1 00:00:05,200 --> 00:00:10,040 TO ALL OF YOU AROUND THE WORLD 2 00:00:10,040 --> 00:00:12,360 WHO ARE WATCHING THIS EIGHTH 3 00:00:12,360 --> 00:00:15,800 PROGRAM, 21st YEAR OF 4 00:00:15,800 --> 00:00:18,040 DEMYSTIFYING MEDICINE AT THE 5 00:00:18,040 --> 00:00:20,320 NIH, I SAY GOOD MORNING, GOOD 6 00:00:20,320 --> 00:00:22,280 AFTERNOON, OR GOOD EVENING, 7 00:00:22,280 --> 00:00:24,800 WHICH EVER IS APPROPRIATE. 8 00:00:24,800 --> 00:00:25,720 WE'RE DELIGHTED YOU'RE JOINING 9 00:00:25,720 --> 00:00:26,400 US. 10 00:00:26,400 --> 00:00:30,280 THE GOAL OF THIS PROGRAM IS TO 11 00:00:30,280 --> 00:00:32,080 BRIDGE THE EXCITING DEVELOPMENTS 12 00:00:32,080 --> 00:00:33,360 IN BIOLOGY AND ENGINEERING WITH 13 00:00:33,360 --> 00:00:34,720 MEDICINE. 14 00:00:34,720 --> 00:00:36,880 NOW, THE LOGO FOR THIS COURSE IS 15 00:00:36,880 --> 00:00:39,280 WHAT MANY OF US THINK IS THE 16 00:00:39,280 --> 00:00:42,120 MOST FAMOUS BRIDGE IN THE 17 00:00:42,120 --> 00:00:43,560 HISTORY OF THE WORLD. 18 00:00:43,560 --> 00:00:46,200 IT IS ALSO, BY THE WAY, THE 19 00:00:46,200 --> 00:00:47,720 FIRST QUESTION ON THE FINAL EXAM 20 00:00:47,720 --> 00:00:55,440 THAT WILL BE GIVEN TO YOU. 21 00:00:55,440 --> 00:00:58,840 IT'S THE BROOKLYN BRIDGE, 22 00:00:58,840 --> 00:01:00,240 CONNECTING BROOKLYN AND 23 00:01:00,240 --> 00:01:04,080 MANHATTAN, SYMBOLIC OF ADVANCES 24 00:01:04,080 --> 00:01:05,080 OF THE BRIDGING BETWEEN 25 00:01:05,080 --> 00:01:06,280 FUNDAMENTAL SCIENCE AND 26 00:01:06,280 --> 00:01:07,000 MEDICINE. 27 00:01:07,000 --> 00:01:09,160 LIKE THE PHYSICAL BRIDGE, THERE 28 00:01:09,160 --> 00:01:10,280 ARE DISAGREEMENTS ON BOTH SIDES 29 00:01:10,280 --> 00:01:12,840 OF A GAP AS TO WHETHER A BRIDGE 30 00:01:12,840 --> 00:01:17,560 SHOULD BE BUILT, AND IF SO HOW, 31 00:01:17,560 --> 00:01:19,920 AND MOST IMPORTANTLY ONCE A 32 00:01:19,920 --> 00:01:20,880 BRIDGE IS BUILT LIFE IS NEVER 33 00:01:20,880 --> 00:01:24,560 THE SAME ON EITHER SIDE. 34 00:01:24,560 --> 00:01:27,920 SO WE HOPE THESE PROGRAMS WHICH 35 00:01:27,920 --> 00:01:32,600 LINK ALL ASPECTS OF BIOLOGY, 36 00:01:32,600 --> 00:01:34,240 ENGINEERING, OCCASIONALLY SPACE, 37 00:01:34,240 --> 00:01:36,080 THE DEEP SEA VENTS OF THE OCEAN 38 00:01:36,080 --> 00:01:39,920 AND NEXT WEEK THE ORIGIN OF LIFE 39 00:01:39,920 --> 00:01:42,680 WILL BE STIMULATING AND PROVOKE 40 00:01:42,680 --> 00:01:45,280 THOSE WHO ATTEND AND LISTEN TO 41 00:01:45,280 --> 00:01:46,280 THINK MORE DEEPLY. 42 00:01:46,280 --> 00:01:50,040 THE INTENT OF THESE SESSIONS IS 43 00:01:50,040 --> 00:01:53,560 NOT TO OVERWHELM YOU WITH 44 00:01:53,560 --> 00:01:56,880 YESTERDAY'S RESEARCH DATA OR A 45 00:01:56,880 --> 00:01:58,880 MASSIVE AMOUNT OF INFORMATION TO 46 00:01:58,880 --> 00:02:01,440 BE REGURGITATED ON SOME TEST. 47 00:02:01,440 --> 00:02:08,680 WE'RE VERY FORTUNATE, NEXT SLIDE 48 00:02:08,680 --> 00:02:09,760 PLEASE, BECAUSE TODAY'S PROGRAM 49 00:02:09,760 --> 00:02:11,680 IS THE FIRST IN WHICH WE HAVE 50 00:02:11,680 --> 00:02:14,320 FIVE PARTICIPANTS. 51 00:02:14,320 --> 00:02:18,680 IT DEALS WITH THE TAXONOMY OF 52 00:02:18,680 --> 00:02:19,680 AUTO-INFLAMMATORY DISEASE. 53 00:02:19,680 --> 00:02:25,880 YOU ALL KNOW THE ANCIENTS 54 00:02:25,880 --> 00:02:27,280 RECOGNIZED INFLAMMATION BY 55 00:02:27,280 --> 00:02:33,120 VIRTUE OF A COMBINATION OF 56 00:02:33,120 --> 00:02:34,560 PAIN, REDNESS, LOSS OF FUNCTION 57 00:02:34,560 --> 00:02:36,720 AND HEAT, OR FEVER. 58 00:02:36,720 --> 00:02:39,720 IN MOST INSTANCES THAT FEVER WAS 59 00:02:39,720 --> 00:02:42,720 DUE TO SOME FORM OF INFECTIOUS 60 00:02:42,720 --> 00:02:43,240 AGENT. 61 00:02:43,240 --> 00:02:47,720 BUT WITH TIME IT TURNS OUT THAT 62 00:02:47,720 --> 00:02:49,600 INFLAMMATION HAS MANY CAUSES 63 00:02:49,600 --> 00:02:51,280 OTHER THAN INFECTION, PER SE. 64 00:02:51,280 --> 00:02:55,120 AND ONE OF THE MORE STRIKING 65 00:02:55,120 --> 00:02:57,600 GROUPS OF INFLAMMATION AND 66 00:02:57,600 --> 00:03:00,880 INFLAMMATORY DISEASES ARE THOSE 67 00:03:00,880 --> 00:03:03,720 THAT RELY UPON INHERITABLE 68 00:03:03,720 --> 00:03:07,240 DEFECTS IN THE BASIC PROCESS 69 00:03:07,240 --> 00:03:11,000 THAT LEADS TO INFLAMMATION, 70 00:03:11,000 --> 00:03:11,640 AUTO-INFLAMMATORY DISEASE. 71 00:03:11,640 --> 00:03:13,080 AND OUR SPEAKERS TODAY, AND 72 00:03:13,080 --> 00:03:15,280 THERE WILL BE THREE, PLUS TWO 73 00:03:15,280 --> 00:03:17,920 PATIENTS, THE FIRST TIME WE HAVE 74 00:03:17,920 --> 00:03:20,000 EVER HAD A QUINTET IN THE 20 75 00:03:20,000 --> 00:03:22,680 YEARS OF THIS FORCE, THEY WILL 76 00:03:22,680 --> 00:03:29,640 BE DISCUSSING UNDER THE TITLE OF 77 00:03:29,640 --> 00:03:33,320 REIMAGINING THE TAXONOMY, THE 78 00:03:33,320 --> 00:03:35,680 CLASSIFICATION, OF 79 00:03:35,680 --> 00:03:36,280 AUTO-INFLAMMATORY DISEASES. 80 00:03:36,280 --> 00:03:37,800 NOW, THE RINGLEADER IN THIS 81 00:03:37,800 --> 00:03:42,720 PROGRAM IS DR. DAN KASTNER, WHO 82 00:03:42,720 --> 00:03:49,280 GRADUATED IN PHILOSOPHY FROM 83 00:03:49,280 --> 00:03:51,520 PRINCETON, MD/PHD FROM BAYLOR, 84 00:03:51,520 --> 00:03:53,040 MEDICAL RESIDENCY, CAME TO NIH 85 00:03:53,040 --> 00:03:56,600 IN 1985, HAS BEEN HERE EVER 86 00:03:56,600 --> 00:03:58,760 SINCE. 87 00:03:58,760 --> 00:04:00,880 HE DID A PROLONGED STINT AS 88 00:04:00,880 --> 00:04:03,040 SCIENTIFIC DIRECTOR OF THE 89 00:04:03,040 --> 00:04:04,280 NATIONAL HUMAN GENOME RESEARCH 90 00:04:04,280 --> 00:04:09,080 INSTITUTE, FROM WHICH HE IS NOW 91 00:04:09,080 --> 00:04:11,480 EMERITUS, IS CURRENTLY AN NIH 92 00:04:11,480 --> 00:04:13,400 DISTINGUISHED INVESTIGATOR AND 93 00:04:13,400 --> 00:04:16,280 CHIEF OF THE INFLAMMATORY 94 00:04:16,280 --> 00:04:17,320 DISEASE SECTION. 95 00:04:17,320 --> 00:04:20,080 HE IS ALSO NOTABLY THE CO-CHAIR 96 00:04:20,080 --> 00:04:25,160 OF THE COURSE IN DEMYSTIFYING 97 00:04:25,160 --> 00:04:25,680 MEDICINE. 98 00:04:25,680 --> 00:04:29,280 DAN'S RESEARCH HAS BEEN OF 99 00:04:29,280 --> 00:04:32,720 EXTRAORDINARY EXCITEMENT AND 100 00:04:32,720 --> 00:04:36,040 IMPORTANCE. 101 00:04:36,040 --> 00:04:40,080 HE BECAME INTERESTED IN 102 00:04:40,080 --> 00:04:41,720 INFLAMMATORY DISEASE, FEVER, FOR 103 00:04:41,720 --> 00:04:43,200 WHICH THERE WAS NO KNOWN 104 00:04:43,200 --> 00:04:43,960 INFECTION. 105 00:04:43,960 --> 00:04:49,480 ONE OF THE MORE COMMON CHIEF 106 00:04:49,480 --> 00:04:50,520 COMPLAINTS OF PATIENTS ADMITTED 107 00:04:50,520 --> 00:04:52,680 TO A HOSPITAL IS FEVER OF 108 00:04:52,680 --> 00:04:54,520 UNKNOWN ORIGIN. 109 00:04:54,520 --> 00:04:56,680 WITHIN THAT LARGE GROUP OF 110 00:04:56,680 --> 00:04:59,200 ETIOLOGIC FACTORS THERE ARE 111 00:04:59,200 --> 00:05:00,880 PATIENTS WHO HAVE GENETIC 112 00:05:00,880 --> 00:05:04,280 DISTURBANCES THAT LEAD TO FEVER, 113 00:05:04,280 --> 00:05:06,080 AND THEY LEAD TO INFLAMMATION 114 00:05:06,080 --> 00:05:06,480 TOO. 115 00:05:06,480 --> 00:05:10,280 AND IT WAS THROUGH THIS STUDY 116 00:05:10,280 --> 00:05:15,360 WHEN HE CAME TO NIH, A FAMILIAL 117 00:05:15,360 --> 00:05:20,640 MEDITERRANEAN FEVER FOR WHICH HE 118 00:05:20,640 --> 00:05:22,280 IDENTIFIED THE FUNDAMENTAL 119 00:05:22,280 --> 00:05:27,160 DEFECT AND DISCOVERED THE AGENT, 120 00:05:27,160 --> 00:05:28,680 PYRIN, LATER PARTICIPATED IN 121 00:05:28,680 --> 00:05:32,000 CLONING THE GENE THAT OPENED THE 122 00:05:32,000 --> 00:05:34,080 DOOR TO AUTO-INFLAMMATORY 123 00:05:34,080 --> 00:05:38,680 DISEASES AS DISORDERS OF THE 124 00:05:38,680 --> 00:05:40,720 INNATE IMMUNE SYSTEM AND PURSUED 125 00:05:40,720 --> 00:05:43,240 THROUGHOUT HIS BRILLIANT CAREER 126 00:05:43,240 --> 00:05:48,080 AT NIH THE ELUCIDATION OF 127 00:05:48,080 --> 00:05:50,880 AUTO-INFLAMMATORY DISEASES, 128 00:05:50,880 --> 00:05:52,080 THEIR MECHANISMS, THEIR GENETICS 129 00:05:52,080 --> 00:05:53,480 AND MEANS OF THERAPY. 130 00:05:53,480 --> 00:05:56,280 FOR THIS WORK DAN HAS RECEIVED 131 00:05:56,280 --> 00:05:58,080 MANY AWARDS AND HONORS, 132 00:05:58,080 --> 00:06:00,280 INCLUDING ELECTION TO THE 133 00:06:00,280 --> 00:06:03,240 NATIONAL ACADEMY OF SCIENCES, 134 00:06:03,240 --> 00:06:08,320 NATIONAL ACADEMY OF MEDICINE, IN 135 00:06:08,320 --> 00:06:11,800 2018 FEDERAL EMPLOYEE OF THE 136 00:06:11,800 --> 00:06:14,560 YEAR, MORE RECENTLY RECEIVED THE 137 00:06:14,560 --> 00:06:20,080 ROSS PRIZE IN MOLECULAR 138 00:06:20,080 --> 00:06:22,560 MEDICINE, AND THE c-RAFFORD 139 00:06:22,560 --> 00:06:24,240 PRIZE IN POLY ARTHRITIS. 140 00:06:24,240 --> 00:06:31,000 HE WILL BE JOINED BY 141 00:06:31,000 --> 00:06:33,280 PROFESSIONAL COLLEAGUES DR. 142 00:06:33,280 --> 00:06:39,160 DANIELA SCHWARTZ, GRADUATED FROM 143 00:06:39,160 --> 00:06:44,280 RICE, M.D. WAKE FOREST, MEDICAL 144 00:06:44,280 --> 00:06:44,920 RESIDENCY VIRGINIA COMMONWEALTH 145 00:06:44,920 --> 00:06:45,640 UNIVERSITY, CLINICAL 146 00:06:45,640 --> 00:06:49,800 RHEUMATOLOGY AT NIH, FOLLOWED BY 147 00:06:49,800 --> 00:06:52,560 MEDSKER FELLOWSHIP WITH JOHN OH 148 00:06:52,560 --> 00:06:59,240 HEY AT NIH, AND IN 2018 GAME 149 00:06:59,240 --> 00:07:00,400 ASSISTANT CLINICAL INVESTIGATOR 150 00:07:00,400 --> 00:07:05,000 IN NIAID INTRAMURAL RESEARCH 151 00:07:05,000 --> 00:07:05,440 PROGRAM. 152 00:07:05,440 --> 00:07:08,120 NOTABLY WAS RECIPIENT OF THE 153 00:07:08,120 --> 00:07:12,680 PRESTIGIOUS AMERICAN SOCIETY OF 154 00:07:12,680 --> 00:07:15,480 CLINICAL INVESTIGATION YOUNG 155 00:07:15,480 --> 00:07:16,520 PHYSICIAN-SCIENTIST AWARD IN 156 00:07:16,520 --> 00:07:17,480 2020. 157 00:07:17,480 --> 00:07:24,280 AND SHE WILL BE JOINED BY DR. 158 00:07:24,280 --> 00:07:26,680 KALPANA MANTHIRAM, ASSISTANT 159 00:07:26,680 --> 00:07:30,440 CLINICAL INVESTIGATOR IN NIAID, 160 00:07:30,440 --> 00:07:30,680 AS WELL. 161 00:07:30,680 --> 00:07:33,960 KALPANA RECEIVED HER MEDICAL 162 00:07:33,960 --> 00:07:36,280 DEGREE FROM UNIVERSITY OF TEXAS 163 00:07:36,280 --> 00:07:38,680 SOUTHWESTERN, RESIDENCY IN 164 00:07:38,680 --> 00:07:42,440 PEDIATRICS AT BOSTON CHILDREN'S 165 00:07:42,440 --> 00:07:43,440 AND BOSTON MEDICAL CENTER, 166 00:07:43,440 --> 00:07:44,880 PEDIATRIC INFECTIOUS DISEASE 167 00:07:44,880 --> 00:07:46,000 FELLOWSHIP AT VANDERBILT, AND IT 168 00:07:46,000 --> 00:07:49,960 WAS THERE THAT SHE BEGAN TO WORK 169 00:07:49,960 --> 00:07:52,280 ON THE MOST COMMON PERIODIC 170 00:07:52,280 --> 00:07:54,520 FEVER SYNDROME IN CHILDREN. 171 00:07:54,520 --> 00:07:56,960 SHE THEN WAS A POSTDOCTORAL 172 00:07:56,960 --> 00:07:59,680 RESEARCHER IN THE KASTNER LAB IN 173 00:07:59,680 --> 00:08:01,960 THE GENOME INSTITUTE WHERE SHE 174 00:08:01,960 --> 00:08:08,160 HAS STUDIED GENETIC RISK LOCI 175 00:08:08,160 --> 00:08:10,080 AND PATHOGENESIS OF PERIODIC 176 00:08:10,080 --> 00:08:14,640 FEVER, HAVE HAD IN IMMUNOLOGIC 177 00:08:14,640 --> 00:08:15,480 MECHANISM OF MUCOSAL 178 00:08:15,480 --> 00:08:18,320 INFLAMMATORY DISEASES, TO 179 00:08:18,320 --> 00:08:21,480 DEVELOP TREATMENT GUIDELINES AND 180 00:08:21,480 --> 00:08:25,280 SHE PROVIDES MEDICAL CARE FOR 181 00:08:25,280 --> 00:08:27,960 PATIENTS WITH AUTO-INFLAMMATORY 182 00:08:27,960 --> 00:08:28,800 DISEASES. 183 00:08:28,800 --> 00:08:32,880 SO, WITH THIS INTRODUCTION, WE 184 00:08:32,880 --> 00:08:36,840 ALL ARE ANXIOUSLY AWAITING THE 185 00:08:36,840 --> 00:08:38,080 EXCITING PRESENTATION TO FOLLOW, 186 00:08:38,080 --> 00:08:41,760 AND SO, DAN, PLEASE CARRY ON. 187 00:08:41,760 --> 00:08:43,000 >> WIN, THAT WAS A WONDERFUL, 188 00:08:43,000 --> 00:08:43,720 KIND INTRODUCTION. 189 00:08:43,720 --> 00:08:46,600 IT IS MY ENORMOUS HONOR AND 190 00:08:46,600 --> 00:08:47,960 PLEASURE TO BE HERE THIS 191 00:08:47,960 --> 00:08:49,880 AFTERNOON, OR THIS MORNING, OR 192 00:08:49,880 --> 00:08:53,080 THIS EVENING, WHENEVER IT IS FOR 193 00:08:53,080 --> 00:08:54,720 THOSE OF YOU WHO ARE 194 00:08:54,720 --> 00:08:55,840 PARTICIPATING IN THIS EVENT. 195 00:08:55,840 --> 00:08:58,880 IN ANY CASE, WE'RE GOING TO BE 196 00:08:58,880 --> 00:09:00,320 TALKING ABOUT THE 197 00:09:00,320 --> 00:09:01,200 AUTO-INFLAMMATORY DISEASES AND 198 00:09:01,200 --> 00:09:04,720 THINKING ABOUT HOW THEY ARE 199 00:09:04,720 --> 00:09:05,640 ORGANIZED, AND PROBABLY BEFORE 200 00:09:05,640 --> 00:09:07,320 WE GO EVEN A LITTLE BIT FURTHER 201 00:09:07,320 --> 00:09:09,160 THERE'S A LITTLE BIT OF 202 00:09:09,160 --> 00:09:10,760 HOUSEKEEPING THAT WE HAVE TO DO. 203 00:09:10,760 --> 00:09:13,600 I SHOULD DISCLOSE TO YOU THAT IN 204 00:09:13,600 --> 00:09:16,560 FACT I AND MY COLLEAGUES, DR. 205 00:09:16,560 --> 00:09:37,400 SCHWARTZ AND DR. MANHATTAN 206 00:09:37,400 --> 00:09:38,320 MANTHIRAM HAVE NO RELEVANT 207 00:09:38,320 --> 00:09:41,000 , AND EXPLAIN HOW THE TOOLS OF 208 00:09:41,000 --> 00:09:43,800 HUMAN GENOMICS HAVE ADVANCED OUR 209 00:09:43,800 --> 00:09:45,720 UNDERSTANDING OF THE 210 00:09:45,720 --> 00:09:46,800 AUTO-INFLAMMATORY DISEASES. 211 00:09:46,800 --> 00:09:49,040 AND IN THE SPIRIT OF THESE 212 00:09:49,040 --> 00:09:53,040 SESSIONS, AS DR. ARIAS POINTED 213 00:09:53,040 --> 00:09:54,800 OUT, WE ARE ALL ABOUT BUILDING 214 00:09:54,800 --> 00:09:55,000 BRIDGES. 215 00:09:55,000 --> 00:09:56,960 HERE YOU SEE A PHOTOGRAPH OF MY 216 00:09:56,960 --> 00:10:00,440 LAB TAKEN BEFORE THE PANDEMIC, 217 00:10:00,440 --> 00:10:02,400 SO SOCIAL DISTANCING WAS NOT 218 00:10:02,400 --> 00:10:03,200 IMAGINED AT THAT TIME. 219 00:10:03,200 --> 00:10:08,080 NO ONE WAS WEARING A MASK. 220 00:10:08,080 --> 00:10:11,400 MY LAB AND CLINICAL TEAM ALSO 221 00:10:11,400 --> 00:10:13,520 BEFORE THE PANDEMIC. 222 00:10:13,520 --> 00:10:16,080 OF COURSE, THE BRIDGE THAT 223 00:10:16,080 --> 00:10:21,360 BRINGS THEM TOGETHER IS OUR 224 00:10:21,360 --> 00:10:22,720 PATIENTS, WHAT INSPIRES US IN 225 00:10:22,720 --> 00:10:26,520 TERMS OF POSING NEW QUESTIONS, 226 00:10:26,520 --> 00:10:27,760 THAT DRIVES US TO TRY TO 227 00:10:27,760 --> 00:10:34,200 UNDERSTAND HUMAN DISEASE AND 228 00:10:34,200 --> 00:10:35,720 DEVELOP TARGETED THERAPIES. 229 00:10:35,720 --> 00:10:36,400 FOR THOSE NOT IMMUNOLOGISTS JUST 230 00:10:36,400 --> 00:10:39,160 A LITTLE BIT ABOUT THE TWO 231 00:10:39,160 --> 00:10:40,280 FLAVORS OF IMMUNITY. 232 00:10:40,280 --> 00:10:42,800 FIRST OF ALL ON THE LEFT WE HAVE 233 00:10:42,800 --> 00:10:43,640 ADAPTIVE IMMUNITY. 234 00:10:43,640 --> 00:10:45,640 THE FORM OF IMMUNITY THAT MANY 235 00:10:45,640 --> 00:10:48,480 OF YOU THINK OF, WHEN WE TALK 236 00:10:48,480 --> 00:10:51,040 ABOUT THE IMMUNE SYSTEM. 237 00:10:51,040 --> 00:10:52,920 IN WHICH T AND B LYMPHOCYTES ARE 238 00:10:52,920 --> 00:10:56,800 THE MAJOR PLAYERS, IN WHICH THE 239 00:10:56,800 --> 00:11:03,000 GENES FOR RECEPTORS, SOMATICALLY 240 00:11:03,000 --> 00:11:05,200 REARRANGE AND MUTATE, AND 241 00:11:05,200 --> 00:11:06,880 AUTOIMMUNE DISEASES ARE 242 00:11:06,880 --> 00:11:09,800 CHARACTERIZED BY HIGH TITER 243 00:11:09,800 --> 00:11:10,480 AUTOANTIBODIES OR ANTIGEN 244 00:11:10,480 --> 00:11:12,360 SPECIFIC T CELLS. 245 00:11:12,360 --> 00:11:21,320 ON THE OTHER HAND WE HAVE PHYLO 246 00:11:21,320 --> 00:11:22,760 GENETICALLY SYSTEM, MYELOCYTES 247 00:11:22,760 --> 00:11:24,720 OR MONOCYTES OR MACROPHAGES ARE 248 00:11:24,720 --> 00:11:27,440 THE MAJOR EFFECTORS, WHERE 249 00:11:27,440 --> 00:11:30,400 RECEPTORS OR GENES FOR RECEPTORS 250 00:11:30,400 --> 00:11:35,400 ARE HARD WIRED IN THE GERMLINE 251 00:11:35,400 --> 00:11:36,000 GENOME, AUTO-INFLAMMATORY 252 00:11:36,000 --> 00:11:45,480 DISEASES ARE CHARACTERIZEDDED BY 253 00:11:45,480 --> 00:11:46,600 SEEMINGLY UNPROVOKED 254 00:11:46,600 --> 00:11:47,600 INFLAMMATION. 255 00:11:47,600 --> 00:11:49,560 MY INTRODUCTION TO THE 256 00:11:49,560 --> 00:11:56,520 AUTO-INFLAMMATORY DISEASES 257 00:11:56,520 --> 00:11:59,240 OCCURRED BEFORE THE TERM 258 00:11:59,240 --> 00:12:01,200 AUTO-INFLAMMATORY EXISTED, IN 259 00:12:01,200 --> 00:12:02,520 1985, I AS A NEW RHEUMATOLOGY 260 00:12:02,520 --> 00:12:06,240 FELLOW AT NIH SAW A PATIENT, A 261 00:12:06,240 --> 00:12:07,800 YOUNG MAN OF ARMENIA ANCESTRY, 262 00:12:07,800 --> 00:12:10,960 WHO PRESENTED TO US WITH A 263 00:12:10,960 --> 00:12:13,400 HISTORY OF LIFELONG ATTACKS OF 264 00:12:13,400 --> 00:12:16,240 FEVER USUALLY ON THE ORDER OF 265 00:12:16,240 --> 00:12:18,120 ONCE A MONTH, WITH ARTHRITIS, 266 00:12:18,120 --> 00:12:19,880 AFFECTING EITHER ONE JOINT OR 267 00:12:19,880 --> 00:12:21,520 SOMETIMES A COUPLE JOINTS AT A 268 00:12:21,520 --> 00:12:21,720 TIME. 269 00:12:21,720 --> 00:12:23,440 USUALLY IT WOULD BE THE KNEE OR 270 00:12:23,440 --> 00:12:24,400 ANKLE. 271 00:12:24,400 --> 00:12:26,560 THE KNEE COULD SWELL UP TO AN 272 00:12:26,560 --> 00:12:28,800 ENORMOUS SIZE, LIKE A 273 00:12:28,800 --> 00:12:30,800 GRAPEFRUIT, AS THEY SAY. 274 00:12:30,800 --> 00:12:32,440 AND AFTER HEARING HIS STORY, I 275 00:12:32,440 --> 00:12:34,800 DIDN'T KNOW WHAT REALLY HE HAD 276 00:12:34,800 --> 00:12:36,520 BUT FORTUNATELY THERE WERE 277 00:12:36,520 --> 00:12:38,600 COLLEAGUES OF MINE IN THE LAB 278 00:12:38,600 --> 00:12:39,760 FROM ISRAEL WHO DID RECOGNIZE 279 00:12:39,760 --> 00:12:42,240 THIS STORY VERY WELL AND POINTED 280 00:12:42,240 --> 00:12:45,600 OUT TO ME THAT THIS WAS PROBABLY 281 00:12:45,600 --> 00:12:46,720 FAMILIAL MEDITERRANEAN FEVER. 282 00:12:46,720 --> 00:12:49,680 SO FOR THOSE OF YOU WHO ARE NOT 283 00:12:49,680 --> 00:12:51,800 FAMILIAR WITH FMF LET ME DIGRESS 284 00:12:51,800 --> 00:12:54,640 FOR A MOMENT TO SAY FMF WAS 285 00:12:54,640 --> 00:12:56,800 FIRST DESCRIBED AT LEAST AS A 286 00:12:56,800 --> 00:12:58,520 SERIES OF PATIENTS BY DR. 287 00:12:58,520 --> 00:13:01,160 SHEPARD SEGAL, A PHYSICIAN AT 288 00:13:01,160 --> 00:13:06,000 MOUNT SINAI HOSPITAL IN NEW YORK 289 00:13:06,000 --> 00:13:06,880 IN 1945. 290 00:13:06,880 --> 00:13:09,200 AT THAT TIME, HE DESCRIBED 10 291 00:13:09,200 --> 00:13:11,600 PATIENTS WHO WERE OF JEWISH 292 00:13:11,600 --> 00:13:14,600 ANCESTRY, AND HAD A HISTORY OF 293 00:13:14,600 --> 00:13:17,760 RECURRENT EPISODES OF SEVERE 294 00:13:17,760 --> 00:13:18,280 ABDOMINAL PAIN, SOMETIMES 295 00:13:18,280 --> 00:13:24,480 PROMPTING EXPLORATORY 296 00:13:24,480 --> 00:13:25,080 LAPAROTOMY. 297 00:13:25,080 --> 00:13:29,080 IT WAS NOT CANCER, NO DISEASE 298 00:13:29,080 --> 00:13:36,280 ASSOCIATED WITH IT, BENIGN 299 00:13:36,280 --> 00:13:37,800 PAROXYSMAL PERITONITIS, 300 00:13:37,800 --> 00:13:39,000 RECOGNIZED AS JEWISH POPULATIONS 301 00:13:39,000 --> 00:13:41,560 WITH EMIGRATING TO ISRAEL IN THE 302 00:13:41,560 --> 00:13:47,520 1950s, DUBBED FAMILIAR 303 00:13:47,520 --> 00:13:48,320 FAMILIAL MEDITERRANEAN FEVER, 304 00:13:48,320 --> 00:13:52,600 DETERMINED IT WAS A RECESSIVELY 305 00:13:52,600 --> 00:13:54,640 INHERITED DISEASE AND OTHER 306 00:13:54,640 --> 00:13:57,520 GROUPS FOUND FAMILIAL 307 00:13:57,520 --> 00:14:00,080 MEDITERRANEAN FEVER COMMON IN 308 00:14:00,080 --> 00:14:01,440 JEWISH, ARAB, ARMENIA, TURKISH 309 00:14:01,440 --> 00:14:03,680 POPULATIONS AS WELL AS SOME 310 00:14:03,680 --> 00:14:06,000 OTHER MEDITERRANEAN POPULATIONS. 311 00:14:06,000 --> 00:14:07,800 CLINICAL FEATURES OF FMF INCLUDE 312 00:14:07,800 --> 00:14:15,480 AS THE NAME SAYS FEVER, ALSO 313 00:14:15,480 --> 00:14:16,200 STERILE PERITONITIS, ARTHRITIS 314 00:14:16,200 --> 00:14:19,280 AS WAS THE CASE FOR MY FIRST 315 00:14:19,280 --> 00:14:22,400 PATIENT, PLEURISY, SOME PATIENTS 316 00:14:22,400 --> 00:14:23,880 WILL HAVE DEPOSITION OF 317 00:14:23,880 --> 00:14:26,200 INFLAMMATORY PROTEIN, CLEAVAGE 318 00:14:26,200 --> 00:14:27,400 PRODUCT OF INFLAMMATORY PROTEIN 319 00:14:27,400 --> 00:14:29,840 IN THE KIDNEYS AND OTHER VITAL 320 00:14:29,840 --> 00:14:32,480 ORGANS, AND BEFORE THERE WERE 321 00:14:32,480 --> 00:14:35,320 TREATMENTS FOR FMF THOSE 322 00:14:35,320 --> 00:14:36,200 PATIENTS WOULD DEVELOP KIDNEY 323 00:14:36,200 --> 00:14:38,240 FAILURE, EVEN DIE FROM THE 324 00:14:38,240 --> 00:14:38,600 KIDNEY FAILURE. 325 00:14:38,600 --> 00:14:41,520 SO, BACK WHEN I FIRST SAW THAT 326 00:14:41,520 --> 00:14:42,680 PATIENT THIS WAS INCREDIBLY 327 00:14:42,680 --> 00:14:43,760 EXCITING, AS AN INTERESTING 328 00:14:43,760 --> 00:14:45,800 DISEASE, CAUSE OF IT WAS NOT 329 00:14:45,800 --> 00:14:46,440 KNOWN. 330 00:14:46,440 --> 00:14:48,080 IT WAS VERY STIMULATING TO THINK 331 00:14:48,080 --> 00:14:50,240 ABOUT WHAT COULD BE THE CAUSE OF 332 00:14:50,240 --> 00:14:50,400 IT. 333 00:14:50,400 --> 00:14:52,960 AND CERTAINLY AT THAT TIME THE 334 00:14:52,960 --> 00:14:54,800 HUMAN GENOME PROJECT WAS JUST 335 00:14:54,800 --> 00:14:57,200 COMING TO THE FORE, AS A WAY 336 00:14:57,200 --> 00:15:00,040 MAYBE OF FIGURING OUT WHAT THE 337 00:15:00,040 --> 00:15:01,160 CAUSE OF FMF MIGHT BE. 338 00:15:01,160 --> 00:15:09,040 I SORT OF TOOK TO THIS IN IN 339 00:15:09,040 --> 00:15:10,680 EARNEST WHEN I FINISHED MY 340 00:15:10,680 --> 00:15:11,920 CLINICAL WORK IN 1988. 341 00:15:11,920 --> 00:15:14,240 IN 1988 COULD WE FIND THE 342 00:15:14,240 --> 00:15:17,280 RECESSIVE GENE THAT IS MUTATED 343 00:15:17,280 --> 00:15:19,160 IN FAMILIAL MEDITERRANEAN FEVER? 344 00:15:19,160 --> 00:15:24,400 JUST AS BACKGROUND ON THAT, IN 345 00:15:24,400 --> 00:15:27,400 1978, TEN YEARS BEFORE, DR. YW 346 00:15:27,400 --> 00:15:32,280 KAHN, WHO WAS AND STILL IS A 347 00:15:32,280 --> 00:15:32,800 PROFESSOR OF HEMATOLOGY AT 348 00:15:32,800 --> 00:15:33,440 UNIVERSITY OF CALIFORNIA, SAN 349 00:15:33,440 --> 00:15:35,800 FRANCISCO, FOR THE FIRST TIME 350 00:15:35,800 --> 00:15:37,840 EVER FOUND THAT A POLYMORPHISM 351 00:15:37,840 --> 00:15:41,400 IN DNA, A VARIATION IN DNA, 352 00:15:41,400 --> 00:15:44,360 COULD BE IDENTIFIED AND POST 353 00:15:44,360 --> 00:15:45,960 SEGREGATED WITH DISEASE IN A 354 00:15:45,960 --> 00:15:46,320 FAMILY. 355 00:15:46,320 --> 00:15:47,880 A FAMILY WITH SICKLE CELL 356 00:15:47,880 --> 00:15:48,120 ANEMIA. 357 00:15:48,120 --> 00:15:51,800 THE FIRST TIME A DNA MARKER THAT 358 00:15:51,800 --> 00:15:53,760 SEGREGATED WITH DISEASE IN A 359 00:15:53,760 --> 00:15:57,040 FAMILY HAD BEEN IDENTIFIED. 360 00:15:57,040 --> 00:15:57,240 1978. 361 00:15:57,240 --> 00:16:00,920 AND THEN A COUPLE YEARS LATER, 362 00:16:00,920 --> 00:16:02,240 IN 1980 DAVID BOTSTEIN SAID, 363 00:16:02,240 --> 00:16:05,080 WELL, IF YOU CAN DO THAT WITH 364 00:16:05,080 --> 00:16:06,400 ONE MARKER IN ONE FAMILY, THEN 365 00:16:06,400 --> 00:16:08,400 WE COULD MAKE A WHOLE BUNCH OF 366 00:16:08,400 --> 00:16:10,640 MARKERS AND A WHOLE BUNCH OF -- 367 00:16:10,640 --> 00:16:13,640 FROM A WHOLE BUNCH OF FAMILIES, 368 00:16:13,640 --> 00:16:15,400 AND IN FACT IDENTIFY A MAP, 369 00:16:15,400 --> 00:16:17,800 BUILD A MAP OF MARKERS 370 00:16:17,800 --> 00:16:19,280 THROUGHOUT THE HUMAN GENOME, AND 371 00:16:19,280 --> 00:16:22,360 COULD USE THAT TO MAP HUMAN 372 00:16:22,360 --> 00:16:24,080 DISEASE GENES AND EVEN TO 373 00:16:24,080 --> 00:16:27,280 IDENTIFY THOSE GENES EVENTUALLY. 374 00:16:27,280 --> 00:16:27,560 1980. 375 00:16:27,560 --> 00:16:30,600 AND THEN IN 1988, HERE'S FRANCIS 376 00:16:30,600 --> 00:16:33,880 COLLINS, HOT IN THE PURSUIT OF 377 00:16:33,880 --> 00:16:35,440 THE GENE FOR CYSTIC FIBROSIS, 378 00:16:35,440 --> 00:16:39,160 ALTHOUGH HE HAD NOT YET FOUND IT 379 00:16:39,160 --> 00:16:39,920 IN 1988. 