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 --> 00:00:46,520 Learn more by visiting us online at http://clinicalcenter.nih.gov 11 00:00:46,520 --> 00:00:49,800 >>TODAY WE ARE HONORED TO HAVE 12 00:00:49,800 --> 00:00:53,800 DR. STEVEN HOLLAND 13 00:00:53,800 --> 00:00:58,080 NIH DISTINGUISHED INVESTIGATOR, 14 00:00:58,080 --> 00:01:01,040 SCIENTIFIC INVESTOR FOR ALLERGY 15 00:01:01,040 --> 00:01:02,080 AND INFECTIOUS DISEASES. 16 00:01:02,080 --> 00:01:04,600 DR. HOLLAND EARNED HIS MEDICAL 17 00:01:04,600 --> 00:01:05,920 DEGREE FROM JOHNS HOPKINS 18 00:01:05,920 --> 00:01:08,520 UNIVERSITY WHERE HE REMAINED FOR 19 00:01:08,520 --> 00:01:11,280 INTERNAL MEDICINE RESIDENCY, 20 00:01:11,280 --> 00:01:14,400 CHIEF RESIDENCY AND FELLOWSHIP 21 00:01:14,400 --> 00:01:15,480 IN INFECTIOUS DISEASE. 22 00:01:15,480 --> 00:01:19,120 HE CAME TO NIAD FROM A 23 00:01:19,120 --> 00:01:24,200 LABORATORY OF MOLECULAR BIOLOGY 24 00:01:24,200 --> 00:01:26,840 WORKING ON TRANSCRIPTIONAL 25 00:01:26,840 --> 00:01:28,320 REVELATION OF HIV. 26 00:01:28,320 --> 00:01:29,440 HE SHIFTED HIS RESEARCH TO THE 27 00:01:29,440 --> 00:01:33,800 HOST SIDE WITH A FOCUS ON 28 00:01:33,800 --> 00:01:35,640 PHAGOCYTE DEFECTS AND ASSOCIATED 29 00:01:35,640 --> 00:01:37,200 INFECTIONS. 30 00:01:37,200 --> 00:01:39,760 THE FOCUS OF THIS RESEARCH IN 31 00:01:39,760 --> 00:01:40,560 THE IMMUNOPATHOGENESIS SECTION 32 00:01:40,560 --> 00:01:42,640 IS A FULLY INTEGRATED APPROACH 33 00:01:42,640 --> 00:01:45,720 TO INFECTIOUS DISEASE, 34 00:01:45,720 --> 00:01:47,400 INCORPORATED THE MOLECULAR 35 00:01:47,400 --> 00:01:50,600 GENETICS OF THE HOET AND THE 36 00:01:50,600 --> 00:01:52,360 PATHOGEN AS WELL AS MECHANISMS 37 00:01:52,360 --> 00:01:54,160 OF THE PATHOGENESIS. 38 00:01:54,160 --> 00:01:56,600 TO GAIN NEW INSIGHTS INTO 39 00:01:56,600 --> 00:01:57,800 MECHANISMS OF ACTION AND AVENUES 40 00:01:57,800 --> 00:01:59,040 OF THERAPY. 41 00:01:59,040 --> 00:02:01,760 THE INTEGRATED BENCH TO BEDSIDE 42 00:02:01,760 --> 00:02:04,120 MODEL IS INTRINSIC TO HIS 43 00:02:04,120 --> 00:02:06,080 SECTIONS APPROACH AND IS 44 00:02:06,080 --> 00:02:08,080 REFLECTED IN THE CLOSE 45 00:02:08,080 --> 00:02:09,360 INVOLVEMENT OF M.D. AND PH.D. 46 00:02:09,360 --> 00:02:11,720 TRAININGS IN LABORATORY WORK AND 47 00:02:11,720 --> 00:02:14,040 IN HIS CLINICAL APPRECIATION OF 48 00:02:14,040 --> 00:02:16,400 DISEASE, WHICH TOGETHER ADD NEW 49 00:02:16,400 --> 00:02:18,080 INSIGHT INTO AMERICA NICHLS OF 50 00:02:18,080 --> 00:02:20,280 ACTION AND AVENUES OF THERAPY. 51 00:02:20,280 --> 00:02:23,480 DR. HOLLAND IS A RECIPIENT OF 52 00:02:23,480 --> 00:02:26,600 NUMEROUS AWARDS, THE NIH 53 00:02:26,600 --> 00:02:29,680 DIRECTOR'S AWARD FOR DISCOVERY 54 00:02:29,680 --> 00:02:33,520 OF JOB AND CO-DISCOVERY OF -- IN 55 00:02:33,520 --> 00:02:33,720 2010. 56 00:02:33,720 --> 00:02:35,360 HE RECEIVED THE AMERICAN COLLEGE 57 00:02:35,360 --> 00:02:37,760 OF PHYSICIANS AWARD FOR SCIENCE, 58 00:02:37,760 --> 00:02:41,640 BOYLE FROM THE IMMUNE DEFICIENCY 59 00:02:41,640 --> 00:02:44,520 FOUNDATION AND AMERICAN SOCIETY 60 00:02:44,520 --> 00:02:47,080 FOR MICROBIOLOGY AWARD. 61 00:02:47,080 --> 00:02:49,080 AND THE NIH DISTINGUISHED 62 00:02:49,080 --> 00:02:49,840 CLINICAL TEACHER AWARD AMONG 63 00:02:49,840 --> 00:02:51,120 OTHER HONOR. 64 00:02:51,120 --> 00:02:53,720 HE IS RECOGNIZED GLOBALLY FOR 65 00:02:53,720 --> 00:02:55,680 HIS SCIENTIFIC EXPERTISE AND HIS 66 00:02:55,680 --> 00:02:59,720 TRUE ROLE AS A ROLE MODEL OF A 67 00:02:59,720 --> 00:03:01,040 CARING, COMPASSIONATE CLINICIAN 68 00:03:01,040 --> 00:03:03,040 TO ALL OF HIS PATIENTS. 69 00:03:03,040 --> 00:03:07,480 THE TITLE OF DR. HOLLAND'S 70 00:03:07,480 --> 00:03:09,080 PRESENTATION IS DISEASE 71 00:03:09,080 --> 00:03:09,680 DISCOVERY AT THE NIH CLINICAL 72 00:03:09,680 --> 00:03:10,320 CENTER: TRANSLATIONAL APPROACHES 73 00:03:10,320 --> 00:03:11,720 TO RARE DISEASES. 74 00:03:11,720 --> 00:03:13,800 PLEASE JOIN ME IN WELCOMING OUR 75 00:03:13,800 --> 00:03:14,040 SPEAKER. 76 00:03:14,040 --> 00:03:19,360 [ APPLAUSE ] 77 00:03:19,360 --> 00:03:20,280 >>OKAY. 78 00:03:20,280 --> 00:03:22,560 THANK YOU, JOYCE. 79 00:03:22,560 --> 00:03:25,640 IT REALLY IS A BLAST TO BE BACK 80 00:03:25,640 --> 00:03:25,840 HERE. 81 00:03:25,840 --> 00:03:27,600 IT IS GREAT TO SEE MORE THAN 82 00:03:27,600 --> 00:03:29,280 FIVE PEOPLE IN THE AUDIENCE. 83 00:03:29,280 --> 00:03:31,400 I COULD GET USED TO THIS AGAIN. 84 00:03:31,400 --> 00:03:33,320 I HOPE THAT WE ALL GET USED TO 85 00:03:33,320 --> 00:03:37,480 IT AND CAN KEEP IT GOING. 86 00:03:37,480 --> 00:03:39,880 SO I BELIEVE THAT TODAY IS 87 00:03:39,880 --> 00:03:43,120 REALLY MOSTLY FOR THE INCOMING 88 00:03:43,120 --> 00:03:43,320 FELLOWS. 89 00:03:43,320 --> 00:03:45,400 AND I CAN TELL YOU THAT'S WHAT 90 00:03:45,400 --> 00:03:48,120 I'M REALLY GOING TO BE FOCUSING 91 00:03:48,120 --> 00:03:48,320 ON. 92 00:03:48,320 --> 00:03:51,160 FOR THOSE OF YOU WHO ARE NEITHER 93 00:03:51,160 --> 00:03:54,880 INCOMING NOR FELLOWS NOR MAYBE 94 00:03:54,880 --> 00:03:58,400 EVEN NOT NEW, THIS IS A GREAT 95 00:03:58,400 --> 00:04:00,520 OPPORTUNITY FOR A NAP AND THE 96 00:04:00,520 --> 00:04:03,000 CHAIRS ARE WELL UPHOLSTERED AND 97 00:04:03,000 --> 00:04:06,400 HAVE BEEN RENOVATED DURING THE 98 00:04:06,400 --> 00:04:07,640 PERIOD OF THE PANDEMIC. 99 00:04:07,640 --> 00:04:09,880 SO PLEASE FEEL FREE TO RELAX. 100 00:04:09,880 --> 00:04:12,600 I'M GOING TO START OUT BY 101 00:04:12,600 --> 00:04:14,680 REMINDING US ALL THE FIRST 102 00:04:14,680 --> 00:04:17,240 HIPPOCRATIC APHORISM POINTS OUT 103 00:04:17,240 --> 00:04:20,640 LIFE IS SHORT, THE ART IS LONG, 104 00:04:20,640 --> 00:04:22,240 OPPORTUNITY FLEETING, EXPERIENCE 105 00:04:22,240 --> 00:04:24,080 MISLEADING AND JUDGMENT 106 00:04:24,080 --> 00:04:26,320 DIFFICULT. 107 00:04:26,320 --> 00:04:27,280 AND, YOU KNOW, I WOULD LOVE TO 108 00:04:27,280 --> 00:04:29,920 BE ABLE TO SAY I MEMORIZED THIS 109 00:04:29,920 --> 00:04:32,800 IN ALL THE DIFFERENT LANGUAGES. 110 00:04:32,800 --> 00:04:33,680 THAT AIN'T TRUE. 111 00:04:33,680 --> 00:04:35,360 BUT IT IS TRUE NO MATTER WHAT 112 00:04:35,360 --> 00:04:37,240 LANGUAGE YOU ARE DEALING WITH. 113 00:04:37,240 --> 00:04:39,760 EACH ONE OF THOSE ASPECTS OF THE 114 00:04:39,760 --> 00:04:43,600 FIRST HIPPOCRATIC APHORISM TURNS 115 00:04:43,600 --> 00:04:45,800 OUT TO BE IMPORTANT. 116 00:04:45,800 --> 00:04:49,640 THE OTHERS GET A WHOLE LOT LESS 117 00:04:49,640 --> 00:04:50,320 INTERESTING, BUT AT LEAST THEY 118 00:04:50,320 --> 00:04:51,920 FRONT LOADED IT FOR THE GOOD 119 00:04:51,920 --> 00:04:52,200 STUFF. 120 00:04:52,200 --> 00:04:55,640 I'M GOING TO TRY TO ILLUSTRATE 121 00:04:55,640 --> 00:04:58,880 BETWEEN NOW AND 3:00 SOME OF THE 122 00:04:58,880 --> 00:04:59,120 ASPECTS. 123 00:04:59,120 --> 00:05:04,760 FOR THOSE OF YOU WHO ARE NEW, 124 00:05:04,760 --> 00:05:08,200 SOME FROM THIS REGION, SOME NOT, 125 00:05:08,200 --> 00:05:10,280 I WANT TO TRY TO MAKE THIS AS 126 00:05:10,280 --> 00:05:12,280 CLEAR AS POSSIBLE. 127 00:05:12,280 --> 00:05:13,160 WE ARE RIGHT THERE IN 128 00:05:13,160 --> 00:05:13,760 WASHINGTON, D.C. 129 00:05:13,760 --> 00:05:16,240 IN FACT, WE ARE RIGHT HERE IN AN 130 00:05:16,240 --> 00:05:19,840 AREA CARVED OUT IN THE STATES OF 131 00:05:19,840 --> 00:05:21,440 MARYLAND AND VIRGINIA AND WE ARE 132 00:05:21,440 --> 00:05:24,880 IN THIS LOCATION KNOWN AS 133 00:05:24,880 --> 00:05:25,120 BETHESDA. 134 00:05:25,120 --> 00:05:26,680 AND WE ARE SMACK HERE BETWEEN 135 00:05:26,680 --> 00:05:29,800 TWO OF THE MAJOR ARTERIES IN 136 00:05:29,800 --> 00:05:32,160 BETHESDA, OLD GEORGETOWN AND 137 00:05:32,160 --> 00:05:32,440 WISCONSIN. 138 00:05:32,440 --> 00:05:34,200 AND WE ARE NOW IN THIS BUILDING, 139 00:05:34,200 --> 00:05:35,200 BUILDING 10, THE CLINICAL 140 00:05:35,200 --> 00:05:36,840 CENTER. 141 00:05:36,840 --> 00:05:39,280 IF YOU ARE NOT FROM HERE OR 142 00:05:39,280 --> 00:05:43,040 DON'T HAPPEN TO HAVE A REALLY 143 00:05:43,040 --> 00:05:45,240 COOL DRONE, THIS IS THE NORTH 144 00:05:45,240 --> 00:05:47,200 FACE OF THE BUILDING WHERE WE 145 00:05:47,200 --> 00:05:48,240 CURRENTLY HAVE THE ENTRANCE THAT 146 00:05:48,240 --> 00:05:50,880 TAKES YOU RIGHT INTO THE ATRIUM 147 00:05:50,880 --> 00:05:52,680 WHERE AT LEAST ONE OF THE 148 00:05:52,680 --> 00:05:55,320 CRITICAL COFFEE BARS IS LOCATED. 149 00:05:55,320 --> 00:05:57,360 AND IF YOU HAPPEN TO HAVE A 150 00:05:57,360 --> 00:05:59,360 DIFFERENT DRONE FROM A DIFFERENT 151 00:05:59,360 --> 00:06:00,560 LOCATION, THIS IS THE SOUTH SIDE 152 00:06:00,560 --> 00:06:03,200 OF THE BUILDING THAT USED TO BE 153 00:06:03,200 --> 00:06:05,800 THE FRONT ENTRANCE AND HAS BEEN 154 00:06:05,800 --> 00:06:06,960 REORIENTING. 155 00:06:06,960 --> 00:06:08,760 REORIENTING IS A CRITICAL PART 156 00:06:08,760 --> 00:06:10,440 OF WHAT EDUCATION IS SUPPOSED TO 157 00:06:10,440 --> 00:06:11,160 DO. 158 00:06:11,160 --> 00:06:12,120 TAKING YOU FROM WHERE YOU 159 00:06:12,120 --> 00:06:13,800 STARTED TO WHERE YOU END. 160 00:06:13,800 --> 00:06:16,360 THE ARROW POINTS OUT WHERE THE 161 00:06:16,360 --> 00:06:17,960 LIPSETT AUDITORIUM SORT OF IS, 162 00:06:17,960 --> 00:06:19,120 ALTHOUGH IT DOESN'T HAVE THAT 163 00:06:19,120 --> 00:06:21,920 DIRECT POINTER THERE, BUT IT IS 164 00:06:21,920 --> 00:06:24,280 HOW WE UNDERSTAND WHERE WE ARE. 165 00:06:24,280 --> 00:06:25,480 I POINT ALL THIS OUT BECAUSE, 166 00:06:25,480 --> 00:06:27,360 YOU KNOW, AS YOU KNOW, IF YOU 167 00:06:27,360 --> 00:06:30,000 CAME IN HERE TODAY, UNLESS YOU 168 00:06:30,000 --> 00:06:32,320 HAVE BEEN SEQUESTERED HERE FOR 169 00:06:32,320 --> 00:06:33,560 QUITE A WHILE, YOU CAME IN 170 00:06:33,560 --> 00:06:35,320 THROUGH THE GATES. 171 00:06:35,320 --> 00:06:36,760 YOU KNOW WE NOW HAVE A FENCE 172 00:06:36,760 --> 00:06:38,480 AROUND IT. 173 00:06:38,480 --> 00:06:44,000 THAT IS A REMINDER, ALBEIT TOO 174 00:06:44,000 --> 00:06:46,160 STARK THAT INTRAMURAL MEANS 175 00:06:46,160 --> 00:06:49,480 INSIDE THE WALL, EXTRA MURAL 176 00:06:49,480 --> 00:06:51,640 OUTSIDE THE WALL. 177 00:06:51,640 --> 00:06:53,840 THE EXTRAMURAL COMMUNITY WHERE 178 00:06:53,840 --> 00:06:56,160 EVERY SINGLE ONE OF US CAME FROM 179 00:06:56,160 --> 00:06:59,240 IS COMPOSED OF HOSPITALS, 180 00:06:59,240 --> 00:06:59,880 UNIVERSITIES, RESEARCH 181 00:06:59,880 --> 00:07:01,800 INSTITUTIONS AND MEDICAL SCHOOLS 182 00:07:01,800 --> 00:07:03,200 AS WELL AS FACILITIES ALL AROUND 183 00:07:03,200 --> 00:07:05,480 THE WORLD AND THAT IS WHERE 184 00:07:05,480 --> 00:07:09,320 ABOUT 90% OF OUR TREASURE GOES 185 00:07:09,320 --> 00:07:10,640 TO SUPPORTING AND FOSTERING THAT 186 00:07:10,640 --> 00:07:11,960 ACTIVITY. 187 00:07:11,960 --> 00:07:14,320 AND THAT IS IMPORTANT. 188 00:07:14,320 --> 00:07:16,400 BUT INSIDE THE WALL, WHERE YOU 189 00:07:16,400 --> 00:07:19,200 ARE NOW, AND IF YOU ARE A NEW 190 00:07:19,200 --> 00:07:20,720 FELLOW, WHERE YOU WILL BE FOR AT 191 00:07:20,720 --> 00:07:23,000 LEAST THE NEXT SEVERAL YEARS, 192 00:07:23,000 --> 00:07:24,520 THE INTRAMURAL COMMUNITY IS 193 00:07:24,520 --> 00:07:26,840 COMPOSED OF NOT ONLY WHAT IS 194 00:07:26,840 --> 00:07:29,160 HERE INSIDE THESE WALLS BUT 195 00:07:29,160 --> 00:07:30,600 SEVERAL OTHER AREAS AS WELL. 196 00:07:30,600 --> 00:07:33,800 WE IN NIAD HAPPEN TO HAVE A 197 00:07:33,800 --> 00:07:37,120 CAMPUS IN MONTANA, AT HAMILTON, 198 00:07:37,120 --> 00:07:39,320 MONTANA, WHERE WE DO A LOT OF 199 00:07:39,320 --> 00:07:41,480 OUR BSL4 WORK. 200 00:07:41,480 --> 00:07:42,720 I STRONGLY ENCOURAGE YOU TO 201 00:07:42,720 --> 00:07:43,840 THINK ABOUT TRAVELING OUT THERE. 