1 00:00:05,840 --> 00:00:08,440 >>I'D LIKE TO INTRODUCE MY 2 00:00:08,440 --> 00:00:12,400 VERY GOOD FRIEND AND COLLEAGUE, 3 00:00:12,400 --> 00:00:17,840 DR. DAN KASTNER WHO OBTAINED HIS 4 00:00:17,840 --> 00:00:19,840 A.B. SUMMA CUM LAUDE FROM 5 00:00:19,840 --> 00:00:21,960 PRINCETON UNIVERSITY IN 1973 AND 6 00:00:21,960 --> 00:00:24,000 Ph.D. AND M.D. FROM BAYLOR 7 00:00:24,000 --> 00:00:30,000 COLLEGE OF MEDICINE IN 1982. 8 00:00:30,000 --> 00:00:33,240 AFTER COMPLETING INTERNAL 9 00:00:33,240 --> 00:00:35,120 MEDICINE RESIDENCY HE MOVED TO 10 00:00:35,120 --> 00:00:39,520 THE NATIONAL INSTITUTES OF 11 00:00:39,520 --> 00:00:42,960 HEALTH 1985 AND IS AN NIH 12 00:00:42,960 --> 00:00:44,960 DISTINGUISHED INVESTIGATOR CHIEF 13 00:00:44,960 --> 00:00:45,760 OF THE INFLAMMATORY DISEASE 14 00:00:45,760 --> 00:00:48,600 SECTION AND SCIENTIFIC DIRECTOR 15 00:00:48,600 --> 00:00:52,400 EMERITUS OF THE DIVISION OF 16 00:00:52,400 --> 00:00:53,280 INTRAMURAL PROGRAM AT THE 17 00:00:53,280 --> 00:00:53,720 NATIONAL INSTITUTE. 18 00:00:53,720 --> 00:00:57,840 THAT IS VERY IMPORTANT TO ME 19 00:00:57,840 --> 00:01:00,680 BECAUSE DAN MENTORED ME AND I'M 20 00:01:00,680 --> 00:01:02,720 NOT DOING HIS FUNCTION AS A 21 00:01:02,720 --> 00:01:03,280 SCIENTIFIC DIRECTOR AN 22 00:01:03,280 --> 00:01:05,240 OPPORTUNITY TO THANK DAN FOR 23 00:01:05,240 --> 00:01:06,160 MAKING THE HOUSE VERY STABLE FOR 24 00:01:06,160 --> 00:01:06,680 ME TO STEP IN. 25 00:01:06,680 --> 00:01:09,640 THANKS, DAN. 26 00:01:09,640 --> 00:01:13,720 THROUGHOUT HIS CAREER AT THE NIH 27 00:01:13,720 --> 00:01:17,840 DOING RESEARCH HAS FOCUSSED ON 28 00:01:17,840 --> 00:01:21,800 GENOMIC STRATEGY TO UNDERSTAND 29 00:01:21,800 --> 00:01:24,520 DISORDERS OF INFLAMMATION WITH 30 00:01:24,520 --> 00:01:28,640 PATIENTS RELATIVELY RARE 31 00:01:28,640 --> 00:01:29,440 DISORDERS SEEN AT THE NIH 32 00:01:29,440 --> 00:01:30,760 CLINICAL CENTER HOSPITAL. 33 00:01:30,760 --> 00:01:33,840 THIS WORK HAS PROVIDED DETAILED 34 00:01:33,840 --> 00:01:36,720 MOLECULAR EXPLANATION FOR THE 35 00:01:36,720 --> 00:01:40,360 ILLNESS AND HAS ESTABLISHED THE 36 00:01:40,360 --> 00:01:41,840 CONCEPTUAL BASIS FOR HIGHLY 37 00:01:41,840 --> 00:01:43,960 ELECTIVE TARGETED THERAPIES. 38 00:01:43,960 --> 00:01:46,360 AND HAS INFORMED OUR 39 00:01:46,360 --> 00:01:48,200 UNDERSTANDING OF MORE COMMON 40 00:01:48,200 --> 00:01:48,960 ILLNESSES. 41 00:01:48,960 --> 00:01:53,720 DAN'S GROUP PROPOSED THE NOW 42 00:01:53,720 --> 00:01:57,840 WIDELY ACCEPTED CONCEPT OF 43 00:01:57,840 --> 00:01:59,160 AUTOINFLAMMATORY DISEASE 44 00:01:59,160 --> 00:02:04,080 DISORDERS OF THE EVOLUTIONARY 45 00:02:04,080 --> 00:02:05,200 PATIENT OF THE IMMUNE SYSTEM. 46 00:02:05,200 --> 00:02:07,000 DAN HAS WON A NUMBER OF AWARDS 47 00:02:07,000 --> 00:02:07,760 AND HONORS. 48 00:02:07,760 --> 00:02:10,320 THAT IS ABSOLUTELY CORRECT AND 49 00:02:10,320 --> 00:02:12,040 THE LIST WOULD GO ON BUT I'M 50 00:02:12,040 --> 00:02:15,840 GOING TO SUMMARIZE IT QUICKLY. 51 00:02:15,840 --> 00:02:17,160 INCLUDING ELECTION TO THE 52 00:02:17,160 --> 00:02:18,800 NATIONAL ACADEMY OF SCIENCE IN 53 00:02:18,800 --> 00:02:21,360 2010, TO THE NATIONAL ACADEMY OF 54 00:02:21,360 --> 00:02:23,800 MEDICINE IN 2012 AND RECOGNITION 55 00:02:23,800 --> 00:02:29,200 AS THE FEDERAL EMPLOYEE OF THE 56 00:02:29,200 --> 00:02:31,680 YEAR IN 2018 AND THE PRIZE IN 57 00:02:31,680 --> 00:02:35,160 MOLECULAR MEDICINE IN 2019 AND 58 00:02:35,160 --> 00:02:37,040 CRAWFORD PRIZE FROM THE ROYAL 59 00:02:37,040 --> 00:02:38,920 SWEDISH ACADEMY OF SCIENCE AND 60 00:02:38,920 --> 00:02:41,840 THE CRAWFORD FOUNDATION IN 61 00:02:41,840 --> 00:02:44,560 202137 -- 2021. 62 00:02:44,560 --> 00:02:53,720 I WELCOME DR. KASTNER. 63 00:02:53,720 --> 00:02:56,240 >>THANK YOU FOR THE KIND 64 00:02:56,240 --> 00:02:56,880 INTRODUCTION. 65 00:02:56,880 --> 00:02:58,760 AND I WANT TO THANK YOU AND ALL 66 00:02:58,760 --> 00:03:01,000 OF THE BOARD OF SCIENTIFIC 67 00:03:01,000 --> 00:03:03,560 DIRECTORS FOR HAVING CHOSEN ME 68 00:03:03,560 --> 00:03:09,840 FOR THIS VERY HIGH HONOR OF 69 00:03:09,840 --> 00:03:13,840 GIVING THIS THE 2023 MIDER 70 00:03:13,840 --> 00:03:14,280 LECTURE. 71 00:03:14,280 --> 00:03:16,240 DR. MIDER ON THE SLIDE RIGHT 72 00:03:16,240 --> 00:03:21,560 HERE THE OPENING SLIDE. 73 00:03:21,560 --> 00:03:23,200 HE WAS THE FIRST HE WAS A 74 00:03:23,200 --> 00:03:24,560 DIRECTOR OF LABORATORIES AND 75 00:03:24,560 --> 00:03:29,080 CLINICS WHICH IS THE EQUIVALENT 76 00:03:29,080 --> 00:03:32,160 OF THE DEPUTY DIRECTOR FOR 77 00:03:32,160 --> 00:03:32,600 INTRAMURAL RESEARCH. 78 00:03:32,600 --> 00:03:34,560 I HOPE DURING THE COURSE OF MY 79 00:03:34,560 --> 00:03:36,600 TALK YOU'LL SEE HOW WE CAN BRING 80 00:03:36,600 --> 00:03:37,800 TOGETHER WHAT GOES ON IN THE 81 00:03:37,800 --> 00:03:39,880 LABORATORY AND WHAT GOES ON IN 82 00:03:39,880 --> 00:03:41,400 THE CLINICS. 83 00:03:41,400 --> 00:03:43,920 IN THIS PARTICULAR CASE LOOKING 84 00:03:43,920 --> 00:03:44,760 AT AUTOINFLAMMATORY DISEASE AND 85 00:03:44,760 --> 00:03:47,000 THE HUMAN CONDITION. 86 00:03:47,000 --> 00:03:49,720 BUT BEFORE WE LAUNCH INTO THAT, 87 00:03:49,720 --> 00:03:53,840 I MUST REMIND YOU THAT I HAVE NO 88 00:03:53,840 --> 00:03:56,720 FINANCIAL RELATIONSHIPS TO 89 00:03:56,720 --> 00:03:56,960 DISCLOSE. 90 00:03:56,960 --> 00:03:58,320 IN ANY EVENT STARTING OUT FOR 91 00:03:58,320 --> 00:04:05,880 THOSE NOT FAMILIAR WITH THE 92 00:04:05,880 --> 00:04:09,800 SYSTE 93 00:04:09,800 --> 00:04:11,040 SYSTEMIC AUTOINFLAMMATORY 94 00:04:11,040 --> 00:04:12,840 DISEASE THESE ARE EPISODES OF 95 00:04:12,840 --> 00:04:15,320 SEEMINGLY UNPROVOKED, LOCALIZED 96 00:04:15,320 --> 00:04:17,840 OR SYSTEMIC INFLAMMATION WITHOUT 97 00:04:17,840 --> 00:04:21,640 THE HIGH TITER ANTIBODIES OR T 98 00:04:21,640 --> 00:04:27,080 CELLS ONE WOULD TYPICALLY SEE IN 99 00:04:27,080 --> 00:04:29,160 THE AUTO IMMUNE DISEASE AND THEY 100 00:04:29,160 --> 00:04:32,840 CAN HAVE DRAMATIC EVIDENCE OF 101 00:04:32,840 --> 00:04:33,680 INFLAMMATION I'LL ILLUSTRATE 102 00:04:33,680 --> 00:04:35,400 WITH A FEW PHOTOS ON THE SLIDE. 103 00:04:35,400 --> 00:04:40,360 THIS HAPPENS TO BE THE FOREARM 104 00:04:40,360 --> 00:04:43,960 OF A YOUNG MAN FROM KANSAS CITY 105 00:04:43,960 --> 00:04:49,000 WITH A SYNDROME OF PYO GENIC 106 00:04:49,000 --> 00:04:51,040 ARTHRITIS AND ACNE. 107 00:04:51,040 --> 00:04:53,640 THIS PARTICULAR CASE THE SKIN 108 00:04:53,640 --> 00:04:56,680 LESIONS ONE OF THE SKIN LESIONS 109 00:04:56,680 --> 00:04:56,960 CAN HAVE. 110 00:04:56,960 --> 00:04:59,320 THIS TOOK SEVERAL MONTHS FOR THE 111 00:04:59,320 --> 00:05:00,560 PATIENT TO HEAL. 112 00:05:00,560 --> 00:05:05,200 HERE WE HAVE AN MRI OF THE LEG 113 00:05:05,200 --> 00:05:08,560 OF A PATIENT WITH THE TNF 114 00:05:08,560 --> 00:05:09,840 RECEPTOR ASSOCIATED SYNDROME. 115 00:05:09,840 --> 00:05:12,240 THESE PATIENTS CAN HAVE 116 00:05:12,240 --> 00:05:15,360 INFLAMMATION GOING DOWN INTO THE 117 00:05:15,360 --> 00:05:20,760 MUSCLE COMPARTMENT OF FASCIITIS 118 00:05:20,760 --> 00:05:23,840 THAT MIGRATES DOWN THE LOW. 119 00:05:23,840 --> 00:05:24,600 A RELATIVELY NEW INFLAMMATORY 120 00:05:24,600 --> 00:05:31,000 DISEASE ROSEA THAT PRESENTS WITH 121 00:05:31,000 --> 00:05:33,840 VISION LOSS AND THE PATIENTS 122 00:05:33,840 --> 00:05:37,120 DEVELOP A POLY ARTICULAR 123 00:05:37,120 --> 00:05:39,560 ARTHRITIS AND THE LAST EXAMPLE 124 00:05:39,560 --> 00:05:48,000 IS DAD2 THE DEFICIENT WHICH IS A 125 00:05:48,000 --> 00:05:48,760 DISEASE YOUNG CHILDREN CAN 126 00:05:48,760 --> 00:05:51,520 PRESENT WITH UNEXPLAINED FEVERS 127 00:05:51,520 --> 00:05:55,000 SOMETIMES STROKES OR SOMETIMES 128 00:05:55,000 --> 00:05:57,840 INFLAMMATION OF THE BLOOD 129 00:05:57,840 --> 00:05:59,520 VESSELS VASCULITIS. 130 00:05:59,520 --> 00:06:01,560 THIS TURN OUT TO BE DISORDERS OF 131 00:06:01,560 --> 00:06:05,840 THE PHYLOGENETICALLY ANCIENT 132 00:06:05,840 --> 00:06:06,480 INNATE BRANCH OF THE IMMUNE 133 00:06:06,480 --> 00:06:09,520 SYSTEM AND PROVIDED NEW INSIGHTS 134 00:06:09,520 --> 00:06:10,160 INTO HUMAN BIOLOGY AND 135 00:06:10,160 --> 00:06:13,160 OPPORTUNITIES FOR TARGETED 136 00:06:13,160 --> 00:06:18,360 THERAPIES. 137 00:06:18,360 --> 00:06:21,840 NOW TO PUT THIS IN HISTORICAL 138 00:06:21,840 --> 00:06:24,840 PERSPECTIVE I PRESENT THE IMAGE 139 00:06:24,840 --> 00:06:26,480 OF PAUL ERLIC. 140 00:06:26,480 --> 00:06:28,320 AN IMMUNOLOGIST OF THE 20th 141 00:06:28,320 --> 00:06:31,000 CENTURY AND WON THE NOBEL PRIZE 142 00:06:31,000 --> 00:06:37,360 IN PHYSIOLOGY AND MEDICINE IN 143 00:06:37,360 --> 00:06:45,320 AND PROPOSED OF HORROR 144 00:06:45,320 --> 00:06:48,760 AUTOTOXICUS THAT IT WOULD BE 145 00:06:48,760 --> 00:06:50,320 PERSON FOR THE NETWORK IT TURN 146 00:06:50,320 --> 00:06:53,840 AGAINST THE HOME AND THE DOGMA 147 00:06:53,840 --> 00:07:04,360 IN THE EARLY 20th CENTURY WAS 148 00:07:05,200 --> 00:07:06,560 AUTO COMMUNITY WOULDN'T BE 149 00:07:06,560 --> 00:07:13,040 POSSIBLE AND THERE WAS HASHI 150 00:07:13,040 --> 00:07:16,200 MOTO'S DISEASE AND THE LATTER 151 00:07:16,200 --> 00:07:21,760 HALF OF THE 20th CENTURY WAS THE 152 00:07:21,760 --> 00:07:23,080 TIME WHEN AUTOIMMUNE DISEASES 153 00:07:23,080 --> 00:07:24,960 SORT WE USUALLY THINK OF WERE 154 00:07:24,960 --> 00:07:25,840 FIRST CHARACTERIZED. 