEGIN TO PURSUE WITH THE 929 00:43:49,925 --> 00:43:51,694 GAIN OF FUNCTION STUDIES. 930 00:43:51,694 --> 00:43:55,498 SO WHAT WE'RE DOING RIGHT NOW IS 931 00:43:55,498 --> 00:44:00,202 OVER EXPRESSING DLX1 WITH AN HH 932 00:44:00,202 --> 00:44:03,806 TAG TO CHIP IT AND LOOKING AT 933 00:44:03,806 --> 00:44:05,174 THE TIME COURSE RAND GENE 934 00:44:05,174 --> 00:44:06,175 EXPRESSION AND THE NEURONS. 935 00:44:06,175 --> 00:44:08,144 I ALSO WANTED TO SHARE WITH 936 00:44:08,144 --> 00:44:09,845 GREAT EXCITEMENT WE SAW RECENTLY 937 00:44:09,845 --> 00:44:15,751 A NEW PRE PRINT DROPPED IN 938 00:44:15,751 --> 00:44:19,555 COLLABORATION AND IN A MODEL 939 00:44:19,555 --> 00:44:22,925 SYSTEM OF THE SONIC HEDGEHOG 940 00:44:22,925 --> 00:44:26,695 LOCUS IN VIVO AND WHAT MIGHT 941 00:44:26,695 --> 00:44:28,564 ENCODE OR ASSIST IN THE 942 00:44:28,564 --> 00:44:28,898 INTERACTIONS. 943 00:44:28,898 --> 00:44:33,202 AND SIMILAR TO OUR WORK BUT 944 00:44:33,202 --> 00:44:34,904 WHERE THEY CAN DO THESE IN VIVO 945 00:44:34,904 --> 00:44:38,707 THEY FOUND THE SAME MOTIF 946 00:44:38,707 --> 00:44:41,310 PARTICIPATING IN THE FORMATION 947 00:44:41,310 --> 00:44:44,413 OR DISRUPTION OF LOOPING 948 00:44:44,413 --> 00:44:47,583 INTERACTION AND OVEREXPRESSING 949 00:44:47,583 --> 00:44:49,685 IN AN IN VITRO MODEL AND DOING 950 00:44:49,685 --> 00:44:52,455 CRISPR MUTATIONS IN AN IN VIVO 951 00:44:52,455 --> 00:44:55,024 MODEL AND WE'RE TRYING TO ATTACK 952 00:44:55,024 --> 00:44:59,061 THIS QUESTION FROM TWO ANGLES IN 953 00:44:59,061 --> 00:44:59,395 COLLABORATION. 954 00:44:59,395 --> 00:45:01,097 OKAY, SO I WANT TO END HERE BY 955 00:45:01,097 --> 00:45:03,199 BRINGING THIS FORWARD AS 956 00:45:03,199 --> 00:45:07,903 SOMETHING THAT I CAN SAY JOHN 957 00:45:07,903 --> 00:45:11,474 SADERLY AND OTHER PROGRAM 958 00:45:11,474 --> 00:45:14,477 OFFICERS HAVE CHALLENGED US IN 959 00:45:14,477 --> 00:45:18,013 THE COMMUNITY WE SPEND TIME IN 960 00:45:18,013 --> 00:45:20,116 EFFORT AND BLOOD, SWEAT AND 961 00:45:20,116 --> 00:45:23,586 TEARS BUILDING THE COMPUTATIONAL 962 00:45:23,586 --> 00:45:25,387 TECHNOLOGIES TO MAP AND 963 00:45:25,387 --> 00:45:26,689 UNDERSTAND HOW THE GENOME FOLDS 964 00:45:26,689 --> 00:45:28,324 AND EVEN IF WE THINK IT MATTERS 965 00:45:28,324 --> 00:45:31,193 FOR GENE EXPRESSION, WHAT IS THE 966 00:45:31,193 --> 00:45:32,261 PHYSIOLOGIC SIGNIFICANCE? 967 00:45:32,261 --> 00:45:33,762 WE WONDERED IF THERE WOULD BE 968 00:45:33,762 --> 00:45:36,499 SOMETHING WITHIN OUR SYSTEM TO 969 00:45:36,499 --> 00:45:37,600 HELP US UNDERSTAND. 970 00:45:37,600 --> 00:45:39,869 WE LOOKED FIRST AT OUR NEURONS 971 00:45:39,869 --> 00:45:42,438 WE KNOW HAVE MASSIVELY DISRUPTED 972 00:45:42,438 --> 00:45:47,510 LOOPS AS WELL GENE EXPRESSION 973 00:45:47,510 --> 00:45:53,149 AND THOSE WHO ARE MICROSCOPISTS 974 00:45:53,149 --> 00:45:54,216 WE SAW NO DIFFERENCE. 975 00:45:54,216 --> 00:45:57,052 WHERE THE INSIGHT CAME WAS WHERE 976 00:45:57,052 --> 00:45:59,855 WE BEGAN TO DO MORE ANALYSIS AT 977 00:45:59,855 --> 00:46:01,891 THE SINGLE CELL LEVEL. 