1 00:00:05,138 --> 00:00:06,840 IN THE INTEREST OF TIME, WE 2 00:00:06,840 --> 00:00:10,444 THOUGHT WE'D GO AHEAD AND START. 3 00:00:10,444 --> 00:00:13,881 AND IT'S MY ABSOLUTE PLEASURE TO 4 00:00:13,881 --> 00:00:15,682 BE ABLE TO INTRODUCE I'M 5 00:00:15,682 --> 00:00:19,219 CHRISTINA ABRAHAM FROM THE 6 00:00:19,219 --> 00:00:19,853 NATIONAL INSTITUTE OF DIABETES 7 00:00:19,853 --> 00:00:20,387 AND DIGESTIVE AND KIDNEY 8 00:00:20,387 --> 00:00:22,089 DISEASES AND I'M THRILLED TO BE 9 00:00:22,089 --> 00:00:24,458 ABLE TO INTRODUCE DR. GRIF 10 00:00:24,458 --> 00:00:26,326 RODGERS OR INSTITUTE DIRECTOR 11 00:00:26,326 --> 00:00:29,029 AND HAS BEEN THE INSTITUTE 12 00:00:29,029 --> 00:00:30,430 DIRECTOR SINCE 2007. 13 00:00:30,430 --> 00:00:32,399 SO, NEARLY NOT QUITE BUT NEARLY 14 00:00:32,399 --> 00:00:35,035 ALL OF MY TENURE AT NIDDK HAS 15 00:00:35,035 --> 00:00:37,871 WITHIN UNDER GRIFFIN. 16 00:00:37,871 --> 00:00:40,407 HE'S BEEN VERY SUPPORTIVE OF 17 00:00:40,407 --> 00:00:42,442 TYPE I RESEARCH, DIABETES 18 00:00:42,442 --> 00:00:46,446 RESEARCH IN GENERAL AND THE 19 00:00:46,446 --> 00:00:47,247 HERN. 20 00:00:47,247 --> 00:00:48,282 HE WAS GRACIOUS ENOUGH TO RETURN 21 00:00:48,282 --> 00:00:50,450 AND GIVE US OPENING REMARK SO, 22 00:00:50,450 --> 00:00:52,519 GRIF. 23 00:00:52,519 --> 00:01:02,462 [APPLAUSE] 24 00:01:02,462 --> 00:01:06,466 >> 25 00:01:06,466 --> 00:01:08,302 >> THANKS SO MUCH FOR THE KIND 26 00:01:08,302 --> 00:01:12,639 INTRODUCTION. 27 00:01:12,639 --> 00:01:14,641 GOOD MORNING TO YOU ALL AND ON 28 00:01:14,641 --> 00:01:17,978 BEHALF OF NIDDK I WANT IT 29 00:01:17,978 --> 00:01:19,379 WELCOME TO YOU THE 10th 30 00:01:19,379 --> 00:01:20,747 ANNIVERSARY SYMPOSIUM. 31 00:01:20,747 --> 00:01:25,352 IT'S GREAT TO SEE SO MANY PEOPLE 32 00:01:25,352 --> 00:01:27,187 HERE TO CELEBRATE HERN'S 33 00:01:27,187 --> 00:01:28,188 ACCOMPLISHMENTS AND DISCUSS 34 00:01:28,188 --> 00:01:28,989 EXCITING OPPORTUNITIES IN THE 35 00:01:28,989 --> 00:01:31,825 RESEARCH YOU ALL DO. 36 00:01:31,825 --> 00:01:35,929 I'M HAPPY TO REPORT THAT L.A. 37 00:01:35,929 --> 00:01:38,899 PLANS TO HIGHLIGHT HERN IN AN 38 00:01:38,899 --> 00:01:40,867 UPCOMING ANNUAL REPORT. 39 00:01:40,867 --> 00:01:44,504 THAT WILL BE POSTED ON OUR 40 00:01:44,504 --> 00:01:46,373 WEBSITE LATE JANUARY AS WE'RE 41 00:01:46,373 --> 00:01:50,010 EXTREMELY PROUD OF ALL OF ITS 42 00:01:50,010 --> 00:01:50,377 ACCOMPLISHMENTS. 43 00:01:50,377 --> 00:01:54,181 LET ME FIRST START BY NOTING 44 00:01:54,181 --> 00:01:56,016 NIDDK IS CELEBRATING ITS 45 00:01:56,016 --> 00:01:57,384 ANNIVERSARY THIS YEAR. 46 00:01:57,384 --> 00:01:59,653 THIS YEAR WILL MARK THE 75th 47 00:01:59,653 --> 00:02:00,721 ANNIVERSARY OF THE INSTITUTE AND 48 00:02:00,721 --> 00:02:04,691 AS WE LOOK FORWARD PARTICULARLY 49 00:02:04,691 --> 00:02:06,526 DURING ANY TIME OF TRANSITION, I 50 00:02:06,526 --> 00:02:09,363 CAN ENSURE YOU THAT NIDDK WILL 51 00:02:09,363 --> 00:02:11,465 REMAIN COMMITTED TO SUPPORTING 52 00:02:11,465 --> 00:02:13,834 THE BEST SCIENCE JUST AS WE HAVE 53 00:02:13,834 --> 00:02:15,802 FOR THE LAST 75 YEARS. 54 00:02:15,802 --> 00:02:20,440 WE PLAN TO KEEP A FOCUS ON 55 00:02:20,440 --> 00:02:22,476 SCIENCE, CONTINUE TO ACHIEVE 56 00:02:22,476 --> 00:02:23,410 SIGNIFICANT RESEARCH PROGRESS 57 00:02:23,410 --> 00:02:26,513 THROUGH HERN AND OUR OTHER 58 00:02:26,513 --> 00:02:29,750 EFFORTS AND CONTINUE TRANSLATING 59 00:02:29,750 --> 00:02:32,386 THAT PROGRESS INTO IMPROVING THE 60 00:02:32,386 --> 00:02:42,763 HEALTH OF ALL PEOPLE. 61 00:02:44,831 --> 00:02:48,668 AS WE'RE HERE TO CELEBRATE THE 62 00:02:48,668 --> 00:02:51,438 10th ANNIVERSARY OF HIRN IT'S 63 00:02:51,438 --> 00:02:53,740 PART OF THE NIDDK DIABETES 64 00:02:53,740 --> 00:02:56,009 RESEARCH PORTFOLIO. 65 00:02:56,009 --> 00:02:57,010 THIS SHOWS SEVERAL DIFFERENT 66 00:02:57,010 --> 00:02:59,112 LONG-TERM COLLABORATIVE 67 00:02:59,112 --> 00:03:01,948 CONSORTIA INCLUDING HIRN MADE 68 00:03:01,948 --> 00:03:03,283 POSSIBLE BY THE SPECIAL DIABETES 69 00:03:03,283 --> 00:03:03,517 PROGRAM. 70 00:03:03,517 --> 00:03:07,120 THESE ARE TACKLING ALL STAGES OF 71 00:03:07,120 --> 00:03:09,256 TYPE I FROM EARLY STAGE DISEASE 72 00:03:09,256 --> 00:03:11,925 THROUGH ITS COMPLICATIONS. 73 00:03:11,925 --> 00:03:14,995 AND SOME OF THESE PROGRAMS LIKE 74 00:03:14,995 --> 00:03:20,100 THE TYPE I DIABETES TRIAL NET 75 00:03:20,100 --> 00:03:29,543 AND T TEDDY AND OTHER UNMET 76 00:03:29,543 --> 00:03:29,743 NEEDS. 77 00:03:29,743 --> 00:03:31,678 TYPE I TRIAL NET AND TEDDY HAVE 78 00:03:31,678 --> 00:03:33,647 BEEN GOING ON OR DECADES AND 79 00:03:33,647 --> 00:03:35,916 OTHER AREAS ARE MORE RECENT 80 00:03:35,916 --> 00:03:37,984 INCLUDING THOSE THAT ARE 81 00:03:37,984 --> 00:03:42,889 ADDRESSING UNMET NEEDS IN TYPE I 82 00:03:42,889 --> 00:03:43,723 DIABETES. 83 00:03:43,723 --> 00:03:45,125 SUCH AS NEUROCOGNITIVE 84 00:03:45,125 --> 00:03:46,927 COMPLICATIONS AND CARDIOVASCULAR 85 00:03:46,927 --> 00:03:49,629 DISEASE IN TYPE I DIABETES. 86 00:03:49,629 --> 00:03:51,932 THEY'RE ALL ADDRESSING KEY AREAS 87 00:03:51,932 --> 00:03:53,333 TO ADDRESS PROGRESS IN TYPE I 88 00:03:53,333 --> 00:03:54,534 DIABETES RESEARCH AND IMPROVE 89 00:03:54,534 --> 00:03:55,335 THE LIVES OF INDIVIDUALS WITH 90 00:03:55,335 --> 00:04:01,208 THE DISEASE. 91 00:04:01,208 --> 00:04:09,683 NOW, TODAY'S SYMPOSIA LOOKS BACK 92 00:04:09,683 --> 00:04:13,186 AT HOW IT STARTED. 93 00:04:13,186 --> 00:04:18,158 THE PREDECESSOR OF HIRN WAS BCBC 94 00:04:18,158 --> 00:04:20,160 ANOTHER EXTREMELY SUCCESSFUL 95 00:04:20,160 --> 00:04:20,393 EFFORT. 96 00:04:20,393 --> 00:04:27,467 AS NIDDK WAS LOOKING TO BUILD ON 97 00:04:27,467 --> 00:04:29,436 BCCC'S SUCCESS, THERE WERE A FEW 98 00:04:29,436 --> 00:04:32,939 KEY GOALS THAT WERE SET UP. 99 00:04:32,939 --> 00:04:35,242 FIRST, WAS TO BUILD A RESEARCH 100 00:04:35,242 --> 00:04:38,578 EFFORT THAT WOULD FOCUS ON HUMAN 101 00:04:38,578 --> 00:04:39,212 DISEASE. 102 00:04:39,212 --> 00:04:40,814 AT A TIME WHEN MOST OF OUR 103 00:04:40,814 --> 00:04:43,049 KNOWLEDGE ABOUT WHAT WAS 104 00:04:43,049 --> 00:04:44,951 HAPPENING IN THE PANCREAS, AT 105 00:04:44,951 --> 00:04:46,753 THE TISSUE AND CELLULAR AND 106 00:04:46,753 --> 00:04:48,788 MOLECULAR LEVELS WAS GATHERED 107 00:04:48,788 --> 00:04:52,425 FROM RODENT MODELS OF DIABETES. 108 00:04:52,425 --> 00:04:55,562 SECOND, NIDDK WANTED TO CREATE A 109 00:04:55,562 --> 00:04:57,430 COLLABORATIVE NIMBLE STRUCTURE 110 00:04:57,430 --> 00:05:00,934 THAT ORIGINAL STRUCTURE IS SHOWN 111 00:05:00,934 --> 00:05:01,468 HERE. 112 00:05:01,468 --> 00:05:05,138 WE DECIDED TO ORGANIZE HIRN AS 113 00:05:05,138 --> 00:05:07,574 AN INDIVIDUAL CONSORTIUM WITH 114 00:05:07,574 --> 00:05:10,076 THEIR OWN SCIENTIFIC MISSION. 115 00:05:10,076 --> 00:05:15,015 THIS MODULAR STRUCTURE WOULD 116 00:05:15,015 --> 00:05:19,252 ALLOW COLLABORATIONS WITHIN 117 00:05:19,252 --> 00:05:22,422 THESE CONSORTIUM AND ALLOW IT TO 118 00:05:22,422 --> 00:05:23,490 EVOLVE OVER TIME. 119 00:05:23,490 --> 00:05:25,492 IT WAS SEEN SOME WOULD END AS 120 00:05:25,492 --> 00:05:28,495 RESEARCH GOALS WERE MET AND NEW 121 00:05:28,495 --> 00:05:29,129 CONSORTIA WOULD FORM AS NOVEL 122 00:05:29,129 --> 00:05:32,065 OPPORTUNITIES AROSE. 123 00:05:32,065 --> 00:05:35,101 AND IN ANOTHER KEY GOAL IN 124 00:05:35,101 --> 00:05:40,207 ESTABLISHING HIRN WAS TO BOLSTER 125 00:05:40,207 --> 00:05:42,342 THE INTERACTION BETWEEN BETA 126 00:05:42,342 --> 00:05:45,712 CELL BIOLOGISTS AND 127 00:05:45,712 --> 00:05:46,980 IMMUNOLOGISTS RECOGNIZING THAT 128 00:05:46,980 --> 00:05:49,516 ADDRESSING AUTO IMMUNITY WAS 129 00:05:49,516 --> 00:05:50,283 CRITICAL TO HIRN'S SCIENTIFIC 130 00:05:50,283 --> 00:05:54,354 GOALS OF PROTECTING OR REPLACING 131 00:05:54,354 --> 00:05:56,456 BETA CELLS FROM PEOPLE WITH TYPE 132 00:05:56,456 --> 00:05:58,992 I DIABETES AND IMMUNOLOGISTS 133 00:05:58,992 --> 00:06:03,797 HAVE BEEN CRITICAL CONTRIBUTORS 134 00:06:03,797 --> 00:06:09,502 TO HIRN AS HAVE THE NUMBER OF 135 00:06:09,502 --> 00:06:11,037 MULTI-DISCIPLINARY PARTICIPANTS. 136 00:06:11,037 --> 00:06:12,806 THEY FOUNDED THE CONSORTIUM 137 00:06:12,806 --> 00:06:15,575 SHOWN HERE AND THE ENHANCEMENT 138 00:06:15,575 --> 00:06:17,143 CENTERS THAT COORDINATE NETWORK 139 00:06:17,143 --> 00:06:21,114 OPERATIONS. 140 00:06:21,114 --> 00:06:25,752 IN 2016 HIRN WAS EXPANDED WITH 141 00:06:25,752 --> 00:06:26,953 THE ADDITION OF LARGE DATA 142 00:06:26,953 --> 00:06:29,489 GENERATION PROGRAM CALLED THE 143 00:06:29,489 --> 00:06:35,428 HUMAN PANCREAS PROGRAM OR HPAP 144 00:06:35,428 --> 00:06:37,998 T1D WITH PERFORMING THE DEEP 145 00:06:37,998 --> 00:06:39,633 FUNCTIONAL AND MOLECULAR 146 00:06:39,633 --> 00:06:41,901 PHENOTYPING OF HUMAN PANCREATIC 147 00:06:41,901 --> 00:06:42,736 TISSUES FROM DISEASE DONORS. 148 00:06:42,736 --> 00:06:45,472 AND THE SHARING OF THE RELATED 149 00:06:45,472 --> 00:06:48,275 DATA SETS WITH THE SCIENTIFIC 150 00:06:48,275 --> 00:06:49,376 COMMUNITY WITHOUT ANY STRINGS 151 00:06:49,376 --> 00:06:50,443 ATTACHED. 152 00:06:50,443 --> 00:06:52,979 THIS WAS FOLLOWED IN 2018 BY THE 153 00:06:52,979 --> 00:06:57,350 CREATION OF THE HUMAN PANCREAS 154 00:06:57,350 --> 00:06:58,585 ANALYSIS CONSORTIUM IN 2019 BY 155 00:06:58,585 --> 00:07:04,157 AN EXPANSION OF THE SCOPE OF 156 00:07:04,157 --> 00:07:07,460 HPAP TO PHENOTYPING FROM DONORS 157 00:07:07,460 --> 00:07:15,135 WITH TYPE II DIABETES. 158 00:07:15,135 --> 00:07:18,338 IN 2024 TO TAKE ADVANTAGE OF THE 159 00:07:18,338 --> 00:07:19,606 RAPID DEVELOPMENT OF 160 00:07:19,606 --> 00:07:22,442 COMPUTATIONAL ANALYSIS IN LARGE 161 00:07:22,442 --> 00:07:23,009 DATA SETS AND ARTIFICIAL 162 00:07:23,009 --> 00:07:26,613 INTELLIGENCE TOOLS, THE 163 00:07:26,613 --> 00:07:29,916 KNOWLEDGE BASE KNOWN AS PANC 164 00:07:29,916 --> 00:07:32,419 BASE WAS CREATED TO HELP THE 165 00:07:32,419 --> 00:07:36,990 SCIENTIFIC COMMUNITY TO ACCESS 166 00:07:36,990 --> 00:07:38,458 THE RELEVANT DATA SETS AS WELL 167 00:07:38,458 --> 00:07:42,429 AS A NEW CONSORTIUM ON MODELLING 168 00:07:42,429 --> 00:07:44,197 AUTO IMMUNE DIABETES. 169 00:07:44,197 --> 00:07:46,800 SO AS ENVISIONED FROM THE 170 00:07:46,800 --> 00:07:50,437 OUTSET, HIRN CONTINUES TO EVOLVE 171 00:07:50,437 --> 00:07:52,038 IT EMERGING CONSORTIA AND 172 00:07:52,038 --> 00:07:55,542 BUILDING ON A THE NETWORK'S 173 00:07:55,542 --> 00:07:56,576 TREMENDOUS SUCCESSES AND 174 00:07:56,576 --> 00:07:57,944 CAPITALIZE ON NEW RESEARCH 175 00:07:57,944 --> 00:07:59,479 OPPORTUNITIES. 176 00:07:59,479 --> 00:08:01,081 HIRN'S OUTSTANDING SCIENTIFIC 177 00:08:01,081 --> 00:08:02,782 TALENT ALONG WITH ITS NIMBLE 178 00:08:02,782 --> 00:08:05,118 STRUCTURE HAVE BEEN CRITICAL FOR 179 00:08:05,118 --> 00:08:10,623 THE NETWORKS ACCOMPLISHMENTS. 180 00:08:10,623 --> 00:08:14,761 I'LL MENTION JUST A FEW OF THE 181 00:08:14,761 --> 00:08:15,862 ACCOMPLISHMENTS IT LITERALLY 182 00:08:15,862 --> 00:08:21,034 WOULD TAKE ALL TWO DAYS OF THE 183 00:08:21,034 --> 00:08:22,402 SYMPOSIA TO MENTION ALL SO I'LL 184 00:08:22,402 --> 00:08:23,737 GIVE A FEW EXAMPLES. 185 00:08:23,737 --> 00:08:26,473 HIRN PUBLISHED OVER 1,000 PAPERS 186 00:08:26,473 --> 00:08:29,876 AND PUBLISHED ABOUT 100 NEW 187 00:08:29,876 --> 00:08:32,746 PAPERS EACH YEAR UNDER SCORING 188 00:08:32,746 --> 00:08:35,081 ITS ROBUST SCIENTIFIC 189 00:08:35,081 --> 00:08:35,415 PRODUCTIVITY. 190 00:08:35,415 --> 00:08:36,983 SOME OF THAT PRODUCT IS 191 00:08:36,983 --> 00:08:38,451 HIGHLIGHTED HERE INCLUDING 192 00:08:38,451 --> 00:08:43,456 HIRN'S CONTRIBUTED NEW INSIGHT 193 00:08:43,456 --> 00:08:46,059 INTO THE TYPE I DIABETES DISEASE 194 00:08:46,059 --> 00:08:46,960 PROCESS IDENTIFIED POTENTIAL 195 00:08:46,960 --> 00:08:48,094 THERAPEUTIC TARGETS SOME OF 196 00:08:48,094 --> 00:08:51,798 WHICH HAVE BEEN TARGETS IN 197 00:08:51,798 --> 00:08:54,934 CLINICAL TRIALS, DEVELOPED NEW 198 00:08:54,934 --> 00:08:56,302 MODELS OF TYPE I DIABETES 199 00:08:56,302 --> 00:08:58,505 FACILITATING NOVEL STUDIES OF 200 00:08:58,505 --> 00:09:00,740 DISEASE PATHOPHYSIOLOGY AND 201 00:09:00,740 --> 00:09:02,275 SERVING AS PLATFORMS FOR 202 00:09:02,275 --> 00:09:05,011 PRE-CLINICAL TESTING OF NEW 203 00:09:05,011 --> 00:09:05,278 THERAPIES. 204 00:09:05,278 --> 00:09:07,514 IT'S CREATED RESOURCES THAT ARE 205 00:09:07,514 --> 00:09:11,284 BEING USED BY THE BROADER 206 00:09:11,284 --> 00:09:12,419 SCIENTIFIC COMMUNITY AND MANY 207 00:09:12,419 --> 00:09:15,321 MANY MORE. 208 00:09:15,321 --> 00:09:17,924 ANOTHER IMPORTANT ACCOMPLISHMENT 209 00:09:17,924 --> 00:09:20,226 AND LONG LASTING LEGACY OF HIRN 210 00:09:20,226 --> 00:09:21,795 THE NETWORK DEVELOPED INNOVATIVE 211 00:09:21,795 --> 00:09:23,229 WAYS TO PROMOTE CAREER 212 00:09:23,229 --> 00:09:25,832 DEVELOPMENT WHICH IS A PRIORITY 213 00:09:25,832 --> 00:09:28,968 AREA OF NIDDK'S STRATEGIC PLAN. 214 00:09:28,968 --> 00:09:32,372 AND TO ENGAGE WITH EARLY STAGE 215 00:09:32,372 --> 00:09:34,441 INVESTIGATORS SUCH AS THROUGH 216 00:09:34,441 --> 00:09:37,444 THE EMERGING LEADERS AWARD NEW 217 00:09:37,444 --> 00:09:38,812 INVESTIGATORS AWARD. 218 00:09:38,812 --> 00:09:40,213 GATEWAY AWARDS. 219 00:09:40,213 --> 00:09:42,148 THESE PROGRAMS HAVE ALLOWED 220 00:09:42,148 --> 00:09:46,453 AWARDEES STOW BE EMBEDDED IN THE 221 00:09:46,453 --> 00:09:48,621 RICH INTELLECTUAL ENVIRONMENT OF 222 00:09:48,621 --> 00:09:52,091 HIRN AND IT LEARN FROM AND 223 00:09:52,091 --> 00:09:53,693 COLLABORATE WITH ESTABLISH HIRN 224 00:09:53,693 --> 00:09:54,461 SCIENTISTS. 225 00:09:54,461 --> 00:09:56,896 ADDITIONALLY, HIRN HAS GIVEN 226 00:09:56,896 --> 00:09:59,699 EARLY CAREER SCIENTISTS 227 00:09:59,699 --> 00:10:02,302 OPPORTUNITIES TO TAKE LEADERSHIP 228 00:10:02,302 --> 00:10:04,037 ROLES WHICH GIVES THEM A 229 00:10:04,037 --> 00:10:05,038 VALUABLE MANAGEMENT EXPERIENCE 230 00:10:05,038 --> 00:10:08,041 NEEDED FOR CAREER DEVELOPMENT. 231 00:10:08,041 --> 00:10:10,643 AS ONE EXAMPLE OF HOW HIRN HAS 232 00:10:10,643 --> 00:10:14,447 QUICKLY STEPPED IN TO FILL THE 233 00:10:14,447 --> 00:10:16,583 EARLY STAGE SCIENTISTS THE 234 00:10:16,583 --> 00:10:19,519 EMERGING LEADERS PROGRAM WAS 235 00:10:19,519 --> 00:10:20,954 LAUNCHED DURING COVID WHEN THE 236 00:10:20,954 --> 00:10:25,225 PANDEMIC WAS NEGATIVELY 237 00:10:25,225 --> 00:10:28,361 AFFECTING POSTDOCS READY TO 238 00:10:28,361 --> 00:10:29,963 TRANSITION TO INDEPENDENT 239 00:10:29,963 --> 00:10:30,630 FACULTY POSITIONS BUT EVERYTHING 240 00:10:30,630 --> 00:10:33,233 WAS ON HOLD BECAUSE OF THE 241 00:10:33,233 --> 00:10:33,500 PANDEMIC. 242 00:10:33,500 --> 00:10:35,335 AND HIRN PROVIDING FUNDING TO 243 00:10:35,335 --> 00:10:37,737 SUPPORT THE POSTDOCTORAL 244 00:10:37,737 --> 00:10:39,873 RESEARCHERS DURING THIS TIME OF 245 00:10:39,873 --> 00:10:40,607 UNCERTAINTY UNTIL IT WAS 246 00:10:40,607 --> 00:10:41,474 FEASIBLE FOR THEM TO MOVE TO A 247 00:10:41,474 --> 00:10:46,446 NEW POSITION. 248 00:10:46,446 --> 00:10:47,647 OVER ALL HIRN'S CAREER 249 00:10:47,647 --> 00:10:50,049 DEVELOPMENT EFFORTS HAVE BEEN 250 00:10:50,049 --> 00:10:53,019 HUGELY SUCCESSFUL AND A WIN-WIN 251 00:10:53,019 --> 00:10:55,121 AND HIRN IS HELPING FOSTER 252 00:10:55,121 --> 00:10:58,525 CAREER DEVELOPMENT AND IN TURN 253 00:10:58,525 --> 00:11:00,927 HIRN AND NIDDK ARE WELCOMING 254 00:11:00,927 --> 00:11:02,562 EXTREMELY TALENTED SCIENTISTS TO 255 00:11:02,562 --> 00:11:03,329 THE STUDY OF TYPE I DIABETES 256 00:11:03,329 --> 00:11:11,571 RESEARCH. 257 00:11:11,571 --> 00:11:14,841 I'LL CHOSE BY CONGRATING HIRN 258 00:11:14,841 --> 00:11:16,776 AND YOU WILL OF YOU ON ITS MANY 259 00:11:16,776 --> 00:11:17,911 ACCOMPLISHMENTS AND INVITE TO 260 00:11:17,911 --> 00:11:20,446 YOU VISIT OUR WEBSITE FOR MORE 261 00:11:20,446 --> 00:11:22,448 INFORMATION ON NIDDK'S 262 00:11:22,448 --> 00:11:23,082 ACTIVITIES AND CONNECT WITH US 263 00:11:23,082 --> 00:11:25,618 ON SOCIAL MEDIA. 264 00:11:25,618 --> 00:11:27,987 THANK YOU AND SORRY FOR THE 265 00:11:27,987 --> 00:11:29,923 PROBLEM GETTING THROUGH THE 266 00:11:29,923 --> 00:11:30,356 GATEWAY. 267 00:11:30,356 --> 00:11:33,426 THIS IS A TIME OF TRANSITION 268 00:11:33,426 --> 00:11:43,870 I'LL JUST END IT AT THAT. 269 00:11:55,081 --> 00:11:57,016 >> HERE SEEING MORE PEOPLE 270 00:11:57,016 --> 00:11:58,618 TRICKLING AND IN WE CAN BEGIN 271 00:11:58,618 --> 00:12:00,186 THE PROGRAM FOR GOOD. 272 00:12:00,186 --> 00:12:02,956 NEXT UP IS GOING TO BE SOME 273 00:12:02,956 --> 00:12:03,222 COMMENTS. 274 00:12:03,222 --> 00:12:08,094 I'M HAPPY TO INTRODUCE DR. JOHN 275 00:12:08,094 --> 00:12:11,431 KADDIS A PROFESSOR IN THE DWEPT 276 00:12:11,431 --> 00:12:13,666 OF CANCER AND DIABETES DISCOVERY 277 00:12:13,666 --> 00:12:16,336 SCIENCE AT THE CITY OF HOPE. 278 00:12:16,336 --> 00:12:19,706 JOHN IS A CO-P.I. ON THE HIRN 279 00:12:19,706 --> 00:12:21,274 COORDINATING CENTER WE REFER TO 280 00:12:21,274 --> 00:12:22,976 AS THE RESEARCH ENHANCEMENT 281 00:12:22,976 --> 00:12:23,209 CENTER. 282 00:12:23,209 --> 00:12:26,646 HE'S GOING TO GIVE MORE 283 00:12:26,646 --> 00:12:28,114 BACKGROUND ABOUT HIRN AND WHERE 284 00:12:28,114 --> 00:12:34,454 IT'S COME FROM AND HOPEFULLY 285 00:12:34,454 --> 00:12:44,764 WHERE IT'S GOING. 286 00:12:57,944 --> 00:12:58,978 >> HI, EVERYONE. 287 00:12:58,978 --> 00:13:00,546 AS A PRIMER FOR THE PLENARY 288 00:13:00,546 --> 00:13:02,649 TALKS YOU'LL SEE THIS MORNING 289 00:13:02,649 --> 00:13:03,950 YOU'LL GET A MORE BROADER 290 00:13:03,950 --> 00:13:05,418 PERSPECTIVE OF THE OVERVIEW AND 291 00:13:05,418 --> 00:13:10,456 CHANGES THAT HAVE BEEN HAPPENING 292 00:13:10,456 --> 00:13:13,926 IN TYPE I DIABETES. 293 00:13:13,926 --> 00:13:16,162 SO, I THINK MOST WILL AGREE THE 294 00:13:16,162 --> 00:13:19,432 BETA CELL IS ONE OF THE HARDEST, 295 00:13:19,432 --> 00:13:22,168 IF NOT THE HARDEST WORKING CELL 296 00:13:22,168 --> 00:13:23,603 IN THE BODY IT'S GOT TO MAKE 297 00:13:23,603 --> 00:13:27,106 MILLIONS AND MILLIONS OF HORMONE 298 00:13:27,106 --> 00:13:30,710 MOLECULES AND SYNTHESIZE AND 299 00:13:30,710 --> 00:13:34,247 MAINTAIN AND LOOK AT THE SIGNALS 300 00:13:34,247 --> 00:13:36,149 AARON IT AND HAS TO DO THAT MANY 301 00:13:36,149 --> 00:13:37,450 TIME THROUGHOUT THE DAY. 302 00:13:37,450 --> 00:13:39,786 WHAT COMES INTO KEEN FOCUS IN 303 00:13:39,786 --> 00:13:41,654 THE LAST 10 YEARS IS JUST HOW 304 00:13:41,654 --> 00:13:44,457 VULNERABLE THE BETA CELL IS VERY 305 00:13:44,457 --> 00:13:47,026 EARLY ON IN THE DISEASE AND WHAT 306 00:13:47,026 --> 00:13:50,196 I MEAN HERE IS NOT ONLY THOSE 307 00:13:50,196 --> 00:13:54,834 THAT HAVE A MULTIPLE ANDS BUT AS 308 00:13:54,834 --> 00:13:56,269 MANY AS ONE AUTO ANTIBODY. 309 00:13:56,269 --> 00:14:01,040 WE TEND TO THINK AND STUDY 310 00:14:01,040 --> 00:14:03,042 SOMETIMES OF TYPE I DIABETES AS 311 00:14:03,042 --> 00:14:04,410 A SINGLE CELL DISEASE BUT THAT 312 00:14:04,410 --> 00:14:06,079 IN FACT IS NOT THE DISEASE. 313 00:14:06,079 --> 00:14:09,115 THERE'S LOTS OF HORMONES AND 314 00:14:09,115 --> 00:14:10,783 THERE'S A LARGE CAST OF PLAYERS 315 00:14:10,783 --> 00:14:12,885 SUPPORTING THE BETA CELL AND 316 00:14:12,885 --> 00:14:15,221 OTHER CELLS AROUND THE PANCREAS 317 00:14:15,221 --> 00:14:18,291 AND YOU'RE GOING TO HEAR IN 318 00:14:18,291 --> 00:14:19,792 TALKS TODAY THAT EVEN IF YOU 319 00:14:19,792 --> 00:14:21,694 TAKE OUT ONE MUCH THOSE CAST 320 00:14:21,694 --> 00:14:25,598 MEMBERS YOU CAN SEE DYSFUNCTION 321 00:14:25,598 --> 00:14:27,700 IN THE ISLET AND BETA CELL EARLY 322 00:14:27,700 --> 00:14:28,367 ON IN THE DISEASE PROCESS. 323 00:14:28,367 --> 00:14:30,670 AND JUST LIKE THE BETA CELL 324 00:14:30,670 --> 00:14:32,572 CAN'T WORK ALONE, NEITHER CAN 325 00:14:32,572 --> 00:14:32,739 WE. 326 00:14:32,739 --> 00:14:35,641 SO THE QUESTION IS, HOW DO THESE 327 00:14:35,641 --> 00:14:36,275 DEVELOPMENTS COME ABOUT? 328 00:14:36,275 --> 00:14:39,946 AND SO WHAT I WANT TO DO IS SORT 329 00:14:39,946 --> 00:14:40,780 OF ELABORATE MORE ON WHAT 330 00:14:40,780 --> 00:14:42,815 DR. RODGERS WAS TELLING YOU 331 00:14:42,815 --> 00:14:46,152 ABOUT AND START WITH THE BETA 332 00:14:46,152 --> 00:14:48,855 CELL BIOLOGY CONSORTIUM WHICH 333 00:14:48,855 --> 00:14:50,823 STARTED IN 2001 AND LAST ABOUT 334 00:14:50,823 --> 00:14:51,491 15 YEARS. 335 00:14:51,491 --> 00:14:56,763 WHAT THE BCBC GAVE US IS GAVE US 336 00:14:56,763 --> 00:14:57,964 A LOT OF MICE AND LOTS OF 337 00:14:57,964 --> 00:15:00,032 ANTIBODIES AND FOCUS ON THE BETA 338 00:15:00,032 --> 00:15:03,970 CELL AND FOCUS ON DEVELOPMENTAL 339 00:15:03,970 --> 00:15:06,439 BIOLOGY WHICH WAS GREAT. 340 00:15:06,439 --> 00:15:08,174 THEN SHORTLY AFTER THAT CAME 341 00:15:08,174 --> 00:15:11,010 WHAT IS NOW KNOWN AS THE 342 00:15:11,010 --> 00:15:12,612 INTEGRATED ISLET DISTRIBUTION 343 00:15:12,612 --> 00:15:15,281 PROGRAM AND THAT WAS GIVEN BOTH 344 00:15:15,281 --> 00:15:16,916 THROUGH EARLY EFFORTS THAT SOME 345 00:15:16,916 --> 00:15:19,118 OF YOU HERE STARTED IN THE EARLY 346 00:15:19,118 --> 00:15:22,455 2000 WHEN THERE WAS A FOCUS ON 347 00:15:22,455 --> 00:15:25,191 THE CLINICAL ASPECTS AND 348 00:15:25,191 --> 00:15:26,459 CLINICAL TRANSPLANTATION AND 349 00:15:26,459 --> 00:15:28,361 THIS CAME ABOUT TRUE THE ISLET 350 00:15:28,361 --> 00:15:30,029 CELL RESOURCES CENTER. 351 00:15:30,029 --> 00:15:32,331 THE FIRST SHIPMENT OF HUMAN 352 00:15:32,331 --> 00:15:34,400 ISLETS WENT OUT IN 2004 AND HAVE 353 00:15:34,400 --> 00:15:36,702 BEEN GOING STRONG OVER 20 YEARS. 354 00:15:36,702 --> 00:15:39,071 MOST OF US IN THE FIELD ALSO 355 00:15:39,071 --> 00:15:41,040 KNOW ABOUT THE EFFORTS OF NPOD 356 00:15:41,040 --> 00:15:43,509 WHICH WAS THEN A PRETTY 357 00:15:43,509 --> 00:15:45,611 AMBITIOUS EFFORT TO ESSENTIALLY 358 00:15:45,611 --> 00:15:48,481 MAKE NOT ONLY THE ISLETS 359 00:15:48,481 --> 00:15:52,351 AVAILABLE THAT THE IIDP STARTED 360 00:15:52,351 --> 00:15:54,020 TO GET BUT ALSO TISSUE AND 361 00:15:54,020 --> 00:15:55,888 TISSUE NOT ONLY FROM THE 362 00:15:55,888 --> 00:15:57,590 PANCREAS BUT SURROUNDING TISSUES 363 00:15:57,590 --> 00:16:00,159 AND CELLS AS WELL. 364 00:16:00,159 --> 00:16:01,794 NPOD HAS BEEN GOING FOR ALMOST 365 00:16:01,794 --> 00:16:02,395 20 YEARS AS WELL. 366 00:16:02,395 --> 00:16:05,231 AND THE FOCUS OF TODAY IS HIRN. 367 00:16:05,231 --> 00:16:07,733 AS YOU'VE HEARD DR. RODGERS 368 00:16:07,733 --> 00:16:09,135 POINT OUT THE LATEST PLAYER, THE 369 00:16:09,135 --> 00:16:11,537 NEW KID ON THE BLOCK WHICH IS 370 00:16:11,537 --> 00:16:13,706 THE CARDIOVASCULAR REPOSITORY IN 371 00:16:13,706 --> 00:16:14,841 TYPE 1 DIABETES. 372 00:16:14,841 --> 00:16:17,810 NOW, I KNOW THIS IS AN 373 00:16:17,810 --> 00:16:19,345 INCOMPLETE TIME LINE BUT IT DOES 374 00:16:19,345 --> 00:16:21,347 HELP TO POINT OUT TWO THINGS. 375 00:16:21,347 --> 00:16:24,083 ONE, IT CAN TAKE A DECADE OR 376 00:16:24,083 --> 00:16:27,019 MORE FOR THESE INITIATIVES TO 377 00:16:27,019 --> 00:16:27,887 ACTUALLY BEAR FRUIT. 378 00:16:27,887 --> 00:16:32,291 SO THERE IS A TIME COMPONENT 379 00:16:32,291 --> 00:16:32,625 THERE. 380 00:16:32,625 --> 00:16:38,431 AND IT TAKES CONSISTENT ENGAGED 381 00:16:38,431 --> 00:16:41,033 COMMUNITY AND COLLABORATIVE 382 00:16:41,033 --> 00:16:43,669 EFFORTS IN ORDER TO SEE THE 383 00:16:43,669 --> 00:16:46,806 CHANGE IN CONCEPTS IN THE 384 00:16:46,806 --> 00:16:48,975 PLENARY SESSIONS. 385 00:16:48,975 --> 00:16:50,710 STARTING SOMETHING IS NEVER EASY 386 00:16:50,710 --> 00:16:53,012 AND IT HAD IT OWN SET OF 387 00:16:53,012 --> 00:16:54,447 CHALLENGES LISTED HERE THAT WILL 388 00:16:54,447 --> 00:16:56,415 BE TOUCHED UPON IN THE PLENARY 389 00:16:56,415 --> 00:16:56,682 SESSIONS. 390 00:16:56,682 --> 00:16:58,451 I'VE BRIEFLY GIVEN YOU AN 391 00:16:58,451 --> 00:17:00,620 EXAMPLE IN TERMS OF THE EARLY 392 00:17:00,620 --> 00:17:02,221 PATHOGENIC EVENTS THAT HAPPENED 393 00:17:02,221 --> 00:17:03,422 THROUGHOUT THE DISEASE. 394 00:17:03,422 --> 00:17:04,991 BUT WITH EVERY GOOD CHALLENGE 395 00:17:04,991 --> 00:17:07,627 THERE'S ALSO A SET OF 396 00:17:07,627 --> 00:17:10,429 OPPORTUNITIES AGAIN ALL OF THESE 397 00:17:10,429 --> 00:17:11,664 WILL BE HIGHLIGHTED LATER ON 398 00:17:11,664 --> 00:17:14,433 DURING THE PLENARY SESSIONS BUT 399 00:17:14,433 --> 00:17:16,269 FOR EXAMPLE WE CAN'T TAKE FOR 400 00:17:16,269 --> 00:17:19,939 GRANTED THE FACT WE HAVE HUMAN 401 00:17:19,939 --> 00:17:22,475 PANCREATIC TISSUE, ISLET, ALL 402 00:17:22,475 --> 00:17:24,510 THESE CELLS AND TISSUES 403 00:17:24,510 --> 00:17:26,078 AVAILABLE BECAUSE PEOPLE SPEND 404 00:17:26,078 --> 00:17:27,847 THEIR CAREERS ESSENTIALLY 405 00:17:27,847 --> 00:17:29,348 PROVIDING THIS FOR US AND MOVING 406 00:17:29,348 --> 00:17:30,716 THINGS FORWARD. 407 00:17:30,716 --> 00:17:33,886 SO WITH THAT THE MISSION OF HIRN 408 00:17:33,886 --> 00:17:35,788 WAS AND IS UP HERE WHICH IS TO 409 00:17:35,788 --> 00:17:38,424 UNDERSTAND HOW HUMAN BETA CELLS 410 00:17:38,424 --> 00:17:40,927 ARE LOST IN THE DISEASE AND FIND 411 00:17:40,927 --> 00:17:42,428 INNOVATIVE STRATEGIES TO PROTECT 412 00:17:42,428 --> 00:17:45,364 OR REPLACE FUNCTIONAL BETA CELL 413 00:17:45,364 --> 00:17:45,765 MASS. 414 00:17:45,765 --> 00:17:47,633 WHAT I'LL EMPHASIZE HERE IS ONE 415 00:17:47,633 --> 00:17:49,902 OF THE THINGS THAT WE'RE LOOKING 416 00:17:49,902 --> 00:17:51,337 AT IS EARLY DISEASE DEVELOPMENT 417 00:17:51,337 --> 00:17:53,339 BECAUSE WHAT WE'D LIKE IS TO 418 00:17:53,339 --> 00:17:57,310 PREVENT THE DISEASE FROM 419 00:17:57,310 --> 00:17:59,011 BEGINNING AT ALL. 420 00:17:59,011 --> 00:18:01,580 THE WAY THIS STARTED WAS THROUGH 421 00:18:01,580 --> 00:18:03,616 A GROUP AND EACH ONE OF THESE 422 00:18:03,616 --> 00:18:06,919 BOX HERE AS DR. RODGERS POINTS 423 00:18:06,919 --> 00:18:08,521 OUT REPRESENTS A DIFFERENT 424 00:18:08,521 --> 00:18:09,555 THEME. 425 00:18:09,555 --> 00:18:11,891 EACH ONE OF THESE THEM HAD FROM 426 00:18:11,891 --> 00:18:15,361 FOUR TO SIX GROUPS WORKING 427 00:18:15,361 --> 00:18:18,297 TOGETHER TO MEET SPECIFIC 428 00:18:18,297 --> 00:18:18,564 OBJECTIVE. 429 00:18:18,564 --> 00:18:22,768 THIS IS HOW IT LOOKED BACK IN 430 00:18:22,768 --> 00:18:23,202 2014. 431 00:18:23,202 --> 00:18:25,338 SOME OF YOU WILL HOPEFULLY 432 00:18:25,338 --> 00:18:26,839 RECOGNIZE WHAT IT LOOKS LIKE 433 00:18:26,839 --> 00:18:28,641 TODAY BUT THIS IS ABOUT 10 YEARS 434 00:18:28,641 --> 00:18:30,476 AGO AND AGAIN DOWN THE STREET 435 00:18:30,476 --> 00:18:32,979 WHEN WE STARTED. 436 00:18:32,979 --> 00:18:34,580 FAST FORWARD TO NOT LAST WE'RE 437 00:18:34,580 --> 00:18:37,383 BUT THE END OF THE YEAR BEFORE 438 00:18:37,383 --> 00:18:41,821 THAT IN 2023, THIS WAS OUR LAST 439 00:18:41,821 --> 00:18:42,755 HIRN MEETING. 440 00:18:42,755 --> 00:18:44,957 SO, HOW DO YOU TAKE A BUNCH OF 441 00:18:44,957 --> 00:18:47,860 PEOPLE WORKING INDIVIDUALLY OR 442 00:18:47,860 --> 00:18:48,627 WITHIN THEIR GROUPS AND START 443 00:18:48,627 --> 00:18:49,729 GETTING THEM TO WORK TOGETHER. 444 00:18:49,729 --> 00:18:52,398 THIS IS A DIFFERENT LOOK AT THE 445 00:18:52,398 --> 00:18:54,867 SLIDE DR. RODGERS SHOWED YOU 446 00:18:54,867 --> 00:18:56,202 OUTLINING THE EVOLUTION OF HIRN. 447 00:18:56,202 --> 00:18:57,903 AND I'D LIKE TO GO THROUGH SOME 448 00:18:57,903 --> 00:19:00,506 OF THAT WITH YOU. 449 00:19:00,506 --> 00:19:02,441 AGAIN IN 2014 WE STARTED OFF NOT 450 00:19:02,441 --> 00:19:06,045 BEING CONNECTED WITH ONE ANOTHER 451 00:19:06,045 --> 00:19:08,681 ADVANCING THROUGH IN 2019 TO 452 00:19:08,681 --> 00:19:10,983 WHAT YOU SEE HERE TODAY. 453 00:19:10,983 --> 00:19:12,718 SO LET ME WALK YOU THROUGH THESE 454 00:19:12,718 --> 00:19:13,085 QUICKLY. 455 00:19:13,085 --> 00:19:17,089 FIRST WE HAVE THE COORDINATING 456 00:19:17,089 --> 00:19:19,125 CENTER AND THE BIO INFORMATICS 457 00:19:19,125 --> 00:19:25,398 CENTER MERGING TO 42 HUMAN 458 00:19:25,398 --> 00:19:28,200 RESEARCH CENTER AND I WON'T 459 00:19:28,200 --> 00:19:29,668 COVER THAT THERE'S A POSTER FOR 460 00:19:29,668 --> 00:19:31,771 THAT AND THE HUMAN ANALYSIS 461 00:19:31,771 --> 00:19:32,972 CONSORTIUM AND GIVEN FROM 462 00:19:32,972 --> 00:19:39,045 EFFORTS IN 2016 AS DR. RODGERS 463 00:19:39,045 --> 00:19:39,912 SAID WHEN THERE WAS A 464 00:19:39,912 --> 00:19:41,714 PHENOTYPING OF THE HUMAN 465 00:19:41,714 --> 00:19:45,084 PANCREAS AND MAKING WIDELY 466 00:19:45,084 --> 00:19:45,351 AVAILABLE. 467 00:19:45,351 --> 00:19:46,886 IN THE BREAKOUT SESSIONS IF 468 00:19:46,886 --> 00:19:49,255 YOU'RE INTERESTED ABOUT FINDING 469 00:19:49,255 --> 00:19:52,525 OUT ABOUT THE PANCDB I THINK 470 00:19:52,525 --> 00:19:54,260 THAT SESSION WILL HAPPEN LATER 471 00:19:54,260 --> 00:19:56,429 SO YOU CAN FIND OUT MORE ABOUT 472 00:19:56,429 --> 00:19:56,662 THAT. 473 00:19:56,662 --> 00:20:00,733 AS DR. RODGERS ELUDED TO, HIRN 474 00:20:00,733 --> 00:20:02,501 WAS NEVER DESIGN TO BE A 475 00:20:02,501 --> 00:20:05,871 STAGNANT ORGANIZATION CONTR 476 00:20:05,871 --> 00:20:08,441 CONTRASTING ON THE LATEST NEEDS. 477 00:20:08,441 --> 00:20:10,509 THE CONSORTIUM TARGETING 478 00:20:10,509 --> 00:20:12,812 REGENERATION FOLDED INTO THE 479 00:20:12,812 --> 00:20:18,284 CONSORTIUM ON BETA CELL DEATH 480 00:20:18,284 --> 00:20:22,221 AND SURVIVAL. 481 00:20:22,221 --> 00:20:24,356 LIKEWISE THE CONE SHUM EMERGED 482 00:20:24,356 --> 00:20:26,459 TO THE NEWEST KID ON THE BLOCK 483 00:20:26,459 --> 00:20:30,863 THE CONSORTIUM ON MODELLING AUTO 484 00:20:30,863 --> 00:20:31,897 IMMUNE DISEASE. 485 00:20:31,897 --> 00:20:33,099 SO NEW THEY'LL BE MEETING FOR 486 00:20:33,099 --> 00:20:34,300 THE FIRST TIME THIS MONTH. 487 00:20:34,300 --> 00:20:38,003 LAST BUT NOT LEAST AS YOU HEARD 488 00:20:38,003 --> 00:20:41,073 THE AGAIN AMBITIOUS EFFORTS TO 489 00:20:41,073 --> 00:20:43,075 BRING HUMAN PANCREAS TOGETHER 490 00:20:43,075 --> 00:20:45,811 AND DATA NOT ONLY FROM HIRN, 491 00:20:45,811 --> 00:20:47,012 OUTSIDE OF HIRN AND I'LL 492 00:20:47,012 --> 00:20:49,482 HIGHLIGHT THERE'S A BREAKOUT 493 00:20:49,482 --> 00:20:50,850 SESSION THAT WILL BE HAPPENING 494 00:20:50,850 --> 00:20:54,019 TOMORROW TO ADDRESS THAT. 495 00:20:54,019 --> 00:20:55,154 NOW, EVERY ONE OF THESE 496 00:20:55,154 --> 00:20:57,523 TRANSITIONS WERE PRECEDED BY AN 497 00:20:57,523 --> 00:20:58,057 RFA. 498 00:20:58,057 --> 00:20:59,024 THESE ARE OPEN OPPORTUNITIES 499 00:20:59,024 --> 00:21:00,826 FROM ANYONE IN THE COMMUNITY TO 500 00:21:00,826 --> 00:21:02,328 GET INVOLVED IN HIRN. 501 00:21:02,328 --> 00:21:04,230 SO THE QUESTION IS WITH THIS 502 00:21:04,230 --> 00:21:07,133 INFRASTRUCTURE IN PLACE, WHAT IS 503 00:21:07,133 --> 00:21:08,601 HIRN ACCOMPLISHED AND WHERE IS 504 00:21:08,601 --> 00:21:09,535 IT GOING? 505 00:21:09,535 --> 00:21:11,137 THE PLENARY TALKS ARE GOING TO 506 00:21:11,137 --> 00:21:13,706 ADDRESS THE SCIENCE OF WHERE 507 00:21:13,706 --> 00:21:15,508 HIRN IS PLACED BUT I WANT TO 508 00:21:15,508 --> 00:21:21,046 LOOK AT TWO DIFFERENT OTHER 509 00:21:21,046 --> 00:21:22,114 ACCOMPLISHMENTS AND ONE IS IN 510 00:21:22,114 --> 00:21:23,649 TERMS OF THE COLLABORATION AND 511 00:21:23,649 --> 00:21:24,850 SCIENCE IN TERMS OF WHAT IT HAS 512 00:21:24,850 --> 00:21:25,985 DONE TO THE COMMUNITY. 513 00:21:25,985 --> 00:21:30,356 WHAT YOU'RE LOOKING AT HERE IS 514 00:21:30,356 --> 00:21:32,424 AN ANALYSIS AROUND ABOUT 1,000 515 00:21:32,424 --> 00:21:33,692 PAPERS HIRN PUBLISHED IN THE 516 00:21:33,692 --> 00:21:35,027 LAST DECADE. 517 00:21:35,027 --> 00:21:38,097 THE YELLOW DOTS ARE 300 OR SO 518 00:21:38,097 --> 00:21:40,533 INVESTIGATORS FROM HIRN. 519 00:21:40,533 --> 00:21:43,102 THE GREEN DOTS ARE OVER 4,000 520 00:21:43,102 --> 00:21:44,703 INDIVIDUALS WHO HAVE NO 521 00:21:44,703 --> 00:21:46,906 AFFILIATION FROM HIRN AND THOSE 522 00:21:46,906 --> 00:21:49,341 BLUE LINES ARE 18,000 523 00:21:49,341 --> 00:21:52,344 CONNECTIONS BETWEEN HIRN AND THE 524 00:21:52,344 --> 00:21:53,579 COMMUNITY AROUND IT. 525 00:21:53,579 --> 00:21:54,880 THERE IS ROOM FOR IMPROVEMENT 526 00:21:54,880 --> 00:21:57,316 BUT WHAT I WANT TO POINT OUT IS 527 00:21:57,316 --> 00:22:03,222 THAT OVER THE LAST DECADE HIRN 528 00:22:03,222 --> 00:22:05,291 HAS AFFECTED OR CHANGES IN 12 529 00:22:05,291 --> 00:22:08,294 COUNTRIES IN TERMS OF THESE 530 00:22:08,294 --> 00:22:08,661 COLLABORATIONS. 531 00:22:08,661 --> 00:22:10,896 109 INSTITUTIONS, OVER 800 532 00:22:10,896 --> 00:22:12,865 INVESTIGATORS AND WHAT I MEAN BY 533 00:22:12,865 --> 00:22:14,934 THAT IS THIS COULD BE TRAINEES, 534 00:22:14,934 --> 00:22:18,304 THESE COULD BE POSTDOCS, THESE 535 00:22:18,304 --> 00:22:20,873 COULD BE MPIs. 536 00:22:20,873 --> 00:22:21,707 EVERYONE WHO HAS COME THROUGH 537 00:22:21,707 --> 00:22:23,742 HIRN LABS AND AS I SAID OVER 538 00:22:23,742 --> 00:22:26,545 18,000 CONNECTIONS. 539 00:22:26,545 --> 00:22:29,949 THE SECOND EXAMPLE I WANT TO 540 00:22:29,949 --> 00:22:32,084 HIGHLIGHT ARE THESE CAREER 541 00:22:32,084 --> 00:22:32,418 ADVANCEMENTS. 542 00:22:32,418 --> 00:22:34,119 AND HOW THESE HAPPEN IS ONE OF 543 00:22:34,119 --> 00:22:34,920 TWO WAYS. 544 00:22:34,920 --> 00:22:37,756 FIRST, OPEN ANNOUNCEMENTS FROM 545 00:22:37,756 --> 00:22:39,425 NIH IN WHICH INDIVIDUALS CAN 546 00:22:39,425 --> 00:22:40,559 COME IN THROUGH HIRN. 547 00:22:40,559 --> 00:22:43,195 THE SECOND WAY IS THAT HIRN 548 00:22:43,195 --> 00:22:45,397 ACTUALLY HAS ITS OWN FUNDING 549 00:22:45,397 --> 00:22:47,066 ANNOUNCEMENT AND OWN FUNDING 550 00:22:47,066 --> 00:22:48,767 OPPORTUNITIES AND SO INDIVIDUALS 551 00:22:48,767 --> 00:22:50,803 CAN COME IN HERE AND I'M 552 00:22:50,803 --> 00:22:53,038 HIGHLIGHTING FOR YOU FACULTY 553 00:22:53,038 --> 00:22:55,107 MEMBERS THAT VERY RECENTLY IN 554 00:22:55,107 --> 00:22:57,476 THE LAST FIVE TO SEVEN YEARS 555 00:22:57,476 --> 00:22:58,978 EITHER GOT THEIR FACULTY 556 00:22:58,978 --> 00:23:01,513 APPOINTMENT OR PROMOTED DURING 557 00:23:01,513 --> 00:23:03,515 THE COURSE OF HIRN SO THERE'S A 558 00:23:03,515 --> 00:23:05,551 FEW DIFFERENT FACES HERE, A 559 00:23:05,551 --> 00:23:07,653 NUMBER OF THEM YOU'LL SEE TODAY 560 00:23:07,653 --> 00:23:09,288 AS PART OF THIS PROGRAM. 561 00:23:09,288 --> 00:23:12,725 IT ISN'T ONLY FACULTY POSITIONS, 562 00:23:12,725 --> 00:23:14,093 PEOPLE GO FROM LABS. 563 00:23:14,093 --> 00:23:15,094 THEY GO TO POLICY. 564 00:23:15,094 --> 00:23:16,395 THEY GO TO INDUSTRY. 565 00:23:16,395 --> 00:23:17,596 SO THERE'S A LOT OF DIFFERENT 566 00:23:17,596 --> 00:23:21,367 WAYS THAT HIRN IS AFFECTING 567 00:23:21,367 --> 00:23:22,001 CAREER GROWTH AND PROMOTION IN 568 00:23:22,001 --> 00:23:25,704 THE FIELD. 569 00:23:25,704 --> 00:23:27,973 SO THE OTHER THING I WANT TO 570 00:23:27,973 --> 00:23:29,308 POINT OUT IS THESE OPPORTUNITIES 571 00:23:29,308 --> 00:23:31,343 COME UP PERIODICALLY AND IN THE 572 00:23:31,343 --> 00:23:32,511 BREAKOUT SESSIONS NOT ONLY WILL 573 00:23:32,511 --> 00:23:34,246 YOU SEE A LOT OF THE THINGS THAT 574 00:23:34,246 --> 00:23:36,649 WE'VE BEEN TALKING ABOUT TODAY 575 00:23:36,649 --> 00:23:37,983 BUT ALSO FUNDING OPPORTUNITIES 576 00:23:37,983 --> 00:23:39,785 AND SOME RECENT FUNDING 577 00:23:39,785 --> 00:23:42,321 OPPORTUNITIES THAT WILL BE 578 00:23:42,321 --> 00:23:43,822 COMING UP IN HIRN AS WELL AND 579 00:23:43,822 --> 00:23:45,858 WE'LL BE TALKING ABOUT THAT 580 00:23:45,858 --> 00:23:47,026 DURING THE DAY 2. 581 00:23:47,026 --> 00:23:51,397 SO WITH THAT OVER THE COURSE OF 582 00:23:51,397 --> 00:23:52,665 10 YEARS WE'VE HAD OVER 20 583 00:23:52,665 --> 00:23:53,465 STRATEGIC PARTNERS. 584 00:23:53,465 --> 00:23:56,335 I HIGHLIGHTED SOME OF THOSE 585 00:23:56,335 --> 00:23:56,835 HERE. 586 00:23:56,835 --> 00:23:59,104 I HAVEN'T GOTTEN A CHANCE TO 587 00:23:59,104 --> 00:24:02,174 TALK ABOUT THEM LIKE DK NET 588 00:24:02,174 --> 00:24:03,375 HELPING WITH DATA INFORMATION 589 00:24:03,375 --> 00:24:04,576 AND EXCHANGE AND SUCH AND POINT 590 00:24:04,576 --> 00:24:07,179 OUT THE GENEROUS GIVING OF 591 00:24:07,179 --> 00:24:09,381 FAMILIES THAT GIVE US THEIR 592 00:24:09,381 --> 00:24:10,249 TISSUES AND APPRECIATION ORGANS 593 00:24:10,249 --> 00:24:11,250 FOR US TO STUDY. 594 00:24:11,250 --> 00:24:14,420 I DO WANT TO ACKNOWLEDGE SO 595 00:24:14,420 --> 00:24:17,022 REALLY IN MY LAB WHO CREATE THE 596 00:24:17,022 --> 00:24:19,124 FIGURE AND OTHER DATA THAT 597 00:24:19,124 --> 00:24:20,426 DIDN'T SHOW UP IN THE 598 00:24:20,426 --> 00:24:22,061 PRESENTATION TODAY AND SOME OF 599 00:24:22,061 --> 00:24:25,864 OUR PARTNERS THAT MAKE THE 600 00:24:25,864 --> 00:24:27,933 COFFEE AND THE TEA AND DRINKS SO 601 00:24:27,933 --> 00:24:29,034 KINDLY AVAILABLE TO US. 602 00:24:29,034 --> 00:24:33,005 BUT I WOULD BE REMISS IF I ALSO 603 00:24:33,005 --> 00:24:34,006 NOT ACKNOWLEDGE THE PLANNING 604 00:24:34,006 --> 00:24:34,440 COMMITTEE AS WELL. 605 00:24:34,440 --> 00:24:38,043 THIS IS A GROUP OF PEOPLE THAT 606 00:24:38,043 --> 00:24:39,111 HAVE BEEN MEETING OVER THE LAST 607 00:24:39,111 --> 00:24:43,549 SEVERAL MONTHS, CALLS, E-MAILS, 608 00:24:43,549 --> 00:24:45,951 COMMUNICATION TO BRING THIS 609 00:24:45,951 --> 00:24:46,952 MEETING TOGETHER WITH YOU AND 610 00:24:46,952 --> 00:24:48,921 THEN ALSO I WANT TO POINT OUT TO 611 00:24:48,921 --> 00:24:52,925 YOU JUST TO HIGHLIGHT A FEW 612 00:24:52,925 --> 00:24:53,158 PEOPLE. 613 00:24:53,158 --> 00:24:56,962 RAFAEL AND RODRIGO AND LEO 614 00:24:56,962 --> 00:25:07,706 TERROROOO -- FERERRO AND CHRIS D 615 00:25:09,408 --> 00:25:11,643 ABRAHAM WHO HAVE BEEN GREAT 616 00:25:11,643 --> 00:25:13,445 CONTACTS IN FACILITATING 617 00:25:13,445 --> 00:25:18,450 EVERYTHING ON THE NIH CAMPUS AND 618 00:25:18,450 --> 00:25:27,192 THEN I WILL EMBARRASS NELL Y 619 00:25:27,192 --> 00:25:28,794 BERGER AND FOR THOSE INVOLVED 620 00:25:28,794 --> 00:25:30,262 YOU KNOW THEY FACILITATE A LOT 621 00:25:30,262 --> 00:25:31,697 OF THINGS. 622 00:25:31,697 --> 00:25:33,866 AS I SUSPECT TODAY AS YOU HAVE 623 00:25:33,866 --> 00:25:36,101 QUESTIONS, THESE ARE THE FACES 624 00:25:36,101 --> 00:25:38,837 YOU WANT TO BE LOOKING FOR. 625 00:25:38,837 --> 00:25:42,241 NOW, HIRN IS DIFFERENT IN SOME 626 00:25:42,241 --> 00:25:45,144 WAYS IN THERE IS HEAVY 627 00:25:45,144 --> 00:25:50,416 PROGRAMATIC INVOLVEMENT AND THAT 628 00:25:50,416 --> 00:25:53,419 MAKES SIRN -- HIRN A SUCCESS 629 00:25:53,419 --> 00:25:58,390 AND I WANT TO ACKNOWLEDGE THE 630 00:25:58,390 --> 00:25:59,324 OFFICIALS THAT PARTICIPATE 631 00:25:59,324 --> 00:26:00,759 THREE, FOUR, FIVE TIMES ON THE 632 00:26:00,759 --> 00:26:02,861 CALLS AND BEING ACTIVELY ENGAGED 633 00:26:02,861 --> 00:26:04,596 WITH THE COMMUNITY AND THAT'S 634 00:26:04,596 --> 00:26:08,000 BEEN A REAL HELP AS WELL. 635 00:26:08,000 --> 00:26:11,737 CAREEN WHO I DIDN'T OUT UP BUT 636 00:26:11,737 --> 00:26:13,439 WAS INVOLVED IN OUR COORDINATING 637 00:26:13,439 --> 00:26:13,972 CENTER EFFORT. 638 00:26:13,972 --> 00:26:15,307 I REMEMBER THAT AS WELL. 639 00:26:15,307 --> 00:26:17,042 WITH ALL THAT NOW WE CAN JUMP 640 00:26:17,042 --> 00:26:19,044 INTO THE SCIENCE WHICH I THINK 641 00:26:19,044 --> 00:26:21,146 YOU ALL ARE EXCITED TO HEAR 642 00:26:21,146 --> 00:26:21,346 ABOUT. 643 00:26:21,346 --> 00:26:24,450 THIS IS PROBABLY THE EASIEST 644 00:26:24,450 --> 00:26:25,884 PRESENTATION OR EASIEST 645 00:26:25,884 --> 00:26:28,287 INTRODUCTION I HAVE TO GIVE. 646 00:26:28,287 --> 00:26:33,625 MOST OF US KNOW DR. MARK 647 00:26:33,625 --> 00:26:36,061 ATKINSON AT THE UNIVERSITY OF 648 00:26:36,061 --> 00:26:38,230 FLORIDA, SCHOLAR. 649 00:26:38,230 --> 00:26:41,099 HE PUBLISH CLOSE TO 450 PAPERS 650 00:26:41,099 --> 00:26:42,601 AND HIS LIFE'S PASSION IS 651 00:26:42,601 --> 00:26:46,271 LEARNING ABOUT THE PATHOGENESIS 652 00:26:46,271 --> 00:26:47,606 OF HIS DISEASE AND MANY OF US 653 00:26:47,606 --> 00:26:49,641 KNOW ABOUT HIS HUMANITARIAN 654 00:26:49,641 --> 00:26:49,908 EFFORTS. 655 00:26:49,908 --> 00:26:51,844 40 YEARS HE'S BEEN IN THE FIELD 656 00:26:51,844 --> 00:26:53,045 OF TYPE I DIABETES AND I'VE HAD 657 00:26:53,045 --> 00:26:55,781 THE PRIVILEGE OF WORKING 658 00:26:55,781 --> 00:26:57,649 ALONGSIDE HIM 20 OF THOSE YEARS. 659 00:26:57,649 --> 00:27:00,619 MOST WILL AGREE WHEN WE SAY MARK 660 00:27:00,619 --> 00:27:02,387 IS A GENEROUS MAN IN TERMS OF 661 00:27:02,387 --> 00:27:04,623 HIS TIME AND ENCOURAGING TO THE 662 00:27:04,623 --> 00:27:06,492 YOUNGER FACULTY. 663 00:27:06,492 --> 00:27:08,861 SO WITH THAT I'D LIKE TO 664 00:27:08,861 --> 00:27:12,998 INTRODUCE MARK. 665 00:27:12,998 --> 00:27:16,201 >> IS ALL THAT APPLAUSE IS TO 666 00:27:16,201 --> 00:27:16,602 YOU. 667 00:27:16,602 --> 00:27:17,202 AND THANK YOU EVERYBODY FOR 668 00:27:17,202 --> 00:27:27,513 COMING HERE TODAY. 669 00:27:33,085 --> 00:27:34,920 >> MY GOAL IS TALKING ABOUT THE 670 00:27:34,920 --> 00:27:37,756 SUCCESS STORIES AFFILIATED WITH 671 00:27:37,756 --> 00:27:41,093 THE IN TYPE I DIABETES. 672 00:27:41,093 --> 00:27:45,364 IN SETTING UP THE TALK TODAY AND 673 00:27:45,364 --> 00:27:48,166 WHERE DO WE BEGIN THE STORY WITH 674 00:27:48,166 --> 00:27:50,669 OUR JOURNEY. 675 00:27:50,669 --> 00:27:53,138 LET'S GO BACK ABOUT 100 YEARS TO 676 00:27:53,138 --> 00:27:58,477 WHERE WE KNOW ABOUT THE 677 00:27:58,477 --> 00:28:08,754 PRE-INSULIN ERA. 678 00:28:14,493 --> 00:28:19,364 >> YOU'D HAVE TWO-THIRDS TO 75% 679 00:28:19,364 --> 00:28:20,933 MORTALITY BECAUSE THERE WAS NO 680 00:28:20,933 --> 00:28:21,300 REAL MEANS. 681 00:28:21,300 --> 00:28:25,237 THIS AGAIN, THIS IS THE 682 00:28:25,237 --> 00:28:26,772 PRE-INSULIN AREA TO TREAT. 683 00:28:26,772 --> 00:28:32,311 AND A BIO CHEMIST CAME ALONG 684 00:28:32,311 --> 00:28:34,313 NAMED FRED ALLEN AND HE CAME UP 685 00:28:34,313 --> 00:28:38,483 WITH THE NOVEL CONCEPT YOU HEAR 686 00:28:38,483 --> 00:28:42,387 ABOUT, THE LOW CARBOHYDRATE PLUS 687 00:28:42,387 --> 00:28:42,955 EXERCISE DIET. 688 00:28:42,955 --> 00:28:48,527 FRED TOOK DOGS AND CATS AND DID 689 00:28:48,527 --> 00:28:56,301 PARTIAL PANCREECTOMY AND LOOKED 690 00:28:56,301 --> 00:28:57,936 AT YOUNG PATIENTS WITH DIABETES 691 00:28:57,936 --> 00:29:00,205 AND TALKED ABOUT A MIRACLE 692 00:29:00,205 --> 00:29:03,875 FACILITY YOU CAN SEE ON THE 693 00:29:03,875 --> 00:29:04,509 RIGHT-HAND SIDE THE BUILDING 694 00:29:04,509 --> 00:29:06,478 DR. ALLEN AND THE PATIENTS COME 695 00:29:06,478 --> 00:29:07,746 IN THE MORNING AND SPEND AN HOUR 696 00:29:07,746 --> 00:29:10,482 OR SO RUNNING UP AND DOWN THE 697 00:29:10,482 --> 00:29:14,186 STAIRS AND THEN GIVEN THESE 698 00:29:14,186 --> 00:29:16,421 DIETS NO LOWER THAN 150 CALORIES 699 00:29:16,421 --> 00:29:20,425 AND ABOUT 400 CALORIES A DAY AND 700 00:29:20,425 --> 00:29:22,461 NO MORE THAN 1,000 CALORIES A 701 00:29:22,461 --> 00:29:23,061 DAY. 702 00:29:23,061 --> 00:29:27,265 IT IF KEEP A CERTAIN PERCENTAGE 703 00:29:27,265 --> 00:29:29,901 OF PEOPLE ALIVE BUT THE REAL 704 00:29:29,901 --> 00:29:32,838 BREAKTHROUGH IS WHAT WE 705 00:29:32,838 --> 00:29:34,473 CELEBRATED WITH THE CENTENNIAL 706 00:29:34,473 --> 00:29:36,041 OF THE DISEASE IN CANADA AND 707 00:29:36,041 --> 00:29:42,347 TAKING BOVINE AND PORCINE 708 00:29:42,347 --> 00:29:49,221 PANCREASES AND TAKING THIS AND 709 00:29:49,221 --> 00:29:51,456 ROLLING THIS OUT AND SENDING IT 710 00:29:51,456 --> 00:29:54,226 OVER TO DEVELOP TO DEVELOP THE 711 00:29:54,226 --> 00:29:54,893 PRODUCT OF INSULIN. 712 00:29:54,893 --> 00:29:57,663 AGAIN, MOST OF US HAVE SEEN THIS 713 00:29:57,663 --> 00:30:02,134 PICTURE HERE OF THE CHILD ON THE 714 00:30:02,134 --> 00:30:05,470 LEFT-HAND SIDE AND THEN THE 715 00:30:05,470 --> 00:30:07,339 CHILD AFTER HAVING RECEIVED 716 00:30:07,339 --> 00:30:09,207 INSULIN BUT THE CHILD ON THE 717 00:30:09,207 --> 00:30:12,778 LEFT WAS TREATED WITH THE ALLEN 718 00:30:12,778 --> 00:30:15,313 DIET AND YOU CAN SEE HOW MUCH 719 00:30:15,313 --> 00:30:17,015 BETTER INSULIN IS FOR SOMEBODY 720 00:30:17,015 --> 00:30:18,450 WITH THIS DISEASE. 721 00:30:18,450 --> 00:30:20,886 AGAIN, IN THE TORONTO PAPERS AT 722 00:30:20,886 --> 00:30:21,953 THE TIME THE NOTION WAS THAT 723 00:30:21,953 --> 00:30:23,789 WE'RE ON THE CUSP OF A YOU'RE 724 00:30:23,789 --> 00:30:26,224 FOR DIABETES. 725 00:30:26,224 --> 00:30:30,962 SO THIS IS EARLY, EARLY IN THE 726 00:30:30,962 --> 00:30:31,196 JOURNEY. 727 00:30:31,196 --> 00:30:33,432 THANKFULLY THERE HAS BEEN MANY 728 00:30:33,432 --> 00:30:34,966 MANY MANY ADVANCES SINCE THEN 37 729 00:30:34,966 --> 00:30:36,401 IF YOU LOOK OVER THAT TIME 730 00:30:36,401 --> 00:30:38,236 PERIOD AND I'M NOT GOING TO ALL 731 00:30:38,236 --> 00:30:41,173 THE WAYS THAT THERE ARE BUT FROM 732 00:30:41,173 --> 00:30:44,910 THE WAY WE MEASURE COMPLIANCE TO 733 00:30:44,910 --> 00:30:46,845 MEASURE INSULIN AND DIFFERENT 734 00:30:46,845 --> 00:30:49,915 TYPES OF INSULIN WE HAD AND 735 00:30:49,915 --> 00:30:51,817 AGAIN WE'VE MADE THE DISEASE 736 00:30:51,817 --> 00:30:54,352 MORE MANAGEABLE AND THE 737 00:30:54,352 --> 00:30:55,287 TREATMENT HAS CHANGED 738 00:30:55,287 --> 00:30:57,889 DRAMATICALLY BUT WE DON'T HAVE A 739 00:30:57,889 --> 00:30:59,691 CURE YET. 740 00:30:59,691 --> 00:31:00,792 AND SO I DON'T WANT ANYBODY TO 741 00:31:00,792 --> 00:31:01,893 BE DISCOURAGED. 742 00:31:01,893 --> 00:31:04,162 I HAVE A FRIEND AND JORDAN IF 743 00:31:04,162 --> 00:31:06,898 YOU CAN SWITCH OVER, I HAVE AN 744 00:31:06,898 --> 00:31:08,567 INDIVIDUAL THAT LIVES A COUPLE 745 00:31:08,567 --> 00:31:14,339 HOURS SOUTH OF ME IN ORLANDO, 746 00:31:14,339 --> 00:31:14,573 FLORIDA. 747 00:31:14,573 --> 00:31:16,975 HE WAS DIAGNOSED WITH TYPE I AT 748 00:31:16,975 --> 00:31:20,679 THE AGE OF 6 IN 1957 AND I'VE 749 00:31:20,679 --> 00:31:22,280 ASKED HER TO SHARE HOW THE 750 00:31:22,280 --> 00:31:24,616 JOURNEY HAS BEEN FOR HER AND 751 00:31:24,616 --> 00:31:25,650 MORE IMPORTANTLY HOW RESEARCH 752 00:31:25,650 --> 00:31:29,354 THE TYPE OF RESEARCH YOU DO AS 753 00:31:29,354 --> 00:31:30,622 CHANGED HER LIFE AND SO JORDAN, 754 00:31:30,622 --> 00:31:32,624 PLEASE. 755 00:31:32,624 --> 00:31:35,527 >> HI, I'M BRENDA MARTINEZ. 756 00:31:35,527 --> 00:31:40,165 I'M 74 YEARS OLD AND DIAGNOSED 757 00:31:40,165 --> 00:31:43,535 WITH TYPE I DIABETES IN 1967, I 758 00:31:43,535 --> 00:31:44,569 WAS 6-YEAR-OLD OLD. 759 00:31:44,569 --> 00:31:47,005 MOM WAS GIVEN A STRICT DIET FOR 760 00:31:47,005 --> 00:31:48,473 ME TO FOLLOW AND INSTRUCTIONS 761 00:31:48,473 --> 00:31:50,108 HOW TO ADMINISTER INSULIN. 762 00:31:50,108 --> 00:31:52,277 MOM GAVE ME ONE SHOT PER DAY. 763 00:31:52,277 --> 00:31:55,147 ONCE THE INSULIN WAS IN MY BODY 764 00:31:55,147 --> 00:31:56,681 I HAD TO EAT REGARDLESS OF 765 00:31:56,681 --> 00:31:56,948 APPETITE. 766 00:31:56,948 --> 00:32:00,485 WE FOUND OUT QUICKLY I HAD TO 767 00:32:00,485 --> 00:32:02,487 EAT ON TIME FOR ALL MEALS OR 768 00:32:02,487 --> 00:32:05,991 SUFFER THE RESULTS OF LOW BLOOD 769 00:32:05,991 --> 00:32:06,658 SUGAR. 770 00:32:06,658 --> 00:32:10,629 TO HELP THE DOCTOR DETERMINE 771 00:32:10,629 --> 00:32:12,097 EFFICACY OF THE REGIMENT WE 772 00:32:12,097 --> 00:32:13,398 LOGGED THE RESULTS OF TESTS FOUR 773 00:32:13,398 --> 00:32:14,666 TIMES A DAY. 774 00:32:14,666 --> 00:32:20,105 WHEN I WAS ABOUT 11 I BEGAN TO 775 00:32:20,105 --> 00:32:21,807 TAKE MY OWN SHOTS AND MANAGE 776 00:32:21,807 --> 00:32:24,409 WAYS FOR MY BLOOD SUGAR AND 777 00:32:24,409 --> 00:32:26,711 FOLLOWED THIS FOR AT LEAST 16 778 00:32:26,711 --> 00:32:26,912 YEARS. 779 00:32:26,912 --> 00:32:29,347 THE NEXT GAME CHANGER WAS THE 780 00:32:29,347 --> 00:32:31,650 HOME BLOOD GLUCOSE MONITOR. 781 00:32:31,650 --> 00:32:33,418 FOR THE FIRST TIME I COULD SEE 782 00:32:33,418 --> 00:32:37,756 MY BLOOD SUGAR LEVEL IN REAL 783 00:32:37,756 --> 00:32:39,658 TIME AND COULD ADJUST MY DIET 784 00:32:39,658 --> 00:32:41,593 ACCORDING TO THOSE RESULTS. 785 00:32:41,593 --> 00:32:44,229 1996 BROUGHT TWO WONDERFUL 786 00:32:44,229 --> 00:32:44,563 CHANGES. 787 00:32:44,563 --> 00:32:47,899 RAPID ACTING INSULIN AND INSULIN 788 00:32:47,899 --> 00:32:48,466 PROMPT. 789 00:32:48,466 --> 00:32:50,569 RAPID ACTING INSULIN BEGAN 790 00:32:50,569 --> 00:32:53,004 ACTING MORE QUICKLY THAN THE 791 00:32:53,004 --> 00:32:54,840 OLDER INSULINS DID. 792 00:32:54,840 --> 00:32:57,409 THE INSULIN PUMP FREED ME FROM 793 00:32:57,409 --> 00:32:59,077 HAVING TO EAT FOOD TO MATCH MY 794 00:32:59,077 --> 00:32:59,344 INSULIN. 795 00:32:59,344 --> 00:33:01,746 NOW I COULD TAKE IT TO MATCH 796 00:33:01,746 --> 00:33:05,617 WHAT I ATE WHEN I CHOSE TO EAT. 797 00:33:05,617 --> 00:33:07,652 CONTINUOUS GLUCOSE MONITORS HAVE 798 00:33:07,652 --> 00:33:09,387 BEEN THE BIGGEST GAME CHANGER 799 00:33:09,387 --> 00:33:09,621 YET. 800 00:33:09,621 --> 00:33:10,922 I'M NOT LIMITED TOE CHECK IN 801 00:33:10,922 --> 00:33:12,858 JUST FOUR TIMES A DAY. 802 00:33:12,858 --> 00:33:17,095 NOW I CAN ALWAYS KNOW WHAT MY 803 00:33:17,095 --> 00:33:19,464 BLOOD SUGAR IS. 804 00:33:19,464 --> 00:33:20,098 I'VE TAUGHT CHILDREN FOR 30 805 00:33:20,098 --> 00:33:22,467 YEARS AND IN MY LAST YEAR I HAD 806 00:33:22,467 --> 00:33:23,635 THREE STUDENTS WITH DIABETES. 807 00:33:23,635 --> 00:33:26,471 WE HAD A SPECIAL UNDERSTANDING 808 00:33:26,471 --> 00:33:30,642 ALMOST AN EXCLUSIVE CLUB BECAUSE 809 00:33:30,642 --> 00:33:32,277 WE GOT IT. 810 00:33:32,277 --> 00:33:33,812 ENCOURAGED WITH THE KNOWLEDGE WE 811 00:33:33,812 --> 00:33:34,746 AND SCIENTISTS ARE WORKING TO 812 00:33:34,746 --> 00:33:38,083 NOT ONLY FIND A CURE BUT RAISED 813 00:33:38,083 --> 00:33:40,518 TO MAKE OUR LIVES WITH DIABETES 814 00:33:40,518 --> 00:33:44,689 EASIER IN THE MEANTIME IS 815 00:33:44,689 --> 00:33:44,990 INVALUABLE. 