380 00:16:39,920 --> 00:16:41,240 AT THAT POINT IT SEEMED LIKE 381 00:16:41,240 --> 00:16:44,640 MAYBE WE COULD FIND THE GENE FOR 382 00:16:44,640 --> 00:16:46,120 FAMILIAL MEDITERRANEAN FEVER, IT 383 00:16:46,120 --> 00:16:47,400 HADN'T YET BEEN DONE IN EXACTLY 384 00:16:47,400 --> 00:16:48,960 THAT WAY, THAT FAR. 385 00:16:48,960 --> 00:16:51,200 BUT MAYBE WORTH A TRY. 386 00:16:51,200 --> 00:16:53,680 AND SO I ESTABLISHED A 387 00:16:53,680 --> 00:16:54,920 COLLABORATION WITH THE SHEBA 388 00:16:54,920 --> 00:16:56,160 MEDICAL CENTER IN ISRAEL, AND 389 00:16:56,160 --> 00:17:01,680 HAD A FIELD TRIP IN THE SUMMER 390 00:17:01,680 --> 00:17:06,200 OF 1989 WITH MY COLLEAGUE AND 391 00:17:06,200 --> 00:17:07,560 COLLABORATOR, WE VISITED A 392 00:17:07,560 --> 00:17:10,200 NUMBER OF FAMILIES WITH FAMILIAL 393 00:17:10,200 --> 00:17:11,400 MEDITERRANEAN FEVER, IN ISRAEL, 394 00:17:11,400 --> 00:17:14,000 SOME CAME TO HIS CLINIC, SOME WE 395 00:17:14,000 --> 00:17:15,200 WENT TO THEIR HOUSES. 396 00:17:15,200 --> 00:17:16,800 HERE IS A PHOTOGRAPH OF ONE OF 397 00:17:16,800 --> 00:17:19,600 THOSE FAMILIES, THIS PHOTOGRAPH 398 00:17:19,600 --> 00:17:22,520 HAS BEEN ADJUSTED TO COMPLY WITH 399 00:17:22,520 --> 00:17:26,120 HIPAA REQUIREMENTS SO THAT NO 400 00:17:26,120 --> 00:17:27,800 CONFIDENTIALITY WOULD BE 401 00:17:27,800 --> 00:17:28,320 BREACHED. 402 00:17:28,320 --> 00:17:29,240 IN ANY CASE, HERE THEY ARE, ONE 403 00:17:29,240 --> 00:17:32,160 OF THOSE FAMILIES. 404 00:17:32,160 --> 00:17:35,000 HERE'S A WHOLE SET OF PEDIGREEES 405 00:17:35,000 --> 00:17:37,920 WE DREW BLOOD FROM DURING THAT 406 00:17:37,920 --> 00:17:38,160 TIME. 407 00:17:38,160 --> 00:17:42,720 AND HERE'S MY LAB A YEAR OR SO 408 00:17:42,720 --> 00:17:43,200 LATER. 409 00:17:43,200 --> 00:17:45,120 MY FIRST POSTDOC WHO HAS GONE ON 410 00:17:45,120 --> 00:17:50,280 TO HAVE A DISTINGUISHED YEAR IN 411 00:17:50,280 --> 00:17:52,400 HUMAN GENETICS, LUIS GRU BRERG, 412 00:17:52,400 --> 00:17:53,680 WHO BECAME A CASHEDDOLOGYIST, 413 00:17:53,680 --> 00:17:56,240 TRYING TO USE NEW TECHNIQUES OF 414 00:17:56,240 --> 00:17:58,320 HUMAN GENOMICS TO FIND THAT GENE 415 00:17:58,320 --> 00:18:00,880 BUT AT THAT TIME THERE WERE ONLY 416 00:18:00,880 --> 00:18:02,520 ABOUT 300 MARKERS THROUGHOUT THE 417 00:18:02,520 --> 00:18:03,200 WHOLE HUMAN GENOME. 418 00:18:03,200 --> 00:18:05,840 SO THERE WAS AT LEAST A CHANCE 419 00:18:05,840 --> 00:18:09,000 THAT WE'D NEVER FIND IT, IF THE 420 00:18:09,000 --> 00:18:10,480 GENE WAS IN THE WRONG PLACE 421 00:18:10,480 --> 00:18:13,760 RELATIVE TO THE MARKERS. 422 00:18:13,760 --> 00:18:15,600 WELL, FORTUNATELY, WE PERSISTED 423 00:18:15,600 --> 00:18:17,280 AND EVENTUALLY DID FIGURE OUT 424 00:18:17,280 --> 00:18:20,320 THAT THE GENE FOR FMF, THIS WAS 425 00:18:20,320 --> 00:18:22,640 IN 1992, IS ON THE SHORT ARM OF 426 00:18:22,640 --> 00:18:23,840 CHROMOSOME 16. 427 00:18:23,840 --> 00:18:25,680 SO THAT WAS GREAT. 428 00:18:25,680 --> 00:18:27,720 BUT THEN WE HAD OUR NEXT JOB CUT 429 00:18:27,720 --> 00:18:30,240 OUT FOR US, WHICH WAS ACTUALLY 430 00:18:30,240 --> 00:18:32,560 TO DEVELOP MAPS OF THAT REGION 431 00:18:32,560 --> 00:18:34,160 OF CHROMOSOME 16 BECAUSE IT HAD 432 00:18:34,160 --> 00:18:34,800 NOT BEEN MAPPED. 433 00:18:34,800 --> 00:18:38,240 AND SO IT WAS UP TO US AS THE 434 00:18:38,240 --> 00:18:40,400 EXPLORERS OF THAT REGION OF 435 00:18:40,400 --> 00:18:42,880 CHROMOSOME 16 AND WE HAD A 436 00:18:42,880 --> 00:18:45,600 COUPLE OF GENETIC MARKERS THAT 437 00:18:45,600 --> 00:18:46,480 ULTIMATELY WE HAD NARROWED 438 00:18:46,480 --> 00:18:50,920 THINGS DOWN TO AND THEN WE USED 439 00:18:50,920 --> 00:18:56,840 A SET OF COSMIDS THAT HAD BEEN 440 00:18:56,840 --> 00:18:59,960 DEVELOPED AT A LABORATORY AT 441 00:18:59,960 --> 00:19:01,120 DEPARTMENT OF ENERGY AT LOS 442 00:19:01,120 --> 00:19:07,400 ALAMOS, HOME OF THE ATOMIC BOMB. 443 00:19:07,400 --> 00:19:10,000 I SET UP A COLLABORATION WITH 444 00:19:10,000 --> 00:19:10,200 THEM. 445 00:19:10,200 --> 00:19:12,800 WE ESTABLISHED THIS MAP GOING 446 00:19:12,800 --> 00:19:15,400 FROM TELOMERES TO THE 447 00:19:15,400 --> 00:19:17,440 CENTROMERE, ULTIMATELY WE WERE 448 00:19:17,440 --> 00:19:23,400 ABLE TO CREATE THESE OVERLAPPING 449 00:19:23,400 --> 00:19:26,200 COSMIDS IS, A MAP OF OVERLAPPING 450 00:19:26,200 --> 00:19:28,600 COMS, A MILLION BASE PAIRS IN 451 00:19:28,600 --> 00:19:32,440 SIZE COVERED BY 170 OR SO 452 00:19:32,440 --> 00:19:35,920 COMSES, USING THAT WERE ABLE TO 453 00:19:35,920 --> 00:19:38,080 NARROW THINGS DOWN TO 100,000 454 00:19:38,080 --> 00:19:40,240 BASE CARES, 100 KB. 455 00:19:40,240 --> 00:19:42,560 THEN WE USED A TYPE OF PLASMID 456 00:19:42,560 --> 00:19:47,080 THAT ALLOWED US TO PULL OUT 457 00:19:47,080 --> 00:19:47,280 EXONS. 458 00:19:47,280 --> 00:19:55,360 YOU SEE THE COSMIDS HAD NOT 459 00:19:55,360 --> 00:19:57,040 BEEN SEQUENCED, THE TOE HOLD TO 460 00:19:57,040 --> 00:19:59,400 FIND THE GENE, THAT TOOK US 461 00:19:59,400 --> 00:20:00,480 UNTIL 1997. 462 00:20:00,480 --> 00:20:02,400 SO NINE YEARS ALTOGETHER FROM 463 00:20:02,400 --> 00:20:05,160 THE TIME OF STARTING THIS 464 00:20:05,160 --> 00:20:11,800 PROJECT TO ACTUALLY FINDING THE 465 00:20:11,800 --> 00:20:17,000 GENE MUTATED, AND DENOTED THAT 466 00:20:17,000 --> 00:20:17,600 AS PYRIN. 467 00:20:17,600 --> 00:20:18,520 IT WAS ABSOLUTELY WORTH IT 468 00:20:18,520 --> 00:20:20,240 BECAUSE THIS TURNED OUT TO BE A 469 00:20:20,240 --> 00:20:25,800 GENE THAT ENCODED A PROTEIN THAT 470 00:20:25,800 --> 00:20:27,400 WAS NOT KNOWN BEFORE, THAT WAS 471 00:20:27,400 --> 00:20:28,160 THE BEAUTY ESPECIALLY AT THE 472 00:20:28,160 --> 00:20:31,240 TIME, YOU COULD FIND THESE 473 00:20:31,240 --> 00:20:34,640 THINGS THAT WERE TOTALLY NEW AND 474 00:20:34,640 --> 00:20:37,240 HADN'T BEEN SEEN BEFORE, 475 00:20:37,240 --> 00:20:38,200 RECOGNIZED BEFORE, IMAGINED 476 00:20:38,200 --> 00:20:38,920 BEFORE EVEN. 477 00:20:38,920 --> 00:20:41,040 AND OF COURSE I HAD A NUMBER OF 478 00:20:41,040 --> 00:20:42,520 COLLABORATORS, WE HAD A NUMBER 479 00:20:42,520 --> 00:20:48,800 OF COLLABORATORS AT THAT TIME. 480 00:20:48,800 --> 00:20:50,760 RIGHT OFF WE FOUND INTERESTING 481 00:20:50,760 --> 00:20:51,600 THINGS ABOUT POPULATION BIOLOGY 482 00:20:51,600 --> 00:20:52,800 OF FMF. 483 00:20:52,800 --> 00:20:56,160 WE FOUND THAT MODERN DAY 484 00:20:56,160 --> 00:20:59,400 CARRIERS OF FMF MUTATIONS IN 485 00:20:59,400 --> 00:21:02,680 FACT ARE DESCENDED FROM ANCIENT 486 00:21:02,680 --> 00:21:04,200 FOUNDERS FROM BIBLICAL TIMES 487 00:21:04,200 --> 00:21:04,440 PROBABLY. 488 00:21:04,440 --> 00:21:07,720 SO THAT, FOR EXAMPLE, THERE'S 489 00:21:07,720 --> 00:21:12,280 THIS ONE MUTATION CALLED V726A, 490 00:21:12,280 --> 00:21:15,680 PROJECTED PATH IS SHOWN ON THIS 491 00:21:15,680 --> 00:21:16,120 MAP. 492 00:21:16,120 --> 00:21:18,400 SO V726A IS FOUND IN THE 493 00:21:18,400 --> 00:21:20,240 ASHKENAZI JEWISH POPULATION OF 494 00:21:20,240 --> 00:21:23,840 EASTERN EUROPE, IT'S FOUND IN 495 00:21:23,840 --> 00:21:27,200 TURKISH POPULATION, ARMENIANS, 496 00:21:27,200 --> 00:21:28,360 IRAQI JEWS, EVEN AN ISOLATED 497 00:21:28,360 --> 00:21:30,080 POPULATION IN THE MIDDLE EAST. 498 00:21:30,080 --> 00:21:31,400 HOW DO WE KNOW THEY ARE 499 00:21:31,400 --> 00:21:32,440 CONNECTED WITH ONE ANOTHER? 500 00:21:32,440 --> 00:21:34,840 BECAUSE THEY HAVE THE SAME 501 00:21:34,840 --> 00:21:38,760 MUTATION ON THE SAME DNA 502 00:21:38,760 --> 00:21:39,480 FINGERPRINT OF CHROMOSOMES, AND 503 00:21:39,480 --> 00:21:42,880 SO BASICALLY WE CAN TELL BY THE 504 00:21:42,880 --> 00:21:44,600 OTHER DNA MARKERS THAT IN FACT 505 00:21:44,600 --> 00:21:48,640 THERE WAS A COMMON ANCESTOR. 506 00:21:48,640 --> 00:21:49,640 SIMILARLY FOR THE M694V MUTATION 507 00:21:49,640 --> 00:21:51,920 YOU SEE THE DOTTED LINE HERE, 508 00:21:51,920 --> 00:21:56,240 DASHED LINE. 509 00:21:56,240 --> 00:21:58,600 THAT MUTATION IS SEEN IN THE 510 00:21:58,600 --> 00:22:01,400 SAFARDI JEWISH POPULATION OF 511 00:22:01,400 --> 00:22:02,560 NORTH AFRICA, TURKISH, ARMENIA, 512 00:22:02,560 --> 00:22:05,640 IRAQI JEWISH POPULATION AS WELL. 513 00:22:05,640 --> 00:22:08,880 AGAIN, SAME MUTATION ON THE SAME 514 00:22:08,880 --> 00:22:10,720 ANCESTRAL CHROMOSOME, A 515 00:22:10,720 --> 00:22:12,800 DIFFERENT ANCESTRAL CHROMOSOME 516 00:22:12,800 --> 00:22:14,800 FROM V 726A. 517 00:22:14,800 --> 00:22:16,560 WE'LL COME BACK TO THAT 518 00:22:16,560 --> 00:22:17,680 FASCINATING OBSERVATION. 519 00:22:17,680 --> 00:22:19,120 IN ADDITION, WE DID LEARN 520 00:22:19,120 --> 00:22:22,680 SOMETHING ABOUT THE BIOLOGY OF 521 00:22:22,680 --> 00:22:23,000 INFLAMMATION. 522 00:22:23,000 --> 00:22:23,960 WE LEARNED EVENTUALLY, NOT RIGHT 523 00:22:23,960 --> 00:22:25,400 AWAY, IT TOOK A LITTLE BIT OF 524 00:22:25,400 --> 00:22:27,600 TIME, BUT WE LEARNED THAT IN 525 00:22:27,600 --> 00:22:30,440 FACT THE N-TERMINUS OF THIS 526 00:22:30,440 --> 00:22:32,320 PROTEIN, PYRIN PROTEIN ENCODED 527 00:22:32,320 --> 00:22:36,640 BY THE GENE MUTATED IN FMF, 528 00:22:36,640 --> 00:22:42,760 ENCODES A DOMAIN CALLED THE 529 00:22:42,760 --> 00:22:45,240 PYRIN DOMAIN. 530 00:22:45,240 --> 00:22:50,880 THIS ALLOWS FOR THE FORMATION OF 531 00:22:50,880 --> 00:22:53,480 A CHARGE DIPOLE, YOU CAN SEE THE 532 00:22:53,480 --> 00:22:54,480 POSITIVE CHARGES IN BLUE, 533 00:22:54,480 --> 00:22:56,240 NEGATIVE CHARGES ARE IN RED, AND 534 00:22:56,240 --> 00:22:59,000 SO YOU CAN HAVE A SITUATION 535 00:22:59,000 --> 00:23:04,720 WHERE THE PYRIN DOMAIN OF ONE 536 00:23:04,720 --> 00:23:10,600 PROTEIN INTERACTS WITH PYRIN 537 00:23:10,600 --> 00:23:12,440 DOMAIN BY VIRTUE OF 538 00:23:12,440 --> 00:23:13,720 POSITIVE-NEGATIVE CHARGES, A 539 00:23:13,720 --> 00:23:16,800 FUNDAMENTAL WAY PROTEINS OF THE 540 00:23:16,800 --> 00:23:17,600 INNATE IMMUNE SYSTEM CAN 541 00:23:17,600 --> 00:23:24,200 INTERACT WITH EACH OTHER IS BY 542 00:23:24,200 --> 00:23:25,040 COGNATE PYRIN DOMAIN 543 00:23:25,040 --> 00:23:27,400 INTERACTIONS, THERE ARE SOME 20 544 00:23:27,400 --> 00:23:29,200 PROTEINS IN THE HUMAN GENOME 545 00:23:29,200 --> 00:23:31,400 THAT HAVE A PYRIN DOMAIN. 546 00:23:31,400 --> 00:23:33,200 WHO ILLUSTRATE WHAT HAPPENS, WE 547 00:23:33,200 --> 00:23:34,720 HAVE A SILENT MOVIE. 548 00:23:34,720 --> 00:23:37,000 SO HERE WE GO. 549 00:23:37,000 --> 00:23:42,040 THIS MOVIE IS ENTITLED THE 550 00:23:42,040 --> 00:23:43,200 INFLAMMASOME, IT'S A 551 00:23:43,200 --> 00:23:45,680 MACROMOLECULAR COMPLEX THAT 552 00:23:45,680 --> 00:23:46,560 ACTIVATES CERTAIN CYTOKINES, 553 00:23:46,560 --> 00:23:47,400 CERTAIN MEDIATORS OF 554 00:23:47,400 --> 00:23:47,720 INFLAMMATION. 555 00:23:47,720 --> 00:23:53,400 WE SEE THE STAR OF THE SHOW, THE 556 00:23:53,400 --> 00:23:55,760 INACTIVE NLRP 3, NOT PYRIN, IT'S 557 00:23:55,760 --> 00:24:03,200 LIKE PYRIN, HAS A PYRIN DOMAIN 558 00:24:03,200 --> 00:24:05,800 AT THE END, N-TERMINUS, THE RED 559 00:24:05,800 --> 00:24:15,400 CLOWN NOSE APPEARANCE ON THE END 560 00:24:15,400 --> 00:24:20,880 OF THE NLLRP 3. 3. 561 00:24:20,880 --> 00:24:22,760 THE NLRP 3 PEOPLE MADE THE 562 00:24:22,760 --> 00:24:23,200 MOVIE. 563 00:24:23,200 --> 00:24:25,800 HERE YOU SEE THE DISC FORMING, 564 00:24:25,800 --> 00:24:29,920 BY THE INTERACTION OF PYRIN 565 00:24:29,920 --> 00:24:30,800 DOMAINS, LIFE-LIKE INTERACTIONS 566 00:24:30,800 --> 00:24:32,120 FROM DIFFERENT PROTEINS. 567 00:24:32,120 --> 00:24:34,320 HERE IT IS COMING ON A SIDE 568 00:24:34,320 --> 00:24:36,840 VIEW, LOOKS LIKES A FLYING 569 00:24:36,840 --> 00:24:38,200 SAUCER COMING IN. 570 00:24:38,200 --> 00:24:39,400 NOW YOU'LL SEE SOMETHING 571 00:24:39,400 --> 00:24:40,320 INCREDIBLE HAPPEN. 572 00:24:40,320 --> 00:24:42,480 THAT IS THAT YOU HAVE OTHER 573 00:24:42,480 --> 00:24:44,080 MOLECULES COMING IN THAT ARE 574 00:24:44,080 --> 00:24:44,960 CALLED ASC. 575 00:24:44,960 --> 00:24:48,600 I WON'T TELL YOU WHAT IT STANDS 576 00:24:48,600 --> 00:24:50,160 FOR, THEY HAVE A RED PYRIN 577 00:24:50,160 --> 00:24:51,480 DOMAIN AT ONE END. 578 00:24:51,480 --> 00:24:55,400 YOU SEE IT'S FORMING A FILAMENT 579 00:24:55,400 --> 00:24:56,680 OF LIKE-LIKE INTERACTIONS, AND 580 00:24:56,680 --> 00:24:58,600 STICKING OUT ON THE OUTSIDE ARE 581 00:24:58,600 --> 00:25:02,920 THESE BROWN DOMAINS, WHICH ARE 582 00:25:02,920 --> 00:25:04,720 CALLED CARD DOMAINS, SIMILAR TO 583 00:25:04,720 --> 00:25:06,200 PYRIN DOMAINS BUT HAVE THEIR OWN 584 00:25:06,200 --> 00:25:07,400 SET OF INTERACTIONS. 585 00:25:07,400 --> 00:25:10,400 NOW YOU'RE GOING TO SEE TEST 586 00:25:10,400 --> 00:25:13,200 BASE 1, ENZYME THAT CAN CLEAVE 587 00:25:13,200 --> 00:25:15,440 CYTOKINES, IT'S COMING IN AND 588 00:25:15,440 --> 00:25:18,640 BINDING TO THESE FILAMENTS BY 589 00:25:18,640 --> 00:25:20,680 VIRTUE OF CAR DOMAIN 590 00:25:20,680 --> 00:25:21,000 INTERACTION. 591 00:25:21,000 --> 00:25:23,400 YOU SEE CASPASE 1 HAS A CARD 592 00:25:23,400 --> 00:25:25,360 DOMAIN, AND ASC HAS A CARD 593 00:25:25,360 --> 00:25:27,400 DOMAIN. 594 00:25:27,400 --> 00:25:29,760 NOW THEY ARE ASSEMBLED, 595 00:25:29,760 --> 00:25:30,560 SELF-ACTIVATING, CLEAVING 596 00:25:30,560 --> 00:25:33,960 MOLECULES OF IL-1 AND IL-18, 597 00:25:33,960 --> 00:25:34,600 WHICH ARE PRO-INFLAMMATORY 598 00:25:34,600 --> 00:25:38,360 CYTOKINES, AND NOW HERE YOU SEE 599 00:25:38,360 --> 00:25:45,160 COMING IN THE BLUE AND GRAY 600 00:25:45,160 --> 00:25:47,360 MOLECULE, GASORIMIN D, THE 601 00:25:47,360 --> 00:25:47,840 N-TERMINAL FRAGMENTS ARE 602 00:25:47,840 --> 00:25:51,400 FLOATING OFF TO THE RIGHT NOW, 603 00:25:51,400 --> 00:25:52,360 THE INFLAMMASOME IS 604 00:25:52,360 --> 00:25:53,680 DISASSEMBLING AND FLOATING OFF. 605 00:25:53,680 --> 00:25:59,000 AND IN A MOMENT WE'RE GOING TO 606 00:25:59,000 --> 00:26:03,000 SEE THE N-TERMINAL FRAGMENTS 607 00:26:03,000 --> 00:26:06,560 COMING IN FOR THE FINAL ACTION 608 00:26:06,560 --> 00:26:09,600 SO HERE WE SEE THE GASORIMIN 609 00:26:09,600 --> 00:26:12,240 MOLECULES, YOU SEE THE GRAY 610 00:26:12,240 --> 00:26:13,720 N-TERMINAL FRAGMENTS, THEY ARE 611 00:26:13,720 --> 00:26:16,400 GOING TO FORM A CIRCLE, AND THAT 612 00:26:16,400 --> 00:26:18,800 CIRCLE IS GOING TO FORM A POREE 613 00:26:18,800 --> 00:26:21,000 THAT CAN INSERT ITSELF INTO THE 614 00:26:21,000 --> 00:26:26,680 CELL MEMBRANE, DISRUPT OSMOTIC 615 00:26:26,680 --> 00:26:35,400 GRADIENT, CAUSE THE CELL TO 616 00:26:35,400 --> 00:26:37,280 BURST. 617 00:26:37,280 --> 00:26:41,600 THEN THE CYTOSINES THAT WERE 618 00:26:41,600 --> 00:26:42,640 ACTIVATED IL-1 AND IL-18 GET 619 00:26:42,640 --> 00:26:44,320 RELEASED AND OTHER THINGS THAT 620 00:26:44,320 --> 00:26:45,800 TRIGGER INFLAMMATION ALSO GET 621 00:26:45,800 --> 00:26:47,000 RELEASED. 622 00:26:47,000 --> 00:26:50,080 SO THAT IS THE STORY OF HOW THIS 623 00:26:50,080 --> 00:26:51,680 ALL WORKS. 624 00:26:51,680 --> 00:26:51,880 OOPS. 625 00:26:51,880 --> 00:26:56,000 AND WITH REGARD TO PYRIN, PYRIN 626 00:26:56,000 --> 00:27:03,400 CAN FORM AN INFLAMMASOME, 627 00:27:03,400 --> 00:27:07,200 REGULATED BY THE MOLECULE RHO A, 628 00:27:07,200 --> 00:27:11,440 ACTIVATES A PROCESS BY WHICH 629 00:27:11,440 --> 00:27:16,640 PYRIN IS PHOSPHORYLATED AND 630 00:27:16,640 --> 00:27:19,480 THERE'S AN INHIBITOR MOLECULE 631 00:27:19,480 --> 00:27:23,400 THAT PREVENTS FORMATION OF PYRIN 632 00:27:23,400 --> 00:27:25,760 IN INFLAMMASOME. 633 00:27:25,760 --> 00:27:27,240 WHEN RHO A IS DISRUPTED, THE 634 00:27:27,240 --> 00:27:29,320 PROCESS IS STOPPED. 635 00:27:29,320 --> 00:27:33,000 WHAT CAUSES RHO A TO BE 636 00:27:33,000 --> 00:27:35,320 DISRUPTED? 637 00:27:35,320 --> 00:27:36,360 ACTUALLY BACTERIAL TOXINS, 638 00:27:36,360 --> 00:27:39,600 BACTERIAL TOXINS DISRUPT RHO A. 639 00:27:39,600 --> 00:27:41,000 PYRIN INFLAMMASOME IS CAUSED 640 00:27:41,000 --> 00:27:43,280 WHEN A CELL GETS INFECTED BY 641 00:27:43,280 --> 00:27:45,120 CERTAIN BACTERIA, IT'S A DEFENSE 642 00:27:45,120 --> 00:27:46,640 AGAINST THOSE BACTERIA. 643 00:27:46,640 --> 00:27:49,000 NOW, ONE CAN ALSO ASK, AT LEAST 644 00:27:49,000 --> 00:27:50,680 SOMEONE MIGHT ASK, I WAS ASKING, 645 00:27:50,680 --> 00:27:52,080 WE WERE ASKING, OUR GROUP WAS 646 00:27:52,080 --> 00:27:54,400 ASKING, AND I THINK YOU WOULD 647 00:27:54,400 --> 00:27:56,640 WANT TO KNOW TOO, WHY IS IT THAT 648 00:27:56,640 --> 00:28:00,000 THERE ARE SUCH HIGH CARRIER 649 00:28:00,000 --> 00:28:01,600 FREQUENCES FOR FAMILIAL 650 00:28:01,600 --> 00:28:02,880 MEDITERRANEAN FEVER IN MULTIPLE 651 00:28:02,880 --> 00:28:04,360 MIDDLE EASTERN POPULATIONS? 652 00:28:04,360 --> 00:28:06,200 YOU PROBABLY DIDN'T KNOW THERE 653 00:28:06,200 --> 00:28:09,280 WERE SUCH HIGH CARRIER 654 00:28:09,280 --> 00:28:12,640 FREQUENCIES BUT THERE ARE. 655 00:28:12,640 --> 00:28:20,880 TOTAL FOR FMF MUTATIONS IN 656 00:28:20,880 --> 00:28:21,520 TURKISH, ARMENIA, NON-ASHKENAZI, 657 00:28:21,520 --> 00:28:23,920 BETWEEN 10 AND 12% CARRIERANCY. 658 00:28:23,920 --> 00:28:31,760 IS FREQUENCY. 659 00:28:31,760 --> 00:28:34,400 FOR CYSTIC FIBROSIS, MOST COMMON 660 00:28:34,400 --> 00:28:36,080 IN NORTH AMERICA, 4%. 661 00:28:36,080 --> 00:28:37,600 CARRIER FREQUENCY FOR THE SICKLE 662 00:28:37,600 --> 00:28:40,480 CELL TRAIT IN THE AFRICAN 663 00:28:40,480 --> 00:28:42,960 AMERICAN POPULATION IS 6 TO 8%. 664 00:28:42,960 --> 00:28:45,480 SO, 10 TO 12%, THAT IS HIGH. 665 00:28:45,480 --> 00:28:46,880 AND THAT DOES MAKE ONE THINK 666 00:28:46,880 --> 00:28:49,200 THAT MAYBE THERE WAS SOMETHING 667 00:28:49,200 --> 00:28:51,200 THAT WAS SELECTING FOR THOSE 668 00:28:51,200 --> 00:28:52,560 HIGH CARRIER FREQUENCIES BUT TO 669 00:28:52,560 --> 00:28:54,240 PROVE THAT YOU'VE GOT TO DO MORE 670 00:28:54,240 --> 00:28:56,760 THAN JUST THINK IT. 671 00:28:56,760 --> 00:28:58,000 YOU HAVE TO ACTUALLY CHECK TO 672 00:28:58,000 --> 00:29:02,240 SEE WHAT IS THE SIZE OF THE DNA 673 00:29:02,240 --> 00:29:03,440 FINGERPRINT, THE HAPLOTYPE, THAT 674 00:29:03,440 --> 00:29:06,360 IS ASSOCIATED WITH THE MUTATION 675 00:29:06,360 --> 00:29:07,400 IN CERTAIN HIGH RISK 676 00:29:07,400 --> 00:29:07,800 POPULATIONS. 677 00:29:07,800 --> 00:29:12,000 WE HAPPEN TO HAVE DATA FOR THAT 678 00:29:12,000 --> 00:29:13,720 FROM THE TURKISH POPULATION AND 679 00:29:13,720 --> 00:29:17,560 CAN SAY THE HAPLOTYPE ASSOCIATED 680 00:29:17,560 --> 00:29:19,040 WITH THE M 694V MUTATION CAN GO 681 00:29:19,040 --> 00:29:21,000 OUT AS MUCH AS A MEGABASE, A 682 00:29:21,000 --> 00:29:22,000 MILLION BASE PAIRS ON EITHER 683 00:29:22,000 --> 00:29:25,400 SIDE OF THE GENE. 684 00:29:25,400 --> 00:29:26,320 WHEREAS THE ANCESTRAL ALLELE, 685 00:29:26,320 --> 00:29:27,960 WILDTYPE ALLELE, IT'S LIKE A 686 00:29:27,960 --> 00:29:28,520 SPIKE THERE. 687 00:29:28,520 --> 00:29:30,360 IT DOES NOT HAVE A WIDE 688 00:29:30,360 --> 00:29:30,600 HAPLOTYPE. 689 00:29:30,600 --> 00:29:31,680 THAT'S THE KIND OF THING YOU 690 00:29:31,680 --> 00:29:33,960 WANT TO SEE IF YOU'RE LOOKING 691 00:29:33,960 --> 00:29:35,120 FOR EVIDENCE OF SELECTION, YOU 692 00:29:35,120 --> 00:29:38,600 CAN ALSO SAY THAT THAT HAPLOTYPE 693 00:29:38,600 --> 00:29:43,800 IS ON THE TAIL OF THE CURVE OF 694 00:29:43,800 --> 00:29:44,960 DISTRIBUTION OF SIMILAR 695 00:29:44,960 --> 00:29:46,320 HAPLOTYPES, HAPLOTYPES OF 696 00:29:46,320 --> 00:29:48,280 SIMILAR FREQUENCY IN THE TURKISH 697 00:29:48,280 --> 00:29:48,600 POPULATION. 698 00:29:48,600 --> 00:29:53,040 IT SHOULD BE AT THE TAIL OF THE 699 00:29:53,040 --> 00:29:54,800 CURVE IF THERE'S SELECTION GOING 700 00:29:54,800 --> 00:29:55,240 ON. 701 00:29:55,240 --> 00:29:56,400 CAN YOU BY MATHEMATICAL 702 00:29:56,400 --> 00:29:59,440 APPROACHES, YOU CAN CALCULATE A 703 00:29:59,440 --> 00:30:01,600 COEFFICIENT OF SELECTION, FOR 704 00:30:01,600 --> 00:30:03,160 FMF MUTATIONS IN THE TURKISH 705 00:30:03,160 --> 00:30:07,800 POPULATION, AND THAT TURNS OUT 706 00:30:07,800 --> 00:30:09,600 TO BE 0.077. 707 00:30:09,600 --> 00:30:11,640 PUT THAT IN PERSPECTIVE, THE 708 00:30:11,640 --> 00:30:14,400 SELECTION CO-EFFICIENT FOR LACK 709 00:30:14,400 --> 00:30:19,560 CASE PERSISTENCE, ABILITY 710 00:30:19,560 --> 00:30:24,280 ABILITY TO DIGEST COWS MILK IN 711 00:30:24,280 --> 00:30:26,880 THE YOUR POPULATION, 0.056, SO 712 00:30:26,880 --> 00:30:28,240 QUITE HIGH COLLECTION 713 00:30:28,240 --> 00:30:29,800 COEFFICIENT, THAT ALLOWS US TO 714 00:30:29,800 --> 00:30:32,520 ESTIMATE THE AGE OF THESE FMF 715 00:30:32,520 --> 00:30:34,720 MUTATIONS, IT RANGES SOME 716 00:30:34,720 --> 00:30:36,000 WHETHER BETWEEN TWO AND FIVE 717 00:30:36,000 --> 00:30:37,680 THOUSAND YEARS, PROBABLY IT DID 718 00:30:37,680 --> 00:30:38,800 ARISE IN BIBLICAL TIMES. 719 00:30:38,800 --> 00:30:40,920 SO THEN OF COURSE YOU CAN ASK 720 00:30:40,920 --> 00:30:41,840 THE QUESTION, WELL, WHAT WOULD 721 00:30:41,840 --> 00:30:46,480 HAVE BEEN SELECTING FOR THESE 722 00:30:46,480 --> 00:30:48,480 HIGH FMF CARRIER FREQUENCIES? 723 00:30:48,480 --> 00:30:50,600 ILLUSTRATED ON THIS SLIDE, WE OF 724 00:30:50,600 --> 00:30:53,480 COURSE WERE THINKING ABOUT THE 725 00:30:53,480 --> 00:30:57,440 USUAL SUSPECTS AND CERTAINLY 726 00:30:57,440 --> 00:31:00,760 YERSINIA PESTIS IS A SUSPECT. 727 00:31:00,760 --> 00:31:03,160 THE PLAGUE BACTERIUM DOES MAKE 728 00:31:03,160 --> 00:31:08,080 TOXINS WHICH CAN ACTIVATE THE 729 00:31:08,080 --> 00:31:10,040 PYRIN INFLAMMASOME, YOP-E AND 730 00:31:10,040 --> 00:31:14,240 YOP-T AND SHOULD BE A DEFENSE 731 00:31:14,240 --> 00:31:23,400 BUT IN APLAGUES PLAGUE MAKES A 732 00:31:23,400 --> 00:31:26,640 TOXIN WHICH INACTIVES, POISONS. 733 00:31:26,640 --> 00:31:28,600 BUT WITH FMF IT IS IMMUNE TO 734 00:31:28,600 --> 00:31:31,200 THAT ACTIVATING PROCESS. 735 00:31:31,200 --> 00:31:33,320 ON THIS SLIDE IT SHOWS IN NORMAL 736 00:31:33,320 --> 00:31:37,200 PEOPLE WHO HAVE A NORMAL VERSION 737 00:31:37,200 --> 00:31:39,720 OF THE FMF GENE, THAT FMF 738 00:31:39,720 --> 00:31:42,160 PROTEIN PYRIN GETS HEAVILY 739 00:31:42,160 --> 00:31:49,680 PHOSPHORYLATED BY THE PLAGUE 740 00:31:49,680 --> 00:31:50,640 YOP-M TOXIN. 741 00:31:50,640 --> 00:31:53,680 PEOPLE WITH FMF, PYRIN IS 742 00:31:53,680 --> 00:31:55,120 RESISTANCE, THEY DO NOT HAVE THE 743 00:31:55,120 --> 00:31:57,040 SAME EFFECT OF PLAGUE TOXIN. 744 00:31:57,040 --> 00:31:59,360 THAT RESULTS IN INCREASED IL-1 745 00:31:59,360 --> 00:32:01,800 PRODUCTION, BOTH BY CARRIERS OF 746 00:32:01,800 --> 00:32:05,120 THE FMF MUTATION AND PEOPLE THAT 747 00:32:05,120 --> 00:32:07,360 HAVE FMF, WE'VE MADE KNOCK-IN 748 00:32:07,360 --> 00:32:09,320 MICE THAT HAVE THESE MUTATIONS 749 00:32:09,320 --> 00:32:15,280 AND THEY ARE TO SOME EXTENT 750 00:32:15,280 --> 00:32:16,560 PROTECTED FROM INFECTION BY 751 00:32:16,560 --> 00:32:19,200 YERSINIA PESTIS AND ONE CAN 752 00:32:19,200 --> 00:32:20,240 SIMULATE FREQUENCY OF FMF 753 00:32:20,240 --> 00:32:23,680 MUTATIONS FOR EXAMPLE IN THE 754 00:32:23,680 --> 00:32:24,760 TURKISH POPULATIONS USING 755 00:32:24,760 --> 00:32:25,640 INFORMATION IN TERMS OF 756 00:32:25,640 --> 00:32:27,880 SELECTION OF COEFFICIENT, AGE OF 757 00:32:27,880 --> 00:32:30,280 MUTATION, SOME HISTORICAL DATA 758 00:32:30,280 --> 00:32:31,000 AND CARRIER FREQUENCIES ARE 759 00:32:31,000 --> 00:32:33,280 PRETTY MUCH WHAT ONE WOULD 760 00:32:33,280 --> 00:32:35,080 EXPECT BASED ON WHAT WE HAVE 761 00:32:35,080 --> 00:32:36,480 SEEN IN THAT POPULATION. 