155 00:07:25,840 --> 00:07:28,080 IT WAS NOT UNTIL THE END OF THE 156 00:07:28,080 --> 00:07:33,440 20th CENTURY ACTUALLY THAT THIS 157 00:07:33,440 --> 00:07:34,280 CONCEPT OF AUTOINFLAMMATORY 158 00:07:34,280 --> 00:07:36,160 DISEASE CAME TO THE FORE. 159 00:07:36,160 --> 00:07:39,440 MY FIRST EXPOSURE TO A PATIENT 160 00:07:39,440 --> 00:07:41,640 WHO TURNED OUT TO HAVE WHAT WE 161 00:07:41,640 --> 00:07:42,480 NOW CALL AUTOINFLAMMATORY 162 00:07:42,480 --> 00:07:45,480 DISEASE WAS ACTUALLY WHEN I WAS 163 00:07:45,480 --> 00:07:49,000 A BEGINNING FELLOW IN 164 00:07:49,000 --> 00:07:52,680 RHEUMATOLOGY HERE AT THE NIH. 165 00:07:52,680 --> 00:07:55,960 HERE YOU SEE THIS WAS A 166 00:07:55,960 --> 00:07:57,840 HAND-WRITTEN NOTE THAT I WROTE 167 00:07:57,840 --> 00:08:01,320 ON NOVEMBER 14 OF 1985 AFTER I 168 00:08:01,320 --> 00:08:03,840 HAD SEEN THIS PATIENT IN CLINIC. 169 00:08:03,840 --> 00:08:06,640 A YOUNG MAN OF ARMENIAN ANCESTRY 170 00:08:06,640 --> 00:08:10,920 WITH A LIFE LONG HISTORY OF 171 00:08:10,920 --> 00:08:16,080 RECURRENT FEVERS AND ARTICULAR 172 00:08:16,080 --> 00:08:18,280 ARTHRITIS AND TURNED OUT TO HAVE 173 00:08:18,280 --> 00:08:28,840 FAMILIAL MET -- MEDITERRANEAN 174 00:08:30,880 --> 00:08:33,600 DISEASE AND IT WAS THOUGHT TO BE 175 00:08:33,600 --> 00:08:36,280 AN RECESSIVELY INHERITED DISEASE 176 00:08:36,280 --> 00:08:39,560 BUT NO ONE KNEW WHAT THE GENE 177 00:08:39,560 --> 00:08:42,800 WAS OR ANYTHING ABOUT THE 178 00:08:42,800 --> 00:08:43,640 PATHOPHYSIOLOGY OF THE DISEASE 179 00:08:43,640 --> 00:08:46,040 IN ANY SERIOUS WAY. 180 00:08:46,040 --> 00:08:49,000 IN ANY CASE IT'S SEEN IN PEOPLE 181 00:08:49,000 --> 00:08:53,200 OF ARMENIAN, ARAB, TURKISH, 182 00:08:53,200 --> 00:08:59,880 ITALIAN AND JEWISH ANCESTRY. 183 00:08:59,880 --> 00:09:01,840 IT'S CHARACTERIZED BY ONE TO 184 00:09:01,840 --> 00:09:07,000 THREE DAY EPISODES OF FEVER WITH 185 00:09:07,000 --> 00:09:12,440 STERILE PERI TINNITUS OR SOME 186 00:09:12,440 --> 00:09:13,840 PATIENTS DEVELOP ARTHRITIS AND 187 00:09:13,840 --> 00:09:24,360 AT LEAST IN SOME CASES THEY CAN 188 00:09:31,120 --> 00:09:32,120 HAVE OTHER SYMPTOMS. 189 00:09:32,120 --> 00:09:34,640 THIS IS A DRAMATIC DISEASE FOR 190 00:09:34,640 --> 00:09:36,480 ME SEEING THE PATIENT. 191 00:09:36,480 --> 00:09:47,000 THERE WAS A TREATMENT WHICH WAS 192 00:09:49,080 --> 00:09:51,880 GREAT BUT IT DID DEF -- THIS WAS 193 00:09:51,880 --> 00:09:54,480 AT THE MAGICAL TIME AT THE 194 00:09:54,480 --> 00:09:57,840 BEGINNING OF THE GENOME PROJECT 195 00:09:57,840 --> 00:10:02,120 AND THE POSSIBILITY OF DOING AT 196 00:10:02,120 --> 00:10:04,520 SCALE SOME SCREENING THE WHOLE 197 00:10:04,520 --> 00:10:05,280 GENOME TO DISCOVER THE CAUSE OF 198 00:10:05,280 --> 00:10:07,000 THE SQUEEZE YOU DIDN'T HAVE A 199 00:10:07,000 --> 00:10:12,240 CLUE AS TO WHAT WAS GOING ON. 200 00:10:12,240 --> 00:10:13,800 THAT WAS FANTASTIC AND 201 00:10:13,800 --> 00:10:17,400 EVENTUALLY TOOK TIME FOR ME TO 202 00:10:17,400 --> 00:10:19,920 GET INVOLVED IN THIS BUT BY THE 203 00:10:19,920 --> 00:10:21,840 SUMMER OF 1989 I WAS HARD AT IT 204 00:10:21,840 --> 00:10:25,040 IN TERM OF TRYING TO FIND THE 205 00:10:25,040 --> 00:10:31,680 NEED FAMILIAL MEDITERRANEAN 206 00:10:31,680 --> 00:10:32,440 SYNDROME AND BECAUSE OF THE FACT 207 00:10:32,440 --> 00:10:34,720 THERE WERE FEW MARKERS IN THE 208 00:10:34,720 --> 00:10:36,360 HUMAN GENOME THAT WERE KNOWN AT 209 00:10:36,360 --> 00:10:37,960 THAT TIME ONLY ABOUT 300 MARKERS 210 00:10:37,960 --> 00:10:41,160 OF DNA MARKERS IN THE WHOLE 211 00:10:41,160 --> 00:10:42,600 HUMAN GENOME YOU HAD TO HAVE 212 00:10:42,600 --> 00:10:45,480 LOTS OF FAMILIES IN ORDER TO BE 213 00:10:45,480 --> 00:10:46,120 ABLE TO ACTUALLY MAP A DISEASE 214 00:10:46,120 --> 00:10:48,480 GENE. 215 00:10:48,480 --> 00:10:51,000 HERE YOU SEE THE EXPEDITION I 216 00:10:51,000 --> 00:10:54,000 WENT ON IN THE SUMMER OF 1989 217 00:10:54,000 --> 00:11:01,040 AND HERE I'M VISITING A FAMILY 218 00:11:01,040 --> 00:11:11,520 IN THIS AREA AND HERE'S MY 219 00:11:24,520 --> 00:11:25,800 COLLABORATOR IN THESE ADVENTURES 220 00:11:25,800 --> 00:11:29,440 AND THIS PARTICULAR FAMILY IS A 221 00:11:29,440 --> 00:11:30,880 FAMILY WHERE THE PARENTS WERE 222 00:11:30,880 --> 00:11:32,840 FIRST COUSINS OF ONE ANOTHER AND 223 00:11:32,840 --> 00:11:35,040 YOU CAN SEE THE FAMILIAL 224 00:11:35,040 --> 00:11:35,680 RESEMBLANCE BETWEEN THE TWO OF 225 00:11:35,680 --> 00:11:43,280 THEM. 226 00:11:43,280 --> 00:11:47,120 IT WAS A GREAT FAMILY FOR DOING 227 00:11:47,120 --> 00:11:49,840 THE GENETIC LINKAGE ANALYSIS. 228 00:11:49,840 --> 00:11:52,600 ALL TOGETHER WE DREW BLOOD ON 229 00:11:52,600 --> 00:11:55,440 248 INDIVIDUALS AND MADE EVB 230 00:11:55,440 --> 00:11:57,280 CELL LINES ON THESE PEOPLE AND 231 00:11:57,280 --> 00:12:00,000 WHAT WE DID BACK IN THOSE DAY TO 232 00:12:00,000 --> 00:12:01,000 MAP A DISEASE GENE. 233 00:12:01,000 --> 00:12:02,520 AFTER A COUPLE YEARS WE WERE 234 00:12:02,520 --> 00:12:06,840 SUCCESSFUL IN MAPPING THE GENE 235 00:12:06,840 --> 00:12:13,840 TO THE CHROMOSOME 16 THEN WE 236 00:12:13,840 --> 00:12:17,640 DEVELOPED GENOMIC AND 237 00:12:17,640 --> 00:12:18,840 TRANSCRIPTAL MAPS AND SEQUENCING 238 00:12:18,840 --> 00:12:22,280 ALL THE GENES WE FOUND IN 200KB 239 00:12:22,280 --> 00:12:23,640 INTERVAL WE THEN HAD TO SCREEN 240 00:12:23,640 --> 00:12:25,840 FOR MUTATIONS AND ULTIMATELY IT 241 00:12:25,840 --> 00:12:32,520 WAS THE TENTH OF THE 10 GENES 242 00:12:32,520 --> 00:12:34,600 THAT WERE ASSOCIATED WITH FMF 243 00:12:34,600 --> 00:12:37,040 AND WE FOUND WHAT WE HAD BEEN 244 00:12:37,040 --> 00:12:39,680 HOPING FOR THIS BRAND NEW GENE 245 00:12:39,680 --> 00:12:41,720 NOBODY KNEW ANYTHING ABOUT IT 246 00:12:41,720 --> 00:12:47,440 BEFORE AND WE NAMED THE ENCODED 247 00:12:47,440 --> 00:12:50,720 PROTEIN PYRIN AFTER THE FEVER 248 00:12:50,720 --> 00:12:53,840 AND THAT WAS EXCITING. 249 00:12:53,840 --> 00:12:59,960 IT WE DIDN'T KNOW HOW IT WORKED 250 00:12:59,960 --> 00:13:01,800 OR WHATEVER AND WERE FACED WITH 251 00:13:01,800 --> 00:13:04,280 THE PUZZLE OF FIGURING OUT HOW 252 00:13:04,280 --> 00:13:05,800 THAT WORKED WHICH HAS BEEN 253 00:13:05,800 --> 00:13:07,320 SOMETHING THAT HAS TAKEN US A 254 00:13:07,320 --> 00:13:09,240 BIT OF TIME TO FIGURE OUT. 255 00:13:09,240 --> 00:13:13,040 ONE OF THE EARLY CLUES IS THE 256 00:13:13,040 --> 00:13:15,640 END TERMAL 90 AMINO ACID OF THE 257 00:13:15,640 --> 00:13:19,040 PROTEIN IS A PROTOTYPE FOR A 258 00:13:19,040 --> 00:13:22,400 DOMAIN KNOWN AS THE PYRIN DOMAIN 259 00:13:22,400 --> 00:13:24,720 AND FORMS SIX ALPHA HELICES YOU 260 00:13:24,720 --> 00:13:27,440 CAN SEE HERE AND THAT ALLOWS FOR 261 00:13:27,440 --> 00:13:29,680 THE FORM OF A CHARGE WITH 262 00:13:29,680 --> 00:13:31,000 POSITIVE CHARGES IN BLUE AND 263 00:13:31,000 --> 00:13:33,280 NEGATIVE IN RED AND BASICALLY 264 00:13:33,280 --> 00:13:37,000 THAT ALLOWS FOR THE 265 00:13:37,000 --> 00:13:38,800 SELF-SELF-INTERACTION, THE COG 266 00:13:38,800 --> 00:13:41,840 NATE INTERACTION OF THE PYRIN 267 00:13:41,840 --> 00:13:42,840 DOMAIN FROM ONE DOMAIN TO 268 00:13:42,840 --> 00:13:43,640 ANOTHER PROTEIN. 269 00:13:43,640 --> 00:13:49,880 THAT'S HOW A NUMBER OF THE 270 00:13:49,880 --> 00:13:51,680 PROTEINS IN THE INNATE IMMUNE 271 00:13:51,680 --> 00:13:53,120 SYSTEM INTERACT AND THERE'S 20 272 00:13:53,120 --> 00:13:57,240 THAT HAVE PYRIN DOMAIN. 273 00:13:57,240 --> 00:13:58,920 THAT'S ONE OF THE GREAT THINGS 274 00:13:58,920 --> 00:14:00,760 WE LEARNED EARLY ON. 275 00:14:00,760 --> 00:14:02,880 ONE THING THAT WAS GREAT TOO AND 276 00:14:02,880 --> 00:14:03,600 KEEPING THE CONNECTION BETWEEN 277 00:14:03,600 --> 00:14:05,880 THE LAB AND THE CLINIC IS SO 278 00:14:05,880 --> 00:14:07,640 IMPORTANT IS THAT WE STARTED 279 00:14:07,640 --> 00:14:09,840 SEEING PATIENTS THAT CAME TO THE 280 00:14:09,840 --> 00:14:12,800 NIH WHO WERE REFERRED WITH THE 281 00:14:12,800 --> 00:14:14,080 POSSIBILITY THEY MIGHT HAVE FMF 282 00:14:14,080 --> 00:14:15,960 AND WE HAD A GENETIC TEST AND 283 00:14:15,960 --> 00:14:17,440 COULD TELL IF THEY DID OR NOT 284 00:14:17,440 --> 00:14:19,440 AND SOME DID BUT THEN THERE WERE 285 00:14:19,440 --> 00:14:21,400 SOME THAT DID NOT. 286 00:14:21,400 --> 00:14:24,440 WE IDENTIFIED A COHORT OF 287 00:14:24,440 --> 00:14:26,800 INDIVIDUALS WITH DOMINANTLY 288 00:14:26,800 --> 00:14:28,560 INHERITED RATHER THAN 289 00:14:28,560 --> 00:14:37,520 RECESSIVELY INHER ITTED FEATURES 290 00:14:37,520 --> 00:14:44,200 AND DIFFERENT TREATMENT FROM FMF 291 00:14:44,200 --> 00:14:45,800 AND TURNED OUT A COUPLE YEARS 292 00:14:45,800 --> 00:14:48,880 AFTER WE FOUND THE GENE FOR FMF 293 00:14:48,880 --> 00:14:52,240 FOUND THOSE PATIENTS HAD 294 00:14:52,240 --> 00:14:56,280 MUTATIONS IN THE P55 TNF 295 00:14:56,280 --> 00:14:58,680 RECEPTOR AND WE CALL THAT 296 00:14:58,680 --> 00:15:01,200 DISEASE TRAPS THE TNF RECEPTOR 297 00:15:01,200 --> 00:15:02,720 ASSOCIATED PERIODIC SYNDROME AND 298 00:15:02,720 --> 00:15:07,440 THOUGHT MAYBE WE WERE SEEING AN 299 00:15:07,440 --> 00:15:12,400 EMERGING FAMILY OF NEW DISEASES 300 00:15:12,400 --> 00:15:14,800 THAT WERE DIFFERENT FROM THE 301 00:15:14,800 --> 00:15:16,640 AUTOIMMUNE DISEASES BECAUSE THEY 302 00:15:16,640 --> 00:15:17,880 DIDN'T HAVE EVIDENCE OF T CELL 303 00:15:17,880 --> 00:15:24,040 INVOLVEMENT. 