1 00:00:05,560 --> 00:00:08,320 I'M KEN JACOBSON OF THE NATIONAL 2 00:00:08,320 --> 00:00:10,360 DIABETES AND 3 00:00:10,360 --> 00:00:11,120 DIGESTIVE AND KIDNEY DISEASES 4 00:00:11,120 --> 00:00:15,000 AND I WOULD LIKE TO WELCOME YOU 5 00:00:15,000 --> 00:00:17,600 TO THE 2023 JOHN DALY LECTURE. 6 00:00:17,600 --> 00:00:19,920 THE WE'VE HELD THIS ANNUAL 7 00:00:19,920 --> 00:00:22,920 LECTURE SINCE 209, A YEAR AFTER 8 00:00:22,920 --> 00:00:25,440 JOHN DALY DIED. 9 00:00:25,440 --> 00:00:26,520 THE NIDDK INTRAMURAL RESEARCH 10 00:00:26,520 --> 00:00:28,880 PROGRAM AND THE LABORATORY OF 11 00:00:28,880 --> 00:00:29,920 BIOORGANIC CHEMISTRY TO WHICH I 12 00:00:29,920 --> 00:00:32,560 BELONG AND NOW HEADED BY CAROL 13 00:00:32,560 --> 00:00:34,320 [INDISCERNIBLE] ARE PLEASED TO 14 00:00:34,320 --> 00:00:37,920 NOW RESUME THIS TRADITION POST 15 00:00:37,920 --> 00:00:38,120 COVID. 16 00:00:38,120 --> 00:00:41,000 THIS EVEN SERVES TO HONOR JOHN'S 17 00:00:41,000 --> 00:00:43,960 MEMORY BY RECOGNIZING LEADING 18 00:00:43,960 --> 00:00:46,840 RECEPTOR AND NATURAL PRODUCT 19 00:00:46,840 --> 00:00:49,800 RESEARCHERS SUCH AS BRIAN ROTH 20 00:00:49,800 --> 00:00:56,160 WHO TYPIFIED JOHN DALY'S 21 00:00:56,160 --> 00:00:57,320 SCIENTIFIC IDEALS. 22 00:00:57,320 --> 00:00:59,800 AND WE'VE ALSO RANGED FOR 23 00:00:59,800 --> 00:01:01,880 TROPICAL WEATHER TO GIVE YOU THE 24 00:01:01,880 --> 00:01:06,880 IDEA OF JOHN DALY IN THE RAIN 25 00:01:06,880 --> 00:01:07,320 FOREST. 26 00:01:07,320 --> 00:01:11,920 JOHN W. DALY WAS A PIONEER IN 27 00:01:11,920 --> 00:01:13,520 NATURAL PRODUCTS AND 28 00:01:13,520 --> 00:01:14,560 PHARMAICOLOGGIC RESEARCH FOR 29 00:01:14,560 --> 00:01:20,560 NEARLY 50 YEARS, CAN YOU SO 30 00:01:20,560 --> 00:01:22,560 PHOTOS OF HIS ILLUSTRIUS CAREER 31 00:01:22,560 --> 00:01:22,880 AT NIH. 32 00:01:22,880 --> 00:01:25,520 HE WAS AN INSPIRING MENTOR AND 33 00:01:25,520 --> 00:01:27,800 FRIEND TO MANY NIDDK CHEMISTS. 34 00:01:27,800 --> 00:01:30,800 HE CAME TO NIH AS A POST DOC 35 00:01:30,800 --> 00:01:32,840 WORKING WITH [INDISCERNIBLE] AND 36 00:01:32,840 --> 00:01:37,120 HE LEARNED PHARMACOLOGY FROM THE 37 00:01:37,120 --> 00:01:40,800 NIMH NOBEL LAUREATE JULIUS 38 00:01:40,800 --> 00:01:42,520 AXELROD, HE WAS WELL KNOWN FOR 39 00:01:42,520 --> 00:01:46,440 HIS WORK ON FROG ALKALOIDS, 40 00:01:46,440 --> 00:01:47,680 TOXINS, METABOLISM, SECOND 41 00:01:47,680 --> 00:01:50,400 MESSENGER PATHWAYS, ION CHANNELS 42 00:01:50,400 --> 00:01:52,800 AND NEUROTRANSMITTER RECEPTORS. 43 00:01:52,800 --> 00:01:54,320 HE INTRODUCED MANY OF THE 44 00:01:54,320 --> 00:01:57,240 CENTRAL TOOLS FOR 45 00:01:57,240 --> 00:01:58,200 PHARMAICOLOGICAL RESEARCH, SUCH 46 00:01:58,200 --> 00:02:00,920 AS [INDISCERNIBLE] THE ACTIVATOR 47 00:02:00,920 --> 00:02:04,560 OF ADEN LATE CYCLE ACE, 48 00:02:04,560 --> 00:02:05,360 NICOTINIC AGONIST AND 49 00:02:05,360 --> 00:02:07,240 [INDISCERNIBLE] 1 OF THE MOST 50 00:02:07,240 --> 00:02:10,760 TOXIC SUBSTANCES KNOWN TO HUMAN 51 00:02:10,760 --> 00:02:11,320 KIND. 52 00:02:11,320 --> 00:02:12,920 JOHN WAS PASSIONATE ABOUT 53 00:02:12,920 --> 00:02:16,800 RESEARCH ON GPROTEIN COUPLES 54 00:02:16,800 --> 00:02:18,120 RECEPTORS, THAT IS GPC Rs AND 55 00:02:18,120 --> 00:02:21,040 THE CONCEPT OF STRUCTURE 56 00:02:21,040 --> 00:02:22,320 ACTIVITY RELATIONSHIP IN 57 00:02:22,320 --> 00:02:23,120 MEDICINAL CHEMISTRY. 58 00:02:23,120 --> 00:02:24,760 HE WAS 1 OF THE FIRST TO 59 00:02:24,760 --> 00:02:27,440 RECOGNIZE THAT EACH PART OF A 60 00:02:27,440 --> 00:02:30,400 MOLECULE SERVES ITS OWN ROLE IN 61 00:02:30,400 --> 00:02:30,920 BIOLOGICAL INTERACTIONS. 62 00:02:30,920 --> 00:02:34,720 WHICH ARE NOW BEING REVEALED IN 63 00:02:34,720 --> 00:02:37,520 EXQUISITE AND DYNAMIC DETAIL BY 64 00:02:37,520 --> 00:02:39,680 STRUCTURAL STUDIES. 65 00:02:39,680 --> 00:02:41,400 HE EXPLORED INTRACELLULAR 66 00:02:41,400 --> 00:02:44,280 SIGNALING PATHWAYS INDUCED BY 67 00:02:44,280 --> 00:02:45,640 NATURAL SUBSTANCES, FROM FLORA 68 00:02:45,640 --> 00:02:47,600 AND FAUNA WHICH HE AVIDLY 69 00:02:47,600 --> 00:02:50,320 COLLECTED IN THE JUNGLES OF 70 00:02:50,320 --> 00:02:52,560 SOUTH AND CENTRAL AMERICA, MAD 71 00:02:52,560 --> 00:02:58,960 GAS CAR AND AUSTRALIA, EVEN IN 72 00:02:58,960 --> 00:03:00,640 HIS FINAL YEARS. 73 00:03:00,640 --> 00:03:03,880 THIS YEAR'S RECIPIENT DR. BRIAN 74 00:03:03,880 --> 00:03:06,400 ROTH, MD Ph.D. IS AT THE 75 00:03:06,400 --> 00:03:08,240 FOREFRONT OF BOTH FORMA LOGICAL 76 00:03:08,240 --> 00:03:10,520 AND STRUCTURAL RESEARCH ON GPC 77 00:03:10,520 --> 00:03:10,960 Rs. 78 00:03:10,960 --> 00:03:13,800 HE IS THE MICHAEL HOOKER 79 00:03:13,800 --> 00:03:14,760 DISTINGUISHED PROFESSOR OF 80 00:03:14,760 --> 00:03:15,680 PHARMACOLOGY AT THE UNIVERSITY 81 00:03:15,680 --> 00:03:17,880 OF NORTH CAROLINA SCHOOL OF 82 00:03:17,880 --> 00:03:19,280 MEDICINE AT CHAPEL HILL. 83 00:03:19,280 --> 00:03:20,920 HE COMPLETED HIS DOCTORAL 84 00:03:20,920 --> 00:03:22,560 STUDIES AT ST. LEWIS UNIVERSITY 85 00:03:22,560 --> 00:03:26,760 SCHOOL OF MEDICINE IN 1983, AND 86 00:03:26,760 --> 00:03:29,120 SUBSEQUENTLY TRAINED IN 87 00:03:29,120 --> 00:03:31,640 PHARMAICOLOGY AT NIMH AND THEN, 88 00:03:31,640 --> 00:03:33,800 IN MOLECULAR BIOLOGY AND 89 00:03:33,800 --> 00:03:34,680 PSYCHIATRY AT STANFORD. 90 00:03:34,680 --> 00:03:37,520 HE ACHIEVED THE RANK OF FULL 91 00:03:37,520 --> 00:03:39,000 PROFESSOR OF PSYCHIATRY AND 92 00:03:39,000 --> 00:03:42,760 BIOCHEMISTRY AT CASE WESTERN 93 00:03:42,760 --> 00:03:43,920 RESERVE UNIVERSITY SCHOOL OF 94 00:03:43,920 --> 00:03:45,680 MEDICINE IN CLEVELAND BEFORE 95 00:03:45,680 --> 00:03:48,640 JOINING UNC. 96 00:03:48,640 --> 00:03:50,880 HIS CLINICAL SPECIALTY WAS 97 00:03:50,880 --> 00:03:51,480 TREATMENT RESISTANT 98 00:03:51,480 --> 00:03:52,680 SCHIZOPHRENIA, WHICH HAS LED TO 99 00:03:52,680 --> 00:03:54,720 A BROAD RESEARCH FOCUS ON GPC 100 00:03:54,720 --> 00:03:58,480 Rs AS THE TARGET OF 101 00:03:58,480 --> 00:03:59,920 PSYCHOACTIVE SUBSTANCES. 102 00:03:59,920 --> 00:04:01,560 DR. ROTH AS PUBLISHED ROUGHLY 103 00:04:01,560 --> 00:04:05,800 500 PAPERS IN DIVERSE AREAS OF 104 00:04:05,800 --> 00:04:06,600 MOLECULAR PHARMACOLOGY, 105 00:04:06,600 --> 00:04:08,200 STRUCTURAL BIOLOGY AND SYNTHETIC 106 00:04:08,200 --> 00:04:11,600 BIOLOGY WHICH ARE TYPICALLY 107 00:04:11,600 --> 00:04:16,320 CITED 8000 TIMES A YEAR AND HIS 108 00:04:16,320 --> 00:04:17,120 H-INDEX IS 141. 109 00:04:17,120 --> 00:04:19,800 PERHAPS HE IS BEST KNOWN FOR THE 110 00:04:19,800 --> 00:04:23,240 CHEMO GENETIC PLATFORM 111 00:04:23,240 --> 00:04:25,280 ABBREVIATED DREAD DESIGNER 112 00:04:25,280 --> 00:04:27,840 RECEPTOR EXCLUSIVELY ACTIVATED 113 00:04:27,840 --> 00:04:30,080 BY DESIGNER DRUGS THAT IS WIDELY 114 00:04:30,080 --> 00:04:33,160 USED IN NEUROSCIENCE AND 115 00:04:33,160 --> 00:04:34,960 PSYCHOLOGY LABS AND FOR TD 116 00:04:34,960 --> 00:04:37,000 RECENT ELUCIDATION OF RECEPTOR 117 00:04:37,000 --> 00:04:40,520 STRUCTURES TARGETED BY DRUGS OF 118 00:04:40,520 --> 00:04:43,040 ABUSE AND ANTIPSYCHOTIC DRUGS. 119 00:04:43,040 --> 00:04:45,800 BRIAN ALSO OPERATES THE PDSP, IF 120 00:04:45,800 --> 00:04:47,920 YOU DON'T KNOW WHAT IT STANDS 121 00:04:47,920 --> 00:04:50,120 FOR IT'S THE PSYCHOACTIVE DRUG 122 00:04:50,120 --> 00:04:52,240 SCREENING PROGRAM AT UNC 123 00:04:52,240 --> 00:04:54,080 SPONSORED BY NIMH AS A KIND OF 124 00:04:54,080 --> 00:04:56,280 SERVICE TO THE FIELD WHICH 125 00:04:56,280 --> 00:04:59,720 ALLOWS MANY RESEARCHERS TO 126 00:04:59,720 --> 00:05:01,760 EXPLORE THE POLYPHARMAICOLOGY OF 127 00:05:01,760 --> 00:05:04,520 THEIR FAVORITE CNS ACTIVE 128 00:05:04,520 --> 00:05:05,480 MOLECULES. 129 00:05:05,480 --> 00:05:06,520 HIS LECTURE THEMEATICALLY MERGES 130 00:05:06,520 --> 00:05:10,080 2 OF JOHN'S INTERESTS AND IS 131 00:05:10,080 --> 00:05:13,520 TITLED NATURAL PRODUCTS REVEALED 132 00:05:13,520 --> 00:05:15,200 RECEPTORS FOR PERCEPTION. 133 00:05:15,200 --> 00:05:16,960 AFTER THE LECTURE A QUESTION AND 134 00:05:16,960 --> 00:05:19,240 ANSWER PERIOD, WE WILL HOLD A 135 00:05:19,240 --> 00:05:21,960 RECEPTION WITH BRIAN OUTSIDE 136 00:05:21,960 --> 00:05:23,040 THIS HALL. 137 00:05:23,040 --> 00:05:26,080 IT IS NOW MY DISTINCT HONOR IS 138 00:05:26,080 --> 00:05:28,200 PLEASURE TO INVITE DR. BRIAN 139 00:05:28,200 --> 00:05:30,640 ROTH TO RECEIVE THE AWARD PLAQUE 140 00:05:30,640 --> 00:05:34,680 AND TO DELIVER THE 2023 JOHN 141 00:05:34,680 --> 00:05:35,800 DALY LECTURE. 142 00:05:35,800 --> 00:05:48,080 [ APPLAUSE ] 143 00:05:48,080 --> 00:05:56,160 >>THANKS SO MUCH 144 00:05:56,160 --> 00:05:57,360 FOR THE WONDERFUL INTRODUCTION 145 00:05:57,360 --> 00:05:58,880 AND THE OPPORTUNITY TO VISIT NIH 146 00:05:58,880 --> 00:06:00,560 AGAIN, IT'S BEEN A WHILE SINCE 147 00:06:00,560 --> 00:06:02,880 I'VE BEEN HERE BEFORE COVID. 148 00:06:02,880 --> 00:06:05,480 AND IT'S WONDERFUL TO SEE PEOPLE 149 00:06:05,480 --> 00:06:07,560 IN THE FLESH AS WE SAY. 150 00:06:07,560 --> 00:06:09,800 SO THIS IS A FIGURE THAT WAS 151 00:06:09,800 --> 00:06:16,080 MADE BY A POST DOC OF MINE RYAN 152 00:06:16,080 --> 00:06:16,800 GUMPER. 153 00:06:16,800 --> 00:06:23,200 I FOUND OUT LAST WEEK AT OUR 154 00:06:23,200 --> 00:06:25,800 YEARLY--THE ADMINISTRATIVE PART 155 00:06:25,800 --> 00:06:26,760 OF OUR DEPARTMENTAL MEETINGS 156 00:06:26,760 --> 00:06:28,600 THAT I'M SUPPOSED TO HAVE A 157 00:06:28,600 --> 00:06:29,760 DISCLOSURE SLIDE WHENEVER I GIVE 158 00:06:29,760 --> 00:06:35,680 A TALK SO HERE IT IS. 159 00:06:35,680 --> 00:06:39,360 JUST A FEW THINGS ABOUT JOHN 160 00:06:39,360 --> 00:06:42,880 DALY, I NEVER MET JOHN DALY IN 161 00:06:42,880 --> 00:06:44,080 PERSON, I DON'T EVEN--I WAS 162 00:06:44,080 --> 00:06:45,600 TRYING TO THINK IF I EVER SAW 163 00:06:45,600 --> 00:06:53,160 HIM GIVE A TALK, I NEVER DID, 164 00:06:53,160 --> 00:06:54,600 SADLY. 165 00:06:54,600 --> 00:06:59,680 BUT OF COURSE FORSKOLIN IS USED 166 00:06:59,680 --> 00:07:05,680 IN MY LAB DAILY ACTIVATING 167 00:07:05,680 --> 00:07:07,080 ADENYLATE SIGNIFY CLAYS, AND OF 168 00:07:07,080 --> 00:07:08,240 COURSE CAFFEINE IS USED BY ME 169 00:07:08,240 --> 00:07:10,240 ALL THE TIME TO XEEP ME AWAKE 170 00:07:10,240 --> 00:07:18,320 AND THROUGH THE CENTER, WE USE 171 00:07:18,320 --> 00:07:19,160 EPIBATIDINE, FOR BINDING DATA. 172 00:07:19,160 --> 00:07:27,000 I HAVE NEVER USED THE 173 00:07:27,000 --> 00:07:28,960 BATRACHOTOXINS BUT WE HAVE 174 00:07:28,960 --> 00:07:30,840 GOTTEN INTERESTED IN FROGS SO I 175 00:07:30,840 --> 00:07:31,680 DON'T HAVE ANYTHING TODAY BUT 176 00:07:31,680 --> 00:07:32,720 MAYBE IN THE FUTURE. 177 00:07:32,720 --> 00:07:35,320 SO THE OUTLINE OF MY TALK I WILL 178 00:07:35,320 --> 00:07:37,120 FIRST DISCUSS MY FORAYS INTO 179 00:07:37,120 --> 00:07:41,080 NATURAL PRODUCTS AND THEN, TALK 180 00:07:41,080 --> 00:07:43,400 ABOUT A SUBSET OF THESE THAT ARE 181 00:07:43,400 --> 00:07:44,240 A PSYCHOACTIVE SUBSTANCE AND 182 00:07:44,240 --> 00:07:45,720 TALK ABOUT THE RECEPTORS. 183 00:07:45,720 --> 00:07:48,800 AND THEN GIVE YOU SOME NEW 184 00:07:48,800 --> 00:07:51,320 INSIGHTS INTO A PARTICULAR 185 00:07:51,320 --> 00:07:55,200 NATURAL PRODUCT THAT WE'VE BEEN 186 00:07:55,200 --> 00:07:57,440 INTERESTED IN SOMETIME SILLY 187 00:07:57,440 --> 00:08:00,720 SIGNIN WHICH IS THE PSYCHEDELIC 188 00:08:00,720 --> 00:08:04,160 COMPOUND FROM PSYCHEDELIC 189 00:08:04,160 --> 00:08:04,440 MUSHROOMS. 190 00:08:04,440 --> 00:08:06,920 SO WHEN I THINK ABOUT CHEMICAL 191 00:08:06,920 --> 00:08:14,360 BIOLOGY, I ALWAYS THINK ABOUT 192 00:08:14,360 --> 00:08:16,200 THIS JOURNAL--THIS AND I WILL 193 00:08:16,200 --> 00:08:17,520 RETURN TO THIS THEME TOWARD THE 194 00:08:17,520 --> 00:08:19,400 END OF IT, BUT THIS HIGHLIGHTS 195 00:08:19,400 --> 00:08:22,280 SORT OF A PAPER WE PUBLISHED 196 00:08:22,280 --> 00:08:25,800 SOME YEARS AGO WITH BRYAN 197 00:08:25,800 --> 00:08:26,360 [INDISCERNIBLE]'S LAB. 198 00:08:26,360 --> 00:08:27,760 WE WERE TRYING TO DETERMINE 199 00:08:27,760 --> 00:08:29,040 WHETHER IT'S USEFUL OR NOT TO 200 00:08:29,040 --> 00:08:31,280 ACTUALLY SOLVE A STRUCTURE OF A 201 00:08:31,280 --> 00:08:33,240 RECEPTOR FOR STRUCTURE GUIDED 202 00:08:33,240 --> 00:08:33,640 DRUG DISCOVERY. 203 00:08:33,640 --> 00:08:35,320 AND SO WHAT WE DID IN THIS 204 00:08:35,320 --> 00:08:39,720 PARTICULAR PAPER WAS WE DID A 205 00:08:39,720 --> 00:08:41,080 DOCKING CAMPAIGN AGAINST A 206 00:08:41,080 --> 00:08:43,560 RECEPTOR STRUCTURE WAS THE D3 207 00:08:43,560 --> 00:08:44,920 DOPAMINE RECEPTOR AS WELL AS A 208 00:08:44,920 --> 00:08:47,960 MODEL OF THE RECEPTOR. 209 00:08:47,960 --> 00:08:50,880 AND THAT WAS MADE BY HOMOLOGY, 210 00:08:50,880 --> 00:08:52,160 AND THE STRUCTURES WERE 211 00:08:52,160 --> 00:08:54,760 DIFFERENT BUT BOTH OF THEM WERE 212 00:08:54,760 --> 00:08:56,240 EQUALLY EFFECTIVE FOR 213 00:08:56,240 --> 00:08:57,800 IDENTIFYING COMPOUNDS WITH HIGH 214 00:08:57,800 --> 00:09:00,520 AFFINITY FOR THE D3 RECEPTOR 215 00:09:00,520 --> 00:09:03,040 WITH THE CAVEAT THAT THE 216 00:09:03,040 --> 00:09:04,800 UNIVERSES OF COMPOUNDS THAT WERE 217 00:09:04,800 --> 00:09:06,520 IDENTIFIED FROM EITHER THE MODEL 218 00:09:06,520 --> 00:09:08,720 BASED DOCKING OR THE STRUCTURED 219 00:09:08,720 --> 00:09:10,920 BASE DOCKING WERE COMPLETELY 220 00:09:10,920 --> 00:09:11,200 DISTINCT. 