1 00:00:11,757 --> 00:00:20,877 HERE IS DR. BOB DATTA,HE 2 00:00:20,877 --> 00:00:22,779 COMES FROM LONG BEACH, 3 00:00:22,779 --> 00:00:23,079 CALIFORNIA. 4 00:00:23,079 --> 00:00:24,614 BUT THEN COMPLETED MUCH OF HIS 5 00:00:24,614 --> 00:00:26,482 TRAINING IN THE NORTHEAST. 6 00:00:26,482 --> 00:00:29,752 HE RECEIVED A B.S. IN MOLECULAR 7 00:00:29,752 --> 00:00:31,354 BIO PHYSICS AND HISTORY FROM 8 00:00:31,354 --> 00:00:33,256 YALE. 9 00:00:33,256 --> 00:00:34,891 PRIOR TO MATRICULATING TO 10 00:00:34,891 --> 00:00:36,759 HARVARD'S MEDICAL SCHOOL WHERE 11 00:00:36,759 --> 00:00:39,729 HE COMPLETED HIS M.D. AND Ph.D. 12 00:00:39,729 --> 00:00:41,431 IN NEUROBIOLOGY. 13 00:00:41,431 --> 00:00:43,499 FOLLOWING THAT HE RELOCATED TO 14 00:00:43,499 --> 00:00:44,300 COLUMBIA UNIVERSITY WHERE HE 15 00:00:44,300 --> 00:00:47,704 WAS ABLE TO WORK WITH NOBLE 16 00:00:47,704 --> 00:00:49,072 LAUREATE RICHARD AXLE, BOB, I 17 00:00:49,072 --> 00:00:50,406 ASSUME AROUND THE SAME TIME YOU 18 00:00:50,406 --> 00:00:52,442 WERE TRAINING. 19 00:00:52,442 --> 00:00:54,544 SO AN INTERESTING TIME TO BE 20 00:00:54,544 --> 00:00:55,912 PART OF THE LAB. 21 00:00:55,912 --> 00:00:58,381 FOLLOWING THAT HE JOINED 22 00:00:58,381 --> 00:00:59,916 HARVARD AS FACULTY. 23 00:00:59,916 --> 00:01:03,519 THIS WAS IN 2009. 24 00:01:03,519 --> 00:01:05,622 AND PROCEEDED THROUGH THE RANKS 25 00:01:05,622 --> 00:01:07,257 QUITE QUICKLY, REACHING THE 26 00:01:07,257 --> 00:01:09,025 RANK OF PROFESSOR JUST 12 YEARS 27 00:01:09,025 --> 00:01:10,426 LATER IN 2021. 28 00:01:10,426 --> 00:01:14,264 BOB IS A SCIENTIFIC ADVISOR, 29 00:01:14,264 --> 00:01:15,431 MEMBER OF ADVISORY BOARDS 30 00:01:15,431 --> 00:01:16,165 THROUGHOUT THE COUNTRY AND 31 00:01:16,165 --> 00:01:18,701 WORLD. 32 00:01:18,701 --> 00:01:20,770 HE SUPPORTS INDUSTRY, ACADEMIA, 33 00:01:20,770 --> 00:01:23,006 AS WELL AS HERE AT HOME WHERE 34 00:01:23,006 --> 00:01:24,874 HE IS AN ADVISORY BOARD MEMBER 35 00:01:24,874 --> 00:01:26,209 OF OUR NATIONAL SMELL AND TASTE 36 00:01:26,209 --> 00:01:30,513 CENTER. 37 00:01:30,513 --> 00:01:33,850 BOB HAS CONTRIBUTED TO PEER 38 00:01:33,850 --> 00:01:35,718 REVIEW, THE NIH, NSF, MULTIPLE 39 00:01:35,718 --> 00:01:37,887 OTHER PLACES AND IS TRULY A 40 00:01:37,887 --> 00:01:39,989 RESOURCE. 41 00:01:39,989 --> 00:01:43,092 A LEADING VOICE WITHIN THE 42 00:01:43,092 --> 00:01:46,129 OLFACTION AND SENSATION 43 00:01:46,129 --> 00:01:47,563 COMMUNITIES. 44 00:01:47,563 --> 00:01:49,866 BOB STUDIES HOW THE BRAIN 45 00:01:49,866 --> 00:01:51,034 ORGANIZES AND INTEGRATES 46 00:01:51,034 --> 00:01:53,202 INFORMATION ABOUT SENSATION TO 47 00:01:53,202 --> 00:01:55,004 DRIVE MEANINGFUL INTERACTIONS. 48 00:01:55,004 --> 00:01:56,673 HOW WE TAKE SIGNALS FROM THE 49 00:01:56,673 --> 00:02:00,743 WORLD AROUND US AND INTEGRATE 50 00:02:00,743 --> 00:02:02,278 THAT INTO BRAIN FUNCTION AND 51 00:02:02,278 --> 00:02:05,014 INTERACTIONS. 52 00:02:05,014 --> 00:02:08,751 THIS HAS SPANNED FROM DETECTION 53 00:02:08,751 --> 00:02:10,453 TO CNS INTEGRATION, ALL THE WAY 54 00:02:10,453 --> 00:02:13,623 FORWARD TO ACTION. 55 00:02:13,623 --> 00:02:14,991 AND I'M INCREDIBLY EXCITED TO 56 00:02:14,991 --> 00:02:18,528 HEAR SOME OF HIS NEWER FINDINGS 57 00:02:18,528 --> 00:02:20,196 AND WORK I BELIEVE HAS THE 58 00:02:20,196 --> 00:02:23,399 POTENTIAL TO TRULY PUSH OUR 59 00:02:23,399 --> 00:02:24,867 FIELD FORWARD. 60 00:02:24,867 --> 00:02:26,336 SO WITH THAT, AND NO PRESSURE, 61 00:02:26,336 --> 00:02:26,936 BOB? 62 00:02:26,936 --> 00:02:32,942 [ APPLAUSE ] 63 00:02:32,942 --> 00:02:34,811 I HAD TWO TASKS AND BOB, JUST 64 00:02:34,811 --> 00:02:36,212 ONE SECOND. 65 00:02:36,212 --> 00:02:37,613 FOR EVERYONE JOINING US, IF YOU 66 00:02:37,613 --> 00:02:39,682 WOULD LIKE TO RECEIVE CME 67 00:02:39,682 --> 00:02:43,386 CREDIT FOR THIS EVENT, PLEASE 68 00:02:43,386 --> 00:02:46,656 ENTER THE CODE 57691 IN THE 69 00:02:46,656 --> 00:02:48,057 JOHNS HOPKINS CME PORTAL. 70 00:02:48,057 --> 00:02:48,991 THANK YOU. 71 00:02:48,991 --> 00:02:50,626 >> Sandeep Datta: GREAT, THANKS 72 00:02:50,626 --> 00:02:52,028 SO MUCH, JOSH FOR THAT REALLY 73 00:02:52,028 --> 00:02:52,795 KIND INTRODUCTION. 74 00:02:52,795 --> 00:02:54,297 AND THANKS TO ALL OF YOU HERE 75 00:02:54,297 --> 00:02:56,032 AT THE NIH. 76 00:02:56,032 --> 00:02:58,167 THIS IS REALLY AN HONOR FOR ME 77 00:02:58,167 --> 00:03:01,471 AND MY LAB, THIS IS THE 78 00:03:01,471 --> 00:03:01,971 NATION'S PREEMINENT BIO 79 00:03:01,971 --> 00:03:03,106 INSTITUTE. 80 00:03:03,106 --> 00:03:04,841 I'M GRATEFUL TO CATCH UP WITH 81 00:03:04,841 --> 00:03:05,942 OLD FRIENDS, ALL OF YOU AND 82 00:03:05,942 --> 00:03:08,044 SHARE SOME OF OUR SCIENCE. 83 00:03:08,044 --> 00:03:09,679 AS JOSH MENTIONED MY LAB'S MAIN 84 00:03:09,679 --> 00:03:11,814 INTEREST IS THINKING ABOUT HOW 85 00:03:11,814 --> 00:03:12,749 THE BRAIN TAKES SENSORY 86 00:03:12,749 --> 00:03:15,852 INFORMATION AND GENERATES 87 00:03:15,852 --> 00:03:16,519 NATURAL BEHAVIORS IN THE REAL 88 00:03:16,519 --> 00:03:17,487 WORLD. 89 00:03:17,487 --> 00:03:19,122 TODAY I'M NOT GOING TO TALK AT 90 00:03:19,122 --> 00:03:23,292 ALL ABOUT THE WORK MY LAB DOES, 91 00:03:23,292 --> 00:03:24,494 INSTEAD I WANT TO TALK ABOUT 92 00:03:24,494 --> 00:03:26,295 SOME WORK WE HAVE BEEN DOING, 93 00:03:26,295 --> 00:03:35,238 EXPLORING THE SENSE THAT IS 94 00:03:35,238 --> 00:03:36,672 MOST IMPORTANT FOR MOST ANIMALS. 95 00:03:36,672 --> 00:03:40,777 WE THINK OF SMELL BEING PRIMAL 96 00:03:40,777 --> 00:03:43,246 TO ANIMALS, IT ALLOWS THEM TO 97 00:03:43,246 --> 00:03:44,847 SMELL FOOD, ANIMALS AND THREATS. 98 00:03:44,847 --> 00:03:46,949 FOR HUMANS WE THINK OF SMELL AS 99 00:03:46,949 --> 00:03:49,952 BEING KIND OF AESTHETIC, 100 00:03:49,952 --> 00:03:51,354 ALTHOUGH OF COURSE SMELLS ARE 101 00:03:51,354 --> 00:03:56,225 CAPABLE OF ELICITING DEEP 102 00:03:56,225 --> 00:03:58,661 MEMORIES AND EMOTION. 103 00:03:58,661 --> 00:04:00,630 PEOPLE WHO ACUTELY LOSE THEIR 104 00:04:00,630 --> 00:04:03,232 SENSE OF SMELL FEEL BEREFT AND 105 00:04:03,232 --> 00:04:07,103 INCREASED RISK OF PSYCHIATRIC 106 00:04:07,103 --> 00:04:09,338 DISORDERS LIKE DEPRESSION. 107 00:04:09,338 --> 00:04:11,574 BECAUSE OF SMELL AND MEMORY, 108 00:04:11,574 --> 00:04:13,509 RISK OF NEURODEGENERATION. 109 00:04:13,509 --> 00:04:15,411 IT'S IMPORTANT WE UNDERSTAND 110 00:04:15,411 --> 00:04:17,280 SMELL NOT JUST BECAUSE IT HELPS 111 00:04:17,280 --> 00:04:20,049 US MAKE SENSE OF THE WORLD BUT 112 00:04:20,049 --> 00:04:21,050 IMPORTANT FOR HUMAN HEALTH AND 113 00:04:21,050 --> 00:04:22,418 WELLNESS. 114 00:04:22,418 --> 00:04:29,725 TODAY I WILL TELL YOU ABOUT THE 115 00:04:29,725 --> 00:04:31,260 CANONICAL OF SMELL AND WHY WE 116 00:04:31,260 --> 00:04:33,362 THINK A LOT OF IT IS WRONG. 117 00:04:33,362 --> 00:04:34,697 I WANT TO TALK ABOUT MAPS. 118 00:04:34,697 --> 00:04:36,799 WHAT IS A MAP? 119 00:04:36,799 --> 00:04:38,267 A SYMBOLIC REPRESENTATION THAT 120 00:04:38,267 --> 00:04:41,170 CAPTURES SOME FEATURE ABOUT THE 121 00:04:41,170 --> 00:04:41,671 WORLD, WHICH MAINTAINS 122 00:04:41,671 --> 00:04:42,338 RELATIONSHIPS. 123 00:04:42,338 --> 00:04:46,242 SO A GREAT EXAMPLE OF A MAP IS 124 00:04:46,242 --> 00:04:48,578 THIS MAP OF THE UNITED STATES. 125 00:04:48,578 --> 00:04:50,947 SO HERE, THE FEATURE THAT IS 126 00:04:50,947 --> 00:04:52,114 BEING CAPTURED IS ELEVATION. 127 00:04:52,114 --> 00:04:54,217 AND THE RELATIONSHIPS THAT ARE 128 00:04:54,217 --> 00:04:55,251 BEING MAINTAINED ARE SPATIAL. 129 00:04:55,251 --> 00:05:00,756 SO ARMED WITH THIS KIND OF MAP, 130 00:05:00,756 --> 00:05:01,924 YOU CAN MAKE PREDICTIONS HOW 131 00:05:01,924 --> 00:05:04,494 HARD IT WILL BE TO BICYCLE FROM 132 00:05:04,494 --> 00:05:05,928 POINT A TO POINT B. 133 00:05:05,928 --> 00:05:08,264 MAPS DON'T JUST HAVE TO CAPTURE 134 00:05:08,264 --> 00:05:08,865 PHYSICAL FEATURES ABOUT THE 135 00:05:08,865 --> 00:05:10,132 WORLD. 136 00:05:10,132 --> 00:05:16,005 THEY OBVIOUSLY CAN CAPTURE MORE 137 00:05:16,005 --> 00:05:17,540 ABSTRACT THINGS LIKE POLITICAL 138 00:05:17,540 --> 00:05:18,374 BOUNDARIES. 139 00:05:18,374 --> 00:05:20,943 ONE OF THE GREAT THINGS ABOUT 140 00:05:20,943 --> 00:05:24,013 MAPS THEY ARE EASILY REPRODUCED 141 00:05:24,013 --> 00:05:26,816 AND TRANSFORMED IN THIS FAMOUS 142 00:05:26,816 --> 00:05:28,150 PAINTING CALLED MAP CALLED 143 00:05:28,150 --> 00:05:30,586 JASPER JOHN. 144 00:05:30,586 --> 00:05:31,721 THE POLITICAL BORDER THAT'S 145 00:05:31,721 --> 00:05:33,389 SEPARATE THE STATES AND REMIND 146 00:05:33,389 --> 00:05:34,757 US WE ALLBEE LONG TO THE SAME 147 00:05:34,757 --> 00:05:38,561 COUNTRY. 148 00:05:38,561 --> 00:05:39,428 MAPS ARE PERVASIVE IN THE 149 00:05:39,428 --> 00:05:41,397 NERVOUS SYSTEM. 150 00:05:41,397 --> 00:05:44,400 THE MAPS WE UNDERSTAND THE BEST 151 00:05:44,400 --> 00:05:46,669 CREATE EXTERNAL WORLD FOR OUR 152 00:05:46,669 --> 00:05:46,903 SENSES. 153 00:05:46,903 --> 00:05:49,906 WE PARTICULARLY UNDERSTAND 154 00:05:49,906 --> 00:05:51,007 THOSE FOR TOUCH, FOR SIGHT AND 155 00:05:51,007 --> 00:05:52,275 FOR HEARING. 156 00:05:52,275 --> 00:05:56,145 SO FOR EXAMPLE, WE KNOW THE 157 00:05:56,145 --> 00:05:57,547 RETINA CONTAINS A RETINA 158 00:05:57,547 --> 00:06:00,116 TOPICAL MAP OF THE VISUAL WORLD. 159 00:06:00,116 --> 00:06:03,920 THERE ARE NEURONS THAT TEND TO 160 00:06:03,920 --> 00:06:05,321 REPRESENT OBJECTS THAT MIRROR 161 00:06:05,321 --> 00:06:09,292 EACH OTHER IN VISUAL SPACE. 162 00:06:09,292 --> 00:06:11,627 THE COCHLEA HAS NEURONS NEAR 163 00:06:11,627 --> 00:06:13,229 EACH OTHER IN PHYSICAL SPACE 164 00:06:13,229 --> 00:06:15,531 TEND TO RESPOND TO SOUNDS OF 165 00:06:15,531 --> 00:06:16,065 SIMILAR FREQUENCIES CHBLT 166 00:06:16,065 --> 00:06:19,468 MAPPED OUT IN A PHYSICAL SPACE 167 00:06:19,468 --> 00:06:20,503 ARE KEY CHARACTERISTICS IN 168 00:06:20,503 --> 00:06:21,837 THESE MAPS. 169 00:06:21,837 --> 00:06:24,607 AND IMPORTANTLY, THE STRUCTURES 170 00:06:24,607 --> 00:06:27,677 OF THESE MAPS ARE MAINTAINED AS 171 00:06:27,677 --> 00:06:28,711 INFORMATION PROGRESSES FROM 172 00:06:28,711 --> 00:06:30,713 PERIPHERAL SENSE ORGANS FROM 173 00:06:30,713 --> 00:06:37,820 THE THALAMUS AND CORTEX, WHICH 174 00:06:37,820 --> 00:06:39,221 ITSELF CONTAINS TOPIC MAPS. 175 00:06:39,221 --> 00:06:41,090 WE KNOW HOW THESE MAPS ARE 176 00:06:41,090 --> 00:06:42,358 BUILT AND PROPAGATED FROM ONE 177 00:06:42,358 --> 00:06:43,693 BRAIN AREA TO THE NEXT. 178 00:06:43,693 --> 00:06:46,262 THE MAIN THEME IS GRADIENTS, 179 00:06:46,262 --> 00:06:47,463 CHEMICAL GRADIENTS PLAY AN 180 00:06:47,463 --> 00:06:48,698 IMPORTANT ROLE IN THE 181 00:06:48,698 --> 00:06:49,565 DEVELOPMENT AND MAINTENANCE OF 182 00:06:49,565 --> 00:06:56,706 THESE MAPS. 183 00:06:56,706 --> 00:07:05,114 A MOLECULE FAA AND THALAMUS 184 00:07:05,114 --> 00:07:07,016 CONTAINS EPHRIN-A. 185 00:07:07,016 --> 00:07:08,884 THEY HELP GUIDE AXONS IN A 186 00:07:08,884 --> 00:07:15,191 GUIDE TO GUIDE MANNER ALONG 187 00:07:15,191 --> 00:07:25,301 THIS. 188 00:07:47,356 --> 00:07:52,762 THESE ARE EXPRESSED IN THE 189 00:07:52,762 --> 00:07:54,764 CILIOSENSORY NEURONS THAT LIVE 190 00:07:54,764 --> 00:07:55,898 HERE IN THE OLFACTORY 191 00:07:55,898 --> 00:07:56,565 ESPECIALLY THEME YUM IN YOUR 192 00:07:56,565 --> 00:07:58,501 NOSE. 193 00:07:58,501 --> 00:08:00,903 THROUGH MECHANISMS WE DON'T 194 00:08:00,903 --> 00:08:03,005 FULLY UNDERSTAND THAT MATURAL 195 00:08:03,005 --> 00:08:05,141 OLFACTORY SENSORY NEURONS 196 00:08:05,141 --> 00:08:07,243 CHOOSE TO EXPRESS ONE AND ONLY 197 00:08:07,243 --> 00:08:11,013 ONE OF SAY THOUSAND POSSIBLE 198 00:08:11,013 --> 00:08:12,214 ODOR RECEPTORS THAT COULD BE 199 00:08:12,214 --> 00:08:13,716 EXPRESSED IN THE MOUSE. 200 00:08:13,716 --> 00:08:16,152 THERE ARE THOUSANDS OF 201 00:08:16,152 --> 00:08:17,553 OLFACTORY SUBTYPES, EACH ONE OF 202 00:08:17,553 --> 00:08:19,288 WHICH IS DEFINED BY WHICH 203 00:08:19,288 --> 00:08:20,356 RECEPTOR IT EXPRESSES. 204 00:08:20,356 --> 00:08:23,426 WE HAVE A THOUSAND DIFFERENT 205 00:08:23,426 --> 00:08:24,794 TYPES OF RECEPTORS HOW ARE THEY 206 00:08:24,794 --> 00:08:26,762 ORGANIZED IN SPACE IN THE 207 00:08:26,762 --> 00:08:28,030 EPITHELIUM? 208 00:08:28,030 --> 00:08:29,331 IS THERE A SENSORY MAP HERE IN 209 00:08:29,331 --> 00:08:30,399 THE NOSE? 210 00:08:30,399 --> 00:08:32,234 WHAT ARE YOU LOOKING AT HERE ON 211 00:08:32,234 --> 00:08:37,239 THE RIGHT IS A WHOLE MOUNT OF A 212 00:08:37,239 --> 00:08:37,940 MOUSE GENETICALLY MODIFIED, 213 00:08:37,940 --> 00:08:40,710 THEY EXPRESS THE SAME ODOR 214 00:08:40,710 --> 00:08:42,945 RECEPTOR, ONE CHANNEL OUT OF A 215 00:08:42,945 --> 00:08:44,914 THOUSAND. 216 00:08:44,914 --> 00:08:46,649 THESE NEURONS ARE ARRAYED ALONG 217 00:08:46,649 --> 00:08:49,351 A STRIPE WHICH IN THE FIELD IS 218 00:08:49,351 --> 00:08:52,221 REFERRED TO AS A ZONE AND ZONE 219 00:08:52,221 --> 00:08:54,290 TRAVERSES THE EXTENT OF THE 220 00:08:54,290 --> 00:08:56,325 EPITHELIUM AND OCCUPIES ABOUT A 221 00:08:56,325 --> 00:08:58,394 QUARTER OF THE EPITHELIUM. 222 00:08:58,394 --> 00:09:00,362 IT'S THOUGHT THERE ARE FOUR OF 223 00:09:00,362 --> 00:09:02,665 THESE SO-CALLED ZONES. 224 00:09:02,665 --> 00:09:03,566 EACH RECEPTOR IS SOMEHOW 225 00:09:03,566 --> 00:09:04,967 THOUGHT DURING DEVELOPMENT TO 226 00:09:04,967 --> 00:09:07,770 BE A SIGN-IN A STEREOTYPE 227 00:09:07,770 --> 00:09:09,839 MANNER ONE OF THESE FOUR ZONES 228 00:09:09,839 --> 00:09:11,707 AND LIVE IN ONE OF THESE FOUR 229 00:09:11,707 --> 00:09:13,109 STRIPES. 