304 00:15:24,040 --> 00:15:25,840 AND THOUGHT TO CALL IT 305 00:15:25,840 --> 00:15:28,760 AUTOINFLAMMATORY DISEASES 306 00:15:28,760 --> 00:15:29,240 INSTEAD. 307 00:15:29,240 --> 00:15:30,520 IT'S JUST A GUESS THAT MIGHT BE 308 00:15:30,520 --> 00:15:31,880 THE CASE. 309 00:15:31,880 --> 00:15:34,800 THE FOLLOWING YEAR ACTUALLY WE 310 00:15:34,800 --> 00:15:36,560 PUBLISHED AN OPINION ARTICLE IN 311 00:15:36,560 --> 00:15:39,320 WHICH WE SPECULATED ON ALL OF 312 00:15:39,320 --> 00:15:41,720 THE DIFFERENT DISEASES THAT 313 00:15:41,720 --> 00:15:43,120 THERE MIGHT BE THAT COULD BE 314 00:15:43,120 --> 00:15:45,520 AUTOINFLAMMATORY BASED ON THE 315 00:15:45,520 --> 00:15:52,280 IDEA THESE PATIENTS HAD 316 00:15:52,280 --> 00:15:53,720 INFLAMMATION WITHOUT AUTO 317 00:15:53,720 --> 00:15:56,640 ANTIBODIES AND WE HAVE THE 318 00:15:56,640 --> 00:15:57,840 CLASSIFICATION SCHEME AND A 319 00:15:57,840 --> 00:16:00,520 COUPLE FIT INTO THE SYNDROMES 320 00:16:00,520 --> 00:16:10,240 WHERE YOU HAVE THE FAMILIAL 321 00:16:10,240 --> 00:16:11,720 URTICARIA OR A SYNDROME WHERE 322 00:16:11,720 --> 00:16:12,480 THEY DON'T NEED CODE TO BE 323 00:16:12,480 --> 00:16:21,920 INDUCED TO DO THAT. 324 00:16:21,920 --> 00:16:29,640 THEN IT WAS MAGICAL. 325 00:16:29,640 --> 00:16:32,440 HAL HOFFMAN AT THE UNIVERSITY 326 00:16:32,440 --> 00:16:34,480 SAN DIEGO IDENTIFIED THE GENE 327 00:16:34,480 --> 00:16:36,200 MUTATING IN THE TWO CELL 328 00:16:36,200 --> 00:16:37,640 DISEASES I JUST SHOWED ON THE 329 00:16:37,640 --> 00:16:38,600 LAST SLIDE. 330 00:16:38,600 --> 00:16:43,000 IT TURNED OUT THE GENE MUTATED 331 00:16:43,000 --> 00:16:49,560 IN THOSE DISEASES HAS THE PI 332 00:16:49,560 --> 00:16:52,760 PIRE -- PYRIN DOMAIN AND THAT 333 00:16:52,760 --> 00:16:54,480 WAS GREAT FOR US AND THEN THE 334 00:16:54,480 --> 00:16:56,600 OTHER THING THAT WAS HAPPENING 335 00:16:56,600 --> 00:17:01,840 WAS IN SWITZERLAND THERE WAS 336 00:17:01,840 --> 00:17:04,280 THIS GUY INTERESTED IN IL1 GETS 337 00:17:04,280 --> 00:17:04,880 ACTIVATED. 338 00:17:04,880 --> 00:17:07,880 THERE'S A PRO FORM OF IL1 AND IT 339 00:17:07,880 --> 00:17:09,040 HAS TO GET CLEAVED TO BE 340 00:17:09,040 --> 00:17:10,840 ACTIVATED AND HE FIGURED OUT 341 00:17:10,840 --> 00:17:14,520 THERE WAS A MACRO MOLECULAR 342 00:17:14,520 --> 00:17:17,840 COMPLEX CALLED THE INFLAMMASOME 343 00:17:17,840 --> 00:17:23,440 AND GUESS WHAT WAS AT THE HUB? 344 00:17:23,440 --> 00:17:28,000 NLRP3 THE SAME PROTEIN THAT IS 345 00:17:28,000 --> 00:17:32,400 THE PROTEIN THAT HAL HOFFMAN 346 00:17:32,400 --> 00:17:35,120 FOUND WITH THE PYRIN DOMAIN. 347 00:17:35,120 --> 00:17:38,440 WE HAD AN IDEA OF OF 348 00:17:38,440 --> 00:17:39,800 AUTOINFLAMMATION AND CLUE THREES 349 00:17:39,800 --> 00:17:41,640 DISEASES HAD SOMETHING TO DO 350 00:17:41,640 --> 00:17:42,720 WITH IL1. 351 00:17:42,720 --> 00:17:45,680 THEN AS IF THE STORY IS NOT 352 00:17:45,680 --> 00:17:46,440 MIRACULOUS ENOUGH THERE'S 353 00:17:46,440 --> 00:17:49,840 ANOTHER PIECE TOO AND THAT IS 354 00:17:49,840 --> 00:17:53,520 THAT IVONA AND OTHERS DISCOVERED 355 00:17:53,520 --> 00:17:55,160 AN EVEN MORE SEVERE DISEASE THAN 356 00:17:55,160 --> 00:18:02,840 THE ONES I TOLD YOU ABOUT IN 357 00:18:02,840 --> 00:18:08,160 FACT ALSO ARE MUTATIONS AND 358 00:18:08,160 --> 00:18:09,760 THOSE PATIENTS NOT ONLY GET 359 00:18:09,760 --> 00:18:13,040 FEVERS AND HIVES BUT ALSO 360 00:18:13,040 --> 00:18:17,840 DEVELOP ASEPTIC MENINGITIS 361 00:18:17,840 --> 00:18:21,320 LEADING TO BLINDNESS, DEAFNESS 362 00:18:21,320 --> 00:18:22,080 AND DISABILITY AND THIS IS 363 00:18:22,080 --> 00:18:23,800 SHOWING THE MUTATIONS ARE ALL IN 364 00:18:23,800 --> 00:18:26,600 THE SAME DOMAIN FOR THE THREE 365 00:18:26,600 --> 00:18:26,880 DISEASES. 366 00:18:26,880 --> 00:18:30,760 SO IN ANY CASE THAT LED THE GOOD 367 00:18:30,760 --> 00:18:34,360 DOCTOR MANSKI TO ORGANIZE A 368 00:18:34,360 --> 00:18:35,800 TRIAL HERE AT THE NIH CLINICAL 369 00:18:35,800 --> 00:18:40,560 CENTER LOOKING AT AN IL1 370 00:18:40,560 --> 00:18:43,920 INHIBITOR IN 18 CHILDREN THAT 371 00:18:43,920 --> 00:18:44,960 HAVE THE INFLAMMATORY DISEASE. 372 00:18:44,960 --> 00:18:47,880 THIS IS A DISEASE THE PROGNOSIS 373 00:18:47,880 --> 00:18:48,880 IN THESE KIDS WOULD BE HORRIBLE 374 00:18:48,880 --> 00:18:51,720 AND IF YOU LOOK AT THE BEFORE 375 00:18:51,720 --> 00:18:52,840 AND AFTER OF WHAT HAPPENED SO 376 00:18:52,840 --> 00:18:57,520 BEFORE TREATMENT YOU CAN SEE THE 377 00:18:57,520 --> 00:19:00,760 HIVES-LIKE RASH AND 378 00:19:00,760 --> 00:19:01,840 CONJUNCTIVITIS AND THE WHITE 379 00:19:01,840 --> 00:19:11,680 INDICATES INFLAMMATION OF THE 380 00:19:11,680 --> 00:19:19,040 MENINGES AND THE COCHLEA AND THE 381 00:19:19,040 --> 00:19:25,000 HIVES-LIKE RASH AND CONJUNC 382 00:19:25,000 --> 00:19:26,880 CONJUNCTIVITIS GOES AWAY AND THE 383 00:19:26,880 --> 00:19:28,160 OTHER SYMPTOMS GO AWAY. 384 00:19:28,160 --> 00:19:30,640 HAVE A COHORT OF CHILDREN WHO 385 00:19:30,640 --> 00:19:35,160 HAD A HORRIBLE PROGNOSIS WHO NOW 386 00:19:35,160 --> 00:19:36,480 ARE SKILL ON THE MEDICATION. 387 00:19:36,480 --> 00:19:39,920 WE SAW ONE ON A MEETING AT 388 00:19:39,920 --> 00:19:40,560 AUTOINFLAMMATORY DISEASES THREE 389 00:19:40,560 --> 00:19:44,560 WEEKS AGO IS NOW A GRADUATE 390 00:19:44,560 --> 00:19:45,800 STUDENT STUDYING 391 00:19:45,800 --> 00:19:48,480 AUTOINFLAMMATORY DISEASES. 392 00:19:48,480 --> 00:19:49,840 IT'S A WONDERFUL, WONDERFUL 393 00:19:49,840 --> 00:19:50,600 OUTCOME OF THAT. 394 00:19:50,600 --> 00:19:56,680 IN ANY CASE THE FIELD HAS TAKEN 395 00:19:56,680 --> 00:20:06,320 OFF AT THIS POINT MIKE MCDERMOTT 396 00:20:06,320 --> 00:20:08,040 SPECULATES THEY'RE TWO ENDS OF 397 00:20:08,040 --> 00:20:09,120 THE CASE. 398 00:20:09,120 --> 00:20:10,760 SETH MASTERS IN MY LAB PUBLISHED 399 00:20:10,760 --> 00:20:16,480 AN ARTICLE THAT SORT OF 400 00:20:16,480 --> 00:20:19,000 SUMMARIZES 10 YEARS AFTER THE 401 00:20:19,000 --> 00:20:20,680 PROPOSAL OF THE CONCEPT OF 402 00:20:20,680 --> 00:20:21,840 AUTOINFLAMMATION WHAT WAS THE 403 00:20:21,840 --> 00:20:24,560 MOLECULAR CLASSIFICATION AT THAT 404 00:20:24,560 --> 00:20:26,360 TIME AND SORT OF TONGUE AND 405 00:20:26,360 --> 00:20:31,040 CHEEK HE CAME UP WITH THE TITER 406 00:20:31,040 --> 00:20:35,280 HORROR IN FLAMATICA AND THE 407 00:20:35,280 --> 00:20:42,680 CONCEPT HORROR AUTOTOXICUS AND 408 00:20:42,680 --> 00:20:44,040 AUTOINFLAMMATION WAS IMPOSSIBLE 409 00:20:44,040 --> 00:20:47,000 AND THIS ARTICLE INTRODUCES ALL 410 00:20:47,000 --> 00:20:48,880 SORTS OF AUTOINFLAMMATORY 411 00:20:48,880 --> 00:20:51,240 DISEASES BEING DESCRIBED AND 412 00:20:51,240 --> 00:20:55,320 DISCUSSED IN TERMS OF THEIR 413 00:20:55,320 --> 00:20:58,680 PATHOPHYSIOLOGY. 414 00:20:58,680 --> 00:21:05,480 SHORTLY THEREAFTER RON LASKER 415 00:21:05,480 --> 00:21:08,120 PUBLISHED A TEXTBOOK OF 416 00:21:08,120 --> 00:21:09,320 AUTOINFLAMMATORY 800 PAGES LONG 417 00:21:09,320 --> 00:21:12,720 AND THERE WAS A MEETING OF THE 418 00:21:12,720 --> 00:21:13,800 INTERNATIONAL SOCIETY ON 419 00:21:13,800 --> 00:21:15,360 SYSTEMIC AUTOINFLAMMATORY 420 00:21:15,360 --> 00:21:21,800 DISEASES WITH LIKE 360 PEOPLE 421 00:21:21,800 --> 00:21:27,400 THERE MORE THAN 50 DISEASES. 422 00:21:27,400 --> 00:21:29,240 IT'S NOT GOING TO BE POSSIBLE 423 00:21:29,240 --> 00:21:32,840 FOR THE ONE HOUR IN THE LECTURE 424 00:21:32,840 --> 00:21:34,320 A LOTTED TO ME TO GO THROUGH THE 425 00:21:34,320 --> 00:21:36,400 50 DISEASES WE COULD TALK ABOUT 426 00:21:36,400 --> 00:21:39,120 SO I'LL TALK ABOUT ONE OF THEM 427 00:21:39,120 --> 00:21:41,120 THAT'S IMPORTANT BECAUSE OF ITS 428 00:21:41,120 --> 00:21:43,000 FREQUENCY AND BECAUSE OF ITS 429 00:21:43,000 --> 00:21:44,320 SEVERITY AND BECAUSE THERE'S A 430 00:21:44,320 --> 00:21:46,720 TREATMENT FOR IT AND ANOTHER 431 00:21:46,720 --> 00:21:49,840 THAT'S A REAL RECENT ONE. 432 00:21:49,840 --> 00:21:53,680 THE FIRST ONE IS THIS DISEASE 433 00:21:53,680 --> 00:21:57,840 DADA EFFICIENT OF ADA2. 434 00:21:57,840 --> 00:22:00,520 A DISEASE WE COVERED AND 435 00:22:00,520 --> 00:22:01,720 COLLEAGUES DISCOVERED 436 00:22:01,720 --> 00:22:03,600 INDEPENDENTLY AT ABOUT THE SAME 437 00:22:03,600 --> 00:22:05,040 TIME AND THE TWO PUBLICATIONS 438 00:22:05,040 --> 00:22:07,040 WERE PUBLISHED BACK TO BACK IN 439 00:22:07,040 --> 00:22:08,960 THE NEW ENGLAND JOURNAL. 