1 00:00:11,440 --> 00:00:13,640 Welcome to the Clinical Center Grand Rounds, 2 00:00:13,640 --> 00:00:17,440 a weekly series of educational lectures for physicians and 3 00:00:17,440 --> 00:00:20,080 health care professionals broadcast from the Clinical 4 00:00:20,080 --> 00:00:23,040 Center at the National Institutes of Health in 5 00:00:23,040 --> 00:00:24,840 Bethesda, MD. 6 00:00:24,840 --> 00:00:28,400 The NIH Clinical Center is the world's largest hospital totally 7 00:00:28,400 --> 00:00:32,080 dedicated to investigational research and leads the global 8 00:00:32,080 --> 00:00:35,040 effort in training today's investigators and discovering 9 00:00:35,040 --> 00:00:37,200 tomorrow's cures. 10 00:00:37,200 --> 00:00:46,920 Learn more by visiting us online at http://clinicalcenter.nih.gov 11 00:00:46,920 --> 00:00:50,600 TODAY IT IS MY GREAT HONOR TO 12 00:00:50,600 --> 00:00:58,800 PRESENT TWO SPEAKERS DR. STEVE 13 00:00:58,800 --> 00:01:01,840 HOLLAND, AND DR. DENNIS 14 00:01:01,840 --> 00:01:03,840 HICKSTEIN, OUR FIRST SPEAKER IS 15 00:01:03,840 --> 00:01:05,000 DR. HOLLAND, SCIENTIFIC DIRECTOR 16 00:01:05,000 --> 00:01:08,160 OF NIAID AS WELL AS ITS DIRECTOR 17 00:01:08,160 --> 00:01:10,320 OF INTRAMURAL RESEARCH AND CHIEF 18 00:01:10,320 --> 00:01:12,760 OF THE IMMUNO PATHOGENESIS 19 00:01:12,760 --> 00:01:13,120 SECTION OR NIAID. 20 00:01:13,120 --> 00:01:14,160 DR. HOLLAND EARNED HIS MEDICAL 21 00:01:14,160 --> 00:01:16,440 DEGREE FROM JOHNS HOPKINS 22 00:01:16,440 --> 00:01:18,320 UNIVERSITY WHERE HE STAYED FOR 23 00:01:18,320 --> 00:01:19,760 HIS INTERNAL MEDICINE RESIDENCY, 24 00:01:19,760 --> 00:01:22,080 CHIEF RESIDENCY AND FELLOWSHIP 25 00:01:22,080 --> 00:01:23,680 IN INFECTIOUS DISEASES. 26 00:01:23,680 --> 00:01:26,920 HE CAME TO NIAID, THE NATIONAL 27 00:01:26,920 --> 00:01:29,920 RESEARCH COUNCIL FELLOW IN 1989 28 00:01:29,920 --> 00:01:31,760 TO THE LABORATORY OF MOLECULAR 29 00:01:31,760 --> 00:01:34,080 MIKE O BIOLOGY, WORKING ON 30 00:01:34,080 --> 00:01:36,920 TRANSCRIPTIONAL REGULATION OF 31 00:01:36,920 --> 00:01:37,160 HIV. 32 00:01:37,160 --> 00:01:41,840 IN 1992 HE JOINED A NEWEL FORMED 33 00:01:41,840 --> 00:01:44,360 LABORATORY OF HOST INTERESTS, 34 00:01:44,360 --> 00:01:46,920 SHIFTING HIS INTEREST TO HOST 35 00:01:46,920 --> 00:01:48,800 SIDE FOCUSING ON INFECTIONS. 36 00:01:48,800 --> 00:01:50,640 HIS WORK FOCUSED ON THE 37 00:01:50,640 --> 00:01:51,360 PATHOGENESIS OF CHRONIC LUNG 38 00:01:51,360 --> 00:01:54,920 DISEASES AS WELL AS IMMUNE 39 00:01:54,920 --> 00:01:57,840 DEFECTS, FAIG O SIGHTS 40 00:01:57,840 --> 00:01:58,760 ESPECIALLY THOSE PREDISPOSED TO 41 00:01:58,760 --> 00:01:59,840 MICROBACTERIAL DISEASES, HE WAS 42 00:01:59,840 --> 00:02:02,120 THE CHIEF OF THE LABORATORY OF 43 00:02:02,120 --> 00:02:06,360 CLINICAL INFECT YOWZ DISEASES IN 44 00:02:06,360 --> 00:02:08,320 2004-2016 AND THEN BECAME 45 00:02:08,320 --> 00:02:11,160 SCIENTIFIC DIRECTOR FOR NIAID IN 46 00:02:11,160 --> 00:02:11,760 2016. 47 00:02:11,760 --> 00:02:13,680 DR. HOLLAND IS ALSO AN ASSOCIATE 48 00:02:13,680 --> 00:02:18,600 PROFESSOR AT MEDICINE AT JOHNS 49 00:02:18,600 --> 00:02:19,360 HOPKINS. 50 00:02:19,360 --> 00:02:20,680 DR. HOLLAND LEADS THE IMMUNO 51 00:02:20,680 --> 00:02:25,240 PATHOGENESIS SECTION WHICH TAKES 52 00:02:25,240 --> 00:02:28,000 A FULL APPROACH OF LOOKING AT 53 00:02:28,000 --> 00:02:30,160 DISEASE WITH PATHOGENS AND 54 00:02:30,160 --> 00:02:31,160 MECHANISMS OF PATHOGENESIS TO 55 00:02:31,160 --> 00:02:34,040 IDENT FIELD FUNCTIONS NOVEL 56 00:02:34,040 --> 00:02:34,560 THERAPEUTICS. 57 00:02:34,560 --> 00:02:36,320 THE CLOSEST BIOLOGIST OF THESE 58 00:02:36,320 --> 00:02:39,800 MDs, Ph.D.s AND 59 00:02:39,800 --> 00:02:41,000 BACCALAUREATE CREATE A 60 00:02:41,000 --> 00:02:42,800 ENVIRONMENT WHERE HAPPEN LO 61 00:02:42,800 --> 00:02:44,040 INSUFFICIENCY WAS FIRST 62 00:02:44,040 --> 00:02:46,320 PHENOTYPICALLY AND GENO 63 00:02:46,320 --> 00:02:47,360 TYPICALLY IDENTIFIED AND HIS 64 00:02:47,360 --> 00:02:50,760 GROUP NOW FOLLOWS OVER 100 65 00:02:50,760 --> 00:02:54,160 PATIENTS FOR PREE AND POST 66 00:02:54,160 --> 00:02:55,200 TRANSPLANT. 67 00:02:55,200 --> 00:02:58,320 DR. HOLLAND IS THE RECIPIENT OF 68 00:02:58,320 --> 00:02:59,960 NUMEROUS AWARDS, BOARD CERTIFIED 69 00:02:59,960 --> 00:03:02,040 IN INFECT YOWZ DISEASES AND HAS 70 00:03:02,040 --> 00:03:04,400 OVER 600 PEER REVIEWED 71 00:03:04,400 --> 00:03:05,080 PUBLICATIONS. 72 00:03:05,080 --> 00:03:07,680 OUR SECOND SPEAKER AND 73 00:03:07,680 --> 00:03:09,960 DR. HICKSTEIN WITH THE THERAPY 74 00:03:09,960 --> 00:03:11,280 PROGRAM AND THE CENTER FOR 75 00:03:11,280 --> 00:03:14,560 CANCER RESEARCH AT THE NCI. 76 00:03:14,560 --> 00:03:16,040 DR. HICKSTEIN EARNED HIS MEDICAL 77 00:03:16,040 --> 00:03:16,800 DEGREE FROM THE UNIVERSITY OF 78 00:03:16,800 --> 00:03:20,160 NEBRASKA, COLLEGE OF MEDICINE IN 79 00:03:20,160 --> 00:03:21,520 1978 AND CONTINUED MEDICAL 80 00:03:21,520 --> 00:03:25,600 TRAINING WITH AN INTERNSHIP AND 81 00:03:25,600 --> 00:03:26,560 RESIDENCY OF INTERNAL MEDICINE 82 00:03:26,560 --> 00:03:28,200 AT THE MEDICAL CENTER. 83 00:03:28,200 --> 00:03:29,800 HE THEN COMPLETED TRAINING AT 84 00:03:29,800 --> 00:03:30,920 THE HEMEATOLOGY AT THE 85 00:03:30,920 --> 00:03:32,280 WASHINGTON SCHOOL OF MEDICINE 86 00:03:32,280 --> 00:03:34,200 AND A FRED HUTCHISON CANCER 87 00:03:34,200 --> 00:03:35,120 RESEARCH CENTER IN SEATTLE 88 00:03:35,120 --> 00:03:37,080 WASHINGTON WHERE HE WORKED IN 89 00:03:37,080 --> 00:03:40,160 HIS DIRECTION OF NOBEL PRIZE 90 00:03:40,160 --> 00:03:42,120 WINNER EDONALD THOMAS. 91 00:03:42,120 --> 00:03:43,400 DR. HICK STEIN BEGAN HIS 92 00:03:43,400 --> 00:03:44,840 ACADEMIC CAREER AT THE 93 00:03:44,840 --> 00:03:45,720 UNIVERSITY OF WASHINGTON SCHOOL 94 00:03:45,720 --> 00:03:48,680 OF MEDICINE AND THE DIVISION OF 95 00:03:48,680 --> 00:03:50,080 HEMEATOLOGY AND HELD EFFECTIVE 96 00:03:50,080 --> 00:03:52,400 EQUIPMENTSA THE VETERAN AFFAIR 97 00:03:52,400 --> 00:03:54,720 PIEWJET SOUND SYSTEMS AND THE 98 00:03:54,720 --> 00:03:56,040 FRED HUTCHISON CANCER RESEARCH 99 00:03:56,040 --> 00:03:56,400 CENTER. 100 00:03:56,400 --> 00:04:01,680 IN 2000 DR. HICKSTEIN WAS 101 00:04:01,680 --> 00:04:04,600 RECRUITED TO JOIN THE NCI IN 102 00:04:04,600 --> 00:04:06,080 GENE TRANSPLANTATION AND THERAPY 103 00:04:06,080 --> 00:04:08,760 FOR CHILDREN AND ADULTS WITH 104 00:04:08,760 --> 00:04:12,080 GENETIC IMMUNO DEFICIENCY 105 00:04:12,080 --> 00:04:13,360 DISEASES. 106 00:04:13,360 --> 00:04:14,880 DR. HICKSTEIN'S LAB FOCUSES ON 107 00:04:14,880 --> 00:04:17,600 RECEIPTLY DESCRIBED BONE FAILURE 108 00:04:17,600 --> 00:04:18,920 SYNDROME AND GATA INSUFFICIENCY, 109 00:04:18,920 --> 00:04:22,200 IN PARTICULAR THE LAB IS 110 00:04:22,200 --> 00:04:23,680 INVESTIGATING NUMEROUS MUTATIONS 111 00:04:23,680 --> 00:04:25,960 OUTSIDE OF GATA 2 EXONS IN 112 00:04:25,960 --> 00:04:28,520 PATIENTS WITH CAD WHAT SYNDROME 113 00:04:28,520 --> 00:04:32,200 AND MYELOID PATIENTS WHO HAVE 114 00:04:32,200 --> 00:04:33,040 DEFICIENCY OF MYELOID 115 00:04:33,040 --> 00:04:34,520 PROGRESSION AND DEVELOPING NEW 116 00:04:34,520 --> 00:04:37,440 APPROACHES TO THE TREATMENT OF 117 00:04:37,440 --> 00:04:40,160 THE DEFICIENCY WITH STEM CELL 118 00:04:40,160 --> 00:04:41,080 TRANSPLANTEDDATION, 119 00:04:41,080 --> 00:04:42,760 DR. HICKSTEIN IS THE AUTHOR OF 120 00:04:42,760 --> 00:04:44,320 OVER 100 PEER REVIEW ARTICLES 121 00:04:44,320 --> 00:04:45,920 AND AMERICAN OF THE COLLEGE OF 122 00:04:45,920 --> 00:04:47,480 PHYSICIANS AND AMERICAN SOCIETY 123 00:04:47,480 --> 00:04:49,080 OF HEMEATOLOGY AND AMERICAN 124 00:04:49,080 --> 00:04:50,160 SOCIETY OF CLINICAL 125 00:04:50,160 --> 00:04:50,920 INVESTIGATION. 126 00:04:50,920 --> 00:04:52,440 HE IS BOARD CERTIFIED IN 127 00:04:52,440 --> 00:04:54,000 HEMEATOLOGY AND INTERNAL 128 00:04:54,000 --> 00:04:54,680 MEDICINE. 129 00:04:54,680 --> 00:04:55,720 PLEASE WELCOME OUR FIRST SPEAKER 130 00:04:55,720 --> 00:04:59,000 DR. HOLLAND FOR HIS TALK 131 00:04:59,000 --> 00:05:00,440 ENTITLED MICROBACTERIA 132 00:05:00,440 --> 00:05:01,760 MONOSIGHTED O PENIA, DISPLASSIA 133 00:05:01,760 --> 00:05:05,160 COME TPGHT AT GATA 2. 134 00:05:05,160 --> 00:05:06,400 >> THANK YOU SO MUCH TOM. 135 00:05:06,400 --> 00:05:10,040 IT REALLY IS A GREAT PLEASURE TO 136 00:05:10,040 --> 00:05:13,240 BE HERE AND HAVE THE PRIVILEGE 137 00:05:13,240 --> 00:05:15,440 TO SPEAK TO YOU TODAY ABOUT THIS 138 00:05:15,440 --> 00:05:18,000 TOPIC THAT I THINK IS EXCITING 139 00:05:18,000 --> 00:05:19,240 FOR US AND DENNIS AND I HAVE 140 00:05:19,240 --> 00:05:21,680 BEEN WORKING ON THIS FOR A 141 00:05:21,680 --> 00:05:22,360 LANGUAGE TIME TOGETHER. 142 00:05:22,360 --> 00:05:23,880 OF COURSE AS IS TRUE FOR SO MANY 143 00:05:23,880 --> 00:05:27,080 OF MY COLLEAGUES HERE, I HAVE NO 144 00:05:27,080 --> 00:05:27,720 FINANCIAL DISCLOSURES. 145 00:05:27,720 --> 00:05:29,680 IN TERMS OF LEARNING 146 00:05:29,680 --> 00:05:32,120 OBJECTEDDIVES I'M ALWAYS A 147 00:05:32,120 --> 00:05:34,040 LITTLE CONFUSED, FOR MANY OF 148 00:05:34,040 --> 00:05:35,960 THESE TOPICS ARE COMPLEX, BUT IF 149 00:05:35,960 --> 00:05:46,320 I COULD GET YOU TO APPRECIATE 150 00:05:46,320 --> 00:05:47,960 HOW EXCITING THE DISCOVERY WAS 151 00:05:47,960 --> 00:05:49,680 AND HOW DIFFICULT THE 152 00:05:49,680 --> 00:05:50,360 PRESENTATIONS ARE TO RECOGNIZE 153 00:05:50,360 --> 00:05:51,720 AND THEN WHY IT'S SO IMPORTANT 154 00:05:51,720 --> 00:05:55,280 TO MOVE ON FOR TRANSPLANT FOR 155 00:05:55,280 --> 00:05:56,560 THESE PATIENTS, I WILL HAVE FELT 156 00:05:56,560 --> 00:05:57,720 THAT I HAVE DONE MY JOB. 157 00:05:57,720 --> 00:06:01,400 SO GATA 2 IS THE QUINTESSENTIAL 158 00:06:01,400 --> 00:06:02,600 EXAMPLE OF THE BLIND AND THE 159 00:06:02,600 --> 00:06:04,080 ELEPHANT AND AS I WILL TRY AND 160 00:06:04,080 --> 00:06:05,480 SHOW YOU MANY DIFFERENT GROUPS 161 00:06:05,480 --> 00:06:10,320 AROUND THE WORLD OVER MANY YEARS 162 00:06:10,320 --> 00:06:11,720 HAVE SEEN THIS DISEASE AND 163 00:06:11,720 --> 00:06:13,440 RECOGNIZED IT IN OTHER SORT OF 164 00:06:13,440 --> 00:06:15,000 CONTEXT WITH DIFFERENT 165 00:06:15,000 --> 00:06:15,680 APPROACHES. 166 00:06:15,680 --> 00:06:17,720 SO IT REALLY CAN SHOW UP AS 167 00:06:17,720 --> 00:06:20,520 EVERYTHING SHOWN ON THIS SLIDE, 168 00:06:20,520 --> 00:06:23,640 AML, PULMONARY HYPE OR TENSION, 169 00:06:23,640 --> 00:06:24,640 LYMPHDEEMIA, PROGNOSIS AND IT 170 00:06:24,640 --> 00:06:27,120 WAS VERY DIFFICULT FOR PEOPLE TO 171 00:06:27,120 --> 00:06:29,240 COME UP WITH RECOGNITION THAT 172 00:06:29,240 --> 00:06:33,000 ALL OF THIS WAS 1 SINGLE 173 00:06:33,000 --> 00:06:33,440 COMPREHENSIVE BEAST. 174 00:06:33,440 --> 00:06:39,000 SO OUR STORY STARTS HERE IN 1984 175 00:06:39,000 --> 00:06:41,920 WHEN WHEN IN [INDISCERNIBLE] 176 00:06:41,920 --> 00:06:42,760 MASSACHUSETTS A 13 YEAR-OLD GIRL 177 00:06:42,760 --> 00:06:45,720 PRESENTED TO THE MEDICAL CENTER 178 00:06:45,720 --> 00:06:48,720 WITH LIFE THREATENING VERA CELLA 179 00:06:48,720 --> 00:06:50,120 INFECTION, BAD CHICKEN POX, HER 180 00:06:50,120 --> 00:06:52,160 BODY WAS COVERED WITH CHICKEN 181 00:06:52,160 --> 00:06:53,240 POX LESIONS AND THERE WAS 182 00:06:53,240 --> 00:06:54,960 CLINICAL AND X-RAY EVIDENCE FOR 183 00:06:54,960 --> 00:06:56,920 PNEUMONIA CAUSED BY THIS. 184 00:06:56,920 --> 00:06:58,240 THEY TREATED HER VERY PROPERTILY 185 00:06:58,240 --> 00:07:01,400 WITH ALL THE RIGHT DRUGS AT THE 186 00:07:01,400 --> 00:07:02,560 TIME, STILL FRANKLY, THE DRUGS 187 00:07:02,560 --> 00:07:05,120 WE WOULD USE NOW BUT THEY 188 00:07:05,120 --> 00:07:06,080 REALIZED THAT SHE HADN'T BEEN 189 00:07:06,080 --> 00:07:08,760 WELL ALL HER LIFE AND SHE HAD 190 00:07:08,760 --> 00:07:10,560 RECURRENT EAR INFECTIONS WITH 191 00:07:10,560 --> 00:07:13,760 PERFORATIONS AND HAD A LOW WHITE 192 00:07:13,760 --> 00:07:15,400 COUNT. 193 00:07:15,400 --> 00:07:17,400 AND THEY WERE VERY CONCERNED 194 00:07:17,400 --> 00:07:19,840 THAT HER WHITE CELL COUNT RANGED 195 00:07:19,840 --> 00:07:20,400 SOMEWHERE BETWEEN NORMAL AND 196 00:07:20,400 --> 00:07:23,640 HALF OF WHAT IT SHOULD BE BUT 197 00:07:23,640 --> 00:07:26,920 THERE WAS NO FAMILY HISTORY. 198 00:07:26,920 --> 00:07:28,240 BECAUSE IT WAS 1984, BECAUSE 199 00:07:28,240 --> 00:07:29,360 BONE MARROW TRANSPLANT WAS NOT 200 00:07:29,360 --> 00:07:31,760 AS AVAILABLE AND NOT AS GOOD, 201 00:07:31,760 --> 00:07:34,880 FRANKLY, SHE DIDN'T MAKE IT ALL 202 00:07:34,880 --> 00:07:36,760 THE WAY TO TRANSPLANT. 203 00:07:36,760 --> 00:07:39,320 BUT THE GROUP THAT MET HER LED 204 00:07:39,320 --> 00:07:40,920 BY JOHN SULLIVAN, THE GROUP THAT 205 00:07:40,920 --> 00:07:42,720 MET HER THOUGHT THAT THEY SAW 206 00:07:42,720 --> 00:07:47,200 SOMETHING IMPORTANT BECAUSE IN 207 00:07:47,200 --> 00:07:49,400 THAT LEUKOPENIA SHE HAD VERY FEW 208 00:07:49,400 --> 00:07:52,120 OR NO NK CELLS, THAT IS NATURAL 209 00:07:52,120 --> 00:07:53,800 KILLER CELLS FOR KILLING VIRUS 210 00:07:53,800 --> 00:07:56,040 INFECTED CELLS AND THEY DID THE 211 00:07:56,040 --> 00:07:56,960 EXPERIMENTS SHOWN HERE FROM 212 00:07:56,960 --> 00:07:58,920 THEIR PAPER, IN WHICH THEY 213 00:07:58,920 --> 00:08:02,240 SHOWED THAT THE CELLS FROM THE 214 00:08:02,240 --> 00:08:04,280 PATIENT DIDN'T KILL TARGET CELLS 215 00:08:04,280 --> 00:08:08,040 THAT WERE VIRUS INFECTED OR 216 00:08:08,040 --> 00:08:09,280 SURROGATES FOR VIRUS INFECTION 217 00:08:09,280 --> 00:08:09,480 INVITRO. 