1 00:00:11,440 --> 00:00:13,640 Welcome to the Clinical Center Grand Rounds, 2 00:00:13,640 --> 00:00:17,440 a weekly series of educational lectures for physicians and 3 00:00:17,440 --> 00:00:20,080 health care professionals broadcast from the Clinical 4 00:00:20,080 --> 00:00:23,040 Center at the National Institutes of Health in 5 00:00:23,040 --> 00:00:24,840 Bethesda, MD. 6 00:00:24,840 --> 00:00:28,400 The NIH Clinical Center is the world's largest hospital totally 7 00:00:28,400 --> 00:00:32,080 dedicated to investigational research and leads the global 8 00:00:32,080 --> 00:00:35,040 effort in training today's investigators and discovering 9 00:00:35,040 --> 00:00:37,200 tomorrow's cures. 10 00:00:37,200 --> 00:00:47,520 Learn more by visiting us online at http://clinicalcenter.nih.gov 11 00:00:47,520 --> 00:00:50,400 SO ON BEHALF OF THE NIH GREAT 12 00:00:50,400 --> 00:00:51,600 TEACHER SELECTION COMMITTEE IT 13 00:00:51,600 --> 00:00:54,920 IS MY GREAT HONOR TO INTRODUCE 14 00:00:54,920 --> 00:01:05,400 TODAY'S SPEAKER DAN KASTNER. 15 00:01:08,200 --> 00:01:10,000 DR. KASTNER EARNED HIS MD AND 16 00:01:10,000 --> 00:01:12,600 PhD FROM BAYLOR COLLEGE OF 17 00:01:12,600 --> 00:01:15,160 MEDICINE AFTER COMPLETING HIS 18 00:01:15,160 --> 00:01:23,800 BACHELOR OF ARTS DEGREE IN 19 00:01:23,800 --> 00:01:26,640 PHILOSOPHY. 20 00:01:26,640 --> 00:01:29,440 THROUGHOUT HIS NIH CAREER 21 00:01:29,440 --> 00:01:30,880 DR. KASTNER'S RESEARCH HAS 22 00:01:30,880 --> 00:01:34,640 FOCUSED ON THE GENETIC AND 23 00:01:34,640 --> 00:01:42,080 GENOMIC STRATEGIES. 24 00:01:42,080 --> 00:01:43,920 AS YOU WILL SEE HIS WORK HAS LED 25 00:01:43,920 --> 00:01:46,600 TO THE DISCOVERY OF THE 26 00:01:46,600 --> 00:01:48,960 MOLECULAR BASES FOR MANY OF 27 00:01:48,960 --> 00:01:51,920 THESE CONDITIONS. 28 00:01:51,920 --> 00:01:54,120 AND THIS HAS INFORMED OUR 29 00:01:54,120 --> 00:01:56,240 UNDERSTANDING OF MORE COMMON IN 30 00:01:56,240 --> 00:01:58,880 FLAM FERRY ILLNESSES. 31 00:01:58,880 --> 00:02:03,080 ALSO PROPOSED THE CONCEPT OF 32 00:02:03,080 --> 00:02:07,120 AUTO INFLAMMATION. 33 00:02:07,120 --> 00:02:08,480 DR. KASTNER HAS WON NUMEROUS 34 00:02:08,480 --> 00:02:15,280 AWARDS AND HONORS. 35 00:02:15,280 --> 00:02:23,920 * THE FEDERAL EMPLOYEE OF THE 36 00:02:23,920 --> 00:02:27,040 YEAR IN 2018 AND THE ROSS PRIZE 37 00:02:27,040 --> 00:02:31,880 AND MOLECULAR MEDICINE IN 2019. 38 00:02:31,880 --> 00:02:34,080 IN 2021 HE E RECEIVED THE 39 00:02:34,080 --> 00:02:36,400 CRAWFORD PRIZE FROM THE ROYAL 40 00:02:36,400 --> 00:02:46,920 SWEETERS ACADEMY OF SCIENCES. 41 00:02:47,320 --> 00:02:55,400 HE IS PERSONABLE AND SELF-A 42 00:02:55,400 --> 00:02:56,240 FACING. 43 00:02:56,240 --> 00:02:58,680 YOU ARE IN FOR A TREAT. 44 00:02:58,680 --> 00:03:00,600 HELPING TO ADVANCE THE CARE OF 45 00:03:00,600 --> 00:03:03,120 OUR PATIENTS AND THAT WILL 46 00:03:03,120 --> 00:03:04,880 QUICKLY BECOME SELF-EVIDENCE. 47 00:03:04,880 --> 00:03:07,760 I WOULD LIKE TO WELCOME OUR 48 00:03:07,760 --> 00:03:13,480 SPEAKER DR. DAN KASTNER. 49 00:03:13,480 --> 00:03:17,360 THANK YOU SO, SO MUCH FOR THAT 50 00:03:17,360 --> 00:03:18,440 VERY KIND INTRODUCTION. 51 00:03:18,440 --> 00:03:21,880 I HOPE THAT I CAN MEASURE UP TO 52 00:03:21,880 --> 00:03:23,120 THIS HIGH BAR THAT HAS BEEN 53 00:03:23,120 --> 00:03:25,560 ESTABLISHED FOR ME BUT I WILL 54 00:03:25,560 --> 00:03:28,520 GIVE IT MY BEST ANY WAY. 55 00:03:28,520 --> 00:03:31,320 IT IS JUST MY ENORMOUS PLEASURE 56 00:03:31,320 --> 00:03:34,080 TO BE HERE TODAY AND IT IS SUCH 57 00:03:34,080 --> 00:03:37,600 A GREAT HONOR TO BE SELECTED TO 58 00:03:37,600 --> 00:03:40,160 GIVE THIS TALK IN THE GREAT 59 00:03:40,160 --> 00:03:42,600 TEACHER'S LECTURE SERIES. 60 00:03:42,600 --> 00:03:46,160 AS ED HAS SAID THE TITLE OF THIS 61 00:03:46,160 --> 00:03:48,880 TALK IS FACT STRANGER THAN 62 00:03:48,880 --> 00:03:51,000 FICTION: ADVENTURES IN THE 63 00:03:51,000 --> 00:03:53,360 GENOMICS OF INFLAMMATION AND I 64 00:03:53,360 --> 00:03:55,240 HOPE OVER THE COURSE OF THE NEXT 65 00:03:55,240 --> 00:03:58,360 HOUR THAT YOU TOO WILL SEE JUST 66 00:03:58,360 --> 00:04:01,640 HOW MUCH FUN IT IS DOING THIS 67 00:04:01,640 --> 00:04:04,400 KIND OF WORK AND WHAT ADVENTURE 68 00:04:04,400 --> 00:04:06,680 IT HAS BEEN FOLLOWING SOME OF 69 00:04:06,680 --> 00:04:09,720 THE LEADS OVER COURSE OF THE 70 00:04:09,720 --> 00:04:14,120 LAST 37 YEARS ACTUALLY HERE AT 71 00:04:14,120 --> 00:04:16,040 THE NIH CLINICAL CENTER. 72 00:04:16,040 --> 00:04:18,280 SO TO GET ON WITH IT FIRST OF 73 00:04:18,280 --> 00:04:25,640 ALL WE HAVE THE OH LICK P -- OBY 74 00:04:25,640 --> 00:04:26,840 SLIDE I HAVE NOTHING TO 75 00:04:26,840 --> 00:04:27,280 DISCLOSE. 76 00:04:27,280 --> 00:04:31,160 AT THE END OF THE LECTURE THE 77 00:04:31,160 --> 00:04:32,720 PARTICIPANT OUGHT TO BE ABLE TO 78 00:04:32,720 --> 00:04:35,520 DO THIS, EXPLAIN THE DIFFERENCE 79 00:04:35,520 --> 00:04:38,040 BETWEEN AUTOIMMUNE AND AUTO 80 00:04:38,040 --> 00:04:40,480 INFLAMMATORY DISEASE. 81 00:04:40,480 --> 00:04:43,680 SECOND, RECOGNIZE THE CLINICAL 82 00:04:43,680 --> 00:04:44,560 FEATURES. 83 00:04:44,560 --> 00:04:46,800 AND THIRD, DISCUSS THE EVOLVING 84 00:04:46,800 --> 00:04:48,800 ROLE OF GENOMICS IN THE 85 00:04:48,800 --> 00:04:51,320 DISCOVERY OF NEW AUTO 86 00:04:51,320 --> 00:04:53,600 INFLAMMATORY DISEASES IN PATIENT 87 00:04:53,600 --> 00:04:54,240 DIAGNOSIS. 88 00:04:54,240 --> 00:04:56,600 BEFORE WE GET STARTED MAYBE WE 89 00:04:56,600 --> 00:05:00,560 SHOULD PUT THIS IN AN HISTORICAL 90 00:05:00,560 --> 00:05:00,960 PERSPECTIVE. 91 00:05:00,960 --> 00:05:04,480 THIS IS IN SOME WAYS REALLY HARD 92 00:05:04,480 --> 00:05:05,040 TO BELIEVE. 93 00:05:05,040 --> 00:05:08,000 BACK AT THE BEGINNING OF THE 94 00:05:08,000 --> 00:05:16,520 20th CENTURY THIS GUY PAUL 95 00:05:16,520 --> 00:05:18,880 EHRLICH. 96 00:05:18,880 --> 00:05:23,800 HE WAS A PROMINENT I'M OLOGIST. 97 00:05:23,800 --> 00:05:28,440 * WHAT THAT MEANT WAS THAT THE 98 00:05:28,440 --> 00:05:32,320 IMMUNE SYSTEM IS SO POTENT SO 99 00:05:32,320 --> 00:05:34,400 FORMIDABLE THAT IT WOULD BE 100 00:05:34,400 --> 00:05:36,920 UNIMAGINABLE FOR THE IMMUNE 101 00:05:36,920 --> 00:05:38,680 SYSTEM TO TURN AGAINST ITS HOST. 102 00:05:38,680 --> 00:05:42,200 SO THE PREVAILING DOCTRINE WHICH 103 00:05:42,200 --> 00:05:44,760 LASTED FOR THE FIRST HALF OF THE 104 00:05:44,760 --> 00:05:47,480 20th CENTURY WAS THAT 105 00:05:47,480 --> 00:05:49,680 AUTOIMMUNITY WAS CONCEPTUALLY 106 00:05:49,680 --> 00:05:51,600 IMPOSSIBLE TO HAPPEN. 107 00:05:51,600 --> 00:05:54,840 AND SO THAT WAS THE PREVAILING 108 00:05:54,840 --> 00:05:59,400 VIEW UP TO AROUND 1950 AND AT 109 00:05:59,400 --> 00:06:02,680 THAT TIME -- THEY DISCOVERED 110 00:06:02,680 --> 00:06:06,800 AUTO ANTIBODIES IN DISEASE OF 111 00:06:06,800 --> 00:06:08,880 THE THYROID AND THAT WAS THE 112 00:06:08,880 --> 00:06:11,120 BEGINNING OF THE DOCUMENTATION 113 00:06:11,120 --> 00:06:12,920 OF AUTOIMMUNITY. 114 00:06:12,920 --> 00:06:15,200 SO FOR THE FIRST HALF OF THE 115 00:06:15,200 --> 00:06:18,440 20th CENTURY IT WAS DEEM TO BE 116 00:06:18,440 --> 00:06:21,960 IMPOSSIBLE AND THEN AROUND 1950 117 00:06:21,960 --> 00:06:23,360 AUTOIMMUNITY WAS DISCOVERED. 118 00:06:23,360 --> 00:06:26,600 IT WAS THEN UNTIL THE END OF THE 119 00:06:26,600 --> 00:06:28,040 20th CENTURY BEFORE THIS 120 00:06:28,040 --> 00:06:31,840 CONCEPT OF AUTO INFLAMMATORY 121 00:06:31,840 --> 00:06:33,080 DISEASE CAME ABOUT. 122 00:06:33,080 --> 00:06:35,280 SO WE'LL TALK ABOUT HOW THAT 123 00:06:35,280 --> 00:06:37,280 HAPPENED OVER THE COURSE OF THE 124 00:06:37,280 --> 00:06:39,160 LAST FEW YEARS. 125 00:06:39,160 --> 00:06:42,040 SO THE STORY STARTS WITH A 126 00:06:42,040 --> 00:06:44,000 PATIENT AND THAT OF COURSE IS 127 00:06:44,000 --> 00:06:47,400 REALLY THE NAME OF THE GAME. 128 00:06:47,400 --> 00:06:49,840 REALLY, PATIENTS ARE THE CENTER 129 00:06:49,840 --> 00:06:52,160 OF OUR EXISTENCE AT THE CLINICAL 130 00:06:52,160 --> 00:06:53,960 CENTER AS THEY SHOULD BE THE 131 00:06:53,960 --> 00:06:59,000 CENTER OF OUR EXISTENCE AS 132 00:06:59,000 --> 00:07:01,200 CLINICAL INVESTIGATORS, 133 00:07:01,200 --> 00:07:02,440 PHYSICIAN SCIENTISTS, 134 00:07:02,440 --> 00:07:04,360 INDIVIDUALS WHO WANT TO ADVANCE 135 00:07:04,360 --> 00:07:06,320 OUR UNDERSTANDING OF MEDICINE SO 136 00:07:06,320 --> 00:07:09,880 WHEN I CAME HERE IN 1985 SHORTLY 137 00:07:09,880 --> 00:07:14,280 AFTER I ARRIVED IN NOVEMBER OF 138 00:07:14,280 --> 00:07:16,640 1985 I HAPPENED TO SEE A NEW 139 00:07:16,640 --> 00:07:20,040 PATIENT IN RHEUMATOLOGY CLINIC. 140 00:07:20,040 --> 00:07:22,920 A YOUNG MAN WHO HAD A LIFELONG 141 00:07:22,920 --> 00:07:26,560 HISTORY OF EPISODES OF FEVER 142 00:07:26,560 --> 00:07:30,440 OFTEN TIMES WITH MONO OR ARCTIC 143 00:07:30,440 --> 00:07:33,200 EULAR ARTHRITIS. 144 00:07:33,200 --> 00:07:35,160 *. 