1 00:00:06,520 --> 00:00:09,240 >> I'M DAN KASTNER 2 00:00:09,240 --> 00:00:12,760 AN ACTIVE SENIOR INVESTIGATOR 3 00:00:12,760 --> 00:00:16,440 FOR THE NATIONAL HUMAN GENOME 4 00:00:16,440 --> 00:00:18,240 INSTITUTE IT'S AND MY PLEASURE 5 00:00:18,240 --> 00:00:20,640 TO WELCOME YOU TO THE EAST COAST 6 00:00:20,640 --> 00:00:22,720 UNITED STATES TIME THE SIXTH 7 00:00:22,720 --> 00:00:26,480 INSTALLMENT OF THE 22nd YEAR OF 8 00:00:26,480 --> 00:00:27,600 DEMYSTIFYING MEDICINE. 9 00:00:27,600 --> 00:00:28,880 OF COURSE IT'S ESTABLISHED TO 10 00:00:28,880 --> 00:00:31,200 BRIDGE THE EXCITING DEVELOPMENTS 11 00:00:31,200 --> 00:00:32,360 IN BIOLOGY AND ENGINEERING WITH 12 00:00:32,360 --> 00:00:35,920 ADVANCES IN MEDICINE. 13 00:00:35,920 --> 00:00:38,400 AND WE HAVE THE ICON PHOTO OF 14 00:00:38,400 --> 00:00:39,800 THE CONSTRUCTION OF THE BROOKLYN 15 00:00:39,800 --> 00:00:41,560 BRIDGE WHICH IS SUPPOSED TO 16 00:00:41,560 --> 00:00:44,640 CONVEY TO US THIS IDEA THAT WE 17 00:00:44,640 --> 00:00:46,960 ARE BUILDING BRIDGES IN THIS 18 00:00:46,960 --> 00:00:47,360 COURSE. 19 00:00:47,360 --> 00:00:54,480 BRIDGES BETWEEN MEDICINE AND 20 00:00:54,480 --> 00:01:04,040 SCIENCE MEDICINE AND ENGINEERING 21 00:01:04,040 --> 00:01:07,280 AND BRIDGING THEM AND THE TWO 22 00:01:07,280 --> 00:01:09,200 GUYS ON THE BRIDGE ONE FROM 23 00:01:09,200 --> 00:01:10,440 BROOKLYN, ONE FROM MANHATTAN 24 00:01:10,440 --> 00:01:12,400 ABLE TO DISCUSS THE LATEST 25 00:01:12,400 --> 00:01:16,400 ISSUES OF THE 1870s WITH REGARD 26 00:01:16,400 --> 00:01:18,240 TO SCIENCE AND MEDICINE. 27 00:01:18,240 --> 00:01:20,920 TODAY, THIS AFTERNOON WE A 28 00:01:20,920 --> 00:01:21,720 NATIVE NEW YORKER AND 29 00:01:21,720 --> 00:01:25,120 TRANSPLANTED NEW YORKER. 30 00:01:25,120 --> 00:01:30,480 WE'LL ALSO BE TALKING ABOUT THE 31 00:01:30,480 --> 00:01:32,520 LATEST INTERESTS IN JAK 32 00:01:32,520 --> 00:01:37,400 INHIBITERS AND AUTOIMMUNITY. 33 00:01:37,400 --> 00:01:39,920 THE LEAD-OFF SPEAKER IS 34 00:01:39,920 --> 00:01:46,600 DR. ANGELA CHRISTIANO THE 35 00:01:46,600 --> 00:01:49,200 PROFESSOR OF DERMATOLOGY AND 36 00:01:49,200 --> 00:01:50,000 DEVELOPMENT AT THE COLUMBIA 37 00:01:50,000 --> 00:01:51,440 COLLEGE OF PHYSICIANS AND 38 00:01:51,440 --> 00:01:51,720 SURGEONS. 39 00:01:51,720 --> 00:01:56,960 SHE GOT HER BACHELOR'S, MASTER'S 40 00:01:56,960 --> 00:02:01,280 AND Ph.D. DEGREES FROM RUTGERS 41 00:02:01,280 --> 00:02:02,960 AND WENT TO PHILADELPHIA TO DO 42 00:02:02,960 --> 00:02:05,160 HER POST-DOCTORAL TRAINING AT 43 00:02:05,160 --> 00:02:06,280 JEFFERSON MEDICAL COLLEGE. 44 00:02:06,280 --> 00:02:10,960 SHE'S WON A NORM NUMBER OF 45 00:02:10,960 --> 00:02:15,280 AWARDS AND HONORS INCLUDING THE 46 00:02:15,280 --> 00:02:19,000 WILLIAM MANTEGNA LECTURESHIP FOR 47 00:02:19,000 --> 00:02:19,920 INVESTIGATIVE DERMATOLOGY AND 48 00:02:19,920 --> 00:02:22,480 FROM THE NATIONAL ACADEMY OF 49 00:02:22,480 --> 00:02:22,720 SCIENCE. 50 00:02:22,720 --> 00:02:25,560 HER LABORATORY STUDIES INHERITED 51 00:02:25,560 --> 00:02:27,000 SKIN AND HAIR DISORDERS IN 52 00:02:27,000 --> 00:02:29,000 HUMANS AND MICE TAKING A 53 00:02:29,000 --> 00:02:31,400 CLASSICAL GENETIC APPROACH THEY 54 00:02:31,400 --> 00:02:37,400 ALSO WORK ON THE TRANSCRIPTIONAL 55 00:02:37,400 --> 00:02:41,760 REGULATION OF ENDOGENS AND THEY 56 00:02:41,760 --> 00:02:45,000 DO WORK ON THE GENETIC AND 57 00:02:45,000 --> 00:02:46,520 CELL-BASED THERAPIES FOR SKIN 58 00:02:46,520 --> 00:02:49,000 AND HAIR DISEASES. 59 00:02:49,000 --> 00:02:54,440 THE SECOND SPEAKER IS THE GOOD 60 00:02:54,440 --> 00:02:56,160 DOCTOR JOHN O'SHEA THE 61 00:02:56,160 --> 00:02:58,480 SCIENTIFIC DIRECTOR AND CHIEF OF 62 00:02:58,480 --> 00:02:59,080 IMMUNOLOGY AND INFORMATION 63 00:02:59,080 --> 00:03:01,240 BRANCH AT THE NATIONAL INSTITUTE 64 00:03:01,240 --> 00:03:11,760 OF ARTHRITIS AND MUSCULOSKELETAL 65 00:03:14,840 --> 00:03:17,960 SKIN DISEASE AND DID HIS 66 00:03:17,960 --> 00:03:20,680 TRAINING IN SYRACUSE AND 67 00:03:20,680 --> 00:03:22,960 ALLERGY, IMMUNOLOGY SUBTRAINING 68 00:03:22,960 --> 00:03:25,000 AT THE NIH. 69 00:03:25,000 --> 00:03:28,920 HE'S PROUD TO SAY HE WAS THE 70 00:03:28,920 --> 00:03:29,920 IRISH IMMUNOLOGIST OF THE YEAR 71 00:03:29,920 --> 00:03:35,640 AND HAD THE PUBLIC LECTURE AWARD 72 00:03:35,640 --> 00:03:40,040 SEVERAL YEARS AGO AND THE 73 00:03:40,040 --> 00:03:44,160 RECIPIENT OF THE HOWLEY PRIZE 74 00:03:44,160 --> 00:03:46,680 AND ROSS PRIZE AND MILSTEIN 75 00:03:46,680 --> 00:03:49,880 PRIZE AND NATIONAL ACADEMY OF 76 00:03:49,880 --> 00:03:56,960 MEDICINE AND DEMONSTRATED THE 77 00:03:56,960 --> 00:04:06,440 ROLE OF JAK 3'S ROLE IN COMBINED 78 00:04:06,440 --> 00:04:08,680 IMMUNODEFICIENCY DISEASE AND T 79 00:04:08,680 --> 00:04:10,960 CELL DIFFERENTIATION AND 80 00:04:10,960 --> 00:04:14,480 CYTOKINE SIGNALLING IN HEALTH 81 00:04:14,480 --> 00:04:16,760 AND DISEASE AND THERAPEUTIC USE 82 00:04:16,760 --> 00:04:22,400 OF JAK INHIBITERS IN AUTOIMMUNE 83 00:04:22,400 --> 00:04:22,920 DISEASE. 84 00:04:22,920 --> 00:04:24,000 TAKE IT AWAY. 85 00:04:24,000 --> 00:04:26,160 >>WHAT A WARM WELCOME AND THANK 86 00:04:26,160 --> 00:04:28,360 YOU TO DR. ARIAS AND FOR YOU FOR 87 00:04:28,360 --> 00:04:29,760 HAVING US IN THIS SERIES. 88 00:04:29,760 --> 00:04:30,440 WHAT AN HONOR. 89 00:04:30,440 --> 00:04:38,560 WE'RE SO HAPPY TO BE HERE. 90 00:04:38,560 --> 00:04:42,040 I USUALLY FOLLOW JOHN AND IT 91 00:04:42,040 --> 00:04:44,080 MAKES MY JOB EASY AND TODAY HE 92 00:04:44,080 --> 00:04:47,880 SUGGESTED WE CHANGE IT UP A BIT. 93 00:04:47,880 --> 00:04:50,080 WE'LL DO A BIT OF A SPLIT TALK 94 00:04:50,080 --> 00:04:53,440 AND I'LL INTRODUCE YOU TO A 95 00:04:53,440 --> 00:05:04,120 DISEASE CLOSE TO MY HEART,ALL 96 00:05:26,880 --> 00:05:37,080 ALOPICIA AREATA. 97 00:05:42,440 --> 00:05:45,320 THIS IS WHERE THE BODY 98 00:05:45,320 --> 00:05:47,400 RECOGNIZES ITS OWN HAIR DISEASE 99 00:05:47,400 --> 00:05:50,360 AS FOREIGN AND AFFECTS ROUGHLY 7 100 00:05:50,360 --> 00:05:50,960 MILLION PEOPLE IN THE 101 00:05:50,960 --> 00:05:52,360 U.S. ALONE. 102 00:05:52,360 --> 00:05:54,360 IT'S AN EQUAL OPPORTUNITY 103 00:05:54,360 --> 00:05:54,640 DISORDER. 104 00:05:54,640 --> 00:05:57,560 IT HAS NO GENDER BIAS. 105 00:05:57,560 --> 00:06:02,040 IT AFFECTS ALL ETHNIC GROUPS 106 00:06:02,040 --> 00:06:02,440 EQUALLY. 107 00:06:02,440 --> 00:06:04,760 AND IT COMES IN A WHOLE SPECTRUM 108 00:06:04,760 --> 00:06:05,800 OF SEVERITY RANGING FROM SMALL 109 00:06:05,800 --> 00:06:09,760 PATCHES THAT BEGIN HERE ON THE 110 00:06:09,760 --> 00:06:11,000 SCALP AND SOMETIMES ON THE BEARD 111 00:06:11,000 --> 00:06:13,560 IN MALE PATIENTS THEY CAN GROW 112 00:06:13,560 --> 00:06:13,800 LARGER. 113 00:06:13,800 --> 00:06:16,600 THEY CAN COALESCE TO FORM LARGER 114 00:06:16,600 --> 00:06:18,920 REGIONS HERE AND EVENTUALLY CAN 115 00:06:18,920 --> 00:06:23,800 COVER THE ENTIRE SCALP OR BODY. 116 00:06:23,800 --> 00:06:26,960 FOR MANY YEARS THE IMMUNE 117 00:06:26,960 --> 00:06:30,760 INFILTRATE THAT SURROUNDS THE 118 00:06:30,760 --> 00:06:32,880 HAIR FOLLICLE HAS BEEN A 119 00:06:32,880 --> 00:06:33,120 MYSTERY. 120 00:06:33,120 --> 00:06:34,960 WE KNEW IT WAS A COMPLEX SET OF 121 00:06:34,960 --> 00:06:36,600 IMMUNE CELL TYPES AND BEGINNING 122 00:06:36,600 --> 00:06:38,880 TO DISSECT WHAT THOSE CELLS DO 123 00:06:38,880 --> 00:06:45,600 AND HOW THEY ACT. 124 00:06:45,600 --> 00:06:47,000 THINK OF IT AS THE FRAMEWORK OF 125 00:06:47,000 --> 00:06:54,960 THE LARGER FAMILY OF SKIN 126 00:06:54,960 --> 00:06:58,960 AUTOMATIC DISEASE AND I'LL 127 00:06:58,960 --> 00:07:01,040 INTRODUCE TO YOU ONE THE CONCEPT 128 00:07:01,040 --> 00:07:02,920 OF IMMUNE PRIVILEGE BECAUSE IT'S 129 00:07:02,920 --> 00:07:08,200 SOMETHING WE'LL TALK ABOUT 130 00:07:08,200 --> 00:07:10,560 THROUGH THE REST OF TODAY AND 131 00:07:10,560 --> 00:07:13,120 UNLIKE OTHER TISSUE SITES AND 132 00:07:13,120 --> 00:07:15,920 THE HAIR FOLLICLE IN ITS NORMAL 133 00:07:15,920 --> 00:07:17,560 STATE EXISTS IN A STATE OF 134 00:07:17,560 --> 00:07:20,520 IMMUNE PRIVILEGE. 135 00:07:20,520 --> 00:07:22,240 MEANING IT'S PROTECTED BY 136 00:07:22,240 --> 00:07:26,880 RECOGNITION BY THE IMMUNE SYSTEM 137 00:07:26,880 --> 00:07:29,280 BY OVER EXPRESSION OF WHAT IS 138 00:07:29,280 --> 00:07:34,440 CALLED IMMUNE PRIVILEGE 139 00:07:34,440 --> 00:07:40,840 GUARDIANS. 140 00:07:40,840 --> 00:07:42,960 AND THE STATE OF IMMUNE 141 00:07:42,960 --> 00:07:47,520 PRIVILEGE CAN BE DISRUPTED AND 142 00:07:47,520 --> 00:07:49,640 LOWERS THE SHIELD ALLOWS AN 143 00:07:49,640 --> 00:07:52,400 IMMUNE RESPONSE TO TAKE PLACE 144 00:07:52,400 --> 00:07:54,520 WHEREBY THE HAIR FOLLICLE 145 00:07:54,520 --> 00:07:55,400 RECRUITS IMMUNE CELLS FROM 146 00:07:55,400 --> 00:07:57,000 BEYOND AND DRAWS THEM TO THE 147 00:07:57,000 --> 00:07:59,920 ENVIRONMENT AND SETS UP THE 148 00:07:59,920 --> 00:08:01,120 VICIOUS CYCLE WHEREBY DANGEROUS 149 00:08:01,120 --> 00:08:03,000 SYMPTOMS ARE EXPRESSED THAT 150 00:08:03,000 --> 00:08:04,440 RECRUIT IMMUNE CELLS WHICH ADD 151 00:08:04,440 --> 00:08:06,960 TO THE FIRE AND SET UP THIS 152 00:08:06,960 --> 00:08:12,480 VICIOUS CYCLE. 153 00:08:12,480 --> 00:08:15,880 THERE'S SEVERAL PLACES WE CAN 154 00:08:15,880 --> 00:08:16,320 THINK OF INTERVENING. 155 00:08:16,320 --> 00:08:18,680 ONE IS AT THE LEVEL OF IMMUNE 156 00:08:18,680 --> 00:08:20,280 CELLS AND AT THE LEVEL OF 157 00:08:20,280 --> 00:08:21,760 RESTORING THE HAIR FOLLICLE BACK 158 00:08:21,760 --> 00:08:24,600 TO THE STATE OF IMMUNE 159 00:08:24,600 --> 00:08:25,200 PRIVILEGE. 160 00:08:25,200 --> 00:08:26,800 WHEN WE THINK ABOUT 161 00:08:26,800 --> 00:08:27,400 THERAPEUTICALLY TARGETING THE 162 00:08:27,400 --> 00:08:29,800 DISEASE IT'S COMPLICATED BUT 163 00:08:29,800 --> 00:08:31,000 IT'S ALSO ONE THAT'S RIPE WIN 164 00:08:31,000 --> 00:08:32,480 OPPORTUNITY. 165 00:08:32,480 --> 00:08:36,000 IMPORTANTLY, ALSO THE HAIR 166 00:08:36,000 --> 00:08:36,960 FOLLICLE DOES NOT UNDER GO 167 00:08:36,960 --> 00:08:38,760 PERMANENT DAMAGE IN THE DISEASE. 168 00:08:38,760 --> 00:08:40,600 THE IMMUNE RESPONSE IS THE 169 00:08:40,600 --> 00:08:42,280 BOTTOM OF THE HAIR FOLLICLE. 170 00:08:42,280 --> 00:08:46,280 THE PART THAT TURNS OVER ON A 171 00:08:46,280 --> 00:08:47,880 REGULAR BASIS. 172 00:08:47,880 --> 00:08:49,120 THE STEM CELL COMPARTMENT IS 173 00:08:49,120 --> 00:08:51,120 FAIR AND FOR PEOPLE WHO HAD 174 00:08:51,120 --> 00:08:55,440 ALOPECIA AREATA FOR DECADES THE 175 00:08:55,440 --> 00:08:58,200 HARDWARE OF THE HAIR FOLLICLE IS 176 00:08:58,200 --> 00:09:01,480 IN TACK AND IN THEORY IF WE CAN 177 00:09:01,480 --> 00:09:03,000 REVERSE THE IMMUNE RESPONSE 178 00:09:03,000 --> 00:09:05,120 EVERYTHING NEEDED TO MAKE A HAIR 179 00:09:05,120 --> 00:09:08,440 SHAFT IS INTACT AND HAS BEEN 180 00:09:08,440 --> 00:09:09,240 SPARED IN THE DISEASE AND THAT'S 181 00:09:09,240 --> 00:09:12,440 AN ADVANTAGE WHEN WE THINK OF 182 00:09:12,440 --> 00:09:18,960 HOW TO GO ABOUT TAKING IT A 183 00:09:18,960 --> 00:09:19,160 PART. 184 00:09:19,160 --> 00:09:23,000 ALOPECIA AREATA COMES UP IN THE 185 00:09:23,000 --> 00:09:24,440 NEWS BECAUSE IT'S A COMMON 186 00:09:24,440 --> 00:09:28,040 DISORDER BUT WHEN CELEBRITIES OR 187 00:09:28,040 --> 00:09:31,440 ACTORS OR ATHLETES EXPERIENCE 188 00:09:31,440 --> 00:09:33,800 THIS THEY BEGAN TO EMBRACE IT 189 00:09:33,800 --> 00:09:35,520 AND BE OPEN AND WHERE PEOPLE 190 00:09:35,520 --> 00:09:37,840 WOULD WEAR A HAIR PIECE OR 191 00:09:37,840 --> 00:09:40,240 PROSTHETIC TO DISGUISE IT. 192 00:09:40,240 --> 00:09:44,000 WE TEND TO THINK THAT ALOPECIA 193 00:09:44,000 --> 00:09:46,960 IS A RECENT DISCOVERY HOWEVER, 194 00:09:46,960 --> 00:09:53,480 WHAT I WANTED TO DO TODAY IS 195 00:09:53,480 --> 00:10:01,680 TAKE I BACK IN TIME AND NOT JUST 196 00:10:01,680 --> 00:10:03,520 FOR OBSERVATIONAL PURPOSES BUT 197 00:10:03,520 --> 00:10:07,640 CLUES FOR WHAT PEOPLE WERE ING 198 00:10:07,640 --> 00:10:18,200 ABOUT ALOPECIA AREATA AND THIS 199 00:10:19,040 --> 00:10:21,280 IS AN ARTICLE BY MY COLLEAGUE 200 00:10:21,280 --> 00:10:24,000 WHO WROTE A BEAUTIFUL AND 201 00:10:24,000 --> 00:10:26,960 ILLUSTRATED HISTORY OF ALOPECIA 202 00:10:26,960 --> 00:10:34,960 AREATA AND SHARED WITH ME HIS 203 00:10:34,960 --> 00:10:36,640 SLIDE. 204 00:10:36,640 --> 00:10:39,560 THE EARLIEST KNOWN RECORDING OF 205 00:10:39,560 --> 00:10:46,560 THIS IS 1500 B.C. AND YOU'LL 206 00:10:46,560 --> 00:10:49,040 FIND PLANT MIXTURES OR ELIXIRS 207 00:10:49,040 --> 00:10:59,560 THAT WERE THOUGHT TO BE APPLIED 208 00:10:59,920 --> 00:11:02,760 THE FIRST APPEARANCE OF THE WORD 209 00:11:02,760 --> 00:11:07,280 ALOPECIA IS HERE AND WE'LL TALK 210 00:11:07,280 --> 00:11:12,400 ABOUT WHY IT'S CALLED THIS. 211 00:11:12,400 --> 00:11:13,880 AND IF YOU LOOK AT THE 212 00:11:13,880 --> 00:11:18,040 LITERATURE THE WORD COMES FROM 213 00:11:18,040 --> 00:11:21,000 THE WORD FOR SNAKE AND YOU SEE 214 00:11:21,000 --> 00:11:21,920 EARLY DESCRIPTION SAYING 215 00:11:21,920 --> 00:11:22,920 WHATEVER IS DRIVING THIS DISEASE 216 00:11:22,920 --> 00:11:25,880 IS NOT A PROBLEM OF A WESTERN 217 00:11:25,880 --> 00:11:26,120 DIET. 218 00:11:26,120 --> 00:11:27,120 FOR EXAMPLE BECAUSE IT'S EXISTED 219 00:11:27,120 --> 00:11:29,800 LONG BEFORE MANY OF THE 220 00:11:29,800 --> 00:11:34,720 ENVIRONMENTAL CHALLENGES WE 221 00:11:34,720 --> 00:11:45,000 CURRENTLY KNOW AND THINK ABOUT 222 00:11:45,000 --> 00:11:47,000 AND YOU SEE THERE WAS THOUGHT 223 00:11:47,000 --> 00:11:49,920 THEY HAD BEEN TOUCHED BY AN EVIL 224 00:11:49,920 --> 00:11:52,480 SPIRIT OR GHOST. 225 00:11:52,480 --> 00:11:55,000 IT COULD BE A ROUND CIRCLE OR IN 226 00:11:55,000 --> 00:12:00,960 THE SHAPE OF FINGER OR SNAKE. 227 00:12:00,960 --> 00:12:05,800 IT'S NOT ITCHY. 228 00:12:05,800 --> 00:12:14,960 THIS IS A QUIET INFLAMMATORY 229 00:12:14,960 --> 00:12:25,520 STATE AP AND IT WAS DESCRIBED 230 00:12:28,840 --> 00:12:31,000 TO LOOK LIKE A MANGY FOX AND 231 00:12:31,000 --> 00:12:33,920 THIS WORLD ALOPECIA NOW REFERS 232 00:12:33,920 --> 00:12:36,080 TO MANY TYPES OF HAIR LOSS BUT 233 00:12:36,080 --> 00:12:45,600 THE PARTICULAR TYPE OF ALOPECIA 234 00:12:45,600 --> 00:12:49,760 AREATA ARE SNEAKY PATTERNS OF 235 00:12:49,760 --> 00:12:51,800 HAIR LOSS AND THIS NOW IS THE 236 00:12:51,800 --> 00:12:55,000 WORD WE USE THAT FIRST APPEARED 237 00:12:55,000 --> 00:12:59,560 1700 AS ALOPECIA AREATA. 238 00:12:59,560 --> 00:13:00,960 THIS DISEASE GOES BACK IN 239 00:13:00,960 --> 00:13:02,760 HISTORY AND KEVIN DID AN 240 00:13:02,760 --> 00:13:08,080 EXTRAORDINARY JOB OF COLLECTING 241 00:13:08,080 --> 00:13:10,760 THE HISTORICAL REPRESENTATIONS 242 00:13:10,760 --> 00:13:11,960 IN THE MEDICAL LITERATURE FOR 243 00:13:11,960 --> 00:13:12,240 YEARS. 244 00:13:12,240 --> 00:13:13,880 THIS FROM 1817. 245 00:13:13,880 --> 00:13:16,600 THE FIRST MODERN DESCRIPTIONS OF 246 00:13:16,600 --> 00:13:17,800 THE DISEASE. 247 00:13:17,800 --> 00:13:22,840 READ CAREFULLY. 248 00:13:22,840 --> 00:13:27,000 PATCHES OF THAT SURROUND IT ARE 249 00:13:27,000 --> 00:13:37,080 THICK. 250 00:13:38,040 --> 00:13:40,280 THERE WERE ATTEMPTS TO EXPLAIN 251 00:13:40,280 --> 00:13:43,400 WHAT MAY CAUSE THE DISEASE AND 252 00:13:43,400 --> 00:13:45,960 NUTRITION, STRESS, INFLAMMATION 253 00:13:45,960 --> 00:13:48,520 AND ENDOCRINE DISORDERS AND 254 00:13:48,520 --> 00:13:52,160 FINALLY IN THE 1950s THE CONCEPT 255 00:13:52,160 --> 00:13:55,440 OF MAYBE IT'S AUTOIMMUNE. 256 00:13:55,440 --> 00:13:58,640 BRIEFLY TO LOOK AT DO WE THINK 257 00:13:58,640 --> 00:14:01,680 OF MICROBES OR FUNGAL INFECTIONS 258 00:14:01,680 --> 00:14:04,000 AND CAREFULLY OBSERVING AND 259 00:14:04,000 --> 00:14:05,840 WATCHING THE ONSET OF THE 260 00:14:05,840 --> 00:14:09,400 DISEASE AS IT GOES ALONG WITH 261 00:14:09,400 --> 00:14:10,960 VARIETAL TRIGGERS HERE AND 262 00:14:10,960 --> 00:14:14,880 THEY'RE TALKING ABOUT NUTRITION. 