1 00:00:05,920 --> 00:00:10,720 WANTED TO START WITH A FEW 2 00:00:10,720 --> 00:00:14,800 HOUSEKEEPING ITEMS. I'M JANICE 3 00:00:14,800 --> 00:00:18,080 LEE AND CLINICAL DIRECTOR FOR 4 00:00:18,080 --> 00:00:19,800 NIDCR. MAKING NOTE THERE WILL 5 00:00:19,800 --> 00:00:23,360 BE A 15 MINUTE COFFEE BREAK AND 6 00:00:23,360 --> 00:00:27,080 VISUAL HISTORY WITH POSTERS ON 7 00:00:27,080 --> 00:00:28,800 FAES TERRACE AND NOTE THERE WERE 8 00:00:28,800 --> 00:00:34,840 NO NIDCR APPROPRIATED FUNDS USED 9 00:00:34,840 --> 00:00:40,760 FOR RECEPTION. I HAD TO SAY 10 00:00:40,760 --> 00:00:43,040 THAT. BREAK IS AT 10:45. 11 00:00:43,040 --> 00:00:48,000 WELCOME TO THE NIDCR CELEBRATION 12 00:00:48,000 --> 00:00:51,080 OF 25 YEARS OF RESEARCH HERE AT 13 00:00:51,080 --> 00:00:55,880 THE NIH THAT COINCIDES WITH 75TH 14 00:00:55,880 --> 00:00:58,800 ANNIVERSARY WITH NIDCR AS AN 15 00:00:58,800 --> 00:01:01,040 INSTITUTE AND THE SYMPOSIUM IS 16 00:01:01,040 --> 00:01:04,480 ONE OF SPECIAL EVENTS FOR OUR 17 00:01:04,480 --> 00:01:06,240 YEAR-LONG CELEBRATION AND IS 18 00:01:06,240 --> 00:01:07,720 SEPTEMBER ELEVENTH AND 19 00:01:07,720 --> 00:01:09,000 ACKNOWLEDGING THE TRAGEDY OF 20 00:01:09,000 --> 00:01:11,840 THAT DAY NOW 22 YEARS AGO. WE 21 00:01:11,840 --> 00:01:15,000 WILL NOT FORGET. MUCH HAS 22 00:01:15,000 --> 00:01:17,360 CHANGED SINCE THAT TIME. TODAY, 23 00:01:17,360 --> 00:01:20,200 MUCH HAS CHANGED IN 24 00:01:20,200 --> 00:01:23,240 UNDERSTANDING OF FIBRO DYSPLASIA 25 00:01:23,240 --> 00:01:25,400 AND [INDISCERNIBLE] BECAUSE OF 26 00:01:25,400 --> 00:01:27,680 THE TREMENDOUS RESEARCH AND 27 00:01:27,680 --> 00:01:28,720 DISCOVERIES THAT OCCURRED HERE 28 00:01:28,720 --> 00:01:31,720 AT NIH THAT YOU WILL HEAR ABOUT 29 00:01:31,720 --> 00:01:34,600 THROUGH THE LINEUP OF SPEAKERS 30 00:01:34,600 --> 00:01:37,160 TODAY. THE INDIVIDUALS 31 00:01:37,160 --> 00:01:39,560 PERSONIFY JOURNEY OF EARLY 32 00:01:39,560 --> 00:01:42,280 DISCOVERIES OF GENETIC MUTATIONS 33 00:01:42,280 --> 00:01:44,440 AND MECHANISTIC UNDERSTANDING OF 34 00:01:44,440 --> 00:01:47,320 THIS DISEASE AND TREATMENTS 35 00:01:47,320 --> 00:01:48,280 BEING STUDIED. 36 00:01:48,280 --> 00:01:50,560 IT IS THROUGH A COLLABORATIVE 37 00:01:50,560 --> 00:01:53,640 EFFORT AND SPIRIT THAT A COMMON 38 00:01:53,640 --> 00:01:56,280 THEME IS WOVEN INTO OUR STORY 39 00:01:56,280 --> 00:01:59,680 YOU WILL HEAR FROM NIDCR 40 00:01:59,680 --> 00:02:02,000 INVESTIGATORS AND OTHER IC 41 00:02:02,000 --> 00:02:03,480 INVESTIGATORS AS WELL AS 42 00:02:03,480 --> 00:02:04,560 INTERNATIONAL COLLEAGUES WHO 43 00:02:04,560 --> 00:02:07,400 CONTINUE TO TACKLE THIS DISEASE. 44 00:02:07,400 --> 00:02:08,840 MOST IMPORTANTLY YOU WILL HEAR 45 00:02:08,840 --> 00:02:11,160 FROM PATIENTS WHO ARE AT THE 46 00:02:11,160 --> 00:02:13,680 CENTER OF OUR RESEARCH AND 47 00:02:13,680 --> 00:02:16,080 ADVOCACY GROUPS BRINGING 48 00:02:16,080 --> 00:02:17,720 AWARENESS TO THIS DISEASE. 49 00:02:17,720 --> 00:02:22,400 AND TO THE RESEARCH THAT IS 50 00:02:22,400 --> 00:02:24,720 HELPING US TREAT AND CURE FOR 51 00:02:24,720 --> 00:02:25,040 PATIENTS. 52 00:02:25,040 --> 00:02:29,480 FIRST SPEAKER TODAY, DR. ALLEN 53 00:02:29,480 --> 00:02:31,840 SPIEGEL WHO IS DEAN AND 54 00:02:31,840 --> 00:02:33,680 PROFESSOR AT ALBERT EINSTEIN 55 00:02:33,680 --> 00:02:36,160 COLLEGE OF MEDICINE IN NEW YORK 56 00:02:36,160 --> 00:02:39,240 AND IS ACTUALLY THE DEAN 57 00:02:39,240 --> 00:02:41,040 EMERITUS AND PLEASED TO WELCOME 58 00:02:41,040 --> 00:02:44,640 HIM BACK AT NIH. HE BEGAN HIS 59 00:02:44,640 --> 00:02:47,280 CAREER AT NIH IN 1973 AS A 60 00:02:47,280 --> 00:02:49,760 CLINICAL ASSOCIATE IN THE 61 00:02:49,760 --> 00:02:51,520 ENDOCRINOLOGY PROGRAM AND WORKED 62 00:02:51,520 --> 00:02:54,080 WAY THROUGH RANKS OF NIH AS 63 00:02:54,080 --> 00:02:57,800 SENIOR INVESTIGATOR, BRANCH 64 00:02:57,800 --> 00:03:00,360 CHIEF AND SCIENTIFIC DIRECTOR OF 65 00:03:00,360 --> 00:03:03,360 NIDD INTRA MURAL PROGRAM AND 66 00:03:03,360 --> 00:03:07,400 BECAME DIRECTOR OF NIDDK IN 67 00:03:07,400 --> 00:03:09,000 1999. PROGRESSION SEEMS NATURAL 68 00:03:09,000 --> 00:03:11,280 BUT DOESN'T HAPPEN TO ALL OF US. 69 00:03:11,280 --> 00:03:14,160 HE BECAME THE DEAN OF ALBERT 70 00:03:14,160 --> 00:03:16,640 EINSTEIN COLLEGE OF MEDICINE IN 71 00:03:16,640 --> 00:03:21,200 2006. DR. SPOOEG ELIS A WORLD 72 00:03:21,200 --> 00:03:24,480 RENOWNED SCIENTIST WHOSE WORK ON 73 00:03:24,480 --> 00:03:26,920 DISCOVERY OF GS VARIANTS AND 74 00:03:26,920 --> 00:03:30,000 SYNDROME WAS PUBLISHED IN NEW 75 00:03:30,000 --> 00:03:33,400 ENGLAND JOURNAL IN 1991. DR. 76 00:03:33,400 --> 00:03:36,800 SPIEGEL, PLEASE DO US THE HONOR 77 00:03:36,800 --> 00:03:40,280 TO START OUR JOURNEY. 78 00:03:40,280 --> 00:03:40,840 >> AUDIENCE: [APPLAUSE]. 79 00:03:40,840 --> 00:03:46,200 >> DR. LEE, COLLEAGUES, 80 00:03:46,200 --> 00:03:49,440 DISTINGUISHED GUESTS, PATIENTS, 81 00:03:49,440 --> 00:03:52,440 MEMBERS OF PATIENT ADVOCACY 82 00:03:52,440 --> 00:03:54,280 ORGANIZATION. IT IS A PRIVILEGE 83 00:03:54,280 --> 00:03:57,160 TO SPEAK IN THIS SYMPOSIUM. I'M 84 00:03:57,160 --> 00:03:58,760 ASKED TO DESCRIBE THE HISTORY OF 85 00:03:58,760 --> 00:04:03,760 THE DISCOVERY OF GS ALFALFA 86 00:04:03,760 --> 00:04:09,720 VARIANTS AS CAUSE OF FIBROUS 87 00:04:09,720 --> 00:04:10,400 DYSPLASIA WE WILL REFER TO 88 00:04:10,400 --> 00:04:14,000 FIBROUS DISPLACE YUSH/ACUTE 89 00:04:14,000 --> 00:04:16,200 SYNDROME. YOU WILL SEE WHY. I 90 00:04:16,200 --> 00:04:18,440 WILL DESCRIBING THAT HISTORY 91 00:04:18,440 --> 00:04:20,200 PROVIDE A HISTORICAL PERSPECTIVE 92 00:04:20,200 --> 00:04:25,200 AND ANCIENT HISTORY IN SOME 93 00:04:25,200 --> 00:04:25,440 SENSE. 94 00:04:25,440 --> 00:04:27,520 I HOPE YOU WILL BEAR WITH ME. I 95 00:04:27,520 --> 00:04:30,560 WILL BE SOMEWHAT SELF-INDULGENT 96 00:04:30,560 --> 00:04:32,840 IN DESCRIBING MY PERSONAL 97 00:04:32,840 --> 00:04:35,520 TRAJECTORY AS AN INVESTIGATOR 98 00:04:35,520 --> 00:04:37,360 INTERESTED IN MECHANISM OF 99 00:04:37,360 --> 00:04:38,440 HORMONE ACTION REALLY SINCE 100 00:04:38,440 --> 00:04:40,160 WORKING AS AN UNDERGRADUATE IN 101 00:04:40,160 --> 00:04:44,800 THE LABORATORY OF THE LATE MARK 102 00:04:44,800 --> 00:04:46,720 BOTENSKY WHO EMERGED AS A 103 00:04:46,720 --> 00:04:49,280 RESEARCH ASSOCIATE FROM NIH 104 00:04:49,280 --> 00:04:51,680 INTRAMURAL PROGRAM SETTING UP 105 00:04:51,680 --> 00:04:54,720 HIS LAB AT NYU. HE INTRODUCED 106 00:04:54,720 --> 00:04:56,880 ME TO THE SECOND MESSENGER 107 00:04:56,880 --> 00:04:59,720 SYSTEM ABOUT HORMONES AS FIRST 108 00:04:59,720 --> 00:05:03,640 MESSENGERS. IN THIS CASE ADENO 109 00:05:03,640 --> 00:05:07,040 CYCLASE GENERATING FROM ATP AND 110 00:05:07,040 --> 00:05:08,600 SO-CALLED SECOND MESSENGER AND 111 00:05:08,600 --> 00:05:13,080 WORKING ON THIS SYSTEM AS AN 112 00:05:13,080 --> 00:05:18,240 UNDERGRADUATE THIS WAS AN AREA 113 00:05:18,240 --> 00:05:22,800 PYRON EARED BY EARL SUJERLAND 114 00:05:22,800 --> 00:05:26,200 WHOSE GROUP RECEIVED THE NOBLE 115 00:05:26,200 --> 00:05:29,680 PRIZE IN 1991. HE CAME TO GIVE 116 00:05:29,680 --> 00:05:35,080 A SEMINAR AND ATTENDED BUT 117 00:05:35,080 --> 00:05:39,760 NUMBER OF NIH INTRAMURAL 118 00:05:39,760 --> 00:05:41,600 INVESTIGATORS. ONE, MARTY 119 00:05:41,600 --> 00:05:42,720 RODBELL WAS THE PERSON 120 00:05:42,720 --> 00:05:46,120 RESPONSIBLE FOR SHOWING ABSOLUTE 121 00:05:46,120 --> 00:05:48,360 DEPENDENCE ON HORMONE 122 00:05:48,360 --> 00:05:52,600 STIMULATION ON CYCLIC AMP ON 123 00:05:52,600 --> 00:05:55,080 GUANINE NUCLEOTIDES SOMETHING 124 00:05:55,080 --> 00:06:05,640 THAT UNTIL HIS DISCOVERY ELUDED 125 00:06:06,280 --> 00:06:09,440 -- RODBELL AND HIS ASSOCIATES 126 00:06:09,440 --> 00:06:11,920 THEREFORE PUT G-PROTEINS AND 127 00:06:11,920 --> 00:06:15,520 EVENTUALLY WE WILL SEE 128 00:06:15,520 --> 00:06:16,240 G-PROTEIN-COUPLED-RECEPTORS ON 129 00:06:16,240 --> 00:06:18,840 THE MAP AND FOR THIS WORK 130 00:06:18,840 --> 00:06:21,960 RODBELL SHARED THE NOBLE PRIZE 131 00:06:21,960 --> 00:06:25,360 IN 1994. 132 00:06:25,360 --> 00:06:29,200 I WAS FORTUNATE TO COME TO THE 133 00:06:29,200 --> 00:06:32,840 LAB OF R BACH IN 1973 AT NIH. 134 00:06:32,840 --> 00:06:35,040 THIS WAS MY OPPORTUNITY TO 135 00:06:35,040 --> 00:06:38,480 BECOME AN ENDOCRINOLOGIST THAT 136 00:06:38,480 --> 00:06:42,440 IS PARADIGMATIC BENCH TO BEDSIDE 137 00:06:42,440 --> 00:06:45,200 AND BACK MEDICAL SUBSPECIALTY. 138 00:06:45,200 --> 00:06:47,680 I HAD TO TESTIFY IN CONGRESS ON 139 00:06:47,680 --> 00:06:52,240 BEHALF OF NIH APROPRIATION. 140 00:06:52,240 --> 00:06:55,920 RALPH REPUBLICAN OF OHIO WAS 141 00:06:55,920 --> 00:06:59,040 CHAIR OF THE ANIH APROBE RATION 142 00:06:59,040 --> 00:07:02,160 COMMITTEE WE HAD THEME BENCH TO 143 00:07:02,160 --> 00:07:03,840 BEDSIDE HE MISREAD AND SAID 144 00:07:03,840 --> 00:07:06,320 BEACH TO BEDSIDE. THAT VAGUE 145 00:07:06,320 --> 00:07:10,080 ARY IS TESTIFYING IN CONFR 146 00:07:10,080 --> 00:07:13,080 GREYS. R BACH HAD NUMBER OF 147 00:07:13,080 --> 00:07:16,720 ACCOMPLISHMENTS IN NIH 148 00:07:16,720 --> 00:07:19,720 INTRAMURAL PROGRAM AND GAVE 149 00:07:19,720 --> 00:07:23,760 FURTHER OPPORTUNITIES TO PURSUE 150 00:07:23,760 --> 00:07:25,680 HORMONE MECHANISM TRANSLATION IN 151 00:07:25,680 --> 00:07:27,440 A TRANSLATIONAL WAY AND FROM 152 00:07:27,440 --> 00:07:30,200 THIS WORK WE EVOLVED CONCEPT OF 153 00:07:30,200 --> 00:07:33,520 INBORN ERRORS OF SIGNAL 154 00:07:33,520 --> 00:07:36,640 TRANSDUCTION. WE ARE STEALING 155 00:07:36,640 --> 00:07:38,920 THE TERMINOLOGY OF 156 00:07:38,920 --> 00:07:41,040 [INDISCERNIBLE] WHERE A GENETIC 157 00:07:41,040 --> 00:07:44,440 DEFECT LEADING TO ENZYME 158 00:07:44,440 --> 00:07:45,840 DEFICIENCY CAUSES DISEASE 159 00:07:45,840 --> 00:07:51,640 THROUGH BUILDUP OF SUBSTRATE 160 00:07:51,640 --> 00:07:57,400 FETAL KINNURIA OR -- LOSS OF 161 00:07:57,400 --> 00:07:59,560 FUNCTION MUTATION IN SOME 162 00:07:59,560 --> 00:08:01,720 SIGNALING COMPONENT AND THIS 163 00:08:01,720 --> 00:08:04,560 WOULD LEAD TO HORMONE RESISTANCE 164 00:08:04,560 --> 00:08:08,680 BECAUSE OF THE HOMEO STATIC 165 00:08:08,680 --> 00:08:10,600 FEEDBACK STIMULATING HORMONE 166 00:08:10,600 --> 00:08:14,360 WOULD BE HIGH DETECTED BY RADIO 167 00:08:14,360 --> 00:08:17,320 ASSAY AND HORMONE WAS DEFICIENT 168 00:08:17,320 --> 00:08:21,200 IN HORMONE RESPONSE. INBORN 169 00:08:21,200 --> 00:08:23,440 ERRORS OF METABOLISMIN BORN 170 00:08:23,440 --> 00:08:26,480 ERRORS OF SIGNAL TRANSDUCTION 171 00:08:26,480 --> 00:08:29,520 COULD HAVE OPPOSITE TYPE GAIN OF 172 00:08:29,520 --> 00:08:35,320 A SINGLE COMPONENT HYPERWHATEVER 173 00:08:35,320 --> 00:08:42,760 THE ENDOCRINE FUNCTION IS AND 174 00:08:42,760 --> 00:08:44,240 FEEDBACK A DEPRESSION OF 175 00:08:44,240 --> 00:08:47,040 STIMULUS HORMONE AND ELUDED TO A 176 00:08:47,040 --> 00:08:48,680 COLLEAGUE THAT IS FROM HARVARD 177 00:08:48,680 --> 00:08:50,360 MEDICAL SCHOOL TO THE FACT I 178 00:08:50,360 --> 00:08:53,240 WOULD SHOW A SLIDE PICTURING IN 179 00:08:53,240 --> 00:08:57,160 THIS CASE ANCIENT BULL FINCH 180 00:08:57,160 --> 00:08:58,760 BUILDING AT MASS GENERAL 181 00:08:58,760 --> 00:09:00,160 HOSPITAL SPENDING MANY SLEEPLESS 182 00:09:00,160 --> 00:09:03,000 NIGHTS AS AN INTERN AND 183 00:09:03,000 --> 00:09:04,320 RESIDENT. BULL FINCH BUILDING 184 00:09:04,320 --> 00:09:07,840 WAS THE SITE OF WORK OF FULLER 185 00:09:07,840 --> 00:09:11,160 ALBRIGHT ONE OF THE GIANTS OF 186 00:09:11,160 --> 00:09:13,840 ENDOCRINOLOGY BY NOT TOTAL 187 00:09:13,840 --> 00:09:14,800 COINCIDENCE HAD OPPORTUNITY TO 188 00:09:14,800 --> 00:09:17,000 DESCRIBE GENETIC BASIS OF TWO 189 00:09:17,000 --> 00:09:21,640 DISEASES THAT CARRY HIS EPIN 190 00:09:21,640 --> 00:09:25,600 EMIC NAME 191 00:09:25,600 --> 00:09:27,280 PSEUDOHYPOPARATHYROIDISM AND 192 00:09:27,280 --> 00:09:32,160 SUBJECT OF TODAY'S SYMPOSIUM THE 193 00:09:32,160 --> 00:09:44,200 MCKUHN ALBRIGHT SCUNE ALB-ALBRI 194 00:09:52,840 --> 00:09:55,640 IS THE WORK OF LEE WEINSTEIN A 195 00:09:55,640 --> 00:09:57,680 POST DOC IN THE LAB AND BRANCH 196 00:09:57,680 --> 00:10:00,520 CHIEF OF MY FORMER BRANCH 197 00:10:00,520 --> 00:10:02,040 METABOLIC DISEASES BRANCH AND WE 198 00:10:02,040 --> 00:10:07,920 WILL SEE SUBJECT OF TODAY'S 199 00:10:07,920 --> 00:10:10,960 SYMPOSIUM GAIN -- THE G-PROTEIN 200 00:10:10,960 --> 00:10:14,720 COUPLED RECEPTORS COULD BE THE 201 00:10:14,720 --> 00:10:18,320 SITE OF LESIONS AND SHOWED 202 00:10:18,320 --> 00:10:25,640 NEPHRO GENIC DIABETES INSIPIDUS 203 00:10:25,640 --> 00:10:30,560 WAS LOSS OF MUTATIONS IN VASO 204 00:10:30,560 --> 00:10:31,960 RECEPTOR SUPPRESSOR AND POST DOC 205 00:10:31,960 --> 00:10:34,720 IN LABORATORY WORKING 206 00:10:34,720 --> 00:10:36,720 INDEPENDENTLY SHOWING GAIN OF 207 00:10:36,720 --> 00:10:39,200 FUNCTION MUTATION IN LUTEINIZING 208 00:10:39,200 --> 00:10:41,200 HORMONE RECEPTOR COULD BE 209 00:10:41,200 --> 00:10:44,560 GENETIC CAUSE OF FAMILIAL MAIL 210 00:10:44,560 --> 00:10:50,080 PREKOESHS PUBERTY. THIS IS 211 00:10:50,080 --> 00:10:53,680 GTPACE SCHEMA AND 7 212 00:10:53,680 --> 00:10:56,000 TRANSMEMBRANE RECEPTOR COUPLED 213 00:10:56,000 --> 00:11:00,080 TO THIS THAT CAUSES CYCLIC AMP 214 00:11:00,080 --> 00:11:02,240 PRODUCTION AND BETA GAMMA 215 00:11:02,240 --> 00:11:06,480 TIGHTLY BOUND SUBUNITS. GDP 216 00:11:06,480 --> 00:11:09,480 TIGHTLY BOUND AND WHEN AGONIST 217 00:11:09,480 --> 00:11:13,520 BINDS TO RECEPTOR ACTIVATING 218 00:11:13,520 --> 00:11:16,880 G-PROTEIN SO GTP EXCHANGES FOR 219 00:11:16,880 --> 00:11:20,280 GDP BUT ALLOWS EFFECTOR 220 00:11:20,280 --> 00:11:22,760 STIMULATION CYCLIC AMP 221 00:11:22,760 --> 00:11:26,200 STIMULATION -- AND PHYSIOLOGIC 222 00:11:26,200 --> 00:11:26,480 RESPONSES. 223 00:11:26,480 --> 00:11:31,640 THE INTRINSIC GTPACE HALTS 224 00:11:31,640 --> 00:11:33,840 STIMULATION BUT THAT INTRINSIC 225 00:11:33,840 --> 00:11:37,680 GTPACE COULD BE BLOCKED BY ALPHA 226 00:11:37,680 --> 00:11:41,160 ACTIVATING MUTATION WE WILL SEE 227 00:11:41,160 --> 00:11:45,920 AND BY EXTERIOR TOXIN WHERE 228 00:11:45,920 --> 00:11:47,680 MARTHA VAUGHN IN PROGRAM OF 229 00:11:47,680 --> 00:11:50,720 HEART AND LUNG SHOWED PARTICULAR 230 00:11:50,720 --> 00:11:51,960 ARJINNINE RESIDENT DUE THAT WE 231 00:11:51,960 --> 00:11:55,280 WILL SOON BE FAMILIAR WITH IS 232 00:11:55,280 --> 00:11:58,800 SITE OF ADP -- COVALENT 233 00:11:58,800 --> 00:12:00,600 MODIFICATION BLOCKING GTPACE 234 00:12:00,600 --> 00:12:03,160 LEADING TO UNREGULATED 235 00:12:03,160 --> 00:12:07,120 STIMULATION OF CYCLIC AMP 236 00:12:07,120 --> 00:12:12,040 FORMATION AND -- WE WERE 237 00:12:12,040 --> 00:12:13,600 FORTUNATE TO HAVE COLLEAGUES IN 238 00:12:13,600 --> 00:12:15,400 CHILD HEALTH INSTITUTE AT THE 239 00:12:15,400 --> 00:12:17,800 TIME STUDYING TREATMENT OF 240 00:12:17,800 --> 00:12:20,440 PREKROERGS PUBERTY LYNNE AND 241 00:12:20,440 --> 00:12:22,760 GLORIA AND OTHER COLLEAGUES AND 242 00:12:22,760 --> 00:12:26,160 ONE DISEASE THEY STUDIED WAS 243 00:12:26,160 --> 00:12:29,680 MCKUHN ALBRIGHT SYNDROME THAT 244 00:12:29,680 --> 00:12:33,200 PREKOESHS PUBERTY IS A SYNDROME. 245 00:12:33,200 --> 00:12:35,840 STAGE 2 BREAST DEVELOPMENT IS 246 00:12:35,840 --> 00:12:38,920 FEATURED IN A YOUNG GIRL OBVIOUS 247 00:12:38,920 --> 00:12:40,800 CAFE OLAY PIGMENTATION. THIS IS 248 00:12:40,800 --> 00:12:43,640 A BODY CAST BECAUSE OF FRACTURES 249 00:12:43,640 --> 00:12:45,680 DUE TO FIBROUS DYSPLASIA THAT 250 00:12:45,680 --> 00:12:48,320 ARE CARDINAL FEATURES OF A 251 00:12:48,320 --> 00:12:51,160 TRIIAD THAT CHARACTERIZES MCKUHN 252 00:12:51,160 --> 00:12:55,040 ALBRIGHT SYNDROME. NOW, IT IS 253 00:12:55,040 --> 00:12:58,360 VERY INTERESTING TO LOOK BACK AT 254 00:12:58,360 --> 00:13:04,560 ORIGINAL PUBLICATIONSCARDINAL F 255 00:13:04,560 --> 00:13:05,080 THAT CHARACTERIZES MCKUHN 256 00:13:05,080 --> 00:13:05,720 ALBRIGHT SYNDROME. NOW, IT IS 257 00:13:05,720 --> 00:13:06,360 VERY INTERESTING TO LOOK BACK AT 258 00:13:06,360 --> 00:13:09,680 ORIGINAL PUBLICATIONS -- THAT 259 00:13:09,680 --> 00:13:13,240 HAS PRECOCIOUS PUBERTY AND 260 00:13:13,240 --> 00:13:16,000 HYPERTHYROIDISM AND SAYS BASIC 261 00:13:16,000 --> 00:13:19,000 PROBLEMS IN NORMAL AND 262 00:13:19,000 --> 00:13:21,360 PATHOLOGIC PHYSIOLOGY IN THIS 263 00:13:21,360 --> 00:13:23,120 CHILD PRESENTS REMAINS UNSOLVED 264 00:13:23,120 --> 00:13:25,560 AND WOULD REMAIN UNSOLVED FOR 265 00:13:25,560 --> 00:13:28,560 ANOTHER 54 OR SO YEARS. 266 00:13:28,560 --> 00:13:31,360 REASON IT IS MCKUHN ALBRIGHT 267 00:13:31,360 --> 00:13:35,560 SYNDROME SIMULTANEOUSLY IN 1937 268 00:13:35,560 --> 00:13:40,800 IN NEW ENGLAND JOURNAL PAPER 269 00:13:40,800 --> 00:13:45,160 ALBRIGHT DESCRIBES ANOTHER 270 00:13:45,160 --> 00:13:46,800 DISORDER OSTEOFIBROSIS DISSEMIN 271 00:13:46,800 --> 00:13:55,400 ATA THAT IS NOW FIBROUS -- IF 272 00:13:55,400 --> 00:13:58,000 PATHOLOGIC MANIFESTATIONS THAT 273 00:13:58,000 --> 00:14:00,320 AT FIRST SEEM TO BE TOTALLY 274 00:14:00,320 --> 00:14:01,920 DISCONNECTED ARE FOUND TO OCCUR 275 00:14:01,920 --> 00:14:04,400 TOGETHER IN SUFFICIENT SERIES OF 276 00:14:04,400 --> 00:14:05,720 PATIENTS SOME RELATION BETWEEN 277 00:14:05,720 --> 00:14:08,360 THEM IS APPARENT AND SUCH IS THE 278 00:14:08,360 --> 00:14:10,600 CASE IN THE BIZARRE SYNDROME 279 00:14:10,600 --> 00:14:12,400 WHICH IS THE SUBJECT OF THIS 280 00:14:12,400 --> 00:14:16,800 PAPER AND ELUDES TO MCKUHN CASE 281 00:14:16,800 --> 00:14:19,680 AT PRESBYTERIAN HOSPITAL IN NEW 282 00:14:19,680 --> 00:14:22,160 YORK AND POINT THAT PEEKED MY 283 00:14:22,160 --> 00:14:24,680 INTEREST IS DISPARATE 284 00:14:24,680 --> 00:14:26,360 MANIFESTATIONS WHAT UNIFYING 285 00:14:26,360 --> 00:14:27,640 HYPOTHESIS COULD BRING THEM ALL 286 00:14:27,640 --> 00:14:31,400 TOGETHER. CAN'T BE OCCURRING BY 287 00:14:31,400 --> 00:14:41,360 CHA 288 00:14:41,360 --> 00:14:44,080 CHANCE. A GERMAN DERMATOLOGIST 289 00:14:44,080 --> 00:14:48,280 HOPLY SPECULATED THAT MCCUNE 290 00:14:48,280 --> 00:14:51,880 ALBRIGHT SYNDROME HAD A LETHAL 291 00:14:51,880 --> 00:15:03,160 GENE SURVIVING BY MOEZ AISSAMOS 292 00:15:06,200 --> 00:15:09,160 AT FIRST AS A DERMATOLOGIST HE 293 00:15:09,160 --> 00:15:10,760 LOOKED AT PIGMENTATION THEY 294 00:15:10,760 --> 00:15:13,280 DIDN'T FOLLOW DETERMINE ATOID 295 00:15:13,280 --> 00:15:16,360 LINES BUT LINES OF BLASH CO A 296 00:15:16,360 --> 00:15:17,960 DEVELOPMENTAL MORPHOLOGY. WHAT 297 00:15:17,960 --> 00:15:20,200 HE THOUGHT IS THAT THE DISEASE 298 00:15:20,200 --> 00:15:24,560 WAS CAUSED BY AUTOSOMAL DOMINANT 299 00:15:24,560 --> 00:15:25,840 LETHAL GENE THAT COULDN'T 300 00:15:25,840 --> 00:15:27,480 SURVIVE IN THE ZYGOTE. IF THERE 301 00:15:27,480 --> 00:15:31,440 WAS A LATER SOMATIC MUTATION, 302 00:15:31,440 --> 00:15:33,080 THAT LATER SOMATIC MUTATION 303 00:15:33,080 --> 00:15:36,280 COULD SURVIVE AND LEAD TO AN IS 304 00:15:36,280 --> 00:15:38,000 SO-CALLED MOSAIC DISTRIBUTION 305 00:15:38,000 --> 00:15:41,520 THAT WE WERE ENCOURAGED BY THAT 306 00:15:41,520 --> 00:15:42,920 HYPOTHESIS AND FURTHER 307 00:15:42,920 --> 00:15:44,600 ENCOURAGED BY THIS PAPER 308 00:15:44,600 --> 00:15:47,960 PUBLISHED IN 1989 IN NATURE FROM 309 00:15:47,960 --> 00:15:51,000 HENRY BORNE'S LAB AT UCSF AND 310 00:15:51,000 --> 00:15:54,840 GROUP OF ITALIAN INVESTIGATORS. 311 00:15:54,840 --> 00:15:58,400 THEY EXAMINED THE PITUITARY 312 00:15:58,400 --> 00:16:04,800 TUMORS SO-CALLEDSOME ATTOTROVE 313 00:16:04,800 --> 00:16:09,600 TUM 314 00:16:09,600 --> 00:16:09,840 TUMORS. 315 00:16:09,840 --> 00:16:20,120 SOME ATTO 316 00:16:25,360 --> 00:16:28,880 FOCAL SOMATIC MUTATION CAUSING 317 00:16:28,880 --> 00:16:34,440 ISOLATED ENDOCRINE HYPOMALFUFRJS 318 00:16:34,440 --> 00:16:38,560 THAT INVOLVED ARGININE 201 THAT 319 00:16:38,560 --> 00:16:42,160 HAPPENS TO BE SITE OF ATPRB 320 00:16:42,160 --> 00:16:43,720 OSCILLATION AND THAT 321 00:16:43,720 --> 00:16:45,080 MODIFICATION BECAUSE THAT 322 00:16:45,080 --> 00:16:47,200 RESIDENT DUE IS IN APPROXIMATE 323 00:16:47,200 --> 00:16:49,520 TO GDP TIGHTLY BOUND BY WHAT YOU 324 00:16:49,520 --> 00:16:52,200 CAN SEE HERE IS ALPHA SUBUNIT 325 00:16:52,200 --> 00:16:54,880 THAT IS BETA AND TIGHTLY BOUND 326 00:16:54,880 --> 00:16:57,200 GAMMA AND WILL SEE ELEGANT 327 00:16:57,200 --> 00:17:00,200 STRUCTURAL PICTURES BY 328 00:17:00,200 --> 00:17:04,000 PIONEERING WORK IN SEMINAR AND 329 00:17:04,000 --> 00:17:05,200 RECEPTOR CRUMB WILLING TO 330 00:17:05,200 --> 00:17:08,040 G-PROTEIN ALLOWING EXCHANGE OF 331 00:17:08,040 --> 00:17:10,240 GTP AND CRUCIAL ROLE FOR THIS IS 332 00:17:10,240 --> 00:17:13,320 YOU WILL NOTICE A GLUTAMINE 227 333 00:17:13,320 --> 00:17:14,840 IN APPROXIMATE CAUSE THAT RARELY 334 00:17:14,840 --> 00:17:18,440 YOU COULD HAVE MUTATIONS IN THAT 335 00:17:18,440 --> 00:17:19,880 GLUTAMINE. PRIMARILY THIS 336 00:17:19,880 --> 00:17:25,760 ARGININE 201 WAS THE SITE OF THE 337 00:17:25,760 --> 00:17:26,360 MUTATIONS. 338 00:17:26,360 --> 00:17:27,960 NOW, THIS IS THE PAPER 339 00:17:27,960 --> 00:17:31,040 ULTIMATELY PUBLISHED IN 1991 340 00:17:31,040 --> 00:17:35,920 ELUDED TO ALREADY BY DR. LEE LEE 341 00:17:35,920 --> 00:17:37,560 WEINSTEIN AND ANDY SHANKER AND 342 00:17:37,560 --> 00:17:39,960 COLLEAGUES AT NIH SHOWED 343 00:17:39,960 --> 00:17:45,800 MUTATIONS OF AXON NIH INCREASED 344 00:17:45,800 --> 00:17:47,960 ACTIVITY OF GS PROTEIN AND 345 00:17:47,960 --> 00:17:50,560 INCREASED CYCLIC AMP FORMATION 346 00:17:50,560 --> 00:17:52,200 AND PRESENT IN VARIOUS TISSUES 347 00:17:52,200 --> 00:17:55,360 OF PATIENTS WITH MCCUNE ALBRIGHT 348 00:17:55,360 --> 00:17:57,680 SYNDROME THIS IS SOMATIC 349 00:17:57,680 --> 00:18:00,360 MUTATION LEADING TO THIS MOSAIC 350 00:18:00,360 --> 00:18:01,760 DISTRIBUTION. 351 00:18:01,760 --> 00:18:04,400 HERE IS SOME OF THE ACTUAL DATA. 352 00:18:04,400 --> 00:18:07,400 AGAIN, ANCIENT HISTORY AND THIS 353 00:18:07,400 --> 00:18:11,560 IS BY NOW OUTMODE TECHNIQUE 354 00:18:11,560 --> 00:18:14,480 NATURE GRADIENT GEL 355 00:18:14,480 --> 00:18:16,000 ELECTROPHORESIS NEGATIVE AND 356 00:18:16,000 --> 00:18:17,320 POSITIVE CONTROL AND TISSUE 357 00:18:17,320 --> 00:18:18,680 SAMPLES FROM A REPRESENTATIVE 358 00:18:18,680 --> 00:18:22,000 PATIENT AND IDEA IS ON THIS 359 00:18:22,000 --> 00:18:24,320 DENATURE GELL -- SOME SEGMENTS 360 00:18:24,320 --> 00:18:26,600 WILL MIGRATE DIFFERENTLY AND A 361 00:18:26,600 --> 00:18:31,080 MORE FOCAL TEST IS ALLELE 362 00:18:31,080 --> 00:18:34,000 SPECIFIC OLIGONUCLEOTIDE -- 363 00:18:34,000 --> 00:18:35,240 NEGATIVE AND POSITIVE CONTROL 364 00:18:35,240 --> 00:18:37,600 AND TISSUE SAMPLES ONLY IN THE 365 00:18:37,600 --> 00:18:40,080 POSITIVE CONTROL AND TO VARYING 366 00:18:40,080 --> 00:18:42,600 DEGREES IN TISSUE SAMPLES DOES 367 00:18:42,600 --> 00:18:45,680 ONE SEE MUTANT INSTEAD OF 368 00:18:45,680 --> 00:18:49,440 ARGININE 201 CYSTINE MUTATION 369 00:18:49,440 --> 00:18:54,480 AND CG DINUCLEOTIDE FROM CODON 370 00:18:54,480 --> 00:18:58,760 BEING A HOTSPOT AND THIS 371 00:18:58,760 --> 00:19:00,520 MUTATION COULD OCCUR IN PATIENTS 372 00:19:00,520 --> 00:19:02,480 WITH MCCUNE ALBRIGHT AND FURTHER 373 00:19:02,480 --> 00:19:05,480 ANATOMIC DATA YOU FROM PAPER 374 00:19:05,480 --> 00:19:07,760 SUBJECT WITH PROKOESHS PUBERTY 375 00:19:07,760 --> 00:19:11,440 AND HAD OVARY REMOVED AND NORMAL 376 00:19:11,440 --> 00:19:14,640 APPEARING OVARY WITH NORMAL 377 00:19:14,640 --> 00:19:18,800 FOLLICLES NO DETECTION OF R201C 378 00:19:18,800 --> 00:19:22,240 MUTATION AND DNA ABNORMAL 379 00:19:22,240 --> 00:19:23,160 INAPPROPRIATE DEVELOPED FOLLICLE 380 00:19:23,160 --> 00:19:26,920 AND FROM THIS ABNORMAL AREA 381 00:19:26,920 --> 00:19:30,840 THERE WAS COPIOUS AMOUNTS OF 382 00:19:30,840 --> 00:19:34,760 R201C MUTATION AND IN SUMMARY 383 00:19:34,760 --> 00:19:37,360 FIBROUS DYSPLASIA MCCUNE 384 00:19:37,360 --> 00:19:39,200 ALBRIGHT SYNDROME DUE TO 385 00:19:39,200 --> 00:19:44,400 SPORADIC PLEAO TROEBIC PHENOTYPE 386 00:19:44,400 --> 00:19:49,600 CAFE OLAY SKIN PIGMENTATION 387 00:19:49,600 --> 00:19:52,800 GONADSOME ATTOTROVE ADRENAL -- 388 00:19:52,800 --> 00:19:55,480 STIMULATOR ENDOCRINE AND 389 00:19:55,480 --> 00:19:56,960 MELANOCYTE GROW IN FUNCTION AND 390 00:19:56,960 --> 00:19:59,440 FACT YOU HAVE UNREGULATED 391 00:19:59,440 --> 00:20:01,880 HORMONE STIMULATION OF CYCLIC 392 00:20:01,880 --> 00:20:03,920 AMP COULD EXPLAIN PATHOGENESIS 393 00:20:03,920 --> 00:20:05,960 AND IN CASE OF BONE A 394 00:20:05,960 --> 00:20:07,880 COMPLICATED SITUATION THAT WE 395 00:20:07,880 --> 00:20:12,320 WILL HEAR ABOUT LATER IN THE 396 00:20:12,320 --> 00:20:15,760 SYMPOSIUM FROM PAM AND MARA THE 397 00:20:15,760 --> 00:20:19,160 SOMATIC MUTATION OF GS ALPHA 398 00:20:19,160 --> 00:20:22,840 ARGININE 201 AND RARELY IF AT 399 00:20:22,840 --> 00:20:27,240 ALL GLUTAMINE 227 SPECULATIVELY 400 00:20:27,240 --> 00:20:33,280 GERM LINE LETHAL AND MOSAIC 401 00:20:33,280 --> 00:20:36,200 PHENOTYPE -- ANDY DESCRIBED 402 00:20:36,200 --> 00:20:38,440 PATIENTS WITH EARLY SOMATIC 403 00:20:38,440 --> 00:20:41,640 MUTATIONS THAT HAD SEVERE 404 00:20:41,640 --> 00:20:43,280 WIDESPREAD DISEASE VERSUS LATE 405 00:20:43,280 --> 00:20:47,600 FOCAL SOMATIC MUTATION 406 00:20:47,600 --> 00:20:51,200 TIPPIVEFIED BY ISOLATEDSOME 407 00:20:51,200 --> 00:20:52,480 ATTOTROVE PITUITARY TUMOR. WE 408 00:20:52,480 --> 00:20:57,360 WILL HEAR IN DETAIL FROM MICHAEL 409 00:20:57,360 --> 00:20:59,320 COLLINS ALLISON BOYCE ABOUT 410 00:20:59,320 --> 00:21:01,600 CLINICAL STUDIES INVOLVING 411 00:21:01,600 --> 00:21:03,760 PATHOGENESIS AND TREATMENT OF 412 00:21:03,760 --> 00:21:07,480 LINKED SYNDROMES. THANKS FOR 413 00:21:07,480 --> 00:21:08,320 YOUR ATTENTION. 414 00:21:08,320 --> 00:21:09,040 >> AUDIENCE: [APPLAUSE]. 415 00:21:09,040 --> 00:21:19,560 >> >> THANK YOU DR. SPIEGEL. 416 00:21:21,960 --> 00:21:25,200 NEXT SPEAKER IS PAM ROBEY WHO 417 00:21:25,200 --> 00:21:29,880 STARTED POST DOCTORAL WORK AT 418 00:21:29,880 --> 00:21:33,120 NIAMS AND NAEI AND YOU WILL 419 00:21:33,120 --> 00:21:36,840 NOTICE A THEME WHERE THERE IS 420 00:21:36,840 --> 00:21:37,520 INTERDISCIPLINARY COLLABORATION 421 00:21:37,520 --> 00:21:39,200 AND INTER-IC COLLABORATION AND 422 00:21:39,200 --> 00:21:44,040 SHE JOINED NIDCR IN 1983 AND IS 423 00:21:44,040 --> 00:21:46,160 CURRENTLY SENIOR INVESTIGATOR 424 00:21:46,160 --> 00:21:50,720 AND CHIEF OF SKELETAL BIOLOGY 425 00:21:50,720 --> 00:21:53,080 SECTION AND CRANIOFACIAL 426 00:21:53,080 --> 00:21:54,720 DISEASES BRANCH AND MIKE COLLINS 427 00:21:54,720 --> 00:21:57,720 AND I CUT TEETH ON BONE BIOLOGY 428 00:21:57,720 --> 00:21:59,760 TO UNDERSTAND BONE DISORDERS AND 429 00:21:59,760 --> 00:22:03,800 IN 1993 DR. ROBEY RECEIVED FULL 430 00:22:03,800 --> 00:22:07,840 BOX OF BONE SPECIMENS FROM 431 00:22:07,840 --> 00:22:09,600 ENDOCRINOLOGIST AT NIH AND HE 432 00:22:09,600 --> 00:22:13,680 ASKED HER TO IDENTIFY WHAT THE 433 00:22:13,680 --> 00:22:16,400 MUTATION AND HOW THE 434 00:22:16,400 --> 00:22:17,640 ABNORMALITIES OF THIS PARTICULAR 435 00:22:17,640 --> 00:22:19,680 GENE WOULD THEN RESULT IN THE 436 00:22:19,680 --> 00:22:23,320 BONE PHENOTYPE AND BEGAN HER 437 00:22:23,320 --> 00:22:27,320 QUEST ITALIAN COLLEAGUES PAULO 438 00:22:27,320 --> 00:22:29,680 AND MARA WHO ARE HERE TODAY TO 439 00:22:29,680 --> 00:22:31,000 UNDERSTAND IMPACT OF MUTATION ON 440 00:22:31,000 --> 00:22:36,600 BONES OF PATIENTS WITH FD AND 441 00:22:36,600 --> 00:22:41,680 MAS A SKELETAL DISEASE. DR. 442 00:22:41,680 --> 00:22:45,240 ROBEY? 443 00:22:45,240 --> 00:22:45,920 >> AUDIENCE: [APPLAUSE]. 444 00:22:45,920 --> 00:22:47,520 >> I'M FINE, THANKS. 445 00:22:47,520 --> 00:22:49,560 >> THANK YOU, JANICE. I 446 00:22:49,560 --> 00:22:51,280 APPRECIATE THE INTRODUCTION. 447 00:22:51,280 --> 00:22:53,520 THANK YOU ALL FOR COMING TO HEAR 448 00:22:53,520 --> 00:22:55,320 ABOUT OUR JOURNEY DURING THE 449 00:22:55,320 --> 00:22:57,200 LAST 25 YEARS. 450 00:22:57,200 --> 00:22:59,160 SO, I WILL START OFF WITH A 451 00:22:59,160 --> 00:23:01,160 LITTLE BIT ABOUT WHAT SKELETAL 452 00:23:01,160 --> 00:23:03,960 STEM CELLS ARE. A LITTLE OF THE 453 00:23:03,960 --> 00:23:09,240 HISTORY OF FD/MAS AT NIDCR AND 454 00:23:09,240 --> 00:23:11,000 ROLE OF SKELETAL STEM CELLS AND 455 00:23:11,000 --> 00:23:14,640 DISEASE AND WHY FD/MAS IS A STEM 456 00:23:14,640 --> 00:23:15,560 CELL DISEASE. 457 00:23:15,560 --> 00:23:18,840 SO, FIRST, A LITTLE BIT OF 458 00:23:18,840 --> 00:23:21,200 REFRESHER WHAT A STEM CELL IS. 459 00:23:21,200 --> 00:23:24,280 DEFINING FEATURES OF A STEM CELL 460 00:23:24,280 --> 00:23:27,320 ARE TWO. ONE, IT HAS THE 461 00:23:27,320 --> 00:23:29,840 ABILITY TO SELF-RENEW. THE 462 00:23:29,840 --> 00:23:34,040 SECOND IS THAT A SINGLE CELL IS 463 00:23:34,040 --> 00:23:37,600 ABLE TO REPLENISH AND REFORM AN 464 00:23:37,600 --> 00:23:40,760 ENTIRE TISSUE. THE SO-CALLED 465 00:23:40,760 --> 00:23:42,840 POTENCY OF THE CELL. THE WAY 466 00:23:42,840 --> 00:23:45,280 THAT A STEM CELL REFRESHES 467 00:23:45,280 --> 00:23:48,200 ITSELF IS BY A SELF-RENEWING 468 00:23:48,200 --> 00:23:51,480 DIVISION WHERE STEM CELL DIVIDES 469 00:23:51,480 --> 00:23:52,920 ASYMMETRICALLY AND ONE IS A MORE 470 00:23:52,920 --> 00:23:55,760 COMMITTED CELL GOING ON TO 471 00:23:55,760 --> 00:23:56,520 TRANSIENTLY AMPLIFY AND THEN 472 00:23:56,520 --> 00:23:58,560 AFTER A CERTAIN AMOUNT OF 473 00:23:58,560 --> 00:24:01,560 PROLIFERATION GOES ON TO 474 00:24:01,560 --> 00:24:04,360 DIFFERENTIATE THAT IS THROUGH 475 00:24:04,360 --> 00:24:06,120 SYMMETRIC DIVISION AND SECOND 476 00:24:06,120 --> 00:24:08,520 DAUGHTER OF THE STEM CELL 477 00:24:08,520 --> 00:24:11,240 REMAINS STEM CELL SO-CALLED 478 00:24:11,240 --> 00:24:12,720 ASYMMETRIC DIVISION THAT IS NOT 479 00:24:12,720 --> 00:24:15,040 THAT SIMPLE AND MAY ACTUALLY 480 00:24:15,040 --> 00:24:17,560 TOGGLE BACK AND FORTH BETWEEN 481 00:24:17,560 --> 00:24:19,160 SYMMETRIC AND ASYMMETRIC 482 00:24:19,160 --> 00:24:20,400 DEPENDING ON THE SITUATION. 483 00:24:20,400 --> 00:24:22,800 THIS IS A WORKING PARADIGM AND 484 00:24:22,800 --> 00:24:26,080 TWO PROPERTIES THAT DEFINE A 485 00:24:26,080 --> 00:24:29,360 STEM CELL THAT THE DEFINITION OF 486 00:24:29,360 --> 00:24:31,240 STEM CELLS IS OFTEN KIND OF 487 00:24:31,240 --> 00:24:33,560 DISREGARDED AND MANY CELLS ARE 488 00:24:33,560 --> 00:24:37,800 CALLED STEM CELLS WITHOUT BEING 489 00:24:37,800 --> 00:24:39,720 TRUE STEM CELLS WITHOUT RIGOROUS 490 00:24:39,720 --> 00:24:41,760 CRITERIA AND DURING DEVELOPMENT 491 00:24:41,760 --> 00:24:43,760 WE HAVE WHAT SOME WOULD CALL THE 492 00:24:43,760 --> 00:24:47,280 MOTHER OF ALL STEM CELLS, THE 493 00:24:47,280 --> 00:24:51,520 FERTILIZED EGG THAT ISTODY 494 00:24:51,520 --> 00:24:52,720 POTENT WITH ABILITY TO FORM NOT 495 00:24:52,720 --> 00:24:55,880 ONLY CELLS IN BODY BUT PLACENTAL 496 00:24:55,880 --> 00:24:58,240 AND OTHER MEMBRANES. 497 00:24:58,240 --> 00:25:00,840 THIS GOES ON TO DIVIDE TO FORM 498 00:25:00,840 --> 00:25:04,640 THE BLASTOCYST WHERE YOU HAVE 499 00:25:04,640 --> 00:25:06,240 TRIFEKTO DETERMINE ON OUTER 500 00:25:06,240 --> 00:25:08,760 SURFACE AND CLUMP OF CELLS IN 501 00:25:08,760 --> 00:25:11,200 MIDDLE INNER CELL MA S THAT IS 502 00:25:11,200 --> 00:25:12,840 PLURIPOTENT MEANING THEY WILL 503 00:25:12,840 --> 00:25:15,960 MAKE CELLS OF EMBRYO BUT NOT 504 00:25:15,960 --> 00:25:18,800 PLACENTAL MEMBRANES AND INNER 505 00:25:18,800 --> 00:25:22,040 CELL MATH GIVES RISE TO ESL 506 00:25:22,040 --> 00:25:25,680 CELLS WE USE IN THE LABORATORY 507 00:25:25,680 --> 00:25:27,640 AND BLASTOCYSTS DEVELOP AND WE 508 00:25:27,640 --> 00:25:32,520 HAVE GASTROFORMATION AND GERM 509 00:25:32,520 --> 00:25:34,080 LAYERS ECTOGERM NEED AZ 510 00:25:34,080 --> 00:25:35,680 DETERMINE AND ENDODETERMINE AND 511 00:25:35,680 --> 00:25:38,160 COMMITTED TO LINEAGES THAT LOST 512 00:25:38,160 --> 00:25:43,960 POTENCY AND WE CALL THEM 513 00:25:43,960 --> 00:25:45,040 MULTIPOTENT AND AFTER BIRTH WE 514 00:25:45,040 --> 00:25:47,800 HAVE MATURE DIFFERENTIATED CELLS 515 00:25:47,800 --> 00:25:49,320 AND MAINTAIN A CERTAIN 516 00:25:49,320 --> 00:25:50,920 POPULATION OF STEM CELLS AND 517 00:25:50,920 --> 00:25:53,240 PROBABLY ALL TISSUES IN THE 518 00:25:53,240 --> 00:25:56,480 BODY. ADULT STEM CELLS ARE 519 00:25:56,480 --> 00:25:58,920 ABSOLUTELY NECESSARY FOR TISSUE 520 00:25:58,920 --> 00:26:00,640 SELF-RENEWAL AND REFRESHMENT. 521 00:26:00,640 --> 00:26:04,480 SO, IN THE BONE MARROW, 522 00:26:04,480 --> 00:26:05,920 ALEXANDER FREEDEN STEIN I'M 523 00:26:05,920 --> 00:26:09,680 SORRY WORKING WITH MAUREEN OWEN 524 00:26:09,680 --> 00:26:11,960 FIRST DEFINED BONE MARROW 525 00:26:11,960 --> 00:26:13,840 STROMAL CELLS A SUBSET WHICH 526 00:26:13,840 --> 00:26:15,920 WERE MULTIPOTENT STEM CELLS. 527 00:26:15,920 --> 00:26:18,960 WHAT HE DID WAS TAKE A SINGLE 528 00:26:18,960 --> 00:26:22,760 CELL SUSPENSION OF BONE MARROW 529 00:26:22,760 --> 00:26:25,200 AND PLAYED IT AT VERY LOW 530 00:26:25,200 --> 00:26:28,960 DENSITY AND RAPIDLY ADHERIENT 531 00:26:28,960 --> 00:26:39,800 FIBRO BLAST CELL THAT CELL PROL 532 00:26:40,160 --> 00:26:44,640 COLONY TAKING CELLS TO PUT ON 533 00:26:44,640 --> 00:26:45,480 APPROPRIATE SCAFFOLD AND TRANCE 534 00:26:45,480 --> 00:26:47,320 PLANT INTO MICE AND GET 535 00:26:47,320 --> 00:26:51,400 FORMATION OF ECTOPICOSICLE WITH 536 00:26:51,400 --> 00:26:54,400 BONE AND STROMA AND MARROW DIPPO 537 00:26:54,400 --> 00:26:58,520 CITES OF DONOR ORIGIN AND STROMA 538 00:26:58,520 --> 00:27:01,320 SUPPORTS FORMATION OF HEM 539 00:27:01,320 --> 00:27:03,360 ATTOPOEESIS THAT IS RECIPIENT 540 00:27:03,360 --> 00:27:05,680 ORIGIN THAT IS A DEFINING 541 00:27:05,680 --> 00:27:07,960 FEATURE OF BONE SKELETAL STEM 542 00:27:07,960 --> 00:27:09,960 CELL. THESE CELLS ARE ALSO VERY 543 00:27:09,960 --> 00:27:12,400 IMPORTANT IN TERMS OF SUPPORTING 544 00:27:12,400 --> 00:27:14,520 FORMATION OF OSTEOCLASTS. 545 00:27:14,520 --> 00:27:16,720 THESE CELLS ARE IMPORTANT REALLY 546 00:27:16,720 --> 00:27:20,320 IN SKELETAL HOMEOSTASIS AND WE 547 00:27:20,320 --> 00:27:22,320 FOUND BY DOING TRANSPLANTATION 548 00:27:22,320 --> 00:27:26,520 ASSAY IS ONLY 1 OUT OF 5 OF CFUF 549 00:27:26,520 --> 00:27:29,360 ARE IN FACT MULTIPOTIENT AND 550 00:27:29,360 --> 00:27:33,360 SKELETAL STEM CELLS ARE CFUFS 551 00:27:33,360 --> 00:27:35,360 AND NOT ALL ARE SKELETAL STEM 552 00:27:35,360 --> 00:27:38,320 CELLS AND PROVED BY DOING SERIAL 553 00:27:38,320 --> 00:27:40,960 TRANSPLANTATION THAT CELLS DO IN 554 00:27:40,960 --> 00:27:45,600 FACT SELF-RENEW AND ARE 555 00:27:45,600 --> 00:27:48,640 BONIVEFIED ADULT STEM CELLS AND 556 00:27:48,640 --> 00:27:52,480 YOU HEARD FROM JANICE AND ALLEN 557 00:27:52,480 --> 00:28:03,640 WE BEGAN TO TO STUDY -- HE SAID 558 00:28:31,320 --> 00:28:34,200 IDEA WHY THEY HAVE FIBROUS 559 00:28:34,200 --> 00:28:37,360 DYSPLASIA THAT BEGAN OUR JOURNEY 560 00:28:37,360 --> 00:28:41,600 AND AT TIME MARA RIMINUCCI WAS A 561 00:28:41,600 --> 00:28:44,440 FELLOW IN THE LAB AND THEY 562 00:28:44,440 --> 00:28:46,800 STARTED TO LOOK AT PARAFIN 563 00:28:46,800 --> 00:28:49,160 BLOCKS DISCOVERING THIS WAS AN 564 00:28:49,160 --> 00:28:50,440 INTERESTING DISEASE AND HAVING 565 00:28:50,440 --> 00:28:52,760 HARD TIME GETTING LIVE TISSUE. 