762 00:32:36,480 --> 00:32:37,960 SO, IN ANY EVENT, THAT'S JUST A 763 00:32:37,960 --> 00:32:40,080 LITTLE BIT, MAYBE MORE THAN WHAT 764 00:32:40,080 --> 00:32:41,800 YOU WANTED TO KNOW, BUT IT'S 765 00:32:41,800 --> 00:32:44,120 INTERESTING, I THINK ANYWAY, 766 00:32:44,120 --> 00:32:45,720 INFORMATION ON FMF. 767 00:32:45,720 --> 00:32:49,040 WELL, ALL THAT WAS GOING ON, WE 768 00:32:49,040 --> 00:32:51,560 WERE SEEING OTHER PATIENTS THAT 769 00:32:51,560 --> 00:32:52,920 HAVE UNEXPLAINED RECURRENT 770 00:32:52,920 --> 00:32:53,400 FEVERS. 771 00:32:53,400 --> 00:32:56,920 AND IT TURNED OUT THAT A GROUP 772 00:32:56,920 --> 00:32:58,840 OF THOSE PATIENTS ACTUALLY HAD A 773 00:32:58,840 --> 00:33:00,600 DIFFERENT KIND OF PERIODIC FEVER 774 00:33:00,600 --> 00:33:05,800 WHERE THE ATTACKS LASTED MUCH 775 00:33:05,800 --> 00:33:09,280 LONGER THAN IN FMF, DOMINANTLY 776 00:33:09,280 --> 00:33:10,400 INHERENTED RATHER THAN 777 00:33:10,400 --> 00:33:11,000 RECESSANT, PATIENTS DIDN'T 778 00:33:11,000 --> 00:33:14,320 RESPOND TO USUAL TREATMENT FOR 779 00:33:14,320 --> 00:33:14,480 FMF. 780 00:33:14,480 --> 00:33:20,800 IN 1999, A COUPLE YEARS AFTER WE 781 00:33:20,800 --> 00:33:23,280 HAD FOUND GENE, SOME HAVE 782 00:33:23,280 --> 00:33:25,440 MUTATIONS IN TNF RECEPTOR GENE, 783 00:33:25,440 --> 00:33:30,960 WE CALLED THAT DISEASE TRAPS, 784 00:33:30,960 --> 00:33:33,800 AND CAME UP WITH THE TERM 785 00:33:33,800 --> 00:33:35,400 AUTO-INFLAMMATORY SYNDROMES THE 786 00:33:35,400 --> 00:33:36,000 THAT TIME. 787 00:33:36,000 --> 00:33:37,920 IN BOTH CASES THESE ARE DISEASES 788 00:33:37,920 --> 00:33:41,240 IN WHICH PATIENTS HAVE RECURRENT 789 00:33:41,240 --> 00:33:43,400 FEVERS SEEMINGLY UNPROVOKED 790 00:33:43,400 --> 00:33:45,000 WITHOUT HIGH TITER 791 00:33:45,000 --> 00:33:46,200 AUTOANTIBODIES OR ANTIGENS, T 792 00:33:46,200 --> 00:33:48,480 CELLS OF AUTOIMMUNE DISEASE. 793 00:33:48,480 --> 00:33:49,800 SO WE DIDN'T KNOW WHETHER THERE 794 00:33:49,800 --> 00:33:51,920 WERE GOING TO BE MORE 795 00:33:51,920 --> 00:33:52,600 AUTO-INFLAMMATORY DISEASES OR 796 00:33:52,600 --> 00:33:55,600 NOT BUT WE LET THE IMAGINATION 797 00:33:55,600 --> 00:33:59,120 RUN WILD AND WE WROTE THIS PAPER 798 00:33:59,120 --> 00:34:01,680 IN 2000 SUGGESTING WHAT OTHER 799 00:34:01,680 --> 00:34:03,400 DISEASES MIGHT BE 800 00:34:03,400 --> 00:34:04,760 AUTO-INFLAMMATORY DISEASES AND 801 00:34:04,760 --> 00:34:07,040 EVEN PROPOSING A CLASSIFICATION 802 00:34:07,040 --> 00:34:09,200 SCHEME FOR THEM. 803 00:34:09,200 --> 00:34:15,040 AND ONE GROUP OF THEM WE 804 00:34:15,040 --> 00:34:18,480 SUGGESTED WAS THE FAMILIAL 805 00:34:18,480 --> 00:34:19,480 URTICARIAL SYNDROMES, FEVERS AND 806 00:34:19,480 --> 00:34:21,760 PEOPLE BREAK OUT WITH HIVES WITH 807 00:34:21,760 --> 00:34:23,200 FEVERS, THERE ARE SUCH DISEASES 808 00:34:23,200 --> 00:34:24,920 AS THAT. 809 00:34:24,920 --> 00:34:27,840 THEN A YEAR LATER, MUCH TO OUR 810 00:34:27,840 --> 00:34:30,160 SURPRISE AND DELIGHT, DR. HAL 811 00:34:30,160 --> 00:34:31,400 HOFFMAN AT THE UNIVERSITY OF 812 00:34:31,400 --> 00:34:32,440 CALIFORNIA SAN DIEGO PUBLISHED A 813 00:34:32,440 --> 00:34:36,000 PAPER IN WHICH HE SHOWED THAT 814 00:34:36,000 --> 00:34:41,080 THOSE TWO DISEASES, FAMILIAL 815 00:34:41,080 --> 00:34:44,080 URTICARIAL, GENE MUTATED IN 816 00:34:44,080 --> 00:34:50,120 THOSE DISEASES ENCODES A PYRIN 817 00:34:50,120 --> 00:34:53,760 DOMAIN, NLRP 3, AT THAT POINT IT 818 00:34:53,760 --> 00:34:55,000 AND IL-1 ACTIVATION WAS 819 00:34:55,000 --> 00:34:56,840 BEGINNING TO BE UNDERSTOOD, LED 820 00:34:56,840 --> 00:34:59,360 US TO THINK PERHAPS WE COULD 821 00:34:59,360 --> 00:35:02,480 TREAT PATIENTS WITH THE MOST 822 00:35:02,480 --> 00:35:03,920 SEVERE FORM OF DISEASE OF THAT 823 00:35:03,920 --> 00:35:06,240 SORT, WE COULD TREAT THEM WITH 824 00:35:06,240 --> 00:35:07,360 IL-1 INHIBITORS. 825 00:35:07,360 --> 00:35:17,880 THIS IS WORK OF MY COLLEAGUE, 826 00:35:17,880 --> 00:35:19,760 RAFAEL GOLDBACH-MANSKI, ON 827 00:35:19,760 --> 00:35:21,560 NEONATAL ONSET MULTI-SYSTEM 828 00:35:21,560 --> 00:35:22,160 INFLAMMATORY DISEASE, THIS IS 829 00:35:22,160 --> 00:35:23,840 THE BEFORE AND AFTER. 830 00:35:23,840 --> 00:35:26,800 BEFORE TREATMENT THESE PATIENTS 831 00:35:26,800 --> 00:35:27,320 HAD HIVES, CONJUNCTIVITIS, 832 00:35:27,320 --> 00:35:28,280 INFLAMMATION OF THE LINING 833 00:35:28,280 --> 00:35:29,720 AROUND THE BRAIN WHICH COULD 834 00:35:29,720 --> 00:35:32,000 LEAD TO BLINDNESS AND DEAFNESS 835 00:35:32,000 --> 00:35:33,800 AND INTELLECTUAL DISABILITY. 836 00:35:33,800 --> 00:35:35,040 THEY HAD INFLAMMATION OF THE 837 00:35:35,040 --> 00:35:40,000 COCHLEA THAT COULD LEAD TO 838 00:35:40,000 --> 00:35:40,560 DEAFNESS. 839 00:35:40,560 --> 00:35:53,600 AFTER A COURSE OF A POTENT 840 00:35:53,600 --> 00:35:55,080 INHIBITOR, IT WENT AWAY, THE 841 00:35:55,080 --> 00:35:59,640 FOUNDATION FOR FDA APPROVAL OF 842 00:35:59,640 --> 00:36:01,600 THIS DRUG, THIS BIOLOGIC, AND IN 843 00:36:01,600 --> 00:36:03,360 FACT THE KIDS THAT HAD BEEN 844 00:36:03,360 --> 00:36:07,000 TREATED WITH THIS ARE STILL ON 845 00:36:07,000 --> 00:36:08,080 ANAKENRA 20 YEARS LATER. 846 00:36:08,080 --> 00:36:13,080 INSTEAD OF HAVING A VERY POOR 847 00:36:13,080 --> 00:36:14,800 PROGNOSIS WE KNOW OF A NUMBER OF 848 00:36:14,800 --> 00:36:15,440 THEM ATTENDING COLLEGE. 849 00:36:15,440 --> 00:36:17,600 SO IT'S REALLY A WONDERFUL THING 850 00:36:17,600 --> 00:36:19,040 TO SEE. 851 00:36:19,040 --> 00:36:21,080 SO, NOW WE'RE ON TO THE NEXT 852 00:36:21,080 --> 00:36:23,080 CHAPTERS AND TO MY COLLEAGUES. 853 00:36:23,080 --> 00:36:26,400 SO THE NEXT CHAPTERS, WELL, THEY 854 00:36:26,400 --> 00:36:31,440 ARE WRITTEN BECAUSE THE COST OF 855 00:36:31,440 --> 00:36:34,720 DNA SEQUENCING WENT DOWN 856 00:36:34,720 --> 00:36:36,280 DRAMATICALLY AFTER 2007, SO THIS 857 00:36:36,280 --> 00:36:40,080 IS THIS HAS LED TO EXPLOSION IN 858 00:36:40,080 --> 00:36:41,920 TERMS OF THE NUMBER OF 859 00:36:41,920 --> 00:36:43,200 AUTO-INFLAMMATORY DISEASES WE 860 00:36:43,200 --> 00:36:45,000 CAN IDENTIFY IN WHICH PATHWAYS 861 00:36:45,000 --> 00:36:47,760 OTHER THAN IL-1 ARE INVOLVED. 862 00:36:47,760 --> 00:36:50,840 IN WHICH THERE ARE MANY 863 00:36:50,840 --> 00:36:52,360 MONOGENIC DISEASES, AND IN WHICH 864 00:36:52,360 --> 00:36:54,560 IN FACT THERE ARE GENETICALLY 865 00:36:54,560 --> 00:36:55,680 COMPLEX DISORDERS AS WELL. 866 00:36:55,680 --> 00:36:59,000 THIS IS JUST A FIGURE FROM A 867 00:36:59,000 --> 00:36:59,720 PAPER THAT WAS PUBLISHED IN 868 00:36:59,720 --> 00:37:03,240 "SCIENCE," A FEW MONTHS AGO, ON 869 00:37:03,240 --> 00:37:04,680 THE AUTO-INFLAMMATORY DISEASES 870 00:37:04,680 --> 00:37:07,600 JUST HIGHLIGHTING TEN OF THE 871 00:37:07,600 --> 00:37:08,120 DISEASES. 872 00:37:08,120 --> 00:37:13,600 THERE ARE NOW AROUND 50 873 00:37:13,600 --> 00:37:14,400 MONOGENIC AUTO-INFLAMMATORY 874 00:37:14,400 --> 00:37:17,080 DISEASES, LOTS OF ROOM FOR 875 00:37:17,080 --> 00:37:18,200 CHANGING THE TAXONOMY, IMPROVING 876 00:37:18,200 --> 00:37:20,400 THE TAXONOMY OF THESE DISEASES. 877 00:37:20,400 --> 00:37:23,000 AND WE'RE GOING TO FOCUS FOR THE 878 00:37:23,000 --> 00:37:25,720 REST OF THIS SESSION ON 879 00:37:25,720 --> 00:37:28,520 DISORDERS IN WHICH PATIENTS 880 00:37:28,520 --> 00:37:32,040 PRESENT WITH FEVER BUT ALSO WITH 881 00:37:32,040 --> 00:37:33,200 PAINFUL ORAL ULCERS, PAINFUL 882 00:37:33,200 --> 00:37:34,640 SORES IN THEIR MOUTH. 883 00:37:34,640 --> 00:37:38,280 ONE SUCH DISEASE IS A DISEASE 884 00:37:38,280 --> 00:37:39,000 CALLED BEHCET'S DISEASE, SEEN IN 885 00:37:39,000 --> 00:37:42,320 THE MIDDLE EAST, AS WELL AS 886 00:37:42,320 --> 00:37:43,440 ALONG MARCO POLO'S SILK ROUTE 887 00:37:43,440 --> 00:37:47,400 GOING TO THE FAR EAST, TO CHINA, 888 00:37:47,400 --> 00:37:50,200 JAPAN, KOREA. 889 00:37:50,200 --> 00:37:57,080 AND PATIENTS WITH BEHCET DISEASE 890 00:37:57,080 --> 00:37:58,200 ARE PAINFUL ORAL DISEASE, PUS IN 891 00:37:58,200 --> 00:38:10,800 THE CHAMBER OF THE EYE, , 892 00:38:10,800 --> 00:38:11,920 ULCERATION OF THE GENITAL 893 00:38:11,920 --> 00:38:16,160 REGION, THEY MAY DEVELOP A 894 00:38:16,160 --> 00:38:18,520 PUSTULE, A FASCINATING GROUP OF 895 00:38:18,520 --> 00:38:23,960 DISEASES, I'M SURE YOU'LL BE 896 00:38:23,960 --> 00:38:31,080 DELIGHTED AS DOCTORS SWATHS AND 897 00:38:31,080 --> 00:38:32,480 DR. MANTHIRAM REGALE YOU. 898 00:38:32,480 --> 00:38:47,360 I WILL TURN THINGS OVER TO DR. 899 00:38:47,360 --> 00:38:49,000 DANI SCHWARTZ. 900 00:38:49,000 --> 00:38:49,840 >> HELLO, ALL. 901 00:38:49,840 --> 00:38:51,040 CAN YOU SEE MY SCREEN? 902 00:38:51,040 --> 00:38:51,840 >> YES. 903 00:38:51,840 --> 00:38:52,680 >> OKAY. 904 00:38:52,680 --> 00:38:55,320 I'M GOING TO PUT MYSELF ON LASER 905 00:38:55,320 --> 00:38:57,880 POINTER AND I WANT TO START BY 906 00:38:57,880 --> 00:39:00,600 THANKING YOU FOR THE OPPORTUNITY 907 00:39:00,600 --> 00:39:02,000 TO SHARE THIS RESEARCH WITH YOU. 908 00:39:02,000 --> 00:39:03,600 I WILL BE TALKING TO YOU ABOUT A 909 00:39:03,600 --> 00:39:09,520 DISEASE THAT IS VERY NEAR AND 910 00:39:09,520 --> 00:39:15,040 DEAR TO MY HEART, AND AFTER DR. 911 00:39:15,040 --> 00:39:16,440 KASTNER TOLD YOU ABOUT 912 00:39:16,440 --> 00:39:19,240 AUTO-INFLAMMATORY DISEASES, I'M 913 00:39:19,240 --> 00:39:21,400 GOING TO TELL BUT SITUATIONS 914 00:39:21,400 --> 00:39:24,920 WHERE AUTOINFLAMMATION ISN'T 915 00:39:24,920 --> 00:39:27,120 JUST AUTO INFLAMMATION, USING 916 00:39:27,120 --> 00:39:29,200 HA20 AS A CARDINAL EXAMPLE. 917 00:39:29,200 --> 00:39:30,200 AS A DISCLOSURE I WANT TO LET 918 00:39:30,200 --> 00:39:32,480 YOU KNOW I WILL DISCUSS THE 919 00:39:32,480 --> 00:39:34,280 GENERAL CONCEPT OF TARGETED 920 00:39:34,280 --> 00:39:37,120 OFF-LABEL THERAPIES FOR THIS 921 00:39:37,120 --> 00:39:39,600 DISEASE USING VARIOUS NUMBER OF 922 00:39:39,600 --> 00:39:40,800 TARGETED TREATMENTS THAT WE'VE 923 00:39:40,800 --> 00:39:43,200 USED FOR THESE PATIENTS THAT ARE 924 00:39:43,200 --> 00:39:43,640 OFF LABEL. 925 00:39:43,640 --> 00:39:46,160 I WOULD LIKE TO START BY TELLING 926 00:39:46,160 --> 00:39:48,480 YOU ABOUT ONE OF THE INDEX 927 00:39:48,480 --> 00:39:50,080 PATIENTS FOR THIS DISEASE, A 928 00:39:50,080 --> 00:39:51,320 PATIENT WHO YOU'LL BE HEARING 929 00:39:51,320 --> 00:39:54,600 FROM DIRECTLY AT THE END OF THIS 930 00:39:54,600 --> 00:39:54,800 TALK. 931 00:39:54,800 --> 00:39:56,480 AND THIS YOUNG LADY WAS 932 00:39:56,480 --> 00:39:59,240 DIAGNOSED AT THE AGE OF 10 WITH 933 00:39:59,240 --> 00:40:00,800 JUVENILE IDIOPATHIC ARTHRITIS, 934 00:40:00,800 --> 00:40:02,680 THIS IS BECAUSE SHE DEVELOPED 935 00:40:02,680 --> 00:40:05,120 VERY SEVERE ARTHRITIS WITH 936 00:40:05,120 --> 00:40:07,640 SYSTEMIC INFLAMMATION, HAD SOME 937 00:40:07,640 --> 00:40:08,800 RESPONSE TO STANDARD BIOLOGICS 938 00:40:08,800 --> 00:40:10,360 THAT YOU USE TO TREAT THIS 939 00:40:10,360 --> 00:40:11,400 DISEASE BUT NOT COMPLETE 940 00:40:11,400 --> 00:40:11,680 RESPONSE. 941 00:40:11,680 --> 00:40:14,320 YOU CAN SEE HERE THESE AREN'T 942 00:40:14,320 --> 00:40:17,280 HER JOINTS, THIS IS ANOTHER 943 00:40:17,280 --> 00:40:19,000 HA20, THIS IS A VERY TYPICAL 944 00:40:19,000 --> 00:40:20,720 EXAMPLE OF WHAT SHE HAD. 945 00:40:20,720 --> 00:40:23,920 AS TIME WENT BY, AT THE AGE OF 946 00:40:23,920 --> 00:40:26,800 14, HER DISEASE WORSENED DESPITE 947 00:40:26,800 --> 00:40:29,480 TREATMENT WITH STANDARD 948 00:40:29,480 --> 00:40:30,120 BIOLOGICS FOR JUVENILE 949 00:40:30,120 --> 00:40:35,400 IDIOPATHIC ARTHRITIS AND BEGAN 950 00:40:35,400 --> 00:40:38,000 TO DEVELOP ORAL ULCERS, SEVERE 951 00:40:38,000 --> 00:40:39,880 NEUROLOGIC DISEASE, 952 00:40:39,880 --> 00:40:42,360 UNCONTROLLABLE MOVEMENTS, SEVERE 953 00:40:42,360 --> 00:40:45,480 RETINAL INFLAMMATIONS THAT LED 954 00:40:45,480 --> 00:40:48,400 TO BLINDNESS WITH RAPID ONSET, 955 00:40:48,400 --> 00:40:53,480 DIAGNOSED WITH SYSTEMIC LUPUS, 956 00:40:53,480 --> 00:40:55,040 TREATED WITH LUPUS THERAPY, 957 00:40:55,040 --> 00:40:56,520 INCOMPLETE RESPONSE AND 958 00:40:56,520 --> 00:41:00,000 CONTINUED TO SUFFER FROM BOTH 959 00:41:00,000 --> 00:41:01,200 NEUROLOGIC DISEASE AND CONTINUED 960 00:41:01,200 --> 00:41:03,400 JOINT DISEASE AND ORAL ULCERS. 961 00:41:03,400 --> 00:41:07,720 AT THIS POINT AT THE AGE OF 15 962 00:41:07,720 --> 00:41:09,760 WAS REFERRED TO THE NATIONAL 963 00:41:09,760 --> 00:41:13,760 INSTITUTES OF HEALTH LUPUS 964 00:41:13,760 --> 00:41:15,280 PROTOCOL FOR EXPERIMENTAL 965 00:41:15,280 --> 00:41:16,600 AUTOLOGOUS BONE MARROW 966 00:41:16,600 --> 00:41:20,920 TRANSLANT, RECEIVED HER OWN BONE 967 00:41:20,920 --> 00:41:22,480 MARROW, INTENSIVE CONDITIONING 968 00:41:22,480 --> 00:41:25,720 AND IMMUNOSUPPRESSIVE REG 969 00:41:25,720 --> 00:41:26,400 MESSAGE. 970 00:41:26,400 --> 00:41:27,240 HER SYMPTOMS TRANSIENTLY GOT 971 00:41:27,240 --> 00:41:29,160 BETTER FOR ABOUT A FEW YEARS, 972 00:41:29,160 --> 00:41:31,520 BUT THEN BETWEEN THE AGES OF 973 00:41:31,520 --> 00:41:33,240 ABOUT 22 TO 23 THEY CAME BACK 974 00:41:33,240 --> 00:41:36,800 AND CAME BACK WITH A VENGEANCE. 975 00:41:36,800 --> 00:41:38,640 SHE HAD WORSENING NEUROLOGIC 976 00:41:38,640 --> 00:41:41,800 SYMPTOMS, WOULD HAVE EPISODES OF 977 00:41:41,800 --> 00:41:42,640 AGAIN UNCONTROLLED MOVEMENTS, 978 00:41:42,640 --> 00:41:48,320 PLATELETS BEGAN TO BE 979 00:41:48,320 --> 00:41:50,040 DESTROYED, ITP, ORAL ULCERS CAME 980 00:41:50,040 --> 00:41:51,360 BACK, JOINT INFLAMMATION CAME 981 00:41:51,360 --> 00:41:54,440 BACK, SHE BEGAN TO ALSO 982 00:41:54,440 --> 00:41:55,960 EXPERIENCE GENITAL ULCERS. 983 00:41:55,960 --> 00:41:57,040 AND THIS REALLY BEGAN TO LEAVE 984 00:41:57,040 --> 00:41:58,720 THE DOMAIN OF WHAT YOU WOULD 985 00:41:58,720 --> 00:42:01,200 TYPICALLY SEE IN A PATIENT WITH 986 00:42:01,200 --> 00:42:03,360 LUPUS, AND AROUND THIS TIME DUE 987 00:42:03,360 --> 00:42:07,800 TO HER EXTENSIVE FAMILY HISTORY, 988 00:42:07,800 --> 00:42:09,800 GENETIC TESTING WAS PERFORMED BY 989 00:42:09,800 --> 00:42:12,320 OUR GROUP AND WE INDEED 990 00:42:12,320 --> 00:42:16,200 IDENTIFIED A MUTATION IN THIS 991 00:42:16,200 --> 00:42:18,160 GENE TNFAIP 3 WHICH INCODES FOR 992 00:42:18,160 --> 00:42:19,800 PROTEIN A20. 993 00:42:19,800 --> 00:42:22,120 YOU CAN SEE P6 IS OUR PATIENT. 994 00:42:22,120 --> 00:42:23,400 THIS IS HER FAMILY. 995 00:42:23,400 --> 00:42:26,080 WE FOUND THAT SHE HAD A 996 00:42:26,080 --> 00:42:28,400 BIOLOGICAL SISTER, MOTHER, AUNT 997 00:42:28,400 --> 00:42:31,400 WHO HAD SIMILAR SYMPTOMS, TO 998 00:42:31,400 --> 00:42:31,840 HER. 999 00:42:31,840 --> 00:42:33,640 AND THIS MUTATION SEGREGATED 1000 00:42:33,640 --> 00:42:37,360 DISEASE AROUND THE SAME TIME 1001 00:42:37,360 --> 00:42:38,640 FOLLOWING ANOTHER FAMILY AND 1002 00:42:38,640 --> 00:42:43,640 FOUND MUTATIONS IN THE SAME GENE 1003 00:42:43,640 --> 00:42:45,240 IN THAT FAMILY. 1004 00:42:45,240 --> 00:42:46,440 AND THROUGH WORKING WITH 1005 00:42:46,440 --> 00:42:48,040 COLLABORATORS WHO FOLLOWED OTHER 1006 00:42:48,040 --> 00:42:53,360 FAMILIES WITH INHERITED FORMS OF 1007 00:42:53,360 --> 00:42:54,320 BECHETS'S FOUND MUTATIONS IN 1008 00:42:54,320 --> 00:42:57,480 THREE ADDITIONAL FAMILIES AS 1009 00:42:57,480 --> 00:43:00,040 WELL AS ONE OTHER FAMILY FROM A 1010 00:43:00,040 --> 00:43:01,640 LARGER COHORT OF TURKISH AND 1011 00:43:01,640 --> 00:43:02,400 JAPANESE PATIENT. 1012 00:43:02,400 --> 00:43:04,600 WE WENT ON AND HERE YOU SEE THIS 1013 00:43:04,600 --> 00:43:05,800 IS OUR PATIENT. 1014 00:43:05,800 --> 00:43:10,680 WE'RE ABLE TO SEE COMPARED WITH 1015 00:43:10,680 --> 00:43:12,240 A HEALTHY VOLUNTEER, THE 1016 00:43:12,240 --> 00:43:14,400 EXPRESSION OF A20 PROTEIN WAS 1017 00:43:14,400 --> 00:43:15,760 REDUCED IN THIS PATIENT'S CELLS, 1018 00:43:15,760 --> 00:43:18,240 SO THIS WAS A HAPLOINEFFICIENCY, 1019 00:43:18,240 --> 00:43:20,160 NOT ENOUGH OF THE PROTEIN, SHE 1020 00:43:20,160 --> 00:43:21,560 DID NOT EXPRESS THE MUTANT FORM 1021 00:43:21,560 --> 00:43:24,440 SO REALLY IT WAS JUST SHE DIDN'T 1022 00:43:24,440 --> 00:43:29,560 HAVE ENOUGH OF THIS PROTEINS 1023 00:43:29,560 --> 00:43:31,120 WHICH BRINGS US TO HOW DID THIS 1024 00:43:31,120 --> 00:43:35,800 LACK OF A 20 COME TO CAUSE 1025 00:43:35,800 --> 00:43:36,040 DISEASE? 1026 00:43:36,040 --> 00:43:40,000 A20 PRIOR, SO IN ITS FIRST DAYS 1027 00:43:40,000 --> 00:43:42,400 BEST STUDIES AS INHIBITOR OF 1028 00:43:42,400 --> 00:43:43,280 NF-kappaB SIGNALING, SO DR. 1029 00:43:43,280 --> 00:43:47,640 KASTNER TOLD YOU ABOUT MUTATIONS 1030 00:43:47,640 --> 00:43:49,120 IN TNF RECEPTOR. 1031 00:43:49,120 --> 00:43:52,200 WHEN IT ACTIVATES IN INDUCTION 1032 00:43:52,200 --> 00:43:58,280 OF INFLAMMATION, THIS ACTIVATION 1033 00:43:58,280 --> 00:44:00,440 LEADS TO UBIQUITINATION, TAGGING 1034 00:44:00,440 --> 00:44:02,400 ON OF MOLECULES INTO VARIOUS 1035 00:44:02,400 --> 00:44:03,400 POSITIONS OF DOWNSTREAM 1036 00:44:03,400 --> 00:44:06,000 SIGNALING MOLECULES, AND SOME OF 1037 00:44:06,000 --> 00:44:07,600 THESE MODIFICATIONS ACTIVATE AND 1038 00:44:07,600 --> 00:44:10,720 SOME OF THEM INACTIVATE. 1039 00:44:10,720 --> 00:44:11,840 TWO OF THE ACTIVATING 1040 00:44:11,840 --> 00:44:15,320 MODIFICATIONS ARE THE STICKING 1041 00:44:15,320 --> 00:44:21,120 ON OF UBIQUITIN TO LYSINE 63, 1042 00:44:21,120 --> 00:44:29,400 AND LINEAR, A20 REMOVES K63 AND 1043 00:44:29,400 --> 00:44:34,640 LINEAR UBIQUITIN, LIKE RIP 1, 1044 00:44:34,640 --> 00:44:35,600 THESE ACTIVATE REMOVAL 1045 00:44:35,600 --> 00:44:37,800 INACTIVATES SIGNALING MOLECULES. 1046 00:44:37,800 --> 00:44:43,520 ADDITIONALLY, UBIQUITINS CAN BE 1047 00:44:43,520 --> 00:44:45,360 LAGGED ON LYSINE 48, TARGETS 1048 00:44:45,360 --> 00:44:51,600 MOLECULES FOR DEGRADATION. 1049 00:44:51,600 --> 00:44:53,800 A20 ALSO WILL ADD UBIQUITINS AND 1050 00:44:53,800 --> 00:45:01,320 TARGET THE SAME MOLECULES TO 1051 00:45:01,320 --> 00:45:02,080 DEGRADATIONS SO THREE 1052 00:45:02,080 --> 00:45:04,320 MECHANISMS, TARGETS 1053 00:45:04,320 --> 00:45:05,400 INFLAMMATORY -- THIS 1054 00:45:05,400 --> 00:45:07,840 INFLAMMATORY PATHWAY FOR 1055 00:45:07,840 --> 00:45:08,200 INFLAMMATION. 1056 00:45:08,200 --> 00:45:11,000 NOT ENOUGH A20, TOO MUCH 1057 00:45:11,000 --> 00:45:12,560 NF-kappaB SIGNALING, INCREASED 1058 00:45:12,560 --> 00:45:13,160 INFLAMMATION. 1059 00:45:13,160 --> 00:45:15,640 AND INDEED WHEN YOU LOOK AT 1060 00:45:15,640 --> 00:45:17,760 CELLS FROM OUR PATIENT WITH HA20 1061 00:45:17,760 --> 00:45:21,280 THAT'S WHAT YOU SEE. 1062 00:45:21,280 --> 00:45:22,920 YOU SEE INCREASED 1063 00:45:22,920 --> 00:45:29,280 PHOSPHORYLATION IN OUR PATIENT, 1064 00:45:29,280 --> 00:45:30,880 INCREASED ALPHA DEGRADATION AND 1065 00:45:30,880 --> 00:45:33,520 SO THAT INCREASED NF-kappaB 1066 00:45:33,520 --> 00:45:36,200 SIGNALING VERY CONSISTENT WITH 1067 00:45:36,200 --> 00:45:37,440 ENHANCED INFLAMMATION AND 1068 00:45:37,440 --> 00:45:39,400 REDUCED A20 IN OUR PATIENTS. 1069 00:45:39,400 --> 00:45:46,440 BUT WHAT INFLAMMATORY PATHWAY 1070 00:45:46,440 --> 00:45:51,080 ISN'T ENOUGH, A20 INHIBITS THE 1071 00:45:51,080 --> 00:45:54,480 NLRP 3 INFLAMMASOME. 1072 00:45:54,480 --> 00:45:55,600 WORK HAS DEMONSTRATED THIS, 1073 00:45:55,600 --> 00:45:57,480 INDEED WHEN YOU LOOK BACK AT OUR 1074 00:45:57,480 --> 00:46:00,720 PATIENT YOU SEE SHE ALSO HAS 1075 00:46:00,720 --> 00:46:03,320 INCREASED IL-1 BETA RELATIVE TO 1076 00:46:03,320 --> 00:46:05,840 HEALTHY VOLUNTEER, AND THIS DOES 1077 00:46:05,840 --> 00:46:09,160 GO THROUGH THE INFLAMMASOME, 1078 00:46:09,160 --> 00:46:12,320 TREAT AND THEY NO LONGER 1079 00:46:12,320 --> 00:46:14,720 OVERPRODUCE IL-1 BETA. 1080 00:46:14,720 --> 00:46:20,120 BUT APPARENTLY, TWO INFLAMMATORY 1081 00:46:20,120 --> 00:46:22,480 PATHWAYS STILL, A20 IS IMPORTANT 1082 00:46:22,480 --> 00:46:23,680 FOR INHIBITING THIS INFLAMMATORY 1083 00:46:23,680 --> 00:46:29,080 FORM OF CELL DEATH KNOWN AS 1084 00:46:29,080 --> 00:46:29,880 NECROPTOSIS, AND DEFECTS IN 1085 00:46:29,880 --> 00:46:33,160 NECROPTOSIS CAN LEAD TO 1086 00:46:33,160 --> 00:46:35,160 AUTOINFLAMMATION IN A SYNDROME 1087 00:46:35,160 --> 00:46:36,240 CALLED CREA. 1088 00:46:36,240 --> 00:46:39,280 WORK HAS SHOWN IN AN A20 1089 00:46:39,280 --> 00:46:42,520 DEFICIENT CELL YOU'LL SEE 1090 00:46:42,520 --> 00:46:44,240 ENHANCED NECROPTOSIS, OR 1091 00:46:44,240 --> 00:46:45,680 INFLAMMATORY CELL DEATH, AND 1092 00:46:45,680 --> 00:46:49,600 THERE IS YET A FOURTH 1093 00:46:49,600 --> 00:46:50,840 INFLAMMATORY PATHWAY THAT A0 1094 00:46:50,840 --> 00:46:54,000 SEEMS TO REPRESS, THAT IS TYPE I 1095 00:46:54,000 --> 00:46:55,440 INTERFERON SIGNALING, WHICH HAS 1096 00:46:55,440 --> 00:46:57,600 BEEN DESCRIBED IN THE 1097 00:46:57,600 --> 00:47:00,320 PATHOGENESIS OF OTHER 1098 00:47:00,320 --> 00:47:02,720 AUTO-INFLAMMATORY DISEASES BY 1099 00:47:02,720 --> 00:47:07,160 DR. MANSKIS GROUP, AND WE HAVE 1100 00:47:07,160 --> 00:47:11,480 SEEN THAT PATIENTS WITH 1101 00:47:11,480 --> 00:47:18,840 HAPLOINAS FAR IN-- SUFFICIENCY 1102 00:47:18,840 --> 00:47:20,840 HAVE INCREASED PHOSPHORYLATION 1103 00:47:20,840 --> 00:47:22,520 OF STAT1, ACTIVATED DOWNSTREAM 1104 00:47:22,520 --> 00:47:23,200 OF TYPE I INTERFERONS. 1105 00:47:23,200 --> 00:47:25,800 NOW WE HAVE A SITUATION WHERE 1106 00:47:25,800 --> 00:47:27,400 RATHER THAN HAVING ONE 1107 00:47:27,400 --> 00:47:29,680 DYSREGULATED PATHWAY WE HAVE AT 1108 00:47:29,680 --> 00:47:31,120 LEAST FOUR POTENTIAL 1109 00:47:31,120 --> 00:47:32,400 INFLAMMATORY PATHWAYS THAT ARE 1110 00:47:32,400 --> 00:47:33,360 DYSREGULATED. 1111 00:47:33,360 --> 00:47:36,000 AND TO MAKE MATTERS EVEN MORE 1112 00:47:36,000 --> 00:47:39,600 COMPLICATED, I TOLD YOU THAT A20 1113 00:47:39,600 --> 00:47:42,920 HAS MULTIPLE FUNCTIONS THAT ARE 1114 00:47:42,920 --> 00:47:43,760 INVOLVED IN UBIQUITIN EDITING, 1115 00:47:43,760 --> 00:47:47,040 AND EACH DOMAIN OF THE PROTEIN 1116 00:47:47,040 --> 00:47:48,200 IS IMPORTANT FOR DIFFERENT 1117 00:47:48,200 --> 00:47:50,560 UBIQUITIN EDITING FUNCTION. 1118 00:47:50,560 --> 00:47:52,400 FOR EXAMPLE, THIS ZINC FINGER 7 1119 00:47:52,400 --> 00:47:57,200 DOMAIN IS VERY IMPORTANT FOR 1120 00:47:57,200 --> 00:47:59,400 LINEAR UBIQUITINNATION AND 1121 00:47:59,400 --> 00:48:02,040 DEUBIQUITINNATION, THIS DOMAIN, 1122 00:48:02,040 --> 00:48:03,360 IS IMPORTANT FOR TAKING OFF 1123 00:48:03,360 --> 00:48:04,440 CASES, THAT'S PART OF THE 1124 00:48:04,440 --> 00:48:09,000 ACTIVATION THAT I TOLD YOU ABOUT 1125 00:48:09,000 --> 00:48:11,920 OF NF-kappaB, WHEREAS THIS 1126 00:48:11,920 --> 00:48:16,160 HERE ZINC FINGER 4 IS IMPORTANT 1127 00:48:16,160 --> 00:48:17,800 FOR K48 EQUILIBRIUMATION. 1128 00:48:17,800 --> 00:48:20,240 RECENT WORK HAS SHOWN THIS 1129 00:48:20,240 --> 00:48:24,040 DOMAIN HERE IS VERY IMPORTANT 1130 00:48:24,040 --> 00:48:26,000 FOR PREVENTING ARTHRITIS AND TNF 1131 00:48:26,000 --> 00:48:28,120 DEPENDENT RESPONSES, WHEREAS YOU 1132 00:48:28,120 --> 00:48:31,280 NEED BOTH ZINC FINGER 4 AND ZINC 1133 00:48:31,280 --> 00:48:34,200 FINGER 7 TOGETHER IN ORDER TO 1134 00:48:34,200 --> 00:48:35,480 SUPPRESS THE INFLAMMASOME AND 1135 00:48:35,480 --> 00:48:37,000 IL-1 BETA PRODUCTION. 