263 00:14:14,880 --> 00:14:18,960 WE KNOW IRON DEFICIENCY OR 264 00:14:18,960 --> 00:14:22,520 HORMONE CAN INFLUENCE HAIR 265 00:14:22,520 --> 00:14:22,920 GROWTH. 266 00:14:22,920 --> 00:14:28,400 THINKING ABOUT ALL SORTS OF 267 00:14:28,400 --> 00:14:30,400 THINGS THIS THEORY HAS BEEN 268 00:14:30,400 --> 00:14:34,200 AROUND AND IN THE 1800s IT WAS 269 00:14:34,200 --> 00:14:35,600 THOUGHT THIS COULD HAPPEN 270 00:14:35,600 --> 00:14:39,000 OVERNIGHT OR BEING STRUCK BY 271 00:14:39,000 --> 00:14:42,080 LIGHTNING OR TRAUMATIC BLOW TO 272 00:14:42,080 --> 00:14:43,760 THE HEAD. 273 00:14:43,760 --> 00:14:45,240 SOME LOCAL INFLAMMATORY RESPONSE 274 00:14:45,240 --> 00:14:50,200 OR EVEN A PSYCHOSOCIAL SHOCK OR 275 00:14:50,200 --> 00:14:52,920 TRAUMATIC INJURY AND IN HISTORY 276 00:14:52,920 --> 00:14:54,960 WE KNOW THE MOST FAMOUS EXAMPLE 277 00:14:54,960 --> 00:14:57,320 OF SOMETHING THAT'S CALLED 278 00:14:57,320 --> 00:14:59,920 SUDDEN WHITENING OF THE HAIR 279 00:14:59,920 --> 00:15:01,960 WHERE IT QUOTE TURNS WHITE 280 00:15:01,960 --> 00:15:02,200 OVERNIGHT. 281 00:15:02,200 --> 00:15:09,000 SOME OF THE EARLIEST DOCUMENTS 282 00:15:09,000 --> 00:15:19,520 ARE IS MARIE ANTOINETTE WHOSE 283 00:15:24,680 --> 00:15:26,120 HAIR TURNED WHITE BEFORE SHE WAS 284 00:15:26,120 --> 00:15:26,360 EXECUTED. 285 00:15:26,360 --> 00:15:32,360 WHEN WE THINK OF WHAT IS THE 286 00:15:32,360 --> 00:15:33,160 AUTOREACTIVE T CELL AND IT'S 287 00:15:33,160 --> 00:15:35,640 INTERESTING TO GO BACK TO THE 288 00:15:35,640 --> 00:15:36,960 HISTORICAL ACCOUNTS AND THINK 289 00:15:36,960 --> 00:15:39,120 WHERE THE NOTIONS IN THE FIELD 290 00:15:39,120 --> 00:15:45,520 ORIGINATED. 291 00:15:45,520 --> 00:15:49,160 THERE WAS AN IDEA THERE WERE 292 00:15:49,160 --> 00:15:54,480 COMPULSIONS OR THINGS THAT COULD 293 00:15:54,480 --> 00:16:04,880 TRIGGER ALOPECIAARY 294 00:16:15,560 --> 00:16:20,280 THIS SHOWS INFILTRATE AND 295 00:16:20,280 --> 00:16:23,280 INFLAMMATION AROUND THE HAIR 296 00:16:23,280 --> 00:16:23,560 FOLLICLE. 297 00:16:23,560 --> 00:16:26,400 THE FIRST THOUGHT OF IT BEING AN 298 00:16:26,400 --> 00:16:27,960 INFLAMMATORY DISEASE CAME FROM 299 00:16:27,960 --> 00:16:30,840 ITALY AND LEUKOCYTES BRINGING 300 00:16:30,840 --> 00:16:36,920 THIS STRANGE INFILTRATION AND 301 00:16:36,920 --> 00:16:41,960 AFFECTING THE HAIR FOLLICLE AND 302 00:16:41,960 --> 00:16:42,880 CAREFUL OBSERVATIONS WE TOUCH ON 303 00:16:42,880 --> 00:16:47,520 AND THEN IN THE 1950s STEVEN 304 00:16:47,520 --> 00:16:51,000 ROTHMAN IN THE FIELD OF 305 00:16:51,000 --> 00:16:57,880 DETERMINE -- DERMATOLOGY AND 306 00:16:57,880 --> 00:17:08,640 LOOKED AT THESE ANTO GGENS AND 307 00:17:15,040 --> 00:17:18,360 HAVE TREATMENTS WE'RE USING TO 308 00:17:18,360 --> 00:17:22,960 THIS DAY IN ALOPECIA AND 309 00:17:22,960 --> 00:17:25,240 REPROGRAMMING OR RESETTING THE 310 00:17:25,240 --> 00:17:26,240 IMMUNE RESPONSE USING ANOTHER 311 00:17:26,240 --> 00:17:30,480 KIND OF IRRITANT HAS AROUND 300 312 00:17:30,480 --> 00:17:30,960 YEARS NOT A NEW IDEA. 313 00:17:30,960 --> 00:17:32,600 THE NOTION OF STEROIDS GREW IN 314 00:17:32,600 --> 00:17:36,640 THE 1950s BY DR. ROTHMAN AND 315 00:17:36,640 --> 00:17:38,680 OTHERS WHO TREATED PATIENTS WITH 316 00:17:38,680 --> 00:17:41,240 TOPICAL OR INJECTED STEROIDS AT 317 00:17:41,240 --> 00:17:45,000 THE TIME AND GOT REGROWTH IN A 318 00:17:45,000 --> 00:17:46,000 GENERIC WAY. 319 00:17:46,000 --> 00:17:52,280 THIS LAID THE GROUND WORK FOR 320 00:17:52,280 --> 00:18:00,960 THE GROUND WORK IMMUNOMODULATORY 321 00:18:00,960 --> 00:18:05,680 AFFECTS ARE IN PLAY AND MAYBE 322 00:18:05,680 --> 00:18:09,880 ALOPECIA AREATA IS A ONE OFF OF 323 00:18:09,880 --> 00:18:12,640 PSORIASIS AND ECTOPIC DERMATITIS 324 00:18:12,640 --> 00:18:15,520 AND THE APPROACH WAS TO TAKE A 325 00:18:15,520 --> 00:18:18,960 NEWLY APPROVED DRUG AND TESTING 326 00:18:18,960 --> 00:18:29,520 IT IN THIS AND HAVING THEM FAIL. 327 00:18:31,040 --> 00:18:33,720 AND NONE OF THEM COULD CREATE 328 00:18:33,720 --> 00:18:34,880 REVERSAL OF ALOPECIA AREATA AND 329 00:18:34,880 --> 00:18:37,160 WHY IS THAT? 330 00:18:37,160 --> 00:18:39,920 RIGHT NOW YOU'RE PROBABLY 331 00:18:39,920 --> 00:18:41,280 FEELING LIKE I FELT WHEN I 332 00:18:41,280 --> 00:18:46,280 ENTERED THE FIELD. 333 00:18:46,280 --> 00:18:49,320 THERE'S SO MANY THINGS INVOKED 334 00:18:49,320 --> 00:18:53,600 TO EXPLAIN WHY THE HAIR MAY BE 335 00:18:53,600 --> 00:18:54,960 SUDDENLY FALLING OUT AND WHERE 336 00:18:54,960 --> 00:18:58,840 THE DISEASE IS NOT SO OUTWARDLY 337 00:18:58,840 --> 00:18:59,080 VISIBLE. 338 00:18:59,080 --> 00:19:00,640 PEOPLE HAVE BEEN FASCINATED WITH 339 00:19:00,640 --> 00:19:02,600 THE DISEASE FOR CENTURIES MAINLY 340 00:19:02,600 --> 00:19:03,600 BECAUSE IT'S SO VISIBLE. 341 00:19:03,600 --> 00:19:06,680 IT'S A DOUBLE-EDGED SWORD. 342 00:19:06,680 --> 00:19:08,480 FOR PATIENTS IT'S A DISTRESSING 343 00:19:08,480 --> 00:19:10,840 THING FOR THE WORLD TO SEE WHAT 344 00:19:10,840 --> 00:19:12,280 THEY'RE GOING THROUGH AND FROM 345 00:19:12,280 --> 00:19:13,120 THE SCIENCE SIDE IT MAKES IT 346 00:19:13,120 --> 00:19:18,480 DIFFICULT TO DECIDE WHERE WILL 347 00:19:18,480 --> 00:19:24,240 YOU ENTER THE CONVERSATION AND 348 00:19:24,240 --> 00:19:32,200 TRY TO GET AN INROAD TO WHAT'S 349 00:19:32,200 --> 00:19:36,000 HAPPENING AND THE DRUMBEAT GREW 350 00:19:36,000 --> 00:19:39,000 LOUDER MOSTLY BASED ON CASE 351 00:19:39,000 --> 00:19:41,640 REPORTS OF TWINS OR MULTIPLEX 352 00:19:41,640 --> 00:19:44,760 FAMILIES WITH NUMEROUS FAMILY 353 00:19:44,760 --> 00:19:48,880 MEMBERS AFFECTED NOT PARENT TO 354 00:19:48,880 --> 00:19:49,800 CHILD TRANSMISSIONS BUT 355 00:19:49,800 --> 00:19:54,360 IMMIGRATION IN THE LIVING ROOM 356 00:19:54,360 --> 00:20:00,960 OF FIRST GENERATION A GIRS 357 00:20:00,960 --> 00:20:04,920 DEGREE RELATIVE AND THINGS 358 00:20:04,920 --> 00:20:06,480 ADVANCE THEY'D BEGAN TO PAY MORE 359 00:20:06,480 --> 00:20:09,000 ATTENTION TO THE NOTION PERHAPS 360 00:20:09,000 --> 00:20:14,360 THERE'S A GENETIC DRIVE AND THEY 361 00:20:14,360 --> 00:20:16,680 LOOK AT THE TWIN STUDIES WHICH 362 00:20:16,680 --> 00:20:24,280 SHOWED COULD BE CORDAN ANAN AAN 363 00:20:24,280 --> 00:20:26,600 CONCORDANCE OF 21% AND THERE 364 00:20:26,600 --> 00:20:30,920 MUST BE ANOTHER ENVIRONMENTAL 365 00:20:30,920 --> 00:20:32,880 TRIGGERING AFFECT THAT BRINGS 366 00:20:32,880 --> 00:20:38,920 THE GEEPT IN -- GEN 367 00:20:42,240 --> 00:20:43,840 GENETIC FACTORS. 368 00:20:43,840 --> 00:20:49,040 AND THEN IN THE '90s AND EARLY 369 00:20:49,040 --> 00:20:50,480 2000s CANDIDATE GENES WERE 370 00:20:50,480 --> 00:20:54,160 TESTED AND AS GENES WERE 371 00:20:54,160 --> 00:20:55,440 IMPLICATED FROM OTHER 372 00:20:55,440 --> 00:20:56,880 AUTOINFLAMMATORY AND AUTOIMMUNE 373 00:20:56,880 --> 00:20:57,880 DISEASES THEY WOULD BE TESTED IN 374 00:20:57,880 --> 00:21:00,240 A BIASSED WAY BY LOOKING ONE 375 00:21:00,240 --> 00:21:02,080 GENE AT A TIME. 376 00:21:02,080 --> 00:21:08,880 THE BEGINNINGS OF DISEASE 377 00:21:08,880 --> 00:21:10,960 ASSOCIATIONS BEGAN TO GROW 378 00:21:10,960 --> 00:21:13,800 DURING THAT TIME. 379 00:21:13,800 --> 00:21:17,560 FOR ME THIS CHANGED MAY 10, 380 00:21:17,560 --> 00:21:18,840 1996. 381 00:21:18,840 --> 00:21:20,200 THE REASON IS BECAUSE I 382 00:21:20,200 --> 00:21:20,920 DEVELOPED ALOPECIA AREATA. 383 00:21:20,920 --> 00:21:24,320 THIS IS MY SCALP. 384 00:21:24,320 --> 00:21:25,280 I EVENTUALLY DEVELOPED TEN SPOTS 385 00:21:25,280 --> 00:21:28,320 LIKE THIS OVER THE COURSE OF A 386 00:21:28,320 --> 00:21:30,440 TWO-YEAR PERIOD AND EVEN THOUGH 387 00:21:30,440 --> 00:21:32,760 I HAD WORKED IN DERMATOLOGY AT 388 00:21:32,760 --> 00:21:34,960 AS A POST-DOCTORAL FELLOW I 389 00:21:34,960 --> 00:21:40,040 WORKED AND A DIFFERENT GROUP OF 390 00:21:40,040 --> 00:21:41,200 DISEASES AND JUST MOVED TO 391 00:21:41,200 --> 00:21:46,680 COLUMBIA TO SET UP MY OWN LAB 392 00:21:46,680 --> 00:21:48,560 WAS LOOKING FOR WHAT I'D BE 393 00:21:48,560 --> 00:21:52,040 DOING THE REST OF MY INDEPENDENT 394 00:21:52,040 --> 00:21:53,560 CAREER AND THEN SIX MONTHS LATER 395 00:21:53,560 --> 00:21:57,000 ALOPECIA AREATA CAME KNOCKING ON 396 00:21:57,000 --> 00:21:58,800 MY DOOR AND I BECAME VERY 397 00:21:58,800 --> 00:21:59,680 INTERESTED IN THE BACKGROUND 398 00:21:59,680 --> 00:22:02,680 LITERATURE BECAUSE OF MY 399 00:22:02,680 --> 00:22:06,720 TRAINING IN GENETICS WHEN I 400 00:22:06,720 --> 00:22:09,120 LOOKED AT THIS AND I KNEW VERY 401 00:22:09,120 --> 00:22:09,360 LITTLE. 402 00:22:09,360 --> 00:22:12,960 THERE WERE NO LINKAGE OR GWAS 403 00:22:12,960 --> 00:22:14,960 STUDY REALLY NOTHING TO BUILD 404 00:22:14,960 --> 00:22:16,800 OFF OF. 405 00:22:16,800 --> 00:22:19,000 AROUND THIS TIME AND WHEN THEY 406 00:22:19,000 --> 00:22:20,600 WERE GETTING ATTENTION FOR THEIR 407 00:22:20,600 --> 00:22:22,000 POTENTIAL IN IDENTIFYING DISEASE 408 00:22:22,000 --> 00:22:24,000 RELEVANT PATHWAYS AND 409 00:22:24,000 --> 00:22:24,600 POTENTIALLY MOVING DRUGS TOWARDS 410 00:22:24,600 --> 00:22:25,440 THE CLINIC. 411 00:22:25,440 --> 00:22:29,200 IT WAS VERY TEMPTING AS A YOUNG 412 00:22:29,200 --> 00:22:30,800 FACULTY MEMBER TO DREAM OF THE 413 00:22:30,800 --> 00:22:34,960 IDEA TO DO A GWAS STUDY IN 414 00:22:34,960 --> 00:22:44,000 ALOPECIA AREATA SOME DAY. 415 00:22:44,000 --> 00:22:48,280 THERE WERE NO COLLECTIONS 416 00:22:48,280 --> 00:22:49,560 SITTING AROUND OF MULTIPLEX 417 00:22:49,560 --> 00:22:52,200 FAMILIES AND NO LARGE CASES OR 418 00:22:52,200 --> 00:22:55,000 CONTROLS TO BE DRIVEN OFF THE 419 00:22:55,000 --> 00:22:57,080 SHELF AND IN 199 WE DIDN'T EVEN 420 00:22:57,080 --> 00:23:00,440 HAVE A FULLY ANNOTATED GENOME SO 421 00:23:00,440 --> 00:23:02,960 IT WAS EARLY DAYS. 422 00:23:02,960 --> 00:23:06,760 I'M GRATEFUL TO NIAMS AND THE 423 00:23:06,760 --> 00:23:07,560 NATIONAL ALOPECIA FOUNDATION 424 00:23:07,560 --> 00:23:09,880 SAYING IF WE WANT TO MAKE A DENT 425 00:23:09,880 --> 00:23:15,680 IN THE DISEASE WE'LL NEED A 426 00:23:15,680 --> 00:23:15,920 COHORT. 427 00:23:15,920 --> 00:23:18,360 THE NIH FOUNDED AND FUNDED A 428 00:23:18,360 --> 00:23:21,000 REGISTRY FOR 10 YEARS. 429 00:23:21,000 --> 00:23:27,000 WE WERE ONE OF FIVE SITES 430 00:23:27,000 --> 00:23:30,240 TOGETHER TO ALLOW THE COLLECTION 431 00:23:30,240 --> 00:23:32,120 AND ASCERTAINMENT OF 3,000 432 00:23:32,120 --> 00:23:33,440 PATIENTS AND CONTROLS AS WELL AS 433 00:23:33,440 --> 00:23:35,840 WE WERE ABLE TO USE AND ACCESS 434 00:23:35,840 --> 00:23:37,640 TO A CONTROLLED DATABASE FROM 435 00:23:37,640 --> 00:23:38,040 NEW YORK. 436 00:23:38,040 --> 00:23:42,680 THIS WAS EARLY IN THE DAYS OF 437 00:23:42,680 --> 00:23:44,560 GWAS THEY WERE DOING 1,000 438 00:23:44,560 --> 00:23:46,720 PATIENTS VERSUS 1,000 CONTROLS 439 00:23:46,720 --> 00:23:48,800 AND WAS NOT HOPEFUL WE'D FIND 440 00:23:48,800 --> 00:23:49,120 ANYTHING. 441 00:23:49,120 --> 00:23:51,320 TO OUR SURPRISE THE GWAS STUDY 442 00:23:51,320 --> 00:23:52,000 WAS CLEAN. 443 00:23:52,000 --> 00:23:54,360 THE REASON FOR THAT IS BECAUSE 444 00:23:54,360 --> 00:23:56,400 THE PATIENTS WERE VERY CAREFULLY 445 00:23:56,400 --> 00:23:58,280 PHENOTYPED FROM THE OUTSET. 446 00:23:58,280 --> 00:24:00,240 THE SAME GROUP OF DERMATOLOGISTS 447 00:24:00,240 --> 00:24:05,640 SAW AND COLLECTED ALL THE 448 00:24:05,640 --> 00:24:09,000 SAMPLES AND THE PURITY OF THAT 449 00:24:09,000 --> 00:24:10,560 INFORMATION LED TO THIS AND THEY 450 00:24:10,560 --> 00:24:13,320 HAD EIGHT REGIONS AT THE 451 00:24:13,320 --> 00:24:14,080 BEGINNING. 452 00:24:14,080 --> 00:24:18,960 OF COURSE THE HLA BECAUSE WE 453 00:24:18,960 --> 00:24:20,880 BELIEVE ALOPECIA AREATA IS AN 454 00:24:20,880 --> 00:24:21,880 AUTOIMMUNE DISEASE AND THE 455 00:24:21,880 --> 00:24:27,000 SECOND MOST SIGNIFICANT HIT IS 456 00:24:27,000 --> 00:24:37,480 THE LOCUS CALLED PRDX5 AND 457 00:24:39,240 --> 00:24:41,080 THEY'RE DANGER SIGNALS WHEN THEY 458 00:24:41,080 --> 00:24:44,080 SAY COME IN AND KILL ME FROM THE 459 00:24:44,080 --> 00:24:45,640 IMMUNE SYSTEM. 460 00:24:45,640 --> 00:24:47,840 THEY CAPTURED OUR ATTENTION. 461 00:24:47,840 --> 00:24:49,240 OTHER THINGS THAT WERE 462 00:24:49,240 --> 00:24:51,080 DISCOVERED THAT WAS EXCITING 463 00:24:51,080 --> 00:24:54,920 PEOPLE IS A GENETICISTS ALWAYS 464 00:24:54,920 --> 00:24:58,240 LOVES WHEN WE GET WHAT WE CALL A 465 00:24:58,240 --> 00:25:01,880 SMOKING GUN AND IF THIS WAS 466 00:25:01,880 --> 00:25:06,120 THESE OTHERS NOT SO EXCITING BUT 467 00:25:06,120 --> 00:25:09,280 THIS ONE WAS UNIQUE AND STILL 468 00:25:09,280 --> 00:25:09,440 IS. 469 00:25:09,440 --> 00:25:14,960 THERE'S NO OTHERS HAVE THE 470 00:25:14,960 --> 00:25:21,120 LIGAND AS THEIR CANDIDATE LOCI 471 00:25:21,120 --> 00:25:23,360 AND WERE EXCITED THIS WAS 472 00:25:23,360 --> 00:25:28,360 LEADING US DOWN A PATH THAT WAS 473 00:25:28,360 --> 00:25:28,680 DIFFERENT. 474 00:25:28,680 --> 00:25:33,040 AND THE SECOND THING THAT CAME 475 00:25:33,040 --> 00:25:38,760 FROM THE STUDY IS THE 476 00:25:38,760 --> 00:25:41,560 REALIGNMENT OF WHAT ALOPECIA 477 00:25:41,560 --> 00:25:45,040 AREATA MAY BE RELATED TO AND IT 478 00:25:45,040 --> 00:25:53,480 MAY RESEMBLE VITILIGO AND 479 00:25:53,480 --> 00:26:03,920 DERMATITIS BUT IT RESEMBLED 480 00:26:13,280 --> 00:26:13,840 RHEUMATOID ARTHRITIS AND THERE'S 481 00:26:13,840 --> 00:26:16,880 WORK ON THE DISEASES AND ALL ARE 482 00:26:16,880 --> 00:26:19,000 UNITED BY THE FACT THEY'RE 483 00:26:19,000 --> 00:26:22,960 DRIVEN BY SIMILAR CYTOKINE 484 00:26:22,960 --> 00:26:26,640 SIGNALLING AND THE AXIS IS 485 00:26:26,640 --> 00:26:28,480 CENTRAL TO ALL OF THEM. 486 00:26:28,480 --> 00:26:32,240 THE GWAS STUDY WAS LATER 487 00:26:32,240 --> 00:26:33,760 REPLICATED BY A LARGER COHORT 488 00:26:33,760 --> 00:26:35,440 PUT TOGETHER WITH COLLEAGUES IN 489 00:26:35,440 --> 00:26:36,840 GERMANY AND THEY'RE GETTING THE 490 00:26:36,840 --> 00:26:39,000 CASE COUNTS UP CLOSER TO 3,000 491 00:26:39,000 --> 00:26:46,120 AND EVENTUALLY 7,000 CONTROLS. 492 00:26:46,120 --> 00:26:51,560 THEY WERE REP KATED AND THE 493 00:26:51,560 --> 00:26:54,240 STRENGTH -- REPLICATED AND THE 494 00:26:54,240 --> 00:26:55,040 STRENGTH OF THE SIGNAL SHOWED 495 00:26:55,040 --> 00:26:57,560 THE UNIQUENESS OF THE GENES AND 496 00:26:57,560 --> 00:26:58,920 THE STRENGTH OF THE SIGNAL WERE 497 00:26:58,920 --> 00:27:00,080 TELLING US IT SEEMED LIKE A 498 00:27:00,080 --> 00:27:05,480 FRUITFUL PLACE TO BEGIN TO LOOK. 499 00:27:05,480 --> 00:27:06,960 WE SCANNED THE LITERATURE AND 500 00:27:06,960 --> 00:27:08,120 WANTED TO LEARN EVERYTHING WE 501 00:27:08,120 --> 00:27:10,960 COULD ABOUT THE LIGANDS IN THESE 502 00:27:10,960 --> 00:27:15,560 DISEASES AND TURNED OUT IN 503 00:27:15,560 --> 00:27:22,200 RHEUMATOID ARTHRITIS AND CELIAC 504 00:27:22,200 --> 00:27:23,000 DISEASE THERE'S A RELATION IN 505 00:27:23,000 --> 00:27:26,960 THE END ORGANS OF THESE 506 00:27:26,960 --> 00:27:30,960 DISORDERS. 507 00:27:30,960 --> 00:27:33,040 OUR QUESTION WAS DID WE SEE THE 508 00:27:33,040 --> 00:27:38,640 SAME IN THE HAIR FOLLICLE. 509 00:27:38,640 --> 00:27:40,360 THIS IS OUTLINED IN BLUE WITH 510 00:27:40,360 --> 00:27:46,960 RED STAINING FOR THE LIGANDS 511 00:27:46,960 --> 00:27:49,680 ULBP3 AND YOU SEE HERE A MASSIVE 512 00:27:49,680 --> 00:27:52,040 UP REGULATION IN THE OUTER MOST 513 00:27:52,040 --> 00:27:52,840 PART OF THE HAIR FOLLICLE AND 514 00:27:52,840 --> 00:27:58,640 WE'LL TALK ABOUT THAT LATER. 515 00:27:58,640 --> 00:28:02,320 WE WOULD HOPE WE SEE THE 516 00:28:02,320 --> 00:28:04,400 RECEPTOR ON THE SURFACE OF T 517 00:28:04,400 --> 00:28:06,840 CELLS SURROUNDING THE HAIR FOL 518 00:28:06,840 --> 00:28:08,000 KALZ AND HERE YOU CAN SEE THAT'S 519 00:28:08,000 --> 00:28:11,640 THE CASE WE HAVE COEXPRESSION OF 520 00:28:11,640 --> 00:28:15,000 PD8 AND THE T CELLS SURROUNDING 521 00:28:15,000 --> 00:28:16,240 THE HAIR FOLLICLE. 