221 00:09:11,200 --> 00:09:13,240 AND THAT'S SOMETHING I WILL 222 00:09:13,240 --> 00:09:17,280 RETURN TO LATER IN THE ERA OF 223 00:09:17,280 --> 00:09:17,760 ALPHA FOLD. 224 00:09:17,760 --> 00:09:20,000 AND I'M GOING TO TALK ABOUT 1 225 00:09:20,000 --> 00:09:21,320 TARGET CLASS IN PARTICULAR, 226 00:09:21,320 --> 00:09:23,560 THESE ARE GPROTEIN COUPLED 227 00:09:23,560 --> 00:09:25,920 RECEPTORS, THIS IS A FILE O GRAM 228 00:09:25,920 --> 00:09:28,680 OF ALL THE GENES, ALL THE OPEN 229 00:09:28,680 --> 00:09:31,440 READING FRAMES IN YOUR GENOME, 230 00:09:31,440 --> 00:09:34,160 THIS IS FROM CRAIG VENTER'S 231 00:09:34,160 --> 00:09:37,920 ORIGINAL PAPER, THIS IS CRAIG 232 00:09:37,920 --> 00:09:38,640 VENTER'S GENOME. 233 00:09:38,640 --> 00:09:39,400 AND WHEN THIS FIRST CAME OUT 234 00:09:39,400 --> 00:09:40,640 THERE WERE 2 THINGS THAT WERE 235 00:09:40,640 --> 00:09:42,640 REALLY INTERESTING TO ME, THE 236 00:09:42,640 --> 00:09:46,880 FIRST IS THAT IF YOU LOOK AT 237 00:09:46,880 --> 00:09:49,760 THIS, THIS SLICE HERE DEVOTED TO 238 00:09:49,760 --> 00:09:50,640 SIGNAL TRANSDUCTION, THAT'S LIKE 239 00:09:50,640 --> 00:09:52,440 AN EIGHTH OF THE GENOME, YOU 240 00:09:52,440 --> 00:09:57,880 VOTED A SIGNAL TRANSDUCTION, IS 241 00:09:57,880 --> 00:09:59,400 GPC Rs CORRESPOND TO ROUGHLY 4 242 00:09:59,400 --> 00:10:02,400 OR 5% OF THE GENOMES, SO THAT'S 243 00:10:02,400 --> 00:10:05,480 A HUGE CHUNK OF YOUR DNA, THAT'S 244 00:10:05,480 --> 00:10:06,800 DEVOTED TO SIGNALING EITHER 245 00:10:06,800 --> 00:10:09,840 UPSTREAM OR DOWN STREAM OF GPC 246 00:10:09,840 --> 00:10:14,480 RS SO THESE ARE--THESE ARE 247 00:10:14,480 --> 00:10:17,840 EXTREMELY IMPORTANT TARGETS AND 248 00:10:17,840 --> 00:10:18,680 TARGETS FOR PHYSIOLOGY. 249 00:10:18,680 --> 00:10:22,040 AND AS I'M SURE YOU ALL KNOW, 250 00:10:22,040 --> 00:10:22,720 G-PROTEIN COUPLED RECEPTORS GET 251 00:10:22,720 --> 00:10:26,360 THEIR NAME BECAUSE THEY COUPLE 252 00:10:26,360 --> 00:10:27,720 TO HETEROPRIMARY G-PROTEINS. 253 00:10:27,720 --> 00:10:29,360 THIS IS A LITTLE CARTOON OF 254 00:10:29,360 --> 00:10:32,080 THEIR ACTION FOLLOWING AGONIST 255 00:10:32,080 --> 00:10:32,320 BINDING. 256 00:10:32,320 --> 00:10:35,760 THERE'S DISASSOCIATION OF THE 257 00:10:35,760 --> 00:10:38,360 HETEROTRI MERRIC G-PROTEIN, AN 258 00:10:38,360 --> 00:10:40,680 EXCHANGE OF GDP FOR GTP AND THEN 259 00:10:40,680 --> 00:10:43,600 THE ALPHA AND BETA SUBGAMMAUE 260 00:10:43,600 --> 00:10:44,520 UNITS ACTIVATE VARIOUS DOWN 261 00:10:44,520 --> 00:10:45,240 STREAM EFFECTORS. 262 00:10:45,240 --> 00:10:47,680 IN THIS CASE HAD IS A PLC 263 00:10:47,680 --> 00:10:49,200 MEDIATED SIGNALING SO ULTIMATELY 264 00:10:49,200 --> 00:10:51,880 YOU WILL GET CALCIUM THAT'S 265 00:10:51,880 --> 00:10:52,960 RELEASED AND THIS--THIS ENTIRE 266 00:10:52,960 --> 00:10:59,600 PATHWAY IS GENERALLY CONSIDERED 267 00:10:59,600 --> 00:11:04,200 TO BE CANONICLE G-RECEPTOR 268 00:11:04,200 --> 00:11:05,360 SIGNALING, RECEPTORS ARE 269 00:11:05,360 --> 00:11:09,520 PHOSPHORYLATED BY THE G-PROTEIN 270 00:11:09,520 --> 00:11:09,880 KINASES. 271 00:11:09,880 --> 00:11:12,760 ARRESTINS BIND AND SERVE TO STOP 272 00:11:12,760 --> 00:11:13,680 SIGNALING THROUGH G-PROTEINS AND 273 00:11:13,680 --> 00:11:15,880 THEN THEY SERVE AS SCAFFOLDS FOR 274 00:11:15,880 --> 00:11:18,640 THEIR OWN FOR DISTINCT SIGNALING 275 00:11:18,640 --> 00:11:21,600 EVENTS ALTHOUGH I MUST SAY IT 276 00:11:21,600 --> 00:11:23,240 STILL REMAINS CONTROVERSIAL AS 277 00:11:23,240 --> 00:11:26,080 EXACTLY WHAT SIGNALING EVENTS 278 00:11:26,080 --> 00:11:27,480 ARE POTENTIALLY MEDIATED BY 279 00:11:27,480 --> 00:11:29,520 ARRESTINS AND WHAT ARE MEDIATED 280 00:11:29,520 --> 00:11:30,880 BY G-PROTEINS BUT YOU GET THE 281 00:11:30,880 --> 00:11:33,080 SENSE HERE THAT FOLLOWING A 282 00:11:33,080 --> 00:11:35,040 SINGLE BINDING EVENT THERE'S 283 00:11:35,040 --> 00:11:36,640 TREMENDOUS DOWN STREAM 284 00:11:36,640 --> 00:11:37,840 APPLICATIONSPLIFICATION AND ALSO 285 00:11:37,840 --> 00:11:38,880 DIVERSIFICATION OF SIGNALING AND 286 00:11:38,880 --> 00:11:39,960 OF COURSE, IT IMMEDIATELY COMES 287 00:11:39,960 --> 00:11:42,600 TO MIND THAT IF WE COULD MAKE 288 00:11:42,600 --> 00:11:44,520 DRUGS THAT BUY A SIGNALING AND 289 00:11:44,520 --> 00:11:46,840 EERLGT OF THOSE PATH--EITHER OF 290 00:11:46,840 --> 00:11:48,840 THOSE PATHWAYS, THEY MIGHT BE 291 00:11:48,840 --> 00:11:50,800 DIFFERENT FROM MEDICATIONS THAT 292 00:11:50,800 --> 00:11:51,840 ARE CURRENTLY AVAILABLE, EITHER 293 00:11:51,840 --> 00:11:53,080 BETTER OR WORSE. 294 00:11:53,080 --> 00:11:53,440 OKAY? 295 00:11:53,440 --> 00:11:55,560 NOW OVER THE YEARS, PRIMARILY 296 00:11:55,560 --> 00:11:57,720 THROUGH THE SCREENING CENTER 297 00:11:57,720 --> 00:11:59,840 THAT I RUN, AND I WAS JUST HAPPY 298 00:11:59,840 --> 00:12:01,600 TO HEAR IT WAS RENEWED FOR 299 00:12:01,600 --> 00:12:04,720 ANOTHER 5 YEARS. 300 00:12:04,720 --> 00:12:07,280 SO CONGRATULATIONS, FOLKS. 301 00:12:07,280 --> 00:12:13,520 WE SET UP A--BASICALLY A UNIQUE, 302 00:12:13,520 --> 00:12:16,800 CONTINUES TO BE UNIQUE SCREENING 303 00:12:16,800 --> 00:12:17,840 RESOURCE WHERE INSTEAD OF 304 00:12:17,840 --> 00:12:19,600 SCREENING AGAINST A SINGLE 305 00:12:19,600 --> 00:12:21,320 MOLECULAR TARGET LIKE IT'S DONE 306 00:12:21,320 --> 00:12:23,840 HERE AT NCATS AND PROBABLY AT 307 00:12:23,840 --> 00:12:26,160 MANY LABS HERE, WE SCREEN LARGE 308 00:12:26,160 --> 00:12:29,360 NUMBERS OF MOLECULAR TARGETS IN 309 00:12:29,360 --> 00:12:30,680 A PARALLEL FASHION AND AS I WILL 310 00:12:30,680 --> 00:12:32,680 SHOW YOU WE HAVE CAPABILITY TO 311 00:12:32,680 --> 00:12:35,480 SCREEN ESSENTIALLY ALL THE GPCR, 312 00:12:35,480 --> 00:12:38,560 ALL THE DRUGGABLE GPC Rs IN A 313 00:12:38,560 --> 00:12:41,320 GENOME IN A SINGLE G-WELL 34 314 00:12:41,320 --> 00:12:41,520 PLATE. 315 00:12:41,520 --> 00:12:44,200 SO WE'RE THEN ABLE TO SCREEN 316 00:12:44,200 --> 00:12:45,960 SINGLE MOLECULES OR CHEMICAL 317 00:12:45,960 --> 00:12:48,960 LIBRARIES AGAINST A VAST 318 00:12:48,960 --> 00:12:49,840 DIVERSITY OF TARGETS. 319 00:12:49,840 --> 00:12:52,240 AND I BASICALLY HAVE USED THIS 320 00:12:52,240 --> 00:12:54,280 RESOURCE, RUN AS A CONTRACT BY 321 00:12:54,280 --> 00:12:56,960 MY LAB AS KEN SAID MAINLY AS A 322 00:12:56,960 --> 00:12:58,240 SERVICE TO THE SCIENTIFIC 323 00:12:58,240 --> 00:12:58,480 COMMUNITY. 324 00:12:58,480 --> 00:13:00,840 SO ANYONE HERE THAT HAS AN 325 00:13:00,840 --> 00:13:02,320 INTERESTING SMALL MOLECULE WE 326 00:13:02,320 --> 00:13:05,480 URGE YOU JUST TO SUBMIT IT FOR 327 00:13:05,480 --> 00:13:05,720 SCREENING. 328 00:13:05,720 --> 00:13:07,160 THERE ARE 3 THINGS I LIKE TO 329 00:13:07,160 --> 00:13:09,360 TELL PEOPLE ABOUT SCREENING, 330 00:13:09,360 --> 00:13:11,440 FIRST IT'S FREE SO IT WON'T COST 331 00:13:11,440 --> 00:13:12,960 YOU ANYTHING OTHER THAN WHATEVER 332 00:13:12,960 --> 00:13:15,320 IT COSTS TO YOU PUT THE COMPOUND 333 00:13:15,320 --> 00:13:17,440 IN A VIAL, SECOND, IT'S 334 00:13:17,440 --> 00:13:18,520 CONFIDENTIAL, SO WE DON'T SHARE 335 00:13:18,520 --> 00:13:20,680 THE INFORMATION WITH ANYONE, 336 00:13:20,680 --> 00:13:21,960 OTHER THAN YOU AND YOU DON'T 337 00:13:21,960 --> 00:13:24,600 HAVE TO TELL US WHAT THE 338 00:13:24,600 --> 00:13:26,000 STRUCTURE OF THE COMPOUND IS. 339 00:13:26,000 --> 00:13:28,840 WE DO NEED TO KNOW THE MOLECULAR 340 00:13:28,840 --> 00:13:30,640 WEIGHT THOUGH AND THE SOLUBILITY 341 00:13:30,640 --> 00:13:32,000 BUT WE DON'T NEED TO KNOW ANY 342 00:13:32,000 --> 00:13:33,120 OTHER INFORMATION ABOUT THE 343 00:13:33,120 --> 00:13:35,840 COMPOUND AND THE THIRD THING 344 00:13:35,840 --> 00:13:37,880 ABOUT THE PROGRAM IS IT'S IP 345 00:13:37,880 --> 00:13:39,880 NEUTRAL SO WE KNOW KNOWN OF THE 346 00:13:39,880 --> 00:13:41,040 INTELLECT RULINNATED ANTIGENS 347 00:13:41,040 --> 00:13:42,520 PROPERTY THAT'S GENERATED ON 348 00:13:42,520 --> 00:13:43,840 COMPOUNDS YOU MIGHT SEND, OKAY? 349 00:13:43,840 --> 00:13:45,520 SO FROM A PATENT PERSPECTIVE 350 00:13:45,520 --> 00:13:47,320 WE'RE CONSIDERED A PAIR OF 351 00:13:47,320 --> 00:13:48,680 HANDS. 352 00:13:48,680 --> 00:13:50,560 SO IT'S FREE, IT'S CONFIDENTIAL 353 00:13:50,560 --> 00:13:53,760 AND IT'S IP NEUTRAL SO 354 00:13:53,760 --> 00:13:55,240 IT'S--THERE'S NOTHING NEGATIVE 355 00:13:55,240 --> 00:13:59,080 THAT COULD COME FROM USING THE 356 00:13:59,080 --> 00:14:01,240 PROGRAM AND TO GIVE YOU A SENSE 357 00:14:01,240 --> 00:14:05,880 OF HOW LARGE THIS PROGRAM IS, I 358 00:14:05,880 --> 00:14:08,040 HAD TO PUT THIS INFORMATION 359 00:14:08,040 --> 00:14:10,960 TOGETHER RECENTLY FOR THE MOST 360 00:14:10,960 --> 00:14:12,160 RECENT REVIEW IN THE LAST 5 361 00:14:12,160 --> 00:14:14,360 YEARS WE WORK WIDE MORE THAN 500 362 00:14:14,360 --> 00:14:16,200 LABS AROUND THE WORLD. 363 00:14:16,200 --> 00:14:18,720 WE CONTRIBUTED TO MORE THAN 500 364 00:14:18,720 --> 00:14:18,960 PAPERS. 365 00:14:18,960 --> 00:14:26,000 SO IT'S A HUGE, HUGE PROGRAM. 366 00:14:26,000 --> 00:14:27,960 AND THESE ARE JUST THE HIGH 367 00:14:27,960 --> 00:14:29,240 IMPACT PAPERS THAT HAVE COME 368 00:14:29,240 --> 00:14:32,000 FROM MY LAB ALONE USING THIS 369 00:14:32,000 --> 00:14:32,240 RESOURCE. 370 00:14:32,240 --> 00:14:33,840 SO WHEY TELL PEOPLE IS IF 371 00:14:33,840 --> 00:14:35,160 THERE'S RESOURCE HAS BEEN USEFUL 372 00:14:35,160 --> 00:14:36,560 FOR ME, IT PROBABLY WOULD BE 373 00:14:36,560 --> 00:14:42,480 USEFUL FOR YOU AS WELL. 374 00:14:42,480 --> 00:14:45,600 AND WE WERE ABLE TO MAKE 375 00:14:45,600 --> 00:14:46,640 SIGNIFICANT ENHANCEMENTS OF THE 376 00:14:46,640 --> 00:14:50,600 SCREENING THROUGH THE DRUGGABLE 377 00:14:50,600 --> 00:14:51,800 GENOME INITIATIVE. 378 00:14:51,800 --> 00:14:55,320 NOW THESE DAYS, THE SCREENING IS 379 00:14:55,320 --> 00:14:58,440 BASICALLY ROBOTIC, AND THE 380 00:14:58,440 --> 00:14:59,240 ANALYSIS IS AUTOMATED. 381 00:14:59,240 --> 00:15:02,120 AND THERE IS MUSIC THAT PLAYS 382 00:15:02,120 --> 00:15:05,080 BUT IT'S USUALLY NOT DAVE 383 00:15:05,080 --> 00:15:07,240 BRUBECK QUARTET BUT THIS GIVES 384 00:15:07,240 --> 00:15:10,080 YOU A SENSE OF BASICALLY THE 385 00:15:10,080 --> 00:15:13,200 SCALE HERE SO WE DO THOUSANDS OF 386 00:15:13,200 --> 00:15:15,120 THESE ASSAYS EVERY DAY, WORKING 387 00:15:15,120 --> 00:15:19,640 WITH ROBOTS. 388 00:15:19,640 --> 00:15:20,960 SO THAT'S OUR SCREENING PROJECT 389 00:15:20,960 --> 00:15:24,800 AND WHAT I WANT TO DO NEXT IS 390 00:15:24,800 --> 00:15:26,800 TAKE YOU THROUGH, FIRST 1 391 00:15:26,800 --> 00:15:28,800 DISCOVERY, WHICH RELATES TO 392 00:15:28,800 --> 00:15:32,480 NATURALLY CONSIDERING 393 00:15:32,480 --> 00:15:33,280 PSYCHOACTIVE SUBSTANCES AND 394 00:15:33,280 --> 00:15:34,640 THERE'S A LITTLE BIT OF A STORY 395 00:15:34,640 --> 00:15:36,000 BEHIND THIS, I THINK SOME OF YOU 396 00:15:36,000 --> 00:15:37,000 PROBABLY NOT MOST OF YOU BUT 397 00:15:37,000 --> 00:15:40,800 SOME OF YOU HAVE SEEN THIS VIDEO 398 00:15:40,800 --> 00:15:45,320 BEFORE, SO, BACK IN THE LATE 399 00:15:45,320 --> 00:15:48,040 1990S, PROBABLY 1998 OR 1999 400 00:15:48,040 --> 00:15:49,800 WHEN I GOT THE VERY FIRST 401 00:15:49,800 --> 00:15:53,160 CONTRACT FOR THE SCREENING 402 00:15:53,160 --> 00:15:55,120 CENTER, I WAS AT CASE WESTERN 403 00:15:55,120 --> 00:15:57,480 RESERVE AND AN UNDERGRAD CAME TO 404 00:15:57,480 --> 00:15:58,880 ME WHO HAD--WHO HAD AN 405 00:15:58,880 --> 00:15:59,720 EXPERIENCE VERY SIMILAR TO WHAT 406 00:15:59,720 --> 00:16:04,320 YOU'RE GOING TO SEE HERE, SO LET 407 00:16:04,320 --> 00:16:08,240 ME START THIS HERE. 408 00:16:08,240 --> 00:16:10,440 SO THIS IS SOMETHING I 409 00:16:10,440 --> 00:16:13,480 DOWNLOADED FROM YouTUBE SO 410 00:16:13,480 --> 00:16:15,040 THAT'S A BONG IN CASE PEOPLE 411 00:16:15,040 --> 00:16:21,800 DON'T KNOW WHAT THAT IS. 412 00:16:21,800 --> 00:16:24,800 SO HERE THIS INDIVIDUAL HAS 413 00:16:24,800 --> 00:16:27,120 BASICALLY TAKEN 1 INHALATION 414 00:16:27,120 --> 00:16:30,800 FROM THIS STUFF HE WAS TOLD IS 415 00:16:30,800 --> 00:16:31,640 BETTER THAN MARIJUANA AND IT'S 416 00:16:31,640 --> 00:16:34,080 GOING TO HAVE A VERY DRAMATIC 417 00:16:34,080 --> 00:16:42,720 EFFECT ON HIM. 418 00:16:42,720 --> 00:16:53,080 SO INITIALLY LAUGHTER. 419 00:16:55,920 --> 00:17:03,280 [LAUGHTER] 420 00:17:03,280 --> 00:17:05,440 AND NOW HE'S HAVING 421 00:17:05,440 --> 00:17:05,800 HALLUCINATIONS. 