1 00:00:06,383 --> 00:00:08,919 >> WELL, GREETINGS AND 2 00:00:08,919 --> 00:00:09,787 SALUTATIONS! 3 00:00:09,787 --> 00:00:12,089 I'M DAN KASTNER, THE SCIENTIFIC 4 00:00:12,089 --> 00:00:13,724 DIRECTOR EMERITUS OF THE 5 00:00:13,724 --> 00:00:15,626 NATIONAL HUMAN GENOME RESEARCH 6 00:00:15,626 --> 00:00:17,328 INSTITUTE AND STILL AN ACTIVE 7 00:00:17,328 --> 00:00:18,963 PHYSICIAN SCIENTIST HERE IN THE 8 00:00:18,963 --> 00:00:21,065 INTRAMURAL RESEARCH PROGRAM OF 9 00:00:21,065 --> 00:00:21,265 NHGRI. 10 00:00:21,265 --> 00:00:24,001 IT IS MY WONDERFUL DELIGHT TO 11 00:00:24,001 --> 00:00:27,404 WELCOME YOU TODAY TO THIS, THE 12 00:00:27,404 --> 00:00:32,409 11TH INSTALLMENT IN THE 2024 13 00:00:32,409 --> 00:00:33,310 SESSIONS OF DEMYSTIFYING 14 00:00:33,310 --> 00:00:33,577 MEDICINE. 15 00:00:33,577 --> 00:00:35,279 A SET OF SESSIONS SET UP TO 16 00:00:35,279 --> 00:00:37,114 BRIDGE THE EXCITING DEVELOPMENTS 17 00:00:37,114 --> 00:00:39,750 IN BIOLOGY AND ENGINEERING WITH 18 00:00:39,750 --> 00:00:41,185 MEDICINE. 19 00:00:41,185 --> 00:00:42,553 AND OF COURSE ALONG THE LINES OF 20 00:00:42,553 --> 00:00:47,224 THE BRIDGE, WE HAVE THE ICONIC 21 00:00:47,224 --> 00:00:48,559 PHOTO OF THE BROOKLYN BRIDGE 22 00:00:48,559 --> 00:00:50,728 SPANNING THE EAST RIVER BETWEEN 23 00:00:50,728 --> 00:00:52,262 MANHATTAN AND, GUESS WHAT, 24 00:00:52,262 --> 00:00:52,529 BROOKLYN! 25 00:00:52,529 --> 00:00:55,566 AND YOU CAN SEE ON THE CATWALK 26 00:00:55,566 --> 00:00:59,036 UP IN THE LEFT-HAND SIDE OF THE 27 00:00:59,036 --> 00:01:00,270 PHOTO TWO GENTLEMEN. 28 00:01:00,270 --> 00:01:01,772 ONE OF THEM I'M SURE FROM 29 00:01:01,772 --> 00:01:03,407 BROOKLYN, THE OTHER FROM 30 00:01:03,407 --> 00:01:05,275 MANHATTAN, WHO WERE DISCUSSING 31 00:01:05,275 --> 00:01:06,910 THE SCIENTIFIC ISSUES OF THE 32 00:01:06,910 --> 00:01:09,313 DAY, BRINGING TOGETHER BASIC 33 00:01:09,313 --> 00:01:10,981 SCIENCE AND CLINICAL MEDICINE. 34 00:01:10,981 --> 00:01:14,485 AND TODAY, WE HAVE A SIMILAR 35 00:01:14,485 --> 00:01:15,886 SUCH SITUATION IN WHICH WE ARE 36 00:01:15,886 --> 00:01:17,554 BRINGING TOGETHER BASIC SCIENCE 37 00:01:17,554 --> 00:01:20,391 AND CLINICAL MEDICINE IN THE 38 00:01:20,391 --> 00:01:21,258 DISCUSSION OF PARKINSON'S 39 00:01:21,258 --> 00:01:23,894 DISEASE, AND WE HAVE ACTUALLY 40 00:01:23,894 --> 00:01:26,597 TWO THIRDS OF THE RECIPIENTS OF 41 00:01:26,597 --> 00:01:28,932 THIS YEAR'S BREAKTHROUGH PRIZE, 42 00:01:28,932 --> 00:01:31,101 MY GOODNESS, JUST TALKING MADE 43 00:01:31,101 --> 00:01:34,471 THE THING GO FORWARD, 44 00:01:34,471 --> 00:01:36,573 BREAKTHROUGH PRIZE THAT WILL BE 45 00:01:36,573 --> 00:01:40,511 AWARDED IN APRIL, THOMAS GASSER 46 00:01:40,511 --> 00:01:42,913 IS THE THIRD RECIPIENT OF THAT, 47 00:01:42,913 --> 00:01:45,983 BUT WE HAVE DR. ANDY SINGLETON 48 00:01:45,983 --> 00:01:48,252 AND DR. ELLEN SIDRANSKY HERE, 49 00:01:48,252 --> 00:01:50,888 WHO ARE GOING TO BE TALKING TO 50 00:01:50,888 --> 00:01:52,656 US ABOUT THE LATEST INFORMATION 51 00:01:52,656 --> 00:01:55,692 BOTH ON THE GENETICS AND 52 00:01:55,692 --> 00:01:56,360 THERAPEUTICS RELATED TO 53 00:01:56,360 --> 00:01:57,795 PARKINSON'S DISEASE. 54 00:01:57,795 --> 00:02:01,165 SO IN ANY CASE, THIS IS A SERIES 55 00:02:01,165 --> 00:02:03,967 OF TALKS THAT OCCURS TUESDAYS, 56 00:02:03,967 --> 00:02:05,536 AS YOU CAN SEE ON THE SLIDE, 57 00:02:05,536 --> 00:02:07,638 FROM 4:00 TO 6:00 P.M., FROM 58 00:02:07,638 --> 00:02:08,939 JANUARY THROUGH MAY. 59 00:02:08,939 --> 00:02:11,341 YOU CAN WATCH ON THE VIDEOCAST 60 00:02:11,341 --> 00:02:12,209 LINK THAT'S SHOWN THERE. 61 00:02:12,209 --> 00:02:14,411 FOR THOSE OF YOU WHO WANT CME 62 00:02:14,411 --> 00:02:18,348 CREDIT, YOU CAN GET IT USING THE 63 00:02:18,348 --> 00:02:27,224 CODE 5296, ANDTHE -- YOU CAN USE 64 00:02:27,224 --> 00:02:28,459 FEEDBACK ON THE VIDEOCAST 65 00:02:28,459 --> 00:02:29,293 DISPLAY TO TURN IN YOUR 66 00:02:29,293 --> 00:02:30,160 QUESTIONS AND WE'RE ACTUALLY 67 00:02:30,160 --> 00:02:33,664 GOING TO HAVE A DIZZYING BACK 68 00:02:33,664 --> 00:02:36,166 AND FORTH OF SPEAKERS TODAY WITH 69 00:02:36,166 --> 00:02:38,268 DR. SINGLETON LEADING OFF AND 70 00:02:38,268 --> 00:02:43,941 THEN DR. SIDRANSKY AND ALL OF 71 00:02:43,941 --> 00:02:44,808 THE QUESTIONS WILL BE SAVED 72 00:02:44,808 --> 00:02:46,477 UNTIL THE END. 73 00:02:46,477 --> 00:02:48,412 ALL OF THE PREVIOUS SESSIONS ARE 74 00:02:48,412 --> 00:02:50,814 ARCHIVED AND YOU CAN GO TO THE 75 00:02:50,814 --> 00:02:52,683 LINK THERE TO SEE THEM AND FOR 76 00:02:52,683 --> 00:02:55,119 ADDITIONAL INFORMATION, THERE'S 77 00:02:55,119 --> 00:02:56,520 AN EMAIL ADDRESS FOR THAT. 78 00:02:56,520 --> 00:02:59,056 AND OF COURSE NOT TO FORGET, WE 79 00:02:59,056 --> 00:03:01,225 HAVE BEEN BRIDGING SILOS AT THE 80 00:03:01,225 --> 00:03:02,893 NIH SINCE 1999. 81 00:03:02,893 --> 00:03:05,829 WE DO NOT WANT TO HAVE SILOS, WE 82 00:03:05,829 --> 00:03:08,332 WANT TO GET PEOPLE TOGETHER, AND 83 00:03:08,332 --> 00:03:11,401 EVEN WITH A FEW CORNY JOKES TO 84 00:03:11,401 --> 00:03:14,671 MAKE THAT HAPPEN. 85 00:03:14,671 --> 00:03:17,207 SO IN ANY EVENT, MORE ON THE CME 86 00:03:17,207 --> 00:03:20,911 INFORMATION, THE CODE AGAIN, 87 00:03:20,911 --> 00:03:21,145 52096. 88 00:03:21,145 --> 00:03:24,414 IN TERMS OF DISCLOSURES, 89 00:03:24,414 --> 00:03:25,382 DR. SIDRANSKY REPORTS GRANT OR 90 00:03:25,382 --> 00:03:27,484 RESEARCH SUPPORT FROM ROCHE, AND 91 00:03:27,484 --> 00:03:29,019 LET'S JUST GET STARTED WITH THE 92 00:03:29,019 --> 00:03:30,053 INTRODUCTIONS OF OUR TWO 93 00:03:30,053 --> 00:03:32,489 SPEAKERS. 94 00:03:32,489 --> 00:03:33,924 FIRST THE GOOD DR. ANDREW 95 00:03:33,924 --> 00:03:34,358 SINGLETON. 96 00:03:34,358 --> 00:03:36,894 HE IS AN NIH DISTINGUISHED 97 00:03:36,894 --> 00:03:38,362 INVESTIGATOR, DIRECTOR OF THE 98 00:03:38,362 --> 00:03:40,063 CENTER FOR ALZHEIMER'S AND 99 00:03:40,063 --> 00:03:41,532 RELATED DEMENTIAS, AND CHIEF OF 100 00:03:41,532 --> 00:03:43,133 THE MOLECULAR GENETICS SECTION 101 00:03:43,133 --> 00:03:44,902 OF THE LABORATORY OF 102 00:03:44,902 --> 00:03:46,103 NEUROGENETICS IN THE NATIONAL 103 00:03:46,103 --> 00:03:47,704 INSTITUTE OF AGING. 104 00:03:47,704 --> 00:03:49,306 HE GOT HIS BACHELOR'S DEGREE 105 00:03:49,306 --> 00:03:51,875 WITH HONORS IN APPLIED 106 00:03:51,875 --> 00:03:55,445 PHYSIOLOGY AT THE UNIVERSITY OF 107 00:03:55,445 --> 00:03:56,880 SUNDERLAND AND DOCTORAL DEGREE 108 00:03:56,880 --> 00:03:57,614 IN NEUROSCIENCE FROM THE 109 00:03:57,614 --> 00:03:59,950 UNIVERSITY OF NEW CASTLE UPON 110 00:03:59,950 --> 00:04:01,051 TYNE IN THE UK. 111 00:04:01,051 --> 00:04:02,553 HE DID HIS DOCTORAL FELLOWSHIP 112 00:04:02,553 --> 00:04:04,354 AT THE MAYO CLINIC IN 113 00:04:04,354 --> 00:04:05,422 JACKSONVILLE, AND HIS LAB WORKS 114 00:04:05,422 --> 00:04:10,894 ON THE JE NE GENETIC BASES OF ME 115 00:04:10,894 --> 00:04:12,396 NEUROLOGIC DISORDERS INCLUDING 116 00:04:12,396 --> 00:04:13,363 MOVEMENT DISORDERS, DEMENTIAS 117 00:04:13,363 --> 00:04:14,064 AND ALS. 118 00:04:14,064 --> 00:04:18,168 HE WAS THE FIRST RE RECIPIENT OF 119 00:04:18,168 --> 00:04:20,304 THE JAY VAN ANDEL AWARD FOR 120 00:04:20,304 --> 00:04:21,405 OUTSTANDING ACHIEVEMENT IN 121 00:04:21,405 --> 00:04:22,372 PARKINSON'S DISEASE RESEARCH, 122 00:04:22,372 --> 00:04:24,141 AND AS I MENTIONED BEFORE, HE'S 123 00:04:24,141 --> 00:04:25,309 THE RECIPIENT, ONE OF THE 124 00:04:25,309 --> 00:04:26,977 RECIPIENTS OF THIS YEAR'S 125 00:04:26,977 --> 00:04:29,279 BREAKTHROUGH PRIZE IN THE LIFE 126 00:04:29,279 --> 00:04:29,913 SCIENCES. 127 00:04:29,913 --> 00:04:31,882 HIS GROUP HAS DISCOVERED A 128 00:04:31,882 --> 00:04:34,952 NUMBER OF GENETIC MUTATIONS THAT 129 00:04:34,952 --> 00:04:36,386 CAUSED PARKINSON'S DISEASE AND 130 00:04:36,386 --> 00:04:38,455 WE'LL HEAR A NUMBER IN HIS TALK 131 00:04:38,455 --> 00:04:40,657 INCLUDING THE ALPHA SYNUCLEIN 132 00:04:40,657 --> 00:04:41,725 MULTIPLICATION MUTATION AND 133 00:04:41,725 --> 00:04:43,060 MUTATIONS IN LRRK2. 134 00:04:43,060 --> 00:04:44,895 AND HE'S A FOUNDING MEMBER OF 135 00:04:44,895 --> 00:04:47,097 THE INTERNATIONAL PARKINSON 136 00:04:47,097 --> 00:04:48,532 DISEASE GENOMICS CONSORTIUM AND 137 00:04:48,532 --> 00:04:50,434 THE GLOBAL PARKINSON'S GENETICS 138 00:04:50,434 --> 00:04:51,602 PROGRAM. 139 00:04:51,602 --> 00:04:52,669 OUR SECOND SPEAKER -- WELL, 140 00:04:52,669 --> 00:04:56,840 ACTUALLY IT WILL BE OUR 141 00:04:56,840 --> 00:04:59,576 SECOND -- IS DR. ELLEN 142 00:04:59,576 --> 00:05:00,444 SIDRANSKY, SENIOR INVESTIGATOR 143 00:05:00,444 --> 00:05:02,512 AND HEAD OF THE MOLECULAR 144 00:05:02,512 --> 00:05:03,146 NEUROGENETICS SECTION AND CHIEF 145 00:05:03,146 --> 00:05:04,514 OF THE MEDICAL GENETICS BRANCH 146 00:05:04,514 --> 00:05:06,250 OF THE NATIONAL HUMAN GENOME 147 00:05:06,250 --> 00:05:06,917 RESEARCH INSTITUTE. 148 00:05:06,917 --> 00:05:10,954 SHE GOT HER BACHELOR'S DEGREE 149 00:05:10,954 --> 00:05:12,356 MAGNA CUM LAUDE IN BIOLOGY FROM 150 00:05:12,356 --> 00:05:13,991 BRANDEIS AND HER MEDICAL DEGREE 151 00:05:13,991 --> 00:05:14,324 FROM TULANE. 152 00:05:14,324 --> 00:05:15,892 SHE DID A RESIDENCY IN 153 00:05:15,892 --> 00:05:18,395 PEDIATRICS AT NORTHWESTERN AND A 154 00:05:18,395 --> 00:05:20,564 FELLOWSHIP HERE AT THE NIH IN 155 00:05:20,564 --> 00:05:21,331 CLINICAL GENETICS. 156 00:05:21,331 --> 00:05:23,066 SHE WAS THE FIRST PERSON, AND 157 00:05:23,066 --> 00:05:25,836 THIS IS REALLY AN ASTUTE 158 00:05:25,836 --> 00:05:27,137 CLINICIAN STORY. 159 00:05:27,137 --> 00:05:30,073 FIRST PERSON TO ESTABLISH THE 160 00:05:30,073 --> 00:05:32,042 RELATIONSHIP BETWEEN 161 00:05:32,042 --> 00:05:34,144 GBA1 MUTATIONS, WHICH CAN CAUSE 162 00:05:34,144 --> 00:05:36,446 GAUCHER DISEASE, AND THE RISK OF 163 00:05:36,446 --> 00:05:37,514 DEVELOPING EITHER PARKINSON'S 164 00:05:37,514 --> 00:05:39,182 DISEASE OR LEWY BODY DEMENTIA. 165 00:05:39,182 --> 00:05:41,351 SHE'S WON A NUMBER OF DIFFERENT 166 00:05:41,351 --> 00:05:43,220 AWARDS INCLUDING THE 167 00:05:43,220 --> 00:05:43,854 BREAKTHROUGH PRIZE AS I 168 00:05:43,854 --> 00:05:45,055 MENTIONED BEFORE AND THE 169 00:05:45,055 --> 00:05:45,956 OVERARCHING GOALS OF HER 170 00:05:45,956 --> 00:05:47,691 RESEARCH GROUP ARE, ONE, TO 171 00:05:47,691 --> 00:05:50,260 ELUCIDATE THE RELATIONSHIP 172 00:05:50,260 --> 00:05:51,094 BETWEEN GLUCOCEREBROSIGH DAYS 173 00:05:51,094 --> 00:05:53,263 AND PARKINSON'S DISEASE TO 174 00:05:53,263 --> 00:05:54,464 IDENTIFY FACTORS THAT CONTRIBUTE 175 00:05:54,464 --> 00:05:56,266 TO CLINICAL HETEROGENEITY AND 176 00:05:56,266 --> 00:05:58,201 SINGLE GENE DISORDERS AND TO 177 00:05:58,201 --> 00:05:59,503 DEVELOP NEW THERAPIES FOR 178 00:05:59,503 --> 00:06:02,306 PATIENTS. 179 00:06:02,306 --> 00:06:03,473 AND WITHOUT FURTHER ADO, I THINK 180 00:06:03,473 --> 00:06:08,278 IT IS TIME FOR US TO WELCOME DR. 181 00:06:08,278 --> 00:06:09,012 DR. SINGLETON, PLEASE. 182 00:06:09,012 --> 00:06:19,189 [APPLAUSE] 183 00:06:19,456 --> 00:06:21,325 >> SO THANKS, IT'S A REAL 184 00:06:21,325 --> 00:06:22,326 PLEASURE TO SPEAK HERE TODAY, 185 00:06:22,326 --> 00:06:23,527 PARTICULARLY WITH ELLEN. 186 00:06:23,527 --> 00:06:28,398 I THINK I GAVE A DEMYSTIFYING 187 00:06:28,398 --> 00:06:29,633 TALK ABOUT 15 OR 16 YEARS AGO, 188 00:06:29,633 --> 00:06:30,634 AND THE REASON I KIND OF 189 00:06:30,634 --> 00:06:32,102 REMEMBERED THAT IT WAS 15 OR 16 190 00:06:32,102 --> 00:06:33,170 IS MY OLD ELLEN SIDRANSKY 191 00:06:33,170 --> 00:06:34,671 DAUGHTER IS 22. 192 00:06:34,671 --> 00:06:36,973 SHE'S A SENIOR AT COLLEGE NOW, 193 00:06:36,973 --> 00:06:38,442 AND I REMEMBER COMING HOME THE 194 00:06:38,442 --> 00:06:41,244 FIRST TIME I GAVE ONE OF THESE 195 00:06:41,244 --> 00:06:44,214 TALKS, SHE WAS ABOUT YEA HIGH 196 00:06:44,214 --> 00:06:47,517 AND SHE HAD A PAD WITH TICS ON 197 00:06:47,517 --> 00:06:49,119 IT, LIKE HUNDREDS OF TICS. 198 00:06:49,119 --> 00:06:51,021 SHE WATCHED THE VIDEO ONLINE AND 199 00:06:51,021 --> 00:06:54,057 SHE SAID I TICKED EVERY TIME YOU 200 00:06:54,057 --> 00:06:55,125 SAID "UM." 201 00:06:55,125 --> 00:06:56,660 SO NOW I'M VERY AWARE, NOT AWARE 202 00:06:56,660 --> 00:06:59,062 ENOUGH BUT VERY AWARE OF SAYING 203 00:06:59,062 --> 00:07:00,497 UM A LOT. 204 00:07:00,497 --> 00:07:01,565 I THINK OF THAT EVERY TIME I 205 00:07:01,565 --> 00:07:02,332 GIVE A TALK. 206 00:07:02,332 --> 00:07:04,101 SO THANK YOU TO THIS LECTURE FOR 207 00:07:04,101 --> 00:07:05,302 MAKING ME THINK OF THAT, AT 208 00:07:05,302 --> 00:07:05,736 LEAST. 209 00:07:05,736 --> 00:07:07,170 SO ELLEN AND I ARE GOING TO HAVE 210 00:07:07,170 --> 00:07:08,472 A BIT OF BACK AND FORTH TODAY. 211 00:07:08,472 --> 00:07:09,439 WE'RE GOING TO TALK ABOUT THE 212 00:07:09,439 --> 00:07:11,241 GENETICS OF PARKINSON'S DISEASE, 213 00:07:11,241 --> 00:07:14,044 AND ACTUALLY HOW THIS FIELD HAS 214 00:07:14,044 --> 00:07:18,115 EVOLVED FROM EARLY GENETIC 215 00:07:18,115 --> 00:07:19,583 DISCOVERIES, AND ACTUALLY THE 216 00:07:19,583 --> 00:07:21,151 FIRST GENETIC DISCOVERY IN 217 00:07:21,151 --> 00:07:21,818 PARKINSON'S DISEASE WAS MADE 218 00:07:21,818 --> 00:07:25,322 HERE AT NIH, THROUGH TO THE 219 00:07:25,322 --> 00:07:26,523 REALIZATION OF THAT GENETICS 220 00:07:26,523 --> 00:07:30,127 WORK WHICH IS AROUND FINDING 221 00:07:30,127 --> 00:07:31,895 THERAPEUTIC TARGETS. 222 00:07:31,895 --> 00:07:34,731 WE'RE GOING TO START QUICKLY 223 00:07:34,731 --> 00:07:36,266 WITHOUT CHANGING SLIDES, ELLEN 224 00:07:36,266 --> 00:07:37,801 IS GOING TO GIVE A LITTLE BIT OF 225 00:07:37,801 --> 00:07:38,735 BACKGROUND ON PARKINSON'S 226 00:07:38,735 --> 00:07:40,737 DISEASE AND THE CLINICAL AND 227 00:07:40,737 --> 00:07:41,938 NEUROPATHOLOGICAL FEATURES OF 228 00:07:41,938 --> 00:07:43,073 PARKINSON'S DISEASE AND THEN 229 00:07:43,073 --> 00:07:44,775 I'LL TAKE YOU THROUGH THE ORDER 230 00:07:44,775 --> 00:07:48,645 OF THE REST OF THE DISCUSSION. 231 00:07:48,645 --> 00:07:49,279 >> THANK YOU. 232 00:07:49,279 --> 00:07:51,715 I ALSO WANT TO ECHO, IT'S GREAT 233 00:07:51,715 --> 00:07:53,650 TO BE HERE TOGETHER WITH ANDY, 234 00:07:53,650 --> 00:07:56,253 IT MAY BE THE FIRST OF MANY. 235 00:07:56,253 --> 00:07:57,921 WE'VE KNOWN EACH OTHER FOR QUITE 236 00:07:57,921 --> 00:07:59,356 A WHILE. 237 00:07:59,356 --> 00:08:01,224 I JUST THOUGHT I WOULD GIVE A 238 00:08:01,224 --> 00:08:02,826 VERY BRIEF CLINICAL OVERVIEW OF 239 00:08:02,826 --> 00:08:06,096 WHAT PARKINSON'S DISEASE IS, MAY 240 00:08:06,096 --> 00:08:07,764 NOT BE. 241 00:08:07,764 --> 00:08:09,833 I'M NEW TO MOST OF THE PEOPLE IN 242 00:08:09,833 --> 00:08:10,934 THE AUDIENCE TODAY, BUT JUST 243 00:08:10,934 --> 00:08:12,569 WANTED TO REVIEW THAT PARKINSON 244 00:08:12,569 --> 00:08:14,337 DISEASE IS REALLY A CLINICALLY 245 00:08:14,337 --> 00:08:17,174 AND PATHOLOGICALLY DEFINED 246 00:08:17,174 --> 00:08:17,941 ENTITY. 247 00:08:17,941 --> 00:08:20,610 IT INCLUDES THE CRITERIA IS YOU 248 00:08:20,610 --> 00:08:23,180 MUST HAVE BRADYKINESIA, WHICH IS 249 00:08:23,180 --> 00:08:24,815 SLOWNESS OF MOVEMENT, AND AT 250 00:08:24,815 --> 00:08:26,783 LEAST ONE OF THE FOLLOWING, 251 00:08:26,783 --> 00:08:28,652 MUSCULAR RIGIDITY, A REST TREMOR 252 00:08:28,652 --> 00:08:30,287 AND POSTURAL INSTABILITY. 253 00:08:30,287 --> 00:08:32,255 THE CARTOON THAT I'VE SHOWN 254 00:08:32,255 --> 00:08:33,457 THAT'S KIND OF A CLASSIC JUST 255 00:08:33,457 --> 00:08:36,193 SHOWS A FEW OF THE OTHER COMMON 256 00:08:36,193 --> 00:08:37,394 FEATURES THAT YOU ENCOUNTER IN 257 00:08:37,394 --> 00:08:39,796 PATIENTS WITH PARKINSON DISEASE. 258 00:08:39,796 --> 00:08:42,199 A TERM THAT WE MAY USE IS 259 00:08:42,199 --> 00:08:43,200 PARKINSONISM, AND THAT USUALLY 260 00:08:43,200 --> 00:08:46,036 DESCRIBES THE MOTOR FEATURES OF 261 00:08:46,036 --> 00:08:46,570 PARKINSON DISEASE. 262 00:08:46,570 --> 00:08:48,238 THOUGH THERE ARE ALSO NON-MOTOR 263 00:08:48,238 --> 00:08:49,639 FEATURES THAT ARE VERY 264 00:08:49,639 --> 00:08:49,973 IMPORTANT. 265 00:08:49,973 --> 00:08:51,408 AND THE OTHER THING THAT WE 266 00:08:51,408 --> 00:08:53,009 MIGHT MENTION IS DEMENTIA WITH 267 00:08:53,009 --> 00:08:54,878 LEWY BODIES OR DLB, WHICH MANY 268 00:08:54,878 --> 00:08:57,848 OF YOU HEARD FROM SONIA 269 00:08:57,848 --> 00:09:01,351 SCHULTZ'S TALK LAST WEEK. 270 00:09:01,351 --> 00:09:03,620 THIS IS -- MANY FEATURES ARE 271 00:09:03,620 --> 00:09:04,521 SIMILAR, ESPECIALLY THE MOTOR 272 00:09:04,521 --> 00:09:06,056 FEATURES ARE SIMILAR TO 273 00:09:06,056 --> 00:09:07,157 PARKINSON DISEASE, BUT THERE'S 274 00:09:07,157 --> 00:09:09,459 MORE SEVERE COGNITIVE DEFICITS 275 00:09:09,459 --> 00:09:10,760 AND MORE RAPID DISEASE 276 00:09:10,760 --> 00:09:11,962 PROGRESSION. 277 00:09:11,962 --> 00:09:14,130 THE OTHER THING THAT WE MIGHT 278 00:09:14,130 --> 00:09:16,900 REFER TO THESE DISORDERS AS LEWY 279 00:09:16,900 --> 00:09:19,402 BODY DISORDERS, OR 280 00:09:19,402 --> 00:09:20,704 SYNUCLEINOPATHIES. 281 00:09:20,704 --> 00:09:21,905 SO LEWY BODIES ARE THESE 282 00:09:21,905 --> 00:09:24,641 INCLUSIONS THAT WE SEE, THEY'RE 283 00:09:24,641 --> 00:09:26,176 INCLUSIONS OF PROTEINS WITHIN 284 00:09:26,176 --> 00:09:28,812 NEURONS, AND ONE OF THE MAIN 285 00:09:28,812 --> 00:09:31,081 COMPONENTS OF THESE LEWY BODIES 286 00:09:31,081 --> 00:09:32,315 ARE A PROTEIN THAT YOU'LL HEAR 287 00:09:32,315 --> 00:09:34,584 ABOUT FROM ANDY CALLED ALPHA 288 00:09:34,584 --> 00:09:34,885 SYNUCLEIN. 289 00:09:34,885 --> 00:09:39,956 IT'S KIND OF AN AMORPHOUS SMALL 290 00:09:39,956 --> 00:09:43,660 NOT VERY STRUCTURED THING THAT 291 00:09:43,660 --> 00:09:45,896 CAN EITHER AGGREGATE INTO 292 00:09:45,896 --> 00:09:48,398 AGGREGATES OR FIBRILS, AND THEY 293 00:09:48,398 --> 00:09:49,799 ARE PRESENT IN THE LEWY BODIES. 294 00:09:49,799 --> 00:09:53,103 YOU CAN SEE THIS IS FROM THE 295 00:09:53,103 --> 00:09:54,504 BRAIN OF ONE OF OUR PATIENTS 296 00:09:54,504 --> 00:09:57,674 ACTUALLY, AND THE LEWY BODY 297 00:09:57,674 --> 00:09:58,675 STAINED POSITIVE FOR ALPHA 298 00:09:58,675 --> 00:09:59,276 SYNUCLEIN. 299 00:09:59,276 --> 00:10:01,845 SO PARKINSON DISEASE IS VERY 300 00:10:01,845 --> 00:10:02,913 COMMON. 301 00:10:02,913 --> 00:10:04,681 IT AFFECTS ABOUT 2% OF THE 302 00:10:04,681 --> 00:10:06,850 POPULATION OVER AGE 65, AND GOES 303 00:10:06,850 --> 00:10:09,819 UP THE OLDER YOU GO. 304 00:10:09,819 --> 00:10:11,354 THERE'S ABOUT 40,000 NEW CASES 305 00:10:11,354 --> 00:10:12,556 PER YEAR HERE IN THE UNITED 306 00:10:12,556 --> 00:10:13,957 STATES. 307 00:10:13,957 --> 00:10:15,292 THEY THINK CLOSE TO A MILLION 308 00:10:15,292 --> 00:10:17,694 PEOPLE IN THE UNITED STATES HAVE 309 00:10:17,694 --> 00:10:18,995 PARKINSON DISEASE, AND I DON'T 310 00:10:18,995 --> 00:10:21,298 THINK THERE'S AN ACCURATE NUMBER 311 00:10:21,298 --> 00:10:23,166 WORLDWIDE, BUT -- AND I'VE SEEN 312 00:10:23,166 --> 00:10:24,134 10 MILLION, MY GUESS IS IT 313 00:10:24,134 --> 00:10:25,235 HIGHER THAN THAT. 314 00:10:25,235 --> 00:10:27,637 THE NUMBER IS GROWING RAPIDLY AS 315 00:10:27,637 --> 00:10:29,839 THE POPULATION AGES, BUT WE'RE 316 00:10:29,839 --> 00:10:32,776 NOT EVEN SURE IF THAT'S THE ONLY 317 00:10:32,776 --> 00:10:34,678 COMPONENT, BECAUSE IT SEEMS TO 318 00:10:34,678 --> 00:10:36,580 BE THAT THERE COULD ALSO AT THE 319 00:10:36,580 --> 00:10:39,916 SAME TIME BE EVOLVING INCREASED 320 00:10:39,916 --> 00:10:41,851 ENVIRONMENTAL AND OTHER 321 00:10:41,851 --> 00:10:43,286 INFLUENCES, BUT IT DOES TEND TO 322 00:10:43,286 --> 00:10:47,891 BE THE FAST ELLEN SIDRAEST GROWG 323 00:10:47,891 --> 00:10:49,225 NEUROLOGIC DISORDER AND IT 324 00:10:49,225 --> 00:10:50,293 PROBABLY HAS CONTRIBUTIONS OF 325 00:10:50,293 --> 00:10:53,229 BOTH JE GENETIC AND ENVIRONMENL 326 00:10:53,229 --> 00:10:54,497 FACTORS BUT OUR FOCUS TODAY IS 327 00:10:54,497 --> 00:10:55,198 ON THE GENES. 328 00:10:55,198 --> 00:10:56,633 EXP 329 00:10:56,633 --> 00:10:57,834 >> GREAT, THANKS, ELLEN. 330 00:10:57,834 --> 00:10:58,802 SO THIS IS GOING TO BE THE 331 00:10:58,802 --> 00:10:59,903 STRUCTURE OF WHAT WE'RE GOING TO 332 00:10:59,903 --> 00:11:00,670 TALK ABOUT TODAY. 333 00:11:00,670 --> 00:11:02,872 HOW FAR HAVE WE COME IN GENETIC 334 00:11:02,872 --> 00:11:03,940 DISCOVERY, I'LL COVER THAT, AND 335 00:11:03,940 --> 00:11:08,011 REALLY FOCUSING ON THESE 336 00:11:08,011 --> 00:11:10,647 GENOME-WIDE EFFORTS, ROOKI LOOKT 337 00:11:10,647 --> 00:11:12,616 THOUSANDS OF PATIENTS MAKING 338 00:11:12,616 --> 00:11:13,416 INFERENCES ABOUT GENETICS FROM 339 00:11:13,416 --> 00:11:13,917 THAT GROUP. 340 00:11:13,917 --> 00:11:15,685 THEN WE'LL COME FROM THE OTHER 341 00:11:15,685 --> 00:11:17,654 ASPECT, WHICH IS FROM ELLEN, 342 00:11:17,654 --> 00:11:19,155 CLUES FROM A SINGLE PATIENT, AND 343 00:11:19,155 --> 00:11:21,891 THIS NOTION OF REALLY ASTUTE 344 00:11:21,891 --> 00:11:24,294 CLINICAL OBSERVATION LEADING TO 345 00:11:24,294 --> 00:11:25,729 A BREAKTHROUGH UNDERSTANDING OF 346 00:11:25,729 --> 00:11:28,999 THE GENETIC BASIS OF DISEASE. 347 00:11:28,999 --> 00:11:30,333 WE'LL THEN PITCH BACK TO ME TO 348 00:11:30,333 --> 00:11:31,868 TALK ABOUT HOW DO WE FIND WHAT'S 349 00:11:31,868 --> 00:11:33,837 LEFT, LIKE WHERE ARE WE HEADING 350 00:11:33,837 --> 00:11:35,772 IN OUR UNDERSTANDING OF THE 351 00:11:35,772 --> 00:11:36,873 GENETIC BASIS OF DISEASE, AND 352 00:11:36,873 --> 00:11:39,175 THEN LASTLY, WE'LL HEAD TOWARDS 353 00:11:39,175 --> 00:11:41,444 THERAPEUTICS, GIVING AN EXAMPLE 354 00:11:41,444 --> 00:11:42,679 OF THERAPEUTIC APPROACHES. 355 00:11:42,679 --> 00:11:46,082 THERE ARE MANY TRIALS, BOTH 356 00:11:46,082 --> 00:11:47,651 SYMPTOMATIC AND ETIOLOGIC-BASED 357 00:11:47,651 --> 00:11:48,918 TRIALS IN PARKINSON'S DISEASE, 358 00:11:48,918 --> 00:11:50,620 BUT THIS WILL SERVE AS ONE 359 00:11:50,620 --> 00:11:52,756 EXAMPLE OF HOW GENETICS LEADS US 360 00:11:52,756 --> 00:11:54,724 TOWARDS A POTENTIAL THERAPEUTIC 361 00:11:54,724 --> 00:11:56,793 AVENUES OF RESEARCH. 362 00:11:56,793 --> 00:12:01,097 SO THIS IS A PRETTY OBVIOUS 363 00:12:01,097 --> 00:12:01,965 SLIDE, I THINK. 364 00:12:01,965 --> 00:12:02,832 THIS COMES TO ANSWER THE 365 00:12:02,832 --> 00:12:04,801 QUESTION WHY DO WE DO GENETICS. 366 00:12:04,801 --> 00:12:06,870 REALLY THE IDEA IS TO UNDERSTAND 367 00:12:06,870 --> 00:12:10,373 BIOLOGY, AND IF WE CAN 368 00:12:10,373 --> 00:12:11,808 UNDERSTAND BIOLOGY OR BIOLOGIES 369 00:12:11,808 --> 00:12:14,844 OF DISEASE, WE CAN THEN FIND 370 00:12:14,844 --> 00:12:16,546 VIABLE THERAPEUTIC TARGETS, 371 00:12:16,546 --> 00:12:17,914 RATIONAL THINGS FOR US TO TRY 372 00:12:17,914 --> 00:12:18,481 AND ATTACK. 373 00:12:18,481 --> 00:12:22,619 SO THAT WE'RE NOT SIMPLY TRYING 374 00:12:22,619 --> 00:12:23,920 TO DEAL WITH SYMPTOMS, WE'RE 375 00:12:23,920 --> 00:12:25,255 REALLY TRYING TO ATTACK THE 376 00:12:25,255 --> 00:12:26,022 UNDERLYING BIOLOGY OF DISEASE 377 00:12:26,022 --> 00:12:28,858 AND I THINK THESE ARE LIKELY TO 378 00:12:28,858 --> 00:12:31,061 BE MANY, MANY TARGETS. 379 00:12:31,061 --> 00:12:32,228 THE OTHER PORTION THAT I THINK 380 00:12:32,228 --> 00:12:33,663 GENETICS MIGHT HELP US IS TO 381 00:12:33,663 --> 00:12:34,197 DISSECT DISEASE. 382 00:12:34,197 --> 00:12:36,266 SO WHAT I MEAN HERE IS, 383 00:12:36,266 --> 00:12:38,034 UNDERSTAND HOW DIFFERENT 384 00:12:38,034 --> 00:12:40,103 MECHANISMS CONTRIBUTE IN AN 385 00:12:40,103 --> 00:12:42,105 INDIVIDUAL, AND ALSO TO PREDICT 386 00:12:42,105 --> 00:12:43,606 COURSE AND OCCURRENCE OF DISEASE 387 00:12:43,606 --> 00:12:44,708 IN AN INDIVIDUAL. 388 00:12:44,708 --> 00:12:47,444 SO THIS IS ALL AROUND THE IDEA 389 00:12:47,444 --> 00:12:48,878 OF IDENTIFYING THE RIGHT 390 00:12:48,878 --> 00:12:49,846 THERAPEUTIC TARGET AND MATCHING 391 00:12:49,846 --> 00:12:55,318 TO THE RIGHT PATIENT AND 392 00:12:55,318 --> 00:12:56,086 DELIVERING THAT THERAPY AT THE 393 00:12:56,086 --> 00:12:57,954 RIGHT TIME, SO RIGHT TARGET, 394 00:12:57,954 --> 00:12:59,055 RIGHT PATIENT, RIGHT TIME. 395 00:12:59,055 --> 00:13:00,990 SO WHERE ARE WE IN THE CONTEXT 396 00:13:00,990 --> 00:13:02,325 OF THE GENETICS OF PARKINSON'S 397 00:13:02,325 --> 00:13:03,093 DISEASE? 398 00:13:03,093 --> 00:13:06,796 SO LIKE MOST NEUROLOGICAL 399 00:13:06,796 --> 00:13:09,099 DISORDERS, WE REALLY FOCUSED ON 400 00:13:09,099 --> 00:13:10,300 MONOGENIC DISEASE IN THE FIRST 401 00:13:10,300 --> 00:13:10,867 INSTANCE. 402 00:13:10,867 --> 00:13:12,936 SO CASES WHERE DISEASE OCCURS 403 00:13:12,936 --> 00:13:14,137 MORE OFTEN THAN ONE WOULD EXPECT 404 00:13:14,137 --> 00:13:17,974 IN A FAMILY, LEADING US TO 405 00:13:17,974 --> 00:13:19,175 SUGGEST THERE IS A SINGLE 406 00:13:19,175 --> 00:13:20,043 MUTATION THAT'S DRIVING DISEASE 407 00:13:20,043 --> 00:13:20,810 IN THAT FAMILY. 408 00:13:20,810 --> 00:13:23,780 THERE ARE AROUND A DOZEN OR SO 409 00:13:23,780 --> 00:13:25,849 GENES THAT CONTAIN MUTATIONS 410 00:13:25,849 --> 00:13:28,151 THAT ARE CAUSATIVE OF 411 00:13:28,151 --> 00:13:28,885 PARKINSON'S DISEASE. 412 00:13:28,885 --> 00:13:30,553 I'VE PUT THEM HERE ON THIS 413 00:13:30,553 --> 00:13:31,588 CIRCULAR GENOME SO YOU'VE GOT 414 00:13:31,588 --> 00:13:34,758 THE AUTO SOMES GOING FROM ONE 415 00:13:34,758 --> 00:13:35,158 THROUGH 22. 