202 00:07:43,840 --> 00:07:46,320 IF YOU WANT TO GO OUT THERE, 203 00:07:46,320 --> 00:07:47,520 THESE TALK TO ME ABOUT IT. 204 00:07:47,520 --> 00:07:50,000 I THINK IT IS A CRITICAL PART OF 205 00:07:50,000 --> 00:07:52,280 THE INTRAMURAL PROGRAM AND I 206 00:07:52,280 --> 00:07:53,760 DON'T WANT ANYMORE TO NOT 207 00:07:53,760 --> 00:07:55,680 EXPERIENCE IT BECAUSE OF 208 00:07:55,680 --> 00:07:56,960 LIMITATIONS OF DISTANCE AND 209 00:07:56,960 --> 00:07:57,160 COST. 210 00:07:57,160 --> 00:07:59,000 I'M NOT TALKING ABOUT SKI 211 00:07:59,000 --> 00:07:59,840 SEASON. 212 00:07:59,840 --> 00:08:01,320 I'M TALKING ABOUT I'M GETTING 213 00:08:01,320 --> 00:08:04,040 OUT THERE BECAUSE THERE IS 214 00:08:04,040 --> 00:08:05,560 REALLY SPECTACULAR SCIENCE. 215 00:08:05,560 --> 00:08:07,920 THERE ARE CAMPUSES IN ARIZONA, 216 00:08:07,920 --> 00:08:09,840 NORTH CAROLINA, MASSACHUSETTS, 217 00:08:09,840 --> 00:08:11,880 MICHIGAN AND OTHER PLACES AS 218 00:08:11,880 --> 00:08:15,480 WELL AS FACILITIES THAT ARE AN 219 00:08:15,480 --> 00:08:17,760 INTEGRAL PART OF THE INTRAMURAL 220 00:08:17,760 --> 00:08:20,360 PROGRAM IN COUNTRIES AROUND THE 221 00:08:20,360 --> 00:08:22,800 WORLD, IN PARTICULAR AFRICA AND 222 00:08:22,800 --> 00:08:25,040 ASIA AND I KNOW OTHER INSTITUTES 223 00:08:25,040 --> 00:08:25,520 DO AS WELL. 224 00:08:25,520 --> 00:08:26,800 THE INTRAMURAL PROGRAM GETS 225 00:08:26,800 --> 00:08:29,800 ABOUT 10% OF THE FUNDING OF THE 226 00:08:29,800 --> 00:08:31,640 NIH AS A WHOLE. 227 00:08:31,640 --> 00:08:33,800 BUT WHAT IS IT THAT MAKES THE 228 00:08:33,800 --> 00:08:34,760 INTRAMURAL PROGRAM DIFFERENT? 229 00:08:34,760 --> 00:08:39,400 I WANT TO JUST TAKE A MOMENT TO 230 00:08:39,400 --> 00:08:41,040 EMPHASIZE THIS BECAUSE IT IS WHY 231 00:08:41,040 --> 00:08:42,280 SOME OF US STAY. 232 00:08:42,280 --> 00:08:44,280 IT IS WHY SOME GO. 233 00:08:44,280 --> 00:08:46,520 AND ONE OF THE THINGS THAT MAKES 234 00:08:46,520 --> 00:08:48,520 IT DIFFERENT IN THE INTRAMURAL 235 00:08:48,520 --> 00:08:51,360 PROGRAM IS RETROSPECTIVE REVIEW. 236 00:08:51,360 --> 00:08:54,400 SPEAKING NOW TO YOU NEW 237 00:08:54,400 --> 00:08:56,480 TRAINEES, THE THREE MOST 238 00:08:56,480 --> 00:08:59,680 DANGEROUS LETTERS IN THE ENGLISH 239 00:08:59,680 --> 00:09:01,720 LANGUAGE ARE BSC. 240 00:09:01,720 --> 00:09:02,840 THAT IS WHAT HAPPENS EVERY FOUR 241 00:09:02,840 --> 00:09:05,440 YEARS WHEN YOUR PI GETS 242 00:09:05,440 --> 00:09:05,840 REVIEWED. 243 00:09:05,840 --> 00:09:09,840 IT IS A RETROPEKTIVE REVIEW. 244 00:09:09,840 --> 00:09:12,080 THE PARABLE OF THE 10 TALENTS. 245 00:09:12,080 --> 00:09:14,640 YOU ARE GIVEN THE 10 TALENTS AND 246 00:09:14,640 --> 00:09:16,200 SOMEBODY COMES BACK AND SAYS 247 00:09:16,200 --> 00:09:16,960 WHAT DID YOU DO. 248 00:09:16,960 --> 00:09:19,800 AT THE END OF THE FOUR YEARS YOU 249 00:09:19,800 --> 00:09:21,520 BETTER BE ABLE TO SAY WHAT YOU 250 00:09:21,520 --> 00:09:21,920 DID. 251 00:09:21,920 --> 00:09:24,240 IN THE OUTSIDE WORLD IT IS 252 00:09:24,240 --> 00:09:26,800 PROSPECTIVE REVIEW, YOU SUBMIT A 253 00:09:26,800 --> 00:09:29,680 GRANT, IT GETS EVALUATED, HERE 254 00:09:29,680 --> 00:09:32,960 IT IS NOT THAT WAY. 255 00:09:32,960 --> 00:09:34,840 SO RETROSPECTIVE REVIEW MAKES US 256 00:09:34,840 --> 00:09:41,040 DIFFERENT AND WE REVEL IN THAT 257 00:09:41,040 --> 00:09:41,360 DIFFERENCE. 258 00:09:41,360 --> 00:09:42,480 WE HAVE TABLE RESOURCES THAT 259 00:09:42,480 --> 00:09:43,760 CONTINUE FOR THE MOST PART FROM 260 00:09:43,760 --> 00:09:45,080 YEAR TO YEAR. 261 00:09:45,080 --> 00:09:48,440 THAT STABILITY ALLOWS YOU TO 262 00:09:48,440 --> 00:09:50,360 FOCUS ON LONG-TERM RESEARCH 263 00:09:50,360 --> 00:09:53,520 PROJECTS THAT CAN BE COMPLEX AND 264 00:09:53,520 --> 00:09:57,800 ARE HIGHLY SUSCEPTIBLE TO 265 00:09:57,800 --> 00:09:58,240 FAILURE. 266 00:09:58,240 --> 00:10:01,800 DON'T BE AFRAID OF THE FAILURES. 267 00:10:01,800 --> 00:10:03,440 YOU WILL LEARN MORE FROM THEM 268 00:10:03,440 --> 00:10:04,400 THAN THE SUCCESSES. 269 00:10:04,400 --> 00:10:06,680 I MEAN, YOU WANT TO HAVE 270 00:10:06,680 --> 00:10:06,960 SUCCESSES. 271 00:10:06,960 --> 00:10:07,640 DON'T GET ME WRONG. 272 00:10:07,640 --> 00:10:10,160 IT IS OKAY TO HAVE THINGS GO 273 00:10:10,160 --> 00:10:11,840 WRONG AS LONG AS YOU WRITE IT 274 00:10:11,840 --> 00:10:12,120 UP. 275 00:10:12,120 --> 00:10:14,360 FINALLY, WHAT MAKES THE PROGRAM 276 00:10:14,360 --> 00:10:16,440 HERE VERY DISTINCT AND THE 277 00:10:16,440 --> 00:10:17,640 STRUCTURE OF THE BUILDINGS 278 00:10:17,640 --> 00:10:18,960 DISTINCT IS THE HOSPITAL AND 279 00:10:18,960 --> 00:10:20,560 LABORATORIES ARE FULLY 280 00:10:20,560 --> 00:10:20,920 INTEGRATED. 281 00:10:20,920 --> 00:10:23,160 IN FACT, IT IS SO INTEGRATED YOU 282 00:10:23,160 --> 00:10:26,160 CAN PUT AN ORDER IN THAT SAYS 283 00:10:26,160 --> 00:10:27,200 PLEASE DELIVER BLOOD TO MY LAB. 284 00:10:27,200 --> 00:10:28,760 THAT IS EXTRAORDINARY. 285 00:10:28,760 --> 00:10:34,040 THAT MEANS WE ARE COMMITTED AT 286 00:10:34,040 --> 00:10:37,280 EVERY FASICAL OF THE BEING OF 287 00:10:37,280 --> 00:10:39,080 THE ORGANIZATION TO MAKE SURE 288 00:10:39,080 --> 00:10:40,160 INTEGRATION OF PATIENT CARE AND 289 00:10:40,160 --> 00:10:45,800 RESEARCH IS COMPLETE AND 290 00:10:45,800 --> 00:10:46,040 CONSTANT. 291 00:10:46,040 --> 00:10:48,840 AN HOUR, AGAIN, FOR THE CLINICAL 292 00:10:48,840 --> 00:10:51,600 FELLOWS, THIS MAY HAVE BEEN GONE 293 00:10:51,600 --> 00:11:00,320 OVER, IN WHICH CASE JUST SNOOZE. 294 00:11:00,320 --> 00:11:02,440 YOU WILL DO CLINICAL TRAINING 295 00:11:02,440 --> 00:11:04,000 AND THEN YOU CHOOSE A 296 00:11:04,000 --> 00:11:05,760 LABORATORY, IT CAN BE A DRY LAB 297 00:11:05,760 --> 00:11:08,400 OR A WET LAB, BUT YOU WILL SPEND 298 00:11:08,400 --> 00:11:10,160 A FEW YEARS THERE. 299 00:11:10,160 --> 00:11:11,680 AFTER THAT YOU HAVE TO DECIDE 300 00:11:11,680 --> 00:11:12,480 WHAT TO DO. 301 00:11:12,480 --> 00:11:14,880 YOU CAN STAY IN THAT LAB, BECOME 302 00:11:14,880 --> 00:11:18,640 A STAFF CLINICIAN, AN ASSOCIATE, 303 00:11:18,640 --> 00:11:20,440 AN ASSISTANT CLINICAL 304 00:11:20,440 --> 00:11:22,200 INVESTIGATOR OR YOU CAN GO OFF 305 00:11:22,200 --> 00:11:23,240 AND DO OTHER THINGS. 306 00:11:23,240 --> 00:11:25,400 THE PATHWAYS OUTLINED HERE FROM 307 00:11:25,400 --> 00:11:27,040 THESE DIFFERENT CATEGORIES YOU 308 00:11:27,040 --> 00:11:29,400 CAN TURN INTO OTHER SORT OF 309 00:11:29,400 --> 00:11:29,640 THINGS. 310 00:11:29,640 --> 00:11:40,160 THE METAMORPHASIS CAN TAKE TIME. 311 00:11:41,360 --> 00:11:44,480 BUT THIS IS THE STRUCTURE OF 312 00:11:44,480 --> 00:11:47,400 INTRAMURAL PROGRESS MIGHT LOOK 313 00:11:47,400 --> 00:11:47,600 LIKE. 314 00:11:47,600 --> 00:11:49,320 THE ASSISTANT CLINICAL 315 00:11:49,320 --> 00:11:52,840 INVESTIGATOR, A PRETENURE TRACT 316 00:11:52,840 --> 00:11:53,040 PROGRAM. 317 00:11:53,040 --> 00:11:54,520 ALLOWS YOU THREE TO FIVE YEARS 318 00:11:54,520 --> 00:11:57,800 TO DEVELOP YOUR OWN PORTFOLIO OF 319 00:11:57,800 --> 00:12:01,320 RESEARCH SO YOU CAN GO BACK AND 320 00:12:01,320 --> 00:12:04,120 CREATE SOMETHING TO APPLY FOR A 321 00:12:04,120 --> 00:12:07,120 TENURE TRACK POSITION. 322 00:12:07,120 --> 00:12:11,520 THERE IS THE NIH LASKER PROGRAM 323 00:12:11,520 --> 00:12:13,360 THAT ALLOWS YOU TO APPLY FOR A 324 00:12:13,360 --> 00:12:15,320 POSITION THAT WILL GIVE YOU FIVE 325 00:12:15,320 --> 00:12:16,760 YEARS OF INTRAMURAL TIME AND IF 326 00:12:16,760 --> 00:12:20,200 YOU WANT YOU CAN GO OUT TO THE 327 00:12:20,200 --> 00:12:21,200 EXTRAMURAL COMMUNITY AFTER THAT. 328 00:12:21,200 --> 00:12:26,640 AND FINALLY, THERE IS THE 329 00:12:26,640 --> 00:12:27,960 STATMAN SCHOLARS PROGRAM, WHICH 330 00:12:27,960 --> 00:12:31,840 ALLOWS YOU TO TAKE A MORE BASIC 331 00:12:31,840 --> 00:12:32,880 SCIENCE ORIENTED APPROACH THAT 332 00:12:32,880 --> 00:12:35,360 ALLOWS FOR A SIX TO SEVEN-YEAR 333 00:12:35,360 --> 00:12:37,240 CLOCK TOWARD TENURE. 334 00:12:37,240 --> 00:12:38,720 ALL OF THESE ARE AVAILABLE 335 00:12:38,720 --> 00:12:40,640 TOWARD THE END OF YOUR 336 00:12:40,640 --> 00:12:41,880 FELLOWSHIP OR AFTER YOUR 337 00:12:41,880 --> 00:12:43,520 FELLOWSHIP, IF THAT IS WHEN IT 338 00:12:43,520 --> 00:12:44,600 IS MOST APPROPRIATE FOR YOU. 339 00:12:44,600 --> 00:12:47,080 I ALSO WANT TO MAKE SURE TO 340 00:12:47,080 --> 00:12:49,760 EMPHASIZE THERE ARE WAYS TO 341 00:12:49,760 --> 00:12:52,200 PARTICIPATE IN PH.D. TRAINING, 342 00:12:52,200 --> 00:12:54,400 IF THAT IS SOMETHING YOU AS AN 343 00:12:54,400 --> 00:12:58,080 M.D. HAVE NOT DONE ALREADY. 344 00:12:58,080 --> 00:13:04,400 THE OXCAM PROGRAM IS A GREAT 345 00:13:04,400 --> 00:13:05,480 OPPORTUNITY. 346 00:13:05,480 --> 00:13:06,880 I STRONGLY URGE YOU TO SPECIOUS 347 00:13:06,880 --> 00:13:07,080 IT. 348 00:13:07,080 --> 00:13:09,760 THESE PEOPLE WHO RUN THE PROGRAM 349 00:13:09,760 --> 00:13:11,080 ARE AVAILABLE AND KEEN TO TELL 350 00:13:11,080 --> 00:13:11,920 YOU ABOUT IT. 351 00:13:11,920 --> 00:13:13,720 BY THE TIME YOU ARE DONE WITH 352 00:13:13,720 --> 00:13:16,280 YOUR FELLOWSHIP, YOU HAVE OTHER 353 00:13:16,280 --> 00:13:17,000 OPTIONS AS WELL. 354 00:13:17,000 --> 00:13:20,720 YOU HAVE OPTIONS OUTSIDE THE 355 00:13:20,720 --> 00:13:21,800 INTRAMURAL WORLD. 356 00:13:21,800 --> 00:13:26,960 I HAVE BEEN HERE SO LONG, I 357 00:13:26,960 --> 00:13:29,320 DON'T KNOW ABOUT THEM EXCEPT 358 00:13:29,320 --> 00:13:33,360 HERE SAY AND TIKTOK VIDEOS. 359 00:13:33,360 --> 00:13:39,200 THE THING THAT IS REFERRED TO 360 00:13:39,200 --> 00:13:41,680 LOVINGLY BY SOME, WITH FEAR BY 361 00:13:41,680 --> 00:13:42,960 OTHERS AS THE REAL WORLD. 362 00:13:42,960 --> 00:13:44,560 YOU CAN GO TO ANY OF THOSE AND 363 00:13:44,560 --> 00:13:45,960 I'M ACCOUNT YOUR TRAINING HERE 364 00:13:45,960 --> 00:13:47,880 WILL GET YOU PREPARED FOR THEM. 365 00:13:47,880 --> 00:13:57,200 SO IN SUMMARY, LIKE ALL OF GALL 366 00:13:57,200 --> 00:13:59,400 MY TALK ENDS HERE. 367 00:13:59,400 --> 00:14:00,720 YOU ARE THE INSIDE. 368 00:14:00,720 --> 00:14:04,160 YOU WILL GET A LOT OF CLINICAL 369 00:14:04,160 --> 00:14:04,640 LABORATORY RESEARCH. 370 00:14:04,640 --> 00:14:06,440 YOU ARE GOING TO HAVE A LOT OF 371 00:14:06,440 --> 00:14:07,200 OPTIONS. 372 00:14:07,200 --> 00:14:08,680 I ENCOURAGE YOU TO TAKE 373 00:14:08,680 --> 00:14:09,440 ADVANTAGE OF THOSE. 374 00:14:09,440 --> 00:14:11,720 YOU WILL GET A LOT OF SUPPORT 375 00:14:11,720 --> 00:14:12,480 WHEN YOU ARE HERE. 376 00:14:12,480 --> 00:14:15,320 WHEN I CAME HERE, ONE OF MY 377 00:14:15,320 --> 00:14:17,680 SENIOR MENTORS GARY HOFFMANN 378 00:14:17,680 --> 00:14:20,480 TURNED TO ME AND SAID, STEVE, IF 379 00:14:20,480 --> 00:14:23,320 YOU CAN'T MAKE IT AT THE NIH, 380 00:14:23,320 --> 00:14:26,600 YOU CAN'T MAKE IT ANYWHERE ELSE. 381 00:14:26,600 --> 00:14:29,320 NO PLACE ELSE IS GOING TO WORK 382 00:14:29,320 --> 00:14:30,920 AS HARD ON YOUR BEHALF. 383 00:14:30,920 --> 00:14:33,000 I HAVE FOUND THAT TO BE 384 00:14:33,000 --> 00:14:33,520 ABSOLUTELY RIGHT. 385 00:14:33,520 --> 00:14:35,280 TAKE ADVANTAGE OF WHAT YOU HAVE. 386 00:14:35,280 --> 00:14:41,800 NOW I'M DONE WITH THE 387 00:14:41,800 --> 00:14:42,560 PROSELYT 388 00:14:42,560 --> 00:14:49,200 PROSELYTIZEDD . 