422 00:17:05,800 --> 00:17:08,200 SO THIS GOES ON FOR ABOUT 20 423 00:17:08,200 --> 00:17:12,160 MINUTES AND THEN HE'S FINE. 424 00:17:12,160 --> 00:17:14,240 AND SO, THE STUDENT HAD COME TO 425 00:17:14,240 --> 00:17:14,520 ME. 426 00:17:14,520 --> 00:17:17,800 HE WAS WRITING A PAPER ON THIS 427 00:17:17,800 --> 00:17:21,400 AND HE WANTED TO KNOW WHAT IT 428 00:17:21,400 --> 00:17:23,760 WAS, GET MORE INFORMATION ON IT. 429 00:17:23,760 --> 00:17:28,960 SO I ASKED HIM WHAT IT WAS AND 430 00:17:28,960 --> 00:17:33,320 WHERE HE GOT IT AND THIS IS IT. 431 00:17:33,320 --> 00:17:41,040 IT'S THIS PLANT S 432 00:17:41,040 --> 00:17:42,560 ALVIA DE MENORA, SIMILAR TO THE 433 00:17:42,560 --> 00:17:44,160 SALVIA DIA THAT GROWS IN YOUR 434 00:17:44,160 --> 00:17:46,360 GARDEN ALTHOUGH IT'S NOT 435 00:17:46,360 --> 00:17:48,440 PSYCHOACTIVE AND THAT GENTLEMEN 436 00:17:48,440 --> 00:17:52,080 THERE IS DANIEL SEBERT WHO 437 00:17:52,080 --> 00:17:54,200 FOUNDED SAGE WISDOM BOTANICALS 438 00:17:54,200 --> 00:17:56,920 AND IN THE EARLY 2000S YOU COULD 439 00:17:56,920 --> 00:17:58,640 PURCHASE THIS OVER THE INTERNET 440 00:17:58,640 --> 00:18:01,480 BASICALLY AND THE ACTIVE GREET 441 00:18:01,480 --> 00:18:06,720 IS SOMETHING CALLED SALVIA 442 00:18:06,720 --> 00:18:10,240 DIVINORUM A, I WILL SHOW YOU THE 443 00:18:10,240 --> 00:18:10,880 STRUCTURE SHORTLY. 444 00:18:10,880 --> 00:18:12,400 SO I LOOKED AT THE STRUCTURE OF 445 00:18:12,400 --> 00:18:16,800 THE COMPOUND AND IT LOOKS LIKE 446 00:18:16,800 --> 00:18:19,360 NO OTHER KNOWN HALLUCIN O GENIC 447 00:18:19,360 --> 00:18:23,240 OR COMPOUND, IT LOOKS LIKE 448 00:18:23,240 --> 00:18:26,920 CHOLESTEROL IF ANYTHING, IT'S 449 00:18:26,920 --> 00:18:28,000 TECHNICALLY A DITERPIN AND I DID 450 00:18:28,000 --> 00:18:31,880 READING ON IT AND I WAS ABLE TO 451 00:18:31,880 --> 00:18:35,200 FIND THE VERY FIRST ACCOUNT BY 452 00:18:35,200 --> 00:18:42,920 DANIEL SEBERT OF SOMEONE SPOKING 453 00:18:42,920 --> 00:18:45,040 PURIFIED SALVINORIN A, SO HE 454 00:18:45,040 --> 00:18:48,160 SAID BASICALLY HE HAD A RAPIDLY 455 00:18:48,160 --> 00:18:48,880 INDUCED PSYCHEDELIC EXPERIENCE 456 00:18:48,880 --> 00:18:51,120 IN WHICH HE WAS TRANSPORTED TO 457 00:18:51,120 --> 00:18:54,720 AN ALTERNATIVE SPACE AND TIME. 458 00:18:54,720 --> 00:18:58,480 SO IT INDUCES SPATIAL TEMPORAL 459 00:18:58,480 --> 00:18:58,800 DISLOCATION. 460 00:18:58,800 --> 00:19:01,320 AND MOST PEOPLE FIND THIS 461 00:19:01,320 --> 00:19:09,720 EXTREMELY FRIGHTENING BUT HE 462 00:19:09,720 --> 00:19:12,280 SAID UREKA I HAVE STUMBLED UPON 463 00:19:12,280 --> 00:19:20,720 THE PSYCHEDELIC ESSENCE OF 464 00:19:20,720 --> 00:19:21,680 SALVIARCS DIVINORUN, SO I SEBT 465 00:19:21,680 --> 00:19:24,160 AN E-MAIL AND ASK HIM IF HE 466 00:19:24,160 --> 00:19:28,440 WOULD SEND US 10-MILLIGRAMS OR 467 00:19:28,440 --> 00:19:31,840 SO OF SALVIA DIVINORUM. 468 00:19:31,840 --> 00:19:34,800 HE JUST WANTED TO KNOW FOR 2 469 00:19:34,800 --> 00:19:36,240 THINGS, RESEARCH PURPOSES OR 470 00:19:36,240 --> 00:19:38,120 PERSONAL USE AND I SAID RESEARCH 471 00:19:38,120 --> 00:19:39,440 PURPOSES AND HE SAID IN THAT 472 00:19:39,440 --> 00:19:40,640 CASE, IT'S FREE. 473 00:19:40,640 --> 00:19:45,040 SO WE RECEIVED A--WE SENT TO 474 00:19:45,040 --> 00:19:48,720 KENTER RICE HERE TO VERIFY THAT 475 00:19:48,720 --> 00:19:49,800 WAS INDEED WHAT WE THOUGHT IT 476 00:19:49,800 --> 00:19:51,160 WAS AND IT WAS SO THIS IS THE 477 00:19:51,160 --> 00:19:56,200 STRUCTURE HERE OF THE COMPOUND, 478 00:19:56,200 --> 00:19:57,240 VERY INTERESTING STRUCTURE. 479 00:19:57,240 --> 00:20:04,280 IT PROVED TO BE SOMEWHAT OF A 480 00:20:04,280 --> 00:20:06,200 CHALLENGE FOR MEDICINAL CHEMISTS 481 00:20:06,200 --> 00:20:07,920 TO MAKE FROM FIRST PRINCIPLES 482 00:20:07,920 --> 00:20:13,600 BUT THEY'RE ARE NOW 3 OR 4 TOTAL 483 00:20:13,600 --> 00:20:15,480 SYNTHESIS OF SALVIA DIVINORUM 484 00:20:15,480 --> 00:20:17,560 AND WE SCREENED IT AGAINST THIS 485 00:20:17,560 --> 00:20:18,480 COLLECTION OF MOLECULAR TARGETS 486 00:20:18,480 --> 00:20:20,520 WE HAVE AND YOU CAN SEE IT WAS 487 00:20:20,520 --> 00:20:22,800 HIGHLY SELECTIVE FOR A SINGLE 488 00:20:22,800 --> 00:20:25,520 TARGET CAN THAT WAS THE CAPPA 489 00:20:25,520 --> 00:20:26,200 OPIATE RECEPTOR AND BY 490 00:20:26,200 --> 00:20:27,840 COMPARISON, AND I WILL RETURN TO 491 00:20:27,840 --> 00:20:29,600 THIS LATER IN THE TALK, WE 492 00:20:29,600 --> 00:20:34,880 SCREENED LSD AND WE KNEW EVEN 493 00:20:34,880 --> 00:20:36,080 LSD HITS MANY, MANY TARGETS. 494 00:20:36,080 --> 00:20:37,920 SO THIS WAS A BIT UNUSUAL THAT 495 00:20:37,920 --> 00:20:39,960 HERE WE HAVE THIS LIPID 496 00:20:39,960 --> 00:20:40,720 BASICALLY THAT'S ACTIVATING 497 00:20:40,720 --> 00:20:43,640 RECEPTOR FOR PEPTIDES AND IT 498 00:20:43,640 --> 00:20:47,840 DOES IT IN A VERY, VERY 499 00:20:47,840 --> 00:20:49,840 SELECTIVE WAY. 500 00:20:49,840 --> 00:20:51,040 SO DANIEL SEBERT WAS VERY 501 00:20:51,040 --> 00:20:52,160 INTERESTED IN THIS INFORMATION. 502 00:20:52,160 --> 00:20:58,040 SO I SENT IT TO HIM. 503 00:20:58,040 --> 00:21:01,200 AND HIS LIFE HAS BASICALLY BEEN 504 00:21:01,200 --> 00:21:02,640 DEVOTED TO STUDYING THIS PLANT. 505 00:21:02,640 --> 00:21:04,800 HE WAS A LITTLE BIT DISAPPOINTED 506 00:21:04,800 --> 00:21:08,040 THAT IT WAS THE CAPPA OPIATE 507 00:21:08,040 --> 00:21:09,760 RECEPTOR AND HE SAID HE DID NOT 508 00:21:09,760 --> 00:21:12,440 BELIEVE THAT IT WAS THE CAPPA 509 00:21:12,440 --> 00:21:14,200 OPIATE RECEPTOR, HE FELT THERE 510 00:21:14,200 --> 00:21:18,200 HAD TO BE--BECAUSE IT INDUCED 511 00:21:18,200 --> 00:21:20,240 SUCH A MARVELOUS EXPERIENCE IT 512 00:21:20,240 --> 00:21:23,040 COULD NOT POSSIBLY DUE TO CAPPA 513 00:21:23,040 --> 00:21:24,120 OPERATING GLOBALLY PILOT 514 00:21:24,120 --> 00:21:25,560 PROJECTATE RECEPTOR BECAUSE WHAT 515 00:21:25,560 --> 00:21:30,080 THE DOGMA S&P THAT CAPPA 516 00:21:30,080 --> 00:21:30,920 AGONISTS ARE DISFOREVERRIC. 517 00:21:30,920 --> 00:21:31,920 THAT'S TRUE IN ANYTHING OTHER 518 00:21:31,920 --> 00:21:36,040 THAN YOU HAD HANS, IT TURNS OUT. 519 00:21:36,040 --> 00:21:39,760 HUMANS ARE NOT DYSPH ORIC, SO HE 520 00:21:39,760 --> 00:21:42,160 PROPOSED THIS EXPERIMENT WHERE 521 00:21:42,160 --> 00:21:46,280 HE WOULD PRETREAT HIMSELF WITH 522 00:21:46,280 --> 00:21:49,000 NARCAN AND THEN HE WOULD SMOKE 523 00:21:49,000 --> 00:21:50,160 SALVIA DIVINORUM AND THEN IT 524 00:21:50,160 --> 00:21:53,160 BLOCKS THE CAPPA U AND OPIATE 525 00:21:53,160 --> 00:21:54,680 RECEPTORS AND I SENT HIM BACK AN 526 00:21:54,680 --> 00:21:59,480 E-MAIL SAYING I THINK THIS IS 527 00:21:59,480 --> 00:22:00,960 VERY BAD IDEA. 528 00:22:00,960 --> 00:22:03,280 YOU COULD DIE. 529 00:22:03,280 --> 00:22:05,080 AND 1 OF THE CONCERNS I HAD WAS 530 00:22:05,080 --> 00:22:07,120 THAT HE WOULD BE DEAD. 531 00:22:07,120 --> 00:22:09,360 AND THERE WOULD BE AN E-MAIL IN 532 00:22:09,360 --> 00:22:12,280 HIS HANDS SAYING, YES THIS IS A 533 00:22:12,280 --> 00:22:13,880 GREAT EXPERIMENT GO AHEAD AND DO 534 00:22:13,880 --> 00:22:14,160 IT. 535 00:22:14,160 --> 00:22:14,560 [LAUGHTER] 536 00:22:14,560 --> 00:22:16,800 SO I WOULD END UP IN THE 537 00:22:16,800 --> 00:22:18,600 NEW YORK TIMES FOR THE WRONG 538 00:22:18,600 --> 00:22:20,480 REASON BUT I TOLD HIM THAT WAS A 539 00:22:20,480 --> 00:22:21,880 VERY BAD IDEA AND I DON'T 540 00:22:21,880 --> 00:22:23,000 RECOMMEND IT BUT I WANT YOU TO 541 00:22:23,000 --> 00:22:27,800 TAKE A LOOK AT THE DATE, IT SAYS 542 00:22:27,800 --> 00:22:28,360 27 MARCH, 2002. 543 00:22:28,360 --> 00:22:31,880 YOU CAN SEE A TIME STAMP 1:53 IN 544 00:22:31,880 --> 00:22:33,400 THE AFTERNOON, OKAY. 545 00:22:33,400 --> 00:22:35,440 SO I WENT HOME. 546 00:22:35,440 --> 00:22:40,400 NEXT DAY, I HAD THIS 28 547 00:22:40,400 --> 00:22:42,920 MARCH 0800, OH THE OTHER THING I 548 00:22:42,920 --> 00:22:44,920 TOLD HIM WAS IF YOU DO THIS 549 00:22:44,920 --> 00:22:46,200 EXPERIMENT, SO BY THEN WE HAD 550 00:22:46,200 --> 00:22:47,640 WRITTEN UP A PAPER AND I SAID 551 00:22:47,640 --> 00:22:49,240 WE'RE NOT GOING TO ENCLUED THE 552 00:22:49,240 --> 00:22:52,560 HUMAN DATA IN THE PAPER, OKAY? 553 00:22:52,560 --> 00:22:54,000 BECAUSE WE NEED HUMAN USE AND 554 00:22:54,000 --> 00:22:56,520 ALL THAT STUFF, BUT HE DID THE 555 00:22:56,520 --> 00:22:57,840 EXPERIMENT AND LOW AND BEHOLD 556 00:22:57,840 --> 00:23:01,800 THE EFFECTS WERE BLOCKED, MORE 557 00:23:01,800 --> 00:23:04,920 OR LESS COMPLETELY BY 558 00:23:04,920 --> 00:23:08,400 SALVIA DIVINORUM A AND BY 559 00:23:08,400 --> 00:23:09,760 NALOXONE, AND SUBSEQUENTLY AS I 560 00:23:09,760 --> 00:23:16,320 WILL SHOW YOU, IT'S CLEAR THAT'S 561 00:23:16,320 --> 00:23:17,120 HOW IT WORKS. 562 00:23:17,120 --> 00:23:18,520 BUT I PULLED EVERYBODY IN MY LAB 563 00:23:18,520 --> 00:23:20,600 TO LOOK AT THIS BECAUSE I SAID 564 00:23:20,600 --> 00:23:21,880 LOOK, THIS IS SOMETHING THAT 565 00:23:21,880 --> 00:23:24,960 WILL NEVER HAPPEN TO YOU IN YOUR 566 00:23:24,960 --> 00:23:27,400 LIFE WHERE YOU MAKE A DISCOVERY 567 00:23:27,400 --> 00:23:32,240 IN THE LAB AND THE NEXT DAY IT'S 568 00:23:32,240 --> 00:23:35,800 VALIDATED IN HUMANS OKAY, SO, SO 569 00:23:35,800 --> 00:23:36,360 THERE YOU GO. 570 00:23:36,360 --> 00:23:40,800 SO OF COURSE, WE DID THE SORT OF 571 00:23:40,800 --> 00:23:43,200 CLASSICAL STUDIES, LOOKED AT 572 00:23:43,200 --> 00:23:45,920 CAPPA KNOCKOUT MICE, HAS NO 573 00:23:45,920 --> 00:23:46,200 EFFECT. 574 00:23:46,200 --> 00:23:49,560 OPIATE EFFECT BLOCKS IT IN 575 00:23:49,560 --> 00:23:50,760 NONHUMAN PRIMATES. 576 00:23:50,760 --> 00:23:55,600 AND SUBSEQUENTLY THERE HAVE BEEN 577 00:23:55,600 --> 00:23:59,000 MULTIPLE STUDIES SHOWING THAT 578 00:23:59,000 --> 00:23:59,840 THE APPROPRIATE OPIATE 579 00:23:59,840 --> 00:24:01,600 ANTAGONIST WILL BLOCK IT IN 580 00:24:01,600 --> 00:24:04,000 HUMANS SO IT WORKS THROUGH CAPPA 581 00:24:04,000 --> 00:24:04,240 RECEPTORS. 582 00:24:04,240 --> 00:24:04,680 NO QUESTION. 583 00:24:04,680 --> 00:24:06,520 SO THE QUESTION THAT WAS 584 00:24:06,520 --> 00:24:07,440 LINGERING THOUGH IS ARE THERE 585 00:24:07,440 --> 00:24:10,920 ANY OTHER MOLECULAR TARGETS THAT 586 00:24:10,920 --> 00:24:11,680 THIS COMPOUND INTERACTS WITH 587 00:24:11,680 --> 00:24:14,280 BECAUSE AT THE TIME WE HAD 588 00:24:14,280 --> 00:24:15,440 THIS--IT WAS FOR THE SCIENTIFIC 589 00:24:15,440 --> 00:24:16,840 COMMUNITY IT WAS A BIG 590 00:24:16,840 --> 00:24:18,360 COLLECTION OF MOLECULAR TARGETS 591 00:24:18,360 --> 00:24:20,240 BUT STILL RELATIVELY SMALL. 592 00:24:20,240 --> 00:24:23,880 AND SO, A NUMBER OF YEARS LATER, 593 00:24:23,880 --> 00:24:27,720 WE BUILT THIS RESOURCE WHICH IS 594 00:24:27,720 --> 00:24:28,840 AVAILABLE THROUGH AGENE WHICH WE 595 00:24:28,840 --> 00:24:33,520 CALL PREOF THE O-TANGO WHICH 596 00:24:33,520 --> 00:24:34,600 ALLOWS A SINGLE 384 WELL PLATE 597 00:24:34,600 --> 00:24:36,360 THE ABILITY TO SCREEN ALL THE 598 00:24:36,360 --> 00:24:38,640 RECEPTORS ON THIS, THIS IS A 599 00:24:38,640 --> 00:24:43,200 FILE O GRAM OF THE HUMAN GPC R, 600 00:24:43,200 --> 00:24:46,320 SO EVERY PLACE THERE'S A CIRCLE 601 00:24:46,320 --> 00:24:47,280 FILLED OR COLORED THAT'S WHERE 602 00:24:47,280 --> 00:24:49,720 WE HAVE A VALIDATED ASSAY AND 603 00:24:49,720 --> 00:24:51,440 YOU CAN ORDER THE ENTIRE THING 604 00:24:51,440 --> 00:24:53,200 FOR ABOUT A THOUSAND DOLLARS IN 605 00:24:53,200 --> 00:24:53,720 AJENE. 606 00:24:53,720 --> 00:24:56,440 AND SO THIS ALLOWS FOR UNBIAS 607 00:24:56,440 --> 00:24:59,120 SCREENING OF NEARLY THE ENTIRE 608 00:24:59,120 --> 00:25:00,360 DRUGGABLE GPCR AND WE'RE NOT 609 00:25:00,360 --> 00:25:02,800 ABLE TO GET FRIZZLED OR TASTING 610 00:25:02,800 --> 00:25:06,640 RECEPTORS YET THROUGH THIS ASSAY 611 00:25:06,640 --> 00:25:06,880 SYSTEM. 612 00:25:06,880 --> 00:25:09,440 SO WE THROUGH THE ALIEWMINATING 613 00:25:09,440 --> 00:25:13,520 DRUG INITIATIVE, WE TESTED THE 614 00:25:13,520 --> 00:25:14,440 SALVIA DIVINORUM A AGAINST THIS 615 00:25:14,440 --> 00:25:15,960 AND OTHER TARGETS AND NO 616 00:25:15,960 --> 00:25:18,280 SURPRISE IT'S A CAPPA AGONIST. 617 00:25:18,280 --> 00:25:20,280 HAS ABOUT A THOUSAND FOLD LESS 618 00:25:20,280 --> 00:25:21,560 AFFINITY FROM NEW RECEPTORS AND 619 00:25:21,560 --> 00:25:24,040 HITS NO OTHER TARGET SO THIS 620 00:25:24,040 --> 00:25:25,680 IS--AS THESE THINGS GO, THIS IS 621 00:25:25,680 --> 00:25:28,600 VERY, VERY UNUSUAL TO GET A 622 00:25:28,600 --> 00:25:30,600 COMPOUND WHICH IS EXTREMELY 623 00:25:30,600 --> 00:25:35,320 POTENT FOR A SINGLE MOLECULAR 624 00:25:35,320 --> 00:25:37,440 TARGET AND IS A NATURAL PRODUCT. 625 00:25:37,440 --> 00:25:42,640 SO THIS IS--THIS IS VERY 626 00:25:42,640 --> 00:25:44,240 UNUSUAL, WE ULTIMATELY WERE 627 00:25:44,240 --> 00:25:45,880 INTERESTED IN UNDERSTANDING HOW 628 00:25:45,880 --> 00:25:48,200 IT IS THAT SALVIA DIVINORUM A 629 00:25:48,200 --> 00:25:50,320 AND OTHER DRUGS BIND TO CAPPA 630 00:25:50,320 --> 00:25:51,400 RECEPTORS, AND ULTIMATELY WE'RE 631 00:25:51,400 --> 00:25:53,800 ABLE TO GET A--SOMEBODY WAS 632 00:25:53,800 --> 00:25:56,240 ASKING ABOUT NANO BODIES, 1 OF 633 00:25:56,240 --> 00:25:58,320 THE STUDENTS SO THIS A NANO BODY 634 00:25:58,320 --> 00:26:01,120 ACTIVE STATE OF THE CAPPA 635 00:26:01,120 --> 00:26:05,280 RECEPTOR THAT WE SAW BY X-RAY 636 00:26:05,280 --> 00:26:06,560 CRYSTALLOGRAPHY BACK IN THE DAYS 637 00:26:06,560 --> 00:26:08,960 WHEN PEOPLE WERE STILL DOING 638 00:26:08,960 --> 00:26:09,960 X-RAY CRYSTALLOGRAPHY AND THIS 639 00:26:09,960 --> 00:26:11,680 ALLOWED US TO GET USE OF 640 00:26:11,680 --> 00:26:15,360 INSIGHTS INTO DRUG BINDING AND 641 00:26:15,360 --> 00:26:18,120 SALVIA DIVINORUM A BINDINGA THE 642 00:26:18,120 --> 00:26:18,400 RECEPTOR. 