416 00:13:35,158 --> 00:13:36,793 THESE HAVE BEEN INCREDIBLY 417 00:13:36,793 --> 00:13:38,094 INFORMATIVE AND INCREDIBLY 418 00:13:38,094 --> 00:13:41,798 INFLINFLUENTIAL IN TERMS OF HOWE 419 00:13:41,798 --> 00:13:43,333 TRY TO MODEL DISEASE AND 420 00:13:43,333 --> 00:13:45,668 UNDERSTAND THE MOLECULAR BIOLOGY 421 00:13:45,668 --> 00:13:46,169 OF DISEASE. 422 00:13:46,169 --> 00:13:48,037 THE VERY FIRST MUTATION 423 00:13:48,037 --> 00:13:49,038 DISCOVERED AS A CAUSE OF 424 00:13:49,038 --> 00:13:50,006 PARKINSON'S DISEASE WAS FOUND 425 00:13:50,006 --> 00:13:55,278 HERE IN 1997. 426 00:13:55,278 --> 00:13:57,447 THIS REALLY CHANGED THE FIELD 427 00:13:57,447 --> 00:13:58,314 ENTIRELY. 428 00:13:58,314 --> 00:14:00,383 SO PARKINSON'S DISEASE WAS OFTEN 429 00:14:00,383 --> 00:14:01,918 THOUGHT OF AS A NON-GENETIC 430 00:14:01,918 --> 00:14:04,988 DISEASE ENTITY, AND EVEN WHEN 431 00:14:04,988 --> 00:14:06,523 THERE WAS SOME EVIDENCE THAT 432 00:14:06,523 --> 00:14:07,957 THERE WAS A GENETIC BASIS TO THE 433 00:14:07,957 --> 00:14:09,159 DISEASE, IT WAS A GENERAL 434 00:14:09,159 --> 00:14:10,126 THOUGHT THAT WHATEVER WAS FOUND 435 00:14:10,126 --> 00:14:11,461 IN FAMILIES JUST WOULDN'T BE 436 00:14:11,461 --> 00:14:14,097 RELEVANT TO THE TYPICAL DISEASE. 437 00:14:14,097 --> 00:14:15,732 SO THIS FINDING REALLY CHANGED 438 00:14:15,732 --> 00:14:16,032 EVERYTHING. 439 00:14:16,032 --> 00:14:17,667 IT SHOWED QUITE SIMPLY THAT 440 00:14:17,667 --> 00:14:20,970 MUTATIONS IN A GENE CALLED ALPHA 441 00:14:20,970 --> 00:14:22,505 SYNUCLEIN ENCODING A PROTEIN 442 00:14:22,505 --> 00:14:24,140 CALLED SYNUCLEIN WHICH ELLEN HAS 443 00:14:24,140 --> 00:14:25,341 ALREADY TALKED ABOUT CAN CAUSE 444 00:14:25,341 --> 00:14:25,675 DISEASE. 445 00:14:25,675 --> 00:14:28,411 SO THE FIRST MUTATIONS FOUND 446 00:14:28,411 --> 00:14:31,481 WERE A53T MUTATION AND THEN AN 447 00:14:31,481 --> 00:14:33,550 E30P MUTATION. 448 00:14:33,550 --> 00:14:35,418 THE FORMER FOUND IN AN ITALIAN 449 00:14:35,418 --> 00:14:37,353 GREEK KINDRED, AGAIN BY 450 00:14:37,353 --> 00:14:38,354 RESEARCHERS HERE, AND 451 00:14:38,354 --> 00:14:39,222 IMMEDIATELY AFTER THAT, IT WAS 452 00:14:39,222 --> 00:14:41,324 SHOWN THAT THE PROTEIN THAT WAS 453 00:14:41,324 --> 00:14:43,493 ENCODED BY THIS GENE, SYNUCLEIN, 454 00:14:43,493 --> 00:14:46,129 WAS A MAJOR COMPONENT OF LEWY 455 00:14:46,129 --> 00:14:48,531 BODIES SO IT LINKED DISEASE IN 456 00:14:48,531 --> 00:14:51,601 THESE REALLY RARE FAMILIES, THAT 457 00:14:51,601 --> 00:14:53,670 LOOKED LIKE THEY HAD A SUPER 458 00:14:53,670 --> 00:14:54,637 RARE PARKINSON'S DISEASE COULD 459 00:14:54,637 --> 00:14:56,439 BE LINKED TO THE PATHOLOGICAL 460 00:14:56,439 --> 00:14:59,042 HALLMARKS OF ALL PARKINSON'S 461 00:14:59,042 --> 00:15:00,243 DISEASE, SHOWING THE GENETIC 462 00:15:00,243 --> 00:15:02,412 BASIS OF RARE DISORDERS CAN BE 463 00:15:02,412 --> 00:15:03,379 INCREDIBLY INFORMATIVE IN TERMS 464 00:15:03,379 --> 00:15:04,514 OF UNDERSTANDING DISEASE AS A 465 00:15:04,514 --> 00:15:06,249 WHOLE. 466 00:15:06,249 --> 00:15:08,318 FOR THE NEXT SIX OR SEVEN YEARS 467 00:15:08,318 --> 00:15:10,954 AFTER THAT, SEVERAL GENES WERE 468 00:15:10,954 --> 00:15:12,388 IDENTIFIED AND THERE WAS A GREAT 469 00:15:12,388 --> 00:15:15,124 DEAL OF WORK ON UNDERSTANDING 470 00:15:15,124 --> 00:15:16,593 WHAT QUALITATIVE CHANGES IN 471 00:15:16,593 --> 00:15:19,596 SYNUCLEIN WOULD DO IN TERMS OF 472 00:15:19,596 --> 00:15:22,665 DISEASE RISK. 473 00:15:22,665 --> 00:15:24,500 OUR GROUP FOUND MUTATIONS THAT 474 00:15:24,500 --> 00:15:25,735 CHANGED QUANTITATIVELY THE 475 00:15:25,735 --> 00:15:27,904 AMOUNT OF SYNUCLEIN THAT WAS 476 00:15:27,904 --> 00:15:29,539 PRODUCED IN 2003, SO ABOUT FIVE 477 00:15:29,539 --> 00:15:31,507 OR SIX YEARS AFTER THE ORIGINAL 478 00:15:31,507 --> 00:15:33,376 SYNUCLEIN MUTATION. 479 00:15:33,376 --> 00:15:37,413 AND DISEASE IN THESE FAMILIES, 480 00:15:37,413 --> 00:15:40,250 THE WATERS MILLER KINDRED, ARE 481 00:15:40,250 --> 00:15:42,652 SIMPLY DRIVEN BY TOO MUCH 482 00:15:42,652 --> 00:15:42,919 SYNUCLEIN. 483 00:15:42,919 --> 00:15:45,822 SO IN THIS ORIGINAL FAMILY, THE 484 00:15:45,822 --> 00:15:47,690 PATIENTS HAVE FOUR COPIES OF 485 00:15:47,690 --> 00:15:50,059 SYNUCLEIN, SO THREE ON ONE 486 00:15:50,059 --> 00:15:51,094 CHROMOSOME, FOUR -- ONE ON THE 487 00:15:51,094 --> 00:15:52,528 OTHER CHROMOSOME, FOUR, AND JUST 488 00:15:52,528 --> 00:15:55,265 HAVING TOO MUCH CAN DRIVE 489 00:15:55,265 --> 00:15:55,698 DISEASE. 490 00:15:55,698 --> 00:15:57,767 IT CAUSES A FAIRLY TYPICAL 491 00:15:57,767 --> 00:15:59,836 PARKINSON'S DISEASE, ALBEIT WITH 492 00:15:59,836 --> 00:16:01,905 PRETTY PROMINENT PATHOLOGY, 493 00:16:01,905 --> 00:16:03,873 PROMINENT DEMENTIA, BUT A FAIRLY 494 00:16:03,873 --> 00:16:05,608 TYPICAL PARKINSON'S DISEASE. 495 00:16:05,608 --> 00:16:07,710 SO QUALITATIVE CHANGES IN 496 00:16:07,710 --> 00:16:09,045 SYNUCLEIN CAN DRIVE DISEASE, AND 497 00:16:09,045 --> 00:16:10,246 JUST INCREASING THE AMOUNT OF 498 00:16:10,246 --> 00:16:14,717 SYNUCLEIN CAN CAUSE DISEASE. 499 00:16:14,717 --> 00:16:16,886 A YEAR OR SO LATER, OUR GROUP 500 00:16:16,886 --> 00:16:19,322 FOUND THE NEXT MUTATION, SOME 501 00:16:19,322 --> 00:16:24,327 MUTATIONS IN A GENE CALLED LRC 502 00:16:24,327 --> 00:16:25,628 IT. 503 00:16:25,628 --> 00:16:26,529 WE CO-DISCOVERED THIS EXACTLY AT 504 00:16:26,529 --> 00:16:28,398 THE SAME TIME AS TOM GASSER'S 505 00:16:28,398 --> 00:16:29,065 GROUP FOUND THIS. 506 00:16:29,065 --> 00:16:30,700 WHAT WAS INTERESTING ABOUT THIS 507 00:16:30,700 --> 00:16:33,536 PARTICULAR MUTATION IS IT WAS 508 00:16:33,536 --> 00:16:35,171 VERY COMMON. 509 00:16:35,171 --> 00:16:38,441 SO AROUND 2% OF ALL NORTHERN 510 00:16:38,441 --> 00:16:39,976 EUROPEAN ANCESTRY CASES CARRIED 511 00:16:39,976 --> 00:16:40,410 THIS MUTATION. 512 00:16:40,410 --> 00:16:42,345 IT GOES UP TO ABOUT 5 OR 6% IF 513 00:16:42,345 --> 00:16:43,713 YOU LOOK AT FAMILIAL CASES, IT 514 00:16:43,713 --> 00:16:46,783 GOES UP TO 20% IF YOU LOOK AT 515 00:16:46,783 --> 00:16:48,284 THE JEWISH POPULATIONS, UP TO 516 00:16:48,284 --> 00:16:50,720 40% IF YOU LOOK IN NORTH AFRICAN 517 00:16:50,720 --> 00:16:51,921 ARAB POPULATIONS. 518 00:16:51,921 --> 00:16:54,424 THIS PARTICULAR MUTATION IS IN 519 00:16:54,424 --> 00:16:55,959 THE KINASE DOMAIN. 520 00:16:55,959 --> 00:16:58,695 IT SEEMS TO INCREASE KINASE 521 00:16:58,695 --> 00:16:59,662 ACTIVITY AND I THINK 522 00:16:59,662 --> 00:17:00,630 IMMEDIATELY, WITHIN A MONTH OR 523 00:17:00,630 --> 00:17:02,532 TWO OF MAKING THE DISCOVERY, IT 524 00:17:02,532 --> 00:17:05,134 BECAME CLEAR THAT KINASE 525 00:17:05,134 --> 00:17:06,569 ACTIVITY WAS A GOOD THERAPEUTIC 526 00:17:06,569 --> 00:17:08,304 TARGET, AND INDEED THIS IS A 527 00:17:08,304 --> 00:17:09,405 THERAPEUTIC TARGET THAT'S BEEN 528 00:17:09,405 --> 00:17:10,707 PURSUED VERY HEAVILY BY MANY 529 00:17:10,707 --> 00:17:11,908 GROUPS AROUND THE WORLD. 530 00:17:11,908 --> 00:17:14,010 THERE'S NOW A LARGE PHASE 531 00:17:14,010 --> 00:17:16,179 3 CLINICAL TRIAL AIMED AT 532 00:17:16,179 --> 00:17:17,413 REDUCING KINASE ACTIVITY, AS 533 00:17:17,413 --> 00:17:19,349 WELL AS OTHER GENETIC-BASED 534 00:17:19,349 --> 00:17:21,985 TRIALS FOR LRRK2. 535 00:17:21,985 --> 00:17:23,319 SEVERAL OTHER MUTATIONS I NOTED 536 00:17:23,319 --> 00:17:26,689 A DOZEN OR SO. 537 00:17:26,689 --> 00:17:29,425 I INCLUDE THREE HERE WHICH WE 538 00:17:29,425 --> 00:17:30,960 ALSO FOUND. 539 00:17:30,960 --> 00:17:33,463 WE HAD A ROLE IN THE DISCOVERY 540 00:17:33,463 --> 00:17:34,998 OF SOME OF THE OTHERS, BUT 541 00:17:34,998 --> 00:17:36,199 THERE'S CONTINUED DISCOVERY. 542 00:17:36,199 --> 00:17:37,967 THERE'S CONTINUED DISCOVERY OF 543 00:17:37,967 --> 00:17:40,169 NEW GENES THAT CONTAIN RARE 544 00:17:40,169 --> 00:17:50,546 MUTATIONS THAT CAUSE DISEASE. 545 00:17:50,546 --> 00:17:52,181 MODERATE RISK VARIANTS, ELLEN IS 546 00:17:52,181 --> 00:17:53,916 GOING TO TALK MORE SIGNIFICANTLY 547 00:17:53,916 --> 00:17:56,419 ABOUT ONE OF THESE, GBA, WHICH 548 00:17:56,419 --> 00:17:57,620 HAS BEEN INCREDIBLY INFORMATIVE 549 00:17:57,620 --> 00:18:00,056 IN OUR UNDERSTANDING OF 550 00:18:00,056 --> 00:18:01,357 SYNUCLEINOPATHIES, NOT JUST 551 00:18:01,357 --> 00:18:03,493 PARKINSON'S DISEASE BUT ALSO 552 00:18:03,493 --> 00:18:04,427 DEMENTIA WITH LEWY BODIES. 553 00:18:04,427 --> 00:18:05,561 THEN MOST RECENTLY, MY LAB HAS 554 00:18:05,561 --> 00:18:08,464 BEEN WORKING ON UNDERSTANDING 555 00:18:08,464 --> 00:18:12,301 THE JE GENETIC BASIS OF COMMON 556 00:18:12,301 --> 00:18:13,703 PARKINSON'S DISEASE, SO THOSE 557 00:18:13,703 --> 00:18:15,138 CASES WHERE THERE ISN'T A 558 00:18:15,138 --> 00:18:15,905 PARTICULARLY STRONG FAMILY 559 00:18:15,905 --> 00:18:16,773 HISTORY, AND WE'VE BEEN DOING 560 00:18:16,773 --> 00:18:18,608 THIS USING GENOME-WIDE 561 00:18:18,608 --> 00:18:21,911 ASSOCIATION STUDY, SO REALLY AT 562 00:18:21,911 --> 00:18:24,547 THE MOST BASIC WHAT THIS IS IS 563 00:18:24,547 --> 00:18:26,082 DOING VERY DENSE GENOTYPING 564 00:18:26,082 --> 00:18:28,284 THROUGHOUT THE GENOME, SO AROUND 565 00:18:28,284 --> 00:18:30,686 A MILLION OR SO SITES IN A VERY 566 00:18:30,686 --> 00:18:32,855 LARGE NUMBER OF INDIVIDUALS. 567 00:18:32,855 --> 00:18:34,390 SO THIS PARTICULAR GENOME-WIDE 568 00:18:34,390 --> 00:18:35,558 ASSOCIATION STUDY WHICH WAS 569 00:18:35,558 --> 00:18:37,894 PUBLISHED ABOUT TWO OR THREE 570 00:18:37,894 --> 00:18:40,096 YEARS AGO INCLUDED SOMEWHERE IN 571 00:18:40,096 --> 00:18:41,764 THE REGION OF 50 TO 60,000 572 00:18:41,764 --> 00:18:44,667 PATIENTS AND ABOUT 1 1/2 MILLION 573 00:18:44,667 --> 00:18:45,001 CONTROLS. 574 00:18:45,001 --> 00:18:48,037 AND YOU SIMPLY LOOK AT THE 575 00:18:48,037 --> 00:18:48,604 DIFFERENCE IN VARIABILITY 576 00:18:48,604 --> 00:18:49,806 BETWEEN THE CASES AND THE 577 00:18:49,806 --> 00:18:51,007 CONTROLS, AND THIS LEADS YOU TO 578 00:18:51,007 --> 00:18:52,642 REGIONS OF THE GENOME THAT 579 00:18:52,642 --> 00:18:56,045 IMPART RISK. 580 00:18:56,045 --> 00:18:57,046 I'M GOING TO COME BACK TO THIS 581 00:18:57,046 --> 00:18:59,215 KIND OF STUDY LATER AND TALK 582 00:18:59,215 --> 00:19:00,583 ABOUT THE KIND OF DIRECTION 583 00:19:00,583 --> 00:19:01,851 WE'RE HEADED IN TO FURTHER 584 00:19:01,851 --> 00:19:03,352 UNDERSTAND THE GENETIC BASIS OF 585 00:19:03,352 --> 00:19:03,920 DISEASE. 586 00:19:03,920 --> 00:19:05,354 BUT AS OF THIS PUBLICATION, 587 00:19:05,354 --> 00:19:06,556 AGAIN, THIS WAS PUBLISHED ABOUT 588 00:19:06,556 --> 00:19:08,091 THREE YEARS AGO, THERE ARE 589 00:19:08,091 --> 00:19:10,059 AROUND 90 OR SO REGIONS IN THE 590 00:19:10,059 --> 00:19:12,128 GENOME THAT CONTAIN RISK 591 00:19:12,128 --> 00:19:12,895 VARIANTS FOR PARKINSON'S 592 00:19:12,895 --> 00:19:15,631 DISEASE. 593 00:19:15,631 --> 00:19:17,366 THERE'S A HUGE AMOUNT LEFT TO BE 594 00:19:17,366 --> 00:19:18,801 FOUND, SO IF WE LOOK AT THE 595 00:19:18,801 --> 00:19:21,204 POPULATIONS THAT WE STARTED 596 00:19:21,204 --> 00:19:22,271 USING GENOME WIDE ASSOCIATION 597 00:19:22,271 --> 00:19:28,277 STUDY, THERE'S 90 RISK LOHSE LOY 598 00:19:28,277 --> 00:19:29,879 REPRESENT ABOUT A THIRD OF THE 599 00:19:29,879 --> 00:19:30,980 INHERITABLE COMPONENT SO WE'VE 600 00:19:30,980 --> 00:19:34,150 ONLY FOUND THE MINORITY OF THE 601 00:19:34,150 --> 00:19:35,017 GENETIC INFLUENCE WE KNOW HAS TO 602 00:19:35,017 --> 00:19:35,685 BE THERE. 603 00:19:35,685 --> 00:19:37,019 BASED ON OTHER COMPLEX TRAITS 604 00:19:37,019 --> 00:19:38,121 LIKE HEIGHT, THERE ARE GOING TO 605 00:19:38,121 --> 00:19:40,156 BE THOUSANDS OF OTHER RISK LOCI 606 00:19:40,156 --> 00:19:41,924 TO BE DISCOVERED. 607 00:19:41,924 --> 00:19:45,094 SO A KEY QUESTION IS, WHY DO WE 608 00:19:45,094 --> 00:19:46,829 LOOK, WHY DO WE CONTINUE TO LOOK 609 00:19:46,829 --> 00:19:50,533 FOR GENETIC VARIABILITY? 610 00:19:50,533 --> 00:19:51,134 PARTICULARLY SOMETHING THAT'S 611 00:19:51,134 --> 00:19:53,069 ASKED IS WHY DO WE LOOK FOR 612 00:19:53,069 --> 00:19:54,070 COMMON GENETIC VARIABILITY WHICH 613 00:19:54,070 --> 00:19:55,271 TENDS TO BE OF LOW EFFECT? 614 00:19:55,271 --> 00:19:56,472 SO THERE ARE A COUPLE OF ANSWERS 615 00:19:56,472 --> 00:19:58,207 TO THIS. 616 00:19:58,207 --> 00:19:59,642 FIRST OF ALL AT EVERY NEW 617 00:19:59,642 --> 00:20:01,711 ASSOCIATION THAT WE FIND, GIVES 618 00:20:01,711 --> 00:20:03,246 US SOME BIOLOGICAL INSIGHT INTO 619 00:20:03,246 --> 00:20:04,881 THE DISEASE PROCESS, RIGHT? 620 00:20:04,881 --> 00:20:08,718 IT'S ANOTHER WINDOW INTO THE 621 00:20:08,718 --> 00:20:09,819 MECHANISM OF THE UNDERLYING 622 00:20:09,819 --> 00:20:12,021 BIOLOGY. 623 00:20:12,021 --> 00:20:14,090 THE SECOND PART IS REALLY BORNE 624 00:20:14,090 --> 00:20:15,791 BY THIS PAPER, WHICH I THINK IS 625 00:20:15,791 --> 00:20:17,360 A BEAUTIFUL PAPER FOR 626 00:20:17,360 --> 00:20:18,995 GENETICISTS, WHICH SHOWS QUITE 627 00:20:18,995 --> 00:20:21,297 SIMPLY THAT IF YOU ARE LOOKING 628 00:20:21,297 --> 00:20:22,732 AT A DRUG TARGET, THE SUCCESS OF 629 00:20:22,732 --> 00:20:24,567 TURNING THAT DRUG TARGET INTO A 630 00:20:24,567 --> 00:20:26,102 THERAPEUTIC IS ABOUT TWICE AS 631 00:20:26,102 --> 00:20:28,838 HIGH IF YOU HAVE GENETIC DATA, 632 00:20:28,838 --> 00:20:30,606 GENETIC EVIDENCE SUPPORTING THAT 633 00:20:30,606 --> 00:20:33,342 TARGET, THAN IF YOU DON'T. 634 00:20:33,342 --> 00:20:35,144 AND IT IS NOT DEPENDENT ON HOW 635 00:20:35,144 --> 00:20:36,946 STRONG THE GENETIC EFFECT IS. 636 00:20:36,946 --> 00:20:38,581 IT'S JUST DEPENDENT ON WHETHER 637 00:20:38,581 --> 00:20:39,982 THAT GENETIC EFFECT IS REAL OR 638 00:20:39,982 --> 00:20:40,316 NOT. 639 00:20:40,316 --> 00:20:43,052 SO THE SIZE OF EFFECT IS 640 00:20:43,052 --> 00:20:44,053 IRRELEVANT WHEN YOU'RE LOOKING 641 00:20:44,053 --> 00:20:45,788 FOR GOOD THERAPEUTIC TARGETS. 642 00:20:45,788 --> 00:20:48,057 SO THE MORE GENES WE CAN FIND 643 00:20:48,057 --> 00:20:49,525 ASSOCIATED WITH DISEASE, THE 644 00:20:49,525 --> 00:20:50,726 MORE INSIGHT WE HAVE INTO 645 00:20:50,726 --> 00:20:52,795 BIOLOGY, THE MORE DIRECT TARGETS 646 00:20:52,795 --> 00:20:55,064 WE HAVE AND THE MORE INDIRECT 647 00:20:55,064 --> 00:20:57,066 TARGETS WE CAN CREATE AS WE 648 00:20:57,066 --> 00:20:59,368 START TO TIE ALL OF THESE GENES 649 00:20:59,368 --> 00:21:00,469 TOGETHER AND THEIR FUNCTIONS 650 00:21:00,469 --> 00:21:02,538 TOGETHER. 651 00:21:02,538 --> 00:21:03,306 I'M ALSO GOING TO SAY PART OF 652 00:21:03,306 --> 00:21:04,507 THE REASON WHY WE NEED TO 653 00:21:04,507 --> 00:21:06,175 CONTINUE LOOKING IS, THIS 654 00:21:06,175 --> 00:21:07,910 PICTURE I'VE SHOWN YOU IS A LIE, 655 00:21:07,910 --> 00:21:09,045 BECAUSE THIS PICTURE I'VE SHOWN 656 00:21:09,045 --> 00:21:12,715 YOU IS GENERALLY THE GENETIC 657 00:21:12,715 --> 00:21:13,683 ARCHITECTURE IN NORTHERN 658 00:21:13,683 --> 00:21:15,351 EUROPEAN ANCESTRY POPULATION. 659 00:21:15,351 --> 00:21:17,086 WE ALMOST KNOW ALMOST NOTHING 660 00:21:17,086 --> 00:21:18,387 THE GENETIC ARCHITECTURE OF 661 00:21:18,387 --> 00:21:20,156 DISEASES IN POPULATIONS OUTSIDE 662 00:21:20,156 --> 00:21:22,558 OF NORTHERN EUROPE. 663 00:21:22,558 --> 00:21:24,160 IF WE THINK OF PARKINSON'S AS A 664 00:21:24,160 --> 00:21:25,394 GLOBAL DISEASE, WHICH IT IS, AND 665 00:21:25,394 --> 00:21:28,998 IF WE BELIEVE THIS CONCEPT THAT 666 00:21:28,998 --> 00:21:30,299 WE NEED TO UNDERSTAND THE BASIS 667 00:21:30,299 --> 00:21:31,300 OF DISEASE IN ORDER TO BE ABLE 668 00:21:31,300 --> 00:21:34,237 TO TREAT IT, WE THEN NEED TO BE 669 00:21:34,237 --> 00:21:36,672 DOING GENETICS IN POP LAITIONS 670 00:21:36,672 --> 00:21:37,306 AROUND THE WORLD. 671 00:21:37,306 --> 00:21:38,541 WE NEED TO UNDERSTAND THE BASIS 672 00:21:38,541 --> 00:21:39,609 OF DISEASE IN IMLOABL 673 00:21:39,609 --> 00:21:40,576 POPULATIONS, KNOW WHAT'S THE 674 00:21:40,576 --> 00:21:41,677 SAME, KNOW WHAT'S DIFFERENT SO 675 00:21:41,677 --> 00:21:42,812 WE CAN TIE TREATMENTS TO 676 00:21:42,812 --> 00:21:46,515 INDIVIDUALS. 677 00:21:46,515 --> 00:21:47,817 WE'RE GOING TO SKIP TO THE NEXT 678 00:21:47,817 --> 00:21:49,685 PRESENTATION NOW. 679 00:21:49,685 --> 00:21:52,722 ELLEN IS GOING TO TAKE US FROM 680 00:21:52,722 --> 00:21:53,923 THIS BROAD VIEW LOOKING AT THE 681 00:21:53,923 --> 00:21:55,157 WHOLE GENOME IN THOUSANDS OF 682 00:21:55,157 --> 00:21:59,195 INDIVIDUALS TO INSIGHTS IN VERY 683 00:21:59,195 --> 00:21:59,996 CAREFULLY CHARACTERIZED 684 00:21:59,996 --> 00:22:10,206 INDIVIDUALS. 685 00:22:11,207 --> 00:22:11,974 >> OKAY. 686 00:22:11,974 --> 00:22:13,175 WELL, IT IS KIND OF FUN TO GO 687 00:22:13,175 --> 00:22:14,844 AFTER ANDY, BECAUSE IT'S SORT OF 688 00:22:14,844 --> 00:22:16,078 LIKE GOING FROM THE TELESCOPE TO 689 00:22:16,078 --> 00:22:19,115 THE MICROSCOPE. 690 00:22:19,115 --> 00:22:20,850 I CAN'T IMAGINE EVER COLLECTING 691 00:22:20,850 --> 00:22:24,353 40,000 SAMPLES OF ANYTHING, 692 00:22:24,353 --> 00:22:25,755 BECAUSE MY CAREER HAS MAINLY 693 00:22:25,755 --> 00:22:28,291 BEEN STUDYING RARE DISEASES. 694 00:22:28,291 --> 00:22:29,825 I LIKE TO TELL PEOPLE THAT I 695 00:22:29,825 --> 00:22:31,460 LIVE IN A VERY SMALL HOUSE, BUT 696 00:22:31,460 --> 00:22:33,095 MY WINDOWS LOOK OUT AT A VERY 697 00:22:33,095 --> 00:22:38,234 LARGE WORLD, AND MY VERY SMALL 698 00:22:38,234 --> 00:22:41,704 HOUSE HAS BEEN A DISEASE CALLED 699 00:22:41,704 --> 00:22:43,272 GAUCHER DISEASE WHICH I'VE SPENT 700 00:22:43,272 --> 00:22:45,908 MY WHOLE CAREER ON, INHERITED 701 00:22:45,908 --> 00:22:50,579 LYSOSOMAL STORAGE DISORDER, AND 702 00:22:50,579 --> 00:22:54,083 FROM THIS WINDOW, I HAVE STARTED 703 00:22:54,083 --> 00:22:54,917 STUDYING PARKINSON DISEASE, 704 00:22:54,917 --> 00:22:56,619 WHICH WAS A DID BIG STRETCH 705 00:22:56,619 --> 00:22:57,920 BECAUSE AS YOU HEARD, I WAS 706 00:22:57,920 --> 00:22:59,655 TRAINED AS A PEDIATRICIAN AND 707 00:22:59,655 --> 00:23:00,556 IT'S PROBABLY ONE DISORDER THAT 708 00:23:00,556 --> 00:23:06,595 I KNEW ABSOLUTELY NOTHING ABOUT. 709 00:23:06,595 --> 00:23:09,765 UNLIKE GAUCHER DISEASE, WE KNOW 710 00:23:09,765 --> 00:23:11,200 IT'S A COMMON COMPLEX DISORDER, 711 00:23:11,200 --> 00:23:12,835 BUT OUR LAB NOW IS REALLY 712 00:23:12,835 --> 00:23:14,704 FOCUSED ON STUDYING THE 713 00:23:14,704 --> 00:23:15,805 CONNECTION BETWEEN THESE TWO IN 714 00:23:15,805 --> 00:23:18,841 A BENCH TO BEDSIDE TRANSLATIONAL 715 00:23:18,841 --> 00:23:20,076 APPROACH WHERE WE COMBINE ALL 716 00:23:20,076 --> 00:23:23,679 DIFFERENT TYPE OF MODALITIES, BE 717 00:23:23,679 --> 00:23:25,414 IT STUDYING THAT POLG, CLINICAL 718 00:23:25,414 --> 00:23:28,050 STUDIES, IMAGING, GENETIC 719 00:23:28,050 --> 00:23:28,918 STUDIES, CELL BUY OCIALTION 720 00:23:28,918 --> 00:23:30,453 PROTEIN STUDIES, SOME OF WHICH 721 00:23:30,453 --> 00:23:31,654 I'M GOING TO TRY TO TALK TO YOU 722 00:23:31,654 --> 00:23:33,289 ABOUT IN THE NEXT FEW MINUTES 723 00:23:33,289 --> 00:23:35,591 AND OTHERS, WE'LL GO FOR ANOTHER 724 00:23:35,591 --> 00:23:36,092 DAY. 725 00:23:36,092 --> 00:23:38,094 BUT I THINK THAT YOU WILL COME 726 00:23:38,094 --> 00:23:40,730 TO APPRECIATE THE RARE GENETIC 727 00:23:40,730 --> 00:23:42,231 DISORDERS CAN PROVIDE A WINDOW 728 00:23:42,231 --> 00:23:47,303 INTO COMMON COMPLEX DISORDERS. 729 00:23:47,303 --> 00:23:50,339 SO GAUCHER DISEASE WAS FIRST 730 00:23:50,339 --> 00:23:54,276 DESCRIBED BY PHILIPE GAUCHER 731 00:23:54,276 --> 00:23:54,710 BACK IN 1882. 732 00:23:54,710 --> 00:23:55,945 HE WAS A MEDICAL STUDENT WHEN HE 733 00:23:55,945 --> 00:23:57,012 MADE THE OBSERVATION, WHICH I 734 00:23:57,012 --> 00:23:58,347 ALWAYS LIKE TO STRESS WHEN I'M 735 00:23:58,347 --> 00:23:59,982 SPEAKING TO STUDENT GROUPS. 736 00:23:59,982 --> 00:24:03,586 I LIKE TO THINK OF IT AS AN NIH 737 00:24:03,586 --> 00:24:04,687 DISORDER BECAUSE IN THE PAST SIX 738 00:24:04,687 --> 00:24:07,323 OR SEVEN DECADES, MOST OF THE 739 00:24:07,323 --> 00:24:09,325 ADVANCES HAVE OCCURRED ACTUALLY 740 00:24:09,325 --> 00:24:11,594 AT THE CLINICAL CENTER, MOSTLY 741 00:24:11,594 --> 00:24:14,530 FROM THE WORK OF ROSCOE BRADY, 742 00:24:14,530 --> 00:24:16,932 WHO IDENTIFIED THE ENZYMATIC 743 00:24:16,932 --> 00:24:19,835 DEFECT IN 1965, AND WAS THE 744 00:24:19,835 --> 00:24:22,171 FIRST TO OFFER TREATMENT FOR 745 00:24:22,171 --> 00:24:24,407 GAUCHER DISEASE IN THE FORM OF A 746 00:24:24,407 --> 00:24:26,642 HIGHLY EFFECTIVE ENZYME 747 00:24:26,642 --> 00:24:27,109 REPLACEMENT. 748 00:24:27,109 --> 00:24:32,214 MY MENTOR, ED GINZ, WAS THE 749 00:24:32,214 --> 00:24:34,016 FIRST TO CLONE THE GENE AND 750 00:24:34,016 --> 00:24:36,719 IDENTIFIED THE FIRST MUTATIONS 751 00:24:36,719 --> 00:24:38,287 AND MAKE THE FIRST ANIMAL MODEL, 752 00:24:38,287 --> 00:24:39,789 AND THE PARKINSON'S STORY 753 00:24:39,789 --> 00:24:40,890 ACTUALLY CAME FROM HERE IN THE 754 00:24:40,890 --> 00:24:41,657 CLINICAL CENTER. 755 00:24:41,657 --> 00:24:44,260 SO GAUCHER DISEASE IS THE 756 00:24:44,260 --> 00:24:46,462 INHERITED DEFICIENCY OF THIS 757 00:24:46,462 --> 00:24:49,064 ENZYME GLUCOCEREBROCYTASE THAT 758 00:24:49,064 --> 00:24:51,834 BREAKS DOWN A LIPID INTO 759 00:24:51,834 --> 00:24:53,369 CERAMIDE AND GLUCOSE, AND WE 760 00:24:53,369 --> 00:24:55,771 OFTEN REFER TO THE ENZYME AS G 761 00:24:55,771 --> 00:25:02,678 CASE AND THE GENE AS GBA1. 762 00:25:02,678 --> 00:25:04,146 SO IT'S AN ENZYME THAT FUNCTIONS 763 00:25:04,146 --> 00:25:07,550 IN THE LYSOSOME LIKE MAYBE 60 764 00:25:07,550 --> 00:25:11,220 OTHER LYSOSOMAL ENZYMES. 765 00:25:11,220 --> 00:25:13,189 IT'S A DISORDER PRIMARILY OF 766 00:25:13,189 --> 00:25:16,025 MACROPHAGES WHERE LYSOSOMES 767 00:25:16,025 --> 00:25:17,226 WITHIN MACROPHAGES BECOME 768 00:25:17,226 --> 00:25:18,093 ENGORGED WITH THIS STORAGE 769 00:25:18,093 --> 00:25:21,030 MATERIAL, GIVING RISE TO THE 770 00:25:21,030 --> 00:25:22,031 CHARACTERISTIC-APPEARING GAUCHER 771 00:25:22,031 --> 00:25:23,132 CELL, WHICH IS SOMETIMES THE 772 00:25:23,132 --> 00:25:24,967 ONLY IMAGE THAT PEOPLE REMEMBER 773 00:25:24,967 --> 00:25:27,636 FROM MEDICAL SCHOOL. 774 00:25:27,636 --> 00:25:33,442 THE GENE IS LOAK LOCATED ON 775 00:25:33,442 --> 00:25:34,944 CHROMOSOME ONE, THERE WAS A 776 00:25:34,944 --> 00:25:36,312 HIGHLY HOMOLOGOUS SEQUENCE 777 00:25:36,312 --> 00:25:39,448 SHARING ABOUT 97% SEQUENCE 778 00:25:39,448 --> 00:25:40,749 HOMOLOGY WITH THE GENE. 779 00:25:40,749 --> 00:25:42,418 AND THIS WAS IMPORTANT WHEN -- 780 00:25:42,418 --> 00:25:48,824 FOR LOTS OF REASONS. 781 00:25:48,824 --> 00:25:51,760 TODAY WE KNOW OF 600 DIFFERENT 782 00:25:51,760 --> 00:25:53,329 PATHOGENIC VARIANTS IN THIS GENE 783 00:25:53,329 --> 00:25:54,296 IDENTIFIED IN PATIENTS WITH 784 00:25:54,296 --> 00:25:55,064 GAUCHER DISEASE. 785 00:25:55,064 --> 00:25:57,032 MOST OF THESE 600 ARE RARE. 786 00:25:57,032 --> 00:25:58,667 THERE ARE A FEW THAT ARE COMMON. 787 00:25:58,667 --> 00:26:03,606 THE MOST COMMON VARIANT IN 788 00:26:03,606 --> 00:26:06,976 ASHKENAZI JEWS IS N370S, WHICH 789 00:26:06,976 --> 00:26:09,044 IS ASSOCIATED WITH RELATIVELY 790 00:26:09,044 --> 00:26:09,845 MILD DISEASE. 791 00:26:09,845 --> 00:26:14,383 AND ABOUT 1 IN 12 TO 1 IN 14 792 00:26:14,383 --> 00:26:16,118 ASHKENAZI JEWS CARRY A MUTATION 793 00:26:16,118 --> 00:26:18,921 IN THE GBA GENE. 794 00:26:18,921 --> 00:26:23,192 L44P IS PROP BLI PROBABLY THE MN 795 00:26:23,192 --> 00:26:24,727 MUTATION WORLDWIDE, MORE OFTEN 796 00:26:24,727 --> 00:26:29,765 WHEN IT'S HOMOOLILIC IT'S 797 00:26:29,765 --> 00:26:30,833 ASSOCIATED WITH GAUCHER DISEASE, 798 00:26:30,833 --> 00:26:33,802 BUT THERE'S OTHER MUTATIONS 799 00:26:33,802 --> 00:26:34,970 SPREAD THROUGH ALL THE 11 EXONS 800 00:26:34,970 --> 00:26:36,305 OF THE GENE, AND AS YOU'RE GOING 801 00:26:36,305 --> 00:26:38,707 TO HEAR FROM ANDY A LITTLE BIT, 802 00:26:38,707 --> 00:26:43,846 SOMETIMES IN THE INTRON REGIONS. 803 00:26:43,846 --> 00:26:45,414 SOME PATIENTS ACTUALLY HAVE WHAT 804 00:26:45,414 --> 00:26:47,583 WE CALL RECOMBINANT ALLELES, 805 00:26:47,583 --> 00:26:49,351 WHERE CHUNKS OF THE PSEUDOGENE 806 00:26:49,351 --> 00:26:50,986 GET INTEGRATED INTO THE GENE, 807 00:26:50,986 --> 00:26:52,521 AND THAT'S ANOTHER FORM OF 808 00:26:52,521 --> 00:26:53,489 MUTANT ALLELE. 809 00:26:53,489 --> 00:26:55,124 IT'S ALSO IMPORTANT BECAUSE WHEN 810 00:26:55,124 --> 00:26:58,627 YOU DESIGN PCR PRIMERS OR TRY TO 811 00:26:58,627 --> 00:27:00,062 ALIGN SEQUENCE, YOU HAVE TO BE 812 00:27:00,062 --> 00:27:02,565 AWARE OF THIS HIGHLY HOMOLOGOUS 813 00:27:02,565 --> 00:27:04,767 NEARBY SEQUENCE. 814 00:27:04,767 --> 00:27:07,169 SO GAUCHER DISEASE IS A 815 00:27:07,169 --> 00:27:09,338 MULTIORGAN DISORDER WITH 816 00:27:09,338 --> 00:27:10,339 VARIABLE MANIFESTATIONS. 817 00:27:10,339 --> 00:27:11,640 SOME OF THE KEY FEATURES ARE 818 00:27:11,640 --> 00:27:15,144 SHOWN HERE ON THIS CARTOON. 819 00:27:15,144 --> 00:27:17,346 YOU CAN HAVE GAUCHER CELLS IN 820 00:27:17,346 --> 00:27:21,817 YOUR LIVER, YOU CAN HAVE 821 00:27:21,817 --> 00:27:23,552 ENORMOUS HEPATOSPLENOMEGALY. 822 00:27:23,552 --> 00:27:25,521 FORTUNATELY WE DON'T SEE THIS 823 00:27:25,521 --> 00:27:26,388 ANYMORE HERE BECAUSE PATIENTS 824 00:27:26,388 --> 00:27:27,690 ARE STARTED EARLIER IN 825 00:27:27,690 --> 00:27:29,258 TREATMENT, BUT IN MY FREEZER, 826 00:27:29,258 --> 00:27:32,094 YOU CAN FIND THESE SIX, SEVEN, 827 00:27:32,094 --> 00:27:33,629 EIGHT-KILO SPLEENS THAT WERE 828 00:27:33,629 --> 00:27:35,598 TAKEN OUT PRIOR TO THE ADVENT OF 829 00:27:35,598 --> 00:27:38,534 ENZYME REPLACEMENT THERAPY. 