145 00:07:35,160 --> 00:07:37,000 ESSENTIALLY HE WAS REFERRED TO 146 00:07:37,000 --> 00:07:39,000 US WITH THE IDEA OF MAYBE WE 147 00:07:39,000 --> 00:07:41,240 COULD FIGURE OUT WHAT HE HAD. 148 00:07:41,240 --> 00:07:43,440 AT FIRST I DIDN'T RECOGNIZE WHAT 149 00:07:43,440 --> 00:07:46,800 HE HAD FOR WHAT IT WAS. 150 00:07:46,800 --> 00:07:49,800 FORTUNATELY THERE WAS A FELLA 151 00:07:49,800 --> 00:07:51,360 FROM ISRAEL FROM THE LAB I WAS 152 00:07:51,360 --> 00:07:54,480 WORKING IN AND WE CAME UP WITH 153 00:07:54,480 --> 00:07:56,920 THE HYPOTHESIS THAT HE MIGHT 154 00:07:56,920 --> 00:07:59,760 HAVE THIS CONDITION CALLED 155 00:07:59,760 --> 00:08:02,440 FAMILIAL MEDICINE FEVER. 156 00:08:02,440 --> 00:08:03,560 SO IS THAT? 157 00:08:03,560 --> 00:08:07,520 IT'S A DISEASE FIRST RECOGNIZED 158 00:08:07,520 --> 00:08:10,880 BACK IN 1945 BY A DIFFERENT 159 00:08:10,880 --> 00:08:12,000 NAME. 160 00:08:12,000 --> 00:08:15,120 AND BASICALLY THERE WERE 10 161 00:08:15,120 --> 00:08:18,960 CASES DESCRIBED IN THE ANNALS OF 162 00:08:18,960 --> 00:08:19,800 INTERNAL MEDICINE. 163 00:08:19,800 --> 00:08:21,400 THESE WERE CASES OF INDIVIDUALS 164 00:08:21,400 --> 00:08:24,160 WHO HAD STERILE PERFECT TOE 165 00:08:24,160 --> 00:08:25,120 NIGHT US. 166 00:08:25,120 --> 00:08:28,320 *. 167 00:08:28,320 --> 00:08:30,680 LATER WITH THE IMMIGRATION OF 168 00:08:30,680 --> 00:08:32,880 MANY JEWISH PEOPLE TO ISRAEL IT 169 00:08:32,880 --> 00:08:37,080 WAS RECOGNIZED THIS IS A DISEASE 170 00:08:37,080 --> 00:08:41,360 OF THE JEWISH POPULATION. 171 00:08:41,360 --> 00:08:42,920 HERE ARE SOME OF THE KEY 172 00:08:42,920 --> 00:08:43,640 FEATURES. 173 00:08:43,640 --> 00:08:46,440 IT WAS RECOGNIZED AT THE TIME 174 00:08:46,440 --> 00:08:48,240 THAT WE FIRST SAW OUR PATIENT 175 00:08:48,240 --> 00:08:53,480 THAT IT WAS A GENETIC DISORDER. 176 00:08:53,480 --> 00:08:55,680 CHARACTERIZED BY EPISODES OF 177 00:08:55,680 --> 00:08:57,480 FEVER THAT MIGHT LAST ON THE 178 00:08:57,480 --> 00:08:59,920 ORDER OF ONE TO THREE DAYS. 179 00:08:59,920 --> 00:09:04,960 AND PATIENTS COULD ALSO HAVE 180 00:09:04,960 --> 00:09:07,560 STERILE -- ARTHRITIS AS WAS THE 181 00:09:07,560 --> 00:09:09,280 CASE FOR THE PATIENT THAT I SAW. 182 00:09:09,280 --> 00:09:11,840 SOME OF THE PATIENTS CAN HAVE A 183 00:09:11,840 --> 00:09:15,720 RASH ON THE ANKLE OR FOOT OR 184 00:09:15,720 --> 00:09:17,080 LOWER LEG. 185 00:09:17,080 --> 00:09:20,720 AND SOME PATIENTS COULD ALSO 186 00:09:20,720 --> 00:09:23,240 HAVE THE DEPOSITION OF A 187 00:09:23,240 --> 00:09:25,680 CLEAVAGE PRODUCT OF ONE OF THE 188 00:09:25,680 --> 00:09:29,800 ACUTE FACE REACT ANTS AND IT WAS 189 00:09:29,800 --> 00:09:33,880 A MAJOR CAUSE OF KIDNEY FAILURE 190 00:09:33,880 --> 00:09:36,520 AND DEATH BACK BEFORE THE ADVENT 191 00:09:36,520 --> 00:09:41,440 OF CULTURE TREATMENT. 192 00:09:41,440 --> 00:09:43,240 FORTUNATELY IT WAS AVAILABLE. 193 00:09:43,240 --> 00:09:46,360 WE PUT HIM ON IT AS A 194 00:09:46,360 --> 00:09:47,120 THERAPEUTIC TRIAL. 195 00:09:47,120 --> 00:09:50,000 HE RESPONDED BEAUTIFULLY AND 196 00:09:50,000 --> 00:09:52,280 THAT WAS CERTAINLY PART OF THE 197 00:09:52,280 --> 00:09:53,400 CONFIRMATION OF THE DIAGNOSIS AT 198 00:09:53,400 --> 00:09:54,640 THE TIME. 199 00:09:54,640 --> 00:09:56,960 BUT IN ANY CASE AT THAT TIME IT 200 00:09:56,960 --> 00:09:58,960 WAS THE DAWN OF THE GENOME 201 00:09:58,960 --> 00:09:59,200 PROJECT. 202 00:09:59,200 --> 00:10:01,840 SO WHEN I WAS THINKING ABOUT 203 00:10:01,840 --> 00:10:03,600 WHAT SORT OF A PROJECT COULD I 204 00:10:03,600 --> 00:10:06,280 DO IN MY FELLOWSHIP ONE IDEA 205 00:10:06,280 --> 00:10:09,720 THAT CAME TO MIND WAS POSSIBLY 206 00:10:09,720 --> 00:10:11,600 THE IDEA OF FINDING THE GENE 207 00:10:11,600 --> 00:10:16,680 THAT IS MU INDICATED. 208 00:10:16,680 --> 00:10:18,280 -- MUTATED. 209 00:10:18,280 --> 00:10:21,240 IT WAS WORKING ON THE SHOULDERS 210 00:10:21,240 --> 00:10:22,600 OF GIANTS. 211 00:10:22,600 --> 00:10:24,360 SO THE FIRST PERSON THAT 212 00:10:24,360 --> 00:10:28,040 RECOGNIZED THAT POLLY MORE 213 00:10:28,040 --> 00:10:33,880 OFISMS IN * DNA WAS THIS GUY 214 00:10:33,880 --> 00:10:36,800 HERE. 215 00:10:36,800 --> 00:10:39,280 YW -- KHAN. 216 00:10:39,280 --> 00:10:45,280 AND HE SHOWED THAT -- IT 217 00:10:45,280 --> 00:10:47,720 CO-SEGREGATED WITH SICKLE-CELL 218 00:10:47,720 --> 00:10:49,920 ANEMIA IN A FAMILY. 219 00:10:49,920 --> 00:10:56,520 SHORTLY THEREAFTER DAVID 220 00:10:56,520 --> 00:10:58,840 BOBSTEIN -- MAYBE WE COULD MAKE 221 00:10:58,840 --> 00:11:02,960 A MAP OF THE HUMAN GENOME BASED 222 00:11:02,960 --> 00:11:13,360 ON DNA POLLY MORPHISMS. 223 00:11:17,480 --> 00:11:19,960 * AND THEN WE HAVE OF COURSE THE 224 00:11:19,960 --> 00:11:23,800 GOOD DR. COLLINS OUR FORMER NIH 225 00:11:23,800 --> 00:11:27,440 DIRECTOR WHO EARLIER IN HIS 226 00:11:27,440 --> 00:11:30,000 CAREER WAS VERY INVOLVED IN AND 227 00:11:30,000 --> 00:11:33,440 A PIONEER IN THIS FIELD OF USING 228 00:11:33,440 --> 00:11:36,840 THE APPROACH OF POSITIONAL 229 00:11:36,840 --> 00:11:39,400 CLONING AS IT WAS CALLED TO 230 00:11:39,400 --> 00:11:41,880 IDENTIFY HUMAN DISEASE GENES AND 231 00:11:41,880 --> 00:11:45,680 THE FIRST TARGET WAS CYSTIC 232 00:11:45,680 --> 00:11:47,080 FIBROSIS WHICH IS A DISORDER 233 00:11:47,080 --> 00:11:51,240 THAT IS ALSO RECESSIVELY 234 00:11:51,240 --> 00:11:53,760 INHERITED. 235 00:11:53,760 --> 00:11:57,520 SO IN ORDER TO EMULATE I MADE A 236 00:11:57,520 --> 00:11:59,280 FIELD TRIP TO ISRAEL AND YOU SEE 237 00:11:59,280 --> 00:12:03,720 ME WITH MY COLLABORATOR VISITING 238 00:12:03,720 --> 00:12:08,680 A FAMILY IN A CITY IN NORTHERN 239 00:12:08,680 --> 00:12:11,000 ISRAEL AND YOU CAN SEE THIS 240 00:12:11,000 --> 00:12:14,200 PHOTO HAS BEEN ALTERED TO MEET 241 00:12:14,200 --> 00:12:16,960 HIPAA REQUIREMENTS SO EVERYBODY 242 00:12:16,960 --> 00:12:18,600 HAS MY FACE THERE. 243 00:12:18,600 --> 00:12:21,560 BUT ANY WAY IT'S A FAMILY IN 244 00:12:21,560 --> 00:12:24,160 WHICH IT WAS SEGREGATING. 245 00:12:24,160 --> 00:12:29,360 THE FATHER AND MOTHER IN THE 246 00:12:29,360 --> 00:12:32,240 FAMILY WERE FIRST COUSINS TO ONE 247 00:12:32,240 --> 00:12:34,560 ANOTHER AND THEN MULTIPLE 248 00:12:34,560 --> 00:12:35,800 MEMBERS OF THE FAMILY. 249 00:12:35,800 --> 00:12:39,200 ALL TOGETHER IN THE SUMMER OF 250 00:12:39,200 --> 00:12:40,920 1989 WE WERE ABLE TO COLLECT 251 00:12:40,920 --> 00:12:43,800 BLOOD SAMPLES FROM 62 FAMILIES 252 00:12:43,800 --> 00:12:46,560 WITH MULTIPLE MEMBERS AND OVER 253 00:12:46,560 --> 00:12:48,800 THE COURSE OF THE NEXT COUPLE OF 254 00:12:48,800 --> 00:12:52,560 YEARS CULMINATING IN A PAPER 255 00:12:52,560 --> 00:12:54,120 PUBLISHED IN THE NEW ENGLAND 256 00:12:54,120 --> 00:12:56,040 JOURNAL OF MEDICINE WE 257 00:12:56,040 --> 00:12:59,680 IDENTIFIED THE CHROMOSOMAL 258 00:12:59,680 --> 00:13:03,160 LOCATION OF THE GENE. 259 00:13:03,160 --> 00:13:06,160 THEN WE BECAME A GENOME PROJECT 260 00:13:06,160 --> 00:13:08,920 FOR THAT AREA OF CHROMOSOME 16 261 00:13:08,920 --> 00:13:12,680 AND WITH COLLABORATORS AROUND 262 00:13:12,680 --> 00:13:14,680 THE WORLD WE WERE ABLE TO 263 00:13:14,680 --> 00:13:16,680 DEVELOP GENETIC MAPS AND THEN 264 00:13:16,680 --> 00:13:20,040 PHYSICAL MAPS AND 265 00:13:20,040 --> 00:13:20,920 TRANSCRIPTIONAL MAPS AND 266 00:13:20,920 --> 00:13:24,440 SEQUENCE DATA FROM THIS REGION 267 00:13:24,440 --> 00:13:26,880 OF CHROMOSOME 16 NARROWING THE 268 00:13:26,880 --> 00:13:30,200 AREA OF INTEREST UNTIL WE GOT 269 00:13:30,200 --> 00:13:38,480 DOWN SYNDROME TO THE DNA. 270 00:13:38,480 --> 00:13:42,680 AND EVENTUALLY WE FOUND THAT IT 271 00:13:42,680 --> 00:13:44,920 WAS THE 10 THE THAT THE WE 272 00:13:44,920 --> 00:13:47,360 LOOKED AT THAT TURNED OUT TO BE 273 00:13:47,360 --> 00:13:50,440 THE GENE HARBORING MUTATIONS 274 00:13:50,440 --> 00:13:53,040 THAT CO-SEGREGATED. 275 00:13:53,040 --> 00:14:00,160 AND WE PROPOSED THE NAME PYRON. 276 00:14:00,160 --> 00:14:02,880 IT WAS A DREAM COME TRUE FOR US 277 00:14:02,880 --> 00:14:04,720 IN THE SENSE THAT IT TURNED OUT 278 00:14:04,720 --> 00:14:07,560 TO BE A GENE THAT HAD NOT BEEN 279 00:14:07,560 --> 00:14:08,880 RECOGNIZED BEFORE. 280 00:14:08,880 --> 00:14:10,160 NOBODY KNEW ANYTHING ABOUT WHAT 281 00:14:10,160 --> 00:14:13,120 IT WAS OR WHAT IT ENCODED BUT 282 00:14:13,120 --> 00:14:16,560 ONCE WE GOT OVER THE ELATION OF 283 00:14:16,560 --> 00:14:19,200 ALL OF THAT WE REALIZED WE HAD 284 00:14:19,200 --> 00:14:21,080 TO FIGURE THAT OUT WHICH WAS NOT 285 00:14:21,080 --> 00:14:23,240 A TRIVIAL MATTER TO SAY THE 286 00:14:23,240 --> 00:14:23,640 LEAST. 287 00:14:23,640 --> 00:14:26,520 ONE OF THE INITIAL CLUES THAT 288 00:14:26,520 --> 00:14:29,280 CAME UP SOON WITHIN A COUPLE OF 289 00:14:29,280 --> 00:14:34,960 YEARS WAS THAT THE END TERMINAL 290 00:14:34,960 --> 00:14:44,920 90 OR SO AMINO ACIDS -- THE 291 00:14:44,920 --> 00:14:46,560 PYRIN DOMAIN. 292 00:14:46,560 --> 00:14:50,000 IT ALLOWS FOR THE FORMATION OF A 293 00:14:50,000 --> 00:14:54,240 CHARGED DIPOL. 