816 00:33:44,990 --> 00:33:46,424 >> MY THANKS AGAIN TO BRENDA. 817 00:33:46,424 --> 00:33:48,727 IT WAS AN AMAZING INTERVIEW WITH 818 00:33:48,727 --> 00:33:50,362 HER AND IT WAS A CUT DOWN 819 00:33:50,362 --> 00:33:53,565 VERSION OF IT BUT IT SHOWS HOW 820 00:33:53,565 --> 00:33:56,868 AGAIN RESEARCH CAN IMPACT THE 821 00:33:56,868 --> 00:33:58,737 LIFE AND IT IT'S TO KNOW GOING 822 00:33:58,737 --> 00:34:00,972 FROM ONE SHOT A DAY INSULIN TO 823 00:34:00,972 --> 00:34:06,344 THIS WHERE WE ARE TODAY IS A BIG 824 00:34:06,344 --> 00:34:06,878 FACTOR. 825 00:34:06,878 --> 00:34:08,780 LET'S NOW SWITCH GEARS JUST A 826 00:34:08,780 --> 00:34:14,219 LITTLE BIT AND WHAT I WANTED TO 827 00:34:14,219 --> 00:34:17,088 DO IS TO SAY, ALL RIGHT, WHETHER 828 00:34:17,088 --> 00:34:19,257 YOU MENTIONED A NUMBER OF THESE 829 00:34:19,257 --> 00:34:20,425 CHANGES, LET'S GO THROUGH THEM 830 00:34:20,425 --> 00:34:23,261 WHAT WE'VE SEEN AND THEN TAKE 831 00:34:23,261 --> 00:34:26,498 SOME OF THEM THAT HAVE IMPACT 832 00:34:26,498 --> 00:34:27,966 WITH HIRN. 833 00:34:27,966 --> 00:34:30,802 I POLLED EXPERTS ACROSS THE 834 00:34:30,802 --> 00:34:31,636 COUNTRY FAR SMARTER THAN ME AND 835 00:34:31,636 --> 00:34:34,205 SAID I HAVE A PILOT LIST AND 836 00:34:34,205 --> 00:34:37,242 WITH A FEW ADDITIONS IT WAS 837 00:34:37,242 --> 00:34:38,443 UNIVERSALLY THOUGHT EVERYBODY 838 00:34:38,443 --> 00:34:41,112 MAY HAVE THEIR OPINIONS. 839 00:34:41,112 --> 00:34:43,682 EVERY ONE OF THESE ADVANCEMENTS 840 00:34:43,682 --> 00:34:47,018 THANKS TO NIDDK AND THEY'RE 841 00:34:47,018 --> 00:34:47,852 CELEBRATING THEIR 75th 842 00:34:47,852 --> 00:34:50,288 ANNIVERSARY AND SOME LIKE THE 843 00:34:50,288 --> 00:34:53,091 INSULIN FORMULATIONS AND THE CGM 844 00:34:53,091 --> 00:34:54,993 BRENDA MEASURED AND MANAGEMENT 845 00:34:54,993 --> 00:34:57,762 TOOLS ARE DIRECTLY IMPACTED BY 846 00:34:57,762 --> 00:34:58,863 WHAT YOU AS HIRN INVESTIGATORS 847 00:34:58,863 --> 00:35:01,633 WILL DO ONE DAY BUT THE BOTTOM 848 00:35:01,633 --> 00:35:04,502 FIVE I THINK ARE MORE DIRECTLY 849 00:35:04,502 --> 00:35:05,904 RELATED AND LET'S SEE HOW WHAT I 850 00:35:05,904 --> 00:35:08,807 WANT TO DO IS GO THROUGH THEM 851 00:35:08,807 --> 00:35:11,543 AND SEE HOW HIRN CAN MAKE A 852 00:35:11,543 --> 00:35:13,611 DIFFERENCE AND IMPACT. 853 00:35:13,611 --> 00:35:15,914 THE FIRST ONE I WANT TO TALK 854 00:35:15,914 --> 00:35:18,783 WITH IS DEFINING DIABETES AS AN 855 00:35:18,783 --> 00:35:19,918 AUTO IMMUNE DISEASE. 856 00:35:19,918 --> 00:35:22,454 ON THE RIGHT SIDE OF THE SCREEN 857 00:35:22,454 --> 00:35:27,025 IS THE THREE DIMENSIONAL VIEW OF 858 00:35:27,025 --> 00:35:31,563 HUMAN INSULINITIS AND IT WAS A 859 00:35:31,563 --> 00:35:33,732 DESCRIPTION FIRST FOUND IN 1903 860 00:35:33,732 --> 00:35:36,401 BY A GERMAN PATHOLOGIST NOTING 861 00:35:36,401 --> 00:35:38,136 SOME PEOPLE WHO HAD THIS FORM OF 862 00:35:38,136 --> 00:35:40,372 DIABETES HAD A WHITE BLOOD CELL 863 00:35:40,372 --> 00:35:44,743 OR CELLULAR INFILTRATE OF IT. 864 00:35:44,743 --> 00:35:47,278 WE NOW KNOW WE HAVE LOSS OF BETA 865 00:35:47,278 --> 00:35:49,147 CELLS AND IN THE OTHER THOUGHT 866 00:35:49,147 --> 00:35:53,018 IS THIS FORMS A FUNDAMENTAL 867 00:35:53,018 --> 00:35:56,721 BASIS FOR TYPE I DIABETES AND 868 00:35:56,721 --> 00:35:59,991 AUTO IMMUNE DISEASE BUT THE 869 00:35:59,991 --> 00:36:10,535 PANCREAS IS NOT A TISSUE YOU CAN 870 00:36:18,176 --> 00:36:19,944 BIOPSY AND SOME GROUPS IT WERE 871 00:36:19,944 --> 00:36:22,414 DIRECTLY RELATED AND WE NEED 872 00:36:22,414 --> 00:36:23,348 GREATER BIOMEDICALS THAT MAY 873 00:36:23,348 --> 00:36:26,084 TELL US WHAT IS GOING ON AT THE 874 00:36:26,084 --> 00:36:27,352 SITE OF THE DESCRIPTIONIVE 875 00:36:27,352 --> 00:36:27,585 PROCESS. 876 00:36:27,585 --> 00:36:28,219 MANY OF THE HIRN GROUPS ARE 877 00:36:28,219 --> 00:36:30,422 WORKING ON THAT. 878 00:36:30,422 --> 00:36:36,261 SO A VERY EFFECTIVE USE OF HIRN. 879 00:36:36,261 --> 00:36:38,196 ANOTHER MAJOR TOP 10 ADVANCE HAS 880 00:36:38,196 --> 00:36:44,402 BEEN IN THE AREA OF GENETICS AND 881 00:36:44,402 --> 00:36:46,304 SEROLOGICAL BIOMARKERS AND 882 00:36:46,304 --> 00:36:48,640 PEOPLE THOUGHT THERE WERE ONE TO 883 00:36:48,640 --> 00:36:53,945 THREE GENES OR LOCI THAT FORM 884 00:36:53,945 --> 00:36:57,182 THE GENETIC BASIS OF TYPE I 885 00:36:57,182 --> 00:36:59,517 DIABETES AND NOW WE KNOW THERE'S 886 00:36:59,517 --> 00:37:03,254 OVER 100 AND THE BIG ONE IS HLA1 887 00:37:03,254 --> 00:37:05,190 HIGHLIGHTED IN BLUE, THE 888 00:37:05,190 --> 00:37:09,394 MOLECULE THAT IS POLY GENIC BY 889 00:37:09,394 --> 00:37:12,530 NATURE AND VARIES BETWEEN US BUT 890 00:37:12,530 --> 00:37:15,767 INDIVIDUALS WITH A FORM OF HLA 891 00:37:15,767 --> 00:37:19,270 FORM THE LARGEST FORM OF 892 00:37:19,270 --> 00:37:21,940 INDIVIDUALS WITH TYPE I DIABETES 893 00:37:21,940 --> 00:37:23,108 AND THERE'S OTHER GENES INVOLVED 894 00:37:23,108 --> 00:37:26,277 IN MANY THINGS FROM BETA CELLS 895 00:37:26,277 --> 00:37:28,313 TO PANCREAS DEVELOPMENT TO 896 00:37:28,313 --> 00:37:30,448 IMMUNE RESPONSE SHOWN HERE THAT 897 00:37:30,448 --> 00:37:33,051 FORM PART OF THESE LOCI AND SO 898 00:37:33,051 --> 00:37:39,190 HIRN HAS A CHANCE TO REALLY GET 899 00:37:39,190 --> 00:37:41,593 INVOLVED HERE AND TRY TO FIND 900 00:37:41,593 --> 00:37:47,098 WHAT IT DOES. 901 00:37:47,098 --> 00:37:49,868 ANOTHER NEW DEVELOPMENT IS TO 902 00:37:49,868 --> 00:37:52,270 TAKE WHEN YOU HAVE SO MANY LOCI 903 00:37:52,270 --> 00:37:53,738 HOW CAN YOU COMBINED THEM TO 904 00:37:53,738 --> 00:37:56,608 MAKE THEM SOMETHING MORE 905 00:37:56,608 --> 00:38:03,882 EFFECTIVE IN TERMS OF AND HAVE 906 00:38:03,882 --> 00:38:14,425 IMPACT AND THAT'S SHOEB HERE 1 907 00:38:18,463 --> 00:38:21,866 >> WITH GENETIC RISK SCORES AND 908 00:38:21,866 --> 00:38:24,235 SEPARATE THOSE WITH TYPE I OR 909 00:38:24,235 --> 00:38:25,336 MONOGENIC DIABETES. 910 00:38:25,336 --> 00:38:30,808 IN THIS STAGE IN DIAGNOSIS HAS 911 00:38:30,808 --> 00:38:34,245 IMPLICATIONS THE RATE PATIENT IS 912 00:38:34,245 --> 00:38:35,180 TREATED WITH WITH THE RIGHT DRUG 913 00:38:35,180 --> 00:38:37,048 AT THE RIGHT TIME. 914 00:38:37,048 --> 00:38:38,817 AND ANOTHER AREA IS ABOUT THE 915 00:38:38,817 --> 00:38:40,952 BENEFITS OF THE SEROLOGICAL 916 00:38:40,952 --> 00:38:47,859 MARKER DISCOVERIES STARTED OUT 917 00:38:47,859 --> 00:38:58,369 IN THE MID TO MID '70s AND 918 00:39:06,511 --> 00:39:08,446 ANTIBODIES AND MANY LISTED HERE 919 00:39:08,446 --> 00:39:10,648 AND THERE'S A WHOLE CONSORTIUM 920 00:39:10,648 --> 00:39:11,883 WITH MANY DIFFERENT SITES 921 00:39:11,883 --> 00:39:14,185 WORKING ON THESE DATA AND OTHERS 922 00:39:14,185 --> 00:39:20,058 LIKE IT, IT WAS FOUND WHEN YOU 923 00:39:20,058 --> 00:39:25,964 FOLLOW RELATIVES AT RISK FOR 924 00:39:25,964 --> 00:39:27,999 TYPE I DIABETES AT ONE TIME AND 925 00:39:27,999 --> 00:39:31,135 IF YOU HAVE ONE ANTIBODY THE 926 00:39:31,135 --> 00:39:32,537 OVER ALL RISK FOR DEVELOPING 927 00:39:32,537 --> 00:39:35,106 TYPE I IN 10 OR 20 YEARS IS 928 00:39:35,106 --> 00:39:37,242 LOWER THAN FOR SOMETHING WITH 929 00:39:37,242 --> 00:39:44,682 THREE AUTO ANTIBODIES AND WE 930 00:39:44,682 --> 00:39:47,552 KNOW SIMILAR FINDINGS OCCUR. 931 00:39:47,552 --> 00:39:50,121 WHAT'S THE BIG DEAL ABOUT MOVING 932 00:39:50,121 --> 00:39:50,989 TO GENERAL POPULATION? 933 00:39:50,989 --> 00:39:55,226 IT'S CURRENTLY ESTIMATED BETWEEN 934 00:39:55,226 --> 00:39:58,596 85% AND 92% OF NEW ONSET CASES 935 00:39:58,596 --> 00:40:00,465 OF DIABETES DON'T OCCUR IN 936 00:40:00,465 --> 00:40:01,933 INDIVIDUAL WITH A FAMILY HISTORY 937 00:40:01,933 --> 00:40:02,433 OF DISEASE. 938 00:40:02,433 --> 00:40:05,570 THAT'S THE GREAT FRONTIER AND 939 00:40:05,570 --> 00:40:08,273 MANY PROGRAMS HAVE BEEN FORMED 940 00:40:08,273 --> 00:40:11,042 AND INTERNATIONAL DATA ON THIS. 941 00:40:11,042 --> 00:40:13,578 BUT THERE ARE NEEDS THERE. 942 00:40:13,578 --> 00:40:14,579 THEY PROVIDE BENEFIT. 943 00:40:14,579 --> 00:40:16,281 IF YOU SCREEN YOU HAVE REDUCED 944 00:40:16,281 --> 00:40:18,316 RISK FOR DKA. 945 00:40:18,316 --> 00:40:20,051 WE CAN IDENTIFY PEOPLE TO BE PUT 946 00:40:20,051 --> 00:40:20,652 IN TRIALS. 947 00:40:20,652 --> 00:40:23,087 BUT THERE ARE NEEDS FOR MORE. 948 00:40:23,087 --> 00:40:24,722 WE NEED BIOMARKERS THAT CAN BE 949 00:40:24,722 --> 00:40:29,027 USED WITH AUTO ANTIBODIES AND WE 950 00:40:29,027 --> 00:40:30,528 NEED TO FIND OUT WHAT TAKES 951 00:40:30,528 --> 00:40:31,829 SOMETHING FROM RISK TO DISEASE 952 00:40:31,829 --> 00:40:35,266 TO DEVELOPMENT AND HIRN STUDIES 953 00:40:35,266 --> 00:40:36,434 HAVE THE OPPORTUNITY TO ADD TO 954 00:40:36,434 --> 00:40:37,835 THAT KNOWLEDGE BASE. 955 00:40:37,835 --> 00:40:39,370 AND ANOTHER ONE AND THIS MAY BE 956 00:40:39,370 --> 00:40:40,638 ONE OF MY FAVORITE ADVANCES IN 957 00:40:40,638 --> 00:40:43,775 THE JOURNEY IS IMPROVED STUDIES 958 00:40:43,775 --> 00:40:45,076 OF THE NATURAL HISTORY OF 959 00:40:45,076 --> 00:40:47,111 DIABETES STARTING IN 1986 AND 960 00:40:47,111 --> 00:40:51,449 THIS IS PROBABLY THE MOST SHOWN 961 00:40:51,449 --> 00:40:53,318 FIGURE AND POWER POINT 962 00:40:53,318 --> 00:40:56,321 PRESENTATIONS IN THE LAST 50 963 00:40:56,321 --> 00:40:59,157 YEARS IS THIS MODEL OF NATURAL 964 00:40:59,157 --> 00:41:01,225 HISTORY STARTING WITH A BETA 965 00:41:01,225 --> 00:41:02,994 CELLS FOR REASONS STILL UNKNOWN 966 00:41:02,994 --> 00:41:05,730 THERE BEGINS A PROCESS OF LOSS 967 00:41:05,730 --> 00:41:07,265 OF BETA CELLS THAT EVENTUALLY 968 00:41:07,265 --> 00:41:13,538 RESULTS IN INSULIN DEPENDENCE. 969 00:41:13,538 --> 00:41:15,973 SOME OF THESE INITIAL THOUGHTS 970 00:41:15,973 --> 00:41:20,678 HAVE UNDER GONE MODIFICATION BUT 971 00:41:20,678 --> 00:41:22,513 SERVED AS AN INCREDIBLE ROAD MAP 972 00:41:22,513 --> 00:41:23,982 FOR GENERATIONS TO UNDERSTAND 973 00:41:23,982 --> 00:41:24,515 THE DISEASE. 974 00:41:24,515 --> 00:41:25,950 FAST FORWARD TO DISEASE AND THE 975 00:41:25,950 --> 00:41:27,819 MODEL ON THE RIGHT SIDE IS 976 00:41:27,819 --> 00:41:30,455 UNDERGOING CHANGES BUT NOW YOU 977 00:41:30,455 --> 00:41:33,224 LEARN A FEW TALKS TODAY ABOUT 978 00:41:33,224 --> 00:41:37,061 STAGES OF TYPE I. 979 00:41:37,061 --> 00:41:39,564 WE TALK ABOUT STAGE I DISEASE 980 00:41:39,564 --> 00:41:42,000 PEOPLE WITH TWO OR MORE 981 00:41:42,000 --> 00:41:45,636 ANTIBODIES AND NO DISCERNIBLE 982 00:41:45,636 --> 00:41:46,471 METABOLIC ABNORMALITIES AND 983 00:41:46,471 --> 00:41:49,474 STAGE II, MULTIPLE ANTIBODIES 984 00:41:49,474 --> 00:41:55,646 AND ASSOCIATED WITH DYSGLYCEMIA 985 00:41:55,646 --> 00:42:04,389 AND STAGE II THE DIAGNOSIS OF 986 00:42:04,389 --> 00:42:07,125 DIABETES AND DESCRIBING 987 00:42:07,125 --> 00:42:08,459 INSULINITIS AND WHEN IT OCCURS 988 00:42:08,459 --> 00:42:10,561 AND AT WHAT STAGE WE DON'T KNOW 989 00:42:10,561 --> 00:42:12,830 WHAT TO CALL IT YET MANY SOME 990 00:42:12,830 --> 00:42:21,305 CALL IT STAGE ZERO OR SOME CALL 991 00:42:21,305 --> 00:42:26,944 IT STAGE .5, THERE ARE BETA CELL 992 00:42:26,944 --> 00:42:27,979 ABNORMALITIES OCCUR BEFORE 993 00:42:27,979 --> 00:42:29,347 PEOPLE DEVELOP MULTIPLE 994 00:42:29,347 --> 00:42:30,081 ANTIBODIES AND THEY'RE 995 00:42:30,081 --> 00:42:31,682 CONTINUING TO PUSH FORWARD IN 996 00:42:31,682 --> 00:42:38,456 STUDIES ON ENVIRONMENTAL AGENT. 997 00:42:38,456 --> 00:42:42,527 -- AGENTS. 998 00:42:42,527 --> 00:42:44,962 THE NEXT THING IS AUTO IMMUNE 999 00:42:44,962 --> 00:42:45,263 THERAPIES. 1000 00:42:45,263 --> 00:42:47,298 THIS MAY BE OBVIOUS WITH ALL THE 1001 00:42:47,298 --> 00:42:49,434 HIRN PROJECTS THAT HAVE 1002 00:42:49,434 --> 00:42:51,436 IMMUNOLOGY IN THEM BUT IT'S NOT 1003 00:42:51,436 --> 00:42:56,574 A NEW CONCEPT. 1004 00:42:56,574 --> 00:43:07,051 THE FIRST TRIALS BEGAN WITH 1005 00:43:10,087 --> 00:43:12,824 CYCLOSPORIN AND THE TOXICITIES 1006 00:43:12,824 --> 00:43:15,793 ASSOCIATED WITH IT PRECLUDED ITS 1007 00:43:15,793 --> 00:43:18,429 USE BUT WHERE DID IT LEAVE US? 1008 00:43:18,429 --> 00:43:28,739 THAT DIDN'T STALL. 1009 00:43:29,173 --> 00:43:36,481 IT'S ESTIMATED SINCE 1010 00:43:36,481 --> 00:43:41,719 CYCLOSPORINE MANY HAVE 1011 00:43:41,719 --> 00:43:48,025 PARTICIPATED IN THE TRIALS. 1012 00:43:48,025 --> 00:43:53,097 IT'S BEEN INEFFICIENT AND WE RUN 1013 00:43:53,097 --> 00:43:54,832 CLINICAL TRIALS VERY WELL IN 1014 00:43:54,832 --> 00:43:55,533 THANKS DUE TO EFFORTS 1015 00:43:55,533 --> 00:44:02,440 DR. RODGERS MENTIONED. 1016 00:44:02,440 --> 00:44:05,343 THE PROBLEM OF SUCCESS STORIES 1017 00:44:05,343 --> 00:44:07,712 HAS BEEN LOW. 1018 00:44:07,712 --> 00:44:10,882 THAT CHANGED WITH THIS NTCD3 1019 00:44:10,882 --> 00:44:12,817 SHOWN ON THE RIGHT. 1020 00:44:12,817 --> 00:44:15,953 THE FIRST IN-CLASS FDA APPROVED 1021 00:44:15,953 --> 00:44:20,925 DRUG THAT AS IS SHOWN IN THE 1022 00:44:20,925 --> 00:44:22,593 MIDDLE THERE AND IN MATCH 1023 00:44:22,593 --> 00:44:23,895 POPULATIONS AT RISK FOR DIABETES 1024 00:44:23,895 --> 00:44:28,933 IF YOU ADMINISTER THIS DRUG YOU 1025 00:44:28,933 --> 00:44:32,637 HAVE THE POTENTIAL TO DELAY 1026 00:44:32,637 --> 00:44:35,106 SYMPTOMATIC ONSET FROM 27 MONTHS 1027 00:44:35,106 --> 00:44:36,374 OUT TO THREE YEARS. 1028 00:44:36,374 --> 00:44:38,643 EFFORTS ARE GOING ON TO IMPROVE 1029 00:44:38,643 --> 00:44:41,245 THAT BUT WE DO HAVE A SUCCESS 1030 00:44:41,245 --> 00:44:43,814 STORY NOW. 1031 00:44:43,814 --> 00:44:46,450 IT'S FUNNY AFTER ALL THESE YEARS 1032 00:44:46,450 --> 00:44:51,155 OF HAVING LIMITED SUCCESS NOW WE 1033 00:44:51,155 --> 00:44:52,156 HAVE A LOT OF DRUGS SHOWING 1034 00:44:52,156 --> 00:44:53,491 SUCCESS AND THIS ARTICLE WAS 1035 00:44:53,491 --> 00:44:55,426 LATE LAST YEAR IN THE LANCET 1036 00:44:55,426 --> 00:44:58,696 SHOWING WE NOW HAVE ABOUT 10 1037 00:44:58,696 --> 00:45:04,302 DRUGS IMMUNE MODULATORS WITH THE 1038 00:45:04,302 --> 00:45:14,712 ABILITY TO PROVIDE BENEFIT BUT 1039 00:45:14,712 --> 00:45:18,449 WE STILL DON'T KNOW WHAT CAUSES 1040 00:45:18,449 --> 00:45:24,555 TYPE I DIABETES AT A MOLECULAR 1041 00:45:24,555 --> 00:45:26,490 LEVEL AND HIRN IS WORKING ON 1042 00:45:26,490 --> 00:45:27,792 THAT AND THERE'S OTHER ISSUES 1043 00:45:27,792 --> 00:45:29,327 THE COMMUNITY HAS TO WORK ON 1044 00:45:29,327 --> 00:45:34,632 INCLUDING HOW TO TREAT WHEN AND 1045 00:45:34,632 --> 00:45:44,809 WHAT WITH. 1046 00:45:48,412 --> 00:45:54,085 THERE'S TWO MORE AREAS AND MANY 1047 00:45:54,085 --> 00:45:56,654 PATIENTS BENEFIT FROM PANCREAS 1048 00:45:56,654 --> 00:45:58,456 AND KIDNEY TRANSPLANTATION. 1049 00:45:58,456 --> 00:46:02,226 YOU WANT TO TALK ABOUT THE GROUP 1050 00:46:02,226 --> 00:46:07,331 IN ST. LOUIS OR THEIR 1051 00:46:07,331 --> 00:46:09,233 PREDECESS 1052 00:46:09,233 --> 00:46:15,339 PREDECESSORS AND THE GROUP BACK 1053 00:46:15,339 --> 00:46:19,176 IN 2004 AND THE FIRST CARTICO 1054 00:46:19,176 --> 00:46:23,347 STEROID FREE USE OF ISLETS 1055 00:46:23,347 --> 00:46:27,018 SHOWING POSITIVE BENEFIT AND TWO 1056 00:46:27,018 --> 00:46:29,020 CAREERS LATER THIS WAS PUT 1057 00:46:29,020 --> 00:46:29,787 THROUGH AN INTERNATIONAL 1058 00:46:29,787 --> 00:46:30,821 CONSORTIUM TO REPEAT. 1059 00:46:30,821 --> 00:46:40,631 WE'VE LEARNED A LOT FROM ISLET 1060 00:46:40,631 --> 00:46:45,069 CELL TRANSPLANTATION AND 55 1061 00:46:45,069 --> 00:46:47,238 PATIENTS AND 10,000 ORGAN DONORS 1062 00:46:47,238 --> 00:46:51,842 THERE'S A MATH PROBLEM. 1063 00:46:51,842 --> 00:46:58,449 BUS WHEN YOU TALK ABOUT AL 1064 00:46:58,449 --> 00:47:01,218 ALLOGENEIC SETTING AND SHOWING 1065 00:47:01,218 --> 00:47:02,453 IS THIS OPTIMAL? 1066 00:47:02,453 --> 00:47:04,155 THE LAST BIG DISCOVERY I WANT TO 1067 00:47:04,155 --> 00:47:06,290 GO THROUGH BEFORE I CLOSE OUT IS 1068 00:47:06,290 --> 00:47:11,662 THAT THE WHOLE PROCESS OF ISLET 1069 00:47:11,662 --> 00:47:13,431 ISOLATION AND STUDIES IN ISLET 1070 00:47:13,431 --> 00:47:19,804 BIOLOGY AND CELL DEVELOPMENT AND 1071 00:47:19,804 --> 00:47:22,640 REPLICATION AND TALKING WITH 1072 00:47:22,640 --> 00:47:25,910 AUDREY AND THEY WERE SAYING THE 1073 00:47:25,910 --> 00:47:27,344 STEM CELL FIELD WOULD NOT BE 1074 00:47:27,344 --> 00:47:29,080 WHERE IT IS WITHOUT THIS AREA OF 1075 00:47:29,080 --> 00:47:29,447 ADVANCE. 1076 00:47:29,447 --> 00:47:32,149 YOU CAN GO FROM THE RECORDING 1077 00:47:32,149 --> 00:47:35,486 CHAMBERS SYSTEM HERE OF 25 YEARS 1078 00:47:35,486 --> 00:47:37,588 AGO TO ISOLATE ISLETS. 1079 00:47:37,588 --> 00:47:41,926 WE LEARNED HOW TO STUDY ISLETS 1080 00:47:41,926 --> 00:47:44,462 THROUGH THESE NOTIONS BUT ISSUES 1081 00:47:44,462 --> 00:47:46,363 FROM COST, SCALABILITY, UNKNOWNS 1082 00:47:46,363 --> 00:47:47,765 ARE OUT THERE. 1083 00:47:47,765 --> 00:47:49,366 SO THE FUTURE AND AGAIN I'M NOT 1084 00:47:49,366 --> 00:47:51,869 GOING IN DEEP HERE BECAUSE 1085 00:47:51,869 --> 00:47:55,339 YOU'LL HEAR WITH THE NEXT TWO 1086 00:47:55,339 --> 00:47:58,442 SPEAKERS A LOT OF THE FUTURE IS 1087 00:47:58,442 --> 00:48:08,686 IN STEM CELLS. 1088 00:48:09,053 --> 00:48:14,391 IS IS IS CAN CAN 1089 00:48:14,825 --> 00:48:21,799 AGE IS ON THE BOTTOM AND OUR 1090 00:48:21,799 --> 00:48:24,702 INDICATOR OF MANAGEMENT IS ON 1091 00:48:24,702 --> 00:48:25,436 THE OTHER AXIS. 1092 00:48:25,436 --> 00:48:31,709 WHAT YOU CAN SEE IS WITH TIME WE 1093 00:48:31,709 --> 00:48:33,210 ARE GETTING A LITTLE BIT BETTER 1094 00:48:33,210 --> 00:48:35,846 BUT AT THE BOTTOM OUR ADA 1095 00:48:35,846 --> 00:48:39,350 TARGETS ARE 7 AND SOME ARE 1096 00:48:39,350 --> 00:48:41,085 MEETING IT BUT THE VAST MAJORITY 1097 00:48:41,085 --> 00:48:43,888 DON'T MEET AND THERE'S A GAP 1098 00:48:43,888 --> 00:48:45,422 BETWEEN MEETING CLINICAL 1099 00:48:45,422 --> 00:48:46,857 THERAPEUTIC TARGETS AND WHERE 1100 00:48:46,857 --> 00:48:49,160 WARE AND THE REASONS RANK FROM 1101 00:48:49,160 --> 00:48:50,861 COST, EDUCATION, DEVICE, TRYING 1102 00:48:50,861 --> 00:48:53,364 TO EDUCATE PEOPLE TO USE IT, 1103 00:48:53,364 --> 00:48:54,465 REIMBURSEMENT AND ACCESS ISSUES 1104 00:48:54,465 --> 00:48:57,067 IF YOU START TO THINK ABOUT 1105 00:48:57,067 --> 00:48:58,202 GLOBALLY. 1106 00:48:58,202 --> 00:49:00,437 WE NEED TO DO THINGS BETTER 1107 00:49:00,437 --> 00:49:01,539 DESPITE EVERYTHING BRENDA SAID 1108 00:49:01,539 --> 00:49:04,608 AND SHE'S HAPPY AS CAN BE BUT 1109 00:49:04,608 --> 00:49:05,109 THERE'S MORE. 1110 00:49:05,109 --> 00:49:08,279 AND THERE'S ALL THE MENTAL 1111 00:49:08,279 --> 00:49:10,347 HEALTH CARE ISSUES WE'VE BEEN 1112 00:49:10,347 --> 00:49:11,182 AFRAID TO SPEAK OF. 1113 00:49:11,182 --> 00:49:13,818 THE FEAR OF COMPLICATIONS AND 1114 00:49:13,818 --> 00:49:14,652 LIFESTYLE ISSUES AND MENTAL 1115 00:49:14,652 --> 00:49:16,487 HEALTH CARE COSTS AND THE 1116 00:49:16,487 --> 00:49:18,355 CHALLENGES BOTH WITHIN THE 1117 00:49:18,355 --> 00:49:19,723 FAMILY, WITHIN THE COMMUNITY AND 1118 00:49:19,723 --> 00:49:22,459 WITHIN EMPLOYMENT SETTINGS AND 1119 00:49:22,459 --> 00:49:25,963 SCHOOL SETTINGS. 1120 00:49:25,963 --> 00:49:27,765 AND HERE'S AS LOU PHILLIPSON 1121 00:49:27,765 --> 00:49:29,266 TOLD ME ABOUT THIS AND I SAID 1122 00:49:29,266 --> 00:49:30,434 WHERE DID YOU HEAR THIS AND I 1123 00:49:30,434 --> 00:49:34,872 LOOKED IT UP. 1124 00:49:34,872 --> 00:49:38,375 PEOPLE WITH TYPE II DIABETES 1125 00:49:38,375 --> 00:49:40,845 TAKE MORE THAN 180 ADDITIONAL 1126 00:49:40,845 --> 00:49:42,613 DECISIONS A DAY AND MARK THAT 1127 00:49:42,613 --> 00:49:45,382 OUT BY WEEKS, MONTHS, YEARS, 1128 00:49:45,382 --> 00:49:46,717 THAT'S A LOT OF THOUGHTS. 1129 00:49:46,717 --> 00:49:51,121 IF IT'S LACED WITH THESE 1130 00:49:51,121 --> 00:49:52,456 CONCEPTUALIZATIONS, THERE'S A 1131 00:49:52,456 --> 00:49:55,626 NEED FOR IMPROVEMENT. 1132 00:49:55,626 --> 00:49:57,728 HIRN HELPED CHANGE THIS COURSE 1133 00:49:57,728 --> 00:49:59,029 AND MY THOUGHT WAS WHAT HAPPENED 1134 00:49:59,029 --> 00:50:01,165 IN THE PAST AND WHAT IS HIRN 1135 00:50:01,165 --> 00:50:03,234 POISED TO DO AND WHAT HAS IT 1136 00:50:03,234 --> 00:50:06,770 DONE IN ITS 10 YEARS. 1137 00:50:06,770 --> 00:50:11,408 THIS ONE WHEN WE TALKED TO 1138 00:50:11,408 --> 00:50:13,077 OLIVIER AND THE NUMBER ONE 1139 00:50:13,077 --> 00:50:16,847 ACCOMPLISHMENT OF HIRN IS IT 1140 00:50:16,847 --> 00:50:18,716 FACILITATED A FOCUS OF IT TYPE I 1141 00:50:18,716 --> 00:50:20,484 DIABETES IS A STUDY OF HUMAN 1142 00:50:20,484 --> 00:50:22,786 DISEASE AND HUMAN TISSUES. 1143 00:50:22,786 --> 00:50:25,322 THE GROUP YOU'VE SEEN WITH ALL 1144 00:50:25,322 --> 00:50:28,058 THE REPORTS ARE DOWNLOADABLE AS 1145 00:50:28,058 --> 00:50:28,259 PDFs. 1146 00:50:28,259 --> 00:50:30,261 THERE'S THE SITE FOR IT SO IF 1147 00:50:30,261 --> 00:50:32,930 YOU WANT TO GET REAL IN DEPTH TO 1148 00:50:32,930 --> 00:50:34,265 WHAT HIRN'S DONE THE REPORTS ARE 1149 00:50:34,265 --> 00:50:37,067 GOOD AS IS THE SPECIAL ISSUE OF 1150 00:50:37,067 --> 00:50:38,469 MOLECULAR METABOLISM THAT CAME 1151 00:50:38,469 --> 00:50:41,105 OUT. 1152 00:50:41,105 --> 00:50:42,640 AND NOT GOING TO SPEND TOO MUCH 1153 00:50:42,640 --> 00:50:45,075 TIME HERE BECAUSE JOHN WENT 1154 00:50:45,075 --> 00:50:47,378 THROUGH IT BUT ONE THE MAIN 1155 00:50:47,378 --> 00:50:49,280 ACHIEVEMENTS OF HIRN IN THE 10 1156 00:50:49,280 --> 00:50:51,415 YEARS HAS BEEN TO DEFINE THE 1157 00:50:51,415 --> 00:50:56,720 MANY MANY ROLES FOR BETA AND 1158 00:50:56,720 --> 00:50:59,356 ISLET CELL DISEASE AND AGAIN 1159 00:50:59,356 --> 00:51:02,459 YOU'LL HEAR PEOPLE FROM 1160 00:51:02,459 --> 00:51:04,328 RICHARDSON TO KRAUS AND OTHERS 1161 00:51:04,328 --> 00:51:05,129 THROUGHOUT THIS TALK BRING UP 1162 00:51:05,129 --> 00:51:07,798 SOME OF THESE. 1163 00:51:07,798 --> 00:51:10,434 THIS IS A FUNDAMENTAL CHANGE OF 1164 00:51:10,434 --> 00:51:11,435 THOUGHT. 1165 00:51:11,435 --> 00:51:13,304 AGAIN, FOR MOST OF MY EXISTENCE 1166 00:51:13,304 --> 00:51:16,874 THE BETA CELLS WERE FINE WHILE 1167 00:51:16,874 --> 00:51:18,642 MAYBE THEY HAD CHALLENGES AND 1168 00:51:18,642 --> 00:51:24,048 SOME STRESS BUT THE CHINK OF -- 1169 00:51:24,048 --> 00:51:26,216 CHUNK WAS ON THE IMMUNE SIDE AND 1170 00:51:26,216 --> 00:51:27,785 WE'RE STARTING TO POKE THE BEAR 1171 00:51:27,785 --> 00:51:29,453 ON THAT ONE AND SEE WHAT'S 1172 00:51:29,453 --> 00:51:30,654 INVOLVED HERE. 1173 00:51:30,654 --> 00:51:31,689 ANOTHER THING I THINK TALKING 1174 00:51:31,689 --> 00:51:35,092 ABOUT TRANSLATIONAL IS THE WAY 1175 00:51:35,092 --> 00:51:39,430 HIRN HAS HELPED DEFINE THE BETA 1176 00:51:39,430 --> 00:51:40,197 CELL PROLIFERATION. 1177 00:51:40,197 --> 00:51:42,466 TALK ABOUT A BLACK BOX FOR 1178 00:51:42,466 --> 00:51:43,500 DECADES. 1179 00:51:43,500 --> 00:51:46,370 HOW DO YOU GET A BETA CELL 1180 00:51:46,370 --> 00:51:48,105 DESIGN AND WHAT'S THE DIFFERENCE 1181 00:51:48,105 --> 00:51:52,109 BETWEEN MOUSE AND HUMAN BETA 1182 00:51:52,109 --> 00:51:56,213 CELLS AND HUGE PROGRESS AND HIRN 1183 00:51:56,213 --> 00:51:58,882 CAN TAKE PRIDE IN THAT IN IN 1184 00:51:58,882 --> 00:52:00,718 VITRO AND IN VIVO MOVING FORWARD 1185 00:52:00,718 --> 00:52:04,989 AND DEVELOPING NOVEL SYSTEMS AND 1186 00:52:04,989 --> 00:52:05,322 TECHNOLOGIES. 1187 00:52:05,322 --> 00:52:08,993 THEY BROUGHT TOGETHER BIO 1188 00:52:08,993 --> 00:52:11,061 MEDICAL ENGINEERS AND BIOLOGISTS 1189 00:52:11,061 --> 00:52:13,964 AND CELL BIOLOGISTS AND 1190 00:52:13,964 --> 00:52:15,132 DEVELOPED SYSTEMS AND SOME LABS 1191 00:52:15,132 --> 00:52:18,435 DON'T LOOK LIKE MY LAB IN THE 1192 00:52:18,435 --> 00:52:19,837 LOWER LEFT WHERE THERE'S DESIGN 1193 00:52:19,837 --> 00:52:23,874 KITS TO DO STUFF AND MAKING 1194 00:52:23,874 --> 00:52:26,577 MODULAR DEVICES TO GO FROM A 1195 00:52:26,577 --> 00:52:31,415 PANCREAS ON A CHIP AND THE AREA 1196 00:52:31,415 --> 00:52:38,455 IN THE PURPLE IS AN ISLET AND 1197 00:52:38,455 --> 00:52:40,858 YOU CAN VISUALIZE BETA CELL 1198 00:52:40,858 --> 00:52:41,291 KILLING. 1199 00:52:41,291 --> 00:52:46,397 AND BOTH SPEAKERS MENTIONED HIRN 1200 00:52:46,397 --> 00:52:50,868 AND WE THANK KLAUS AND THE GROUP 1201 00:52:50,868 --> 00:52:58,575 THERE FOR MAKING PANCDB SPECIAL. 1202 00:52:58,575 --> 00:53:00,044 THEY SAID OPEN ACCESS SHARING 1203 00:53:00,044 --> 00:53:03,347 WAS AN IMPORTANT FEATURE AND IT 1204 00:53:03,347 --> 00:53:04,782 MADE IT A VERY DIFFERENT 1205 00:53:04,782 --> 00:53:05,115 FEATURE. 1206 00:53:05,115 --> 00:53:08,952 THE OPPOSING FEATURE OF NPOD AND 1207 00:53:08,952 --> 00:53:12,556 THEY GIVE UM SAMPLES AND HOPE 1208 00:53:12,556 --> 00:53:14,992 DATA COMES BACK AND HIRN GETS 1209 00:53:14,992 --> 00:53:17,294 THE SAMPLES AND ANALYZES THE 1210 00:53:17,294 --> 00:53:20,197 DATA AND THE TWO IN TANDEM WORK 1211 00:53:20,197 --> 00:53:22,433 TOGETHER INCREDIBLY WELL. 1212 00:53:22,433 --> 00:53:24,168 THAT'S IMPORTANT. 1213 00:53:24,168 --> 00:53:26,070 THE FINAL THING I THINK HIRN HAS 1214 00:53:26,070 --> 00:53:28,906 DONE IS HIT HARD ON THE 1215 00:53:28,906 --> 00:53:31,875 INTERFACE OF BETA CELL AND AUTO 1216 00:53:31,875 --> 00:53:32,142 IMMUNITY. 1217 00:53:32,142 --> 00:53:34,478 WE AGAIN HISTORICALLY WE'VE BEEN 1218 00:53:34,478 --> 00:53:36,447 SILOED AS A COMMUNITY. 1219 00:53:36,447 --> 00:53:39,783 WE HAVE CLINICAL CONFERENCES AND 1220 00:53:39,783 --> 00:53:41,018 CELL BIOLOGY CONFERENCES AND 1221 00:53:41,018 --> 00:53:43,554 AUTO IMMUNITY CONFERENCES AND I 1222 00:53:43,554 --> 00:53:46,123 THINK WITHIN HIRN IT'S ONE OF 1223 00:53:46,123 --> 00:53:47,124 THE RICHEST GROUPS OUT THERE 1224 00:53:47,124 --> 00:53:49,126 BECAUSE YOU HAVE IT ALL HERE. 1225 00:53:49,126 --> 00:53:52,663 AND YET IT'S GOING TO TAKE THAT 1226 00:53:52,663 --> 00:53:53,897 TYPE OF EFFORT IN ORDER TO 1227 00:53:53,897 --> 00:53:54,598 FIGURE OUT THESE TYPES OF NEEDS 1228 00:53:54,598 --> 00:53:58,435 AND INTERACTION. 1229 00:53:58,435 --> 00:54:01,738 SO, HIRN IS POISED TO CHANGE THE 1230 00:54:01,738 --> 00:54:03,440 COURSE AND IMPROVE TYPE I 1231 00:54:03,440 --> 00:54:04,842 DIABETES MANAGEMENT IN THE 1232 00:54:04,842 --> 00:54:05,075 FUTURE. 1233 00:54:05,075 --> 00:54:06,710 I FIRMLY BELIEVE THAT. 1234 00:54:06,710 --> 00:54:12,049 WHAT I DON'T KNOW IS WHAT BOXES 1235 00:54:12,049 --> 00:54:12,916 ARE YOU AS HIRN INVESTIGATORS 1236 00:54:12,916 --> 00:54:14,451 GOING TO FILL IN. 1237 00:54:14,451 --> 00:54:17,087 WHAT ADVANCES WILL YOU TAKE IN 1238 00:54:17,087 --> 00:54:20,457 TERMS OF ADDING ANOTHER COG TO 1239 00:54:20,457 --> 00:54:22,159 THIS TURNING. 1240 00:54:22,159 --> 00:54:23,427 WITH THAT THANK YOU AND TO NIDDK 1241 00:54:23,427 --> 00:54:25,696 AND ALL THE HUNDREDS OF HIRN 1242 00:54:25,696 --> 00:54:27,765 INVESTIGATORS AND ORGAN DONORS 1243 00:54:27,765 --> 00:54:29,133 AND THEIR FAMILIES WHO MAKE 1244 00:54:29,133 --> 00:54:30,367 THESE POSSIBLE AND PATIENTS 1245 00:54:30,367 --> 00:54:33,537 THEMSELVES WITH THEIR 1246 00:54:33,537 --> 00:54:37,441 WILLINGNESS TO PARTICIPATE AND 1247 00:54:37,441 --> 00:54:38,442 RESEARCH IN THE COURSE OF THE 1248 00:54:38,442 --> 00:54:38,675 DISEASE. 1249 00:54:38,675 --> 00:54:42,980 THANK YOU. 1250 00:54:42,980 --> 00:54:50,454 [APPLAUSE] 1251 00:54:50,454 --> 00:54:52,756 >> OKAY. 1252 00:54:52,756 --> 00:54:54,691 IT'S BREAK TIME BUT WE'RE STILL 1253 00:54:54,691 --> 00:54:58,295 GOING TO COME BACK AT 10:20. 1254 00:54:58,295 --> 00:55:00,697 WE WERE STILL RUNNING AHEAD OF 1255 00:55:00,697 --> 00:55:01,565 SCHEDULE TECHNICALLY. 1256 00:55:01,565 --> 00:55:02,199 WE'LL START AT 10:20. 1257 00:55:02,199 --> 00:55:03,133 CATCH YOU IN A FEW MINUTES. THANK YOU. 1258 00:55:03,133 --> 00:55:04,401 WE'RE GOING TO START THE 1259 00:55:04,401 --> 00:55:08,205 SECOND HALF OF THE PLENARY 1260 00:55:08,205 --> 00:55:08,539 SESSIONS. 1261 00:55:08,539 --> 00:55:10,207 IN THE FIRST HALF, MARK WAS 1262 00:55:10,207 --> 00:55:10,941 LOOKING IN THE PAST AND 1263 00:55:10,941 --> 00:55:11,975 PROJECTING WHAT WE NEEDED FOR 1264 00:55:11,975 --> 00:55:15,045 THE FUTURE BUT WE HAVE AN 1265 00:55:15,045 --> 00:55:16,780 EXCITING SET OF TALKS THIS 1266 00:55:16,780 --> 00:55:18,081 MORNING WHERE WE'RE GOING TO 1267 00:55:18,081 --> 00:55:20,384 EXAMINE IN SOME DETAIL THE 1268 00:55:20,384 --> 00:55:22,920 FUTURE AND SO I HAVE THE 1269 00:55:22,920 --> 00:55:24,922 PRIVILEGE OF SHARING WITH YOU 1270 00:55:24,922 --> 00:55:27,424 OUR FIRST SPEAKER IN THIS 1271 00:55:27,424 --> 00:55:33,030 SESSION, DR. HOLGER RUSS WHO IS 1272 00:55:33,030 --> 00:55:40,404 AN ASSOCIATE PROFESSOR CAN 1273 00:55:40,404 --> 00:55:41,572 ANYBODY HEAR THIS. 1274 00:55:41,572 --> 00:55:43,240 SORRY, I GUESS THAT WOULD 1275 00:55:43,240 --> 00:55:46,009 EXPLAIN WHY EVERYBODY KEEPS 1276 00:55:46,009 --> 00:55:46,443 TALKING. 1277 00:55:46,443 --> 00:55:48,245 SO WE ARE GOING TO START THE 1278 00:55:48,245 --> 00:55:50,781 SECOND SESSION HEAR SO IF YOU 1279 00:55:50,781 --> 00:55:52,549 CAN FIND YOUR -- HERE AND SO IF 1280 00:55:52,549 --> 00:55:58,088 YOU CAN FIND YOUR SEAT AND HAVE 1281 00:55:58,088 --> 00:55:58,388 T 1282 00:55:58,388 --> 00:56:00,624 PRIVILEGE OF INTRODUCING HOLGER 1283 00:56:00,624 --> 00:56:04,294 RUSS TO YOU AT THE UNIVERSITY OF 1284 00:56:04,294 --> 00:56:05,128 FLORIDA. 1285 00:56:05,128 --> 00:56:15,639 HOLGER'S BEEN DOING FANTASTIC 1286 00:56:18,775 --> 00:56:18,909 WORK. 1287 00:56:18,909 --> 00:56:21,345 LET'S WELCOME HOLGER. 1288 00:56:21,345 --> 00:56:23,380 >> THANK YOU, JOHN. 1289 00:56:23,380 --> 00:56:25,749 NICE TO SEE FAMILIAR FACES AND 1290 00:56:25,749 --> 00:56:26,717 UNFAMILIAR FACES HOPEFULLY WE'LL 1291 00:56:26,717 --> 00:56:28,218 GET TO KNOW LATER IN THE 1292 00:56:28,218 --> 00:56:28,819 AUDIENCE. 1293 00:56:28,819 --> 00:56:32,189 I'M HUMBLED AND IN A SENSE 1294 00:56:32,189 --> 00:56:33,824 HONORED TO GIVE THIS 1295 00:56:33,824 --> 00:56:36,860 PRESENTATION A NEW DAWN IN TYPE 1296 00:56:36,860 --> 00:56:39,096 I DIABETES RESEARCH WITH AUDREY 1297 00:56:39,096 --> 00:56:40,897 PARENT ASSOCIATE PROFESSOR AT 1298 00:56:40,897 --> 00:56:42,933 UCSF AND I'LL HAND OVER THE 1299 00:56:42,933 --> 00:56:44,201 FLOOR LATER TO HER. 1300 00:56:44,201 --> 00:56:48,905 I WANT TO START OFF WITH THE 1301 00:56:48,905 --> 00:56:50,707 FUNDAMENTALS ABOUT LIKE WHAT 1302 00:56:50,707 --> 00:56:53,110 HIRN STANDS FOR AND THIS GOES IN 1303 00:56:53,110 --> 00:56:57,881 A WAY AS PROBABLY MANY IN THE 1304 00:56:57,881 --> 00:56:59,416 AUDIENCE FOR ME MY CAREER 1305 00:56:59,416 --> 00:57:01,118 DEVELOPMENT WENT ALONG AND I'M 1306 00:57:01,118 --> 00:57:03,587 PROBABLY A PRODUCT IMPRINTED BY 1307 00:57:03,587 --> 00:57:04,755 WHAT HIRN STANDS FOR. 1308 00:57:04,755 --> 00:57:06,423 THE KEY MISSION AND I READ THAT 1309 00:57:06,423 --> 00:57:10,294 OUT AGAIN, UNDERSTAND HOW HUMAN 1310 00:57:10,294 --> 00:57:11,995 BETA CELLS ARE LOST IN TYPE I 1311 00:57:11,995 --> 00:57:14,698 DIABETES AND FIND INNOVATIVE 1312 00:57:14,698 --> 00:57:19,569 WAYS TO PROTECT OR REPLACE 1313 00:57:19,569 --> 00:57:21,772 FUNCTIONAL BETA CELL MASS IN 1314 00:57:21,772 --> 00:57:23,307 PEOPLE WITH THE DISEASE. 1315 00:57:23,307 --> 00:57:24,107 THERE'S BEEN TREMENDOUS 1316 00:57:24,107 --> 00:57:25,409 IMPROVEMENT IN OUR DISEASE 1317 00:57:25,409 --> 00:57:26,543 UNDERSTANDING IN THE HUMAN 1318 00:57:26,543 --> 00:57:29,980 CONTEXT THROUGH HER. 1319 00:57:29,980 --> 00:57:31,948 YET, IS A LOT OF THE 1320 00:57:31,948 --> 00:57:34,918 TRANSLATIONAL WORK FROM BEFORE 1321 00:57:34,918 --> 00:57:37,054 STILL HAS SUFFERED FROM 1322 00:57:37,054 --> 00:57:37,354 TRANSLATION. 1323 00:57:37,354 --> 00:57:39,923 I THINK NOW WHAT WE NEED TO 1324 00:57:39,923 --> 00:57:41,892 EMPHASIZE WITH THE IMMUNE 1325 00:57:41,892 --> 00:57:43,393 MODULATION AND MANY DIFFERENT 1326 00:57:43,393 --> 00:57:44,761 APPROACHES THAT WE ACTUALLY 1327 00:57:44,761 --> 00:57:46,697 START TO HARVEST THE FRUIT FROM 1328 00:57:46,697 --> 00:57:48,832 LOOKING MORE INTO THE DETAILED 1329 00:57:48,832 --> 00:57:52,803 MECHANISM OF THE DISEASE. 1330 00:57:52,803 --> 00:57:53,837 HOWEVER, WE STILL DON'T 1331 00:57:53,837 --> 00:57:55,539 UNDERSTAND THE FUNDAMENTAL 1332 00:57:55,539 --> 00:57:58,975 DETAILS OF THE DISEASE 1333 00:57:58,975 --> 00:58:01,812 ESPECIALLY IN A STRATIFIED 1334 00:58:01,812 --> 00:58:02,379 PERSONALIZED MANNER. 1335 00:58:02,379 --> 00:58:03,714 YOU NEED TO UNDERSTAND THE 1336 00:58:03,714 --> 00:58:05,949 PROBLEM TO INTELLIGENTLY FIX IT. 1337 00:58:05,949 --> 00:58:07,818 WE HAVE THIS STATEMENT DOWN IN 1338 00:58:07,818 --> 00:58:10,053 MY MIND MAYBE ON MY HOME PAGE AS 1339 00:58:10,053 --> 00:58:12,923 WELL THAT WE NEED DETAILED 1340 00:58:12,923 --> 00:58:14,024 UNDERSTANDING MOLECULAR AND 1341 00:58:14,024 --> 00:58:16,193 CELLULAR MECHANISMS THAT RESULT 1342 00:58:16,193 --> 00:58:20,430 AND TRIGGER THE DISEASE AND ITS 1343 00:58:20,430 --> 00:58:22,466 PROGRESSION AND THAT WILL ALLOW 1344 00:58:22,466 --> 00:58:24,034 FORWARD PAYMENT TO DEVELOPING 1345 00:58:24,034 --> 00:58:26,203 NOVEL BIOMEDICALS AND 1346 00:58:26,203 --> 00:58:27,504 INTERVENTION MODALITIES. 1347 00:58:27,504 --> 00:58:29,940 SO IN THE LAST COUPLE TALKS WE 1348 00:58:29,940 --> 00:58:32,843 HEARD A LOT ABOUT HIRN AND I 1349 00:58:32,843 --> 00:58:36,046 WANT TO EMPHASIZE THERE'S THREE 1350 00:58:36,046 --> 00:58:36,680 MAIN POINTS. 1351 00:58:36,680 --> 00:58:38,181 ONE IS COLLABORATION. 1352 00:58:38,181 --> 00:58:39,416 WE'RE ALL DIFFERENT INDIVIDUALS 1353 00:58:39,416 --> 00:58:41,952 WITH DIFFERENT VIEW POINTS AND 1354 00:58:41,952 --> 00:58:43,286 WE COME TOGETHER TO DISCUSS AND 1355 00:58:43,286 --> 00:58:44,187 CHALLENGE EACH OTHER AND MOVE 1356 00:58:44,187 --> 00:58:49,793 THE FIELD FORWARD AND THEN THE 1357 00:58:49,793 --> 00:58:54,898 OTHER PART IS THE HUMAN DEEP 1358 00:58:54,898 --> 00:58:55,999 PHENOTYPING, CHARACTERIZATION OF 1359 00:58:55,999 --> 00:58:59,269 DISEASE STAGES COMBINED WITH THE 1360 00:58:59,269 --> 00:59:00,203 MODELLING ASPECT AND 1361 00:59:00,203 --> 00:59:01,471 REDISTRICTING OF FOCUS WE'RE NOW 1362 00:59:01,471 --> 00:59:04,241 FOCUSSING ON THE HUMAN PANCREAS 1363 00:59:04,241 --> 00:59:06,309 UNDER STUDIED AREAS OF THE 1364 00:59:06,309 --> 00:59:06,676 DISEASE. 1365 00:59:06,676 --> 00:59:13,350 HOW'S THAT LOOK IN REAL LIFE? 1366 00:59:13,350 --> 00:59:17,220 HPAP AND INDDP HAVE DONE A 1367 00:59:17,220 --> 00:59:18,889 TREMENDOUS JOB IN ESTABLISHING 1368 00:59:18,889 --> 00:59:22,759 LARGE COLLECTIONS OF PRIMARY 1369 00:59:22,759 --> 00:59:23,160 TISSUE. 1370 00:59:23,160 --> 00:59:26,196 AND THROUGH DISCOVERY AND 1371 00:59:26,196 --> 00:59:26,963 CHARACTERIZATION OF AVAILABLE 1372 00:59:26,963 --> 00:59:28,031 TECHNOLOGY WE UNDERSTAND THE 1373 00:59:28,031 --> 00:59:29,132 DISEASE IN THE HUMAN CONTEXT 1374 00:59:29,132 --> 00:59:31,101 BETTER AND THAT WE CAN SHARE AND 1375 00:59:31,101 --> 00:59:33,136 MAKE ACCESSIBLE TO THE 1376 00:59:33,136 --> 00:59:34,738 SCIENTIFIC COMMUNITY. 1377 00:59:34,738 --> 00:59:35,772 SO PROMOTE INNOVATION BUT AT THE 1378 00:59:35,772 --> 00:59:37,073 SAME TIME WE CAN USE THE 1379 00:59:37,073 --> 00:59:40,310 KNOWLEDGE AND INTEGRATE IT WITH 1380 00:59:40,310 --> 00:59:41,812 DISEASE MODELLING AND DISEASE 1381 00:59:41,812 --> 00:59:47,517 MODELLING IS ALWAYS A REDUCTIVE 1382 00:59:47,517 --> 00:59:48,518 PROCESS WHERE WE TRY TO BREAK 1383 00:59:48,518 --> 00:59:53,924 DOWN THE FUNDAMENTALS AND LOOK 1384 00:59:53,924 --> 00:59:57,861 AT A PERSPECTIVE ACTION OF THE 1385 00:59:57,861 --> 00:59:58,094 DISEASE. 1386 00:59:58,094 --> 00:59:59,930 WE NEED COMPLEMENTARY APPROACHES 1387 00:59:59,930 --> 01:00:03,333 TO DO THIS AND THEY BENEFIT FROM 1388 01:00:03,333 --> 01:00:04,734 NOVEL TECHNOLOGY DEVELOPMENT 1389 01:00:04,734 --> 01:00:07,337 WITH OTHER FIELDS AND OUR FIELD 1390 01:00:07,337 --> 01:00:09,239 AS WELL AS NEW SCIENTIFIC 1391 01:00:09,239 --> 01:00:10,874 CONCEPT AND AS SUCH BECAUSE MORE 1392 01:00:10,874 --> 01:00:13,210 PEOPLE THINK OF THE DISEASE WE 1393 01:00:13,210 --> 01:00:14,144 ATTRACT TALENT. 1394 01:00:14,144 --> 01:00:14,845 THEN WHAT WE LEARN IN THE 1395 01:00:14,845 --> 01:00:16,513 DISEASE MODELLING CONTEXT WHERE 1396 01:00:16,513 --> 01:00:19,883 WE CAN MANIPULATE AND USE GENOME 1397 01:00:19,883 --> 01:00:21,485 ENGINEERING AND LOOK AT DISTINCT 1398 01:00:21,485 --> 01:00:24,788 FEATURES WE CAN NOW RE-INTEGRATE 1399 01:00:24,788 --> 01:00:27,424 THIS KNOWLEDGE INTO THE LARGE 1400 01:00:27,424 --> 01:00:28,458 DATABASES AND TEST IS WHAT WE 1401 01:00:28,458 --> 01:00:30,861 LEARNED IN A REDUCTIVE MODELS 1402 01:00:30,861 --> 01:00:31,394 ACTUALLY HOLDING TRUE IN 1403 01:00:31,394 --> 01:00:41,571 PATIENTS. 1404 01:00:41,805 --> 01:00:43,106 FLIES THERE'S ANOTHER COMPONENT 1405 01:00:43,106 --> 01:00:45,375 AND THE SINGLE CELL DEVELOP THE 1406 01:00:45,375 --> 01:00:50,080 IS KEY AND APPRECIATE MORE THAN 1407 01:00:50,080 --> 01:00:51,915 IMMUNE CELLS ARE CHANGED IN THE 1408 01:00:51,915 --> 01:00:58,288 DISEASE ESPECIALLY EARLY ON. 1409 01:00:58,288 --> 01:01:00,824 WE WILL HEAR ON ALL THESE POINTS 1410 01:01:00,824 --> 01:01:05,629 COMING UP ON DETAIL AND WITH THE 1411 01:01:05,629 --> 01:01:07,631 LARGE DATA SETS WE CANNOT JUST 1412 01:01:07,631 --> 01:01:12,669 LOOK AT ONE MODALITY BUT USE 1413 01:01:12,669 --> 01:01:14,237 MULTI-OMIC AND PLUG AND PLAY 1414 01:01:14,237 --> 01:01:15,071 MACHINE LEARNING AND ARTIFICIAL 1415 01:01:15,071 --> 01:01:16,006 INTELLIGENCE IN THERE. 1416 01:01:16,006 --> 01:01:18,542 WHAT IS ALSO HAPPENING NOW ONCE 1417 01:01:18,542 --> 01:01:19,409 THE RESOURCES ARE ESTABLISHED 1418 01:01:19,409 --> 01:01:24,347 THE CAN BE UTILIZED IN THE CYCLE 1419 01:01:24,347 --> 01:01:26,683 OF RESEARCH AND USE SPATIAL 1420 01:01:26,683 --> 01:01:27,751 TRANSCRIPTOMICS WHERE WE LEARN 1421 01:01:27,751 --> 01:01:30,253 HOW THE CHANGED CELLS ARE IN 1422 01:01:30,253 --> 01:01:31,888 RELATION TO EACH OTHER. 1423 01:01:31,888 --> 01:01:34,891 ANOTHER FRONTIER. 1424 01:01:34,891 --> 01:01:35,158 OKAY. 1425 01:01:35,158 --> 01:01:39,796 SO THIS REDEFINED OUR 1426 01:01:39,796 --> 01:01:41,531 UNDERSTANDING OF TYPE I DIABETES 1427 01:01:41,531 --> 01:01:42,899 BUT WHAT ARE THE QUESTIONS THAT 1428 01:01:42,899 --> 01:01:51,341 REVISED DERIVED FROM THAT? 1429 01:01:51,341 --> 01:01:54,711 WE HAVE OXIDATIVE STRESS, ER 1430 01:01:54,711 --> 01:01:57,447 STRESS, NEOEPITOPE FORMATION AND 1431 01:01:57,447 --> 01:02:03,420 AUTOPHAGY AND PROCESSING IS 1432 01:02:03,420 --> 01:02:06,556 CHANGED, SENESCENCE AND HLA IS A 1433 01:02:06,556 --> 01:02:09,292 HIGH INFORMATION WHICH PROBABLY 1434 01:02:09,292 --> 01:02:14,397 INCREASES IMMUNE GENICITY AND 1435 01:02:14,397 --> 01:02:16,900 PLL1 AND HOW CAN WE MODEL THEM 1436 01:02:16,900 --> 01:02:17,734 IN THE DISH? 1437 01:02:17,734 --> 01:02:20,103 WE CAN USE DIFFERENT APPROACHES. 1438 01:02:20,103 --> 01:02:23,340 WE CHANGE METABOLIC DEMAND AND 1439 01:02:23,340 --> 01:02:24,908 CYTOKINES AND HEAR ABOUT THE 1440 01:02:24,908 --> 01:02:29,546 FINE TUBING IN TALKS AND MIMIC 1441 01:02:29,546 --> 01:02:31,815 VIRAL INFECTION AND IN THE 1442 01:02:31,815 --> 01:02:34,050 FUTURE WHAT WE SHOULD AIM TO 1443 01:02:34,050 --> 01:02:36,052 REALLY ASK OURSELVES, DO WE 1444 01:02:36,052 --> 01:02:38,388 MODEL THE DISEASE IN A 1445 01:02:38,388 --> 01:02:39,055 PHYSIOLOGICAL RELEVANT MANNER? 1446 01:02:39,055 --> 01:02:41,625 DO WE HAVE TO DO BETTER? 1447 01:02:41,625 --> 01:02:43,893 AND WE HAVE TO HARBOR ON THIS 1448 01:02:43,893 --> 01:02:46,463 POINT BECAUSE WE DON'T WANT TO 1449 01:02:46,463 --> 01:02:48,198 GO DOWN THE WRONG RABBIT HOLE. 1450 01:02:48,198 --> 01:02:50,000 WE WANT TO BE WITHIN THE REALM 1451 01:02:50,000 --> 01:02:52,202 OF WHAT HAPPENS IN A PATIENT 1452 01:02:52,202 --> 01:02:53,837 BECAUSE WE MODEL THE DISEASE. 1453 01:02:53,837 --> 01:02:55,205 THAT BRINGS OF COURSE THE 1454 01:02:55,205 --> 01:02:57,507 QUESTION OF OKAY, I LIST ALL 1455 01:02:57,507 --> 01:02:59,676 THESE POTENTIAL OUTCOMES AND 1456 01:02:59,676 --> 01:03:01,945 STRESS FACTORS SO WHAT DOES EACH 1457 01:03:01,945 --> 01:03:03,346 STRESS FACTOR DO? 1458 01:03:03,346 --> 01:03:05,715 WHAT DOES IT CHANGE WITHIN THE 1459 01:03:05,715 --> 01:03:07,584 CELLS AND IS THERE SYNERGY 1460 01:03:07,584 --> 01:03:10,320 BETWEEN THE DIFFERENT FACTORS? 1461 01:03:10,320 --> 01:03:12,288 NOW, WHEN WE DO OUR MANIPULATION 1462 01:03:12,288 --> 01:03:16,493 AND LOOK AT THE CELLS WE 1463 01:03:16,493 --> 01:03:17,460 SHOULDN'T USE THE FLASHLIGHT 1464 01:03:17,460 --> 01:03:19,829 EFFECT AND THIS IS OUR FAVORITE 1465 01:03:19,829 --> 01:03:21,631 SPOT WITH THE FLASHLIGHT BUT 1466 01:03:21,631 --> 01:03:23,800 FOCUS ON UNBIASSED ANALYSIS 1467 01:03:23,800 --> 01:03:26,836 APPROACHES WE CAN SEE THE WHOLE 1468 01:03:26,836 --> 01:03:28,705 PICTURE WHICH ALSO LEADS INTO 1469 01:03:28,705 --> 01:03:32,375 THAT WE NEED TO EVALUATE UNKNOWN 1470 01:03:32,375 --> 01:03:35,011 OR UNDER STATED FACTORS AND 1471 01:03:35,011 --> 01:03:36,846 PATHWAYS WITHIN THE DISEASE 1472 01:03:36,846 --> 01:03:37,147 PROGRESSION. 1473 01:03:37,147 --> 01:03:38,548 THIS TROPE OF KNOWLEDGE WE HAVE 1474 01:03:38,548 --> 01:03:38,715 NOW. 1475 01:03:38,715 --> 01:03:40,817 SO WHAT IS MISSING FROM THIS 1476 01:03:40,817 --> 01:03:41,117 PATH? 1477 01:03:41,117 --> 01:03:43,653 LET'S LOOK IN THE AREAS WHERE 1478 01:03:43,653 --> 01:03:47,457 NOT EVERYBODY'S LOOKING. 1479 01:03:47,457 --> 01:03:50,193 OKAY, THIS IS JUST EXTERNAL 1480 01:03:50,193 --> 01:03:50,660 ENVIRONMENTAL STRESS. 1481 01:03:50,660 --> 01:03:54,297 HOW DOES THAT RELATE TO GENETIC 1482 01:03:54,297 --> 01:03:54,497 RISK. 1483 01:03:54,497 --> 01:03:57,434 WE KNOW OVER 100 LOCI ARE HAVING 1484 01:03:57,434 --> 01:03:59,069 DIFFERENT RATIOS OF RISK FOR 1485 01:03:59,069 --> 01:03:59,969 DEVELOPING THE DISEASE. 1486 01:03:59,969 --> 01:04:01,905 SO WE NEED TO UNDERSTAND THE 1487 01:04:01,905 --> 01:04:04,174 MODE OF ACTION OF EACH ONE OF 1488 01:04:04,174 --> 01:04:05,508 THEM. 1489 01:04:05,508 --> 01:04:08,545 WE WANT TO PRIORITIZE HIGHEST 1490 01:04:08,545 --> 01:04:10,380 RISK ON AND THEN COMBINE THIS 1491 01:04:10,380 --> 01:04:13,650 WITH EXTERNAL STRESS. 1492 01:04:13,650 --> 01:04:16,086 YOU CAN APPRECIATE THIS GETS 1493 01:04:16,086 --> 01:04:16,853 EXCEEDINGLY COMPLICATED. 1494 01:04:16,853 --> 01:04:20,490 I LIKE TO THINK OF IT THAT 1495 01:04:20,490 --> 01:04:23,259 DISEASE WITH PHENOTYPIC IMPACT 1496 01:04:23,259 --> 01:04:24,994 WAS DISGUISED DISTRIBUTION YOU 1497 01:04:24,994 --> 01:04:27,597 CAN HAVE A DIFFERENT PROFILE FOR 1498 01:04:27,597 --> 01:04:28,698 EACH LOCI AND WITH OTHER STRESS 1499 01:04:28,698 --> 01:04:31,067 FACTORS YOU CAN GET A SHIFT NOT 1500 01:04:31,067 --> 01:04:32,702 JUST INTO MORE RISK BUT INTO 1501 01:04:32,702 --> 01:04:38,374 LESS RISK WHERE WE ULTIMATELY 1502 01:04:38,374 --> 01:04:38,975 LOOK. 1503 01:04:38,975 --> 01:04:41,478 OF COURSE WHEN WE NOW GET 1504 01:04:41,478 --> 01:04:43,646 INSIGHTS FROM THESE STUDIES THE 1505 01:04:43,646 --> 01:04:46,149 MODEL SYSTEMS WE NEED TO VERIFY 1506 01:04:46,149 --> 01:04:49,319 THIS AND BLOCK IT BACK INTO 1507 01:04:49,319 --> 01:04:52,088 LARGE DATA SETS WHICH PEOPLE 1508 01:04:52,088 --> 01:04:52,756 ALREADY DO. 1509 01:04:52,756 --> 01:04:54,357 YOU CAN DOWNLOAD THE DATA AND 1510 01:04:54,357 --> 01:04:58,194 TEST YOUR HYPOTHESIS AND THIS A 1511 01:04:58,194 --> 01:04:59,462 GREAT WAY FORWARD. 1512 01:04:59,462 --> 01:05:01,397 BUT THIS IS ONLY THE BETA CELL 1513 01:05:01,397 --> 01:05:03,900 AS I TALKED ABOUT. 1514 01:05:03,900 --> 01:05:05,869 WHAT ABOUT INTEGRATION OF OTHER 1515 01:05:05,869 --> 01:05:06,603 CELL TYPES? 1516 01:05:06,603 --> 01:05:08,271 IT WILL BE CRITICAL MOVING 1517 01:05:08,271 --> 01:05:11,741 FORWARD TO REALLY HAVE CULTURES 1518 01:05:11,741 --> 01:05:13,843 AND INTERACTION MODEL OF CELLS. 1519 01:05:13,843 --> 01:05:14,911 CELLS FROM THE PERSPECTIVE NOW 1520 01:05:14,911 --> 01:05:16,412 WHEN I STARTED IN THE FIELD 1521 01:05:16,412 --> 01:05:21,251 THERE WAS REALLY LIKE SILOS. 1522 01:05:21,251 --> 01:05:24,187 SO BETA CELL BIOLOGISTS AND 1523 01:05:24,187 --> 01:05:24,521 IMMUNOLOGISTS. 1524 01:05:24,521 --> 01:05:29,425 AND WHEN I STARTED I THOUGHT CDs 1525 01:05:29,425 --> 01:05:30,226 SUCH AS MUSIC BUT TURNS OUT 1526 01:05:30,226 --> 01:05:31,694 THEY'RE SURFACE MARKERS. 1527 01:05:31,694 --> 01:05:33,797 SO THEY NEED TO TALK TO EACH 1528 01:05:33,797 --> 01:05:35,131 OTHER AND I JUST USE THE TWO 1529 01:05:35,131 --> 01:05:36,599 GROUPS AS AN EXAMPLE. 1530 01:05:36,599 --> 01:05:39,502 ACTUALLY, WE NEED TO BRING MUCH 1531 01:05:39,502 --> 01:05:41,271 MORE PEOPLE AND YOU ARE THE 1532 01:05:41,271 --> 01:05:43,439 REPRESENTATIVE OF THE GROUP 67 1533 01:05:43,439 --> 01:05:47,744 PEOPLE TOGETHER TO ILLUMINATE 1534 01:05:47,744 --> 01:05:49,579 THE BLACK BOX OF TYPE I DIABETES 1535 01:05:49,579 --> 01:05:49,813 BETTER. 1536 01:05:49,813 --> 01:05:52,182 WE START WITH WHAT WE KNOW BEST 1537 01:05:52,182 --> 01:05:53,716 WHICH IS THE T CELL WHICH 1538 01:05:53,716 --> 01:05:57,220 UNDOUBTEDLY IS CRITICAL FOR THE 1539 01:05:57,220 --> 01:06:00,190 CONSTRUCTION OF BETA CELLS AND 1540 01:06:00,190 --> 01:06:01,758 PROBABLY THE BEST STUDIED TODAY. 1541 01:06:01,758 --> 01:06:06,029 AND WE HAVE THROUGH STUDIES WE 1542 01:06:06,029 --> 01:06:09,732 HAVE A GOOD UNDERSTANDING OF 1543 01:06:09,732 --> 01:06:12,235 INFORMATION ON TCR NATURAL GAS 1544 01:06:12,235 --> 01:06:15,371 AND ISLETS FROM TYPE I PATIENTS. 1545 01:06:15,371 --> 01:06:19,709 SO CAN WE USE THEM TO START TO 1546 01:06:19,709 --> 01:06:21,911 EVALUATE HOW GENETIC AND 1547 01:06:21,911 --> 01:06:24,180 ENVIRONMENTAL RISK IN THOSE TWO 1548 01:06:24,180 --> 01:06:27,684 CELL TYPES WHEN PUT TOGETHER 1549 01:06:27,684 --> 01:06:28,718 INTERACT WITH EACH OTHER. 1550 01:06:28,718 --> 01:06:30,920 ARE THEY PROTECTIVE OR 1551 01:06:30,920 --> 01:06:35,425 ACTIVATING MECHANISMS? 1552 01:06:35,425 --> 01:06:40,597 WHAT IS IT DOING IN EACH CONCEPT 1553 01:06:40,597 --> 01:06:45,301 AND THE PERMUTATIONS ARE QUITE 1554 01:06:45,301 --> 01:06:47,904 LARGE AND IN A PHYSIOLOGICAL 1555 01:06:47,904 --> 01:06:48,104 LEVEL. 1556 01:06:48,104 --> 01:06:49,138 THERE'S GOOD EXAMPLES OF THIS. 1557 01:06:49,138 --> 01:06:54,477 FOR EXAMPLE, WHEN WE LOOK AT 1558 01:06:54,477 --> 01:06:56,312 IMMUNE MODULATION IN SENESCENCE 1559 01:06:56,312 --> 01:06:58,648 AND HAS BEEN SHOWN TO PROTECT IN 1560 01:06:58,648 --> 01:07:00,383 REAL LIFE EXAMPLE HUMAN BETA 1561 01:07:00,383 --> 01:07:04,187 CELLS SO IF YOU EXPOSE HUMAN 1562 01:07:04,187 --> 01:07:06,256 BETA CELLS WITH PROINFLAMMATORY 1563 01:07:06,256 --> 01:07:09,158 ENVIRONMENT THEY UPREGULATE 1564 01:07:09,158 --> 01:07:09,692 PDL-1. 1565 01:07:09,692 --> 01:07:12,829 IT'S ALSO USED IN CERTAIN 1566 01:07:12,829 --> 01:07:13,062 CANCERS. 1567 01:07:13,062 --> 01:07:15,498 CANCER PATIENTS WHO RECEIVE 1568 01:07:15,498 --> 01:07:17,600 IMMUNE CHECKPOINT INHIBITERS TO 1569 01:07:17,600 --> 01:07:23,439 MESS WITH THIS PATHWAY SOME 1570 01:07:23,439 --> 01:07:25,241 DEVELOP DIABETES WHICH IS AN 1571 01:07:25,241 --> 01:07:26,576 AUTO IMMUNE DIABETES CELL PROVEN 1572 01:07:26,576 --> 01:07:30,113 THE BETA CELL HAS THE ABILITY TO 1573 01:07:30,113 --> 01:07:32,181 PROTECT ITSELF FROM AUTO 1574 01:07:32,181 --> 01:07:33,082 IMMUNITY. 1575 01:07:33,082 --> 01:07:35,151 CAN WE IDENTIFY OTHER PATHWAYS? 1576 01:07:35,151 --> 01:07:37,620 YOU CAN THINK OF AND THIS A 1577 01:07:37,620 --> 01:07:43,259 REDUCTION AREA AND WHAT IS THE 1578 01:07:43,259 --> 01:07:48,197 INFLUENCE OF PARACRINE 1579 01:07:48,197 --> 01:07:52,602 MECHANISMS AND THE CELL-CELL 1580 01:07:52,602 --> 01:07:53,937 CONNECTIVITY AND EXTRA CELLULAR 1581 01:07:53,937 --> 01:07:56,806 VESICLES AND WHAT PROTECTS THE 1582 01:07:56,806 --> 01:07:57,573 CELLS WHICH IS IN THE DISEASE 1583 01:07:57,573 --> 01:08:05,315 PROTECTING IT. 1584 01:08:05,315 --> 01:08:06,349 ANOTHER POINT WHICH INTERESTED 1585 01:08:06,349 --> 01:08:09,886 IN HEARING ABOUT TOMORROW IS A 1586 01:08:09,886 --> 01:08:12,822 LOT OF THE TCRs IN PATIENTS ARE 1587 01:08:12,822 --> 01:08:15,425 REACTIVE TO ANTIGENS FOREMOST 1588 01:08:15,425 --> 01:08:17,093 INSULIN WHICH IS A KEY ROLE BUT 1589 01:08:17,093 --> 01:08:18,361 MANY ARE UNKNOWN. 1590 01:08:18,361 --> 01:08:23,599 SO THERE'S A ROLE FOR LOOKING AT 1591 01:08:23,599 --> 01:08:33,076 NEOOPEN NEOEPITOPE AND IS THERE 1592 01:08:33,076 --> 01:08:36,112 A ROLE FOR UNKNOWN EPITOPES TO 1593 01:08:36,112 --> 01:08:39,649 BREAK THE DISEASE AND BREAK T 1594 01:08:39,649 --> 01:08:40,249 TOLERA 1595 01:08:40,249 --> 01:08:40,516 TOLERANCE. 1596 01:08:40,516 --> 01:08:47,457 WE NEED TO GET TO THESE QUES 1597 01:08:47,457 --> 01:08:48,191 QUESTIQUESTION 1598 01:08:48,191 --> 01:08:54,530 S TO DEFINE THE DISEASE BETTER 1599 01:08:54,530 --> 01:08:57,467 AND IT'S MORE COMPLICATED WHEN 1600 01:08:57,467 --> 01:09:00,837 YOU LOOK CLOSER AND CAN SUB 1601 01:09:00,837 --> 01:09:04,207 DIVIDE BY TRANSCRIPTOMIC 1602 01:09:04,207 --> 01:09:06,743 ANALYSIS THERE ARE MANY BETA 1603 01:09:06,743 --> 01:09:06,943 CELLS. 1604 01:09:06,943 --> 01:09:08,544 THAT'S THE T CELL BUT THERE'S 1605 01:09:08,544 --> 01:09:10,346 MANY MORE IMMUNE CELLS I'M NOT 1606 01:09:10,346 --> 01:09:15,251 AN EXPERT IN BUT THERE ARE MORE. 1607 01:09:15,251 --> 01:09:18,421 WHAT ABOUT THE B CELLS AND 1608 01:09:18,421 --> 01:09:19,355 DENDRITIC CELLS BUT OVER ALL 1609 01:09:19,355 --> 01:09:21,524 THERE IS MORE CHANGES NOT JUST 1610 01:09:21,524 --> 01:09:24,193 IN THE BETA CELL BUT IN THE 1611 01:09:24,193 --> 01:09:28,197 PRESENTATION OF HUMAN DIABETES 1612 01:09:28,197 --> 01:09:31,534 IN GENERAL. 