218 00:08:09,480 --> 00:08:11,320 AND YOU CAN SEE IN THE RED 219 00:08:11,320 --> 00:08:13,400 BOXES, THE PATIENT CELLS ARE 220 00:08:13,400 --> 00:08:15,520 DOING NADA WHEREAS NORMAL CELLS 221 00:08:15,520 --> 00:08:16,520 ARE DOING PLENTY. 222 00:08:16,520 --> 00:08:19,360 AND THEY WENT TO TO PUBLISH THIS 223 00:08:19,360 --> 00:08:20,960 IN THE NEW ENGLAND JOURNAL 5 224 00:08:20,960 --> 00:08:22,800 YEARS AFTER THIS CHILD 225 00:08:22,800 --> 00:08:23,280 PRESENTED. 226 00:08:23,280 --> 00:08:25,560 SO REMEMBER, THAT 5 YEAR LEG, 227 00:08:25,560 --> 00:08:28,040 THAT'S A THEME THAT WILL KEEP 228 00:08:28,040 --> 00:08:30,000 COMING BACK AND THEY POINTED OUT 229 00:08:30,000 --> 00:08:33,360 THIS WAS SEVERE HERPES VIRUS 230 00:08:33,360 --> 00:08:36,800 INFECTION, IN AN ADOLESCENT 231 00:08:36,800 --> 00:08:37,720 WITHOUT NK CELLS. 232 00:08:37,720 --> 00:08:39,680 WELL, AT THE SAME TIME THEY 233 00:08:39,680 --> 00:08:40,960 PUBLISHED THAT IN 1989, I WAS 234 00:08:40,960 --> 00:08:43,480 COMING HERE TO THE NIH AND SORT 235 00:08:43,480 --> 00:08:44,920 OF STANDING AROUND IN THE FIELD 236 00:08:44,920 --> 00:08:46,320 WAITING FOR MEDICAL LIGHTNING TO 237 00:08:46,320 --> 00:08:51,480 STRIKE AND IT WAS IN 1992 IN THE 238 00:08:51,480 --> 00:08:53,720 LAB RUN BY JOHN GOWAN THAT I 239 00:08:53,720 --> 00:08:57,280 FIRST GOT REFERRED THIS PATIENT 240 00:08:57,280 --> 00:09:00,200 SHOWN HERE, A 41 YEAR-OLD WOMAN 241 00:09:00,200 --> 00:09:03,880 WHO HAD SEVERE REFRACTORY 242 00:09:03,880 --> 00:09:04,960 MICROBACTERIUM AVIAN COMPLEX 243 00:09:04,960 --> 00:09:06,960 INFECTION, NOW FOR THOSE WHO ARE 244 00:09:06,960 --> 00:09:08,160 LIKE, FM THIS 245 00:09:08,160 --> 00:09:11,640 NOT REMEMBER THAT BACK IN THE 246 00:09:11,640 --> 00:09:17,520 1980S AND 90S, DISSEMINATED MAC, 247 00:09:17,520 --> 00:09:19,800 THE ORGANISM THAT LIVES IN WATER 248 00:09:19,800 --> 00:09:21,240 AND DIRT ALL AROUND THE WORLD 249 00:09:21,240 --> 00:09:22,760 THAT INFECTION WAS JUST PROFOUND 250 00:09:22,760 --> 00:09:24,320 IN PATIENTS WITH ADVANCED HIV 251 00:09:24,320 --> 00:09:26,080 INFECTION AND WE WERE TRYING 252 00:09:26,080 --> 00:09:27,120 DESPERATELY TO UNDERSTAND WHAT 253 00:09:27,120 --> 00:09:30,920 IT WAS, WHAT TO DO ABOUT IT, HOW 254 00:09:30,920 --> 00:09:31,400 TO TREAT IT. 255 00:09:31,400 --> 00:09:32,680 SO WE WERE VERY INTERESTED IN 256 00:09:32,680 --> 00:09:35,320 PATIENTS WHO DID NOT HAVE HIV 257 00:09:35,320 --> 00:09:37,200 INFECTION WHO HAD THESE 258 00:09:37,200 --> 00:09:39,160 DISSEMINATED INFECTIONS. 259 00:09:39,160 --> 00:09:44,480 AND THIS WOMAN AT AGE 41 HAD THE 260 00:09:44,480 --> 00:09:46,920 M-AI HAVE UMKC ON THE SIDE OF 261 00:09:46,920 --> 00:09:48,240 THE SCREEN, HUGE PUOF THULES 262 00:09:48,240 --> 00:09:49,880 THAT WERE OOZING, AND SHE WAS 263 00:09:49,880 --> 00:09:50,520 COMPLAINING OF TROUBLE WITH HER 264 00:09:50,520 --> 00:09:53,600 VISION AND IN FACT, HER RIGHT 265 00:09:53,600 --> 00:09:55,040 EYE--SORRY HER LEFT EYE HAD THIS 266 00:09:55,040 --> 00:09:56,920 MASS AT THE BACK OF IT, YOU SEE 267 00:09:56,920 --> 00:09:58,880 WITH THE ARROW THAT TURNED OUT 268 00:09:58,880 --> 00:10:00,640 TO BE A SMOOTH MUSCLE TUMOR THAT 269 00:10:00,640 --> 00:10:04,600 WAS CHOKED FULL OF EPSTEIN BAR 270 00:10:04,600 --> 00:10:04,800 VIRUS. 271 00:10:04,800 --> 00:10:06,280 SO WHAT WAS THE STORY WITH THIS 272 00:10:06,280 --> 00:10:09,760 WOMAN, WELL SHE HAD A NORMAL 273 00:10:09,760 --> 00:10:12,240 CHILDHOOD, BUT STARTING IN LATE 274 00:10:12,240 --> 00:10:13,640 ADOLESCENT AND EARLY ADULTHOOD 275 00:10:13,640 --> 00:10:15,680 SHE HAD SEVERE WARTS THAT KEPT 276 00:10:15,680 --> 00:10:17,960 ON OCCURRING IN THE VAGINAL AND 277 00:10:17,960 --> 00:10:20,240 ANNAL AREA, IN HER THIRDS SHE 278 00:10:20,240 --> 00:10:22,040 DEVELOPED PNEUMONIA WHICH WAS 279 00:10:22,040 --> 00:10:23,200 TREATED WITH A LOBECTOMY, 280 00:10:23,200 --> 00:10:25,640 NONAPOPTOTIC THE YOUR TYPICAL 281 00:10:25,640 --> 00:10:26,760 APPROACH TO PNEUMONIA THERAPY 282 00:10:26,760 --> 00:10:28,560 BUT THAT TELLS YOU HOW DESPERATE 283 00:10:28,560 --> 00:10:30,640 THEY WERE TO GET HER PNEUMONIA 284 00:10:30,640 --> 00:10:31,760 UNDER CONTROL AND HOW UNABLE 285 00:10:31,760 --> 00:10:33,760 THEY WERE TO DO IT WITH 286 00:10:33,760 --> 00:10:35,400 ANTIBIOTICS AND THEN IN HER LATE 287 00:10:35,400 --> 00:10:38,160 30S SHE DEVELOPED THIS 288 00:10:38,160 --> 00:10:38,800 DISSEMINATED MICROBABLGHTERIAL 289 00:10:38,800 --> 00:10:39,760 INFECTION THAT REAL LE THEY WERE 290 00:10:39,760 --> 00:10:42,200 NONAPOPTOTIC THE SUCCESSFUL IN 291 00:10:42,200 --> 00:10:42,520 HANDLING. 292 00:10:42,520 --> 00:10:43,640 WHEN THEY SENT HER TO US WE 293 00:10:43,640 --> 00:10:44,760 REALIZED THAT AMONG ALL THE 294 00:10:44,760 --> 00:10:47,400 OTHER PROBLEMS THAT SHE HAD IN 295 00:10:47,400 --> 00:10:48,880 HER PERHIVERAL BLOOD, THERE WERE 296 00:10:48,880 --> 00:10:51,600 NO MONOCYTES, NO B-CELLS AND NO 297 00:10:51,600 --> 00:10:54,200 NK CELLS, DESPITE THAT, SHE HAD 298 00:10:54,200 --> 00:10:55,480 NORMAL IMMUNOGLOBULINS AND HER 299 00:10:55,480 --> 00:10:59,920 T-CELL NUMBER WAS ROUGHLY OKAY. 300 00:10:59,920 --> 00:11:03,320 SO AT THE TIME, UNDER JOHN 301 00:11:03,320 --> 00:11:04,480 GOWAN'S LEADERSHIP BECAUSE OF 302 00:11:04,480 --> 00:11:06,280 THE EXPERIENCE IN CHRONIC 303 00:11:06,280 --> 00:11:08,560 GRANULA'S DISEASE, WE TREATED 304 00:11:08,560 --> 00:11:09,760 HER WITH INTERFERON-GAMMA FOR A 305 00:11:09,760 --> 00:11:10,600 VARIETY OF REASONS WHICH TURNED 306 00:11:10,600 --> 00:11:12,440 OUT TO BE GOOD REASONS BECAUSE 307 00:11:12,440 --> 00:11:14,920 IN ADDITION TO THE DRUGS SHE WAS 308 00:11:14,920 --> 00:11:16,080 RECEIVING HER MICROBACTERIAL 309 00:11:16,080 --> 00:11:18,560 DISEASE REALLY DISAPPEARED AND 310 00:11:18,560 --> 00:11:20,240 IT WAS EXTREMELY GRATIFYING TO 311 00:11:20,240 --> 00:11:22,160 WATCH THAT HAPPEN. 312 00:11:22,160 --> 00:11:24,520 HOWEVER, ABOUT 2 YEARS INTO HER 313 00:11:24,520 --> 00:11:26,640 TREATMENT SHE DEVELOPED CHRONIC 314 00:11:26,640 --> 00:11:27,600 MILE O MONOSITTIC LEUKEMIA AND 315 00:11:27,600 --> 00:11:28,800 BECAUSE OF THAT WE WERE WORRIED 316 00:11:28,800 --> 00:11:30,560 THAT OUR DRUG MIGHT HAVE BEEN 317 00:11:30,560 --> 00:11:34,920 RESPONSIBLE, WE STOPPED THE 318 00:11:34,920 --> 00:11:36,800 INTERFERON-GAMMA, AND SENT HER 319 00:11:36,800 --> 00:11:37,560 MIKE PROBACTERIAL INFECTION DID 320 00:11:37,560 --> 00:11:39,360 RETURN BUT BY THAT TIME WE HAD 321 00:11:39,360 --> 00:11:41,080 SENT HER ON TO BONE MARROW 322 00:11:41,080 --> 00:11:43,600 TRANSPLANT DOWN AT HER HOME IN 323 00:11:43,600 --> 00:11:44,160 TEXAS. 324 00:11:44,160 --> 00:11:48,160 SHE HAD A SUCCESSFUL TRANSPLANT 325 00:11:48,160 --> 00:11:49,400 BUT UNFORTUNATELY DEVELOPED A 326 00:11:49,400 --> 00:11:52,720 PNEUMONIA BACK WHEN SHE HAD 327 00:11:52,720 --> 00:11:55,400 RETURNED HOME WITH HER COMMUNITY 328 00:11:55,400 --> 00:11:56,880 RESPIRATORY VIRUS AND SHE DIED. 329 00:11:56,880 --> 00:12:00,920 BUT AS PART OF OUR COMMITMENT TO 330 00:12:00,920 --> 00:12:01,800 UNDERSTANDING THESE DISEASES WE 331 00:12:01,800 --> 00:12:10,840 BROUGHT HER BACK FOR AN 332 00:12:10,840 --> 00:12:12,960 AUTOPSIES SO I WANT TO SAY HOW 333 00:12:12,960 --> 00:12:15,000 CRITICALLY IMPORTANT IT IS TO DO 334 00:12:15,000 --> 00:12:16,360 THOSE AUTOPSIESS, IN THAT LAST 335 00:12:16,360 --> 00:12:17,680 MEASURE OF DEVOTION TO THE 336 00:12:17,680 --> 00:12:18,680 FAMILY, TO THE DISEASE TO FIGURE 337 00:12:18,680 --> 00:12:19,640 OUT WHAT WAS GOING ON. 338 00:12:19,640 --> 00:12:21,280 AND IN THE AUTOPSIES WE SAW 339 00:12:21,280 --> 00:12:22,680 COUPLE THINGS THAT WERE REALLY 340 00:12:22,680 --> 00:12:23,560 SORT EVER SURPRISING. 341 00:12:23,560 --> 00:12:25,600 NUMBER 1, DESPITE THE FACT THAT 342 00:12:25,600 --> 00:12:27,600 SHE HAD NO MONOCYTES IN HER 343 00:12:27,600 --> 00:12:29,120 PERIPHERAL BLOOD, THERE WERE 344 00:12:29,120 --> 00:12:30,680 LOTS OF MACROPHAGES IN HER 345 00:12:30,680 --> 00:12:34,040 TISSUE AND YOU CAN SEE HERE IN 346 00:12:34,040 --> 00:12:35,560 THE BROWN STAINING, THE 347 00:12:35,560 --> 00:12:37,080 MACROPHAGES THAT WE SAW IN HER 348 00:12:37,080 --> 00:12:38,320 TISSUE, AND DESPITE THE FACT 349 00:12:38,320 --> 00:12:41,040 THAT SHE HAD NO B-CELLS IN HER 350 00:12:41,040 --> 00:12:42,680 PERIPHERAL BLOOD, SHE HAD PLENTY 351 00:12:42,680 --> 00:12:44,280 OF PLASMA CELLS IN HER TISSUE 352 00:12:44,280 --> 00:12:48,640 AND AS I MENTIONED, HER IMMUNO 353 00:12:48,640 --> 00:12:50,400 GLOBEUE LYNN LEVELS WERE NORMAL. 354 00:12:50,400 --> 00:12:51,520 THIS WAS ALL REALLY CONFUSING 355 00:12:51,520 --> 00:12:54,040 AND I CAN TELL YOU THERE WERE 356 00:12:54,040 --> 00:12:56,200 PLENTY OF DISCUSSIONS ABOUT 357 00:12:56,200 --> 00:12:57,040 DIFFERENT POSSIBILITIES, MOST OF 358 00:12:57,040 --> 00:12:59,640 WHICH TURNED OUT TO BE WRONG. 359 00:12:59,640 --> 00:13:02,640 SO IN THE PROCESS OF WORKING HER 360 00:13:02,640 --> 00:13:04,840 UP FOR HER TRANSPLANT, WE HAD TO 361 00:13:04,840 --> 00:13:05,880 EVALUATE HER FAMILY MEMBERS TO 362 00:13:05,880 --> 00:13:08,000 LOOK FOR A DONOR, SO SHOWN HERE 363 00:13:08,000 --> 00:13:10,800 WITH THE ARROW IS OUR INDEX 364 00:13:10,800 --> 00:13:13,720 PATIENT WHO HAD WARTS, MAC AND 365 00:13:13,720 --> 00:13:16,960 AS YOU SEE NO B-CELLS, MONOOR NK 366 00:13:16,960 --> 00:13:19,200 CELLS AND THEN DEVELOPED CMML, 367 00:13:19,200 --> 00:13:21,560 YOU ALSO SEE THERA HER METHOD 368 00:13:21,560 --> 00:13:24,160 INTERESTING ENOUGH HAD DIED IN 369 00:13:24,160 --> 00:13:27,280 HER EARLY 50S WITH CHRONIC MILE 370 00:13:27,280 --> 00:13:29,520 O MONOSITTIC LEUKEMIA AND 371 00:13:29,520 --> 00:13:30,440 MICROBACTERIAL DISEASE, SHE DIED 372 00:13:30,440 --> 00:13:32,920 BEFORE WE MET HER BUT HER SISTER 373 00:13:32,920 --> 00:13:37,160 IN THE PROCESS OF OUR TRYING TO 374 00:13:37,160 --> 00:13:37,920 EVALUATE FOR TRANSPLANT, WE 375 00:13:37,920 --> 00:13:40,400 REALIZE THAT HER SISTER ALSO HAD 376 00:13:40,400 --> 00:13:43,040 SEVERE WARTS, AND NO B-CELLS, 377 00:13:43,040 --> 00:13:44,320 MONOCYTES OR NK CELLS ALTHOUGH 378 00:13:44,320 --> 00:13:48,040 SHE HAD NOT AT THAT TIME HAD ANY 379 00:13:48,040 --> 00:13:49,000 OTHER SERIOUS INFECTIONS. 380 00:13:49,000 --> 00:13:50,600 NOW WE REALIZED LOOKINGA THE 381 00:13:50,600 --> 00:13:53,600 THIS PATTERN, THIS IS A VERTICAL 382 00:13:53,600 --> 00:13:53,840 DISEASE. 383 00:13:53,840 --> 00:13:57,200 IT'S GOT TO BE BEING TRANSMITTED 384 00:13:57,200 --> 00:13:59,000 FROM GENERATION TO GENERATION BY 385 00:13:59,000 --> 00:13:59,480 A SINGLE GENE. 386 00:13:59,480 --> 00:14:04,680 AND IF IT'S A SINGLE GENE OUR 387 00:14:04,680 --> 00:14:05,440 HYPOTHESIS WAS IN 1992 THAT WE 388 00:14:05,440 --> 00:14:07,760 SHOULD BE ABLE TO FIND IT. 389 00:14:07,760 --> 00:14:09,240 NOW JUST TAKING A DIVERSION FOR 390 00:14:09,240 --> 00:14:11,480 A SECOND ABOUT HER SISTER, HER 391 00:14:11,480 --> 00:14:13,760 34 YEAR-OLD SISTER WHO WAS--YOU 392 00:14:13,760 --> 00:14:14,520 KNOW PHENOTYPICALLY FINE, SHE 393 00:14:14,520 --> 00:14:19,320 WAS LIVING IN DENVER, HAD 394 00:14:19,320 --> 00:14:20,880 SEVERAL CHILDREN, WHEN WE 395 00:14:20,880 --> 00:14:23,680 EVALUATED HER AND WE LOOKED AT 396 00:14:23,680 --> 00:14:25,520 HER PERIPHERAL BLOOD COUNTS. 397 00:14:25,520 --> 00:14:27,280 WE SAID WE PROBABLY OUGHT TO 398 00:14:27,280 --> 00:14:28,440 LOOK AT YOUR CHEST TO MAKE SURE 399 00:14:28,440 --> 00:14:30,040 IT'S OKAY, AND YOU CAN SEE HER 400 00:14:30,040 --> 00:14:31,560 CHEST CT WAS NOT OKAY, YOU CAN 401 00:14:31,560 --> 00:14:34,840 SEE THAT THERE WAS SOME VERY 402 00:14:34,840 --> 00:14:35,640 SUBTLE DIFFUSE ABNORMALITIES, 403 00:14:35,640 --> 00:14:37,120 THE LUNG FIELDS THAT ARE IN THE 404 00:14:37,120 --> 00:14:39,760 CENTER OF THE CT SCAN THERE, 405 00:14:39,760 --> 00:14:41,840 SHOULD BE PRETTY, YOU KNOW BLACK 406 00:14:41,840 --> 00:14:43,280 AND CLEAR AND HERS WEREN'T. 407 00:14:43,280 --> 00:14:46,360 AND SO, WE SAID TO HER, YOU 408 00:14:46,360 --> 00:14:48,000 KNOW, IT MIGHT BE WORTH DOING A 409 00:14:48,000 --> 00:14:50,120 LUNG BIOPSY AND SHE SAID, I LIVE 410 00:14:50,120 --> 00:14:51,840 IN DENVER, I'M FEELING FINE, I'M 411 00:14:51,840 --> 00:14:53,920 TAKING CARE OF MY KIDS, YOU'RE 412 00:14:53,920 --> 00:14:55,320 CRAZY AND I THOUGHT, YOU KNOW 413 00:14:55,320 --> 00:14:59,920 THAT'S NOT A BAD ARGUMENT, SO WE 414 00:14:59,920 --> 00:15:01,800 SAID WE'LL KEEP IN TOUCH AND SEE 415 00:15:01,800 --> 00:15:03,320 HOW THINGS GO. 416 00:15:03,320 --> 00:15:07,120 UNFORTUNATELY 9 YEARS LATER, SHE 417 00:15:07,120 --> 00:15:09,320 CAME BACK AND NOW HE WASN'T SO 418 00:15:09,320 --> 00:15:11,440 OKAY, AND SHE WASN'T LIVING IN 419 00:15:11,440 --> 00:15:13,800 DENVER AND THIS DIFFUSE PROCESS 420 00:15:13,800 --> 00:15:18,880 THAT YOU SEE HERE IS CALLED 421 00:15:18,880 --> 00:15:20,280 PULMONARY ALVEOLAR PROGNOSIS IN 422 00:15:20,280 --> 00:15:22,560 WHICH THE SECRETIONS INSIDE THE 423 00:15:22,560 --> 00:15:23,920 ALVEOLAR SPACE ACCUMULATE 424 00:15:23,920 --> 00:15:25,320 BECAUSE THE MACROPHAGES IN THE 425 00:15:25,320 --> 00:15:28,280 LUNG CAN'T DIGEST IT AND EXCRETE 426 00:15:28,280 --> 00:15:29,480 IT. 427 00:15:29,480 --> 00:15:31,360 AND THE COMMON--THE MOST COMMON 428 00:15:31,360 --> 00:15:37,800 CAUSE OF THIS ARE AUTO 429 00:15:37,800 --> 00:15:39,400 ANTIBODIES TO GMCSF, THAT WAS 430 00:15:39,400 --> 00:15:40,640 NOT IT, IT WAS SOMETHING ELSE 431 00:15:40,640 --> 00:15:43,000 RELATED TO THIS DISEASE. 