294 00:14:54,240 --> 00:14:57,840 AND BASICALLY THROUGH 295 00:14:57,840 --> 00:15:01,000 ELECTROSTATIC INTERACTIONS THE 296 00:15:01,000 --> 00:15:05,160 DOMAIN CAN INTERACT AND THERE 297 00:15:05,160 --> 00:15:08,920 ARE SOME 20 HUMAN PROTEINS. 298 00:15:08,920 --> 00:15:12,720 THAT IN ONE WAY OR ANOTHER HAVE 299 00:15:12,720 --> 00:15:16,560 A PYRIN DOMAIN. 300 00:15:16,560 --> 00:15:17,560 THAT WAS GOOD. 301 00:15:17,560 --> 00:15:20,960 THAT WAS HAPPENING WHILE AT THE 302 00:15:20,960 --> 00:15:22,120 SAME TIME WE WERE CONTINUING TO 303 00:15:22,120 --> 00:15:25,200 SEE PATIENTS BECAUSE AS I SAID 304 00:15:25,200 --> 00:15:28,240 THAT IS ONE OF THE PARAMOUNT 305 00:15:28,240 --> 00:15:29,880 THINGS IS TO CONTINUE TO SEE 306 00:15:29,880 --> 00:15:30,960 PATIENTS. 307 00:15:30,960 --> 00:15:33,400 SO WE WERE REFERRED PATIENTS. 308 00:15:33,400 --> 00:15:36,080 SOME OF THEM WERE SENT TO US 309 00:15:36,080 --> 00:15:43,120 WITH THE QUESTION DO THEY HAVE 310 00:15:43,120 --> 00:15:43,760 FMF. 311 00:15:43,760 --> 00:15:45,920 AND THE ANSWER WAS YES. 312 00:15:45,920 --> 00:15:47,960 BUT THEN WE STARTED TO SEE OTHER 313 00:15:47,960 --> 00:15:49,960 PATIENTS. 314 00:15:49,960 --> 00:15:52,000 THEY DID NOT. 315 00:15:52,000 --> 00:15:53,600 THERE WERE VARIOUS THINGS THAT 316 00:15:53,600 --> 00:15:54,360 DIDN'T FIT. 317 00:15:54,360 --> 00:15:57,000 THEY MAY NOT HAVE HAD MUTATION 318 00:15:57,000 --> 00:15:59,600 IN THE CAUSATIVE GENE. 319 00:15:59,600 --> 00:16:03,480 THEY WERE NOT FROM THE 320 00:16:03,480 --> 00:16:06,240 MIDDLE-EAST OR THE MEDITERRANEAN 321 00:16:06,240 --> 00:16:07,080 AREA. 322 00:16:07,080 --> 00:16:10,160 THE ATTACKS WERE TOO LONG. 323 00:16:10,160 --> 00:16:13,080 NOT RESPONSIVE. 324 00:16:13,080 --> 00:16:14,800 SO IN ANY EVENT OVER THE COURSE 325 00:16:14,800 --> 00:16:19,200 OF A COUPLE OF YEARS -- THEY 326 00:16:19,200 --> 00:16:24,960 WERE ABLE TO TRACK DOWN THE NEXT 327 00:16:24,960 --> 00:16:27,720 PERIODIC FEVER GENE WHICH ENCODE 328 00:16:27,720 --> 00:16:30,960 THE RECEPTOR. 329 00:16:30,960 --> 00:16:33,400 SO AT THAT POINT WE HAD WITHIN A 330 00:16:33,400 --> 00:16:35,520 COUPLE OF YEARS A PERIOD OF TIME 331 00:16:35,520 --> 00:16:37,840 IDENTIFIED A COUPLE OF GENES 332 00:16:37,840 --> 00:16:42,000 THAT WHEN MUTATED LED TO 333 00:16:42,000 --> 00:16:43,440 RECURRENT FAVORS AND 334 00:16:43,440 --> 00:16:44,680 INFLAMMATION BUT IN WHICH THE 335 00:16:44,680 --> 00:16:47,520 PATIENTS DID NOT HAVE AUTO. 336 00:16:47,520 --> 00:16:49,720 BODIES AS ONE WOULD SEE IN THE 337 00:16:49,720 --> 00:16:53,960 CHAT CALL AUTOIMMUNE DISEASES. 338 00:16:53,960 --> 00:16:56,240 MAYBE THIS IS AN EMERGING NEWS 339 00:16:56,240 --> 00:16:59,440 SET OF DISEASES AND WE PROPOSED 340 00:16:59,440 --> 00:17:04,160 THE TERM AUTO INFLAMMATORY. 341 00:17:04,160 --> 00:17:07,240 WHICH WAS TONGUE IN CHEEK BUT 342 00:17:07,240 --> 00:17:08,720 PERHAPS WE THOUGHT THERE WAS 343 00:17:08,720 --> 00:17:10,040 SOMETHING TO IT. 344 00:17:10,040 --> 00:17:12,800 WE PUB LEARNED A PAPER IN WHICH 345 00:17:12,800 --> 00:17:16,360 WE HYPOTHESIZED ON WHAT OTHER 346 00:17:16,360 --> 00:17:20,680 DISEASES MIGHT POSSIBLY BE AUTO 347 00:17:20,680 --> 00:17:23,880 INFLAMMATORY BASED ON CLINICAL 348 00:17:23,880 --> 00:17:27,240 FINDINGS. 349 00:17:27,240 --> 00:17:30,480 AND SO WE CAME ONE THIS 350 00:17:30,480 --> 00:17:32,360 CLASSIFICATION SCHEME THIS 351 00:17:32,360 --> 00:17:33,160 TENTATIVE CLASSIFICATION SCHEME 352 00:17:33,160 --> 00:17:36,360 AND A COUPLE OF DISEASES THAT WE 353 00:17:36,360 --> 00:17:39,000 PROPOSED AS POSSIBLY BEING AUTO 354 00:17:39,000 --> 00:17:41,800 INFLAMMATORY FELL INTO THIS 355 00:17:41,800 --> 00:17:42,440 CATEGORY. 356 00:17:42,440 --> 00:17:46,960 THESE WERE DISEASES IN WHICH 357 00:17:46,960 --> 00:17:50,120 PATIENTS WOULD HAVE AN INHERITED 358 00:17:50,120 --> 00:17:53,800 CONDITION IN THESE TWO CASES 359 00:17:53,800 --> 00:17:56,720 WHERE ON VARIOUS EXPOSURES OR 360 00:17:56,720 --> 00:17:59,920 SOMETIMES NOT WITH EXPOSURES 361 00:17:59,920 --> 00:18:04,880 THEY COULD DEVELOP FEVERS AND 362 00:18:04,880 --> 00:18:06,040 BREAK OUT IN HIVES. 363 00:18:06,040 --> 00:18:08,120 AND WITHIN A YEAR OF THAT AND 364 00:18:08,120 --> 00:18:10,400 THIS IS WHERE IT'S FACT STRANGER 365 00:18:10,400 --> 00:18:12,640 THAN FICTION INDEED THERE 366 00:18:12,640 --> 00:18:18,200 APPEARED IN NATURE GENETICS THIS 367 00:18:18,200 --> 00:18:22,440 PAPER AND THEY HAD IDENTIFIED 368 00:18:22,440 --> 00:18:29,120 THE GENE THAT IS M MUTATED. 369 00:18:29,120 --> 00:18:36,440 AND THE GENE TURNS OUT TO HAVE A 370 00:18:36,440 --> 00:18:37,320 PYRIN DOMAIN. 371 00:18:37,320 --> 00:18:43,000 WE HAD SOMETHING THAT GAVE US A 372 00:18:43,000 --> 00:18:43,800 CLUE. 373 00:18:43,800 --> 00:18:46,320 A COMMON THEME THAT WAS TYING 374 00:18:46,320 --> 00:18:47,320 TOGETHER SOME OF THE DISEASES 375 00:18:47,320 --> 00:18:50,560 THAT WE HAD PROPOSED AS BEING 376 00:18:50,560 --> 00:18:52,920 AUTO INFLAMMATORY. 377 00:18:52,920 --> 00:18:55,160 IN ANY CASE AT THE SAME TIME 378 00:18:55,160 --> 00:18:57,280 THAT THAT WAS GOING ON AS IF 379 00:18:57,280 --> 00:18:59,320 THIS WAS NOT ALREADY INCREDIBLE 380 00:18:59,320 --> 00:19:02,520 ENOUGH THERE WAS THIS GUY OVER 381 00:19:02,520 --> 00:19:05,720 IN SWITZERLAND WHO HAS PASSED 382 00:19:05,720 --> 00:19:06,360 AWAY. 383 00:19:06,360 --> 00:19:10,760 WHO WAS STUDYING THE ACTIVATION. 384 00:19:10,760 --> 00:19:15,720 AND HE HAD IDENTIFIED THIS MACRO 385 00:19:15,720 --> 00:19:19,240 MOLECULAR COMPLEX -- IT WAS 386 00:19:19,240 --> 00:19:21,840 RESPONSIBLE FOR ACTIVATION. 387 00:19:21,840 --> 00:19:25,840 A MAJOR MEDIATOR OF FAVOR AND 388 00:19:25,840 --> 00:19:27,280 INFLAMMATION * AND THE THING 389 00:19:27,280 --> 00:19:28,880 THAT WAS INTERESTING IS THAT ONE 390 00:19:28,880 --> 00:19:33,880 OF THE HALL COOLS TURNED OUT TO 391 00:19:33,880 --> 00:19:40,080 BE NRLP3 WHICH IS THE SAME 392 00:19:40,080 --> 00:19:44,640 MOLECULE THAT WAS FOUND MUTATED. 393 00:19:44,640 --> 00:19:50,760 WE HAD THE CONNECTION WITH 394 00:19:50,760 --> 00:19:52,920 PYRIN. 395 00:19:52,920 --> 00:19:56,240 THE INFLAMMASOME CONNECTION AS 396 00:19:56,240 --> 00:19:56,640 WELL. 397 00:19:56,640 --> 00:19:59,520 THAT COULD GIVE US AN IDEA AS TO 398 00:19:59,520 --> 00:20:02,640 WHAT WAS GOING ON BIOLOGICALLY. 399 00:20:02,640 --> 00:20:07,520 AND JUST FOR YOUR EDUCATION WHY 400 00:20:07,520 --> 00:20:10,760 DON'T WE LOOK AT WHAT COULD BE * 401 00:20:10,760 --> 00:20:15,200 HAPPENING AND THIS WAS A MOVIE 402 00:20:15,200 --> 00:20:25,800 MADE THAT ILLUSTRATES THE NL -- 403 00:20:36,280 --> 00:20:43,560 NLRP3 INFLAMMASOME. 404 00:20:43,560 --> 00:20:46,080 IT CAN INTERACT. 405 00:20:46,080 --> 00:20:50,160 HERE YOU SEE IT GETTING 406 00:20:50,160 --> 00:20:51,000 ACTIVATED. 407 00:20:51,000 --> 00:20:54,400 VARIOUS BACTERIAL TOXINS OR 408 00:20:54,400 --> 00:20:57,000 STRESS FACTORS CAN ACTIVATE IT 409 00:20:57,000 --> 00:20:59,320 AND NOW YOU SEE THAT IT'S 410 00:20:59,320 --> 00:20:59,760 ACTIVATED. 411 00:20:59,760 --> 00:21:03,920 WE ARE HAVING INTERACTIONS AMONG 412 00:21:03,920 --> 00:21:08,040 THE DOMAINS AND YOU SEE A DISK 413 00:21:08,040 --> 00:21:09,440 FORMING AS A RESULT. 414 00:21:09,440 --> 00:21:11,880 AND WE'RE LOOKING AT IT FIRST 415 00:21:11,880 --> 00:21:14,000 FROM A TOP VIEW AND THEN WE'LL 416 00:21:14,000 --> 00:21:18,840 LOOK AT IT FROM A SIDE VIEW AND 417 00:21:18,840 --> 00:21:20,960 YOU'LL SEE NOW THAT ANOTHER 418 00:21:20,960 --> 00:21:24,720 MOLECULE THAT IS CALLED ASC THAT 419 00:21:24,720 --> 00:21:26,920 ALSO HAS A DOMAIN. 420 00:21:26,920 --> 00:21:29,560 AND YOU SEE THAT WE'RE FORMING 421 00:21:29,560 --> 00:21:35,400 FILAMENTS HERE BASICALLY CAUSED 422 00:21:35,400 --> 00:21:41,520 BY THE DOMAIN INTERACTIONS. 423 00:21:41,520 --> 00:21:44,480 AND THEN INTERACTIONS OF DOMAINS 424 00:21:44,480 --> 00:21:47,920 AMONG THE ASC MOLECULES AND THEN 425 00:21:47,920 --> 00:21:50,480 STICKING OUT ARE THESE BROWN 426 00:21:50,480 --> 00:21:52,600 DOMAINS WHICH ARE CALLED CARD 427 00:21:52,600 --> 00:21:54,200 DOMAINS WHICH HAVE A SIMILAR 428 00:21:54,200 --> 00:21:54,800 STRUCTURE. 429 00:21:54,800 --> 00:21:57,960 AND AND ALLOW FOR 430 00:21:57,960 --> 00:21:59,960 SELF-INTERACTIONS THAT ARE NOW 431 00:21:59,960 --> 00:22:02,160 DECORATING THESE FILLMEANT. 432 00:22:02,160 --> 00:22:05,200 YOU HAVE MOLECULES WHICH ARE 433 00:22:05,200 --> 00:22:08,240 THEN ABLE TO ACTIVATE INTEREST 434 00:22:08,240 --> 00:22:14,800 LUC IN ONE AND 18 TWO MAJOR 435 00:22:14,800 --> 00:22:18,600 INFLAMMATORY CYTOKINES. 436 00:22:18,600 --> 00:22:20,720 AND THEN THE FRAGMENTS GOING OFF 437 00:22:20,720 --> 00:22:26,320 AND NOW WE HAVE ANOTHER MOLECULE 438 00:22:26,320 --> 00:22:30,600 AND YOU SEE THE FRAGMENTS 439 00:22:30,600 --> 00:22:32,320 FLOATING OFF AND WE'LL SEE THEM 440 00:22:32,320 --> 00:22:34,320 IN A COUPLE OF MINUTES DOING 441 00:22:34,320 --> 00:22:36,200 WHAT THEY DO WELL WHICH IS TO 442 00:22:36,200 --> 00:22:37,520 BLOW UP THE CELL. 443 00:22:37,520 --> 00:22:41,720 SO NOW WE'RE GOING TO SEE THE 444 00:22:41,720 --> 00:22:43,280 INFLAMMASOME FADE OFF INTO THE 445 00:22:43,280 --> 00:22:48,480 SUN SET AND WE'LL FOCUS US ON 446 00:22:48,480 --> 00:22:50,520 THE D MOLECULES. 