1 00:00:04,660 --> 00:00:06,162 I'M JOE MARCOTRIGIANO. 2 00:00:06,162 --> 00:00:11,334 I AM THE CHAIR OF THIS YEAR'S 3 00:00:11,334 --> 00:00:12,335 SALZMAN COMMITTEE. 4 00:00:12,335 --> 00:00:16,272 ON BEHALF OF THE COMMITTEE AND 5 00:00:16,272 --> 00:00:17,507 FOUNDATION FOR THE NIH AND 6 00:00:17,507 --> 00:00:20,776 MRS. SALZMAN WELCOME TO THE 7 00:00:20,776 --> 00:00:28,518 NORMAN P SALZMAN ANNUAL MEMORIAL 8 00:00:28,518 --> 00:00:30,286 SIM PODIUM AND AWARDS IN BASIC 9 00:00:30,286 --> 00:00:33,356 AND CLINICAL VIROLOGY. 10 00:00:33,356 --> 00:00:36,559 IT'S A MILESTONE FOR US THIS 11 00:00:36,559 --> 00:00:36,759 YEAR. 12 00:00:36,759 --> 00:00:38,594 ANOTHER MAJOR MILESTONE IS WE'RE 13 00:00:38,594 --> 00:00:41,297 BACK IN PERSON FIRST TIME IN 14 00:00:41,297 --> 00:00:41,631 THREE YEARS. 15 00:00:41,631 --> 00:00:45,902 SO I THINK THAT IS A MAJOR 16 00:00:45,902 --> 00:00:47,670 ACHIEVEMENT FOR OUR FIELD 17 00:00:47,670 --> 00:00:49,338 WORLDWIDE THAT WE'VE BATTLED THE 18 00:00:49,338 --> 00:00:50,640 PANDEMIC AND WE'RE SOMEWHAT BACK 19 00:00:50,640 --> 00:00:52,742 TO NORMAL AGAIN. 20 00:00:52,742 --> 00:00:53,709 SO, IT'S GREAT TO BE BACK AND 21 00:00:53,709 --> 00:00:54,377 GREAT TO BE HERE. 22 00:00:54,377 --> 00:00:56,712 WE HAVE A VERY EXCITING DAY 23 00:00:56,712 --> 00:00:59,916 PLANNED AND A KIND OF WANT TO 24 00:00:59,916 --> 00:01:01,350 KICK IT OFF. 25 00:01:01,350 --> 00:01:11,861 FIRST UP IS DR. JULIE LOUISE 26 00:01:13,029 --> 00:01:18,234 GERBERDING THE PRESIDENT AND 27 00:01:18,234 --> 00:01:22,104 CHIEF EXECUTIVE OFFICER OF THE 28 00:01:22,104 --> 00:01:22,305 FNIH. 29 00:01:22,305 --> 00:01:23,940 >> THANK YOU FOR YOUR ONGOING 30 00:01:23,940 --> 00:01:25,007 SUPPORT OF THIS VERY IMPORTANT 31 00:01:25,007 --> 00:01:25,274 OCCASION. 32 00:01:25,274 --> 00:01:28,144 WHEN I WAS THINKING ABOUT 33 00:01:28,144 --> 00:01:31,013 DR. SALZMAN I WAS WONDERING IF 34 00:01:31,013 --> 00:01:33,816 HE WERE HERE TODAY AND COMING 35 00:01:33,816 --> 00:01:35,718 OUT OF THE CORONAVIRUS PANDEMIC 36 00:01:35,718 --> 00:01:36,419 WOULD HE BE SURPRISED. 37 00:01:36,419 --> 00:01:39,155 AND I THINK I WOULD HAVE TO SAY 38 00:01:39,155 --> 00:01:40,389 PROBABLY NOT BECAUSE HE SPENT A 39 00:01:40,389 --> 00:01:42,525 GREAT DEAL OF TIME IN HIS CAREER 40 00:01:42,525 --> 00:01:46,796 STUDYING PATHOGENS LIKE POLIO 41 00:01:46,796 --> 00:01:47,830 AND SMALLPOX AND AIDS. 42 00:01:47,830 --> 00:01:49,599 I THOUGHT HE WOULD HAVE BEEN 43 00:01:49,599 --> 00:01:51,634 PARTICULARLY SURPRISED TO SEE 44 00:01:51,634 --> 00:01:54,570 THAT WE WERE PLAGUED WITH YET 45 00:01:54,570 --> 00:01:56,205 ANOTHER RESPIRATORY DISEASE THAT 46 00:01:56,205 --> 00:01:58,207 CAUSED GLOBAL CALAMITY. 47 00:01:58,207 --> 00:02:01,010 I WAS WONDERING WOULD HE BE 48 00:02:01,010 --> 00:02:02,211 SURPRISED ABOUT THE mRNA 49 00:02:02,211 --> 00:02:03,412 VACCINES AND I REALIZED PROBABLY 50 00:02:03,412 --> 00:02:05,648 NOT BECAUSE HE WAS ONE OF THE 51 00:02:05,648 --> 00:02:07,350 PEOPLE WHO FIRST DEFINED BIO 52 00:02:07,350 --> 00:02:09,819 CHEMISTRY OF MESSENGER RNA AND 53 00:02:09,819 --> 00:02:11,053 NO DOUBT UNDERSTOOD AS IT 54 00:02:11,053 --> 00:02:12,355 EVOLVED HOW IMPORTANT THAT 55 00:02:12,355 --> 00:02:13,222 ULTIMATELY COULD BE FOR HUMAN 56 00:02:13,222 --> 00:02:23,099 HEALTH. 57 00:02:23,099 --> 00:02:24,533 BUT I THINK HE'D BE PLEASED HIS 58 00:02:24,533 --> 00:02:26,535 WIFE, FAMILY AND NIH INTEREST 59 00:02:26,535 --> 00:02:28,204 GROUP IN THE AREA AND ORGANIZING 60 00:02:28,204 --> 00:02:29,438 COMMITTEE COMMITTED TO 61 00:02:29,438 --> 00:02:31,007 MAINTAINING THE FOCUS ON EARLY 62 00:02:31,007 --> 00:02:35,911 CAREER SCIENTISTS AND THEIR 63 00:02:35,911 --> 00:02:39,548 MENTORS AND THAT LEGACY IS 64 00:02:39,548 --> 00:02:39,849 CONTINUING. 65 00:02:39,849 --> 00:02:40,750 THANK YOU SO MUCH FOR ENSURING 66 00:02:40,750 --> 00:02:42,084 THAT CONTINUES TO HAPPEN. 67 00:02:42,084 --> 00:02:43,019 THANK YOU ALL WORKING IN THE 68 00:02:43,019 --> 00:02:46,455 FIELD OF VIROLOGY FOR YOUR 69 00:02:46,455 --> 00:02:46,856 CONTRIBUTIONS. 70 00:02:46,856 --> 00:02:49,659 I'M AN INFECTIOUS DISEASE DOCTOR 71 00:02:49,659 --> 00:02:51,227 AND A HARDLY THINK THEY COULD BE 72 00:02:51,227 --> 00:02:52,862 MORE IMPORTANT THAN THEY'VE BEEN 73 00:02:52,862 --> 00:02:54,130 THE LAST THREE YEARS AND 74 00:02:54,130 --> 00:02:58,534 HOPEFULLY THE EYES OF THE WORLD 75 00:02:58,534 --> 00:03:00,002 ARE OPENED UP AND PEOPLE CAN 76 00:03:00,002 --> 00:03:02,371 RECOGNIZE WHAT AN EXCITING TIME 77 00:03:02,371 --> 00:03:08,210 THIS IS IN SCIENCE AND ALSO HOW 78 00:03:08,210 --> 00:03:09,211 CRITICALLY IMPORTANT AND THE 79 00:03:09,211 --> 00:03:13,015 PIPELINE OF THE BEST AND 80 00:03:13,015 --> 00:03:15,284 BRIGHTEST SCIENTISTS AND SUSTAIN 81 00:03:15,284 --> 00:03:17,253 OUR INTRAMURAL WORK IN THE 82 00:03:17,253 --> 00:03:18,854 INTERESTS OF THE HONOR WE'RE 83 00:03:18,854 --> 00:03:19,889 BESTOWING TODAY. 84 00:03:19,889 --> 00:03:20,556 THANK YOU SO MUCH AND THANK YOU 85 00:03:20,556 --> 00:03:22,191 JOE AND I LOOK FORWARD TO 86 00:03:22,191 --> 00:03:25,027 HEARING THE REMARKS THAT FOLLOW. 87 00:03:25,027 --> 00:03:35,204 THANK YOU. 88 00:03:43,279 --> 00:03:45,314 CHARLES RICE IS FROM THE 89 00:03:45,314 --> 00:03:46,015 ROCKEFELLER UNIVERSITY AND 90 00:03:46,015 --> 00:03:47,016 SCIENTIFIC AND EXECUTIVE 91 00:03:47,016 --> 00:03:48,851 DIRECTOR NOR CENTER FOR THE 92 00:03:48,851 --> 00:03:50,686 STUDY OF HEPATITIS C. 93 00:03:50,686 --> 00:03:54,557 CHARLIE STARTED HI GRADUATE 94 00:03:54,557 --> 00:03:57,827 STUDIES AT KAL TECH AND GYM AND 95 00:03:57,827 --> 00:04:01,163 HIS WIFE ELLEN ARE PIONEERS IN 96 00:04:01,163 --> 00:04:04,600 THE IMPLEMENTATION OF MOLECULAR 97 00:04:04,600 --> 00:04:06,168 BIOLOGY TECHNIQUES TO STUDY RNA 98 00:04:06,168 --> 00:04:09,905 VIRUS BIOLOGY SPECIFICALLY IN 99 00:04:09,905 --> 00:04:14,210 ALPHA VIRUSES PIONEERS IN 100 00:04:14,210 --> 00:04:14,510 GENERAL. 101 00:04:14,510 --> 00:04:18,848 CHARLIE DID HEROIC WORK AT THE 102 00:04:18,848 --> 00:04:20,816 TIME THEY SEEM SIMPLE NOW WITH 103 00:04:20,816 --> 00:04:25,654 LOTS OF SEQUENCING AND CLOTH OF 104 00:04:25,654 --> 00:04:28,290 THE STRUCTURAL PROTEINS AND 105 00:04:28,290 --> 00:04:30,860 STAYED ON AS A POSTDOC AND DID 106 00:04:30,860 --> 00:04:34,230 WORK ON VIRUSES SPECIFICALLY 107 00:04:34,230 --> 00:04:36,766 YELLOW FEVER AND 17B STRAIN THE 108 00:04:36,766 --> 00:04:39,568 VACCINE STRAIN FOR YELLOW FEVER. 109 00:04:39,568 --> 00:04:42,471 IT'S CONSIDERED TO BE ONE OF THE 110 00:04:42,471 --> 00:04:44,974 SAFEST AND MOST EFFECTIVE 111 00:04:44,974 --> 00:04:47,009 VACCINES EVER PRODUCED AND MOVED 112 00:04:47,009 --> 00:04:49,345 TO WASH-U IN ST. LOUIS MAKING 113 00:04:49,345 --> 00:04:51,180 THE FIRST CLONES FOR YELLOW 114 00:04:51,180 --> 00:04:53,983 FEVER 17D AND ENABLED THE 115 00:04:53,983 --> 00:04:56,352 PRODUCTION OF mRNA WHICH THEN 116 00:04:56,352 --> 00:04:58,454 CAN BE PUT INTO CELLS. 117 00:04:58,454 --> 00:05:00,890 IT'S A REALLY IMPORTANT 118 00:05:00,890 --> 00:05:01,157 MILESTONE. 119 00:05:01,157 --> 00:05:03,526 HERE AT THE CLINICAL CENTER, 120 00:05:03,526 --> 00:05:06,862 HARVEY ALTER THE STUDY 121 00:05:06,862 --> 00:05:09,465 TRANSFUSIONS PEOPLE WHO 122 00:05:09,465 --> 00:05:11,734 DEVELOPED HEPATITIS POST 123 00:05:11,734 --> 00:05:13,569 TRANSFUSION AND THEY HAD BEEN 124 00:05:13,569 --> 00:05:15,471 SCREENED FOR HEPATITIS A AND B 125 00:05:15,471 --> 00:05:26,015 AND WORKING WITH BOB PURCELL AT 126 00:05:29,218 --> 00:05:37,026 NIAD AND WE USED AN EXPRESSION 127 00:05:37,026 --> 00:05:41,664 CLONING METHOD IDENTIFY A 128 00:05:41,664 --> 00:05:42,731 PATHOGEN AND BOOT STRAP TO GET 129 00:05:42,731 --> 00:05:47,803 MOST THE GENOME AND TURNED OUT 130 00:05:47,803 --> 00:05:50,806 TO BE A NEW VIRUS AT THE TIME. 131 00:05:50,806 --> 00:05:51,740 THAT'S WHEN CHARLIE GOT BACK 132 00:05:51,740 --> 00:05:54,210 INVOLVED THROUGH THE 133 00:05:54,210 --> 00:05:56,478 INTERACTIONS WITH STEVE 134 00:05:56,478 --> 00:05:58,781 FINESTONE WHO I THINK IS HERE 135 00:05:58,781 --> 00:06:01,150 AND STEVE GOT CHARLIE BACK INTO 136 00:06:01,150 --> 00:06:03,285 WORKING ON HEPATITIS C VIRUS. 137 00:06:03,285 --> 00:06:05,754 CHARLIE AND HIS LAB FIGURED OUT 138 00:06:05,754 --> 00:06:08,490 THE POLY PROTEIN PROCESSING OF 139 00:06:08,490 --> 00:06:12,595 THE VIRUS AND THE PRIME END 140 00:06:12,595 --> 00:06:14,230 WHICH THEN ALLOWED FOR IN VITRO 141 00:06:14,230 --> 00:06:16,932 METHODS TO EVOLVE AND MAKE THE 142 00:06:16,932 --> 00:06:18,467 CLONE IN LABORATORY AND THEN 143 00:06:18,467 --> 00:06:25,040 MAKE AN mRNA AND PUT THAT INTO A 144 00:06:25,040 --> 00:06:27,810 CHIMPANZEE'S LEVER AND CAME OUT 145 00:06:27,810 --> 00:06:29,912 AS HEPATITIS C VIRUS. 