522 00:28:16,240 --> 00:28:18,600 THIS WAS AN IMPORTANT MOMENT FOR 523 00:28:18,600 --> 00:28:20,480 BECAUSE IT WAS THE FIRST TIME WE 524 00:28:20,480 --> 00:28:22,480 HAD A BIT OF DEFINITION ABOUT 525 00:28:22,480 --> 00:28:23,880 THE NATURE OF THIS INFILTRATE 526 00:28:23,880 --> 00:28:27,000 AND I WAS WORKING WITH A 527 00:28:27,000 --> 00:28:31,000 BRILLIANT IMMUNOLOGY COLLEGIATE 528 00:28:31,000 --> 00:28:33,560 THE TIME AT COLUMBIA AND THEY 529 00:28:33,560 --> 00:28:34,880 STUDIED THEM IN TYPE 1 DIABETES 530 00:28:34,880 --> 00:28:35,840 AND CANCER. 531 00:28:35,840 --> 00:28:38,480 AND THE FIELD KNOWS A LOT ABOUT 532 00:28:38,480 --> 00:28:40,080 THE CELLS TOO ESPECIALLY WHAT'S 533 00:28:40,080 --> 00:28:42,400 REQUIRED TO KEEP THEM ALIVE. 534 00:28:42,400 --> 00:28:45,240 THEY REQUIRE IL15 SIGNALLING FOR 535 00:28:45,240 --> 00:28:48,640 THEIR SURVIVAL AND WHEN 536 00:28:48,640 --> 00:28:50,760 ACTIVATED IN ANGRY THEY CREATE 537 00:28:50,760 --> 00:28:51,400 INTERFERON GAMMA. 538 00:28:51,400 --> 00:28:53,520 AGAIN, THIS IS EARLY DAYS OF THE 539 00:28:53,520 --> 00:28:57,560 LITERATURE BUT WE BEGAN TO 540 00:28:57,560 --> 00:28:59,920 ALREADY THINK ABOUT HOW COULD WE 541 00:28:59,920 --> 00:29:04,720 INTERRUPT THE SIGNALLING AND 542 00:29:04,720 --> 00:29:09,040 RATHER THAN TAKE THE APPROACH OF 543 00:29:09,040 --> 00:29:12,640 USING BLOCKING ANTIBODIES 544 00:29:12,640 --> 00:29:15,960 BECAUSE ALOPECIA AREATA HAS A 545 00:29:15,960 --> 00:29:17,920 COSMETIC DISEASE AND NO KNOWN 546 00:29:17,920 --> 00:29:21,040 COMORBIDITY SAFETY WAS TOP OF 547 00:29:21,040 --> 00:29:22,960 MIND AND THE THOUGHT OF 548 00:29:22,960 --> 00:29:26,080 INTERVENING DOWN STREAM THE IL15 549 00:29:26,080 --> 00:29:29,200 PATHWAY BECAME SOMETHING WE 550 00:29:29,200 --> 00:29:30,960 FOCUSSED ON AND DOWN STREAM 551 00:29:30,960 --> 00:29:33,800 YOU'LL LEARN IN A FEW MINUTES 552 00:29:33,800 --> 00:29:34,960 VERY WELL ABOUT THE JAK 553 00:29:34,960 --> 00:29:35,840 SIGNALLING PATHWAY. 554 00:29:35,840 --> 00:29:39,920 BECAUSE WE KNEW WE HAD BOTH IL15 555 00:29:39,920 --> 00:29:44,280 AND INTERFERON GAMMA AS OUR 556 00:29:44,280 --> 00:29:49,760 CYTOKINE AXIS WE BEGAN TO FOCUS 557 00:29:49,760 --> 00:29:52,760 ON TRYING TO IDENTIFY JAK 558 00:29:52,760 --> 00:29:53,760 INHIBITERS TO TEST IN THE 559 00:29:53,760 --> 00:29:56,360 DISEASE. 560 00:29:56,360 --> 00:30:02,040 IL15 AND THE SIGNAL THROUGH JAK 561 00:30:02,040 --> 00:30:06,040 1 OR JAK 2 OR JAK 3 AND THE TIME 562 00:30:06,040 --> 00:30:14,160 THE DRUGS WERE COMING TO MARKET 563 00:30:14,160 --> 00:30:21,640 AND YOU'LL NOTICE THIS GOES TO 564 00:30:21,640 --> 00:30:23,480 THIS AND HE'LL TELL YOU ABOUT 565 00:30:23,480 --> 00:30:25,440 THE JAK INHIBITORS IN HIS WORK 566 00:30:25,440 --> 00:30:27,760 AND I'LL COME BACK WHEN HE'S 567 00:30:27,760 --> 00:30:29,200 FINISHED AND TALK ABOUT HOW WE 568 00:30:29,200 --> 00:30:30,960 BEGIN TO APPLY THAT KNOWLEDGE IN 569 00:30:30,960 --> 00:30:33,000 THE SETTING OF ALOPECIA AREATA. 570 00:30:33,000 --> 00:30:38,240 I'LL TURN IT OVER TO JOHN. 571 00:30:38,240 --> 00:30:41,040 THIS IS ITHE 30th ANNIVERSARY 572 00:30:41,040 --> 00:30:43,200 OF THE JAK STAT PATHWAY AND IT'S 573 00:30:43,200 --> 00:30:45,840 BEEN A DECADE SINCE WE STARTED 574 00:30:45,840 --> 00:30:48,840 HAVING JAK INHIBITERS AND MY 575 00:30:48,840 --> 00:30:53,640 JOB IS TO TALK ABOUT CYTOKINE 576 00:30:53,640 --> 00:30:59,440 SIGNALLING AND THE RATIONALE AND 577 00:30:59,440 --> 00:31:09,960 HISTORY OF THIS JAKINIBS AND 578 00:31:11,760 --> 00:31:13,640 THINK OF CYTOKINE SIGNALLING 579 00:31:13,640 --> 00:31:15,720 WHICH STARTED IN THE LATE '80s 580 00:31:15,720 --> 00:31:20,440 AND '90s AND HOW WE THINK OF 581 00:31:20,440 --> 00:31:25,560 CYTOKINE SIGNAL. 582 00:31:25,560 --> 00:31:28,600 THESE ARE REFERENCES OR IF YOU 583 00:31:28,600 --> 00:31:31,880 HAVE TO GIVE LECTURES SEND ME A 584 00:31:31,880 --> 00:31:35,040 NOTE I'M HAPPY TO SEND MY SLIDES 585 00:31:35,040 --> 00:31:38,240 WITH MY CARTOONS TO GIVE ME TALK 586 00:31:38,240 --> 00:31:39,360 AS WELL. 587 00:31:39,360 --> 00:31:41,440 HERE'S ARE MY DISCLOSURES. 588 00:31:41,440 --> 00:31:44,960 THE NIH HAS A PATENT ASSOCIATED 589 00:31:44,960 --> 00:31:46,640 WITH JAK INHIBITERS AND I GET 590 00:31:46,640 --> 00:31:49,200 ROYALTIES FROM THAT AND WE HAD A 591 00:31:49,200 --> 00:31:50,840 LONG-STANDING COLLABORATION WITH 592 00:31:50,840 --> 00:31:57,240 PFIZER WHICH ENDED. 593 00:31:57,240 --> 00:31:59,840 AND WHEN YOU THINK BROADLY HOW 594 00:31:59,840 --> 00:32:04,400 WE FACE ALL THE MANY TYPES OF 595 00:32:04,400 --> 00:32:14,400 MICROBIAL PATHOGENS WE FACE WE 596 00:32:14,400 --> 00:32:15,680 HAVE MANY CELLS INVOLVED WITH 597 00:32:15,680 --> 00:32:17,640 HOST DEFENSE AND HOW DO THEY 598 00:32:17,640 --> 00:32:18,440 COMMUNICATE WITH EACH OTHER? 599 00:32:18,440 --> 00:32:21,200 ONE OF THE BIGGEST SOLUTIONS FOR 600 00:32:21,200 --> 00:32:22,080 THE COMMUNICATION BETWEEN THE 601 00:32:22,080 --> 00:32:29,280 CELLS AS ANGELA POINTED OUT, 602 00:32:29,280 --> 00:32:32,920 HAVE LOADS AND LOADS OF 603 00:32:32,920 --> 00:32:34,640 CYTOKINES PRODUCED BY DIFFERENT 604 00:32:34,640 --> 00:32:36,480 CELLS AND THEY RESPOND TO THE 605 00:32:36,480 --> 00:32:38,600 CYTOKINES AND THEY'RE IMPORTANT 606 00:32:38,600 --> 00:32:39,920 FOR HOST DEFENSE BUT A NUMBER OF 607 00:32:39,920 --> 00:32:45,000 THINGS TO THINK ABOUT. 608 00:32:45,000 --> 00:32:47,160 IT'S IMPORTANT FOR THINK OF 609 00:32:47,160 --> 00:32:51,880 EFFICACY AND ADVERSE EVENTS. 610 00:32:51,880 --> 00:32:54,480 CYTOKINE IS A HISTORICAL TERM 611 00:32:54,480 --> 00:32:57,400 AND DOESN'T REFER TO A 612 00:32:57,400 --> 00:32:59,320 PARTICULAR STRUCTURAL CLASS OF 613 00:32:59,320 --> 00:33:03,160 LIGANDS OR RECEPTORS AND USED 614 00:33:03,160 --> 00:33:05,240 WIDELY FOR THINGS AND IT'S 615 00:33:05,240 --> 00:33:11,600 IMPORTANT FOR HOST DEFENSE AND 616 00:33:11,600 --> 00:33:16,400 CYTOKINES ACT ON CELLS AND 617 00:33:16,400 --> 00:33:17,440 EVOLUTIONARY ALL CELLS START 618 00:33:17,440 --> 00:33:21,600 FROM INVERTEBRATES HAVE A NEED 619 00:33:21,600 --> 00:33:22,800 TO COMMUNICATE WITH ONE ANOTHER 620 00:33:22,800 --> 00:33:27,840 AND THE LIKE AND SO IN FACT 621 00:33:27,840 --> 00:33:29,840 CYTOKINES GO BACK TO 622 00:33:29,840 --> 00:33:36,440 INVERTEBRATES AND THE JAK STAT 623 00:33:36,440 --> 00:33:41,480 PATHWAY IS EVIDENCED IN INSECTS. 624 00:33:41,480 --> 00:33:45,240 THIS WAY OF TALKING AMONGST 625 00:33:45,240 --> 00:33:48,440 CELLS IS AN ANCIENT ASPECT OF 626 00:33:48,440 --> 00:33:53,600 CELL-CELL COMMUNICATION. 627 00:33:53,600 --> 00:33:55,120 IT'S CRITICAL FOR HOST DEFENSE 628 00:33:55,120 --> 00:33:57,160 AND REPAIR AND HOMEOSTASIS AND 629 00:33:57,160 --> 00:33:59,120 I'LL GET TO THAT IN A MOMENT. 630 00:33:59,120 --> 00:34:02,480 THIS IS MY WAY OF THINKING OF 631 00:34:02,480 --> 00:34:08,400 CYTOKINES AND THIS IS ONE WAY OF 632 00:34:08,400 --> 00:34:09,840 CATEGORIZING CYTOKINES. 633 00:34:09,840 --> 00:34:13,400 THERE'S TYPE 1 AND TYPE 2 634 00:34:13,400 --> 00:34:13,680 CYTOKINES. 635 00:34:13,680 --> 00:34:21,120 AND YOU SEE RECEPTORS AND THIS 636 00:34:21,120 --> 00:34:22,800 IS AN ANCIENT PATHWAY GOING BACK 637 00:34:22,800 --> 00:34:25,040 TO INVERTEBRATES AND EVEN PLANT 638 00:34:25,040 --> 00:34:27,960 HAVE SOME ASPECTS OF THIS 639 00:34:27,960 --> 00:34:29,360 PATHWAY. 640 00:34:29,360 --> 00:34:34,760 17 RECEPTOR ALSO IN 641 00:34:34,760 --> 00:34:36,400 INVERTEBRATES THEN THERE ARE 642 00:34:36,400 --> 00:34:42,040 SOME CYTOKINES THAT USE RECEPTOR 643 00:34:42,040 --> 00:34:46,240 AND KINASES AND SEVEN TRANS 644 00:34:46,240 --> 00:34:47,680 MEMBRANE RECEPTORS ARE OTHER 645 00:34:47,680 --> 00:34:58,120 RECEPTORS FOR CHEMOKINES. 646 00:35:00,160 --> 00:35:03,560 AND YOU'LL SEE RHEUMATOID 647 00:35:03,560 --> 00:35:04,280 ARTHRITIS CLOSE TO ALOPECIA 648 00:35:04,280 --> 00:35:06,000 AREATA AND THERE'S CYTOKINES 649 00:35:06,000 --> 00:35:07,880 INVOLVED IN THE PATHOGENESIS. 650 00:35:07,880 --> 00:35:09,600 IF YOU THINK ABOUT THIS EVERY 651 00:35:09,600 --> 00:35:11,280 DAY AND THINK ABOUT HOW TO WE 652 00:35:11,280 --> 00:35:15,200 CAN USE THIS INFORMATION ON A 653 00:35:15,200 --> 00:35:17,520 DAILY BASIS IT JUST SEEMS LIKE A 654 00:35:17,520 --> 00:35:20,240 MORASS OF NUMBERS AND THE LIKE. 655 00:35:20,240 --> 00:35:22,560 THERE'S PROBABLY MORE THAN 200 656 00:35:22,560 --> 00:35:28,400 OR SO THINGS YOU CAN CALL 657 00:35:28,400 --> 00:35:34,680 CYTOKINES IN THE GENOME. 658 00:35:34,680 --> 00:35:38,240 IT'S IMPORTANT THEY DRIVE 659 00:35:38,240 --> 00:35:42,600 AUTOIMMUNE DISEASE AND 660 00:35:42,600 --> 00:35:44,320 CYTOKINES' NAMES ARE SOMETIMES 661 00:35:44,320 --> 00:35:49,600 MISLEADING IN BROAD FUNCTIONS 662 00:35:49,600 --> 00:35:51,040 AND CYTOKINE CAN INCLUDE GROWTH 663 00:35:51,040 --> 00:35:54,480 FACTORS AND INTERLEUKINS AND 664 00:35:54,480 --> 00:35:56,400 STIMULATING FACTORS. 665 00:35:56,400 --> 00:36:00,400 IT DIDN'T MISS OR INDUSTRY 666 00:36:00,400 --> 00:36:03,400 DIDN'T MISS THE EXPLOSION OF 667 00:36:03,400 --> 00:36:05,400 CYTOKINE RECEPTORS AND LED TO 668 00:36:05,400 --> 00:36:08,400 NOT JUST THE MOLECULAR BIOLOGY 669 00:36:08,400 --> 00:36:09,760 REVOLUTION OF DISCOVERY BUT ALSO 670 00:36:09,760 --> 00:36:16,800 BIO ONICS IN TERMS OF TARGETING 671 00:36:16,800 --> 00:36:18,320 CYTOKINES AND I'M GIVING 672 00:36:18,320 --> 00:36:20,040 EXAMPLES OF DIFFERENT CLASSES 673 00:36:20,040 --> 00:36:20,640 SHOWN HERE. 674 00:36:20,640 --> 00:36:24,160 DESPITE THE EFFICACY OF THESE 675 00:36:24,160 --> 00:36:28,440 DRUGS, THEY'RE REALLY 676 00:36:28,440 --> 00:36:30,920 EXTRAORDINARILY EFFICACIOUS AND 677 00:36:30,920 --> 00:36:34,640 I'LL RETURN TO THE CLASS OF TNF 678 00:36:34,640 --> 00:36:36,560 RECEPTORS AND NOT ALL PATIENTS 679 00:36:36,560 --> 00:36:46,960 RESPOND TO THE DRUGS. 680 00:36:47,800 --> 00:36:53,000 I'LL FOCUS ON CYTOKINE RECEPTOR 681 00:36:53,000 --> 00:36:54,480 AND THIS IS ME ON THE RIGHT AND 682 00:36:54,480 --> 00:36:55,240 DAN CAN TELL YOU THE STORY 683 00:36:55,240 --> 00:37:05,360 LATER. 684 00:37:19,440 --> 00:37:25,000 AND I WENT TO A LOT OF MEETINGS 685 00:37:25,000 --> 00:37:35,480 WITH PEOPLE LIKE AND BECAME 686 00:37:40,480 --> 00:37:44,400 INTERESTED IN PHOSPHORYLATION 687 00:37:44,400 --> 00:37:49,800 AND ARD AND I REMEMBER VIVIDLY 688 00:37:49,800 --> 00:37:53,280 HEARING PRESENTATIONS ABOUT 689 00:37:53,280 --> 00:37:55,120 PEOPLE WHO STUDY GROWTH FACTORS 690 00:37:55,120 --> 00:37:57,280 LIKE INSULIN AND OTHER FACTORS 691 00:37:57,280 --> 00:37:59,520 AS WELL THESE RECEPTORS HAVE 692 00:37:59,520 --> 00:38:01,320 INTRINSIC KINASE AND THE 693 00:38:01,320 --> 00:38:04,400 RECEPTORS WITH KINASE ACTIVITY 694 00:38:04,400 --> 00:38:06,480 INTRINSICALLY AND INDUCED 695 00:38:06,480 --> 00:38:08,640 PHOSPHORYLATION OF SUBSTRATES IN 696 00:38:08,640 --> 00:38:08,880 THE CELL. 697 00:38:08,880 --> 00:38:12,440 I WAS INTRIGUED BY THE IDEA 698 00:38:12,440 --> 00:38:13,600 CYTOKINES DID THIS AND THE 699 00:38:13,600 --> 00:38:16,640 PATHWAY AT THE TIME WAS NOT 700 00:38:16,640 --> 00:38:17,320 CLEAR. 701 00:38:17,320 --> 00:38:20,360 THE FIELD BLEW UP BY PEOPLE AND 702 00:38:20,360 --> 00:38:24,240 THE LAB OF GEORGE STARK WITH 703 00:38:24,240 --> 00:38:28,400 SANDRA AND JIM DARNELL. 704 00:38:28,400 --> 00:38:33,360 AND THE APPROACH MANY OF US TOOK 705 00:38:33,360 --> 00:38:35,160 WE STARTED SCREENING LIBRARIES 706 00:38:35,160 --> 00:38:40,440 FOR KINASES TO SEE IF THEY FIT 707 00:38:40,440 --> 00:38:48,920 THE BILL FOR SIGNALLING AND THEY 708 00:38:48,920 --> 00:38:54,160 GENERATED CELL LINES THEY USE TO 709 00:38:54,160 --> 00:38:56,240 THIS DAY FOR CELL LINES 710 00:38:56,240 --> 00:39:06,720 INSENSITIVE TO INTERFERONS. 711 00:39:08,920 --> 00:39:12,040 AND THIS KINASE RESTORED 712 00:39:12,040 --> 00:39:13,840 SIGNALLING IN THE INTERFERON 713 00:39:13,840 --> 00:39:17,680 SENSITIVE LINE. 714 00:39:17,680 --> 00:39:22,200 AROUND THE SAME TIME THEY USED 715 00:39:22,200 --> 00:39:25,640 THE SAME STRATEGY THINKING ABOUT 716 00:39:25,640 --> 00:39:29,240 LOCI THAT ARE RESPONSIVE TO 717 00:39:29,240 --> 00:39:30,520 INTERFERONS AND HE USED 718 00:39:30,520 --> 00:39:37,720 PROMOTERS FROM THE GENES AS BAIT 719 00:39:37,720 --> 00:39:40,240 TO LOOK AT INTERFERONS AND 720 00:39:40,240 --> 00:39:42,040 DISCOVERED THE STAT PATHWAY AND 721 00:39:42,040 --> 00:39:44,280 STANDS FOR SIGNAL TRANSDUCER AND 722 00:39:44,280 --> 00:39:46,600 ACTIVATOR OF TRANSCRIPTION. 723 00:39:46,600 --> 00:39:48,400 ACTUALLY WHEN JIM CAME HOME AND 724 00:39:48,400 --> 00:39:53,840 SAID TO HIS WIFE, I DISCOVERED 725 00:39:53,840 --> 00:39:55,200 THESE THINGS THAT GIVE THIS 726 00:39:55,200 --> 00:39:56,400 RAPID RESPONSE TO INTERFERONS 727 00:39:56,400 --> 00:39:58,560 AND WAS THINKING I DON'T KNOW 728 00:39:58,560 --> 00:40:04,400 WHAT TO CALL IT AND THIS IS A 729 00:40:04,400 --> 00:40:08,400 TRUE STORY AND HIS WIFE SAID 730 00:40:08,400 --> 00:40:10,600 WHAT DO YOU GUYS SAY WHEN 731 00:40:10,600 --> 00:40:12,200 SOMETHING HAPPENS QUICKLY, YOU 732 00:40:12,200 --> 00:40:14,040 SAY STAT. 733 00:40:14,040 --> 00:40:14,880 IT'S QUICK. 734 00:40:14,880 --> 00:40:25,440 AND JIM THEN TOOK STAT AND USED 735 00:40:26,120 --> 00:40:28,600 THIS AS AN PATHWAY AND IT'S USED 736 00:40:28,600 --> 00:40:36,240 BY CYTOKINES AND THE POWER OF 737 00:40:36,240 --> 00:40:40,400 THESE LINES GENERATED BY GEORGE 738 00:40:40,400 --> 00:40:46,760 STARK WAS OBVIOUSLY VERY CLEAR 739 00:40:46,760 --> 00:40:50,040 WE DIDN'T KNOW THE IN VIVO 740 00:40:50,040 --> 00:40:52,240 CRITICALITY OF JAK AND YOU WOULD 741 00:40:52,240 --> 00:40:55,320 THINK PEOPLE WOULD MAKE VARIOUS 742 00:40:55,320 --> 00:40:57,280 KNOCKOUT MICE WHICH WAS DONE BUT 743 00:40:57,280 --> 00:41:00,400 THE IN VIVO CRITICALITY CAME 744 00:41:00,400 --> 00:41:10,760 ABOUT A DIFFERENT WAY. 745 00:41:19,760 --> 00:41:21,080 WE WERE TRYING TO CLONE KINASES 746 00:41:21,080 --> 00:41:28,120 AND I FOCUSSED ON KINASES AND 747 00:41:28,120 --> 00:41:30,960 LEUKOCYTES IN CATOLYTIC CELLS 748 00:41:30,960 --> 00:41:34,520 AND WE CLONED JAK 3 AND NOTICED 749 00:41:34,520 --> 00:41:35,560 IT WAS HIGHLY EXPRESSED IN 750 00:41:35,560 --> 00:41:36,280 IMMUNE CELLS. 751 00:41:36,280 --> 00:41:40,440 THAT GOT ME THINKING TO WHAT 752 00:41:40,440 --> 00:41:46,600 MIGHT IT BE USED FOR. 753 00:41:46,600 --> 00:41:48,400 AND A COLLABORATOR FOR A LONG 754 00:41:48,400 --> 00:41:54,040 TIME FOUND THE CYTOKINES, HERE 755 00:41:54,040 --> 00:41:58,120 SIGNAL THROUGH THIS RECEPTOR SUB 756 00:41:58,120 --> 00:42:00,440 UNIT REFERRED TO AS THE COMMON 757 00:42:00,440 --> 00:42:04,400 GAMMA CHANGE AND IT UNDER LIE 758 00:42:04,400 --> 00:42:06,520 THE DISEASE IMMUNODEFICIENCY OR 759 00:42:06,520 --> 00:42:08,400 THE BUBBLE BOY DISEASE. 760 00:42:08,400 --> 00:42:13,840 AND WE WERE THINKING MAYBE IT 761 00:42:13,840 --> 00:42:18,520 ASSOCIATED WITH THIS RECEPTOR 762 00:42:18,520 --> 00:42:21,920 AND PROPOSE IF MUTATIONS TO THE 763 00:42:21,920 --> 00:42:23,680 COMMON GAMMA CHAIN AND YOU GET 764 00:42:23,680 --> 00:42:26,160 THIS DISEASE MAYBE IF YOU HAD 765 00:42:26,160 --> 00:42:27,840 MUTATIONS THIS DISEASE AFFECTS 766 00:42:27,840 --> 00:42:32,440 BOYS BUT YOU MIGHT IMAGINE AND 767 00:42:32,440 --> 00:42:35,440 THERE WERE GIRLS WHO HAD A 768 00:42:35,440 --> 00:42:40,120 SIMILAR DISEASE MUTATIONS OF JAK 769 00:42:40,120 --> 00:42:46,200 3 MAY CAUSE A SIMILAR DISEASE 770 00:42:46,200 --> 00:42:55,360 AND TURNED OUT TO BE TRUE AND WE 771 00:42:55,360 --> 00:43:00,840 IDENTIFIED PATIENTS WITH JAK 3 772 00:43:00,840 --> 00:43:05,240 MUTATIONS AND LAUREN AND I 773 00:43:05,240 --> 00:43:06,880 COLLABORATED WITH A LAB AT DUKE 774 00:43:06,880 --> 00:43:10,680 AND SHE ALSO HAD A COHORT OF 775 00:43:10,680 --> 00:43:12,400 PATIENTS. 