447 00:22:50,520 --> 00:22:54,720 THEY WILL FORM RINGS ESSENTIALLY 448 00:22:54,720 --> 00:22:56,920 WHICH CAN BE INSERTED IN THE 449 00:22:56,920 --> 00:23:00,320 CELL MEMBRANE FORMING PORES THAT 450 00:23:00,320 --> 00:23:03,640 DISRUPT THE GRADIENT IN THESE 451 00:23:03,640 --> 00:23:05,200 WHITE BLOOD CELLS AND LEAD TO 452 00:23:05,200 --> 00:23:09,000 THE -- OF THE WHITE BLOOD CELL 453 00:23:09,000 --> 00:23:13,400 AND THE RELEASE AND BASICALLY 454 00:23:13,400 --> 00:23:15,680 LEADING TO INFLAMMATION. 455 00:23:15,680 --> 00:23:18,120 SO, THAT IS THE CONCEPT OF HOW 456 00:23:18,120 --> 00:23:19,120 THIS WORKS. 457 00:23:19,120 --> 00:23:22,680 NOW SINCE WE KNEW THIS AT THAT 458 00:23:22,680 --> 00:23:25,000 POINT THEN ONE COULD SAY WELL 459 00:23:25,000 --> 00:23:27,760 ONE OUGHT TO BE ABLE TO TREAT 460 00:23:27,760 --> 00:23:30,960 PATIENTS WITH THIS MUTATION WITH 461 00:23:30,960 --> 00:23:37,160 AN INHIBITOR AND RAFAEL CAME UP 462 00:23:37,160 --> 00:23:39,840 WITH THE IDEA OF TREATING A 463 00:23:39,840 --> 00:23:41,960 COHORT OF 18 PATIENTS THAT WE 464 00:23:41,960 --> 00:23:45,160 HAD WITH THE MOST SEVERE FORM OF 465 00:23:45,160 --> 00:23:48,240 DISEASE CAUSED BY MUTATIONS. 466 00:23:48,240 --> 00:23:52,920 A DISEASE CALLED NOMAD. 467 00:23:52,920 --> 00:23:55,160 AND THIS IS A DISORDER WHERE NOT 468 00:23:55,160 --> 00:23:58,640 ONLY DO THE PATIENTS HAVE FAVORS 469 00:23:58,640 --> 00:24:03,240 AND-S BUT THEY HAVE A SEPTIC 470 00:24:03,240 --> 00:24:08,640 MENINGITIS. 471 00:24:08,640 --> 00:24:12,640 AND SO THIS IS A PAPER THAT WAS 472 00:24:12,640 --> 00:24:15,120 PUBLISHED BACK IN 2006 THE 473 00:24:15,120 --> 00:24:16,600 BEFORE AND AFTER. 474 00:24:16,600 --> 00:24:23,240 YOU CAN SEE THE-S AND RASH, THE 475 00:24:23,240 --> 00:24:26,840 WHITE REPRESENTS THE MENINGITIS. 476 00:24:26,840 --> 00:24:29,880 ON DAILY INJECTIONS YOU CAN SEE 477 00:24:29,880 --> 00:24:34,200 THAT THE-S GO AWAY. 478 00:24:34,200 --> 00:24:36,200 CONJUNCTIVITIS GOES AWAY WITHIN 479 00:24:36,200 --> 00:24:38,920 TWO OR THREE MONTHS. 480 00:24:38,920 --> 00:24:49,800 THE MEN E-- MENINGITIS GOES AWA. 481 00:24:54,680 --> 00:24:57,240 SOME OF THEM ARE NOW GRADUATING 482 00:24:57,240 --> 00:25:00,160 FROM COLLEGE WHEREAS THE 483 00:25:00,160 --> 00:25:01,480 PROGNOSIS WOULD HAD BEEN BLEAK 484 00:25:01,480 --> 00:25:04,040 HAD THEY NOT BE TREATED. 485 00:25:04,040 --> 00:25:06,880 SO WE HAVE THEN THIS CONCEPT OF 486 00:25:06,880 --> 00:25:09,120 AUTO INFLAMMATION WITH TWO 487 00:25:09,120 --> 00:25:11,280 FLAVORS OF IMMUNITY. 488 00:25:11,280 --> 00:25:21,800 ADAPTIVE IMMUNITY AND AUTOIMMUNE 489 00:25:24,000 --> 00:25:26,800 DISEASES. 490 00:25:26,800 --> 00:25:30,200 THE INNATE IMMUNE SYSTEM IS A 491 00:25:30,200 --> 00:25:36,360 MORE PRIMITIVE BRANCH -- THE 492 00:25:36,360 --> 00:25:38,800 RECEPTORS ARE HARDWIRED AND THE 493 00:25:38,800 --> 00:25:42,120 AUTO INFLAMMATORY DISEASES ARE 494 00:25:42,120 --> 00:25:46,640 CHARACTERIZED BY UNPROVOKED 495 00:25:46,640 --> 00:25:49,280 INFLAMMATION. 496 00:25:49,280 --> 00:25:51,720 SO LET'S GO BACK FOR A BRIEF 497 00:25:51,720 --> 00:25:56,240 MOMENT TO TALK ABOUT THE PYRIN 498 00:25:56,240 --> 00:25:57,360 INFLAMMASOME. 499 00:25:57,360 --> 00:26:02,000 IT ALSO ACTIVATES AISLE 1 AND 500 00:26:02,000 --> 00:26:02,760 I'LL 18. 501 00:26:02,760 --> 00:26:05,240 BUT IT'S REGULATED IN A VERY 502 00:26:05,240 --> 00:26:07,120 INTERESTING WAY. 503 00:26:07,120 --> 00:26:10,880 IT IS REGULATED BY A MOLECULE 504 00:26:10,880 --> 00:26:13,240 CALLED ROW A WHICH LIVES ON THE 505 00:26:13,240 --> 00:26:16,040 INSIDE OF THE CELL MEMBRANE. 506 00:26:16,040 --> 00:26:18,040 AND ORDINARILY IT CAN TRIGGER 507 00:26:18,040 --> 00:26:24,800 THE ACTIVATION OF PKN. 508 00:26:24,800 --> 00:26:27,560 THAT LEADS TO INHIBITORY 509 00:26:27,560 --> 00:26:37,520 PROTEINS BINDING TO PIE RING. 510 00:26:37,520 --> 00:26:39,680 HOWEVER CERTAIN BACTERIA MAYBE 511 00:26:39,680 --> 00:26:41,360 TO BE INS. 512 00:26:41,360 --> 00:26:43,800 THEY DO THAT BECAUSE ROW A 513 00:26:43,800 --> 00:26:48,520 ACTUALLY IS VERY IMPORTANT IN 514 00:26:48,520 --> 00:26:51,440 THE ORGANIZATION OF THE 515 00:26:51,440 --> 00:26:54,320 CYTOSKELETON. 516 00:26:54,320 --> 00:26:57,720 AND SO, ITS A STRATEGY THAT 517 00:26:57,720 --> 00:27:00,040 BACTERIA USE TO IN ACTIVATE 518 00:27:00,040 --> 00:27:02,480 WHITE BLOOD CELLS. 519 00:27:02,480 --> 00:27:06,000 TO IN ACTIVATE ROW A BUT THAT 520 00:27:06,000 --> 00:27:08,560 THEN LEADS TO LESS INFORMATION 521 00:27:08,560 --> 00:27:11,840 FOR LACKS OF PYRIN AND * AND 522 00:27:11,840 --> 00:27:12,440 ACTIVATION. 523 00:27:12,440 --> 00:27:21,560 SO THE PYRIN INFLAMMASOME DOES 524 00:27:21,560 --> 00:27:24,160 NOT BIND TO THOSE TO BE INS. 525 00:27:24,160 --> 00:27:26,960 IT'S RESPONDING TO PHYSIOLOGICAL 526 00:27:26,960 --> 00:27:29,560 CHANGES IN THE CELL THAT ARE 527 00:27:29,560 --> 00:27:34,120 INDUCED BY BACTERIAL TOXINS. 528 00:27:34,120 --> 00:27:38,840 AND THE PYRIN INFLAMMASOME WAS 529 00:27:38,840 --> 00:27:41,720 ONE OF THE EARLY EXAMPLES OF HOW 530 00:27:41,720 --> 00:27:44,240 WE HUMANS ARE LIKE PLANTS. 531 00:27:44,240 --> 00:27:46,720 IF YOU LOOK AT THESE SITES IF 532 00:27:46,720 --> 00:27:50,480 YOU HAVE MUTATIONS BASICALLY YOU 533 00:27:50,480 --> 00:27:55,280 GET A DISEASE CALLED PAAND. 534 00:27:55,280 --> 00:27:59,880 WHICH LEADS TO A CONTINUOUS FORM 535 00:27:59,880 --> 00:28:02,720 OF DETERMINES TO US. 536 00:28:02,720 --> 00:28:03,560 *. 537 00:28:03,560 --> 00:28:05,600 WE WERE ALSO INTERESTED IN WHY 538 00:28:05,600 --> 00:28:08,200 THERE WAS SUCH A HIGH CARRIER 539 00:28:08,200 --> 00:28:11,280 FREQUENCY OF FMF MUTATIONS IN 540 00:28:11,280 --> 00:28:13,120 MIDDLE EASTERN POPULATIONS. 541 00:28:13,120 --> 00:28:15,880 SO LOOKING AT THE SIZE OF THE 542 00:28:15,880 --> 00:28:18,240 DNA FINGERPRINT ASSOCIATED 543 00:28:18,240 --> 00:28:20,880 EITHER WITH THE MUTANT VERSION 544 00:28:20,880 --> 00:28:23,280 OF THE GENE THAT IS SHOWN IN 545 00:28:23,280 --> 00:28:26,200 BLUE HERE OR THE WILD TYPE SHOWN 546 00:28:26,200 --> 00:28:27,480 IN ORANGE. 547 00:28:27,480 --> 00:28:30,520 WHAT YOU CAN SEE IS THE EXTENT 548 00:28:30,520 --> 00:28:35,800 OF THAT DNA FINGERPRINT IS MUCH 549 00:28:35,800 --> 00:28:36,240 BROADER. 550 00:28:36,240 --> 00:28:38,560 THAT IS SOMETHING THAT YOU SEE 551 00:28:38,560 --> 00:28:40,560 WHEN A MUTATION IS UNDER 552 00:28:40,560 --> 00:28:42,200 SELECTION AND WHAT YOU WOULD 553 00:28:42,200 --> 00:28:48,760 EXPECT THEN WOULD BE THAT THE 554 00:28:48,760 --> 00:28:50,320 SIZE OF THE ASSOCIATED 555 00:28:50,320 --> 00:28:52,200 FINGERPRINT WOULD BE AT THE END 556 00:28:52,200 --> 00:28:55,720 OF THE BELL CURVE FOR OTHER 557 00:28:55,720 --> 00:28:57,960 GENES THAT HAVE A SIMILAR 558 00:28:57,960 --> 00:28:58,360 FREQUENCY. 559 00:28:58,360 --> 00:29:00,520 OTHER MUTATIONS THAT HAVE A 560 00:29:00,520 --> 00:29:03,120 SIMILAR FREQUENCY AND SURE 561 00:29:03,120 --> 00:29:04,320 ENOUGH IT IS. 562 00:29:04,320 --> 00:29:06,720 WITH THAT ONE CAN CALCULATE WHAT 563 00:29:06,720 --> 00:29:09,360 WOULD BE THE SELECTION CO-E 564 00:29:09,360 --> 00:29:11,320 FISHES. 565 00:29:11,320 --> 00:29:14,000 * * IT'S QUITE HIGH. 566 00:29:14,000 --> 00:29:17,000 HIGHER THAN THE SELECTION 567 00:29:17,000 --> 00:29:26,640 COEFFICIENT. 568 00:29:26,640 --> 00:29:28,720 SO THIS IS DEFINITELY SOMETHING 569 00:29:28,720 --> 00:29:30,440 THAT HAS BEEN UNDER SELECTION IN 570 00:29:30,440 --> 00:29:33,400 THE MIDDLE-EAST AND ONE CAN USE 571 00:29:33,400 --> 00:29:36,040 THESE ANALYSIS TO ESTIMATE THE 572 00:29:36,040 --> 00:29:38,600 AGE OF THE MUTATION AND THAT IS 573 00:29:38,600 --> 00:29:41,240 SOMETHING WHERE BETWEEN TWO AND 574 00:29:41,240 --> 00:29:42,720 FIVE THOUSAND YEARS THAT THIS 575 00:29:42,720 --> 00:29:45,360 PARTICULAR MUTATION AROSE IN THE 576 00:29:45,360 --> 00:29:46,880 MIDDLE-EAST. 577 00:29:46,880 --> 00:29:48,400 BIBLICAL TIMES. 578 00:29:48,400 --> 00:29:49,640 WHAT COULD HAD BEEN SELECTING 579 00:29:49,640 --> 00:29:53,320 FOR THESE HIGH CARRIER 580 00:29:53,320 --> 00:29:53,800 FREQUENCIES. 581 00:29:53,800 --> 00:29:59,560 ONE OF THE POSSIBILITIES IS YOUR 582 00:29:59,560 --> 00:30:04,080 -- THE ORGANISM THAT CAUSES 583 00:30:04,080 --> 00:30:06,240 BUBONIC PLAGUE. 584 00:30:06,240 --> 00:30:10,640 IT MAKES A TOXIN THAT LEADS TO 585 00:30:10,640 --> 00:30:12,320 THE INFORMATION FOR LACKS OF 586 00:30:12,320 --> 00:30:14,800 PYRIN. 587 00:30:14,800 --> 00:30:19,640 BLOCKING. 588 00:30:19,640 --> 00:30:22,280 IT IS RELATIVELY RESISTANT TO 589 00:30:22,280 --> 00:30:25,520 THAT. 590 00:30:25,520 --> 00:30:28,240 BUT EVEN THE CARRIERS ARE ALSO 591 00:30:28,240 --> 00:30:30,640 RESISTANT TO IT WHICH THEN 592 00:30:30,640 --> 00:30:33,040 EXPLAINS THE SELECTION. 