566 00:28:52,760 --> 00:28:57,480 THAT WAS REALLY A CHALLENGE. 567 00:28:57,480 --> 00:29:00,840 SHLOMA SUGGESTED WHY NOT START A 568 00:29:00,840 --> 00:29:04,200 CLINICAL STUDY TISSUE 569 00:29:04,200 --> 00:29:06,760 PROCUREMENT STUDY AND AT THAT 570 00:29:06,760 --> 00:29:07,320 TIME [INDISCERNIBLE] WAS 571 00:29:07,320 --> 00:29:09,080 INENDOCRINE FELLOW WHO DECIDE 572 00:29:09,080 --> 00:29:11,600 TODAY LEARN ABOUT BONES AND CAME 573 00:29:11,600 --> 00:29:14,240 TO THE LAB. WE GOT TOGETHER AND 574 00:29:14,240 --> 00:29:15,800 PUT TOGETHER A SERIES OF 575 00:29:15,800 --> 00:29:19,000 CLINICAL PROTOCOLS. ONE WAS 576 00:29:19,000 --> 00:29:20,680 NATURAL HISTORY. ONE WAS 577 00:29:20,680 --> 00:29:24,480 TREATMENT OF THE DISEASE WITH 578 00:29:24,480 --> 00:29:35,800 ADRONATE -- ALLEN DROENNDRODRO 579 00:29:50,560 --> 00:29:53,720 WITH US DURING 25 YEARS AND 580 00:29:53,720 --> 00:29:55,360 BASICALLY THE BOTTOM LINE WAS WE 581 00:29:55,360 --> 00:29:56,880 HAVE -- WE KNOW WHAT THE 582 00:29:56,880 --> 00:29:59,160 MUTATION IS. ACTIVATING 583 00:29:59,160 --> 00:30:02,640 MUTATION OF GS ALPHA CAUSING 584 00:30:02,640 --> 00:30:04,280 EXCESS CYCLIC AMP PRODUCTION AND 585 00:30:04,280 --> 00:30:06,080 WHAT DOES IT MEAN TO BONE? 586 00:30:06,080 --> 00:30:07,880 THAT WAS REALLY OUR GOAL 587 00:30:07,880 --> 00:30:10,040 THROUGHOUT ALL OF THE STUDIES. 588 00:30:10,040 --> 00:30:12,800 THEN I WAS WORKING ON BONE 589 00:30:12,800 --> 00:30:14,480 SKELETAL STEM CELLS AT SAME 590 00:30:14,480 --> 00:30:16,360 TIME. I THOUGHT, GEEZ. MAYBE 591 00:30:16,360 --> 00:30:18,720 THERE IS A LINK BETWEEN THE 592 00:30:18,720 --> 00:30:21,000 SKELETAL STEM CELL AND FIBROUS 593 00:30:21,000 --> 00:30:22,840 DYSPLASIA OF BONE. THIS WAS A 594 00:30:22,840 --> 00:30:24,760 THOUGHT THAT OCCURRED TO US 595 00:30:24,760 --> 00:30:27,640 BECAUSE WE THOUGHT, OKAY. 596 00:30:27,640 --> 00:30:28,920 SKELETAL STEM CELLS ARE 597 00:30:28,920 --> 00:30:32,280 IMPORTANT IN CONTROLLING BONE 598 00:30:32,280 --> 00:30:33,400 FORMATION AND BONE DESTRUCTION. 599 00:30:33,400 --> 00:30:36,280 THEY CONTROL FORMATION OF 600 00:30:36,280 --> 00:30:37,920 OSTEOMRAFTS AND REASONED THAT 601 00:30:37,920 --> 00:30:41,120 ANY GENETIC MUTATION OR DMAFRNG 602 00:30:41,120 --> 00:30:43,920 ACTIVITY CAUSED BY CHANGES IN 603 00:30:43,920 --> 00:30:46,360 SURROUNDINGS WILL RESULT IN A 604 00:30:46,360 --> 00:30:48,120 SKELETAL DISEASE OR DISORDER. 605 00:30:48,120 --> 00:30:50,480 WE CHOSE TO WORK ON FIBROUS 606 00:30:50,480 --> 00:31:00,920 DYSPLASIA TO SEE IF THIS 607 00:31:03,400 --> 00:31:03,840 HYPOTHESIS WAS CORRECT. 608 00:31:03,840 --> 00:31:06,320 WE HAVE TISSUES REPRESENTATIVE 609 00:31:06,320 --> 00:31:12,320 OF THREE GERM LAYERS -- WE HAVE 610 00:31:12,320 --> 00:31:18,440 AXIAL AND APPENDICULAR CRANIAL 611 00:31:18,440 --> 00:31:23,560 FIBROUS DYSPLASIA AND WE HAVE 612 00:31:23,560 --> 00:31:27,200 PERKOESHS PUBERTY THAT COMES 613 00:31:27,200 --> 00:31:30,800 ENDODERM AND PATTERN IN MCCUNE 614 00:31:30,800 --> 00:31:33,040 ALBRIGHT SYNDROME REASONED THAT 615 00:31:33,040 --> 00:31:35,920 MUTATION MUST BE OCCURRING IN 616 00:31:35,920 --> 00:31:40,880 INNER CELL MAST OF DEVELOPING 617 00:31:40,880 --> 00:31:43,320 BLASTOCYSTS. WE GET CYST 618 00:31:43,320 --> 00:31:48,160 MUTATIONS OR HISTADEAN MUTATIONS 619 00:31:48,160 --> 00:31:50,800 DEPENDENT ON METHYLATION AND 620 00:31:50,800 --> 00:31:53,400 DEAMINATION THAT OCCURS DURING 621 00:31:53,400 --> 00:31:55,840 EPIGENETIC RE-PROGRAMMING OF THE 622 00:31:55,840 --> 00:31:59,200 INNER CELL MASS DURING DEVELOP 623 00:31:59,200 --> 00:31:59,520 ME 624 00:31:59,520 --> 00:32:07,680 DEVELOP 625 00:32:07,680 --> 00:32:08,040 DEVELOPMENT. 626 00:32:08,040 --> 00:32:13,680 LOOKING AT LESIONAL BONE THIS IS 627 00:32:13,680 --> 00:32:24,280 ALKALPHATASE -- THEY 628 00:32:45,920 --> 00:32:48,280 WEREN'T ON STEROIDS BUT HAD 629 00:32:48,280 --> 00:32:50,080 SOMETHING RELATED TO STEROIDS. 630 00:32:50,080 --> 00:32:52,240 THAT WAS OUR WORKING 631 00:32:52,240 --> 00:32:52,840 HYPOTHESIS. 632 00:32:52,840 --> 00:32:54,680 WHAT WE NOTICE IS THAT IT ALSO 633 00:32:54,680 --> 00:32:59,120 HAS A LOT OF VARIATION, THAT 634 00:32:59,120 --> 00:33:00,840 DEPENDING ON LOCATION OF LESIONS 635 00:33:00,840 --> 00:33:02,720 WE COULD HAVE CHINESE WRITING 636 00:33:02,720 --> 00:33:08,800 KIND OF PATTERN AND HAVE 637 00:33:08,800 --> 00:33:11,840 SCLEROTIC AND PATH ETTOID 638 00:33:11,840 --> 00:33:13,120 PATTERNS PRIMARILY IN BASE OF 639 00:33:13,120 --> 00:33:15,320 THE SKULL AND HAD HYPERCELLULAR 640 00:33:15,320 --> 00:33:19,600 PATTERN THAT IS PRIMARILY IN THE 641 00:33:19,600 --> 00:33:22,960 NATHIC BONES IT IS A 642 00:33:22,960 --> 00:33:24,480 HETEROGENOUS DISEASE DEPENDING 643 00:33:24,480 --> 00:33:27,520 ON THE LOCATION AND LOOKED 644 00:33:27,520 --> 00:33:31,320 FURTHER AND PAOLO AND MARA FOUND 645 00:33:31,320 --> 00:33:34,000 THAT THIS DISPLASTIC BONE IS 646 00:33:34,000 --> 00:33:35,880 ABNORMAL AND WOVEN BONE YOU CAN 647 00:33:35,880 --> 00:33:39,840 SEE IN POLARIZED LIGHT MIKE ROSS 648 00:33:39,840 --> 00:33:42,640 COPY AND IS UNDERMINERALIZED NOT 649 00:33:42,640 --> 00:33:44,640 NORMAL MINERAL CONTENT AND 650 00:33:44,640 --> 00:33:47,040 LOOKING BY STANDARD H & E YOU 651 00:33:47,040 --> 00:33:49,320 SEE THAT NORMAL MARROW IS 652 00:33:49,320 --> 00:33:51,600 REPLACED BY FIBROTIC MARROW WITH 653 00:33:51,600 --> 00:33:54,800 NO BLOOD FORMATION AND NO 654 00:33:54,800 --> 00:33:58,360 ADIPOCYTES YOU CAN SEE CELLS 655 00:33:58,360 --> 00:34:01,600 RETRACTING AWAY FROM SURFACE OF 656 00:34:01,600 --> 00:34:04,760 THE BONE MAKING SHARPIE FIBRO 657 00:34:04,760 --> 00:34:06,960 BONE THAT IS DUE TO 658 00:34:06,960 --> 00:34:10,040 OVERPRODUCTION OF CYCLIC AMP 659 00:34:10,040 --> 00:34:12,120 CAUSING FIBRO BLASTIC CELLS TO 660 00:34:12,120 --> 00:34:14,680 RETRACT THAT IS DEFINING FEATURE 661 00:34:14,680 --> 00:34:17,200 OF FIBROUS DYSPLASIA AND WE 662 00:34:17,200 --> 00:34:20,440 NOTICED TAKING FIBROTIC MARROW 663 00:34:20,440 --> 00:34:23,280 AND DO THE STANDARD COLONY 664 00:34:23,280 --> 00:34:24,920 FORMING EFFICIENCY WHICH IS 665 00:34:24,920 --> 00:34:27,320 FIRST THING WE DO WITH A BONE 666 00:34:27,320 --> 00:34:29,520 DISEASE LOOKING AT NUMBER OF 667 00:34:29,520 --> 00:34:31,560 COLONIES FORMED BECAUSE IT IS 668 00:34:31,560 --> 00:34:33,720 APPROXIMATION OF NUMBER OF STEM 669 00:34:33,720 --> 00:34:36,720 AND PROGENITOR CELLS AND WE SAW 670 00:34:36,720 --> 00:34:39,160 THAT THESE CELLS WERE VERY 671 00:34:39,160 --> 00:34:41,760 IMMATURE AND COLONY FORMING 672 00:34:41,760 --> 00:34:43,080 EFFICIENCY WAS SKY HIGH COMPARED 673 00:34:43,080 --> 00:34:44,800 TO THE NORMAL MARROW. 674 00:34:44,800 --> 00:34:49,320 THEN WE THOUGHT, OKAY. WE HAVE 675 00:34:49,320 --> 00:34:51,800 GOT THESE LARGE NUMBER OF COLONY 676 00:34:51,800 --> 00:34:53,640 FORMING UNITS AND HOW DOES IT 677 00:34:53,640 --> 00:34:54,840 CAUSE THE DISEASE? 678 00:34:54,840 --> 00:34:58,640 WHAT WE DID WAS WE DID CLONAL 679 00:34:58,640 --> 00:35:02,720 ANALYSIS AND PLATED THE CELLS AT 680 00:35:02,720 --> 00:35:04,760 CLONAL DENSITY AND GATHERING UP 681 00:35:04,760 --> 00:35:07,760 ALL CLONES AND PUT THEM INTO OUR 682 00:35:07,760 --> 00:35:10,000 TRANSPLANT, WHAT WE GOT WAS A 683 00:35:10,000 --> 00:35:13,240 COMPLETE REPLICA OF FIBROUS 684 00:35:13,240 --> 00:35:15,040 DISPLASTIC TISSUE REMINISCIENT 685 00:35:15,040 --> 00:35:16,840 OF TISSUE WE GOT FROM THE 686 00:35:16,840 --> 00:35:18,600 PATIENT THEMSELVES AND WAS PROOF 687 00:35:18,600 --> 00:35:21,000 OF PRINCIPLE THAT WE ACTUALLY 688 00:35:21,000 --> 00:35:24,840 COULD USE SKELETAL STEM CELLS TO 689 00:35:24,840 --> 00:35:26,240 RECAPITULATE A SKELETAL DISEASE 690 00:35:26,240 --> 00:35:29,680 BY USING AN IN VIVO 691 00:35:29,680 --> 00:35:30,880 TRANSPLANTATION MODEL IN A 692 00:35:30,880 --> 00:35:31,240 MOUSE. 693 00:35:31,240 --> 00:35:33,720 IF WE TOOK NORMAL CELLS AND 694 00:35:33,720 --> 00:35:36,680 NORMAL CLONES AND GOT A 695 00:35:36,680 --> 00:35:38,040 NORMALOSICLELE AS WE EXPECTED 696 00:35:38,040 --> 00:35:40,560 AND WHAT WE GOT WHEN WE 697 00:35:40,560 --> 00:35:43,400 TRANSPLANTED MUTANT CELLS IS WE 698 00:35:43,400 --> 00:35:44,920 HAD NONNOSICLE AND CELLS 699 00:35:44,920 --> 00:35:46,760 BASICALLY DIED AND DID NOT FORM 700 00:35:46,760 --> 00:35:47,280 BONES. 701 00:35:47,280 --> 00:35:50,400 THIS, AGAIN, WAS PROOF OF 702 00:35:50,400 --> 00:35:52,560 HAPPENLES HYPOTHESIS THAT THIS 703 00:35:52,560 --> 00:35:54,080 MUTATION ONLY SURVIVES WHEN YOU 704 00:35:54,080 --> 00:35:56,680 HAVE NORMAL AND MUTANT CELLS 705 00:35:56,680 --> 00:35:58,840 TOGETHER THAT MUTANT CELLS BY 706 00:35:58,840 --> 00:36:02,840 THEMSELVES WILL NOT SURVIVE. 707 00:36:02,840 --> 00:36:04,760 SO, ANOTHER THING WE NOTICED AS 708 00:36:04,760 --> 00:36:07,640 WE LOOKED AT COLONY FORMING 709 00:36:07,640 --> 00:36:10,480 EFFICIENCY ASSAYS IS WE HAD HUGE 710 00:36:10,480 --> 00:36:12,520 NUMBERS IN YOUNG PATIENTS UNDER 711 00:36:12,520 --> 00:36:15,720 THE AGE OF 30. I THINK WE CAN 712 00:36:15,720 --> 00:36:17,080 REDEFINE YOUNG MAYBE UNDER THE 713 00:36:17,080 --> 00:36:20,080 AGE OF 50. I DON'T KNOW. 714 00:36:20,080 --> 00:36:23,360 IN OLDER PATIENTS, THERE WAS A 715 00:36:23,360 --> 00:36:25,240 DRAMATIC DECREASE IN THE NUMBER 716 00:36:25,240 --> 00:36:27,920 OF COLONY FORMING UNITS THAT 717 00:36:27,920 --> 00:36:30,680 THIS CORRELATED VERY, VERY 718 00:36:30,680 --> 00:36:33,200 TIGHTLY WITH AGE THAT OLDER THE 719 00:36:33,200 --> 00:36:35,480 PATIENT, FEWER THE CFUFS. 720 00:36:35,480 --> 00:36:37,360 THE QUESTION IS WHY? 721 00:36:37,360 --> 00:36:39,920 SO, WE STARTED TO LOOK AT THIS 722 00:36:39,920 --> 00:36:41,520 MORE CAREFULLY LOOKING AT X-RAYS 723 00:36:41,520 --> 00:36:44,280 HERE YOU CAN SEE THERE IS AN 724 00:36:44,280 --> 00:36:46,360 OBVIOUS LESION AND BASICALLY WE 725 00:36:46,360 --> 00:36:49,360 COULD SEE THESE LESIONS AT 10, 726 00:36:49,360 --> 00:36:52,040 21 AND 41 YEARS OLD. LOOKING AT 727 00:36:52,040 --> 00:36:54,640 THEM HISTOLOGICALLY THEY WERE 728 00:36:54,640 --> 00:36:56,080 QUITE DIFFERENT. IN YOUNG 729 00:36:56,080 --> 00:36:58,160 LESIONS WE SAW POORLY 730 00:36:58,160 --> 00:37:00,560 MINERALIZED MATRIX THIS IS 731 00:37:00,560 --> 00:37:02,200 OSTEOID THAT IS NOT MINERALIZED 732 00:37:02,200 --> 00:37:04,800 AND THIS IS FIBROUS DISPLASTIC 733 00:37:04,800 --> 00:37:06,800 MARROW AND IN OLDER PATIENT WE 734 00:37:06,800 --> 00:37:08,880 SAW ALMOST A NORMAL STRUCTURE 735 00:37:08,880 --> 00:37:12,080 THAT ONLY HAD VERY LIMITED AREAS 736 00:37:12,080 --> 00:37:17,680 OF UNMINERALIZED OSTEOID AND IN 737 00:37:17,680 --> 00:37:19,920 OLDER PATIENT THIS WAS A 738 00:37:19,920 --> 00:37:22,200 COMPLETELY NORMAL SAMPLE TAKEN 739 00:37:22,200 --> 00:37:24,120 FROM ILLIAC CREST THAT IS 740 00:37:24,120 --> 00:37:25,920 NORMALLY YELLOW MARROW AT THIS 741 00:37:25,920 --> 00:37:28,520 AGE. YOU WILL -- AS YOU WILL 742 00:37:28,520 --> 00:37:32,920 HEAR, THIS IS ALL DUE TO THE 743 00:37:32,920 --> 00:37:35,800 OSTEOID IS ALL DUE TO EXCESS 744 00:37:35,800 --> 00:37:37,400 FIBRO BLAST GROWTH FACTOR 23 745 00:37:37,400 --> 00:37:39,360 THAT YOU WILL HEAR MORE ABOUT 746 00:37:39,360 --> 00:37:41,840 THAT LATER. WHEN WE LOOKED AT 747 00:37:41,840 --> 00:37:44,400 SAMPLES AGAIN AND DID THE TUNNEL 748 00:37:44,400 --> 00:37:46,480 ASSAY WE NOTICED IN YOUNG 749 00:37:46,480 --> 00:37:48,280 PATIENTS THERE WAS A HUGE AMOUNT 750 00:37:48,280 --> 00:37:51,560 OF CELL DEATHS AS SHOWN HERE BY 751 00:37:51,560 --> 00:37:55,000 THE TUNNEL ASSAY. YOU CAN SEE 752 00:37:55,000 --> 00:37:56,600 APOPTOTIC BODIES THAT ARE 753 00:37:56,600 --> 00:37:59,480 IMBEDDED IN THE BONE AND IN THE 754 00:37:59,480 --> 00:38:02,960 STROMA. THE CELLS WERE DYING. 755 00:38:02,960 --> 00:38:06,440 SO, THIS LED US TO KIND OF PUT 756 00:38:06,440 --> 00:38:08,000 TOGETHER OUR HYPOTHESIS ABOUT 757 00:38:08,000 --> 00:38:10,800 WHAT IS HAPPENING WITH AGING, A 758 00:38:10,800 --> 00:38:12,520 PROCESS WE CALL NORMALIZATION. 759 00:38:12,520 --> 00:38:15,360 IN THE LESION, WE HAVE A MIXTURE 760 00:38:15,360 --> 00:38:20,160 OF NORMAL AND MUTANT STROMAL 761 00:38:20,160 --> 00:38:22,080 PROGENITOR CELLS AND MUTATION 762 00:38:22,080 --> 00:38:24,240 CAUSES INITIALLY HUGE INCREASE 763 00:38:24,240 --> 00:38:26,640 IN PROLIFERATION AND STROMAL 764 00:38:26,640 --> 00:38:28,160 CELLS BEING ON STEROIDS THAT 765 00:38:28,160 --> 00:38:29,720 THEY TAKE OVER THE WHOLE MARROW 766 00:38:29,720 --> 00:38:33,080 AND IS INCREASE, OF COURSE, IN 767 00:38:33,080 --> 00:38:36,880 CYCLIC AMP AND GS ALPHA ITSELF 768 00:38:36,880 --> 00:38:39,000 THAT CAUSES ABNORMAL FORMATION 769 00:38:39,000 --> 00:38:42,000 OF BONE WITH THESE RETRACTED 770 00:38:42,000 --> 00:38:44,960 CELLS THAT UNDERGO APOPTOSIS AND 771 00:38:44,960 --> 00:38:48,760 WITH AGING AS APOPTOSIS IS 772 00:38:48,760 --> 00:38:51,160 OCCURRING, WE LOSE THE MUTANT 773 00:38:51,160 --> 00:38:55,040 SKELETAL STEM CELLS AND NORMAL 774 00:38:55,040 --> 00:38:56,680 SKELETAL STEM CELLS SURVIVE AND 775 00:38:56,680 --> 00:38:59,520 THOSE CELLS GO ON TO FORM NORMAL 776 00:38:59,520 --> 00:39:03,680 BONE AND SUPPORT NORMAL 777 00:39:03,680 --> 00:39:06,800 HEMATOPOEESIS AND FORMATION OF 778 00:39:06,800 --> 00:39:10,720 MARROW ADIPOCYTES AND WHY WAS 779 00:39:10,720 --> 00:39:13,200 THE X-RAY ABNORMAL? NORMAL 780 00:39:13,200 --> 00:39:16,960 MUTANT CELL REMODELED ON AN 781 00:39:16,960 --> 00:39:19,280 ABNORMAL SCAFFOLD AND ABNORMAL 782 00:39:19,280 --> 00:39:20,840 ARCHITECTURE WAS MAINTAINED EVEN 783 00:39:20,840 --> 00:39:23,240 THOUGH THE BONE WAS PRETTY MUCH 784 00:39:23,240 --> 00:39:26,960 NORMAL AND SUPPORTED NORMAL HEM 785 00:39:26,960 --> 00:39:27,280 ATTOPOEESIS. 786 00:39:27,280 --> 00:39:30,200 SO, WHAT DOES THIS MEAN TO THE 787 00:39:30,200 --> 00:39:31,920 SKELETAL STEM CELL? 788 00:39:31,920 --> 00:39:36,120 WHAT WE HYPOTHESIZE IS WHEN THE 789 00:39:36,120 --> 00:39:38,680 MUTANT STEM CELL DIVIDES IT 790 00:39:38,680 --> 00:39:41,400 DIVIDES SYMMETRICALLY SO BOTH 791 00:39:41,400 --> 00:39:43,440 DAUGHTERS ARE SOMEWHAT COMMITTED 792 00:39:43,440 --> 00:39:47,320 TO OSTEOGENIC LINEAGE AND 793 00:39:47,320 --> 00:39:48,560 PROLIFERATING LIKE BATS OUT OF 794 00:39:48,560 --> 00:39:52,440 HELL AND REPLACING THE NORMAL 795 00:39:52,440 --> 00:39:54,440 MARROW WITH FIBROTIC MARROW AND 796 00:39:54,440 --> 00:39:56,680 AT A CERTAIN POINT CELLS START 797 00:39:56,680 --> 00:39:59,920 TO APOP TOES AND BASICALLY KILL 798 00:39:59,920 --> 00:40:02,280 THEMSELVES OFF SO THAT THE 799 00:40:02,280 --> 00:40:03,880 NORMAL CELLS SURVIVE. 800 00:40:03,880 --> 00:40:07,880 SO, THIS TELLS US THAT CYCLIC 801 00:40:07,880 --> 00:40:10,720 AMP IS VERY IMPORTANT TO CONTROL 802 00:40:10,720 --> 00:40:15,360 DURING THE ASYMMETRIC 803 00:40:15,360 --> 00:40:16,840 SELF-RENEWING DIVISION OF A 804 00:40:16,840 --> 00:40:17,520 SKELETAL STEM CELL. 805 00:40:17,520 --> 00:40:20,200 IN SUMMARY, BASICALLY I HAVE 806 00:40:20,200 --> 00:40:24,200 TOLD YOU THAT BONE MARROW 807 00:40:24,200 --> 00:40:26,240 CONTAINS MULTIPOTENT STROMAL 808 00:40:26,240 --> 00:40:29,520 CELLS THAT ARE SUBSETS OF BONE 809 00:40:29,520 --> 00:40:31,160 MARROW STROMAL CELL POPULATION 810 00:40:31,160 --> 00:40:33,680 FORMING BONE STROMA SUPPORTING 811 00:40:33,680 --> 00:40:36,280 BLOOD FORMATION AND MARROW 812 00:40:36,280 --> 00:40:38,480 ADIPOCYTES CONTROLLING 813 00:40:38,480 --> 00:40:43,480 OSTEOCLASTS KREN TLAL MEDIATORS 814 00:40:43,480 --> 00:40:46,840 OF HOMEOSTASIS AND ARISE IN 815 00:40:46,840 --> 00:40:48,680 MULTIPOTENT EPIBLASTS IN INNER 816 00:40:48,680 --> 00:40:52,840 CELL MASTS AND DERIVATIVES OF 817 00:40:52,840 --> 00:40:54,800 MUTANT EPIBLASTS GIVE RISE TO 818 00:40:54,800 --> 00:40:58,000 TISSUES IN ALL THREE GERM LAYER 819 00:40:58,000 --> 00:41:00,960 AND MUTATIONS DISRUPT FUNCTION 820 00:41:00,960 --> 00:41:04,840 OF THE STEM CELL LEADING TO 821 00:41:04,840 --> 00:41:08,160 ABNORMAL BONE AND ABNORMAL 822 00:41:08,160 --> 00:41:10,600 SULFATE CHOICES LEADING TO 823 00:41:10,600 --> 00:41:12,320 FIBROUS TISSUE AND MUTANT CELLS 824 00:41:12,320 --> 00:41:15,920 DON'T SELF-RENEW AND APOP TOES 825 00:41:15,920 --> 00:41:19,040 AND NORMAL CELLS BEGIN TO RESUME 826 00:41:19,040 --> 00:41:22,000 NORMAL BONE FORMATION AND 827 00:41:22,000 --> 00:41:24,960 QUALITIES DO CHARACTERIZE 828 00:41:24,960 --> 00:41:26,800 FIBROUS DYSPLASIA AS A STEM CELL 829 00:41:26,800 --> 00:41:27,400 DISEASE. 830 00:41:27,400 --> 00:41:31,000 SO, AT THIS POINT, IF I WERE TO 831 00:41:31,000 --> 00:41:33,040 MAKE A LIST OF ALL PEOPLE TO 832 00:41:33,040 --> 00:41:34,560 ACKNOWLEDGE WE WOULD BE HERE 833 00:41:34,560 --> 00:41:36,400 FOREVER. I WILL GET EMOTIONAL. 834 00:41:36,400 --> 00:41:40,720 I ALWAYS DO. I WOULD LIKE TO 835 00:41:40,720 --> 00:41:48,120 THANK KENNY -- HENNING BURKE ED 836 00:41:48,120 --> 00:41:50,440 ALL HANSEN FOR THEY HAS PASS AD 837 00:41:50,440 --> 00:41:52,880 WAY I'M GETTING EMOTIONAL AND 838 00:41:52,880 --> 00:41:55,600 LARRY TABAK THAT ALSO THIS CRAZY 839 00:41:55,600 --> 00:41:57,960 LADY THAT WANTED TO DO THESE 840 00:41:57,960 --> 00:42:00,560 STUDIES AND HAVE THEIR SUPPORT 841 00:42:00,560 --> 00:42:02,000 WAS REALLY GREAT AND ALLEN YOU 842 00:42:02,000 --> 00:42:03,520 WERE ONE OF MY BIGGEST STARS 843 00:42:03,520 --> 00:42:05,640 THANK YOU SO MUCH. I HAD THE 844 00:42:05,640 --> 00:42:09,600 BEST COLLEAGUES EVER WITH LARRY 845 00:42:09,600 --> 00:42:12,360 FISCHER MAIRIAN YOUNG MIKE, AVA 846 00:42:12,360 --> 00:42:15,480 AND MY FORMER BRANCH AND 847 00:42:15,480 --> 00:42:16,800 SKELETAL BIOLOGY SECTION AND 848 00:42:16,800 --> 00:42:20,120 FORMER CELL FELLOWS SERR GAY AND 849 00:42:20,120 --> 00:42:25,720 NATASHA AND MAH ESHGS SH HAS 850 00:42:25,720 --> 00:42:29,920 PASSED AWAY UNFORTUNATELY AND 851 00:42:29,920 --> 00:42:34,440 MARA AND HER GROUP AT SAPIENZA 852 00:42:34,440 --> 00:42:36,840 AND PENNY WHO WE HIRED JANICE TO 853 00:42:36,840 --> 00:42:39,520 WORK WITH PENNY AND GOT ONE OF 854 00:42:39,520 --> 00:42:41,600 THE FIRST BENCH TO BEDSIDE 855 00:42:41,600 --> 00:42:46,000 AWARDS AT NIH RESEARCH NURSES IN 856 00:42:46,000 --> 00:42:48,080 INSTITUTE AND ENDOCRINE TRAINING 857 00:42:48,080 --> 00:42:49,600 PROGRAM AND EVERYBODY. THANKS 858 00:42:49,600 --> 00:42:51,080 SO MUCH. I APPRECIATE IT. HERE 859 00:42:51,080 --> 00:42:52,880 IS TO BETTER TREATMENT AND CURE 860 00:42:52,880 --> 00:42:54,680 DURING THE NEXT 25 YEARS PRAFR 861 00:42:54,680 --> 00:42:58,400 YOU WILL HEAR ABOUT THAT. 862 00:42:58,400 --> 00:42:59,240 >> AUDIENCE: [APPLAUSE]. 863 00:42:59,240 --> 00:43:09,800 >> >> LET ME THINK OF SOMETHING 864 00:43:25,200 --> 00:43:30,720 FUNNY. SHE SHOWED THAT OUR 865 00:43:30,720 --> 00:43:36,960 BONES CAN GET BETTER. 866 00:43:36,960 --> 00:43:42,480 DR. RIM UNUCHI STUDIES BONE 867 00:43:42,480 --> 00:43:44,680 MARROW -- FIBROUS DYSPLASIA AND 868 00:43:44,680 --> 00:43:47,440 RECEIVED MEDICAL DEGREE AND PHD 869 00:43:47,440 --> 00:43:53,000 AT SAPIENZA UNIVERSITY AS IS 870 00:43:53,000 --> 00:43:54,120 BOARD CERTIFIED PATHOLOGIST AND 871 00:43:54,120 --> 00:43:57,680 SPENT 2 YEARS IN CSDB WORKING IN 872 00:43:57,680 --> 00:43:59,520 PAM'S LAG AT FOGARTY 873 00:43:59,520 --> 00:44:01,560 INTERNATIONAL FELLOW USING A 874 00:44:01,560 --> 00:44:05,000 MOUSE MODEL IDENTIFIED ANTIRANK 875 00:44:05,000 --> 00:44:07,240 LIGAN ANTIBODY. 876 00:44:07,240 --> 00:44:08,960 SHE HAS WORKED CLOSELY WITH 877 00:44:08,960 --> 00:44:12,120 CLINICAL COLLEAGUES AT NIDCR TO 878 00:44:12,120 --> 00:44:14,440 LEAD THE WAY INTO POTENTIAL 879 00:44:14,440 --> 00:44:16,160 THERAPEUTICS OF LESIONS AND 880 00:44:16,160 --> 00:44:18,200 TODAY WILL DESCRIBE MODELS AND 881 00:44:18,200 --> 00:44:20,040 HER WORK ADVANCING OUR 882 00:44:20,040 --> 00:44:24,840 UNDERSTANDING OF THE BIOLOGY OF 883 00:44:24,840 --> 00:44:28,680 FIBROUS DYSPLASIA. 884 00:44:28,680 --> 00:44:31,960 >> AUDIENCE: [APPLAUSE]. 885 00:44:31,960 --> 00:44:34,120 >> THANK YOU, JANICE. THANK YOU 886 00:44:34,120 --> 00:44:37,880 TO ALL OF THE ORGANIZERS FOR 887 00:44:37,880 --> 00:44:41,080 HAVING ME HERE TODAY TO TALK 888 00:44:41,080 --> 00:44:43,640 ABOUT FIBRO DYSPLASIA AND MODELS 889 00:44:43,640 --> 00:44:45,520 THAT HELP US TO CLARIFY IT. 890 00:44:45,520 --> 00:44:48,000 ALSO, ABOUT THE QUESTIONS THAT 891 00:44:48,000 --> 00:44:49,760 THESE EXPERIMENTAL MODELS ARE 892 00:44:49,760 --> 00:44:52,760 NOW RAISING THAT WE HAVE TO 893 00:44:52,760 --> 00:44:54,400 ADDRESS IN THE NEXT FUTURE. 894 00:44:54,400 --> 00:44:57,680 BEFORE STARTING MY PRESENTATION, 895 00:44:57,680 --> 00:45:00,160 I WOULD LIKE TO MENTION ONCE 896 00:45:00,160 --> 00:45:03,560 AGAIN MENTOR PAULO AND HIS 897 00:45:03,560 --> 00:45:04,440 CONTRIBUTION TO THE 898 00:45:04,440 --> 00:45:06,120 UNDERSTANDING OF THIS DISEASE. 899 00:45:06,120 --> 00:45:09,120 WHEN WE FIRST STARTED STUDIES 900 00:45:09,120 --> 00:45:11,400 FIBROUS DYSPLASIA WAS COMMONLY 901 00:45:11,400 --> 00:45:14,720 REFERRED TO AS A DISEASE WITH 902 00:45:14,720 --> 00:45:18,560 FIBROUS OSTEOMETAMRASHIA AND 903 00:45:18,560 --> 00:45:20,840 DISEASE WITH COLLAGEN FIBROUSING 904 00:45:20,840 --> 00:45:23,600 TO BONE AND EXAMPLE OF 905 00:45:23,600 --> 00:45:26,800 OSTEOBLASTS IN THE EXAMPLE HERE 906 00:45:26,800 --> 00:45:29,080 AND THINK THAT THIS FIRM 907 00:45:29,080 --> 00:45:32,560 REJECTION OF THIS VIEW AND 908 00:45:32,560 --> 00:45:33,840 METAPLASTIC BONE AT LARGE IS 909 00:45:33,840 --> 00:45:35,480 IMPORTANT TO SET DIRECTION OF 910 00:45:35,480 --> 00:45:39,360 FOLLOWING STUDIES WE HAVE THEN 911 00:45:39,360 --> 00:45:42,120 PERFORMED WITH DR. COLLINS AND 912 00:45:42,120 --> 00:45:44,920 MANY COLLEAGUES HERE AT NIH AND 913 00:45:44,920 --> 00:45:46,160 TO WHICH INDEED WE HAVE 914 00:45:46,160 --> 00:45:50,040 UNDERSTOOD THAT AS WE HAVE JUST 915 00:45:50,040 --> 00:45:52,160 HEARD THAT FIBROUS BONE 916 00:45:52,160 --> 00:45:54,400 FORMATION NORMAL BONE FORMATION 917 00:45:54,400 --> 00:45:57,680 IN FIBROUS DYSPLASIA MEANING 918 00:45:57,680 --> 00:46:01,680 POSITION OF WOVEN BONE WITH 919 00:46:01,680 --> 00:46:05,160 FIBERS HYPERMINERALIZED MATRIX 920 00:46:05,160 --> 00:46:07,840 AND FEATURES OF [INDISCERNIBLE] 921 00:46:07,840 --> 00:46:09,680 THAT IS [INDISCERNIBLE] MAY BE 922 00:46:09,680 --> 00:46:12,560 ASCRIBED TO ABNORMAL 923 00:46:12,560 --> 00:46:15,320 DIFFERENTIATION AND/OR EXPANSION 924 00:46:15,320 --> 00:46:20,960 OF CELLS OSTEOGENERALICALLY 925 00:46:20,960 --> 00:46:24,080 BROUGHT ABOUT BY MUTATIONS AND 926 00:46:24,080 --> 00:46:26,840 IDENTIFY MOLECULAR BASIS OF THIS 927 00:46:26,840 --> 00:46:27,160 FUNCTION. 928 00:46:27,160 --> 00:46:29,160 ALL IN SIZE TO WHICH WE GAIN AT 929 00:46:29,160 --> 00:46:31,960 THE BEGINNING OF THE NATURE OF 930 00:46:31,960 --> 00:46:34,800 THIS DISEASE BY STUDYING HUMAN 931 00:46:34,800 --> 00:46:37,680 SAMPLES HAVE BEEN CONFIRMED BY 932 00:46:37,680 --> 00:46:38,880 MULTIPLE TRANSGENIC MOUSE MODELS 933 00:46:38,880 --> 00:46:40,360 THAT HAVE BEEN DEVELOPED OVER 934 00:46:40,360 --> 00:46:44,000 THE YEARS CLEARLY SHOWING THAT 935 00:46:44,000 --> 00:46:45,600 FIBROUS DYSPLASIA LIKE PHENOTYPE 936 00:46:45,600 --> 00:46:51,760 IS REPRODUCED WHEN THE MUTATION 937 00:46:51,760 --> 00:46:54,320 IS EXPRESSED IN IN WHOLE 938 00:46:54,320 --> 00:46:57,560 OSTEOGENERALICALLY BY USING 939 00:46:57,560 --> 00:46:59,360 EITHER UBIQUITOUSLY OR 940 00:46:59,360 --> 00:47:02,400 CONSTITTIVELY EXPRESSED 941 00:47:02,400 --> 00:47:05,960 PROMOTORS SUCH AS EXOGENOUS 942 00:47:05,960 --> 00:47:07,760 PROMOTORS PGK OR [INDISCERNIBLE] 943 00:47:07,760 --> 00:47:10,800 BY OUR GROUP OR EARLY 944 00:47:10,800 --> 00:47:13,160 [INDISCERNIBLE] SUCH AS PRX1 945 00:47:13,160 --> 00:47:17,320 THAT IS USED BY ZAO AND 946 00:47:17,320 --> 00:47:20,640 COLLEAGUE AND CANYON AND 947 00:47:20,640 --> 00:47:23,760 COLLEAGUES AND [INDISCERNIBLE] 948 00:47:23,760 --> 00:47:25,720 WHICH IS EXPRESSED BY BONE 949 00:47:25,720 --> 00:47:28,760 MARROW STROMAL CELLS OR USING 950 00:47:28,760 --> 00:47:32,280 [INDISCERNIBLE] THAT MARKS EARLY 951 00:47:32,280 --> 00:47:33,480 OSTEOGENERAL CAL [INDISCERNIBLE] 952 00:47:33,480 --> 00:47:40,000 SHOWED BY CANYON A COLLEAGUE Z * 953 00:47:40,000 --> 00:47:43,520 AND COLLEAGUES. AND WHEN 954 00:47:43,520 --> 00:47:45,680 EXPRESSION IS DRIVEN BY 955 00:47:45,680 --> 00:47:47,280 PROMOTORS SPECIFICALLY DEFINING 956 00:47:47,280 --> 00:47:50,640 BONE FORMING CELLS SUCH AS 2.3 957 00:47:50,640 --> 00:47:52,760 COLLAGEN FRAGMENT OF COLLAGEN 958 00:47:52,760 --> 00:47:54,920 TYPE 1 PROMOTOR MEANING MUTATION 959 00:47:54,920 --> 00:47:59,120 IS RESTRICTED TO OSTEOBLASTIC 960 00:47:59,120 --> 00:48:00,760 CELLS MIGHT DEVELOP DIFFERENT 961 00:48:00,760 --> 00:48:03,560 HIGH BONE MASS PHENOTYPE AND ALL 962 00:48:03,560 --> 00:48:08,080 TOGETHER THIS DATA AND 963 00:48:08,080 --> 00:48:13,160 TRANSGENIC MODELS HAVE LED US TO 964 00:48:13,160 --> 00:48:21,480 RECLASSIFY FIBROUS DISSIA -- 965 00:48:21,480 --> 00:48:25,720 DYSPLASIA AND CRITICAL ROLE OF 966 00:48:25,720 --> 00:48:30,480 STEM CELL IN ITS BIOLOGY. 967 00:48:30,480 --> 00:48:32,160 HOWEVER, AS FOR MANY OTHER 968 00:48:32,160 --> 00:48:34,160 ORGANS REASON OF DEVELOPMENT AND 969 00:48:34,160 --> 00:48:35,560 APPLICATION OF NEW TECHNOLOGIES 970 00:48:35,560 --> 00:48:40,600 TO STUDY OF BONE AND BONE MARROW 971 00:48:40,600 --> 00:48:43,640 BIOLOGY IS RAISING MANY 972 00:48:43,640 --> 00:48:45,600 QUESTIONS IN FIBROUS DYSPLASIA 973 00:48:45,600 --> 00:48:50,120 FOR EXAMPLE USING TECHNIQUES 974 00:48:50,120 --> 00:48:53,240 SUCH AS MOUSE LINEAGE TRACING 975 00:48:53,240 --> 00:48:55,720 AND WE HAVE RECENTLY LEARNED 976 00:48:55,720 --> 00:48:58,040 THAT IN BOTH HUMAN AND MICE 977 00:48:58,040 --> 00:48:59,640 THERE ARE MULTIPLE POPULATIONS 978 00:48:59,640 --> 00:49:01,800 OF SKELETALS THEMSELVES WITH 979 00:49:01,800 --> 00:49:04,800 DIFFERENT DISTRIBUTION IN TIME 980 00:49:04,800 --> 00:49:10,840 AND SPACE BONE MARROW STROMA 981 00:49:10,840 --> 00:49:14,040 LONG KNOWN AS GENUS COMPARTMENT 982 00:49:14,040 --> 00:49:16,760 IS MORE COMPLEX THAN WE 983 00:49:16,760 --> 00:49:18,800 PREVIOUSLY THOUGHT SUCH AS STEM 984 00:49:18,800 --> 00:49:21,680 CELLS AND SKELETAL FIBROBLASTS 985 00:49:21,680 --> 00:49:23,200 FUNCTIONAL WHICH IS STILL 986 00:49:23,200 --> 00:49:25,560 UNKNOWN AND KEEPING IN MIND THAT 987 00:49:25,560 --> 00:49:28,440 FIBROUS DYSPLASIA IS A MOSAIC 988 00:49:28,440 --> 00:49:29,880 DISEASE AND AT THIS POINT THERE 989 00:49:29,880 --> 00:49:31,400 ARE SOME IMPORTANT QUESTIONS WE 990 00:49:31,400 --> 00:49:34,000 NEED TO ADDRESS. FOR EXAMPLE, 991 00:49:34,000 --> 00:49:39,640 DO ALL THESE DIFFERENT CELL 992 00:49:39,640 --> 00:49:43,200 POPULATIONS GENERATE FIBROUS 993 00:49:43,200 --> 00:49:44,560 DYSPLASIA EXPRESSING CAUSATIVE 994 00:49:44,560 --> 00:49:49,360 MUTATIONS OR WHAT IS THE ROLE OF 995 00:49:49,360 --> 00:49:50,720 THESE DIFFERENT STROMAL CELL 996 00:49:50,720 --> 00:49:53,120 SUBSET OTHERS THAN SKELETAL STEM 997 00:49:53,120 --> 00:49:55,040 CELLS IN DEVELOPMENT OF THE 998 00:49:55,040 --> 00:49:55,600 DISEASE? 999 00:49:55,600 --> 00:49:58,840 THERE IS OBVIOUSLY A SUBSTANTIAL 1000 00:49:58,840 --> 00:50:01,520 AMOUNT OF WORK TO CLARIFY POINTS 1001 00:50:01,520 --> 00:50:03,680 AND SOME PRELIMINARY IN SIZE 1002 00:50:03,680 --> 00:50:07,440 HAVE BEEN RECENTLY PROVIDED BY 1003 00:50:07,440 --> 00:50:09,760 THESE TRANSGENIC MOUSE MODELS WE 1004 00:50:09,760 --> 00:50:11,760 GENERATED IN OUR LAB IN WHICH 1005 00:50:11,760 --> 00:50:15,560 THE FUNCTION OF MUTATION OF GS 1006 00:50:15,560 --> 00:50:20,200 ALPHA IS RESTRICTED TO A 1007 00:50:20,200 --> 00:50:22,200 POPULATION OF STROMAL CELLS 1008 00:50:22,200 --> 00:50:25,400 MARKED BY EXPRESSION OF MOUSE 1009 00:50:25,400 --> 00:50:27,640 AND PROMOTER AND CONNECTING 1010 00:50:27,640 --> 00:50:30,000 POSITIVE STROMAL CELLS HAVE BEEN 1011 00:50:30,000 --> 00:50:33,040 ORIGINALLY REPORTED AS 1012 00:50:33,040 --> 00:50:35,880 POPULATION OF VASCULAR MARROW 1013 00:50:35,880 --> 00:50:38,160 STROMAL CELLS ACTING AS MAJOR 1014 00:50:38,160 --> 00:50:41,440 SOURCE OF LYINGAND IN BONE AND 1015 00:50:41,440 --> 00:50:44,280 BONE MARROW MIGRAINE ENVIRONMENT 1016 00:50:44,280 --> 00:50:46,360 AND POPULATION OF COMMITTED 1017 00:50:46,360 --> 00:50:51,040 CELLS WITH NO OSTEOGENIC 1018 00:50:51,040 --> 00:50:52,120 ACTIVITY THAT IS REASON WHY 1019 00:50:52,120 --> 00:50:53,560 DEVELOPING MOUSE MOD HEELS 1020 00:50:53,560 --> 00:50:54,800 INTERESTED IN UNDERSTANDING 1021 00:50:54,800 --> 00:50:57,440 EFFECT OF MUTATION OF BONE 1022 00:50:57,440 --> 00:51:00,040 MARROW SITES AND HOWEVER WHEN WE 1023 00:51:00,040 --> 00:51:03,640 CROSSED THE LINE WITH MTMG 1024 00:51:03,640 --> 00:51:04,960 REPORTER LINE SO THAT IN 1025 00:51:04,960 --> 00:51:07,640 [INDISCERNIBLE] CONNECTING CELLS 1026 00:51:07,640 --> 00:51:11,040 ARE GREEN ON RED BACKGROUND WE 1027 00:51:11,040 --> 00:51:14,120 OBSERVED THAT FIRST THESE CELLS 1028 00:51:14,120 --> 00:51:16,840 COULD BE FOUND AROUND BLOOD 1029 00:51:16,840 --> 00:51:20,200 VESSELS AND AROUND BLOOD VESSELS 1030 00:51:20,200 --> 00:51:29,600 THAT RUN ACROSS -- DURING MOUSE 1031 00:51:29,600 --> 00:51:33,280 GROWTH CELLS CONTRIBUTE TO 1032 00:51:33,280 --> 00:51:34,760 [INDISCERNIBLE] BONE FORMATION 1033 00:51:34,760 --> 00:51:39,680 AT HEMATOPOETIC SITES SUCH AS 1034 00:51:39,680 --> 00:51:41,880 [INDISCERNIBLE] AND LONG BONES 1035 00:51:41,880 --> 00:51:45,680 WE ASSUME THEY ACT OR HAVE 1036 00:51:45,680 --> 00:51:48,800 MULTIPOTENT SKELETAL STEM CELLS 1037 00:51:48,800 --> 00:51:54,880 WHEREAS [INDISCERNIBLE] SUCH AS 1038 00:51:54,880 --> 00:51:56,920 DETAIL, SORRY. 1039 00:51:56,920 --> 00:51:59,960 OKAY. SUCH AS DETAIL THEY 1040 00:51:59,960 --> 00:52:02,000 GENERATE SITES THAT ARE BEHAVING 1041 00:52:02,000 --> 00:52:04,800 AS COMMITTED PROGENITORS AND 1042 00:52:04,800 --> 00:52:09,680 WHEN THE MUTATION IN SPECIFIC 1043 00:52:09,680 --> 00:52:15,120 CASE IS RESTRICTED TO CELL 1044 00:52:15,120 --> 00:52:17,920 POPULATION, MICE TRANSGENIC MICE 1045 00:52:17,920 --> 00:52:22,120 FIRST DEVELOP OSTEOPEENIC 1046 00:52:22,120 --> 00:52:26,400 PHENOTYPE WITH LOW BONE MASS 1047 00:52:26,400 --> 00:52:27,160 GENERALIZE [INDISCERNIBLE] 1048 00:52:27,160 --> 00:52:29,200 INTRACORTICAL LESIONS AND THIS 1049 00:52:29,200 --> 00:52:31,560 IS CONSISTENT AND IN AGREEMENT 1050 00:52:31,560 --> 00:52:36,200 WITH STIMULATION OF RANK LIGAND 1051 00:52:36,200 --> 00:52:38,000 SECRETION BY MUTATION AND 1052 00:52:38,000 --> 00:52:40,240 HOWEVER DURING MOUSE GROWTH AT 1053 00:52:40,240 --> 00:52:43,960 SIZE AT HEMATOPOETIC SITES AND 1054 00:52:43,960 --> 00:52:46,680 SITES THAT THESE CELLS HAVE 1055 00:52:46,680 --> 00:52:48,680 OSTEOGENIC ACTIVITY THIS 1056 00:52:48,680 --> 00:52:50,280 PHENOTYPE IS CONVERTED TO BONE 1057 00:52:50,280 --> 00:52:53,200 MASS PHENOTYPE AND SUSTAIN IT BY 1058 00:52:53,200 --> 00:52:54,400 CONNECTING POSITIVE CELLS THAT 1059 00:52:54,400 --> 00:52:59,440 THESE CELLS IN FEMALE MICE 1060 00:52:59,440 --> 00:53:03,560 PRODUCE ALSO ECTOPIC 1061 00:53:03,560 --> 00:53:05,160 PERIVASCULAR INTRAMODULEARY BONE 1062 00:53:05,160 --> 00:53:07,600 AND IMPORTANT TO NOTE IS IN BOTH 1063 00:53:07,600 --> 00:53:09,760 CASES THIS BONE IS NORMAL BONE 1064 00:53:09,760 --> 00:53:12,760 AND LARGELY [INDISCERNIBLE] AND 1065 00:53:12,760 --> 00:53:15,040 IS MINERALIZED AND THERE IS NO 1066 00:53:15,040 --> 00:53:20,960 MICRO FIBROSIS EXCEPT FOR VERY 1067 00:53:20,960 --> 00:53:24,200 FEW FIBROTIC FIBRO BLAST CELLS 1068 00:53:24,200 --> 00:53:28,760 THAT ARE AT VERY RAPID BONE 1069 00:53:28,760 --> 00:53:30,520 POSITION. AT THESE SITES IN 1070 00:53:30,520 --> 00:53:35,200 WHICH SITES ARE OSTEOGENIC 1071 00:53:35,200 --> 00:53:36,800 LESIONS DURING MOUSE GROWTH AS 1072 00:53:36,800 --> 00:53:39,160 OUR FIELD WITH EITHER NEWLY 1073 00:53:39,160 --> 00:53:41,200 FORMED BONE OR HEMATOPOEESIS 1074 00:53:41,200 --> 00:53:42,760 THAT IS ANOTHER INTERESTING 1075 00:53:42,760 --> 00:53:44,320 FINDING THAT IS CONSISTENT WITH 1076 00:53:44,320 --> 00:53:47,240 WHAT WE HAVE OBSERVED A FEW 1077 00:53:47,240 --> 00:53:51,960 YEARS AGO BY USING IN VITRO 1078 00:53:51,960 --> 00:53:54,120 MODEL EXPERIMENTAL MODEL OF THE 1079 00:53:54,120 --> 00:53:58,120 DISEASE OBTAINED BY TRANCE 1080 00:53:58,120 --> 00:54:01,520 DEUCING HUMAN BONE STEM CELLS 1081 00:54:01,520 --> 00:54:03,120 WITH [INDISCERNIBLE] AND WE HAVE 1082 00:54:03,120 --> 00:54:05,360 OBSERVED THAT MUTATION 1083 00:54:05,360 --> 00:54:07,760 UPREGULATES OSTEOGENIC GENES AND 1084 00:54:07,760 --> 00:54:11,600 GENES INVOLVED IN HEMATOPOE 1085 00:54:11,600 --> 00:54:14,720 EATIC FUNCTIONS AND SUGGESTS 1086 00:54:14,720 --> 00:54:20,800 THAT WE DO NOT FIND HEMATOPOETIC 1087 00:54:20,800 --> 00:54:22,920 CELLS IN LESIONS AND 1088 00:54:22,920 --> 00:54:24,320 [INDISCERNIBLE] ITSELF DOESN'T 1089 00:54:24,320 --> 00:54:26,480 APPEAR ABILITY OF PROGENITOR 1090 00:54:26,480 --> 00:54:31,160 CELLS TO SUPPORT HEMATOPOEESIS. 1091 00:54:31,160 --> 00:54:35,080 IN CONTRAST AT SITES THAT CELLS 1092 00:54:35,080 --> 00:54:39,840 DO NO THE HAVE OSTEOGENIC 1093 00:54:39,840 --> 00:54:41,600 ACTIVITY LYTIC LESIONS OF MOUSE 1094 00:54:41,600 --> 00:54:44,840 GROUJ ARE CONVERTED TO FIBROUS 1095 00:54:44,840 --> 00:54:46,480 LESIONS OR [INDISCERNIBLE] OF 1096 00:54:46,480 --> 00:54:49,040 FIBROUS DYSPLASIA AND WHAT IS 1097 00:54:49,040 --> 00:54:50,440 IMPORTANTLY INTERESTING TO NOTE 1098 00:54:50,440 --> 00:54:54,960 HERE IS FIBROTIC TISSUE IS 1099 00:54:54,960 --> 00:54:58,200 LARGELY MADE BY TOMATO POSITIVE 1100 00:54:58,200 --> 00:54:59,680 CELLS CONNECTING NEGATIVE CELLS 1101 00:54:59,680 --> 00:55:02,200 NONMUTED CELLS THAT IS IN 1102 00:55:02,200 --> 00:55:04,320 AGREEMENT WITH WHAT REPORTED AND 1103 00:55:04,320 --> 00:55:08,520 HAS BEEN PREVIOUSLY REPORTED BY 1104 00:55:08,520 --> 00:55:10,080 CANON COLLEAGUES AND 1105 00:55:10,080 --> 00:55:12,360 [INDISCERNIBLE] MOUSE MODEL THAT 1106 00:55:12,360 --> 00:55:15,960 THEY HAVE SHOWN THAT FIBROSIS IS 1107 00:55:15,960 --> 00:55:21,520 A NONCELLULAR EFFECT OF EXTREME 1108 00:55:21,520 --> 00:55:23,680 EXPRESSION OF [INDISCERNIBLE] 1109 00:55:23,680 --> 00:55:34,240 AND SO ALTHOUGH THE EXISTENCE -- 1110 00:55:57,640 --> 00:56:00,280 THIS MAY DEPEND ON SPECIFIC 1111 00:56:00,280 --> 00:56:03,440 NATURE OF STEM CELL POPULATION 1112 00:56:03,440 --> 00:56:05,680 OR ON MICRO ENVIRONMENT WHICH 1113 00:56:05,680 --> 00:56:08,360 THIS POPULATION IS WORKING AND 1114 00:56:08,360 --> 00:56:11,200 THEY ALSO SHOW AND HAVE SHOWN 1115 00:56:11,200 --> 00:56:14,520 THAT STROMAL CELLS SUBSET OTHER 1116 00:56:14,520 --> 00:56:16,720 THAN SKELETAL STEM CELLS MAY 1117 00:56:16,720 --> 00:56:18,840 TRIGGER OR CONTRIBUTE TO THE 1118 00:56:18,840 --> 00:56:21,720 DEVELOPMENT OF THE DISEASE AND 1119 00:56:21,720 --> 00:56:23,640 FOR EXAMPLE THEY MAY TRIGGER 1120 00:56:23,640 --> 00:56:26,320 DEVELOPMENT OF DELETIONS. 