146 00:06:29,912 --> 00:06:33,048 CHARLIE CONTINUED WITH REPLICONS 147 00:06:33,048 --> 00:06:34,650 AND INFECTIOUS CLONES IN THE 148 00:06:34,650 --> 00:06:38,454 LATE '90s AND EARLY 2000s. 149 00:06:38,454 --> 00:06:41,690 I CONTACTED CHARLIE AROUND 2000 150 00:06:41,690 --> 00:06:44,326 ABOUT BECOMING A POSTDOC IN HIS 151 00:06:44,326 --> 00:06:46,328 LAB AND I WAS CONVINCED HE 152 00:06:46,328 --> 00:06:48,364 WOULDN'T RESPOND TO MY E-MAIL 153 00:06:48,364 --> 00:06:49,498 BECAUSE WHY WOULD HE WANT A 154 00:06:49,498 --> 00:06:53,335 STRUCTURAL PERSON IN HIS LAB AND 155 00:06:53,335 --> 00:06:54,136 I WAS VERY WRONG. 156 00:06:54,136 --> 00:06:56,772 HE CONTACTED ME BACK AND INVITED 157 00:06:56,772 --> 00:06:59,041 ME TO COME AND CHARLIE AT THAT 158 00:06:59,041 --> 00:07:01,110 TIME WAS ASSEMBLING A VERY 159 00:07:01,110 --> 00:07:02,511 DIVERSE GROUP OF PEOPLE TO BRING 160 00:07:02,511 --> 00:07:05,214 DIFFERENT TECHNIQUES TO WORK ON 161 00:07:05,214 --> 00:07:08,083 HEPATITIS C VIRUS. 162 00:07:08,083 --> 00:07:10,319 AFTER ABOUT A YEAR LAST DOWN IN 163 00:07:10,319 --> 00:07:12,588 CHARLIE'S OFFICE AND SAID 164 00:07:12,588 --> 00:07:15,457 THERE'S ONLY 10 PROTEINS IN HCV. 165 00:07:15,457 --> 00:07:18,093 THE DRUG COMPANIES FIGURED OUT 166 00:07:18,093 --> 00:07:21,430 THE POLYMERASE AND PROTEASE AND 167 00:07:21,430 --> 00:07:25,034 WE HAVE TO DO MORE AND WE SET 168 00:07:25,034 --> 00:07:28,037 ABOUT SOLVING STRUCTURES IN NS2 169 00:07:28,037 --> 00:07:29,405 AND CHARLIE WAS RIGHT. 170 00:07:29,405 --> 00:07:32,942 ONCE WE HAD REPLICON SYSTEMS AND 171 00:07:32,942 --> 00:07:36,512 HIGH THROUGHPUT SCREENING 172 00:07:36,512 --> 00:07:37,446 METHODS AND COMPOUNDS WERE 173 00:07:37,446 --> 00:07:39,281 POTENT AND FOUND IN THE 174 00:07:39,281 --> 00:07:47,890 LABORATORY THAT INHIBITED HCV AT 175 00:07:47,890 --> 00:07:48,223 PI 176 00:07:48,223 --> 00:07:51,260 PICOMOLE CONCENTRATIONS AND IT 177 00:07:51,260 --> 00:07:53,462 WAS A NEW CLASS OF ANTIVIRALS 178 00:07:53,462 --> 00:07:58,901 AND NOW NS5A INHIBITORS ARE 179 00:07:58,901 --> 00:08:02,204 CURING GREATER THAN 95% OF THE 180 00:08:02,204 --> 00:08:03,806 CHRONIC INFECTIONS OF HEPATITIS 181 00:08:03,806 --> 00:08:05,941 C VIRUS AND CHARLIE SORT OF LAID 182 00:08:05,941 --> 00:08:09,044 THE FOUNDATION FOR US TO DO THAT 183 00:08:09,044 --> 00:08:09,712 WORK STRUCTURALLY AND HELPED IN 184 00:08:09,712 --> 00:08:12,781 THE MECHANISM AND DESIGN OF THE 185 00:08:12,781 --> 00:08:13,048 COMPOUNDS. 186 00:08:13,048 --> 00:08:16,585 NOW WE'RE CURING MILLIONS OF 187 00:08:16,585 --> 00:08:20,622 PEOPLE YEAR TO DATE AND LOTS OF 188 00:08:20,622 --> 00:08:24,326 PEOPLE HAVE BEEN CURED OF HCV TO 189 00:08:24,326 --> 00:08:26,228 THIS DATE AND CHARLIE'S BEEN AN 190 00:08:26,228 --> 00:08:28,464 EXCELLENT MENTOR FOR YEARS. 191 00:08:28,464 --> 00:08:30,065 HE'S ALWAYS VERY SUPPORT 192 00:08:30,065 --> 00:08:30,366 SUPPORTIVE. 193 00:08:30,366 --> 00:08:31,767 HE ANSWERS MY PHONE CALLS WHICH 194 00:08:31,767 --> 00:08:32,968 I'M SURPRISED HE DOES AND 195 00:08:32,968 --> 00:08:34,803 ACCEPTS MY INVITATION TO COME 196 00:08:34,803 --> 00:08:35,537 AND SPEAK TODAY. 197 00:08:35,537 --> 00:08:46,015 WITH MORE, CHARLIE, PLEASE. 198 00:08:48,350 --> 00:08:49,985 >> WELL, I CAN ZIP THROUGH THE 199 00:08:49,985 --> 00:08:54,790 FIRST PART OF MY TALK. 200 00:08:54,790 --> 00:08:58,761 IT'S A REAL PLEASURE AND HONOR 201 00:08:58,761 --> 00:08:59,595 TO BE HERE. 202 00:08:59,595 --> 00:09:03,665 I THINK THIS SYMPOSIUM IN HONOR 203 00:09:03,665 --> 00:09:06,268 OF NORMAN SORT OF EMPHASIZES 204 00:09:06,268 --> 00:09:13,042 SORT OF THE MENTORS AND MENTEES 205 00:09:13,042 --> 00:09:15,177 AND IS A WONDERFUL LEGACY 206 00:09:15,177 --> 00:09:18,180 BECAUSE I KNOW FROM READING 207 00:09:18,180 --> 00:09:23,919 ABOUT NORMAN AND HAVING MET HIM, 208 00:09:23,919 --> 00:09:28,991 THIS WAS A VERY IMPORTANT ASPECT 209 00:09:28,991 --> 00:09:31,326 OF HOW SCIENTISTS CAN CHANGE THE 210 00:09:31,326 --> 00:09:34,229 FUTURE AND HELPING THE NEXT 211 00:09:34,229 --> 00:09:43,105 GENERATION OF YOUNG SCIENTISTS 212 00:09:43,105 --> 00:09:45,908 AS JOE SAID WE DO HAVE A CURE 213 00:09:45,908 --> 00:09:49,178 FOR HEPATITIS C AND THAT LEAVES 214 00:09:49,178 --> 00:09:51,713 A MOLECULAR VIROLOGIST WITH THE 215 00:09:51,713 --> 00:09:53,082 QUESTION WHAT TO DO NEXT. 216 00:09:53,082 --> 00:10:03,625 AT LEAST IN TERMS OF MY LAB WE 217 00:10:06,361 --> 00:10:08,130 HAVE STARTED TO WORK IN 218 00:10:08,130 --> 00:10:10,833 DIFFERENT AREAS AND I'LL MENTION 219 00:10:10,833 --> 00:10:14,036 A FEW AT THEN OF THE TALK BUT 220 00:10:14,036 --> 00:10:15,804 THERE'S STILL A LOT OF 221 00:10:15,804 --> 00:10:18,207 CHALLENGES AHEAD BOTH IN 222 00:10:18,207 --> 00:10:22,211 HEPATITIS C AND OTHER INFECTIOUS 223 00:10:22,211 --> 00:10:25,814 DISEASES WE'VE SEEN. 224 00:10:25,814 --> 00:10:27,883 SO THE SUCCESS STORY, LET'S SEE 225 00:10:27,883 --> 00:10:36,258 IF THIS IS GOING TO WORK. 226 00:10:36,258 --> 00:10:41,430 SO I THINK AS JOE SAID THIS 227 00:10:41,430 --> 00:10:43,832 MYSTERIOUS AGING OF 228 00:10:43,832 --> 00:10:45,834 POST-TRANSFUSION HEPATITIS 229 00:10:45,834 --> 00:10:48,704 NOTICED BY HARVEY ALTAR AND 230 00:10:48,704 --> 00:10:52,641 OTHERS NOT DUE TO HEPATITIS A OR 231 00:10:52,641 --> 00:10:55,878 B HAPPENED IN THE 1970s. 232 00:10:55,878 --> 00:10:59,014 THIS REALLY WAS QUITE A MYSTERY. 233 00:10:59,014 --> 00:11:02,217 THE INFECTION COULD BE TREATED 234 00:11:02,217 --> 00:11:12,427 WITH INTERFERON BUT VERY POORLY 235 00:11:12,427 --> 00:11:13,829 IS THAT GAVE RISE TO AN 236 00:11:13,829 --> 00:11:15,597 INCREDIBLE EFFORT TO TRY TO 237 00:11:15,597 --> 00:11:17,666 FIGURE OUT WHAT THE AGENT WAS. 238 00:11:17,666 --> 00:11:21,036 AS JOE SAID, THAT WAS 239 00:11:21,036 --> 00:11:22,304 ACCOMPLISHED BY MICHAEL HOUTMAN 240 00:11:22,304 --> 00:11:30,979 AND HIS TEAM AT CHIREON IN 1989 241 00:11:30,979 --> 00:11:32,748 AND LOOKED VERY MUCH LIKE YELLOW 242 00:11:32,748 --> 00:11:35,050 FEVER A VIRUS I HAD BEEN WORKING 243 00:11:35,050 --> 00:11:35,217 ON. 244 00:11:35,217 --> 00:11:36,985 AND THE EARLY STUDIES SHOWED THE 245 00:11:36,985 --> 00:11:38,420 ASSOCIATION OF THE AGENT WITH 246 00:11:38,420 --> 00:11:45,494 LIVER DISEASE, SEMINOLE WORK BY 247 00:11:45,494 --> 00:11:48,964 BOB PURCELL AND UNDERSTANDING 248 00:11:48,964 --> 00:11:52,401 THE PROPERTIES OF THE AGENT OF 249 00:11:52,401 --> 00:11:52,968 THE CHIMPANZEE MODEL AND 250 00:11:52,968 --> 00:11:58,373 CHALLENGING AND TERRIFIC WORK. 251 00:11:58,373 --> 00:12:04,079 IN 1989 WITH THE USE OF A PANEL 252 00:12:04,079 --> 00:12:07,516 OF PEDIGREE EXAMPLES HARVEY 253 00:12:07,516 --> 00:12:11,753 COLLECTED IN MOLECULAR BIOLOGY 254 00:12:11,753 --> 00:12:13,555 IN THE CHIRON ROUTE AND NON A 255 00:12:13,555 --> 00:12:18,227 AND B WAS UNVEILED AND 256 00:12:18,227 --> 00:12:19,027 DIAGNOSTICS SHORTLY THEREAFTER A 257 00:12:19,027 --> 00:12:21,797 LOT OF MOLECULAR VIROLOGISTS 258 00:12:21,797 --> 00:12:25,033 LIKE MY LAB GOT INVOLVED AND IN 259 00:12:25,033 --> 00:12:26,535 2011 THE FIRST AGENTS THAT 260 00:12:26,535 --> 00:12:29,838 DIRECTLY WERE TARGETING THESE 261 00:12:29,838 --> 00:12:30,973 DIRECT-ACTING ANTIVIRALS 262 00:12:30,973 --> 00:12:32,908 PROTEASE INHIBITORS WERE ADDED 263 00:12:32,908 --> 00:12:37,346 TO THE CURRENT TREATMENT OF PEG 264 00:12:37,346 --> 00:12:40,649 INTERFERON AND THEN IN 2014, 265 00:12:40,649 --> 00:12:43,986 '15, IT BECAME POSSIBLE TO GO 266 00:12:43,986 --> 00:12:46,922 WITH AN ALL-ORAL TREATMENT FOR 267 00:12:46,922 --> 00:12:48,557 HEPATITIS C WHICH COULD CURE 268 00:12:48,557 --> 00:12:50,826 MORE THAN 95% OF THOSE THAT WERE 269 00:12:50,826 --> 00:12:51,260 INFECTED. 270 00:12:51,260 --> 00:12:55,998 IN FACT THAT NUMBER IS PROBABLY 271 00:12:55,998 --> 00:12:59,601 99.9% OF THOSE INFECTED. 272 00:12:59,601 --> 00:13:03,438 SO I HAD TO SORT OF SHOW THIS 273 00:13:03,438 --> 00:13:05,274 SLIDE AND JOE HAS ALL RIGHT 274 00:13:05,274 --> 00:13:06,808 INTRODUCED IT BECAUSE THERE YOU 275 00:13:06,808 --> 00:13:13,315 SEE THE THREE POSTER CHILDREN 276 00:13:13,315 --> 00:13:20,522 THE VIRAL TARGETS THAT BECAME 277 00:13:20,522 --> 00:13:22,224 PART OF THE TARGETS AND THE 278 00:13:22,224 --> 00:13:24,026 PROTEIN I HAVE TO SAY WAS A 279 00:13:24,026 --> 00:13:25,360 LUCKY DAY FOR ME WHEN JOE DID 280 00:13:25,360 --> 00:13:28,263 SEND THE E-MAIL AND ASKED ABOUT 281 00:13:28,263 --> 00:13:29,498 BECOMING A POSTDOC IN THE LAB 282 00:13:29,498 --> 00:13:34,303 BECAUSE IT ALLOWED US TO REALLY 283 00:13:34,303 --> 00:13:38,206 EXPAND OUR ATTACK ON THIS USING 284 00:13:38,206 --> 00:13:40,042 STATE OF THE ART STRUCTURAL 285 00:13:40,042 --> 00:13:41,176 VIROLOGY APPROACHES. 286 00:13:41,176 --> 00:13:42,911 WE DO HAVE THESE REMARKABLE 287 00:13:42,911 --> 00:13:43,945 TREATMENTS AND THIS SHOWS YOU 288 00:13:43,945 --> 00:13:45,580 SOME OF THEM, TWO TO THREE 289 00:13:45,580 --> 00:13:49,584 MONTHS OF TREATMENT THE VIRUS IS 290 00:13:49,584 --> 00:13:49,785 GONE. 291 00:13:49,785 --> 00:13:52,921 SO IT HAS -- I THINK ONE OF THE 292 00:13:52,921 --> 00:13:55,324 THINGS WE WERE ALL PUZZLING OVER 293 00:13:55,324 --> 00:13:57,492 WAS SINCE ACD IS SO DIVERSE, HOW 294 00:13:57,492 --> 00:14:00,929 COULD YOU COME UP WITH A DRUG 295 00:14:00,929 --> 00:14:04,666 REGIMENT THAT WOULD ACTUALLY 296 00:14:04,666 --> 00:14:06,068 COVER THAT INCREDIBLY HUGE VIRAL 297 00:14:06,068 --> 00:14:07,636 SEQUENCE SPACE. 