389 00:14:49,200 --> 00:14:51,720 WHY DO WE STUDY RARE DISEASES? 390 00:14:51,720 --> 00:14:54,480 THE TRUTH IS WE STUDY THE RARE 391 00:14:54,480 --> 00:14:55,120 THINGS IN ORDER TO UNDERSTAND 392 00:14:55,120 --> 00:14:55,720 THE COMMON THINGS. 393 00:14:55,720 --> 00:14:58,080 ONE OF THE REAL MISCONCEPTIONS 394 00:14:58,080 --> 00:15:00,480 THAT PEOPLE HAVE IS THAT WHEN 395 00:15:00,480 --> 00:15:02,680 YOU SEE A RARE INFECTION AND YOU 396 00:15:02,680 --> 00:15:08,920 SAY, OH, THAT PERSON MUST HAVE 397 00:15:08,920 --> 00:15:12,040 IMMUNODEFICIENCY BECAUSE THEY 398 00:15:12,040 --> 00:15:19,080 HAVE PNEUMOSISTIS. 399 00:15:19,080 --> 00:15:21,000 THEY ARE SICK. 400 00:15:21,000 --> 00:15:22,720 EVERYBODY IS EXPOSED. 401 00:15:22,720 --> 00:15:24,640 IT IS PRECISELY THE FACTS THAT 402 00:15:24,640 --> 00:15:26,920 THOSE PEOPLE WHO GOT SICK DIDN'T 403 00:15:26,920 --> 00:15:28,960 CONTROL IT THAT TELLS YOU THEY 404 00:15:28,960 --> 00:15:30,120 MIGHT BE SICK. 405 00:15:30,120 --> 00:15:33,560 WHAT WE ARE REALLY STUDYING ARE 406 00:15:33,560 --> 00:15:35,400 COMMON INFECTIONS THAT ARE NOT 407 00:15:35,400 --> 00:15:35,800 WELL CONTROLLED. 408 00:15:35,800 --> 00:15:37,720 SO OUR INTEREST IS IN THE 409 00:15:37,720 --> 00:15:39,280 INFECTIONS THAT ARE CAUSED BY 410 00:15:39,280 --> 00:15:41,680 COMMON ORGANISMS AND OUR 411 00:15:41,680 --> 00:15:43,040 HYPOTHESIS, WHICH SO FAR I HAVE 412 00:15:43,040 --> 00:15:45,600 SEEN TO BE QUITE CORRECT, IS YOU 413 00:15:45,600 --> 00:15:47,960 ONLY GET THREE CHOICES IN 414 00:15:47,960 --> 00:15:50,280 INFECTIOUS DISEASES, THAT IS WHY 415 00:15:50,280 --> 00:15:54,440 I WIND UP, BAD BUG, THINK OF 416 00:15:54,440 --> 00:15:57,800 ANTHRAX OR SMALLPOX, IT IS A BAD 417 00:15:57,800 --> 00:15:58,320 EXPOS 418 00:15:58,320 --> 00:15:59,120 EXPOSURE, SOMEBODY GOT INJECTED 419 00:15:59,120 --> 00:16:00,720 OR IT IS A HOST PROBLEM. 420 00:16:00,720 --> 00:16:02,880 AND FRANKLY, OUR ASSUMPTION IS 421 00:16:02,880 --> 00:16:04,720 THAT NO MATTER WHICH OF THOSE IT 422 00:16:04,720 --> 00:16:07,200 IS, WE CAN FIGURE IT OUT. 423 00:16:07,200 --> 00:16:09,600 AND IF WE WORK HARD ENOUGH, WE 424 00:16:09,600 --> 00:16:11,800 SHOULD BE ABLE TO DISSECT THOSE 425 00:16:11,800 --> 00:16:12,520 THINGS OUT. 426 00:16:12,520 --> 00:16:14,880 A WORD ABOUT HOW I WOUND UP 427 00:16:14,880 --> 00:16:15,080 HERE. 428 00:16:15,080 --> 00:16:18,280 I DID MY TRAINING IN BATTLE AS 429 00:16:18,280 --> 00:16:19,240 JOYCE SAID. 430 00:16:19,240 --> 00:16:21,640 I CAME DOWN HERE IN 1989 IN 431 00:16:21,640 --> 00:16:26,040 ORDER TO LEARN A LITTLE MORE 432 00:16:26,040 --> 00:16:27,080 MOLECULAR BIOLOGY. 433 00:16:27,080 --> 00:16:33,120 I WAS IN THE LAB OF MEL MARTIN, 434 00:16:33,120 --> 00:16:36,000 AND AS I WAS WORKING THERE THIS 435 00:16:36,000 --> 00:16:39,080 FRIEND OF MINE NAPED SKIP 436 00:16:39,080 --> 00:16:40,800 FRANCIS, WHO IS NOW ONE OF THE 437 00:16:40,800 --> 00:16:43,120 FINER GOALIES OF THE THE BEER 438 00:16:43,120 --> 00:16:45,760 LEAGUE IN WHICH WE PLAY ICE 439 00:16:45,760 --> 00:16:48,000 HOCKEY, SKIP CAME BY AND SAID, 440 00:16:48,000 --> 00:16:50,240 THERE IS THIS GUY OVER IN 441 00:16:50,240 --> 00:16:52,280 BUILDING 10 WHO'S GOT AN OPENING 442 00:16:52,280 --> 00:16:54,040 THAT YOU SHOULD REALLY GO AND 443 00:16:54,040 --> 00:16:54,840 LOOK AT. 444 00:16:54,840 --> 00:17:02,360 THIS GUY'S NAME IS JOHN GALLIN. 445 00:17:02,360 --> 00:17:05,320 I SAID, YEAH, YEAH, YEAH I'M 446 00:17:05,320 --> 00:17:06,840 WORKING ON HIV. 447 00:17:06,840 --> 00:17:08,040 I'M DOING SOMETHING IMPORTANT. 448 00:17:08,040 --> 00:17:10,280 SKIP SAID, YEAH, YEAH. 449 00:17:10,280 --> 00:17:12,040 HE CAME BACK A FEW WEEKS LATER 450 00:17:12,040 --> 00:17:13,800 AND SAID, DID YOU TALK TO JOHN? 451 00:17:13,800 --> 00:17:16,960 I SAID, NO, SKIP, I'M DOING 452 00:17:16,960 --> 00:17:18,600 REALLY IMPORTANT THINGS HERE. 453 00:17:18,600 --> 00:17:21,200 HE SAID, UH-HUH, UH-HUH, YOU 454 00:17:21,200 --> 00:17:22,360 HAVE TO GO DO. 455 00:17:22,360 --> 00:17:24,040 THANK GOD HE DID THAT BECAUSE IT 456 00:17:24,040 --> 00:17:26,440 CHANGED MY TRAJECTORY ENTIRELY. 457 00:17:26,440 --> 00:17:29,760 I WENT TO MEET THIS GUY JOHN 458 00:17:29,760 --> 00:17:31,320 GALLIN, THE SCIENTIFIC DIRECTOR 459 00:17:31,320 --> 00:17:33,800 OF THE INSTITUTE. 460 00:17:33,800 --> 00:17:36,720 HE SAID YOU CAN COME OVER HERE 461 00:17:36,720 --> 00:17:41,600 AND WORK ON ANYTHING YOU WANT AS 462 00:17:41,600 --> 00:17:47,840 LONG AS IT IS NEUTROPHILS. 463 00:17:47,840 --> 00:17:50,240 I SAID THAT IS A TOUGH OFFER. 464 00:17:50,240 --> 00:17:52,680 HE SAID, LOOK, THE WARD IS 50 465 00:17:52,680 --> 00:17:53,800 YARDS AWAY FROM YOUR LAB. 466 00:17:53,800 --> 00:17:55,760 YOU CAN GO BACK AND FORTH ALL 467 00:17:55,760 --> 00:17:58,280 DAY LONG, ALL NIGHT LONG IF YOU 468 00:17:58,280 --> 00:18:00,080 WANT AND TAKE CARE OF PATIENTS 469 00:18:00,080 --> 00:18:01,360 AND STUDY THEM IN THE 470 00:18:01,360 --> 00:18:01,640 LABORATORY. 471 00:18:01,640 --> 00:18:04,280 I SAID THAT IS AN EXTRAORDINARY 472 00:18:04,280 --> 00:18:04,560 OPPORTUNITY. 473 00:18:04,560 --> 00:18:06,600 THEN HE SAID, AFTER YOU DO ALL 474 00:18:06,600 --> 00:18:09,240 THAT, AFTER YOU TAKE CARE OF ALL 475 00:18:09,240 --> 00:18:10,880 THE PATIENTS I HAVE BEEN 476 00:18:10,880 --> 00:18:12,120 STUDYING THE LAST NUMBER OF 477 00:18:12,120 --> 00:18:13,800 YEARS, THEN YOU CAN GO OFF AND 478 00:18:13,800 --> 00:18:15,640 FIND YOUR OWN DISEASES AND 479 00:18:15,640 --> 00:18:16,640 THAT'S YOUR PROBLEM. 480 00:18:16,640 --> 00:18:19,680 I SAID, THAT SOUNDS RIDICULOUS. 481 00:18:19,680 --> 00:18:22,320 WHO GOES AROUND FINDING 482 00:18:22,320 --> 00:18:22,720 DISEASES. 483 00:18:22,720 --> 00:18:24,800 IT IS NOT LIKE THEY GROW ON 484 00:18:24,800 --> 00:18:25,000 TREES. 485 00:18:25,000 --> 00:18:27,400 I DIDN'T KNOW ABOUT WHAT THE 486 00:18:27,400 --> 00:18:28,480 INTRAMURAL PROGRAM WAS LIKE. 487 00:18:28,480 --> 00:18:30,640 THIS IS WHERE THE TREES ARE 488 00:18:30,640 --> 00:18:32,120 PLANTED. 489 00:18:32,120 --> 00:18:36,120 SO I CAME INTO JOHN'S LAB AND I 490 00:18:36,120 --> 00:18:39,160 PICKED UP THE PHONE ON AN 491 00:18:39,160 --> 00:18:42,280 AFTERNOON, I'M SURE IT WAS A 492 00:18:42,280 --> 00:18:45,080 FRIDAY AFTERNOON, THESE THINGS 493 00:18:45,080 --> 00:18:46,560 ALWAYS ARE. 494 00:18:46,560 --> 00:18:53,560 IT WAS A PEDIATRICIAN FROM 495 00:18:53,560 --> 00:18:54,880 FLORIDA CALLING ME FROM HIS CELL 496 00:18:54,880 --> 00:18:55,800 PHONE. 497 00:18:55,800 --> 00:18:57,040 THIS IS WHAT A CELL PHONE LOOKED 498 00:18:57,040 --> 00:18:58,800 LIKE IN 1992. 499 00:18:58,800 --> 00:19:00,800 THIS PROBABLY WASN'T 1992, THIS 500 00:19:00,800 --> 00:19:02,360 WAS PROBABLY 1994. 501 00:19:02,360 --> 00:19:04,040 I HAD NEVER BEEN CALLED ON A 502 00:19:04,040 --> 00:19:05,800 CELL PHONE FROM A CAR BEFORE. 503 00:19:05,800 --> 00:19:06,840 IT WAS PRETTY COOL. 504 00:19:06,840 --> 00:19:09,040 HE TOLD ME ABOUT THIS FAMILY IN 505 00:19:09,040 --> 00:19:15,480 WHICH A 5-YEAR-OLD BOY WAS SO 506 00:19:15,480 --> 00:19:18,960 SICK HE WAS ON PARENTERAL 507 00:19:18,960 --> 00:19:26,160 NUTRITION AND HE WAS GROWING 508 00:19:26,160 --> 00:19:27,760 AVIUM FROM HIS BOWEL. 509 00:19:27,760 --> 00:19:29,080 HE HAD TWO UNCLES WITH THE SAME 510 00:19:29,080 --> 00:19:32,160 THING. 511 00:19:32,160 --> 00:19:38,840 JOHN ESTABLISHED THE CHRONIC 512 00:19:38,840 --> 00:19:40,640 GRANULOMATOUS DISEASE. 513 00:19:40,640 --> 00:19:42,560 THESE GUYS SAID I WONDER IF THEY 514 00:19:42,560 --> 00:19:46,600 HAVE CHRONIC GRANULOMATOUS 515 00:19:46,600 --> 00:19:47,000 DISEASE? 516 00:19:47,000 --> 00:19:49,320 COULD THAT BE WHAT IS GOING ON 517 00:19:49,320 --> 00:19:53,560 AND WOULD YOU BE WILLING TO SEE 518 00:19:53,560 --> 00:19:53,760 THEM. 519 00:19:53,760 --> 00:19:59,680 M AVIUM COMPLEX IS IN THE FAMILY 520 00:19:59,680 --> 00:20:05,800 OF MICROBACTERIA. 521 00:20:05,800 --> 00:20:08,600 WHEN THE CAUSE OF TB WAS 522 00:20:08,600 --> 00:20:10,600 DISCOVERED, HE INVITED EVERYONE 523 00:20:10,600 --> 00:20:12,600 TO SEE HIS DISCOVERY. 524 00:20:12,600 --> 00:20:15,680 HE HAD IT IN HIS HOUSE IN HIS 525 00:20:15,680 --> 00:20:17,800 KITCHEN UNDER THE MIB SCOPE. 526 00:20:17,800 --> 00:20:21,520 HE SAID, LOOK, LOOK WHAT I 527 00:20:21,520 --> 00:20:21,720 FOUND. 528 00:20:21,720 --> 00:20:23,080 NO YOU DIDN'T. 529 00:20:23,080 --> 00:20:32,680 THAT COUNT BE THE SKAUZ OF 530 00:20:32,680 --> 00:20:33,800 TUBERCULOSIS. 531 00:20:33,800 --> 00:20:38,680 HE DEVELOPED OVER YEARS COX 532 00:20:38,680 --> 00:20:40,120 POSTULATES TO PROVE WHAT YOU 533 00:20:40,120 --> 00:20:41,160 THOUGHT WAS PORNTS IS IMPORTANT. 534 00:20:41,160 --> 00:20:43,480 HE LOST THE OPPORTUNITY TO HAVE 535 00:20:43,480 --> 00:20:45,480 ANYBODY OVER FOR DINNER EVER 536 00:20:45,480 --> 00:20:45,680 AGAIN. 537 00:20:45,680 --> 00:20:53,680 THAT WAS 141 YEARS AGO. 538 00:20:53,680 --> 00:20:57,520 IN THE IMPORTANT DISCOVERY THERE 539 00:20:57,520 --> 00:21:00,960 ARE 150 SPECIES OUT THERE. 540 00:21:00,960 --> 00:21:03,120 TUBERCULOSIS IS A BAD ACTOR AND 541 00:21:03,120 --> 00:21:05,560 CAUSES DISEASE IN LOTS OF PEOPLE 542 00:21:05,560 --> 00:21:06,960 AND RESPONSIBLE FOR HUMAN TO 543 00:21:06,960 --> 00:21:07,560 HUMAN SPREAD. 544 00:21:07,560 --> 00:21:12,400 THESE OTHER MICROBACTERIA DOWN 545 00:21:12,400 --> 00:21:17,520 HERE, THE NONTUBERCULOUS 546 00:21:17,520 --> 00:21:20,520 BACTERIA ARE ACQUIRED THROUGH 547 00:21:20,520 --> 00:21:21,520 AIR, THROUGH WATER, THROUGH 548 00:21:21,520 --> 00:21:21,800 SOIL. 549 00:21:21,800 --> 00:21:26,640 THEY ARE NOT AVOIDABLE. 550 00:21:26,640 --> 00:21:29,120 AND SO, YOU KNOW, WE THOUGHT 551 00:21:29,120 --> 00:21:36,000 EARLY ON THE WE UNDERSTOOD ABOUT 552 00:21:36,000 --> 00:21:39,160 NONTUBERCULOUS ORGANISMS WE 553 00:21:39,160 --> 00:21:40,480 WOULD LEARN MORE ABOUT 554 00:21:40,480 --> 00:21:49,360 TUBERCULOSIS. 555 00:21:49,360 --> 00:21:52,040 MAVIUM WHEN THERE WAS NO DRUG 556 00:21:52,040 --> 00:21:54,480 FOR HIV TREATMENT, IT WAS WITH 557 00:21:54,480 --> 00:22:02,280 THIS ORGANIZE HERE CALLED MAC. 558 00:22:02,280 --> 00:22:06,120 THIS GUY SAID I THINK IT IS 559 00:22:06,120 --> 00:22:09,800 CHRONIC MACROLOMA DISEASE. 560 00:22:09,800 --> 00:22:13,720 HE SAID, CDG DOESN'T GET 561 00:22:13,720 --> 00:22:15,960 DISSEMINATED MAC. 562 00:22:15,960 --> 00:22:18,480 I THOUGHT THREE MALES CONNECTED 563 00:22:18,480 --> 00:22:21,200 BY AN ASYMPTOMATIC FEMALE, THE 564 00:22:21,200 --> 00:22:24,240 MOTHER OF MY PATIENT SAYS A IT 565 00:22:24,240 --> 00:22:26,040 IS GENETIC, B IT IS PROBABLY ON 566 00:22:26,040 --> 00:22:28,040 THE X CHROMOSOME AND IF IT IS 567 00:22:28,040 --> 00:22:30,080 ANY OF THOSE THINGS WE SHOULD BE 568 00:22:30,080 --> 00:22:31,280 ABLE TO DISCOVER IT. 569 00:22:31,280 --> 00:22:33,720 I'M NOT SURE WHAT TO SAY HERE, 570 00:22:33,720 --> 00:22:36,200 BUT WHY DON'T YOU SEND US THAT 571 00:22:36,200 --> 00:22:37,480 PATIENT HERE TO THE NIH. 572 00:22:37,480 --> 00:22:38,840 AND THE WHOLE FAMILY. 573 00:22:38,840 --> 00:22:40,320 WE'LL TAKE THEM ALL. 574 00:22:40,320 --> 00:22:42,640 THAT REALLY IS WHY WE HAVE A 575 00:22:42,640 --> 00:22:45,240 HOSPITAL ATTACHED TO A 576 00:22:45,240 --> 00:22:45,800 LABORATORY. 