643 00:26:18,400 --> 00:26:20,560 SUBSEQUENTLY MY MOST DOC HERE 644 00:26:20,560 --> 00:26:23,520 TAU, NOW HAS A FAC UMENTY 645 00:26:23,520 --> 00:26:24,840 POSITION AT WASHINGTON 646 00:26:24,840 --> 00:26:26,600 UNIVERSITY IN ST. LOUIS AND JUST 647 00:26:26,600 --> 00:26:28,480 A FEW MONTHS AGO HE PUBLISHED A 648 00:26:28,480 --> 00:26:30,960 BEAUTIFUL PAPER IN NATURE 649 00:26:30,960 --> 00:26:33,240 SHOWING SALVIA DIVINORUM A 650 00:26:33,240 --> 00:26:35,440 ANALOGUE BOUND TO THE 651 00:26:35,440 --> 00:26:35,720 B-RECEPTOR. 652 00:26:35,720 --> 00:26:39,200 SO IT TURNS OUT, NONE OF OUR 653 00:26:39,200 --> 00:26:41,560 MODELS WERE CORRECT AND THE 654 00:26:41,560 --> 00:26:44,720 STRUCTURE WE THINK IS CORRECT. 655 00:26:44,720 --> 00:26:49,000 AND ALONG THE WAY, MY LAB 656 00:26:49,000 --> 00:26:51,040 INITIALLY WITH RAY STEVENS WHO 657 00:26:51,040 --> 00:26:56,480 WAS THE FIRST, I GUESS THE FIRST 658 00:26:56,480 --> 00:27:00,520 LECTURER HERE, STARTING IN I 659 00:27:00,520 --> 00:27:04,600 THINK 2007 OR SO WE STARTED 660 00:27:04,600 --> 00:27:06,920 COLLABORATING WITH HIM ON 661 00:27:06,920 --> 00:27:08,560 SOLVING AND CHARACTERIZING GPCR 662 00:27:08,560 --> 00:27:10,560 STRUCTURES, SOLVE A NUMBER OF 663 00:27:10,560 --> 00:27:14,920 THOSE WITH HIM AND BADEEM, AND 664 00:27:14,920 --> 00:27:16,320 MORE RECENTLY COLLABORATED WITH 665 00:27:16,320 --> 00:27:17,360 ERIC [INDISCERNIBLE]'S LAB AND 666 00:27:17,360 --> 00:27:20,000 THEN OF COURSE MY OWN LAB HAS 667 00:27:20,000 --> 00:27:23,160 SOLVED MANY, MANY, MANY 668 00:27:23,160 --> 00:27:24,680 STRUCTURES AND I WILL JUST TELL 669 00:27:24,680 --> 00:27:27,240 YOU ABOUT A COUPLE OF THEM TODAY 670 00:27:27,240 --> 00:27:28,640 BUT THOSE ARE--THOSE ARE LISTED 671 00:27:28,640 --> 00:27:29,680 THERE. 672 00:27:29,680 --> 00:27:32,080 SO THIS IS--THIS HAS BEEN A VERY 673 00:27:32,080 --> 00:27:34,240 FRUITFUL AREA OF RESEARCH IF FOR 674 00:27:34,240 --> 00:27:35,440 NOTHING ELSE, MY POST DOCKS HAVE 675 00:27:35,440 --> 00:27:39,640 BEEN ABLE TO GET JOBS AFTER THEY 676 00:27:39,640 --> 00:27:41,200 PUBLISHED THEIR PAPERS AND THERE 677 00:27:41,200 --> 00:27:45,880 ARE JUST 2 RECENT PAPERS I WANT 678 00:27:45,880 --> 00:27:46,200 TO HIGHLIGHT. 679 00:27:46,200 --> 00:27:50,400 THE TOP 1 I THINK, I CONSIDER 680 00:27:50,400 --> 00:27:53,200 THIS 1 OF THE 2 BEST PAPERS I 681 00:27:53,200 --> 00:27:54,840 EVER PUBLISHED IN MY LIFE. 682 00:27:54,840 --> 00:27:57,520 THIS PROBABLY MEANS NO 1 READS 683 00:27:57,520 --> 00:28:00,320 IT BUT FOR THOSE OF YOU WHO WORK 684 00:28:00,320 --> 00:28:03,080 WITH CHEMO GENETICS, I KNOW 685 00:28:03,080 --> 00:28:08,280 PEOPLE--IF YOU'RE IN THE 686 00:28:08,280 --> 00:28:09,080 NEUROSCIENCES, EVERYBODY USES 687 00:28:09,080 --> 00:28:09,520 THEM. 688 00:28:09,520 --> 00:28:13,960 IT REALLY SHOWS VERY NICELY HOW 689 00:28:13,960 --> 00:28:17,720 WE ARRIVED AT THOSE BY DIRECTED 690 00:28:17,720 --> 00:28:18,440 EVOLUTION AND THE SECOND IS 691 00:28:18,440 --> 00:28:20,120 AGAIN THIS WILL BE A LEGACY 692 00:28:20,120 --> 00:28:21,720 PAPER, THIS WILL BE THE 693 00:28:21,720 --> 00:28:24,480 STRUCTURE OF THE ENTIRE HUMAN 694 00:28:24,480 --> 00:28:29,440 OPIATE RECEPTOR HUMAN FAMILY WE 695 00:28:29,440 --> 00:28:30,360 DID WITH ERIC XU. 696 00:28:30,360 --> 00:28:30,840 ALL RIGHT. 697 00:28:30,840 --> 00:28:33,720 SO THE OTHER THING WE WANTED TO 698 00:28:33,720 --> 00:28:34,960 REALLY UNDERSTAND ABOUT 699 00:28:34,960 --> 00:28:37,400 SALVIA DIVINORUM A IS WE 700 00:28:37,400 --> 00:28:38,840 BASICALLY VERIFIED IT'S HIGHLY 701 00:28:38,840 --> 00:28:41,120 SELECTIVE AT THE CAPPA RECEPTOR 702 00:28:41,120 --> 00:28:42,640 ARE THERE ANY DOWN STREAM OF THE 703 00:28:42,640 --> 00:28:44,960 CAPPA RECEPTOR IS THERE ANYTHING 704 00:28:44,960 --> 00:28:46,240 THAT'S UNUSUAL ABOUT 705 00:28:46,240 --> 00:28:51,560 SALVIA DIVINORUM A VERSUS OTHER 706 00:28:51,560 --> 00:28:52,480 CAPPA AGONISTS? 707 00:28:52,480 --> 00:28:53,760 AND WHEN WE REALLY GOT 708 00:28:53,760 --> 00:28:56,080 INTERESTED IN THIS THERE WERE NO 709 00:28:56,080 --> 00:28:56,640 REALLY READILY AVAILABLE 710 00:28:56,640 --> 00:28:58,760 RESOURCES TO LOOK AT ALL THE 711 00:28:58,760 --> 00:29:00,200 VARIOUS G-PROTEINS AND ARRESTINS 712 00:29:00,200 --> 00:29:03,120 THAT ARE DOWN STREAM OF A SINGLE 713 00:29:03,120 --> 00:29:05,200 RECEPTOR SO WE BUILT A RESOURCE, 714 00:29:05,200 --> 00:29:08,080 WE CALL IT TRUE PATH. 715 00:29:08,080 --> 00:29:11,680 IT ALLOWS FOR THE UNBIASED 716 00:29:11,680 --> 00:29:13,240 SCREENING, AND PROFILING OF DRUG 717 00:29:13,240 --> 00:29:17,480 ACTIONS DOWN STREAM OF EVERY 718 00:29:17,480 --> 00:29:20,520 ALPHA SUBUNIT, EVERY BETA AND 719 00:29:20,520 --> 00:29:22,400 ALPHA SUBUNIT, EVERY CONCEIVABLE 720 00:29:22,400 --> 00:29:24,480 COMBINATION AS WELL AS ALL THE 721 00:29:24,480 --> 00:29:24,760 ARRESTINS. 722 00:29:24,760 --> 00:29:27,200 AND TO MAKE A LONG STORY SHORT 723 00:29:27,200 --> 00:29:28,560 WE FOUND THAT SALVIA DIVINORUM A 724 00:29:28,560 --> 00:29:30,360 IS NOT PARTICULARLY UNUSUAL 725 00:29:30,360 --> 00:29:32,040 PREPARED TO OTHER CAPPA AGONISTS 726 00:29:32,040 --> 00:29:34,000 IN TERMS OF DOWN STREAM 727 00:29:34,000 --> 00:29:36,120 DIGINALLING BUT THERE ARE OTHER 728 00:29:36,120 --> 00:29:37,160 RECEPTORS AS WELL. 729 00:29:37,160 --> 00:29:40,240 AND AGAIN THIS IS AVAILABLE 730 00:29:40,240 --> 00:29:40,600 THROUGH AJENE. 731 00:29:40,600 --> 00:29:45,840 SO I WANT TO BRIEFLY HIGH LIE 732 00:29:45,840 --> 00:29:48,120 OTHER--SO, IN TERMS WAS THEME OF 733 00:29:48,120 --> 00:29:49,400 MY TALK WHICH IS NATURAL 734 00:29:49,400 --> 00:29:52,320 PRODUCTS AND THE RECEPTORS OF 735 00:29:52,320 --> 00:29:54,720 PERCEPTION, SO, YOU CAN SEE THAT 736 00:29:54,720 --> 00:29:56,200 THIS SINGLE MOLECULE 737 00:29:56,200 --> 00:29:57,040 SALVIA DIVINORUM A HIGHLY 738 00:29:57,040 --> 00:29:58,560 SELECTIVE FOR THE CAPPA RECEPTOR 739 00:29:58,560 --> 00:30:00,840 HAS A HUGE EFFECT ON HOW PEOPLE 740 00:30:00,840 --> 00:30:03,000 VIEW REALITY, HOW THEY PERCEIVE 741 00:30:03,000 --> 00:30:03,240 REALITY. 742 00:30:03,240 --> 00:30:04,160 OKAY, SO BECAUSE OF THAT, I 743 00:30:04,160 --> 00:30:05,640 WOULD SAY THAT THE CAPPA 744 00:30:05,640 --> 00:30:08,840 RECEPTOR IS A RECEPTOR FOR 745 00:30:08,840 --> 00:30:09,160 PERCEPTION. 746 00:30:09,160 --> 00:30:10,240 IT'S JUST NOT FOR THE TYPE OF 747 00:30:10,240 --> 00:30:12,320 PERCEPTION THAT WE NORMALLY 748 00:30:12,320 --> 00:30:15,920 THINK, IT'S PERCEPTION THAT'S 749 00:30:15,920 --> 00:30:16,600 INTERNALLY GENERATED, OKAY? 750 00:30:16,600 --> 00:30:20,640 WHAT ABOUT OTHER TYPES OF 751 00:30:20,640 --> 00:30:20,880 SENSATION? 752 00:30:20,880 --> 00:30:22,160 WELL ANOTHER TYPE OF PERCEPTION 753 00:30:22,160 --> 00:30:26,520 IS THE SENSE OF ITCH, RIGHT? 754 00:30:26,520 --> 00:30:30,160 SO THIS IS MORPHINE. 755 00:30:30,160 --> 00:30:31,440 FOR THOSE WHO ARE INTERESTED IN 756 00:30:31,440 --> 00:30:35,440 THE HISTORY OF NATURAL PRODUCTS, 757 00:30:35,440 --> 00:30:37,480 THIS IS TYPICALLY DESIGNATED AS 758 00:30:37,480 --> 00:30:39,960 THE FIRST NATURAL PRODUCT THAT 759 00:30:39,960 --> 00:30:44,240 WAS PURIFIED IN THE 1800S AND 760 00:30:44,240 --> 00:30:46,960 GIVEN THE NAME MORPHINE AFTER 761 00:30:46,960 --> 00:30:50,240 THE GOD MORPHUOUS, THE GOD OF 762 00:30:50,240 --> 00:30:50,880 SLEEP OR DREAMS. 763 00:30:50,880 --> 00:30:52,640 AND TYPICALLY WHEN YOU THINK 764 00:30:52,640 --> 00:30:54,480 ABOUT MORPHINE YOU THINK ABOUT 765 00:30:54,480 --> 00:30:55,320 THE CLASSICAL OPIATE RECEPTORS 766 00:30:55,320 --> 00:30:57,640 BUT THERE ARE A NUMBER OF VERY 767 00:30:57,640 --> 00:31:00,920 INTERESTING SIDE EFFECTS OR 768 00:31:00,920 --> 00:31:04,160 ADVERSE EEIVETS THAT OCCUR WITH 769 00:31:04,160 --> 00:31:08,040 MANY OPIOIDS, 1 OF WHICH IS 770 00:31:08,040 --> 00:31:09,440 ITCH. 771 00:31:09,440 --> 00:31:12,840 SO MANY, MANY PEOPLE HAVE 772 00:31:12,840 --> 00:31:15,040 EXTREME ITCHING BOUTS WHEN THEY 773 00:31:15,040 --> 00:31:16,720 TAKE OPIATES. 774 00:31:16,720 --> 00:31:19,160 AND IT TURNS OUT THAT THIS IS 775 00:31:19,160 --> 00:31:21,360 DUE TO A PSEUDOALLERGIC REACTION 776 00:31:21,360 --> 00:31:22,840 DUE TO THE INTERACTION OF 777 00:31:22,840 --> 00:31:24,480 MORPHINE WITH A PARTICULAR 778 00:31:24,480 --> 00:31:27,440 RECEPTOR THAT'S FOUND ON MASS 779 00:31:27,440 --> 00:31:29,520 CELLS THAT CAUSES MASS CELL 780 00:31:29,520 --> 00:31:33,720 DEGRANULATION, THIS IS THE 781 00:31:33,720 --> 00:31:36,440 RECEPTOR MRGPRX2, FOR MASS 782 00:31:36,440 --> 00:31:37,800 G-PROTEIN COUPLED RECEPTOR 783 00:31:37,800 --> 00:31:41,560 EXCLUSIVELY FOUND IN PRIMATES 784 00:31:41,560 --> 00:31:41,960 MRPMRX2. 785 00:31:41,960 --> 00:31:45,480 AND BASED ON THIS SINGLE FINDING 786 00:31:45,480 --> 00:31:48,360 THAT MORPHINE WAS A POTENT PLUS 787 00:31:48,360 --> 00:31:50,640 PLUS AND MINUS MORPHINE ARE 788 00:31:50,640 --> 00:32:01,240 EQUALLY GOOD AGONISTS FOR 789 00:32:01,240 --> 00:32:04,000 MRGPRX2, BUT FENTYNL IS NOT. 790 00:32:04,000 --> 00:32:08,080 THIS RECEPTOR IS ALSO ACTIVATED 791 00:32:08,080 --> 00:32:15,440 BY NEUROPEPTIDES, INCLUDING 792 00:32:15,440 --> 00:32:17,040 OPIATE LIKE COTTERY STATIN AND 793 00:32:17,040 --> 00:32:19,520 BASED ON THIS WE WERE ABLE TO 794 00:32:19,520 --> 00:32:21,280 SOLVE STRUCTURES BY ELECTRON 795 00:32:21,280 --> 00:32:23,480 MICROSCOPY OF THIS PARTICULAR 796 00:32:23,480 --> 00:32:26,040 RECEPTOR, TURNS OUT IT'S COUPLES 797 00:32:26,040 --> 00:32:27,160 TO MULTIPLE G-PROTEINS, THERE IS 798 00:32:27,160 --> 00:32:29,280 SOME DEBATE IN THE FIELD ABOUT 799 00:32:29,280 --> 00:32:30,880 WHICH G-PROTEIN ACTUALLY IS 800 00:32:30,880 --> 00:32:33,360 INVOLVED IN MASS CELL 801 00:32:33,360 --> 00:32:34,880 DEGRANULATION, OTHERS SAY GQ, 802 00:32:34,880 --> 00:32:37,560 OTHER SAY GI, WE SAY BOTH A 803 00:32:37,560 --> 00:32:38,520 SMALL MOLECULE AGONIST, AND 804 00:32:38,520 --> 00:32:43,360 THERE ARE NOW SMALL MOLECULE 805 00:32:43,360 --> 00:32:44,800 ANTAGONIST FOR MRGPR X2 THAT ARE 806 00:32:44,800 --> 00:32:46,600 IN CLINICAL TRIALS FOR TREATING 807 00:32:46,600 --> 00:32:54,040 ITCH AND A VARIETY OF OTHER 808 00:32:54,040 --> 00:32:54,840 INDICATIONS. 809 00:32:54,840 --> 00:32:56,000 SO OPIATES ARE ALSO RESPONSIBLE 810 00:32:56,000 --> 00:32:57,120 FOR THE SENSATION OF PAIN AND OF 811 00:32:57,120 --> 00:33:01,360 COURSE WE HAVE SOLVED MANY, MANY 812 00:33:01,360 --> 00:33:02,720 OPIATE RECEPTOR STRUCTURES. 813 00:33:02,720 --> 00:33:06,240 THERE ALSO IS THIS--IS THIS SORT 814 00:33:06,240 --> 00:33:09,000 OF RELATED RECEPTOR MRGPR X1 SO 815 00:33:09,000 --> 00:33:10,760 THIS IS A RECEPTOR IN THIS 816 00:33:10,760 --> 00:33:14,720 FAMILY ALTHOUGH IT APPEARS TO 817 00:33:14,720 --> 00:33:18,560 BE--TO HAVE BEEN EVOLVED TO GATE 818 00:33:18,560 --> 00:33:21,080 SENSATIONS OF PAIN THROUGH 819 00:33:21,080 --> 00:33:22,400 DORSAL ROOT GANGLIA NEURONS. 820 00:33:22,400 --> 00:33:25,480 IN FACT FOR THOSE WHO STUDY 821 00:33:25,480 --> 00:33:26,320 NEURONEURON SAYS THERE ARE 822 00:33:26,320 --> 00:33:28,160 EXPRESSING NEURONS THAT ARE VERY 823 00:33:28,160 --> 00:33:32,640 SPECIFIC SO IT TURNS OUT THAT 824 00:33:32,640 --> 00:33:36,680 OPIATE PEPTIDES ALSO INARCT WITH 825 00:33:36,680 --> 00:33:38,080 MRGPRX1 BUT IT TURNS OUT IT'S 826 00:33:38,080 --> 00:33:39,480 THE OTHER END OF THE PEPTIDE SO 827 00:33:39,480 --> 00:33:41,800 TO GIVE YOU AN EXAMPLE, THERE'S 828 00:33:41,800 --> 00:33:45,760 THIS OPIATE PEPTIDE CALLED BAM 829 00:33:45,760 --> 00:33:46,000 1-22. 830 00:33:46,000 --> 00:33:48,120 WHERE THE FIRST 8 OR SO AMINO 831 00:33:48,120 --> 00:33:50,440 ACIDS BASICALLY ARE DISCIPLINARY 832 00:33:50,440 --> 00:33:50,800 NOEVERIN. 833 00:33:50,800 --> 00:33:53,000 AND INTERACT WITH OPIATE 834 00:33:53,000 --> 00:33:55,800 RECEPTORS, AND THEN THE AMINO 835 00:33:55,800 --> 00:33:57,440 ACIDS 8-22 ACTUALLY ACTIVATE 836 00:33:57,440 --> 00:33:58,200 THIS PARTICULAR RECEPTOR. 837 00:33:58,200 --> 00:34:04,080 SO YOU HAVE THIS VERY 838 00:34:04,080 --> 00:34:07,040 INTERESTING SITUATION, WHERE 1 839 00:34:07,040 --> 00:34:09,240 CLEAVAGE PRODUCT, BAM 1-8 840 00:34:09,240 --> 00:34:10,640 ACTIVATE OPIATE RECEPTORS TO 841 00:34:10,640 --> 00:34:14,880 REDUCE PAIN AND THEN 8-22 842 00:34:14,880 --> 00:34:16,040 ACTIVATES MRGPRX1 RECEPTORS TO 843 00:34:16,040 --> 00:34:16,400 REDUCE PAIN. 844 00:34:16,400 --> 00:34:19,520 SO WE THINK THIS IS PROBABLY A 845 00:34:19,520 --> 00:34:23,880 REALLY GOOD TARGET AGAIN FOR 846 00:34:23,880 --> 00:34:24,240 PAIN. 847 00:34:24,240 --> 00:34:27,160 BIOACIDS, IT TURNS OUT ALSO 848 00:34:27,160 --> 00:34:29,680 INDUCE ITCH UNLIKE OPIATE 849 00:34:29,680 --> 00:34:31,800 PEPTIDES AND SMALL MOLECULE 850 00:34:31,800 --> 00:34:32,920 OPIOIDS THESE ARE NEGATIVELY 851 00:34:32,920 --> 00:34:34,800 CHARGED SO 1 OF THE THINGS 852 00:34:34,800 --> 00:34:40,680 THAT'S VERY COMMON AMONG DRUG 853 00:34:40,680 --> 00:34:42,440 THAT ACTIVATE MRGPH X2 IS 854 00:34:42,440 --> 00:34:44,600 THEY'RE AUGHT PROFILES, THERE'S 855 00:34:44,600 --> 00:34:47,840 THIS COMPANION RECEPTOR CALLED 856 00:34:47,840 --> 00:34:50,640 MRGPRX4 WHICH IS ACTIVATED BY 857 00:34:50,640 --> 00:34:51,240 NEGATIVELY CHARGED SUBSTANCES. 