1121 00:56:26,320 --> 00:56:28,920 AND I THINK THAT BOTH THESE 1122 00:56:28,920 --> 00:56:30,800 POINTS ACTUALLY LEAD TO ONE 1123 00:56:30,800 --> 00:56:32,640 SINGLE HYPOTHESIS THAT IS MAYBE 1124 00:56:32,640 --> 00:56:36,200 WHAT IS VERY CRITICAL TO FIBROUS 1125 00:56:36,200 --> 00:56:38,920 DYSPLASIA BIOLOGY IS A LOCAL 1126 00:56:38,920 --> 00:56:41,880 PERSISTENT UNBALANCED 1127 00:56:41,880 --> 00:56:44,040 STIMULATION OF BONE FORMATION 1128 00:56:44,040 --> 00:56:45,600 MEANING EXCESS STIMULATION OF 1129 00:56:45,600 --> 00:56:46,920 BONE [INDISCERNIBLE] COMPARED TO 1130 00:56:46,920 --> 00:56:49,160 BONE FORMATION THAT WE HAVE SEEN 1131 00:56:49,160 --> 00:56:51,720 IN DETAIL OF THESE MICE. 1132 00:56:51,720 --> 00:56:54,360 DUE FOR EXAMPLE TO NATURE OF 1133 00:56:54,360 --> 00:56:57,560 CELLS WITH DIFFERENT COMBINATION 1134 00:56:57,560 --> 00:56:59,200 OF CELLS. 1135 00:56:59,200 --> 00:57:01,720 THIS BRINGS US TO THE OTHER SIDE 1136 00:57:01,720 --> 00:57:05,400 OF FIBROUS DYSPLASIA BIOLOGY AND 1137 00:57:05,400 --> 00:57:09,080 BONE ABSORPTION AND WE KNOW 1138 00:57:09,080 --> 00:57:10,920 ALREADY THAT BONE ABSORPTION 1139 00:57:10,920 --> 00:57:14,920 PLAYS A MAJOR ROLE IN 1140 00:57:14,920 --> 00:57:16,360 PATHOGENESIS OF THIS DISEASE 1141 00:57:16,360 --> 00:57:19,040 SHOWN BY EFFECT OF RANK LIGAND 1142 00:57:19,040 --> 00:57:21,080 AND [INDISCERNIBLE] IN BOTH MICE 1143 00:57:21,080 --> 00:57:24,320 AND HUMANS. 1144 00:57:24,320 --> 00:57:27,960 WE KNOW THAT IN MICE TREATMENT 1145 00:57:27,960 --> 00:57:29,480 WITH MOUSE RANK LIGAND AND 1146 00:57:29,480 --> 00:57:31,720 [INDISCERNIBLE] LEADS TO 1147 00:57:31,720 --> 00:57:35,160 REPLACEMENT OF FIBROTIC TISSUE 1148 00:57:35,160 --> 00:57:36,880 WITH HYPERMINERALIZED BONE AND 1149 00:57:36,880 --> 00:57:39,200 PREVENTS DEVELOPMENT OF NEW 1150 00:57:39,200 --> 00:57:40,360 LESIONS AS SHOWN BY OUR GROUP A 1151 00:57:40,360 --> 00:57:43,640 FEW YEARS AING THAT HAS SHOWN 1152 00:57:43,640 --> 00:57:46,640 RECENTLY BY OTHER GROUPS. 1153 00:57:46,640 --> 00:57:50,840 WE ALSO KNOW THAT IN PATIENTS 1154 00:57:50,840 --> 00:57:55,960 TREATMENT WITH KNOW ASSUME AB 1155 00:57:55,960 --> 00:57:57,440 CAUSES REDUCTION WITH 1156 00:57:57,440 --> 00:57:59,600 IMPROVEMENT RECENTLY SHOWN BY 1157 00:57:59,600 --> 00:58:01,480 CLINICAL TRIAL GOING HERE AT 1158 00:58:01,480 --> 00:58:03,560 NIH. 1159 00:58:03,560 --> 00:58:06,040 WE ALSO KNOW THAT THERE IS A 1160 00:58:06,040 --> 00:58:07,480 MAJOR DRAWBACK WITH THE 1161 00:58:07,480 --> 00:58:10,240 TREATMENT. SO, THE TREATMENT 1162 00:58:10,240 --> 00:58:13,160 CAN BE AN EFFICIENT TREATMENT 1163 00:58:13,160 --> 00:58:15,040 FOR FIBROUS DYSPLASIA AND KNOW 1164 00:58:15,040 --> 00:58:17,640 THERE IS A MAJOR DRAWBACK THAT 1165 00:58:17,640 --> 00:58:21,480 IS SEVERE REBOUND OF THE DISEASE 1166 00:58:21,480 --> 00:58:23,040 AT TREATMENT DISCONTINUATION. 1167 00:58:23,040 --> 00:58:25,680 IT MEANS HERE THERE ARE NEW 1168 00:58:25,680 --> 00:58:27,320 QUESTIONS WE NEED TO ADDRESS IF 1169 00:58:27,320 --> 00:58:29,760 IN THE NEXT FUTURE TO NOT ONLY 1170 00:58:29,760 --> 00:58:32,720 BETTER UNDERSTAND BIOLOGY OF THE 1171 00:58:32,720 --> 00:58:35,560 DISEASE BUT ALSO TO REFINE THESE 1172 00:58:35,560 --> 00:58:38,280 THERAPEUTIC APPROACH. 1173 00:58:38,280 --> 00:58:41,160 FOR EXAMPLE, I THINK WE NEED TO 1174 00:58:41,160 --> 00:58:42,600 BETTER UNDERSTAND THE MECHANISMS 1175 00:58:42,600 --> 00:58:46,080 THAT ARE LEADING TO OSTEOBLAST 1176 00:58:46,080 --> 00:58:48,400 FORMATION IN FIBROUS DYSPLASIA. 1177 00:58:48,400 --> 00:58:51,360 FOR EXAMPLE, WE NEED TO 1178 00:58:51,360 --> 00:58:56,320 UNDERSTAND HOW WE CAN STIMULATE 1179 00:58:56,320 --> 00:58:58,880 OSTEOGENIC DIFFERENTIATION 1180 00:58:58,880 --> 00:59:01,720 WITHIN FIBROTIC TISSUE WITHOUT 1181 00:59:01,720 --> 00:59:04,200 INCREASING OSTEOBLAST FORMATION 1182 00:59:04,200 --> 00:59:06,560 AND SHOWING HERE THIS WORK BY 1183 00:59:06,560 --> 00:59:09,560 CANON COLLEAGUES THAT THEY HAVE 1184 00:59:09,560 --> 00:59:12,120 CROSSED [INDISCERNIBLE] WITH 1185 00:59:12,120 --> 00:59:15,040 MOUSE LINE WITH GENETIC 1186 00:59:15,040 --> 00:59:17,680 DOWNREGULATION OF WIND PATHWAY 1187 00:59:17,680 --> 00:59:21,320 SHOWING THAT PROGENY MICRO 1188 00:59:21,320 --> 00:59:24,840 FIBROSIS IS RESCUED AND 1189 00:59:24,840 --> 00:59:25,800 OSTEOBLAST [INDISCERNIBLE] IS 1190 00:59:25,800 --> 00:59:28,040 INCREASED COMPARED TO WILD TYPE 1191 00:59:28,040 --> 00:59:29,520 MICE AND ANOTHER QUESTION THAT I 1192 00:59:29,520 --> 00:59:33,080 THINK IS INTERESTING IS THAT 1193 00:59:33,080 --> 00:59:34,720 AREN'T THERE OTHER SOURCES OF 1194 00:59:34,720 --> 00:59:36,920 RANK LIGAND AND OTHER SORTS THAT 1195 00:59:36,920 --> 00:59:41,360 MAY CONTRIBUTE TO NORMAL 1196 00:59:41,360 --> 00:59:44,440 OSTEOBLASTOGENESIS AND KNOW THAT 1197 00:59:44,440 --> 00:59:45,520 MUTATED STROMAL CELLS ARE MAJOR 1198 00:59:45,520 --> 00:59:47,600 PLAYER WE AGREE ON THIS AND 1199 00:59:47,600 --> 00:59:49,680 CAN'T EXCLUDE CONTRIBUTION OF 1200 00:59:49,680 --> 00:59:52,000 OTHER CELL TYPES AND AT THIS 1201 00:59:52,000 --> 00:59:55,160 TIME I CAN TELL YOU IMMUNE CELLS 1202 00:59:55,160 --> 00:59:58,080 THAT ARE MAJOR PRODUCERS OF RANK 1203 00:59:58,080 --> 01:00:01,480 LIGAND IN BODY THAT WE FIND IN 1204 01:00:01,480 --> 01:00:03,080 SKELETON NOT INVOLVED IN THE 1205 01:00:03,080 --> 01:00:07,560 PROCESS. WITH WE CROSSED OUR FD 1206 01:00:07,560 --> 01:00:10,320 MICE WITH KID MICE TO EXPRESS 1207 01:00:10,320 --> 01:00:12,440 MUTATION ON IMMUNOCOMPROMISED 1208 01:00:12,440 --> 01:00:13,760 BACKGROUND WE HAVE SEEN 1209 01:00:13,760 --> 01:00:19,360 DEVELOPMENT OF NOT TYPICAL FDA 1210 01:00:19,360 --> 01:00:21,000 PHENOTYPE AND CAN'T EXCLUDE 1211 01:00:21,000 --> 01:00:22,720 CONTRIBUTION OF OTHER CELL TYPES 1212 01:00:22,720 --> 01:00:25,800 FOR EXAMPLE VASCULAR ENDOTHELIAL 1213 01:00:25,800 --> 01:00:29,160 CELLS AND BLOOD CELLS BASED ON 1214 01:00:29,160 --> 01:00:33,440 FREQUENT OBSERVATION OF ATOPIC 1215 01:00:33,440 --> 01:00:35,920 -- THIS IS VERY RARE FIND. I 1216 01:00:35,920 --> 01:00:38,680 THINK THAT FIBROUS DYSPLASIA IS 1217 01:00:38,680 --> 01:00:40,280 PROBABLY UNIQUE DISEASE IN WHICH 1218 01:00:40,280 --> 01:00:43,200 WE CAN FIENTD OSTEOBLAST 1219 01:00:43,200 --> 01:00:46,080 FORMATION WITHIN BLOOD VESSELS 1220 01:00:46,080 --> 01:00:49,400 AND NEITHER CAN WE EXCLUDE A 1221 01:00:49,400 --> 01:00:52,240 CELL AUTONOMOUS EFFECT OF 1222 01:00:52,240 --> 01:00:53,200 FORMATION AND SHOWING THIS 1223 01:00:53,200 --> 01:00:55,600 SECTION APPROACHING WHICH WE 1224 01:00:55,600 --> 01:00:57,680 COLLECTED MANY OSTEOBLASTS FROM 1225 01:00:57,680 --> 01:00:59,240 SAME PATIENTS BY THIS SECTION 1226 01:00:59,240 --> 01:01:02,080 AND WE HAVE OBSERVED THAT 1227 01:01:02,080 --> 01:01:05,080 OSTEOBLASTS IN HUMAN FIBROUS 1228 01:01:05,080 --> 01:01:08,000 DYSPLASIA MUTATED ALLELE AND 1229 01:01:08,000 --> 01:01:10,080 WOULD LIKE YOU TO NOTE THAT THIS 1230 01:01:10,080 --> 01:01:13,560 PATIENT IN WHICH WE HAVE FOUND 1231 01:01:13,560 --> 01:01:15,360 MUTATED SEQUENCE IN OSTEOBLASTS 1232 01:01:15,360 --> 01:01:18,000 AND NOT IN THE SURROUNDING 1233 01:01:18,000 --> 01:01:19,760 FIBROTIC TISSUE NEITHER IN BONE 1234 01:01:19,760 --> 01:01:22,040 THAT IS KWON FIRMING VALIDITY OF 1235 01:01:22,040 --> 01:01:23,040 OUR APPROACH. 1236 01:01:23,040 --> 01:01:25,040 SO, AGAIN, THIS IS SOMETHING 1237 01:01:25,040 --> 01:01:26,600 THAT WE NEED TO FURTHER EXPLORE 1238 01:01:26,600 --> 01:01:28,160 IN THE FUTURE. 1239 01:01:28,160 --> 01:01:31,320 I THINK THAT THE MOST 1240 01:01:31,320 --> 01:01:32,400 INTERESTING QUESTION AT THIS 1241 01:01:32,400 --> 01:01:35,240 TIME RELAETDED TO OSTEOBLASTS 1242 01:01:35,240 --> 01:01:38,440 AND OSTEOBLAST INHIBITION IN 1243 01:01:38,440 --> 01:01:41,680 FIBROUS DYSPLASIA IS HOW -- WHAT 1244 01:01:41,680 --> 01:01:43,480 IS MECHANISM THROUGH INHIBITION 1245 01:01:43,480 --> 01:01:46,360 OF RANK LIGAND AND OSTEOBLASTS 1246 01:01:46,360 --> 01:01:49,480 LEADS TO BONE FORMATION MEANING 1247 01:01:49,480 --> 01:01:52,520 LEADS TO REPLACEMENT OF FIBROUS 1248 01:01:52,520 --> 01:01:55,360 TISSUE WITH MINERALIZED BONE IN 1249 01:01:55,360 --> 01:01:57,040 MICE AND LEADING TO BONE 1250 01:01:57,040 --> 01:01:59,800 IMPROVEMENT IN HUMANS AND SO 1251 01:01:59,800 --> 01:02:03,880 DOES IT STIMULATE OSTEOGENIC 1252 01:02:03,880 --> 01:02:05,720 DIFFERENTIATION OF FIBROTIC 1253 01:02:05,720 --> 01:02:07,200 TISSUE OR OTHER MECHANISMS WE 1254 01:02:07,200 --> 01:02:08,760 HAVE TO CLARIFY? 1255 01:02:08,760 --> 01:02:12,040 SO, IN AN ATTEMPT TO START TO 1256 01:02:12,040 --> 01:02:15,840 CLARIFY THIS POINT, WE RECENTLY 1257 01:02:15,840 --> 01:02:20,680 HAVE PERFORMED THESE TYPES OF 1258 01:02:20,680 --> 01:02:23,200 EXPERIMENTS WE TREATED OUR FD 1259 01:02:23,200 --> 01:02:25,120 MICE WITH FOUR DOSES OF 1260 01:02:25,120 --> 01:02:27,560 [INDISCERNIBLE] AND TWO DOSES OF 1261 01:02:27,560 --> 01:02:30,520 CALCIUM AND WE HAVE IN 17 DAYS 1262 01:02:30,520 --> 01:02:34,480 AND COMPARED TREATED MICE WITH 1263 01:02:34,480 --> 01:02:37,240 UNTREATED FD MICE AND WILD TYPE 1264 01:02:37,240 --> 01:02:40,080 MICE USING NANOSTREAM 1265 01:02:40,080 --> 01:02:42,600 [INDISCERNIBLE] ALLOWING 1266 01:02:42,600 --> 01:02:45,040 MOLECULAR ANALYSIS ON CALCIFIED 1267 01:02:45,040 --> 01:02:48,160 AND TISSUES THAT WE HAVE BEEN 1268 01:02:48,160 --> 01:02:51,520 ABLE TO COMPARE MOLECULAR AND 1269 01:02:51,520 --> 01:02:53,240 HISTLOGICAL CHANGES ON SAME 1270 01:02:53,240 --> 01:02:55,320 SAMPLES AND ON THE SAME SAMPLES 1271 01:02:55,320 --> 01:02:58,720 AND MOLECULAR CHANGES WE USED A 1272 01:02:58,720 --> 01:03:00,360 PANEL OF SELECTED GENES AND 1273 01:03:00,360 --> 01:03:03,040 GENES INVOLVING 1274 01:03:03,040 --> 01:03:04,960 OSTEOBLASTOGENESIS AND 1275 01:03:04,960 --> 01:03:06,800 [INDISCERNIBLE] BIOLOGY AT LARGE 1276 01:03:06,800 --> 01:03:10,920 LAND SHOW YOU MOST SIGNIFICANT 1277 01:03:10,920 --> 01:03:13,600 RESULTS. 1278 01:03:13,600 --> 01:03:16,480 WE OBSERVED DOWNREGULATION OF 1279 01:03:16,480 --> 01:03:17,680 MOST GENES. 1280 01:03:17,680 --> 01:03:20,080 THIS IS NOT BREATHTAKING RESULTS 1281 01:03:20,080 --> 01:03:22,880 OR EXPECTED RESULTS. 1282 01:03:22,880 --> 01:03:26,080 STILL, I THINK THAT THERE ARE 1283 01:03:26,080 --> 01:03:27,400 SOME POINTS THAT ARE 1284 01:03:27,400 --> 01:03:29,200 CONSIDERATION FOR EXAMPLE WE 1285 01:03:29,200 --> 01:03:34,080 HAVE SEEN THAT CSF1 CYTOKINE 1286 01:03:34,080 --> 01:03:36,640 THAT IS INVOLVED IN EARLY STAGES 1287 01:03:36,640 --> 01:03:40,960 OF OSTEOBLASTS PROLIFERATION AND 1288 01:03:40,960 --> 01:03:43,200 DIFFERENTIATION THAT IS 1289 01:03:43,200 --> 01:03:44,840 UPREGULATED IN FD LESIONS 1290 01:03:44,840 --> 01:03:47,840 COMPARED TO NORMAL BONE IS NOT 1291 01:03:47,840 --> 01:03:50,680 EFFECTED BY TREATMENT. IN THIS 1292 01:03:50,680 --> 01:03:53,680 SUGGESTS THAT DURING ANTI-RANK 1293 01:03:53,680 --> 01:03:56,040 LIGAND TREATMENT WE DON'T SEE 1294 01:03:56,040 --> 01:03:59,760 DIFFERENTIATED OSTEOBLASTS OR 1295 01:03:59,760 --> 01:04:02,760 OSTEOBLASTS OR [INDISCERNIBLE] 1296 01:04:02,760 --> 01:04:04,200 PROGENITORS STILL FORM AND 1297 01:04:04,200 --> 01:04:05,960 ACCUMULATE MAYBE GETTING READY 1298 01:04:05,960 --> 01:04:08,160 FOR REBOUND EFFECT AT END OF THE 1299 01:04:08,160 --> 01:04:11,040 TREATMENT. 1300 01:04:11,040 --> 01:04:12,080 OBVIOUSLY, REDUCTION OF DOWN 1301 01:04:12,080 --> 01:04:14,680 REGULATION OF THIS MARKER 1302 01:04:14,680 --> 01:04:16,080 ASSOCIATES WITH REDUCTION IN 1303 01:04:16,080 --> 01:04:19,240 NUMBER OF OSTEOBLASTS AND 1304 01:04:19,240 --> 01:04:22,640 CON10SATION OF COLLAGEN FIBERS 1305 01:04:22,640 --> 01:04:25,320 AND SURPRISING, HOWEVER, WE HAVE 1306 01:04:25,320 --> 01:04:27,400 OBSERVED ALSO THAT TREATMENT 1307 01:04:27,400 --> 01:04:29,680 CAUSES A GENERAL REDUCTION IN 1308 01:04:29,680 --> 01:04:33,560 THE OSTEOGENIC ACTIVITY OF 1309 01:04:33,560 --> 01:04:37,360 TREATED FD LESIONS AND SHOWN BY 1310 01:04:37,360 --> 01:04:40,480 DOWNREGULATION OF OSTEOGENIC 1311 01:04:40,480 --> 01:04:45,240 GENES ALL OSTEOGENIC GENES BY 1312 01:04:45,240 --> 01:04:47,920 PATTERN OF EXPRESSION OF THE 1313 01:04:47,920 --> 01:04:51,720 CRITICAL OSTEOGENIC MARKERS THAT 1314 01:04:51,720 --> 01:04:55,240 IS ABSOLUTELY SIMILAR IN TREATED 1315 01:04:55,240 --> 01:04:58,000 COMPARED TO TREATED MICE THAT IS 1316 01:04:58,000 --> 01:05:01,680 ALWAYS RESTRICTED IN MICE TO 1317 01:05:01,680 --> 01:05:05,080 BONE SURFACE AND AS SHOWN BY 1318 01:05:05,080 --> 01:05:07,320 CALCIUM LABELING SHOWING CLEAR 1319 01:05:07,320 --> 01:05:10,280 REDUCTION IN NUMBER OF BONE 1320 01:05:10,280 --> 01:05:12,520 METRICS POSITION SIZE IN TREATED 1321 01:05:12,520 --> 01:05:15,280 MICE COMPARED TO UNTREATED MICE 1322 01:05:15,280 --> 01:05:19,240 AND, AGAIN, THESE SIDES OF BONE 1323 01:05:19,240 --> 01:05:21,560 METRIC DEPOSITION ARE OBSERVED 1324 01:05:21,560 --> 01:05:25,640 CLOSE TO BONE SURFACE IN MICE AT 1325 01:05:25,640 --> 01:05:28,240 LEAST. TO CONCLUDE, I THINK 1326 01:05:28,240 --> 01:05:32,240 THESE SUGGEST A VERY SIMPLE 1327 01:05:32,240 --> 01:05:35,320 MECHANISM THROUGH WHICH DURING 1328 01:05:35,320 --> 01:05:38,080 BASED ON WHICH DURING INHIBITION 1329 01:05:38,080 --> 01:05:40,840 OF BONE ABSORPTION AND BONE 1330 01:05:40,840 --> 01:05:44,400 REMODELING, OSTEOBLASTIC CELLS, 1331 01:05:44,400 --> 01:05:46,720 CELLS ARE MORE DIFFERENTIATED 1332 01:05:46,720 --> 01:05:49,600 ALONG BONE SURFACE MAY SIMPLY 1333 01:05:49,600 --> 01:05:52,960 CONTINUE TO PRODUCE BONE TO 1334 01:05:52,960 --> 01:05:54,800 REVEAL ABSORPTION AND MAYBE THEY 1335 01:05:54,800 --> 01:05:57,680 CONTINUE TO PRODUCE BONE ON 1336 01:05:57,680 --> 01:06:00,680 SCAFFOLD PROVIDED BY COLLAGEN 1337 01:06:00,680 --> 01:06:02,440 FIBERS IN FIBROTIC TISSUE. IF 1338 01:06:02,440 --> 01:06:04,840 THIS IS CORRECT, OBVIOUSLY, THIS 1339 01:06:04,840 --> 01:06:07,200 IS PRELIMINARY DATA ON MICE. IF 1340 01:06:07,200 --> 01:06:09,040 THIS IS CORRECT, THIS SUGGESTS 1341 01:06:09,040 --> 01:06:10,520 THAT MAYBE WE REALLY DON'T NEED 1342 01:06:10,520 --> 01:06:14,400 TO STIMULATE THE OSTEOGENIC 1343 01:06:14,400 --> 01:06:18,200 ACTIVITY OF FD CELLS BUT WE NEED 1344 01:06:18,200 --> 01:06:20,000 SIMPLY TO GIVE THEM TIME TO DO 1345 01:06:20,000 --> 01:06:21,520 BONE AND DO WHAT THEY KNOW HOW 1346 01:06:21,520 --> 01:06:22,640 TO DO. 1347 01:06:22,640 --> 01:06:25,240 I THINK THAT MAYBE THIS WAS MY 1348 01:06:25,240 --> 01:06:27,160 LAST SLIDE. I THANK YOU VERY 1349 01:06:27,160 --> 01:06:30,760 MUCH FOR YOUR ATTENTION. 1350 01:06:30,760 --> 01:06:33,680 >> AUDIENCE: [APPLAUSE]. 1351 01:06:33,680 --> 01:06:43,120 >> THANK YOU, MARA. OUR NEXT 1352 01:06:43,120 --> 01:06:45,480 SPEAKER NEEDS NO INTRODUCTION. 1353 01:06:45,480 --> 01:06:49,680 HE IS PRACTICALLY SYNONYMOUS 1354 01:06:49,680 --> 01:06:51,680 WITH FIBROUS -- IS 1355 01:06:51,680 --> 01:06:53,240 ENDOCRINOLOGIST AND SENIOR 1356 01:06:53,240 --> 01:06:54,800 INVESTIGATOR OF CHIEF OF 1357 01:06:54,800 --> 01:06:58,480 SKELETAL DISEASES AND MINERAL 1358 01:06:58,480 --> 01:07:02,480 HOMEOSTASIS SECTION AT NIDCR AND 1359 01:07:02,480 --> 01:07:05,400 RECEIVES MEDICAL DEGREE AND 1360 01:07:05,400 --> 01:07:07,400 COMPLETED ENDOCRINOLOGY 1361 01:07:07,400 --> 01:07:09,760 FELLOWSHIP AT NIH AND DR. 1362 01:07:09,760 --> 01:07:13,800 COLLINS STARTED WITH DR. PENNIES 1363 01:07:13,800 --> 01:07:18,160 AND PAM TO TAKE A DEEP DIVE INTO 1364 01:07:18,160 --> 01:07:22,800 FIBROUS DYSPLASIA MCCUNE 1365 01:07:22,800 --> 01:07:25,080 ALBRIGHT SYNDROME AND 1366 01:07:25,080 --> 01:07:28,960 PROTOENROLLED 300 PATIENT AND 1367 01:07:28,960 --> 01:07:30,960 PATIENT ADVOCACY IS LEGENDARY. 1368 01:07:30,960 --> 01:07:33,600 HE WILL DESCRIBE PARADIGM OF 1369 01:07:33,600 --> 01:07:35,400 RARE DISEASE INFORMING BONE 1370 01:07:35,400 --> 01:07:38,520 BIOLOGY AND BONE TREATMENT. 1371 01:07:38,520 --> 01:07:44,720 THANK YOU, MIKE. 1372 01:07:44,720 --> 01:07:47,120 >> THANK YOU JANICE FOR THAT 1373 01:07:47,120 --> 01:07:48,680 NICE INTRODUCTION. 1374 01:07:48,680 --> 01:07:51,880 SO, THIS IS THE TITLE OF MY 1375 01:07:51,880 --> 01:07:52,280 TALK. 1376 01:07:52,280 --> 01:07:54,600 THIS IS FIBROUS DYSPLASIA. WE 1377 01:07:54,600 --> 01:07:55,840 HAVE BEEN HEARING ABOUT THIS. 1378 01:07:55,840 --> 01:07:58,840 THIS IS WHAT PATIENTS LOOK LIKE. 1379 01:07:58,840 --> 01:08:02,200 IT CAN EFFECT ANY PART OF THE 1380 01:08:02,200 --> 01:08:04,880 SKELETON CRANIAL AXIAL 1381 01:08:04,880 --> 01:08:06,200 APPENDICULAR SKELETON AND HAS 1382 01:08:06,200 --> 01:08:08,240 MANY CONSEQUENCES YOU CAN SEE 1383 01:08:08,240 --> 01:08:11,760 HERE SURGERIES SCOLIOSIS 1384 01:08:11,760 --> 01:08:15,280 DEFORMITY FRACTURES AND PAIN AND 1385 01:08:15,280 --> 01:08:17,960 PROETEE OE AN DISEASE WITH MANY 1386 01:08:17,960 --> 01:08:20,360 COMPLICATIONS THAT OFTEN RUNS 1387 01:08:20,360 --> 01:08:22,880 TOGETHER WITH EXTRA SKELETAL 1388 01:08:22,880 --> 01:08:24,360 MANIFESTATIONS WHEN YOU HAVE 1389 01:08:24,360 --> 01:08:27,960 EXTRA SKELETAL MANIFESTATIONS WE 1390 01:08:27,960 --> 01:08:30,560 CALL THIS MCCUNE ALBRIGHT 1391 01:08:30,560 --> 01:08:32,240 SYNDROME ANY COMBINATION YOU CAN 1392 01:08:32,240 --> 01:08:35,120 HAVE ONE ORE 2 OR MANY. 1393 01:08:35,120 --> 01:08:39,960 IT IS AN INCREDIBLY COMPLICATED 1394 01:08:39,960 --> 01:08:42,280 DISORDER. YOU CAN HAVE GROWTH 1395 01:08:42,280 --> 01:08:45,400 HORMONE ACCESS OSTEOMALACIA AND 1396 01:08:45,400 --> 01:08:47,760 NUMBER OF NEOPLASMS AND IS TRULY 1397 01:08:47,760 --> 01:08:50,480 I THINK ONE OF THE MOST 1398 01:08:50,480 --> 01:08:51,560 COMPLICATED MEDICAL DISORDERS 1399 01:08:51,560 --> 01:08:55,120 THERE IS. AS I SAW EARLIER PART 1400 01:08:55,120 --> 01:08:59,120 OF THE COMPLICATEDNESS OF THE 1401 01:08:59,120 --> 01:09:00,720 DISORDER IS DUE TO SOMATIC 1402 01:09:00,720 --> 01:09:03,120 EXPRESSION OF MUTATED VARIANT OF 1403 01:09:03,120 --> 01:09:08,680 G ALPHA S THAT IS UBIQUITOUSLY 1404 01:09:08,680 --> 01:09:11,280 EXPRESSED PROTEIN TO 1405 01:09:11,280 --> 01:09:12,440 THEORETICALLY INVOLVE TISSUE. 1406 01:09:12,440 --> 01:09:17,160 IT CAN THEORETICALLY INVOLVE ANY 1407 01:09:17,160 --> 01:09:19,360 TISSUE. THIS IS FURTHER 1408 01:09:19,360 --> 01:09:23,240 COMPLICATED AND DEPENDING ON 1409 01:09:23,240 --> 01:09:26,560 TISSUE IF MELANO -- THERE IS 1410 01:09:26,560 --> 01:09:29,760 LIGAND INDEPENDENT ACTIVATION 1411 01:09:29,760 --> 01:09:37,160 MELANIN IS PRODUCED OVARIES AND 1412 01:09:37,160 --> 01:09:38,880 ESTROE DIAL -- RESPONSIBLE FOR 1413 01:09:38,880 --> 01:09:40,600 RETRIEVING SPECIMENS AND DOING 1414 01:09:40,600 --> 01:09:43,560 WORK TO FIND THE VARIANT. 1415 01:09:43,560 --> 01:09:45,120 THIS IS FURTHER COMPLICATED 1416 01:09:45,120 --> 01:09:46,600 THOUGH AS WE GET INVOLVED WITH 1417 01:09:46,600 --> 01:09:47,920 TREATMENT AND TRYING TO FIGURE 1418 01:09:47,920 --> 01:09:52,520 THIS OUT. THERE IS 10 1419 01:09:52,520 --> 01:09:54,400 ADENOCYCLASES EXPRESSED IN BONE 1420 01:09:54,400 --> 01:09:57,160 AND PHOSPHO DIESTERACES IN 1421 01:09:57,160 --> 01:09:58,840 PATHWAY THAT ARE ALSO INVOLVED 1422 01:09:58,840 --> 01:10:01,240 IN THIS PHENOTYPE AND 1423 01:10:01,240 --> 01:10:03,360 POTENTIALLY THERAPEUTIC TARGET 1424 01:10:03,360 --> 01:10:05,600 AS WELL. 1425 01:10:05,600 --> 01:10:08,560 INCREDIBLY COMPLICATED DISEASE. 1426 01:10:08,560 --> 01:10:11,560 SO, AS THIS IS SHOWN GRAPHICALLY 1427 01:10:11,560 --> 01:10:13,040 IN DIFFERENT WAY WHAT PAM 1428 01:10:13,040 --> 01:10:14,480 DESCRIBED EARLIER WAY THIS 1429 01:10:14,480 --> 01:10:16,360 HAPPENS AND DATA THAT SUPPORTS 1430 01:10:16,360 --> 01:10:18,560 THIS SO FAR IS STEM CELL 1431 01:10:18,560 --> 01:10:20,000 SOMEWHERE EARLIER IN DEVELOPMENT 1432 01:10:20,000 --> 01:10:21,760 DEVELOPS THIS BY CHANCE VARIANT 1433 01:10:21,760 --> 01:10:26,720 IN GNAS THIS DISEASE-CAUSING 1434 01:10:26,720 --> 01:10:29,400 VARIANT DURING GASTROLATION AND 1435 01:10:29,400 --> 01:10:31,360 VARIANT SPREADS OUT TO INVOLVE 1436 01:10:31,360 --> 01:10:35,160 GERM LAYERS PROPAGATED OUT 1437 01:10:35,160 --> 01:10:37,520 THROUGH EMBREEO GENESIS. 1438 01:10:37,520 --> 01:10:39,840 WE THINK THAT THE MAP OF ECTED 1439 01:10:39,840 --> 01:10:42,760 DISEASE IS ESTABLISHED IN UTERO. 1440 01:10:42,760 --> 01:10:45,160 DEPENDING TEMPORALLY WHEN 1441 01:10:45,160 --> 01:10:47,160 MUTATION OCCURS AND ANATOMICALLY 1442 01:10:47,160 --> 01:10:49,520 WHERE MUTATION OCCURS WILL 1443 01:10:49,520 --> 01:10:50,960 DEFINE FINAL PHENOTYPE THAT WE 1444 01:10:50,960 --> 01:10:54,920 SEE IN THE PATIENTS. 1445 01:10:54,920 --> 01:10:58,920 THIS IS MY ORIGIN STORY HOW THE 1446 01:10:58,920 --> 01:11:02,600 STUDIES STARTED. I WAS A FELLOW 1447 01:11:02,600 --> 01:11:04,440 IN INTERINENDOCRINE TRAINING 1448 01:11:04,440 --> 01:11:06,720 PROGRAM THAT IS MAJOR SUPPORT OF 1449 01:11:06,720 --> 01:11:08,280 THIS DISORDER FROM VERY 1450 01:11:08,280 --> 01:11:11,240 BEGINNING. 1997 FIRST YEAR 1451 01:11:11,240 --> 01:11:21,920 DURING FELLOWSHIP WORKED WITH 1452 01:11:22,160 --> 01:11:24,120 ALLEN SPIEGEL AND STEVE MARKS I 1453 01:11:24,120 --> 01:11:26,320 WAS HAPPY ABOUT IT AND FIRED UP 1454 01:11:26,320 --> 01:11:28,080 ABOUT NOTION OF TRANSLATIONAL 1455 01:11:28,080 --> 01:11:29,560 RESEARCH THAT IS A NEW CONCEPT 1456 01:11:29,560 --> 01:11:31,720 AT THE TIME. I WENT TO ALLEN 1457 01:11:31,720 --> 01:11:34,760 FOR A CAREER TALK. I SAID, 1458 01:11:34,760 --> 01:11:36,080 ALLEN, I'M INTERESTED IN STAYING 1459 01:11:36,080 --> 01:11:40,000 AT NIH TO DO TRANSLATIONAL 1460 01:11:40,000 --> 01:11:42,960 RESEARCH. ALLEN AND HIS 1461 01:11:42,960 --> 01:11:43,600 [INDISCERNIBLE] STRAIGHT FORWARD 1462 01:11:43,600 --> 01:11:45,600 AND MUCH APPRECIATED WAY SAID 1463 01:11:45,600 --> 01:11:47,320 WELL THAT IS FINE MIKE THERE IS 1464 01:11:47,320 --> 01:11:51,360 NO PLACE RIGHT NOW FOR YOU IN 1465 01:11:51,360 --> 01:11:53,160 NIDDK. YOU COULD ALWAYS GET A 1466 01:11:53,160 --> 01:11:55,480 STRAIGHT ANSWER FROM ALLEN AND 1467 01:11:55,480 --> 01:11:57,960 STILL CAN. I WAS UNDAUNTED AND 1468 01:11:57,960 --> 01:12:00,800 INTERESTED IN BONE MARROW 1469 01:12:00,800 --> 01:12:02,800 HOMOOSTASIS AND WENT TO BEST LAB 1470 01:12:02,800 --> 01:12:04,920 ON CAMPUS WHERE THEY DID THAT 1471 01:12:04,920 --> 01:12:06,840 PAM ROBEY CELL BIOLOGIST I 1472 01:12:06,840 --> 01:12:08,920 TALKED TO PAM AND I'M REALLY 1473 01:12:08,920 --> 01:12:10,440 INTERESTED IN BONE AND SHE DREW 1474 01:12:10,440 --> 01:12:12,280 A CARTOON I HAVE TO THIS DAY 1475 01:12:12,280 --> 01:12:13,720 STILL HAVE ON WALL IN MY OFFICE 1476 01:12:13,720 --> 01:12:16,000 AND NO THE THAT MUCH HAS REALLY 1477 01:12:16,000 --> 01:12:17,480 CHANGED ABOUT IT. 1478 01:12:17,480 --> 01:12:20,440 ANYWAY, SO, AS YOU CAN SEE SHE 1479 01:12:20,440 --> 01:12:23,840 HIGHLIGHTED GS ALPHA HERE THAT 1480 01:12:23,840 --> 01:12:28,720 WAS INVOLVED IN THIS AT THAT 1481 01:12:28,720 --> 01:12:32,160 TIME WE ARE WORKING ON CLINICAL 1482 01:12:32,160 --> 01:12:33,920 STUDY IN FIBROUS DYSPLASIA YOU 1483 01:12:33,920 --> 01:12:35,760 ARE A DOCTOR WANT TO HELP? I 1484 01:12:35,760 --> 01:12:37,200 WAS HESITANT AT FIRST. I WILL 1485 01:12:37,200 --> 01:12:41,040 TELL YOU WHY. ANYWAY, WAY I 1486 01:12:41,040 --> 01:12:50,120 REMEMBER SHE CREATE THE FIRST 1487 01:12:50,120 --> 01:12:52,360 DRAFT OF PROTOCOL AND IN CHILD 1488 01:12:52,360 --> 01:12:56,120 HEALTH WE WERE STUDYING AND 1489 01:12:56,120 --> 01:12:58,120 TREATED PRECOCIOUS PUBERTY OF 1490 01:12:58,120 --> 01:13:01,040 PATIENTS LARGELY IGNORING 1491 01:13:01,040 --> 01:13:02,440 FIBROUS DYSPLASIA AND CLEAR TO 1492 01:13:02,440 --> 01:13:04,720 ME IN MOST PATIENTS THIS WAS 1493 01:13:04,720 --> 01:13:07,600 BIGGEST PROBLEM. I LOOKED UP 1494 01:13:07,600 --> 01:13:11,000 NOT MUCH ON FIBROUS DYSPLASIA 1495 01:13:11,000 --> 01:13:12,200 COMPLICATED DISEASE AND THINKING 1496 01:13:12,200 --> 01:13:15,960 NOT SURE, PAM. SHOWING FIRST 1497 01:13:15,960 --> 01:13:18,120 DRAFT OF PROTOCOL. FD IS A 1498 01:13:18,120 --> 01:13:23,240 DIFFICULT DISEASE. CAN I SEE 1499 01:13:23,240 --> 01:13:29,680 PROTOCOL? 1500 01:13:29,680 --> 01:13:32,960 I LOOKED AT IT. 20 PAGES OF 1501 01:13:32,960 --> 01:13:35,040 BACKGROUND THAT WAS ELOQUENT BUT 1502 01:13:35,040 --> 01:13:36,560 NOTHING WHAT WOULD WE MEASURE 1503 01:13:36,560 --> 01:13:39,640 HOW WOULD WE DO THAT HUGE 1504 01:13:39,640 --> 01:13:43,680 PROTOCOL TURNED INTO THREE 1505 01:13:43,680 --> 01:13:45,560 PROTOCOLS THAT PAM DESCRIBED 1506 01:13:45,560 --> 01:13:47,760 EARLIER AND SETTLED ON THIS 1507 01:13:47,760 --> 01:13:49,480 STUDY THAT IS BACKBONE WHAT WE 1508 01:13:49,480 --> 01:13:52,440 DID IN ANALYSIS AND CONTINUES TO 1509 01:13:52,440 --> 01:13:55,040 GENERATE MASSIVE AMOUNT OF DATA 1510 01:13:55,040 --> 01:13:56,280 DEFINING NATURAL HISTORY OF 1511 01:13:56,280 --> 01:13:57,680 SPECTRUM AND EFFECTIVE 1512 01:13:57,680 --> 01:13:58,640 TREATMENTS OF THIS DISORDER AND 1513 01:13:58,640 --> 01:14:00,120 DON'T THINK THERE IS ANY PLACE 1514 01:14:00,120 --> 01:14:02,040 IN WORLD YOU COULD DO A STUDY 1515 01:14:02,040 --> 01:14:03,720 LIKE THIS ESPECIALLY AS LONG AS 1516 01:14:03,720 --> 01:14:07,080 WE HAVE DONE IT AT NIH AND FOR 1517 01:14:07,080 --> 01:14:10,120 THAT WE SUPPORT LEADERSHIP AND 1518 01:14:10,120 --> 01:14:12,560 INSTITUTES THAT HAVE BEEN 1519 01:14:12,560 --> 01:14:14,200 PARTNERS ENDOCRINE TRAINING 1520 01:14:14,200 --> 01:14:16,200 PROGRAM THAT ENABLED A 1521 01:14:16,200 --> 01:14:17,880 TREMENDOUS AMOUNT OF RESEARCH TO 1522 01:14:17,880 --> 01:14:20,720 BE DONE. COHORT STUDY 1523 01:14:20,720 --> 01:14:21,840 PROSPECTIVE STANDARDIZED 1524 01:14:21,840 --> 01:14:25,320 COLLECTION OF DATA AND SPECIMENS 1525 01:14:25,320 --> 01:14:28,760 THAT WE PERFORM RETROSPECTIVE 1526 01:14:28,760 --> 01:14:32,040 ANALYSIS AND ARE NICELY ABLE TO 1527 01:14:32,040 --> 01:14:33,080 DEFINE SPECTRUM NATURAL HISTORY 1528 01:14:33,080 --> 01:14:35,040 OF DISORDER THAT IS CRITICAL FOR 1529 01:14:35,040 --> 01:14:37,200 DEVELOPMENT OF THERAPIES FOR 1530 01:14:37,200 --> 01:14:39,520 THESE PATIENTS HAS BEEN 1531 01:14:39,520 --> 01:14:40,360 INCREDIBLY SUCCESSFUL. HAVE 1532 01:14:40,360 --> 01:14:44,240 SEEN OVER 300 SUBJECTS AND PAM 1533 01:14:44,240 --> 01:14:46,840 SAID FROM ONE-TO-ONE 02 AND 25 1534 01:14:46,840 --> 01:14:49,880 YEARS OF FOLLOW UP AND 150 1535 01:14:49,880 --> 01:14:52,000 PUBLICATIONS ON IT AND 6 1536 01:14:52,000 --> 01:14:52,600 INTERVENTIONAL TRIALS. 1537 01:14:52,600 --> 01:14:55,600 SO, I WANTED TO TALK ABOUT THREE 1538 01:14:55,600 --> 01:14:57,680 AREAS OF THIS EARLY WORK THAT I 1539 01:14:57,680 --> 01:14:58,840 THINK ARE PARTICULARLY 1540 01:14:58,840 --> 01:14:59,200 IMPORTANT. 1541 01:14:59,200 --> 01:15:01,720 THIS IS WORK DONE BY ELIZABETH 1542 01:15:01,720 --> 01:15:03,440 HEART THAT IS A MEDICAL STUDENT 1543 01:15:03,440 --> 01:15:06,320 AT THE TIME AND ELIZABETH IS A 1544 01:15:06,320 --> 01:15:09,720 BRANCH CHIEF AT FDA OVERSEES 1545 01:15:09,720 --> 01:15:12,320 STUDIES OF RARE DISORDERS AND 1546 01:15:12,320 --> 01:15:15,320 CAN'T HELP BUT THINK SHE GOT 1547 01:15:15,320 --> 01:15:17,400 TURNED ON TO IT DOING THIS WORK 1548 01:15:17,400 --> 01:15:18,880 AND ONE THING ABOUT THE STUDY 1549 01:15:18,880 --> 01:15:21,240 LIKE THIS YOU BEGIN TO SEE 1550 01:15:21,240 --> 01:15:23,600 PATTERNS YOU THINK YOU NEED THEM 1551 01:15:23,600 --> 01:15:27,240 AND IF PATTERNS EXIST GOING BACK 1552 01:15:27,240 --> 01:15:29,160 QUERYING DATA AND WHAT WE DID 1553 01:15:29,160 --> 01:15:31,440 AND SEEMED TO US PATIENTS IF 1554 01:15:31,440 --> 01:15:33,480 THEY DEVELOP NEW LESIONS IT WAS 1555 01:15:33,480 --> 01:15:35,040 QUITE EARLY IN THEIR LIFE AND 1556 01:15:35,040 --> 01:15:37,720 RELATIVELY EARLY AGE THAT ALL 1557 01:15:37,720 --> 01:15:39,280 DISEASE THAT THEY WILL GET WAS 1558 01:15:39,280 --> 01:15:40,920 ESTABLISHED AND IS IMPORTANT FOR 1559 01:15:40,920 --> 01:15:43,160 PATIENTS ESPECIALLY. THEY CAN 1560 01:15:43,160 --> 01:15:45,360 KNOW THESE PARENTS THAT SUFFER 1561 01:15:45,360 --> 01:15:47,520 SO MUCH WITH CHILDREN IN THE 1562 01:15:47,520 --> 01:15:48,560 BEGINNING THAT THIS WON'T 1563 01:15:48,560 --> 01:15:50,240 CONTINUE ENTIRE LIFE AND WILL 1564 01:15:50,240 --> 01:15:53,720 SLOW DOWN AT SOME POINT IN TIME. 1565 01:15:53,720 --> 01:15:55,920 WE FOUND REALLY QUITE SURPRISING 1566 01:15:55,920 --> 01:15:59,600 AND BEFORE AGE OF 5 AND 90% OF 1567 01:15:59,600 --> 01:16:02,320 CRANIO FASHIAL LESIONS ARE 1568 01:16:02,320 --> 01:16:04,640 PRESENT AND APPENDICULAR LESIONS 1569 01:16:04,640 --> 01:16:06,640 AND AXIAL LESIONS ARE PRESENT AS 1570 01:16:06,640 --> 01:16:08,960 WELL. THIS CONFIRMED THIS DATA 1571 01:16:08,960 --> 01:16:11,840 AND HYPOTHESIS THAT THIS 1572 01:16:11,840 --> 01:16:13,880 IDENTIFIED THE PERIOD OF 1573 01:16:13,880 --> 01:16:16,240 ACQUISITION VERY EARLY AND IS 1574 01:16:16,240 --> 01:16:17,920 CRITICAL DEVELOP AGO I DRUG AND 1575 01:16:17,920 --> 01:16:19,520 TREATMENT FOR THIS YOU THINK YOU 1576 01:16:19,520 --> 01:16:22,000 WILL PREVENT LESIONS. IF YOU 1577 01:16:22,000 --> 01:16:23,600 TREAT HERE NO WAY ALREADY OVER 1578 01:16:23,600 --> 01:16:26,040 YOU HAVE TO START HERE EARLY. 1579 01:16:26,040 --> 01:16:27,440 ALLISON WILL TALK ABOUT THAT 1580 01:16:27,440 --> 01:16:27,920 LATER. 1581 01:16:27,920 --> 01:16:30,280 NEXT, I THINK IT WAS A VERY 1582 01:16:30,280 --> 01:16:31,680 IMPORTANT FINDING THAT IS ONE 1583 01:16:31,680 --> 01:16:33,520 THING THAT WE LEARNED EARLY ON 1584 01:16:33,520 --> 01:16:35,720 THAT THINGS NOT TO DO BY 1585 01:16:35,720 --> 01:16:37,040 OBSERVING PATIENTS. 1586 01:16:37,040 --> 01:16:40,160 SO, WHEN WE FIRST STARTED, ONE 1587 01:16:40,160 --> 01:16:42,600 COMMON PROCEDURES PERFORMED WITH 1588 01:16:42,600 --> 01:16:45,880 PATIENTS WITH FIBROUS DYSPLASIA 1589 01:16:45,880 --> 01:16:49,760 IS CURE ATAUJ AND GRAFTING AND 1590 01:16:49,760 --> 01:16:53,160 DIGS OUT FIBROUS DYSPLASIA 1591 01:16:53,160 --> 01:16:57,080 PUTTING BONE COMMENT AND TISSUE 1592 01:16:57,080 --> 01:17:01,720 REPLACEMENTS IN BONE COMMENT OR 1593 01:17:01,720 --> 01:17:09,840 WHATE 1594 01:17:09,840 --> 01:17:10,120 WHATEVER. 1595 01:17:10,120 --> 01:17:12,240 PASH YERPTS COULD COME TO US 1596 01:17:12,240 --> 01:17:14,280 HAVING HAD THESE PROCEDURES OVER 1597 01:17:14,280 --> 01:17:18,600 AND OVER. WE LOOKED AT 23 1598 01:17:18,600 --> 01:17:20,880 PATIENTS AND 20 YEARS OF FOLLOW 1599 01:17:20,880 --> 01:17:24,120 UP AND 52 GRAFTS. NO MATTER 1600 01:17:24,120 --> 01:17:25,920 WHAT GRAFT WAS IT WAS READILY 1601 01:17:25,920 --> 01:17:29,200 AND RAPIDLY REABSORBED IN YOUNG 1602 01:17:29,200 --> 01:17:32,120 PATIENTS. THIS WAS A FUTILE 1603 01:17:32,120 --> 01:17:32,880 PROCEDURE AND SOMETHING THAT 1604 01:17:32,880 --> 01:17:35,400 SHOULD BE AVOIDED IN PATIENTS 1605 01:17:35,400 --> 01:17:39,480 ABLE TO SHOW WITH THIS CURETTAGE 1606 01:17:39,480 --> 01:17:42,720 GRAFTING AND LIMITED VALUE IN 1607 01:17:42,720 --> 01:17:44,800 FIBROUS DYSPLASIA. I WANTED TO 1608 01:17:44,800 --> 01:17:48,160 GO TO NEXT ANOTHER ISSUE THAT 1609 01:17:48,160 --> 01:17:50,160 ALLISON AND ENCOUNTERED 1610 01:17:50,160 --> 01:17:52,360 FREQUENTLY AND ONCE A WEEK OR 1611 01:17:52,360 --> 01:17:54,760 MORE OFTEN GET INQUIRIES FROM 1612 01:17:54,760 --> 01:17:56,960 AROUND COUNTRY AND WORLD HOW WE 1613 01:17:56,960 --> 01:17:58,920 TAKE CARE OF THESE PATIENTS 1614 01:17:58,920 --> 01:18:00,440 COMPLICATED PATIENTS YOU WOULD 1615 01:18:00,440 --> 01:18:01,800 IMAGINE AND PUT TOGETHER A LIST 1616 01:18:01,800 --> 01:18:03,960 OF THINGS SEND OUT OVER AND OVER 1617 01:18:03,960 --> 01:18:05,920 AND OVER AGAIN AND WRITE A PAPER 1618 01:18:05,920 --> 01:18:07,800 ABOUT THIS. THIS IS WHAT WE 1619 01:18:07,800 --> 01:18:09,520 DID. WHAT THIS REPRESENTED WAS 1620 01:18:09,520 --> 01:18:13,600 TREATMENT ALGORITHMS FOR FIBROUS 1621 01:18:13,600 --> 01:18:15,320 DYSPLASIA THAT IS EVIDENCE-BASED 1622 01:18:15,320 --> 01:18:17,080 AND EXPERT OPINION AND DEVELOPED 1623 01:18:17,080 --> 01:18:20,200 SIMPLE USER FRIENDLY ALGORITHMS 1624 01:18:20,200 --> 01:18:22,280 THAT WAS INITIALLY DISTILLATION 1625 01:18:22,280 --> 01:18:25,200 OF 57 PUBLICATIONS ON THIS 1626 01:18:25,200 --> 01:18:27,960 EXPANDED IN 2019 TO 85 1627 01:18:27,960 --> 01:18:29,960 PUBLICATIONS AND PUBLISHING IN 1628 01:18:29,960 --> 01:18:32,320 2015 AND 2019 AND USEFUL TOOL 1629 01:18:32,320 --> 01:18:36,160 FOR CLINICIANS AND ADVOCACY 1630 01:18:36,160 --> 01:18:37,720 GROUPS LEARN TODAY GIVE THIS 1631 01:18:37,720 --> 01:18:41,320 PUBLICATION TO THEIR PATIENTS. 1632 01:18:41,320 --> 01:18:44,160 GENE REVIEWS AS OPEN ACCESS TO 1633 01:18:44,160 --> 01:18:46,520 TAKE PUBLICATIONS AND ALGORITHMS 1634 01:18:46,520 --> 01:18:49,240 TO CLINICIANS THAT HAS BEEN MOST 1635 01:18:49,240 --> 01:18:51,560 HELPFUL ASPECT OF DISSEMINATING 1636 01:18:51,560 --> 01:18:53,240 INFORMATION AND DEVELOPING 1637 01:18:53,240 --> 01:18:54,920 TREATMENTS FOR PATIENTS. 