577 00:22:45,800 --> 00:22:48,360 THERE IS NO OTHER GOOD REASON 578 00:22:48,360 --> 00:22:49,240 FOR THAT. 579 00:22:49,240 --> 00:22:51,240 THE WORLD DOESN'T NEED MORE 580 00:22:51,240 --> 00:22:51,520 HOSPITALS. 581 00:22:51,520 --> 00:22:53,600 THE WORLD HAS PLENTY OF 582 00:22:53,600 --> 00:22:54,000 LABORATORIES. 583 00:22:54,000 --> 00:22:56,200 WHAT WE HAVE IS UNIQUE IN 584 00:22:56,200 --> 00:22:57,800 PUTTING THOSE TWO TOGETHER. 585 00:22:57,800 --> 00:23:00,240 SO WHAT WE WERE THINKING ABOUT 586 00:23:00,240 --> 00:23:04,760 IS THE FACT IN THE 1990s WE KNEW 587 00:23:04,760 --> 00:23:13,800 MICROBACTERIA INFECT 588 00:23:13,800 --> 00:23:17,320 MACROPHAGES, AND THE INTERFERE 589 00:23:17,320 --> 00:23:19,640 RON GAMMA ACTIVATES A RECEPTOR 590 00:23:19,640 --> 00:23:22,960 AND THAT WAS LINKED IN BEING IN 591 00:23:22,960 --> 00:23:27,400 CONTROL OF MICROBACTERIA. 592 00:23:27,400 --> 00:23:29,720 MYCO BACTERIA. 593 00:23:29,720 --> 00:23:35,280 THIS WAS 1991 TO 1992. 594 00:23:35,280 --> 00:23:39,280 INTERFERON GAMMA, THE FIRST 595 00:23:39,280 --> 00:23:44,080 CYTOKINE CLONED WAS USED AND IT 596 00:23:44,080 --> 00:23:45,800 WAS CLEAR IT MADE THE DISEASE 597 00:23:45,800 --> 00:23:47,000 HAVE LESS INFECTIONS. 598 00:23:47,000 --> 00:23:50,600 SO WE SAID, OKAY, WHAT DOES THAT 599 00:23:50,600 --> 00:23:50,760 DO? 600 00:23:50,760 --> 00:23:55,600 AND BY THE EARLY 1990s IT WAS 601 00:23:55,600 --> 00:23:59,680 CLEAR WHAT INTERFERON GAMMA 602 00:23:59,680 --> 00:24:02,600 ACTIVATED THE RECEPTOR, IT 603 00:24:02,600 --> 00:24:04,360 BINDS, AGGREGATED THE RECEPTOR, 604 00:24:04,360 --> 00:24:08,360 BRINGS THESE COMPONENTS 605 00:24:08,360 --> 00:24:13,800 TOGETHER, LEADS TO THE 606 00:24:13,800 --> 00:24:16,800 PHOPORILATION AND ACTIVATED 607 00:24:16,800 --> 00:24:19,640 INTERFERON GAMMA IN THE NUCLEUS. 608 00:24:19,640 --> 00:24:29,440 IT PRUSZS MORE SUPEROXIDE, NI 609 00:24:29,440 --> 00:24:32,000 NIGHT -- AS WELL AS PRODUCTION 610 00:24:32,000 --> 00:24:34,920 OF OTHER CYTOKINES. 611 00:24:34,920 --> 00:24:37,240 WE KNEW THAT FROM BASIC STUDIES 612 00:24:37,240 --> 00:24:39,440 BEFORE WE MET THESE PATIENTS AND 613 00:24:39,440 --> 00:24:42,920 SAID, OKAY, LET'S BRING THEM UP. 614 00:24:42,920 --> 00:24:46,080 THEY ARE GETTING 615 00:24:46,080 --> 00:24:46,440 ANTI-MICROBIALS. 616 00:24:46,440 --> 00:24:46,880 THAT IS NOT ENOUGH. 617 00:24:46,880 --> 00:24:50,120 IT IS A GENETIC PROBLEM. 618 00:24:50,120 --> 00:24:54,160 HOW ARE WE GOING TO TREAT THEM. 619 00:24:54,160 --> 00:24:55,560 REGARDLESS OF THE PROTOCOL YOU 620 00:24:55,560 --> 00:24:57,760 ARE FOLLOWING YOU HAVE TO BE 621 00:24:57,760 --> 00:24:59,800 THINKING, HOW AM I GOING TO 622 00:24:59,800 --> 00:25:00,880 TREAT THIS PATIENT. 623 00:25:00,880 --> 00:25:02,240 PATIENTS ARE RELUCTANT TO HEAR 624 00:25:02,240 --> 00:25:03,760 WHY THEY ARE SO SICK. 625 00:25:03,760 --> 00:25:05,600 THEY WANT TO HEAR WHY THEY ARE 626 00:25:05,600 --> 00:25:07,840 SICK AND HOW YOU ARE GOING TO 627 00:25:07,840 --> 00:25:11,640 MAKE THEM BETTER. 628 00:25:11,640 --> 00:25:15,240 LET'S TREAT THESE PATIENTS WITH 629 00:25:15,240 --> 00:25:24,600 INTERDOCTORS FERON GAMMA. 630 00:25:24,600 --> 00:25:28,720 IF WE COULD ACTIVATE MACROPHAGES 631 00:25:28,720 --> 00:25:30,000 IT WOULD WORK. 632 00:25:30,000 --> 00:25:33,800 WE WERE VERY LUCKY THE FIRST 633 00:25:33,800 --> 00:25:36,600 PATIENTS WE CHOSE IN WHOM TO DO 634 00:25:36,600 --> 00:25:37,800 THIS WORKED. 635 00:25:37,800 --> 00:25:40,360 THIS IS A 5-YEAR-OLD BOY. 636 00:25:40,360 --> 00:25:43,200 HIS GROWTH HAD BEEN STYMIED FOR 637 00:25:43,200 --> 00:25:48,040 QUITE A WHILE AT AGE 4 TO 5. 638 00:25:48,040 --> 00:25:52,720 HIS HEIGHT AND SERUM ALBUMEN IS 639 00:25:52,720 --> 00:25:53,800 INDICATION OF NUTRITION. 640 00:25:53,800 --> 00:25:56,080 HE GREW AND CAME UP TO HIS 641 00:25:56,080 --> 00:25:57,640 NORMAL SIZE AND WITH TREATMENT 642 00:25:57,640 --> 00:26:04,080 WE WERE ABLE TO GET HIS ALBUMEN 643 00:26:04,080 --> 00:26:07,240 OFF, TAKE HIM OFF HIS PARENTAL 644 00:26:07,240 --> 00:26:09,560 NUTRITION AND GET BACK TO ORAL 645 00:26:09,560 --> 00:26:11,160 TREATMENT AND HE WENT BACK TO 646 00:26:11,160 --> 00:26:12,600 HAVING A NORMAL LIFE. 647 00:26:12,600 --> 00:26:15,520 THIS GUY AT THE BOTTOM HAD 648 00:26:15,520 --> 00:26:16,880 SEVERE DISEASE. 649 00:26:16,880 --> 00:26:21,360 HE KEPT ON ACCUMULATING ACYTES. 650 00:26:21,360 --> 00:26:23,560 EVERY WEEK WE HAD TO TAKE FOUR 651 00:26:23,560 --> 00:26:29,800 TO FIVE LITERS OF ACYTES OUT OF 652 00:26:29,800 --> 00:26:33,600 HIS BELLY. 653 00:26:33,600 --> 00:26:35,000 EVERY WEEK. 654 00:26:35,000 --> 00:26:39,600 THIS IS THE VOLUME WE REMOVED 655 00:26:39,600 --> 00:26:42,880 EACH MONTH. 656 00:26:42,880 --> 00:26:50,400 WITH INTERFERON HE HAS NO CYTES. 657 00:26:50,400 --> 00:26:51,800 WE THOUGHT WE STRUCK GOLD. 658 00:26:51,800 --> 00:26:55,080 WE PUBLISHED THAT PAPER AND 659 00:26:55,080 --> 00:26:58,000 PEOPLE WENT, WOW, THAT IS GREAT. 660 00:26:58,000 --> 00:27:04,200 LET'S SEND YOU THE REFRACTORY 661 00:27:04,200 --> 00:27:05,600 MICROBACTERIA WE'VE GOT. 662 00:27:05,600 --> 00:27:07,480 SO THEY DID. 663 00:27:07,480 --> 00:27:18,000 THE NEXT YEAR WE WERE SENT AN 664 00:27:20,200 --> 00:27:22,880 18-MONTH-OLD BOY PAKISTANI WHO 665 00:27:22,880 --> 00:27:23,800 LIVED IN NEW YORK. 666 00:27:23,800 --> 00:27:26,520 THEY READ OUR PAPER, STARTS HIM 667 00:27:26,520 --> 00:27:29,640 ON INTERFERON GAMMA AND HE 668 00:27:29,640 --> 00:27:31,240 DIDN'T GET BETTER. 669 00:27:31,240 --> 00:27:33,600 THEY CALLED AND SAID WHAT IS THE 670 00:27:33,600 --> 00:27:33,840 PROBLEM? 671 00:27:33,840 --> 00:27:35,880 IS I SAID LORD IF I KNOW. 672 00:27:35,880 --> 00:27:37,800 WHY DON'T YOU REFER US THE 673 00:27:37,800 --> 00:27:38,080 PATIENT. 674 00:27:38,080 --> 00:27:39,680 WE WOULD BE HAPPY TO TAKE A 675 00:27:39,680 --> 00:27:39,880 LOOK. 676 00:27:39,880 --> 00:27:42,320 HERE IS AN EXAMPLE OF THE 677 00:27:42,320 --> 00:27:42,560 PROBLEM. 678 00:27:42,560 --> 00:27:50,160 WHEN YOU EXPOSE CELLS TO 679 00:27:50,160 --> 00:27:51,960 ENDSOTOXIN, THEY MAKE --. 680 00:27:51,960 --> 00:27:54,240 WHEN YOU ADD INTERS THERE FERON 681 00:27:54,240 --> 00:27:59,160 GAMMA TO THE ENDOTOXIN, THEY 682 00:27:59,160 --> 00:28:01,120 MAKE BOAT LOADS MORE. 683 00:28:01,120 --> 00:28:04,360 AND THE PATIENT DIDN'T. 684 00:28:04,360 --> 00:28:06,560 THAT SUGGESTED HIS PROBLEM WAS 685 00:28:06,560 --> 00:28:09,800 HANDLING INTERFERON GAMMA WHICH 686 00:28:09,800 --> 00:28:12,400 IS WHY IT DIDN'T WORK WHEN THEY 687 00:28:12,400 --> 00:28:13,640 TREATED HIM WITH IT. 688 00:28:13,640 --> 00:28:20,400 HE HAD A MUTATION IN THE 689 00:28:20,400 --> 00:28:25,800 INTERFERON RECEPTOR MAKING IT 690 00:28:25,800 --> 00:28:29,200 IMPOSSIBLE TO UPLOAD THE FACTOR. 691 00:28:29,200 --> 00:28:32,360 THE NEXT PATIENT WE GOT CALLED 692 00:28:32,360 --> 00:28:36,840 ABOUT HAS PERFECTLY LEVELS OF 693 00:28:36,840 --> 00:28:39,280 INTERFERON GAMMA 1, BUT DIDN'T 694 00:28:39,280 --> 00:28:41,480 RESPOND TO STIMULATION. 695 00:28:41,480 --> 00:28:43,920 A 2-YEAR-OLD BOY WHOSE PARENTS 696 00:28:43,920 --> 00:28:47,000 WERE MIXED ENGLISH AND 697 00:28:47,000 --> 00:28:48,480 PORTUGUESE BACKGROUND WHO ALSO 698 00:28:48,480 --> 00:28:50,600 WAS BEING TREATED WITH 699 00:28:50,600 --> 00:28:52,840 INTERFERON GAMMA AND NOT GETTING 700 00:28:52,840 --> 00:28:53,080 BETTER. 701 00:28:53,080 --> 00:28:57,760 YOU CAN SEE THE PRODUCTION OF 702 00:28:57,760 --> 00:29:04,600 TNF IN RESPONSE TO ENDOTOXIN WAS 703 00:29:04,600 --> 00:29:04,880 NORMAL. 704 00:29:04,880 --> 00:29:07,400 THEIR PARENTS UPREGULATED, HE 705 00:29:07,400 --> 00:29:07,640 DID NOT. 706 00:29:07,640 --> 00:29:11,360 ONE WAS NORMAL. 707 00:29:11,360 --> 00:29:12,560 WHERE IS HIS PROBLEM? 708 00:29:12,560 --> 00:29:16,280 IN INTERFERON GAMMA RECEPTOR 2. 709 00:29:16,280 --> 00:29:19,480 THIS HELPED US BEGIN TO SAY, 710 00:29:19,480 --> 00:29:21,120 OKAY, WHAT ELSE IS GOING ON IN 711 00:29:21,120 --> 00:29:22,600 THIS PATHWAY. 712 00:29:22,600 --> 00:29:24,880 WE KNOW WE CAN TREAT THESE 713 00:29:24,880 --> 00:29:26,760 INFECTIONS IF PEOPLE HAVE AN 714 00:29:26,760 --> 00:29:28,160 INTACT PATHWAY, BUT IF THEY 715 00:29:28,160 --> 00:29:31,360 DON'T, WHAT DO WE NEED TO DO? 716 00:29:31,360 --> 00:29:33,640 THE OVER THE YEARS, LOTS MORE 717 00:29:33,640 --> 00:29:35,440 GENES HAVE BEEN IDENTIFIED IN 718 00:29:35,440 --> 00:29:37,800 THE PATHWAY THAT IS RESPONSIBLE 719 00:29:37,800 --> 00:29:41,640 FOR THE CONTROL OF MYCO BACTERIA 720 00:29:41,640 --> 00:29:41,840 DISEASE. 721 00:29:41,840 --> 00:29:48,120 IT IS MENDELLIAN SUSCEPTIBILITY. 722 00:29:48,120 --> 00:29:50,560 IT IS A CATCHY NAME, ROLLS RIGHT 723 00:29:50,560 --> 00:29:53,320 OFF THE TONGUE. 724 00:29:53,320 --> 00:29:56,520 IT IS NICE BUT MISSES THE FACT 725 00:29:56,520 --> 00:30:00,200 THIS PATHWAY CONTROLLING 726 00:30:00,200 --> 00:30:00,880 SUSCEPTIBILITY TO ORGANISMS THAT 727 00:30:00,880 --> 00:30:08,160 LIKE TO LIVE IN THE MACROPHAGE. 728 00:30:08,160 --> 00:30:10,800 MOST OF THESE THINGS, AS I HAVE 729 00:30:10,800 --> 00:30:11,960 ALREADY TRIED TO SHOW, PRESENT 730 00:30:11,960 --> 00:30:13,800 IN CHILDHOOD. 731 00:30:13,800 --> 00:30:17,200 AND SO OUR NEXT DILEMMA CAME 732 00:30:17,200 --> 00:30:19,040 WHEN WE STARTED TO GET MORE 733 00:30:19,040 --> 00:30:20,280 PEOPLE REFERRED. 734 00:30:20,280 --> 00:30:24,920 NOW, AGAIN, WHO WEREN'T 735 00:30:24,920 --> 00:30:28,920 RESPONDING TO INTERFERON GAMMA 736 00:30:28,920 --> 00:30:30,000 BUT NOW WEREN'T CHILDREN. 737 00:30:30,000 --> 00:30:32,520 THIS PATIENT A 60-YEAR-OLD WOMAN 738 00:30:32,520 --> 00:30:34,720 FROM VIETNAM, SURVIVED THE WAR, 739 00:30:34,720 --> 00:30:37,040 CAME OUT ON A BOAT LIFT, WHO 740 00:30:37,040 --> 00:30:38,200 CLEARLY HAD BEEN THROUGH A LOT 741 00:30:38,200 --> 00:30:41,520 OF EXPOSURES IN HER LIFE WAS 742 00:30:41,520 --> 00:30:44,240 FINE UNTIL SHE WAS IN HER LATE 743 00:30:44,240 --> 00:30:47,360 50s, BEGAN TO LOSE WEIGHT AND 744 00:30:47,360 --> 00:30:49,040 DESPITE GETTING PERFECTLY GOOD 745 00:30:49,040 --> 00:30:52,800 TREATMENT HAD PLENTY PERSISTENT 746 00:30:52,800 --> 00:30:53,800 DISEASE. 747 00:30:53,800 --> 00:31:04,360 THESE LESIONS WERE COMING FROM 748 00:31:04,360 --> 00:31:06,760 OSTEOMYOLITIS LEADING TO 749 00:31:06,760 --> 00:31:11,480 FRACTURES IN HER CLAVICLE. 750 00:31:11,480 --> 00:31:16,040 SO WE HAVE SEEN A LOT OF GENETIC 751 00:31:16,040 --> 00:31:16,400 SUSCEPTIBILITY. 752 00:31:16,400 --> 00:31:22,480 WE KNOW THOSE GENETIC CONDITIONS 753 00:31:22,480 --> 00:31:23,920 ARE PRESENT FROM CONCEPTION. 754 00:31:23,920 --> 00:31:26,120 WHAT IS GOING ON HERE THAT SHE 755 00:31:26,120 --> 00:31:27,360 COULD HAVE GOTTEN THROUGH SO 756 00:31:27,360 --> 00:31:27,560 MUCH? 757 00:31:27,560 --> 00:31:31,400 IT LOOKS LIKE A GENETIC DISEASE, 758 00:31:31,400 --> 00:31:34,600 ACTS LIKE A GENETIC DISEASE, IT 759 00:31:34,600 --> 00:31:36,440 COMES ON LATER IN LIFE. 760 00:31:36,440 --> 00:31:40,120 I'M NOT SAYING 60 IS OLD, BUT IT 761 00:31:40,120 --> 00:31:41,360 IS NOT CHILDHOOD. 762 00:31:41,360 --> 00:31:42,920 SO WE HAVE TO THINK FURTHER 763 00:31:42,920 --> 00:31:44,040 OUTSIDE THE BOX. 764 00:31:44,040 --> 00:31:46,960 SO WE LOOKED AT ALL OF THE -- WE 765 00:31:46,960 --> 00:31:48,800 ROUNDED UP THE USUAL SUSPECTS, 766 00:31:48,800 --> 00:31:50,640 AS THEY SAY, AND DIDN'T FIND 767 00:31:50,640 --> 00:31:53,280 ANYBODY WE RECOGNIZED HERE. 768 00:31:53,280 --> 00:31:56,240 SO WHERE IS THE LESION? 