230 00:09:13,109 --> 00:09:16,378 HOWEVER, WITHIN EACH IT IS 231 00:09:16,378 --> 00:09:18,013 THOUGHT CELLS PICKED RANDOMLY 232 00:09:18,013 --> 00:09:20,149 FROM ONE IN 150 RECEPTORS. 233 00:09:20,149 --> 00:09:24,587 TO THE EXTENT THERE'S A MAP IN 234 00:09:24,587 --> 00:09:27,123 THE ZONE, THE VIBE OF THE NOSE 235 00:09:27,123 --> 00:09:29,024 BASICALLY NEURONS DEVELOP AND 236 00:09:29,024 --> 00:09:29,558 RANDOMLY PICK A RECEPTOR. 237 00:09:29,558 --> 00:09:30,893 OKAY? 238 00:09:30,893 --> 00:09:33,229 IT'S IMPORTANT TO NOTE THIS 239 00:09:33,229 --> 00:09:35,598 PROCESS OF ODOR RECEPTOR CHOICE 240 00:09:35,598 --> 00:09:37,199 DOESN'T JUST HAPPEN DURING 241 00:09:37,199 --> 00:09:38,367 DEVELOPMENT BUT CONTINUOUSLY 242 00:09:38,367 --> 00:09:40,469 THROUGHOUT THE LIFE SPAN. 243 00:09:40,469 --> 00:09:44,507 JUST UNDERNEATH A LAYER OF 244 00:09:44,507 --> 00:09:46,776 OLFACTORY SENSORY NEURONS IS 245 00:09:46,776 --> 00:09:49,011 STEM CELLS CONTINUOUSLY 246 00:09:49,011 --> 00:09:50,412 SPITTING OUT NEURAL PRECURSORS 247 00:09:50,412 --> 00:09:53,716 AND GENERATING A WHOLE NEW SET 248 00:09:53,716 --> 00:09:54,717 OF MATURE OLFACTORY SENSORY 249 00:09:54,717 --> 00:09:57,019 NEURONS THAT HAVE TO CHOOSE NEW 250 00:09:57,019 --> 00:09:57,953 RECEPTORS AND CONTINUOUSLY 251 00:09:57,953 --> 00:09:58,988 BEING INTEGRATED INTO THIS 252 00:09:58,988 --> 00:10:00,256 CIRCUIT. 253 00:10:00,256 --> 00:10:01,423 HOW DOES INFORMATION GET FROM 254 00:10:01,423 --> 00:10:09,498 THE NOSE TO BRAIN? 255 00:10:09,498 --> 00:10:11,867 ALL THOSE NEURONS, THEY 256 00:10:11,867 --> 00:10:13,035 ELABORATE AXONS AND PUNCTURE 257 00:10:13,035 --> 00:10:13,702 THIS PLATE AT THE BASE OF THE 258 00:10:13,702 --> 00:10:14,904 SKULL. 259 00:10:14,904 --> 00:10:17,706 THEY ALL CONVERGE ON A SINGLE 260 00:10:17,706 --> 00:10:19,108 INSULAR STRUCTURE WITHIN THE 261 00:10:19,108 --> 00:10:22,144 OLFACTORY BULB IN THE BASAL 262 00:10:22,144 --> 00:10:27,316 FOREBRAIN AND IT'S CALLED A 263 00:10:27,316 --> 00:10:28,918 GLOMERULUS. 264 00:10:28,918 --> 00:10:32,254 THERE ARE A THOUSAND GLOMERULI 265 00:10:32,254 --> 00:10:35,090 IN THE OLFACTORY BULB. 266 00:10:35,090 --> 00:10:38,127 TURNS OUT THE SPATIAL POSITION 267 00:10:38,127 --> 00:10:39,361 IS INVARIANT FROM MOUSE TO 268 00:10:39,361 --> 00:10:41,163 MOUSE TO MOUSE. 269 00:10:41,163 --> 00:10:44,934 AND HUMAN, TO HUMAN, TO HUMAN. 270 00:10:44,934 --> 00:10:47,336 THAT HAS AN IMPORTANT 271 00:10:47,336 --> 00:10:49,538 CONSEQUENCE. 272 00:10:49,538 --> 00:10:52,541 DIFFERENT ODORS WILL ACTIVATE 273 00:10:52,541 --> 00:10:55,744 DIFFERENT RECEPTORS TO ACTIVATE 274 00:10:55,744 --> 00:10:56,679 DIFFERENT PATTERNS OF GLOMERULI. 275 00:10:56,679 --> 00:10:59,682 YOU COULD SEE THE SPATIAL 276 00:10:59,682 --> 00:11:04,119 PATTERN FOR JASMINE IS 277 00:11:04,119 --> 00:11:06,789 DIFFERENT OF ROSE. 278 00:11:06,789 --> 00:11:09,058 AND BECAUSE IT'S INVARIANT 279 00:11:09,058 --> 00:11:10,993 ACROSS ANIMALS, LOOKED AT ONE 280 00:11:10,993 --> 00:11:12,862 OF THESE PATTERNS AND TELL YOU 281 00:11:12,862 --> 00:11:14,463 WHAT SMELL THE MOUSE IS 282 00:11:14,463 --> 00:11:16,765 SMELLING AT ANY MOMENT IN TIME. 283 00:11:16,765 --> 00:11:18,667 THERE'S A PRECISE MAP OF ODOR 284 00:11:18,667 --> 00:11:22,671 IDENTITY BUILT BY THE PRECISION 285 00:11:22,671 --> 00:11:23,405 LOCALIZATION OF GLOMERULI IN 286 00:11:23,405 --> 00:11:24,306 THE OLFACTORY BULB. 287 00:11:24,306 --> 00:11:26,609 WHERE DOES IT GO FROM HERE? 288 00:11:26,609 --> 00:11:29,411 SENT TO MULTIPLE HIGHER BRAIN 289 00:11:29,411 --> 00:11:30,813 REGIONS RESPONSIBLE FOR ODOR 290 00:11:30,813 --> 00:11:31,447 IDENTIFICATION AND MEMORY AND 291 00:11:31,447 --> 00:11:32,681 EMOTION. 292 00:11:32,681 --> 00:11:35,050 SOMEHOW THEY COLLABORATE IN 293 00:11:35,050 --> 00:11:37,386 ORDER TO BUILD ODOR PERCEPTION. 294 00:11:37,386 --> 00:11:38,721 WHAT HAVE I TOLD YOU? 295 00:11:38,721 --> 00:11:40,689 I TOLD YOU THAT BASICALLY, 296 00:11:40,689 --> 00:11:42,324 UNLIKE THE OTHER SENSES, THE 297 00:11:42,324 --> 00:11:43,392 NOSE BARELY HAS A MAP. 298 00:11:43,392 --> 00:11:44,927 RIGHT? 299 00:11:44,927 --> 00:11:45,728 THERE ARE THESE FOUR WEIRD 300 00:11:45,728 --> 00:11:47,263 ZONES. 301 00:11:47,263 --> 00:11:51,300 BASICALLY EACH NEURON IN THE 302 00:11:51,300 --> 00:11:52,468 OLFACTORY EPITHELIUM RANDOMLY 303 00:11:52,468 --> 00:11:53,035 CHOOSES WHICH RECEPTOR TO 304 00:11:53,035 --> 00:11:53,669 EXPRESS. 305 00:11:53,669 --> 00:11:56,438 SO THE NOSE IS DISORDERED. 306 00:11:56,438 --> 00:11:58,040 SOMEHOW THROUGH MECHANISMS WE 307 00:11:58,040 --> 00:11:59,108 STILL DON'T UNDERSTAND AXONS 308 00:11:59,108 --> 00:12:01,343 FROM THE NOSE GET TO THE BULB 309 00:12:01,343 --> 00:12:04,313 WHERE THEY BUILD AN INCREDIBLY 310 00:12:04,313 --> 00:12:10,019 PRECISE MAP OF GLOMERULAR 311 00:12:10,019 --> 00:12:11,120 IDENTITY. 312 00:12:11,120 --> 00:12:12,621 THE BRAIN READ THAT'S CODE TO 313 00:12:12,621 --> 00:12:14,890 GENERATE PERCEPTION. 314 00:12:14,890 --> 00:12:17,826 I WANT TO TALKED TO ABOUT THIS 315 00:12:17,826 --> 00:12:18,994 IDEA OF DISORDER IN THE ZONES 316 00:12:18,994 --> 00:12:20,095 IN THE NOSE. 317 00:12:20,095 --> 00:12:22,064 I WANT TO EXPLAIN ABOUT THESE 318 00:12:22,064 --> 00:12:22,898 ZONES. 319 00:12:22,898 --> 00:12:24,099 THIS IS THE IMAGE I SHOWED YOU 320 00:12:24,099 --> 00:12:25,501 BEFORE. 321 00:12:25,501 --> 00:12:29,238 THIS IS THE WHOLE MOUNT. 322 00:12:29,238 --> 00:12:31,440 CARTOON DEPICTING ZONES FROM 323 00:12:31,440 --> 00:12:32,708 DORSAL TO VENTRAL. 324 00:12:32,708 --> 00:12:35,144 WE TEND TO NOT DO THESE WHOLE 325 00:12:35,144 --> 00:12:43,218 MOUNTS, INSTEAD WE TEND TO CUT 326 00:12:43,218 --> 00:12:44,920 CORONAL SECTIONS. 327 00:12:44,920 --> 00:12:47,489 THIS DORSAL TO CENTRAL ANATOMY 328 00:12:47,489 --> 00:12:49,124 MAPS IN THIS KERNEL SECTION, 329 00:12:49,124 --> 00:12:50,526 SUCH THAT THE DORSAL IN THIS 330 00:12:50,526 --> 00:12:53,095 VIEW IS KIND OF MEDIAL OR 331 00:12:53,095 --> 00:12:56,565 PROXIMAL HERE IN THE EPITHELIUM 332 00:12:56,565 --> 00:12:57,499 AND VENTRAL IS LATERAL OR 333 00:12:57,499 --> 00:12:59,401 DISTAL. 334 00:12:59,401 --> 00:13:01,070 THIS STUFF IS MEDIAL. 335 00:13:01,070 --> 00:13:03,272 MEDIAL OR DORSAL AND THIS IS 336 00:13:03,272 --> 00:13:05,774 LATERAL OR VENTRAL. 337 00:13:05,774 --> 00:13:07,176 THIS VENTRAL, OLFACTORY SENSORY 338 00:13:07,176 --> 00:13:08,577 NEURON, ONE OF THESE VENTRAL 339 00:13:08,577 --> 00:13:12,147 ZONES, IF YOU LOOK AT THAT 340 00:13:12,147 --> 00:13:15,451 EXACT RECEPTOR IN THE CORONAL 341 00:13:15,451 --> 00:13:16,919 SECTION THAT IS TO ORIENT YOU 342 00:13:16,919 --> 00:13:18,721 TO THE DATA THAT IS COMING. 343 00:13:18,721 --> 00:13:20,589 A QUESTION YOU MIGHT ASK, HOW 344 00:13:20,589 --> 00:13:22,925 ARE THESE ZONES SHOWN HERE IN 345 00:13:22,925 --> 00:13:25,661 THE EPITHELIUM RELATED TO WHERE 346 00:13:25,661 --> 00:13:27,196 OLFACTORY SENSORY NEURONS 347 00:13:27,196 --> 00:13:29,865 PROJECT THEIR AXONS IN THE BULB? 348 00:13:29,865 --> 00:13:31,967 IT TURNS OUT THERE ARE FOUR 349 00:13:31,967 --> 00:13:36,438 ZONES IN THE EPITHELIUM, THEY 350 00:13:36,438 --> 00:13:38,007 ROUGHLY CORRESPOND TO FOUR 351 00:13:38,007 --> 00:13:40,209 ZONES IN THE BULB RUNNING 352 00:13:40,209 --> 00:13:41,276 DORSAL TO VENTRAL. 353 00:13:41,276 --> 00:13:42,911 WE THINK THERE'S SOME MAPPING 354 00:13:42,911 --> 00:13:44,146 FROM HERE TO HERE, KIND OF VERY 355 00:13:44,146 --> 00:13:44,847 CRUDELY. 356 00:13:44,847 --> 00:13:46,882 WE KNOW ABOUT THE MOLECULAR 357 00:13:46,882 --> 00:13:47,683 MECHANISMS THAT SUPPORT THAT. 358 00:13:47,683 --> 00:13:50,252 WE KNOW THERE'S A MARKER 359 00:13:50,252 --> 00:13:53,055 PROTEIN THAT MARKS THE 360 00:13:53,055 --> 00:13:55,824 OLFACTORY BULB DORSAL ROOT. 361 00:13:55,824 --> 00:13:57,693 A COUPLE AXONS THAT SEEM LIKE 362 00:13:57,693 --> 00:13:59,795 THEY MIGHT PLAY A ROLE IN 363 00:13:59,795 --> 00:14:00,729 CONVERTING THIS ZONAL 364 00:14:00,729 --> 00:14:03,132 ORGANIZATION IN THE EPITHELIUM 365 00:14:03,132 --> 00:14:05,467 TO AN APPROPRIATE DORSAL 366 00:14:05,467 --> 00:14:06,201 VENTRAL ORGANIZATION OF 367 00:14:06,201 --> 00:14:07,336 GLOMERULI IN THE BULB. 368 00:14:07,336 --> 00:14:10,839 I WANT TO REMIND YOU THE 369 00:14:10,839 --> 00:14:11,440 OLFACTORY BULB IS INCREDIBLY 370 00:14:11,440 --> 00:14:14,176 PRECISE. 371 00:14:14,176 --> 00:14:17,613 ALL 1,000 GLOMERULI ARE 372 00:14:17,613 --> 00:14:18,013 PRECISELY LOCATED. 373 00:14:18,013 --> 00:14:20,649 THIS POSSIBLE ZONE TO ZONE 374 00:14:20,649 --> 00:14:21,817 MECHANISM CANNOT EXPLAIN HOW IT 375 00:14:21,817 --> 00:14:24,386 IS THAT WE HAVE SUCH A PRECISE 376 00:14:24,386 --> 00:14:25,320 CODE FOR ODOR IDENTITY IN THE 377 00:14:25,320 --> 00:14:26,455 BULB. 378 00:14:26,455 --> 00:14:28,824 SO NOW LET'S TALK ABOUT SCIENCE 379 00:14:28,824 --> 00:14:29,992 INSTEAD OF BACKGROUND. 380 00:14:29,992 --> 00:14:32,294 THE QUESTION WE WANTED TO ASK 381 00:14:32,294 --> 00:14:34,630 IS, COULD WE IDENTIFY SOMEHOW 382 00:14:34,630 --> 00:14:35,798 MOLECULAR MARKERS THAT IDENTIFY 383 00:14:35,798 --> 00:14:36,498 ALL THE DIFFERENT ZONES IN THE 384 00:14:36,498 --> 00:14:37,633 NOSE? 385 00:14:37,633 --> 00:14:38,801 THERE'S FOUR ZONES. 386 00:14:38,801 --> 00:14:40,669 WE WANTED TO KNOW IF WE COULD 387 00:14:40,669 --> 00:14:42,004 IDENTIFY A MARKER FOR ZONE TWO 388 00:14:42,004 --> 00:14:43,439 OR THREE. 389 00:14:43,439 --> 00:14:45,040 REASONING IF WE COULD IDENTIFY 390 00:14:45,040 --> 00:14:46,942 SUCH A MARKER WE WOULD BE ABLE 391 00:14:46,942 --> 00:14:48,644 TO UNDERSTAND HOW ODOR AND 392 00:14:48,644 --> 00:14:49,845 RECEPTORS ARE LIMITED TO ONE OF 393 00:14:49,845 --> 00:14:50,746 THESE FOUR ZONES. 394 00:14:50,746 --> 00:14:51,914 THAT WAS OUR GOAL. 395 00:14:51,914 --> 00:14:53,549 HOW DID WE DO THIS? 396 00:14:53,549 --> 00:14:55,417 WE DID WHAT YOU WOULD EXPECT US 397 00:14:55,417 --> 00:14:58,420 TO DO, A TON OF CELL SEQUENCING. 398 00:14:58,420 --> 00:15:02,024 WE TOOK EPITHELIUM OUT OF MOUSE 399 00:15:02,024 --> 00:15:07,429 CELL ZONE. 400 00:15:07,429 --> 00:15:08,630 DEVELOP TRANSCRIPTOMES. 401 00:15:08,630 --> 00:15:13,702 YOU ARE LOOKING AT A U-MAP PLOT. 402 00:15:13,702 --> 00:15:15,938 PROXIMITY OF POIBTS IN THE PLOT 403 00:15:15,938 --> 00:15:18,440 REPRESENT SIMILARITY IN THE 404 00:15:18,440 --> 00:15:19,708 TRANSCRIPTOMES. 405 00:15:19,708 --> 00:15:21,343 WE GET BOTH PRECURSOR AND 406 00:15:21,343 --> 00:15:22,945 MATURE CELLS. 407 00:15:22,945 --> 00:15:24,813 IN THIS PLOT MATURE CELLS ARE 408 00:15:24,813 --> 00:15:26,682 HIGHLIGHTED BY THE MARKER OMP 409 00:15:26,682 --> 00:15:28,350 WHICH IS SHOWN HERE IN YELLOW. 410 00:15:28,350 --> 00:15:29,985 I WANT TO EMPHASIZE A COUPLE 411 00:15:29,985 --> 00:15:31,186 POINTS ABOUT THESE DATA. 412 00:15:31,186 --> 00:15:32,788 FIRST IN ORDER TO DO THE 413 00:15:32,788 --> 00:15:33,789 EXPERIMENTS I'M ABOUT TO 414 00:15:33,789 --> 00:15:35,824 DESCRIBE WE GENERATED THE 415 00:15:35,824 --> 00:15:39,795 LARGEST SINGLE CELL SEQUENCING 416 00:15:39,795 --> 00:15:42,598 SET EVER FOR NEURAL TISSUE, 417 00:15:42,598 --> 00:15:45,634 ABOUT 5.5 MILLION INTEGRATED 418 00:15:45,634 --> 00:15:48,904 CELLS INCLUDING 2.5 MATURE 419 00:15:48,904 --> 00:15:49,738 NEURAL OLFACTORY SENSORY AND 420 00:15:49,738 --> 00:15:51,006 PRECURSORS. 421 00:15:51,006 --> 00:15:54,009 ANALYZING DATA AT SCALE LIKE 422 00:15:54,009 --> 00:15:55,811 THIS REQUIRES SOPHISTICATED 423 00:15:55,811 --> 00:15:56,645 COMPUTATIONAL METHODS. 424 00:15:56,645 --> 00:15:58,714 I PROMISE NOT TO SHOW YOU MATH 425 00:15:58,714 --> 00:15:59,815 BUT UNDERSTAND IT'S A BIG 426 00:15:59,815 --> 00:16:01,216 ENGINE. 427 00:16:01,216 --> 00:16:03,485 USING THAT ENGINE WE CAREFULLY 428 00:16:03,485 --> 00:16:08,490 SEARCHED FOR GENES THAT MIGHT 429 00:16:08,490 --> 00:16:10,159 MARK THESE DIFFERENT ZONES AND 430 00:16:10,159 --> 00:16:11,960 WE FOUND NONE. 431 00:16:11,960 --> 00:16:13,595 EVEN THOUGH WE BELIEVE THE 432 00:16:13,595 --> 00:16:15,731 ZONES ARE REAL, OR HAD BELIEVED 433 00:16:15,731 --> 00:16:17,332 TURNS OUT TO BE WRONG. 434 00:16:17,332 --> 00:16:18,734 WE DECIDED TO ASK A MUCH HARDER 435 00:16:18,734 --> 00:16:20,869 QUESTION. 436 00:16:20,869 --> 00:16:25,274 CAN WE IDENTIFY GENES THAT 437 00:16:25,274 --> 00:16:25,941 SYSTEMATICALLY VARY ACROSS 438 00:16:25,941 --> 00:16:28,377 OLFACTORY SUBTYPES. 439 00:16:28,377 --> 00:16:31,180 WE TOOK A THOUSAND CELLS THAT 440 00:16:31,180 --> 00:16:33,015 EXPRESS ORA AND ORB. 441 00:16:33,015 --> 00:16:34,449 WE DEVELOPED A THOUSAND SUCH 442 00:16:34,449 --> 00:16:37,019 BINS AND ASKED CAN WE IDENTIFY 443 00:16:37,019 --> 00:16:39,655 ANY HIGHLY VARIABLE CHAINS THAT 444 00:16:39,655 --> 00:16:40,856 VARY ACROSS THE OLFACTORY 445 00:16:40,856 --> 00:16:42,925 SENSORY SUBTYPES. 446 00:16:42,925 --> 00:16:44,793 THE CANONICAL VIEW AND SUBTYPES 447 00:16:44,793 --> 00:16:46,962 EACH IS THE SAME EXCEPT THE 448 00:16:46,962 --> 00:16:48,530 RECEPTOR THAT EXPRESSES SO WE 449 00:16:48,530 --> 00:16:49,932 EXPECTED TO FIND NOTHING. 450 00:16:49,932 --> 00:16:54,369 INSTEAD WE WERE ABLE TO 451 00:16:54,369 --> 00:16:55,437 IDENTIFY 1200 HIGHLY VARIABLE 452 00:16:55,437 --> 00:16:56,972 GENES. 