858 00:34:51,240 --> 00:34:54,720 SO IT TURNS OUT THAT WE HAVE 859 00:34:54,720 --> 00:34:57,360 THIS RECEPTOR SYSTEM THAT HAS 860 00:34:57,360 --> 00:35:01,560 EVOLVED IN THE CASE OF X2 AND 861 00:35:01,560 --> 00:35:04,080 X4, PROBABLY DOES NOT HAVE 862 00:35:04,080 --> 00:35:06,920 ENDOGENOUS LIGANDS BUT HAS 863 00:35:06,920 --> 00:35:09,800 EVOLVED AS A SENSOR FOR NOXIOUS 864 00:35:09,800 --> 00:35:11,040 SUBSTANCES IN THE ENVIRONMENT, 865 00:35:11,040 --> 00:35:11,280 OKAY? 866 00:35:11,280 --> 00:35:17,000 AND IN THIS CASE, 1 RECEPTOR HAS 867 00:35:17,000 --> 00:35:19,200 BEEN--HAS EVOLVED TO SORT OF BE 868 00:35:19,200 --> 00:35:21,680 SENSITIVE TO POSITIVELY CHARGED 869 00:35:21,680 --> 00:35:23,960 PURE ANTIGEN AND THE OTHER TO 870 00:35:23,960 --> 00:35:25,200 NEGATIVELY CHARGE FOR ANTIGENS. 871 00:35:25,200 --> 00:35:26,200 VERY INTERESTING AND WHEN YOU 872 00:35:26,200 --> 00:35:28,120 LOOK AT THE STRUCTURES IT MAKES 873 00:35:28,120 --> 00:35:29,680 COMPLETE SENSE BY THE STRUCTURE. 874 00:35:29,680 --> 00:35:31,760 IN 1 CASE THERE'S A HUGE 875 00:35:31,760 --> 00:35:32,680 POSITIVELY CHARGED WELL, THE 876 00:35:32,680 --> 00:35:35,120 OTHER CASE A NEGATIVELY CHARGED 877 00:35:35,120 --> 00:35:35,320 WELL. 878 00:35:35,320 --> 00:35:44,320 SO VERY, VERY INTERESTING. 879 00:35:44,320 --> 00:35:44,920 AND THAT'S MORPHINE. 880 00:35:44,920 --> 00:35:48,800 ALL RIGHT, SO, ONCE WE HAD ALL 881 00:35:48,800 --> 00:35:50,080 THESE STRUCTURES I USED TO TELL 882 00:35:50,080 --> 00:35:53,160 THIS JOKE THAT AT THE END OF 883 00:35:53,160 --> 00:35:55,200 EVERY STRUCTURE PAPER, THE LAST 884 00:35:55,200 --> 00:35:56,840 SENTENCE OF EVERY ABSTRACT AND 885 00:35:56,840 --> 00:35:58,640 THE LAST SENTENCE OF ANY 886 00:35:58,640 --> 00:35:59,680 DISCUSSION IS THIS STRUCTURE 887 00:35:59,680 --> 00:36:02,960 WILL BE IMPORTANT FOR DRUG 888 00:36:02,960 --> 00:36:03,560 DISCOVERY, RIGHT? 889 00:36:03,560 --> 00:36:04,960 AND THEN THAT'S IT, YOU NEVER 890 00:36:04,960 --> 00:36:07,320 HEAR ANYTHING ELSE ABOUT IT. 891 00:36:07,320 --> 00:36:07,680 [LAUGHTER] 892 00:36:07,680 --> 00:36:10,520 OKAY, SO WE DECIDED TO DO 893 00:36:10,520 --> 00:36:11,120 SOMETHING ABOUT THAT. 894 00:36:11,120 --> 00:36:14,400 SO OVER THE YEARS I COLLABORATED 895 00:36:14,400 --> 00:36:16,280 MAINLY WITH THE [INDISCERNIBLE] 896 00:36:16,280 --> 00:36:18,440 LAB AT UCSF, TO MAKE SMALL 897 00:36:18,440 --> 00:36:21,040 MOLECULE PROBES FOR A NUMBER OF 898 00:36:21,040 --> 00:36:21,960 THESE PRIMARILY UNDERSTUDIED 899 00:36:21,960 --> 00:36:26,280 RECEPTORS FOR WHICH WE HAD 900 00:36:26,280 --> 00:36:27,000 STRUCTURES OR STRUCTURAL 901 00:36:27,000 --> 00:36:28,840 INFORMATION, SO THESE ARE JUST 902 00:36:28,840 --> 00:36:35,720 VARIOUS, YOU KNOW VARIOUS 903 00:36:35,720 --> 00:36:36,080 RECEPTORS HERE. 904 00:36:36,080 --> 00:36:37,200 IF YOU--IF YOU'RE INTERESTED IN 905 00:36:37,200 --> 00:36:43,880 READING ANY OF THESE PAPERS, I 906 00:36:43,880 --> 00:36:48,280 WOULD HIGHLIGHT 2, SO THIS IS A 907 00:36:48,280 --> 00:36:49,440 REALLY INTERESTING PAPER, WHERE 908 00:36:49,440 --> 00:36:52,360 WE USE STRUCTURE TO OPTIMIZE A 909 00:36:52,360 --> 00:36:54,720 COMPOUND THAT WAS IN THE PATENT 910 00:36:54,720 --> 00:36:56,960 LITERATURE WHICH IS A COMMON 911 00:36:56,960 --> 00:36:57,760 PROBLEM BASICALLY, IF THERE'S 912 00:36:57,760 --> 00:36:59,320 SOMETHING GOOD IN THE PATENT 913 00:36:59,320 --> 00:37:00,160 LITERATURE BUT IT'S NOT GOOD 914 00:37:00,160 --> 00:37:01,480 ENOUGH AND YOU NEED TO OPTIMIZE 915 00:37:01,480 --> 00:37:04,800 IT, YOU DON'T KNOW HOW, SO WE 916 00:37:04,800 --> 00:37:07,200 GOT A STRUCTURE. 917 00:37:07,200 --> 00:37:08,680 AND BY COMPARISON, AROUND THE 918 00:37:08,680 --> 00:37:12,480 SAME TIME WE PUBLISHED A PAPER 919 00:37:12,480 --> 00:37:13,880 IN J-MED CHEM WHERE WE DIDN'T 920 00:37:13,880 --> 00:37:15,400 HAVE A STRUCTURE BUT WE DID 921 00:37:15,400 --> 00:37:16,920 DOCKING AGAINST A MODEL AND IT 922 00:37:16,920 --> 00:37:20,080 TURNED OUT THE COMPOUND THAT WE 923 00:37:20,080 --> 00:37:21,800 GOT FROM STRUCTURE GUIDED 924 00:37:21,800 --> 00:37:23,760 DISCOVERY WAS SELECTIVE AND 925 00:37:23,760 --> 00:37:25,240 POTENT AND THE COMPOUND WE GOT 926 00:37:25,240 --> 00:37:27,680 FROM IT WAS STRICTLY MODELING 927 00:37:27,680 --> 00:37:30,880 BASED APPROACH WAS NOT, NOT AS, 928 00:37:30,880 --> 00:37:35,360 SO IT DOES, IT DOES HELP AND I 929 00:37:35,360 --> 00:37:36,280 THINK THAT'S--THAT PAPER IN THIS 930 00:37:36,280 --> 00:37:37,880 PARTICULAR IS A PRETTY GOOD 1. 931 00:37:37,880 --> 00:37:40,400 THE OTHER 1 IS--AND THAT COMES 932 00:37:40,400 --> 00:37:41,680 COMPLETELY FROM MY LAB, THE 933 00:37:41,680 --> 00:37:46,760 OTHER 1 IS THIS NICE 1 ON THE 934 00:37:46,760 --> 00:37:48,160 CB2 RECEPTOR FROM 935 00:37:48,160 --> 00:37:50,440 [INDISCERNIBLE]'S LAB AND MY 936 00:37:50,440 --> 00:37:54,640 LAB, WHERE HE HAS DEVISED A 937 00:37:54,640 --> 00:37:55,720 NOVEL APPROACH FOR ULTRA LARGE 938 00:37:55,720 --> 00:38:01,480 SCALE DOCKING THAT HE CALLS 939 00:38:01,480 --> 00:38:02,760 D-SYNTHESIS FOR VIRTUAL SYNTH 940 00:38:02,760 --> 00:38:05,840 COPD AND IT INVOLVES THE DOCKING 941 00:38:05,840 --> 00:38:07,480 OF FRAGMENTS OF BUILT BY 942 00:38:07,480 --> 00:38:08,760 COMPUTER BY BUILDING PLOKS AND 943 00:38:08,760 --> 00:38:11,920 USING THIS YEAR NOW ABLE TO 944 00:38:11,920 --> 00:38:15,440 INTERROGATE TRILLIONS OF 945 00:38:15,440 --> 00:38:15,960 MOLECULES COMPUTATIONALLY. 946 00:38:15,960 --> 00:38:18,120 SO THESE ARE BOTH REALLY, REALLY 947 00:38:18,120 --> 00:38:20,560 NICE EXAMPLES OF THAT. 948 00:38:20,560 --> 00:38:21,920 SO THE TIME THEY HAVE REMAINING 949 00:38:21,920 --> 00:38:27,400 I WANT TO TALK ABOUT 950 00:38:27,400 --> 00:38:29,120 PSYCHEDELICS. 951 00:38:29,120 --> 00:38:34,560 AND PSYCHEDELICS HAVE SORT OF A 952 00:38:34,560 --> 00:38:36,600 CHECKERED HISTORY BUT YOU KNOW 953 00:38:36,600 --> 00:38:38,040 RECENTLY LIKE LAST 3 YEARS OR 954 00:38:38,040 --> 00:38:41,960 SO, 3 OR 4 YEARS THEY'VE BECOME 955 00:38:41,960 --> 00:38:44,240 QUITE POPULAR IN THE 956 00:38:44,240 --> 00:38:45,720 NONSCIENTIFIC AREA. 957 00:38:45,720 --> 00:38:50,480 AND SOMEWHAT POPULAR AMONG 958 00:38:50,480 --> 00:38:50,920 SCIENTISTS AS WELL. 959 00:38:50,920 --> 00:38:52,560 AND BEFORE I TALK TO THEM, I 960 00:38:52,560 --> 00:38:54,400 WOULD LIKE TO GIVE EVERYBODY MY 961 00:38:54,400 --> 00:38:56,920 DEFINITION OF A PSYCHEDELIC. 962 00:38:56,920 --> 00:38:59,120 SO, THIS IS MY DEFINITION, IT 963 00:38:59,120 --> 00:39:01,000 ALSO TURNS OUT THIS IS THE 964 00:39:01,000 --> 00:39:03,280 DEFINITION THAT THE FDA USES, 965 00:39:03,280 --> 00:39:05,400 IT'S ALSO THE DEFINITION THAT 966 00:39:05,400 --> 00:39:09,040 THE DEA USES AND IT'S ALSO THE 967 00:39:09,040 --> 00:39:12,680 DEFINITION THAT THE EUROPEAN 968 00:39:12,680 --> 00:39:14,280 REGULATORY AGENCIES USE, OKAY? 969 00:39:14,280 --> 00:39:15,480 AND THIS IS THE DEFINITION THAT 970 00:39:15,480 --> 00:39:17,560 MY LAB AND EVERYBODY ELSE IN THE 971 00:39:17,560 --> 00:39:21,040 FIELD HAS USED SINCE THE 1970S, 972 00:39:21,040 --> 00:39:21,400 BASICALLY. 973 00:39:21,400 --> 00:39:27,560 SO PSYCHEDELIC DRUGS ARE 5 HT2A 974 00:39:27,560 --> 00:39:29,240 AGONIST WHICH INDUCE LSD-LICK 975 00:39:29,240 --> 00:39:29,720 ACTIONS IN HUMANS. 976 00:39:29,720 --> 00:39:33,760 SO IF YOU READ, MDMA, SO ECSTAS 977 00:39:33,760 --> 00:39:38,440 EXPE KETAMINE, THESE ARE NOT 978 00:39:38,440 --> 00:39:40,120 PSYCHEDELIC DRUGS, THEY'RE 979 00:39:40,120 --> 00:39:40,680 HALLUC NO GENERATEDS. 980 00:39:40,680 --> 00:39:42,600 THE REASON I GO INTO THIS IS 981 00:39:42,600 --> 00:39:46,640 THAT I FREQUENTLY GET 982 00:39:46,640 --> 00:39:50,920 INTERVIEWED BY NEWS MEDIA BY 983 00:39:50,920 --> 00:39:51,720 PSYCHEDELICS SINCE I'M 1 OF THE 984 00:39:51,720 --> 00:39:54,120 FEW PEOPLE WHO HAS A GRANT TO 985 00:39:54,120 --> 00:39:55,720 STUDY PSYCHEDELICS SO I'M 1 OF 986 00:39:55,720 --> 00:39:59,680 THE FEW SCIENTIFIC EXPERTS OUT 987 00:39:59,680 --> 00:40:01,680 THERE AND WHAT I HAVE FOUND IS 988 00:40:01,680 --> 00:40:04,320 TAKEN--THEY KETAMINE IS 989 00:40:04,320 --> 00:40:05,840 CONSIDERED A PSYCHEDELIC, MDMA 990 00:40:05,840 --> 00:40:07,480 IS A PSYCHEDELIC, IT'S ALMOST 991 00:40:07,480 --> 00:40:09,640 LIKE ANY DRUG THAT ALTERS HOW 992 00:40:09,640 --> 00:40:12,640 YOU FEEL IS CONSIDERED A 993 00:40:12,640 --> 00:40:12,920 PSYCHEDELIC. 994 00:40:12,920 --> 00:40:15,040 OKAY, BUT WHAT I LIKE TO POINT 995 00:40:15,040 --> 00:40:18,800 OUT IS THERE'S A SCIENCE BEHIND 996 00:40:18,800 --> 00:40:21,680 THIS, SO, THESE ARE--THESE DRUGS 997 00:40:21,680 --> 00:40:24,000 ARE CLASSIFIED AS HALLUCIN O 998 00:40:24,000 --> 00:40:26,880 GENIC AGENTS BECAUSE THEY INDUCE 999 00:40:26,880 --> 00:40:28,280 HA LIEWTIONZINATIONS AND WHICH 1000 00:40:28,280 --> 00:40:34,840 INCLUDE DRUGS LIE LSD, 1001 00:40:34,840 --> 00:40:36,800 PSILOCYBIN AND THERE ARE DRUGS 1002 00:40:36,800 --> 00:40:40,880 THAT INDUCE DELERIUM, SO THESE 1003 00:40:40,880 --> 00:40:43,760 ARE GABBA RECEPTOR MODULATORS 1004 00:40:43,760 --> 00:40:47,680 FROM AMINITTA AS WELL AS 1005 00:40:47,680 --> 00:40:49,080 [INDISCERNIBLE] OCCASIONS FROM 1006 00:40:49,080 --> 00:40:51,840 MUSHROOMS AND OTHER SOURCES SO 1007 00:40:51,840 --> 00:40:53,120 THEY INDUCE A DELERIUM AND THERE 1008 00:40:53,120 --> 00:40:55,080 ARE DRUGS THAT INDUCE A DREAM 1009 00:40:55,080 --> 00:40:59,560 LIKE STATE THAT ARE CALLED 1010 00:40:59,560 --> 00:41:02,640 ONERAGENSS AND THESE ARE 1S LIKE 1011 00:41:02,640 --> 00:41:03,080 SALVIA DIVINORUM AND 1012 00:41:03,080 --> 00:41:03,440 [INDISCERNIBLE]. 1013 00:41:03,440 --> 00:41:06,200 NOW THE THING ABOUT THIS 1014 00:41:06,200 --> 00:41:08,040 CLASSIFICATION SCHEME IS THAT 1015 00:41:08,040 --> 00:41:10,080 EVERYTHING IS CLASSIFIED BY 1016 00:41:10,080 --> 00:41:13,960 MECHANISM OF ACTION, SO THESE 1017 00:41:13,960 --> 00:41:19,800 ARE CAPPA AGONIST, SCOPOLAMINE 1018 00:41:19,800 --> 00:41:24,240 AND AMANITA, IS ARE AGONISTS AND 1019 00:41:24,240 --> 00:41:27,680 ALL THOSE DRUGS ARE THE HTMP2 A 1020 00:41:27,680 --> 00:41:27,960 AGONISTS. 1021 00:41:27,960 --> 00:41:29,600 AND THOSE ARE THE DRUGS I'M 1022 00:41:29,600 --> 00:41:31,280 GOING TO TALK ABOUT IN THE TIME 1023 00:41:31,280 --> 00:41:32,120 I HAVE REMAINING. 1024 00:41:32,120 --> 00:41:33,800 NOW THEY HAVE DIFFERENT EFFECTS 1025 00:41:33,800 --> 00:41:41,240 IN HUMANS SO KETAMINE IS 1026 00:41:41,240 --> 00:41:42,360 DIFFERENT FROM PSILOCYBIN, IN 1027 00:41:42,360 --> 00:41:42,920 HUMANS. 1028 00:41:42,920 --> 00:41:45,840 SO THIS IS AN OLD VIDEO I PULLED 1029 00:41:45,840 --> 00:41:48,240 FROM YouTUBE OF A WOMAN IN THE 1030 00:41:48,240 --> 00:41:50,800 1950 WHO IS WAS GIVEN LSD AND 1031 00:41:50,800 --> 00:41:57,640 SHE'S HAVING A PSYCHEDELIC 1032 00:41:57,640 --> 00:41:58,520 EXPERIENCE HERE. 1033 00:41:58,520 --> 00:42:03,480 IT'S HERE, CAN YOU FEEL IT? 1034 00:42:03,480 --> 00:42:04,880 EVERYTHING IS COLORED AND I CAN 1035 00:42:04,880 --> 00:42:06,640 FEEL THE AIR. 1036 00:42:06,640 --> 00:42:13,200 SO SHE'S HAVING SYNESTHESIA, 1037 00:42:13,200 --> 00:42:13,400 RIGHT? 1038 00:42:13,400 --> 00:42:17,840 I'M FINE WITH IT, CAN'T YOU SEE 1039 00:42:17,840 --> 00:42:23,960 IT? 1040 00:42:23,960 --> 00:42:24,840 >>I'M TRYING. 1041 00:42:24,840 --> 00:42:25,800 >>I FEEL FREE. 1042 00:42:25,800 --> 00:42:31,440 >>OKAY, SO THAT'S A PSYCHEDELIC 1043 00:42:31,440 --> 00:42:31,880 EXPERIENCE. 1044 00:42:31,880 --> 00:42:33,040 >>OKAY, SOME PEOPLE HAVE MAYBE 1045 00:42:33,040 --> 00:42:34,200 EXPERIENCED THAT. 1046 00:42:34,200 --> 00:42:40,960 AND HERE IS A RECENT KETAMINE 1047 00:42:40,960 --> 00:42:41,400 EXPERIENCE. 1048 00:42:41,400 --> 00:42:43,560 [♪ MUSIC ♪] 1049 00:42:43,560 --> 00:42:44,800 >>SO FIRST THING TO NOTICE IS 1050 00:42:44,800 --> 00:42:52,320 HE DOESN'T KNOW WHERE HE IS. 1051 00:42:52,320 --> 00:43:00,080 SO HE'S PRETTY OUT OF IT. 1052 00:43:00,080 --> 00:43:00,600 >>[INDISCERNIBLE] 1053 00:43:00,600 --> 00:43:01,000 >>INCREDIBLE. 1054 00:43:01,000 --> 00:43:06,320 >>WHAT ARE THE THOUGHTS IN YOUR 1055 00:43:06,320 --> 00:43:06,680 MIND? 1056 00:43:06,680 --> 00:43:17,200 >>THAT WE'RE ALL CONNECTED. 1057 00:43:17,960 --> 00:43:20,040 THAT WE'RE ALTOGETHER. 1058 00:43:20,040 --> 00:43:22,560 WE--IT'S JUST SO CLEAR--WE ARE 1059 00:43:22,560 --> 00:43:26,960 ALL IN THIS TOGETHER. 1060 00:43:26,960 --> 00:43:28,640 WHAT IS THIS, WE'RE ALL IN THIS 1061 00:43:28,640 --> 00:43:34,840 TOGETHER IN WHAT IS THIS? 1062 00:43:34,840 --> 00:43:38,280 >>WELL I MEAN LIKE OUR LIVES, 1063 00:43:38,280 --> 00:43:42,480 OUR PURPOSE, OUR SOUL. 1064 00:43:42,480 --> 00:43:47,600 WE'RE ALL--IT'S CRAZY HOW WE'RE 1065 00:43:47,600 --> 00:43:48,120 ALL FEELING. 