769 00:31:56,240 --> 00:31:58,720 WELL, WE DECIDED IN ORDER TO 770 00:31:58,720 --> 00:32:00,320 STUDY THIS CAREFULLY, WE WOULD 771 00:32:00,320 --> 00:32:02,520 NEED TO TWO TO THE SOURCE. 772 00:32:02,520 --> 00:32:04,840 THIS WOMAN WAS FROM VIETNAM. 773 00:32:04,840 --> 00:32:09,640 WE HAD A COLLABORATOR IN 774 00:32:09,640 --> 00:32:12,360 THAILAND WHERE THEY HAD MANY 775 00:32:12,360 --> 00:32:14,800 OPPORTUNISTIC INFECTIONS IN 776 00:32:14,800 --> 00:32:18,200 ADULTS WHO HAD NOT HAD ANYTHING 777 00:32:18,200 --> 00:32:19,560 IN CHILDHOOD. 778 00:32:19,560 --> 00:32:21,800 AND WHAT DID THESE PATIENTS LOOK 779 00:32:21,800 --> 00:32:22,160 LIKE. 780 00:32:22,160 --> 00:32:26,760 THIS MAN HAS DISSEMINATED 781 00:32:26,760 --> 00:32:28,760 TALAROMYCES, A FUNGUS. 782 00:32:28,760 --> 00:32:38,720 THIS WOMAN HAS A SALMONELLA 783 00:32:38,720 --> 00:32:39,040 LYMPHADENITIS. 784 00:32:39,040 --> 00:32:43,000 WHEN WE WENT TO THAILAND, WE 785 00:32:43,000 --> 00:32:46,240 IDENTIFIED THESE PATIENTS HAD 786 00:32:46,240 --> 00:32:46,760 AUTOANTIBODIES. 787 00:32:46,760 --> 00:32:48,720 WE LOOKED AT PEOPLE RESPONDING 788 00:32:48,720 --> 00:32:53,800 TO INTERFERON GAMMA, PEOPLE WHO 789 00:32:53,800 --> 00:32:55,360 FAILED TO RESPOND AND NOW 790 00:32:55,360 --> 00:32:58,640 STARTING TO ACCUMULATE PEOPLE 791 00:32:58,640 --> 00:32:59,960 WHO IN ADULTHOOD FAIL TO RESPOND 792 00:32:59,960 --> 00:33:10,280 TO INTERFERON GAMMA. 793 00:33:11,320 --> 00:33:13,120 THIS IS SOMETHING WE CONTINUE TO 794 00:33:13,120 --> 00:33:15,360 STUDY IN SOME DETAIL. 795 00:33:15,360 --> 00:33:17,720 PEOPLE ARE NOT KEEN TO BE TOLD 796 00:33:17,720 --> 00:33:19,400 AT LEAST WE UNDERSTAND WHY YOU 797 00:33:19,400 --> 00:33:20,560 ARE GOING TO DIE. 798 00:33:20,560 --> 00:33:21,760 THEY TOLERATE IT. 799 00:33:21,760 --> 00:33:23,800 THAT IS NOT WHERE WE WANT TO BE. 800 00:33:23,800 --> 00:33:25,080 WE WANT TO SAY WE UNDERSTAND WHY 801 00:33:25,080 --> 00:33:27,600 YOU ARE SICK AND WE ARE GOING TO 802 00:33:27,600 --> 00:33:29,800 FIX IT. 803 00:33:29,800 --> 00:33:33,040 AN ANTIBODY PROBLEM PRODUCED BY 804 00:33:33,040 --> 00:33:35,080 ABRANT B CELLS THAT ARE NO 805 00:33:35,080 --> 00:33:37,840 LONGER REGULATED, YOU CAN GO 806 00:33:37,840 --> 00:33:41,560 AFTER THOSE B CELLS AND TRY TO 807 00:33:41,560 --> 00:33:43,720 ATTACK THEM. 808 00:33:43,720 --> 00:33:48,880 THE DRUG RETUXEMAB CAN BE QUITE 809 00:33:48,880 --> 00:33:49,320 EFFECTIVE. 810 00:33:49,320 --> 00:33:52,760 WHEN WE TREATED THESE PATIENTS, 811 00:33:52,760 --> 00:33:57,120 THIS IS THEIR STARTING THE 812 00:33:57,120 --> 00:34:00,280 TIGHTER, WHEN WE STOPPED GIVING 813 00:34:00,280 --> 00:34:01,840 HER THE DRUG, HE LEVELS CAME 814 00:34:01,840 --> 00:34:03,800 BACK UP, WE GAVE IT TO HER 815 00:34:03,800 --> 00:34:05,120 AGAIN, THEY CAME BACK DOWN. 816 00:34:05,120 --> 00:34:07,680 ALL OF THESE PATIENTS THAT 817 00:34:07,680 --> 00:34:09,360 RESPONDED TO THERAPY CLEARED 818 00:34:09,360 --> 00:34:11,080 THEIR INFECTIONS AND HAVE GONE 819 00:34:11,080 --> 00:34:14,280 BACK TO NORMAL LIVES. 820 00:34:14,280 --> 00:34:15,760 NOW, JUST I'LL POINT OUT IN 821 00:34:15,760 --> 00:34:17,800 PASSES THAT THIS IS JUST THE TIP 822 00:34:17,800 --> 00:34:19,320 OF THE ICEBERG. 823 00:34:19,320 --> 00:34:24,440 WE'VE ALL HEARD ABOUT 824 00:34:24,440 --> 00:34:24,920 AUTOANTIBODIES. 825 00:34:24,920 --> 00:34:29,760 THEY ARE INVOLVED IN LUPUS, ITP 826 00:34:29,760 --> 00:34:32,920 AND NEPHOTIC. 827 00:34:32,920 --> 00:34:37,160 THEY BIND DIRECTLY TO CYTOKINES 828 00:34:37,160 --> 00:34:39,240 AND INHIBIT THEM TO SIGNAL AND 829 00:34:39,240 --> 00:34:40,760 ARE RESPONSIBLE FOR INFECTIONS. 830 00:34:40,760 --> 00:34:42,040 YOU MIGHT THINK THAT IS A 831 00:34:42,040 --> 00:34:44,600 PROBLEM FOR JUST US IN THE 832 00:34:44,600 --> 00:34:47,280 INFECTIOUS DISEASE WORLD, BUT, 833 00:34:47,280 --> 00:34:55,920 NO, IT IS PROBLEM IN NEUROLOGY, 834 00:34:55,920 --> 00:35:00,400 WHERE IT CAUSES NEUROMYOLITIS 835 00:35:00,400 --> 00:35:02,080 OPTS THERE ICA AND OTHER 836 00:35:02,080 --> 00:35:02,480 CONDITIONS. 837 00:35:02,480 --> 00:35:03,960 THESE ARE GENERALIZED PROBLEMS 838 00:35:03,960 --> 00:35:05,760 AND IF YOU ARE NOT STOPPING TO 839 00:35:05,760 --> 00:35:08,400 THINK ABOUT THEM, YOU ARE I 840 00:35:08,400 --> 00:35:11,400 PROMISE MISSING A WHOLE LIMB OF 841 00:35:11,400 --> 00:35:11,640 DEFECTS. 842 00:35:11,640 --> 00:35:14,200 I SAY THAT AS SOMEBODY WHO 843 00:35:14,200 --> 00:35:16,720 MISSED THAT LIMB FOR DECADES. 844 00:35:16,720 --> 00:35:17,560 DON'T FOLLOW MY EXAMPLE. 845 00:35:17,560 --> 00:35:19,840 THESE ARE EXAMPLES HERE OF SOME 846 00:35:19,840 --> 00:35:24,600 OF THE AUTOANTIBODIES THAT ARE 847 00:35:24,600 --> 00:35:26,640 CURRENTLY WELL RECOGNIZED AND 848 00:35:26,640 --> 00:35:29,080 CLEARLY PATHOLOGIC. 849 00:35:29,080 --> 00:35:30,920 TO SUMMARIZE THIS PART OF MY 850 00:35:30,920 --> 00:35:32,640 TALK, JUST ANSWER THE PHONE. 851 00:35:32,640 --> 00:35:32,840 OKAY. 852 00:35:32,840 --> 00:35:34,840 ANSWER THE DAMN PHONE. 853 00:35:34,840 --> 00:35:35,960 IT IS NOT THAT HARD. 854 00:35:35,960 --> 00:35:37,320 IT IS NOT THAT PAINFUL. 855 00:35:37,320 --> 00:35:39,960 IT IS OKAY IF IT GOES TO 856 00:35:39,960 --> 00:35:40,600 VOICEMAIL. 857 00:35:40,600 --> 00:35:41,680 BUT TALK TO PEOPLE. 858 00:35:41,680 --> 00:35:44,000 AND IF YOU ANSWER THE PHONE 859 00:35:44,000 --> 00:35:44,920 ESPECIALLY FROM PEOPLE CALLING 860 00:35:44,920 --> 00:35:47,320 YOU UP BECAUSE THEY'VE GOT A 861 00:35:47,320 --> 00:35:48,880 PROBLEM, YOU'LL BE AMAZED WHAT 862 00:35:48,880 --> 00:35:51,040 THEY HAVE TO SAY TO YOU. 863 00:35:51,040 --> 00:35:52,480 THEY CALL YOU BECAUSE THEY HAVE 864 00:35:52,480 --> 00:35:52,880 A PROBLEM. 865 00:35:52,880 --> 00:35:54,240 SOMETIMES IT IS A PATIENT. 866 00:35:54,240 --> 00:35:56,360 SOMETIMES IT IS A DOCTOR. 867 00:35:56,360 --> 00:35:58,480 SOMETIMES IT'S SOMEBODY WHO IS 868 00:35:58,480 --> 00:35:59,560 LOOKING TO REFER THEM OUT. 869 00:35:59,560 --> 00:36:03,960 IT REALLY CAN BE TRANSFORMATIVE. 870 00:36:03,960 --> 00:36:05,800 COMPLETELY CHANGED MY LIFE. 871 00:36:05,800 --> 00:36:07,920 AND I WOULD ENCOURAGE YOU TO 872 00:36:07,920 --> 00:36:09,320 EMBRACE THE UNEXPECTED. 873 00:36:09,320 --> 00:36:11,240 THAT IS WHERE THE NOVELTY IS. 874 00:36:11,240 --> 00:36:13,480 THINGS THAT WORK OUT THE WAY YOU 875 00:36:13,480 --> 00:36:15,280 EXPECT, OKAY, FINE. 876 00:36:15,280 --> 00:36:17,960 THINGS THAT WORK OUT THE WAY YOU 877 00:36:17,960 --> 00:36:19,200 DON'T EXPECT, THAT IS WHERE THE 878 00:36:19,200 --> 00:36:21,800 FUN IS, THAT IS WHAT I HOPE WILL 879 00:36:21,800 --> 00:36:23,520 KEEP YOU UP AT NIGHT AND MAKE 880 00:36:23,520 --> 00:36:25,320 YOU GET INTERESTED IN DOING 881 00:36:25,320 --> 00:36:27,600 MORE. 882 00:36:27,600 --> 00:36:28,760 I CAN'T EMPHASIZE ENOUGH HOW 883 00:36:28,760 --> 00:36:30,280 IMPORTANT IT IS TO ADMIT TO THE 884 00:36:30,280 --> 00:36:32,120 HOSPITAL AND CARE FOR THE 885 00:36:32,120 --> 00:36:32,520 PATIENTS. 886 00:36:32,520 --> 00:36:33,760 I KNOW THERE IS A GENERAL 887 00:36:33,760 --> 00:36:35,800 FEELING THAT WE HAVE MOVED INTO 888 00:36:35,800 --> 00:36:37,640 A PHASE WHERE EVERYTHING CAN BE 889 00:36:37,640 --> 00:36:39,000 DONE OUTPATIENT. 890 00:36:39,000 --> 00:36:40,520 HIPS CAN BE REPLACED. 891 00:36:40,520 --> 00:36:41,960 KNEES CAN BE REPLACED. 892 00:36:41,960 --> 00:36:44,640 HEARTS CAN BE FIXED 893 00:36:44,640 --> 00:36:45,680 PREDOMINANTLY OUTPATIENT. 894 00:36:45,680 --> 00:36:47,280 IT IS AN EXTRAORDINARY WORLD. 895 00:36:47,280 --> 00:36:48,360 I GET THAT. 896 00:36:48,360 --> 00:36:50,880 IT IS ALSO A WORLD IN WHICH 897 00:36:50,880 --> 00:36:52,280 HOSPITALS ARE OVERWHELMED WITH 898 00:36:52,280 --> 00:36:53,560 SICK INPATIENTS. 899 00:36:53,560 --> 00:36:55,840 WE HAVE A HOSPITAL THAT CAN DO 900 00:36:55,840 --> 00:36:57,720 THAT AND WITHOUT REGARD FOR 901 00:36:57,720 --> 00:37:00,680 INSURANCE, FOR MONEY, FOR 902 00:37:00,680 --> 00:37:03,440 ETHNICITY, FOR LEGALITY OF 903 00:37:03,440 --> 00:37:04,240 RESIDE 904 00:37:04,240 --> 00:37:04,480 RESIDENCE. 905 00:37:04,480 --> 00:37:05,600 THIS IS AN OPPORTUNITY THAT YOU 906 00:37:05,600 --> 00:37:07,160 SHOULD TAKE ADVANTAGE OF. 907 00:37:07,160 --> 00:37:10,440 AND FINALLY, PLEASE BE 908 00:37:10,440 --> 00:37:10,720 SKEPTICAL. 909 00:37:10,720 --> 00:37:13,760 NOT OF ME, BUT PLEASE BE 910 00:37:13,760 --> 00:37:14,960 SKEPTICAL OF WHAT EXPLANATIONS 911 00:37:14,960 --> 00:37:17,200 PEOPLE GIVE YOU. 912 00:37:17,200 --> 00:37:19,000 WE ALL HAVE EXPLANATIONS THAT WE 913 00:37:19,000 --> 00:37:20,400 USE TO GET THROUGH ROUNDS, TO 914 00:37:20,400 --> 00:37:21,800 GET THROUGH THE AFTERNOON. 915 00:37:21,800 --> 00:37:25,640 MANY OF WHICH, SEE, EVEN HARRY 916 00:37:25,640 --> 00:37:27,360 POTTER KNOWS, MANY OF WHICH DO 917 00:37:27,360 --> 00:37:28,720 NOT HAPPEN TO BE CORRECT. 918 00:37:28,720 --> 00:37:31,160 AND WE HAVE A CHANCE HERE TO 919 00:37:31,160 --> 00:37:32,640 LEARN WHAT IS TRUE. 920 00:37:32,640 --> 00:37:33,040 OKAY. 921 00:37:33,040 --> 00:37:33,920 THE LAST COMPONENT I'M GOING TO 922 00:37:33,920 --> 00:37:40,440 TALK ABOUT IS A LITTLE BIT ABOUT 923 00:37:40,440 --> 00:37:44,160 WHAT NEUTRPHIS DO. 924 00:37:44,160 --> 00:37:47,640 THIS IS MY HOMAGE TO JOHN 925 00:37:47,640 --> 00:37:47,880 GALLIN. 926 00:37:47,880 --> 00:37:49,160 THEY HAVE A COMPLEX JOB. 927 00:37:49,160 --> 00:37:53,240 THEY HAVE TO ROLL ALONG THE 928 00:37:53,240 --> 00:37:57,200 ENDOTHELIUM WHERE THEY ARE 929 00:37:57,200 --> 00:37:59,120 CONSTANTLY WAITING FOR SOMEONE 930 00:37:59,120 --> 00:38:02,040 TO SAY, DINNER. 931 00:38:02,040 --> 00:38:09,400 WHEN THE NEUTROPHIL HEARS THAT 932 00:38:09,400 --> 00:38:13,720 CALL, IT PRODUCES SBEGRINS AND 933 00:38:13,720 --> 00:38:17,120 BINDS TO I CAMS AND GOES OUT 934 00:38:17,120 --> 00:38:20,160 INTO THE TISSUE. 935 00:38:20,160 --> 00:38:26,840 IF THE NUTROPHIL CAN'T STICK, IT 936 00:38:26,840 --> 00:38:28,720 CAN'T GET OUT AND IF IT CAN'T 937 00:38:28,720 --> 00:38:32,520 GET OUT, ALL HELL BREAKS LOOSE. 938 00:38:32,520 --> 00:38:43,400 THIS IS LEUKOCYTE DEFICIENDEFIC. 939 00:38:44,040 --> 00:38:46,200 WE HAVE A BIG INTEREST GOING 940 00:38:46,200 --> 00:38:47,400 BACK 40 YEARS. 941 00:38:47,400 --> 00:38:49,400 THIS IS LOOKING AT THE ABILITY 942 00:38:49,400 --> 00:38:55,160 OF A NUTROPHIL TO STICK TO A 943 00:38:55,160 --> 00:38:56,360 GLASS SLIDE. 944 00:38:56,360 --> 00:38:59,920 THIS IS WHAT IT DOES, I LOVE 945 00:38:59,920 --> 00:39:00,240 GLASS. 946 00:39:00,240 --> 00:39:02,120 THE PEOPLE WITH THE DEFICIENCY, 947 00:39:02,120 --> 00:39:03,400 THEY CAN'T DO THAT. 948 00:39:03,400 --> 00:39:05,000 THIS IS WHY GLASS SLIDES ARE 949 00:39:05,000 --> 00:39:06,960 SUCH AN ENDANGERED SPECIES. 950 00:39:06,960 --> 00:39:08,560 WHAT DOES THAT MEAN IN THE 951 00:39:08,560 --> 00:39:08,840 HUMAN? 952 00:39:08,840 --> 00:39:12,080 WHAT DOES THAT MEAN HERE? 953 00:39:12,080 --> 00:39:16,480 SO NUTROPHILS ARE REQUIRED FOR A 954 00:39:16,480 --> 00:39:18,520 WHOLE PILE OF THINGS. 955 00:39:18,520 --> 00:39:21,600 NOT ONLY TO MAKE THE UM BELL CAL 956 00:39:21,600 --> 00:39:23,880 CORD DETACH AFTER DELIVERY. 