453 00:16:56,972 --> 00:16:59,007 THIS VARIATION IS SUCH IF YOU 454 00:16:59,007 --> 00:17:01,577 JUST TELL ME 100 OF THESE 455 00:17:01,577 --> 00:17:02,778 HIGHLY VARIABLE GENES AND HOW 456 00:17:02,778 --> 00:17:05,080 MUCH THEY ARE EXPRESSED I COULD 457 00:17:05,080 --> 00:17:09,618 WITH 100% ACCURACY TELL YOU 458 00:17:09,618 --> 00:17:10,519 WHICH ODOR RECEPTOR IS IN THAT 459 00:17:10,519 --> 00:17:12,654 CELL. 460 00:17:12,654 --> 00:17:14,756 SO RESPONDS TO OMP SUBTYPE. 461 00:17:14,756 --> 00:17:17,059 THE REASON THESE 1200 GENES 462 00:17:17,059 --> 00:17:20,095 WERE ORGANIZED INTO COHERENT 463 00:17:20,095 --> 00:17:22,364 GENE PROGRAMS, GROUPS THAT CO 464 00:17:22,364 --> 00:17:23,232 VARY THEIR EXPRESSION UP OR 465 00:17:23,232 --> 00:17:25,400 DOWN. 466 00:17:25,400 --> 00:17:29,204 WE USED CONSENSUS NINE MATRIX 467 00:17:29,204 --> 00:17:32,007 TO IDENTIFY SEVEN SUCH PROGRAMS. 468 00:17:32,007 --> 00:17:34,309 TODAY I WILL ONLY FOCUS ON TWO, 469 00:17:34,309 --> 00:17:35,911 WHICH ARE SHOWN HERE. 470 00:17:35,911 --> 00:17:44,953 THIS AGAIN IS A U-MAP PLOT. 471 00:17:44,953 --> 00:17:47,522 MATURE OLFACTORY SENSORY NEURON. 472 00:17:47,522 --> 00:17:50,792 THERE'S 150 GENES THAT BELONG 473 00:17:50,792 --> 00:17:53,695 TO GEP DORSAL AND 150 TO GEP 474 00:17:53,695 --> 00:17:55,097 VENTRAL. 475 00:17:55,097 --> 00:17:57,666 I WILL HEAT MAP THAT OVER EACH 476 00:17:57,666 --> 00:17:59,334 CELL, I WILL CALL THAT GEP 477 00:17:59,334 --> 00:18:01,203 USAGE. 478 00:18:01,203 --> 00:18:05,407 SOME CELLS USE GEP DORSAL AND 479 00:18:05,407 --> 00:18:07,142 SOME USE GEP VENTRAL BUT NO 480 00:18:07,142 --> 00:18:08,710 CELLS USE BOTH. 481 00:18:08,710 --> 00:18:11,713 YOU MIGHT ASK WHY DID WE NAME 482 00:18:11,713 --> 00:18:13,282 THESE THIS. 483 00:18:13,282 --> 00:18:17,286 ONE OF THE 150 GENES IN THE GEP 484 00:18:17,286 --> 00:18:18,920 IS FOR THE DORSAL DOMAIN. 485 00:18:18,920 --> 00:18:21,023 WE THOUGHT MAYBE THIS GEP 486 00:18:21,023 --> 00:18:21,723 REPRESENTS SOMETHING ABOUT 487 00:18:21,723 --> 00:18:23,025 BEING IN THE DORSAL PART OF THE 488 00:18:23,025 --> 00:18:23,825 EPITHELIUM. 489 00:18:23,825 --> 00:18:27,062 WE KNEW SOME OF THE AXON 490 00:18:27,062 --> 00:18:28,463 GUIDANCE GENES WHICH HELP GUIDE 491 00:18:28,463 --> 00:18:31,733 AXONS FROM THE NOSE TO THE BULB 492 00:18:31,733 --> 00:18:34,202 WE KNOW A COUPLE ARE EXPRESSED 493 00:18:34,202 --> 00:18:35,237 VENTRALLY. 494 00:18:35,237 --> 00:18:40,909 WE KIND OF PROVISIONALLY MADE 495 00:18:40,909 --> 00:18:43,578 THESE BASED ON THE HYPOTHESIS 496 00:18:43,578 --> 00:18:45,247 THEY MAY CONVEY INFORMATION 497 00:18:45,247 --> 00:18:47,349 WHETHER THE NEURON RESIDES IN 498 00:18:47,349 --> 00:18:50,118 THE DORSAL OR VENTRAL PART OF 499 00:18:50,118 --> 00:18:51,153 THE EPITHELIUM. 500 00:18:51,153 --> 00:18:53,255 WE WANTED TO LOOK AT THEM MORE, 501 00:18:53,255 --> 00:18:57,459 SO WE DECIDED TO LOOK AT 502 00:18:57,459 --> 00:18:57,993 OLFACTORY SENSORY NEURON 503 00:18:57,993 --> 00:18:58,860 SUBTYPE. 504 00:18:58,860 --> 00:19:00,162 ALL THOSE NEURON THAT'S EXPRESS 505 00:19:00,162 --> 00:19:01,663 THE SAME RECEPTOR. 506 00:19:01,663 --> 00:19:03,398 SO THERE'S A THOUSAND DOTS IN 507 00:19:03,398 --> 00:19:04,733 THIS PLOT. 508 00:19:04,733 --> 00:19:08,136 YOU SEE EACH OLFACTORY SENSORY 509 00:19:08,136 --> 00:19:09,771 NEURON EITHER EXPRESSES GEP 510 00:19:09,771 --> 00:19:11,406 DORSAL OR VENTRAL BUT NOT BOTH, 511 00:19:11,406 --> 00:19:13,308 GENERALLY. 512 00:19:13,308 --> 00:19:14,910 IF YOU EXPRESS GEP VENTRAL YOU 513 00:19:14,910 --> 00:19:16,345 CAN USE IT MORE OR LESS, YOU 514 00:19:16,345 --> 00:19:22,851 CAN KIND OF USE IT MORE OR LESS. 515 00:19:22,851 --> 00:19:24,319 THE COMPLEMENTARY MEANS WE CAN 516 00:19:24,319 --> 00:19:27,856 SUMMARIZE THE USE OF ALL 300 517 00:19:27,856 --> 00:19:32,060 GENE THAT'S BELONG TO GEP 518 00:19:32,060 --> 00:19:34,629 DORSAL AND VENTRAL AND TRACKING 519 00:19:34,629 --> 00:19:38,433 AND CREATING A DORSAL VENTRAL 520 00:19:38,433 --> 00:19:39,968 SCORE. 521 00:19:39,968 --> 00:19:42,471 OR DV SCORE. 522 00:19:42,471 --> 00:19:48,510 CELLS THAT HAVE LOW USE A LOT. 523 00:19:48,510 --> 00:19:52,447 THAT HAVE HIGH DV SCORES USE IT 524 00:19:52,447 --> 00:19:55,283 A LOT. 525 00:19:55,283 --> 00:19:56,151 IT'S SUMMARIZING THESE 300 526 00:19:56,151 --> 00:19:57,419 GENES. 527 00:19:57,419 --> 00:20:01,089 WHAT WE SEE IS THAT EACH 528 00:20:01,089 --> 00:20:01,990 OLFACTORY SENSORY NEURON 529 00:20:01,990 --> 00:20:05,293 SUBTYPE IS ASSOCIATED WITH A 530 00:20:05,293 --> 00:20:08,029 UNIQUE MEAN D.V. SCORE. 531 00:20:08,029 --> 00:20:09,431 EACH OLFACTORY SENSORY NEURON 532 00:20:09,431 --> 00:20:11,299 SUBTYPE IS USING THIS SET OF 533 00:20:11,299 --> 00:20:13,635 300 GENES IN A UNIQUE WAY. 534 00:20:13,635 --> 00:20:16,138 HERE YOU SEE UNIQUE EXAMPLES 535 00:20:16,138 --> 00:20:17,172 AND DISTRIBUTIONS AND HERE YOU 536 00:20:17,172 --> 00:20:19,474 SEE ALL THE OLFACTORY SENSORY 537 00:20:19,474 --> 00:20:21,543 NEURON SUBTYPES ORDERED BY 538 00:20:21,543 --> 00:20:23,211 THEIR MEAN D.V. SCORE. 539 00:20:23,211 --> 00:20:24,613 EACH HAS A DISTRIBUTION. 540 00:20:24,613 --> 00:20:26,882 IT'S NOT EVERY CELL THAT 541 00:20:26,882 --> 00:20:30,385 BELONGS TO EACH SUBTYPE HAS THE 542 00:20:30,385 --> 00:20:32,320 SAME EXACT D.V. SCORE BUT THEY 543 00:20:32,320 --> 00:20:35,357 ALL HAVE A MEAN AND THIS PLOT 544 00:20:35,357 --> 00:20:36,958 TILES THE POSSIBLE D.V. SCORES. 545 00:20:36,958 --> 00:20:38,193 WHAT ARE THE INDIVIDUAL GENES 546 00:20:38,193 --> 00:20:40,128 THAT MAKE UP A D.V. SCORE 547 00:20:40,128 --> 00:20:41,463 ACTUALLY LOOK LIKE? 548 00:20:41,463 --> 00:20:43,999 AND WHAT ARE THEY? 549 00:20:43,999 --> 00:20:47,736 HERE ON THE Y AXIS YOU ARE 550 00:20:47,736 --> 00:20:50,305 LOOKING AT THE MEAN 300 GENES. 551 00:20:50,305 --> 00:20:53,141 WE ARE LOOKING AT SUBTYPES AND 552 00:20:53,141 --> 00:20:54,609 ORDER WHETHER THEY HAVE LOW OR 553 00:20:54,609 --> 00:20:55,944 HIGH D.V. SCORES. 554 00:20:55,944 --> 00:20:58,046 WHAT YOU SEE QUITE CLEARLY IS 555 00:20:58,046 --> 00:21:00,615 ALL OF THE D.V. GENES WE 556 00:21:00,615 --> 00:21:02,484 IDENTIFY VIA THIS METHOD SEEM 557 00:21:02,484 --> 00:21:04,586 TO BE ORGANIZED INTO GRADIENTS. 558 00:21:04,586 --> 00:21:07,689 THERE'S A GRADING OF EXPRESSION 559 00:21:07,689 --> 00:21:09,925 OF GEP VENTRAL AND DORSAL THAT 560 00:21:09,925 --> 00:21:12,661 VARIES DEPENDING ON WHAT YOUR 561 00:21:12,661 --> 00:21:13,495 CELLS D.V. SCORE IS. 562 00:21:13,495 --> 00:21:16,298 IF YOU LOOK AT GENES IN A MAKE 563 00:21:16,298 --> 00:21:17,699 UP THESE GEP'S WE FIND THEY 564 00:21:17,699 --> 00:21:19,334 INCLUDE A TON OF GENES THAT ARE 565 00:21:19,334 --> 00:21:21,236 ABOUT THE FUNCTION OF OLFACTORY 566 00:21:21,236 --> 00:21:22,404 SENSORY NEURONS AND TWO 567 00:21:22,404 --> 00:21:24,272 PARTICULAR TYPES OF GENES WE 568 00:21:24,272 --> 00:21:27,375 WERE REALLY INTERESTED IN, 569 00:21:27,375 --> 00:21:29,110 INCLUDING TRANSCRIPTION FACTORS. 570 00:21:29,110 --> 00:21:31,913 WE WERE INTERESTED IN 571 00:21:31,913 --> 00:21:32,614 TRANSCRIPTION THEY HELPED 572 00:21:32,614 --> 00:21:34,950 .CELL IDENTIFY. 573 00:21:34,950 --> 00:21:37,018 AND AXON IDENTITY THEY CAN HELP 574 00:21:37,018 --> 00:21:38,653 IN PRINCIPLE HELP AXONS GET 575 00:21:38,653 --> 00:21:40,088 FROM THE OLFACTORY EPITHELIUM 576 00:21:40,088 --> 00:21:42,390 TO THE APPROPRIATE LOCATION IN 577 00:21:42,390 --> 00:21:44,025 THE OLFACTORY BULB. 578 00:21:44,025 --> 00:21:45,694 LET ME GIVE YOU A FEW EXAMPLES 579 00:21:45,694 --> 00:21:48,597 OF THE GENES WE IDENTIFIED TO 580 00:21:48,597 --> 00:21:50,432 GIVE YOU A FLAVOR OF WHAT THE 581 00:21:50,432 --> 00:21:51,600 ACTUAL DATA LOOK LIKE. 582 00:21:51,600 --> 00:21:53,702 HERE WE ARE GOING TO LOOK IN 583 00:21:53,702 --> 00:21:56,505 THIS QUADRANT AT THE EXPRESSION 584 00:21:56,505 --> 00:21:57,639 OF THREE TRANSCRIPTION FACTOR 585 00:21:57,639 --> 00:22:00,141 THAT'S BELONG TO THE N.F.I. 586 00:22:00,141 --> 00:22:02,844 FAMILY, I WILL BRING UP LATER, 587 00:22:02,844 --> 00:22:03,478 IMPORTANT FOR OLFACTORY SENSORY 588 00:22:03,478 --> 00:22:04,513 DEVELOPMENT. 589 00:22:04,513 --> 00:22:06,214 ALL THREE ARE EXPRESSED AS 590 00:22:06,214 --> 00:22:08,984 GRADIENTS THAT VARY AS A 591 00:22:08,984 --> 00:22:14,823 FUNCTION OF THE D.V. SCORE. 592 00:22:14,823 --> 00:22:16,658 NQO1 THOUGHT TO MARK THE DORSAL 593 00:22:16,658 --> 00:22:18,293 DOMAIN OF THE EPITHELIUM. 594 00:22:18,293 --> 00:22:20,395 THIS MARKER IS NOT EXPRESSED IN 595 00:22:20,395 --> 00:22:24,866 SCORES THAT HAVE A VENTRAL D.V. 596 00:22:24,866 --> 00:22:26,968 SCORE. 597 00:22:26,968 --> 00:22:28,136 IT'S NOT EXPRESSED UNIFORMLY 598 00:22:28,136 --> 00:22:29,104 BUT IN A GRADIENT. 599 00:22:29,104 --> 00:22:34,709 HERE ARE THE TWO AXON HAD HELP 600 00:22:34,709 --> 00:22:35,911 GUIDE THE ZONE IN THE NOSE TO 601 00:22:35,911 --> 00:22:37,445 THE BULB. 602 00:22:37,445 --> 00:22:39,781 THESE ARE BOTH THEMSELVES 603 00:22:39,781 --> 00:22:40,482 ORGANIZED AS GRADIENTS, 604 00:22:40,482 --> 00:22:41,449 FUNCTION OF THE D.V. SCORE. 605 00:22:41,449 --> 00:22:44,052 THE PRESENCE OF ALL THESE 606 00:22:44,052 --> 00:22:46,655 GRADIENTS, TOGETHER WITH THE 607 00:22:46,655 --> 00:22:50,392 IDEA THAT MAYBE THE GEP DORSAL 608 00:22:50,392 --> 00:22:54,129 AND VENTRAL ARE CONVEYING ABOUT 609 00:22:54,129 --> 00:22:55,263 DORSALITY OR VENTRALITY 610 00:22:55,263 --> 00:22:55,964 SUGGESTED THERE MAYBE AREN'T 611 00:22:55,964 --> 00:22:58,767 FOUR ZONES. 612 00:22:58,767 --> 00:23:01,102 MAYBE INSTEAD EACH NEURON HAS A 613 00:23:01,102 --> 00:23:02,537 UNIQUE D.V. SCORE AND THAT 614 00:23:02,537 --> 00:23:04,639 REPRESENTS WHERE IN THE 615 00:23:04,639 --> 00:23:05,373 EPITHELIUM GOING DORSAL TO 616 00:23:05,373 --> 00:23:06,308 VENTRAL. 617 00:23:06,308 --> 00:23:08,176 IF THAT'S TRUE, INSTEAD OF 618 00:23:08,176 --> 00:23:10,245 HAVING FOUR ZONES, BECAUSE EACH 619 00:23:10,245 --> 00:23:12,581 OLFACTORY SENSORY NEURON, ON 620 00:23:12,581 --> 00:23:14,716 AVERAGE, HAS A UNIQUE D.V. 621 00:23:14,716 --> 00:23:16,418 SCORE ASSOCIATED WITH THE 622 00:23:16,418 --> 00:23:17,719 PARTICULAR RECEPTOR CHOSEN YOU 623 00:23:17,719 --> 00:23:19,354 WOULD IMAGINE A THOUSAND ZONES 624 00:23:19,354 --> 00:23:21,690 OR THOUSAND PEEKS OF EXPRESS 625 00:23:21,690 --> 00:23:23,124 GOING FROM DORSAL TO VENTRAL. 626 00:23:23,124 --> 00:23:24,292 IS THAT TRUE? 627 00:23:24,292 --> 00:23:25,927 WE DECIDED TO EXPLORE THAT 628 00:23:25,927 --> 00:23:28,763 POSSIBILITY VIA THE USE OF THE 629 00:23:28,763 --> 00:23:34,970 TECHNIQUE WHICH ALLOWS US TO DO 630 00:23:34,970 --> 00:23:36,371 IN-SITU TO DO ALL AT ONCE IN 631 00:23:36,371 --> 00:23:38,773 PARALLEL. 632 00:23:38,773 --> 00:23:42,744 HERE IS A KERNEL SECTION. 633 00:23:42,744 --> 00:23:46,648 YOU CAN SEE THEM SUPPORT CELLS 634 00:23:46,648 --> 00:23:46,881 IN RED. 635 00:23:46,881 --> 00:23:49,884 AND CELL THAT'S BELONG TO THE 636 00:23:49,884 --> 00:23:50,619 LAMINA PROPRIA I WILL GET BACK 637 00:23:50,619 --> 00:23:51,753 TO. 638 00:23:51,753 --> 00:23:53,321 THE TECHNIQUE WORKS. 639 00:23:53,321 --> 00:23:57,792 YOU ARE LOOKING MERFISH. 640 00:23:57,792 --> 00:24:00,295 I WANT TO MENTION OF COURSE THE 641 00:24:00,295 --> 00:24:02,130 ACTUAL CELLS ARE VERY SMALL SO 642 00:24:02,130 --> 00:24:04,065 WE HAVE BLOWN UP THESE DOTS 100 643 00:24:04,065 --> 00:24:05,500 TIMES. 644 00:24:05,500 --> 00:24:07,636 YOU COULD SEE A SPATIAL 645 00:24:07,636 --> 00:24:08,870 DISTRIBUTION FOR THIS 646 00:24:08,870 --> 00:24:10,171 PARTICULAR VENTRAL RECEPTOR 647 00:24:10,171 --> 00:24:13,041 THAT COULD BE EASILY DETECTED 648 00:24:13,041 --> 00:24:17,379 BY MERFISH. 649 00:24:17,379 --> 00:24:19,214 WE HAVE NC2 DATA FOR THE DV 650 00:24:19,214 --> 00:24:20,649 SCORE. 651 00:24:20,649 --> 00:24:23,451 DOES IT IN FACT DESCRIBE AXIS 652 00:24:23,451 --> 00:24:24,686 THAT RUNS FROM DORSAL TO 653 00:24:24,686 --> 00:24:26,254 VENTRAL? 654 00:24:26,254 --> 00:24:27,689 AND ARE ODOR RECEPTORS BUILDING 655 00:24:27,689 --> 00:24:30,358 A MAP RUNNING FROM DORSAL TO 656 00:24:30,358 --> 00:24:30,592 VENTRAL? 657 00:24:30,592 --> 00:24:36,331 THIS IS WHAT WE SEE. 658 00:24:36,331 --> 00:24:38,833 ON THE LEFT WE WILL COLOR IT BY 659 00:24:38,833 --> 00:24:40,568 ITS D.V. SCORE. 660 00:24:40,568 --> 00:24:42,904 YOU SEE THIS BEAUTIFUL GRADIENT 661 00:24:42,904 --> 00:24:44,773 RUNNING MEDIAL TO DISTAL, 662 00:24:44,773 --> 00:24:46,207 DORSAL TO VENTRAL GOING FROM 663 00:24:46,207 --> 00:24:48,109 HERE TO HERE, FROM RED TO BLUE. 664 00:24:48,109 --> 00:24:51,112 ALONG EACH ONE OF THESE LITTLE 665 00:24:51,112 --> 00:24:52,047 TERMINATES. 666 00:24:52,047 --> 00:24:53,682 THAT TELLS YOU EACH CELL IN THE 667 00:24:53,682 --> 00:24:58,019 NOSE HAS A UNIQUE D.V. SCORE 668 00:24:58,019 --> 00:24:59,754 THAT CORRESPONDS DIRECTLY TO 669 00:24:59,754 --> 00:25:02,323 THE CELL SPATIAL POSITION 670 00:25:02,323 --> 00:25:04,092 DORSAL TO VENTRAL TOP TO BOTTOM 671 00:25:04,092 --> 00:25:05,326 IN THE EPITHELIUM. 672 00:25:05,326 --> 00:25:06,995 IS THERE A MAP BUILT OF ODOR 673 00:25:06,995 --> 00:25:09,064 RECEPTORS? 674 00:25:09,064 --> 00:25:12,100 HERE WE HAVE TAKEN OUT CURLY 675 00:25:12,100 --> 00:25:14,436 Q'S AND ZOOMED IN SO YOU COULD 676 00:25:14,436 --> 00:25:16,271 SEE THE SPATIAL GRADIENTS. 677 00:25:16,271 --> 00:25:18,907 IS THERE ACTUALLY A MAP OF ODOR 678 00:25:18,907 --> 00:25:20,542 RECEPTORS? 