776 00:43:12,400 --> 00:43:15,080 THIS WAS THE FIRST KNOCKOUT IN 777 00:43:15,080 --> 00:43:17,960 THE JAK STAPP STAT PATHWAY AND A 778 00:43:17,960 --> 00:43:19,320 NUMBER OF GROUPS MADE VARIOUS 779 00:43:19,320 --> 00:43:23,280 KNOCKOUT MICE. 780 00:43:23,280 --> 00:43:25,360 IN THE PAPER WE PROPOSED IF YOU 781 00:43:25,360 --> 00:43:26,800 GENERATED A NEW CLASS OF DRUGS 782 00:43:26,800 --> 00:43:30,520 YOU'D HAVE A NEW CLASS OF 783 00:43:30,520 --> 00:43:32,400 IMMUNOEXPIMMUNO 784 00:43:32,400 --> 00:43:38,640 EXPRESS SUPPRESSANTS AND THAT 785 00:43:38,640 --> 00:43:40,440 WAS BOLD AND WHEN I FIRST DID 786 00:43:40,440 --> 00:43:43,120 THIS IN 1993 THIS WAS A MEETING 787 00:43:43,120 --> 00:43:45,400 WHEN I FIRST PRESENT THE CLOTH 788 00:43:45,400 --> 00:43:47,440 AND RAN INTO PAUL. 789 00:43:47,440 --> 00:43:50,800 AND WE HAD BEEN COLLABORATORS ON 790 00:43:50,800 --> 00:43:52,120 DIFFERENT PROJECTS BEFORE HE 791 00:43:52,120 --> 00:43:52,960 MOVED TO PFIZER. 792 00:43:52,960 --> 00:43:56,160 AND PAUL WAS LOOKING FOR 793 00:43:56,160 --> 00:44:00,400 POTENTIALLY TARGETS FOR PFIZER 794 00:44:00,400 --> 00:44:10,800 TO START A PROJECT ON. 795 00:44:14,400 --> 00:44:19,720 AND THIS IS DEPOSITED TO START 796 00:44:19,720 --> 00:44:20,000 SIGNALLING. 797 00:44:20,000 --> 00:44:22,920 THIS IS THE CHALLENGE AHEAD OF 798 00:44:22,920 --> 00:44:23,360 US. 799 00:44:23,360 --> 00:44:24,920 YOU MIGHT IMAGINE IF WE SAID TO 800 00:44:24,920 --> 00:44:27,240 YOU RIGHT NOW WE WANT TO MAKE 801 00:44:27,240 --> 00:44:30,360 DRUGS THAT TARGET ATP, YOU MIGHT 802 00:44:30,360 --> 00:44:32,360 THINK THAT'S PRETTY FOOLISH. 803 00:44:32,360 --> 00:44:36,600 BUT THAT FIELD AND THERE WAS MET 804 00:44:36,600 --> 00:44:42,480 WITH PLENTY OF SKEPTICISM BACK 805 00:44:42,480 --> 00:44:50,800 IN THE MID 90s OR SO. 806 00:44:50,800 --> 00:44:57,760 A NUMBER OF DRUGS HAD REVERSIBLE 807 00:44:57,760 --> 00:44:58,120 PHOSPHORYLATION. 808 00:44:58,120 --> 00:45:01,280 AT THE TIME PEOPLE DIDN'T KNOW 809 00:45:01,280 --> 00:45:05,960 THE BIO CHEMISTRY AND LOOKING AT 810 00:45:05,960 --> 00:45:09,400 BIOLOGICS GENERATED FROM 811 00:45:09,400 --> 00:45:15,320 PRODUCTS AND BACTERIAL PRODUCTS 812 00:45:15,320 --> 00:45:15,920 ETCETERA. 813 00:45:15,920 --> 00:45:18,480 WE DIDN'T KNOW THE DRUGS WERE 814 00:45:18,480 --> 00:45:20,400 ALTERING PHOSPHORYLATION BUT IT 815 00:45:20,400 --> 00:45:27,240 TOOK TARGETED THERAPY OF KINASES 816 00:45:27,240 --> 00:45:33,480 AND THAT'S THE WORK AND TARGETED 817 00:45:33,480 --> 00:45:39,520 THESE IN CML AND GENERATED A 818 00:45:39,520 --> 00:45:43,760 DRUG THAT SELECTIVELY TARGET THE 819 00:45:43,760 --> 00:45:46,120 KINASE AND YOU MAY THINK 820 00:45:46,120 --> 00:45:49,760 TARGETING ATP WOULD BE A GOOD 821 00:45:49,760 --> 00:45:51,680 IDEA THIS FLIPPED THE SWITCH AND 822 00:45:51,680 --> 00:45:54,520 TARGETING KINASES IN THIS MANNER 823 00:45:54,520 --> 00:45:59,080 BECAME A VERY ACTIVE AREA. 824 00:45:59,080 --> 00:46:03,000 THIS IS WHAT HAPPENED WITH JAK 825 00:46:03,000 --> 00:46:03,320 INHIBITERS. 826 00:46:03,320 --> 00:46:06,560 FIRST JACK INHIBITERS WERE 827 00:46:06,560 --> 00:46:16,840 APPROVED IN 2012. 828 00:46:19,440 --> 00:46:24,400 AND THERE'S MANY JAK INHIBITERS 829 00:46:24,400 --> 00:46:29,560 FOR ARTHRITIS IN CHILDREN AND 830 00:46:29,560 --> 00:46:34,720 ULCERATIVE COLITIS AND 831 00:46:34,720 --> 00:46:37,400 DERMATITIS AND ALOPECIA AREATA 832 00:46:37,400 --> 00:46:47,960 AND PLAQUE SORIASIS AND THIS IS 833 00:46:54,600 --> 00:46:57,920 ASSOCIATED WITH DAN CASTNER'S 834 00:46:57,920 --> 00:47:00,400 EXTENDED LAB. 835 00:47:00,400 --> 00:47:04,120 THIS IS LEO 6 YEARS OLD WAS WELL 836 00:47:04,120 --> 00:47:06,280 UNTIL THREE YEARS BEFORE HE 837 00:47:06,280 --> 00:47:11,720 PRESENTED TO THE NIH AND RASH 838 00:47:11,720 --> 00:47:14,760 AND ITCHING AND SCRATCHING AND 839 00:47:14,760 --> 00:47:16,400 TREATED WITH STEROIDS AND GOT 840 00:47:16,400 --> 00:47:18,880 PUT ON A JACK INHIBITOR AND YOU 841 00:47:18,880 --> 00:47:21,400 SEE LEO THREE WEEKS AFTER BEING 842 00:47:21,400 --> 00:47:21,600 TREAT. 843 00:47:21,600 --> 00:47:27,160 THIS IS TO REMIND YOU THERE IS 844 00:47:27,160 --> 00:47:30,520 IN FACT JAK CANINE INHIBITERS AS 845 00:47:30,520 --> 00:47:35,080 WELL AS HUMAN. 846 00:47:35,080 --> 00:47:37,600 MANY DISEASES BEING TESTED AND A 847 00:47:37,600 --> 00:47:39,280 LOT OF ACTIVITY AT THE NIH AND 848 00:47:39,280 --> 00:47:40,640 WHERE PEOPLE STUDY ARE DIFFERENT 849 00:47:40,640 --> 00:47:48,400 DISEASES. 850 00:47:48,400 --> 00:47:52,400 THERE'S INTERESTING WORK FROM AN 851 00:47:52,400 --> 00:47:56,920 NIH ALUM NOW IN NEW YORK WHO 852 00:47:56,920 --> 00:48:01,040 POINTED OUT NERVES HAVE CYTOKINE 853 00:48:01,040 --> 00:48:04,840 RECEPTORS AND JAK INHIBITERS CAN 854 00:48:04,840 --> 00:48:06,560 RAPIDLY AFFECT ITCH AND THEY 855 00:48:06,560 --> 00:48:09,080 ALSO IMPACT PAIN. 856 00:48:09,080 --> 00:48:10,880 THIS IS AN IMPORTANT AREA GOING 857 00:48:10,880 --> 00:48:16,400 FORWARD TO BE THINKING ABOUT NOT 858 00:48:16,400 --> 00:48:19,480 JUST CYTOKINE RECEPTORS ON 859 00:48:19,480 --> 00:48:21,240 IMMUNE CELLS AND NON-IMMUNE 860 00:48:21,240 --> 00:48:22,760 CELLS AND HOW IT PARTICIPATES IN 861 00:48:22,760 --> 00:48:26,080 OTHER ASPECTS OF DISEASE 862 00:48:26,080 --> 00:48:26,960 ASSOCIATED WITH INFLAMMATORY AND 863 00:48:26,960 --> 00:48:32,560 IMMUNE MEDIATED DISEASE. 864 00:48:32,560 --> 00:48:36,200 AGAIN, DRUGS ARE TYPICALLY 865 00:48:36,200 --> 00:48:38,440 ASSOCIATED WITH ADVERSE EVENTS 866 00:48:38,440 --> 00:48:40,400 AND JAK INHIBITERS ARE NO 867 00:48:40,400 --> 00:48:45,560 EXCEPTION. 868 00:48:45,560 --> 00:48:48,400 THE THING WE EXPECTED EARLY ON 869 00:48:48,400 --> 00:48:50,760 IS SEEING SERIOUS INFECTION WITH 870 00:48:50,760 --> 00:48:54,320 JACK INHIBITORS AND IN 871 00:48:54,320 --> 00:48:56,160 PARTICULAR HERPES ZOSTER IS A 872 00:48:56,160 --> 00:48:58,840 DISEASE THAT CAN BE IN PATIENTS 873 00:48:58,840 --> 00:49:01,480 TREATED WITH JACK INHIBITERS AND 874 00:49:01,480 --> 00:49:10,760 YOU SEE CYTOPENIA AND 875 00:49:10,760 --> 00:49:17,840 HYPERLIPIDEMIA AND PULMONARY 876 00:49:17,840 --> 00:49:20,360 EMBOLI AND THE IDEA THEY'RE 877 00:49:20,360 --> 00:49:22,280 BLOCKING GAMMA AND THE AFFECT OF 878 00:49:22,280 --> 00:49:24,560 IMMUNE CELLS THAT ARE KEEPING 879 00:49:24,560 --> 00:49:32,320 CANCER UNDER CONTROL SO THERE'S 880 00:49:32,320 --> 00:49:33,520 CONCERN THERE'S ASSOCIATION WIN 881 00:49:33,520 --> 00:49:35,240 CANCER AND MANY DISEASES ARE 882 00:49:35,240 --> 00:49:38,440 ASSOCIATED WITH INFLAMMATION ARE 883 00:49:38,440 --> 00:49:42,520 ASSOCIATED WITH ACCELERATED 884 00:49:42,520 --> 00:49:43,080 CARDIOVASCULAR DISEASE AND 885 00:49:43,080 --> 00:49:53,360 CANCER AS WELL. 886 00:49:54,680 --> 00:49:56,440 THERE'S A LOT OF WORK TO 887 00:49:56,440 --> 00:49:58,880 UNDERSTAND THE ISSUES AND THIS 888 00:49:58,880 --> 00:50:01,920 IS THE BIGGEST TRIAL AND IT 889 00:50:01,920 --> 00:50:02,960 INCLUDED MORE THAN 4,000 890 00:50:02,960 --> 00:50:06,520 PATIENTS AND WAS A FOUR-YEAR 891 00:50:06,520 --> 00:50:17,000 OPEN LABEL NON-INFERRIORITY 892 00:50:22,920 --> 00:50:25,800 TRIAL AND THE DATA SHOWED THE 893 00:50:25,800 --> 00:50:30,520 RISK OF CARDIOVASCULAR EVENTS 894 00:50:30,520 --> 00:50:33,560 AND VENUS THROMBOSIS IN CANCER 895 00:50:33,560 --> 00:50:36,400 AND THERE WAS A GREATER 896 00:50:36,400 --> 00:50:40,200 LIKELIHOOD THAN TNF INHIBITERS 897 00:50:40,200 --> 00:50:43,480 AGAIN IN A NON-INFERIORITY TRIAL 898 00:50:43,480 --> 00:50:45,800 AND THE CONFIDENCE INTERVAL 899 00:50:45,800 --> 00:50:49,240 EXCEEDED 1.7. 900 00:50:49,240 --> 00:50:53,320 SO IN THIS CASE IT WAS A BROAD 901 00:50:53,320 --> 00:50:54,080 RANGE OF RISKS. 902 00:50:54,080 --> 00:51:03,120 BUT THE WAY THE TRIAL WAS DESIGN 903 00:51:03,120 --> 00:51:04,400 NON-INFERIORITY WAS FAILED AND 904 00:51:04,400 --> 00:51:07,960 THAT'S THE WAY THE TRIALS WORK 905 00:51:07,960 --> 00:51:12,600 AND I'M NOT A STATISTICIAN SO WE 906 00:51:12,600 --> 00:51:13,560 CAN DISCUSS THAT HEARD. 907 00:51:13,560 --> 00:51:20,240 SERIOUS INFECTION IS WHAT A 908 00:51:20,240 --> 00:51:25,400 THOUGHT BASED ON PATIENTS WITH 909 00:51:25,400 --> 00:51:30,520 SKID AND IT TURNS OUT IT THIS 910 00:51:30,520 --> 00:51:36,400 WAS SIMILAR TO TNF INHIBITORS 911 00:51:36,400 --> 00:51:46,960 AND IF YOU LOOK DEEPLY YOU SEE 912 00:51:47,440 --> 00:51:48,520 THE SITUATION WITH INDIVIDUALS 913 00:51:48,520 --> 00:51:52,400 WHO ARE GREATER THAN 65 OR 914 00:51:52,400 --> 00:51:55,880 SMOKED THEY HAVE HIGHER RISK 915 00:51:55,880 --> 00:51:57,880 FACTOR WITH JAK INHIBITERS 916 00:51:57,880 --> 00:51:59,640 VERSUS TNF INHIBITERS AND IF YOU 917 00:51:59,640 --> 00:52:04,400 LOOK AT OTHER SUBJECTS YOUNGER 918 00:52:04,400 --> 00:52:07,360 THAN AGE 65 AND DIDN'T SMOKE 919 00:52:07,360 --> 00:52:09,080 THEIR INCIDENTS OF 920 00:52:09,080 --> 00:52:12,400 CARDIOVASCULAR EVENTS WERE MUCH 921 00:52:12,400 --> 00:52:21,000 DIFFERENT. 922 00:52:21,000 --> 00:52:22,480 HAVE IMPORTANT TO THINK WHO IS 923 00:52:22,480 --> 00:52:23,680 GETTING THE DRUGS AND PART OF 924 00:52:23,680 --> 00:52:25,280 THE TRIAL WAS THAT THERE WAS NO 925 00:52:25,280 --> 00:52:32,400 IN OF UNTREATED CONTROL GROUPS. 926 00:52:32,400 --> 00:52:35,200 THESE DISEASES ARE ASSOCIATED 927 00:52:35,200 --> 00:52:36,400 WITH INCREASED CARDIOVASCULAR 928 00:52:36,400 --> 00:52:41,920 EVENTS AND RHEUMATOID ARTHRITIS. 929 00:52:41,920 --> 00:52:46,720 WE DON'T REALLY KNOW THEY HAD 930 00:52:46,720 --> 00:52:48,440 FEWER SIDE EFFECTS WITH THESE 931 00:52:48,440 --> 00:52:51,960 WITH RISK FACTORS BUT WERE THEY 932 00:52:51,960 --> 00:52:54,520 EFFECTIVE AND MAYBE TNF 933 00:52:54,520 --> 00:53:00,000 INHIBITERS WERE NOT AS EFFECTIVE 934 00:53:00,000 --> 00:53:00,480 IN PREVENTING THE RISK. 935 00:53:00,480 --> 00:53:02,200 LET ME REPEAT. 936 00:53:02,200 --> 00:53:05,960 THE QUESTION IS WHETHER JAK 937 00:53:05,960 --> 00:53:07,120 INHIBITERS COULD IMPROVE RISK 938 00:53:07,120 --> 00:53:11,200 BUT NOT AS GOOD AS TNF INHIBITOR 939 00:53:11,200 --> 00:53:13,480 IN MINIMIZING THE EVENTS IN 940 00:53:13,480 --> 00:53:14,920 PATIENTS WITH RHEUMATOID 941 00:53:14,920 --> 00:53:17,960 ARTHRITIS WITH INCREASED EVENTS 942 00:53:17,960 --> 00:53:18,880 INCLUDING CARDIOVASCULAR EVENTS 943 00:53:18,880 --> 00:53:23,600 AND CANCER. 944 00:53:23,600 --> 00:53:28,960 WE'RE STILL IN THIS UNCLEAR TIME 945 00:53:28,960 --> 00:53:30,520 WHERE IT'S NOT GOING TO SHOW 946 00:53:30,520 --> 00:53:33,200 WHAT POPULATION WILL BENEFIT 947 00:53:33,200 --> 00:53:36,960 MOST FROM JAK INHIBITORS. 948 00:53:36,960 --> 00:53:39,400 AND WE DON'T HAVE A FULL 949 00:53:39,400 --> 00:53:41,000 UNDERSTANDING OF THE MECHANISM 950 00:53:41,000 --> 00:53:51,520 OF CARDIOVASCULAR DISEASE AGAIN. 951 00:53:52,480 --> 00:53:54,640 OR VENOUS THROMBOSIS AND THEY 952 00:53:54,640 --> 00:54:00,400 MAY OR MAY NOT RELATE TO JAK 953 00:54:00,400 --> 00:54:01,200 INHIBITERS. 954 00:54:01,200 --> 00:54:03,440 WHAT CAN WE DO ABOUT GETTING 955 00:54:03,440 --> 00:54:06,480 BETTER INHIBITERS AND BETTER 956 00:54:06,480 --> 00:54:07,640 COMBINATIONS AND MAYBE BETTER 957 00:54:07,640 --> 00:54:09,720 PATIENT SELECTION. 958 00:54:09,720 --> 00:54:11,840 CAN WE IMPROVE SELECTIVELY AND 959 00:54:11,840 --> 00:54:18,680 CAN WE AVOID JAK 2 INHIBITION AS 960 00:54:18,680 --> 00:54:29,320 THE SIGCYTOKINES IMPACT 961 00:54:36,000 --> 00:54:37,640 HEMATOPOIETIC CELLS. 962 00:54:37,640 --> 00:54:40,080 AGAIN, THESE ARE THE FOUR JAKS, 963 00:54:40,080 --> 00:54:47,960 1, 2 AND 3 AND THE FIRST JAK 964 00:54:47,960 --> 00:54:57,040 FAMILY MEMBER AND SOME ARE 965 00:54:57,040 --> 00:54:59,920 IMPORTANT FOR MULTIPLE CYTOKINES 966 00:54:59,920 --> 00:55:02,560 AND SOME LIKE JAK 3 ARE 967 00:55:02,560 --> 00:55:04,160 IMPORTANT FOR A LIMITED NUMBER 968 00:55:04,160 --> 00:55:05,480 OF CYTOKINES. 969 00:55:05,480 --> 00:55:10,640 YOU THINK MAYBE IT'S A GOOD 970 00:55:10,640 --> 00:55:14,200 THING TO BLOCK CYTOKINES TO GIVE 971 00:55:14,200 --> 00:55:17,080 EFFICACY IN DISEASES BUT CAN 972 00:55:17,080 --> 00:55:23,440 ALSO GIVE MORE SIDE EFFECTS AND 973 00:55:23,440 --> 00:55:25,800 IT'S IMPORTANT FOR A LOT OF 974 00:55:25,800 --> 00:55:28,400 CYTOKINES SHOWN HERE AND HORMONE 975 00:55:28,400 --> 00:55:31,160 LIKE CYTOKINES AND GROWTH 976 00:55:31,160 --> 00:55:41,600 HORMONE AND ETCETERA. 977 00:55:41,600 --> 00:55:45,480 ARE ARE THE CYTOKINES THAT USEK 978 00:55:45,480 --> 00:55:47,400 AND A FIRST GENERATION JAK 979 00:55:47,400 --> 00:55:50,520 INHIBITOR THAT HAVE THE CAPACITY 980 00:55:50,520 --> 00:55:52,400 TO BLOCK ALL THE 57 CYTOKINES IN 981 00:55:52,400 --> 00:56:00,400 PRINCIPLE. 982 00:56:00,400 --> 00:56:03,280 NOW WE HAVE THESE SELECTIVE JAK 983 00:56:03,280 --> 00:56:06,200 2 AND JAK 3 INHIBITORS AND WE 984 00:56:06,200 --> 00:56:10,440 HAVE THE CAPACITY TO TARGET 985 00:56:10,440 --> 00:56:12,280 LIMITED NUMBERS OF CYTOKINES AND 986 00:56:12,280 --> 00:56:14,600 COMPARE AND CONTRAST THE 987 00:56:14,600 --> 00:56:16,400 EFFICACY AND SAFETY WITH THE 988 00:56:16,400 --> 00:56:26,680 DIFFERENT DRUGS. 989 00:56:31,840 --> 00:56:38,880 THIS IS THE DRUG AND YOU SEE IT 990 00:56:38,880 --> 00:56:42,280 BLOCKS IN THE SAME SITE BUT HAS 991 00:56:42,280 --> 00:56:44,680 THE CAPACITY TO SELECTIVELY BIND 992 00:56:44,680 --> 00:56:45,880 WITH SOME KINASES AND NOT 993 00:56:45,880 --> 00:56:46,160 OTHERS. 994 00:56:46,160 --> 00:56:48,000 WE HAVE OTHER OPTIONS. 995 00:56:48,000 --> 00:56:49,440 AND FINALLY AFTER 30 YEARS WE 996 00:56:49,440 --> 00:56:55,360 NOW HAVE THE COMPLETE STRUCTURE 997 00:56:55,360 --> 00:56:56,800 OF KINASES AND THAT WAS SHOWN AT 998 00:56:56,800 --> 00:56:58,880 THE END OF 2022. 999 00:56:58,880 --> 00:57:03,880 THIS IS WHAT THE STRUCTURE LOOKS 1000 00:57:03,880 --> 00:57:04,080 LIKE. 1001 00:57:04,080 --> 00:57:06,520 THIS IS THE KINASE AND NAME OF 1002 00:57:06,520 --> 00:57:09,840 JAK INHIBITERS AND SEE THE 1003 00:57:09,840 --> 00:57:11,360 FUNCTION OF THE KINASE DOMAIN 1004 00:57:11,360 --> 00:57:13,680 WHICH MAKES IT HANDSHAKE WITH 1005 00:57:13,680 --> 00:57:14,440 THE OTHER JAK. 1006 00:57:14,440 --> 00:57:18,000 THAT'S HOW IT TRIGGERS 1007 00:57:18,000 --> 00:57:22,440 SIGNALLING IN CELLS. 1008 00:57:22,440 --> 00:57:27,720 IN PRINCIPLE YOU THINK 1009 00:57:27,720 --> 00:57:28,840 UNDERSTANDING THE JAK STRUCTURE 1010 00:57:28,840 --> 00:57:30,520 WE'LL BE ABLE TO MAKE BETTER 1011 00:57:30,520 --> 00:57:39,600 DRUGS. 1012 00:57:39,600 --> 00:57:47,200 WE TARGET THE DOMAIN AND YOU NOW 1013 00:57:47,200 --> 00:57:54,040 THEY HAVE ALLOSTERIC DOMAINS AND 1014 00:57:54,040 --> 00:57:58,480 THAT INCLUDES LIKE A JAK 1 1015 00:57:58,480 --> 00:57:59,320 INHIBITOR. 1016 00:57:59,320 --> 00:58:04,520 YOU IMAGINE WE GET MORE 1017 00:58:04,520 --> 00:58:15,080 SPECIFICITY WITH THESE DRUGS AND 1018 00:58:16,440 --> 00:58:19,560 AND SOME AVOID TICK 2 AND USING 1019 00:58:19,560 --> 00:58:26,360 OTHER INHIBITERS YOU GET MORE 1020 00:58:26,360 --> 00:58:26,760 SPECIFICITY. 1021 00:58:26,760 --> 00:58:32,400 TO UP THE TALK THIS IS HOW WE 1022 00:58:32,400 --> 00:58:37,880 SAW THINGS IN THE '90s IN THE 1023 00:58:37,880 --> 00:58:39,160 JAK STAT PATHWAY AND DIDN'T 1024 00:58:39,160 --> 00:58:40,120 INCLUDE ALL THE INFORMATION 1025 00:58:40,120 --> 00:58:45,600 LEARNED WITH THE DISCOVERY OF 1026 00:58:45,600 --> 00:58:50,680 THE HUMAN GENOME AND ONLY 2% 1027 00:58:50,680 --> 00:58:51,880 WERE GENES. 1028 00:58:51,880 --> 00:58:53,480 AND THE PROPOSAL WAS MAYBE THE 1029 00:58:53,480 --> 00:58:57,640 REST OF THE GENOME IS JUNK AND 1030 00:58:57,640 --> 00:59:01,400 WHAT WE NOW KNOW IS IT GOES 1031 00:59:01,400 --> 00:59:02,400 BEYOND TRANSCRIPTION FACTORS 1032 00:59:02,400 --> 00:59:04,400 GOING TO THE LIMITED PARTS OF 1033 00:59:04,400 --> 00:59:06,560 THE GENOME. 