440 00:22:08,960 --> 00:22:16,080 WE HAD SEEN A NUMBER OF KIDS 441 00:22:16,080 --> 00:22:17,680 HERE THAT PRESENTED WITH FEVERS 442 00:22:17,680 --> 00:22:18,320 AND STROKES. 443 00:22:18,320 --> 00:22:20,120 PHIL HAD SEEN A GROUP OF 444 00:22:20,120 --> 00:22:22,800 CHILDREN WITH FEVERS AND 445 00:22:22,800 --> 00:22:23,960 SOMETIMES INFLAMMATION OF THE 446 00:22:23,960 --> 00:22:24,920 BLOOD VESSELS BUT BOTH TURNED 447 00:22:24,920 --> 00:22:27,800 OUT TO HAVE MUTATIONS IN THE 448 00:22:27,800 --> 00:22:32,280 SAME GENE WHICH IS THIS GENE 449 00:22:32,280 --> 00:22:33,040 ADA2. 450 00:22:33,040 --> 00:22:37,040 YOU CAN SEE HERE ON THE SLIDE 451 00:22:37,040 --> 00:22:40,960 THE ARROWS POINT THE STROKES IN 452 00:22:40,960 --> 00:22:48,280 THE DEEP BRAIN NUCLEI AND THIS 453 00:22:48,280 --> 00:22:51,160 IS VASCULITIS A NECROTIC AREA OF 454 00:22:51,160 --> 00:22:52,920 THE EAR OF A PATIENT. 455 00:22:52,920 --> 00:22:55,960 IN ANY CASE, A PROBLEM WITH THIS 456 00:22:55,960 --> 00:22:58,200 WAS THAT THESE KIDS CONTINUED TO 457 00:22:58,200 --> 00:23:01,000 HAVE STROKES NO MATTER WHAT THE 458 00:23:01,000 --> 00:23:05,240 TREATMENT SEEMED TO BE. 459 00:23:05,240 --> 00:23:15,680 AND SHOWN HERE IS DR. AMANDA 460 00:23:15,680 --> 00:23:18,480 OMBRELLO SHOWING TNF INHIBITERS 461 00:23:18,480 --> 00:23:19,680 IS EFFECTIVE UP THESE PATIENTS 462 00:23:19,680 --> 00:23:20,920 AND IT'S BECOME STANDARD OF CARE 463 00:23:20,920 --> 00:23:21,520 AT THIS POINT. 464 00:23:21,520 --> 00:23:24,600 THE OTHER DISEASE I WANT TO 465 00:23:24,600 --> 00:23:28,520 MENTION IS DISABLING PANS 466 00:23:28,520 --> 00:23:29,800 SCLEROTIC MORPHIA. 467 00:23:29,800 --> 00:23:32,560 THIS IS A DISEASE THAT'S NOT A 468 00:23:32,560 --> 00:23:35,040 HOUSEHOLD NAME OR NOT IN MOST 469 00:23:35,040 --> 00:23:35,400 HOUSEHOLDS. 470 00:23:35,400 --> 00:23:36,720 IT'S A DISEASE IN WHICH PATIENT 471 00:23:36,720 --> 00:23:37,840 HAVE THICKENING OF THE SKIN, A 472 00:23:37,840 --> 00:23:42,280 FORM OF FIBROSIS THAT GOES DOWN 473 00:23:42,280 --> 00:23:44,800 DEEP BELOW THE SKIN, SUB 474 00:23:44,800 --> 00:23:47,080 CUTANEOUS AND MUSCLE TISSUE TO 475 00:23:47,080 --> 00:23:48,080 THE BONE. 476 00:23:48,080 --> 00:23:50,280 THESE PATIENTS ALSO CAN HAVE 477 00:23:50,280 --> 00:23:53,240 PROBLEMS WITH POOR WOUND HEALING 478 00:23:53,240 --> 00:23:57,800 AND CAN DEVELOP SQUAMOUS CELL 479 00:23:57,800 --> 00:24:01,000 CARCINOMA AND THE DIAGNOSIS IS 480 00:24:01,000 --> 00:24:02,800 TO LIVE 10 YEARS AFTER 481 00:24:02,800 --> 00:24:03,080 DIAGNOSIS. 482 00:24:03,080 --> 00:24:04,800 IT'S A SEVERE DISEASE. 483 00:24:04,800 --> 00:24:07,560 IT SO HAPPENED I WAS GIVING A 484 00:24:07,560 --> 00:24:08,840 VIRTUAL GRAND ROUNDS TO THE 485 00:24:08,840 --> 00:24:09,680 UNIVERSITY OF CALIFORNIA SAN 486 00:24:09,680 --> 00:24:13,200 DIEGO ABOUT A YEAR AGO FEBRUARY 487 00:24:13,200 --> 00:24:13,720 OF 2022. 488 00:24:13,720 --> 00:24:16,360 AT THE END OF MY TALK I WAS 489 00:24:16,360 --> 00:24:19,480 MEETING WITH VARIOUS PEOPLE 490 00:24:19,480 --> 00:24:23,240 VIRTUALLY EVERYTHING IS 491 00:24:23,240 --> 00:24:23,880 IMAGINARY, WHATEVER. 492 00:24:23,880 --> 00:24:27,280 IN ANY EVENT I WAS TALKING TO 493 00:24:27,280 --> 00:24:28,400 LORI BRODERICK ON THE FACULTY 494 00:24:28,400 --> 00:24:31,000 THERE AND TELLING US ABOUT THE 495 00:24:31,000 --> 00:24:36,080 FAMILY SHE WAS CARING FOR THIS 496 00:24:36,080 --> 00:24:39,440 DISEASE AND THE STORIES WITH YOU 497 00:24:39,440 --> 00:24:42,120 HORRIFIC OF A YOUNG MAN ABOUT 20 498 00:24:42,120 --> 00:24:48,120 OR SO WHO HAS THIS CONDITION 499 00:24:48,120 --> 00:24:52,040 PANSCLEROTIC MORPHEA AND HAD 500 00:24:52,040 --> 00:24:53,040 DOUBLE AMPUTATION OF BOTH ARMS 501 00:24:53,040 --> 00:24:56,360 AND LEGS BECAUSE OF UNCONTROLLED 502 00:24:56,360 --> 00:24:58,920 INFECTION AND SQUAMOUS CELL 503 00:24:58,920 --> 00:24:59,240 CARCINOMAS. 504 00:24:59,240 --> 00:25:00,080 AS IF THAT WASN'T TERRIBLE 505 00:25:00,080 --> 00:25:02,920 ENOUGH HIS OLDER BROTHER STARTED 506 00:25:02,920 --> 00:25:06,080 TO DEVELOP THE SAME KINDS OF 507 00:25:06,080 --> 00:25:06,760 LESIONS. 508 00:25:06,760 --> 00:25:09,680 SO AT THAT POINT THE PHYSICIANS 509 00:25:09,680 --> 00:25:11,840 CARING FOR THAT FAMILY REFERRED 510 00:25:11,840 --> 00:25:14,760 THE FAMILY TO DR. BRODERICK WHO 511 00:25:14,760 --> 00:25:16,120 DID EXOME SEQUENCING AND FOUND A 512 00:25:16,120 --> 00:25:17,800 GAIN OF FUNCTION OF WHAT LOOKED 513 00:25:17,800 --> 00:25:20,120 TO BE A GAIN OF FUNCTION 514 00:25:20,120 --> 00:25:21,400 MUTATION IN STAT 4. 515 00:25:21,400 --> 00:25:24,400 THE PROBLEM WAS SHE ONLY HAD THE 516 00:25:24,400 --> 00:25:27,360 ONE FAMILY AND SO SHE COULDN'T 517 00:25:27,360 --> 00:25:29,600 REALLY PUBLISH BECAUSE USUALLY 518 00:25:29,600 --> 00:25:37,800 YOU HAVE A CONFIRM TRY -- 519 00:25:37,800 --> 00:25:39,440 CONFIRMATORY FAMILY AND OUR 520 00:25:39,440 --> 00:25:41,800 GROUP COLLABORATING WITH THE 521 00:25:41,800 --> 00:25:44,160 UNIVERSITY OF PITTSBURGH HAD THE 522 00:25:44,160 --> 00:25:44,800 MISSING LINK. 523 00:25:44,800 --> 00:25:45,800 WE HAD ANOTHER FAMILY WHERE 524 00:25:45,800 --> 00:25:49,320 THERE WAS A CHILD WITH A DE NOVO 525 00:25:49,320 --> 00:25:54,360 MUTATION THAT ALSO HAD A SIMILAR 526 00:25:54,360 --> 00:25:56,680 PHENOTYPE AND THEN ACTUALLY BILL 527 00:25:56,680 --> 00:26:00,560 GAHL HAD A THIRD FAMILY. 528 00:26:00,560 --> 00:26:03,120 ALL OF A SUDDEN IT BECAME A MORE 529 00:26:03,120 --> 00:26:04,760 CONVINCING STORY. 530 00:26:04,760 --> 00:26:07,000 JOHN O'SHEA WAS ALSO IMPORTANT 531 00:26:07,000 --> 00:26:11,280 IN HELPING US THROUGH ALL THE 532 00:26:11,280 --> 00:26:14,320 SIGNALLING WITH STAT 4 AND HIS 533 00:26:14,320 --> 00:26:17,800 EXCELLENT POSTDOC RACHEL 534 00:26:17,800 --> 00:26:21,200 PHILLIPS AND THE OUTSTANDING 535 00:26:21,200 --> 00:26:24,200 Ph.D. STUDENT SARAH BLACKSTONE 536 00:26:24,200 --> 00:26:26,800 DOES THE FUNCTIONAL STUDYING AND 537 00:26:26,800 --> 00:26:37,360 HERE'S PHOTOS WITH PATIENT WITH 538 00:26:41,920 --> 00:26:44,400 PANSCLEROTIC MORPHEA AND THE AND 539 00:26:44,400 --> 00:26:46,440 THEN THE MUTATIONS. 540 00:26:46,440 --> 00:26:49,760 THEY'RE ALL IN THE SH2 DOMAIN 541 00:26:49,760 --> 00:26:53,120 WHICH IS AN IMPORTANT ACTIVATION 542 00:26:53,120 --> 00:26:54,600 DOMAIN OF STAT 4. 543 00:26:54,600 --> 00:26:56,200 IN ANY CASE, ONE OF THE FIRST 544 00:26:56,200 --> 00:26:59,040 THINGS THAT WE NEEDED TO DO WAS 545 00:26:59,040 --> 00:27:00,240 TO ACTUALLY DEMONSTRATE THESE 546 00:27:00,240 --> 00:27:04,120 ARE GAIN OF FUNCTION MUTATIONS 547 00:27:04,120 --> 00:27:09,240 AND THIS IMAGE JUST SHOWS 548 00:27:09,240 --> 00:27:10,760 COMPARING STAT 4 PHOSPHORYLATION 549 00:27:10,760 --> 00:27:12,160 BETWEEN THE WILD TYPE WHICH IS 550 00:27:12,160 --> 00:27:13,800 IN BLUE AND THE OTHER COLORS YOU 551 00:27:13,800 --> 00:27:16,120 CAN SEE THE OTHER COLORS ARE 552 00:27:16,120 --> 00:27:18,600 SHIFTED TO THE RIGHT AND THERE'S 553 00:27:18,600 --> 00:27:19,920 INCREASE PHOSPHORYLATION AUDIT 554 00:27:19,920 --> 00:27:21,640 IN THIS WAY AND THEN IF THE 555 00:27:21,640 --> 00:27:24,480 CELLS ARE STIMULATED THAT WAS 556 00:27:24,480 --> 00:27:24,800 UNSTIMULATED. 557 00:27:24,800 --> 00:27:27,960 IF THE CELLS ARE STIMULATED 558 00:27:27,960 --> 00:27:29,800 THERE'S PERSISTENT 559 00:27:29,800 --> 00:27:30,800 PHOSPHORYLATION COMPARED WITH 560 00:27:30,800 --> 00:27:33,000 THE WILD TYPE. 561 00:27:33,000 --> 00:27:36,920 LARRY BRODERICK ALSO DID AN 562 00:27:36,920 --> 00:27:42,640 ASSAY LOOKING AT WOUND HEALING 563 00:27:42,640 --> 00:27:45,800 IN VITRO AND IF YOU TAKE A 564 00:27:45,800 --> 00:27:49,000 FIBROBLAST WITH THE PIPETTE IT 565 00:27:49,000 --> 00:27:50,520 WILL GROW BACK AND YOU CAN 566 00:27:50,520 --> 00:27:54,760 MEASURE HOW LONG THAT TAKES. 567 00:27:54,760 --> 00:27:57,760 YOU CAN SEE FOR THE WILD TYPE 568 00:27:57,760 --> 00:28:00,960 THEY FROZE UP THE CUT AND CLOSES 569 00:28:00,960 --> 00:28:03,400 UP WITHIN ABOUT 24 HOURS FOR THE 570 00:28:03,400 --> 00:28:07,000 MUTATION IT'S STILL OPEN AT 24 571 00:28:07,000 --> 00:28:13,040 HOURS AND IF YOU LOOK AT THE 572 00:28:13,040 --> 00:28:17,240 CULTURES THERE'S A LOT OF IL6 573 00:28:17,240 --> 00:28:18,800 BEING RELEASED IN THE MUTATION 574 00:28:18,800 --> 00:28:22,720 AND IN FACT IF YOU LOOK AT THE 575 00:28:22,720 --> 00:28:26,920 WOUND HEALING IF YOU TAKE EITHER 576 00:28:26,920 --> 00:28:28,280 COMPARING THE WILD TYPE WITH THE 577 00:28:28,280 --> 00:28:30,200 MUTANT YOU CAN SEE THE MUTANT 578 00:28:30,200 --> 00:28:35,600 DOESN'T CLOSE UP BUT IF YOU ADD 579 00:28:35,600 --> 00:28:37,480 IL6 TO THE WILD TYPE IT GETS 580 00:28:37,480 --> 00:28:39,800 ALSO HAVING A PROBLEM WITH 581 00:28:39,800 --> 00:28:41,840 REGARD TO THE WOUND HEALING. 