1638 01:18:54,920 --> 01:18:55,480 OKAY. 1639 01:18:55,480 --> 01:18:57,640 ONE OF THE BIG THINGS THAT 1640 01:18:57,640 --> 01:19:00,320 ESPECIALLY TO ME AS AN 1641 01:19:00,320 --> 01:19:02,840 ENDOCRINOLOGIST THAT WAS 1642 01:19:02,840 --> 01:19:05,240 INTERESTING ABOUT THIS DISORDER 1643 01:19:05,240 --> 01:19:07,200 IS PHENOMENON OF LOW BLOOD 1644 01:19:07,200 --> 01:19:11,600 PHOSPHATE IN FIBROUS DISMRASHIO 1645 01:19:11,600 --> 01:19:13,040 HYPOPHOSPHO TEEMIA IT IS 1646 01:19:13,040 --> 01:19:15,600 CRITICAL TO MINERALIZE BONE AND 1647 01:19:15,600 --> 01:19:20,280 SAW HISTLOGIC SECTIONS OF 1648 01:19:20,280 --> 01:19:22,600 UNMINERALIZED -- LEADING TO 1649 01:19:22,600 --> 01:19:24,040 SCOLIOSIS AND OTHER PROBLEMS AS 1650 01:19:24,040 --> 01:19:26,880 WELL AND STARTED OUR ASSUMPTION 1651 01:19:26,880 --> 01:19:28,720 WAS THIS WAS DUE TO MUTANT 1652 01:19:28,720 --> 01:19:31,920 VARIANT IN THE KIDNEY AND MADE 1653 01:19:31,920 --> 01:19:34,520 SENSE. PARATHYROID HORMONE 1654 01:19:34,520 --> 01:19:38,880 THROUGH GS ALPHA LEADS TO CYCLIC 1655 01:19:38,880 --> 01:19:42,480 AMP IN URINE AND IF THIS IS CASE 1656 01:19:42,480 --> 01:19:45,440 RENAL TUBE YOU'LL MUTANT GS 1657 01:19:45,440 --> 01:19:50,720 ALPHA ONE SHOULD SEE INCREASED 1658 01:19:50,720 --> 01:19:52,400 PHOSPHATE AND [INDISCERNIBLE] 1659 01:19:52,400 --> 01:19:54,960 AND THERE WAS NEWLY DISCOVERED 1660 01:19:54,960 --> 01:19:57,240 HORMONE FGF23 THAT WAS CAPABLE 1661 01:19:57,240 --> 01:20:00,280 OF STIMULATING ELEVATED 1662 01:20:00,280 --> 01:20:02,960 PHOSPHATE IN URINE AND IN CASE 1663 01:20:02,960 --> 01:20:09,200 OF FG23 CYCLIC AMP IS NORMAL AND 1664 01:20:09,200 --> 01:20:11,480 ANOTHER DIFFERENCE BETWEEN TWO 1665 01:20:11,480 --> 01:20:12,600 HYPOTHESIS IS APPROXIMATE MA'AM 1666 01:20:12,600 --> 01:20:15,880 TUBE YOU'LL CELLS EXPRESSED 1 1667 01:20:15,880 --> 01:20:19,400 ALPHA HYDROXYLACE THAT ACTIVATED 1668 01:20:19,400 --> 01:20:24,280 VITAMIN 125D AND IF MUTANT GSA 1669 01:20:24,280 --> 01:20:26,960 MEDIATED WE WOULD SEE INVERSE 1670 01:20:26,960 --> 01:20:31,280 RELATIONSHIP AND IF IT WERE FG23 1671 01:20:31,280 --> 01:20:32,800 MEDIATED EXPECTED TO SEE 1672 01:20:32,800 --> 01:20:34,120 POSITIVE CORRELATION BETWEEN THE 1673 01:20:34,120 --> 01:20:36,920 TWO. NOW HAVING LARGE BODY 1674 01:20:36,920 --> 01:20:40,280 RETROSPECTIVE DATA TO GO BACK TO 1675 01:20:40,280 --> 01:20:42,520 WE HAD BEEN PRESSING ENOUGH TO 1676 01:20:42,520 --> 01:20:43,760 COLLECT APPROPRIATE INFORMATION 1677 01:20:43,760 --> 01:20:47,120 IN STUDY IN BEGINNING AND LOOKED 1678 01:20:47,120 --> 01:20:49,800 BACK AND QUERIED RETROSPECTIVE 1679 01:20:49,800 --> 01:20:52,320 DATA AND WHAT WE SAW WAS CLEAR 1680 01:20:52,320 --> 01:20:56,840 AND PATIENT SEEN WITH 1681 01:20:56,840 --> 01:20:57,480 HYPERPARATHYROIDISM AND SURE 1682 01:20:57,480 --> 01:21:01,560 ENOUGH AS EXPECTED THEY ELEVATED 1683 01:21:01,560 --> 01:21:04,560 NEF ROTH NOWS CYCLIC AMP AND IT 1684 01:21:04,560 --> 01:21:07,240 WAS NORMAL AND FURTHER MORE 1685 01:21:07,240 --> 01:21:09,560 CORRELATION BETWEEN 125D AND 1686 01:21:09,560 --> 01:21:12,600 PHOSPHORUS WAS CONSISTENT FDF23 1687 01:21:12,600 --> 01:21:15,720 RATHER THAN MUTANT GS IN KIDNEY 1688 01:21:15,720 --> 01:21:18,960 AND BONE TURNOVER SKELETAL 1689 01:21:18,960 --> 01:21:20,520 DISEASE BURDEN CORRELATED 1690 01:21:20,520 --> 01:21:22,360 PHOSPHATE LO S THAT POINTED TO 1691 01:21:22,360 --> 01:21:26,640 FD BONE AS POTENTIALLY SOURCE OF 1692 01:21:26,640 --> 01:21:28,600 FGF23 AND LED TO MOST IMPORTANT 1693 01:21:28,600 --> 01:21:30,960 STUDY THAT WE HAVE BEEN ABLE TO 1694 01:21:30,960 --> 01:21:31,920 DO IN THIS CONDITION. 1695 01:21:31,920 --> 01:21:33,000 THAT IS SHOWN HERE. 1696 01:21:33,000 --> 01:21:34,600 THAT IS WHERE WE WERE ABLE TO 1697 01:21:34,600 --> 01:21:39,040 SHOW THAT DEGREE OF ELEVATION OF 1698 01:21:39,040 --> 01:21:41,440 FDF23 CORRELATED WITH AMOUNT OF 1699 01:21:41,440 --> 01:21:45,200 FIBROUS DYSPLASIA AND IN SITU 1700 01:21:45,200 --> 01:21:47,720 HYBRIDIZATION THAT FGF23 WAS 1701 01:21:47,720 --> 01:21:51,360 EXPRESSED HIGHLY IN WOVEN BONE 1702 01:21:51,360 --> 01:21:52,760 DYSPLASIA AND WE WERE 1703 01:21:52,760 --> 01:21:54,960 IMPORTANTLY ABLE TO SHOW THAT 1704 01:21:54,960 --> 01:21:57,160 FGF23 WAS PRESENT IN NORMAL BONE 1705 01:21:57,160 --> 01:21:58,920 AND THIS REALLY IDENTIFIED 1706 01:21:58,920 --> 01:22:02,120 NORMAL BONE AS SOURCE OF FGF23 1707 01:22:02,120 --> 01:22:03,760 AND IS A MAJOR FINDING IN THE 1708 01:22:03,760 --> 01:22:06,400 FIELD AND ONE OF THE REASONS AS 1709 01:22:06,400 --> 01:22:08,240 YOU POINTED OUT ALLEN THAT WE 1710 01:22:08,240 --> 01:22:11,600 STUDY RARE DISEASES BECAUSE THEY 1711 01:22:11,600 --> 01:22:14,520 FORM COMMON BIOLOGY. 1712 01:22:14,520 --> 01:22:18,880 THIS REALLY LEAD TO AND OPENED 1713 01:22:18,880 --> 01:22:21,720 DOOR TO LIST OF DISORDERS WE 1714 01:22:21,720 --> 01:22:25,720 STUDIED AND FIBROUS DISMRASHIO 1715 01:22:25,720 --> 01:22:30,640 TUMOR INDUCED OSTEOMALACIA AND 1716 01:22:30,640 --> 01:22:37,720 HYPOPARATHYROIDISM -- PHYSIOLOGY 1717 01:22:37,720 --> 01:22:39,800 OF MINERAL HOMEOSTASIS AND LOOK 1718 01:22:39,800 --> 01:22:43,200 AT DISORDER OF FGF23 DEFICIENCY 1719 01:22:43,200 --> 01:22:45,320 AND THESE DISORDERS ALLOW US 1720 01:22:45,320 --> 01:22:46,840 WINDOWS INTO UNDERSTANDING 1721 01:22:46,840 --> 01:22:48,440 BIOLOGY AND PHYSIOLOGY OF 1722 01:22:48,440 --> 01:22:48,680 PATIENTS. 1723 01:22:48,680 --> 01:22:51,680 I'M COMING DOWN TO A CLOSE HERE. 1724 01:22:51,680 --> 01:22:53,160 THERE IS ONE MORE CONDITION THAT 1725 01:22:53,160 --> 01:22:56,920 I WANT TO FOCUS ON A LITTLE BIT 1726 01:22:56,920 --> 01:23:01,760 THAT IS CUTANEOUS SKELETAL 1727 01:23:01,760 --> 01:23:03,640 HYPOPHOSFATEMIA SYNDROME. IT IS 1728 01:23:03,640 --> 01:23:05,440 INTERESTING. IT REMINDED ME OF 1729 01:23:05,440 --> 01:23:07,400 A PATIENT WE SAW THAT WAS 1730 01:23:07,400 --> 01:23:10,760 SIMILAR TO WHAT WE DID THIS WEEK 1731 01:23:10,760 --> 01:23:15,400 WITH PATIENTS WITH PATIENT 1732 01:23:15,400 --> 01:23:18,880 COMMITTEE AND AT FD/MAS 1733 01:23:18,880 --> 01:23:21,360 COMMITTEE MEETING IN 2013 I 1734 01:23:21,360 --> 01:23:22,000 ENCOUNTERED THIS MOTHER HERE 1735 01:23:22,000 --> 01:23:24,600 CAME TO THE MEETING WITH BIG 1736 01:23:24,600 --> 01:23:29,920 BINDER FULL OF RECORDS AND J 1737 01:23:29,920 --> 01:23:31,080 X-RAYS AND THEY WERE REFERRED TO 1738 01:23:31,080 --> 01:23:33,480 AS BINDER MOMS MOST OF TIMES IT 1739 01:23:33,480 --> 01:23:36,880 WAS MOMS AND THEY BROUGHT 1740 01:23:36,880 --> 01:23:38,920 COMPUTERS TO THE MEETING 1741 01:23:38,920 --> 01:23:39,360 YESTERDAY. 1742 01:23:39,360 --> 01:23:43,640 HER SON HAD A SKIN LESION LIKE 1743 01:23:43,640 --> 01:23:46,280 THIS. 1744 01:23:46,280 --> 01:23:50,440 PIGMENTED MAC YULE FOR SURE AND 1745 01:23:50,440 --> 01:23:52,560 MOSAIC DISTRIBUTION OF SKELETAL 1746 01:23:52,560 --> 01:23:55,920 DISEASE RIGHT HAND EFFECTED LEFT 1747 01:23:55,920 --> 01:23:59,960 NOT LEFT ILLI AT CREST WAS 1748 01:23:59,960 --> 01:24:02,080 EFFECTED BUT NOT RIGHT. SHE WAS 1749 01:24:02,080 --> 01:24:05,000 A REMARKABLE WOMAN AS HIS PARENT 1750 01:24:05,000 --> 01:24:08,760 AND AS MANY OF THESE. SHE SAID 1751 01:24:08,760 --> 01:24:12,600 HIS DOCTOR TOLD ME THIS WAS 1752 01:24:12,600 --> 01:24:14,680 FIBROUS DYSPLASIA MCCUNE 1753 01:24:14,680 --> 01:24:16,040 ALBRIGHT SYNDROME I DON'T THINK 1754 01:24:16,040 --> 01:24:17,520 IT IS I SAID I THINK YOU ARE 1755 01:24:17,520 --> 01:24:19,440 RIGHT I DON'T KNOW WHAT IT IS 1756 01:24:19,440 --> 01:24:21,520 BUT BET WE CAN FIGURE IT OUT. 1757 01:24:21,520 --> 01:24:23,040 THIS IS AN INCREDIBLE THING WE 1758 01:24:23,040 --> 01:24:25,320 CAN DO HERE. WHEN PATIENTS COME 1759 01:24:25,320 --> 01:24:28,080 TO US AT NIH AND DON'T KNOW WHAT 1760 01:24:28,080 --> 01:24:30,080 THEY HAVE WE CAN HAVE LEVEL OF 1761 01:24:30,080 --> 01:24:30,960 CONFIDENCE WE WILL BE ABLE TO 1762 01:24:30,960 --> 01:24:33,680 FIGURE IT OUT. WE WERE ABLE TO 1763 01:24:33,680 --> 01:24:35,920 SURE ENOUGH. SHORTLY AFTER THAT 1764 01:24:35,920 --> 01:24:38,720 SAW A COUPLE PASHGENTS ONE HAD 1765 01:24:38,720 --> 01:24:41,440 BEEN SEEN BY KEITH AT YALE 1766 01:24:41,440 --> 01:24:42,800 UNIVERSITY AND TOGETHER WE PUT 1767 01:24:42,800 --> 01:24:44,440 TOGETHER A COLLECTION OF FIVE 1768 01:24:44,440 --> 01:24:47,040 PATIENTS ALL OF THE PATIENTS WE 1769 01:24:47,040 --> 01:24:55,800 FOUND SOMATIC VARIANCE IN DTPACE 1770 01:24:56,080 --> 01:24:59,240 HRAS AND CALLED IT CUTANEOUS 1771 01:24:59,240 --> 01:25:03,400 SKELETAL HYPOPHOSPHATEMIA 1772 01:25:03,400 --> 01:25:05,040 SYNDROME. 1773 01:25:05,040 --> 01:25:14,200 ANOTHER IMPORTANT FEATURE THOUGH 1774 01:25:14,200 --> 01:25:15,800 ASPECTS WERE IN [INDISCERNIBLE] 1775 01:25:15,800 --> 01:25:18,760 AND GOT INTO LITERATURE WAY TO 1776 01:25:18,760 --> 01:25:20,880 TREAT THIS DOING LARGE EXCISIONS 1777 01:25:20,880 --> 01:25:23,200 OF SKIN LESIONS AND THOUGHT THAT 1778 01:25:23,200 --> 01:25:29,400 IT WAS COMING FROM BONE, FGF23. 1779 01:25:29,400 --> 01:25:31,640 NEVERTHELESS PATIENTS GOING 1780 01:25:31,640 --> 01:25:33,680 THROUGH LARGE PAINFUL EXCISIONS 1781 01:25:33,680 --> 01:25:38,080 OF LESIONS TO NO AVAIL. WE 1782 01:25:38,080 --> 01:25:39,960 DEVELOPED A MOUSE MODEL THAT WAS 1783 01:25:39,960 --> 01:25:42,040 DONE INITIALLY STARTED BY 1784 01:25:42,040 --> 01:25:43,800 [INDISCERNIBLE] WHO WAS A FELLOW 1785 01:25:43,800 --> 01:25:47,200 WHO CAME HERE FROM SPAIN TO WORK 1786 01:25:47,200 --> 01:25:50,280 WITH US. 1787 01:25:50,280 --> 01:25:52,880 DEANNA HAD NEVER TOUCHED A 1788 01:25:52,880 --> 01:25:55,840 PIPETTE WHEN SHE GOT HERE AND 1789 01:25:55,840 --> 01:25:57,840 GOT INITIAL STEPS TO DEVELOP 1790 01:25:57,840 --> 01:26:01,600 MOUSE MODEL THAT LUIZ HAS TAKEN 1791 01:26:01,600 --> 01:26:04,080 FORWARD AND DONE WORKING WITH IN 1792 01:26:04,080 --> 01:26:05,120 DOING INTERESTING WORK WITH THAT 1793 01:26:05,120 --> 01:26:07,440 YOU WILL SEE AS WELL. ANYWAY, 1794 01:26:07,440 --> 01:26:08,800 WHAT IS INTERESTING IS THIS IS 1795 01:26:08,800 --> 01:26:11,680 THE EXACT SAME MODEL WE USE FOR 1796 01:26:11,680 --> 01:26:13,680 FIBROUS DYSPLASIA A MODEL THAT 1797 01:26:13,680 --> 01:26:19,360 MARA TALKED ABOUT AND PUT IN PRX 1798 01:26:19,360 --> 01:26:21,920 MOUSE AND PUT IN ALPHA GS 1799 01:26:21,920 --> 01:26:25,680 MUTATION WE GET PROLIFERATION OF 1800 01:26:25,680 --> 01:26:28,760 SKELETAL CELLS IN END OSTE OM IN 1801 01:26:28,760 --> 01:26:33,480 THE MARROW AND USING THIS 1802 01:26:33,480 --> 01:26:36,240 MUTATION SAME MODEL GET THIS 1803 01:26:36,240 --> 01:26:39,840 PROLIFERATION THAT RISES FROM 1804 01:26:39,840 --> 01:26:43,560 PERIOSTEUM AND IN TACT FGF23 1805 01:26:43,560 --> 01:26:46,880 LEVELS ARE HIGH IN THIS ANIMAL 1806 01:26:46,880 --> 01:26:49,680 AND THESE MICE HAVE 1807 01:26:49,680 --> 01:26:52,440 HYPOPHOSFATEMIA AND SURE ENOUGH 1808 01:26:52,440 --> 01:26:55,720 IN THE MICE WE SEE LARGE LESIONS 1809 01:26:55,720 --> 01:27:02,000 ARISING FROM PERIOSTEUM AND 1810 01:27:02,000 --> 01:27:05,240 QUESTION SEE FGF23 EXPRESSION IN 1811 01:27:05,240 --> 01:27:08,240 NORMAL BONE AND WHAT LUIS 1812 01:27:08,240 --> 01:27:10,240 OBSERVED THAT IS A CRITICAL 1813 01:27:10,240 --> 01:27:11,240 OBSERVATION FIRST OF ALL WHEN 1814 01:27:11,240 --> 01:27:17,880 YOU PUT AN RAS MUTATION YOU GET 1815 01:27:17,880 --> 01:27:18,880 PERIOSTAL DISEASE AND WHAT HE 1816 01:27:18,880 --> 01:27:21,680 OBSERVED ALSO IS THIS. VERY, 1817 01:27:21,680 --> 01:27:27,000 VERY ROUTINELY FGF23 EXPRESSING 1818 01:27:27,000 --> 01:27:29,200 CELLS IN MICE REALLY ARE CLOSE 1819 01:27:29,200 --> 01:27:35,080 TO THE PERIOSTEAL SURFACE NOT 1820 01:27:35,080 --> 01:27:36,880 INDEOSTAL SURFACE AND LEAD TO 1821 01:27:36,880 --> 01:27:38,600 WORKING HYPOTHESIS THAT IT 1822 01:27:38,600 --> 01:27:41,240 APPEARS TO BE CONFINED TO WILD 1823 01:27:41,240 --> 01:27:43,240 TYPE ANIMALS AND THAT IS POINT 1824 01:27:43,240 --> 01:27:45,920 THAT MARA MADE EARLIER ABOUT 1825 01:27:45,920 --> 01:27:47,720 DIFFERENT TYPES OF SKIN CELLS WE 1826 01:27:47,720 --> 01:27:49,120 HAVE BEEN DISAPPOINTED THAT 1827 01:27:49,120 --> 01:27:51,280 MOUSE MODEL OF FIBROUS DYSPLASIA 1828 01:27:51,280 --> 01:27:54,840 HAVE NOT HELPED WITH FGF23 AND 1829 01:27:54,840 --> 01:27:56,360 DIDN'T FIGURE IT OUT SO WELL AND 1830 01:27:56,360 --> 01:27:57,760 THINK IT WILL HELP US FIGURE 1831 01:27:57,760 --> 01:27:58,960 SOME OF THIS OUT. 1832 01:27:58,960 --> 01:28:03,560 IN FACT, I WANT TO MAKE THIS 1833 01:28:03,560 --> 01:28:09,000 OBSERVATION IN THE 2023 PAPER 1834 01:28:09,000 --> 01:28:13,000 SHOWING LOTS OF FGF23 EXPRESSION 1835 01:28:13,000 --> 01:28:18,240 IN NORMAL BONE THIS IS -- IN 1836 01:28:18,240 --> 01:28:19,240 RETROSPECT IT TIES THIS TOGETHER 1837 01:28:19,240 --> 01:28:21,280 AND IS VERY INTERESTING. 1838 01:28:21,280 --> 01:28:25,640 SO, I WILL CLOSE NOW. THERE IS 1839 01:28:25,640 --> 01:28:27,800 A MILLION PEOPLE TO THANK. I 1840 01:28:27,800 --> 01:28:30,720 HOPE I AM ABLE TO KEEP IT 1841 01:28:30,720 --> 01:28:31,800 TOGETHER BETTER THAN PAM DID. 1842 01:28:31,800 --> 01:28:34,960 THERE IS A TON OF PEOPLE AND 1843 01:28:34,960 --> 01:28:37,080 LOTS OF PEOPLE WHO ARE VERY 1844 01:28:37,080 --> 01:28:39,720 CRITICAL AND MY MENTORS OF 1845 01:28:39,720 --> 01:28:42,200 COURSE PAM AND STEVE AND MARK 1846 01:28:42,200 --> 01:28:45,720 AND LEE WEINSTEIN INCREDIBLY 1847 01:28:45,720 --> 01:28:49,960 HELPFUL AND MY CURRENT GROUP 1848 01:28:49,960 --> 01:28:54,080 RACHEL GAV ANY WHO I HAVE WORKED 1849 01:28:54,080 --> 01:28:55,640 WITH WHOLE TIME I HAVE BEEN HERE 1850 01:28:55,640 --> 01:28:57,680 WE WERE FELLOWS TOGETHER AND 1851 01:28:57,680 --> 01:29:01,520 GREAT FELLOWS DEANNA AND I WANT 1852 01:29:01,520 --> 01:29:03,320 TO THANK INTERINSTITUTE 1853 01:29:03,320 --> 01:29:05,280 ENDOCRINE TRAINING PROGRAM 1854 01:29:05,280 --> 01:29:08,320 INCREDIBLE SUPPORTERS OF OUR 1855 01:29:08,320 --> 01:29:11,040 WORK THE WHOLE TIME. 1856 01:29:11,040 --> 01:29:17,000 UNFORTUNATELY NICHD PEDIATRIC 1857 01:29:17,000 --> 01:29:19,960 ENDOCRINE TRAINING PROGRAM THAT 1858 01:29:19,960 --> 01:29:20,600 RAINED RACHEL AND 1859 01:29:20,600 --> 01:29:22,880 [INDISCERNIBLE] IS NO LONGER 1860 01:29:22,880 --> 01:29:24,920 HERE AND LOSS INSTITUTE AND HOPE 1861 01:29:24,920 --> 01:29:27,560 IT COMES BACK AND PROVIDED 1862 01:29:27,560 --> 01:29:29,160 INCREDIBLE NUMBER OF VERY 1863 01:29:29,160 --> 01:29:30,880 TALENTED MEDICAL STUDENTS THAT 1864 01:29:30,880 --> 01:29:33,280 HAVE GONE ON TO INVESTIGATORS AS 1865 01:29:33,280 --> 01:29:34,480 WELL AND PEOPLE FROM OUTSIDE 1866 01:29:34,480 --> 01:29:38,080 THAT I HAVE WORKED WITH AND NOW 1867 01:29:38,080 --> 01:29:40,240 FOR A BIG SLIDE THAT IN 2024 1868 01:29:40,240 --> 01:29:43,960 AFTER 25 YEARS, I WILL BE 1869 01:29:43,960 --> 01:29:46,880 LEAVING NIH FOR HORIZONS YET TO 1870 01:29:46,880 --> 01:29:53,000 BE DETERMINED. THAT IS IT. 1871 01:29:53,000 --> 01:29:53,880 >> AUDIENCE: [APPLAUSE]. 1872 01:29:53,880 --> 01:30:04,280 >> >> THANK YOU, MIKE. 1873 01:30:14,320 --> 01:30:17,440 BEFORE WE GO ON BREAK, I WANT TO 1874 01:30:17,440 --> 01:30:21,200 SPEND A LITTLE TIME THANKING THE 1875 01:30:21,200 --> 01:30:24,280 ORGANIZING COMMITTEE AND MIKE, 1876 01:30:24,280 --> 01:30:26,320 ALLISON AND PAM HAVE PLAYED A 1877 01:30:26,320 --> 01:30:27,800 HUGE ROLE GETTING THIS TOGETHER 1878 01:30:27,800 --> 01:30:30,320 AND PULLING TOGETHER A WONDERFUL 1879 01:30:30,320 --> 01:30:32,480 LINEUP OF AMAZING SPEAKERS AND 1880 01:30:32,480 --> 01:30:33,840 PEOPLE THAT HAVE MADE A 1881 01:30:33,840 --> 01:30:35,280 DIFFERENCE IN THIS DISEASE AND 1882 01:30:35,280 --> 01:30:38,720 THANKING MY STAFF IN OFFICE OF 1883 01:30:38,720 --> 01:30:40,160 CLINICAL DIRECTOR FOR ALL THEIR 1884 01:30:40,160 --> 01:30:42,840 BEHIND THE SCENES WORK AND STAFF 1885 01:30:42,840 --> 01:30:46,000 OF DR. DESOOUZA WHO ALSO HELPED 1886 01:30:46,000 --> 01:30:47,920 AND COMMUNICATIONS TEAM THAT 1887 01:30:47,920 --> 01:30:49,720 PLAYED A BIG ROLE MAKING SURE 1888 01:30:49,720 --> 01:30:50,960 INFORMATION WAS OUT THERE AND 1889 01:30:50,960 --> 01:30:52,720 WILL INVITE EVERYONE TO THE 1890 01:30:52,720 --> 01:30:54,560 COFFEE BREAK. I WOULD LIKE TO 1891 01:30:54,560 --> 01:30:57,800 ASK THE PATIENTS AND PATIENT 1892 01:30:57,800 --> 01:30:59,600 ADVOCACY GROUPS TO COME FORWARD 1893 01:30:59,600 --> 01:31:02,440 SOON AS YOU HAVE HAD COFFEE AND 1894 01:31:02,440 --> 01:31:04,080 COOKIES TO COME FORWARD. WE 1895 01:31:04,080 --> 01:31:05,680 WILL START THE NEXT SESSION IN 1896 01:31:05,680 --> 01:31:12,960 10 OR 15 MINUTES. 1897 01:31:12,960 --> 01:31:14,880 I WOULD LIKE TO START THE FINAL 1898 01:31:14,880 --> 01:31:18,320 HALF AND FIRST SPEAKER IS 1899 01:31:18,320 --> 01:31:21,920 ALLISON BOYCE HAVING TRAINED AND 1900 01:31:21,920 --> 01:31:32,320 COMPLETED PEDIATRIC -- 1901 01:31:33,800 --> 01:31:36,880 PRESTIGIOUS AND COMPETITIVE 1902 01:31:36,880 --> 01:31:39,400 TENURE TRACK AWARD FOR 1903 01:31:39,400 --> 01:31:40,640 EXCEPTIONAL CLINICAL 1904 01:31:40,640 --> 01:31:44,800 INVESTIGATORS SHE RECEIVED IN 1905 01:31:44,800 --> 01:31:45,000 2020. 1906 01:31:45,000 --> 01:31:48,400 SHE TOOK THE LEAD ON THE FD/MAS 1907 01:31:48,400 --> 01:31:51,880 STUDY AT NIH IN 2016 AND 1908 01:31:51,880 --> 01:31:53,680 INTERNATIONAL REPUTATION IS WELL 1909 01:31:53,680 --> 01:31:55,280 BISHED AND WILL SHARE CURRENT 1910 01:31:55,280 --> 01:31:57,520 STATUS OF PROGRAM AND NEXT PHASE 1911 01:31:57,520 --> 01:31:59,720 OF THE JOURNEY INCLUDING FOCUS 1912 01:31:59,720 --> 01:32:01,360 ON TREATMENT AND HOPEFULLY SOME 1913 01:32:01,360 --> 01:32:09,280 DAY A CURE. THANKS. 1914 01:32:09,280 --> 01:32:12,720 >> THANK YOU VERY MUCH DR. LEE 1915 01:32:12,720 --> 01:32:14,440 FOR THAT INTRODUCTION. IT IS AN 1916 01:32:14,440 --> 01:32:17,680 HONOR AND PRIVILEGE TO BE HERE I 1917 01:32:17,680 --> 01:32:20,600 JOINED THE INTRAMURAL PROGRAM 13 1918 01:32:20,600 --> 01:32:23,440 YEARS AGO TO WORK IN MIKE 1919 01:32:23,440 --> 01:32:24,560 COLLIN'S LAB AND COULDN'T HAVE 1920 01:32:24,560 --> 01:32:26,880 ASKED FOR A BETTER ENVIRONMENT 1921 01:32:26,880 --> 01:32:31,160 TO GROW AND DEVELOP AS A 1922 01:32:31,160 --> 01:32:33,520 SCIENTIST. INTRA MURAL PROGRAM 1923 01:32:33,520 --> 01:32:35,240 HAS BEEN SUPPORTIVE AND RIGOROUS 1924 01:32:35,240 --> 01:32:37,160 AND MY PLEASURE TO SHARE WORK 1925 01:32:37,160 --> 01:32:40,320 THAT HAS BEEN ONGOING IN FD/MAS 1926 01:32:40,320 --> 01:32:42,560 AND SHOW YOU HOW WE WILL TAKE IT 1927 01:32:42,560 --> 01:32:44,400 INTO THE FUTURE. 1928 01:32:44,400 --> 01:32:47,400 SO, AS DR. COLLINS SHARES 1929 01:32:47,400 --> 01:32:48,600 NATURAL HISTORY STUDY WAS 1930 01:32:48,600 --> 01:32:52,960 FOUNDED IN 1998 AND SINCE THEN 1931 01:32:52,960 --> 01:32:55,200 SERVED AS BACKBONE OF RESEARCH 1932 01:32:55,200 --> 01:32:58,680 OVER PAST 25 YEARS CAPITALIZING 1933 01:32:58,680 --> 01:33:02,680 ON UNIQUE RESOURCES OF NIH 1934 01:33:02,680 --> 01:33:05,760 CLINICAL CENTER THIS RECRUITED A 1935 01:33:05,760 --> 01:33:08,160 COHORT OF PATIENTS UNPARALLEL 1936 01:33:08,160 --> 01:33:10,960 INNED IN THE FIELD RESEARCH IN 1937 01:33:10,960 --> 01:33:13,160 FIELD HAS BEEN PRODUCTIVE 1938 01:33:13,160 --> 01:33:14,640 GREATER THAN 50 PUBLICATIONS 1939 01:33:14,640 --> 01:33:17,600 GENERATED AND 6 CLINICAL TRIALS 1940 01:33:17,600 --> 01:33:20,040 AND TOGETHER HAS FORMED BULK OF 1941 01:33:20,040 --> 01:33:21,400 DEFINITIVE CLINICAL LITERATURE 1942 01:33:21,400 --> 01:33:23,480 IN FD/MAS. 1943 01:33:23,480 --> 01:33:26,040 I WANTED TO SHARE AN EXAMPLE HOW 1944 01:33:26,040 --> 01:33:27,440 RESEARCH ON NATURAL HISTORY 1945 01:33:27,440 --> 01:33:30,600 STUDY HAS TRANSFORMED CARE FOR 1946 01:33:30,600 --> 01:33:32,400 PASH YERPTS OPTIC CANAL IS A 1947 01:33:32,400 --> 01:33:34,760 BEAU ENE STRUCTURE LOCATED AT 1948 01:33:34,760 --> 01:33:38,920 BACK OF ORITY SERVING THROUGH 1949 01:33:38,920 --> 01:33:40,120 TUNNEL OPTIC NERVE CHANNELS 1950 01:33:40,120 --> 01:33:41,520 CONNECTING EYE AND BRAIN IF THIS 1951 01:33:41,520 --> 01:33:44,160 IS SQUEEZED OR STRETCHED IT CAN 1952 01:33:44,160 --> 01:33:45,480 DAMAGE THE NERVE AND CAUSE 1953 01:33:45,480 --> 01:33:47,720 BLINDNESS AND AT TIME THAT 1954 01:33:47,720 --> 01:33:48,880 NATURAL HISTORY STUDY STARTED 1955 01:33:48,880 --> 01:33:52,400 STANDARD OF CARE WAS TO PERFORM 1956 01:33:52,400 --> 01:33:55,720 A SURGERY CALLED OPTIC CANAL 1957 01:33:55,720 --> 01:33:57,480 DECOMPRESSION TO WIDEN CANAL AND 1958 01:33:57,480 --> 01:34:00,200 PREVENT THE NERVE FROM CAUSING 1959 01:34:00,200 --> 01:34:02,920 -- PREVENTING BONE FROM CAUSING 1960 01:34:02,920 --> 01:34:04,280 VISION LOSS IN PATIENTS WITH 1961 01:34:04,280 --> 01:34:05,680 NORMAL VISION AND CLINICIANS 1962 01:34:05,680 --> 01:34:08,000 THOUGHT THIS WAS NECESSARY TO 1963 01:34:08,000 --> 01:34:10,200 PREVENT FD FROM CAUSING 1964 01:34:10,200 --> 01:34:12,440 BLINDNESS AND ONE OF THE 1965 01:34:12,440 --> 01:34:13,800 EARLIEST OBSERVATIONS AFTER 1966 01:34:13,800 --> 01:34:15,560 NATURAL HISTORY STUDY STARTED 1967 01:34:15,560 --> 01:34:17,800 WAS FAIRLY LARGE PROPORTION OF 1968 01:34:17,800 --> 01:34:20,160 PATIENTS HAD VISION LOSS WHEN 1969 01:34:20,160 --> 01:34:22,240 INVESTIGATORS COMPARED PATIENTS 1970 01:34:22,240 --> 01:34:24,280 ACROSS COHORT THEY NOTED LARGEST 1971 01:34:24,280 --> 01:34:25,880 RISK FACTOR FOR VISION LOSS WAS 1972 01:34:25,880 --> 01:34:28,760 HISTORY OF HAVING HAD OPTIC 1973 01:34:28,760 --> 01:34:30,560 NERVE DECOMPRESSION SURGERY AND 1974 01:34:30,560 --> 01:34:32,640 THIS DATA SUGGESTS STANDARD OF 1975 01:34:32,640 --> 01:34:37,440 CARE SURGERY INCREASED VISION 1976 01:34:37,440 --> 01:34:39,720 LOSS AND NERVE DAMAGE 1977 01:34:39,720 --> 01:34:40,680 INTEROPERATIVELY AND OVER NEXT 1978 01:34:40,680 --> 01:34:42,560 SEVERAL YEARS WE STUDIED THIS 1979 01:34:42,560 --> 01:34:44,960 TOPIC MUCH MORE CLOSELY 1980 01:34:44,960 --> 01:34:47,240 INVESTIGATORS PERFORMED 1981 01:34:47,240 --> 01:34:49,240 METAANALYSIS SHOWING WATCHFUL 1982 01:34:49,240 --> 01:34:50,760 WAITING CLOSE VISION MONITORING 1983 01:34:50,760 --> 01:34:53,480 LED TO SUPERIOR OUTCOMES 1984 01:34:53,480 --> 01:34:55,920 COMPARED TO OPTIC NERVE 1985 01:34:55,920 --> 01:34:58,440 DECOMPRESSION AND COHORT GREW 1986 01:34:58,440 --> 01:35:01,000 LARGER IDENTIFIED GROWTH HORMONE 1987 01:35:01,000 --> 01:35:02,400 EXCESS WAS FACTOR FOR VISION 1988 01:35:02,400 --> 01:35:05,200 LOSS AND EARLY TREATMENT COULD 1989 01:35:05,200 --> 01:35:07,560 PREVENT THIS MORBIDITY AND 1990 01:35:07,560 --> 01:35:09,480 RECENTLY DEFINED STANDARDS 1991 01:35:09,480 --> 01:35:12,000 MEASURING THICKNESS OF FIBER 1992 01:35:12,000 --> 01:35:13,440 LAYER SURROUNDING OPTIC NERVE TO 1993 01:35:13,440 --> 01:35:16,440 ALLOW TO IDENTIFY EARLY SIGNS OF 1994 01:35:16,440 --> 01:35:18,240 NERVE COMPRESSION BEFORE 1995 01:35:18,240 --> 01:35:19,960 PATIENTS DEVELOP VISION LOSS AND 1996 01:35:19,960 --> 01:35:21,320 TAKING TOGETHER THIS LINE OF 1997 01:35:21,320 --> 01:35:24,400 RESEARCH TRANSFORMED CARE OF 1998 01:35:24,400 --> 01:35:26,560 OPTIC CANAL FD FROM INVASIVE 1999 01:35:26,560 --> 01:35:28,400 MORBID SURGERIES TO REFINED 2000 01:35:28,400 --> 01:35:30,240 APPROACH BASED PRIMARILY ON 2001 01:35:30,240 --> 01:35:33,200 MONITORING AND MEDICAL 2002 01:35:33,200 --> 01:35:35,600 MANAGEMENT. 2003 01:35:35,600 --> 01:35:39,520 RELATIONSHIP BETWEEN GROWTH 2004 01:35:39,520 --> 01:35:41,240 HORMONE EXCESS IS WORTH 2005 01:35:41,240 --> 01:35:43,480 EMPHASIZING EARLY EVIDENCE THAT 2006 01:35:43,480 --> 01:35:45,280 EARLY INTERVENTION COULD HAVE 2007 01:35:45,280 --> 01:35:49,040 MORBIDITY PATIENTS WITH EQUAL 2008 01:35:49,040 --> 01:35:50,760 VOLUMEMENT AND SEVERITY OF 2009 01:35:50,760 --> 01:35:52,960 GROWTH HORMONE ACCESS PATIENT ON 2010 01:35:52,960 --> 01:35:55,320 TOP WASN'T DIAGNOSED OR STARTED 2011 01:35:55,320 --> 01:35:56,920 ON TREATMENT UNTIL AGE 8 TA 2012 01:35:56,920 --> 01:35:58,880 ENAND DEVELOPED MA SSIVE 2013 01:35:58,880 --> 01:36:01,240 OVERGROWTH OF SKULL AND JAWS AND 2014 01:36:01,240 --> 01:36:03,440 ORBITS OCCOLLUSION OF OPTIC 2015 01:36:03,440 --> 01:36:05,120 CANALS THAT IS UNFORTUNATELY 2016 01:36:05,120 --> 01:36:07,840 BLIND AND DEVELOPED HEARING LOSS 2017 01:36:07,840 --> 01:36:10,600 AND PATIENT ON BOTTOM SCREENED 2018 01:36:10,600 --> 01:36:12,160 EARLY AND YOU CAN SEE THAT SKULL 2019 01:36:12,160 --> 01:36:15,160 IS GENERALLY OVERALL SYMMETRIC 2020 01:36:15,160 --> 01:36:17,600 AND HAS NORMAL VISION AND NORMAL 2021 01:36:17,600 --> 01:36:19,920 HEARING AND THINK IT IS AN 2022 01:36:19,920 --> 01:36:22,080 ENCOURAGING SIGN THAT EARLY 2023 01:36:22,080 --> 01:36:24,120 INTERVENTION CAN TRANSFORM 2024 01:36:24,120 --> 01:36:24,360 OUTCOMES. 2025 01:36:24,360 --> 01:36:25,840 SO, I WILL SWITCH GEARS A LITTLE 2026 01:36:25,840 --> 01:36:28,040 BIT AND TALK ABOUT RESEARCH 2027 01:36:28,040 --> 01:36:30,440 IDENTIFYING THERAPEUTIC TARGETS 2028 01:36:30,440 --> 01:36:32,880 AND FIBROUS DYSPLASIA AND LINE 2029 01:36:32,880 --> 01:36:34,600 OF RESEARCH ARISEN OUT OF 2030 01:36:34,600 --> 01:36:36,320 OBSERVATION THAT FD LESIONS ARE 2031 01:36:36,320 --> 01:36:38,600 IN STATE OF HIGH BONE REMODELING 2032 01:36:38,600 --> 01:36:41,720 SEEING CLINICALLY DR. COLLINS 2033 01:36:41,720 --> 01:36:44,040 SHARED DURING CHILDHOOD LESIONS 2034 01:36:44,040 --> 01:36:48,480 EXPAND AND INVADE AREAS OF -- 2035 01:36:48,480 --> 01:36:50,960 FORMATION AND REABSORPTION IN 2036 01:36:50,960 --> 01:36:52,400 PATIENTS LEVELS CORRELATE WITH 2037 01:36:52,400 --> 01:36:54,120 OVERALL AMOUNT OF SKELETAL 2038 01:36:54,120 --> 01:36:55,880 DISEASE BURDEN. 2039 01:36:55,880 --> 01:36:58,160 HISTLOGICALLY WE SEE LARGE 2040 01:36:58,160 --> 01:37:00,640 AREAS OF ABNORMAL BONE FORMATION 2041 01:37:00,640 --> 01:37:04,440 AND PROMINENT OSTEOCLAST GENESIS 2042 01:37:04,440 --> 01:37:07,480 AND LED TO ASK QUESTION COULD 2043 01:37:07,480 --> 01:37:08,960 TARGETING -- BE EFFECTIVE 2044 01:37:08,960 --> 01:37:13,320 TREATMENT STRATEGY FOR FD? 2045 01:37:13,320 --> 01:37:17,920 SO, BIPHOSFENATE ARE SYNTHETIC 2046 01:37:17,920 --> 01:37:19,520 ANALOGS INCORPORATED INTO 2047 01:37:19,520 --> 01:37:23,040 SKELETAL MATRIXES INACTIVATING 2048 01:37:23,040 --> 01:37:24,760 OSTEOCLASTS INCORPORATED INTO 2049 01:37:24,760 --> 01:37:28,400 BONE LONG HALF LIFE OF GREATER 2050 01:37:28,400 --> 01:37:30,920 THAN 10 YEARS WITH GREAT 2051 01:37:30,920 --> 01:37:32,280 SUSTAINED EFFECT OF BONE DENSITY 2052 01:37:32,280 --> 01:37:34,720 AND TREATMENTS OF OSTEOPOROSIS 2053 01:37:34,720 --> 01:37:36,480 AND BONE TUMORS. 2054 01:37:36,480 --> 01:37:40,000 YOU HEARD EARLIER TO INVESTIGATE 2055 01:37:40,000 --> 01:37:43,680 ROLE OF BIPHOSFENATE AND FD 2056 01:37:43,680 --> 01:37:45,520 PLACEBO CONTROLLED TRIAL USING 2057 01:37:45,520 --> 01:37:48,800 ORAL FORMULATION AWILL ENDROE 2058 01:37:48,800 --> 01:37:53,440 LITE AND STUDY IN TWO YEAR 2059 01:37:53,440 --> 01:37:56,560 ENROLLING 36 PATIENTS AND HAD NO 2060 01:37:56,560 --> 01:37:58,880 EFFECT ON BONE FORMATION 2061 01:37:58,880 --> 01:37:59,280 MARKERS. 2062 01:37:59,280 --> 01:38:02,240 WE SAW INCREASE IN DENSITY OF FD 2063 01:38:02,240 --> 01:38:05,120 LESIONS ON DECHLA SCANNINGS ON 2064 01:38:05,120 --> 01:38:06,960 CHILDREN AND WERE NO EFFECT ON 2065 01:38:06,960 --> 01:38:07,280 ADULTS. 2066 01:38:07,280 --> 01:38:10,520 THERE WAS NO EFFECT ON BONE 2067 01:38:10,520 --> 01:38:11,760 PAIN AND DISAPPOINTINGLY NO 2068 01:38:11,760 --> 01:38:14,960 CHANGE IN CLINICALLY RELEVANT 2069 01:38:14,960 --> 01:38:16,320 OUTCOMES MEASURES SUCH AS 2070 01:38:16,320 --> 01:38:18,160 FRACTURES AND PHYSICAL 2071 01:38:18,160 --> 01:38:19,880 PERFORMANCE MEASURES OR IN RADIO 2072 01:38:19,880 --> 01:38:22,200 GRAPHIC APPEARANCE OF FD 2073 01:38:22,200 --> 01:38:24,840 LESIONS. HOWEVER, THERE IS A 2074 01:38:24,840 --> 01:38:27,240 MECHANISM FOR TARGETING 2075 01:38:27,240 --> 01:38:28,880 OSTEOCLASTS THROUGH PROTEIN 2076 01:38:28,880 --> 01:38:32,480 RANKLE RECENTO ACTIVATOR AND 2077 01:38:32,480 --> 01:38:35,800 PROTEIN IS MEMBER OF TUMOR 2078 01:38:35,800 --> 01:38:37,520 NECROSIS FACTOR SUPER FAMILY 2079 01:38:37,520 --> 01:38:39,880 HIGHLY EXPRESSED BY OWE OF THEO 2080 01:38:39,880 --> 01:38:44,040 BLASTS AND PROGENITOR CELLS AND 2081 01:38:44,040 --> 01:38:46,920 ALL OF WHICH PARTICIPATE IN OST 2082 01:38:46,920 --> 01:38:50,480 EO CLAST GENESIS AND BINDING TO 2083 01:38:50,480 --> 01:38:54,120 OSTEOCLASS PRECURSORS ACTIVATES 2084 01:38:54,120 --> 01:38:56,400 DIFFERENTIATION AND INFUSION OF 2085 01:38:56,400 --> 01:38:58,640 OSTEOCLASTS AND NUMBER OF YEARS 2086 01:38:58,640 --> 01:38:59,240 HAD GROWING EVIDENCE THAT 2087 01:38:59,240 --> 01:39:01,920 MICHAEL SEEMS TO PLAY A ROPE IN 2088 01:39:01,920 --> 01:39:05,640 FD PATHOGENESIS AND LEVELS IN 2089 01:39:05,640 --> 01:39:07,240 PATIENTS BLOOD AND CORRELATES 2090 01:39:07,240 --> 01:39:09,280 WITH OVERALL AMOUNT OF SKELETAL 2091 01:39:09,280 --> 01:39:11,800 DISEASE BURDEN AND HIGH LEVELS 2092 01:39:11,800 --> 01:39:14,560 OF EXPRESSION IN FD TISSUE AND 2093 01:39:14,560 --> 01:39:16,120 CORRELATES ALSO WITH HIGH AREAS 2094 01:39:16,120 --> 01:39:21,720 OF OSTEOGENIC CELL PROLIFERATION 2095 01:39:21,720 --> 01:39:28,240 AND SERIAL -- THIS IS CLINICALLY 2096 01:39:28,240 --> 01:39:38,800 RELEVANT RANKL -- SO, WE 2097 01:39:41,520 --> 01:39:43,800 HYPOTHESIZED THAT RANKL 2098 01:39:43,800 --> 01:39:45,720 INHIBITION WITH DENNO ASSUME AB 2099 01:39:45,720 --> 01:39:48,200 WOULD BE A STRATEGY TO DECREASE 2100 01:39:48,200 --> 01:39:50,600 LESION ACTIVITY AND INCREASE 2101 01:39:50,600 --> 01:40:01,160 MINERALIZATION IN FD LESIONS -- 2102 01:40:05,960 --> 01:40:09,000 WHEN MEDICATION IS STOPPED BONE 2103 01:40:09,000 --> 01:40:10,840 TURNOVER CAN REBOUND INCREASE 2104 01:40:10,840 --> 01:40:12,960 TEMPORARILY TO LEVELS HIGHER 2105 01:40:12,960 --> 01:40:14,080 THAN PRE-TREATMENT AND BECAUSE 2106 01:40:14,080 --> 01:40:16,120 OF THAT WAS IMPORTANT TO US IN 2107 01:40:16,120 --> 01:40:18,320 THE STUDY TO INVESTIGATE SAFETY 2108 01:40:18,320 --> 01:40:21,840 OF STOPPING DENOSUMAB AND 2109 01:40:21,840 --> 01:40:24,280 INCLUDED EXTENSIVE INTENSIVE 2110 01:40:24,280 --> 01:40:26,080 POST-TREATMENT MONITORING 2111 01:40:26,080 --> 01:40:28,360 PERIOD. PRIMARY ENDPOINT OF 2112 01:40:28,360 --> 01:40:32,400 STUDY WAS BONE TURNOVER MARKERS 2113 01:40:32,400 --> 01:40:35,040 SECONDARY ENDPOINTS HAD PAIN AND 2114 01:40:35,040 --> 01:40:37,440 FUNCTION AND EFFECTS IN FD 2115 01:40:37,440 --> 01:40:40,360 LESION BONE BIOPSIES. 2116 01:40:40,360 --> 01:40:44,720 SO, DENOSUMAB HAD A PROFOUND AND 2117 01:40:44,720 --> 01:40:45,880 SUSTAINED EFFECT ON BONE 2118 01:40:45,880 --> 01:40:48,640 TURNOVER MARKERS SEEING DECLINES 2119 01:40:48,640 --> 01:40:53,240 IN P1 AND P3 AND BONE FORMATION 2120 01:40:53,240 --> 01:40:54,520 MARKER AND BONE ABSORPTION 2121 01:40:54,520 --> 01:40:57,440 MARKER AND CONTRAST TO STUDY IN 2122 01:40:57,440 --> 01:40:59,720 AWILL ENDROE LATE DON'T SEE 2123 01:40:59,720 --> 01:41:03,680 EFFECT ON MARKERS AND SODIUM 2124 01:41:03,680 --> 01:41:07,840 FLUORIDE PET CT IS ANATOMICAL 2125 01:41:07,840 --> 01:41:09,720 IMAGING TECHNIQUE MEASURING 2126 01:41:09,720 --> 01:41:11,240 AMOUNT OF TRACER TAKEN UP INTO 2127 01:41:11,240 --> 01:41:13,280 LESIONS THAT YOU CAN SEE AFTER 6 2128 01:41:13,280 --> 01:41:17,000 MONTHS OF DENOSUMAB WE SEE A 2129 01:41:17,000 --> 01:41:19,840 PROFOUND DECREASE AND LESIONAL 2130 01:41:19,840 --> 01:41:22,240 ACTIVITY TO PHYSIOLOGIC LEVELS 2131 01:41:22,240 --> 01:41:24,480 IN SOME PATIENTS AND WHAT 2132 01:41:24,480 --> 01:41:26,320 ENCOURAGING THIS IS A COMPANY BY 2133 01:41:26,320 --> 01:41:27,880 PROFOUND IMPROVEMENTS IN 2134 01:41:27,880 --> 01:41:29,080 CLINICAL OUTCOMES. 2135 01:41:29,080 --> 01:41:31,640 FOR EXAMPLE, THIS PATIENT HERE 2136 01:41:31,640 --> 01:41:34,080 AND THIS ONE THAT HAS REALLY 2137 01:41:34,080 --> 01:41:37,120 SEVERE THORACIC FD INVOLVEMENT 2138 01:41:37,120 --> 01:41:39,960 HAD SUCH RIB EXPANSION SHE HAD 2139 01:41:39,960 --> 01:41:43,600 PULMONARY RESTRICTION REQUIRING 2140 01:41:43,600 --> 01:41:44,480 CONTINUOUS OXYGEN THERAPY AND IN 2141 01:41:44,480 --> 01:41:49,000 A MONTH OF STARTING DENOSUMAB 2142 01:41:49,000 --> 01:41:50,240 HER PULMONARY FUNCTION IMPROVED 2143 01:41:50,240 --> 01:41:52,560 AND SHE WAS ABLE TO DISCONTINUE 2144 01:41:52,560 --> 01:41:58,000 OXYGEN. THIS WAS ENCOURAGING 2145 01:41:58,000 --> 01:42:00,120 EFFECTS SAW WERE PERFORMED IN 2146 01:42:00,120 --> 01:42:02,920 SAME SITE BEFORE AND AFTER 2147 01:42:02,920 --> 01:42:04,840 DENOSUMAB TREATMENT INCREASE IN 2148 01:42:04,840 --> 01:42:06,640 BONE CONTENT AND REDUCTION IN 2149 01:42:06,640 --> 01:42:09,360 EXPRESSION IN CELL PROLIFERATION 2150 01:42:09,360 --> 01:42:12,160 MARKER AND INCREASE IN THE 2151 01:42:12,160 --> 01:42:13,360 EXPRESSION OF THE MATURE 2152 01:42:13,360 --> 01:42:14,960 MINERALIZATION MARKER. SO, WHEN 2153 01:42:14,960 --> 01:42:17,240 WE PUT THIS TOGETHER IT SEEMS TO 2154 01:42:17,240 --> 01:42:23,120 SUGGEST A PATTERN WHERE 2155 01:42:23,120 --> 01:42:25,040 ANTI-RANKL INHIBITION -- ALLOWS 2156 01:42:25,040 --> 01:42:29,080 THEM TO ADOPT A MATURE PATTERN 2157 01:42:29,080 --> 01:42:35,920 OF DIFFER ENTI 2158 01:42:35,920 --> 01:42:37,800 DIFFERENTIATION THAT COULD MAKE 2159 01:42:37,800 --> 01:42:38,480 MORE BONE. 2160 01:42:38,480 --> 01:42:41,040 IN THIS MOUSE MODEL IT EXPRESSES 2161 01:42:41,040 --> 01:42:46,840 HUMAN G ALPHA S VARIANT. MICE 2162 01:42:46,840 --> 01:42:48,880 DEVELOP EXPANSILE FIBROUS 2163 01:42:48,880 --> 01:42:52,200 LESIONS THAT MIMIC FD RADIO 2164 01:42:52,200 --> 01:42:54,040 GRAPHICALLY AND HISTLOGICALLY 2165 01:42:54,040 --> 01:42:56,200 AND TREATMENT OF ANTI-RANKL YOU 2166 01:42:56,200 --> 01:42:59,080 CAN SEE THAT THE LESIONS DEVELOP 2167 01:42:59,080 --> 01:43:01,920 SUBSTANTIAL INCREASE IN 2168 01:43:01,920 --> 01:43:03,600 MINERALIZATION AS EVIDENCE ON 2169 01:43:03,600 --> 01:43:06,120 MICRO CT. HISTLOGICALLY WE SEE 2170 01:43:06,120 --> 01:43:11,200 SIMILAR FINDINGS TO HUMAN TISSUE 2171 01:43:11,200 --> 01:43:13,640 AND REDUCTION IN CELLULARITY AND 2172 01:43:13,640 --> 01:43:15,640 REDUCTION IN CELL PROLIFERATION 2173 01:43:15,640 --> 01:43:16,680 MARKERS AND DECREASE IN 2174 01:43:16,680 --> 01:43:19,480 EXPRESSION OF EARLY OSTEOGENIC 2175 01:43:19,480 --> 01:43:23,760 MARKER AND INCREASE IN MATURE 2176 01:43:23,760 --> 01:43:26,200 OSTEOGENIC MARKER SCLER OSTEN. 2177 01:43:26,200 --> 01:43:27,840 TO INVESTIGATE INTERACTIONS 2178 01:43:27,840 --> 01:43:29,880 BETWEEN CELL TYPES AND FD 2179 01:43:29,880 --> 01:43:33,160 LESIONS WE DEVELOPED AN FD 2180 01:43:33,160 --> 01:43:34,680 EX-VIVO CELL CULTURE MODEL AND 2181 01:43:34,680 --> 01:43:37,080 BONE MARROW CELLS FROM FD MOUSE 2182 01:43:37,080 --> 01:43:40,120 WERE ISOLATED AND CULTURED AND 2183 01:43:40,120 --> 01:43:42,240 THEN G ALPHA S VARIANT 2184 01:43:42,240 --> 01:43:44,080 EXPRESSION WAS INDUCED 2185 01:43:44,080 --> 01:43:48,160 SPECIFICALLY IN OSTEOPROGENITOR 2186 01:43:48,160 --> 01:43:51,280 CELLS VIA DEOXY CYCLING AND THEY 2187 01:43:51,280 --> 01:43:54,480 PRODUCE OSTEOCLASTIC SIGNALING 2188 01:43:54,480 --> 01:43:57,800 FACTORS THAT INCREASE PRODUCTION 2189 01:43:57,800 --> 01:43:59,840 AND ACTIVITY OF OSTEOCLASTS AND 2190 01:43:59,840 --> 01:44:02,440 SIMILAR TO EFFECTS IN HUMAN AND 2191 01:44:02,440 --> 01:44:12,400 MOUSE TISSH RANKLLE INHIBITION - 2192 01:44:12,400 --> 01:44:17,560 DEOXY CYCLEAN WE SAW INCREASE IN 2193 01:44:17,560 --> 01:44:19,600 OSTEOGENERALITIOR CELLS AND WHEN 2194 01:44:19,600 --> 01:44:22,760 WE TREAT WITH ANTI-RANKL WE SEE 2195 01:44:22,760 --> 01:44:24,000 DECLINE IN EXPRESSION OF THE 2196 01:44:24,000 --> 01:44:25,920 LEVELS AND HIGH LEVELS OF 2197 01:44:25,920 --> 01:44:27,840 PROLIFERATION ARE NO LONGER 2198 01:44:27,840 --> 01:44:28,600 SEEN. 2199 01:44:28,600 --> 01:44:31,280 SO, PUTTING THIS LINE TOGETHER, 2200 01:44:31,280 --> 01:44:33,560 WE CONCLUDE THAT RANKL 2201 01:44:33,560 --> 01:44:36,000 INHIBITION DECREASES 2202 01:44:36,000 --> 01:44:38,960 PROLIFERATION AND INCREASES 2203 01:44:38,960 --> 01:44:42,040 MATURATION OF FD CELLS. 