432 00:15:43,000 --> 00:15:45,720 UNDER THE GUIDANCE OF KEN 433 00:15:45,720 --> 00:15:47,800 OLIVIER, MAJOR PULMONARY 434 00:15:47,800 --> 00:15:49,640 COLLABORATOR HERE, SHE UNDER 435 00:15:49,640 --> 00:15:51,800 WENT WHOLE LUNG LAVAGE AND YOU 436 00:15:51,800 --> 00:15:53,080 SEE THAT THE FLUID GOES FROM 437 00:15:53,080 --> 00:15:55,280 BEING OPAQUE AT THE TOP LEFT TO 438 00:15:55,280 --> 00:15:56,560 BE VERY CLEAR AT THE LOW RIGHT 439 00:15:56,560 --> 00:16:00,400 AND WHEN WE LOOKEDDA THE THAT 440 00:16:00,400 --> 00:16:03,920 FLUID WE SAW PLENTY OF ALVEOLAR 441 00:16:03,920 --> 00:16:06,400 MACK RAPHAGES AND YET THERE HAD 442 00:16:06,400 --> 00:16:08,360 BEEN NONE IN HER CIRCULATING 443 00:16:08,360 --> 00:16:08,560 BLOOD. 444 00:16:08,560 --> 00:16:12,000 SO WE BEGIN TO SAY, WOW, THIS IS 445 00:16:12,000 --> 00:16:13,160 REALLY AN UNUSUAL SYNDROME. 446 00:16:13,160 --> 00:16:17,800 SO YOU REMEMBER WE STARTED IN 447 00:16:17,800 --> 00:16:18,960 1992 WITH OUR FIRST PATIENT. 448 00:16:18,960 --> 00:16:20,680 THIS PATIENT WE SAW BACK IN THE 449 00:16:20,680 --> 00:16:25,200 EARLY PART OF THE 2000S AND INTO 450 00:16:25,200 --> 00:16:27,400 THE MIDPART OF THE FIRST DECADE 451 00:16:27,400 --> 00:16:28,600 OF THE CENTURY. 452 00:16:28,600 --> 00:16:31,200 AND THOSE 18 PATIENTS THAT WE 453 00:16:31,200 --> 00:16:34,240 SAW OVER THAT TIME WE COLLECTED 454 00:16:34,240 --> 00:16:37,120 18 PATIENTS OVER 18 YEARS INTO A 455 00:16:37,120 --> 00:16:38,200 PAPER DESCRIBING THE PHENOTYPE 456 00:16:38,200 --> 00:16:40,880 OF THIS CONDITION THAT WE KNEW 457 00:16:40,880 --> 00:16:42,840 HAD TO BE A SINGLE DISEASE 458 00:16:42,840 --> 00:16:45,080 BECAUSE THERE WAS SUCH A 459 00:16:45,080 --> 00:16:48,200 SIMILARITY IN THE PATIENTS THEY 460 00:16:48,200 --> 00:16:49,920 HAD MICROBACTERIAL INFECTIONS AS 461 00:16:49,920 --> 00:16:53,280 YOU CAN SEE, HPV INFECTIONS AS 462 00:16:53,280 --> 00:16:57,840 WELL AS MANY OF THEM GOING TO TO 463 00:16:57,840 --> 00:16:58,640 DEVELOP MYELODYSPLASIA, LEUKEMIA 464 00:16:58,640 --> 00:17:00,480 AND MANY OTHER PROBLEMS AND THIS 465 00:17:00,480 --> 00:17:04,240 WAS DONE OVER MANY YEARS BY DON 466 00:17:04,240 --> 00:17:07,280 VINH AND SMITA, P A TEL OVER 467 00:17:07,280 --> 00:17:07,720 SEVERAL YEARS. 468 00:17:07,720 --> 00:17:09,080 AND WHAT DID THIS COHORT LOOK 469 00:17:09,080 --> 00:17:10,960 LIKE TO GIVE A FEW EXAMPLES, 470 00:17:10,960 --> 00:17:12,840 THIS 1 MAN SHOWN HERE, A 32 471 00:17:12,840 --> 00:17:17,120 YEAR-OLD MAN WHO WAS THE 1 472 00:17:17,120 --> 00:17:18,000 IDENTIFIED THERE WITH THE 473 00:17:18,000 --> 00:17:19,200 HISTOPLASMOSIS AND MAC, CAN YOU 474 00:17:19,200 --> 00:17:24,080 SEE ON THE TOP SCREEN THERE'S 475 00:17:24,080 --> 00:17:25,400 MAC IN HIS ALVEOLAR LAVAGE AND 476 00:17:25,400 --> 00:17:27,720 AT THE BOTTOM YOU CAN SEE A 477 00:17:27,720 --> 00:17:29,720 MACROPHAGE CHOKED FULL OF 478 00:17:29,720 --> 00:17:30,880 HISTOPLASMA, BUT WHAT YOU ALSO 479 00:17:30,880 --> 00:17:34,000 SEE IN HIS FAMILY TREE IS THAT 480 00:17:34,000 --> 00:17:39,080 HIS SISTER HAD DIED AT AGE 12 OF 481 00:17:39,080 --> 00:17:40,840 DISSEMINATED VERA CELLA ZOSTER 482 00:17:40,840 --> 00:17:42,520 VIRUS JUST LIKE THE GIRL IN THE 483 00:17:42,520 --> 00:17:48,560 1989 CASE REPORT AND THAT HIS 484 00:17:48,560 --> 00:17:50,960 MOTHER AT 61 HAD LIMP EDEMA AND 485 00:17:50,960 --> 00:17:53,680 THAT'S HER LEG THERE, IT'S 486 00:17:53,680 --> 00:17:54,840 SWOLLEN COMPARED TO THE LEFT 487 00:17:54,840 --> 00:17:56,400 LEG, AND SHE HAS MULTIPLE SPOTS, 488 00:17:56,400 --> 00:17:58,000 THEY LOOK LIKE SCARS OR BURNS 489 00:17:58,000 --> 00:18:00,720 BUT IN FACT THEY ARE FLAT WARTS, 490 00:18:00,720 --> 00:18:04,200 WARTS THAT ARE VERY TYPICAL FOR, 491 00:18:04,200 --> 00:18:05,960 YOU KNOW IMMUNO DEFICIENT VIRAL 492 00:18:05,960 --> 00:18:08,360 INFECTIONS AND WE REALIZED THAT 493 00:18:08,360 --> 00:18:09,800 THE RATE OF SEVERE HPV INFECTION 494 00:18:09,800 --> 00:18:13,520 JUST LIKE IN OUR INDEX CASE AND 495 00:18:13,520 --> 00:18:14,840 HER SISTER WAS REALLY A PROBLEM 496 00:18:14,840 --> 00:18:16,680 AND THE NUMBER OF THESE PEOPLE, 497 00:18:16,680 --> 00:18:19,560 YOUNG WOMEN WHO HAD SEVERE HPV 498 00:18:19,560 --> 00:18:22,360 INFECTION IN THE VAGINAL AND 499 00:18:22,360 --> 00:18:24,040 ANALL REGION AND IN THE CERVIX 500 00:18:24,040 --> 00:18:25,800 WAS TERRIBLE AND IT WAS 501 00:18:25,800 --> 00:18:27,520 DEVASTATING BECAUSE OF 502 00:18:27,520 --> 00:18:28,280 VUFULLECTOMYS AND EXTENSIVE 503 00:18:28,280 --> 00:18:30,200 SURGERY AS WELL AS THEN WARDS 504 00:18:30,200 --> 00:18:33,960 THAT PERSISTED ON MANY DIFFERENT 505 00:18:33,960 --> 00:18:35,840 BODY SURFACES, WELL INTO 506 00:18:35,840 --> 00:18:38,120 ADULTHOOD AND THEN THIS UNIFYING 507 00:18:38,120 --> 00:18:42,120 PROBLEM WAS THAT MANY OF THESE 508 00:18:42,120 --> 00:18:43,840 PATIENTS HAD MYELODYSPLASIA AND 509 00:18:43,840 --> 00:18:48,280 WHAT YOU SEE HERE IS THIS ENDITY 510 00:18:48,280 --> 00:18:49,600 OF HYPOBONE MARROW, THAT IS THE 511 00:18:49,600 --> 00:18:51,360 BONE MARROW SHOULD HAVE THE 512 00:18:51,360 --> 00:18:52,720 PURPLE ELEMENTS, THE RED 513 00:18:52,720 --> 00:18:55,040 ELEMENTS ARE BONE, THE PURPLE 514 00:18:55,040 --> 00:18:56,440 ELEMENTS ARE CELLS AND THE WHITE 515 00:18:56,440 --> 00:18:57,920 ELEMENTS ARE FAT AND FOR MOST 516 00:18:57,920 --> 00:18:59,680 PEOPLE BELOW THE AGE OF 50, YOU 517 00:18:59,680 --> 00:19:01,280 WOULD LIKE TO SEE IT'S MORE 518 00:19:01,280 --> 00:19:02,800 CELLS AND BONE THAN IT IS FAT 519 00:19:02,800 --> 00:19:04,760 AND THAT'S NOT THE CASE HERE, IN 520 00:19:04,760 --> 00:19:07,640 ADDITION, YOU SEE ALL OF THESE 521 00:19:07,640 --> 00:19:08,600 ABNORMAL MEGACARIO SIGHTS, THIS 522 00:19:08,600 --> 00:19:13,240 IS WORK DONE WITH CATHY CALVO, 523 00:19:13,240 --> 00:19:14,920 OUR CRITICAL HEMEAT O PATHOLOGY 524 00:19:14,920 --> 00:19:16,360 COLLABORATOR AND YOU CAN SEE 525 00:19:16,360 --> 00:19:18,720 THAT THESE EUKARYOTE SIGHTS HAVE 526 00:19:18,720 --> 00:19:21,120 SEPARATED NUCLEI WHICH IS 527 00:19:21,120 --> 00:19:26,520 ABNORMAL AND ATYPICAL AND A 528 00:19:26,520 --> 00:19:27,000 HALLMARK FOR DISPLASSIA. 529 00:19:27,000 --> 00:19:30,000 SO THEN OUR PROBLEM HERE IS THAT 530 00:19:30,000 --> 00:19:32,080 AFTER 18 YEARS I'M ABLE TO SAY, 531 00:19:32,080 --> 00:19:33,400 YEAH, THAT'S ABNORMAL AND WE'VE 532 00:19:33,400 --> 00:19:37,280 GOT A SERIES OF PATIENTS THAT 533 00:19:37,280 --> 00:19:39,680 HAVE CYTOPENIAS, INFECTIONS, 534 00:19:39,680 --> 00:19:50,080 BONE MARROW DYSFUNCTION, 535 00:19:51,640 --> 00:19:53,520 LYMPHDEMA, PULMONARY FOR A 536 00:19:53,520 --> 00:19:55,200 SINGLE GENE AND HO WILL WE PUT 537 00:19:55,200 --> 00:19:57,200 ALL THAT TOGETHER AND THEY SAY 538 00:19:57,200 --> 00:19:58,720 GOOD JUDGMENT COMES FROM BAD 539 00:19:58,720 --> 00:19:59,960 JUDGMENT AND I UNDERWENT MANY 540 00:19:59,960 --> 00:20:01,040 YEARS OF BAD JUDGMENT ABOUT THIS 541 00:20:01,040 --> 00:20:03,360 BUT IT WAS REALLY THE KRILICAL 542 00:20:03,360 --> 00:20:05,960 INSIGHT OF AMY SUH A BIOLOGIST 543 00:20:05,960 --> 00:20:07,720 IN THE LAB AT THAT TIME THAT 544 00:20:07,720 --> 00:20:10,040 SAID IT ALL HAS TO BE IN THE 545 00:20:10,040 --> 00:20:11,360 HEMATOPOIETIC STEM CELL AND THIS 546 00:20:11,360 --> 00:20:12,480 IS HOW THEY ALL CONNECT. 547 00:20:12,480 --> 00:20:14,480 YOU CAN SEE THAT THE SOLID RED 548 00:20:14,480 --> 00:20:15,680 LINE THERE TIES EVERYTHING 549 00:20:15,680 --> 00:20:18,640 TOGETHER EXCEPT THE T-CELLS 550 00:20:18,640 --> 00:20:20,840 WHICH WERE ROUGHLY NORMAL AND 551 00:20:20,840 --> 00:20:21,480 SUGGESTED THAT SOMETHING NORTH 552 00:20:21,480 --> 00:20:23,320 OF THOSE CELLS SHOULD BE THE 553 00:20:23,320 --> 00:20:25,680 PROBLEM. 554 00:20:25,680 --> 00:20:28,280 AND ON MAY THIRD, 2011 AMY 555 00:20:28,280 --> 00:20:33,160 CALLED ME UP, SHOUTING INTO THE 556 00:20:33,160 --> 00:20:35,160 PHONE THAT ALL THE PATIENTS THAT 557 00:20:35,160 --> 00:20:37,160 SHE SEQUENCED FOR THIS 558 00:20:37,160 --> 00:20:37,920 PARTICULAR GENE GATA 2 HAD 559 00:20:37,920 --> 00:20:38,880 SPECIFIC MUTATIONS IN IT. 560 00:20:38,880 --> 00:20:40,200 AND WHY IS THAT IMPORTANT? 561 00:20:40,200 --> 00:20:43,440 BECAUSE THIS IS A TRANSCRIPTION 562 00:20:43,440 --> 00:20:44,040 FACTOR. 563 00:20:44,040 --> 00:20:46,480 THAT IS TRANSCRIPTION FACTORS 564 00:20:46,480 --> 00:20:48,520 CAN SUBTEND MANY DIFFERENT ARCS 565 00:20:48,520 --> 00:20:50,960 AND ARE ABLE TO CONTROL MULTIPLE 566 00:20:50,960 --> 00:20:51,760 DIFFERENT PATHWAYS WHICH IS 567 00:20:51,760 --> 00:20:54,280 EXACTLY WHAT WE WANTED FOR THE 568 00:20:54,280 --> 00:20:57,960 COMPLEXITY OF WHAT WE SAW HERE. 569 00:20:57,960 --> 00:20:59,360 SO THAT WAS MAY THIRD AND FROM 570 00:20:59,360 --> 00:21:01,920 MAY THIRD TO THE TIME THIS PAPER 571 00:21:01,920 --> 00:21:03,520 WAS PUBLISHED ON JUNE 13th IN 572 00:21:03,520 --> 00:21:07,760 BLOOD, IT WAS ONLY ABOUT 5 AND 573 00:21:07,760 --> 00:21:09,400 HALF WEEKS, DESPITE THAT, THAT 574 00:21:09,400 --> 00:21:11,400 EXTRAORDINARY OUTPUT OF WORK 575 00:21:11,400 --> 00:21:15,040 THAT AMY DID, IT DID TAKE ME 19 576 00:21:15,040 --> 00:21:17,440 YEARS FROM THE TIME WE STARTED 577 00:21:17,440 --> 00:21:20,280 TO SEE THIS DISEASE TO GET IT 578 00:21:20,280 --> 00:21:20,440 OUT. 579 00:21:20,440 --> 00:21:22,600 NOW 1 OF THE REALITIES OF 580 00:21:22,600 --> 00:21:24,960 SCIENCE IS THAT IT'S AWFULLY 581 00:21:24,960 --> 00:21:26,680 HARD TO HAVE A COMPLETELY 582 00:21:26,680 --> 00:21:28,040 ORIGINAL IDEA, I DON'T SAY IT 583 00:21:28,040 --> 00:21:29,960 DOESN'T HAPPEN BUT IT DOESN'T 584 00:21:29,960 --> 00:21:31,080 HAPPEN TO ME VERY OFTEN. 585 00:21:31,080 --> 00:21:33,120 AND IN FACT WHILE WE WERE DOING 586 00:21:33,120 --> 00:21:35,600 THIS, IT TURNED OUT OTHER GROUPS 587 00:21:35,600 --> 00:21:37,080 WERE IDENTIFYING EXACTLY THE 588 00:21:37,080 --> 00:21:39,440 SAME GENE BUT WITH DIFFERENT 589 00:21:39,440 --> 00:21:43,080 MANIFESTATIONS, SO THIS GROUP 590 00:21:43,080 --> 00:21:44,800 FROM AUSTRALIA AND SEATTLE 591 00:21:44,800 --> 00:21:48,680 RECOGNIZED GATA 2 MUTATIONS WITH 592 00:21:48,680 --> 00:21:51,640 MILE DISPLASSIA AND ACUTE 593 00:21:51,640 --> 00:21:52,120 LEUKEMIA. 594 00:21:52,120 --> 00:21:54,840 THIS GROUP FROM ENGLAND 595 00:21:54,840 --> 00:21:56,680 RECOGNIZED THE DENDRITIC CELL 596 00:21:56,680 --> 00:21:59,120 MONOCYTE I HAVE AN NK CELL 597 00:21:59,120 --> 00:22:00,280 DEFICIENCY AND EVENTUALLY WENT 598 00:22:00,280 --> 00:22:02,680 ON, THIS IS THEIR PHENOTYPIC 599 00:22:02,680 --> 00:22:04,600 DESCRIPTION, WENT ON TO IDENTIFY 600 00:22:04,600 --> 00:22:07,160 THE GENE IN THEIR COHORT 601 00:22:07,160 --> 00:22:07,520 SUBSEQUENTLY. 602 00:22:07,520 --> 00:22:09,520 THIS GROUP FROM EUROPE 603 00:22:09,520 --> 00:22:11,040 IDENTIFIED MUTATIONS IN GATA 2 604 00:22:11,040 --> 00:22:15,880 IN THOSE WHO HAD LYMPHDEEMIA AND 605 00:22:15,880 --> 00:22:17,240 DEAFNESS AND ACUTE LEUKEMIA AND 606 00:22:17,240 --> 00:22:19,560 THEN WE--AS WE REALIZE THAT ALL 607 00:22:19,560 --> 00:22:22,400 OF THESE WERE MANIFESTATIONS OF 608 00:22:22,400 --> 00:22:23,960 GATA 2 DEFICIENCY, IT MADE US 609 00:22:23,960 --> 00:22:26,400 STOP AND GO BACK AND SAY WAIT A 610 00:22:26,400 --> 00:22:29,600 MINUTE THAT VERY FIRST CASE FROM 611 00:22:29,600 --> 00:22:31,840 1989, THAT GIRL SOUNDS LIKE 612 00:22:31,840 --> 00:22:33,480 SOMEBODY THAT WOULD BE IN OUR 613 00:22:33,480 --> 00:22:36,560 COHORT AND SO I CALLED CHRISTINE 614 00:22:36,560 --> 00:22:38,560 BYRON AND JOHN SULLIVAN, AND 615 00:22:38,560 --> 00:22:39,520 SAID, YOU KNOW WE THINK THAT 616 00:22:39,520 --> 00:22:42,080 YOUR PATIENT MIGHT HAVE OUR 617 00:22:42,080 --> 00:22:42,320 PROBLEM. 618 00:22:42,320 --> 00:22:45,080 AND THEY SAID, WELL, YOU KNOW, 619 00:22:45,080 --> 00:22:47,400 THAT SOUNDS POSSIBLE, LET'S SEE. 620 00:22:47,400 --> 00:22:50,240 AND JOHN WAS ABLE TO SEND ME 621 00:22:50,240 --> 00:22:52,120 CELLS AND IN FACT WHEN AMY 622 00:22:52,120 --> 00:22:57,680 SEQUENCED IT, THIS GIRL ALSO HAD 623 00:22:57,680 --> 00:23:00,320 A DELETION IN THE GATA 2 GENE 624 00:23:00,320 --> 00:23:01,480 LEADING TO GATA 2 DEFICIENCY, SO 625 00:23:01,480 --> 00:23:03,680 AFTER ALL OF THIS TIME, WE WERE 626 00:23:03,680 --> 00:23:06,480 ABLE TO SAY THERE ARE 5 NAMES 627 00:23:06,480 --> 00:23:08,720 FOR 1 DISEASE, WE CALLED IT 628 00:23:08,720 --> 00:23:10,040 MONOMAC, BUT OTHERS HAD OTHER 629 00:23:10,040 --> 00:23:12,880 NAMES FOR IT, THEY'RE ALL THE 630 00:23:12,880 --> 00:23:18,280 SAME, AND IT IS A RIDICULOUS 631 00:23:18,280 --> 00:23:19,480 HUGHING TO REGIONAL PREJUDICE TO 632 00:23:19,480 --> 00:23:21,560 CONTINUE TO CALL IT BY OUR 633 00:23:21,560 --> 00:23:22,400 DIFFERENT ACRONYMS, I STILL DO 634 00:23:22,400 --> 00:23:24,480 BUT THE TRUTH IS, IT'S 1 DISEASE 635 00:23:24,480 --> 00:23:27,120 THAT HAS MANY DIFFERENT 636 00:23:27,120 --> 00:23:27,480 MANIFESTATIONS. 