298 00:14:07,636 --> 00:14:10,539 BUT THESE COMBINATIONS DO. 299 00:14:10,539 --> 00:14:14,209 AND SO RESISTANCE IS REALLY NOT 300 00:14:14,209 --> 00:14:18,380 A GREAT PROBLEM. 301 00:14:18,380 --> 00:14:23,585 SO, WHERE WE ARE NOW AND I THINK 302 00:14:23,585 --> 00:14:25,987 FRANCIS COLLINS HAS TAKEN UP THE 303 00:14:25,987 --> 00:14:29,291 CHARGE TO GET CLOSER TO THIS 304 00:14:29,291 --> 00:14:30,959 ERADICATION BUT THERE ARE SOME 305 00:14:30,959 --> 00:14:32,761 THINGS WE FACE AND THEY'RE 306 00:14:32,761 --> 00:14:37,032 REALLY IN THE ARENA OF ECONOMICS 307 00:14:37,032 --> 00:14:37,599 AND PUBLIC HEALTH. 308 00:14:37,599 --> 00:14:40,802 ALSO, SINCE THIS IS A RELATIVELY 309 00:14:40,802 --> 00:14:51,279 ASYSTEMATIC -- ASYMPTOMATIC 310 00:14:53,915 --> 00:14:55,150 TREATMENT AND IT USED TO BE THE 311 00:14:55,150 --> 00:14:58,787 OLD TREATMENTS THERE WERE GROUPS 312 00:14:58,787 --> 00:15:00,756 LIKE HIV AND CO-INFECTED 313 00:15:00,756 --> 00:15:02,157 PATIENTS HARDER TO TREAT. 314 00:15:02,157 --> 00:15:03,525 THAT'S NOT REALLY THE CASE NOW 315 00:15:03,525 --> 00:15:07,496 FOR THE DIRECT-ACTING ANTIVIRAL 316 00:15:07,496 --> 00:15:08,397 COCKTAILS. 317 00:15:08,397 --> 00:15:10,265 VIRUS RESISTANCE IS NOT A HUGE 318 00:15:10,265 --> 00:15:14,236 PROBLEM AND WE STILL SORT OF 319 00:15:14,236 --> 00:15:14,903 LACK SOME ACTION. 320 00:15:14,903 --> 00:15:16,605 THERE'S STILL A LONG WAYS TO GO 321 00:15:16,605 --> 00:15:17,105 IN THE UNITED STATES. 322 00:15:17,105 --> 00:15:18,940 AND IN EGYPT THEY MANAGED TO 323 00:15:18,940 --> 00:15:21,476 CURE OVER 90% OF THEIR 324 00:15:21,476 --> 00:15:24,946 POPULATION BY HAVING A REALLY 325 00:15:24,946 --> 00:15:26,148 TIGHT GOVERNMENT PROGRAM AND 326 00:15:26,148 --> 00:15:30,519 COMING UP WITH A WAY OF MAKING 327 00:15:30,519 --> 00:15:31,987 SHE'S DRUGS AFFORDABLE. 328 00:15:31,987 --> 00:15:37,159 WE'VE STILL GOT A WAYS TO GO. 329 00:15:37,159 --> 00:15:40,262 THERE IS SOME UNFINISHED 330 00:15:40,262 --> 00:15:41,663 BUSINESS FOR HEPATITIS C. 331 00:15:41,663 --> 00:15:43,865 I'LL JUST SORT OF POINT OUT THAT 332 00:15:43,865 --> 00:15:51,740 TO SOME EXTENT BECAUSE OF THE 333 00:15:51,740 --> 00:15:52,774 CHALLENGES WITH THIS PARTICULAR 334 00:15:52,774 --> 00:15:56,611 CHRONIC VIRAL INFECTION AND HOW 335 00:15:56,611 --> 00:16:00,449 MANY FEEL A VACCINE IS NEEDED TO 336 00:16:00,449 --> 00:16:01,683 ACHIEVE GLOBAL VIRAL CONTROL OF 337 00:16:01,683 --> 00:16:02,184 THIS VIRUS. 338 00:16:02,184 --> 00:16:07,255 AND I THINK GIVEN THE SUCCESS OF 339 00:16:07,255 --> 00:16:10,792 THE COVID-19 VACCINE THIS REALLY 340 00:16:10,792 --> 00:16:12,828 HAS RESURRECTED MORE ACTIVITY IN 341 00:16:12,828 --> 00:16:17,866 THE HIV SPACE TO DEVELOP A 342 00:16:17,866 --> 00:16:20,168 VACCINE AND JAKE LIANG IN THE 343 00:16:20,168 --> 00:16:22,537 AUDIENCE HERE REALLY I THINK 344 00:16:22,537 --> 00:16:25,807 HELPING TO FACILITATE THAT BY 345 00:16:25,807 --> 00:16:28,243 CALLING FOR US TO CONSIDER THE 346 00:16:28,243 --> 00:16:30,312 POSSIBILITY OF DOING CONTROLLED 347 00:16:30,312 --> 00:16:33,248 HUMAN INFECTION MODELS FOR 348 00:16:33,248 --> 00:16:34,749 TESTING OUT VACCINE REGIMENTS 349 00:16:34,749 --> 00:16:37,552 AND I THINK THAT WOULD REALLY 350 00:16:37,552 --> 00:16:44,526 GREATLY ACCESS -- ACCELERATE 351 00:16:44,526 --> 00:16:46,695 WITH A SMALL CLINICAL PROGRAM 352 00:16:46,695 --> 00:16:50,799 WHAT KINDS OF VACCINE MODALITIES 353 00:16:50,799 --> 00:16:54,202 WILL WORK BEFORE YOU GO INTO 354 00:16:54,202 --> 00:16:57,439 MORE EXPENSIVE TRIALS. 355 00:16:57,439 --> 00:16:58,773 SO IN TERMS OF DISEASE 356 00:16:58,773 --> 00:17:01,042 PROGRESSION, I THINK WE HAVE A 357 00:17:01,042 --> 00:17:02,944 LOT OF DESCRIPTIVE DATA FROM 358 00:17:02,944 --> 00:17:07,015 ACTUALLY ANALYZING LIVER SAMPLES 359 00:17:07,015 --> 00:17:10,485 FROM HIV-INFECTED PEOPLE AND 360 00:17:10,485 --> 00:17:12,654 REALLY WHAT DRIVES THE 361 00:17:12,654 --> 00:17:18,593 PROGRESSION TO CIRRHOSIS AND THE 362 00:17:18,593 --> 00:17:20,295 DEVELOPMENT OF WHAT DRIVES LIVER 363 00:17:20,295 --> 00:17:22,163 CANCER IS NOT COMPLETELY CLEAR. 364 00:17:22,163 --> 00:17:24,232 AND THE GOOD NEWS IS SHOWN HERE 365 00:17:24,232 --> 00:17:26,735 ON THE LEFT THIS IS A STUDY THAT 366 00:17:26,735 --> 00:17:30,772 CAME OUT ABOUT A YEAR AGO WHICH 367 00:17:30,772 --> 00:17:35,176 SHOWS YOU THE DIFFERENCE IN THE 368 00:17:35,176 --> 00:17:41,049 PATTOCELLULAR CARCINOMA INCI 369 00:17:41,049 --> 00:17:43,251 INCIDENTS IN VIRAL CURE 370 00:17:43,251 --> 00:17:44,486 POPULATION AND YOU CAN SEE IT'S 371 00:17:44,486 --> 00:17:47,322 BETTER IF YOU'RE TREATED BUT IF 372 00:17:47,322 --> 00:17:49,024 YOU LOOK AT THAT THERE'S ALSO 373 00:17:49,024 --> 00:17:52,294 SOME BAD NEWS AND THAT IS IF 374 00:17:52,294 --> 00:17:54,629 YOU'RE CHRONICALLY INFECTED WITH 375 00:17:54,629 --> 00:17:56,264 HEPATITIS C AND B IS NOT GOOD 376 00:17:56,264 --> 00:18:00,669 BUT EVEN IF YOU'RE CURED OF 377 00:18:00,669 --> 00:18:02,971 HEPATITIS C OR HAVE SUPPRESSED 378 00:18:02,971 --> 00:18:05,040 HPV YOU'RE STILL IN THE HIGHER 379 00:18:05,040 --> 00:18:06,708 RISK GROUP OF DEVELOPING LIVER 380 00:18:06,708 --> 00:18:06,942 CANCER. 381 00:18:06,942 --> 00:18:13,048 THOUGH WE GET RID OF THE VIRUS 382 00:18:13,048 --> 00:18:15,050 PRESUMABLY IN THE CASE OF HCV 383 00:18:15,050 --> 00:18:19,454 THE FACTOR ARE GIVEN RISE TO AN 384 00:18:19,454 --> 00:18:20,889 ONCOGENIC EVENT HAVE ALREADY 385 00:18:20,889 --> 00:18:21,856 OCCURRED IN SOME PEOPLE. 386 00:18:21,856 --> 00:18:22,757 THOUGH THE VIRUS IS GONE THEY 387 00:18:22,757 --> 00:18:27,729 DEVELOP CANCER. 388 00:18:27,729 --> 00:18:30,999 SOW WE'VE BEEN TRYING FOR 389 00:18:30,999 --> 00:18:32,934 LONGER -- SO WE'VE BEEN TRYING 390 00:18:32,934 --> 00:18:37,772 FOR LONGER THAN I'D LIKE TO 391 00:18:37,772 --> 00:18:39,374 ADMIT FOR DEVELOPING THIS AND 392 00:18:39,374 --> 00:18:42,611 THIS OCCUPIED TIME AND EFFORT. 393 00:18:42,611 --> 00:18:44,012 SOME OF THAT JOE IS IN THE LAB 394 00:18:44,012 --> 00:18:49,784 SO HE PROBABLY REMEMBERS SOME OF 395 00:18:49,784 --> 00:18:57,626 THIS AND PEOPLE HAVE TRIED TO 396 00:18:57,626 --> 00:19:00,395 ADAPT IT TO MOUSE CELLS AND 397 00:19:00,395 --> 00:19:01,730 PEOPLE ARE STILL TRYING TO DO 398 00:19:01,730 --> 00:19:03,765 THAT AND CREATE AN INFECTION 399 00:19:03,765 --> 00:19:06,267 MODEL THAT MIMICS WHAT WE SEE IN 400 00:19:06,267 --> 00:19:14,442 PEOPLE. 401 00:19:14,442 --> 00:19:19,014 AND TRYING TO IDENTIFY FACTORS 402 00:19:19,014 --> 00:19:22,217 THAT WERE HUMAN SPECIFIC 403 00:19:22,217 --> 00:19:24,953 DIFFERENT IN MICE AND POSSIBLY 404 00:19:24,953 --> 00:19:29,858 WE COULD THEN ENGINEER ANIMALS. 405 00:19:29,858 --> 00:19:32,260 THAT DID WORK AND WE MANAGED TO 406 00:19:32,260 --> 00:19:34,229 MAKE TRANSGENIC MICE FOR ATP 407 00:19:34,229 --> 00:19:37,298 REPRODUCTION AND ENTRY BUT IT 408 00:19:37,298 --> 00:19:41,336 DIDN'T ESTABLISH A CHRONIC 409 00:19:41,336 --> 00:19:41,603 INFECTION. 410 00:19:41,603 --> 00:19:43,204 SO IT WAS VERY LOW-LEVEL 411 00:19:43,204 --> 00:19:44,873 REPLICATION. 412 00:19:44,873 --> 00:19:48,810 SO THE OTHER THING WHICH I THINK 413 00:19:48,810 --> 00:19:52,447 IS ALSO BEEN USEFUL IN THE 414 00:19:52,447 --> 00:19:53,782 HEPATITIS C WORLD WITH DUCK 415 00:19:53,782 --> 00:19:55,917 HEPATITIS IS LOOKING FOR A 416 00:19:55,917 --> 00:19:59,087 RELATIVE OF HEPATITIS C THAT 417 00:19:59,087 --> 00:20:02,223 NATURALLY INFECTED SMALL ANIMAL 418 00:20:02,223 --> 00:20:05,927 LIKE THE LABORATORY MOUSE SO WE 419 00:20:05,927 --> 00:20:07,696 GOT INVOLVED IN THIS AND SORT OF 420 00:20:07,696 --> 00:20:10,965 WITH THE ADVENT OF NEXT 421 00:20:10,965 --> 00:20:13,268 GENERATION SEQUENCING, PEOPLE 422 00:20:13,268 --> 00:20:15,637 WERE BEGINNING TO FIND HEPATITIS 423 00:20:15,637 --> 00:20:18,406 C RELATIVES ALL OVER THE PLACE 424 00:20:18,406 --> 00:20:23,478 IN NATURE. 425 00:20:23,478 --> 00:20:26,081 THIS UNFOLDED I WAS AT THE 426 00:20:26,081 --> 00:20:31,119 SCHOOL OF PUBLIC HEALTH AND IAN 427 00:20:31,119 --> 00:20:33,888 IS WHAT YOU WOULD CALL A VIRUS 428 00:20:33,888 --> 00:20:35,290 HUNTER AND THEY WOULD SEQUENCE 429 00:20:35,290 --> 00:20:37,092 ANIMAL SAMPLES AND LOOKING TO 430 00:20:37,092 --> 00:20:39,294 SEE IF THEY FOUND ANY 431 00:20:39,294 --> 00:20:40,895 INTERESTING INFECTIOUS AGENT. 432 00:20:40,895 --> 00:20:43,064 THE FIRST THEY FOUND WAS ONE 433 00:20:43,064 --> 00:20:46,134 THAT ACTUALLY INFECTED THE FIRST 434 00:20:46,134 --> 00:20:49,037 REPORT WAS DOGS BUT THAT TURNED 435 00:20:49,037 --> 00:20:49,504 OUT NOT TO BE RIGHT. 436 00:20:49,504 --> 00:20:55,877 IT ACTUALLY INFECTS HORSES. 437 00:20:55,877 --> 00:20:58,747 SOW AT LEAST ON THE ROCKEFELLER 438 00:20:58,747 --> 00:21:02,183 CAMPUS HORSES ARE NOT ALLOWED 439 00:21:02,183 --> 00:21:04,219 BUT NONETHELESS WE STARTED 440 00:21:04,219 --> 00:21:05,720 WORKING ON THIS IN COLLABORATION 441 00:21:05,720 --> 00:21:10,992 WITH A GROUP IN CORNELL IN 442 00:21:10,992 --> 00:21:12,660 ITHACA IT'S NOT THE SMALL ANIMAL 443 00:21:12,660 --> 00:21:14,629 MODEL WE WANTED. 