1613 01:09:31,534 --> 01:09:37,740 WE SEE LESS INSULITIS AND YOU 1614 01:09:37,740 --> 01:09:40,209 CAN HAVE ONE THAT LOOKS HEALTHY 1615 01:09:40,209 --> 01:09:44,480 AND ANOTHER THAT HAS ACTIVE AUTO 1616 01:09:44,480 --> 01:09:44,747 IMMUNITY. 1617 01:09:44,747 --> 01:09:47,250 WHAT TRIGGERS THE DIFFERENCE? 1618 01:09:47,250 --> 01:09:48,951 HOW IS IT IMPORTANT AND HOW DO 1619 01:09:48,951 --> 01:09:54,957 THE T CELLS COME TO THE SITE OF 1620 01:09:54,957 --> 01:09:58,728 THE AND THE SITE OF ACTION IS 1621 01:09:58,728 --> 01:10:00,129 WHERE IT HAPPENS? 1622 01:10:00,129 --> 01:10:02,498 THESE ARE THINGS WE NEED TO 1623 01:10:02,498 --> 01:10:03,833 REALLY ADDRESS. 1624 01:10:03,833 --> 01:10:06,803 I DON'T EVEN KNOW HOW WE CAN GET 1625 01:10:06,803 --> 01:10:09,839 AT THE DIFFERENTIAL PROGRESSION 1626 01:10:09,839 --> 01:10:11,607 TIME BETWEEN PATIENTS BUT WE 1627 01:10:11,607 --> 01:10:13,376 NEED TO START THINKING ABOUT 1628 01:10:13,376 --> 01:10:15,978 THIS AND OVER ALL UNDERSTANDING 1629 01:10:15,978 --> 01:10:17,146 THE CONTRIBUTION OF IMMUNE CELLS 1630 01:10:17,146 --> 01:10:18,514 AND CAN WE DEVELOP BETTER MODELS 1631 01:10:18,514 --> 01:10:21,718 TO GET THE IDEA TO MANIPULATE 1632 01:10:21,718 --> 01:10:23,352 AND TEST AGAIN IN PRIMARY 1633 01:10:23,352 --> 01:10:24,053 TISSUE. 1634 01:10:24,053 --> 01:10:26,956 IT TRIGGERS IN A WAY THE CHICKEN 1635 01:10:26,956 --> 01:10:28,925 AND EGG QUESTION. 1636 01:10:28,925 --> 01:10:32,728 NOW WE HAVE PANCREAS AND IMMUNE 1637 01:10:32,728 --> 01:10:35,598 CELLS AND IS IT ALWAYS THE 1638 01:10:35,598 --> 01:10:35,865 MECHANISM? 1639 01:10:35,865 --> 01:10:37,633 I DON'T THINK IT'S TYPE I BUT 1640 01:10:37,633 --> 01:10:38,234 TYPE 100. 1641 01:10:38,234 --> 01:10:39,936 YOU HAVE PROBABLY DIFFERENT WAYS 1642 01:10:39,936 --> 01:10:43,573 THAT CAB RESULT IN TO THE SAME 1643 01:10:43,573 --> 01:10:45,141 OUTCOME DESTRUCTION OF BETA 1644 01:10:45,141 --> 01:10:46,442 CELLS. 1645 01:10:46,442 --> 01:10:46,642 OKAY. 1646 01:10:46,642 --> 01:10:51,581 WHAT ABOUT OTHER CELL TYPES, NOT 1647 01:10:51,581 --> 01:10:53,783 THAT I ALREADY RAMBLED ON ABOUT 1648 01:10:53,783 --> 01:10:55,218 ENOUGH OF THEM BUT WHAT ABOUT 1649 01:10:55,218 --> 01:10:57,353 OTHER ONES WE PREVIOUSLY HAVEN'T 1650 01:10:57,353 --> 01:10:59,188 THOUGHT OF? 1651 01:10:59,188 --> 01:11:03,359 WE'LL SEE A NICE TALK THAT SHOWS 1652 01:11:03,359 --> 01:11:05,895 THAT ALPHA CELLS THAT DON'T 1653 01:11:05,895 --> 01:11:08,164 HAVE -- NOT TARGETS BY AUTO 1654 01:11:08,164 --> 01:11:11,901 IMMUNITY ARE IMPAIRED EVEN 1655 01:11:11,901 --> 01:11:12,935 BEFORE STAGE 1? 1656 01:11:12,935 --> 01:11:14,537 WHAT IS THE ROLE? 1657 01:11:14,537 --> 01:11:16,973 DO THEY HAVE AN ACTIVE ROLE BY 1658 01:11:16,973 --> 01:11:17,874 TRIGGER BETA CELLS IN THE 1659 01:11:17,874 --> 01:11:18,941 DISEASE PROGRESSION? 1660 01:11:18,941 --> 01:11:20,977 CAN WE LEARN WHY THEY'RE NOT 1661 01:11:20,977 --> 01:11:21,644 GETTING DESTROYED? 1662 01:11:21,644 --> 01:11:25,915 THESE ARE THINGS TO CONSIDER. 1663 01:11:25,915 --> 01:11:28,684 THERE'S MANY MORE CHANGES IN THE 1664 01:11:28,684 --> 01:11:30,353 PANCREAS IN GENERAL THAT HAPPEN 1665 01:11:30,353 --> 01:11:30,987 EARLY ON. 1666 01:11:30,987 --> 01:11:36,225 THERE'S A LOSS OF THE BASAL 1667 01:11:36,225 --> 01:11:39,028 MEMBRANE WHICH DIRECTS T CELLS 1668 01:11:39,028 --> 01:11:42,398 TO COME IN EARLIER AND 1669 01:11:42,398 --> 01:11:45,768 SYMPATHETIC INNERVATION AND THE 1670 01:11:45,768 --> 01:11:47,470 TISSUE IS SMALLER. 1671 01:11:47,470 --> 01:11:50,273 HOW CAN WE MAKE SENSE OF THIS 1672 01:11:50,273 --> 01:11:51,774 AND LEVERAGE THE KNOWLEDGE OVER 1673 01:11:51,774 --> 01:11:56,212 THE LAST 10 YEARS HAS EMERGED 1674 01:11:56,212 --> 01:11:59,448 FROM HIRN AND THE WIDER TYPE I 1675 01:11:59,448 --> 01:12:00,950 RESEARCH SPACE FOR THE BENEFIT 1676 01:12:00,950 --> 01:12:03,586 OF PATIENTS. 1677 01:12:03,586 --> 01:12:12,028 I PUT UP THE ISENBERG CURVE AND 1678 01:12:12,028 --> 01:12:17,099 THERE'S EARLY IMPAIRMENTS IN 1679 01:12:17,099 --> 01:12:18,935 MULTIPLE TISSUES AND CELL TYPES. 1680 01:12:18,935 --> 01:12:24,974 CAN WE NOW FIND WAYS TO BETTER 1681 01:12:24,974 --> 01:12:26,809 PREDICT THE DISEASE? 1682 01:12:26,809 --> 01:12:29,045 DOES IT HAVE TO BE IN A PATIENT 1683 01:12:29,045 --> 01:12:30,279 SPECIFIC MANNER AND USE IT FOR 1684 01:12:30,279 --> 01:12:32,181 DISCOVERY AND ULTIMATELY CAN WE 1685 01:12:32,181 --> 01:12:34,483 MODULATE THE CHANGES IN 1686 01:12:34,483 --> 01:12:36,619 INDIVIDUAL CELL TYPES OR IN CELL 1687 01:12:36,619 --> 01:12:40,223 TYPES TOGETHER TO REALLY PREVENT 1688 01:12:40,223 --> 01:12:41,457 THE DISEASE FROM OCCURRING IN 1689 01:12:41,457 --> 01:12:44,560 THE FIRST PLACE? 1690 01:12:44,560 --> 01:12:48,231 AND THIS IS TO ME AT LEAST A 1691 01:12:48,231 --> 01:12:50,099 PRIME EXAMPLE HOW THE FORESIGHT 1692 01:12:50,099 --> 01:12:51,634 INVESTING INTO BASIC RESEARCH 1693 01:12:51,634 --> 01:12:52,268 AND UNDERSTANDING FUNDAMENTAL 1694 01:12:52,268 --> 01:12:56,706 DISEASE MECHANISM IN A HUMAN 1695 01:12:56,706 --> 01:12:59,609 CONTEXT IS NOW ALLOWING US AND 1696 01:12:59,609 --> 01:13:00,643 WE SEE THE DISEASE MODIFYING 1697 01:13:00,643 --> 01:13:03,779 THERAPIES THAT ARE FDA APPROVED 1698 01:13:03,779 --> 01:13:06,315 AND MANY MORE AS WE LEARN IN THE 1699 01:13:06,315 --> 01:13:06,582 PIPELINE. 1700 01:13:06,582 --> 01:13:08,217 I THINK THIS IS THE DIRECT 1701 01:13:08,217 --> 01:13:08,451 RESULT. 1702 01:13:08,451 --> 01:13:09,552 THIS IS GREAT. 1703 01:13:09,552 --> 01:13:10,920 SHOULD WE ONLY FOCUS ON WHAT WE 1704 01:13:10,920 --> 01:13:15,424 LEARNED SO FAR OR HOW DO WE PAY 1705 01:13:15,424 --> 01:13:16,225 FORWARD MOVING ON? 1706 01:13:16,225 --> 01:13:18,928 I DON'T ARGUE WE HAVE A ROAD MAP 1707 01:13:18,928 --> 01:13:26,535 BY THE PANCREAS HOW WE DID IN 1708 01:13:26,535 --> 01:13:28,571 DEPTH COHORTS AND DO THAT WITH 1709 01:13:28,571 --> 01:13:30,940 CELL TYPES ASSOCIATED WITH THE 1710 01:13:30,940 --> 01:13:33,542 DISEASE AND THYMUS? 1711 01:13:33,542 --> 01:13:36,479 IS THERE A WILL DEFECT IN THE 1712 01:13:36,479 --> 01:13:39,181 EDUCATION OF THE REPERTOIRE AND 1713 01:13:39,181 --> 01:13:41,517 WHAT IS THE ROLE OF THE LYMPH 1714 01:13:41,517 --> 01:13:42,952 NODE FOR THE ACTIVATION OF THE 1715 01:13:42,952 --> 01:13:47,256 IMMUNE SYSTEM AND SPLEEN AND 1716 01:13:47,256 --> 01:13:48,991 PROBABLY MORE I HAVEN'T THOUGHT 1717 01:13:48,991 --> 01:13:49,859 OF MORE. 1718 01:13:49,859 --> 01:13:52,228 AND WHEN WE PHENOTYPE WE NEED TO 1719 01:13:52,228 --> 01:13:57,967 BE ABLE TO MANIPULATE IT AND 1720 01:13:57,967 --> 01:14:03,005 FUNNEL IT BACK TO OUR PRIMARY 1721 01:14:03,005 --> 01:14:04,006 TISSUES. 1722 01:14:04,006 --> 01:14:06,709 AND I BELIEVE THAT'S HOPEFULLY 1723 01:14:06,709 --> 01:14:08,244 NOT 10 YEARS BUT SEVEN WILL 1724 01:14:08,244 --> 01:14:16,152 RESULT IN BETTER PREDICTIVE 1725 01:14:16,152 --> 01:14:21,457 MEASUREMENT AND READ WHAT TYPE I 1726 01:14:21,457 --> 01:14:23,192 DIABETES IS IN THE LARGER 1727 01:14:23,192 --> 01:14:24,226 CONTEXT. 1728 01:14:24,226 --> 01:14:25,461 WHEN I WAS ON THE PHONE CALL 1729 01:14:25,461 --> 01:14:28,230 WITH THE PANELISTS AND THE 1730 01:14:28,230 --> 01:14:29,865 PLANNING COMMITTEE, IT'S 1731 01:14:29,865 --> 01:14:31,133 ACTUALLY WAS SUGGESTED TO ME 1732 01:14:31,133 --> 01:14:32,968 WE'RE NOT GOING IN CIRCLES. 1733 01:14:32,968 --> 01:14:35,271 WE'RE ACTUALLY GOING DOWN THE 1734 01:14:35,271 --> 01:14:37,506 RABBIT HOLE LIKE ALICE. 1735 01:14:37,506 --> 01:14:40,209 WE'RE FALLING DOWN THIS SPIRAL 1736 01:14:40,209 --> 01:14:43,379 AND CONTINUOUSLY IMPROVING BY 1737 01:14:43,379 --> 01:14:44,313 INTEGRATING NOVEL TECHNOLOGY, 1738 01:14:44,313 --> 01:14:46,115 SCIENTIFIC CONCEPTS AND NOW 1739 01:14:46,115 --> 01:14:49,151 WE'RE AT THE STAGE WE CAN TAKE 1740 01:14:49,151 --> 01:14:51,721 EVEN INSIGHTS FROM HUMAN TRIAL 1741 01:14:51,721 --> 01:14:53,990 DATA BECAUSE THE FIRST 1742 01:14:53,990 --> 01:14:57,426 INTERVENTIONS AND IDEAS WE HAVE 1743 01:14:57,426 --> 01:14:58,494 REALLY MANIFEST IN BENEFIT FOR 1744 01:14:58,494 --> 01:14:59,195 THE PATIENT. 1745 01:14:59,195 --> 01:15:01,564 WE CAN INTEGRATE THIS INTO OUR 1746 01:15:01,564 --> 01:15:04,200 KNOWLEDGE BASE TO MOVE ON DOWN, 1747 01:15:04,200 --> 01:15:05,201 SHARE WITH THE SCIENTIFIC 1748 01:15:05,201 --> 01:15:06,502 COMMUNITY NOT JUST SHARE BUT 1749 01:15:06,502 --> 01:15:10,106 MAKE THE DATA ACCESSIBLE AND 1750 01:15:10,106 --> 01:15:11,640 ACCELERATE INNOVATION IN THIS TO 1751 01:15:11,640 --> 01:15:14,009 HOPEFULLY FIND A CURE. 1752 01:15:14,009 --> 01:15:17,113 SO, IF THIS WAS A BIT MUCH, WHAT 1753 01:15:17,113 --> 01:15:19,315 I HOPE YOU CAN TAKE TAKEAWAY 1754 01:15:19,315 --> 01:15:23,819 FROM THIS IS TYPE I IS A 1755 01:15:23,819 --> 01:15:25,988 COMPLEX, MULTI-FACTORIAL DISEASE 1756 01:15:25,988 --> 01:15:27,289 THAT I HOPE YOU APPRECIATE 1757 01:15:27,289 --> 01:15:30,459 FUNDAMENTAL DISEASE 1758 01:15:30,459 --> 01:15:32,161 UNDERSTANDING IS NEEDED AND 1759 01:15:32,161 --> 01:15:35,765 NEEDS TO BE DONE RIGHT. 1760 01:15:35,765 --> 01:15:37,133 WE NEED TO EVALUATE TYPE I 1761 01:15:37,133 --> 01:15:39,101 ASSOCIATED OR MEDIATING FACTORS 1762 01:15:39,101 --> 01:15:42,371 IN A SINGLE BUT MUCH MORE 1763 01:15:42,371 --> 01:15:43,472 IMPORTANT NETWORK LEVEL. 1764 01:15:43,472 --> 01:15:45,474 THAT WE NEED TO CAPITALIZE OR 1765 01:15:45,474 --> 01:15:46,842 CONTINUE CAPITALIZING ON 1766 01:15:46,842 --> 01:15:50,846 EXISTING OFFICES AND 1767 01:15:50,846 --> 01:15:52,681 INFRASTRUCTURE AND CONTINUE 1768 01:15:52,681 --> 01:15:53,682 PAVING THE BASIC RESEARCH FOR 1769 01:15:53,682 --> 01:15:56,218 WAR AND HAVE UNBIASSED DIGITAL 1770 01:15:56,218 --> 01:15:58,254 ANALYSIS APPROACHES OVER YANG 1771 01:15:58,254 --> 01:16:02,591 ANALOG APPROACHES AND WHAT WE 1772 01:16:02,591 --> 01:16:03,993 HAVEN'T DONE YET AS A COMMUNITY 1773 01:16:03,993 --> 01:16:06,929 FROM MY PERSPECTIVE IS FOCUS ON 1774 01:16:06,929 --> 01:16:09,698 INDIVIDUALS THAT ARE PROTECTED. 1775 01:16:09,698 --> 01:16:12,935 THOSE INDIVIDUALS THAT HAVE TWO 1776 01:16:12,935 --> 01:16:13,736 ALTERED ANTIBODIES BUT NEVER 1777 01:16:13,736 --> 01:16:15,104 DEVELOPED THE DISEASE. 1778 01:16:15,104 --> 01:16:16,071 HOW IS THAT? 1779 01:16:16,071 --> 01:16:26,549 AND CAN WE LEARN FROM THIS? 1780 01:16:27,116 --> 01:16:32,455 FOR THE YOUNGER GENERATIONS 1781 01:16:32,455 --> 01:16:34,123 QUESTION ESTABLISHED HYPOTHESIS. 1782 01:16:34,123 --> 01:16:36,192 GO BACK, READ THE OLD PAPERS. 1783 01:16:36,192 --> 01:16:40,229 THINK OF HOW TO USE NEW 1784 01:16:40,229 --> 01:16:41,730 TECHNOLOGY TO QUESTION IN MORE 1785 01:16:41,730 --> 01:16:44,066 DETAIL THE EXISTING DOGMAS AND 1786 01:16:44,066 --> 01:16:46,702 THINK OUTSIDE OF THE BOX BECAUSE 1787 01:16:46,702 --> 01:16:48,838 WE NEED STILL A LOT OF 1788 01:16:48,838 --> 01:16:50,639 INNOVATION AND THE OTHER TAKE 1789 01:16:50,639 --> 01:16:52,208 HOME IS IT TAKES A VILLAGE. 1790 01:16:52,208 --> 01:16:55,911 WE NEED TO WORK TOGETHER AND 1791 01:16:55,911 --> 01:16:58,280 FOSTER DIALOGUE AND CHALLENGE 1792 01:16:58,280 --> 01:17:02,084 EACH OTHER AND SHARE OUR 1793 01:17:02,084 --> 01:17:05,287 KNOWLEDGE FREELY AND THAT IS IN 1794 01:17:05,287 --> 01:17:08,691 THE SPIRIT OF KEEPING OUR EYES 1795 01:17:08,691 --> 01:17:11,727 ON THE PRIZE AND FOSTER THE WORK 1796 01:17:11,727 --> 01:17:13,429 BECAUSE I THINK WE'RE ALL 1797 01:17:13,429 --> 01:17:15,097 WORKING REALLY HARD FOR THIS AND 1798 01:17:15,097 --> 01:17:18,234 MAYBE WE CAN LOOK BACK ON OUR 1799 01:17:18,234 --> 01:17:20,135 SUCCESSES IN A LITTLE WHILE. 1800 01:17:20,135 --> 01:17:24,139 SO, WITH THIS WHILE THIS WAS ALL 1801 01:17:24,139 --> 01:17:25,975 CONCEPTUALLY DRIVEN I WANT TO 1802 01:17:25,975 --> 01:17:28,143 HAND THE FLOOR OVER TO AUDREY 1803 01:17:28,143 --> 01:17:29,378 PARENT ASSOCIATE PROFESSOR AT 1804 01:17:29,378 --> 01:17:31,814 UCSF TO TELL YOU MORE IN ACUTE 1805 01:17:31,814 --> 01:17:33,816 OR CONCRETE STEPS HOW THIS CAN 1806 01:17:33,816 --> 01:17:34,183 BE FACILITATED. 1807 01:17:34,183 --> 01:17:44,493 THANK YOU SO MUCH. 1808 01:17:48,998 --> 01:17:51,333 >> HOLGER, THANK YOU, THAT WAS 1809 01:17:51,333 --> 01:17:52,868 EXCITING AND SETS THE STAGE FOR 1810 01:17:52,868 --> 01:17:54,904 MY PART. 1811 01:17:54,904 --> 01:17:56,138 HOW THAT WE HEARD ABOUT OUR 1812 01:17:56,138 --> 01:17:58,607 THINKING OF THE DISEASE AND 1813 01:17:58,607 --> 01:18:00,776 ESPECIALLY THE EARLY STAGE OF 1814 01:18:00,776 --> 01:18:02,645 THE DISEASE IS EVOLVING I WANT 1815 01:18:02,645 --> 01:18:04,713 TO DIG INTO HOW TO VALIDATE 1816 01:18:04,713 --> 01:18:06,782 THESE IDEAS AND TRANSLATE THE 1817 01:18:06,782 --> 01:18:08,751 MECHANISTIC OBSERVATIONS AND 1818 01:18:08,751 --> 01:18:11,020 TURN THEM INTO BETTER CLINICAL 1819 01:18:11,020 --> 01:18:11,287 OUTCOMES. 1820 01:18:11,287 --> 01:18:12,221 I'LL SPEND A LITTLE BIT OF TIME 1821 01:18:12,221 --> 01:18:15,191 TALKING ABOUT THE TOOLS AND 1822 01:18:15,191 --> 01:18:16,325 MODELS IS INEVITABLE TO VALIDATE 1823 01:18:16,325 --> 01:18:19,094 SOME OF THE FINDINGS THAT WERE 1824 01:18:19,094 --> 01:18:23,532 GENERATED TO THE CYCLE HOLGER 1825 01:18:23,532 --> 01:18:26,168 DESCRIBED AND HOW TO DO THAT 1826 01:18:26,168 --> 01:18:27,636 KEEPING AN EYE ON INFORMATION 1827 01:18:27,636 --> 01:18:29,038 AND CLOSE WITH SOME DISCUSSION 1828 01:18:29,038 --> 01:18:31,073 ABOUT WHAT ARE THE CURRENT 1829 01:18:31,073 --> 01:18:33,008 THERAPIES THAT ARE UNDER 1830 01:18:33,008 --> 01:18:33,842 EVALUATION IN PATIENTS AND ALSO 1831 01:18:33,842 --> 01:18:36,211 TOUCH ON SOME OF THE REMAINING 1832 01:18:36,211 --> 01:18:37,479 BARRIERS AND HOW RESEARCH CAN 1833 01:18:37,479 --> 01:18:40,215 HELP ADDRESS SOME OF THESE 1834 01:18:40,215 --> 01:18:40,783 BARRIERS. 1835 01:18:40,783 --> 01:18:44,286 SO WHEN WE THINK ABOUT MODELLING 1836 01:18:44,286 --> 01:18:45,621 TYPE I DIABETES ONE OF THE 1837 01:18:45,621 --> 01:18:48,924 CHALLENGES IS THE COMPLEXITY OF 1838 01:18:48,924 --> 01:18:49,692 THE DISEASE. 1839 01:18:49,692 --> 01:18:52,661 THIS IS MY TAKE ON IT. 1840 01:18:52,661 --> 01:18:54,129 THERE'S A LOT OF DIFFERENT CELL 1841 01:18:54,129 --> 01:18:54,330 TYPES. 1842 01:18:54,330 --> 01:18:55,631 IT'S PROBABLY ALREADY MISSING 1843 01:18:55,631 --> 01:18:57,933 SOME AND EVOLVING QUITE RAPIDLY 1844 01:18:57,933 --> 01:19:00,202 BUT THE POINT I WANTED TO MAKE 1845 01:19:00,202 --> 01:19:02,237 IS IT'S COMPLICATED AND WHEN WE 1846 01:19:02,237 --> 01:19:04,440 ARE TALKING ABOUT PLATFORMS TO 1847 01:19:04,440 --> 01:19:06,408 MODEL WE NEED TO TAKE THIS INTO 1848 01:19:06,408 --> 01:19:07,710 ACCOUNT AND FOCUS ON INTEGRATING 1849 01:19:07,710 --> 01:19:10,045 THE COMPLICATED INTERACTIONS. 1850 01:19:10,045 --> 01:19:12,348 ANOTHER POINT IS WE NEED TO 1851 01:19:12,348 --> 01:19:15,217 INTEGRATE AS MUCH AS POSSIBLE 1852 01:19:15,217 --> 01:19:18,053 HUMANIZED COMPONENT. 1853 01:19:18,053 --> 01:19:20,656 SO THERE ARE A LOT OF CELL TYPE 1854 01:19:20,656 --> 01:19:22,591 SPECIFIC DIFFERENCES BETWEEN 1855 01:19:22,591 --> 01:19:24,393 SPECIES AND AWAY HEARD ABOUT 1856 01:19:24,393 --> 01:19:26,495 MOUSE BETA CELLS NOT BEING 1857 01:19:26,495 --> 01:19:29,465 EQUIVALENT TO HUMAN BETA CELLS 1858 01:19:29,465 --> 01:19:30,699 AND THERE WERE EXCELLENT MOUSE 1859 01:19:30,699 --> 01:19:32,901 BETA CELLS AND HAD NO EFFECT AT 1860 01:19:32,901 --> 01:19:35,070 ALL ON HUMAN BETA CELLS AND 1861 01:19:35,070 --> 01:19:38,807 MAKES THE CASE FOR STUDYING 1862 01:19:38,807 --> 01:19:39,975 HUMAN CELLS AS MUCH POSSIBLE. 1863 01:19:39,975 --> 01:19:41,076 WHAT DO WE HAVE AVAILABLE TO 1864 01:19:41,076 --> 01:19:42,778 START BUILDING THE COMPLEX 1865 01:19:42,778 --> 01:19:43,012 MODELS. 1866 01:19:43,012 --> 01:19:44,847 THERE'S A LOT OF THINGS BUT I 1867 01:19:44,847 --> 01:19:45,714 WANTED TO HIGHLIGHT TWO AREAS 1868 01:19:45,714 --> 01:19:47,116 WHICH I THINK HAVE EVOLVED IN 1869 01:19:47,116 --> 01:19:48,183 THE LAST FEW YEARS. 1870 01:19:48,183 --> 01:19:51,220 ONE IS ACCESS TO HUMAN DONOR 1871 01:19:51,220 --> 01:19:54,890 TISSUE CONTROL AND TYPE I 1872 01:19:54,890 --> 01:19:55,157 DIABETES. 1873 01:19:55,157 --> 01:19:57,126 THERE'S A LOT OF THINGS 1874 01:19:57,126 --> 01:19:59,762 AVAILABLE WHETHER IT'S BLOOD, 1875 01:19:59,762 --> 01:20:04,800 STEM CELLS, PANCREAS, THYMUS, 1876 01:20:04,800 --> 01:20:05,668 THERE'S A LOT OF THINGS I CAN 1877 01:20:05,668 --> 01:20:08,003 USE AND LIMITATIONS OF ALL THESE 1878 01:20:08,003 --> 01:20:09,538 THINGS WHEN WE TALK ABOUT HUMAN 1879 01:20:09,538 --> 01:20:11,140 DONORS ONE THING IS TO GET THEM 1880 01:20:11,140 --> 01:20:12,641 FROM PATIENTS SO YOU CAN WORK 1881 01:20:12,641 --> 01:20:13,742 WITH T CELLS THAT WERE PULLED 1882 01:20:13,742 --> 01:20:16,211 OUT OF THE PANCREAS FROM THE 1883 01:20:16,211 --> 01:20:17,379 TYPE 1 PATIENT. 1884 01:20:17,379 --> 01:20:18,881 HOWEVER, THERE'S LIMITATION IN 1885 01:20:18,881 --> 01:20:19,848 TERMS OF MATCHING THESE 1886 01:20:19,848 --> 01:20:20,683 DIFFERENT CELL TYPES. 1887 01:20:20,683 --> 01:20:22,117 WE'VE BEEN TALKING ABOUT LOOKING 1888 01:20:22,117 --> 01:20:23,986 AT INTERACTIONS BETWEEN CELLS IF 1889 01:20:23,986 --> 01:20:26,522 YOU WANT TO LOOK AT ISLETS AND T 1890 01:20:26,522 --> 01:20:28,524 CELLS, ONE OF THE KEY COMPONENT 1891 01:20:28,524 --> 01:20:29,625 IS IT THEY NEED TO BE 1892 01:20:29,625 --> 01:20:30,693 GENETICALLY MATCHED. 1893 01:20:30,693 --> 01:20:33,595 IF THEY DON'T HAVE THE SAME HLAs 1894 01:20:33,595 --> 01:20:35,464 YOU'RE NOT GOING TOE LOOK AT 1895 01:20:35,464 --> 01:20:37,700 AUTO IMMUNITY BUT TRANSPLANT 1896 01:20:37,700 --> 01:20:39,468 REJECTION WHICH IS A DIFFERENT 1897 01:20:39,468 --> 01:20:39,735 MECHANISM. 1898 01:20:39,735 --> 01:20:41,136 THAT'S ONE OF THE LIMITATION AND 1899 01:20:41,136 --> 01:20:42,771 THE VARIABILITY BETWEEN DONORS 1900 01:20:42,771 --> 01:20:44,106 IS SOMETHING TO TAKE INTO 1901 01:20:44,106 --> 01:20:44,440 ACCOUNT. 1902 01:20:44,440 --> 01:20:46,909 SO ANYONE THAT'S WORKED WITH 1903 01:20:46,909 --> 01:20:48,010 HUMAN ISLETS KNOWS THERE'S A 1904 01:20:48,010 --> 01:20:51,547 WIDE RANGE OF NORMAL WHEN IT 1905 01:20:51,547 --> 01:20:54,616 COMES TO THESE ISLETS. 1906 01:20:54,616 --> 01:20:59,888 AS AN ALTERNATIVE WE'VE BEEN 1907 01:20:59,888 --> 01:21:06,061 PUTTING EFFORT INTO PLURIPOTENT 1908 01:21:06,061 --> 01:21:07,262 STEM CELLS AND IT'S SCALABILITY 1909 01:21:07,262 --> 01:21:09,298 AND YOU CAN MAKE A TON OF THEM 1910 01:21:09,298 --> 01:21:12,000 AND GIVE RISE TO ANY CELL TYPE 1911 01:21:12,000 --> 01:21:12,601 IN THE BODY. 1912 01:21:12,601 --> 01:21:15,604 FOR EXAMPLE WE ALREADY HAVE 1913 01:21:15,604 --> 01:21:18,907 PROTOCOLS TO GENERATE THE 1914 01:21:18,907 --> 01:21:20,242 DIFFERENT CELLS AND IT'S A 1915 01:21:20,242 --> 01:21:23,512 POWERFUL SYSTEM. 1916 01:21:23,512 --> 01:21:25,848 THE MAIN MANAGE IS THEY'LL BE 1917 01:21:25,848 --> 01:21:26,582 GENETICALLY IDENTICAL GETTING 1918 01:21:26,582 --> 01:21:30,953 RID OF THE HLA MATCHING PROBLEM 1919 01:21:30,953 --> 01:21:32,788 AND YOU CAN INTRODUCE WHATEVER 1920 01:21:32,788 --> 01:21:34,723 GENETIC MANIPULATION YOU'RE 1921 01:21:34,723 --> 01:21:35,324 INTERESTED IN. 1922 01:21:35,324 --> 01:21:36,325 HOWEVER, SOMETHING TO KEEP IN 1923 01:21:36,325 --> 01:21:38,994 MIND IN GENERAL THEY TEND TO BE 1924 01:21:38,994 --> 01:21:42,765 LESS MATURE THAN THEIR PRIMARY 1925 01:21:42,765 --> 01:21:43,198 COU 1926 01:21:43,198 --> 01:21:43,832 COUNTERPARTS SO SOMETHING TO 1927 01:21:43,832 --> 01:21:44,733 KEEP IN MIND. 1928 01:21:44,733 --> 01:21:47,102 ONCE YOU IDENTIFY TO THE SOURCE 1929 01:21:47,102 --> 01:21:48,270 HOW DO YOU GO GOOD LOOKING AT 1930 01:21:48,270 --> 01:21:50,506 THE DIFFERENT INTERACTIONS. 1931 01:21:50,506 --> 01:21:51,507 THERE'S A LOT OF IN VITRO 1932 01:21:51,507 --> 01:21:52,207 MODELS. 1933 01:21:52,207 --> 01:21:54,977 I WANTED TO TALK ABOUT THESE TWO 1934 01:21:54,977 --> 01:21:56,512 BECAUSE THEY HIGHLIGHT THE 1935 01:21:56,512 --> 01:21:58,447 IMPORTANCE OF LOOKING AT 1936 01:21:58,447 --> 01:22:01,183 DIFFERENT CELL TYPES AND HOW 1937 01:22:01,183 --> 01:22:03,519 THEY INTERACT AND ONE IS THE 1938 01:22:03,519 --> 01:22:04,620 TISSUE IN A CHIP. 1939 01:22:04,620 --> 01:22:06,622 A LOT OF THE WORK HAS BEEN 1940 01:22:06,622 --> 01:22:08,056 SPEARHEADED BY HIRN 1941 01:22:08,056 --> 01:22:08,390 INVESTIGATORS. 1942 01:22:08,390 --> 01:22:11,093 SO BASICALLY THE GOAL IS TO 1943 01:22:11,093 --> 01:22:12,227 INTEGRATE THE ISLETS INTO 1944 01:22:12,227 --> 01:22:15,264 DEVICES AND TRY TO RECREATE AS 1945 01:22:15,264 --> 01:22:16,765 MUCH POSSIBLE THEIR 1946 01:22:16,765 --> 01:22:17,900 MICROENVIRONMENT WHETHER IT'S 1947 01:22:17,900 --> 01:22:22,304 EXTRA CELLULAR MATRIX, VASCU 1948 01:22:22,304 --> 01:22:22,938 VASCULARIZATION AND FLOW OF 1949 01:22:22,938 --> 01:22:24,973 CELLS WHICH ALLOWS YOU TO GET A 1950 01:22:24,973 --> 01:22:27,509 MORE PHYSIOLOGICAL SYSTEM. 1951 01:22:27,509 --> 01:22:29,945 YOU CAN USE THAT TO LOOK AT CELL 1952 01:22:29,945 --> 01:22:31,146 MIGRATION AND LOOK AT CELL 1953 01:22:31,146 --> 01:22:33,482 INTERACTIONS IN A WAY NOT 1954 01:22:33,482 --> 01:22:35,083 POSSIBLE WITH STATIC CULTURES. 1955 01:22:35,083 --> 01:22:37,152 THE OTHER ONE I WANTED TO 1956 01:22:37,152 --> 01:22:38,554 INTRODUCE IS THE LIVING 1957 01:22:38,554 --> 01:22:40,422 PANCREATIC SLICES. 1958 01:22:40,422 --> 01:22:41,990 THIS IS A LITTLE BIT NEWER 1959 01:22:41,990 --> 01:22:44,359 PLATFORM BUT THIS IS BASICALLY 1960 01:22:44,359 --> 01:22:46,762 TAKING A FRESH PIECE OF PANCREAS 1961 01:22:46,762 --> 01:22:51,967 AND SLICE IT AND PUT THEM INTO 1962 01:22:51,967 --> 01:22:52,201 CULTURE. 1963 01:22:52,201 --> 01:22:56,205 YOU LOOK AT ISLETS EMBEDDED IN 1964 01:22:56,205 --> 01:22:58,340 THEIR NORMAL MICROENVIRONMENT 1965 01:22:58,340 --> 01:23:00,943 AND YOU HAVE VASCULARIZATION AND 1966 01:23:00,943 --> 01:23:02,077 NEURONS AND DIFFERENT CELL TYPES 1967 01:23:02,077 --> 01:23:02,444 STILL PRESENT. 1968 01:23:02,444 --> 01:23:05,881 WHEN YOU THINK HOW TO MODEL CELL 1969 01:23:05,881 --> 01:23:08,150 TO CELL INTERACTION IT'S A NICE 1970 01:23:08,150 --> 01:23:08,350 MODEL. 1971 01:23:08,350 --> 01:23:11,320 AND NOT GOING MUCH INTO DETAIL. 1972 01:23:11,320 --> 01:23:12,855 THERE'S SOME TALKS LATER IN THE 1973 01:23:12,855 --> 01:23:14,389 MEETING TO SHOW YOU REAL LIFE 1974 01:23:14,389 --> 01:23:15,557 APPLICATION OF THESE MODELS. 1975 01:23:15,557 --> 01:23:17,993 LOOKING FORWARD TO SEEING THEM. 1976 01:23:17,993 --> 01:23:20,195 ONE POINT I DID WANT TO MAKE IS 1977 01:23:20,195 --> 01:23:21,930 THAT ESPECIALLY FOR THE TISSUE 1978 01:23:21,930 --> 01:23:25,400 ON A CHIP PART, THIS IS A REAL 1979 01:23:25,400 --> 01:23:27,636 GOOD EXAMPLE OF HOW HIRN HAS 1980 01:23:27,636 --> 01:23:29,404 BEEN ABLE TO BRING TOGETHER 1981 01:23:29,404 --> 01:23:30,973 EXPERTISE FROM DIFFERENT PEOPLE 1982 01:23:30,973 --> 01:23:33,942 IN ORDER TO MAKE TISSUE ON A TIP 1983 01:23:33,942 --> 01:23:37,880 TECHNOLOGY YOU NEED BIO 1984 01:23:37,880 --> 01:23:39,948 ENGINEERS, YOU NEED VASCULAR 1985 01:23:39,948 --> 01:23:40,782 BIOLOGISTS TO ALL WORK TOGETHER. 1986 01:23:40,782 --> 01:23:43,051 IT'S A SUCCESS STORY OF THE IDEA 1987 01:23:43,051 --> 01:23:44,286 OF BRINGING PEOPLE TOGETHER AND 1988 01:23:44,286 --> 01:23:48,390 PROMOTING TEAM SCIENCE. 1989 01:23:48,390 --> 01:23:54,663 I'M GOING TO TOUCH ON IN VIVO. 1990 01:23:54,663 --> 01:23:56,565 THERE'S ALWAYS TO BE A PLACE FOR 1991 01:23:56,565 --> 01:23:58,433 IN VIVO ESPECIALLY IF YOU THINK 1992 01:23:58,433 --> 01:24:01,937 OF CLINICAL TRANSLATION. 1993 01:24:01,937 --> 01:24:02,938 THERE'S A LOT OF DIFFERENT 1994 01:24:02,938 --> 01:24:05,140 OPTIONS AND DEPENDING ON YOUR 1995 01:24:05,140 --> 01:24:06,208 QUESTION IT'S WORTH LOOKING INTO 1996 01:24:06,208 --> 01:24:07,476 THE DIFFERENT MODELS. 1997 01:24:07,476 --> 01:24:10,679 FOR EXAMPLE IF YOU'RE INTERESTED 1998 01:24:10,679 --> 01:24:13,882 IN ISLET SURVIVAL AND 1999 01:24:13,882 --> 01:24:14,449 IMMUNODEFICIENT MODELS ARE 2000 01:24:14,449 --> 01:24:16,785 PERFECTLY FINE. 2001 01:24:16,785 --> 01:24:20,522 AS WE MOVE TOWARDS INTERACTION 2002 01:24:20,522 --> 01:24:23,992 IMMUNE CELL IMMUNIZED MOUSE 2003 01:24:23,992 --> 01:24:24,793 MODELS MAY BE REQUIRED. 2004 01:24:24,793 --> 01:24:26,862 I DON'T HAVE TIME TO GO INTO 2005 01:24:26,862 --> 01:24:30,966 DETAILS BUT THESE ARE HIGHLY 2006 01:24:30,966 --> 01:24:34,803 CUSTOMIZABLE DEPENDING STRAIN 2007 01:24:34,803 --> 01:24:36,104 YOU'LL GET DIFFERENT FLAVORS OF 2008 01:24:36,104 --> 01:24:37,406 THE IMMUNE SYSTEM. 2009 01:24:37,406 --> 01:24:40,075 SO IT'S WORTH DIGGING INTO THE 2010 01:24:40,075 --> 01:24:41,977 LIMITATION OF EACH MODEL AND 2011 01:24:41,977 --> 01:24:43,812 THINKING THROUGH YOU'RE RESEARCH 2012 01:24:43,812 --> 01:24:46,848 QUESTION SO YOU CAN PICK THE 2013 01:24:46,848 --> 01:24:47,316 RIGHT MODEL TO ANSWER. 2014 01:24:47,316 --> 01:24:51,253 THEN I WANTED TO ALSO HAVE UP 2015 01:24:51,253 --> 01:24:58,493 THERE IMMUNOCOMPETENT MODEL AND 2016 01:24:58,493 --> 01:24:59,928 NO MOUSE MODEL REPLICATES THE 2017 01:24:59,928 --> 01:25:00,963 DISEASE AND PART OF THE 2018 01:25:00,963 --> 01:25:02,631 PROCESSES WE WANT TO STUDY. 2019 01:25:02,631 --> 01:25:05,734 SO SOMETIMES YOU NEED A WHOLE 2020 01:25:05,734 --> 01:25:06,535 IMMUNE SYSTEM. 2021 01:25:06,535 --> 01:25:07,703 THERE'S STILL A PLACE FOR MODELS 2022 01:25:07,703 --> 01:25:09,404 THAT HAVE BEEN CRITICAL TO GET 2023 01:25:09,404 --> 01:25:11,239 US TO THE POINT WHERE WE ARE 2024 01:25:11,239 --> 01:25:11,406 NOW. 2025 01:25:11,406 --> 01:25:12,507 THERE'S NEW TECHNOLOGIES THAT 2026 01:25:12,507 --> 01:25:16,378 CAN BE APPLIED TO THAT AND 2027 01:25:16,378 --> 01:25:22,584 INTRODUCE HUMAN GENES THE TRANS 2028 01:25:22,584 --> 01:25:28,824 IMMUNE MICE AND REPRODUCE IT AND 2029 01:25:28,824 --> 01:25:31,059 TO LOOK AT THE CELL TYPES AND 2030 01:25:31,059 --> 01:25:35,964 MODELS FOR PIG AND NON HUMAN 2031 01:25:35,964 --> 01:25:37,232 PRIMATES AND WANTED TO HAVE THEM 2032 01:25:37,232 --> 01:25:39,301 UP THERE. 2033 01:25:39,301 --> 01:25:42,971 ANOTHER PLACE WHERE I THINK THE 2034 01:25:42,971 --> 01:25:44,873 COMPLEMENTARY EXPERTISE IS 2035 01:25:44,873 --> 01:25:47,509 HIGHLIGHTED IS IN THE DEVELOPED 2036 01:25:47,509 --> 01:25:49,211 HUMAN MOUSE MODELS AND IT'S 2037 01:25:49,211 --> 01:25:50,612 COMPLICATED AND TAKES A VILLAGE 2038 01:25:50,612 --> 01:25:52,714 TO MAKE IT HAPPEN AND HIRN HAS 2039 01:25:52,714 --> 01:25:54,116 BEEN GREAT AT SUPPORTING AND 2040 01:25:54,116 --> 01:25:55,817 PUTTING RESOURCES BEHIND THE 2041 01:25:55,817 --> 01:25:56,385 COMPLICATED PROBLEM. 2042 01:25:56,385 --> 01:25:58,153 SO WE HAVE THESE MODELS. 2043 01:25:58,153 --> 01:26:00,956 HOW CAN WE ACTUALLY USE THEM TO 2044 01:26:00,956 --> 01:26:03,525 ACCELERATE TRANSLATION? 2045 01:26:03,525 --> 01:26:05,360 IT'S A COMPLICATED PROBLEM. 2046 01:26:05,360 --> 01:26:08,196 AS WE HEARD WE GENERATED ALL 2047 01:26:08,196 --> 01:26:09,131 THIS INFORMATION AND HAVE A LOT 2048 01:26:09,131 --> 01:26:11,500 OF NEW HYPOTHESIS BUT HOW CAN WE 2049 01:26:11,500 --> 01:26:15,203 START TO HAVE THE INFORMATION 2050 01:26:15,203 --> 01:26:18,440 AND GET TO THE PATHWAY IS 2051 01:26:18,440 --> 01:26:19,608 CRITICAL FOR DISEASE PROGRESSION 2052 01:26:19,608 --> 01:26:21,543 AND THE TARGETS LIKELY TO LEAD 2053 01:26:21,543 --> 01:26:22,511 TO SUCCESSFUL TRANSLATION? 2054 01:26:22,511 --> 01:26:24,112 I THINK THIS IS WHERE THE MODELS 2055 01:26:24,112 --> 01:26:24,980 ARE REALLY IMPORTANT. 2056 01:26:24,980 --> 01:26:27,349 THEY CAN TAKE US FROM HYPOTHESIS 2057 01:26:27,349 --> 01:26:28,917 GENERATING STUDIES TO FUNCTIONAL 2058 01:26:28,917 --> 01:26:29,951 STUDIES TO REALLY VALIDATE SOME 2059 01:26:29,951 --> 01:26:40,262 OF THESE TARGETS. 2060 01:26:46,935 --> 01:26:49,037 YOU CAN MAKE A MUTATION IN YOUR 2061 01:26:49,037 --> 01:26:59,514 CELLS AND OVERPRESS IT AND 2062 01:27:03,051 --> 01:27:06,955 INTRODUCE ENVIRONMENTAL FACTOR 2063 01:27:06,955 --> 01:27:14,896 AND TRESS THE CELLS AND LAYER 2064 01:27:14,896 --> 01:27:16,431 FACTORS AND DOES IT AFFECT THEIR 2065 01:27:16,431 --> 01:27:17,766 TRANSACTION DOES IT MAKE IT MORE 2066 01:27:17,766 --> 01:27:20,202 OR LESS IMMUNOGENIC? 2067 01:27:20,202 --> 01:27:24,372 DOES IT CHANGE THE BIOMARKER 2068 01:27:24,372 --> 01:27:25,941 YOU'RE INTERESTED IN AND START 2069 01:27:25,941 --> 01:27:28,243 TO DIG INTO THE MECHANISM OF 2070 01:27:28,243 --> 01:27:28,477 THIS. 2071 01:27:28,477 --> 01:27:33,548 YOU CAN DO DRUG SKREEJ -- 2072 01:27:33,548 --> 01:27:35,450 SCREENING AND IT'S A GOOD WAY TO 2073 01:27:35,450 --> 01:27:36,485 START GETTING DATA FOR PRE 2074 01:27:36,485 --> 01:27:37,986 CLINICAL TESTING. 2075 01:27:37,986 --> 01:27:40,055 THIS IS PROBABLY AN OPPORTUNITY 2076 01:27:40,055 --> 01:27:41,723 TO START LOOKING AT COMBINATION 2077 01:27:41,723 --> 01:27:42,090 THERAPIES. 2078 01:27:42,090 --> 01:27:43,425 I'LL TOUCH OWN THAT LATER BUT 2079 01:27:43,425 --> 01:27:46,094 MOST LIKELY WE'LL HAVE TO 2080 01:27:46,094 --> 01:27:47,395 COMBINE DIFFERENT STRATEGIES. 2081 01:27:47,395 --> 01:27:49,531 IT'S A NOT THAT EASY TO DO IN 2082 01:27:49,531 --> 01:27:50,966 PATIENTS SO I THINK THERE'S 2083 01:27:50,966 --> 01:27:55,170 OPPORTUNITIES HERE TO GATHER 2084 01:27:55,170 --> 01:28:05,714 SOME PROOF OF CONCEPT AND WE'LL 2085 01:28:13,054 --> 01:28:15,423 LIKELY HAVE TO GO WITH A 2086 01:28:15,423 --> 01:28:16,758 MULTI-PRONGED APPROACH. 2087 01:28:16,758 --> 01:28:18,393 A LOT OF DIFFERENT STRATEGIES 2088 01:28:18,393 --> 01:28:20,095 ARE BEING DEVELOPED MOST OF THEM 2089 01:28:20,095 --> 01:28:21,963 FALL INTO CATEGORIES EITHER THE 2090 01:28:21,963 --> 01:28:25,734 TARGET OF THE IMMUNE SYSTEM WE 2091 01:28:25,734 --> 01:28:30,972 NEED TO SOLVE THAT ISSUE AND THE 2092 01:28:30,972 --> 01:28:36,211 OTHER ARM IS PROTECTING BETA 2093 01:28:36,211 --> 01:28:41,983 CELL FUNCTION AND LOOK AT THOSE 2094 01:28:41,983 --> 01:28:45,921 TWO THINGS TOGETHER. 2095 01:28:45,921 --> 01:28:48,123 THERE'S DIFFERENT OPTIONS BEING 2096 01:28:48,123 --> 01:28:48,957 TESTED. 2097 01:28:48,957 --> 01:28:52,327 SOME FAILED AND SOME ARE LOOKING 2098 01:28:52,327 --> 01:28:56,932 PROMPTING. 2099 01:28:56,932 --> 01:29:01,136 THERE'S CELL BASED THERAPIES AND 2100 01:29:01,136 --> 01:29:03,038 A LOT OF THEM HAVE THE AIM AIM 2101 01:29:03,038 --> 01:29:08,210 TO REBALANCE THE IMMUNE SYSTEM. 2102 01:29:15,116 --> 01:29:17,319 4:AND YOU CAN HAVE TOO MUCH 2103 01:29:17,319 --> 01:29:18,987 ACTIVITY IN YOUR IMMUNE SYSTEM 2104 01:29:18,987 --> 01:29:19,921 AND NOT ENOUGH SUPPRESSION. 2105 01:29:19,921 --> 01:29:20,922 WHENEVER THE TREATMENT IS THE 2106 01:29:20,922 --> 01:29:22,557 GOAL IS IT TO REBALANCE THIS BY 2107 01:29:22,557 --> 01:29:24,125 REDUCING THE ACTIVITY OF THE 2108 01:29:24,125 --> 01:29:26,861 IMMUNE SYSTEM OR INCREASING 2109 01:29:26,861 --> 01:29:27,162 SUPPRESSION. 2110 01:29:27,162 --> 01:29:31,600 YOU CAN DO THAT BY TARGETING A 2111 01:29:31,600 --> 01:29:35,103 LOT OF DIFFERENT CELL TYPES AND 2112 01:29:35,103 --> 01:29:37,472 IMPROVE SUPPRESSION BY STANDING 2113 01:29:37,472 --> 01:29:42,978 TREGS AND TREAT WITH JACK 2114 01:29:42,978 --> 01:29:43,278 INHIBITERS. 2115 01:29:43,278 --> 01:29:52,020 THERE'S DIFFERENT OPPORTUNITIES 2116 01:29:52,020 --> 01:29:56,758 AND YOU CAN DISCUSS THE 2117 01:29:56,758 --> 01:29:57,392 DIFFERENT ATTORNEY GENERALS. 2118 01:29:57,392 --> 01:30:00,195 MOVING ON TO THE STRATEGIES MORE 2119 01:30:00,195 --> 01:30:10,605 FOCUSSED ON BETA CELLS. 2120 01:30:14,576 --> 01:30:16,711 AND THINK ABOUT CELL REPLACEMENT 2121 01:30:16,711 --> 01:30:17,078 THERAPIES. 2122 01:30:17,078 --> 01:30:20,048 I CO WANT TO TALK A BIT ABOUT 2123 01:30:20,048 --> 01:30:21,950 CELL REPLACEMENT THERAPIES. 2124 01:30:21,950 --> 01:30:22,984 THERE'S A LOT OF EXCITING THINGS 2125 01:30:22,984 --> 01:30:25,854 HAPPENING IN THAT SPACE. 2126 01:30:25,854 --> 01:30:30,859 I'VE BEEN WORKING IN THE FIELD 2127 01:30:30,859 --> 01:30:32,594 MANY YEARS NOW AND THERE'S A 2128 01:30:32,594 --> 01:30:37,065 CHANGE IN THE WAY WE THINK ABOUT 2129 01:30:37,065 --> 01:30:37,899 THIS. 2130 01:30:37,899 --> 01:30:40,201 IT'S EXCITING TIME TO BE WORKING 2131 01:30:40,201 --> 01:30:42,237 ON THIS. 2132 01:30:42,237 --> 01:30:45,240 I WANTED TO PUT THE FIGURE UP 2133 01:30:45,240 --> 01:30:47,075 HERE AND TAKE THIS FROM A ROW 2134 01:30:47,075 --> 01:30:47,976 VIEW WHERE THOUGHT LEADERS IN 2135 01:30:47,976 --> 01:30:52,514 THE FIELD WITH THE SUPPORTERS 2136 01:30:52,514 --> 01:31:00,221 BUILD THE ROAD MAP HOW WE THINK 2137 01:31:00,221 --> 01:31:04,192 ABOUT THEY WILL WE PLACEMENT 2138 01:31:04,192 --> 01:31:05,627 THERAPY WITH BROAD 2139 01:31:05,627 --> 01:31:06,227 IMMUNOEXPRESSION. 2140 01:31:06,227 --> 01:31:06,995 THAT WORKS. 2141 01:31:06,995 --> 01:31:08,396 THERE'S SOME ISSUES WITH 2142 01:31:08,396 --> 01:31:09,664 SCALABILITY AND IMMUNE 2143 01:31:09,664 --> 01:31:09,964 EXPRESSION. 2144 01:31:09,964 --> 01:31:12,167 THERE STILL NEEDS TO BE 2145 01:31:12,167 --> 01:31:12,667 ALTERNATIVES DEVELOPED. 2146 01:31:12,667 --> 01:31:15,270 THE FIRST GENERATION IS LIKELY 2147 01:31:15,270 --> 01:31:18,239 GOING TO BE STEM CELL DERIVED 2148 01:31:18,239 --> 01:31:18,973 ISLETS. 2149 01:31:18,973 --> 01:31:19,908 THERE ARE CURRENT CLINICAL 2150 01:31:19,908 --> 01:31:21,609 TRIALS AND THE VERTEX TRIAL AND 2151 01:31:21,609 --> 01:31:23,445 THERE WAS A PATIENT IN CHINA WHO 2152 01:31:23,445 --> 01:31:28,416 GOT TREATED WITH THEIR OWN IPS 2153 01:31:28,416 --> 01:31:31,152 DERIVED ISLETS AND TURNED THEM 2154 01:31:31,152 --> 01:31:32,120 INTO STEM CELLS AND TRANSPLANT 2155 01:31:32,120 --> 01:31:32,754 THEM BACK. 2156 01:31:32,754 --> 01:31:34,255 THIS IS EXCITING. 2157 01:31:34,255 --> 01:31:42,931 THIS IS DONE UNDER PNEUMO 2158 01:31:42,931 --> 01:31:43,631 EXPRES -- 2159 01:31:43,631 --> 01:31:44,065 IMM 2160 01:31:44,065 --> 01:31:44,466 IMMUNOEXPRESSION. 2161 01:31:44,466 --> 01:31:47,769 THE NEXT GENERATION WILL REDUCE 2162 01:31:47,769 --> 01:31:49,537 IMMUNE GENICITY AND I'M EXCITED 2163 01:31:49,537 --> 01:31:52,207 TO SEE WHAT'S GOING TO HAPPEN 2164 01:31:52,207 --> 01:32:02,317 THERE. 2165 01:32:06,621 --> 01:32:10,592 ONE EXAMPLE IS THE LACK OF 2166 01:32:10,592 --> 01:32:12,193 THERAPEUTICS WHETHER IT'S SMALL 2167 01:32:12,193 --> 01:32:14,929 MOLECULES OR ANTIBODIES OR SOME 2168 01:32:14,929 --> 01:32:15,697 CELL-BASED THERAPIES I THINK WE 2169 01:32:15,697 --> 01:32:18,299 CAN DO BETTER IN TERMS OF 2170 01:32:18,299 --> 01:32:19,868 INCREASING THE SPECIFICITY. 2171 01:32:19,868 --> 01:32:22,404 HOW CAN WE DELIVER THEM TO THE 2172 01:32:22,404 --> 01:32:23,238 RIGHT PLACE. 2173 01:32:23,238 --> 01:32:24,973 HOW CAN WE GET THEM TO GO 2174 01:32:24,973 --> 01:32:28,209 STRAIGHT TO THE BETA CELLS AND 2175 01:32:28,209 --> 01:32:28,810 ACTIVATE LOCALLY. 2176 01:32:28,810 --> 01:32:30,912 THERE'S OPPORTUNITIES THERE 2177 01:32:30,912 --> 01:32:32,213 ESPECIALLY WITH CELL-BASED 2178 01:32:32,213 --> 01:32:33,848 THERAPY AND WE'LL HEAR ABOUT 2179 01:32:33,848 --> 01:32:36,217 SOME OF THE STRATEGIES LATER 2180 01:32:36,217 --> 01:32:38,787 DURING THE MEET. 2181 01:32:38,787 --> 01:32:39,087 -- MEETING. 2182 01:32:39,087 --> 01:32:42,991 ANOTHER THING I THINK IS REALLY 2183 01:32:42,991 --> 01:32:45,160 CHALLENGING WITH IMMUNE 2184 01:32:45,160 --> 01:32:47,495 MODULATION THERAPY IS MATCHING 2185 01:32:47,495 --> 01:32:52,033 THE RIGHT PATIENT WITH THE RIGHT 2186 01:32:52,033 --> 01:32:52,834 AGENT AT THE RIGHT STAGE. 2187 01:32:52,834 --> 01:32:55,670 WHEN YOU LOOK AT A PATIENT 2188 01:32:55,670 --> 01:32:56,871 POPULATION I PUT THIS FIGURE UP 2189 01:32:56,871 --> 01:32:57,572 THERE TO TRY TO ILLUSTRATE THE 2190 01:32:57,572 --> 01:32:59,541 POINT. 2191 01:32:59,541 --> 01:33:01,309 THIS IS IMPORTANT FOR CLINICAL 2192 01:33:01,309 --> 01:33:03,812 TRIAL DESIGN AND WILL BE 2193 01:33:03,812 --> 01:33:05,914 IMPORTANT WHEN IT'S TIME TO PICK 2194 01:33:05,914 --> 01:33:07,315 AN INTERVENTION FOR A PATIENT. 2195 01:33:07,315 --> 01:33:08,917 IF YOU'RE IN A POOL OF PATIENT 2196 01:33:08,917 --> 01:33:10,652 YOU PROBABLY HAVE A SET OF 2197 01:33:10,652 --> 01:33:14,656 PEOPLE THAT WILL NEVER PROGRESS. 2198 01:33:14,656 --> 01:33:17,358 YOU HAVE TO RECRUIT MORE PEOPLE 2199 01:33:17,358 --> 01:33:19,260 IN YOUR TRIAL BECAUSE MANY WILL 2200 01:33:19,260 --> 01:33:20,495 NOT PROGRESSION TO TYPE I 2201 01:33:20,495 --> 01:33:20,762 DIABETES. 2202 01:33:20,762 --> 01:33:22,530 THREES A POOL OF RESPONDERS. 2203 01:33:22,530 --> 01:33:24,365 THOSE ARE THE ONES YOU WANT TO 2204 01:33:24,365 --> 01:33:25,500 FOCUS ON AND THERE ARE PEOPLE 2205 01:33:25,500 --> 01:33:26,601 THAT WILL NOT RESPOND. 2206 01:33:26,601 --> 01:33:27,769 WHETHER IT'S TOO EARLY IN THE 2207 01:33:27,769 --> 01:33:32,207 DISEASE OR TO -- TOO LATE OR THE 2208 01:33:32,207 --> 01:33:34,909 WRONG MECHANISM OR DON'T HAVE 2209 01:33:34,909 --> 01:33:36,411 ENOUGH BETA CELL FUNCTION 2210 01:33:36,411 --> 01:33:37,278 READOUT YOU MAY NOT GET THE 2211 01:33:37,278 --> 01:33:39,547 RESULTS YOU'RE LOOKING FOR. 2212 01:33:39,547 --> 01:33:42,617 BASICALLY HOW CAN WE UNDERSTAND 2213 01:33:42,617 --> 01:33:43,852 BETTER THIS POOL OF PATIENT AND 2214 01:33:43,852 --> 01:33:46,488 CAN WE IDENTIFY THEM BETTER IN 2215 01:33:46,488 --> 01:33:48,189 EARLY STAGES? 2216 01:33:48,189 --> 01:33:50,992 CAN WE TELL MORE EFFICIENTLY WHO 2217 01:33:50,992 --> 01:33:53,328 IS MORE LIKELY TO PROGRESS? 2218 01:33:53,328 --> 01:33:55,296 TELL RESPONDERS VERSUS 2219 01:33:55,296 --> 01:33:57,432 NON-RESPONDERS AND SHOULD WE BE 2220 01:33:57,432 --> 01:33:58,099 THINKING ABOUT USING DIFFERENT 2221 01:33:58,099 --> 01:33:59,634 OUTCOMES DEPENDING ON THE 2222 01:33:59,634 --> 01:34:00,969 INTERVENTIONS OR SHOULD WE BE 2223 01:34:00,969 --> 01:34:03,037 LOOKING AT IMMUNOLOGICAL 2224 01:34:03,037 --> 01:34:05,273 OUTCOMES INSTEAD OF BETA CELL 2225 01:34:05,273 --> 01:34:05,540 FUNCTION? 2226 01:34:05,540 --> 01:34:05,974 A LOT OF QUESTIONS. 2227 01:34:05,974 --> 01:34:08,209 I DON'T HAVE ANSWERS FOR ALL OF 2228 01:34:08,209 --> 01:34:09,911 THEM BUT WANTED TO PUT THEM OUT 2229 01:34:09,911 --> 01:34:10,178 THERE. 2230 01:34:10,178 --> 01:34:11,980 ONE THING THAT I THINK WE CAN 2231 01:34:11,980 --> 01:34:16,184 ALSO DO TO HELP SO HOLGER 2232 01:34:16,184 --> 01:34:17,118 TOUCHED ON THIS A LITTLE BIT BUT 2233 01:34:17,118 --> 01:34:18,486 I THINK AT THE END OF THE DAY 2234 01:34:18,486 --> 01:34:20,722 THE BEST MODEL WE HAVE FOR HUMAN 2235 01:34:20,722 --> 01:34:23,491 TYPE I DIABETES ARE THE 2236 01:34:23,491 --> 01:34:23,758 PATIENTS. 2237 01:34:23,758 --> 01:34:25,026 SO HOW CAN WE USE INFORMATION 2238 01:34:25,026 --> 01:34:28,997 THAT'S COMING OUT OF THESE 2239 01:34:28,997 --> 01:34:30,231 CLINICAL TRIALS BETTER TO INFORM 2240 01:34:30,231 --> 01:34:33,501 OUR DISEASE MODELLING EFFORTS? 2241 01:34:33,501 --> 01:34:35,570 SO CAN WE ACTUALLY MAKE A 2242 01:34:35,570 --> 01:34:37,739 CONSCIOUS EFFORT AS A GROUP TO 2243 01:34:37,739 --> 01:34:39,440 BETTER DESIGN CLINICAL TRIALS SO 2244 01:34:39,440 --> 01:34:41,876 THERE'S SAMPLES BEING CONNECTED 2245 01:34:41,876 --> 01:34:47,048 SEND BACK TO THE RESEARCHERS TO 2246 01:34:47,048 --> 01:34:49,317 GET BETTER INSIGHT HOW OUR DRUG 2247 01:34:49,317 --> 01:34:54,289 WORKS IN HUMANS AND MAKE OUR 2248 01:34:54,289 --> 01:34:54,722 MODELS BETTER? 2249 01:34:54,722 --> 01:34:56,491 LAST POINT I WANTED TO MAKE IS 2250 01:34:56,491 --> 01:34:59,994 HOW CAN WE LEARN FROM OTHER 2251 01:34:59,994 --> 01:35:00,261 DISEASES? 2252 01:35:00,261 --> 01:35:02,363 AND THERE ARE PATIENTS OUT THERE 2253 01:35:02,363 --> 01:35:06,200 THAT HAVE DISEASES THAT LOOK A 2254 01:35:06,200 --> 01:35:08,403 LOT LIKE TYPE I DIABETES AND 2255 01:35:08,403 --> 01:35:11,406 PATIENTS BEING TREATED WITH 2256 01:35:11,406 --> 01:35:12,240 CHECKPOINT BLOCKADE DEVELOP 2257 01:35:12,240 --> 01:35:12,707 QUICK DIABETES. 2258 01:35:12,707 --> 01:35:14,943 CAN WE LEARN FROM THEM? 2259 01:35:14,943 --> 01:35:17,145 IS THERE SOMETHING THERE ABOUT 2260 01:35:17,145 --> 01:35:20,615 THE INHIBITORY PATHWAYS WE CAN 2261 01:35:20,615 --> 01:35:20,949 STUDY? 2262 01:35:20,949 --> 01:35:23,451 SAME THING FOR OTHER AUTO IMMUNE 2263 01:35:23,451 --> 01:35:23,718 DISEASES? 2264 01:35:23,718 --> 01:35:25,753 FOR EXAMPLE THERE'S EXCITING 2265 01:35:25,753 --> 01:35:29,757 WORK BEING DONE WITH CAR T CELLS 2266 01:35:29,757 --> 01:35:32,193 IN THE CONTEXT OF AUTO IMMUNE 2267 01:35:32,193 --> 01:35:34,996 DISEASES AND THEY'RE BEING USED 2268 01:35:34,996 --> 01:35:40,168 FOR DISEASES THAT HAVE A LEVY -- 2269 01:35:40,168 --> 01:35:43,004 HEAVY B CELL LIKE LUPUS AND 2270 01:35:43,004 --> 01:35:44,205 MULTIPLE SCLEROSIS BUT THERE'S 2271 01:35:44,205 --> 01:35:45,506 EXCITING DATA IN THE AREA. 2272 01:35:45,506 --> 01:35:49,177 IS THERE AN OPPORTUNITY TO 2273 01:35:49,177 --> 01:35:50,378 TRANSLATE THAT TO TYPE I 2274 01:35:50,378 --> 01:35:54,048 DIABETES AND LEARN ABOUT THE 2275 01:35:54,048 --> 01:35:55,016 ROLE OF B CELLS IN TYPE I 2276 01:35:55,016 --> 01:35:57,752 DIABETES AND TRYING TO KEEP AN 2277 01:35:57,752 --> 01:35:59,520 OPEN MIND OF WHAT'S GOING ON IN 2278 01:35:59,520 --> 01:36:00,154 OTHER FIELDS. 2279 01:36:00,154 --> 01:36:02,423 SO, CONCLUSION I HOPE WITH THE 2280 01:36:02,423 --> 01:36:04,692 TALKS THIS MORNING WE'VE 2281 01:36:04,692 --> 01:36:05,226 CONVINCED YOU CONTINUED 2282 01:36:05,226 --> 01:36:07,996 INVESTMENT IN NETWORKS LIKE HIRN 2283 01:36:07,996 --> 01:36:09,330 AND BASIC RESEARCH IS IMPORTANT. 2284 01:36:09,330 --> 01:36:11,199 IT ENABLES THE DEVELOPMENT OF 2285 01:36:11,199 --> 01:36:12,367 RESOURCES AND TECHNOLOGIES THAT 2286 01:36:12,367 --> 01:36:15,637 ARE REALLY CRITICAL TO THE TYPE 2287 01:36:15,637 --> 01:36:16,137 I RESEARCH COMMUNITY. 2288 01:36:16,137 --> 01:36:18,706 I HOPE YOU GUYS ARE AWARE OF IT 2289 01:36:18,706 --> 01:36:20,141 AND TAKE ADVANTAGE IT AND WE 2290 01:36:20,141 --> 01:36:25,280 MENTIONED THE BREAKOUT SESSIONS 2291 01:36:25,280 --> 01:36:26,147 ABOUT PANC DB AND IF YOU DON'T 2292 01:36:26,147 --> 01:36:28,049 KNOW WHERE TO START ATTEND THE 2293 01:36:28,049 --> 01:36:29,250 BREAKOUT SESSIONS. 2294 01:36:29,250 --> 01:36:34,622 WITHOUT THESE NOVEL INSIGHTS 2295 01:36:34,622 --> 01:36:36,190 THAT ARE GAINED FROM THESE NOVEL 2296 01:36:36,190 --> 01:36:38,393 STUDIES I HOPE WE GAVE YOU HOW 2297 01:36:38,393 --> 01:36:40,662 THEY CAN RESULT IN FASTER 2298 01:36:40,662 --> 01:36:42,463 CLINICAL TRANSLATION OF 2299 01:36:42,463 --> 01:36:44,098 THERAPIES AND IMPROVE CARE OF 2300 01:36:44,098 --> 01:36:44,365 PATIENTS. 2301 01:36:44,365 --> 01:36:45,400 OKAY. 2302 01:36:45,400 --> 01:36:47,201 I DON'T THINK WE HAVE TIME FOR 2303 01:36:47,201 --> 01:36:49,337 DISCUSSION BUT I JUST WANTED TO 2304 01:36:49,337 --> 01:36:52,206 MENTION THAT THAT WITH THE TALKS 2305 01:36:52,206 --> 01:36:55,009 THIS MORNING WE'VE SHOWN SOME OF 2306 01:36:55,009 --> 01:36:55,943 THE PROGRESS. 2307 01:36:55,943 --> 01:36:57,845 WE ALSO PUT OUT SOME OF THE 2308 01:36:57,845 --> 01:36:58,112 QUESTIONS. 2309 01:36:58,112 --> 01:36:59,514 WE'VE RAISED A LOT OF QUESTIONS. 2310 01:36:59,514 --> 01:37:00,682 I HOPE IT WILL STIMULATE 2311 01:37:00,682 --> 01:37:03,084 DISCUSSIONS FOR THE REST OF THE 2312 01:37:03,084 --> 01:37:03,751 MEETING. 2313 01:37:03,751 --> 01:37:05,219 PLEASE PARTICIPATE IN POSTER 2314 01:37:05,219 --> 01:37:06,587 SESSIONS AND BREAKOUT SESSIONS. 2315 01:37:06,587 --> 01:37:09,190 WE WANT TO HEAR FEEDBACK FROM 2316 01:37:09,190 --> 01:37:11,559 THE COMMUNITY AND LEARN FROM YOU 2317 01:37:11,559 --> 01:37:14,429 GUYS AND GET INPUT HOW WHERE THE 2318 01:37:14,429 --> 01:37:16,197 FIELD IS HEADING IN THE NEXT FEW 2319 01:37:16,197 --> 01:37:16,397 YEARS. 2320 01:37:16,397 --> 01:37:25,840 THANK YOU. 2321 01:37:25,840 --> 01:37:27,008 >> OKAY. 2322 01:37:27,008 --> 01:37:27,275 EVERYONE. 2323 01:37:27,275 --> 01:37:31,212 IT IS NOW LUNCH TIME AND POSTER 2324 01:37:31,212 --> 01:37:32,413 SESSION TIME 2325 01:37:32,413 --> 01:37:36,150 WE'RE GOING TO GET STARTED. 2326 01:37:36,150 --> 01:37:38,019 SO IF YOU'RE OUTSIDE THE MEETING 2327 01:37:38,019 --> 01:37:39,287 ROOM AND HEARING THIS, PLEASE 2328 01:37:39,287 --> 01:37:43,825 COME ON IN AND FIND A SEAT. 2329 01:37:43,825 --> 01:37:47,628 THIS IS THE FIRST OF THREE 2330 01:37:47,628 --> 01:37:48,730 SCIENTIFIC SESSIONS THAT WE'VE 2331 01:37:48,730 --> 01:37:49,063 PLANNED. 2332 01:37:49,063 --> 01:37:51,599 YOU NOTICE THE THEME OF TODAY, 2333 01:37:51,599 --> 01:37:53,434 THE TEAM OF THE MEETING, IN 2334 01:37:53,434 --> 01:37:57,238 TERMS OF THE TOPIC AREAS, HAVE 2335 01:37:57,238 --> 01:37:58,339 BEEN DISCOVERY, ETIOLOGY, 2336 01:37:58,339 --> 01:37:58,873 THERAPEUTICS. 2337 01:37:58,873 --> 01:38:01,743 AND WE ARE GOING TO START THAT 2338 01:38:01,743 --> 01:38:02,977 MISSION WITH DISCOVERY. 2339 01:38:02,977 --> 01:38:05,146 I'D LIKE TO ASK OUR MODERATORS 2340 01:38:05,146 --> 01:38:09,617 TO COME UP AND KICK OFF THE 2341 01:38:09,617 --> 01:38:10,318 DISCUSSION. 2342 01:38:10,318 --> 01:38:12,920 KICK OFF THE TALKS, NOT THE 2343 01:38:12,920 --> 01:38:13,254 DISCUSSION. 2344 01:38:13,254 --> 01:38:21,896 MAYBE BOTH, I GUESS. 2345 01:38:21,896 --> 01:38:23,765 >> GOOD AFTERNOON, WELCOME TO 2346 01:38:23,765 --> 01:38:25,700 THE FIRST OF THE SESSIONS. 2347 01:38:25,700 --> 01:38:27,702 THIS SESSION IS ON EMERGING 2348 01:38:27,702 --> 01:38:29,871 APPROACHES AND DISCOVERIES IN 2349 01:38:29,871 --> 01:38:30,638 TYPE 1 DIABETES RESEARCH. 2350 01:38:30,638 --> 01:38:38,746 I'M ONE OF THE CO-CHAIRS, ROW 2351 01:38:38,746 --> 01:38:39,180 ROHIT 2352 01:38:39,180 --> 01:38:41,149 KULKARNI FROM JOSLIN DIABETES 2353 01:38:41,149 --> 01:38:46,854 CENTER AND MY CO-CHAIR. 2354 01:38:46,854 --> 01:38:47,455 >> JUAN ALVAREZ, ASSISTANT 2355 01:38:47,455 --> 01:38:48,256 PROFESSOR, UNIVERSITY OF 2356 01:38:48,256 --> 01:38:48,589 PENNSYLVANIA. 2357 01:38:48,589 --> 01:38:50,324 >> I WANT TO GIVE YOU LOGISTICS 2358 01:38:50,324 --> 01:38:51,993 FOR THE SESSION. 2359 01:38:51,993 --> 01:38:54,595 FOUR EXCELLENT SPEAKERS ON THIS 2360 01:38:54,595 --> 01:38:57,565 VERY, VERY EXCITING TOPIC. 2361 01:38:57,565 --> 01:39:00,535 THE SESSION WAS EACH OF THE 2362 01:39:00,535 --> 01:39:02,403 SPEAKERS WILL PRESENT FOR 18-20 2363 01:39:02,403 --> 01:39:03,371 MINUTES EACH. 2364 01:39:03,371 --> 01:39:05,139 WE WON'T HAVE QUESTIONS AT THE 2365 01:39:05,139 --> 01:39:07,108 END OF THAT SESSION, BUT AFTER 2366 01:39:07,108 --> 01:39:09,544 ALL THE FOUR SPEAKERS HAVE 2367 01:39:09,544 --> 01:39:11,078 FINISHED THEIR TALKS, WE'LL 2368 01:39:11,078 --> 01:39:12,713 BRING THEM UP FOR THE PANEL 2369 01:39:12,713 --> 01:39:15,049 DISCUSSION AND WE'LL HAVE AN 2370 01:39:15,049 --> 01:39:16,517 EXTENSIVE PANEL DISCUSSION AT 2371 01:39:16,517 --> 01:39:17,318 THE END. 2372 01:39:17,318 --> 01:39:18,820 PLEASE KEEP YOUR QUESTIONS NOTED 2373 01:39:18,820 --> 01:39:20,488 SO YOU CAN BRING THEM UP DURING 2374 01:39:20,488 --> 01:39:20,922 THE DISCUSSION. 2375 01:39:20,922 --> 01:39:22,423 WE THOUGHT THAT WAS THE MOST 2376 01:39:22,423 --> 01:39:25,493 EFFECTIVE WAY TO DO THAT. 2377 01:39:25,493 --> 01:39:28,896 ALSO WANT TO EMPHASIZE TO TURN 2378 01:39:28,896 --> 01:39:30,765 OFF YOUR AUDIO ON YOUR 2379 01:39:30,765 --> 01:39:32,300 iPHONES, ALSO REQUEST THE 2380 01:39:32,300 --> 01:39:35,236 SPEAKERS TO KEEP TO TIME, SO YOU 2381 01:39:35,236 --> 01:39:36,671 HAVE 18-20 MINUTES EACH. 2382 01:39:36,671 --> 01:39:38,973 SO WITH THAT, I'LL REQUEST MY 2383 01:39:38,973 --> 01:39:40,508 CO-CHAIR TO GIVE AN OVERVIEW OF 2384 01:39:40,508 --> 01:39:42,376 THE SESSION SO THAT YOU GET AN 2385 01:39:42,376 --> 01:39:43,678 IDEA AS TO WHERE THE FOCUS IS 2386 01:39:43,678 --> 01:39:45,980 GOING TO BE AND WHAT EACH OF THE 2387 01:39:45,980 --> 01:39:47,381 SPEAKERS WILL TALK ABOUT. 2388 01:39:47,381 --> 01:39:54,722 AND THEN WE'LL ON TO THE FIRST 2389 01:39:54,722 --> 01:39:55,089 SPEAKER. 2390 01:39:55,089 --> 01:39:55,923 DR. ALVAREZ. 2391 01:39:55,923 --> 01:39:59,961 >> COULD WE MOVE TO THE INTRO 2392 01:39:59,961 --> 01:40:10,104 SLIDES. 2393 01:40:10,872 --> 01:40:12,240 SO THAT'S CHERIE'S SLIDES. 2394 01:40:12,240 --> 01:40:15,409 SESSION 1 IS THE TITLE. 2395 01:40:15,409 --> 01:40:17,812 YES, THAT ONE. 2396 01:40:17,812 --> 01:40:18,913 ALL RIGHT. 2397 01:40:18,913 --> 01:40:19,914 PERFECT. 2398 01:40:19,914 --> 01:40:23,417 SO, WELCOME TO THE FIRST SESSION 2399 01:40:23,417 --> 01:40:25,386 OF THE MEETING TODAY. 2400 01:40:25,386 --> 01:40:31,626 WE'LL HAVE SOME SCIENCE TO 2401 01:40:31,626 --> 01:40:35,029 DISCUSS TODAY. 2402 01:40:35,029 --> 01:40:40,301 WE'RE ORGANIZED AREN'T THREE 2403 01:40:40,301 --> 01:40:40,701 THINGS 2404 01:40:40,701 --> 01:40:42,169 FIRST SESSION IS DISCOVERY. 2405 01:40:42,169 --> 01:40:49,477 WE'LL HAVE A MICROCOSM AT THE 2406 01:40:49,477 --> 01:40:49,644 END. 2407 01:40:49,644 --> 01:40:51,746 A QUOTE, PROGRESS IN SCIENCE 2408 01:40:51,746 --> 01:40:53,948 DEPENDS ON NEW TECHNIQUES, NEW 2409 01:40:53,948 --> 01:40:55,483 DISCOVERIES, NEW IDEAS. 2410 01:40:55,483 --> 01:40:57,785 PROBABLY IN THAT ORDER. 