1136 00:48:37,000 --> 00:48:43,800 AND SO NOW COMING BACK TO OUR 1137 00:48:43,800 --> 00:48:44,760 SYNDROME, HAPLOINSUFFICIENCY OF 1138 00:48:44,760 --> 00:48:46,840 A 20, WE HAVE MULTIPLE DOMAINS 1139 00:48:46,840 --> 00:48:48,760 THAT INHIBIT DIFFERENT 1140 00:48:48,760 --> 00:48:56,000 INFLAMMATORY INFLAMMATORY 1141 00:48:56,000 --> 00:48:57,440 PATHWAYS, FOUR PATHWAYS, COULD 1142 00:48:57,440 --> 00:49:00,800 THIS CAUSE A DIFFERENT PHENOTYPE 1143 00:49:00,800 --> 00:49:03,240 IN PATIENTS WITH 1144 00:49:03,240 --> 00:49:06,480 HAPLOINSUFFICIENCY OF A20, 1145 00:49:06,480 --> 00:49:07,200 DESCRIBED AS BEHCET-LIKE 1146 00:49:07,200 --> 00:49:07,440 DISEASE. 1147 00:49:07,440 --> 00:49:09,600 I'M GOING TO TAKE YOU BACK TO 1148 00:49:09,600 --> 00:49:11,320 SOMETHING DR. KASTNER TOLD US 1149 00:49:11,320 --> 00:49:15,120 THEY BEGINNING OF THE TALK, THAT 1150 00:49:15,120 --> 00:49:19,640 AUTOINFLAMMATION IS CAUSED BY 1151 00:49:19,640 --> 00:49:20,960 DYSREGULATED OR OVERACTIVATED 1152 00:49:20,960 --> 00:49:26,400 INNATE IMMUNE RESPONSE WITHOUT 1153 00:49:26,400 --> 00:49:27,720 HIGH TITER AUTOANTIBODIES, 1154 00:49:27,720 --> 00:49:28,360 DYSREGULATED RESPONSE, A CLASSIC 1155 00:49:28,360 --> 00:49:31,360 FEW OF THE DISORDERS OF IMMUNE 1156 00:49:31,360 --> 00:49:33,600 DYSREGULATION WHERE EACH HAS ITS 1157 00:49:33,600 --> 00:49:34,000 OWN BIN. 1158 00:49:34,000 --> 00:49:37,320 BUT THIS IS THE VIEW IN 2022. 1159 00:49:37,320 --> 00:49:39,360 SO AS SEQUENCING HAS BECOME 1160 00:49:39,360 --> 00:49:40,120 CHEAPER AND CHEAPER, WE'VE 1161 00:49:40,120 --> 00:49:42,480 DISCOVERED MORE OF THESE 1162 00:49:42,480 --> 00:49:44,200 DISEASES, WE CAN SEE THAT THERE 1163 00:49:44,200 --> 00:49:47,160 ARE GENES THAT ARE EXPRESSED IN 1164 00:49:47,160 --> 00:49:48,120 INNATE CELLS AND IN ADAPTIVE 1165 00:49:48,120 --> 00:49:50,720 CELLS, AND THAT ARE IMPORTANT 1166 00:49:50,720 --> 00:49:52,800 FOR INNATE IMMUNITY AND ADAPTIVE 1167 00:49:52,800 --> 00:49:56,360 IMMUNITY, AND I THINK THAT NO 1168 00:49:56,360 --> 00:50:00,080 DISEASE IS MORE EMBLEMATIC THAN 1169 00:50:00,080 --> 00:50:02,360 HA20 BECAUSE TNF A-3 IS 1170 00:50:02,360 --> 00:50:03,080 EXPRESSED EVERYWHERE, IMPORTANT 1171 00:50:03,080 --> 00:50:07,800 FOR MANY TYPES OF BIOLOGIC 1172 00:50:07,800 --> 00:50:09,120 PROCESSES. 1173 00:50:09,120 --> 00:50:11,040 AND SO, FOR EXAMPLE, A20 1174 00:50:11,040 --> 00:50:11,920 MUTATIONS DO CAUSE AUTOIMMUNITY, 1175 00:50:11,920 --> 00:50:14,480 IF YOU LOOK AT PATIENTS WITH 1176 00:50:14,480 --> 00:50:16,960 HAPLOINSUFFICIENCY OF A 20, MANY 1177 00:50:16,960 --> 00:50:20,080 DO HAVE BONA FIDE HIGH TITER 1178 00:50:20,080 --> 00:50:21,480 AUTOANTIBODIES, THAT YOU DON'T 1179 00:50:21,480 --> 00:50:27,400 SEE IN DISEASES LIKE FMF OR 1180 00:50:27,400 --> 00:50:32,720 TRAPS, AUTOIMMUNE THYROID 1181 00:50:32,720 --> 00:50:37,720 DISEASE, KIDNEY DISEASE THAT 1182 00:50:37,720 --> 00:50:38,920 LOOKS INDISTINGUISHABLE FROM 1183 00:50:38,920 --> 00:50:39,120 LUPUS. 1184 00:50:39,120 --> 00:50:41,080 AUTOIMMUNITY IS NOT THE ONLY 1185 00:50:41,080 --> 00:50:42,320 TYPE OF IMMUNE DYSREGULATION. 1186 00:50:42,320 --> 00:50:44,640 WE ALSO SOMETIMES WILL SEE 1187 00:50:44,640 --> 00:50:46,120 PATIENTS WITH IMMUNE DEFICIENCY, 1188 00:50:46,120 --> 00:50:49,480 IN SOME PATIENTS THAT MANIFESTS 1189 00:50:49,480 --> 00:50:51,200 WITH CURRENT RESPIRATORY 1190 00:50:51,200 --> 00:50:52,120 INFECTION BUT WE'VE SEEN 1191 00:50:52,120 --> 00:50:55,000 PATIENTS WHO PRESENT WITH 1192 00:50:55,000 --> 00:50:56,120 CURRENT GASTROINTESTINAL 1193 00:50:56,120 --> 00:50:59,680 INFECTION, DISEASES THAT MIMIC 1194 00:50:59,680 --> 00:51:01,160 SEVERE COMBINED 1195 00:51:01,160 --> 00:51:01,560 IMMUNODEFICIENCY. 1196 00:51:01,560 --> 00:51:02,520 AND THEN SOMETIMES WE'LL SEE 1197 00:51:02,520 --> 00:51:05,480 PATIENTS WITH YET ANOTHER TYPE 1198 00:51:05,480 --> 00:51:09,760 OF IMMUNE DYSREGULATION, A20 IS 1199 00:51:09,760 --> 00:51:11,360 ALSO IMPORTANT FOR CELLULAR 1200 00:51:11,360 --> 00:51:12,400 PROLIFERATION, AND SOMATIC 1201 00:51:12,400 --> 00:51:15,920 MUTATIONS IN A20 OR LINKED TO 1202 00:51:15,920 --> 00:51:16,200 LYMPHOMA. 1203 00:51:16,200 --> 00:51:20,120 AND SO HAPLOINSUFFICIENCY OF A20 1204 00:51:20,120 --> 00:51:24,680 HAS BEEN DESCRIBED TO CAUSE 1205 00:51:24,680 --> 00:51:25,280 LYMPHOPROLIFERATIVE INHERITED 1206 00:51:25,280 --> 00:51:28,200 DISEASES, YET ANOTHER TYPE OF 1207 00:51:28,200 --> 00:51:30,400 IMMUNE DYSREGULATION, AND 1208 00:51:30,400 --> 00:51:33,120 FINALLY JUST LAST YEAR DID A 1209 00:51:33,120 --> 00:51:37,760 POPULATION SURVEY OF MULTIPLE 1210 00:51:37,760 --> 00:51:38,600 AUTO-INFLAMMATORY DISEASES, 1211 00:51:38,600 --> 00:51:41,200 FOUND SIGNATURE FOR CLINICAL AND 1212 00:51:41,200 --> 00:51:43,240 IMMUNOPHENOTYPIC FINDINGS 1213 00:51:43,240 --> 00:51:48,000 CONSISTENT WITH ALLERGY IN 1214 00:51:48,000 --> 00:51:48,840 PATIENTS WITH 1215 00:51:48,840 --> 00:51:49,760 HAPLOINSUFFICIENCY, LINKED TO 1216 00:51:49,760 --> 00:51:50,800 DEVELOPMENT OF COMMON ASTHMA. 1217 00:51:50,800 --> 00:51:53,840 NOW WE HAVE A DISEASE THAT 1218 00:51:53,840 --> 00:51:56,360 CROSSES MULTIPLE DIFFERENT TYPES 1219 00:51:56,360 --> 00:51:58,200 OF IMMUNE DYSREGULATION AND 1220 00:51:58,200 --> 00:51:58,800 REALLY DOES EXPAND OUR 1221 00:51:58,800 --> 00:52:02,600 CONCEPTION OF WHAT IT MEANS TO 1222 00:52:02,600 --> 00:52:04,600 HAVE AN AUTO-INFLAMMATORY 1223 00:52:04,600 --> 00:52:06,600 DISEASE. 1224 00:52:06,600 --> 00:52:08,720 AND THEN THE QUESTION BECOMES 1225 00:52:08,720 --> 00:52:09,960 THIS ISN'T SOMETHING LIKE A 1226 00:52:09,960 --> 00:52:11,440 PYRIN MUTATION WHERE YOU HAVE 1227 00:52:11,440 --> 00:52:13,720 ONE PATHWAY AND CAN TARGET THAT 1228 00:52:13,720 --> 00:52:21,080 PATHWAY OR IN THE CASE, YOU 1229 00:52:21,080 --> 00:52:24,200 TARGET IL-1, HOW CAN WE TREAT 1230 00:52:24,200 --> 00:52:24,960 THESE PATIENTS? 1231 00:52:24,960 --> 00:52:29,200 WE'RE LEFT WITH TRYING TO TARGET 1232 00:52:29,200 --> 00:52:33,640 SOME THE CYTOKINES AND PATHWAYS 1233 00:52:33,640 --> 00:52:35,040 A20 IS IMPORTANT FOR REPRESSING. 1234 00:52:35,040 --> 00:52:43,400 WE CAN USE INHIBITORS OF TNF 1235 00:52:43,400 --> 00:52:45,040 REPRESSING DOWNSTREAM OR TARGET 1236 00:52:45,040 --> 00:52:47,560 IL-1 BETA BECAUSE WE KNOW THAT 1237 00:52:47,560 --> 00:52:51,360 A20 IS IMPORTANT FOR REPRESSING 1238 00:52:51,360 --> 00:52:51,680 INFLAMMASOME. 1239 00:52:51,680 --> 00:52:56,400 OR WE CAN USE CLINICAL JAK/STAT 1240 00:52:56,400 --> 00:52:58,600 INHIBITORS TO TARGET RESPONSES 1241 00:52:58,600 --> 00:53:00,400 DOWNSTREAM OF TYPE I INTERFERON. 1242 00:53:00,400 --> 00:53:02,640 WE'VE DONE ALL THESE THINGS IN 1243 00:53:02,640 --> 00:53:04,040 VARIOUS PATIENTS WITH SOME 1244 00:53:04,040 --> 00:53:06,040 SUCCESS AND SO COMING BACK TO 1245 00:53:06,040 --> 00:53:09,560 OUR PATIENT, HOW DID WE TARGET 1246 00:53:09,560 --> 00:53:09,840 HER DISEASE? 1247 00:53:09,840 --> 00:53:13,000 WELL, I TOLD THAT YOU AT THE AGE 1248 00:53:13,000 --> 00:53:16,000 OF 23, WE DIAGNOSED OUR PATIENT 1249 00:53:16,000 --> 00:53:18,520 WITH HAPLOINSUFFICIENCY OF A20. 1250 00:53:18,520 --> 00:53:20,640 AND WE SAW THAT SHE HAD 1251 00:53:20,640 --> 00:53:22,160 INCREASED PRODUCTION OF IL-1 1252 00:53:22,160 --> 00:53:23,440 BETA. 1253 00:53:23,440 --> 00:53:25,720 AND SO WE KNEW 1254 00:53:25,720 --> 00:53:27,400 INFLAMMASOME-TARGETED TREATMENT 1255 00:53:27,400 --> 00:53:31,160 WAS A SUCCESSFUL WAY TO ADDRESS 1256 00:53:31,160 --> 00:53:36,520 MANY OF THESE OTHER 1257 00:53:36,520 --> 00:53:37,720 AUTO-INFLAMMATORY DISEASES, THE 1258 00:53:37,720 --> 00:53:41,600 INFLAMMASOME WAS ACTIVATED THIS 1259 00:53:41,600 --> 00:53:44,240 WAS SUCCESSFUL FOR SIX YEARS, 1260 00:53:44,240 --> 00:53:45,360 NEARLY IN REMISSION, VERY LOW 1261 00:53:45,360 --> 00:53:46,640 DISEASE ACTIVITY WITH SOME 1262 00:53:46,640 --> 00:53:48,760 FLARES THAT COULD BE ADDRESSED 1263 00:53:48,760 --> 00:53:49,680 WITH INCREASED DOSE. 1264 00:53:49,680 --> 00:53:53,320 AND SHE WAS VERY SUCCESSFULLY 1265 00:53:53,320 --> 00:53:55,680 TREATED, UNTIL ABOUT AGE 29. 1266 00:53:55,680 --> 00:53:58,040 AND AT THAT AGE SHE BEGINS TO 1267 00:53:58,040 --> 00:53:59,400 DEVELOP INCREASED BACK PAIN 1268 00:53:59,400 --> 00:54:02,360 WHICH THEN PROGRESSED TO 1269 00:54:02,360 --> 00:54:05,040 INCREASED ARTHRITIS, INCREASED 1270 00:54:05,040 --> 00:54:05,840 SYSTEMIC INFLAMMATION, THEN 1271 00:54:05,840 --> 00:54:07,560 FINALLY NEUROLOGIC SYMPTOMS. 1272 00:54:07,560 --> 00:54:10,640 AND THIS LED TO AN ESCALATION OF 1273 00:54:10,640 --> 00:54:15,400 HER THERAPY UNTIL WE WERE 1274 00:54:15,400 --> 00:54:17,480 SUPPRESSING MULTIPLE 1275 00:54:17,480 --> 00:54:19,240 A20-ASSOCIATED PATHWAYS 1276 00:54:19,240 --> 00:54:21,400 INCLUDING INFRAM SO MANY AND 1277 00:54:21,400 --> 00:54:25,600 JAK/STAT SIGNALING, SYSTEMIC 1278 00:54:25,600 --> 00:54:27,880 STEROIDS, CONTINUED TO HAVE 1279 00:54:27,880 --> 00:54:31,000 FLARES WITH NEURAL INFLAMMATION 1280 00:54:31,000 --> 00:54:32,520 DESPITE VERY INTENSIVE IMMUNE 1281 00:54:32,520 --> 00:54:35,400 SUPPRESSION WITH MANY DIFFERENT 1282 00:54:35,400 --> 00:54:36,680 PATHWAYS BEING TARGETED. 1283 00:54:36,680 --> 00:54:40,200 THE QUESTION BECAME DID WE HAVE 1284 00:54:40,200 --> 00:54:42,000 ANYTHING ELSE TO OFFER THIS 1285 00:54:42,000 --> 00:54:44,240 PATIENT OR PATIENT LIKE HER WHO 1286 00:54:44,240 --> 00:54:45,760 IS ON MULTIPLE TARGETED 1287 00:54:45,760 --> 00:54:48,680 THERAPIES OR EVEN BROAD 1288 00:54:48,680 --> 00:54:51,080 THERAPIES AND STILL UNCONTROLLED 1289 00:54:51,080 --> 00:54:52,840 WITH POTENTIALLY ORGAN 1290 00:54:52,840 --> 00:54:53,280 THREATENING DISEASE. 1291 00:54:53,280 --> 00:54:55,760 AND THE ANSWER IS THAT, YES, 1292 00:54:55,760 --> 00:54:57,320 THERE IS. 1293 00:54:57,320 --> 00:55:00,800 THIS IS VERY, VERY NEW DATA. 1294 00:55:00,800 --> 00:55:03,360 BUT IN TWO PATIENTS NOW THERE 1295 00:55:03,360 --> 00:55:06,280 HAVE BEEN REPORTS THAT AN 1296 00:55:06,280 --> 00:55:07,200 ALLOGENEIC STEM CELL TRANSPLANT, 1297 00:55:07,200 --> 00:55:08,240 DIFFERENT FROM THE TRANSPLANT 1298 00:55:08,240 --> 00:55:10,120 OUR PATIENT HAD HAD WHICH HAD 1299 00:55:10,120 --> 00:55:16,160 BEEN AUTOLOGOUS, GIVING A 1300 00:55:16,160 --> 00:55:21,000 PATIENT SOMEBODY ELSE'S IMMUNE 1301 00:55:21,000 --> 00:55:22,560 SYSTEM, TWO PEDIATRIC TREATMENTS 1302 00:55:22,560 --> 00:55:24,800 THAT WERE NOT SUCCESSFUL TREATED 1303 00:55:24,800 --> 00:55:26,720 WITH ALLOGENEIC STEM CELL 1304 00:55:26,720 --> 00:55:28,400 TRANSPLANTS AND WERE ABLE TO GET 1305 00:55:28,400 --> 00:55:31,680 OFF OF THEIR MEDICATIONS AND 1306 00:55:31,680 --> 00:55:33,080 HAVE VERY SUCCESSFUL OUTCOMES. 1307 00:55:33,080 --> 00:55:34,960 THEY DID HAVE SOME DAMAGE FROM 1308 00:55:34,960 --> 00:55:36,000 PRIOR DISEASE BUT THEY WERE 1309 00:55:36,000 --> 00:55:38,280 SUCCESSFUL BOTH IN TERMS OF 1310 00:55:38,280 --> 00:55:39,800 THEIR ENGRAFTMENT AND RESPONSE 1311 00:55:39,800 --> 00:55:41,400 TO TRANSPLANT. 1312 00:55:41,400 --> 00:55:42,920 AND THAT IS INDEED THE COURSE 1313 00:55:42,920 --> 00:55:46,080 THAT WE CHOSE TO FOLLOW WITH OUR 1314 00:55:46,080 --> 00:55:46,320 PATIENT. 1315 00:55:46,320 --> 00:55:48,600 SHE DID ELECT TO PURSUE 1316 00:55:48,600 --> 00:55:50,080 TRANSPLANT WHICH WE HOPE WILL 1317 00:55:50,080 --> 00:55:51,600 BE -- WILL START WITHIN THE NEXT 1318 00:55:51,600 --> 00:55:53,240 COUPLE WEEKS. 1319 00:55:53,240 --> 00:55:54,440 SHE WAS ADMITTED JUST THIS WEEK 1320 00:55:54,440 --> 00:55:57,800 WHICH IS WHY SHE COULDN'T BE 1321 00:55:57,800 --> 00:55:59,800 HERE IN PERSON TODAY. 1322 00:55:59,800 --> 00:56:01,360 AND WHY HER INTERVIEW WAS 1323 00:56:01,360 --> 00:56:01,880 RECORDED. 1324 00:56:01,880 --> 00:56:03,640 BEFORE I PROCEED ONWARD TO HER 1325 00:56:03,640 --> 00:56:05,040 INTERVIEW I WANT TO FIRST 1326 00:56:05,040 --> 00:56:09,560 ACKNOWLEDGE AND THANK ALL THE 1327 00:56:09,560 --> 00:56:12,000 PEOPLE WHO CONTRIBUTED TO THIS 1328 00:56:12,000 --> 00:56:14,000 WHIRLWIND OF RESEARCH OF HA20 1329 00:56:14,000 --> 00:56:16,600 THAT I'VE PUT YOU THROUGH. 1330 00:56:16,600 --> 00:56:18,360 AND THAT INCLUDES STUDENTS AND 1331 00:56:18,360 --> 00:56:25,000 MEMBERS OF MY GROUP AND MOST 1332 00:56:25,000 --> 00:56:26,000 PARTICULARLY SARAH BLACKSTONE 1333 00:56:26,000 --> 00:56:27,200 WITH INTERFERON 20 PRODUCTION AS 1334 00:56:27,200 --> 00:56:29,320 WELL AS MY MENTORS AT NIAID, 1335 00:56:29,320 --> 00:56:35,000 JOSH AND PAM, OF COURSE THE BIG 1336 00:56:35,000 --> 00:56:36,760 GROUP AT NHGRI INSTRUMENTAL IN 1337 00:56:36,760 --> 00:56:39,840 MY FELLOWSHIP AND HA 20 PATIENTS 1338 00:56:39,840 --> 00:56:40,920 AND FAMILIES THAT GENEROUSLY 1339 00:56:40,920 --> 00:56:45,800 AGREED TO PARTICIPATE IN THE 1340 00:56:45,800 --> 00:56:46,120 RESEARCH. 1341 00:56:46,120 --> 00:56:47,640 I'M GOING TO ALLOW US TO PROCEED 1342 00:56:47,640 --> 00:56:49,040 TO THE RECORDED INTERVIEW WITH 1343 00:56:49,040 --> 00:56:50,480 THE PATIENT WHO GENEROUSLY 1344 00:56:50,480 --> 00:56:53,200 AGREED TO SHARE HER THOUGHTS 1345 00:56:53,200 --> 00:56:53,920 DESPITE PREPARING FOR HER 1346 00:56:53,920 --> 00:56:59,280 TRANSPLANT. 1347 00:56:59,280 --> 00:57:02,280 >> THANK YOU FOR SHARING YOUR 1348 00:57:02,280 --> 00:57:03,240 EXPERIENCES LIVING WITH HA20. 1349 00:57:03,240 --> 00:57:05,240 I'M GOING TO ASK YOU SOME 1350 00:57:05,240 --> 00:57:07,880 QUESTIONS BOTH ABOUT LIVING WITH 1351 00:57:07,880 --> 00:57:11,600 HA 20 AS WELL AS BEING A PATIENT 1352 00:57:11,600 --> 00:57:12,400 WITH COMPLEX INFLAMMATORY 1353 00:57:12,400 --> 00:57:14,760 DISEASE MORE GENERALLY. 1354 00:57:14,760 --> 00:57:16,480 I'M GOING TO ASK YOU IF YOU 1355 00:57:16,480 --> 00:57:17,680 COULD PLEASE DESCRIBE TO US THE 1356 00:57:17,680 --> 00:57:19,800 SYMPTOMS THAT YOU AND YOUR 1357 00:57:19,800 --> 00:57:22,560 FAMILY MEMBERS HAVE HAD OVER THE 1358 00:57:22,560 --> 00:57:23,400 LAST SEVERAL YEARS AND 1359 00:57:23,400 --> 00:57:25,080 SPECIFICALLY HOW THEY MIGHT BE 1360 00:57:25,080 --> 00:57:26,800 SIMILAR OR DIFFERENT BETWEEN YOU 1361 00:57:26,800 --> 00:57:29,200 AND YOUR FAMILY MEMBERS. 1362 00:57:29,200 --> 00:57:30,600 >> THANKS FOR HAVING ME IN 1363 00:57:30,600 --> 00:57:31,080 TODAY. 1364 00:57:31,080 --> 00:57:34,000 THE INTERESTING THING ABOUT MY 1365 00:57:34,000 --> 00:57:38,160 FAMILY AND I IS THAT THE WAY IN 1366 00:57:38,160 --> 00:57:40,480 WHICH OUR DISEASE MANIFESTS WAS 1367 00:57:40,480 --> 00:57:42,080 SYMPTOMS REALLY VARYING IN SCOPE 1368 00:57:42,080 --> 00:57:43,360 AND SEVERITY. 1369 00:57:43,360 --> 00:57:46,720 WE'VE ALL EXPERIENCED AT ONE 1370 00:57:46,720 --> 00:57:48,280 POINT OR ANOTHER SKIN 1371 00:57:48,280 --> 00:57:49,280 INFLAMMATION, JOINT 1372 00:57:49,280 --> 00:57:51,400 INFLAMMATION, ORAL AND GENITAL 1373 00:57:51,400 --> 00:57:51,600 SORES. 1374 00:57:51,600 --> 00:57:52,960 IN ADDITION TO SYMPTOMS, ONE OF 1375 00:57:52,960 --> 00:57:54,880 MY FAMILY MEMBERS ALSO 1376 00:57:54,880 --> 00:58:06,080 EXPERIENCES G I AND KIDNEY 1377 00:58:06,080 --> 00:58:06,880 INFLAMMATION, I'VE EXPERIENCED 1378 00:58:06,880 --> 00:58:09,720 EYE INFLAMMATION, KIDNEY AND 1379 00:58:09,720 --> 00:58:12,080 G.I. INFLAMMATION, ITP. 1380 00:58:12,080 --> 00:58:13,680 >> A LOT OF VARIABILITY BETWEEN 1381 00:58:13,680 --> 00:58:15,920 YOU AND YOUR FAMILY MEMBERS AS 1382 00:58:15,920 --> 00:58:18,000 WELL AS SOME COMMON THINGS. 1383 00:58:18,000 --> 00:58:20,000 AND LOOKING BACK WE'VE REVIEWED 1384 00:58:20,000 --> 00:58:23,000 YOUR MEDICAL HISTORY, WHICH WAS 1385 00:58:23,000 --> 00:58:24,000 VERY LONG AND COMPLEX, DURING 1386 00:58:24,000 --> 00:58:26,400 THIS TALK, AND I WAS WONDERING 1387 00:58:26,400 --> 00:58:27,880 IF YOU COULD TELL US WHAT 1388 00:58:27,880 --> 00:58:30,640 SYMPTOMS YOU MIGHT HAVE HAD THAT 1389 00:58:30,640 --> 00:58:34,920 COULD HAVE PROMPTED CONCERN FOR 1390 00:58:34,920 --> 00:58:36,080 PERIODIC FEVER OR 1391 00:58:36,080 --> 00:58:37,440 AUTO-INFLAMMATORY GENETIC 1392 00:58:37,440 --> 00:58:38,480 SYNDROME, THINGS LIKE FEVERS, 1393 00:58:38,480 --> 00:58:40,920 DISCRETE FLARES DURING THE 1394 00:58:40,920 --> 00:58:44,000 COURSE OF YOUR DISEASE. 1395 00:58:44,000 --> 00:58:46,600 SURE, SO ONE COMMON THING THAT 1396 00:58:46,600 --> 00:58:54,680 MOST PATIENTS THAT LIVE WITH 1397 00:58:54,680 --> 00:58:55,680 CHRONIC ILLNESS, THEY DON'T 1398 00:58:55,680 --> 00:58:57,360 SOUND THE ALARM WITH MINOR 1399 00:58:57,360 --> 00:58:58,480 SYMPTOMS. 1400 00:58:58,480 --> 00:59:02,400 I FALL UNDER THAT CATEGORY. 1401 00:59:02,400 --> 00:59:03,880 BUT THINKING BACK, ESPECIALLY, 1402 00:59:03,880 --> 00:59:06,600 YOU KNOW, DURING THIS FLARE OVER 1403 00:59:06,600 --> 00:59:08,480 THE PAST TWO YEARS, THINKING 1404 00:59:08,480 --> 00:59:10,440 ABOUT WHAT THE MINOR SYMPTOMS 1405 00:59:10,440 --> 00:59:12,880 WERE IN THE BEGINNING, WHICH 1406 00:59:12,880 --> 00:59:15,480 INCLUDES SEVERE HEAD AND BACK 1407 00:59:15,480 --> 00:59:22,360 PAIN, G.I. INFLAMMATION, HAIR 1408 00:59:22,360 --> 00:59:24,480 LOSS, SKIN INFLAMMATION, THEN 1409 00:59:24,480 --> 00:59:26,840 ALSO EXCESSIVE SLEEPING, 1410 00:59:26,840 --> 00:59:28,400 EXCESSIVE FATIGUE. 1411 00:59:28,400 --> 00:59:30,880 >> DO YOU FEEL LIKE YOUR 1412 00:59:30,880 --> 00:59:32,600 SYMPTOMS OCCURRED MORE IN 1413 00:59:32,600 --> 00:59:35,160 DISCRETE FLARES OR MORE OF A 1414 00:59:35,160 --> 00:59:35,840 CONTINUOUS ESCALATION OF YOUR 1415 00:59:35,840 --> 00:59:42,040 SYMPTOMS THAT STAYED THERE ALL 1416 00:59:42,040 --> 00:59:43,280 THE TIME? 1417 00:59:43,280 --> 00:59:47,000 >> SO, PRIOR TO RECEIVING MY 1418 00:59:47,000 --> 00:59:53,480 FIRST TRANSPLANT, MY FLARES 1419 00:59:53,480 --> 00:59:56,440 DEFINITELY, YOU KNOW, LASTED A 1420 00:59:56,440 --> 01:00:01,080 CONSIDERABLE AMOUNT OF TIME, AND 1421 01:00:01,080 --> 01:00:04,000 THEY -- NEVER GOT BETTER. 1422 01:00:04,000 --> 01:00:05,600 THEY WOULD ADD A MEDICATION OR 1423 01:00:05,600 --> 01:00:08,400 CHANGE A MEDICATION, I WOULD 1424 01:00:08,400 --> 01:00:11,080 FEEL SLIGHTLY BETTER, I WOULD 1425 01:00:11,080 --> 01:00:12,440 REGRESS AGAIN. 1426 01:00:12,440 --> 01:00:14,720 IT WASN'T REALLY UNTIL JUNE 2013 1427 01:00:14,720 --> 01:00:20,320 I RECEIVED THE RIGHT DIAGNOSIS 1428 01:00:20,320 --> 01:00:22,480 AND RIGHT TREATMENT OPTION THAT 1429 01:00:22,480 --> 01:00:24,080 MY DISEASE REALLY, YOU KNOW, WAS 1430 01:00:24,080 --> 01:00:26,240 UNDER CONTROL AT THAT POINT. 1431 01:00:26,240 --> 01:00:27,760 AND I STILL EXPERIENCED, YOU 1432 01:00:27,760 --> 01:00:29,720 KNOW, MORE MINOR FLARES AND 1433 01:00:29,720 --> 01:00:32,680 DISEASE ACTIVITY, BUT THEY WERE 1434 01:00:32,680 --> 01:00:33,200 VERY MANAGEABLE WITH JUST 1435 01:00:33,200 --> 01:00:36,160 INCREASING A LITTLE BIT WITH THE 1436 01:00:36,160 --> 01:00:38,280 PREDNISONE OR WITH THE ANAKINRO, 1437 01:00:38,280 --> 01:00:41,600 I WAS ABLE TO GET BACK TO 1438 01:00:41,600 --> 01:00:44,600 BASELINE DOSES. 1439 01:00:44,600 --> 01:00:45,680 >> THINKING BACK THROUGHOUT, YOU 1440 01:00:45,680 --> 01:00:47,080 STARTED TO HAVE SYMPTOMS WHEN 1441 01:00:47,080 --> 01:00:48,120 YOU WERE QUITE YOUNG AND HAVE 1442 01:00:48,120 --> 01:00:49,880 NOW BEEN DEALING WITH THIS FOR 1443 01:00:49,880 --> 01:00:50,960 MANY YEARS. 1444 01:00:50,960 --> 01:00:54,680 HOW DO YOU FEEL THAT HAVING A 1445 01:00:54,680 --> 01:00:56,280 GENETIC INFLAMMATORY DISORDER 1446 01:00:56,280 --> 01:00:59,520 HAS AFFECTED YOUR LIFE? 1447 01:00:59,520 --> 01:00:59,800 >> SURE. 1448 01:00:59,800 --> 01:01:02,760 SO, OBVIOUS ANSWER TO THIS IS, 1449 01:01:02,760 --> 01:01:07,880 YOU KNOW, BECAUSE I HAD THE 1450 01:01:07,880 --> 01:01:12,480 RETINA INFLAMMATION IN 2005, 1451 01:01:12,480 --> 01:01:14,720 THAT LED TO DISABILITY, LIKE 1452 01:01:14,720 --> 01:01:15,880 THIS HAD THE MOST PROFOUND 1453 01:01:15,880 --> 01:01:17,920 IMPACT ON MY DAILY LIFE AND WILL 1454 01:01:17,920 --> 01:01:22,800 CONTINUE FOR THE REST OF MY 1455 01:01:22,800 --> 01:01:23,000 LIFE. 1456 01:01:23,000 --> 01:01:24,080 BUT THINKING REALLY BACK TO, YOU 1457 01:01:24,080 --> 01:01:27,760 KNOW, THESE PAST TWO YEARS AND 1458 01:01:27,760 --> 01:01:29,920 THIS CURRENT FLARE, IT HAS 1459 01:01:29,920 --> 01:01:35,200 BEEN -- WHAT HAS BEEN HARDER TO 1460 01:01:35,200 --> 01:01:36,600 DEAL WITH IS MENTAL ANGUISH AND 1461 01:01:36,600 --> 01:01:38,280 UNCERTAINTY OF HAVING A CHRONIC 1462 01:01:38,280 --> 01:01:40,120 ILLNESS ESPECIALLY IN THE MIDST 1463 01:01:40,120 --> 01:01:43,360 OF A PANDEMIC. 1464 01:01:43,360 --> 01:01:47,160 THE FEAR AND PANIC OF, YOU KNOW, 1465 01:01:47,160 --> 01:01:50,000 HAVING A VERY COMPLEX CONDITION 1466 01:01:50,000 --> 01:01:53,160 WHILE ALSO MANAGING -- ALSO 1467 01:01:53,160 --> 01:01:54,800 LIVING DURING A PANDEMIC HAS 1468 01:01:54,800 --> 01:01:56,280 BEEN VERY CHALLENGING. 1469 01:01:56,280 --> 01:01:58,280 AND IT'S REALLY ONE OF THE 1470 01:01:58,280 --> 01:02:01,080 REASONS WHY, YOU KNOW, THIS 1471 01:02:01,080 --> 01:02:02,360 UNCERTAINTY AS TO WHY I'VE 1472 01:02:02,360 --> 01:02:05,320 DECIDED TO MOVE TOWARDS HAVING 1473 01:02:05,320 --> 01:02:07,600 THE TRANSPLANT BECAUSE, YOU 1474 01:02:07,600 --> 01:02:11,120 KNOW, I KNOW THAT THE PANDEMIC 1475 01:02:11,120 --> 01:02:14,280 WILL END, BUT MY LIFE WILL NOT 1476 01:02:14,280 --> 01:02:14,760 GET BETTER. 1477 01:02:14,760 --> 01:02:17,520 AND THIS FEAR AND UNCERTAINTY 1478 01:02:17,520 --> 01:02:19,080 AND UNKNOWN IS GOING TO 1479 01:02:19,080 --> 01:02:19,320 CONTINUE. 1480 01:02:19,320 --> 01:02:24,080 SO THIS IS MY OPPORTUNITY TO GET 1481 01:02:24,080 --> 01:02:26,360 BACK TO HAVING MY LIFE BACK. 1482 01:02:26,360 --> 01:02:27,280 >> AND I WANT TO ACKNOWLEDGE 1483 01:02:27,280 --> 01:02:30,360 THAT THIS REALLY HAS BEEN A VERY 1484 01:02:30,360 --> 01:02:31,800 DIFFICULT TWO YEARS FOR YOU. 1485 01:02:31,800 --> 01:02:32,800 ESPECIALLY THE LAST SIX MONTHS 1486 01:02:32,800 --> 01:02:35,000 OR SO AS WE'VE SORT OF 1487 01:02:35,000 --> 01:02:35,680 APPROACHED THIS TRANSPLANT. 1488 01:02:35,680 --> 01:02:36,880 AND ONCE AGAIN THANK YOU FOR 1489 01:02:36,880 --> 01:02:38,200 SHARING THAT WITH US. 1490 01:02:38,200 --> 01:02:41,080 BECAUSE I KNOW IT'S BEEN HARD 1491 01:02:41,080 --> 01:02:44,200 HAVING GONE THROUGH IT TOGETHER 1492 01:02:44,200 --> 01:02:44,800 WITH YOU. 1493 01:02:44,800 --> 01:02:48,320 HOW DO YOU FEEL THAT COMING TO 1494 01:02:48,320 --> 01:02:52,400 THE NIH HAS HELPED YOU? 1495 01:02:52,400 --> 01:02:54,160 >> YES, I'VE BEEN COMING TO NIH 1496 01:02:54,160 --> 01:02:56,800 SINCE 2005 AND HAD MY FIRST 1497 01:02:56,800 --> 01:02:59,200 TRANSPLANT IN 2006. 1498 01:02:59,200 --> 01:03:02,040 AND I'VE BEEN RECEIVING CARE IN 1499 01:03:02,040 --> 01:03:04,560 MANY CASE SINCE THEN. 1500 01:03:04,560 --> 01:03:08,480 AND HAVING ACCESS TO THIS 1501 01:03:08,480 --> 01:03:10,320 MEDICAL CARE IS TRULY 1502 01:03:10,320 --> 01:03:10,640 INVALUABLE. 1503 01:03:10,640 --> 01:03:13,120 BUT I THINK, YOU KNOW, ALSO 1504 01:03:13,120 --> 01:03:14,240 REALLY IMPORTANT TO MENTION IS 1505 01:03:14,240 --> 01:03:19,360 AS A PATIENT WITH A CHRONIC RARE 1506 01:03:19,360 --> 01:03:26,840 CONDITION, THAT IS VERY COMPLEX, 1507 01:03:26,840 --> 01:03:29,400 YOU KNOW, FINDING MOMENTS WHERE 1508 01:03:29,400 --> 01:03:34,920 YOU'RE MORE AT PEACE ARE HARD TO 1509 01:03:34,920 --> 01:03:35,240 COME BY. 1510 01:03:35,240 --> 01:03:38,160 AND NIH GIVES THOSE MOMENTS TO 1511 01:03:38,160 --> 01:03:38,440 PATIENTS. 