593 00:30:33,040 --> 00:30:36,280 WELL, IN ANY CASE WHY DON'T WE 594 00:30:36,280 --> 00:30:37,840 MOVE ON TO SOME OF THE OTHER 595 00:30:37,840 --> 00:30:39,160 DISEASES THAT WE'VE BEEN 596 00:30:39,160 --> 00:30:40,280 INTERESTED IN OVER THE YEARS AND 597 00:30:40,280 --> 00:30:46,320 THIS GRAPH SIMPLY TELLS US 598 00:30:46,320 --> 00:30:50,320 AROUND 2007 THE COST OF DNA 599 00:30:50,320 --> 00:30:52,400 SEQUENCING DROPPED WITH THE 600 00:30:52,400 --> 00:30:53,840 NexGen SEQUENCING 601 00:30:53,840 --> 00:30:54,160 REVOLUTION. 602 00:30:54,160 --> 00:30:56,400 YOU CAN SEE THE COST RELATIVE TO 603 00:30:56,400 --> 00:30:58,160 THE COST OF COMPUTING. 604 00:30:58,160 --> 00:31:03,880 AND THEY WERE IN PARALLEL UP TO 605 00:31:03,880 --> 00:31:06,200 ROUND 2007 AND THEN SEQUENCING 606 00:31:06,200 --> 00:31:08,480 BECAME MUCH LESS EXPENSIVE. 607 00:31:08,480 --> 00:31:11,880 SO IT ALLOWED FOR DNA SEQUENCING 608 00:31:11,880 --> 00:31:14,560 TO BE USED IN MANY RESEARCH 609 00:31:14,560 --> 00:31:16,000 SETTINGS AND ONE THAT I WILL 610 00:31:16,000 --> 00:31:18,920 TELL YOU ABOUT IS THE STORY OF A 611 00:31:18,920 --> 00:31:21,440 LITTLE GIRL FROM NEW JERSEY WHO 612 00:31:21,440 --> 00:31:23,440 WAS REFERRED TO US AT THE SAGE 613 00:31:23,440 --> 00:31:24,240 OF 2. 614 00:31:24,240 --> 00:31:26,600 AT THAT POINT SHE HAD ALREADY 615 00:31:26,600 --> 00:31:34,080 HAD RECURRENT FEVERS AND THEN A 616 00:31:34,080 --> 00:31:36,240 CATASTROPHIC NEUROLOGICAL EVENT 617 00:31:36,240 --> 00:31:41,200 MAYBE THIS WAS NOMAD AND CAUSED 618 00:31:41,200 --> 00:31:47,280 MEMENINGITIS. 619 00:31:47,280 --> 00:31:51,520 TURNED OUT THE PATIENT DID NOT 620 00:31:51,520 --> 00:31:53,000 HAVE THIS. 621 00:31:53,000 --> 00:31:55,560 INSTEAD HAD MULTIPLE SMALL 622 00:31:55,560 --> 00:32:02,360 STROKES IN THE DEEP BRAIN NUCLEI 623 00:32:02,360 --> 00:32:07,520 FOR WHICH WE DID NOT HAVE AN 624 00:32:07,520 --> 00:32:08,680 EXPLANATION. 625 00:32:08,680 --> 00:32:11,040 THEN ABOUT 10 YEARS LATER 626 00:32:11,040 --> 00:32:13,360 ACTUALLY THROUGH THE UNDIAGNOSED 627 00:32:13,360 --> 00:32:15,200 DISEASES PROGRAM WE HEARD ABOUT 628 00:32:15,200 --> 00:32:18,040 A LITTLE GIRL FROM TEXAS WHO WAS 629 00:32:18,040 --> 00:32:19,400 SIX YEARS OLD AND OVER THE 630 00:32:19,400 --> 00:32:21,840 COURSE OF HER SIX YEARS OF LIFE 631 00:32:21,840 --> 00:32:24,600 SHE HAD NOT ONLY RECURRENT 632 00:32:24,600 --> 00:32:26,120 FEVERS BUT SIX STROKES. 633 00:32:26,120 --> 00:32:28,360 IN THE SAME DISTRIBUTION AS THE 634 00:32:28,360 --> 00:32:29,560 LITTLE GIRL FROM NEW JERSEY. 635 00:32:29,560 --> 00:32:35,840 MAYBE IF WE DID SEQUENCING THAT 636 00:32:35,840 --> 00:32:38,320 MAYBE WE COULD FIND SOMETHING IN 637 00:32:38,320 --> 00:32:40,080 COMMON AND I WOULDN'T BE TELLING 638 00:32:40,080 --> 00:32:43,120 YOU THIS STORY IF WE HADN'T. 639 00:32:43,120 --> 00:32:45,080 WE DEFINED SOMETHING IN COMMON 640 00:32:45,080 --> 00:32:50,080 BASED ON RECESSIVE MODEL OF 641 00:32:50,080 --> 00:32:50,600 INHERITANCE. 642 00:32:50,600 --> 00:32:55,920 THERE WAS A GENE CALLED CECR1. 643 00:32:55,920 --> 00:33:00,960 NOW WE CALL IT -- TYPE 2 WHICH 644 00:33:00,960 --> 00:33:02,880 WAS MU INDICATED IN BOTH OF 645 00:33:02,880 --> 00:33:05,080 THESE CHILDREN AND THEN WE FOUND 646 00:33:05,080 --> 00:33:09,920 OTHER CHILDREN AS WELL WHO HAD 647 00:33:09,920 --> 00:33:12,960 EITHER THE SAME OR OTHER 648 00:33:12,960 --> 00:33:14,240 MUTATIONS IN THIS GENE. 649 00:33:14,240 --> 00:33:19,440 AND SO WE PROPOSED THE NAME 650 00:33:19,440 --> 00:33:29,920 DEFICIENCY -- IT IS MUTATED IN 651 00:33:30,800 --> 00:33:33,600 SEVERE DISEASE. 652 00:33:33,600 --> 00:33:35,720 ADA2 ALSO DOES HAVE SOME 653 00:33:35,720 --> 00:33:39,800 ACTIVITY IN TERMS OF CATALYZING 654 00:33:39,800 --> 00:33:40,440 AVERSION. 655 00:33:40,440 --> 00:33:43,200 BUT IT IS AN EXTRA CELLULAR 656 00:33:43,200 --> 00:33:45,880 PROTEIN AND HAS A ROLE IN BOTH 657 00:33:45,880 --> 00:33:51,160 AS A GROWTH FACTOR AS WELL AS 658 00:33:51,160 --> 00:33:54,680 FOR -- ENDOTHELIAL CELLS. 659 00:33:54,680 --> 00:33:56,880 THIS IS THE PAPER IN WHICH WE 660 00:33:56,880 --> 00:33:58,480 REPORTED AND YOU CAN SEE THE 661 00:33:58,480 --> 00:34:00,400 SMALL STROKES THAT SOME OF THESE 662 00:34:00,400 --> 00:34:01,800 PATIENTS HAD. 663 00:34:01,800 --> 00:34:06,280 THIS WAS A HEMORRHAGIC STROKE. 664 00:34:06,280 --> 00:34:08,960 THIS IS WHAT THE PATIENTS CAN 665 00:34:08,960 --> 00:34:11,360 HAVE AND IT SHOULD RAISE THE 666 00:34:11,360 --> 00:34:14,440 QUESTION OF WHETHER IT'S 667 00:34:14,440 --> 00:34:17,320 DEFICIENCY OF ADA2 AND SOME 668 00:34:17,320 --> 00:34:20,840 PATIENTS CAN ALSO DEVELOP -- A 669 00:34:20,840 --> 00:34:26,240 LESION OF THE EXTERNAL EAR. 670 00:34:26,240 --> 00:34:30,200 THIS GRAPH JUST SHOWS THE VERY 671 00:34:30,200 --> 00:34:31,880 LOW LEVELS IN THE BLOOD IN 672 00:34:31,880 --> 00:34:34,760 PATIENTS COMPARED WITH THEIR 673 00:34:34,760 --> 00:34:38,960 UNAFFECTED PARENTS, CARRIER 674 00:34:38,960 --> 00:34:41,040 PARENTS. 675 00:34:41,040 --> 00:34:43,240 THIS PRESENTED US WITH A SIMILAR 676 00:34:43,240 --> 00:34:46,240 KIND OF PROBLEM TO WHAT WE HAD 677 00:34:46,240 --> 00:34:48,880 WITH NOMAD AND THAT WAS A COHORT 678 00:34:48,880 --> 00:34:51,640 OF PATIENTS WITH THIS NEWLY 679 00:34:51,640 --> 00:34:53,200 DISCOVERED DISEASE BUT NOT A 680 00:34:53,200 --> 00:34:55,080 GOOD WAY OF TREATING IT BECAUSE 681 00:34:55,080 --> 00:34:57,560 IT TURNED OUT THAT THE PATIENTS 682 00:34:57,560 --> 00:34:59,560 THAT WERE REFERRED TO US WERE 683 00:34:59,560 --> 00:35:02,800 CONTINUING TO HAVE STROKES AT 684 00:35:02,800 --> 00:35:06,640 ABOUT A FREQUENCY OF MAYBE ONCE 685 00:35:06,640 --> 00:35:08,600 EVERY THREE YEARS OR SO ON THE 686 00:35:08,600 --> 00:35:09,360 AVERAGE. 687 00:35:09,360 --> 00:35:11,280 AND THESE PATIENTS HAD BEEN 688 00:35:11,280 --> 00:35:15,160 TREATED WITH MANY DIFFERENT 689 00:35:15,160 --> 00:35:20,400 IMMUNE KNOW SUPPRESSANT AGENTS 690 00:35:20,400 --> 00:35:21,800 WITHOUT AVAIL. 691 00:35:21,800 --> 00:35:27,120 ONE WAS THE FACT THAT WE SAW TNF 692 00:35:27,120 --> 00:35:31,080 ON SKIN BIOPSIES IN THE PERRY 693 00:35:31,080 --> 00:35:34,640 VASCULAR AREAS AND * AND A 694 00:35:34,640 --> 00:35:38,280 COLLEAGUE IN ISRAEL WHO HAD A 695 00:35:38,280 --> 00:35:43,640 PATIENT HAD TREATED THE PATIENT 696 00:35:43,640 --> 00:35:46,680 WITH BENEFICIAL RESULTS. 697 00:35:46,680 --> 00:35:49,360 SO WE STARTED TREATING OUR 698 00:35:49,360 --> 00:35:52,280 PATIENTS WITH TNF INHIBITORS IN 699 00:35:52,280 --> 00:35:54,920 THE HOPES THAT MAYBE WE COULD DO 700 00:35:54,920 --> 00:35:56,760 SOMETHING FOR THEM. 701 00:35:56,760 --> 00:35:59,040 AND THESE ARE THE RESULTS. 702 00:35:59,040 --> 00:36:04,240 THEY DID MARKETLY IMPROVE ON TNF 703 00:36:04,240 --> 00:36:04,840 INHIBITORS. 704 00:36:04,840 --> 00:36:12,880 BEFORE THEY HAD HAD 55 STROKES. 705 00:36:12,880 --> 00:36:16,920 AFTER GOING ON THE INHIBITORS WE 706 00:36:16,920 --> 00:36:18,520 HAD 700 PATIENT OBSERVATIONS AND 707 00:36:18,520 --> 00:36:21,800 THE NUMBER OF STROKES WAS ZERO. 708 00:36:21,800 --> 00:36:27,520 SO TNF INHIBITION IS VERY 709 00:36:27,520 --> 00:36:29,080 BENEFICIAL IN PREVENTING THE 710 00:36:29,080 --> 00:36:35,960 STROKES. 711 00:36:35,960 --> 00:36:39,080 IT HAS BEEN DRAMATIC IN ITS 712 00:36:39,080 --> 00:36:41,680 EFFECT ON THE PROGNOSIS OF THIS 713 00:36:41,680 --> 00:36:43,280 CONDITION. 714 00:36:43,280 --> 00:36:48,200 JUST A FEW OTHER HAVE I NETS OF 715 00:36:48,200 --> 00:36:50,440 MONOGENIC * DISEASES THAT WE'VE 716 00:36:50,440 --> 00:36:52,760 WORKED ON OVER THE LAST SEVERAL 717 00:36:52,760 --> 00:36:54,160 YEARS. 718 00:36:54,160 --> 00:36:56,680 BEING THE BENEFICIARIES OF THIS 719 00:36:56,680 --> 00:36:57,800 NexGen SEQUENCING 720 00:36:57,800 --> 00:36:58,440 REVOLUTION. 721 00:36:58,440 --> 00:37:00,480 ONE OF THE DISEASES IS A 722 00:37:00,480 --> 00:37:03,000 DISORDER IN WHICH PATIENTS HAVE 723 00:37:03,000 --> 00:37:09,960 MU MUTATIONS IN A SIGNALING 724 00:37:09,960 --> 00:37:16,280 MOLECULE CALLED RIP K1. 725 00:37:16,280 --> 00:37:18,880 AGAIN WE'RE -- YOU CAN ACCUSE US 726 00:37:18,880 --> 00:37:22,160 OF BEING SLOW OR VERY PERSISTENT 727 00:37:22,160 --> 00:37:26,440 BUT IN ANY CASE WE DID FIND 728 00:37:26,440 --> 00:37:30,440 DOMINANT INHERITANCE OF A 729 00:37:30,440 --> 00:37:31,760 MUTATION IN THIS THREE 730 00:37:31,760 --> 00:37:33,360 GENERATION FAMILY AND THEN A 731 00:37:33,360 --> 00:37:36,240 COUPLE OF -- MUTATIONS IN THESE 732 00:37:36,240 --> 00:37:37,600 OTHER TWO FAMILIES. 733 00:37:37,600 --> 00:37:41,680 AND THESE PATIENTS CLINICALLY 734 00:37:41,680 --> 00:37:47,400 HAVE DIFFUSED PAINFUL -- AND 735 00:37:47,400 --> 00:37:52,880 ORGAN MEGALY. 736 00:37:52,880 --> 00:37:57,280 324 OF THIS MOLECULE THAT IS A 737 00:37:57,280 --> 00:38:00,240 PRO INFLAMMATORY MOLECULE THAT 738 00:38:00,240 --> 00:38:02,640 IS CALLED RIP K1. 