444 00:21:14,629 --> 00:21:16,598 AND THE NEXT CALL FROM IAN CAME 445 00:21:16,598 --> 00:21:24,038 FROM AND HE'D IDENTIFIED A NEW 446 00:21:24,038 --> 00:21:32,313 VIRUS IN DEER MICE THE THOUGHT 447 00:21:32,313 --> 00:21:34,215 THIS IS GREAT. 448 00:21:34,215 --> 00:21:38,186 WE HAVE A VIRUS AND TRIED TO 449 00:21:38,186 --> 00:21:39,621 INFECT LABORATORY MICE AND THAT 450 00:21:39,621 --> 00:21:45,760 FAILED AND EVEN IF WE HAD 451 00:21:45,760 --> 00:21:47,428 SUCCEEDED EVEN USING THIS MODEL 452 00:21:47,428 --> 00:21:49,564 IN ITS NATURAL HOST IS NOT A 453 00:21:49,564 --> 00:21:57,138 GOOD IDEA BECAUSE THE DEER MICE 454 00:21:57,138 --> 00:22:03,678 ARE FAR DISTANT GENETICALLY AND 455 00:22:03,678 --> 00:22:05,713 WHAT WE HAVE FOR DOING 456 00:22:05,713 --> 00:22:06,548 LABORATORY STUDIES IN MICE WOULD 457 00:22:06,548 --> 00:22:10,151 HAVE TO BE REINVENTED FOR THAT 458 00:22:10,151 --> 00:22:11,553 MODEL. 459 00:22:11,553 --> 00:22:13,054 SO OTHERS HAVE FOUND VIRUSES IN 460 00:22:13,054 --> 00:22:15,390 BATS WHICH HAVE SORT OF A 461 00:22:15,390 --> 00:22:18,226 POPULAR RESERVOIR FOR MANY KINDS 462 00:22:18,226 --> 00:22:18,526 OF VIRUSES. 463 00:22:18,526 --> 00:22:25,233 . 464 00:22:25,233 --> 00:22:27,802 AGAIN, NOT BE AN EASY LABORATORY 465 00:22:27,802 --> 00:22:30,705 MODEL AND IN GIBBONS NOT A SMALL 466 00:22:30,705 --> 00:22:35,276 ANIMAL MODEL AND NON-HUMAN 467 00:22:35,276 --> 00:22:38,112 PRIMATE MODEL AND SO IT TURNED 468 00:22:38,112 --> 00:22:43,518 OUT IAN TEAMED UP WITH A COUPLE 469 00:22:43,518 --> 00:22:46,254 PEST CONTROL GROUPS IN THE NEW 470 00:22:46,254 --> 00:22:49,958 YORK CITY AREA AND TRAPPED A 471 00:22:49,958 --> 00:22:52,594 BUNCH OF RATS AND SLICED AND 472 00:22:52,594 --> 00:22:56,297 DICED AND SEQUENCED THESE GUYS 473 00:22:56,297 --> 00:23:02,203 AND FOUND TWO TYPES OF NORWAY 474 00:23:02,203 --> 00:23:08,509 RAT HEPATOVIRUS AND TELL YOU 475 00:23:08,509 --> 00:23:10,445 WHAT WE FOUND USING THE MODEL 476 00:23:10,445 --> 00:23:13,047 AND TRY TO BE SHORT SO I DON'T 477 00:23:13,047 --> 00:23:15,583 RUN OVER TOO MUCH TIME BUT IT IS 478 00:23:15,583 --> 00:23:17,685 KIND OF IRONIC THE POTENTIAL 479 00:23:17,685 --> 00:23:19,053 ANIMAL MODEL WE'VE BEEN 480 00:23:19,053 --> 00:23:23,224 SEARCHING FOR DECADES WAS 481 00:23:23,224 --> 00:23:25,860 ACTUALLY SCURRYING AROUND THE 482 00:23:25,860 --> 00:23:29,364 STREETS AND DINING ON NEW YORK 483 00:23:29,364 --> 00:23:30,198 CITY GARBAGE BEFORE IT GOT 484 00:23:30,198 --> 00:23:40,241 PICKED UP AND SO ON. 485 00:23:40,241 --> 00:23:46,214 WE GOT THESE VIRUSES FROM IAN 486 00:23:46,214 --> 00:23:56,691 AND WE HAVE A VARIANT THAT 487 00:24:03,731 --> 00:24:14,108 DIFFERS BY THREE OR FOUR. 488 00:24:16,110 --> 00:24:19,280 I'LL SHOW YOU SOME PROPERTIES. 489 00:24:19,280 --> 00:24:22,216 ONE OF THE THINGS THE VIRUS DOES 490 00:24:22,216 --> 00:24:24,052 IS REPLICATE AS YOU CAN SEE IN 491 00:24:24,052 --> 00:24:26,254 THE UPPER LEFT HAND PANEL TO 492 00:24:26,254 --> 00:24:28,022 HIGH LEVELS QUICKLY. 493 00:24:28,022 --> 00:24:33,861 IT'S CLEARED USUALLY IN TWO TO 494 00:24:33,861 --> 00:24:36,164 THREE WEEKS IN THE C57 BLACK 6 495 00:24:36,164 --> 00:24:38,066 MICE IS A POPULAR STRAIN OF 496 00:24:38,066 --> 00:24:38,900 LABORATORY MICE. 497 00:24:38,900 --> 00:24:41,903 THIS INCREASE IN VIREMIA LATER 498 00:24:41,903 --> 00:24:44,405 ON, NOT AT THE BEGINNING, IS 499 00:24:44,405 --> 00:24:54,916 ASSOCIATED WITH A RISE IN AL 500 00:24:58,286 --> 00:24:59,620 ALOMINO TRANSFERASE AND IN K 501 00:24:59,620 --> 00:25:01,456 CELLS THEY COME TO THE LIVER 502 00:25:01,456 --> 00:25:03,591 QUICKLY AFTER OF THE INFECTION 503 00:25:03,591 --> 00:25:05,193 AND ACCUMULATE THERE. 504 00:25:05,193 --> 00:25:06,995 BUT WE KNOW THEY'RE NOT 505 00:25:06,995 --> 00:25:08,062 IMPORTANT FOR VIRAL CLEARANCE 506 00:25:08,062 --> 00:25:09,097 BECAUSE IF YOU GET RID OF THEM 507 00:25:09,097 --> 00:25:11,599 THE VIRUS IS STILL CLEARED WITH 508 00:25:11,599 --> 00:25:14,969 APPROXIMATELY THE SAME KINETICS. 509 00:25:14,969 --> 00:25:15,303 . 510 00:25:15,303 --> 00:25:17,638 YOU LOOK AT CELLS INVOLVED IN 511 00:25:17,638 --> 00:25:26,447 THE CD4T CELLS YOU CAN SEE A 512 00:25:26,447 --> 00:25:28,883 PEAK THAT SHOW UP IN THE LIVER 513 00:25:28,883 --> 00:25:32,186 SORT OF AFTER SEVERAL DAYS AFTER 514 00:25:32,186 --> 00:25:32,453 INFECTION. 515 00:25:32,453 --> 00:25:36,224 AND A VA WENT ON TO SHOW CD4s 516 00:25:36,224 --> 00:25:37,792 WERE IMPORTANT BUT IT WAS 517 00:25:37,792 --> 00:25:40,762 PROBABLY CD8s ANTIGEN SPECIFIC 518 00:25:40,762 --> 00:25:43,998 THAT WERE IMPORTANT SORT OF IN 519 00:25:43,998 --> 00:25:44,499 CLEARANCE. 520 00:25:44,499 --> 00:25:46,901 SO THIS IS GREAT. 521 00:25:46,901 --> 00:25:49,303 AND IT'S A POTENTIAL MODEL FOR 522 00:25:49,303 --> 00:25:50,905 LOOKING AT THINGS YOU CAN LOOK 523 00:25:50,905 --> 00:25:54,208 AT WITH AN ACUTE INFECTION MODEL 524 00:25:54,208 --> 00:25:57,879 LIKE THIS. 525 00:25:57,879 --> 00:26:00,782 BUT IT'S NOT LIKE HEPATITIS C IN 526 00:26:00,782 --> 00:26:03,051 HUMANS WHERE 70% OF HUMANS 527 00:26:03,051 --> 00:26:04,986 BECOME CHRONICALLY INFECTED AND 528 00:26:04,986 --> 00:26:06,220 OFTEN DON'T KNOW THEY'RE 529 00:26:06,220 --> 00:26:07,522 INFECTED. 530 00:26:07,522 --> 00:26:13,861 IT TURNS OUT IF YOU DEPLETE CD8 531 00:26:13,861 --> 00:26:20,935 AS YOU CAN SEE HERE IN THE GRAY 532 00:26:20,935 --> 00:26:22,703 DOTS IT SLOWS CLEARANCE AND IF 533 00:26:22,703 --> 00:26:24,939 YOU DEPLETE CD4 CELLS BEFORE 534 00:26:24,939 --> 00:26:26,808 VIRUS INFECTION AND IN 535 00:26:26,808 --> 00:26:29,510 ADDITIONAL TREATMENTS AFTER 536 00:26:29,510 --> 00:26:31,045 VIRUS INFECTION THE ANIMALS 537 00:26:31,045 --> 00:26:34,182 BECOME CHRONICALLY INFECTED. 538 00:26:34,182 --> 00:26:39,153 SO THIS GIVES US BASICALLY A 539 00:26:39,153 --> 00:26:40,588 CHRONIC INFECTION CAPACITY VIRUS 540 00:26:40,588 --> 00:26:43,357 MODEL WHERE IT WORKS IN 541 00:26:43,357 --> 00:26:44,358 LABORATORY MICE. 542 00:26:44,358 --> 00:26:49,030 AND THE CD4s COME BACK AND ONCE 543 00:26:49,030 --> 00:26:50,865 THE ANTIBODY USED TO DEPLETE IT 544 00:26:50,865 --> 00:26:53,601 BUT IT DOESN'T INFLUENCE THE 545 00:26:53,601 --> 00:26:54,702 NATURE OF THIS CHRONIC 546 00:26:54,702 --> 00:26:54,969 INFECTION. 547 00:26:54,969 --> 00:26:58,206 MOST THE ANIMALS STILL REMAIN 548 00:26:58,206 --> 00:26:59,140 CHRONICALLY INFECTED. 549 00:26:59,140 --> 00:27:01,642 SO SOME OF THE THINGS WE'VE 550 00:27:01,642 --> 00:27:03,945 LEARNED FROM THIS ARE THAT WE 551 00:27:03,945 --> 00:27:06,714 BELIEVE THIS INFECTION IS 552 00:27:06,714 --> 00:27:10,251 EXCLUSIVELY FOR HEPATOCYTES IN 553 00:27:10,251 --> 00:27:16,691 THE LIVER AND BECAUSE A SMALL 554 00:27:16,691 --> 00:27:19,760 MICRO RNA FOUND IN HEPATOCYTES 555 00:27:19,760 --> 00:27:21,462 IS REQUIRED FOR THE REPLICATION 556 00:27:21,462 --> 00:27:23,164 OF THE VIRUS AS IT IS FOR 557 00:27:23,164 --> 00:27:24,565 HEPATITIS C. 558 00:27:24,565 --> 00:27:28,269 SO WE BELIEVE IT'S PROBABLY AN 559 00:27:28,269 --> 00:27:33,474 EXCLUSIVE HEPATOTROPIC INFECTION 560 00:27:33,474 --> 00:27:35,109 UNLIKE OTHER MODELS AND HE WAS 561 00:27:35,109 --> 00:27:38,846 ABLE TO SHOW YOU GENERATE A 562 00:27:38,846 --> 00:27:42,917 STRONG IMMUNE RESPONSE AND THERE 563 00:27:42,917 --> 00:27:46,154 IS IMMUNITY OF T CELL DEPENDENT 564 00:27:46,154 --> 00:27:48,890 CLEARANCE AND THESE ANIMALS ARE 565 00:27:48,890 --> 00:27:50,158 SUSCEPTIBLE TO REINFECTION 566 00:27:50,158 --> 00:27:52,160 THOUGH IT'S CLEARED MORE QUICKLY 567 00:27:52,160 --> 00:27:57,031 AND WITH THE INCREASE INFECTION 568 00:27:57,031 --> 00:28:00,468 AND I THINK THIS IS A REALLY 569 00:28:00,468 --> 00:28:06,841 INTERESTED MODEL TO STUDY BASIC 570 00:28:06,841 --> 00:28:09,410 ANTIVIRAL IMMUNOLOGY FROM HIRES 571 00:28:09,410 --> 00:28:10,778 HOST INTERACTIONS AND IT IS 572 00:28:10,778 --> 00:28:12,680 THOUGH THE DETAILS IN TERMS OF 573 00:28:12,680 --> 00:28:14,782 THE ACTUAL ANTIGENS ARE GOING TO 574 00:28:14,782 --> 00:28:16,317 BE DIFFERENT THAN HEPATITIS C IT 575 00:28:16,317 --> 00:28:24,091 CAN BE USED AS A PLATFORM TO TRY 576 00:28:24,091 --> 00:28:28,362 AND TEST DIFFERENT IMMUNIZATION 577 00:28:28,362 --> 00:28:28,663 STRATEGIES. 578 00:28:28,663 --> 00:28:30,264 THE QUESTION WAS IS THIS A MODEL 579 00:28:30,264 --> 00:28:33,668 FOR ATV RELATED LIVER DISEASE 580 00:28:33,668 --> 00:28:37,071 LONGER TERM WHICH IS WHAT WE'RE 581 00:28:37,071 --> 00:28:39,607 TRYING TO UNDERSTAND IN THE CASE 582 00:28:39,607 --> 00:28:41,375 OF CHRONIC HEPATITIS C 583 00:28:41,375 --> 00:28:41,642 INFECTION. 