1512 01:03:38,440 --> 01:03:44,480 WHAT I MEAN BY THAT IS 1513 01:03:44,480 --> 01:03:45,880 BECAUSE -- BECAUSE NIH IS 1514 01:03:45,880 --> 01:03:47,520 UNMATCHED IN MY OPINION TO ANY 1515 01:03:47,520 --> 01:03:50,480 OTHER CARE YOU CAN RECEIVE 1516 01:03:50,480 --> 01:03:54,760 ANYWHERE ELSE, YOU KNOW, FROM 1517 01:03:54,760 --> 01:03:59,120 MEDICAL STAFF, DOCTORS, NURSES, 1518 01:03:59,120 --> 01:04:00,080 STAFF ACROSS ALL DEPARTMENTS, 1519 01:04:00,080 --> 01:04:02,560 YOU KNOW, THERE'S NEVER A MOMENT 1520 01:04:02,560 --> 01:04:03,680 WHERE I THINK MY CARE OR 1521 01:04:03,680 --> 01:04:08,040 TREATMENT IS GOING TO BE 1522 01:04:08,040 --> 01:04:09,680 COMPROMISED OR I WON'T BE GIVEN 1523 01:04:09,680 --> 01:04:11,560 THE BEST OPTIONS. 1524 01:04:11,560 --> 01:04:14,280 SO BECAUSE I DON'T HAVE TO WORRY 1525 01:04:14,280 --> 01:04:16,440 AS MUCH ABOUT THAT, YOU KNOW, I 1526 01:04:16,440 --> 01:04:20,280 GET THESE MOMENTS OF PEACE. 1527 01:04:20,280 --> 01:04:24,080 AND THAT'S -- FOR PATIENTS GOING 1528 01:04:24,080 --> 01:04:26,160 THROUGH INCREDIBLE HEALTH 1529 01:04:26,160 --> 01:04:27,800 CHALLENGES, THAT'S TRULY A GIFT. 1530 01:04:27,800 --> 01:04:28,480 >> YEAH, THANK YOU. 1531 01:04:28,480 --> 01:04:30,280 I'M REALLY GLAD TO HEAR THAT 1532 01:04:30,280 --> 01:04:32,680 WE'VE BEEN ABLE TO HELP YOU LIKE 1533 01:04:32,680 --> 01:04:32,960 THAT. 1534 01:04:32,960 --> 01:04:35,320 AND THEN THE LAST THING I WANT 1535 01:04:35,320 --> 01:04:37,840 TO ASK YOU IS WHAT YOU WOULD 1536 01:04:37,840 --> 01:04:39,920 LIKE THE MEDICAL COMMUNITY AND 1537 01:04:39,920 --> 01:04:43,080 SORT OF THE BIOMEDICAL RESEARCH 1538 01:04:43,080 --> 01:04:45,080 COMMUNITY TO KNOW BOTH ABOUT 1539 01:04:45,080 --> 01:04:47,880 HA20 AND MORE GENERALLY ABOUT 1540 01:04:47,880 --> 01:04:50,880 LIVING WITH A COMPLEX GENETIC 1541 01:04:50,880 --> 01:04:52,720 INFLAMMATORY DISEASE. 1542 01:04:52,720 --> 01:04:55,160 SURE. 1543 01:04:55,160 --> 01:04:57,920 SO, WHEN I THINK ABOUT THE 1544 01:04:57,920 --> 01:05:02,200 ENTIRETY OF MY MEDICAL JOURNEY, 1545 01:05:02,200 --> 01:05:07,280 ONE THING THAT HAS REMAINED TRUE 1546 01:05:07,280 --> 01:05:08,720 AND CONSTANT IS HAVING TRUST IN 1547 01:05:08,720 --> 01:05:12,080 YOUR MEDICAL TEAM AND YOUR 1548 01:05:12,080 --> 01:05:12,280 DOCTORS. 1549 01:05:12,280 --> 01:05:14,440 AND THAT'S SOMETHING THAT I HAVE 1550 01:05:14,440 --> 01:05:15,440 CERTAINLY FOUND AT NIH. 1551 01:05:15,440 --> 01:05:19,640 AND TRUST CAN BE REALLY FOUND IN 1552 01:05:19,640 --> 01:05:20,080 MANY WAYS. 1553 01:05:20,080 --> 01:05:23,680 AND FOR ME, WHAT THAT REALLY 1554 01:05:23,680 --> 01:05:26,840 MEANS IS THAT HAVING THIS RARE 1555 01:05:26,840 --> 01:05:27,960 GENETIC CONDITION MEANS MY 1556 01:05:27,960 --> 01:05:29,360 MEDICAL TEAM WILL THINK OUTSIDE 1557 01:05:29,360 --> 01:05:32,280 THE BOX AND OUTSIDE THE SCOPE OF 1558 01:05:32,280 --> 01:05:35,200 WHAT IS THE GENERAL THINKING. 1559 01:05:35,200 --> 01:05:38,880 AND THEN KIND OF TRANSLATING 1560 01:05:38,880 --> 01:05:46,480 THAT TO ME, YOU KNOW, MAKING 1561 01:05:46,480 --> 01:05:47,720 DECISIONS THAT NOT ONLY WILL 1562 01:05:47,720 --> 01:05:49,280 IMPACT MY LIFE TODAY BUT ALSO 1563 01:05:49,280 --> 01:05:51,280 THINKING ABOUT HOW IT'S GOING TO 1564 01:05:51,280 --> 01:05:53,480 IMPACT MY FUTURE. 1565 01:05:53,480 --> 01:05:56,640 AND SO TRUST IS REALLY CRUCIAL 1566 01:05:56,640 --> 01:06:00,200 TO ME AS A PATIENT WITH A 1567 01:06:00,200 --> 01:06:00,600 CHRONIC CONDITION. 1568 01:06:00,600 --> 01:06:02,360 >> THANK YOU VERY MUCH FOR 1569 01:06:02,360 --> 01:06:04,880 SHARING WITH US ALL OF THAT. 1570 01:06:04,880 --> 01:06:06,080 I KNOW THIS WAS DIFFICULT AND 1571 01:06:06,080 --> 01:06:07,520 PARTICULARLY IN THIS TIME AS 1572 01:06:07,520 --> 01:06:08,960 YOU'VE BEEN SORT OF APPROACHING 1573 01:06:08,960 --> 01:06:11,680 THE TRANSPLANT SO WE REALLY 1574 01:06:11,680 --> 01:06:12,160 APPRECIATE IT. 1575 01:06:12,160 --> 01:06:14,240 AND THANK YOU ONCE AGAIN. 1576 01:06:14,240 --> 01:06:18,000 NOW I'M GOING TO GO BACK TO THE 1577 01:06:18,000 --> 01:06:18,200 TALK. 1578 01:06:18,200 --> 01:06:20,840 >> THANK YOU. 1579 01:06:20,840 --> 01:06:23,640 1580 01:06:23,640 --> 01:06:26,840 >> AND I THINK THAT I CAN'T SAY 1581 01:06:26,840 --> 01:06:29,200 ANYTHING MORE ELOQUENT THAN MY 1582 01:06:29,200 --> 01:06:31,160 PATIENT HAS SAID ABOUT LIVING 1583 01:06:31,160 --> 01:06:31,920 WITH A CHRONIC INFLAMMATORY 1584 01:06:31,920 --> 01:06:32,280 DISEASE. 1585 01:06:32,280 --> 01:06:36,080 WITH THAT I'M GOING TO TURN THIS 1586 01:06:36,080 --> 01:06:44,160 TALK OVER TO MY COLLEAGUE DR. 1587 01:06:44,160 --> 01:06:48,680 MANTHIRAM WHO IS GOING TO TELL 1588 01:06:48,680 --> 01:06:50,080 US ABOUT GENETIC ARCHITECTURE OF 1589 01:06:50,080 --> 01:06:51,640 DISEASES ON THE SPECTRUM. 1590 01:06:51,640 --> 01:06:52,120 >> THANK YOU, DR. SCHWARTZ. 1591 01:06:52,120 --> 01:06:54,240 THANK YOU VERY MUCH FOR THE 1592 01:06:54,240 --> 01:06:57,000 OPPORTUNITY TO SPEAK WITH YOU IN 1593 01:06:57,000 --> 01:06:58,320 THIS DEMYSTIFYING MEDICINE 1594 01:06:58,320 --> 01:06:58,560 SERIES. 1595 01:06:58,560 --> 01:07:00,600 NOW, I WANTED TO SHARE WITH YOU 1596 01:07:00,600 --> 01:07:05,720 THE STORY OF A PECULIAR BUT 1597 01:07:05,720 --> 01:07:08,720 FAIRLY COMMON PERIODIC FEVER 1598 01:07:08,720 --> 01:07:10,720 SYNDROME, PFAPA SYNDROME, HOW IT 1599 01:07:10,720 --> 01:07:15,920 MAY BE A FACET OF BEHCETEST 1600 01:07:15,920 --> 01:07:16,120 DISEASE. 1601 01:07:16,120 --> 01:07:17,520 I'LL DISCUSS OFF LABEL USE OF 1602 01:07:17,520 --> 01:07:21,080 THE MEDICATIONS LISTED ON THE 1603 01:07:21,080 --> 01:07:21,280 SLIDE. 1604 01:07:21,280 --> 01:07:28,120 WHAT IS FPAPA SYNDROME? 1605 01:07:28,120 --> 01:07:37,280 IT'S AN ACRONYM, PERIODIC FEVER, 1606 01:07:37,280 --> 01:07:39,440 APTHOUS STOMATITIS, PHARYNGITIS, 1607 01:07:39,440 --> 01:07:41,680 ADENITIS, DESCRIBED AT 1608 01:07:41,680 --> 01:07:42,840 VANDERBILT AFTER RESEARCHERS LED 1609 01:07:42,840 --> 01:07:45,040 BY DR. EDWARDS SERIES A SERIES 1610 01:07:45,040 --> 01:07:47,760 OF PATIENTS WITH RECURRENT FEVER 1611 01:07:47,760 --> 01:07:52,320 EPISODES THAT STARTED IN TODDLER 1612 01:07:52,320 --> 01:07:55,600 TO PRESCHOOL AGE RANGE, HIGHLY 1613 01:07:55,600 --> 01:07:56,400 STEREOTYPICAL, INTERESTINGLY 1614 01:07:56,400 --> 01:07:59,400 THESE EPISODES HAD REGULAR 1615 01:07:59,400 --> 01:08:01,680 TIMING, AND IN SOME PATIENTS 1616 01:08:01,680 --> 01:08:02,960 REGULARITY OF THE EPISODES WAS 1617 01:08:02,960 --> 01:08:04,680 SO REGULAR THAT PARENTS COULD 1618 01:08:04,680 --> 01:08:06,040 PREDICT APPROXIMATELY WHEN THE 1619 01:08:06,040 --> 01:08:08,040 NEXT EPISODE WOULD OCCUR AND 1620 01:08:08,040 --> 01:08:09,720 WOULD START PLANNING THEIR 1621 01:08:09,720 --> 01:08:11,920 VACATIONS AND MAJOR FAMILY 1622 01:08:11,920 --> 01:08:14,920 EVENTS AROUND THAT TIME. 1623 01:08:14,920 --> 01:08:16,200 TYPICALLY EPISODES LASTED FROM 3 1624 01:08:16,200 --> 01:08:17,840 TO 5 DAYS, HAPPENED 1625 01:08:17,840 --> 01:08:19,200 APPROXIMATELY EVERY MONTH, SO 1626 01:08:19,200 --> 01:08:21,240 SOME PATIENTS HAVE DESCRIBED IT 1627 01:08:21,240 --> 01:08:25,080 AS A FEVER MENSTRUAL CYCLE. 1628 01:08:25,080 --> 01:08:31,160 DURING FLARES PATIENTS HAVE IN 1629 01:08:31,160 --> 01:08:37,720 ADDITION TO FEVER, CANKER SORES, 1630 01:08:37,720 --> 01:08:40,440 INFLAMMATION OF TONSILS, 1631 01:08:40,440 --> 01:08:41,720 CERVICAL ADENITIS, LYMPH NODES 1632 01:08:41,720 --> 01:08:53,840 IN THE NECK, ASIDE FROM THIS 1633 01:08:53,840 --> 01:08:55,680 ASYMPTOMATIC BETWEEN. 1634 01:08:55,680 --> 01:08:56,360 PREDNISONE ABORTED THE FLARES 1635 01:08:56,360 --> 01:08:58,880 WITHIN HOURS, THE FEVER WOULD 1636 01:08:58,880 --> 01:08:59,200 RESOLVE. 1637 01:08:59,200 --> 01:09:00,160 BUT UNFORTUNATELY IN MANY 1638 01:09:00,160 --> 01:09:02,680 PATIENTS THE EPISODES WOULD 1639 01:09:02,680 --> 01:09:04,120 OCCUR MORE FREQUENTLY WITH 1640 01:09:04,120 --> 01:09:05,400 STEROID TREATMENT. 1641 01:09:05,400 --> 01:09:07,960 LATER IT WAS FOUND THAT 1642 01:09:07,960 --> 01:09:09,720 TONSILLECTOMY LEADS TO COMPLETE 1643 01:09:09,720 --> 01:09:11,760 CESSATION OF FLARES IN MOST 1644 01:09:11,760 --> 01:09:14,400 PATIENTS WITH FPAPA. 1645 01:09:14,400 --> 01:09:16,040 WE BELIEVE IT'S LIKELY 1646 01:09:16,040 --> 01:09:17,720 UNDERDIAGNOSED, AS MANY PATIENTS 1647 01:09:17,720 --> 01:09:21,720 ARE MISDIAGNOSED AS HAVING 1648 01:09:21,720 --> 01:09:23,720 RECURRENT VIRAL INFECTIONS, 1649 01:09:23,720 --> 01:09:27,520 RECURRENT TONSILLITIS, IT REALLY 1650 01:09:27,520 --> 01:09:28,120 REQUIRES OBSERVANT PART, ASTUTE 1651 01:09:28,120 --> 01:09:30,920 CLINICIAN TO SEE THE EPISODES 1652 01:09:30,920 --> 01:09:31,920 ARE HIGHLY STEREOTYPICAL, 1653 01:09:31,920 --> 01:09:38,920 THERE'S REGULAR TIMING TO THE 1654 01:09:38,920 --> 01:09:41,520 FLARES, OR THERE'S APTHOUS 1655 01:09:41,520 --> 01:09:42,600 ULCERS, SO MANY GO UNDIAGNOSED, 1656 01:09:42,600 --> 01:09:46,720 SOME OF YOU MAY REALIZE YOU HAVE 1657 01:09:46,720 --> 01:09:47,320 SYMPTOMS, SOMETHING SIMILAR, 1658 01:09:47,320 --> 01:09:52,320 WHEN YOU WERE A CHILD. 1659 01:09:52,320 --> 01:09:53,920 THESE ARE PICTURES OF CANKER 1660 01:09:53,920 --> 01:09:56,560 SORES ON THE INSIDE OF THE LIP 1661 01:09:56,560 --> 01:10:01,480 OR INSIDE OF THE CHEEK AND IN 1662 01:10:01,480 --> 01:10:02,880 MOST PATIENTS, UNDER A 1663 01:10:02,880 --> 01:10:04,720 CENTIMETER IN SIZE, RESOLVE IN A 1664 01:10:04,720 --> 01:10:06,560 FEW DAYS, THERE ARE SOME 1665 01:10:06,560 --> 01:10:09,400 PATIENTS WHO HAVE MORE SEVERE 1666 01:10:09,400 --> 01:10:09,720 ULCERS. 1667 01:10:09,720 --> 01:10:12,400 AND THIS IS AN IMAGE OF EXUDATES 1668 01:10:12,400 --> 01:10:14,560 THAT MIGHT BE SEEN ON TONSILS OF 1669 01:10:14,560 --> 01:10:21,320 A PATIENT DURING A FLARE. 1670 01:10:21,320 --> 01:10:25,720 SO LONG TERM PATIENTS, FPAPA 1671 01:10:25,720 --> 01:10:26,920 MOST HAVE FLARES, LONG-TERM 1672 01:10:26,920 --> 01:10:28,440 FOLLOW-UP STUDY OF PATIENTS OVER 1673 01:10:28,440 --> 01:10:30,960 THE COURSE OF 20 YEARS FROM 1674 01:10:30,960 --> 01:10:34,320 VANDERBILT, YOU CAN SEE WITH 1675 01:10:34,320 --> 01:10:35,320 TIME EPISODES BECOME SHORTER, 1676 01:10:35,320 --> 01:10:38,040 FROM FIVE DAYS TO LATER CLOSE TO 1677 01:10:38,040 --> 01:10:39,720 THREE DAYS, EPISODES BECOME LESS 1678 01:10:39,720 --> 01:10:40,760 FREQUENT UNTIL THEY SORT OF 1679 01:10:40,760 --> 01:10:42,120 PETER OUT. 1680 01:10:42,120 --> 01:10:44,560 AND IN THIS STUDY ABOUT MOST 1681 01:10:44,560 --> 01:10:46,080 PATIENTS WHO HAD RESOLUTION OF 1682 01:10:46,080 --> 01:10:48,560 FLARES HAD FLARES FOR ABOUT SIX 1683 01:10:48,560 --> 01:10:49,080 YEARS. 1684 01:10:49,080 --> 01:10:52,520 HOWEVER, THERE WERE A GROUP OF 1685 01:10:52,520 --> 01:10:54,240 PATIENTS, NINE OUT OF 60, 1686 01:10:54,240 --> 01:10:55,520 PERSISTENT FEVER EPISODES AT THE 1687 01:10:55,520 --> 01:10:57,680 TIME OF FOLLOW-UP, ONE WAS 1688 01:10:57,680 --> 01:11:01,640 EVENTUALLY DIAGNOSED AS HAVING 1689 01:11:01,640 --> 01:11:03,920 BECCET'S DISEASE. 1690 01:11:03,920 --> 01:11:06,320 MOST PATIENTS CONTINUE TO HAVE 1691 01:11:06,320 --> 01:11:13,800 APTHOUS ULCERS AFTER FEVERS 1692 01:11:13,800 --> 01:11:18,080 RESOLVE AND GENITAL RASHES, 1693 01:11:18,080 --> 01:11:24,720 ATYPICAL, CONSISTENT WITH 1694 01:11:24,720 --> 01:11:25,720 BEHCET'S DISEASE, CONCLUDING 1695 01:11:25,720 --> 01:11:29,000 FPAPA MAY BE RELATED TO 1696 01:11:29,000 --> 01:11:29,480 ULCERATIVE DISORDERS. 1697 01:11:29,480 --> 01:11:31,480 WE NOTICED ABOUT A QUARTER OF 1698 01:11:31,480 --> 01:11:33,560 PATIENTS WITH FPAPA HAD A FAMILY 1699 01:11:33,560 --> 01:11:34,920 MEMBER WITH THE SYNDROME, AND 1700 01:11:34,920 --> 01:11:36,640 MANY OF THESE FAMILY MEMBERS 1701 01:11:36,640 --> 01:11:37,720 DIDN'T EVEN REALIZE THAT THEY 1702 01:11:37,720 --> 01:11:38,400 HAD FPAPA. 1703 01:11:38,400 --> 01:11:41,680 IT WAS ONLY AFTER WE TOOK A 1704 01:11:41,680 --> 01:11:43,480 CLOSE HISTORY THAT WE REALIZED 1705 01:11:43,480 --> 01:11:45,200 THEIR FEVER EPISODES MET THE 1706 01:11:45,200 --> 01:11:47,320 CRITERIA FOR THE SYNDROME. 1707 01:11:47,320 --> 01:11:49,640 BUT IN ADDITION TO FPAPA ITSELF, 1708 01:11:49,640 --> 01:11:51,280 FAMILY MEMBERS OF PATIENTS WITH 1709 01:11:51,280 --> 01:11:53,680 THIS SYNDROME ALSO ARE MORE 1710 01:11:53,680 --> 01:11:59,160 LIKELY TO HAVE RECURRENT 1711 01:11:59,160 --> 01:12:01,720 TONSILLITIS, UNDERGONE 1712 01:12:01,720 --> 01:12:02,480 TONSILLECTOMY, RECURRENT APTHOUS 1713 01:12:02,480 --> 01:12:04,240 ULCERS, THIS SHOWS PERCENTAGE OF 1714 01:12:04,240 --> 01:12:06,320 SIBLINGS OF PATIENTS WITH FPAPA 1715 01:12:06,320 --> 01:12:09,720 TWO HAVE RECURRENT APTHOUS 1716 01:12:09,720 --> 01:12:10,520 ULCERS, HIGHER THAN THAT OF 1717 01:12:10,520 --> 01:12:15,320 CONTROLS WITHOUT THE SYNDROME. 1718 01:12:15,320 --> 01:12:16,640 FAMILIAL CLUSTERING OF FPAPA 1719 01:12:16,640 --> 01:12:18,840 PROMPTED US TO SEARCH FOR 1720 01:12:18,840 --> 01:12:20,760 GENETIC RISK VARIANTS, SO 1721 01:12:20,760 --> 01:12:23,000 INITIALLY WE DID WHOLE EXOME 1722 01:12:23,000 --> 01:12:25,520 SEQUENCING ON FAMILIAL CASES BUT 1723 01:12:25,520 --> 01:12:28,000 UNFORTUNATELY WE WEREN'T ABLE TO 1724 01:12:28,000 --> 01:12:28,600 IDENTIFY RARE VARIANTS THAT 1725 01:12:28,600 --> 01:12:30,400 EXPLAINED THE DISEASE IN MOST OF 1726 01:12:30,400 --> 01:12:32,640 OUR PATIENTS. 1727 01:12:32,640 --> 01:12:34,120 AND SO WE HYPOTHESIZED INSTEAD 1728 01:12:34,120 --> 01:12:37,640 THAT FPAPA IS A COMPLEX GENETIC 1729 01:12:37,640 --> 01:12:38,880 DISORDERS, MANY COMMON GENETIC 1730 01:12:38,880 --> 01:12:39,880 VARIANTS CONTRIBUTE TO THE RISK. 1731 01:12:39,880 --> 01:12:42,720 AND IN FACT MANY OF THESE 1732 01:12:42,720 --> 01:12:43,800 VARIANTS MAY BE NON-CODING 1733 01:12:43,800 --> 01:12:46,680 REGIONS WHERE THEY AFFECT 1734 01:12:46,680 --> 01:12:48,040 EXPRESSION OF NEARBY GENES. 1735 01:12:48,040 --> 01:12:52,120 SO AS WE BEGIN TO SHIFT OUR 1736 01:12:52,120 --> 01:12:54,520 STUDY OF FPAPA, TO COMPLEX 1737 01:12:54,520 --> 01:12:56,080 DISORDER, THERE WERE GENOMIC 1738 01:12:56,080 --> 01:12:57,280 STUDIES OF TWO ULCERATIVE 1739 01:12:57,280 --> 01:13:01,680 DISEASES THAT CAUGHT OUR 1740 01:13:01,680 --> 01:13:02,120 ATTENTION. 1741 01:13:02,120 --> 01:13:02,920 FIRST IS BEHCET'S DISEASE. 1742 01:13:02,920 --> 01:13:06,800 DR. SCHWARTZ GAVE US A WONDERFUL 1743 01:13:06,800 --> 01:13:08,080 PRESENTATION ABOUT A MONOGENIC 1744 01:13:08,080 --> 01:13:13,400 FORM CAUSED BY RARE VARIANTS IN 1745 01:13:13,400 --> 01:13:15,440 THE TNFAIP3 GENE, THESE 1746 01:13:15,440 --> 01:13:16,760 MUTATIONS HAVE HIGH EFFECT SIZE 1747 01:13:16,760 --> 01:13:21,000 IN THE RISK OF AN INDIVIDUAL TO 1748 01:13:21,000 --> 01:13:22,400 DEVELOP BEHCET'S DISEASE. 1749 01:13:22,400 --> 01:13:24,320 TO IDENTIFY COMMON VARIANTS 1750 01:13:24,320 --> 01:13:27,720 WHICH EACH HAVE LOW EFFECT SIZE, 1751 01:13:27,720 --> 01:13:30,920 GENOME-WIDE ASSOCIATION STUDIES 1752 01:13:30,920 --> 01:13:35,040 ARE USED, GWAS, IN A GWAS STUDY 1753 01:13:35,040 --> 01:13:36,920 THOUSANDS TO MILLIONS OF SINGLE 1754 01:13:36,920 --> 01:13:37,720 NUCLEOTIDE POLYMORPHISMS FROM 1755 01:13:37,720 --> 01:13:38,920 ACROSS THE GENOME ARE GENOTYPED 1756 01:13:38,920 --> 01:13:40,960 IN A LARGE NUMBER OF 1757 01:13:40,960 --> 01:13:42,280 INDIVIDUALS, WITH THE DISEASE 1758 01:13:42,280 --> 01:13:44,920 AND THOSE WITHOUT THE DISEASE. 1759 01:13:44,920 --> 01:13:47,680 AND THEN THE SNPs ENRICHED OR 1760 01:13:47,680 --> 01:13:48,720 REDUCED AMONG INDIVIDUALS WITH 1761 01:13:48,720 --> 01:13:50,320 THE DISORDER ARE IDENTIFIED AND 1762 01:13:50,320 --> 01:13:53,720 THESE ARE RISK VARIANTS FOR THE 1763 01:13:53,720 --> 01:13:53,920 DISEASE. 1764 01:13:53,920 --> 01:13:58,680 WHEN YOU LOOK AT THE RISK 1765 01:13:58,680 --> 01:14:01,080 VARIANTS YOU CAN BEGIN TO 1766 01:14:01,080 --> 01:14:05,520 UNDERSTAND MECHANISM OF VARIOUS 1767 01:14:05,520 --> 01:14:06,000 COMPLEX DISEASES. 1768 01:14:06,000 --> 01:14:08,720 SO FOR BEHCET'S DISEASE, DR. 1769 01:14:08,720 --> 01:14:12,920 KASTNER AND THEIR GROUP HAVE 1770 01:14:12,920 --> 01:14:14,800 DONE MULTIPLE GWASs, THIS IS 1771 01:14:14,800 --> 01:14:17,320 INSTRUMENTAL IN HELPING US 1772 01:14:17,320 --> 01:14:19,160 UNDERSTAND THE PATHOGENESIS OF 1773 01:14:19,160 --> 01:14:21,320 THIS ULCERATIVE DISORDER. 1774 01:14:21,320 --> 01:14:24,920 AND THEY FOUND THAT THE MOST 1775 01:14:24,920 --> 01:14:26,520 SIGNIFICANT RISK FACTOR WAS AT 1776 01:14:26,520 --> 01:14:36,280 THE MHC LOCUS, IN FACT THE MOST 1777 01:14:36,280 --> 01:14:39,800 IMPORTANT RISK -- MHC TYPE WAS A 1778 01:14:39,800 --> 01:14:44,480 CLASS 1 MHC AND POLYMORPHISMS IN 1779 01:14:44,480 --> 01:14:46,880 ERAP 1, THAT TRIMS PEPTIDES TO 1780 01:14:46,880 --> 01:14:51,400 BE LOADED WERE ALSO RISK FACTORS 1781 01:14:51,400 --> 01:14:53,040 IN INDIVIDUALS WITH HLAB 51. 1782 01:14:53,040 --> 01:14:56,120 IN ADDITION THEY FOUND MANY 1783 01:14:56,120 --> 01:14:59,160 VARIANTS NEAR THESE GENES, MANY 1784 01:14:59,160 --> 01:15:01,720 OF WHICH ARE INFLAMMATORY GENES 1785 01:15:01,720 --> 01:15:05,600 THAT WERE RISK FACTORS FOR 1786 01:15:05,600 --> 01:15:09,080 BEHCET'S DISEASE, INVOLVED IN 1787 01:15:09,080 --> 01:15:10,840 Th1 AND Th17 ACTIVATION, CD8 1788 01:15:10,840 --> 01:15:13,960 POSITIVE T DEVELOP ACTIVATION 1789 01:15:13,960 --> 01:15:15,640 MYELOID INFLAMMATION IN ADDITION 1790 01:15:15,640 --> 01:15:17,720 TO MAINTAINING INTEGRITY OF THE 1791 01:15:17,720 --> 01:15:19,040 MUCOSAL BARRIER. 1792 01:15:19,040 --> 01:15:25,000 SO IN AGGREGATE THESE GENES RISK 1793 01:15:25,000 --> 01:15:27,800 LOCI HAVE BEGUN TO HELP US 1794 01:15:27,800 --> 01:15:31,240 UNDERSTAND PATHOPHYSIOLOGY OF 1795 01:15:31,240 --> 01:15:33,000 BEHCET'S DISEASE. 1796 01:15:33,000 --> 01:15:38,960 ANOTHER GWAS WAS PUBLISHED FOR 1797 01:15:38,960 --> 01:15:41,720 RECURRENT APTHOUS ULCERS, 1798 01:15:41,720 --> 01:15:43,480 COLLABORATION WITH 23ANDME AND 1799 01:15:43,480 --> 01:15:45,480 U.K. BIOBANK INCLUDED A LARGE 1800 01:15:45,480 --> 01:15:46,080 NUMBER OF INDIVIDUALS HAVING 1801 01:15:46,080 --> 01:15:47,920 PEOPLE HAVE YOU EVER HAD CANKER 1802 01:15:47,920 --> 01:15:49,680 SORES, AND THEY CHECKED YES, 1803 01:15:49,680 --> 01:15:52,800 THEY WERE CASES, IF NOT THEY 1804 01:15:52,800 --> 01:15:53,920 WERE CONTROLS. 1805 01:15:53,920 --> 01:15:57,280 THEY IDENTIFIED MANY RISK LOCI 1806 01:15:57,280 --> 01:15:58,280 FOR RECURRENT APTHOUS ULCERS, 1807 01:15:58,280 --> 01:16:01,640 RUN OF THE MILL PER SE CANKER 1808 01:16:01,640 --> 01:16:01,920 SORES. 1809 01:16:01,920 --> 01:16:04,520 INTERESTINGLY, MANY OF THE EXACT 1810 01:16:04,520 --> 01:16:07,840 SAME GENETIC RISK VARIANTS OR 1811 01:16:07,840 --> 01:16:14,680 LOCI DR. KASTNER AND DR. REMMERS 1812 01:16:14,680 --> 01:16:17,760 CHARACTERIZED WERE VARIANTS FOR 1813 01:16:17,760 --> 01:16:18,400 APTHOUS ULCERS. 1814 01:16:18,400 --> 01:16:23,480 RECURRENT APTHOUS ULCERS AND 1815 01:16:23,480 --> 01:16:25,720 BEHCET'S DISEASE ARE OVERLAP, 1816 01:16:25,720 --> 01:16:31,040 QUESTIONING -- BEGGING THE 1817 01:16:31,040 --> 01:16:32,560 QUESTION, PHENOTYPIC OVERLAP 1818 01:16:32,560 --> 01:16:35,920 WITH THE DISEASES DOES IT ALSO 1819 01:16:35,920 --> 01:16:36,840 HAVE GENOTYPICAL OVERLAP. 1820 01:16:36,840 --> 01:16:39,760 SO IN ORDER TO ADDRESS THIS WE 1821 01:16:39,760 --> 01:16:42,520 SCREENED THREE COHORTS OF 1822 01:16:42,520 --> 01:16:47,880 CAUCASIAN INDIVIDUALS WITH FPAPA 1823 01:16:47,880 --> 01:16:49,880 FOR RISK VARIANTS AND WE 1824 01:16:49,880 --> 01:16:51,720 COMPARED THOSE VARIANT 1825 01:16:51,720 --> 01:16:52,560 FREQUENCES TO THOSE AMONG 1826 01:16:52,560 --> 01:16:54,360 EUROPEANS IN THE GENERAL 1827 01:16:54,360 --> 01:16:55,880 POPULATION FROM LARGE DATABASES. 1828 01:16:55,880 --> 01:16:58,520 AND WE FOUND THAT MANY OF THESE 1829 01:16:58,520 --> 01:17:00,760 VARIANTS WERE ALSO SIGNIFICANTLY 1830 01:17:00,760 --> 01:17:04,920 ASSOCIATED WITH FPAPA, IN FACT 1831 01:17:04,920 --> 01:17:07,520 THIS ONE NEAR THE IL-12A GENE 1832 01:17:07,520 --> 01:17:09,720 HAD ODDS RATIO OVER 2, QUITE 1833 01:17:09,720 --> 01:17:14,800 HIGH FOR A COMPLEX GENETIC 1834 01:17:14,800 --> 01:17:15,320 DISORDER. 1835 01:17:15,320 --> 01:17:16,320 THE COMMONALITY OF GENETIC 1836 01:17:16,320 --> 01:17:17,520 SUSCEPTIBILITY LOCI AMONG THE 1837 01:17:17,520 --> 01:17:19,440 THREE DISORDERS WE BELIEVE PUTS 1838 01:17:19,440 --> 01:17:22,640 THEN IN A COMMON FAMILY, IN FACT 1839 01:17:22,640 --> 01:17:24,240 WE PROPOSED THAT THESE DISORDERS 1840 01:17:24,240 --> 01:17:28,120 BE GROUPED ON A SPECTRUM OF 1841 01:17:28,120 --> 01:17:30,280 DISEASE CALLED BEHCET'S SPECTRUM 1842 01:17:30,280 --> 01:17:34,600 DISORDERS, AND THIS IS ON THE 1843 01:17:34,600 --> 01:17:37,200 SEVERE END, CURRENT APTHOUS 1844 01:17:37,200 --> 01:17:38,760 ULCERS ON MILD END, FPAPA IN 1845 01:17:38,760 --> 01:17:39,000 BETWEEN. 1846 01:17:39,000 --> 01:17:42,720 THIS MADE A LOT OF SENSE BECAUSE 1847 01:17:42,720 --> 01:17:44,600 WE SEE PATIENTS WHO FALL IN 1848 01:17:44,600 --> 01:17:46,680 BETWEEN, PATIENTS WHO HAVE 1849 01:17:46,680 --> 01:17:48,040 GENITAL ULCERS, RASHES DURING 1850 01:17:48,040 --> 01:17:49,760 THEIR REGULAR FEVER FLARES, ALSO 1851 01:17:49,760 --> 01:17:53,520 SEE PATIENTS WHO HAVE RECURRENT 1852 01:17:53,520 --> 01:17:54,600 APTHOUS ULCERS WITH SYSTEMIC 1853 01:17:54,600 --> 01:17:58,160 SYMPTOMS BUT DON'T HAVE FEVER. 1854 01:17:58,160 --> 01:18:00,120 AND SO THIS CONCEPT OF THE 1855 01:18:00,120 --> 01:18:01,320 SPECTRUM HAS BEEN REALLY 1856 01:18:01,320 --> 01:18:03,880 IMPORTANT FOR US TO UNDERSTAND 1857 01:18:03,880 --> 01:18:06,520 PATIENTS THAT DON'T QUITE FIT 1858 01:18:06,520 --> 01:18:08,120 INTO THESE EXISTING DIAGNOSTIC 1859 01:18:08,120 --> 01:18:10,560 ENTITIES AND WHO SORT OF FALL 1860 01:18:10,560 --> 01:18:12,040 SOMEWHERE IN BETWEEN, IT'S BEEN 1861 01:18:12,040 --> 01:18:13,760 HELPFUL FOR US TO UNDERSTAND THE 1862 01:18:13,760 --> 01:18:14,760 MECHANISM OF THEIR DISEASE AND 1863 01:18:14,760 --> 01:18:17,560 THINK ABOUT WHAT TREATMENT 1864 01:18:17,560 --> 01:18:20,360 MODALITIES WE MAY USE. 1865 01:18:20,360 --> 01:18:28,080 SO, IN TERMS OF GENETIC RISK 1866 01:18:28,080 --> 01:18:36,240 LOCI, STRONGEST WAS UPSTREAM OF 1867 01:18:36,240 --> 01:18:38,040 IL-12A, AND IN ORDER TO 1868 01:18:38,040 --> 01:18:39,680 UNDERSTAND THE FUNCTIONAL 1869 01:18:39,680 --> 01:18:42,040 SIGNIFICANCE OF THIS VARIANT WE 1870 01:18:42,040 --> 01:18:43,280 OBTAINED BLOOD FROM INDIVIDUALS 1871 01:18:43,280 --> 01:18:45,440 WHO CAME TO THE NIH BLOOD BANK 1872 01:18:45,440 --> 01:18:48,360 AND GENOTYPED THEM FOR THIS RISK 1873 01:18:48,360 --> 01:18:51,040 ALLELE, THOSE WHO ARE 1874 01:18:51,040 --> 01:18:52,360 HETEROZYGOUS IN RED, HOMOZYGOUS 1875 01:18:52,360 --> 01:18:54,080 FOR RISK ALLELE? 1876 01:18:54,080 --> 01:18:54,360 GREEN. 1877 01:18:54,360 --> 01:18:55,520 WE EXTRACTED MONOCYTES AND 1878 01:18:55,520 --> 01:18:57,960 STIMULATED THEM WITH INTERFERON 1879 01:18:57,960 --> 01:18:59,840 AND LPS AND MEASURED IL-12 1880 01:18:59,840 --> 01:19:00,680 PRODUCTION. 