978 00:46:01,891 --> 00:46:06,729 WE DID SINGLE NUCLEUS RNA SEQ 979 00:46:06,729 --> 00:46:09,198 FOR THE NEURONS AND FOUND IN 980 00:46:09,198 --> 00:46:15,204 LARGE PART THE WILD TYPE NEURONS 981 00:46:15,204 --> 00:46:17,673 WERE EXCITATORY IN CHARACTER BUT 982 00:46:17,673 --> 00:46:19,175 IN THE MUTATION THOUGH NOT 983 00:46:19,175 --> 00:46:21,143 OBVIOUS BY MORPHOLOGY THE 984 00:46:21,143 --> 00:46:23,946 NEURONS SHIFTED THEIR 985 00:46:23,946 --> 00:46:26,749 COMPOSITION AND SUBSTATE TO NOW 986 00:46:26,749 --> 00:46:28,784 BE ALMOST ENTIRELY INHIBITORY IN 987 00:46:28,784 --> 00:46:29,818 CHARACTER BUT WOULDN'T HAVE 988 00:46:29,818 --> 00:46:30,753 DETECTED IT. 989 00:46:30,753 --> 00:46:33,756 SO THIS IS VERY SURPRISING TO US 990 00:46:33,756 --> 00:46:34,657 AND WE'RE DOING SUBSEQUENT 991 00:46:34,657 --> 00:46:37,193 FOLLOW-UP STUDIES NOW BUT THE 992 00:46:37,193 --> 00:46:39,228 EMERGING MODEL FROM OUR WORK IS 993 00:46:39,228 --> 00:46:41,030 AS FOLLOWS. 994 00:46:41,030 --> 00:46:43,566 IN WILD TYPE HUMAN NEURONS 995 00:46:43,566 --> 00:46:45,634 DERIVED FROM IPS CELLS WE USED 996 00:46:45,634 --> 00:46:51,040 CRISPR TO ADD HOMOZYGOUS RARE 997 00:46:51,040 --> 00:46:54,610 AUTO SOMAL CASES LINKED TO EARLY 998 00:46:54,610 --> 00:46:56,979 ONSET ALZHEIMER'S AND WE SEE 999 00:46:56,979 --> 00:46:59,615 THERE'S MANY LONG RANGE LOOPING 1000 00:46:59,615 --> 00:47:01,250 INTERACTIONS AND CAN BE 1001 00:47:01,250 --> 00:47:02,918 DISRUPTED DUE TO THE MUTATION. 1002 00:47:02,918 --> 00:47:04,753 AT THE BASE OF THE DISRUPTED 1003 00:47:04,753 --> 00:47:09,391 LOOPS ARE THE MOTIF AT THE 1004 00:47:09,391 --> 00:47:12,728 ENHANCERS TTA AND WE ALSO SEE 1005 00:47:12,728 --> 00:47:14,797 GAINED LOOPS IN THE SAME MODEL 1006 00:47:14,797 --> 00:47:15,030 SYSTEM. 1007 00:47:15,030 --> 00:47:23,372 THEY ALSO HAVE TAA, TTA AND IF 1008 00:47:23,372 --> 00:47:29,778 YOU LOOK RAT THE -- AT THE BASE 1009 00:47:29,778 --> 00:47:36,552 OF THE LOOPS IT'S OFTEN 1010 00:47:36,552 --> 00:47:39,054 INHIBITORY, EXCITATORY GENES 1011 00:47:39,054 --> 00:47:41,557 DISRUPTED AND SHIFTS WITH THE 1012 00:47:41,557 --> 00:47:43,592 GENE EXPRESSION TO BE MORE 1013 00:47:43,592 --> 00:47:45,294 INHIBITORY IN CHARACTER AND THIS 1014 00:47:45,294 --> 00:47:50,299 PLAY BE ONE IMPORTANT PLACE 1015 00:47:50,299 --> 00:47:51,934 WHERE THEY MATTER FOR THE 1016 00:47:51,934 --> 00:47:55,871 CELLULAR STATE OF NEURONS IN 1017 00:47:55,871 --> 00:48:00,075 HUMAN DISEASE AND HAVE A 1018 00:48:00,075 --> 00:48:02,478 RELATIONSHIP BETWEEN 1019 00:48:02,478 --> 00:48:04,980 DYSREGULATED AND EXCITATORY AND 1020 00:48:04,980 --> 00:48:05,648 INHIBITORY GENE EXPRESSION AND 1021 00:48:05,648 --> 00:48:09,985 IT APPEARS IN OUR MODEL TO OCCUR 1022 00:48:09,985 --> 00:48:15,190 PRIOR TO THE DEPOSITION OF BIO 1023 00:48:15,190 --> 00:48:15,791 CHEMI 1024 00:48:15,791 --> 00:48:20,763 CHEMICAL HALLMARKS OF AMYLOID 1025 00:48:20,763 --> 00:48:22,531 PLAQUE AND TAU. 1026 00:48:22,531 --> 00:48:23,932 THIS IS A BEAUTIFUL EDITORIAL 1027 00:48:23,932 --> 00:48:25,601 THAT SUMMARIZED THE WORK OF SOME 1028 00:48:25,601 --> 00:48:27,803 OF MY COLLEAGUES WHERE THE USED 1029 00:48:27,803 --> 00:48:30,205 SIMULATION TO CAPTURE THE 1030 00:48:30,205 --> 00:48:32,041 IMAGINATION OF HOW DIFFICULT THE 1031 00:48:32,041 --> 00:48:34,810 3-D GENOME FOLDING HAS BEEN OVER 1032 00:48:34,810 --> 00:48:35,911 THE LAST 10 YEARS. 1033 00:48:35,911 --> 00:48:37,413 I'M SHOWING SOME THINGS THAT IN 1034 00:48:37,413 --> 00:48:40,282 THE EARLY DAYS WE DID NOT KNOW 1035 00:48:40,282 --> 00:48:42,551 IF THIS WOULD BE A TRACKABLE 1036 00:48:42,551 --> 00:48:43,952 PROBLEM AND IT WAS HARD BUT FUN 1037 00:48:43,952 --> 00:48:46,989 AND NOW I WANT TO DO IT AGAIN. 