584 00:28:41,642 --> 00:28:44,645 THIS IS ONE OF THOSE THINGS THAT 585 00:28:44,645 --> 00:28:49,917 SORT OF POPS UP BY CHANCE IN 586 00:28:49,917 --> 00:28:53,287 SCIENCE AND WE HAD A COUPLE OF 587 00:28:53,287 --> 00:28:55,089 THESE ANIMALS THESE MICE 588 00:28:55,089 --> 00:28:57,858 CHRONICALLY INFECTIONS WITH NRHV 589 00:28:57,858 --> 00:29:03,731 THAT SOMEHOW IT ESCAPED 590 00:29:03,731 --> 00:29:13,975 SACRIFICE IN THE ANIMAL FACILITY 591 00:29:13,975 --> 00:29:18,913 AND SOMEHOW THESE TWO MICE WERE 592 00:29:18,913 --> 00:29:21,115 APPROACHES TWO YEARS OLD HAD 593 00:29:21,115 --> 00:29:25,519 MANAGED TO HIDE OUT -- THIS WAS 594 00:29:25,519 --> 00:29:28,122 LIKE RETIREMENT COMMUNITY FOR 595 00:29:28,122 --> 00:29:28,723 LABORATORY MICE. 596 00:29:28,723 --> 00:29:30,157 ANYWAY, WHEN THEY WERE 597 00:29:30,157 --> 00:29:31,359 SACRIFICED WE FIND THAT THERE 598 00:29:31,359 --> 00:29:33,995 WAS PRETTY STRIKING PATHOLOGY IN 599 00:29:33,995 --> 00:29:37,164 THE LIVER ALMOST KIND OF IN A 600 00:29:37,164 --> 00:29:40,368 CIRRHOTIC AND YOU DON'T REALLY 601 00:29:40,368 --> 00:29:42,503 KNOW IF THIS IS JUST A PHENOTYPE 602 00:29:42,503 --> 00:29:44,038 OF OLD MICE. 603 00:29:44,038 --> 00:29:46,140 IT'S NOT LIKE WE HAD UNINFECTED 604 00:29:46,140 --> 00:29:46,407 CONTROLS. 605 00:29:46,407 --> 00:29:49,143 WE ONLY HAD A FEW ANIMALS. 606 00:29:49,143 --> 00:29:51,746 BUT IT GOT US INTEREST IN MAYBE 607 00:29:51,746 --> 00:29:54,215 TRYING SOME LONGER TERM 608 00:29:54,215 --> 00:29:54,849 INFECTION MODELS AND SEEING WHAT 609 00:29:54,849 --> 00:29:59,754 HAPPENS. 610 00:29:59,754 --> 00:30:01,756 DO THEY DEVELOP ADVANCED 611 00:30:01,756 --> 00:30:02,623 PATHOLOGY AND THAT'S WHAT I'M 612 00:30:02,623 --> 00:30:04,158 GOING TO FOCUS ON FOR THE REST 613 00:30:04,158 --> 00:30:04,792 OF THE TALK. 614 00:30:04,792 --> 00:30:08,696 THIS IS WORK THAT WAS REALLY 615 00:30:08,696 --> 00:30:19,240 CARRIED OUT BY MARIANNA BATISTA 616 00:30:20,741 --> 00:30:22,943 AND SCOTT CHENG AT KETTERING AND 617 00:30:22,943 --> 00:30:25,946 A GRADUATE STUDENT AND WE HAVE 618 00:30:25,946 --> 00:30:27,515 KIND OF AN INTERNATIONAL 619 00:30:27,515 --> 00:30:30,217 COLLABORATION WITH VARIOUS LABS 620 00:30:30,217 --> 00:30:34,322 TO WORK IN THIS SPACE BUT BRAD 621 00:30:34,322 --> 00:30:37,091 ROSENBERG AND OTHERS ON THE 622 00:30:37,091 --> 00:30:38,693 IMMUNOLOGY SIDE AND TIM SHEEHAN 623 00:30:38,693 --> 00:30:44,198 ON THE MOUSE GENETICS SIDE AND 624 00:30:44,198 --> 00:30:47,501 SCOTT LOWE ON THE CANCER SIDE. 625 00:30:47,501 --> 00:30:53,040 WE SET UP THIS RATHER LARGE 626 00:30:53,040 --> 00:30:59,647 PILOT EXPERIENCE WITH 95C57 627 00:30:59,647 --> 00:31:02,016 BLACK 6 MICE AND A MIXTURE OF 628 00:31:02,016 --> 00:31:05,019 MALES AND FEMALES SO IF YOU LOOK 629 00:31:05,019 --> 00:31:08,222 AT THIS SCHEME HERE CD4s WERE 630 00:31:08,222 --> 00:31:10,524 DEPLETED AT DAY MINUS 3 AND THEN 631 00:31:10,524 --> 00:31:13,027 ON DAY ZERO THEY WERE EITHER 632 00:31:13,027 --> 00:31:17,898 SORT OF SHAM INOCULATED WITH PBS 633 00:31:17,898 --> 00:31:20,735 OR WITH VIRUS AND THIS IS A VERY 634 00:31:20,735 --> 00:31:21,836 HOT VIRUS. 635 00:31:21,836 --> 00:31:24,538 IT'S 10 TO THE FOURTH GENOME 636 00:31:24,538 --> 00:31:26,907 EQUIVALENCE AND THERE WAS 637 00:31:26,907 --> 00:31:29,677 ANOTHER CD4 DEPLETION IN 10 638 00:31:29,677 --> 00:31:31,979 WEEKS AND WE'RE GOING TO TAKE 639 00:31:31,979 --> 00:31:33,514 MONTHLY BLEEDS AND LOOK AT 640 00:31:33,514 --> 00:31:35,549 THINGS IN THE PERIPHERY BUT HAVE 641 00:31:35,549 --> 00:31:36,984 TERMINAL TIME POINTS AND COLLECT 642 00:31:36,984 --> 00:31:39,720 SAMPLES TO DO ALL KINDS OF 643 00:31:39,720 --> 00:31:45,292 THINGS AT 6, 12 AND 18 MONTHS. 644 00:31:45,292 --> 00:31:47,361 THAT WAS ALL WELL AND GOOD AND 645 00:31:47,361 --> 00:31:48,362 INITIATED. 646 00:31:48,362 --> 00:31:54,468 AT THE SIX-MONTH HARVEST TIME 647 00:31:54,468 --> 00:31:55,669 COVID-19 SHOWED UP.SO A LOT OF 648 00:31:55,669 --> 00:31:59,340 THE FACILITIES WE WERE PLANNING 649 00:31:59,340 --> 00:32:00,775 ON USING TO AND EVEN GETTING IN 650 00:32:00,775 --> 00:32:05,579 THE ANIMAL FACILITY FOR THINGS 651 00:32:05,579 --> 00:32:07,081 THAT WERE NOT CORONAVIRUS 652 00:32:07,081 --> 00:32:07,681 FOCUSSED WAS VERY CHALLENGING. 653 00:32:07,681 --> 00:32:14,755 . 654 00:32:14,755 --> 00:32:17,191 AND MANY OF THESE SAMPLES ARE 655 00:32:17,191 --> 00:32:21,629 STILL SORT OF UNDER ANALYSIS. 656 00:32:21,629 --> 00:32:23,130 I WILL SHOW YOU A LITTLE BIT 657 00:32:23,130 --> 00:32:23,597 ABOUT WHAT HAPPENED. 658 00:32:23,597 --> 00:32:27,134 IF YOU LOOK AT THIS SLIDE IN THE 659 00:32:27,134 --> 00:32:30,805 UPPER LEFT THIS SHOWS VIREMIA 660 00:32:30,805 --> 00:32:33,841 OVER TIME AND SEE THIS HIGH 661 00:32:33,841 --> 00:32:36,710 LEVEL OF VIREMIA AND SORT OF 662 00:32:36,710 --> 00:32:38,212 THIS PERSISTS FOR A WHILE AND 663 00:32:38,212 --> 00:32:41,449 THEN BASICALLY IT LEVELS OUT AND 664 00:32:41,449 --> 00:32:42,817 PLATEAUS BY ABOUT SIX MONTHS. 665 00:32:42,817 --> 00:32:44,618 THERE DOESN'T REALLY SEEM TO BE 666 00:32:44,618 --> 00:32:47,555 ANY DIFFERENCE BETWEEN THE MALE 667 00:32:47,555 --> 00:32:51,725 OR THE FEMALE MICE. 668 00:32:51,725 --> 00:32:52,526 AND THE OTHER THING THAT'S 669 00:32:52,526 --> 00:32:54,195 INTERESTING IS THAT WE DO SEE 670 00:32:54,195 --> 00:32:55,429 LATE CLEARANCE IN SOME OF THESE 671 00:32:55,429 --> 00:32:58,199 ANIMALS AND AT LEAST IN THIS 672 00:32:58,199 --> 00:33:00,067 PILOT EXPERIMENT THE NUMBERS ARE 673 00:33:00,067 --> 00:33:00,267 SMALL. 674 00:33:00,267 --> 00:33:03,070 THE FEMALE MICE SEEM TO DO A 675 00:33:03,070 --> 00:33:04,905 LITTLE BIT BETTER IN TERMS OF 676 00:33:04,905 --> 00:33:07,441 CLEARING THE VIRUS BUT ACTUALLY 677 00:33:07,441 --> 00:33:10,277 NEITHER SEX IS ALL THAT GOOD AT 678 00:33:10,277 --> 00:33:14,615 CLEARING THE VIRUS. 679 00:33:14,615 --> 00:33:16,383 THAT SHOWS YOU A LITTLE BIT AND 680 00:33:16,383 --> 00:33:18,052 SUGGESTS THERE MIGHT BE SOME 681 00:33:18,052 --> 00:33:19,386 SORT OF SEX-DEPENDENT 682 00:33:19,386 --> 00:33:22,223 DIFFERENCES WHICH IS SOMETHING 683 00:33:22,223 --> 00:33:25,025 WE SEE IN HEPATITIS C 684 00:33:25,025 --> 00:33:25,960 PATHOGENESIS AS WELL. 685 00:33:25,960 --> 00:33:26,594 THAT'S SOMETHING WE'RE KEEPING 686 00:33:26,594 --> 00:33:30,331 OUR EYE ON. 687 00:33:30,331 --> 00:33:32,833 SO WE FROM THESE TERMINAL TIME 688 00:33:32,833 --> 00:33:37,771 POINTS WE COLLECTED LIVER 689 00:33:37,771 --> 00:33:39,840 SAMPLES AND ASKED A LIVER 690 00:33:39,840 --> 00:33:43,177 PATHOLOGIST AT NYU WE WORKED 691 00:33:43,177 --> 00:33:46,280 WITH FOR MANY YEARS TO TAKE A 692 00:33:46,280 --> 00:33:50,084 LOOK AT THESE LIVERS AND WHAT HE 693 00:33:50,084 --> 00:33:52,620 SAW IS SHOWN AND THIS IS A GRAPH 694 00:33:52,620 --> 00:33:55,523 THAT HAS BASICALLY INFLAMMATION 695 00:33:55,523 --> 00:33:57,858 ON THE Y AXIS AND FIBROSIS ON 696 00:33:57,858 --> 00:34:01,428 THE X AXIS AND YOU CAN SEE AT 697 00:34:01,428 --> 00:34:04,632 SEVEN MONTHS POST INFECTION 698 00:34:04,632 --> 00:34:07,034 THESE INFECTED ANIMALS, MALES 699 00:34:07,034 --> 00:34:08,903 AND FEMALES WERE SHOWING 700 00:34:08,903 --> 00:34:10,371 EVIDENCE OF LIVER DAMAGE. 701 00:34:10,371 --> 00:34:14,041 THAT SORT OF GETS WORSE AT 12 702 00:34:14,041 --> 00:34:15,709 MONTHS POSTINFECTION AND THEN AT 703 00:34:15,709 --> 00:34:18,245 18 MONTHS THE TREND IS STILL 704 00:34:18,245 --> 00:34:20,814 THERE BUT AGAIN THERE'S MORE 705 00:34:20,814 --> 00:34:22,182 HETEROGENEITY IN THE OLDER MICE 706 00:34:22,182 --> 00:34:23,284 IN TERMS OF THE LIVER PATHOLOGY 707 00:34:23,284 --> 00:34:28,722 THAT THEY SHOW. 708 00:34:28,722 --> 00:34:30,190 EVEN IN THE ONES IN THE INFECTED 709 00:34:30,190 --> 00:34:31,926 AND IF YOU LOOK AT THE LEFT AT 710 00:34:31,926 --> 00:34:33,694 THE HISTOLOGY YOU SEE 711 00:34:33,694 --> 00:34:37,097 DIFFERENCES IN TWO THINGS THAT 712 00:34:37,097 --> 00:34:41,235 WE SEE IN HUMAN HEPATITIS C 713 00:34:41,235 --> 00:34:45,339 FIBROSIS IN THE LOWER LEFT PANEL 714 00:34:45,339 --> 00:34:52,646 AND INFLAMMATION AND SIMILARITY 715 00:34:52,646 --> 00:34:56,650 TO HCV AND STARTING AT 12 MONTHS 716 00:34:56,650 --> 00:35:02,189 AND BECOMING EVIDENT BY 18 717 00:35:02,189 --> 00:35:06,961 MONTHS IF YOU LOOK AT THE MOCK 718 00:35:06,961 --> 00:35:09,029 LIVERS THEY LOOK LIKE NICE 719 00:35:09,029 --> 00:35:11,699 HEALTHY LIVERS BUT IF YOU LOOK 720 00:35:11,699 --> 00:35:16,270 AT THE ONES BY THE VIRUS FOR 18 721 00:35:16,270 --> 00:35:17,972 MONTHS, BASICALLY WE SAW THE 722 00:35:17,972 --> 00:35:23,477 LIVER TUMORS THAT WERE POPPING 723 00:35:23,477 --> 00:35:26,213 UP AND THIS WAS INTERESTING IN 724 00:35:26,213 --> 00:35:28,315 THE SENSE THAT IN MALES THE 725 00:35:28,315 --> 00:35:30,317 FREQUENCY WAS SURVIVORS OF 18 726 00:35:30,317 --> 00:35:33,354 MONTHS WITH BASICALLY 100% SO 727 00:35:33,354 --> 00:35:37,391 THIS IS REALLY A REMARKABLE 728 00:35:37,391 --> 00:35:40,661 NATURAL INFECTION MODEL THAT 729 00:35:40,661 --> 00:35:42,529 LEADS TO HIGH INCIDENTS OF LIVER 730 00:35:42,529 --> 00:35:43,597 CANCER. 731 00:35:43,597 --> 00:35:46,100 THERE'S BEEN SUGGESTIONS BY 732 00:35:46,100 --> 00:35:48,836 GRANT REVIEWERS THAT WELL, THIS 733 00:35:48,836 --> 00:35:50,704 ISN'T WHAT HAPPENS IN HEPATITIS 734 00:35:50,704 --> 00:35:51,105 C. 735 00:35:51,105 --> 00:35:54,208 NOT EVERYONE GETS CHRONICALLY 736 00:35:54,208 --> 00:35:56,844 INFECTED GETS INFECTED WITH 737 00:35:56,844 --> 00:35:59,647 LIVER CANCER BUT IN THIS 738 00:35:59,647 --> 00:36:01,115 UNIFORMITY WE SEE IS AN ASSET 739 00:36:01,115 --> 00:36:03,317 NOT A LIABILITY. 