2411 01:40:57,785 --> 01:41:01,522 ACCORDING TO SIDNEY BRENNER, A 2412 01:41:01,522 --> 01:41:05,126 PIONEER IN GENETICS. 2413 01:41:05,126 --> 01:41:09,931 SO, GOING WITH TECHNIQUES, OUR 2414 01:41:09,931 --> 01:41:11,566 FIRST SPEAKER IS DR. CHERIE 2415 01:41:11,566 --> 01:41:13,100 STABLER, PROFESSOR AT UNIVERSITY 2416 01:41:13,100 --> 01:41:18,472 OF FLORIDA, TALKING TO US ABOUT 2417 01:41:18,472 --> 01:41:19,974 ENGINEERING MICRO PHYSIOLOGY 2418 01:41:19,974 --> 01:41:20,775 SYSTEMS. 2419 01:41:20,775 --> 01:41:23,844 FOR TEN YEARS HAS SUPPORTED 2420 01:41:23,844 --> 01:41:25,579 DEVELOPING BREAKTHROUGH DEVICE 2421 01:41:25,579 --> 01:41:27,648 TECHNOLOGIES TO IMPROVE 2422 01:41:27,648 --> 01:41:28,716 UNDERSTANDING OF TIE 1 DIABETES, 2423 01:41:28,716 --> 01:41:32,486 A GRAND CHALLENGE TO BE TO BUILD 2424 01:41:32,486 --> 01:41:34,488 SYSTEMS THAT RECREATE FUNCTIONAL 2425 01:41:34,488 --> 01:41:39,060 ISLET NICHE TO TEASE APART 2426 01:41:39,060 --> 01:41:42,897 TISSUE TO TISSUE INTERACTION, 2427 01:41:42,897 --> 01:41:43,864 TISSUE-ENVIRONMENT INTERACTIONS, 2428 01:41:43,864 --> 01:41:45,499 OFFERING ADVANTAGES SUCH AS 2429 01:41:45,499 --> 01:41:48,135 PRECISE CONTROL OVER CHEMICAL 2430 01:41:48,135 --> 01:41:49,236 ENVIRONMENT, NUTRIENTS, OXYGEN, 2431 01:41:49,236 --> 01:41:50,671 SECRETED FACTORS, AND PHYSICAL 2432 01:41:50,671 --> 01:41:51,639 PARAMETERS WE'RE NOT USED TO 2433 01:41:51,639 --> 01:41:54,575 THINKING ABOUT SUCH AS 2434 01:41:54,575 --> 01:41:56,911 MECHANICAL FORCES, SPATIAL 2435 01:41:56,911 --> 01:41:58,546 PARAMETERS, ELECTRICAL FEATURES. 2436 01:41:58,546 --> 01:42:03,784 AND SO CHERIE WILL TELL US TODAY 2437 01:42:03,784 --> 01:42:04,685 HOW MICROPHYSIOLOGICAL SYSTEMS 2438 01:42:04,685 --> 01:42:06,087 PUSHING BOUNDARIES OF WHAT IS 2439 01:42:06,087 --> 01:42:07,955 POSSIBLE TO MODEL AND BETTER 2440 01:42:07,955 --> 01:42:09,256 UNDERSTAND TYPE 1 DIABETES AT 2441 01:42:09,256 --> 01:42:11,025 THE BENCH. 2442 01:42:11,025 --> 01:42:13,761 SECOND IS ROBERTO MALLONE, 2443 01:42:13,761 --> 01:42:20,201 MD/PHD, PROFESSOR AT UNIVERSITY 2444 01:42:20,201 --> 01:42:23,270 OF PARIS CITE, DIABETES AS A 2445 01:42:23,270 --> 01:42:25,172 DISEASE OF IMMUNE CELLS 2446 01:42:25,172 --> 01:42:26,474 CROSS-DOCKING WITH BETA CELLS, 2447 01:42:26,474 --> 01:42:29,176 HE HAS INVESTIGATED ROLE OF BETA 2448 01:42:29,176 --> 01:42:34,248 CELLS AND DEMISE BY QUESTIONS, 2449 01:42:34,248 --> 01:42:36,650 DO BETA CELLS INITIATE T CELL 2450 01:42:36,650 --> 01:42:38,319 KILLING, THE NOTION BETA CELLS 2451 01:42:38,319 --> 01:42:42,790 MAY PLAY A ROLE IN INITIATING 2452 01:42:42,790 --> 01:42:45,192 AUTOIMMUNITY DUE TO STRESS OR 2453 01:42:45,192 --> 01:42:46,160 DYSFUNCTION. 2454 01:42:46,160 --> 01:42:48,362 SECOND, DO BETA CELLS ENHANCE T 2455 01:42:48,362 --> 01:42:52,733 CELL KILLING ITSELF, THE NOTION 2456 01:42:52,733 --> 01:42:55,036 THAT THROUGH INTERFERONS THEY 2457 01:42:55,036 --> 01:42:58,673 CAN BECOME DETECTABLE PRIOR TO 2458 01:42:58,673 --> 01:43:01,275 THE DEVELOPMENT OF ANTIBODIES. 2459 01:43:01,275 --> 01:43:02,710 THIRD QUESTION DO BETA CELLS 2460 01:43:02,710 --> 01:43:04,678 FINALIZE KILLING THROUGH 2461 01:43:04,678 --> 01:43:07,648 SUICIDE, INTRIGUING ROLE THAT 2462 01:43:07,648 --> 01:43:11,752 PERHAPS SELF-DETRIMENTAL VERSUS 2463 01:43:11,752 --> 01:43:16,457 PROTECTIVE PROCESSES TO FINALIZE 2464 01:43:16,457 --> 01:43:17,925 ULTIMATE OUTCOME. 2465 01:43:17,925 --> 01:43:19,260 JULIA PANZER REMINDS US TYPE 1 2466 01:43:19,260 --> 01:43:21,896 DIABETES IS ALSO A DISEASE OF 2467 01:43:21,896 --> 01:43:25,499 THE ALPHA CELL, WHICH IS DEEPLY 2468 01:43:25,499 --> 01:43:28,269 ENGAGED IN CROSS-TALK WITH BETA 2469 01:43:28,269 --> 01:43:29,770 CELL, PARTICULARLY THROUGH 2470 01:43:29,770 --> 01:43:32,506 FAILURE TO RESPOND TO 2471 01:43:32,506 --> 01:43:33,841 LIFE-THREATENING HYPOGLYCEMIA. 2472 01:43:33,841 --> 01:43:36,043 A KEY MECHANISM, IS THAT 2473 01:43:36,043 --> 01:43:38,179 GLUTAMATE RECEPTOR SIGNALING IS 2474 01:43:38,179 --> 01:43:40,081 EFFECTIVE IN TYPE 1 DIABETES 2475 01:43:40,081 --> 01:43:45,252 PATIENTS, SHE HAS RECENTLY SHOWN 2476 01:43:45,252 --> 01:43:46,487 POSITIVE ALLOSTERIC MONOLAYERS 2477 01:43:46,487 --> 01:43:49,690 CAN RESCUE THE DEFECT IN VITRO 2478 01:43:49,690 --> 01:43:54,862 AND IN VIVO. 2479 01:43:54,862 --> 01:44:04,705 AND THEN A TRIP ON A MOST 2480 01:44:04,705 --> 01:44:08,976 PROMISING STRATEGY THROUGH 2481 01:44:08,976 --> 01:44:10,511 ACTIVATING BETA CELL INHIBITION, 2482 01:44:10,511 --> 01:44:13,147 NOW KEY CHALLENGES INCLUDING CAN 2483 01:44:13,147 --> 01:44:17,751 WE NOW DELIVER THEM SPECIFICALLY 2484 01:44:17,751 --> 01:44:18,285 IN HUMANS, REVERSIVELY AND 2485 01:44:18,285 --> 01:44:20,688 SAFELY, CAN WE USE THEM TO 2486 01:44:20,688 --> 01:44:22,790 RESTORE BETA CELL MASS THAT IS 2487 01:44:22,790 --> 01:44:24,592 FUNCTIONAL SO THEY CAN ALLEVIATE 2488 01:44:24,592 --> 01:44:28,996 DIABETES, AND ULTIMATELY CAN THE 2489 01:44:28,996 --> 01:44:31,165 NEW CELLS EVADE EXISTENT 2490 01:44:31,165 --> 01:44:32,133 AUTOIMMUNE ATTACK PROBLEM. 2491 01:44:32,133 --> 01:44:34,268 BRINGING IT BACK TO THE FIRST 2492 01:44:34,268 --> 01:44:36,237 SPEAKER I'LL ASK CHERIE TO JOIN 2493 01:44:36,237 --> 01:44:39,039 US ON THE STAGE. 2494 01:44:39,039 --> 01:44:41,275 [APPLAUSE] 2495 01:44:41,275 --> 01:44:48,482 2496 01:44:48,482 --> 01:44:50,284 2497 01:44:50,284 --> 01:44:50,551 >> OKAY. 2498 01:44:50,551 --> 01:44:51,385 THANK YOU FOR THE OPPORTUNITY TO 2499 01:44:51,385 --> 01:44:52,553 PRESENT SOME OF THE WORK HERE 2500 01:44:52,553 --> 01:45:03,097 TODAY AND GIVE AN OVERVIEW OF MY 2501 01:45:04,798 --> 01:45:05,699 MICROPHYSIOLOGICAL SYSTEMS. 2502 01:45:05,699 --> 01:45:07,668 AS YOU'VE SEEN THIS MORNING 2503 01:45:07,668 --> 01:45:09,270 REALLY JUST DISCUSSING THE 2504 01:45:09,270 --> 01:45:10,771 PATHOLOGY OF TYPE 1 DIABETES, 2505 01:45:10,771 --> 01:45:13,374 THERE'S A LOT THAT MAY BE KNOWN, 2506 01:45:13,374 --> 01:45:20,247 A LOT UNKNOWN. 2507 01:45:20,247 --> 01:45:22,316 WE SUSPECT THIS TRANSPORT TO THE 2508 01:45:22,316 --> 01:45:24,084 DRAINING LYMPH NODES, AND THEN 2509 01:45:24,084 --> 01:45:26,587 THESE ACTIVATED T CELLS THAT 2510 01:45:26,587 --> 01:45:29,223 HONE TO THE PANCREAS, DIRECTLY 2511 01:45:29,223 --> 01:45:30,224 KILL BETA CELLS. 2512 01:45:30,224 --> 01:45:33,060 BUT WE DON'T KNOW WHAT 2513 01:45:33,060 --> 01:45:34,495 PRECIPITATES THIS, THE PATHWAYS, 2514 01:45:34,495 --> 01:45:39,500 TIMELINES, WE DON'T ACTUALLY 2515 01:45:39,500 --> 01:45:42,002 KNOW ANTIGEN SPECIFICITY OR 2516 01:45:42,002 --> 01:45:43,003 DIFFERENT TYPES OF ANTIGENS 2517 01:45:43,003 --> 01:45:43,571 RELEVANT. 2518 01:45:43,571 --> 01:45:44,972 THERE'S A LOT UNKNOWN DESPITE 2519 01:45:44,972 --> 01:45:45,973 WHAT IS KNOWN. 2520 01:45:45,973 --> 01:45:48,275 AND WHILE MUCH IS UNKNOWN WE DO 2521 01:45:48,275 --> 01:45:51,712 KNOW THAT IT IS SPATIALLY 2522 01:45:51,712 --> 01:45:53,314 DISTRIBUTED AND MULTI-ORGAN 2523 01:45:53,314 --> 01:45:57,818 TISSUE PROCESS. 2524 01:45:57,818 --> 01:45:58,819 INVOLVES PANCREAS, VASCULATURE, 2525 01:45:58,819 --> 01:46:01,455 LYMPH NODES, AND CELLS THAT PLAY 2526 01:46:01,455 --> 01:46:01,989 A ROLE. 2527 01:46:01,989 --> 01:46:03,290 IT'S ALSO SOLUBLE GRADIENTS PLAY 2528 01:46:03,290 --> 01:46:04,959 KEY ROLES, THE WAYS IN WHICH 2529 01:46:04,959 --> 01:46:07,895 CELLS SIGNAL TO EACH OTHER SO 2530 01:46:07,895 --> 01:46:09,430 CELLULAR GRADIENTS ARE IMPORTANT 2531 01:46:09,430 --> 01:46:11,198 IN DIRECTING CELL RECRUITMENT, 2532 01:46:11,198 --> 01:46:13,467 SIGNALING, MANY OTHER THINGS. 2533 01:46:13,467 --> 01:46:19,173 WE KNOW THERE'S A UNIQUELY 2534 01:46:19,173 --> 01:46:19,873 HUMAN-CENTRIC PATHWAY. 2535 01:46:19,873 --> 01:46:21,375 WHAT WE'RE LEARNING FROM THE 2536 01:46:21,375 --> 01:46:22,943 MOUSE MAY NOT BE TRANSLATABLE TO 2537 01:46:22,943 --> 01:46:25,546 HUMANS, THE SAME FOR ANY OTHER 2538 01:46:25,546 --> 01:46:26,547 MODELS THAT WE COLLECT. 2539 01:46:26,547 --> 01:46:29,049 WHEN WE THINK ABOUT TOOLS WE'RE 2540 01:46:29,049 --> 01:46:32,887 USING TO STUDY TYPE 1 DIABETES, 2541 01:46:32,887 --> 01:46:35,389 THESE ARE TOOLS IN A TOOLBOX. 2542 01:46:35,389 --> 01:46:37,825 A HAMMER IS EFFECTIVE IN DRIVING 2543 01:46:37,825 --> 01:46:39,893 A NAIL, SCREWDRIVER EFFECTIVE IN 2544 01:46:39,893 --> 01:46:41,462 TURNING SCREWS, AND YOU WOULDN'T 2545 01:46:41,462 --> 01:46:42,830 NECESSARILY BE MAD AT A 2546 01:46:42,830 --> 01:46:45,900 SCREWDRIVER FOR NOT BEING 2547 01:46:45,900 --> 01:46:47,001 EFFECTIVE AT HAMMERING, RIGHT? 2548 01:46:47,001 --> 01:46:49,069 IT'S EFFECTIVE IN WHAT IT DOES. 2549 01:46:49,069 --> 01:46:50,804 ALL THESE TOOLS ARE EFFECTIVE. 2550 01:46:50,804 --> 01:46:53,107 WE JUST NEED TO UNDERSTAND THEIR 2551 01:46:53,107 --> 01:46:53,407 LIMITATIONS. 2552 01:46:53,407 --> 01:46:55,309 SO IF WE THINK ABOUT IN VIVO 2553 01:46:55,309 --> 01:46:57,511 MODELS, WE HAVE LARGE 2554 01:46:57,511 --> 01:46:59,246 PRE-CLINICAL MODELS DOWN TO 2555 01:46:59,246 --> 01:47:01,248 SMALL ANIMAL MURINE MODELS, 2556 01:47:01,248 --> 01:47:02,950 THESE PROVIDE UNIQUE INSIGHTS. 2557 01:47:02,950 --> 01:47:08,989 THEY CAN BE VALUABLE PROVIDING 2558 01:47:08,989 --> 01:47:09,857 PHYSIOLOGICAL MICROENVIRONMENT, 2559 01:47:09,857 --> 01:47:11,058 WE WITH HUMANIZED CAN USE HUMAN 2560 01:47:11,058 --> 01:47:13,127 CELLS AND WE HAVE THIS MODEL 2561 01:47:13,127 --> 01:47:15,896 THAT'S PRESENT, BUT THERE ARE 2562 01:47:15,896 --> 01:47:19,767 SOME DISADVANTAGES. 2563 01:47:19,767 --> 01:47:20,834 EXPENSIVE, REQUIRE EXPERTISE. 2564 01:47:20,834 --> 01:47:22,369 TRANSLATION TO HUMANS IS NOT 2565 01:47:22,369 --> 01:47:22,603 DIRECT. 2566 01:47:22,603 --> 01:47:23,737 A LOT OF LESSONS WE'RE LEARNING 2567 01:47:23,737 --> 01:47:26,473 FROM THESE IN VIVO MODELS ARE 2568 01:47:26,473 --> 01:47:27,775 NOT DIRECTLY TRANSLATABLE, IT'S 2569 01:47:27,775 --> 01:47:28,976 DIFFICULT TO KNOW WHAT'S 2570 01:47:28,976 --> 01:47:30,277 TRANSLATABLE AND NOT, MAYBE SOME 2571 01:47:30,277 --> 01:47:32,046 FEATURES ARE, OTHERS ARE NOT. 2572 01:47:32,046 --> 01:47:34,014 THE OTHER THING THAT IN VIVO WE 2573 01:47:34,014 --> 01:47:35,316 HAVE LIMITED TEMPORAL INSIGHT 2574 01:47:35,316 --> 01:47:36,650 INTO WHAT'S HAPPENING. 2575 01:47:36,650 --> 01:47:40,020 WE CAN'T INVADE THAT PANCREAS 2576 01:47:40,020 --> 01:47:41,221 AND ASSESS, INTRAVITAL IMAGING 2577 01:47:41,221 --> 01:47:45,526 IS POSSIBLE BUT QUITE LIMITED. 2578 01:47:45,526 --> 01:47:47,828 WE HAVE BISTANDARD EVALUATION OF 2579 01:47:47,828 --> 01:47:50,898 BLOOD, GLYCEMIC CONTROL, THINGS 2580 01:47:50,898 --> 01:47:52,199 LIKE, THAT AUTOANTIBODY MARKERS, 2581 01:47:52,199 --> 01:47:55,803 BIOMARKERS, BUT BEING ABLE TO 2582 01:47:55,803 --> 01:48:02,943 INTIMATELY EVALUATE HOW CELLS 2583 01:48:02,943 --> 01:48:04,478 MIGRATE IS LIMITED. 2584 01:48:04,478 --> 01:48:06,780 WE CAN CULTURE, EXPLORE, USE 2585 01:48:06,780 --> 01:48:08,649 HUMAN CELLS. 2586 01:48:08,649 --> 01:48:11,285 GET CADAVERIC HUMAN TISSUES TO 2587 01:48:11,285 --> 01:48:12,619 STUDY DISEASE. 2588 01:48:12,619 --> 01:48:17,591 WE HAVE FOR THE CADAVERIC 2589 01:48:17,591 --> 01:48:20,494 TISSUES, HIGH HETEROGENEITY, 2590 01:48:20,494 --> 01:48:21,261 INTRA AND INTERHETEROGENEITY. 2591 01:48:21,261 --> 01:48:23,364 WE CAN'T DETERMINE WHEN A 2592 01:48:23,364 --> 01:48:24,465 DONOR -- THE STATE OF THEIR 2593 01:48:24,465 --> 01:48:25,432 DISEASE. 2594 01:48:25,432 --> 01:48:29,036 WE ALSO HAVE LIMITED ACCESS. 2595 01:48:29,036 --> 01:48:33,107 TO THE CELL CULTURE WE CAN GET 2596 01:48:33,107 --> 01:48:35,075 CELLS, CELL LINES, STEM CELLS 2597 01:48:35,075 --> 01:48:37,244 WHICH ARE VALUABLE, BUT IS THIS 2598 01:48:37,244 --> 01:48:38,379 A PHYSIOLOGIC PLATFORM? 2599 01:48:38,379 --> 01:48:39,480 WHEN WE PULL THEM OUT OF THE 2600 01:48:39,480 --> 01:48:42,316 BODY AND CULTURE ON PLASTIC DISH 2601 01:48:42,316 --> 01:48:48,889 THEY DON'T BEHAVE IN WAYS THEY 2602 01:48:48,889 --> 01:48:49,790 DO IN VIVO. 2603 01:48:49,790 --> 01:48:51,959 S THEY ARE GREAT TOOLS, THEY 2604 01:48:51,959 --> 01:48:52,726 HAVE LIMITATIONS. 2605 01:48:52,726 --> 01:48:54,895 ONE THING WE'VE IDENTIFIED AS 2606 01:48:54,895 --> 01:48:56,897 WELL AS MANY OTHERS, WE WEREN'T 2607 01:48:56,897 --> 01:49:01,468 UNIQUE IN THAT, THAT CAN WE 2608 01:49:01,468 --> 01:49:04,004 IMPROVE 2D MODELS TO ADDRESS 2609 01:49:04,004 --> 01:49:04,838 LIMITATIONS? 2610 01:49:04,838 --> 01:49:08,709 THE SYSTEM IS LIMITED, LACK OF 2611 01:49:08,709 --> 01:49:10,344 PHYSIOLOGICAL GRADIENTS FORCING 2612 01:49:10,344 --> 01:49:11,345 CELLS TOGETHER, TAKE IMMUNE 2613 01:49:11,345 --> 01:49:12,379 CELLS, BETA CELLS, BEAUTIFUL 2614 01:49:12,379 --> 01:49:16,817 CELLS, WE PUT THEM IN A ROUND 2615 01:49:16,817 --> 01:49:23,490 BOTTOM FLASK, FORCING THEM TOE 2616 01:49:23,490 --> 01:49:25,759 INTERACT, MESSING UP SIGNALING, 2617 01:49:25,759 --> 01:49:30,264 DON'T HAVE CONTROL OF FEATURES. 2618 01:49:30,264 --> 01:49:31,899 3D CAN BE BENEFICIAL. 2619 01:49:31,899 --> 01:49:34,067 THESE ARE WAYS THEY ARE 2620 01:49:34,067 --> 01:49:36,637 INCORPORATING -- DO I HAVE A 2621 01:49:36,637 --> 01:49:37,171 LASER? 2622 01:49:37,171 --> 01:49:38,205 NO. 2623 01:49:38,205 --> 01:49:40,340 OH, INTERESTING. 2624 01:49:40,340 --> 01:49:40,541 OKAY. 2625 01:49:40,541 --> 01:49:42,609 SO, MANY PEOPLE ARE DEVELOPING 2626 01:49:42,609 --> 01:49:44,945 VARIOUS -- THIS IS NOT GOING TO 2627 01:49:44,945 --> 01:49:45,612 WORK. 2628 01:49:45,612 --> 01:49:47,347 MANY PEOPLE ARE DEVELOPING 2629 01:49:47,347 --> 01:49:50,417 DIFFERENT ORGANS, YOU CAN HAVE 2630 01:49:50,417 --> 01:49:52,586 DISCRETE THREE DIMENSIONAL 2631 01:49:52,586 --> 01:49:52,853 PATTERNS. 2632 01:49:52,853 --> 01:49:53,921 YOU CAN HAVE MONOLAYERS, 2633 01:49:53,921 --> 01:49:55,422 BARRIERS, YOU CAN HAVE ORGANOIDS 2634 01:49:55,422 --> 01:49:58,158 WITHIN THAT SYSTEM. 2635 01:49:58,158 --> 01:49:59,393 THIS PROVIDES SIGNIFICANT 2636 01:49:59,393 --> 01:50:01,795 ADVANTAGE, ELEVATION OF CLASSIC 2637 01:50:01,795 --> 01:50:02,463 2D SYSTEMS. 2638 01:50:02,463 --> 01:50:04,631 AND IT WAS RECOGNIZED THROUGH 2639 01:50:04,631 --> 01:50:10,437 INVESTMENT IN CONSORTIUM WITH 2640 01:50:10,437 --> 01:50:14,174 HUMAN ISLET BIOMEDICS, THE CHIP, 2641 01:50:14,174 --> 01:50:15,476 CREATE ISLET PANCREAS OR 2642 01:50:15,476 --> 01:50:16,710 DIABETES ON A CHIP. 2643 01:50:16,710 --> 01:50:19,313 CELLS INCORPORATING IN SYSTEMS 2644 01:50:19,313 --> 01:50:22,082 WE CAN USE CADAVERIC HUMAN SUCH 2645 01:50:22,082 --> 01:50:25,052 AS PANCREATIC SLICES, ISOLATED 2646 01:50:25,052 --> 01:50:27,120 ISLETS, VALUABLE, BUT WITH 2647 01:50:27,120 --> 01:50:29,289 ADVENT OF TECHNOLOGY HAVE 2648 01:50:29,289 --> 01:50:32,359 CAPACITY TO INCORPORATE STEM 2649 01:50:32,359 --> 01:50:34,995 CELL DERIVED T1D RELEVANT CELLS 2650 01:50:34,995 --> 01:50:36,597 TO CREATE ISOGENIC SYSTEMS TO 2651 01:50:36,597 --> 01:50:39,066 STUDY IMMUNOLOGIC PATHWAYS IN 2652 01:50:39,066 --> 01:50:46,139 THE ABSENCE OF ALLOIMMUNE 2653 01:50:46,139 --> 01:50:46,406 RESPONSES. 2654 01:50:46,406 --> 01:50:48,175 THEY ARE AVAILABLE, GENE EDITING 2655 01:50:48,175 --> 01:50:50,777 CAN LOOK AT RISK ALLELES, WE CAN 2656 01:50:50,777 --> 01:50:54,314 GET STEM CELL FROM DIFFERENT 2657 01:50:54,314 --> 01:50:56,783 DONORS, EXPLORE DIFFERENT T C 2658 01:50:56,783 --> 01:50:57,017 AVATARS. 2659 01:50:57,017 --> 01:50:57,885 BEAUTIFUL CELLS ARE AVAILABLE 2660 01:50:57,885 --> 01:51:00,821 BUT IF WE PLACE THEM IN IN A 2661 01:51:00,821 --> 01:51:02,356 PETRI DISH WE'RE USING OUR 2662 01:51:02,356 --> 01:51:03,557 CAPACITY HERE. 2663 01:51:03,557 --> 01:51:05,559 WE WANT TO TRANSLATE TO ORGANS 2664 01:51:05,559 --> 01:51:09,162 ON A CHIP, AND THREE DIMENSIONAL 2665 01:51:09,162 --> 01:51:10,664 THEY ARE MORE ELEVATED. 2666 01:51:10,664 --> 01:51:13,066 IN DESIGNING AN ORGAN ON A CHIP 2667 01:51:13,066 --> 01:51:17,104 OR DIABETES ON A CHIP WE THINK 2668 01:51:17,104 --> 01:51:18,772 ABOUT ENGINEERING DESIGN DRIVEN 2669 01:51:18,772 --> 01:51:23,911 BY EXPERIMENTAL QUESTIONS OR 2670 01:51:23,911 --> 01:51:24,912 HYPOTHESES, THERE'S MANY TOOLS 2671 01:51:24,912 --> 01:51:25,946 TO CREATE BUT THINK ABOUT THE 2672 01:51:25,946 --> 01:51:27,648 QUESTIONS YOU WANT TO ASK. 2673 01:51:27,648 --> 01:51:29,383 IN TERMS OF CREATING THAT NICHE 2674 01:51:29,383 --> 01:51:33,520 WHERE THIS CLUSTER OR, BETA 2675 01:51:33,520 --> 01:51:35,622 CLUSTER OR ISLET IS GOING TO GO, 2676 01:51:35,622 --> 01:51:38,191 DO YOU WANT IT EMBEDDED IN 2677 01:51:38,191 --> 01:51:40,761 EXTRACELLULAR MATRIX, WHAT IS 2678 01:51:40,761 --> 01:51:42,296 THE COMPOSITION, WHAT OTHER 2679 01:51:42,296 --> 01:51:43,597 CELLS, VASCULAR NETWORK AS 2680 01:51:43,597 --> 01:51:44,264 DEVELOP? 2681 01:51:44,264 --> 01:51:47,100 WHAT FLOW AND STIMULI, HOW DO 2682 01:51:47,100 --> 01:51:48,936 YOU CONTROL MICROENVIRONMENT? 2683 01:51:48,936 --> 01:51:52,039 HOW DO WE DELIVER FLUIDS, DRIVE 2684 01:51:52,039 --> 01:51:53,006 THAT FLUIDIC FIELD, CONTROL 2685 01:51:53,006 --> 01:51:55,876 THAT, DO YOU DO IT THROUGH, SAY, 2686 01:51:55,876 --> 01:51:57,511 GRAVITY-DRIVEN FLOW OR 2687 01:51:57,511 --> 01:51:59,146 CONTROLLED PUMPS AND SENSORS? 2688 01:51:59,146 --> 01:52:01,682 AND THEN ALSO THAT THEN DRIVES 2689 01:52:01,682 --> 01:52:03,050 THE OVERALL SPATIAL FEATURES OF 2690 01:52:03,050 --> 01:52:03,784 THAT DEVICE. 2691 01:52:03,784 --> 01:52:06,086 YOU CAN HAVE SOMETHING AS SIMPLE 2692 01:52:06,086 --> 01:52:08,255 AS A MONOLAYER TO THREE 2693 01:52:08,255 --> 01:52:08,922 DIMENSIONAL CLUSTERS TO 2694 01:52:08,922 --> 01:52:10,424 COMBINATIONS OF THE TWO WITH 2695 01:52:10,424 --> 01:52:11,124 DIFFERENT FLOW STREAMS. 2696 01:52:11,124 --> 01:52:13,827 AND SO WHILE THERE'S NUMEROUS 2697 01:52:13,827 --> 01:52:14,595 MICROPHYSIOLOGICAL SYSTEMS I 2698 01:52:14,595 --> 01:52:15,929 COULD TALK ABOUT TODAY IN THE 2699 01:52:15,929 --> 01:52:18,098 INTEREST OF TIME I'M JUST GOING 2700 01:52:18,098 --> 01:52:20,000 TO FOCUS ON THREE OF THE 2701 01:52:20,000 --> 01:52:21,201 PLATFORMS THAT HAVE BEEN 2702 01:52:21,201 --> 01:52:24,237 INVESTED IN BY THE CHIP 2703 01:52:24,237 --> 01:52:30,611 CONSORTIUM, AND THAT'S LED BY 2704 01:52:30,611 --> 01:52:32,679 MICAH SANDERS, STANGER AND OUR 2705 01:52:32,679 --> 01:52:32,879 GROUP. 2706 01:52:32,879 --> 01:52:34,448 DIFFERENT TOOLS HAVE DIFFERENT 2707 01:52:34,448 --> 01:52:36,183 FEATURES, DIFFERENT VALUE. 2708 01:52:36,183 --> 01:52:40,887 SO WITH SANDERS GROUP IT'S A 2709 01:52:40,887 --> 01:52:42,856 MULTI-DISCIPLINARY TEAM, 2710 01:52:42,856 --> 01:52:43,423 IMMUNOLOGY, ENGINEERING, 2711 01:52:43,423 --> 01:52:44,157 BIOMATERIALS, STEM CELL WORK, 2712 01:52:44,157 --> 01:52:45,926 AND THROUGH THAT WHAT THEY 2713 01:52:45,926 --> 01:52:51,298 STARTED FIRST WAS WITH A 2714 01:52:51,298 --> 01:52:52,633 VASCULAR NETWORK SYSTEM, 2715 01:52:52,633 --> 01:52:55,702 VASCULARIZED MINI ORGAN, THREE 2716 01:52:55,702 --> 01:52:57,671 DIMENSIONAL NICHE, LOAD HYDROGEL 2717 01:52:57,671 --> 01:53:00,507 AND ENDOTHELIAL TO STROMAL 2718 01:53:00,507 --> 01:53:01,708 CELLS, FORMING A VASCULAR 2719 01:53:01,708 --> 01:53:07,314 NETWORK IN THE SYSTEM. 2720 01:53:07,314 --> 01:53:09,282 IT ALSO HAS INLETS, OUTLETS, YOU 2721 01:53:09,282 --> 01:53:11,251 CAN ADD PERFUSION TO THAT. 2722 01:53:11,251 --> 01:53:12,819 IT'S A GRAVITY-DRIVEN SYSTEM SO 2723 01:53:12,819 --> 01:53:14,121 YOU CAN HAVE THIS PERFUSE 2724 01:53:14,121 --> 01:53:16,857 THROUGH THE SYSTEM. 2725 01:53:16,857 --> 01:53:20,560 THEN YOU CAN SEE -- OOH, I DO 2726 01:53:20,560 --> 01:53:21,995 HAVE A MOUSE -- VASCULAR 2727 01:53:21,995 --> 01:53:23,463 NETWORKS THAT ARE FORMED IN THE 2728 01:53:23,463 --> 01:53:23,964 SYSTEM. 2729 01:53:23,964 --> 01:53:25,165 THEY CAN INCORPORATE ISLETS INTO 2730 01:53:25,165 --> 01:53:27,901 THAT SO YOU CAN SEE ISLETS ARE 2731 01:53:27,901 --> 01:53:29,369 INTEGRATED INTO THE VASCULAR 2732 01:53:29,369 --> 01:53:29,603 NETWORK. 2733 01:53:29,603 --> 01:53:32,973 THEY HAVE OBSERVED ISLETS 2734 01:53:32,973 --> 01:53:37,911 INCORPORATE INTO VASCULARIZED 2735 01:53:37,911 --> 01:53:39,413 INTO MINI ORGANS, BETTER 2736 01:53:39,413 --> 01:53:40,981 RETENTION, SEEING ALREADY SOME 2737 01:53:40,981 --> 01:53:42,716 BENEFITS OF THAT SYSTEM. 2738 01:53:42,716 --> 01:53:45,452 THEY CAN ALSO PERFORM GLUCOSE 2739 01:53:45,452 --> 01:53:49,289 STIMULATED INSULIN RELEASE, 2740 01:53:49,289 --> 01:53:53,894 ASSESS GSARs IN THAT, THEY 2741 01:53:53,894 --> 01:53:55,295 ADDED PBMCs AS 2742 01:53:55,295 --> 01:53:56,163 PROOF-OF-CONCEPT, THEY CAN 2743 01:53:56,163 --> 01:53:58,932 PERFUSE THROUGH THE SYSTEM, 2744 01:53:58,932 --> 01:54:01,201 INTEGRATING INTO VASCULARIZED 2745 01:54:01,201 --> 01:54:02,636 NETWORK SHOWN IN GREEN, 2746 01:54:02,636 --> 01:54:07,774 ENDOTHELIAL CELLS IN RED. 2747 01:54:07,774 --> 01:54:08,875 CIRCLES WHERE ISLETS ARE 2748 01:54:08,875 --> 01:54:11,178 PRESENT, THEY MIGRATE INTO THE 2749 01:54:11,178 --> 01:54:12,846 REGION, BLOCKED THROUGH MHC 2750 01:54:12,846 --> 01:54:13,146 BLOCKER. 2751 01:54:13,146 --> 01:54:18,752 YOU CAN ALSO ANALYZE THIS AND 2752 01:54:18,752 --> 01:54:22,789 QUANTIFY OVER TIME. 2753 01:54:22,789 --> 01:54:26,293 OKAY. 2754 01:54:26,293 --> 01:54:28,495 THANK YOU SO MUCH. 2755 01:54:28,495 --> 01:54:28,695 OKAY. 2756 01:54:28,695 --> 01:54:30,897 YOU CAN SEE THOSE BLOCK THROUGH 2757 01:54:30,897 --> 01:54:33,033 AND QUANTIFY OVER TIME SO YOU 2758 01:54:33,033 --> 01:54:34,768 CAN GET TEMPORAL ASSESSMENT AND 2759 01:54:34,768 --> 01:54:35,669 QUANTIFY WITHIN THE FIELD OF 2760 01:54:35,669 --> 01:54:37,804 VIEW WHAT'S HAPPENING IN THE 2761 01:54:37,804 --> 01:54:38,138 SYSTEM. 2762 01:54:38,138 --> 01:54:41,007 SO I HOPE THIS HIGHLIGHTS AND 2763 01:54:41,007 --> 01:54:41,975 SPURS NEW IDEAS. 2764 01:54:41,975 --> 01:54:44,044 MY GOAL IS REALLY TO HELP YOU 2765 01:54:44,044 --> 01:54:46,780 GUYS SPUR NEW IDEAS OF WHAT 2766 01:54:46,780 --> 01:54:47,681 THESE MICROPHYSIOLOGICAL SYSTEMS 2767 01:54:47,681 --> 01:54:49,082 CAN DO, WHETHER YOU'RE FROM 2768 01:54:49,082 --> 01:54:52,152 ENGINEERING SIDE TO CREATE NEW 2769 01:54:52,152 --> 01:54:53,587 ONES OR WANT TO UTILIZE THEM, 2770 01:54:53,587 --> 01:54:55,222 WHAT QUESTIONS YOU MAY BE ABLE 2771 01:54:55,222 --> 01:54:58,391 TO ASK FROM THAT SYSTEM. 2772 01:54:58,391 --> 01:55:01,461 THIS IS THE STANGER GROUP, PENN 2773 01:55:01,461 --> 01:55:04,197 CHOP GROUP, MANY PEOPLE ARE 2774 01:55:04,197 --> 01:55:07,768 INVOLVED ACROSS MANY SPACES, I'M 2775 01:55:07,768 --> 01:55:08,368 FOCUSED ON MICROPHYSIOLOGICAL 2776 01:55:08,368 --> 01:55:10,637 BUT THEY DID WORK IN STEM CELL 2777 01:55:10,637 --> 01:55:10,937 DEVELOPMENT. 2778 01:55:10,937 --> 01:55:16,243 DAN'S CHIP HAS BEEN USED FOR THE 2779 01:55:16,243 --> 01:55:20,614 SYSTEM, ORIGINATED FROM A L LUM 2780 01:55:20,614 --> 01:55:21,715 PROTOTYPE. 2781 01:55:21,715 --> 01:55:24,584 THIS IS THE HYDROGEL WITH 2782 01:55:24,584 --> 01:55:26,119 PERFUSED BLOOD VESSELS, USING 2783 01:55:26,119 --> 01:55:27,320 SIMILAR FORMATION OF VASCULAR 2784 01:55:27,320 --> 01:55:31,057 NETWORKS, THIS IS A BETTER 2785 01:55:31,057 --> 01:55:31,358 RESOLUTION. 2786 01:55:31,358 --> 01:55:33,660 THIS IS WITHIN THE HYDROGEL AREA 2787 01:55:33,660 --> 01:55:35,395 WHERE THE VASCULAR NETWORKS 2788 01:55:35,395 --> 01:55:38,465 FORM, THESE ARE PRIMARY CHANNELS 2789 01:55:38,465 --> 01:55:40,867 IN GREEN, FLOW THINGS THROUGH, 2790 01:55:40,867 --> 01:55:42,202 THROUGH THIS MICROVASCULAR BED. 2791 01:55:42,202 --> 01:55:44,604 THEY HAVE BEEN ABLE TO SHOWCASE 2792 01:55:44,604 --> 01:55:46,573 THAT THESE ARE COMPETENT LUMENS, 2793 01:55:46,573 --> 01:55:51,378 AND INTEGRATE ISLETS IN GREEN, 2794 01:55:51,378 --> 01:55:52,913 INTEGRATED INTO THE SYSTEM, ABLE 2795 01:55:52,913 --> 01:55:54,781 TO CULTURE THESE ISLETS OVER A 2796 01:55:54,781 --> 01:55:55,515 TIME PERIOD. 2797 01:55:55,515 --> 01:55:57,384 THIS IS TWO WEEKS. 2798 01:55:57,384 --> 01:55:59,052 YOU CAN SEE VASCULAR NETWORK 2799 01:55:59,052 --> 01:56:00,720 BECOMES MORE FORMED OVER TIME. 2800 01:56:00,720 --> 01:56:02,355 AND WHAT THEY HAVE OBSERVED IS 2801 01:56:02,355 --> 01:56:04,090 SIMILAR TO WHAT THE CALIFORNIA 2802 01:56:04,090 --> 01:56:08,028 GROUP OBSERVED, IS THAT THESE 2803 01:56:08,028 --> 01:56:08,795 PERFUSABLE REVASCULARIZED ISLETS 2804 01:56:08,795 --> 01:56:10,430 PERFORM BETTER WITHIN THE SYSTEM 2805 01:56:10,430 --> 01:56:11,765 THAN WHEN IN THE EXTRACELLULAR 2806 01:56:11,765 --> 01:56:13,834 MATRIX IN TERMS OF RETENTION OF 2807 01:56:13,834 --> 01:56:16,903 BETA CELLS AS WELL AS ALPHA 2808 01:56:16,903 --> 01:56:17,904 CELLS. 2809 01:56:17,904 --> 01:56:19,739 THEY EXPLORE DEGREE OF 2810 01:56:19,739 --> 01:56:23,476 VASCULARIZATION, THEY LOOKED AT 2811 01:56:23,476 --> 01:56:24,778 HYPERVASCULARIZED OR 2812 01:56:24,778 --> 01:56:27,514 NON-VASCULARIZED, HOW THAT 2813 01:56:27,514 --> 01:56:31,017 CORRELATES WITH GLUCOSTIMULATED 2814 01:56:31,017 --> 01:56:33,086 INSULIN RELEASE. 2815 01:56:33,086 --> 01:56:40,794 RELEASE IS MOST IDEAL, TOO 2816 01:56:40,794 --> 01:56:44,164 VASCULARIZED CAN AFFECT THE 2817 01:56:44,164 --> 01:56:44,397 ISLETS. 2818 01:56:44,397 --> 01:56:45,999 THEY HAVE INCORPORATED CAR-T 2819 01:56:45,999 --> 01:56:47,767 CELLS, SHOWN HERE IN YELLOW, YOU 2820 01:56:47,767 --> 01:56:49,736 CAN SEE THEM MOVING THROUGH THE 2821 01:56:49,736 --> 01:56:53,573 VASCULATURE, INTO THE ISLET 2822 01:56:53,573 --> 01:56:54,774 ITSELF. 2823 01:56:54,774 --> 01:56:55,976 DISCRETE-TIME POINTS COLLECTED 2824 01:56:55,976 --> 01:56:59,045 SUPERNATANT, LACKED AT ELEVATION 2825 01:56:59,045 --> 01:57:08,922 IN INTERFERON GAMMA, GRANZYME 2826 01:57:08,922 --> 01:57:10,657 AND INTERFERON ALPHA, 2827 01:57:10,657 --> 01:57:13,059 HIGHLIGHTING CAPACITY TO HAVE 2828 01:57:13,059 --> 01:57:14,160 VASCULARIZED NETWORKS 2829 01:57:14,160 --> 01:57:24,704 INCORPORATE IMMUNE CELLS AND ASK 2830 01:57:31,344 --> 01:57:32,579 QUESTIONS ABOUT EXTRAVISATION. 2831 01:57:32,579 --> 01:57:41,888 WE CAN LOOK AT MIGRATION. 2832 01:57:41,888 --> 01:57:48,461 WE HAVE AN OPEN PLATFORM AND 2833 01:57:48,461 --> 01:57:49,529 HAVE PERFUSION, TRANSPARENT 2834 01:57:49,529 --> 01:57:58,171 WHICH ALLOWS FOR TERM POLL IMAGE 2835 01:57:58,171 --> 01:57:59,506 OF THE NICHE. 2836 01:57:59,506 --> 01:58:01,808 YOU CAN SEE TRACKING OF 2837 01:58:01,808 --> 01:58:03,877 APOPTOSIS AND NECROSIS. 2838 01:58:03,877 --> 01:58:05,879 WE OBSERVED CELLS PERFORM BETTER 2839 01:58:05,879 --> 01:58:07,747 UNDER FLOW THAN STATIC 2840 01:58:07,747 --> 01:58:08,481 CONDITIONS, AGAIN VALIDATING 2841 01:58:08,481 --> 01:58:10,817 WHAT THE OTHER TWO GROUPS 2842 01:58:10,817 --> 01:58:12,118 OBSERVED AS WELL. 2843 01:58:12,118 --> 01:58:20,760 WE WERE ABLE TO TEMPORALLY 2844 01:58:20,760 --> 01:58:22,195 ADDRESS MURINE ISLETS, 2845 01:58:22,195 --> 01:58:23,163 STIMULATED WITH GLUCOSE 2846 01:58:23,163 --> 01:58:24,898 CHALLENGE, HOW THE ISLETS CHANGE 2847 01:58:24,898 --> 01:58:27,100 OVER TIME, FOR HUMAN AS WELL. 2848 01:58:27,100 --> 01:58:33,573 AND YOU CAN ENVISION THIS COULD 2849 01:58:33,573 --> 01:58:37,410 BE USED FOR DRUG SCREENING OR 2850 01:58:37,410 --> 01:58:41,881 LOOKING AT PERFUSION. 2851 01:58:41,881 --> 01:58:43,316 WE INCORPORATED BIOSENSORS, 2852 01:58:43,316 --> 01:58:45,051 LOOKED AT CALCIUM IMAGING, WHAT 2853 01:58:45,051 --> 01:58:48,455 HAPPENS TO ISLETS WHEN EXPOSED 2854 01:58:48,455 --> 01:58:51,725 TO GLUCOSE LIPO TOXIC TREATMENT, 2855 01:58:51,725 --> 01:58:52,625 OBSERVED, QUICKLY, SIGNIFICANT 2856 01:58:52,625 --> 01:58:57,030 SHIFTS IN CALCIUM SIGNALING, 2857 01:58:57,030 --> 01:58:58,531 ELEVATION OF CELL DEATH, BOTH 2858 01:58:58,531 --> 01:59:00,100 PRE AND POST STIMULI, AND 2859 01:59:00,100 --> 01:59:03,870 CHARACTERIZE WHAT'S HAPPENING IN 2860 01:59:03,870 --> 01:59:06,172 THE SYSTEM. 2861 01:59:06,172 --> 01:59:09,242 THIS WAS TRANSLATE TO PANCREATIC 2862 01:59:09,242 --> 01:59:10,910 SLICES, CONDUCTED SIMILAR WORK 2863 01:59:10,910 --> 01:59:14,647 IN TISSUE SLICES, THERE'S VERY 2864 01:59:14,647 --> 01:59:15,248 CONTROLLED MICROENVIRONMENTS, 2865 01:59:15,248 --> 01:59:17,851 VERY STABLE SYSTEM IN WHICH YOU 2866 01:59:17,851 --> 01:59:19,252 CAN THEN DO REPEATED PERFUSION 2867 01:59:19,252 --> 01:59:22,655 AND EXAMINATION OF GSIS IN THESE 2868 01:59:22,655 --> 01:59:23,857 PANCREATIC SLICES. 2869 01:59:23,857 --> 01:59:25,925 WHAT WE'VE ALSO DONE IS EXPLORED 2870 01:59:25,925 --> 01:59:30,964 THAT ISLET NICHE ITSELF, SO 2871 01:59:30,964 --> 01:59:31,965 INCORPORATING MATRICES THAT 2872 01:59:31,965 --> 01:59:33,366 ALLOW SPATIAL PLACEMENT, EXAMINE 2873 01:59:33,366 --> 01:59:34,901 THOUSAND T CELLS BEHAVE AND 2874 01:59:34,901 --> 01:59:36,536 MIGRATE THROUGH THE SYSTEM. 2875 01:59:36,536 --> 01:59:42,475 WHAT WE FOUND IS THAT OUR -- 2876 01:59:42,475 --> 01:59:44,444 USING DECELLULARIZED PIG 2877 01:59:44,444 --> 01:59:45,145 PANCREAS WAS EFFECTING, 2878 01:59:45,145 --> 01:59:46,646 PRESERVING THEIR FUNCTION. 2879 01:59:46,646 --> 01:59:49,916 WE CAN ALSO INCORPORATE T CELLS 2880 01:59:49,916 --> 01:59:53,753 INTO THAT SYSTEM. 2881 01:59:53,753 --> 01:59:56,156 AND T CELLS WILL MIGRATE WITHIN 2882 01:59:56,156 --> 01:59:58,992 THIS MATRIX IN THREE DIMENSIONAL 2883 01:59:58,992 --> 01:59:59,259 MANNER. 2884 01:59:59,259 --> 02:00:00,760 WE CAN ACTUALLY CULTURE OVER 2885 02:00:00,760 --> 02:00:01,761 EXTENDED TIME PERIODS, DIFFERENT 2886 02:00:01,761 --> 02:00:03,696 THAN WHAT WE CAN OBSERVE IN 2887 02:00:03,696 --> 02:00:05,265 STATIC SYSTEMS, SO UNDER STATIC 2888 02:00:05,265 --> 02:00:06,666 SYSTEMS WHAT WILL HAPPEN AFTER A 2889 02:00:06,666 --> 02:00:08,201 FEW HOURS IS ANY CURRENTS WILL 2890 02:00:08,201 --> 02:00:11,604 CAUSE THESE CELLS TO MOVE AROUND 2891 02:00:11,604 --> 02:00:11,938 RANDOMLY. 2892 02:00:11,938 --> 02:00:13,339 WE CAN DIGEST EXTRACELLULAR 2893 02:00:13,339 --> 02:00:15,975 MATRIX AND LOOK AT T CELL 2894 02:00:15,975 --> 02:00:17,610 PHENOTYPE, IN THIS CASE THAT THE 2895 02:00:17,610 --> 02:00:20,447 MATRIX DOES NOT ACTIVATE CELLS, 2896 02:00:20,447 --> 02:00:23,416 DOESN'T ALTER PHENOTYPE, DOESN'T 2897 02:00:23,416 --> 02:00:24,384 CHANGE VIABILITY BUT SUPPORTS 2898 02:00:24,384 --> 02:00:26,252 NATIVE MOTILITY. 2899 02:00:26,252 --> 02:00:30,323 CAN USE IMAGE ANALYSIS, TRACK 2900 02:00:30,323 --> 02:00:31,624 MATE TO QUANTIFY BEHAVIOR, 2901 02:00:31,624 --> 02:00:33,693 GLOBAL ANALYSIS OF THINGS LIKE 2902 02:00:33,693 --> 02:00:34,494 TRACK DISPLACEMENT, SPEED TO 2903 02:00:34,494 --> 02:00:36,663 LOOK AT HOW T CELLS ARE BEING 2904 02:00:36,663 --> 02:00:36,896 ALTERED. 2905 02:00:36,896 --> 02:00:38,498 ONE THING WE REALLY ALSO WANT TO 2906 02:00:38,498 --> 02:00:43,603 DEVELOP WAS TOOL SET TO ANSWER 2907 02:00:43,603 --> 02:00:44,838 DIFFERENT ADDITIONAL QUESTIONS, 2908 02:00:44,838 --> 02:00:50,743 TO ALLOW US TO DO DETAILED 2909 02:00:50,743 --> 02:00:52,045 ASSESSMENT OF TRAJECTORY 2910 02:00:52,045 --> 02:00:52,445 CLASSIFICATION AND 2911 02:00:52,445 --> 02:00:53,413 QUANTIFICATION, THIS IS ONE 2912 02:00:53,413 --> 02:00:56,249 EXAMPLE IN TERMS OF TRACKING T 2913 02:00:56,249 --> 02:01:00,720 CELL MIGRATION OVER TIME, WE CAN 2914 02:01:00,720 --> 02:01:04,424 SET TRACKS TO ZERO AND LOOKS AT 2915 02:01:04,424 --> 02:01:05,859 PREFERENTIAL MIGRATION, NO 2916 02:01:05,859 --> 02:01:08,828 STIMULI OR GRADIENT. 2917 02:01:08,828 --> 02:01:11,097 WE CAN CHARACTERIZE HOW BEHAVIOR 2918 02:01:11,097 --> 02:01:12,866 CHANGES WITH PHENOTYPE, 2919 02:01:12,866 --> 02:01:13,633 STIMULATED VERSUS UNSTIMULATED, 2920 02:01:13,633 --> 02:01:16,169 YOU CAN SEE BEHAVIOR SHIFT AS 2921 02:01:16,169 --> 02:01:17,670 THEY SEEK COGNATE. 2922 02:01:17,670 --> 02:01:18,471 COLLECT THREE DIMENSIONAL IMAGES 2923 02:01:18,471 --> 02:01:19,205 AS WELL. 2924 02:01:19,205 --> 02:01:20,406 I HOPE YOU CAN APPRECIATE 2925 02:01:20,406 --> 02:01:22,909 THROUGH THE TRACKS WHAT WE'RE 2926 02:01:22,909 --> 02:01:24,244 OBSERVING IS THIS BEHAVIOR 2927 02:01:24,244 --> 02:01:25,879 BECAUSE THEY ARE ACTIVATED 2928 02:01:25,879 --> 02:01:28,615 TRYING TO FIND THEIR 2929 02:01:28,615 --> 02:01:30,049 COMPLEMENTARY ANTIGEN. 2930 02:01:30,049 --> 02:01:31,918 WE CAN EXAMINE AND CLASSIFY 2931 02:01:31,918 --> 02:01:33,419 BEHAVIOR SO WE KNOW T CELLS 2932 02:01:33,419 --> 02:01:38,358 PRIOR TO STIMULI WILL EXHIBIT 2933 02:01:38,358 --> 02:01:41,661 MORE OF A SUBTUSIVE BEHAVIOR, 2934 02:01:41,661 --> 02:01:44,264 WHEN ACTIVATED EXHIBIT LEVY 2935 02:01:44,264 --> 02:01:46,132 WALK, WITH A GRADIENT WILL 2936 02:01:46,132 --> 02:01:48,101 EXHIBIT BALLISTIC MOVEMENT AND 2937 02:01:48,101 --> 02:01:49,402 WE CAN CLASSIFY BEHAVIOR. 2938 02:01:49,402 --> 02:01:51,871 AND SO WE CAN SEE IN THIS 2939 02:01:51,871 --> 02:01:53,540 CLASSIC EXAMPLE OF UNSTIMULATED 2940 02:01:53,540 --> 02:01:54,908 VERSUS ACTIVATED T CELLS WHEN 2941 02:01:54,908 --> 02:01:55,675 THEY BECOME ACTIVATED THEY 2942 02:01:55,675 --> 02:02:05,218 EXHIBIT MORE OF A LEVY WALK 2943 02:02:05,218 --> 02:02:10,790 SHIFT FROM UNSTIMULATED TO 2944 02:02:10,790 --> 02:02:12,992 STIMULATE WE ISLETS, MURINE, TO 2945 02:02:12,992 --> 02:02:14,460 BUILD AND EVALUATE. 2946 02:02:14,460 --> 02:02:18,798 WE FOUND THIS IS A NON-ANTIGEN 2947 02:02:18,798 --> 02:02:22,969 SPECIFIC SYSTEM, B 6 CTLs, T 2948 02:02:22,969 --> 02:02:25,705 CELLS IN GREEN. 2949 02:02:25,705 --> 02:02:28,541 HOLD ON. 2950 02:02:28,541 --> 02:02:28,741 OKAY. 2951 02:02:28,741 --> 02:02:30,743 SO YOU SEE T CELLS SAMPLING, 2952 02:02:30,743 --> 02:02:34,113 ACTIVATED TRYING TO FIND 2953 02:02:34,113 --> 02:02:36,749 COGNATE, EXPLORING, BUT MOVING 2954 02:02:36,749 --> 02:02:38,718 IN AND OUT IN DIRECT CONTRAST TO 2955 02:02:38,718 --> 02:02:39,919 WHAT I HOPE TO SHOW. 2956 02:02:39,919 --> 02:02:41,554 THERE WE GO. 2957 02:02:41,554 --> 02:02:42,989 IN THE ANTIGEN SPECIFIC SYSTEM 2958 02:02:42,989 --> 02:02:44,958 ONCE THEY COME INTO INTERACTING 2959 02:02:44,958 --> 02:02:47,227 WITH ISLET THEY ACTUALLY SHIFT 2960 02:02:47,227 --> 02:02:49,862 MIGRATION BEHAVIOR AND KIND OF 2961 02:02:49,862 --> 02:02:50,863 SAMPLE THAT ENVIRONMENT LIKELY 2962 02:02:50,863 --> 02:02:55,101 BECAUSE THEY ARE INTERACTED WITH 2963 02:02:55,101 --> 02:02:55,335 ANTIGEN. 2964 02:02:55,335 --> 02:02:56,636 THIS IS THE HIGH RESOLUTION 2965 02:02:56,636 --> 02:02:57,737 IMAGE OF IT. 2966 02:02:57,737 --> 02:03:01,474 IT'S NOT GOING TO SHOW. 2967 02:03:01,474 --> 02:03:04,077 WE NEED MORE POWER ON THIS 2968 02:03:04,077 --> 02:03:04,577 COMPUTER. 2969 02:03:04,577 --> 02:03:05,178 NOPE, OKAY. 2970 02:03:05,178 --> 02:03:07,480 WELL, YOU CAN SEE THE T CELLS 2971 02:03:07,480 --> 02:03:09,048 MIGRATING AROUND. 2972 02:03:09,048 --> 02:03:10,984 WE CAN DO IMAGE SEGMENTATION, 2973 02:03:10,984 --> 02:03:12,285 ASK QUESTIONS ABOUT SPATIAL 2974 02:03:12,285 --> 02:03:14,687 PLACEMENT, SO IN THIS CASE WE 2975 02:03:14,687 --> 02:03:15,888 CAN LOOK AT ACCUMULATION, LOOK 2976 02:03:15,888 --> 02:03:18,758 AT WITHIN THE ISLET OR OUTSIDE 2977 02:03:18,758 --> 02:03:20,260 THE ISLET, AND ACTUALLY 2978 02:03:20,260 --> 02:03:23,763 CHARACTERIZE THAT SO LOOKING AT 2979 02:03:23,763 --> 02:03:32,739 TOTAL CELL COUNTS, ACCELERATION 2980 02:03:32,739 --> 02:03:33,840 ACCUMULATION AS EXPECTED, 2981 02:03:33,840 --> 02:03:34,941 OUTSIDE ACTUALLY DEATH BECAUSE 2982 02:03:34,941 --> 02:03:38,111 THEY ARE NOT STIMULATED. 2983 02:03:38,111 --> 02:03:42,148 WE CAN FURTHER CLASSIFY 2984 02:03:42,148 --> 02:03:43,283 BEHAVIOR. 2985 02:03:43,283 --> 02:03:46,219 LOOKING AT INSIDE, HOW T CELLS 2986 02:03:46,219 --> 02:03:47,754 INTERACT INSIDE VERSUS OUTSIDE. 2987 02:03:47,754 --> 02:03:50,056 AND THEN WE CAN CHARACTERIZE 2988 02:03:50,056 --> 02:03:51,691 BEHAVIOR LOOKING AT GLOBAL 2989 02:03:51,691 --> 02:03:55,094 PARAMETERS AS WELL AS MIGRATION 2990 02:03:55,094 --> 02:03:55,762 CHARACTERISTICS, CLASSIFICATION, 2991 02:03:55,762 --> 02:04:00,466 SO WE CAN TAKE TRACKS AND SAY 2992 02:04:00,466 --> 02:04:02,435 HOW IS IT BEHAVING BEFORE VERSUS 2993 02:04:02,435 --> 02:04:04,070 AFTER IT INTERACTS WITH ISLET 2994 02:04:04,070 --> 02:04:05,171 AND FOR THIS NON-ANTIGEN 2995 02:04:05,171 --> 02:04:07,140 SPECIFIC SYSTEM YOU SEE NO 2996 02:04:07,140 --> 02:04:09,509 CHANGE IN BEHAVIOR VERSUS 2997 02:04:09,509 --> 02:04:10,410 ANTIGEN SPECIFIC SYSTEM YOU SEE 2998 02:04:10,410 --> 02:04:11,711 THE SHIFT DOWN. 2999 02:04:11,711 --> 02:04:14,480 ONCE IT INTERACTS WITH ISLET IT 3000 02:04:14,480 --> 02:04:16,983 EXHIBITS DECREASES LEVY WALK 3001 02:04:16,983 --> 02:04:22,989 BEHAVIOR, EXHIBITS MORE 3002 02:04:22,989 --> 02:04:23,956 SUBDIFFUSIVE MIGRATION. 3003 02:04:23,956 --> 02:04:26,726 THIS IS LOOKING AT THEM 3004 02:04:26,726 --> 02:04:29,228 INTERACTING AND SHIFTING TOWARDS 3005 02:04:29,228 --> 02:04:37,103 CELLULAR TOXIC PHENOTYPE. 3006 02:04:37,103 --> 02:04:40,773 FIRST 24 HOURS, GREEN IS 3007 02:04:40,773 --> 02:04:42,809 APOPTOSIS, SHIFTING NECROSIS, T 3008 02:04:42,809 --> 02:04:47,480 CELLS KILLING, BECOMES MORE 3009 02:04:47,480 --> 02:04:48,147 EXACERBATED. 3010 02:04:48,147 --> 02:04:50,650 OVER THE NEXT 24-48 HOURS WE SEE 3011 02:04:50,650 --> 02:04:51,884 ACCELERATED CELL DEATH. 3012 02:04:51,884 --> 02:04:53,519 WE CAN QUANTIFY. 3013 02:04:53,519 --> 02:04:54,921 YOU CAN SEE NOT MUCH DIFFERENCE 3014 02:04:54,921 --> 02:04:56,589 IN THE ANTIGEN VERSUS 3015 02:04:56,589 --> 02:04:57,490 NON-ANTIGEN SPECIFIC SYSTEM IN 3016 02:04:57,490 --> 02:04:59,625 THE FIRST 24 HOURS BUT THAT 3017 02:04:59,625 --> 02:05:02,362 LATTER ONE WE SEE INFLECTION AND 3018 02:05:02,362 --> 02:05:03,996 ACTIVATION, I HOPE THIS MAYBE 3019 02:05:03,996 --> 02:05:05,331 STIMULATES QUESTIONS ABOUT 3020 02:05:05,331 --> 02:05:06,733 IMMUNE THERAPIES, DIFFERENT ONCE 3021 02:05:06,733 --> 02:05:11,738 WE CAN SCREEN USING THE SYSTEM. 3022 02:05:11,738 --> 02:05:12,305 WE'RE TRANSLATING TO 3023 02:05:12,305 --> 02:05:13,706 HUMAN-CENTRIC SYSTEMS. 3024 02:05:13,706 --> 02:05:19,345 I'LL HIGHLIGHT ONE WE'VE BEEN 3025 02:05:19,345 --> 02:05:20,980 COLLABORATING, BETA CELLS WITH 3026 02:05:20,980 --> 02:05:24,717 PPIT CELLS, JUST AN EXAMPLE OF A 3027 02:05:24,717 --> 02:05:25,418 CONTROL. 3028 02:05:25,418 --> 02:05:27,553 LET ME TRY AGAIN. 3029 02:05:27,553 --> 02:05:29,322 T CELLS INTERACTING. 3030 02:05:29,322 --> 02:05:34,761 GFP BETA CELLS, RED ARE DEAD 3031 02:05:34,761 --> 02:05:35,762 CELLS, VERSUS TREATED. 3032 02:05:35,762 --> 02:05:36,562 SIGNIFICANT DIFFERENCES IN 3033 02:05:36,562 --> 02:05:39,832 AMOUNT OF CELL DEATH OVER TIME 3034 02:05:39,832 --> 02:05:42,235 AND VISUALLY TRACK AND GET 3035 02:05:42,235 --> 02:05:43,970 SPATIAL INFORMATION FROM THAT. 3036 02:05:43,970 --> 02:05:45,838 WHAT TIME AM I AT NOW? 3037 02:05:45,838 --> 02:05:47,273 FIVE MINUTES? 3038 02:05:47,273 --> 02:05:48,908 DONE. 3039 02:05:48,908 --> 02:05:49,342 OKAY. 3040 02:05:49,342 --> 02:05:51,644 FUTURE DIRECTIONS, I'M SORRY 3041 02:05:51,644 --> 02:05:52,612 THERE'S NO CLOCK HERE. 3042 02:05:52,612 --> 02:05:55,581 I HAVE NO SENSE OF TIME. 3043 02:05:55,581 --> 02:05:57,550 FUTURE DIRECTIONS IS SCALE UP 3044 02:05:57,550 --> 02:06:00,286 MANUFACTURING, BEING ABLE TO 3045 02:06:00,286 --> 02:06:02,488 MODIFY STEM CELL REPERTOIRE, 3D 3046 02:06:02,488 --> 02:06:04,357 PRINTING AND LEVERAGING THAT 3047 02:06:04,357 --> 02:06:06,859 WOULD BE EXCITING, SPATIAL 3048 02:06:06,859 --> 02:06:08,828 DISTRIBUTION, AS WELL AS USING 3049 02:06:08,828 --> 02:06:13,232 SPATIAL OMICS INTEGRATE AS WELL 3050 02:06:13,232 --> 02:06:16,269 AS 3D PRINTING THE CHIP, 3051 02:06:16,269 --> 02:06:18,037 LEVERAGING SHEER EFFECTS, THAT'S 3052 02:06:18,037 --> 02:06:19,772 A SPACE WE'VE NOT EXPLORED, 3053 02:06:19,772 --> 02:06:21,307 CELLS ARE SENSITIVE TO SHEER, T 3054 02:06:21,307 --> 02:06:23,810 CELLS ARE AS WELL. 3055 02:06:23,810 --> 02:06:25,111 WE CAN START ASKING QUESTIONS 3056 02:06:25,111 --> 02:06:29,182 ABOUT FLOW EFFECT. 3057 02:06:29,182 --> 02:06:33,886 MY LAST SLIDE, WE HAVE A UNIQUE 3058 02:06:33,886 --> 02:06:35,421 OPPORTUNITY CROSS-VALIDATE USING 3059 02:06:35,421 --> 02:06:36,522 ANIMAL MODELS. 3060 02:06:36,522 --> 02:06:40,460 SO WHILE MPS ARE USED FOR HUMAN 3061 02:06:40,460 --> 02:06:42,995 CELLS, INTERESTING TO USE IN 3062 02:06:42,995 --> 02:06:44,063 ANIMAL CELLS AND CROSS-VALIDATE 3063 02:06:44,063 --> 02:06:47,467 WITH ANIMAL MODELS, SEE HOW 3064 02:06:47,467 --> 02:06:47,934 PREDICTIVE MPS. 3065 02:06:47,934 --> 02:06:49,769 WE DON'T KNOW HOW PREDICTIVE 3066 02:06:49,769 --> 02:06:51,304 THEY ARE BECAUSE WE STAND STUDY 3067 02:06:51,304 --> 02:06:52,572 HUMANS THE WAY WE CAN STUDY 3068 02:06:52,572 --> 02:06:54,373 CHIPS OF THE THIS MAY BE 3069 02:06:54,373 --> 02:06:56,042 INTERESTING TO VALIDATE THAT. 3070 02:06:56,042 --> 02:06:57,443 I'LL ACKNOWLEDGE -- SORRY IF I 3071 02:06:57,443 --> 02:06:58,110 WENT OVER TIME. 3072 02:06:58,110 --> 02:07:08,621 THANK YOU FOR YOUR ATTENTION. 3073 02:07:15,027 --> 02:07:16,262 [APPLAUSE] 3074 02:07:16,262 --> 02:07:17,797 >> THANKS VERY MUCH. 3075 02:07:17,797 --> 02:07:21,767 NEXT SPEAKER DR. ROBERTO MALONE, 3076 02:07:21,767 --> 02:07:26,906 CLINICAL IMMUNOLOGIST IN FRANCE, 3077 02:07:26,906 --> 02:07:28,107 ALSO HOLDS SENIOR INVESTIGATOR 3078 02:07:28,107 --> 02:07:28,741 POSITION. 3079 02:07:28,741 --> 02:07:34,547 I THINK THE CLOCK IS UP. 3080 02:07:34,547 --> 02:07:36,949 3081 02:07:36,949 --> 02:07:40,987 >> THANK YOU TO THE ORGANIZERS 3082 02:07:40,987 --> 02:07:42,321 FOR THE INVITATION. 3083 02:07:42,321 --> 02:07:52,832 TODAY I WOULD LIKE TO TELL YOU 3084 02:07:54,534 --> 02:07:56,903 ABOUT THE SPATIAL FEAT BETWEEN 3085 02:07:56,903 --> 02:08:00,339 BETA CELLS AND INTERFERON ON ONE 3086 02:08:00,339 --> 02:08:04,043 SIDE, PARTICULARLY TYPE TYPE I 3087 02:08:04,043 --> 02:08:05,778 INTERFERONS, AND CD 8 T CELLS. 3088 02:08:05,778 --> 02:08:08,180 THE START OF THE STORY DATES 3089 02:08:08,180 --> 02:08:11,817 BACK TO SOME OBSERVATION WE DID 3090 02:08:11,817 --> 02:08:18,057 SOME YEARS AGO, WHEN WE STARTED 3091 02:08:18,057 --> 02:08:22,762 ISLET REACTIVE CD8 T CELLS, 3092 02:08:22,762 --> 02:08:24,964 ISOLATING PBMCs FROM TYPE 1 3093 02:08:24,964 --> 02:08:28,334 DIABETES PATIENTS, AND HEALTHY 3094 02:08:28,334 --> 02:08:29,468 CONTROLS. 3095 02:08:29,468 --> 02:08:31,404 WE MADE SOME SURPRISING 3096 02:08:31,404 --> 02:08:34,574 OBSERVATIONS THAT THE FREQUENCY 3097 02:08:34,574 --> 02:08:35,775 OF THESE CIRCULATING HIGHLY 3098 02:08:35,775 --> 02:08:38,978 REACTIVE CD8 CELLS YOU SEE HERE 3099 02:08:38,978 --> 02:08:40,513 REACTIVE TO DIFFERENT PEPTIDES 3100 02:08:40,513 --> 02:08:44,016 DERIVED FROM BETA CELL ANTIGENS 3101 02:08:44,016 --> 02:08:49,055 WERE ACTUALLY SIMILAR, 3102 02:08:49,055 --> 02:08:51,891 IRRESPECTIVE OF DISEASE. 3103 02:08:51,891 --> 02:08:55,428 ACQUIRED FREQUENCY RANGE. 3104 02:08:55,428 --> 02:08:56,963 AND MOREOVER, THESE CIRCULATING 3105 02:08:56,963 --> 02:09:01,233 CD8 T CELLS EXPRESSED A LARGELY 3106 02:09:01,233 --> 02:09:06,172 NAIVE PHENOTYPE SUGGESTING THEY 3107 02:09:06,172 --> 02:09:09,675 WERE NOT ACTIVELY ENGAGED IN 3108 02:09:09,675 --> 02:09:10,776 AUTOIMMUNE PROCESS. 3109 02:09:10,776 --> 02:09:15,915 AND THIS WAS KIND OF AN 3110 02:09:15,915 --> 02:09:16,782 INCONVENIENT TRUTH BECAUSE 3111 02:09:16,782 --> 02:09:22,888 COMPLICATES A BIT THE USE OF T 3112 02:09:22,888 --> 02:09:24,457 CELLS CIRCULATING BIOMARKERS, 3113 02:09:24,457 --> 02:09:27,727 YET THERE IS ALSO SPACE FOR A 3114 02:09:27,727 --> 02:09:31,797 LOT OF OPPORTUNITIES AS I WILL 3115 02:09:31,797 --> 02:09:33,199 DEVELOP LATER IN THE TALK. 3116 02:09:33,199 --> 02:09:35,167 WHY WAS THIS MISSED BEFORE? 3117 02:09:35,167 --> 02:09:35,701 FOR SEVERAL REASONS. 3118 02:09:35,701 --> 02:09:37,703 ONE OF THOSE IS THAT WE'RE 3119 02:09:37,703 --> 02:09:41,641 LOOKING AT VERY LOW CD8 T CELL 3120 02:09:41,641 --> 02:09:42,408 FREQUENCIES, AND SO THE 3121 02:09:42,408 --> 02:09:45,011 CENTERING THAT YOU DO IN PBMCs 3122 02:09:45,011 --> 02:09:46,779 IS QUITE IMPORTANT. 3123 02:09:46,779 --> 02:09:49,649 YOU NEED TO SAMPLE ENOUGH TOTAL 3124 02:09:49,649 --> 02:09:54,220 CD8 T CELLS, ENOUGH PBMCs TO 3125 02:09:54,220 --> 02:09:57,056 BE ABLE TO CHARACTERIZE IN 3126 02:09:57,056 --> 02:09:58,157 RELIABLE WAY THE FREQUENCIES AND 3127 02:09:58,157 --> 02:10:04,530 YOU SEE HERE THAT WE OPTIMIZE 3128 02:10:04,530 --> 02:10:05,031 OUR TETRAMER HLA CLASS 1 3129 02:10:05,031 --> 02:10:10,369 TETRAMER STAINING TO BE ABLE TO 3130 02:10:10,369 --> 02:10:11,470 DO SO. 3131 02:10:11,470 --> 02:10:15,307 PART OF THE OBSERVATION IN 3132 02:10:15,307 --> 02:10:15,941 COLLABORATION WITH PISA, LOOKED 3133 02:10:15,941 --> 02:10:18,944 AT THE SAME TYPE OF ISLET 3134 02:10:18,944 --> 02:10:22,314 REACTIVE CD8 T CELLS USING HLA 3135 02:10:22,314 --> 02:10:25,718 CLASS 1 TETRAMER STAINING THIS 3136 02:10:25,718 --> 02:10:28,888 TIME IN SITU, USING FROZEN 3137 02:10:28,888 --> 02:10:31,724 TISSUE SECTIONS. 3138 02:10:31,724 --> 02:10:35,127 YOU SEE THAT CELLS ARE ENRICHED 3139 02:10:35,127 --> 02:10:38,964 IN PANCREAS OF TYPE 1 DIABETIC 3140 02:10:38,964 --> 02:10:40,433 PATIENTS AS COMPARED TO CONTROLS 3141 02:10:40,433 --> 02:10:44,103 SUGGESTING THAT OVER THE COURSE 3142 02:10:44,103 --> 02:10:45,404 OF DISEASE, THESE AUTOIMMUNE T 3143 02:10:45,404 --> 02:10:48,374 CELLS ARE NEW FEATURE, NOTABLY 3144 02:10:48,374 --> 02:10:50,109 BEING ABLE TO COME TO THE 3145 02:10:50,109 --> 02:10:54,613 PANCREAS WHERE WE FIND THEM 3146 02:10:54,613 --> 02:10:54,914 ENRICHED. 3147 02:10:54,914 --> 02:10:57,883 BASED ON THIS WE PROPOSED THE 3148 02:10:57,883 --> 02:11:01,253 IDEA OF UNIVERSAL STATE OF 3149 02:11:01,253 --> 02:11:02,455 BENIGN ISLET AUTOIMMUNITY THAT 3150 02:11:02,455 --> 02:11:07,393 IS GOING ON IN ALL INDIVIDUALS, 3151 02:11:07,393 --> 02:11:09,395 AND THAT EVOLVES TOWARDS 3152 02:11:09,395 --> 02:11:11,297 PATHOLOGIC TYPE 1 DIABETES 3153 02:11:11,297 --> 02:11:15,034 AUTOIMMUNITY, ONLY IN A FEW OF 3154 02:11:15,034 --> 02:11:16,936 THEM, CHARACTERIZED BY THESE 3155 02:11:16,936 --> 02:11:19,238 CIRCULATING CD8 T CELLS THAT 3156 02:11:19,238 --> 02:11:29,715 LOOK AT LEAST SUPERFICIALLY 3157 02:11:34,653 --> 02:11:34,820 SIMILAR. 3158 02:11:34,820 --> 02:11:37,223 THEY ARE UNDERLYING HOW IT IS 3159 02:11:37,223 --> 02:11:38,858 CRITICAL TO COMPARE WHAT IS 3160 02:11:38,858 --> 02:11:41,627 GOING ON IN THE TISSUE, WITH ITS 3161 02:11:41,627 --> 02:11:45,331 REFLECTION IN THE BLOOD TO 3162 02:11:45,331 --> 02:11:47,199 REALLY UNDERSTAND DISEASE 3163 02:11:47,199 --> 02:11:47,533 PATHOGENESIS. 3164 02:11:47,533 --> 02:11:49,502 BASED ON THESE OBSERVATIONS WE 3165 02:11:49,502 --> 02:11:51,270 STARTED TO ASK WHETHER THERE WAS 3166 02:11:51,270 --> 02:11:55,207 KEY DIFFERENCE IN THE BETA CELLS 3167 02:11:55,207 --> 02:11:59,879 THAT WAS RESPONSIBLE FOR THESE 3168 02:11:59,879 --> 02:12:01,213 SURPRISING OBSERVATIONS. 3169 02:12:01,213 --> 02:12:03,816 AND WE FOCUS OUR ATTENTION ON 3170 02:12:03,816 --> 02:12:05,918 THE ROLE OF INTERFERONS THAT IS 3171 02:12:05,918 --> 02:12:07,887 KNOWN SINCE LONG TIME. 3172 02:12:07,887 --> 02:12:09,755 FIRST OF ALL, THESE OBSERVATIONS 3173 02:12:09,755 --> 02:12:18,831 THAT DATE BACK TO THE LATE 3174 02:12:18,831 --> 02:12:22,535 BOTTAZZO, IN DIABETIC PATIENTS, 3175 02:12:22,535 --> 02:12:23,569 PROBABLY RELATED TO THIS TYPE I 3176 02:12:23,569 --> 02:12:24,403 INTERFERON SIGNATURE THAT HAS 3177 02:12:24,403 --> 02:12:27,072 BEEN DESCRIBED IN A NUMBER OF 3178 02:12:27,072 --> 02:12:35,714 PAPERS, AND YOU SEE IT PRECEDES 3179 02:12:35,714 --> 02:12:37,817 THE AUTOANTIBODY SEROCONVERSION. 3180 02:12:37,817 --> 02:12:41,687 AND INDEED YOU CAN REPRODUCE 3181 02:12:41,687 --> 02:12:45,057 THESE IN VITRO WHEN YOU EXPOSE 3182 02:12:45,057 --> 02:12:47,560 ISLETS OR BETA CELLS TO 3183 02:12:47,560 --> 02:12:48,127 INTERFERONS. 3184 02:12:48,127 --> 02:12:51,764 YOU SEE THAT YOU UPREGULATE HLA 3185 02:12:51,764 --> 02:12:55,534 CLASS 1 EXPRESSION, AND THESE 3186 02:12:55,534 --> 02:12:57,303 RESULTS IN INCREASED 3187 02:12:57,303 --> 02:12:58,170 PRESENTATION OF THE PEPTIDES 3188 02:12:58,170 --> 02:13:01,240 THAT ARE PRESENT BY THESE HLA 3189 02:13:01,240 --> 02:13:03,342 CLASS 1 MOLECULES. 3190 02:13:03,342 --> 02:13:06,478 SO THIS WAS FROM OUR PREVIOUS 3191 02:13:06,478 --> 02:13:09,348 WORK OF INITIAL CHARACTERIZATION 3192 02:13:09,348 --> 02:13:12,318 OF THE PEPTIDE ANTIGENIC PEPTIDE 3193 02:13:12,318 --> 02:13:15,688 DISPLAY OF BETA CELLS, UPON 3194 02:13:15,688 --> 02:13:18,657 EXPOSURE TO INFLAMMATORY 3195 02:13:18,657 --> 02:13:24,663 CYTOKINES, WHAT WE DID NOT 3196 02:13:24,663 --> 02:13:27,733 ADDRESS IN THIS WAS THIS DISPLAY 3197 02:13:27,733 --> 02:13:29,935 OF ANTIGENIC PEPTIDES CHANGING 3198 02:13:29,935 --> 02:13:32,238 UPON EXPOSURE PARTICULARLY TO 3199 02:13:32,238 --> 02:13:34,974 INTERFERON ALPHA WHICH IS THE 3200 02:13:34,974 --> 02:13:36,709 SIGNATURE TYPE I INTERFERON 3201 02:13:36,709 --> 02:13:41,146 CYTOKINE OF TYPE 1 DIABETES. 3202 02:13:41,146 --> 02:13:47,286 TO DO SO WE DEVELOPED THIS 3203 02:13:47,286 --> 02:13:51,323 WORKFLOW, USING MAINLY BETA CELL 3204 02:13:51,323 --> 02:13:55,761 LINES THAT HAVE CARRIED COMMON 3205 02:13:55,761 --> 02:13:57,897 HLA CLASS 1 VARIANTS, 3206 02:13:57,897 --> 02:14:00,466 PARTICULARLY A2, EXPOSED TO 3207 02:14:00,466 --> 02:14:03,702 INTERFERON ALPHA. 3208 02:14:03,702 --> 02:14:07,306 THEY WERE ALIVE, PEPTIDE HLA 3209 02:14:07,306 --> 02:14:10,809 COMPLEXES IMMUNOPRECIPITATED TO 3210 02:14:10,809 --> 02:14:13,979 ALLUDE TO PEPTIDES AND IDENTIFY 3211 02:14:13,979 --> 02:14:14,747 MY MASS SPECTROMETRY. 