1038 00:48:46,989 --> 00:48:49,358 AND THE IDEA THAT HAS CALLED OUT 1039 00:48:49,358 --> 00:48:52,094 SO US I THINK IS ANOTHER 1040 00:48:52,094 --> 00:48:53,395 CONNECTIVITY PROBLEM OF THE 1041 00:48:53,395 --> 00:48:54,897 NEURAL CONNECTOME AND WE STARTED 1042 00:48:54,897 --> 00:48:57,232 THE PROCESS OF THINKING HOW TO 1043 00:48:57,232 --> 00:49:02,404 YOU THE PRINCIPLES COMPUTATIONAL 1044 00:49:02,404 --> 00:49:05,708 AND EXPERIMENTAL AND BEGIN TO 1045 00:49:05,708 --> 00:49:08,277 THINK OF WAYS TO DO MOLECULAR 1046 00:49:08,277 --> 00:49:10,346 MAPS OF THE SYNAPTIC CONNECTOME 1047 00:49:10,346 --> 00:49:13,015 AND THAT'S WHAT WE'RE WORKING ON 1048 00:49:13,015 --> 00:49:18,354 NOW THINKING OF CREATING SYNAPSE 1049 00:49:18,354 --> 00:49:20,923 RESOLUTION ACTIVITY. 1050 00:49:20,923 --> 00:49:27,096 IT WILL BE HARD BUT SKIESEXCITE 1051 00:49:27,096 --> 00:49:30,899 WORK WITH NEW YOUNG PEOPLE TO 1052 00:49:30,899 --> 00:49:32,601 TACKLE THE PROBLEM AND WHEN 1053 00:49:32,601 --> 00:49:40,376 THERE'S PERSISTENT CRHROMATIN HS 1054 00:49:40,376 --> 00:49:41,477 TO GET BACK AND HOW THEY ARE 1055 00:49:41,477 --> 00:49:44,913 CHANGE IN A DYNAMIC MANNER AND 1056 00:49:44,913 --> 00:49:46,849 PROVING THE RNAs MATTER IN SOME 1057 00:49:46,849 --> 00:49:48,784 WAYS FOR BEHAVIOR AND THOUGH 1058 00:49:48,784 --> 00:49:51,220 I'VE SHOWN AN EXAMPLE OF 1059 00:49:51,220 --> 00:49:53,956 ALZHEIMER'S WHERE I FOCUS ALMOST 1060 00:49:53,956 --> 00:49:56,458 ENTIRELY ON CHROMATIN WE HOPE TO 1061 00:49:56,458 --> 00:50:00,629 UNDERSTAND HOW THE LOOPS MIGHT 1062 00:50:00,629 --> 00:50:06,969 METER FOR THE THE PLASTICITY MAY 1063 00:50:06,969 --> 00:50:07,903 BE DYSREGULATED. 1064 00:50:07,903 --> 00:50:09,204 OUR INTEREST IS IN FOCUSSING ON 1065 00:50:09,204 --> 00:50:12,341 A FEW MODEL SYSTEMS. 1066 00:50:12,341 --> 00:50:14,710 AND THINKING FROM THE NUCLEUS 1067 00:50:14,710 --> 00:50:16,945 OUT TO THE SYNAPSE AND OUR HOPE 1068 00:50:16,945 --> 00:50:20,382 IS OVER TIME WE CAN PERHAPS IN 1069 00:50:20,382 --> 00:50:23,619 THE NEXT 10, 20 YEARS FIND 1070 00:50:23,619 --> 00:50:26,622 INSIGHTS TO GIVE GENUINE HELP 1071 00:50:26,622 --> 00:50:28,824 FOR THOSE WHO CONTINUE TO SUFFER 1072 00:50:28,824 --> 00:50:30,926 AND THE MYRIAD OF PROBLEMS THIS 1073 00:50:30,926 --> 00:50:33,862 WORLD FACES IN THE POST-PANDEMIC 1074 00:50:33,862 --> 00:50:34,630 WORLD. 1075 00:50:34,630 --> 00:50:37,699 I'D LIKE TO CLOSE AND HIGHLIGHT 1076 00:50:37,699 --> 00:50:40,836 THE WORK OF MY GROUP PAST AND 1077 00:50:40,836 --> 00:50:45,274 PRESENT AND IT'S BEEN A 1078 00:50:45,274 --> 00:50:47,609 PRIVILEGE TO WORK WITH THEM AND 1079 00:50:47,609 --> 00:50:49,678 KEEP ME YOUNG AND THANK YOU TO 1080 00:50:49,678 --> 00:50:51,613 ALL WHO LISTENED AND INVESTED IN 1081 00:50:51,613 --> 00:50:54,583 OUR LAB AND WORKING WITH ME AND 1082 00:50:54,583 --> 00:50:57,586 ALSO VERY IMPORTANT JOHN ALLUDED 1083 00:50:57,586 --> 00:50:58,821 TO JUST THANK YOU VERY MUCH TO 1084 00:50:58,821 --> 00:51:02,558 THE NIH AND COLLEAGUES AT TO THE 1085 00:51:02,558 --> 00:51:05,527 NIH AND I THINK THE SMALL 1086 00:51:05,527 --> 00:51:10,799 CONSISTENT SUPPORT MAYBE IN ONE 1087 00:51:10,799 --> 00:51:16,839 SINGLE INSTANCE PLAY NOT AFFECT 1088 00:51:16,839 --> 00:51:19,741 A PERSON THAT MUCH BUT SUSTAINS 1089 00:51:19,741 --> 00:51:21,376 CAN SUPPORT PEOPLE AND HOW IT'S 1090 00:51:21,376 --> 00:51:23,612 IMPACTED ALL IN MY GROUP. 1091 00:51:23,612 --> 00:51:24,513 THANK YOU AGAIN FOR HAVING ME 1092 00:51:24,513 --> 00:51:25,347 AND I'LL BE HAPPY TO ANSWER 1093 00:51:25,347 --> 00:51:30,219 QUESTIONS. 