740 00:36:03,317 --> 00:36:08,722 IN THIS PILOT WE SAW A LOWER 741 00:36:08,722 --> 00:36:10,624 INCIDENTS OF TUMOR FORMATION IN 742 00:36:10,624 --> 00:36:12,259 FEMALE MICE. 743 00:36:12,259 --> 00:36:14,995 IF YOU LOOK AT TUMOR VOLUME 744 00:36:14,995 --> 00:36:17,665 AGAIN THERE SEEMED TO BE A TREND 745 00:36:17,665 --> 00:36:19,767 THOUGH I THINK IT'S NOT HOLDING 746 00:36:19,767 --> 00:36:20,768 UP IN A SECOND EXPERIMENT WE'VE 747 00:36:20,768 --> 00:36:24,138 DONE TO FOLLOW THIS UP IN TUMOR 748 00:36:24,138 --> 00:36:25,406 VOLUME BETWEEN THE FEMALE MICE 749 00:36:25,406 --> 00:36:35,716 AND THE MALE MICE. 750 00:36:45,125 --> 00:36:52,199 IF YOU LOOK AT THE HISTOLOGY AND 751 00:36:52,199 --> 00:36:53,967 THE INFLAMMATION WHICH IS 752 00:36:53,967 --> 00:36:56,403 VARIABLE FROM MOUSE TO MOUSE AND 753 00:36:56,403 --> 00:36:59,873 THE PRESENCE OF THESE LYMPHOID 754 00:36:59,873 --> 00:37:03,577 AGGREGATES WHICH IS COMMONLY 755 00:37:03,577 --> 00:37:07,347 FOUND IN HUMAN HCV BUT WE DON'T 756 00:37:07,347 --> 00:37:17,758 KNOW WHAT THEY'RE UP TO. 757 00:37:20,294 --> 00:37:23,597 THERE'S A CONVERGENCE INFECTED 758 00:37:23,597 --> 00:37:25,265 VERSUS NORMAL AND THERE'S A HIGH 759 00:37:25,265 --> 00:37:27,201 CONVERGENCE OF THINGS SHOWN IN 760 00:37:27,201 --> 00:37:30,738 RED OR DOWN IN BLUE. 761 00:37:30,738 --> 00:37:34,208 AND WE BEGAN TO LOOK AT THE 762 00:37:34,208 --> 00:37:42,216 GENETICS OF THESE TUMORS AND 763 00:37:42,216 --> 00:37:46,987 AGAIN WE FIND THEIR QUITE 764 00:37:46,987 --> 00:37:48,188 HETEROGENOUS AND LOCI ASSOCIATED 765 00:37:48,188 --> 00:37:50,190 WITH CANCERS AND YOU CAN SEE IF 766 00:37:50,190 --> 00:37:51,558 YOUR SAMPLE SHOWS ANY OF THESE 767 00:37:51,558 --> 00:37:53,393 AND FIND A SIGNATURE IN SOME OF 768 00:37:53,393 --> 00:37:54,695 THESE TUMORS. 769 00:37:54,695 --> 00:37:58,565 THIS IS SEVEN TUMORS LOOKED AT 770 00:37:58,565 --> 00:38:01,468 IN SOME DETAIL AND THREE APPEAR 771 00:38:01,468 --> 00:38:05,072 TO HAVE SUSPICIOUS K RAS 772 00:38:05,072 --> 00:38:06,006 MUTATIONS THAT COULD BE DRIVING 773 00:38:06,006 --> 00:38:09,042 THIS AND IF YOU LOOK AT THE 774 00:38:09,042 --> 00:38:11,712 TRANSCRIPTOME AND KRAS TUMORS 775 00:38:11,712 --> 00:38:14,515 WITH PROTEIN AND OTHER THINGS 776 00:38:14,515 --> 00:38:20,420 SEEN AS TRANSCRIPTIONAL CHANGES 777 00:38:20,420 --> 00:38:21,588 IN ATV. 778 00:38:21,588 --> 00:38:23,757 I'M GOING A LITTLE TOO LONG BUT 779 00:38:23,757 --> 00:38:25,592 I THINK IT'S INTERESTING THAT 780 00:38:25,592 --> 00:38:28,395 THIS MODEL SORT OF DOES LEAD TO 781 00:38:28,395 --> 00:38:30,197 HEPATITIS FIBROSIS IN CANCER. 782 00:38:30,197 --> 00:38:31,832 THERE ARE POSSIBLE DIFFERENCES 783 00:38:31,832 --> 00:38:33,834 BETWEEN MALES AND FEMALES WHICH 784 00:38:33,834 --> 00:38:36,637 WE'RE GOING TO LOOK AT MORE 785 00:38:36,637 --> 00:38:37,104 CAREFULLY. 786 00:38:37,104 --> 00:38:38,872 THEY'RE HETEROGENOUS. 787 00:38:38,872 --> 00:38:42,209 THERE ARE SOME COMMON HUMAN ATC 788 00:38:42,209 --> 00:38:44,978 MARKERS UPREGULATED AND MANY K 789 00:38:44,978 --> 00:38:47,247 RAS IS ACTUALLY AN INFREQUENT 790 00:38:47,247 --> 00:38:50,117 DRIVER OF ATV ASSOCIATED LIVER 791 00:38:50,117 --> 00:38:51,418 CANCER BUT STILL EARLY DAYS I 792 00:38:51,418 --> 00:38:54,221 DON'T KNOW WHAT OTHER THINGS 793 00:38:54,221 --> 00:38:55,656 WE'RE GOING TO FIND. 794 00:38:55,656 --> 00:39:00,494 AND SO I THINK WE FINALLY HAVE A 795 00:39:00,494 --> 00:39:03,197 PHYSIOLOGICALLY RELEVANT MOUSE 796 00:39:03,197 --> 00:39:04,464 MODEL TO DISCOVER NEW INSTANCES 797 00:39:04,464 --> 00:39:06,900 AND I WANT TO HAVE A FOOT NOTE 798 00:39:06,900 --> 00:39:07,835 HERE I DON'T KNOW HOW MANY OF 799 00:39:07,835 --> 00:39:10,904 YOU ARE FAMILIAR WITH THE 800 00:39:10,904 --> 00:39:15,442 COLLABORATIVE CROSS GENETIC 801 00:39:15,442 --> 00:39:17,377 MOUSE RESOURCE. 802 00:39:17,377 --> 00:39:19,279 AND WE'VE BEEN EXAMINING THIS TO 803 00:39:19,279 --> 00:39:21,215 SEE IF WE SEE ANY DIFFERENCE IN 804 00:39:21,215 --> 00:39:25,319 THE BEHAVIOR IN THE DIFFERENT 805 00:39:25,319 --> 00:39:27,754 COLLABORATIVE CROSSES AND THIS 806 00:39:27,754 --> 00:39:29,489 IS WORK TIM SHEEHAN HAS BEEN 807 00:39:29,489 --> 00:39:31,158 DOING AT THE UNIVERSITY OF 808 00:39:31,158 --> 00:39:34,494 CALIFORNIA OR UNIVERSITY OF 809 00:39:34,494 --> 00:39:37,998 NORTH CAROLINA. 810 00:39:37,998 --> 00:39:39,833 THE COLLABORATIVE CROSS INCLUDES 811 00:39:39,833 --> 00:39:42,636 A COLLECTION OF PARENTAL MOUSE 812 00:39:42,636 --> 00:39:46,173 STRAINS GENETICALLY VERY DIVERSE 813 00:39:46,173 --> 00:39:48,175 AND GENETICALLY INBRED BUT 814 00:39:48,175 --> 00:39:49,843 DISTINCT FROM EACH OTHER YOU CAN 815 00:39:49,843 --> 00:39:51,511 TAKE A LOOK AT THE STRAINS WITH 816 00:39:51,511 --> 00:39:54,781 WHATEVER YOU'RE INTERESTED IN 817 00:39:54,781 --> 00:39:58,185 LOOKING AT AND BASICALLY SEE IF 818 00:39:58,185 --> 00:40:00,020 YOU SEE AN INTERESTING 819 00:40:00,020 --> 00:40:07,027 PHENOTYPIC DIFFERENCE WITH YOUR 820 00:40:07,027 --> 00:40:10,197 PERTURBATION. 821 00:40:10,197 --> 00:40:12,532 SO AND WHAT TIM HAS DISCOVERED 822 00:40:12,532 --> 00:40:16,336 IS THAT IF YOU AND THIS SHOWS 823 00:40:16,336 --> 00:40:19,072 BASICALLY HOW THE VIRUS BEHAVES 824 00:40:19,072 --> 00:40:23,076 IN THE BLACK 6 MICE AND 71 AND 825 00:40:23,076 --> 00:40:28,215 80 AND POINT OUT CCO71 BECAUSE 826 00:40:28,215 --> 00:40:31,118 THIS MOUSE STRAIN ACTUALLY 827 00:40:31,118 --> 00:40:33,587 ALLOWS INFECTION AND CHRONIC 828 00:40:33,587 --> 00:40:35,322 INFECTION WITHOUT CD84 829 00:40:35,322 --> 00:40:35,756 DEPLETION. 830 00:40:35,756 --> 00:40:40,294 THIS IS A NATURAL MOUSE GENETIC 831 00:40:40,294 --> 00:40:42,963 BACKGROUND THAT ALLOWS THIS 832 00:40:42,963 --> 00:40:44,431 VIRUS TO ESTABLISH A FOOTHOLD. 833 00:40:44,431 --> 00:40:46,199 SO WE'RE ACTUALLY VERY EXCITED 834 00:40:46,199 --> 00:40:47,701 ABOUT THAT. 835 00:40:47,701 --> 00:40:54,975 WE DO SEE IN THE CC071 MODEL 836 00:40:54,975 --> 00:40:56,143 FIBROSIS OVER TIME. 837 00:40:56,143 --> 00:40:57,377 IT'S AN INTERESTING MODEL. 838 00:40:57,377 --> 00:40:59,046 WE'RE WAITING ON THE ANIMALS TO 839 00:40:59,046 --> 00:41:00,614 SEE IF THEY DEVELOP CANCER AFTER 840 00:41:00,614 --> 00:41:04,351 LONGER INFECTIONS BUT THERE'S 841 00:41:04,351 --> 00:41:05,352 SOME ENCOURAGING INDICATIONS IN 842 00:41:05,352 --> 00:41:06,687 THAT DIRECTION. 843 00:41:06,687 --> 00:41:08,522 SO WE'RE REALLY EXCITED ABOUT 844 00:41:08,522 --> 00:41:11,491 THIS MODEL. 845 00:41:11,491 --> 00:41:16,596 IT'S BEEN A CHANCE DIVERSION IN 846 00:41:16,596 --> 00:41:18,966 THE AGING MICE BUT I THINK IT 847 00:41:18,966 --> 00:41:20,600 DOES PROVIDE A PLATFORM TO 848 00:41:20,600 --> 00:41:26,206 REALLY BEGIN TO UNDERSTAND HOW 849 00:41:26,206 --> 00:41:27,507 CHRONIC INFECTION CAN LEAD TO 850 00:41:27,507 --> 00:41:28,942 CANCER AND WE'LL BEGIN LOOKING 851 00:41:28,942 --> 00:41:31,111 AT SEX AND COMORBIDITIES LIKE 852 00:41:31,111 --> 00:41:31,712 ALCOHOL AND DIET. 853 00:41:31,712 --> 00:41:33,847 THE ROLE OF FIBROSIS. 854 00:41:33,847 --> 00:41:36,149 ONE OF THE NICE THINGS THAT 855 00:41:36,149 --> 00:41:38,919 SCOTT LOWE'S LAB IS DEVELOPED IS 856 00:41:38,919 --> 00:41:43,223 A CAR T APPROACH FOR SENESCENT 857 00:41:43,223 --> 00:41:44,958 CELLS THAT CAN REVERSE THE 858 00:41:44,958 --> 00:41:46,660 ABILITY OF THE INSULTS TO 859 00:41:46,660 --> 00:41:47,527 GENERATE FIBROSIS. 860 00:41:47,527 --> 00:41:51,298 THE QUESTION IS IF WE TRY THAT 861 00:41:51,298 --> 00:41:56,103 INTERVENTION IS IT GOING TO 862 00:41:56,103 --> 00:41:59,439 PREVENT THE ANIMALS FROM CANCER. 863 00:41:59,439 --> 00:42:02,476 THE IMPACT OF CURE AND I ALLUDED 864 00:42:02,476 --> 00:42:04,745 TO THAT PEOPLE WITH MORE 865 00:42:04,745 --> 00:42:05,612 ADVANCED LIVER DISEASE EVEN WHEN 866 00:42:05,612 --> 00:42:07,547 THE VIRUS IS GONE ARE STILL AT 867 00:42:07,547 --> 00:42:08,782 RISK OF DEVELOPING CANCER. 868 00:42:08,782 --> 00:42:10,784 SO WE CAN ACTUALLY USE THIS 869 00:42:10,784 --> 00:42:12,986 MODEL TO FIND OUT WHAT'S THE 870 00:42:12,986 --> 00:42:14,354 TIMING OF THAT. 871 00:42:14,354 --> 00:42:15,789 IF YOU GET OF THE INFECTION AND 872 00:42:15,789 --> 00:42:19,026 WE BELIEVE WE CAN DO THAT QUITE 873 00:42:19,026 --> 00:42:20,260 EFFECTIVELY HOW LONG DO THEY 874 00:42:20,260 --> 00:42:21,895 HAVE TO BE CHRONICALLY INFECTED 875 00:42:21,895 --> 00:42:22,996 WHERE IT DOESN'T MAKE A 876 00:42:22,996 --> 00:42:25,365 DIFFERENCE IF YOU GET RID OF THE 877 00:42:25,365 --> 00:42:25,565 VIRUS. 878 00:42:25,565 --> 00:42:28,035 VERY INTERESTED IN USING THIS AS 879 00:42:28,035 --> 00:42:31,338 A MODEL FOR LOOKING AT NOT ONLY 880 00:42:31,338 --> 00:42:32,739 IMMUNE FUNCTION AND DYSFUNCTION 881 00:42:32,739 --> 00:42:35,575 AND ALSO TESTING 882 00:42:35,575 --> 00:42:36,410 IMMUNOTHERAPIES. 