1881 01:19:00,680 --> 01:19:04,400 WE FOUND THAT INDIVIDUALS WHO 1882 01:19:04,400 --> 01:19:08,040 CARRIED THE VARIANT PRODUCED 1883 01:19:08,040 --> 01:19:09,720 MON -- MONOCYTES PRODUCED MORE 1884 01:19:09,720 --> 01:19:13,920 IL-12 AND MORE IL-23 WHICH IS 1885 01:19:13,920 --> 01:19:15,400 ANOTHER PRO-INFLAMMATORY 1886 01:19:15,400 --> 01:19:15,800 CYTOKINE. 1887 01:19:15,800 --> 01:19:17,720 PREVIOUSLY THIS VARIANT NEAR 1888 01:19:17,720 --> 01:19:20,960 STAT 4 HAS BEEN ASSOCIATED WITH 1889 01:19:20,960 --> 01:19:21,720 INCREASED STAT4 EXPRESSION AND 1890 01:19:21,720 --> 01:19:25,200 STAT4 IS IMPORTANT IN DOWNSTREAM 1891 01:19:25,200 --> 01:19:29,080 SIGNALING FROM IL-12 AND IL-23. 1892 01:19:29,080 --> 01:19:35,520 THIS VARIANT NEAR IL-10 1893 01:19:35,520 --> 01:19:38,440 ASSOCIATED WITH EXPRESSION, AND 1894 01:19:38,440 --> 01:19:42,240 THIS VARIANT IS ASSOCIATED WITH 1895 01:19:42,240 --> 01:19:44,160 DECREASED CCR 1 EXPRESSION, A 1896 01:19:44,160 --> 01:19:45,840 CHEMOKINE RECEPTOR THAT HELPS 1897 01:19:45,840 --> 01:19:49,680 MONOCYTES TRAFFIC TO SITES OF 1898 01:19:49,680 --> 01:19:54,760 INFLAMMATION SO IT'S 1899 01:19:54,760 --> 01:19:57,160 HYPOTHESIZED DECREASED CCR1 MAY 1900 01:19:57,160 --> 01:19:59,600 CONTRIBUTE TO DIMINISHED MUCOSAL 1901 01:19:59,600 --> 01:20:01,120 BARRIER, MAY HAVE OTHER 1902 01:20:01,120 --> 01:20:05,000 FUNCTIONS AS WELL. 1903 01:20:05,000 --> 01:20:06,240 SO, IN AGGREGATE THESE VARIANTS 1904 01:20:06,240 --> 01:20:12,600 ARE -- APPEAR TO BE LINKED TO 1905 01:20:12,600 --> 01:20:14,080 HEIGHTENED ANTIGEN PRESENTING 1906 01:20:14,080 --> 01:20:16,360 CELL, ELEVATED IL-12 DOWNSTREAM 1907 01:20:16,360 --> 01:20:18,080 SIGNALING WITH STAT4 POLARIZES 1908 01:20:18,080 --> 01:20:21,120 AND ACTIVATES Th1 CELLS TO 1909 01:20:21,120 --> 01:20:24,360 PRODUCE INTERFERON GAMMA, 1910 01:20:24,360 --> 01:20:26,520 ELEVATED IL-23 AND STAT4 1911 01:20:26,520 --> 01:20:29,440 POLARIZE TOWARD Th17 PHENOTYPE 1912 01:20:29,440 --> 01:20:33,200 AND DECREASED IL-10 LEADS TO 1913 01:20:33,200 --> 01:20:34,320 FURTHER ACTIVATION OF T CELLS. 1914 01:20:34,320 --> 01:20:37,920 AND THIS FIT WELL WITH WHAT WAS 1915 01:20:37,920 --> 01:20:40,760 KNOWN ABOUT THE IMMUNOLOGY OF 1916 01:20:40,760 --> 01:20:42,360 FPAPA FLARES, SO PATIENTS WERE 1917 01:20:42,360 --> 01:20:45,680 FOUND TO HAVE HIGH EXPRESSION OF 1918 01:20:45,680 --> 01:20:47,800 INTERFERON GAMMA IN THESE GENES, 1919 01:20:47,800 --> 01:20:49,520 HIGH EXPRESSION OF Th1 1920 01:20:49,520 --> 01:20:50,800 CHEMOKINES IN THEIR BLOOD, ALSO 1921 01:20:50,800 --> 01:20:51,880 IN THE TONSIL. 1922 01:20:51,880 --> 01:20:54,920 WE'VE FOUND THAT THEY HAVE HIGH 1923 01:20:54,920 --> 01:20:58,160 EXPRESSION OF THE SUBUNITS OF 1924 01:20:58,160 --> 01:20:59,480 IL-12 DURING THEIR MONOCYTES 1925 01:20:59,480 --> 01:21:00,880 DURING FLARES. 1926 01:21:00,880 --> 01:21:04,760 AND I MENTIONED EARLIER THAT 1927 01:21:04,760 --> 01:21:05,560 TONSILLECTOMY LEADS TO 1928 01:21:05,560 --> 01:21:07,520 RESOLUTION OF FLARES IN MANY 1929 01:21:07,520 --> 01:21:08,360 PATIENTS, SO WE'VE BEGUN TO LOOK 1930 01:21:08,360 --> 01:21:10,320 AT THE IMMUNOLOGY OF THE TONSILS 1931 01:21:10,320 --> 01:21:13,520 AS WELL, AND WE FOUND THAT THE 1932 01:21:13,520 --> 01:21:15,200 CD4 POSITIVE T CELLS IN THE 1933 01:21:15,200 --> 01:21:18,960 TONSILS OF PATIENTS WITH FPAPA 1934 01:21:18,960 --> 01:21:21,600 HAVE ELEVATED Th1 AND Th17 1935 01:21:21,600 --> 01:21:23,960 RELATED CYTOKINES COMPARED TO 1936 01:21:23,960 --> 01:21:28,920 TONSILS FROM CONTROLS WHO HAVE 1937 01:21:28,920 --> 01:21:29,720 ANATOMIC ISSUES. 1938 01:21:29,720 --> 01:21:31,760 WE FOUND CD4 POSITIVE T CELLS IN 1939 01:21:31,760 --> 01:21:33,800 PATIENTS WITH FPAPA ALSO PRODUCE 1940 01:21:33,800 --> 01:21:35,720 SIGNIFICANTLY MORE INTERFERON 1941 01:21:35,720 --> 01:21:40,600 GAM AND IL-17 UPON STIMULATION 1942 01:21:40,600 --> 01:21:45,960 WITH PMA IONAMYCIN. 1943 01:21:45,960 --> 01:21:47,840 WE FOUND ASSOCIATIONS, MOST OF 1944 01:21:47,840 --> 01:21:49,480 THESE WERE UNIQUE TO FPAPA, THEY 1945 01:21:49,480 --> 01:21:56,000 WEREN'T RELATED TO THE OTHER 1946 01:21:56,000 --> 01:21:59,920 DISORDERS ON THE BECHECT 1947 01:21:59,920 --> 01:22:03,000 SPECTRUM EXCEPT ONE. 1948 01:22:03,000 --> 01:22:09,720 ALONG THE SPECTRUM HLA IS STRONG 1949 01:22:09,720 --> 01:22:11,720 RESPECTER FOR BECHET'S DISEASE, 1950 01:22:11,720 --> 01:22:21,240 FPAPA APPEARS TO BE IN THE MIDDLE. 1951 01:22:21,240 --> 01:22:23,520 HLR RISK ALLELES MAY BE 1952 01:22:23,520 --> 01:22:25,440 DIFFERENT AND MAY AFFECT THE 1953 01:22:25,440 --> 01:22:26,840 PHENOTYPE ALONG THE SPECTRUM. 1954 01:22:26,840 --> 01:22:27,920 IT'S WITH GREAT PLEASURE THAT 1955 01:22:27,920 --> 01:22:33,560 I'D LIKE TO INTRODUCE TO YOU ONE 1956 01:22:33,560 --> 01:22:35,080 OF MY PATIENTS, HOLLI IS A 1957 01:22:35,080 --> 01:22:36,520 PHYSICIAN, I'VE HAD THE 1958 01:22:36,520 --> 01:22:38,520 PRIVILEGE OF FOLLOWING HER AND 1959 01:22:38,520 --> 01:22:41,600 HER CHILDREN AT THE NIH FOR THE 1960 01:22:41,600 --> 01:22:42,680 PAST SIX YEARS. 1961 01:22:42,680 --> 01:22:45,080 HOLLI PRESENTED TO US WITH 1962 01:22:45,080 --> 01:22:48,080 INFLAMMATORY DISEASE THAT HAD 1963 01:22:48,080 --> 01:22:50,920 SOME FEATURES OF BEHCET'S 1964 01:22:50,920 --> 01:22:53,400 DISEASE BUT SHE AND CHILDREN ARE 1965 01:22:53,400 --> 01:22:54,680 FPAPA WHEN YOUNGER, BEFORE WE 1966 01:22:54,680 --> 01:22:56,080 REALIZED THE CONNECTION BETWEEN 1967 01:22:56,080 --> 01:23:00,560 THE SYNDROMES THAT WE BEGAN 1968 01:23:00,560 --> 01:23:02,840 SEEING HER. 1969 01:23:02,840 --> 01:23:05,280 SO, I HOPE HOLLI CAN HEAR ME. 1970 01:23:05,280 --> 01:23:05,600 THERE'S HOLLI. 1971 01:23:05,600 --> 01:23:06,400 THANK YOU. 1972 01:23:06,400 --> 01:23:07,920 THANK YOU VERY MUCH, HOLLI, FOR 1973 01:23:07,920 --> 01:23:11,440 BEING HERE WITH US TODAY AND FOR 1974 01:23:11,440 --> 01:23:12,360 SHARING YOUR STORY. 1975 01:23:12,360 --> 01:23:15,120 I WANTED TO START BY ASKING YOU 1976 01:23:15,120 --> 01:23:16,520 TO SHARE YOU AND YOUR CHILDREN'S 1977 01:23:16,520 --> 01:23:18,920 SYMPTOMS OF FPAPA AND HOW YOU 1978 01:23:18,920 --> 01:23:19,600 WERE DIAGNOSED. 1979 01:23:19,600 --> 01:23:20,080 >> YES. 1980 01:23:20,080 --> 01:23:21,040 THANKS FOR HAVING ME. 1981 01:23:21,040 --> 01:23:24,560 IT'S AN HONOR TO BE HERE AND 1982 01:23:24,560 --> 01:23:25,720 SHARING OUR STORY. 1983 01:23:25,720 --> 01:23:27,320 I THINK WHEN EVERYTHING STARTED 1984 01:23:27,320 --> 01:23:29,240 OUR DAUGHTER WAS 11 MONTHS OLD. 1985 01:23:29,240 --> 01:23:31,320 SHE'S THE YOUNGER OF OUR TWO 1986 01:23:31,320 --> 01:23:31,600 CHILDREN. 1987 01:23:31,600 --> 01:23:33,720 SHE STARTED HAVING FEVERS. 1988 01:23:33,720 --> 01:23:35,960 THEY WOULD BE 104, 105, AND SHE 1989 01:23:35,960 --> 01:23:37,720 WOULD PLAY THROUGH IT BUT 1990 01:23:37,720 --> 01:23:39,760 WOULDN'T DRINK A WHOLE LOT. 1991 01:23:39,760 --> 01:23:41,520 AND MY KIDS WEREN'T IN DAY CARE. 1992 01:23:41,520 --> 01:23:43,280 WE HAD A NANNY IN THE HOUSE. 1993 01:23:43,280 --> 01:23:44,400 SHE WOULD HAVE THESE FEVERS. 1994 01:23:44,400 --> 01:23:45,760 IT WOULD BE EVERY THREE, THREE 1995 01:23:45,760 --> 01:23:47,600 AND A HALF WEEKS, WE COULD 1996 01:23:47,600 --> 01:23:49,200 ALMOST SET AN ALARM TO IT. 1997 01:23:49,200 --> 01:23:51,200 I KIND OF LAUGHED IN YOUR 1998 01:23:51,200 --> 01:23:54,200 PRESENTATION, YOU MENTIONED THE 1999 01:23:54,200 --> 01:23:54,480 VACATIONS. 2000 01:23:54,480 --> 01:23:57,120 AND WE WOULD SCHEDULE THINGS 2001 01:23:57,120 --> 01:23:58,400 BECAUSE OF BECKY'S FEVERS. 2002 01:23:58,400 --> 01:23:59,880 WE WOULD GO TO THE PEDIATRICS, 2003 01:23:59,880 --> 01:24:02,120 THEY WOULD TELL US, OH, SHE HAS 2004 01:24:02,120 --> 01:24:03,520 ULCERS AND SWOLLEN LYMPH NODES, 2005 01:24:03,520 --> 01:24:06,480 IT'S JUST A VIRUS. 2006 01:24:06,480 --> 01:24:09,480 AND FINALLY I SAID, LOOK, SHE 2007 01:24:09,480 --> 01:24:10,800 HAS NO ILL CONTACTS. 2008 01:24:10,800 --> 01:24:12,200 THERE'S SOMETHING GOING ON HERE. 2009 01:24:12,200 --> 01:24:14,400 WE CAN SET AN ALARM TO IT, 2010 01:24:14,400 --> 01:24:17,240 NOBODY ELSE IS SICK. 2011 01:24:17,240 --> 01:24:20,080 AND SO A WORKUP WAS DONE. 2012 01:24:20,080 --> 01:24:23,480 THEY DID GENETIC TESTING FOR THE 2013 01:24:23,480 --> 01:24:25,440 FAMILIAL MEDITERRANEAN FEVER, IT 2014 01:24:25,440 --> 01:24:25,760 WAS NEGATIVE. 2015 01:24:25,760 --> 01:24:28,520 THEN I DID READ A LITTLE BIT 2016 01:24:28,520 --> 01:24:31,200 ABOUT THE FPAPA SYNDROME, I'M 2017 01:24:31,200 --> 01:24:32,040 GOING TO TRY PREDNISONE. 2018 01:24:32,040 --> 01:24:35,040 I DID TELL THE PEDIATRICIAN 2019 01:24:35,040 --> 01:24:37,520 AFTER THE FACT, THE FEVER WENT 2020 01:24:37,520 --> 01:24:37,920 AWAY, MIRACULOUS. 2021 01:24:37,920 --> 01:24:40,880 WE CONTINUED THAT BUT OVER TIME 2022 01:24:40,880 --> 01:24:47,800 THE FEVERS BECAME FOR FREQUENT 2023 01:24:47,800 --> 01:24:52,520 INSTEAD INSTEAD OF 3 WEEKS WAS 2 2024 01:24:52,520 --> 01:24:52,800 1/2. 2025 01:24:52,800 --> 01:24:57,720 BECKY HAD TONSILS OUT AT 23 2026 01:24:57,720 --> 01:24:59,520 MONTHS OLD, FEVER WENT AWAY, IT 2027 01:24:59,520 --> 01:25:00,000 WAS GREAT. 2028 01:25:00,000 --> 01:25:03,800 OUR SON WAS 8, THIRD OR FOURTH 2029 01:25:03,800 --> 01:25:04,600 GREAT STARTED GETTING FEVERS AND 2030 01:25:04,600 --> 01:25:04,920 SORE THROATS. 2031 01:25:04,920 --> 01:25:06,360 I SAID TO THE PEDIATRICS DO YOU 2032 01:25:06,360 --> 01:25:08,200 THINK IT'S THE SAME THING AS OUR 2033 01:25:08,200 --> 01:25:09,640 DAUGHTER HAD? 2034 01:25:09,640 --> 01:25:12,280 SHE SAID YES, I DO. 2035 01:25:12,280 --> 01:25:15,120 THE ENT TOOK HIS TONSILS OUT. 2036 01:25:15,120 --> 01:25:16,720 MY MOTHER SAID, YOU KNOW, YOU 2037 01:25:16,720 --> 01:25:18,960 ALWAYS HAD FEVERS. 2038 01:25:18,960 --> 01:25:20,760 AND I DID. 2039 01:25:20,760 --> 01:25:22,720 I REMEMBER MISSING 21 DAYS OF 2040 01:25:22,720 --> 01:25:24,000 SCHOOL IN THIRD GRADE OVER 2041 01:25:24,000 --> 01:25:25,240 FEVERS AND SORE THROATS AND 2042 01:25:25,240 --> 01:25:26,200 WOULD FEEL PRETTY WELL. 2043 01:25:26,200 --> 01:25:28,000 MY MOTHER WOULD LOOK AT ME AND 2044 01:25:28,000 --> 01:25:29,320 SHE KNEW I HAD THE FEVER. 2045 01:25:29,320 --> 01:25:31,880 AND WHEN WE WENT TO ENT THEY 2046 01:25:31,880 --> 01:25:34,560 SAID, WELL, WE'RE NOT TAKING 2047 01:25:34,560 --> 01:25:35,560 TONSILS OUT, IT'S GETTING WARM, 2048 01:25:35,560 --> 01:25:37,720 SHE'S NOT GOING TO GET SICK. 2049 01:25:37,720 --> 01:25:39,680 MY MOTHER ARGUED AND SHE SAID 2050 01:25:39,680 --> 01:25:41,320 HE'LL GET A FEVER, IT WILL COME 2051 01:25:41,320 --> 01:25:43,120 IN TWO WEEKS, SURE ENOUGH IT 2052 01:25:43,120 --> 01:25:43,320 DID. 2053 01:25:43,320 --> 01:25:44,960 I HAD MY TONSILS OUT. 2054 01:25:44,960 --> 01:25:46,920 BETWEEN THIRD AND FOURTH GRADE. 2055 01:25:46,920 --> 01:25:51,760 DIDN'T MISS MUCH SCHOOL AFTER 2056 01:25:51,760 --> 01:25:52,040 THAT. 2057 01:25:52,040 --> 01:25:53,320 THE EFFECT WAS DIFFICULT. 2058 01:25:53,320 --> 01:25:53,880 I REMEMBER MISSING SO MUCH 2059 01:25:53,880 --> 01:25:55,360 SCHOOL I DIDN'T KNOW HOW TO 2060 01:25:55,360 --> 01:25:59,560 ADDRESS AN ENVELOPE ONE TIME. 2061 01:25:59,560 --> 01:26:00,760 I REMEMBER THIS. 2062 01:26:00,760 --> 01:26:02,080 MY KIDS -- SAL MISSED QUITE A 2063 01:26:02,080 --> 01:26:05,240 BIT IN THE PROCESS TOO. 2064 01:26:05,240 --> 01:26:07,080 AND I HAVE CONTINUED TO HAVE -- 2065 01:26:07,080 --> 01:26:08,800 MY FEVERS WENT AWAY BUT I'VE 2066 01:26:08,800 --> 01:26:09,920 CONTINUED TO HAVE ULCERS THROUGH 2067 01:26:09,920 --> 01:26:12,720 THE YEARS AND SOME JOINT PAINS. 2068 01:26:12,720 --> 01:26:14,760 AS THIS WAS GOING WITH MY KIDS, 2069 01:26:14,760 --> 01:26:16,920 I WAS SEEING A RHEUMATOLOGIST 2070 01:26:16,920 --> 01:26:18,400 BECAUSE I'D HAVE JOINT THINGS 2071 01:26:18,400 --> 01:26:21,000 WHERE I CURRENT TURN DOORKNOBS, 2072 01:26:21,000 --> 01:26:22,160 HAVING DIFFICULTY BUT NOBODY 2073 01:26:22,160 --> 01:26:24,760 COULD EVER PUT A FINGER ON 2074 01:26:24,760 --> 01:26:25,720 ANYTHING. 2075 01:26:25,720 --> 01:26:27,560 AND OUR SON WAS BETTER, AND THEN 2076 01:26:27,560 --> 01:26:31,440 THREE YEARS AFTER HE HAD HIS 2077 01:26:31,440 --> 01:26:32,520 TONSILS OUT STARTED GETTING -- 2078 01:26:32,520 --> 01:26:34,480 WOULD HAVE SHORTNESS OF BREATH 2079 01:26:34,480 --> 01:26:36,080 EPISODES AND I WORKED IN THE 2080 01:26:36,080 --> 01:26:38,080 E.R. FOR 18 YEARS, HE WOULD COME 2081 01:26:38,080 --> 01:26:43,800 IN THE E.R. AND, OH, HE HAS 2082 01:26:43,800 --> 01:26:44,080 PNEUMONIA. 2083 01:26:44,080 --> 01:26:46,280 I NEVER LOOKED AT X-RAYS. 2084 01:26:46,280 --> 01:26:52,320 HE HAD PLURAL EFFUSION TWICE, 2085 01:26:52,320 --> 01:26:56,080 MYOCARDITIS AND PERICARDITIS. 2086 01:26:56,080 --> 01:26:57,400 THE RHEUMATOLOGIST SAID DOES HE 2087 01:26:57,400 --> 01:26:58,320 HAVE JOINT PAIN? 2088 01:26:58,320 --> 01:26:58,520 NO. 2089 01:26:58,520 --> 01:27:01,720 WE THOUGHT ABOUT IT. 2090 01:27:01,720 --> 01:27:04,880 MULTIPLE TIMES BOTH OF OUR KIDS 2091 01:27:04,880 --> 01:27:10,720 ARE JOINT STUFF, SAL DIDN'T 2092 01:27:10,720 --> 01:27:12,840 ACOLYTE ONE TIME BECAUSE HE 2093 01:27:12,840 --> 01:27:13,160 COULDN'T WALK. 2094 01:27:13,160 --> 01:27:15,400 WE WERE REFERRED TO THE NIH, A 2095 01:27:15,400 --> 01:27:16,520 WONDERFUL EXPERIENCE. 2096 01:27:16,520 --> 01:27:18,720 >> THANK YOU FOR SHARING THAT. 2097 01:27:18,720 --> 01:27:20,680 YOUR STORY REALLY SHOWS HOW IT 2098 01:27:20,680 --> 01:27:24,120 CAN TAKE SOME TIME TO REACH THE 2099 01:27:24,120 --> 01:27:27,040 DIAGNOSIS, AND I THINK IT REALLY 2100 01:27:27,040 --> 01:27:29,680 REQUIRES OBSERVANT PARENT AS YOU 2101 01:27:29,680 --> 01:27:31,120 WERE FOR YOUR KIDS. 2102 01:27:31,120 --> 01:27:33,760 SO YOU STARTED TO MENTION THAT 2103 01:27:33,760 --> 01:27:35,480 EVEN AFTER TONSILLECTOMY YOU 2104 01:27:35,480 --> 01:27:38,000 BEGAN TO HAVE SOME -- NEW 2105 01:27:38,000 --> 01:27:40,640 SYMPTOMS, AFTERWARDS, THAT WERE 2106 01:27:40,640 --> 01:27:41,800 MORE INDICATIVE OF BEHCET'S 2107 01:27:41,800 --> 01:27:43,880 DISEASE, I WONDERED IF YOU COULD 2108 01:27:43,880 --> 01:27:46,880 MENTION SOME OF THOSE AND WHEN 2109 01:27:46,880 --> 01:27:47,920 YOU STARTED TO REALIZE THAT 2110 01:27:47,920 --> 01:27:51,160 THERE WAS SOMETHING ELSE GOING 2111 01:27:51,160 --> 01:27:51,480 ON. 2112 01:27:51,480 --> 01:27:53,200 >> WELL, I'VE HAD -- I'VE ALWAYS 2113 01:27:53,200 --> 01:27:54,400 REMEMBERED HAVING ULCERS. 2114 01:27:54,400 --> 01:27:57,600 I WOULD COMPLAIN ABOUT IT. 2115 01:27:57,600 --> 01:28:00,240 SOMETIMES IT'S HARD TO EAT AND 2116 01:28:00,240 --> 01:28:01,440 SPEAK WITH AN ULCER. 2117 01:28:01,440 --> 01:28:05,960 MY MOM WOULD SAY YOU ATE TOO 2118 01:28:05,960 --> 01:28:09,040 MANY TOMATO SANDWICH OR ORANGES. 2119 01:28:09,040 --> 01:28:09,880 WE DIDN'T KNOW DIFFERENT. 2120 01:28:09,880 --> 01:28:11,520 THERE WOULD BE TIMES I WAS WORSE 2121 01:28:11,520 --> 01:28:12,800 THAN OTHERS. 2122 01:28:12,800 --> 01:28:15,200 LOOKING BACK I THINK STRESS MAY 2123 01:28:15,200 --> 01:28:16,440 HAVE AGGRAVATED SOME OF THAT. 2124 01:28:16,440 --> 01:28:17,720 I ALWAYS HAD SOME SORT OF JOINT 2125 01:28:17,720 --> 01:28:19,640 PAIN WHERE I WOULDN'T BE ABLE TO 2126 01:28:19,640 --> 01:28:21,440 RAISE MY SHOULDER AND WE WENT TO 2127 01:28:21,440 --> 01:28:23,440 ORTHOPEDICS AND THEY WOULD TELL 2128 01:28:23,440 --> 01:28:26,720 ME, OH, YOU KNOW, IT'S FROM 2129 01:28:26,720 --> 01:28:27,880 SWIMMING OR CHEERLEADING. 2130 01:28:27,880 --> 01:28:30,160 IN COLLEGE I COULDN'T WALK ONE 2131 01:28:30,160 --> 01:28:31,080 WEEKEND, BECAUSE MY KNEE HURT. 2132 01:28:31,080 --> 01:28:35,360 IT SWELLED UP. 2133 01:28:35,360 --> 01:28:37,720 I WAS CRAWLING IN MY DORM ROOM, 2134 01:28:37,720 --> 01:28:43,920 STUDENT HEALTH TOLD ME, OH, YOU 2135 01:28:43,920 --> 01:28:45,040 HAVE OSGOOD SLAUGHTER'S DISEASE, 2136 01:28:45,040 --> 01:28:48,040 THAT DOESN'T HAPPEN TO A 2137 01:28:48,040 --> 01:28:48,840 22-YEAR-OLD, THERE WAS SOMETHING 2138 01:28:48,840 --> 01:28:50,040 MORE GOING ON. 2139 01:28:50,040 --> 01:28:51,600 I DID HAVE PERIODS WHERE I WOULD 2140 01:28:51,600 --> 01:28:57,880 BE OKAY, AND WHEN I WAS A 2141 01:28:57,880 --> 01:29:00,080 RESIDENT, I WAS 26, 27, I HAD 2142 01:29:00,080 --> 01:29:05,720 EYE ISSUES, TROUBLE WITH VISION, 2143 01:29:05,720 --> 01:29:08,440 GOT SENT TO OPHTHALMOLOGY, 2144 01:29:08,440 --> 01:29:09,760 UVIITIS, NOBODY COULD PUT THE 2145 01:29:09,760 --> 01:29:11,120 PIECES TOGETHER. 2146 01:29:11,120 --> 01:29:16,720 THEY SAID TO ME, WELL, MAYBE 2147 01:29:16,720 --> 01:29:22,040 IT'S A THYROID PROBLEM. 2148 01:29:22,040 --> 01:29:23,880 DOWN THE ROAD I WAS DIAGNOSED, 2149 01:29:23,880 --> 01:29:24,800 THAT'S BEEN UNDER CONTROL AS 2150 01:29:24,800 --> 01:29:27,400 WELL BUT I THINK IN THE LAST FEW 2151 01:29:27,400 --> 01:29:29,160 YEARS MY BIGGEST PROBLEMS HAVE 2152 01:29:29,160 --> 01:29:31,120 BEEN THE JOINT ISSUES AND ULCERS 2153 01:29:31,120 --> 01:29:45,680 HAVE GOTTEN WORSE BUT RIGHT NOW 2154 01:29:45,680 --> 01:29:46,480 I'M ON AN INHIBITOR, 2155 01:29:46,480 --> 01:29:49,600 [AUDIO DISTORTION] 2156 01:29:49,600 --> 01:29:50,360 >> THANKS, HOLLI. 2157 01:29:50,360 --> 01:29:54,560 YEAH, AS TIME WENT ON LIKE A LOT 2158 01:29:54,560 --> 01:29:58,320 MORE OF THESE BEHCET'S FEATURES 2159 01:29:58,320 --> 01:29:59,800 CAME UP, SIGNIFICANT ORAL ULCERS 2160 01:29:59,800 --> 01:30:04,000 MORE SEVERE THAN THE MILDER ONES 2161 01:30:04,000 --> 01:30:04,920 WE SEE IN FPAPA SYNDROME. 2162 01:30:04,920 --> 01:30:09,120 REMEMBER YOU HAD ALSO TOLD ME 2163 01:30:09,120 --> 01:30:10,240 YOU HAD RASHES AND THERE WERE 2164 01:30:10,240 --> 01:30:12,080 TIMES YOU MENTIONED THAT YOU 2165 01:30:12,080 --> 01:30:14,200 WOULD DEVELOP LESIONS AT THE 2166 01:30:14,200 --> 01:30:16,080 SITE OF TRAUMA TO YOUR SKIN. 2167 01:30:16,080 --> 01:30:17,720 COULD YOU DESCRIBE THAT A LITTLE 2168 01:30:17,720 --> 01:30:18,960 BIT FOR US? 2169 01:30:18,960 --> 01:30:20,720 >> YEAH, PROBABLY LIKE A YEAR 2170 01:30:20,720 --> 01:30:22,680 AND A HALF AGO, I DON'T KNOW, I 2171 01:30:22,680 --> 01:30:25,360 FELL AND HAD A SCRAPE ON MY 2172 01:30:25,360 --> 01:30:25,720 KNEE. 2173 01:30:25,720 --> 01:30:26,520 NO BIG DEAL. 2174 01:30:26,520 --> 01:30:29,240 A WEEK OR SO LATER I GET LIKE A 2175 01:30:29,240 --> 01:30:31,240 BOLUS KIND OF LESION AT THAT 2176 01:30:31,240 --> 01:30:31,440 SITE. 2177 01:30:31,440 --> 01:30:33,120 EVERY NOW AND THEN IF I BUMP 2178 01:30:33,120 --> 01:30:35,080 THAT, IT DOES COME BACK. 2179 01:30:35,080 --> 01:30:36,560 I NEVER HAD THAT WITH BLOOD 2180 01:30:36,560 --> 01:30:37,080 WORK. 2181 01:30:37,080 --> 01:30:39,960 I'VE HAD A LOT OF BLOOD WORK, 2182 01:30:39,960 --> 01:30:41,400 MORE WHEN IT'S SOME SORT OF 2183 01:30:41,400 --> 01:30:43,440 TRAUMA I SEE THAT WITH OR IF I 2184 01:30:43,440 --> 01:30:44,720 SCRATCH REALLY HARD SOMETIMES 2185 01:30:44,720 --> 01:30:49,680 AND BREAK SOMETHING OPEN I'LL 2186 01:30:49,680 --> 01:30:51,680 SEE THAT. 2187 01:30:51,680 --> 01:30:53,360 I ALSO REMEMBER HAVING A RASH 2188 01:30:53,360 --> 01:30:56,200 WHERE THEY WERE RED WHEELS AND 2189 01:30:56,200 --> 01:30:57,480 HAD CENTRALIZED CLEARING. 2190 01:30:57,480 --> 01:31:00,160 I WENT TO STUDENT HEALTH AT THAT 2191 01:31:00,160 --> 01:31:00,640 POINT. 2192 01:31:00,640 --> 01:31:03,960 PROBABLY WAS SECOND YEAR MEDICAL 2193 01:31:03,960 --> 01:31:04,240 SCHOOL. 2194 01:31:04,240 --> 01:31:05,720 AND IT WAS VERY STRESSFUL TIME. 2195 01:31:05,720 --> 01:31:07,200 NOBODY COULD FIGURE IT OUT. 2196 01:31:07,200 --> 01:31:10,520 EVENTUALLY IT WENT AWAY. 2197 01:31:10,520 --> 01:31:11,920 I'VE HAD STRANGE RASHES THROUGH 2198 01:31:11,920 --> 01:31:12,480 THE YEARS. 2199 01:31:12,480 --> 01:31:18,200 A FEW YEARS AGO HAD ANOTHER ONE, 2200 01:31:18,200 --> 01:31:19,400 THAT WAS BIOPSIED, SHOWED 2201 01:31:19,400 --> 01:31:19,880 INFLAMMATORY REACTION. 2202 01:31:19,880 --> 01:31:21,720 >> I THINK YOUR DISEASE 2203 01:31:21,720 --> 01:31:23,720 EXEMPLIFIES HOW IT'S HARD TO 2204 01:31:23,720 --> 01:31:27,320 PINPOINT EXACTLY WHAT IT IS THAT 2205 01:31:27,320 --> 01:31:32,240 YOU HAVE, LIKE A CLEAR DISEASE 2206 01:31:32,240 --> 01:31:34,040 ENTITY THAT DEFIES EXISTING 2207 01:31:34,040 --> 01:31:35,320 DISEASE CLASSIFICATIONS IN SOME 2208 01:31:35,320 --> 01:31:35,560 CASE. 2209 01:31:35,560 --> 01:31:37,120 I WAS WONDERING IF YOU COULD 2210 01:31:37,120 --> 01:31:40,000 TALK TO US ABOUT HOW HAVING AN 2211 01:31:40,000 --> 01:31:43,840 INFLAMMATORY DISEASE LIKE THIS 2212 01:31:43,840 --> 01:31:47,440 HAS AFFECTED YOUR LIFE. 2213 01:31:47,440 --> 01:31:49,520 2214 01:31:49,520 --> 01:31:54,960 >> OH, I TRY NOT -- I THINK I 2215 01:31:54,960 --> 01:31:56,960 COULD RELATE -- 2216 01:31:56,960 --> 01:31:58,440 [AUDIO DISTORTION] 2217 01:31:58,440 --> 01:32:01,280 IGNORE IT, I DON'T KNOW THAT'S 2218 01:32:01,280 --> 01:32:02,840 ALWAYS BEEN THE BEST THING. 2219 01:32:02,840 --> 01:32:04,800 BUT COMING TO THE NIH HAS BEEN 2220 01:32:04,800 --> 01:32:05,880 EXTREMELY HELPFUL. 2221 01:32:05,880 --> 01:32:09,360 AND I REMEMBER AT ONE POINT I 2222 01:32:09,360 --> 01:32:10,120 WAS FRUSTRATED NOBODY COULD 2223 01:32:10,120 --> 01:32:11,720 FIGURE OUT WHAT WE HAVE. 2224 01:32:11,720 --> 01:32:13,920 DR. COLBERT GAVE ME THE BEST 2225 01:32:13,920 --> 01:32:16,000 ADVICE AS A PATIENT, AND I THINK 2226 01:32:16,000 --> 01:32:17,440 BEING A PHYSICIAN SOMETIMES 2227 01:32:17,440 --> 01:32:18,400 MAKES IT DIFFICULT BECAUSE I 2228 01:32:18,400 --> 01:32:22,520 WANT TO KNOW WHAT I HAVE. 2229 01:32:22,520 --> 01:32:25,720 PART OF MY TYPE A PERSONALITY 2230 01:32:25,720 --> 01:32:28,400 DOESN'T HELP BUT THAT BUT DR. 2231 01:32:28,400 --> 01:32:30,080 COLBERT SAID GIVE IT TIME. 2232 01:32:30,080 --> 01:32:33,560 DON'T NET ANYBODY -- LET ANYBODY 2233 01:32:33,560 --> 01:32:34,080 LABEL YOU. 2234 01:32:34,080 --> 01:32:35,640 WE'LL FIGURE IT OUT. 2235 01:32:35,640 --> 01:32:37,200 IF WE LABEL YOU, WE MIGHT GIVE 2236 01:32:37,200 --> 01:32:38,200 YOU THE WRONG TREATMENT. 2237 01:32:38,200 --> 01:32:39,840 IT'S OKAY NOT TO LABEL YOU. 2238 01:32:39,840 --> 01:32:41,720 THAT WAS THE BEST ADVICE ANYONE 2239 01:32:41,720 --> 01:32:42,800 HAD GIVEN TO ME. 2240 01:32:42,800 --> 01:32:44,040 BECAUSE I'VE BEEN MORE PATIENT 2241 01:32:44,040 --> 01:32:44,680 WITH IT. 2242 01:32:44,680 --> 01:32:47,920 AND I KNOW HAVENING -- HAVING 2243 01:32:47,920 --> 01:32:50,480 THE GROUP AT THE NIH IS 2244 01:32:50,480 --> 01:32:52,040 WONDERFUL, YOU'VE BEEN 2245 01:32:52,040 --> 01:32:55,320 SUPPORTIVE, LIKE DR. SCHWARTZ'S 2246 01:32:55,320 --> 01:32:58,160 PATIENT HAVING TRUST IN 2247 01:32:58,160 --> 01:32:58,720 EVERYBODY. 2248 01:32:58,720 --> 01:33:00,080 AS A PHYSICIAN, ESPECIALLY IN 2249 01:33:00,080 --> 01:33:02,080 THE E.R., WHEN YOU SEE 2250 01:33:02,080 --> 01:33:03,120 PEDIATRICIANS, EVERYBODY IS SO 2251 01:33:03,120 --> 01:33:04,680 WORRIED ABOUT GETTING PEOPLE OUT 2252 01:33:04,680 --> 01:33:06,080 THE DOOR THAT WE DON'T ALWAYS 2253 01:33:06,080 --> 01:33:09,760 TAKE THE TIME TO LISTEN TO OUR 2254 01:33:09,760 --> 01:33:10,360 PATIENTS. 2255 01:33:10,360 --> 01:33:11,920 AND I THINK THAT'S WHAT MADE THE 2256 01:33:11,920 --> 01:33:13,280 DIFFERENCE AT THE NIH. 2257 01:33:13,280 --> 01:33:16,680 YOU GUYS HAVE SAT DOWN AND 2258 01:33:16,680 --> 01:33:18,640 YOU'VE LISTENED. 