1094 00:51:30,219 --> 00:51:30,652 >> THANK YOU. 1095 00:51:30,652 --> 00:51:35,123 OF COURSE ANYONE HERE SHOULD BE 1096 00:51:35,123 --> 00:51:36,992 USING THE MIKES. 1097 00:51:36,992 --> 00:51:44,500 WE HAVE A ROBUSTION -- ROBUST 1098 00:51:44,500 --> 00:51:45,634 ONLINE QUESTION. 1099 00:51:45,634 --> 00:51:47,603 CAN ANY SAMPLES BE DONE WITH THE 1100 00:51:47,603 --> 00:51:50,606 HUMAN ABLATED SAMPLES? 1101 00:51:50,606 --> 00:51:53,976 >> WE THINK THINK THEY COULD BE 1102 00:51:53,976 --> 00:51:56,578 DONE WITH SURGICALLY ABLATED 1103 00:51:56,578 --> 00:51:56,812 SAMPLES. 1104 00:51:56,812 --> 00:51:59,615 PERHAPS NOT SOME OF THE GENOME 1105 00:51:59,615 --> 00:52:06,154 ENGINEERING BUT MANY OF THE 1106 00:52:06,154 --> 00:52:06,889 SINGLE CELL TECHNOLOGY IT'S 1107 00:52:06,889 --> 00:52:08,123 POSSIBLE AND TRACING OF THE 1108 00:52:08,123 --> 00:52:10,526 CIRCUITS AND GETTING OUT NOT 1109 00:52:10,526 --> 00:52:13,996 ONLY THE TRAPPED NEURONS ACTIVE 1110 00:52:13,996 --> 00:52:18,634 DURING BEHAVIOR BUT IT'S GETTING 1111 00:52:18,634 --> 00:52:19,635 TO THE PHYSIOLOGICALLY RELEVANT 1112 00:52:19,635 --> 00:52:22,938 NEURONS THAT FOR US HAS BEEN THE 1113 00:52:22,938 --> 00:52:24,439 MOST DIFFICULT PIECE AND WILL BE 1114 00:52:24,439 --> 00:52:27,543 CRITICAL AND CHANGE WITH EVERY 1115 00:52:27,543 --> 00:52:28,243 BEHAVIOR AND EXPERIMENT AND 1116 00:52:28,243 --> 00:52:28,544 EXPERIENCE. 1117 00:52:28,544 --> 00:52:35,918 YOU HAVE TO GET IT JUST RIGHT. 1118 00:52:35,918 --> 00:52:39,187 LUCKILY THERE'S BEAUTIFUL WORK 1119 00:52:39,187 --> 00:52:40,989 TO TRACE AND GET. 1120 00:52:40,989 --> 00:52:41,557 6: 1121 00:52:41,557 --> 00:52:51,199 >> I'M VERY INTRIGUED BY THE AKC 1122 00:52:51,199 --> 00:52:53,268 DERIVED NEURONS FROM SINGLE 1123 00:52:53,268 --> 00:52:55,003 MUTATIONS. 1124 00:52:55,003 --> 00:52:58,307 AND WONDERING WHETHER YOU HAVE 1125 00:52:58,307 --> 00:53:03,278 DONE HETER ZYGOUS CELL LINE WITH 1126 00:53:03,278 --> 00:53:08,650 A MORE INHIBITORY NEURON, FIRST 1127 00:53:08,650 --> 00:53:08,917 QUESTION. 1128 00:53:08,917 --> 00:53:10,018 SECOND QUESTION I THINK THERE'S 1129 00:53:10,018 --> 00:53:12,988 MICE FOR THE MUTATION BUT DON'T 1130 00:53:12,988 --> 00:53:18,627 REMEMBER DRAMATIC CHANGE OF THE 1131 00:53:18,627 --> 00:53:23,932 NEURON PRESENTATION THE 1132 00:53:23,932 --> 00:53:25,734 INHIBITORY IS HUGE SO HOW DO YOU 1133 00:53:25,734 --> 00:53:28,103 VERIFY THE FINDING OF THE IN 1134 00:53:28,103 --> 00:53:28,837 VIVO MODEL. 1135 00:53:28,837 --> 00:53:30,372 >> THANK YOU FOR YOUR QUESTION 1136 00:53:30,372 --> 00:53:33,275 AROUND TWO PARTS SUMMARIZED FOR 1137 00:53:33,275 --> 00:53:36,011 THE LIVE ONLINE AUDIENCE. 1138 00:53:36,011 --> 00:53:40,816 WE USE HOMOZYGOUS MUTATION OF A 1139 00:53:40,816 --> 00:53:43,151 RARE AUTOSOMAL DOMINANT MUTATION 1140 00:53:43,151 --> 00:53:45,253 ON PURPOSE. 1141 00:53:45,253 --> 00:53:50,492 WE WANTED TO USE FIRST PASS 1142 00:53:50,492 --> 00:53:53,295 BECAUSE WE WANTED TO GET THE 1143 00:53:53,295 --> 00:53:55,631 HIGH 1144 00:53:55,631 --> 00:53:57,766 HIGHEST SIGNAL TO NOISE AND THEN 1145 00:53:57,766 --> 00:54:00,636 MOVE TO RAY DIFFERENT STUDY. 1146 00:54:00,636 --> 00:54:03,872 WE SAW SEVERE CHANGES. 1147 00:54:03,872 --> 00:54:06,208 THE EXCITATORY TO INHIBITORY 1148 00:54:06,208 --> 00:54:08,744 SHIFT WAS DRAMATIC AND SEVERE. 