582 00:28:41,840 --> 00:28:44,520 IT APPEARS IL6 IS PLAYING AT 583 00:28:44,520 --> 00:28:46,840 LEAST SOME ROLE IN THAT. 584 00:28:46,840 --> 00:28:49,040 IT SUGGESTS A POSSIBLE POSITIVE 585 00:28:49,040 --> 00:28:52,160 FEEDBACK LOOP AND IL6 IS DOWN 586 00:28:52,160 --> 00:28:54,920 STREAM OF STAT 4 AND IL6 CAN BE 587 00:28:54,920 --> 00:28:57,680 PRODUCED AND FIBROBLASTS HAVE 588 00:28:57,680 --> 00:29:01,800 RECEPTORS THAT SIGNAL THROUGH 589 00:29:01,800 --> 00:29:03,480 STAT 4. 590 00:29:03,480 --> 00:29:06,040 AND THE KINASES ARE INVOLVED. 591 00:29:06,040 --> 00:29:07,920 USING A JACK INHIBITOR WOULD 592 00:29:07,920 --> 00:29:12,280 MAKE A CERTAIN AMOUNT OF SENSE 593 00:29:12,280 --> 00:29:19,760 AND ONE CAN SEE IN VITRO IT 594 00:29:19,760 --> 00:29:30,400 REDUCE THE IL6 USING THE 595 00:29:30,400 --> 00:29:33,800 RUXOLITINIB AND ONE CAN HELP THE 596 00:29:33,800 --> 00:29:44,320 MUTANT CELLS WITH THE RUXO 597 00:29:55,080 --> 00:29:56,080 RUXOLITNIB. 598 00:29:56,080 --> 00:29:57,240 THIS WAS PUBLISHED IN THE NEW 599 00:29:57,240 --> 00:29:58,200 ENGLAND JOURNAL OF MEDICINE 600 00:29:58,200 --> 00:30:07,320 ONLINE ONE WEEK AGO TODAY. 601 00:30:07,320 --> 00:30:08,440 IT'S NOT IN THE PRINT VERSION OF 602 00:30:08,440 --> 00:30:10,000 THE JOURNAL YES. 603 00:30:10,000 --> 00:30:12,480 IN ANY CASE THE TITLE OF THE 604 00:30:12,480 --> 00:30:15,240 TALK IS HIGH SOUNDING TITLE. 605 00:30:15,240 --> 00:30:17,880 AUTOINFLAMMATORY DISEASE AND THE 606 00:30:17,880 --> 00:30:26,760 HUMAN CONDITION. 607 00:30:26,760 --> 00:30:29,120 AND WHAT IN GENERAL CAN WE SAY 608 00:30:29,120 --> 00:30:30,280 ABOUT AUTOINFLAMMATORY DISEASE 609 00:30:30,280 --> 00:30:31,280 AND THE HUMAN CONDITION. 610 00:30:31,280 --> 00:30:34,040 EITHER YOU FORGOT THE QUESTION 611 00:30:34,040 --> 00:30:39,200 BY NOW OR JUST DYING TO KNOW. 612 00:30:39,200 --> 00:30:41,680 THE FIRST THING I CAN SAY IS WE 613 00:30:41,680 --> 00:30:45,480 LEARNED THAT MICROBIAL 614 00:30:45,480 --> 00:30:48,600 INFECTION, INNATE IMMUNE AND 615 00:30:48,600 --> 00:30:50,640 CELL BIOLOGY ARE INFERETRINSICA 616 00:30:50,640 --> 00:30:50,880 RELATED. 617 00:30:50,880 --> 00:30:53,040 ONE THING THAT CAME FROM THE 618 00:30:53,040 --> 00:30:54,600 STUDY OF THE DISEASES IS WE'VE 619 00:30:54,600 --> 00:30:57,080 SLOWLY BUT SURELY FIGURED OUT 620 00:30:57,080 --> 00:30:58,440 THE MECHANISM OF THE DISEASE 621 00:30:58,440 --> 00:30:59,800 MORE THAN JUST KNOWING SUCH AND 622 00:30:59,800 --> 00:31:01,960 SUCH A GENE HAS MUTATED. 623 00:31:01,960 --> 00:31:05,680 I'LL JUST SHOW YOU THIS ONE 624 00:31:05,680 --> 00:31:07,880 EXAMPLE OF FMF AND IT TOOK 625 00:31:07,880 --> 00:31:09,440 ALMOST 20 YEARS FROM THE TIME WE 626 00:31:09,440 --> 00:31:11,720 FOUND THE GENE TO THE TIME WE 627 00:31:11,720 --> 00:31:13,040 FIGURED OUT THE PATHWAY AND A 628 00:31:13,040 --> 00:31:14,400 NUMBER OF OTHER PEOPLE WERE 629 00:31:14,400 --> 00:31:17,560 INVOLVED IN THIS TOO. 630 00:31:17,560 --> 00:31:22,200 IN ANY EVENT THE STORY -- YOU 631 00:31:22,200 --> 00:31:25,640 MIGHT THINK THAT PYRIN, THE FMF 632 00:31:25,640 --> 00:31:26,920 PROTEIN IS A SENSOR FOR 633 00:31:26,920 --> 00:31:32,720 SOMETHING THAT'S A RECEPTOR FOR 634 00:31:32,720 --> 00:31:35,040 SOME SORT OF MICROBIAL PATHOGEN 635 00:31:35,040 --> 00:31:37,640 YOU'LL HAVE A DIAGRAM OR A 636 00:31:37,640 --> 00:31:38,920 PATHOGEN THAT BINDS TO PYRIN. 637 00:31:38,920 --> 00:31:40,640 THAT WAS THE MIND SET WE HAD AT 638 00:31:40,640 --> 00:31:41,040 THE BEGINNING. 639 00:31:41,040 --> 00:31:44,000 THAT WOULD BE THE WAY IT WOULD 640 00:31:44,000 --> 00:31:44,320 WORK. 641 00:31:44,320 --> 00:31:47,920 IT TURNED OUT THAT WAS WRONG. 642 00:31:47,920 --> 00:31:50,480 SO IN THIS FIGURE YOU CAN SEE 643 00:31:50,480 --> 00:31:52,840 JUST HERE THESE WILL TWO PYRIN 644 00:31:52,840 --> 00:31:56,760 MOLECULES THAT ARE BEGINNING TO 645 00:31:56,760 --> 00:31:59,400 FORM AN INFLAMMASOME AND THE 646 00:31:59,400 --> 00:32:03,840 REGULATION OF IT OCCURS IT 647 00:32:03,840 --> 00:32:06,680 STARTS HERE INSIDE THE MOLECULE 648 00:32:06,680 --> 00:32:07,400 WITH ROW A. 649 00:32:07,400 --> 00:32:15,800 IT'S THE GTP ACE THAT CAN 650 00:32:15,800 --> 00:32:17,800 CONNECT KINASES WHICH LEADS TO 651 00:32:17,800 --> 00:32:21,800 THE PHOSPHORYLATION OF PYRIN AND 652 00:32:21,800 --> 00:32:26,400 IT'S BOUND BY THE INHIBITOR 1433 653 00:32:26,400 --> 00:32:26,680 MOLECULES. 654 00:32:26,680 --> 00:32:28,440 IN THE NORMAL SITUATION WHERE 655 00:32:28,440 --> 00:32:33,000 YOU HAVE ALL THIS WORKING YOU 656 00:32:33,000 --> 00:32:36,840 HAVE BASICALLY A TONIC 657 00:32:36,840 --> 00:32:44,360 INHIBITION OF THE PYRIN 658 00:32:44,360 --> 00:32:47,080 INFLAMESOME AND THEY ARE TOXIN 659 00:32:47,080 --> 00:32:49,000 WILL DISRUPT ROW A AND WHEN THAT 660 00:32:49,000 --> 00:32:53,720 HAPPENS YOU DON'T GET 661 00:32:53,720 --> 00:32:56,320 PHOSPHORYLATION OF PYRIN AND CAN 662 00:32:56,320 --> 00:33:04,600 GET ACTIVATION OF THE IN FLAM 663 00:33:04,600 --> 00:33:07,040 -- INFLAMMASOME AND IT TURNS 664 00:33:07,040 --> 00:33:13,040 OUT CERTAIN BACTERIA MAKE TOXINS 665 00:33:13,040 --> 00:33:21,520 THAT INACTIVATE ROW A AND IS A 666 00:33:21,520 --> 00:33:32,080 KEY MOLECULE FOR THE ACTIN CY 667 00:33:33,760 --> 00:33:36,040 CYTOSKELETON AND IT'S IMPORTANT 668 00:33:36,040 --> 00:33:37,840 FOR MITOSIS AND DEGRANULATION 669 00:33:37,840 --> 00:33:41,840 AND THEY NEED A FUNCTIONING ROW 670 00:33:41,840 --> 00:33:50,720 A AND HAVE TOXINS THAT 671 00:33:50,720 --> 00:33:53,640 INACTIVATE ROW A AND THE PYRIN 672 00:33:53,640 --> 00:33:54,920 INFLAMMASOME IS THE EVOLUTIONARY 673 00:33:54,920 --> 00:33:55,680 RESPONSE TO THAT. 674 00:33:55,680 --> 00:34:01,040 THIS IS AN EXAMPLE OF WHERE THE 675 00:34:01,040 --> 00:34:02,720 INNATE IMMUNE SYSTEM WORKS 676 00:34:02,720 --> 00:34:06,920 INDIRECTLY AND HOSOFTEN IT'S 677 00:34:06,920 --> 00:34:09,840 SENSING CHANGES IN CELLULAR 678 00:34:09,840 --> 00:34:13,040 MOMENT YO STAVES. 679 00:34:13,040 --> 00:34:15,000 -- HOMEOSTASIS THAN BINDING TO A 680 00:34:15,000 --> 00:34:17,840 BACTERIAL OR VIRAL PRODUCT. 681 00:34:17,840 --> 00:34:24,000 IT'S AN INTERESTING THING. 682 00:34:24,000 --> 00:34:29,840 THIS IS A PHOTO OF A PATIENT IN 683 00:34:29,840 --> 00:34:35,600 THE PHOSPHORYLATION SITE AND 684 00:34:35,600 --> 00:34:41,840 HAVE CONTINUOUS AND HAVE A 685 00:34:41,840 --> 00:34:49,040 NEUTROPHILIC DERMATOSIS. 686 00:34:49,040 --> 00:34:49,840 WE HAVE A CAT AND MOUT 687 00:34:49,840 --> 00:35:00,080 RELATIONSHIP. 688 00:35:01,680 --> 00:35:05,640 HERE THIS STRAIN MAKES BUBONIC 689 00:35:05,640 --> 00:35:10,680 PLAGUE AND YOU SAY OKAY SO THE 690 00:35:10,680 --> 00:35:13,040 PYRIN INFLAMMASOME IS A DEFENSE 691 00:35:13,040 --> 00:35:14,440 AGAINST PLAGUE EXCEPT THAT 692 00:35:14,440 --> 00:35:17,840 PLAGUE HAS EVOLVED ANOTHER TOXIN 693 00:35:17,840 --> 00:35:23,120 GAP M THAT CAN PHOSPHORYLATE 694 00:35:23,120 --> 00:35:30,040 PYRIN AND HIJACKS SO THAT BLOCKS 695 00:35:30,040 --> 00:35:33,640 THE PYRIN INFLAMMASOME AND HAVE 696 00:35:33,640 --> 00:35:44,360 A BACK AND FORTH AND THEN AND 697 00:35:44,360 --> 00:35:46,440 YOU SEE THE PHOSPHORYLATION OF 698 00:35:46,440 --> 00:35:48,600 PYRIN IN HEALTHY INDIVIDUALS ON 699 00:35:48,600 --> 00:35:52,200 THE LEFT BUT IN INDIVIDUALS WITH 700 00:35:52,200 --> 00:35:55,040 FMF THEY ACTUALLY DON'T SEE 701 00:35:55,040 --> 00:35:56,280 INCREASED PHOSPHORYLATION OF 702 00:35:56,280 --> 00:35:57,680 THEIR PYRIN. 703 00:35:57,680 --> 00:36:03,840 THE CARRIER STATE FOR FMF IS A 704 00:36:03,840 --> 00:36:05,120 DEFENSE AGAINST PLAGUE. 705 00:36:05,120 --> 00:36:08,320 SO ONE WOULD THINK THEN THIS 706 00:36:08,320 --> 00:36:10,840 LEADS TO SELECTION FOR FMF 707 00:36:10,840 --> 00:36:13,840 MUTATIONS SO WE LOOKED IN THE 708 00:36:13,840 --> 00:36:15,280 TURKISH POPULATION TO SEE IF 709 00:36:15,280 --> 00:36:17,480 THERE WAS EVIDENCE FOR SELECTION 710 00:36:17,480 --> 00:36:20,880 OF FMF MUTATIONS. 711 00:36:20,880 --> 00:36:23,200 SO ONE OF THE TELLTALE SIGNS OF 712 00:36:23,200 --> 00:36:26,960 SELECTION IS IF YOU HAVE A VERY 713 00:36:26,960 --> 00:36:28,800 BIG HAPLOTYPE, A BIG DNA 714 00:36:28,800 --> 00:36:30,760 FINGERPRINT ASSOCIATED WITH THE 715 00:36:30,760 --> 00:36:31,040 MUTATION. 716 00:36:31,040 --> 00:36:35,280 YOU CAN SEE THE WIDTH OF THE 717 00:36:35,280 --> 00:36:36,240 BLUE PEAK HERE. 718 00:36:36,240 --> 00:36:39,040 THAT'S THE WIDTH OF HAPLOTYPES 719 00:36:39,040 --> 00:36:42,400 ASSOCIATED WITH THE FMF MUTATION 720 00:36:42,400 --> 00:36:45,120 WHEREAS THE ORANGE SORT OF 721 00:36:45,120 --> 00:36:47,680 NEEDLE POINT THERE IS THE WIDTH 722 00:36:47,680 --> 00:36:49,520 OF THE WILD TYPE ALLELE. 723 00:36:49,520 --> 00:36:52,880 THERE'S DEFINITELY A MUCH LARGER 724 00:36:52,880 --> 00:36:55,320 HAPLOTYPE ASSOCIATED AND IT'S ON 725 00:36:55,320 --> 00:36:57,840 THE TAIL OF THE BELL CURVE AND 726 00:36:57,840 --> 00:37:00,400 ONE CAN CALCULATE A SELECTION 727 00:37:00,400 --> 00:37:02,600 COEFFICIENT NOR MUTATION THAT 728 00:37:02,600 --> 00:37:06,040 TURNS OUT TO BE 0.077 WHICH IS 729 00:37:06,040 --> 00:37:09,120 HIGHER THAN THE SELECTION 730 00:37:09,120 --> 00:37:15,080 COEFFICIENT FOR LACTASE 731 00:37:15,080 --> 00:37:17,120 PERSISTENCE AND THE ABILITY TO 732 00:37:17,120 --> 00:37:19,920 DIGEST COW'S MILK AS AN ADULT IS 733 00:37:19,920 --> 00:37:21,000 THOUGHT TO BE IN SELECTION IN 734 00:37:21,000 --> 00:37:21,840 THE EUROPEAN POPULATION. 