2204 01:44:42,040 --> 01:44:45,560 THIS IS EVEN BEYOND EXPECTED 2205 01:44:45,560 --> 01:44:46,920 ANTI-ABSORPTIVE EFFECTS 2206 01:44:46,920 --> 01:44:49,520 HIGHLIGHTING ROLE OF OSTEOBLAST 2207 01:44:49,520 --> 01:44:52,120 SIGNALING IN FD PATHOPHYSIOLOGY. 2208 01:44:52,120 --> 01:44:54,040 AGAIN, THIS IS QUITE EXCITING 2209 01:44:54,040 --> 01:44:55,880 HOWEVER WE RANNISH AUTO YOUS 2210 01:44:55,880 --> 01:44:57,480 WITH BONE TURNOVER REBOUND AND 2211 01:44:57,480 --> 01:45:01,120 ALL PATIENTS IN STUDY WERE 2212 01:45:01,120 --> 01:45:04,280 TREATED WITH [INDISCERNIBLE] AT 2213 01:45:04,280 --> 01:45:11,600 TIME -- FOUR PATIENTS CTX BONE 2214 01:45:11,600 --> 01:45:14,240 ABSORPTION MARKER RETREATED TO 2215 01:45:14,240 --> 01:45:16,680 ABOVE PATIENT LEVELS EXTREMELY 2216 01:45:16,680 --> 01:45:19,600 SEVERE INCREASING 600% OF 2217 01:45:19,600 --> 01:45:22,120 BASELINE LEVEL ASSOCIATED WITH 2218 01:45:22,120 --> 01:45:26,360 SEVERE HYPERCALCEMIA TO 23 2219 01:45:26,360 --> 01:45:29,000 MILLIGRAMS PER DECILITER. 2220 01:45:29,000 --> 01:45:32,400 PATIENT HOSPITALIZED AND SHE 2221 01:45:32,400 --> 01:45:34,240 RECOVERED WITHOUT ANY SEC WELLA 2222 01:45:34,240 --> 01:45:36,400 AND CLEARLY HIGHLIGHTS IMPORTANT 2223 01:45:36,400 --> 01:45:40,120 ADVERSE EVENT THAT WE NEED TO BE 2224 01:45:40,120 --> 01:45:42,600 AWARE OF. 2225 01:45:42,600 --> 01:45:44,080 DENOSUMAB FOR FD WHERE ARE WE NO 2226 01:45:44,080 --> 01:45:46,280 YOU? EXCITING POTENTIAL TO HAVE 2227 01:45:46,280 --> 01:45:49,360 EFFECT ON FD LESION ACTIVITY AND 2228 01:45:49,360 --> 01:45:52,680 COMPOSITION AND SEVERE POST 2229 01:45:52,680 --> 01:45:54,120 DISCONTINUATION HYPERKALGSEMIA 2230 01:45:54,120 --> 01:45:57,760 OCCURS IN SUBSET OF PATIENTS IN 2231 01:45:57,760 --> 01:45:59,760 IMPORTANT ADVERSE EVENT AND 2232 01:45:59,760 --> 01:46:00,880 QUESTIONS WE NEED TO STILL 2233 01:46:00,880 --> 01:46:03,560 ANSWER. WHO SHOULD WE TREAT? 2234 01:46:03,560 --> 01:46:04,920 DOESN'T NEED TO MEET MEDICATION 2235 01:46:04,920 --> 01:46:06,560 FOR EVERYONE WITH FD AND COULD 2236 01:46:06,560 --> 01:46:08,800 BE POWERFUL TOOL FOR PATIENTS 2237 01:46:08,800 --> 01:46:10,840 WITH SEVERE MORBIDITY AND HOW 2238 01:46:10,840 --> 01:46:13,200 LONG WE SHOULD TREAT PATIENTS 2239 01:46:13,200 --> 01:46:14,640 IMPORTANT CONCLUSION FROM ADULT 2240 01:46:14,640 --> 01:46:20,880 STUDY TO MAINTAIN BENEFITS OF 2241 01:46:20,880 --> 01:46:22,680 DENOSUMAB WE HAVE TO CONTINUE. 2242 01:46:22,680 --> 01:46:27,960 WE SAW DRAMATIC EFFECTS 6 MONTHS 2243 01:46:27,960 --> 01:46:29,280 OF TREATMENT IMPORTANT AMOUNT OF 2244 01:46:29,280 --> 01:46:30,760 TIME IN SKELETAL PHYSIOLOGY AND 2245 01:46:30,760 --> 01:46:33,400 COULD GET AWAY WITH TREATING AT 2246 01:46:33,400 --> 01:46:35,360 MUCH LOWER DOSE AND MAINTAIN 2247 01:46:35,360 --> 01:46:35,640 BENEFITS . 2248 01:46:35,640 --> 01:46:37,360 FURTHER STUDIES NEEDED TO 2249 01:46:37,360 --> 01:46:39,680 DETERMINE CLINICAL UTILITY OF 2250 01:46:39,680 --> 01:46:41,160 DENOSUMAB THAT IS PARTICULARLY 2251 01:46:41,160 --> 01:46:43,160 THE CASE IN CHILDREN. 2252 01:46:43,160 --> 01:46:46,240 SO, AS DR. COLLINS SHARED AN 2253 01:46:46,240 --> 01:46:47,800 IMPORTANT OBSERVATION FROM 2254 01:46:47,800 --> 01:46:51,240 NATURAL HISTORY STUDY IS FD 2255 01:46:51,240 --> 01:46:55,080 LESIONS PROGRESS IN CHILDHOOD -- 2256 01:46:55,080 --> 01:46:56,400 THIS CREATES WINDOW OF 2257 01:46:56,400 --> 01:46:59,280 OPPORTUNITY WHERE IF WE CAN FIND 2258 01:46:59,280 --> 01:47:00,720 INTERVENTION THAT WILL PREVENT 2259 01:47:00,720 --> 01:47:02,520 FD LESIONS FROM FORMING AND 2260 01:47:02,520 --> 01:47:04,080 EXPANDING THAT IS HOW WE CAN 2261 01:47:04,080 --> 01:47:05,720 HAVE A TRANSFORMATIONAL EFFECT 2262 01:47:05,720 --> 01:47:07,760 ON THE DISEASE AND CURRENTLY 2263 01:47:07,760 --> 01:47:11,480 CONDUCTING A PHASE 2 STUDY OF 2264 01:47:11,480 --> 01:47:17,960 DENOSUMAB WITH PRIMARY GOAL OF 2265 01:47:17,960 --> 01:47:19,640 FD LESION PROGRESSION IN KIDS 2266 01:47:19,640 --> 01:47:21,680 AND EXPANSION AND COMPARING TO 2267 01:47:21,680 --> 01:47:23,640 UNTREATED PATIENTS FROM NATURAL 2268 01:47:23,640 --> 01:47:25,280 HISTORY STUDY FURTHER 2269 01:47:25,280 --> 01:47:26,680 CAPITALIZING ON THAT UNIQUE DATA 2270 01:47:26,680 --> 01:47:28,800 WE HAVE BEEN ABLE TO GATHER OVER 2271 01:47:28,800 --> 01:47:30,480 THE PAST 25 YEARS. 2272 01:47:30,480 --> 01:47:32,040 ANOTHER -- SO, BASED ON WHAT WE 2273 01:47:32,040 --> 01:47:34,000 HAVE LEARNED FROM THE ADULT 2274 01:47:34,000 --> 01:47:36,200 STUDY WE WILL USE A VERY, VERY 2275 01:47:36,200 --> 01:47:39,680 LOW DOSE OF DENOSUMAB ABOUT 2276 01:47:39,680 --> 01:47:43,200 12-FOLD LOIER AND WILL GIVE THIS 2277 01:47:43,200 --> 01:47:44,640 MEDICATION MONTHLY AND THIS 2278 01:47:44,640 --> 01:47:46,400 STUDY IS CURRENTLY ENROLLING AND 2279 01:47:46,400 --> 01:47:48,040 WOULD LIKE TO CLOSE BY SHARING 2280 01:47:48,040 --> 01:47:49,560 ABOUT ANOTHER ONE OF OUR 2281 01:47:49,560 --> 01:47:51,320 EXCITING STUDIES THAT IS 2282 01:47:51,320 --> 01:47:52,800 STARTING THAT RELATES TO 2283 01:47:52,800 --> 01:47:56,800 TREATMENT OF FGF23 EXCESS AND 2284 01:47:56,800 --> 01:48:01,640 DR. COLLINS SHARED -- LEADING TO 2285 01:48:01,640 --> 01:48:03,680 LOW BLOOD PHOSPHORUS LEVELS 2286 01:48:03,680 --> 01:48:05,080 LEADING TO CLINICAL 2287 01:48:05,080 --> 01:48:07,960 COMPLICATIONS RICK ETS AND 2288 01:48:07,960 --> 01:48:08,960 OSTEOMALACIA AND INCREASES RISK 2289 01:48:08,960 --> 01:48:12,360 OF FD RELATED COMPLICATIONS 2290 01:48:12,360 --> 01:48:15,800 FRACTURES AND DEFORMITIES YEARS 2291 01:48:15,800 --> 01:48:17,720 ON NATURAL THRIFT STUDY PATIENT 2292 01:48:17,720 --> 01:48:19,840 AS PEAR TO BE PARTICULARLY 2293 01:48:19,840 --> 01:48:22,520 VULNERABLE TO EFFECTS OF PHOSPHO 2294 01:48:22,520 --> 01:48:25,800 TEEMIA AND REVIEW OF 240 2295 01:48:25,800 --> 01:48:27,320 PATIENTS NUND PHOSPHORUS LEVELS 2296 01:48:27,320 --> 01:48:29,680 AT LOWER PART OF THE NORMAL 2297 01:48:29,680 --> 01:48:31,880 RANGE ARE ASSOCIATED WITH HIGHER 2298 01:48:31,880 --> 01:48:34,560 RATES OF FRACTURES AND 2299 01:48:34,560 --> 01:48:35,760 ORTHOPEDIC SURGERIES AND 2300 01:48:35,760 --> 01:48:38,320 SUGGESTS THAT PATIENTS WITH FD 2301 01:48:38,320 --> 01:48:40,840 MAY BENEFIT MAINTAINING 2302 01:48:40,840 --> 01:48:42,640 PHOSPHORUS LEVELS IN HIGH RANGE 2303 01:48:42,640 --> 01:48:46,840 TO PROTECT THEIR BONES. TESTING 2304 01:48:46,840 --> 01:48:48,720 THIS PROVIDING PHASE 2 TRIAL -- 2305 01:48:48,720 --> 01:48:51,440 THIS TREATMENT ALLOWS US TO FINE 2306 01:48:51,440 --> 01:48:54,720 TUNE PHOSPHORUS LEAVELES. SO, 2307 01:48:54,720 --> 01:48:56,320 OUR PRIMARY ENDPOINT WILL AIM TO 2308 01:48:56,320 --> 01:48:59,560 ACHIEVE A HIGH NORMAL PHOSPHORUS 2309 01:48:59,560 --> 01:49:01,800 LEVEL AT TOP OF THE RANGE AND IF 2310 01:49:01,800 --> 01:49:04,640 FIND FRGZ STUDY ARE SUPPORTIVE 2311 01:49:04,640 --> 01:49:07,480 HAS POTENTIAL TO TRANSFORM 2312 01:49:07,480 --> 01:49:11,200 MANAGEMENT OF FGF23 EXCESS AND 2313 01:49:11,200 --> 01:49:14,400 FD AND THANKING GROUP METABOLIC 2314 01:49:14,400 --> 01:49:16,840 BONE DISORDERS UNIT THAT ARE 2315 01:49:16,840 --> 01:49:18,680 WONDERFUL AND MAKE COMING TO 2316 01:49:18,680 --> 01:49:20,880 WORK A PLEASURE EVERY DAY AND SO 2317 01:49:20,880 --> 01:49:23,720 MANY COLLABORATORS OFFICE OF THE 2318 01:49:23,720 --> 01:49:25,240 CLINICAL DIRECTOR AND 2319 01:49:25,240 --> 01:49:26,400 INTERNATIONALLY AS WELL. OF 2320 01:49:26,400 --> 01:49:29,200 COURSE, NONE OF THIS WITH BE 2321 01:49:29,200 --> 01:49:30,600 POSSIBLE WITHOUT CLOSE 2322 01:49:30,600 --> 01:49:31,800 PARTNERSHIP WITH PATIENT 2323 01:49:31,800 --> 01:49:33,600 COMMUNITY AND IS QUITE UNIQUE 2324 01:49:33,600 --> 01:49:36,040 ABOUT HOW THE RESEARCH AND NIDCR 2325 01:49:36,040 --> 01:49:38,000 HAS PAIRED WITH PATIENT 2326 01:49:38,000 --> 01:49:40,840 COMMUNITY FROM DAY 1 THAT REALLY 2327 01:49:40,840 --> 01:49:42,080 ACCELERATED BOTH THE AMOUNT AND 2328 01:49:42,080 --> 01:49:43,360 QUALITY OF RESEARCH WE HAVE BEEN 2329 01:49:43,360 --> 01:49:53,920 ABLE TO DO. THANKS VERY MUCH. 2330 01:49:55,720 --> 01:49:56,400 >> AUDIENCE: [APPLAUSE]. 2331 01:49:56,400 --> 01:49:59,840 >> THAT WAS THE PERFECT SEGUE. 2332 01:49:59,840 --> 01:50:01,320 ALLISON OR DR. BOYCE HAS 2333 01:50:01,320 --> 01:50:03,200 MENTIONED WE COULDN'T BE HERE 2334 01:50:03,200 --> 01:50:05,080 DOING RESEARCH AND BEING AS 2335 01:50:05,080 --> 01:50:06,760 SUCCESSFUL WITHOUT OUR PATIENT 2336 01:50:06,760 --> 01:50:09,880 PARTNERS AND WITHOUT ADVOCACY 2337 01:50:09,880 --> 01:50:10,760 GROUPS THAT HAVE BEEN SUCH 2338 01:50:10,760 --> 01:50:11,880 LEADERS IN THE FIELD AS WELL. 2339 01:50:11,880 --> 01:50:14,840 I WOULD LIKE TO INVITE 2340 01:50:14,840 --> 01:50:16,920 MRS. MCBRIDE WHO IS EXECUTIVE 2341 01:50:16,920 --> 01:50:19,600 DIRECTOR OF FD/MAS ALLIANCE WITH 2342 01:50:19,600 --> 01:50:22,400 OVER 15 YEARS EXPERIENCE IN 2343 01:50:22,400 --> 01:50:24,280 NON-PROFIT SECTOR LEADERSHIP 2344 01:50:24,280 --> 01:50:24,640 ROLES. 2345 01:50:24,640 --> 01:50:26,720 IT IS HARD TO MENTION THE 2346 01:50:26,720 --> 01:50:28,440 ALLIANCE WITHOUT RECOGNIZING IT 2347 01:50:28,440 --> 01:50:30,880 WAS ORIGINALLY THE FD FOUNDATION 2348 01:50:30,880 --> 01:50:33,440 AND WITHOUT ACKNOWLEDGING 2349 01:50:33,440 --> 01:50:35,600 CHARLIE HARLOUS WHO FOUNDED THE 2350 01:50:35,600 --> 01:50:38,120 GROUP AND WHOSE PRESENCE IS FELT 2351 01:50:38,120 --> 01:50:40,440 STILL TODAY. I'M PLEASED TO 2352 01:50:40,440 --> 01:50:42,000 HAVE MRS. MCBRIDE HERE TODAY TO 2353 01:50:42,000 --> 01:50:44,000 TELL US A LITTLE ABOUT THE WORK 2354 01:50:44,000 --> 01:50:47,280 OF FD/MAS ALLIANCE AND RECENT 2355 01:50:47,280 --> 01:50:50,400 CONFERENCE THAT JUST HAPPENED 2356 01:50:50,400 --> 01:50:53,520 OVERTHE WEEKEND. THANK YOU. 2357 01:50:53,520 --> 01:50:55,760 >> GOOD MORNING. IT IS A 2358 01:50:55,760 --> 01:50:57,560 PRIVILEGE TO BE HERE AND 2359 01:50:57,560 --> 01:50:59,720 PRIVILEGE FOR ME TO REPRESENT 2360 01:50:59,720 --> 01:51:02,840 FD/MAS ALLIANCE. FD/MAS 2361 01:51:02,840 --> 01:51:05,160 ALLIANCE HAS A PRETTY SIMPLE 2362 01:51:05,160 --> 01:51:07,160 MISSION, NEWLY DIAGNOSED NEED A 2363 01:51:07,160 --> 01:51:08,960 PLACE TO TURN AND ACCESS TO 2364 01:51:08,960 --> 01:51:11,720 WORLD CLASS RESEARCHERS AND 2365 01:51:11,720 --> 01:51:12,800 ACCURATE INFORMATION IS CRITICAL 2366 01:51:12,800 --> 01:51:15,560 AT EVERY STEP AND STAGE OF THIS 2367 01:51:15,560 --> 01:51:19,280 CHRONIC DISEASE AND WE WORK AS 2368 01:51:19,280 --> 01:51:22,080 ORGANIZING PRESENCE ENCOURAGING 2369 01:51:22,080 --> 01:51:23,600 RESEARCHERS TO ADVANCE AND 2370 01:51:23,600 --> 01:51:26,040 MAKING SURE PATIENT PRIORITIES 2371 01:51:26,040 --> 01:51:27,600 REMAIN AT THE FOREFRONT. 2372 01:51:27,600 --> 01:51:32,760 I ALSO WANT TO SAY THAT FD/MAS 2373 01:51:32,760 --> 01:51:35,960 ALLIANCE IS A MEMBER OF NIDCR, 2374 01:51:35,960 --> 01:51:38,680 PATIENT ADVOCACY COUNCIL 2375 01:51:38,680 --> 01:51:41,560 ADVOCATING ON BEHALF OF NIDCR 2376 01:51:41,560 --> 01:51:45,240 AND NIH ON CAPITOL HILL AND 2377 01:51:45,240 --> 01:51:47,800 JOINT LETTERS AND VISITING 2378 01:51:47,800 --> 01:51:50,240 MEMBERS OF CONGRESS AND PROUD TO 2379 01:51:50,240 --> 01:51:53,280 SAY WE WORK CLOSELY WITH ALLISON 2380 01:51:53,280 --> 01:51:55,080 BOYCE WHO IS CHAIR OF MEDICAL 2381 01:51:55,080 --> 01:51:58,920 ADVISORY COUNCIL AND MEMBER OF 2382 01:51:58,920 --> 01:52:00,920 STEERING COMMITTEE AND DR. 2383 01:52:00,920 --> 01:52:02,520 MICHAEL COLLIN WHO'S IS KIND AND 2384 01:52:02,520 --> 01:52:05,120 GENEROUS WITH ME SERVES AS CHAIR 2385 01:52:05,120 --> 01:52:13,600 OF FD/MAS SCIENCE ADVISORY -- 2386 01:52:13,600 --> 01:52:15,240 AND MY COLLEAGUES WILL SPEAK 2387 01:52:15,240 --> 01:52:18,760 MORE ABOUT THAT FD/MAS ALLIANCE 2388 01:52:18,760 --> 01:52:20,720 IS A FOUNDING MEMBER AND REASON 2389 01:52:20,720 --> 01:52:25,120 I LOOK TIRED IS WE HAD A 2390 01:52:25,120 --> 01:52:29,880 THREE-DAY CONFERENCE THAT WAS A 2391 01:52:29,880 --> 01:52:31,600 WONDERFUL WONDERFUL EXPERIENCE 2392 01:52:31,600 --> 01:52:34,360 WITH COLLABORATION, COOPERATION 2393 01:52:34,360 --> 01:52:37,120 AND COME RAD REAND COLLEAGUE 2394 01:52:37,120 --> 01:52:38,480 WILL SPEAK MORE ABOUT THAT. 2395 01:52:38,480 --> 01:52:41,760 I WANT TO SHARE ABOUT THE FDMA 2396 01:52:41,760 --> 01:52:44,200 ALLIANCE AND ACCOMPLISHMENTS IF 2397 01:52:44,200 --> 01:52:45,280 IN RESEARCH. 2398 01:52:45,280 --> 01:52:48,160 WE RAISED OVER $160,000 IN 2399 01:52:48,160 --> 01:52:50,920 RESEARCH FUNDING PARTNERING WITH 2400 01:52:50,920 --> 01:52:53,440 U PEN MILLION DOLLAR BIKE RIDE 2401 01:52:53,440 --> 01:52:55,320 THIS SPRING AND NO. 1 2402 01:52:55,320 --> 01:52:56,640 FUNDRAISING TEAM FOR SECOND YEAR 2403 01:52:56,640 --> 01:52:57,440 IN A ROW. 2404 01:52:57,440 --> 01:52:59,960 THIS MEANS WE ARE NO. 1 OF 30 2405 01:52:59,960 --> 01:53:05,360 RARE DISEASE PATIENT ADVOCACY 2406 01:53:05,360 --> 01:53:06,800 ORGANIZATIONS. WE ARE NO. 1 2407 01:53:06,800 --> 01:53:08,400 BECAUSE OUR GROUP IS SO 2408 01:53:08,400 --> 01:53:08,760 PASSIONATE. 2409 01:53:08,760 --> 01:53:11,520 THIS YEAR WE WILL BE ABLE TO 2410 01:53:11,520 --> 01:53:14,200 OFFER AT LEAST FOUR GROUPS. 2411 01:53:14,200 --> 01:53:15,160 BETWEEN 2 AND 4 GRANTS. 2412 01:53:15,160 --> 01:53:17,560 WE HAVE BEEN DOING THIS SINCE 2413 01:53:17,560 --> 01:53:20,080 2014 AND SUPPORTED OVER 17 2414 01:53:20,080 --> 01:53:23,000 RESEARCH PROJECTS FUNDING OVER A 2415 01:53:23,000 --> 01:53:26,760 MILLION DOLLARS IN RESEARCH. 2416 01:53:26,760 --> 01:53:29,480 I WENT THE WRONG WAY. 2417 01:53:29,480 --> 01:53:32,160 NO. WHAT DID I DO? 2418 01:53:32,160 --> 01:53:32,960 >> AUDIENCE: [APPLAUSE]. 2419 01:53:32,960 --> 01:53:36,960 >> OKAY. ALSO PROUD TO SAY 2420 01:53:36,960 --> 01:53:39,120 BECAUSE OUR ADVOCATES WE HAVE 2421 01:53:39,120 --> 01:53:42,320 BEEN INCLUDED IN PEER REVIEWED 2422 01:53:42,320 --> 01:53:44,320 MEDICAL RESEARCH PROGRAM PARTNER 2423 01:53:44,320 --> 01:53:46,840 OF DEFENSE PROGRAM RESEARCH 2424 01:53:46,840 --> 01:53:51,160 INITIATIVE 4TH YEAR IN A ROW AND 2425 01:53:51,160 --> 01:53:53,360 2023 FIRST FD PROPOSAL TO 2426 01:53:53,360 --> 01:53:55,840 RECEIVE FULL FUNDING THIS YEAR 2427 01:53:55,840 --> 01:53:58,640 AND DR.S YANG AND WEIN WERE 2428 01:53:58,640 --> 01:54:01,320 AWARDED OVER $3.4 MILLION TO 2429 01:54:01,320 --> 01:54:06,240 STUDY FD/MAS AND NIH RECENTLY 2430 01:54:06,240 --> 01:54:09,080 AWARDED R01 GRANT TO THREE 2431 01:54:09,080 --> 01:54:10,760 FORMER MILLION DOLLAR BIKE RIDE 2432 01:54:10,760 --> 01:54:19,000 WINNERS AWARDEES. DR. CHAO, DR. 2433 01:54:19,000 --> 01:54:21,200 FERERRO AND DR.UENT WORTH AND IS 2434 01:54:21,200 --> 01:54:22,760 REMARKABLE FOR A SMALL GROUP 2435 01:54:22,760 --> 01:54:23,320 LIKE US. 2436 01:54:23,320 --> 01:54:26,120 THIS YEAR WE DID LOTS WITH 2437 01:54:26,120 --> 01:54:27,960 COMMUNITY SUPPORT AND MOST 2438 01:54:27,960 --> 01:54:30,000 IMPORTANT THING WE HAVE DONE IS 2439 01:54:30,000 --> 01:54:31,600 LAUNCHED A PATIENT ADVISORY 2440 01:54:31,600 --> 01:54:33,440 COUNCIL TO MAKE SURE WE ARE 2441 01:54:33,440 --> 01:54:36,240 TRULY TRULY REFLECTING VOICE OF 2442 01:54:36,240 --> 01:54:38,280 THE PATIENTS POSTING SOCIALS AND 2443 01:54:38,280 --> 01:54:40,800 CONTESTS AND PROVIDE SUPPORT 2444 01:54:40,800 --> 01:54:41,080 SERVICES. 2445 01:54:41,080 --> 01:54:43,320 THANK YOU TO GLOBAL GENES 2446 01:54:43,320 --> 01:54:45,120 FINANCIAL LITERACY GRANTED WE 2447 01:54:45,120 --> 01:54:47,760 HOSTED 2 WEBINARS HELPING 2448 01:54:47,760 --> 01:54:49,480 PATIENT NAVIGATE DISABILITY 2449 01:54:49,480 --> 01:54:50,640 BENEFITS FEDERAL DISABILITY 2450 01:54:50,640 --> 01:54:54,480 BENEFITS AND CREATED A PAGE ON 2451 01:54:54,480 --> 01:54:55,760 OUR WEBSITE FOR THAT. 2452 01:54:55,760 --> 01:54:59,280 IN 2024 WE ARE LOOKING FOR 2453 01:54:59,280 --> 01:55:01,360 UPDATES FOR NEW MILLION DOLLAR 2454 01:55:01,360 --> 01:55:03,560 AWARDEES AND ARE GETTING A NEW 2455 01:55:03,560 --> 01:55:05,440 PLATFORM FOR PATIENT REGISTRY. 2456 01:55:05,440 --> 01:55:07,480 WE WANT TO CONTINUE TO SUPPORT 2457 01:55:07,480 --> 01:55:09,160 FEDERAL RESEARCH FUNDING AND 2458 01:55:09,160 --> 01:55:11,840 COMMUNITY INITIATIVES. 2459 01:55:11,840 --> 01:55:16,360 BUT, WHAT I WANT TO REALLY SHOW 2460 01:55:16,360 --> 01:55:19,560 IS THIS VIDEO A TESTAMENT AND 2461 01:55:19,560 --> 01:55:20,720 RESILIENCE AND STRENGTH TO 2462 01:55:20,720 --> 01:55:24,320 COMMUNITY MEMBERS WHICH IS WHY 2463 01:55:24,320 --> 01:55:31,440 I'M HERE. 2464 01:55:31,440 --> 01:55:33,480 >> AUDIENCE: [APPLAUSE]. 2465 01:55:33,480 --> 01:55:35,960 >> LEA WAS BORN CLOSE TO FULL 2466 01:55:35,960 --> 01:55:38,200 TERM. RIGHT AWAY WE NOTICED 2467 01:55:38,200 --> 01:55:40,400 SOMETHING WASN'T RIGHT. HE WAS 2468 01:55:40,400 --> 01:55:43,760 HAVING SEVERE VOMITING AND 2469 01:55:43,760 --> 01:55:54,560 DEVELOPED CAFE OE AU LAIT SPOTS 2470 01:55:59,680 --> 01:56:03,040 >> HER ENDOCRINOLOGIST SUGGESTED 2471 01:56:03,040 --> 01:56:06,800 IT WAS OUTLIAR COULD BE MCCUNE 2472 01:56:06,800 --> 01:56:07,600 ALBRIGHT SYNDROME. 2473 01:56:07,600 --> 01:56:09,000 >> I THOUGHT IT WAS 2474 01:56:09,000 --> 01:56:10,800 DISREGULATION AND PERIODS WHEN I 2475 01:56:10,800 --> 01:56:13,800 WAS 16 I WENT BLIND IN RIGHT EYE 2476 01:56:13,800 --> 01:56:18,480 AND FOUND OUT I HAD IRIS 2477 01:56:18,480 --> 01:56:18,800 DYSPLASIA. 2478 01:56:18,800 --> 01:56:20,880 >> -- A RARE DISEASE AND BY 2479 01:56:20,880 --> 01:56:22,000 DEFINITION THEREFORE EFFECTS 2480 01:56:22,000 --> 01:56:24,480 LESS THAN 200,000 PEOPLE IN THE 2481 01:56:24,480 --> 01:56:24,960 UNITED STATES. 2482 01:56:24,960 --> 01:56:28,840 >> FD/MAS ARISES DUE TO 2483 01:56:28,840 --> 01:56:30,520 MUTATIONS IN GNAS GENE THAT 2484 01:56:30,520 --> 01:56:32,760 INCLUDES A RECEPTOR THAT IS 2485 01:56:32,760 --> 01:56:34,360 IMPORTANT FOR SIGNALING IN 2486 01:56:34,360 --> 01:56:35,680 MULTIPLE DIFFERENT TYPES OF 2487 01:56:35,680 --> 01:56:39,000 TISSUES AND ESPECIALLY BONE AND 2488 01:56:39,000 --> 01:56:44,840 ENDOCRINE SYSTEM. WHEN MUTATION 2489 01:56:44,840 --> 01:56:47,320 -- IN BONE EXCESS RECEPTOR 2490 01:56:47,320 --> 01:56:50,800 SIGNALING LEADS TO FORMATION OF 2491 01:56:50,800 --> 01:56:54,960 FIBEROSOUS BONE LESIONS CAUSING 2492 01:56:54,960 --> 01:56:56,280 PROBLEMS FACIALLY SYMMETRY 2493 01:56:56,280 --> 01:56:59,080 BLINDNESS DEAFNESS FRACTURES AND 2494 01:56:59,080 --> 01:56:59,960 PHYSICAL DISABILITY. 2495 01:56:59,960 --> 01:57:02,480 >> WE WENT TO A THEME PARK. 2496 01:57:02,480 --> 01:57:04,680 HE WAS STANDING ON A STROLLER 2497 01:57:04,680 --> 01:57:07,240 TYPE OF THING AND I MOVED IT OUT 2498 01:57:07,240 --> 01:57:08,440 OF THE WAY. 2499 01:57:08,440 --> 01:57:10,720 HE FELL OFF IT AND BROKE A LEG. 2500 01:57:10,720 --> 01:57:13,400 >> DURING THE SCHOOL YEAR, 2501 01:57:13,400 --> 01:57:16,800 TEACHERS WATCH HER LIKE HAWKS 2502 01:57:16,800 --> 01:57:18,960 AND KNOW SHE IS LED ON THE 2503 01:57:18,960 --> 01:57:20,840 SWINGS DON'T LET HER CLIMB 2504 01:57:20,840 --> 01:57:21,080 ANYTHING. 2505 01:57:21,080 --> 01:57:22,640 >> CONSIDER WHAT IT IS LIKE TO 2506 01:57:22,640 --> 01:57:24,240 GO TO THE PLAYGROUND AND NOT DO 2507 01:57:24,240 --> 01:57:27,280 WHAT YOU WANT TO DO. 2508 01:57:27,280 --> 01:57:28,600 >> I WANT TO [INDISCERNIBLE] MOM 2509 01:57:28,600 --> 01:57:30,800 SAID NO, NO, NO, NO. 2510 01:57:30,800 --> 01:57:33,600 >> FIRST TIME I HAD PLEASURE 2511 01:57:33,600 --> 01:57:36,800 SEEING GIANA WE COULD SEE EARLY 2512 01:57:36,800 --> 01:57:39,880 EVIDENCE OF FIBROUS DYSPLASIA 2513 01:57:39,880 --> 01:57:41,240 SINKING FEELING KNOWING LESIONS 2514 01:57:41,240 --> 01:57:43,880 ARE THERE AND NOTHING WE CAN DO 2515 01:57:43,880 --> 01:57:44,320 ABOUT IT. 2516 01:57:44,320 --> 01:57:46,600 >> I'M CURRENT PRESIDENT OF 2517 01:57:46,600 --> 01:57:49,400 FD/MAS ALLIANCE AND MISSION AT 2518 01:57:49,400 --> 01:57:50,680 ALLIANCE IS TO DEVELOP THIS 2519 01:57:50,680 --> 01:57:52,680 COMMUNITY FOR PATIENTS, PARENTS 2520 01:57:52,680 --> 01:57:54,360 AND FAMILIES TO DRIVE THE 2521 01:57:54,360 --> 01:57:59,120 RESEARCH THAT IS REQUIRED TO 2522 01:57:59,120 --> 01:58:00,640 FIND THAT TREATMENT OR CURE. 2523 01:58:00,640 --> 01:58:03,760 >> FD/MAS ALLIANCE PLAYS 2524 01:58:03,760 --> 01:58:06,600 CRITICAL CUTTING EDGE ROLE IN 2525 01:58:06,600 --> 01:58:09,880 PRESENT AND FUTURE RESEARCH OF 2526 01:58:09,880 --> 01:58:10,120 FD/MAS. 2527 01:58:10,120 --> 01:58:12,040 >> THE FUTURE OF THE ALLIANCE IS 2528 01:58:12,040 --> 01:58:15,040 KEY TO SUCCESSFUL RECRUITMENT TO 2529 01:58:15,040 --> 01:58:16,800 NIH. THIS IS EXTREMELY RARE 2530 01:58:16,800 --> 01:58:18,720 DISEASE AND WE HAVE OVER 300 2531 01:58:18,720 --> 01:58:20,400 PATIENTS ON NATURAL HISTORY 2532 01:58:20,400 --> 01:58:22,840 STUDY THAT ARE EXTENSIVELY 2533 01:58:22,840 --> 01:58:24,400 PHENOTYPED WHEN WE HAVE A 2534 01:58:24,400 --> 01:58:26,000 MEDICATION WE CAN COMPARE 2535 01:58:26,000 --> 01:58:28,360 OUTCOMES TO EXTENSIVE HISTORICAL 2536 01:58:28,360 --> 01:58:28,840 CONTROL DATA. 2537 01:58:28,840 --> 01:58:30,840 >> PATIENT ARE EDGETRY HAS 2538 01:58:30,840 --> 01:58:32,920 INFORMATION ON OVER 1,000 2539 01:58:32,920 --> 01:58:34,200 PATIENTS AND WE HAVE INFORMATION 2540 01:58:34,200 --> 01:58:36,920 ON ALL ASPECTS OF LIVES OF 2541 01:58:36,920 --> 01:58:39,160 PATIENTS. IRB APPROVED AND 2542 01:58:39,160 --> 01:58:41,280 PARTNERED WITH NORD TO HELP US 2543 01:58:41,280 --> 01:58:43,640 MAKE THIS AVAILABLE TO MORE 2544 01:58:43,640 --> 01:58:45,360 RESEARCHERS THAT CAN ASK US TO 2545 01:58:45,360 --> 01:58:46,840 ADD QUESTIONS SPECIFICALLY FOR 2546 01:58:46,840 --> 01:58:48,400 THEIR RESEARCH PROJECTS. 2547 01:58:48,400 --> 01:58:52,400 >> FD/MAS ALLIANCE HELPS FOCUS 2548 01:58:52,400 --> 01:58:54,400 RESEARCH ON TRYING TO SOLVE 2549 01:58:54,400 --> 01:58:57,080 PROBLEMS MOST IMPACTING PATIENTS 2550 01:58:57,080 --> 01:58:59,280 AND WE HAVE EXTENSIVE EXPERIENCE 2551 01:58:59,280 --> 01:59:01,000 CONDUCTING INTERVENTIONAL 2552 01:59:01,000 --> 01:59:02,560 STUDIES THAT ESTABLISH STANDARD 2553 01:59:02,560 --> 01:59:06,120 OF CARE FOR ENDOCRINE TREATMENTS 2554 01:59:06,120 --> 01:59:08,720 AND CHALLENGE IS IDENTIFYING 2555 01:59:08,720 --> 01:59:09,800 EFFECTIVE TREATMENT FOR BONE 2556 01:59:09,800 --> 01:59:11,880 DISEASE AND WHAT WE ARE MOTIVATE 2557 01:59:11,880 --> 01:59:13,320 TODAY DO NEXT. 2558 01:59:13,320 --> 01:59:16,880 >> HEADWAY MADE IN FD/MAS AND 2559 01:59:16,880 --> 01:59:19,360 TARGETING ALPHA GS WILL HAVE 2560 01:59:19,360 --> 01:59:20,360 BROADER EFFECTS AND OTHER 2561 01:59:20,360 --> 01:59:21,360 CONDITIONS INCLUDING CERTAIN 2562 01:59:21,360 --> 01:59:23,120 TYPES OF CANCERS AND GOOD DRIVER 2563 01:59:23,120 --> 01:59:24,600 FOR PEOPLE TO BE INTERESTED AND 2564 01:59:24,600 --> 01:59:27,840 BE INVESTED AND TO WORK IN THIS 2565 01:59:27,840 --> 01:59:28,400 AREA. 2566 01:59:28,400 --> 01:59:31,040 >> FD/MAS ALLIANCE IS COMMIT 2567 01:59:31,040 --> 01:59:33,960 TODAY SUPPORTING RESEARCH AND 2568 01:59:33,960 --> 01:59:35,240 REACHED MILLIONTH DOLLAR RAISE 2569 01:59:35,240 --> 01:59:37,960 IN 2022 AND HAVE ABILITY TO FUND 2570 01:59:37,960 --> 01:59:41,960 MULTIPLE RESEARCH GRANTS EVERY 2571 01:59:41,960 --> 01:59:43,760 YEAR SDMR GROUP INVESTIGATORS 2572 01:59:43,760 --> 01:59:45,640 BENEFITING FROM RESEARCH MONEY 2573 01:59:45,640 --> 01:59:48,360 ARE COLLABORATIVE AND REAL 2574 01:59:48,360 --> 01:59:51,000 PROGRESS MADE AND NEW TRIALS ON 2575 01:59:51,000 --> 01:59:53,640 THE WAY AND NEW THERAPIES IN 2576 01:59:53,640 --> 01:59:55,840 LABORATORY NOW MIGHT BE 2577 01:59:55,840 --> 01:59:56,960 TREATMENTS FOR FD/MAS IN THE 2578 01:59:56,960 --> 01:59:57,160 FUTURE. 2579 01:59:57,160 --> 01:59:59,640 >> HAVING SOMETHING TO TAKE THE 2580 01:59:59,640 --> 02:00:01,120 EDGE OFF WOULD MAKE GREATEST 2581 02:00:01,120 --> 02:00:02,800 DIFFERENCE LIVING WITH CHRONIC 2582 02:00:02,800 --> 02:00:06,320 PAIN OR EPISODIC SEVERE PAIN 2583 02:00:06,320 --> 02:00:10,120 THAT COULD BE DEBILITATING IS 2584 02:00:10,120 --> 02:00:10,440 EXHAUSTING. 2585 02:00:10,440 --> 02:00:13,080 >> MY HOPE IS FOR HER TO SET HER 2586 02:00:13,080 --> 02:00:14,080 SIGHTS ON ANYTHING AND 2587 02:00:14,080 --> 02:00:15,920 ACCOMPLISH THAT AND KNOW WITH A 2588 02:00:15,920 --> 02:00:18,160 CURE AND THE RIGHT MEDICINE THAT 2589 02:00:18,160 --> 02:00:20,720 IS POSSIBLE FOR HER. 2590 02:00:20,720 --> 02:00:23,040 >> I WANT FOR HIM TO BE ABLE TO 2591 02:00:23,040 --> 02:00:24,640 SEE AND FOR HIM TO BE ABLE TO 2592 02:00:24,640 --> 02:00:28,560 WALK AND TO BE ABLE TO BE SEEN 2593 02:00:28,560 --> 02:00:32,240 IN PUBLIC WITHOUT THAT FACIAL 2594 02:00:32,240 --> 02:00:34,200 DEFORMITY WHERE YOU CAN'T WALK 2595 02:00:34,200 --> 02:00:35,000 DOWN THE STREET WITHOUT 2596 02:00:35,000 --> 02:00:36,760 [INDISCERNIBLE] LOOKING AT YOU. 2597 02:00:36,760 --> 02:00:42,160 >> FD/MAS ALLIANCE HAS DONE 2598 02:00:42,160 --> 02:00:42,640 GROUNDWORK ALREADY. 2599 02:00:42,640 --> 02:00:45,480 >> CREATING SITUATION WHERE. 2600 02:00:45,480 --> 02:00:48,360 >> THE ALLIANCE IS READY AND 2601 02:00:48,360 --> 02:00:50,400 PATIENTS THERE AND ARE ON CUSP 2602 02:00:50,400 --> 02:00:54,560 ADVANCING TREATMENTS IN FIBROUS 2603 02:00:54,560 --> 02:00:59,120 DYSPLASIA MCCUNE ALBRIGHT 2604 02:00:59,120 --> 02:01:04,400 SYNDROME. 2605 02:01:04,400 --> 02:01:06,360 >> THANK YOU. THANK YOU TO 2606 02:01:06,360 --> 02:01:14,080 EVERYBODY IN THE VIDEO. 2607 02:01:14,080 --> 02:01:18,160 >> AS YOU CAN SEE, WHILE WE CAN 2608 02:01:18,160 --> 02:01:20,880 DO RESEARCH HERE AT THE NIH, 2609 02:01:20,880 --> 02:01:22,080 PATIENT COMMUNITY REALLY NEEDS 2610 02:01:22,080 --> 02:01:24,040 THE ADVOCACY. 2611 02:01:24,040 --> 02:01:26,400 WHAT THEY DO IS AMAZING. 2612 02:01:26,400 --> 02:01:28,400 PATIENTS HAVE DAY-TO-DAY ISSUES 2613 02:01:28,400 --> 02:01:30,920 AND HAVE ADVOCACY GROUPS WORKING 2614 02:01:30,920 --> 02:01:32,680 TO MAKE SURE THAT OUR PATIENTS 2615 02:01:32,680 --> 02:01:34,800 ARE CARED FOR AND FOR ALL LITTLE 2616 02:01:34,800 --> 02:01:36,560 THINGS THEY REALLY DO NEED TO 2617 02:01:36,560 --> 02:01:40,000 LEAD NORMAL LIVES. THANK YOU 2618 02:01:40,000 --> 02:01:40,800 VERY MUCH. 2619 02:01:40,800 --> 02:01:44,400 THE NEXT ADVOCACY GROUP HERE 2620 02:01:44,400 --> 02:01:46,040 REPRESENTED BY MAR TEEN DECKER 2621 02:01:46,040 --> 02:01:50,160 IS INTERNATIONAL CONSORTIUM FOR 2622 02:01:50,160 --> 02:01:51,760 FD/MAS THAT STARTED IN 2014 2623 02:01:51,760 --> 02:01:55,160 GROUP OF CLINICIANS PATIENTS AND 2624 02:01:55,160 --> 02:01:56,000 RESEARCHERS FROM AROUND THE 2625 02:01:56,000 --> 02:01:57,600 WORLD PASSIONATE ABOUT ADVANCING 2626 02:01:57,600 --> 02:01:59,280 CLINICAL CARE RESEARCH FOR 2627 02:01:59,280 --> 02:02:01,960 INDIVIDUALS WITH FIBROUS 2628 02:02:01,960 --> 02:02:04,240 DYSPLASIA MCCUNE ALBRIGHT 2629 02:02:04,240 --> 02:02:06,680 SYNDROME. IT LAUNCHED LAST YEAR 2630 02:02:06,680 --> 02:02:07,920 CONGRATULATIONS MREENDZED TO 2631 02:02:07,920 --> 02:02:09,560 HAVE MRS. MAR TEEN DECKER HERE 2632 02:02:09,560 --> 02:02:13,080 AS A MEMBER OF INTERNATIONAL 2633 02:02:13,080 --> 02:02:14,400 CONSORTIUM SHARE A FEW WORDS 2634 02:02:14,400 --> 02:02:16,600 ABOUT THE CONSORTIUM AND IMPACT 2635 02:02:16,600 --> 02:02:20,800 IT IS HAVING ON ALL OUR PATIENTS 2636 02:02:20,800 --> 02:02:24,360 WORLDWIDE. THANK YOU 2637 02:02:24,360 --> 02:02:24,640 [APPLAUSE]. 2638 02:02:24,640 --> 02:02:27,680 >> THANK YOU. GOOD MORNING, 2639 02:02:27,680 --> 02:02:29,880 EVERYONE. I'M MARTINA DECKER 2640 02:02:29,880 --> 02:02:33,520 AND PATIENT MONOSTATIC FIBROUS 2641 02:02:33,520 --> 02:02:36,280 DYSPLASIA. AFTER DIAGNOSIS I 2642 02:02:36,280 --> 02:02:37,560 INITIATED DUTCH PATIENT 2643 02:02:37,560 --> 02:02:39,560 ASSOCIATION AND NOW INVOLVED 2644 02:02:39,560 --> 02:02:43,360 WITH INTERNATIONAL CONSORTIUM 2645 02:02:43,360 --> 02:02:46,920 FOR FIBROUS DYSPLASIA MCCUNE 2646 02:02:46,920 --> 02:02:48,120 ALBRIGHT SYNDROME. YES. LET'S 2647 02:02:48,120 --> 02:02:53,640 GO. BASICALLY, THE BASIC 2648 02:02:53,640 --> 02:02:55,160 INTERNATIONAL CONSORTIUM 2649 02:02:55,160 --> 02:02:57,520 ORIGINATES FROM SIMPLY A COUPLE 2650 02:02:57,520 --> 02:03:00,840 PEOPLE COMING TOGETHER IN 2015 2651 02:03:00,840 --> 02:03:02,000 AS WAS ALREADY SAID. 2652 02:03:02,000 --> 02:03:04,360 SHARING IDEAS AND SHARING 2653 02:03:04,360 --> 02:03:07,320 UPDATES ON RESEARCH. 2654 02:03:07,320 --> 02:03:11,160 EVER SINCE IT WAS I THINK A 2655 02:03:11,160 --> 02:03:12,400 BIANNUAL MEETING COMING TOGETHER 2656 02:03:12,400 --> 02:03:16,040 ON AN INFORMAL BASIS. 2657 02:03:16,040 --> 02:03:18,240 VERY QUICKLY DURING MEETINGS, 2658 02:03:18,240 --> 02:03:22,000 THE INITIATIVE WAS TAKEN TO 2659 02:03:22,000 --> 02:03:23,520 DEVELOP INTERNATIONAL GUIDELINES 2660 02:03:23,520 --> 02:03:25,920 FOR PATIENT HEALTHCARE AND 2661 02:03:25,920 --> 02:03:28,840 PATIENTS WITH FD/MAS THAT WAS 2662 02:03:28,840 --> 02:03:31,040 BASICALLY START OF MORE AND MORE 2663 02:03:31,040 --> 02:03:32,560 COLLABORATION WITH VARIOUS 2664 02:03:32,560 --> 02:03:34,280 STAKEHOLDERS AND ESPECIALLY 2665 02:03:34,280 --> 02:03:36,960 RESEARCHERS AND PATIENT 2666 02:03:36,960 --> 02:03:38,280 ASSOCIATIONS AND AT SOME POINT 2667 02:03:38,280 --> 02:03:39,720 BECAME NEED FOR MORE STRUCTURAL 2668 02:03:39,720 --> 02:03:42,720 AND ORGANIZED INTERNATIONAL 2669 02:03:42,720 --> 02:03:44,360 CORPORATION AND WRITING GROUP 2670 02:03:44,360 --> 02:03:47,040 WAS SET UP TO RIGHT TO TERMS OF 2671 02:03:47,040 --> 02:03:51,320 REFERENCE TO START THIS FORMAL 2672 02:03:51,320 --> 02:03:53,000 CONSORTIUM. 2673 02:03:53,000 --> 02:03:55,120 INDEED AT THE END LAST YEAR IN 2674 02:03:55,120 --> 02:03:57,920 FEBRUARY DURING CELEBRATION OF 2675 02:03:57,920 --> 02:03:59,080 FD/MAS GLOBAL AWARENESS WEEK WE 2676 02:03:59,080 --> 02:04:01,280 HAVE BEEN ABLE TO LAUNCH 2677 02:04:01,280 --> 02:04:04,360 OFFICIALLY INTERNATIONAL 2678 02:04:04,360 --> 02:04:07,680 CONSORTIUM FIBROUS DYSPLASIA 2679 02:04:07,680 --> 02:04:10,480 MCCUNE ALBRIGHT SYNDROME 2680 02:04:10,480 --> 02:04:11,080 INTRODUCE BOARD OF DIRECTORS TO 2681 02:04:11,080 --> 02:04:13,200 YOU HERE. INTENTION IS TO HAVE 2682 02:04:13,200 --> 02:04:14,640 ALWAYS REPRESENTED IN THE BOARD 2683 02:04:14,640 --> 02:04:18,080 OF THE CONSORTIUM BOTH VARIOUS 2684 02:04:18,080 --> 02:04:19,360 STAKEHOLDERS SO BOTH 2685 02:04:19,360 --> 02:04:23,000 RESEARCHERS, SCIENTISTS AND 2686 02:04:23,000 --> 02:04:23,720 PATIENT REPRESENTATION AND 2687 02:04:23,720 --> 02:04:27,400 PREFERABLY FROM DIFFERENT 2688 02:04:27,400 --> 02:04:27,800 COUNTRIES. 2689 02:04:27,800 --> 02:04:31,600 WHAT DO WE WANT TO ACHIEVE WITH 2690 02:04:31,600 --> 02:04:32,560 CONSORTIUM? 2691 02:04:32,560 --> 02:04:35,320 ALSO ON WEBSITE WE IDENTIFIED 2692 02:04:35,320 --> 02:04:38,000 MISSION WITH FOUR MAIN POINTS TO 2693 02:04:38,000 --> 02:04:40,120 IMPROVE CARE AND FINE SOLUTIONS 2694 02:04:40,120 --> 02:04:41,800 FOR UNMET NEEDS OF PATIENTS AND 2695 02:04:41,800 --> 02:04:44,360 CARE PROVIDERS ENCOURAGING 2696 02:04:44,360 --> 02:04:46,120 TESTING AND DEVELOPMENT OF 2697 02:04:46,120 --> 02:04:49,920 POTENTIAL ENCOURAGING TREATMENT 2698 02:04:49,920 --> 02:04:51,720 TO IMPROVE ACCESS TO INFORMATION 2699 02:04:51,720 --> 02:04:56,160 WORLDWIDE AND SUPPORT DEVELOP 2700 02:04:56,160 --> 02:04:57,640 COOPERATIVE SCIENTIFIC STUDIES 2701 02:04:57,640 --> 02:05:00,400 AND INITIATIVES AND BEING A 2702 02:05:00,400 --> 02:05:02,560 CONTACT PLATFORM SO PATIENTS AND 2703 02:05:02,560 --> 02:05:04,520 SPECIALISTS ARE ABLE TO FIND US 2704 02:05:04,520 --> 02:05:06,720 AND REACH US AND WEBSITE AND 2705 02:05:06,720 --> 02:05:09,080 SOCIALS WE ARE ON LINKEDIN AND 2706 02:05:09,080 --> 02:05:11,440 PLAY A CENTRAL ROLE IN THIS. 2707 02:05:11,440 --> 02:05:14,720 DEFINITELY ALSO LIKE LIVE 2708 02:05:14,720 --> 02:05:16,200 MEETINGS LIKE WE HAD YESTERDAY. 2709 02:05:16,200 --> 02:05:17,560 IN A SHORT PERIOD OF TIME WHAT 2710 02:05:17,560 --> 02:05:21,320 HAS BEEN ACHIEVED SO FAR. 2711 02:05:21,320 --> 02:05:24,880 WELL, IT IS TREMENDOUS THAT 2712 02:05:24,880 --> 02:05:28,080 FD/MAS COMMUNITY IS GROWING SO 2713 02:05:28,080 --> 02:05:28,360 FAST. 2714 02:05:28,360 --> 02:05:31,360 THE LAST YEAR OR SO, A LOT OF 2715 02:05:31,360 --> 02:05:33,720 NEW COUNTRIES HAVE JOINED ALSO 2716 02:05:33,720 --> 02:05:37,360 THE INTERNATIONAL PATIENT 2717 02:05:37,360 --> 02:05:38,160 ASSOCIATION MEETINGS. 2718 02:05:38,160 --> 02:05:40,400 THEY DO NOT ONLY BRING EXTRA 2719 02:05:40,400 --> 02:05:42,040 PATIENTS BUT EXTRA RESEARCHERS 2720 02:05:42,040 --> 02:05:46,640 AND SPECIALISTS TO FD/MAS 2721 02:05:46,640 --> 02:05:46,920 COMMUNITY. 2722 02:05:46,920 --> 02:05:48,200 THAT IS VERY GOOD. 2723 02:05:48,200 --> 02:05:50,760 EVERY MONTH THE INTERNATIONAL 2724 02:05:50,760 --> 02:05:52,360 PATIENT ASSOCIATIONS MEET ONLINE 2725 02:05:52,360 --> 02:05:54,560 THAT IS QUITE CHALLENGING 2726 02:05:54,560 --> 02:05:55,760 CONSIDERING ALL DIFFERENT TIME 2727 02:05:55,760 --> 02:05:57,760 ZONES INVOLVED THAT WE TRY TO 2728 02:05:57,760 --> 02:05:58,120 MANAGE. 2729 02:05:58,120 --> 02:06:00,800 IT IS REALLY GREAT TO HAVE ALL 2730 02:06:00,800 --> 02:06:04,280 THESE DIFFERENT NATIONALITIES 2731 02:06:04,280 --> 02:06:05,960 WORKING TOGETHER AND WE SPEAK 2732 02:06:05,960 --> 02:06:07,720 ABOUT COMMON GOALS AND 2733 02:06:07,720 --> 02:06:10,880 CHALLENGES AND HELP EACH OTHER 2734 02:06:10,880 --> 02:06:15,320 OUT WHEREVER WE CAN. 2735 02:06:15,320 --> 02:06:17,560 AND WELL WE QUITE ACHIEVED 2736 02:06:17,560 --> 02:06:19,720 WORKING ON PROJECTS TOGETHER AND 2737 02:06:19,720 --> 02:06:22,520 ACHIEVING QUITE A BIT OF THINGS 2738 02:06:22,520 --> 02:06:24,040 AMONGST THINGS FROM LAST YEAR 2739 02:06:24,040 --> 02:06:26,720 HAVE BEEN ABLE TO DEFINE AND 2740 02:06:26,720 --> 02:06:28,080 PRESENT PRIORITIES IN PATIENT 2741 02:06:28,080 --> 02:06:30,600 CARE FOR PATIENTS WITH FD/MAS 2742 02:06:30,600 --> 02:06:32,360 AND CAN ALSO BE FOUND ON ONE OF 2743 02:06:32,360 --> 02:06:35,040 THE POSTERS YOU WILL FIND IN THE 2744 02:06:35,040 --> 02:06:37,280 COFFEE AREA IN MORE DETAIL. 