679 00:25:20,542 --> 00:25:23,344 HERE WE IDENTIFIED THE ODOR 680 00:25:23,344 --> 00:25:25,480 EXPRESSED BY EACH NEURON AND 681 00:25:25,480 --> 00:25:27,615 LOOKED UP THE D.V. SCORE, AGAIN 682 00:25:27,615 --> 00:25:31,086 WE SEE THIS BEAUTIFUL GRADIENT 683 00:25:31,086 --> 00:25:32,854 GOING DORSAL TO VENTRAL ALONG 684 00:25:32,854 --> 00:25:34,155 THE CURLY Q'S. 685 00:25:34,155 --> 00:25:37,926 THE FACT WE SEE CONTINUOUS 686 00:25:37,926 --> 00:25:41,996 GRADIENTS GIVEN THAT EVERY OSM 687 00:25:41,996 --> 00:25:44,833 SUBTYPE MEANS THERE ARE 1,000 688 00:25:44,833 --> 00:25:46,701 DIFFERENT PEEKS OF ODOR 689 00:25:46,701 --> 00:25:47,569 RECEPTOR ON AVERAGE ORGANIZED 690 00:25:47,569 --> 00:25:48,303 INTO A MAP. 691 00:25:48,303 --> 00:25:50,438 THERE'S A MAP OF ODOR RECEPTOR 692 00:25:50,438 --> 00:25:51,873 EXPRESSION IN THE NOSE. 693 00:25:51,873 --> 00:25:54,075 THERE AREN'T FOUR STONES. 694 00:25:54,075 --> 00:25:54,909 ZONES. 695 00:25:54,909 --> 00:25:56,111 THERE ARE A THOUSAND ZONES 696 00:25:56,111 --> 00:25:59,647 WHERE THE POSITION OF EACH ODOR 697 00:25:59,647 --> 00:26:00,815 RECEPTOR VARIES CONTINUOUSLY 698 00:26:00,815 --> 00:26:02,884 FROM RECEPTOR ZERO HERE TO 699 00:26:02,884 --> 00:26:03,852 RECEPTOR 1,000 OVER HERE. 700 00:26:03,852 --> 00:26:05,487 IF YOU JUST WANT TO SEE 701 00:26:05,487 --> 00:26:07,856 DISTRIBUTIONS A LITTLE MORE TO 702 00:26:07,856 --> 00:26:08,823 CONVINCE YOURSELVES HERE YOU 703 00:26:08,823 --> 00:26:10,425 ARE LOOKING AT CUMULATIVE 704 00:26:10,425 --> 00:26:11,126 EXPRESSION IN SPACE. 705 00:26:11,126 --> 00:26:13,928 IF YOU LOOK AT TWOE RECEPTORS 706 00:26:13,928 --> 00:26:15,096 WITH SIMILAR D.V. SCORES AND 707 00:26:15,096 --> 00:26:16,965 ASK WHAT ARE THEIR SPATIAL 708 00:26:16,965 --> 00:26:18,867 POSITIONS THEY HAVE HIGHLY 709 00:26:18,867 --> 00:26:19,434 OVERLAPPING DISTRIBUTIONS, 710 00:26:19,434 --> 00:26:22,871 WHICH IS TO BE EX PECKED BUT 711 00:26:22,871 --> 00:26:24,806 THE MEANS ARE CLEARLY 712 00:26:24,806 --> 00:26:26,107 DISTINGUISHABLE. 713 00:26:26,107 --> 00:26:28,877 THAT MEANS WE CAN MAKE ACCURATE 714 00:26:28,877 --> 00:26:30,278 PREDICTIONS BASED UPON 715 00:26:30,278 --> 00:26:31,012 INDIVIDUAL CELLS D.V. SCORE 716 00:26:31,012 --> 00:26:32,981 WHERE IT WILL BE IN THE 717 00:26:32,981 --> 00:26:33,848 EPITHELIUM. 718 00:26:33,848 --> 00:26:38,787 IF YOU GIVE ME A SPOT I CAN 719 00:26:38,787 --> 00:26:40,188 GIVE A PREDICTION, CONSISTENT 720 00:26:40,188 --> 00:26:42,056 WITH THE IDEA THERE'S SOME 721 00:26:42,056 --> 00:26:47,295 UNDERLYING MAP. 722 00:26:47,295 --> 00:26:48,696 I SHOWED IN-SITUS PREVIOUSLY, 723 00:26:48,696 --> 00:26:50,198 THE VALUE OF EACH RECEPTOR IS 724 00:26:50,198 --> 00:26:51,266 BROAD. 725 00:26:51,266 --> 00:26:53,635 HOW COULD THERE BE A MAP OF 726 00:26:53,635 --> 00:26:54,769 1,000 THINGS IF THEY ARE SO 727 00:26:54,769 --> 00:26:55,737 OVERLAPPING. 728 00:26:55,737 --> 00:26:58,273 HERE WE ARE LOOKING AT 729 00:26:58,273 --> 00:27:02,710 DISTRIBUTION OF D.V. SCORES FOR 730 00:27:02,710 --> 00:27:06,014 EACH OSM SUBTYPE IN SCRNA-SEQ 731 00:27:06,014 --> 00:27:08,416 AND MERFISH. 732 00:27:08,416 --> 00:27:09,851 THE THERE'S THE SHARP PEEK OF 733 00:27:09,851 --> 00:27:10,752 EXPRESSION IN THE ESPECIALLY 734 00:27:10,752 --> 00:27:12,153 THEME YUM BUT THERE'S A 735 00:27:12,153 --> 00:27:13,087 DISTRIBUTION. 736 00:27:13,087 --> 00:27:16,157 I THINK IT DESCRIBES WHY 737 00:27:16,157 --> 00:27:17,025 PREVIOUSLY RESEARCHERS BELIEVED 738 00:27:17,025 --> 00:27:26,067 THERE WERE ZONES. 739 00:27:26,067 --> 00:27:27,969 ONE THING WE CAN DO BECAUSE WE 740 00:27:27,969 --> 00:27:31,439 HAVE SO MUCH DATA WE CAN ASK IF 741 00:27:31,439 --> 00:27:32,941 THE RANK ORDER IS SHARED ACROSS 742 00:27:32,941 --> 00:27:33,808 INDIVIDUALS. 743 00:27:33,808 --> 00:27:35,677 IF THIS IS REALLY A MAP, THE 744 00:27:35,677 --> 00:27:37,078 MAP IN MY NOSE SHOULD BE THE 745 00:27:37,078 --> 00:27:39,013 SAME AS THE MAP IN YOUR NOSE. 746 00:27:39,013 --> 00:27:41,049 WHAT WE FIND FROM THESE DATA 747 00:27:41,049 --> 00:27:43,818 THERE'S A 0.9 9 CORRELATION IN 748 00:27:43,818 --> 00:27:46,421 THE RANK ORDER OF ODOR 749 00:27:46,421 --> 00:27:48,256 RECEPTORS VENTRAL TO DORSAL. 750 00:27:48,256 --> 00:27:50,925 THE MAP IS INCREDIBLY PRECISE 751 00:27:50,925 --> 00:27:51,492 AND CONSERVED ACROSS 752 00:27:51,492 --> 00:27:52,093 INDIVIDUALS MAKING IT A REAL 753 00:27:52,093 --> 00:27:53,094 MAP. 754 00:27:53,094 --> 00:27:54,229 SO THIS RAISES THE BROAD SET OF 755 00:27:54,229 --> 00:27:56,130 QUESTIONS. 756 00:27:56,130 --> 00:27:57,532 WHAT IS THE RELATIONSHIP 757 00:27:57,532 --> 00:27:59,267 BETWEEN SPACE, THE D.V. SCORE 758 00:27:59,267 --> 00:28:00,535 AND O.R. EXPRESSION? 759 00:28:00,535 --> 00:28:02,170 EVERYTHING I HAVE SHOWN YOU 760 00:28:02,170 --> 00:28:04,038 SUGGESTS ALL THREE ARE RELATED. 761 00:28:04,038 --> 00:28:06,608 ALMOST CERTAINLY TO THE D.V. 762 00:28:06,608 --> 00:28:07,208 SCORE REPRESENTS POSITION IN 763 00:28:07,208 --> 00:28:08,243 SPACE. 764 00:28:08,243 --> 00:28:09,677 BUT THERE MUST BE SOME 765 00:28:09,677 --> 00:28:11,746 RELATIONSHIP BETWEEN THE SPACE 766 00:28:11,746 --> 00:28:13,615 IN D.V. SCORE AND O.R. 767 00:28:13,615 --> 00:28:15,483 EXPRESSION IN SOME WAY, IT'S 768 00:28:15,483 --> 00:28:17,118 CLEAR O.R.'S ARE ORGANIZED IN 769 00:28:17,118 --> 00:28:18,720 THIS PATTERN A THOUSAND 770 00:28:18,720 --> 00:28:19,888 DIFFERENT STRIPES FROM DORSAL 771 00:28:19,888 --> 00:28:21,322 TO VENTRAL. 772 00:28:21,322 --> 00:28:23,391 WHAT MIGHT ESTABLISH THESE 773 00:28:23,391 --> 00:28:25,793 RELATIONSHIPS? ONE NAIVE IDEA 774 00:28:25,793 --> 00:28:28,396 IS MAYBE ACTIVITY DOWNSTREAM OF 775 00:28:28,396 --> 00:28:29,864 EACH RECEPTOR WHICH WOULD BE 776 00:28:29,864 --> 00:28:32,367 EXPECTED TO BE UNIQUE IN EACH 777 00:28:32,367 --> 00:28:33,334 ODOR ENVIRONMENT IS DETERMINING 778 00:28:33,334 --> 00:28:34,969 WHERE IT IS IN SPACE OR 779 00:28:34,969 --> 00:28:35,904 DETERMINING THE D.V. SCORE. 780 00:28:35,904 --> 00:28:38,740 THAT TURNS OUT TO BE NOT TO BE 781 00:28:38,740 --> 00:28:40,141 TRUE. 782 00:28:40,141 --> 00:28:42,076 IF YOU CLOSE ONE NOSTRIL YOU 783 00:28:42,076 --> 00:28:44,779 DENY ONE HALF OF THE NOSE ANY 784 00:28:44,779 --> 00:28:46,014 ODOR STIMULATION, WE CAN 785 00:28:46,014 --> 00:28:47,415 SEQUENCE OUTSIDE OF THE NOSE 786 00:28:47,415 --> 00:28:49,317 AND COMPARE TO THE NOSTRIL OPEN 787 00:28:49,317 --> 00:28:51,986 AND WE SEE D.V. SCORES DON'T 788 00:28:51,986 --> 00:28:53,054 CHANGE AT ALL. 789 00:28:53,054 --> 00:28:56,791 WE CAN GENERATE A MOUSE WITH A 790 00:28:56,791 --> 00:28:58,393 MONOCLONAL NOSE THAT LARGELY 791 00:28:58,393 --> 00:29:00,528 EXPRESSS IN 95 PERCENT OF 792 00:29:00,528 --> 00:29:02,163 NEURONS ONE ODOR RECEPTOR AND 793 00:29:02,163 --> 00:29:04,299 IT IS SPRAYED OUT OVER THE 794 00:29:04,299 --> 00:29:05,400 ENTIRE EPITHELIUM. 795 00:29:05,400 --> 00:29:08,269 IF THE O.R. OR O.R. ACTIVITY IS 796 00:29:08,269 --> 00:29:09,370 DETERMINING D.V. SCORES YOU 797 00:29:09,370 --> 00:29:13,274 WOULD EXPECTING ALL TO HAVE THE 798 00:29:13,274 --> 00:29:14,375 SAME D.V. SCORE. 799 00:29:14,375 --> 00:29:16,711 INSTEAD THEY HAVE A COMPLETE 800 00:29:16,711 --> 00:29:18,479 DIVERSITY OF D.V. SCORES 801 00:29:18,479 --> 00:29:19,180 SUGGESTING THEY REPRESENT WHERE 802 00:29:19,180 --> 00:29:21,015 YOU ARE IN SPACE AND THEY 803 00:29:21,015 --> 00:29:23,584 AREN'T DETERMINED IN ANY WAY BY 804 00:29:23,584 --> 00:29:24,419 THE ODOR RECEPTOR BEING 805 00:29:24,419 --> 00:29:26,154 EXPRESSED. 806 00:29:26,154 --> 00:29:29,090 OR NEURAL ACTIVITY. 807 00:29:29,090 --> 00:29:30,992 OKAY, SO IF THAT'S TRUE, WHAT 808 00:29:30,992 --> 00:29:32,627 YOU MIGHT IMAGINE A MODEL YOU 809 00:29:32,627 --> 00:29:34,462 MIGHT BUILD IN YOUR HEAD IS 810 00:29:34,462 --> 00:29:35,730 MAYBE SPACE DETERMINES THE D.V. 811 00:29:35,730 --> 00:29:37,966 SCORES. 812 00:29:37,966 --> 00:29:39,600 MAYBE SOME WAY D.V. SCORES 813 00:29:39,600 --> 00:29:41,469 DETERMINE WHICH WAY O.R. IS 814 00:29:41,469 --> 00:29:42,470 EXPRESSED, IF THAT MODEL IS 815 00:29:42,470 --> 00:29:44,272 TRUE FROM SPACE TO D.V. SCORE 816 00:29:44,272 --> 00:29:47,742 TO O.R.'S YOU WOULD EXPECT THE 817 00:29:47,742 --> 00:29:49,644 D.V. SCORE GENES, SOME 300 818 00:29:49,644 --> 00:29:53,381 GENES SHOULD NOT JUST BE 819 00:29:53,381 --> 00:29:55,516 EXPRESSED IN MATURE OLFACTORY 820 00:29:55,516 --> 00:29:56,918 SENSORY NEURONS BUT PRECURSORS 821 00:29:56,918 --> 00:29:59,287 BEFORE O.R.'S ARE CHOSEN. 822 00:29:59,287 --> 00:30:01,389 MAYBE THE D.V. SCORES GUIDE THE 823 00:30:01,389 --> 00:30:03,024 CHOICE BASED UPON SPACE. 824 00:30:03,024 --> 00:30:03,858 SO WE CAN BEGIN TO THINK ABOUT 825 00:30:03,858 --> 00:30:05,159 THIS. 826 00:30:05,159 --> 00:30:08,396 AGAIN, IN OUR DATASET WE HAVE 827 00:30:08,396 --> 00:30:09,564 400,000 OLFACTORY STEM CELLS 828 00:30:09,564 --> 00:30:10,765 AND PRECURSORS. 829 00:30:10,765 --> 00:30:13,334 HERE WE WILL ISOLATE JUST THE 830 00:30:13,334 --> 00:30:15,203 400,000 CELLS AND EXCLUDE ALL 831 00:30:15,203 --> 00:30:16,404 THE MATURE OLFACTORY SENSORY 832 00:30:16,404 --> 00:30:17,772 NEURONS AND HERE YOU COULD SEE 833 00:30:17,772 --> 00:30:20,808 A CARTOON OF THE DIFFERENT 834 00:30:20,808 --> 00:30:21,242 INTERMEDIATE STAGES. 835 00:30:21,242 --> 00:30:24,712 AND WE WILL EMBED ALL TO A 836 00:30:24,712 --> 00:30:26,047 U-MAP PLOT. 837 00:30:26,047 --> 00:30:27,715 EACH IS A CELL. 838 00:30:27,715 --> 00:30:32,320 WE WILL COLOR EACH CELL BY 839 00:30:32,320 --> 00:30:35,156 WHAT'S CALLED PSEUDO TIME, THE 840 00:30:35,156 --> 00:30:36,758 TRAJECTORY THEY TAKE FROM STEM 841 00:30:36,758 --> 00:30:38,993 CELLS TO NEAR FULLY DEVELOPED 842 00:30:38,993 --> 00:30:40,695 OLFACTORY SENSORY NEURONS. 843 00:30:40,695 --> 00:30:42,096 MARKER GENES KNOWN TO BE 844 00:30:42,096 --> 00:30:46,334 ASSOCIATED WITH THE STAGES THEY 845 00:30:46,334 --> 00:30:47,035 ARE RELIABLY EXPRESSED ALONG 846 00:30:47,035 --> 00:30:48,636 THIS AXIS. 847 00:30:48,636 --> 00:30:50,405 THIS AXIS REALLY DOES REFLECT 848 00:30:50,405 --> 00:30:51,906 DEVELOPMENTAL TIME. 849 00:30:51,906 --> 00:30:53,641 THESE STEM CELLS ARE ABOUT TO 850 00:30:53,641 --> 00:30:55,243 BE MATURE AND THEY ARE JUST 851 00:30:55,243 --> 00:30:59,881 ABOUT TO EXPRESS ODOR RECEPTORS. 852 00:30:59,881 --> 00:31:01,516 DO THEY EXPRESS D.V. GENES? 853 00:31:01,516 --> 00:31:06,054 THE ANSWER TURNS OUT TO BE YES. 854 00:31:06,054 --> 00:31:07,455 HERE WE WILL ILLUSTRATE 855 00:31:07,455 --> 00:31:09,057 EXPRESSION ON D.V. ON THE MAP 856 00:31:09,057 --> 00:31:11,626 PLOT. 857 00:31:11,626 --> 00:31:14,262 SOME STEM CELLS HAVE HIGH D.V. 858 00:31:14,262 --> 00:31:17,165 SCORES AND SOME HAVE LOW. 859 00:31:17,165 --> 00:31:20,201 HERE THERE ARE CELLS WITH HIGH 860 00:31:20,201 --> 00:31:23,738 D.V. SCORES AND INTERMEDIATE 861 00:31:23,738 --> 00:31:28,609 AND LOW. 862 00:31:28,609 --> 00:31:30,244 LONG BEFORE CHOSEN, CELLS KNOW 863 00:31:30,244 --> 00:31:31,879 WHAT THEIR D.V. SCORES ARE, 864 00:31:31,879 --> 00:31:32,847 THEREFORE THEY MUST KNOW WHERE 865 00:31:32,847 --> 00:31:34,449 THEY ARE IN SPACE. 866 00:31:34,449 --> 00:31:36,818 IF WE LOOK AT OUR MERFISH DATA 867 00:31:36,818 --> 00:31:40,021 AND LOOK AT THE STEM CELL LAYER 868 00:31:40,021 --> 00:31:41,622 UNDER THE OLFACTORY SENSORY 869 00:31:41,622 --> 00:31:43,491 NEURON LAYER WE SEE NICE 870 00:31:43,491 --> 00:31:44,892 GRADIENTS CONSISTENT WITH THE 871 00:31:44,892 --> 00:31:46,994 IDEA THAT STEM CELLS KNOW WHERE 872 00:31:46,994 --> 00:31:51,666 THEY ARE IN SPACE. 873 00:31:51,666 --> 00:31:54,936 WE KNOW SPACE IS DETERMINING 874 00:31:54,936 --> 00:31:56,537 D.V. SCORES SOMEHOW INFLUENCING 875 00:31:56,537 --> 00:31:57,271 ODOR RECEPTOR CHOICE. 876 00:31:57,271 --> 00:31:59,440 YOU MIGHT HAVE THE IDEA THE 877 00:31:59,440 --> 00:32:01,008 RECEPTORS KNOW WHERE THEY ARE 878 00:32:01,008 --> 00:32:03,911 IN SPACE AND SOMEHOW FADED TO 879 00:32:03,911 --> 00:32:04,679 GENERATE A PARTICULAR ODOR 880 00:32:04,679 --> 00:32:05,780 RECEPTOR. 881 00:32:05,780 --> 00:32:07,882 LIKE A FATE RELATIONSHIP. 882 00:32:07,882 --> 00:32:11,385 LIKE EACH STEM CELL IS ASSIGNED 883 00:32:11,385 --> 00:32:14,555 TO EACH RECEPTOR AND THAT'S HOW 884 00:32:14,555 --> 00:32:16,991 YOU GET THEM ORDERED FROM 885 00:32:16,991 --> 00:32:18,392 DORSAL TO VENTRAL. 886 00:32:18,392 --> 00:32:21,529 WE DID THE FIRST COMPREHENSIVE 887 00:32:21,529 --> 00:32:22,763 FATE MAPPING EVER PERFORMED IN 888 00:32:22,763 --> 00:32:24,332 THE OLFACTORY SYSTEM. 889 00:32:24,332 --> 00:32:26,200 WE TOOK AN ANIMAL WITH ITS NOSE 890 00:32:26,200 --> 00:32:28,302 AND GAVE IT A DRUG THAT KILLED 891 00:32:28,302 --> 00:32:31,606 ALL OF THE MATURE SENSORY 892 00:32:31,606 --> 00:32:32,974 NEURONS LEAVING ONLY THE STEM 893 00:32:32,974 --> 00:32:34,876 CELLS BELOW. 894 00:32:34,876 --> 00:32:36,777 WE THEN INFECTED THE NOSE WITH 895 00:32:36,777 --> 00:32:43,751 A BAR CODED LENTI VIRUS. 896 00:32:43,751 --> 00:32:45,887 LABELED THOEM. 897 00:32:45,887 --> 00:32:48,890 WE WAITED A MONTH OR SO THESE 898 00:32:48,890 --> 00:32:50,892 STEM CELLS DIVIDED AND REBUILT 899 00:32:50,892 --> 00:32:53,794 THE EPITHELIUM FROM SCRATCH. 900 00:32:53,794 --> 00:32:54,729 NEW MATURE OLFACTORY SENSORY 901 00:32:54,729 --> 00:32:55,696 NEURONS. 