957 00:39:23,880 --> 00:39:25,760 IF THEY ARE NOT FUNCTIONING, YOU 958 00:39:25,760 --> 00:39:27,920 CAN'T GET THE UMBILICAL CORD TO 959 00:39:27,920 --> 00:39:30,280 DROP OFF SO IT STAYS ON EXTRA 960 00:39:30,280 --> 00:39:30,680 LONG. 961 00:39:30,680 --> 00:39:37,800 THAT IS TO REMIND YOU THAT 962 00:39:37,800 --> 00:39:41,760 NUTROPHIS ARE RESPONSIBLE FOR 963 00:39:41,760 --> 00:39:44,840 REMODELING TISSUE WITH SCABBING. 964 00:39:44,840 --> 00:39:47,160 THIS SCAB HAD BEEN ON HIS LEG 965 00:39:47,160 --> 00:39:47,680 FOR MONTHS. 966 00:39:47,680 --> 00:39:49,760 WE HAD TO GET A SURGEON TO TAKE 967 00:39:49,760 --> 00:39:50,520 IT OFF. 968 00:39:50,520 --> 00:39:52,080 ON THE OCCASION WHEN THE WOUNDS 969 00:39:52,080 --> 00:39:57,760 DO HEAL ON THEIR OWN, THEY GET A 970 00:39:57,760 --> 00:40:03,040 CHARACTERISTIC DYSMORPHIC. 971 00:40:03,040 --> 00:40:07,440 THIS IS REFERRED TO AS CIGARETTE 972 00:40:07,440 --> 00:40:09,280 PAPER SCARRING, WHICH MIGHT MEAN 973 00:40:09,280 --> 00:40:12,040 MORE TO CHILDREN OF THE 60s THAN 974 00:40:12,040 --> 00:40:13,440 YOU. 975 00:40:13,440 --> 00:40:14,440 THIS IS TYPICAL. 976 00:40:14,440 --> 00:40:19,280 IT IS SORT OF EMBODIED IN THIS 977 00:40:19,280 --> 00:40:22,400 PICK CHUR HERE FROM THE COLON OF 978 00:40:22,400 --> 00:40:25,240 A YOUNG MAN HAVING ACTIVE 979 00:40:25,240 --> 00:40:25,480 COLITIS. 980 00:40:25,480 --> 00:40:29,520 THESE ARE COLONIC GLANDS. 981 00:40:29,520 --> 00:40:39,960 HERE IS THE INTERSTIUM. 982 00:40:41,400 --> 00:40:43,640 THIS IS IN THE VASCULAR SPACE 983 00:40:43,640 --> 00:40:46,600 BUT NONE ARE GETTING OUT IN THE 984 00:40:46,600 --> 00:40:47,480 TISSUE. 985 00:40:47,480 --> 00:40:48,520 THIS IS THE FUNDAMENTAL PROBLEM. 986 00:40:48,520 --> 00:40:50,320 THEY KNOW THERE IS A PROBLEM, 987 00:40:50,320 --> 00:40:51,760 BUT THEY CAN'T GET THERE TO DEAL 988 00:40:51,760 --> 00:40:52,240 WITH IT. 989 00:40:52,240 --> 00:40:55,280 AND ONE OF THE CONSEQUENCES OF 990 00:40:55,280 --> 00:40:57,080 THIS DISEASE THAT REALLY LED ME, 991 00:40:57,080 --> 00:41:01,960 IT CHANGED THE WAY I THOUGHT 992 00:41:01,960 --> 00:41:05,760 ABOUT DISEASE IS THEIR TEETH. 993 00:41:05,760 --> 00:41:08,520 SO TYPICALLY THE GINGIVA IS 994 00:41:08,520 --> 00:41:11,600 WHERE LOTS OF THE INSIDE WORLD 995 00:41:11,600 --> 00:41:13,800 MEETS THE OUTSIDE WORLD. 996 00:41:13,800 --> 00:41:16,200 I DON'T MEAN JUST FLOSS. 997 00:41:16,200 --> 00:41:18,640 BACTERIA AND CELLS AND ALL SORTS 998 00:41:18,640 --> 00:41:21,360 OF THINGS COMING TOGETHER AND 999 00:41:21,360 --> 00:41:25,800 USUALLY PATIENTS WITH LEUKOCYTE 1000 00:41:25,800 --> 00:41:27,640 DEFICIENCY DISEASE LOSE ALL 1001 00:41:27,640 --> 00:41:30,760 THEIR TEETH IN LATE ADOLESCENTS. 1002 00:41:30,760 --> 00:41:33,320 THIS WOMAN AGE 18 HER TEETH WERE 1003 00:41:33,320 --> 00:41:35,720 SO UNCOMFORTABLE AND LOOSE, YOU 1004 00:41:35,720 --> 00:41:37,120 CAN SEE THEY ARE BARELY BEING 1005 00:41:37,120 --> 00:41:38,040 HELD IN. 1006 00:41:38,040 --> 00:41:40,280 SHE HAD TROUBLE EATING BECAUSE 1007 00:41:40,280 --> 00:41:43,240 HER TEETH WAS SO LOOSE AND 1008 00:41:43,240 --> 00:41:43,560 PAINFUL. 1009 00:41:43,560 --> 00:41:46,200 AFTER THIS PICTURE WAS TAKEN HER 1010 00:41:46,200 --> 00:41:48,760 TEETH WERE REMOVED AND SHE WAS 1011 00:41:48,760 --> 00:41:50,480 MORE COMFORTABLE AND WAS ABLE TO 1012 00:41:50,480 --> 00:41:51,640 DO MUCH BETTER. 1013 00:41:51,640 --> 00:41:51,920 OKAY. 1014 00:41:51,920 --> 00:41:53,800 THAT IS THE BACKGROUND. 1015 00:41:53,800 --> 00:41:56,040 WHAT WE THOUGHT WE KNEW ABOUT 1016 00:41:56,040 --> 00:41:59,760 THIS DISEASE IS NUTROPHILS ARE 1017 00:41:59,760 --> 00:42:00,240 ABUNDANT. 1018 00:42:00,240 --> 00:42:02,880 THEY ARE GETTING PLENTY OF 1019 00:42:02,880 --> 00:42:05,240 SIGNALS TO MAKE MORE, BUT CAN'T 1020 00:42:05,240 --> 00:42:08,400 GET IN THE TISSUE. 1021 00:42:08,400 --> 00:42:11,000 THEY SENSE THE SIGNALS BUT CAN'T 1022 00:42:11,000 --> 00:42:13,480 GET OUT. 1023 00:42:13,480 --> 00:42:20,720 PATIENTS HAVE TISSUE NUTROPENIA. 1024 00:42:20,720 --> 00:42:25,240 THAT LEADS TO RECURRING 1025 00:42:25,240 --> 00:42:27,240 INFECTIONS AND GINGIVITIS IN 1026 00:42:27,240 --> 00:42:27,960 PARTICULAR. 1027 00:42:27,960 --> 00:42:30,440 I RAN INTO SOMEBODY WHO WAS KIND 1028 00:42:30,440 --> 00:42:33,680 ENOUGH TO TELL ME WHY I WAS SO 1029 00:42:33,680 --> 00:42:34,280 MISGUIDED. 1030 00:42:34,280 --> 00:42:35,720 IF YOU CAN'T TRUST YOUR FRIENDS 1031 00:42:35,720 --> 00:42:37,560 AND COLLEAGUES TO TELL YOU WHEN 1032 00:42:37,560 --> 00:42:39,840 YOU GET IT WRONG, WHO ARE YOU 1033 00:42:39,840 --> 00:42:41,760 GOING TO TRUST? 1034 00:42:41,760 --> 00:42:44,680 TIKTOK? 1035 00:42:44,680 --> 00:42:45,120 NO. 1036 00:42:45,120 --> 00:42:46,160 THIS IS IMPORTANT THAT SOMEBODY 1037 00:42:46,160 --> 00:42:48,040 THINKS IT IS WORTH THEIR TIME TO 1038 00:42:48,040 --> 00:42:49,720 TRY TO EDUCATE YOU. 1039 00:42:49,720 --> 00:42:53,400 A TENURED INVESTIGATOR IN THE 1040 00:42:53,400 --> 00:42:55,120 DENTAL INSTITUTE SAID I THINK 1041 00:42:55,120 --> 00:42:57,360 YOU NEED TO REASSESS WHAT IS 1042 00:42:57,360 --> 00:43:07,800 GOING ON IN ORAL DISEASE. 1043 00:43:09,680 --> 00:43:11,080 IT CULMINATED IN THIS. 1044 00:43:11,080 --> 00:43:13,000 WE DIDN'T TEACH MICE HOW TO 1045 00:43:13,000 --> 00:43:13,720 BRUSH. 1046 00:43:13,720 --> 00:43:15,120 THEY ALREADY KNEW HOW. 1047 00:43:15,120 --> 00:43:16,520 EXPERIMENTS YOU DO IN MICE HAVE 1048 00:43:16,520 --> 00:43:18,280 TO BE DONE IN HUMANS IN ORDER TO 1049 00:43:18,280 --> 00:43:22,160 MAKE SURE THEY MAKE SENSE. 1050 00:43:22,160 --> 00:43:24,480 WHAT NIKI WORKED OUT BEFORE WE 1051 00:43:24,480 --> 00:43:28,240 GOT TO THE PATIENT GOES LIKE 1052 00:43:28,240 --> 00:43:28,440 THIS. 1053 00:43:28,440 --> 00:43:31,880 NEUTROPHILS ARE IN THE BLOOD 1054 00:43:31,880 --> 00:43:32,320 VES 1055 00:43:32,320 --> 00:43:35,360 VESSEL. 1056 00:43:35,360 --> 00:43:37,320 MACROPHAGES ARE IN THE TISSUE 1057 00:43:37,320 --> 00:43:40,800 CONSTANTLY SAYING I WANT TO EAT 1058 00:43:40,800 --> 00:43:41,680 A NEUTROPHIL. 1059 00:43:41,680 --> 00:43:44,480 THEY PRODUCE A CYTOKINE THAT 1060 00:43:44,480 --> 00:43:49,200 ACTS ON T-CELLS TO PRODUCE AISLE 1061 00:43:49,200 --> 00:43:51,680 17 THAT LEADS TO GCSF, WHICH 1062 00:43:51,680 --> 00:43:53,480 DRIVES UP THE PRODUCTION OF 1063 00:43:53,480 --> 00:43:53,760 NEUTROPHILS. 1064 00:43:53,760 --> 00:43:56,720 IT HAPPENS TO LEAD TO BONE LOSS 1065 00:43:56,720 --> 00:43:58,480 AND INFLAMMATION. 1066 00:43:58,480 --> 00:44:03,720 SO WHEN MACROPHAGES ARE BEING 1067 00:44:03,720 --> 00:44:05,800 SATISFIED, BY GETTING A 1068 00:44:05,800 --> 00:44:08,440 NEUTROPHIL OUT IN THE TISSUE, 1069 00:44:08,440 --> 00:44:10,840 THEY STOP MAKING IL23. 1070 00:44:10,840 --> 00:44:15,160 THEY STOP MAKING IL17 AND 1071 00:44:15,160 --> 00:44:17,280 INFLAMMATION SHUTS OFF AND THE 1072 00:44:17,280 --> 00:44:20,120 DRIVING FORCE TO PRODUCE MORE 1073 00:44:20,120 --> 00:44:21,760 NEUTROPHILS GETS SHUT OFF. 1074 00:44:21,760 --> 00:44:24,920 WHY DO I TELL YOU? 1075 00:44:24,920 --> 00:44:29,240 IN LEUKOCYTE DEFICIENT, THEY 1076 00:44:29,240 --> 00:44:31,200 CAN'T GET OUT. 1077 00:44:31,200 --> 00:44:37,400 SO A MACROPHAGE IS HANGRY. 1078 00:44:37,400 --> 00:44:47,880 I WANT MINUTE -- I WANT MY 1079 00:44:48,840 --> 00:44:49,760 NEUTROPHIL. 1080 00:44:49,760 --> 00:44:53,760 IT GENERATES IL27, TO GENERATE 1081 00:44:53,760 --> 00:44:57,680 MORE IL17 AND LEADS TO MORE 1082 00:44:57,680 --> 00:44:59,200 INFLAMMATION AND IN THE SETTING 1083 00:44:59,200 --> 00:45:01,080 OF THE TEETH MORE BONE LOSS. 1084 00:45:01,080 --> 00:45:02,800 SO WHY AM I TELLS YOU THIS 1085 00:45:02,800 --> 00:45:03,000 STORY? 1086 00:45:03,000 --> 00:45:07,720 I WAS AT A MEETING IN ITALY AND 1087 00:45:07,720 --> 00:45:10,000 I WAS SORT OF APPROACHED BY A 1088 00:45:10,000 --> 00:45:12,000 YOUNG MAN AND HIS PARENTS. 1089 00:45:12,000 --> 00:45:20,160 AND THIS YOUNG MAN SAID I HAVE 1090 00:45:20,160 --> 00:45:25,000 LEUKOCYTE DEFICIENCY. 1091 00:45:25,000 --> 00:45:27,160 MY DENTIST SAID I SHOULD HAVE 1092 00:45:27,160 --> 00:45:29,040 ALL MY TEETH EXTRACTED. 1093 00:45:29,040 --> 00:45:33,760 HE LOOKED AT ME VERY SINCERELY 1094 00:45:33,760 --> 00:45:35,120 AND SAID, DO YOU KNOW HOW HARD 1095 00:45:35,120 --> 00:45:37,680 IT IS TO DATE WITH NO TEETH? 1096 00:45:37,680 --> 00:45:39,760 THAT IS WHAT HAD HIM WORRIED. 1097 00:45:39,760 --> 00:45:41,400 I SAID, I CAN IDENTIFY WITH 1098 00:45:41,400 --> 00:45:41,600 THAT. 1099 00:45:41,600 --> 00:45:43,800 AND THAT WAS REALLY ALL HE 1100 00:45:43,800 --> 00:45:46,920 WORRIED ABOUT. 1101 00:45:46,920 --> 00:45:49,200 AND SO OVER THE COURSE OF 1102 00:45:49,200 --> 00:45:51,120 SEVERAL MONTHS WE CORRESPONDED. 1103 00:45:51,120 --> 00:45:54,160 THIS IS WHAT HIS TEETH LOOKED 1104 00:45:54,160 --> 00:45:54,440 LIKE. 1105 00:45:54,440 --> 00:45:58,520 THIS PANOREX, YOU CAN SEE THE 1106 00:45:58,520 --> 00:46:00,360 BLUE LINE IS WHERE HIS BONE 1107 00:46:00,360 --> 00:46:02,680 OUGHT TO BE TO HOLD HIS TEETH IN 1108 00:46:02,680 --> 00:46:03,680 PLACE IN HIS JAW. 1109 00:46:03,680 --> 00:46:05,760 THE WHITE LINE IS WHERE THE BONE 1110 00:46:05,760 --> 00:46:06,720 ACTUALLY IS. 1111 00:46:06,720 --> 00:46:10,480 HERE ON THESE BITE WING SHOTS 1112 00:46:10,480 --> 00:46:12,600 THAT YOU SEE HERE YOU CAN SEE 1113 00:46:12,600 --> 00:46:16,880 HOW THE BONE IS COMPLETELY 1114 00:46:16,880 --> 00:46:17,880 RESORBED AND THE TEETH IS HELD 1115 00:46:17,880 --> 00:46:20,440 BY THE GUM SO WHEN HE CHEWS, IT 1116 00:46:20,440 --> 00:46:21,920 IS HARD. 1117 00:46:21,920 --> 00:46:24,040 SO WE EVENTUALLY THOUGHT THAT WE 1118 00:46:24,040 --> 00:46:25,960 HAD ENOUGH DATA TO REALLY BRING 1119 00:46:25,960 --> 00:46:30,480 HIM OVER HERE AND TO TRY TO WORK 1120 00:46:30,480 --> 00:46:34,640 ON GETTING HIS TEETH FIXED UP. 1121 00:46:34,640 --> 00:46:36,440 AND WHEN HE CAME, THIS IS WHAT 1122 00:46:36,440 --> 00:46:37,600 HIS TEETH LOOKED LIKE. 1123 00:46:37,600 --> 00:46:40,600 WHAT YOU SEE IS THE GUMS ARE 1124 00:46:40,600 --> 00:46:42,000 INFLAMED AND VERY RED. 1125 00:46:42,000 --> 00:46:45,280 YOU CAN SEE SOME RECESSION WITH 1126 00:46:45,280 --> 00:46:47,080 A FAIR AMOUNT OF PLAQUE BUILDUP. 1127 00:46:47,080 --> 00:46:50,240 WHEN NIKI GOT SAMPLES FROM HIS 1128 00:46:50,240 --> 00:46:52,000 GUMS, THIS IS WHAT SHE FOUND. 1129 00:46:52,000 --> 00:46:55,160 THAT JUST AS WE WOULD HAVE 1130 00:46:55,160 --> 00:46:57,760 PREDICTED, HIS LEVELS OF IL23 1131 00:46:57,760 --> 00:47:03,040 AND IL17 IN THE TISSUE WERE 1132 00:47:03,040 --> 00:47:04,680 ELEVATED, EXACTLY WHAT WE WOULD 1133 00:47:04,680 --> 00:47:06,160 PREDICT FOR LAD1. 1134 00:47:06,160 --> 00:47:07,920 HE HAS AN INFLAMMATORY REACTION 1135 00:47:07,920 --> 00:47:11,760 IN RESPONSE TO THE INABILITY OF 1136 00:47:11,760 --> 00:47:13,080 HIS NEUTROPHILS TO GET OUT IN 1137 00:47:13,080 --> 00:47:15,000 THE TISSUE AND THAT IS DRIVING A 1138 00:47:15,000 --> 00:47:16,480 LOT OF THE INFLAMMATION. 1139 00:47:16,480 --> 00:47:17,000 OKAY. 1140 00:47:17,000 --> 00:47:18,560 THAT SEEMED STRAIGHT FORWARD. 1141 00:47:18,560 --> 00:47:19,800 WHAT WE DIDN'T EXPECT WAS THAT 1142 00:47:19,800 --> 00:47:22,960 WHEN WE ACTUALLY WENT TO EXAMINE 1143 00:47:22,960 --> 00:47:26,200 THE PATIENT, WHAT HE DIDN'T EVEN 1144 00:47:26,200 --> 00:47:28,800 TELL US ABOUT WAS THAT FOR TWO 1145 00:47:28,800 --> 00:47:34,360 YEARS HE HAD THIS WOUND ON HIS 1146 00:47:34,360 --> 00:47:35,000 SACRUM. 1147 00:47:35,000 --> 00:47:40,400 HE SAID HE GOT IT WHILE RIDING A 1148 00:47:40,400 --> 00:47:41,200 MOTORBIKE. 1149 00:47:41,200 --> 00:47:43,000 IT WAS GETTING WORSE. 