2745 02:06:37,280 --> 02:06:39,080 WE OFTEN HAVE COORDINATED 2746 02:06:39,080 --> 02:06:41,960 AWARENESS CAMPAIGNS DURING 2747 02:06:41,960 --> 02:06:44,000 FD/MAS AWARENESS WEEK THAT IS 2748 02:06:44,000 --> 02:06:46,040 ALWAYS ON THE 20TH OF FEBRUARY. 2749 02:06:46,040 --> 02:06:48,320 OUR SPANISH COLLEAGUES HAVE 2750 02:06:48,320 --> 02:06:50,480 DEVELOPED A CHILDREN'S BOOK, A 2751 02:06:50,480 --> 02:06:53,680 GIFT CALLED MATEO AVAILABLE IN 2752 02:06:53,680 --> 02:06:56,760 VARIOUS LANGUAGES AND WIDELY 2753 02:06:56,760 --> 02:06:59,080 AVAILABLE ON AMAZON AND THIS 2754 02:06:59,080 --> 02:07:01,040 WEEK LAUNCHED CHILDREN'S 2755 02:07:01,040 --> 02:07:04,320 INFORMATION FLYER ABOUT FD/MAS 2756 02:07:04,320 --> 02:07:05,800 GIVING CHILDREN ABILITY TO 2757 02:07:05,800 --> 02:07:07,040 EXPLAIN THEIR DISEASE TO THEIR 2758 02:07:07,040 --> 02:07:09,680 FRIENDS OR TEACHERS IN A 2759 02:07:09,680 --> 02:07:11,040 CLASSROOM AND MADE ANIMATION 2760 02:07:11,040 --> 02:07:15,040 VIDEO ON FD/MAS. 2761 02:07:15,040 --> 02:07:16,800 NOT ONLY PATIENT ASSOCIATION 2762 02:07:16,800 --> 02:07:18,640 HAVE BEEN WORKING TOGETHER. 2763 02:07:18,640 --> 02:07:21,160 OTHER STAKEHOLDERS BEING 2764 02:07:21,160 --> 02:07:24,000 RESEARCHERS AND OTHER 2765 02:07:24,000 --> 02:07:26,400 SPECIALISTS HAVE BEEN WORKING 2766 02:07:26,400 --> 02:07:28,080 TOGETHER MORE AND MORE AND LED 2767 02:07:28,080 --> 02:07:32,080 TO WIDE VARIETY OF PUBLICATIONS. 2768 02:07:32,080 --> 02:07:34,720 AS I ALREADY INDICATED, ONE MAIN 2769 02:07:34,720 --> 02:07:36,000 ACHIEVEMENT IN THIS IS 2770 02:07:36,000 --> 02:07:38,720 INTERNATIONAL GUIDELINES FOR 2771 02:07:38,720 --> 02:07:42,280 HEALTHCARE PATIENTS FOR FD/MAS 2772 02:07:42,280 --> 02:07:44,360 CLINICAL PATHWAY AND FROM THAT 2773 02:07:44,360 --> 02:07:45,360 MADE TRANSLATION INTO PATIENT 2774 02:07:45,360 --> 02:07:48,400 GUIDE THAT IS BASICALLY USED AS 2775 02:07:48,400 --> 02:07:50,640 A TOOL FOR PATIENTS TO HELP THEM 2776 02:07:50,640 --> 02:07:53,280 WITH DOCTORS APPOINTMENTS AND 2777 02:07:53,280 --> 02:07:54,560 ENHANCES ALSO COMMUNICATION 2778 02:07:54,560 --> 02:07:57,800 BETWEEN PATIENT AND DOCTOR AND 2779 02:07:57,800 --> 02:07:58,960 ENHANCES ALSO UNDERSTANDING 2780 02:07:58,960 --> 02:08:00,120 ABOUT THE DISEASE. 2781 02:08:00,120 --> 02:08:02,320 THESE BOTH GUIDELINES AND 2782 02:08:02,320 --> 02:08:04,680 PATIENTS GUIDE HAVE BEEN 2783 02:08:04,680 --> 02:08:05,520 REVIEWED YESTERDAY IN 2784 02:08:05,520 --> 02:08:07,920 YESTERDAY'S MEETING AND WILL 2785 02:08:07,920 --> 02:08:11,600 UPDATE IT IN THE COMING TIME. 2786 02:08:11,600 --> 02:08:12,560 SO, THIS WAS YESTERDAY. 2787 02:08:12,560 --> 02:08:16,800 I THINK THAT ONE OF THE 2788 02:08:16,800 --> 02:08:17,920 CONCLUSIONS WE HAD IN 2789 02:08:17,920 --> 02:08:20,000 YESTERDAY'S MEETING IS IN RECENT 2790 02:08:20,000 --> 02:08:21,960 YEARS LOTS OF PROGRESS HAS BEEN 2791 02:08:21,960 --> 02:08:24,320 MADE ON RESEARCH AND ON HEALTH 2792 02:08:24,320 --> 02:08:27,840 CARE AND ALSO ON INCLUSION OF 2793 02:08:27,840 --> 02:08:32,960 PATIENT INVOLVEMENT IN ALL THIS. 2794 02:08:32,960 --> 02:08:37,440 I THINK CELEBRATING 25 YEARS OF 2795 02:08:37,440 --> 02:08:40,840 RESEARCH SHOWS COMMITMENT AND 2796 02:08:40,840 --> 02:08:43,840 ALSO THE CLINICAL RESEARCHERS 2797 02:08:43,840 --> 02:08:46,960 INVOLVEMENT OF NIH AND FD/MAS 2798 02:08:46,960 --> 02:08:50,680 COMMUNITY AND DR. ALLISON BOYCE 2799 02:08:50,680 --> 02:08:52,760 AND MIKE COLLINS HAVE BEEN 2800 02:08:52,760 --> 02:08:54,280 INVOLVED FROM THE BEGINNING AND 2801 02:08:54,280 --> 02:08:56,840 WITH SETUP OF INTERNATIONAL 2802 02:08:56,840 --> 02:08:59,040 CONSORTIUM AND ARE GREAT 2803 02:08:59,040 --> 02:09:00,240 INTERNATIONAL CORPORATION HAS 2804 02:09:00,240 --> 02:09:02,440 BEEN, WELL, GREAT VALUE TO 2805 02:09:02,440 --> 02:09:05,000 INTERNATIONAL FD/MAS COMMUNITY. 2806 02:09:05,000 --> 02:09:11,080 WE ARE REALLY GRATEFUL FOR THAT. 2807 02:09:11,080 --> 02:09:13,720 BIG HAIRY GOAL AS I ALWAYS CALL 2808 02:09:13,720 --> 02:09:15,360 IT, I HOPE TODAY I HAVE BEEN 2809 02:09:15,360 --> 02:09:17,920 ABLE TO SHOW YOU WE HAVE VERY 2810 02:09:17,920 --> 02:09:19,960 MUCH GROWING COMMUNITY AND ALSO 2811 02:09:19,960 --> 02:09:23,800 VERY ACTIVE ONE. I HOPE THIS 2812 02:09:23,800 --> 02:09:26,120 ENCOURAGES ALL RESEARCHERS TO 2813 02:09:26,120 --> 02:09:28,120 CONTINUE THEIR GREAT WORK WITH 2814 02:09:28,120 --> 02:09:30,080 AIM OF REACHING BIG AND HAIRY 2815 02:09:30,080 --> 02:09:33,480 GOAL AND UNRAVELING SECRETS AND 2816 02:09:33,480 --> 02:09:38,560 MYSTERIES ON FD/MAS AND POSSIBLE 2817 02:09:38,560 --> 02:09:39,120 SOLUTIONS. 2818 02:09:39,120 --> 02:09:41,720 GO FOR IT. 2819 02:09:41,720 --> 02:09:44,280 THANK YOU. 2820 02:09:44,280 --> 02:09:46,960 >> AUDIENCE: [APPLAUSE]. 2821 02:09:46,960 --> 02:09:49,120 >> I LOVE WHAT YOU SAID ABOUT 2822 02:09:49,120 --> 02:09:51,760 PATIENTS LEADING RESEARCHERS AND 2823 02:09:51,760 --> 02:09:54,160 CLINICIANS AND REALLY TAKING A 2824 02:09:54,160 --> 02:09:56,120 LEAD BECAUSE SOMETIMES IT IS THE 2825 02:09:56,120 --> 02:10:00,400 PATIENT WHO EDUCATES US. 2826 02:10:00,400 --> 02:10:02,120 WE WILL SHAKE IT UP A LITTLE 2827 02:10:02,120 --> 02:10:05,040 BIT. I SEE TWO PEOPLE AND TWO 2828 02:10:05,040 --> 02:10:06,800 BOUNCING BEANS BACK THERE. WE 2829 02:10:06,800 --> 02:10:08,640 WILL HAVE A PATIENT AND 2830 02:10:08,640 --> 02:10:10,240 PROFESSIONAL PANEL. I WOULD 2831 02:10:10,240 --> 02:10:12,560 LIKE TO INVITE OUR PATIENT 2832 02:10:12,560 --> 02:10:14,480 GUESTS AND DR. BOYCE AND DR. 2833 02:10:14,480 --> 02:10:20,000 COLLINS TO COME TO THE FRONT. 2834 02:10:20,000 --> 02:10:23,960 YOU WILL HEAR FROM THOSE WHO 2835 02:10:23,960 --> 02:10:27,080 LIVE WITH THIS CONDITION. 2836 02:10:27,080 --> 02:10:27,920 >> AUDIENCE: [APPLAUSE]. 2837 02:10:27,920 --> 02:10:38,680 >> I THINK I'M SUPPOSED TO SH S 2838 02:10:42,360 --> 02:10:42,520 THERE. 2839 02:10:42,520 --> 02:10:44,640 >> THANK YOU VERY MUCH. 2840 02:10:44,640 --> 02:10:46,880 SHOUTOUT TO PATIENT SUPPOSED TO 2841 02:10:46,880 --> 02:10:49,520 ATTEND TODAY. TIFFANY MYER AND 2842 02:10:49,520 --> 02:10:51,360 HOPE SHE IS WATCHING FROM 2843 02:10:51,360 --> 02:10:54,200 ONLINE. SHE UNEXPECTEDLY HAD A 2844 02:10:54,200 --> 02:10:55,720 HOSPITALIZATION. SHE WON'T BE 2845 02:10:55,720 --> 02:10:58,120 ABLE TO JOIN US. SHE HAS BEEN 2846 02:10:58,120 --> 02:10:59,760 PART OF NATURAL HISTORY STUDY 2847 02:10:59,760 --> 02:11:02,560 FROM BEGINNING AND SENT A BRIEF 2848 02:11:02,560 --> 02:11:04,280 STATEMENT I WILL READ. I WOULD 2849 02:11:04,280 --> 02:11:06,200 TELL EVERYONE I KEEP COMING TO 2850 02:11:06,200 --> 02:11:07,800 NIH. I RECEIVE CARE FROM 2851 02:11:07,800 --> 02:11:09,760 FOREMOST RESEARCH CENTER IN 2852 02:11:09,760 --> 02:11:11,000 COUNTRY AND DOCTORS AND NURSES 2853 02:11:11,000 --> 02:11:13,200 THERE ARE LIKE FAMILY. YOU AND 2854 02:11:13,200 --> 02:11:14,880 ALL DOCTORS THERE CARE SO MUCH 2855 02:11:14,880 --> 02:11:16,160 ABOUT THEIR PATIENTS. 2856 02:11:16,160 --> 02:11:17,480 I TELL PEOPLE ALL THE TIME ARE 2857 02:11:17,480 --> 02:11:20,360 YOU FAMILIAR WITH THE NATIONAL 2858 02:11:20,360 --> 02:11:22,040 INSTITUTES OF HEALTH? I'M LUCKY 2859 02:11:22,040 --> 02:11:23,520 ENOUGH TO GO THERE FOR MEDICAL 2860 02:11:23,520 --> 02:11:24,880 CARE I CAN HELP OTHERS THERE IN 2861 02:11:24,880 --> 02:11:27,160 THE PROCESS IF I CAN CHANGE THE 2862 02:11:27,160 --> 02:11:28,920 FACT I HAVE MY CONDITION I 2863 02:11:28,920 --> 02:11:30,880 WOULDN'T. I HAVE MET SO MANY 2864 02:11:30,880 --> 02:11:32,320 WONDERFUL PEOPLE BECAUSE OF IT 2865 02:11:32,320 --> 02:11:36,120 AND IT MAKES ME A COMPASSIONATE 2866 02:11:36,120 --> 02:11:36,880 AND POSITIVE PERSON AND THANK 2867 02:11:36,880 --> 02:11:41,200 YOU FOR ALL YOU DO FOR ME AND MY 2868 02:11:41,200 --> 02:11:45,360 PARENTS AND MY HUSBAND. 2869 02:11:45,360 --> 02:11:46,000 >> AUDIENCE: [APPLAUSE]. 2870 02:11:46,000 --> 02:11:47,800 >> WE HAVE CLEARLY MANY 2871 02:11:47,800 --> 02:11:49,000 WONDERFUL PATIENTS. 2872 02:11:49,000 --> 02:11:53,440 DO YOU WANT TO INTRODUCE 2873 02:11:53,440 --> 02:11:54,640 YOURSELVES? 2874 02:11:54,640 --> 02:11:58,920 >> WE ARE FANCY AND HAVE -- WE 2875 02:11:58,920 --> 02:12:02,040 ARE MICCED UP. I'M IVONNE AND 2876 02:12:02,040 --> 02:12:05,080 MOTHER OF GIANA. WE HAVE WORKED 2877 02:12:05,080 --> 02:12:08,920 WITH DR. BOYCE FOR THE LAST FIVE 2878 02:12:08,920 --> 02:12:11,640 YEARS SINCE GIANA'S DIAGNOSIS 2879 02:12:11,640 --> 02:12:15,840 AND PLEASURE TO BE HERE TODAY. 2880 02:12:15,840 --> 02:12:17,000 THANK YOU. 2881 02:12:17,000 --> 02:12:26,120 >> HI. I'M GIANA. 2882 02:12:26,120 --> 02:12:32,720 I AM 7 YEARS OLD. YES. 2883 02:12:32,720 --> 02:12:35,280 >> WOULD YOU LIKE ME TO 2884 02:12:35,280 --> 02:12:37,200 INTRODUCE YOU? WE HAVE HERE 2885 02:12:37,200 --> 02:12:39,160 LUCY WHO IS 7 YEARS OLD. 2886 02:12:39,160 --> 02:12:39,360 >> 8. 2887 02:12:39,360 --> 02:12:42,520 >> SORRY SHE IS 8 YEARS OLD. 2888 02:12:42,520 --> 02:12:46,320 LUCY AND GIANA ARE PATIENTS ON 2889 02:12:46,320 --> 02:12:48,120 NIH STUDIES AND THEY GOT TO 2890 02:12:48,120 --> 02:12:50,200 ACTUALLY MEET RECENTLY AT NIH 2891 02:12:50,200 --> 02:12:52,520 WHEN THEY CAME TO THE CLINICAL 2892 02:12:52,520 --> 02:12:52,760 CENTER. 2893 02:12:52,760 --> 02:12:54,240 MAYBE WANT TO SHARE A LITTLE BIT 2894 02:12:54,240 --> 02:12:56,680 ABOUT WHAT IT WAS LIKE TO MEET 2895 02:12:56,680 --> 02:12:59,280 SOMEONE WITHIN NIH EITHER MOM OR 2896 02:12:59,280 --> 02:13:01,600 GIRLS OR WHOEVER WOULD LIKE TO 2897 02:13:01,600 --> 02:13:04,800 SHARE? WANT TO GO? 2898 02:13:04,800 --> 02:13:10,120 >> IT WAS REALLY DIFFERENT 2899 02:13:10,120 --> 02:13:12,040 BECAUSE EVER SINCE HAVING TO GO 2900 02:13:12,040 --> 02:13:14,000 THERE, I ALWAYS JUST HAVE TO BE 2901 02:13:14,000 --> 02:13:19,320 BY MYSELF AND NO ONE THERE. 2902 02:13:19,320 --> 02:13:20,800 THAT IS IT. 2903 02:13:20,800 --> 02:13:24,400 >> YEAH. IT WAS -- IT IS A 2904 02:13:24,400 --> 02:13:26,200 POTENTIALLY LONELY JOURNEY. 2905 02:13:26,200 --> 02:13:28,320 LIKE THE WAY YOU HAVE ALL 2906 02:13:28,320 --> 02:13:31,240 DESCRIBED HOW THIS IS A REALLY 2907 02:13:31,240 --> 02:13:32,400 INCREDIBLY RARE CONDITION AND 2908 02:13:32,400 --> 02:13:33,680 LEARNING TO TALK ABOUT IT AND 2909 02:13:33,680 --> 02:13:37,000 LEARNING HOW TO ADVOCATE IS 2910 02:13:37,000 --> 02:13:38,760 LONELY WHEN YOU DON'T HAVE 2911 02:13:38,760 --> 02:13:40,400 ANYBODY ELSE YOU COULD SAY LIKE 2912 02:13:40,400 --> 02:13:42,120 SLOW DOWN AND LIKE I GET IT. I 2913 02:13:42,120 --> 02:13:46,800 GET IT. SO, WHEN THE GIRLS 2914 02:13:46,800 --> 02:13:49,160 STARTED THEIR DENOSUMAB 2915 02:13:49,160 --> 02:13:50,800 TREATMENT IT WAS FIRST TIME I 2916 02:13:50,800 --> 02:13:53,000 MET ANOTHER PARENT, LAURA, WHO 2917 02:13:53,000 --> 02:13:54,600 JUST UNDERSTOOD EVERYTHING I WAS 2918 02:13:54,600 --> 02:13:57,520 GOING THROUGH. TO HAVE GIANA 2919 02:13:57,520 --> 02:13:59,720 NOT HAVE TO EXPLAIN TO KIDS LIKE 2920 02:13:59,720 --> 02:14:01,440 WHAT? WHY CAN'T YOU JUST RUN 2921 02:14:01,440 --> 02:14:04,120 WITH ME? WHY CAN'T YOU -- AND 2922 02:14:04,120 --> 02:14:06,720 FOR IT TO BE LUCY WHO IS LIKE 2923 02:14:06,720 --> 02:14:09,240 YEAH. LET'S SLOW DOWN. WE ARE 2924 02:14:09,240 --> 02:14:11,080 CHILLING. WE ARE FINE AND TO 2925 02:14:11,080 --> 02:14:13,720 LOOK AT EACH OTHER AND KNOW AND 2926 02:14:13,720 --> 02:14:15,080 SHARE THE STORY WITHOUT HAVING 2927 02:14:15,080 --> 02:14:17,040 TO HAVE WEIRD LOOKS OR HAVE THE 2928 02:14:17,040 --> 02:14:19,080 QUESTIONS WAS REALLY POWERFUL. 2929 02:14:19,080 --> 02:14:20,800 SO, DR. BOYCE HAS BEEN TRYING TO 2930 02:14:20,800 --> 02:14:23,440 GET US TO MEET FOR LITERALLY THE 2931 02:14:23,440 --> 02:14:24,160 LAST FIVE YEARS. 2932 02:14:24,160 --> 02:14:26,400 WE HAVE BEEN IN THE NIH TOGETHER 2933 02:14:26,400 --> 02:14:28,440 AND JUST MISSED EACH OTHER. FOR 2934 02:14:28,440 --> 02:14:31,000 THEM TO GO THROUGH ONE FULL WEEK 2935 02:14:31,000 --> 02:14:33,640 STAYING AT NIH WHICH COULD BE 2936 02:14:33,640 --> 02:14:35,800 AREALLY SCARY AS A KID TO BE IN 2937 02:14:35,800 --> 02:14:37,400 THE HOSPITAL OVERNIGHT. THEY 2938 02:14:37,400 --> 02:14:42,640 HAD PLAY DATES ON A DAILY BASIS. 2939 02:14:42,640 --> 02:14:44,440 ENTIRE NURSING STAFF IN ONE END. 2940 02:14:44,440 --> 02:14:46,120 >> 1 NORTHWEST, YES. 2941 02:14:46,120 --> 02:14:48,640 >> THEY WERE INCREDIBLE AND 2942 02:14:48,640 --> 02:14:50,520 HELPING US SET UP PLAY DATES 2943 02:14:50,520 --> 02:14:52,160 TOGETHER AND GIVING GIRLS SPACE 2944 02:14:52,160 --> 02:14:54,960 TO WATCH MOVIES AND GO ON 2945 02:14:54,960 --> 02:14:56,240 PLAYGROUNDS AT CHILDREN'S IN AND 2946 02:14:56,240 --> 02:14:58,040 IT WAS SOMETHING THAT COULD BE 2947 02:14:58,040 --> 02:15:00,160 REALLY SCARY TURNED INTO 2948 02:15:00,160 --> 02:15:03,000 SOMETHING THAT WAS A POWERFUL 2949 02:15:03,000 --> 02:15:04,400 OPPORTUNITY TO BUILD 2950 02:15:04,400 --> 02:15:05,440 RELATIONSHIP AND FIND SOMEBODY 2951 02:15:05,440 --> 02:15:10,680 THAT EXPERIENCED THE SAME THING. 2952 02:15:10,680 --> 02:15:12,400 NOT A LOT ARE THIS YOUNG BUT 2953 02:15:12,400 --> 02:15:14,480 THREE THERE AT SAME TIME AND ARE 2954 02:15:14,480 --> 02:15:16,400 BESTIES TO THIS DAY AND GET TO 2955 02:15:16,400 --> 02:15:17,840 TALK AND CONNECT WITH EACH OTHER 2956 02:15:17,840 --> 02:15:19,400 AND HAVE SOMEBODY WHO GETS THEM. 2957 02:15:19,400 --> 02:15:21,840 I HAVE A PARENT THAT GETS ME. 2958 02:15:21,840 --> 02:15:23,320 IT IS REALLY BEAUTIFUL. 2959 02:15:23,320 --> 02:15:26,440 >> I REALLY APPRECIATE YOU 2960 02:15:26,440 --> 02:15:28,280 BRINGING UP ONE NORTHWEST 2961 02:15:28,280 --> 02:15:30,480 NURSING UNIT. AS HIGHLIGHTED AS 2962 02:15:30,480 --> 02:15:32,280 WELL, NONE OF THIS WOULD BE 2963 02:15:32,280 --> 02:15:33,880 POSSIBLE WITHOUT SUPPORT FROM NI 2964 02:15:33,880 --> 02:15:36,800 HAD. AND NIH CLINICAL CENTER IN 2965 02:15:36,800 --> 02:15:38,240 PARTICULAR. WE ARE GRATEFUL FOR 2966 02:15:38,240 --> 02:15:39,840 THAT. CAN YOU THINK OF ANYTHING 2967 02:15:39,840 --> 02:15:41,360 THAT WAS NICE ABOUT COMING TO 2968 02:15:41,360 --> 02:15:43,760 THE CLINICAL CENTER? I'M TRYING 2969 02:15:43,760 --> 02:15:45,840 TO PRY SOMETHING OUT OF YOU. I 2970 02:15:45,840 --> 02:15:48,080 KNOW YOU HAVE FUN WITH SOME 2971 02:15:48,080 --> 02:15:50,120 GUINEA PIGS. 2972 02:15:50,120 --> 02:15:52,920 WANT TO SHARE ABOUT THAT? 2973 02:15:52,920 --> 02:15:55,680 >> YES. THERE IS A GUINEA PIG. 2974 02:15:55,680 --> 02:15:57,880 SHE WAS LIKE I THINK 7 YEARS 2975 02:15:57,880 --> 02:15:59,920 OLD. SHE WAS REALLY CUTE AND 2976 02:15:59,920 --> 02:16:02,280 REALLY WAL M. AND JUST LIKE 2977 02:16:02,280 --> 02:16:05,200 VERY, VERY NICE TO BE WITH. 2978 02:16:05,200 --> 02:16:07,280 >> DON'T URNL WILL I GET TO PLAY 2979 02:16:07,280 --> 02:16:10,080 WITH A GUINEA PIG WHEN IN THE 2980 02:16:10,080 --> 02:16:10,360 HOSPITAL. 2981 02:16:10,360 --> 02:16:11,480 >> CAN I SAY SOMETHING? 2982 02:16:11,480 --> 02:16:12,120 >> OF COURSE. 2983 02:16:12,120 --> 02:16:14,120 >> IT WAS MY FIRST TIME ACTUALLY 2984 02:16:14,120 --> 02:16:18,320 SEEING A GUINEA PIG IN REAL 2985 02:16:18,320 --> 02:16:21,240 LIFE. IT WAS SCARY AND FUN AT 2986 02:16:21,240 --> 02:16:22,160 THE SAME TIME. 2987 02:16:22,160 --> 02:16:25,800 I JUST LOVED IT. 2988 02:16:25,800 --> 02:16:28,560 THAT IS IT. 2989 02:16:28,560 --> 02:16:31,360 >> [LAUGHING]. 2990 02:16:31,360 --> 02:16:34,440 >> GREAT. DR. COLLINS DID YOU 2991 02:16:34,440 --> 02:16:36,520 WANT TO ASK ANY QUESTION SNZ I'M 2992 02:16:36,520 --> 02:16:37,560 HOGGING THE MIC HERE. 2993 02:16:37,560 --> 02:16:39,440 >> I WONDER IF YOU COULD TELL 2994 02:16:39,440 --> 02:16:41,400 MORE ABOUT THE PHENOMENON OF THE 2995 02:16:41,400 --> 02:16:43,240 FIRST TIME MEETING ANOTHER 2996 02:16:43,240 --> 02:16:43,600 PATIENT. 2997 02:16:43,600 --> 02:16:46,880 THIS IS SUCH A UNIVERSAL FEATURE 2998 02:16:46,880 --> 02:16:49,720 OF PATIENTS WITH RARE DISEASES 2999 02:16:49,720 --> 02:16:51,880 AND NEVER REALIZED WHAT IT WAS 3000 02:16:51,880 --> 02:16:53,400 JUST A UNIVERSAL FINDING AND 3001 02:16:53,400 --> 02:16:55,400 WHAT IT MEANS AND BEING INVOLVED 3002 02:16:55,400 --> 02:16:58,120 WITH THE FOUNDATION. 3003 02:16:58,120 --> 02:16:59,080 >> YEAH. 3004 02:16:59,080 --> 02:17:02,160 YEAH. ONE THING I WILL SAY IS 3005 02:17:02,160 --> 02:17:04,000 ORIGINALLY WITH DR. BOYCE, SHE 3006 02:17:04,000 --> 02:17:07,480 WHO LET ME TELL YOU I'M ONE OF 3007 02:17:07,480 --> 02:17:09,760 THOSE PARENTS I HAVE NO MEDICAL 3008 02:17:09,760 --> 02:17:11,160 BACKGROUND BUT I'M A LEARNER AND 3009 02:17:11,160 --> 02:17:13,880 I'M SO CURIOUS AND LIKE TO BE 3010 02:17:13,880 --> 02:17:16,240 ABLE TO TALK. IT IS A UNIQUE 3011 02:17:16,240 --> 02:17:17,280 CONDITION THAT I WANT TO BE ABLE 3012 02:17:17,280 --> 02:17:19,640 TO TALK ABOUT IT. I ASKED MAYBE 3013 02:17:19,640 --> 02:17:22,640 UP TO THIS POINT 5 MILLION 3014 02:17:22,640 --> 02:17:23,720 QUESTIONS TO DR. BOYCE ABOUT ALL 3015 02:17:23,720 --> 02:17:25,760 THESE THINGS AND REASON FOR IT, 3016 02:17:25,760 --> 02:17:27,680 I WANTED TO HAVE LANGUAGE TO 3017 02:17:27,680 --> 02:17:30,440 TALK WITH HER AND TEACHERS AND 3018 02:17:30,440 --> 02:17:35,040 OTHER DOCTORS AND DAYCARES ABOUT 3019 02:17:35,040 --> 02:17:36,280 WHAT THIS CONDITION IS AND WHAT 3020 02:17:36,280 --> 02:17:39,120 IS TRICKY, SHE IS 7 AND TO HAVE 3021 02:17:39,120 --> 02:17:40,360 LANGUAGE TO TALK ABOUT HER 3022 02:17:40,360 --> 02:17:44,600 CONDITION TO OTHER KIDS IS 3023 02:17:44,600 --> 02:17:45,760 TOUGH. 3024 02:17:45,760 --> 02:17:48,240 >> I HAVE DONE IT 5 MILLION 3025 02:17:48,240 --> 02:17:48,480 TIMES. 3026 02:17:48,480 --> 02:17:51,000 >> YOU HAVE DONE IT 5 MILLION 3027 02:17:51,000 --> 02:17:51,480 TIMES, RIGHT. 3028 02:17:51,480 --> 02:17:54,560 >> I HAVE TO SAY TO COUSINS TO 3029 02:17:54,560 --> 02:17:57,520 AND EVERYONE AND SO TIMELY ONE 3030 02:17:57,520 --> 02:18:00,280 TIME DO I HAVE TO. 3031 02:18:00,280 --> 02:18:01,000 >> YEAH. 3032 02:18:01,000 --> 02:18:03,760 >> WHAT WAS IT LIKE FOR YOU TO 3033 02:18:03,760 --> 02:18:05,960 HAVE LUCY TO -- TO -- YEAH. TO 3034 02:18:05,960 --> 02:18:07,200 HAVE LUCY WHEN YOU FIRST MET HER 3035 02:18:07,200 --> 02:18:08,960 AND TALKING ABOUT WHAT WAS GOING 3036 02:18:08,960 --> 02:18:12,400 ON WITH YOU AND HOW WAS THAT? 3037 02:18:12,400 --> 02:18:14,200 >> IT WAS ACTUALLY REALLY FUN 3038 02:18:14,200 --> 02:18:18,960 AND FIRST TIME I WANTED TO GO TO 3039 02:18:18,960 --> 02:18:20,640 NIH BECAUSE YEAH. SHE MADE ME 3040 02:18:20,640 --> 02:18:25,880 HAVE A GOOD TIME AND WE ALWAYS 3041 02:18:25,880 --> 02:18:26,080 PLAY. 3042 02:18:26,080 --> 02:18:26,280 YEAH. 3043 02:18:26,280 --> 02:18:27,120 >> YEAH. 3044 02:18:27,120 --> 02:18:29,720 >> SO, I THINK JUST HAVING FOR 3045 02:18:29,720 --> 02:18:31,520 ME HAVING HER AND HAVING THEM 3046 02:18:31,520 --> 02:18:33,000 TALK ABOUT AND HEARING ABOUT HOW 3047 02:18:33,000 --> 02:18:34,840 THEY TALKED ABOUT IT TO EACH 3048 02:18:34,840 --> 02:18:37,080 OTHER WAS USEFUL. SHE GOT TO GO 3049 02:18:37,080 --> 02:18:38,680 BACK TO THE SCHOOL AND HAVE 3050 02:18:38,680 --> 02:18:40,080 DIFFERENT WAYS TO TALK ABOUT IT 3051 02:18:40,080 --> 02:18:42,280 AND HAVING A PARENT EVEN TALK 3052 02:18:42,280 --> 02:18:43,920 ABOUT WELL WHAT DO YOU ALL DO 3053 02:18:43,920 --> 02:18:46,680 FOR RECESS AND WHAT ARE 3054 02:18:46,680 --> 02:18:47,960 ACCOMMODATIONS MADE FOR YOU AND 3055 02:18:47,960 --> 02:18:50,560 WHAT DO YOU DO DURING PE? 3056 02:18:50,560 --> 02:18:52,160 THINGS WHERE I EXPLAIN THE 3057 02:18:52,160 --> 02:18:54,400 CONDITION AND COOL. I STILL 3058 02:18:54,400 --> 02:18:55,880 DON'T KNOW WHAT WE SHOULD AND 3059 02:18:55,880 --> 02:18:57,240 SHOULDN'T LET HER DO. TO HEAR 3060 02:18:57,240 --> 02:18:59,640 DIFFERENT APPROACHES I LEARNED 3061 02:18:59,640 --> 02:19:02,000 INSTEAD OF HAVING HER GO OUT TO 3062 02:19:02,000 --> 02:19:03,880 RESEARCH AND LIKE, YOU KNOW, SIT 3063 02:19:03,880 --> 02:19:05,520 HERE AND HAVE DIFFERENT THINGS 3064 02:19:05,520 --> 02:19:07,520 YOU CAN DO WHILE YOU WATCH 3065 02:19:07,520 --> 02:19:09,880 FRIENDS PLAY WHY DON'T YOU BE A 3066 02:19:09,880 --> 02:19:11,120 TEACHER'S AID? 3067 02:19:11,120 --> 02:19:13,640 HEARING WHAT LUCY DOES IN HER 3068 02:19:13,640 --> 02:19:17,320 SCHOOL AND GIANA NOW HAS HER 3069 02:19:17,320 --> 02:19:19,400 FIRST JOB YA'LL AT 7 YEARS OLD. 3070 02:19:19,400 --> 02:19:23,160 SHE IS A TEACHER'S AID DURING 3071 02:19:23,160 --> 02:19:25,960 RECESS IN A PRE-K CLASSROOM CAN 3072 02:19:25,960 --> 02:19:28,760 TELL YOU WHAT IT IS ABOUT IT WAS 3073 02:19:28,760 --> 02:19:30,400 INSPIRED BY LUCY'S JOURNEY AND 3074 02:19:30,400 --> 02:19:32,000 WE CAN IMPROVE THE QUALITY OF 3075 02:19:32,000 --> 02:19:33,280 LIFE IN SCHOOL BECAUSE OF 3076 02:19:33,280 --> 02:19:34,880 CONNECTIONS WE MADE THROUGH THE 3077 02:19:34,880 --> 02:19:36,400 STUDY AND THROUGH OUR STAY HERE. 3078 02:19:36,400 --> 02:19:37,840 DO YOU WANT TO TALK ABOUT THAT 3079 02:19:37,840 --> 02:19:38,480 AT ALL? 3080 02:19:38,480 --> 02:19:44,600 >> YES. MY FIRST DAY ON THE JOB 3081 02:19:44,600 --> 02:19:48,800 WAS REALLY CRAZY AND I HAD TO 3082 02:19:48,800 --> 02:19:53,080 TAKE CARE OF A LOT OF KIDS. 3083 02:19:53,080 --> 02:19:56,200 I ACTUALLY FELT LIKE A REAL 3084 02:19:56,200 --> 02:19:58,120 TEACHER BECAUSE I DIDN'T HAVE TO 3085 02:19:58,120 --> 02:20:01,120 JUST STAY OUTSIDE LOOKING AT 3086 02:20:01,120 --> 02:20:02,360 KIDS DOING NOTHING. 3087 02:20:02,360 --> 02:20:04,600 I ACTUALLY CAN LIKE DO STUFF AND 3088 02:20:04,600 --> 02:20:08,360 IT ACTUALLY FELT REALLY HAPPY 3089 02:20:08,360 --> 02:20:11,440 AND AT THE SAME TIME IT FELT 3090 02:20:11,440 --> 02:20:14,920 LIKE OH, MY GOSH. SO, YEAH. 3091 02:20:14,920 --> 02:20:16,400 THAT IS IT. 3092 02:20:16,400 --> 02:20:18,880 >> YEAH. MAYBE JUST ONE MORE 3093 02:20:18,880 --> 02:20:20,120 QUESTION. I HAVE KNOWN BOTH 3094 02:20:20,120 --> 02:20:23,720 THESE GIRLS FOR A LONG TIME AND 3095 02:20:23,720 --> 02:20:25,360 GIANA IN PARTICULAR I THINK WAS 3096 02:20:25,360 --> 02:20:26,040 REALLY NICE. 3097 02:20:26,040 --> 02:20:29,120 AS SOON AS THE PUZZLE WAS PUT 3098 02:20:29,120 --> 02:20:31,760 TOGETHER SHE HAD MCCUNE ALBRIGHT 3099 02:20:31,760 --> 02:20:34,000 SYNDROME WE WERE ABLE TO SWOOP 3100 02:20:34,000 --> 02:20:35,240 IN RIGHT AWAY. COULD YOU SHARE 3101 02:20:35,240 --> 02:20:38,000 WHAT IT WAS LIKE TO COME TO NIH 3102 02:20:38,000 --> 02:20:44,400 AND WORK THROUGH THAT DIAGNOSIS? 3103 02:20:44,400 --> 02:20:49,000 >> YOU WOULD LIKE TOO. DO YOU 3104 02:20:49,000 --> 02:20:49,720 REMEMBER? 3105 02:20:49,720 --> 02:20:50,400 I KNOW. 3106 02:20:50,400 --> 02:20:53,360 >> SO, MY FIRST TIME EVER THERE 3107 02:20:53,360 --> 02:20:57,320 WAS REALLY SCARY BECAUSE I WAS 3108 02:20:57,320 --> 02:20:59,120 ONLY TWO AT THE TIME. I DIDN'T 3109 02:20:59,120 --> 02:21:01,720 KNOW WHAT TO DO AND BLAH, BLAH, 3110 02:21:01,720 --> 02:21:02,040 BLAH. 3111 02:21:02,040 --> 02:21:04,200 FIVE YEARS LATER I FEEL LIKE IT 3112 02:21:04,200 --> 02:21:08,400 IS REALLY FUN. NOW I HAVE A 3113 02:21:08,400 --> 02:21:09,960 FRIEND, LUCY. 3114 02:21:09,960 --> 02:21:12,880 AND NOW I'M JUST USED TO THIS 3115 02:21:12,880 --> 02:21:13,120 STUFF. 3116 02:21:13,120 --> 02:21:15,040 >> YEAH. YEAH. I WILL TELL A 3117 02:21:15,040 --> 02:21:17,480 LITTLE ABOUT OUR JOURNEY. 3118 02:21:17,480 --> 02:21:20,960 SHE HAS THIS BEAUTIFUL DRESS ON 3119 02:21:20,960 --> 02:21:24,960 AND SHE WRAPS HER LEGS MOST OF 3120 02:21:24,960 --> 02:21:27,400 THE TIME LEGS OUT AND IN THE 3121 02:21:27,400 --> 02:21:29,200 VIDEO YOU SEE SHE WAS BORN WITH 3122 02:21:29,200 --> 02:21:32,400 A SIGNIFICANT AMOUNT OF CAFE AU 3123 02:21:32,400 --> 02:21:34,920 LAIT SPOTS AND THAT IS DIFFERENT 3124 02:21:34,920 --> 02:21:36,200 AND WENT TO SEVERAL 3125 02:21:36,200 --> 02:21:37,560 DERMATOLOGISTS TO TRY TO FIGURE 3126 02:21:37,560 --> 02:21:38,160 OUT. 3127 02:21:38,160 --> 02:21:39,880 >> TEACHERS YOU MEAN DOCTORS? 3128 02:21:39,880 --> 02:21:43,040 >> YES. A SPECIALIST. A SKIN 3129 02:21:43,040 --> 02:21:44,400 DOCTOR. JUST TRYING TO FIGURE 3130 02:21:44,400 --> 02:21:46,080 OUT WHAT DOES THIS MEAN OR WHAT 3131 02:21:46,080 --> 02:21:49,680 IS THIS HAPPENING NO ONE KNEW IT 3132 02:21:49,680 --> 02:21:51,760 WAS MOW SDACISM AND AS LONG AS 3133 02:21:51,760 --> 02:21:54,480 NOT CANCEROUS WE ARE OKAY NOBODY 3134 02:21:54,480 --> 02:21:56,080 KNEW ANYTHING BEYOND THAT. 3135 02:21:56,080 --> 02:21:58,520 >> SORRY ME AND MY MOM -- WELL, 3136 02:21:58,520 --> 02:22:01,360 ME JUST THOUGHT IT WAS BIRTH 3137 02:22:01,360 --> 02:22:01,600 MARKS. 3138 02:22:01,600 --> 02:22:03,720 >> YEAH. BIRTH MARKS; RIGHT? 3139 02:22:03,720 --> 02:22:07,760 THAT IS ONE PIECE OF THE PUZZLE. 3140 02:22:07,760 --> 02:22:08,640 NO DERMATOLOGIST PUT ANYTHING 3141 02:22:08,640 --> 02:22:10,240 TOGETHER. WHEN SHE WAS A BABY 3142 02:22:10,240 --> 02:22:12,880 SHE STARTED TO BLEED. THAT IS 3143 02:22:12,880 --> 02:22:14,560 DEFINITELY DIFFERENT. WE WENT 3144 02:22:14,560 --> 02:22:17,880 TO SEVERAL GYNECOLOGISTS AND 3145 02:22:17,880 --> 02:22:18,600 PEDIATRIC GYNECOLOGISTS AND NO 3146 02:22:18,600 --> 02:22:22,280 ONE COULD STILL FIGURE OUT WHAT 3147 02:22:22,280 --> 02:22:25,240 WAS HAPPENING UNTIL DR. GOMEZ 3148 02:22:25,240 --> 02:22:27,440 LOBO WAS LIKE WAIT A MINUTE. 3149 02:22:27,440 --> 02:22:31,280 THE SPOTS, THE BLEEDING, SHE HAS 3150 02:22:31,280 --> 02:22:32,680 THIS INCREDIBLY RARE CONDITION 3151 02:22:32,680 --> 02:22:35,080 AND THAT IS WHEN SHE INTRODUCED 3152 02:22:35,080 --> 02:22:37,120 US TO DR. BOYCE. SOMEBODY 3153 02:22:37,120 --> 02:22:38,920 FINALLY PUT IT TOGETHER. YA'LL 3154 02:22:38,920 --> 02:22:41,040 WE HAD BEEN TO MAYBE 8 OR 9 3155 02:22:41,040 --> 02:22:43,480 DOCTORS AT THAT POINT. A 3156 02:22:43,480 --> 02:22:47,400 GAZILLION DOCTORS AND NO ONE PUT 3157 02:22:47,400 --> 02:22:52,520 PIECES TOGETHER UNTIL DR. LOBOS 3158 02:22:52,520 --> 02:22:54,840 SAID I GOT IT AND HIT THE GROUND 3159 02:22:54,840 --> 02:22:57,840 RUNNING AND 5 YEARS LATER YOU 3160 02:22:57,840 --> 02:22:58,400 STILL KNOW HER. 3161 02:22:58,400 --> 02:23:00,640 WHAT WAS INTERESTING IS THERE IS 3162 02:23:00,640 --> 02:23:02,840 A CONFERENCE THAT ADRIAN TOLD 3163 02:23:02,840 --> 02:23:05,560 YOU ABOUT WITH FD/MAS ALLIANCE 3164 02:23:05,560 --> 02:23:07,640 HAPPENED A FEW WEEKS AFTER WE 3165 02:23:07,640 --> 02:23:09,280 WERE DIAGNOSED. DR. BOYCE WAS 3166 02:23:09,280 --> 02:23:11,400 LIKE YOU HAVE TO COME TO IT. IT 3167 02:23:11,400 --> 02:23:13,560 WAS VERY LONELY AND LOOKED IT UP 3168 02:23:13,560 --> 02:23:15,480 ONLINE AND WHAT? EXTREMES WHAT 3169 02:23:15,480 --> 02:23:17,360 IT COULD BE COULD BE EITHER 3170 02:23:17,360 --> 02:23:19,040 NOTHING OR SHE COULD BE BLIND. 3171 02:23:19,040 --> 02:23:21,040 OKAY. ABSOLUTELY NOTHING OR SHE 3172 02:23:21,040 --> 02:23:22,880 MIGHT LOSE ALL HER HEARING. 3173 02:23:22,880 --> 02:23:24,200 WHAT? THERE WERE ALL THESE 3174 02:23:24,200 --> 02:23:27,080 QUESTIONS. GOING TO THAT FIRST 3175 02:23:27,080 --> 02:23:27,920 CONFERENCE AND DR. BOYCE JUST 3176 02:23:27,920 --> 02:23:32,400 SAT AND MAYBE JUST THE FIRST 3177 02:23:32,400 --> 02:23:37,080 MEETING W WAS HOURS WHERE I 3178 02:23:37,080 --> 02:23:39,320 LITERALLY I'M AN ACADEMIC NOT A 3179 02:23:39,320 --> 02:23:40,800 DOCTOR BUT CAME IN WITH MAYBE 50 3180 02:23:40,800 --> 02:23:42,120 QUESTIONS. THERE IS NO WAY THIS 3181 02:23:42,120 --> 02:23:43,720 WOMAN WILL SIT WITH ME. WE 3182 02:23:43,720 --> 02:23:45,400 MIGHT HAVE SAT A COUPLE OF HOURS 3183 02:23:45,400 --> 02:23:46,360 THE VERY FIRST TIME. 3184 02:23:46,360 --> 02:23:48,320 >> A BILLION HOURS. 3185 02:23:48,320 --> 02:23:49,760 >> SHE MET AND ANSWERED EVERY 3186 02:23:49,760 --> 02:23:51,720 SINGLE QUESTION. AT THE END SHE 3187 02:23:51,720 --> 02:23:53,160 ASKED, IS THERE MORE? ANYTHING 3188 02:23:53,160 --> 02:23:56,000 ELSE? I HAVE NEVER FELT SO 3189 02:23:56,000 --> 02:23:57,600 CARED FOR THAN I DO WITH ANY 3190 02:23:57,600 --> 02:24:00,400 DOCTOR THAT I SEE AT THE NIH OR 3191 02:24:00,400 --> 02:24:04,800 EVEN I DON'T KNOW IF DR. TOSEY 3192 02:24:04,800 --> 02:24:07,520 IS HERE BUT SHE IS OUR 3193 02:24:07,520 --> 02:24:09,560 ORTHOPEDIC SURGEON. YES. 3194 02:24:09,560 --> 02:24:12,120 PLEASE GIVE IT UP FOR DR. TOSEY. 3195 02:24:12,120 --> 02:24:13,200 >> AUDIENCE: [APPLAUSE]. 3196 02:24:13,200 --> 02:24:14,880 >> SITTING THROUGH WITH US AND 3197 02:24:14,880 --> 02:24:16,320 ANSWERING ALL OUR QUESTIONS IS 3198 02:24:16,320 --> 02:24:17,720 THE PART THAT MAKES ME KNOW SHE 3199 02:24:17,720 --> 02:24:20,360 WILL BE OKAY. DR. BOYCE SAID WE 3200 02:24:20,360 --> 02:24:22,680 HAVE A TEAM FOR HER AND WILL BE 3201 02:24:22,680 --> 02:24:23,960 HER TEAM FOR LIFE. 3202 02:24:23,960 --> 02:24:25,160 >> FOR LIFE? 3203 02:24:25,160 --> 02:24:26,000 >> AUDIENCE: [LAUGHING]. 3204 02:24:26,000 --> 02:24:28,200 >> WELL, THANK YOU GUYS SO MUCH. 3205 02:24:28,200 --> 02:24:32,400 THIS HAS BEEN WONDERFUL TO GET 3206 02:24:32,400 --> 02:24:32,800 YOUR PERSPECTIVE. 3207 02:24:32,800 --> 02:24:33,360 >> THANK YOU. 3208 02:24:33,360 --> 02:24:39,000 >> BIG ROUND AFTER MOF APPLAUS 3209 02:24:39,000 --> 02:24:40,000 THESE GIRLS. 3210 02:24:40,000 --> 02:24:41,000 >> AUDIENCE: [APPLAUSE]. 3211 02:24:41,000 --> 02:24:43,000 >> I HOPE YOU GATHERED FROM THE 3212 02:24:43,000 --> 02:24:45,440 PANEL THIS CONCEPT OF BUILDING 3213 02:24:45,440 --> 02:24:47,720 BELONGING IS IN LINE WITH WHAT 3214 02:24:47,720 --> 02:24:49,240 NIDCR HAS BEEN WORKING TO 3215 02:24:49,240 --> 02:24:51,520 ACHIEVE AND IS WONDERFUL TO HAVE 3216 02:24:51,520 --> 02:24:53,640 PATIENTS HERE AND PATIENT 3217 02:24:53,640 --> 02:24:54,720 ADVOCATES AND FINAL PRESENTATION 3218 02:24:54,720 --> 02:24:57,160 FOR THE DAY IS A VERY SPECIAL 3219 02:24:57,160 --> 02:24:59,880 GUEST. I WILL ASK DR. MIKE 3220 02:24:59,880 --> 02:25:03,200 COLLINS TO INTRODUCE KELLY COHEN 3221 02:25:03,200 --> 02:25:06,240 WHO IS A MOM OF ONE OF OUR 3222 02:25:06,240 --> 02:25:08,240 PATIENTS. KELLY WILL BE THE ONE 3223 02:25:08,240 --> 02:25:10,880 TO INTRODUCE OUR FINAL SPEAKER. 3224 02:25:10,880 --> 02:25:14,520 >> PLEASURE TO INTRODUCE KELLY 3225 02:25:14,520 --> 02:25:16,960 COHEN WHO YOU SAW IN THE VIDEO 3226 02:25:16,960 --> 02:25:20,520 FROM FD/MAS ALLIANCE AND ASKED 3227 02:25:20,520 --> 02:25:24,800 HER TO INTRODUCE DR. KAB ILL KA. 3228 02:25:24,800 --> 02:25:30,440 SHE INTRODUCE MD HE TO DR. 3229 02:25:30,440 --> 02:25:34,200 KABIKKA. IT IS AN INSPIRING 3230 02:25:34,200 --> 02:25:37,160 STORY. ALL THESE PARENTS ARE 3231 02:25:37,160 --> 02:25:38,040 INSPIRING STORIES. 3232 02:25:38,040 --> 02:25:38,600 >> AUDIENCE: [APPLAUSE]. 3233 02:25:38,600 --> 02:25:44,800 >> THANK YOU, MIKE. 3234 02:25:44,800 --> 02:25:47,520 THANK YOU ALL FOR TAKING THE NIH 3235 02:25:47,520 --> 02:25:50,800 AND NIDCR AND PATH OF DOING 3236 02:25:50,800 --> 02:25:52,480 RESEARCH ON MCCUNE-ALBRIGHT 3237 02:25:52,480 --> 02:25:54,440 SYNDROME FOR THE LAST 25 YEARS. 3238 02:25:54,440 --> 02:25:55,760 BECAUSE OF WHAT YOU STARTED HAD 3239 02:25:55,760 --> 02:25:57,880 HERE AND THE NETWORK OF AMAZING 3240 02:25:57,880 --> 02:26:00,240 DOCTORS AND RESEARCHERS YOU HAVE 3241 02:26:00,240 --> 02:26:03,120 PUT TOGETHER MY SON LIAM HAS 3242 02:26:03,120 --> 02:26:05,240 ENJOYED A MUCH IMPROVED QUALITY 3243 02:26:05,240 --> 02:26:09,640 OF LIFE THAN WE COULD HAVE 3244 02:26:09,640 --> 02:26:10,040 IMAGINED. 3245 02:26:10,040 --> 02:26:11,800 HE ALSO HAS THE MOST IMPORTANT 3246 02:26:11,800 --> 02:26:15,560 THING. HE HAS HOPE. HOPE FOR A 3247 02:26:15,560 --> 02:26:17,520 BETTER FUTURE. 3248 02:26:17,520 --> 02:26:21,200 ON A VERY PERSONAL NOTE, DR. 3249 02:26:21,200 --> 02:26:24,400 COLLINS AND DR. BOYCE, YOUR 3250 02:26:24,400 --> 02:26:26,200 TIRELESS EFFORTS FROM EVERY 3251 02:26:26,200 --> 02:26:26,920 PATIENT IN THE UNITED STATES AND 3252 02:26:26,920 --> 02:26:31,000 EVERY FAMILY AND FAMILIES 3253 02:26:31,000 --> 02:26:34,600 ABROAD, WE THANK YOU. 3254 02:26:34,600 --> 02:26:35,440 >> AUDIENCE: [APPLAUSE]. 3255 02:26:35,440 --> 02:26:43,200 >> NOW, I HAVE THE DISTINCT 3256 02:26:43,200 --> 02:26:46,880 HONOR OF INTRODUCING YOU TO DR. 3257 02:26:46,880 --> 02:26:49,520 BRIAN KAB ILL KA, THE KEYNOTE 3258 02:26:49,520 --> 02:26:50,720 SPEAKER TODAY AND WILL DO THIS 3259 02:26:50,720 --> 02:26:53,800 BY WAY OF TELLING YOU THE STORY 3260 02:26:53,800 --> 02:26:57,080 HOW DR. KABILKA BECAME INVOLVED 3261 02:26:57,080 --> 02:27:00,960 WITH THE TEAM HERE. MY SON LIAM 3262 02:27:00,960 --> 02:27:03,680 HAS MCCUNE ALBRIGHT SYNDROME AND 3263 02:27:03,680 --> 02:27:05,320 SYMPTOMATIC SINCE BIRTH HE HAS 3264 02:27:05,320 --> 02:27:07,360 SEVERE PRESENCE OF DISEASE HIS 3265 02:27:07,360 --> 02:27:08,920 INFANCY WASN'T A TYPICAL 3266 02:27:08,920 --> 02:27:10,120 PRESENTATION. THROUGHOUT HIS 3267 02:27:10,120 --> 02:27:12,600 FIRST YEAR OF LIFE LIAM WAS BY 3268 02:27:12,600 --> 02:27:15,520 MY SIDE 247 REQUIRING CONSTANT 3269 02:27:15,520 --> 02:27:17,080 FEEDING. HE WAS ALWAYS IN PAIN. 3270 02:27:17,080 --> 02:27:19,200 GOING FROM DOCTOR TO DOCTOR AND 3271 02:27:19,200 --> 02:27:22,040 GETTING FREQUENTLY MISDIAGNOSED 3272 02:27:22,040 --> 02:27:23,840 OR BRUSHED OFF AND FRACTURED 3273 02:27:23,840 --> 02:27:26,720 EASILY AND FREQUENTLY INCLUDING 3274 02:27:26,720 --> 02:27:29,080 FRACTURING HIS FEMUR MULTIPLE 3275 02:27:29,080 --> 02:27:30,880 TIMES BEFORE HIS FIFTH BIRTHDAY 3276 02:27:30,880 --> 02:27:32,240 EACH TIME REQUIRING COMPLETE 3277 02:27:32,240 --> 02:27:34,280 MOBILIZATIONS FOR WEEKS AT A 3278 02:27:34,280 --> 02:27:36,000 TIME. HAD THYROID REMOVED AT 3279 02:27:36,000 --> 02:27:37,920 AGE 4 THAT IS MUCH EARLIER THAN 3280 02:27:37,920 --> 02:27:40,040 THAT SURGERY IS TYPICALLY 3281 02:27:40,040 --> 02:27:43,240 PERFORMED INCREASING THE RISK OF 3282 02:27:43,240 --> 02:27:44,520 PERMANENT NERVE INJURY. EVERY 3283 02:27:44,520 --> 02:27:48,600 VACATION WE TOOK AS A FAMILY, 3284 02:27:48,600 --> 02:27:51,800 WHICH IS WHERE MY HUSBAND AND I 3285 02:27:51,800 --> 02:27:54,440 WERE INTERVIEWED WAS ALWAYS 3286 02:27:54,440 --> 02:27:57,040 AROUND SURGERY OR GOING TO JAIL 3287 02:27:57,040 --> 02:28:00,680 TO GET HIS THYROID REMOVED. IF 3288 02:28:00,680 --> 02:28:04,080 YOU ASK LIAM ABOUT HIS SUMMER HE 3289 02:28:04,080 --> 02:28:06,520 WILL TALK ABOUT VACATION GOING 3290 02:28:06,520 --> 02:28:10,360 DOWN EARLY OR TO DISNEY OR SEE 3291 02:28:10,360 --> 02:28:12,480 ALLIGATORS. IT IS A WAY OF LIFE 3292 02:28:12,480 --> 02:28:14,080 AS A FAMILY. 