1149 00:54:08,744 --> 00:54:10,912 WHAT THE QUESTION THOUGH THEY 1150 00:54:10,912 --> 00:54:14,049 DIDN'T RAISE IT WAS PROBABLY 1151 00:54:14,049 --> 00:54:18,253 ALLUDED TO IS EARLY ONSET 1152 00:54:18,253 --> 00:54:20,055 ALZHEIMER'S YOU DON'T SEE THIS 1153 00:54:20,055 --> 00:54:23,425 DRAMATIC SHIFT TO INHIBITORY 1154 00:54:23,425 --> 00:54:26,962 NEURONS AND WE PUT IN TWO COPIES 1155 00:54:26,962 --> 00:54:36,138 OF THIS RARE AUTOSOMAL DOMINANT 1156 00:54:36,138 --> 00:54:41,243 MUTATION AND WE ARE WORKING WITH 1157 00:54:41,243 --> 00:54:45,881 DOMINICK TO VALIDATE THE LINES 1158 00:54:45,881 --> 00:54:55,390 AND ENSURE THEIR EUKARYOT TYPE 1159 00:54:55,390 --> 00:54:57,392 MUTATION AND WE HAVE TO USE 1160 00:54:57,392 --> 00:54:58,560 SINGLE CELL TECHNOLOGIES TO 1161 00:54:58,560 --> 00:54:59,428 LOOK. 1162 00:54:59,428 --> 00:55:00,095 THE SECOND PRART OF THE QUESTION 1163 00:55:00,095 --> 00:55:02,097 WAS A DIFFERENT ASPECT WHICH IS 1164 00:55:02,097 --> 00:55:04,099 THINK BEING ABOUT MOUSE STUDIES 1165 00:55:04,099 --> 00:55:07,469 THAT HAVE -- IF I UNDERSTOOD 1166 00:55:07,469 --> 00:55:11,473 CORRECTLY WAS A HUMANIZED MOUSE 1167 00:55:11,473 --> 00:55:12,240 THAT KNOCKED IN PERHAPS A 1168 00:55:12,240 --> 00:55:14,209 PARTICULAR GENE WITH A MUTATION 1169 00:55:14,209 --> 00:55:19,314 AND SAYING WE LOOK BACK AT THAT 1170 00:55:19,314 --> 00:55:24,252 LITERATURE AND LOOK AT THE 1171 00:55:24,252 --> 00:55:27,255 EXCITATORY TO INHIBITORY 1172 00:55:27,255 --> 00:55:28,790 POPULATION AND EXCELLENT 1173 00:55:28,790 --> 00:55:29,091 SUGGESTION. 1174 00:55:29,091 --> 00:55:33,261 >> I HAVE A QUESTION ON YOUR 1175 00:55:33,261 --> 00:55:39,067 LOOPING WORK. 1176 00:55:39,067 --> 00:55:40,035 YOU SHOWED THE MORE LOOPS YOU 1177 00:55:40,035 --> 00:55:48,810 LOSE YOU SEE A DECREASE IN GENE 1178 00:55:48,810 --> 00:55:49,111 EXPRESSION. 1179 00:55:49,111 --> 00:55:50,979 ARE MOST GENES REGULATED BY ONE 1180 00:55:50,979 --> 00:55:52,080 OR TWO LOOPS? 1181 00:55:52,080 --> 00:55:55,817 IS THAT HOW THAT WORKS OR AM I 1182 00:55:55,817 --> 00:55:57,285 MISUNDERSTANDING HOW TO REC 1183 00:55:57,285 --> 00:55:59,121 RECONCILE THESE TWO? 1184 00:55:59,121 --> 00:56:02,758 >> I THINK YOU'RE REFERRING TO 1185 00:56:02,758 --> 00:56:06,128 THE WORK IN COLLABORATION WITH 1186 00:56:06,128 --> 00:56:15,270 WE KNOCKED OUT COHESSIN AND 1187 00:56:15,270 --> 00:56:20,942 LOOKED AT THE DISRUPTION OF 1188 00:56:20,942 --> 00:56:21,276 LOOPS. 1189 00:56:21,276 --> 00:56:25,347 >> THE WORK IN VIVO VERSUS THE 1190 00:56:25,347 --> 00:56:29,818 MULTI-LOOP MODEL WITH 1191 00:56:29,818 --> 00:56:31,319 ALZHEIMER'S, IN VIVO WORK EN 1192 00:56:31,319 --> 00:56:35,056 ELLY 51, WHEN YOU KNOCK OUT 1193 00:56:35,056 --> 00:56:38,026 COHESSIN THERE'S SEVERE GENE 1194 00:56:38,026 --> 00:56:39,094 EXPRESSION DYSREGULATION DURING 1195 00:56:39,094 --> 00:56:39,594 MATURATION IN VIVO. 1196 00:56:39,594 --> 00:56:43,598 WE TOOK THE NEURONS OUT AND IN 1197 00:56:43,598 --> 00:56:48,904 VITRO USED PHARMACOLOGIC AGENTS 1198 00:56:48,904 --> 00:56:59,447 AND TO FIRE AND THEY ARE DIDN'T 1199 00:57:04,820 --> 00:57:07,289 MATTER IN LATER THAT'S WHEN 1200 00:57:07,289 --> 00:57:10,492 LOOPS MATTERED QUITE A BIT. 1201 00:57:10,492 --> 00:57:12,327 IN THAT CASE WE DIDN'T LOOK AT 1202 00:57:12,327 --> 00:57:14,029 THE MULTI-LOOPING IDEA. 1203 00:57:14,029 --> 00:57:17,966 IT WAS PUBLISHED BEFORE WE FOUND 1204 00:57:17,966 --> 00:57:23,572 IT IN THE LATER STUDY SO CANNOT 1205 00:57:23,572 --> 00:57:26,408 COMMENT IF IT'S A PHENOMENON FOR 1206 00:57:26,408 --> 00:57:27,576 ACTIVITY EXPRESSION? 1207 00:57:27,576 --> 00:57:30,779 >> DO YOU SEE PLAQUE BUILD UP IN 1208 00:57:30,779 --> 00:57:32,080 THE 2-D NEURON CULTURES? 