1150 00:47:43,000 --> 00:47:45,720 HE HAD SEVERAL SURGERIES AND HE 1151 00:47:45,720 --> 00:47:48,360 WAS ON ANTIBIOTICS. 1152 00:47:48,360 --> 00:47:50,160 HE DIDN'T MENTION THAT. 1153 00:47:50,160 --> 00:47:51,960 THAT DIDN'T WORRY HIM BECAUSE HE 1154 00:47:51,960 --> 00:47:53,400 THOUGHT HE COULD HANDLE THAT. 1155 00:47:53,400 --> 00:47:55,560 WE WERE A LITTLE SURPRISED, JUST 1156 00:47:55,560 --> 00:47:59,040 TO BE HONEST, HE HAD NOT THOUGHT 1157 00:47:59,040 --> 00:48:00,600 THIS WAS WORTH MENTIONS. 1158 00:48:00,600 --> 00:48:03,400 ALL HE WANTED TO TALK ABOUT WAS 1159 00:48:03,400 --> 00:48:04,680 HIS ORAL HEALTH PROBLEMS. 1160 00:48:04,680 --> 00:48:06,400 SO WE STARTED TO SAY, OKAY, NOW 1161 00:48:06,400 --> 00:48:08,440 WE HAVE A BIGGER PROBLEM THAN WE 1162 00:48:08,440 --> 00:48:08,760 THOUGHT. 1163 00:48:08,760 --> 00:48:12,560 AND WE REASONED THAT IF THIS 1164 00:48:12,560 --> 00:48:14,440 MECHANISM ABOUT NEUTROPHIL 1165 00:48:14,440 --> 00:48:17,400 INABILITY TO SATISFY THE 1166 00:48:17,400 --> 00:48:19,640 MACROPHAGE WAS A PROBLEM, WE HAD 1167 00:48:19,640 --> 00:48:21,560 OVERPRODUCTION OF IL23 AND THAT 1168 00:48:21,560 --> 00:48:23,400 WAS LEADING TO INFLAMMATION AND 1169 00:48:23,400 --> 00:48:25,800 THE WAY WE ARE GOING TO ADDRESS 1170 00:48:25,800 --> 00:48:29,800 THIS IS TO BLOCK IL23 1171 00:48:29,800 --> 00:48:30,720 SIGNALLING. 1172 00:48:30,720 --> 00:48:37,400 SO THE ANTIBODY USTEKINUMAB IS 1173 00:48:37,400 --> 00:48:47,920 USED FOR PSOARIASIS AND WE USED 1174 00:48:50,040 --> 00:48:52,760 THAT TO TREAT HIS INFLAMMATION. 1175 00:48:52,760 --> 00:48:55,200 IN THE COURSE OF 10 MONTHS, HIS 1176 00:48:55,200 --> 00:48:56,000 TEETH IMPROVED. 1177 00:48:56,000 --> 00:48:58,560 YOU CAN SEE THE REDUCTION IN 1178 00:48:58,560 --> 00:48:59,800 PLAQUE AND IMPROVEMENT IN GUM 1179 00:48:59,800 --> 00:49:00,040 HEALTH. 1180 00:49:00,040 --> 00:49:02,680 THIS IS THE AMOUNT OF BLEEDING 1181 00:49:02,680 --> 00:49:04,200 THAT HAPPENED WHEN PEOPLE WOULD 1182 00:49:04,200 --> 00:49:06,520 PROBE THE GUM TO SEE HOW 1183 00:49:06,520 --> 00:49:09,040 INFLAMED IT WAS. 1184 00:49:09,040 --> 00:49:10,320 REALLY DRAMATIC IMPROVEMENT. 1185 00:49:10,320 --> 00:49:14,880 OF COURSE, WHAT WE WERE MORE 1186 00:49:14,880 --> 00:49:19,360 INTERESTED IN WAS WHAT WAS GOING 1187 00:49:19,360 --> 00:49:23,880 ON ON HIS BACKSIDE. 1188 00:49:23,880 --> 00:49:26,240 AFTER 16 MONTHS, HIS WOUND 1189 00:49:26,240 --> 00:49:27,960 HEALED UP ENTIRELY AND HE WAS 1190 00:49:27,960 --> 00:49:30,000 ABLE TO GO BACK AND FINISH NOW 1191 00:49:30,000 --> 00:49:33,800 HIS GRADUATE DEGREE. 1192 00:49:33,800 --> 00:49:36,800 SO WE WERE ABLE TO PUBLISH THIS 1193 00:49:36,800 --> 00:49:39,720 AS A SINGLE CASE REPORT BECAUSE 1194 00:49:39,720 --> 00:49:41,600 IT ILLUSTRATED ELEMENTS OF 1195 00:49:41,600 --> 00:49:44,680 MECHANISM, PATHOPHYSIOLOGY AND 1196 00:49:44,680 --> 00:49:44,960 TREATMENT. 1197 00:49:44,960 --> 00:49:47,480 THAT HAS LED US GO ON TO DEVELOP 1198 00:49:47,480 --> 00:49:50,720 A PROSPECTIVE TRIAL IN WHICH WE 1199 00:49:50,720 --> 00:49:52,200 HAVE TREATED SIX PATIENTS. 1200 00:49:52,200 --> 00:49:54,520 IT IS A VERY RARE DISEASE, BUT 1201 00:49:54,520 --> 00:49:57,440 IT TAUGHT US A LOT IN TERMS OF 1202 00:49:57,440 --> 00:50:00,760 ORAL INFLAMMATION AND ORAL 1203 00:50:00,760 --> 00:50:00,960 HEALTH. 1204 00:50:00,960 --> 00:50:02,720 PART 3 AND I'M ALMOST DONE HERE. 1205 00:50:02,720 --> 00:50:06,880 WHEN ALL ELSE FAILS, AS THE 1206 00:50:06,880 --> 00:50:08,160 ADDAGE GOES, EXAMINE THE 1207 00:50:08,160 --> 00:50:08,440 PATIENT. 1208 00:50:08,440 --> 00:50:11,000 IT IS AMAZING WHAT YOU CAN FIND. 1209 00:50:11,000 --> 00:50:12,480 AT LEAST WHAT I FIND WITH MANY 1210 00:50:12,480 --> 00:50:15,240 TRAINEES, THEY FORGET THAT THERE 1211 00:50:15,240 --> 00:50:16,960 IS ACTUALLY, OF COURSE, AND IT 1212 00:50:16,960 --> 00:50:19,560 IS EASY WHEN EVERYONE IS WEARING 1213 00:50:19,560 --> 00:50:20,280 A MASK. 1214 00:50:20,280 --> 00:50:21,680 THERE IS AN ORAL CAVITY. 1215 00:50:21,680 --> 00:50:24,000 IT IS WORTH TAKING A LOOK IN 1216 00:50:24,000 --> 00:50:24,200 THERE. 1217 00:50:24,200 --> 00:50:26,520 IT HAS FASCINATING THINGS IN 1218 00:50:26,520 --> 00:50:26,760 THERE. 1219 00:50:26,760 --> 00:50:29,920 TEETH, TONSILS, TONGUE, THE 1220 00:50:29,920 --> 00:50:36,120 WHOLE AREA BELOW THE NAVEL THAT 1221 00:50:36,120 --> 00:50:39,320 NO ONE WANTS TO EXPLORE, BUT IT 1222 00:50:39,320 --> 00:50:41,400 IS ALSO WHERE PEOPLE HIDE 1223 00:50:41,400 --> 00:50:41,920 EMBARRASSMENT. 1224 00:50:41,920 --> 00:50:43,240 THIS IS WHAT HAPPENED IN THIS 1225 00:50:43,240 --> 00:50:45,000 YOUNG MAN'S CASE. 1226 00:50:45,000 --> 00:50:46,360 HE DIDN'T WANT TO TELL PEOPLE 1227 00:50:46,360 --> 00:50:49,040 WHAT WAS GOING ON BECAUSE HE WAS 1228 00:50:49,040 --> 00:50:49,800 EMBARRASSED ABOUT IT. 1229 00:50:49,800 --> 00:50:51,800 ONLY BECAUSE WE WERE ABLE TO 1230 00:50:51,800 --> 00:50:52,920 DEAL WITH THAT WERE WE ABLE TO 1231 00:50:52,920 --> 00:50:54,080 HELP HIM. 1232 00:50:54,080 --> 00:50:56,640 I ENCOURAGE YOU TO DARE TO 1233 00:50:56,640 --> 00:50:57,600 RETHINK THE PROBLEM. 1234 00:50:57,600 --> 00:51:00,280 IF A PROBLEM PERSISTS FOR A LONG 1235 00:51:00,280 --> 00:51:01,760 TIME IT COULD SIMPLY BE YOU HAVE 1236 00:51:01,760 --> 00:51:03,560 THE WRONG HYPOTHESIS. 1237 00:51:03,560 --> 00:51:09,760 MAN, I HAVE HAD SO MANY WRONG 1238 00:51:09,760 --> 00:51:14,560 HIYPOTH 1239 00:51:14,560 --> 00:51:15,200 HYPOTH 1240 00:51:15,200 --> 00:51:15,480 HYPOTHESIS. 1241 00:51:15,480 --> 00:51:17,320 F IF YOU DON'T SAY COULD I 1242 00:51:17,320 --> 00:51:19,240 EXPLORE THOSE BETTER, YOU WON'T 1243 00:51:19,240 --> 00:51:21,800 HAVE THE OPPORTUNITY TO DO IT. 1244 00:51:21,800 --> 00:51:25,520 FINALLY, I URGE YOU TO GET 1245 00:51:25,520 --> 00:51:27,080 COMFORTABLE WITH ERROR. 1246 00:51:27,080 --> 00:51:29,080 YOU ARE HERE BECAUSE YOU ARE 1247 00:51:29,080 --> 00:51:31,840 UNSATISFIED WITH THE MAY 1248 00:51:31,840 --> 00:51:32,720 MEDICINE IS TODAY. 1249 00:51:32,720 --> 00:51:35,120 IF YOU ARE NOT UNSATISFIED, YOU 1250 00:51:35,120 --> 00:51:37,080 ARE NOT PAYING ATTENTION. 1251 00:51:37,080 --> 00:51:39,240 THERE IS PLENTY THAT AIN'T GOING 1252 00:51:39,240 --> 00:51:39,560 GOOD. 1253 00:51:39,560 --> 00:51:42,280 YOUR JOB IS TO MAKE SURE THE 1254 00:51:42,280 --> 00:51:44,640 STUPID THINGS I TOLD YOU GET 1255 00:51:44,640 --> 00:51:44,880 UNTOLD. 1256 00:51:44,880 --> 00:51:46,400 THE SMART THINGS YOU HAVE TO BE 1257 00:51:46,400 --> 00:51:47,120 NICE ABOUT. 1258 00:51:47,120 --> 00:51:48,240 PAY ATTENTION. 1259 00:51:48,240 --> 00:51:49,680 WE HAVE A LOT WRONG AND YOU ARE 1260 00:51:49,680 --> 00:51:51,720 HERE TO GET IT RIGHT. 1261 00:51:51,720 --> 00:51:53,720 DON'T LET THE FEAR OF BEING 1262 00:51:53,720 --> 00:51:55,520 WRONG GET IN THE WAY. 1263 00:51:55,520 --> 00:51:58,680 SOMETIMES YOU JUST ARE WRONG. 1264 00:51:58,680 --> 00:52:01,520 AND SOMETIMES YOU HAVE TO SAY 1265 00:52:01,520 --> 00:52:02,520 THAT, TO YOURSELF, YOUR 1266 00:52:02,520 --> 00:52:04,400 COLLEAGUES AND SOMETIMES TO YOUR 1267 00:52:04,400 --> 00:52:04,680 PATIENTS. 1268 00:52:04,680 --> 00:52:06,320 THOSE ARE HARD CONVERSATIONS AND 1269 00:52:06,320 --> 00:52:07,880 YET IF YOU DON'T GO IN TO SAY 1270 00:52:07,880 --> 00:52:11,440 THAT WHEN IT HAPPENS, TO SAY, 1271 00:52:11,440 --> 00:52:13,000 YOU KNOW, THAT WAS A MISTAKE. 1272 00:52:13,000 --> 00:52:14,200 WE HAD THE WRONG IDEA. 1273 00:52:14,200 --> 00:52:15,480 WE HAVE TO DO SOMETHING 1274 00:52:15,480 --> 00:52:16,160 DIFFERENT. 1275 00:52:16,160 --> 00:52:18,360 IT IS MUCH EASIER TO MAKE SURE 1276 00:52:18,360 --> 00:52:19,960 THEY ARE ON YOUR SIDE WHEN YOU 1277 00:52:19,960 --> 00:52:21,320 ARE ON THEIR SIDE AND THEY KNOW 1278 00:52:21,320 --> 00:52:25,400 YOU ARE WILLING TO MAKE THAT 1279 00:52:25,400 --> 00:52:25,640 SACRIFICE. 1280 00:52:25,640 --> 00:52:25,840 OKAY. 1281 00:52:25,840 --> 00:52:28,640 SO I'M GOING TO STOP HERE AND 1282 00:52:28,640 --> 00:52:31,240 JUST SAY CLINICAL MEDICINE 1283 00:52:31,240 --> 00:52:34,120 REALLY IS A TEAM SPORT AND I 1284 00:52:34,120 --> 00:52:35,560 CERTAINLY DON'T TO GET TO DO ANY 1285 00:52:35,560 --> 00:52:37,280 OF THIS ON MY OWN. 1286 00:52:37,280 --> 00:52:38,680 THERE ARE A LOT OF EXTRAORDINARY 1287 00:52:38,680 --> 00:52:41,120 INDIVIDUALS WHO HAVE MADE THE 1288 00:52:41,120 --> 00:52:42,720 CLINICAL CARE THE BASIC 1289 00:52:42,720 --> 00:52:44,480 OBSERVATIONS, THE SCIENCE 1290 00:52:44,480 --> 00:52:44,840 POSSIBLE. 1291 00:52:44,840 --> 00:52:47,800 AND I REALLY COULD NOT DO IT 1292 00:52:47,800 --> 00:52:48,440 WITHOUT THIS TEAM. 1293 00:52:48,440 --> 00:52:50,440 I HAVE TRIED TO ACKNOWLEDGE SOME 1294 00:52:50,440 --> 00:52:52,160 OF THEM AS WE HAVE GONE ALONG 1295 00:52:52,160 --> 00:52:54,440 AND I WANT TO MAKE SURE I SHOW 1296 00:52:54,440 --> 00:52:55,200 YOU WHO THEY ARE. 1297 00:52:55,200 --> 00:52:56,720 BECAUSE I KNOW YOU ARE GOING TO 1298 00:52:56,720 --> 00:52:57,240 SEE THEM. 1299 00:52:57,240 --> 00:52:59,360 NOW THEY ARE NOT WEARING MASKS 1300 00:52:59,360 --> 00:53:01,480 AND NEITHER ARE YOU, YOU MIGHT 1301 00:53:01,480 --> 00:53:03,680 EVEN RECOGNIZE THEM. 1302 00:53:03,680 --> 00:53:05,240 I'M GOING TO CONCLUDE BY SAYING, 1303 00:53:05,240 --> 00:53:07,080 YOU KNOW, IN MY CAREER I HAVE 1304 00:53:07,080 --> 00:53:10,720 LEARNED A LOT FROM MY MISTAKES. 1305 00:53:10,720 --> 00:53:12,960 AND I'M SURE I WILL MAKE MANY 1306 00:53:12,960 --> 00:53:13,320 MORE. 1307 00:53:13,320 --> 00:53:15,400 AND I REALLY DO HOPE THAT YOU 1308 00:53:15,400 --> 00:53:16,520 HAVE THE CHANCE TO AS WELL. 1309 00:53:16,520 --> 00:53:19,280 AND THAT YOU GET THE OPPORTUNITY 1310 00:53:19,280 --> 00:53:20,440 TO RECOGNIZE THE THINGS YOU DID 1311 00:53:20,440 --> 00:53:22,520 RIGHT AND THE THINGS YOU DID 1312 00:53:22,520 --> 00:53:22,960 WRONG. 1313 00:53:22,960 --> 00:53:25,240 BECAUSE THAT'S REALLY WHERE THE 1314 00:53:25,240 --> 00:53:29,400 OPPORTUNITIES FOR GROWTH AND FOR 1315 00:53:29,400 --> 00:53:30,440 DEVELOPMENT ARE. 1316 00:53:30,440 --> 00:53:32,200 AND THERE WILL BE PLENTY OF 1317 00:53:32,200 --> 00:53:34,040 PEOPLE WHO WANT TO POINT THEM 1318 00:53:34,040 --> 00:53:35,600 OUT TO YOU. 1319 00:53:35,600 --> 00:53:38,600 IT IS NOT SO VALUABLE WHEN 1320 00:53:38,600 --> 00:53:40,280 SOMEONE ELSE POINTS IT OUT. 1321 00:53:40,280 --> 00:53:42,160 IT IS REALLY VALUABLE TO FIGURE 1322 00:53:42,160 --> 00:53:43,480 IT OUT ON YOUR OWN. 1323 00:53:43,480 --> 00:53:44,440 I HOPE YOU HAVE THE OPPORTUNITY 1324 00:53:44,440 --> 00:53:45,280 TO DO THAT. 1325 00:53:45,280 --> 00:53:46,960 I WELCOME YOU TO THE NIH. 1326 00:53:46,960 --> 00:53:49,440 I LOOK FORWARD TO INTERACTING 1327 00:53:49,440 --> 00:53:52,080 WITH YOU ON THE WARDS, THE UNITS 1328 00:53:52,080 --> 00:53:53,760 AND LABORATORIES FOR YEARS TO 1329 00:53:53,760 --> 00:53:53,960 COME. 1330 00:53:53,960 --> 00:53:54,200 THANK YOU. 1331 00:53:54,200 --> 00:53:55,920 [ APPLAUSE ] 1332 00:53:55,920 --> 00:53:57,720 >>THANK YOU SO MUCH FOR 1333 00:53:57,720 --> 00:53:57,920 YOUR TALK. 1334 00:53:57,920 --> 00:53:59,920 IT WAS VERY INTERESTING. 1335 00:53:59,920 --> 00:54:03,520 MY QUESTION WAS ABOUT THE 1336 00:54:03,520 --> 00:54:04,880 SECOND -- YOUR SECOND PART WITH 1337 00:54:04,880 --> 00:54:08,720 THE OLDER PATIENTS WHO HAD 1338 00:54:08,720 --> 00:54:09,120 AUTOANTIBODIES. 