1066 00:43:48,120 --> 00:43:53,160 >>ALL RIGHT, SO YOU CAN SEE 1067 00:43:53,160 --> 00:43:54,760 THAT'S A DIFFERENT--DIFFERENT 1068 00:43:54,760 --> 00:43:55,200 EXPERIENCE. 1069 00:43:55,200 --> 00:43:57,960 THEY'RE BOTH HAVING AN APPARENT 1070 00:43:57,960 --> 00:43:59,760 EXPERIENCE OF 1NESS BUT THE 1071 00:43:59,760 --> 00:44:01,560 PHENOMENOLOGY OF THE EXPERIENCE 1072 00:44:01,560 --> 00:44:03,760 IS QUITE DIFFERENT THAT'S WHY I 1073 00:44:03,760 --> 00:44:05,960 LIKE TO REFER TO PSYCHEDELICS AS 1074 00:44:05,960 --> 00:44:09,120 DIFFERENT DRUGS SO THEY HAVE 1075 00:44:09,120 --> 00:44:14,080 UNIQUE PROPERTIES WHICH HAVE 1076 00:44:14,080 --> 00:44:17,120 RECENTLY BEEN IN LARGE PART THE 1077 00:44:17,120 --> 00:44:20,520 REASON FOR THEIR, I WOULD SAY 1078 00:44:20,520 --> 00:44:22,920 INTEREST AMONG MEDICAL 1079 00:44:22,920 --> 00:44:23,760 PROFESSIONALS AND OTHERS AND 1080 00:44:23,760 --> 00:44:25,720 THESE WERE STUDIES THAT WERE 1081 00:44:25,720 --> 00:44:30,240 DONE PRIMARILY BY 2 GROUPS, 1082 00:44:30,240 --> 00:44:32,080 GRIFFITH'S GROUP AT HOPKINS AND 1083 00:44:32,080 --> 00:44:34,960 THE GROUP AT NYU BASICALLY 1084 00:44:34,960 --> 00:44:36,400 PUBLISHED BACK-TO-BACK PAPERS IN 1085 00:44:36,400 --> 00:44:46,920 2016 SHOWING THAT A SINGLE DOSE 1086 00:44:49,600 --> 00:44:51,240 OF PSILOCYBIN, SHOWED A RAPID 1087 00:44:51,240 --> 00:44:52,960 EFFECT ON DEPRESSION, SO MUCH SO 1088 00:44:52,960 --> 00:44:55,440 THAT A LOT OF PATIENTS WERE NO 1089 00:44:55,440 --> 00:45:00,200 LONGER DEPRESSED AFTER A DOSE OF 1090 00:45:00,200 --> 00:45:01,960 PSILOCYBIN, THEY WERE STILL NOT 1091 00:45:01,960 --> 00:45:03,360 DEPRESSED AFTER A YEAR, SO THESE 1092 00:45:03,360 --> 00:45:05,560 WERE PEOPLE THAT WERE TREATMENT 1093 00:45:05,560 --> 00:45:07,800 RESISTANT, HAD VERY, VERY 1094 00:45:07,800 --> 00:45:09,280 SERIOUS DEPRESSION, HAD BEEN 1095 00:45:09,280 --> 00:45:11,520 TRIED WITH MULTIPLE OTHER 1096 00:45:11,520 --> 00:45:12,560 MEDICATIONS, NO EFFECT. 1097 00:45:12,560 --> 00:45:15,640 BASICALLY GIVEN A SINGLE SORT OF 1098 00:45:15,640 --> 00:45:17,040 REALLY A MAZZIVE DOSE OF 1099 00:45:17,040 --> 00:45:20,280 PSILOCYBIN AND THEY HAD A 1100 00:45:20,280 --> 00:45:21,000 INTENSE PSYCHEDELIC EXPERIENCE, 1101 00:45:21,000 --> 00:45:23,080 THE NEXT DAY THEY WERE FINE AND 1102 00:45:23,080 --> 00:45:24,160 THEIR DEPRESSION WAS GONE FOR UP 1103 00:45:24,160 --> 00:45:27,840 TO A YEAR. 1104 00:45:27,840 --> 00:45:30,920 OKAY, SO THIS IS IN LARGE 1105 00:45:30,920 --> 00:45:32,760 MEASURE HAS BEEN FUELING THE 1106 00:45:32,760 --> 00:45:34,360 RECENT INTEREST IN PSYCHEDELICS 1107 00:45:34,360 --> 00:45:37,960 BECAUSE OF THE POTENTIAL FOR 1108 00:45:37,960 --> 00:45:38,840 THEIR TRANSFORMATIVE THERAPEUTIC 1109 00:45:38,840 --> 00:45:41,720 UTILITY FOR NEARLY EVERY 1110 00:45:41,720 --> 00:45:42,400 NEUROPSYCHIATRIC DISORDER WITH 1111 00:45:42,400 --> 00:45:44,480 THE EXPRESSION OF DISEASES LIKE 1112 00:45:44,480 --> 00:45:46,240 SCETS FRENNIA AND BIPOLAR 1113 00:45:46,240 --> 00:45:53,800 DISORDER WHERE THEY WOULD MAKE 1114 00:45:53,800 --> 00:45:54,280 YOU WORSE, BASICALLY. 1115 00:45:54,280 --> 00:45:56,480 AND MDMA WHICH IS NOT A 1116 00:45:56,480 --> 00:45:58,080 PSYCHEDELIC BUT SOMETIMES LUMPED 1117 00:45:58,080 --> 00:46:00,720 INTO THAT NOW HAS 2 POSITIVE 1118 00:46:00,720 --> 00:46:04,840 PHASE 3 CLINICAL TRIALS FOR 1119 00:46:04,840 --> 00:46:05,680 TREATING POST-TRAUMATIC STRESS 1120 00:46:05,680 --> 00:46:08,320 DISORDER AND FOR THOSE WHO ARE 1121 00:46:08,320 --> 00:46:10,280 INTERESTED, I URGE YOU TO READ 1122 00:46:10,280 --> 00:46:13,440 THE ORIGINAL PAPER WHICH WAS TUB 1123 00:46:13,440 --> 00:46:14,880 PUBLISHED ONINATE AND YOU ARE 1124 00:46:14,880 --> 00:46:17,080 MEDICINE ASK TREAT A LOT OF 1125 00:46:17,080 --> 00:46:19,400 PEOPLE WITH PTSD IN MY DAY WHEN 1126 00:46:19,400 --> 00:46:20,800 I WAS TREATING PSYCHIATRY THERE 1127 00:46:20,800 --> 00:46:23,040 WAS NOTHING THAT HAD THIS EFFECT 1128 00:46:23,040 --> 00:46:23,920 OF MDMA. 1129 00:46:23,920 --> 00:46:27,680 THE EFFECT IS HUMONGOUS AND IS 1130 00:46:27,680 --> 00:46:28,160 ROBUST. 1131 00:46:28,160 --> 00:46:29,880 AND LIKELY MDMA WILL BE APPROVED 1132 00:46:29,880 --> 00:46:32,680 NEXT YEAR AND IT WILL TRANSFORM 1133 00:46:32,680 --> 00:46:34,640 HOW WE TREAT POST-TRAUMATIC 1134 00:46:34,640 --> 00:46:35,000 STRESS DISORDER. 1135 00:46:35,000 --> 00:46:36,880 AS WELL THE PSYCHEDELIC DRUGS 1136 00:46:36,880 --> 00:46:41,280 LIKELY WILL BE APPROVED FOR 1137 00:46:41,280 --> 00:46:41,960 DEPRESSION, OBSESSIVE COMPULSIVE 1138 00:46:41,960 --> 00:46:43,120 DISORDER ISSUES CLUSTER 1139 00:46:43,120 --> 00:46:45,960 HEADACHES A HUGE SWATH OF 1140 00:46:45,960 --> 00:46:48,640 THINGS, THIS IS ALSO HOW 1141 00:46:48,640 --> 00:46:49,520 PSYCHIATRIC CARE WILL BE GIVEN 1142 00:46:49,520 --> 00:46:50,640 IN THE UNITED STATES AND 1143 00:46:50,640 --> 00:46:52,240 ELSEWHERE, THE PROBLEM IS WE 1144 00:46:52,240 --> 00:46:53,440 HAVE ALMOST NO INFORMATION ABOUT 1145 00:46:53,440 --> 00:46:55,440 HOW THEY WORK. 1146 00:46:55,440 --> 00:46:55,640 OKAY? 1147 00:46:55,640 --> 00:47:00,640 SO SOME YEARS AGO, WHEN THE NIH 1148 00:47:00,640 --> 00:47:02,680 FINALLY FUNDED ME TO STUDY 1149 00:47:02,680 --> 00:47:04,320 PSYCHEDELICS, I TOLD THE 1150 00:47:04,320 --> 00:47:05,720 STUDENTS, I WROTE GRANTS TO 1151 00:47:05,720 --> 00:47:06,880 STUDY PSYCHEDELICS FROM THE 1152 00:47:06,880 --> 00:47:09,280 1990S AND I THEY NEVER GOT 1153 00:47:09,280 --> 00:47:09,640 FUNDED. 1154 00:47:09,640 --> 00:47:11,920 MY FIRST GRANT GOT FUNDED IN 1155 00:47:11,920 --> 00:47:14,760 2017 SO IT TOOK A LONG TIME BUT 1156 00:47:14,760 --> 00:47:17,920 THE FIRST THING WE DID WAS JUST 1157 00:47:17,920 --> 00:47:19,600 LOOK AT PHARMAICOLOGY AND WE 1158 00:47:19,600 --> 00:47:21,640 FOUND IT HAS A EXTREMELY 1159 00:47:21,640 --> 00:47:22,560 COMPLICATED PHARMAICOLOGY AND 1160 00:47:22,560 --> 00:47:25,200 YOU CAN SEE INTERACTING WITH 1161 00:47:25,200 --> 00:47:26,960 EVERY BIOGENIC AMINE RECEPTOR IN 1162 00:47:26,960 --> 00:47:28,800 THE HUMAN GENOME BUT WE THINK 1163 00:47:28,800 --> 00:47:29,960 IT'S ONLY THE INTERACTION WITH 1164 00:47:29,960 --> 00:47:33,200 THAT 1 RECEPTOR HERE, THE 5 HT2 1165 00:47:33,200 --> 00:47:38,760 A THAT'S RESPONSIBLE FOR ITS 1166 00:47:38,760 --> 00:47:39,000 ACTION. 1167 00:47:39,000 --> 00:47:41,800 AND YOU KNOW AS I SAID WE HAD 1168 00:47:41,800 --> 00:47:46,160 BUILT ALL OF THESE RESOURCES TO 1169 00:47:46,160 --> 00:47:48,040 SCREEN DRUGS SO WE DECIDED TO 1170 00:47:48,040 --> 00:47:50,360 MAKE A FORAY INTO THE 1171 00:47:50,360 --> 00:47:56,160 PSYCHEDELIC DRUG SPACE AND SO WE 1172 00:47:56,160 --> 00:47:57,640 IDENTIFIED ULTIMATELY 44 IKE 1173 00:47:57,640 --> 00:47:58,240 DELATWALLIC DRUGS, DRUGS THAT 1174 00:47:58,240 --> 00:48:01,040 ARE KNOWN TO BE PSYCHEDELIC IN 1175 00:48:01,040 --> 00:48:03,240 DRUGS IN HUMANS OF VARIOUS 1176 00:48:03,240 --> 00:48:04,960 CHEMICAL CLASSES AND THEN WE 1177 00:48:04,960 --> 00:48:06,680 SCREENED THEM USING THE VARIOUS 1178 00:48:06,680 --> 00:48:10,280 ASSAY PLATFORMS THAT I MENTIONED 1179 00:48:10,280 --> 00:48:12,360 SO AGAIN 320 GPC Rs AND THEN 1180 00:48:12,360 --> 00:48:13,680 QUAWBTIFIED THE SIGNALING 1181 00:48:13,680 --> 00:48:17,560 THROUGH EVERY TRANSDUCER. 1182 00:48:17,560 --> 00:48:19,680 AND THIS IS WHAT WE GET, SO THIS 1183 00:48:19,680 --> 00:48:21,440 IS A HEAT MAP OF THE DATA SO 1184 00:48:21,440 --> 00:48:24,400 THESE ARE DRUGS GOING DOWN HERE 1185 00:48:24,400 --> 00:48:26,080 THESE ARE YOU ARE RECEPTORS 1186 00:48:26,080 --> 00:48:26,560 GOING UP HERE. 1187 00:48:26,560 --> 00:48:32,040 YOU CAN IMAGINE THIS WAS A LOT 1188 00:48:32,040 --> 00:48:33,160 OF WORK BY [INDISCERNIBLE] AND 1189 00:48:33,160 --> 00:48:36,040 YOU CAN SEE THIS IS AN LSD 1190 00:48:36,040 --> 00:48:37,200 ANALOGUE, IT'S ACTIVE IN 1191 00:48:37,200 --> 00:48:40,080 EVERYTHING, IT'S BECAUSE IT 1192 00:48:40,080 --> 00:48:45,480 INHIBITS LUCIFERASE DEGRADATIO, 1193 00:48:45,480 --> 00:48:47,320 SO IT'S A LUCIFERASE STABILIZER 1194 00:48:47,320 --> 00:48:48,920 BUT CAN YOUEE THERE ARE 3 1195 00:48:48,920 --> 00:48:52,160 GENERAL FAMILIES OF RECEPTORS 1196 00:48:52,160 --> 00:48:54,720 THAT ACTIVATE, SEROTONIN, 1197 00:48:54,720 --> 00:48:56,000 DOPAMINE AND ADRENAL CANCERERGIC 1198 00:48:56,000 --> 00:48:58,280 BUT YOU WOULD BE HARD PRESSED TO 1199 00:48:58,280 --> 00:49:01,240 IDIDN'TIFY SINGLE RECEPTOR OR A 1200 00:49:01,240 --> 00:49:02,720 SINGLE TRANSDUCTION PATHWAY THAT 1201 00:49:02,720 --> 00:49:04,840 IS SHARED BY ALL PSYCHEDELICS. 1202 00:49:04,840 --> 00:49:07,840 IT TURNS OUT THAT IT'S--THIS 1203 00:49:07,840 --> 00:49:12,600 IS--THIS IS PROBABLY THE MAGIC 1204 00:49:12,600 --> 00:49:14,720 REGION HERE BUT AGAIN IF YOU 1205 00:49:14,720 --> 00:49:17,240 WERE--IF YOU HAD--IF YOU HAD NO 1206 00:49:17,240 --> 00:49:18,320 IDEA HOW THESE DRUGS WORKED 1207 00:49:18,320 --> 00:49:19,840 THERE WOULD BE NO WAY YOU WOULD 1208 00:49:19,840 --> 00:49:23,280 PICK THIS OUT, BASICALLY, 1209 00:49:23,280 --> 00:49:25,760 THERE'S NO INFORMATION FROM 1210 00:49:25,760 --> 00:49:27,680 SEQUENCING YOUR GENOME, DOING 1211 00:49:27,680 --> 00:49:29,680 SINGLE CELL RNA, LOOKING AT THE 1212 00:49:29,680 --> 00:49:31,600 ALAN BRAINAT LAS PINTAS, ET 1213 00:49:31,600 --> 00:49:34,120 CETERA, WHATEVER LEADS YOU TO 1214 00:49:34,120 --> 00:49:36,400 THE 5 HT2 A RECEPTOR, THE ONLY 1215 00:49:36,400 --> 00:49:38,400 WAY YOU WOULD KNOW THAT IS 1216 00:49:38,400 --> 00:49:39,080 THROUGH PHARMACOLOGY, AND THE 1217 00:49:39,080 --> 00:49:45,160 REASON WE KNOW THIS IS BECAUSE 1218 00:49:45,160 --> 00:49:47,440 OF THIS DATA HERE. 1219 00:49:47,440 --> 00:49:50,480 SO IT WAS KNOWN BY RICHARD 1220 00:49:50,480 --> 00:49:53,040 GLENON BACK IN THE 1980S THAT 1221 00:49:53,040 --> 00:49:54,960 THE PSYCHEDELIC ACTIONS OF THOSE 1222 00:49:54,960 --> 00:49:56,520 DRUGS CORRELATED VERY WELL WITH 1223 00:49:56,520 --> 00:49:58,800 THEIR AFFINITY TO BIND TO THE 1224 00:49:58,800 --> 00:50:02,000 ACTIVE STATE OF THE 5 HT2 A 1225 00:50:02,000 --> 00:50:06,000 RECEPTOR AND THEN SOME YEARS 1226 00:50:06,000 --> 00:50:08,200 LATER GONZALEZ MASO DID STUDIES 1227 00:50:08,200 --> 00:50:10,120 IN KNOCKOUT MICE AND WE FOUND 1228 00:50:10,120 --> 00:50:12,000 THEY DON'T RESPOND TO 1229 00:50:12,000 --> 00:50:13,240 PSYCHEDELICS BUT REALLY THE BEST 1230 00:50:13,240 --> 00:50:14,680 EVIDENCE ACTUALLY IS THE HUMAN 1231 00:50:14,680 --> 00:50:15,040 DATA. 1232 00:50:15,040 --> 00:50:16,880 SO THERE ARE NOW A NUMBER OF 1233 00:50:16,880 --> 00:50:23,200 STUDIES, THIS WAS DONE BY FRAN 1234 00:50:23,200 --> 00:50:26,240 [INDISCERNIBLE] GROUP IN 1235 00:50:26,240 --> 00:50:27,880 SWITZERLAND WHERE THEY DID THE 1236 00:50:27,880 --> 00:50:29,840 STUDY THAT DANIEL SEBERT DID 1237 00:50:29,840 --> 00:50:32,280 ONLY THEY DID IT WITH 1238 00:50:32,280 --> 00:50:36,560 PSYCHEDELICS SO THEY PRETREATED 1239 00:50:36,560 --> 00:50:37,600 HUMANS WITH KETANSERIN, AND THEN 1240 00:50:37,600 --> 00:50:40,720 THEY GAVE THEM A WHOPPING DOSE 1241 00:50:40,720 --> 00:50:42,600 OF LSD OR PSILOCYBIN AND THEY 1242 00:50:42,600 --> 00:50:44,440 THE EFFECTS WERE THERE WERE NO 1243 00:50:44,440 --> 00:50:44,920 EFFECTS. 1244 00:50:44,920 --> 00:50:47,640 THE PSYCHEDELIC OOSKTS WERE 1245 00:50:47,640 --> 00:50:48,680 TOTALLY BLOCKED. 1246 00:50:48,680 --> 00:50:49,040 OKAY? 1247 00:50:49,040 --> 00:50:54,160 AND I HAVE HEARD SUBSEQUENTLY 1248 00:50:54,160 --> 00:50:56,040 FROM ANECDOTAL RESPORTS WHERE 1249 00:50:56,040 --> 00:50:56,680 INDIVIDUALS HAVE DOSED 1250 00:50:56,680 --> 00:50:59,680 THEMSELVES WITH EVEN MORE 1251 00:50:59,680 --> 00:51:04,200 SELECTIVE 5 HT2 A ANTAGGIST AND 1252 00:51:04,200 --> 00:51:05,240 [INDISCERNIBLE] THAT IT'S 1253 00:51:05,240 --> 00:51:06,040 IDENTICAL. 1254 00:51:06,040 --> 00:51:08,720 IF YOU TAKE M1907 AND THEN TAKE 1255 00:51:08,720 --> 00:51:12,000 LSD YOU WILL NOT HAVE ANY EFFECT 1256 00:51:12,000 --> 00:51:12,560 OF LSD. 1257 00:51:12,560 --> 00:51:15,280 SO IT'S CLEAR THAT THE 1258 00:51:15,280 --> 00:51:18,000 PSYCHEDELIC ACTIONS ARE MEDIATED 1259 00:51:18,000 --> 00:51:20,240 BY THE PSYCHEDELIC RECEPTOR, 1260 00:51:20,240 --> 00:51:21,640 THAT WAS--AND I'M JUST GOING TO 1261 00:51:21,640 --> 00:51:22,920 FINISH UP HERE, I WILL NOT GO 1262 00:51:22,920 --> 00:51:24,440 THROUGH ALL THE SLIDES BUT I 1263 00:51:24,440 --> 00:51:27,440 WANT TO LEAVE TIME FOR QUESTIONS 1264 00:51:27,440 --> 00:51:30,400 AND THAT WAS--THAT WAS IN A WAY 1265 00:51:30,400 --> 00:51:31,440 THAT WAS CONVENIENT FOR ME 1266 00:51:31,440 --> 00:51:33,680 BECAUSE THAT WAS THE RECEPTOR I 1267 00:51:33,680 --> 00:51:37,400 STUDIED, SO, WHEN I BECAME A 1268 00:51:37,400 --> 00:51:38,560 YOUNG--ASSISTANT PROFESSOR, THE 1269 00:51:38,560 --> 00:51:40,480 5 HT-2 A RECEPTOR, WAS THE 1270 00:51:40,480 --> 00:51:43,040 RECEPTOR I DID STRUCTURE, 1271 00:51:43,040 --> 00:51:45,040 FUNCTION STUDIES ON, AND THIS 1272 00:51:45,040 --> 00:51:48,360 IS--SO DAVE WILL LIKE THIS, THIS 1273 00:51:48,360 --> 00:51:51,000 IS OUR MODEL OF RGOTTA MIN 1274 00:51:51,000 --> 00:51:54,360 VERSUS LSD BINDING THAT WE 1275 00:51:54,360 --> 00:51:55,080 PUBLISHED IN 1995. 