1209 00:57:32,080 --> 00:57:35,584 >> THE NEXT QUESTION IS ABOUT 1210 00:57:35,584 --> 00:57:37,652 THE FAD AND IF HE QUESTION IS IF 1211 00:57:37,652 --> 00:57:45,026 WE WAIT LONG ENOUGH IN 2-D DO WE 1212 00:57:45,026 --> 00:57:46,995 EVENTUALLY SEE PLAQUE OR 1213 00:57:46,995 --> 00:57:48,997 PHOSPHORYLATED TAU. 1214 00:57:48,997 --> 00:57:52,033 I NEVER EVEN TRIED TO CONVINCE 1215 00:57:52,033 --> 00:57:57,806 THE STUDENTS TO KEEP THE NEURONS 1216 00:57:57,806 --> 00:58:02,077 GOING FOR ANOTHER 100 DAYS. 1217 00:58:02,077 --> 00:58:03,578 THERE'S BEAUTIFUL WORK ALREADY 1218 00:58:03,578 --> 00:58:07,115 OUT DIFFICULT WITH IPS MODELS OF 1219 00:58:07,115 --> 00:58:12,420 ALZHEIMER'S IN 2-D FLAT CULTURE 1220 00:58:12,420 --> 00:58:14,389 TO HAVE AN AGGREGATION. 1221 00:58:14,389 --> 00:58:16,825 WE THOUGHT THAT WOULD BE 1222 00:58:16,825 --> 00:58:18,026 INTRACTABLE AND FORTUNATE IN 1223 00:58:18,026 --> 00:58:26,468 TRYING THE ORGANOIDS AND WHEN WE 1224 00:58:26,468 --> 00:58:28,470 HARVESTED THERE WAS NOTHING AND 1225 00:58:28,470 --> 00:58:29,137 WE WERE GETTING NERVOUS AT THAT 1226 00:58:29,137 --> 00:58:29,337 POINT. 1227 00:58:29,337 --> 00:58:33,275 >> THANK YOU. 1228 00:58:33,275 --> 00:58:34,843 >> VERY INTERESTING TALK. 1229 00:58:34,843 --> 00:58:37,112 I WAS TRYING TO CONNECT THE DOTS 1230 00:58:37,112 --> 00:58:39,080 BETWEEN THE DIFFERENT PARTS OF 1231 00:58:39,080 --> 00:58:40,982 YOUR TALK AND THERE WAS ONE PART 1232 00:58:40,982 --> 00:58:43,084 OF THE TALK WHERE YOU WERE 1233 00:58:43,084 --> 00:58:45,887 EMPHASIZING THE IMPORTANCE OF 1234 00:58:45,887 --> 00:58:47,589 THE FORMING OF THESE DIFFERENT 1235 00:58:47,589 --> 00:58:50,158 LOOPS AND CONNECTIONS BETWEEN 1236 00:58:50,158 --> 00:58:51,893 DIFFERENT PARTS AND WASN'T SURE 1237 00:58:51,893 --> 00:58:53,161 WHETHER THAT WAS IN CONNECTION 1238 00:58:53,161 --> 00:58:58,800 WITH RANDOM ACTIVITY AND 1239 00:58:58,800 --> 00:59:02,370 LEARNING BUT WAS IT LEARNING OR 1240 00:59:02,370 --> 00:59:03,571 RANDOM ACTIVITY? 1241 00:59:03,571 --> 00:59:05,307 >> IN THE CASE OF THE ACTIVITY 1242 00:59:05,307 --> 00:59:08,476 DEPENDENT LOOPING IS IT RELATED 1243 00:59:08,476 --> 00:59:12,147 IF IN VITRO SPONTANEOUS FIRING 1244 00:59:12,147 --> 00:59:14,716 OR INVOKED POTENTIAL AND WITH 1245 00:59:14,716 --> 00:59:17,552 THE IN VIVO DATA FROM BEHAVIORAL 1246 00:59:17,552 --> 00:59:21,189 OR EXPERIENCE-INDUCED OR 1247 00:59:21,189 --> 00:59:23,224 OPTOGENETIC STIMULATION. 1248 00:59:23,224 --> 00:59:26,895 FOR THE IN VITRO DATA THAT'S 1249 00:59:26,895 --> 00:59:28,063 PHARMACOLOGICALLY INDUCED ACTION 1250 00:59:28,063 --> 00:59:29,297 POTENTIAL FIRING NOT SPON 1251 00:59:29,297 --> 00:59:31,733 TRAINIOUS AND OUR CONTROL IS TT 1252 00:59:31,733 --> 00:59:33,935 X. 1253 00:59:33,935 --> 00:59:36,604 WE ENSURE USING THAT 1254 00:59:36,604 --> 00:59:39,741 PHARMACOLOGIC AGENT FOR FIRING 1255 00:59:39,741 --> 00:59:41,409 AS MUCH AS POSSIBLE. 1256 00:59:41,409 --> 00:59:44,879 FOR THE IN VIVO SITUATION WE 1257 00:59:44,879 --> 00:59:46,948 USED CONTEXTUAL FEAR 1258 00:59:46,948 --> 00:59:50,452 CONDITIONING AND USED THAT 1259 00:59:50,452 --> 00:59:51,486 BEHAVIOR FOR INJECTION IN THE 1260 00:59:51,486 --> 00:59:53,788 TRAP 2 ANIMAL TO FIRE ACTION 1261 00:59:53,788 --> 00:59:56,057 POTENTIAL DURING THE WINDOW OF 1262 00:59:56,057 --> 00:59:56,324 BEHAVIOR. 