637 00:23:27,480 --> 00:23:28,440 AND THESE AREN'T ALL OF THEM. 638 00:23:28,440 --> 00:23:30,200 THERE ARE LOTS OF OTHER WAYS 639 00:23:30,200 --> 00:23:32,960 THAT THIS CAN PRESENT, THESE 640 00:23:32,960 --> 00:23:33,880 HYPOPLASTIC MARROW DISORDERS, 641 00:23:33,880 --> 00:23:36,840 ABOUT 50% OF CHILDREN WITH 642 00:23:36,840 --> 00:23:38,040 MONOSTUDIES OF MULTIPLE 643 00:23:38,040 --> 00:23:40,400 ENDOCRINEY 7 HAVE UNDERLYING 644 00:23:40,400 --> 00:23:42,200 GATA 2 DEFICIENCY, ABOUT 5% OF 645 00:23:42,200 --> 00:23:43,680 THE APLASTIC ANEMIA THAT HAVE 646 00:23:43,680 --> 00:23:45,040 BEEN SEEN HERE TURN OUT TO HAVE 647 00:23:45,040 --> 00:23:47,120 THIS AS WELL AS CHILDREN WITH 648 00:23:47,120 --> 00:23:49,800 NEWT ROW PENIA, PEOPLE WITH CMML 649 00:23:49,800 --> 00:23:52,920 AND EVEN CASES OF COMMON 650 00:23:52,920 --> 00:23:54,680 VARIABLE IMMUNO DEFICIENCY THAT 651 00:23:54,680 --> 00:23:57,880 TURN OUT TO BE GATA 2 652 00:23:57,880 --> 00:23:58,240 DEFICIENCY. 653 00:23:58,240 --> 00:24:01,440 NOW, YOU KNOW AT SOME LEVEL, 654 00:24:01,440 --> 00:24:05,400 PEOPLE SAY MY GOD WHAT WAS ALL 655 00:24:05,400 --> 00:24:07,240 THIS GOING ON ABOUT MAKING A 656 00:24:07,240 --> 00:24:08,360 GENETIC DIAGNOSIS, WHO CARES? 657 00:24:08,360 --> 00:24:09,440 YOU KNOW HAVE YOU A DISEASE, YOU 658 00:24:09,440 --> 00:24:11,000 KNOW YOU HAVE TO TREAT IT WHY 659 00:24:11,000 --> 00:24:13,280 NOT JUST GET TO BUSINESS AND 660 00:24:13,280 --> 00:24:14,560 STOPIACKING ABOUT IT BUT YOU 661 00:24:14,560 --> 00:24:17,880 GOTTA HAVE THE GENE, WHY? 662 00:24:17,880 --> 00:24:20,920 BECAUSE IT MAKES POSSIBLE 663 00:24:20,920 --> 00:24:21,560 DIAGNOSIS, PROGNOSIS, FIGURING 664 00:24:21,560 --> 00:24:23,080 OUT WHAT THE EXPRESSION AND 665 00:24:23,080 --> 00:24:25,000 PENETRANTS OF THE DISEASE ARE, 666 00:24:25,000 --> 00:24:26,560 TARGETED THERAPY AS OPPOSE TO 667 00:24:26,560 --> 00:24:27,680 THIS SORT OF SLEDGE HAMMER THAT 668 00:24:27,680 --> 00:24:29,680 WE USE AS WELL AS THE CRITICAL 669 00:24:29,680 --> 00:24:30,840 ISSUE ABOUT MAKING SURE YOU 670 00:24:30,840 --> 00:24:32,720 CHOOSE THE RIGHT DONOR FOR THE 671 00:24:32,720 --> 00:24:33,240 TRANSPLANT. 672 00:24:33,240 --> 00:24:35,840 IF YOU CHOOSE A SIBLING WHO'S 673 00:24:35,840 --> 00:24:37,640 ALSO MUTATED YOU COULD MAKE A 674 00:24:37,640 --> 00:24:39,480 DISASTROUS MISTAKE AND THEN 675 00:24:39,480 --> 00:24:40,880 FINALLY, GENO TYPE, PHENOTYPE 676 00:24:40,880 --> 00:24:41,960 CORRELATION, I'M ONLY GOING TO 677 00:24:41,960 --> 00:24:44,080 TOUCH ON 3 OF THOSE IN THE NEXT 678 00:24:44,080 --> 00:24:45,680 COUPLE OF MINUTES. 679 00:24:45,680 --> 00:24:47,840 NUMBER 1, ONCE YOU HAVE THE 680 00:24:47,840 --> 00:24:50,520 GENE, CAN YOU IDENTIFY PEOPLE 681 00:24:50,520 --> 00:24:51,760 BEFORE THEY'RE PHENOTYPICALLY 682 00:24:51,760 --> 00:24:52,720 EFFECTIVE. 683 00:24:52,720 --> 00:24:54,720 AND SO, WITH THAT INFORMATION, 684 00:24:54,720 --> 00:24:56,520 WE WERE ABLE TO START LOOKING 685 00:24:56,520 --> 00:24:57,640 WITHIN FAMILIES AND SAY, YOU 686 00:24:57,640 --> 00:25:00,560 KNOW WE KNOW THAT THIS PERSON 687 00:25:00,560 --> 00:25:01,760 CARRIES THE SAME GENE AND WE 688 00:25:01,760 --> 00:25:04,960 COULD BEGIN TO SAY, LOOK AT HOW 689 00:25:04,960 --> 00:25:06,400 THE BLOOD COUNTS CHANGE OVER 690 00:25:06,400 --> 00:25:06,600 TIME. 691 00:25:06,600 --> 00:25:08,760 WE DIDN'T KNOW AT THE BEGINNING 692 00:25:08,760 --> 00:25:09,680 WAS THIS SOMETHING THEY WERE 693 00:25:09,680 --> 00:25:11,840 BORN WITH AND ONLY SHOWED NUP 694 00:25:11,840 --> 00:25:13,600 ADULTHOOD OR THEY WERE BORN 695 00:25:13,600 --> 00:25:14,920 NORMAL AND IT CHANGED IN 696 00:25:14,920 --> 00:25:15,760 ADULTHOOD, NOW THAT WE HAVE THE 697 00:25:15,760 --> 00:25:17,800 GENE, WE CAN SAY, OH, LOOK AT 698 00:25:17,800 --> 00:25:18,120 THAT. 699 00:25:18,120 --> 00:25:20,000 IF PEOPLE HAVE NO SYMPTOMS, 700 00:25:20,000 --> 00:25:21,880 THEIR CELL COUNTS ARE PRETTY 701 00:25:21,880 --> 00:25:24,720 MUCH NORMAL, HERE WE'RE LOOKING 702 00:25:24,720 --> 00:25:28,040 AT B-CELLS, NK-CELLS AND CD4 703 00:25:28,040 --> 00:25:29,480 CELLS, BUT AS TIME GOES ON AND 704 00:25:29,480 --> 00:25:32,720 DISEASE GETS MORE SEVERE, THE 705 00:25:32,720 --> 00:25:33,360 CYTOPENIA PROGRESSES SUGGESTING 706 00:25:33,360 --> 00:25:35,160 THAT THE BONE MARROW IS FAILING 707 00:25:35,160 --> 00:25:35,560 OVER TIME. 708 00:25:35,560 --> 00:25:38,040 IT'S NOT BORN THAT WAY, IT 709 00:25:38,040 --> 00:25:39,400 DEVELOPS, THAT MEANS THERE'S A 710 00:25:39,400 --> 00:25:41,400 WINDOW AT WHICH WE COULD DO 711 00:25:41,400 --> 00:25:41,800 THINGS. 712 00:25:41,800 --> 00:25:44,800 IT ALSO TURNS OUT THAT THERE'S A 713 00:25:44,800 --> 00:25:46,040 SIGNIFICANT AMOUNT OF LUNG 714 00:25:46,040 --> 00:25:48,000 DISEASE THAT A COMPANY'S GATA 2 715 00:25:48,000 --> 00:25:49,200 DEFICIENCY AND THAT LUNG DISEASE 716 00:25:49,200 --> 00:25:50,840 VARIES OVER TIME HERE, HERE YOU 717 00:25:50,840 --> 00:25:53,680 SEE RIGHT BELOW THE WALL OF THE 718 00:25:53,680 --> 00:25:55,800 CHEST AND ALONG THE FISHER'S IN 719 00:25:55,800 --> 00:25:57,800 THE LUNG, YOU SEE THAT THERE ARE 720 00:25:57,800 --> 00:26:02,920 THESE SMALL CYSTS THAT ARE 721 00:26:02,920 --> 00:26:04,040 FORMING THAT'S PARASEPTORSAL 'EM 722 00:26:04,040 --> 00:26:05,920 SEEMA WHICH A COMMON PROBLEM IN 723 00:26:05,920 --> 00:26:06,240 THIS DISEASE. 724 00:26:06,240 --> 00:26:07,680 NOW THERE ARE LOTS OF DIFFERENT 725 00:26:07,680 --> 00:26:09,840 PROBLEMS THAT SHOW UP IN GATA 2 726 00:26:09,840 --> 00:26:11,200 DEFICIENCY ONCE YOU KNOW THAT 727 00:26:11,200 --> 00:26:13,480 PEOPLE HAVE DISEASE. 728 00:26:13,480 --> 00:26:15,280 EVERYTHING FROM INFILTRATES LIKE 729 00:26:15,280 --> 00:26:18,720 PNEUMONIAS TO THIS POLARIZED 730 00:26:18,720 --> 00:26:20,080 MONITORARY ALVEOLAR PROGNOSIS I 731 00:26:20,080 --> 00:26:21,680 MENTIONED EARLYY BUT WITH THE 732 00:26:21,680 --> 00:26:23,040 GENE YOU CAN SAY WHAT ABOUT THE 733 00:26:23,040 --> 00:26:24,880 PEOPLE WHO ARE SICK COMPARED 734 00:26:24,880 --> 00:26:26,280 THOSE THAT AREN'T SICK? 735 00:26:26,280 --> 00:26:28,840 AND IN THOSE RELATIVES THAT ARE 736 00:26:28,840 --> 00:26:31,400 MUTATED BUT NOT CLINICALLY ILL 737 00:26:31,400 --> 00:26:33,600 YET, YOU CAN SEE THAT LEGAL 738 00:26:33,600 --> 00:26:35,280 THEIR DIFFUSION CAPACITY FOR 739 00:26:35,280 --> 00:26:41,200 CARBON MONOXIDE, A MEASURE OF 740 00:26:41,200 --> 00:26:42,040 LUNG MEMBRANE THICKNESS, EVEN 741 00:26:42,040 --> 00:26:43,240 THOUGH THEY'RE CERTAINLY BETTER 742 00:26:43,240 --> 00:26:44,600 THAN THOSE THAT ARE SICK, 743 00:26:44,600 --> 00:26:46,200 THEY'RE STILL NOT COMPLETELY 744 00:26:46,200 --> 00:26:48,160 NORMAL SUGGESTING THAT EVEN IN 745 00:26:48,160 --> 00:26:50,120 THOSE WHO ARE--WHO ARE NOT 746 00:26:50,120 --> 00:26:51,880 CLINICALLY AFFECTED, THERE ARE 747 00:26:51,880 --> 00:26:56,280 STILL EFFECTS OF THIS. 748 00:26:56,280 --> 00:26:57,640 FINALLY, AS WE BEGIN TO LOOK 749 00:26:57,640 --> 00:27:00,040 THEN AT THE DIFFERENT MUTATIONS 750 00:27:00,040 --> 00:27:02,280 IN THE GENE, WE BEGENERATED TO 751 00:27:02,280 --> 00:27:04,480 PICK OUT DIFFERENT ISSUES. 752 00:27:04,480 --> 00:27:05,520 SO, IN THIS SCHEMA HERE WHAT YOU 753 00:27:05,520 --> 00:27:07,560 SEE IS THE JEAN ON THE TOP IS 754 00:27:07,560 --> 00:27:10,880 THE WILD-TYPE NORMAL COPY OF THE 755 00:27:10,880 --> 00:27:12,960 GENE, ZF1 AND 2 REFER TO THE 756 00:27:12,960 --> 00:27:15,840 ZINC FINGERS SO THIS IS A 2 757 00:27:15,840 --> 00:27:17,160 DIGIT ZINC FINGER TRANSCRIPTION 758 00:27:17,160 --> 00:27:20,000 FACTOR THAT USES THOSE 2 FINGERS 759 00:27:20,000 --> 00:27:22,520 TO BIND TO THE DNA AND RECRUIT 760 00:27:22,520 --> 00:27:23,400 OTHER TRANSCRIPTION FACTORS, 761 00:27:23,400 --> 00:27:24,680 WELL, THERE ARE REALLY 5 762 00:27:24,680 --> 00:27:26,920 DIFFERENT KINDS OF MUTATIONS 763 00:27:26,920 --> 00:27:27,120 HERE. 764 00:27:27,120 --> 00:27:28,800 ONE OF THEM, THE 1 IN PURPLE IS 765 00:27:28,800 --> 00:27:30,880 WHERE IT'S JUST THE AMOUNT 766 00:27:30,880 --> 00:27:32,800 THAT'S MADE IS LOW, IT'S NOT 767 00:27:32,800 --> 00:27:33,680 ABSENT, IT'S JUST LOW BUT 768 00:27:33,680 --> 00:27:36,160 EVERYTHING THAT'S MADE IS NORMAL 769 00:27:36,160 --> 00:27:37,200 QUALITY, JUST THE QUANTITY IS 770 00:27:37,200 --> 00:27:37,560 DOWN. 771 00:27:37,560 --> 00:27:38,600 AND THEN THERE ARE THOSE WHO 772 00:27:38,600 --> 00:27:40,360 HAVE MUTATIONS IN THE SECOND 773 00:27:40,360 --> 00:27:42,480 ZINC FINGER IN RED, THOSE WHO 774 00:27:42,480 --> 00:27:45,320 HAVE MUTATIONS IN THE 775 00:27:45,320 --> 00:27:46,720 C-TERMINUS, DOWN @ AT THE 776 00:27:46,720 --> 00:27:48,400 C-TERMINUS DOWN TO THE RIGHT 777 00:27:48,400 --> 00:27:49,760 SIDE, THOSE WHO HAVE TRUNCATIONS 778 00:27:49,760 --> 00:27:52,240 OF LARGE PARTS OF THE MOLECULES 779 00:27:52,240 --> 00:27:53,600 SHOWN IN BRIGHT GREEN AT THE 780 00:27:53,600 --> 00:27:55,640 BOTTOM, AND AT THE VERY BOTTOM, 781 00:27:55,640 --> 00:27:57,240 THOSE WHO HAVE NO ALLELE AT ALL 782 00:27:57,240 --> 00:28:01,840 BECAUSE OF A BIG DELETION IN THE 783 00:28:01,840 --> 00:28:02,120 GENE. 784 00:28:02,120 --> 00:28:04,040 AND SO JUST A COUPLE OF 785 00:28:04,040 --> 00:28:05,360 INTERESTING POINTS THAT AGAIN 786 00:28:05,360 --> 00:28:07,440 HAVING THE GENE LETS YOU SORT 787 00:28:07,440 --> 00:28:07,680 OUT. 788 00:28:07,680 --> 00:28:10,880 NUMBER 1, THE RATE OF DISEASE IN 789 00:28:10,880 --> 00:28:13,360 MALES AND FEMALES IS PRETTY MUCH 790 00:28:13,360 --> 00:28:15,640 THE SAME, HOWEVER, THE KIND OF 791 00:28:15,640 --> 00:28:16,920 DISEASE IS NOT AND WHAT YOU SEE 792 00:28:16,920 --> 00:28:19,960 AT THE BOTTOM LEFT IS THAT MALES 793 00:28:19,960 --> 00:28:22,960 SHOW UP WITH MUCH MORE 794 00:28:22,960 --> 00:28:24,560 MICROBACTERIAL DISEASE THAN DO 795 00:28:24,560 --> 00:28:25,320 FEMALES WHERE FEMALES SHOW UP 796 00:28:25,320 --> 00:28:28,600 WITH ALL THE OTHER INFECTIONS IN 797 00:28:28,600 --> 00:28:29,280 PARTICULAR, THE HPV. 798 00:28:29,280 --> 00:28:31,600 WE HAVE BEEN REFERRED MULTIPLE 799 00:28:31,600 --> 00:28:33,640 YOUNG WOMEN NOW WHO HAVE BEEN 800 00:28:33,640 --> 00:28:34,880 FOLLOWED BY GYNECOLOGISTS FOR 801 00:28:34,880 --> 00:28:37,680 YEARS BEFORE SOMEBODY SAYS, YOU 802 00:28:37,680 --> 00:28:39,360 KNOW THAT'S TOO MANY HPV 803 00:28:39,360 --> 00:28:40,760 SURGERIES FOR YOU IN YOUR EARLY 804 00:28:40,760 --> 00:28:46,520 20S AND IT'S THE GYNECOLOGY I 805 00:28:46,520 --> 00:28:47,120 ISTS 806 00:28:47,120 --> 00:28:48,440 WHO ARE FIGURING OUT, BOY, YOU 807 00:28:48,440 --> 00:28:50,080 HAVE A PROBLEM YOU NEED TO BE 808 00:28:50,080 --> 00:28:51,160 WORKED UP FOR THAT. 809 00:28:51,160 --> 00:28:53,160 BUT THEN WHEN WE DISSECT IT OUT 810 00:28:53,160 --> 00:28:55,240 FURTHER AND THIS IS ALL WORK 811 00:28:55,240 --> 00:28:57,560 THAT AMY HSU HAS DONE CHA IS 812 00:28:57,560 --> 00:28:59,240 UNDER REVIEW, WHEN YOU DISSECT 813 00:28:59,240 --> 00:29:00,400 IT OUT FURTHER, IT TURNS OUT 814 00:29:00,400 --> 00:29:01,600 THERE ARE REALLY ARE DIFFERENCES 815 00:29:01,600 --> 00:29:02,560 BETWEEN THE DIFFERENT MUTATIONS 816 00:29:02,560 --> 00:29:04,200 IN THE GENE, SO THOSE THAT HAVE 817 00:29:04,200 --> 00:29:06,640 THE ENHANCER MUTATION THAT IS 818 00:29:06,640 --> 00:29:08,080 THE RIGHT QUALITY, LOW QUANTITY, 819 00:29:08,080 --> 00:29:09,760 THEY'VE ACTUALLY GOT THE BEST 820 00:29:09,760 --> 00:29:12,480 SURVIVAL SO HERE WE'RE LOOKINGA 821 00:29:12,480 --> 00:29:13,720 THE PERCENT ASYMPTOMATIC AT A 822 00:29:13,720 --> 00:29:14,080 CERTAIN HAIJ. 823 00:29:14,080 --> 00:29:16,800 SO YOU SEE THAT BY AGE 50, ABOUT 824 00:29:16,800 --> 00:29:19,880 50% OF THE PEOPLE WHO HAVE 825 00:29:19,880 --> 00:29:21,360 ENHANCER MUTATIONS ARE STILL 826 00:29:21,360 --> 00:29:21,760 OKAY. 827 00:29:21,760 --> 00:29:23,360 WHEREAS FOR THE OTHER MUTATIONS, 828 00:29:23,360 --> 00:29:24,720 THAT'S NOT THE CASE. 829 00:29:24,720 --> 00:29:28,080 AND IN FACT, WHEN WE LOOK EVEN 830 00:29:28,080 --> 00:29:30,040 FURTHER AND DISSECT OUT AMONG 831 00:29:30,040 --> 00:29:32,120 THOSE WITH YOU HADITATIONS IN 832 00:29:32,120 --> 00:29:33,560 THE SECOND ZINC FINGER THERE ARE 833 00:29:33,560 --> 00:29:35,120 CLEARLY DIFFERENCES IN THAT 834 00:29:35,120 --> 00:29:38,440 GROUP AS WELL WITH THE MUTATIONS 835 00:29:38,440 --> 00:29:42,080 LIKE A396 AND 354 BEING THE MOST 836 00:29:42,080 --> 00:29:43,640 SEVERE AND R398 BEING LESS 837 00:29:43,640 --> 00:29:44,160 SEVERE. 838 00:29:44,160 --> 00:29:45,960 THEY'RE STILL BAD, BUT IT'S 839 00:29:45,960 --> 00:29:46,960 ABOUT DEGREES OF BAD. 840 00:29:46,960 --> 00:29:48,960 AGAIN, THIS SHOWS US WHERE THE 841 00:29:48,960 --> 00:29:52,120 WINDOW IS THAT WE CAN SNEAK IN 842 00:29:52,120 --> 00:29:55,320 AND TRY TO LOOK FOR HOW TO MAKE 843 00:29:55,320 --> 00:29:55,640 DIFFERENCES. 844 00:29:55,640 --> 00:29:57,360 SO WE CAN PUT ALL OF THIS ON A 845 00:29:57,360 --> 00:29:59,120 CURVE THAT HELPS US UNDERSTAND 846 00:29:59,120 --> 00:30:01,960 THIS DEC BETTER AND HELPS US 847 00:30:01,960 --> 00:30:03,360 UNDERSTAND EXACTLY WHAT IT IS 848 00:30:03,360 --> 00:30:07,600 THAT WE'VE GOT AN OPPORTUNITY TO 849 00:30:07,600 --> 00:30:08,440 ADDRESS. 850 00:30:08,440 --> 00:30:09,960 SO IN SUMMARY, WHAT MAKES THIS 851 00:30:09,960 --> 00:30:11,680 DISEASE SO IMPORTANT TO 852 00:30:11,680 --> 00:30:13,520 UNDERSTAND IS THAT PEOPLE ARE 853 00:30:13,520 --> 00:30:16,440 BORN NORMAL AND DEVELOP 854 00:30:16,440 --> 00:30:16,920 CYTOPENIAS OVER TIME. 855 00:30:16,920 --> 00:30:18,520 THERE ARE A VARIETY OF 856 00:30:18,520 --> 00:30:20,160 INFECTIONS, EVERYTHING FROM 857 00:30:20,160 --> 00:30:21,800 VIRUSES TO FUNGI THAT ARE 858 00:30:21,800 --> 00:30:24,000 CHARACTERISTIC OF THIS DISEASE. 