830 00:27:38,534 --> 00:27:41,737 BONE DISEASE IS A COMMON CAUSE 831 00:27:41,737 --> 00:27:42,805 OF MORBIDITY. 832 00:27:42,805 --> 00:27:46,308 YOU CAN HAVE VERY EXQUISITELY 833 00:27:46,308 --> 00:27:48,477 PAINFUL CRISES LIKE SICKLE CELL 834 00:27:48,477 --> 00:27:50,579 PATIENTS HAVE, OR YOU CAN HAVE 835 00:27:50,579 --> 00:27:53,215 DEFORMITIES WITH NOT TOO MANY 836 00:27:53,215 --> 00:27:53,749 SYMPTOMS. 837 00:27:53,749 --> 00:27:54,950 THE CLASSIC RADIOGRAPHIC FIND 838 00:27:54,950 --> 00:27:58,454 SOMETHING WHAT THEY CALL THERLIN 839 00:27:58,454 --> 00:27:59,755 MEYER FLASK DEFORMITY OF THE 840 00:27:59,755 --> 00:28:01,290 DISTAL FEMUR, AND WE SEE THAT IN 841 00:28:01,290 --> 00:28:02,091 MOST PATIENTS EVEN THOUGH 842 00:28:02,091 --> 00:28:06,228 THEY'RE NOT AWARE OF IT. 843 00:28:06,228 --> 00:28:09,198 AND IN SOME PATIENT, THE RARE 844 00:28:09,198 --> 00:28:11,033 ONES, THERE CAN BE BRAIN 845 00:28:11,033 --> 00:28:11,600 INVOLVEMENT. 846 00:28:11,600 --> 00:28:13,302 THOUGH WE DON'T SIGO HSIEH CELLS 847 00:28:13,302 --> 00:28:19,041 SEE GAUCHERCELLS IN THE BRAIN, Y 848 00:28:19,041 --> 00:28:20,309 THEY'RE SEEN PERIVASCULARLY. 849 00:28:20,309 --> 00:28:23,345 SO HOW DO WE EXPLAIN THIS VAST 850 00:28:23,345 --> 00:28:23,679 DISORDER? 851 00:28:23,679 --> 00:28:25,214 WHEN I FIRST CAME TO NIH, THE 852 00:28:25,214 --> 00:28:26,749 GENE HAD JUST BEEN CLONED AND I 853 00:28:26,749 --> 00:28:29,251 THOUGHT VERY NAIVELY THAT I 854 00:28:29,251 --> 00:28:30,552 WOULD IDENTIFY MUTATIONS, 855 00:28:30,552 --> 00:28:31,787 PHENOTYPE PEOPLE, PUT IT ALL 856 00:28:31,787 --> 00:28:34,189 TOGETHER AND BE ABLE TO EXPLAIN 857 00:28:34,189 --> 00:28:35,290 EVERYTHING AND 30 YEARS LATER, 858 00:28:35,290 --> 00:28:37,026 NO WAY, BUT IN ANY CASE, THE 859 00:28:37,026 --> 00:28:38,093 DISEASE HAS BEEN CLASSICALLY 860 00:28:38,093 --> 00:28:40,095 GROUPED INTO THREE TYPES. 861 00:28:40,095 --> 00:28:43,032 TYPE 1 BY DEFINITION IS NON 862 00:28:43,032 --> 00:28:45,668 NON-NEURONOPA THICK, THE MOST 863 00:28:45,668 --> 00:28:48,504 COMMON IN ASHKENAZI JEWS AND 864 00:28:48,504 --> 00:28:50,239 ACTUALLY THE MOST COMMON FORM IN 865 00:28:50,239 --> 00:28:51,340 THE UNITED STATES. 866 00:28:51,340 --> 00:28:53,409 TYPE 2 IS A HORRIBLE DEVASTATING 867 00:28:53,409 --> 00:28:54,076 NEURODEGENERATIVE DISORDER THAT 868 00:28:54,076 --> 00:28:56,378 BEGINS IN INFANCY. 869 00:28:56,378 --> 00:28:59,114 AND WE REALLY HAVE NO EFFECTIVE 870 00:28:59,114 --> 00:29:00,315 TREATMENTS FOR. 871 00:29:00,315 --> 00:29:01,950 AND TYPE 3, BY DEFINITION, IS 872 00:29:01,950 --> 00:29:04,420 ANY PATIENT THAT SURVIVES THE 873 00:29:04,420 --> 00:29:05,888 FIRST YEARS OF LIFE BUT HAS ANY 874 00:29:05,888 --> 00:29:08,524 FORM OF NEUROLOGIC INVOLVEMENT, 875 00:29:08,524 --> 00:29:12,428 OFTEN JUST THE SLOWING OF THE SI 876 00:29:12,428 --> 00:29:13,495 KA TICK EYE MOVEMENTS. 877 00:29:13,495 --> 00:29:15,097 BUT THE MORE I'VE SEEN PATIENTS 878 00:29:15,097 --> 00:29:16,098 HERE OVER THE YEARS AND I'VE 879 00:29:16,098 --> 00:29:17,266 BEEN DOING THIS NOW MORE THAN 880 00:29:17,266 --> 00:29:19,168 THREE DECADES, I'VE BEGUN TO SEE 881 00:29:19,168 --> 00:29:23,539 THIS AS A SPECTRUM RANGING FROM 882 00:29:23,539 --> 00:29:24,606 ASYMPTOMATIC OCTO JE NARIANS 883 00:29:24,606 --> 00:29:26,375 THAT ARE ONLY DIAGNOSED BECAUSE 884 00:29:26,375 --> 00:29:28,010 A FAMILY MEMBER OR THERE'S SOME 885 00:29:28,010 --> 00:29:29,845 SCREENING GOING ON, EVEN RIGHT 886 00:29:29,845 --> 00:29:33,382 NOW FROM PARKINSON CLINICS, ALL 887 00:29:33,382 --> 00:29:36,385 THE WAY DOWN TO BABIES THAT DIE 888 00:29:36,385 --> 00:29:39,154 IN UTERO WITH A BIG SPECTRUM IN 889 00:29:39,154 --> 00:29:40,923 BETWEEN, AND OUR PARKINSON'S 890 00:29:40,923 --> 00:29:44,560 STORY FITS SOMEWHERE WITHIN THIS 891 00:29:44,560 --> 00:29:47,129 SPECTRUM. 892 00:29:47,129 --> 00:29:48,864 SO FOR ME, THE STORY BEGAN IN MY 893 00:29:48,864 --> 00:29:50,933 CLINIC BACK IN 1996 WITH A 894 00:29:50,933 --> 00:29:52,167 SINGLE PATIENT I'M GOING TO TRY 895 00:29:52,167 --> 00:29:53,769 AND SHOW YOU, EVEN THOUGH IT'S A 896 00:29:53,769 --> 00:29:54,570 GRAINY OLD VIDEO. 897 00:29:54,570 --> 00:29:55,537 LET'S SEE IF IT WORKS. 898 00:29:55,537 --> 00:30:01,577 IT DID. 899 00:30:01,577 --> 00:30:04,313 SO MARJORIE WAS DIAGNOSED WITH 900 00:30:04,313 --> 00:30:06,148 GAUCHER DISEASE AT AGE 19, HER 901 00:30:06,148 --> 00:30:08,584 TREMOR BEGAN AT AGE 42. 902 00:30:08,584 --> 00:30:10,652 SHE STARTED HAVING PROGRESSIVE 903 00:30:10,652 --> 00:30:10,953 RIGIDITY. 904 00:30:10,953 --> 00:30:12,421 I THINK YOU SEE HER HERE AT 905 00:30:12,421 --> 00:30:13,922 ABOUT AGE 48. 906 00:30:13,922 --> 00:30:15,557 SHE HAS TROUBLE GETTING UP FROM 907 00:30:15,557 --> 00:30:17,659 A CHAIR. 908 00:30:17,659 --> 00:30:19,862 DIFFICULTY INITIATING MOVEMENTS. 909 00:30:19,862 --> 00:30:29,671 SHE HAS THAT MASK FAY MASK F F. 910 00:30:29,671 --> 00:30:31,206 SHE DEVELOPED UNFORTUNATELY 911 00:30:31,206 --> 00:30:32,107 PROGRESSIVE DEMENTIA. 912 00:30:32,107 --> 00:30:33,542 SHE DIED, WE SAW HER SEVERAL 913 00:30:33,542 --> 00:30:36,311 TIMES, SHE DIED AT AGE 54. 914 00:30:36,311 --> 00:30:38,013 SHE WAS FROM NEW HAMPSHIRE AND 915 00:30:38,013 --> 00:30:39,548 ACTUALLY AGREED TO HAVE HER BODY 916 00:30:39,548 --> 00:30:43,786 SHIPPED HERE SO WE COULD DO THE 917 00:30:43,786 --> 00:30:44,353 NEUROPATHOLOGY HERE. 918 00:30:44,353 --> 00:30:46,221 SO AT THE TIME, I WONDERED WHAT 919 00:30:46,221 --> 00:30:47,723 COULD THIS JUST BE A COINCIDENCE 920 00:30:47,723 --> 00:30:49,391 JUST BECAUSE YOU HAVE A RARE 921 00:30:49,391 --> 00:30:51,460 DISEASE DOESN'T MEAN YOU'RE 922 00:30:51,460 --> 00:30:52,895 IMMUNE FROM COMMON DISEASES, OF 923 00:30:52,895 --> 00:30:53,996 COURSE. 924 00:30:53,996 --> 00:30:55,964 BUT WHEN I STARTED TALKING TO 925 00:30:55,964 --> 00:30:58,901 OTHER PEOPLE AT MEETINGS AND 926 00:30:58,901 --> 00:31:00,235 GOING THROUGH THE OLD 927 00:31:00,235 --> 00:31:01,336 LITERATURE, ALMOST EVERY GAUCHER 928 00:31:01,336 --> 00:31:03,172 CLINIC HAD A FEW PATIENTS THAT 929 00:31:03,172 --> 00:31:05,574 HAD DEVELOPED PARKINSON DISEASE. 930 00:31:05,574 --> 00:31:07,009 WE TRIED TO GET THEM TO SEE WHAT 931 00:31:07,009 --> 00:31:10,512 THEY SHARED AND IN 2003, WE 932 00:31:10,512 --> 00:31:13,215 PUBLISHED A SERIES OF 17 933 00:31:13,215 --> 00:31:15,217 PATIENTS THAT HAD GAUCHER AND 934 00:31:15,217 --> 00:31:15,984 PARKINSON DISEASE. 935 00:31:15,984 --> 00:31:20,589 AND THE STORY SORT OF MIGHT HAVE 936 00:31:20,589 --> 00:31:21,557 STOPPED THERE BUT THERE WERE TWO 937 00:31:21,557 --> 00:31:21,890 OTHER THINGS. 938 00:31:21,890 --> 00:31:23,525 WE STARTED REALIZING THAT WHEN 939 00:31:23,525 --> 00:31:26,028 WE INTERVIEWED FAMILIES 940 00:31:26,028 --> 00:31:31,066 CAREFULLY, WE TALLIED THE 12 OUT 941 00:31:31,066 --> 00:31:32,701 OF 45 CONSECUTIVE PATIENTS HAD 942 00:31:32,701 --> 00:31:34,903 RELATIVES THAT HAD PARKINSON 943 00:31:34,903 --> 00:31:36,538 DISEASE, OFTEN A PARENT OR A 944 00:31:36,538 --> 00:31:39,174 GRANDPARENT WHO WAS AN OBLIGATE 945 00:31:39,174 --> 00:31:41,777 CARRIER, AND THEN WE ALSO FOUND 946 00:31:41,777 --> 00:31:43,445 OUT THERE WAS SIMILAR THINGS 947 00:31:43,445 --> 00:31:46,281 BEING SEEN IN OTHER GAUCHER 948 00:31:46,281 --> 00:31:47,983 CENTERS, INCLUDING THE LARGE ONE 949 00:31:47,983 --> 00:31:48,450 IN JERUSALEM. 950 00:31:48,450 --> 00:31:49,985 SO THIS WAS THE FIRST EVIDENCE 951 00:31:49,985 --> 00:31:52,487 THAT HETEROZYGOTES WERE ALSO AT 952 00:31:52,487 --> 00:31:53,722 INCREASED RISK FOR PARKINSON 953 00:31:53,722 --> 00:31:53,956 DISEASE. 954 00:31:53,956 --> 00:31:56,558 AND THEN THE PLOT THICKENS, AS 955 00:31:56,558 --> 00:31:57,759 DR. KASTNER WOULD SAY. 956 00:31:57,759 --> 00:32:02,898 I GOT A CALL FROM CATHY, HOWARD 957 00:32:02,898 --> 00:32:04,233 HUGHES MEDICAL STUDENT IN OUR 958 00:32:04,233 --> 00:32:05,901 LAB IN THE 80s OR 90s, AND 959 00:32:05,901 --> 00:32:09,037 SHE SAID SHE WAS NOW CHIEF 960 00:32:09,037 --> 00:32:09,872 NEUROPATHOLOGY FELLOW AT MASS 961 00:32:09,872 --> 00:32:11,206 GENERAL AND SHE WAS DOING AN 962 00:32:11,206 --> 00:32:13,408 AUTOPSY ON A CASE WITH 963 00:32:13,408 --> 00:32:15,143 PARKINSON'S DISEASE AND SHE READ 964 00:32:15,143 --> 00:32:16,111 THE CHART. 965 00:32:16,111 --> 00:32:16,912 GOOD PATHOLOGIST. 966 00:32:16,912 --> 00:32:18,547 AND SAW THAT THE GUY HAD 967 00:32:18,547 --> 00:32:21,183 GAUCHER, DID A GOOGLE, FOUND OUR 968 00:32:21,183 --> 00:32:23,018 PAPERS, AND ASKED ME IF I WANTED 969 00:32:23,018 --> 00:32:26,855 ANYTHING FROM THE AUTOPSY, WHICH 970 00:32:26,855 --> 00:32:30,158 WAS REALLY GENERAL CUSS. 971 00:32:30,158 --> 00:32:30,692 GENEROUS. 972 00:32:30,692 --> 00:32:33,095 BUT I SAID YES BUT I DON'T HAVE 973 00:32:33,095 --> 00:32:35,397 ANY IDIOPATHIC PARKINSON'S 974 00:32:35,397 --> 00:32:36,732 DISEASE, CAN YOU SEND ME A FEW. 975 00:32:36,732 --> 00:32:38,367 SO SHE PACKAGED ME UP A PACKAGE 976 00:32:38,367 --> 00:32:40,669 ON DRY ICE WITH THREE LITTLE 977 00:32:40,669 --> 00:32:42,104 SNPPETS OF BRAIN, AND WHEN IT 978 00:32:42,104 --> 00:32:43,405 GOT HERE, I COULDN'T RECOGNIZE 979 00:32:43,405 --> 00:32:47,676 THE LABELS, AS OFTEN HAPPENS ON 980 00:32:47,676 --> 00:32:49,244 DRY ICE AND MINUS 80 FREEZERS. 981 00:32:49,244 --> 00:32:50,545 SO I HAD THE PEOPLE IN MY LAB 982 00:32:50,545 --> 00:32:53,382 CHIP OFF A PIECE AND DO ENZYME 983 00:32:53,382 --> 00:32:54,516 ACTIVITY. 984 00:32:54,516 --> 00:32:55,450 AND LO AND BEHOLD, ONE OF THE 985 00:32:55,450 --> 00:32:56,618 SAMPLES WAS EXTREMELY LOW AND 986 00:32:56,618 --> 00:32:58,320 THAT WAS THE THE ONE THAT I 987 00:32:58,320 --> 00:32:59,955 THINK SHE WAS REFERRING, BUT THE 988 00:32:59,955 --> 00:33:01,023 OTHER TWO WERE ALSO LOWER THAN 989 00:33:01,023 --> 00:33:01,690 WE EXPECTED. 990 00:33:01,690 --> 00:33:03,125 SO WE SCRATCHED OUR HEAD AND 991 00:33:03,125 --> 00:33:06,295 SAID WHAT'S GOING ON HERE, AND 992 00:33:06,295 --> 00:33:07,829 WE SAID WELL, GO CHIP OFF 993 00:33:07,829 --> 00:33:09,831 ANOTHER PIECE AND WE'LL SEQUENCE 994 00:33:09,831 --> 00:33:10,365 THE DNA. 995 00:33:10,365 --> 00:33:15,170 ONE WAS AN N370 HOMOZYGOTE BUT 996 00:33:15,170 --> 00:33:20,542 THE OTHER TWO BOTH CARRIED -- WE 997 00:33:20,542 --> 00:33:21,510 CONTACTED CATHY AND ASKED HER TO 998 00:33:21,510 --> 00:33:25,981 SEND US MORE BRAINS AND I WENT 999 00:33:25,981 --> 00:33:27,182 TO MULTIPLE BRAIN BANKS WITHIN 1000 00:33:27,182 --> 00:33:28,083 THE UNITED STATES AND WITHIN A 1001 00:33:28,083 --> 00:33:30,819 FEW MONTHS, WE COLLECTED 57 1002 00:33:30,819 --> 00:33:32,454 CASES, AND 12 HAD VARIANTS IN 1003 00:33:32,454 --> 00:33:34,523 THE GBA GENE. 1004 00:33:34,523 --> 00:33:38,360 THAT WAS LIKE REALLY HARD TO GET 1005 00:33:38,360 --> 00:33:41,063 ACCEPTED IN THE COMMUNITY FIRST 1006 00:33:41,063 --> 00:33:43,832 OF ALL, FOR SOME REASON GWAS AT 1007 00:33:43,832 --> 00:33:46,368 THAT POINT HADN'T PICKED UP GBA. 1008 00:33:46,368 --> 00:33:48,003 SO THEY THOUGHT MAYBE THERE WAS 1009 00:33:48,003 --> 00:33:54,009 SOME BIAS, MAYBE THEY WERE ALL 1010 00:33:54,009 --> 00:33:55,978 ASHKENAZI DONORS, SO WE WENT 1011 00:33:55,978 --> 00:33:57,546 BACK TO KATHY AND THE OTHER 1012 00:33:57,546 --> 00:34:00,582 BRAIN BANKS AND SEQUENCED GBA 1013 00:34:00,582 --> 00:34:02,484 AND 44 CONTROLS AND DIDN'T FIND 1014 00:34:02,484 --> 00:34:04,119 ANY VARIANTS. 1015 00:34:04,119 --> 00:34:05,988 SO SENT THIS OUT TO MULTIPLE 1016 00:34:05,988 --> 00:34:08,390 JOURNALS, EVENTUALLY WE GOT IT 1017 00:34:08,390 --> 00:34:11,226 PUBLISHED IN A GENETICS JOURNAL, 1018 00:34:11,226 --> 00:34:12,995 AND THEN OTHER GROUPS STARTED 1019 00:34:12,995 --> 00:34:14,196 LOOKING IN THEIR COHORT, AND 1020 00:34:14,196 --> 00:34:15,931 AGAIN, THEY KEPT ON FINDING THAT 1021 00:34:15,931 --> 00:34:18,133 THERE WERE MORE GBA VARIANTS 1022 00:34:18,133 --> 00:34:21,670 THAN YOU'D EXPECT, BUT STILL IT 1023 00:34:21,670 --> 00:34:23,638 DIDN'T REALLY GAIN MOMENTUM 1024 00:34:23,638 --> 00:34:25,741 UNTIL JOHN HARDIG CHALLENGED US 1025 00:34:25,741 --> 00:34:27,175 TO PUT TOGETHER AN INTERNATIONAL 1026 00:34:27,175 --> 00:34:29,678 STUDY OF GBA MUTATIONS IN 1027 00:34:29,678 --> 00:34:30,078 PARKINSON DISEASE. 1028 00:34:30,078 --> 00:34:33,482 AND AT THAT POINT, WE ASSEMBLED 1029 00:34:33,482 --> 00:34:35,283 16 CENTERS, FOUR CONTINENTS, WE 1030 00:34:35,283 --> 00:34:37,285 HAD ABOUT 5,000 PATIENTS WITH 1031 00:34:37,285 --> 00:34:39,688 PARKINSON DISEASE AND 5,000 WITH 1032 00:34:39,688 --> 00:34:40,355 CONTROLS. 1033 00:34:40,355 --> 00:34:42,958 WE SENT A PANEL TO SEE WHICH 1034 00:34:42,958 --> 00:34:47,462 MUTATIONS EACH LAB COULD PICK 1035 00:34:47,462 --> 00:34:47,629 UP. 1036 00:34:47,629 --> 00:34:49,331 THEY COULDN'T PICK THEM UP A UP 1037 00:34:49,331 --> 00:34:51,199 BUT AT LEAST THE TWO COMMON ONES 1038 00:34:51,199 --> 00:34:54,469 SEEMED FAIR ENOUGH, SO JUST 1039 00:34:54,469 --> 00:34:56,238 BASED ON THOSE TWO COMMON 1040 00:34:56,238 --> 00:34:57,773 MUTATION, WE FOUND PATIENTS WITH 1041 00:34:57,773 --> 00:34:58,640 PARKINSON'S DISEASE WERE FIVE 1042 00:34:58,640 --> 00:35:00,609 TIMES MORE LIKELY TO HAVE A GBA 1043 00:35:00,609 --> 00:35:01,076 VARIANT. 1044 00:35:01,076 --> 00:35:02,811 ALREADY FROM THIS EARLY PAPER, 1045 00:35:02,811 --> 00:35:04,913 WE FOUND THAT THE GBA CARRIERS 1046 00:35:04,913 --> 00:35:06,982 TENDED TO HAVE EARLIER PARKINSON 1047 00:35:06,982 --> 00:35:08,283 ONSET AND MORE COGNITIVE 1048 00:35:08,283 --> 00:35:10,152 DEFICITS. 1049 00:35:10,152 --> 00:35:11,586 ACTUALLY A FEW YEARS LATER, WE 1050 00:35:11,586 --> 00:35:13,155 WENT BACK TO THE SAME CENTERS, 1051 00:35:13,155 --> 00:35:15,424 AND TRIED TO DO REPLICATE TYPE 1052 00:35:15,424 --> 00:35:19,828 OF STUDY DEMENTIA WITH LEWY 1053 00:35:19,828 --> 00:35:22,431 BODIES, RARE DISORDER, WE ONLY 1054 00:35:22,431 --> 00:35:26,268 HAVE 721 CASES, BUT ACTUALLY THE 1055 00:35:26,268 --> 00:35:35,177 GLB, THE DLB, THE ODDS RATIO WAN 1056 00:35:35,177 --> 00:35:39,448 HIGHER, SO WHY IS IT IMPORTANT? 1057 00:35:39,448 --> 00:35:42,517 WELL, AS ANDY MENTIONED, FINDING 1058 00:35:42,517 --> 00:35:44,052 A GENE CAN FOCUS YOUR ATTENTION 1059 00:35:44,052 --> 00:35:45,554 AND SOMETIMES TO A NEW PATHWAY, 1060 00:35:45,554 --> 00:35:46,655 COMPARED TO A LOT OF THE OTHER 1061 00:35:46,655 --> 00:35:49,391 GENES AT THE TIME, WE KNEW A LOT 1062 00:35:49,391 --> 00:35:51,493 ABOUT GBA1 AND IT'S ROLE IN THE 1063 00:35:51,493 --> 00:35:53,662 LYSOSOME, AND IN FACT, 1064 00:35:53,662 --> 00:35:55,097 SUBSEQUENTLY, WE'RE BECOMING 1065 00:35:55,097 --> 00:35:56,231 AWARE THAT MANY OF THE GENES 1066 00:35:56,231 --> 00:35:58,834 THAT RUTH BADER GINSBURG 1067 00:35:58,834 --> 00:36:00,569 THAT ARE BEING IDENTIFIED FALL 1068 00:36:00,569 --> 00:36:02,771 INTO LYSOSOMAL PATHWAYS. 1069 00:36:02,771 --> 00:36:04,973 TODAY IF YOU GOOGLE OR DO A 1070 00:36:04,973 --> 00:36:08,043 PUBMED ON GBA YOU'LL FIND 10 1071 00:36:08,043 --> 00:36:09,377 TIMES MORE PAPERS ABOUT 1072 00:36:09,377 --> 00:36:10,679 PARKINSON'S DISEASE THAN YOU 1073 00:36:10,679 --> 00:36:12,848 WILL ABOUT GAUCHER DISEASE. 1074 00:36:12,848 --> 00:36:13,982 AND MANY DIFFERENT PARKINSON 1075 00:36:13,982 --> 00:36:17,252 GROUPS ARE FUNDING WORK ON THE 1076 00:36:17,252 --> 00:36:20,322 GLUCOVEE ROW SIDASE GENE 1077 00:36:20,322 --> 00:36:21,523 INCLUDING MICHAEL J. FOX AND THE 1078 00:36:21,523 --> 00:36:23,925 BIG INITIATIVE AND MOST BIG 1079 00:36:23,925 --> 00:36:26,027 PHARMA THAT ARE INTERESTED IN 1080 00:36:26,027 --> 00:36:29,264 NEURODEGENERATION NOW HAVE GBA 1081 00:36:29,264 --> 00:36:31,366 PROGRAMS. 1082 00:36:31,366 --> 00:36:33,135 WHICH IS GREAT FOR PATIENTS WITH 1083 00:36:33,135 --> 00:36:33,768 GAUCHER DISEASE BECAUSE THEY 1084 00:36:33,768 --> 00:36:41,109 NEVER HAD THAT MUCH ATTENTION. 1085 00:36:41,109 --> 00:36:42,978 SO FOR SOME TIME NOW WE'VE BEEN 1086 00:36:42,978 --> 00:36:44,679 DOING A PROSPECTIVE STUDY AT THE 1087 00:36:44,679 --> 00:36:46,715 NIH TO SEE IF WE COULD FIND 1088 00:36:46,715 --> 00:36:48,483 EARLY CLINICAL FEATURES THAT 1089 00:36:48,483 --> 00:36:52,053 MIGHT BE PREDICTIVE OF 1090 00:36:52,053 --> 00:36:54,089 PARKINSON'S, A MOVEMENT DISORDER 1091 00:36:54,089 --> 00:36:55,490 PERSON IN MY GROUP HAS BEEN 1092 00:36:55,490 --> 00:36:57,125 DOING THESE EVALUATIONS. 1093 00:36:57,125 --> 00:36:58,760 WE RECRUIT PATIENTS THAT HAVE 1094 00:36:58,760 --> 00:36:59,861 GAUCHER DISEASE AND PARKINSON 1095 00:36:59,861 --> 00:37:01,696 DISEASE AND ALSO GAUCHER 1096 00:37:01,696 --> 00:37:03,365 CARRIERS WITH PARKINSON DISEASE. 1097 00:37:03,365 --> 00:37:05,000 BUT AT THE SAME TIME, WE'RE 1098 00:37:05,000 --> 00:37:06,234 RECRUITING PATIENTS WITH GAUCHER 1099 00:37:06,234 --> 00:37:07,769 DISEASE AND GAUCHER CARRIERS WHO 1100 00:37:07,769 --> 00:37:08,970 DON'T IS PARKINSON DISEASE, BUT 1101 00:37:08,970 --> 00:37:10,939 THEY HAVE A STRONG FAMILY 1102 00:37:10,939 --> 00:37:15,744 HISTORY IN A PARENT OR SIBLING. 1103 00:37:15,744 --> 00:37:17,946 THEY COME AND UNDERGO A PRETTY 1104 00:37:17,946 --> 00:37:19,915 UNIFORM CLINICAL SET OF STUDIES 1105 00:37:19,915 --> 00:37:21,983 THAT HAS BEEN GOING ON FOR OVER 1106 00:37:21,983 --> 00:37:22,884 15 YEARS. 1107 00:37:22,884 --> 00:37:25,187 THEY HAVE A PHYSICAL EXAM, 1108 00:37:25,187 --> 00:37:27,389 NEUROLOGIC EXAM, NEUROCOGNITIVE 1109 00:37:27,389 --> 00:37:27,889 EVALUATIONS. 1110 00:37:27,889 --> 00:37:29,791 WE TEST THEIR ABILITY TO SMELL, 1111 00:37:29,791 --> 00:37:32,961 WE SCREEN FOR OTHER NON-MOTOR 1112 00:37:32,961 --> 00:37:34,296 FEATURES, AND THEN FOR A WHILE, 1113 00:37:34,296 --> 00:37:35,830 WE'VE BEEN DOING DIFFERENT 1114 00:37:35,830 --> 00:37:37,899 IMAGING STUDIES INCLUDING MRI, 1115 00:37:37,899 --> 00:37:47,008 PET SCANS, AND TRANSCRANIAL SEW 1116 00:37:47,008 --> 00:37:47,442 SONOGRAPHY. 1117 00:37:47,442 --> 00:37:49,511 SO TO SUMMARIZE LIKE 15 YEARS OF 1118 00:37:49,511 --> 00:37:53,248 STUDY ON ONE SLIDE, GENERALLY WE 1119 00:37:53,248 --> 00:37:57,519 FIND THAT OUR PATIENTS THAT HAVE 1120 00:37:57,519 --> 00:38:02,357 GAUCHER DISEASE AND PARKINSON 1121 00:38:02,357 --> 00:38:03,425 DISEASE HAVE CLINICAL AND 1122 00:38:03,425 --> 00:38:07,395 POTASSIUM LOGIC FINDINGS THAT 1123 00:38:07,395 --> 00:38:09,564 PATHOLOGIC FINDINGS THAT REALLY 1124 00:38:09,564 --> 00:38:10,465 RESEMBLE IDIOPATHIC PARKINSON 1125 00:38:10,465 --> 00:38:10,799 DISEASE. 1126 00:38:10,799 --> 00:38:12,200 SOME DO HAVE CLINICAL AND 1127 00:38:12,200 --> 00:38:12,968 PATHOLOGIC FEATURES THAT ARE 1128 00:38:12,968 --> 00:38:15,503 MORE SIMILAR TO DEMENTIA WITH 1129 00:38:15,503 --> 00:38:16,171 LEWY BODIES. 1130 00:38:16,171 --> 00:38:17,305 THEY SEEM TO HAVE SIMILAR 1131 00:38:17,305 --> 00:38:19,708 TREATMENT RESPONSES TO L-DOPA. 1132 00:38:19,708 --> 00:38:22,210 THE AGE OF PD ONSET TENDS TO BE 1133 00:38:22,210 --> 00:38:23,979 YOUNGER BY ABOUT TWO TO SIX 1134 00:38:23,979 --> 00:38:28,583 YEARS WITH A MEAN OF ABOUT 47. 1135 00:38:28,583 --> 00:38:30,218 THEY ARE MORE LIKELY TO HAVE A 1136 00:38:30,218 --> 00:38:31,853 POSITIVE FAMILY HISTORY, 1137 00:38:31,853 --> 00:38:34,856 NON-MOTOR SYMPTOMS ARE COMMON, 1138 00:38:34,856 --> 00:38:36,725 ESPECIALLY OLFACTION SEEMS TO BE 1139 00:38:36,725 --> 00:38:37,259 IMPACTED. 1140 00:38:37,259 --> 00:38:38,460 PROGRESSION MAY BE A LITTLE 1141 00:38:38,460 --> 00:38:40,895 FASTER, AND THERE MAY BE MORE 1142 00:38:40,895 --> 00:38:41,763 COGNITIVE DYSFUNCTION, BUT I 1143 00:38:41,763 --> 00:38:43,732 ALWAYS LIKE TO EMPHASIZE NOT 1144 00:38:43,732 --> 00:38:45,166 ALWAYS, ESPECIALLY WHEN I'M 1145 00:38:45,166 --> 00:38:48,270 COUNSELING PATIENTS. 1146 00:38:48,270 --> 00:38:49,871 HOWEVER, IN OUR RISK COHORT, NOW 1147 00:38:49,871 --> 00:38:52,507 WE'VE SEEN ABOUT 113 PATIENTS, 1148 00:38:52,507 --> 00:38:54,309 SOME OF WHOM HAVE BEEN FOLLOWED 1149 00:38:54,309 --> 00:38:58,913 FOR UP TO PIRN TO 13 TO 15 YEARE 1150 00:38:58,913 --> 00:39:00,749 ONLY HAD ONE CONVERT, WHICH HAS 1151 00:39:00,749 --> 00:39:01,950 REALLY BEEN FRUSTRATING FOR US 1152 00:39:01,950 --> 00:39:02,884 BECAUSE WE'VE PUT IN A LOT OF 1153 00:39:02,884 --> 00:39:04,719 EFFORT TO TRY TO PREDICT THE 1154 00:39:04,719 --> 00:39:05,820 CONVERTERS, BUT IT'S GREAT NEWS 1155 00:39:05,820 --> 00:39:08,790 FOR OUR PATIENTS. 1156 00:39:08,790 --> 00:39:11,326 SO CLEARLY NOT ALL PATIENTS WITH 1157 00:39:11,326 --> 00:39:15,163 MUTATIONS ARE ON A PARKINSON 1158 00:39:15,163 --> 00:39:16,364 TRAJECTORY. 1159 00:39:16,364 --> 00:39:17,732 THIS IS JUST SUMMARIZING SOME OF 1160 00:39:17,732 --> 00:39:19,100 THE PATIENTS WITH GAUCHER AND 1161 00:39:19,100 --> 00:39:23,171 PARKINSON DISEASE THAT WE'VE 1162 00:39:23,171 --> 00:39:24,372 SEEN. 1163 00:39:24,372 --> 00:39:26,441 AGAIN SOME OF THEM HAVE PRETTY 1164 00:39:26,441 --> 00:39:27,575 CLASSIC PARKINSON COURSE THOUGH 1165 00:39:27,575 --> 00:39:28,843 OTHERS HAVE THE MORE AGGRESSIVE 1166 00:39:28,843 --> 00:39:30,178 EARLY ONSET FORM. 1167 00:39:30,178 --> 00:39:33,148 THE N370S MUTATION, WHICH IS 1168 00:39:33,148 --> 00:39:35,784 CONSIDERED NON-NEUROLOGIC IN 1169 00:39:35,784 --> 00:39:37,986 GAUCHER DISEASE IS IN THE UNITED 1170 00:39:37,986 --> 00:39:39,287 STATES THE MOST COMMON MUTATION. 1171 00:39:39,287 --> 00:39:42,023 THERE ARE FEW VARIANTS THAT ARE 1172 00:39:42,023 --> 00:39:43,725 SEEN I -- IN THE GENE THAT ARE 1173 00:39:43,725 --> 00:39:45,427 SEEN IN PARKINSON DISEASE THAT 1174 00:39:45,427 --> 00:39:46,528 DON'T CAUSE GAUCHER DISEASE THAT 1175 00:39:46,528 --> 00:39:49,497 MAY BE MORE COMMON, BUT MOST OF 1176 00:39:49,497 --> 00:39:54,436 OUR PATIENTS RESPOND WELL TO 1177 00:39:54,436 --> 00:40:01,109 L-DOPA OLFACTION AND COGNITION 1178 00:40:01,109 --> 00:40:02,744 ARE COMMONLY IMPAIRED. 1179 00:40:02,744 --> 00:40:04,079 THIS IS WHAT WE SEE, THE FIRST 1180 00:40:04,079 --> 00:40:05,113 WOMAN ON OUR LEFT WAS DIAGNOSED 1181 00:40:05,113 --> 00:40:06,948 IN HER 40s BUT HAD A 28-YEAR 1182 00:40:06,948 --> 00:40:08,249 COURSE AND ONLY HAD LATE 1183 00:40:08,249 --> 00:40:09,017 COGNITIVE FINDINGS. 1184 00:40:09,017 --> 00:40:11,419 THE GENTLEMAN IN THE MIDDLE CAME 1185 00:40:11,419 --> 00:40:13,455 TO US NEWLY DIAGNOSED IN HIS 1186 00:40:13,455 --> 00:40:17,359 LATE '50S, ALREADY CONFUSED WITH 1187 00:40:17,359 --> 00:40:18,326 BOOKKEEPER, COULDN'T KEEP THE 1188 00:40:18,326 --> 00:40:19,894 NUMBERS STRAIGHT, DIED A FEW 1189 00:40:19,894 --> 00:40:21,730 YEARS LATER WITH PROGRESSIVE 1190 00:40:21,730 --> 00:40:22,163 DEMENTIA. 1191 00:40:22,163 --> 00:40:24,699 AND THE GENTLEMAN ON YOUR FAR 1192 00:40:24,699 --> 00:40:28,436 LEFT IS ACTUALLY AN ISRAELI 1193 00:40:28,436 --> 00:40:29,437 PROFESSOR SEEN HERE SEVERAL 1194 00:40:29,437 --> 00:40:30,138 TIMES. 1195 00:40:30,138 --> 00:40:31,840 HE KNEW SEVEN LANGUAGES. 1196 00:40:31,840 --> 00:40:34,876 HE WOULD SPEAK TO THE X-RAY TECH 1197 00:40:34,876 --> 00:40:37,746 ON THE PET MACHINE IN CHINESE, 1198 00:40:37,746 --> 00:40:39,848 AND DIED FROM UNRELATED CAUSES 1199 00:40:39,848 --> 00:40:41,916 WITH NORMAL COGNITION. 1200 00:40:41,916 --> 00:40:43,585 SO YOU KNOW, EVEN THOUGH THERE'S 1201 00:40:43,585 --> 00:40:45,887 TRENDS, YOU HAVE TO APPRECIATE 1202 00:40:45,887 --> 00:40:50,592 THAT THERE IS THIS RANGE. 1203 00:40:50,592 --> 00:40:51,826 ONE APPROACH THAT WE'VE HAD IS 1204 00:40:51,826 --> 00:40:53,795 WE'VE BEEN FOCUSING A LOT ON 1205 00:40:53,795 --> 00:40:55,964 SIBLINGS, AND WE'VE COLLECTED 1206 00:40:55,964 --> 00:40:59,701 NOW 10 SIBLINGS -- WHERE BOTH 1207 00:40:59,701 --> 00:41:00,835 SIBLINGS HAVE GAUCHER DISEASE 1208 00:41:00,835 --> 00:41:02,237 BUT ONLY ONE DEVELOPED PARKINSON 1209 00:41:02,237 --> 00:41:02,971 DISEASE. 1210 00:41:02,971 --> 00:41:04,973 WE'VE SEEN THESE SIBLINGS NOW, 1211 00:41:04,973 --> 00:41:06,374 SOME OF THEM UP TO SEVEN OR 1212 00:41:06,374 --> 00:41:08,176 EIGHT TIMES OVER THE LAST 16 1213 00:41:08,176 --> 00:41:09,277 YEARS, AND EACH TIME THEY GO 1214 00:41:09,277 --> 00:41:11,346 THROUGH THE WHOLE BATTERY OF 1215 00:41:11,346 --> 00:41:11,813 EVALUATIONS. 1216 00:41:11,813 --> 00:41:13,248 SO FAR WE HAVEN'T SEEN ANY 1217 00:41:13,248 --> 00:41:14,783 INDICATIONS OF PARKINSON DISEASE 1218 00:41:14,783 --> 00:41:18,052 OR CHANGES IN PET SCAN IN THE 1219 00:41:18,052 --> 00:41:21,356 NON-PARKINSON DISEASE SIBLING, 1220 00:41:21,356 --> 00:41:22,891 BUT WE COLLECT ALL KINDS OF 1221 00:41:22,891 --> 00:41:25,493 SAMPLES INCLUDING DNA, RNA, 1222 00:41:25,493 --> 00:41:26,294 FIBROBLASTS, ET CETERA, BECAUSE 1223 00:41:26,294 --> 00:41:28,730 I THINK THAT THESE KIND OF 1224 00:41:28,730 --> 00:41:29,364 DISCORDANT SIBLINGS WILL BE 1225 00:41:29,364 --> 00:41:32,333 IMPORTANT AS WE TRY TO EVALUATE 1226 00:41:32,333 --> 00:41:35,637 WHAT PROTECTS OR WHAT CONFERS 1227 00:41:35,637 --> 00:41:36,070 MORE RISK. 1228 00:41:36,070 --> 00:41:37,939 BECAUSE REMEMBER, MOST GAUCHER 1229 00:41:37,939 --> 00:41:39,240 PATIENTS AND CARRIERS NEVER 1230 00:41:39,240 --> 00:41:40,241 DEVELOP PARKINSON DISEASE. 1231 00:41:40,241 --> 00:41:41,676 IT JUST A RISK FACTOR. 