902 00:32:55,696 --> 00:32:59,200 WE CAN TAKE THESE RECOVERED 903 00:32:59,200 --> 00:33:02,270 NOSES BR*NG BREAK THEM UP AND 904 00:33:02,270 --> 00:33:03,838 DO SINGLE CELL SEQUENCING AND 905 00:33:03,838 --> 00:33:05,973 ASK ABOUT THE PROGENY IT 906 00:33:05,973 --> 00:33:06,908 GENERATED. 907 00:33:06,908 --> 00:33:09,243 ONE THING YOU MIGHT IMAGINE 908 00:33:09,243 --> 00:33:10,878 MAYBE EACH STEM CELL ONLY GIVES 909 00:33:10,878 --> 00:33:14,715 RISE TO ONE TYPE OF O.S.N. 910 00:33:14,715 --> 00:33:16,584 MAYBE EACH STEM CELL IS FATED 911 00:33:16,584 --> 00:33:18,719 TO PICK A PARTICULAR RECEPTOR. 912 00:33:18,719 --> 00:33:22,690 THAT TURNS OUT NOT TO BE TRUE. 913 00:33:22,690 --> 00:33:24,192 INSTEAD EACH STEM CELL SEEMS TO 914 00:33:24,192 --> 00:33:26,294 PICK A VERY RESTRICTED SET OF 915 00:33:26,294 --> 00:33:28,396 RECEPTORS THAT HOVER AROUND THE 916 00:33:28,396 --> 00:33:30,131 MEAN D.V. SCORE ASSOCIATED WITH 917 00:33:30,131 --> 00:33:31,899 THAT STEM CELL. 918 00:33:31,899 --> 00:33:34,235 HERE YOU SEE THE D.V. SCORES OF 919 00:33:34,235 --> 00:33:38,005 ALL OF THE PROGENY ELICITED BY, 920 00:33:38,005 --> 00:33:38,639 ASSOCIATED BY THE DIFFERENT 921 00:33:38,639 --> 00:33:39,640 CLONES WE HAVE. 922 00:33:39,640 --> 00:33:41,709 THEY ALL HAVE A MEAN D.V. SCORE 923 00:33:41,709 --> 00:33:44,045 THAT HAS A VERY NARROW BAND. 924 00:33:44,045 --> 00:33:47,982 IF WE LOOK AT THE DISTRIBUTION 925 00:33:47,982 --> 00:33:50,318 THERE'S A VERY SHARP PEEK WITH 926 00:33:50,318 --> 00:33:52,253 A LITTLE DISTRIBUTION AROUND IT. 927 00:33:52,253 --> 00:33:53,854 WHAT THIS MEANS PRACTICALLY, 928 00:33:53,854 --> 00:33:56,390 EACH OLFACTORY STEM CELL HAS AN 929 00:33:56,390 --> 00:33:58,059 IDEAL FAVORITE TYPE OF RECEPTOR 930 00:33:58,059 --> 00:34:01,162 IT WANTS TO PICK. 931 00:34:01,162 --> 00:34:03,030 AND IT VERY FREQUENTLY PICKS 932 00:34:03,030 --> 00:34:04,899 THAT RECEPTOR, BUT OFTEN IT 933 00:34:04,899 --> 00:34:06,534 MAKES MISTAKES BECAUSE OF 934 00:34:06,534 --> 00:34:08,402 BIOLOGY WHICH EXPLAINS THIS 935 00:34:08,402 --> 00:34:11,672 DISTRIBUTION AND EXPLAINS WHY 936 00:34:11,672 --> 00:34:14,208 THERE'S A SPATIAL DISTRIBUTION 937 00:34:14,208 --> 00:34:18,879 ALONG THE DORSAL VENTRAL AXIS. 938 00:34:18,879 --> 00:34:21,182 HERE I'M DESCRIBING HOW IT IS 939 00:34:21,182 --> 00:34:24,518 SPACE MIGHT INFLUENCE ODORANT 940 00:34:24,518 --> 00:34:24,952 RECEPTOR CHOICE. 941 00:34:24,952 --> 00:34:25,886 BUT WHAT I HAVEN'T TOLD YOU 942 00:34:25,886 --> 00:34:28,956 ABOUT IS HOW IT IS THE STEM 943 00:34:28,956 --> 00:34:30,124 CELLS KNOW ANYTHING ABOUT SPACE. 944 00:34:30,124 --> 00:34:31,292 HOW DO THEY KNOW? 945 00:34:31,292 --> 00:34:33,194 WE WERE GUIDED BY WORK OTHERS 946 00:34:33,194 --> 00:34:34,595 HAD DONE AND BY SOME 947 00:34:34,595 --> 00:34:37,198 INTERESTING PROPERTIES OF OUR 948 00:34:37,198 --> 00:34:38,866 DATASET WHICH SUGGESTED MAYBE 949 00:34:38,866 --> 00:34:43,504 THE WAY SPACE IS ENCODED IN THE 950 00:34:43,504 --> 00:34:46,440 EPITHELIUM IS GRADIENT OF 951 00:34:46,440 --> 00:34:48,242 RETINOIC ACID. 952 00:34:48,242 --> 00:34:51,979 EXPRESSED IN THE LAMINA PROPRIA 953 00:34:51,979 --> 00:34:52,680 UNDERNEATH THE OLFACTORY 954 00:34:52,680 --> 00:34:53,881 EPITHELIUM. 955 00:34:53,881 --> 00:34:57,418 THIS ENZYME, AS YOU CAN SEE 956 00:34:57,418 --> 00:35:00,221 HERE IN OUR MERFISH DATA IS 957 00:35:00,221 --> 00:35:01,956 FROM A DORSAL TO VENTRAL 958 00:35:01,956 --> 00:35:03,491 GRADIENT. 959 00:35:03,491 --> 00:35:07,128 SUGGESTING THERE'S A GRADIENT 960 00:35:07,128 --> 00:35:08,396 OF RETINOIC ACID. 961 00:35:08,396 --> 00:35:10,264 INTERESTINGLY, IF WE LOOK AT 962 00:35:10,264 --> 00:35:11,699 THE GENES THAT BELONG TO THE 963 00:35:11,699 --> 00:35:13,768 D.V. SCORE WE SEE A TON OF 964 00:35:13,768 --> 00:35:17,104 GENES THAT ARE ALL ORGANIZED IN 965 00:35:17,104 --> 00:35:18,272 DORSAL VENTRAL GRADIENTS THAT 966 00:35:18,272 --> 00:35:24,845 SEEM TO BE INVOLVED IN RETINO 967 00:35:24,845 --> 00:35:26,280 ACID METABOLISM, OR BINDING TO, 968 00:35:26,280 --> 00:35:29,817 SUGGESTING IT MIGHT BE A MASTER 969 00:35:29,817 --> 00:35:31,218 CONTROLLER THAT TELLS STEM 970 00:35:31,218 --> 00:35:36,590 CELLS AND PROGENY WHERE THEY 971 00:35:36,590 --> 00:35:36,891 ARE. 972 00:35:36,891 --> 00:35:40,194 WE CAN TEST THIS BY ADDING TO 973 00:35:40,194 --> 00:35:43,731 THE NOSE RETINO ACID INHIBITOR 974 00:35:43,731 --> 00:35:46,334 OR ADDING TO THE EPITHELIUM. 975 00:35:46,334 --> 00:35:48,169 IF WE DO THAT, WE CAN FIND WE 976 00:35:48,169 --> 00:35:51,272 CAN SHIFT THE POSITION OF 977 00:35:51,272 --> 00:35:52,640 RECEPTORS ALONG THE DORSAL 978 00:35:52,640 --> 00:35:54,308 VENTRAL AXIS. 979 00:35:54,308 --> 00:36:01,082 IF WE INHIBIT RETINO ACID, IT 980 00:36:01,082 --> 00:36:04,385 TENDS TO GENERATE CELLS WITH 981 00:36:04,385 --> 00:36:06,253 MORE DORSAL D.V. SCORES AND 982 00:36:06,253 --> 00:36:09,757 TENDS TO PICK MORE DORSAL AND 983 00:36:09,757 --> 00:36:11,125 FEWER VENTRAL CELLS AND 984 00:36:11,125 --> 00:36:11,892 RECEPTORS. 985 00:36:11,892 --> 00:36:14,395 CONVERSELY IF WE ADD MORE 986 00:36:14,395 --> 00:36:16,197 RETINOIC ACID WE SEE THE 987 00:36:16,197 --> 00:36:17,898 OPPOSITE PATTERN. 988 00:36:17,898 --> 00:36:20,434 IT TENDS TO PICK MORE VENTRAL 989 00:36:20,434 --> 00:36:22,069 RECEPTORS AND EXPRESS MORE 990 00:36:22,069 --> 00:36:24,205 VENTRAL D.V. SCORES AND 991 00:36:24,205 --> 00:36:25,606 DEEXPRESS DORSAL RECEPTORS AND 992 00:36:25,606 --> 00:36:28,976 TENDS TO HAVE FEWER DORSAL D.V. 993 00:36:28,976 --> 00:36:30,978 SCORES AMONGST ITSELFS. 994 00:36:30,978 --> 00:36:33,581 IN OTHER WORDS BY MANIPULATING 995 00:36:33,581 --> 00:36:35,950 RETINOIC ACID UP OR DOWN I CAN 996 00:36:35,950 --> 00:36:37,385 SHIFT THIS UP OR DOWN IN SPACE. 997 00:36:37,385 --> 00:36:39,720 THE SHIFT WE ARE SEEING UP AND 998 00:36:39,720 --> 00:36:42,757 DOWN IN SPACE IS NOT ONLY 999 00:36:42,757 --> 00:36:44,625 APPARENT IN MATURE OLFACTORY 1000 00:36:44,625 --> 00:36:45,526 SENSORY NEURONS BUT IN STEM 1001 00:36:45,526 --> 00:36:46,994 CELLS. 1002 00:36:46,994 --> 00:36:52,299 IT SEEMS RETINOIC ACID IS A KEY 1003 00:36:52,299 --> 00:36:54,034 SIGNALING MOLECULE THAT TELLS 1004 00:36:54,034 --> 00:36:55,569 STEM CELLS WHERE THEY ARE IN 1005 00:36:55,569 --> 00:36:58,139 SPACE AND KICKS OFF CASCADE 1006 00:36:58,139 --> 00:37:00,608 THAT ENSURES THE CORRECT 1007 00:37:00,608 --> 00:37:01,876 RECEPTOR IS CHOSEN IN THE RIGHT 1008 00:37:01,876 --> 00:37:03,944 PLACE IN THE EPITHELIUM. 1009 00:37:03,944 --> 00:37:06,180 HOW MIGHT THAT PROCESS ACTUALLY 1010 00:37:06,180 --> 00:37:07,681 OCCUR? 1011 00:37:07,681 --> 00:37:09,517 WE HYPOTHESIZE MAYBE THE 1012 00:37:09,517 --> 00:37:14,388 PROMOTERS OF EACH O.R. GENE 1013 00:37:14,388 --> 00:37:15,689 CONTAIN COMBINING SITES. 1014 00:37:15,689 --> 00:37:18,025 HERE WE ARE DOING AN ANALYSIS 1015 00:37:18,025 --> 00:37:21,996 OF NUMBER OF BINDING SITES FOR 1016 00:37:21,996 --> 00:37:22,530 PARTICULAR TRANSCRIPTION 1017 00:37:22,530 --> 00:37:24,265 FACTORS. 1018 00:37:24,265 --> 00:37:27,601 I WON'T DISCUSS THESE TWO FOR 1019 00:37:27,601 --> 00:37:29,670 NOW THOUGH THEY ARE IMPORTANT 1020 00:37:29,670 --> 00:37:30,638 BUT NOTICE THESE TRANSCRIPTION 1021 00:37:30,638 --> 00:37:33,741 FACTORS. 1022 00:37:33,741 --> 00:37:35,810 YOU COULD SEE RAR HAS AN 1023 00:37:35,810 --> 00:37:38,179 INCREASING NUMBER OF BINDING 1024 00:37:38,179 --> 00:37:40,714 SITES AS CELLS BECOME MORE AND 1025 00:37:40,714 --> 00:37:42,082 MORE VENTRAL. 1026 00:37:42,082 --> 00:37:45,553 I TOLD YOU RETINOIC, THE LIGAND 1027 00:37:45,553 --> 00:37:46,587 IS ALSO EXPRESSED. 1028 00:37:46,587 --> 00:37:49,824 YOU MIGHT IMAGINE THIS PATTERN 1029 00:37:49,824 --> 00:37:51,225 WOULD ALLOW INDIVIDUAL ODORANT 1030 00:37:51,225 --> 00:37:54,028 RECEPTORS TO BE ORGANIZED ALONG 1031 00:37:54,028 --> 00:37:55,696 THE DORSAL VENTRAL AXIS. 1032 00:37:55,696 --> 00:38:00,434 THE FACTORS I SHOWED YOU AT THE 1033 00:38:00,434 --> 00:38:02,336 BEGINNING, FOR NFI ARE ALSO 1034 00:38:02,336 --> 00:38:04,472 ENRICHED IN MORE VENTRAL 1035 00:38:04,472 --> 00:38:05,673 RECEPTORS COMPARED TO MORE 1036 00:38:05,673 --> 00:38:07,475 DORSAL. 1037 00:38:07,475 --> 00:38:09,310 COMBINED YOU CAN IMAGINE THE 1038 00:38:09,310 --> 00:38:12,646 DIFFERENCES IN FRONT OF ODORANT 1039 00:38:12,646 --> 00:38:14,248 RECEPTORS TAKEN WITH THE 1040 00:38:14,248 --> 00:38:15,483 GRADIENTS COULD BUILD THE 1041 00:38:15,483 --> 00:38:16,116 THOUSAND DIFFERENT STRIPES. 1042 00:38:16,116 --> 00:38:19,153 I WILL TELL YOU BUT I WON'T 1043 00:38:19,153 --> 00:38:20,588 SHOW YOU WE HAVE PROVEN IN A 1044 00:38:20,588 --> 00:38:22,223 NUMBER OF WAYS. 1045 00:38:22,223 --> 00:38:24,592 ONE SIMPLE WAY IS MAKING A 1046 00:38:24,592 --> 00:38:26,460 GENETICALLY MODIFIED MOUSE AND 1047 00:38:26,460 --> 00:38:30,564 TAKING PROMOTER OF ONE AND 1048 00:38:30,564 --> 00:38:32,199 PUTTING IN FRONT OF ANOTHER, 1049 00:38:32,199 --> 00:38:34,301 THAT MOVES THE RECEPTOR IN A 1050 00:38:34,301 --> 00:38:35,970 PREDICTABLE WAY IN SPACE, 1051 00:38:35,970 --> 00:38:38,572 CONSISTENT WITH THE IDEA THE 1052 00:38:38,572 --> 00:38:41,141 GENOME ITSELF DETERMINES WHERE 1053 00:38:41,141 --> 00:38:42,543 IN THE EPITHELIUM EACH WILL BE 1054 00:38:42,543 --> 00:38:43,978 EXPRESSED. 1055 00:38:43,978 --> 00:38:45,646 THIS DESCRIBES A LITTLE WHAT WE 1056 00:38:45,646 --> 00:38:47,348 THINK IS GOING ON WITH THE 1057 00:38:47,348 --> 00:38:48,282 TRANSCRIPTION FACTORS PART OF 1058 00:38:48,282 --> 00:38:49,850 THE D.V. SCORE. 1059 00:38:49,850 --> 00:38:51,018 REMEMBER THERE'S THAT OTHER 1060 00:38:51,018 --> 00:38:53,387 CLASS OF GENES I TOLD YOU ABOUT? 1061 00:38:53,387 --> 00:38:55,956 I TOLD YOU 30 AXON GUIDANCE 1062 00:38:55,956 --> 00:38:57,391 GENES ALL EXPRESSED IN 1063 00:38:57,391 --> 00:38:58,726 GRADIENTS IN THE OLFACTORY 1064 00:38:58,726 --> 00:39:02,296 EPITHELIUM. 1065 00:39:02,296 --> 00:39:03,464 YOU MIGHT IMAGINE BECAUSE 1066 00:39:03,464 --> 00:39:05,566 THERE'S SO MANY THEY MIGHT BE 1067 00:39:05,566 --> 00:39:06,967 SUFFICIENT TO ENABLE AN 1068 00:39:06,967 --> 00:39:10,237 OLFACTORY SENSORY NEURON IN THE 1069 00:39:10,237 --> 00:39:11,171 EPITHELIUM BASED ON ITS 1070 00:39:11,171 --> 00:39:15,376 POSITION TO FIND IT'S CORRECT 1071 00:39:15,376 --> 00:39:16,076 GLOMERULAR POSITION. 1072 00:39:16,076 --> 00:39:18,445 THE POSITION IN THE NOSE MIGHT 1073 00:39:18,445 --> 00:39:19,713 ENTAIL THE EXISTENCE OF A MAP 1074 00:39:19,713 --> 00:39:21,515 IN THE BULB. 1075 00:39:21,515 --> 00:39:24,318 WE WANTED TO TEST THAT IDEA, WE 1076 00:39:24,318 --> 00:39:30,925 TOOK ADVANTAGE OF A DATA SET MY 1077 00:39:30,925 --> 00:39:36,297 COLLEAGUE AXLE FLEISCHMANN AT 1078 00:39:36,297 --> 00:39:38,432 BROWN USED TRANSCRIPTOMICS. 1079 00:39:38,432 --> 00:39:41,969 WE KNOW WITH THE MOUSE THE 1080 00:39:41,969 --> 00:39:44,071 MOLECULAR IDENTITY THAT 1081 00:39:44,071 --> 00:39:45,005 INNERVATES EVERY OLFACTORY 1082 00:39:45,005 --> 00:39:46,173 RECEPTOR IN THE BULB. 1083 00:39:46,173 --> 00:39:48,776 WE COULD ASK IN THE OLFACTORY 1084 00:39:48,776 --> 00:39:52,379 BULB ITSELF WHETHER OR NOT THE 1085 00:39:52,379 --> 00:39:54,481 LEVEL OF D.V. SCORE GENE 1086 00:39:54,481 --> 00:39:57,284 EXPRESSION BY THE INNERVATING 1087 00:39:57,284 --> 00:39:58,619 SENSORY NEURONS HAS ANY PATTERN 1088 00:39:58,619 --> 00:39:59,420 IN THE BULB. 1089 00:39:59,420 --> 00:40:00,955 ONE THING I WANT TO MENTION 1090 00:40:00,955 --> 00:40:02,723 THAT I GLOSSED OVER AT THE 1091 00:40:02,723 --> 00:40:05,693 BEGINNING, EACH BULB IS MIRROR 1092 00:40:05,693 --> 00:40:11,165 SYMMETRIC AND CONTAINS TWO 1093 00:40:11,165 --> 00:40:11,432 HEMIBULBS. 1094 00:40:11,432 --> 00:40:13,434 IF YOU COLOR GLOMERULUS BY THE 1095 00:40:13,434 --> 00:40:19,873 D.V. SCORE OF INNERVATING OSN'S 1096 00:40:19,873 --> 00:40:21,508 IT CREATES BEAUTIFUL GRADIENTS, 1097 00:40:21,508 --> 00:40:24,511 SUGGESTING THAT THE GENES THAT 1098 00:40:24,511 --> 00:40:26,380 CONTAIN THE D.V. SCORE CONTAIN 1099 00:40:26,380 --> 00:40:28,949 INFORMATION TO GUIDE AXON TO 1100 00:40:28,949 --> 00:40:34,321 ITS EVENTUAL DORSAL LOCATION IN 1101 00:40:34,321 --> 00:40:35,656 THE OLFACTORY BULB. 1102 00:40:35,656 --> 00:40:38,225 THEY DO A GREAT JOB PREDICTING 1103 00:40:38,225 --> 00:40:41,729 THE D.V. SCORE IMPUTED BY 1104 00:40:41,729 --> 00:40:42,563 SPATIAL POSITIONING IN THE 1105 00:40:42,563 --> 00:40:45,232 OLFACTORY BULB. 1106 00:40:45,232 --> 00:40:47,101 IMPORTANTLY IF WE USE THE D.V. 1107 00:40:47,101 --> 00:40:52,039 SCORE TO PREDICT THE ACTUAL 3D 1108 00:40:52,039 --> 00:40:53,907 POSITION OF GLOMERULI WE COULD 1109 00:40:53,907 --> 00:40:55,376 DO ACCURATELY WITH A 400 MICRON 1110 00:40:55,376 --> 00:40:57,177 ERROR. 1111 00:40:57,177 --> 00:41:00,114 EACH GLOMERULUS IS ABOUT 150 1112 00:41:00,114 --> 00:41:00,881 MICRONS BIG. 1113 00:41:00,881 --> 00:41:02,983 WITH THE SINGLE NUMBER I COULD 1114 00:41:02,983 --> 00:41:05,052 PREDICT THE THREE LOCATION OF 1115 00:41:05,052 --> 00:41:10,491 GLOMERULI WITH A ONE TO TWO 1116 00:41:10,491 --> 00:41:14,728 GLOMERULUS STRUCTURE, SEVERAL 1117 00:41:14,728 --> 00:41:17,898 MILLION METERS BIG. 1118 00:41:17,898 --> 00:41:20,200 SUGGESTING THAT THE MAP IN THE 1119 00:41:20,200 --> 00:41:23,103 NOSE REALLY CAN ENTAIL THE MAP 1120 00:41:23,103 --> 00:41:23,470 IN THE BULB. 1121 00:41:23,470 --> 00:41:27,775 OKAY, LAST SLIDE. 1122 00:41:27,775 --> 00:41:29,910 I TOLD YOU KEY SENSORY FEATURES 1123 00:41:29,910 --> 00:41:31,145 WERE ORGANIZED IN MAPS IN THE 1124 00:41:31,145 --> 00:41:33,180 RETINA AND IN THE COCHLEA. 