859 00:30:24,000 --> 00:30:29,800 THEY ALSO DEVELOP YOU KNOW 860 00:30:29,800 --> 00:30:30,440 POLARIZED MONITORARY 861 00:30:30,440 --> 00:30:31,760 AVEALULOSEIS, AND I'VE NOT 862 00:30:31,760 --> 00:30:35,120 TALKED ABOUT THOSE TODAY AND A 863 00:30:35,120 --> 00:30:37,160 STRONG CORRELATION AND A 864 00:30:37,160 --> 00:30:38,400 PENETRANTS THAT VARIES FROM 1 865 00:30:38,400 --> 00:30:39,640 MUTATION TO THE NEXT AND AS 866 00:30:39,640 --> 00:30:41,520 DENNIS WILL GO ON TO SHOW YOU 867 00:30:41,520 --> 00:30:42,960 TRANSPLANT IS VERY SUCCESSFUL 868 00:30:42,960 --> 00:30:44,720 AND SO HAVE ARE IMPORTANT TO TEE 869 00:30:44,720 --> 00:30:46,640 PEOPLE UP FROM THE VERY GET GO. 870 00:30:46,640 --> 00:30:49,400 SO HOW DOES GATA 2 DO ALL THIS? 871 00:30:49,400 --> 00:30:51,880 IT'S GOT REG LA THORY EFFECTS IN 872 00:30:51,880 --> 00:30:53,680 NUMEROUS TISSUES EACH 1 BEING A 873 00:30:53,680 --> 00:30:54,520 LITTLE BIT DIFFERENT. 874 00:30:54,520 --> 00:30:59,560 THERE ARE ABNORMAL VESSELS IN 875 00:30:59,560 --> 00:31:03,320 LYMPHATICS, OVERLAPPING TARGETS 876 00:31:03,320 --> 00:31:08,320 OF THE GATA 2, EARLY POPULATION 877 00:31:08,320 --> 00:31:11,320 MACROPHAGES AND PLASMA CELLS, 878 00:31:11,320 --> 00:31:14,000 IMPAIRED DEFINITIVE HEMEAT O 879 00:31:14,000 --> 00:31:14,800 POETICESIS, INFECTION-DRIVEN 880 00:31:14,800 --> 00:31:16,760 BONE MARROW EXHAUSTION AND 881 00:31:16,760 --> 00:31:18,080 SECONDARY MUTATIONS AND 882 00:31:18,080 --> 00:31:18,800 CYTOGENETIC DEFECTS. 883 00:31:18,800 --> 00:31:20,360 SO LASTLY WHY ARE WE GOING TO 884 00:31:20,360 --> 00:31:21,320 KEEP GOING ON THIS? 885 00:31:21,320 --> 00:31:22,840 BECAUSE WE HAVE LOTS OF 886 00:31:22,840 --> 00:31:23,240 REQUESTYS TO ANSWER. 887 00:31:23,240 --> 00:31:25,000 WHAT IS IT THAT DETERMINES PEN 888 00:31:25,000 --> 00:31:26,760 TRABTS, WHAT ARE THE FACTORS 889 00:31:26,760 --> 00:31:28,600 OUTSIDE OF GATA 2 THAT MIGHT BE 890 00:31:28,600 --> 00:31:28,920 AFFECTING IT. 891 00:31:28,920 --> 00:31:29,920 WHY DOES IT COME ON LATER IN 892 00:31:29,920 --> 00:31:31,120 LIFE, WHAT IS IT THAT CHILDREN 893 00:31:31,120 --> 00:31:32,800 ARE DOING SO RIGHT AND ADULTS 894 00:31:32,800 --> 00:31:34,400 ARE DOING SO WRONG. 895 00:31:34,400 --> 00:31:36,720 WHAT ARE THE TRANSFACTORS ON 896 00:31:36,720 --> 00:31:38,680 OTHER GENES THAT ARE INVOLVED IN 897 00:31:38,680 --> 00:31:40,080 GATA 2 REGULATION, IS THERE ANY 898 00:31:40,080 --> 00:31:48,600 WAY WE COULD GO ON TO PREVENT 899 00:31:48,600 --> 00:31:48,800 MDS/AML? 900 00:31:48,800 --> 00:31:51,680 AND WHEN DO YOU DECIDE TO 901 00:31:51,680 --> 00:31:52,800 TRANSPLANT WHEN THEY'RE ILL, 902 00:31:52,800 --> 00:31:54,160 IT'S HARDER TO FIGURE OUT, HOW 903 00:31:54,160 --> 00:31:55,600 DO YOU KNOW SOMEONE'S NOT GOING 904 00:31:55,600 --> 00:31:57,520 TO GET SICK SO YOU NEVER WIND UP 905 00:31:57,520 --> 00:31:58,880 WAITING JUST 1 DAY TOO LONG. 906 00:31:58,880 --> 00:32:01,480 SO I TRIED TO INTRODUCE YOU TO 907 00:32:01,480 --> 00:32:02,280 MY FAVORITE ELEPHANT AND TELL 908 00:32:02,280 --> 00:32:03,640 YOU A LITTLE BIT ABOUT IT AND 909 00:32:03,640 --> 00:32:05,920 TRY TO SHOW YOU ALL THE 910 00:32:05,920 --> 00:32:06,720 DIFFERENT MANIFESTATIONS THAT 911 00:32:06,720 --> 00:32:07,840 WE'VE DEALT WITH OR AT LEAST 912 00:32:07,840 --> 00:32:09,120 SOME OF THE MANIFESTATIONS, 913 00:32:09,120 --> 00:32:10,440 THERE ARE MANY MORE AND I DON'T 914 00:32:10,440 --> 00:32:11,840 DOUBT FOR A MOMENT THERE WILL 915 00:32:11,840 --> 00:32:14,040 CONTINUE TO BE MANY MORE TO COME 916 00:32:14,040 --> 00:32:16,960 BUT I HOPE THAT WE'VE GOT THE 917 00:32:16,960 --> 00:32:18,200 TOOLS IN PLACE, AND I KNOW THAT 918 00:32:18,200 --> 00:32:21,120 WE HAVE THE TEAM IN PLACE TO 919 00:32:21,120 --> 00:32:21,800 REALLY MAKE THIS WORK. 920 00:32:21,800 --> 00:32:24,600 I JUST WANT TO ACKNOWLEDGE IN 921 00:32:24,600 --> 00:32:25,800 PARTICULAR, THE CRITICAL PEOPLE 922 00:32:25,800 --> 00:32:29,640 IN THIS IN MY OWN GROUP, AMY 923 00:32:29,640 --> 00:32:33,880 HSU, LAUREN, MIKE, OUR 924 00:32:33,880 --> 00:32:35,320 COLLABORATORS, CATHY, MIKE, 925 00:32:35,320 --> 00:32:37,120 STEPHANIA, AND SO MANY OF OUR 926 00:32:37,120 --> 00:32:38,800 COLLABORATORS WHO HAVE BEEN 927 00:32:38,800 --> 00:32:39,680 CRITICAL TO IT. 928 00:32:39,680 --> 00:32:41,320 DENNIS I WILL WILL TAKE IT AWAY 929 00:32:41,320 --> 00:32:44,760 ON THE CLINICAL SIDE ON OUR OWN 930 00:32:44,760 --> 00:32:48,160 SIDE, WE'VE HAD SOME SPECTACULAR 931 00:32:48,160 --> 00:32:51,440 ID AND IMMUNOLOGY COLLABORATORS 932 00:32:51,440 --> 00:32:51,760 LISTED HERE. 933 00:32:51,760 --> 00:32:53,880 SO I WILL STOP THERE AND SAY 934 00:32:53,880 --> 00:32:54,560 THANK YOU VERY MUCH. 935 00:32:54,560 --> 00:32:55,760 I LOOK FORWARD TO TAKING YOUR 936 00:32:55,760 --> 00:32:59,680 QUESTIONS AT THE END. 937 00:32:59,680 --> 00:33:02,840 THIS IS DENNIS HICKSTEIN, THANK 938 00:33:02,840 --> 00:33:04,920 YOU SO MUCH FOR TEEING UP THE 939 00:33:04,920 --> 00:33:06,480 PATIENTS FOR TRANSPLANT AND 940 00:33:06,480 --> 00:33:07,240 TEEING ME UP FOR PART 2 OF THIS. 941 00:33:07,240 --> 00:33:10,240 SO I WILL TALK ABOUT THE ROLE OF 942 00:33:10,240 --> 00:33:11,600 ALOE GENERATED AIC TRANSPLANT 943 00:33:11,600 --> 00:33:15,040 AND GATA 2 DEFICIENCY WITH A 944 00:33:15,040 --> 00:33:15,800 SHAKESPEAREAN QUOTE THAT THE 945 00:33:15,800 --> 00:33:17,160 PAST IS PROLOGUE TO THE FUTURE. 946 00:33:17,160 --> 00:33:19,280 SO I HAVE NO FINANCIAL 947 00:33:19,280 --> 00:33:20,720 DISCLOSURES, THE MAIN LEARNING 948 00:33:20,720 --> 00:33:22,720 OBJECTIVE IS HAVE YOU THINK LIKE 949 00:33:22,720 --> 00:33:24,040 A TRANSPLANTER ABOUT THIS 950 00:33:24,040 --> 00:33:24,320 DISEASE. 951 00:33:24,320 --> 00:33:25,760 SO REALLY TO UNDERSTAND THE ROLE 952 00:33:25,760 --> 00:33:28,520 OF ALOE GENERATED AIC TRANSPLANT 953 00:33:28,520 --> 00:33:30,560 AND GENETIC BLOOD SEIZES 954 00:33:30,560 --> 00:33:33,440 ESPECIALLY GATA 2 DEFICIENCY. 955 00:33:33,440 --> 00:33:34,880 SO THE FIRST QUESTION, I THINK 956 00:33:34,880 --> 00:33:37,120 STEVE GAVE A GREAT BACKGROUND OF 957 00:33:37,120 --> 00:33:38,280 WHRA THESE PATIENTS WERE LIKE, 958 00:33:38,280 --> 00:33:39,560 HARD TO CONVEY HOW REALLY SICK 959 00:33:39,560 --> 00:33:42,280 THE FIRST 1S WE SAW WERE, THEY 960 00:33:42,280 --> 00:33:43,520 HAD BEEN LINGERING WITH THIS 961 00:33:43,520 --> 00:33:45,440 DISEASE FOR A DECADE OR MORE. 962 00:33:45,440 --> 00:33:47,560 SO WE KNOW THE PATIENTS OF GATA 963 00:33:47,560 --> 00:33:50,240 2 DEFICIENCY, ONCE THEY BECOME 964 00:33:50,240 --> 00:33:51,280 SYMPTOMATIC WE'RE AT HIGH RISK 965 00:33:51,280 --> 00:33:53,160 OF DEATH, THE INFECTIONS CAN 966 00:33:53,160 --> 00:33:57,440 KILL THEM, THESE TERRIBLE 967 00:33:57,440 --> 00:33:58,440 NONTUBERCULOSE MICROIN 968 00:33:58,440 --> 00:34:00,880 INFECTIONS WE SEE LESS PULMONARY 969 00:34:00,880 --> 00:34:01,840 PROGNOSIS, BUT THAT CAN BE 970 00:34:01,840 --> 00:34:04,200 LETHAL AND THEN THE DREADED 971 00:34:04,200 --> 00:34:08,200 COMPLICATION THAT THEY CAN TURN 972 00:34:08,200 --> 00:34:10,320 INTO LEUKEMIA, SO, WE THOUGHT AT 973 00:34:10,320 --> 00:34:11,920 THE BEGINNING IT LOOKED LIKE A 974 00:34:11,920 --> 00:34:13,640 STEM CELL DISEASE, GATA 2 IS A 975 00:34:13,640 --> 00:34:16,640 MARKER OF STEM CELLS AND IT 976 00:34:16,640 --> 00:34:18,520 LOOKED LIKE NORMAL DONOR 977 00:34:18,520 --> 00:34:19,600 SEMESTER CELLS SHOULD REVERSE 978 00:34:19,600 --> 00:34:20,520 THE PHENOTYPE. 979 00:34:20,520 --> 00:34:22,960 WE KNOW TRANSPLANT CAN CURE 980 00:34:22,960 --> 00:34:26,920 IMMUNO DEFICIENCY DISEASES AS 981 00:34:26,920 --> 00:34:27,600 WELL AS LEUKEMIA. 982 00:34:27,600 --> 00:34:28,600 SO THE QUESTION I WILL GET INTO 983 00:34:28,600 --> 00:34:31,680 IN A IF YOU MINUTES IS WHEN TO 984 00:34:31,680 --> 00:34:33,160 TRANSPLANT THEM AND'S REALLY 985 00:34:33,160 --> 00:34:35,680 TRICKY AS FAR AS THE OPTIMAL 986 00:34:35,680 --> 00:34:36,160 TIME. 987 00:34:36,160 --> 00:34:40,800 TRANSPLANTS NOT A BENIGN 988 00:34:40,800 --> 00:34:41,280 UNDERTAKING. 989 00:34:41,280 --> 00:34:42,280 SO THEN THE QUESTION THAT CAME 990 00:34:42,280 --> 00:34:44,800 TO US IS HOW TO TRANSPLANT THESE 991 00:34:44,800 --> 00:34:46,000 PATIENTS, THESE ARE VERY HIGH 992 00:34:46,000 --> 00:34:47,640 RISK PATIENTS AT THE TIME BACK 993 00:34:47,640 --> 00:34:49,480 IN 2009, THAT WAS 2 YEARS BEFORE 994 00:34:49,480 --> 00:34:51,040 WE KNEW IT WAS GATA 2. 995 00:34:51,040 --> 00:34:53,520 AND THEY WERE NOT POPULAR 996 00:34:53,520 --> 00:34:55,560 PATIENTS BECAUSE THE LEUKEMIA 997 00:34:55,560 --> 00:34:56,360 DOCTORS WERE INTERESTED IN THEM 998 00:34:56,360 --> 00:34:58,280 BECAUSE THEY HAD SO MANY 999 00:34:58,280 --> 00:34:59,560 INFECTIONS, THE INFECT YOWZ 1000 00:34:59,560 --> 00:35:00,520 DISEASE DOCTORS WEREN'T 1001 00:35:00,520 --> 00:35:01,480 INTERESTED IN TRANSPLANTING THEM 1002 00:35:01,480 --> 00:35:03,000 BECAUSE THEY HAD LEUKEMIA. 1003 00:35:03,000 --> 00:35:06,040 SO YOU HAVE TO FIND THE BALANCE, 1004 00:35:06,040 --> 00:35:08,520 HOW--IF YOU GIVE THEM TOO MUCH 1005 00:35:08,520 --> 00:35:10,200 CHEMO OR RADIATION TO GET THEM 1006 00:35:10,200 --> 00:35:11,080 READY FOR TRANSPLANT, YOU WILL 1007 00:35:11,080 --> 00:35:13,080 HAVE A LOT OF MORBIDITIES AND 1008 00:35:13,080 --> 00:35:14,360 THESE PATIENTS WERE VERY SICK. 1009 00:35:14,360 --> 00:35:16,120 ON THE OTHER HAND IF YOU GIVE 1010 00:35:16,120 --> 00:35:18,040 THEM TOO LITTLE CHEMO THERAPY TO 1011 00:35:18,040 --> 00:35:19,920 PREPARE THEM, THEY CAN REJECT 1012 00:35:19,920 --> 00:35:24,240 THE DONOR CELLS OR IF THEY HAVE 1013 00:35:24,240 --> 00:35:25,440 MYELOID DISPLASTIC SYNDROME IT 1014 00:35:25,440 --> 00:35:27,360 CAN PERSIST OR RECUR. 1015 00:35:27,360 --> 00:35:32,040 SO YOU'RE TRYING TO GO BETWEEN 1016 00:35:32,040 --> 00:35:33,600 TOO LITTLE AND TOO MUCH. 1017 00:35:33,600 --> 00:35:35,200 AND WHAT TYPE OF DONORS YOU ARE 1018 00:35:35,200 --> 00:35:36,400 GOING TO USE, WE WORK ON THIS 1019 00:35:36,400 --> 00:35:37,800 AND THINK ABOUT THIS A LOT 1020 00:35:37,800 --> 00:35:43,160 WHETHER YOU HAVE MATCH SIBLING, 1021 00:35:43,160 --> 00:35:46,440 UNRELATED DONOR UMBILICAL CORD 1022 00:35:46,440 --> 00:35:48,000 BLOOD AND HAPLO AND OUR OPROACH 1023 00:35:48,000 --> 00:35:49,000 HAS EVOLVED OVER TIME. 1024 00:35:49,000 --> 00:35:51,480 SO TO GET YOU TO THINK LIKE A 1025 00:35:51,480 --> 00:35:56,360 TRANSPLANTER, HAVE YOU HAVE YOK 1026 00:35:56,360 --> 00:35:57,400 ABOUT TRANSPLANT AS A PACKAGE, 1027 00:35:57,400 --> 00:35:58,400 YOU HAVE TO THINK ABOUT THE 1028 00:35:58,400 --> 00:35:59,520 DISEASE, WHERE IS THE PATIENT IN 1029 00:35:59,520 --> 00:36:00,760 THE NATURAL HISTORY DISEASE, WE 1030 00:36:00,760 --> 00:36:02,520 KNOW THAT FROM LEUKEMIA, YOU 1031 00:36:02,520 --> 00:36:04,880 WANT TO TRANSPLANT PEOPLE IN 1032 00:36:04,880 --> 00:36:06,040 REMISSION, SO STANDARD TREATMENT 1033 00:36:06,040 --> 00:36:07,840 IS TO INDUCE THEM INTO REMISSION 1034 00:36:07,840 --> 00:36:09,440 WITH A COUPLE CYCLES OF CHEMO 1035 00:36:09,440 --> 00:36:12,280 THERAPY AND THEN GO TO 1036 00:36:12,280 --> 00:36:12,560 TRANSPLANT. 1037 00:36:12,560 --> 00:36:15,160 WE THINK A LOT ABOUT THE DONOR 1038 00:36:15,160 --> 00:36:16,520 AND THE DONOR PRODUCT, BACK AND 1039 00:36:16,520 --> 00:36:19,320 FORTH AS TO DIFFERENT DONOR 1040 00:36:19,320 --> 00:36:20,560 ADVANTAGES, DISADVANTAGES AND 1041 00:36:20,560 --> 00:36:23,720 THEN WE THINK ABOUT THE BIG 1042 00:36:23,720 --> 00:36:25,600 THING IS HOW WE PREPARE THEM FOR 1043 00:36:25,600 --> 00:36:28,040 TRANSPLANT WHAT KIND OF CHEMO 1044 00:36:28,040 --> 00:36:29,560 THERAPY OR CONDITIONING REGIMEN 1045 00:36:29,560 --> 00:36:36,760 AND THEN THE LAST 2 GRAFT 1046 00:36:36,760 --> 00:36:41,520 REJECTION, YOU DON'T WANT TO 1047 00:36:41,520 --> 00:36:42,800 DEAL WITH REJECTION, YOU WANT TO 1048 00:36:42,800 --> 00:36:46,320 GET THAT GRAFT IN AND MAKE IT 1049 00:36:46,320 --> 00:36:47,120 STICK. 1050 00:36:47,120 --> 00:36:49,040 SOME PEOPLE DEVELOP GRAFT VERSUS 1051 00:36:49,040 --> 00:36:51,560 HOST DISEASE, HIGH DOSE 1052 00:36:51,560 --> 00:36:53,520 STEROIDS, OTHER INFECTIONS LIKE 1053 00:36:53,520 --> 00:36:55,040 ASPER GILLIS, SO THOSE ARE ALL 1054 00:36:55,040 --> 00:36:56,400 THE THINGS A TRANSPLANTER IS 1055 00:36:56,400 --> 00:36:59,280 THINKING ABOUT IN HIS REGIMEN. 1056 00:36:59,280 --> 00:37:01,960 SO,--SO START WITH THE DISEASE, 1057 00:37:01,960 --> 00:37:05,520 STEVE DID A NICE JOB OF 1058 00:37:05,520 --> 00:37:09,880 SUMMARIZING GATA 2, WE GOT 1 1059 00:37:09,880 --> 00:37:12,120 CLUE CORRECTION USING 1060 00:37:12,120 --> 00:37:13,040 HEMATOPOIETIC STEM CELL 1061 00:37:13,040 --> 00:37:13,960 TRANSPLANT COULD CORRECT THE 1062 00:37:13,960 --> 00:37:15,520 DISEASE, THAT WAS THE 1 PATIENT 1063 00:37:15,520 --> 00:37:17,920 WHO GOT A GRAFT IN TEXAS AND 1064 00:37:17,920 --> 00:37:19,720 THEN DIED OF COMPLICATIONS OF 1065 00:37:19,720 --> 00:37:20,160 TRANSPLANT. 1066 00:37:20,160 --> 00:37:24,040 SO IT LOOKED LIKE YOU COULD GET 1067 00:37:24,040 --> 00:37:26,440 GRAFTS IN, BECAUSE--AND THEN 1068 00:37:26,440 --> 00:37:28,400 WHAT ARE THE NONHEMATOPOIETIC 1069 00:37:28,400 --> 00:37:29,440 MANIFESTATIONS, I THINK 1070 00:37:29,440 --> 00:37:32,000 DR. HOLLAND SHOWED YOU THE 1071 00:37:32,000 --> 00:37:32,960 PICTURE OF THE LYMPHDEEMIA IN 1072 00:37:32,960 --> 00:37:34,600 THAT PATIENT, THAT DOES NOT GET 1073 00:37:34,600 --> 00:37:35,440 BETTER WITH TRANSPLANT, IT'S THE 1074 00:37:35,440 --> 00:37:39,040 VALVES AND THE VAINS DON'T FIT 1075 00:37:39,040 --> 00:37:42,320 RIGHT, THEY'RE LEAKY AND AND WE 1076 00:37:42,320 --> 00:37:45,600 CORRECT THE BONE MARROW BUT WE 1077 00:37:45,600 --> 00:37:47,120 DON'T FIX THE LYMPHDEEMIA AND 1078 00:37:47,120 --> 00:37:47,960 THEN YOU COULD FIGURE OUT IF YOU 1079 00:37:47,960 --> 00:37:50,160 HAVE I MOUSE MODEL AND IN 2009 1080 00:37:50,160 --> 00:37:53,920 WE DIDN'T KNOW IT WAS GATA 2, IS 1081 00:37:53,920 --> 00:37:55,120 HOW MUCH CORRECTION IS NEEDED. 