1232 00:41:41,676 --> 00:41:43,545 BUT OUR CHALLENGE IS TO IDENTIFY 1233 00:41:43,545 --> 00:41:48,149 THE OTHER FACTORS OR GENES THAT 1234 00:41:48,149 --> 00:41:49,818 EITHER INCREASE OR DECREASE 1235 00:41:49,818 --> 00:41:52,987 ONE'S RISK FOR PARKINSON 1236 00:41:52,987 --> 00:41:53,955 DISEASE, BUT I THINK WE'RE 1237 00:41:53,955 --> 00:41:55,190 FINALLY AT THE POINT WHERE WE 1238 00:41:55,190 --> 00:41:56,691 CAN USE SOME GENOMIC APPROACHES 1239 00:41:56,691 --> 00:41:58,359 ALSO. 1240 00:41:58,359 --> 00:42:00,228 AS YOU HEARD FROM ANDY, THERE'S 1241 00:42:00,228 --> 00:42:03,531 ALL KINDS OF NEW TECHNOLOGICAL 1242 00:42:03,531 --> 00:42:05,600 ADVANCES THAT ARE ENABLING US SO 1243 00:42:05,600 --> 00:42:08,236 BETTER UNRAVEL ALL THE DIFFERENT 1244 00:42:08,236 --> 00:42:10,472 FACTORS THAT CONTRIBUTE TO OUR 1245 00:42:10,472 --> 00:42:12,974 COMPLEX INDIVIDUAL TAPESTRIES, 1246 00:42:12,974 --> 00:42:15,944 AND IN THE CASE OF PARKINSON 1247 00:42:15,944 --> 00:42:18,146 DISEASE, WE CAN USE STRATEGIES 1248 00:42:18,146 --> 00:42:21,115 LIKE LOOKING AT GENOMES, 1249 00:42:21,115 --> 00:42:22,183 EPIGENOMES, TRANSCRIPTOMES, TO 1250 00:42:22,183 --> 00:42:26,254 SEE SOME DIFFERENCES. 1251 00:42:26,254 --> 00:42:28,356 WE CAN LOOK AT PATIENTS WITH 1252 00:42:28,356 --> 00:42:29,891 PARKINSON'S DISEASE WITHOUT GBA 1253 00:42:29,891 --> 00:42:30,992 MUTATIONS AND I KNOW ANDY HAS 1254 00:42:30,992 --> 00:42:32,260 DONE SOME OF THAT WORK ALREADY. 1255 00:42:32,260 --> 00:42:34,062 IT CAN COME FROM ALL THESE BIG 1256 00:42:34,062 --> 00:42:35,163 PARKINSON CONSORTIUMS. 1257 00:42:35,163 --> 00:42:37,065 AND OTHER APPROACH IS TO LOOK AT 1258 00:42:37,065 --> 00:42:38,800 PATIENTS WITH GAUCHER DISEASE 1259 00:42:38,800 --> 00:42:40,268 WITH AND WITHOUT PARKINSON 1260 00:42:40,268 --> 00:42:41,236 DISEASE AND WE'VE BEEN TRYING 1261 00:42:41,236 --> 00:42:41,970 THAT TOO. 1262 00:42:41,970 --> 00:42:42,770 UNFORTUNATELY THE NUMBERS ARE 1263 00:42:42,770 --> 00:42:44,105 NOT WHAT YOU USUALLY NEED FOR 1264 00:42:44,105 --> 00:42:45,740 THESE KIND OF STUDIES. 1265 00:42:45,740 --> 00:42:47,842 SO COLLABORATION IS REALLY 1266 00:42:47,842 --> 00:42:50,345 ESSENTIAL IN ORDER TO REACH 1267 00:42:50,345 --> 00:42:56,050 POWER THAT WILL BE USEFUL. 1268 00:42:56,050 --> 00:42:57,252 SO I'M NOT GOING TO SPEND A LOT 1269 00:42:57,252 --> 00:42:58,253 OF TIME ON MECHANISM. 1270 00:42:58,253 --> 00:42:59,254 THERE'S BEEN LOTS OF THEORIES 1271 00:42:59,254 --> 00:43:00,889 AND I JUST DON'T FEEL THAT ANY 1272 00:43:00,889 --> 00:43:04,759 OF THEM HAVE BEEN ADEQUATELY 1273 00:43:04,759 --> 00:43:05,093 SUBSTANTIATED. 1274 00:43:05,093 --> 00:43:06,728 WE DO KNOW THAT THERE IS SOME 1275 00:43:06,728 --> 00:43:08,696 KIND OF LINK BETWEEN ALPHA 1276 00:43:08,696 --> 00:43:11,132 SYNUCLEIN AND GLUCOCEREBROSIDASE 1277 00:43:11,132 --> 00:43:12,433 BUT IT'S AN INVERSE 1278 00:43:12,433 --> 00:43:14,202 RELATIONSHIP, AND IN FACT, 1279 00:43:14,202 --> 00:43:17,906 PATIENTS WITH JUST PARKINSON 1280 00:43:17,906 --> 00:43:19,474 DISEASE WHO DON'T HAVE GBA 1281 00:43:19,474 --> 00:43:22,644 MUTATIONS TEND TO HAVE LESS 1282 00:43:22,644 --> 00:43:23,077 GLUCOCEREBROSIDASE. 1283 00:43:23,077 --> 00:43:25,613 SO I DON'T KNOW -- AS I KEEP ON 1284 00:43:25,613 --> 00:43:27,815 TELLING YOU, NOT ALL PEOPLE THAT 1285 00:43:27,815 --> 00:43:30,752 HAVE DEFICIENT 1286 00:43:30,752 --> 00:43:31,953 GLUCOCEREBROSIDASE GET PARKINSON 1287 00:43:31,953 --> 00:43:32,987 DISEASE BUT MAYBE THERE'S SOME 1288 00:43:32,987 --> 00:43:33,955 COMPONENTS WITH AGING WHERE WE 1289 00:43:33,955 --> 00:43:35,823 TEND TO HAVE MORE SYNUCLEIN, WE 1290 00:43:35,823 --> 00:43:39,127 HAVE LESS GOOD LYSOSOMAL 1291 00:43:39,127 --> 00:43:42,330 FUNCTION AND APPARENTLY 1292 00:43:42,330 --> 00:43:43,197 GLUCOCEREBROSIDE LEVELS COME 1293 00:43:43,197 --> 00:43:43,831 DOWN SO MAYBE THERE'S SOMETHING 1294 00:43:43,831 --> 00:43:45,733 IN AGING THAT CAN SHIFT THE 1295 00:43:45,733 --> 00:43:47,735 BALANCE, OR MAYBE 1296 00:43:47,735 --> 00:43:48,369 GLUCOCEREBROSIDASE JUST HAS 1297 00:43:48,369 --> 00:43:50,204 ANOTHER ROLE THAT WE'VE STILL 1298 00:43:50,204 --> 00:43:52,507 NOT ELUCIDATED. 1299 00:43:52,507 --> 00:43:54,976 SO MY TAKE-HOME MESSAGE IS FOR 1300 00:43:54,976 --> 00:43:57,278 THIS SHORT PART ARE THAT 1301 00:43:57,278 --> 00:43:59,047 MUTATIONS IN GBA ARE A RISK 1302 00:43:59,047 --> 00:44:00,882 FACTOR EVEN IN CARRIERS. 1303 00:44:00,882 --> 00:44:02,317 MOST PATIENTS AND CARRIERS NEVER 1304 00:44:02,317 --> 00:44:04,719 DEVELOP PARKINSON DISEASE. 1305 00:44:04,719 --> 00:44:06,087 BUT I TRULY BELIEVE THAT 1306 00:44:06,087 --> 00:44:07,288 LEARNING MORE ABOUT THIS 1307 00:44:07,288 --> 00:44:08,489 CONNECTION WILL IMPROVE OUR 1308 00:44:08,489 --> 00:44:10,258 UNDERSTANDING REALLY OF BOTH 1309 00:44:10,258 --> 00:44:12,260 DISEASES AND WILL HELP INFORM 1310 00:44:12,260 --> 00:44:13,795 DRUG DEVELOPMENT, WHICH I'LL 1311 00:44:13,795 --> 00:44:17,432 TALK ABOUT LATER. 1312 00:44:17,432 --> 00:44:18,366 >> GREAT. 1313 00:44:18,366 --> 00:44:21,235 THANKS, ELLEN. 1314 00:44:21,235 --> 00:44:28,142 OKAY. 1315 00:44:28,142 --> 00:44:31,212 SO WE'VE TALKED A BILL LITTLE 1316 00:44:31,212 --> 00:44:34,983 ABOUT HOW FAR WE'VE COME IN 1317 00:44:34,983 --> 00:44:36,184 GENETIC DISCOVERY, AND HOPEFULLY 1318 00:44:36,184 --> 00:44:38,252 WE'VE MADE A PERSUASIVE ARGUMENT 1319 00:44:38,252 --> 00:44:39,787 THAT UNDERSTANDING THE GENETIC 1320 00:44:39,787 --> 00:44:40,822 BASIS OF DISEASES IS KIND OF 1321 00:44:40,822 --> 00:44:42,557 IMPORTANT IF WE WANT TO COME UP 1322 00:44:42,557 --> 00:44:47,295 WITHWITH RATIONAL TARGETS FOR 1323 00:44:47,295 --> 00:44:48,262 THERAPEUTIC DEVELOPMENT AND 1324 00:44:48,262 --> 00:44:49,364 MATCH THOSE THERAPIES TO 1325 00:44:49,364 --> 00:44:51,232 PATIENTS. 1326 00:44:51,232 --> 00:44:52,934 SO I GUESS THE CRITICAL QUESTION 1327 00:44:52,934 --> 00:44:56,971 IS HOW DO WE CONTINUE TO 1328 00:44:56,971 --> 00:44:58,072 DISCOVER GENETIC DRIVERS OF 1329 00:44:58,072 --> 00:44:58,406 DISEASE? 1330 00:44:58,406 --> 00:45:02,543 SO I'M GOING TO TALK ABOUT ONE 1331 00:45:02,543 --> 00:45:03,578 MECHANISM THAT WE'VE BEEN USING 1332 00:45:03,578 --> 00:45:05,446 TO TRY AND DO THIS, AND TO TRY 1333 00:45:05,446 --> 00:45:07,515 AND DO THIS ON A GLOBAL SCALE SO 1334 00:45:07,515 --> 00:45:09,083 THIS IS A PROGRAM CALLED THE 1335 00:45:09,083 --> 00:45:11,152 GLOBAL PARKINSON'S GENETICS 1336 00:45:11,152 --> 00:45:15,657 PROGRAM, WHICH I LEAD ALONG WITH 1337 00:45:15,657 --> 00:45:20,495 CORNELIS PLAUWENDRAAT BUT REALLY 1338 00:45:20,495 --> 00:45:27,835 INCLUDES THOUSANDS OF PEOPLE. 1339 00:45:27,835 --> 00:45:31,172 SO THE MISSION OF GP2 IS A VERY 1340 00:45:31,172 --> 00:45:33,007 SIMPLE ONE, TO DRAMATICALLY 1341 00:45:33,007 --> 00:45:34,442 EXPAND OUR UNDERSTANDING OF THE 1342 00:45:34,442 --> 00:45:35,910 GENETIC BASIS OF DISEASE, BUT TO 1343 00:45:35,910 --> 00:45:39,080 DO THAT IN A GLOBAL CONTEXT. 1344 00:45:39,080 --> 00:45:40,715 AGAIN WITH THIS NOTION OF IF 1345 00:45:40,715 --> 00:45:42,050 WE'RE GOING TO TREAT A GLOBAL 1346 00:45:42,050 --> 00:45:43,184 DISEASE, WE NEED TO UNDERSTAND 1347 00:45:43,184 --> 00:45:45,019 THE BASIS OF THAT DISEASE ACROSS 1348 00:45:45,019 --> 00:45:47,321 WORLDWIDE POPULATIONS. 1349 00:45:47,321 --> 00:45:49,023 SO THE OVERARCHING THEME IS 1350 00:45:49,023 --> 00:45:49,557 GLOBAL DISEASE. 1351 00:45:49,557 --> 00:45:52,627 WE KIND OF HAVE THESE SEPARATE 1352 00:45:52,627 --> 00:45:54,162 AREAS OF COMPLEX DISEASE AND 1353 00:45:54,162 --> 00:45:55,163 MONOGENIC DISEASE BUT THEY'RE 1354 00:45:55,163 --> 00:45:57,699 REALLY A CONTINUUM. 1355 00:45:57,699 --> 00:45:59,434 THEY'RE JUST SEPARATED BECAUSE 1356 00:45:59,434 --> 00:46:00,768 IT MAKES WORK GROUPS A BIT 1357 00:46:00,768 --> 00:46:01,302 EASIER. 1358 00:46:01,302 --> 00:46:02,336 ESSENTIALLY WHAT WE'LL BE DOING 1359 00:46:02,336 --> 00:46:05,073 IS GENERATING GENETIC 1360 00:46:05,073 --> 00:46:06,708 INFORMATION AROUND 200,000 1361 00:46:06,708 --> 00:46:08,710 INDIVIDUALS, SO DENSE 1362 00:46:08,710 --> 00:46:10,678 GENOME-WIDE GENOTYPING ON AROUND 1363 00:46:10,678 --> 00:46:11,979 200,000, AND A SHIFT TO WHOLE 1364 00:46:11,979 --> 00:46:13,314 GENOME SEQUENCING ON A LARGE 1365 00:46:13,314 --> 00:46:14,716 PROPORTION OF THOSE. 1366 00:46:14,716 --> 00:46:16,217 THERE ARE SOME REALLY KEY 1367 00:46:16,217 --> 00:46:19,287 STRUCTURAL PRIORITIES FOR GP2. 1368 00:46:19,287 --> 00:46:22,824 I THINK THAT TYPICALLY WHAT'S 1369 00:46:22,824 --> 00:46:24,459 HAPPENED IS, WHEN WE'VE TRIED TO 1370 00:46:24,459 --> 00:46:27,662 LOOK AT DISEASE ACROSS WORLDWIDE 1371 00:46:27,662 --> 00:46:28,663 POPULATIONS, WHAT'S HAPPENED IS 1372 00:46:28,663 --> 00:46:30,064 REALLY WELL-FUNDED LABS HAVE 1373 00:46:30,064 --> 00:46:31,499 GONE INTO THOSE POPULATIONS, 1374 00:46:31,499 --> 00:46:32,834 WORKED WITH LOCAL INVESTIGATORS, 1375 00:46:32,834 --> 00:46:34,268 COLLECTED SAMPLES, BROUGHT THEM 1376 00:46:34,268 --> 00:46:35,803 BACK, ANALYZED THEM, PUBLISHED 1377 00:46:35,803 --> 00:46:36,404 THEM, THE END. 1378 00:46:36,404 --> 00:46:38,439 WHAT WE'RE TRYING TO DO HERE IN 1379 00:46:38,439 --> 00:46:39,207 GB2 IS SLIGHTLY DIFFERENT IN 1380 00:46:39,207 --> 00:46:41,809 THAT WE'RE TRYING TO ENABLE 1381 00:46:41,809 --> 00:46:43,811 RESEARCH IN THE VERY POPULATIONS 1382 00:46:43,811 --> 00:46:45,012 WHERE THOSE SAMPLES ARE 1383 00:46:45,012 --> 00:46:45,279 COLLECTED. 1384 00:46:45,279 --> 00:46:49,183 SO THERE'S A REALLY LARGE FOCUS 1385 00:46:49,183 --> 00:46:50,651 ON DEMOCRATIZATION OF THE 1386 00:46:50,651 --> 00:46:52,286 RESEARCH PROCESS, SO MAKING DATA 1387 00:46:52,286 --> 00:46:56,124 AVAILABLE, USABLE AND ACTION 1388 00:46:56,124 --> 00:46:56,424 ACTIONABLE. 1389 00:46:56,424 --> 00:46:58,226 BY RESEARCHERS AROUND THE WORLD, 1390 00:46:58,226 --> 00:46:59,393 COLLABORATING, COOPERATING, 1391 00:46:59,393 --> 00:47:00,862 SHARING DATA IN A SAFE, 1392 00:47:00,862 --> 00:47:02,330 RESPONSIBLE WAY, BEING EXTREMELY 1393 00:47:02,330 --> 00:47:03,498 TRANSPARENT IN HOW WE DO OUR 1394 00:47:03,498 --> 00:47:04,832 RESEARCH AND MAKING SURE THAT 1395 00:47:04,832 --> 00:47:06,701 THE RESEARCHERS ARE REPRESENTED 1396 00:47:06,701 --> 00:47:09,670 FROM THE POPULATIONS THAT 1397 00:47:09,670 --> 00:47:11,639 PATIENTS ARE COLLECTED. 1398 00:47:11,639 --> 00:47:14,809 SO REALLY THERE ARE FOUR THEMES 1399 00:47:14,809 --> 00:47:20,014 THAT ARE PULLED TOGETHER, THINGS 1400 00:47:20,014 --> 00:47:22,183 LIKE BUILDING LOCAL 1401 00:47:22,183 --> 00:47:24,252 INFRASTRUCTURE, IMPROVING 1402 00:47:24,252 --> 00:47:26,154 TRAINING AND SKILLSETS IN LOCAL 1403 00:47:26,154 --> 00:47:27,155 INVESTIGATORS, FACILITATING 1404 00:47:27,155 --> 00:47:28,122 COLLABORATION AND NETWORK 1405 00:47:28,122 --> 00:47:30,625 BUILDING WITH THOSE 1406 00:47:30,625 --> 00:47:31,626 INVESTIGATORS, GROWING THE NEXT 1407 00:47:31,626 --> 00:47:33,427 GENERATION OF LEADERS, SO 1408 00:47:33,427 --> 00:47:36,264 FINDING YOUNG INVESTIGATORS, NEW 1409 00:47:36,264 --> 00:47:38,666 INVESTIGATORS TO PD RESEARCH AND 1410 00:47:38,666 --> 00:47:40,134 GIVING THEM OPPORTUNITIES FOR 1411 00:47:40,134 --> 00:47:41,903 GROWTH AND PLACES TO DO THEIR 1412 00:47:41,903 --> 00:47:44,939 WORK. 1413 00:47:44,939 --> 00:47:46,040 APPLYING TRANSFORMATIVE GENETIC 1414 00:47:46,040 --> 00:47:46,607 METHODS. 1415 00:47:46,607 --> 00:47:48,075 SO I TALKED A LITTLE ABOUT 1416 00:47:48,075 --> 00:47:49,610 GENOME WIDE ASSOCIATION, WHOLE 1417 00:47:49,610 --> 00:47:55,216 GENOME GENOTYPING, LONG READ 1418 00:47:55,216 --> 00:47:56,450 SEQUENCING, THINGS LIKE THAT, 1419 00:47:56,450 --> 00:47:57,385 REALLY TRANSFORMATIVE METHODS. 1420 00:47:57,385 --> 00:47:59,320 AND THEN ACCELERATING DISCOVERY 1421 00:47:59,320 --> 00:48:00,188 BY DEMOCRATIZING DATA. 1422 00:48:00,188 --> 00:48:03,024 WHAT I MEAN HERE IS, I THINK IN 1423 00:48:03,024 --> 00:48:03,891 THE GENETICS COMMUNITY, WE'VE 1424 00:48:03,891 --> 00:48:05,927 BEEN PRETTY GOOD AT SHARING DATA 1425 00:48:05,927 --> 00:48:08,763 FOR A FAIRLY LONG TIME. 1426 00:48:08,763 --> 00:48:10,231 BUT YOU NEED RESOURCES AND 1427 00:48:10,231 --> 00:48:11,432 SKILLS TO BE ABLE TO DO ANYTHING 1428 00:48:11,432 --> 00:48:12,633 USEFUL WITH THAT DATA. 1429 00:48:12,633 --> 00:48:15,436 SO AS PART OF GP2, WE'VE CREATED 1430 00:48:15,436 --> 00:48:16,504 AN INFRASTRUCTURE THAT NOT ONLY 1431 00:48:16,504 --> 00:48:19,040 MAKES THE DATA AVAILABLE, 1432 00:48:19,040 --> 00:48:19,841 PROVIDES COMPUTE INFRASTRUCTURE, 1433 00:48:19,841 --> 00:48:21,909 SO ALL YOU NEED IS A CONNECTION, 1434 00:48:21,909 --> 00:48:23,077 AN INTERNET CONNECTION TO THE 1435 00:48:23,077 --> 00:48:24,011 DATA, AND TRAINING IN ORDER TO 1436 00:48:24,011 --> 00:48:25,246 BE ABLE TO ACTUALLY DO THE 1437 00:48:25,246 --> 00:48:28,282 ANALYSES THAT YOU NEED TO DO. 1438 00:48:28,282 --> 00:48:29,183 AND I'LL MENTION A COUPLE THINGS 1439 00:48:29,183 --> 00:48:29,951 ABOUT THAT. 1440 00:48:29,951 --> 00:48:31,419 SO WHAT THIS PRODUCES IS REALLY 1441 00:48:31,419 --> 00:48:34,055 A SELF-PROPAGATING DISCOVERY 1442 00:48:34,055 --> 00:48:35,356 ENGINE. 1443 00:48:35,356 --> 00:48:37,124 RESEARCHERS SCATTERED AROUND THE 1444 00:48:37,124 --> 00:48:39,560 WORLD, MAKING AN ENABLING 1445 00:48:39,560 --> 00:48:40,228 TRANSFORMATIVE DISCOVERIES. 1446 00:48:40,228 --> 00:48:42,864 IN TERMS OF TRAINING, SO WE HAVE 1447 00:48:42,864 --> 00:48:44,398 CREATED A SERIES OF VIDEOS, 1448 00:48:44,398 --> 00:48:46,300 ABOUT 80 COURSES NOW, WHICH 1449 00:48:46,300 --> 00:48:48,402 ALLOW YOU TO LEARN HOW TO DO 1450 00:48:48,402 --> 00:48:49,036 GENETIC ANALYSIS. 1451 00:48:49,036 --> 00:48:50,504 THE MOST BASIC ONE IS GENETICS 1452 00:48:50,504 --> 00:48:53,908 FOR THE P.I., WHICH I'M IN, AND 1453 00:48:53,908 --> 00:48:55,309 SHOWS YOU HOW IF YOU DON'T KNOW 1454 00:48:55,309 --> 00:48:57,678 HOW TO DO ANY CODING, YOU CAN GO 1455 00:48:57,678 --> 00:48:59,313 FROM ZERO TO 60 FAIRLY QUICKLY, 1456 00:48:59,313 --> 00:49:02,149 AND THEN THROUGH TO VERY 1457 00:49:02,149 --> 00:49:03,951 COMPREHENSIVE GENETIC ANALYSIS 1458 00:49:03,951 --> 00:49:04,619 METHODS. 1459 00:49:04,619 --> 00:49:05,620 THESE 80 COURSES ARE AVAILABLE 1460 00:49:05,620 --> 00:49:06,954 FOR FREE IN MORE THAN 100 1461 00:49:06,954 --> 00:49:08,589 DIFFERENT LANGUAGES, WE HAVE 1462 00:49:08,589 --> 00:49:09,490 ALMOST A THOUSAND USERS AROUND 1463 00:49:09,490 --> 00:49:10,691 THE WORLD NOW, INCLUDING A THIRD 1464 00:49:10,691 --> 00:49:12,793 OF WHICH ARE FROM LOW AND MEDIUM 1465 00:49:12,793 --> 00:49:13,661 INCOME COUNTRIES. 1466 00:49:13,661 --> 00:49:15,196 SO AN INVESTIGATOR CAN COME 1467 00:49:15,196 --> 00:49:16,530 ALONG FROM ANYWHERE IN THE 1468 00:49:16,530 --> 00:49:20,167 WORLD, ACCESS THE DATA, ONCE 1469 00:49:20,167 --> 00:49:21,502 THEIR DATA ACCESS HAS BEEN 1470 00:49:21,502 --> 00:49:23,771 APPROVED, THEY HAVE THE 1471 00:49:23,771 --> 00:49:28,910 COMPUTATIONAL METHODS AND POWER 1472 00:49:28,910 --> 00:49:30,111 AVAILABLE IN THE CLOUD, ALL OF 1473 00:49:30,111 --> 00:49:31,279 THE COMPUTATION IS ATTACHED, AND 1474 00:49:31,279 --> 00:49:32,914 THEY CAN LEARN HOW TO DO THESE 1475 00:49:32,914 --> 00:49:34,482 ANALYSIS, SO YOU CAN DO 1476 00:49:34,482 --> 00:49:36,350 EXTREMELY COMPLEX ANALYSES ON 1477 00:49:36,350 --> 00:49:38,219 LARGE DATASETS. 1478 00:49:38,219 --> 00:49:40,955 WE ALSO BUILD GLOBAL RESEARCH 1479 00:49:40,955 --> 00:49:42,390 CAPACITY BY BRINGING PEOPLE 1480 00:49:42,390 --> 00:49:44,825 TOGETHER, SO WE'VE HAD SEVERAL 1481 00:49:44,825 --> 00:49:47,561 MEETINGS, TWO IN-PERSON ANNUAL 1482 00:49:47,561 --> 00:49:49,330 MEETINGS FOR THE ENTIRE 1483 00:49:49,330 --> 00:49:50,331 CONSORTIUM, SO LAST YEAR'S 1484 00:49:50,331 --> 00:49:52,400 MEETING HAD ALMOST 300 ATTENDEES 1485 00:49:52,400 --> 00:49:53,234 FROM 60 DIFFERENT COUNTRIES. 1486 00:49:53,234 --> 00:49:54,969 THAT WAS HELD IN COPENHAGEN. 1487 00:49:54,969 --> 00:49:56,270 I'VE JUST COME BACK FROM A 1488 00:49:56,270 --> 00:49:59,173 REGIONAL MEETING FOR SOUTH AND 1489 00:49:59,173 --> 00:50:04,211 CENTRAL AMERICA IN CARTAGENA. 1490 00:50:04,211 --> 00:50:11,819 WE HAD MEETINGS IN KUALA LUMPUR, 1491 00:50:11,819 --> 00:50:14,221 AND AFRICA, FIND RESEARCHERS, 1492 00:50:14,221 --> 00:50:16,457 WORK WITH THEM TO MAKE SURE THEY 1493 00:50:16,457 --> 00:50:17,992 HAVE THEIR NEEDS MET TO DO THIS 1494 00:50:17,992 --> 00:50:19,193 RESEARCH. 1495 00:50:19,193 --> 00:50:20,728 WE'VE ALSO HELPED TO BUILD SOME 1496 00:50:20,728 --> 00:50:24,231 LOCAL CAPACITY LIKE BUILDING A 1497 00:50:24,231 --> 00:50:26,334 LOCAL BIOBANK, TRAINING PEOPLE 1498 00:50:26,334 --> 00:50:27,635 HOW TO DO TRAINING WORKSHOPS SO 1499 00:50:27,635 --> 00:50:30,604 WE HAVE THIS KIND OF 1500 00:50:30,604 --> 00:50:31,973 SELF-FULFILLING GRIP OF 1501 00:50:31,973 --> 00:50:33,507 INVESTIGATORS WHO CONTINUE TO 1502 00:50:33,507 --> 00:50:35,142 TRAIN OTHER INVESTIGATORS IN 1503 00:50:35,142 --> 00:50:36,010 DATA ANALYSIS AND CLINICAL 1504 00:50:36,010 --> 00:50:39,080 RESEARCH. 1505 00:50:39,080 --> 00:50:41,849 WE ALSO HAVE PH.D. AND MASTERS 1506 00:50:41,849 --> 00:50:42,783 STUDENTS SCATTERED AROUND THE 1507 00:50:42,783 --> 00:50:43,084 WORLD. 1508 00:50:43,084 --> 00:50:45,586 YOU CAN SEE HERE THE LATEST 1509 00:50:45,586 --> 00:50:47,388 SWATH WERE FIVE ADDITIONAL PH.D. 1510 00:50:47,388 --> 00:50:50,024 STUDENTS, SO AGAIN, TRAINING 1511 00:50:50,024 --> 00:50:50,891 INVESTIGATORS FROM THE VERY 1512 00:50:50,891 --> 00:50:52,026 SITES WHERE WE'RE GETTING 1513 00:50:52,026 --> 00:50:53,127 SAMPLES FROM WITH THIS NOTION 1514 00:50:53,127 --> 00:50:57,164 THAT WE HAVE REALLY INTERESTED, 1515 00:50:57,164 --> 00:50:59,900 DRIVEN SCIENTISTS WHO CAN PUSH 1516 00:50:59,900 --> 00:51:03,037 THE NEEDLE FORWARD. 1517 00:51:03,037 --> 00:51:04,238 SO WHERE ARE WE? 1518 00:51:04,238 --> 00:51:05,973 THERE ARE AROUND 170,000 SAMPLES 1519 00:51:05,973 --> 00:51:09,777 IN OUR PIPELINE, 45,000 HAVE 1520 00:51:09,777 --> 00:51:11,012 BEEN GENOTYPED AND ARE AVAILABLE 1521 00:51:11,012 --> 00:51:11,178 NOW. 1522 00:51:11,178 --> 00:51:16,150 YOU CAN GO TO AMP PD, THE NIH'S 1523 00:51:16,150 --> 00:51:18,152 PUBLIC-PRIVATE PARTNERSHIP AND 1524 00:51:18,152 --> 00:51:20,121 ACCESS GENETIC DATA ON 45,000 1525 00:51:20,121 --> 00:51:20,988 SAMPLES NOW. 1526 00:51:20,988 --> 00:51:22,857 IT'S A VERY SHORT APPLICATION 1527 00:51:22,857 --> 00:51:23,457 PROCESS. 1528 00:51:23,457 --> 00:51:24,558 THEY JUST MAKE SURE YOU'RE A 1529 00:51:24,558 --> 00:51:26,527 BONA FIDE RESEARCHER AND THEN 1530 00:51:26,527 --> 00:51:27,895 YOU HAVE ACCESS TO THE DATA. 1531 00:51:27,895 --> 00:51:29,130 THE COMPUTE RESOURCES, ALL OF 1532 00:51:29,130 --> 00:51:30,531 THE TRAINING MATERIALS AND YOU 1533 00:51:30,531 --> 00:51:32,066 CAN DO WHATEVER ANALYSIS YOU'D 1534 00:51:32,066 --> 00:51:32,566 LIKE TO DO. 1535 00:51:32,566 --> 00:51:34,635 YOU CAN SEE WE'RE FAIRLY 1536 00:51:34,635 --> 00:51:36,270 SCATTERED AROUND THE WORLD, SO 1537 00:51:36,270 --> 00:51:37,371 THERE'S STILL LOTS OF PLACES FOR 1538 00:51:37,371 --> 00:51:39,607 US TO GO AND EXPAND, BUT WE'RE 1539 00:51:39,607 --> 00:51:41,776 WELL ON OUR WAY TO COLLECTING 1540 00:51:41,776 --> 00:51:43,310 THE 200,000 SAMPLES WE SAID WE 1541 00:51:43,310 --> 00:51:43,744 WOULD. 1542 00:51:43,744 --> 00:51:45,479 WE HAVE THROUGH 2029 TO FINISH 1543 00:51:45,479 --> 00:51:47,448 THIS. 1544 00:51:47,448 --> 00:51:49,817 SO WHAT DOES THIS PRODUCE? 1545 00:51:49,817 --> 00:51:52,386 WE'RE STILL FAIRLY EARLY IN THIS 1546 00:51:52,386 --> 00:51:53,954 PROCESS, SO I'M GOING TO GIVE 1547 00:51:53,954 --> 00:51:56,223 YOU TWO EXAMPLES OF WHAT THIS 1548 00:51:56,223 --> 00:51:58,025 WOULD -- WHAT KINDS OF RESEARCH 1549 00:51:58,025 --> 00:52:00,594 THIS WILL PRODUCE. 1550 00:52:00,594 --> 00:52:02,329 BUT THESE ARE FAIRLY 1551 00:52:02,329 --> 00:52:02,630 PRELIMINARY. 1552 00:52:02,630 --> 00:52:04,532 PRELIMINARY BUT PRETTY COOL. 1553 00:52:04,532 --> 00:52:05,833 SO MULTI-ANCESTRY GENOME WIDE 1554 00:52:05,833 --> 00:52:06,734 ASSOCIATION STUDY. 1555 00:52:06,734 --> 00:52:10,071 THIS WAS JUST PUBLISHED IN 1556 00:52:10,071 --> 00:52:11,806 GENETICS A FEW WEEKS AGO. 1557 00:52:11,806 --> 00:52:13,741 HERE THE POWER IS NOT 1558 00:52:13,741 --> 00:52:15,609 NECESSARILY IN NUMBERS BUT IN 1559 00:52:15,609 --> 00:52:16,811 COMPARING GENETIC ASSOCIATION 1560 00:52:16,811 --> 00:52:20,548 ACROSS DIFFERENT POPULATIONS. 1561 00:52:20,548 --> 00:52:23,317 SO FOUR DIFFERENT POPULATIONS, 1562 00:52:23,317 --> 00:52:25,953 EUROPEAN, EAST ASIAN, LATINO, 1563 00:52:25,953 --> 00:52:27,655 WITH FAIRLY MODEST SAMPLES FROM 1564 00:52:27,655 --> 00:52:30,157 EAST ASIA, LATIN AMERICAN 1565 00:52:30,157 --> 00:52:32,393 COUNTRIES AND AFRICA. 1566 00:52:32,393 --> 00:52:34,261 BUT REMARKABLE DISCOVERIES, EVEN 1567 00:52:34,261 --> 00:52:36,330 ADDING ONLY A SMALL NUMBER OF 1568 00:52:36,330 --> 00:52:37,865 SAMPLES FROM DIFFERENT 1569 00:52:37,865 --> 00:52:39,400 POPULATIONS HAS GIVEN US ANOTHER 1570 00:52:39,400 --> 00:52:41,469 DOZEN OR SO RISK LOCI, INCLUDING 1571 00:52:41,469 --> 00:52:42,303 THINGS THAT ARE DIFFERENT IN 1572 00:52:42,303 --> 00:52:43,070 DIFFERENT POPULATIONS. 1573 00:52:43,070 --> 00:52:46,307 SO WE SEE ABOUT 30% OF THE KNOWN 1574 00:52:46,307 --> 00:52:50,277 RISK VARIANTS ARE DIFFERENT WHEN 1575 00:52:50,277 --> 00:52:52,213 YOU GO TO VARIED ANCESTRAL 1576 00:52:52,213 --> 00:52:52,546 GROUPS. 1577 00:52:52,546 --> 00:52:54,181 THEY'RE EITHER IN A DIFFERENT 1578 00:52:54,181 --> 00:52:55,683 DIRECTION OR THERE'S A DIFFERENT 1579 00:52:55,683 --> 00:52:57,852 UNDERLYING VARIANT. 1580 00:52:57,852 --> 00:52:58,786 AGAIN POINTING THIS NOTION THAT 1581 00:52:58,786 --> 00:53:01,422 WE REALLY NEED TO UNDERSTAND 1582 00:53:01,422 --> 00:53:03,057 GENETIC ARCHITECTURE IN 1583 00:53:03,057 --> 00:53:06,460 DIFFERENT ANCESTRAL GROUPS. 1584 00:53:06,460 --> 00:53:07,995 THE OTHER STORY I WANTED TO TELL 1585 00:53:07,995 --> 00:53:12,867 BUT IS AGAIN A VERY PRELIMINARY 1586 00:53:12,867 --> 00:53:14,401 STORY OR ACTUALLY IT'S A MATURE 1587 00:53:14,401 --> 00:53:16,270 STORY BUT IT'S EARLY ON IN THE 1588 00:53:16,270 --> 00:53:16,904 STUDY. 1589 00:53:16,904 --> 00:53:18,105 SO I TALKED A LITTLE BIT ABOUT 1590 00:53:18,105 --> 00:53:19,707 THE FACT THAT WE WANT TO TRAIN 1591 00:53:19,707 --> 00:53:24,345 INVESTIGATORS ON HOWL TO ANALYZE 1592 00:53:24,345 --> 00:53:25,079 THEIR DATA. 1593 00:53:25,079 --> 00:53:26,247 ONE OF THE WAYS WE DO THIS IS WE 1594 00:53:26,247 --> 00:53:27,515 HAVE TRAINING GROUPS WITH 1595 00:53:27,515 --> 00:53:28,516 REPRESENTATIVES FROM VARIOUS 1596 00:53:28,516 --> 00:53:29,984 COUNTRIES THAT COME TOGETHER AND 1597 00:53:29,984 --> 00:53:30,818 ANALYZE PRELIMINARY DATA. 1598 00:53:30,818 --> 00:53:34,822 SO ONE OF THESE WAS A GROUP THAT 1599 00:53:34,822 --> 00:53:38,225 WAS CENTERED AT NIH HERE AT 1600 00:53:38,225 --> 00:53:40,594 UNIVERSITY COLLEGE LONDON, AND 1601 00:53:40,594 --> 00:53:44,165 AT UNIVERSITY OF LEGOUS IN 1602 00:53:44,165 --> 00:53:47,034 NIGERIA, ANALYZING DATA FROM 1603 00:53:47,034 --> 00:53:50,804 AFRICAN ANCESTRY INDIVIDUALS 1604 00:53:50,804 --> 00:53:52,239 WITH PARKINSON'S DISEASE. 1605 00:53:52,239 --> 00:53:53,841 SO WORKING ON THIS SHARED DATA 1606 00:53:53,841 --> 00:53:55,843 ANALYSIS USING THE TERRA 1607 00:53:55,843 --> 00:53:57,878 PLATFORM REALLY IS A TRAINING 1608 00:53:57,878 --> 00:54:01,148 EXERCISE, DOING A GWAS IN JUST A 1609 00:54:01,148 --> 00:54:02,750 THOUSAND, 1500 OR SO CASES, 1610 00:54:02,750 --> 00:54:04,318 SOMETHING LIKE THAT, EXPECTING 1611 00:54:04,318 --> 00:54:04,818 TO SEE NOTHING. 1612 00:54:04,818 --> 00:54:06,253 WHAT HE WITH SAW WAS AN 1613 00:54:06,253 --> 00:54:07,955 INCREDIBLE PEAK, GENOME-WIDE 1614 00:54:07,955 --> 00:54:09,023 SIGNIFICANT, 10 TO THE MINUS 14, 1615 00:54:09,023 --> 00:54:11,625 A P VALUE OF 10 TO THE MINUS 14 1616 00:54:11,625 --> 00:54:12,826 ON CHROMOSOME 1. 1617 00:54:12,826 --> 00:54:15,095 RIGHT OVER THE TOP OF ELLEN'S 1618 00:54:15,095 --> 00:54:16,530 FAVORITE GENE, GBA1. 1619 00:54:16,530 --> 00:54:18,232 THIS WAS INCREDIBLY SURPRISING. 1620 00:54:18,232 --> 00:54:19,900 WE NEVER WOULD HAVE EXPECTED TO 1621 00:54:19,900 --> 00:54:21,835 SEE SOMETHING LIKE THIS. 1622 00:54:21,835 --> 00:54:24,772 AFTER A LARGE AMOUNT OF WORK, 1623 00:54:24,772 --> 00:54:28,475 WHAT WAS CLEARLY SHOWN IS THAT 1624 00:54:28,475 --> 00:54:30,110 THE SENTINAL VARIANT, THE THING 1625 00:54:30,110 --> 00:54:31,545 THAT'S TAGGING THIS ASSOCIATION, 1626 00:54:31,545 --> 00:54:35,216 IS A NON-CODING VARIANT IN THE 1627 00:54:35,216 --> 00:54:37,952 INTRON OF GBA1, SO NOT IN THE 1628 00:54:37,952 --> 00:54:39,420 PROTEIN CODING PORTION BUT IN 1629 00:54:39,420 --> 00:54:41,956 BETWEEN TWO AXONS. 1630 00:54:41,956 --> 00:54:43,591 CARRYING A SINGLE ONE OF THESE 1631 00:54:43,591 --> 00:54:46,193 VARIANTS INCREASES RISK ABOUT 1632 00:54:46,193 --> 00:54:48,028 1.3 FOLD, CARRYING TWO INCREASES 1633 00:54:48,028 --> 00:54:50,664 RISK ABOUT 4 FOLD. 1634 00:54:50,664 --> 00:54:51,432 3 1/2 TO 4 FOLD. 1635 00:54:51,432 --> 00:54:53,467 BUT THIS IS REMARKABLY COMMON. 1636 00:54:53,467 --> 00:54:55,636 ABOUT HALF OF ALL PARKINSON'S 1637 00:54:55,636 --> 00:54:59,273 DISEASE PATIENTS FROM NIGERIA 1638 00:54:59,273 --> 00:55:02,943 CARRY THIS VARIANT, AND ABOUT 1639 00:55:02,943 --> 00:55:04,144 ONE IN EIGHT PARKINSON'S DISEASE 1640 00:55:04,144 --> 00:55:06,981 PATIENTS ARE HOMOZYGOUS FOR THIS 1641 00:55:06,981 --> 00:55:08,382 VARIANT, PATIENTS OF AFRICAN 1642 00:55:08,382 --> 00:55:08,782 ANCESTRY. 