883 00:42:36,410 --> 00:42:38,245 AND AS I'VE MENTIONED THE ROLE 884 00:42:38,245 --> 00:42:42,382 OF HOST GENETICS AND INFECTION 885 00:42:42,382 --> 00:42:43,350 AND OUTCOME. 886 00:42:43,350 --> 00:42:45,085 WITH THAT I ACKNOWLEDGE THE 887 00:42:45,085 --> 00:42:46,620 PEOPLE INVOLVED IN THIS. 888 00:42:46,620 --> 00:42:51,458 I'VE POINTED OUT THE PEOPLE THAT 889 00:42:51,458 --> 00:42:52,692 HAVE REALLY BEEN INVOLVED IN THE 890 00:42:52,692 --> 00:42:54,127 PILOT EXPERIMENTS. 891 00:42:54,127 --> 00:42:57,431 THE OTHER REPRESENT GROUPS THAT 892 00:42:57,431 --> 00:43:01,034 WERE COLLABORATING WITH AROUND 893 00:43:01,034 --> 00:43:06,339 THE WORLD AND THERE'S A PICTURE 894 00:43:06,339 --> 00:43:08,975 OF OUR LAB THAT MEETS EVERY 895 00:43:08,975 --> 00:43:09,876 WEDNESDAY WHICH INCLUDES LABS 896 00:43:09,876 --> 00:43:15,582 FROM OTHER FOLKS IN THE NEW YORK 897 00:43:15,582 --> 00:43:15,782 AREA. 898 00:43:15,782 --> 00:43:22,255 YOU CAN SEE THE THREE THAT HANG 899 00:43:22,255 --> 00:43:23,890 OUT IN THE OFFICE AND PROVIDE 900 00:43:23,890 --> 00:43:24,324 SOME ENTERTAINMENT. 901 00:43:24,324 --> 00:43:27,227 I WON'T HAVE TIME TO TALK ABOUT 902 00:43:27,227 --> 00:43:28,929 IT TODAY BUT MAYBE I'LL ZIP 903 00:43:28,929 --> 00:43:30,997 THROUGH THESE BECAUSE I THINK 904 00:43:30,997 --> 00:43:32,566 THEY'RE TOPICS THAT PLAY BE FUND 905 00:43:32,566 --> 00:43:34,201 TO DISCUSS IN THE AFTERNOON. 906 00:43:34,201 --> 00:43:36,703 WE'RE DOING A LOT OF WORK IN 907 00:43:36,703 --> 00:43:39,005 HEPATITIS B AS MANY FOLKS 908 00:43:39,005 --> 00:43:41,041 SHIFTED THEIR ATTENTION FROM HCV 909 00:43:41,041 --> 00:43:51,718 CURE TO A FUNCTIONAL CURE FOR 910 00:43:53,186 --> 00:43:54,821 HBV AND THE VACCINE STRAIN THAT 911 00:43:54,821 --> 00:43:59,192 HAS ONE SHOT LIFE LONG 912 00:43:59,192 --> 00:43:59,860 PROTECTION BUT THERE ARE 913 00:43:59,860 --> 00:44:02,662 UNFORTUNATE VACCINEES OF YELLOW 914 00:44:02,662 --> 00:44:04,698 FEVER THAT DEVELOP THIS ATROPIC 915 00:44:04,698 --> 00:44:04,931 DISEASE. 916 00:44:04,931 --> 00:44:06,266 IT TURNS OUT AGAIN I WON'T SHOW 917 00:44:06,266 --> 00:44:08,835 YOU THE DATA THE DIFFERENCE 918 00:44:08,835 --> 00:44:12,839 BETWEEN THE VACCINE STRAIN AND 919 00:44:12,839 --> 00:44:15,742 THE VIRULENT STRAIN HAS A LOT OF 920 00:44:15,742 --> 00:44:16,543 DO WITH INTERFERON. 921 00:44:16,543 --> 00:44:18,011 IF AN INDIVIDUAL WHO GETS THE 922 00:44:18,011 --> 00:44:21,648 VACCINE IS DEFECTIVE IN TYPE 1 923 00:44:21,648 --> 00:44:26,753 INTERFERON SIGNALLING THEY'RE AT 924 00:44:26,753 --> 00:44:29,523 RISK AT DEVELOPING THE DISEASE 925 00:44:29,523 --> 00:44:32,759 AND IT CAN GO WILD AND CAUSE 926 00:44:32,759 --> 00:44:33,293 PROBLEMS. 927 00:44:33,293 --> 00:44:35,996 VIRUS-HOST INTERACTION. 928 00:44:35,996 --> 00:44:38,698 WE GOT INTERESTED IN INTERFERON 929 00:44:38,698 --> 00:44:41,334 BEING USED TO TREAT HEPATITIS C 930 00:44:41,334 --> 00:44:42,602 AND INFORMATION HOW IT MAY BLOCK 931 00:44:42,602 --> 00:44:45,572 IT IT MAY PROVIDE INCLUDE HOW TO 932 00:44:45,572 --> 00:44:49,142 MOVE FORWARD TO IN MOVE 933 00:44:49,142 --> 00:44:51,111 TREATMENT OVER SYSTEMIC 934 00:44:51,111 --> 00:44:52,512 INTERFERON AND EVEN THOUGH THAT 935 00:44:52,512 --> 00:44:57,150 DIDN'T PAN OUT AND THE DAA TOOK 936 00:44:57,150 --> 00:44:58,385 OVER THE PLAYING FIELD IN TERMS 937 00:44:58,385 --> 00:45:00,620 OF TREATMENT WE DID GET HOOKED 938 00:45:00,620 --> 00:45:02,422 ON TRYING TO UNDERSTAND HOW 939 00:45:02,422 --> 00:45:04,791 INTERFERON WORKS AND IT'S 940 00:45:04,791 --> 00:45:05,225 FASCINATING. 941 00:45:05,225 --> 00:45:06,760 MORE LATELY WE'VE BECOME 942 00:45:06,760 --> 00:45:09,362 INTERESTED IN A PHENOMENON 943 00:45:09,362 --> 00:45:13,133 PEOPLE CALL ANTIGEN INDEPENDENT 944 00:45:13,133 --> 00:45:13,900 INNATE IMMUNITY. 945 00:45:13,900 --> 00:45:16,770 THIS HAS TO DO WITH A MODEL THAT 946 00:45:16,770 --> 00:45:19,506 A LAB HAS BEEN WORKING ON WHERE 947 00:45:19,506 --> 00:45:21,575 IF YOU INFECT A MOUSE WITH SARS 948 00:45:21,575 --> 00:45:27,314 COV2 AND SEE A TRANSIENT WEIGHT 949 00:45:27,314 --> 00:45:28,782 LOSS AS A RESULT WHAT HAPPENS IF 950 00:45:28,782 --> 00:45:33,753 YOU CHALLENGE THAT ANIMAL WITH A 951 00:45:33,753 --> 00:45:36,223 RESPIRATORY PATHOGEN NOT RELATED 952 00:45:36,223 --> 00:45:38,825 TO SARS COV2 AND WHAT ALEX HAS 953 00:45:38,825 --> 00:45:40,026 SHOWN AND FIGURED OUT SOME OF 954 00:45:40,026 --> 00:45:44,231 THE MECHANISMS INVOLVED HERE IS 955 00:45:44,231 --> 00:45:47,133 THAT THESE ANIMALS AT LEAST FOR 956 00:45:47,133 --> 00:45:49,669 A PERIOD OF TIME ARE HIGHLY 957 00:45:49,669 --> 00:45:52,339 RESISTANT TO A CHALLENGE OF 958 00:45:52,339 --> 00:45:52,606 INFLUENZA. 959 00:45:52,606 --> 00:45:54,674 THE INITIAL INFECTION OF SARS 960 00:45:54,674 --> 00:46:01,147 COV2 CHANGED THE BEHAVIOR AND 961 00:46:01,147 --> 00:46:06,286 ALVEOLAR MACRO PHAGES SO 962 00:46:06,286 --> 00:46:07,687 INFLUENZA IS RESOLVED RATHER 963 00:46:07,687 --> 00:46:08,855 THAN LETHAL. 964 00:46:08,855 --> 00:46:13,159 WITH THAT I'LL READ A QUOTE FROM 965 00:46:13,159 --> 00:46:15,729 LOUIS THOMAS WHO WROTE THIS TO 966 00:46:15,729 --> 00:46:23,737 COMMEMORATE THE 40 YEARS OF THE 967 00:46:23,737 --> 00:46:25,872 LASKAR PRIZES MOST THE 968 00:46:25,872 --> 00:46:26,473 CELEBRATED ACHIEVEMENT HAVE 969 00:46:26,473 --> 00:46:28,808 THEIR ORIGINS AND MOMENTS OF 970 00:46:28,808 --> 00:46:29,709 SURPRISE IN THE LABORATORY 971 00:46:29,709 --> 00:46:33,780 UNPLANNED FOR, UNANTICIPATED, 972 00:46:33,780 --> 00:46:34,080 UNPREDICTED. 973 00:46:34,080 --> 00:46:36,249 NO COMMITTEE TO SURVEY THE 974 00:46:36,249 --> 00:46:38,585 FUTURE PROSPECT FOR BIO MEDICAL 975 00:46:38,585 --> 00:46:40,053 RESEARCH CAN POSSIBLY GUESS AT 976 00:46:40,053 --> 00:46:41,755 THE THINGS THAT LAY AHEAD. 977 00:46:41,755 --> 00:46:43,923 NO BRANCH OF GOVERNMENT COULD 978 00:46:43,923 --> 00:46:46,293 HAVE LAID DETAILED PLANS NOR 979 00:46:46,293 --> 00:46:47,794 SCIENTIFIC NEEDS OF THE FUTURE 980 00:46:47,794 --> 00:46:49,963 BEYOND ASSERTING WHAT THE 981 00:46:49,963 --> 00:46:50,930 COUNTRY NEEDED WAS MORE 982 00:46:50,930 --> 00:46:52,999 FUNDAMENTAL KNOWLEDGE ABOUT 983 00:46:52,999 --> 00:46:54,934 HUMAN FORM AND FUNCTION, ABOUT 984 00:46:54,934 --> 00:46:58,972 THE AGENTS AND INFLUENCE OF 985 00:46:58,972 --> 00:47:00,106 RESPONSIBLE DISEASE AND IN 986 00:47:00,106 --> 00:47:01,474 NATURE ITSELF. 987 00:47:01,474 --> 00:47:02,175 SCIENTIFIC RESEARCH WORKS AND 988 00:47:02,175 --> 00:47:05,378 IT'S THE ONLY WAY TO GET AT THE 989 00:47:05,378 --> 00:47:06,046 UNDERLYING MECHANISMS OF DISEASE 990 00:47:06,046 --> 00:47:07,080 AND THE ONLY WAY TO LEARN WHAT 991 00:47:07,080 --> 00:47:09,149 TO DO ABOUT THEY WILL. 992 00:47:09,149 --> 00:47:12,052 AND I THINK THAT IS AS TRUE 993 00:47:12,052 --> 00:47:17,857 TODAY AS IT WAS WHEN LOUIS WROTE 994 00:47:17,857 --> 00:47:20,794 THIS AND I'LL CLOSE BY THINKING 995 00:47:20,794 --> 00:47:28,001 BACK TO MY OWN ORIGINS WHERE 996 00:47:28,001 --> 00:47:29,903 CURIOSITY DRIVEN RESEARCH IN THE 997 00:47:29,903 --> 00:47:32,005 OLD DAYS THAT JOE MENTIONED WITH 998 00:47:32,005 --> 00:47:37,043 THE STRAUSS LAB WE WERE SETTING 999 00:47:37,043 --> 00:47:40,547 AN ENVELOPE STRAND RNA VIRUS 1000 00:47:40,547 --> 00:47:46,019 THAT'S NOT A BIG DISEASE THREAT. 1001 00:47:46,019 --> 00:47:48,588 CHIKUNGUNYA TURNS OUT TO BE ONE 1002 00:47:48,588 --> 00:47:53,893 AND I THINK THE NIH AND NIAID IN 1003 00:47:53,893 --> 00:47:57,030 PARTICULAR TO THE SUPPORT OF 1004 00:47:57,030 --> 00:47:59,032 THIS WORK AT CAL TECH AND 1005 00:47:59,032 --> 00:48:02,769 THROUGHOUT MY CAREER HAS HAD THE 1006 00:48:02,769 --> 00:48:06,206 FORESIGHT TO FUND THINGS 1007 00:48:06,206 --> 00:48:07,073 OBVIOUSLY TRANSLATIONAL 1008 00:48:07,073 --> 00:48:11,878 POTENTIAL AND ALSO THINGS THAT 1009 00:48:11,878 --> 00:48:13,980 ENRICH OUR KNOWLEDGE ABOUT 1010 00:48:13,980 --> 00:48:15,115 BIOLOGY AND REGARDLESS OF REALLY 1011 00:48:15,115 --> 00:48:17,117 TRYING TO BE ABLE TO PREDICT 1012 00:48:17,117 --> 00:48:18,184 WHAT THE IMPACT THAT'S GOING TO 1013 00:48:18,184 --> 00:48:20,320 BE IN THE FUTURE AND I THINK 1014 00:48:20,320 --> 00:48:22,555 IT'S VERY IMPORTANT THAT WE 1015 00:48:22,555 --> 00:48:24,457 MAINTAIN THE RIGHT BALANCE 1016 00:48:24,457 --> 00:48:24,657 THERE. 1017 00:48:24,657 --> 00:48:24,991 SO THANK YOU. 1018 00:48:24,991 --> 00:48:35,101 SORRY. 1019 00:48:36,369 --> 00:48:40,106 QUESTIONS? 1020 00:48:40,106 --> 00:48:45,245 >> I THINK THERE'S ALSO A LOT OF 1021 00:48:45,245 --> 00:48:46,513 PEOPLE ONLINE DON'T KNOW. 1022 00:48:46,513 --> 00:48:49,482 >> CHARLIE, IMPRESSIVE AND 1023 00:48:49,482 --> 00:48:52,552 CUTTING EDGE RESEARCH EVEN ON 1024 00:48:52,552 --> 00:48:54,020 THE VIRUS MANY PEOPLE THINK WE 1025 00:48:54,020 --> 00:48:56,689 SHOULDN'T AND DON'T NEED TO 1026 00:48:56,689 --> 00:48:57,390 STUDY ANYMORE OBVIOUSLY YOU 1027 00:48:57,390 --> 00:48:59,459 PROVED THEM WRONG. 