3212 02:14:14,747 --> 02:14:17,182 SOME OF THIS WORK I'VE PRESENTED 3213 02:14:17,182 --> 02:14:20,552 BEFORE, NOW EXTENDING, NOW THIS 3214 02:14:20,552 --> 02:14:23,088 WORK IS IN NATURAL 3215 02:14:23,088 --> 02:14:24,023 COMMUNICATION. 3216 02:14:24,023 --> 02:14:27,660 SO, THE FIRST OBSERVATION IS 3217 02:14:27,660 --> 02:14:31,397 THAT OBSERVED BEFORE WITH 3218 02:14:31,397 --> 02:14:34,199 INTERFERON GAMMA, INTERFERON 3219 02:14:34,199 --> 02:14:36,101 ALPHA UPREGULATED HLA CLASS 1 3220 02:14:36,101 --> 02:14:37,169 EXPRESSION, RESULTED IN 3221 02:14:37,169 --> 02:14:38,170 PRESENTATION OF MUCH LARGER 3222 02:14:38,170 --> 02:14:44,610 NUMBER OF PEPTIDES SO SUGGESTING 3223 02:14:44,610 --> 02:14:46,278 THIS INTERFERON WAS INCREASING 3224 02:14:46,278 --> 02:14:47,746 VISIBILITY BY EXPOSING MORE 3225 02:14:47,746 --> 02:14:48,013 PEPTIDES. 3226 02:14:48,013 --> 02:14:51,283 THE NATURE OF THESE PEPTIDES WAS 3227 02:14:51,283 --> 02:14:52,952 ALSO PARTLY CHANGING, AND WE 3228 02:14:52,952 --> 02:14:55,888 FOCUSED ON DIFFERENT TYPES OF 3229 02:14:55,888 --> 02:14:58,424 PEPTIDES, YOU SEE THOUGH HUER 3230 02:14:58,424 --> 02:15:01,694 SOME THAT WE IDENTIFIED AS 3231 02:15:01,694 --> 02:15:03,329 POST-TRANSLATIONAL MODIFIED WITH 3232 02:15:03,329 --> 02:15:06,198 DIFFERENT CHEMICAL ADDITION THAT 3233 02:15:06,198 --> 02:15:12,638 WE COULD IDENTIFY BIOLOGICAL NOT 3234 02:15:12,638 --> 02:15:14,073 INDUCED SPURIOUSLY BY THE 3235 02:15:14,073 --> 02:15:15,274 ACQUISITION PROCEDURE AND THIS 3236 02:15:15,274 --> 02:15:19,011 ONE WE FIND IT PARTICULARLY 3237 02:15:19,011 --> 02:15:23,749 INTERESTING BECAUSE YOU SEE IT'S 3238 02:15:23,749 --> 02:15:29,154 QUITE BULKY POST-TRANSLATIONAL 3239 02:15:29,154 --> 02:15:31,824 MODIFICATION, THREE PEPTIDE, KEY 3240 02:15:31,824 --> 02:15:36,495 RESPONSE IN BETA CELLS, PERHAPS 3241 02:15:36,495 --> 02:15:39,365 REFLECTING THE OXIDATIVE STRESS 3242 02:15:39,365 --> 02:15:44,269 SITUATION OF BETA CELLS UNDER 3243 02:15:44,269 --> 02:15:47,573 INFLAMMATORY CONDITIONS. 3244 02:15:47,573 --> 02:15:50,843 TOGETHER WITH TEDESIO IDENTIFIED 3245 02:15:50,843 --> 02:15:52,911 ALTERNATIVE SPLICING OF 3246 02:15:52,911 --> 02:15:57,983 MESSENGER RNA, GIVING RISE TO 3247 02:15:57,983 --> 02:16:00,052 NEOEPITOPES, YOU SEE A VARIANT 3248 02:16:00,052 --> 02:16:05,090 THAT GIVES RISE TO THIS NEW 3249 02:16:05,090 --> 02:16:07,393 PEPTIDE THAT WE'RE STUDYING AS 3250 02:16:07,393 --> 02:16:10,796 POTENTIAL NEW ANTIGEN. 3251 02:16:10,796 --> 02:16:15,834 THE OTHER OBSERVATION OF THIS 3252 02:16:15,834 --> 02:16:18,804 WORK WAS THAT PROTEINS WERE 3253 02:16:18,804 --> 02:16:20,005 CONTRIBUTING MORE PEPTIDES TO 3254 02:16:20,005 --> 02:16:23,308 DISPLAY OF BETA CELLS WERE 3255 02:16:23,308 --> 02:16:29,348 DERIVED FROM INSULIN GRANULES 3256 02:16:29,348 --> 02:16:32,084 YOU SEE HERE, ASSOCIATED WITH 3257 02:16:32,084 --> 02:16:34,086 GRANULES WITH MIGRATION LIKE KEY 3258 02:16:34,086 --> 02:16:37,222 1 ALPHA MAP 1 BETA. 3259 02:16:37,222 --> 02:16:38,957 THE MOST REPRESENTED PEPTIDES 3260 02:16:38,957 --> 02:16:44,997 OUT OF ALL WAS THESE VERY WELL 3261 02:16:44,997 --> 02:16:46,532 KNOWN PPI 1524, YOU SEE THERE'S 3262 02:16:46,532 --> 02:16:49,802 SOME LOG OF DIFFERENCE COMPARED 3263 02:16:49,802 --> 02:16:51,437 TO ALL OTHER PEPTIDES, 3264 02:16:51,437 --> 02:16:52,738 BIOLOGICAL REASON FOR THIS IS 3265 02:16:52,738 --> 02:16:57,042 THAT THIS IS THE VERY END OF THE 3266 02:16:57,042 --> 02:17:01,513 SIGNAL PEPTIDE SO EVERY TIME 3267 02:17:01,513 --> 02:17:04,917 CREATES NEW INSULIN MOLECULE, 3268 02:17:04,917 --> 02:17:13,325 THIS FRAGMENT GOES TO FEED THE 3269 02:17:13,325 --> 02:17:15,727 HLA PATHWAY, ABUNDANTLY PRESENT. 3270 02:17:15,727 --> 02:17:17,696 WE DID CONFIRMATORY EXPERIMENTS 3271 02:17:17,696 --> 02:17:20,099 IN ISLETS, VERY INTERESTING 3272 02:17:20,099 --> 02:17:22,534 INFORMATION HERE LINKING TO THE 3273 02:17:22,534 --> 02:17:23,735 FOLLOWING TALK BY JULIA, 3274 02:17:23,735 --> 02:17:28,207 ACTUALLY WHEN YOU LOOK AT THE 3275 02:17:28,207 --> 02:17:29,308 ISLETS, MOST REPRESENTED 3276 02:17:29,308 --> 02:17:31,944 PROTEIN, AT LEAST EQUALLY 3277 02:17:31,944 --> 02:17:38,617 REPRESENTED, AS INSULIN IS 3278 02:17:38,617 --> 02:17:40,152 GLUCAGON, SUGGESTING ALPHA CELLS 3279 02:17:40,152 --> 02:17:41,787 HAS SAME ANTIGENIC VISIBILITY OF 3280 02:17:41,787 --> 02:17:44,423 BETA CELLS BUT FOR SOME REASON 3281 02:17:44,423 --> 02:17:45,724 THEY DON'T GET DESTROYED TO THE 3282 02:17:45,724 --> 02:17:51,763 SAME EXTENT OF BETA CELLS, SO 3283 02:17:51,763 --> 02:17:55,467 THIS NUMBER OF GLUCAGON-DERIVED 3284 02:17:55,467 --> 02:17:56,101 PEPTIDES IDENTIFIED MAY 3285 02:17:56,101 --> 02:17:58,837 CONSTITUTE USEFUL RESOURCE FOR 3286 02:17:58,837 --> 02:18:01,039 FOLLOW-UP STUDIES. 3287 02:18:01,039 --> 02:18:04,643 WHY ARE THESE GRANULE PROTEINS 3288 02:18:04,643 --> 02:18:05,344 IMPORTANT? 3289 02:18:05,344 --> 02:18:09,815 WE THINK IT'S BECAUSE BASED ON 3290 02:18:09,815 --> 02:18:11,450 MODEL PROPOSED THESE PROTEINS 3291 02:18:11,450 --> 02:18:13,752 MAY ACTUALLY FUNCTION AS 3292 02:18:13,752 --> 02:18:16,455 ANTIGENS THAT CAN SENSITIZE 3293 02:18:16,455 --> 02:18:19,758 IMMUNE SYSTEM AT DISTANCE BY 3294 02:18:19,758 --> 02:18:21,727 BEING CAPTURED BY 3295 02:18:21,727 --> 02:18:23,695 ANTIGEN-PRESENTING CELLS AND 3296 02:18:23,695 --> 02:18:25,564 PRIMING T CELLS, IDENTIFIED THAT 3297 02:18:25,564 --> 02:18:27,833 PEPTIDES DERIVED FROM THESE 3298 02:18:27,833 --> 02:18:30,569 GRANULE PROTEINS ARE ACTUALLY 3299 02:18:30,569 --> 02:18:33,672 SHARED BY MANY DIFFERENT HLAs, 3300 02:18:33,672 --> 02:18:42,648 HLA CLASS 1 IN HUMANS, 2 3301 02:18:42,648 --> 02:18:46,218 4, WORK WITH JAMES, AND IN THE 3302 02:18:46,218 --> 02:18:48,887 MOUSE COULD DEMONSTRATE T CELLS 3303 02:18:48,887 --> 02:18:54,159 RECOGNIZE THESE NOVEL GRANULE 3304 02:18:54,159 --> 02:18:57,196 PROTEINS YOU SEE HERE, WHEN YOU 3305 02:18:57,196 --> 02:18:59,398 INJECT THEM INTO IMMUNODEFICIENT 3306 02:18:59,398 --> 02:19:02,234 MICE THEY CAN ACTUALLY TRANSFER 3307 02:19:02,234 --> 02:19:07,072 DISEASE EFFICIENTLY, SIMILAR TO 3308 02:19:07,072 --> 02:19:11,143 WHAT IS OBTAINED WITH CD8 T 3309 02:19:11,143 --> 02:19:12,211 CELLS. 3310 02:19:12,211 --> 02:19:13,412 THE OTHER VERY SURPRISING 3311 02:19:13,412 --> 02:19:17,149 OBSERVATION OF THIS WORK IS THAT 3312 02:19:17,149 --> 02:19:20,652 THE EXPOSURE OF BETA CELLS TO 3313 02:19:20,652 --> 02:19:24,623 INTERFERON ALPHA ACTUALLY 3314 02:19:24,623 --> 02:19:26,491 COMPLETELY CHANGED THE 3315 02:19:26,491 --> 02:19:28,126 RESTRICTION ELEMENT, HLA CLASS 1 3316 02:19:28,126 --> 02:19:30,062 MOLECULE THAT WAS PRESENT IN THE 3317 02:19:30,062 --> 02:19:31,263 PEPTIDES IN THE TWO CONDITIONS. 3318 02:19:31,263 --> 02:19:36,101 YOU SEE THERE WAS A MAJOR SHIFT 3319 02:19:36,101 --> 02:19:39,137 IN PEPTIDES PRESENTED BY THE 3320 02:19:39,137 --> 02:19:41,340 SUBFAMILY OF HLA-B. 3321 02:19:41,340 --> 02:19:43,642 THIS WAS THROUGH IN TERMS OF 3322 02:19:43,642 --> 02:19:47,246 NUMBER OF PEPTIDES, YOU SEE NOT 3323 02:19:47,246 --> 02:19:51,984 MUCH DIFFERENCE FOR HLA-A BUT 3324 02:19:51,984 --> 02:19:53,719 BIG JUMP FOR B, IN TERMS OF 3325 02:19:53,719 --> 02:19:54,820 QUANTITY OF EACH INDIVIDUAL 3326 02:19:54,820 --> 02:19:55,053 PEPTIDE. 3327 02:19:55,053 --> 02:19:58,090 YOU SEE NO DIFFERENCE FOR HLA-A 3328 02:19:58,090 --> 02:20:03,362 BUT MAJOR SHIFT FOR HLA-B AND 3329 02:20:03,362 --> 02:20:04,429 SOMETHING INTERMEDIATE FOR 3330 02:20:04,429 --> 02:20:04,863 HLA-C. 3331 02:20:04,863 --> 02:20:08,700 LOOKING AT WHETHER THIS 3332 02:20:08,700 --> 02:20:10,369 CORRESPONDED TO PREFERENTIAL 3333 02:20:10,369 --> 02:20:13,538 UPREGULATION OF HLA-B, AND YOU 3334 02:20:13,538 --> 02:20:16,174 SEE HERE THAT INDEED THIS WAS 3335 02:20:16,174 --> 02:20:17,175 THE CASE USING DIFFERENT 3336 02:20:17,175 --> 02:20:21,179 INTERFERONS, THIS IS THE LEVEL 3337 02:20:21,179 --> 02:20:22,914 OF GENE EXPRESSION IN BETA CELL 3338 02:20:22,914 --> 02:20:27,085 LINE, YOU SEE THERE IS 3339 02:20:27,085 --> 02:20:30,155 PREFERENTIAL UPREGULATION OF 3340 02:20:30,155 --> 02:20:33,892 HLA-B, IT IS TRUE AT THE PROTEIN 3341 02:20:33,892 --> 02:20:36,595 LEVEL BY FLOW CYTOMETRY AND 3342 02:20:36,595 --> 02:20:38,263 WESTERN BLOT AND COULD CONFIRM 3343 02:20:38,263 --> 02:20:40,699 IN PRIMARY HUMAN ISLETS WITH 3344 02:20:40,699 --> 02:20:44,536 SOME HETEROGENEITY BUT STILL 3345 02:20:44,536 --> 02:20:47,272 HLA-B WAS LARGELY FAVORED, IT 3346 02:20:47,272 --> 02:20:55,247 LOOKED FOR US CELLS THIS 3347 02:20:55,247 --> 02:20:58,650 PHENOMENON MORE BIASED TO HLA-C. 3348 02:20:58,650 --> 02:21:01,620 ACTUALLY THIS OBSERVATION IS 3349 02:21:01,620 --> 02:21:03,255 PRESENT IN DIFFERENT PAPERS, 3350 02:21:03,255 --> 02:21:05,991 ALTHOUGH IT WENT PRETTY MUCH 3351 02:21:05,991 --> 02:21:06,258 UNNOTICED. 3352 02:21:06,258 --> 02:21:12,431 YOU SEE HERE TWO EXAMPLES, THESE 3353 02:21:12,431 --> 02:21:16,134 ARE RNAseq STUDIES IN TYPE 1 3354 02:21:16,134 --> 02:21:18,103 DIABETES VERSUS NON-DIABETIC 3355 02:21:18,103 --> 02:21:18,971 ISLETS, YOU SEE THE EXACT 3356 02:21:18,971 --> 02:21:20,205 HIERARCHY WE DESCRIBED IN THE IN 3357 02:21:20,205 --> 02:21:22,174 VITRO EXPERIMENT. 3358 02:21:22,174 --> 02:21:23,809 AND THESE ARE MORE RECENT WORK 3359 02:21:23,809 --> 02:21:26,011 ALSO SHOWING KIND OF THE SAME 3360 02:21:26,011 --> 02:21:26,244 PATTERN. 3361 02:21:26,244 --> 02:21:31,083 AND MECHANIC IN THIS PARTICULAR 3362 02:21:31,083 --> 02:21:33,518 REASON FOR THIS GOES BACK TO 3363 02:21:33,518 --> 02:21:35,721 DIFFERENT PAPERS PUBLISHED QUITE 3364 02:21:35,721 --> 02:21:38,890 MANY YEARS AGO SHOWING THAT 3365 02:21:38,890 --> 02:21:42,294 INTERFERON RESPONSIVE ELEMENT 3366 02:21:42,294 --> 02:21:44,596 PRESENT IN HLA-B LOCUS HAS 3367 02:21:44,596 --> 02:21:47,399 HIGHER AFFINITY TO REGULATORY 3368 02:21:47,399 --> 02:21:50,936 FACTORS 1 AND 2 THAN INTERFERON 3369 02:21:50,936 --> 02:21:53,572 RESPONSIVE ELEMENTS OF HLA-A 3370 02:21:53,572 --> 02:21:56,641 LOCUS, SO INTERFERON EXPOSURE 3371 02:21:56,641 --> 02:22:01,880 FAVORS THESE HLA UPREGULATIONS, 3372 02:22:01,880 --> 02:22:03,982 BIAS TOWARDS THIS HLA-B. 3373 02:22:03,982 --> 02:22:07,386 THE OTHER QUESTION WE ASKED WAS 3374 02:22:07,386 --> 02:22:09,688 WHETHER THE LONGER KNOWN HLA 3375 02:22:09,688 --> 02:22:11,356 CLASS 1 HYPER EXPRESSION PRESENT 3376 02:22:11,356 --> 02:22:15,093 IN THE ISLETS OF TYPE 1 DIABETES 3377 02:22:15,093 --> 02:22:16,261 PATIENTS COULD ALSO REFLECT 3378 02:22:16,261 --> 02:22:19,865 MOSTLY HLA-B, AND YOU SEE HERE 3379 02:22:19,865 --> 02:22:23,935 IN THESE STAININGS FOR DIFFERENT 3380 02:22:23,935 --> 02:22:24,469 ANTIBODIES, DATED FOR 3381 02:22:24,469 --> 02:22:25,237 SPECIFICITY, BUT THIS SEEMS TO 3382 02:22:25,237 --> 02:22:27,773 BE THE CASE. 3383 02:22:27,773 --> 02:22:29,307 THESE ARE REPRESENTATIVE 3384 02:22:29,307 --> 02:22:34,112 STAININGS, AND YOU SEE HERE 3385 02:22:34,112 --> 02:22:36,548 OVERALL CUMULATIVE DATA SHOWING 3386 02:22:36,548 --> 02:22:44,856 THAT HLA-B IS MORE UPREGULATED 3387 02:22:44,856 --> 02:22:48,960 IN A, IN BOTH CELLS. 3388 02:22:48,960 --> 02:22:50,062 TRANSLATED INTO DIFFERENT 3389 02:22:50,062 --> 02:22:58,904 RECOGNITION BY T CELLS WAS THIS 3390 02:22:58,904 --> 02:23:02,974 UPREGULATION MOSTLY INVOLVED 3391 02:23:02,974 --> 02:23:03,608 HLA-B, YOU COULD EXPECT 3392 02:23:03,608 --> 02:23:07,345 RESTRICTED CELLS TO BE MORE 3393 02:23:07,345 --> 02:23:09,314 POTENTIATED IN RECOGNITION OF 3394 02:23:09,314 --> 02:23:11,049 BETA CELLS EXPOSED TO 3395 02:23:11,049 --> 02:23:13,785 INTERFERONS, AND YOU SEE HERE 3396 02:23:13,785 --> 02:23:18,490 THE FIRST EXPERIMENT TESTING 3397 02:23:18,490 --> 02:23:22,828 THIS USING BOTH HLA-A RESTRICTED 3398 02:23:22,828 --> 02:23:27,098 OR HbA-B 4 RESTRICTED, 3399 02:23:27,098 --> 02:23:31,736 FLUORESCENT REPORTERS WITH THE 3400 02:23:31,736 --> 02:23:35,774 MODEL USING BETA CELLS THAT 3401 02:23:35,774 --> 02:23:38,977 EXPRESS INSULIN, CD8 T CELLS 3402 02:23:38,977 --> 02:23:40,512 RECOGNIZE INSULIN PEPTIDES, YOU 3403 02:23:40,512 --> 02:23:44,649 SEE WHEN YOU EXPOSE THE BETA 3404 02:23:44,649 --> 02:23:48,587 CELLS TO INTERFERONS, AND TO 3405 02:23:48,587 --> 02:23:49,788 HLA-2 RESTRICTED CD8 CELLS 3406 02:23:49,788 --> 02:23:51,656 THERE'S NOT MUCH DIFFERENCE IN 3407 02:23:51,656 --> 02:23:56,895 THE TWO CONDITIONS, WHILE YOU 3408 02:23:56,895 --> 02:23:58,763 HAVE VERY SIGNIFICANT 3409 02:23:58,763 --> 02:24:02,601 UPREGULATION OF THE ACTIVATION 3410 02:24:02,601 --> 02:24:05,537 OF THESE CD8 T CELLS, HLA 3411 02:24:05,537 --> 02:24:08,173 RESTRICTED WHEN EXPOSED TO 3412 02:24:08,173 --> 02:24:09,708 INTERFERON-TREATED BETA CELLS 3413 02:24:09,708 --> 02:24:13,011 VERSUS THE BETA CELLS NOT 3414 02:24:13,011 --> 02:24:15,413 TREATED, HERE SHOWN IN LIGHT 3415 02:24:15,413 --> 02:24:15,814 BLUE. 3416 02:24:15,814 --> 02:24:20,118 THIS TRANSLATES INTO AN 3417 02:24:20,118 --> 02:24:22,153 INCREASED LINK BY HLA-B 3418 02:24:22,153 --> 02:24:22,954 RESTRICTED CELLS, WE'VE DONE 3419 02:24:22,954 --> 02:24:27,325 THIS IN THE OTHER EXPERIMENTS 3420 02:24:27,325 --> 02:24:30,295 USING REACTIVE MODEL TO CONTROL 3421 02:24:30,295 --> 02:24:33,565 AMOUNT OF PEPTIDE PRESENTED IN 3422 02:24:33,565 --> 02:24:38,503 EACH CONDITION, AND YOU SEE NO 3423 02:24:38,503 --> 02:24:40,171 DIFFERENCE IN BETA CELLS EXPOSED 3424 02:24:40,171 --> 02:24:45,544 TO INTERFERON ALPHA, YOU GET THE 3425 02:24:45,544 --> 02:24:50,015 SAME CYTOTOXICITY, WHILE IT GETS 3426 02:24:50,015 --> 02:24:53,318 SIGNIFICANTLY ENHANCED FOR HLA 3427 02:24:53,318 --> 02:24:54,886 RESTRICTED T CELLS. 3428 02:24:54,886 --> 02:24:57,455 WE ALSO WENT TO LOOK AT 3429 02:24:57,455 --> 02:25:02,761 DIFFERENT CD8 T CELL LINES THAT 3430 02:25:02,761 --> 02:25:05,063 SHE HAS GENERATED INFILTRATING T 3431 02:25:05,063 --> 02:25:09,568 CELLS WHERE THESE WOULD 3432 02:25:09,568 --> 02:25:12,504 RECOGNIZE RESTRICTED PEPTIDES 3433 02:25:12,504 --> 02:25:16,107 THAT WE'VE IDENTIFIED, YOU SEE 3434 02:25:16,107 --> 02:25:20,045 FIRST USING PEPTIDE DONE BY 3435 02:25:20,045 --> 02:25:21,012 CONVOLUTING WITH INDIVIDUAL 3436 02:25:21,012 --> 02:25:25,517 PEPTIDES WE FIND A NUMBER OF 3437 02:25:25,517 --> 02:25:27,185 HITS, HERE I HIGHLIGHT SOME THAT 3438 02:25:27,185 --> 02:25:29,788 HAVE BEEN SHOWN IN AT LEAST TWO 3439 02:25:29,788 --> 02:25:40,332 DIFFERENT CELL LINES, WITH SOME 3440 02:25:42,133 --> 02:25:43,602 ENVELOPE ANTIGENS IDENTIFIED, 3441 02:25:43,602 --> 02:25:49,074 PRESENCE OF RECOGNITION OF SOME 3442 02:25:49,074 --> 02:25:56,948 POST-TRANSLATIONALLY MODIFIED 3443 02:25:56,948 --> 02:26:01,853 PEPTIDES PARTICULARLY THIS ONE. 3444 02:26:01,853 --> 02:26:03,088 PREVIOUS OBSERVATIONS OF LACK OF 3445 02:26:03,088 --> 02:26:06,491 DIFFERENCE OF BETWEENS OF THESE 3446 02:26:06,491 --> 02:26:09,761 CD8 T CELLS BETWEEN TYPE 1 3447 02:26:09,761 --> 02:26:10,528 DIABETIC AND NON-DIABETIC 3448 02:26:10,528 --> 02:26:12,931 INDIVIDUALS ALL THIS WORK HAS 3449 02:26:12,931 --> 02:26:18,203 BEEN DONE BY FOCUSING ON HLA-A2 3450 02:26:18,203 --> 02:26:20,171 RESTRICTED CD8 T CELLS, IN THE 3451 02:26:20,171 --> 02:26:21,773 LITERATURE THERE'S BEEN VERY 3452 02:26:21,773 --> 02:26:24,643 LITTLE ATTENTION GIVEN TO THE 3453 02:26:24,643 --> 02:26:26,845 EPITOPES THAT ARE PRESENTED BY 3454 02:26:26,845 --> 02:26:27,912 HLA-B ALLELES. 3455 02:26:27,912 --> 02:26:29,714 YOU SEE THE NUMBER OF EPITOPES 3456 02:26:29,714 --> 02:26:32,317 THAT ARE KNOWN IN THE LITERATURE 3457 02:26:32,317 --> 02:26:33,852 IS EXTREMELY SMALL. 3458 02:26:33,852 --> 02:26:36,154 AND NOW WE HAVE SOME HUNDRED 3459 02:26:36,154 --> 02:26:39,658 NOVEL CANDIDATES THAT WE CAN 3460 02:26:39,658 --> 02:26:43,828 TEST TO SEE WHETHER THEY CAN 3461 02:26:43,828 --> 02:26:46,331 PROVIDE BETTER MARKERS OF 3462 02:26:46,331 --> 02:26:47,866 SECURITY MARKERS OF TYPE 1 3463 02:26:47,866 --> 02:26:49,167 DIABETES AUTOIMMUNITY. 3464 02:26:49,167 --> 02:26:52,003 WHY DO WE THINK THIS IS 3465 02:26:52,003 --> 02:26:52,270 IMPORTANT? 3466 02:26:52,270 --> 02:26:54,739 WELL, BECAUSE MAYBE THIS COULD 3467 02:26:54,739 --> 02:26:59,778 BE ANOTHER MECHANISM OF LOSS OF 3468 02:26:59,778 --> 02:27:02,414 IMMUNE, YOU SEE THE SITUATION OF 3469 02:27:02,414 --> 02:27:05,450 ANTI-ISLET, WITH LOW EXPRESSION 3470 02:27:05,450 --> 02:27:10,155 OF HLA-A, NOT HLA-B. 3471 02:27:10,155 --> 02:27:13,224 WHEN YOU GET INTERFERON RESPONSE 3472 02:27:13,224 --> 02:27:16,194 INCREASING IMMUNE VISIBILITY, 3473 02:27:16,194 --> 02:27:18,029 HLA UPREGULATION IS RELATIVELY 3474 02:27:18,029 --> 02:27:19,831 MINOR WITH MAJOR UPREGULATION SO 3475 02:27:19,831 --> 02:27:22,767 YOU MAY HAVE RECRUITMENT OF 3476 02:27:22,767 --> 02:27:27,372 COMPLETELY DISTINCT SET OF CD8 T 3477 02:27:27,372 --> 02:27:29,974 CELLS RECOGNIZING DIFFERENT 3478 02:27:29,974 --> 02:27:32,077 REPERTOIRE OF ANTIGENIC PEPTIDES 3479 02:27:32,077 --> 02:27:34,913 AND SO ON LEFT SIDE THESE 3480 02:27:34,913 --> 02:27:37,882 NEGLECTED CD8 T CELLS REPERTOIRE 3481 02:27:37,882 --> 02:27:40,885 MAY HAVE VERY IMPORTANT 3482 02:27:40,885 --> 02:27:44,422 PATHOGENIC ROLE, AND ON THE 3483 02:27:44,422 --> 02:27:48,293 OTHER MAY CONSTITUTE BETTER 3484 02:27:48,293 --> 02:27:49,828 BIOMARKERS OF ONGOING 3485 02:27:49,828 --> 02:27:50,595 AUTOIMMUNITY. 3486 02:27:50,595 --> 02:27:53,765 AND ONE LAST SLIDE TO THANK THE 3487 02:27:53,765 --> 02:27:58,470 PEOPLE THAT HAS DONE THE JOB, 3488 02:27:58,470 --> 02:28:00,538 THAT'S PARTICULARLY THE JOB OF 3489 02:28:00,538 --> 02:28:05,910 PREVIOUS Ph.D. STUDENT IN THE 3490 02:28:05,910 --> 02:28:08,079 LAB WITH TWO POSTDOCS IN 3491 02:28:08,079 --> 02:28:11,149 COLLABORATION ALSO WITH OUR 3492 02:28:11,149 --> 02:28:16,321 SATELLITE LAB IN INDIANAPOLIS, 3493 02:28:16,321 --> 02:28:18,289 AND OUR COLLABORATORS, TEAM WORK 3494 02:28:18,289 --> 02:28:21,359 THAT HAS BEEN A VERY PLEASANT 3495 02:28:21,359 --> 02:28:23,428 JOURNEY WITH DIFFERENT 3496 02:28:23,428 --> 02:28:29,601 COLLEAGUES I'VE MENTIONED 3497 02:28:29,601 --> 02:28:30,568 THROUGHOUT, IN DENVER, AND MY 3498 02:28:30,568 --> 02:28:40,411 NEIGHBOR, AND OF COURSE OUR 3499 02:28:40,411 --> 02:28:42,947 SPONSORS, IN PARTICULAR THE 3500 02:28:42,947 --> 02:28:52,690 TRUST, AND THANK YOU FOR YOUR 3501 02:28:52,690 --> 02:28:55,427 ATTENTION. 3502 02:28:55,427 --> 02:28:56,694 >> JULIA PANZER, RIGGS DIABETES 3503 02:28:56,694 --> 02:29:04,102 INSTITUTE OF CITY OF HOPE. 3504 02:29:04,102 --> 02:29:05,537 >> I'M GOING TO SWITCH GEARS. 3505 02:29:05,537 --> 02:29:10,141 WHICH POINTER AM I USING? 3506 02:29:10,141 --> 02:29:11,776 AND TALK ABOUT THE ALPHA CELL, 3507 02:29:11,776 --> 02:29:13,545 WHICH DESERVES A LITTLE MORE 3508 02:29:13,545 --> 02:29:14,979 ATTENTION THAN IT'S GETTING 3509 02:29:14,979 --> 02:29:15,413 CURRENTLY. 3510 02:29:15,413 --> 02:29:22,086 I'M GOING TO TELL YOU WHY. 3511 02:29:22,086 --> 02:29:23,922 BECAUSE SECRETION IS THE MOST 3512 02:29:23,922 --> 02:29:25,557 IMPORTANT DEFENSE MECHANISM. 3513 02:29:25,557 --> 02:29:27,292 OBVIOUSLY SOMETHING IS GOING 3514 02:29:27,292 --> 02:29:32,363 WRONG IN TYPE 1 DIABETES. 3515 02:29:32,363 --> 02:29:33,665 THIS IS NOT WORKING. 3516 02:29:33,665 --> 02:29:35,967 SO, IF WE LOOK AT GLYCEMIC 3517 02:29:35,967 --> 02:29:38,136 PROFILE OF A PATIENT WITH TYPE 1 3518 02:29:38,136 --> 02:29:39,771 DIABETES WE CAN SEE ALMOST EVERY 3519 02:29:39,771 --> 02:29:44,943 SINGLE DAY THIS PATIENT FACES A 3520 02:29:44,943 --> 02:29:48,880 HYPOGLYCEMIC EPISODE WITH SEVERE 3521 02:29:48,880 --> 02:29:49,214 CONSEQUENCES. 3522 02:29:49,214 --> 02:29:51,049 TO QUOTE, HYPOGLYCEMIA IS THE 3523 02:29:51,049 --> 02:29:52,150 LIMITING FACTOR IN MANAGEMENT OF 3524 02:29:52,150 --> 02:29:53,985 DIABETES, IF IT WEREN'T FOR 3525 02:29:53,985 --> 02:29:55,653 THAT, WE COULD TREAT DIABETES 3526 02:29:55,653 --> 02:29:57,755 MORE AGGRESSIVELY BUT ALSO MORE 3527 02:29:57,755 --> 02:29:58,957 SAFELY WITH INSULIN THERAPY. 3528 02:29:58,957 --> 02:30:00,491 ALSO WE COULD GIVE PATIENTS MORE 3529 02:30:00,491 --> 02:30:04,295 PEACE OF MIND BEFORE THEY GO TO 3530 02:30:04,295 --> 02:30:04,529 BED. 3531 02:30:04,529 --> 02:30:07,365 SO THE QUESTION IS WHERE IS 3532 02:30:07,365 --> 02:30:11,836 GOING WRONG WITH THE ALPHA CELL? 3533 02:30:11,836 --> 02:30:14,172 SO IF WE LOOK AT THE MORPHOLOGY 3534 02:30:14,172 --> 02:30:15,740 YOU CAN SEE TWO PANCREATIC 3535 02:30:15,740 --> 02:30:17,775 TISSUE SLICES, ON THE LEFT FROM 3536 02:30:17,775 --> 02:30:19,744 HEALTHY INDIVIDUAL, ON THE RIGHT 3537 02:30:19,744 --> 02:30:21,846 FROM AN AGE MATCHED DONOR WITH 3538 02:30:21,846 --> 02:30:23,781 TYPE 1 DIABETES STAINED FOR BETA 3539 02:30:23,781 --> 02:30:26,751 CELLS, FOR INSULIN IN GREEN, 3540 02:30:26,751 --> 02:30:29,487 ALPHA CELLS FOR GLUCAGON IN 3541 02:30:29,487 --> 02:30:29,988 MAGENTA. 3542 02:30:29,988 --> 02:30:33,224 THERE'S A LOSS OF BETA CELLS IN 3543 02:30:33,224 --> 02:30:35,526 TYPE 1 DIABETES, ALPHA CELLS 3544 02:30:35,526 --> 02:30:36,728 REMAIN, CLUSTERED TOGETHER IN 3545 02:30:36,728 --> 02:30:39,998 WHAT WE CAN ASSUME WHERE WERE 3546 02:30:39,998 --> 02:30:40,765 ISLETS BEFORE. 3547 02:30:40,765 --> 02:30:42,767 THERE'S NOT LOSS OF ALPHA CELLS, 3548 02:30:42,767 --> 02:30:44,135 NOT THAT THERE'S A LOSS OF 3549 02:30:44,135 --> 02:30:46,804 GLUCAGON A CON PER SE, WHAT IS 3550 02:30:46,804 --> 02:30:51,776 THE PROBLEM? 3551 02:30:51,776 --> 02:30:52,944 THEY DON'T SEEM TO SECRETE. 3552 02:30:52,944 --> 02:30:56,347 YOU CAN SEE HERE FROM HEALTHY 3553 02:30:56,347 --> 02:30:56,915 INDIVIDUALS, ON GENE 3554 02:30:56,915 --> 02:30:57,615 CORRESPONDING INSULIN TRACE. 3555 02:30:57,615 --> 02:30:59,317 THIS IS WHAT WE WOULD EXPECT 3556 02:30:59,317 --> 02:31:02,720 FROM AN ALPHA CELL. 3557 02:31:02,720 --> 02:31:06,758 THERE'S BASELINE SECRETION, THEN 3558 02:31:06,758 --> 02:31:07,625 THERE'S DECREASED GLUCAGON 3559 02:31:07,625 --> 02:31:10,361 SECRETION, TWO TO THREE-FOLD 3560 02:31:10,361 --> 02:31:13,031 INCREASE ON THE LOW GLUCOSE 3561 02:31:13,031 --> 02:31:13,665 LEVELS. 3562 02:31:13,665 --> 02:31:15,233 IN TYPE 1 DIABETES THIS 3563 02:31:15,233 --> 02:31:17,669 SECRETION IS COMPLETELY ABSENT. 3564 02:31:17,669 --> 02:31:22,473 THERE'S NOT ONLY THE LOSS DURING 3565 02:31:22,473 --> 02:31:26,611 HYPOGLYCEMIA, THERE'S THE CHANGE 3566 02:31:26,611 --> 02:31:27,712 RESPONSE UNDER HIGH GLUCOSE 3567 02:31:27,712 --> 02:31:28,713 LEVELS. 3568 02:31:28,713 --> 02:31:32,317 THIS IS NOT SIGNIFICANTLY 3569 02:31:32,317 --> 02:31:36,888 DIFFERENT IN GLUCAGON CONTENT 3570 02:31:36,888 --> 02:31:37,755 COMPARING HEALTHY INDIVIDUALS, 3571 02:31:37,755 --> 02:31:41,492 IN EXPLAIN WE CAN EXPLAIN BY 3572 02:31:41,492 --> 02:31:43,261 LOSS OF BETA CELLS. 3573 02:31:43,261 --> 02:31:45,797 SO THIS BRINGS ME TO THE CURRENT 3574 02:31:45,797 --> 02:31:46,965 MODEL THAT WE THINK IS HAPPENING 3575 02:31:46,965 --> 02:31:48,399 IN THE ALPHA CELL. 3576 02:31:48,399 --> 02:31:52,770 WE THINK THERE ARE TWO STATES. 3577 02:31:52,770 --> 02:31:54,606 THE SECRETORY AND INACTIVE 3578 02:31:54,606 --> 02:31:54,806 STATE. 3579 02:31:54,806 --> 02:31:58,343 SO WE KNOW THAT ALPHA CELLS ARE 3580 02:31:58,343 --> 02:31:59,978 ELECTRICALLY EXCITABLE, WORK 3581 02:31:59,978 --> 02:32:01,613 WITH FIRING ACTION POTENTIALS, 3582 02:32:01,613 --> 02:32:04,682 WHICH ACTIVATE CHANNELS, THIS 3583 02:32:04,682 --> 02:32:06,417 LEADS TO CONFLICT IN SECRETION. 3584 02:32:06,417 --> 02:32:07,852 THESE ACTION POTENTIAL HAVE TO 3585 02:32:07,852 --> 02:32:09,954 REACH A CERTAIN THRESHOLD 3586 02:32:09,954 --> 02:32:12,457 BECAUSE ONLY ABOVE THIS 3587 02:32:12,457 --> 02:32:14,192 THRESHOLD GLUCAGON SECRETION 3588 02:32:14,192 --> 02:32:14,659 OCCURS. 3589 02:32:14,659 --> 02:32:15,827 MULTIPLE STUDIES HAVE SHOWN 3590 02:32:15,827 --> 02:32:17,462 THESE ACTION POTENTIALS GET 3591 02:32:17,462 --> 02:32:19,998 SMALLER OVER TIME WHICH LEADS TO 3592 02:32:19,998 --> 02:32:25,236 THE INACTIVATED STATE AND 3593 02:32:25,236 --> 02:32:26,904 INACTIVATION OF CHANNELS. 3594 02:32:26,904 --> 02:32:28,640 SO WHAT THIS MEANS I'LL SHOW IN 3595 02:32:28,640 --> 02:32:30,608 THE SECRETION TRACE. 3596 02:32:30,608 --> 02:32:33,111 WHAT WE DID WAS SIMPLE 3597 02:32:33,111 --> 02:32:34,345 EXPERIMENT, EXPOSED HUMAN ISLETS 3598 02:32:34,345 --> 02:32:39,250 FOR A LONG TIME TO LOW GLUCOSE 3599 02:32:39,250 --> 02:32:39,684 CONCENTRATIONS. 3600 02:32:39,684 --> 02:32:42,320 THERE'S A RESPONSE WITH 3601 02:32:42,320 --> 02:32:43,621 INCREASED GLUCAGON SECRETION, 3602 02:32:43,621 --> 02:32:46,024 HOWEVER THIS LASTS FOR 30-60 3603 02:32:46,024 --> 02:32:46,891 MINUTES. 3604 02:32:46,891 --> 02:32:48,760 AFTER THIS GLUCAGON SECRETION 3605 02:32:48,760 --> 02:32:50,628 DECLINES, ALTHOUGH WE'RE STILL 3606 02:32:50,628 --> 02:32:52,730 IN ONE MILLIMOLAR GLUCOSE, 3607 02:32:52,730 --> 02:32:56,434 DECLINES AND DROPS AS LOW AS THE 3608 02:32:56,434 --> 02:32:58,069 LEVELS ARE WITH ACTIVE 3609 02:32:58,069 --> 02:32:59,604 INHIBITION DURING HIGH GLUCOSE. 3610 02:32:59,604 --> 02:33:02,340 THIS IS SPECIFIC FOR THE ALPHA 3611 02:33:02,340 --> 02:33:04,542 CELL BECAUSE THIS BEAUTIFUL 3612 02:33:04,542 --> 02:33:06,811 STUDY PERFORMED ON INSULIN 3613 02:33:06,811 --> 02:33:07,612 SECRETION SHOWS THAT THERE'S 3614 02:33:07,612 --> 02:33:09,047 AFTER THE FIRST RESPONSE OF 3615 02:33:09,047 --> 02:33:11,015 INSULIN RELEASE THERE'S A 3616 02:33:11,015 --> 02:33:12,116 PLATEAU, THIS LASTS FOR AS LONG 3617 02:33:12,116 --> 02:33:17,922 AS YOU STIMULATE THEM WITH HIGH 3618 02:33:17,922 --> 02:33:20,191 GLUCOSE. 3619 02:33:20,191 --> 02:33:21,726 COMPARED, SECRETION IS NOT 3620 02:33:21,726 --> 02:33:22,260 SUSTAINED. 3621 02:33:22,260 --> 02:33:25,563 THIS HAS BEEN SHOWN IN VITRO BUT 3622 02:33:25,563 --> 02:33:30,268 ALSO IN VIVO WITH HYPOGLYCEMIC 3623 02:33:30,268 --> 02:33:32,236 IN HUMAN, YOU CAN SEE, AGAIN, 3624 02:33:32,236 --> 02:33:35,073 THERE'S RESPONSE OF ABOUT 60 3625 02:33:35,073 --> 02:33:36,507 MINUTES, AFTERWARDS GLUCAGON 3626 02:33:36,507 --> 02:33:38,443 SECRETION DROPS, RESPONSE IS 3627 02:33:38,443 --> 02:33:39,877 ABSENT IN PATIENTS WITH TYPE 1 3628 02:33:39,877 --> 02:33:45,783 DIABETES, ALSO BEEN SHOWN IN 3629 02:33:45,783 --> 02:33:46,784 DOGS, ALSO IN RATS. 3630 02:33:46,784 --> 02:33:51,689 SO HOW DO WE GET ALPHA CELL BACK 3631 02:33:51,689 --> 02:33:52,790 TO SECRETORY STATE? 3632 02:33:52,790 --> 02:33:54,325 THIS HAPPENS BY THE WHOLE 3633 02:33:54,325 --> 02:33:56,727 ENVIRONMENT OF THE ALPHA CELL, 3634 02:33:56,727 --> 02:34:07,205 MEANING BY PARACRINE CELL. 3635 02:34:07,972 --> 02:34:11,309 THIS CLOSES THE CYCLE, LEADS TO 3636 02:34:11,309 --> 02:34:12,844 REPOLARIZATION, ACTIVE RESET OF 3637 02:34:12,844 --> 02:34:14,812 ALPHA CELL, SO IT'S NOT ONLY 3638 02:34:14,812 --> 02:34:16,247 IMPORTANT WHAT ACTIVATES THE 3639 02:34:16,247 --> 02:34:17,648 ALPHA CELL; IT'S EQUALLY 3640 02:34:17,648 --> 02:34:18,749 IMPORTANT WHAT INACTIVATES THE 3641 02:34:18,749 --> 02:34:21,686 CELL IN ORDER FOR IT TO 3642 02:34:21,686 --> 02:34:22,787 FUNCTION. 3643 02:34:22,787 --> 02:34:24,455 SO WE THINK IN TYPE 1 DIABETES 3644 02:34:24,455 --> 02:34:26,224 BECAUSE OF THESE CONSTANT 3645 02:34:26,224 --> 02:34:28,726 CONDITIONS, THE CELL REMAINS IN 3646 02:34:28,726 --> 02:34:29,894 THE INACTIVATED STATE, AND 3647 02:34:29,894 --> 02:34:33,131 BECAUSE THERE'S THE LOSS OF 3648 02:34:33,131 --> 02:34:34,766 PARACRINE SIGNALS BECAUSE WE 3649 02:34:34,766 --> 02:34:36,734 LOSE BETA CELLS IT CANNOT GO 3650 02:34:36,734 --> 02:34:38,603 BACK TO SECRETORY STATE. 3651 02:34:38,603 --> 02:34:42,073 HYPOTHESIS IS THAT IF WE CAN 3652 02:34:42,073 --> 02:34:43,508 REACTIVATE SIGNALS WE CAN 3653 02:34:43,508 --> 02:34:48,112 RESTORE ALPHA CELL'S ABILITY TO 3654 02:34:48,112 --> 02:34:49,747 RESPONSE TO HYPOGLYCEMIA. 3655 02:34:49,747 --> 02:34:51,716 SO, TO PROVE IF THIS IS ACCURATE 3656 02:34:51,716 --> 02:34:53,151 WE DID A VERY SIMPLE EXPERIMENT 3657 02:34:53,151 --> 02:34:54,986 TO START WITH. 3658 02:34:54,986 --> 02:34:56,554 AGAIN, WE EXPOSED HUMAN ISLETS 3659 02:34:56,554 --> 02:35:02,360 FOR A LONG TIME TO LOW GLUCOSE, 3660 02:35:02,360 --> 02:35:04,762 YOU SEE THE PROFILE, 60-MINUTE 3661 02:35:04,762 --> 02:35:05,730 RESPONSE, GLUCAGON SECRETION 3662 02:35:05,730 --> 02:35:06,063 DECLINES. 3663 02:35:06,063 --> 02:35:09,133 THEN WE THOUGHT WE JUST TRIED TO 3664 02:35:09,133 --> 02:35:10,201 RECOVER THIS BY RESETTING ALPHA 3665 02:35:10,201 --> 02:35:12,503 CELL BY ADDING A SHORT PERIOD OF 3666 02:35:12,503 --> 02:35:13,704 HIGH GLUCOSE AND STARTED WITH 3667 02:35:13,704 --> 02:35:14,472 FIVE MINUTES. 3668 02:35:14,472 --> 02:35:17,308 AND YOU CAN SEE ON TOP THE 3669 02:35:17,308 --> 02:35:19,277 RESPONSE OF INSULIN, YOU CAN 3670 02:35:19,277 --> 02:35:22,680 ALSO SEE GLUCAGON SECRETION IS 3671 02:35:22,680 --> 02:35:22,947 INHIBITED. 3672 02:35:22,947 --> 02:35:24,649 HOWEVER, THE REBOND EXCITATION 3673 02:35:24,649 --> 02:35:27,485 DOES NOT EXCEED THE NO RESET. 3674 02:35:27,485 --> 02:35:29,353 IF WE INCREASE THIS PERIOD TO 15 3675 02:35:29,353 --> 02:35:33,124 MINUTES YOU CAN ACTUALLY SEE THE 3676 02:35:33,124 --> 02:35:34,959 REBOUND EXCITATION GOES BACK TO 3677 02:35:34,959 --> 02:35:36,460 BASICALLY THE FIRST -- AS HIGH 3678 02:35:36,460 --> 02:35:37,895 AS THE FIRST RESPONSE BEFORE. 3679 02:35:37,895 --> 02:35:40,431 THIS IS VERY SIMILAR TO 30 3680 02:35:40,431 --> 02:35:41,232 MINUTES RESET. 3681 02:35:41,232 --> 02:35:44,235 SO BASICALLY IF WE GIVE ALPHA 3682 02:35:44,235 --> 02:35:46,103 CELL 15 MINUTE RESET TIME WE CAN 3683 02:35:46,103 --> 02:35:47,638 RESTORE ITS CAPACITY AND BRING 3684 02:35:47,638 --> 02:35:51,142 IT BACK FROM THE INACTIVATED TO 3685 02:35:51,142 --> 02:35:52,677 THE ACTIVATED STATE. 3686 02:35:52,677 --> 02:35:54,212 NOW HIGH GLUCOSE CONDITIONS IN 3687 02:35:54,212 --> 02:35:56,080 HEALTHY EYE LET WE ACTIVATE ALL 3688 02:35:56,080 --> 02:35:59,150 KINDS OF CELLS, RIGHT? 3689 02:35:59,150 --> 02:36:00,651 BETA CELL, PROBABLY DELTA CELL, 3690 02:36:00,651 --> 02:36:09,627 NEXT QUESTION WAS IS IT A 3691 02:36:09,627 --> 02:36:12,363 SPECIFIC PARACRINE SIGNAL 3692 02:36:12,363 --> 02:36:16,834 WITHOUT HIGH GLUCOSE CELLS. 3693 02:36:16,834 --> 02:36:18,169 WE USED TWO. 3694 02:36:18,169 --> 02:36:23,841 AND FOR BOTH OF THESE YOU CAN 3695 02:36:23,841 --> 02:36:25,142 SEE -- A LITTLE BLURRY, SORRY. 3696 02:36:25,142 --> 02:36:27,578 YOU CAN SEE FOR BOTH OF THEM 3697 02:36:27,578 --> 02:36:29,881 THAT IF WE USE THEM IN THE 3698 02:36:29,881 --> 02:36:33,284 PRESENCE OF LOW GLUCOSE WE CAN 3699 02:36:33,284 --> 02:36:34,485 INACTIVATE GLUCAGON SECRETION, 3700 02:36:34,485 --> 02:36:36,921 AND THIS IS ON THE RIGHT 3701 02:36:36,921 --> 02:36:39,223 NORMALIZED, YOU CAN SEE WE CAN 3702 02:36:39,223 --> 02:36:40,424 INHIBIT BY 50%. 3703 02:36:40,424 --> 02:36:43,160 IT ALSO LEADS TO REBOUND 3704 02:36:43,160 --> 02:36:44,462 EXCITATION AFTERWARDS. 3705 02:36:44,462 --> 02:36:47,431 SO BOTH OF THESE PARACRINE 3706 02:36:47,431 --> 02:36:50,268 SIGNALS ARE CAPABLE OF 3707 02:36:50,268 --> 02:36:52,470 INHIBITING THE ALPHA CELL. 3708 02:36:52,470 --> 02:36:54,772 WE CAN ALSO USE ANTAGONIST 3709 02:36:54,772 --> 02:37:01,445 AGAINST SPECIFIC SIGNALS, SO WE 3710 02:37:01,445 --> 02:37:04,081 USED ONE SPECIFICALLY AGAINST 3711 02:37:04,081 --> 02:37:05,816 THEIR 5HD 1 RESET, SPECIFIC IN 3712 02:37:05,816 --> 02:37:09,854 ALPHA CELLS, IF WE GIVE THIS 3713 02:37:09,854 --> 02:37:11,422 RECEPTOR ANTAGONIST UNDER LOW 3714 02:37:11,422 --> 02:37:12,923 GLUCOSE CONDITIONS WE CAN DOUBLE 3715 02:37:12,923 --> 02:37:14,792 GLUCAGON SECRETION WHICH SHOWS 3716 02:37:14,792 --> 02:37:17,094 US THAT THESE CELLS ARE ACTUALLY 3717 02:37:17,094 --> 02:37:18,396 INHIBITED EVEN IN THE LOW 3718 02:37:18,396 --> 02:37:19,930 GLUCOSE CONDITIONS, MAYBE JUST A 3719 02:37:19,930 --> 02:37:21,465 SUBSET OF THEM IS INHIBITED. 3720 02:37:21,465 --> 02:37:25,202 WHAT YOU CAN ALSO SEE IS THAT 3721 02:37:25,202 --> 02:37:27,071 THEY CAN STILL BE INHIBITED 3722 02:37:27,071 --> 02:37:28,706 UNDER HIGH GLUCOSE, PROBABLY NOT 3723 02:37:28,706 --> 02:37:31,943 ONE OF THESE SIGNALS, PROBABLY 3724 02:37:31,943 --> 02:37:33,644 THE NETWORK OF ALL OF THEM THAT 3725 02:37:33,644 --> 02:37:35,713 WORKS TOGETHER ON THE ALPHA CELL 3726 02:37:35,713 --> 02:37:42,620 TO BRING IT BACK TO ITS STATE. 3727 02:37:42,620 --> 02:37:45,489 NOW, DOES CAN WE ACTUALLY 3728 02:37:45,489 --> 02:37:54,031 RECOVER GLUCAGON SECRETION BY 3729 02:37:54,031 --> 02:37:56,000 REACTIVE WAITING PATHWAYS. 3730 02:37:56,000 --> 02:37:57,868 YOU CAN SEE GLUCAGON SECRETION 3731 02:37:57,868 --> 02:38:01,806 IS DEFECTIVE IN DONORS WITH TYPE 3732 02:38:01,806 --> 02:38:06,644 1 DIABETES. 3733 02:38:06,644 --> 02:38:08,512 NEXT, CONTINUES EXACTLY -- AFTER 3734 02:38:08,512 --> 02:38:11,816 THE 120 MINUTES, SO WE JUST 3735 02:38:11,816 --> 02:38:16,721 CONTINUE WITH THE TRACE, AND 3736 02:38:16,721 --> 02:38:18,055 EDIT SEROTONIN OR SOMATOSTATIN 3737 02:38:18,055 --> 02:38:20,124 TO THE CELLS, Y-AXIS IS TEN-FOLD 3738 02:38:20,124 --> 02:38:23,194 HIGHER, WE GET THIS HUGE 3739 02:38:23,194 --> 02:38:25,830 RESPONSE WHILE THEY ARE IN 3740 02:38:25,830 --> 02:38:27,231 SEROTONIN OR SOMATOSTATIN, EVEN 3741 02:38:27,231 --> 02:38:29,200 AFTERWARDS WHEN THE SIGNALS ARE 3742 02:38:29,200 --> 02:38:38,509 GONE WE HAVE SIGNIFICANTLY 3743 02:38:38,509 --> 02:38:40,044 INCREASED GLUCAGON SECRETION. 3744 02:38:40,044 --> 02:38:41,379 THEY ARE SUPPOSED TO INHIBIT 3745 02:38:41,379 --> 02:38:44,115 ALPHA CELL BUT WE GET THIS HUGE 3746 02:38:44,115 --> 02:38:44,382 RECOVERY. 3747 02:38:44,382 --> 02:38:48,285 SO WE THINK THE ANSWER TO THIS 3748 02:38:48,285 --> 02:38:53,524 ARE THE G-PROTEIN GATED 3749 02:38:53,524 --> 02:38:54,825 RECTIFYING POTASSIUM CHANNELS, 3750 02:38:54,825 --> 02:38:57,695 THE SO ACTIVATE OF THESE 3751 02:38:57,695 --> 02:39:05,803 CHANNELS LEADS TO DECREASED 3752 02:39:05,803 --> 02:39:14,545 ALPHA CELL EXCITABILITY AND 3753 02:39:14,545 --> 02:39:15,646 GLUCAGON INHIBITION. 3754 02:39:15,646 --> 02:39:17,381 THESE CHANNELS ARE PRESENT IN 3755 02:39:17,381 --> 02:39:18,682 HUMAN ISLETS. 3756 02:39:18,682 --> 02:39:21,986 AND ESPECIALLY PRESENT IN HUMAN 3757 02:39:21,986 --> 02:39:27,925 ALPHA CELL, BOTH GIRK 1 AND 2. 3758 02:39:27,925 --> 02:39:31,095 WHAT HAPPENS IF WE ACTIVATE OR 3759 02:39:31,095 --> 02:39:35,366 BLOCK? 3760 02:39:35,366 --> 02:39:44,742 AGAIN YOU SEE TYPICAL PROFILE. 3761 02:39:44,742 --> 02:39:51,682 NOW WE USE A BLOCKER, TERTIAPIN, 3762 02:39:51,682 --> 02:39:55,052 AND AN ACTIVATOR OF THIS. 3763 02:39:55,052 --> 02:39:57,021 SO WE ADDED DRUG UNDER BASELINE 3764 02:39:57,021 --> 02:40:01,192 CONDITIONS, LEFT IT THERE EVEN 3765 02:40:01,192 --> 02:40:02,893 UNDER HIGH GLUCOSE CONDITIONS. 3766 02:40:02,893 --> 02:40:04,895 THE CHANNEL BLOCKER LEADS TO A 3767 02:40:04,895 --> 02:40:06,931 DOUBLING OF GLUCAGON SECRETION 3768 02:40:06,931 --> 02:40:08,299 UNDER BASELINE CONDITIONS, YOU 3769 02:40:08,299 --> 02:40:11,135 CAN SEE NO MORE INHIBITION UNDER 3770 02:40:11,135 --> 02:40:13,204 HIGH GLUCOSE, EVEN AFTERWARDS 3771 02:40:13,204 --> 02:40:16,040 LEADS TO INCREASED GLUCAGON 3772 02:40:16,040 --> 02:40:16,507 SECRETION. 3773 02:40:16,507 --> 02:40:18,142 ACTIVATOR OF THE CHANNELS LEADS 3774 02:40:18,142 --> 02:40:19,743 TO COMPLETE BLOCKAGE OF GLUCAGON 3775 02:40:19,743 --> 02:40:22,079 CON SECRETION, SO IT IS 3776 02:40:22,079 --> 02:40:23,647 INHIBITED TO LEVELS ALMOST 3777 02:40:23,647 --> 02:40:25,816 UNDETECTABLE SO WE CAN ALMOST 3778 02:40:25,816 --> 02:40:27,451 COMPLETELY BLOCK GLUCAGON 3779 02:40:27,451 --> 02:40:27,785 SECRETION. 3780 02:40:27,785 --> 02:40:29,253 THERE'S NO DIFFERENCE IN INSULIN 3781 02:40:29,253 --> 02:40:33,724 SECRETION USING EITHER OF THESE, 3782 02:40:33,724 --> 02:40:36,227 ACTIVATOR OR CHANNEL BLOCKER. 3783 02:40:36,227 --> 02:40:37,428 SECONDLY WANTED TO KNOW WHETHER 3784 02:40:37,428 --> 02:40:38,896 WEIR WEEK RECOVER GLUCAGON CON 3785 02:40:38,896 --> 02:40:41,899 SECRETION AFTER IN THE ACTIVATED 3786 02:40:41,899 --> 02:40:50,207 STATE, IF WE ADD TERTIAPIN-Q WE 3787 02:40:50,207 --> 02:40:57,948 CAN RECOVER OVER THOUGH AT ITS 3788 02:40:57,948 --> 02:41:00,384 LOWEST POINT. 3789 02:41:00,384 --> 02:41:02,453 USING ACTIVATOR CAN FURTHER DO 3790 02:41:02,453 --> 02:41:05,956 THIS, ALREADY AT THE LOW POINT 3791 02:41:05,956 --> 02:41:06,924 OF 20 MINUTES. 3792 02:41:06,924 --> 02:41:08,125 LAST THING WANTED TO CHECK 3793 02:41:08,125 --> 02:41:10,995 WHETHER THIS IS SPECIFIC EFFECT 3794 02:41:10,995 --> 02:41:14,298 ON SOMATOSTATIN AND SEROTONIN SO 3795 02:41:14,298 --> 02:41:18,569 WE ADDED THIS DRUG IN THE 3796 02:41:18,569 --> 02:41:22,873 PRESENCE OF SOMATOSTATIN OR 3797 02:41:22,873 --> 02:41:26,477 SEROTONIN, YOU CAN SEE 3798 02:41:26,477 --> 02:41:28,012 SOMATOSTATIN UNDER LOW GLUCOSE 3799 02:41:28,012 --> 02:41:32,283 CONDITIONS, IF WE ADD THIS BEE 3800 02:41:32,283 --> 02:41:34,685 TOXIN INCREASE SECRETION AND 3801 02:41:34,685 --> 02:41:35,553 THERE'S NO INHIBITION WITH 3802 02:41:35,553 --> 02:41:38,389 SOMATOSTATIN SO WE CAN BLOCK 3803 02:41:38,389 --> 02:41:39,723 THIS EFFECT ALMOST ENTIRELY SO 3804 02:41:39,723 --> 02:41:41,692 HERE I'M SHOWING THE 3805 02:41:41,692 --> 02:41:42,993 NORMALIZATION, YOU CAN SEE 3806 02:41:42,993 --> 02:41:44,862 SOMATOSTATIN ITSELF IS CAPABLE 3807 02:41:44,862 --> 02:41:53,904 OF INHIBITING GLUCAGON SECRETION 3808 02:41:53,904 --> 02:41:59,310 BY 75%, COMPLETELY GONE WITH BY 3809 02:41:59,310 --> 02:42:00,344 BLOCKING GIRK CHANNELS. 3810 02:42:00,344 --> 02:42:06,083 THE AREA UNDER THE CURVE IS 3811 02:42:06,083 --> 02:42:10,020 SIGNIFICANTLY DIFFERENT. 3812 02:42:10,020 --> 02:42:11,689 SEROTONIN IS CAPABLE OF 3813 02:42:11,689 --> 02:42:16,493 INHIBITING GLUCAGON SECRETION, 3814 02:42:16,493 --> 02:42:22,967 LESS IF WE BLOCK THE GIRK 3815 02:42:22,967 --> 02:42:23,734 CHANNELS. 3816 02:42:23,734 --> 02:42:27,037 40% STILL THERE THROUGH 3817 02:42:27,037 --> 02:42:30,307 SEROTONIN, SIGNIFICANTLY BLOCKED 3818 02:42:30,307 --> 02:42:34,478 BY BLOCKING THE GIRK 3819 02:42:34,478 --> 02:42:34,778 CHANNELINGS. 3820 02:42:34,778 --> 02:42:35,679 FUTURE PROSPECTIVE WE WANT TO 3821 02:42:35,679 --> 02:42:39,183 TEST IN VIVO, HOWEVER WE HAVE TO 3822 02:42:39,183 --> 02:42:40,484 FACE MAJOR CHALLENGES BECAUSE SO 3823 02:42:40,484 --> 02:42:43,454 FAR ALL THE DATA THAT'S OUT 3824 02:42:43,454 --> 02:42:45,089 THERE THAT IS LOOKING AT THE 3825 02:42:45,089 --> 02:42:46,824 GIRK CHANNELS IN MICE DOESN'T 3826 02:42:46,824 --> 02:42:48,826 REFLECT WHAT WE SEE IN HUMAN, 3827 02:42:48,826 --> 02:42:49,927 MIGHT BE DIFFERENTLY EXPRESSED 3828 02:42:49,927 --> 02:42:51,895 IN ALPHA CELLS SO THE WAY TO GO 3829 02:42:51,895 --> 02:42:53,964 FOR US WOULD BE TO TRANSPLANT 3830 02:42:53,964 --> 02:42:58,502 HUMAN ISLETS INTO MICE AND USE 3831 02:42:58,502 --> 02:43:02,740 DIFFERENT MODEL SYSTEMS, FOR 3832 02:43:02,740 --> 02:43:05,142 EXAMPLE, STZ MOUSE, THE MODEL, 3833 02:43:05,142 --> 02:43:09,880 OR LOOK AT NOD MODEL, ULTIMATE 3834 02:43:09,880 --> 02:43:11,815 GOAL TO FIND FDA-APPROVED DRUGS 3835 02:43:11,815 --> 02:43:13,584 LIKE FOR THE GLUTAMATE STORY AND 3836 02:43:13,584 --> 02:43:16,020 REPURPOSE THOSE SO WE CAN USE 3837 02:43:16,020 --> 02:43:18,288 THEM ON TISSUES FROM TYPE 1 3838 02:43:18,288 --> 02:43:22,760 DIABETIC DONORS AND HOPEFULLY WE 3839 02:43:22,760 --> 02:43:24,728 CAN SEE IMPROVEMENT AND RECOVER 3840 02:43:24,728 --> 02:43:26,630 GLUCAGON SECRETION, WE HAVE TO 3841 02:43:26,630 --> 02:43:30,367 FACE CHALLENGES OF SPECIFICITY 3842 02:43:30,367 --> 02:43:32,636 AND ALSO AVAILABILITY OF HUMAN 3843 02:43:32,636 --> 02:43:33,170 DONOR ORGANS. 3844 02:43:33,170 --> 02:43:36,140 WITH THIS I WOULD LIKE TO 3845 02:43:36,140 --> 02:43:38,075 ACKNOWLEDGE MY CURRENT LAB, MY 3846 02:43:38,075 --> 02:43:39,176 FORMER MENTOR WHO I STILL 3847 02:43:39,176 --> 02:43:43,013 COLLABORATE WITH A LOT, THE 3848 02:43:43,013 --> 02:43:44,782 WHOLE TEAM IN GAINESVILLE, 3849 02:43:44,782 --> 02:43:47,084 FUNDING AGENCIES, OF COURSE 3850 02:43:47,084 --> 02:43:47,518 DONORS AND FAMILIES. 3851 02:43:47,518 --> 02:43:51,121 [APPLAUSE] 3852 02:43:51,121 --> 02:43:55,726 3853 02:43:55,726 --> 02:44:00,664 3854 02:44:00,664 --> 02:44:03,600 >> THANK YOU, RIGHT ON TIME SO 3855 02:44:03,600 --> 02:44:07,404 WE HAVE A FINAL SPEAKER, MY OWN 3856 02:44:07,404 --> 02:44:12,576 LAB WORKS ON THIS, SO IT'S GREAT 3857 02:44:12,576 --> 02:44:15,179 TO HAVE PROFESSOR GARCIA-OCANA, 3858 02:44:15,179 --> 02:44:25,723 CHAIR OF DEPARTMENT OF MOLECULAR 3859 02:44:29,059 --> 02:44:30,127 AND CELLULAR ENDOCRINOLOGY, 3860 02:44:30,127 --> 02:44:30,861 RIGGS CENTER. 3861 02:44:30,861 --> 02:44:41,305 >> CAN I USE THE MOUSE? 3862 02:44:45,375 --> 02:44:55,352 3863 02:44:56,687 --> 02:44:59,556 >> FIRST LET ME START BY THANK 3864 02:44:59,556 --> 02:45:02,292 YOU FOR YOUR KIND INTRODUCTION, 3865 02:45:02,292 --> 02:45:06,330 CONGRATULATIONS TO THE HUMAN 3866 02:45:06,330 --> 02:45:07,464 ISLET RESEARCH NETWORK. 3867 02:45:07,464 --> 02:45:15,405 AND THANK YOU TO THE ORGANIZERS 3868 02:45:15,405 --> 02:45:17,608 TO GIVE A TALK, THANK YOU FOR 3869 02:45:17,608 --> 02:45:18,475 THAT. 3870 02:45:18,475 --> 02:45:21,845 AND THANK YOU ALSO FOR 3871 02:45:21,845 --> 02:45:24,848 OPPORTUNITY TO TALK ABOUT OUR 3872 02:45:24,848 --> 02:45:26,150 LATEST STUDIES ON DYRK1A 3873 02:45:26,150 --> 02:45:36,326 INHIBITORS, HOW THEY CAN BE USED 3874 02:45:36,326 --> 02:45:38,328 IN TYPE 1 DIABETES IN THE 3875 02:45:38,328 --> 02:45:39,129 FUTURE. 3876 02:45:39,129 --> 02:45:44,768 I'M GOING TO STATE THE OBVIOUS. 3877 02:45:44,768 --> 02:45:47,938 THAT IS ACTUALLY THAT DIABETES 3878 02:45:47,938 --> 02:45:49,907 RESULTS FROM INSUFFICIENT AMOUNT 3879 02:45:49,907 --> 02:45:59,516 OF BETA CELLS, IN TYPE 1 3880 02:45:59,516 --> 02:46:09,927 DIABETES, LEADING TO OR 3881 02:46:10,327 --> 02:46:16,500 TRIGGERING AUTOIMMUNE RESPONSE. 3882 02:46:16,500 --> 02:46:26,810 HOLD ON A SECOND. 3883 02:46:29,146 --> 02:46:33,116 THANK YOU. 3884 02:46:33,116 --> 02:46:36,186 SO INCREASING EXTRINSIC AND 3885 02:46:36,186 --> 02:46:39,022 INTRINSIC, LEADING TO BETA CELL 3886 02:46:39,022 --> 02:46:41,758 DEATH, CELL DEMISE, INSULIN 3887 02:46:41,758 --> 02:46:44,828 DEFICIENCY. 3888 02:46:44,828 --> 02:46:51,935 IT'S IMPORTANT, THESE ARE 3889 02:46:51,935 --> 02:46:53,704 STUDIES, DIABETIC PATIENTS MOST 3890 02:46:53,704 --> 02:46:55,873 STILL HAVE BETA CELLS IN THERE. 3891 02:46:55,873 --> 02:46:58,308 WE'RE THINKING TO STUDIES TO 3892 02:46:58,308 --> 02:47:01,478 TREAT TYPE 1 DIABETES, WE THINK 3893 02:47:01,478 --> 02:47:04,448 ABOUT MAYBE ONE MORE WE HEARD 3894 02:47:04,448 --> 02:47:08,051 JULIA TALKING ABOUT. 3895 02:47:08,051 --> 02:47:12,890 BUT INCREASED POTENTIAL USING 3896 02:47:12,890 --> 02:47:13,423 BETA CELL REPLACEMENT. 3897 02:47:13,423 --> 02:47:17,160 MORE THINGS ON THE MENU, THE 3898 02:47:17,160 --> 02:47:17,461 BETTER. 3899 02:47:17,461 --> 02:47:21,965 ALSO TO PROTECT THOSE THAT WE'RE 3900 02:47:21,965 --> 02:47:23,166 GENERATING, DEFINITELY TO 3901 02:47:23,166 --> 02:47:25,002 RECOVER AND MAINTAIN THE BETA 3902 02:47:25,002 --> 02:47:26,870 CELL FUNCTION IN THERAPY THAT'S 3903 02:47:26,870 --> 02:47:33,010 PRESENT IN THOSE BETA CELLS, AND 3904 02:47:33,010 --> 02:47:37,047 WE HAVE AUTOIMMUNITY TO SILENCE 3905 02:47:37,047 --> 02:47:41,318 AUTOIMMUNITY, ENHANCE TOLERANCE. 3906 02:47:41,318 --> 02:47:43,053 HOW CAN WE -- THERE ARE MULTIPLE 3907 02:47:43,053 --> 02:47:44,588 WAYS THAT HAVE BEEN REPORTED 3908 02:47:44,588 --> 02:47:47,891 OVER THE YEARS THAT COULD BE 3909 02:47:47,891 --> 02:47:50,961 USEFUL TO ENHANCE BETA CELL MASS 3910 02:47:50,961 --> 02:47:52,829 AND STRONG WORK, GREAT WORK 3911 02:47:52,829 --> 02:47:57,100 BEING LEARNED ON HOW TO CONVERT 3912 02:47:57,100 --> 02:48:00,804 STEM CELLS. 3913 02:48:00,804 --> 02:48:02,739 WORK TO COMPARE ALPHA CELLS INTO 3914 02:48:02,739 --> 02:48:10,547 FOR EXAMPLE BETA CELLS, HOW TO 3915 02:48:10,547 --> 02:48:15,352 CONVERT, THINKING ABOUT HOW TO 3916 02:48:15,352 --> 02:48:16,219 CONVERT. 3917 02:48:16,219 --> 02:48:20,057 WE HAVE BEEN WORKING HOW TO 3918 02:48:20,057 --> 02:48:20,924 ENHANCE REPUTATION OF PERSISTING 3919 02:48:20,924 --> 02:48:25,429 BETA CELLS WITH IDEA OF 3920 02:48:25,429 --> 02:48:26,496 EXPANDING PARTICULAR PRESENT IN 3921 02:48:26,496 --> 02:48:29,800 THE PANCREAS. 3922 02:48:29,800 --> 02:48:30,701 IT'S BEEN CHALLENGING. 3923 02:48:30,701 --> 02:48:32,869 AND IN THE BREAKOUT ROOMS THAT 3924 02:48:32,869 --> 02:48:36,606 WE HAD, WE WERE TALKING ABOUT 3925 02:48:36,606 --> 02:48:40,210 THE DIFFERENCE BETWEEN MOUSE AND 3926 02:48:40,210 --> 02:48:42,613 HUMAN, WORKING ON AGENTS THAT 3927 02:48:42,613 --> 02:48:44,715 COULD INCREASE PROLIFERATION, 3928 02:48:44,715 --> 02:48:47,217 THAT THEY FAIL OR INDUCE MILD 3929 02:48:47,217 --> 02:48:51,054 EFFECTS ON HUMAN BETA CELLS. 3930 02:48:51,054 --> 02:48:53,023 AND WE RECENTLY LEARNED IN THE 3931 02:48:53,023 --> 02:48:55,125 LAST TEN YEARS THAT ACTUALLY 3932 02:48:55,125 --> 02:49:05,669 BETA CELLS, HUMAN BETA CELLS ARE 3933 02:49:06,536 --> 02:49:07,904 RECALCITRANT TO PREFERRATION, 3934 02:49:07,904 --> 02:49:09,973 DECLINES IN CHILDHOOD GOING TO 3935 02:49:09,973 --> 02:49:10,774 ADOLESCENCE WHERE PROLIFERATION 3936 02:49:10,774 --> 02:49:13,577 IS LOW AND IN ADULTS VERY LOW. 3937 02:49:13,577 --> 02:49:15,679 SO IT'S CHALLENGING TO FIND 3938 02:49:15,679 --> 02:49:18,382 AGENTS THAT CAN INCREASE 3939 02:49:18,382 --> 02:49:19,049 PROLIFERATION OF HUMAN BETA 3940 02:49:19,049 --> 02:49:21,585 CELLS IN VITRO AND OF COURSE 3941 02:49:21,585 --> 02:49:25,522 EVEN MORE IN VIVO. 3942 02:49:25,522 --> 02:49:29,693 THAT WAS THE CASE UNTIL 2015 IN 3943 02:49:29,693 --> 02:49:30,761 WHICH ACTUALLY THE STEWART WITH 3944 02:49:30,761 --> 02:49:35,132 THE SCOTT GROUP AND MY OWN 3945 02:49:35,132 --> 02:49:39,736 GROUP, ACTUALLY WE FOUND HUGE 3946 02:49:39,736 --> 02:49:42,005 WORK DONE BY THE LEADER OF THE 3947 02:49:42,005 --> 02:49:43,440 STUDY THROUGH HUNDREDS OF 3948 02:49:43,440 --> 02:49:44,975 THOUSANDS OF COMPOUNDS WERE ABLE 3949 02:49:44,975 --> 02:49:51,248 TO FIND A FEW THAT COULD 3950 02:49:51,248 --> 02:49:52,983 ACTUALLY ENHANCE EXPRESSION IN 3951 02:49:52,983 --> 02:49:55,018 BETA CELLS AND THOSE COMPOUNDS 3952 02:49:55,018 --> 02:49:57,487 IN PARTICULAR COMPOUND 1 WERE 3953 02:49:57,487 --> 02:49:58,789 ABLE TO INCREASE PROLIFERATION 3954 02:49:58,789 --> 02:50:03,427 OF HUMAN BETA CELLS IN ISLETS IN 3955 02:50:03,427 --> 02:50:04,628 RATS. 3956 02:50:04,628 --> 02:50:06,363 THAT WAS NOT THE GOAL. 3957 02:50:06,363 --> 02:50:09,666 THE GOAL WAS TO ENHANCE HUMAN 3958 02:50:09,666 --> 02:50:11,735 BETA PROLIFERATION, SO WHEN THEY 3959 02:50:11,735 --> 02:50:13,370 TESTED DIFFERENT COMPOUNDS, IN 3960 02:50:13,370 --> 02:50:15,138 PARTICULARLY COMPOUND NUMBER ONE 3961 02:50:15,138 --> 02:50:17,340 FOUND THERE WAS INCREASING 3962 02:50:17,340 --> 02:50:18,008 PROLIFERATION SIMILAR TO WHAT I 3963 02:50:18,008 --> 02:50:21,144 JUST SHOWED IN TERMS OF 3964 02:50:21,144 --> 02:50:24,648 PROLIFERATION IN HUMANS. 3965 02:50:24,648 --> 02:50:29,686 AND THIS COMPOUND NUMBER 1 WAS 3966 02:50:29,686 --> 02:50:33,490 HARMINE, GOLD STANDARD IN 3967 02:50:33,490 --> 02:50:35,692 INDUCING PROLIFERATION, USED 3968 02:50:35,692 --> 02:50:38,328 WITH MANY COMBINATIONS TO 3969 02:50:38,328 --> 02:50:40,197 ENHANCE PROLIFERATION, MORE 3970 02:50:40,197 --> 02:50:48,305 RECENTLY FUNCTION AND SURVIVAL 3971 02:50:48,305 --> 02:50:49,272 OF THE CELLS. 3972 02:50:49,272 --> 02:50:55,712 PRESENT IN SOME PLANTS AROUND 3973 02:50:55,712 --> 02:51:02,853 THE WORLD, AND BECOMING THAT, 3974 02:51:02,853 --> 02:51:13,263 MECHANISM WORKS THROUGH 3975 02:51:16,900 --> 02:51:17,734 INCUBATION, PHOSPHORYLATION 3976 02:51:17,734 --> 02:51:18,068 KINASE. 3977 02:51:18,068 --> 02:51:23,740 NOW IN FACT CAN GO. 3978 02:51:23,740 --> 02:51:25,275 THAT HAPPENS BECAUSE OF THE 3979 02:51:25,275 --> 02:51:29,679 FIRST THAT ELIMINATES THAT 3980 02:51:29,679 --> 02:51:32,949 PHOSPHATE, INCREASES PRESENCE OF 3981 02:51:32,949 --> 02:51:34,518 NFAT INTO THE NUCLEUS. 3982 02:51:34,518 --> 02:51:37,120 IN HUMAN BETA CELLS WE FIND AS 3983 02:51:37,120 --> 02:51:42,259 WELL IN VIVO ACTUALLY INDUCTION 3984 02:51:42,259 --> 02:51:44,427 OF HARMINE COULD INDUCE 3985 02:51:44,427 --> 02:51:52,002 PROLIFERATION IN HUMAN BETA 3986 02:51:52,002 --> 02:51:54,237 CELLS. 3987 02:51:54,237 --> 02:51:55,705 THE FOLLOWING PUBLICATION IN 3988 02:51:55,705 --> 02:51:57,807 2020 FROM A GROUP IN 3989 02:51:57,807 --> 02:51:58,909 COLLABORATION WITH GROUPS IN 3990 02:51:58,909 --> 02:52:01,545 MOUNT SINAI, WHEN I WAS OVER 3991 02:52:01,545 --> 02:52:01,745 THERE. 3992 02:52:01,745 --> 02:52:10,487 THAT CAME OUT ACTUALLY STEM FROM 3993 02:52:10,487 --> 02:52:12,589 THE FOLLOWING THOUGHT THAT 3994 02:52:12,589 --> 02:52:15,859 INHIBIT 1A, NOW PRESENT IN 3995 02:52:15,859 --> 02:52:17,093 CYTOPLASM, PHOSPHORYLATED, HOW 3996 02:52:17,093 --> 02:52:19,196 CAN YOU ENHANCE ACTIVITY SO YOU 3997 02:52:19,196 --> 02:52:25,535 CAN SEND MORE IN FACT TO THE 3998 02:52:25,535 --> 02:52:26,970 NUCLEUS, TO ENHANCE 3999 02:52:26,970 --> 02:52:29,706 PROLIFERATION OF BETA CELLS. 