1125 00:41:33,180 --> 00:41:35,516 SO YOU MIGHT IMAGINE THAT KEY 1126 00:41:35,516 --> 00:41:36,450 CHEMICAL FEATURES ARE SPATIALLY 1127 00:41:36,450 --> 00:41:37,584 ORGANIZED IN THE NOSE. 1128 00:41:37,584 --> 00:41:44,958 THIS IS AN OLD IDEA CALLED 1129 00:41:44,958 --> 00:41:46,960 KHEMOTOPY. 1130 00:41:46,960 --> 00:41:49,063 MAYBE THE REASON WHILE THERE'S 1131 00:41:49,063 --> 00:41:50,297 THIS HIGHLY PRECISE MAP IS TO 1132 00:41:50,297 --> 00:41:51,665 SUPPORT THE GENERATION OF THE 1133 00:41:51,665 --> 00:41:53,300 CHEMICAL MAP IN YOUR NOSE. 1134 00:41:53,300 --> 00:41:55,202 IS THAT TRUE? 1135 00:41:55,202 --> 00:42:00,340 MY LAB HAS DEVELOPED A 1136 00:42:00,340 --> 00:42:02,276 TECHNIQUE CALLED AK SEEK TO 1137 00:42:02,276 --> 00:42:03,844 FIND ALL THAT RESPOND TO THAT 1138 00:42:03,844 --> 00:42:04,978 ODOR. 1139 00:42:04,978 --> 00:42:08,015 JUST KNOW FOR A BUNCH OF ODORS, 1140 00:42:08,015 --> 00:42:10,584 22, 50, MAYBE 100 ODORS A 1141 00:42:10,584 --> 00:42:12,219 COMPLETE SET OF RECEPTORS THAT 1142 00:42:12,219 --> 00:42:12,953 RESPOND TO THOSE ODORS. 1143 00:42:12,953 --> 00:42:17,658 I COULD GO TO THE OLFACTORY 1144 00:42:17,658 --> 00:42:19,026 EPITHELIUM MERFISH AND COLOR IN 1145 00:42:19,026 --> 00:42:20,194 THE NEURONS IN THEIR POSITION 1146 00:42:20,194 --> 00:42:21,895 IN SPACE THAT ARE RESPONSIVE TO 1147 00:42:21,895 --> 00:42:23,464 ANY GIVEN ODOR. 1148 00:42:23,464 --> 00:42:24,565 YOU SEE BASICALLY TWO THINGS IN 1149 00:42:24,565 --> 00:42:25,532 THESE DATA. 1150 00:42:25,532 --> 00:42:31,205 THE FIRST IS THAT ACIDS LIKE 1151 00:42:31,205 --> 00:42:33,307 OCTANOIC TEND TO ACTIVATE ONLY 1152 00:42:33,307 --> 00:42:34,241 DORSAL CELLS. 1153 00:42:34,241 --> 00:42:35,476 THAT'S SOMETHING WELL KNOWN IN 1154 00:42:35,476 --> 00:42:37,478 THE OLFACTORY LITERATURE. 1155 00:42:37,478 --> 00:42:39,580 THERE'S ENRICHMENT FOR SOME 1156 00:42:39,580 --> 00:42:41,248 REASON FOR ACID RESPONSIVE 1157 00:42:41,248 --> 00:42:42,416 RECEPTORS IN THE DORSAL DOMAIN. 1158 00:42:42,416 --> 00:42:44,785 I WILL SAY FOR THOSE INTERESTED 1159 00:42:44,785 --> 00:42:46,019 IN OLFACTION WE THINK IT'S THE 1160 00:42:46,019 --> 00:42:48,222 ONE REAL ZONE IN THE BULB SEEMS 1161 00:42:48,222 --> 00:42:49,890 TO BE SPECIAL AND ENRICHED FOR 1162 00:42:49,890 --> 00:42:51,959 A PARTICULAR TYPE OF RECEPTOR. 1163 00:42:51,959 --> 00:42:56,263 BUT P FOR ALL THESE OTHER 1164 00:42:56,263 --> 00:42:57,698 GENERIC ODORANTS ESSENTIALLY 1165 00:42:57,698 --> 00:43:00,033 THEY ACTIVATE ALL THE DOMAIN. 1166 00:43:00,033 --> 00:43:01,401 INTERMINGLED. 1167 00:43:01,401 --> 00:43:05,939 IF YOU LOOK THERE'S NO WAY TO 1168 00:43:05,939 --> 00:43:11,411 DETERMINE AN ANIMAL SMELLING 1169 00:43:11,411 --> 00:43:13,013 OCTANOIC OR PENTYL ACETATE. 1170 00:43:13,013 --> 00:43:18,619 IF YOU TELL ME THE IDENTITY 1171 00:43:18,619 --> 00:43:20,187 WITH 100% ACCURACY I COULD TELL 1172 00:43:20,187 --> 00:43:22,756 THE ODORS APART. 1173 00:43:22,756 --> 00:43:24,258 ODOR RECEPTORS IN THE NOSE BUT 1174 00:43:24,258 --> 00:43:27,995 IT DOES NOT ORGANIZE CHEMISTRY. 1175 00:43:27,995 --> 00:43:29,663 LET ME SUMMARIZE WHAT I TOLD 1176 00:43:29,663 --> 00:43:31,031 YOU, WE STARTED WITH DISCUSSION 1177 00:43:31,031 --> 00:43:34,334 WHERE WE WERE WITH OLFACTION 1178 00:43:34,334 --> 00:43:36,670 AND DESCRIBED BASIC IDEA ODOR 1179 00:43:36,670 --> 00:43:37,437 CHOICE IS RANDOM, THERE'S 1180 00:43:37,437 --> 00:43:39,807 DISORDER IN THE NOSE AND 1181 00:43:39,807 --> 00:43:41,008 APPEARS IN THE OLFACTORY BULB. 1182 00:43:41,008 --> 00:43:42,376 WHAT I HAVE SHOWN YOU TODAY THE 1183 00:43:42,376 --> 00:43:45,012 NOSE IS JUST LIKE THE OTHER 1184 00:43:45,012 --> 00:43:46,346 PERIPHERAL SENSORY ORGANS. 1185 00:43:46,346 --> 00:43:48,615 AT LONG LAST WE HAVE DISCOVERED 1186 00:43:48,615 --> 00:43:50,050 MAP FOR OLFACTION. 1187 00:43:50,050 --> 00:43:54,922 THIS MAP ORGANIZES ALONG THE 1188 00:43:54,922 --> 00:43:57,324 DORSAL VENTRAL AXIS ALL 1,000 1189 00:43:57,324 --> 00:44:01,762 PEEKS RUN FROM TOP TO BOTTOM IN 1190 00:44:01,762 --> 00:44:03,197 A PRESCRIBED ORDER CONSERVED 1191 00:44:03,197 --> 00:44:05,032 ANIMAL TO ANIMAL TO ANIMAL. 1192 00:44:05,032 --> 00:44:06,466 THAT, I WOULD ARGUE MEANS THE 1193 00:44:06,466 --> 00:44:09,303 NOSE IS THE MOST PATTERNED 1194 00:44:09,303 --> 00:44:10,504 NERVOUS TISSUE IN YOUR ENTIRE 1195 00:44:10,504 --> 00:44:11,138 BODY. 1196 00:44:11,138 --> 00:44:12,573 WHICH I THINK IS RATHER 1197 00:44:12,573 --> 00:44:13,273 REMARKABLE. 1198 00:44:13,273 --> 00:44:14,441 I WILL SAY THAT PART OF THE 1199 00:44:14,441 --> 00:44:16,310 REASON, IF YOU READ THE 1200 00:44:16,310 --> 00:44:18,378 LITERATURE THAT PEOPLE FOR SO 1201 00:44:18,378 --> 00:44:20,981 LONG HAD THE IDEA THAT 1202 00:44:20,981 --> 00:44:22,382 RECEPTORS MUST BE CHOSEN 1203 00:44:22,382 --> 00:44:24,017 RANDOMLY BECAUSE NO ONE COULD 1204 00:44:24,017 --> 00:44:25,419 IMAGINE THAT DEVELOPMENT COULD 1205 00:44:25,419 --> 00:44:27,955 SOLVE THE PROBLEM OF PUTTING 1206 00:44:27,955 --> 00:44:29,122 1,000 THINGS IN PRECISE PLACES. 1207 00:44:29,122 --> 00:44:30,958 WHAT I SHOW HERE IN FACT IS IT 1208 00:44:30,958 --> 00:44:31,925 CAN. 1209 00:44:31,925 --> 00:44:33,093 WHY BUILD THIS MAP? 1210 00:44:33,093 --> 00:44:35,596 AS I STRIEBED IT'S NOT TO 1211 00:44:35,596 --> 00:44:36,864 ORGANIZE CHEMICAL SPACE. 1212 00:44:36,864 --> 00:44:38,799 WE THINK TWO LIKELY REASON, ONE 1213 00:44:38,799 --> 00:44:41,268 IS FOR ROBUSTNESS. 1214 00:44:41,268 --> 00:44:43,403 CHEMICAL TUNING OF INDIVIDUAL 1215 00:44:43,403 --> 00:44:44,771 RECEPTORS ARE BROAD AND 1216 00:44:44,771 --> 00:44:45,739 REDUNDANT. 1217 00:44:45,739 --> 00:44:47,474 BY TILING THE NOSE WITH ALL 1218 00:44:47,474 --> 00:44:48,575 THESE DIFFERENT RECEPTORS IF 1219 00:44:48,575 --> 00:44:51,144 YOU INJURY ONE PART OF THE NOSE 1220 00:44:51,144 --> 00:44:53,013 YOU WILL STILL SMELL ODOR SPACE 1221 00:44:53,013 --> 00:44:54,648 WITH THE REMAINDER PART OF THE 1222 00:44:54,648 --> 00:44:55,649 NOSE, SOMETHING NOT POSSIBLE IF 1223 00:44:55,649 --> 00:44:56,783 THEY WERE ORGANIZED IN CHEMICAL 1224 00:44:56,783 --> 00:44:57,251 SPACE. 1225 00:44:57,251 --> 00:44:59,052 WE THINK THIS IS A MECHANISM 1226 00:44:59,052 --> 00:45:00,020 FOR ROBUSTNESS. 1227 00:45:00,020 --> 00:45:03,056 WE ALSO THINK THIS IS PROBABLY 1228 00:45:03,056 --> 00:45:04,124 IMPORTANT BECAUSE IT ALLOWS 1229 00:45:04,124 --> 00:45:06,093 SPATIAL POSITION IN THE NOSE TO 1230 00:45:06,093 --> 00:45:07,594 DETERMINE THE SPATIAL POSITION 1231 00:45:07,594 --> 00:45:09,162 OF GLOMERULI IN THE BULB. 1232 00:45:09,162 --> 00:45:11,265 IN OTHER WORDS THROUGH ONE 1233 00:45:11,265 --> 00:45:14,101 PROGRAM IN WHICH RETINOIC ACID 1234 00:45:14,101 --> 00:45:19,206 DETERMINES T.D.V. GENES YOU 1235 00:45:19,206 --> 00:45:20,607 SOLVE TWO REALLY HARD PROBLEMS 1236 00:45:20,607 --> 00:45:21,308 JUST ONCE. 1237 00:45:21,308 --> 00:45:25,145 I WILL MENTION I THINK THIS 1238 00:45:25,145 --> 00:45:26,813 WORK HAS SUBSTANTIAL 1239 00:45:26,813 --> 00:45:27,748 IMPLICATIONS FOR THERAPEUTICS, 1240 00:45:27,748 --> 00:45:28,949 THERE ARE MILLIONS OF AMERICANS 1241 00:45:28,949 --> 00:45:29,883 WHO HAVE LOST THEIR SENSE OF 1242 00:45:29,883 --> 00:45:30,817 SMELL. 1243 00:45:30,817 --> 00:45:33,587 WE ARE REALLY INTERESTED IN 1244 00:45:33,587 --> 00:45:34,988 BUILDING PROSTHESIS OR USING 1245 00:45:34,988 --> 00:45:37,324 STEM CELLS AND UNDERSTANDING 1246 00:45:37,324 --> 00:45:38,959 BASIC PHYSIOLOGY IS ESSENTIAL 1247 00:45:38,959 --> 00:45:40,460 IF WE FIX PEOPLE WITH BROKEN 1248 00:45:40,460 --> 00:45:42,462 NOSES. 1249 00:45:42,462 --> 00:45:46,400 PRECISION OF MECHANISMS REALLY 1250 00:45:46,400 --> 00:45:48,669 SUGGEST THAT ACROSS THE ENTIRE 1251 00:45:48,669 --> 00:45:50,070 BRAIN WOULD HAVE PROFOUND 1252 00:45:50,070 --> 00:45:51,838 FUNCTIONAL CONSEQUENCES. 1253 00:45:51,838 --> 00:45:53,073 THINK IT CHANGES THE WAY WE 1254 00:45:53,073 --> 00:45:54,741 THINK A LITTLE BIT ABOUT NEURAL 1255 00:45:54,741 --> 00:45:55,575 DEVELOPMENT. 1256 00:45:55,575 --> 00:45:57,945 ALL OF THE WORK I'VE SHOWN YOU 1257 00:45:57,945 --> 00:45:59,746 TODAY WAS DONE BY THIS GUY, 1258 00:45:59,746 --> 00:46:01,481 DAVID BRAND. 1259 00:46:01,481 --> 00:46:04,551 A GRAD STUDENT IN MY LAB. 1260 00:46:04,551 --> 00:46:06,987 BRILLIANT GRADUATE STUDENT, 1261 00:46:06,987 --> 00:46:13,293 ALONG WITH WORK BY SUI AND TOM 1262 00:46:13,293 --> 00:46:13,994 BOSE'S LAB AT NORTHWESTERN. 1263 00:46:13,994 --> 00:46:24,004 NOW IS THE TIME I THANK NIH AND 1264 00:46:24,004 --> 00:46:27,307 I'M TRULY FWRAITFUL GRATEFUL. 1265 00:46:27,307 --> 00:46:28,909 IT'S TAUGHT US A LOT AND I'M 1266 00:46:28,909 --> 00:46:30,010 PROUD OF WHAT WE HAVE 1267 00:46:30,010 --> 00:46:32,446 ACCOMPLISHED. 1268 00:46:32,446 --> 00:46:35,248 I THINK AS YOU KNOW FUNDING AT 1269 00:46:35,248 --> 00:46:37,084 HARVARD HAS BEEN TERMINATED. 1270 00:46:37,084 --> 00:46:38,285 WE DON'T HAVE FUNDING ANY MORE 1271 00:46:38,285 --> 00:46:39,486 TO FUND THIS WORK. 1272 00:46:39,486 --> 00:46:41,788 I THINK THERE ARE PERVASIVELY 1273 00:46:41,788 --> 00:46:42,756 CHALLENGING THINGS ABOUT THAT. 1274 00:46:42,756 --> 00:46:45,559 I WANT TO FOCUS ABOUT THE 1275 00:46:45,559 --> 00:46:47,661 CONSEQUENCES FOR THE TRAINEES 1276 00:46:47,661 --> 00:46:49,496 WE ARE FACING UNPRECEDENTED 1277 00:46:49,496 --> 00:46:50,664 AMOUNT OF UNCERTAINTY. 1278 00:46:50,664 --> 00:46:53,233 TAIF 1279 00:46:53,233 --> 00:46:56,770 DAVID IS A GENIUS, IF YOU ASK 1280 00:46:56,770 --> 00:46:59,773 WHY HE DOES SCIENCE, HE IS 1281 00:46:59,773 --> 00:47:01,441 CURIOUS, HE DOES IT BECAUSE HE 1282 00:47:01,441 --> 00:47:03,777 FEELS IT'S A WAY HE CAN 1283 00:47:03,777 --> 00:47:05,645 CONTRIBUTE TO THIS COUNTRY. 1284 00:47:05,645 --> 00:47:07,314 HE FEELS IN DOING SCIENCE AND 1285 00:47:07,314 --> 00:47:10,283 ADDING TO THE LITERATURE HE IS 1286 00:47:10,283 --> 00:47:11,485 HELPING US BE THE BEST 1287 00:47:11,485 --> 00:47:13,920 AMERICANS WE CAN BE AND VIEWS 1288 00:47:13,920 --> 00:47:15,222 SCIENCE FUNDAMENTALLY AS A 1289 00:47:15,222 --> 00:47:16,823 SERVICE, A VIEW I VERY MUCH 1290 00:47:16,823 --> 00:47:17,791 SHARE. 1291 00:47:17,791 --> 00:47:20,360 ALL OF YOU HERE AT NIH YOU ARE 1292 00:47:20,360 --> 00:47:21,561 INVOLVED IN CUTTING EDGE 1293 00:47:21,561 --> 00:47:22,963 RESEARCH IN MEDICAL CARE. 1294 00:47:22,963 --> 00:47:24,398 BUT TRULY I THINK ALL OF US 1295 00:47:24,398 --> 00:47:25,966 APPRECIATE THAT ALL OF YOU ARE 1296 00:47:25,966 --> 00:47:29,736 DOING SCIENCE AS A SERVICE. 1297 00:47:29,736 --> 00:47:31,138 SPEAKING FROM MY SEAT AT 1298 00:47:31,138 --> 00:47:32,773 HARVARD WE KNOW THERE'S A LOT 1299 00:47:32,773 --> 00:47:34,441 OF STUFF GOING ON AT HARVARD 1300 00:47:34,441 --> 00:47:35,809 AND HERE, I WANT YOU ALL TO 1301 00:47:35,809 --> 00:47:37,911 KNOW WE SEE YOU AND WE ARE 1302 00:47:37,911 --> 00:47:39,513 SUPER GRATEFUL FOR EVERYTHING 1303 00:47:39,513 --> 00:47:43,316 YOU HAVE DONE, BOTH ON THE 1304 00:47:43,316 --> 00:47:44,251 INTRAMURAL AND EXTRA MURAL 1305 00:47:44,251 --> 00:47:45,719 SIDE, WE SEE YOUR SERVICE AND 1306 00:47:45,719 --> 00:47:46,820 WE APPRECIATE IT. 1307 00:47:46,820 --> 00:47:47,821 THANK YOU FOR EVERYTHING YOU 1308 00:47:47,821 --> 00:47:48,722 ARE ALL DOING. 1309 00:47:48,722 --> 00:47:49,890 THANK YOU FOR YOUR ATTENTION 1310 00:47:49,890 --> 00:47:51,058 AND I WILL TAKE ANY QUESTIONS 1311 00:47:51,058 --> 00:47:51,525 YOU MIGHT HAVE. 1312 00:47:51,525 --> 00:47:59,332 [ APPLAUSE ] 1313 00:47:59,332 --> 00:48:00,700 >> THANK YOU, PEOPLE HERE 1314 00:48:00,700 --> 00:48:01,501 CERTAINLY KNOW WHERE THE MICS 1315 00:48:01,501 --> 00:48:02,369 ARE. 1316 00:48:02,369 --> 00:48:03,970 WE HAVE SOME QUESTIONS COMING? 1317 00:48:03,970 --> 00:48:05,372 NO WE DON'T. 1318 00:48:05,372 --> 00:48:06,540 OKAY, BUT I DO HAVE A FEW 1319 00:48:06,540 --> 00:48:07,707 ONLINE. 1320 00:48:07,707 --> 00:48:09,376 I CAN'T QUITE SEE BEHIND ME. 1321 00:48:09,376 --> 00:48:16,683 OKAY, WE WILL START IN HERE. 1322 00:48:16,683 --> 00:48:17,918 >> THANK YOU VERY MUCH, 1323 00:48:17,918 --> 00:48:20,620 WONDERFUL TALK. 1324 00:48:20,620 --> 00:48:23,223 RETINOIC ACID LOOKS LIKE MUSTER 1325 00:48:23,223 --> 00:48:24,424 REGULATOR OF MANY SCENES. 1326 00:48:24,424 --> 00:48:29,362 DO YOU HAVE A MAP OF LAMINA 1327 00:48:29,362 --> 00:48:30,564 PROPRIA CELLS, WHAT TYPE OF 1328 00:48:30,564 --> 00:48:31,965 CELLS ARE MAKING IT? 1329 00:48:31,965 --> 00:48:36,470 >> Sandeep Datta: YEAH, SO WE 1330 00:48:36,470 --> 00:48:37,838 THINK THAT LAMINA PROPRIA, 1331 00:48:37,838 --> 00:48:44,411 THAT'S AS FAR CONTAIN A MET 1332 00:48:44,411 --> 00:48:46,513 BOLEIC ENZYME THAT CONVERTS. 1333 00:48:46,513 --> 00:48:50,016 WHAT WILL BE AMAZING IF WE CAN 1334 00:48:50,016 --> 00:48:50,817 VISUALIZE THE RETINOIC ACID 1335 00:48:50,817 --> 00:48:51,451 GRADIENT. 1336 00:48:51,451 --> 00:48:52,619 THERE ARE TOOLS. 1337 00:48:52,619 --> 00:48:54,988 THAT'S WHAT WE ARE DOING NOW. 1338 00:48:54,988 --> 00:48:56,857 LET'S TALK ABOUT IT FOR A 1339 00:48:56,857 --> 00:48:58,959 SECOND, THIS IS AN EXAMPLE THE 1340 00:48:58,959 --> 00:48:59,726 CARTILAGE IS PATTERNING THE 1341 00:48:59,726 --> 00:49:00,861 NERVOUS SYSTEM. 1342 00:49:00,861 --> 00:49:03,096 LET'S THINK ABOUT THAT FOR A 1343 00:49:03,096 --> 00:49:03,330 SECOND. 