1643 00:55:08,782 --> 00:55:10,985 SO THE POPULATION ATTRIBUTED TO 1644 00:55:10,985 --> 00:55:12,620 RISK, THE AMOUNT OF DISEASE 1645 00:55:12,620 --> 00:55:14,788 LIABILITY DRIVEN BY THIS VARIANT 1646 00:55:14,788 --> 00:55:16,624 IN WEST AFRICAN POPULATION IS 1647 00:55:16,624 --> 00:55:18,792 VERY, VERY HIGH. 1648 00:55:18,792 --> 00:55:21,729 EACH ALLELE YOU CARRY TEE DECRES 1649 00:55:21,729 --> 00:55:22,896 YOUR AGE OF ONSET BY ABOUT THREE 1650 00:55:22,896 --> 00:55:24,531 YEARS. 1651 00:55:24,531 --> 00:55:26,400 SO THE QUESTION THEN IS, WHEN WE 1652 00:55:26,400 --> 00:55:28,369 FIND A GENOME-WIDE SIGNIFICANT 1653 00:55:28,369 --> 00:55:29,970 HIT, WE HAVE TO GO AND TRY AND 1654 00:55:29,970 --> 00:55:31,372 UNDERSTAND WHAT IT DOING 1655 00:55:31,372 --> 00:55:32,873 FUNCTIONALLY, WHICH GENE IS IT 1656 00:55:32,873 --> 00:55:34,008 AFFECTING, HOW IS IT AFFECTING 1657 00:55:34,008 --> 00:55:34,508 THAT GENE. 1658 00:55:34,508 --> 00:55:35,709 AND THAT USUALLY TAKES QUITE A 1659 00:55:35,709 --> 00:55:36,243 LONG TIME. 1660 00:55:36,243 --> 00:55:39,913 THIS IS WORK THAT'S LED BY 1661 00:55:39,913 --> 00:55:43,217 CORNELIS, A PI HERE AT NIH, AND 1662 00:55:43,217 --> 00:55:44,585 REALLY WANTED TO ASK THESE TWO 1663 00:55:44,585 --> 00:55:46,553 QUESTIONS, WHAT'S THE KAU SHALL 1664 00:55:46,553 --> 00:55:48,188 VARIANT AND WHAT'S THE 1665 00:55:48,188 --> 00:55:49,957 BIOLOGICAL MECHANISM. 1666 00:55:49,957 --> 00:55:51,458 THIS WORK IS IN PRE-PRINT. 1667 00:55:51,458 --> 00:55:52,993 IT'S UNDER REVIEW AT THE MOMENT. 1668 00:55:52,993 --> 00:55:54,962 BUT YOU CAN GO SEE THIS WORK IN 1669 00:55:54,962 --> 00:55:56,196 MORE DETAIL IF YOU'RE 1670 00:55:56,196 --> 00:56:02,236 INTERESTED, IT'S ON MED ARCHIVE. 1671 00:56:02,236 --> 00:56:03,337 SO CLEARLY SOMETHING THAT THIS 1672 00:56:03,337 --> 00:56:04,571 VARIANT WAS ASSOCIATED WITH VERY 1673 00:56:04,571 --> 00:56:06,340 QUICKLY IS A CHANGE IN 1674 00:56:06,340 --> 00:56:07,541 EXPRESSION. 1675 00:56:07,541 --> 00:56:09,510 SO THE VARIANT THAT'S TAGGING AN 1676 00:56:09,510 --> 00:56:10,577 ASSOCIATION, THE ONE THAT'S 1677 00:56:10,577 --> 00:56:11,945 ASSOCIATED WITH RISK FOR 1678 00:56:11,945 --> 00:56:13,280 DISEASE, AND IT COULD JUST BE A 1679 00:56:13,280 --> 00:56:15,649 SENTINEL OR IT COULD BE "THE" 1680 00:56:15,649 --> 00:56:17,284 VARIANT, IS ASSOCIATED WITH 1681 00:56:17,284 --> 00:56:18,385 INCREASED EXPRESSION. 1682 00:56:18,385 --> 00:56:21,188 SO THE RISK ALLELE IS ASSOCIATED 1683 00:56:21,188 --> 00:56:21,722 WITH INCREASED EXPRESSION. 1684 00:56:21,722 --> 00:56:23,223 THAT'S KIND OF COUNTERINTUITIVE 1685 00:56:23,223 --> 00:56:26,193 TO WHAT WE KNOW ABOUT GBA1. 1686 00:56:26,193 --> 00:56:27,394 WE ASSUME NOT EVERYONE ASSUMES 1687 00:56:27,394 --> 00:56:30,331 BUT MANY OF US ASSUME THAT 1688 00:56:30,331 --> 00:56:31,398 GBA1 VARIANTS LEAD TO A LOSS OF 1689 00:56:31,398 --> 00:56:32,232 FUNCTION IN SOME WAY. 1690 00:56:32,232 --> 00:56:33,434 SO YOU WOULD HAVE EXPECTED THIS 1691 00:56:33,434 --> 00:56:36,070 TO BE THE OTHER WAY AROUND. 1692 00:56:36,070 --> 00:56:37,671 YOU WOULD HAVE EXPECTED OUR RISK 1693 00:56:37,671 --> 00:56:41,275 VARIANT TO LEAD TO DECREASED 1694 00:56:41,275 --> 00:56:42,142 GBA1 EXPRESSION. 1695 00:56:42,142 --> 00:56:43,477 THIS IS A COMPLICATED STORY 1696 00:56:43,477 --> 00:56:46,246 BECAUSE AS ELLEN HAS SAID, 1697 00:56:46,246 --> 00:56:47,581 GBA1 IS A COMPLICATED GENE. 1698 00:56:47,581 --> 00:56:48,949 THERE'S LOTS OF SPLICING GOING 1699 00:56:48,949 --> 00:56:50,718 ON, THERE'S A PSEUDOGENE RIGHT 1700 00:56:50,718 --> 00:56:52,119 NEXT TO IT, SO YOU CAN'T ALWAYS 1701 00:56:52,119 --> 00:56:54,021 RELY ON MEASURES OF EXPRESSION. 1702 00:56:54,021 --> 00:56:55,789 SO ONE OF THE NEXT THINGS THAT 1703 00:56:55,789 --> 00:56:59,727 WAS DONE WAS TO TAKE LONG READ 1704 00:56:59,727 --> 00:57:02,296 RNA SEQUENCING AND SEQUENCE 1705 00:57:02,296 --> 00:57:03,731 SAMPLES THAT CARRIED THIS 1706 00:57:03,731 --> 00:57:04,098 VARIANT. 1707 00:57:04,098 --> 00:57:05,599 AND WHAT YOU SHOULD SEE WHEN YOU 1708 00:57:05,599 --> 00:57:07,901 DO LONG READ RNA SEQUENCING IS 1709 00:57:07,901 --> 00:57:09,269 SEQUENCE OVER THE AXONS, RIGHT? 1710 00:57:09,269 --> 00:57:11,672 SO YOU'D SEE YOUR LONG STRAND OF 1711 00:57:11,672 --> 00:57:13,307 RNA AND IT WOULD ALIGN WITH AN 1712 00:57:13,307 --> 00:57:15,142 EXON, THERE WOULD BE A GAP WHERE 1713 00:57:15,142 --> 00:57:15,776 THERE'S AN INTRON, IT WOULD 1714 00:57:15,776 --> 00:57:17,211 ALIGN WITH THE NEXT AXON. 1715 00:57:17,211 --> 00:57:20,047 BUT WHAT WE SAW HERE IS ACTUALLY 1716 00:57:20,047 --> 00:57:21,448 SOME SEQUENCE IN THE INTRON. 1717 00:57:21,448 --> 00:57:23,650 SO THIS IS THE EXON HERE AND 1718 00:57:23,650 --> 00:57:25,919 THIS IS THE INTRON HERE. 1719 00:57:25,919 --> 00:57:30,257 SO SOMETHING IS BEING 1720 00:57:30,257 --> 00:57:33,460 TRANSCRIBED FROM TH THE INTRON, 1721 00:57:33,460 --> 00:57:34,762 TURNING INTO A PIECE OF RNA THAT 1722 00:57:34,762 --> 00:57:38,432 WOULD THEN EITHER BE TRANSLATED 1723 00:57:38,432 --> 00:57:39,199 OR DECAYED. 1724 00:57:39,199 --> 00:57:41,502 AND WE ONLY SAW THESE READS IN 1725 00:57:41,502 --> 00:57:42,970 PEOPLE WHO CARRIED THE RISK 1726 00:57:42,970 --> 00:57:43,203 VARIANT. 1727 00:57:43,203 --> 00:57:45,072 SO YOU NEVER SEE THESE REIN 1728 00:57:45,072 --> 00:57:47,474 ANYBODY ELSE. 1729 00:57:47,474 --> 00:57:48,409 READS IN 1730 00:57:48,409 --> 00:57:50,277 ANYBODY ELSE. 1731 00:57:50,277 --> 00:57:51,278 CORNELIS THEN WENT TO ASK THE 1732 00:57:51,278 --> 00:57:52,479 QUESTION, THE VARIANT THAT WE'RE 1733 00:57:52,479 --> 00:57:54,815 SEEING, IS THAT THE FUNCTIONAL 1734 00:57:54,815 --> 00:57:59,953 VARIANT SO THE CRISPRED THIS, 1735 00:57:59,953 --> 00:58:02,589 EDITED IN IN PEOPLE WHO DON'T 1736 00:58:02,589 --> 00:58:06,293 CARRY IT AND EDITED IT OUT IN 1737 00:58:06,293 --> 00:58:08,695 PEOPLE THAT DO CARRY IT. 1738 00:58:08,695 --> 00:58:10,631 IT COMPLETELY REVERSED -- SO THE 1739 00:58:10,631 --> 00:58:12,065 VARIANT WE SEE IS OUR LEAD 1740 00:58:12,065 --> 00:58:13,801 VARIANT FOR GWAS IS HAVING THIS 1741 00:58:13,801 --> 00:58:15,068 FUNCTIONAL EFFECT. 1742 00:58:15,068 --> 00:58:17,404 IT LEADING TO TRANSCRIPTION OF 1743 00:58:17,404 --> 00:58:19,807 THIS INTRONIC REGION. 1744 00:58:19,807 --> 00:58:22,075 SO WHEN YOU THINK ABOUT PROTEINS 1745 00:58:22,075 --> 00:58:25,379 BEING PRODUCED, AND THE SPLICING 1746 00:58:25,379 --> 00:58:28,182 OF EXONS, THERE ARE SEVERAL KEY 1747 00:58:28,182 --> 00:58:29,416 THINGS IN AN INTRON OR RIGHT 1748 00:58:29,416 --> 00:58:31,318 NEXT TO THE AXON THAT LEAD TO 1749 00:58:31,318 --> 00:58:32,719 SPLICING OUT OF THE INTRON AND 1750 00:58:32,719 --> 00:58:35,155 JOINING OF THE EXONS. 1751 00:58:35,155 --> 00:58:36,590 THOSE ARE THE SPLICED DONORS AND 1752 00:58:36,590 --> 00:58:38,926 THE SPLICED ACCEPTORS, WHICH 1753 00:58:38,926 --> 00:58:39,927 WE'RE ALWAYS REALLY FAMILIAR 1754 00:58:39,927 --> 00:58:41,328 WITH BUT THERE'S ALSO THIS 1755 00:58:41,328 --> 00:58:42,162 BRANCH POINT SITE WHICH OCCURS 1756 00:58:42,162 --> 00:58:43,363 IN MANY INTRONS. 1757 00:58:43,363 --> 00:58:45,766 IT'S AN A, ABOUT 40 BASE PAIRS, 1758 00:58:45,766 --> 00:58:48,469 BEFORE THE EXON, AND INDEED OUR 1759 00:58:48,469 --> 00:58:49,770 VARIANTS, THE ONE THAT IS THE 1760 00:58:49,770 --> 00:58:51,972 LEAD VARIANT FOR GENOME WIDE 1761 00:58:51,972 --> 00:58:54,007 ASSOCIATION HERE, IS THE BRANCH 1762 00:58:54,007 --> 00:58:54,341 POINT SITE. 1763 00:58:54,341 --> 00:58:58,212 SO OUR VARIANT CHANGES THIS A TO 1764 00:58:58,212 --> 00:59:02,216 A C. 1765 00:59:02,216 --> 00:59:04,284 SO WHAT THIS DOES IS DESTROY 1766 00:59:04,284 --> 00:59:05,686 THIS BRANCH POINT SITE AND MESS 1767 00:59:05,686 --> 00:59:07,321 UP SPLICING. 1768 00:59:07,321 --> 00:59:10,691 SO AN ALTERNATIVE BRANCH POINT 1769 00:59:10,691 --> 00:59:14,995 SITE SEEMS TO BEING USED, 1770 00:59:14,995 --> 00:59:16,563 ALTERNATIVE SPLIET SITE POINT 1771 00:59:16,563 --> 00:59:18,098 SEEMS TO BE USED, SO WHAT WE 1772 00:59:18,098 --> 00:59:19,666 ACTUALLY SEE IS PRODUCTION OF A 1773 00:59:19,666 --> 00:59:20,701 TRAB SCRIPT THAT WE DON'T THINK 1774 00:59:20,701 --> 00:59:22,035 IS BEING TRANSLATED AND THAT 1775 00:59:22,035 --> 00:59:24,438 LEADS US TO HAVE SOMETHING THAT 1776 00:59:24,438 --> 00:59:26,006 WE THINK LOOKS LIKE INCREASED 1777 00:59:26,006 --> 00:59:26,473 EXPRESSION. 1778 00:59:26,473 --> 00:59:28,242 SO YOU'VE GOT THE RISK VARIANT 1779 00:59:28,242 --> 00:59:31,411 THAT LEADS TO MISSPLICING. 1780 00:59:31,411 --> 00:59:32,713 THE MISS SPLICING LEADS TO 1781 00:59:32,713 --> 00:59:35,516 APPARENT INCREASE IN GB RNA BUT 1782 00:59:35,516 --> 00:59:36,950 WE THINK MUCH OF THAT INCREASE 1783 00:59:36,950 --> 00:59:38,585 IS IN TRANSCRIPTS WHICH ARE NOT 1784 00:59:38,585 --> 00:59:39,019 FUNCTIONAL. 1785 00:59:39,019 --> 00:59:40,287 WE DON'T KNOW THAT FOR SURE BUT 1786 00:59:40,287 --> 00:59:41,488 THAT'S WHAT WE THINK. 1787 00:59:41,488 --> 00:59:44,024 AND THE NET RESULT IS THEN 1788 00:59:44,024 --> 00:59:45,392 DECREASED GBA PROTEIN. 1789 00:59:45,392 --> 00:59:47,494 SO WHEN WE LOOK AT PROTEIN 1790 00:59:47,494 --> 00:59:48,495 QUANTITATIVE TRAIT LOCUS PLOT, 1791 00:59:48,495 --> 00:59:50,230 WHICH IS WHAT WE HAVE HERE ON 1792 00:59:50,230 --> 00:59:52,032 THE RIGHT-HAND SIDE, WE CAN SEE 1793 00:59:52,032 --> 00:59:54,902 THAT INDEED THAT IS THE CASE. 1794 00:59:54,902 --> 00:59:56,670 CARRIERS OF THE RISK GENOTYPE, 1795 00:59:56,670 --> 01:00:00,908 GG OR GT, HAVE LOWER PROTEIN 1796 01:00:00,908 --> 01:00:03,176 GBA1 LEVELS THAN THOSE WHO CARRY 1797 01:00:03,176 --> 01:00:06,113 THE PROTECTIVE GENOTYPE. 1798 01:00:06,113 --> 01:00:07,748 SO APPARENT INCREASE IN RNA BUT 1799 01:00:07,748 --> 01:00:10,517 NOT USEFUL RNA LEADS TO AN 1800 01:00:10,517 --> 01:00:11,752 APPARENT DECREASE IN PROTEIN 1801 01:00:11,752 --> 01:00:14,721 LEVELS. 1802 01:00:14,721 --> 01:00:16,123 AND THIS ALSO LEADS TO A 1803 01:00:16,123 --> 01:00:18,559 DECREASE IN GLUCOCEREBROSIDASE 1804 01:00:18,559 --> 01:00:19,626 ACTIVITY. 1805 01:00:19,626 --> 01:00:21,261 SO THIS WORK WAS DONE IN 1806 01:00:21,261 --> 01:00:23,196 COLLABORATION WITH A COMPANY 1807 01:00:23,196 --> 01:00:27,267 CALLED CENTEGENE, AND YOU CAN 1808 01:00:27,267 --> 01:00:29,036 SEE THE AFRICAN CARRIERS ON THE 1809 01:00:29,036 --> 01:00:30,404 RIGHT-HAND SIDE HAVE DECREASED 1810 01:00:30,404 --> 01:00:32,906 LEVELS OF GCASE ACTIVITY 1811 01:00:32,906 --> 01:00:34,975 ALTHOUGH NOT AS DECREASED AS 1812 01:00:34,975 --> 01:00:37,177 THOSE SEEN IN GBA CARRIERS. 1813 01:00:37,177 --> 01:00:39,379 AND I SHOULD NOTE THAT THIS 1814 01:00:39,379 --> 01:00:40,981 VARIANT NEVER CAUSES GAUCHER 1815 01:00:40,981 --> 01:00:41,715 DISEASE. 1816 01:00:41,715 --> 01:00:43,817 ELLEN MENTIONED THAT THERE ARE 1817 01:00:43,817 --> 01:00:44,885 SEVERAL GCASE VARIANTS THAT ARE 1818 01:00:44,885 --> 01:00:48,889 RISK FACTORS FOR PD OR LBD THAT 1819 01:00:48,889 --> 01:00:50,324 DON'T CAUSE GAUCHER'S DISEASE 1820 01:00:50,324 --> 01:00:53,160 AND INDEED THIS IS ONE OF THEM. 1821 01:00:53,160 --> 01:00:56,330 SO I THINK IDENTIFYING THE 1822 01:00:56,330 --> 01:00:58,298 GENETIC BASIS OF DECEMBER IS 1823 01:00:58,298 --> 01:00:59,032 ABSOLUTELY CRITICAL TO 1824 01:00:59,032 --> 01:01:01,768 UNDERSTAND BIOLOGY, AND IN SO 1825 01:01:01,768 --> 01:01:03,203 SUPPORTING THERAPEUTIC TARGETS. 1826 01:01:03,203 --> 01:01:04,805 IF WE BELIEVE THIS NOTION OF 1827 01:01:04,805 --> 01:01:06,340 PRECISION MEDICINE, OF TREATING 1828 01:01:06,340 --> 01:01:07,341 THE PATIENT AT THE RIGHT TIME 1829 01:01:07,341 --> 01:01:08,909 WITH THE RIGHT THERAPEUTIC, WE 1830 01:01:08,909 --> 01:01:10,811 NEED TO UNDERSTAND THE 1831 01:01:10,811 --> 01:01:12,546 MECHANISTIC BASIS OF DISEASE IN 1832 01:01:12,546 --> 01:01:13,614 PATIENTS ALL AROUND THE WORLD. 1833 01:01:13,614 --> 01:01:16,550 THIS IS WHY I THINK GP2 IS 1834 01:01:16,550 --> 01:01:19,286 REALLY KEY. 1835 01:01:19,286 --> 01:01:20,420 EVEN AT THIS PRELIMINARY STAGE, 1836 01:01:20,420 --> 01:01:22,122 WE'RE ONLY THREE OR FOUR YEARS 1837 01:01:22,122 --> 01:01:23,757 INTO THIS 10-YEAR STUDY, AND 1838 01:01:23,757 --> 01:01:24,725 REALLY NOW STARTING TO GET UP 1839 01:01:24,725 --> 01:01:28,128 AND RUNNING IN ANALYZING GENETIC 1840 01:01:28,128 --> 01:01:28,462 DATA. 1841 01:01:28,462 --> 01:01:30,063 EVEN THIS PRELIMINARY WORK SHOWS 1842 01:01:30,063 --> 01:01:31,498 COMBINING KAY F DATA ACROSS 1843 01:01:31,498 --> 01:01:32,833 POPULATIONS IS INCREDIBLY 1844 01:01:32,833 --> 01:01:34,301 POWERFUL, AND THAT WE CAN FIND 1845 01:01:34,301 --> 01:01:36,403 GENETIC ASSOCIATIONS THAT WE 1846 01:01:36,403 --> 01:01:38,672 WOULDN'T EXPECT IN UNDERSTUDIED 1847 01:01:38,672 --> 01:01:39,006 POPULATIONS. 1848 01:01:39,006 --> 01:01:41,942 THIS IS REALLY SUGGESTING THAT 1849 01:01:41,942 --> 01:01:44,011 THE WEST AFRICAN POPULATION IS 1850 01:01:44,011 --> 01:01:45,312 AN EXCELLENT POPULATION IN WHICH 1851 01:01:45,312 --> 01:01:47,614 TO CONSIDER RUNNING CLINICAL 1852 01:01:47,614 --> 01:01:52,719 TRIALS AGAINST GBA, THOSE 1853 01:01:52,719 --> 01:01:54,254 FOCUSED ON GBA ACTIVITY. 1854 01:01:54,254 --> 01:01:55,455 REALLY THIS IS A POPULATION THAT 1855 01:01:55,455 --> 01:01:56,456 WOULD NOT HAVE BEEN CONSIDERED 1856 01:01:56,456 --> 01:01:58,291 FOR THESE CLINICAL TRIALS UP 1857 01:01:58,291 --> 01:02:01,128 UNTIL THIS STUDY. 1858 01:02:01,128 --> 01:02:02,896 SO HOPEFULLY I'VE GIVEN YOU A 1859 01:02:02,896 --> 01:02:04,164 SENSE OF WHERE WE'RE HEADED. 1860 01:02:04,164 --> 01:02:05,599 I'M JUST GOING TO FLASH THIS UP 1861 01:02:05,599 --> 01:02:07,267 HERE, AND START TO TRANSFER 1862 01:02:07,267 --> 01:02:11,638 ELLEN OVER, BUT THIS WORK 1863 01:02:11,638 --> 01:02:13,674 INVOLVES AS I MENTIONED REALLY 1864 01:02:13,674 --> 01:02:16,943 THOUSANDS OF PEOPLE, BOTH THOSE 1865 01:02:16,943 --> 01:02:19,112 WITHIN THE LABORATORY OF 1866 01:02:19,112 --> 01:02:21,081 NEUROGENETICS, WHERE I'VE WORKED 1867 01:02:21,081 --> 01:02:22,516 FOR 22 YEARS WITHIN THE CENTER 1868 01:02:22,516 --> 01:02:23,450 FOR ALZHEIMER'S, WHERE I'VE BEEN 1869 01:02:23,450 --> 01:02:24,985 FOR A COUPLE YEARS, AND MORE 1870 01:02:24,985 --> 01:02:27,054 BROADLY, WITHIN THE GLOBAL 1871 01:02:27,054 --> 01:02:27,921 PARKINSON'S GENETICS PROGRAM, 1872 01:02:27,921 --> 01:02:29,890 WHICH AGAIN INVOLVES VERY LARGE 1873 01:02:29,890 --> 01:02:31,391 NUMBERS OF INDIVIDUALS AROUND 1874 01:02:31,391 --> 01:02:33,493 THE WORLD, AND HUNDREDS OF 1875 01:02:33,493 --> 01:02:36,129 THOUSANDS OF PATIENTS. 1876 01:02:36,129 --> 01:02:37,664 SO WE'VE GIVEN YOU A SENSE OF 1877 01:02:37,664 --> 01:02:41,668 WHERE WE ARE IN GENETIC 1878 01:02:41,668 --> 01:02:43,570 DISCOVERY, THE KIND OF INSIGHTS 1879 01:02:43,570 --> 01:02:44,871 THAT CAN BE MADE BY LOOKING AT 1880 01:02:44,871 --> 01:02:45,906 INDIVIDUAL PATIENTS, WHERE WE'RE 1881 01:02:45,906 --> 01:02:47,541 HEADED IN GENETIC DISCOVERY, AND 1882 01:02:47,541 --> 01:02:48,542 I THINK NOW WE'RE GOING TO END 1883 01:02:48,542 --> 01:02:49,643 WITH A DISCUSSION OF WHAT THIS 1884 01:02:49,643 --> 01:02:51,712 ALL MEANS FROM A THERAPEUTIC 1885 01:02:51,712 --> 01:02:54,347 PERSPECTIVE AND A KIND OF 1886 01:02:54,347 --> 01:02:56,416 EXAMPLE OF HOW THIS CAN BE 1887 01:02:56,416 --> 01:03:00,120 TRANSLATED. 1888 01:03:00,120 --> 01:03:01,221 >> GREAT. 1889 01:03:01,221 --> 01:03:03,056 SO THERE ARE LOTS OF DIFFERENT 1890 01:03:03,056 --> 01:03:06,359 APPROACHES TO THERAPEUTICS FOR 1891 01:03:06,359 --> 01:03:07,194 PARKINSON DISEASE, BUT WHAT I'M 1892 01:03:07,194 --> 01:03:08,729 GOING TO TRY TO FOCUS ON RIGHT 1893 01:03:08,729 --> 01:03:10,263 NOW IS WHAT WE'VE BEEN LEARNING 1894 01:03:10,263 --> 01:03:12,632 ABOUT GBA ASSOCIATED PARKINSON 1895 01:03:12,632 --> 01:03:16,403 DISEASE AND HOW WE MAY BE ABLE 1896 01:03:16,403 --> 01:03:18,105 TO UTILIZE THAT TOWARDS 1897 01:03:18,105 --> 01:03:21,608 THERAPEUTIC DEVELOPMENT. 1898 01:03:21,608 --> 01:03:23,577 SO THERE ARE AS I MENTIONED GOOD 1899 01:03:23,577 --> 01:03:24,311 GAUCHER DRUGS. 1900 01:03:24,311 --> 01:03:26,947 THERE'S ENZYME REPLACEMENT THAT 1901 01:03:26,947 --> 01:03:29,116 REVERSES THESE LARGE SPLEENS AND 1902 01:03:29,116 --> 01:03:31,718 MAKES OUR PATIENTS WITH TYPE 1903 01:03:31,718 --> 01:03:33,220 1 GAUCHER DISEASE MUCH BETTER. 1904 01:03:33,220 --> 01:03:35,021 THERE'S ALSO SOMETHING CALLED 1905 01:03:35,021 --> 01:03:36,957 SUBSTRATE REDUCTION THERAPY, 1906 01:03:36,957 --> 01:03:38,825 WHICH WORKS TO REDUCE PRODUCTION 1907 01:03:38,825 --> 01:03:41,561 OF THE SUBSTRATE AND MANY OF OUR 1908 01:03:41,561 --> 01:03:42,662 PATIENTS ARE DOING VERY WELL ON 1909 01:03:42,662 --> 01:03:43,196 THAT. 1910 01:03:43,196 --> 01:03:46,133 BOTH DRUGS ARE VERY EXPENSIVE, 1911 01:03:46,133 --> 01:03:46,900 OVER $300,000 PER PATIENT PER 1912 01:03:46,900 --> 01:03:48,335 YEAR. 1913 01:03:48,335 --> 01:03:50,137 THEY'RE INCONVENIENT, ESPECIALLY 1914 01:03:50,137 --> 01:03:51,571 THE ENZYME BECAUSE IT MEANS YOU 1915 01:03:51,571 --> 01:03:53,640 NEED AN I.V. INFUSION EVERY TWO 1916 01:03:53,640 --> 01:03:56,576 WEEKS, AND MOST IMPORTANTLY, FOR 1917 01:03:56,576 --> 01:03:58,445 PARKINSON DISEASE, IT DOESN'T 1918 01:03:58,445 --> 01:03:59,913 CROSS THE BLOOD-BRAIN BARRIER, 1919 01:03:59,913 --> 01:04:01,615 AND WE'VE HAD PATIENTS WHO HAVE 1920 01:04:01,615 --> 01:04:03,450 BEEN TREATED WITH ENZYME 1921 01:04:03,450 --> 01:04:06,419 REPLACEMENT WHO STILL DEVELOP 1922 01:04:06,419 --> 01:04:07,087 PARKINSONISM. 1923 01:04:07,087 --> 01:04:09,589 SO IT DOESN'T SEEM TO HAVE ANY 1924 01:04:09,589 --> 01:04:12,058 AFFECT FOR THAT. 1925 01:04:12,058 --> 01:04:13,193 SO THERE'S OTHER APPROACHES THAT 1926 01:04:13,193 --> 01:04:15,495 WE CAN THINK ABOUT, ABOUT 1927 01:04:15,495 --> 01:04:18,765 GETTING ENZYME TO THE BRAIN. 1928 01:04:18,765 --> 01:04:20,066 SOME OF THEM ARE ON THIS 1929 01:04:20,066 --> 01:04:21,468 DIAGRAM, A LITTLE HARD TO SEE. 1930 01:04:21,468 --> 01:04:24,638 ONE IS STILL ENZYME REPLACEMENT 1931 01:04:24,638 --> 01:04:26,406 BUT NOT JUST PERIPHERAL ENZYME 1932 01:04:26,406 --> 01:04:28,008 REPLACEMENT. 1933 01:04:28,008 --> 01:04:31,411 THERE MAY BE WAYS TO GET THE 1934 01:04:31,411 --> 01:04:35,782 ENZYME INTO THE BRAIN BY USING 1935 01:04:35,782 --> 01:04:37,417 THINGS LIKE THE TRANSFERRIN 1936 01:04:37,417 --> 01:04:38,718 RECEPTOR OR WHAT THEY CALL 1937 01:04:38,718 --> 01:04:40,787 TROJAN HORSE TYPE OF WAYS OF 1938 01:04:40,787 --> 01:04:42,422 GETTING PROTEINS INTO THE BRAIN. 1939 01:04:42,422 --> 01:04:45,025 SO THAT WOULD BE ONE WAY. 1940 01:04:45,025 --> 01:04:46,259 SUBSTRATE REDUCTION WAS ANOTHER 1941 01:04:46,259 --> 01:04:47,260 ONE THAT WAS CONSIDERED, AND IN 1942 01:04:47,260 --> 01:04:50,163 FACT IT WENT ALL THE WAY TO 1943 01:04:50,163 --> 01:04:51,031 STAGE THREE CLINICAL TRIAL, AND 1944 01:04:51,031 --> 01:04:52,899 IT DIDN'T WORK. 1945 01:04:52,899 --> 01:04:56,069 SO IT TAUGHT US SOME THINGS, BUT 1946 01:04:56,069 --> 01:04:57,370 IT ALSO SORT OF TAUGHT US THAT 1947 01:04:57,370 --> 01:04:58,471 MAYBE WE NEEDED TO KNOW A LITTLE 1948 01:04:58,471 --> 01:04:59,372 BIT MORE ABOUT THE BIOLOGY 1949 01:04:59,372 --> 01:05:04,344 BEFORE WE JUMPED THAT FAST. 1950 01:05:04,344 --> 01:05:05,846 A THIRD APPROACH IS -- WELL, THE 1951 01:05:05,846 --> 01:05:07,514 FOURTH APPROACH IS GOAN THERAPY 1952 01:05:07,514 --> 01:05:10,717 AND, IN FACT, THERE IS ALREADY 1953 01:05:10,717 --> 01:05:13,420 ONE COMPANY THAT'S TRYING GENE 1954 01:05:13,420 --> 01:05:15,255 THERAPY TO -- DIRECTLY TO THE 1955 01:05:15,255 --> 01:05:18,124 BRAIN FOR GBA PARKINSON DISEASE. 1956 01:05:18,124 --> 01:05:20,160 AND THE ONE THAT IS NEAR AND 1957 01:05:20,160 --> 01:05:21,695 DEAR TO MY HEART IS THIS NUMBER 1958 01:05:21,695 --> 01:05:23,997 THREE, WHICH IS CALLED ENZYME 1959 01:05:23,997 --> 01:05:28,134 CHAPERONES. 1960 01:05:28,134 --> 01:05:30,403 SO FOR, I DON'T KNOW, ALMOST 15 1961 01:05:30,403 --> 01:05:32,172 YEARS NOW, WE'VE BEEN FOCUSED ON 1962 01:05:32,172 --> 01:05:35,008 TRYING TO DEVELOP CHAPERONE 1963 01:05:35,008 --> 01:05:36,243 THERAPY FOR GAUCHER DISEASE, AND 1964 01:05:36,243 --> 01:05:38,178 NOW FOR PARKINSON DISEASE, AND 1965 01:05:38,178 --> 01:05:42,883 THE IDEA IS THAT OFTEN PROTEINS 1966 01:05:42,883 --> 01:05:45,952 ARE PL MISFOLDED, ESPECIALLY IF 1967 01:05:45,952 --> 01:05:47,120 THERE'S A MUTATION, BUT IF THERE 1968 01:05:47,120 --> 01:05:48,755 WAS A WAY WE COULD PROMOTE 1969 01:05:48,755 --> 01:05:53,793 FOLDING TO GET THE RESIDUAL 1970 01:05:53,793 --> 01:05:55,428 ENZYME INTO THE LYSOSOME, IT 1971 01:05:55,428 --> 01:05:57,063 MIGHT STILL BE ABLE TO FUNCTION 1972 01:05:57,063 --> 01:06:00,033 ADEQUATELY. 1973 01:06:00,033 --> 01:06:01,334 AND I THINK THAT NOW SINCE 1974 01:06:01,334 --> 01:06:03,603 PATIENTS WITH IDIOPATHIC 1975 01:06:03,603 --> 01:06:06,339 PARKINSON DISEASE ALSO MAY HAVE 1976 01:06:06,339 --> 01:06:07,774 LOW GLUCOCEREBROSIDASE AND THOSE 1977 01:06:07,774 --> 01:06:10,610 WITHOUT REALLY MUTATIONS BUT 1978 01:06:10,610 --> 01:06:12,879 VARIANT MAY HAVE LOWER 1979 01:06:12,879 --> 01:06:13,880 GLUCOCEREBROSIDASE AND EVEN WILD 1980 01:06:13,880 --> 01:06:15,415 TYPE PROTEINS CAN BE MISFOLDED, 1981 01:06:15,415 --> 01:06:17,250 IT MAY PROVIDE A THERAPEUTIC 1982 01:06:17,250 --> 01:06:18,351 APPROACH FOR PARKINSON DISEASE 1983 01:06:18,351 --> 01:06:21,187 IN GENERAL. 1984 01:06:21,187 --> 01:06:24,357 SO I BEGAN THIS PROJECT WHEN 1985 01:06:24,357 --> 01:06:29,229 NCATS WAS FIRST FOUNDED ABOUT 15 1986 01:06:29,229 --> 01:06:29,729 YEARS AGO. 1987 01:06:29,729 --> 01:06:31,464 IT'S BEEN A LONG AND FRUITFUL 1988 01:06:31,464 --> 01:06:34,534 COLLABORATION WITH PEOPLE THERE. 1989 01:06:34,534 --> 01:06:35,402 THE FIRST SCREEN WE DID WAS ONE 1990 01:06:35,402 --> 01:06:37,570 OF THE FIRST THAT NCATS DID. 1991 01:06:37,570 --> 01:06:40,340 AT THE TIME WE USED THE 1992 01:06:40,340 --> 01:06:42,142 RECOMBINANT ENZYME THAT'S USED 1993 01:06:42,142 --> 01:06:45,679 FOR THERAPY AND WE DID A SCREEN 1994 01:06:45,679 --> 01:06:46,880 OF A COUPLE HUNDRED THOUSAND 1995 01:06:46,880 --> 01:06:48,281 SMALL MOLECULES, AND WE 1996 01:06:48,281 --> 01:06:49,683 IDENTIFIED HITS BUT THEY WERE 1997 01:06:49,683 --> 01:06:51,217 MOSTLY INHIBITORY CHAPERONES 1998 01:06:51,217 --> 01:06:52,419 BECAUSE THAT'S WHAT YOU WOULD 1999 01:06:52,419 --> 01:06:54,521 PROBABLY FIND FROM A WILD TYPE 2000 01:06:54,521 --> 01:06:55,322 PROTEIN. 2001 01:06:55,322 --> 01:06:57,490 WE THEN DECIDED WE SHOULD DO A 2002 01:06:57,490 --> 01:06:58,925 SCREEN WITH MUTANT PROTEIN, BUT 2003 01:06:58,925 --> 01:07:01,194 WE DIDN'T HAVE PURIFIED MUTANT 2004 01:07:01,194 --> 01:07:03,063 PROTEIN, BUT WE DID HAVE THESE 2005 01:07:03,063 --> 01:07:04,431 ENORMOUS SPLEENS IN MY FREEZER, 2006 01:07:04,431 --> 01:07:07,200 SO WE TOOK A CHUNK OF THIS 2007 01:07:07,200 --> 01:07:08,535 MUTANT SPLEEN AND ACTUALLY USED 2008 01:07:08,535 --> 01:07:10,904 THAT AS THE SOURCE OF THE ENZYME 2009 01:07:10,904 --> 01:07:12,238 FOR A SCREEN OF ABOUT A QUARTER 2010 01:07:12,238 --> 01:07:14,407 OF A MILLION COMPOUNDS. 2011 01:07:14,407 --> 01:07:17,577 AND NOW FOR THE FIRST TIME, WE 2012 01:07:17,577 --> 01:07:19,112 DID IDENTIFY NON-INHIBITORY 2013 01:07:19,112 --> 01:07:20,613 CHAPERONES THAT WE WERE QUITE 2014 01:07:20,613 --> 01:07:21,614 EXCITED ABOUT. 2015 01:07:21,614 --> 01:07:25,318 WE HAD TWO LEAD COMPOUNDS, CALL 2016 01:07:25,318 --> 01:07:31,558 IT NCTC758 AND 607. 2017 01:07:31,558 --> 01:07:33,393 758 WAS OUT LICENSES AND 2018 01:07:33,393 --> 01:07:34,995 ACTUALLY IS NOW IN SOME CLINICAL 2019 01:07:34,995 --> 01:07:35,996 TRIALS THAT WE'RE NOT 2020 01:07:35,996 --> 01:07:39,399 PARTICULARLY CONNECTED TO, BUT 2021 01:07:39,399 --> 01:07:40,934 WE TESTED THEM IN VARIOUS 2022 01:07:40,934 --> 01:07:42,035 SYSTEMS AND THESE WERE SOME OF 2023 01:07:42,035 --> 01:07:44,337 OUR EARLY IPS -- WELL, EARLY 2024 01:07:44,337 --> 01:07:46,406 STUDIES WITH GAUCHER 2025 01:07:46,406 --> 01:07:46,940 MACROPHAGES. 2026 01:07:46,940 --> 01:07:50,977 WE HAD PATIENT MACROPHAGES AND 2027 01:07:50,977 --> 01:07:52,846 THEN IP SC MACROPHAGES, AND WE 2028 01:07:52,846 --> 01:07:54,681 FOUND THESE LEAD COMPOUNDS COULD 2029 01:07:54,681 --> 01:07:56,483 INCREASE THE ENZYME ACTIVITY, 2030 01:07:56,483 --> 01:08:00,687 REVERSE LIP YOU LIPID STORAGE,N 2031 01:08:00,687 --> 01:08:02,322 SEE BY THE FLUORESCENCE GOING 2032 01:08:02,322 --> 01:08:04,090 AWAY, AND RESTORE PROBLEMS OF 2033 01:08:04,090 --> 01:08:06,793 MACROPHAGE FUNCTION. 2034 01:08:06,793 --> 01:08:10,397 BUT THIS KIND OF ASSAY WAS NOT 2035 01:08:10,397 --> 01:08:13,666 OPTIMAL FOR DRUG DEVELOPMENT. 2036 01:08:13,666 --> 01:08:15,769 AND WE NEEDED TO DO LARGE SCALE 2037 01:08:15,769 --> 01:08:19,372 SAR AND TRYING TO GET 2038 01:08:19,372 --> 01:08:20,440 MACROPHAGES JUST WASN'T 2039 01:08:20,440 --> 01:08:20,874 FEASIBLE. 2040 01:08:20,874 --> 01:08:22,509 WE ALSO WANTED TO HAVE SOME KIND 2041 01:08:22,509 --> 01:08:24,711 OF CELL-BASED SCREEN AND SOME 2042 01:08:24,711 --> 01:08:30,517 KIND OF PROBE THAT LET US KNOW 2043 01:08:30,517 --> 01:08:31,618 WHAT WAS HAPPENING TO THE ENZYME 2044 01:08:31,618 --> 01:08:33,319 WHEN IT GOT TO THE LYSOSOME. 2045 01:08:33,319 --> 01:08:34,988 IT WASN'T ENOUGH TO SEE WHAT WAS 2046 01:08:34,988 --> 01:08:36,189 HAPPENING WHEN YOU HAD A CELL 2047 01:08:36,189 --> 01:08:36,556 EXTRACT. 