4000 02:52:29,706 --> 02:52:31,808 AND THIS GROUP TESTED MANY 4001 02:52:31,808 --> 02:52:34,878 COMPOUNDS THAT COULD ACTUALLY 4002 02:52:34,878 --> 02:52:42,219 ENHANCE AND FLUX INTO THE CELL, 4003 02:52:42,219 --> 02:52:44,187 THEY FOUND ACTUALLY SOME IN 4004 02:52:44,187 --> 02:52:51,161 PARTICULAR WAS COULD INCREASE 4005 02:52:51,161 --> 02:52:53,063 CALCIUM, SO WHAT THEY FOUND IN 4006 02:52:53,063 --> 02:52:57,200 THIS PAPER IS THAT WHEN THEY 4007 02:52:57,200 --> 02:53:07,744 COMBINE GLP-1 THAT HAS NO EFFECT 4008 02:53:08,245 --> 02:53:09,713 WITH HARMINE, NOW ENHANCED. 4009 02:53:09,713 --> 02:53:12,349 IMPORTANT POINT ACTUALLY. 4010 02:53:12,349 --> 02:53:15,885 IT ALLOWS NOW TO HUGE LOWER DOSE 4011 02:53:15,885 --> 02:53:18,622 OF HARMINE IN COMBINATION WITH 4012 02:53:18,622 --> 02:53:21,358 WOULD PRODUCE SAME EFFECT AS 4013 02:53:21,358 --> 02:53:25,295 HIGHER DOSES OF HARMINE, YOU CAN 4014 02:53:25,295 --> 02:53:32,202 LOWER THOSE OF A DRUG GENERALLY, 4015 02:53:32,202 --> 02:53:34,604 TO LOWER LEVEL, SECONDLY NOW YOU 4016 02:53:34,604 --> 02:53:37,674 CAN HAVE SYNERGISTIC EFFECT IN 4017 02:53:37,674 --> 02:53:42,045 DOSE THAT HAVE GLP 1 RECEPTORS, 4018 02:53:42,045 --> 02:53:46,016 BETTER WAY TO FIND BY CHALLENGE 4019 02:53:46,016 --> 02:53:49,686 OR BY I THINK THAT ACTUALLY THE 4020 02:53:49,686 --> 02:53:50,787 COMBINATION ENHANCE WITH 4021 02:53:50,787 --> 02:53:55,959 SPECIFICITY AND POTENCY OF A 4022 02:53:55,959 --> 02:53:57,694 DRUG SPECIFICALLY FOR BETA 4023 02:53:57,694 --> 02:53:58,228 CELLS. 4024 02:53:58,228 --> 02:54:05,969 IMPORTANT POINT IN THIS PAPER 4025 02:54:05,969 --> 02:54:11,741 WAS THAT CELLS WERE RESPONDING 4026 02:54:11,741 --> 02:54:14,844 TO COMBINATION, TYPE 2 DIABETES, 4027 02:54:14,844 --> 02:54:19,449 DIABETIC CELLS WERE ABLE TO 4028 02:54:19,449 --> 02:54:21,051 RESPOND, INCREASING 4029 02:54:21,051 --> 02:54:23,620 PROLIFERATION, SO NOT ONLY 4030 02:54:23,620 --> 02:54:25,588 NON-DIABETIC BUT ALSO DIABETIC 4031 02:54:25,588 --> 02:54:26,890 CELLS WERE RESPONSIVE. 4032 02:54:26,890 --> 02:54:32,028 SO WE HAVE THE STUDY, THERE WAS 4033 02:54:32,028 --> 02:54:35,965 ALWAYS THIS -- I WOULD SAY 4034 02:54:35,965 --> 02:54:37,233 CONCERN OR COMMENT, ACTUALLY, 4035 02:54:37,233 --> 02:54:39,803 FROM REVIEWERS OF THE PAPER 4036 02:54:39,803 --> 02:54:45,175 SAYING THIS IS FANTASTIC, 4037 02:54:45,175 --> 02:54:46,609 BEAUTIFUL STAINING, SHOW ME THE 4038 02:54:46,609 --> 02:54:49,179 MONEY THAT I CAN INCREASE THE 4039 02:54:49,179 --> 02:54:55,852 ACTUAL HUMAN BETA CELL NUMBER IN 4040 02:54:55,852 --> 02:54:57,687 VIVO IN SITUATIONS BASED ON 4041 02:54:57,687 --> 02:54:57,954 POSITIONS. 4042 02:54:57,954 --> 02:55:03,159 IT TOOK US A FEW YEARS ACTUALLY 4043 02:55:03,159 --> 02:55:05,895 THE WORK BY COSTELOT, AND MANY 4044 02:55:05,895 --> 02:55:07,664 OTHERS AT MOUNT SINAI IN CAB 4045 02:55:07,664 --> 02:55:16,306 LAYINGS WITH STANLEY, AN EXPERT 4046 02:55:16,306 --> 02:55:23,747 IN NEUROENDOCRINOLOGY AND 4047 02:55:23,747 --> 02:55:28,885 NEUROIMAGING, APPLY TECHNIQUE 3D 4048 02:55:28,885 --> 02:55:32,055 IMAGING OF IMMUNOLABEL SOLVENT 4049 02:55:32,055 --> 02:55:38,395 HERE, TO ACTUALLY USE THAT 4050 02:55:38,395 --> 02:55:39,496 TECHNIQUE FOR STAINING HUMAN 4051 02:55:39,496 --> 02:55:43,099 ALLOGRAFT TO SEE IN 3D AND 4052 02:55:43,099 --> 02:55:45,201 CALCULATE VOLUME OF SPECIFIC 4053 02:55:45,201 --> 02:55:47,303 HUMAN ALLOGRAFTS TRANSPLANTED 4054 02:55:47,303 --> 02:55:47,937 INTO MICE. 4055 02:55:47,937 --> 02:55:50,774 WITH MICE FOR SEVERAL DAYS WITH 4056 02:55:50,774 --> 02:55:51,975 DIFFERENT DRUGS COULD TAKE THOSE 4057 02:55:51,975 --> 02:55:58,481 AND MEASURE THE VOLUME AND SEE 4058 02:55:58,481 --> 02:56:00,650 WHERE ACTIVE TREATMENTS IN THE 4059 02:56:00,650 --> 02:56:01,718 VOLUME OF BETA CELLS THAT WOULD 4060 02:56:01,718 --> 02:56:04,788 TELL US THE NUMBER OF CELLS IS 4061 02:56:04,788 --> 02:56:08,858 INCREASING AFTER TREATMENT IN 4062 02:56:08,858 --> 02:56:19,102 THIS CASE WITH HARMINE. 4063 02:56:19,102 --> 02:56:21,137 TRANSLATED HUMAN ISLETS, 4064 02:56:21,137 --> 02:56:28,978 EXPERIMENT IN DIABETIC MICE, WE 4065 02:56:28,978 --> 02:56:30,380 TREAT THEM WITH HARMINE, LOWER 4066 02:56:30,380 --> 02:56:34,451 DOSES BECAUSE AS I MENTIONED 4067 02:56:34,451 --> 02:56:38,721 BEFORE THE COMBINATION 4068 02:56:38,721 --> 02:56:40,457 SYNERGISTIC, AND TREAT MICE FOR 4069 02:56:40,457 --> 02:56:43,293 FOUR WEEKS, EIGHT WEEKS, OR 4070 02:56:43,293 --> 02:56:48,898 TWELVE WEEKS ACTUALLY. 4071 02:56:48,898 --> 02:56:50,533 AND FOLLOWING AFTER THOSE, 4072 02:56:50,533 --> 02:56:55,472 HARVEST THE GRAFT ACTUALLY IN 4073 02:56:55,472 --> 02:56:56,439 BOTH AND PERFORM 4074 02:56:56,439 --> 02:56:57,407 IMMUNOHISTOCHEMISTRY TO MEASURE 4075 02:56:57,407 --> 02:56:59,742 THE VOLUME OF THE HUMAN ISLET 4076 02:56:59,742 --> 02:57:01,711 AFTER TREATMENT FOR THREE MONTHS 4077 02:57:01,711 --> 02:57:05,982 WITH THE COMBINATION OF DRUGS. 4078 02:57:05,982 --> 02:57:16,392 WE FOUND IT WAS MARKEDLY 4079 02:57:16,793 --> 02:57:20,263 INCREASED, SO YOU CAN SEE HERE 4080 02:57:20,263 --> 02:57:22,899 THAT INCREASE IN HUMAN BETA CELL 4081 02:57:22,899 --> 02:57:32,208 VOLUME IN THREE MONTHS, 4082 02:57:32,208 --> 02:57:33,643 EXTENDING FOR TREATED MICE. 4083 02:57:33,643 --> 02:57:40,316 AND WE SHOW A MILD INCREASE, NOT 4084 02:57:40,316 --> 02:57:41,851 SIGNIFICANT, WITH HARMINE ALONE 4085 02:57:41,851 --> 02:57:43,953 BECAUSE WE USED A LOWER DOSE, IN 4086 02:57:43,953 --> 02:57:45,154 PART. 4087 02:57:45,154 --> 02:57:54,764 IMPORTANTLY WE DIDN'T SEE 4088 02:57:54,764 --> 02:57:57,500 INCREASE IN THE VOLUME. 4089 02:57:57,500 --> 02:58:01,004 MORE STUDIES DONE, THAT PAPER, 4090 02:58:01,004 --> 02:58:06,042 MANY DIFFERENT TIME POINTS. 4091 02:58:06,042 --> 02:58:07,010 STOPPING TREATMENT AFTER THREE 4092 02:58:07,010 --> 02:58:09,612 MONTHS, SEE WHAT WAS THE RESULT, 4093 02:58:09,612 --> 02:58:10,947 MANY ASPECTS THERE. 4094 02:58:10,947 --> 02:58:15,151 I DON'T WANT TO GO INTO THOSE 4095 02:58:15,151 --> 02:58:18,721 BUT I WILL TELL YOU A MECHANISM 4096 02:58:18,721 --> 02:58:20,990 BEHIND ALL OF THAT, YOU ARE 4097 02:58:20,990 --> 02:58:22,559 THINKING PROBABLY JUST ABOUT 4098 02:58:22,559 --> 02:58:23,226 ENHANCING BETA CELL 4099 02:58:23,226 --> 02:58:31,734 PROLIFERATION BUT I CAN TELL YOU 4100 02:58:31,734 --> 02:58:32,936 THERE'S MORE. 4101 02:58:32,936 --> 02:58:39,142 FOR INCREASING THESE HUMAN BETA 4102 02:58:39,142 --> 02:58:46,449 CELL MASS IN TREATMENT, 4103 02:58:46,449 --> 02:58:48,151 INCREASED PROLIFERATION, FOR THE 4104 02:58:48,151 --> 02:58:50,453 SAME TIME, WITH DIFFERENT DRUGS, 4105 02:58:50,453 --> 02:58:53,556 OR COMBINATION, WE FOUND 4106 02:58:53,556 --> 02:58:57,560 PROLIFERATION WAS 0.3 TO 1% 4107 02:58:57,560 --> 02:59:00,096 MAXIMUM HUMAN BETA CELL 4108 02:59:00,096 --> 02:59:00,763 PROLIFERATION. 4109 02:59:00,763 --> 02:59:04,133 WITH THAT PROLIFERATION IT'S 4110 02:59:04,133 --> 02:59:06,336 DIFFICULT TO THINK OF THE 4111 02:59:06,336 --> 02:59:09,138 INCREASE, SOMETHING MAYBE ALL 4112 02:59:09,138 --> 02:59:11,074 MECHANISMS INVOLVED IN THIS 4113 02:59:11,074 --> 02:59:11,441 EFFECT. 4114 02:59:11,441 --> 02:59:12,709 IMMEDIATELY WE THOUGHT MAYBE 4115 02:59:12,709 --> 02:59:20,149 CELLS ARE BIGGER IN SIZE, 4116 02:59:20,149 --> 02:59:21,651 HYPERTROPHY, THIS FACTOR 4117 02:59:21,651 --> 02:59:24,320 INCREASES CELL MASS. 4118 02:59:24,320 --> 02:59:27,056 AT THREE MONTHS MEASURE, NOT 4119 02:59:27,056 --> 02:59:31,194 DIFFERENT AMONG DIFFERENT 4120 02:59:31,194 --> 02:59:34,697 GROUPS, SIZE WAS NOT A FACTOR 4121 02:59:34,697 --> 02:59:40,803 ACTUALLY INFLUENCING BETA CELL 4122 02:59:40,803 --> 02:59:48,711 MASS INDUCED BY HARMINE. 4123 02:59:48,711 --> 02:59:49,912 THIS BEAUTIFUL STUDY ACTUALLY, 4124 02:59:49,912 --> 02:59:56,152 FOUND AND REPORTED LIKE MONTHS 4125 02:59:56,152 --> 02:59:59,756 AGO IN CELL REPORTS MEDICINE, AT 4126 02:59:59,756 --> 03:00:04,894 LEAST IN VITRO, OKAY, IN HUMAN, 4127 03:00:04,894 --> 03:00:07,730 THIS ENHANCING AMOUNT, ALPHA 4128 03:00:07,730 --> 03:00:10,900 CELLS THAT THEY HAVE 4129 03:00:10,900 --> 03:00:12,435 PROLIFERATION OF THESE CELLS, 4130 03:00:12,435 --> 03:00:14,404 ACTUALLY ALPHA CELLS, YOU CAN 4131 03:00:14,404 --> 03:00:18,708 SEE HOW TREATMENT WITH HARMINE 4132 03:00:18,708 --> 03:00:27,817 ALONE OR PLUS HGLP ENHANCES THE 4133 03:00:27,817 --> 03:00:30,353 CELLS. 4134 03:00:30,353 --> 03:00:34,957 YOU CAN SEE THIS, DIFFERENT 4135 03:00:34,957 --> 03:00:36,392 MARKERS OF INSULIN. 4136 03:00:36,392 --> 03:00:39,328 SO NOW SOME ALPHA CELLS THAT 4137 03:00:39,328 --> 03:00:42,732 PERHAPS THEY ARE BECOMING 4138 03:00:42,732 --> 03:00:43,933 INSULIN POSITIVE CELLS. 4139 03:00:43,933 --> 03:00:48,905 AND TO DO THAT WITH STAINING AS 4140 03:00:48,905 --> 03:00:49,338 WELL. 4141 03:00:49,338 --> 03:00:54,911 AND FOUND THAT CELLS WERE 4142 03:00:54,911 --> 03:00:56,212 PRESENT IN LARGER NUMBER IN 4143 03:00:56,212 --> 03:00:59,282 VITRO IN THESE CONDITIONS, SO IT 4144 03:00:59,282 --> 03:01:03,820 COULD BE ANOTHER ASPECT, ANOTHER 4145 03:01:03,820 --> 03:01:05,288 CELLULAR MECHANISM INVOLVED IN 4146 03:01:05,288 --> 03:01:08,191 HUMAN BETA CELLS IN VIVO. 4147 03:01:08,191 --> 03:01:10,793 OF COURSE MORE STUDIES ARE 4148 03:01:10,793 --> 03:01:14,630 NEEDED, NEED TO EXPAND INTO IN 4149 03:01:14,630 --> 03:01:16,699 VIVO SITUATION, THESE ARE EX 4150 03:01:16,699 --> 03:01:17,233 VIVO. 4151 03:01:17,233 --> 03:01:19,535 DIFFERENT STUDY, MORE WORK TO DO 4152 03:01:19,535 --> 03:01:24,240 IN THAT SENSE. 4153 03:01:24,240 --> 03:01:27,310 OF COURSE ALSO WE FOUND NOVEL 4154 03:01:27,310 --> 03:01:28,277 BETA CELLS PROTECTIVE ACTIONS OF 4155 03:01:28,277 --> 03:01:33,316 THE THERAPY, HOW DID WE FIND 4156 03:01:33,316 --> 03:01:35,551 THIS? 4157 03:01:35,551 --> 03:01:44,127 EVERYTHING I SHOWED BEFORE, 4158 03:01:44,127 --> 03:01:45,428 TREATMENT WITH HARMINE 4159 03:01:45,428 --> 03:01:48,064 IMMEDIATELY AND WITH 4160 03:01:48,064 --> 03:01:48,398 PROLIFERATION. 4161 03:01:48,398 --> 03:01:51,033 IF WE WAIT ONE MONTH, ALLOW 4162 03:01:51,033 --> 03:01:53,336 ISLETS TO ENGRAFT AND STARTED 4163 03:01:53,336 --> 03:01:53,703 TREATMENT. 4164 03:01:53,703 --> 03:02:00,042 IN THAT SITUATION WHAT WE FOUND 4165 03:02:00,042 --> 03:02:03,312 STILL BETA CELL MASS IN THESE 4166 03:02:03,312 --> 03:02:06,616 ANIMALS WASN'T AS LARGE AS WE 4167 03:02:06,616 --> 03:02:09,252 FOUND WHEN WE TREAT THE MICE 4168 03:02:09,252 --> 03:02:12,855 IMMEDIATELY AFTER 4169 03:02:12,855 --> 03:02:13,823 TRANSPLANTATION. 4170 03:02:13,823 --> 03:02:15,625 SUGGESTING PERHAPS ADVANTAGE TO 4171 03:02:15,625 --> 03:02:18,895 ISLET TO ENGRAFT AND THAT WAY 4172 03:02:18,895 --> 03:02:21,164 YOU HAVE MORE MATERIAL TO EXPAND 4173 03:02:21,164 --> 03:02:23,466 FROM, HOW YOU GET 6% INCREASE IN 4174 03:02:23,466 --> 03:02:24,567 BETA CELL MASS. 4175 03:02:24,567 --> 03:02:30,807 WE MEASURE ONE WEEK AFTER 4176 03:02:30,807 --> 03:02:31,808 TRANSPLANTATION, EFFECT OF 4177 03:02:31,808 --> 03:02:33,543 HARMINE, 50% MORE MASS AT ONE 4178 03:02:33,543 --> 03:02:36,445 WEEK ALREADY AFTER THE TREATMENT 4179 03:02:36,445 --> 03:02:39,348 WITH THIS DRUG IN THE GRAFT, 4180 03:02:39,348 --> 03:02:40,983 BASICALLY SAYING 50% MORE BETA 4181 03:02:40,983 --> 03:02:47,256 CELLS FROM THE BEGINNING, AND 4182 03:02:47,256 --> 03:02:48,224 TREATMENT, SO EFFECT, PLUS 4183 03:02:48,224 --> 03:02:49,959 POTENTIAL CHANGES OF ALPHA CELLS 4184 03:02:49,959 --> 03:03:00,470 INTO BETA, SO IT'S A CONTINUUM 4185 03:03:04,407 --> 03:03:06,542 OF MANY DIFFERENT, AND FOUND 4186 03:03:06,542 --> 03:03:16,986 DECREASED ONE WEEK AFTER 4187 03:03:17,854 --> 03:03:19,355 PLANTATION, HARMINE PROTECTS, 4188 03:03:19,355 --> 03:03:21,624 INDICATING IT'S A TRULY 4189 03:03:21,624 --> 03:03:24,560 PROTECTOR OF BETA CELLS IN VIVO 4190 03:03:24,560 --> 03:03:27,096 AND IN VITRO. 4191 03:03:27,096 --> 03:03:28,631 SO TAKEHOME MESSAGES FROM THIS 4192 03:03:28,631 --> 03:03:33,436 PART OF MY TALK, EVERYTHING HAS 4193 03:03:33,436 --> 03:03:34,971 BEEN PUBLISHED, INCREASED HUMAN 4194 03:03:34,971 --> 03:03:40,243 BETA CELL IN VIVO IN MICE, 4195 03:03:40,243 --> 03:03:45,715 TRANSPLANTED, HOWEVER, DOES NOT 4196 03:03:45,715 --> 03:03:46,816 SIGNIFICANTLY INCREASE, 4197 03:03:46,816 --> 03:03:47,116 SPECIFICITY. 4198 03:03:47,116 --> 03:03:48,551 INCREASING MASS PERSISTS AT 4199 03:03:48,551 --> 03:03:51,954 LEAST ONE MONTH AFTER DRUG 4200 03:03:51,954 --> 03:03:53,556 WITHDRAWAL. 4201 03:03:53,556 --> 03:03:58,294 BASICALLY REMOVE THE DRUG, THE 4202 03:03:58,294 --> 03:04:03,566 LEVELS OF THE DRUG, 4203 03:04:03,566 --> 03:04:05,201 PROLIFERATION, NO EVIDENCE OF 4204 03:04:05,201 --> 03:04:07,703 ABNORMAL PRO LIVATION OF TISSUE 4205 03:04:07,703 --> 03:04:09,272 HISTOLOGY, NO POSTURING, FEEDING 4206 03:04:09,272 --> 03:04:12,675 OR GROOMING BEHAVIORS OBSERVED 4207 03:04:12,675 --> 03:04:16,178 IN MICE WITH THIS COMBINATION, 4208 03:04:16,178 --> 03:04:21,484 HAVING SAID THAT THIS IS IN THE 4209 03:04:21,484 --> 03:04:28,791 STUDY WE USED ALSO ANOTHER 4210 03:04:28,791 --> 03:04:31,727 INHIBITERROR CROSSING THE 4211 03:04:31,727 --> 03:04:35,965 BLOOD-BRAIN BARRIER, THAT'S 4212 03:04:35,965 --> 03:04:40,803 IMPORTANT, AND ISLET 4213 03:04:40,803 --> 03:04:42,004 VASCULARIZATION, IN VIVO, 4214 03:04:42,004 --> 03:04:43,339 UNEXPLORED CELLULAR PROCESS 4215 03:04:43,339 --> 03:04:44,073 REQUIRED. 4216 03:04:44,073 --> 03:04:48,578 PHASE 1 CLINICAL TRIAL HAS BEEN 4217 03:04:48,578 --> 03:04:51,180 INCREASINGLY PUBLISHED, ACTUALLY 4218 03:04:51,180 --> 03:04:58,521 BY STEWART, SAFE AND TOLERABLE 4219 03:04:58,521 --> 03:05:00,289 DOSE OF HARMINE, LEVELS HIGHER 4220 03:05:00,289 --> 03:05:02,558 THAN THE LEVELS IN THE HUMAN 4221 03:05:02,558 --> 03:05:04,727 PROLIFERATION, JUST IN SAFETY. 4222 03:05:04,727 --> 03:05:09,565 WE BELIEVE THE COMBINATION OF 4223 03:05:09,565 --> 03:05:13,202 DYRK1A INHIBITORS AND LLP 1R 4224 03:05:13,202 --> 03:05:14,170 AGONIST IS REALISTIC APPROACH. 4225 03:05:14,170 --> 03:05:19,508 NOW THE PART THAT'S NOT 4226 03:05:19,508 --> 03:05:19,775 PUBLISHED. 4227 03:05:19,775 --> 03:05:23,746 STUDIES DONE BY LOU BRYANT IN MY 4228 03:05:23,746 --> 03:05:25,514 LAB, BASED ON THE PROTECTIVE 4229 03:05:25,514 --> 03:05:32,421 EFFECTS WE THOUGHT COULD IT BE 4230 03:05:32,421 --> 03:05:33,756 ALSO PROTECTIVE AGAINST 4231 03:05:33,756 --> 03:05:35,458 CYTOKINES, IMPORTANT THERAPEUTIC 4232 03:05:35,458 --> 03:05:39,462 EFFECTS IN TYPE 1 DIABETES. 4233 03:05:39,462 --> 03:05:42,064 THE COMBINATION PROTECTIVE 4234 03:05:42,064 --> 03:05:43,366 EFFECT AGAINST CYTOKINES IN IN 4235 03:05:43,366 --> 03:05:51,040 VITRO, IN HUMAN ISLETS, COMPARED 4236 03:05:51,040 --> 03:05:55,444 WITH INDIVIDUAL DRUGS. 4237 03:05:55,444 --> 03:05:57,613 AS WELL PERFORMED SINGLE CELL 4238 03:05:57,613 --> 03:05:59,815 RNAseq ANALYSIS, DIFFERENT 4239 03:05:59,815 --> 03:06:02,752 DRUG AND DRUG COMBINATIONS, AND 4240 03:06:02,752 --> 03:06:03,853 BASICALLY CONFIRMED ACTUALLY IN 4241 03:06:03,853 --> 03:06:06,155 BETA CELL CLUSTER THE ACTIVATION 4242 03:06:06,155 --> 03:06:09,892 OF CYTOKINE PATHWAYS THAT OCCURS 4243 03:06:09,892 --> 03:06:12,928 WITH CYTOKINES IS CONTINUING TO 4244 03:06:12,928 --> 03:06:22,371 DIMINISH BY HARMINE, BUT ALSO 4245 03:06:22,371 --> 03:06:28,377 IMPORTANTLY APOPTOSIS PATHWAYS 4246 03:06:28,377 --> 03:06:32,248 ALSO REDUCED. 4247 03:06:32,248 --> 03:06:36,485 CONFIRMING EFFECTS WE SEE. 4248 03:06:36,485 --> 03:06:40,089 BUT ACTUALLY LOOKING AT OTHER 4249 03:06:40,089 --> 03:06:43,592 GENOTYPES ACTUALLY IMPORTANT FOR 4250 03:06:43,592 --> 03:06:47,696 TYPE 1 DIABETES WITH CYTOKINES 4251 03:06:47,696 --> 03:06:52,902 OR DIFFERENT DRUGS FOUND 4252 03:06:52,902 --> 03:07:01,444 ACTUALLY FOR EXAMPLE THE CXCL 9, 4253 03:07:01,444 --> 03:07:04,713 10, 11, NOW TREATMENT WITH 4254 03:07:04,713 --> 03:07:05,915 COMBINATION IS REDUCING THESE 4255 03:07:05,915 --> 03:07:10,319 LEVELS AS WELL. 4256 03:07:10,319 --> 03:07:13,389 THIS WAS FURTHER CONFIRMED BY 4257 03:07:13,389 --> 03:07:17,093 CXCL 10 RELEASE IN THE MEDIA 4258 03:07:17,093 --> 03:07:18,861 SHOWING LEVELS ARE DECREASED BY 4259 03:07:18,861 --> 03:07:20,930 TREATMENT IN THE CYTOKINE 4260 03:07:20,930 --> 03:07:21,297 PRESENT. 4261 03:07:21,297 --> 03:07:25,835 ALSO IT'S IMPORTANT TO SHOW 4262 03:07:25,835 --> 03:07:28,137 ACTUALLY HLA-A, B, AND C GO UP 4263 03:07:28,137 --> 03:07:30,339 WITH CYTOKINE TREATMENT, ALSO 4264 03:07:30,339 --> 03:07:34,310 ARE REDUCED BY THE TREATMENT 4265 03:07:34,310 --> 03:07:37,813 TOGETHER, AND THIS IS ALSO 4266 03:07:37,813 --> 03:07:43,486 CONFIRMED BY IMMUNOSTAINING AND 4267 03:07:43,486 --> 03:07:44,787 ANALYSIS OF IMMUNOFLUORESCENCE, 4268 03:07:44,787 --> 03:07:46,655 TREATMENT WITH DIFFERENT DRUGS, 4269 03:07:46,655 --> 03:07:47,923 COMBINATION, SEEING THAT ONE 4270 03:07:47,923 --> 03:07:48,190 REDUCED. 4271 03:07:48,190 --> 03:07:52,895 ON THE OTHER HAND, WE SAW 4272 03:07:52,895 --> 03:07:58,167 INHIBITOR HLA-E ALSO ENHANCED BY 4273 03:07:58,167 --> 03:08:00,002 CYTOKINE BY ITSELF OR TOGETHER 4274 03:08:00,002 --> 03:08:02,872 AND AGAIN CONFIRMED BY 4275 03:08:02,872 --> 03:08:07,710 IMMUNOSTAINING WITH ANTIBODIES 4276 03:08:07,710 --> 03:08:08,777 AGAINST HLA. 4277 03:08:08,777 --> 03:08:15,217 IN ADDITION, ALSO MEASURED RATIO 4278 03:08:15,217 --> 03:08:16,652 WITH CYTOKINES AND FOUND THE 4279 03:08:16,652 --> 03:08:21,791 TREATMENT WAS ABLE TO REDUCE 4280 03:08:21,791 --> 03:08:26,495 RATIO OF INSULIN, DECREASING PRO 4281 03:08:26,495 --> 03:08:29,498 INSULIN SECRETION, MOSTLY 4282 03:08:29,498 --> 03:08:34,737 BECAUSE OF PRO INSULIN 4283 03:08:34,737 --> 03:08:35,905 SECRETION. 4284 03:08:35,905 --> 03:08:41,744 LET'S USE THE NOD MOUSE MODEL 4285 03:08:41,744 --> 03:08:45,314 AND NOW TREATMENT AND SEE BY 4286 03:08:45,314 --> 03:08:47,216 ITSELF OR COMBINATION, WE COULD 4287 03:08:47,216 --> 03:08:50,286 REVERSE TYPE 1 DIABETES IN THESE 4288 03:08:50,286 --> 03:08:50,819 MICE. 4289 03:08:50,819 --> 03:08:55,858 FROM THAT ACTUALLY WE FIRST TRY 4290 03:08:55,858 --> 03:09:00,996 TO INJECT WITH AND PUT IN PUMPS, 4291 03:09:00,996 --> 03:09:10,839 ONE OR THE OTHER OR COMBINATION, 4292 03:09:10,839 --> 03:09:13,742 NOW THESE MICE, IT'S NOT 4293 03:09:13,742 --> 03:09:14,910 MODERATED ACTUALLY, THERE WILL 4294 03:09:14,910 --> 03:09:20,516 BE NO CHANCE FOR BETA CELLS TO 4295 03:09:20,516 --> 03:09:23,552 BE REGENERATED. 4296 03:09:23,552 --> 03:09:25,855 90 TO 100% DIABETIC AT THE END 4297 03:09:25,855 --> 03:09:27,389 OF THE STUDY. 4298 03:09:27,389 --> 03:09:32,862 WE TREATED MICE FOR THREE DAYS, 4299 03:09:32,862 --> 03:09:38,234 WITH LOW DOSE PREVIOUSLY 4300 03:09:38,234 --> 03:09:41,503 PUBLISHED, AND THEY TREAT THE 4301 03:09:41,503 --> 03:09:44,440 MICE WITH FOLLOWING THOSE THREE 4302 03:09:44,440 --> 03:09:50,779 DAYS OF TREATMENT, AND WE FOUND 4303 03:09:50,779 --> 03:09:51,413 ACTUALLY ALTHOUGH IMPROVE BLOOD 4304 03:09:51,413 --> 03:09:54,750 GLUCOSE LEVELS IN THE MICE, 4305 03:09:54,750 --> 03:09:59,288 APPROXIMATELY 40% OF THEM AT 4306 03:09:59,288 --> 03:10:00,923 THIS POINT, TREATMENT BY 4307 03:10:00,923 --> 03:10:03,092 THEMSELVES DON'T GIVE YOU MUCH 4308 03:10:03,092 --> 03:10:05,494 MORE THAN THE 40, 50% OF 4309 03:10:05,494 --> 03:10:06,061 IMPROVEMENT. 4310 03:10:06,061 --> 03:10:09,365 ONLY WHEN YOU COMBINE FOR THREE 4311 03:10:09,365 --> 03:10:12,201 DAYS, YOU PUT PUMPS, YOU SHOW 4312 03:10:12,201 --> 03:10:13,636 REACTION OF BLOOD GLUCOSE LEVELS 4313 03:10:13,636 --> 03:10:16,238 WITH APPROXIMATELY 85 TO 90% OF 4314 03:10:16,238 --> 03:10:18,440 THE MICE REVERSING DIABETES. 4315 03:10:18,440 --> 03:10:27,216 SO AT LEAST THE IDEA THE 4316 03:10:27,216 --> 03:10:31,353 COMBINATION CAN IMPROVE BLOOD 4317 03:10:31,353 --> 03:10:32,655 GLUCOSE LEVELS AND REVERSE 4318 03:10:32,655 --> 03:10:43,032 DIABETES IN THE MICE. 4319 03:10:43,365 --> 03:10:45,367 WE FOUND THAT PREPARATION WAS 4320 03:10:45,367 --> 03:10:48,771 INCREASED AS SUSPECTED OF BETA 4321 03:10:48,771 --> 03:10:51,840 CELLS, LEADING TO INCREASE IN 4322 03:10:51,840 --> 03:10:54,143 THESE MICE. 4323 03:10:54,143 --> 03:10:57,880 THEY IMMUNE LEVEL FOUND CD8 AND 4324 03:10:57,880 --> 03:11:00,916 INTERFERON GAMMA CD8S AND CD4 4325 03:11:00,916 --> 03:11:04,353 POSITIVE CELLS REDUCED BY THE 4326 03:11:04,353 --> 03:11:14,563 TREATMENT. . 4327 03:11:16,565 --> 03:11:19,435 WE FOUND INCREASE OF THE 4328 03:11:19,435 --> 03:11:29,979 MARKERS, THESE ARE THE MARKERS. 4329 03:11:44,159 --> 03:11:45,327 THIS COMBINATION REDUCES HUMAN 4330 03:11:45,327 --> 03:11:48,697 BETA CELL IMMUNITY IN 4331 03:11:48,697 --> 03:11:52,434 INFLAMMATORY ENVIRONMENT, AND 4332 03:11:52,434 --> 03:11:53,535 TOGETHER WITH IMMUNOMODULATORS, 4333 03:11:53,535 --> 03:11:58,040 WE LEARNED OF MANY DIFFERENT 4334 03:11:58,040 --> 03:12:01,744 IMMUNOMODULATORS USED, OR 4335 03:12:01,744 --> 03:12:03,045 TESTED, WITH DYRK1A INHIBITORS, 4336 03:12:03,045 --> 03:12:05,781 REVERSE IN MICE, WE THINK THAT 4337 03:12:05,781 --> 03:12:08,417 COMBINATION ACTUALLY CAN BE 4338 03:12:08,417 --> 03:12:10,419 THERAPEUTIC APPROACH FOR TYPE 1 4339 03:12:10,419 --> 03:12:11,520 DIABETES REVERSAL, AND JUST TO 4340 03:12:11,520 --> 03:12:14,156 THANK THE MEMBERS OF MY LAB, IN 4341 03:12:14,156 --> 03:12:16,558 PARTICULAR BRIAN AND RANDY, WHO 4342 03:12:16,558 --> 03:12:20,462 HAVE RUN MANY OF THESE STUDIES, 4343 03:12:20,462 --> 03:12:24,333 PREVIEWS, COLLABORATORS AT MOUNT 4344 03:12:24,333 --> 03:12:27,703 SINAI, AND THE GROUPS BY ANDY, 4345 03:12:27,703 --> 03:12:30,172 DON, AND BOB, AND SARAH, WHO 4346 03:12:30,172 --> 03:12:32,341 WORK ON THESE STUDIES WITH ME, 4347 03:12:32,341 --> 03:12:35,110 TOGETHER, AND MY NEW PARTNERS 4348 03:12:35,110 --> 03:12:45,621 ACTUALLY AT CITY OF HOPE, AND 4349 03:12:52,428 --> 03:12:56,131 THE DONORS. 4350 03:12:56,131 --> 03:12:56,398 THANK YOU. 4351 03:12:56,398 --> 03:13:01,403 [APPLAUSE] 4352 03:13:01,403 --> 03:13:05,574 >> THANKS VERY MUCH. 4353 03:13:05,574 --> 03:13:08,811 AN EXCITING PROVOCATIVE STUDY 4354 03:13:08,811 --> 03:13:10,712 NEAR THE END OF THE STUDY. 4355 03:13:10,712 --> 03:13:11,814 ALL FOUR SPEAKERS WILL COME ON 4356 03:13:11,814 --> 03:13:13,549 THE PODIUM. 4357 03:13:13,549 --> 03:13:19,021 I REQUEST THEM TO COME UP HERE, 4358 03:13:19,021 --> 03:13:20,689 SO THAT WE CAN BEGIN A LIVELY 4359 03:13:20,689 --> 03:13:21,223 DISCUSSION. 4360 03:13:21,223 --> 03:13:23,659 I HOPE YOU HAD ENOUGH COFFEE TO 4361 03:13:23,659 --> 03:13:25,627 ENGAGE YOURSELVES FOR THE NEXT 4362 03:13:25,627 --> 03:13:26,762 40 OR 45 MINUTES ON A DISCUSSION 4363 03:13:26,762 --> 03:13:36,839 FROM EACH OF THE TOPICS, 4364 03:13:36,839 --> 03:13:39,975 ENGINEERING, BETA CELLS, T 4365 03:13:39,975 --> 03:13:42,377 CELLS, INTERFERONS, AND JULIA 4366 03:13:42,377 --> 03:13:44,446 SPOKE ON RESTORING ALPHA CELL 4367 03:13:44,446 --> 03:13:47,649 FUNCTION, AND DYRK 1 INHIBITION. 4368 03:13:47,649 --> 03:13:49,818 THESE ARE RELEVANT FOR TYPE 1 4369 03:13:49,818 --> 03:13:55,824 DIABETES. 4370 03:13:55,824 --> 03:13:58,460 I WANT TO INITIATE DISCUSSION 4371 03:13:58,460 --> 03:14:08,837 MAKE SURE YOU IDENTIFY 4372 03:14:11,006 --> 03:14:11,607 YOURSELVES. 4373 03:14:11,607 --> 03:14:16,745 MAYBE WE CAN START ON THE RIGHT 4374 03:14:16,745 --> 03:14:17,179 SIDE. 4375 03:14:17,179 --> 03:14:17,412 >> HI. 4376 03:14:17,412 --> 03:14:17,746 UMass. 4377 03:14:17,746 --> 03:14:21,884 I HAVE A QUESTION FOR JULIA AND 4378 03:14:21,884 --> 03:14:22,117 ADOLFO. 4379 03:14:22,117 --> 03:14:27,689 JULIA, SEEMS TO ME THAT YOU 4380 03:14:27,689 --> 03:14:29,892 COULD IN A PATIENT WITH 4381 03:14:29,892 --> 03:14:31,760 LONGSTANDING TYPE 1 DIABETES 4382 03:14:31,760 --> 03:14:34,062 INFUSE SOMATO SATIN AND 4383 03:14:34,062 --> 03:14:35,697 SEROTONIN AND SEE IF CLINICALLY 4384 03:14:35,697 --> 03:14:37,332 YOU COULD SEE RECOVERY BECAUSE 4385 03:14:37,332 --> 03:14:42,137 THAT COULD BE QUICKLY TRANSLATED 4386 03:14:42,137 --> 03:14:44,239 TO PATIENTS WITH INSULIN PUMPS, 4387 03:14:44,239 --> 03:14:45,774 EVERY 2 OR 3 HOURS, 15 MINUTES 4388 03:14:45,774 --> 03:14:47,609 OF THOSE DRUGS IF YOU SEE A 4389 03:14:47,609 --> 03:14:55,050 RECOVERY OF ALPHA CELL FUNCTION. 4390 03:14:55,050 --> 03:14:56,151 >> NOT IN VIVO. 4391 03:14:56,151 --> 03:14:57,553 >> THEORETICALLY YOU SHOULD SEE 4392 03:14:57,553 --> 03:14:59,321 THAT EFFECT BASED ON DATA OR B 4393 03:14:59,321 --> 03:15:00,422 TOXIN, ET CETERA. 4394 03:15:00,422 --> 03:15:04,226 >> YES, THE PROBLEM IS 4395 03:15:04,226 --> 03:15:06,995 AVAILABILITY OF TISSUE. 4396 03:15:06,995 --> 03:15:14,570 >> NO, DO IT IN CLINICAL. 4397 03:15:14,570 --> 03:15:16,738 >> YEAH, YEAH. 4398 03:15:16,738 --> 03:15:19,241 WANTED TO TEST FIRST IN VITRO, 4399 03:15:19,241 --> 03:15:22,177 AVAILABILITY IS A PROBLEM. 4400 03:15:22,177 --> 03:15:24,313 >> FDA APPROVED DRUGS, SHOULD BE 4401 03:15:24,313 --> 03:15:26,515 A DOABLE THING, COULD BE 4402 03:15:26,515 --> 03:15:28,684 IMMEDIATELY IMPLEMENTED, TAKE 4403 03:15:28,684 --> 03:15:30,652 PATIENTS WITH SEVERE RECURRENT 4404 03:15:30,652 --> 03:15:32,154 HYPOGLYCEMIA, IDEAL CANDIDATES 4405 03:15:32,154 --> 03:15:36,224 TO PUT EVERY 3 HOURS. 4406 03:15:36,224 --> 03:15:39,194 >> BUT WE ALSO HAD GLUTAMATE 4407 03:15:39,194 --> 03:15:40,062 STORY, FDA-APPROVED DRUGS BUT 4408 03:15:40,062 --> 03:15:42,998 GETTING TO THE CLINIC AND DOING 4409 03:15:42,998 --> 03:15:48,704 IT IS NOT AS EASY AS THAT. 4410 03:15:48,704 --> 03:15:48,971 >> TRUE. 4411 03:15:48,971 --> 03:15:49,905 >> ADOLFO, I THOUGHT YOU SHOWED 4412 03:15:49,905 --> 03:15:52,975 AT LEAST ONE OF THE MECHANISMS 4413 03:15:52,975 --> 03:15:56,144 WAS ALPHA CELL TO BETA CELL 4414 03:15:56,144 --> 03:15:56,845 POSSIBLE TRANSDIFFERENTIATION 4415 03:15:56,845 --> 03:15:57,913 BUT YOUR CONCLUSION YOU SAID 4416 03:15:57,913 --> 03:16:01,817 THERE WAS NO INCREASE IN ALPHA 4417 03:16:01,817 --> 03:16:03,018 CELL NUMBER, AND I THOUGHT YOU 4418 03:16:03,018 --> 03:16:07,322 DO SHOW INCREASE. 4419 03:16:07,322 --> 03:16:08,557 DID I MISUNDERSTAND? 4420 03:16:08,557 --> 03:16:11,693 >> INCREASE IN ALPHA CELL 4421 03:16:11,693 --> 03:16:15,430 NUMBER, RIGHT, BECAUSE DOSES IN 4422 03:16:15,430 --> 03:16:17,366 VIVO ARE LOWER THAN IN VITRO, 4423 03:16:17,366 --> 03:16:18,800 COMMON IN THAT ACTUALLY. 4424 03:16:18,800 --> 03:16:20,836 SO WHAT WE THINK IS HAPPENING, 4425 03:16:20,836 --> 03:16:23,138 IF THAT'S HAPPENING IN VIVO IS 4426 03:16:23,138 --> 03:16:27,009 SMALL IN TERMS OF THE DONORS 4427 03:16:27,009 --> 03:16:29,311 WE'RE USING, ACTUALLY GOING TO 4428 03:16:29,311 --> 03:16:31,079 MAKE LOW PERCENTAGE OF ALPHA 4429 03:16:31,079 --> 03:16:32,814 CELLS BECOME BETA CELLS, WE 4430 03:16:32,814 --> 03:16:35,851 DON'T SEE EXPANSION OF THAT 4431 03:16:35,851 --> 03:16:42,691 PARTICULAR OPERATION. 4432 03:16:42,691 --> 03:16:44,126 >> THANK YOU. 4433 03:16:44,126 --> 03:16:45,093 >> UNIVERSITY OF MINNESOTA, I 4434 03:16:45,093 --> 03:16:48,830 HAVE ALSO A QUESTION FOR ADOLFO. 4435 03:16:48,830 --> 03:16:52,868 BEAUTIFUL WORK. 4436 03:16:52,868 --> 03:16:53,835 THE ISSUE IS 4437 03:16:53,835 --> 03:16:57,706 TRANSDIFFERENTIATION, HAVE YOU 4438 03:16:57,706 --> 03:16:59,675 EVER TRIED TO DELETE TRACING 4439 03:16:59,675 --> 03:17:03,912 STUDIES AT ALL? 4440 03:17:03,912 --> 03:17:07,449 >> GREAT QUESTION. 4441 03:17:07,449 --> 03:17:09,318 I DON'T THINK DOING 4442 03:17:09,318 --> 03:17:12,587 DEMONSTRATION IN HUMAN ISLET, 4443 03:17:12,587 --> 03:17:13,588 HUMAN BETA CELLS. 4444 03:17:13,588 --> 03:17:17,859 >> IN THE MOUSE. 4445 03:17:17,859 --> 03:17:23,298 >> IN THE MOUSE, NO, THAT'S 4446 03:17:23,298 --> 03:17:24,733 PROBABLY -- ACTUALLY, IN MICE, 4447 03:17:24,733 --> 03:17:26,702 COMBINING THEM WITH 4448 03:17:26,702 --> 03:17:28,737 DEMONSTRATION MICE WE CAN SEE 4449 03:17:28,737 --> 03:17:33,942 BECOMING BETA CELLS IN VIVO IN 4450 03:17:33,942 --> 03:17:38,814 MICE, ACTUALLY AFTER TREATMENT 4451 03:17:38,814 --> 03:17:39,648 WITH HARMINE. 4452 03:17:39,648 --> 03:17:41,750 >> THANK YOU FOR THE SUGGESTION, 4453 03:17:41,750 --> 03:17:43,251 IT'S A GREAT SUGGESTION. 4454 03:17:43,251 --> 03:17:46,755 WE HAVEN'T MADE PLANS OF DOING 4455 03:17:46,755 --> 03:17:49,057 THESE STUDIES IN MICE BUT WE 4456 03:17:49,057 --> 03:17:50,258 STARTING WORK WITH STEM CELL 4457 03:17:50,258 --> 03:17:53,128 BASED OR STEM CELL DERIVED 4458 03:17:53,128 --> 03:17:55,530 ISLETS, BECAUSE THEY ARE EASIER 4459 03:17:55,530 --> 03:17:58,266 TO MANIPULATE AND THIS WORK HAS 4460 03:17:58,266 --> 03:17:59,134 BEEN INITIATED, HOPEFULLY SOON 4461 03:17:59,134 --> 03:18:04,306 I'LL BE ABLE TO REPORT THE 4462 03:18:04,306 --> 03:18:05,173 RESULTS. 4463 03:18:05,173 --> 03:18:11,313 >> WE'RE WORKING ON CROSSING 4464 03:18:11,313 --> 03:18:15,217 GLUCAGON AND AALLELE, WHICH 4465 03:18:15,217 --> 03:18:18,620 TAKES TWO YEARS. 4466 03:18:18,620 --> 03:18:21,590 >> GREAT FOR COLLABORATION. 4467 03:18:21,590 --> 03:18:23,692 >> GO AHEAD. 4468 03:18:23,692 --> 03:18:28,597 >> ROBERTO CASTRO, UCSF, FOR THE 4469 03:18:28,597 --> 03:18:30,132 OTHER ROBERTO, FOR HLA-B 4470 03:18:30,132 --> 03:18:31,533 CO-CULTURES THAT YOU DID, ALL 4471 03:18:31,533 --> 03:18:35,470 THE PEPTIDES YOU FOUND, DO THEY 4472 03:18:35,470 --> 03:18:37,873 HAVE DIFFERENT AFFINITIES 4473 03:18:37,873 --> 03:18:41,510 TOWARDS HLA-B, DO YOU MEASURE IF 4474 03:18:41,510 --> 03:18:43,945 THEY BIND STRONGER TO HLA-B, OR 4475 03:18:43,945 --> 03:18:49,417 DO YOU THINK IT'S JUST BECAUSE 4476 03:18:49,417 --> 03:18:55,657 THERE'S MORE HLA-B? 4477 03:18:55,657 --> 03:18:58,927 >> SO, YEAH, THIS WORK HAS BEEN 4478 03:18:58,927 --> 03:19:00,595 BASED ON PREDICTION, REVIEW 4479 03:19:00,595 --> 03:19:06,134 BASED ON DIFFERENCE OF 4480 03:19:06,134 --> 03:19:08,336 PREDICTION SCORES, SO WE CAN 4481 03:19:08,336 --> 03:19:09,437 REASONABLY SAY THERE'S A 4482 03:19:09,437 --> 03:19:12,607 PRESENTATION BUT WE HAVEN'T 4483 03:19:12,607 --> 03:19:14,676 FORMALLY TESTED FOR MOST OF 4484 03:19:14,676 --> 03:19:17,279 THESE PEPTIDES WHETHER THEY BIND 4485 03:19:17,279 --> 03:19:19,381 TO HLA-B, THIS IS THE WORK THAT 4486 03:19:19,381 --> 03:19:20,682 IS ONGOING, WE'RE MAKING 4487 03:19:20,682 --> 03:19:23,885 TETRAMERS FOR ALL THESE PEPTIDES 4488 03:19:23,885 --> 03:19:28,557 AND SEEING WHERE WE SEE AN 4489 03:19:28,557 --> 03:19:30,992 INCREASED FREQUENCY OF HLA-B 4490 03:19:30,992 --> 03:19:32,394 RESTRICTED ISLET REACTIVE CD8 4491 03:19:32,394 --> 03:19:38,733 CELLS IN TYPE 1 VERSUS NON-DIE 4492 03:19:38,733 --> 03:19:40,168 BEATIC DONORS WE DIDN'T SAY 4493 03:19:40,168 --> 03:19:42,804 BEFORE FOR AGE RESTRICTED CELLS. 4494 03:19:42,804 --> 03:19:45,140 >> LET ME JUMP IN TO THE ENTIRE 4495 03:19:45,140 --> 03:19:45,340 PANEL. 4496 03:19:45,340 --> 03:19:49,945 I'M SURE ALL OF YOU KNOW ABOUT 4497 03:19:49,945 --> 03:19:53,982 THE LOBULAR PATTERN, SO FOR ME, 4498 03:19:53,982 --> 03:19:54,749 PRESENTATIONS, STARTING WITH 4499 03:19:54,749 --> 03:19:57,118 ROBERTO PERHAPS AND THE OTHERS 4500 03:19:57,118 --> 03:19:59,321 AS WELL, HOW IS IT THAT THE 4501 03:19:59,321 --> 03:20:01,857 MÉNAGE À TROIS IS NOT WORKING IN 4502 03:20:01,857 --> 03:20:03,925 SOME LOBES BUT AFFECTING ONLY 4503 03:20:03,925 --> 03:20:05,927 CERTAIN LOBES, AND SAME QUESTION 4504 03:20:05,927 --> 03:20:07,562 PERHAPS ALPHA CELLS, YOU THINK 4505 03:20:07,562 --> 03:20:08,964 SOME LOBES ARE FUNCTIONING 4506 03:20:08,964 --> 03:20:10,732 NORMALLY AND THEN GOING TO 4507 03:20:10,732 --> 03:20:12,801 ADOLFO, DO YOU THINK BETA CELL 4508 03:20:12,801 --> 03:20:14,102 REGENERATION COULD AFFECT ALL 4509 03:20:14,102 --> 03:20:17,606 THE LOBES IN THE ISLETS? 4510 03:20:17,606 --> 03:20:19,174 SO LOBULAR PATTERN IS A 4511 03:20:19,174 --> 03:20:20,942 HAPPENING ITEM IN TYPE 1, SO HOW 4512 03:20:20,942 --> 03:20:23,879 DO YOU ADDRESS THAT PARTICULAR 4513 03:20:23,879 --> 03:20:25,881 QUESTION? 4514 03:20:25,881 --> 03:20:29,784 >> IF I CAN START WITH A 4515 03:20:29,784 --> 03:20:32,420 COMMENT, FIRST FACTOR IN THIS 4516 03:20:32,420 --> 03:20:35,490 COULD BE THE SIZE OF THE ISLET, 4517 03:20:35,490 --> 03:20:38,093 BECAUSE THE EXPOSURE TO 4518 03:20:38,093 --> 03:20:40,295 INTERFERONS COULD BE DIFFERENT. 4519 03:20:40,295 --> 03:20:42,631 AND THERE IS DATA, SO YOU 4520 03:20:42,631 --> 03:20:45,267 SUPPORT OF THIS POSSIBILITY. 4521 03:20:45,267 --> 03:20:48,837 IT'S NOT THE ONLY FACTOR THAT 4522 03:20:48,837 --> 03:20:56,745 COULD BE AFFECT. 4523 03:20:56,745 --> 03:20:57,746 >> I'LL TALK. 4524 03:20:57,746 --> 03:21:01,149 SO I COMPLETELY AGREE WITH YOU. 4525 03:21:01,149 --> 03:21:02,551 >> TWO MICROPHONES. 4526 03:21:02,551 --> 03:21:07,589 >> COMPLETELY AGREE WITH YOU. 4527 03:21:07,589 --> 03:21:11,526 4528 03:21:11,526 --> 03:21:15,563 >> I AGREE WITH YOU. 4529 03:21:15,563 --> 03:21:18,333 DIFFERENT POPULATIONS INSIDE OF 4530 03:21:18,333 --> 03:21:21,269 THE ISLET, NOT THE PROPORTION OF 4531 03:21:21,269 --> 03:21:23,004 BETA CELLS IS MAINTAINED 4532 03:21:23,004 --> 03:21:24,339 CONSTANTLY IN ALL THE ISLETS, 4533 03:21:24,339 --> 03:21:26,641 PROBABLY THERE ARE DIFFERENCES. 4534 03:21:26,641 --> 03:21:37,319 SO, MOST LIKELY THE RESPONSE OF 4535 03:21:37,319 --> 03:21:38,787 ISLETS, DIFFERENT, EXPLAINING 4536 03:21:38,787 --> 03:21:42,524 THAT EXPRESSION OF HLA MAYBE IN 4537 03:21:42,524 --> 03:21:52,701 SOME ISLETS, THAN THE OTHER. 4538 03:21:52,701 --> 03:21:58,406 >> MAINTAINING CONSTANT NUMBER, 4539 03:21:58,406 --> 03:22:00,041 PROPORTION OF CELLS. 4540 03:22:00,041 --> 03:22:01,076 >> THAT DOESN'T HAPPEN, RIGHT? 4541 03:22:01,076 --> 03:22:04,946 >> YEAH, I THINK IT'S VARIABLE 4542 03:22:04,946 --> 03:22:09,317 JUST LIKE STEM CELL. 4543 03:22:09,317 --> 03:22:11,519 WE'RE USING WITH A LOT OF 4544 03:22:11,519 --> 03:22:13,188 QUALITY CONTROL, CLUSTER TO 4545 03:22:13,188 --> 03:22:15,156 CLUSTER THERE'S VARIABILITY, AND 4546 03:22:15,156 --> 03:22:17,993 THE QUESTIONS WE DEFINITELY WANT 4547 03:22:17,993 --> 03:22:19,861 TO EXPLORE, IF WE HAVE 20 ISLETS 4548 03:22:19,861 --> 03:22:24,366 IN FIELD OF VIEW, TRACKING, 4549 03:22:24,366 --> 03:22:25,033 RESPONSIVE, CROSS-CORRELATE TO 4550 03:22:25,033 --> 03:22:27,335 COMPOSITION, THE NEXT STEP THAT 4551 03:22:27,335 --> 03:22:28,636 WE'RE EXPLORING CAN RETRIEVE 4552 03:22:28,636 --> 03:22:30,605 THOSE CELLS, CAN WE FIX THEM AND 4553 03:22:30,605 --> 03:22:32,907 DO SPATIAL PROTEOMICS AND BE 4554 03:22:32,907 --> 03:22:36,244 ABLE TO CROSS-CORRELATE 4555 03:22:36,244 --> 03:22:37,946 MIGRATION AND KILLING WE'VE 4556 03:22:37,946 --> 03:22:40,148 LEARNED WITH COMPOSITION OF THE 4557 03:22:40,148 --> 03:22:42,350 CELLS OR DIFFERENT PHENOTYPES OF 4558 03:22:42,350 --> 03:22:44,319 THE T CELLS, BUT I THINK THERE'S 4559 03:22:44,319 --> 03:22:45,854 A LOT OF EVIDENCE HETEROGENEITY 4560 03:22:45,854 --> 03:22:47,922 IS LINK, AS YOU SAID, RELATED TO 4561 03:22:47,922 --> 03:22:50,859 COMPOSITION, COULD BE RELATED TO 4562 03:22:50,859 --> 03:22:52,293 FORMATION OF THE PANCREAS, THAT 4563 03:22:52,293 --> 03:22:54,396 VARIABILITY FROM TAIL TO HEAD, 4564 03:22:54,396 --> 03:22:55,497 MATRIX COMPOSITION, SO MANY 4565 03:22:55,497 --> 03:22:57,565 FACTORS MAY LEAD TO THAT, WHICH 4566 03:22:57,565 --> 03:23:03,338 IS WHY WE'RE SEEING INCREDIBLE 4567 03:23:03,338 --> 03:23:03,638 VARIABILITY. 4568 03:23:03,638 --> 03:23:07,308 >> I THINK YOU'RE SHOWING 4569 03:23:07,308 --> 03:23:08,977 ORGANOIDS THAT ARE USED, IMMUNE 4570 03:23:08,977 --> 03:23:13,014 CELLS, ET CETERA, ANY PLANS FOR 4571 03:23:13,014 --> 03:23:13,615 USING ALSO NEURONS? 4572 03:23:13,615 --> 03:23:18,253 >> THAT WOULD BE VERY COOL. 4573 03:23:18,253 --> 03:23:26,928 MONEY FOR THAT, I GUESS. 4574 03:23:26,928 --> 03:23:37,305 >> I HAVE A QUESTION. 4575 03:23:45,713 --> 03:23:55,623 HOW DO WE IDENTIFY 4576 03:23:55,623 --> 03:24:05,500 NEUROPEPTIDES, HOW IS THAT 4577 03:24:05,500 --> 03:24:07,669 IDENTIFIED? 4578 03:24:07,669 --> 03:24:10,738 >> THE QUESTION IS WHICH 4579 03:24:10,738 --> 03:24:15,343 NEOPEPTIDES WOULD BE RELEVANT IN 4580 03:24:15,343 --> 03:24:15,610 PATIENTS? 4581 03:24:15,610 --> 03:24:17,812 >> YEAH, IN VITRO DISCOVERY 4582 03:24:17,812 --> 03:24:25,954 DATA TO THE IN SITU, HUMAN 4583 03:24:25,954 --> 03:24:28,056 PATIENTS, LIKE MANY NEOPEPTIDE 4584 03:24:28,056 --> 03:24:30,692 IDENTIFY FROM IN VITRO, WE HAVE 4585 03:24:30,692 --> 03:24:33,128 NO IDEA PEPTIDES EXIST IN HUMAN 4586 03:24:33,128 --> 03:24:35,296 PATIENTS, WHAT DO WE HAVE TO 4587 03:24:35,296 --> 03:24:36,164 CONNECT. 4588 03:24:36,164 --> 03:24:39,100 >> YEAH, ABSOLUTELY RIGHT. 4589 03:24:39,100 --> 03:24:41,402 SO THESE DATA DEMONSTRATE THAT 4590 03:24:41,402 --> 03:24:43,171 THESE PEPTIDES ARE PRESENTED BY 4591 03:24:43,171 --> 03:24:44,372 BETA CELLS. 4592 03:24:44,372 --> 03:24:44,706 >> YES. 4593 03:24:44,706 --> 03:24:47,642 >> IT'S IN VITRO. 4594 03:24:47,642 --> 03:24:50,178 SO, NOT NECESSARILY THE SAME IN 4595 03:24:50,178 --> 03:24:52,113 VIVO, AND THE FACT THAT THESE 4596 03:24:52,113 --> 03:24:53,882 PEPTIDES ARE PRESENTED BY BETA 4597 03:24:53,882 --> 03:24:56,417 CELLS DOESN'T NECESSARILY MEAN 4598 03:24:56,417 --> 03:24:59,120 THAT THE T CELLS -- WE'VE SHOWN 4599 03:24:59,120 --> 03:25:04,492 THIS FOR SOME OF THEM, THANKS TO 4600 03:25:04,492 --> 03:25:05,793 USING T CELL LINES, THE 4601 03:25:05,793 --> 03:25:09,164 FOLLOW-UP OF THE WORK IS TO LOOK 4602 03:25:09,164 --> 03:25:12,167 AT THE T CELL RECOGNITION IN 4603 03:25:12,167 --> 03:25:15,770 TYPE 1 DIABETIC PATIENTS OF 4604 03:25:15,770 --> 03:25:16,404 THESE PEPTIDES IDENTIFIED, 4605 03:25:16,404 --> 03:25:19,807 LOOKING IN THE BLOOD USING 4606 03:25:19,807 --> 03:25:22,677 PBMCs, LOOKING ALSO IN LOCAL 4607 03:25:22,677 --> 03:25:24,746 TISSUES, USING TISSUE SECTIONS 4608 03:25:24,746 --> 03:25:26,781 FROM THE PANCREAS, FROM 4609 03:25:26,781 --> 03:25:29,117 PANCREATIC LYMPH NODES, AND THAT 4610 03:25:29,117 --> 03:25:36,457 WOULD BE ANOTHER EVIDENCE OF 4611 03:25:36,457 --> 03:25:38,126 RELEVANCE IN PATHOGENESIS, YEAH. 4612 03:25:38,126 --> 03:25:40,662 >> PLEASE GO AHEAD. 4613 03:25:40,662 --> 03:25:41,362 >> LEO FERRERA, MEDICAL 4614 03:25:41,362 --> 03:25:44,332 UNIVERSITY OF SOUTH CAROLINA. 4615 03:25:44,332 --> 03:25:46,367 TWO RELATED QUESTIONS, DR. 4616 03:25:46,367 --> 03:25:47,135 MALONE. 4617 03:25:47,135 --> 03:25:52,907 FASCINATING BETA CELLS 4618 03:25:52,907 --> 03:25:55,109 SPECIFICALLY UPREGULATE HLAV, I 4619 03:25:55,109 --> 03:25:58,179 USED TO WORK ON DIFFERENTIALLY 4620 03:25:58,179 --> 03:26:00,248 REGULATION TROPHOBLASTS IN 4621 03:26:00,248 --> 03:26:00,848 PREGNANCY, WONDERING QUESTION 4622 03:26:00,848 --> 03:26:07,188 ONE, DO YOU HAVE A SENSE OF WHAT 4623 03:26:07,188 --> 03:26:10,792 TRANSCRIPTION FACTORS OR 4624 03:26:10,792 --> 03:26:12,093 ENHANCERS ELEMENTS ARE INVOLVED? 4625 03:26:12,093 --> 03:26:15,196 IS THIS A DRIVING MECHANISM OR 4626 03:26:15,196 --> 03:26:19,234 SYMPTOM OF SOMETHING BIGGER, 4627 03:26:19,234 --> 03:26:20,034 SAME TRANSCRIPTIONAL NETWORK IS 4628 03:26:20,034 --> 03:26:23,938 DOING OTHER THINGS FOR THE BETA 4629 03:26:23,938 --> 03:26:34,115 CELLS, REALLY THE ONES IMPORTANT 4630 03:26:34,115 --> 03:26:35,216 IN PATHOLOGY. 4631 03:26:35,216 --> 03:26:38,152 >> TRANSCRIPTION FACTORS, DATA 4632 03:26:38,152 --> 03:26:39,354 IN LITERATURE SUGGESTING THIS 4633 03:26:39,354 --> 03:26:41,289 DIFFERENCE IN AFFINITY OF THE 4634 03:26:41,289 --> 03:26:45,727 INTERFERON RESPONSIVE ELEMENT IN 4635 03:26:45,727 --> 03:26:49,330 THE HLA-B VERSUS HLA-LOCUS, ALSO 4636 03:26:49,330 --> 03:26:51,165 LITERATURE SUGGESTING MECHANISM 4637 03:26:51,165 --> 03:26:59,774 OF UBIQUITINATION THAT CAN 4638 03:26:59,774 --> 03:27:00,608 REGULATE EXPRESSION, I DON'T 4639 03:27:00,608 --> 03:27:02,577 THINK THIS IS SOMETHING SPECIFIC 4640 03:27:02,577 --> 03:27:10,451 TO BETA CELLS. 4641 03:27:10,451 --> 03:27:12,854 IT'S PROBABLY SOMETHING QUITE 4642 03:27:12,854 --> 03:27:14,622 GENERAL PHENOMENON OF TISSUES 4643 03:27:14,622 --> 03:27:16,057 EXPOSED TO INTERFERONS, ALSO THE 4644 03:27:16,057 --> 03:27:21,629 PARADIGM MAY APPLY TO OTHER 4645 03:27:21,629 --> 03:27:22,263 AUTOIMMUNE DISEASES, DISPLAYING 4646 03:27:22,263 --> 03:27:25,466 INTERFERON TYPE I INTERFERON 4647 03:27:25,466 --> 03:27:31,472 SIGNAL THAT IS QUITE COMMON. 4648 03:27:31,472 --> 03:27:34,008 IT COULD SERVE IN INFLAMMATORY 4649 03:27:34,008 --> 03:27:37,045 CONDITIONS TO DIVERSIFY THE 4650 03:27:37,045 --> 03:27:39,347 PEPTIDES THAT HAVE RECOGNIZED, 4651 03:27:39,347 --> 03:27:44,619 NOT ONLY MORE PEPTIDES, 4652 03:27:44,619 --> 03:27:46,921 POTENTIALLY VIRAL PEPTIDES, ALSO 4653 03:27:46,921 --> 03:27:51,492 YOU CHANGE RESTRICTION, 4654 03:27:51,492 --> 03:27:55,330 PREVALENT RESTRICTION ELEMENTS. 4655 03:27:55,330 --> 03:27:55,863 INCIDENTALLY THERE'S SOME 4656 03:27:55,863 --> 03:27:59,934 LITERATURE, FOR EXAMPLE, IN THE 4657 03:27:59,934 --> 03:28:03,871 CANCER FIELD SHOWING THAT CANCER 4658 03:28:03,871 --> 03:28:08,009 CELLS THAT EVADE IMMUNE 4659 03:28:08,009 --> 03:28:11,279 RECOGNITION MORE FORTUNATELY 4660 03:28:11,279 --> 03:28:12,914 DOWNREGULATE HLA-B, OTHER THAN 4661 03:28:12,914 --> 03:28:16,351 HLA-A, ALSO DATA IN THE 4662 03:28:16,351 --> 03:28:19,087 TRANSPLANTATION SETTING SHOWING 4663 03:28:19,087 --> 03:28:24,659 THAT HLA-B IS MATCHING, IS 4664 03:28:24,659 --> 03:28:28,696 STRONGER PROGNOSTIC FACTOR FOR 4665 03:28:28,696 --> 03:28:32,867 ALLOGRAFT REJECTION AS COMPARED 4666 03:28:32,867 --> 03:28:34,736 TO HLA-A, MISMATCH, SUGGESTING 4667 03:28:34,736 --> 03:28:37,138 THIS COULD BE SOMETHING MORE 4668 03:28:37,138 --> 03:28:39,107 GENERAL IN THE AUTOIMMUNE FIELD 4669 03:28:39,107 --> 03:28:43,077 THAN IN OTHER DISEASE SETTINGS, 4670 03:28:43,077 --> 03:28:49,717 LINKED TO INTERFERON RESPONSES. 4671 03:28:49,717 --> 03:28:50,618 >> THANK YOU. 4672 03:28:50,618 --> 03:28:51,219 >> MOUNT SINAI SCHOOL OF 4673 03:28:51,219 --> 03:28:52,253 MEDICINE IN NEW YORK. 4674 03:28:52,253 --> 03:28:56,290 I HAVE A QUESTION TO DR. PANZER. 4675 03:28:56,290 --> 03:28:57,225 A FASCINATING TALK. 4676 03:28:57,225 --> 03:29:00,695 I HAVE TO ADMIT I HAVEN'T BEEN 4677 03:29:00,695 --> 03:29:01,996 THINKING EXTENSIVELY ABOUT ALPHA 4678 03:29:01,996 --> 03:29:03,297 CELL MALFUNCTION IN THE CONTEXT 4679 03:29:03,297 --> 03:29:06,234 OF TYPE 1, I'VE LEARNED A LOT. 4680 03:29:06,234 --> 03:29:07,402 BUT ONE THING I HAVE BEEN AND 4681 03:29:07,402 --> 03:29:09,237 ALSO THE REST OF THE FIELD HAS 4682 03:29:09,237 --> 03:29:12,039 BEEN THINKING A LOT ABOUT IS 4683 03:29:12,039 --> 03:29:14,342 HETEROGENEITY OF CELL TIMES. 4684 03:29:14,342 --> 03:29:15,443 SO I WAS JUST THINKING, 4685 03:29:15,443 --> 03:29:17,879 WONDERING IF YOU'VE EVER 4686 03:29:17,879 --> 03:29:21,182 APPROACHED FROM A HETEROGENEITY 4687 03:29:21,182 --> 03:29:25,119 POINT OF VIEW AND TRIED TO 4688 03:29:25,119 --> 03:29:26,754 IDENTIFY FUNCTIONAL SUBSETS OF 4689 03:29:26,754 --> 03:29:27,388 ALL THE CELLS? 4690 03:29:27,388 --> 03:29:29,257 >> YEAH, VERY GOOD POINTS. 4691 03:29:29,257 --> 03:29:32,860 EXACTLY WHAT I WROTE IN MY K 4692 03:29:32,860 --> 03:29:33,861 AWARD. 4693 03:29:33,861 --> 03:29:35,396 SO, I DO SEE A LOT OF 4694 03:29:35,396 --> 03:29:36,697 HETEROGENEITY IN ALPHA CELLS. 4695 03:29:36,697 --> 03:29:39,534 AND I MEAN IT'S VERY HARD TO 4696 03:29:39,534 --> 03:29:43,905 LOOK AT IT IF YOU LOOK AT 4697 03:29:43,905 --> 03:29:45,006 SECRETION, YOU LOOK AT WHATEVER 4698 03:29:45,006 --> 03:29:47,074 COMES OUT. 4699 03:29:47,074 --> 03:29:49,410 WHEN I DID A LOT OF CALCIUM 4700 03:29:49,410 --> 03:29:53,981 IMAGING YOU CAN SEE THERE ARE A 4701 03:29:53,981 --> 03:29:55,283 LOT OF SUBPOPULATIONS RESPONDING 4702 03:29:55,283 --> 03:29:56,217 TO DIFFERENT STIMULI. 4703 03:29:56,217 --> 03:29:59,587 I THINK THERE'S SOME CELLS THAT 4704 03:29:59,587 --> 03:30:01,756 RESPOND TO GLUCOSE SPECIFICALLY, 4705 03:30:01,756 --> 03:30:03,524 SOME GET ACTIVATED, THERE'S SOME 4706 03:30:03,524 --> 03:30:04,492 THAT INHIBIT IT. 4707 03:30:04,492 --> 03:30:08,563 AND THAT ALL OF THEM HAVE A 4708 03:30:08,563 --> 03:30:09,764 COMPLETELY DIFFERENT FUNCTION, 4709 03:30:09,764 --> 03:30:11,833 PROBABLY SOME OF THEM ARE 4710 03:30:11,833 --> 03:30:14,135 DYSFUNCTIONING IN DIABETES, THE 4711 03:30:14,135 --> 03:30:15,369 OTHERS ARE NOT. 4712 03:30:15,369 --> 03:30:17,438 IN THIS WHOLE NETWORK DOESN'T 4713 03:30:17,438 --> 03:30:18,506 PLAY TOGETHER ANYMORE, THEN 4714 03:30:18,506 --> 03:30:20,141 THAT'S WHEN EVERYTHING GETS 4715 03:30:20,141 --> 03:30:22,443 MESSED UP. 4716 03:30:22,443 --> 03:30:24,579 BUT, YEAH, THEY DEFINITELY -- 4717 03:30:24,579 --> 03:30:25,279 >> THANK YOU. 4718 03:30:25,279 --> 03:30:26,280 >> QUESTION ON THE RIGHT. 4719 03:30:26,280 --> 03:30:27,381 >> HE WAS FIRST. 4720 03:30:27,381 --> 03:30:30,318 GO AHEAD. 4721 03:30:30,318 --> 03:30:31,853 >> GO AHEAD. 4722 03:30:31,853 --> 03:30:32,186 >> SORRY. 4723 03:30:32,186 --> 03:30:38,326 I ENJOYED ALL THE TALKS BUT THIS 4724 03:30:38,326 --> 03:30:41,729 IS SPECIFICALLY FOR DR. 4725 03:30:41,729 --> 03:30:42,897 GARCIA-OCANA. 4726 03:30:42,897 --> 03:30:48,369 FIRST, IN THE CYTOKINE-TREATED 4727 03:30:48,369 --> 03:30:53,107 CELLS LOOKING AT HARMINE, IS THE 4728 03:30:53,107 --> 03:30:57,144 PROLIFERATION MARKER THE SAME? 4729 03:30:57,144 --> 03:31:02,083 INCREASED PROLIFERATION WITH 4730 03:31:02,083 --> 03:31:03,384 HARMINE EXTENDIN, SECONDLY 4731 03:31:03,384 --> 03:31:11,692 LOOKING AT PROLIFERATION YOU GET 4732 03:31:11,692 --> 03:31:13,127 NEUROEPITOPES, NOW YOU'RE 4733 03:31:13,127 --> 03:31:15,730 GETTING EXPRESSION OF NEW 4734 03:31:15,730 --> 03:31:20,601 EPITOPES BECAUSE CELLS ARE 4735 03:31:20,601 --> 03:31:21,168 PROLIFERATIONS. 4736 03:31:21,168 --> 03:31:25,840 >> GREAT QUESTION, GREAT IDEA, 4737 03:31:25,840 --> 03:31:29,010 SOMETHING WE SHOULD DO, SINGLE 4738 03:31:29,010 --> 03:31:31,312 CELL RNAseq, IF CELLS ARE 4739 03:31:31,312 --> 03:31:34,081 RESPONDING, NON-RESPONDING TO 4740 03:31:34,081 --> 03:31:34,615 CYTOKINES CHANGING 4741 03:31:34,615 --> 03:31:37,752 IMMUNOGENICITY AT THE SAME TIME 4742 03:31:37,752 --> 03:31:41,722 THEY ARE -- THERE'S A CYCLE 4743 03:31:41,722 --> 03:31:43,524 MACHINERY, WE HAVEN'T DONE THAT. 4744 03:31:43,524 --> 03:31:43,824 GREAT POINT. 4745 03:31:43,824 --> 03:31:50,431 THANK YOU FOR THE SUGGESTION. 4746 03:31:50,431 --> 03:31:55,369 >> CLASS 1 EXPRESSED WHEN 4747 03:31:55,369 --> 03:31:57,772 HARMINE CELLS INCREASED, NEW 4748 03:31:57,772 --> 03:31:58,039 EPITOPES. 4749 03:31:58,039 --> 03:31:59,640 >> EXACTLY WHAT WE HAVE TO DO, 4750 03:31:59,640 --> 03:31:59,840 YEAH. 4751 03:31:59,840 --> 03:32:00,841 GREAT POINT. 4752 03:32:00,841 --> 03:32:03,978 THANK YOU. 4753 03:32:03,978 --> 03:32:04,612 >> RUSSELL COCHRANE, MEDICAL 4754 03:32:04,612 --> 03:32:06,213 UNIVERSITY OF SOUTH CAROLINA. 4755 03:32:06,213 --> 03:32:10,051 MY QUESTION FOR JULIA. 4756 03:32:10,051 --> 03:32:13,454 I WANT TO ECHO REFRESHING TO SEE 4757 03:32:13,454 --> 03:32:14,655 ALPHA CELLS AND GLUCAGON, YOU 4758 03:32:14,655 --> 03:32:17,291 DON'T SEE THAT MUCH. 4759 03:32:17,291 --> 03:32:23,230 I WANT TO CLARIFY YOU MADE THE 4760 03:32:23,230 --> 03:32:33,641 POINT SEROTONIN, BEFORE, 4761 03:32:34,675 --> 03:32:38,212 INHIBITS GLUCAGON SECRETION, 4762 03:32:38,212 --> 03:32:40,381 SSRIs LOWER GLYCEMIA, AND MORE 4763 03:32:40,381 --> 03:32:46,721 IN PATIENTS USING CORRELATED 4764 03:32:46,721 --> 03:32:49,991 PROBABLY TO THE MECHANISM? 4765 03:32:49,991 --> 03:32:53,861 >>> POINT, YEAH. 4766 03:32:53,861 --> 03:32:57,131 >> THE OTHER POINT WAS I WANTED 4767 03:32:57,131 --> 03:32:58,766 TO KNOW FUTURE DIRECTIONS, ARE 4768 03:32:58,766 --> 03:33:06,641 YOU GOING DOWN THE ROAD OF USING 4769 03:33:06,641 --> 03:33:12,446 TERTIAPIN Q OR MORE WITH 4770 03:33:12,446 --> 03:33:13,481 SEROTONIN SENDING. 4771 03:33:13,481 --> 03:33:13,814 >> BOTH. 4772 03:33:13,814 --> 03:33:16,117 WE WANT TO FIND THE DRUG WE CAN 4773 03:33:16,117 --> 03:33:18,719 USE FOR PATIENTS WITH TYPE 1, 4774 03:33:18,719 --> 03:33:20,721 IDEALLY DIRECTLY TO THE CLINIC, 4775 03:33:20,721 --> 03:33:21,789 AS SUGGESTED, BUT OF COURSE WE 4776 03:33:21,789 --> 03:33:23,858 NEED TO FIGURE OUT MORE ABOUT 4777 03:33:23,858 --> 03:33:27,128 THE PATHWAY AND THAT IS REALLY 4778 03:33:27,128 --> 03:33:28,562 WHAT'S HAPPENING AND HOW EXACTLY 4779 03:33:28,562 --> 03:33:30,231 THIS IS HAPPENING. 4780 03:33:30,231 --> 03:33:34,502 SO WE ALSO WANT TO LOOK AT 4781 03:33:34,502 --> 03:33:38,239 ELECTROPHYSIOLOGY AND ALTHOUGH 4782 03:33:38,239 --> 03:33:40,541 WE COULD USE TPX, IT'S A BEE 4783 03:33:40,541 --> 03:33:43,611 TOXIN, MAYBE THERE OTHER DRUGS 4784 03:33:43,611 --> 03:33:46,981 THAT COULD BE REPURPOSED THAT 4785 03:33:46,981 --> 03:33:53,888 ARE MORE SUITABLE. 4786 03:33:53,888 --> 03:33:54,422 >> THANK YOU. 4787 03:33:54,422 --> 03:33:57,858 >> I HAVE A QUESTION TO JULIA, 4788 03:33:57,858 --> 03:34:00,127 ALSO A COMMENT. 4789 03:34:00,127 --> 03:34:03,698 WHAT DO YOU THINK IT IS THAT 4790 03:34:03,698 --> 03:34:05,833 STARTS OR INITIATES DYSFUNCTION 4791 03:34:05,833 --> 03:34:08,836 IN GLUCAGON? 4792 03:34:08,836 --> 03:34:17,678 IS IT THE GLYCEMIA OR RECURRENT 4793 03:34:17,678 --> 03:34:18,345 HYPOGLYCEMIA? 4794 03:34:18,345 --> 03:34:28,923 OLD DAYS WE GIVE INSULIN 4795 03:34:28,923 --> 03:34:29,590 INTRAVENOUSLY, OUR EXPERIENCE IF 4796 03:34:29,590 --> 03:34:32,359 YOU GAVE IT TO PEOPLE NOT 4797 03:34:32,359 --> 03:34:38,599 DIABETIC YET YOU COULD GIVE HIGH 4798 03:34:38,599 --> 03:34:42,570 DOSES WITHOUT EVER HAVING 4799 03:34:42,570 --> 03:34:43,971 HYPOGLYCEMIC BUT WHEN THEY 4800 03:34:43,971 --> 03:34:50,311 DEVELOP STAGE 3 YOU HAD TO GIVE 4801 03:34:50,311 --> 03:34:51,212 MUCH LOWER DOSES, IMMEDIATELY 4802 03:34:51,212 --> 03:34:52,646 WENT INTO HYPOGLYCEMIA. 