1034 00:59:06,560 --> 00:59:12,240 INSTEAD MUCH IS ACTIVE AND 1035 00:59:12,240 --> 00:59:14,480 THERE'S THOUSANDS OF ENHANCERS. 1036 00:59:14,480 --> 00:59:16,400 MUCH OF THE GENOME IS 1037 00:59:16,400 --> 00:59:21,040 TRANSCRIBED IN NON-CANONICAL 1038 00:59:21,040 --> 00:59:31,560 GENES THAT DON'T ENCOAT PROTEIN 1039 00:59:38,440 --> 00:59:41,840 SO WE LOOK AT ENHANCER DEFINED 1040 00:59:41,840 --> 00:59:46,160 BY DIFFERENT FACTS AND CHIP SEQ 1041 00:59:46,160 --> 00:59:56,680 AND THEN WHAT WE ALSO KNOW IS 1042 01:00:04,360 --> 01:00:05,920 HAVE THIS IN PERIMETER AND 1043 01:00:05,920 --> 01:00:11,000 HERE'S THIS TINY GENE AND ALL 1044 01:00:11,000 --> 01:00:13,560 AROUND ARE REGULATORY ENHANCERS 1045 01:00:13,560 --> 01:00:16,880 AND DEFINED BY P300 AND 1046 01:00:16,880 --> 01:00:23,280 ENHANCERS ARE PRESENT IN TH1 1047 01:00:23,280 --> 01:00:28,400 CELLS AND THIS IS ALL PRETTY 1048 01:00:28,400 --> 01:00:38,600 VACANT HERE. 1049 01:00:44,440 --> 01:00:47,640 HERE'S REFERRED TO INTERFERON 1050 01:00:47,640 --> 01:00:48,960 GAMMA A AND DESCRIBED IN THIS 1051 01:00:48,960 --> 01:00:49,680 DIRECTION. 1052 01:00:49,680 --> 01:00:52,080 ENHANCERS ARE ENRICHED WITH THE 1053 01:00:52,080 --> 01:00:56,120 LINK RNAs. 1054 01:00:56,120 --> 01:00:58,760 THIS IS LINKED TO IBD IN HUMANS 1055 01:00:58,760 --> 01:01:00,680 AND WE FOUND IF WE DELETE THIS 1056 01:01:00,680 --> 01:01:03,040 YOU HAVE INCREASED 1057 01:01:03,040 --> 01:01:04,400 SUSCEPTIBILITY TO INFECTION AND 1058 01:01:04,400 --> 01:01:09,640 DECREASED PRODUCTION AND THE 1059 01:01:09,640 --> 01:01:20,160 WORK WAS DONE HERE IN MY LAB. 1060 01:01:21,640 --> 01:01:24,400 WE FOUND YOU SEE THIS IN 1061 01:01:24,400 --> 01:01:26,640 PATIENTS WHO HAVE BEEN 1062 01:01:26,640 --> 01:01:28,400 VACCINATED WITH YELLOW FEVER 10 1063 01:01:28,400 --> 01:01:32,040 YEARS AFTER THEIR VACCINATION. 1064 01:01:32,040 --> 01:01:36,240 SO WE HYPOTHESIZE THE PRODUCTION 1065 01:01:36,240 --> 01:01:39,000 OF THIS ENCODING RNA IS RELEVANT 1066 01:01:39,000 --> 01:01:42,560 ACUTELY AND POSSIBLY IN MEMORY 1067 01:01:42,560 --> 01:01:52,400 AND VACCINES, ETCETERA. 1068 01:01:52,400 --> 01:01:54,080 THE YOU HAVE THE INTERACTIONS 1069 01:01:54,080 --> 01:01:59,600 AND THE STRUCTURE MATTERS IN 1070 01:01:59,600 --> 01:02:07,640 TERMS OF EXPRESSION OF GENES 1071 01:02:07,640 --> 01:02:17,360 THIS IS WITH IL22 AND AN 1072 01:02:17,360 --> 01:02:18,280 INVESTIGATOR WAS INTERESTED HOW 1073 01:02:18,280 --> 01:02:23,200 THE ORGANIZATION OF THE GENOME 1074 01:02:23,200 --> 01:02:25,120 CHANGES WHEN YOU TAKE NAIVE 1075 01:02:25,120 --> 01:02:28,280 CELLS AND POLARIZE THEM TO 1076 01:02:28,280 --> 01:02:29,840 INTERFERON GAMMA AND YOU SEE 1077 01:02:29,840 --> 01:02:34,080 REORGANIZATION OF THE HUMAN 1078 01:02:34,080 --> 01:02:38,160 GENOME AND NOTICED THE PEEK OF 1079 01:02:38,160 --> 01:02:40,160 THE ARCHITECTURAL PROTEIN 1080 01:02:40,160 --> 01:02:48,400 BINDING IN PROXIMITY OF THE 1081 01:02:48,400 --> 01:02:52,360 WHOLE CYTOKINE LUCAS TO THE 1082 01:02:52,360 --> 01:02:56,400 ENCODING RNA BEYOND THIS 1083 01:02:56,400 --> 01:02:59,880 CYTOKINE AND THEY THOUGHT WHAT 1084 01:02:59,880 --> 01:03:01,640 HAPPENS IF WE TAKE OUT THIS 1085 01:03:01,640 --> 01:03:04,400 PIECE OF RNA AND WHAT HAPPENS IS 1086 01:03:04,400 --> 01:03:11,480 YOU ALTER THE ARCHITECT TURE OF 1087 01:03:11,480 --> 01:03:16,400 THIS LOCUS AND IT SPARES 1088 01:03:16,400 --> 01:03:19,320 INTERFERON PRODUCERS IN CD8 T 1089 01:03:19,320 --> 01:03:21,160 CELLS BUT BLOCKS THE PRODUCTION 1090 01:03:21,160 --> 01:03:22,840 OF GAMMA IN DEVELOPING TH1 1091 01:03:22,840 --> 01:03:23,640 CELLS. 1092 01:03:23,640 --> 01:03:26,200 THIS IS WHAT WE WERE HOPING TO 1093 01:03:26,200 --> 01:03:27,560 SEE. 1094 01:03:27,560 --> 01:03:29,000 ARCHITECTURE IS IMPORTANT BUT 1095 01:03:29,000 --> 01:03:30,600 IT'S IMPORTANT IN THE CELL 1096 01:03:30,600 --> 01:03:35,440 SPECIFIC MANNER. 1097 01:03:35,440 --> 01:03:36,760 THIS IS THE LAST STORY I'LL TELL 1098 01:03:36,760 --> 01:03:39,600 YOU NOW THAT WE HAVE INCREASED 1099 01:03:39,600 --> 01:03:40,880 ABILITY TO SEQUENCE LOTS OF 1100 01:03:40,880 --> 01:03:42,560 PATIENTS YOU CAN BEGIN LOOKING 1101 01:03:42,560 --> 01:03:49,120 AT PATIENTS WITH SEVERE ALLERGIC 1102 01:03:49,120 --> 01:03:49,360 DISEASE. 1103 01:03:49,360 --> 01:03:54,600 THIS SAY WORLD WIDE 1104 01:03:54,600 --> 01:03:56,040 COLLABORATION AND THROUGHOUT THE 1105 01:03:56,040 --> 01:04:02,480 WORLD HE HAD GAIN OF FUNCTION 1106 01:04:02,480 --> 01:04:06,560 MUTATIONS AND THIS IS A STATIN 1107 01:04:06,560 --> 01:04:10,720 MOLECULE AROUND DNA AND THIS 1108 01:04:10,720 --> 01:04:14,480 GIVES YOU GAIN OF FUNCTION 1109 01:04:14,480 --> 01:04:17,680 ACTIVITY AND THAT RESULTS OF A 1110 01:04:17,680 --> 01:04:19,880 VARIETY OF ALLERGIC DISEASES 1111 01:04:19,880 --> 01:04:20,920 ESPECIALLY SEEN IN YOUNG 1112 01:04:20,920 --> 01:04:22,360 CHILDREN AND THAT GIVES US THE 1113 01:04:22,360 --> 01:04:23,800 OPPORTUNITY TO TREAT THESE 1114 01:04:23,800 --> 01:04:29,720 PATIENTS WITH BIOLOGICS AND JAK 1115 01:04:29,720 --> 01:04:30,200 INHI 1116 01:04:30,200 --> 01:04:30,520 INHIBITERS. 1117 01:04:30,520 --> 01:04:36,480 YOU CAN THINK OF BIOLOGICS AS AN 1118 01:04:36,480 --> 01:04:43,520 ON AND OFF SWITCH YOU CAN BLOCK 1119 01:04:43,520 --> 01:04:44,240 THE CYTOKINE. 1120 01:04:44,240 --> 01:04:52,400 THE DAMAGE IS THAT IT'S VERY 1121 01:04:52,400 --> 01:05:02,960 SPECIFIC THERE'S MANY SWITCHES. 1122 01:05:36,360 --> 01:05:38,360 AND WHEN YOU THINK OF THE INPUTS 1123 01:05:38,360 --> 01:05:42,600 THAT TURN ON THE CYTOKINE GENES 1124 01:05:42,600 --> 01:05:47,280 WE KNOW SOME OF THE MOST 1125 01:05:47,280 --> 01:05:55,320 EFFECTIVE ARE COMBINCOMBINATORI 1126 01:05:55,320 --> 01:06:00,400 WE CAN CAPITALIZE AS WE 1127 01:06:00,400 --> 01:06:10,760 UNDERSTAND THE GENE EXPRESSION. 1128 01:06:10,760 --> 01:06:13,600 IT WOULD BE NICE IF WE CAN 1129 01:06:13,600 --> 01:06:24,120 MEASURE THESE IN PATIENTS AND 1130 01:06:32,240 --> 01:06:42,280 NOW OVER TO YOU, ANGELA. 1131 01:06:42,280 --> 01:06:47,920 >>I THINK YOU CAN SEE WHY WE 1132 01:06:47,920 --> 01:06:50,920 WERE SO EXCITED WHEN WE GOT TO 1133 01:06:50,920 --> 01:06:53,120 THE POINT OF REALIZING THESE 1134 01:06:53,120 --> 01:06:59,200 WERE BEING DRIVEN BY CYTOKINE 1135 01:06:59,200 --> 01:07:02,040 PATHWAYS AND THIS WAS AROUND 1136 01:07:02,040 --> 01:07:04,400 WHEN THE INHIBITERS WERE 1137 01:07:04,400 --> 01:07:10,720 APPROVED. 1138 01:07:10,720 --> 01:07:14,960 AND THERE'S A ROBUST ANIMAL 1139 01:07:14,960 --> 01:07:18,880 MODEL. 1140 01:07:18,880 --> 01:07:21,400 WE WERE INVITED TO BEGIN THE 1141 01:07:21,400 --> 01:07:24,400 EFFICACY OF THE DRUGS IN THE 1142 01:07:24,400 --> 01:07:27,200 MOUSE MODEL. 1143 01:07:27,200 --> 01:07:37,760 AND THEN TO SEE THIS ONLY 15% OF 1144 01:07:46,000 --> 01:07:47,520 FEMALES WILL DEVELOP SPONTANEOUS 1145 01:07:47,520 --> 01:07:48,280 ALOPECIA AREATA AND THAT'S A 1146 01:07:48,280 --> 01:07:50,560 LONG TIME AND UNPREDICTABLE 1147 01:07:50,560 --> 01:07:51,840 MODEL. 1148 01:07:51,840 --> 01:07:55,040 TO GENERATE A MORE STEREOTYPED 1149 01:07:55,040 --> 01:08:00,000 MORE RAPID MODEL OF ALOPECIA 1150 01:08:00,000 --> 01:08:10,560 AREATA AND THEY GRAFTED AND IF 1151 01:08:14,080 --> 01:08:15,560 YOU WAIT SIX WEEKS OR SO THE 1152 01:08:15,560 --> 01:08:25,760 MICE BEGIN TO LOSE THEIR HAIR. 1153 01:08:25,760 --> 01:08:28,120 AND THEY CAN LOSE HAIR ALL OVER 1154 01:08:28,120 --> 01:08:31,240 THE BODY AND USED THESE AS 1155 01:08:31,240 --> 01:08:38,400 MODELS FOR ALOPECIA AREATA AND 1156 01:08:38,400 --> 01:08:39,600 LATE MORE SEVERE ALOPECIA AND WE 1157 01:08:39,600 --> 01:08:42,080 CAN USE IT IN A NUMBER OF WAYS. 1158 01:08:42,080 --> 01:08:43,680 IF WE GIVE THE DRUG AT THE SAME 1159 01:08:43,680 --> 01:08:46,560 TIME WE ADMINISTER THE GRAFT, WE 1160 01:08:46,560 --> 01:08:48,920 CAN MEASURE WHETHER THE DRUG 1161 01:08:48,920 --> 01:08:50,320 PREVENTS THE DEVELOPMENT OF 1162 01:08:50,320 --> 01:08:50,720 ALOPECIA AREATA. 1163 01:08:50,720 --> 01:08:54,160 THAT'S THE EASY EXPERIMENT. 1164 01:08:54,160 --> 01:08:54,920 AND THEN IN THE TREATMENT 1165 01:08:54,920 --> 01:08:59,480 CONTEXT IF WE GRAFT AND WAITFUL 1166 01:08:59,480 --> 01:09:01,200 THE -- WAIT UNTIL THE MOUSE 1167 01:09:01,200 --> 01:09:06,200 BEGINS TO LOSE ITS HAIR WE'RE 1168 01:09:06,200 --> 01:09:07,320 TALKING DISEASE REVERSAL WHICH 1169 01:09:07,320 --> 01:09:09,520 IS HARDER TO DO AND MIMICS THE 1170 01:09:09,520 --> 01:09:10,840 HUMAN SITUATION YOU MAY 1171 01:09:10,840 --> 01:09:12,040 ENCOUNTER WITH A PATIENT. 1172 01:09:12,040 --> 01:09:17,800 THE MOUSE MODEL'S BEEN 1173 01:09:17,800 --> 01:09:22,760 INCREDIBLY USEFUL TO US TO 1174 01:09:22,760 --> 01:09:25,320 ENABLE TO US LOOK AT JAK 1175 01:09:25,320 --> 01:09:25,600 INHIBITERS. 1176 01:09:25,600 --> 01:09:27,120 MICE GIVEN THIS AS A PREVENTION 1177 01:09:27,120 --> 01:09:30,560 EXPERIMENT AT THE TIME OF 1178 01:09:30,560 --> 01:09:33,040 GRAFTING ALL KEPT THEIR HAIR AND 1179 01:09:33,040 --> 01:09:36,400 THE ONES THAT GOT IT DOWN HERE 1180 01:09:36,400 --> 01:09:42,040 ALL LOST THEIR HAIR AND SO AND 1181 01:09:42,040 --> 01:09:43,520 THE PROTECTED MICE HAVE HAIR 1182 01:09:43,520 --> 01:09:46,840 FOLLICLES STILL IN THE CYCLE 1183 01:09:46,840 --> 01:09:48,400 WITH A LITTLE BIT OF IMMUNE 1184 01:09:48,400 --> 01:09:52,400 INFILTRATE AND THE MICE WHO LOST 1185 01:09:52,400 --> 01:09:58,120 THEIR HAIR HAVE DYSTROPIC 1186 01:09:58,120 --> 01:09:58,400 FOLLICLES. 1187 01:09:58,400 --> 01:10:05,160 THE LYMPH NODE AND SPLEEN OF THE 1188 01:10:05,160 --> 01:10:07,920 MICE REMAINED THE SAME AS THE 1189 01:10:07,920 --> 01:10:16,400 NORMAL MICE AND THE SAME IS TRUE 1190 01:10:16,400 --> 01:10:21,360 FOR MICE GIVEN THESE AND WERE 1191 01:10:21,360 --> 01:10:23,320 PROTECTED AND YOU SEE THE NICE 1192 01:10:23,320 --> 01:10:26,360 THICK FOLLICLES AND THE MICE 1193 01:10:26,360 --> 01:10:30,240 WITH PBS HAVE A DENSE LAYER ON 1194 01:10:30,240 --> 01:10:35,880 THE FOLLICLES AND SUGGESTING THE 1195 01:10:35,880 --> 01:10:38,200 DISEASE NEVER GOT STARTED WE 1196 01:10:38,200 --> 01:10:44,200 SWITCHED THEM TO SYSTEMIC 1197 01:10:44,200 --> 01:10:45,680 DELIVERY AND WANTED TO SEE IF 1198 01:10:45,680 --> 01:10:47,920 THIS COULD INDUCE PREVENTION. 1199 01:10:47,920 --> 01:10:49,000 THESE ARED MICE COMPARED TO 1200 01:10:49,000 --> 01:10:54,240 UNTREATED AND LOOKING AT 1201 01:10:54,240 --> 01:10:58,000 STAINING AND THIS IS COMPARED TO 1202 01:10:58,000 --> 01:10:58,440 THE ANTIBODY. 1203 01:10:58,440 --> 01:11:04,400 AND BOTH JAK INHIBITERS PUT IT 1204 01:11:04,400 --> 01:11:08,160 BACK IN THE CYCLE. 1205 01:11:08,160 --> 01:11:09,400 THIS IS BEGINNING TO GO DOWN. 1206 01:11:09,400 --> 01:11:13,160 YOU CAN SEE IN THE TREATED MICE 1207 01:11:13,160 --> 01:11:18,480 WE'RE RESTORING THE IMMUNE 1208 01:11:18,480 --> 01:11:21,640 PRIVILEGE. 1209 01:11:21,640 --> 01:11:27,560 WE'RE NORMALIZING THE HAIR 1210 01:11:27,560 --> 01:11:32,960 FOLLICLES AND THE CELLS ARE 1211 01:11:32,960 --> 01:11:35,000 ABSENT FROM THE TREATED MICE 1212 01:11:35,000 --> 01:11:40,400 SUGGESTING THEY NEVER GET START 1213 01:11:40,400 --> 01:11:44,400 ED FROM THE TIME OF GRAFTING 1214 01:11:44,400 --> 01:11:46,760 COMPARED TO 20% IN THE UNTREATED 1215 01:11:46,760 --> 01:11:46,960 MICE. 1216 01:11:46,960 --> 01:11:51,080 IT'S A MASSIVE AM OF CELLS AND 1217 01:11:51,080 --> 01:11:53,440 BEGINNING TO GIVE A WINDOW OF 1218 01:11:53,440 --> 01:11:54,840 WHAT A THERAPEUTIC RESPONSE MAY 1219 01:11:54,840 --> 01:12:02,840 LOOK LIKE. 1220 01:12:02,840 --> 01:12:05,280 HERE WE'RE LOOKING AT TOPICAL 1221 01:12:05,280 --> 01:12:10,680 TREATMENT AND NOW WE'RE LOOKING 1222 01:12:10,680 --> 01:12:13,880 AT THE MICE TREATED WITH A JAK 1223 01:12:13,880 --> 01:12:15,800 INHIBITOR WITH ONE AND TWO 1224 01:12:15,800 --> 01:12:17,880 MONTHS AND SEE ROBUST AIR GROWTH 1225 01:12:17,880 --> 01:12:23,480 WITH EITHER ONE OF THESE JAK 1226 01:12:23,480 --> 01:12:28,400 INHIBITERS. 1227 01:12:28,400 --> 01:12:30,600 WE SEE THE INFLAMMATORY SIGNALS 1228 01:12:30,600 --> 01:12:31,960 IN THE FOLLICLE. 1229 01:12:31,960 --> 01:12:33,640 THE RETURN OF THE HAIR FOLLICLE 1230 01:12:33,640 --> 01:12:37,360 INTO THE CYCLE AND CLEARANCE OF 1231 01:12:37,360 --> 01:12:40,400 THOSE 20% OF CD8 POSITIVE T 1232 01:12:40,400 --> 01:12:46,720 CELLS FROM THE SKIN. 1233 01:12:46,720 --> 01:12:51,120 SO FAR WE DON'T HAVE A HUMAN JAK 1234 01:12:51,120 --> 01:12:57,320 INHIBITER THAT WORKS FORR ALR 1235 01:12:57,320 --> 01:13:01,440 OWE -- FOR ALOPECIA AND YOU CAN 1236 01:13:01,440 --> 01:13:04,440 CLEAR THE DISEASE AND GIVEN WE 1237 01:13:04,440 --> 01:13:07,600 HAD AN EXTRAORDINARILY FORWARD 1238 01:13:07,600 --> 01:13:08,400 LOOKING CLINICAL PARTNER AT 1239 01:13:08,400 --> 01:13:11,240 COLUMBIA ON THE BASIS OF OUR 1240 01:13:11,240 --> 01:13:16,680 MOUSE DATA THEY STARTED CLINICAL 1241 01:13:16,680 --> 01:13:27,160 STUDIES USING OFF LABEL FOR 1242 01:13:36,440 --> 01:13:39,080 THESE PHARMACEUTICALS AND THEY 1243 01:13:39,080 --> 01:13:45,480 ONLY HAD 30% AND THEY REGREW 1244 01:13:45,480 --> 01:13:47,040 THEIR SCALP, FACIAL AND BODY 1245 01:13:47,040 --> 01:13:49,920 HAIR AND WE HAVE PATIENTS WITH 1246 01:13:49,920 --> 01:13:51,000 LONG STANDING DISEASE, NINE YEAR 1247 01:13:51,000 --> 01:13:56,240 WITH NO HAIR AT ALL HAD COMPLETE 1248 01:13:56,240 --> 01:13:57,680 REGROWTH. 1249 01:13:57,680 --> 01:14:04,400 AND WE CONDUCTED A SIMILAR TRIAL 1250 01:14:04,400 --> 01:14:14,880 WITH TOFACITINIB AND PATIENTS 1251 01:14:16,320 --> 01:14:18,240 HAD TO HAVE A DOSE ESCALATION 1252 01:14:18,240 --> 01:14:24,400 BUT ON THE HIGHER DOSES HAD 1253 01:14:24,400 --> 01:14:34,520 ROBUST NEAR COMPLETE WITH THE 1254 01:14:34,520 --> 01:14:37,200 INHIBITOR AND THIS IS A TIME 1255 01:14:37,200 --> 01:14:38,000 COURSE. 1256 01:14:38,000 --> 01:14:39,520 THIS SHOWS NICELY THE HAIR 1257 01:14:39,520 --> 01:14:41,400 ESSENTIALLY GOES BACK INTO CYCLE 1258 01:14:41,400 --> 01:14:43,640 UNIFORMLY ACROSS THE SCALP. 1259 01:14:43,640 --> 01:14:45,840 IT DOESN'T FILL IN IN PATCHES 1260 01:14:45,840 --> 01:14:47,400 HERE AND THERE SUGGESTING THAT 1261 01:14:47,400 --> 01:14:52,040 BY REMOVING THE IMMUNE RESPONSE 1262 01:14:52,040 --> 01:14:54,040 WE LATER SHOWED HAVING A DIRECT 1263 01:14:54,040 --> 01:14:57,320 EFFECT ON THE FOLLICLE YOU CAN 1264 01:14:57,320 --> 01:14:58,400 STIMULATE RAPID ONSET OF 1265 01:14:58,400 --> 01:15:00,920 PATIENTS UNDERGOING TREATMENT. 1266 01:15:00,920 --> 01:15:07,360 THESE STUDIES WERE DONE EARLY IN 1267 01:15:07,360 --> 01:15:07,560 2016. 1268 01:15:07,560 --> 01:15:10,440 SINCE THAT TIME THERE'S MANY 1269 01:15:10,440 --> 01:15:12,400 REPORTS AND OPEN LABEL STUDIES 1270 01:15:12,400 --> 01:15:17,280 AND WE WERE EXTREMELY FORTUNATE 1271 01:15:17,280 --> 01:15:19,000 AS A FIELD THE PHARMACEUTICAL 1272 01:15:19,000 --> 01:15:20,440 INDUSTRY TOOK NOTE OF OUR EARLY 1273 01:15:20,440 --> 01:15:24,400 WORK AND BECAME INTERESTED IN 1274 01:15:24,400 --> 01:15:27,480 PURSUING THIS BECAUSE THERE WAS 1275 01:15:27,480 --> 01:15:35,720 NO FDA APPROVED TREATMENT AND 1276 01:15:35,720 --> 01:15:41,000 RUXOLITINIB RECEIVED APPROVAL 1277 01:15:41,000 --> 01:15:51,480 LAST YEAR AND BACICITNIB IS 1278 01:15:55,720 --> 01:16:00,400 EXPECTED TO BE APPROVED THIS 1279 01:16:00,400 --> 01:16:10,960 YEAR AND THESE ARE DRUGS FOR HAS 1280 01:16:16,000 --> 01:16:24,400 BEEN APPROVED AND 1281 01:16:24,400 --> 01:16:26,640 >>IT EXEMPLIFIES AS A FIELD TO 1282 01:16:26,640 --> 01:16:37,200 MOVE IT INTO THE REALM OF BONA 1283 01:16:40,480 --> 01:16:45,280 FIDE AUTOIMMUNE DISEASE IS 1284 01:16:45,280 --> 01:16:51,200 LOOKING AT THE UNMET NEED. 1285 01:16:51,200 --> 01:16:53,600 IT'S BIN EXTRAORDINARY YEARS FOR 1286 01:16:53,600 --> 01:16:55,720 THE PATIENT COMMUNITY AND 1287 01:16:55,720 --> 01:17:00,000 HOPEFULLY SOME TOPICALS AS WELL. 1288 01:17:00,000 --> 01:17:03,240 I WANT TO CLOSE BY AMPLIFYING ON 1289 01:17:03,240 --> 01:17:05,080 THE THEME HOW CAN WE DO IT 1290 01:17:05,080 --> 01:17:06,600 BETTER? 