2048 01:08:36,556 --> 01:08:38,892 SO FOR THE CELL-BASED ASSAY, WE 2049 01:08:38,892 --> 01:08:42,962 DID TURN TO IPFCs, PROBABLY 2050 01:08:42,962 --> 01:08:44,697 MOST OF YOU KNOW THE EXERCISE 2051 01:08:44,697 --> 01:08:48,301 WHERE YOU TAKE SKIN SAMPLE FROM 2052 01:08:48,301 --> 01:08:51,337 PATIENTS, MAKE A FIBROBLAST 2053 01:08:51,337 --> 01:08:52,505 CULTURE AND THEN REPROGRAM THE 2054 01:08:52,505 --> 01:08:55,608 CELLS WITH A BUNCH OF DIFFERENT 2055 01:08:55,608 --> 01:08:58,912 COCKTAIL OF GROWTH FACTORS AND 2056 01:08:58,912 --> 01:09:00,980 THEY BECOME -- INDUCE 2057 01:09:00,980 --> 01:09:02,282 PLURIPOTENT CELLS THAT YOU CAN 2058 01:09:02,282 --> 01:09:03,683 THEN DIFFERENTIATE INTO 2059 01:09:03,683 --> 01:09:06,019 DIFFERENT LINEAGES, AND THE 2060 01:09:06,019 --> 01:09:07,253 PATHOLOGICALLY RELEVANT LINAGES 2061 01:09:07,253 --> 01:09:11,057 FOR US HAVE BEEN CORTICAL AND 2062 01:09:11,057 --> 01:09:12,892 MAINLY DOPAMINERGIC NEURONS, AND 2063 01:09:12,892 --> 01:09:14,427 WE'VE FOCUSED ON MACROPHAGES AND 2064 01:09:14,427 --> 01:09:16,496 WE'RE BEGINNING TO MOVE TOWARDS 2065 01:09:16,496 --> 01:09:20,533 MICROGLIA ALSO. 2066 01:09:20,533 --> 01:09:22,535 SO FROM OUR EARLIEST STUDIES, WE 2067 01:09:22,535 --> 01:09:26,139 MADE NEURONAL MODELS FROM THE 2068 01:09:26,139 --> 01:09:27,974 FIBROBLASTS FROM PATIENTS WITH 2069 01:09:27,974 --> 01:09:29,309 GAUCHER DISEASE, WITH GAUCHER 2070 01:09:29,309 --> 01:09:33,246 AND PARKINSON TYPE 2 GOA SLAY 2071 01:09:33,246 --> 01:09:34,481 DISEASE, AND APPROPRIATELY WE 2072 01:09:34,481 --> 01:09:36,282 FOUND THAT THE DOPAMINERGIC 2073 01:09:36,282 --> 01:09:39,452 NEURONS WE MADE HAD DECREASED 2074 01:09:39,452 --> 01:09:39,886 GLUCOCEREBROSIDASE. 2075 01:09:39,886 --> 01:09:41,521 THEY STORED LIPID, AND WHEN YOU 2076 01:09:41,521 --> 01:09:44,791 TREATED THEM, THIS IS A 2077 01:09:44,791 --> 01:09:47,527 COLOCALIZATION WHERE GREEN IS 2078 01:09:47,527 --> 01:09:48,528 GLUCOCEREBROSIDASE AND RED IS 2079 01:09:48,528 --> 01:09:55,301 THE LYSOSOMAL MARKER. 2080 01:09:55,301 --> 01:09:56,669 YOU COULD SEE MUCH MORE DELIVERY 2081 01:09:56,669 --> 01:10:00,473 OF THE ENZYME TO THE LYSOSOME. 2082 01:10:00,473 --> 01:10:02,775 SO THE NEURONS RECAPITULATED 2083 01:10:02,775 --> 01:10:04,511 ASPECTS OF THE GAUCHER 2084 01:10:04,511 --> 01:10:05,912 PHENOTYPE, AND THIS PHENOTYPE 2085 01:10:05,912 --> 01:10:07,247 LOOKED LIKE IT COULD BE REVERSED 2086 01:10:07,247 --> 01:10:09,883 WITH OUR LEAD CHAPERONES, BUT 2087 01:10:09,883 --> 01:10:12,152 BOTH THE PURITY AND THE YIELD 2088 01:10:12,152 --> 01:10:13,253 WERE INADEQUATE FOR US TO 2089 01:10:13,253 --> 01:10:15,021 PERFORM BIG SCREENS. 2090 01:10:15,021 --> 01:10:17,624 SO A FEW YEARS AGO, ROBYN CHEN 2091 01:10:17,624 --> 01:10:18,958 JOINED MY LAB AND SORT OF 2092 01:10:18,958 --> 01:10:20,493 CHANGED OUR PROTOCOL. 2093 01:10:20,493 --> 01:10:26,032 WE NOW ARE USING SENDI VIRUS TO 2094 01:10:26,032 --> 01:10:28,234 MAKE THESE IPSCs. 2095 01:10:28,234 --> 01:10:29,435 HE'S BEEN FOCUSING ON PATIENTS 2096 01:10:29,435 --> 01:10:30,737 WITH GAUCHER DISEASE WITH AND 2097 01:10:30,737 --> 01:10:35,675 WITHOUT PARKINSON DISEASE. 2098 01:10:35,675 --> 01:10:41,347 AND HE'S INTRODUCED THIS 2099 01:10:41,347 --> 01:10:43,616 SELECTION TAG THAT ENABLES US TO 2100 01:10:43,616 --> 01:10:44,684 PURIFY DOPAMINERGIC CULTURES 2101 01:10:44,684 --> 01:10:49,189 WHERE WE CAN USE FLOW CYTOMETRY 2102 01:10:49,189 --> 01:10:52,592 TO GENERATE REALLY QUITE PURE 2103 01:10:52,592 --> 01:10:53,826 DOPAMINERGIC NEURONS FOR FURTHER 2104 01:10:53,826 --> 01:10:56,529 STUDY. 2105 01:10:56,529 --> 01:10:58,064 THE OTHER THING HE'S BEEN DOING 2106 01:10:58,064 --> 01:11:01,901 IS WHAT'S CALLED ISOGENIC GBA 2107 01:11:01,901 --> 01:11:02,235 LINES. 2108 01:11:02,235 --> 01:11:03,636 ONE OF THE PROBLEMS FROM OUR 2109 01:11:03,636 --> 01:11:05,505 FIRST STUDY IS THERE'S A LOT OF 2110 01:11:05,505 --> 01:11:06,706 DIFFERENCES AND GENETIC 2111 01:11:06,706 --> 01:11:07,574 BACKGROUND FROM PATIENT TO 2112 01:11:07,574 --> 01:11:08,775 PATIENT, SO IT'S KIND OF HARD TO 2113 01:11:08,775 --> 01:11:09,509 MAKE COMPARISONS. 2114 01:11:09,509 --> 01:11:11,844 SO WHAT HE DID IS HE STARTED 2115 01:11:11,844 --> 01:11:13,413 FROM ONE PATIENT THAT HAD 2116 01:11:13,413 --> 01:11:16,216 GAUCHER DISEASE AND PARKINSON 2117 01:11:16,216 --> 01:11:18,751 DISEASE, HE WAS MALE, COMMON IN 2118 01:11:18,751 --> 01:11:21,788 370 -- SN370-S GENOTYPE. 2119 01:11:21,788 --> 01:11:25,625 HE THEN ENGINEERED IT SO THAT 2120 01:11:25,625 --> 01:11:27,260 THE LINE HAD A TOTAL KNOCKOUT, 2121 01:11:27,260 --> 01:11:29,028 AND THEN, AND THIS WAS TRICKY 2122 01:11:29,028 --> 01:11:31,197 BECAUSE OF THE PSEUDOGENE, HE 2123 01:11:31,197 --> 01:11:32,899 MANAGED TO EDIT IT PACK SO IT 2124 01:11:32,899 --> 01:11:35,368 WAS WILD TYPE. 2125 01:11:35,368 --> 01:11:35,902 BACK SO IT 2126 01:11:35,902 --> 01:11:36,869 WAS WILD TYPE. 2127 01:11:36,869 --> 01:11:38,638 SOME STUDENTS IN THE LAB, ONE OF 2128 01:11:38,638 --> 01:11:40,173 WHOM IS IN THE AUDIENCE TODAY, 2129 01:11:40,173 --> 01:11:43,109 WORKED ON ENGINEERING IN OTHER 2130 01:11:43,109 --> 01:11:44,210 MUTATIONS INTO THE WILD TYPE. 2131 01:11:44,210 --> 01:11:48,381 SO WE HAVE THIS NOW SUITE OF 2132 01:11:48,381 --> 01:11:54,153 FIVE ICEGENIC LINES T ISOGENIC Y 2133 01:11:54,153 --> 01:11:55,355 WITH, WHICH IS USEFUL FOR 2134 01:11:55,355 --> 01:11:56,656 ESTABLISHING MECHANISM BUT IT'S 2135 01:11:56,656 --> 01:12:00,393 ALSO USEFUL FOR THERAPEUTIC 2136 01:12:00,393 --> 01:12:00,727 ASSAYS. 2137 01:12:00,727 --> 01:12:03,663 THE OTHER THING HE DID IS HE 2138 01:12:03,663 --> 01:12:07,367 EDITED IN A LYSOIP TAG, SO THIS 2139 01:12:07,367 --> 01:12:08,468 IS A TRICK WHERE YOU'RE PUTTING 2140 01:12:08,468 --> 01:12:13,973 IN A TAG AND THEN YOU CAN 2141 01:12:13,973 --> 01:12:15,275 ISOLATE LYSOSOMES VERY LIGHTLY 2142 01:12:15,275 --> 01:12:16,576 FROM THE CULTURES EVEN AFTER 2143 01:12:16,576 --> 01:12:20,079 THEY DID -- THEY'RE DECH REN 2144 01:12:20,079 --> 01:12:21,214 SHAITED AND SEE WHAT'S GOING ON 2145 01:12:21,214 --> 01:12:22,248 IN THE LYSOSOME. 2146 01:12:22,248 --> 01:12:25,118 WE ALSO FOCUSED SOME YEARS NOW 2147 01:12:25,118 --> 01:12:26,486 ON IMPROVING TOOLS WE COULD USE 2148 01:12:26,486 --> 01:12:26,986 FOR SCREENING. 2149 01:12:26,986 --> 01:12:29,622 SO I MENTIONED THAT WE NEEDED TO 2150 01:12:29,622 --> 01:12:31,024 HAVE A PROBE THAT TOLD US WHAT 2151 01:12:31,024 --> 01:12:33,159 WAS GOING ON IN THE LYSOSOME, 2152 01:12:33,159 --> 01:12:35,528 AND EVENTUALLY TOGETHER WITH 2153 01:12:35,528 --> 01:12:38,698 DAVID IN CANADA, WE HAVE BEEN 2154 01:12:38,698 --> 01:12:42,101 WORKING ON THIS LYSOFIX GBA 2155 01:12:42,101 --> 01:12:44,504 ACTIVITY PROBE, WHICH WE CAN 2156 01:12:44,504 --> 01:12:46,406 NICELY SEE -- IT'S QUENCHED, AND 2157 01:12:46,406 --> 01:12:48,007 THEN WE CAN SEE EXACTLY WHERE 2158 01:12:48,007 --> 01:12:51,844 THE ACTIVITY IS IN THE CELLS. 2159 01:12:51,844 --> 01:12:57,984 WE'VE ALSO PUT A SMALL HIBIT TAG 2160 01:12:57,984 --> 01:12:59,152 SO WE CAN FOLLOW WHAT'S GOING ON 2161 01:12:59,152 --> 01:13:01,020 WITH IT USING A LUMINESCENCE 2162 01:13:01,020 --> 01:13:02,021 ASSAY. 2163 01:13:02,021 --> 01:13:03,756 AND THIRDLY, WE DEVELOPED A NEW 2164 01:13:03,756 --> 01:13:04,757 ANTIBODY IN COLLABORATION WITH 2165 01:13:04,757 --> 01:13:07,393 ROCHE THAT'S REALLY GOOD FOR 2166 01:13:07,393 --> 01:13:09,662 COLOCALIZATION ASSAYS. 2167 01:13:09,662 --> 01:13:13,833 SO THIS IS WILD TYPE AND YOU SEE 2168 01:13:13,833 --> 01:13:16,369 GLUCOCEREBROSIDASE AND LYSOSOMAL 2169 01:13:16,369 --> 01:13:18,905 MARKER MERGING NICELY. 2170 01:13:18,905 --> 01:13:21,374 WHEN YOU TAKE L44P LINES, THEY 2171 01:13:21,374 --> 01:13:24,444 HAVE VERY LITTLE 2172 01:13:24,444 --> 01:13:25,411 GLUCOCEREBROSIDASE IN THE 2173 01:13:25,411 --> 01:13:26,312 LYSOSOME. 2174 01:13:26,312 --> 01:13:28,614 AND IN FACT, THIS ANTIBODY 2175 01:13:28,614 --> 01:13:29,816 DOESN'T RECOGNIZE ANY OF IT, BUT 2176 01:13:29,816 --> 01:13:31,584 WHEN IT DOES GET FOLDED 2177 01:13:31,584 --> 01:13:32,652 CORRECTLY, YOU ARE ABLE TO PICK 2178 01:13:32,652 --> 01:13:35,088 IT UP IN THE LYSOSOME, SO IT'S A 2179 01:13:35,088 --> 01:13:36,723 NICE VALIDATION ASSAY. 2180 01:13:36,723 --> 01:13:38,691 SO WE NOW THINK FINALLY AFTER 2181 01:13:38,691 --> 01:13:40,760 ALL THESE YEARS THAT WE HAVE THE 2182 01:13:40,760 --> 01:13:44,263 PIPELINE READY. 2183 01:13:44,263 --> 01:13:49,769 WE STARTED OFF WITH A LINE THAT 2184 01:13:49,769 --> 01:13:51,938 HAS L44P AND WE PARTIALLY 2185 01:13:51,938 --> 01:13:59,145 EDUCATED OURSELVES USING VER USL 2186 01:13:59,145 --> 01:13:59,979 SCREENS. 2187 01:13:59,979 --> 01:14:01,347 WE USED LIBRARIES NCATS HAPPENED 2188 01:14:01,347 --> 01:14:03,449 TO HAVE ON HAND FOR OUR FIRST 2189 01:14:03,449 --> 01:14:03,883 SCREENS. 2190 01:14:03,883 --> 01:14:06,085 WE GROW THE CELLS, WE DISPENSE 2191 01:14:06,085 --> 01:14:08,721 THEM, TRANSFER THE COMPOUNDS AND 2192 01:14:08,721 --> 01:14:12,425 THEN LOOK AT OUR READOUT WITH 2193 01:14:12,425 --> 01:14:15,495 THE -- FIRST WITH THE HIBIT 2194 01:14:15,495 --> 01:14:17,096 ASSAY AND THEN WE CAN VALIDATE 2195 01:14:17,096 --> 01:14:18,865 IT USING THE COLOCALIZATION WITH 2196 01:14:18,865 --> 01:14:21,701 THE ANTIBODY AND THE LYSOSOMAL 2197 01:14:21,701 --> 01:14:22,335 ACTIVITY PROBE. 2198 01:14:22,335 --> 01:14:23,503 IN OUR FIRST SCREENS, THIS IS 2199 01:14:23,503 --> 01:14:28,641 ALL DONE BY NCATS ROBOTS, WE 2200 01:14:28,641 --> 01:14:32,211 IDENTIFIED BOTH PHARMACOLOGIC 2201 01:14:32,211 --> 01:14:34,947 CHAPERONES AND PROTEOSTASIS 2202 01:14:34,947 --> 01:14:35,248 REGULATORS. 2203 01:14:35,248 --> 01:14:36,282 WE HAD HITS OF ABOUT 140 AND 2204 01:14:36,282 --> 01:14:39,352 THEN HAVE DONE ALL KINDS OF 2205 01:14:39,352 --> 01:14:40,219 SECONDARY ASSAYS ON THESE. 2206 01:14:40,219 --> 01:14:41,854 WE ALSO DISCOVERED THAT MAYBE 2207 01:14:41,854 --> 01:14:44,924 TWO DRUGS MIGHT WORK BETTER THAN 2208 01:14:44,924 --> 01:14:45,358 ONE. 2209 01:14:45,358 --> 01:14:49,295 OUR BEST CHAPERONE IS THIS 2210 01:14:49,295 --> 01:14:52,698 CHAPERONE WHICH MADE US HAPPY 2211 01:14:52,698 --> 01:14:55,935 BECAUSE IT IS VERY SIMILAR TO 2212 01:14:55,935 --> 01:14:57,270 ONE OF OUR OTHER CHAPERONES FROM 2213 01:14:57,270 --> 01:14:59,572 THE EARLIER TRIALS, AND ALL OF 2214 01:14:59,572 --> 01:15:01,240 THOSE WERE PICKED UP BY THIS NEW 2215 01:15:01,240 --> 01:15:03,409 ASSAY SYSTEM. 2216 01:15:03,409 --> 01:15:04,944 BUT THE OTHER THING THAT WE 2217 01:15:04,944 --> 01:15:06,045 WEREN'T EXPECTING IS WE PULLED 2218 01:15:06,045 --> 01:15:08,681 OUT A BUNCH OF PROTEOSTASIS 2219 01:15:08,681 --> 01:15:10,416 REGULATORS, AND IN FACT, WE'VE 2220 01:15:10,416 --> 01:15:12,618 DONE THESE MATRIX COMBINATION 2221 01:15:12,618 --> 01:15:14,053 SCREENS THAT INDICATE THAT 2222 01:15:14,053 --> 01:15:15,087 TOGETHER, THEY MAY FUNCTION 2223 01:15:15,087 --> 01:15:17,023 BETTER THAN ALONE, SO HERE YOU 2224 01:15:17,023 --> 01:15:18,658 CAN SEE, THIS IS ACTUALLY 2225 01:15:18,658 --> 01:15:27,433 LOOKING AT THE LIPIDS THAT THE 2226 01:15:27,433 --> 01:15:28,534 CHAPERONE 326 DECREASES LIPID 2227 01:15:28,534 --> 01:15:31,170 LEVELS BUT THE COMBINATION 2228 01:15:31,170 --> 01:15:34,440 DECREASES IT EVEN FURTHER. 2229 01:15:34,440 --> 01:15:36,209 SO THIS WORK IS NOW BEING 2230 01:15:36,209 --> 01:15:39,812 SUBMITTED TODAY, I HOPE, AND 2231 01:15:39,812 --> 01:15:41,481 WE'LL CONTINUE TO USE THE PIPE 2232 01:15:41,481 --> 01:15:43,516 LINE FOR BIGGER LIBRARIES LATER 2233 01:15:43,516 --> 01:15:44,851 ON AND I THINK IT'S GOING TO BE 2234 01:15:44,851 --> 01:15:48,020 REALLY USEFUL. 2235 01:15:48,020 --> 01:15:49,222 SO I THINK THAT THESE NEW TOOLS 2236 01:15:49,222 --> 01:15:50,990 ARE GIVING US SOME NEW 2237 01:15:50,990 --> 01:15:51,324 OPPORTUNITIES. 2238 01:15:51,324 --> 01:15:53,826 WE CAN NOW LOOK AT LYSOSOMES AT 2239 01:15:53,826 --> 01:15:56,596 SUBCELLULAR RESOLUTION WITH 2240 01:15:56,596 --> 01:15:57,029 LYSO-IP. 2241 01:15:57,029 --> 01:15:58,631 IT MIGHT HELP US IDENTIFY 2242 01:15:58,631 --> 01:16:01,167 GENETIC MODIFIERS USING THESE 2243 01:16:01,167 --> 01:16:02,702 ISOGENIC LINES. 2244 01:16:02,702 --> 01:16:05,137 WE CAN LOOK ACTUALLY AT 2245 01:16:05,137 --> 01:16:07,306 LYSOSOMES IN NEURONS AND IT CAN 2246 01:16:07,306 --> 01:16:09,709 HELP US MOVE TOWARDS NEXT 2247 01:16:09,709 --> 01:16:12,011 GENERATIONAL RESEARCH. 2248 01:16:12,011 --> 01:16:15,214 I FORGOT TO PUSH, BUT ANYWAY, 2249 01:16:15,214 --> 01:16:17,517 LEADING TO IDENTIFICATION OF 2250 01:16:17,517 --> 01:16:18,818 DISEASE-RELEVANT MECHANISMS, WE 2251 01:16:18,818 --> 01:16:20,786 CAN VALIDATE THEN IN ANIMAL AND 2252 01:16:20,786 --> 01:16:23,623 HUMAN MODELS AND CAN COME UP 2253 01:16:23,623 --> 01:16:24,624 WITH NOVEL TARGETS AND 2254 01:16:24,624 --> 01:16:25,691 THERAPIES. 2255 01:16:25,691 --> 01:16:28,127 SO I'D LIKE TO TELL PEOPLE, KEEP 2256 01:16:28,127 --> 01:16:29,562 LOOKING OUT THE WINDOWS, YOU 2257 01:16:29,562 --> 01:16:30,763 NEVER KNOW WHAT THE NEXT PATIENT 2258 01:16:30,763 --> 01:16:33,165 THAT WALKS INTO YOUR CLINIC MAY 2259 01:16:33,165 --> 01:16:33,933 TEACH YOU. 2260 01:16:33,933 --> 01:16:37,103 AND THIS CASE, STUDYING THIS 2261 01:16:37,103 --> 01:16:40,172 RARE DISORDER HAS PROVIDED US 2262 01:16:40,172 --> 01:16:42,241 INTO A REALLY NICE WINDOW INTO 2263 01:16:42,241 --> 01:16:44,243 SEEMINGLY UNRELATED COMPLEX 2264 01:16:44,243 --> 01:16:46,078 DISORDER, WHICH ULTIMATELY MAY 2265 01:16:46,078 --> 01:16:47,513 LEAD TO NEW THERAPIES BOTH FOR 2266 01:16:47,513 --> 01:16:51,017 THE RARE AND COMMON DISEASE. 2267 01:16:51,017 --> 01:16:52,151 AND OF COURSE THIS WORK ISN'T 2268 01:16:52,151 --> 01:16:53,319 DONE IN A VACUUM. 2269 01:16:53,319 --> 01:16:54,654 I WANT TO REALLY ACKNOWLEDGE THE 2270 01:16:54,654 --> 01:16:56,188 PEOPLE IN MY LAB THAT HAVE DONE 2271 01:16:56,188 --> 01:16:57,823 ALL THE EXPERIMENTS AND ALL THE 2272 01:16:57,823 --> 01:17:00,893 HARD WORK, AND MY LONG TERM 2273 01:17:00,893 --> 01:17:03,863 COLLABORATORS AT NCATS, 2274 01:17:03,863 --> 01:17:07,800 DIFFERENT NHGRI COURSE AND 2275 01:17:07,800 --> 01:17:09,001 TECHNOLOGY TRANSFER 2276 01:17:09,001 --> 01:17:11,137 COLLABORATORS AROUND THE WORLD. 2277 01:17:11,137 --> 01:17:12,972 AND AT NIH. 2278 01:17:12,972 --> 01:17:15,741 THIS TEAM THAT I HAVE WITH ASAP, 2279 01:17:15,741 --> 01:17:17,810 IT AN INTERNATIONAL GROUP THAT 2280 01:17:17,810 --> 01:17:20,646 WORKS TOGETHER AND WE RECEIVE 2281 01:17:20,646 --> 01:17:23,616 FUNDING IN COMMON, AND ALWAYS 2282 01:17:23,616 --> 01:17:25,351 I'D LIKE TO GIVE SPECIAL THANKS 2283 01:17:25,351 --> 01:17:27,453 TO OUR PATIENTS, THEIR FAMILY 2284 01:17:27,453 --> 01:17:30,089 MEMBERS, THEIR CAREGIVERS AND 2285 01:17:30,089 --> 01:17:31,057 REFERRING PHYSICIANS THAT MAKE 2286 01:17:31,057 --> 01:17:31,891 THIS KIND OF WORK POSSIBLE. 2287 01:17:31,891 --> 01:17:32,959 THANK YOU. 2288 01:17:32,959 --> 01:17:40,499 [APPLAUSE] 2289 01:17:40,499 --> 01:17:42,034 >> WELL, THANK YOU SO, SO MUCH 2290 01:17:42,034 --> 01:17:46,072 FOR THIS REALLY FANTASTIC 2291 01:17:46,072 --> 01:17:50,543 PRESENTATION, DR. SINGLETON AND 2292 01:17:50,543 --> 01:17:51,243 DR. SIDRANSKY. 2293 01:17:51,243 --> 01:17:55,081 SO ANYWAY, WE HAVE A VERY 2294 01:17:55,081 --> 01:17:55,915 INQUISITIVE GROUP ONLINE WHO 2295 01:17:55,915 --> 01:17:57,016 HAVE ALREADY SUBMITTED TO US 2296 01:17:57,016 --> 01:18:00,319 OVER A DOZEN QUESTIONS. 2297 01:18:00,319 --> 01:18:04,557 ENTEINTERROGATING OUR SPEAKERS. 2298 01:18:04,557 --> 01:18:06,892 AND SO ELLEN, WE HAVE SOME 2299 01:18:06,892 --> 01:18:08,194 QUESTIONS FROM THE AUDIENCE HERE 2300 01:18:08,194 --> 01:18:09,528 AS WELL. 2301 01:18:09,528 --> 01:18:10,062 WHAT'S THAT? 2302 01:18:10,062 --> 01:18:11,397 >> MICS ARE THERE. 2303 01:18:11,397 --> 01:18:13,065 >> YES, INDEED. 2304 01:18:13,065 --> 01:18:14,300 YES, PLEASE GO TO THE MICROPHONE 2305 01:18:14,300 --> 01:18:15,835 IF YOU HAVE A QUESTION THAT 2306 01:18:15,835 --> 01:18:20,206 YOU'D LIKE TO POSE, BUT WHILE 2307 01:18:20,206 --> 01:18:22,341 OUR AUDIENCE IS GOING TO THE 2308 01:18:22,341 --> 01:18:23,142 MICROPHONE -- HERE'S ONE. 2309 01:18:23,142 --> 01:18:24,910 THIS IS JUST A SIMPLE ONE. 2310 01:18:24,910 --> 01:18:26,479 YOU KNOW, JUST TO GET THINGS 2311 01:18:26,479 --> 01:18:28,748 STARTED. 2312 01:18:28,748 --> 01:18:30,616 SO DR. SIDRANSKY MENTIONED 2313 01:18:30,616 --> 01:18:33,919 SOMETHING ABOUT CHANGES IN SME 2314 01:18:33,919 --> 01:18:35,121 SMELLING IN PATIENTS WITH 2315 01:18:35,121 --> 01:18:36,656 PARKINSON DISEASE. 2316 01:18:36,656 --> 01:18:39,592 IS THERE ANY EXPLANATION FOR 2317 01:18:39,592 --> 01:18:40,926 THAT? 2318 01:18:40,926 --> 01:18:45,631 WHY THE PROBLEMS WITH OLFACTORY 2319 01:18:45,631 --> 01:18:49,602 SENSATION? 2320 01:18:49,602 --> 01:18:51,671 >> WELL, IT SEEMS TO BE THAT THE 2321 01:18:51,671 --> 01:18:52,672 NEURONS IN THAT REGION OF THE 2322 01:18:52,672 --> 01:18:57,376 BRAIN ARE IMPACTED. 2323 01:18:57,376 --> 01:18:58,144 SOMETHING THAT WE SCREEN WITH 2324 01:18:58,144 --> 01:18:59,445 JUST LIKE ON ONE OF THESE 2325 01:18:59,445 --> 01:19:02,515 SCRATCH AND SNIFF TESTS, IT 2326 01:19:02,515 --> 01:19:06,052 OFTEN PRECEDES THE ONSET OF THE 2327 01:19:06,052 --> 01:19:08,554 MOTOR SYMPTOMS OF PARKINSON 2328 01:19:08,554 --> 01:19:09,555 DISEASE. 2329 01:19:09,555 --> 01:19:12,191 BUT RIGHT NOW, WE JUST HAD A 2330 01:19:12,191 --> 01:19:14,360 PANDEMIC AND EVERYBODY GOT COVID 2331 01:19:14,360 --> 01:19:15,361 AND LOSS OF SMELL IS ALSO A 2332 01:19:15,361 --> 01:19:18,197 PROBLEM WITH COVID, SO I 2333 01:19:18,197 --> 01:19:19,298 WOULDN'T GET REALLY WORKED UP IF 2334 01:19:19,298 --> 01:19:20,332 YOU'RE HAVING A PROBLEM WITH 2335 01:19:20,332 --> 01:19:22,168 SMELLING RIGHT NOW. 2336 01:19:22,168 --> 01:19:23,803 IT'S COMPLICATING THE WHOLE 2337 01:19:23,803 --> 01:19:29,508 PICTURE. 2338 01:19:29,508 --> 01:19:31,711 IT'S REALLY -- WELL, SINCE THE 2339 01:19:31,711 --> 01:19:33,579 TASTE -- WHAT YOU TASTE IS 2340 01:19:33,579 --> 01:19:34,814 IMPACTED BY YOUR SENSE OF SMELL, 2341 01:19:34,814 --> 01:19:38,184 BUT I DON'T THINK IT AFFECTS THE 2342 01:19:38,184 --> 01:19:39,051 TASTE BUDS. 2343 01:19:39,051 --> 01:19:39,518 >> I SEE, I SEE. 2344 01:19:39,518 --> 01:19:40,419 ALL RIGHT. 2345 01:19:40,419 --> 01:19:41,353 WELL, WE HAVE A QUESTION NOW 2346 01:19:41,353 --> 01:19:42,221 FROM THE AUDIENCE. 2347 01:19:42,221 --> 01:19:45,691 >> A QUESTION AND A COMMENT. 2348 01:19:45,691 --> 01:19:49,729 SO TODAY I WAS VERY LUCKY, I'VE 2349 01:19:49,729 --> 01:19:55,801 HAD THREE LASKER AWARDEES, AND 2350 01:19:55,801 --> 01:19:58,370 TWO BREAKTHROUGH PRIZE WINNERS 2351 01:19:58,370 --> 01:20:00,873 HERE IN THE PARKINSON DISEASE. 2352 01:20:00,873 --> 01:20:03,542 SO MY QUESTION IS, WE ARE ALL 2353 01:20:03,542 --> 01:20:05,611 AFRICANS, BUT AGAIN, WE HAVE 2354 01:20:05,611 --> 01:20:07,046 GENETIC VARIATIONS THAT HAPPENED 2355 01:20:07,046 --> 01:20:09,448 WHICH ARE DIFFERENT THAN 2356 01:20:09,448 --> 01:20:10,316 EUROPEANS. 2357 01:20:10,316 --> 01:20:12,618 SO WHAT IS IT THAT HAPPENS 2358 01:20:12,618 --> 01:20:14,053 STARTING FROM AFRICA, THOSE 2359 01:20:14,053 --> 01:20:17,757 VARIANTS TAKE OVER, AND IS THERE 2360 01:20:17,757 --> 01:20:18,891 SOME GENETIC CHANGES THAT HAPPEN 2361 01:20:18,891 --> 01:20:24,163 AS WE ARE EVOLVING FROM AFRICA? 2362 01:20:24,163 --> 01:20:26,332 >> THERE'S NOT A SIMPLE ANSWER 2363 01:20:26,332 --> 01:20:29,268 TO THAT, BUT CERTAINLY 2364 01:20:29,268 --> 01:20:30,369 POPULATIONS OUTSIDE OF AFRICA 2365 01:20:30,369 --> 01:20:31,904 HAVE GONE THROUGH BOTTLENECKS 2366 01:20:31,904 --> 01:20:34,240 THAT HAVE REDUCED GENETIC 2367 01:20:34,240 --> 01:20:37,076 DIVERSITY IN THOSE POPULATIONS. 2368 01:20:37,076 --> 01:20:39,311 KIND OF A DIFFERENT WAY OF 2369 01:20:39,311 --> 01:20:41,781 ANSWERING YOUR QUESTION. 2370 01:20:41,781 --> 01:20:43,048 KIND OF IGNORING YOUR QUESTION 2371 01:20:43,048 --> 01:20:49,755 TO SUIT MY OWN NEEDS, THERE IS 2372 01:20:49,755 --> 01:20:50,856 SOME CONCEPT THAT SOME OF THE 2373 01:20:50,856 --> 01:20:52,625 GENE VARIANTS THAT ARE RISK 2374 01:20:52,625 --> 01:20:53,726 FACTORS FOR PARKINSON DISEASE 2375 01:20:53,726 --> 01:20:56,562 ARE MORE COMMON THAN ONE WOULD 2376 01:20:56,562 --> 01:20:58,330 EXPECT. 2377 01:20:58,330 --> 01:21:01,167 SO THERE IS QUITE A LOT OF 2378 01:21:01,167 --> 01:21:02,268 INTEREST IN UNDERSTANDING WHERE 2379 01:21:02,268 --> 01:21:06,972 THE MUTATIONS IN LRRK2 AND 2380 01:21:06,972 --> 01:21:08,641 GBA1 MIGHT CONFER SOME KIND OF 2381 01:21:08,641 --> 01:21:11,577 SELECTIVE ADVANTAGE PREVIOUS TO 2382 01:21:11,577 --> 01:21:13,345 RISK, WHETHER THERE MIGHT BE 2383 01:21:13,345 --> 01:21:17,917 SOME SIGNS OF SELECTION FOR, FOR 2384 01:21:17,917 --> 01:21:19,451 INSTANCE, RESISTANCE TO 2385 01:21:19,451 --> 01:21:21,887 INFECTION OR THINGS LIKE THAT. 2386 01:21:21,887 --> 01:21:24,290 SO YOU CAN IMAGINE THAT THERE 2387 01:21:24,290 --> 01:21:26,725 KIND OF RANDOM BOTTLENECK 2388 01:21:26,725 --> 01:21:28,360 EFFECTS WHICH CHANGES WITH 2389 01:21:28,360 --> 01:21:28,994 VARIANTS ARE AVAILABLE IN 2390 01:21:28,994 --> 01:21:30,629 DIFFERENT POPULATIONS BUT ALSO 2391 01:21:30,629 --> 01:21:32,097 SOME POTENTIAL DRIVERS SUCH AS 2392 01:21:32,097 --> 01:21:35,668 EXPOSURE TO INFECTIOUS DISEASE, 2393 01:21:35,668 --> 01:21:38,304 WHICH MIGHT CHANGE VARIANT 2394 01:21:38,304 --> 01:21:38,604 FREQUENCIES. 2395 01:21:38,604 --> 01:21:41,173 >> AND ALSO IT IS AMAZING, THE 2396 01:21:41,173 --> 01:21:42,741 LARGE NUMBER OF THESE PATIENTS, 2397 01:21:42,741 --> 01:21:47,012 THE VARIANTS, THEY SURVIVED. 2398 01:21:47,012 --> 01:21:49,448 SO IS IT PURE LUCK? 2399 01:21:49,448 --> 01:21:51,283 I GUESS WE ALL NEED LUCK IN SOME 2400 01:21:51,283 --> 01:21:51,450 WAY. 2401 01:21:51,450 --> 01:21:53,485 >> WHAT DO YOU MEAN, THE VARIANT 2402 01:21:53,485 --> 01:21:53,819 SURVIVED OR -- 2403 01:21:53,819 --> 01:21:54,920 >> SOME OF THE PATIENTS YOU GUYS 2404 01:21:54,920 --> 01:21:56,555 ARE FOLLOWING, THEY NEVER 2405 01:21:56,555 --> 01:21:57,857 DEVELOP PARKINSON DISEASE. 2406 01:21:57,857 --> 01:22:00,292 SO WHAT IS IT THAT'S SAVING 2407 01:22:00,292 --> 01:22:00,492 THEM? 2408 01:22:00,492 --> 01:22:02,595 >> YEAH, WELL, ELLEN KIND OF 2409 01:22:02,595 --> 01:22:06,532 HINTED AT THIS AT THE BEGINNING 2410 01:22:06,532 --> 01:22:08,934 IN THAT WE BELIEVE THAT THE 2411 01:22:08,934 --> 01:22:11,670 DISEASE IS AN INTERPLAY BETWEEN 2412 01:22:11,670 --> 01:22:12,338 GENETICS AND ENVIRONMENT. 2413 01:22:12,338 --> 01:22:15,007 IT'S KIND OF THE HAND-WAVY 2414 01:22:15,007 --> 01:22:15,841 ANSWER TO YOUR QUESTION, ABOUT 2415 01:22:15,841 --> 01:22:17,042 YOU ONE WOULD SUSPECT -- WE 2416 01:22:17,042 --> 01:22:18,677 ALREADY HAVE EVIDENCE THAT PART 2417 01:22:18,677 --> 01:22:22,014 OF THE PENETRANCE OF GBA 2418 01:22:22,014 --> 01:22:24,850 VARIANTS AND LRRK2 VARIANTS IS 2419 01:22:24,850 --> 01:22:25,718 DRIVEN BY GENETICS. 2420 01:22:25,718 --> 01:22:29,121 WE CAN FIND MODIFIERS, SO 2421 01:22:29,121 --> 01:22:30,322 GENERAL GENETIC RISK VARIANTS 2422 01:22:30,322 --> 01:22:32,391 ALSO SEEM TO MODIFY RISK THAT'S 2423 01:22:32,391 --> 01:22:35,060 IMPARTED BY GBA1 AND LRRK2, BUT 2424 01:22:35,060 --> 01:22:36,262 THEY CERTAINLY DON'T EXPLAIN 2425 01:22:36,262 --> 01:22:36,695 EVERYTHING. 2426 01:22:36,695 --> 01:22:41,200 I TALKED A LITTLE ABOUT THE 2427 01:22:41,200 --> 01:22:42,735 HERITABLE COMPONENT OF DISEASE, 2428 01:22:42,735 --> 01:22:44,503 REPRESENTS ABOUT 30 OR 40% OF 2429 01:22:44,503 --> 01:22:47,673 THE TOTAL LIABILITY, SO ONLY 2430 01:22:47,673 --> 01:22:49,208 LIKE 30 OR 40% OF THE REASON WHY 2431 01:22:49,208 --> 01:22:51,510 A TYPICAL CASE HAS DISEASES IS 2432 01:22:51,510 --> 01:22:53,379 DUE TO HERITABLE GENETICS. 2433 01:22:53,379 --> 01:22:54,813 SO ONE WOULD ASSUME THAT THERE'S 2434 01:22:54,813 --> 01:22:55,347 SOMETHING ELSE. 2435 01:22:55,347 --> 01:22:56,982 THAT COULD BE ENVIRONMENT, IT 2436 01:22:56,982 --> 01:23:00,719 COULD BE CHANCE STOCHASTIC 2437 01:23:00,719 --> 01:23:02,922 EVENTS OR KIND OF RARE VARIANTS 2438 01:23:02,922 --> 01:23:05,891 OR MOSAIC EVENTS, BUT THE BEST 2439 01:23:05,891 --> 01:23:07,960 GUESS IS WHAT'S MODERATING RISK 2440 01:23:07,960 --> 01:23:10,396 EVEN IN MU TAKE CARRIERS IS 2441 01:23:10,396 --> 01:23:11,964 OTHER GENETICS AND ENVIRONMENT. 2442 01:23:11,964 --> 01:23:14,867 >> SO THE LAST QUESTION IS ABOUT 2443 01:23:14,867 --> 01:23:17,636 THTHESE PARKINSON'S PATIENTS. 2444 01:23:17,636 --> 01:23:22,107 DO ALL PATIENTS WITH THE 2445 01:23:22,107 --> 01:23:23,676 GLUCOCEREBROSIDASE -- WITH ALPHA 2446 01:23:23,676 --> 01:23:25,744 SYNUCLEIN, DO THEY GET BENEFITS 2447 01:23:25,744 --> 01:23:27,012 FROM -- THERAPY? 2448 01:23:27,012 --> 01:23:29,782 >> YEAH, THEY DO. 2449 01:23:29,782 --> 01:23:33,452 PRETTY MUCH THE SAME AS ANY RUN 2450 01:23:33,452 --> 01:23:34,620 OF THE MILL PARKINSON PATIENTS 2451 01:23:34,620 --> 01:23:36,956 DO. 2452 01:23:36,956 --> 01:23:38,691 >> ALL RIGHT. 2453 01:23:38,691 --> 01:23:40,759 CONGRATULATIONS, MORE POWER TO 2454 01:23:40,759 --> 01:23:41,327 YOU. 2455 01:23:41,327 --> 01:23:42,594 KEEP FINDING. 