735 00:37:21,840 --> 00:37:23,360 TO SUM THIS UP AND MAYBE TO 736 00:37:23,360 --> 00:37:25,040 THINK A LITTLE BIT THEN ABOUT 737 00:37:25,040 --> 00:37:29,840 THE HUMAN CONDITION, WE HAVE 738 00:37:29,840 --> 00:37:33,800 THIS ORGANISM THAT LEADS TO THE 739 00:37:33,800 --> 00:37:36,360 PHOSPHORYLATION OF PYRIN AS A 740 00:37:36,360 --> 00:37:40,280 WAY OF SABOTAGING THE IMMUNE 741 00:37:40,280 --> 00:37:41,880 SYSTEM. 742 00:37:41,880 --> 00:37:52,480 HAVE A DISEASE FAMILIAL 743 00:37:52,480 --> 00:37:53,840 MEDITERRANEAN DISEASE AND 744 00:37:53,840 --> 00:38:00,560 THEY'RE PROTECTED AND YOU HAVE 745 00:38:00,560 --> 00:38:03,360 THE HUMANS AND PLAGUE WHEREBY WE 746 00:38:03,360 --> 00:38:05,840 GET RESISTANCE TO PLAGUE IN A 747 00:38:05,840 --> 00:38:09,640 LARGER PROPORTION OF THE 748 00:38:09,640 --> 00:38:12,880 POPULATION IN EXCHANGE FOR 749 00:38:12,880 --> 00:38:16,040 INDIVIDUALS DEVELOPING A 750 00:38:16,040 --> 00:38:16,760 POTENTIALLY LETHAL ILLNESS 751 00:38:16,760 --> 00:38:20,880 THAT'S LESS COMMON BECAUSE OF 752 00:38:20,880 --> 00:38:25,840 THE FACT IT'S A RECESSIVELY 753 00:38:25,840 --> 00:38:28,560 INHERE 754 00:38:28,560 --> 00:38:29,840 INHERENTED -- INHERITED DISEASE. 755 00:38:29,840 --> 00:38:31,360 ONE THING I THINK IS GROWING 756 00:38:31,360 --> 00:38:33,680 OLD. 757 00:38:33,680 --> 00:38:36,920 SO GROWING OLD AND THE RISK OF 758 00:38:36,920 --> 00:38:37,320 AUTOINFLAMMATION. 759 00:38:37,320 --> 00:38:39,720 THAT'S THE NEXT TOPIC HERE. 760 00:38:39,720 --> 00:38:41,600 IT HAS TO DO WITH THE HUMAN 761 00:38:41,600 --> 00:38:41,880 CONDITION. 762 00:38:41,880 --> 00:38:43,840 YOU KNOW IT'S BETTER TO GROW OLD 763 00:38:43,840 --> 00:38:45,040 THAN NOT TO GROW OLD. 764 00:38:45,040 --> 00:38:45,840 YOU HAVE TO THINK OF IT IN THAT 765 00:38:45,840 --> 00:38:49,880 WAY TOO. 766 00:38:49,880 --> 00:38:52,440 THIS IS THE WORK OF DAVID BECK 767 00:38:52,440 --> 00:38:56,800 WHO WAS AN EXCELLENT POSTDOC IN 768 00:38:56,800 --> 00:38:59,920 LAB NOW A JUNIOR FACULTY MEMBER 769 00:38:59,920 --> 00:39:03,480 AT NYU AND PETER GRAYSON A 770 00:39:03,480 --> 00:39:09,480 TENURE TRACK INVESTIGATOR IN 771 00:39:09,480 --> 00:39:13,080 NAIMS AND ANOTHER WHO IS A STAFF 772 00:39:13,080 --> 00:39:18,440 CLINICIAN IN MY GROUP. 773 00:39:18,440 --> 00:39:22,480 THEY FELT WE WERE NOT GOING FAST 774 00:39:22,480 --> 00:39:25,080 ENOUGH IN TERMS OF FINDING 775 00:39:25,080 --> 00:39:27,720 DISEASE GENES AND ONE SHOULD 776 00:39:27,720 --> 00:39:31,360 TAKE ANOTHER APPROACH THAN THE 777 00:39:31,360 --> 00:39:33,840 SORT OF STODGY OLD APPROACH OF 778 00:39:33,840 --> 00:39:34,440 PHENOTYPE FIRST. 779 00:39:34,440 --> 00:39:36,640 SO PHENOTYPE FIRST IS WHERE YOU 780 00:39:36,640 --> 00:39:38,480 GROUP TOGETHER A BUNCH OF 781 00:39:38,480 --> 00:39:39,040 PATIENTS THAT HAVE SOME 782 00:39:39,040 --> 00:39:41,040 PHENOTYPE IN COMMON AND THEN TLI 783 00:39:41,040 --> 00:39:44,120 TO FIND A GENE THAT EXPLAINS 784 00:39:44,120 --> 00:39:45,440 THAT PHENOTYPE. 785 00:39:45,440 --> 00:39:47,200 THAT'S TRIED AND TRUE WAY OF 786 00:39:47,200 --> 00:39:48,440 DOING IT. 787 00:39:48,440 --> 00:39:50,280 BUT THE GENOTYPE FIRST APPROACH 788 00:39:50,280 --> 00:39:51,960 INSTEAD IS THAT YOU COME UP WITH 789 00:39:51,960 --> 00:39:54,200 A LIST OF GENES THAT YOU'RE 790 00:39:54,200 --> 00:39:55,440 INTERESTED IN AND IN DAVID'S 791 00:39:55,440 --> 00:39:57,160 CASE HE WAS INTERESTED IN ALL OF 792 00:39:57,160 --> 00:40:00,840 THE GENES THAT HAVE ANYTHING TO 793 00:40:00,840 --> 00:40:11,240 DO WITH REGULATING YOU 794 00:40:19,960 --> 00:40:22,480 UBIQUI 795 00:40:22,480 --> 00:40:26,240 UBIQUITYLATION AND WE DISCOVERED 796 00:40:26,240 --> 00:40:28,240 GENES CAUSED BY THIS AND HE 797 00:40:28,240 --> 00:40:29,480 THOUGHT THIS WAS A GREAT LIST 798 00:40:29,480 --> 00:40:31,280 AND USED THE LIST OF 841 GENES 799 00:40:31,280 --> 00:40:37,080 TO INTERROGATE 477 EXOMES OR 800 00:40:37,080 --> 00:40:41,840 GENOMES AND 1,083 FROM THE 801 00:40:41,840 --> 00:40:52,400 UNDIAGNOSED DISEASES COHORT AND 802 00:40:55,720 --> 00:40:59,960 THEY'RE SHARED AMONGST CASES AND 803 00:40:59,960 --> 00:41:06,000 FOUND AFTER DOING THIS HERCULEAN 804 00:41:06,000 --> 00:41:09,200 FEAT HE FOUND THREE MIDDLE AGED 805 00:41:09,200 --> 00:41:12,040 MEN WHO SEEMED TO BE 806 00:41:12,040 --> 00:41:13,680 HETEROZYGOUS AT RESIDUE 41 OF 807 00:41:13,680 --> 00:41:15,120 THE UBA1 GENE. 808 00:41:15,120 --> 00:41:17,400 THAT SEEMED PRETTY GOOD ON THE 809 00:41:17,400 --> 00:41:19,800 FACE EXCEPT UBA1 IS LIKE THE 810 00:41:19,800 --> 00:41:25,080 GENE THAT ENCODES THE PROTEIN 811 00:41:25,080 --> 00:41:28,600 INVOLVED INITIATING ALL 812 00:41:28,600 --> 00:41:30,640 UBIQUITYLATION SO HOW CAN YOU 813 00:41:30,640 --> 00:41:32,040 LIVE WITH SERIOUS MUTATIONS IN 814 00:41:32,040 --> 00:41:32,680 THE GENE. 815 00:41:32,680 --> 00:41:34,440 THAT'S ONE PROBLEM. 816 00:41:34,440 --> 00:41:35,760 THEN THE REAL PROBLEM CAME AND 817 00:41:35,760 --> 00:41:41,120 THAT IS UBA1 IS ENCODED ON THE X 818 00:41:41,120 --> 00:41:45,840 CHROMOSOME AND THESE PATIENTS 819 00:41:45,840 --> 00:41:49,760 ARE MEN WHO ARE HETEROZYGOUS AND 820 00:41:49,760 --> 00:41:56,160 MEN ONLY HAVE USUALLY ONE X 821 00:41:56,160 --> 00:41:56,840 CHROMO 822 00:41:56,840 --> 00:41:57,160 CHROMOSOME. 823 00:41:57,160 --> 00:41:59,360 IS IT A SEQUENCING ERROR? 824 00:41:59,360 --> 00:42:01,040 HE CHECKED AND IT WASN'T AND I 825 00:42:01,040 --> 00:42:05,120 WON'T BE TELLING YOU IF IT WAS. 826 00:42:05,120 --> 00:42:08,320 THIS IS AN EXTRA X CHROMOSOME. 827 00:42:08,320 --> 00:42:11,640 WE CHECKED AND IT WASN'T THAT 828 00:42:11,640 --> 00:42:12,080 EITHER. 829 00:42:12,080 --> 00:42:14,200 COULD IT BE A SOMATIC MUTATION 830 00:42:14,200 --> 00:42:18,840 WHERE THE DNA WAS DERIVED FROM 831 00:42:18,840 --> 00:42:21,080 PERIPHERAL BLOOD LEUKOCYTES AND 832 00:42:21,080 --> 00:42:21,840 RATHER THAN ALL HAVING THE WILD 833 00:42:21,840 --> 00:42:24,280 TYPE AND MUTANT FORM, SOME WOULD 834 00:42:24,280 --> 00:42:26,600 HAVE THE WILD TYPE FORM AND SOME 835 00:42:26,600 --> 00:42:30,120 WOULD HAVE THE MUTANT FORM. 836 00:42:30,120 --> 00:42:31,840 THAT WAS THE IDEA. 837 00:42:31,840 --> 00:42:35,120 SO DAVID PROCEEDED TO TEST THAT 838 00:42:35,120 --> 00:42:37,720 HYPOTHESIS AND SURE ENOUGH HE 839 00:42:37,720 --> 00:42:38,560 WAS RIGHT. 840 00:42:38,560 --> 00:42:41,480 IF YOU LOOK AT THE NEUTROPHILS 841 00:42:41,480 --> 00:42:45,840 AND LEUKOCYTES AND THE MYELOID 842 00:42:45,840 --> 00:42:51,400 CELLS HAVE THIS RESIDUE AND 843 00:42:51,400 --> 00:42:53,120 LYMPHOCYTES AND T CELLS AND B 844 00:42:53,120 --> 00:42:53,840 CELLS DO NOT. 845 00:42:53,840 --> 00:42:55,480 THAT WAS NEAT WE FOUND EVIDENCE 846 00:42:55,480 --> 00:43:01,080 OF A SOMATIC MUTATION OF THE 847 00:43:01,080 --> 00:43:02,800 MIDDLE AGED MEN AND THEN COMES 848 00:43:02,800 --> 00:43:04,320 THE FACT STRANGER THAN FICTION. 849 00:43:04,320 --> 00:43:09,840 THAT IS THAT WE WASN'T TO SEE 850 00:43:09,840 --> 00:43:15,720 THE HEMATOPATHOLOGY SUITE AND 851 00:43:15,720 --> 00:43:17,840 BECAUSE HE'S THESE PATIENTS HAD 852 00:43:17,840 --> 00:43:21,840 A HEMATOLOGIC CONDITION WE 853 00:43:21,840 --> 00:43:24,120 LOOKED AT THE BONE MARROW AND 854 00:43:24,120 --> 00:43:34,640 THEY ALL HAD FUNNY LOOKING MACK 855 00:43:35,720 --> 00:43:38,560 -- MACULES AND WE CAME BACK 856 00:43:38,560 --> 00:43:40,600 LATER AND SHE PRESENTED ME WITH 857 00:43:40,600 --> 00:43:45,840 TWO REPORTS OF PATIENTS WITH THE 858 00:43:45,840 --> 00:43:55,720 VACUUM -- VACUOLES AND THEY HAD 859 00:43:55,720 --> 00:43:59,200 BONE MARROW FROM EIGHT YEARS 860 00:43:59,200 --> 00:44:01,120 BEFORE AND THEY HAD MYELOID 861 00:44:01,120 --> 00:44:02,800 RESTRICTIVE SOMATIC RESTRICTIONS 862 00:44:02,800 --> 00:44:03,120 AS WELL. 863 00:44:03,120 --> 00:44:07,120 THEY WERE MIDDLE-AGED MEN THAT 864 00:44:07,120 --> 00:44:11,960 APPEARED TO BE HETEROZYGOUS FOR 865 00:44:11,960 --> 00:44:16,360 IBA1 AND ONE HAD RELAPSE POLY 866 00:44:16,360 --> 00:44:26,440 C 867 00:44:28,040 --> 00:44:29,840 CONDRITIS AND BEFORE YOU KNOW IT 868 00:44:29,840 --> 00:44:33,600 WE HAD A COHORT OF 25 PATIENTS 869 00:44:33,600 --> 00:44:41,840 THAT ALL OF THEM WERE MEN WITH 870 00:44:41,840 --> 00:44:45,080 SOMEWHAT EXPLAINED FEVERS AND 871 00:44:45,080 --> 00:44:46,840 INFLAMMATION THAT HAD VARIOUS 872 00:44:46,840 --> 00:44:57,360 DIAGNOSES AND RELAPSING POLY 873 00:45:02,760 --> 00:45:06,440 CHONDRITIS AND BEING AFICIONADOS 874 00:45:06,440 --> 00:45:07,920 OF NAMING THINGS WE THOUGHT IT 875 00:45:07,920 --> 00:45:10,520 WAS A NAMING OPPORTUNITY AND WE 876 00:45:10,520 --> 00:45:13,840 THOUGHT IT SHOULD CONVEY WHAT'S 877 00:45:13,840 --> 00:45:16,600 GOING ON AND CALL IT VEXAS. 