4803 03:34:52,646 --> 03:34:54,815 LOOKS LIKE A RICH HAPPENING 4804 03:34:54,815 --> 03:34:56,684 CLINICALLY, IN THE ALPHA CELL 4805 03:34:56,684 --> 03:34:59,086 FUNCTION, AND I WAS JUST CURIOUS 4806 03:34:59,086 --> 03:35:02,256 IF YOU HAVE A HYPOTHESIS? 4807 03:35:02,256 --> 03:35:06,627 >> YES, VERY HARD-TO-ANSWER 4808 03:35:06,627 --> 03:35:08,829 QUESTION BECAUSE SO WE DO SEE, 4809 03:35:08,829 --> 03:35:11,766 FOR EXAMPLE, IN THE NOD MOUSE 4810 03:35:11,766 --> 03:35:15,136 MODEL BEFORE THEY BECOME 4811 03:35:15,136 --> 03:35:15,703 COMPLETELY HYPERGLYCEMIC, 4812 03:35:15,703 --> 03:35:19,006 THERE'S LOSS OF ALPHA CELL 4813 03:35:19,006 --> 03:35:19,440 FUNCTION. 4814 03:35:19,440 --> 03:35:19,673 ALREADY. 4815 03:35:19,673 --> 03:35:22,276 BUT THEN ON THE OTHER HAND WE 4816 03:35:22,276 --> 03:35:24,512 CAN SEE IN PATIENTS WITH TYPE 1 4817 03:35:24,512 --> 03:35:26,714 DIABETES THAT STILL HAVE CERTAIN 4818 03:35:26,714 --> 03:35:29,216 AMOUNT OF REMAINING BETA CELLS 4819 03:35:29,216 --> 03:35:31,685 THE ALPHA SEEM TO FUNCTION 4820 03:35:31,685 --> 03:35:35,990 BETTER THAN THE ONEs WHERE 4821 03:35:35,990 --> 03:35:36,857 IT'S COMPLETELY LOST. 4822 03:35:36,857 --> 03:35:38,058 I'M NOT SURE WHAT'S HAPPENING 4823 03:35:38,058 --> 03:35:40,494 BUT IN SOME CASES WE CAN SEE -- 4824 03:35:40,494 --> 03:35:43,531 MAYBE THIS IS ALSO LINKED TO 4825 03:35:43,531 --> 03:35:44,431 HETEROGENEITY OF ALPHA CELLS, 4826 03:35:44,431 --> 03:35:46,600 MAYBE SOMETHING IS HAPPENING IN 4827 03:35:46,600 --> 03:35:47,835 A CERTAIN POPULATION BEFORE 4828 03:35:47,835 --> 03:35:49,870 THERE'S A COMPLETE LOSS OF BETA 4829 03:35:49,870 --> 03:35:50,538 CELLS. 4830 03:35:50,538 --> 03:35:54,375 BUT I'M NOT EXACTLY SURE AT THIS 4831 03:35:54,375 --> 03:35:54,575 POINT. 4832 03:35:54,575 --> 03:35:57,578 >> DO YOU THINK IT COULD BE ALSO 4833 03:35:57,578 --> 03:35:58,546 INTERACTION BETWEEN ALPHA CELLS, 4834 03:35:58,546 --> 03:36:02,483 BETA CELLS, THAT NOW IS LOST AND 4835 03:36:02,483 --> 03:36:05,986 NOW THAT CHANGES IN BETWEEN, 4836 03:36:05,986 --> 03:36:06,720 PLAYS A ROLE? 4837 03:36:06,720 --> 03:36:08,389 >> ABSOLUTELY, THE MORE WE 4838 03:36:08,389 --> 03:36:10,124 KNOW, THE MORE WE GET TO KNOW, 4839 03:36:10,124 --> 03:36:12,126 THE MORE WE KNOW THAT ALL OF 4840 03:36:12,126 --> 03:36:13,961 THESE CELLS INTERACT WITH EACH 4841 03:36:13,961 --> 03:36:15,296 OTHER AND THEY NEED THIS 4842 03:36:15,296 --> 03:36:17,364 COMMUNICATION AND I MEAN I HOPE 4843 03:36:17,364 --> 03:36:20,234 I CONVINCED YOU THAT 4844 03:36:20,234 --> 03:36:22,736 SPECIFICALLY THE ALPHA CELL 4845 03:36:22,736 --> 03:36:24,638 NEEDS FEEDBACK FROM ALL OF THESE 4846 03:36:24,638 --> 03:36:24,839 CELLS. 4847 03:36:24,839 --> 03:36:26,473 IF EVEN ONE CONNECTION IS NOT 4848 03:36:26,473 --> 03:36:34,448 THERE THIS LEADS TO DYSFUNCTION 4849 03:36:34,448 --> 03:36:36,851 >> MAYBE WE'RE THE ONLY ONES IN 4850 03:36:36,851 --> 03:36:40,020 THE ROOM OLD ENOUGH TO REMEMBER, 4851 03:36:40,020 --> 03:36:44,425 ROGER UNGER DID A TRIAL IN THE 4852 03:36:44,425 --> 03:36:45,826 '60s, INFUSED SOMATOSTATIN IN 4853 03:36:45,826 --> 03:36:47,628 PATIENTS WITH TYPE 1 DIABETES, 4854 03:36:47,628 --> 03:36:51,232 WAS MORE ABLE TO CONTROL 4855 03:36:51,232 --> 03:36:52,633 DIABETES PROBABLY BECAUSE BETA 4856 03:36:52,633 --> 03:36:54,635 CELLS ARE ALREADY DEAD, HE WAS 4857 03:36:54,635 --> 03:36:57,004 WAKING UP ALPHA CELLS, GOOD 4858 03:36:57,004 --> 03:36:58,672 HYPOTHESIS TO TEST, PUBLISHED IN 4859 03:36:58,672 --> 03:36:59,773 NEW ENGLAND JOURNAL, ROGER 4860 03:36:59,773 --> 03:37:02,543 UNGER, IF YOU WANT TO LOOK FOR 4861 03:37:02,543 --> 03:37:03,978 IT. 4862 03:37:03,978 --> 03:37:08,449 ROBERTO, IF YOU WENT BACK TO 4863 03:37:08,449 --> 03:37:11,051 THERESA CALVO AND MATISSE VON 4864 03:37:11,051 --> 03:37:15,189 HARRIS, HLA CLASS 1 DO YOU HAVE 4865 03:37:15,189 --> 03:37:17,157 REAGENTS THAT CAN STAIN FOR 4866 03:37:17,157 --> 03:37:20,928 HLA-B TO SEE HOW MUCH 4867 03:37:20,928 --> 03:37:23,731 UPREGULATION RELATIVE TO A AND C 4868 03:37:23,731 --> 03:37:24,465 IN THE HUMAN SAMPLES? 4869 03:37:24,465 --> 03:37:28,569 >> SO, THERE IS PART OF THE 4870 03:37:28,569 --> 03:37:33,274 WORK WAS TO IDENTIFY HLA-B 4871 03:37:33,274 --> 03:37:36,377 ANTIBODIES, REASONABLY SPECIFIC. 4872 03:37:36,377 --> 03:37:37,912 AND WE CHARACTERIZE QUITE 4873 03:37:37,912 --> 03:37:41,382 EXTENSIVELY A COUPLE OF WHICH 4874 03:37:41,382 --> 03:37:44,018 ONE WORKS IN IMMUNOFLUORESCENCE. 4875 03:37:44,018 --> 03:37:50,591 IT'S CALLED HC-10, AND IT'S 4876 03:37:50,591 --> 03:37:51,792 EPITOPE MAPPING, EXTENSIVELY 4877 03:37:51,792 --> 03:37:53,761 CHARACTERIZED, SO SOME 4878 03:37:53,761 --> 03:37:55,629 CROSS-ACTIVITY WITH SOME 4879 03:37:55,629 --> 03:38:00,000 SPECIFIC HLA-A ALLELES, SO WE 4880 03:38:00,000 --> 03:38:03,070 TOOK CARE IN EXCLUDING DONORS 4881 03:38:03,070 --> 03:38:05,806 WITH HLA-A ALLELES TO AVOID 4882 03:38:05,806 --> 03:38:11,378 POTENTIAL CROSS-REACTIVITY, WITH 4883 03:38:11,378 --> 03:38:21,355 THAT LIMITATION CAN BE USED IN 4884 03:38:21,355 --> 03:38:23,223 IMMUNO FLUORESCENT STUDIES, 4885 03:38:23,223 --> 03:38:30,431 SARAH RICHARDSON HAS DONE THESE, 4886 03:38:30,431 --> 03:38:32,866 SHE DOES HLA-B UPREGULATION THAT 4887 03:38:32,866 --> 03:38:39,673 IS HIGHER THAN WHAT IS SEEN FOR 4888 03:38:39,673 --> 03:38:39,873 HLA-A. 4889 03:38:39,873 --> 03:38:42,810 >> I'D LIKE TO THINK EACH OF OF 4890 03:38:42,810 --> 03:38:51,251 YOU PLACED AN EASTER EGG, I'LL 4891 03:38:51,251 --> 03:38:52,686 START WITH CHERIE, DIFFERENT 4892 03:38:52,686 --> 03:38:54,488 IMMUNE CELLS SENSITIVE TO SHEER. 4893 03:38:54,488 --> 03:38:59,259 MY QUESTION WAS DO YOU KNOW OF 4894 03:38:59,259 --> 03:39:00,961 RELATION BETWEEN SHEER AND 4895 03:39:00,961 --> 03:39:02,963 MIGRATION CAPACITY, WHETHER THEY 4896 03:39:02,963 --> 03:39:09,203 ARE TARGETING SPECIFIC HLA? 4897 03:39:09,203 --> 03:39:10,971 >> STUDIES EXPLORED SIMPLE 4898 03:39:10,971 --> 03:39:11,572 SHEER EXPERIMENTS, OBSERVED 4899 03:39:11,572 --> 03:39:20,147 ALMOST DOING LIKE A SLINGBACK 4900 03:39:20,147 --> 03:39:21,248 MECHANISM, PROPEL THEMSELVES 4901 03:39:21,248 --> 03:39:22,783 BACKWARDS, REVERSE TO SHEER AS 4902 03:39:22,783 --> 03:39:24,952 OPPOSED TO STATIC EXHIBITING 4903 03:39:24,952 --> 03:39:26,620 UNIQUE PHENOMENON, STUDIES 4904 03:39:26,620 --> 03:39:30,324 LOOKED AT T CELL ADHESION ON 4905 03:39:30,324 --> 03:39:31,658 ENDOTHELIAL CELL LAYERS, WHEN 4906 03:39:31,658 --> 03:39:34,461 EXPOSED TO SHEER THEY ALTER 4907 03:39:34,461 --> 03:39:35,929 PHENOTYPE, AND THEN WHEN YOU CAN 4908 03:39:35,929 --> 03:39:37,765 ADD T CELLS TO THAT YOU SEE 4909 03:39:37,765 --> 03:39:40,734 DIFFERENT PHENOMENON IN TERMS OF 4910 03:39:40,734 --> 03:39:42,069 ADHESION AND TRANSMIGRATION. 4911 03:39:42,069 --> 03:39:44,571 THOSE STUDIES HAVE BEEN QUITE 4912 03:39:44,571 --> 03:39:46,173 LIMITED USUALLY MONOLAYERS, 4913 03:39:46,173 --> 03:39:46,840 MAYBE THERE'S A LITTLE SPACE 4914 03:39:46,840 --> 03:39:55,049 UNDER KNEAD WHERE THEY LOOK AT 4915 03:39:55,049 --> 03:39:56,817 MIGRATION, MOST IN TRANSWELLS, A 4916 03:39:56,817 --> 03:39:59,119 NEED TO EXPLORE LONG-TERM SHEER 4917 03:39:59,119 --> 03:40:00,754 ON T CELLS, RECIRCULATION, WHICH 4918 03:40:00,754 --> 03:40:03,257 IS NOT PUBLISHED. 4919 03:40:03,257 --> 03:40:04,358 PEOPLE HAVEN'T REALLY SHOWN THAT 4920 03:40:04,358 --> 03:40:04,925 SIDE. 4921 03:40:04,925 --> 03:40:06,860 THERE'S A LOT WE DON'T KNOW 4922 03:40:06,860 --> 03:40:08,429 THAT'S BEEN OBSERVED IN VIVO, 4923 03:40:08,429 --> 03:40:10,831 THAT WE NEED TO START 4924 03:40:10,831 --> 03:40:11,598 TRANSLATING IN VIVO. 4925 03:40:11,598 --> 03:40:14,234 >> DO WE KNOW IF THE ENGINEERED 4926 03:40:14,234 --> 03:40:16,303 T CELLS SUCH AS CAR-T CELLS HAVE 4927 03:40:16,303 --> 03:40:18,138 THAT PROPERTY OR CAN THE SYSTEM 4928 03:40:18,138 --> 03:40:19,773 HELP US? 4929 03:40:19,773 --> 03:40:27,681 >> NOT THAT I'M AWARE OF. 4930 03:40:27,681 --> 03:40:29,750 >> AND I THINK ADOLFO, YOU SAID 4931 03:40:29,750 --> 03:40:33,153 WE KNOW MECHANISM FOR THIS WHICH 4932 03:40:33,153 --> 03:40:36,757 WOULD BE PROLIFERATION, HOW 4933 03:40:36,757 --> 03:40:37,524 ABOUT MECHANISM FOR PROTECTION 4934 03:40:37,524 --> 03:40:43,330 AGAINST STRESS, DO WE HAVE CLUES 4935 03:40:43,330 --> 03:40:43,564 ON THAT? 4936 03:40:43,564 --> 03:40:48,502 >> YES. 4937 03:40:48,502 --> 03:40:55,742 ACTUALLY WE'RE DOING DGs, 4938 03:40:55,742 --> 03:40:56,844 ANALYSIS, CYTOKINE TREATMENT, 4939 03:40:56,844 --> 03:41:00,247 GENES ARE INVOLVED IN APOPTOSIS, 4940 03:41:00,247 --> 03:41:02,216 THEY ARE ACTIVATED BY HARMINE, 4941 03:41:02,216 --> 03:41:04,284 STILL HAVE TO BE CONFIRMED 4942 03:41:04,284 --> 03:41:07,888 BEFORE I NAME NAMES OF GENES 4943 03:41:07,888 --> 03:41:11,492 THAT THEY ARE INVOLVED. 4944 03:41:11,492 --> 03:41:12,392 SORRY. 4945 03:41:12,392 --> 03:41:12,826 BUT, YEAH. 4946 03:41:12,826 --> 03:41:20,033 >> IS THIS ONLY KINASE THAT WE 4947 03:41:20,033 --> 03:41:23,303 KNOW. 4948 03:41:23,303 --> 03:41:25,205 >> DEFINITELY NOT. 4949 03:41:25,205 --> 03:41:25,739 HARMINE. 4950 03:41:25,739 --> 03:41:26,640 INHIBITORS INHIBIT OTHER KINASES 4951 03:41:26,640 --> 03:41:30,711 AS WELL THAT THEY ARE INVOLVED 4952 03:41:30,711 --> 03:41:34,281 IN OTHER PATHWAYS, SOME FROM THE 4953 03:41:34,281 --> 03:41:38,218 SAME FAMILY, ACTUALLY, SOME 4954 03:41:38,218 --> 03:41:39,419 CRKs, INVOLVED IN 4955 03:41:39,419 --> 03:41:41,288 PROLIFERATION, SOME KINASES 4956 03:41:41,288 --> 03:41:43,090 INVOLVED IN APOPTOSIS, AND 4957 03:41:43,090 --> 03:41:45,225 INFLAMMATION SUCH AS, FOR 4958 03:41:45,225 --> 03:41:48,395 EXAMPLE, HEAT KINASES, THE SAME 4959 03:41:48,395 --> 03:41:48,729 FAMILY. 4960 03:41:48,729 --> 03:41:51,031 WE'RE WORKING ON THAT ASPECT AS 4961 03:41:51,031 --> 03:41:51,331 WELL. 4962 03:41:51,331 --> 03:41:53,534 IT'S MORE COMPLICATED THAN WE 4963 03:41:53,534 --> 03:41:54,301 EXPECTED. 4964 03:41:54,301 --> 03:41:59,673 BUT, YEAH, I MEAN THOSE ARE -- 4965 03:41:59,673 --> 03:42:06,213 KINASES AS WELL TARGETED BY 4966 03:42:06,213 --> 03:42:08,315 HARMINE, HARMALOGS. 4967 03:42:08,315 --> 03:42:10,517 THINK OF SOMETHING. 4968 03:42:10,517 --> 03:42:13,086 COMBINE TO OTHER MOLECULES, 4969 03:42:13,086 --> 03:42:14,021 METABOLIZE, WE DON'T KNOW. 4970 03:42:14,021 --> 03:42:20,360 A LOT OF THINGS TO STUDY THERE. 4971 03:42:20,360 --> 03:42:22,196 >> SO WE STILL HAVE TIME FOR 4972 03:42:22,196 --> 03:42:24,598 QUESTIONS, FOLKS. 4973 03:42:24,598 --> 03:42:25,265 PLEASE DON'T HESITATE. 4974 03:42:25,265 --> 03:42:28,435 I WANT TO TALK TO CHERIE AND 4975 03:42:28,435 --> 03:42:29,536 ROBERTO ABOUT ONE FACTOR WHICH 4976 03:42:29,536 --> 03:42:33,040 DID COME UP IN DISCUSSIONS, GUT 4977 03:42:33,040 --> 03:42:33,407 MICROBIOME. 4978 03:42:33,407 --> 03:42:42,749 SO HOW ARE YOU FACTORING IN YOUR 4979 03:42:42,749 --> 03:42:43,750 PHYSIOLOGICAL OR 4980 03:42:43,750 --> 03:42:45,485 MICROPHYSIOLOGICAL SYSTEMS THE 4981 03:42:45,485 --> 03:42:45,919 GUT. 4982 03:42:45,919 --> 03:42:47,688 GUT TISSUE IS ALSO AN IMPORTANT 4983 03:42:47,688 --> 03:42:50,123 COMPONENT OF THE GUT MICROBIOME, 4984 03:42:50,123 --> 03:42:54,595 HOW DOES THAT FIGURE INTO YOUR 4985 03:42:54,595 --> 03:42:56,463 MÉNAGE À TROIS? 4986 03:42:56,463 --> 03:42:58,198 >> FUN QUESTION. 4987 03:42:58,198 --> 03:43:00,601 THERE'S A LOT OF WORK INVESTING 4988 03:43:00,601 --> 03:43:01,868 IN CONNECTING DIFFERENT ORGANS. 4989 03:43:01,868 --> 03:43:07,507 THERE IS A LOT OF WORK IN TERMS 4990 03:43:07,507 --> 03:43:11,945 OF GUT ON A CHIP, EXPLORE 4991 03:43:11,945 --> 03:43:14,514 MICROBIOMES, A LOT OF 4992 03:43:14,514 --> 03:43:16,016 CONDITIONS, IBS, CROHNS, MODELS 4993 03:43:16,016 --> 03:43:17,351 ARE RELEVANT, CAN EXPLORE THE 4994 03:43:17,351 --> 03:43:18,552 ROLE OF MICROBIOME ON THAT. 4995 03:43:18,552 --> 03:43:20,520 THAT WOULD BE A FASCINATING 4996 03:43:20,520 --> 03:43:24,157 STUDY TO REALLY EXPLORE THOSE 4997 03:43:24,157 --> 03:43:26,693 TWO CONNECTED, AND SEE 4998 03:43:26,693 --> 03:43:31,632 ALTERATIONS OR SEE IF T CELLS 4999 03:43:31,632 --> 03:43:33,000 ARE EXPOSED VERSUS CIRCULATING 5000 03:43:33,000 --> 03:43:35,102 THROUGH THE PANCREAS ON A CHIP, 5001 03:43:35,102 --> 03:43:36,436 HOW THAT ADJUSTS, LOTS OF FUN 5002 03:43:36,436 --> 03:43:36,970 THINGS COULD BE DONE. 5003 03:43:36,970 --> 03:43:44,411 I DON'T THINK ANYONE IS WORKING 5004 03:43:44,411 --> 03:43:54,721 ON THAT JUST YET. 5005 03:43:57,524 --> 03:44:01,361 >> TWO DIFFERENT ANGLES, ONE IS 5006 03:44:01,361 --> 03:44:03,997 CROSS-ACTIVITY OF THE REACTIVE 5007 03:44:03,997 --> 03:44:07,701 CD8 T CELLS, WITH POTENTIAL 5008 03:44:07,701 --> 03:44:10,771 PEPTIDES FROM GUT MICROBIOMES 5009 03:44:10,771 --> 03:44:14,408 THAT COULD POSSIBLY FAVOR THE 5010 03:44:14,408 --> 03:44:15,075 ACTIVATION OF THESE AUTOREACTIVE 5011 03:44:15,075 --> 03:44:16,376 T CELLS. 5012 03:44:16,376 --> 03:44:19,880 THE OTHER QUESTION IS ABOUT THE 5013 03:44:19,880 --> 03:44:22,516 ROLE OF ENTEROVIRUSES, WHICH IS 5014 03:44:22,516 --> 03:44:27,321 ANOTHER ACTIVE LINE OF RESEARCH 5015 03:44:27,321 --> 03:44:31,024 IN THE LAB, SO WE'VE 5016 03:44:31,024 --> 03:44:35,295 CHARACTERIZED A NUMBER OF 5017 03:44:35,295 --> 03:44:37,364 COXSACKIE EPITOPES IN BETA CELLS 5018 03:44:37,364 --> 03:44:38,799 INFECTED BY THESE VIRUSES, NOW 5019 03:44:38,799 --> 03:44:41,535 LOOKING AT WHAT HAPPENS AT THE 5020 03:44:41,535 --> 03:44:44,871 LEVEL OF ENTRY SITE IN THE GUT 5021 03:44:44,871 --> 03:44:46,773 TO SEE WHETHER THE SAME 5022 03:44:46,773 --> 03:44:48,208 PHENOMENON IN THE BETA CELLS 5023 03:44:48,208 --> 03:44:54,348 APPLY TO THE GUT AND WHETHER WE 5024 03:44:54,348 --> 03:44:56,983 SEE A SIMILAR EXPOSURE OF THE 5025 03:44:56,983 --> 03:45:02,556 SAME EPITOPES AND WE'RE ALSO 5026 03:45:02,556 --> 03:45:05,225 USING SOME GUT MICROORGANS, 5027 03:45:05,225 --> 03:45:07,260 ORGANOIDS, FOR LOOKING MORE 5028 03:45:07,260 --> 03:45:11,965 SPECIFICALLY AT INTERACTION OF 5029 03:45:11,965 --> 03:45:12,966 DIFFERENT IMMUNE CELLS BECAUSE 5030 03:45:12,966 --> 03:45:15,268 WITH VIRUS INFECTION WE DON'T 5031 03:45:15,268 --> 03:45:16,436 HAVE THE NATURAL INTERFERON 5032 03:45:16,436 --> 03:45:17,904 RESPONSE SO WE WOULD LIKE TO 5033 03:45:17,904 --> 03:45:20,307 HAVE A SYSTEM WHERE THIS IS 5034 03:45:20,307 --> 03:45:23,810 PRESERVED, THE GUT ORGANS CAN BE 5035 03:45:23,810 --> 03:45:24,911 A GOOD STARTING POINT. 5036 03:45:24,911 --> 03:45:28,749 >> I HAVE A QUESTION FOR DR. 5037 03:45:28,749 --> 03:45:29,750 PANZER. 5038 03:45:29,750 --> 03:45:34,554 THE NIH PUT IN A LOT OF FUNDING 5039 03:45:34,554 --> 03:45:36,957 ON CROSS-TALK, IN YOUR SYSTEMS 5040 03:45:36,957 --> 03:45:38,058 SPECIFICALLY LOOKING ONLY AT 5041 03:45:38,058 --> 03:45:44,731 ALPHA CELLS, HOW DO YOU FACTOR 5042 03:45:44,731 --> 03:45:51,838 IN EFFECT OF EXOCRINE TISSUE 5043 03:45:51,838 --> 03:45:52,939 DURING INITIATION OR 5044 03:45:52,939 --> 03:45:53,640 HYPOGLYCEMIA. 5045 03:45:53,640 --> 03:45:55,709 >> THE ALPHA CELL IS INFLUENCED 5046 03:45:55,709 --> 03:45:57,644 BY A LOT OF FACTORS INCLUDING 5047 03:45:57,644 --> 03:45:59,179 NEURONS, THE GUT TOO. 5048 03:45:59,179 --> 03:46:01,782 AND I MEAN WE HAVEN'T EVEN 5049 03:46:01,782 --> 03:46:03,884 STARTED LOOKING AT ALL OF -- WE 5050 03:46:03,884 --> 03:46:06,953 CAN NOW THAT ALSO WE CAN USE THE 5051 03:46:06,953 --> 03:46:09,356 SLIDE SYSTEM, WE CAN LOOK AT 5052 03:46:09,356 --> 03:46:12,559 EFFECT OF WHATEVER CELLS IN THE 5053 03:46:12,559 --> 03:46:14,127 PANCREAS, OBVIOUSLY USE WHATEVER 5054 03:46:14,127 --> 03:46:16,263 COMES FROM THE BLOOD VESSELS OR 5055 03:46:16,263 --> 03:46:18,465 EVEN THE GUT, BUT WE HAVEN'T 5056 03:46:18,465 --> 03:46:19,666 LOOKED INTO THAT YET. 5057 03:46:19,666 --> 03:46:21,635 BUT I THINK THERE ARE A LOT OF 5058 03:46:21,635 --> 03:46:24,137 FACTORS THAT INFLUENCE THE ALPHA 5059 03:46:24,137 --> 03:46:27,974 CELL, OUTSIDE OF THE ISLET 5060 03:46:27,974 --> 03:46:28,775 MICROENVIRONMENT. 5061 03:46:28,775 --> 03:46:30,410 >> PLEASE, YES. 5062 03:46:30,410 --> 03:46:32,712 >> LAST-MINUTE QUESTION ABOUT 5063 03:46:32,712 --> 03:46:35,882 THE BETA CELL. 5064 03:46:35,882 --> 03:46:40,353 LIKE WHEN YOU TREATED THE MICE 5065 03:46:40,353 --> 03:46:42,422 WITH JUST THE COMBINATION 5066 03:46:42,422 --> 03:46:48,662 WITHOUT THE CD3 YOU DID NOT SEE 5067 03:46:48,662 --> 03:46:55,769 ANY, I WAS THINKING WHEN THE 5068 03:46:55,769 --> 03:47:00,273 CELL PROLIFERATES, LIKE WOULDN'T 5069 03:47:00,273 --> 03:47:04,644 THAT BE A PROBLEM FOR MAKING 5070 03:47:04,644 --> 03:47:07,047 CELLS MORE VULNERABLE TO TYPE 1 5071 03:47:07,047 --> 03:47:07,314 DIABETES? 5072 03:47:07,314 --> 03:47:08,248 >> GREAT POINT, ACTUALLY, AND 5073 03:47:08,248 --> 03:47:11,218 THAT GOES WITH THE QUESTION FROM 5074 03:47:11,218 --> 03:47:14,354 SOMEBODY IN THE AUDIENCE BEFORE 5075 03:47:14,354 --> 03:47:15,889 ABOUT ACTUALLY THOSE CELLS 5076 03:47:15,889 --> 03:47:18,525 PROLIFERATING, THE ONES THAT ARE 5077 03:47:18,525 --> 03:47:24,331 CHANGING EXPRESSION OF DIFFERENT 5078 03:47:24,331 --> 03:47:25,198 IMMUNOGENETIC MARKERS. 5079 03:47:25,198 --> 03:47:26,199 THE ANSWER IS I DON'T KNOW, 5080 03:47:26,199 --> 03:47:26,933 THAT'S FOR SURE. 5081 03:47:26,933 --> 03:47:31,071 I COULD ANSWER, FOR EXAMPLE, 5082 03:47:31,071 --> 03:47:34,641 THAT STILL I THINK WE'RE 5083 03:47:34,641 --> 03:47:35,509 THINKING INCREASING 5084 03:47:35,509 --> 03:47:36,743 PROLIFERATION DECREASES FINE 5085 03:47:36,743 --> 03:47:38,378 CELLS, SO IF INCREASING 5086 03:47:38,378 --> 03:47:39,479 PROLIFERATION OF THOSE CELLS 5087 03:47:39,479 --> 03:47:41,748 MAYBE ARE MAKING THEM LESS 5088 03:47:41,748 --> 03:47:43,416 IMMUNOGENIC, THAT WAY THEY ARE 5089 03:47:43,416 --> 03:47:46,052 LESS ATTACKED BY THE IMMUNE 5090 03:47:46,052 --> 03:47:51,291 SYSTEM, AND THAT'S WHY WHEN WE 5091 03:47:51,291 --> 03:47:53,393 HAVE DISEASE IN THE ENVIRONMENT, 5092 03:47:53,393 --> 03:47:54,561 COULD BE, THAT'S SOMETHING WE 5093 03:47:54,561 --> 03:47:58,098 NEED TO EXPLORE AS WELL, BUT 5094 03:47:58,098 --> 03:47:58,932 IT'S ANOTHER IDEA. 5095 03:47:58,932 --> 03:48:03,537 THANK YOU FOR THE QUESTION. 5096 03:48:03,537 --> 03:48:03,870 5097 03:48:03,870 --> 03:48:05,405 >> A FOLLOW-UP ON THAT, WERE YOU 5098 03:48:05,405 --> 03:48:07,240 THINKING OF LESS FUNCTION FOR 5099 03:48:07,240 --> 03:48:09,342 REPLICATING BETA CELL, WOULD A 5100 03:48:09,342 --> 03:48:10,877 REPLICATING ALPHA CELL ALSO BE 5101 03:48:10,877 --> 03:48:12,078 LESS FUNCTIONAL? 5102 03:48:12,078 --> 03:48:19,753 AND DO WE HAVE ANY EVIDENCE OF 5103 03:48:19,753 --> 03:48:27,961 HYPOGLYCEMIA RISK WITH TREATMENT 5104 03:48:27,961 --> 03:48:28,261 OF HARMINE? 5105 03:48:28,261 --> 03:48:30,363 >> I DON'T KNOW AT THIS POINT. 5106 03:48:30,363 --> 03:48:34,634 >> BOTH OF YOU WORK IN THE SAME 5107 03:48:34,634 --> 03:48:35,402 SECTOR, RIGHT? 5108 03:48:35,402 --> 03:48:38,371 [LAUGHTER] 5109 03:48:38,371 --> 03:48:44,077 >> WE'RE ACTUALLY WORKING ON 5110 03:48:44,077 --> 03:48:44,277 THIS. 5111 03:48:44,277 --> 03:48:45,612 >> GREAT QUESTION. 5112 03:48:45,612 --> 03:48:50,584 IT'S SOMETHING AS WELL WE 5113 03:48:50,584 --> 03:48:55,355 HAVEN'T EXAMINED, MAYBE SINGLE 5114 03:48:55,355 --> 03:48:57,757 CELL RNAseq OF MARKER FUNCTION 5115 03:48:57,757 --> 03:48:59,859 THAT COULD PERHAPS COULD GUIDE 5116 03:48:59,859 --> 03:49:03,229 US WHETHER THIS THERAPY COULD 5117 03:49:03,229 --> 03:49:05,065 CHANGE ACTUALLY, COULD CHANGE 5118 03:49:05,065 --> 03:49:09,903 THE FATE OF THOSE ALPHA CELLS OR 5119 03:49:09,903 --> 03:49:10,370 RESPONSE. 5120 03:49:10,370 --> 03:49:16,343 >> WE HAVE LOOKED AT BETA CELLS, 5121 03:49:16,343 --> 03:49:19,079 WITH HARMINE TREATMENT THERE'S 5122 03:49:19,079 --> 03:49:22,349 HIGHER EXPRESSION OF THE BETA 5123 03:49:22,349 --> 03:49:23,783 CELL MARKERS, MATURATION CELL 5124 03:49:23,783 --> 03:49:25,385 MARKERS, IF YOU WILL, BUT FOR 5125 03:49:25,385 --> 03:49:28,054 THE ALPHA CELLS PERHAPS I WAS 5126 03:49:28,054 --> 03:49:30,023 TOO FOCUSED ON CYCLING ALPHA, 5127 03:49:30,023 --> 03:49:31,658 THEY ARE NOT GAINING AN ALPHA 5128 03:49:31,658 --> 03:49:33,426 CELL MARKER EXPRESSION. 5129 03:49:33,426 --> 03:49:34,761 THEY DO EXPRESS ALPHA CELL 5130 03:49:34,761 --> 03:49:38,565 MARKERS BUT WITHIN THAT CYCLING 5131 03:49:38,565 --> 03:49:39,566 THERE'S SUBSETS AS WELL. 5132 03:49:39,566 --> 03:49:41,301 ONE OF WHICH LOOKS MORE 5133 03:49:41,301 --> 03:49:44,704 ALPHA-LIKE AND ANOTHER ONE WHICH 5134 03:49:44,704 --> 03:49:45,905 LOOKS MORE BETA-LIKE. 5135 03:49:45,905 --> 03:49:48,642 SO IF YOU LOOK AT OTHER TWO 5136 03:49:48,642 --> 03:49:50,710 ALPHA CELL SUBTYPES THAT WE 5137 03:49:50,710 --> 03:49:52,078 HAVE, AGAIN I DON'T HAVE THE 5138 03:49:52,078 --> 03:49:53,680 INFORMATION OFF THE TOP OF MY 5139 03:49:53,680 --> 03:49:56,850 HEAD BUT I DO NOT RECALL SEEING 5140 03:49:56,850 --> 03:49:59,586 MORE EXPRESSION OF ALPHA CELL 5141 03:49:59,586 --> 03:50:02,756 MARKERS BUT I CAN DOUBLE CHECK. 5142 03:50:02,756 --> 03:50:04,257 >> IT'S GOING TO BE TRICKY TO 5143 03:50:04,257 --> 03:50:05,792 FIND THESE FEW CELLS BECAUSE 5144 03:50:05,792 --> 03:50:07,694 FIRST WE HAVE LESS ALPHA CELLS, 5145 03:50:07,694 --> 03:50:11,698 AND THEN THE ONES THAT REALLY 5146 03:50:11,698 --> 03:50:13,366 CONVERT OR PROLIFERATE, SO YOU 5147 03:50:13,366 --> 03:50:17,404 HAVE TO LOOK AT INDIVIDUAL 5148 03:50:17,404 --> 03:50:18,838 CELLS, DO FUNCTIONAL STUDIES ON 5149 03:50:18,838 --> 03:50:20,373 CELLULAR LEVEL, AND THEN YOU 5150 03:50:20,373 --> 03:50:21,775 NEED TO BE ABLE TO FIND THE 5151 03:50:21,775 --> 03:50:27,447 NEEDLE IN THE HAYSTACK, THE ONE 5152 03:50:27,447 --> 03:50:28,715 CONVERTING OR PROLIFERATING. 5153 03:50:28,715 --> 03:50:36,523 SO I THINK THAT'S CHALLENGING. 5154 03:50:36,523 --> 03:50:37,857 BUT NOT IMPOSSIBLE. 5155 03:50:37,857 --> 03:50:40,026 >> A QUESTION FOR DR. PANZER. 5156 03:50:40,026 --> 03:50:43,129 I KNOW IN A HEALTHY SYSTEM 5157 03:50:43,129 --> 03:50:44,964 ADRENALINE IS ALSO SOMETHING 5158 03:50:44,964 --> 03:50:45,832 THAT MIGHT STIMULATE THE 5159 03:50:45,832 --> 03:50:46,499 SECRETION OF GLUCAGON. 5160 03:50:46,499 --> 03:50:48,902 DO YOU KNOW WHETHER THAT'S 5161 03:50:48,902 --> 03:50:51,471 MAINTAINED IN DIABETIC PATIENTS? 5162 03:50:51,471 --> 03:50:52,739 >> YEAH, GREAT POINT. 5163 03:50:52,739 --> 03:50:55,275 IT DOES. 5164 03:50:55,275 --> 03:50:57,677 AND IT IS. 5165 03:50:57,677 --> 03:51:01,281 >> IS THAT VIA THE SAME PATHWAY 5166 03:51:01,281 --> 03:51:03,917 THAT YOU EXPLAINED THAT 5167 03:51:03,917 --> 03:51:05,452 SEROTONIN INHIBITS? 5168 03:51:05,452 --> 03:51:12,892 AND CAN THIS PATHWAY BE USED IN 5169 03:51:12,892 --> 03:51:14,661 TREATMENTING HYPOGLYCEMIC 5170 03:51:14,661 --> 03:51:14,928 EPISODES? 5171 03:51:14,928 --> 03:51:16,930 >> SO ADRENALINE WORKS 5172 03:51:16,930 --> 03:51:18,598 DIFFERENTLY, IT ACTIVATES 5173 03:51:18,598 --> 03:51:23,403 GLUCAGON SECRETION, ALSO IS ONE 5174 03:51:23,403 --> 03:51:25,939 OF THE MAJOR STEPS AS A DEFENSE 5175 03:51:25,939 --> 03:51:26,606 AGAINST HYPOGLYCEMIA. 5176 03:51:26,606 --> 03:51:29,976 IF WE LOOK AT TISSUES FROM TYPE 5177 03:51:29,976 --> 03:51:31,578 1 DIABETICS, WE SEE THE RESPONSE 5178 03:51:31,578 --> 03:51:36,316 TO ADRENALINE IS STILL THERE. 5179 03:51:36,316 --> 03:51:39,085 SO, IT'S NOT AFFECTED IN THE 5180 03:51:39,085 --> 03:51:40,153 SAME WAY. 5181 03:51:40,153 --> 03:51:45,225 >> DO WE KNOW WHY THAT FUNCTION 5182 03:51:45,225 --> 03:51:47,293 IS MAINTAINED? 5183 03:51:47,293 --> 03:51:48,728 THANK YOU. 5184 03:51:48,728 --> 03:51:50,029 >> FOLLOWING UP ON THAT, JULIA, 5185 03:51:50,029 --> 03:51:51,765 YOU SAID YOU WANT YOUR PATIENTS 5186 03:51:51,765 --> 03:51:54,634 TO SLEEP BETTER AT NIGHT. 5187 03:51:54,634 --> 03:51:57,137 AND SO IS THERE PLANS TO STUDY 5188 03:51:57,137 --> 03:51:59,739 THE TIMING IN WHICH YOU WOULD 5189 03:51:59,739 --> 03:52:05,245 TREAT THE MICE, IN VIVO, WHETHER 5190 03:52:05,245 --> 03:52:08,882 YOU APPLY AT NIGHT WHEN THE MOST 5191 03:52:08,882 --> 03:52:11,618 FREQUENT HYPOGLYCEMIC EVENTS 5192 03:52:11,618 --> 03:52:13,052 WOULD HAPPEN? 5193 03:52:13,052 --> 03:52:15,021 >> YEAH, SO, YES, THERE ARE. 5194 03:52:15,021 --> 03:52:17,657 THE PROBLEM IS ALSO WHEN WE -- 5195 03:52:17,657 --> 03:52:23,329 SO LIKE THE SUGGESTION TO YOU, 5196 03:52:23,329 --> 03:52:26,199 JUST SEROTONIN, THERE'S A LOT OF 5197 03:52:26,199 --> 03:52:28,001 SOMATOSTATIN IN YOUR SYSTEM, BUT 5198 03:52:28,001 --> 03:52:29,803 IT'S DIFFERENT AND ALSO HAS 5199 03:52:29,803 --> 03:52:30,804 DIFFERENT FUNCTIONS. 5200 03:52:30,804 --> 03:52:33,873 SO THE PROBLEM IS WHATEVER WE 5201 03:52:33,873 --> 03:52:35,175 GIVE UNTO THE ISLET PER SE MIGHT 5202 03:52:35,175 --> 03:52:38,878 NOT WORK IF WE GIVE IT IN VIVO. 5203 03:52:38,878 --> 03:52:40,213 SO I THINK THERE'S A LOT MORE 5204 03:52:40,213 --> 03:52:42,715 THAT WE HAVE TO FIGURE OUT, AND 5205 03:52:42,715 --> 03:52:47,120 THEN OF COURSE WE NEED TO TEST 5206 03:52:47,120 --> 03:52:47,854 WHAT EFFECTS THESE DIFFERENT 5207 03:52:47,854 --> 03:52:49,722 DRUGS MIGHT HAVE BECAUSE WE ALSO 5208 03:52:49,722 --> 03:52:57,630 DON'T WANT THEM TO INFLUENCE 5209 03:52:57,630 --> 03:52:59,165 INSULIN SECRETION, BECAUSE THAT 5210 03:52:59,165 --> 03:53:01,034 WOULDN'T BE GOOD IN WE FURTHER 5211 03:53:01,034 --> 03:53:01,968 INCREASE GLYCEMIA. 5212 03:53:01,968 --> 03:53:03,970 YEAH, THERE'S A LOT OF THINGS TO 5213 03:53:03,970 --> 03:53:06,272 DO, BUT TIMING IS IMPORTANT TO 5214 03:53:06,272 --> 03:53:08,541 LOOK AT AS WELL. 5215 03:53:08,541 --> 03:53:10,543 >> GO AHEAD. 5216 03:53:10,543 --> 03:53:12,412 >> UNIVERSITY OF PENNSYLVANIA. 5217 03:53:12,412 --> 03:53:15,849 A COMMENT, JULIA, RELATED TO THE 5218 03:53:15,849 --> 03:53:18,017 ALPHA CELL SECRETION IN VIVO, 5219 03:53:18,017 --> 03:53:19,719 ONE THING, REMEMBER, OUR 5220 03:53:19,719 --> 03:53:21,888 PATIENTS WITH TYPE 1 DIABETES 5221 03:53:21,888 --> 03:53:23,923 DEVELOP HYPOGLYCEMIA WHEN THEY 5222 03:53:23,923 --> 03:53:26,793 HAVE A THERAPEUTIC INSULIN 5223 03:53:26,793 --> 03:53:29,496 EXCESS, SO RESPONSES OF THE 5224 03:53:29,496 --> 03:53:31,130 ALPHA CELL TO EPINEPHRINE IS 5225 03:53:31,130 --> 03:53:32,131 INHIBITED IN PRESENCE OF INSULIN 5226 03:53:32,131 --> 03:53:36,402 SO WHEN WE LOOK AT ALPHA CELL 5227 03:53:36,402 --> 03:53:44,510 RESPONSES, TYPICALLY GLUCAGON 5228 03:53:44,510 --> 03:53:46,579 INCREASING, OTHER REGULATORY 5229 03:53:46,579 --> 03:53:47,580 HORMONES AMPLIFY, WITH INSULIN 5230 03:53:47,580 --> 03:53:49,415 HIGH THEY DON'T HAVE EFFECT ON 5231 03:53:49,415 --> 03:53:50,650 INCREASING ALPHA CELL FUNCTION 5232 03:53:50,650 --> 03:53:53,086 SO SOMEONE WITH TYPE 1 DIABETES 5233 03:53:53,086 --> 03:53:57,123 HAVE HAVE A NORMAL EPINEPHRINE 5234 03:53:57,123 --> 03:53:58,324 RESPONSE, NO INCREASE IN 5235 03:53:58,324 --> 03:54:01,160 GLUCAGON, THAT'S A REAL 5236 03:54:01,160 --> 03:54:05,331 CHALLENGING CONUNDRUM WHEN 5237 03:54:05,331 --> 03:54:10,670 MOVING TO TESTING IN THE IN VIVO 5238 03:54:10,670 --> 03:54:10,937 SITUATION. 5239 03:54:10,937 --> 03:54:14,941 >> GREAT COMMENT. 5240 03:54:14,941 --> 03:54:16,142 THANK YOU. 5241 03:54:16,142 --> 03:54:17,944 >> MAYBE ONE FINAL POINT. 5242 03:54:17,944 --> 03:54:20,647 FANTASTIC PRESENTATIONS FROM 5243 03:54:20,647 --> 03:54:22,949 EACH ONE OF YOU. 5244 03:54:22,949 --> 03:54:26,352 ALL EXCITING THINGS, BETA CELL 5245 03:54:26,352 --> 03:54:28,821 PROLIFERATION, ALWAYS VERY COOL 5246 03:54:28,821 --> 03:54:30,623 BECAUSE TRADITIONALLY TYPE 1 5247 03:54:30,623 --> 03:54:31,591 DIABETES, THERAPEUTICS HAS 5248 03:54:31,591 --> 03:54:33,226 ALWAYS BEEN IMMUNE RELATED, 5249 03:54:33,226 --> 03:54:33,426 RIGHT? 5250 03:54:33,426 --> 03:54:36,396 LAST 30 OR 40 YEARS. 5251 03:54:36,396 --> 03:54:37,263 I THINK THERE'S POTENTIAL 5252 03:54:37,263 --> 03:54:39,465 STRENGTH HERE IN TERMS OF 5253 03:54:39,465 --> 03:54:44,203 PUSHING THE PROLIFERATION, I 5254 03:54:44,203 --> 03:54:48,474 MEAN, DYRK 1 INHIBITION IS ONE, 5255 03:54:48,474 --> 03:54:49,676 THERE ARE MULTIPLE FACTORS 5256 03:54:49,676 --> 03:54:53,813 COMING OUT, THE CHALLENGE IS TO 5257 03:54:53,813 --> 03:54:55,682 PUSH THE PROLIFERATION, 5258 03:54:55,682 --> 03:54:56,482 SOMETHING SUPPRESSING IMMUNE 5259 03:54:56,482 --> 03:54:58,651 SYSTEM, SO THAT SEEMS TO BE 5260 03:54:58,651 --> 03:55:01,721 EXTREMELY EXCITING IN THIS AREA. 5261 03:55:01,721 --> 03:55:04,257 IN TERMS OF THE EFFECT OF 5262 03:55:04,257 --> 03:55:09,395 DYRK1A, DO YOU KNOW THE 5263 03:55:09,395 --> 03:55:12,765 MECHANISM HOW GLP-1 ENHANCES 5264 03:55:12,765 --> 03:55:15,168 EFFECT, CREB PHOSPHORYLATION 5265 03:55:15,168 --> 03:55:20,106 EVENT, DOES IT LINK WITH DYRK1A 5266 03:55:20,106 --> 03:55:21,307 AT ALL. 5267 03:55:21,307 --> 03:55:23,943 >> NO, IT'S INVOLVED IN CALCIUM 5268 03:55:23,943 --> 03:55:27,880 FLUX, ACTUALLY ACTIVATES CALCIUM 5269 03:55:27,880 --> 03:55:31,284 MURINES, HELPING IN FACT GOING 5270 03:55:31,284 --> 03:55:33,686 TO THE NUCLEUS, WHILE INHIBITING 5271 03:55:33,686 --> 03:55:34,988 1A IN THAT SENSE. 5272 03:55:34,988 --> 03:55:37,957 YEAH, I MEAN, THAT WAS THE IDEA. 5273 03:55:37,957 --> 03:55:40,360 ANY WAY YOU CAN INCREASE 5274 03:55:40,360 --> 03:55:43,096 CALCIUM, THAT WILL ACTUALLY 5275 03:55:43,096 --> 03:55:46,833 FAVOR THE CREATION IN INHIBITORY 5276 03:55:46,833 --> 03:55:52,205 SITUATION IN WHICH DYRK1A IS 5277 03:55:52,205 --> 03:55:52,839 INHIBITED, ENHANCES 5278 03:55:52,839 --> 03:55:55,008 PROLIFERATION, THERE ARE MANY 5279 03:55:55,008 --> 03:55:56,242 OTHER KINASES THAT MAYBE 5280 03:55:56,242 --> 03:55:58,644 PARTICIPATE NOT JUST IN 5281 03:55:58,644 --> 03:55:59,979 PROLIFERATION BUT IN SURVIVAL, 5282 03:55:59,979 --> 03:56:01,047 PARTICIPATE IN CONVERSION OF 5283 03:56:01,047 --> 03:56:06,319 ALPHA CELLS TO BETA CELLS, NOT 5284 03:56:06,319 --> 03:56:07,453 AS SIMPLE AS INCREASED 5285 03:56:07,453 --> 03:56:09,822 PROLIFERATION THAT WAY. 5286 03:56:09,822 --> 03:56:11,891 IT'S MORE COMPLICATED THAT WAY. 5287 03:56:11,891 --> 03:56:14,293 >> DO WE KNOW EFFECT ON THE GUT? 5288 03:56:14,293 --> 03:56:17,830 THERE'S A LOT OF GLP-1 RECEPTOR 5289 03:56:17,830 --> 03:56:18,264 THERE. 5290 03:56:18,264 --> 03:56:19,832 >> IT'S IMPORTANT, LET ME SAY 5291 03:56:19,832 --> 03:56:20,566 THIS AGAIN. 5292 03:56:20,566 --> 03:56:24,704 I SAID IT DURING MY TALK. 5293 03:56:24,704 --> 03:56:29,275 THE DISCOVERY THAT ACTUALLY 5294 03:56:29,275 --> 03:56:30,943 GLP-1 SYNERGIZE WITH INHIBITOR 5295 03:56:30,943 --> 03:56:33,613 IS IMPORTANT BECAUSE IT ALLOWS 5296 03:56:33,613 --> 03:56:38,184 ACTUALLY TO FIRST OF ALL REDUCE 5297 03:56:38,184 --> 03:56:41,587 THOSE OF HARMINES, THAT IS 5298 03:56:41,587 --> 03:56:46,325 ACTING, THAT COULD EXPRESS 1A, 5299 03:56:46,325 --> 03:56:48,161 NOW THE DOSE GLP-1 RECEPTOR WILL 5300 03:56:48,161 --> 03:56:55,401 HAVE EFFECT PERHAPS HAPPENING IN 5301 03:56:55,401 --> 03:56:56,903 THE GUT, PERHAPS BECOME INSULIN, 5302 03:56:56,903 --> 03:56:57,904 WE HAVEN'T LOOKED AT THE GUT 5303 03:56:57,904 --> 03:56:59,439 THAT WAY. 5304 03:56:59,439 --> 03:57:04,477 WE LOOKED TO SEE WHETHER 5305 03:57:04,477 --> 03:57:05,244 INCREASING PROLIFERATION, 5306 03:57:05,244 --> 03:57:06,779 MICROLESIONS, WE DIDN'T FIND 5307 03:57:06,779 --> 03:57:09,315 ANYTHING THAT BUT DIDN'T LOOK AT 5308 03:57:09,315 --> 03:57:11,184 INSULIN POSITIVITY. 5309 03:57:11,184 --> 03:57:14,687 MAYBE IT'S ANOTHER AREA. 5310 03:57:14,687 --> 03:57:16,322 >> THANK YOU SO MUCH. 5311 03:57:16,322 --> 03:57:19,358 JOIN ME IN CONGRATULATING EACH 5312 03:57:19,358 --> 03:57:23,696 OF THE SPEAKERS FOR A GREAT 5313 03:57:23,696 --> 03:57:23,896 TALK. 5314 03:57:23,896 --> 03:57:27,066 A LOT OF EXCITEMENT FOR TEN 5315 03:57:27,066 --> 03:57:27,366 YEARS. 5316 03:57:27,366 --> 03:57:29,502 WE'RE GOING TO TAKE A 15-MINUTE 5317 03:57:29,502 --> 03:57:31,637 BREAK AND COME BACK FOR THE 5318 03:57:31,637 --> 03:57:32,939 KEYNOTE PRESENTATION, SO PLEASE 5319 03:57:32,939 --> 03:57:35,475 MAKE SURE YOU'RE BACK HERE AT 5320 03:57:35,475 --> 03:57:36,275 5:00 SHARP. 5321 03:57:36,275 --> 03:57:40,580 THANK YOU. 5322 03:57:40,580 --> 03:57:42,982 WE'LL START THIS FINAL KEYNOTE 5323 03:57:42,982 --> 03:57:43,983 TALK. 5324 03:57:43,983 --> 03:57:54,527 I'D LIKE TO INVITE DR. KAESTNER 5325 03:57:57,396 --> 03:58:00,933 UP. 5326 03:58:00,933 --> 03:58:11,511 >> A GREAT PLEASURE TO INTRODUCE 5327 03:58:17,517 --> 03:58:18,151 DR. ANETTE-GABRIELE ZEIGLER. 5328 03:58:18,151 --> 03:58:21,020 MOST OF YOU WILL HAVE HEARD 5329 03:58:21,020 --> 03:58:22,655 ABOUT HER AMAZING WORK OVER THE 5330 03:58:22,655 --> 03:58:23,156 YEARS. 5331 03:58:23,156 --> 03:58:29,762 A BIT MORE ABOUT HER HISTORY. 5332 03:58:29,762 --> 03:58:30,763 STUDIED MEDICINE IN MUNICH 5333 03:58:30,763 --> 03:58:33,699 BEFORE A POSTDOC AT THE JOSLIN 5334 03:58:33,699 --> 03:58:36,068 DIABETES CENTER IN BOSTON WITH 5335 03:58:36,068 --> 03:58:40,907 GEORGE EISSENBERG, RETURNED BACK 5336 03:58:40,907 --> 03:58:42,675 TO MUNICH, FURTHERED HER CAREER, 5337 03:58:42,675 --> 03:58:46,179 NOW DIRECTOR OF THE DIABETES 5338 03:58:46,179 --> 03:58:47,580 RESEARCH INSTITUTE AT THE 5339 03:58:47,580 --> 03:58:49,916 HELMHOLTZ CENTER IN MUNICH, 5340 03:58:49,916 --> 03:58:53,152 PROFESSOR AND CHAIR OF DIABETES 5341 03:58:53,152 --> 03:59:03,629 AT THE UNIVERSITY OF IMMUNE 5342 03:59:08,234 --> 03:59:08,401 DISEASE. 5343 03:59:08,401 --> 03:59:09,268 SHE'S RECEIVED MULTIPLE AWARDS 5344 03:59:09,268 --> 03:59:13,105 DURING HER CAREER. 5345 03:59:13,105 --> 03:59:19,979 SHE RECEIVED MARY TAYLOR MOORE 5346 03:59:19,979 --> 03:59:23,716 EXCELLENCE AWARD FROM JDRS, 5347 03:59:23,716 --> 03:59:29,055 GEORGE EISSENBERG AWARD FOR TYPE 5348 03:59:29,055 --> 03:59:32,458 1 DIABETES PREVENTION, ALSO FROM 5349 03:59:32,458 --> 03:59:33,359 GERMAN DIABETES ASSOCIATION, 5350 03:59:33,359 --> 03:59:36,862 HIGHEST HONOR IN GERMANY FOR 5351 03:59:36,862 --> 03:59:38,798 THAT FIELD. 5352 03:59:38,798 --> 03:59:40,499 SHE'S ALSO PRINCIPAL 5353 03:59:40,499 --> 03:59:42,201 INVESTIGATOR OF THE TEDDY STUDY, 5354 03:59:42,201 --> 03:59:44,070 AND PRINCIPAL INVESTIGATOR OF 5355 03:59:44,070 --> 03:59:48,107 THE TRIAL NETWORK, AND SHE ALSO 5356 03:59:48,107 --> 03:59:49,976 IS CO-LEADER OF EUROPEAN HORIZON 5357 03:59:49,976 --> 03:59:55,114 EFFORT IN THE SAME FIELD. 5358 03:59:55,114 --> 03:59:56,849 DR. ZEIGLER PUBLISHED OVER 500 5359 03:59:56,849 --> 03:59:58,718 PEER REVIEWED PAPERS, HIGHLY 5360 03:59:58,718 --> 04:00:01,454 CITED, A GREAT HONOR TO HAVE HER 5361 04:00:01,454 --> 04:00:08,027 AND TELL US ABOUT THE VULNERABLE 5362 04:00:08,027 --> 04:00:09,095 PERIOD FOR ISLET AUTOIMMUNITY. 5363 04:00:09,095 --> 04:00:14,667 >> THANK YOU VERY MUCH FOR THIS 5364 04:00:14,667 --> 04:00:19,171 VERY KIND INTRODUCTION. 5365 04:00:19,171 --> 04:00:19,405 OKAY. 5366 04:00:19,405 --> 04:00:21,007 YEAH, IT IS REALLY A GREAT HONOR 5367 04:00:21,007 --> 04:00:23,542 FOR ME TO BE INVITED TO THIS 5368 04:00:23,542 --> 04:00:26,479 MEETING, AND A GREAT MEETING. 5369 04:00:26,479 --> 04:00:29,482 THANK YOU SO MUCH FOR HAVING ME 5370 04:00:29,482 --> 04:00:30,883 HERE. 5371 04:00:30,883 --> 04:00:36,255 HERE ARE MY DISCLOSURES, ONE 5372 04:00:36,255 --> 04:00:39,692 OTHER, I'M WORKING MORE ON THE 5373 04:00:39,692 --> 04:00:40,526 PERIPHERY, PERIPHERAL BLOOD, 5374 04:00:40,526 --> 04:00:44,463 THIS IS WHAT I'M PRESENTING. 5375 04:00:44,463 --> 04:00:48,634 SO, MY TALK WILL BE MAINLY ABOUT 5376 04:00:48,634 --> 04:00:50,236 THE PERIOD LEADING TO 5377 04:00:50,236 --> 04:00:54,206 AUTOIMMUNITY, BUT AT THE END 5378 04:00:54,206 --> 04:00:56,175 WILL ALSO BRIEFLY SPEAK ABOUT 5379 04:00:56,175 --> 04:00:57,510 PROGRESSION FROM AUTOIMMUNITY TO 5380 04:00:57,510 --> 04:00:58,811 CLINICAL DIABETES. 5381 04:00:58,811 --> 04:01:03,616 AND I WILL PRESENT THREE 5382 04:01:03,616 --> 04:01:05,251 COHORTS, LONGITUDINAL BIRTH 5383 04:01:05,251 --> 04:01:07,219 COHORTS, WITH MULTIPLE SAMPLES 5384 04:01:07,219 --> 04:01:09,422 FROM BIRTH THROUGHOUT MANY, MANY 5385 04:01:09,422 --> 04:01:13,993 YEARS, ONE IS THE FIRST BIRTH 5386 04:01:13,993 --> 04:01:18,497 COHORT STUDY I INITIATED IN 5387 04:01:18,497 --> 04:01:20,366 GERMANY, EXCLUSIVELY IN FIRST 5388 04:01:20,366 --> 04:01:25,304 DEGREE RELATIVES, CHILDREN WITH 5389 04:01:25,304 --> 04:01:27,239 FATHER, SIBLING, OR MOTHER WITH 5390 04:01:27,239 --> 04:01:28,474 DIABETES. 5391 04:01:28,474 --> 04:01:29,775 FROM THE TEDDY STUDY, FOLLOWING 5392 04:01:29,775 --> 04:01:37,316 CHILDREN ALSO FROM THE GENERAL 5393 04:01:37,316 --> 04:01:43,656 POPULATION, AND SELECTED BY AGE 5394 04:01:43,656 --> 04:01:44,623 SUSCEPTIBILITY, AND POINT, 5395 04:01:44,623 --> 04:01:50,196 COLLECTED BY GENETIC RISK SCORE, 5396 04:01:50,196 --> 04:01:51,430 HIGH GENETIC RISK ALSO INCLUDING 5397 04:01:51,430 --> 04:01:53,065 GENERAL POPULATION. 5398 04:01:53,065 --> 04:01:55,468 A BIT PARTICULAR, SPEAKING ABOUT 5399 04:01:55,468 --> 04:01:59,739 THIS COHORT RECRUITED THROUGHOUT 5400 04:01:59,739 --> 04:02:02,375 THE PANDEMIC. 5401 04:02:02,375 --> 04:02:03,776 SO THIS IS THE VULNERABLE 5402 04:02:03,776 --> 04:02:04,643 PERIOD. 5403 04:02:04,643 --> 04:02:06,512 WHAT IS SPECIAL ABOUT 5404 04:02:06,512 --> 04:02:06,846 AUTOIMMUNITY? 5405 04:02:06,846 --> 04:02:10,149 WE'VE SHOWN FIRST IN THE 5406 04:02:10,149 --> 04:02:13,185 BABYDIET STUDY, IT'S NOT 5407 04:02:13,185 --> 04:02:14,186 INITIATING THROUGHOUT LIFE AT 5408 04:02:14,186 --> 04:02:15,187 THE SAME PACE. 5409 04:02:15,187 --> 04:02:17,790 THERE'S A PEAK PERIOD OF ISLET 5410 04:02:17,790 --> 04:02:18,991 AUTOIMMUNITY, VERY EARLY IN 5411 04:02:18,991 --> 04:02:22,928 LIFE, WHAT YOU SEE HERE IS THE 5412 04:02:22,928 --> 04:02:24,997 INCIDENCE OF ISLET 5413 04:02:24,997 --> 04:02:27,633 AUTOANTIBODIES, SO THE START, 5414 04:02:27,633 --> 04:02:31,904 SEROCONVERSION OF THESE 5415 04:02:31,904 --> 04:02:32,938 ANTIBODIES, IN WONDERING IF THIS 5416 04:02:32,938 --> 04:02:34,774 IS THE SAME IN THE GENERAL 5417 04:02:34,774 --> 04:02:36,275 POPULATION. 5418 04:02:36,275 --> 04:02:39,145 IN THE TEDDY STUDY, IT'S REALLY 5419 04:02:39,145 --> 04:02:40,012 THE SAME PEAK. 5420 04:02:40,012 --> 04:02:42,415 BECAUSE OF THIS PEAK THIS 5421 04:02:42,415 --> 04:02:46,352 ACTUALLY ENABLES US TO STUDY 5422 04:02:46,352 --> 04:02:48,187 THIS PERIOD BEFORE, AND ALSO ASK 5423 04:02:48,187 --> 04:02:58,731 THE QUESTION, WHY THERE IS SUCH 5424 04:03:01,100 --> 04:03:02,635 A SUSS SUSCEPTIBLE PERIOD IN 5425 04:03:02,635 --> 04:03:03,135 EARLY LIFE. 5426 04:03:03,135 --> 04:03:06,038 THIS IS A VERY GOOD AGE TO 5427 04:03:06,038 --> 04:03:08,040 DIAGNOSE, AND LASTLY TO DO 5428 04:03:08,040 --> 04:03:09,008 PRIMARY PREVENTION STUDIES 5429 04:03:09,008 --> 04:03:13,078 BECAUSE WE HAVE A VERY SHORT 5430 04:03:13,078 --> 04:03:14,914 READOUT, NAMELY THIS PEAK VERY 5431 04:03:14,914 --> 04:03:17,883 EARLY IN LIFE. 5432 04:03:17,883 --> 04:03:19,452 SO, THERE IS SOME HETEROGENEITY, 5433 04:03:19,452 --> 04:03:23,789 AND I'M JUST GIVING YOU ONE 5434 04:03:23,789 --> 04:03:26,559 EXAMPLE. 5435 04:03:26,559 --> 04:03:27,960 YOU CAN SEE MALES HAVE EARLIER 5436 04:03:27,960 --> 04:03:31,363 AND HIGHER PEAK OF THIS 5437 04:03:31,363 --> 04:03:32,765 AUTOIMMUNITY THAN FEMALES. 5438 04:03:32,765 --> 04:03:33,866 OTHER FACTORS INFLUENCE THE PEAK 5439 04:03:33,866 --> 04:03:36,735 BUT I JUST WANTED TO GIVE ONE 5440 04:03:36,735 --> 04:03:37,269 EXAMPLE. 5441 04:03:37,269 --> 04:03:40,105 AND I'M ALSO SHOWING YOU THAT IF 5442 04:03:40,105 --> 04:03:42,508 ONE LOOKS AT THAT, A BIT OF A 5443 04:03:42,508 --> 04:03:44,577 DIFFERENT WAY, NOT AS AN 5444 04:03:44,577 --> 04:03:47,546 INCIDENCE CURVE BUT JUST AS THE 5445 04:03:47,546 --> 04:03:50,716 RELATIVE RISK TO DEVELOP THIS 5446 04:03:50,716 --> 04:03:53,919 ISLET ANTIBODY, THERE ARE 5447 04:03:53,919 --> 04:03:55,988 FACTORS LIKE GENETIC FACTORS, 5448 04:03:55,988 --> 04:03:58,290 PROBABLY ENVIRONMENTAL FACTORS 5449 04:03:58,290 --> 04:03:59,625 THAT HAVE DIFFERENT IMPACT ON 5450 04:03:59,625 --> 04:04:03,963 THE RISK DEPENDING ON THE AGE. 5451 04:04:03,963 --> 04:04:07,466 YOU SEE HERE THE INCREASE OF 5452 04:04:07,466 --> 04:04:10,636 RISK FOR THE INSULIN GENOTYPE IS 5453 04:04:10,636 --> 04:04:13,806 TWO-FOLD IN EARLY AGE GROUPS BUT 5454 04:04:13,806 --> 04:04:17,543 GOES DOWN BELOW 1, THAT MEANS IF 5455 04:04:17,543 --> 04:04:20,346 YOU DEVELOP ANTIBODIES LATER ON, 5456 04:04:20,346 --> 04:04:22,581 THIS GENOTYPE, FOR EXAMPLE, 5457 04:04:22,581 --> 04:04:23,349 DOESN'T MATTER ANYMORE. 5458 04:04:23,349 --> 04:04:25,985 BUT IF YOU DEVELOP IT EARLY, IT 5459 04:04:25,985 --> 04:04:27,386 INCREASES THE RISK. 5460 04:04:27,386 --> 04:04:28,954 AND THIS IS THE FACT, THE SAME 5461 04:04:28,954 --> 04:04:33,526 WITH HLA AND OTHER GENETIC 5462 04:04:33,526 --> 04:04:36,262 FACTORS, SO THESE IMPACT MAINLY 5463 04:04:36,262 --> 04:04:36,896 FOR EARLY PEAK AUTOIMMUNITY, NOT 5464 04:04:36,896 --> 04:04:37,630 SO MUCH LATER ON. 5465 04:04:37,630 --> 04:04:41,400 THIS IS WHY I THINK WE HAVE ALSO 5466 04:04:41,400 --> 04:04:43,269 TO LOOK AT ENVIRONMENTAL 5467 04:04:43,269 --> 04:04:44,470 FACTORS, TRIGGERS, IN A 5468 04:04:44,470 --> 04:04:46,539 DIFFERENT WAY AND VERY AGE 5469 04:04:46,539 --> 04:04:47,206 DEPENDENT. 5470 04:04:47,206 --> 04:04:49,942 SO WHY ARE CHILDREN SO 5471 04:04:49,942 --> 04:04:51,277 SUSCEPTIBLE IN THE FIRST YEARS? 5472 04:04:51,277 --> 04:04:54,013 BECAUSE YOU ARE VERY MUCH 5473 04:04:54,013 --> 04:04:55,514 INTERESTED IN BETA CELLS, AND 5474 04:04:55,514 --> 04:04:56,615 JUST STARTING WITH BETA CELL, 5475 04:04:56,615 --> 04:04:58,684 WHAT WE DID IN THIS POINT STUDY 5476 04:04:58,684 --> 04:05:04,256 FOR SAFETY REASONS, WE MONITORED 5477 04:05:04,256 --> 04:05:05,724 GLUCOSE LEVELS IN THE CHILDREN 5478 04:05:05,724 --> 04:05:06,559 INTENSIVELY OVER THE FIRST 5479 04:05:06,559 --> 04:05:10,863 YEARS, AND WHEN WE LOOKED AT ALL 5480 04:05:10,863 --> 04:05:13,299 THE CHILDREN, JUST WITH GENETIC 5481 04:05:13,299 --> 04:05:15,467 RISK SCORE, SAW GLUCOSE LEVELS 5482 04:05:15,467 --> 04:05:17,403 ARE NOT STABLE OVER FIRST YEARS 5483 04:05:17,403 --> 04:05:18,270 OF LIFE. 5484 04:05:18,270 --> 04:05:22,341 THEY DECREASE AND THEY INCREASE. 5485 04:05:22,341 --> 04:05:25,511 AND THIS KIND OF MIRRORS ALMOST 5486 04:05:25,511 --> 04:05:27,146 THE PEAK INCIDENCE OF 5487 04:05:27,146 --> 04:05:31,750 AUTOIMMUNITY, IN LIFE. 5488 04:05:31,750 --> 04:05:34,286 SO GLUCOSE METABOLISM LIKELY 5489 04:05:34,286 --> 04:05:35,254 PANCREATIC ISLETS UNDERGO 5490 04:05:35,254 --> 04:05:36,355 SUBSTANTIAL MODIFICATIONS DURING 5491 04:05:36,355 --> 04:05:37,990 THE FIRST YEAR OF LIFE, AND THIS 5492 04:05:37,990 --> 04:05:40,292 IS A FIRST INDICATION THAT MAYBE 5493 04:05:40,292 --> 04:05:42,261 DURING THIS TIME THE BETA CELL 5494 04:05:42,261 --> 04:05:45,431 IS VERY ACTIVE, AND MAYBE EVEN 5495 04:05:45,431 --> 04:05:49,468 MORE VULNERABLE AND THIS IS WHY 5496 04:05:49,468 --> 04:05:50,669 AUTOIMMUNITY HAPPENS DURING THIS 5497 04:05:50,669 --> 04:05:52,004 ACTIVITY PHASE. 5498 04:05:52,004 --> 04:05:55,741 WHAT WE DID, WE LOOKED AT 5499 04:05:55,741 --> 04:05:58,043 FACTORS THAT INFLUENCED THE 5500 04:05:58,043 --> 04:05:59,645 DECREASE AND ALSO INCREASE, WE 5501 04:05:59,645 --> 04:06:01,614 WERE CUTTING THIS CURVE KIND OF 5502 04:06:01,614 --> 04:06:02,615 IN HALF. 5503 04:06:02,615 --> 04:06:04,817 YOU SEE AGAIN SEX MATTERS. 5504 04:06:04,817 --> 04:06:06,986 SO BOYS HAVE HIGHER LEVELS THAN 5505 04:06:06,986 --> 04:06:07,419 GIRLS. 5506 04:06:07,419 --> 04:06:09,188 I SHOWED YOU JUST BEFORE THAT 5507 04:06:09,188 --> 04:06:11,824 THE PEAK INCIDENCE OF 5508 04:06:11,824 --> 04:06:12,791 AUTOIMMUNITY IS SOMEHOW ALSO 5509 04:06:12,791 --> 04:06:15,427 DIFFERENT BY SEX. 5510 04:06:15,427 --> 04:06:17,062 YOU SEE ALSO INSULIN PHENOTYPE 5511 04:06:17,062 --> 04:06:17,296 MATTERS. 5512 04:06:17,296 --> 04:06:19,231 IF YOU HAVE THE SUSCEPTIBLE 5513 04:06:19,231 --> 04:06:21,233 GENOTYPE, HAVE YOU SOME OF 5514 04:06:21,233 --> 04:06:22,901 HIGHER AND STEEPER FALL OF THE 5515 04:06:22,901 --> 04:06:25,504 GLUCOSE LEVELS THAN THE OTHERS. 5516 04:06:25,504 --> 04:06:28,774 SO THESE FACTORS SEEM TO SOMEHOW 5517 04:06:28,774 --> 04:06:30,175 INFLUENCE EARLY GLUCOSE AND BETA 5518 04:06:30,175 --> 04:06:32,945 CELL ACTIVITY AS THEY DO 5519 04:06:32,945 --> 04:06:33,579 AUTOIMMUNITY. 5520 04:06:33,579 --> 04:06:34,713 SO, OF COURSE, WE ALSO LOOKED, 5521 04:06:34,713 --> 04:06:37,016 THESE WERE IN ALL CHILDREN, JUST 5522 04:06:37,016 --> 04:06:41,286 INDEPENDENT WHETHER THEY 5523 04:06:41,286 --> 04:06:42,588 DEVELOPED AUTOIMMUNITY OR NOT. 5524 04:06:42,588 --> 04:06:44,556 WE LOOKED AT GLUCOSE LEVELS TO 5525 04:06:44,556 --> 04:06:47,226 THE TIME OF SEROCONVERSION. 5526 04:06:47,226 --> 04:06:51,463 AND WHAT WAS KIND OF STRIKING TO 5527 04:06:51,463 --> 04:07:01,974 US WE COLLECTED PRE-PLANNEDDAL 5528 04:07:07,379 --> 04:07:10,182 AND POSTPRANDIAL, THERE WAS 5529 04:07:10,182 --> 04:07:17,389 AFTERWARDS RISE IN THIS, 5530 04:07:17,389 --> 04:07:19,358 DIFFERENCE OF 15-MILLIGRAM THIS 5531 04:07:19,358 --> 04:07:22,995 RISE WAS WITHIN THE NORMAL 5532 04:07:22,995 --> 04:07:23,962 GLYCEMIC LEVELS. 5533 04:07:23,962 --> 04:07:25,464 THE QUESTION IS DOES THIS 5534 04:07:25,464 --> 04:07:26,899 SUGGEST BETA CELL INJURY BEFORE 5535 04:07:26,899 --> 04:07:30,069 THE START OF AUTOIMMUNITY? 5536 04:07:30,069 --> 04:07:33,572 AND JUST AS A FIRST BRIEF 5537 04:07:33,572 --> 04:07:34,473 SUMMARY, BLOOD GLUCOSE 5538 04:07:34,473 --> 04:07:40,579 METABOLISM AS I SHOWED INVERSELY 5539 04:07:40,579 --> 04:07:42,014 FOLLOWS AUTOIMMUNITY INCIDENCE, 5540 04:07:42,014 --> 04:07:43,449 MAY INDICATE PERIOD OF 5541 04:07:43,449 --> 04:07:45,984 VULNERABILITY AND ACTIVITY, AND 5542 04:07:45,984 --> 04:07:50,255 THIS SUDDEN RISE IN 5543 04:07:50,255 --> 04:07:52,624 POST-PARANDIAL MAY BE CONSISTENT 5544 04:07:52,624 --> 04:07:54,059 WITH EVENT THAT AFFECTS ISLET 5545 04:07:54,059 --> 04:07:54,560 FUNCTION. 5546 04:07:54,560 --> 04:07:57,463 WHAT COULD BE SUCH AN EVENT? 5547 04:07:57,463 --> 04:08:01,200 WHAT WE ALSO DID, WE STARTED 5548 04:08:01,200 --> 04:08:03,368 INTENSIVELY DURING THIS VERY 5549 04:08:03,368 --> 04:08:05,437 EARLY PERIOD, EVERYTHING SOMEHOW 5550 04:08:05,437 --> 04:08:07,106 RELATED TO INFECTION AND 5551 04:08:07,106 --> 04:08:07,439 INFLAMMATION. 5552 04:08:07,439 --> 04:08:11,009 AND YOU CAN SEE IN THIS TEDDY 5553 04:08:11,009 --> 04:08:13,746 STUDY JUST LOOKING AT 5554 04:08:13,746 --> 04:08:15,380 RESPIRATORY INFECTION EPISODES, 5555 04:08:15,380 --> 04:08:17,149 THAT ALSO THOSE ARE QUITE 5556 04:08:17,149 --> 04:08:20,853 FREQUENT IN THIS VERY EARLY AGE 5557 04:08:20,853 --> 04:08:25,591 PERIOD, AND THEY DECLINE, ALSO 5558 04:08:25,591 --> 04:08:27,226 SOMEHOW ALMOST MIRRORING 5559 04:08:27,226 --> 04:08:29,962 AUTOIMMUNITY INCIDENCE. 5560 04:08:29,962 --> 04:08:34,433 WE STUDIED CHILDREN OVER 800 5561 04:08:34,433 --> 04:08:37,503 CHILDREN FOR A CD 169 EXPRESSION 5562 04:08:37,503 --> 04:08:38,403 ON MONOCYTES. 5563 04:08:38,403 --> 04:08:41,140 HERE YOU CAN SEE THAT THERE IS 5564 04:08:41,140 --> 04:08:43,108 MUCH MORE INFLAMMATION OF THESE 5565 04:08:43,108 --> 04:08:45,277 MONOCYTES EARLY IN AGE, AND THAT 5566 04:08:45,277 --> 04:08:46,812 DECREASES OVER TIME. 5567 04:08:46,812 --> 04:08:48,280 THIS IS PROBABLY REFLECTING 5568 04:08:48,280 --> 04:08:51,650 THESE CHILDREN HAVE MANY MORE 5569 04:08:51,650 --> 04:08:53,719 INFECTIONS, AND ARE EXPOSED TO 5570 04:08:53,719 --> 04:08:54,553 NEW ENVIRONMENTAL FACTORS, AND 5571 04:08:54,553 --> 04:08:58,557 THIS IS WHY THERE IS A LOT OF 5572 04:08:58,557 --> 04:08:59,124 INFLAMMATION. 5573 04:08:59,124 --> 04:09:01,827 THIS WAS ALREADY SHOWN BY 5574 04:09:01,827 --> 04:09:04,663 ROBERTO BEFORE. 5575 04:09:04,663 --> 04:09:07,633 WE ALSO SEE INDEED TYPE I 5576 04:09:07,633 --> 04:09:08,934 INTERFERON TRANSCRIPTIONAL 5577 04:09:08,934 --> 04:09:10,569 SIGNATURE PRECEDES ISLET 5578 04:09:10,569 --> 04:09:11,837 AUTOIMMUNITY SEROCONVERSION. 5579 04:09:11,837 --> 04:09:15,274 ALSO AN INDICATION THAT THERE 5580 04:09:15,274 --> 04:09:17,476 MAY BE INFLAMMATION HAPPENING, 5581 04:09:17,476 --> 04:09:20,879 INFECTION HAPPENING, BEFORE THE 5582 04:09:20,879 --> 04:09:22,748 AUTOIMMUNITY STARTS. 5583 04:09:22,748 --> 04:09:25,450 AND IN FACT WHAT WE DID THAT WE 5584 04:09:25,450 --> 04:09:27,886 INCUBATED, THIS IS IN VITRO 5585 04:09:27,886 --> 04:09:33,592 DATA, T CELLS WITH THESE 5586 04:09:33,592 --> 04:09:34,193 INFLAMED CYCLIC MONOCYTES 5587 04:09:34,193 --> 04:09:35,227 COMPARED TO THOSE NEGATIVE. 5588 04:09:35,227 --> 04:09:38,630 YOU SEE IN VITRO IN CHILDREN 5589 04:09:38,630 --> 04:09:43,001 WITH SUSCEPTIBLE GENOTYPES YOU 5590 04:09:43,001 --> 04:09:45,637 SEE MORE REACTIVITY TO INSULIN 5591 04:09:45,637 --> 04:09:52,811 FROM CD4 T CELLS UNDER THIS 5592 04:09:52,811 --> 04:09:54,379 INFLAMED CONDITION, JUST 5593 04:09:54,379 --> 04:09:55,247 INDICATING INFLAMMATION 5594 04:09:55,247 --> 04:09:59,084 INFECTION ALSO PROVIDES SOME 5595 04:09:59,084 --> 04:10:00,219 PROPENSITY TO AUTOREACTIVITY. 5596 04:10:00,219 --> 04:10:07,392 AND THERE'S ALSO SOME DATA FROM 5597 04:10:07,392 --> 04:10:09,728 DREY SON STUDDING ANTIGEN 5598 04:10:09,728 --> 04:10:11,330 RESPONSIVE EFT CELLS AT THE AGE 5599 04:10:11,330 --> 04:10:14,533 OF SIX MONTHS IN CHILDREN, THAT 5600 04:10:14,533 --> 04:10:18,103 WERE ALL BEFORE THEY DEVELOPED 5601 04:10:18,103 --> 04:10:18,804 AUTOIMMUNITY. 