1263 00:59:56,324 --> 00:59:59,427 >> SO THE QUESTION FOR ME WAS SO 1264 00:59:59,427 --> 01:00:09,938 THAT WAS COOL AND EXCITING AND 1265 01:00:09,938 --> 01:00:11,406 TALKED ABOUT ALZHEIMER'S AND 1266 01:00:11,406 --> 01:00:14,275 MAKING ORGANOIDS AND THE GENES I 1267 01:00:14,275 --> 01:00:15,677 SAW AS DEVELOPMENTAL GENES 1268 01:00:15,677 --> 01:00:17,045 THOUGH THEY PLAY HAVE OTHER 1269 01:00:17,045 --> 01:00:17,412 ROLES. 1270 01:00:17,412 --> 01:00:19,347 SO I WAS TRYING TO FIGURE OUT 1271 01:00:19,347 --> 01:00:21,683 THE CONNECTION BETWEEN LOOPS 1272 01:00:21,683 --> 01:00:29,391 THAT YOU HAD ESTABLISHED IN THE 1273 01:00:29,391 --> 01:00:31,426 CONTEXT OF LEARNING OR TASK AND 1274 01:00:31,426 --> 01:00:36,865 WHAT'S HAPPENING IN AN ORGANOID. 1275 01:00:36,865 --> 01:00:38,400 >> FOR THOSE ONLINE THE QUESTION 1276 01:00:38,400 --> 01:00:41,469 IS RELATED TO HOW DO WE CONNECT 1277 01:00:41,469 --> 01:00:43,605 THE WORK HAPPENING IN CIRCUITS 1278 01:00:43,605 --> 01:00:47,609 WITH THE IN VITRO HUMAN MODEL OF 1279 01:00:47,609 --> 01:00:49,778 ALZHEIMER'S DISEASE WHERE WE'RE 1280 01:00:49,778 --> 01:00:52,280 CLEARLY AND SURPRISINGLY SEEING 1281 01:00:52,280 --> 01:00:53,882 CHANGES IN DEVELOPMENT GENES AND 1282 01:00:53,882 --> 01:00:54,716 LOOPING INTERACTIONS. 1283 01:00:54,716 --> 01:00:58,353 WHAT I HAVE TO SAY IS OUR PLAN 1284 01:00:58,353 --> 01:00:59,554 IN THE FUTURE IS TO NOW IN THE 1285 01:00:59,554 --> 01:01:05,293 ALZHEIMER'S MODEL BEGIN TO LOOK 1286 01:01:05,293 --> 01:01:06,895 AT ACTION POTENTIAL FIRING AND 1287 01:01:06,895 --> 01:01:08,396 THAT'S THE DIRECTION WE'RE GOING 1288 01:01:08,396 --> 01:01:10,965 AND YOU COULD PROBABLY GUESS 1289 01:01:10,965 --> 01:01:14,169 WHERE WE'RE PUSHING TOWARDS O 1290 01:01:14,169 --> 01:01:19,207 ORGANOIDS AND LOOK TO DO 1291 01:01:19,207 --> 01:01:22,277 SOMETHING IN VIVO IN BREEDING 1292 01:01:22,277 --> 01:01:24,479 WITH THE TAP 2 ANIMAL AND WHAT 1293 01:01:24,479 --> 01:01:26,581 I'LL SAY ON THE RECORD IS NO ONE 1294 01:01:26,581 --> 01:01:29,350 MORE THAN ME WAS MORE SHOCKED 1295 01:01:29,350 --> 01:01:30,919 THAN THE WIDESPREAD NATURE OF 1296 01:01:30,919 --> 01:01:33,755 THE LOOP DYSREGULATION AND THE 1297 01:01:33,755 --> 01:01:36,691 FACT IT WAS A LOT OF DEVELOPMENT 1298 01:01:36,691 --> 01:01:38,326 AND EARLY SYNAPTIC PLASTICITY 1299 01:01:38,326 --> 01:01:40,095 GENES AND IT'S LIKELY PARTIALLY 1300 01:01:40,095 --> 01:01:43,098 PART OF THE MODEL SYSTEM BECAUSE 1301 01:01:43,098 --> 01:01:45,300 WE HAVE A HOMOZYGOUS MUTATION 1302 01:01:45,300 --> 01:01:47,602 BUT THERE'S REAL INSIGHT THERE 1303 01:01:47,602 --> 01:01:50,071 BECAUSE YOU'RE STARTING TO SEE 1304 01:01:50,071 --> 01:01:54,809 IN CONFERENCES ACROSS DISORDERS 1305 01:01:54,809 --> 01:01:56,010 THEY'RE STARTING TO BE MISS 1306 01:01:56,010 --> 01:01:57,745 MOVEMENT OF HOW SOON DO WE HAVE 1307 01:01:57,745 --> 01:02:00,915 TO LOOK IN DEVELOPMENT IN EARLY 1308 01:02:00,915 --> 01:02:03,585 ADULTHOOD TO SEE THE INITIAL 1309 01:02:03,585 --> 01:02:05,353 UNRAVELLING AND ONSET OF 1310 01:02:05,353 --> 01:02:05,887 DISEASE. 1311 01:02:05,887 --> 01:02:06,788 IT'S POSSIBLE OVER THE YEARS 1312 01:02:06,788 --> 01:02:10,058 WE'LL START TO SEE THE DEFECTS 1313 01:02:10,058 --> 01:02:11,726 AT THE MOLECULAR LEVEL HAPPEN 1314 01:02:11,726 --> 01:02:14,896 SOONER THAN SOME OF THE SEVERE 1315 01:02:14,896 --> 01:02:15,497 CLINICAL PRESENTATIONS. 