1291 01:17:06,600 --> 01:17:12,400 THOSE ARE THE INITIAL GENERATION 1292 01:17:12,400 --> 01:17:15,800 OF JACK INHIBITERS AND WANTED TO 1293 01:17:15,800 --> 01:17:17,160 MAKE THE WINDOWS OF EFFICACY 1294 01:17:17,160 --> 01:17:20,000 MORE SPECIFIC AND NEARO. 1295 01:17:20,000 --> 01:17:22,720 NARROW AND WE WENT BACK TO THE 1296 01:17:22,720 --> 01:17:24,840 DATA AND TOOK JOHN'S QUESTIONS 1297 01:17:24,840 --> 01:17:31,840 TO HEART, HOW CRITICAL IS JAK 2 1298 01:17:31,840 --> 01:17:34,680 INHIBITION IN REVERSAL AND CAN 1299 01:17:34,680 --> 01:17:36,400 WE LIVE WITHOUT IS AND STILL 1300 01:17:36,400 --> 01:17:38,200 MAINTAIN EFFICACY? 1301 01:17:38,200 --> 01:17:41,280 WE NEVER SAW EVIDENCE FOR A 1302 01:17:41,280 --> 01:17:47,400 STRONG JAK 2 IF ANY IN OUR BULK 1303 01:17:47,400 --> 01:17:52,160 DATA IN SKIN AND THE NOTION IS 1304 01:17:52,160 --> 01:17:54,560 HOW NARROW CAN WE GET AND STILL 1305 01:17:54,560 --> 01:17:58,600 MAINTAIN THE ALOPECIA REVERSAL. 1306 01:17:58,600 --> 01:18:00,600 I'LL SHOW THE BROAD INHIBITERS 1307 01:18:00,600 --> 01:18:01,640 YOU JUST SAW. 1308 01:18:01,640 --> 01:18:05,120 WE HAVE SOME WORK NOW USING THE 1309 01:18:05,120 --> 01:18:06,800 ISOFORM SPECIFIC ONES. 1310 01:18:06,800 --> 01:18:14,000 ONLY JAK 1, ONLY JAK 2 AND JAK 3 1311 01:18:14,000 --> 01:18:19,880 AND USING THE TOTALS IN THE 1312 01:18:19,880 --> 01:18:23,920 MOUSE MODEL WE'VE BEEN ABLE TO 1313 01:18:23,920 --> 01:18:26,160 ESTABLISH JAK 2 IS DISPENSABLE 1314 01:18:26,160 --> 01:18:29,040 FOR REVERSAL OF ALOPECIA. 1315 01:18:29,040 --> 01:18:34,200 OUR PAPER'S IN THE LITERATURE 1316 01:18:34,200 --> 01:18:38,080 NOW BUT WE MAINTAIN THIS WITH 1317 01:18:38,080 --> 01:18:44,360 THE JAK 3 SELECTIVE OR 1318 01:18:44,360 --> 01:18:48,400 PREFERENTIAL INHIBITOR BUT THEY 1319 01:18:48,400 --> 01:18:51,480 HAVE NO EFFECT ON REVERSING 1320 01:18:51,480 --> 01:18:52,160 ALOPECIA AREATA. 1321 01:18:52,160 --> 01:18:54,320 THIS IS IMPORTANT CLINICALLY 1322 01:18:54,320 --> 01:19:00,360 BECAUSE MANY OF THE HEMATOLOGIC 1323 01:19:00,360 --> 01:19:08,440 SIDE EFFECTS COME FROM THE JAK 2 1324 01:19:08,440 --> 01:19:11,440 INHIBITION MAY LIMIT POTENTIAL 1325 01:19:11,440 --> 01:19:17,160 FOR SOME OF THE SIDE EFFECTS 1326 01:19:17,160 --> 01:19:22,040 WE'D RATHER NOT HAVE BLOCKING 1327 01:19:22,040 --> 01:19:24,400 THE GAMMA CYTOKINES WAS 1328 01:19:24,400 --> 01:19:28,360 SUFFICIENT TO REVERSE THESE. 1329 01:19:28,360 --> 01:19:30,560 WE WERE SURPRISED BY THIS AND 1330 01:19:30,560 --> 01:19:32,960 GAVE US THE CHANCE TO TEASE A 1331 01:19:32,960 --> 01:19:36,400 PART WHAT'S THE CHICKEN AND EGG. 1332 01:19:36,400 --> 01:19:38,400 THE CYTOKINE SIGNALLING IS 1333 01:19:38,400 --> 01:19:39,400 ENOUGH TO REVERSE DISEASE. 1334 01:19:39,400 --> 01:19:47,840 IT SAYS TO US PERHAPS AN IMMUNE 1335 01:19:47,840 --> 01:19:54,560 RESPONSE IS THE PLACE TO START 1336 01:19:54,560 --> 01:20:01,680 AND WE WERE AWE STRUCK BY THE 1337 01:20:01,680 --> 01:20:02,920 REVELATION. 1338 01:20:02,920 --> 01:20:05,680 THE RECENT EXPERIENCE OF THE 1339 01:20:05,680 --> 01:20:06,360 ALOPECIA COMMUNITY GOING THROUGH 1340 01:20:06,360 --> 01:20:08,800 TRIALS WITH JAK INHIBITERS HAS 1341 01:20:08,800 --> 01:20:12,400 UNCOVERED I THINK AND INVITED 1342 01:20:12,400 --> 01:20:14,600 NEW CLINICAL QUESTIONS BASED ON 1343 01:20:14,600 --> 01:20:15,400 WHAT'S COMING OUT OF THE TRIALS. 1344 01:20:15,400 --> 01:20:20,160 WHAT I MEAN BY THAT IS CAN WE 1345 01:20:20,160 --> 01:20:21,160 FRAME SOME OF THE OBSERVATIONS 1346 01:20:21,160 --> 01:20:26,080 INTO KNEW QUESTIONS. 1347 01:20:26,080 --> 01:20:29,720 FOR EXAMPLE, NEARLY EVERYONE TO 1348 01:20:29,720 --> 01:20:33,200 TAKE A JAK INHIBITOR WILL 1349 01:20:33,200 --> 01:20:35,080 RELAPSE WHEN THEY STOP AND WHAT 1350 01:20:35,080 --> 01:20:38,920 CAN WE DO TO PROTECT THE NEWLY 1351 01:20:38,920 --> 01:20:40,160 RECOVERED HAIR FOLLICLES FROM 1352 01:20:40,160 --> 01:20:42,040 ATTACK DURING THE NEXT CYCLE. 1353 01:20:42,040 --> 01:20:44,600 WE KNOW THE JAK INHIBITERS ARE 1354 01:20:44,600 --> 01:20:47,840 NOT A CURE, SO TO SPEAK BUT THE 1355 01:20:47,840 --> 01:20:50,640 QUESTION IS ONCE WE REGROW, HOW 1356 01:20:50,640 --> 01:20:53,640 CAN WE COME AT THIS PROBLEM TO 1357 01:20:53,640 --> 01:20:58,000 MITIGATE RELAPSE AND GET DURABLE 1358 01:20:58,000 --> 01:20:58,280 RESPONSES? 1359 01:20:58,280 --> 01:21:00,080 I'LL SHOW YOU WHAT WE'RE 1360 01:21:00,080 --> 01:21:00,320 THINKING. 1361 01:21:00,320 --> 01:21:02,760 FOR PEOPLE WHO DON'T RESPOND AND 1362 01:21:02,760 --> 01:21:04,160 FOR THE 65% THAT DO RESPOND, ONE 1363 01:21:04,160 --> 01:21:10,200 THIRD -- ONE-THIRD THAT DON'T 1364 01:21:10,200 --> 01:21:15,400 WANT WE LOOK AT THE INITIATING 1365 01:21:15,400 --> 01:21:19,800 EVENTS WITHIN THE HAIR FOLLICLE 1366 01:21:19,800 --> 01:21:23,720 CAN WE STOP THEM IN PATIENTS 1367 01:21:23,720 --> 01:21:24,600 WHO'S WE RECEIVER AND USE 1368 01:21:24,600 --> 01:21:27,640 BLOCKADE OF THE INITIATING EVENT 1369 01:21:27,640 --> 01:21:32,440 TO AVOID RE. 1370 01:21:32,440 --> 01:21:33,040 AND THERE'S SOME THOUGHTS ON 1371 01:21:33,040 --> 01:21:43,240 ENVIRONMENT. 1372 01:21:47,560 --> 01:21:49,200 SOME WILL FLARE AND IS THIS AN 1373 01:21:49,200 --> 01:21:52,400 INDICATION OF AN VIESHLTAL 1374 01:21:52,400 --> 01:21:54,400 FACTOR THAT'S IMPEDING -- 1375 01:21:54,400 --> 01:21:55,560 ENVIRONMENTAL FACTOR THAT'S 1376 01:21:55,560 --> 01:21:59,400 IMPEDING RESPONSE AND WE TALKED 1377 01:21:59,400 --> 01:22:04,400 ABOUT THE MICROBIOME AND 1378 01:22:04,400 --> 01:22:07,000 EXPANDED THINKING BEYOND THE 1379 01:22:07,000 --> 01:22:09,360 DISEASE BEYOND THE IMMUNE 1380 01:22:09,360 --> 01:22:10,680 PRIVILEGE PART TO START SAYING 1381 01:22:10,680 --> 01:22:16,120 IS THIS MORE OF A THREE-LEGGED 1382 01:22:16,120 --> 01:22:17,360 PARADIGM WHERE WE HAVE THE HAIR 1383 01:22:17,360 --> 01:22:18,560 FOLLICLE PART AND WE'LL TALK 1384 01:22:18,560 --> 01:22:19,800 ABOUT THIS AND FINALLY SOME 1385 01:22:19,800 --> 01:22:22,040 ENVIRONMENTAL TRIGGER AND THE 1386 01:22:22,040 --> 01:22:26,360 ONE WE FOCUS MOST ON LATELY HAS 1387 01:22:26,360 --> 01:22:35,840 BEEN THE GUT MICROBIOME AND 1388 01:22:35,840 --> 01:22:39,440 THERE'S INTRINSIC DEFECTS IN THE 1389 01:22:39,440 --> 01:22:43,320 HAIR FOLLICLE WHICH CAN BE A 1390 01:22:43,320 --> 01:22:48,400 CONTRIBUTING FACTOR IF THE 1391 01:22:48,400 --> 01:22:51,520 DISEASE AND THOUGH WE WERE 1392 01:22:51,520 --> 01:22:52,760 FOCUSSED ON THIS PATHWAY WE 1393 01:22:52,760 --> 01:22:54,840 STARTED TO THINK OF HOW TO STOP 1394 01:22:54,840 --> 01:22:58,800 THIS. 1395 01:22:58,800 --> 01:23:01,080 THERE'S UNPUBLISHED DATA HOW THE 1396 01:23:01,080 --> 01:23:03,440 T CELLS GET IN THE HAIR 1397 01:23:03,440 --> 01:23:04,240 FOLLICLES DURING THE ATTACK AND 1398 01:23:04,240 --> 01:23:05,600 HOW DO THEY GET BACK OUT. 1399 01:23:05,600 --> 01:23:08,920 THIS IS OUR THINKING AGAIN OF 1400 01:23:08,920 --> 01:23:11,880 HOW DO WE THINK ABOUT RELAPSE. 1401 01:23:11,880 --> 01:23:16,320 THESE ARE MICROSCOPY IMAGES OF 1402 01:23:16,320 --> 01:23:20,400 NORMAL MOUSE FOLLICLE AND ONE 1403 01:23:20,400 --> 01:23:24,560 BEING ATTACKED BY THE YELLOW T 1404 01:23:24,560 --> 01:23:30,920 CELLS. 1405 01:23:30,920 --> 01:23:36,400 THIS IS A MASSIVE AMOUNT OF 1406 01:23:36,400 --> 01:23:38,360 INFILTRATING T CELLS. 1407 01:23:38,360 --> 01:23:40,840 AND WE'VE DONE WORK TO WATCH THE 1408 01:23:40,840 --> 01:23:50,800 ATTACK ON THE HAIR FOLLICLE. 1409 01:23:50,800 --> 01:23:52,400 AND THIS IS SHOWING WHERE THE 1410 01:23:52,400 --> 01:23:54,560 CELLS ARE BEGINNING TO DIE ONCE 1411 01:23:54,560 --> 01:23:58,760 THEY'RE ATTACKED. 1412 01:23:58,760 --> 01:24:01,360 YOU CAN SEE THE CELLS START 1413 01:24:01,360 --> 01:24:04,400 LAUNCHING THEIR ATTACK AND THE 1414 01:24:04,400 --> 01:24:06,600 FOL 1415 01:24:06,600 --> 01:24:09,720 FOLLICLE BECOMES CLEARED OF T 1416 01:24:09,720 --> 01:24:19,880 CELLS UNTIL WE TAKE A DEEP ER 1417 01:24:19,880 --> 01:24:24,720 LOOK AND THE T CELLS NEVER TRULY 1418 01:24:24,720 --> 01:24:28,760 EXIT AND ONCE IT'S REGRESSED AND 1419 01:24:28,760 --> 01:24:30,560 SHRUNKEN DOWN WE FIND T CELL 1420 01:24:30,560 --> 01:24:33,200 MEMORY CELLS LODGED INSIDE THE 1421 01:24:33,200 --> 01:24:39,040 HAIR FOLLICLE EPITHELIUM POISED 1422 01:24:39,040 --> 01:24:44,480 AND READY TO ATTACK IF THE HAIR 1423 01:24:44,480 --> 01:24:46,520 GOES BACK IN THE CYCLE AND WE 1424 01:24:46,520 --> 01:24:49,600 ARE NOT ONLY CLEARING THE CELLS 1425 01:24:49,600 --> 01:24:50,800 BUT WE HAD A HUNCH THEY WOULD 1426 01:24:50,800 --> 01:24:53,160 LEAVE AND GO BACK TO THE 1427 01:24:53,160 --> 01:24:54,600 SURROUNDING DERMIS BUT THAT'S 1428 01:24:54,600 --> 01:25:00,120 NOT WHAT'S HAPPENING HERE. 1429 01:25:00,120 --> 01:25:02,960 OUR KILLERS ARE SETTING UP SO 1430 01:25:02,960 --> 01:25:07,080 ANY ATTEMPT TO A NEW HAIR 1431 01:25:07,080 --> 01:25:08,400 FOLLICLE WOULD MAKE THEM SUBJECT 1432 01:25:08,400 --> 01:25:17,640 TO THE SAME ATTACK. 1433 01:25:17,640 --> 01:25:23,200 YOU CAN SEE THESE ARE RESIDENT 1434 01:25:23,200 --> 01:25:24,080 MEMORY T CELLS WHO ARE IN THE 1435 01:25:24,080 --> 01:25:27,880 RIGHT PLACE TO LAUNCH A NEW 1436 01:25:27,880 --> 01:25:29,720 ATTACK ON NEWLY REGROWN HAIR 1437 01:25:29,720 --> 01:25:30,000 FOLLICLES. 1438 01:25:30,000 --> 01:25:35,160 IT'S A CHALLENGE FOR US AND 1439 01:25:35,160 --> 01:25:42,600 RAISED THE BAR IN OUR WAYS OF 1440 01:25:42,600 --> 01:25:44,400 THINKING ERADICATING THEM AND 1441 01:25:44,400 --> 01:25:51,720 GETTING THEM CLEATLY -- 1442 01:25:51,720 --> 01:25:53,240 COMPLETELY AND WE'VE DONE 1443 01:25:53,240 --> 01:25:55,200 STUDIES TO SHOW HOW THE HAIR 1444 01:25:55,200 --> 01:25:57,080 FOLLICLES ARE PENETRATED BY THE 1445 01:25:57,080 --> 01:25:57,480 ATTACKING T CELLS. 1446 01:25:57,480 --> 01:25:59,960 IF YOU FOLLOW THE STAGED TIMED 1447 01:25:59,960 --> 01:26:03,880 IMAGES YOU CAN FOLLOW THE PURPLE 1448 01:26:03,880 --> 01:26:05,800 T CELL CRAWLING THROUGH THE BLUE 1449 01:26:05,800 --> 01:26:08,400 LAYER OF THE HAIR FOLLICLE AND 1450 01:26:08,400 --> 01:26:10,560 ENTERING INTO THE FOLLICLE 1451 01:26:10,560 --> 01:26:11,040 EPITHELIAL LAYERS. 1452 01:26:11,040 --> 01:26:15,400 IF WE FOLLOW THAT OVER TIME 1453 01:26:15,400 --> 01:26:17,240 INTERESTINGLY THE T CELLS WILL 1454 01:26:17,240 --> 01:26:18,600 KEEP GOING AND KEEP CRAWLING IN 1455 01:26:18,600 --> 01:26:26,480 THE FOLLICLE UNTIL THEY HIT ONE 1456 01:26:26,480 --> 01:26:31,320 SPECIFIC LAYER. 1457 01:26:31,320 --> 01:26:34,280 THEN THEY REORGANIZE AND SET UP 1458 01:26:34,280 --> 01:26:37,320 AN IMMUNE SYNAPSE AND GET READY 1459 01:26:37,320 --> 01:26:42,560 TO KILL THE CELL THEY SET THEIR 1460 01:26:42,560 --> 01:26:48,720 SIGHT ON AND YOU CAN SEE THE 1461 01:26:48,720 --> 01:26:56,200 COMPONE 1462 01:26:56,200 --> 01:26:58,840 COMPONENTS IT SETS UP AND 1463 01:26:58,840 --> 01:27:00,400 TARGETS AND KILLS CELL KILLING 1464 01:27:00,400 --> 01:27:09,920 WITHIN THE LAYER SHOWN HERE. 1465 01:27:09,920 --> 01:27:13,000 REMEMBER IN THE HUMAN WE CALLED 1466 01:27:13,000 --> 01:27:16,040 OUR DANGER SIGNAL ULBP3 AND IN 1467 01:27:16,040 --> 01:27:19,760 THE MOUSE THE LIGAND SIGNAL IS 1468 01:27:19,760 --> 01:27:21,240 CALLED H60. 1469 01:27:21,240 --> 01:27:24,120 IN WHITE THE LAYERS OF THE MASS 1470 01:27:24,120 --> 01:27:26,880 HAIR FOLLICLE THAT EXPRESSES THE 1471 01:27:26,880 --> 01:27:28,040 H60. 1472 01:27:28,040 --> 01:27:30,320 IT LOOKS AS THOUGH THE T CELLS 1473 01:27:30,320 --> 01:27:31,720 CRAWL TOWARDS THE LAYER THAT 1474 01:27:31,720 --> 01:27:33,400 EXPRESS THE LIGANDS AND THEY 1475 01:27:33,400 --> 01:27:36,400 STOP THERE AND SET UP AN IMMUNE 1476 01:27:36,400 --> 01:27:38,160 SYNAPSE AND KILL AND TARGET THE 1477 01:27:38,160 --> 01:27:43,120 LAYER OF THE FOLLICLE. 1478 01:27:43,120 --> 01:27:44,320 IT'S BEEN SURPRISE BEING THE T 1479 01:27:44,320 --> 01:27:45,720 CELLS SEEM TO BE ON A MISSION TO 1480 01:27:45,720 --> 01:27:47,520 GET TO THAT PLAYER AND ONCE THEY 1481 01:27:47,520 --> 01:27:49,800 GET THERE THEY STOP AND KILL AND 1482 01:27:49,800 --> 01:27:51,800 THEN SET UP CAMP AND STAY THERE 1483 01:27:51,800 --> 01:27:56,200 UNTIL THE NEXT HAIR CYCLE BUT IT 1484 01:27:56,200 --> 01:27:57,600 GIVES US ANOTHER CLUE. 1485 01:27:57,600 --> 01:28:02,040 IF WE KNOW THEY MAKE THE SYNAPSE 1486 01:28:02,040 --> 01:28:03,720 THERE ARE DRUGS TO TARGET THE 1487 01:28:03,720 --> 01:28:04,400 FORMATION OF THAT IMMUNE 1488 01:28:04,400 --> 01:28:09,120 SYNAPSE. 1489 01:28:09,120 --> 01:28:11,560 THERE WAS A DRUG TAKEN OFF THE 1490 01:28:11,560 --> 01:28:15,880 MARKET DUE TO MANY SIDE S BUT 1491 01:28:15,880 --> 01:28:17,720 THE GOAL WAS TO BLOCK THE 1492 01:28:17,720 --> 01:28:21,520 FORMATION OF THE IMMUNE SYNAPSE. 1493 01:28:21,520 --> 01:28:24,360 SINCE THE TIME IT'S BEEN OFF THE 1494 01:28:24,360 --> 01:28:29,600 MARKET INTERESTINGLY THERE'S 1495 01:28:29,600 --> 01:28:33,840 TOPICAL SMALL MOLECULE DEVELOPED 1496 01:28:33,840 --> 01:28:35,840 FOR DRY EYE DISEASE AND IT'S TO 1497 01:28:35,840 --> 01:28:37,360 BLOCK THE FORMATION OF THE 1498 01:28:37,360 --> 01:28:40,400 IMMUNE SYNAPSE. 1499 01:28:40,400 --> 01:28:43,080 GIVEN WE HAVE THE OPPORTUNITY TO 1500 01:28:43,080 --> 01:28:49,960 WORK ON THIS WE BEGAN TO REVISIT 1501 01:28:49,960 --> 01:28:52,040 THE BLOCKING OF SYNAPSE AND WE 1502 01:28:52,040 --> 01:28:53,440 HAVE EXCITING DATA THIS MAY 1503 01:28:53,440 --> 01:28:53,720 WORK. 1504 01:28:53,720 --> 01:28:57,040 AND PERHAPS NOT IN THE PRIMARY 1505 01:28:57,040 --> 01:28:59,880 MEANS OF REVERSING DISEASE BUT 1506 01:28:59,880 --> 01:29:02,360 PERHAPS AT THE ADJUNCT WHEN IT'S 1507 01:29:02,360 --> 01:29:04,560 REGROWN WITH A JAK INHIBITOR 1508 01:29:04,560 --> 01:29:08,400 COULD BE A WAY TO MAINTAIN THAT 1509 01:29:08,400 --> 01:29:12,400 AND PREVENT THE SUBSEQUENT HAIR 1510 01:29:12,400 --> 01:29:17,320 FOLLICLE FROM BEING ATTACKED. 1511 01:29:17,320 --> 01:29:19,680 I WANT TO COME BACK TO THE IDEA 1512 01:29:19,680 --> 01:29:21,720 OF WHAT THE GENES ARE TELLING US 1513 01:29:21,720 --> 01:29:22,720 IN THIS DISEASE. 1514 01:29:22,720 --> 01:29:29,160 THE GWAS POINTED AT THE IMMUNE 1515 01:29:29,160 --> 01:29:29,520 CELLS. 1516 01:29:29,520 --> 01:29:35,160 WE HAD NO GWAS SIGNAL THAT 1517 01:29:35,160 --> 01:29:37,440 INDICATED THIS AND THE STUDY IS 1518 01:29:37,440 --> 01:29:46,440 DESIGN TO GIVE COMMON VARIANTS. 1519 01:29:46,440 --> 01:29:50,280 AND THIS SHOULD GIVE US INCLUDE 1520 01:29:50,280 --> 01:29:54,080 WHAT IT MAY BE OTHER THAN THE NK 1521 01:29:54,080 --> 01:29:54,280 LIGAND. 1522 01:29:54,280 --> 01:29:55,680 WE WENT BACK TO THE DRAWING 1523 01:29:55,680 --> 01:29:57,600 BOARD AND WANTED TO DO DIFFERENT 1524 01:29:57,600 --> 01:30:00,120 GENETIC STUDIES TO SAY WHAT IS 1525 01:30:00,120 --> 01:30:05,600 THE CONTRIBUTION OF RARE 1526 01:30:05,600 --> 01:30:05,880 VARIANTS. 1527 01:30:05,880 --> 01:30:11,400 WHAT THAT MEANS IS GWAS STUDIES 1528 01:30:11,400 --> 01:30:15,400 LOOK AT VARIANTS AND EACH ADDS 1529 01:30:15,400 --> 01:30:20,600 ON TO SUSCEPTIBILITY. 1530 01:30:20,600 --> 01:30:22,880 IN THIS DIRECTION THESE ARE MORE 1531 01:30:22,880 --> 01:30:23,520 RARE DISEASE TYPE GENES FOUND 1532 01:30:23,520 --> 01:30:24,600 ONLY IN FAMILIES. 1533 01:30:24,600 --> 01:30:26,880 THESE ARE DONE IN FAMILIES AND 1534 01:30:26,880 --> 01:30:28,720 THESE ARE DONE ACROSS THE 1535 01:30:28,720 --> 01:30:34,000 POPULATION IN GWAS AND THE ONE 1536 01:30:34,000 --> 01:30:42,600 IN THE MIDDLE ARE DESIGN TO 1537 01:30:42,600 --> 01:30:44,160 OVERLIE THESE VARIANTS AND THE 1538 01:30:44,160 --> 01:30:46,680 JAK INHIBITERS WERE ELIMINATED 1539 01:30:46,680 --> 01:30:48,440 BY THE GWAS STUDY BUT WANTED TO 1540 01:30:48,440 --> 01:30:50,760 FOCUS TO SEE IF THERE WAS A 1541 01:30:50,760 --> 01:30:54,600 LAYERING OF GENETIC AFFECTS AND 1542 01:30:54,600 --> 01:30:57,440 THE PARADIGM IS ECTOPIC 1543 01:30:57,440 --> 01:30:59,200 DERMATITIS WHERE THERE'S GWAS 1544 01:30:59,200 --> 01:31:02,880 ASSOCIATED GENES AND THERE'S A 1545 01:31:02,880 --> 01:31:05,200 MAJOR GENE THAT INTRODUCES A 1546 01:31:05,200 --> 01:31:06,760 MAJOR EFFECT ON THE SKIN 1547 01:31:06,760 --> 01:31:16,920 BARRIER. 