2456 01:23:42,594 --> 01:23:43,062 >> THANK YOU. 2457 01:23:43,062 --> 01:23:46,498 >> SO DR. ARIAS, I THINK HAS A 2458 01:23:46,498 --> 01:23:46,765 QUESTION. 2459 01:23:46,765 --> 01:23:49,435 >> FIRST OF ALL, THANK YOU FOR 2460 01:23:49,435 --> 01:23:54,506 REALLY AN INCREDIBLE STORY THAT 2461 01:23:54,506 --> 01:23:57,109 HAS BROAD IMPLICATIONS WAY 2462 01:23:57,109 --> 01:23:59,445 BEYOND EVEN PARKINSON'S DISEASE 2463 01:23:59,445 --> 01:24:02,514 THAT WE SHOULD NARROW OUR VISION 2464 01:24:02,514 --> 01:24:04,683 TO WHAT WE LOOK AT AND LOOK AT 2465 01:24:04,683 --> 01:24:05,351 THE BIG PICTURES. 2466 01:24:05,351 --> 01:24:07,786 SO I HAVE A QUESTION. 2467 01:24:07,786 --> 01:24:11,924 IT SEEMS TO ME, I RECALL THAT 2468 01:24:11,924 --> 01:24:14,326 PARKINSON'S DISEASE USUALLY HAS 2469 01:24:14,326 --> 01:24:17,930 A LONG HISTORY OF PEOPLE 2470 01:24:17,930 --> 01:24:22,468 BEGINNING VERY OFTEN WITH 2471 01:24:22,468 --> 01:24:23,569 GASTROINTESTINAL SYMPTOMS, 2472 01:24:23,569 --> 01:24:23,902 CONSTIPATION. 2473 01:24:23,902 --> 01:24:25,838 I REMEMBER A CLINICAL STUDY 2474 01:24:25,838 --> 01:24:28,841 WHERE SOMEBODY CLAIMED THAT 2475 01:24:28,841 --> 01:24:30,376 CONSTIPATION WAS ALMOST A 2476 01:24:30,376 --> 01:24:31,977 CONSTANT OCCURRING ANYWHERE FROM 2477 01:24:31,977 --> 01:24:34,747 FIVE TO 20 YEARS PERSISTENTLY 2478 01:24:34,747 --> 01:24:36,148 BEFORE THERE WERE NEUROLOGIC 2479 01:24:36,148 --> 01:24:37,850 THINGS. 2480 01:24:37,850 --> 01:24:40,886 SO DOES THIS HAVE IMPLICATIONS 2481 01:24:40,886 --> 01:24:44,056 THAT THE DISEASE ACTUALLY MAY 2482 01:24:44,056 --> 01:24:47,693 BEGIN OUTSIDE OF THE BRAIN? 2483 01:24:47,693 --> 01:24:48,994 AND AS SORT OF THE COROLLARY TO 2484 01:24:48,994 --> 01:24:50,329 IT, I KNOW THIS IS A BIT OF A 2485 01:24:50,329 --> 01:24:53,866 WILD IDEA, BUT IN ANY OF THE 2486 01:24:53,866 --> 01:24:55,601 ANIMAL-TYPE MODELS, IS IT 2487 01:24:55,601 --> 01:24:57,336 TRANSMISSIBLE OR ARE YOU DEALING 2488 01:24:57,336 --> 01:24:59,571 WITH SOMETHING LIKE A PRION THAT 2489 01:24:59,571 --> 01:25:02,541 COULD BE ACTIVATING THIS SYSTEM 2490 01:25:02,541 --> 01:25:04,810 THAT YOU DESCRIBE, PARTICULARLY 2491 01:25:04,810 --> 01:25:07,713 IN THE PRESENCE OF RISK FACTORS? 2492 01:25:07,713 --> 01:25:11,550 >> YEAH, SO -- WELL, WHAT I'M 2493 01:25:11,550 --> 01:25:13,485 ABOUT TO SAY, I DON'T KNOW THAT 2494 01:25:13,485 --> 01:25:15,154 THERE'S -- THERE'S REALLY STRONG 2495 01:25:15,154 --> 01:25:16,455 EVIDENCE IN FAVOR OR AGAINST, 2496 01:25:16,455 --> 01:25:18,557 BUT THERE'S A HUGE AMOUNT OF 2497 01:25:18,557 --> 01:25:20,959 INTEREST IN THIS NOTION THAT 2498 01:25:20,959 --> 01:25:22,194 SYNUCLEIN MIGHT ACT A BIT LIKE A 2499 01:25:22,194 --> 01:25:22,628 PRION. 2500 01:25:22,628 --> 01:25:23,629 I THINK WE HAVE TO BE CAREFUL 2501 01:25:23,629 --> 01:25:26,799 WITH THE USE OF THE WORD 2502 01:25:26,799 --> 01:25:27,232 TRANSMISSIBLE. 2503 01:25:27,232 --> 01:25:28,901 I DON'T THINK THAT THIS IS A 2504 01:25:28,901 --> 01:25:29,635 TRANSMISSIBLE DISEASE IN THE 2505 01:25:29,635 --> 01:25:33,939 SAME WAY THAT A PRION IS, LIKE 2506 01:25:33,939 --> 01:25:34,940 CURO OR ANYTHING LIKE THAT. 2507 01:25:34,940 --> 01:25:36,475 BUT THERE IS A NOTION THAT A 2508 01:25:36,475 --> 01:25:40,079 COMPONENT OF THIS MIGHT BE 2509 01:25:40,079 --> 01:25:41,947 CELL-TO-CELL TRANSFER AND 2510 01:25:41,947 --> 01:25:43,182 PERMISSIVE TEMPLATING. 2511 01:25:43,182 --> 01:25:46,685 SO A MALFORMED STRAIN OF SIGH 2512 01:25:46,685 --> 01:25:51,256 KSYNUCLEIN LEADS TO THE CREATION 2513 01:25:51,256 --> 01:25:53,392 OF MORE MALFORMED STRAINS OF 2514 01:25:53,392 --> 01:25:54,026 SYNUCLEIN AND SO FORTH. 2515 01:25:54,026 --> 01:25:57,763 PART OF THIS IS DRIVEN BY YOUR 2516 01:25:57,763 --> 01:26:00,833 COMMENT EARLIER AROUND THE FACT 2517 01:26:00,833 --> 01:26:03,569 THAT YOU CAN SEE PROBLEMS IN THE 2518 01:26:03,569 --> 01:26:07,606 GUT AND THAT YOU SEPA THOLG IN Y 2519 01:26:07,606 --> 01:26:09,842 IN THE GUT PRETTY EARLY ON. 2520 01:26:09,842 --> 01:26:12,411 SO ONE OF THE QUESTIONS EARLIER 2521 01:26:12,411 --> 01:26:15,614 WAS ABOUT ANOSMIA AND SMELL. 2522 01:26:15,614 --> 01:26:17,950 ANOSMIA SEEMS TO BE AN EARLY 2523 01:26:17,950 --> 01:26:18,817 FEATURE, TIGHTLY ASSOCIATED WITH 2524 01:26:18,817 --> 01:26:20,919 A FAIRLY NEW ASSAY CALLED 2525 01:26:20,919 --> 01:26:22,821 SYNUCLEIN SEEDING AMPLIFICATION 2526 01:26:22,821 --> 01:26:26,325 ASSAY, WHICH IS LIKE A PCR FOR 2527 01:26:26,325 --> 01:26:27,826 MALFORMED SYNUCLEIN. 2528 01:26:27,826 --> 01:26:31,263 SO YOU CAN SEE THE SYNUCLEIN 2529 01:26:31,263 --> 01:26:33,332 AGGREGATE ASSAY POSITIVITY IN 2530 01:26:33,332 --> 01:26:35,100 PEOPLE WELL BEFORE THEY GET 2531 01:26:35,100 --> 01:26:36,502 DISEASE. 2532 01:26:36,502 --> 01:26:39,271 YOU ALSO SEE OTHER FEATURES LIKE 2533 01:26:39,271 --> 01:26:40,906 REM SLEEP BEHAVIORAL DISORDER, 2534 01:26:40,906 --> 01:26:44,510 THAT'S PRETTY YON. 2535 01:26:44,510 --> 01:26:45,010 COMMON, 2536 01:26:45,010 --> 01:26:48,147 CONSTIPATION, LOTS OF 2537 01:26:48,147 --> 01:26:49,047 DISAUTONOMIC FEATURES, LOTS 2538 01:26:49,047 --> 01:26:49,648 GOING ON. 2539 01:26:49,648 --> 01:26:52,918 >> A BIG KIND OF CONTROVERSY, 2540 01:26:52,918 --> 01:26:53,886 BRAIN FIRST, BODY FIRST, BUT 2541 01:26:53,886 --> 01:26:55,087 THERE IS A LOT OF EVIDENCE FOR 2542 01:26:55,087 --> 01:26:57,489 THE BODY FIRST PART. 2543 01:26:57,489 --> 01:26:59,258 ALSO CARDIAC INNERVATION AND 2544 01:26:59,258 --> 01:27:02,127 THOSE STUDIES FROM DR. GOLDSTEIN 2545 01:27:02,127 --> 01:27:06,398 ARE ALSO SUGGESTING THAT YOU CAN 2546 01:27:06,398 --> 01:27:07,499 SEE PRODROMAL PARKINSON THAT 2547 01:27:07,499 --> 01:27:07,833 WAY. 2548 01:27:07,833 --> 01:27:09,368 THE SPREAD ACTUALLY HAS BEEN 2549 01:27:09,368 --> 01:27:10,903 DOCUMENTED IN ANIMAL MODELS, 2550 01:27:10,903 --> 01:27:14,306 WHERE IF YOU DO INJECT FIBRILS 2551 01:27:14,306 --> 01:27:16,175 OF SYNUCLEIN, YOU CAN INDUCE A 2552 01:27:16,175 --> 01:27:19,011 PARKINSON TYPE OF DISEASE. 2553 01:27:19,011 --> 01:27:21,980 >> ONE OF THE DRIVERS -- SO THIS 2554 01:27:21,980 --> 01:27:23,715 IDEA HAS BEEN AROUND FOR QUITE A 2555 01:27:23,715 --> 01:27:24,283 WHILE. 2556 01:27:24,283 --> 01:27:26,685 I WOULD SAY IT WENT DORMANT FOR 2557 01:27:26,685 --> 01:27:28,120 A NUMBER OF YEARS, AND SOMETHING 2558 01:27:28,120 --> 01:27:30,556 THAT RE-ENERGIZED IT A LITTLE 2559 01:27:30,556 --> 01:27:34,960 BIT WAS A COUPLE OF PAPERS, ONE 2560 01:27:34,960 --> 01:27:38,130 FROM JEFF CORDOV AND ONE FROM 2561 01:27:38,130 --> 01:27:40,766 PATRICK BRUNDIN WHICH SHOWS THAT 2562 01:27:40,766 --> 01:27:42,968 IN PATIENTS WHO RECEIVED FETAL 2563 01:27:42,968 --> 01:27:44,403 TRANSPLANT, DOPAMINERGIC 2564 01:27:44,403 --> 01:27:46,338 NEURONS, MANY YEARS LATER, AT 2565 01:27:46,338 --> 01:27:48,073 AUTOPSY, YOU SEE LEWY BODIES IN 2566 01:27:48,073 --> 01:27:49,441 THE TRANSPLANT. 2567 01:27:49,441 --> 01:27:52,711 SO THIS KIND OF STARTED TO 2568 01:27:52,711 --> 01:27:54,146 REVITALIZE THIS IDEA OF SPREAD 2569 01:27:54,146 --> 01:27:55,614 THAT YOU COULD HAVE THIS 2570 01:27:55,614 --> 01:27:56,815 PATHOLOGIC SPECIES THAT SPREADS 2571 01:27:56,815 --> 01:27:59,451 FROM TISSUE TO TISSUE. 2572 01:27:59,451 --> 01:28:01,720 >> SO ALONG THOSE LINES THEN, 2573 01:28:01,720 --> 01:28:03,956 ARE THERE ANY DATA WITH REGARD 2574 01:28:03,956 --> 01:28:08,227 TO FAMILY MEMBERS, YOU KNOW, 2575 01:28:08,227 --> 01:28:10,829 SPOUSES AS OPPOSED TO 2576 01:28:10,829 --> 01:28:12,097 GENETICALLY RELATED FAMILY 2577 01:28:12,097 --> 01:28:13,899 MEMBERS WHERE THEY CATCH IT? 2578 01:28:13,899 --> 01:28:16,902 >> NO, NO EVIDENCE OF 2579 01:28:16,902 --> 01:28:18,437 TRANSMISSIBILITY IN THAT WAY 2580 01:28:18,437 --> 01:28:21,573 OUTSIDE OF THE GERMLINE. 2581 01:28:21,573 --> 01:28:22,407 >> ALL RIGHT. 2582 01:28:22,407 --> 01:28:24,042 WELL, HERE WE HAVE ANOTHER 2583 01:28:24,042 --> 01:28:27,012 QUESTION FROM THE AUDIENCE. 2584 01:28:27,012 --> 01:28:29,114 SO WHAT IS THE ROLE OF 2585 01:28:29,114 --> 01:28:30,749 INFLAMMATION IN PARKINSON 2586 01:28:30,749 --> 01:28:34,353 DISEASE, AND HAVE ANY SPECIFIC 2587 01:28:34,353 --> 01:28:35,120 CYTOKINE INHIBITORS EVER BEEN 2588 01:28:35,120 --> 01:28:37,990 TESTED IN PATIENT WITH 2589 01:28:37,990 --> 01:28:38,624 PARKINSON'S? 2590 01:28:38,624 --> 01:28:40,425 EXPWR THE 2591 01:28:40,425 --> 01:28:45,564 >> THERE'S NO QUESTION THAT IB T 2592 01:28:45,564 --> 01:28:47,633 INFLAMMATION, MICROGLIA, 2593 01:28:47,633 --> 01:28:50,602 ASTROCYTOSIS IS SEEN IN THE 2594 01:28:50,602 --> 01:28:53,272 BRAIN IN ANIMALS WITH 2595 01:28:53,272 --> 01:28:54,373 PARKINSON'S DISEASE, BUT WE 2596 01:28:54,373 --> 01:28:55,007 DON'T KNOW ABOUT THE THERAPY 2597 01:28:55,007 --> 01:28:55,540 QUESTION. 2598 01:28:55,540 --> 01:28:55,741 SORRY. 2599 01:28:55,741 --> 01:28:58,543 >> FROM A GENETIC PERSPECTIVE, 2600 01:28:58,543 --> 01:28:59,645 SO ONE OF THE THINGS THAT WE'VE 2601 01:28:59,645 --> 01:29:03,382 BEEN DOING IS TO COMBINE GENETIC 2602 01:29:03,382 --> 01:29:05,150 DATA AND SINGLE CELL EXPRESSION 2603 01:29:05,150 --> 01:29:06,451 DATA TO TRY AND UNDERSTAND WHAT 2604 01:29:06,451 --> 01:29:09,521 THE CELLULAR CONTEXT OF GENETIC 2605 01:29:09,521 --> 01:29:12,824 RISK LO LOOKS LIKE. 2606 01:29:12,824 --> 01:29:16,561 WHEN YOU LOOK AT A DISEASE, IT 2607 01:29:16,561 --> 01:29:24,469 VERY CLEAR THERE'S A MONOCYTE -- 2608 01:29:24,469 --> 01:29:27,639 NOT COMPLETELY BUT MAINLY 2609 01:29:27,639 --> 01:29:29,675 DOPAMINERGIC -- MAYBE ASTROCYTE 2610 01:29:29,675 --> 01:29:30,075 COMPONENT TOO. 2611 01:29:30,075 --> 01:29:31,343 SO I THINK IT'S A MIX OF THINGS 2612 01:29:31,343 --> 01:29:34,813 TO BE HOB EL HONEST. 2613 01:29:34,813 --> 01:29:36,014 >> HERE'S ANOTHER QUESTION FROM 2614 01:29:36,014 --> 01:29:38,950 THE AUDIENCE. 2615 01:29:38,950 --> 01:29:41,720 SO YOU HAVE HIGHLIGHTED THE 2616 01:29:41,720 --> 01:29:44,256 POSSIBLE GENETIC OVERLAP BETWEEN 2617 01:29:44,256 --> 01:29:47,092 PARKINSON DISEASE AND LEWY BODY 2618 01:29:47,092 --> 01:29:47,626 DEMENTIA. 2619 01:29:47,626 --> 01:29:49,895 SO IS THERE ANY GENETIC OVERLAP 2620 01:29:49,895 --> 01:29:52,064 WITH THINGS LIKE BIPOLAR 2621 01:29:52,064 --> 01:29:54,266 DISORDER OR SCHIZOPHRENIA? 2622 01:29:54,266 --> 01:29:56,435 >> WE DON'T REALLY SEE MUCH, SO 2623 01:29:56,435 --> 01:29:59,871 WE'VE LOOKED AT -- IN TERMS OF 2624 01:29:59,871 --> 01:30:00,439 COMPLEX GENETICS. 2625 01:30:00,439 --> 01:30:02,240 SO IN TERMS OF LOOKING AT THE 2626 01:30:02,240 --> 01:30:03,308 CUMULATIVE RISK FACTORS 2627 01:30:03,308 --> 01:30:05,844 IDENTIFIED IN DISEASES LIKE 2628 01:30:05,844 --> 01:30:07,512 SCHIZOPHRENIA, BIPOLAR, 2629 01:30:07,512 --> 01:30:09,448 PARKINSON'S, ALZHEIMER'S, WE 2630 01:30:09,448 --> 01:30:11,116 DON'T SEE A LOT OF OVERLAP. 2631 01:30:11,116 --> 01:30:12,784 THERE'S THERE ARE SOME THINGS 2632 01:30:12,784 --> 01:30:16,054 LIKE HLA IS COMMON BETWEEN PD 2633 01:30:16,054 --> 01:30:17,389 AND ALZHEIMER'S DISEASE, BUT 2634 01:30:17,389 --> 01:30:18,156 ASIDE FROM THAT, NOT A HUGE 2635 01:30:18,156 --> 01:30:21,560 AMOUNT OF OVERLAP, AND CERTAINLY 2636 01:30:21,560 --> 01:30:22,661 NOT WITH MENTAL HEALTH DISORDERS 2637 01:30:22,661 --> 01:30:25,197 YOU MENTIONED. 2638 01:30:25,197 --> 01:30:28,934 >> SO YOU MENTIONED HLA. 2639 01:30:28,934 --> 01:30:31,103 SO IS THIS CLASS 1, CLASS 2, 2640 01:30:31,103 --> 01:30:32,804 CLASS 3, OR DOES ANYONE KNOW AT 2641 01:30:32,804 --> 01:30:33,105 THIS POINT? 2642 01:30:33,105 --> 01:30:33,905 >> WE DON'T KNOW. 2643 01:30:33,905 --> 01:30:35,640 AS YOU KNOW, IT'S KIND OF A 2644 01:30:35,640 --> 01:30:37,275 COMPLEX REGION TO DISSECT 2645 01:30:37,275 --> 01:30:38,110 GENETICALLY. 2646 01:30:38,110 --> 01:30:41,146 AND I WOULD SAY THE FIELD IS HAS 2647 01:30:41,146 --> 01:30:42,581 KIND OF STAYED AWAY FROM IT A 2648 01:30:42,581 --> 01:30:43,415 LITTLE BIT. 2649 01:30:43,415 --> 01:30:45,283 IT'S A FAIRLY MILD RISK FACTOR 2650 01:30:45,283 --> 01:30:46,918 SO WE DON'T REALLY KNOW A HUGE 2651 01:30:46,918 --> 01:30:47,152 AMOUNT. 2652 01:30:47,152 --> 01:30:51,323 >> SO IT'S NOT THE SAME SKY 2653 01:30:51,323 --> 01:30:52,624 SKYSCRAPER OF THE MANHATTAN PLOT 2654 01:30:52,624 --> 01:30:53,725 THAT ONE SEES WITH SOME OF THE 2655 01:30:53,725 --> 01:30:54,860 MOTHER CLASSIC AUTOIMMUNE 2656 01:30:54,860 --> 01:30:55,127 DISEASES. 2657 01:30:55,127 --> 01:30:58,997 >> NO, NO, NO, IT IS -- IF YOU 2658 01:30:58,997 --> 01:31:00,665 DO ANY KIND OF GENETIC 2659 01:31:00,665 --> 01:31:02,100 ASSOCIATION IN PARKINSON'S 2660 01:31:02,100 --> 01:31:03,402 DISEASE, THE FIRST THING YOU SEE 2661 01:31:03,402 --> 01:31:04,636 IS SYNUCLEIN ALWAYS. 2662 01:31:04,636 --> 01:31:06,138 THAT'S THE NUMBER ONE HIT ON 2663 01:31:06,138 --> 01:31:08,807 A -- THAT'S THE SKYSCRAPER, TAW 2664 01:31:08,807 --> 01:31:10,375 IS USUALLY THE SECOND ONE, BUT 2665 01:31:10,375 --> 01:31:11,676 ONLY IN NORTHERN EUROPEAN 2666 01:31:11,676 --> 01:31:12,477 POPULATIONS. 2667 01:31:12,477 --> 01:31:14,112 HLA DOESN'T REALLY POP UP UNTIL 2668 01:31:14,112 --> 01:31:15,046 YOU'RE WELL DOWN THE LIST. 2669 01:31:15,046 --> 01:31:16,081 >> I SEE. 2670 01:31:16,081 --> 01:31:18,683 I SEE. 2671 01:31:18,683 --> 01:31:19,851 ALL RIGHT. 2672 01:31:19,851 --> 01:31:21,820 SO THEN YOU'VE SORT OF TOUCHED 2673 01:31:21,820 --> 01:31:23,989 UPON THIS A LITTLE BIT WITH 2674 01:31:23,989 --> 01:31:25,957 REGARD TO SLEEP, BUT THIS 2675 01:31:25,957 --> 01:31:28,093 QUESTION SORT OF CAME FROM, I 2676 01:31:28,093 --> 01:31:30,729 THINK, THE OPPOSITE DIRECTION. 2677 01:31:30,729 --> 01:31:34,199 WHAT'S THE ROLE OF SLEEP IN 2678 01:31:34,199 --> 01:31:35,200 PARKINSON DISEASE 2679 01:31:35,200 --> 01:31:35,567 PREDISPOSITION? 2680 01:31:35,567 --> 01:31:37,302 IN OTHER WORDS, IF YOU WERE TO 2681 01:31:37,302 --> 01:31:39,171 SLEEP DEPRIVE SOMEONE, WOULD 2682 01:31:39,171 --> 01:31:40,806 THAT INCREASE THEIR RISK OF 2683 01:31:40,806 --> 01:31:43,208 PARKINSON DISEASE? 2684 01:31:43,208 --> 01:31:44,776 INTO I DON'T KNOW IF WE REALLY 2685 01:31:44,776 --> 01:31:45,644 HAVE DATA ON THAT. 2686 01:31:45,644 --> 01:31:49,681 WE DO KNOW THAT THIS ALTERED 2687 01:31:49,681 --> 01:31:53,118 SLEEP, REM SLEEP DISORDER IS 2688 01:31:53,118 --> 01:31:54,986 KIND OF WHEN YOU'RE ACTING OUT 2689 01:31:54,986 --> 01:31:56,421 YOUR DREAMS OR YOU MIGHT SOCK 2690 01:31:56,421 --> 01:31:57,689 YOUR SPOUSE OR SOMETHING. 2691 01:31:57,689 --> 01:32:02,327 THAT IS VERY WELL CORRELATED 2692 01:32:02,327 --> 01:32:04,329 WITH THE ODDS OF DEVELOPING 2693 01:32:04,329 --> 01:32:08,700 PARKINSON DISEASE. 2694 01:32:08,700 --> 01:32:10,669 DOES IT HELP -- IS IT PROTECTIVE 2695 01:32:10,669 --> 01:32:11,703 TO GET MORE SLEEP? 2696 01:32:11,703 --> 01:32:13,138 IT'S ALWAYS GOOD TO GET MORE 2697 01:32:13,138 --> 01:32:13,338 SLEEP. 2698 01:32:13,338 --> 01:32:15,740 BUT WE TELL OUR PATIENTS WHAT'S 2699 01:32:15,740 --> 01:32:16,875 REALLY GOOD FOR THEM IS 2700 01:32:16,875 --> 01:32:18,944 EXERCISE. 2701 01:32:18,944 --> 01:32:20,612 >> OKAY. 2702 01:32:20,612 --> 01:32:26,051 HERE'S -- OH, I THINK WE HAVE 2703 01:32:26,051 --> 01:32:28,119 ONE AT THE MICROPHONE THERE. 2704 01:32:28,119 --> 01:32:30,755 >> I KNOW THE TALKS HAVE BEEN 2705 01:32:30,755 --> 01:32:33,391 FOCUSED ON GENETIC COMPONENTS OF 2706 01:32:33,391 --> 01:32:36,228 PARKINSON DISEASE. 2707 01:32:36,228 --> 01:32:38,230 HOWEVER, WE WOULD LOVE TO HEAR 2708 01:32:38,230 --> 01:32:42,701 YOUR OPINION ON THE EXPOSURE TO 2709 01:32:42,701 --> 01:32:44,569 DTT, TO OTHER PESTICIDES, AND 2710 01:32:44,569 --> 01:32:47,372 HOW THAT INTERPLAYS PERHAPS IN 2711 01:32:47,372 --> 01:32:49,140 SOME OF THE PARKINSON DISEASE 2712 01:32:49,140 --> 01:32:51,543 BOTH INCIDENCE AS WELL AS 2713 01:32:51,543 --> 01:32:55,480 THERAPEUTIC OUTCOME. 2714 01:32:55,480 --> 01:32:57,916 >> DO YOU WANT TO TAKE THIS? 2715 01:32:57,916 --> 01:32:58,683 OKAY, THANKS. 2716 01:32:58,683 --> 01:33:01,086 SO THERE'S BEEN QUITE A LOT OF 2717 01:33:01,086 --> 01:33:03,321 EPIDEMIOLOGICAL WORK, ALTHOUGH 2718 01:33:03,321 --> 01:33:05,090 THE NICE THING ABOUT GENETICS IS 2719 01:33:05,090 --> 01:33:06,825 IT'S LARGE BUT FINITE, AND 2720 01:33:06,825 --> 01:33:08,960 FAIRLY EASY TO MEASURE. 2721 01:33:08,960 --> 01:33:12,797 THE ENVIRONMENT IS MUCH MORE 2722 01:33:12,797 --> 01:33:13,565 DIFFICULT TO MEASURE. 2723 01:33:13,565 --> 01:33:14,666 I THINK THERE'S A LOT THAT NEEDS 2724 01:33:14,666 --> 01:33:16,601 TO BE DONE BUT THERE'S CERTAINLY 2725 01:33:16,601 --> 01:33:17,536 VERY INTRIGUING ASSOCIATIONS 2726 01:33:17,536 --> 01:33:21,273 WITH SMOKING, CAFFEINE, DRINKING 2727 01:33:21,273 --> 01:33:25,010 OF WELL WATER, EXPOSURE TO 2728 01:33:25,010 --> 01:33:30,048 PESTICIDES, SOME OF THOSE STUDY, 2729 01:33:30,048 --> 01:33:35,020 I ACTUALLY KIND OF -- SIMILAR TO 2730 01:33:35,020 --> 01:33:36,021 ELLEN'S EXPERIENCE REALLY JUST 2731 01:33:36,021 --> 01:33:37,022 LOOKING AT A SMALL NUMBER OF 2732 01:33:37,022 --> 01:33:39,324 PATIENTS AND THEN GOING OUT FROM 2733 01:33:39,324 --> 01:33:39,524 THERE. 2734 01:33:39,524 --> 01:33:40,792 ONE OF THE EARLY STUDIES WAS 2735 01:33:40,792 --> 01:33:42,961 DONE BY A GUY CALLED BILL LOS 2736 01:33:42,961 --> 01:33:49,768 ANBILLLANGSTON WHO OBSERVED 2737 01:33:49,768 --> 01:33:50,535 PARKINSON'S DISORDER IN PATIENTS 2738 01:33:50,535 --> 01:33:52,137 WHO HAD USED SYNTHETIC HEROIN 2739 01:33:52,137 --> 01:33:54,205 THAT LED TO DEATH OF 2740 01:33:54,205 --> 01:33:54,973 DOPAMINERGIC NEURONS AND THIS 2741 01:33:54,973 --> 01:33:57,042 LED TO THIS WHOLE HYPOTHESIS 2742 01:33:57,042 --> 01:33:59,377 ABOUT TOXICITY AND EFFECT ON 2743 01:33:59,377 --> 01:34:00,912 COMPLEX ONE INHIBITION. 2744 01:34:00,912 --> 01:34:03,748 SO THIS HAS LED TO A WHOLE BUNCH 2745 01:34:03,748 --> 01:34:07,752 OF INVESTIGATION AROUND 2746 01:34:07,752 --> 01:34:08,620 POTENTIAL EXPOSURES AND THEIR 2747 01:34:08,620 --> 01:34:09,588 LINK TO DISEASE. 2748 01:34:09,588 --> 01:34:11,356 I HONESTLY THINK WE JUST DON'T 2749 01:34:11,356 --> 01:34:13,925 REALLY HAVE ENOUGH DATA RIGHT 2750 01:34:13,925 --> 01:34:14,326 NOW. 2751 01:34:14,326 --> 01:34:15,126 ONE OF THE THINGS WE'RE TRYING 2752 01:34:15,126 --> 01:34:19,664 TO TOUCH ON IN GP2 IS TO HAVE A 2753 01:34:19,664 --> 01:34:21,833 UNIFIED EXPOSURE QUESTIONNAIRE. 2754 01:34:21,833 --> 01:34:22,801 IT'S NOT MUCH BUT IT'S SOMETHING 2755 01:34:22,801 --> 01:34:24,002 THAT CAN BE APPLIED TO ALL OF 2756 01:34:24,002 --> 01:34:25,837 THE POPULATIONS THAT WE'RE 2757 01:34:25,837 --> 01:34:26,171 STUDYING. 2758 01:34:26,171 --> 01:34:27,706 MAYBE THAT WILL START TO GIVE US 2759 01:34:27,706 --> 01:34:31,076 SOME ANSWERS. 2760 01:34:31,076 --> 01:34:33,745 CERTAINLY MANY GROUPS HAVE 2761 01:34:33,745 --> 01:34:35,313 ROOKED AT GENE INTERACTION BY 2762 01:34:35,313 --> 01:34:36,514 VIERT BUT THERE'S REALLY NOTHING 2763 01:34:36,514 --> 01:34:40,051 COMPELLING TO BE HONEST. 2764 01:34:40,051 --> 01:34:42,087 >> MAYBE JUST TO FOLLOW THAT 2765 01:34:42,087 --> 01:34:44,322 ENVIRONMENTAL THEME A LITTLE BIT 2766 01:34:44,322 --> 01:34:48,660 FURTHER, ANY ROLE FOR DIET, IN 2767 01:34:48,660 --> 01:34:51,763 TERMS OF INCREASING RISK OR 2768 01:34:51,763 --> 01:34:55,066 MAYBE IN SOME WAY AVERTING 2769 01:34:55,066 --> 01:34:56,735 PARKINSON DISEASE? 2770 01:34:56,735 --> 01:34:59,004 >> NOTHING THAT'S REALLY -- 2771 01:34:59,004 --> 01:35:00,538 NOTHING THAT'S REALLY COMPELLING 2772 01:35:00,538 --> 01:35:02,007 TO BE HONEST. 2773 01:35:02,007 --> 01:35:04,409 >> THERE ISN'T THAT I KNOW OF 2774 01:35:04,409 --> 01:35:05,944 EXCEPT IT'S OKAY TO DRINK A LOT 2775 01:35:05,944 --> 01:35:06,544 OF COFFEE. 2776 01:35:06,544 --> 01:35:07,846 IT'S SUPPOSED TO BE PROTECTIVE. 2777 01:35:07,846 --> 01:35:09,514 >> OH, DRINK A LOT OF COFFEE? 2778 01:35:09,514 --> 01:35:11,349 OH. 2779 01:35:11,349 --> 01:35:11,683 WELL. 2780 01:35:11,683 --> 01:35:13,952 >> I'M JUST SAYING THAT TO YOU 2781 01:35:13,952 --> 01:35:15,253 BECAUSE YOU KNOW THAT'S WHAT YOU 2782 01:35:15,253 --> 01:35:15,420 DO. 2783 01:35:15,420 --> 01:35:16,621 >> I'M IN GOOD SHAPE. 2784 01:35:16,621 --> 01:35:17,155 OKAY. 2785 01:35:17,155 --> 01:35:19,357 ALL RIGHT. 2786 01:35:19,357 --> 01:35:23,828 SO THEN ANOTHER MEMBER OF THE 2787 01:35:23,828 --> 01:35:26,131 AUDIENCE WOULD LIKE TO KNOW 2788 01:35:26,131 --> 01:35:28,266 SOMETHING ABOUT IMPLANTABLE 2789 01:35:28,266 --> 01:35:31,436 ELECTRICAL STIMULATION AND ITS 2790 01:35:31,436 --> 01:35:35,740 THERAPEUTIC ROLE IN PARKINSON'S. 2791 01:35:35,740 --> 01:35:37,842 >> DBS. 2792 01:35:37,842 --> 01:35:40,412 >> YOU'RE TALKING ABOUT DBS? 2793 01:35:40,412 --> 01:35:42,447 SO PEOPLE WHO -- IT IS A 2794 01:35:42,447 --> 01:35:43,415 REALLY -- FOR SOME PEOPLE IT 2795 01:35:43,415 --> 01:35:45,216 HELPS THEM A LOT. 2796 01:35:45,216 --> 01:35:48,920 IT'S USUALLY PEOPLE AT THE STAGE 2797 01:35:48,920 --> 01:35:50,155 WHERE THEY'RE STILL RESPONDING 2798 01:35:50,155 --> 01:35:52,991 TO DOPAMINE, FURTHER ON LATE 2799 01:35:52,991 --> 01:35:56,561 STAGE, IT'S LESS GOOD. 2800 01:35:56,561 --> 01:36:00,965 IT IS -- YO UNIVERSALLY -- IT 2801 01:36:00,965 --> 01:36:01,933 DOESN'T ALWAYS WORK, SO I THINK 2802 01:36:01,933 --> 01:36:05,370 THERE ARE CERTAIN CRITERIA THAT 2803 01:36:05,370 --> 01:36:06,271 NEUROSURGEONS USE IN ORDER TO 2804 01:36:06,271 --> 01:36:08,106 DECIDE WHO'S GOING TO BE A GOOD 2805 01:36:08,106 --> 01:36:09,174 CANDIDATE, BUT IN THOSE 2806 01:36:09,174 --> 01:36:09,941 PATIENTS, SOMETIMES IT GIVES 2807 01:36:09,941 --> 01:36:12,777 THEM QUITE A FEW YEARS OF 2808 01:36:12,777 --> 01:36:16,081 IMPROVED LIFE QUALITY. 2809 01:36:16,081 --> 01:36:18,016 >> OKAY. 2810 01:36:18,016 --> 01:36:20,719 ALL RIGHT. 2811 01:36:20,719 --> 01:36:21,352 LET'S SEE. 2812 01:36:21,352 --> 01:36:26,091 WHAT OTHER QUESTIONS? 2813 01:36:26,091 --> 01:36:27,358 ANOTHER MAYBE ENVIRONMENTALLY 2814 01:36:27,358 --> 01:36:28,159 RELATED QUESTION. 2815 01:36:28,159 --> 01:36:32,397 WHAT IS THE ROLE OF STRESS IN 2816 01:36:32,397 --> 01:36:35,333 PARKINSON DISEASE PREDISPOS 2817 01:36:35,333 --> 01:36:35,700 PREDISPOSITION? 2818 01:36:35,700 --> 01:36:36,167 >> HARD TO MEASURE. 2819 01:36:36,167 --> 01:36:37,068 I DON'T KNOW -- 2820 01:36:37,068 --> 01:36:42,040 >> WE'RE ALL STRESSED. 2821 01:36:42,040 --> 01:36:43,141 >> I ALWAYS THINK A LITTLE 2822 01:36:43,141 --> 01:36:45,009 STRESS IS GOOD, A LOT OF STRESS 2823 01:36:45,009 --> 01:36:45,243 IS BAD. 2824 01:36:45,243 --> 01:36:47,412 >> ALL RIGHT. 2825 01:36:47,412 --> 01:36:51,082 WELL, THAT'S WORDS OF WISDOM. 2826 01:36:51,082 --> 01:36:51,349 [LAUGHTER] 2827 01:36:51,349 --> 01:36:52,550 >> I'M NOT SURE IT IS. 2828 01:36:52,550 --> 01:36:55,253 >> SO HERE'S ANOTHER ONE. 2829 01:36:55,253 --> 01:36:57,255 THAT JUST CAME IN OVER THE WIRE. 2830 01:36:57,255 --> 01:36:59,023 IN RECENT DECADES, NUMEROUS 2831 01:36:59,023 --> 01:37:01,626 STUDIES HAVE FOUND THAT SMOKING 2832 01:37:01,626 --> 01:37:03,661 OR THE INTAKE OF ANY FORM OF 2833 01:37:03,661 --> 01:37:06,297 NICOTINE, SUCH AS SMOKELESS 2834 01:37:06,297 --> 01:37:08,032 TOBACCO, EXPOSURE TO 2835 01:37:08,032 --> 01:37:09,934 ENVIRONMENTAL TOBACCO SMOKE, OR 2836 01:37:09,934 --> 01:37:13,104 EVEN DIETARY SOURCES SUCH AS 2837 01:37:13,104 --> 01:37:15,206 PEPPERS, REDUCES THE RISK OF 2838 01:37:15,206 --> 01:37:16,508 DEVELOPING PARKINSON'S DISEASE. 2839 01:37:16,508 --> 01:37:19,444 HAS THIS BEEN DISCREDITED? 2840 01:37:19,444 --> 01:37:24,449 >> WELL, IT'S AN EPIDEMIOLOGIC 2841 01:37:24,449 --> 01:37:24,883 FINDING. 2842 01:37:24,883 --> 01:37:26,484 IT'S CERTAINLY NOT SOMETHING 2843 01:37:26,484 --> 01:37:30,522 ANYBODY WOULD PRESCRIBE. 2844 01:37:30,522 --> 01:37:32,524 YOU CAN END UP DYING FROM CANCER 2845 01:37:32,524 --> 01:37:33,491 BEFORE YOUR PARKINSON WILL GET 2846 01:37:33,491 --> 01:37:34,793 TO YOU. 2847 01:37:34,793 --> 01:37:37,028 IT LIKE THE COFFEE STORY. 2848 01:37:37,028 --> 01:37:38,696 YOU KNOW, IF YOU LOOK AT BIG 2849 01:37:38,696 --> 01:37:43,001 POPULATIONS AND DO SURVEYS, 2850 01:37:43,001 --> 01:37:44,335 SMOARKS TEND TO HAVE A LITTLE 2851 01:37:44,335 --> 01:37:45,737 BIT LESS, SOME PEOPLE EVEN 2852 01:37:45,737 --> 01:37:47,372 SUGGESTED BACK TO YOUR PREVIOUS 2853 01:37:47,372 --> 01:37:52,043 QUESTION, THAT THERE'S A CERTAIN 2854 01:37:52,043 --> 01:37:52,710 BEHAVIORAL PHENOTYPE OF PEOPLE 2855 01:37:52,710 --> 01:37:56,648 WHO ARE MORE LIKELY TO BE LESS 2856 01:37:56,648 --> 01:37:58,550 RISK TAKERS THAT TEND TO HAVE 2857 01:37:58,550 --> 01:37:59,951 PARKINSON DISEASE, SO MAYBE THE 2858 01:37:59,951 --> 01:38:02,053 SMOKERS ARE THE MORE RISK -- 2859 01:38:02,053 --> 01:38:03,855 IT'S REALLY GOING TO BE HARD TO 2860 01:38:03,855 --> 01:38:04,155 TEASE OUT. 2861 01:38:04,155 --> 01:38:06,391 >> YEAH, YOU CAN IMAGINE WITH A 2862 01:38:06,391 --> 01:38:07,792 DISEASE OF DOPAMINE AND DOPAMINE 2863 01:38:07,792 --> 01:38:10,295 BEING SO HEAVILY INVOLVED IN THE 2864 01:38:10,295 --> 01:38:11,396 REWARD SYSTEM THAT THIS COULD BE 2865 01:38:11,396 --> 01:38:13,565 PART OF A PREMORBID PERSONALITY 2866 01:38:13,565 --> 01:38:16,701 DISORDER. 2867 01:38:16,701 --> 01:38:18,136 SO WE KNOW THAT DISEASE IS 2868 01:38:18,136 --> 01:38:19,470 ONGOING FOR PROBABLY DECADES 2869 01:38:19,470 --> 01:38:21,606 BEFORE A PATIENT SHOWS CLINICAL 2870 01:38:21,606 --> 01:38:22,874 SIGNS AND SYMPTOMS, SO WHAT THEY 2871 01:38:22,874 --> 01:38:24,742 DO IN THOSE DECADES BEFORE COULD 2872 01:38:24,742 --> 01:38:26,511 CERTAINLY BE INFLUENCED BY THE 2873 01:38:26,511 --> 01:38:27,946 DISEASE PROCESS RATHER THAN THE 2874 01:38:27,946 --> 01:38:30,215 OTHER WAY AROUND. 