1276 00:51:55,080 --> 00:52:00,840 AND IT TURNED OUT THIS MODEL WAS 1277 00:52:00,840 --> 00:52:01,440 ACTUALLY SOMEWHAT CORRECT. 1278 00:52:01,440 --> 00:52:07,720 I WILL JUST SAY IT WASN'T 1279 00:52:07,720 --> 00:52:08,320 ENTIRELY INCORRECT. 1280 00:52:08,320 --> 00:52:09,720 AND BUT WE WERE ULTIMATELY ABLE 1281 00:52:09,720 --> 00:52:12,160 TO GET THE STRUCTURE. 1282 00:52:12,160 --> 00:52:13,800 SO WE SAW--WE'VE SOLVED MANY, 1283 00:52:13,800 --> 00:52:16,360 MANY STRUCTURES OF PSYCHEDELICS, 1284 00:52:16,360 --> 00:52:17,560 IT'S ALL PUBLISHED DATA AND I 1285 00:52:17,560 --> 00:52:20,960 JUST WANT TO SHOW YOU THIS 1286 00:52:20,960 --> 00:52:21,560 CARTOON HERE. 1287 00:52:21,560 --> 00:52:24,000 SO THIS IS LSD. 1288 00:52:24,000 --> 00:52:30,760 ANYBODY KNOW WHAT SONG THIS IS? 1289 00:52:30,760 --> 00:52:34,360 THIS IS LSD, IMAGINE SOMEBODY 1290 00:52:34,360 --> 00:52:36,480 JUST TOOK IT AND THEY'RE IN THE 1291 00:52:36,480 --> 00:52:39,760 BACKGROUND IS THE 5 HT2 A 1292 00:52:39,760 --> 00:52:42,520 RECEPTOR, SEE IT'S DANCING 1293 00:52:42,520 --> 00:52:44,480 AROUND AND LSD BINDS IN A 1294 00:52:44,480 --> 00:52:46,560 MULTISTEP WAY TO THE RECEPTOR 1295 00:52:46,560 --> 00:52:49,200 THERE, YOU'LL SEE IN JUST A 1296 00:52:49,200 --> 00:52:49,680 MINUTE. 1297 00:52:49,680 --> 00:52:52,400 AND THEN A LED COMES OVER AND 1298 00:52:52,400 --> 00:52:53,560 THEN THE RECEPTOR IS ACTIVATED 1299 00:52:53,560 --> 00:52:56,240 AND NOW WE'RE GOING TO DIVE 1300 00:52:56,240 --> 00:53:02,040 INSIDE THE CELL HERE IN JUST A 1301 00:53:02,040 --> 00:53:04,360 MINUTE HERE WE GO AND THERE ARE 1302 00:53:04,360 --> 00:53:06,240 THE GPROTEINS, THERE'S THE ALPHA 1303 00:53:06,240 --> 00:53:11,320 SUBUNIT IN BLUE, AND THE BETA 1304 00:53:11,320 --> 00:53:13,720 GAMMA SUBUNITS, AND THIS IS THE 1305 00:53:13,720 --> 00:53:15,240 PSYCHEDELIC EXPERIENCE RIGHT 1306 00:53:15,240 --> 00:53:17,160 HERE, SEE THIS CALCIUM SPARK 1307 00:53:17,160 --> 00:53:19,480 THAT WE THINK, THAT WE THINK IS 1308 00:53:19,480 --> 00:53:21,680 THE PSYCHEDELIC EXPERIENCE, SO 1309 00:53:21,680 --> 00:53:24,200 WHAT THESE DRUGS DO IS THEY 1310 00:53:24,200 --> 00:53:26,680 CAUSE THE NEURON TO FIRE IN A 1311 00:53:26,680 --> 00:53:28,480 VERY IEE, AUDIENCE SYNCHRONOUS 1312 00:53:28,480 --> 00:53:29,360 FASHION, SO GO TO THE IN 1313 00:53:29,360 --> 00:53:29,840 ACCIDENT 1. 1314 00:53:29,840 --> 00:53:32,440 WE DON'T NEED TO SEE THAT MORE 1315 00:53:32,440 --> 00:53:33,280 THAN ONCE. 1316 00:53:33,280 --> 00:53:36,960 IT CAUSES NEURONS TO FIRE IN A 1317 00:53:36,960 --> 00:53:38,040 VERY ASYNCHRONOUS FASHION AND 1318 00:53:38,040 --> 00:53:39,880 THE NEURONS THAT ARE MADE TO 1319 00:53:39,880 --> 00:53:42,280 FIRE IN THIS DISORGANIZE HADED 1320 00:53:42,280 --> 00:53:43,360 FASHION ARE LAYER 5 PATHWAY 1321 00:53:43,360 --> 00:53:45,480 GIVES RAMITTAL NEURONS IN THE 1322 00:53:45,480 --> 00:53:46,280 CORTEX. 1323 00:53:46,280 --> 00:53:47,840 AND THESE RECEPTORS ARE FOUND IN 1324 00:53:47,840 --> 00:53:49,200 A PARTICULAR PART, THEY'RE FOUND 1325 00:53:49,200 --> 00:53:52,520 IN THE APICAL DENDRITE AND SO 1326 00:53:52,520 --> 00:53:54,680 THE APICAL DENDRITE FOR 1327 00:53:54,680 --> 00:53:56,520 PARAMETER NEURONS FOR THOSE WHO 1328 00:53:56,520 --> 00:53:58,160 ARE NOT NEUROSCIENTIST SYSTEM 1329 00:53:58,160 --> 00:53:59,960 EXTREMELY IMPORTANT FOR 1330 00:53:59,960 --> 00:54:01,640 INTEGRATING INFORMATION FROM 1331 00:54:01,640 --> 00:54:04,640 OTHER CORTICALE SITES AND IS 1332 00:54:04,640 --> 00:54:05,920 RESPONSIBLE FOR GIVING US THE 1333 00:54:05,920 --> 00:54:09,840 PICTURE OF REALITY THAT WE 1334 00:54:09,840 --> 00:54:10,440 EXPERIENCE, OKAY? 1335 00:54:10,440 --> 00:54:11,960 SO WHAT PSYCHEDELIC DRUGS DO IS 1336 00:54:11,960 --> 00:54:13,840 THEY CAUSE THIS, THEY BASICALLY 1337 00:54:13,840 --> 00:54:16,560 INJECT NOISE IN THE SYSTEM, AND 1338 00:54:16,560 --> 00:54:19,400 THE NOISE IS INTERPRETED BY THE 1339 00:54:19,400 --> 00:54:22,280 BRAIN AND BY YOUR THOUGHTS AS A 1340 00:54:22,280 --> 00:54:26,840 PSYCHEDELIC EXPERIENCE BUT IT'S 1341 00:54:26,840 --> 00:54:27,240 JUST NOISE. 1342 00:54:27,240 --> 00:54:30,320 AND IF YOU LOOK AT THIS FROM A 1343 00:54:30,320 --> 00:54:31,680 MACROSCALE, AS YOU IMAGINE THERE 1344 00:54:31,680 --> 00:54:33,800 ARE PEOPLE THAT HAVE DONE 1345 00:54:33,800 --> 00:54:35,640 NEUROIMAGING OF INDIVIDUALS ON 1346 00:54:35,640 --> 00:54:37,640 PSYCHEDELICS AND WHAT HAPPENS IS 1347 00:54:37,640 --> 00:54:41,200 THERE'S AN INCREASE IN BRAIN 1348 00:54:41,200 --> 00:54:42,080 ENTROPY OR DISORGANIZATION. 1349 00:54:42,080 --> 00:54:43,600 SO I KNOW I'M GOING A LITTLE 1350 00:54:43,600 --> 00:54:48,120 OVER TIME I AND WANT TO FINISH 1351 00:54:48,120 --> 00:54:51,000 WITH 1 EXPERIMENT, OKAY? 1352 00:54:51,000 --> 00:54:55,640 SO THE QUESTION IS: NOW THAT WE 1353 00:54:55,640 --> 00:54:57,600 HAVE ALPHA FOLD DO WE NEED TO 1354 00:54:57,600 --> 00:55:00,760 SOLVE ANY MORE STRUCTURES? 1355 00:55:00,760 --> 00:55:01,240 OKAY? 1356 00:55:01,240 --> 00:55:04,160 SO WHEN THE ALPHA FOLD PAPER 1357 00:55:04,160 --> 00:55:05,960 CAME OUT IT WAS HIGHLIGHTED IN 1358 00:55:05,960 --> 00:55:08,120 THE NEW YORK SOMETIMES AND MY 1359 00:55:08,120 --> 00:55:09,520 WIFE CALLED ME AND SHE SAID, DID 1360 00:55:09,520 --> 00:55:11,120 YOU READ ABOUT THIS? 1361 00:55:11,120 --> 00:55:14,440 SHE SAID YOU DON'T HAVE TO SOLVE 1362 00:55:14,440 --> 00:55:17,440 ANYMORE STRUCTURES EVER AGAIN. 1363 00:55:17,440 --> 00:55:18,240 [LAUGHTER] 1364 00:55:18,240 --> 00:55:20,800 I SAID YEAH, YEAH, I KNOW ABOUT 1365 00:55:20,800 --> 00:55:27,000 ALPHA FOLD. 1366 00:55:27,000 --> 00:55:29,520 SO, THIS IS UNPUBLISHED DATA SO 1367 00:55:29,520 --> 00:55:31,400 WE DECIDED TO DO THIS VERY 1368 00:55:31,400 --> 00:55:33,960 STRAIGHT FORWARD QUESTION. 1369 00:55:33,960 --> 00:55:37,600 SO, WE HAVE AN ALPHA FOLD MODEL 1370 00:55:37,600 --> 00:55:39,920 OF THE HT2 A 5 STRUCTURE WE ALSO 1371 00:55:39,920 --> 00:55:43,800 HAVE THE STRUCTURE OF THE 5 HT2 1372 00:55:43,800 --> 00:55:48,360 A RECEPTOR WHICH IS BETTER FOR 1373 00:55:48,360 --> 00:55:48,880 DRUG DISCOVERY? 1374 00:55:48,880 --> 00:55:51,160 SO TO TEST THIS HYPOTHESIS, WHAT 1375 00:55:51,160 --> 00:55:53,800 WE DID, WAS HE DID ULTRA LARGE, 1376 00:55:53,800 --> 00:55:57,600 BY WE I MEAN JK LYU, AND JK HAS 1377 00:55:57,600 --> 00:55:59,680 HIS OWN LAB AT ROCKEFELLER. 1378 00:55:59,680 --> 00:56:04,000 SO WHAT JK DID WAS USING ULTRA 1379 00:56:04,000 --> 00:56:07,400 LARGE SCALE DOCKING, WE DOCKED 1380 00:56:07,400 --> 00:56:08,360 1.6 BILLION COMPOUNDS, SO THIS 1381 00:56:08,360 --> 00:56:09,880 WAS A LARGE NUMBER OF COMPOUNDS 1382 00:56:09,880 --> 00:56:14,880 AGAINST THE MODEL OF THE 5 HT2A 1383 00:56:14,880 --> 00:56:16,880 RECEPTOR, AND THEN SCREEN THEM 1384 00:56:16,880 --> 00:56:20,280 AND TESTED THEM. 1385 00:56:20,280 --> 00:56:20,480 OKAY. 1386 00:56:20,480 --> 00:56:23,440 AND THEN WE DID THE SAME THING 1387 00:56:23,440 --> 00:56:25,480 AGAINST A RESTRUCTURE SO WE HAD 1388 00:56:25,480 --> 00:56:29,480 AN UNPUBLISHED STRUCTURE OF THE 1389 00:56:29,480 --> 00:56:31,600 5 HT2A RECEPTOR AND WE DID THE 1390 00:56:31,600 --> 00:56:32,840 EXACT SAME EXPERIMENT, OKAY? 1391 00:56:32,840 --> 00:56:35,880 AND THE QUESTION WAS WHICH 1392 00:56:35,880 --> 00:56:37,680 WORKED BETTER? 1393 00:56:37,680 --> 00:56:40,160 ALPHA FOLD, SO THE MODEL OR THE 1394 00:56:40,160 --> 00:56:42,280 STRUCTURE? 1395 00:56:42,280 --> 00:56:45,240 ANY GUESSES? 1396 00:56:45,240 --> 00:56:45,520 STRUCTURE. 1397 00:56:45,520 --> 00:56:49,800 THAT'S WHAT I THOUGHT. 1398 00:56:49,800 --> 00:56:51,800 I WAS WRONG. 1399 00:56:51,800 --> 00:56:52,160 SO--[LAUGHTER] 1400 00:56:52,160 --> 00:56:53,640 --SO ACTUALLY THEY WORKED 1401 00:56:53,640 --> 00:56:56,000 EQUALLY AS WELL, SO THE MODEL, 1402 00:56:56,000 --> 00:56:59,640 THE MODEL AND THE STRUCTURE BOTH 1403 00:56:59,640 --> 00:57:03,200 ENRICHED THE SAME NUMBER OF 1404 00:57:03,200 --> 00:57:04,920 COMPOUNDS BASICALLY, BUT SIMILAR 1405 00:57:04,920 --> 00:57:06,680 TO THE PAPER THAT I TALKED ABOUT 1406 00:57:06,680 --> 00:57:10,520 ON THE D3 RECEPTOR THE UNIVERSE 1407 00:57:10,520 --> 00:57:14,160 OF COMPOUNDS WAS COMPLETELY 1408 00:57:14,160 --> 00:57:14,400 DIFFERENT. 1409 00:57:14,400 --> 00:57:17,360 SO THE MODEL BASICALLY WHICH--WE 1410 00:57:17,360 --> 00:57:18,560 KNOW IT'S DIFFERENT FROM THE 1411 00:57:18,560 --> 00:57:20,000 STRUCTURE BECAUSE WE COMPARED 1412 00:57:20,000 --> 00:57:21,800 IT, IT'S QUITE DIFFERENT, I CAN 1413 00:57:21,800 --> 00:57:24,680 SHOW THE DETAILS BUT IT'S REALLY 1414 00:57:24,680 --> 00:57:27,440 DIFFERENT, WE THINK THE MODEL IS 1415 00:57:27,440 --> 00:57:29,040 ACTUALLY A STRUCTURE BUT IT'S 1416 00:57:29,040 --> 00:57:32,240 NOT THE STRUCTURE WE CAPTURE BY 1417 00:57:32,240 --> 00:57:32,760 CRYOEM BASICALLY. 1418 00:57:32,760 --> 00:57:38,680 AND IT URNS OUT THAT THAT 1419 00:57:38,680 --> 00:57:40,320 THE--SO THIS WAS OUR BEST 1420 00:57:40,320 --> 00:57:41,480 COMPOUND, THIS CAME FROM ALPHA 1421 00:57:41,480 --> 00:57:46,800 FOLD AND THIS IS A COMPOUND WITH 1422 00:57:46,800 --> 00:57:49,280 A--LET'S SEE 28 NANO MOLAR EC 50 1423 00:57:49,280 --> 00:57:50,960 AND IS COMPLETELY SELECTIVE FOR 1424 00:57:50,960 --> 00:57:53,320 2 A OVER 2 B AND 2 C. 1425 00:57:53,320 --> 00:57:53,520 OKAY? 1426 00:57:53,520 --> 00:57:56,480 THIS IS RIGHT OUT OF THE DOCKING 1427 00:57:56,480 --> 00:57:58,080 CAMPAIGN, WE HAVE A DRUG 1428 00:57:58,080 --> 00:57:58,360 BASICALLY. 1429 00:57:58,360 --> 00:58:01,840 IT HAS GOOD DRUG LIKE 1430 00:58:01,840 --> 00:58:04,160 PROPERTIES, ORALLY AVAILABLE, ET 1431 00:58:04,160 --> 00:58:04,640 CETERA, ET CETERA. 1432 00:58:04,640 --> 00:58:06,840 AND AS I SAID WE'RE NOW DOING 1433 00:58:06,840 --> 00:58:09,080 THESE ULTRA LARGE SCALE DOCKING 1434 00:58:09,080 --> 00:58:12,800 CAMPAIGNS WITH TRILLIONS, 1435 00:58:12,800 --> 00:58:16,480 TRILLIONS OF MOLECULES. 1436 00:58:16,480 --> 00:58:18,760 AND IT--IT'S REALLY SUCCESSFUL. 1437 00:58:18,760 --> 00:58:24,600 SO THAT'S ALL I WANT TO SAY, THE 1438 00:58:24,600 --> 00:58:25,640 NEXT FRONTIER HERE, THE NEXT 1439 00:58:25,640 --> 00:58:29,120 THING MY LAB IS GETTING INTO ARE 1440 00:58:29,120 --> 00:58:32,160 COMPLEXES, SO WE THINK THAT THE 1441 00:58:32,160 --> 00:58:34,800 RECEPTOR, EXISTSAs A SUPER 1442 00:58:34,800 --> 00:58:35,960 MOLECULAR SIGNALING COMPLEX AT 1443 00:58:35,960 --> 00:58:39,480 THE SYNAPSE AND WE'RE TRYING TO 1444 00:58:39,480 --> 00:58:42,120 UNDERSTAND WHAT THE ALL THE 1445 00:58:42,120 --> 00:58:43,760 COMPONENTS OF THIS ARE AND SOLVE 1446 00:58:43,760 --> 00:58:45,040 THE STRUCTURES AND THAT'S WHAT 1447 00:58:45,040 --> 00:58:45,480 WE'RE WORKING ON. 1448 00:58:45,480 --> 00:58:48,200 SO I WANT TO THANK YOU ALL FOR 1449 00:58:48,200 --> 00:58:49,680 YOUR ATTENTION. 1450 00:58:49,680 --> 00:58:53,360 THIS IS THE TEAM THAT DID THIS 1451 00:58:53,360 --> 00:58:53,560 WORK. 1452 00:58:53,560 --> 00:58:56,120 MANY OF THEM HAVE MOVED ON TO 1453 00:58:56,120 --> 00:58:59,000 LABS OF THEIR OWN, CHAN ACTUALLY 1454 00:58:59,000 --> 00:59:02,800 JUST MOVED OUT AS WELL 1455 00:59:02,800 --> 00:59:04,960 TESHANGHAI INSTITUTE OF 1456 00:59:04,960 --> 00:59:05,280 TECHNOLOGY. 1457 00:59:05,280 --> 00:59:06,400 JONATHAN FAYE VERY IMPORTANT FOR 1458 00:59:06,400 --> 00:59:08,600 US, I GUESS HE COLLABORATES HERE 1459 00:59:08,600 --> 00:59:13,520 WITH PEOPLE ON CRYOEM, NOW AT 1460 00:59:13,520 --> 00:59:21,920 UNIVERSITY OF MARYLAND. 1461 00:59:21,920 --> 00:59:24,040 BRIAN SHOICHET'S LAB, AND WE'RE 1462 00:59:24,040 --> 00:59:25,080 ETERNALLY GRATEFUL AND INDEBTED 1463 00:59:25,080 --> 00:59:27,400 TO HIS HELP AS WELL AS DAVE 1464 00:59:27,400 --> 00:59:29,600 NICHOLS WHO'S BEEN INSPIRING FOR 1465 00:59:29,600 --> 00:59:30,920 ALL THINGS PSYCHEDELIC AND OF 1466 00:59:30,920 --> 00:59:33,000 COURSE, THIS WORK IS FUNDED 1467 00:59:33,000 --> 00:59:35,480 ENTIRELY BY YOUR TAX DOLLARS AND 1468 00:59:35,480 --> 00:59:38,000 SO, THANK YOU FOR PAYING YOUR 1469 00:59:38,000 --> 00:59:39,520 TAX TAX ON TIME AND I'M HAPPY TO 1470 00:59:39,520 --> 00:59:40,640 ANSWER ANY QUESTIONS YOU MA I 1471 00:59:40,640 --> 00:59:41,560 HAVE. 1472 00:59:41,560 --> 00:59:42,680 SO THANK YOU. 1473 00:59:42,680 --> 00:59:52,920 [ APPLAUSE ] 1474 00:59:52,920 --> 00:59:55,480 >>THANK YOU FOR MAKING A VERY 1475 00:59:55,480 --> 00:59:57,120 COMPLEX TOPIC VERY 1476 00:59:57,120 --> 00:59:57,880 UNDERSTANDABLE AND PALLETTABLE. 1477 00:59:57,880 --> 00:59:58,760 PLEASE PROCEED TO THE 1478 00:59:58,760 --> 01:00:01,080 MICROPHONES IN THE AISLES AND 1479 01:00:01,080 --> 01:00:02,000 ASK A QUESTION. 1480 01:00:02,000 --> 01:00:04,600 IF YOU'RE ONLINE, CAN YOU PUT A 1481 01:00:04,600 --> 01:00:07,200 COMMENT IN THE CHAT. 1482 01:00:07,200 --> 01:00:14,640 OR YOU CAN YELL OUT YOUR 1483 01:00:14,640 --> 01:00:15,200 QUESTION. 