1316 01:02:15,497 --> 01:02:17,966 SO WE'LL KEEP PUSHING IT AND AS 1317 01:02:17,966 --> 01:02:21,369 SOMEBODY ELSE MENTIONED MAYBE 1318 01:02:21,369 --> 01:02:26,608 BRINGING IN THE HET WILL 1319 01:02:26,608 --> 01:02:37,085 UNDERSTAND THE EFFECT SIZE. 1320 01:02:41,823 --> 01:02:48,029 >> IT PREDICTS THOSE ASSOCIATED 1321 01:02:48,029 --> 01:02:49,397 WITH ALZHEIMER'S MAY 1322 01:02:49,397 --> 01:02:51,266 CONNECTED -- 1323 01:02:51,266 --> 01:02:55,103 >> YES. 1324 01:02:55,103 --> 01:02:56,738 THERE'S AN IMPORTANT IDEA RAISED 1325 01:02:56,738 --> 01:03:00,642 BY THE QUESTIONER IF INDIVIDUAL 1326 01:03:00,642 --> 01:03:01,809 WITH EARLY ONSET ALZHEIMER'S 1327 01:03:01,809 --> 01:03:05,079 SOME WHO MAY HAVE THE MOLECULAR 1328 01:03:05,079 --> 01:03:06,447 DEFECT MAY MANIFEST IN THE 1329 01:03:06,447 --> 01:03:09,284 CLINIC AS HAVING PRESENTATIONS 1330 01:03:09,284 --> 01:03:11,819 MORE TYPICALLY EQUATED WITH 1331 01:03:11,819 --> 01:03:12,754 NEURODEVELOPMENTAL DISORDERS. 1332 01:03:12,754 --> 01:03:20,328 I'M NOT A CLINICIAN SO I DON'T 1333 01:03:20,328 --> 01:03:29,304 KNOW IF AS THE FEATURES 1334 01:03:29,304 --> 01:03:30,305 MOLECULAR AS WELL AS CLINICAL 1335 01:03:30,305 --> 01:03:31,306 PRESENTATIONS AND I THINK IT 1336 01:03:31,306 --> 01:03:32,340 WOULD BE VERY EXCITING IF THAT 1337 01:03:32,340 --> 01:03:39,280 ENDED UP BEING THE CASE. 1338 01:03:39,280 --> 01:03:40,782 >> ONE LAST QUESTION AND WE ARE 1339 01:03:40,782 --> 01:03:43,585 PAST THE HOUR. 1340 01:03:43,585 --> 01:03:48,690 >> MY NAME IS MIKE. 1341 01:03:48,690 --> 01:03:55,096 I'M 90 YEARS OLD AND FOR MANY 1342 01:03:55,096 --> 01:03:58,533 YEARS MY LAB CHIEF WAS MAXINE 1343 01:03:58,533 --> 01:03:59,667 SINGER WHO UNFORTUNATELY DIED 1344 01:03:59,667 --> 01:04:03,605 THIS SUMMER AND I WOULD LIKE TO 1345 01:04:03,605 --> 01:04:05,273 CHALLENGE YOUR TIME FRAME WHICH 1346 01:04:05,273 --> 01:04:10,378 YOU MENTIONED OF A DECADE WHEN I 1347 01:04:10,378 --> 01:04:15,283 LOOK ON TV AT NEWS AND LOOK AT 1348 01:04:15,283 --> 01:04:19,654 THE PHARMA COMPANIES WHICH ARE 1349 01:04:19,654 --> 01:04:25,960 USING MONOCLONAL ANTIBODIES TO 1350 01:04:25,960 --> 01:04:28,830 IDENTIFY SEQUENCES WHICH ARE 1351 01:04:28,830 --> 01:04:33,868 ROLE VANT TO ALZHEIMER'S AND 1352 01:04:33,868 --> 01:04:39,274 WHICH ARE USING ARTIFICIAL 1353 01:04:39,274 --> 01:04:45,213 INTELLIGENCE ENHANCED SEQUENCING 1354 01:04:45,213 --> 01:04:51,286 TO FIND LOW MOLECULAR DRUGS 1355 01:04:51,286 --> 01:04:56,624 WHICH INFLUENCE ALZHEIMER'S AND 1356 01:04:56,624 --> 01:05:01,229 THAT I WOULD SUGGEST IF YOU LOOK 1357 01:05:01,229 --> 01:05:03,064 AT THOSE CAREFULLY AND SEE WHAT 1358 01:05:03,064 --> 01:05:05,433 THEY'RE DOING YOU'LL SEE YOUR 1359 01:05:05,433 --> 01:05:09,237 TIME FRAME SHOULD REALLY BE ON 1360 01:05:09,237 --> 01:05:11,906 THE ORDER OF MONTHS RATHER THAN 1361 01:05:11,906 --> 01:05:15,276 ON DECADES. 1362 01:05:15,276 --> 01:05:22,016 >> THANK YOU. 1363 01:05:22,016 --> 01:05:23,151 >> THANK YOU SO MUCH. 1364 01:05:23,151 --> 01:05:24,485 THANK YOU, JEN. 1365 01:05:24,485 --> 01:05:25,820 I'M HERE TO TELL YOU ALL THAT 1366 01:05:25,820 --> 01:05:29,057 I'M TOLD THERE'S A RECEPTION 1367 01:05:29,057 --> 01:05:30,858 AFTER THIS AND THERE WILL BE 1368 01:05:30,858 --> 01:05:34,195 COOKIES AND POSSIBLY JEN'S 1369 01:05:34,195 --> 01:05:36,397 FAVORITE CHEMICAL, CAFFEINE, 1370 01:05:36,397 --> 01:05:37,398 POSSIBLY. 1371 01:05:37,398 --> 01:05:39,267 WE'D LIKE YOU TO JOIN US TO TALK 1372 01:05:39,267 --> 01:05:41,402 TO JEN DURING THE RECEPTION AND 1373 01:05:41,402 --> 01:05:43,004 JOIN ME IN A ROUND OF APPLAUSE 1374 01:05:43,004 --> 01:05:43,438 FOR AN AWESOME TALK. 1375 01:05:43,438 --> 01:05:43,504