2875 01:38:30,215 --> 01:38:34,018 >> YES, YES. 2876 01:38:34,018 --> 01:38:35,119 OKAY. 2877 01:38:35,119 --> 01:38:38,890 SO HERE'S ONE WHICH I THINK GOES 2878 01:38:38,890 --> 01:38:40,425 ALONG WITH SOME OF THE GLOBAL 2879 01:38:40,425 --> 01:38:42,827 STUDIES THAT YOU'VE SPOKEN 2880 01:38:42,827 --> 01:38:45,797 ABOUT. 2881 01:38:45,797 --> 01:38:46,998 THE QUESTION IS, ARE THERE ANY 2882 01:38:46,998 --> 01:38:50,201 PART OF THE WORLD WHERE THERE'S 2883 01:38:50,201 --> 01:38:54,806 AN ESPECIALLY HIGH RISK OR 2884 01:38:54,806 --> 01:38:57,008 FREQUENCY OF PARKINSON'S 2885 01:38:57,008 --> 01:38:57,242 DISEASE? 2886 01:38:57,242 --> 01:38:59,377 >> YEAH, SO THIS -- REALLY THE 2887 01:38:59,377 --> 01:39:03,181 WAY TO DO THIS IS THAT DOOR TO 2888 01:39:03,181 --> 01:39:05,583 DOOR EPIDEMIOLOGICAL SURVEYS OR 2889 01:39:05,583 --> 01:39:07,719 IF THEY'RE CENTRALIZED 2890 01:39:07,719 --> 01:39:08,353 HEALTHCARE SYSTEMS. 2891 01:39:08,353 --> 01:39:09,587 AND THERE ARE NOT MANY OF EITHER 2892 01:39:09,587 --> 01:39:11,789 OF THOSE THINGS TO ALLOW YOU TO 2893 01:39:11,789 --> 01:39:12,690 REALLY GET GREAT ESTIMATES OF 2894 01:39:12,690 --> 01:39:12,991 THIS. 2895 01:39:12,991 --> 01:39:16,294 WE CERTAINLY KNOW THAT THERE ARE 2896 01:39:16,294 --> 01:39:17,495 RISK VARIANTS THAT ARE MUCH MORE 2897 01:39:17,495 --> 01:39:18,763 COMMON IN SOME POPULATIONS THAN 2898 01:39:18,763 --> 01:39:18,997 OTHERS. 2899 01:39:18,997 --> 01:39:22,467 WE TALKED ABOUT LRRK2. 2900 01:39:22,467 --> 01:39:26,671 40% OF NORTH AFRICAN ARABS WITH 2901 01:39:26,671 --> 01:39:27,572 PARKINSON'S DISEASE CARRY THAT 2902 01:39:27,572 --> 01:39:27,906 MU TAKE. 2903 01:39:27,906 --> 01:39:32,877 WE TALKED ABOUT THE ASHKENAZI 2904 01:39:32,877 --> 01:39:34,512 JEWISH POPULATION, SO I WOULD 2905 01:39:34,512 --> 01:39:36,047 SAY THAT WE KNOW THAT THAT'S 2906 01:39:36,047 --> 01:39:37,148 TRUE. 2907 01:39:37,148 --> 01:39:41,119 WE DON'T KNOW BEYOND ANECDOTE 2908 01:39:41,119 --> 01:39:42,553 WHETHER THERE ARE CERTAIN 2909 01:39:42,553 --> 01:39:43,888 ANCESTRAL GROUPS OR AREAS OF THE 2910 01:39:43,888 --> 01:39:45,189 WORLD WHERE THE DISEASE IS MORE 2911 01:39:45,189 --> 01:39:46,658 COMMON OR LESS COMMON THAN ONE 2912 01:39:46,658 --> 01:39:51,596 WOULD EXPECT. 2913 01:39:51,596 --> 01:39:54,332 >> SO WHAT ARE THE CRITERIA FOR 2914 01:39:54,332 --> 01:39:58,269 A CLINICAL TRIAL IN PATIENTS 2915 01:39:58,269 --> 01:40:00,238 WITH PARKINSON'S DISEASE? 2916 01:40:00,238 --> 01:40:03,875 WHAT IS THE THINKING ABOUT AT 2917 01:40:03,875 --> 01:40:04,676 WHAT STAGE OF THE DISEASE WOULD 2918 01:40:04,676 --> 01:40:08,613 YOU WANT TO INTERVENE, AND HOW 2919 01:40:08,613 --> 01:40:09,580 WOULD YOU DETERMINE WHETHER 2920 01:40:09,580 --> 01:40:10,949 YOU'RE HAVING A BENEFICIAL 2921 01:40:10,949 --> 01:40:12,283 EFFECT? 2922 01:40:12,283 --> 01:40:13,084 >> GREAT QUESTION. 2923 01:40:13,084 --> 01:40:14,452 >> MILLION DOLLAR QUESTION. 2924 01:40:14,452 --> 01:40:17,021 THE BEST WOULD BE IF YOU COULD 2925 01:40:17,021 --> 01:40:19,457 IDENTIFY PATIENTS IN THE 2926 01:40:19,457 --> 01:40:22,393 PRODROMAL PERIOD, AND THAT'S WHY 2927 01:40:22,393 --> 01:40:24,262 WE'RE SO ACTIVELY LOOKING AT 2928 01:40:24,262 --> 01:40:26,764 BIOMARKERS OR GENES OR THINGS 2929 01:40:26,764 --> 01:40:29,567 THAT -- IF YOU CAN FIND THE 2930 01:40:29,567 --> 01:40:33,638 EARLIEST DIAGNOSIS TO PREVENT 2931 01:40:33,638 --> 01:40:35,540 LOSS OF DOPAMINERGIC NEURONS, 2932 01:40:35,540 --> 01:40:36,774 THAT WOULD PROBABLY BE THE BEST 2933 01:40:36,774 --> 01:40:40,044 APPROACHMENT APPROACH. 2934 01:40:40,044 --> 01:40:41,479 RIGHT NOW THEY USE SCALES OF 2935 01:40:41,479 --> 01:40:44,716 MOVEMENT PROBABLY TRIALS SHOULD 2936 01:40:44,716 --> 01:40:50,221 BE NOT TOO LATE IN THE DISEASE. 2937 01:40:50,221 --> 01:40:53,458 >> THE PROBLEM IS THE SCALES ARE 2938 01:40:53,458 --> 01:40:56,260 NOT -- THE SCALES ARE NOT ALWAYS 2939 01:40:56,260 --> 01:40:58,663 PARTICULARLY REPRODUCIBLE. 2940 01:40:58,663 --> 01:41:00,765 AND IT CAN BE A SLOWLY 2941 01:41:00,765 --> 01:41:01,733 PROGRESSING DISEASE, SO THIS 2942 01:41:01,733 --> 01:41:05,803 MEANS THAT TRIALS CAN TAKE A 2943 01:41:05,803 --> 01:41:07,505 VERY LONG TIME, MEANING THEY'RE 2944 01:41:07,505 --> 01:41:08,039 VERY EXPENSIVE. 2945 01:41:08,039 --> 01:41:10,008 I THINK THERE'S A MOVE MORE AND 2946 01:41:10,008 --> 01:41:12,043 MORE, AND I THINK WE SEE THIS IN 2947 01:41:12,043 --> 01:41:13,344 OTHER NEURODEGENERATIVE 2948 01:41:13,344 --> 01:41:14,645 DISEASES, TO TRY AND DEFINE THE 2949 01:41:14,645 --> 01:41:16,414 DISEASE BY ITS UNDERLYING 2950 01:41:16,414 --> 01:41:17,015 BIOLOGY RATHER THAN IT'S 2951 01:41:17,015 --> 01:41:18,116 CLINICAL SIGNS AND SYMPTOMS. 2952 01:41:18,116 --> 01:41:19,684 SO THIS IS PART OF THE RATIONALE 2953 01:41:19,684 --> 01:41:22,754 FOR TRYING TO FIND EARLY 2954 01:41:22,754 --> 01:41:23,988 PRE-CLINICAL BIOMARKERS THAT YOU 2955 01:41:23,988 --> 01:41:26,691 COULD USE AS A READOUT FOR SOME 2956 01:41:26,691 --> 01:41:29,761 KIND OF THERAPEUTIC SUCCESS. 2957 01:41:29,761 --> 01:41:32,230 >> IT WOULD BE GREAT IF THEY 2958 01:41:32,230 --> 01:41:33,064 WERE MORE PENETRANT. 2959 01:41:33,064 --> 01:41:34,699 >> YEAH, IT WOULD MAKE THINGS 2960 01:41:34,699 --> 01:41:34,932 EASIER. 2961 01:41:34,932 --> 01:41:36,868 >> SO ALONG THOSE LINES, 2962 01:41:36,868 --> 01:41:39,837 POLYGENIC RISK SCORE, ARE THERE 2963 01:41:39,837 --> 01:41:41,039 POLYGENIC RISK SCORES THAT NOW 2964 01:41:41,039 --> 01:41:42,006 ARE CALCULATED AND -- 2965 01:41:42,006 --> 01:41:43,574 >> YEAH, THERE ARE POLYGENIC 2966 01:41:43,574 --> 01:41:44,075 RISK SCORES. 2967 01:41:44,075 --> 01:41:46,644 THEY DO OKAY. 2968 01:41:46,644 --> 01:41:48,179 THEY DO FAIRLY WELL WHEN 2969 01:41:48,179 --> 01:41:50,181 COMBINED WITH OTHER FEATURES 2970 01:41:50,181 --> 01:41:54,285 LIKE SEX, FAMILY HISTORY, 2971 01:41:54,285 --> 01:41:56,354 ANOSMIA. 2972 01:41:56,354 --> 01:41:58,322 ANOSMIA IS A GREAT PREDICTOR OF 2973 01:41:58,322 --> 01:41:59,090 DISEASE. 2974 01:41:59,090 --> 01:42:00,958 REM SLEEP, BEHAVIORAL DISORDER. 2975 01:42:00,958 --> 01:42:02,226 WHEN YOU COMBINE THOSE THINGS, 2976 01:42:02,226 --> 01:42:05,263 YOU GET FAIRLY HIGH PREDICTIVE 2977 01:42:05,263 --> 01:42:05,463 POWER. 2978 01:42:05,463 --> 01:42:06,898 >> SO THOSE INDIVIDUAL THEN THAT 2979 01:42:06,898 --> 01:42:09,167 HAVE A HIGH POLYGENIC RISK SCORE 2980 01:42:09,167 --> 01:42:13,104 AND HAVE ANOSMIA, THEY MIGHT BE 2981 01:42:13,104 --> 01:42:14,205 CANDIDATE IF ONE HAD SOME SORT 2982 01:42:14,205 --> 01:42:15,706 OF A PREVENTIVE -- 2983 01:42:15,706 --> 01:42:18,109 >> BUT THEN AGAIN, THAT'S GOING 2984 01:42:18,109 --> 01:42:19,410 TO BE REALLY LONG TRIALS AND IT 2985 01:42:19,410 --> 01:42:21,579 GOING TO BE HARD TO DECIDE 2986 01:42:21,579 --> 01:42:22,547 WHETHER YOUR INTERVENTION MADE 2987 01:42:22,547 --> 01:42:23,848 THE DIFFERENCE OR WHETHER THEY 2988 01:42:23,848 --> 01:42:25,183 WERE -- HOW PREDICTIVE IT REALLY 2989 01:42:25,183 --> 01:42:26,284 IS. 2990 01:42:26,284 --> 01:42:29,720 >> I WOULD SAY FROM A FARMER 2991 01:42:29,720 --> 01:42:30,688 PERSPECTIVE, THE THING THAT WE 2992 01:42:30,688 --> 01:42:33,424 GET ASKED A LOT WITHIN GP2 IS 2993 01:42:33,424 --> 01:42:35,593 CAN YOU PROVIDE PRECISION 2994 01:42:35,593 --> 01:42:38,196 COHORTS FOR FUTURE TRIALS, CAN 2995 01:42:38,196 --> 01:42:39,831 YOU PROVIDE COHORTS WITH THIS 2996 01:42:39,831 --> 01:42:41,766 PARTICULAR MOLECULAR FLAVOR OF 2997 01:42:41,766 --> 01:42:42,767 DISEASE, CAN YOU PROVIDE COHORTS 2998 01:42:42,767 --> 01:42:45,970 WITH THIS PARTICULAR MUTATION. 2999 01:42:45,970 --> 01:42:47,371 >> OKAY, ANOTHER QUESTION. 3000 01:42:47,371 --> 01:42:50,942 CAN YOU SAY ANYTHING MORE ABOUT 3001 01:42:50,942 --> 01:42:52,343 THE ANIMAL MODELS OF PARKINSON 3002 01:42:52,343 --> 01:42:56,714 DISEASE, AND DO THEY PROVIDE -- 3003 01:42:56,714 --> 01:42:58,049 YOU'VE SPOKEN A LITTLE BIT ABOUT 3004 01:42:58,049 --> 01:42:59,650 ANIMAL MODELS, BUT MAYBE JUST TO 3005 01:42:59,650 --> 01:43:00,751 AMPLIFY A BIT. 3006 01:43:00,751 --> 01:43:04,122 >> I THINK THEY'VE BEEN USEFUL. 3007 01:43:04,122 --> 01:43:07,625 I THINK THE MISTAKE THAT WE'VE 3008 01:43:07,625 --> 01:43:09,594 OFTEN MADE AS A FIELD IS TO TRY 3009 01:43:09,594 --> 01:43:12,230 AND RECAPITULATE THE CLINICAL 3010 01:43:12,230 --> 01:43:13,397 DISEASE RATHER THAN TO USE 3011 01:43:13,397 --> 01:43:15,900 MODELS TO UNDERSTAND THE 3012 01:43:15,900 --> 01:43:16,667 MOLECULAR -- INDIVIDUAL 3013 01:43:16,667 --> 01:43:18,769 MOLECULAR BASIS OF DISEASE. 3014 01:43:18,769 --> 01:43:20,972 I THINK IF WE THINK ABOUT THEM, 3015 01:43:20,972 --> 01:43:21,906 ELLEN TALKED A LITTLE ABOUT THIS 3016 01:43:21,906 --> 01:43:24,075 EARLIER WITH THE 3017 01:43:24,075 --> 01:43:24,675 TRANSMISSIBILITY EXPERIMENTS. 3018 01:43:24,675 --> 01:43:26,911 IF WE THINK ABOUT THEM FOR 3019 01:43:26,911 --> 01:43:28,513 TESTING INDIVIDUAL MECHANISTIC 3020 01:43:28,513 --> 01:43:30,381 IDEAS, THEY'VE BEEN GOOD. 3021 01:43:30,381 --> 01:43:32,450 IF YOU THINK ABOUT THEM TO 3022 01:43:32,450 --> 01:43:33,384 RE-CREATE THE DISEASE AS A 3023 01:43:33,384 --> 01:43:34,719 WHOLE, THEY'VE JUST NOT BEEN 3024 01:43:34,719 --> 01:43:37,688 PARTICULARLY SUCCESSFUL. 3025 01:43:37,688 --> 01:43:38,756 >> ALL RIGHT. 3026 01:43:38,756 --> 01:43:39,857 ANOTHER NEW QUESTION THAT JUST 3027 01:43:39,857 --> 01:43:42,860 CAME IN, THE MICROBIOME. 3028 01:43:42,860 --> 01:43:45,263 ANY DATA WITH REGARD TO THE 3029 01:43:45,263 --> 01:43:46,497 MICROBIOME AND ITS RELATIONSHIP? 3030 01:43:46,497 --> 01:43:47,899 >> IT'S THE HOT TOPIC. 3031 01:43:47,899 --> 01:43:49,834 >> YEAH, IT'S A REALLY EARLY 3032 01:43:49,834 --> 01:43:54,105 FIELD IN PARKINSON'S DISEASE. 3033 01:43:54,105 --> 01:43:55,406 IT'S A REALLY EARLY FIELD. 3034 01:43:55,406 --> 01:43:57,909 I WOULD SAY THAT PRELIMINARY 3035 01:43:57,909 --> 01:44:04,582 WORK FOR MICROBIOME HAS BEEN 3036 01:44:04,582 --> 01:44:05,883 SUPERFICIAL BUT OUT OF NECESSITY 3037 01:44:05,883 --> 01:44:08,819 BECAUSE THAT'S WHERE YOU START, 3038 01:44:08,819 --> 01:44:12,190 SO CHARACTERIZING GROUPS OF 3039 01:44:12,190 --> 01:44:14,158 MICROBIOTA RATHER THAN GOING 3040 01:44:14,158 --> 01:44:15,693 INTO MORE DETAIL. 3041 01:44:15,693 --> 01:44:21,566 THERE IS CERTAINLY A MOVE TO 3042 01:44:21,566 --> 01:44:23,000 CERTAINLY MORE DETAILED WORK IN 3043 01:44:23,000 --> 01:44:24,735 THE MICROBIOME. 3044 01:44:24,735 --> 01:44:26,704 ASAP IS SPOB SOARING A LARGE 3045 01:44:26,704 --> 01:44:27,338 MICROBIOME EFFORT. 3046 01:44:27,338 --> 01:44:29,740 SO A LITTLE CONFOUNDED, BECAUSE 3047 01:44:29,740 --> 01:44:31,676 PARKINSON'S PATIENTS ARE 3048 01:44:31,676 --> 01:44:32,109 CONSTIPATED. 3049 01:44:32,109 --> 01:44:35,313 SO HOW DO YOU CONTROL FOR THAT. 3050 01:44:35,313 --> 01:44:36,747 THEIR MICROBIOME IS PROBABLY 3051 01:44:36,747 --> 01:44:39,183 DIFFERENT BECAUSE OF THE 3052 01:44:39,183 --> 01:44:40,184 CONSTIPATION, AND NOT AS A 3053 01:44:40,184 --> 01:44:41,385 DRIVER OF DISEASE. 3054 01:44:41,385 --> 01:44:43,254 SO CONTROLLING FOR THAT CAN BE A 3055 01:44:43,254 --> 01:44:45,356 LITTLE DIFFICULT. 3056 01:44:45,356 --> 01:44:46,624 >> OKAY. 3057 01:44:46,624 --> 01:44:48,793 ANOTHER QUESTION THAT ACTUALLY 3058 01:44:48,793 --> 01:44:52,430 JUST CAME BY CARRIER PIGEON. 3059 01:44:52,430 --> 01:44:55,600 ASSOCIATION WITH COVID-19. 3060 01:44:55,600 --> 01:44:59,170 >> AHH, YEAH, TOUGH ONE. 3061 01:44:59,170 --> 01:45:01,439 WE DON'T KNOW. 3062 01:45:01,439 --> 01:45:04,742 SO I WOULD SAY THAT WE'VE BEEN 3063 01:45:04,742 --> 01:45:07,645 DOING SOME WORK BROADLY IN 3064 01:45:07,645 --> 01:45:09,080 NEURODEGENERATIVE DISEASE TO 3065 01:45:09,080 --> 01:45:11,148 LOOK AT VIRAL INFECTION AS A 3066 01:45:11,148 --> 01:45:13,951 RISK FACTOR FOR ALZHEIMER'S, 3067 01:45:13,951 --> 01:45:16,787 PARKINSON'S, FRONTOTEMPORAL 3068 01:45:16,787 --> 01:45:17,788 DEMENTIA, AND CERTAINLY WE SEE 3069 01:45:17,788 --> 01:45:19,090 AN ASSOCIATION BETWEEN VERY 3070 01:45:19,090 --> 01:45:20,758 SEVERE INFECTION, SO SEVERE THAT 3071 01:45:20,758 --> 01:45:23,427 YOU HAVE TO BE HOSPITALIZED, AND 3072 01:45:23,427 --> 01:45:24,629 I'M NOT TALKING ABOUT COVID 3073 01:45:24,629 --> 01:45:26,030 HERE, I'M TALKING ABOUT OTHER 3074 01:45:26,030 --> 01:45:27,798 INFECTIONS, AND SUBSEQUENT RISK 3075 01:45:27,798 --> 01:45:29,300 FOR NEURODEGENERATIVE DISEASE, 3076 01:45:29,300 --> 01:45:31,269 10, 15 YEARS DOWN THE LINE. 3077 01:45:31,269 --> 01:45:35,206 I THINK THAT WORK, THERE NEEDS 3078 01:45:35,206 --> 01:45:38,175 TO BE FURTHER ANALYSIS IN THAT 3079 01:45:38,175 --> 01:45:39,910 SPACE, AND AGAIN YOU CAN USE 3080 01:45:39,910 --> 01:45:42,179 BIOBANK DATA TO DO THIS. 3081 01:45:42,179 --> 01:45:43,381 COVID-19, WE DON'T SEE MUCH IN 3082 01:45:43,381 --> 01:45:45,016 TERMS OF GENETIC ASSOCIATION 3083 01:45:45,016 --> 01:45:46,417 BETWEEN THE TWO. 3084 01:45:46,417 --> 01:45:49,920 SO WHEN WE LOOK AT WHAT ARE 3085 01:45:49,920 --> 01:45:52,757 DRIVERS FOR SEVERITY ORIS BEING 3086 01:45:52,757 --> 01:45:54,058 OF COVID-19 AND THOSE FOR 3087 01:45:54,058 --> 01:45:55,693 PARKINSON'S DISEASE, WE DON'T 3088 01:45:55,693 --> 01:45:56,794 REALLY SEE MUCH OVERLAP THERE, 3089 01:45:56,794 --> 01:45:59,397 BUT WHETHER THERE'S GOING TO BE 3090 01:45:59,397 --> 01:46:00,931 ANY INCREASED RISK BECAUSE OF 3091 01:46:00,931 --> 01:46:01,999 COVID-19, I DON'T KNOW, IT'S TOO 3092 01:46:01,999 --> 01:46:04,168 EARLY TO SAY, BUT CERTAINLY 3093 01:46:04,168 --> 01:46:07,805 INTERESTING. 3094 01:46:07,805 --> 01:46:09,106 >> ALL RIGHT. 3095 01:46:09,106 --> 01:46:11,942 ANOTHER QUESTION IS SORT OF 3096 01:46:11,942 --> 01:46:12,677 FOLLOWING UP ON A DISCUSSION 3097 01:46:12,677 --> 01:46:16,847 THAT WE HAD LAST WEEK, IN THE 3098 01:46:16,847 --> 01:46:17,081 SESSION. 3099 01:46:17,081 --> 01:46:20,084 IS THERE ANY RELATIONSHIP 3100 01:46:20,084 --> 01:46:23,587 BETWEEN PRIOR STROKE OR OTHER 3101 01:46:23,587 --> 01:46:25,256 NEUROLOGIC DAMAGING DISEASES 3102 01:46:25,256 --> 01:46:30,261 LIKE MULTIPLE SCLEROSIS AND THE 3103 01:46:30,261 --> 01:46:31,429 DEVELOPMENT OF PARKINSON'S 3104 01:46:31,429 --> 01:46:31,662 DISEASE? 3105 01:46:31,662 --> 01:46:33,597 >> I THINK THERE IS SOMETHING 3106 01:46:33,597 --> 01:46:36,334 CALLED VASCULAR PARKINSONISM. 3107 01:46:36,334 --> 01:46:38,536 I'M NOT SURE THAT THE MECHANISM 3108 01:46:38,536 --> 01:46:41,339 IS THE SAME. 3109 01:46:41,339 --> 01:46:43,307 I THINK THAT'S THE ONLY THING I 3110 01:46:43,307 --> 01:46:45,910 COULD SAY ABOUT THAT. 3111 01:46:45,910 --> 01:46:47,945 >> PRETTY UNRELATED. 3112 01:46:47,945 --> 01:46:50,081 >> SO IT'S A RELATIVELY SMALL 3113 01:46:50,081 --> 01:46:51,816 PERCENTAGE OF PEOPLE THAT 3114 01:46:51,816 --> 01:46:55,753 PRESENT WITH CLINICAL 3115 01:46:55,753 --> 01:46:56,587 PARKINSONISM. 3116 01:46:56,587 --> 01:46:56,987 >> YEP. 3117 01:46:56,987 --> 01:46:58,022 >> OKAY. 3118 01:46:58,022 --> 01:46:59,657 SO THEN WE'RE GETTING TOWARDS 3119 01:46:59,657 --> 01:47:02,059 THE END OF THE LIST OF QUESTIONS 3120 01:47:02,059 --> 01:47:03,728 HERE FROM THE AUDIENCE. 3121 01:47:03,728 --> 01:47:07,531 YOU MENTIONED PROTEOSTASIS. 3122 01:47:07,531 --> 01:47:10,368 ARE THERE ANY DATA WITH REGARD 3123 01:47:10,368 --> 01:47:15,272 TO PATIENTS THAT ARE ON 3124 01:47:15,272 --> 01:47:16,507 PROTEOSOME INHIBITORS, FOR 3125 01:47:16,507 --> 01:47:17,274 EXAMPLE, AND WHETHER OR NOT THEY 3126 01:47:17,274 --> 01:47:18,976 DEVELOP THE CLINICAL PICTURE OF 3127 01:47:18,976 --> 01:47:20,644 PARKINSONISM? 3128 01:47:20,644 --> 01:47:25,015 >> I DON'T KNOW OF ANY DATA. 3129 01:47:25,015 --> 01:47:25,750 >> ALL RIGHT. 3130 01:47:25,750 --> 01:47:26,851 WELL, MORE QUESTIONS. 3131 01:47:26,851 --> 01:47:27,718 OH, BOY. 3132 01:47:27,718 --> 01:47:28,819 IN THE BACK. 3133 01:47:28,819 --> 01:47:31,422 YES, I'D NEED A MIRROR SO THAT I 3134 01:47:31,422 --> 01:47:32,523 CAN SEE IN THE BACK. 3135 01:47:32,523 --> 01:47:33,157 >> SORRY. 3136 01:47:33,157 --> 01:47:34,558 I HOPE IT'S OKAY THAT I JUST 3137 01:47:34,558 --> 01:47:36,127 GRABBED THE MIC. 3138 01:47:36,127 --> 01:47:36,660 >> IT GREAT. 3139 01:47:36,660 --> 01:47:37,495 >> OKAY. 3140 01:47:37,495 --> 01:47:41,031 I JUST HAD A QUESTION REGARDING 3141 01:47:41,031 --> 01:47:42,433 GAUCHER AND THE DIFFERENT TYPES 3142 01:47:42,433 --> 01:47:43,868 AND THE AMOUNT OF NEUROPATHOLOGY 3143 01:47:43,868 --> 01:47:45,569 THAT YOU SEE. 3144 01:47:45,569 --> 01:47:47,538 DO YOU BELIEVE THAT HAS TO DO 3145 01:47:47,538 --> 01:47:49,740 WITH SOMATIC MOSAICISM AND THE 3146 01:47:49,740 --> 01:47:52,309 AMOUNT OF NEURAL LYSOSOMES 3147 01:47:52,309 --> 01:47:53,944 AFFECTED OR NEUROINFLAMMATION? 3148 01:47:53,944 --> 01:47:55,379 DO YOU HAVE ANY IDEAS WITH 3149 01:47:55,379 --> 01:47:59,683 REGARDS TO WHAT SEPARATES -- 3150 01:47:59,683 --> 01:48:00,818 >> I WISH I DID. 3151 01:48:00,818 --> 01:48:02,920 I THINK IT'S MOST LIKELY THAT -- 3152 01:48:02,920 --> 01:48:04,522 FIRST OF ALL, THE INITIATIONS DO 3153 01:48:04,522 --> 01:48:05,689 HAVE SOME IMPACT. 3154 01:48:05,689 --> 01:48:07,358 THERE'S SOME MUTATIONS. 3155 01:48:07,358 --> 01:48:10,194 IF YOU HAVE TWO NULL MUTATIONS 3156 01:48:10,194 --> 01:48:15,199 YOU PROBABLY WILL HAVE THE ACUTE 3157 01:48:15,199 --> 01:48:21,205 NEURONEURONOPA THICK FORM. 3158 01:48:21,205 --> 01:48:22,373 IT IS DIFFICULT TO SEE, THERE IS 3159 01:48:22,373 --> 01:48:24,074 A LOT OF NEUROINFLAMMATION IN 3160 01:48:24,074 --> 01:48:26,644 THE BRAIN OF NEURONOPA THICK 3161 01:48:26,644 --> 01:48:27,211 GAUCHER DISEASE. 3162 01:48:27,211 --> 01:48:28,612 WE THINK THAT IT'S PROBABLY SOME 3163 01:48:28,612 --> 01:48:30,581 KIND OF GENETIC MODIFIERS THAT 3164 01:48:30,581 --> 01:48:35,519 WE JUST HAVEN'T YET IDENTIFIED. 3165 01:48:35,519 --> 01:48:37,254 THERE'S PROBABLY MANY OTHER 3166 01:48:37,254 --> 01:48:39,223 GENES THAT WORK IN CONCERT. 3167 01:48:39,223 --> 01:48:40,524 >> THANK YOU. 3168 01:48:40,524 --> 01:48:44,895 >> WE CERTAINLY KNOW THAT IF YOU 3169 01:48:44,895 --> 01:48:46,730 TAKE THE POLYGENIC RISK SCORE 3170 01:48:46,730 --> 01:48:48,032 FOR JUST TYPICAL PARKINSON'S 3171 01:48:48,032 --> 01:48:50,468 DISEASE AND YOU OVERLAY THAT ON 3172 01:48:50,468 --> 01:48:52,102 A GAUCHER'S MUTATION, IT 3173 01:48:52,102 --> 01:48:54,038 INCREASES YOUR RISK OF 3174 01:48:54,038 --> 01:48:54,905 PARKINSON'S DISEASE OR 3175 01:48:54,905 --> 01:48:58,409 PARKINSON'S PATHOLOGY IN THOSE 3176 01:48:58,409 --> 01:48:58,843 CARRIERS. 3177 01:48:58,843 --> 01:49:01,545 SO CERTAINLY MECHANISTICALLY, 3178 01:49:01,545 --> 01:49:05,316 THOSE ARE LINKED. 3179 01:49:05,316 --> 01:49:08,686 >> SO ANCIENT HISTORY, I MEAN, 3180 01:49:08,686 --> 01:49:11,956 FOLLOWING THE GREAT PANDEMIC OF 3181 01:49:11,956 --> 01:49:13,557 INFLUENZA, THERE WAS SOMETHING 3182 01:49:13,557 --> 01:49:16,861 KNOWN AS POST INFLUENZAL 3183 01:49:16,861 --> 01:49:18,295 PARKINSON'S DISEASE, WHICH 3184 01:49:18,295 --> 01:49:21,332 SEEMED TO ATTRACT A GOOD BIT OF 3185 01:49:21,332 --> 01:49:22,967 ATTENTION FOR A LARGE NUMBER OF 3186 01:49:22,967 --> 01:49:25,469 YEARS, AND THEN WAS SORT OF PUT 3187 01:49:25,469 --> 01:49:26,804 TO REST. 3188 01:49:26,804 --> 01:49:29,373 I THINK LARGELY BY EPIDEMIOLOGIC 3189 01:49:29,373 --> 01:49:31,675 STUDIES BUT I'M NOT SURE. 3190 01:49:31,675 --> 01:49:35,246 BUT IN VIEW OF YOUR FINDINGS OF 3191 01:49:35,246 --> 01:49:39,416 RISK FACTORS AND WHAT NOT, IS IT 3192 01:49:39,416 --> 01:49:41,051 CONCEIVABLE THAT SOME OF THAT 3193 01:49:41,051 --> 01:49:43,454 INFORMATION CAN BE RE-EXAMINED 3194 01:49:43,454 --> 01:49:45,956 TO EXAMINE THE POSSIBILITY THAT 3195 01:49:45,956 --> 01:49:48,125 THOSE WHO WERE AFFECTED -- I 3196 01:49:48,125 --> 01:49:50,528 MEAN, OBVIOUSLY YOU DON'T HAVE 3197 01:49:50,528 --> 01:49:56,934 THE TISSUES -- DR. TAUBENBERGER 3198 01:49:56,934 --> 01:49:58,068 HAS TISSUES FROM SOME OF THOSE 3199 01:49:58,068 --> 01:49:59,904 PATIENTS BUT NOT THE 3200 01:49:59,904 --> 01:50:00,204 PARKINSON'S. 3201 01:50:00,204 --> 01:50:01,639 >> YEAH, IT WOULD BE GREAT TO BE 3202 01:50:01,639 --> 01:50:04,808 ABLE TO ACCESS GENETIC MATERIAL. 3203 01:50:04,808 --> 01:50:06,310 SO THAT AS FAR AS I UNDERSTAND 3204 01:50:06,310 --> 01:50:12,016 IT WAS A TAUOPATHIES RATHER THAN 3205 01:50:12,016 --> 01:50:14,318 A SI SYNUCLEINOPATHY. 3206 01:50:14,318 --> 01:50:15,619 ONE OF THE THINGS WE DIDN'T TALK 3207 01:50:15,619 --> 01:50:18,489 ABOUT TODAY WAS LRRK2 PATIENTS, 3208 01:50:18,489 --> 01:50:21,158 SO PATIENTS WHO CARRY A 3209 01:50:21,158 --> 01:50:22,026 LRRK2 MUTATION, WHILE THEY MAY 3210 01:50:22,026 --> 01:50:24,228 LOOK CLINICALLY LIKE THEY'RE 3211 01:50:24,228 --> 01:50:25,195 PARKINSON'S DISEASE, ONLY ABOUT 3212 01:50:25,195 --> 01:50:27,164 70% OF THEM HAVE A 3213 01:50:27,164 --> 01:50:27,531 SYNUCLEINOPATHY. 3214 01:50:27,531 --> 01:50:29,466 SOME OF THEM HAVE A TAUOPATHY, 3215 01:50:29,466 --> 01:50:30,868 SOME HAVE SOME OTHER TYPE OF 3216 01:50:30,868 --> 01:50:31,302 PATHOLOGY. 3217 01:50:31,302 --> 01:50:33,571 SO MORE BROADLY UNDERSTANDING 3218 01:50:33,571 --> 01:50:36,740 WHAT TRIEFS THESE DIFFERENT DRIT 3219 01:50:36,740 --> 01:50:38,208 PATHOLOGIES, THE DIFFERENCE 3220 01:50:38,208 --> 01:50:42,079 BETWEEN SOMEONE WHO HAS A TD 3221 01:50:42,079 --> 01:50:43,480 TDB40OPATHY OR -- IS REALLY 3222 01:50:43,480 --> 01:50:44,582 FASCINATING. 3223 01:50:44,582 --> 01:50:47,184 THE POST ENCEPHALITIS 3224 01:50:47,184 --> 01:50:48,252 PARKINSONISM WOULD BE A REALLY 3225 01:50:48,252 --> 01:50:49,153 INTERESTING PLACE TO LOOK. 3226 01:50:49,153 --> 01:50:50,020 >> ALL RIGHT. 3227 01:50:50,020 --> 01:50:51,989 WELL, THE QUESTIONS JUST KEEP 3228 01:50:51,989 --> 01:50:54,058 FLOWING IN. 3229 01:50:54,058 --> 01:50:57,361 SO WE NOW HAVE A QUESTION WITH 3230 01:50:57,361 --> 01:51:00,831 REGARD TO THE ENDOCRINE SYSTEM 3231 01:51:00,831 --> 01:51:03,434 AND WHETHER OR NOT THERE ARE 3232 01:51:03,434 --> 01:51:06,737 AGE-RELATED CHANGES IN HORMONAL 3233 01:51:06,737 --> 01:51:09,573 FUNCTION SUCH AS HYPOTHYROIDISM 3234 01:51:09,573 --> 01:51:12,009 AND THE RISK FOR DEVELOPING 3235 01:51:12,009 --> 01:51:13,177 PARKINSON DISEASE. 3236 01:51:13,177 --> 01:51:14,712 >> THAT'S ALL YOU, ELLEN. 3237 01:51:14,712 --> 01:51:17,147 >> I DON'T KNOW ANYTHING OF IT. 3238 01:51:17,147 --> 01:51:18,148 >> YEAH, I DON'T KNOW. 3239 01:51:18,148 --> 01:51:20,117 >> WE HAVE STUMPED THE SPEAKERS 3240 01:51:20,117 --> 01:51:20,784 HERE. 3241 01:51:20,784 --> 01:51:22,319 OKAY. 3242 01:51:22,319 --> 01:51:24,688 WELL, THERE'S YET ANOTHER ONE. 3243 01:51:24,688 --> 01:51:26,023 THAT JUST CAME IN. 3244 01:51:26,023 --> 01:51:28,859 WHAT ABOUT THE MECHANISM OF 3245 01:51:28,859 --> 01:51:31,895 PARKINSON PLUS SYNDROMES, LIKE 3246 01:51:31,895 --> 01:51:33,230 PSP, CBD? 3247 01:51:33,230 --> 01:51:35,499 >> YEAH, SO CORTICOBASAL 3248 01:51:35,499 --> 01:51:37,901 SYNDROME, PROGRESS OF 3249 01:51:37,901 --> 01:51:39,670 SUPERNUCLEAR PALSY, MULTIPLE 3250 01:51:39,670 --> 01:51:42,706 CYST TOM ATROPHY AND OTHER 3251 01:51:42,706 --> 01:51:43,307 SYNUCLEINOPATHY. 3252 01:51:43,307 --> 01:51:44,341 THESE TEND TO HAVE DIFFERENT 3253 01:51:44,341 --> 01:51:45,542 PATHOLOGIES. 3254 01:51:45,542 --> 01:51:48,078 MSA IS A SYNUCLEINOPATHY LIKE 3255 01:51:48,078 --> 01:51:49,179 PARKINSON'S DISEASE BUT IT 3256 01:51:49,179 --> 01:51:50,247 ACCUMULATES NOT IN NEURONS BUT 3257 01:51:50,247 --> 01:51:53,183 IN GLIA. 3258 01:51:53,183 --> 01:51:59,256 PROGRESSIVE SUPERVISORNUCLEAR SR 3259 01:51:59,256 --> 01:52:01,825 NUCLEAR PALSY IS A TAUOPATHY. 3260 01:52:01,825 --> 01:52:02,926 WE'RE ANALYZING ALL OF THESE TO 3261 01:52:02,926 --> 01:52:04,662 LOOK FOR COMMONALITIES AND 3262 01:52:04,662 --> 01:52:06,296 DIFFERENCES IN THEIR GENETIC 3263 01:52:06,296 --> 01:52:06,864 ARCHITECTURE. 3264 01:52:06,864 --> 01:52:07,598 PART OF THEIR CHALLENGE IS 3265 01:52:07,598 --> 01:52:09,133 THEY'RE VERY, VERY RARE SO IT'S 3266 01:52:09,133 --> 01:52:10,200 HARD TO COLLECT ENOUGH SAMPLES 3267 01:52:10,200 --> 01:52:13,504 TO MAKE GOOD GENETIC INFERENCES. 3268 01:52:13,504 --> 01:52:15,339 BUT CERTAINLY UNDERSTANDING 3269 01:52:15,339 --> 01:52:16,440 WHAT'S DIFFERENT AND THE LIKE 3270 01:52:16,440 --> 01:52:19,276 BETWEEN ALL OF THESE DEEDS, I 3271 01:52:19,276 --> 01:52:20,911 THINK IS A CENTRAL AIM OF WHAT 3272 01:52:20,911 --> 01:52:21,478 WE'RE TRYING TO DO. 3273 01:52:21,478 --> 01:52:22,346 >> ALL RIGHT. 3274 01:52:22,346 --> 01:52:22,880 WELL, LET'S SEE. 3275 01:52:22,880 --> 01:52:25,616 ARE THERE ANY OTHER QUESTIONS 3276 01:52:25,616 --> 01:52:26,316 HERE? 3277 01:52:26,316 --> 01:52:28,218 I GUESS NOT, SO WE'RE ACTUALLY 3278 01:52:28,218 --> 01:52:31,622 JUST A LITTLE BIT AHEAD OF 6:00, 3279 01:52:31,622 --> 01:52:35,325 BUT I THINK THAT WE'LL CALL TO A 3280 01:52:35,325 --> 01:52:35,526 CLOSE. 3281 01:52:35,526 --> 01:52:37,461 THANK YOU GUYS VERY, VERY MUCH. 3282 01:52:37,461 --> 01:52:39,730 THIS WAS REALLY SPECTACULAR. 3283 01:52:39,730 --> 01:52:40,698 [APPLAUSE] 3284 01:52:40,698 --> 01:52:42,066 SO ANYWAY. 3285 01:52:42,066 --> 01:52:43,033 WE REALLY APPRECIATE IT. 3286 01:52:43,033 --> 01:52:53,277 >> THANK YOU.