1484 01:00:15,200 --> 01:00:16,640 >>SO I'M CURIOUS IN CASE OF THE 1485 01:00:16,640 --> 01:00:18,280 RECEPTOR YOU SHOWED IN THE END, 1486 01:00:18,280 --> 01:00:21,120 YOU THINK THAT THE ALPHA FOLD 1487 01:00:21,120 --> 01:00:22,440 CAPTURES THE STRUCTURE WHICH IS 1488 01:00:22,440 --> 01:00:23,480 SORT OF THE REASON FOR THE 1489 01:00:23,480 --> 01:00:25,760 SUCCESS OF THE PREDICTIONS. 1490 01:00:25,760 --> 01:00:27,640 SO FROM THE OTHER SORT OF 1491 01:00:27,640 --> 01:00:28,680 CAMPAIGNS THAT YOU'VE DONE, DO 1492 01:00:28,680 --> 01:00:32,840 YOU THINK YOU CAN GENERALIZE 1493 01:00:32,840 --> 01:00:34,760 THAT STATEMENT? 1494 01:00:34,760 --> 01:00:36,640 SO WE'VE DONE IT--SO AS CAN YOU 1495 01:00:36,640 --> 01:00:38,840 IMAGINE, IT WAS A HUGE AMOUNT OF 1496 01:00:38,840 --> 01:00:42,200 WORK SO WE DID IT WITH ANOTHER 1497 01:00:42,200 --> 01:00:45,560 TARGET, A NONGPCR, WE GOT THE 1498 01:00:45,560 --> 01:00:46,280 SAME RESULTS, BASICALLY. 1499 01:00:46,280 --> 01:00:48,440 THERE WAS A THIRD TARGET WE DID 1500 01:00:48,440 --> 01:00:50,400 NOT INTERROGATE BECAUSE THE 1501 01:00:50,400 --> 01:00:52,120 STRUCTURE WAS SO DIFFERENT FROM 1502 01:00:52,120 --> 01:00:56,400 THE ALPHA FOLD MODEL. 1503 01:00:56,400 --> 01:01:02,880 SO THIS WAS MRGPRX4, SO THE 1504 01:01:02,880 --> 01:01:05,600 ALPHA FOLD FOR THAT IS QUITE 1505 01:01:05,600 --> 01:01:05,800 WRONG. 1506 01:01:05,800 --> 01:01:07,240 THE BINDING CONTROLLER OF BANK 1507 01:01:07,240 --> 01:01:08,680 POCKET IS IN A DIFFERENT 1508 01:01:08,680 --> 01:01:10,560 ORYEBTATION AND MOST IMPORTANTLY 1509 01:01:10,560 --> 01:01:12,600 THE ELECTROSTATICS ARE ALL 1510 01:01:12,600 --> 01:01:12,880 INCORRECT. 1511 01:01:12,880 --> 01:01:15,320 >>I SEE. 1512 01:01:15,320 --> 01:01:16,520 >>SO, BUT WE THINK ACTUALLY 1513 01:01:16,520 --> 01:01:22,600 THIS MAY BE GENERALIZABLE AT 1514 01:01:22,600 --> 01:01:24,920 LEAST IN THE GPCR CAIN ACE, 1515 01:01:24,920 --> 01:01:27,640 YEAH, IT ACTUALLY MAY BE 1516 01:01:27,640 --> 01:01:28,840 GENERALLY USEFUL. 1517 01:01:28,840 --> 01:01:30,800 >>OKAY, THANK YOU. 1518 01:01:30,800 --> 01:01:32,040 >>WE WERE SURPRISED. 1519 01:01:32,040 --> 01:01:33,760 I BET AGAINST ALPHA FOLD, BUT 1520 01:01:33,760 --> 01:01:35,920 THERE YOU GO. 1521 01:01:35,920 --> 01:01:46,200 >>THANK YOU. 1522 01:01:47,760 --> 01:01:47,920 >>YEAH. 1523 01:01:47,920 --> 01:01:49,600 >>THIS WAS A BEAUTIFUL TALK 1524 01:01:49,600 --> 01:01:51,040 HERE. 1525 01:01:51,040 --> 01:01:55,240 I WANT TO SAY WHEN YOU SAW THE 1526 01:01:55,240 --> 01:01:58,560 BINDING DRUG TO THE RECEPTOR WAS 1527 01:01:58,560 --> 01:02:01,480 THERE ANY OPERATION TO THE 1528 01:02:01,480 --> 01:02:01,720 STRUCTURE? 1529 01:02:01,720 --> 01:02:02,120 >>THERE ISN'T. 1530 01:02:02,120 --> 01:02:09,400 SO THERE'S NOT SO MUCH. 1531 01:02:09,400 --> 01:02:11,880 THERE ARE SOME FINE DETAILS 1532 01:02:11,880 --> 01:02:13,760 ON--SO THE 1 WE LOOKED AT IN THE 1533 01:02:13,760 --> 01:02:18,520 MOST DETAIL IS THE 5 HT2A 1534 01:02:18,520 --> 01:02:20,240 RECEPTOR SO WE HAVE ABOUT A 1535 01:02:20,240 --> 01:02:21,400 DOZEN DIFFERENT STRUCTURES AND 1536 01:02:21,400 --> 01:02:24,200 THERE ARE SOME DIFFERENCES SO 1537 01:02:24,200 --> 01:02:25,600 THERE ARE--IT TURNS OUT THERE 1538 01:02:25,600 --> 01:02:26,920 ARE AGONISTS THAT ACTIVATE THE 1539 01:02:26,920 --> 01:02:29,520 RECEPTOR THAT ARE NOT 1540 01:02:29,520 --> 01:02:30,680 PSYCHEDELIC AND THEY 1541 01:02:30,680 --> 01:02:33,400 ACTUALLY--THE STRUCTURE OF THEM 1542 01:02:33,400 --> 01:02:34,720 IS DIFFERENT THAN THE 1543 01:02:34,720 --> 01:02:35,880 PSYCHEDELIC DRUGS SO WE THINK 1544 01:02:35,880 --> 01:02:38,320 THERE MIGHT BE SOMETHING THERE. 1545 01:02:38,320 --> 01:02:40,560 ONE OF THE THINGS I DIDN'T GET A 1546 01:02:40,560 --> 01:02:46,240 TIME TO GO INTO HERE IS WE'RE 1547 01:02:46,240 --> 01:02:50,000 NOW DOING A LOT OF--WE'RE TRYING 1548 01:02:50,000 --> 01:02:56,640 TO GET INTO BASICALLY TIME 1549 01:02:56,640 --> 01:02:58,040 RESOLVE CRYOEM AS WELL AS 1550 01:02:58,040 --> 01:02:59,560 LOOKING AT DIFFERENT STATES. 1551 01:02:59,560 --> 01:03:02,360 SO, I GUESS YOU DO CRYO--I DON'T 1552 01:03:02,360 --> 01:03:05,200 KNOW HOW MANY CRYOEM PEOPLE 1553 01:03:05,200 --> 01:03:07,520 THERE ARE HERE BUT 1 OF THE NICE 1554 01:03:07,520 --> 01:03:08,600 THINGS ABOUT CRYOEM IS THAT YOU 1555 01:03:08,600 --> 01:03:10,880 GET EVERY STATE THERE. 1556 01:03:10,880 --> 01:03:12,080 THEY'RE ALL THERE ON THE GRID 1557 01:03:12,080 --> 01:03:14,160 AND IT'S JUST A MATTER OF 1558 01:03:14,160 --> 01:03:15,720 PULLING THEM OUT, ACTUALLY. 1559 01:03:15,720 --> 01:03:17,400 SO HAVING LARGE ENOUGH DATA SETS 1560 01:03:17,400 --> 01:03:20,160 AND TRAINING TO PULL THEM OUT. 1561 01:03:20,160 --> 01:03:24,800 SO IT'S UNLIKE CRYSTALLOGRAPHY 1562 01:03:24,800 --> 01:03:26,840 WHERE EVERYTHING IS IN A 1563 01:03:26,840 --> 01:03:28,040 LATTICE, HERE THE INTRINSIC 1564 01:03:28,040 --> 01:03:28,880 FLEXIBILITY IS THERE, WE 1565 01:03:28,880 --> 01:03:31,000 BASICALLY JUST FREEZE IT ON A 1566 01:03:31,000 --> 01:03:33,240 GRID, THAT'S IT, THAT'S ALL 1567 01:03:33,240 --> 01:03:33,760 WE'RE DOING. 1568 01:03:33,760 --> 01:03:37,160 AND YOU GET A NUMBER--IS IT 1569 01:03:37,160 --> 01:03:40,800 POSSIBLE TO SHOW THIS SLIDE 1570 01:03:40,800 --> 01:03:41,000 HERE? 1571 01:03:41,000 --> 01:03:44,080 YEAH, HERE WE GO. 1572 01:03:44,080 --> 01:03:48,640 SO WE'RE USING 3D VARIABILITY 1573 01:03:48,640 --> 01:03:49,920 ANALYSIS, WHEN WE HAVE 1574 01:03:49,920 --> 01:03:52,440 SUFFICIENTLY LARGE DATA SETS, 1575 01:03:52,440 --> 01:03:56,400 AND THIS IS AN EXPERIMENT WE DID 1576 01:03:56,400 --> 01:03:58,240 OR ANALYSIS WHERE WE HAVE ALL 1577 01:03:58,240 --> 01:04:02,160 THESE DRUGS BOUND TO THE 5 HT2A 1578 01:04:02,160 --> 01:04:04,760 RECEPTORS, SOME ARE RESTING SOME 1579 01:04:04,760 --> 01:04:06,280 ARE PSYCHEDELIC, SOME ARE NOT 1580 01:04:06,280 --> 01:04:10,200 PSYCHEDELIC, AND THEN WE CAN 1581 01:04:10,200 --> 01:04:12,480 CREATE 123 MODELS BASED ON THE 1582 01:04:12,480 --> 01:04:14,120 VARIABILITY ANALYSIS FROM THE 1583 01:04:14,120 --> 01:04:18,040 CRYOEM DATA AND THEN WE CAN MAP 1584 01:04:18,040 --> 01:04:20,520 THE PRINCIPLE COMPONENTS OF THAT 1585 01:04:20,520 --> 01:04:22,120 INTO PRINCIPLE COMPONENT SPACE 1586 01:04:22,120 --> 01:04:24,800 AND TO MAKE SOMETHING VERY 1587 01:04:24,800 --> 01:04:26,080 COMPLICATED, NOT COMPLICATED AT 1588 01:04:26,080 --> 01:04:29,760 ALL, WHAT WE FIND IS EACH DRUG 1589 01:04:29,760 --> 01:04:30,440 STABILIZED DISTINCT 1590 01:04:30,440 --> 01:04:33,520 CONFIRMATIONAL ENSEMBLE AND VERY 1591 01:04:33,520 --> 01:04:33,800 INTERESTING. 1592 01:04:33,800 --> 01:04:36,360 SO, HERE--SO HERE IN RED HERE, 1593 01:04:36,360 --> 01:04:38,560 THIS IS BROMO LSD, SO THAT 1594 01:04:38,560 --> 01:04:41,800 DIFFERS FROM LSD BY A SINGLE 1595 01:04:41,800 --> 01:04:44,120 ATOM OF BROMINE, IT'S NOT 1596 01:04:44,120 --> 01:04:44,560 PSYCHEDELIC AT ALL. 1597 01:04:44,560 --> 01:04:51,400 YOU CAN TAKE A GRAM OF BROMINE 1598 01:04:51,400 --> 01:04:55,720 L, D AND YOU WILL NOT HAVE A 1599 01:04:55,720 --> 01:04:56,320 SINGLE PSYCHEDELIC EXPERIENCE, 1600 01:04:56,320 --> 01:04:59,880 AND THERE YOU CAN SEE IT'S WELL 1601 01:04:59,880 --> 01:05:01,400 SEPARATED BASED ON 3D ANALYSIS 1602 01:05:01,400 --> 01:05:03,400 AND WHEN YOU LOOK AT THE FINE 1603 01:05:03,400 --> 01:05:06,040 DETAILS IT REALLY BEGINS TO 1604 01:05:06,040 --> 01:05:07,200 BRING IN--INTO SHARP FOCUS THE 1605 01:05:07,200 --> 01:05:09,440 REASONS FOR THE DIFFERENCES IN 1606 01:05:09,440 --> 01:05:09,800 PHARMAICOLOGY. 1607 01:05:09,800 --> 01:05:12,000 YEAH, SO WE'RE GETTING THERE 1608 01:05:12,000 --> 01:05:13,040 BASICALLY. 1609 01:05:13,040 --> 01:05:15,080 >>THE LAST QUESTION. 1610 01:05:15,080 --> 01:05:15,640 MIKE? 1611 01:05:15,640 --> 01:05:16,960 >>THANK YOU, BRIAN GREATLY 1612 01:05:16,960 --> 01:05:17,800 ENJOYED THE TALK. 1613 01:05:17,800 --> 01:05:19,920 I WAS WONDERING IF YOU COULD 1614 01:05:19,920 --> 01:05:23,440 ELABORATE MORE ON BIAS AGONISTS 1615 01:05:23,440 --> 01:05:27,080 AND THEIR THERAPEUTIC POTENTIAL. 1616 01:05:27,080 --> 01:05:30,120 >>YEAH, SO I HAVE A BIASED 1617 01:05:30,120 --> 01:05:31,520 AGONIST THAT'S IN CLINICAL 1618 01:05:31,520 --> 01:05:34,360 TRIALS RIGHT NOW, IT'S IN PHASE 1619 01:05:34,360 --> 01:05:38,160 2, IT JUST PAST PHASE 1 SO IT'S 1620 01:05:38,160 --> 01:05:42,760 A 5 HT2 C AGONIST THAT IS 1621 01:05:42,760 --> 01:05:43,440 G-PROTEIN BIASED AND WE 1622 01:05:43,440 --> 01:05:45,960 ANTICIPATE THAT IT WILL BE 1623 01:05:45,960 --> 01:05:49,160 BETTER THAN OTHER 5 HT2 C 1624 01:05:49,160 --> 01:05:52,120 AGONISTS BECAUSE IT WON'T SHOW 1625 01:05:52,120 --> 01:05:52,480 DESENSITIZATION. 1626 01:05:52,480 --> 01:05:56,360 SO 1 OF THE--1 OF THE IMMEDIATE 1627 01:05:56,360 --> 01:05:58,560 ADVANTAGES YOU GET FROM MAKING 1628 01:05:58,560 --> 01:06:00,920 SAY A G-PROTEIN BIAS COMPOUND 1629 01:06:00,920 --> 01:06:02,240 FROM AN ARRESTIN BIAS COMPOUND 1630 01:06:02,240 --> 01:06:04,280 IS YOU GET RID OF 1631 01:06:04,280 --> 01:06:05,920 DESENSITIZATION OF TACKY FILL 1632 01:06:05,920 --> 01:06:09,960 AXIS INTIRELY OR TO A GREAT 1633 01:06:09,960 --> 01:06:10,240 EXTENT. 1634 01:06:10,240 --> 01:06:13,120 SO AGONISTS DON'T HAVE LESS 1635 01:06:13,120 --> 01:06:15,440 PROPENSITY TO LOSE THEIR POTENCY 1636 01:06:15,440 --> 01:06:16,360 WITH CHRONIC ADMINISTRATION, 1637 01:06:16,360 --> 01:06:16,560 OKAY? 1638 01:06:16,560 --> 01:06:19,920 THAT'S THE BIG THING. 1639 01:06:19,920 --> 01:06:21,440 THERE HAS, YOU KNOW FOR MANY, 1640 01:06:21,440 --> 01:06:23,320 MANY YEARS THERE'S BEEN THIS 1641 01:06:23,320 --> 01:06:29,160 IDEA THAT G-PROTEIN VERSUS 1642 01:06:29,160 --> 01:06:31,160 ARRESTIN IS IMPORTANT I USED TO 1643 01:06:31,160 --> 01:06:32,440 ENTERTAIN THAT HYPOTHESIS, I 1644 01:06:32,440 --> 01:06:34,600 DON'T SO MUCH ANYMORE, INSTEAD 1645 01:06:34,600 --> 01:06:40,080 WHAT WE'RE FOCUSING ON IS 1646 01:06:40,080 --> 01:06:42,120 DISTINCT G-ALPHA SUBUNITS. 1647 01:06:42,120 --> 01:06:43,960 SO, FOR THOSE OF YOU WHO STUDY 1648 01:06:43,960 --> 01:06:47,080 THE BRAIN, AND IF YOU STUDY 1649 01:06:47,080 --> 01:06:48,800 GI-LINKED RECEPTORS, YOU NEED TO 1650 01:06:48,800 --> 01:06:51,920 LOOK AT GO AND GZ. 1651 01:06:51,920 --> 01:06:53,400 IT TURNS OUT THAT IN THE BRAIN 1652 01:06:53,400 --> 01:06:56,840 THERE ARE 2 MAIN GI PROTEINS, 1 1653 01:06:56,840 --> 01:06:59,880 IS G. O., IT IS MAYBE 1% OF THE 1654 01:06:59,880 --> 01:07:01,600 WHOLE PROTEIN AT THE BRAIN, IT'S 1655 01:07:01,600 --> 01:07:07,840 A BAND ON AN SDSGEL, IF YOU RUN 1656 01:07:07,840 --> 01:07:10,480 A HOMOGINIZER ON IT YOU WILL SEE 1657 01:07:10,480 --> 01:07:12,000 G. O. AS A BAND AND IT'S 1658 01:07:12,000 --> 01:07:14,360 DIFFERENT FROM G. I. AND THEN G. 1659 01:07:14,360 --> 01:07:16,760 Z. IS IN THE G. O. FAMILY AND 1660 01:07:16,760 --> 01:07:17,680 IT'S COMPLETELY DIFFERENT FROM 1661 01:07:17,680 --> 01:07:19,040 G. I. 1662 01:07:19,040 --> 01:07:21,200 WE HAVE STRUCTURES WITH G. Z. 1663 01:07:21,200 --> 01:07:23,440 AND IT BINDS THE RECEPTOR IN AN 1664 01:07:23,440 --> 01:07:25,680 ENTIRELY DIFFERENT WAY, THE 1665 01:07:25,680 --> 01:07:26,720 CONEETICS OF SIGNALING ARE 1666 01:07:26,720 --> 01:07:28,040 DIFFERENT, IT'S NOT TOXIN, IT 1667 01:07:28,040 --> 01:07:30,440 HAS A VERY LONG LASTING SIGNAL 1668 01:07:30,440 --> 01:07:31,880 COMPARED TO GI, SO WE'RE 1669 01:07:31,880 --> 01:07:33,160 ACTUALLY, AND WE HAVE THIS 1670 01:07:33,160 --> 01:07:35,680 PAPER, JUST CAME OUT IN NATURE 1671 01:07:35,680 --> 01:07:38,600 WITH THE LABS SUGGESTING THAT 1672 01:07:38,600 --> 01:07:41,560 GZBIASED AGONISTS MAY HAVE LESS 1673 01:07:41,560 --> 01:07:43,520 FEWER SIDE EFFECTS THAN G. O., I 1674 01:07:43,520 --> 01:07:46,000 DON'T KNOW IF THAT'S--IF THAT'S 1675 01:07:46,000 --> 01:07:48,760 GOING TO PAN OUT OR NOT BUT IT'S 1676 01:07:48,760 --> 01:07:51,080 CLEAR THAT A SINGLE RECEPTOR CAN 1677 01:07:51,080 --> 01:07:53,000 COUPLE THE MULTIPLE G-PROTEINS 1678 01:07:53,000 --> 01:07:55,040 THERA NO QUESTION ABOUT THAT AND 1679 01:07:55,040 --> 01:07:58,680 IN MANY, MANY CASES THESE ARE 1680 01:07:58,680 --> 01:07:59,320 OPPOSITE CELLULAR EFFECTS, AND 1681 01:07:59,320 --> 01:08:01,720 SO IF YOU CAN GET A DRUG THAT 1682 01:08:01,720 --> 01:08:03,160 BIASES TOWARDS 1 VERSUS THE 1683 01:08:03,160 --> 01:08:04,760 OTHER, IT'S DEFINITELY GOING TO 1684 01:08:04,760 --> 01:08:06,320 BE DIFFERENT AND POTENTIALLY 1685 01:08:06,320 --> 01:08:07,640 BETTER SO THAT'S REALLY WHAT 1686 01:08:07,640 --> 01:08:09,160 WE'RE FOCUSING ON NOW. 1687 01:08:09,160 --> 01:08:11,680 >>THANK YOU. 1688 01:08:11,680 --> 01:08:11,960 >>YEAH. 1689 01:08:11,960 --> 01:08:13,720 >>OKAY, I WOULD LIKE TO THANK 1690 01:08:13,720 --> 01:08:15,800 EVERYONE FOR ATTENDING IN PERSON 1691 01:08:15,800 --> 01:08:18,320 AND ALL THE PEOPLE ONLINE. 1692 01:08:18,320 --> 01:08:19,400 I WANT TO CONGRATULATE AND THANK 1693 01:08:19,400 --> 01:08:20,000 BRIAN ONCE AGAIN FOR THE JOHN 1694 01:08:20,000 --> 01:08:21,040 DALY LECTURE. 1695 01:08:21,040 --> 00:00:00,000 [ APPLAUSE ]