1548 01:31:19,600 --> 01:31:21,000 WE HAD THE GOAL OF DISCOVERING 1549 01:31:21,000 --> 01:31:24,400 THE VARIANTS AND THESE IS 1550 01:31:24,400 --> 01:31:24,760 DIFFERENT THAN THE 1551 01:31:27,480 --> 01:31:28,600 GWAS APPROACH AND TAKE THE 1552 01:31:28,600 --> 01:31:30,600 MUTATIONS THAT COULD BE DETECTED 1553 01:31:30,600 --> 01:31:37,000 AND PULL THEM TOGETHER. 1554 01:31:37,000 --> 01:31:39,240 WE HAVE ALL THE BAD VARIANTS AN 1555 01:31:39,240 --> 01:31:40,440 GIVEN AND ADDS TO OUR POWER TO 1556 01:31:40,440 --> 01:31:43,720 BE ABLE TO DO THAT ON A GENE 1557 01:31:43,720 --> 01:31:46,760 BASIS BY PULLING VARIANTS 1558 01:31:46,760 --> 01:31:47,360 TOGETHER. 1559 01:31:47,360 --> 01:31:50,600 WHEN WE DO THAT UNEXPECTEDLY WE 1560 01:31:50,600 --> 01:31:54,000 GOT ONE SINGLE GENE 1561 01:31:54,000 --> 01:31:54,680 SIGNIFICANTLY ASSOCIATED WITH 1562 01:31:54,680 --> 01:31:56,440 ALOPECIA AREATA AND TO OUR 1563 01:31:56,440 --> 01:32:02,600 SURPRISE IT WAS HAIR KERATIN A 1564 01:32:02,600 --> 01:32:07,520 SPECIFIC ONE, 82. 1565 01:32:07,520 --> 01:32:09,800 IT'S ONE LAYER FROM THE LAYER WE 1566 01:32:09,800 --> 01:32:12,440 WERE JUST TALKING ABOUT IN THE 1567 01:32:12,440 --> 01:32:22,280 MOUSE FOLLICLE. 1568 01:32:22,280 --> 01:32:24,400 AND THERE WAS A SPLICING 1569 01:32:24,400 --> 01:32:25,160 MUTATION IN THE GENE. 1570 01:32:25,160 --> 01:32:27,200 THAT'S AN ENORMOUSLY HIGH 1571 01:32:27,200 --> 01:32:27,400 NUMBER. 1572 01:32:27,400 --> 01:32:29,440 THESE ARE NOT SUBTLE MUTATIONS. 1573 01:32:29,440 --> 01:32:34,200 A LOSS OF FUNCTION. 1574 01:32:34,200 --> 01:32:38,760 MANY BEING MUTATIONS SUGGEST THE 1575 01:32:38,760 --> 01:32:40,400 AFFECT IS SIGNIFICANT. 1576 01:32:40,400 --> 01:32:41,680 AS IT DAMAGING THE PROTEIN IN 1577 01:32:41,680 --> 01:32:49,400 THE NON-SUBTLE WAY. 1578 01:32:49,400 --> 01:32:59,960 IT'S EXPRESSED IN A VERY NARROW 1579 01:33:06,640 --> 01:33:15,320 AND THAT CUTICLE PROTECT THE 1580 01:33:15,320 --> 01:33:20,160 INNER HAIR SHAFT AND 1581 01:33:20,160 --> 01:33:24,280 INTERESTINGLY THAT SAME CUTICLE 1582 01:33:24,280 --> 01:33:28,480 LAYER WHEN WEAKENED IS DAMAGING 1583 01:33:28,480 --> 01:33:31,040 IN A MORPHOLOGY. 1584 01:33:31,040 --> 01:33:32,120 THEY LOOK LIKE HAIRS UPSIDE-DOWN 1585 01:33:32,120 --> 01:33:34,880 AND THICKER ON THE TOP THAN 1586 01:33:34,880 --> 01:33:40,400 TOWARDS THE SCALP. 1587 01:33:40,400 --> 01:33:44,080 A 1588 01:33:44,080 --> 01:33:46,720 AND IT'S KNOWN THAT A FRACTURED 1589 01:33:46,720 --> 01:33:48,800 CUTICLE IS ONE OF THE THINGS 1590 01:33:48,800 --> 01:33:52,960 THAT IS CHARACTERISTIC OF AN 1591 01:33:52,960 --> 01:33:56,200 EXCLAMATION MARK AND WHAT IS 1592 01:33:56,200 --> 01:34:01,160 MORE ENTICING AND THERE'S BEEN A 1593 01:34:01,160 --> 01:34:11,880 MOTION AND WE HAVE LOOKED AT 1594 01:34:11,880 --> 01:34:16,800 ANTIBODIES FOR THIS AND OTHERS 1595 01:34:16,800 --> 01:34:20,720 IN THE FIELD SHOWING THESE 1596 01:34:20,720 --> 01:34:22,960 PROTEINS AS AROUND THE SAME 1597 01:34:22,960 --> 01:34:30,560 RANGE AS KERATIN 82 CAN BE SHOWN 1598 01:34:30,560 --> 01:34:32,400 TO DETERMINE WHETHER THIS LOSS 1599 01:34:32,400 --> 01:34:38,400 OF FUNCTION IN THE HUMAN PATIENT 1600 01:34:38,400 --> 01:34:44,400 MAYBE ASSOCIATED WITH THE 1601 01:34:44,400 --> 01:34:46,640 BEGINNINGS OF AUTOIMMUNITY AND 1602 01:34:46,640 --> 01:34:48,400 WE THINK PERHAPS NOW IT WILL 1603 01:34:48,400 --> 01:34:54,400 GIVE US AN INSIGHT INTO THE 1604 01:34:54,400 --> 01:34:56,080 INITIATING DAMAGE THAT MUST GO 1605 01:34:56,080 --> 01:35:01,520 ON WITHIN THE HAIR FOLLICLE THAT 1606 01:35:01,520 --> 01:35:02,320 PRECIPITATES THE IMMUNE RESPONSE 1607 01:35:02,320 --> 01:35:05,760 AND AIL CLOSE WITH FORWARD 1608 01:35:05,760 --> 01:35:08,320 LOOKING ASPIRATIONS TO LOOK AT 1609 01:35:08,320 --> 01:35:12,400 THE ENVIRONMENTAL FACTORS IN 1610 01:35:12,400 --> 01:35:14,760 ALOPECIA AREATA. 1611 01:35:14,760 --> 01:35:22,440 OUR FOCUS HAS BEEN ON THE 1612 01:35:22,440 --> 01:35:25,360 MICROBIOME AND MUCH OF OUR WORK 1613 01:35:25,360 --> 01:35:29,960 FOCUSSED ON THE GUT MICROBIOME. 1614 01:35:29,960 --> 01:35:33,000 WE HAVE SHOWN COMPOSITIONAL 1615 01:35:33,000 --> 01:35:35,840 CHANGES AND NOT IN THE SKIN 1616 01:35:35,840 --> 01:35:37,960 MICROBIOME ARE ASSOCIATED WITH 1617 01:35:37,960 --> 01:35:43,840 THE ONSET OF ALOPECIA IN THE 1618 01:35:43,840 --> 01:35:49,200 MOUSE AND IF WE PUT THEM IN A 1619 01:35:49,200 --> 01:35:49,880 GERM-FREE ENVIRONMENT ALOPECIA 1620 01:35:49,880 --> 01:35:52,400 AREATA ESSENTIALLY DOES NOT 1621 01:35:52,400 --> 01:35:52,760 DEVELOP. 1622 01:35:52,760 --> 01:35:54,640 THE GUT MICROBIOME ITSELF 1623 01:35:54,640 --> 01:35:57,320 APPEARS TO BE REQUIRED TO INDUCE 1624 01:35:57,320 --> 01:36:02,160 THE DISEASE IN THE MICE. 1625 01:36:02,160 --> 01:36:06,600 WE NARROWED IT DOWN TO ONE 1626 01:36:06,600 --> 01:36:08,360 SPECIES IN THE MOUSE. 1627 01:36:08,360 --> 01:36:11,600 OUR MOUSE HAS A SINGLE SPECIES 1628 01:36:11,600 --> 01:36:14,240 APPEARS TO BE OVER REPRESENTED 1629 01:36:14,240 --> 01:36:17,400 IN THE GUT OF MICE WITH ALOPECIA 1630 01:36:17,400 --> 01:36:20,000 AND IT'S A LACTOBACILLUS AND 1631 01:36:20,000 --> 01:36:27,280 IT'S NOT FOUND AS A COMMENSAL IN 1632 01:36:27,280 --> 01:36:30,040 HUMANS BUT IT IS IN MICE AND AN 1633 01:36:30,040 --> 01:36:31,720 OVERREPRESENTING GROUP SEEMS TO 1634 01:36:31,720 --> 01:36:35,640 BE DRIVING THE DYSBIOSIS IN THE 1635 01:36:35,640 --> 01:36:36,560 ALOPECIA MICE AND REQUIRED FOR 1636 01:36:36,560 --> 01:36:39,320 THE ONSET OF DISEASE AND 1637 01:36:39,320 --> 01:36:40,960 RECENTLY WE'VE SHOWN BLOCKING 1638 01:36:40,960 --> 01:36:44,360 THAT BY REMOVING THE MICROBIOME 1639 01:36:44,360 --> 01:36:47,040 CAN MODULATE AND ATTENUATE THE 1640 01:36:47,040 --> 01:36:52,320 ARE RECRUITMENT OF AFFECTED T 1641 01:36:52,320 --> 01:36:58,880 CELLS IN THE SKIN. 1642 01:36:58,880 --> 01:37:01,840 IT'S SHOWED DYSBIOSIS UNDER 1643 01:37:01,840 --> 01:37:02,880 REPRESENTATION AND THE MORE 1644 01:37:02,880 --> 01:37:04,400 INTERESTING DATA COMES FROM 1645 01:37:04,400 --> 01:37:09,800 THESE STUDIES IN THE LITERATURE 1646 01:37:09,800 --> 01:37:16,360 THAT PATIENTS TO HAVAL HAVE ALO 1647 01:37:16,360 --> 01:37:18,600 AREATA THAT RECEIVED A 1648 01:37:18,600 --> 01:37:21,560 TRANSPLANT MAINTAINED HAIR FOR 1649 01:37:21,560 --> 01:37:23,240 MORE THAN A TWO-YEAR PERIOD. 1650 01:37:23,240 --> 01:37:25,000 THIS INDEPENDENT STUDY HAD 1651 01:37:25,000 --> 01:37:28,400 ANOTHER PATIENT WHO HAD RECEIVED 1652 01:37:28,400 --> 01:37:31,800 AGAIN FECAL MICROBIOME 1653 01:37:31,800 --> 01:37:33,960 TRANSPLANT FOR THIS AND MAIN 1654 01:37:33,960 --> 01:37:37,320 MAINTAINED AND REGREW THEIR 1655 01:37:37,320 --> 01:37:37,760 HAIR. 1656 01:37:37,760 --> 01:37:40,280 THE THINKING IS IN PATIENTS THE 1657 01:37:40,280 --> 01:37:41,880 GUT MICROBIOME NOT THE SKIN 1658 01:37:41,880 --> 01:37:44,400 MICROBIOME MAY BE A 1659 01:37:44,400 --> 01:37:46,280 PRECIPITATING ENVIRONMENTAL 1660 01:37:46,280 --> 01:37:49,040 FACTOR FOR ONSET OF ALOPECIA 1661 01:37:49,040 --> 01:37:53,520 AREATA AND POTENTIALLY ONSET 1662 01:37:53,520 --> 01:37:55,600 ROLE IN FLARE OR DURING OR AFTER 1663 01:37:55,600 --> 01:37:56,160 REGROWTH. 1664 01:37:56,160 --> 01:38:01,880 I JUST WANTED TO SHOW THIS AGAIN 1665 01:38:01,880 --> 01:38:03,440 TOLL GIVE YOU THE SENSE OF THE 1666 01:38:03,440 --> 01:38:04,800 DIFFERENT PARTS OF THE DISEASE 1667 01:38:04,800 --> 01:38:15,280 WE HAVE BEGUN TO WORK WITH AND 1668 01:38:15,280 --> 01:38:20,400 CAN CONTROL THE IMMUNE RESPONSES 1669 01:38:20,400 --> 01:38:25,160 AND BEGIN TO ADDRESS THE 1670 01:38:25,160 --> 01:38:25,360 FACTORS. 1671 01:38:25,360 --> 01:38:30,880 WHEN WE STARTED THE WORK WE WERE 1672 01:38:30,880 --> 01:38:35,000 NAIVE WE WOULD BE ABLE TO MAKE 1673 01:38:35,000 --> 01:38:36,400 INROADS IN THE DISEASE AND WITH 1674 01:38:36,400 --> 01:38:41,200 A SMALL COHORT OF OUR GWAS STUDY 1675 01:38:41,200 --> 01:38:42,800 THE FACT WE FOUND ANY ASSOCIATED 1676 01:38:42,800 --> 01:38:45,680 WITH ALOPECIA WAS REMARKABLE AND 1677 01:38:45,680 --> 01:38:51,040 THE FACT THAT ONE LED US TOWARDS 1678 01:38:51,040 --> 01:38:55,240 THE INNOVATION OF USING JAK 1679 01:38:55,240 --> 01:38:57,960 INHIBITERS IS A FORTUNATE SERIES 1680 01:38:57,960 --> 01:38:59,600 OF EVENTS AND SQUARES ON THE 1681 01:38:59,600 --> 01:39:02,920 SHOULDERS OF THOSE WHO SAW AND 1682 01:39:02,920 --> 01:39:05,200 COLLECTED PATIENTS AND THOSE WHO 1683 01:39:05,200 --> 01:39:07,840 DID MOST THE PRE CLINICAL WORK 1684 01:39:07,840 --> 01:39:12,400 AND THE EMBRAVINGS OF THE DATA 1685 01:39:12,400 --> 01:39:15,120 BY INDUSTRY TO BE EXCITED ABOUT 1686 01:39:15,120 --> 01:39:16,400 ALOPECIA AREATA AND GIVE THE 1687 01:39:16,400 --> 01:39:18,720 PATIENT COMMUNITY THEIR FIRST 1688 01:39:18,720 --> 01:39:21,880 APPROVED DRUGS. 1689 01:39:21,880 --> 01:39:28,360 WE SHOWED THIS AT THE BEGINNING 1690 01:39:28,360 --> 01:39:35,120 ABOUT AND I WANTED TO SAY I HAVE 1691 01:39:35,120 --> 01:39:40,120 TREMENDOUS RESPECT FOR THE 1692 01:39:40,120 --> 01:39:44,840 PEOPLE WHO OBSERVED AND YET 1693 01:39:44,840 --> 01:39:47,960 DESPITE THAT THERE'S KEEN POWERS 1694 01:39:47,960 --> 01:39:49,680 OF OBSERVATION AND DOCUMENTING 1695 01:39:49,680 --> 01:39:53,040 AND LISTENING AND WATCHING 1696 01:39:53,040 --> 01:39:54,400 PATIENTS AND OBSERVE ING 1697 01:39:54,400 --> 01:39:56,360 INFLAMMATION. 1698 01:39:56,360 --> 01:39:59,240 RIGHT NOW OUR TOP THREE AREAS MY 1699 01:39:59,240 --> 01:40:00,960 GROUP IS INTERESTED IN IS HERE 1700 01:40:00,960 --> 01:40:02,320 AND IF YOU LOOK DOWN THE LIST 1701 01:40:02,320 --> 01:40:04,360 THE CONCEPTS ARE STILL THERE. 1702 01:40:04,360 --> 01:40:06,400 INFECTIOUS AGENTS AND VACCINES 1703 01:40:06,400 --> 01:40:09,600 AND PLENTY OF PATIENTS WHO 1704 01:40:09,600 --> 01:40:12,200 DEVELOPED ALOPECIA AREATA EITHER 1705 01:40:12,200 --> 01:40:15,960 FROM COVID OR COVID VACCINE OR 1706 01:40:15,960 --> 01:40:16,960 HEPATITIS B VACCINE AND WE DON'T 1707 01:40:16,960 --> 01:40:21,880 KNOW ABOUT THE TRIGGERS. 1708 01:40:21,880 --> 01:40:26,080 AND STRESS IS A FACTOR BUT WE 1709 01:40:26,080 --> 01:40:27,600 HAVE LOOKED AT PSYCHOLOGICAL 1710 01:40:27,600 --> 01:40:32,120 STRESS AND EVERY PATIENT WILL 1711 01:40:32,120 --> 01:40:34,080 TELL YOU THEY'VE HAD 1712 01:40:34,080 --> 01:40:34,520 PSYCHOSOCIAL STRESS. 1713 01:40:34,520 --> 01:40:41,480 THERE'S MORE WORK TO BE DONE. 1714 01:40:41,480 --> 01:40:43,960 THIS IS AN EXTRAORDINARY DISEASE 1715 01:40:43,960 --> 01:40:46,080 AND IT'S RARE TO HAVE A MOUSE 1716 01:40:46,080 --> 01:40:48,920 MODEL TO RECAPITULATE SO MUCH OF 1717 01:40:48,920 --> 01:40:49,840 THE DISEASE STATE. 1718 01:40:49,840 --> 01:40:50,640 PLEASE JOIN US. 1719 01:40:50,640 --> 01:40:52,120 THE FIELD IS OPEN FOR NEW IDEAS 1720 01:40:52,120 --> 01:40:52,520 AND PEOPLE. 1721 01:40:52,520 --> 01:40:58,160 I HOPE BY THE END OF THE TALK 1722 01:40:58,160 --> 01:41:01,680 YOU FEEL LIKE YOU'RE BEGINNING 1723 01:41:01,680 --> 01:41:07,480 TO GET CLARITY ON MAJOR BUCKETS 1724 01:41:07,480 --> 01:41:12,160 OF FACTORS THAT CAN INFLUENCE 1725 01:41:12,160 --> 01:41:12,400 DISEASE. 1726 01:41:12,400 --> 01:41:15,880 I ALWAYS MARK 1996 AS THE 1727 01:41:15,880 --> 01:41:18,320 BEGINNING OF MY INTEREST IN THIS 1728 01:41:18,320 --> 01:41:22,080 DISEASE AND EVERYTHING THAT'S 1729 01:41:22,080 --> 01:41:23,840 GROWN FORWARD FROM THAT AGAIN 1730 01:41:23,840 --> 01:41:28,920 WITHOUT THE PARTICIPATION OF THE 1731 01:41:28,920 --> 01:41:38,120 FOUNDATION AND WITH NIAMS 1732 01:41:38,120 --> 01:41:40,000 SUPPORT IT'S LED TO RECENT 1733 01:41:40,000 --> 01:41:40,280 APPROVALS. 1734 01:41:40,280 --> 01:41:46,480 FOR US WHAT WAS TRULY 1735 01:41:46,480 --> 01:41:50,400 TRANSFORMATIONAL IS THE P50 THAT 1736 01:41:50,400 --> 01:41:52,320 ENABLE WILL US TO BLOW THIS OPEN 1737 01:41:52,320 --> 01:41:54,720 AND CATALYZE THE WORK THAT 1738 01:41:54,720 --> 01:41:58,440 NEEDED TO BE DONE. 1739 01:41:58,440 --> 01:42:04,400 I'LL SAY A WORD OF THANKS TO 1740 01:42:04,400 --> 01:42:14,920 THOSE INVOLVED AND MANY WHO WILL 1741 01:42:23,840 --> 01:42:25,000 HOPEFULLY SET UP THEIR OWN 1742 01:42:25,000 --> 01:42:29,360 CLINIC. 1743 01:42:29,360 --> 01:42:39,040 THANK YOU FOR THE OPPORTUNITY. 1744 01:42:39,040 --> 01:42:39,960 >>THREW 1745 01:42:41,760 --> 01:42:43,480 >>THANK YOU FOR THE SPECTACULAR 1746 01:42:43,480 --> 01:42:43,920 PRESENTATIONS. 1747 01:42:43,920 --> 01:42:46,320 IT'S BEEN A REAL TREAT HAVING 1748 01:42:46,320 --> 01:42:48,360 YOU PRESENT IN THIS TAG TEAM 1749 01:42:48,360 --> 01:42:48,720 FASHION. 1750 01:42:48,720 --> 01:42:52,360 SO WE USUALLY GO UNTIL 6:00. 1751 01:42:52,360 --> 01:42:59,000 I THINK THEY TURN OFF THE 1752 01:42:59,000 --> 01:43:02,600 INTERNET AT 6:01 AND WE HAVE 1753 01:43:02,600 --> 01:43:04,040 LOTS AND LOTS OF QUESTIONS. 1754 01:43:04,040 --> 01:43:04,640 WE HAVE SOMETHING LIKE 25 1755 01:43:04,640 --> 01:43:14,800 QUESTIONS. 1756 01:43:16,440 --> 01:43:26,880 WE MAY GET TO 20 OR WHATEVER. 1757 01:43:27,320 --> 01:43:32,320 WHY CAN ALOPECIA AREATA BE SO 1758 01:43:32,320 --> 01:43:32,600 LOCALIZED? 1759 01:43:32,600 --> 01:43:34,400 DON'T MOST AUTOIMMUNE DISEASES 1760 01:43:34,400 --> 01:43:37,240 AFFECT THE WHOLE BODY? 1761 01:43:37,240 --> 01:43:40,400 WHY WOULD THIS AFFECT JUST PART 1762 01:43:40,400 --> 01:43:42,120 OF THE SCALP. 1763 01:43:42,120 --> 01:43:43,600 WHAT'S PROTECTING THE UNAFFECTED 1764 01:43:43,600 --> 01:43:44,400 AREAS. 1765 01:43:44,400 --> 01:43:54,040 >>GREAT QUESTION. 1766 01:43:54,040 --> 01:43:55,920 IT AFFECTS GROWING HAIR 1767 01:43:55,920 --> 01:44:00,360 FOLLICLES THEY HAVE TO BE IN 1768 01:44:00,360 --> 01:44:02,280 THEIR GROWTH STATE TO BE 1769 01:44:02,280 --> 01:44:08,320 ATTACKED AND MOST ARE IN THEIR 1770 01:44:08,320 --> 01:44:10,040 RESTING PHASE AND GROW A QUARTER 1771 01:44:10,040 --> 01:44:20,560 INCH AND STOP WHEN THEY'RE NOT 1772 01:44:21,280 --> 01:44:21,840 SUSP 1773 01:44:21,840 --> 01:44:24,400 SUSCEPTIBLE AND SOME GO THROUGH 1774 01:44:24,400 --> 01:44:28,040 A SHORT RESTING PHASE. 1775 01:44:28,040 --> 01:44:29,680 THE PREFERENCE IS THE FACT THEY 1776 01:44:29,680 --> 01:44:39,600 SPEND MOST THEIR TIME GROWING. 1777 01:44:39,600 --> 01:44:43,440 HAIR FOLLICLES ON A HUMAN EXCEL. 1778 01:44:43,440 --> 01:44:44,800 THEY'RE INTERMIXED. 1779 01:44:44,800 --> 01:44:50,760 WE DON'T KNOW WHY A PATCH STARTS 1780 01:44:50,760 --> 01:44:53,320 HERE AND WHERE ELSE IT MIGHT GO 1781 01:44:53,320 --> 01:44:57,320 AND THE FOLLOW-ON IS WHEN 1782 01:44:57,320 --> 01:44:59,640 SOMEBODY REGROWS THEIR HAIR 1783 01:44:59,640 --> 01:45:01,120 ALMOST ALWAYS FALLS OUT ON THE 1784 01:45:01,120 --> 01:45:03,400 EXACT SAME PATCH WORK AS THE 1785 01:45:03,400 --> 01:45:03,720 FIRST TIME. 1786 01:45:03,720 --> 01:45:09,760 THEY DON'T HAVE THE RESIDENT T 1787 01:45:09,760 --> 01:45:20,280 CELL S AND T CELLS ARE STUCK AND 1788 01:45:22,720 --> 01:45:22,960 REACTIVATE. 1789 01:45:22,960 --> 01:45:29,480 WE DON'T HAVE AND IF WE LOOK AT 1790 01:45:29,480 --> 01:45:32,520 PATIENTS WITH PATCHY DISEASE AND 1791 01:45:32,520 --> 01:45:36,600 THEIR BULK RNA GENE EXPRESSION 1792 01:45:36,600 --> 01:45:37,800 SOMETIMES THEY'RE SCALP LOOKS 1793 01:45:37,800 --> 01:45:40,360 LIKE A NORMAL CONTROL AND 1794 01:45:40,360 --> 01:45:44,400 SOMETIMES IT LOOKS SO CLOSE TO 1795 01:45:44,400 --> 01:45:48,400 LESIONAL SCALP IT LOOKS POISED 1796 01:45:48,400 --> 01:45:58,200 TO FALL OUT. 1797 01:45:58,200 --> 01:46:00,400 I WISH I HAD A BETTER ANSWER. 