2259 01:33:18,640 --> 01:33:19,880 AND IT'S BEEN GOOD. 2260 01:33:19,880 --> 01:33:22,480 >> WELL, THANK YOU VERY MUCH FOR 2261 01:33:22,480 --> 01:33:23,800 SHARING YOUR STORY. 2262 01:33:23,800 --> 01:33:25,920 I'M SURE MORE QUESTIONS MIGHT 2263 01:33:25,920 --> 01:33:28,680 COME UP IN THE SESSION, SO I'M 2264 01:33:28,680 --> 01:33:31,320 JUST GOING TO -- I HAVE A COUPLE 2265 01:33:31,320 --> 01:33:35,000 MORE SLIDES AND I WILL OPEN FOR 2266 01:33:35,000 --> 01:33:36,120 QUESTIONS. 2267 01:33:36,120 --> 01:33:40,240 THANK YOU VERY MUCH, HOLLI. 2268 01:33:40,240 --> 01:33:44,080 SO, OUR NEXT STEPS ARE TO DO A 2269 01:33:44,080 --> 01:33:48,720 GWAS FOR FPAPA, WE'RE IN THE 2270 01:33:48,720 --> 01:33:49,840 PROCESS OF RECRUITING ENOUGH 2271 01:33:49,840 --> 01:33:52,280 PATIENTS, GIVING US THE 2272 01:33:52,280 --> 01:33:53,720 OPPORTUNITY TO COMPARE THE 2273 01:33:53,720 --> 01:33:56,520 GENETIC ARCHITECTURE OF THREE 2274 01:33:56,520 --> 01:33:59,840 DISORDERS ON THE BEHCET'S 2275 01:33:59,840 --> 01:34:01,680 SPECTRUM AND FURTHER UNDERSTAND 2276 01:34:01,680 --> 01:34:05,320 WHERE FACTORS MAY DETERMINE 2277 01:34:05,320 --> 01:34:09,560 WHERE A PATIENT FALLS ON THE 2278 01:34:09,560 --> 01:34:10,440 SPECTRUM. 2279 01:34:10,440 --> 01:34:11,520 DIAGNOSING FPAPA IS DIFFICULT, 2280 01:34:11,520 --> 01:34:13,320 BASED ON CLINICAL HISTORY SO 2281 01:34:13,320 --> 01:34:16,840 UNDERSTANDING THE MECHANISM MAY 2282 01:34:16,840 --> 01:34:21,560 HELP US BETTER DEVELOP OBJECTIVE 2283 01:34:21,560 --> 01:34:22,080 DIAGNOSTIC MARKERS. 2284 01:34:22,080 --> 01:34:24,320 LASTLY UNDERSTANDING THE 2285 01:34:24,320 --> 01:34:25,240 MECHANISM OF THESE DISEASES 2286 01:34:25,240 --> 01:34:28,520 INCLUDING DISEASES ON THE 2287 01:34:28,520 --> 01:34:30,760 SPECTRUM BETWEEN EXISTING 2288 01:34:30,760 --> 01:34:32,840 CLASSIFICATIONS LIKE HOLLI'S MAY 2289 01:34:32,840 --> 01:34:40,840 OPEN UP NEW OPTIONS FOR 2290 01:34:40,840 --> 01:34:45,160 TREATMENTS, LIKE' PREMO LAST, 2291 01:34:45,160 --> 01:34:46,800 JAK/STAT INHIBITORS, IL6 2292 01:34:46,800 --> 01:34:50,000 INHIBITION HAS BEEN HELPFUL, 2293 01:34:50,000 --> 01:34:50,320 APREMILAST. 2294 01:34:50,320 --> 01:34:52,440 AS WE BETTER UNDERSTAND WE CAN 2295 01:34:52,440 --> 01:34:55,000 HONE IN ON THE RIGHT THERAPIES 2296 01:34:55,000 --> 01:34:56,840 FOR THESE PATIENTS. 2297 01:34:56,840 --> 01:35:00,080 SO WITH THAT I AM GRATEFUL TO 2298 01:35:00,080 --> 01:35:03,920 ALL OF THE CLINICIANS AND 2299 01:35:03,920 --> 01:35:05,760 RESEARCHERS WHO HELP US IN 2300 01:35:05,760 --> 01:35:07,040 RECRUITING PATIENTS FOR OUR 2301 01:35:07,040 --> 01:35:10,160 GENETIC STUDIES AND ARE PART OF 2302 01:35:10,160 --> 01:35:12,040 THE FPAPA GENETICS CONSORTIUM 2303 01:35:12,040 --> 01:35:17,760 AND VERY GRATEFUL TO MY MENTORS, 2304 01:35:17,760 --> 01:35:19,120 DR. KASTNER, DR. REMMERS, WHO 2305 01:35:19,120 --> 01:35:20,120 ARE INSTRUMENTAL IN THIS PROJECT 2306 01:35:20,120 --> 01:35:23,080 AS WELL AS ALL THE OTHER MEMBERS 2307 01:35:23,080 --> 01:35:24,800 OF OUR TEAM. 2308 01:35:24,800 --> 01:35:27,000 I DON'T HAVE TIME TO GO THROUGH 2309 01:35:27,000 --> 01:35:31,160 EVERYONE'S NAME. 2310 01:35:31,160 --> 01:35:33,760 ALSO COLLABORATORS AND PATIENTS 2311 01:35:33,760 --> 01:35:36,760 WHO DONATED TIME, OBSERVATIONS, 2312 01:35:36,760 --> 01:35:40,320 SAMPLES, AND I'D LIKE TO THANK 2313 01:35:40,320 --> 01:35:43,080 HOLLI FOR BEING HERE AND SHARING 2314 01:35:43,080 --> 01:35:43,920 INSIGHTFUL OBSERVATIONS. 2315 01:35:43,920 --> 01:35:50,800 AT THIS POINT WE'RE HAPPY TO 2316 01:35:50,800 --> 01:35:53,720 TAKE QUESTIONS. 2317 01:35:53,720 --> 01:36:04,200 2318 01:36:04,200 --> 01:36:04,560 >> OKAY. 2319 01:36:04,560 --> 01:36:06,880 FIRST OF ALL, I WANT TO ON 2320 01:36:06,880 --> 01:36:12,760 BEHALF OF ALL OF US WHO HAVE 2321 01:36:12,760 --> 01:36:15,000 BEEN LISTENING TO THANK THE 2322 01:36:15,000 --> 01:36:20,080 THREE SPEAKERS, PARTICULARLY THE 2323 01:36:20,080 --> 01:36:23,920 TWO PATIENTS WHO SO ELOQUENTLY 2324 01:36:23,920 --> 01:36:27,200 DESCRIBED THE DIFFICULTIES OF 2325 01:36:27,200 --> 01:36:30,120 THEIR DISEASE. 2326 01:36:30,120 --> 01:36:33,400 SEVERAL YEARS AGO, THERE WAS A 2327 01:36:33,400 --> 01:36:35,800 POSTDOCTORAL FELLOW, Ph.D. 2328 01:36:35,800 --> 01:36:38,440 FELLOW, WHO WROTE TO ME AND 2329 01:36:38,440 --> 01:36:43,520 PRAISED THE IDEA OF HAVING THE 2330 01:36:43,520 --> 01:36:45,080 ABILITY TO SEE PATIENTS, 2331 01:36:45,080 --> 01:36:46,600 NORMALLY Ph.D. SCIENTISTS 2332 01:36:46,600 --> 01:36:48,000 DON'T DO. 2333 01:36:48,000 --> 01:36:50,120 AND HE SAID THAT THE VIRTUE WAS 2334 01:36:50,120 --> 01:36:54,360 THAT IT PUTS A HUMAN FACE ON A 2335 01:36:54,360 --> 01:36:54,720 DISEASE. 2336 01:36:54,720 --> 01:36:56,080 AND I'VE ALWAYS REMEMBERED THAT. 2337 01:36:56,080 --> 01:36:59,880 AND I THINK IT'S A VERY POWERFUL 2338 01:36:59,880 --> 01:37:03,880 ASPECT OF THIS COURSE AND OF THE 2339 01:37:03,880 --> 01:37:04,280 BASIC PRINCIPLES. 2340 01:37:04,280 --> 01:37:08,280 NOW, WE'VE HAD A SERIES OF 2341 01:37:08,280 --> 01:37:13,320 QUESTIONS, AND SO I WILL POSE 2342 01:37:13,320 --> 01:37:18,320 THEM AND THEN PERHAPS WHOEVER -- 2343 01:37:18,320 --> 01:37:20,040 WHICHEVER OF YOU FEEL IS 2344 01:37:20,040 --> 01:37:21,240 APPROPRIATE TO ANSWER. 2345 01:37:21,240 --> 01:37:22,840 ONE QUESTION TO ASK, WHETHER 2346 01:37:22,840 --> 01:37:29,400 THERE WAS A ROLE FOR PROTEASOME 2347 01:37:29,400 --> 01:37:31,920 INHIBITORS, PARTICULARLY 2348 01:37:31,920 --> 01:37:34,040 TARGETING NF-kappaB. 2349 01:37:34,040 --> 01:37:39,520 AND IN THE TREATMENT OF 2350 01:37:39,520 --> 01:37:40,080 AUTO-INFLAMMATORY DISEASES, 2351 01:37:40,080 --> 01:37:42,280 PERHAPS IN GENERAL BUT 2352 01:37:42,280 --> 01:37:43,800 SPECIFICALLY EARLIER ONES THAT 2353 01:37:43,800 --> 01:37:44,480 WERE DISCUSSED. 2354 01:37:44,480 --> 01:37:47,200 WOULD ONE OF YOU LIKE TO 2355 01:37:47,200 --> 01:37:47,840 RESPOND? 2356 01:37:47,840 --> 01:37:49,640 >> MAYBE DR. SCHWARTZ, SHE'S 2357 01:37:49,640 --> 01:37:50,320 BEEN TALKING ABOUT NF-kappaB 2358 01:37:50,320 --> 01:37:52,960 WOULD WANT TO START OFF ANYWAY. 2359 01:37:52,960 --> 01:37:55,920 >> YEAH, I CAN TALK ABOUT IN THE 2360 01:37:55,920 --> 01:38:00,080 SETTING OF HOW 20 AND MAYBE SOME 2361 01:38:00,080 --> 01:38:00,960 OF THE PROTEASOME-RELATED 2362 01:38:00,960 --> 01:38:05,600 DISEASES, AND IN THE SETTING OF 2363 01:38:05,600 --> 01:38:06,320 HA20 AND DISEASES WITH 2364 01:38:06,320 --> 01:38:08,320 INTERFERON SIGNATURE ONE OF THE 2365 01:38:08,320 --> 01:38:12,760 THINGS WE SEE, IT'S A DEFECT IN 2366 01:38:12,760 --> 01:38:13,320 PROTEASOME FUNCTION. 2367 01:38:13,320 --> 01:38:17,520 AND BECAUSE OF THAT YOU CAN GET 2368 01:38:17,520 --> 01:38:18,120 ACTIVATION OF THE UNFOLDED 2369 01:38:18,120 --> 01:38:20,640 PROTEIN RESPONSE LEADS TO 2370 01:38:20,640 --> 01:38:23,720 ENHANCED INFLAMMATION, INCREASED 2371 01:38:23,720 --> 01:38:25,200 INTERFERON SIGNALING, AND IT'S 2372 01:38:25,200 --> 01:38:26,000 DEFECTIVE PROTEASOME FUNCTION 2373 01:38:26,000 --> 01:38:28,720 AND BUILDUP OF THESE DEGRADATION 2374 01:38:28,720 --> 01:38:31,040 PRODUCTS THAT CAUSES THAT 2375 01:38:31,040 --> 01:38:33,960 INFLAMMATORY PATHWAY. 2376 01:38:33,960 --> 01:38:37,360 IN THAT SCENARIO WHERE YOU HAVE 2377 01:38:37,360 --> 01:38:37,920 INCREASED TYPE I INTERFERON 2378 01:38:37,920 --> 01:38:40,120 SIGNALING, I THINK ONE WOULD 2379 01:38:40,120 --> 01:38:43,800 HAVE TO BE CAUTIOUS IN USING 2380 01:38:43,800 --> 01:38:45,000 PROTEASOME INHIBITORS AS OPPOSED 2381 01:38:45,000 --> 01:38:47,480 TO OTHER TARGETED THERAPIES THAT 2382 01:38:47,480 --> 01:38:48,280 I HAD MENTIONED. 2383 01:38:48,280 --> 01:38:51,320 I'M GOING TO PASS TO DR. KASTNER 2384 01:38:51,320 --> 01:38:54,920 TO MENTION WHETHER IN SOME OF 2385 01:38:54,920 --> 01:38:57,000 THE OTHER NEWER SYNDROMES THAT 2386 01:38:57,000 --> 01:38:58,240 THAT'S BEEN DISCUSSED BECAUSE 2387 01:38:58,240 --> 01:39:01,720 THERE'S THAT OVERLAP WITH THE 2388 01:39:01,720 --> 01:39:02,360 MYELODYSPLASTIC SYNDROMES. 2389 01:39:02,360 --> 01:39:04,600 >> YES, THANK YOU VERY MUCH, 2390 01:39:04,600 --> 01:39:05,960 DANI. 2391 01:39:05,960 --> 01:39:10,840 AND I TOTALLY AGREE THAT THERE 2392 01:39:10,840 --> 01:39:11,560 ARE THE PROTEASOME-RELATED 2393 01:39:11,560 --> 01:39:16,640 AUTO-INFLAMMATORY DISEASES WHERE 2394 01:39:16,640 --> 01:39:17,720 IN FACT PROTEASOME DYSFUNCTION 2395 01:39:17,720 --> 01:39:22,760 CAN LEAD TO INFLAMMATION. 2396 01:39:22,760 --> 01:39:27,400 IN VEXUS, A DISEASE CAUSED BY 2397 01:39:27,400 --> 01:39:29,000 SOMATIC MUTATIONS, ACQUIRED 2398 01:39:29,000 --> 01:39:32,040 MUTATIONS IN A PATHWAY THAT 2399 01:39:32,040 --> 01:39:42,280 LEADS TO UBIQUITYLATION, THAT 2400 01:39:42,280 --> 01:39:44,400 CAN LEAD TO PROTEINS THAT OUGHT 2401 01:39:44,400 --> 01:39:47,000 TO BE GOTTEN RID OF, THERE'S 2402 01:39:47,000 --> 01:39:49,080 BEEN DISCUSSION OF PROTEASOME 2403 01:39:49,080 --> 01:39:53,240 INHIBITORS BUT SO FAR TO MY 2404 01:39:53,240 --> 01:39:56,000 KNOWLEDGE THERE HAVE BEEN NO 2405 01:39:56,000 --> 01:40:01,120 TRIALS, THERE'S THE CAUTION THAT 2406 01:40:01,120 --> 01:40:05,320 WE'RE NOT SURE THE IT'S GOING 2407 01:40:05,320 --> 01:40:06,440 TO BE BENEFICIAL OR HARMFUL BUT 2408 01:40:06,440 --> 01:40:08,920 MAY GET RID OF THE CELLS THAT 2409 01:40:08,920 --> 01:40:09,720 ARE THE MUTATION, THAT'S A 2410 01:40:09,720 --> 01:40:10,880 THOUGHT MAYBE THAT WOULD WORK. 2411 01:40:10,880 --> 01:40:12,960 I DON'T THINK THERE HAVE BEEN 2412 01:40:12,960 --> 01:40:17,200 ANY STUDIES OF PROTEASOME 2413 01:40:17,200 --> 01:40:18,600 INHIBITORS THAT HAVE BEEN 2414 01:40:18,600 --> 01:40:19,520 CONDUCTED. 2415 01:40:19,520 --> 01:40:23,560 >> A VERY IMPORTANT QUESTION, 2416 01:40:23,560 --> 01:40:25,080 ARE YOU STILL ENROLLING PATIENTS 2417 01:40:25,080 --> 01:40:26,520 IN THESE STUDIES? 2418 01:40:26,520 --> 01:40:29,600 IF YES, COULD YOU PLEASE POINT 2419 01:40:29,600 --> 01:40:32,080 OUT SOME KEY ELIGIBILITY 2420 01:40:32,080 --> 01:40:32,320 FACTORS. 2421 01:40:32,320 --> 01:40:33,760 IN OTHER WORDS, WHAT DO YOU LOOK 2422 01:40:33,760 --> 01:40:37,240 FOR, FOR A PERSON TO BE 2423 01:40:37,240 --> 01:40:38,800 RECRUITED INTO THESE STUDIES 2424 01:40:38,800 --> 01:40:40,200 BECAUSE MANY PEOPLE HAVE FEVERS, 2425 01:40:40,200 --> 01:40:41,800 MANY PEOPLE HAVE SOME ULCERS. 2426 01:40:41,800 --> 01:40:49,240 WHERE DO YOU DRAW THE LINE? 2427 01:40:49,240 --> 01:40:51,760 IF NOT THE PERSON WANTS TO KNOW 2428 01:40:51,760 --> 01:40:52,920 WHETHER YOU PROVIDE CONSULTATION 2429 01:40:52,920 --> 01:40:56,600 AND WHAT'S THE BEST WAY OF 2430 01:40:56,600 --> 01:40:58,000 CONTACTING YOU FOLKS? 2431 01:40:58,000 --> 01:40:59,960 >> WELL, I'LL START OUT MAYBE 2432 01:40:59,960 --> 01:41:02,760 BUT I THINK MY COLLEAGUES HAVE 2433 01:41:02,760 --> 01:41:05,720 ALSO THINGS THAT THEY WOULD WANT 2434 01:41:05,720 --> 01:41:06,160 TO SAY. 2435 01:41:06,160 --> 01:41:10,320 SO FIRST OF ALL WE DO ACCEPT 2436 01:41:10,320 --> 01:41:13,480 PATIENTS INTO OUR PROTOCOL, OUR 2437 01:41:13,480 --> 01:41:14,840 NATURAL HISTORY PROTOCOL, ON 2438 01:41:14,840 --> 01:41:16,080 AUTO-INFLAMMATORY DISEASES. 2439 01:41:16,080 --> 01:41:19,160 AND WE DO ALSO PROVIDE 2440 01:41:19,160 --> 01:41:20,720 CONSULTATION TO PHYSICIANS WHO 2441 01:41:20,720 --> 01:41:24,800 HAVE QUESTIONS FOR US. 2442 01:41:24,800 --> 01:41:27,320 SO, WITH REGARD TO THE RESEARCH 2443 01:41:27,320 --> 01:41:30,720 PROTOCOL, NATURAL HISTORY 2444 01:41:30,720 --> 01:41:32,040 PROTOCOL, CLEARLY THERE ARE LOTS 2445 01:41:32,040 --> 01:41:34,520 AND LOTS OF PEOPLE WHO HAVE 2446 01:41:34,520 --> 01:41:36,280 UNDIAGNOSED FEVERS. 2447 01:41:36,280 --> 01:41:39,440 THAT'S FOR SURE. 2448 01:41:39,440 --> 01:41:41,920 AND UNFORTUNATELY, MORE OF THEM 2449 01:41:41,920 --> 01:41:45,680 THAN WHAT WE COULD REASONABLY 2450 01:41:45,680 --> 01:41:46,720 ACCOMMODATE. 2451 01:41:46,720 --> 01:41:48,280 SO WE ARE INTERESTED IN 2452 01:41:48,280 --> 01:41:50,320 INDIVIDUALS THAT MAY HAVE 2453 01:41:50,320 --> 01:41:51,360 UNUSUAL MANIFESTATIONS OF THEIR 2454 01:41:51,360 --> 01:41:54,280 CONDITION OR MAY HAVE TOTALLY 2455 01:41:54,280 --> 01:41:55,520 UNDIAGNOSED CONDITIONS WHERE 2456 01:41:55,520 --> 01:41:58,080 THERE'S THE POSSIBILITY THAT WE 2457 01:41:58,080 --> 01:41:59,800 MIGHT DISCOVER A NEW DISEASE IN 2458 01:41:59,800 --> 01:42:02,080 THE COURSE OF EVALUATING THOSE 2459 01:42:02,080 --> 01:42:03,440 INDIVIDUALS. 2460 01:42:03,440 --> 01:42:07,040 AND SO WE DO FOCUS ON PERHAPS 2461 01:42:07,040 --> 01:42:12,000 THOSE VERY DIFFICULT CASES OR 2462 01:42:12,000 --> 01:42:13,600 UNDIAGNOSED CASES, WE WILL 2463 01:42:13,600 --> 01:42:14,200 SOMETIMES DEPENDING ON 2464 01:42:14,200 --> 01:42:17,520 CIRCUMSTANCES AT LEAST FOR MAYBE 2465 01:42:17,520 --> 01:42:19,840 A SINGLE VISIT EVALUATE SOMEONE 2466 01:42:19,840 --> 01:42:21,920 WHO HAS A KNOWN DISEASE WITH 2467 01:42:21,920 --> 01:42:26,320 JUST MAYBE SOME PROBLEM WE COULD 2468 01:42:26,320 --> 01:42:27,800 HELP WITH. 2469 01:42:27,800 --> 01:42:29,640 WITH REGARD TO CONSULTATION FOR 2470 01:42:29,640 --> 01:42:35,480 SURE, IT'S BEST IF WE RECEIVE 2471 01:42:35,480 --> 01:42:36,480 THAT FROM THE PATIENT'S 2472 01:42:36,480 --> 01:42:38,320 PHYSICIAN SO WE CAN GET MEDICAL 2473 01:42:38,320 --> 01:42:39,920 RECORDS ASSOCIATED WITH THAT. 2474 01:42:39,920 --> 01:42:51,480 CERTAINLY I'M MORE THAN HAPPY TO 2475 01:42:51,480 --> 01:42:53,080 RESPOND TO E-MAILS. 2476 01:42:53,080 --> 01:42:59,360 DAN.KASTNER AT NIH.GOV. 2477 01:42:59,360 --> 01:43:05,480 I'M HAPPY TO TRY TO ANSWER THEM. 2478 01:43:05,480 --> 01:43:09,200 AND KALPANA AND DANI, DO YOU 2479 01:43:09,200 --> 01:43:10,400 WANT TO SAY ANYTHING? 2480 01:43:10,400 --> 01:43:16,320 >> I'M ALWAYS HAPPY TO ANSWER 2481 01:43:16,320 --> 01:43:19,040 E-MAILS. 2482 01:43:19,040 --> 01:43:19,880 DANIELA.SCHWARTZ@NIH.GOV. 2483 01:43:19,880 --> 01:43:20,760 I'M NOT RECRUITING PATIENTS 2484 01:43:20,760 --> 01:43:22,680 BECAUSE I'M NOT SURE IF DR. 2485 01:43:22,680 --> 01:43:23,920 ARIAS MENTIONED I WILL BE 2486 01:43:23,920 --> 01:43:25,440 STARTING A TENURE TRACK POSITION 2487 01:43:25,440 --> 01:43:28,360 AT THE UNIVERSITY OF PITTSBURGH 2488 01:43:28,360 --> 01:43:30,920 OVER THE SUMMER AND HOPEFULLY 2489 01:43:30,920 --> 01:43:32,760 RECRUITING PATIENTS THERE BUT NO 2490 01:43:32,760 --> 01:43:35,080 LONGER TO THE NIH CLINICAL 2491 01:43:35,080 --> 01:43:35,720 CENTER ANYMORE. 2492 01:43:35,720 --> 01:43:37,520 HOWEVER, I'M ALWAYS HAPPY TO 2493 01:43:37,520 --> 01:43:40,120 CONSULT OR SPEAK WITH ANY 2494 01:43:40,120 --> 01:43:40,800 INTERESTED PHYSICIANS OR 2495 01:43:40,800 --> 01:43:44,040 PATIENTS WHO HAVE QUESTIONS 2496 01:43:44,040 --> 01:43:45,440 ALTHOUGH AGAIN FORMAL 2497 01:43:45,440 --> 01:43:47,280 CONSULTATIONS SHOULD IDEALLY 2498 01:43:47,280 --> 01:43:51,720 COME FROM PHYSICIANS IF 2499 01:43:51,720 --> 01:43:52,000 POSSIBLE. 2500 01:43:52,000 --> 01:43:52,880 >> I'M CURRENTLY RECRUITING 2501 01:43:52,880 --> 01:43:54,720 PATIENTS WITH FPAPA SYNDROME FOR 2502 01:43:54,720 --> 01:43:58,920 THE GWAS SO I NEED TO GET A 2503 01:43:58,920 --> 01:44:00,720 THOUSAND PATIENTS, QUITE A FEW. 2504 01:44:00,720 --> 01:44:04,400 AND IN ADDITION I'M ALSO SEEING 2505 01:44:04,400 --> 01:44:08,440 PATIENTS WITH SYMPTOMS ON THE 2506 01:44:08,440 --> 01:44:10,120 BEHCET'S SPECTRUM LIKE HOLLI, 2507 01:44:10,120 --> 01:44:11,720 SHE AND HER FAMILY, SHE 2508 01:44:11,720 --> 01:44:13,840 MENTIONED HER SON HAVING OTHER 2509 01:44:13,840 --> 01:44:15,000 INFLAMMATORY FEATURES. 2510 01:44:15,000 --> 01:44:16,480 I THINK FAMILIES LIKE HER HAVE 2511 01:44:16,480 --> 01:44:20,480 REALLY HELPED OPEN OUR EYES TO 2512 01:44:20,480 --> 01:44:23,800 THE CONNECTIONS BETWEEN THESE 2513 01:44:23,800 --> 01:44:25,760 DISORDERS AND MADE US THINK 2514 01:44:25,760 --> 01:44:27,160 OUTSIDE THE BOX AND NOT JUST TO 2515 01:44:27,160 --> 01:44:29,320 SAY THIS IS WHAT YOU HAVE BUT TO 2516 01:44:29,320 --> 01:44:32,040 TRY TO HAVE AN OPEN MIND AND 2517 01:44:32,040 --> 01:44:33,920 THINKING ABOUT THEM. 2518 01:44:33,920 --> 01:44:36,920 SO I THINK IT'S REALLY CRITICAL 2519 01:44:36,920 --> 01:44:38,720 THAT WE HEAR THEIR STORIES AND 2520 01:44:38,720 --> 01:44:57,720 THINK ABOUT WHAT THE PATHOGENESIS. 2521 01:44:57,720 --> 01:44:59,080 I'M KALPANA.MANTHIRAM@NIH.GOV 2522 01:44:59,080 --> 01:45:00,520 AND I'M HAPPY TO LOOK AT 2523 01:45:00,520 --> 01:45:02,240 CLINICAL FEATURES TO SEE IF THEY 2524 01:45:02,240 --> 01:45:05,400 MAY BE ELIGIBLE FOR MY STUDIES. 2525 01:45:05,400 --> 01:45:07,600 >> THERE'S ALSO A 2526 01:45:07,600 --> 01:45:08,440 clinicaltrials.gov WHICH COVERS 2527 01:45:08,440 --> 01:45:11,320 MANY CLINICAL TRIALS WHICH MAY 2528 01:45:11,320 --> 01:45:13,080 BE ANOTHER ENTRY. 2529 01:45:13,080 --> 01:45:18,720 ONE QUESTION THAT COMES UP, MANY 2530 01:45:18,720 --> 01:45:22,440 OF THESE DISORDERS HAVE THE 2531 01:45:22,440 --> 01:45:27,000 DESCRIPTION OF PERIODIC. 2532 01:45:27,000 --> 01:45:28,840 WHAT MAKES THEM PERIODIC? 2533 01:45:28,840 --> 01:45:33,000 >> WELL, THAT'S DR. MANTHIRAM'S 2534 01:45:33,000 --> 01:45:35,120 QUESTION FOR STARTERS. 2535 01:45:35,120 --> 01:45:36,800 >> I'M STUDYING THE MOST 2536 01:45:36,800 --> 01:45:39,520 PERIODIC OF THE PERIODIC FEVERS. 2537 01:45:39,520 --> 01:45:40,920 SO I THINK SHORT ANSWER, WE 2538 01:45:40,920 --> 01:45:42,960 DON'T KNOW QUITE YET BUT WE'RE 2539 01:45:42,960 --> 01:45:45,480 BEGINNING TO LOOK AT THE IMMUNE 2540 01:45:45,480 --> 01:45:46,040 STATE DURING FLARES AND 2541 01:45:46,040 --> 01:45:47,160 NON-FLARE PERIODS. 2542 01:45:47,160 --> 01:45:52,920 WE SEE THE SORT OF OSCILLATION 2543 01:45:52,920 --> 01:45:54,720 DURING FLARE HIGH IMMUNE 2544 01:45:54,720 --> 01:45:57,720 ACTIVATION, DURING FLARING 2545 01:45:57,720 --> 01:45:59,080 IMMUNE SUPPRESSION MONOCYTES 2546 01:45:59,080 --> 01:46:00,680 FAIL TO ACTIVATE NORMALLY. 2547 01:46:00,680 --> 01:46:03,800 SO I THINK THAT MAY PLAY A ROLE. 2548 01:46:03,800 --> 01:46:09,160 IT MAY BE THE NATURAL WAY THE 2549 01:46:09,160 --> 01:46:09,880 IMMUNE SYSTEM STOPS 2550 01:46:09,880 --> 01:46:11,520 OVERACTIVATED STATE BUT THERE 2551 01:46:11,520 --> 01:46:13,840 MAY BE FEEDBACK MECHANISMS THAT 2552 01:46:13,840 --> 01:46:18,960 LEAD TO CYCLING THAT LEAD TO 2553 01:46:18,960 --> 01:46:21,320 EXTREME PERIOD, SEEN IN FPAPA 2554 01:46:21,320 --> 01:46:23,000 BUT THERE DOES APPEAR TO BE 2555 01:46:23,000 --> 01:46:24,560 OSCILLATING ACTIVATION AND SORT 2556 01:46:24,560 --> 01:46:26,800 OF SUPPRESSED STATES DURING THE 2557 01:46:26,800 --> 01:46:28,880 FLARE AND NON-FLARE PERIODS THAT 2558 01:46:28,880 --> 01:46:31,240 WE'RE LOOKING MORE CLOSELY TO 2559 01:46:31,240 --> 01:46:32,240 DEFINE AND UNDERSTAND. 2560 01:46:32,240 --> 01:46:40,280 >> SO I GUESS AS PART OF THAT IS 2561 01:46:40,280 --> 01:46:41,720 YOU MEASURE INFLAMMATORY 2562 01:46:41,720 --> 01:46:43,520 CYTOKINES FOR EXAMPLE AT ONE 2563 01:46:43,520 --> 01:46:47,520 TIME, AT MANY TIMES IN AN 2564 01:46:47,520 --> 01:46:47,800 INDIVIDUAL? 2565 01:46:47,800 --> 01:46:52,320 IS THERE A CIRCADIAN RHYTHM? 2566 01:46:52,320 --> 01:46:56,160 IS IT RELATED TO OTHER ENDOCRINE 2567 01:46:56,160 --> 01:46:57,520 CHANGES? 2568 01:46:57,520 --> 01:46:58,240 MENSTRUATION? 2569 01:46:58,240 --> 01:47:01,000 IS IT RELATED TO -- WHAT ABOUT 2570 01:47:01,000 --> 01:47:03,960 THE SECOND AND THIRD DIMENSION 2571 01:47:03,960 --> 01:47:07,640 OF THE CHANGES OBSERVED IN BLOOD 2572 01:47:07,640 --> 01:47:10,560 LEVELS OR EVEN GENE EXPRESSION, 2573 01:47:10,560 --> 01:47:12,720 OTHER THAN AT SINGLE TIMES IN 2574 01:47:12,720 --> 01:47:14,040 GIVEN GROUPS OF INDIVIDUALS. 2575 01:47:14,040 --> 01:47:15,720 >> GREAT QUESTION. 2576 01:47:15,720 --> 01:47:18,320 I THINK WITH THESE PERIODIC 2577 01:47:18,320 --> 01:47:19,160 SYNDROMES IT'S REALLY IMPORTANT 2578 01:47:19,160 --> 01:47:20,320 TO LOOK LONGITUDINALLY AS 2579 01:47:20,320 --> 01:47:21,800 PATIENTS, NOT AT ONE TIME 2580 01:47:21,800 --> 01:47:22,200 PERIOD. 2581 01:47:22,200 --> 01:47:23,520 SO WE'VE BEEN LOOKING FLARE AND 2582 01:47:23,520 --> 01:47:26,040 NON-FLARE BUT I THINK YOU'RE 2583 01:47:26,040 --> 01:47:28,920 RIGHT, THAT EVEN LOOKING MORE 2584 01:47:28,920 --> 01:47:30,920 CLOSELY AT MORE FREQUENTLY I 2585 01:47:30,920 --> 01:47:33,800 THINK AT WHAT HAPPENS AS THE 2586 01:47:33,800 --> 01:47:37,560 FLARE BEGINS, MAY BE CRITICAL. 2587 01:47:37,560 --> 01:47:38,720 MAYBE THE HORSE IS OUT OF THE 2588 01:47:38,720 --> 01:47:43,280 BARN WHEN YOU GET THE SIGNAL, 2589 01:47:43,280 --> 01:47:44,320 BUT UNDERSTANDING AS EPISODE 2590 01:47:44,320 --> 01:47:45,400 STARTS MAY BE SOMETHING, 2591 01:47:45,400 --> 01:47:46,920 SOMETHING WE'RE LOOKING INTO 2592 01:47:46,920 --> 01:47:48,520 DOING IN THE FUTURE. 2593 01:47:48,520 --> 01:47:50,520 AS FAR AS TRIGGERS I HAVE SOME 2594 01:47:50,520 --> 01:47:52,320 PATIENTS WHO FIND THAT THEIR 2595 01:47:52,320 --> 01:47:55,040 EPISODES ARE WORSE, THESE ARE 2596 01:47:55,040 --> 01:47:55,720 PATIENTS WHO CONTINUE TO HAVE 2597 01:47:55,720 --> 01:47:58,120 FLARES WHEN THEY ARE OLDER. 2598 01:47:58,120 --> 01:48:01,640 THAT THEIR EPISODES ARE WORSE 2599 01:48:01,640 --> 01:48:04,360 WITH STRESS, FEMALES WITH 2600 01:48:04,360 --> 01:48:05,480 MENSTRUAL CYCLES, WONDERING 2601 01:48:05,480 --> 01:48:10,080 MAYBE HOLLI COULD CHIME IN ABOUT 2602 01:48:10,080 --> 01:48:11,840 TRIGGERS FOR HER FLARES AND WHAT 2603 01:48:11,840 --> 01:48:17,120 THINGS MADE IT WORSE FOR HER. 2604 01:48:17,120 --> 01:48:19,880 >> I THINK MY -- STRESS 2605 01:48:19,880 --> 01:48:20,920 DEFINITELY IS A TRIGGER. 2606 01:48:20,920 --> 01:48:23,920 I WORK NIGHT SHIFT IN THE E.R. 2607 01:48:23,920 --> 01:48:25,640 FOR SIX YEARS CONTINUOUS WHEN MY 2608 01:48:25,640 --> 01:48:30,760 KIDS WERE SMALLER, THAT'S WHEN I 2609 01:48:30,760 --> 01:48:33,720 REALLY STARTED GETTING WORSE, 2610 01:48:33,720 --> 01:48:39,160 LACK OF SLEEP, INTERRUPTED 2611 01:48:39,160 --> 01:48:39,520 SLEEP. 2612 01:48:39,520 --> 01:48:41,200 I'M NOW ON AN EIGHT TO FIVE 2613 01:48:41,200 --> 01:48:45,120 SCHEDULE, THAT'S HELPED. 2614 01:48:45,120 --> 01:48:47,280 OUR SON IS IN ALABAMA GOING TO 2615 01:48:47,280 --> 01:48:48,360 COLLEGE, IT'S WARMER. 2616 01:48:48,360 --> 01:48:49,920 WE'RE IN THE NORTHEAST. 2617 01:48:49,920 --> 01:48:52,080 HE'S GETTING LESS FLARES. 2618 01:48:52,080 --> 01:48:53,640 MAYBE THE COLD SOMETIMES 2619 01:48:53,640 --> 01:48:55,200 AGGRAVATED HIS, HE WAS ALWAYS 2620 01:48:55,200 --> 01:49:01,440 WORSE IN THE LATE FALL, WINTER 2621 01:49:01,440 --> 01:49:01,760 PERIODS. 2622 01:49:01,760 --> 01:49:04,920 >> YOU BROUGHT UP A TIMELY 2623 01:49:04,920 --> 01:49:06,200 QUESTION WHICH COMES UP IN EVERY 2624 01:49:06,200 --> 01:49:09,320 ONE OF THESE SESSIONS WE HAVE. 2625 01:49:09,320 --> 01:49:13,840 THAT IS, WHAT'S THE EFFECT OF 2626 01:49:13,840 --> 01:49:17,360 THE COVID INFECTION AND PANDEMIC 2627 01:49:17,360 --> 01:49:19,920 ON THE PARTICULAR -- ANY OF 2628 01:49:19,920 --> 01:49:20,520 THESE DISEASES? 2629 01:49:20,520 --> 01:49:22,280 DO WE HAVE A HANDLE? 2630 01:49:22,280 --> 01:49:25,160 IS THERE SOME -- IS THE VIRUS IT 2631 01:49:25,160 --> 01:49:28,560 SEVER PARTICIPATING IN SOME OF 2632 01:49:28,560 --> 01:49:29,720 THESE INFLAMMATORY PROCESSES? 