3293 02:28:14,080 --> 02:28:18,000 THOSE FIRST YEARS WERE UTTERLY 3294 02:28:18,000 --> 02:28:21,960 EXHAUSTING. I WAS COMPLETELY 3295 02:28:21,960 --> 02:28:23,080 GRIEF-STRICKEN. EVERY NIGHT I 3296 02:28:23,080 --> 02:28:26,960 WOULD HOLD MY BABY IN MY ARMS 3297 02:28:26,960 --> 02:28:28,840 HOPING I COULD DRIP ENOUGH FEEDS 3298 02:28:28,840 --> 02:28:32,200 INTO HIM TO HAVE ENOUGH ENERGY 3299 02:28:32,200 --> 02:28:34,080 FOR THE NEXT DAY. THEY WERE 3300 02:28:34,080 --> 02:28:35,640 DIFFICULT TIMES AND SOMETIMES 3301 02:28:35,640 --> 02:28:37,840 DESPERATE TIMES CREATE DESPERATE 3302 02:28:37,840 --> 02:28:39,760 PEOPLE DOING UNCHARACTERISTIC 3303 02:28:39,760 --> 02:28:43,120 THINGS TO ACCOMPLISH THEIR GOAL. 3304 02:28:43,120 --> 02:28:47,800 MARCH 15TH, 2016 I WAS DOWN A 3305 02:28:47,800 --> 02:28:49,400 RABBIT HOLE SEARCHING 3306 02:28:49,400 --> 02:28:51,800 INFORMATION ON MCCUNE ALBRIGHT 3307 02:28:51,800 --> 02:28:54,800 TRYING TO LEARN MORE ABOUT GENE 3308 02:28:54,800 --> 02:28:58,080 PROTEINS DR. KABILKA'S RESEARCH 3309 02:28:58,080 --> 02:29:00,680 START TODAY POP UP. I WAS 3310 02:29:00,680 --> 02:29:04,080 IMPRESSED AND I SENT AN 3311 02:29:04,080 --> 02:29:05,680 UNSOLICITED E-MAIL TO A NOBLE 3312 02:29:05,680 --> 02:29:07,080 PRIZE WINNER WHY NOT SWING FOR 3313 02:29:07,080 --> 02:29:08,400 THE FENCES? 3314 02:29:08,400 --> 02:29:11,440 AFTER INTRODUCING MYSELF AND SON 3315 02:29:11,440 --> 02:29:13,840 LIAM I WROTE I'M HOPEFUL THERE 3316 02:29:13,840 --> 02:29:14,680 ARE RESEARCHERS LIKE YOURSELF 3317 02:29:14,680 --> 02:29:18,720 WHO MIGHT BE ABLE TO SHED SOME 3318 02:29:18,720 --> 02:29:20,040 INSIGHT INTO THIS VERY 3319 02:29:20,040 --> 02:29:22,800 DEBILITATING SYNDROME IF MCCUNE 3320 02:29:22,800 --> 02:29:24,280 ALBRIGHT AT ALL PEAKS YOUR 3321 02:29:24,280 --> 02:29:25,600 INTEREST LET ME KNOW AND I WILL 3322 02:29:25,600 --> 02:29:28,120 CONNECT YOU WITH THE WORLD'S 3323 02:29:28,120 --> 02:29:32,760 EXPERTS AT NIDCR'S NIH. 3324 02:29:32,760 --> 02:29:34,360 TO MY WONDERMENT JUST A FEW 3325 02:29:34,360 --> 02:29:37,680 SHORT HOURS LATER I RECEIVED A 3326 02:29:37,680 --> 02:29:41,680 REPLY FROM DR. KABILKA THAT I'M 3327 02:29:41,680 --> 02:29:42,880 SURE YOU DON'T KNOW THIS. YOU 3328 02:29:42,880 --> 02:29:45,280 GET THOUSANDS OF E-MAILS AND 3329 02:29:45,280 --> 02:29:46,840 VERY IMPORTANT E-MAILS. 3330 02:29:46,840 --> 02:29:48,920 YOU PROBABLY DON'T REMEMBER THIS 3331 02:29:48,920 --> 02:29:50,800 ONE, BUT IT MEANT MORE THAN 3332 02:29:50,800 --> 02:29:53,160 ANYTHING TO ME. 3333 02:29:53,160 --> 02:29:54,200 THANK YOU. 3334 02:29:54,200 --> 02:29:56,160 DEAR KELLY, THANK YOU FOR YOUR 3335 02:29:56,160 --> 02:29:58,080 E-MAIL OUR RESEARCH INVOLVES 3336 02:29:58,080 --> 02:30:00,400 STUDYING RECEPTORS THAT ACTIVATE 3337 02:30:00,400 --> 02:30:01,920 GS ALPHA. THIS IS OF INTEREST 3338 02:30:01,920 --> 02:30:03,480 TO ME. I WOULD BE INTERESTED IN 3339 02:30:03,480 --> 02:30:06,920 LEARNING MORE ABOUT ONGOING 3340 02:30:06,920 --> 02:30:09,160 NIH-FUNDED RESEARCH EFFORTS. 3341 02:30:09,160 --> 02:30:13,200 BEST WISHES, BRIAN. REALLY? 3342 02:30:13,200 --> 02:30:14,880 [LAUGHING]. 3343 02:30:14,880 --> 02:30:15,800 WOW! 3344 02:30:15,800 --> 02:30:17,920 HOPE! 3345 02:30:17,920 --> 02:30:21,840 AFTER THAT, THE FD/MAS TEAM FROM 3346 02:30:21,840 --> 02:30:27,000 THE NIDCR NOW HAD A NOBLE 3347 02:30:27,000 --> 02:30:28,840 LAUREATE CONTRIBUTING WITH THEM. 3348 02:30:28,840 --> 02:30:32,560 DR. BRIAN KABILKA IS CHAIR IN 3349 02:30:32,560 --> 02:30:36,920 CARDIOLOGY AND PROFESSOR OF 3350 02:30:36,920 --> 02:30:37,480 MOLECULAR AND CELLULAR 3351 02:30:37,480 --> 02:30:39,880 PHYSIOLOGY AT STANFORD 3352 02:30:39,880 --> 02:30:42,880 UNIVERSITY SHARING 2012 NOBLE 3353 02:30:42,880 --> 02:30:45,800 PRIZE IN CHEMISTRY FOR STUDYING 3354 02:30:45,800 --> 02:30:48,120 -- SUCCESSFULLY IDENTIFIED GENE 3355 02:30:48,120 --> 02:30:50,280 THAT REGULATES FORMATION OF THE 3356 02:30:50,280 --> 02:30:53,040 RECEPTOR FOR HORMONE ADRENALINE. 3357 02:30:53,040 --> 02:30:55,760 IT WAS LATER DISCOVERED THERE IS 3358 02:30:55,760 --> 02:30:58,080 AN ENTIRE FAMILY OF RECEPTORS 3359 02:30:58,080 --> 02:31:00,600 THAT LOOK AND ACT IN SIMILAR 3360 02:31:00,600 --> 02:31:01,360 WAYS. 3361 02:31:01,360 --> 02:31:03,600 G-PROTEIN COUPLED RECEPTORS 3362 02:31:03,600 --> 02:31:06,000 APPROXIMATELY HALF OF ALL OF OUR 3363 02:31:06,000 --> 02:31:07,600 MEDICATIONS USED TODAY MAKE USE 3364 02:31:07,600 --> 02:31:09,920 OF THIS KIND OF RECEPTOR. IT IS 3365 02:31:09,920 --> 02:31:12,400 MY DISTINCT HONOR AND PRIVILEGE 3366 02:31:12,400 --> 02:31:21,160 TO INTRODUCE YOU TO DR. BRIAN 3367 02:31:21,160 --> 02:31:21,880 KOBILKA. 3368 02:31:21,880 --> 02:31:22,960 >> AUDIENCE: [APPLAUSE]. 3369 02:31:22,960 --> 02:31:33,240 >> THANK YOU. 3370 02:32:03,240 --> 02:32:06,240 >> SO, THANK YOU FOR THAT 3371 02:32:06,240 --> 02:32:07,520 WONDERFUL INTRODUCTION. I'M 3372 02:32:07,520 --> 02:32:09,480 VERY GRATEFUL THAT YOU CAUGHT ME 3373 02:32:09,480 --> 02:32:12,840 ON A GOOD DAY RESPONDING TO MY 3374 02:32:12,840 --> 02:32:13,480 E-MAIL. 3375 02:32:13,480 --> 02:32:14,200 >> AUDIENCE: [LAUGHING]. 3376 02:32:14,200 --> 02:32:17,560 >> I HATE TO ADMIT I'M NOT SO 3377 02:32:17,560 --> 02:32:19,840 GOOD AT RETURNING E-MAILS AND 3378 02:32:19,840 --> 02:32:22,080 ALSO WANT TO THANK MICHAEL AND 3379 02:32:22,080 --> 02:32:25,040 HIS COLLEAGUES FOR INVITING ME 3380 02:32:25,040 --> 02:32:26,040 TO THE CELEBRATION. 3381 02:32:26,040 --> 02:32:28,400 I'M HONORED TO BE HERE. IT HAS 3382 02:32:28,400 --> 02:32:32,040 BEEN A LEARNING EXPERIENCE FOR 3383 02:32:32,040 --> 02:32:32,560 ME. 3384 02:32:32,560 --> 02:32:36,720 SO, IT IS -- IT IS AMAZING TO 3385 02:32:36,720 --> 02:32:39,520 SEE HOW THIS SPECIAL UNIT WAS 3386 02:32:39,520 --> 02:32:41,360 PUT TOGETHER AND HOW THEY 3387 02:32:41,360 --> 02:32:45,160 LEARNED SO MUCH ABOUT THIS 3388 02:32:45,160 --> 02:32:48,400 DISEASE JUST BY CAREFUL 3389 02:32:48,400 --> 02:32:50,240 HISTORIES OF PATIENTS OVER MANY 3390 02:32:50,240 --> 02:32:53,440 YEARS. SO, ANYWAY, 3391 02:32:53,440 --> 02:32:54,680 UNFORTUNATELY, MY RESEARCH 3392 02:32:54,680 --> 02:32:57,240 DOESN'T DIRECTLY CONTRIBUTE TO 3393 02:32:57,240 --> 02:33:00,840 THIS. THERE IS A RELATIONSHIP 3394 02:33:00,840 --> 02:33:03,160 IN THAT I HAVE BEEN VERY 3395 02:33:03,160 --> 02:33:06,480 INTERESTED IN UNDERSTANDING HOW 3396 02:33:06,480 --> 02:33:07,120 G-PROTEIN-COUPLED-RECEPTORS WORK 3397 02:33:07,120 --> 02:33:08,520 AND THESE ARE RECEPTORS THAT 3398 02:33:08,520 --> 02:33:10,680 HAVE ACTUALLY THE PHYSIOLOGICAL 3399 02:33:10,680 --> 02:33:13,040 ROLE OF ACTIVATING G-PROTEINS 3400 02:33:13,040 --> 02:33:16,200 AND I WOULD LIKE TO TELL YOU 3401 02:33:16,200 --> 02:33:17,680 ABOUT TODAY IS OUR INTEREST IN 3402 02:33:17,680 --> 02:33:20,200 USING WHAT WE LEARNED TO DEVELOP 3403 02:33:20,200 --> 02:33:22,040 DRUGS FOR THESE RECEPTORS. 3404 02:33:22,040 --> 02:33:24,960 SO, I WANT TO TALK ABOUT THE 3405 02:33:24,960 --> 02:33:27,280 CHALLENGES OF DRUG DISCOVERY AND 3406 02:33:27,280 --> 02:33:31,400 FIRST WILL GIVE A BRIEF OVERVIEW 3407 02:33:31,400 --> 02:33:35,200 WHAT G COUPLED PROTEIN RECEPTORS 3408 02:33:35,200 --> 02:33:37,640 ARE AND DISCUSS MAJOR CHALLENGES 3409 02:33:37,640 --> 02:33:41,200 IN DRUG DISCOVERY AND TALK A 3410 02:33:41,200 --> 02:33:42,800 LITTLE ABOUT HOW STRUCTURAL 3411 02:33:42,800 --> 02:33:45,800 BIOLOGY AND WORK THAT WE DO 3412 02:33:45,800 --> 02:33:48,680 MIGHT BEGIN TO ADDRESS SOME OF 3413 02:33:48,680 --> 02:33:50,760 THE CHALLENGES IN DISCOVERING 3414 02:33:50,760 --> 02:33:52,800 DRUGS FOR RECEPTORS. 3415 02:33:52,800 --> 02:33:57,320 I WILL USE PRIMARILY THE MIU 3416 02:33:57,320 --> 02:33:59,840 OPEN YET RECEPTOR AS A MODEL 3417 02:33:59,840 --> 02:34:01,760 SYSTEM FOR THIS. YOU WILL 3418 02:34:01,760 --> 02:34:03,160 PROBABLY UNDERSTAND WHY IN A 3419 02:34:03,160 --> 02:34:08,720 LITTLE BIT. G-PROTEINED COUPLED 3420 02:34:08,720 --> 02:34:10,480 RECEPTORS AND MAJORITY OF 3421 02:34:10,480 --> 02:34:13,480 HORMONES IN NEUROTRANSMIT IRS 3422 02:34:13,480 --> 02:34:16,800 AND PARADIGM FOR HOW THEY WORK, 3423 02:34:16,800 --> 02:34:20,960 THIS WAS WORKED OUT MANY YEARS 3424 02:34:20,960 --> 02:34:22,880 AGO SHOWN IN BOTTOM WHERE 3425 02:34:22,880 --> 02:34:24,880 RECEPTORS ARE ACTIVATED BY 3426 02:34:24,880 --> 02:34:27,800 HORMONE OR NEUROTRANSMITTER AND 3427 02:34:27,800 --> 02:34:31,640 BETA RECEPTOR IS ACTIVATED IN 3428 02:34:31,640 --> 02:34:34,440 ADRENALINE AND G-PROTEINS 3429 02:34:34,440 --> 02:34:36,800 CONSIST OF THREE COMPONENTS 3430 02:34:36,800 --> 02:34:40,000 ALPHA, BETA AND GAMMA SUBUNIT. 3431 02:34:40,000 --> 02:34:43,560 ALPHA IS ONE MUTATED IN MCCUNE 3432 02:34:43,560 --> 02:34:45,600 ALBRIGHT SYNDROME AND UPON 3433 02:34:45,600 --> 02:34:48,080 ACTIVATION G-PROTEIN RELEASES 3434 02:34:48,080 --> 02:34:52,320 GDP AND BINDS GTP AND GOES ON TO 3435 02:34:52,320 --> 02:34:56,640 SPLIT INTO TWO COMPONENTS ALPHA 3436 02:34:56,640 --> 02:35:01,320 SUBUNIT AND BETA GAMMA SUBUNIT 3437 02:35:01,320 --> 02:35:04,400 THAT MODIFY VARIOUS ENZYMES AND 3438 02:35:04,400 --> 02:35:08,560 CHANNELS IN CELL SHOWN IN GS 3439 02:35:08,560 --> 02:35:13,840 ACTIVATING A DENDENO -- AND SUBS 3440 02:35:13,840 --> 02:35:16,360 REASSEMBLE AND CYCLE CAN BEGIN 3441 02:35:16,360 --> 02:35:17,040 AGAIN. 3442 02:35:17,040 --> 02:35:21,000 SO, IN ADDITION TO BEING 3443 02:35:21,000 --> 02:35:23,200 IMPORTANT FOR MEDIATED RESPONSE 3444 02:35:23,200 --> 02:35:28,080 HORMONES AND NEUROTRANSMITTERS 3445 02:35:28,080 --> 02:35:29,760 THEY MEDIATE SENSE OF SIGHT, 3446 02:35:29,760 --> 02:35:31,560 SMELL AND SOME TASTE. THIS IS 3447 02:35:31,560 --> 02:35:33,920 FAMILY TREE AND OVER 800 MEMBERS 3448 02:35:33,920 --> 02:35:37,520 AND 800 G-PROTEIN COUPLED 3449 02:35:37,520 --> 02:35:39,600 RECEPTORS IN THE FAMILY TREE. 3450 02:35:39,600 --> 02:35:42,640 THE MAJORITY OF THESE, THE 3451 02:35:42,640 --> 02:35:43,760 LARGEST FRACTION OF THESE ARE 3452 02:35:43,760 --> 02:35:46,640 FOR SENSE OF SMELL AND ROUGHLY 3453 02:35:46,640 --> 02:35:49,360 400 OLFACTORY RECEPTORS THAT 3454 02:35:49,360 --> 02:35:52,760 THERE ARE FOUR RECEPTORS 3455 02:35:52,760 --> 02:35:56,360 INVOLVED IN VISION. 3456 02:35:56,360 --> 02:35:58,720 SO, THE LARGEST SUBFAMILY AND 3457 02:35:58,720 --> 02:36:00,920 THERE IS FIVE SUBFAMILIES AND 3458 02:36:00,920 --> 02:36:02,840 LARGEST IS WHAT WE CALL FAMILY A 3459 02:36:02,840 --> 02:36:05,520 THAT INCLUDES RECEPTORS FOR 3460 02:36:05,520 --> 02:36:08,600 WHICH MY LAB IS REALLY FOCUSED 3461 02:36:08,600 --> 02:36:11,760 ON ANURGIC RECEPTORS DOPAMINE 3462 02:36:11,760 --> 02:36:13,760 AND CER TONIN AND THEY ARE SOME 3463 02:36:13,760 --> 02:36:16,320 OF THE HORMONES AND 3464 02:36:16,320 --> 02:36:18,040 NEUROTRANSMITTERS YOU MIGHT BE 3465 02:36:18,040 --> 02:36:22,080 FAMILIAR WITH AND ALSO RESPOND 3466 02:36:22,080 --> 02:36:32,360 TO OPIATES AND CAN ABINNOIDS AND 3467 02:36:32,360 --> 02:36:37,440 OPIATE RECEPTOR FAMILY CONSISTS 3468 02:36:37,440 --> 02:36:47,920 OF FOUR MEMBERS AND I WILL 3469 02:36:52,160 --> 02:36:53,680 BRIEFLY MENTION INTERESTING 3470 02:36:53,680 --> 02:36:54,840 MEMBER OF THIS FAMILY THAT 3471 02:36:54,840 --> 02:36:57,800 INCLUDES R--EE CREPTORS FOR 3472 02:36:57,800 --> 02:37:01,160 GLUCAGON GLP THAT YOU MIGHT HAVE 3473 02:37:01,160 --> 02:37:04,120 HEARD OF ALL OF THE RECENT NEWS 3474 02:37:04,120 --> 02:37:07,600 ABOUT DRUGS TARGETING THIS 3475 02:37:07,600 --> 02:37:12,120 RECEPTOR BEING EFFECTIVE IN 3476 02:37:12,120 --> 02:37:14,800 TREATING OBESITY AND PARA 3477 02:37:14,800 --> 02:37:15,720 THYROID HORMONE IMPORTANT IN 3478 02:37:15,720 --> 02:37:20,400 BONE METABOLISM AS WELL. 3479 02:37:20,400 --> 02:37:22,120 BECAUSE THEY PLAY SUCH AN 3480 02:37:22,120 --> 02:37:24,520 IMPORTANT ROLE IN MEDIATING 3481 02:37:24,520 --> 02:37:26,920 CELLULAR RESPONSES TO 3482 02:37:26,920 --> 02:37:28,080 NEUROTRANSMITTERS LARGER CLASS 3483 02:37:28,080 --> 02:37:31,040 OF TARGETS FOR PHARMACEUTICAL 3484 02:37:31,040 --> 02:37:33,640 INDUSTRY AND ROUGHLY TLAE 3% OF 3485 02:37:33,640 --> 02:37:36,560 DRUGS ON MARKET TARGET G COUPLED 3486 02:37:36,560 --> 02:37:40,560 PROTEIN RECEPTORS. HOWEVER, 3487 02:37:40,560 --> 02:37:41,800 SUCCESS RATE FOR CONSIDERING HOW 3488 02:37:41,800 --> 02:37:45,120 MANY RECEPTORS THERE ARE HAS 3489 02:37:45,120 --> 02:37:46,520 BEEN SOMEWHAT DISAPPOINTING. I 3490 02:37:46,520 --> 02:37:50,000 WILL TALK ABOUT THAT A LITTLE 3491 02:37:50,000 --> 02:37:53,480 BIT. 3492 02:37:53,480 --> 02:37:56,560 MY LAB HAS BEEN VERY INTERESTED 3493 02:37:56,560 --> 02:37:58,360 IN UNDERSTANDING STRUCTURAL 3494 02:37:58,360 --> 02:38:00,160 BASIS FOR RECEPTOR FUNCTION. 3495 02:38:00,160 --> 02:38:02,880 WE HAVE USED A VARIETY OF 3496 02:38:02,880 --> 02:38:04,840 DIFFERENT APPROACHES TO ELUS 3497 02:38:04,840 --> 02:38:08,240 DATE THE STRUCTURES TO TRY TO 3498 02:38:08,240 --> 02:38:10,120 UNDERSTAND HOW STRUCTURE 3499 02:38:10,120 --> 02:38:12,760 DICTATES FUNCTION AND THESE ARE 3500 02:38:12,760 --> 02:38:14,960 SOME LANDMARKS IN MY LAB IN 3501 02:38:14,960 --> 02:38:16,360 TERMS OF BEGINNING TO UNDERSTAND 3502 02:38:16,360 --> 02:38:19,240 HOW RECEPTORS WORK AND THEY ARE 3503 02:38:19,240 --> 02:38:21,200 FIRST STRUCTURE OF RECEPTOR THAT 3504 02:38:21,200 --> 02:38:25,400 IS ABSTAINED BY X-RAY 3505 02:38:25,400 --> 02:38:26,720 CYSTOGRAPHY AND THE RECEPTOR 3506 02:38:26,720 --> 02:38:30,440 THAT IS GAMMA RECEPTOR FOR 3507 02:38:30,440 --> 02:38:30,760 ADRENALINE. 3508 02:38:30,760 --> 02:38:32,840 AND WE SUBSEQUENTLY WERE ABLE TO 3509 02:38:32,840 --> 02:38:35,040 GET A STRUCTURE OF AN ACTIVE 3510 02:38:35,040 --> 02:38:38,440 STATE STABILIZED BY AN ANTIBODY 3511 02:38:38,440 --> 02:38:41,480 AND IN 2011 A STRUCTURE OF 3512 02:38:41,480 --> 02:38:43,920 RECEPTOR CAUGHT IN ACT OF 3513 02:38:43,920 --> 02:38:51,120 ACTIVATING G-PROTEIN GS. 3514 02:38:51,120 --> 02:38:53,840 SO TO UNDERSTAND HOW THIS WORKS, 3515 02:38:53,840 --> 02:38:56,320 WE SORT OF LOOK ATTACKTIVE AND 3516 02:38:56,320 --> 02:38:57,680 INACTIVE STATES TO TRY TO 3517 02:38:57,680 --> 02:38:59,200 UNDERSTAND MAJOR CHANGES OF 3518 02:38:59,200 --> 02:39:01,120 STRUCTURE OF RECEPTOR AND HOW IT 3519 02:39:01,120 --> 02:39:03,120 LEADS TO CHANGE OFS IN STRUCTURE 3520 02:39:03,120 --> 02:39:05,440 OF G-PROTEIN AND WHAT I WILL DO 3521 02:39:05,440 --> 02:39:09,600 IN THE NEXT FEW MINUTES IS JUST 3522 02:39:09,600 --> 02:39:11,320 DISCUSS THE RECEPTOR THAT IS 3523 02:39:11,320 --> 02:39:14,720 GOING FROM INACTIVE STATE TO 3524 02:39:14,720 --> 02:39:15,680 ACTIVE STATE. 3525 02:39:15,680 --> 02:39:16,880 MAJOR STRUCTURAL CHANGES THAT 3526 02:39:16,880 --> 02:39:18,320 TAKE PLACE. 3527 02:39:18,320 --> 02:39:21,960 FIRST OF ALL, G-PROTEIN COUPLED 3528 02:39:21,960 --> 02:39:23,640 RECEPTORS CONSIST OF SEVERAL 3529 02:39:23,640 --> 02:39:26,640 MEMBRANE SPANNING DOMAINS THAT 3530 02:39:26,640 --> 02:39:30,080 ARE ALPHA HEELISIES. 3531 02:39:30,080 --> 02:39:33,000 THE MEMBRANE SPANNING DOMAINS ON 3532 02:39:33,000 --> 02:39:35,240 EXTRA CELLULAR SIDE FORM A 3533 02:39:35,240 --> 02:39:37,200 POCKET BINDING HORMONE 3534 02:39:37,200 --> 02:39:37,520 ADRENALINE. 3535 02:39:37,520 --> 02:39:39,440 UPON BINDING HORMONE YOU CAN SEE 3536 02:39:39,440 --> 02:39:41,320 THERE ARE RELATIVELY SMALL 3537 02:39:41,320 --> 02:39:43,040 STRUCTURAL CHANGES THAT TAKE 3538 02:39:43,040 --> 02:39:45,480 PLACE AS A RESULT OF HORMONE 3539 02:39:45,480 --> 02:39:48,440 BINDING THAT PROPAGATE TO MUCH 3540 02:39:48,440 --> 02:39:50,760 LARGER STRUCTURAL CHANGES ON 3541 02:39:50,760 --> 02:39:53,640 INSIDE OF THE CELL. 3542 02:39:53,640 --> 02:39:57,880 THEY CREATE A CAVITY FOR BINDING 3543 02:39:57,880 --> 02:40:01,640 OF THIS LAST COMPONENT OF THE 3544 02:40:01,640 --> 02:40:04,640 ALPHA -- THE RAFT AMEAN OF GS 3545 02:40:04,640 --> 02:40:07,000 ALPHA OR ALPHA SUBUNIT. 3546 02:40:07,000 --> 02:40:09,280 SO, I WANT YOU TO NOTE THAT OF 3547 02:40:09,280 --> 02:40:11,080 ALL OF THE STRUCTURAL CHANGES 3548 02:40:11,080 --> 02:40:14,280 THAT TAKE PLACE, LARGEST THAT IS 3549 02:40:14,280 --> 02:40:16,360 OCCURRING IN THIS TRANSMEMBRANE 3550 02:40:16,360 --> 02:40:19,000 THAT WE CALL TRANSMEMBRANE 6 3551 02:40:19,000 --> 02:40:20,920 THAT MOVES OUT. THIS HELIX FROM 3552 02:40:20,920 --> 02:40:23,720 THE G-PROTEIN MOVES IN. THIS 3553 02:40:23,720 --> 02:40:29,160 ALLOWS THE GDP TO BE RELEASED IN 3554 02:40:29,160 --> 02:40:33,720 GDP DIVIDE. 3555 02:40:33,720 --> 02:40:36,400 SO, AT THE TIME WE OBTAINED 3556 02:40:36,400 --> 02:40:38,760 STRUCTURE OF BETA TWO RECEPTOR, 3557 02:40:38,760 --> 02:40:42,600 IT WAS ONE RECEPTOR OF THE 800 3558 02:40:42,600 --> 02:40:45,320 COUPLING TO ONE SUBTYPE OF 3559 02:40:45,320 --> 02:40:47,680 G-PROTEIN AND THERE ARE MULTIPLE 3560 02:40:47,680 --> 02:40:50,880 G-PROTEIN SUBTYPES. 3561 02:40:50,880 --> 02:40:56,960 WE WANTED TO KNOW WHETHER WHAT 3562 02:40:56,960 --> 02:40:59,240 WE LEARNED ABOUT BETA TWO 3563 02:40:59,240 --> 02:41:01,120 RECEPTOR APPLIED TO LARGER 3564 02:41:01,120 --> 02:41:04,400 FAMILY OF BETA 2 COUPLED 3565 02:41:04,400 --> 02:41:06,200 RECEPTORS AND WANTED TO LEARN 3566 02:41:06,200 --> 02:41:09,960 ABOUT WHY BETA TWO RECEPTOR 3567 02:41:09,960 --> 02:41:11,120 ACTIVATED SPECIFICALLY THIS 3568 02:41:11,120 --> 02:41:16,120 PROTEIN GS AS TO MANY OTHER 3569 02:41:16,120 --> 02:41:17,560 G-PROTEIN SUBTYPES. 3570 02:41:17,560 --> 02:41:21,800 SO, WE STARTED OBTAINING 3571 02:41:21,800 --> 02:41:24,360 STRUCTURES OF OTHER G-PROTEIN 3572 02:41:24,360 --> 02:41:26,360 COUPLED RECEPTORS COUPLED TO 3573 02:41:26,360 --> 02:41:30,000 OTHER G-PROTEINS AND INITIAL 3574 02:41:30,000 --> 02:41:32,320 STRUCTURE BY CRYSTALO GRAPHY AND 3575 02:41:32,320 --> 02:41:34,920 NEVER ABLE TO DO ANY OF THESE 3576 02:41:34,920 --> 02:41:37,360 OTHER COMPLEXES AND DOO YOU TO 3577 02:41:37,360 --> 02:41:41,840 ADVANCES IN CRYOELECTRICAL MIKE 3578 02:41:41,840 --> 02:41:45,520 ROSS COPY IN 2017 ABLE TO USE 3579 02:41:45,520 --> 02:41:48,040 CRYO-EM TO OBTAIN STRUCTURES OF 3580 02:41:48,040 --> 02:41:49,720 RECEPTORS AND G-PROTEIN COMPLEX 3581 02:41:49,720 --> 02:41:51,440 STRUCTURES AND ARE PROBABLY 3582 02:41:51,440 --> 02:41:58,000 LITERALLY OVER 100 NOW SOLVED BY 3583 02:41:58,000 --> 02:42:00,080 CRYOELECTRON MICROSCOPY AND 3584 02:42:00,080 --> 02:42:04,920 POINTING OUT ROGER WHO IS AN 3585 02:42:04,920 --> 02:42:08,520 EXPERT IN G-PROTEINS KNOWING 3586 02:42:08,520 --> 02:42:12,160 ABOUT GS MUTATIONS THAN I DO WAS 3587 02:42:12,160 --> 02:42:14,600 A CRITICAL COLLEAGUE IN 3588 02:42:14,600 --> 02:42:18,600 OBTAINING RECEPTORS OF COMPLEXES 3589 02:42:18,600 --> 02:42:20,720 AT STANFORD WHO HELPED US TO GET 3590 02:42:20,720 --> 02:42:25,080 ALL STRUCTURES BY CRYOELECTRON 3591 02:42:25,080 --> 02:42:26,560 MICROSCOPY AND WHAT DO WE LEARN 3592 02:42:26,560 --> 02:42:28,480 FROM THESE STRUCTURES? 3593 02:42:28,480 --> 02:42:31,560 SO, FIRST OF ALL, NUCLEOTIDE 3594 02:42:31,560 --> 02:42:34,000 FREE. ALL THESE STRUCTURES WERE 3595 02:42:34,000 --> 02:42:35,320 OBTAINED IN AN UNUSUAL STATE 3596 02:42:35,320 --> 02:42:38,480 THAT WE HAD TO GET RID OF 3597 02:42:38,480 --> 02:42:40,400 NUCLEOTIDES TO MAKE SURE ONCE 3598 02:42:40,400 --> 02:42:45,680 GDP WAS RELEASED THAT GTP DIDN'T 3599 02:42:45,680 --> 02:42:48,920 PINED AND COMPLEXES ARE 3600 02:42:48,920 --> 02:42:50,600 NUCLEOTIDE FREE AND ARE VERY 3601 02:42:50,600 --> 02:42:53,000 SIMILAR FOR FAMILY AGING PROTEIN 3602 02:42:53,000 --> 02:42:55,760 COUPLE THE RECEPTORS THAT REALLY 3603 02:42:55,760 --> 02:42:58,240 DIDN'T DEPEND ON G-PROTEIN AND 3604 02:42:58,240 --> 02:43:00,640 STRUCTURAL CHANGES OF G-PROTEIN 3605 02:43:00,640 --> 02:43:01,840 WERE SAME AND STRUCTURAL CHANGES 3606 02:43:01,840 --> 02:43:04,360 IN RECEPTOR WERE THE SAME. 3607 02:43:04,360 --> 02:43:06,880 WHAT I MENTIONED EARLIER ON THAT 3608 02:43:06,880 --> 02:43:08,960 THERE IS ANOTHER FAMILY, FAMILY 3609 02:43:08,960 --> 02:43:12,000 B. THIS FAMILY PLAYS A ROLE AS 3610 02:43:12,000 --> 02:43:15,440 I MENTIONED MINERAL METABOLISM. 3611 02:43:15,440 --> 02:43:16,880 AND THE STRUCTURAL CHANGES IN 3612 02:43:16,880 --> 02:43:19,120 FAMILY B ARE SIMILAR BUT 3613 02:43:19,120 --> 02:43:21,240 ACTUALLY MORE DRAMATIC AND I 3614 02:43:21,240 --> 02:43:23,560 WANTED TO BRIEFLY SHOW AN 3615 02:43:23,560 --> 02:43:23,800 EXAMPLE. 3616 02:43:23,800 --> 02:43:26,400 SO, OUR FAMILY B RECEPTOR WE 3617 02:43:26,400 --> 02:43:28,840 STUDY IS GLUCAGON RECEPTOR THAT 3618 02:43:28,840 --> 02:43:32,400 IS TRURLLY VERY SIMILAR TO 3619 02:43:32,400 --> 02:43:34,120 PARATHYROID HORMONE RECEPTOR 3620 02:43:34,120 --> 02:43:37,720 THAT WE KNOW IS IMPORTANT IN 3621 02:43:37,720 --> 02:43:39,000 MINERAL METABOLISM AND I WANT TO 3622 02:43:39,000 --> 02:43:41,200 COMPARE THE ACTIVATION OF THE 3623 02:43:41,200 --> 02:43:44,360 BETA TWO RECEPTOR THAT YOU CAN 3624 02:43:44,360 --> 02:43:47,640 SEE TRANSMEMBRANE 6 FOR BETA TWO 3625 02:43:47,640 --> 02:43:50,720 RECEPTOR WITH A GRADUAL OUTWARD 3626 02:43:50,720 --> 02:43:52,360 BENDING AS CONSEQUENCE OF 3627 02:43:52,360 --> 02:43:53,480 HORMONE BINDING. 3628 02:43:53,480 --> 02:43:57,200 IN CONTRAST FAMILY B RECEPTORS 3629 02:43:57,200 --> 02:43:59,720 PARATHYROID RECEPTOR AND 3630 02:43:59,720 --> 02:44:02,320 GLUCAGON RECEPTOR HAVE A 3631 02:44:02,320 --> 02:44:05,440 DRAMATIC DISRUPTION IN 3632 02:44:05,440 --> 02:44:07,680 TRANSMEMBRANE 6 AND UNFAVORABLE 3633 02:44:07,680 --> 02:44:09,360 VERY -- THERE IS HIGH ENERGY 3634 02:44:09,360 --> 02:44:11,200 BARRIER TO BE ABLE TO ACCOMPLISH 3635 02:44:11,200 --> 02:44:14,560 THIS. IT IS ASSOCIATED WITH 3636 02:44:14,560 --> 02:44:17,360 VERY DIFFERENT KINETICS BETWEEN 3637 02:44:17,360 --> 02:44:20,040 FAMILY A AND B RECEPTORS 3638 02:44:20,040 --> 02:44:22,840 INCLUDING VERY PROLONGED 3639 02:44:22,840 --> 02:44:25,160 ACTIVATION AND VERY INEFFICIENT 3640 02:44:25,160 --> 02:44:26,920 ACTIVATION AND PROLONGED 3641 02:44:26,920 --> 02:44:28,600 ACTIVATION. NOT ONLY DOES IT 3642 02:44:28,600 --> 02:44:31,720 TAKEN EARTH JI TO CAUSE THE 3643 02:44:31,720 --> 02:44:32,800 STRUCTURAL CHANGE BUT ALSO MAKES 3644 02:44:32,800 --> 02:44:35,800 IT MORE DIFFICULT TO RETURN TO 3645 02:44:35,800 --> 02:44:38,120 INACTIVE STATE. 3646 02:44:38,120 --> 02:44:39,680 SO, WE THINK THAT THIS MAY PLAY 3647 02:44:39,680 --> 02:44:44,480 A ROLE PARTICULARLY IN FAMILY B 3648 02:44:44,480 --> 02:44:47,920 RECEPTORS FOR ROLE IN 3649 02:44:47,920 --> 02:44:50,120 MAINTAINING CARBOHYDRATE AND 3650 02:44:50,120 --> 02:44:50,800 MINERAL BALANCE. 3651 02:44:50,800 --> 02:44:53,280 SO, THE STRUCTURAL CHANGES IN 3652 02:44:53,280 --> 02:44:54,840 G-PROTEINS AND THREE MAJOR 3653 02:44:54,840 --> 02:44:57,440 CLASSES OF G-PROTEINS GS AND 3654 02:44:57,440 --> 02:45:00,160 GQ11 AND GI FAMILY UPON 3655 02:45:00,160 --> 02:45:03,240 ACTIVATION ARE SIMILAR AND ALPHA 3656 02:45:03,240 --> 02:45:05,800 HELICAL DOMAIN OF G-PROTEINS AND 3657 02:45:05,800 --> 02:45:09,560 ALPHA SUBUNIT SHOWN HERE AS TWO 3658 02:45:09,560 --> 02:45:13,240 COMPONENTS AN RAS COMPONENT AND 3659 02:45:13,240 --> 02:45:15,880 ALPHA HELICAL DOMAIN THAT IS 3660 02:45:15,880 --> 02:45:18,120 VERY FLEXIBLE ONCE RECEPTOR IS 3661 02:45:18,120 --> 02:45:22,560 ACTIVATED IT BECOMES VERY 3662 02:45:22,560 --> 02:45:22,920 DYNAMIC. 3663 02:45:22,920 --> 02:45:24,160 WHAT WAS A LITTLE DISAPPOINTING 3664 02:45:24,160 --> 02:45:28,120 IS AFTER GETTING ALL OF THE 3665 02:45:28,120 --> 02:45:29,040 COMPLEXES WE STILL DON'T 3666 02:45:29,040 --> 02:45:32,640 UNDERSTAND COUPLING SPECIFICITY 3667 02:45:32,640 --> 02:45:35,640 AND UNDERSTAND WHY A PARTICULAR 3668 02:45:35,640 --> 02:45:39,160 GCPR WILL PREFER COUPLING TO 3669 02:45:39,160 --> 02:45:41,240 SPECIFIC G-PROTEIN AND WILL BE 3670 02:45:41,240 --> 02:45:42,760 DETERMINED BY A SORT OF 3671 02:45:42,760 --> 02:45:43,920 INTERMEDIATE STATE AND WE HAVE 3672 02:45:43,920 --> 02:45:46,280 OTHER KINDS OF DATA I WON'T HAVE 3673 02:45:46,280 --> 02:45:48,680 TIME TO TELL BUT WHERE WE HAVE 3674 02:45:48,680 --> 02:45:50,160 ACTUALLY EVIDENCE FOR TWO 3675 02:45:50,160 --> 02:45:52,080 INTERMEDIATE STATES THAT WE 3676 02:45:52,080 --> 02:45:54,720 BELIEVE INTERMEDIATE STATES ARE 3677 02:45:54,720 --> 02:45:55,960 PROBABLY DETERMINING WHICH 3678 02:45:55,960 --> 02:45:57,520 G-PROTEIN IT PREFERS AND BY TIME 3679 02:45:57,520 --> 02:46:00,960 IT GETS TO NUCLEOTIDE FREE STATE 3680 02:46:00,960 --> 02:46:04,440 THAT DETERMINATION HAS ALREADY 3681 02:46:04,440 --> 02:46:06,680 OCCURRED. 3682 02:46:06,680 --> 02:46:09,560 SO, NOW I WOULD LIKE TO MOVE ON 3683 02:46:09,560 --> 02:46:12,880 AND TALK ABOUT CHALLENGES IN 3684 02:46:12,880 --> 02:46:15,040 DRUG DISCOVERY AND WONDERFUL 3685 02:46:15,040 --> 02:46:17,240 RECEPTORS AND TARGETS AND TURNS 3686 02:46:17,240 --> 02:46:19,520 OUT THAT THEY HAVE A VERY 3687 02:46:19,520 --> 02:46:20,520 COMPLEX SIGNALING PATHWAYS. 3688 02:46:20,520 --> 02:46:22,520 WHAT I SHOWED YOU IN THE FIRST 3689 02:46:22,520 --> 02:46:27,200 FEW SLIDES WERE SINGLE RECEPTOR 3690 02:46:27,200 --> 02:46:29,640 COUPLING TO SINGLE G2 PROTEIN 3691 02:46:29,640 --> 02:46:32,360 THAT DOESN'T APPLY TO ME WITH 3692 02:46:32,360 --> 02:46:35,960 MANY RECEPTORS [INDISCERNIBLE] 3693 02:46:35,960 --> 02:46:38,760 RECEPTOR IS TARGET FOR MOST 3694 02:46:38,760 --> 02:46:43,080 OPIATE ANALGESICS AND DRUGS FOR 3695 02:46:43,080 --> 02:46:46,120 ABUSE AROUND MIU RECEPTOR 3696 02:46:46,120 --> 02:46:51,800 COUPLES TO 6 NOT 1 DIFFERENT 3697 02:46:51,800 --> 02:46:52,040 ISOFORMS. 3698 02:46:52,040 --> 02:46:54,880 AS WELL AS INTERACTING WITH 3699 02:46:54,880 --> 02:46:58,200 NONG-PROTEIN SIGNALING AND 3700 02:46:58,200 --> 02:47:02,360 REGULATORY PROTEINS. 3701 02:47:02,360 --> 02:47:04,520 SO, THE QUESTION IS WHICH OF THE 3702 02:47:04,520 --> 02:47:06,720 PATHWAYS ARE RESPONSIBLE FOR 3703 02:47:06,720 --> 02:47:08,840 THERAPEUTIC EFFECT THAT IS ANAL 3704 02:47:08,840 --> 02:47:11,240 GEEZIA REALLY AND ARE 3705 02:47:11,240 --> 02:47:12,560 RESPONSIBLE FOR ADVERSE EFFECTS 3706 02:47:12,560 --> 02:47:14,040 IF WE COULD LEARN THIS AND MORE 3707 02:47:14,040 --> 02:47:18,720 ABOUT IT AND IF WE COULD CONTROL 3708 02:47:18,720 --> 02:47:21,040 SIGNALING BEHAVIOR IN THEORY WE 3709 02:47:21,040 --> 02:47:24,840 WOULD HAVE SAFER MORE EFFECTIVE 3710 02:47:24,840 --> 02:47:27,880 ANALGESICS AND PHARMACOLOGY IS 3711 02:47:27,880 --> 02:47:30,240 ALSO COMPLEX AND ARE NOT SIMPLY 3712 02:47:30,240 --> 02:47:32,760 ACTIVATORS AND INHIBITORS AND 3713 02:47:32,760 --> 02:47:34,840 HAVE SPECTRUM OF ACTIVITY THAT 3714 02:47:34,840 --> 02:47:40,120 WE REFER TO AS EFFICACY FROM 3715 02:47:40,120 --> 02:47:48,240 FULL AGONIST TO PARTIAL AGONISTS 3716 02:47:48,240 --> 02:47:51,840 THEY SUPPRESS -- HAVE SOME LEVEL 3717 02:47:51,840 --> 02:47:55,160 OF ACTIVITY IN ABSENCE OF DRUG 3718 02:47:55,160 --> 02:47:59,120 OR HORMONE AND INVERSE AGONISTS 3719 02:47:59,120 --> 02:48:00,480 SUPPRESS THAT ACTIVITY AND 3720 02:48:00,480 --> 02:48:03,760 EXAMPLES OF THIS YOU MIGHT HAVE 3721 02:48:03,760 --> 02:48:08,920 HEARD OF ARE FEN TANNAL AND 3722 02:48:08,920 --> 02:48:12,840 MORPHINE AND HEROIN AND MORPHO 3723 02:48:12,840 --> 02:48:17,080 DON'T ARE PARTIAL AGONISTS AND 3724 02:48:17,080 --> 02:48:20,360 [INDISCERNIBLE] IS A WEAK 3725 02:48:20,360 --> 02:48:25,560 PARTIAL AGONIST AND NAL OXONE IS 3726 02:48:25,560 --> 02:48:28,120 INVERSE AGONIST. IN ADDITION TO 3727 02:48:28,120 --> 02:48:33,440 EFFICACY ISSUES OF AFFINITY AND 3728 02:48:33,440 --> 02:48:44,560 BU PREN OR FEPRENORPHINE IS -- 3729 02:48:56,440 --> 02:48:59,000 IT ILLUMINATED DOES IT CROSS 3730 02:48:59,000 --> 02:49:02,440 BLOOD/BRAIN BARRIER? ALL THESE 3731 02:49:02,440 --> 02:49:07,000 HAVE TO HAVE PROPERTIES TO BE AN 3732 02:49:07,000 --> 02:49:10,080 EFFECTOR DRUG. 3733 02:49:10,080 --> 02:49:12,400 THERE IS TISSUE SPECIFIC 3734 02:49:12,400 --> 02:49:12,680 SIGNALING. 3735 02:49:12,680 --> 02:49:15,840 THERE ARE EXAMPLES ANY DON'T 3736 02:49:15,840 --> 02:49:17,360 HAVE A EXAMPLE FOR OPIATE 3737 02:49:17,360 --> 02:49:20,760 RECEPTOR AND FOR EXAMPLE BETA 3738 02:49:20,760 --> 02:49:22,000 RECEPTORS IN THE HEART HAVE VERY 3739 02:49:22,000 --> 02:49:25,160 SPECIFIC SIGNALING DOMAINS THEY 3740 02:49:25,160 --> 02:49:27,360 RESIDE IN AND EXPRESSING BETA 1 3741 02:49:27,360 --> 02:49:31,200 AND BETA 2 RECEPTOR ON IT 3742 02:49:31,200 --> 02:49:33,200 UNDIFFERENTIATED CELL THEY 3743 02:49:33,200 --> 02:49:35,280 BEHAVE SIMILAR AND CARDIAC 3744 02:49:35,280 --> 02:49:37,400 MYOCITES THEY BEHAVE DIFFERENTLY 3745 02:49:37,400 --> 02:49:41,920 AND RESIDE IN SPECIFIC SIGNALING 3746 02:49:41,920 --> 02:49:42,280 DEPARTMENTS. 3747 02:49:42,280 --> 02:49:44,160 PERHAPS MOST CHALLENGING IS HIGH 3748 02:49:44,160 --> 02:49:46,680 DEGREE OF SEQUENCE SIMILARITY IN 3749 02:49:46,680 --> 02:49:48,960 WHAT WE CALL ORTHOSTATIC BINDING 3750 02:49:48,960 --> 02:49:52,360 POCKET THAT IS THE SITE WHERE 3751 02:49:52,360 --> 02:49:54,960 HORMONES AND NEUROTRANSMITTERS 3752 02:49:54,960 --> 02:49:57,280 NORMALLY BIND AND GIVING YOU AN 3753 02:49:57,280 --> 02:49:59,280 EXAMPLE, AGAIN, NOW, THIS IS 3754 02:49:59,280 --> 02:50:03,680 JUST A FAMILY A TREE THAT I WILL 3755 02:50:03,680 --> 02:50:06,680 FOCUS ON A SUBBRANCH. 3756 02:50:06,680 --> 02:50:10,160 HIGHLIGHTED HERE ARE ADENO 3757 02:50:10,160 --> 02:50:15,960 NURJIC RECEPTORS AND DOPAMINE 5. 3758 02:50:15,960 --> 02:50:20,320 JUST FOCUS IN ON CLUSTER ADENO 3759 02:50:20,320 --> 02:50:21,880 URGIC STRUCTURES ARE SIMILAR TO 3760 02:50:21,880 --> 02:50:25,400 DOPAMINE RECEPTORS AND SEROTONIN 3761 02:50:25,400 --> 02:50:28,360 RECEPTORS AND TRYING TO DEVELOP 3762 02:50:28,360 --> 02:50:32,160 A DRUG FOR CERTIFY TONIN 3763 02:50:32,160 --> 02:50:34,440 RECEPTOR IS DIFFICULT TO DEVELOP 3764 02:50:34,440 --> 02:50:37,560 A SUBTYPE SELECTOR DRUG AND MANY 3765 02:50:37,560 --> 02:50:40,160 CASES THIS TARGETED DRUG COULD 3766 02:50:40,160 --> 02:50:43,720 HAVE EFFECTS ON ADENO NURJIC 3767 02:50:43,720 --> 02:50:47,520 RECEPTORS AND CONSEQUENTLY 3768 02:50:47,520 --> 02:50:49,360 SELECTIVITY IS LOST. 3769 02:50:49,360 --> 02:50:51,880 FINALLY, THERE IS POLYMORPHISMS 3770 02:50:51,880 --> 02:50:54,720 WITH RESPECT TO DRUGS COULD BE 3771 02:50:54,720 --> 02:50:57,640 VARIANCE IN RECEPTORS THEMSELVES 3772 02:50:57,640 --> 02:51:00,920 AND IN MET ABOLIST DRUGS THAT IS 3773 02:51:00,920 --> 02:51:05,120 EXAMPLE OF POLYMORPHISM IN HUMAN 3774 02:51:05,120 --> 02:51:10,000 OPIATE RECEPTORS AT METHIONINE 3775 02:51:10,000 --> 02:51:13,600 BELOW BINDING POCKETS AND IT IS 3776 02:51:13,600 --> 02:51:16,320 SIMILAR TO ENDOGENOUS MET ANO 3777 02:51:16,320 --> 02:51:19,520 KEF LYNNE AND PATIENTS WITH 3778 02:51:19,520 --> 02:51:22,080 METHIONINE TO VAILINE MUTATION 3779 02:51:22,080 --> 02:51:23,760 WITH MARKED REDUCTION IN 3780 02:51:23,760 --> 02:51:27,720 RESPONSE TO OPIATES PARTICULARLY 3781 02:51:27,720 --> 02:51:31,120 MORPH 3782 02:51:31,120 --> 02:51:31,400 MORPHINE. 3783 02:51:31,400 --> 02:51:35,720 SO, HOW MIGHT WE DO A BETTER JOB 3784 02:51:35,720 --> 02:51:38,000 AT IDENTIFYING DRUGS? 3785 02:51:38,000 --> 02:51:42,840 FIRST, CAN WE USE STRUCTURES TO 3786 02:51:42,840 --> 02:51:47,480 HELP IDENTIFY NOVEL DRUGS? 3787 02:51:47,480 --> 02:51:50,240 CONVENTIONAL DRUG DISCOVERY IS 3788 02:51:50,240 --> 02:51:55,080 DONE BY SCREENING EXPERIMENTALLY 3789 02:51:55,080 --> 02:51:57,600 RELATIVELY LARGE LIBRARIES OF 3790 02:51:57,600 --> 02:52:00,760 COMPOUNDS AND LARGE LIBRARY FOR 3791 02:52:00,760 --> 02:52:03,720 DRUG COMPANY TO SCREEN A MILLION 3792 02:52:03,720 --> 02:52:05,840 COMPANY COMPOUNDS AND SCAFFOLD 3793 02:52:05,840 --> 02:52:08,160 DIVERSITY IS SOMEWHAT LIMITED IN 3794 02:52:08,160 --> 02:52:10,520 THAT THERE ARE A MILLION 3795 02:52:10,520 --> 02:52:11,880 COMPOUNDS THAT ARE VERY SIMILAR 3796 02:52:11,880 --> 02:52:14,600 TO EACH OTHER HAVING TO BE 3797 02:52:14,600 --> 02:52:16,480 EXPERIMENTALLY TESTED ON CELLS 3798 02:52:16,480 --> 02:52:19,000 AND RECEPTOR AND PROCESS IS SLOW 3799 02:52:19,000 --> 02:52:22,120 AND EXPENSIVE AND DEVELOPMENTS 3800 02:52:22,120 --> 02:52:26,640 OVER PAST TWO DECADES OR SO 3801 02:52:26,640 --> 02:52:28,000 PARTICULARLY FROM LAB BRANCH 3802 02:52:28,000 --> 02:52:29,200 [INDISCERNIBLE] HAVE DEVELOPED 3803 02:52:29,200 --> 02:52:33,480 DOCKING ALGORITHMS THAT YOU CAN 3804 02:52:33,480 --> 02:52:36,120 DO SCREENING COMPUTATION ALLEY 3805 02:52:36,120 --> 02:52:38,160 AND COMPOUND LIBRARIES COULD BE 3806 02:52:38,160 --> 02:52:40,720 LARGER AND THIS IS A SLIDE THAT 3807 02:52:40,720 --> 02:52:44,560 IS COMPOUND LIBRARIES ARE NOW UP 3808 02:52:44,560 --> 02:52:49,120 TO A BILLION PRO S ES AND 3809 02:52:49,120 --> 02:52:51,200 LIBRARIES HAVE HIGHER SCAFFOLD 3810 02:52:51,200 --> 02:52:53,040 DIVERSITY AND PROCESS IS FAST 3811 02:52:53,040 --> 02:52:56,800 AND ALL DONE ON COMPUTER AND 3812 02:52:56,800 --> 02:53:00,040 EACH COMPOUND IS TESTED IN 3813 02:53:00,040 --> 02:53:03,640 THOUSANDS OF ORIENTATIONS AND IF 3814 02:53:03,640 --> 02:53:06,320 FITS WELL IT IS A HIT AND IF IT 3815 02:53:06,320 --> 02:53:08,480 DOESN'T IT IS DISCARDED AND 3816 02:53:08,480 --> 02:53:10,520 PROCESS IS FAST AND LESS 3817 02:53:10,520 --> 02:53:12,360 EXPENSIVE AND TRIED TO DO WITH 3818 02:53:12,360 --> 02:53:13,840 RECEPTOR THAT IS A NUMBER OF 3819 02:53:13,840 --> 02:53:18,280 YEARS OLD AND I USE IT AS A 3820 02:53:18,280 --> 02:53:18,720 EXAMPLE. 3821 02:53:18,720 --> 02:53:21,880 OUR INITIAL GOAL IN FINDING 3822 02:53:21,880 --> 02:53:23,800 NOVEL DRUG FOR RECEPTOR WAS TO 3823 02:53:23,800 --> 02:53:30,800 TRY TO FIND A DRUG THAT ONLY 3824 02:53:30,800 --> 02:53:33,240 COUPLED G-PROTEINS AND NOT 3825 02:53:33,240 --> 02:53:36,520 SUFFICIENT TO ARESIDENTENCE THAT 3826 02:53:36,520 --> 02:53:40,120 ARE IMPORTANT FOR TOLERANCE 3827 02:53:40,120 --> 02:53:44,720 PEOPLE DESENSITIZE. 3828 02:53:44,720 --> 02:53:48,360 WE WORKED WITH BRIAN AND 3829 02:53:48,360 --> 02:53:52,360 SCREENED LIBRARY OF 5 MILLION 3830 02:53:52,360 --> 02:53:52,680 COMPOUNDS. 3831 02:53:52,680 --> 02:53:56,160 WE SELECTED COMPOUNDS THAT LOOK 3832 02:53:56,160 --> 02:53:57,920 NOTHING LIKE KNOWN OPIATES AND 3833 02:53:57,920 --> 02:54:01,440 IDEA IF WE HAVE NOVEL CHEMISTRY 3834 02:54:01,440 --> 02:54:04,640 MIGHT SEE NOVEL BIOLOGY. 3835 02:54:04,640 --> 02:54:07,120 WE PICKED 20 TOP CANDIDATES THAT 3836 02:54:07,120 --> 02:54:09,520 DID BINDING AND SIGNALING ASSAYS 3837 02:54:09,520 --> 02:54:14,520 AND CHEMICAL OPTIMIZATION AND 3838 02:54:14,520 --> 02:54:16,120 ULTIMATELY WE HAD NOVEL 3839 02:54:16,120 --> 02:54:18,960 COMPOUNDS WE COULD TRY IN 3840 02:54:18,960 --> 02:54:21,000 ANIMALS AND THIS JUST IS A 3841 02:54:21,000 --> 02:54:22,840 COLLECTION OF TOP-SCORING 3842 02:54:22,840 --> 02:54:25,560 COMPOUNDS BINDING TO MANY 3843 02:54:25,560 --> 02:54:27,200 DIFFERENT PLACES IN OPIATE 3844 02:54:27,200 --> 02:54:28,440 BINDING POCKET. 3845 02:54:28,440 --> 02:54:31,920 WHAT WE DID WAS A SIMPLE BINDING 3846 02:54:31,920 --> 02:54:34,160 TEST IDENTIFYING COMPOUNDS THAT 3847 02:54:34,160 --> 02:54:38,840 COULD INHIBIT BINDING TO 3848 02:54:38,840 --> 02:54:40,520 ORTHOSTATIC POCKET. 