1344 00:49:03,330 --> 00:49:04,865 NOT USED TO HOW WE THINK ABOUT 1345 00:49:04,865 --> 00:49:05,031 IT. 1346 00:49:05,031 --> 00:49:06,566 IT'S VERY UNUSUAL AND 1347 00:49:06,566 --> 00:49:07,467 INTERESTING AND OBVIOUSLY A 1348 00:49:07,467 --> 00:49:08,235 THING WE ARE INTERESTED IN 1349 00:49:08,235 --> 00:49:08,869 WORKING ON. 1350 00:49:08,869 --> 00:49:10,337 THANK YOU FOR YOUR QUESTION. 1351 00:49:10,337 --> 00:49:10,770 >> THANK YOU. 1352 00:49:10,770 --> 00:49:12,806 >> THANK YOU FOR YOUR TALK, IT 1353 00:49:12,806 --> 00:49:14,007 WAS BEAUTIFUL. 1354 00:49:14,007 --> 00:49:15,675 I HAVE TWO QUESTIONS, YOU CAN 1355 00:49:15,675 --> 00:49:16,843 PICK SO WE CAN KEEP THE LINE 1356 00:49:16,843 --> 00:49:18,278 GOING. 1357 00:49:18,278 --> 00:49:19,479 I WAS WONDERING FIRST, I 1358 00:49:19,479 --> 00:49:21,114 UNDERSTAND THAT YOU HAVE 1359 00:49:21,114 --> 00:49:22,349 DEVELOPMENTAL TIME EVEN IN THE 1360 00:49:22,349 --> 00:49:24,484 ADULT HERE BECAUSE YOU HAVE 1361 00:49:24,484 --> 00:49:25,585 THIS CONTINUOUSLY REGENERATING. 1362 00:49:25,585 --> 00:49:26,987 I'M WONDERING IF YOU KNOW ABOUT 1363 00:49:26,987 --> 00:49:29,789 HOW THIS MAP IS ESTABLISHED IN 1364 00:49:29,789 --> 00:49:32,025 DEVELOPMENT IN TERMS OF THE 1365 00:49:32,025 --> 00:49:33,760 ANIMAL'S AGE. 1366 00:49:33,760 --> 00:49:35,462 MY OTHER QUESTION WHETHER THERE 1367 00:49:35,462 --> 00:49:37,230 MIGHT BE, THERE DON'T HAVE TO 1368 00:49:37,230 --> 00:49:40,367 BE FUNCTIONAL MAPS BUT WHETHER 1369 00:49:40,367 --> 00:49:43,303 EITHER VALENCE OR ACTION 1370 00:49:43,303 --> 00:49:44,671 SELECTION OR SOURCE MIGHT BE 1371 00:49:44,671 --> 00:49:45,839 OTHER KINDS OF MAPS THAT MIGHT 1372 00:49:45,839 --> 00:49:46,673 BE THERE. 1373 00:49:46,673 --> 00:49:48,008 >> Sandeep Datta: I WILL ANSWER 1374 00:49:48,008 --> 00:49:50,377 BOTH, IF IT'S OKAY. 1375 00:49:50,377 --> 00:49:52,245 THE FIRST QUESTION WAS, I KEEP 1376 00:49:52,245 --> 00:49:53,880 TALKING ABOUT THE ADULT AS IF 1377 00:49:53,880 --> 00:49:56,449 IT'S DEVELOPMENT, BUT IT'S NOT 1378 00:49:56,449 --> 00:49:58,084 DEVELOPMENT, THE MAP ORIGINALLY 1379 00:49:58,084 --> 00:49:59,753 DEVELOPS IN AN EMBRYO AND 1380 00:49:59,753 --> 00:50:01,354 REGENERATED IN THE ADULT. 1381 00:50:01,354 --> 00:50:02,989 I LEVERAGE THE ADULTS TO THINK 1382 00:50:02,989 --> 00:50:08,662 ABOUT THE ONTOGENY OF THE MAP. 1383 00:50:08,662 --> 00:50:10,897 WE THINK OF HOW THINGS ARE 1384 00:50:10,897 --> 00:50:13,433 ORGANIZED IN THE EMBRYO, I 1385 00:50:13,433 --> 00:50:15,569 THINK IT'S HIGHLY UNLIKELY THE 1386 00:50:15,569 --> 00:50:16,203 DETERMINANTS ORIGINALLY BUILT 1387 00:50:16,203 --> 00:50:18,138 THE MAP. 1388 00:50:18,138 --> 00:50:19,773 THIS RETINOIC ACID MECHANISM 1389 00:50:19,773 --> 00:50:20,707 DESCRIBING PROBABLY ISN'T 1390 00:50:20,707 --> 00:50:24,711 SUFFICIENT TO EXPLAIN THE 1391 00:50:24,711 --> 00:50:25,212 EMBRYO GENESIS OF THIS 1392 00:50:25,212 --> 00:50:27,247 STRUCTURE. 1393 00:50:27,247 --> 00:50:28,415 THERE'S PROBABLY OTHER 1394 00:50:28,415 --> 00:50:29,516 GRADIENTS INVOLVED BUT PROBABLY 1395 00:50:29,516 --> 00:50:31,451 SUFFICIENT TO MAINTAIN THE 1396 00:50:31,451 --> 00:50:32,385 ADULT TISSUE. 1397 00:50:32,385 --> 00:50:34,020 THE SECOND QUESTION YOU ASKED, 1398 00:50:34,020 --> 00:50:35,455 I HAVE LOOKED AT CHEMICAL 1399 00:50:35,455 --> 00:50:38,458 SPACE, RIGHT, I SEE THIS WEAK 1400 00:50:38,458 --> 00:50:38,858 DORSAL TO VENTRAL 1401 00:50:38,858 --> 00:50:41,728 DIFFERENTIATION. 1402 00:50:41,728 --> 00:50:43,129 BUT THERE'S MANY OTHER AXIS 1403 00:50:43,129 --> 00:50:44,998 THEY COULD BE ORGANIZED IS IT 1404 00:50:44,998 --> 00:50:47,100 POSSIBLE THOSE ARE ORGANIZED IN 1405 00:50:47,100 --> 00:50:47,300 SPACE. 1406 00:50:47,300 --> 00:50:49,002 MY ANSWER IS YES THAT IS 1407 00:50:49,002 --> 00:50:49,769 ABSOLUTELY POSSIBLE, WE ARE 1408 00:50:49,769 --> 00:50:51,838 LOOKING AT THAT NOW. 1409 00:50:51,838 --> 00:50:53,240 WE ARE CONTINUALLY GENERATING 1410 00:50:53,240 --> 00:50:55,675 THIS FOR DIFFERENT CATEGORIES 1411 00:50:55,675 --> 00:50:56,943 OF ODORANTS. 1412 00:50:56,943 --> 00:50:58,612 YOU MIGHT IMAGINE THERE'S 1413 00:50:58,612 --> 00:50:59,479 SPATIAL ORGANIZATION WHERE THEY 1414 00:50:59,479 --> 00:51:01,114 ARE IN THE ESPECIALLY THEME YUM. 1415 00:51:01,114 --> 00:51:03,416 ONE THING I WANT TO SAY FULL 1416 00:51:03,416 --> 00:51:04,684 DISCLOSURE SO WE ARE ON THE 1417 00:51:04,684 --> 00:51:06,987 SAME PAGE, THE SET OF RECEPTORS 1418 00:51:06,987 --> 00:51:10,290 WE IDENTIFY AS BEING ACTIVE 1419 00:51:10,290 --> 00:51:11,925 DEPENDSES ON THE CONCENTRATION 1420 00:51:11,925 --> 00:51:13,827 OF THE ODOR WE USE. 1421 00:51:13,827 --> 00:51:17,397 IT MAY NOT DEPEND ON THE ACTUAL 1422 00:51:17,397 --> 00:51:18,331 CONCENTRATIONS WE ARE TESTING. 1423 00:51:18,331 --> 00:51:20,800 WE ARE DOING IT ACROSS A RANGE 1424 00:51:20,800 --> 00:51:22,102 OF CONCENTRATIONS. 1425 00:51:22,102 --> 00:51:23,069 WE ARE AWARE THAT'S A 1426 00:51:23,069 --> 00:51:25,438 LIMITATION OF WHAT I SHOWED YOU 1427 00:51:25,438 --> 00:51:27,073 AND WE ARE THINKING ABOUT IT 1428 00:51:27,073 --> 00:51:27,707 CAREFULLY, THANK YOU FOR YOUR 1429 00:51:27,707 --> 00:51:28,508 QUESTION. 1430 00:51:28,508 --> 00:51:31,111 >> THANK YOU, BOB, THIS WAS AN 1431 00:51:31,111 --> 00:51:32,512 INSPIRING TALK AND I'M REALLY 1432 00:51:32,512 --> 00:51:33,213 PLEASED TO SHARE THE TIME WITH 1433 00:51:33,213 --> 00:51:34,881 YOU. 1434 00:51:34,881 --> 00:51:35,815 FOLLOW-UP, SIMILAR QUESTION BUT 1435 00:51:35,815 --> 00:51:37,984 MORE OF A CLINICAL BENZED. 1436 00:51:37,984 --> 00:51:40,520 -- BEND. 1437 00:51:40,520 --> 00:51:43,456 I'M CURIOUS AND HOPEFUL I WILL 1438 00:51:43,456 --> 00:51:44,424 SHARE HYPOTHESIS BUT CURIOUS 1439 00:51:44,424 --> 00:51:46,559 WHAT IT IS, IN THE ESTABLISHED 1440 00:51:46,559 --> 00:51:48,628 MODEL AND FOLLOWING INJURY, 1441 00:51:48,628 --> 00:51:53,700 THINKING OUR PATIENTS WITH PROZ 1442 00:51:53,700 --> 00:51:54,868 MIA OTHER QUALITATIVE OLFACTORY 1443 00:51:54,868 --> 00:51:56,036 DISORDERS DO YOU THINK THERE 1444 00:51:56,036 --> 00:51:57,437 MAY BE ASSOCIATION WITH 1445 00:51:57,437 --> 00:51:59,005 DISRUPTION OF THIS MAP RELATED 1446 00:51:59,005 --> 00:51:59,572 TO THEIR SYMPTOMS? 1447 00:51:59,572 --> 00:52:01,441 >> Sandeep Datta: YEAH, I THINK 1448 00:52:01,441 --> 00:52:01,975 THAT'S A REALLY WONDERFUL 1449 00:52:01,975 --> 00:52:02,409 QUESTION. 1450 00:52:02,409 --> 00:52:05,679 I THINK THE ANSWER IS YES. 1451 00:52:05,679 --> 00:52:07,213 MANY QUESTIONS, STEM CELL 1452 00:52:07,213 --> 00:52:07,947 BIOLOGY GETS CHANGED HERE A 1453 00:52:07,947 --> 00:52:09,015 LITTLE BIT. 1454 00:52:09,015 --> 00:52:11,117 IT COULD RECENTER OUR ATTENTION 1455 00:52:11,117 --> 00:52:12,285 WITH UNDERSTANDING AND 1456 00:52:12,285 --> 00:52:13,687 RESTORING THAT STEM CELL 1457 00:52:13,687 --> 00:52:14,754 BIOLOGY TO BUILD AN APPROPRIATE 1458 00:52:14,754 --> 00:52:16,556 MAP. 1459 00:52:16,556 --> 00:52:18,625 AS I TOLD YOU, IT'S ALMOST 1460 00:52:18,625 --> 00:52:20,760 CERTAIN THAT OVERALL PERCEPTION 1461 00:52:20,760 --> 00:52:21,928 DEPENDSES ON PATTERNS OF 1462 00:52:21,928 --> 00:52:22,896 ACTIVITY IN THE BULB. 1463 00:52:22,896 --> 00:52:27,133 AS I TOLD YOU, THIS ONE GENE 1464 00:52:27,133 --> 00:52:27,834 EXPRESSION PROGRAM COORDINATES 1465 00:52:27,834 --> 00:52:29,402 SPACE IN THE NOSE AND TARGETING 1466 00:52:29,402 --> 00:52:30,904 IN THE BULB. 1467 00:52:30,904 --> 00:52:32,505 SO THE STEM CELL BIOLOGY IS 1468 00:52:32,505 --> 00:52:34,607 CRITICAL AND IMPORTANT TO FOCUS 1469 00:52:34,607 --> 00:52:35,575 ON FOR THERAPEUTICS. 1470 00:52:35,575 --> 00:52:37,410 THANK YOU FOR YOUR QUESTION. 1471 00:52:37,410 --> 00:52:39,012 >> THANK YOU. 1472 00:52:39,012 --> 00:52:42,349 >> I WONDER WHETHER THE 1473 00:52:42,349 --> 00:52:43,516 CAUSATION MIGHT WORK A LITTLE 1474 00:52:43,516 --> 00:52:44,751 DIFFERENTLY FROM THE WAY YOU 1475 00:52:44,751 --> 00:52:45,852 ARE ENVISIONING IT. 1476 00:52:45,852 --> 00:52:50,056 IS IT POSSIBLE THE GLOMERULUS 1477 00:52:50,056 --> 00:52:53,593 THAT THE CELL LEACHES IS NOT 1478 00:52:53,593 --> 00:52:56,730 PRECISELY DETERMINED BUT WHICH 1479 00:52:56,730 --> 00:52:59,232 ONE IT REACHES DETERMINES, TO 1480 00:52:59,232 --> 00:53:00,900 SOME EXTENT, WHICH ODORANT 1481 00:53:00,900 --> 00:53:02,302 RECEPTOR WILL EXPRESS IN OTHER 1482 00:53:02,302 --> 00:53:03,002 FEATURES OF THE CELL? 1483 00:53:03,002 --> 00:53:03,870 >> Sandeep Datta: THAT'S A 1484 00:53:03,870 --> 00:53:05,271 GREAT QUESTION. 1485 00:53:05,271 --> 00:53:10,443 ONE MIGHT IMAGINE YOU BUILD 1486 00:53:10,443 --> 00:53:11,578 THIS TARGETING AND RETROGRADE 1487 00:53:11,578 --> 00:53:13,947 THAT TELLS YOU WHICH TO EXPRESS. 1488 00:53:13,947 --> 00:53:16,483 SORRY I WASN'T CLEAR, TURNS OUT 1489 00:53:16,483 --> 00:53:18,351 THEY ARE EXPRESSED WAY BEFORE 1490 00:53:18,351 --> 00:53:20,019 THE AXONS REACH THEIR TARGET 1491 00:53:20,019 --> 00:53:23,990 AND PEOPLE HAVE LONG THEORIZED 1492 00:53:23,990 --> 00:53:26,526 IT GOVERNS THE EXPRESSION OF 1493 00:53:26,526 --> 00:53:27,927 AXON GUIDANCE CHAINS OR GOVERNS 1494 00:53:27,927 --> 00:53:30,497 IN SOME WAY TO GET AXONS TO THE 1495 00:53:30,497 --> 00:53:31,765 RIGHT TARGET. 1496 00:53:31,765 --> 00:53:33,266 WE SHOW IT'S LARGELY NOT TRUE 1497 00:53:33,266 --> 00:53:35,268 IN THESE DATA. 1498 00:53:35,268 --> 00:53:39,139 THAT IDEA DERIVED FROM THE FACT 1499 00:53:39,139 --> 00:53:41,040 THE RECEPTOR IS CHOSEN EARLY 1500 00:53:41,040 --> 00:53:42,909 BEFORE THE AXON IS ELABORATED. 1501 00:53:42,909 --> 00:53:43,743 I THINK THAT QUESTION IS A GOOD 1502 00:53:43,743 --> 00:53:45,178 QUESTION. 1503 00:53:45,178 --> 00:53:47,080 >> I HAVE A LOT OF QUESTIONS, 1504 00:53:47,080 --> 00:53:50,784 SO I WILL ASK TWO. 1505 00:53:50,784 --> 00:53:53,219 SO ONE IS, THE PROGRAM THAT YOU 1506 00:53:53,219 --> 00:53:54,788 ARE SUGGESTING, PARTICULARLY 1507 00:53:54,788 --> 00:53:59,025 THE DEPENDENCE ON RETINOIC ACID 1508 00:53:59,025 --> 00:54:00,860 FOR DORSAL VENTRAL PATTERNING, 1509 00:54:00,860 --> 00:54:03,530 IS VERY SIMILAR, IT SOUNDS TO 1510 00:54:03,530 --> 00:54:06,065 PATTERNING FOR EXAMPLE OF THE 1511 00:54:06,065 --> 00:54:07,834 INNER EAR PRECURSOR. 1512 00:54:07,834 --> 00:54:10,170 I WAS WONDERING TO WHAT EXTENT 1513 00:54:10,170 --> 00:54:11,805 HAVE YOU LOOKED ACROSS OTHER 1514 00:54:11,805 --> 00:54:14,240 SYSTEMS IN THE BODY THAT HAVE 1515 00:54:14,240 --> 00:54:15,074 DORSAL VENTRAL PATTERNING AND 1516 00:54:15,074 --> 00:54:17,043 HAVE YOU LOOKED FOR 1517 00:54:17,043 --> 00:54:17,510 COMMONALITIES VERSUS 1518 00:54:17,510 --> 00:54:17,877 DIFFERENCES? 1519 00:54:17,877 --> 00:54:19,145 >> Sandeep Datta: THAT IS A 1520 00:54:19,145 --> 00:54:20,713 WONDERFUL QUESTION. 1521 00:54:20,713 --> 00:54:22,081 MY FRIEND AND COLLEAGUE LISA 1522 00:54:22,081 --> 00:54:24,851 GOOD RIDGE HAS A LARGE SINGLE 1523 00:54:24,851 --> 00:54:26,553 CELL SEQUENCING SET OF MANY 1524 00:54:26,553 --> 00:54:27,654 CELL TYPES IN THE EAR. 1525 00:54:27,654 --> 00:54:28,488 WE ARE BEGINNING TO THINK OF 1526 00:54:28,488 --> 00:54:29,322 THAT. 1527 00:54:29,322 --> 00:54:31,424 THE OTHER PLACE THERE ARE 1528 00:54:31,424 --> 00:54:32,592 INTERESTING SIMILARITIES IN 1529 00:54:32,592 --> 00:54:34,494 TERMS OF OVERALL ARE IN 1530 00:54:34,494 --> 00:54:38,364 D.R.G.NEURONS. 1531 00:54:38,364 --> 00:54:40,266 I DON'T HAVE ANYTHING TO SAY 1532 00:54:40,266 --> 00:54:42,836 ABOUT THAT BUT THEY ARE COMMON 1533 00:54:42,836 --> 00:54:43,570 PRINCIPLES THAT I THINK REALLY 1534 00:54:43,570 --> 00:54:44,471 MATTER. 1535 00:54:44,471 --> 00:54:48,074 WE ARE THINKING ABOUT THE 1536 00:54:48,074 --> 00:54:49,442 COMPARATIVE NARRATIVES AS WELL. 1537 00:54:49,442 --> 00:54:54,214 >> MY SECOND QUESTION, I'M AN 1538 00:54:54,214 --> 00:54:56,382 E.N.T. AND TRADITIONAL TEACHING 1539 00:54:56,382 --> 00:54:59,185 IS THAT THE OLFACTORY SENSORY 1540 00:54:59,185 --> 00:55:04,991 EPITHELIUM IS REALLY, IN HUMAN 1541 00:55:04,991 --> 00:55:06,025 LOCATED MORE IN THE -- AREA 1542 00:55:06,025 --> 00:55:08,761 OF THE NOSE. 1543 00:55:08,761 --> 00:55:10,630 HOW DOES THIS MAP CORRELATE 1544 00:55:10,630 --> 00:55:12,265 WITH THE HUMAN SENSORY 1545 00:55:12,265 --> 00:55:12,966 EPITHELIUM? 1546 00:55:12,966 --> 00:55:17,637 >> Sandeep Datta: WE HAVE BEEN 1547 00:55:17,637 --> 00:55:19,339 COLLABORATING WITH BRET 1548 00:55:19,339 --> 00:55:21,508 GOLDSTEIN AT DUKE TO DO 1549 00:55:21,508 --> 00:55:23,243 EXPERIMENTS WHICH ARE FUN. 1550 00:55:23,243 --> 00:55:26,646 MANY OTHERS ARE DOING IT, WE 1551 00:55:26,646 --> 00:55:28,515 ARE ASSEMBLING AN ATLAS, WE 1552 00:55:28,515 --> 00:55:29,649 HAVE THOUSANDS OF NEURONS IN 1553 00:55:29,649 --> 00:55:30,383 THAT ATLAS. 1554 00:55:30,383 --> 00:55:32,952 YOU WOULD EXPECT TO SEE 1555 00:55:32,952 --> 00:55:33,887 GRADIENTS OF DORSAL VENTRAL IN 1556 00:55:33,887 --> 00:55:36,189 THE HUMAN OR NOT DEPENDING THE 1557 00:55:36,189 --> 00:55:37,390 WAY THE ANATOMY IS ORGANIZED 1558 00:55:37,390 --> 00:55:39,125 AND WE ARE JUST GETTING INTO 1559 00:55:39,125 --> 00:55:40,193 THAT ANALYSIS NOW. 1560 00:55:40,193 --> 00:55:44,163 I WILL TELL YOU ABOUT A FUN 1561 00:55:44,163 --> 00:55:44,898 EXPERIMENT I'M SUPER EXCITED, 1562 00:55:44,898 --> 00:55:45,798 IT'S FUN, I THINK YOU WILL LIKE 1563 00:55:45,798 --> 00:55:46,499 IT. 1564 00:55:46,499 --> 00:55:49,435 WE ARE DOING THE FIRST 1565 00:55:49,435 --> 00:55:53,339 MOLECULAR BIOLOGY OF THE 1566 00:55:53,339 --> 00:55:54,240 NERVOUS SYSTEM IN HUMANS. 