5602 04:10:18,804 --> 04:10:21,607 IF YOU COMPARE THOSE WHO DEVELOP 5603 04:10:21,607 --> 04:10:23,609 LATER ANTIBODIES TO ANTIBODY 5604 04:10:23,609 --> 04:10:25,577 NEGATIVE GROUP, YOU ALSO SEE 5605 04:10:25,577 --> 04:10:29,748 HERE THAT THERE IS ACTUALLY A 5606 04:10:29,748 --> 04:10:31,283 SIGNATURE OF PRO-INFLAMMATORY 5607 04:10:31,283 --> 04:10:33,018 T-CELL RESPONSES. 5608 04:10:33,018 --> 04:10:35,854 JUST ALL INDICATING THAT 5609 04:10:35,854 --> 04:10:37,923 INFLAMMATION DURING THIS PERIOD 5610 04:10:37,923 --> 04:10:40,125 MAY REALLY SOMEHOW MATTER FOR 5611 04:10:40,125 --> 04:10:42,427 THE IMMUNE RESPONSE. 5612 04:10:42,427 --> 04:10:45,364 SO, AS A SUMMARY INFLAMMATORY 5613 04:10:45,364 --> 04:10:46,565 PROCESSES ARE QUITE FREQUENT 5614 04:10:46,565 --> 04:10:51,169 EARLY IN LIFE, MAY LEAD TO 5615 04:10:51,169 --> 04:10:52,237 INCREASED PROPENSITY FOR 5616 04:10:52,237 --> 04:10:53,038 AUTOREACTIVITY, THIS ALREADY 5617 04:10:53,038 --> 04:10:56,408 EARLY BETA CELL STRESS OR INJURY 5618 04:10:56,408 --> 04:11:01,914 WHICH INCREASES THE LIKELIHOOD 5619 04:11:01,914 --> 04:11:03,649 OF AUTOIMMUNITY. 5620 04:11:03,649 --> 04:11:06,051 ARE THERE IDENTIFIERS EARLY IN 5621 04:11:06,051 --> 04:11:08,887 LIFE? 5622 04:11:08,887 --> 04:11:12,391 AND I WILL SPEAK ABOUT MYERS, 5623 04:11:12,391 --> 04:11:13,058 BRIEFLY MENTION MATERNAL 5624 04:11:13,058 --> 04:11:15,360 DIABETES BECAUSE I THINK IT'S 5625 04:11:15,360 --> 04:11:19,665 ALSO VERY RELEVANT FOR THE BETA 5626 04:11:19,665 --> 04:11:19,865 CELL. 5627 04:11:19,865 --> 04:11:24,136 YOU ALSO KNOW THAT MANY OF THOSE 5628 04:11:24,136 --> 04:11:26,238 PROSPECTIVE BIRTH COHORT STUDIES 5629 04:11:26,238 --> 04:11:32,244 NOT ONLY BABYDIET AND TEDDY BUT 5630 04:11:32,244 --> 04:11:34,012 DIP, DAISY MEDIA, INSURANCE 5631 04:11:34,012 --> 04:11:38,817 DATA, FOUND AN ASSOCIATION OF 5632 04:11:38,817 --> 04:11:39,418 EARLY MAINLY RESPIRATORY 5633 04:11:39,418 --> 04:11:45,590 INFECTIONS, IN PARTICULAR VIRAL 5634 04:11:45,590 --> 04:11:46,491 INFECTIONS, ASSOCIATED WITH 5635 04:11:46,491 --> 04:11:48,026 INCREASED OF ISLET IMMUNITY. 5636 04:11:48,026 --> 04:11:52,497 YOU SEE FROM TEDDY, EARLY 5637 04:11:52,497 --> 04:11:53,598 INFECTION, SIX TO NINE MONTHS, 5638 04:11:53,598 --> 04:11:58,303 THREE TO SIX MONTHS OR SO, 5639 04:11:58,303 --> 04:11:58,971 ASSOCIATED WITH ISLET 5640 04:11:58,971 --> 04:12:03,342 AUTOIMMUNITY, SIMILAR THING IN 5641 04:12:03,342 --> 04:12:04,376 BABYDIET, BUT NOT 5642 04:12:04,376 --> 04:12:08,680 GASTROINTESTINAL INFECTIONS, 5643 04:12:08,680 --> 04:12:12,884 THEY WERE RESPIRATORY. 5644 04:12:12,884 --> 04:12:14,953 TEDDY DID AMAZING WORK, ONE OF 5645 04:12:14,953 --> 04:12:16,154 THE LARGEST SEQUENCING STUDIES 5646 04:12:16,154 --> 04:12:19,091 OF VIRUSES IN STOOL SAMPLES, 5647 04:12:19,091 --> 04:12:26,465 FURTHER FOUNT ENTEROVIRUS B 5648 04:12:26,465 --> 04:12:28,333 POSITIVITY INCREASES SUSCEPTIBLE 5649 04:12:28,333 --> 04:12:31,403 TO AUTOIMMUNITY, THE SPECIAL 5650 04:12:31,403 --> 04:12:34,573 THING THAT PROLONGED INFECTION 5651 04:12:34,573 --> 04:12:36,975 WERE CRITICAL BECAUSE 5652 04:12:36,975 --> 04:12:40,512 SIGNIFICANCE ONLY THERE IF 5653 04:12:40,512 --> 04:12:41,480 SEVERAL CONSECUTIVE STOOL 5654 04:12:41,480 --> 04:12:45,083 SAMPLES WERE FOUND POSITIVE FOR 5655 04:12:45,083 --> 04:12:48,820 THE SAME VIRUS, FIRST EVIDENCE 5656 04:12:48,820 --> 04:12:52,758 IT IS ENTEROVIRUS, COXSACKIE, 5657 04:12:52,758 --> 04:12:56,495 NOT ONLY INFECTION OR UPPER 5658 04:12:56,495 --> 04:12:57,729 RESPIRATORY, IT'S ONE VIRUS 5659 04:12:57,729 --> 04:13:03,635 CANDIDATE, A DATA IN ISLETS 5660 04:13:03,635 --> 04:13:06,705 WHERE YOU FOUND COXSACKIE AS A 5661 04:13:06,705 --> 04:13:09,708 POSSIBLE VIRUS IN HISTOLOGY 5662 04:13:09,708 --> 04:13:11,309 STUDIES. 5663 04:13:11,309 --> 04:13:13,178 WHAT IS ALSO CLEAR THIS IS NOT 5664 04:13:13,178 --> 04:13:14,279 SO FREQUENT. 5665 04:13:14,279 --> 04:13:16,214 THIS PROLONGED INFECTION WAS 5666 04:13:16,214 --> 04:13:20,285 FOUND IN 30% OF THE CASES, 5667 04:13:20,285 --> 04:13:23,989 COMPARED TO 5.7% OF CONTROLS. 5668 04:13:23,989 --> 04:13:26,124 SO EITHER IT IS NOT FOUND IN 5669 04:13:26,124 --> 04:13:28,593 SCHOOL SAMPLES OR THE TIME, BUT 5670 04:13:28,593 --> 04:13:30,462 IT'S POSSIBLE, OR MAYBE THERE 5671 04:13:30,462 --> 04:13:32,964 ARE ALSO OTHER VIRUSES WHO CAN 5672 04:13:32,964 --> 04:13:36,568 HAVE A SIMILAR EFFECT, OR OTHER 5673 04:13:36,568 --> 04:13:38,870 JUST INFLAMMATORY CONDITIONS 5674 04:13:38,870 --> 04:13:41,373 COULD MAYBE INDUCE AUTOIMMUNITY, 5675 04:13:41,373 --> 04:13:44,342 PROBABLY NOT ALL VIRUS. 5676 04:13:44,342 --> 04:13:47,746 BUT ALSO THEN ALONG CAME COVID. 5677 04:13:47,746 --> 04:13:49,247 AND WE WENT TO SOME NATURAL 5678 04:13:49,247 --> 04:13:51,216 EXPERIMENT, WHERE WE COULD LOOK 5679 04:13:51,216 --> 04:13:56,822 AT INFECTIONS AND BECAUSE WE DID 5680 04:13:56,822 --> 04:13:59,091 THIS CLINICAL TRIAL POINT, WE 5681 04:13:59,091 --> 04:14:03,829 HAD TO LOOK AT STUDY AND STUDY 5682 04:14:03,829 --> 04:14:14,339 ADVERSE EVENTS INTENSIVELY IN 5683 04:14:14,639 --> 04:14:19,010 CHILDREN, 4 TO 9 MONTHS, ET 5684 04:14:19,010 --> 04:14:20,645 CETERA, COMPARED TO PRE-PANDEMIC 5685 04:14:20,645 --> 04:14:22,080 PERIOD, DURING THE PANDEMIC 5686 04:14:22,080 --> 04:14:23,415 PERIOD INFECTIONS AND 5687 04:14:23,415 --> 04:14:23,982 RESPIRATORY INFECTIONS WENT 5688 04:14:23,982 --> 04:14:28,220 DOWN, IF YOU LOOK AT COXSACKIE 5689 04:14:28,220 --> 04:14:29,754 INFECTIONS THEY WERE ALMOST 5690 04:14:29,754 --> 04:14:30,188 ZERO. 5691 04:14:30,188 --> 04:14:36,862 AFTER THE FIRST YEAR OF 5692 04:14:36,862 --> 04:14:38,363 PANDEMIC, LOCKDOWNED RELEASED, 5693 04:14:38,363 --> 04:14:39,498 INFECTIONS SAME BACK TO EVEN 5694 04:14:39,498 --> 04:14:41,733 SLIGHTLY HIGHER LEVEL THAN 5695 04:14:41,733 --> 04:14:42,234 BEFORE. 5696 04:14:42,234 --> 04:14:45,971 LOOK AT ISLET AUTOIMMUNITY, THE 5697 04:14:45,971 --> 04:14:48,373 BLUE CURVE IS PRE-PANDEMIC, THE 5698 04:14:48,373 --> 04:14:48,640 INCIDENCE. 5699 04:14:48,640 --> 04:14:51,977 DURING THIS TIME WHERE THESE 5700 04:14:51,977 --> 04:14:54,079 INFECTIONS AND COXSACKIE 5701 04:14:54,079 --> 04:14:57,349 INFECTIONS WENT DOWN, THE ISLET 5702 04:14:57,349 --> 04:14:59,417 ANTIBODY INCIDENTS WERE 5703 04:14:59,417 --> 04:15:00,085 ABSOLUTELY IDENTICAL. 5704 04:15:00,085 --> 04:15:02,487 AFTERWARDS IT WAS EVEN 5705 04:15:02,487 --> 04:15:04,456 INCREASED, SUGGESTING THAT ALSO 5706 04:15:04,456 --> 04:15:06,525 IT'S NOT ALL COXSACKIE, AND WE 5707 04:15:06,525 --> 04:15:09,694 STARTED IN THIS COHORT ALSO THE 5708 04:15:09,694 --> 04:15:10,695 ASSOCIATION WITH COVID 5709 04:15:10,695 --> 04:15:16,268 INFECTIONS AND WHAT WE SAW THAT 5710 04:15:16,268 --> 04:15:18,136 IN POINT TWO INFECTIONS IN THE 5711 04:15:18,136 --> 04:15:20,405 CHILDREN ACTUALLY INCREASED ALSO 5712 04:15:20,405 --> 04:15:22,073 THE LIKELIHOOD TO DEVELOP THESE 5713 04:15:22,073 --> 04:15:25,911 ANTIBODIES, IF YOU COMPARE ISLET 5714 04:15:25,911 --> 04:15:26,411 ANTIBODY INCIDENCE FROM 5715 04:15:26,411 --> 04:15:28,947 PRE-PANDEMIC IF A CHILD DID NOT 5716 04:15:28,947 --> 04:15:30,815 HAVE A COVID INFECTION, TO THOSE 5717 04:15:30,815 --> 04:15:33,685 WHO WERE INFECTED. 5718 04:15:33,685 --> 04:15:37,055 SARS INFECTION INCREASED IT 5719 04:15:37,055 --> 04:15:37,689 TWO-FOLD. 5720 04:15:37,689 --> 04:15:40,458 WHAT WAS ALSO INTERESTING IS 5721 04:15:40,458 --> 04:15:42,194 THAT IF THAT INFECTION HAPPENED 5722 04:15:42,194 --> 04:15:44,129 BEFORE 18 MONTHS OF LIFE IN THE 5723 04:15:44,129 --> 04:15:46,665 CHILDREN, THEN IT WAS ACTUALLY 5724 04:15:46,665 --> 04:15:54,906 FIVE-FOLD, WHAT YOU CAN SEE 5725 04:15:54,906 --> 04:16:00,812 HERE. 5726 04:16:00,812 --> 04:16:02,147 ALSO TEDDY STUDIED SARS-COV-2 5727 04:16:02,147 --> 04:16:04,883 INFECTION, DID NOT SEE INCREASE 5728 04:16:04,883 --> 04:16:06,751 IN THE TEENAGERS, INDICATING 5729 04:16:06,751 --> 04:16:09,888 THAT IT IS PROBABLY DIFFERENT, 5730 04:16:09,888 --> 04:16:11,656 THIS ENVIRONMENTAL TRIGGERS, HIT 5731 04:16:11,656 --> 04:16:15,260 SOMEONE DURING THIS VULNERABLE 5732 04:16:15,260 --> 04:16:17,996 PERIOD OR LATER ON. 5733 04:16:17,996 --> 04:16:21,099 SO, ALTOGETHER, THERE ARE MANY 5734 04:16:21,099 --> 04:16:23,034 POSSIBILITIES HOW VIRUSES AND 5735 04:16:23,034 --> 04:16:24,236 IMMUNE SYSTEM MIGHT DESTROY BETA 5736 04:16:24,236 --> 04:16:28,506 CELLS, AND THAT CAN BE OF COURSE 5737 04:16:28,506 --> 04:16:29,841 THROUGH DIRECT INFECTION OF BETA 5738 04:16:29,841 --> 04:16:32,577 CELL BUT COULD BE ALSO JUST 5739 04:16:32,577 --> 04:16:34,946 THROUGH STRESS OF THE BETA CELL 5740 04:16:34,946 --> 04:16:35,847 THROUGH INFLAMMATION, AND WE 5741 04:16:35,847 --> 04:16:40,085 KNOW THAT THERE IS ACTUALLY 5742 04:16:40,085 --> 04:16:42,654 TRANSIENT HYPERGLYCEMIA, NOT SO 5743 04:16:42,654 --> 04:16:44,956 UNFREQUENT, DURING INFECTION IN 5744 04:16:44,956 --> 04:16:45,257 CHILDREN. 5745 04:16:45,257 --> 04:16:48,326 AND ALSO I SHOWED YOU SOME 5746 04:16:48,326 --> 04:16:52,197 EVIDENCE THERE'S ACTIVATION OF 5747 04:16:52,197 --> 04:16:52,764 AUTOREACTIVITY DURING 5748 04:16:52,764 --> 04:16:54,132 INFLAMMATION, AND OF COURSE ALSO 5749 04:16:54,132 --> 04:16:55,233 OTHER POSSIBILITIES. 5750 04:16:55,233 --> 04:17:00,939 SO WE LOOKED ALSO IN OTHER POINT 5751 04:17:00,939 --> 04:17:04,009 COHORT, AND WE LOOKED AT 5752 04:17:04,009 --> 04:17:05,277 SARS-COV-2, AND METHYLATION, AND 5753 04:17:05,277 --> 04:17:09,381 WE HAD ACTUALLY, THIS IS 5754 04:17:09,381 --> 04:17:13,118 UNPUBLISHED DATA, SOME KIND OF 5755 04:17:13,118 --> 04:17:16,921 VERY INTERESTING FINDING THAT A 5756 04:17:16,921 --> 04:17:19,457 RECENT SARS-COV-2 INFECTION WAS 5757 04:17:19,457 --> 04:17:21,092 ASSOCIATED WITH MODULATED 5758 04:17:21,092 --> 04:17:21,860 METHYLATION. 5759 04:17:21,860 --> 04:17:24,729 AND THE CHANGES THAT WE FOUND 5760 04:17:24,729 --> 04:17:30,635 THROUGH THE CHROMOSOMES WERE 5761 04:17:30,635 --> 04:17:32,170 MAINLY T ANTI-VIRAL GENES, THAT 5762 04:17:32,170 --> 04:17:37,342 IS EXPECTED, YOU -- BUT WHAT WS 5763 04:17:37,342 --> 04:17:38,076 INTERESTING WE LOOKED AT 5764 04:17:38,076 --> 04:17:40,578 INFLUENZA IN THE CHILDREN AND 5765 04:17:40,578 --> 04:17:44,849 FOUND NO CHANGE IN METHYLATION 5766 04:17:44,849 --> 04:17:45,383 CPTs. 5767 04:17:45,383 --> 04:17:48,019 SO IT SEEMED THAT THERE IS 5768 04:17:48,019 --> 04:17:49,354 SOMETHING THAT SARS INFECTION 5769 04:17:49,354 --> 04:17:51,323 DOES MUCH MORE THAN OTHERS. 5770 04:17:51,323 --> 04:17:55,994 AND WHAT WAS ALSO INTERESTING IS 5771 04:17:55,994 --> 04:18:02,567 THAT THERE WAS ONE GENE ADAR, 5772 04:18:02,567 --> 04:18:04,869 OTHERS HAVE LOOKED AT ADAR 1 5773 04:18:04,869 --> 04:18:08,807 KNOCKOUT MOUSE AND HAVE ACTUALLY 5774 04:18:08,807 --> 04:18:10,308 SEEN THAT MIMICS ALMOST EARLY 5775 04:18:10,308 --> 04:18:14,179 STAGE TYPE 1 DIABETES PHENOTYPES 5776 04:18:14,179 --> 04:18:15,380 WITH MASSIVE INTERFERON 5777 04:18:15,380 --> 04:18:18,083 PRODUCTION, AND ALSO ISLET 5778 04:18:18,083 --> 04:18:20,385 INFLAMMATION, AND BETAS IN THE 5779 04:18:20,385 --> 04:18:23,455 ANIMALS. 5780 04:18:23,455 --> 04:18:25,523 INTERESTING THAT SARS INFECTION 5781 04:18:25,523 --> 04:18:34,499 SEEMS HERE TO MAKE CHANGES IN 5782 04:18:34,499 --> 04:18:36,801 THE METHYLATION ASPECT. 5783 04:18:36,801 --> 04:18:39,738 IT ALTERED DNA METHYLATION, TYPE 5784 04:18:39,738 --> 04:18:42,807 OF BETA 1 GENES. 5785 04:18:42,807 --> 04:18:45,710 SUMMARY HERE, DURING THE 5786 04:18:45,710 --> 04:18:48,613 PANDEMIC FEWER CHILDREN -- FEWER 5787 04:18:48,613 --> 04:18:50,148 CHILDHOOD INFECTIONS WERE 5788 04:18:50,148 --> 04:18:52,350 OBSERVED, INCLUDING COXSACKIE B. 5789 04:18:52,350 --> 04:18:54,519 INCIDENCE OF ISLET AUTOIMMUNITY 5790 04:18:54,519 --> 04:18:56,521 REMAINED THE SAME FOR THE FIRST 5791 04:18:56,521 --> 04:18:59,157 YEAR, HIGHER LATER. 5792 04:18:59,157 --> 04:19:04,062 PRESENCE OF SARS ANTIBODIES WERE 5793 04:19:04,062 --> 04:19:08,099 ALSO ASSOCIATED WITH RISK OF 5794 04:19:08,099 --> 04:19:11,403 ISLET IMMUNITY IN YOUNG 5795 04:19:11,403 --> 04:19:14,672 CHILDREN, AND INFECTION IN YOUNG 5796 04:19:14,672 --> 04:19:16,007 CHILDREN ASSOCIATED WITH 5797 04:19:16,007 --> 04:19:21,913 METHYLATION CHANGES IN TYPE 1 5798 04:19:21,913 --> 04:19:23,448 DIE DETECTIVES-RELEVANT GENE 5799 04:19:23,448 --> 04:19:23,882 REGIONS. 5800 04:19:23,882 --> 04:19:25,316 I WILL MENTION MATERNAL 5801 04:19:25,316 --> 04:19:25,750 DIABETES. 5802 04:19:25,750 --> 04:19:29,087 AS A SECOND POSSIBLE MODIFIER, 5803 04:19:29,087 --> 04:19:32,557 WE KNOW IF A CHILD IS BORN TO A 5804 04:19:32,557 --> 04:19:33,958 MOTHER WITH TYPE 1 DIABETES, HER 5805 04:19:33,958 --> 04:19:38,029 RISK TO HAVE THIS PEAK IS MUCH 5806 04:19:38,029 --> 04:19:40,565 LESS WHEN COMPARED TO A CHILD 5807 04:19:40,565 --> 04:19:42,066 FROM A FATHER WITH TYPE 1 5808 04:19:42,066 --> 04:19:42,767 DIABETES. 5809 04:19:42,767 --> 04:19:45,036 AND THERE ARE MANY, MANY 5810 04:19:45,036 --> 04:19:46,538 DISCUSSIONS, WHY THIS IS THE 5811 04:19:46,538 --> 04:19:46,738 CASE. 5812 04:19:46,738 --> 04:19:49,974 AND I THINK IT IS ALSO OF COURSE 5813 04:19:49,974 --> 04:19:51,176 INTERESTING RELATIVE TO THE BETA 5814 04:19:51,176 --> 04:19:53,545 CELL, BUT BECAUSE IT COULD BE 5815 04:19:53,545 --> 04:19:55,647 THAT THE DIABETES IN THE MOTHER 5816 04:19:55,647 --> 04:19:58,917 ALSO MAY LEAD TO SOME INCREASE 5817 04:19:58,917 --> 04:20:01,019 IN BETA CELL MASS, SO THERE ARE 5818 04:20:01,019 --> 04:20:02,654 A LOT OF PEOPLE I THINK 5819 04:20:02,654 --> 04:20:04,889 INTERESTED IN STUDYING THIS. 5820 04:20:04,889 --> 04:20:07,592 AND WE IN THIS LOOKED ALSO AT 5821 04:20:07,592 --> 04:20:08,026 METHYLATION. 5822 04:20:08,026 --> 04:20:11,129 I'M NOT SHOWING THE DATA BECAUSE 5823 04:20:11,129 --> 04:20:13,097 IT'S FROM MY COLLEAGUE, NOT YET 5824 04:20:13,097 --> 04:20:15,400 PUBLISHED, BUT I JUST CAN ALSO 5825 04:20:15,400 --> 04:20:21,840 SAY THAT WE FOUND SOME 5826 04:20:21,840 --> 04:20:22,941 SIGNIFICANT GENETIC 5827 04:20:22,941 --> 04:20:25,343 MODIFICATIONS, ASSOCIATED WITH 5828 04:20:25,343 --> 04:20:28,313 MATERNAL DIABETES AND IN THE 5829 04:20:28,313 --> 04:20:29,948 TYPE 1 ASSOCIATED TYPE 1 5830 04:20:29,948 --> 04:20:31,616 DIABETES GENES. 5831 04:20:31,616 --> 04:20:36,287 AND THAT MAY ALSO SUGGEST THAT 5832 04:20:36,287 --> 04:20:40,258 MATERNAL DIABETES SOMEHOW 5833 04:20:40,258 --> 04:20:42,560 DECREASES THE DIABETICOGENIC 5834 04:20:42,560 --> 04:20:43,862 EFFECT OF SUSCEPTIBLE GENES, A 5835 04:20:43,862 --> 04:20:46,798 BIT SIMILAR THAT AFFECTS LIKE 5836 04:20:46,798 --> 04:20:50,101 THE SARS-COV-2 INFECTION. 5837 04:20:50,101 --> 04:20:54,138 SO, CAN WE TRANSLATE THIS TO 5838 04:20:54,138 --> 04:20:54,906 PREVENTION? 5839 04:20:54,906 --> 04:20:56,541 WE HAVE ACTUALLY SINCE THE -- 5840 04:20:56,541 --> 04:20:59,811 OTHER THE LAST TEN YEARS 5841 04:20:59,811 --> 04:21:03,882 ESTABLISHED A PREVENTION 5842 04:21:03,882 --> 04:21:05,850 PLATFORM IN EUROPE, THIS 5843 04:21:05,850 --> 04:21:09,120 PLATFORM IS ACTIVE IN MANY 5844 04:21:09,120 --> 04:21:13,491 EUROPEAN COUNTRIES, REALLY TO 5845 04:21:13,491 --> 04:21:19,531 TRANSLATE AND TRY TO TEST IN 5846 04:21:19,531 --> 04:21:21,399 PRIMARY PREVENTION TRIALS. 5847 04:21:21,399 --> 04:21:24,469 TO REDUCE INCIDENCE OF ISLET 5848 04:21:24,469 --> 04:21:24,736 IMMUNITY. 5849 04:21:24,736 --> 04:21:26,905 IN GPPAD WE IDENTIFY WITH A HIGH 5850 04:21:26,905 --> 04:21:28,873 ELEVATED GENETIC RISK BY USING 5851 04:21:28,873 --> 04:21:30,842 RISK SCORES LIKE I SAID IN THIS 5852 04:21:30,842 --> 04:21:34,679 POINT STUDY, POINT IS ONE OF THE 5853 04:21:34,679 --> 04:21:36,748 GPPAD STUDIES, TO PERFORMED 5854 04:21:36,748 --> 04:21:38,283 PRIMARY PREVENTION TRIALS, ALSO 5855 04:21:38,283 --> 04:21:41,352 TO USE IT TO IDENTIFY KEY EVENTS 5856 04:21:41,352 --> 04:21:45,924 AND MECHANISMS IN THE 5857 04:21:45,924 --> 04:21:47,692 PATHOGENESIS. 5858 04:21:47,692 --> 04:21:50,528 THIS IS JUST THE GPPED TEAM AND 5859 04:21:50,528 --> 04:21:51,496 CONSORTIUM, CLINICAL CENTERS 5860 04:21:51,496 --> 04:21:53,097 THAT CONTRIBUTED NOT ONLY TO 5861 04:21:53,097 --> 04:21:56,134 POINT BUT ALSO TO THE OTHER 5862 04:21:56,134 --> 04:21:56,434 STUDIES. 5863 04:21:56,434 --> 04:22:00,505 OVER THE LAST TEN YEARS WE HAVE 5864 04:22:00,505 --> 04:22:03,541 SCREENED OVER 500,000 NEWBORNS 5865 04:22:03,541 --> 04:22:05,209 IN THESE DIFFERENT CLINICAL 5866 04:22:05,209 --> 04:22:07,412 SITES BY USING A 47 SNP RISK 5867 04:22:07,412 --> 04:22:09,380 SCORE TO IDENTIFY CHILDREN FROM 5868 04:22:09,380 --> 04:22:13,351 THE GENERAL POPULATION THAT HAVE 5869 04:22:13,351 --> 04:22:18,156 A 25-FOLD INCREASE IN RISK, AND 5870 04:22:18,156 --> 04:22:20,091 WE IDENTIFY THOSE WITH A VERY 5871 04:22:20,091 --> 04:22:22,260 HIGH RISK. 5872 04:22:22,260 --> 04:22:25,897 THIS IS ABOUT 1.2%, OVER 6,000, 5873 04:22:25,897 --> 04:22:28,733 ASKED THEM TO PARTICIPATE IN 5874 04:22:28,733 --> 04:22:32,704 THESE PRIMARY PREVENTION TRIALS. 5875 04:22:32,704 --> 04:22:33,871 WE HAVE ENROLLED OVER 2,000 5876 04:22:33,871 --> 04:22:37,175 BABIES IN SUCH TRIALS. 5877 04:22:37,175 --> 04:22:38,376 HAVE COMPLETED ENROLLMENT OF TWO 5878 04:22:38,376 --> 04:22:40,378 TRIALS, ONE THE ONE I WAS 5879 04:22:40,378 --> 04:22:45,049 TALKING ABOUT ALL THE TIME, 5880 04:22:45,049 --> 04:22:48,319 PRIMARY INSULIN TRIAL TESTING 5881 04:22:48,319 --> 04:22:52,624 WHETHER ANTIGEN THERAPY, ORAL 5882 04:22:52,624 --> 04:22:54,892 INSULIN THERAPY, CAN PREVENT OR 5883 04:22:54,892 --> 04:22:57,762 REDUCE THE INCIDENCE OF ISLET 5884 04:22:57,762 --> 04:22:58,096 AUTOIMMUNITY. 5885 04:22:58,096 --> 04:23:00,698 SO IT'S NOT GIVEN TO PEOPLE WITH 5886 04:23:00,698 --> 04:23:01,933 ISLET AUTOIMMUNITY, BUT TO 5887 04:23:01,933 --> 04:23:04,869 HEALTHY CHILDREN IN ORDER TO 5888 04:23:04,869 --> 04:23:05,737 PREVENT IT. 5889 04:23:05,737 --> 04:23:07,505 OVER THESE THOUSAND CHILDREN 5890 04:23:07,505 --> 04:23:10,441 ENROLLED, WE WILL EXPECT 5891 04:23:10,441 --> 04:23:12,210 ACTUALLY THE RESULTS THIS YEAR. 5892 04:23:12,210 --> 04:23:20,785 THE SECOND STUDY IS A PROBIOTIC 5893 04:23:20,785 --> 04:23:22,086 STUDY CALLED SINT1A, ENROLLMENT 5894 04:23:22,086 --> 04:23:24,822 COMPLETE, THE TREATMENT PHASE IS 5895 04:23:24,822 --> 04:23:28,326 ALSO OVER ALREADY, JUST ONE 5896 04:23:28,326 --> 04:23:30,294 YEAR, TREATED FOR THREE YEARS, 5897 04:23:30,294 --> 04:23:32,263 AND PROSPECTIVE END IS 27. 5898 04:23:32,263 --> 04:23:35,867 WE JUST INITIATED A NEW TRIAL 5899 04:23:35,867 --> 04:23:38,503 CALLED ANTI-VIRAL ACTION AGAINST 5900 04:23:38,503 --> 04:23:44,609 TYPE 1 DIABETES AUTOIMMUNITY, A 5901 04:23:44,609 --> 04:23:46,911 TRIAL TESTING WHETHER A 5902 04:23:46,911 --> 04:23:48,546 VACCINATION AGAINST SARS-COV-2 5903 04:23:48,546 --> 04:23:52,617 VERY EARLY IN CHILDREN AGE 6, 7, 5904 04:23:52,617 --> 04:23:54,619 9 MONTHS IN REGULAR SCHEME 5905 04:23:54,619 --> 04:23:56,688 AGAINST PLACEBO IN THIS VERY, 5906 04:23:56,688 --> 04:23:59,190 VERY HIGH RISK CHILDREN CAN 5907 04:23:59,190 --> 04:24:00,391 REDUCE ISLET AUTOIMMUNITY. 5908 04:24:00,391 --> 04:24:03,361 AND WE HAVE A SECOND PART IN 5909 04:24:03,361 --> 04:24:06,297 THIS STUDY, WHERE WE DO VERY 5910 04:24:06,297 --> 04:24:08,399 INTENSE INFECTION SURVEILLANCE 5911 04:24:08,399 --> 04:24:11,803 BY COLLECTING WEEKLY SALIVA 5912 04:24:11,803 --> 04:24:13,871 SAMPLES, AND PCR THOSE SAMPLES 5913 04:24:13,871 --> 04:24:17,375 FOR 20 OTHER VIRUSES, TO REALLY 5914 04:24:17,375 --> 04:24:19,677 STUDY INTENSIVELY THE 5915 04:24:19,677 --> 04:24:21,312 CONTRIBUTION OF VIRAL INFECTIONS 5916 04:24:21,312 --> 04:24:22,747 FOR -- DURING THIS VULNERABLE 5917 04:24:22,747 --> 04:24:25,817 PERIOD IN THE CHILDREN. 5918 04:24:25,817 --> 04:24:29,654 PRIMARY OUTCOME IS ISLET 5919 04:24:29,654 --> 04:24:29,987 AUTOIMMUNITY. 5920 04:24:29,987 --> 04:24:32,924 WE NEED OVER 2,000 CHILDREN AND 5921 04:24:32,924 --> 04:24:34,225 STARTED ENROLLING. 5922 04:24:34,225 --> 04:24:37,428 IF YOU'RE INTERESTED, YOU CAN 5923 04:24:37,428 --> 04:24:40,598 LOOK AT OUR WEBSITE AND IF YOU 5924 04:24:40,598 --> 04:24:42,567 ARE IN EUROPE YOU COULD EVEN 5925 04:24:42,567 --> 04:24:46,070 CONTACT US IF YOU'RE INTERESTED 5926 04:24:46,070 --> 04:24:49,574 IN PARTICIPATING. 5927 04:24:49,574 --> 04:24:51,676 SO, VERY, VERY BRIEFLY, I HAVE A 5928 04:24:51,676 --> 04:24:55,146 FEW MORE MINUTES, I WANT ALSO TO 5929 04:24:55,146 --> 04:24:57,782 SAY SOMETHING ABOUT PROGRESSION, 5930 04:24:57,782 --> 04:24:59,417 FROM AUTOIMMUNITY TO SYMPTOMATIC 5931 04:24:59,417 --> 04:25:01,586 DIABETES BECAUSE ALSO HERE I 5932 04:25:01,586 --> 04:25:04,255 THINK BETA CELL FUNCTION IS 5933 04:25:04,255 --> 04:25:06,324 REALLY A VERY IMPORTANT 5934 04:25:06,324 --> 04:25:08,626 PREDICTOR OF PROGRESSION. 5935 04:25:08,626 --> 04:25:10,361 SO, YOU KNOW AN THIS WAS 5936 04:25:10,361 --> 04:25:13,097 MENTIONED BEFORE, WE HAVE 5937 04:25:13,097 --> 04:25:15,967 ACTUALLY IN GERMANY INITIATED A 5938 04:25:15,967 --> 04:25:18,169 LARGE GENERAL POPULATION, 5939 04:25:18,169 --> 04:25:20,138 SCREENING FOR ISLET 5940 04:25:20,138 --> 04:25:22,306 AUTOIMMUNITY, THE PROJECT IS 5941 04:25:22,306 --> 04:25:25,143 CALLED FREEDA, SCREENED IN 5942 04:25:25,143 --> 04:25:26,611 BAVARIA OVER 200,000 5943 04:25:26,611 --> 04:25:30,882 PARTICIPANTS IN THIS AGE RANGE, 5944 04:25:30,882 --> 04:25:34,285 AND HAVE IDENTIFIED 560 CHILDREN 5945 04:25:34,285 --> 04:25:35,386 WITH MULTIPLE ISLET ANTIBODIES, 5946 04:25:35,386 --> 04:25:38,289 AND WE INVITE THEM FOR STAGING. 5947 04:25:38,289 --> 04:25:41,192 THE MAJORITY HAS AT THE 5948 04:25:41,192 --> 04:25:43,594 BEGINNING STAGE 1, ONLY A FEW 5949 04:25:43,594 --> 04:25:45,563 STAGE 2, AND SOME HAVE ALREADY 5950 04:25:45,563 --> 04:25:46,531 OVERT DIABETES. 5951 04:25:46,531 --> 04:25:53,104 WE ASKED THE QUESTION, CAN WE 5952 04:25:53,104 --> 04:25:54,639 SOMEHOW STRATIFY FURTHER WITHIN 5953 04:25:54,639 --> 04:25:56,808 THESE STAGES, AND WHAT ARE THE 5954 04:25:56,808 --> 04:25:58,276 MARKERS THAT PREDICT 5955 04:25:58,276 --> 04:26:00,011 PROGRESSION, AND WE HAD A LOT OF 5956 04:26:00,011 --> 04:26:01,746 CHILDREN OF COURSE ALSO GOING 5957 04:26:01,746 --> 04:26:03,848 THROUGH THESE STAGES FROM STAGE 5958 04:26:03,848 --> 04:26:05,917 1 TO STAGE 2. 5959 04:26:05,917 --> 04:26:08,753 SO, I'M STARTING WITH STAGE 1. 5960 04:26:08,753 --> 04:26:11,722 WE LOOKED AT MULTIPLE PARAMETERS 5961 04:26:11,722 --> 04:26:13,257 IN THE MULTI-VARIABLE ANALYSIS 5962 04:26:13,257 --> 04:26:22,133 AT WHAT WE FOUND, IF THE T IS 5963 04:26:22,133 --> 04:26:25,503 MISSING, THAT I TOO, IT'S THE 5964 04:26:25,503 --> 04:26:28,573 CATEGORY, HIGH, LOW, NEGATIVE, 5965 04:26:28,573 --> 04:26:31,175 HBA1C, 90-MINUTE GLUCOSE AFTER 5966 04:26:31,175 --> 04:26:34,045 ORAL GLUCOSE THE BEST PREDICTORS 5967 04:26:34,045 --> 04:26:36,247 WITHIN THIS STAGE TO PREDICT 5968 04:26:36,247 --> 04:26:36,881 PROGRESSION. 5969 04:26:36,881 --> 04:26:39,283 AND WHEN WE LOOK AT A TWO-YEAR 5970 04:26:39,283 --> 04:26:41,385 RISK IN THE CHILDREN, YOU CAN 5971 04:26:41,385 --> 04:26:44,589 SEE IF THIS PROGRESSION SCORE 5972 04:26:44,589 --> 04:26:46,424 WAS ABOVE 90th PERCENTILE 5973 04:26:46,424 --> 04:26:49,060 CHILDREN HAD A 38% RISK TO 5974 04:26:49,060 --> 04:26:51,896 DEVELOP STAGE 3, WHILE IF IT WAS 5975 04:26:51,896 --> 04:26:55,633 LOW THEN IT WAS ZERO. 5976 04:26:55,633 --> 04:26:59,904 IF YOU JUST TOOK IA2 YOU CAN 5977 04:26:59,904 --> 04:27:01,339 ALSO DISCRIMINATE, MUCH LESS 5978 04:27:01,339 --> 04:27:03,841 THAN IF YOU INCLUDE MARKERS OF 5979 04:27:03,841 --> 04:27:06,711 BETA CELL FUNCTION. 5980 04:27:06,711 --> 04:27:08,713 WE ALSO LOOKED WITHIN STAGE 2, 5981 04:27:08,713 --> 04:27:12,817 AND WITHIN STAGE 2 WE SOLELY 5982 04:27:12,817 --> 04:27:19,924 USED THIS GLYCEMIA MARKERS, USED 5983 04:27:19,924 --> 04:27:22,126 HBA1C, FASTING, 120-MINUTE, OR 5984 04:27:22,126 --> 04:27:23,661 INTERMEDIATE OGTT LEVELS, JUST 5985 04:27:23,661 --> 04:27:25,863 PUBLISHED, WE LOOKED AT VERY 5986 04:27:25,863 --> 04:27:28,165 MANY DIFFERENT COMBINATIONS, BUT 5987 04:27:28,165 --> 04:27:30,468 I JUST TO SIMPLIFY BECAUSE I 5988 04:27:30,468 --> 04:27:32,637 THOUGHT IT IS INTERESTING THAT 5989 04:27:32,637 --> 04:27:37,675 IF YOU LOOK, YOU CAN'T COUNT, 5990 04:27:37,675 --> 04:27:40,077 MAXIMUM CAN HAVE FOUR, IN YOU 5991 04:27:40,077 --> 04:27:43,281 HAVE ONE COMPARED TO TWO 5992 04:27:43,281 --> 04:27:44,348 COMPARED TO THREE TWO-YEAR RISK 5993 04:27:44,348 --> 04:27:47,551 IS HERE ALMOST THE SAME LIKE IN 5994 04:27:47,551 --> 04:27:53,758 STAGE 1 BY THIS PLS BUT THEN 5995 04:27:53,758 --> 04:27:56,994 ABOUT TWO, 66%, 80%, COMBINATION 5996 04:27:56,994 --> 04:27:58,996 HBA1C PLUS ONE OF THESE 5997 04:27:58,996 --> 04:28:00,431 ABNORMALITIES WAS ALSO VERY HIGH 5998 04:28:00,431 --> 04:28:00,998 IN RISK. 5999 04:28:00,998 --> 04:28:03,601 SO I THINK JUST THE BETA CELL 6000 04:28:03,601 --> 04:28:06,337 FUNCTION IN BOTH STAGE 1 AND 6001 04:28:06,337 --> 04:28:10,274 STAGE 2 CAN REALLY STRATIFY HOW 6002 04:28:10,274 --> 04:28:11,909 QUICKLY SOMEBODY DEVELOPS 6003 04:28:11,909 --> 04:28:12,476 DIABETES. 6004 04:28:12,476 --> 04:28:16,847 AND I KNOW THAT YOU ARE TALKING 6005 04:28:16,847 --> 04:28:20,451 ABOUT THE VITILIGO OF THE BETA 6006 04:28:20,451 --> 04:28:22,987 CELL, AND BETA CELLS DO THEY 6007 04:28:22,987 --> 04:28:26,590 FUNCTION OR NOT, BUT I THINK 6008 04:28:26,590 --> 04:28:29,860 THIS SOMEHOW ALSO INDICATES THAT 6009 04:28:29,860 --> 04:28:32,730 REALLY HOW WELL THEY FUNCTION 6010 04:28:32,730 --> 04:28:35,666 CORRELATES EXTREMELY WELL WITH 6011 04:28:35,666 --> 04:28:37,768 PROGRESSION RATES. 6012 04:28:37,768 --> 04:28:39,403 SO, BETA CELL FUNCTION ARE GOOD 6013 04:28:39,403 --> 04:28:41,706 PREDICTORS OF THE PHASE. 6014 04:28:41,706 --> 04:28:44,542 NOW I HAVE TWO MORE ADVERTISING 6015 04:28:44,542 --> 04:28:46,644 SLIDES, I WANTED TO TELL YOU 6016 04:28:46,644 --> 04:28:50,915 THAT WE ARE HAVING A EUROPEAN 6017 04:28:50,915 --> 04:28:52,683 NETWORK CALLED IDENTIFY WITH 28 6018 04:28:52,683 --> 04:28:56,287 PARTNERS, WHERE WE BRING SUCH A 6019 04:28:56,287 --> 04:28:58,923 GENERAL POPULATION TO DIFFERENT 6020 04:28:58,923 --> 04:29:01,759 COUNTRIES IN EUROPE, WITH 6021 04:29:01,759 --> 04:29:04,729 UNIFIED SCREENING, AND ALSO WE 6022 04:29:04,729 --> 04:29:06,197 HAVE ESTABLISH A PRE-TYPE 1 6023 04:29:06,197 --> 04:29:08,132 DIABETES REGISTRY IN EUROPE, 6024 04:29:08,132 --> 04:29:10,868 WHERE WE REGISTER ALL THOSE THAT 6025 04:29:10,868 --> 04:29:12,470 CHILDREN THAT ARE ANTIBODY 6026 04:29:12,470 --> 04:29:15,239 POSITIVE AND HAVE NOT YET 6027 04:29:15,239 --> 04:29:17,708 DEVELOPED DIABETES, TO 6028 04:29:17,708 --> 04:29:21,178 FACILITATE TRIALS. 6029 04:29:21,178 --> 04:29:23,247 AND WITH THOSE CONSORTIA IN THE 6030 04:29:23,247 --> 04:29:27,852 EARLY STAGES AND ALSO IN THE 6031 04:29:27,852 --> 04:29:30,688 PROGRESSION STAGES, WE REALLY 6032 04:29:30,688 --> 04:29:34,091 COLLABORATE AND OFFER DATA, 6033 04:29:34,091 --> 04:29:36,160 OFFER TRIALS, SHARE SAMPLES, AND 6034 04:29:36,160 --> 04:29:39,330 OF COURSE WE ARE ALSO INTERESTED 6035 04:29:39,330 --> 04:29:41,332 TO PARTICIPATE IN TRIALS AND 6036 04:29:41,332 --> 04:29:42,800 COLLABORATE WITH ALL OF YOU. 6037 04:29:42,800 --> 04:29:44,802 SO THANK YOU VERY MUCH. 6038 04:29:44,802 --> 04:29:47,972 I WOULD LOVE TO ACKNOWLEDGE ALL 6039 04:29:47,972 --> 04:29:49,707 THOSE WHO FUNDED MY RESEARCH, 6040 04:29:49,707 --> 04:29:52,910 THAT IS VERY MUCH ALSO HELMSLEY 6041 04:29:52,910 --> 04:29:56,514 BREAK THROUGH TYPE 1D AND ALSO 6042 04:29:56,514 --> 04:30:03,054 THANK YOU TO NIDDK, TO THE 6043 04:30:03,054 --> 04:30:04,588 PATIENTS, THE TEAMS THAT WORK IN 6044 04:30:04,588 --> 04:30:08,092 THE CONSORTIA. 6045 04:30:08,092 --> 04:30:10,928 HERE IS THE TEDDY TEAM, ACTUALLY 6046 04:30:10,928 --> 04:30:12,663 THE LAST TEDDY MEETING NEXT 6047 04:30:12,663 --> 04:30:15,199 WEEK, AGAIN HERE IN THE STATES, 6048 04:30:15,199 --> 04:30:18,402 AFTER SO MANY YEARS OF WORKING 6049 04:30:18,402 --> 04:30:20,604 TOGETHER, AND THIS IS MY TEAM 6050 04:30:20,604 --> 04:30:22,440 THAT I ACKNOWLEDGED ALREADY ALSO 6051 04:30:22,440 --> 04:30:23,307 ON THE SLIDE THROUGHOUT. 6052 04:30:23,307 --> 04:30:26,544 THANK YOU SO MUCH FOR YOUR 6053 04:30:26,544 --> 04:30:26,811 ATTENTION. 6054 04:30:26,811 --> 04:30:35,286 [APPLAUSE] 6055 04:30:35,286 --> 04:30:36,787 >> QUESTIONS FOR DR. ZEIGLER, 6056 04:30:36,787 --> 04:30:37,588 PLEASE. 6057 04:30:37,588 --> 04:30:40,624 GET TO THE MICROPHONE PLEASE. 6058 04:30:40,624 --> 04:30:47,098 STATE YOUR NAME AND AFFILIATION. 6059 04:30:47,098 --> 04:30:49,600 THANK YOU. 6060 04:30:49,600 --> 04:30:53,704 >> DAVID FROM YALE UNIVERSITY. 6061 04:30:53,704 --> 04:30:54,171 NICE TALK. 6062 04:30:54,171 --> 04:30:59,343 A COMMENT ABOUT YOUR PLAN TO 6063 04:30:59,343 --> 04:31:02,046 TEST THE SARS VACCINE FOR 6064 04:31:02,046 --> 04:31:03,714 PREVENTING TYPE 1 DIABETES. 6065 04:31:03,714 --> 04:31:05,783 THERE WERE SEVERAL CASE REPORTS 6066 04:31:05,783 --> 04:31:08,185 OF PEOPLE WHO TOOK THE VACCINE 6067 04:31:08,185 --> 04:31:13,324 AND DEVELOPED TYPE 1 DIABETES. 6068 04:31:13,324 --> 04:31:16,227 AND WHEN GENOTYPED ALREADY HAD 6069 04:31:16,227 --> 04:31:21,966 PREDISPOSITION TO TYPE 1 6070 04:31:21,966 --> 04:31:22,233 DIABETES. 6071 04:31:22,233 --> 04:31:24,502 INHIBITORS, YOU ACTIVATE IMMUNE 6072 04:31:24,502 --> 04:31:25,703 RESPONSE, AND TRIGGER TYPE 1 6073 04:31:25,703 --> 04:31:31,275 DIABETES, SO YOU MAY WANT TO BE 6074 04:31:31,275 --> 04:31:33,244 CONSCIOUS USING THE VACCINE TO 6075 04:31:33,244 --> 04:31:40,484 HAVE THE OPPOSITE EFFECT, WHERE 6076 04:31:40,484 --> 04:31:40,818 AUTOIMMUNITY. 6077 04:31:40,818 --> 04:31:42,419 >> YEAH, I MEAN, I KNOW THAT 6078 04:31:42,419 --> 04:31:45,156 PEOPLE ARE TALKING ABOUT IT. 6079 04:31:45,156 --> 04:31:46,857 UNFORTUNATELY, THERE ARE KNOW 6080 04:31:46,857 --> 04:31:51,095 PUBLICATIONS, AND ALSO IN THE 6081 04:31:51,095 --> 04:31:52,630 DATABASES WE'RE USING BIOTECH 6082 04:31:52,630 --> 04:31:57,234 VACCINE, THESE CASES ARE NOT 6083 04:31:57,234 --> 04:31:58,002 REGISTERED. 6084 04:31:58,002 --> 04:32:01,272 BUT I CAN SAY THAT OF COURSE 6085 04:32:01,272 --> 04:32:03,007 THIS IS A CLINICAL TRIAL, 6086 04:32:03,007 --> 04:32:08,646 REGISTERED AS A CLINICAL TRIAL, 6087 04:32:08,646 --> 04:32:11,482 PLACEBO-CONTROLLED, WITH DSMB, 6088 04:32:11,482 --> 04:32:14,151 ALL MONITORING, LOOKING AT THE 6089 04:32:14,151 --> 04:32:15,886 SAFETY AND IF THERE'S ANY 6090 04:32:15,886 --> 04:32:16,987 WORRYING SIGNAL WE WOULD 6091 04:32:16,987 --> 04:32:19,723 IMMEDIATELY OF COURSE STOP THE 6092 04:32:19,723 --> 04:32:20,357 TRIAL. 6093 04:32:20,357 --> 04:32:24,428 >> THERE ARE A FEW PUBLICATIONS 6094 04:32:24,428 --> 04:32:27,498 GENOTYPE, SOME PEOPLE WHO 6095 04:32:27,498 --> 04:32:31,435 DEVELOP, QUITE ELDER LY, IN THE 6096 04:32:31,435 --> 04:32:33,704 80s, AFTER TAKING THE COVID 6097 04:32:33,704 --> 04:32:35,039 VACCINE DEVELOPED TYPE 1 6098 04:32:35,039 --> 04:32:37,274 DIABETES, IF YOU GENOTYPE THEM 6099 04:32:37,274 --> 04:32:44,915 YOU DO SO MOST OF THEM HAVE HLA 6100 04:32:44,915 --> 04:32:47,785 TYPE I INTERFERON RESPONSE, AN 6101 04:32:47,785 --> 04:32:54,091 OBSERVATION, GOING INTO YOUR 6102 04:32:54,091 --> 04:32:54,291 TRIAL. 6103 04:32:54,291 --> 04:32:55,626 >> THANK YOU. 6104 04:32:55,626 --> 04:33:01,665 >> THANK YOU, DR. ZEIGLER. 6105 04:33:01,665 --> 04:33:05,269 WONDERFUL PRESENTATION. 6106 04:33:05,269 --> 04:33:06,704 ABOUT INFLAMMATORY PROCESSES, 6107 04:33:06,704 --> 04:33:08,105 YOU WERE COMMENTING ABOUT, COULD 6108 04:33:08,105 --> 04:33:10,107 IT BE BECAUSE OF A CHANGE IN THE 6109 04:33:10,107 --> 04:33:13,410 DIET OF THE BABIES, MAYBE 6110 04:33:13,410 --> 04:33:15,246 RELATED BECAUSE OF THE LACK OF 6111 04:33:15,246 --> 04:33:17,081 MODERN MILK OR SOMETHING LIKE 6112 04:33:17,081 --> 04:33:20,818 THAT, IS THERE A CO-FOUNDER 6113 04:33:20,818 --> 04:33:23,153 VARIABLE THAT YOU CHECK TOO? 6114 04:33:23,153 --> 04:33:26,957 >> I DON'T KNOW WHAT YOU MEAN, 6115 04:33:26,957 --> 04:33:30,461 THE CHANGE IN GLUCOSE OR I MEAN 6116 04:33:30,461 --> 04:33:34,765 OF COURSE AT THE TIME WHEN THE 6117 04:33:34,765 --> 04:33:37,368 GLUCOSE LEVELS GLOW DOWN, ALSO 6118 04:33:37,368 --> 04:33:39,470 MAYBE MORE ISLET ACTIVITY, 6119 04:33:39,470 --> 04:33:41,305 PEOPLE ARE CHANGING FROM DIET 6120 04:33:41,305 --> 04:33:43,941 USING ONLY MILK TO SOLID FOOD, 6121 04:33:43,941 --> 04:33:46,477 THAT IS ALSO SOMETHING THAT IS 6122 04:33:46,477 --> 04:33:49,513 OF COURSE VERY CRITICAL, BUT WE 6123 04:33:49,513 --> 04:33:51,282 LOOKED IN TEDDY INTENSIVELY INTO 6124 04:33:51,282 --> 04:33:56,086 DIET AND WE DID NOT REALLY FIND 6125 04:33:56,086 --> 04:34:02,126 MUCH IN TERMS OF DIET AND 6126 04:34:02,126 --> 04:34:02,593 ASSOCIATION WITH ISLET 6127 04:34:02,593 --> 04:34:04,895 AUTOIMMUNITY, A LITTLE IN THE 6128 04:34:04,895 --> 04:34:07,998 AMOUNT OF PROTEIN USED, BUT 6129 04:34:07,998 --> 04:34:11,802 OTHERWISE IT WAS NOT SO MUCH 6130 04:34:11,802 --> 04:34:12,136 ASSOCIATION. 6131 04:34:12,136 --> 04:34:13,103 >> AND AUTOIMMUNITY THAT THE 6132 04:34:13,103 --> 04:34:17,775 MOTHER GIVE TO BABY THROUGH THE 6133 04:34:17,775 --> 04:34:17,975 MILK? 6134 04:34:17,975 --> 04:34:19,910 >> I DON'T KNOW WHAT THE 6135 04:34:19,910 --> 04:34:26,550 QUESTION -- WHAT IS THE 6136 04:34:26,550 --> 04:34:26,817 QUESTION? 6137 04:34:26,817 --> 04:34:28,419 >> SO, THIS AUTOIMMUNITY FOUND 6138 04:34:28,419 --> 04:34:31,088 ON THE PANCREAS, RIGHT, COULD IT 6139 04:34:31,088 --> 04:34:34,124 BE BECAUSE OF THE RECENT CHANGE 6140 04:34:34,124 --> 04:34:36,293 FROM THE MOTHER'S MILK TO 6141 04:34:36,293 --> 04:34:37,061 REGULAR MILK OR FORMULA? 6142 04:34:37,061 --> 04:34:38,162 >> I DON'T KNOW. 6143 04:34:38,162 --> 04:34:41,565 I MEAN, THERE WAS ONE STUDY 6144 04:34:41,565 --> 04:34:44,435 CALLED TRIGGER THAT TESTED 6145 04:34:44,435 --> 04:34:47,705 ACTUALLY FORMULA AND HYDROLYZED 6146 04:34:47,705 --> 04:34:49,406 FORMULAS, AND ALSO 6147 04:34:49,406 --> 04:34:51,308 BREASTFEEDING, AND DID ALSO NOT 6148 04:34:51,308 --> 04:34:54,378 SEE REALLY AN EFFECT, BUT OF 6149 04:34:54,378 --> 04:34:56,013 COURSE I MEAN WE HAVEN'T REALLY 6150 04:34:56,013 --> 04:34:59,516 LOOKED AT THAT OVER TIME TO KNOW 6151 04:34:59,516 --> 04:35:01,051 WHETHER CHANGES OF THE LAST 50 6152 04:35:01,051 --> 04:35:06,323 YEARS MATTERED IN THAT 6153 04:35:06,323 --> 04:35:06,590 DIRECTION. 6154 04:35:06,590 --> 04:35:07,825 >> THANK YOU. 6155 04:35:07,825 --> 04:35:08,826 >> WEILL CORNELL MEDICINE, THANK 6156 04:35:08,826 --> 04:35:10,794 YOU FOR SHARING EXCITING WORK. 6157 04:35:10,794 --> 04:35:14,631 I JUST HAVE QUICK QUESTION, 6158 04:35:14,631 --> 04:35:18,102 CLARIFICATION, YOU SHOWED SOME 6159 04:35:18,102 --> 04:35:21,939 UNPUBLISHED DATA SARS-COV-2 6160 04:35:21,939 --> 04:35:24,775 INFECTION CHANGED METHYLATION 6161 04:35:24,775 --> 04:35:26,543 STATUS, WANT CLARIFICATION FROM 6162 04:35:26,543 --> 04:35:29,613 PBMC OF PATIENT SAMPLES OR IN 6163 04:35:29,613 --> 04:35:33,717 VITRO EXPERIMENT OR IF PBMC HAVE 6164 04:35:33,717 --> 04:35:35,853 YOU HEARD ANY MAJOR EXPERIMENT 6165 04:35:35,853 --> 04:35:40,691 WOULD SEE RESULT? 6166 04:35:40,691 --> 04:35:43,427 >> FROM BLOOD DNA TAKEN IN THE 6167 04:35:43,427 --> 04:35:45,462 CHILDREN, NOT PBMCs. 6168 04:35:45,462 --> 04:35:50,200 >> ARE YOU AWARE OF IN VITRO 6169 04:35:50,200 --> 04:35:50,501 EXPERIMENTS? 6170 04:35:50,501 --> 04:35:51,935 >> NO, I DON'T KNOW WHETHER IT 6171 04:35:51,935 --> 04:35:57,508 WAS SHOWN BEFORE, I DON'T KNOW. 6172 04:35:57,508 --> 04:35:59,343 >> THANK YOU. 6173 04:35:59,343 --> 04:35:59,810 >> THAT WAS AWESOME, 6174 04:35:59,810 --> 04:36:00,844 OUTSTANDING. 6175 04:36:00,844 --> 04:36:02,980 THE NUMBER OF PEOPLE YOU 6176 04:36:02,980 --> 04:36:06,717 SCREENED IS STAGGERING, RIGHT? 6177 04:36:06,717 --> 04:36:07,951 WHEN YOU TALK ABOUT 500,000. 6178 04:36:07,951 --> 04:36:09,653 I'D LIKE YOU TO SPECULATE. 6179 04:36:09,653 --> 04:36:12,856 WE KNOW MAYBE 30 OR 40% OF 6180 04:36:12,856 --> 04:36:14,158 INDIVIDUALS WHO DEVELOP TYPE 1 6181 04:36:14,158 --> 04:36:15,692 DIABETES DEVELOP IT OVER THE AGE 6182 04:36:15,692 --> 04:36:17,661 OF 30. 6183 04:36:17,661 --> 04:36:18,862 SO ARE THERE CONNECTIONS THAT 6184 04:36:18,862 --> 04:36:22,900 YOU WOULD LIKE TO MAKE OR 6185 04:36:22,900 --> 04:36:25,569 SPECULATIONS, IS THAT -- DO 6186 04:36:25,569 --> 04:36:27,738 SIMILAR THINGS HAPPEN IN THAT, 6187 04:36:27,738 --> 04:36:29,273 DOES IT INFORM US AT ALL? 6188 04:36:29,273 --> 04:36:30,507 WHAT ARE YOUR THOUGHTS. 6189 04:36:30,507 --> 04:36:32,009 THANK YOU. 6190 04:36:32,009 --> 04:36:34,311 >> DO YOU MEAN WHETHER BOTH 6191 04:36:34,311 --> 04:36:36,146 PEOPLE WHO DEVELOP THE DIABETES 6192 04:36:36,146 --> 04:36:40,217 AT 30 ARE SIMILAR TO THOSE EARLY 6193 04:36:40,217 --> 04:36:40,417 ONES? 6194 04:36:40,417 --> 04:36:43,053 >> CORRECT. 6195 04:36:43,053 --> 04:36:45,722 IS THERE METABOLIC INSTABILITY 6196 04:36:45,722 --> 04:36:47,758 THAT PRECEDES? 6197 04:36:47,758 --> 04:36:51,495 YOU KNOW HAVE DATA BUT 6198 04:36:51,495 --> 04:36:51,762 SPECULATE. 6199 04:36:51,762 --> 04:36:55,866 >> IF YOU LOOK AT PROGRESSION, 6200 04:36:55,866 --> 04:36:57,067 RELATIVELY STABLE, NO PEAK, 6201 04:36:57,067 --> 04:36:58,368 INCIDENCE OF PROGRESSION, NO 6202 04:36:58,368 --> 04:36:58,769 PEAK. 6203 04:36:58,769 --> 04:37:00,771 SO IF WE MODEL THIS, THAT 6204 04:37:00,771 --> 04:37:04,174 ACTUALLY FROM THOSE WHO DEVELOP 6205 04:37:04,174 --> 04:37:05,709 THIS AUTOIMMUNITY VERY EARLY, 6206 04:37:05,709 --> 04:37:08,679 THERE IS SUBPOPULATION THAT WILL 6207 04:37:08,679 --> 04:37:11,615 PROGRESS TO DIABETES BY 30 YEARS 6208 04:37:11,615 --> 04:37:13,350 ONLY, ABOUT 10 OF HUNDRED WILL 6209 04:37:13,350 --> 04:37:15,552 ACTUALLY TAKE SOME LONG TIME 6210 04:37:15,552 --> 04:37:19,156 UNTIL THEY WILL PROGRESS. 6211 04:37:19,156 --> 04:37:20,791 SO I THINK THEY VERY SIMILAR 6212 04:37:20,791 --> 04:37:23,627 FEATURES BUT THERE ARE OTHER 6213 04:37:23,627 --> 04:37:24,461 AUTOIMMUNITY ARISING THROUGHOUT 6214 04:37:24,461 --> 04:37:32,402 LIFE AND WE HAVE PEOPLE WHO 6215 04:37:32,402 --> 04:37:33,704 SEROCONVERT 18, 19, 20, THEY 6216 04:37:33,704 --> 04:37:34,371 LOOK DIFFERENT. 6217 04:37:34,371 --> 04:37:36,106 MY SPECULATION WOULD BE THAT 6218 04:37:36,106 --> 04:37:38,208 AUTOIMMUNITY THAT IS INITIATED 6219 04:37:38,208 --> 04:37:42,179 LATER IN LIFE HAS PROBABLY OTHER 6220 04:37:42,179 --> 04:37:43,213 FEATURES. 6221 04:37:43,213 --> 04:37:46,216 AND MAYBE ONE CAN SAY MAY BE A 6222 04:37:46,216 --> 04:37:47,084 DIFFERENT ENDOTYPE. 6223 04:37:47,084 --> 04:37:49,052 >> CAN I MAKE SURE I UNDERSTOOD? 6224 04:37:49,052 --> 04:37:51,488 SOME PEOPLE WHO DEVELOP DIABETES 6225 04:37:51,488 --> 04:37:53,657 AT AGE 30, AUTOIMMUNITY MIGHT 6226 04:37:53,657 --> 04:37:57,361 HAVE BEEN INITIATED IN THAT 6227 04:37:57,361 --> 04:37:58,562 VULNERABLE PERIOD OF LIFE? 6228 04:37:58,562 --> 04:38:05,068 >> WE HAVE FROM OUR BABY DIET 6229 04:38:05,068 --> 04:38:07,571 STUDY, EIGHT PEOPLE HAVE OVER 25 6230 04:38:07,571 --> 04:38:09,873 YEARS FOLLOW-UP WITHOUT 6231 04:38:09,873 --> 04:38:13,710 DIABETES, AND STILL ALL MULTIPLE 6232 04:38:13,710 --> 04:38:15,012 ANTIBODY POSITIVE AND ACTUALLY 6233 04:38:15,012 --> 04:38:16,880 FIVE I THINK HAVE FOUR 6234 04:38:16,880 --> 04:38:19,516 ANTIBODIES, THEY HAVE NOT YET 6235 04:38:19,516 --> 04:38:20,250 PROGRESSED. 6236 04:38:20,250 --> 04:38:21,785 SINCE 25 YEARS HAVE INITIATED IN 6237 04:38:21,785 --> 04:38:25,088 THE FIRST TWO YEARS OF LIFE. 6238 04:38:25,088 --> 04:38:27,591 AND SO IT HAPPENS, AND I'M STILL 6239 04:38:27,591 --> 04:38:30,527 CONVINCED THEY WILL DEVELOP THIS 6240 04:38:30,527 --> 04:38:30,761 DISEASE. 6241 04:38:30,761 --> 04:38:31,862 THERE'S NO SIGNS THAT THEY WILL 6242 04:38:31,862 --> 04:38:32,195 NOT. 6243 04:38:32,195 --> 04:38:36,433 AND THEY HAVE NO PROTECTIVE 6244 04:38:36,433 --> 04:38:39,636 GENOTYPES, SO ALSO IT WAS 6245 04:38:39,636 --> 04:38:41,271 MENTIONED THEY ARE PROTECTED 6246 04:38:41,271 --> 04:38:42,472 FOREVER, I THINK THEY WILL 6247 04:38:42,472 --> 04:38:46,843 DEVELOP, BUT THEY ARE JUST VERY 6248 04:38:46,843 --> 04:38:47,277 SLOW. 6249 04:38:47,277 --> 04:38:50,447 AND BUT THERE ARE OTHERS WHO 6250 04:38:50,447 --> 04:38:52,983 INITIATE LATER ON, AND WE HAVE 6251 04:38:52,983 --> 04:38:54,651 THOSE EXAMPLES IN TEDDY AND ALL 6252 04:38:54,651 --> 04:38:56,620 THE STUDIES, THEY ARE MUCH LESS 6253 04:38:56,620 --> 04:38:59,489 THAN THE EARLY PEAK, BUT THEY 6254 04:38:59,489 --> 04:38:59,890 EXIST. 6255 04:38:59,890 --> 04:39:02,426 AND THEY HAVE OFTEN THE SCAD 6256 04:39:02,426 --> 04:39:05,262 PHENOTYPE, AND OTHERS, OR HAVE 6257 04:39:05,262 --> 04:39:07,464 MORE FREQUENTLY ALSO SIMILAR 6258 04:39:07,464 --> 04:39:07,998 ANTIBODIES ONLY. 6259 04:39:07,998 --> 04:39:12,169 SO I THINK THEY MAY BE 6260 04:39:12,169 --> 04:39:12,636 DIFFERENT. 6261 04:39:12,636 --> 04:39:14,238 AND NOT SO THIS INFLAMMATORY 6262 04:39:14,238 --> 04:39:14,671 TYPE. 6263 04:39:14,671 --> 04:39:19,076 I CAN ALSO SAY THAT WE LOOKED AT 6264 04:39:19,076 --> 04:39:21,378 AN ONSET POPULATION IN A 6265 04:39:21,378 --> 04:39:22,913 REGISTRY, AND KIND OF 6266 04:39:22,913 --> 04:39:24,314 CHARACTERIZED AND CLUSTERED 6267 04:39:24,314 --> 04:39:24,681 THEM. 6268 04:39:24,681 --> 04:39:25,415 THOSE CHILDREN WHO DEVELOPED 6269 04:39:25,415 --> 04:39:31,421 VERY EARLY IN LIFE HAD REALLY 6270 04:39:31,421 --> 04:39:32,756 MUCH MORE AUTO-INFLAMMATORY TNF 6271 04:39:32,756 --> 04:39:33,957 INTERFERON GAMMA CLUSTERS AND 6272 04:39:33,957 --> 04:39:36,460 THE OLDER ONES DIDN'T HAVE THAT. 6273 04:39:36,460 --> 04:39:40,130 THEY HAVE HAD EVEN MORE KIND OF 6274 04:39:40,130 --> 04:39:42,065 INSULIN RESISTANT SIGNS, A 6275 04:39:42,065 --> 04:39:44,267 LITTLE BIT, SO I THINK THERE ARE 6276 04:39:44,267 --> 04:39:48,171 OTHER MECHANISMS MAYBE. 6277 04:39:48,171 --> 04:39:49,940 THAT'S VERY SPECULATIVE. 6278 04:39:49,940 --> 04:39:51,575 >> TWO MORE QUESTIONS. 6279 04:39:51,575 --> 04:39:55,646 >> THANK YOU FOR THE EXCELLENT 6280 04:39:55,646 --> 04:39:56,079 TALK. 6281 04:39:56,079 --> 04:39:56,947 CHRISTY FROM VANDERBILT, CURIOUS 6282 04:39:56,947 --> 04:40:00,550 ABOUT IF YOU HAVE THOUGHTS ON 6283 04:40:00,550 --> 04:40:01,685 THE RECENT META-ANALYSIS 6284 04:40:01,685 --> 04:40:03,220 PUBLISHED IN JAMA PEDIATRICS 6285 04:40:03,220 --> 04:40:05,956 THAT SHOWS DAY CARE ATTENDANCE 6286 04:40:05,956 --> 04:40:09,559 SEEMS TO BE PROTECTIVE AGAINST 6287 04:40:09,559 --> 04:40:12,963 TYPE 1, AND HOW YOU RECONCILE 6288 04:40:12,963 --> 04:40:14,064 WITH YOUR QUESTIONSIVE BODY OF 6289 04:40:14,064 --> 04:40:15,599 WORK THAT INDICATES EXPOSURE TO 6290 04:40:15,599 --> 04:40:18,869 MICROBES WHICH HAPPENS IN DAY 6291 04:40:18,869 --> 04:40:20,837 CARE SEEMS TO ACTUALLY BE 6292 04:40:20,837 --> 04:40:21,104 CAUSATIVE? 6293 04:40:21,104 --> 04:40:22,939 >> THANK YOU VERY MUCH FOR 6294 04:40:22,939 --> 04:40:23,674 BRINGING THIS UP. 6295 04:40:23,674 --> 04:40:24,975 I THINK IT'S VERY, VERY 6296 04:40:24,975 --> 04:40:28,912 IMPORTANT THAT CHILDREN ARE 6297 04:40:28,912 --> 04:40:30,580 EXPOSED TO INFECTIONS AND MAYBE 6298 04:40:30,580 --> 04:40:33,083 EXPOSED REGULARLY AND EARLY 6299 04:40:33,083 --> 04:40:34,651 MAYBE ALSO INFLAMMATORY 6300 04:40:34,651 --> 04:40:38,455 RESPONSES MAY BE LESS BECAUSE 6301 04:40:38,455 --> 04:40:40,524 THEY LEARN IMMUNE SYSTEM LEARNS 6302 04:40:40,524 --> 04:40:43,427 TO COPE WITH INFECTION, BUT THIS 6303 04:40:43,427 --> 04:40:45,028 IS ALSO SPECULATION. 6304 04:40:45,028 --> 04:40:48,632 AND IT IS MAYBE ALSO REALLY 6305 04:40:48,632 --> 04:40:51,234 SPECIFIC INFECTIONS THAT MATTER. 6306 04:40:51,234 --> 04:40:55,105 BUT I DON'T KNOW. 6307 04:40:55,105 --> 04:40:56,973 >> THANK YOU. 6308 04:40:56,973 --> 04:40:57,874 >> BRIAN ZANE, ADAPTIVE 6309 04:40:57,874 --> 04:40:58,442 BIOTECHNOLOGIES. 6310 04:40:58,442 --> 04:41:00,477 THANK YOU VERY MUCH. 6311 04:41:00,477 --> 04:41:04,214 I WAS WONDERING I READ ABOUT HLA 6312 04:41:04,214 --> 04:41:06,516 AND THAT THAT CAN CORRELATE WITH 6313 04:41:06,516 --> 04:41:08,685 ONSET SO I'VE READ SOMETHING 6314 04:41:08,685 --> 04:41:10,987 AROUND DQA BEING SECRETARIED 6315 04:41:10,987 --> 04:41:14,491 WITH YOUNGSER ONSET VERSUS DQ 2 6316 04:41:14,491 --> 04:41:16,026 ASSOCIATED WITH OLDER ONSET, 6317 04:41:16,026 --> 04:41:17,327 PERHAPS PHENOTYPE YOU MENTIONED, 6318 04:41:17,327 --> 04:41:18,862 WONDERING DO YOU HAVE HLA TYPING 6319 04:41:18,862 --> 04:41:20,597 AND HAVE YOU LOOKED AT THAT? 6320 04:41:20,597 --> 04:41:25,102 >> YES, WE HAVE HLA TYPING. 6321 04:41:25,102 --> 04:41:27,604 I MEAN, YES, I DIDN'T SHOW THIS, 6322 04:41:27,604 --> 04:41:35,045 JUST SHOWED FOR INSULIN SNP BUT, 6323 04:41:35,045 --> 04:41:36,813 YES, THE HLA MATTERS FOR MORE 6324 04:41:36,813 --> 04:41:38,782 EARLY ONSET. 6325 04:41:38,782 --> 04:41:42,185 AND THOSE WHO DEVELOP DIABETES 6326 04:41:42,185 --> 04:41:45,188 LATER OFTEN HAVE NOT ALWAYS THE 6327 04:41:45,188 --> 04:41:46,356 CLASSICAL HLA GENOTYPES, THEY 6328 04:41:46,356 --> 04:41:49,092 ARE MORE DIVERSE AND HAVE ALSO 6329 04:41:49,092 --> 04:41:51,928 KIND OF NEUTRAL GENOTYPES, ET 6330 04:41:51,928 --> 04:41:52,162 CETERA. 6331 04:41:52,162 --> 04:41:55,766 BUT THERE ARE ALSO CHANGES OVER 6332 04:41:55,766 --> 04:41:56,833 TIME HAPPENING. 6333 04:41:56,833 --> 04:41:58,702 WE COMPARED EARLY COHORTS WITH 6334 04:41:58,702 --> 04:42:01,772 LATER COHORTS, AND WE SEE THE 6335 04:42:01,772 --> 04:42:03,640 EARLY COHORTS ALTOGETHER HAD 6336 04:42:03,640 --> 04:42:05,609 MORE HIGH RISK GENOTYPES, ALSO 6337 04:42:05,609 --> 04:42:08,345 WITHIN THE HLA, THAT THE LATER 6338 04:42:08,345 --> 04:42:10,313 COHORTS, THERE IS ALSO A SHIFT 6339 04:42:10,313 --> 04:42:12,382 THAT THOSE WHO DEVELOPED 6340 04:42:12,382 --> 04:42:16,119 DIABETES TODAY HAVE LESS OF THIS 6341 04:42:16,119 --> 04:42:18,321 OR HIGH RISK GENOTYPES THAN 6342 04:42:18,321 --> 04:42:19,222 THOSE WHO DEVELOP DIABETES 20 6343 04:42:19,222 --> 04:42:20,490 YEARS AGO. 6344 04:42:20,490 --> 04:42:22,192 SO IT'S KIND OF COMPLEX. 6345 04:42:22,192 --> 04:42:25,328 >> THANK YOU. 6346 04:42:25,328 --> 04:42:26,229 >> LAST QUESTION. 6347 04:42:26,229 --> 04:42:26,463 >> HI. 6348 04:42:26,463 --> 04:42:27,197 MOUNT SINAI SCHOOL OF MEDICINE 6349 04:42:27,197 --> 04:42:27,764 IN NEW YORK. 6350 04:42:27,764 --> 04:42:29,933 THANK YOU VERY MUCH FOR THIS 6351 04:42:29,933 --> 04:42:30,901 AMAZING TALK. 6352 04:42:30,901 --> 04:42:33,703 AND IMPRESSIVE BODY OF WORK. 6353 04:42:33,703 --> 04:42:36,106 MY QUESTION IS ABOUT THE 6354 04:42:36,106 --> 04:42:39,276 OBSERVATION THAT YOU MADE ABOUT 6355 04:42:39,276 --> 04:42:39,876 DEVELOPING -- CHANCES OF 6356 04:42:39,876 --> 04:42:41,912 DEVELOPING TYPE 1D IF YOU HAVE A 6357 04:42:41,912 --> 04:42:44,948 MOTHER WITH TYPE 1D VERSUS A 6358 04:42:44,948 --> 04:42:49,453 FATHER WITH TYPE 1D AND WHAT 6359 04:42:49,453 --> 04:42:53,924 COULD BE POTENTIAL MECHANISMS, 6360 04:42:53,924 --> 04:42:56,226 YOU HINTED EPIGENETICS, BROUGHT 6361 04:42:56,226 --> 04:42:59,162 TO MIND GENETIC IMPRINTING, IT'S 6362 04:42:59,162 --> 04:43:00,163 AN IMPORTANT PROCESS, VARIOUS 6363 04:43:00,163 --> 04:43:02,332 ASPECTS OF BIOLOGY AND HUMAN 6364 04:43:02,332 --> 04:43:06,069 DEVELOPMENT AND DISEASE, BUT WE 6365 04:43:06,069 --> 04:43:09,906 ALSO KNOW FROM KASTNER'S WORK 6366 04:43:09,906 --> 04:43:11,208 THAT IMPRINTING ON CHROMOSOME 11 6367 04:43:11,208 --> 04:43:12,542 ARE IMPORTANT. 6368 04:43:12,542 --> 04:43:14,744 I'M JUST THINKING ALONG THE 6369 04:43:14,744 --> 04:43:17,681 LINES OF WHETHER ANY GENES -- 6370 04:43:17,681 --> 04:43:19,950 WHETHER EPIGENETIC CHANGES THAT 6371 04:43:19,950 --> 04:43:21,685 YOU HINTED ON WERE ABOUT 6372 04:43:21,685 --> 04:43:24,321 METHYLATION AND ALSO IF WE COULD 6373 04:43:24,321 --> 04:43:26,656 LEARN ANYTHING ABOUT THE 6374 04:43:26,656 --> 04:43:27,824 IMPRINTED REGIONS ON THE GENOME 6375 04:43:27,824 --> 04:43:32,762 AND IF THIS HAS ANYTHING TO DO 6376 04:43:32,762 --> 04:43:35,165 WITH DIFFERENCE DEVELOPING TYPE 6377 04:43:35,165 --> 04:43:40,504 1D, MANY PEOPLE LOOKED AND 6378 04:43:40,504 --> 04:43:41,505 DIDN'T FIND MUCH DIFFERENCE IN 6379 04:43:41,505 --> 04:43:45,008 GENES, METHYLATION IS DIFFERENT 6380 04:43:45,008 --> 04:43:45,208 STORY. 6381 04:43:45,208 --> 04:43:50,780 IF YOU LOOK AT GENES, GENETIC 6382 04:43:50,780 --> 04:43:52,883 RISK SCORES, NO DIFFERENCE 6383 04:43:52,883 --> 04:43:53,216 REALLY. 6384 04:43:53,216 --> 04:43:54,184 IMPRINTING EARLY DAYS WAS LOOKED 6385 04:43:54,184 --> 04:43:56,953 AT BUT NOT REALLY FOUND AS 6386 04:43:56,953 --> 04:43:58,922 EXPLANATION, THERE WAS ALSO THE 6387 04:43:58,922 --> 04:44:03,293 QUESTION, DO CHILDREN OF MOTHERS 6388 04:44:03,293 --> 04:44:05,061 DIE MORE FREQUENTLY DURING 6389 04:44:05,061 --> 04:44:06,997 ALREADY PREGNANCY AND THAT IS 6390 04:44:06,997 --> 04:44:09,966 KIND OF A SELECTION PROCESS THAT 6391 04:44:09,966 --> 04:44:12,802 I THINK ALL EVIDENCE IS NOT SO 6392 04:44:12,802 --> 04:44:17,007 STRONG FOR EXPLAINING REALLY THE 6393 04:44:17,007 --> 04:44:17,307 DIFFERENCE. 6394 04:44:17,307 --> 04:44:20,010 >> THANK YOU. 6395 04:44:20,010 --> 04:44:22,045 >> LET'S THANK DR. ZEIGLER AND 6396 04:44:22,045 --> 04:44:22,646 ALL THE SPEAKERS. 6397 04:44:22,646 --> 04:44:25,315 [APPLAUSE] 6398 04:44:25,315 --> 04:44:35,315