739 00:38:02,640 --> 00:38:07,360 IT WOULD ORDINARILY BE CLEVED. 740 00:38:07,360 --> 00:38:09,600 AND THIS IS ONE WAY THAT THE 741 00:38:09,600 --> 00:38:11,800 SIGNALING IS TURNED OFF. 742 00:38:11,800 --> 00:38:22,320 ONE OF THE FAMILIES -- THIS IS A 743 00:38:25,240 --> 00:38:27,520 HIGHLY CONSERVED RESIDUE ACROSS 744 00:38:27,520 --> 00:38:29,480 EVOLUTION AND ONE CAN SEE THAT 745 00:38:29,480 --> 00:38:34,080 IN FACT -- THE MUTATIONS DO 746 00:38:34,080 --> 00:38:36,680 RENDER THE PROTEIN RESISTANT TO 747 00:38:36,680 --> 00:38:39,320 CLEAVAGE AND THROUGH A SERIES OF 748 00:38:39,320 --> 00:38:41,240 FUNCTIONAL STUDIES INVOLVING THE 749 00:38:41,240 --> 00:38:43,240 DEVELOPMENT OF MOUSE MODELS WITH 750 00:38:43,240 --> 00:38:48,200 COLLEAGUES IN AUSTRALIA WE FOUND 751 00:38:48,200 --> 00:38:52,640 THAT IT'S A MOLECULAR SWITCH. 752 00:38:52,640 --> 00:38:56,680 AND THIS ACTUALLY WAS SOMETHING 753 00:38:56,680 --> 00:38:59,680 THAT WAS AN IMPORTANT ENOUGH 754 00:38:59,680 --> 00:39:01,600 PRINCIPLE THAT IT WAS PUBLISHED 755 00:39:01,600 --> 00:39:03,440 IN NATURE. 756 00:39:03,440 --> 00:39:05,320 ANOTHER DISEASE THAT WE HAVE NOT 757 00:39:05,320 --> 00:39:12,200 YET PUBLISHED IS A DISEASE 758 00:39:12,200 --> 00:39:16,280 CALLED SHARPENIA. 759 00:39:16,280 --> 00:39:20,080 A YOUNG MAN FROM INDIA -- WHO 760 00:39:20,080 --> 00:39:23,960 HAD EARLY ON SET RECURRENT 761 00:39:23,960 --> 00:39:26,840 FEVERS, ARTHRITIS AND COLITIS 762 00:39:26,840 --> 00:39:28,840 AND HE TURNED OUT TO BE A FRAME 763 00:39:28,840 --> 00:39:32,280 SHIFT MUTATION IN THIS PROTEIN 764 00:39:32,280 --> 00:39:35,320 SHARPEN WHICH IS INVOLVED IN THE 765 00:39:35,320 --> 00:39:38,440 REGULATION OF A VERY IMPORTANT 766 00:39:38,440 --> 00:39:40,920 POST TRANSLATIONAL MODIFICATION 767 00:39:40,920 --> 00:39:43,000 OF PROTEINS PARTICULARLY IN 768 00:39:43,000 --> 00:39:44,080 IMMUNE CELLS. 769 00:39:44,080 --> 00:39:46,400 WE INVITED HIM TO COME TO THE 770 00:39:46,400 --> 00:39:51,240 NIH AND ARE HERE ARE SOME 771 00:39:51,240 --> 00:39:57,160 IMAGING VIEWS. 772 00:39:57,160 --> 00:39:58,640 IT'S POTENTIALLY 773 00:39:58,640 --> 00:39:59,920 LIFE-THREATENING. 774 00:39:59,920 --> 00:40:02,400 BECAUSE IT CAN CAUSE INSTABILITY 775 00:40:02,400 --> 00:40:05,960 OF THE NECK AND HERE COLITIS. 776 00:40:05,960 --> 00:40:08,320 INFLAMMATION IN THE COLON. 777 00:40:08,320 --> 00:40:10,960 SO IN ANY EVENT THROUGH A SERIES 778 00:40:10,960 --> 00:40:13,800 OF FUNCTIONAL STUDIES AND 779 00:40:13,800 --> 00:40:18,480 COMPARISONS WITH MOUSE MODELS WE 780 00:40:18,480 --> 00:40:21,760 HYPOTHESIZED THAT TNF WAS 781 00:40:21,760 --> 00:40:24,640 PROBABLY LEADING TO A FORM OF 782 00:40:24,640 --> 00:40:26,760 CELL DEATH THAT LED TO 783 00:40:26,760 --> 00:40:31,040 INFLAMMATION IN THIS PATIENT. 784 00:40:31,040 --> 00:40:33,600 AND THAT TREATING HIM WITH AN 785 00:40:33,600 --> 00:40:35,000 INHIBITOR WOULD WORK. 786 00:40:35,000 --> 00:40:38,080 WHEN HE CAME TO US HE WAS NOT 787 00:40:38,080 --> 00:40:39,520 TOTALLY WHEELCHAIR BOUND BUT 788 00:40:39,520 --> 00:40:41,400 CERTAINLY NEEDED A WHEELCHAIR IN 789 00:40:41,400 --> 00:40:43,520 ORDER TO GET AROUND. 790 00:40:43,520 --> 00:40:45,840 AND OVER THE COURSE OF A YEAR WE 791 00:40:45,840 --> 00:40:50,680 TREATED HIM FIRST WITH -- AN 792 00:40:50,680 --> 00:40:53,760 INHIBITOR AND THEN ADDED AN 793 00:40:53,760 --> 00:40:59,600 ANTIBODY AND IT DID HAVE A 794 00:40:59,600 --> 00:41:01,800 DRAMATIC EFFECT. 795 00:41:01,800 --> 00:41:03,840 AND HERE HE IS ABOUT A YEAR 796 00:41:03,840 --> 00:41:06,120 AFTER WE STARTED SEEING HIM. 797 00:41:06,120 --> 00:41:07,960 WE'RE SEEING HIM IN THE CLINIC. 798 00:41:07,960 --> 00:41:11,080 HE IS STANDING BUT NOT ONLY 799 00:41:11,080 --> 00:41:13,160 STANDING BUT HE WAS ABLE TO 800 00:41:13,160 --> 00:41:14,840 DANCE. 801 00:41:14,840 --> 00:41:19,920 AND THIS IS SOMETHING THAT WAS 802 00:41:19,920 --> 00:41:21,200 INCREDIBLY GRATIFYING FOR US. 803 00:41:21,200 --> 00:41:24,760 A THIRD DISEASE ANOTHER AUTO 804 00:41:24,760 --> 00:41:27,160 INFLAMMATORY DISORDER THAT 805 00:41:27,160 --> 00:41:31,040 CHRISTINA -- IS WORKING ON A 806 00:41:31,040 --> 00:41:33,840 DISEASE THAT IS CALLED ROSA 807 00:41:33,840 --> 00:41:39,640 WHICH STANDS FOR RETINAL 808 00:41:39,640 --> 00:41:42,400 DYSTROPHY ... 809 00:41:42,400 --> 00:41:45,320 ROSAH. 810 00:41:45,320 --> 00:41:47,120 IT TURNS OUT TO BE A MOLECULE 811 00:41:47,120 --> 00:41:55,360 THAT IS A SENSOR FOR SEVEN 812 00:41:55,360 --> 00:41:57,200 CARBON SUGARS. 813 00:41:57,200 --> 00:41:59,120 WHEN THEY ARE WITHIN THE CELL 814 00:41:59,120 --> 00:42:04,000 THEY TRIGGER THE ACTIVATION OF 815 00:42:04,000 --> 00:42:07,000 RK1 WHICH LEADS TO INFLAMMATION. 816 00:42:07,000 --> 00:42:08,200 WHY WOULD THIS HAPPEN? 817 00:42:08,200 --> 00:42:11,240 IT TURNS OUT THAT BACTERIA SOME 818 00:42:11,240 --> 00:42:13,600 BACTERIA CAN MAKE SEVEN CARBON 819 00:42:13,600 --> 00:42:15,680 SUGARS AND WE CANNOT. 820 00:42:15,680 --> 00:42:18,280 SO TO HAVE AMOLE COOL THAT GETS 821 00:42:18,280 --> 00:42:20,280 TURNED ON AND LEADS TO 822 00:42:20,280 --> 00:42:27,320 INFLAMMATION IS A MECHANISM A AN 823 00:42:27,320 --> 00:42:29,200 INNATE MECHANISM FOR THIS 824 00:42:29,200 --> 00:42:30,680 BACTERIA. 825 00:42:30,680 --> 00:42:34,160 AND THIS IS IN AN OBSCURE 826 00:42:34,160 --> 00:42:34,680 BRANCH. 827 00:42:34,680 --> 00:42:37,000 WE'RE STILL TRYING TO FIGURE OUT 828 00:42:37,000 --> 00:42:37,880 HOW IT WORKS. 829 00:42:37,880 --> 00:42:42,840 THE CLINICAL FEATURES OF ROSAH 830 00:42:42,840 --> 00:42:44,440 ARE SHOWN ON THIS SLIDE AND YOU 831 00:42:44,440 --> 00:42:48,720 CAN SEE THE OPTIC -- AND CALLS 832 00:42:48,720 --> 00:42:52,680 CASE OF THE BASAL GANGLY YA. 833 00:42:52,680 --> 00:42:57,240 THE ARTHRITIS IN THE HANDS. 834 00:42:57,240 --> 00:42:58,880 THESE *. 835 00:42:58,880 --> 00:43:01,920 THESE PATIENTS OVER TIME MANY 836 00:43:01,920 --> 00:43:04,840 DEVELOP VISION LOSS AND GO ON TO 837 00:43:04,840 --> 00:43:05,360 BLINDNESS. 838 00:43:05,360 --> 00:43:14,800 HERE ONE CAN SEE -- VESSEL 839 00:43:14,800 --> 00:43:15,280 LEAKAGE. 840 00:43:15,280 --> 00:43:25,360 YOU CAN ALSO SEE D SEE -- EDEMAE 841 00:43:25,360 --> 00:43:27,880 MACULAR OF THE EYE. 842 00:43:27,880 --> 00:43:32,080 IN THREE PATIENTS THAT ARE IN 843 00:43:32,080 --> 00:43:33,200 THE PROGRESSION OF VISION LOSS 844 00:43:33,200 --> 00:43:35,440 WHERE THEY ARE ON THE ASCENDING 845 00:43:35,440 --> 00:43:38,760 LOOM OF LOSING THEIR VISION AND 846 00:43:38,760 --> 00:43:40,600 ACTUALLY THEY HAVE AT LEAST SO 847 00:43:40,600 --> 00:43:48,200 FAR DONE FAIRLY WELL WITH THE 848 00:43:48,200 --> 00:43:52,400 ANGIE OH GRAMS * IMPROVING. 849 00:43:52,400 --> 00:43:55,920 WELL IN ANY CASE THERE IS LOTS 850 00:43:55,920 --> 00:43:57,560 OF EXAMPLES. 851 00:43:57,560 --> 00:44:02,120 THIS IS JUST THE GALLIES OF A 852 00:44:02,120 --> 00:44:05,880 CHAPTER THAT LISTS MANY OF THE 853 00:44:05,880 --> 00:44:08,360 AUTO INFLAMMATORY SYNDROMES. 854 00:44:08,360 --> 00:44:09,960 IT'S NOT EVEN ALL OF THEM. 855 00:44:09,960 --> 00:44:12,800 THE NUMBER OF THEM IS REMARKABLE 856 00:44:12,800 --> 00:44:14,080 AND CONTINUES TO GROW. 857 00:44:14,080 --> 00:44:16,520 BUT I THINK THAT AT THIS POINT 858 00:44:16,520 --> 00:44:20,200 WHY DON'T WE FINISH UP BY 859 00:44:20,200 --> 00:44:23,600 TALKING NOT ABOUT GERMLINE 860 00:44:23,600 --> 00:44:27,360 MUTATIONS BUT INSTEAD SOMATIC 861 00:44:27,360 --> 00:44:29,320 MUTATIONS AND WE'RE INTERESTED 862 00:44:29,320 --> 00:44:31,880 IN ASKING THE QUESTION HOW DO 863 00:44:31,880 --> 00:44:35,520 OLD PEOPLE GET AUTO INFLAMMATORY 864 00:44:35,520 --> 00:44:35,920 DISEASE? 865 00:44:35,920 --> 00:44:38,280 THIS IS A VEXING PROBLEM FOR ME 866 00:44:38,280 --> 00:44:41,720 AND MY COLLEAGUES IN THE AUTO 867 00:44:41,720 --> 00:44:43,560 INFLAMMATORY DISEASES CLINIC. 868 00:44:43,560 --> 00:44:45,760 FOR CASES WHERE WE HAVE CHILDREN 869 00:44:45,760 --> 00:44:47,760 THAT GREAT TO US WITH SEVERE 870 00:44:47,760 --> 00:44:51,840 AUTO INFLAMMATION ONE CAN 871 00:44:51,840 --> 00:44:56,480 REASONABLY HYPOTHESIZE THAT A 872 00:44:56,480 --> 00:44:59,560 GERMLINE MUTATION CAN BE 873 00:44:59,560 --> 00:45:00,000 RESPONSIBLE. 874 00:45:00,000 --> 00:45:02,320 WHEN SOMEONE WHO'S 50 YEARS OLD 875 00:45:02,320 --> 00:45:04,080 PRESENTING TO THE AUTO 876 00:45:04,080 --> 00:45:07,080 INFLAMMATORY CLINIC FOR THE 877 00:45:07,080 --> 00:45:08,640 FIRST TIME YOU HAVE TO THINK 878 00:45:08,640 --> 00:45:10,120 ABOUT A NUMBER OF OTHER 879 00:45:10,120 --> 00:45:10,760 POSSIBILITIES. 880 00:45:10,760 --> 00:45:14,840 MAYBE THE PERSON HAS AN 881 00:45:14,840 --> 00:45:15,720 INFECTION. 882 00:45:15,720 --> 00:45:17,160 TRAVELED SOMEWHERE AND PICKED 883 00:45:17,160 --> 00:45:19,040 SOMETHING UP. 884 00:45:19,040 --> 00:45:22,320 MAYBE THEY HAVE CANCER AND THIS 885 00:45:22,320 --> 00:45:25,120 IS JUST THE SYNDROME THAT WILL 886 00:45:25,120 --> 00:45:26,720 DECLARE ITSELF AS CANCER LATER 887 00:45:26,720 --> 00:45:27,680 ON. 888 00:45:27,680 --> 00:45:29,760 IT'S A HARD NUT TO CRACK. 