1567 00:55:54,240 --> 00:55:58,278 IN THE MOUTH WE HAVE METHOD AK 1568 00:55:58,278 --> 00:56:00,647 SEEK WHICH LET'S US KNOW WHICH 1569 00:56:00,647 --> 00:56:01,648 NEURONS ARE ACTIVATED FOR A 1570 00:56:01,648 --> 00:56:04,284 GIVEN SMELL. 1571 00:56:04,284 --> 00:56:07,253 YOU TAKE A MOUSE, GIVE IT AN 1572 00:56:07,253 --> 00:56:11,157 ODOR, KILL IT, AND SEQUENCE ITS 1573 00:56:11,157 --> 00:56:14,694 NOSE AND 200-GENE THAT TARGETS 1574 00:56:14,694 --> 00:56:16,563 ACUTE SENSORY NEURON THAT LET'S 1575 00:56:16,563 --> 00:56:19,599 US IDENTIFY ALL THE RECEPTORS 1576 00:56:19,599 --> 00:56:21,301 ACTIVATED AND HOW MUCH THEY ARE 1577 00:56:21,301 --> 00:56:22,468 ACTIVATED. 1578 00:56:22,468 --> 00:56:24,804 TURNS OUT THAT WORKS IN HUMANS. 1579 00:56:24,804 --> 00:56:29,242 WE HAVE BEEN GIVING SMELLS TO 1580 00:56:29,242 --> 00:56:30,610 PATIENTS, LEMON, ORANGE, PIZZA, 1581 00:56:30,610 --> 00:56:32,979 LET THEM SMELL FOR 30 MINUTES, 1582 00:56:32,979 --> 00:56:35,114 WE TAKE A BIOPSY OF THE NOSE 1583 00:56:35,114 --> 00:56:37,684 AND SEQUENCE THE SMELLS AND GET 1584 00:56:37,684 --> 00:56:38,284 THE SAME MOLECULAR SIGNATURES 1585 00:56:38,284 --> 00:56:39,352 BACK. 1586 00:56:39,352 --> 00:56:43,423 THIS PROVES THE IMMEDIATE FOSS 1587 00:56:43,423 --> 00:56:45,725 PROPOSED UBIQUITOUS MARKER OF 1588 00:56:45,725 --> 00:56:48,528 ACTIVITY BY GREENBERG IN 1984 1589 00:56:48,528 --> 00:56:50,296 IS BY NEURAL ACTIVITY IN HUMAN, 1590 00:56:50,296 --> 00:56:53,466 WE SEE A RESPONSE TO A REAL 1591 00:56:53,466 --> 00:56:55,802 CUE, WE THINK THIS COULD BE 1592 00:56:55,802 --> 00:56:59,305 HELPFUL AS USING THE NOSE AS 1593 00:56:59,305 --> 00:57:02,542 BIOMARKER, AFFECTED IN 1594 00:57:02,542 --> 00:57:03,276 PSYCHIATRIC DISORDERS AND 1595 00:57:03,276 --> 00:57:05,111 NEURODEGENERATIVE DISORDERS. 1596 00:57:05,111 --> 00:57:06,045 SENSITIVE TO IMMUNITY. 1597 00:57:06,045 --> 00:57:08,381 IT COULD BE A NEAT WAY OF 1598 00:57:08,381 --> 00:57:11,351 GETTING AT THE UNDERLYING 1599 00:57:11,351 --> 00:57:11,884 MOLECULAR VARIATION AT 1600 00:57:11,884 --> 00:57:13,686 DIFFERENT DISEASE STATES. 1601 00:57:13,686 --> 00:57:14,754 WE ARE BEGINNING TO THINK ABOUT 1602 00:57:14,754 --> 00:57:15,121 THAT AS WELL. 1603 00:57:15,121 --> 00:57:16,522 >> THANK YOU. 1604 00:57:16,522 --> 00:57:17,457 >> HI, GREAT TALK. 1605 00:57:17,457 --> 00:57:23,162 I WAS THINKING ABOUT YOUR 1606 00:57:23,162 --> 00:57:24,130 TRANSCRIPTION FACTOR BINDING 1607 00:57:24,130 --> 00:57:27,000 DATA, YOU ONLY LOOKED AT 1,000, 1608 00:57:27,000 --> 00:57:29,869 I WAS WONDERING IF YOU HAVE 1609 00:57:29,869 --> 00:57:30,670 CHROMATIN LOOPING DATA? 1610 00:57:30,670 --> 00:57:34,273 >> Sandeep Datta: YEAH, MY 1611 00:57:34,273 --> 00:57:39,178 FRIEND AND COLLEAGUE VARTIS AT 1612 00:57:39,178 --> 00:57:41,914 COLUMBIA IS EXPERT LOOKING AT 1613 00:57:41,914 --> 00:57:44,317 WITH RESPECT TO ODORANT 1614 00:57:44,317 --> 00:57:47,520 RECEPTOR GENES IN MATURE 1615 00:57:47,520 --> 00:57:51,190 OLFACTORY SENSORY NEURONS. 1616 00:57:51,190 --> 00:57:53,760 STAVROS THINKS THEY HAPPEN IN 1617 00:57:53,760 --> 00:57:55,161 WINDOW, PERHAPS UPSTREAM BUT 1618 00:57:55,161 --> 00:57:57,697 HIS DATA GUIDED BY HIS WORK, WE 1619 00:57:57,697 --> 00:58:00,967 THINK PRET WHY MUCH THINGS ARE 1620 00:58:00,967 --> 00:58:02,602 CLOSE BY THE O.R. 1621 00:58:02,602 --> 00:58:04,704 THESE ARE THE FASTEST EVOLVING 1622 00:58:04,704 --> 00:58:09,208 GENES IN YOUR GENOME, ALMOST AS 1623 00:58:09,208 --> 00:58:11,277 FAST EVOLVING AS THE IMMUNE 1624 00:58:11,277 --> 00:58:13,646 SYSTEM, THEY EVOLVE THROUGH 1625 00:58:13,646 --> 00:58:14,814 DUPLICATION AND THEN VARIATION. 1626 00:58:14,814 --> 00:58:19,352 YOU KIND OF WANT, IF YOU 1627 00:58:19,352 --> 00:58:20,787 DUPLICATE GENE FAMILY RAPIDLY 1628 00:58:20,787 --> 00:58:23,089 YOU WANT THINGS CLOSE BY TO 1629 00:58:23,089 --> 00:58:26,292 COPY THEM N SO THINGS AREN'T 1630 00:58:26,292 --> 00:58:28,227 BROKEN FREQUENTLY BY EVOLUTION. 1631 00:58:28,227 --> 00:58:29,729 THAT'S THE PRESSURE THAT GUIDES 1632 00:58:29,729 --> 00:58:30,329 THIS PARTICULAR ARCHITECTURE. 1633 00:58:30,329 --> 00:58:31,464 >> THANKS. 1634 00:58:31,464 --> 00:58:33,866 >> CAN I ASK A COUPLE QUESTIONS 1635 00:58:33,866 --> 00:58:35,201 FROM ONLINE? 1636 00:58:35,201 --> 00:58:36,135 IT'S BEEN BUILDING UP. 1637 00:58:36,135 --> 00:58:38,938 THERE'S A QUESTION ABOUT THE 1638 00:58:38,938 --> 00:58:44,744 ALZHEIMER'S DISEASE AND COVID 1639 00:58:44,744 --> 00:58:45,845 CONNECTION TO ANSOMIA. 1640 00:58:45,845 --> 00:58:46,846 WHAT CAN YOU SAY ABOUT THAT? 1641 00:58:46,846 --> 00:58:50,516 >> Sandeep Datta: WE WERE 1642 00:58:50,516 --> 00:58:52,618 ACCUMULATING LARGE DATASET OF 1643 00:58:52,618 --> 00:58:54,687 5.5 MILLION CELLS WHEN COVID 1644 00:58:54,687 --> 00:58:56,122 BROKE OUT. 1645 00:58:56,122 --> 00:58:58,291 WE HAD THE HALF MILLION AND 1646 00:58:58,291 --> 00:59:00,526 HUMAN DATA WE WERE ABLE TO LOOK 1647 00:59:00,526 --> 00:59:02,528 THROUGH THOSE DATA AND COME UP 1648 00:59:02,528 --> 00:59:05,098 WITH A HYPOTHESIS HOW COVID 1649 00:59:05,098 --> 00:59:11,070 MIGHT AFFECT THE SMELL. 1650 00:59:11,070 --> 00:59:13,539 WE BELIEVE BECAUSE THE VIRUS 1651 00:59:13,539 --> 00:59:15,041 ATTACKS THE SUPPORT CELLS BUT 1652 00:59:15,041 --> 00:59:18,044 NOT NEURONS DIRECTLY. 1653 00:59:18,044 --> 00:59:21,748 IN PART EXPLAINS WHY PEOPLE 1654 00:59:21,748 --> 00:59:23,850 TEND TO RECOVER THEIR SENSE OF 1655 00:59:23,850 --> 00:59:25,251 SMELL, THE NERVE CELLS ARE A 1656 00:59:25,251 --> 00:59:27,320 FEKTD BUT WHEN THE WHOLE SYSTEM 1657 00:59:27,320 --> 00:59:29,655 IS CLEAR IT CAN RECOVER. 1658 00:59:29,655 --> 00:59:31,724 FOR ALZHEIMER'S, WE STILL DON'T 1659 00:59:31,724 --> 00:59:34,994 UNDERSTAND THE LEVEL WHICH 1660 00:59:34,994 --> 00:59:35,495 ALZHEIMER'S AFFECTS THE 1661 00:59:35,495 --> 00:59:36,863 OLFACTORY SYSTEM. 1662 00:59:36,863 --> 00:59:38,498 IT'S A HARBINGER, IF YOU LOSE 1663 00:59:38,498 --> 00:59:41,734 YOUR SENSE OF SMELL IT'S 1664 00:59:41,734 --> 00:59:42,902 HARBINGER FOR FUTURE 1665 00:59:42,902 --> 00:59:43,603 DEGENERATIVE DISEASE, RELATIVE 1666 00:59:43,603 --> 00:59:45,238 RISK IS TEN TIMES. 1667 00:59:45,238 --> 00:59:46,873 IF YOU HAVE M.C.I. AND LOSE 1668 00:59:46,873 --> 00:59:48,975 YOUR SENSE OF SMELL. 1669 00:59:48,975 --> 00:59:52,111 MY DAD HAS PARKINSON'S, HE WAS 1670 00:59:52,111 --> 00:59:54,914 ANOSMIC TEN YEARS BEFORE HE 1671 00:59:54,914 --> 00:59:57,583 DEVELOPED P FULL BLOWN 1672 00:59:57,583 --> 00:59:58,451 PARKINSON'S. 1673 00:59:58,451 --> 01:00:00,787 IT HAS SOMETHING TO DO WITH THE 1674 01:00:00,787 --> 01:00:04,423 FACT THE SMELL CENTERS ARE IN 1675 01:00:04,423 --> 01:00:05,525 THE TEMPORAL LOBE. 1676 01:00:05,525 --> 01:00:07,126 I WOULD SAY WE DON'T FULLY 1677 01:00:07,126 --> 01:00:08,361 UNDERSTAND IT. 1678 01:00:08,361 --> 01:00:10,229 >> OKAY, ONE MORE UP THERE AND 1679 01:00:10,229 --> 01:00:11,063 ONE MORE BACK ONLINE. 1680 01:00:11,063 --> 01:00:13,166 >> HI. 1681 01:00:13,166 --> 01:00:14,300 >> Sandeep Datta: HI. 1682 01:00:14,300 --> 01:00:17,336 >> I WAS JUST THINKING THAT 1683 01:00:17,336 --> 01:00:20,173 THERE'S SOME NEURODEVELOPMENTAL 1684 01:00:20,173 --> 01:00:21,574 DISORDERS CHARACTERIZED BY 1685 01:00:21,574 --> 01:00:22,775 FAULTY MIGRATION OF STEM CELLS 1686 01:00:22,775 --> 01:00:24,377 AND I THINK IT WOULD BE REALLY 1687 01:00:24,377 --> 01:00:26,245 INTERESTING TO LOOK AT IF 1688 01:00:26,245 --> 01:00:29,482 THAT'S SOMETHING THAT OCCURS 1689 01:00:29,482 --> 01:00:32,585 WHEN EVEN ADULTHOOD AND THOSE 1690 01:00:32,585 --> 01:00:33,052 INDIVIDUALS WITH 1691 01:00:33,052 --> 01:00:34,887 NEURODEVELOPMENTAL DISORDERS IF 1692 01:00:34,887 --> 01:00:37,456 THAT IMPACTS THE MIGRATION AND 1693 01:00:37,456 --> 01:00:38,391 OLFACTORY ABILITIES AND 1694 01:00:38,391 --> 01:00:40,359 RECEPTOR EXPRESSION ON THAT 1695 01:00:40,359 --> 01:00:40,960 DORSAL VENTRAL AXIS. 1696 01:00:40,960 --> 01:00:43,329 >> Sandeep Datta: I THINK WE 1697 01:00:43,329 --> 01:00:45,198 DON'T UNDERSTAND THERE'S THESE 1698 01:00:45,198 --> 01:00:48,701 STEM CELLS THAT GENERATE 1699 01:00:48,701 --> 01:00:50,570 NEURONS AND WE DON'T UNDERSTAND 1700 01:00:50,570 --> 01:00:52,905 HOW FAR THEY MIGRATE, THE WAYS 1701 01:00:52,905 --> 01:00:55,007 IN WHICH MAYBE A RECEPTOR 1702 01:00:55,007 --> 01:00:56,175 GENERATED BY THE STEM CELL 1703 01:00:56,175 --> 01:00:58,010 MIGHT CHANGE THE WAY IT IS SOME 1704 01:00:58,010 --> 01:00:59,445 SPACE AND HOW MUCH THAT 1705 01:00:59,445 --> 01:01:01,080 INTRODUCES NOISE IN THE SYSTEM 1706 01:01:01,080 --> 01:01:02,782 AND HOW MUCH THE MIGRATION IS 1707 01:01:02,782 --> 01:01:05,785 PRECISE. 1708 01:01:05,785 --> 01:01:06,352 YOUR SUGGESTION IS VERY 1709 01:01:06,352 --> 01:01:07,153 INTERESTING. 1710 01:01:07,153 --> 01:01:08,988 I WILL MENTION ONE OTHER THING 1711 01:01:08,988 --> 01:01:10,189 YOU MIGHT FIND INTERESTING. 1712 01:01:10,189 --> 01:01:12,892 I TOLD YOU THERE WERE SEVEN 1713 01:01:12,892 --> 01:01:13,693 GENE EXPRESSION PROGRAMS. 1714 01:01:13,693 --> 01:01:16,495 TURNS OUT TWO WE PUBLISHED ON A 1715 01:01:16,495 --> 01:01:18,064 PAPER TWO YEARS AGO ACTUALLY 1716 01:01:18,064 --> 01:01:20,466 ENCODE A PROGRAM THAT ADAPTS 1717 01:01:20,466 --> 01:01:23,236 THE CELL TO LEVELS OF ONGOING 1718 01:01:23,236 --> 01:01:24,437 NEURAL ACTIVITY. 1719 01:01:24,437 --> 01:01:26,739 I DON'T WANT TO EXPLAIN IN ANY 1720 01:01:26,739 --> 01:01:27,974 DETAIL BUT ONE IMPORTANT THING 1721 01:01:27,974 --> 01:01:31,644 ABOUT IT, IF YOU LOOK AT A.D.. 1722 01:01:31,644 --> 01:01:33,980 S.D. MODELS GENES INVOLVED IN 1723 01:01:33,980 --> 01:01:36,549 A.S.D. ARE MUTATED WE KNOW 1724 01:01:36,549 --> 01:01:39,118 THOSE ANIMALS AND PATIENTS ARE 1725 01:01:39,118 --> 01:01:41,687 HYPE SENSITIVE, TURNS OUT THAT 1726 01:01:41,687 --> 01:01:42,822 BROKE OLFACTORY SENSORY NEURONS. 1727 01:01:42,822 --> 01:01:45,324 WE THINK HOW THESE GENE 1728 01:01:45,324 --> 01:01:46,993 EXPRESSION PROGRAMS MIGHT SERVE 1729 01:01:46,993 --> 01:01:48,394 DIFFERENT FUNCTIONS IN THE CELL 1730 01:01:48,394 --> 01:01:49,328 AND RELATE TO DISEASE. 1731 01:01:49,328 --> 01:01:50,930 THIS IS ONE EXAMPLE OF THAT. 1732 01:01:50,930 --> 01:01:51,430 >> THAT'S AWESOME. 1733 01:01:51,430 --> 01:01:53,132 THANK YOU. 1734 01:01:53,132 --> 01:01:55,368 >> MAYBE CLOSE WITH THIS ONE 1735 01:01:55,368 --> 01:01:55,968 QUESTION, GENERALLY SPEAKING, 1736 01:01:55,968 --> 01:01:57,970 THE IMPORTANCE OF THE KIND OF 1737 01:01:57,970 --> 01:02:00,106 ANIMAL STUDIES YOU DO, AND 1738 01:02:00,106 --> 01:02:03,209 WHAT'S POSSIBLE AND NOT 1739 01:02:03,209 --> 01:02:04,644 POSSIBLE WITH NON-ANIMAL MODELS 1740 01:02:04,644 --> 01:02:06,545 THAT PEOPLE WANT TO TRANSITION 1741 01:02:06,545 --> 01:02:08,347 TO? 1742 01:02:08,347 --> 01:02:09,916 >> Sandeep Datta: THANK YOU FOR 1743 01:02:09,916 --> 01:02:11,150 THAT QUESTION. 1744 01:02:11,150 --> 01:02:14,787 MY LAB DOES A LOT OF 1745 01:02:14,787 --> 01:02:15,721 COMPUTATIONAL WORK AND MODELING 1746 01:02:15,721 --> 01:02:17,556 OF THE NERVOUS SYSTEM. 1747 01:02:17,556 --> 01:02:18,658 THAT'S A MAIN STAY OF WHAT WE 1748 01:02:18,658 --> 01:02:19,825 DO. 1749 01:02:19,825 --> 01:02:21,694 AT LEAST FOR THE NERVOUS SYSTEM 1750 01:02:21,694 --> 01:02:24,964 I WOULD ARGUE WE ARE NOT AT A 1751 01:02:24,964 --> 01:02:27,433 PLACE WE CAN SUBSTITUTE ANIMAL 1752 01:02:27,433 --> 01:02:28,034 RESEARCH. 1753 01:02:28,034 --> 01:02:29,635 NONE OF THE THINGS I TALKED 1754 01:02:29,635 --> 01:02:32,838 ABOUT TODAY, NONE OF THESE 1755 01:02:32,838 --> 01:02:35,374 INSIGHTS WOULD BE POSSIBLE 1756 01:02:35,374 --> 01:02:38,644 WITHOUT ACCESS TO INVIVO MODELS. 1757 01:02:38,644 --> 01:02:41,480 WE DON'T HAVE THE TRAINING DATA 1758 01:02:41,480 --> 01:02:44,850 YET TO BUILD SOPHISTICATED 1759 01:02:44,850 --> 01:02:46,686 MODELS OF NERVOUS SYSTEM. 1760 01:02:46,686 --> 01:02:47,553 EVERYONE WORKING WITH THAT 1761 01:02:47,553 --> 01:02:48,654 WOULD AGREE. 1762 01:02:48,654 --> 01:02:50,890 I THINK BRAINS ARE EMBODIED. 1763 01:02:50,890 --> 01:02:52,291 I MENTIONED AT THE BEGINNING I 1764 01:02:52,291 --> 01:02:53,926 THINK OF THE RELATIONSHIP 1765 01:02:53,926 --> 01:02:54,860 BETWEEN BRAEN AND NATURAL 1766 01:02:54,860 --> 01:02:59,031 BEHAVIOR IN THE WORLD. 1767 01:02:59,031 --> 01:02:59,932 IT'S HELPING YOU NAVIGATE A 1768 01:02:59,932 --> 01:03:01,233 WORLD WHICH YOU HAVE A BODY 1769 01:03:01,233 --> 01:03:03,102 THAT'S REAL. 1770 01:03:03,102 --> 01:03:03,936 SEPARATING THAT BODY AWAY FROM 1771 01:03:03,936 --> 01:03:05,805 THE BRAIN, I THINK, FROM A 1772 01:03:05,805 --> 01:03:06,906 RESEARCH PERSPECTIVE IS A BIG 1773 01:03:06,906 --> 01:03:08,140 MISTAKE. 1774 01:03:08,140 --> 01:03:13,112 I WOULD ARGUE WHILE IT'S A AN 1775 01:03:13,112 --> 01:03:16,582 IDEAL GOAL SILICON, TOXICITY 1776 01:03:16,582 --> 01:03:18,951 MAY BE CANCEROUS YOU COULD DO 1777 01:03:18,951 --> 01:03:20,553 THAT, FOR NEUROSCIENCE WE 1778 01:03:20,553 --> 01:03:23,289 SHOULD INVEST HEAVILY IN ANIMAL 1779 01:03:23,289 --> 01:03:24,290 RESEARCH WHILE ENCOURAGING 1780 01:03:24,290 --> 01:03:33,332 PEOPLE TO THINK OF ANSILICAL. 1781 01:03:33,332 --> 01:03:34,934 >> THANK YOU. 1782 01:03:34,934 --> 01:03:37,036 THERE'S A RECEPTION OUT THERE. 1783 01:03:37,036 --> 01:03:37,570 LET'S THANK THE SPEAKER. 1784 01:03:37,570 --> 01:03:38,804 >> Sandeep Datta: THANK YOU ALL 1785 01:03:38,804 --> 01:03:40,106 FOR YOUR TIME. 1786 01:03:40,106 --> 01:03:48,914 [ APPLAUSE ]