1798 01:46:00,400 --> 01:46:03,080 MAYBE NEXT TIME. 1799 01:46:03,080 --> 01:46:06,400 >>THE NEXT QUESTION FROM OUR 1800 01:46:06,400 --> 01:46:07,520 AUDIENCE IS THIS PERSON MUST 1801 01:46:07,520 --> 01:46:10,760 HAVE DONE THEIR HOMEWORK. 1802 01:46:10,760 --> 01:46:16,160 THERE ARE 400 CASE REPORTS OF 1803 01:46:16,160 --> 01:46:18,200 ALOPECIA AREATA FOLLOWING COVID 1804 01:46:18,200 --> 01:46:21,280 VACCINE IN CDC. 1805 01:46:21,280 --> 01:46:24,160 THESE ARE SELF-REPORTED AND NOT 1806 01:46:24,160 --> 01:46:25,520 ALL CONFIRMED. 1807 01:46:25,520 --> 01:46:29,840 THIS SEEMS A LARGE NUMBER FOR A 1808 01:46:29,840 --> 01:46:33,360 COMMON DISEASE AN REASON TO 1809 01:46:33,360 --> 01:46:34,880 THINK mRNA VACCINE MAY GENERATE 1810 01:46:34,880 --> 01:46:36,600 MORE CYTOKINES THAN OTHER 1811 01:46:36,600 --> 01:46:37,920 DISEASE. 1812 01:46:37,920 --> 01:46:39,400 >>THERE'S A HISTORY OF ALOPECIA 1813 01:46:39,400 --> 01:46:41,480 AREATA CASES BEING REPORTED 1814 01:46:41,480 --> 01:46:43,680 ESPECIALLY THE MOST COMMON IS 1815 01:46:43,680 --> 01:46:45,880 THE HEPATITIS B VACCINE. 1816 01:46:45,880 --> 01:46:46,840 THERE'S A CASE WHERE THERE'S 75 1817 01:46:46,840 --> 01:46:51,400 OR SO CASES. 1818 01:46:51,400 --> 01:46:54,600 ALOPECIA AREATA IS NOT UNCOMMON 1819 01:46:54,600 --> 01:46:57,080 IF YOU LOOK AT THE PREVALENCE 1820 01:46:57,080 --> 01:47:00,240 REPORTS ARE DONE FROM DOCTOR 1821 01:47:00,240 --> 01:47:01,400 OFFICE VISITS OR MEDICAL RECORD. 1822 01:47:01,400 --> 01:47:03,600 MOST WHO HAVE A SINGLE PATCH OF 1823 01:47:03,600 --> 01:47:06,600 DISEASE IN THEIR BEARD OR SCALP 1824 01:47:06,600 --> 01:47:12,400 DON'T EVEN GO TO DETERMINATION 1825 01:47:12,400 --> 01:47:14,520 AND THE NUMBERS ARE A BIT 1826 01:47:14,520 --> 01:47:18,560 MISLEADINGLY LOW. 1827 01:47:18,560 --> 01:47:20,320 THE REASON WHY THEY'RE PERHAPS 1828 01:47:20,320 --> 01:47:23,480 MORE OF AN ASSOCIATION AND THE 1829 01:47:23,480 --> 01:47:25,720 FLAVOR OF THE CYTOKINE STORM 1830 01:47:25,720 --> 01:47:27,600 INDUCED BY COVID IS REMARKABLY 1831 01:47:27,600 --> 01:47:34,400 SIMILAR TO THE FLAVOR OF THE 1832 01:47:34,400 --> 01:47:38,840 CYTOKINES THAT ARE ACTIVATED IN 1833 01:47:38,840 --> 01:47:41,920 ALOPECIA AREATA. 1834 01:47:41,920 --> 01:47:46,560 IT'S THAT COINCIDENCE THAT 1835 01:47:46,560 --> 01:47:52,680 BARCITINIB IS APPROVED FORRAL -- 1836 01:47:52,680 --> 01:47:57,080 FOR ALOPECIA AND NOW APPROVED 1837 01:47:57,080 --> 01:47:57,440 FOR COVID. 1838 01:47:57,440 --> 01:48:02,240 >>IT MAY TURN OUT THERE'S MORE 1839 01:48:02,240 --> 01:48:04,320 CASES OF ALOPECIA AREATA WHEN 1840 01:48:04,320 --> 01:48:08,080 PEOPLE ARE VERY STRESSED. 1841 01:48:08,080 --> 01:48:10,440 THEIR HAIR IT TURNING WHITE. 1842 01:48:10,440 --> 01:48:19,200 I THINK ONE HAS TO BE HUMBLE AND 1843 01:48:19,200 --> 01:48:19,600 CAUTIOUS. 1844 01:48:19,600 --> 01:48:21,920 YOU SAID IMMUNE CHALLENGES LIKE 1845 01:48:21,920 --> 01:48:29,920 VACCINES MAY PRECIPITATE 1846 01:48:29,920 --> 01:48:30,280 ALOPECIA AREATA. 1847 01:48:30,280 --> 01:48:32,840 MAYBE THE STRESS CAN TRIGGER. 1848 01:48:32,840 --> 01:48:34,640 AND SCIENTIFICALLY THE MOST 1849 01:48:34,640 --> 01:48:40,320 EXCITING PART TO ME IS WHAT I 1850 01:48:40,320 --> 01:48:43,760 WAS REFERRAL TO AND THINKING HOW 1851 01:48:43,760 --> 01:48:54,320 THE IMMUNE SYSTEM WORKS AND ALL 1852 01:48:58,640 --> 01:49:02,520 THESE COME TOGETHER AND NERVE 1853 01:49:02,520 --> 01:49:03,360 HAVE CYTOKINE RECEPTORS. 1854 01:49:03,360 --> 01:49:06,040 THE TRUTH IS WE HAVE TO STUDY 1855 01:49:06,040 --> 01:49:08,400 THESE THINGS RIGOROUSLY AND 1856 01:49:08,400 --> 01:49:16,640 COMPREHENSIVELY. 1857 01:49:16,640 --> 01:49:18,200 >>ANOTHER QUESTION FROM THE 1858 01:49:18,200 --> 01:49:19,680 AUDIENCE, WHAT ARE THE CAUSES 1859 01:49:19,680 --> 01:49:25,120 FOR LOSS OF FUNCTION OF KRT82 1860 01:49:25,120 --> 01:49:25,680 FROM THE ALOPECIA AREATA 1861 01:49:25,680 --> 01:49:28,360 PATIENTS? 1862 01:49:28,360 --> 01:49:35,520 >>THE OVERWHELMING MAJORITY OF 1863 01:49:35,520 --> 01:49:42,640 THE VARIATIONS ARE LOSS OF 1864 01:49:42,640 --> 01:49:42,920 FUNCTION. 1865 01:49:42,920 --> 01:49:53,360 MOST KERATIN DISEASES ARE 1866 01:50:09,880 --> 01:50:11,640 AFFECTED BY THE ABILITY TO FORM 1867 01:50:11,640 --> 01:50:11,920 NORMALLY. 1868 01:50:11,920 --> 01:50:17,840 THE MUTATIONS THEMSELVES THERE 1869 01:50:17,840 --> 01:50:20,880 SEEMS TO BE A HOT SPOT THAT'S 1870 01:50:20,880 --> 01:50:23,000 FOUND IN MORE THAN HALF THE 1871 01:50:23,000 --> 01:50:23,880 PATIENTS. 1872 01:50:23,880 --> 01:50:27,520 THAT'S TYPICAL FOR A KERATIN 1873 01:50:27,520 --> 01:50:27,840 MUTATION. 1874 01:50:27,840 --> 01:50:35,520 MANY OCCUR AT ARGININE BECAUSE 1875 01:50:35,520 --> 01:50:37,760 OF THEIR ABILITY AND IT'S 1876 01:50:37,760 --> 01:50:39,920 BASICALLY FITTING THE PROFILE OF 1877 01:50:39,920 --> 01:50:43,440 WHAT A KERATINOPATHY PATTERN 1878 01:50:43,440 --> 01:50:44,400 SHOULD LOOK LIKE. 1879 01:50:44,400 --> 01:50:50,320 WHAT WE DON'T YET KNOW AND WILL 1880 01:50:50,320 --> 01:50:52,240 BE DIFFICULT TO MODEL IS THE 1881 01:50:52,240 --> 01:50:55,560 AFFECT ON THE FUNCTION AND 1882 01:50:55,560 --> 01:50:59,960 STRUCTURE OF THE FOLLICLE IS IT 1883 01:50:59,960 --> 01:51:02,480 MORE EASILY PENETRATED BY IMMUNE 1884 01:51:02,480 --> 01:51:02,680 T CELLS? 1885 01:51:02,680 --> 01:51:09,200 A LOT FOR US TO THINK ABOUT. 1886 01:51:09,200 --> 01:51:11,520 IT'S A DIFFICULT KERATIN TO WORK 1887 01:51:11,520 --> 01:51:13,560 WITH BECAUSE IT'S A HARD 1888 01:51:13,560 --> 01:51:13,840 KERATIN. 1889 01:51:13,840 --> 01:51:16,360 IT'S INTRACTABLE TO WORK WITH 1890 01:51:16,360 --> 01:51:22,360 BUT WE'RE TRYING OUR BEST. 1891 01:51:22,360 --> 01:51:25,040 IT'S A SURPRISE TO FIND A 1892 01:51:25,040 --> 01:51:27,360 KERATIN THAT'S A MAJOR LOCUS BUT 1893 01:51:27,360 --> 01:51:29,880 WE LOOK AT IT AS A WEAKNESS IN 1894 01:51:29,880 --> 01:51:31,280 THE SKIN BARRIER THAT THEN 1895 01:51:31,280 --> 01:51:38,840 OVERLAYS ON THE BACKGROUND OF 1896 01:51:38,840 --> 01:51:44,120 THEIR IMMUNE RESPONSE AND THE 1897 01:51:44,120 --> 01:51:44,360 MICROBES. 1898 01:51:44,360 --> 01:51:44,600 >> 1899 01:51:44,600 --> 01:51:45,960 >>CAN I ASK A FOLLOW-UP 1900 01:51:45,960 --> 01:51:47,160 QUESTION? 1901 01:51:47,160 --> 01:51:50,800 >>AS I RECALL, ANGELA, ONE OF 1902 01:51:50,800 --> 01:51:52,400 YOUR PAPERS ARGUED JAK 1903 01:51:52,400 --> 01:51:54,240 INHERITORS CAN PROMOTE HAIR 1904 01:51:54,240 --> 01:51:54,480 GROWTH. 1905 01:51:54,480 --> 01:51:58,520 DO I REMEMBER THAT CORRECTLY? 1906 01:51:58,520 --> 01:51:58,960 >>ABSOLUTELY. 1907 01:51:58,960 --> 01:52:00,960 >>DO YOU WANT TO COMMENT ON 1908 01:52:00,960 --> 01:52:01,480 THAT? 1909 01:52:01,480 --> 01:52:04,600 >>IT'S AN OBSERVATION DURING 1910 01:52:04,600 --> 01:52:09,200 TREATING THE ALOPECIA AREATA IN 1911 01:52:09,200 --> 01:52:09,880 MICE. 1912 01:52:09,880 --> 01:52:11,680 AND TO OUR EYE IT APPEARED THE 1913 01:52:11,680 --> 01:52:16,360 MICE WHO RECEIVED TOPICAL JAK 1914 01:52:16,360 --> 01:52:20,200 INHIBITERS REGREW BETTER THAN 1915 01:52:20,200 --> 01:52:22,560 THOSE WHO RECEIVED IT 1916 01:52:22,560 --> 01:52:22,880 SYSTEMICALLY. 1917 01:52:22,880 --> 01:52:26,400 WE MOVED IT OUT OF ALOPECIA 1918 01:52:26,400 --> 01:52:28,800 AREATA AND JUST TO MICE AND 1919 01:52:28,800 --> 01:52:31,520 ASKED IF YOU TAKE A BLACK THICK 1920 01:52:31,520 --> 01:52:34,320 MOUSE IN RESTING PHASE AND APPLY 1921 01:52:34,320 --> 01:52:38,880 A TOPICAL JAK INHIBITOR CAN YOU 1922 01:52:38,880 --> 01:52:40,280 INDUCE A HAIR CYCLE. 1923 01:52:40,280 --> 01:52:44,400 IT SEEMS AS THOUGH THERE'S A 1924 01:52:44,400 --> 01:52:46,720 BLOCK THAT'S MEDIATED BY JAK 1925 01:52:46,720 --> 01:52:48,360 SIGNALLING AND WHEN YOU APPLY 1926 01:52:48,360 --> 01:52:50,600 THE INHIBITOR YOU LOWER THE 1927 01:52:50,600 --> 01:52:53,360 THRESHOLD FOR THE FOLLICLE TO 1928 01:52:53,360 --> 01:52:56,240 REENTER THE GROWTH PHASE. 1929 01:52:56,240 --> 01:52:58,800 THAT WAS A FINDING WE THINK IS 1930 01:52:58,800 --> 01:53:03,400 AN ADDED BENEFIT OF THE JAK 1931 01:53:03,400 --> 01:53:07,640 INHIBITION IN ALOPECIA AREATA 1932 01:53:07,640 --> 01:53:10,440 YOU TAKE AWAY THE IMMUNE AFFECT 1933 01:53:10,440 --> 01:53:12,400 AND ALLOW THEM TO REENTER THE 1934 01:53:12,400 --> 01:53:16,880 HAIR CYCLE. 1935 01:53:16,880 --> 01:53:18,360 IT WAS NOT SOMETHING WE EXPECTED 1936 01:53:18,360 --> 01:53:20,280 AND MORE TO DO TO FIGURE OUT HOW 1937 01:53:20,280 --> 01:53:22,120 IT WORK IT WAS UNEXPECTED. 1938 01:53:22,120 --> 01:53:27,400 >>SO A COUPLE FOLLOW-UP 1939 01:53:27,400 --> 01:53:30,640 QUESTIONS ON THE DISCUSSION YOU 1940 01:53:30,640 --> 01:53:34,080 GUYS HAVE BEEN HAVING. 1941 01:53:34,080 --> 01:53:37,360 ONE IS IN STUDIES OF JACK 1942 01:53:37,360 --> 01:53:46,040 INHIBITERS IN RHEUMATOID 1943 01:53:46,040 --> 01:53:47,320 ARTHRITIS ARE OTHERS TREATED 1944 01:53:47,320 --> 01:53:49,800 WITH A JAK INHIBITOR. 1945 01:53:49,800 --> 01:53:54,640 DO ANY OF THEM EXPECT TO START 1946 01:53:54,640 --> 01:54:03,080 TO GROW MORE HAIR? 1947 01:54:03,080 --> 01:54:08,400 THE HAVE UNDIAGNOSED ALOPECIA 1948 01:54:08,400 --> 01:54:08,600 AREATA? 1949 01:54:08,600 --> 01:54:10,280 >>THERE'S REPORTS OF PATIENTS 1950 01:54:10,280 --> 01:54:15,640 WHO ARE RA AND TAKE THE JAK 1951 01:54:15,640 --> 01:54:20,400 INHIBITOR AND THERE'S REPORTS 1952 01:54:20,400 --> 01:54:30,960 THEY REGREW AND THERE'S SOME FOR 1953 01:54:32,680 --> 01:54:34,120 MEDICATIONS AND IF THEY RESPOND 1954 01:54:34,120 --> 01:54:36,360 AS IN THE CASE OF PSORIASIS ARE 1955 01:54:36,360 --> 01:54:37,200 OUT THERE. 1956 01:54:37,200 --> 01:54:40,120 I THINK YOU'RE ASKING IF YOU SEE 1957 01:54:40,120 --> 01:54:41,040 AN EFFECT OF CONVENTIONAL 1958 01:54:41,040 --> 01:54:51,360 PATTERN HAIR LOSS? 1959 01:54:54,880 --> 01:54:56,400 >>I HAVEN'T SEEN LITERATURE 1960 01:54:56,400 --> 01:54:59,880 LIKE THAT AND IN OUR HANDS IN 1961 01:54:59,880 --> 01:55:01,640 THE MICE WE NEVER SAW THAT 1962 01:55:01,640 --> 01:55:02,800 SYSTEMICALLY IN THE PUMP ONLY 1963 01:55:02,800 --> 01:55:05,800 WITH SUPER HIGH LOCAL DELIVERY 1964 01:55:05,800 --> 01:55:07,960 ON TO THE SKIN INTO THE FOLLICLE 1965 01:55:07,960 --> 01:55:08,360 IN THE MICE. 1966 01:55:08,360 --> 01:55:11,320 MY HUNCH IS WHATEVER THE AFFECT 1967 01:55:11,320 --> 01:55:13,400 IS IT HAS TO HAVE A HIGH ENOUGH 1968 01:55:13,400 --> 01:55:14,680 CONCENTRATION IN THE FOLLICLE 1969 01:55:14,680 --> 01:55:15,120 ITSELF. 1970 01:55:15,120 --> 01:55:17,440 I DON'T KNOW THE SYSTEMIC DOSES 1971 01:55:17,440 --> 01:55:18,400 WILL GET THERE BECAUSE WE DIDN'T 1972 01:55:18,400 --> 01:55:28,920 SEE IT HAPPEN IN THE MICE AND IT 1973 01:55:30,280 --> 01:55:32,040 SEEMS TO ONLY BE DONE TOPICALLY 1974 01:55:32,040 --> 01:55:36,360 AND I THINK OF TOPICAL 1975 01:55:36,360 --> 01:55:40,360 INHIBITERS BECAUSE THE TARGET 1976 01:55:40,360 --> 01:55:44,400 FOR STIMULATING THE FOLLICLE 1977 01:55:44,400 --> 01:55:45,520 IT'S SUPERFICIAL COMPARED TO 1978 01:55:45,520 --> 01:55:47,920 WHERE YOU NEED TO TARGET FOR 1979 01:55:47,920 --> 01:55:48,280 ALOPECIA AREATA. 1980 01:55:48,280 --> 01:55:50,120 IT'S HARD TO GET THE DRUG TO 1981 01:55:50,120 --> 01:55:54,640 PENETRATE LOW IN THE SKIN AND 1982 01:55:54,640 --> 01:55:56,400 THEN STOP AND NOT KEEP GOING IN 1983 01:55:56,400 --> 01:55:57,080 THE CIRCULATION. 1984 01:55:57,080 --> 01:55:59,240 IT'S EASIER THE HIGHER UP YOU 1985 01:55:59,240 --> 01:55:59,920 ARE IN THE SKIN. 1986 01:55:59,920 --> 01:56:03,600 SOME OTHER FORMULATIONS LIKE 1987 01:56:03,600 --> 01:56:05,320 ECTOPIC DERM AND PSORIASIS MAY 1988 01:56:05,320 --> 01:56:07,440 HAVE A BETTER CHANCE OF REACHING 1989 01:56:07,440 --> 01:56:09,320 THE UPPER LAYERS THAN THE 1990 01:56:09,320 --> 01:56:12,360 CHALLENGES FACED SO FAR WITH 1991 01:56:12,360 --> 01:56:19,360 ALOPECIA AREATA. 1992 01:56:19,360 --> 01:56:21,800 >>THERE WAS A QUESTION ABOUT 1993 01:56:21,800 --> 01:56:24,040 THE PATCHY NATURE OF THE 1994 01:56:24,040 --> 01:56:24,640 LESIONS. 1995 01:56:24,640 --> 01:56:34,160 ANY THOUGHTS ABOUT SOMATIC 1996 01:56:34,160 --> 01:56:34,800 MUTATION. 1997 01:56:34,800 --> 01:56:36,400 HAVE YOU LOOKED FOR THAT? 1998 01:56:36,400 --> 01:56:42,920 >>I WISH I COULD. 1999 01:56:42,920 --> 01:56:45,160 >>WE'D LOVE TO EXPLORE IT 2000 01:56:45,160 --> 01:56:45,760 FURTHER AND FIGURE OUT WHAT IT 2001 01:56:45,760 --> 01:56:55,880 DOES. 2002 01:56:58,440 --> 01:57:02,040 >>THE WAY WE THINK OF 2003 01:57:02,040 --> 01:57:04,400 PATCHINESS AND THE FIELD AFFECT 2004 01:57:04,400 --> 01:57:05,720 IN THE DERMAS AND INDEPENDENT OF 2005 01:57:05,720 --> 01:57:08,360 THE CYCLE AND TALKING ABOUT 2006 01:57:08,360 --> 01:57:13,320 COMPETENCE OF A REGION TO ENTER 2007 01:57:13,320 --> 01:57:16,920 THE HAIR SCALP VERSUS SOMETHING 2008 01:57:16,920 --> 01:57:20,120 THAT BLOCKS THE DERMIS FROM 2009 01:57:20,120 --> 01:57:20,360 ENTERING. 2010 01:57:20,360 --> 01:57:24,400 THE PATCH WORK YOU CAN SEE IN 2011 01:57:24,400 --> 01:57:32,160 THE MICE BY THINKING ABOUT 2012 01:57:32,160 --> 01:57:36,400 FACTORS BUT I LOVE THE QUESTION 2013 01:57:36,400 --> 01:57:40,400 WHETHER THERE COULD BE REGIONAL 2014 01:57:40,400 --> 01:57:42,880 OR PATCHY DECEMBER THAT WOULD DO 2015 01:57:42,880 --> 01:57:52,240 THAT. 2016 01:57:52,240 --> 01:57:55,200 WE DON'T KNOW IF WE CAN STUDY 2017 01:57:55,200 --> 01:57:56,200 PLUCKED HAIRS YET BUT 2018 01:57:56,200 --> 01:57:56,760 FASCINATING QUESTION. 2019 01:57:56,760 --> 01:57:57,320 THANK YOU. 2020 01:57:57,320 --> 01:57:58,680 >>THESE ARE FASCINATING 2021 01:57:58,680 --> 01:58:00,320 QUESTIONS IN GENERAL. 2022 01:58:00,320 --> 01:58:02,320 YOU GUYS ARE DONE A WONDERFUL 2023 01:58:02,320 --> 01:58:06,200 JOB OF REALLY FASCINATING US AND 2024 01:58:06,200 --> 01:58:08,600 DEMYSTIFYING MEDICINE FOR SURE. 2025 01:58:08,600 --> 01:58:15,800 NOW, AS IT TURNS OUT SOMEWHERE I 2026 01:58:15,800 --> 01:58:18,440 GUESS IN EUROPE IT'S NOW 2027 01:58:18,440 --> 01:58:20,800 MIDNIGHT AND BECAUSE OF THAT OUR 2028 01:58:20,800 --> 01:58:24,360 CARRIAGE IS TURNING INTO AING 2029 01:58:24,360 --> 01:58:28,240 UP. 2030 01:58:28,240 --> 01:58:30,320 -- TURNING INTO A PUMPKIN AND 2031 01:58:30,320 --> 01:58:34,560 THANK YOU FOR THE WONDERFUL 2032 01:58:34,560 --> 01:58:35,520 PRESENTATIONS AND I DO HAVE 2033 01:58:35,520 --> 01:58:37,120 PLENTY OF OTHER QUESTIONS I CAN 2034 01:58:37,120 --> 01:58:38,360 RELATE TO YOU LATER. 2035 01:58:38,360 --> 01:58:39,800 YOU CAN SPEND THE NEXT WEEK 2036 01:58:39,800 --> 01:58:43,520 ANSWERING THE QUESTIONS FOR US. 2037 01:58:43,520 --> 01:58:44,440 NEXT WEEK WE ARE GOING TO HAVE 2038 01:58:44,440 --> 01:58:46,440 THE GREAT HONOR AND PLEASURE OF 2039 01:58:46,440 --> 01:58:52,360 HEARING ABOUT THE HUMAN GENOME 2040 01:58:52,360 --> 01:58:58,760 AT AGE 20 BUT IN THE MEANTIME 2041 01:58:58,760 --> 01:59:01,960 ANYONE WHO MISSED THE VIDEO 2042 01:59:01,960 --> 01:59:05,040 PRESENTATION IT'S VIDEO ARCHIVED 2043 01:59:05,040 --> 01:59:07,880 AND I ENCOURAGE EVERYONE TO BO 2044 01:59:07,880 --> 01:59:10,640 BACK TO THE WEBSITE AND CATCH 2045 01:59:10,640 --> 01:59:11,800 THE SNIPPETS YOU DIDN'T QUITE 2046 01:59:11,800 --> 01:59:12,920 HEAR CAREFULLY. 2047 01:59:12,920 --> 01:59:15,280 ANYWAY, THANK YOU GUYS VERY 2048 01:59:15,280 --> 01:59:16,400 MUCH. 2049 01:59:16,400 --> 01:59:18,160 THANK EVERYONE FOR PARTICIPATING 2050 01:59:18,160 --> 01:59:20,320 THIS AFTERNOON, THIS MORNING, 2051 01:59:20,320 --> 01:59:22,320 THIS EVENING, WHATEVER TIME IT 2052 01:59:22,320 --> 01:59:28,360 IS TO YOU AND REMEMBER THAT IF 2053 01:59:28,360 --> 01:59:33,280 YOU WANT CME CREDIT AND ENTER 2054 01:59:33,280 --> 01:59:36,120 THE NUMBER 45382. 2055 01:59:36,120 --> 01:59:36,720 THANK YOU ALL VERY MUCH AND 2056 01:59:36,720 --> 00:00:00,000 WE'LL SEE YOU NEXT WEEK.