1082 00:37:55,120 --> 00:37:56,960 IF YOU HAVE A LTLE YOU COULD CUT 1083 00:37:56,960 --> 00:37:58,320 BACK ON YOUR CONDITIONING JUST 1084 00:37:58,320 --> 00:38:00,320 GET A TOE HOLD OF THOSE STEM 1085 00:38:00,320 --> 00:38:01,200 CELLS COMING IN, OTHER DISEASES 1086 00:38:01,200 --> 00:38:05,880 YOU WANT TO GO TO 100%, YOU WANT 1087 00:38:05,880 --> 00:38:06,720 TO ERADICATE THAT DISEASE AND 1088 00:38:06,720 --> 00:38:07,520 THEN WE TALKED ABOUT WHERE IS 1089 00:38:07,520 --> 00:38:08,760 THE PATIENT IN THE NATURAL 1090 00:38:08,760 --> 00:38:12,240 HISTORY AND THAT BECOMES AN 1091 00:38:12,240 --> 00:38:14,400 IMPORTANT ISSUE ISSUE SO LET ME 1092 00:38:14,400 --> 00:38:16,400 JUST SAY A COUPLE THINGS ABOUT 1093 00:38:16,400 --> 00:38:18,280 GATA 2 THOUGH, WHAT WE KNOW IS 1094 00:38:18,280 --> 00:38:19,480 THAT SYMPTOMS GENERALLY APPEAR 1095 00:38:19,480 --> 00:38:22,600 IN CHILDHOOD, THEY CAN WORSEN 1096 00:38:22,600 --> 00:38:24,480 THROUGH EARLY ADULTHOOD, DISEASE 1097 00:38:24,480 --> 00:38:25,400 MANIFESTATIONS ARE HIGHLY 1098 00:38:25,400 --> 00:38:27,560 VARIABLE, WE HAVE A 20 YEAR-OLD 1099 00:38:27,560 --> 00:38:29,240 I TRANSPLANTED BUT HER MOTHER 1100 00:38:29,240 --> 00:38:30,800 HAS A MUTATION, SHE'S FINE, HER 1101 00:38:30,800 --> 00:38:32,160 GRANDMOTHER HAS A MUTATION, 1102 00:38:32,160 --> 00:38:35,560 SHE'S FINE AND HER GREAT GRAND 1103 00:38:35,560 --> 00:38:37,560 MARKET WAS 95 AND SHE HAD THE 1104 00:38:37,560 --> 00:38:39,040 MUTATION SO THERE'S A LOT WE 1105 00:38:39,040 --> 00:38:41,240 DON'T KNOW ABOUT WHO GETS 1106 00:38:41,240 --> 00:38:42,760 SYMPTOMATIC AND WHO DOESN'T. 1107 00:38:42,760 --> 00:38:45,200 WE DO KNOW THEY PROGRESS FROM A 1108 00:38:45,200 --> 00:38:48,000 NORMAL MARROW TO A VERY 1109 00:38:48,000 --> 00:38:50,360 HYPOCELLULAR MARROW THAT CAN 1110 00:38:50,360 --> 00:38:51,720 LOOK AT APLASTIC ANEMIA, AND 1111 00:38:51,720 --> 00:38:54,440 NEAL YOUNG'S GROUP TAKES CARE OF 1112 00:38:54,440 --> 00:38:56,080 APLASTIC ANEMIA, SEND US A HALF 1113 00:38:56,080 --> 00:38:57,720 DOZEN PATIENTS AND THEN THEY CAN 1114 00:38:57,720 --> 00:38:58,960 SEGUE RIGHT ON TO AML. 1115 00:38:58,960 --> 00:39:02,520 AND THAT'S THE DEADLY 1116 00:39:02,520 --> 00:39:04,760 COMPLICATION BECAUSE THIS IS A 1117 00:39:04,760 --> 00:39:06,120 VERY REFRACTORY AML. 1118 00:39:06,120 --> 00:39:08,400 THERE IS SOME SUGGESTION, CAN 1119 00:39:08,400 --> 00:39:10,880 YOU TELL THAT BY DR. HOLLAND'S 1120 00:39:10,880 --> 00:39:12,400 SLIDES OF ANTICIPATION IT SEEMS 1121 00:39:12,400 --> 00:39:15,320 TO APPEAR EARLIER IN EACH 1122 00:39:15,320 --> 00:39:15,840 GENERATION. 1123 00:39:15,840 --> 00:39:19,240 SO WHAT DOES IT LOOK LIKE IN THE 1124 00:39:19,240 --> 00:39:19,520 REAL WORLD. 1125 00:39:19,520 --> 00:39:30,040 THIS IS A WOMAN WE SAW IN A 38 1126 00:39:30,480 --> 00:39:32,880 YEAR-OLD WOMAN, LOT NORMAL 1127 00:39:32,880 --> 00:39:35,560 MARROW, VERY FATTY MARROW, VERY 1128 00:39:35,560 --> 00:39:37,600 LITTLE HEMEAT O POETICESIS, ONLY 1129 00:39:37,600 --> 00:39:41,520 10% IS CELLULAR THE REST IS THE 1130 00:39:41,520 --> 00:39:42,000 FAT TISSUE. 1131 00:39:42,000 --> 00:39:43,960 HOWEVER, IT LOOKED NORMAL IN 1132 00:39:43,960 --> 00:39:46,120 2009, IT WAS HYPOCELLULAR, BUT 1133 00:39:46,120 --> 00:39:48,120 SHE HAD NORMAL LOOKING 1134 00:39:48,120 --> 00:39:50,840 NUTRIFILLS AND METAMILE O 1135 00:39:50,840 --> 00:39:53,040 SIGHTS, NORMAL ARITHROADWAY 1136 00:39:53,040 --> 00:39:53,760 PRECURSORS NO INCREASED BLASTS 1137 00:39:53,760 --> 00:39:55,640 AND THE PLAN WAS TO FOLLOW HER 1138 00:39:55,640 --> 00:39:56,840 EVERY YEAR, HOWEVER, SHE STAYED 1139 00:39:56,840 --> 00:39:59,240 AWAY AND SHOWED UP IN DURANGO 1140 00:39:59,240 --> 00:40:01,120 COLORADO 1 FINE DAY, 2 YEARS 1141 00:40:01,120 --> 00:40:03,200 LATER WITH THIS MARROW. 1142 00:40:03,200 --> 00:40:06,320 ALL RIGHT THIS, IS BAD, HYPER 1143 00:40:06,320 --> 00:40:08,920 CELLULAR, IT'S 95% CELLULAR, 1144 00:40:08,920 --> 00:40:11,240 THIS CAN'T BE GOOD. 1145 00:40:11,240 --> 00:40:13,800 EVEN WORSE, WAS ALL THESE CELLS, 1146 00:40:13,800 --> 00:40:19,240 THESE ARE BLASTS, BIG CELLS, BIG 1147 00:40:19,240 --> 00:40:21,080 NUCLEI, NUCLEI, YOU CAN SEE 1, 1148 00:40:21,080 --> 00:40:25,640 2, 3, 4, 5, 6, 7, 7 BLASTS HERE, 1149 00:40:25,640 --> 00:40:28,440 SHE HAD A TOTAL 10% CELLS WERE 1150 00:40:28,440 --> 00:40:29,560 BLAST IN HERE. 1151 00:40:29,560 --> 00:40:30,480 THIS IS COMPLICATED, YOU GOTTA 1152 00:40:30,480 --> 00:40:32,480 GIVE THEM A CYCLE OF CHEMO 1153 00:40:32,480 --> 00:40:34,160 THERAPY AT LEAST, GET IT TO LESS 1154 00:40:34,160 --> 00:40:38,080 THAN 5% BLASTS AND THEN GO TO 1155 00:40:38,080 --> 00:40:38,360 TRANSPLANT. 1156 00:40:38,360 --> 00:40:40,400 SO SHE SLIPPED THROUGH OUR HANDS 1157 00:40:40,400 --> 00:40:42,760 BUT WE SUCCESSFULLY DID AN 1158 00:40:42,760 --> 00:40:44,760 UNRELATED DONOR TRANSPLANT AND 1159 00:40:44,760 --> 00:40:51,400 SHE'S ALIVE NOW 9 YEARS LATER. 1160 00:40:51,400 --> 00:40:54,040 MORE TRAGIC, SPEAKING OF 1161 00:40:54,040 --> 00:40:56,360 SLIPPING BY, 24 YEAR-OLD WOMAN 1162 00:40:56,360 --> 00:40:58,480 LONG HISTORY OF DYSPLASIA AND 1163 00:40:58,480 --> 00:40:59,480 [INDISCERNIBLE] SHE CAME TO DC 1164 00:40:59,480 --> 00:41:03,680 TO WORK ON THE ROLL OUT OF THE 1165 00:41:03,680 --> 00:41:05,480 AFFORDABLE CARE ACT, THEY WERE 1166 00:41:05,480 --> 00:41:06,720 THE GOOD CONTRACTORS BROUGHT IN 1167 00:41:06,720 --> 00:41:09,480 TO FIX IT, SO WE SAW HER FOR THE 1168 00:41:09,480 --> 00:41:11,080 FIRST TIME IN APLASTIC ANEMIA 1169 00:41:11,080 --> 00:41:13,760 CLINIC AND THEY THOUGHT, THIS 1170 00:41:13,760 --> 00:41:15,440 COULD BE GATA 2 SO THEY DID A 1171 00:41:15,440 --> 00:41:17,520 BONE MARROW, OF THE NORMAL 1172 00:41:17,520 --> 00:41:19,160 CELLULAR, MAYBE THAT WAS A CLUE, 1173 00:41:19,160 --> 00:41:20,960 SHE HAD PROBABLY BEEN 1174 00:41:20,960 --> 00:41:22,000 HYPOCELLULAR ALL THESE YEARS, 1175 00:41:22,000 --> 00:41:23,640 BUT IT WAS A NORMAL LOOKING 1176 00:41:23,640 --> 00:41:24,000 MARROW. 1177 00:41:24,000 --> 00:41:26,000 THESE ARE NORMAL LOOKING 1178 00:41:26,000 --> 00:41:28,360 NUTRIFILLS RIGHT HERE, SHE HAS 1179 00:41:28,360 --> 00:41:29,400 NORMAL LOOKING ERYTH ROADWAY 1180 00:41:29,400 --> 00:41:31,880 PRECURSORS, NO INCREASE IN 1181 00:41:31,880 --> 00:41:33,640 BLASTS, SO WE LOOKED AT THIS 1182 00:41:33,640 --> 00:41:34,880 MANY TIMES, SO THE TESTING WAS 1183 00:41:34,880 --> 00:41:36,880 SET OUT, IT WAS A LITTLE 1184 00:41:36,880 --> 00:41:38,280 CUMBERSOME THEN TO DO, SHE 1185 00:41:38,280 --> 00:41:40,520 FINALLY TURNED OUT TO BE GATA 2 1186 00:41:40,520 --> 00:41:41,040 POSITIVE. 1187 00:41:41,040 --> 00:41:42,920 FOUR MONTHS LATER WE GOT HER 1188 00:41:42,920 --> 00:41:44,960 BACK TO CLINIC, BOOM, 1189 00:41:44,960 --> 00:41:46,760 DR. HOLLAND AND I SAW HER IN THE 1190 00:41:46,760 --> 00:41:48,960 CLINIC, SHE'S BLOODING FROM A 1191 00:41:48,960 --> 00:41:50,000 VENA PUNCTURE WHERE HEBLOOD WAS 1192 00:41:50,000 --> 00:41:51,960 DRAWN AND SHE HAD THIS BONE 1193 00:41:51,960 --> 00:41:54,280 MARROW PACKED WITH CELLS. 1194 00:41:54,280 --> 00:41:57,400 AND WHAT ARE THEY PACKED WITH? 1195 00:41:57,400 --> 00:42:00,200 LEUKEMIA ACUTE MILE O MONOSITTIC 1196 00:42:00,200 --> 00:42:01,720 LEUKEMIA OR MONOBLASTIC 1197 00:42:01,720 --> 00:42:02,280 LEUKEMIA. 1198 00:42:02,280 --> 00:42:04,680 SO SHE AND 4 MONTHS AND A NEW 1199 00:42:04,680 --> 00:42:06,360 CYTOGENIC CHANGES, BOOM WITHIN 4 1200 00:42:06,360 --> 00:42:09,080 MONTHS SHE TURNED INTO ACUTE 1201 00:42:09,080 --> 00:42:09,360 LEUKEMIA. 1202 00:42:09,360 --> 00:42:11,480 THAT EXPLAINS WHY WE HAVE A LOT 1203 00:42:11,480 --> 00:42:12,480 OF VIGILANCE FOR THESE PATIENTS 1204 00:42:12,480 --> 00:42:15,520 BECAUSE NOW THIS WAS A DIFFICULT 1205 00:42:15,520 --> 00:42:15,720 CASE. 1206 00:42:15,720 --> 00:42:17,520 SHE HAD 3 CYCLES OF CHEMO 1207 00:42:17,520 --> 00:42:19,120 THERAPY NEVER GOT A REMISSION, 1208 00:42:19,120 --> 00:42:21,400 WE WENT TO TRANSPLANT, SHE 1209 00:42:21,400 --> 00:42:24,160 RELAPSED AT DAY 30, REPEATED THE 1210 00:42:24,160 --> 00:42:25,640 TRANSPLANT, RELAPSED AT DAY 100 1211 00:42:25,640 --> 00:42:26,400 AND DIED. 1212 00:42:26,400 --> 00:42:28,760 SO A TRAGED EDDIE WHICH PROBABLY 1213 00:42:28,760 --> 00:42:34,040 COULD HAVE BEEN AVERTED HAD WE 1214 00:42:34,040 --> 00:42:34,440 DIAGNOSED EARLIER. 1215 00:42:34,440 --> 00:42:36,400 SO WE'VE BEEN KIND OF IN MY LAB 1216 00:42:36,400 --> 00:42:37,480 TRYING TO FIGURE OUT WHAT 1217 00:42:37,480 --> 00:42:39,360 MUTATIONS CAN HELP TRIGGER GATA 1218 00:42:39,360 --> 00:42:43,600 2, AND WE HAVE A RECENT 1219 00:42:43,600 --> 00:42:45,080 PUBLICATION SHOWING 2 MUTATIONS, 1220 00:42:45,080 --> 00:42:48,280 ASXL1 WHICH IS A CHROMATIN 1221 00:42:48,280 --> 00:42:49,840 REMODELING ENZYME AND STAG 2 1222 00:42:49,840 --> 00:42:51,920 WHICH IS A COHESION MOLECULE, 1223 00:42:51,920 --> 00:42:55,240 COMMON MUTATIONS, THEY ARE IN 1224 00:42:55,240 --> 00:42:57,760 THE MDS, AML TYPE OF PATHWAY, SO 1225 00:42:57,760 --> 00:42:59,400 YOU START SEEING THESE, YOU 1226 00:42:59,400 --> 00:43:00,200 START WORRYING. 1227 00:43:00,200 --> 00:43:02,200 WHAT WAS NOTABLE THOUGH IS WE 1228 00:43:02,200 --> 00:43:04,720 DIDN'T FIND ANY OF THE COMMON 1229 00:43:04,720 --> 00:43:08,160 MDS, AML ASSOCIATED GENES, ALL 1230 00:43:08,160 --> 00:43:09,720 THESE SPLICING FACTORS TATTOO, 1231 00:43:09,720 --> 00:43:13,640 WE DIDN'T SEE THOSE, SO I SAID 1232 00:43:13,640 --> 00:43:16,880 THAT THOSE WERE THE 2 ASXL1, AND 1233 00:43:16,880 --> 00:43:18,360 STAG 2, THESE ARE COMMON IN 25% 1234 00:43:18,360 --> 00:43:21,200 OF THE PATIENTS IN ASXL1 IN 20% 1235 00:43:21,200 --> 00:43:23,520 OF THE PATIENTS SO ARE THEY 1236 00:43:23,520 --> 00:43:24,960 WELL OUR CONCLUSION WAS THAT 1237 00:43:24,960 --> 00:43:27,240 GATA 2 PATIENTS HAVE A NOVEL 1238 00:43:27,240 --> 00:43:28,760 PATHWAY TO LEUKEMIA, AND THAT 1239 00:43:28,760 --> 00:43:31,760 THEY LACK THE COMMON MDSA 1240 00:43:31,760 --> 00:43:34,200 MUTATIONS, AND THAT THEY HAVE 1241 00:43:34,200 --> 00:43:36,240 DIFFERENT MUTATIONS LIKE ASXL1 1242 00:43:36,240 --> 00:43:38,400 AND STAG 2 ARE SECOND HITS. 1243 00:43:38,400 --> 00:43:39,280 AND THOSE ARE PROGNOSTIC AND 1244 00:43:39,280 --> 00:43:42,360 THEY HAVE A LOWER SURVIVAL RATE. 1245 00:43:42,360 --> 00:43:47,200 BUT THAT'S NOT ENOUGH, THOUGH, 1246 00:43:47,200 --> 00:43:49,160 SO THEN THE QUESTION COMES SO 1247 00:43:49,160 --> 00:43:50,920 ARE WE GOING TO TRANSPLANT THEM. 1248 00:43:50,920 --> 00:43:53,200 IT'S ACTUALLY STILL A CLINICAL 1249 00:43:53,200 --> 00:43:56,640 DECISION PRIMARILY, IT'S THE 1250 00:43:56,640 --> 00:43:59,160 RECURRENT SEVERE OPPORTUNISTIC 1251 00:43:59,160 --> 00:44:03,440 INFECTIONS THEY'VE HAD 1 1252 00:44:03,440 --> 00:44:04,360 NONTUBERC LOWIS INFECTION AND 1253 00:44:04,360 --> 00:44:07,920 THEY WILL GET MORE AND BE IN 1254 00:44:07,920 --> 00:44:09,920 WORSE PLACE FOR TRANS. 1255 00:44:09,920 --> 00:44:11,800 WE SEE PEOPLE REQUIRING LAVAGE 1256 00:44:11,800 --> 00:44:13,640 AS PEOPLE SHOWED YOU IN THAT 1257 00:44:13,640 --> 00:44:15,240 WE'RE PICKING UP PATIENTS 1258 00:44:15,240 --> 00:44:15,480 EARLIER. 1259 00:44:15,480 --> 00:44:17,160 THE OTHER THING THAT DRIVES US 1260 00:44:17,160 --> 00:44:19,080 IN ABOUT HALF OUR PATIENTS, IT'S 1261 00:44:19,080 --> 00:44:21,480 CLINICAL AS THE PATIENTS ARE 1262 00:44:21,480 --> 00:44:23,680 MOVING TOWARDS MDS OR AML, THEY 1263 00:44:23,680 --> 00:44:25,800 HAVE INCREASED BLASTS, INCREASED 1264 00:44:25,800 --> 00:44:29,640 CELLULARITY AND NEW CYTOGENIC 1265 00:44:29,640 --> 00:44:31,160 CHANGES SO, IT'S SORT OF A 1266 00:44:31,160 --> 00:44:33,480 COMPOSITE THAT LEADS US TO 1267 00:44:33,480 --> 00:44:34,280 TRANSPLANT, THE INFECTIONS, I 1268 00:44:34,280 --> 00:44:37,880 DON'T SHOW ON HERE, BUT THE BONE 1269 00:44:37,880 --> 00:44:38,480 MARROW'S QUITE IMPORTANT 1270 00:44:38,480 --> 00:44:39,760 ESPECIALLY IF THEY'RE STRARTING 1271 00:44:39,760 --> 00:44:42,760 TO FAIL AND BECOME NEWT ROUGH 1272 00:44:42,760 --> 00:44:45,600 ATOM PENIC, NEWT CYTOGENETIC 1273 00:44:45,600 --> 00:44:48,240 CHANGES, MONO7 AND NOW WE ADD IN 1274 00:44:48,240 --> 00:44:53,960 THESE SOMATIC MUTATIONS THAT I 1275 00:44:53,960 --> 00:44:54,360 ALLUDED TO. 1276 00:44:54,360 --> 00:44:56,160 SO LET ME JUST SAY A FEW THINGS 1277 00:44:56,160 --> 00:44:58,040 TO GET YOU TO THINK LIKE A 1278 00:44:58,040 --> 00:44:59,120 TRANSPLANTER, WE THINK ABOUT 1279 00:44:59,120 --> 00:45:01,200 DONORS A LOT, WE LIKE MATCHED 1280 00:45:01,200 --> 00:45:02,840 SIBLINGS, SO WE'VE TALKED ABOUT 1281 00:45:02,840 --> 00:45:05,200 THE DISEASE, HOWEVER THE PROBLEM 1282 00:45:05,200 --> 00:45:07,760 WITH GATA 2 IS YOU--YOU SEQUENCE 1283 00:45:07,760 --> 00:45:09,080 THESE PEOPLE AND THE CHANCE IS 1284 00:45:09,080 --> 00:45:19,560 50% OF THEIR SIBLINGS CAN BE 1285 00:45:21,640 --> 00:45:24,840 GATA 2 POSITIVE SO THE ODDS ARE 1286 00:45:24,840 --> 00:45:26,040 UNLIKELY FOR A MATCH, BUT YOU 1287 00:45:26,040 --> 00:45:29,880 CAN GET A UNRELATED DONOR AND IF 1288 00:45:29,880 --> 00:45:30,760 YOU'RE OF NORTHERN EUROPEAN 1289 00:45:30,760 --> 00:45:33,080 STOCK YOU HAVE A ABOUT A 60% 1290 00:45:33,080 --> 00:45:34,880 CHANCE OF BEING AN UNRELATED 1291 00:45:34,880 --> 00:45:35,320 DONOR. 