878 00:45:16,600 --> 00:45:21,560 IT STANDS FOR VACUOLES BECAUSE 879 00:45:21,560 --> 00:45:30,280 MOST HAVE VACUOLES AND 880 00:45:30,280 --> 00:45:31,960 UBIQUITIN-ACTIVATING ENZYME AND 881 00:45:31,960 --> 00:45:33,440 LINKED AND INFLAMMATORY AND 882 00:45:33,440 --> 00:45:37,840 SOMATIC AND IT WAS PUBLISHED IN 883 00:45:37,840 --> 00:45:40,960 THE CELEBRATORY NEW YEAR'S EVE 884 00:45:40,960 --> 00:45:41,840 EDITION OF THE NEW ENGLAND 885 00:45:41,840 --> 00:45:44,360 JOURNAL OF MEDICINE IN 2020. 886 00:45:44,360 --> 00:45:45,560 THEN WHAT HAPPENED IS IT TURNS 887 00:45:45,560 --> 00:45:49,040 OUT VEXAS IS MORE COMMON THAN 888 00:45:49,040 --> 00:45:51,760 WHAT WE EVER THOUGHT. 889 00:45:51,760 --> 00:45:53,840 SO DAVID IN COLLABORATION WITH 890 00:45:53,840 --> 00:45:55,920 DOUG STEWART AND THE CANCER 891 00:45:55,920 --> 00:45:58,560 INSTITUTE AND PEOPLE AT THE 892 00:45:58,560 --> 00:46:00,160 GEISINGER CLINIC IN EASTERN 893 00:46:00,160 --> 00:46:01,840 PENNSYLVANIA DID A 894 00:46:01,840 --> 00:46:02,840 POPULATION-BASED STUDY LOOKING 895 00:46:02,840 --> 00:46:04,400 AT THE FREQUENCY IN THEIR CLINIC 896 00:46:04,400 --> 00:46:09,200 AND IT TURNED OUT THERE WERE 12 897 00:46:09,200 --> 00:46:10,960 INDIVIDUALS WHO HAD BEEN GENOME 898 00:46:10,960 --> 00:46:14,120 SEQUENCED POSITIVE OUT OF 899 00:46:14,120 --> 00:46:14,520 163,000. 900 00:46:14,520 --> 00:46:16,760 THAT WORKS OUT TO BE IF YOU LOOK 901 00:46:16,760 --> 00:46:19,840 AT THE MAP 1 IN 4,000 MEN OVER 902 00:46:19,840 --> 00:46:21,960 THE AGE OF 50 WHICH IS QUITE A 903 00:46:21,960 --> 00:46:24,160 LOT. 904 00:46:24,160 --> 00:46:25,200 AN ESTIMATED POPULATION 905 00:46:25,200 --> 00:46:27,400 PREVALENCE OF 74 PER MILLION 906 00:46:27,400 --> 00:46:28,920 ACROSS AGE GROUPS AND MORE 907 00:46:28,920 --> 00:46:30,760 COMMON THAN A LOT OF THE 908 00:46:30,760 --> 00:46:33,440 DIAGNOSIS THAT WERE THE 909 00:46:33,440 --> 00:46:35,600 DIAGNOSES THESE PEOPLE HAD 910 00:46:35,600 --> 00:46:38,160 BEFORE AND EXTENDED THE CLINICAL 911 00:46:38,160 --> 00:46:39,320 PHENOTYPE TO OTHER THINGS AS 912 00:46:39,320 --> 00:46:39,680 WELL. 913 00:46:39,680 --> 00:46:41,840 IN ANY CASE WE'RE GETTING CLOSE 914 00:46:41,840 --> 00:46:43,880 ON TIME. 915 00:46:43,880 --> 00:46:45,200 FORTUNATELY WE'RE GETTING TO THE 916 00:46:45,200 --> 00:46:45,880 END THOUGH WHICH IS UNUSUAL FOR 917 00:46:45,880 --> 00:46:48,120 ME. 918 00:46:48,120 --> 00:46:52,280 SO IN ANY CASE THE LAST LITTLE 919 00:46:52,280 --> 00:46:54,160 VIGNETTE IS A STORY ABOUT COMMON 920 00:46:54,160 --> 00:46:55,040 GENETIC VARIANTS IN THE SPECTRUM 921 00:46:55,040 --> 00:47:00,120 OF DISEASE. 922 00:47:00,120 --> 00:47:01,800 SO THIS LITTLE SEGMENT ON THIS 923 00:47:01,800 --> 00:47:05,760 SLIDE WE LOOK AT IMAGES OF 924 00:47:05,760 --> 00:47:07,560 PATIENTS WITH THIS DISEASE AND 925 00:47:07,560 --> 00:47:10,840 THOSE NOT FAMILIAR IT'S ANOTHER 926 00:47:10,840 --> 00:47:12,440 DISEASE THAT IS SEEN IN THE 927 00:47:12,440 --> 00:47:13,520 MIDDLE EAST AND ACROSS ASIA AND 928 00:47:13,520 --> 00:47:17,160 CHINA AND JAPAN AND IT'S 929 00:47:17,160 --> 00:47:20,600 CHARACTERIZED BY THE TRIAD OF 930 00:47:20,600 --> 00:47:26,480 PAINFUL ULCERATIONS OCULAR 931 00:47:26,480 --> 00:47:30,480 INFLAMMATION AND GENITAL 932 00:47:30,480 --> 00:47:36,840 ULCERATIONS AND SOME DEVELOP 933 00:47:36,840 --> 00:47:38,400 POSTU LES IN THE SKIN. 934 00:47:38,400 --> 00:47:41,920 WE FOUND AT LEAST ONE MONOGENIC 935 00:47:41,920 --> 00:47:46,200 CONDITION THAT'S SORT OF LIKE 936 00:47:46,200 --> 00:47:48,680 THIS DISEASE BUT WE ALSO DONE A 937 00:47:48,680 --> 00:47:52,520 NUMBER OF GWAS STUDIES AND HAVE 938 00:47:52,520 --> 00:47:55,080 IDENTIFIED BESIDES HLAB51 WELL 939 00:47:55,080 --> 00:48:01,080 KNOWN AND 17 OTHER GENES WITH 940 00:48:01,080 --> 00:48:04,480 SUSCEPTIBILITY TO BEHCET'S 941 00:48:04,480 --> 00:48:07,520 DISEASE AND IT WAS CAREFULLY 942 00:48:07,520 --> 00:48:08,920 PHENOTYPED 1,000 PATIENTS AND 943 00:48:08,920 --> 00:48:09,280 CONTROLS. 944 00:48:09,280 --> 00:48:11,480 IT WAS A HUGE JOB. 945 00:48:11,480 --> 00:48:15,240 AND THEN AFTER WE HAD COMPLETED 946 00:48:15,240 --> 00:48:18,280 THAT WORK THE DIRECT TO CONSUMER 947 00:48:18,280 --> 00:48:21,840 COMPANY 23 AND ME CAME OUT WITH 948 00:48:21,840 --> 00:48:27,880 A GENOME WIDE ASSOCIATION STU 949 00:48:27,880 --> 00:48:31,400 STUDIES OF CANKER SOURCE AND 950 00:48:31,400 --> 00:48:33,640 ASKED DO YOU GET FREQUENT CANKER 951 00:48:33,640 --> 00:48:36,800 SORES YES OR SO AND DID A GOOD 952 00:48:36,800 --> 00:48:40,240 WAS AND THE SAME GENES WE FOUND 953 00:48:40,240 --> 00:48:45,240 IN BEHCET'S DISEASE ARE COMMON 954 00:48:45,240 --> 00:48:47,680 WITH CANKER SORES AND SOME ARE 955 00:48:47,680 --> 00:48:50,600 INTERESTING INTERLEUKIN 10 AND 956 00:48:50,600 --> 00:48:57,560 ALPHA AND STAT 4 AND CCR3. 957 00:48:57,560 --> 00:49:00,760 THEN WHAT HAPPENED IS A FELLOW 958 00:49:00,760 --> 00:49:04,760 IN MY LAB WAS STUDYING A 959 00:49:04,760 --> 00:49:08,120 CONDITION IN CHILDREN CALLED 960 00:49:08,120 --> 00:49:09,600 FAPA STANDING FOR PERIODIC 961 00:49:09,600 --> 00:49:13,080 FEVERS WITH PHARYNGITIS AND 962 00:49:13,080 --> 00:49:15,360 CERVICAL ADENOITIS AND THEY GET 963 00:49:15,360 --> 00:49:17,760 SORES IN THEIR MOUTH AND SORE 964 00:49:17,760 --> 00:49:24,520 THROWS AND SWELLING OF THE LYMPH 965 00:49:24,520 --> 00:49:27,040 GLANDS AND IT'S A GENETICALLY 966 00:49:27,040 --> 00:49:27,440 COMPLEX DISEASE. 967 00:49:27,440 --> 00:49:31,080 MOST KIDS GROW OUT OF IT AND 968 00:49:31,080 --> 00:49:33,480 BECAUSE IT'S IN BETWEEN THEY 969 00:49:33,480 --> 00:49:37,080 LOOKED TO SEE IF THE SAME GENES 970 00:49:37,080 --> 00:49:39,120 ARE ASSOCIATED WITH 971 00:49:39,120 --> 00:49:40,360 SUSCEPTIBILITY TO FABA AND THEY 972 00:49:40,360 --> 00:49:40,640 ARE. 973 00:49:40,640 --> 00:49:42,120 YOU HAVE THE SPECTRUM OF 974 00:49:42,120 --> 00:49:45,000 DISEASES ON THE ONE END IS 975 00:49:45,000 --> 00:49:49,440 SEVERE WITH BEHCET'S DISEASE AND 976 00:49:49,440 --> 00:49:56,600 THE OTHERS WITH RECURRENT ULCERS 977 00:49:56,600 --> 00:50:01,200 IN FABA AND SOME ARE PREDISPOSED 978 00:50:01,200 --> 00:50:04,360 TO IMMUNE OR INFLAMMATORY TYPES. 979 00:50:04,360 --> 00:50:09,720 THIS IS IT THE 30,000 FOOT VIEW 980 00:50:09,720 --> 00:50:12,160 AND THESE HAVE TAUGHT US HOW 981 00:50:12,160 --> 00:50:13,800 INNATE IMMUNITY WORKS AND 982 00:50:13,800 --> 00:50:15,760 TARGETED THERAPIES HAVE BEEN 983 00:50:15,760 --> 00:50:17,800 TRANSFORMATIVE WHILE VALIDATING 984 00:50:17,800 --> 00:50:20,120 OUR UNDERSTANDING OF THE 985 00:50:20,120 --> 00:50:21,200 UNDERLYING DISEASE AND THE 986 00:50:21,200 --> 00:50:22,120 IMMUNE SYSTEM MAY PROTECT 987 00:50:22,120 --> 00:50:27,360 AGAINST PATHOGENS BUT 988 00:50:27,360 --> 00:50:30,480 PREDISPOSED TO AUTOINFLAMMATION 989 00:50:30,480 --> 00:50:32,880 AND SOME ACCOUNT FOR EARLY ONSET 990 00:50:32,880 --> 00:50:33,800 OF AUTOINFLAMMATORY DISEASES AND 991 00:50:33,800 --> 00:50:36,680 THINK THERE'S MORE TO BE 992 00:50:36,680 --> 00:50:40,320 DISCOVERED AND GENETIC VARIANTS 993 00:50:40,320 --> 00:50:41,480 CONFER RISK FOR SOME 994 00:50:41,480 --> 00:50:43,080 AUTOINFLAMMATORY CONDITIONS AND 995 00:50:43,080 --> 00:50:43,360 PHENOTYPES. 996 00:50:43,360 --> 00:50:44,880 IN ANY CASE AT THIS POINT I'M 997 00:50:44,880 --> 00:50:45,480 WRAPPING UP. 998 00:50:45,480 --> 00:50:47,800 I WANT TO THANK MY COLLEAGUES IN 999 00:50:47,800 --> 00:50:51,240 THE LAB PICTURED HERE ARE 1000 00:50:51,240 --> 00:50:56,080 CURRENT COLLEAGUES IN THE LAB 1001 00:50:56,080 --> 00:51:02,440 AND IN PARTICULAR TWO 1002 00:51:02,440 --> 00:51:04,280 EXTRAORDINARILY COMPETENT STAFF 1003 00:51:04,280 --> 00:51:09,320 SCIENTISTS AND CERTAINLY A 1004 00:51:09,320 --> 00:51:11,280 NUMBER OF OTHERS TO BE MENTIONED 1005 00:51:11,280 --> 00:51:12,920 COLLEAGUES IN THE CLINIC AND 1006 00:51:12,920 --> 00:51:14,840 THIS IS VERY MUCH A PARTNERSHIP, 1007 00:51:14,840 --> 00:51:19,080 A COLLABORATION BETWEEN THE LAB 1008 00:51:19,080 --> 00:51:24,120 AND CLINIC, STAFF CLINICIANS AND 1009 00:51:24,120 --> 00:51:28,640 A NUMBER OF OTHER INDIVIDUALS AS 1010 00:51:28,640 --> 00:51:28,880 WELL. 1011 00:51:28,880 --> 00:51:30,800 QUITE A FEW COLLABORATORS AND 1012 00:51:30,800 --> 00:51:32,160 THESE ARE SOME OF THE MOST 1013 00:51:32,160 --> 00:51:32,720 RECENT ONES. 1014 00:51:32,720 --> 00:51:34,920 THEN OF COURSE OUR PATIENTS. 1015 00:51:34,920 --> 00:51:37,800 THIS HAPPENS TO BE THE 1016 00:51:37,800 --> 00:51:41,840 MEETING -- THE FIRST 1017 00:51:41,840 --> 00:51:44,120 INTERNATIONAL MEETING OF 1018 00:51:44,120 --> 00:51:49,760 PATIENTS OF ENDADA2 IN 2016 AND 1019 00:51:49,760 --> 00:51:52,960 THIS WORK WOULD NOT BE POSSIBLE 1020 00:51:52,960 --> 00:51:53,800 WITHOUT PATIENTS PLAYING A MAJOR 1021 00:51:53,800 --> 00:51:54,440 ROLE. 1022 00:51:54,440 --> 00:51:57,840 A NUMBER OF PEOPLE THATTED IN 1023 00:51:57,840 --> 00:51:59,840 VARIOUS WAYS TO MY CAREER VERY 1024 00:51:59,840 --> 00:52:03,280 BRIEFLY BOB RICH WHO WAS MY 1025 00:52:03,280 --> 00:52:05,360 GRADUATE SCHOOL ADVISER AND HALF 1026 00:52:05,360 --> 00:52:07,680 A CENTURY AGO NOW INTRODUCED ME 1027 00:52:07,680 --> 00:52:11,320 TO ALL THE FUN AND EXCITEMENT OF 1028 00:52:11,320 --> 00:52:14,160 IMMUNOLOGY SUCH AS IT WAS IN THE 1029 00:52:14,160 --> 00:52:15,880 1970s. 1030 00:52:15,880 --> 00:52:18,240 THE LATE FRED STEINBERG WHO 1031 00:52:18,240 --> 00:52:20,720 HIRED ME AS A CLINICAL FELLOW AT 1032 00:52:20,720 --> 00:52:23,160 THE NIH IN 1985. 