889 00:45:29,760 --> 00:45:31,560 BUT CERTAINLY AN IMPORTANT ONE 890 00:45:31,560 --> 00:45:33,560 AND WE SEE A NUMBER OF CASES 891 00:45:33,560 --> 00:45:35,280 LIKE THIS IN THE CLINIC. 892 00:45:35,280 --> 00:45:38,280 SO THIS WAS THE SETTING FOR NOW 893 00:45:38,280 --> 00:45:41,480 MY FORMER FELLOW DAVID BECK AND 894 00:45:41,480 --> 00:45:48,600 HIS COLLEAGUES WHO WERE 895 00:45:48,600 --> 00:45:50,560 INTERESTED IN THIS ISSUE. 896 00:45:50,560 --> 00:45:54,000 AND THEY DECIDED AND IT WAS 897 00:45:54,000 --> 00:45:56,560 DAVID WHO DID THE WORK IN THE 898 00:45:56,560 --> 00:45:59,400 LAB DECIDED TO TAKE A DIFFERENT 899 00:45:59,400 --> 00:46:01,320 APPROACH TO DISCOVERY. 900 00:46:01,320 --> 00:46:04,680 SO THE USUAL APPROACH THAT WE 901 00:46:04,680 --> 00:46:09,080 MIGHT TAKE IS CALLED PHENOTYPE 902 00:46:09,080 --> 00:46:10,880 APPROACH IN WHICH WE GROUP 903 00:46:10,880 --> 00:46:13,040 TOGETHER PATIENTS THAT HAVE 904 00:46:13,040 --> 00:46:15,240 SIMILAR MANIFESTATIONS AND THEN 905 00:46:15,240 --> 00:46:18,320 USING GENETIC TECHNIQUES WE TRY 906 00:46:18,320 --> 00:46:21,720 TO FIND SOME GENE A VARIANT OR 907 00:46:21,720 --> 00:46:24,520 SET OF VARIANTS THAT COULD 908 00:46:24,520 --> 00:46:25,800 EXPLAIN THE PHENOTYPE. 909 00:46:25,800 --> 00:46:28,120 THAT IS THE USUAL MISSION THAT 910 00:46:28,120 --> 00:46:30,400 WE GO ON IN GENETICS. 911 00:46:30,400 --> 00:46:33,280 BUT DAVID HAD THIS IDEA THAT 912 00:46:33,280 --> 00:46:35,400 RATHER THAN GOING PHENOTYPE 913 00:46:35,400 --> 00:46:37,480 FIRST HE WOULD LIKE TO GO 914 00:46:37,480 --> 00:46:38,440 GENOTYPE FIRST. 915 00:46:38,440 --> 00:46:40,440 SO HE MADE A LIST OF ALL OF THE 916 00:46:40,440 --> 00:46:45,080 GENES THAT HAVE NOTHING TO DO 917 00:46:45,080 --> 00:46:46,360 WITH THIS. 918 00:46:46,360 --> 00:46:47,960 OVER THE PREVIOUS COUPLE OF 919 00:46:47,960 --> 00:46:52,520 YEARS WE DISCOVERED A COUPLE OF 920 00:46:52,520 --> 00:46:55,440 DISEASES BY A PHENOTYPE APPROACH 921 00:46:55,440 --> 00:47:05,800 THAT CAUSED TO BE BY 922 00:47:09,720 --> 00:47:10,840 UBIQUITYLATION. 923 00:47:10,840 --> 00:47:21,480 * THE PROGRAM WAS KIND ENOUGH TO 924 00:47:22,280 --> 00:47:24,800 CONTRIBUTE 1083 GENOMES SO ABOUT 925 00:47:24,800 --> 00:47:29,360 2500 GENOMIC SEQUENCES INTERGET 926 00:47:29,360 --> 00:47:30,760 WITH 841 GENES. 927 00:47:30,760 --> 00:47:32,880 FILTERING CRITERIA INCLUDED THAT 928 00:47:32,880 --> 00:47:35,120 THE GENES WOULD NEED TO BE 929 00:47:35,120 --> 00:47:37,160 RELATIVELY INTOLERANT OF 930 00:47:37,160 --> 00:47:37,680 VARIANTS. 931 00:47:37,680 --> 00:47:45,440 HAVE A PLI SCORCH GREATER THAN 932 00:47:45,440 --> 00:47:47,800 0.9 AND THAT THEY WOULD BE 933 00:47:47,800 --> 00:47:48,440 SHARED. 934 00:47:48,440 --> 00:47:51,880 AND DOING ALL OF THIS WITH THE 935 00:47:51,880 --> 00:47:55,360 2500 OR SO PATIENTS AND THE 841 936 00:47:55,360 --> 00:47:58,160 GENES DAVID FOUND THREE MIDDLE 937 00:47:58,160 --> 00:48:01,920 AGE MEN WHO HAPPENED TO BE 938 00:48:01,920 --> 00:48:04,560 HETERO ZAIRE GUS FOR THIS GENE 939 00:48:04,560 --> 00:48:05,240 UBA1. 940 00:48:05,240 --> 00:48:07,280 *. 941 00:48:07,280 --> 00:48:09,600 AT FIRST BLUSH THAT WOULD SEEM 942 00:48:09,600 --> 00:48:13,480 GREAT BECAUSE UBA1 IS AN 943 00:48:13,480 --> 00:48:15,200 IMPORTANT GENE IN REGULATING. 944 00:48:15,200 --> 00:48:17,440 BUT IT'S SO IMPORTANT THAT ONE 945 00:48:17,440 --> 00:48:19,560 COULD MAYBE SAY HOW IN THE WORLD 946 00:48:19,560 --> 00:48:21,720 COULD SOMEONE HAVE A MUTATION IN 947 00:48:21,720 --> 00:48:25,760 THAT GENE AND STILL BE ALIVE? 948 00:48:25,760 --> 00:48:29,680 WHAT IS MORE IT TURNS OUT THAT 949 00:48:29,680 --> 00:48:35,200 UBA1 IS ENCODED ON THE X 950 00:48:35,200 --> 00:48:39,920 CHROMOSOME. 951 00:48:39,920 --> 00:48:42,960 MEN ONLY HAVE USUALLY ONE X 952 00:48:42,960 --> 00:48:43,480 CHROMOSOME. 953 00:48:43,480 --> 00:48:46,000 SO IT COULD BE A SEQUENCING 954 00:48:46,000 --> 00:48:46,600 ERROR. 955 00:48:46,600 --> 00:48:48,080 WE RULED THAT OUT. 956 00:48:48,080 --> 00:48:51,480 IT COULD BE AN EXTRA X 957 00:48:51,480 --> 00:48:52,200 CHROMOSOME. 958 00:48:52,200 --> 00:48:53,840 WE RULED THAT OUT. 959 00:48:53,840 --> 00:48:57,880 SO INSTEAD IT COULD BE A SOMATIC 960 00:48:57,880 --> 00:48:59,240 MUTATION IN WHICH RATHER THAN 961 00:48:59,240 --> 00:49:02,520 THE DNA WHICH COMES FROM WHITE 962 00:49:02,520 --> 00:49:03,880 BLOOD CELLS. 963 00:49:03,880 --> 00:49:06,320 BASICALLY REPRESENTING THAT IN 964 00:49:06,320 --> 00:49:07,720 ALL OF THE WHITE BLOOD CELLS 965 00:49:07,720 --> 00:49:10,560 THERE IS A MUTANT AND WILD TYPE 966 00:49:10,560 --> 00:49:12,120 VERSION OF THE GENE THAT THERE 967 00:49:12,120 --> 00:49:14,760 MIGHT BE TWO POPULATIONS OF 968 00:49:14,760 --> 00:49:15,400 WHITE BLOOD CELLS. 969 00:49:15,400 --> 00:49:17,480 ONE THAT HAS THE MUTATION. 970 00:49:17,480 --> 00:49:20,160 THE OTHER THAT DOESN'T HAVE THE 971 00:49:20,160 --> 00:49:21,320 MUTATION. 972 00:49:21,320 --> 00:49:25,840 SO HE SET ABOUT TO TEST THAT 973 00:49:25,840 --> 00:49:26,840 HYPOTHESIS. 974 00:49:26,840 --> 00:49:30,160 IN THE BLOOD THE DNA SHOWS TWO 975 00:49:30,160 --> 00:49:30,680 PEAKS. 976 00:49:30,680 --> 00:49:37,560 A MUTE ANNUAL AND A WILD PEAK. 977 00:49:37,560 --> 00:49:43,160 THE BONE MARROW. 978 00:49:43,160 --> 00:49:46,720 HOWEVER, IF YOU FRACTIONATE THE 979 00:49:46,720 --> 00:49:50,080 BLOOD YOU SEE THAT THE MUTANT 980 00:49:50,080 --> 00:49:53,760 PEAK PREDOMINATES STRONGLY 981 00:49:53,760 --> 00:49:59,480 WHEREAS IN THE WILD TYPE PEAK IS 982 00:49:59,480 --> 00:50:03,120 THE PREDOMINANT PEAK. 983 00:50:03,120 --> 00:50:05,560 IT IS NOT THAT ALL OF THE CELLS 984 00:50:05,560 --> 00:50:08,080 HAVE BOTH VERSIONS OF THE GENE. 985 00:50:08,080 --> 00:50:09,520 IT'S THAT SOME OF THE DRILLS 986 00:50:09,520 --> 00:50:11,720 CELLS HAVE THE MUTANT VERSION 987 00:50:11,720 --> 00:50:16,840 AND SOME HAVE THE WILD VERSION 988 00:50:16,840 --> 00:50:20,680 AND IF ONE DOES DIGITAL DROPIC 989 00:50:20,680 --> 00:50:22,320 YOU CAN SEE THAT THE FRACTION 990 00:50:22,320 --> 00:50:26,880 AND FIBROBLAST IS ZERO AND IT'S 991 00:50:26,880 --> 00:50:29,520 ACTUALLY QUITE HIGH IN MYELOID 992 00:50:29,520 --> 00:50:31,160 CELLS. 993 00:50:31,160 --> 00:50:33,400 HERE IS ANOTHER FACT STRANGER 994 00:50:33,400 --> 00:50:35,000 THAN FICTION MOMENT AND THAT IS 995 00:50:35,000 --> 00:50:38,600 THAT WE THEN WENT TO VISIT THE 996 00:50:38,600 --> 00:50:43,120 GOOD DR. KATHY CALVO TO LOOKING 997 00:50:43,120 --> 00:50:45,400 AT THE BONE MARROWS. 998 00:50:45,400 --> 00:50:49,800 AND SHE NOTICED THAT IN FACT THE 999 00:50:49,800 --> 00:50:54,000 MYELOID -- HAD THESE FUNNY 1000 00:50:54,000 --> 00:50:58,160 LOOKING VACUOLES. 1001 00:50:58,160 --> 00:51:00,480 WE CAME BACK A FEW DAYS LATER 1002 00:51:00,480 --> 00:51:03,160 AND SHE TOLD ME EFFICIENTLY TO 1003 00:51:03,160 --> 00:51:05,840 MY SHE GRIN THAT WHERE SHE HAD * 1004 00:51:05,840 --> 00:51:08,360 SEEN IT BEFORE WAS IN A COUPLE 1005 00:51:08,360 --> 00:51:10,480 OF MY PATIENTS FROM 8 YEARS 1006 00:51:10,480 --> 00:51:11,080 BEFORE. 1007 00:51:11,080 --> 00:51:13,760 SO WE WENT BACK AND CHECKED 1008 00:51:13,760 --> 00:51:14,480 THOSE INDIVIDUALS. 1009 00:51:14,480 --> 00:51:16,800 THEY WERE MIDDLE AGED MENACE 1010 00:51:16,800 --> 00:51:22,360 WELL FOR MUTATIONS IN UBA1. 1011 00:51:22,360 --> 00:51:24,640 AND IN FACT WE FOUND EVIDENCE 1012 00:51:24,640 --> 00:51:27,240 FOR SOMATIC MUTATION IN THEM. 1013 00:51:27,240 --> 00:51:31,200 ONE OF THEM TURNED OUT TO BE 1014 00:51:31,200 --> 00:51:39,200 RELAPSING POLLY -- CHONDRITIS. 1015 00:51:39,200 --> 00:51:45,880 * AND WE SOON HAD 15 PATIENTS 1016 00:51:45,880 --> 00:51:49,320 WITH INFLAMMATION AND UBA1 1017 00:51:49,320 --> 00:51:51,920 MUTATIONS. 1018 00:51:51,920 --> 00:51:54,760 MIDDLE AGE MEN AT POSITION 41 1019 00:51:54,760 --> 00:51:57,240 AND THEN BY NOTING OUR NOSES 1020 00:51:57,240 --> 00:51:59,800 WITH OTHER PATIENTS WE FOUND 1021 00:51:59,800 --> 00:52:02,680 THAT THERE WERE PATIENTS WITH 1022 00:52:02,680 --> 00:52:09,400 SWEET SYNDROME, MGUS AND -- ALL 1023 00:52:09,400 --> 00:52:13,000 OF THEM WITH MUTATIONS IN UBA1. 1024 00:52:13,000 --> 00:52:14,720 SOME OF THE PATIENTS CARRIED 1025 00:52:14,720 --> 00:52:16,760 MORE THAN ONE DIAGNOSES WHICH IS 1026 00:52:16,760 --> 00:52:18,640 WHY THE PERCENTAGES ADD UP TO 1027 00:52:18,640 --> 00:52:22,080 MORE THAN 100%. 1028 00:52:22,080 --> 00:52:24,440 SINCE THEY HAVE MUTATIONS IN 1029 00:52:24,440 --> 00:52:26,480 UBA1 WE THOUGHT THAT WE SHOULD 1030 00:52:26,480 --> 00:52:29,000 SAY THEY HAVE THE SAME DISEASE 1031 00:52:29,000 --> 00:52:32,160 WHICH DAVID CAME UP WITH THE 1032 00:52:32,160 --> 00:52:40,200 NEXT VEXAS. 1033 00:52:40,200 --> 00:52:45,040 AND HERE YOU CAN SEE ON A SCAN 1034 00:52:45,040 --> 00:52:55,600 THE PYOU CAN SEE ... 