1339 00:54:09,120 --> 00:54:13,400 WERE YOU ABLE TO LOOK AT KIND OF 1340 00:54:13,400 --> 00:54:17,160 HOMOLOGOUS STRUCTURES AND THE 1341 00:54:17,160 --> 00:54:18,960 EPITOPES THESE ANTIBODIES WERE 1342 00:54:18,960 --> 00:54:21,080 TARGETING WITH OTHER PATHOGENS 1343 00:54:21,080 --> 00:54:22,800 TO SEE WHAT PATHOGEN MAY HAVE 1344 00:54:22,800 --> 00:54:30,960 BEEN INFECTED WITH TO PROVOKE? 1345 00:54:30,960 --> 00:54:31,440 >>GREAT QUESTION. 1346 00:54:31,440 --> 00:54:37,440 THIS IS A DISEASE THAT IS FOR 1347 00:54:37,440 --> 00:54:39,120 THE INTERFERON GAMMA ANTIBODIES, 1348 00:54:39,120 --> 00:54:41,720 THIS IS A DISEASE THAT IS ALMOST 1349 00:54:41,720 --> 00:54:43,160 EXCLUSIVE TO PEOPLE IN SOUTHEAST 1350 00:54:43,160 --> 00:54:43,920 ASIA. 1351 00:54:43,920 --> 00:54:46,600 SOUTHERN CHINA, VIETNAM, 1352 00:54:46,600 --> 00:54:49,440 CAMBODIA, LAOS AND SO ON. 1353 00:54:49,440 --> 00:54:51,360 AS YOU MIGHT EXPECT, WHEN YOU 1354 00:54:51,360 --> 00:54:55,040 GET INTO REGIONS YOU GET INTO 1355 00:54:55,040 --> 00:54:56,800 CERTAIN GENETIC CLUSTERS. 1356 00:54:56,800 --> 00:54:59,120 THIS IS AN HLA. 1357 00:54:59,120 --> 00:55:03,040 THERE ARE TWO PARTICULAR HLA 1358 00:55:03,040 --> 00:55:03,280 ALLELES. 1359 00:55:03,280 --> 00:55:07,400 THE ARGUMENT RUNS THE LAST 10 1360 00:55:07,400 --> 00:55:11,320 AMINO ACIDS ARE IDENTICAL TO 1361 00:55:11,320 --> 00:55:16,200 AMINO ACIDS IN A GENE -- SO 1362 00:55:16,200 --> 00:55:17,840 THEIR ARGUMENT, WHICH I THINK IS 1363 00:55:17,840 --> 00:55:19,600 A GOOD ARGUMENT, PEOPLE ARE 1364 00:55:19,600 --> 00:55:23,360 GETTING EXPOSED TO THE NOCT-2 1365 00:55:23,360 --> 00:55:25,800 GENE AND ARE DEVELOPING 1366 00:55:25,800 --> 00:55:27,920 ANTIBODIES AGAINST NOC-2. 1367 00:55:27,920 --> 00:55:30,200 THAT CROSS REACTS WITH 1368 00:55:30,200 --> 00:55:33,200 INTERFERON GAMMA AND IS LEADING 1369 00:55:33,200 --> 00:55:33,600 TO NEUTRALIZATION. 1370 00:55:33,600 --> 00:55:35,120 I THINK THAT IS A GOOD ARGUMENT. 1371 00:55:35,120 --> 00:55:37,320 SOME OF THE FLAWS OR THE 1372 00:55:37,320 --> 00:55:40,560 FASCINATING THINGS, IT IS ALMOST 1373 00:55:40,560 --> 00:55:43,240 EXCLUSIVELY SOUTHEAST ASIANS. 1374 00:55:43,240 --> 00:55:43,440 OKAY. 1375 00:55:43,440 --> 00:55:45,120 IN SOUTHEAST ASIA THE RATE OF 1376 00:55:45,120 --> 00:55:48,840 MALES AND FEMALES IS ABOUT 1377 00:55:48,840 --> 00:55:49,040 EQUAL. 1378 00:55:49,040 --> 00:55:50,520 ONCE PEOPLE LEAVE SOUTHEAST 1379 00:55:50,520 --> 00:55:53,320 ASIA, IT IS ALMOST EXCLUSIVELY 1380 00:55:53,320 --> 00:55:53,640 WOMEN. 1381 00:55:53,640 --> 00:55:55,760 THAT IS A LITTLE FUNNY. 1382 00:55:55,760 --> 00:55:57,720 AND PEOPLE OF THE SAME ETHNICITY 1383 00:55:57,720 --> 00:55:59,320 BORN IN OTHER COUNTRIES DON'T 1384 00:55:59,320 --> 00:56:00,920 SEEM TO GET IT. 1385 00:56:00,920 --> 00:56:03,720 SO THAT SUGGESTS THAT THERE IS A 1386 00:56:03,720 --> 00:56:06,000 GENETIC COMPONENT, A GEOGRAPHIC 1387 00:56:06,000 --> 00:56:07,800 COMPONENT, COULD BE AN EXPOSURE. 1388 00:56:07,800 --> 00:56:10,560 AND THEN THERE IS A GENDER 1389 00:56:10,560 --> 00:56:10,840 COMPONENT. 1390 00:56:10,840 --> 00:56:12,240 I DON'T UNDERSTAND IT, BUT THAT 1391 00:56:12,240 --> 00:56:14,480 IS THE ARGUMENT AROUND WHAT IS 1392 00:56:14,480 --> 00:56:17,080 REALLY GOING ON IN TERMS OF THE 1393 00:56:17,080 --> 00:56:17,320 MIMICRY. 1394 00:56:17,320 --> 00:56:18,320 >>VERY COOL. 1395 00:56:18,320 --> 00:56:19,080 THANK YOU. 1396 00:56:19,080 --> 00:56:19,680 >>SURE. 1397 00:56:19,680 --> 00:56:21,240 >>HI DR. HOLLAND. 1398 00:56:21,240 --> 00:56:22,760 THANK YOU SO MUCH FOR THE TALK. 1399 00:56:22,760 --> 00:56:24,720 THIS IS MORE OF A GENERAL 1400 00:56:24,720 --> 00:56:27,120 QUESTION, BUT IN YOUR EXPERIENCE 1401 00:56:27,120 --> 00:56:30,040 AS A CLINICIAN SCIENTIST, IS 1402 00:56:30,040 --> 00:56:32,800 THERE A TENSION BETWEEN TREATING 1403 00:56:32,800 --> 00:56:34,840 PATIENTS IN A TIMELY MANNER AND 1404 00:56:34,840 --> 00:56:35,760 TAKING CARE OF RESEARCH. 1405 00:56:35,760 --> 00:56:38,760 HOW DO YOU STRIKE A BALANCE 1406 00:56:38,760 --> 00:56:42,320 BETWEEN THE TWO FACTORS IF THERE 1407 00:56:42,320 --> 00:56:43,520 IS. 1408 00:56:43,520 --> 00:56:46,000 >>I CAN'T THINK ABOUT ANYTHING 1409 00:56:46,000 --> 00:56:47,760 IN LIFE THAT INVOLVES TIME THAT 1410 00:56:47,760 --> 00:56:48,960 DOESN'T INVOLVE TENSION. 1411 00:56:48,960 --> 00:56:50,480 WHETHER IF IT IS TIME FOR 1412 00:56:50,480 --> 00:56:52,640 DINNER, TIME FOR SLEEP, TIME FOR 1413 00:56:52,640 --> 00:56:53,280 ANYTHING ELSE. 1414 00:56:53,280 --> 00:56:55,920 IF YOU ARE ASKING ME DOES TIME 1415 00:56:55,920 --> 00:56:57,400 MAGICALLY APPEAR WHEN YOU WANT 1416 00:56:57,400 --> 00:57:01,440 TO DO RESEARCH OR PATIENT CARE? 1417 00:57:01,440 --> 00:57:01,600 NO. 1418 00:57:01,600 --> 00:57:02,560 IT DOES NOT. 1419 00:57:02,560 --> 00:57:03,960 THERE IS ALWAYS A TENSION WHEN 1420 00:57:03,960 --> 00:57:05,320 YOU HAVE TWO THINGS YOU WANT TO 1421 00:57:05,320 --> 00:57:08,880 DO AT THE SAME TIME. 1422 00:57:08,880 --> 00:57:10,160 AND, YOU KNOW, GOOD LUCK WITH 1423 00:57:10,160 --> 00:57:10,400 THAT. 1424 00:57:10,400 --> 00:57:12,120 BUT I DON'T THINK THAT JUST 1425 00:57:12,120 --> 00:57:14,440 BECAUSE THERE IS TENSION DOESN'T 1426 00:57:14,440 --> 00:57:18,560 MEAN IT IS NOT SOLUBLE. 1427 00:57:18,560 --> 00:57:19,280 AND, OF COURSE, THERE IS A 1428 00:57:19,280 --> 00:57:20,440 TENSION BETWEEN TRYING TO GET 1429 00:57:20,440 --> 00:57:22,280 THROUGH ALL OF THE THINGS YOU 1430 00:57:22,280 --> 00:57:24,160 WANT TO GET THROUGH IN ANY DAY. 1431 00:57:24,160 --> 00:57:25,480 I DON'T KNOW IF YOU MAKE LISTS 1432 00:57:25,480 --> 00:57:27,920 FOR YOUR DAY, YOU KNOW, MOST OF 1433 00:57:27,920 --> 00:57:31,920 US MAKE LISTS THAT DON'T ALWAYS 1434 00:57:31,920 --> 00:57:35,320 GET COMPLETED. 1435 00:57:35,320 --> 00:57:38,600 AND HOW TO STRUCTURE YOUR 1436 00:57:38,600 --> 00:57:40,320 ACTIVITIES SO THAT YOU CAN MAKE 1437 00:57:40,320 --> 00:57:41,920 SURE THAT PATIENTS GET PROVIDED 1438 00:57:41,920 --> 00:57:43,680 THE CARE THEY NEED AND THAT YOU 1439 00:57:43,680 --> 00:57:46,160 CAN DO THE RESEARCH, I WOULD 1440 00:57:46,160 --> 00:57:48,080 JUST SAY ONE MORE THING. 1441 00:57:48,080 --> 00:57:52,640 THAT IS TRYING TO CREATE THIS 1442 00:57:52,640 --> 00:57:55,040 DICHOTOMY IN WHICH RESEARCH AND 1443 00:57:55,040 --> 00:57:58,560 PATIENT CARE ARE OPPOSED TO EACH 1444 00:57:58,560 --> 00:58:00,680 OTHER OR NOT OVERLAPPING WITH 1445 00:58:00,680 --> 00:58:02,520 EACH OTHER, I THINK MISSES THE 1446 00:58:02,520 --> 00:58:07,200 POINT OF WHAT WE CAN DO HERE. 1447 00:58:07,200 --> 00:58:08,760 AND I FIND IT VERY DIFFICULT 1448 00:58:08,760 --> 00:58:10,680 WHEN THERE IS A HARD DISTINCTION 1449 00:58:10,680 --> 00:58:12,200 BETWEEN RESEARCH AND CARE. 1450 00:58:12,200 --> 00:58:13,520 WE DO RESEARCH IN ORDER TO MAKE 1451 00:58:13,520 --> 00:58:15,080 THE CARE BETTER. 1452 00:58:15,080 --> 00:58:17,400 WE DO CARE IN ORDER TO MAKE THE 1453 00:58:17,400 --> 00:58:20,480 RESEARCH RELEVANT. 1454 00:58:20,480 --> 00:58:23,000 I WOULD URGE YOU TO TRY AND FIND 1455 00:58:23,000 --> 00:58:24,800 WAYS TO MAKE THOSE OVERLAP AS 1456 00:58:24,800 --> 00:58:25,600 MUCH AS POSSIBLE. 1457 00:58:25,600 --> 00:58:27,640 AND WHAT I FOUND HERE THAT IS 1458 00:58:27,640 --> 00:58:29,320 DIFFERENT THAN WHAT I FOUND ON 1459 00:58:29,320 --> 00:58:31,480 THE OUTSIDE IS THAT I CAN ADMIT 1460 00:58:31,480 --> 00:58:33,200 ONLY THE PATIENTS THAT I'M GOING 1461 00:58:33,200 --> 00:58:35,320 TO BE STUDYING AND STUDY ONLY 1462 00:58:35,320 --> 00:58:36,920 THE PATIENTS THAT I ADMIT. 1463 00:58:36,920 --> 00:58:38,840 THAT IS WHY WE DON'T HAVE AN 1464 00:58:38,840 --> 00:58:39,760 EMERGENCY ROOM. 1465 00:58:39,760 --> 00:58:41,240 NOT BECAUSE WE DON'T THINK 1466 00:58:41,240 --> 00:58:42,880 EMERGENCY DISEASE IS IRRELEVANT. 1467 00:58:42,880 --> 00:58:45,160 BECAUSE IT IS VERY HARD TO MAKE 1468 00:58:45,160 --> 00:58:47,160 SURE WE CAN DO THE RESEARCH AT 1469 00:58:47,160 --> 00:58:48,200 THE SAME TIME. 1470 00:58:48,200 --> 00:58:50,160 I'M SURE I HAVE EVADED YOUR 1471 00:58:50,160 --> 00:58:52,280 QUESTION VERY CAREFULLY, BUT 1472 00:58:52,280 --> 00:58:53,720 THERE IS PLENTY OF TENSION IN 1473 00:58:53,720 --> 00:58:55,440 LIFE AND THANK GOD FOR THAT. 1474 00:58:55,440 --> 00:58:58,680 >>THANK YOU SO MUCH. 1475 00:58:58,680 --> 00:58:59,920 >>GREAT. 1476 00:58:59,920 --> 00:59:01,040 WONDERFUL TALK. 1477 00:59:01,040 --> 00:59:04,680 I'M WONDERING IF YOU CAN THINK 1478 00:59:04,680 --> 00:59:07,560 ABOUT ONE EXAMPLE FROM YOUR 1479 00:59:07,560 --> 00:59:09,440 EARLY FELLOWSHIP THAT FAILURES 1480 00:59:09,440 --> 00:59:11,200 TAUGHT YOU MORE THAN SUCCESSES. 1481 00:59:11,200 --> 00:59:13,160 SOMETHING THAT HELPED YOU GROW 1482 00:59:13,160 --> 00:59:15,960 AND HOW YOU TRANSFORMED THAT 1483 00:59:15,960 --> 00:59:26,240 INTO A SUCCESS. 1484 00:59:27,200 --> 00:59:29,680 >>I THOUGHT THAT IT WAS OKAY TO 1485 00:59:29,680 --> 00:59:35,400 GO AHEAD AND STOP HIS 1486 00:59:35,400 --> 00:59:35,920 INTRAVENOUS ANTIBIOTICS. 1487 00:59:35,920 --> 00:59:38,600 I THOUGHT WE ACHIEVED ADEQUATE 1488 00:59:38,600 --> 00:59:38,840 CONTROL. 1489 00:59:38,840 --> 00:59:40,480 I THOUGHT HE WAS OKAY. 1490 00:59:40,480 --> 00:59:42,240 I TURNED OUT TO BE TRAGICALLY 1491 00:59:42,240 --> 00:59:42,440 WRONG. 1492 00:59:42,440 --> 00:59:43,720 I DON'T KNOW IF I CONTINUED 1493 00:59:43,720 --> 00:59:45,120 THEM, I WOULD HAVE COME UP WITH 1494 00:59:45,120 --> 00:59:46,960 A DIFFERENT OUTCOME. 1495 00:59:46,960 --> 00:59:50,560 I DO KNOW THAT AFTER I STOPPED, 1496 00:59:50,560 --> 00:59:51,920 THINGS GOT MUCH WORSE. 1497 00:59:51,920 --> 00:59:54,960 YOU KNOW, YOU HAVE TO 1498 00:59:54,960 --> 00:59:56,080 DIFFERENTIATE BETWEEN TRYING TO 1499 00:59:56,080 --> 00:59:59,400 TREAT YOUR LAST ERROR AND TRYING 1500 00:59:59,400 --> 01:00:01,600 TO MOVE FORWARD. 1501 01:00:01,600 --> 01:00:03,920 AND I'VE TRIED TO INCORPORATE 1502 01:00:03,920 --> 01:00:06,200 WHAT I UNDERSTOOD FROM THAT, 1503 01:00:06,200 --> 01:00:08,280 THAT IS DON'T STOP EVEN WHEN YOU 1504 01:00:08,280 --> 01:00:10,280 THINK YOU ARE OKAY, YOU MIGHT 1505 01:00:10,280 --> 01:00:11,360 NOT BE. 1506 01:00:11,360 --> 01:00:13,880 USE AS MANY DIFFERENT TECHNIQUES 1507 01:00:13,880 --> 01:00:15,920 AS POSSIBLE TO FIGURE THAT OUT. 1508 01:00:15,920 --> 01:00:18,120 IT TAUGHT ME A LOT ABOUT WHAT 1509 01:00:18,120 --> 01:00:20,800 YOU CAN DO IN THE SETTING OF 1510 01:00:20,800 --> 01:00:23,880 IMMUNE DEFICIENCY WITH SEVERE 1511 01:00:23,880 --> 01:00:24,120 DISEASE. 1512 01:00:24,120 --> 01:00:27,960 I KNOW WE ARE AT TIME. 1513 01:00:27,960 --> 01:00:28,360 THANK YOU VERY MUCH. 1514 01:00:28,360 --> 01:00:29,240 [ APPLAUSE ] 1515 01:00:29,240 --> 01:00:30,960 >>IT IS WONDERFUL TO SEE THE 1516 01:00:30,960 --> 01:00:31,760 BIG CROWD. 1517 01:00:31,760 --> 01:00:35,040 I WANT TO SAY OUR GRAND ROUNDS 1518 01:00:35,040 --> 01:00:36,440 PROGRAM ARE GOING TO CONCLUDE 1519 01:00:36,440 --> 01:00:37,280 WITH THIS PRESENTATION UNTIL 1520 01:00:37,280 --> 01:00:37,560 SEPTEMBER. 1521 01:00:37,560 --> 01:00:38,600 WONDERFUL TO SEE YOU. 1522 01:00:38,600 --> 01:00:39,920 PLEASE COME BACK IN THE FALL. 1523 01:00:39,920 --> 01:00:42,200 IT IS GREAT TO SEE A CROWD AND 1524 01:00:42,200 --> 01:00:43,200 THE SPEAKERS REALLY APPRECIATE 1525 01:00:43,200 --> 01:00:43,360 IT. 1526 01:00:43,360 --> 01:00:45,360 THANK YOU SO MUCH.