3849 02:54:40,520 --> 02:54:42,080 INITIAL COMPOUND WAS RELATIVELY 3850 02:54:42,080 --> 02:54:44,400 LOW AFFINITY AND THROUGH A 3851 02:54:44,400 --> 02:54:48,280 SERIES OF CHEMICAL OPTIMIZATIONS 3852 02:54:48,280 --> 02:54:49,800 RELATIVELY MINOR OPTIMIZATIONS 3853 02:54:49,800 --> 02:54:53,080 WE WERE ABLE TO GET 3854 02:54:53,080 --> 02:54:56,360 1,000-INCREASE IN POTENCY OF 3855 02:54:56,360 --> 02:54:57,920 THIS COMPOUND. 3856 02:54:57,920 --> 02:55:00,720 THIS IS SOME FUNCTIONAL DATA. 3857 02:55:00,720 --> 02:55:03,640 FIRST WANT TO LOOK AT EFFECT ON 3858 02:55:03,640 --> 02:55:07,760 G-PROTEINS AND DAMGO IS AS I 3859 02:55:07,760 --> 02:55:09,800 MENTIONED ANALOG OF 3860 02:55:09,800 --> 02:55:10,560 [INDISCERNIBLE] ENDOGENOUS 3861 02:55:10,560 --> 02:55:14,040 OPIATE THAT IS A STANDARD FOR 3862 02:55:14,040 --> 02:55:16,600 MEASUREMENTS THAT IS A FULL 3863 02:55:16,600 --> 02:55:16,880 AGONIST. 3864 02:55:16,880 --> 02:55:19,800 YOU CAN SEE MORPHINE IS A STRONG 3865 02:55:19,800 --> 02:55:25,320 PARTIAL AGONIST AND DRUG THAT IS 3866 02:55:25,320 --> 02:55:28,000 PEZIUM21 IS NOT AS EFFICACIOUS 3867 02:55:28,000 --> 02:55:30,800 BUT SIGNIFICANTLY MORE POTENT 3868 02:55:30,800 --> 02:55:32,400 ACTIVATING G-PROTEIN AND 3869 02:55:32,400 --> 02:55:36,000 MORPHINE AND WANTED TO AVOID 3870 02:55:36,000 --> 02:55:39,240 INTERACTION WITH ARRESTIN AND 3871 02:55:39,240 --> 02:55:41,480 YOU SEE ARREST AND RECRUITMENT 3872 02:55:41,480 --> 02:55:44,520 MEASURE HOW RECEPTORS CAN ENGAGE 3873 02:55:44,520 --> 02:55:48,400 ARRESTIN AND DAMGO IS HIGHLY 3874 02:55:48,400 --> 02:55:50,560 EFFECTIVE ARRESTIN RECRUITER AND 3875 02:55:50,560 --> 02:55:54,480 MORPHINE IS MODERATE TO WEAK 3876 02:55:54,480 --> 02:55:57,400 PARTIAL AGONIST FOR ARRESTIN. 3877 02:55:57,400 --> 02:56:02,120 HOW DID IT BEHAVE IN TERMS OF 3878 02:56:02,120 --> 02:56:08,720 ABILITY TO ACT AS ANALGESIC? 3879 02:56:08,720 --> 02:56:16,520 THIS IS A HOT PLATE ASSAY. 3880 02:56:16,520 --> 02:56:19,240 WE MEASURE HOW OFTEN THEY LICK 3881 02:56:19,240 --> 02:56:22,560 PAWS AS INDICATION OF PAIN AND 3882 02:56:22,560 --> 02:56:28,320 MORPHINE IS A VERY EFFECTIVE 3883 02:56:28,320 --> 02:56:31,120 ANALGESIC AND [INDISCERNIBLE] IS 3884 02:56:31,120 --> 02:56:33,800 NOT AS EFFECTIVE AS MORPHINE HAS 3885 02:56:33,800 --> 02:56:36,160 PROLONGED ACTIVITY POSSIBLY DUE 3886 02:56:36,160 --> 02:56:38,800 TO FACT IT DOESN'T RECRUIT 3887 02:56:38,800 --> 02:56:39,160 ARRESTIN. 3888 02:56:39,160 --> 02:56:43,000 WHAT ABOUT ADVERSE EFFECTS? 3889 02:56:43,000 --> 02:56:46,640 MAJOR ADVERSE EFFECTS FOR 3890 02:56:46,640 --> 02:56:50,680 OPIATES ARE THAT IT CAUSES ONE 3891 02:56:50,680 --> 02:56:53,520 STOP BREATHING AND SUPPRESSES 3892 02:56:53,520 --> 02:56:56,120 RESPIRATION AND YOU SEE PZM21 IS 3893 02:56:56,120 --> 02:56:58,440 PRETTY SIMILAR TO VEHICLE 3894 02:56:58,440 --> 02:57:00,080 CONTROL WHEREAS MORPHINE CAUSES 3895 02:57:00,080 --> 02:57:03,400 A PRETTY SEVERE DECREASE IN 3896 02:57:03,400 --> 02:57:07,120 RESPIRATION RELATIVE TO THE 3897 02:57:07,120 --> 02:57:08,600 VEHICLE CONTROL. 3898 02:57:08,600 --> 02:57:11,040 NEXT QUESTION, HOW ABOUT 3899 02:57:11,040 --> 02:57:11,400 ADDICTION? 3900 02:57:11,400 --> 02:57:13,680 THERE IS NOT REALLY GREAT ASSAYS 3901 02:57:13,680 --> 02:57:17,080 FOR ADDICTION IN MICE. 3902 02:57:17,080 --> 02:57:22,160 ONE OF THE ASSAYS THAT SEEMS TO 3903 02:57:22,160 --> 02:57:24,440 COORDINATE OR CORRELATE QUITE 3904 02:57:24,440 --> 02:57:25,880 WELL IS ACTIVITY. 3905 02:57:25,880 --> 02:57:29,400 WHEN YOU GIVE A MOUSE OPIATE IT 3906 02:57:29,400 --> 02:57:33,640 INCREASES ACTIVITY PROBABLY 3907 02:57:33,640 --> 02:57:36,840 BECAUSE IT STIMULATES 3908 02:57:36,840 --> 02:57:38,920 DOPAMINERGIC SYSTEM MORPHINE 3909 02:57:38,920 --> 02:57:41,560 ANIMAL ACTIVE INCREASES 3910 02:57:41,560 --> 02:57:45,920 DRAMATICALLY. FINALLY, ASSAY 3911 02:57:45,920 --> 02:57:47,760 CALLED CONDITION PLACED 3912 02:57:47,760 --> 02:57:48,720 PREFERENCE. 3913 02:57:48,720 --> 02:57:50,840 MOUSE IS PUT INTO A CAGE WITH 3914 02:57:50,840 --> 02:57:56,120 TWO COMPARTMENTS VISUALLY 3915 02:57:56,120 --> 02:58:01,240 DISTINCT HORIZONTAL OR VERTICAL 3916 02:58:01,240 --> 02:58:02,080 STRIPES. 3917 02:58:02,080 --> 02:58:05,320 WHEN OR IN THIS CHAMBER IS GIVEN 3918 02:58:05,320 --> 02:58:06,960 MORPHINE AFTER SEVERAL DAYS OF 3919 02:58:06,960 --> 02:58:09,000 TRIALS AND COME BACK A WEEK 3920 02:58:09,000 --> 02:58:10,520 LATER PUTTING MOUSE INTO THE 3921 02:58:10,520 --> 02:58:12,720 CAGE HE WILL GRAVITATE TOWARDS 3922 02:58:12,720 --> 02:58:16,160 THE COMPARTMENT WHERE HE 3923 02:58:16,160 --> 02:58:17,040 RECEIVED MORPHINE. 3924 02:58:17,040 --> 02:58:20,080 THIS IS A PRETEST SHOWING THAT 3925 02:58:20,080 --> 02:58:21,760 THE MOUSE DOESN'T CARE INITIALLY 3926 02:58:21,760 --> 02:58:24,640 WHICH SIDE OF THE CAGE HE IS ON. 3927 02:58:24,640 --> 02:58:27,240 HOWEVER, AFTER RECEIVING 3928 02:58:27,240 --> 02:58:29,640 MORPHINE YOU CAN SEE MOUSE NOW 3929 02:58:29,640 --> 02:58:30,800 PREFERS MORPHINE CHAMBER AND 3930 02:58:30,800 --> 02:58:34,200 THIS IS NOT THE CASE WITH PZM21 3931 02:58:34,200 --> 02:58:37,560 AND RESULTS SUGGEST THAT IT IS 3932 02:58:37,560 --> 02:58:40,040 POSSIBLE TO DEVELOP A DRUG USING 3933 02:58:40,040 --> 02:58:44,960 UNCONVENTIONAL METHODS AND USING 3934 02:58:44,960 --> 02:58:46,920 CRYSTAL AND CRYO STRUCTURES AND 3935 02:58:46,920 --> 02:58:48,240 WANT TO EXTEND THIS A LITTLE BIT 3936 02:58:48,240 --> 02:58:51,440 TO SAY IT IS POSSIBLE TO IMPROVE 3937 02:58:51,440 --> 02:58:54,560 THAT DRUG WHEN YOU HAVE A 3938 02:58:54,560 --> 02:58:54,880 STRUCTURE. 3939 02:58:54,880 --> 02:58:58,320 SO, ALL OF THE CHEMISTRY IS DONE 3940 02:58:58,320 --> 02:59:00,760 BY PETER'S LAB. 3941 02:59:00,760 --> 02:59:03,760 AFTER GETTING THE STRUCTURE OF 3942 02:59:03,760 --> 02:59:07,840 PZM21 BOUND TO THE OPIATE 3943 02:59:07,840 --> 02:59:12,360 RECEPTOR WE NOTICE THIS RING OWE 3944 02:59:12,360 --> 02:59:17,120 K PIED THIS SPACE. 3945 02:59:17,120 --> 02:59:20,360 WAS A BIT MORE ROOM AND PETER 3946 02:59:20,360 --> 02:59:21,400 DESIGNED NEW COMPOUND THAT FIT 3947 02:59:21,400 --> 02:59:24,280 THIS SPACE BETTER AND ABLE TO 3948 02:59:24,280 --> 02:59:26,720 GET A COMPOUND AND STRUCTURE DID 3949 02:59:26,720 --> 02:59:28,920 WHAT YOU EXPECTED IT TO DO AND 3950 02:59:28,920 --> 02:59:30,640 RESULT OF THIS MODEST CHANGE 3951 02:59:30,640 --> 02:59:32,640 EFFECT OF STIMULATING G-PROTEINS 3952 02:59:32,640 --> 02:59:38,120 IS UNCHANGED BUT HAS A 10-FOLD 3953 02:59:38,120 --> 02:59:40,920 LOWER POTENCY FOR ARRESTIN AND 3954 02:59:40,920 --> 02:59:46,200 IS MORE RESISTANT TO ARRESTIN 3955 02:59:46,200 --> 02:59:49,640 RECRUIT 3956 02:59:49,640 --> 02:59:49,960 RECRUITMENT. 3957 02:59:49,960 --> 02:59:51,760 NEXT TOPIC I WANT TO TALK ABOUT 3958 02:59:51,760 --> 02:59:53,800 IS STRUCTURE GUIDED EVOLUTION OF 3959 02:59:53,800 --> 02:59:57,440 EXISTING OPIATES AND CAN WE TAKE 3960 02:59:57,440 --> 03:00:02,560 A OPIN OPIATE AND MAKE IT BETTE 3961 03:00:02,560 --> 03:00:05,680 ADDING THINGS TO IT OR TAKING 3962 03:00:05,680 --> 03:00:06,600 THINGS AWAY. 3963 03:00:06,600 --> 03:00:08,800 I WA TOPT REMIND YOU THAT ONE OF 3964 03:00:08,800 --> 03:00:11,000 OUR GOALS IS TO SEE IF WE CAN 3965 03:00:11,000 --> 03:00:13,480 NOW DEVELOP. WE HAVE ARRESTIN 3966 03:00:13,480 --> 03:00:16,720 OR G-PROTEIN BIASED DRUGGED AND 3967 03:00:16,720 --> 03:00:18,880 NOW WANT TO SEE IF WE CAN START 3968 03:00:18,880 --> 03:00:20,880 TO ACTUALLY DEVELOP DRUGS THAT 3969 03:00:20,880 --> 03:00:24,920 ARE SELECTED FOR SPECIFIC 3970 03:00:24,920 --> 03:00:26,960 G-PROTEINS AND MAYBE ADVERSE 3971 03:00:26,960 --> 03:00:28,200 EFFECTS WILL DISAPPEAR WHEN WE 3972 03:00:28,200 --> 03:00:31,240 CAN NARROW DOWN TO G-PROTEINS 3973 03:00:31,240 --> 03:00:34,960 RESPONSIBLE FOR ANAL GEEZIA. 3974 03:00:34,960 --> 03:00:36,800 THESE STUDIES WERE DONE IN 3975 03:00:36,800 --> 03:00:37,640 COLLABORATION WITH 3976 03:00:37,640 --> 03:00:40,400 [INDISCERNIBLE] AND CHEMIST 3977 03:00:40,400 --> 03:00:42,840 [INDISCERNIBLE] FROM WASHINGTON 3978 03:00:42,840 --> 03:00:44,760 UNIVERSITY IN ST. LOUIS AND WANT 3979 03:00:44,760 --> 03:00:46,240 TO TALK A LITTLE ABOUT THE 3980 03:00:46,240 --> 03:00:49,040 BINDING POCKET BEFORE THE OPIATE 3981 03:00:49,040 --> 03:00:51,200 RECEPTORS AND UNLIKE MANY 3982 03:00:51,200 --> 03:00:54,880 RECEPTORS INCLUDING ADENO URGIC 3983 03:00:54,880 --> 03:00:57,520 RECEPTOR THIS IS LARGE BINDING 3984 03:00:57,520 --> 03:00:59,600 POCKET THAT BINDS A WIDE VARIETY 3985 03:00:59,600 --> 03:01:03,720 OF COMPOUNDS INCLUDING PEPTIDES 3986 03:01:03,720 --> 03:01:06,880 LIKE METAKEF LYNNE AND DAMGO AND 3987 03:01:06,880 --> 03:01:10,240 IT CAN ALSO BIND TO ANOTHER TYPE 3988 03:01:10,240 --> 03:01:13,720 OF ALKALOID WHICH IS AN OPIATE 3989 03:01:13,720 --> 03:01:16,040 AGONIST AND THERE ARE SYNTHETIC 3990 03:01:16,040 --> 03:01:17,680 AGONISTS THAT ARE SMALLER 3991 03:01:17,680 --> 03:01:20,920 INCLUDING METHO DON'T. 3992 03:01:20,920 --> 03:01:24,000 NOW, THE MOST LETHAL DRUG IS NOT 3993 03:01:24,000 --> 03:01:30,120 FENTANYL THAT IS 100 FOLD MORE 3994 03:01:30,120 --> 03:01:33,600 POTENT THAN FENTANYL AND SAFEST 3995 03:01:33,600 --> 03:01:35,160 DRUG IS [INDISCERNIBLE] AND WE 3996 03:01:35,160 --> 03:01:36,760 WANTED TO SEE FIRST OF ALL HOW 3997 03:01:36,760 --> 03:01:39,000 DO THESE DRUGS FIT IN THIS 3998 03:01:39,000 --> 03:01:39,520 POCKET? 3999 03:01:39,520 --> 03:01:41,160 CAN WE LEARN SOMETHING ABOUT HOW 4000 03:01:41,160 --> 03:01:44,200 TO CHANGE DRUGS TO MAKE THEM 4001 03:01:44,200 --> 03:01:47,400 SAFER OR MORE EFFICACIOUS? 4002 03:01:47,400 --> 03:01:50,840 FIRST OF ALL, WE ARE INTERESTED 4003 03:01:50,840 --> 03:01:53,880 IN UNDERSTANDING WHICH G-PROTEIN 4004 03:01:53,880 --> 03:01:55,880 SUBTYPES THESE DRUGS MIGHT 4005 03:01:55,880 --> 03:01:57,080 PREFERENTIALLY ACTIVATE. 4006 03:01:57,080 --> 03:01:58,920 THIS IS A BUSY SLIDE THAT I 4007 03:01:58,920 --> 03:02:01,080 WON'T GO THROUGH ALL THESE. 4008 03:02:01,080 --> 03:02:03,280 EACH COLOR REPRESENTS ACTIVATION 4009 03:02:03,280 --> 03:02:13,760 OF DIFFERENT G-PROTEIN OR A 4010 03:02:15,440 --> 03:02:16,320 AARRARRE 4011 03:02:16,320 --> 03:02:16,960 ARRESTIN. IN CONTRAST 4012 03:02:16,960 --> 03:02:21,000 [INDISCERNIBLE] IS RELATIVELY 4013 03:02:21,000 --> 03:02:25,400 WEAK. AT MANY OF THESE YOU CAN 4014 03:02:25,400 --> 03:02:29,800 PARTICULARLY SEE GZ HAS HIGHEST 4015 03:02:29,800 --> 03:02:33,600 POTENCY FOR GZ FENTANYL AND 4016 03:02:33,600 --> 03:02:35,480 LOWEST FOR [INDISCERNIBLE] AND 4017 03:02:35,480 --> 03:02:37,680 THIS IS INTERESTING HAS HAS 4018 03:02:37,680 --> 03:02:39,040 DIFFERENT G-PROTEIN SIGNALING 4019 03:02:39,040 --> 03:02:41,280 PROFILE AND ABLE TO GET 4020 03:02:41,280 --> 03:02:42,760 STRUCTURES BOUND TO BOTH OF THE 4021 03:02:42,760 --> 03:02:43,040 COMPOUNDS. 4022 03:02:43,040 --> 03:02:45,560 YOU WILL NOTICE THERE IS A 4023 03:02:45,560 --> 03:02:49,320 POCKET THAT IS DIFFERENT AND IS 4024 03:02:49,320 --> 03:02:51,000 OCCUPIED IN MET WRATH NEEN 4025 03:02:51,000 --> 03:02:51,680 STRUCTURE BUT NOT 4026 03:02:51,680 --> 03:02:54,360 [INDISCERNIBLE] STRUCTURE. WE 4027 03:02:54,360 --> 03:03:00,240 CAN SEE THAT BECAUSE METRAGENINE 4028 03:03:00,240 --> 03:03:02,080 INSERTED INTO POCKET PREVENTED 4029 03:03:02,080 --> 03:03:04,360 INTERACTIONS OF AMINOS IN POCKET 4030 03:03:04,360 --> 03:03:05,240 SHOWN IN [INDISCERNIBLE] 4031 03:03:05,240 --> 03:03:07,480 STRUCTURE AND INTERACTIONS WE 4032 03:03:07,480 --> 03:03:11,120 CALL HYDROGEN BONDS THAT AS A 4033 03:03:11,120 --> 03:03:13,600 RESULT OF INTERACTIONS THERE ARE 4034 03:03:13,600 --> 03:03:16,160 CHANGES THAT OCCUR IN 4035 03:03:16,160 --> 03:03:18,640 CYTOPLASMIC DOMAINS WHERE 4036 03:03:18,640 --> 03:03:20,120 G-PROTEINS COUPLE AND WE BEGIN 4037 03:03:20,120 --> 03:03:22,200 TO SEE HOW OCCUPYING DIFFERENT 4038 03:03:22,200 --> 03:03:24,400 PARTS OF THIS POCKET MIGHT ALLOW 4039 03:03:24,400 --> 03:03:28,120 US TO CHANGE BEHAVIOR OF SOME OF 4040 03:03:28,120 --> 03:03:31,520 THESE EXISTING OPIATES. 4041 03:03:31,520 --> 03:03:36,120 I WILL PASS ON THIS ONE. 4042 03:03:36,120 --> 03:03:38,320 SO, THE FOLLOWING IS A EXAMPLE 4043 03:03:38,320 --> 03:03:40,400 OF A STRUCTURE GUIDED EVOLUTION 4044 03:03:40,400 --> 03:03:41,440 OF [INDISCERNIBLE]. 4045 03:03:41,440 --> 03:03:44,120 WE HAVE A COMPOUND THAT IS SAFE. 4046 03:03:44,120 --> 03:03:48,600 CAN WE MAKE IT SAFER OR MORE 4047 03:03:48,600 --> 03:03:52,200 SELECTIVE? 4048 03:03:52,200 --> 03:03:54,200 WITH [INDISCERNIBLE] DID IS HE 4049 03:03:54,200 --> 03:03:55,520 NOTICED SPACE ABOVE THE COMPOUND 4050 03:03:55,520 --> 03:03:58,000 AND MAYBE HE COULD START TO ADD 4051 03:03:58,000 --> 03:03:58,920 THINGS THAT WOULD EXTEND INTO 4052 03:03:58,920 --> 03:04:01,040 THE SPACE. LOOK WHAT HAPPENS. 4053 03:04:01,040 --> 03:04:02,920 IT IS A TRIAL AND ERROR. 4054 03:04:02,920 --> 03:04:05,400 HE DEVELOPED ONE OF THESE 4055 03:04:05,400 --> 03:04:08,680 COMPOUNDS THAT WE CALL SC103. 4056 03:04:08,680 --> 03:04:11,080 AT FIRST, I WANT TO TAKE YOU 4057 03:04:11,080 --> 03:04:16,240 BACK TO METRAGENINE -- NOW, YOU 4058 03:04:16,240 --> 03:04:20,880 CAN SEE JUST BY ADDING AEROMATIC 4059 03:04:20,880 --> 03:04:23,640 RING ON OUTER SIDE OF PROK ET HE 4060 03:04:23,640 --> 03:04:26,840 CHANGED G-PROTEIN SIGNALING 4061 03:04:26,840 --> 03:04:27,360 PROFILE. 4062 03:04:27,360 --> 03:04:31,240 NOW, GZ IS THE MOST EFFICACIOUS 4063 03:04:31,240 --> 03:04:33,560 HERE. GZ IS LEAST EFFICACIOUS. 4064 03:04:33,560 --> 03:04:35,720 WHAT IS MORE IMPORTANT, IT 4065 03:04:35,720 --> 03:04:39,040 ACTIVATES ONLY THREE PROTEINS 4066 03:04:39,040 --> 03:04:44,320 GZ, GOA, AND GB. HOW DOES IT 4067 03:04:44,320 --> 03:04:46,240 BEHAVE? ANIMALS IN ANAL GEEZIA 4068 03:04:46,240 --> 03:04:48,720 ASSAY IS AS GOOD AS MORPHINE. 4069 03:04:48,720 --> 03:04:54,840 NOT QUITE AS GOOD AS METRAGENINE 4070 03:04:54,840 --> 03:04:57,960 AS POTENCY AND POTENT AND 4071 03:04:57,960 --> 03:05:00,360 EFFICACIOUS AS MORPHINE AND HAS 4072 03:05:00,360 --> 03:05:01,840 NO EFFECT ON RESPIRATORY 4073 03:05:01,840 --> 03:05:04,960 SUPPRESSION AND SUGGESTS THAT WE 4074 03:05:04,960 --> 03:05:10,040 CAN IN FACT BEGIN TO EVOLVE 4075 03:05:10,040 --> 03:05:13,920 DRUGS PERHAPS WITH SIGNALING 4076 03:05:13,920 --> 03:05:14,320 PROFILES. 4077 03:05:14,320 --> 03:05:16,480 WHAT HAVE WE LEARNED FROM 4078 03:05:16,480 --> 03:05:17,400 STUDIES SO FAR? 4079 03:05:17,400 --> 03:05:19,320 WE ARE BEGINNING TO UNDERSTAND 4080 03:05:19,320 --> 03:05:22,240 ROLE OF DIFFERENT G-PROTEINS AND 4081 03:05:22,240 --> 03:05:24,800 BELIEF ALGEEZIA REQUIRES GOA 4082 03:05:24,800 --> 03:05:29,320 AND/OR GOB AND POSSIBLY GOZ AND 4083 03:05:29,320 --> 03:05:30,240 POSSIBLE RESPIRATORY ADDICTION 4084 03:05:30,240 --> 03:05:32,040 THAT IS POSSIBLY A COMBINATION 4085 03:05:32,040 --> 03:05:36,960 OF GZ, GI1 AND GI2 OR GI3 AND 4086 03:05:36,960 --> 03:05:40,600 TOLERANCE IS MEDIATED BY 4087 03:05:40,600 --> 03:05:41,960 ARRESTIN. 4088 03:05:41,960 --> 03:05:44,080 SO, I DON'T KNOW HOW MUCH TIME I 4089 03:05:44,080 --> 03:05:46,000 HAVE. 4090 03:05:46,000 --> 03:05:50,160 OKAY. I HAVE A FIVE-MINUTE 4091 03:05:50,160 --> 03:05:56,320 STO 4092 03:05:56,320 --> 03:05:56,840 STORY. 4093 03:05:56,840 --> 03:06:02,480 I WANT TO MENTION LAST AREA OF 4094 03:06:02,480 --> 03:06:09,440 DRUG DISCOVERY MADE POSSIBLE BY 4095 03:06:09,440 --> 03:06:10,360 [INDISCERN 4096 03:06:10,360 --> 03:06:10,760 [INDISCERNIBLE]. 4097 03:06:10,760 --> 03:06:12,880 SHOWN HERE IS MET AN KEF LYNNE 4098 03:06:12,880 --> 03:06:16,520 SHOWN IN BLUE AND REST OF 4099 03:06:16,520 --> 03:06:18,240 RECEPTOR IS SHOWN IN GREEN. 4100 03:06:18,240 --> 03:06:20,400 THIS REPRESENTS POTENTIAL 4101 03:06:20,400 --> 03:06:22,880 BINDING SITES FOR ALOSTERIC 4102 03:06:22,880 --> 03:06:25,000 MODULATORS THAT ARE OUTSIDE OF 4103 03:06:25,000 --> 03:06:27,680 THE ORTHOSTERIC POCKET AND 4104 03:06:27,680 --> 03:06:30,200 MODULATE OR AUGMENT OR INHIBIT 4105 03:06:30,200 --> 03:06:34,240 RESPONSES TO NATIVE HORMONE OR 4106 03:06:34,240 --> 03:06:36,360 NEUROTRANSMITTER MINIMIZING 4107 03:06:36,360 --> 03:06:37,480 ADVERSE EFFECTS OF 4108 03:06:37,480 --> 03:06:40,200 [INDISCERNIBLE] AND CAN HAVE 4109 03:06:40,200 --> 03:06:41,920 GREATER ACTIVITY SINCE MOST 4110 03:06:41,920 --> 03:06:43,960 HIGHLY CONSERVED PART OF 4111 03:06:43,960 --> 03:06:45,560 RECREPTOR IS A BINDING POCKET 4112 03:06:45,560 --> 03:06:49,480 THAT WE USE DNA ENCODED CHEMICAL 4113 03:06:49,480 --> 03:06:53,480 LIBRARIES TO IDENTIFY NOVEL 4114 03:06:53,480 --> 03:06:55,040 COMPOUNDS THAT ARE HUGE 4115 03:06:55,040 --> 03:06:57,640 LIBRARIES OF COMPOUNDS UP TO 4116 03:06:57,640 --> 03:07:01,160 TRILLION COMPOUND LIBRARIES 4117 03:07:01,160 --> 03:07:02,960 AVAILABLE WHERE EACH COMPOUND 4118 03:07:02,960 --> 03:07:06,480 INCLUDES A DNA BARCODE THAT YOU 4119 03:07:06,480 --> 03:07:07,720 CAN IDENTIFY WHICH COMPOUND 4120 03:07:07,720 --> 03:07:11,280 STICKS TO RECEPTOR BY SEQUENCING 4121 03:07:11,280 --> 03:07:14,080 AND THESE LIBRARIES ARE COVE 4122 03:07:14,080 --> 03:07:15,720 AILIENTLY ATTACHED TO SMALL 4123 03:07:15,720 --> 03:07:18,920 MOLECULES BINDING TO DNA STRANDS 4124 03:07:18,920 --> 03:07:20,760 AND BAR CODES AND LARGER NUMBER 4125 03:07:20,760 --> 03:07:23,920 OF CYCLES THAT YOU ADD MORE 4126 03:07:23,920 --> 03:07:30,200 FRAGMENTS TO LARGER THE LIBRARY. 4127 03:07:30,200 --> 03:07:32,960 JUST BRIEFLY YOU MIX YOUR 4128 03:07:32,960 --> 03:07:34,720 RECEPTOR ACTIVE OR INACTIVE 4129 03:07:34,720 --> 03:07:36,880 STATE WITH LIBRARY AND WASH AWAY 4130 03:07:36,880 --> 03:07:39,400 THINGS THAT DON'T BIND AND ELUDE 4131 03:07:39,400 --> 03:07:40,720 THINGS THAT DON'T BIND AND MIGHT 4132 03:07:40,720 --> 03:07:44,840 DO IT A COUPLE TIMES AND AT END 4133 03:07:44,840 --> 03:07:48,640 YOU SEQUENCE WHAT BOUND AND 4134 03:07:48,640 --> 03:07:51,920 DETERMINE WHICH COMPOUNDS YOU 4135 03:07:51,920 --> 03:07:52,400 FIND. 4136 03:07:52,400 --> 03:07:57,040 YOU CAN USE ACTIVE OPIATE 4137 03:07:57,040 --> 03:08:01,000 RECEPTOR COUPLED TO GI TO 4138 03:08:01,000 --> 03:08:03,400 IDENTIFY POSITIVE ALOSTERIC 4139 03:08:03,400 --> 03:08:05,320 MODULATORS IN INACTIVE STATES TO 4140 03:08:05,320 --> 03:08:07,680 IDENTIFY NEGATIVE MODULATORS 4141 03:08:07,680 --> 03:08:09,760 THAT WE DID THIS WITH A 4142 03:08:09,760 --> 03:08:13,320 RELATIVELY SMALL LIBRARY OF 4 4143 03:08:13,320 --> 03:08:16,360 BILLION COMPOUNDS AND FROM THESE 4144 03:08:16,360 --> 03:08:19,400 WHAT IS REALLY REMARKABLE IS WE 4145 03:08:19,400 --> 03:08:22,040 SELECTED 5 AND HAD LIMITED 4146 03:08:22,040 --> 03:08:24,440 ABILITY TO PAY FOR MORE 4147 03:08:24,440 --> 03:08:25,640 COMPOUNDS AND SAID WE WILL 4148 03:08:25,640 --> 03:08:29,320 SELECT 5. OF THESE WE 4149 03:08:29,320 --> 03:08:32,040 IDENTIFIED 1 PAM AND 1NAM THAT 4150 03:08:32,040 --> 03:08:34,320 IS A VERY HIGH EFFICIENCY RATE 4151 03:08:34,320 --> 03:08:36,320 AND WERE ABLE TO GET STRUCTURES 4152 03:08:36,320 --> 03:08:38,600 OF -- THE RECEPTORS THAT WERE 4153 03:08:38,600 --> 03:08:39,280 BOUND TO THESE. 4154 03:08:39,280 --> 03:08:41,320 I WANT TO SHOW YOU. THEY ARE 4155 03:08:41,320 --> 03:08:42,560 INTERESTING IN WHERE THEY BIND. 4156 03:08:42,560 --> 03:08:46,520 SO, THIS IS A NEGATIVE ALOSTERIC 4157 03:08:46,520 --> 03:08:50,160 MODULATOR THAT BINDS BETWEEN TM7 4158 03:08:50,160 --> 03:08:56,320 AND TM1 AND FORMS OVER NAL OXONE 4159 03:08:56,320 --> 03:08:59,360 [INDISCERNIBLE] ONE PROBLEM WITH 4160 03:08:59,360 --> 03:09:01,200 NAL OXONE TREATING OVERDOSE IS 4161 03:09:01,200 --> 03:09:03,400 HAS A SHORT LIFE AND HOPING THAT 4162 03:09:03,400 --> 03:09:06,440 PERHAPS SOMETHING LIKE THIS NAM 4163 03:09:06,440 --> 03:09:11,040 MIGHT EXTEND NALOXONE'S HALF 4164 03:09:11,040 --> 03:09:13,360 LIFE MAKING IT MORE EFFECTIVE AT 4165 03:09:13,360 --> 03:09:16,280 PREVENTING OVERDOSE DEATHS AND 4166 03:09:16,280 --> 03:09:18,760 PERHAPS STRANGEST COMPOUND IS A 4167 03:09:18,760 --> 03:09:20,880 POSITIVE ALOSTERIC MODULATOR 4168 03:09:20,880 --> 03:09:23,040 THAT BINDS AS SHOWN HERE ON THE 4169 03:09:23,040 --> 03:09:27,520 OUTSIDE OF THE RECEPTOR THAT 4170 03:09:27,520 --> 03:09:33,200 TURNS TRANS MEMBRANES 6 AND 7 4171 03:09:33,200 --> 03:09:35,200 THAT IS IMPORTANT FOR ACTIVATION 4172 03:09:35,200 --> 03:09:37,600 THAT HAS ACTIVE AND INACTIVE 4173 03:09:37,600 --> 03:09:40,240 STATE THAT YOU LOSE BINDING 4174 03:09:40,240 --> 03:09:43,480 POCKET FOR THIS POSITIVE 4175 03:09:43,480 --> 03:09:45,080 ALOSTERIC MODULATOR. I WILL END 4176 03:09:45,080 --> 03:09:47,280 HERE. THIS IS AN ONGOING 4177 03:09:47,280 --> 03:09:49,120 PROCESS AND WE CONTINUE TO LOOK 4178 03:09:49,120 --> 03:09:50,920 FOR BETTER DRUGS AND IMPROVE 4179 03:09:50,920 --> 03:09:52,720 DRUGS WE HAVE AND WE ARE 4180 03:09:52,720 --> 03:09:54,960 INTERESTED IN SUBTYPE SELECTIVE 4181 03:09:54,960 --> 03:09:58,680 DRUGS AS WELL AS DRUGS THAT WORK 4182 03:09:58,680 --> 03:10:03,240 AS ALOSTERIC MODULATORS. 4183 03:10:03,240 --> 03:10:04,760 THESE ARE PEOPLE THAT HAVE DONE 4184 03:10:04,760 --> 03:10:07,440 THE WORK AND PARTICULARLY 4185 03:10:07,440 --> 03:10:10,200 CALLING OUT EVAN THAT DID OPIOID 4186 03:10:10,200 --> 03:10:11,840 RECEPTOR WORK I TALKED ABOUT AND 4187 03:10:11,840 --> 03:10:15,240 THIS IS DONE IN COLLABORATION 4188 03:10:15,240 --> 03:10:18,280 WITH [INDISCERNIBLE] AT 4189 03:10:18,280 --> 03:10:20,000 WASHINGTON UNIVERSITY AND 4190 03:10:20,000 --> 03:10:20,960 APPRECIATE YOUR ATTENTION AND 4191 03:10:20,960 --> 03:10:24,960 APPRECIATE FUNDING FROM NIH. 4192 03:10:24,960 --> 03:10:25,960 THANK YOU. 4193 03:10:25,960 --> 03:10:32,000 >> AUDIENCE: [APPLAUSE]. 4194 03:10:32,000 --> 03:10:36,280 >> THANK YOU, DR. KOBILKA. THIS 4195 03:10:36,280 --> 03:10:38,440 ROOM IS FULL OF YOUNG 4196 03:10:38,440 --> 03:10:38,760 SCIENTISTS. 4197 03:10:38,760 --> 03:10:42,200 YOUR DISCOVERIES ARE 4198 03:10:42,200 --> 03:10:43,640 INSPIRATIONAL. I HOPE THAT 4199 03:10:43,640 --> 03:10:46,160 PEOPLE ARE THINKING ABOUT THE 4200 03:10:46,160 --> 03:10:47,320 APPLICATION AND TARGETED 4201 03:10:47,320 --> 03:10:49,240 THERAPIES AND ALL DISEASES THAT 4202 03:10:49,240 --> 03:10:51,440 WE REALLY CAN ADDRESS AND CURE 4203 03:10:51,440 --> 03:10:52,360 AND TREAT. 4204 03:10:52,360 --> 03:10:54,400 AND AS OUR YOUNGEST GUEST SAID 4205 03:10:54,400 --> 03:10:56,960 JUST EARLIER, GO FOR IT! 4206 03:10:56,960 --> 03:10:57,520 >> AUDIENCE: [LAUGHING]. 4207 03:10:57,520 --> 03:10:59,280 >> I WOULD LIKE TO TAKE THIS 4208 03:10:59,280 --> 03:11:03,320 MOMENT TO INVITE THE DIRECTOR OF 4209 03:11:03,320 --> 03:11:06,440 NIDCR, DR. RENA D'SOUZA TO THE 4210 03:11:06,440 --> 03:11:09,720 PODIUM FOR HER CLOSING REMARKS. 4211 03:11:09,720 --> 03:11:12,240 DR. D'SOUZA PROVIDED TREMENDOUS 4212 03:11:12,240 --> 03:11:14,080 SUPPORT AND IS AN ADVOCATE FOR 4213 03:11:14,080 --> 03:11:16,040 OUR RESEARCH TO APPLY AND 4214 03:11:16,040 --> 03:11:18,880 IMPROVE HEALTH OF OUR PATIENTS. 4215 03:11:18,880 --> 03:11:22,240 DR. D'SOUZA, THANK YOU. 4216 03:11:22,240 --> 03:11:24,480 >> THANK YOU. 4217 03:11:24,480 --> 03:11:25,680 >> AUDIENCE: [APPLAUSE]. 4218 03:11:25,680 --> 03:11:27,480 >> THANK YOU DR. KOBILKA. IT 4219 03:11:27,480 --> 03:11:30,000 WAS JUST FASCINATING TO SEE THE 4220 03:11:30,000 --> 03:11:33,080 JOURNEY FROM TASTE AND SMELL AND 4221 03:11:33,080 --> 03:11:37,960 TOUCH TO GO INTO STRUCTURED 4222 03:11:37,960 --> 03:11:40,760 BIOLOGIES AND TACKLE A PROBLEM 4223 03:11:40,760 --> 03:11:42,480 NATIONWIDE AND DEVASTATING TO 4224 03:11:42,480 --> 03:11:44,520 OUR SOCIETY. THANK YOU FOR 4225 03:11:44,520 --> 03:11:46,280 THAT. IT HAS BEEN 4226 03:11:46,280 --> 03:11:47,760 INSPIRATIONAL. FOR ME, HUMBLING 4227 03:11:47,760 --> 03:11:50,640 AND EQUALLY PROUD OF ALL WE HAVE 4228 03:11:50,640 --> 03:11:51,440 HEARD TODAY. 4229 03:11:51,440 --> 03:11:53,520 FROM TIME I ARRIVED IN OCTOBER 4230 03:11:53,520 --> 03:11:57,080 OF 2020, I HAD THIS THROUGH THE 4231 03:11:57,080 --> 03:11:59,080 IMPORTANCE OF REALIZING PROMISE 4232 03:11:59,080 --> 03:12:00,680 OF SCIENCE AND FOR BENEFIT OF 4233 03:12:00,680 --> 03:12:03,520 OUR PATIENTS AND IN ORAL HEALTH 4234 03:12:03,520 --> 03:12:07,760 THAT IS SO TRUE TODAY. DESPITE 4235 03:12:07,760 --> 03:12:09,640 TECHNOLOGY AND SCIENCE COMING 4236 03:12:09,640 --> 03:12:11,360 TOGETHER UNPRECEDENTEDLY TO MAKE 4237 03:12:11,360 --> 03:12:12,760 IT ACTUALLY POSSIBLE FOR THE 4238 03:12:12,760 --> 03:12:14,760 FIRST TIME IN OUR HISTORY TO 4239 03:12:14,760 --> 03:12:16,680 MAKE THE LIVES OF PATIENTS 4240 03:12:16,680 --> 03:12:18,800 BETTER IS TRULY AN OPPORTUNITY 4241 03:12:18,800 --> 03:12:22,080 THAT WE CAN'T MISS. 4242 03:12:22,080 --> 03:12:25,440 SO, FOR ME, THIS IS TRULY REALLY 4243 03:12:25,440 --> 03:12:27,000 A REVELATION AND MUST SAY THAT 4244 03:12:27,000 --> 03:12:31,440 EVERY TIME I TALK TO ALLISON OR 4245 03:12:31,440 --> 03:12:35,800 KELLY OR RACHEL, THEY SPEAK OF 4246 03:12:35,800 --> 03:12:38,120 YOU, MIKE. FOR YOU, LEGACY YOU 4247 03:12:38,120 --> 03:12:44,400 LEAVE AT NIH IS WONDERFULLY 4248 03:12:44,400 --> 03:12:47,360 BRIGHT AND TALENTED MOTHERS AND 4249 03:12:47,360 --> 03:12:48,760 WOMEN. THANK YOU FOR THAT. LE 4250 03:12:48,760 --> 03:12:50,960 IT IS A LEGACY. WE MISS YOU BUT 4251 03:12:50,960 --> 03:12:54,840 IT WILL LIVE ON AND I KNOW THAT 4252 03:12:54,840 --> 03:12:58,040 YOU WILL STAY CONNECTED WITH NIH 4253 03:12:58,040 --> 03:13:00,920 AND OUTSIDE WORLD. 4254 03:13:00,920 --> 03:13:03,520 JEANNA AND LUCY I'M AN ADVOCATE 4255 03:13:03,520 --> 03:13:05,360 FOR IPHONES FOR YOU. I KNOW YOU 4256 03:13:05,360 --> 03:13:08,520 ASKED ME TO SAY THAT. 4257 03:13:08,520 --> 03:13:09,160 [LAUGHING]. 4258 03:13:09,160 --> 03:13:11,320 EVEN THOUGH YOU HAVE TO USE IT 4259 03:13:11,320 --> 03:13:13,760 IN A CAREFUL WAY I THINK YOU CAN 4260 03:13:13,760 --> 03:13:15,080 COMMUNICATE WITH EACH OTHER AND 4261 03:13:15,080 --> 03:13:17,360 PROBABLY ALL OF THE YOUNG 4262 03:13:17,360 --> 03:13:20,760 INDIVIDUALS LIKE YOU WHO SUFFER 4263 03:13:20,760 --> 03:13:22,320 FROM THIS CONDITION AND MANY 4264 03:13:22,320 --> 03:13:25,000 GOOD WAYS TO CONNECT AND MAKE 4265 03:13:25,000 --> 03:13:26,640 SCIENCE ACTUALLY SO PUBLICIZED 4266 03:13:26,640 --> 03:13:29,640 OR ALL GOOD ASPECTS OF SCIENCE 4267 03:13:29,640 --> 03:13:33,920 TO BE PUBLICIZED IN THIS WORLD 4268 03:13:33,920 --> 03:13:35,400 THAT MISINFORMATION AND 4269 03:13:35,400 --> 03:13:37,640 DISINFORMATION THRIVE; RIGHT? 4270 03:13:37,640 --> 03:13:40,560 SPECIAL THANKS FOR THOSE THAT 4271 03:13:40,560 --> 03:13:44,920 PIONEERED FOUNDATIONAL DISCOVERY 4272 03:13:44,920 --> 03:13:45,800 ENNIGMATIC AND COMPLEX CONDITION 4273 03:13:45,800 --> 03:13:48,840 FOR ALL THAT YOU DID TO UNRAVEL 4274 03:13:48,840 --> 03:13:51,160 THE COMPOUND NATURE OF G-PROTEIN 4275 03:13:51,160 --> 03:13:53,520 COMPLEXES AND RECEPTORS AND FOR 4276 03:13:53,520 --> 03:13:56,400 JANICE AND FOR MAKING THE 4277 03:13:56,400 --> 03:13:58,280 INFRASTRUCTURE AVAILABLE FOR 4278 03:13:58,280 --> 03:14:01,840 ALLISON AND KELLY AND MIKE AND 4279 03:14:01,840 --> 03:14:06,840 OTHERS TO GET DONE WORK THAT IS 4280 03:14:06,840 --> 03:14:09,480 IMPORTANT, THANK YOU FOR WHAT 4281 03:14:09,480 --> 03:14:12,800 YOU DID TO CLINICAL RESEARCH AT 4282 03:14:12,800 --> 03:14:16,320 N IC 4283 03:14:16,320 --> 03:14:20,520 NIDCR, THANK YOU AND PAM AND 4284 03:14:20,520 --> 03:14:23,520 SPIEGEL AND MARA AND MICHAEL AND 4285 03:14:23,520 --> 03:14:25,640 ALLISON AND ALL OF YOU 4286 03:14:25,640 --> 03:14:27,520 EMPHASIZED IMPORTANCE OF THE 4287 03:14:27,520 --> 03:14:28,520 FOUNDATIONAL SCIENCES IN 4288 03:14:28,520 --> 03:14:31,920 CREATING AND MAKING POSSIBLE, 4289 03:14:31,920 --> 03:14:32,600 ACTUALLY, TRANSLATIONAL 4290 03:14:32,600 --> 03:14:34,240 CONTINUUM. IT IS IN FACT A 4291 03:14:34,240 --> 03:14:36,400 CONTINUUM AND NOT BASIC ON ONE 4292 03:14:36,400 --> 03:14:38,840 END AND CLINICAL ON THE OTHER AS 4293 03:14:38,840 --> 03:14:41,240 WE ARE PART GROWING UP IN THE 4294 03:14:41,240 --> 03:14:44,560 NIH WORLD WHERE WE HAD TO BE 4295 03:14:44,560 --> 03:14:46,120 HYPOTHESIS DRIVEN AND 4296 03:14:46,120 --> 03:14:47,800 MECHANISTIC THAT IN FACT THAT 4297 03:14:47,800 --> 03:14:49,680 CONTINUUM IN THE END WITH 4298 03:14:49,680 --> 03:14:52,080 PATIENT IN THE CENTER THAT 4299 03:14:52,080 --> 03:14:55,440 ACTUALLY MAKES A DIFFERENCE AND 4300 03:14:55,440 --> 03:14:59,400 FIBROUS DYSPLASIA AND MCCUNE 4301 03:14:59,400 --> 03:15:03,160 ALBRIGHTS -- UNPREDICTABLE 4302 03:15:03,160 --> 03:15:04,800 CLINICAL PRESENTATIONS QUITE 4303 03:15:04,800 --> 03:15:06,840 BURIED CONFOUNDED MEDICAL 4304 03:15:06,840 --> 03:15:08,120 PROFESSIONALS GENERATIONS 4305 03:15:08,120 --> 03:15:09,720 READING FROM NOTES I DON'T WANT 4306 03:15:09,720 --> 03:15:11,040 TO MISS ANYTHING IMPORTANT I 4307 03:15:11,040 --> 03:15:14,280 TEND TO BE MORE EMOTIONAL THAN 4308 03:15:14,280 --> 03:15:15,720 PAM AND MIKE. 4309 03:15:15,720 --> 03:15:17,560 SO, PURSUIT OF KNOWLEDGE IN 4310 03:15:17,560 --> 03:15:19,320 FIELD BEGAN WITH A SIMPLE 4311 03:15:19,320 --> 03:15:20,600 QUESTION THAT WE KEEP AND SHOULD 4312 03:15:20,600 --> 03:15:22,880 BE ASKING OURSELVES EVERY DAY 4313 03:15:22,880 --> 03:15:25,320 HOW CAN WE UNRAVEL THE MYSTERIES 4314 03:15:25,320 --> 03:15:27,240 OF THE SYNDROME AND ANYTHING 4315 03:15:27,240 --> 03:15:29,520 COMPLEX IN LIFE AND IMPROVE 4316 03:15:29,520 --> 03:15:33,560 LIVES OF THOSE EFFECTED? 4317 03:15:33,560 --> 03:15:36,280 ANSWER LIES IN COLLABORATIVE 4318 03:15:36,280 --> 03:15:37,800 SYNERGY BASIC TRANSLATIONAL AND 4319 03:15:37,800 --> 03:15:39,600 CLINICAL RESEARCH THAT I DEFINE 4320 03:15:39,600 --> 03:15:42,040 AS CONTINUUM AND BASIC RESEARCH 4321 03:15:42,040 --> 03:15:45,640 IS BEDROCK OF SCIENTIFIC 4322 03:15:45,640 --> 03:15:48,440 DISCOVERY AND NIH STAYED TRUE TO 4323 03:15:48,440 --> 03:15:52,240 COURSE AND UNRAVEL GENETIC 4324 03:15:52,240 --> 03:15:54,000 MUTATIONS FOR THIS CONDITION 4325 03:15:54,000 --> 03:15:55,920 SHEDDING LIGHT HOW BONE TISSUE 4326 03:15:55,920 --> 03:16:00,720 IS REPLACED WITH ABNORMAL 4327 03:16:00,720 --> 03:16:03,080 FIBROUS MATERIAL AND HOW 4328 03:16:03,080 --> 03:16:04,960 [INDISCERNIBLE] GOES AWRY AND 4329 03:16:04,960 --> 03:16:07,880 WONDER HOW FIBROBLASTS ARE 4330 03:16:07,880 --> 03:16:08,840 IGNORED IN THIS AND PERHAPS NEED 4331 03:16:08,840 --> 03:16:13,280 TO BE LOOKED AT THEY ARE TEEP 4332 03:16:13,280 --> 03:16:14,880 WHOSE PHENOTYPE IN FUNCTION 4333 03:16:14,880 --> 03:16:16,280 HASN'T BEEN EXPLORED THAT IS 4334 03:16:16,280 --> 03:16:19,000 JUST ME AND HELPING US 4335 03:16:19,000 --> 03:16:20,120 UNDERSTAND MOLECULAR BASIS OF 4336 03:16:20,120 --> 03:16:22,720 DISORDERS CAUSED BY DEFECTS IN 4337 03:16:22,720 --> 03:16:24,960 G-PROTEINS MUTATIONS ARE 4338 03:16:24,960 --> 03:16:26,680 RESPONSIBLE FOR SYNDROMES 4339 03:16:26,680 --> 03:16:29,360 DIVERSE PHENOTYPE OR 4340 03:16:29,360 --> 03:16:30,560 MANIFESTATIONS AND TRANSLATION 4341 03:16:30,560 --> 03:16:32,680 RESEARCH BRIDGED GAP BETWEEN LAB 4342 03:16:32,680 --> 03:16:34,640 DISCOVERIES AND CLINICAL 4343 03:16:34,640 --> 03:16:35,640 APPLICATION AND THIS CRUCIAL 4344 03:16:35,640 --> 03:16:39,560 STEP TRANSFORMS GENETIC INSIGHTS 4345 03:16:39,560 --> 03:16:42,440 INTO POTENTIAL THERAPEUTIC 4346 03:16:42,440 --> 03:16:44,400 STRATEGIES INFORMING HOW 4347 03:16:44,400 --> 03:16:46,280 EXPERIMENTAL TREATMENTS CAN 4348 03:16:46,280 --> 03:16:47,920 TRANSITION FROM BENCH TO BEDSIDE 4349 03:16:47,920 --> 03:16:50,040 AND BACK OFFERING MUCH HOPE AND 4350 03:16:50,040 --> 03:16:51,840 PROMISE TO PATIENTS. 4351 03:16:51,840 --> 03:16:55,840 OUR WORK HAS SHOWN OR YOUR WORK 4352 03:16:55,840 --> 03:16:58,360 HAS SHOWN THAT THE PATH TO 4353 03:16:58,360 --> 03:17:00,840 HARNESSING BODY'S OWN HEALING 4354 03:17:00,840 --> 03:17:03,640 POTENTIAL IS GROUNDBREAKING WORK 4355 03:17:03,640 --> 03:17:05,400 AND WHETHER STEM CELL THERAPIES 4356 03:17:05,400 --> 03:17:11,120 OPENING NEW ORRIZONS OPENING AND 4357 03:17:11,120 --> 03:17:14,120 MANAGING PROBLEM REVERSING 4358 03:17:14,120 --> 03:17:15,560 DEVASTATING EFFECTS IT COMES AND 4359 03:17:15,560 --> 03:17:18,600 REFLECTING ON 25 YEARS OF 4360 03:17:18,600 --> 03:17:19,800 TIRELESS DEDICATION AND 4361 03:17:19,800 --> 03:17:21,680 COLLABORATION I CAN SEE A BETTER 4362 03:17:21,680 --> 03:17:24,760 WAY TO CELEBRATE 75 YEARS FOR 4363 03:17:24,760 --> 03:17:27,960 EXISTENCE AT NIH FOR NIDCR AND 4364 03:17:27,960 --> 03:17:30,240 SEE FRUITS OF LABOR MOVING FROM 4365 03:17:30,240 --> 03:17:36,320 PLACE OF UNCERTAINTY TO ONE OF 4366 03:17:36,320 --> 03:17:38,560 HOPE AND TREATMENT OPTION AND 4367 03:17:38,560 --> 03:17:40,200 PERSONALIZED THERAPIES IN REACH 4368 03:17:40,200 --> 03:17:44,840 AND FIBROUS DYSPLASIA MCCUNE 4369 03:17:44,840 --> 03:17:47,800 ALBRIGHT IS NOT INSURMOUNTABLE 4370 03:17:47,800 --> 03:17:49,600 CHALLENGE BUT FIELD RIPE WITH 4371 03:17:49,600 --> 03:17:51,480 PROMISES AND IS PROMISE TO YOU 4372 03:17:51,480 --> 03:17:55,000 GIANA AND LUCY AND IN CLOSING WE 4373 03:17:55,000 --> 03:17:57,440 REMAIN COMMITTED TO ADVANCING 4374 03:17:57,440 --> 03:17:59,000 INTEGRATION OF BASIC TRANSLATION 4375 03:17:59,000 --> 03:18:01,720 AND CLINICAL RESEARCH NOT ONLY 4376 03:18:01,720 --> 03:18:06,560 FOR FIBROUS DYSPLASIA AND MCCUNE 4377 03:18:06,560 --> 03:18:07,840 ALBRIGHT SYNDROME BUT ALL RARE 4378 03:18:07,840 --> 03:18:09,920 DISEASES TOGETHER WE ARE TORCH 4379 03:18:09,920 --> 03:18:12,120 BEARERS OF HOPE, ARCHITECTS OF 4380 03:18:12,120 --> 03:18:14,120 PROGRESS AND GUARDIANS OF 4381 03:18:14,120 --> 03:18:15,320 BRIGHTER FUTURE FOR ALL THOSE 4382 03:18:15,320 --> 03:18:17,640 THAT DEPEND ON OUR COLLECTIVE 4383 03:18:17,640 --> 03:18:17,920 EFFORTS. 4384 03:18:17,920 --> 03:18:21,720 THANK YOU ALL FOR COMING FOR 4385 03:18:21,720 --> 03:18:24,040 YOUR UNWAIVERING DEDICATION TO 4386 03:18:24,040 --> 03:18:25,400 THE SCIENTISTS THAT MADE THIS 4387 03:18:25,400 --> 03:18:27,640 JOURNEY TRULY INSPIRING FOR 4388 03:18:27,640 --> 03:18:28,800 GENERATIONS TO COME. I THANK 4389 03:18:28,800 --> 03:18:32,840 YOU FROM THE BOTTOM OF MY HEART. 4390 03:18:32,840 --> 03:18:40,640 >> AUDIENCE: [APPLAUSE]. 4391 03:18:40,640 --> 03:18:44,520 >> NOW I WOULD LIKE TO INVITE 4392 03:18:44,520 --> 03:18:48,000 EVERYONE TO FAES TERRACE FOR 4393 03:18:48,000 --> 03:18:50,560 REFRESHMENTS AND VISUAL HISTORY 4394 03:18:50,560 --> 03:18:54,840 OF FDA JOURNEY AND HISTORY OF 4395 03:18:54,840 --> 03:18:57,760 SPEAKERS AND PATIENTS AND 4396 03:18:57,760 --> 03:18:59,200 LEADERS IF YOU CAN STAY BACK FOR 4397 03:18:59,200 --> 03:19:09,640 A FEW MINUTES FOR PHOTOS.