1033 00:52:23,160 --> 00:52:28,760 PAUL PLOTS WHO WAS A ROLE MODEL 1034 00:52:28,760 --> 00:52:31,040 IN TERMS OF A PHYSICIAN 1035 00:52:31,040 --> 00:52:34,480 SCIENTIST AND THE LATE HARRY 1036 00:52:34,480 --> 00:52:36,160 METZKER AND I'LL NEVER FORGOT 1037 00:52:36,160 --> 00:52:37,840 THE WORDS HE SAID WHEN I STARTED 1038 00:52:37,840 --> 00:52:40,040 HE SAID, DAN, HERE'S SOME 1039 00:52:40,040 --> 00:52:40,280 RESOURCES. 1040 00:52:40,280 --> 00:52:43,800 JUST GO AND HAVE SOME FUN AND BE 1041 00:52:43,800 --> 00:52:46,400 SURE TO HAVE DATA READY IN 18 1042 00:52:46,400 --> 00:52:48,120 MONTHS WHEN YOU PRESENT TO THE 1043 00:52:48,120 --> 00:52:49,280 BOARD OF SCIENTIFIC COUNSELORS. 1044 00:52:49,280 --> 00:52:52,720 THAT WAS HENRY. 1045 00:52:52,720 --> 00:52:56,840 AND CERTAINLY I APPRECIATE THE 1046 00:52:56,840 --> 00:52:58,800 LATITUDE HE EXTENDED. 1047 00:52:58,800 --> 00:53:01,040 MY COLLABORATOR IN ISRAEL AND 1048 00:53:01,040 --> 00:53:02,800 MIKE DEAN OF THE CANCER 1049 00:53:02,800 --> 00:53:04,120 INSTITUTE WHO TAUGHT OUR GROUP 1050 00:53:04,120 --> 00:53:06,680 HOW TO DO OUR GENETICS AND 1051 00:53:06,680 --> 00:53:09,200 GENOMICS AT SCALE BEFORE THERE 1052 00:53:09,200 --> 00:53:11,200 WAS A GENOME INSTITUTE. 1053 00:53:11,200 --> 00:53:14,680 AND PAUL BUT WHO HAS BEEN A 1054 00:53:14,680 --> 00:53:15,840 SCIENTIFIC ADMINISTRATIVE 1055 00:53:15,840 --> 00:53:18,000 COLLABORATOR MANY YEARS. 1056 00:53:18,000 --> 00:53:25,240 THE LATE STEVE KAST THE DIRECTOR 1057 00:53:25,240 --> 00:53:32,680 OF NIAMS AND ERIC GREEN FOR 1058 00:53:32,680 --> 00:53:35,760 BEING A WONDERFUL BOSS AND 1059 00:53:35,760 --> 00:53:38,920 SCIENTIFIC AND PERSONAL 1060 00:53:38,920 --> 00:53:41,800 COLLABORATOR AS WELL AND THEN 1061 00:53:41,800 --> 00:53:44,040 MICHAEL GOTTESMAN HERE IN THE 1062 00:53:44,040 --> 00:53:45,200 FRONT ROW. 1063 00:53:45,200 --> 00:53:46,720 MICHAEL FOR THREE DECADES 1064 00:53:46,720 --> 00:53:49,880 CREATED A CULTURE HERE IN THE 1065 00:53:49,880 --> 00:53:54,200 INTRAMURAL PROGRAM. 1066 00:53:54,200 --> 00:53:56,920 WE TALK ABOUT HAVING A 1067 00:53:56,920 --> 00:54:00,720 SCIENTIFIC COMMUNITY IN WHICH WE 1068 00:54:00,720 --> 00:54:08,880 VALUE HIGH-RISK, HIGH-REWARD 1069 00:54:08,880 --> 00:54:12,320 VALUES AND HE INCULCATED THAT 1070 00:54:12,320 --> 00:54:13,800 INTO OUR COMMUNITY AND I THINK 1071 00:54:13,800 --> 00:54:16,840 WE OWE HIM ALL OF US OWE HIM A 1072 00:54:16,840 --> 00:54:23,200 DEBT OF GRATITUDE FOR THAT. 1073 00:54:23,200 --> 00:54:29,720 THEN FINALLY MY WIFE. 1074 00:54:29,720 --> 00:54:35,240 THIS IS OUR WEDDING BAY BACK IN 1075 00:54:35,240 --> 00:54:37,160 1985 WHEN WE WERE SETTING OUT ON 1076 00:54:37,160 --> 00:54:39,680 A BIG ADVENTURE IN BETHESDA AND 1077 00:54:39,680 --> 00:54:45,440 THEN IN SWEDEN WHEN I GOT THE 1078 00:54:45,440 --> 00:54:45,800 PRIZE. 1079 00:54:45,800 --> 00:54:50,760 SHE'S BEEN A SOURCE OF SUPPORT 1080 00:54:50,760 --> 00:54:53,840 AND STRENGTH AND A BEST FRIEND 1081 00:54:53,840 --> 00:54:55,080 OVER ALL THAT PERIOD OF TIME. 1082 00:54:55,080 --> 00:54:58,680 THEN FINALLY THE LAST SLIDE HERE 1083 00:54:58,680 --> 00:55:00,640 THE NIH CLINICAL CENTER WHICH 1084 00:55:00,640 --> 00:55:02,720 MADE THIS POSSIBLE, THREE 1085 00:55:02,720 --> 00:55:05,040 INSTITUTES THAT HAVE PLAYED A 1086 00:55:05,040 --> 00:55:08,720 MAJOR ROLE IN MY WORK AT THE 1087 00:55:08,720 --> 00:55:11,640 NIAMS I STARTED IN AND NGRI 1088 00:55:11,640 --> 00:55:13,840 WHERE I AM NOW AND THE NIAID 1089 00:55:13,840 --> 00:55:16,800 WHICH PROVIDED GREAT 1090 00:55:16,800 --> 00:55:18,680 COLLABORATION AND A NUMBER OF 1091 00:55:18,680 --> 00:55:19,960 CLINICAL TOPICS OVER THE LAST 1092 00:55:19,960 --> 00:55:20,600 COUPLE OF YEARS. 1093 00:55:20,600 --> 00:55:22,920 WITH THAT, I WILL CALL IT TO A 1094 00:55:22,920 --> 00:55:23,120 CLOSE. 1095 00:55:23,120 --> 00:55:25,080 I SEE WE HAVE ABOUT THREE AND A 1096 00:55:25,080 --> 00:55:26,440 HALF MINUTES FOR QUESTIONS. 1097 00:55:26,440 --> 00:55:28,400 I'LL TRY TO ANSWER YOUR 1098 00:55:28,400 --> 00:55:29,160 QUESTIONS. 1099 00:55:29,160 --> 00:55:31,400 >>HOW DO YOU EXPLAIN THE LATE 1100 00:55:31,400 --> 00:55:32,760 ONSET OF DISEASE IN THESE 1101 00:55:32,760 --> 00:55:34,440 PATIENTS IF THE MUTATION HAS 1102 00:55:34,440 --> 00:55:36,280 BEEN THERE FOR THE INDIVIDUAL'S 1103 00:55:36,280 --> 00:55:38,680 ENTIRE LIFE? 1104 00:55:38,680 --> 00:55:41,040 IS THERE A MISSING VARIABLE NOT 1105 00:55:41,040 --> 00:55:41,760 ACCOUNTED FOR? 1106 00:55:41,760 --> 00:55:43,600 >>FOR THOSE DISEASES WHERE 1107 00:55:43,600 --> 00:55:44,920 THERE ARE GERM LINE MUTATIONS 1108 00:55:44,920 --> 00:55:48,000 THAT'S A QUESTION THAT COMES UP. 1109 00:55:48,000 --> 00:55:49,600 CERTAINLY FOR A LOT OF THESE -- 1110 00:55:49,600 --> 00:55:51,080 THE DISEASES THAT I WAS TALKING 1111 00:55:51,080 --> 00:55:54,360 ABOUT THAT ARE THE MONOGENIC 1112 00:55:54,360 --> 00:55:57,240 DISEASES, THEY PRESENT BY 1113 00:55:57,240 --> 00:55:57,640 ADULTHOOD ANYWAY. 1114 00:55:57,640 --> 00:55:59,120 IT'S NOT AS IF PEOPLE ARE GOING 1115 00:55:59,120 --> 00:56:02,160 FOR A LONG LONG TIME BUT IT'S 1116 00:56:02,160 --> 00:56:08,760 STILL A POINT WELL TAKEN THAT WE 1117 00:56:08,760 --> 00:56:09,880 DO NOT UNDERSTAND THE MECHANISMS 1118 00:56:09,880 --> 00:56:12,160 OF THESE DISEASES. 1119 00:56:12,160 --> 00:56:16,440 WE TRIED MAKING MOUSE MODELS AND 1120 00:56:16,440 --> 00:56:20,840 WITH FAMILIAL MEDITERRANEAN 1121 00:56:20,840 --> 00:56:23,760 FEVER WHICH WE DID MAKE AND THEY 1122 00:56:23,760 --> 00:56:26,200 HAVE CONTINUOUS INFLAMMATION 1123 00:56:26,200 --> 00:56:27,200 RATHER THAN EPISODIC. 1124 00:56:27,200 --> 00:56:31,680 THE PRECLUDED US LOOKING FOR 1125 00:56:31,680 --> 00:56:32,520 PROVOCATIVE FACTORS AND THE 1126 00:56:32,520 --> 00:56:33,640 INTERESTING THING WAS WE DID 1127 00:56:33,640 --> 00:56:38,040 THREE DIFFERENT MUTATIONS OF 1128 00:56:38,040 --> 00:56:39,280 DIFFERENT SEVERITY IN HUMANS. 1129 00:56:39,280 --> 00:56:40,160 THERE'S A DIFFERENT SEVERITY IN 1130 00:56:40,160 --> 00:56:41,320 MICE BUT OPPOSITE. 1131 00:56:41,320 --> 00:56:44,240 THE MOST SEVERE IN THE HUMAN IS 1132 00:56:44,240 --> 00:56:46,960 THE LEAST SEVERE IN THE MOUSE 1133 00:56:46,960 --> 00:56:50,360 WHICH IS I GUESS ANOTHER 1134 00:56:50,360 --> 00:56:50,960 DEMONSTRATION WE ARE NOT MICE. 1135 00:56:50,960 --> 00:56:52,920 >>GOOD TO CLARIFY THAT. 1136 00:56:52,920 --> 00:56:56,880 ANOTHER ONE, DR. KASTNER ALWAYS 1137 00:56:56,880 --> 00:56:59,320 A FASCINATING TALK! 1138 00:56:59,320 --> 00:57:00,000 . 1139 00:57:00,000 --> 00:57:04,080 COULD YOU SHARE THOUGHTS ON 1140 00:57:04,080 --> 00:57:06,800 SECONDARY GERM LINE DUE TO 1141 00:57:06,800 --> 00:57:08,960 UNCONTROLLED AUTOIMMUNE DISEASE. 1142 00:57:08,960 --> 00:57:12,320 MORE SPECIFICALLY CAN EPIGENETIC 1143 00:57:12,320 --> 00:57:13,680 CHANGES FROM CHRONIC 1144 00:57:13,680 --> 00:57:15,040 INFLAMMATION MAKE IT LOOK LIKE 1145 00:57:15,040 --> 00:57:16,880 THE NEW ONSET OF INFLAMMATORY 1146 00:57:16,880 --> 00:57:17,160 DISEASE. 1147 00:57:17,160 --> 00:57:19,360 ANY CONNECTION TO MITOCHONDRIAL 1148 00:57:19,360 --> 00:57:21,720 DYSFUNCTION IN THAT SENSE? 1149 00:57:21,720 --> 00:57:24,600 >>ALL EXCELLENT IDEAS. 1150 00:57:24,600 --> 00:57:27,240 WE HAVE NOT TESTED THOSE 1151 00:57:27,240 --> 00:57:28,760 HYPOTHESES BUT CERTAINLY THE 1152 00:57:28,760 --> 00:57:30,400 QUESTION IS CORRECT THAT THERE 1153 00:57:30,400 --> 00:57:32,120 IS VERY MUCH AN INTERACTION 1154 00:57:32,120 --> 00:57:34,440 BETWEEN THE ADAPTIVE AND THE 1155 00:57:34,440 --> 00:57:36,640 INNATE IMMUNE SYSTEM. 1156 00:57:36,640 --> 00:57:39,720 ONE WOULD EXPECT IF SOMEONE HAS 1157 00:57:39,720 --> 00:57:42,440 GERM LINE MUTATION OR 1158 00:57:42,440 --> 00:57:44,640 SUSCEPTIBLE VARIANTS FROM ONE 1159 00:57:44,640 --> 00:57:45,960 SIDE OR THE OTHER ONE COULD 1160 00:57:45,960 --> 00:57:49,760 IMAGINE OVER TIME ONE COULD GET 1161 00:57:49,760 --> 00:57:50,400 SECONDARY EFFECTS THAT WOULD 1162 00:57:50,400 --> 00:57:51,720 BLEED OVER TO THE OTHER DOMAIN 1163 00:57:51,720 --> 00:57:55,040 OF THE IMMUNE SYSTEM. 1164 00:57:55,040 --> 00:57:57,680 I'LL WRAP UP WITH THREE POINTS, 1165 00:57:57,680 --> 00:58:00,520 CME CODE I THINK WAS 44460. 1166 00:58:00,520 --> 00:58:04,160 THERE WILL BE A RECEPTION 1167 00:58:04,160 --> 00:58:06,280 OUTSIDE FOR PEOPLE HERE AND I'M 1168 00:58:06,280 --> 00:58:07,640 PRETTY SURE THE HISTORY OFFICE 1169 00:58:07,640 --> 00:58:10,120 WOULD LOVE A COPY OF THE HAND 1170 00:58:10,120 --> 00:58:13,120 WRITTEN LETTER SOME DAY SHOULD 1171 00:58:13,120 --> 00:58:14,240 YOU WANT TO GIVE IT TO THEM. 1172 00:58:14,240 --> 00:00:00,000 >>THANK YOU.