2633 01:49:29,720 --> 01:49:35,240 WHAT DO WE THOUGH ABOUT THE 2634 01:49:35,240 --> 01:49:37,680 RELATIONSHIP BETWEEN COVID AND 2635 01:49:37,680 --> 01:49:40,720 THE AUTO-INFLAMMATORY DISEASES, 2636 01:49:40,720 --> 01:49:41,360 BOTH AS CLINICAL MANIFESTATIONS, 2637 01:49:41,360 --> 01:49:44,760 ALSO IN TERMS OF THE UNDERLYING 2638 01:49:44,760 --> 01:49:45,160 SCIENCE? 2639 01:49:45,160 --> 01:49:47,080 >> ACTUALLY I WANT TO POINT OUT 2640 01:49:47,080 --> 01:49:54,040 ONE OF OUR COLLEAGUES, DR. 2641 01:49:54,040 --> 01:49:58,160 RAFAELA GOLDBACK, PUBLISHED 2642 01:49:58,160 --> 01:49:58,960 THIS WEEK ADDRESSING THAT 2643 01:49:58,960 --> 01:49:59,240 QUESTION. 2644 01:49:59,240 --> 01:50:01,640 I READ IT THIS MORNING IN 2645 01:50:01,640 --> 01:50:05,720 ANTICIPATION OF THIS EXACT TALK. 2646 01:50:05,720 --> 01:50:09,720 AND SHE FOLLOWED SEVERAL 2647 01:50:09,720 --> 01:50:12,760 PATIENTS WITH MUTATIONS IN NLRP 2648 01:50:12,760 --> 01:50:14,880 3 AND PROTEASOME GENES, THOSE 2649 01:50:14,880 --> 01:50:17,240 PATIENTS SOME OF THEM DID 2650 01:50:17,240 --> 01:50:18,960 DEVELOP COVID-19 INFECTION, ONE 2651 01:50:18,960 --> 01:50:20,520 OF THEM WAS SEVERELY AFFECTED, 2652 01:50:20,520 --> 01:50:24,600 THAT PATIENT HAD UNDERLYING LUNG 2653 01:50:24,600 --> 01:50:24,840 DISEASE. 2654 01:50:24,840 --> 01:50:26,560 AND RESPONDED WELL TO 2655 01:50:26,560 --> 01:50:28,120 IMMUNOMODULATORS USED FOR SEVERE 2656 01:50:28,120 --> 01:50:30,720 COVID, THAT PATIENT RECEIVED IL6 2657 01:50:30,720 --> 01:50:32,920 INHIBITOR, THE OTHER PATIENTS 2658 01:50:32,920 --> 01:50:35,000 HAD MILD DISEASE AND MANY OF 2659 01:50:35,000 --> 01:50:36,600 THEM HAD COVID VACCINATIONS THAT 2660 01:50:36,600 --> 01:50:39,080 WERE TOLERATED REALLY WELL, A 2661 01:50:39,080 --> 01:50:42,360 COUPLE HAD TO TAKE A FEW EXTRA 2662 01:50:42,360 --> 01:50:43,280 DOSES OF ANAKINRA. 2663 01:50:43,280 --> 01:50:46,320 BASED ON THE BEST DATA WE HAVE 2664 01:50:46,320 --> 01:50:50,000 WHICH ARE THOSE DATA, AND 2665 01:50:50,000 --> 01:50:53,160 OBSERVATIONAL SORT OF I GUESS 2666 01:50:53,160 --> 01:50:54,520 FOLLOW-UPS OF PATIENTS IN THE 2667 01:50:54,520 --> 01:50:57,360 COHORT THAT VACCINATION IS WELL 2668 01:50:57,360 --> 01:50:59,200 TOLERATED IN OUR PATIENTS, SOME 2669 01:50:59,200 --> 01:51:03,120 DO NEED A COUPLE EXTRA DOSES OF 2670 01:51:03,120 --> 01:51:04,400 IMMUNE MODULATORS, AND THAT 2671 01:51:04,400 --> 01:51:07,720 SIMILAR TO MANY PATIENTS WITH 2672 01:51:07,720 --> 01:51:09,760 RHEUMATIC DISEASES THERE IS 2673 01:51:09,760 --> 01:51:11,840 PROBABLY INCREASED RISK OF 2674 01:51:11,840 --> 01:51:13,800 SEVERE COVID INFECTION, THEY ARE 2675 01:51:13,800 --> 01:51:14,600 PATIENTS WITH CHRONIC 2676 01:51:14,600 --> 01:51:16,920 INFLAMMATORY DISEASES, BUT THE 2677 01:51:16,920 --> 01:51:20,320 MAJORITY OF THEM CAN DO WELL 2678 01:51:20,320 --> 01:51:23,800 WITH APPROPRIATE MONITORING AND 2679 01:51:23,800 --> 01:51:25,520 CARE, ALTHOUGH IT'S GOOD TO 2680 01:51:25,520 --> 01:51:26,520 INVOLVE THEIR PROVIDERS SOONER 2681 01:51:26,520 --> 01:51:28,520 RATHER THAN LATER. 2682 01:51:28,520 --> 01:51:36,400 DR. KASTNER OR DR. MAN 2683 01:51:36,400 --> 01:51:37,720 MANTHIRAM, DO YOU HAVE ANYTHING 2684 01:51:37,720 --> 01:51:39,200 TO ADD? 2685 01:51:39,200 --> 01:51:40,840 >> I TOTALLY AGREE WITH WHAT DR. 2686 01:51:40,840 --> 01:51:43,880 SCHWARTZ SAID. 2687 01:51:43,880 --> 01:51:46,520 ON BALANCE, WE DEFINITELY 2688 01:51:46,520 --> 01:51:48,760 RECOMMEND IN FAVOR OF 2689 01:51:48,760 --> 01:51:50,800 VACCINATION, IN FAVOR OF 2690 01:51:50,800 --> 01:51:52,440 IMMUNIZATION AGAINST SARS-COV-2 2691 01:51:52,440 --> 01:51:53,880 IN PATIENTS WITH 2692 01:51:53,880 --> 01:51:56,000 AUTO-INFLAMMATORY DISEASE. 2693 01:51:56,000 --> 01:51:58,120 THE RISK/BENEFIT RATIO IS 2694 01:51:58,120 --> 01:51:59,560 DEFINITELY IN FAVOR OF HAVING 2695 01:51:59,560 --> 01:52:00,360 VACCINATION. 2696 01:52:00,360 --> 01:52:03,520 I CAN TELL YOU THAT OCCASIONALLY 2697 01:52:03,520 --> 01:52:04,960 THERE ARE SOME ANECDOTAL CASES 2698 01:52:04,960 --> 01:52:06,240 WE'VE SEEN. 2699 01:52:06,240 --> 01:52:08,920 I SAW ONE PATIENT A FEW MONTHS 2700 01:52:08,920 --> 01:52:10,480 AGO, A WOMAN WITH FAMILIAL 2701 01:52:10,480 --> 01:52:11,320 MEDITERRANEAN FEVER, WHO HAD 2702 01:52:11,320 --> 01:52:12,600 BEEN IN REMISSION. 2703 01:52:12,600 --> 01:52:14,120 SHE WAS IN HER 60s, IN 2704 01:52:14,120 --> 01:52:17,720 REMISSION FOR A NUMBER OF YEARS. 2705 01:52:17,720 --> 01:52:19,920 AND HAD HER VACCINATION AND THEN 2706 01:52:19,920 --> 01:52:21,640 SHE HAD SOME ATTACKS OF FMF THAT 2707 01:52:21,640 --> 01:52:23,400 WERE SORT OF STIRRED UP BY THE 2708 01:52:23,400 --> 01:52:23,720 VACCINATION. 2709 01:52:23,720 --> 01:52:25,960 BUT STILL WE WERE ABLE TO GET 2710 01:52:25,960 --> 01:52:32,000 THAT UNDER GOOD CONTROL EASILY, 2711 01:52:32,000 --> 01:52:33,840 CERTAIN THE RISK ASSOCIATED WITH 2712 01:52:33,840 --> 01:52:35,160 COVID IS SUBSTANTIAL. 2713 01:52:35,160 --> 01:52:38,880 AND SO WE DO RECOMMEND IN FAVOR 2714 01:52:38,880 --> 01:52:41,120 OF VACCINATION FOR OUR PATIENTS. 2715 01:52:41,120 --> 01:52:43,960 >> ALSO IN MY HA20 PATIENTS THE 2716 01:52:43,960 --> 01:52:46,000 FEW THAT HAD INCREASED SYMPTOMS 2717 01:52:46,000 --> 01:52:47,520 OF THEIR DISEASE WITH 2718 01:52:47,520 --> 01:52:48,280 VACCINATION IT'S BEEN VERY 2719 01:52:48,280 --> 01:52:52,480 MANAGEABLE, VERY EASY TO 2720 01:52:52,480 --> 01:52:54,880 CONTROL. 2721 01:52:54,880 --> 01:52:56,320 AND WE'VE BEEN HAPPY TO SEE THEY 2722 01:52:56,320 --> 01:52:58,040 TOLERATED WELL, VERY MUCH 2723 01:52:58,040 --> 01:53:00,960 RECOMMENDED FOR THAT GROUP. 2724 01:53:00,960 --> 01:53:02,440 >> WITH PATIENTS WITH FPAPA, THE 2725 01:53:02,440 --> 01:53:05,520 CONCERN WAS THAT WITH THE 2726 01:53:05,520 --> 01:53:06,920 HEIGHTENED MYELOID CELL AND T 2727 01:53:06,920 --> 01:53:09,320 CELL FUNCTION WHETHER THESE 2728 01:53:09,320 --> 01:53:10,920 PATIENTS MIGHT HAVE HYPERIMMUNE 2729 01:53:10,920 --> 01:53:12,520 RESPONSE TO THE VIRUS BUT WE 2730 01:53:12,520 --> 01:53:17,240 HAVEN'T SEEN THAT TO BE THE 2731 01:53:17,240 --> 01:53:17,680 CASE. 2732 01:53:17,680 --> 01:53:20,080 WE HAVE MOST PATIENTS RESPOND, 2733 01:53:20,080 --> 01:53:22,320 DON'TS SEEM TO HAVE SEVERE SIDE 2734 01:53:22,320 --> 01:53:25,040 EFFECTS WITH THE VACCINATION. 2735 01:53:25,040 --> 01:53:27,240 I THINK HOLLI IS HERE, HER SON 2736 01:53:27,240 --> 01:53:30,280 DID HAVE A FLARE I BELIEVE AFTER 2737 01:53:30,280 --> 01:53:31,360 HIS SECOND DOSE OF THE VACCINE 2738 01:53:31,360 --> 01:53:35,560 AND WE HAVE SEEN THAT AS DR. 2739 01:53:35,560 --> 01:53:37,040 SCHWARTZ AND DR. KASTNER 2740 01:53:37,040 --> 01:53:42,120 MENTIONED, ABLE TO BE UNDER 2741 01:53:42,120 --> 01:53:42,320 CONTROL. 2742 01:53:42,320 --> 01:53:44,280 >> AN INTERESTING QUESTION, DAN, 2743 01:53:44,280 --> 01:53:51,120 THAT MAYBE YOU WOULD REFER TO. 2744 01:53:51,120 --> 01:53:54,200 GIVEN THE GEOGRAPHIC HISTORY OF 2745 01:53:54,200 --> 01:53:59,360 FMF, DOES IT HAVE ANY BEARING ON 2746 01:53:59,360 --> 01:54:02,920 THE ORIGIN OF THE ASHKENAZI? 2747 01:54:02,920 --> 01:54:08,200 AH, WELL, YOU KNOW, IT'S A VERY 2748 01:54:08,200 --> 01:54:10,160 INTERESTING QUESTION WITH REGARD 2749 01:54:10,160 --> 01:54:13,320 TO THE RELATIONSHIP BETWEEN FMF 2750 01:54:13,320 --> 01:54:14,600 MUTATIONS AND ASHKENAZI 2751 01:54:14,600 --> 01:54:15,720 POPULATION. 2752 01:54:15,720 --> 01:54:20,080 AND CERTAINLY WE DO SEE AS I WAS 2753 01:54:20,080 --> 01:54:24,240 SHOWING ON THAT MAP PARTICULAR 2754 01:54:24,240 --> 01:54:25,720 MUTATION, V7236A MUTATION, 2755 01:54:25,720 --> 01:54:28,240 THAT'S SEEN IN THE ASHKENAZI 2756 01:54:28,240 --> 01:54:30,480 POPULATION, AND IS SEEN ON A 2757 01:54:30,480 --> 01:54:32,640 PARTICULAR HAPLOTYPE. 2758 01:54:32,640 --> 01:54:34,880 YOU KNOW, THAT GIVES US REASON 2759 01:54:34,880 --> 01:54:37,720 TO BELIEVE THAT IN FACT AT LEAST 2760 01:54:37,720 --> 01:54:39,160 THE ORIGIN OF THAT POPULATION 2761 01:54:39,160 --> 01:54:42,560 FOR SURE IS IN THE MIDDLE EAST, 2762 01:54:42,560 --> 01:54:45,000 AND, YOU KNOW, IT'S INCREDIBLE 2763 01:54:45,000 --> 01:54:47,560 WHEN WE WENT TO ISRAEL BACK IN 2764 01:54:47,560 --> 01:54:49,720 1989, WHEN I WAS IN ISRAEL 2765 01:54:49,720 --> 01:54:52,360 DRAWING BLOOD ON THE PATIENTS, I 2766 01:54:52,360 --> 01:54:55,760 WENT TO A COUPLE DRUSE VILLAGES, 2767 01:54:55,760 --> 01:54:57,720 THE POPULATION OF PEOPLE THAT 2768 01:54:57,720 --> 01:54:59,920 LIVE IN ISOLATED MOUNTAIN 2769 01:54:59,920 --> 01:55:02,360 VILLAGES, THEY HAVE THEIR OWN 2770 01:55:02,360 --> 01:55:02,920 RELIGION. 2771 01:55:02,920 --> 01:55:04,520 AND HAVE STAYED ISOLATED FROM 2772 01:55:04,520 --> 01:55:05,440 THE REST OF THE POPULATION OF 2773 01:55:05,440 --> 01:55:08,080 THE MIDDLE EAST FOR THE LAST 2774 01:55:08,080 --> 01:55:08,920 THOUSAND YEARS. 2775 01:55:08,920 --> 01:55:11,200 AND THEY HAVE THE SAME MUTATION 2776 01:55:11,200 --> 01:55:13,720 ON THE SAME HAPLOTYPE AS THE 2777 01:55:13,720 --> 01:55:16,520 ASHKENAZI POPULATION DOES. 2778 01:55:16,520 --> 01:55:17,760 SO, IT'S REALLY FASCINATING, YOU 2779 01:55:17,760 --> 01:55:19,640 KNOW, THINKING ABOUT WHAT THIS 2780 01:55:19,640 --> 01:55:21,640 TELLS US IN TERMS OF THE HISTORY 2781 01:55:21,640 --> 01:55:22,960 OF THESE PEOPLE. 2782 01:55:22,960 --> 01:55:26,080 YOU KNOW, OF COURSE IT CAN'T 2783 01:55:26,080 --> 01:55:30,280 TELL US EXACTLY WHAT'S HAPPENED 2784 01:55:30,280 --> 01:55:32,680 STEPPED BY STEP AS THEY HAVE 2785 01:55:32,680 --> 01:55:34,520 SPREAD ACROSS THE WORLD, BUT IT 2786 01:55:34,520 --> 01:55:37,160 CERTAINLY DOES TELL US SOMETHING 2787 01:55:37,160 --> 01:55:42,600 ABOUT THEIR ORIGINS. 2788 01:55:42,600 --> 01:55:44,840 >> IT'S WHAT IAM SHEBA, FOR WHOM 2789 01:55:44,840 --> 01:55:46,840 THE SHEBA MEDICAL CENTER WAS 2790 01:55:46,840 --> 01:55:49,120 NAMED, REFERS TO THIS AS 2791 01:55:49,120 --> 01:55:49,840 GENETICS OF MIGRANT POPULATIONS, 2792 01:55:49,840 --> 01:55:57,240 A AND STUDIED THEM. 2793 01:55:57,240 --> 01:56:01,080 IS THERE INFORMATION ABOUT THOSE 2794 01:56:01,080 --> 01:56:04,160 INDIVIDUALS, SAY, FROM NORTH 2795 01:56:04,160 --> 01:56:07,520 AFRICA, SOUTH AFRICA, THE -- 2796 01:56:07,520 --> 01:56:08,600 I'VE FORGOTTEN SOME NAMES WHERE 2797 01:56:08,600 --> 01:56:12,000 THERE WERE CLAIMS OF ACTUALLY 2798 01:56:12,000 --> 01:56:13,880 BEING DESCENDED FROM ANCIENT 2799 01:56:13,880 --> 01:56:18,920 TIMES, FROM THE HEBREW GROUP AND 2800 01:56:18,920 --> 01:56:20,120 SOME OF THEM. 2801 01:56:20,120 --> 01:56:22,600 >> ARE YOU TALKING ABOUT 2802 01:56:22,600 --> 01:56:22,920 ETHIOPIAN -- 2803 01:56:22,920 --> 01:56:23,400 >> YES, I'M SORRY. 2804 01:56:23,400 --> 01:56:26,320 >> ARE YOU TALKING ABOUT THE 2805 01:56:26,320 --> 01:56:36,720 ETHIOPIAN POPULATIONS THAT 2806 01:56:36,720 --> 01:56:38,000 EMIGRATED IN '80s AND 90s? 2807 01:56:38,000 --> 01:56:39,840 >> THAT'S PART OF IT, AND THE 2808 01:56:39,840 --> 01:56:41,480 DESCRIBE WITH THE MIDDLE EASTERN 2809 01:56:41,480 --> 01:56:43,440 GENE MARKER ON THE Y CHROMOSOME. 2810 01:56:43,440 --> 01:56:44,560 >> YES, YES, YES. 2811 01:56:44,560 --> 01:56:49,160 YES, SO WE HAVEN'T LOOKED AT THE 2812 01:56:49,160 --> 01:56:51,160 FMF MUTATIONS IN THOSE 2813 01:56:51,160 --> 01:56:53,440 INDIVIDUALS BUT YOU'RE RIGHT, 2814 01:56:53,440 --> 01:56:57,240 IT'S A FASCINATING THING, AND 2815 01:56:57,240 --> 01:56:59,360 THE ANTHROPOLOGY OF IT ALL. 2816 01:56:59,360 --> 01:57:02,080 THAT'S PART OF THE REASON I LOVE 2817 01:57:02,080 --> 01:57:04,040 DOING THIS. 2818 01:57:04,040 --> 01:57:07,400 HAVING A CHANCE TO LOOK AT THOSE 2819 01:57:07,400 --> 01:57:09,400 KINDS OF THINGS AND IT'S PEOPLE, 2820 01:57:09,400 --> 01:57:11,400 YOU KNOW, THAT'S THE MOST 2821 01:57:11,400 --> 01:57:12,720 WONDERFUL THING OF IT ALL, YOU 2822 01:57:12,720 --> 01:57:15,720 KNOW, JUST THE FACT THAT WE'RE 2823 01:57:15,720 --> 01:57:18,200 DEALING WITH OTHER PEOPLE. 2824 01:57:18,200 --> 01:57:21,120 >> SO ONE LAST QUESTION OF A 2825 01:57:21,120 --> 01:57:25,680 PRACTICAL ONE THAT HAS COME UP 2826 01:57:25,680 --> 01:57:26,040 BEFORE. 2827 01:57:26,040 --> 01:57:28,040 YOU SAY THAT THE PATIENTS WHOM 2828 01:57:28,040 --> 01:57:30,720 YOU STUDY ARE REFERRED BY THEIR 2829 01:57:30,720 --> 01:57:33,320 PHYSICIANS TO YOU. 2830 01:57:33,320 --> 01:57:37,320 BUT WHAT ABOUT THE INDIVIDUAL 2831 01:57:37,320 --> 01:57:38,840 PATIENTS IN A FAMILY WHERE, YOU 2832 01:57:38,840 --> 01:57:42,920 KNOW, A CHILD, LOTS OF CHILDREN 2833 01:57:42,920 --> 01:57:44,520 HAVE RECURRENT FEVERS AND THERE 2834 01:57:44,520 --> 01:57:45,720 AREN'T MANY ANSWERS, AT WHAT 2835 01:57:45,720 --> 01:57:49,400 POINT DO YOU DRAW THE LINE AS TO 2836 01:57:49,400 --> 01:57:50,920 WHEN YOU BEGIN A PHYSICIAN -- A 2837 01:57:50,920 --> 01:57:54,600 PHYSICIAN SHOULD BEGIN TO THINK 2838 01:57:54,600 --> 01:57:55,880 OF THESE DISEASES, THE CLINICAL 2839 01:57:55,880 --> 01:58:04,920 SCOPE OF WHICH SEEMS TO BE 2840 01:58:04,920 --> 01:58:05,720 EXPANDING, NOT CONTRACTING, SO 2841 01:58:05,720 --> 01:58:08,480 WHAT WOULD YOU ADVISE PATIENT 2842 01:58:08,480 --> 01:58:11,000 AND PHYSICIANS WHEN TO BEGIN TO 2843 01:58:11,000 --> 01:58:11,840 THINK ABOUT -- 2844 01:58:11,840 --> 01:58:16,320 >> WELL, IT'S A GREAT QUESTION. 2845 01:58:16,320 --> 01:58:18,920 AND FOR SURE, YOU KNOW, AT LEAST 2846 01:58:18,920 --> 01:58:20,640 IN TERMS OF THINKING ABOUT 2847 01:58:20,640 --> 01:58:23,240 GENETIC DISORDERS, SOMEONE WHO 2848 01:58:23,240 --> 01:58:25,600 HAS A VERY EARLY ONSET AND WHO 2849 01:58:25,600 --> 01:58:28,960 HAS SEVERE DISEASE, WE FOR SURE 2850 01:58:28,960 --> 01:58:30,120 THINK ABOUT THE POSSIBILITY OF 2851 01:58:30,120 --> 01:58:33,240 GENETIC DISEASE IN THOSE 2852 01:58:33,240 --> 01:58:33,520 INDIVIDUALS. 2853 01:58:33,520 --> 01:58:35,080 NOWADAYS WITH THE AVAILABILITY 2854 01:58:35,080 --> 01:58:37,320 OF GENETIC TESTING, IT HAS 2855 01:58:37,320 --> 01:58:38,320 BECOME EASIER AND EASIER AND 2856 01:58:38,320 --> 01:58:43,280 PHYSICIANS ARE DOING IT MORE AND 2857 01:58:43,280 --> 01:58:45,560 MORE JUST TO SCREEN FOR VARIANTS 2858 01:58:45,560 --> 01:58:47,920 IN THE PERIODIC FEVER GENES IN 2859 01:58:47,920 --> 01:58:49,400 PANELS THAT ARE AVAILABLE FROM 2860 01:58:49,400 --> 01:58:51,240 SOME OF THE COMMERCIAL GENETIC 2861 01:58:51,240 --> 01:58:54,080 TESTING COMPANIES, AND SO IN 2862 01:58:54,080 --> 01:58:56,000 SOME CASES THAT'S THE WAY IT 2863 01:58:56,000 --> 01:58:56,480 HAPPENS. 2864 01:58:56,480 --> 01:58:59,240 BUT I THINK THAT, YOU KNOW, YOUR 2865 01:58:59,240 --> 01:59:01,000 POINT THAT THE SCOPE IS 2866 01:59:01,000 --> 01:59:04,120 INCREASING AND THE NUMBERS ARE 2867 01:59:04,120 --> 01:59:05,720 INCREASING AND SO IT'S IMPORTANT 2868 01:59:05,720 --> 01:59:08,920 FOR PHYSICIANS TO THINK OF THESE 2869 01:59:08,920 --> 01:59:12,760 DISEASES SOONER RATHER THAN 2870 01:59:12,760 --> 01:59:12,960 LATER. 2871 01:59:12,960 --> 01:59:15,680 AND CERTAINLY I WOULD RATHER BE 2872 01:59:15,680 --> 01:59:19,360 ASKED A FEW TOO MANY TIMES AND 2873 01:59:19,360 --> 01:59:21,360 THEN FIND SOMEONE WHO DOES HAVE 2874 01:59:21,360 --> 01:59:23,520 ONE OF THESE CONDITIONS THAT ARE 2875 01:59:23,520 --> 01:59:25,120 TREATABLE, AND, YOU KNOW, IN 2876 01:59:25,120 --> 01:59:27,480 SOME CASES LIKE FOR FAMILIAL 2877 01:59:27,480 --> 01:59:28,440 MEDITERRANEAN FEVER AT LEAST 2878 01:59:28,440 --> 01:59:31,480 SOME PEOPLE THAT HAVE THAT 2879 01:59:31,480 --> 01:59:32,120 DISEASE CAN DEVELOP AMYLOIDOSIS, 2880 01:59:32,120 --> 01:59:34,280 WHICH AS I MENTIONED CAN LEAD TO 2881 01:59:34,280 --> 01:59:36,280 THINGS LIKE KIDNEY FAILURE. 2882 01:59:36,280 --> 01:59:38,720 SO I'D MUCH RATHER ERR ON THE 2883 01:59:38,720 --> 01:59:40,920 SIDE OF ASKING TOO MANY 2884 01:59:40,920 --> 01:59:42,040 QUESTIONS THAN NOT ASKING 2885 01:59:42,040 --> 01:59:43,120 ENOUGH. 2886 01:59:43,120 --> 01:59:45,720 >> YEAH, I WANT TO POINT OUT 2887 01:59:45,720 --> 01:59:47,560 THAT SEQUENCING IS, AS DR. 2888 01:59:47,560 --> 01:59:48,920 KASTNER MENTIONED, BECOMING 2889 01:59:48,920 --> 01:59:52,320 CHEAPER AND CHEAPER TO THE POINT 2890 01:59:52,320 --> 01:59:56,040 WHERE MANY PATIENTS CAN EVEN GO 2891 01:59:56,040 --> 01:59:58,560 AND GET AN EXOME SEQUENCE DONE 2892 01:59:58,560 --> 02:00:00,760 PRIVATELY AND SO IT HAS BECOME 2893 02:00:00,760 --> 02:00:02,800 EASIER TO SAY THIS PATIENT 2894 02:00:02,800 --> 02:00:05,640 DOESN'T FIT INTO A BIN OF A 2895 02:00:05,640 --> 02:00:07,600 CERTAIN DISEASE AND MAYBE 2896 02:00:07,600 --> 02:00:08,880 LOOKING BACK IN RETROSPECT THEY 2897 02:00:08,880 --> 02:00:11,360 HAVE HAD ORAL ULCERS OR GENITAL 2898 02:00:11,360 --> 02:00:11,720 ULCERS. 2899 02:00:11,720 --> 02:00:13,560 WE'VE HAD A PATIENT WHO CAME TO 2900 02:00:13,560 --> 02:00:16,000 US AT THE AGE OF 45 AND, OH BY 2901 02:00:16,000 --> 02:00:18,400 THE WAY, HE'S HAD ORAL ULCERS 2902 02:00:18,400 --> 02:00:20,600 SINCE HE WAS 8, NO ONE THOUGHT 2903 02:00:20,600 --> 02:00:25,360 ANYTHING OF IT BECAUSE EVERY 2904 02:00:25,360 --> 02:00:30,120 EVERYONE GETS THEM, DON'T THEY? 2905 02:00:30,120 --> 02:00:42,000 NOT EVERYONE DOES, THEY HAD A 2906 02:00:42,000 --> 02:00:43,400 HAPLOSUFFICIENCY OF HA20. 2907 02:00:43,400 --> 02:00:44,200 >> DANIELA, MAYBE YOU CAN 2908 02:00:44,200 --> 02:00:45,440 RESPOND TO THIS. 2909 02:00:45,440 --> 02:00:49,320 WHY DOES THE DISEASE SEEM TO GO 2910 02:00:49,320 --> 02:00:52,080 AWAY IN SOME PATIENTS WITH TIME 2911 02:00:52,080 --> 02:00:53,120 OR AT LEAST GREATLY BECOME 2912 02:00:53,120 --> 02:00:55,760 MODIFIED, DO YOU HAVE ANY 2913 02:00:55,760 --> 02:00:56,840 THOUGHTS ABOUT THAT? 2914 02:00:56,840 --> 02:01:00,360 >> ARE YOU TALKING ABOUT 2915 02:01:00,360 --> 02:01:01,760 HAPLOINEFFICIENCY OF A20 GOING 2916 02:01:01,760 --> 02:01:04,320 AWAY OVER TIME? 2917 02:01:04,320 --> 02:01:06,280 >> YEAH, MY UNDERSTANDING FROM 2918 02:01:06,280 --> 02:01:08,400 SOME OF THE PRESENTATION IS THAT 2919 02:01:08,400 --> 02:01:10,280 IT DOESN'T ALWAYS GET WORSE AND 2920 02:01:10,280 --> 02:01:11,280 SOME OF THESE. 2921 02:01:11,280 --> 02:01:17,640 >> OH, THAT'S ACTUALLY FOR DR. 2922 02:01:17,640 --> 02:01:18,000 MANTHIRAM. 2923 02:01:18,000 --> 02:01:20,080 THAT'S HER DISEASE, I WISH MY 2924 02:01:20,080 --> 02:01:21,480 DISEASE WENT AWAY BUT 2925 02:01:21,480 --> 02:01:25,240 UNFORTUNATELY NO, MINE DOES NOT. 2926 02:01:25,240 --> 02:01:27,120 THAT'S NOR DR. MANTHIRAM. 2927 02:01:27,120 --> 02:01:33,600 >> FOR MOST PATIENTS THE 2928 02:01:33,600 --> 02:01:36,480 EPISODES WITH FAPPA, FEVER SEEMS 2929 02:01:36,480 --> 02:01:40,160 TO RESOLVE, MOST HAVE APTHOUS 2930 02:01:40,160 --> 02:01:45,880 ULCERS BEFORE THEY REACH 2931 02:01:45,880 --> 02:01:46,400 ADOLESCENCE. 2932 02:01:46,400 --> 02:01:49,760 ONE MAY BE INVOLUTION OF 2933 02:01:49,760 --> 02:01:50,280 TONSILS. 2934 02:01:50,280 --> 02:01:51,720 TONSILLECTOMY LEADS TO 2935 02:01:51,720 --> 02:01:53,120 RESOLUTION OF THE FEVER EPISODES 2936 02:01:53,120 --> 02:01:54,840 IN MOST PATIENTS WITH THE 2937 02:01:54,840 --> 02:01:59,080 DISEASE, HOLLI IS AN EXCEPTION, 2938 02:01:59,080 --> 02:02:00,800 BUT I THINK THE TONSILS MAY 2939 02:02:00,800 --> 02:02:04,120 NATURALLY GET SMALLER WITH TIME 2940 02:02:04,120 --> 02:02:06,440 SO THAT MIGHT BE ONE FACTOR THAT 2941 02:02:06,440 --> 02:02:09,480 MAYS A ROLE BUT WE HAVEN'T FULLY 2942 02:02:09,480 --> 02:02:11,160 UNDERSTOOD BECAUSE GENETIC RISK 2943 02:02:11,160 --> 02:02:14,240 VARIANTS WE IDENTIFY ARE STILL 2944 02:02:14,240 --> 02:02:18,280 PRESENT EVEN AFTER -- EVEN 2945 02:02:18,280 --> 02:02:19,080 BEYOND CHILDHOOD. 2946 02:02:19,080 --> 02:02:20,280 MORE WORK IS NEEDED. 2947 02:02:20,280 --> 02:02:21,480 TO YOUR PRIOR QUESTION ABOUT 2948 02:02:21,480 --> 02:02:23,080 WHEN TO SUSPECT A PERIODIC 2949 02:02:23,080 --> 02:02:25,120 FEVER, I WANTED TO ADD THAT 2950 02:02:25,120 --> 02:02:28,440 NORMAL CHILDREN CAN HAVE VERY 2951 02:02:28,440 --> 02:02:29,480 FREQUENT VIRAL INFECTIONS, OVER 2952 02:02:29,480 --> 02:02:31,440 TEN PER YEAR THAT CAN BE NORMAL 2953 02:02:31,440 --> 02:02:32,720 BUT ONE QUESTION THAT REALLY IS 2954 02:02:32,720 --> 02:02:34,680 IMPORTANT TO ME ARE THE EPISODES 2955 02:02:34,680 --> 02:02:35,920 ALL THE SAME? 2956 02:02:35,920 --> 02:02:38,080 DO THEY ALL -- THESE PARENTS 2957 02:02:38,080 --> 02:02:39,400 WERE SAY, I JUST KNOW THAT'S 2958 02:02:39,400 --> 02:02:41,160 WHAT IT IS. 2959 02:02:41,160 --> 02:02:42,680 I TRUST THEM BECAUSE THEY SORT 2960 02:02:42,680 --> 02:02:45,240 OF GET A SENSE OF THE PATTERN OF 2961 02:02:45,240 --> 02:02:47,120 THE DISEASE. 2962 02:02:47,120 --> 02:02:48,520 SO I THINK THAT STEREOTYPICAL 2963 02:02:48,520 --> 02:02:50,120 NATURE IS REALLY IMPORTANT AND 2964 02:02:50,120 --> 02:02:51,680 IF ANYONE SUSPECTS THEIR CHILD 2965 02:02:51,680 --> 02:02:54,080 OR THEMSELVES HAS A PERIODIC 2966 02:02:54,080 --> 02:02:55,600 FEVER, REALLY HELPFUL THING TO 2967 02:02:55,600 --> 02:02:57,920 START MAINTAINING A SYMPTOM 2968 02:02:57,920 --> 02:02:58,920 DIARY OR FEVER DIARY. 2969 02:02:58,920 --> 02:03:01,440 SO WE CAN START SEEING IF 2970 02:03:01,440 --> 02:03:05,520 THERE'S A PATTERN TO HOW THESE 2971 02:03:05,520 --> 02:03:05,960 EPISODES PRESENT. 2972 02:03:05,960 --> 02:03:06,720 >> ALL RIGHT. 2973 02:03:06,720 --> 02:03:08,680 ALL GOOD THINGS COME TO AN END. 2974 02:03:08,680 --> 02:03:13,160 I THINK WE THANK YOU ALL FOR 2975 02:03:13,160 --> 02:03:16,200 THIS REALLY EXCITING PANDORA'S 2976 02:03:16,200 --> 02:03:17,280 BOX THAT YOU OPENED FOR THOSE OF 2977 02:03:17,280 --> 02:03:19,320 US WHO DON'T THINK ABOUT THIS 2978 02:03:19,320 --> 02:03:21,280 ALL THE TIME TO THINK ABOUT. 2979 02:03:21,280 --> 02:03:24,280 AND I TRUST THAT THAT'S TRUE FOR 2980 02:03:24,280 --> 02:03:27,320 THE LARGE AUDIENCE THAT WILL BE 2981 02:03:27,320 --> 02:03:27,640 WATCHING. 2982 02:03:27,640 --> 02:03:30,560 PARTICULAR THANKS TO THE TWO 2983 02:03:30,560 --> 02:03:33,120 PATIENTS WHO KINDLY SHARED THEIR 2984 02:03:33,120 --> 02:03:34,400 PERSONAL EXPERIENCES, WHICH IS 2985 02:03:34,400 --> 02:03:35,760 SUCH AN IMPORTANT ITEM. 2986 02:03:35,760 --> 02:03:40,240 I JUST WOULD MENTION IN CLOSING 2987 02:03:40,240 --> 02:03:43,800 TO REMIND YOU THAT NEXT WEEK WE 2988 02:03:43,800 --> 02:03:46,560 HAVE AN EXTRAORDINARY BRIDGE, 2989 02:03:46,560 --> 02:03:49,240 THE BRIDGE BACK TO THE CREATION 2990 02:03:49,240 --> 02:03:49,480 OF LIFE. 2991 02:03:49,480 --> 02:03:56,880 AND SO WE WILL HAVE A LEADING 2992 02:03:56,880 --> 02:03:58,200 BIOCHEMICAL EVOLUTIONARY 2993 02:03:58,200 --> 02:03:59,600 BIOCHEMIST, NICK LANE FROM 2994 02:03:59,600 --> 02:04:01,880 UNIVERSITY COLLEGE, LONDON, AND 2995 02:04:01,880 --> 02:04:04,400 A LEADING CELL BIOLOGIST, 2996 02:04:04,400 --> 02:04:05,160 JENNIFER LIPPINCOTT-SCHWARTZ, 2997 02:04:05,160 --> 02:04:08,840 WE'RE GOING TO DISCUSS THE 2998 02:04:08,840 --> 02:04:12,480 ORIGIN OF LIFE AS VIEWED THROUGH 2999 02:04:12,480 --> 02:04:13,760 THEIR PERSPECTIVES OF THEIR 3000 02:04:13,760 --> 02:04:15,040 INDIVIDUAL RESEARCH. 3001 02:04:15,040 --> 02:04:19,880 SO THANK YOU ALL AGAIN. 3002 02:04:19,880 --> 02:04:20,000 AND PLEASE ENJOY. 3003 02:04:20,000 --> 00:00:00,000 THANK YOU.