1292 00:45:35,320 --> 00:45:36,800 THERE'S A BANK IN GERMANY 1293 00:45:36,800 --> 00:45:40,920 SOPHISTICATEDY IT DROPS DOWN 1294 00:45:40,920 --> 00:45:42,160 HOWEVER IF YOU'RE BLACK OR 1295 00:45:42,160 --> 00:45:44,720 HISPANIC BECAUSE THE UNRELATED 1296 00:45:44,720 --> 00:45:46,600 DONOR BANK IS UNDERREPRESENTED 1297 00:45:46,600 --> 00:45:47,600 FOR THESE POPULATIONS, SO WE 1298 00:45:47,600 --> 00:45:49,440 ALWAYS LOOK AT UNRELATED 1299 00:45:49,440 --> 00:45:53,400 DONORSES ARE WE START OUT USING 1300 00:45:53,400 --> 00:45:54,960 UMBILICAL CORDS, YOU CAN GET 1301 00:45:54,960 --> 00:45:57,040 THEM QUICK, YOU CAN GET THEM IN 1302 00:45:57,040 --> 00:45:58,320 7-14 DAYS, THEY'RE ALREADY IN 1303 00:45:58,320 --> 00:46:01,640 THE FREEZER, THEY REFLECT THE 1304 00:46:01,640 --> 00:46:03,640 OUTBRED NATURE OF SOCIETY, THEY 1305 00:46:03,640 --> 00:46:05,880 COST ABOUT 80 GRAND SO THEY'RE 1306 00:46:05,880 --> 00:46:06,400 NOT CHEAP. 1307 00:46:06,400 --> 00:46:07,680 HERE'S THE PROBLEM, YOU ARE 1308 00:46:07,680 --> 00:46:09,320 DEALING WITH 1 TENTH OF A STEM 1309 00:46:09,320 --> 00:46:12,240 CELLS THAT YOU GET FROM A SIB OR 1310 00:46:12,240 --> 00:46:16,560 MATCHED UNRELATE DONOR SO 1311 00:46:16,560 --> 00:46:17,640 THERE'S INGRAFTMENT, VIRAL 1312 00:46:17,640 --> 00:46:17,960 COMPLICATIONS, 1313 00:46:17,960 --> 00:46:18,560 CERTAINLY--CERTAINLY SPECIALLY 1314 00:46:18,560 --> 00:46:20,080 WITH OUR PATIENTS THAT ARE 1315 00:46:20,080 --> 00:46:21,720 ADULTS THERE'S A SIZE DIFREBTIAL 1316 00:46:21,720 --> 00:46:22,720 SO THE OTHER ALTERNATIVE DONOR 1317 00:46:22,720 --> 00:46:24,040 WHICH IS THE BIG STRAIN COMING 1318 00:46:24,040 --> 00:46:27,120 DOWN THE TRACT OR HAPPEN LO 1319 00:46:27,120 --> 00:46:29,440 IDENTICAL RELATED DONORS THIS IS 1320 00:46:29,440 --> 00:46:33,880 A MOTHER, FATHER, BROTHER, 1321 00:46:33,880 --> 00:46:36,120 SISTER, DAUGHTER SO THESE ARE 1322 00:46:36,120 --> 00:46:37,040 FAST AND MOTIVATED. 1323 00:46:37,040 --> 00:46:39,640 SOEE LOOK FOR DONORS A LOT. 1324 00:46:39,640 --> 00:46:41,320 WE DO LOST LOTS OF SEARCHES WE 1325 00:46:41,320 --> 00:46:43,320 WANT TO GET A 10 OUT OF 10 1326 00:46:43,320 --> 00:46:45,280 MATCHED DONOR, WE USED TO DO 6 1327 00:46:45,280 --> 00:46:49,960 OUT OF 6 BACK AT 2000, NOW WE DO 1328 00:46:49,960 --> 00:46:52,960 10 BY DEN, THE GBH HAS DONE MORE 1329 00:46:52,960 --> 00:46:58,560 BY MATCHING AND THAT TRUMPS ADO, 1330 00:46:58,560 --> 00:46:58,840 EVERYTHING. 1331 00:46:58,840 --> 00:46:59,800 NATURAL DONOR PROGRAM LOOKED 1332 00:46:59,800 --> 00:47:01,600 BACK 10 YEARS AGO AND FOUND 1333 00:47:01,600 --> 00:47:03,560 THERE'S A 15% INCREASE MORTALITY 1334 00:47:03,560 --> 00:47:06,240 FOR EVERY DECADE OVER THE AGE OF 1335 00:47:06,240 --> 00:47:06,520 32. 1336 00:47:06,520 --> 00:47:08,520 SO IF YOU SIGN UP TO THE MATCH 1337 00:47:08,520 --> 00:47:09,520 AND YOU'RE OVER 32, THEY WILL 1338 00:47:09,520 --> 00:47:11,840 CHARGE YOU A HUNDRED DOLLARS TO 1339 00:47:11,840 --> 00:47:13,680 SIGN UP THEN IF YOU CAN GET A 1340 00:47:13,680 --> 00:47:15,440 BLOOD TYPE MATCH, THAT'S 1341 00:47:15,440 --> 00:47:17,480 HELPFUL, THAT WAY YOU DON'T HAVE 1342 00:47:17,480 --> 00:47:18,440 THE RED CELL DEPLETE AND THE 1343 00:47:18,440 --> 00:47:20,840 LIKE, AND THE OTHER THING IS IF 1344 00:47:20,840 --> 00:47:22,440 THE PATIENTS CMV POSITIVE, YOU 1345 00:47:22,440 --> 00:47:25,160 REALLY WANT A DONOR TO BE CMV 1346 00:47:25,160 --> 00:47:26,800 POSITIVE SO THOSE DONOR T-CELLS 1347 00:47:26,800 --> 00:47:28,560 HIT THE GROUND RUNNING AND YOU 1348 00:47:28,560 --> 00:47:31,400 DON'T GET THESE BAD VIRAL 1349 00:47:31,400 --> 00:47:31,800 REACTIVATIONS. 1350 00:47:31,800 --> 00:47:33,200 AND THE OTHER THING YOU DON'T 1351 00:47:33,200 --> 00:47:36,560 WANT A TINY DONOR AND A LARGE 1352 00:47:36,560 --> 00:47:37,240 RECIPIENT AND WE ARE DEALING 1353 00:47:37,240 --> 00:47:40,880 WITH THAT NOW, WE HAVE A TINY 1354 00:47:40,880 --> 00:47:42,040 DONOR LIKE 40-50 KILOGRAMS, 1355 00:47:42,040 --> 00:47:44,720 YOUNG WOMEN AND THE RECIPIENT'S 1356 00:47:44,720 --> 00:47:47,120 120 KILOS SO AUTOMATICALLY WE'RE 1357 00:47:47,120 --> 00:47:47,520 AT A DISADVANTAGE. 1358 00:47:47,520 --> 00:47:48,760 SO THE DONORS WE THINK ABOUT, WE 1359 00:47:48,760 --> 00:47:51,120 THINK ABOUT THE DONOR PRODUCT, 1360 00:47:51,120 --> 00:47:53,560 ARE WE GOING TO COLLECT 1361 00:47:53,560 --> 00:47:54,760 PERIPHERAL BLOOD STEM CELLS, 1362 00:47:54,760 --> 00:47:57,320 THERE'S A LOT MORE LYMPHOCYTES 1363 00:47:57,320 --> 00:47:58,880 THERE, MORE GBH, IT'S A BETTER 1364 00:47:58,880 --> 00:48:00,760 CHOICE IF YOU'RE WORRY BODY 1365 00:48:00,760 --> 00:48:05,040 RELAPSE, IT'S BEEN USED A LOT 94 1366 00:48:05,040 --> 00:48:05,800 DURING COVID BECAUSE PERIPHERAL 1367 00:48:05,800 --> 00:48:09,800 BLOOD STEM CELLS FREEZE BETTER 1368 00:48:09,800 --> 00:48:10,080 THAN MARROW. 1369 00:48:10,080 --> 00:48:14,520 SO THEN THE QUESTION IS 1370 00:48:14,520 --> 00:48:16,160 HAPLO-IDENTICALS CAME UP BECAUSE 1371 00:48:16,160 --> 00:48:17,960 THEY'RE SO MISMATCHED, THEY ARE 1372 00:48:17,960 --> 00:48:20,280 50% MISMATCHED AND THE INITIAL 1373 00:48:20,280 --> 00:48:22,760 STUDIES FROM HOPKINS USED 1374 00:48:22,760 --> 00:48:24,240 EXCLUSIVELY MARROW, NOW HE'S 1375 00:48:24,240 --> 00:48:27,240 TOLD ME THEY'RE BACK TO ABOUT 1376 00:48:27,240 --> 00:48:29,960 50/50 MARROW VERSUS PBS Cs FOR 1377 00:48:29,960 --> 00:48:31,640 THEIR HAPLOs, A LOT OF THINGS 1378 00:48:31,640 --> 00:48:33,120 PEOPLE DO IS I WILL CONSIDER GET 1379 00:48:33,120 --> 00:48:36,800 RID OF THE LYMPHOCYTES, CD34 1380 00:48:36,800 --> 00:48:38,400 SELECT THE STEM CELLS, RISK IS 1381 00:48:38,400 --> 00:48:40,240 THERE'S MORE GRAFT REJECTION 1382 00:48:40,240 --> 00:48:42,720 WHEN YOU DO THESE SELECTIONS. 1383 00:48:42,720 --> 00:48:45,920 A LOT OF GROUPS ARE NOW DOING 1384 00:48:45,920 --> 00:48:46,480 T-CELL RECEPTOR ALPHABETTA 1385 00:48:46,480 --> 00:48:48,680 DELETION, THESE ARE THE TYPE OF 1386 00:48:48,680 --> 00:48:50,280 T-CELLS THAT CAUSE GRAFT VERSUS 1387 00:48:50,280 --> 00:48:51,720 HOST DISEASE, SO YOU PUT THE 1388 00:48:51,720 --> 00:48:53,680 DONOR PRODUCT OVER A COLUMN, 1389 00:48:53,680 --> 00:48:56,400 THESE GUYS STICK AS WELL AS CD19 1390 00:48:56,400 --> 00:48:57,760 CELLS AND THEN YOU TAKE THE FLOW 1391 00:48:57,760 --> 00:48:59,360 THROUGH AND THAT'S WHAT YOU 1392 00:48:59,360 --> 00:49:04,520 INFUSE INTO THE PATIENT. 1393 00:49:04,520 --> 00:49:06,440 CORDS HAVE THEIR PROBLEMS, I 1394 00:49:06,440 --> 00:49:07,680 ALLUDED TO, SMALL NUMBER OF 1395 00:49:07,680 --> 00:49:08,000 CELLS. 1396 00:49:08,000 --> 00:49:10,880 SO LET ME JUST SAY A FEW THINGS 1397 00:49:10,880 --> 00:49:13,240 ABOUT CONDITIONING REGIMENS, 1398 00:49:13,240 --> 00:49:14,600 THAT'S OUR BIG THING, CAN YOU 1399 00:49:14,600 --> 00:49:18,640 GIVE A REALLY--YOU THINK ABOUT 1400 00:49:18,640 --> 00:49:18,920 IT A LOT. 1401 00:49:18,920 --> 00:49:24,080 YOU CAN GET A LOW DOSE 1402 00:49:24,080 --> 00:49:25,200 TRANSPLANT, NONMILE ABLATIVE, 1403 00:49:25,200 --> 00:49:26,080 THEY DON'T RECONSITUTE. 1404 00:49:26,080 --> 00:49:27,320 THIS IS HOW WE START OUT WITH 1405 00:49:27,320 --> 00:49:28,920 GATA 2, THEY WERE SO SICK. 1406 00:49:28,920 --> 00:49:31,040 IF WE GIVE THEM ANYTHING MORE 1407 00:49:31,040 --> 00:49:32,520 THAN THE MINIMUM, IT WILL BE THE 1408 00:49:32,520 --> 00:49:33,200 END OF THEM. 1409 00:49:33,200 --> 00:49:41,200 THREE OF THEM WERE ON OXYGEN, 1410 00:49:41,200 --> 00:49:43,040 THE END IS MILE O ABLATIVE, 1411 00:49:43,040 --> 00:49:45,960 THAT'S WHERE YOU GIVE 1412 00:49:45,960 --> 00:49:47,680 IMMUNOSUPPRESSIVE AND CHEMO 1413 00:49:47,680 --> 00:49:52,880 THERAPY DRUG, AND A LOT DO 1414 00:49:52,880 --> 00:49:54,840 EVERYTHING IN BETWEEN, SOME DO 1415 00:49:54,840 --> 00:49:55,680 SUPPRESSION. 1416 00:49:55,680 --> 00:49:57,320 FOR GRAFT REJECTION, THE BEST 1417 00:49:57,320 --> 00:49:58,680 WAY IS APLATE THEM, YOU KNOCK 1418 00:49:58,680 --> 00:50:00,160 OUT THE MYELOID CELLS AND THEIR 1419 00:50:00,160 --> 00:50:01,760 IMMUNE SYSTEM, THE OTHER THING, 1420 00:50:01,760 --> 00:50:04,280 IT GIVES A PERFECT MATCH, YOU 1421 00:50:04,280 --> 00:50:06,120 CAN GET IT, DON'T MESS WITH THE 1422 00:50:06,120 --> 00:50:07,560 GRAFT, THE MORE YOU T-CELL 1423 00:50:07,560 --> 00:50:09,120 DEPLETE, THE MORE YOUR CHANCE AT 1424 00:50:09,120 --> 00:50:10,160 REJECTION, ALSO IF YOU GET IT, 1425 00:50:10,160 --> 00:50:13,400 USE A HIGH DOSE OF STEM CELLS, 1426 00:50:13,400 --> 00:50:14,400 NOT ALWAYS POSSIBLE DEPENDING ON 1427 00:50:14,400 --> 00:50:18,120 THE DONOR AND THE RECIPIENT. 1428 00:50:18,120 --> 00:50:20,160 AND THEN I TALKED ABOUT BRIEFLY 1429 00:50:20,160 --> 00:50:21,800 GRAFT VERSUS HOST, IT'S BEEN THE 1430 00:50:21,800 --> 00:50:24,440 BUGGA POO OF TRANSPLANT FOR 50 1431 00:50:24,440 --> 00:50:25,240 YEARS, THE METHOTREKSATE WAS 1432 00:50:25,240 --> 00:50:27,920 USED FOR MANY YEARS IN SEATTLE, 1433 00:50:27,920 --> 00:50:30,720 THEN THEY COUPLED IT IN THE 1434 00:50:30,720 --> 00:50:32,480 EARLY 80S WITH CYCLOSPORIN OR 1435 00:50:32,480 --> 00:50:33,880 [INDISCERNIBLE]. 1436 00:50:33,880 --> 00:50:35,960 AND NOW THE BIG TRAIN OVER THE 1437 00:50:35,960 --> 00:50:39,320 LAST 10-15 YEARS AND POST 1438 00:50:39,320 --> 00:50:39,920 TRANSPLANT CYCLOFOSTER NURSED 1439 00:50:39,920 --> 00:50:40,960 FACAS MID AND THAT WILL BE USED 1440 00:50:40,960 --> 00:50:43,720 FOR ALL THE HAPLOs AND USED 1441 00:50:43,720 --> 00:50:46,080 ALMOST FOR EVERYONE MATCH 1442 00:50:46,080 --> 00:50:47,560 RELATED AND UNRELATED BECAUSE IT 1443 00:50:47,560 --> 00:50:50,320 REALLY IS GOOD AT APLATING THE 1444 00:50:50,320 --> 00:50:51,720 DONOR T-CELLS THAT WILL CAUSE 1445 00:50:51,720 --> 00:50:54,240 GRAFT VERSUS HOST SO I WILL 1446 00:50:54,240 --> 00:50:55,240 BRIEFLY SUMMARIZE IN 2009, WE 1447 00:50:55,240 --> 00:50:57,440 DIDN'T KNOW IT WAS GATA 2, ALL 1448 00:50:57,440 --> 00:50:59,040 PATIENTS HAD MAJOR ISSUES, 3 1449 00:50:59,040 --> 00:51:01,080 WERE ON OXYGEN, I SAID I USED 1450 00:51:01,080 --> 00:51:04,680 THIS SEATTLE REGIMEN, THE MOST 1451 00:51:04,680 --> 00:51:05,640 REDUCED INTENSITY OR NONMILE 1452 00:51:05,640 --> 00:51:07,360 ABLATIVE REGIMEN OUT THERE, 1453 00:51:07,360 --> 00:51:11,160 SINGLE LOW DOSE OF RADIATION, 3 1454 00:51:11,160 --> 00:51:12,640 DAYS OF CHEMO THERAPY AND IT 1455 00:51:12,640 --> 00:51:15,560 WASN'T TERRIBLE, WE HAD 3 OUT OF 1456 00:51:15,560 --> 00:51:17,400 4 MATCHED UNRELATED DONORS WHO 1457 00:51:17,400 --> 00:51:19,840 WERE ALIVE AND DISEASE FREE, 1 1458 00:51:19,840 --> 00:51:21,480 REJECTED YOU WOULD EXPECT WITH A 1459 00:51:21,480 --> 00:51:23,480 LOWER DOSE REGIMEN AND DIED OF A 1460 00:51:23,480 --> 00:51:25,280 SECOND TRANSPLANT OF THE MATCHED 1461 00:51:25,280 --> 00:51:27,920 RELATED DONORS THIS IS THE CAP 1462 00:51:27,920 --> 00:51:30,200 LANMIER SURVIVAL CURVE WHICH ALL 1463 00:51:30,200 --> 00:51:31,440 TRANSPLANTERS SHOW, SURVIVAL ON 1464 00:51:31,440 --> 00:51:33,400 THE AXIS AND TIME ON THE X-AXIS 1465 00:51:33,400 --> 00:51:35,480 AND 1 OF THESE MATCHED DONORS 1466 00:51:35,480 --> 00:51:36,880 RELAPSED AND ULTIMATELY DIED. 1467 00:51:36,880 --> 00:51:38,800 THE BIG PROBLEM WITH THE CORDS, 1468 00:51:38,800 --> 00:51:41,840 1 EARLY IN AND 1 EARLY DEATH, 1 1469 00:51:41,840 --> 00:51:44,000 REJECTION AND DEATH WAS A SECOND 1470 00:51:44,000 --> 00:51:48,320 TRANSPLANT AND THEN 1 DONOR CELL 1471 00:51:48,320 --> 00:51:49,240 LEUKEMIA, OCCURRING 2 YEARS 1472 00:51:49,240 --> 00:51:51,040 AFTER TRANSPLANT WHICH IS--THESE 1473 00:51:51,040 --> 00:51:52,320 DONOR CELLS ARE JUST UNDER A LOT 1474 00:51:52,320 --> 00:51:54,680 OF STRESS AND THEY HAVE TO REP 1475 00:51:54,680 --> 00:51:56,880 LITICATE MANY TIMES AND THE 1476 00:51:56,880 --> 00:51:58,680 TELOMERES SHORTEN AND DEVELOP 1477 00:51:58,680 --> 00:52:00,600 STICKY ENDS, NEW TRANSLOCATIONS, 1478 00:52:00,600 --> 00:52:03,920 NEW LE KEEMIAS, THE HAPPEN LO 1479 00:52:03,920 --> 00:52:04,960 SURPRISINGLY ALTHOUGH 1 HAD 1480 00:52:04,960 --> 00:52:06,720 ACUTE LEUKEMIA AND DIED RIGHT 1481 00:52:06,720 --> 00:52:08,440 AWAY WITH TRANSPLANT, THE OTHER 1482 00:52:08,440 --> 00:52:10,920 IS ALIVE NOW, 9 YEARS LATER AND 1483 00:52:10,920 --> 00:52:12,520 SHE WAS ON DETH'S DOOR WHEN SHE 1484 00:52:12,520 --> 00:52:15,720 CAME TO THE NIH. 1485 00:52:15,720 --> 00:52:17,200 SO, THE CONCLUSIONS FROM THAT 1486 00:52:17,200 --> 00:52:19,320 REGIMEN IS THAT TRANSPLANT 1487 00:52:19,320 --> 00:52:21,000 REVERSES THE PHENOTYPE, WE NEED 1488 00:52:21,000 --> 00:52:23,240 TO GET THEM BEFORE THEY WERE SO 1489 00:52:23,240 --> 00:52:24,640 DEBILITATED AND LUKELY DURING 1490 00:52:24,640 --> 00:52:26,840 THIS TIME, STEVE COLLYNN'S GROUP 1491 00:52:26,840 --> 00:52:28,280 IDENTIFIED THE GATA 2 GENES SO 1492 00:52:28,280 --> 00:52:30,320 WE COULD THEN SCREEN DONORS, 1493 00:52:30,320 --> 00:52:31,880 IT'S PRETTY RISKY IF YOU DIDN'T 1494 00:52:31,880 --> 00:52:33,800 KNOW IF THE DONOR HAD IT BUT 1495 00:52:33,800 --> 00:52:36,120 THAT RELAPSE AND THE REJECTION, 1496 00:52:36,120 --> 00:52:38,080 COUPLE PATIENTS REQUIRE TD CHEEM 1497 00:52:38,080 --> 00:52:39,840 TO GET THE TRANSPLANT, WE NEEDED 1498 00:52:39,840 --> 00:52:42,280 MORE CONDITIONING AND WE 1499 00:52:42,280 --> 00:52:43,240 CONCLUDED CORD BLOOD WAS A 1500 00:52:43,240 --> 00:52:46,520 PROBLEM, WE ARE GOING TO DO 1501 00:52:46,520 --> 00:52:47,520 HAPLOs, THE HAPPY STORY IS 1502 00:52:47,520 --> 00:52:49,120 THIS WAS THE FIRST GUY WE DID 1503 00:52:49,120 --> 00:52:53,280 AND HE WAS SO SICK THEY 1504 00:52:53,280 --> 00:52:55,000 WOULDN'T--HE WENT TO SUBSUSH AN 1505 00:52:55,000 --> 00:52:58,800 TO HAVE HIS LUNGS WASHED OUT, 1506 00:52:58,800 --> 00:53:00,200 GOT INBAITED, EXTUBATED AND GOT 1507 00:53:00,200 --> 00:53:00,960 TRANSPLANTED FROM HIS BROTHER 1508 00:53:00,960 --> 00:53:03,000 BEFORE WE KNEW IF HE WAS GATA 2 1509 00:53:03,000 --> 00:53:05,040 NEGATIVE, THAT'S ALL HE HAD, NO 1510 00:53:05,040 --> 00:53:06,400 OTHER NUMBERS, HE LATER WENT ON 1511 00:53:06,400 --> 00:53:08,360 TO GET A LUNG TRANSPLANT BECAUSE 1512 00:53:08,360 --> 00:53:10,080 HIS LUNGS HAD BEEN SO BAD AND 1513 00:53:10,080 --> 00:53:13,080 THEN HE LATER FATHERED A CHILD. 