1035 00:53:00,960 --> 00:53:06,080 AND IF YOU LOOKING LOOK YOU CANT 1036 00:53:06,080 --> 00:53:08,040 THEY LOOK AWFUL. 1037 00:53:08,040 --> 00:53:09,480 SO, IT'S NOT THAT THESE ARE 1038 00:53:09,480 --> 00:53:14,960 CELLS THAT ARE ALMOST CANCEROUS 1039 00:53:14,960 --> 00:53:18,760 THAT ARE PROLIFERATING BUT 1040 00:53:18,760 --> 00:53:22,960 RATHER THEY CAN TOLERATE THE 1041 00:53:22,960 --> 00:53:26,040 MUTATION AND IF ONE LOOKS AT 1042 00:53:26,040 --> 00:53:28,400 GENE EXPRESSION PROFILING THE 1043 00:53:28,400 --> 00:53:31,560 MYELOID CELLS HAVE AN 1044 00:53:31,560 --> 00:53:34,680 INFLAMMATORY PROFILE THAT THE 1045 00:53:34,680 --> 00:53:36,400 LYMPHOCYTES DO NOT. 1046 00:53:36,400 --> 00:53:40,000 USING A GENOTYPE FIRST STRATEGY 1047 00:53:40,000 --> 00:53:46,320 ONE CAN DEFINE NEW ILLNESSES. 1048 00:53:46,320 --> 00:53:51,240 THIS MAY GIVE RISE TO A NEW 1049 00:53:51,240 --> 00:53:57,320 MOLECULAR TAXONOMY. 1050 00:54:06,240 --> 00:54:08,840 WE'RE SUSPECTING THAT AND 1051 00:54:08,840 --> 00:54:13,160 FOLLOWING UP ON THAT IN GENETIC 1052 00:54:13,160 --> 00:54:13,760 STUDIES. 1053 00:54:13,760 --> 00:54:16,640 SO WE PUBLISHED THIS NEW DISEASE 1054 00:54:16,640 --> 00:54:20,000 IN THE NEW YEAR'S EVE EDITION OF 1055 00:54:20,000 --> 00:54:21,360 THE NEW ENGLAND JOURNAL OF 1056 00:54:21,360 --> 00:54:24,040 MEDICINE AT THE END OF 2020 AND 1057 00:54:24,040 --> 00:54:26,560 MUCH TO OUR SURPRISE ANOTHER 1058 00:54:26,560 --> 00:54:28,280 FACT STRANGER THAN FICTION. 1059 00:54:28,280 --> 00:54:31,240 IT TURNED OUT ABOUT THREE MONTHS 1060 00:54:31,240 --> 00:54:34,080 LATER THAT VEXAS HAD ALREADY 1061 00:54:34,080 --> 00:54:41,720 MADE IT TO PRIME TIME TV. 1062 00:54:41,720 --> 00:54:44,240 >> SO IN OTHER WORDS WE STILL 1063 00:54:44,240 --> 00:54:45,080 DON'T KNOW ANYTHING 1064 00:54:45,080 --> 00:54:48,760 >> YOU MIGHT WANT TO GET 1065 00:54:48,760 --> 00:54:50,520 INFECTIOUS DISEASE ON THIS. 1066 00:54:50,520 --> 00:54:54,280 >> THANKS, DOCTOR. 1067 00:54:54,280 --> 00:55:00,840 >> ETHAN, BASED ON SYMPTOMS I 1068 00:55:00,840 --> 00:55:04,280 THINK IT MIGHT BE VEXAS. 1069 00:55:04,280 --> 00:55:07,800 A GENETIC MUTATION. 1070 00:55:07,800 --> 00:55:12,320 IF ONLY DIAGNOSED 25 CASES. 1071 00:55:12,320 --> 00:55:14,640 >> IT WOULD CERTAINLY EXPLAIN 1072 00:55:14,640 --> 00:55:16,680 THE CRAZY CONSTELLATION OF 1073 00:55:16,680 --> 00:55:19,560 SYMPTOMS BUT I'M STILL NOT 1074 00:55:19,560 --> 00:55:25,760 LOOKING FOR ZEBRAS YET. 1075 00:55:25,760 --> 00:55:27,800 HEY, YOU WERE RIGHT. 1076 00:55:27,800 --> 00:55:31,600 GENETIC SEQUENCING FOUND THAT 1077 00:55:31,600 --> 00:55:32,560 MUTATION. 1078 00:55:32,560 --> 00:55:34,080 >> HOT DAMN. 1079 00:55:34,080 --> 00:55:35,640 >> I'VE STARTED TREATMENT. 1080 00:55:35,640 --> 00:55:36,880 AMAZING CATCH MAN. 1081 00:55:36,880 --> 00:55:37,200 >> THANKS. 1082 00:55:37,200 --> 00:55:40,640 THANK YOU. 1083 00:55:40,640 --> 00:55:43,920 >> WELL JUST TO MAYBE PUT A 1084 00:55:43,920 --> 00:55:48,200 LITTLE AIR OF REALITY IN THIS, 1085 00:55:48,200 --> 00:55:51,400 VEXAS IS A VERY DIFFICULT 1086 00:55:51,400 --> 00:55:53,400 CONDITION TO TREAT AND IT WOULD 1087 00:55:53,400 --> 00:55:55,560 NOT BE SO TRIVIAL AS SAYING I 1088 00:55:55,560 --> 00:55:58,000 JUST STARTED TREATMENT NOW BUT 1089 00:55:58,000 --> 00:56:00,600 IN ANY CASE THAT IS WORK FOR 1090 00:56:00,600 --> 00:56:10,520 DAVID BECK BECK. 1091 00:56:10,520 --> 00:56:13,440 DAVID PUBLISHED A PAPER IN THE 1092 00:56:13,440 --> 00:56:14,800 JOURNAL OF THE AMERICAN MEDICAL 1093 00:56:14,800 --> 00:56:17,480 ASSOCIATION LOOKING AT THE 1094 00:56:17,480 --> 00:56:20,560 CLINIC POPULATION. 1095 00:56:20,560 --> 00:56:22,680 163,000 INDIVIDUALS AND FOUND 12 1096 00:56:22,680 --> 00:56:25,880 INDIVIDUALS ACTUALLY WITH UBA1 1097 00:56:25,880 --> 00:56:29,680 MUTATIONS AND THE FREQUENCY OF 1098 00:56:29,680 --> 00:56:32,960 UBA1 MUTATIONS THESE MUTATIONS 1099 00:56:32,960 --> 00:56:36,760 IN MEN OVER THE AGE OF 50 IS 1100 00:56:36,760 --> 00:56:38,440 ABOUT ONE IN 4,000. 1101 00:56:38,440 --> 00:56:41,000 SO, IT'S NOT SUCH A RARE DISEASE 1102 00:56:41,000 --> 00:56:44,720 AFTER ALL. 1103 00:56:44,720 --> 00:56:48,480 CERTAINLY GIVEN THE DISPARATE 1104 00:56:48,480 --> 00:56:51,600 CLINICAL FEATURES OF PATIENTS IT 1105 00:56:51,600 --> 00:56:53,360 HAS GIVEN RISE TO THE THINKING 1106 00:56:53,360 --> 00:56:55,920 THAT MAYBE CLINICAL DIAGNOSIS 1107 00:56:55,920 --> 00:57:00,640 ARE TH -- THE LEAVES OF THE TREE 1108 00:57:00,640 --> 00:57:02,880 BUT THERE MAY BE RELATIONSHIPS 1109 00:57:02,880 --> 00:57:04,600 AT THE LEVEL OF THE ROOTS THAT 1110 00:57:04,600 --> 00:57:06,240 ARE NOT APPRECIATING WHEN WE 1111 00:57:06,240 --> 00:57:09,240 JUST LOOK AT THE CLINICAL 1112 00:57:09,240 --> 00:57:11,440 PICTURE SO IT DOES GIVE RISE TO 1113 00:57:11,440 --> 00:57:13,920 THE THOUGHT THAT MAYBE THERE IS 1114 00:57:13,920 --> 00:57:23,720 A NEW TAXONOMY OF DECEA DI -- D. 1115 00:58:05,520 --> 00:58:07,640 SO WITH THAT I'LL CALL IT TO A 1116 00:58:07,640 --> 00:58:08,200 CLOSE. 1117 00:58:08,200 --> 00:58:10,960 THERE WERE MANY, MANY PEOPLE 1118 00:58:10,960 --> 00:58:13,000 THAT CONTRIBUTED MIGHTILY TO THE 1119 00:58:13,000 --> 00:58:13,400 WORK. 1120 00:58:13,400 --> 00:58:15,240 SOME OF THEM ARE SHOWN ON THIS 1121 00:58:15,240 --> 00:58:16,000 SLIDE. 1122 00:58:16,000 --> 00:58:17,760 PEOPLE AT LEAST AT ONE TIME 1123 00:58:17,760 --> 00:58:19,400 MEMBERS OF MY LAB. 1124 00:58:19,400 --> 00:58:21,040 SOME OF THEM STILL ARE. 1125 00:58:21,040 --> 00:58:23,520 A NUMBER OF COLLABORATORS. 1126 00:58:23,520 --> 00:58:26,080 BOTH AT THE NIH AND ELSEWHERE. 1127 00:58:26,080 --> 00:58:28,840 BUT OF COURSE COMING BACK TO THE 1128 00:58:28,840 --> 00:58:31,520 CENTRAL THEME THIS IS ALL ABOUT 1129 00:58:31,520 --> 00:58:32,560 THE PATIENTS. 1130 00:58:32,560 --> 00:58:37,880 HERE IS A GROUP OF PATIENTS AT 1131 00:58:37,880 --> 00:58:42,280 THE FIRST INTERNATIONAL CONGRESS 1132 00:58:42,280 --> 00:58:44,200 THAT HELPED IN BETHESDA. 1133 00:58:44,200 --> 00:58:46,680 AND I CANNOT END WITHOUT 1134 00:58:46,680 --> 00:58:48,560 MENTIONING THE CLINICAL CENTER 1135 00:58:48,560 --> 00:58:50,800 WHICH AFTER ALL IS WHAT HAS MADE 1136 00:58:50,800 --> 00:58:52,080 ALL OF THIS POSSIBLE. 1137 00:58:52,080 --> 00:58:54,520 SO WITH THAT I WILL CALL IT TO A 1138 00:58:54,520 --> 00:58:55,040 CLOSE. 1139 00:58:55,040 --> 00:58:57,520 THANK YOU VERY MUCH FOR 1140 00:58:57,520 --> 00:58:58,040 LISTENING. 1141 00:58:58,040 --> 00:59:00,680 AVENUE I'M HAPPY TO TRY TO 1142 00:59:00,680 --> 00:59:02,080 ENTERTAIN ANY QUESTIONS YOU MAY 1143 00:59:02,080 --> 00:59:02,640 HAVE. 1144 00:59:02,640 --> 00:59:06,400 >> THANK YOU, DAN. 1145 00:59:06,400 --> 00:59:09,920 ABSOLUTE TOUR DEFOURS AND AUDIO 1146 00:59:09,920 --> 00:59:11,440 VISUAL SPECTACLE AS WELL. 1147 00:59:11,440 --> 00:59:15,680 WE HAVE TIME FOR ONE QUESTION. 1148 00:59:15,680 --> 00:59:18,640 AND SOMEONE HAD SUBMITTED A 1149 00:59:18,640 --> 00:59:21,000 QUESTION WHICH MAY DOVETAIL 1150 00:59:21,000 --> 00:59:26,000 NICELY TO THE ILLUSION OF THE 1151 00:59:26,000 --> 00:59:30,280 TREE AND ROOT TAXONOMY. 1152 00:59:30,280 --> 00:59:34,480 THEY COULD ACTUALLY HAVE AN AUTO 1153 00:59:34,480 --> 00:59:36,480 INFLAMMATORY COMPONENT AND COULD 1154 00:59:36,480 --> 00:59:39,920 THERE BE OVERLAP BETWEEN THE 1155 00:59:39,920 --> 00:59:40,440 DISEASES? 1156 00:59:40,440 --> 00:59:42,920 >> THAT IS A GREAT QUESTION, ED. 1157 00:59:42,920 --> 00:59:46,160 AND THE IDEA OF AUTO 1158 00:59:46,160 --> 00:59:48,920 INFLAMMATORY DISEASE THAT WE HAD 1159 00:59:48,920 --> 00:59:51,440 PROPOSED CERTAINLY IT'S A 1160 00:59:51,440 --> 00:59:55,760 CONCEPT TOILE SCHEMA BUT I DON'T 1161 00:59:55,760 --> 00:59:58,120 WANT ANYONE TO THINK IT HAS TO 1162 00:59:58,120 --> 01:00:00,240 BE MUTUALLY EXCLUSIVE. 1163 01:00:00,240 --> 01:00:02,480 IT'S A SPECTRUM AND CERTAINLY 1164 01:00:02,480 --> 01:00:04,680 THERE ARE SOME CONDITIONS IN 1165 01:00:04,680 --> 01:00:06,280 WHICH THERE SEEM TO BE 1166 01:00:06,280 --> 01:00:07,320 COMPONENTS OF BOTH. 1167 01:00:07,320 --> 01:00:09,440 I THINK IT'S MORE THAT IT HELPS 1168 01:00:09,440 --> 01:00:12,040 US IN THINKING ABOUT DISEASES 1169 01:00:12,040 --> 01:00:14,600 AND AT LEAST INITIALLY AND STILL 1170 01:00:14,600 --> 01:00:17,960 NOW WHEN YOU FIND GENES THAT ARE 1171 01:00:17,960 --> 01:00:21,920 MUTATED IN THESE MONOGENIC 1172 01:00:21,920 --> 01:00:23,160 DISEASES SOMETIMES IT TURNS OUT 1173 01:00:23,160 --> 01:00:25,840 IF THEY ARE AUTO INFLAMMATORY 1174 01:00:25,840 --> 01:00:27,720 THAT THOSE ARE SOME OF THE 1175 01:00:27,720 --> 01:00:34,200 BUILDING BLOCKS OR REGULATORS OF 1176 01:00:34,200 --> 01:00:37,880 THE INNATE IMMUNE SYSTEM 1177 01:00:37,880 --> 01:00:40,880 >> THANK YOU AGAIN FOR AN 1178 01:00:40,880 --> 01:00:41,720 OUTSTANDING TALK. 1179 01:00:41,720 --> 01:00:44,080 WE REALLY DO APPRECIATE IT. 1180 01:00:44,080 --> 01:00:45,720 >> THANK YOU, ED AND THANK 1181 01:00:45,720 --> 01:00:57,240 EVERYONE FOR WATCHING AS WELL.