1514 00:53:13,080 --> 00:53:15,400 SAME WITH THIS GIRL, SHE WAS 1515 00:53:15,400 --> 00:53:17,200 STEVE HOLLAND SPECIAL FROM LA 1516 00:53:17,200 --> 00:53:20,680 COUNTY TO THE ICU TO THE ICU AT 1517 00:53:20,680 --> 00:53:22,320 THE NIH, SHE BARELY LIVED 1518 00:53:22,320 --> 00:53:23,920 THROUGH THE NIGHT IN THE ICU AND 1519 00:53:23,920 --> 00:53:27,320 I SAID IF SHE LIVES THROUGH 1520 00:53:27,320 --> 00:53:29,440 TONIGHT I'LL TRANSPLANT HER FORM 1521 00:53:29,440 --> 00:53:30,920 WE TRANSPLANTED HER IN 2013 FROM 1522 00:53:30,920 --> 00:53:33,360 HER SISTER IN THE DONOR AND NOW 1523 00:53:33,360 --> 00:53:35,320 SHE'S 9 YEARS OUT, SHE'S HAD A 1524 00:53:35,320 --> 00:53:38,360 CHILD, SHE STILL HAS A COLOSTOMY 1525 00:53:38,360 --> 00:53:40,720 BECAUSE SHE HAS 2 LITTLE BOWEL 1526 00:53:40,720 --> 00:53:41,640 TO REANEGHT MOWS, SOPHISTICATEDY 1527 00:53:41,640 --> 00:53:43,320 THAT'S IT, WE WILL DO PROTOCOL, 1528 00:53:43,320 --> 00:53:45,880 I WILL MAKE IT MERCIFUL. 1529 00:53:45,880 --> 00:53:49,480 WE USED A STRAIGHT FORWARD 1530 00:53:49,480 --> 00:53:50,280 LEUKEMIA PROTOCOL, 1531 00:53:50,280 --> 00:53:50,960 [INDISCERNIBLE], WE CHANGED A 1532 00:53:50,960 --> 00:53:53,480 DIFFERENT TYPES OF POST 1533 00:53:53,480 --> 00:53:54,520 TRANSPLANT IMMUNOSUPPRESSION, 1534 00:53:54,520 --> 00:53:57,920 AND WE SWITCHED TO HAPLO-DONORS 1535 00:53:57,920 --> 00:53:59,320 AND WE HAD LONG DISCUSSION AT 1536 00:53:59,320 --> 00:54:00,200 JOHNS HOPKIN WHO IS DEVELOPED 1537 00:54:00,200 --> 00:54:02,520 THAT SO I WILL SHOW YOU THERE 1538 00:54:02,520 --> 00:54:04,560 REGIMEN AND WHAT HE TOLD ME 1539 00:54:04,560 --> 00:54:09,680 THEIR REGIMEN IS YOU GIVE A 1540 00:54:09,680 --> 00:54:13,360 LITTLE BIT OF CYTOXAN, MUCH LIKE 1541 00:54:13,360 --> 00:54:15,800 THE SETTLE REGIMEN BUT THEIR 1542 00:54:15,800 --> 00:54:17,440 PATIENTS ARE HEAVILY PRETREATED 1543 00:54:17,440 --> 00:54:23,880 FOR LEUKEMIAS SO I ADDED CY TO 1544 00:54:23,880 --> 00:54:26,160 THE PLAN AND THEN ON 3 AND 4 1545 00:54:26,160 --> 00:54:28,720 THEY GET TRANSPLANT, AND THIS 1546 00:54:28,720 --> 00:54:31,480 HAS BEEN EFFECTIVE AT PREVENTING 1547 00:54:31,480 --> 00:54:33,280 INFECTION AND PREVENTING GRAFT 1548 00:54:33,280 --> 00:54:33,880 VERSUS HOST DISEASE. 1549 00:54:33,880 --> 00:54:36,240 SO I'LL JUST SAY, OUR DISEASE 1550 00:54:36,240 --> 00:54:38,120 FREE SURVIVAL, THE FIRST 22 1551 00:54:38,120 --> 00:54:41,400 PATIENTS, THIS IS SURVIVAL, 1552 00:54:41,400 --> 00:54:43,400 MONTHS AFTER TRANSPLANT, THEY'RE 1553 00:54:43,400 --> 00:54:45,680 REALLY OVERALL PRETTY GOOD, THE 1554 00:54:45,680 --> 00:54:49,560 HAPLOs WERE ALL ALIVE, DONORS 1555 00:54:49,560 --> 00:54:50,480 WERE ALL ALIVE, UNRELATED 1556 00:54:50,480 --> 00:54:52,680 DONORS, WE HAD A COUPLE DEATHS 1557 00:54:52,680 --> 00:54:54,880 MOSTLY RELATED TO GRAFT VERSUS 1558 00:54:54,880 --> 00:54:58,280 HOST DISEASE, AND THIS IS BEFORE 1559 00:54:58,280 --> 00:55:00,120 THE KRIST TOXIN, AND YOU SEE THE 1560 00:55:00,120 --> 00:55:03,920 PROBLEM WE HAD ACUTE GBHD IN 1561 00:55:03,920 --> 00:55:04,920 THESE TRANSPLANTS. THIS IS 1562 00:55:04,920 --> 00:55:05,840 SERIOUS GRAFT VERSUS HOST 1563 00:55:05,840 --> 00:55:09,000 DISEASE THAT PEOPLE DIE FROM. 1564 00:55:09,000 --> 00:55:11,960 SO THE GOOD NEWS IS WE HAD GOOD 1565 00:55:11,960 --> 00:55:13,520 SURVIVAL WE HAD NASTY GRAFT 1566 00:55:13,520 --> 00:55:16,520 VERSUS HOST DISEASE, SO IN 2017 1567 00:55:16,520 --> 00:55:18,320 I SAID WE WILL GIVE MATCH 1568 00:55:18,320 --> 00:55:19,440 RELATED AND UNRELATED DONORS 1569 00:55:19,440 --> 00:55:22,680 JUST LIKE THE HAPLOs POST 1570 00:55:22,680 --> 00:55:23,240 TRANSPLANT. 1571 00:55:23,240 --> 00:55:26,240 AND OVERALL, NOW, COMPARING ALL 1572 00:55:26,240 --> 00:55:27,840 OF THEM, SINCE 2013, 71 1573 00:55:27,840 --> 00:55:30,360 PATIENTS, WE HAVE 1 YEAR FOLLOW 1574 00:55:30,360 --> 00:55:32,720 UP ON 61, OF THE MATCH RELATED 1575 00:55:32,720 --> 00:55:33,960 DONORS, 1 DEATH, WE THOUGHT HE 1576 00:55:33,960 --> 00:55:35,800 WAS RECTAL CANCER WAS IN 1577 00:55:35,800 --> 00:55:38,520 REMISSION BUT IT WAS RELAPSED 1578 00:55:38,520 --> 00:55:39,920 AFTER TRANSPLANT, THE 30 1579 00:55:39,920 --> 00:55:41,480 UNRELATED DONORS, YOU SEE THESE 1580 00:55:41,480 --> 00:55:43,560 ARE THE EARLY GRAFT VERSUS HOST 1581 00:55:43,560 --> 00:55:46,600 DISEASE DEATHS RELATED TO TACK 1582 00:55:46,600 --> 00:55:50,720 ROUGH ATOM MEX O TREKSATE WHICH 1583 00:55:50,720 --> 00:55:52,040 WASN'T AS GOOD AS 1584 00:55:52,040 --> 00:55:53,000 [INDISCERNIBLE]. 1585 00:55:53,000 --> 00:55:54,680 THIS A REFREQUENTRY AML YOUNG 1586 00:55:54,680 --> 00:55:58,080 WOMEN I MENTIONED IN 1 LATE 1587 00:55:58,080 --> 00:56:02,040 METASTATIC SQ CELL CARCINOMA. 1588 00:56:02,040 --> 00:56:03,320 STRIKING THESE HAPLOOs, WE HAD 1589 00:56:03,320 --> 00:56:07,920 1 DEATH FROM RELAPSE, 2 HAD 1590 00:56:07,920 --> 00:56:11,280 CHRONIC GVHD, THE HAPLOs WERE 1591 00:56:11,280 --> 00:56:15,760 ALMOST PHENOLINAL, ALMOST OVER 1592 00:56:15,760 --> 00:56:18,200 ALL SURVIVAL, 83% EVENT FREE 1593 00:56:18,200 --> 00:56:20,320 SURVIVAL, NO GRAFT VERSUS HOST 1594 00:56:20,320 --> 00:56:21,440 DISEASE, NO SECOND TRANSPLANTS. 1595 00:56:21,440 --> 00:56:23,800 SO JUST TO SHOW YOU THE SURVIVOR 1596 00:56:23,800 --> 00:56:26,720 CURVE ON ALL OF THAT, THE TOTAL 1597 00:56:26,720 --> 00:56:28,320 GROUPS THE HAPLOs DID THE 1598 00:56:28,320 --> 00:56:29,080 BEST, WHO KNEW? 1599 00:56:29,080 --> 00:56:30,080 AND THE SECOND BEST WERE THE 1600 00:56:30,080 --> 00:56:32,400 MATCH RELATED AND UNRELATED GOT 1601 00:56:32,400 --> 00:56:34,320 POST TRANSPLANT SIGNIFY TOXIN 1602 00:56:34,320 --> 00:56:38,840 AND THE LOWEST WAS MATCH RELATED 1603 00:56:38,840 --> 00:56:40,760 AND UNRELATED TO THE MEX O 1604 00:56:40,760 --> 00:56:43,040 TREKSATE, SO AGAIN THE STRIKING 1605 00:56:43,040 --> 00:56:44,920 THING WAS THE GRAFT VERSUS HOST 1606 00:56:44,920 --> 00:56:46,600 DISEASE ISSUES THE HAPLOs HAD 1607 00:56:46,600 --> 00:56:48,560 VERY LITTLE AND THE POST 1608 00:56:48,560 --> 00:56:50,400 TRANSPLANT SIDE MATCH RELATED 1609 00:56:50,400 --> 00:56:51,440 AND UNRELATED DONOR, THAT'S ARE 1610 00:56:51,440 --> 00:56:54,280 RIGHT ALONG BASE LINE, THERE WAS 1611 00:56:54,280 --> 00:56:56,000 NO GRADE 3-4 ACUTE GRAFT VERSUS 1612 00:56:56,000 --> 00:56:58,680 HOST DISEASE, IF YOU GOT POST 1613 00:56:58,680 --> 00:56:59,320 TRANSPLANT SIGNIFY TOXIN. 1614 00:56:59,320 --> 00:57:04,440 SO THAT IS REMARKABLE, I'LL JUST 1615 00:57:04,440 --> 00:57:06,440 SAY THAT THE--AFTER WE PUBLISHED 1616 00:57:06,440 --> 00:57:08,600 OUR HIGHER DOSE REGIMEN, THE 1617 00:57:08,600 --> 00:57:09,280 BRITISH GROUPS PUBLISHED 4 1618 00:57:09,280 --> 00:57:10,720 PATIENTS WHERE THEY HAD LOW 1619 00:57:10,720 --> 00:57:13,440 DOSE, THEY USED REDUCED 1620 00:57:13,440 --> 00:57:14,480 INTENSITY SO THEN ASK ME TO 1621 00:57:14,480 --> 00:57:16,680 WRITE THE REVIEW AND SAID WHOSE 1622 00:57:16,680 --> 00:57:16,880 RIGHT? 1623 00:57:16,880 --> 00:57:18,120 ARE THEY RIGHT OR ARE YOU RIGHT? 1624 00:57:18,120 --> 00:57:20,040 AND I SAID WELL THERE'S A 1625 00:57:20,040 --> 00:57:21,960 SPECTRUM OF BONE MARROW FINDING 1626 00:57:21,960 --> 00:57:23,520 IN GATA 2 IF YOU'RE AT THIS END 1627 00:57:23,520 --> 00:57:28,240 AND YOU HAVE A HYPER CELLULAR 1628 00:57:28,240 --> 00:57:28,960 AND NEUROCYTOGENETICS AND IT'S 1629 00:57:28,960 --> 00:57:32,440 EASY TO GET GRAFTS IN EVEN IF 1630 00:57:32,440 --> 00:57:33,880 YOU HAVE THIS, REDUCED INTENSITY 1631 00:57:33,880 --> 00:57:36,480 WILL WORK IF YOU ARE UP HERE 1632 00:57:36,480 --> 00:57:38,840 WITH HYPER CELLULAR, YOU HAVE 1633 00:57:38,840 --> 00:57:39,840 THESE KIND OF [INDISCERNIBLE] 1634 00:57:39,840 --> 00:57:42,240 YOU WANT A HIGH DOSE REGIMEN SO 1635 00:57:42,240 --> 00:57:43,560 IT REALLY DEPENDS ON WHERE 1636 00:57:43,560 --> 00:57:45,440 YOU'RE AT IN THE COURSE, WHICH 1637 00:57:45,440 --> 00:57:46,880 SEGUES INTO OUR NEWEST REGIMEN 1638 00:57:46,880 --> 00:57:49,320 IS GOING TO USE REALLY TARGET 1639 00:57:49,320 --> 00:57:51,680 THESE 2 GROUPS SO IT'S A NEW 1640 00:57:51,680 --> 00:57:55,480 PROTOCOL FOR GOOD RISK GATA 2S, 1641 00:57:55,480 --> 00:57:57,560 HYPOCELLULAR MARROW, NO 1642 00:57:57,560 --> 00:57:58,480 CYTOGENETIC ABNORMALITIES, NO 1643 00:57:58,480 --> 00:58:00,080 INCREASED BLAST, IT'S GOING TO 1644 00:58:00,080 --> 00:58:02,000 USE A MONOCLONAL ANTIBODY THAT 1645 00:58:02,000 --> 00:58:04,960 BINDS TO C-KIT ON THE HOST STEM 1646 00:58:04,960 --> 00:58:06,520 CELLS, IT STARVES THEM OF STEM 1647 00:58:06,520 --> 00:58:07,880 CELL FACTOR AND YOU GIVE IT 1648 00:58:07,880 --> 00:58:08,920 ABOUT 2 WEEKS BEFORE TRANSPLANT 1649 00:58:08,920 --> 00:58:10,440 AND THE STEM CELLS DIE OFF. 1650 00:58:10,440 --> 00:58:12,600 YOU COUPLE IT WITH A LITTLE LOW 1651 00:58:12,600 --> 00:58:15,760 DOSE TDI AND YOU HAVE CHEMO FREE 1652 00:58:15,760 --> 00:58:16,080 CONDITIONING. 1653 00:58:16,080 --> 00:58:25,960 SO DANNY IS WRITING THAT ARTICLE 1654 00:58:25,960 --> 00:58:29,280 AND THE PROGRAM IS HEADED TO THE 1655 00:58:29,280 --> 00:58:29,800 IRB. 1656 00:58:29,800 --> 00:58:31,040 SO, SO, OKAY, SO WHAT I 1657 00:58:31,040 --> 00:58:33,240 SUMMARIZED A TOLD YOU ALOE 1658 00:58:33,240 --> 00:58:35,240 GENERATED AIC THINK LIKE A 1659 00:58:35,240 --> 00:58:36,920 TRANSPLANTER, KNOW YOUR DISEASE, 1660 00:58:36,920 --> 00:58:38,000 NATURAL HISTORY, DONOR, DONOR 1661 00:58:38,000 --> 00:58:39,800 PRODUCT AND THINK HARD ABOUT 1662 00:58:39,800 --> 00:58:40,520 CONDITIONING REGIMEN AND THINK 1663 00:58:40,520 --> 00:58:41,920 HOW YOU WILL PREVENT GRAFT 1664 00:58:41,920 --> 00:58:43,560 REJECTION AND HOW YOU WILL 1665 00:58:43,560 --> 00:58:44,640 PREVENT GRAFT VERSUS HOST 1666 00:58:44,640 --> 00:58:45,680 DISEASE, THOSE ARE 5 THINGS YOU 1667 00:58:45,680 --> 00:58:48,720 HAVE TO DO TO THINK LIKE A 1668 00:58:48,720 --> 00:58:49,080 TRANSPLANTER. 1669 00:58:49,080 --> 00:58:52,280 I SAID THE PAST IS PART OF THE 1670 00:58:52,280 --> 00:58:54,520 FUTURE IT'S FROM THE TEMPEST BY 1671 00:58:54,520 --> 00:58:55,600 SHAKESPEARE, HIS POINT IS ALL 1672 00:58:55,600 --> 00:58:57,480 OUR LIVES WERE MERELY A PROLOGUE 1673 00:58:57,480 --> 00:58:59,840 TO THE GREAT STORY TO AM CAN. 1674 00:58:59,840 --> 00:59:00,400 EVERYTHING THAT CAME BEFORE 1675 00:59:00,400 --> 00:59:02,200 DOESN'T MATTER BECAUSE A NEW AND 1676 00:59:02,200 --> 00:59:06,360 AND GLORIOUS FUTURE AWAYS BUT I 1677 00:59:06,360 --> 00:59:08,320 LIKE EVERYBODY ELSE USED IT IN 1678 00:59:08,320 --> 00:59:09,960 THE OPPOSITE MEANING, TODAY WE 1679 00:59:09,960 --> 00:59:11,800 USE IT IS THE PAST IS GREAT 1680 00:59:11,800 --> 00:59:13,240 IMPORTANCE BECAUSE IT DEFINES 1681 00:59:13,240 --> 00:59:14,320 THE PRESCRIBING EXPEBT SETS THE 1682 00:59:14,320 --> 00:59:15,640 STAGE FOR THE FUTURE, WHAT WE DO 1683 00:59:15,640 --> 00:59:16,920 WITH GATA 2 IS BASED ON WHAT 1684 00:59:16,920 --> 00:59:18,880 WE'VE DONE WITH THE PAST. 1685 00:59:18,880 --> 00:59:22,880 OKAY, THAT'S THE END OF MY 1686 00:59:22,880 --> 00:59:24,800 STORY. 1687 00:59:24,800 --> 00:59:25,480 I'LL STOP HERE. 1688 00:59:25,480 --> 00:59:26,600 >> THANK YOU DOCTOR, THANK YOU 1689 00:59:26,600 --> 00:59:28,280 FOR SHARING THE STORY AND TO 1690 00:59:28,280 --> 00:59:29,920 DR. HOLLAND AS LI WANT TO THANK 1691 00:59:29,920 --> 00:59:32,240 BOTH OF YOU FOR SHARING THE WORK 1692 00:59:32,240 --> 00:59:33,480 OF YOUR YEARS COLLABORATION 1693 00:59:33,480 --> 00:59:35,360 WHERE FROM THE CLINICAL INSIGHT 1694 00:59:35,360 --> 00:59:38,360 PROVIDED BY DR. HOLLAND AND HIS 1695 00:59:38,360 --> 00:59:39,800 COLLABORATORS, BRIDGING OVER TO 1696 00:59:39,800 --> 00:59:41,480 THE SUCCESSES NOW STEM CELL 1697 00:59:41,480 --> 00:59:43,640 TRANSPLANT, SO AGAIN, THANK YOU 1698 00:59:43,640 --> 00:59:45,480 TO BOTH OF YOU. 1699 00:59:45,480 --> 00:59:47,240 UNFORTUNATELY OR FORTUNATELY IT 1700 00:59:47,240 --> 00:59:48,920 TAKES [INDISCERNIBLE] SO I WON'T 1701 00:59:48,920 --> 00:59:50,440 BE ABLE TO SHARE ANY QUESTIONS 1702 00:59:50,440 --> 00:59:53,040 WITH YOU ALL TODAY, THERE ARE A 1703 00:59:53,040 --> 00:59:54,200 COUPLE CAME IN TO THE 1704 00:59:54,200 --> 00:59:54,720 CERTAINLY--CERTAINLY MAIL 1705 00:59:54,720 --> 00:59:56,000 VIDEOCAST AND I WILL SHARE THAT 1706 00:59:56,000 --> 00:59:58,840 WITH YOU BUT I WANT TO SAY THANK 1707 00:59:58,840 --> 01:00:00,280 YOU GONE FOR PRESENTING TO THE 1708 01:00:00,280 --> 01:00:01,680 NIH COMMUNITY AND EVERYONE, I 1709 01:00:01,680 --> 01:00:03,560 WISH EVERYONE A GREAT AFTERNOON 1710 01:00:03,560 --> 00:00:00,000 THANK YOU.