1028 00:48:59,459 --> 00:49:06,566 TWO QUICK QUESTIONS, IN TYPE 1 1029 00:49:06,566 --> 00:49:09,602 INTERFERON INDUCED OR INVOLVED 1030 00:49:09,602 --> 00:49:12,405 IN THE HV INFECTION IN VIVO? 1031 00:49:12,405 --> 00:49:16,176 THE SECOND QUESTION WOULD BE IS 1032 00:49:16,176 --> 00:49:18,812 IT SENSITIVE TO THE DAAs? 1033 00:49:18,812 --> 00:49:20,180 HAVE YOU TRIED THAT IN YOUR 1034 00:49:20,180 --> 00:49:20,380 MODEL? 1035 00:49:20,380 --> 00:49:27,454 >> WE HAVE LOOKED AT THE 1036 00:49:27,454 --> 00:49:29,289 BEHAVIOR OF THE VIRUS IN 1037 00:49:29,289 --> 00:49:30,623 DIFFERENT KNOCKOUT MICE. 1038 00:49:30,623 --> 00:49:31,424 WE DO SEE INTERESTING 1039 00:49:31,424 --> 00:49:34,027 DIFFERENCES DEPENDING ON WHETHER 1040 00:49:34,027 --> 00:49:38,865 OR NOT THEY'RE DEFECTIVE IN 1041 00:49:38,865 --> 00:49:39,833 INNATE IMMUNITY OR NOT. 1042 00:49:39,833 --> 00:49:42,769 BUT I DON'T THINK INNATE 1043 00:49:42,769 --> 00:49:44,537 IMMUNITY IN AND OF ITSELF IS 1044 00:49:44,537 --> 00:49:46,506 SUFFICIENT TO CONTROL INFECTION. 1045 00:49:46,506 --> 00:49:47,373 IF FOR INSTANCE IF YOU LOOK AT 1046 00:49:47,373 --> 00:49:52,812 THE BEHAVIOR OF THIS AND IN OUR 1047 00:49:52,812 --> 00:49:55,815 GENE MOUSE THAT LACKS T AND B 1048 00:49:55,815 --> 00:49:57,717 CELLS AND STILL HAS INNATE 1049 00:49:57,717 --> 00:49:59,118 IMMUNITY THOSE GET INFECTED TO 1050 00:49:59,118 --> 00:50:02,622 HIGH LEVELS AND STAY THAT WAY. 1051 00:50:02,622 --> 00:50:04,390 SO FAR WE HAVEN'T SEEN -- WE 1052 00:50:04,390 --> 00:50:06,559 HAVEN'T DONE A CONTROLLED 1053 00:50:06,559 --> 00:50:08,561 EXPERIMENT AND HAVEN'T SEEN ANY 1054 00:50:08,561 --> 00:50:10,230 EVIDENCE THE UKRAINECALLY 1055 00:50:10,230 --> 00:50:13,199 INFECTED IMMUNODEFICIENT ANIMAL 1056 00:50:13,199 --> 00:50:15,802 DEVELOPED PATHOLOGY. 1057 00:50:15,802 --> 00:50:18,171 AND -- AND THE SECOND 1058 00:50:18,171 --> 00:50:18,872 QUESTION -- WHETHER 1059 00:50:18,872 --> 00:50:21,841 >> WHETHER THE VIRUSES ARE 1060 00:50:21,841 --> 00:50:22,342 SUSCEPTIBLE -- 1061 00:50:22,342 --> 00:50:32,886 >> TIM HAS BEEN LOOKING AT THAT 1062 00:50:39,125 --> 00:50:40,126 LOOKS LIKE WE'LL COME UP WITH 1063 00:50:40,126 --> 00:50:43,263 CONDITIONS TO CURE. 1064 00:50:43,263 --> 00:50:44,531 WE'RE THOUGHT THERE YET BUT 1065 00:50:44,531 --> 00:50:45,532 THAT'S SOMETHING WE WANT TO BE 1066 00:50:45,532 --> 00:50:47,333 ABLE TO DO TO STUDY THE IMPACT 1067 00:50:47,333 --> 00:50:48,902 OF THAT ON PATHOGENESIS. 1068 00:50:48,902 --> 00:50:59,078 >> THANKS. 1069 00:50:59,779 --> 00:51:06,219 >> OH, NO. 1070 00:51:06,219 --> 00:51:16,763 >> YOU MAKE ME WANT TO UNRETIRE. 1071 00:51:25,438 --> 00:51:28,708 ONE OF THE QUESTIONS WE'VE HAD 1072 00:51:28,708 --> 00:51:30,176 ALONG IS HOW IMPORTANT IS 1073 00:51:30,176 --> 00:51:33,947 CIRRHOSIS IN THE DEVELOPMENT OF 1074 00:51:33,947 --> 00:51:34,180 CANCER? 1075 00:51:34,180 --> 00:51:35,848 AND THE DIFFERENCES BETWEEN THE 1076 00:51:35,848 --> 00:51:37,584 U.S. AND JAPAN WHERE HERE WE 1077 00:51:37,584 --> 00:51:41,487 MOSTLY HAVE CIRRHOSIS AS A 1078 00:51:41,487 --> 00:51:43,389 PRECEDING EVENT, JAPAN, THEY 1079 00:51:43,389 --> 00:51:45,291 DON'T ALWAYS HAVE THAT. 1080 00:51:45,291 --> 00:51:47,694 SOMETHING TO LOOK AT IN THIS 1081 00:51:47,694 --> 00:51:49,729 MODEL AND WONDERING OF THE 1082 00:51:49,729 --> 00:51:51,531 ANIMALS THAT DID DEVELOP CANCER, 1083 00:51:51,531 --> 00:51:53,800 HOW MANY HAVE PRE-EXISTING 1084 00:51:53,800 --> 00:51:55,702 CIRRHOSIS OR ADVANCED FIBROSIS? 1085 00:51:55,702 --> 00:51:58,605 >> GREAT POINT AND GREAT 1086 00:51:58,605 --> 00:51:58,871 QUESTION. 1087 00:51:58,871 --> 00:52:01,207 SOMETHING I DON'T KNOW THE 1088 00:52:01,207 --> 00:52:02,642 ANSWER TO BUT IT SEEMS THAT 1089 00:52:02,642 --> 00:52:06,245 THESE MOUSE MODELS IN GENERAL 1090 00:52:06,245 --> 00:52:10,783 ARE NOT PRONE TO DEVELOPING 1091 00:52:10,783 --> 00:52:13,019 CIRRHOSIS AND SO WE RARELY SEE 1092 00:52:13,019 --> 00:52:15,488 THAT IN OUR ANIMALS. 1093 00:52:15,488 --> 00:52:18,424 SO I KNOW THAT PEOPLE SORT OF 1094 00:52:18,424 --> 00:52:22,095 DRAW THIS LINEAR PROGRESSION OF 1095 00:52:22,095 --> 00:52:25,198 FIBROSIS, CIRRHOSIS, CANCER BUT 1096 00:52:25,198 --> 00:52:28,434 I'M NOT CONVINCED THAT CIRRHOSIS 1097 00:52:28,434 --> 00:52:32,372 IS CAUSAL AS OPPOSED TO BEING A 1098 00:52:32,372 --> 00:52:37,210 MARKER FOR BASICALLY MORE SEVERE 1099 00:52:37,210 --> 00:52:42,715 LIVER DAMAGE IN PEOPLE. 1100 00:52:42,715 --> 00:52:44,751 AT LEAST IN THE MOUSE MODEL IT'S 1101 00:52:44,751 --> 00:52:53,526 NOT A NECESSARY PRECURSOR. 1102 00:52:53,526 --> 00:52:58,164 THERE'S NO PERFECT MODEL AS YOU 1103 00:52:58,164 --> 00:52:59,232 KNOW BUT IT'S INTERESTING AND 1104 00:52:59,232 --> 00:53:04,303 I'D BE INTERESTED TO HEAR YOUR 1105 00:53:04,303 --> 00:53:11,911 THOUGHTS IS SCIRRHOSIS A MARKER 1106 00:53:11,911 --> 00:53:19,218 AND CORRELATES WITH ACC BUT 1107 00:53:19,218 --> 00:53:29,362 ZVENLT 1108 00:53:31,397 --> 00:53:32,598 BUT WE'VE ALWAYS THOUGHT IN 1109 00:53:32,598 --> 00:53:35,268 GENERAL IT WAS THE REGENERATION 1110 00:53:35,268 --> 00:53:37,370 THAT IN THE PROCESS OF 1111 00:53:37,370 --> 00:53:42,442 REGENERATING THE LIVER TO 1112 00:53:42,442 --> 00:53:46,079 OVERCOME CIRRHOTIC EVENTS OF THE 1113 00:53:46,079 --> 00:53:48,748 MUTATIONS OCCUR INSIDE OF CANCER 1114 00:53:48,748 --> 00:53:53,953 BUT NOBODY'S IN VIVO REEL PROVEN 1115 00:53:53,953 --> 00:53:54,153 THAT. 1116 00:53:54,153 --> 00:53:55,922 >> THE IMMUNE SURVEILLANCE THAT 1117 00:53:55,922 --> 00:53:58,191 CAN'T GET RID OF THE VIRUS WILL 1118 00:53:58,191 --> 00:54:00,960 BE TRIGGERING A LOT OF 1119 00:54:00,960 --> 00:54:02,228 REGENERATIVE ACTIVITY IN THE 1120 00:54:02,228 --> 00:54:02,729 LIVER. 1121 00:54:02,729 --> 00:54:06,199 WE HAVEN'T DONE A CAREFUL JOB OF 1122 00:54:06,199 --> 00:54:07,934 LOOKING AT THAT OVER TIME. 1123 00:54:07,934 --> 00:54:09,969 BUT YEAH. 1124 00:54:09,969 --> 00:54:12,939 >> THANK YOU, JOHN. 1125 00:54:12,939 --> 00:54:14,540 >> IT'S AN INTERESTING MODEL TO 1126 00:54:14,540 --> 00:54:19,245 STUDY CANCER AND TO STUDY LIVER 1127 00:54:19,245 --> 00:54:22,548 FIBROSIS AND YESTERDAY IT'S A 1128 00:54:22,548 --> 00:54:23,082 VIRUS. 1129 00:54:23,082 --> 00:54:25,585 DO THE RATS DEVELOP CANCER LATS 1130 00:54:25,585 --> 00:54:26,085 THAT LIVE IN SANITARY 1131 00:54:26,085 --> 00:54:27,320 ENVIRONMENTS AND NOT IN THE 1132 00:54:27,320 --> 00:54:28,521 STREETS OF NEW YORK THAT ARE NOT 1133 00:54:28,521 --> 00:54:32,959 EXPOSED TO ANY OTHER TOXIN? 1134 00:54:32,959 --> 00:54:34,527 >> I'M NOT SURE THE LIFE SPAN IN 1135 00:54:34,527 --> 00:54:42,168 THE STREETS OF NEW YORK. 1136 00:54:42,168 --> 00:54:47,140 >> WE'VE LOOKED AT THE RAT MODEL 1137 00:54:47,140 --> 00:54:49,242 AND I DON'T THINK THEY'VE SEEN 1138 00:54:49,242 --> 00:54:50,309 EVIDENCE OF CANCER IN RATS IN 1139 00:54:50,309 --> 00:54:53,746 LABORATORY RATS. 1140 00:54:53,746 --> 00:54:59,118 >> AND THEN I WONDER IF WE PUT 1141 00:54:59,118 --> 00:55:06,259 THE VIRUS INTO MICE WITH MICE 1142 00:55:06,259 --> 00:55:07,693 MICROBIOTA AND A TYPE OF IMMUNE 1143 00:55:07,693 --> 00:55:08,895 RESPONSE THEY MAY DEVELOP CANCER 1144 00:55:08,895 --> 00:55:13,633 FASTER. 1145 00:55:13,633 --> 00:55:16,736 >> I HAVEN'T BEEN ABLE TO 1146 00:55:16,736 --> 00:55:19,539 REROUTE OR MICROBIOME FOLKS AND 1147 00:55:19,539 --> 00:55:23,409 WE DON'T KNOW HOW THIS BEHAVES 1148 00:55:23,409 --> 00:55:24,610 IN GERM-FREE MICE. 1149 00:55:24,610 --> 00:55:28,314 IT WOULD BE INTERESTING TO LOOK 1150 00:55:28,314 --> 00:55:35,154 AT IT IN OTHER MOUSE MODELS TO 1151 00:55:35,154 --> 00:55:41,727 SEE HOW IT THE PATHOLOGY AND 1152 00:55:41,727 --> 00:55:42,061 PATHOGENESIS. 1153 00:55:42,061 --> 00:55:43,095 >> AND I HAVE A QUESTION. 1154 00:55:43,095 --> 00:55:46,999 I WAS WONDERING IF YOU'RE DOING 1155 00:55:46,999 --> 00:55:52,038 A MORE BROAD SHOTGUN APPROACH OR 1156 00:55:52,038 --> 00:55:57,276 MORE IN THE DIVERSITY OUTBRED 1157 00:55:57,276 --> 00:56:02,882 MODEL OR 1158 00:56:02,882 --> 00:56:05,785 >> THERE ARE A LOT OF 1159 00:56:05,785 --> 00:56:08,254 COLLABORATIVE CROSS STRAINS AND 1160 00:56:08,254 --> 00:56:09,689 THIS WAS A PILOT EXPERIMENT 1161 00:56:09,689 --> 00:56:11,424 TAKING ADVANTAGE OF THE FOUNDERS 1162 00:56:11,424 --> 00:56:17,396 THEY HAVE TIM SHEEHAN HAD ACCESS 1163 00:56:17,396 --> 00:56:27,874 TO OTHER THAN IT WOULD BE A 1164 00:56:28,107 --> 00:56:29,976 COMPREHENSIVE THING TO DO AND 1165 00:56:29,976 --> 00:56:32,678 TIM HAS GONE AHEAD AND DONE THAT 1166 00:56:32,678 --> 00:56:35,615 FOR CHRONIC VERSUS ACUTE 1167 00:56:35,615 --> 00:56:42,188 RESOLVED INFECTION THE CC071 AND 1168 00:56:42,188 --> 00:56:47,727 C57 BLACK 6 MICE. 1169 00:56:47,727 --> 00:56:48,494 WE KNOW WHAT'S RESPONSIBLE FOR 1170 00:56:48,494 --> 00:56:50,096 THIS AND I WON'T TELL YOU 1171 00:56:50,096 --> 00:56:53,933 BECAUSE THAT'S HIS STORY. 1172 00:56:53,933 --> 00:56:54,367 >> THANK YOU. 1173 00:56:54,367 --> 00:57:04,510 >> OKAY. 1174 00:57:09,982 --> 00:57:11,550 >> HI. 1175 00:57:11,550 --> 00:57:13,853 MY NAME IS ALAN RYAN AND I'M 1176 00:57:13,853 --> 00:57:17,490 GOING TO BRIEFLY INTRODUCE OUR 1177 00:57:17,490 --> 00:57:23,496 NEXT SPEAKER, CHANTAL ABERGEL IN 1178 00:57:23,496 --> 00:57:24,764 MARSEILLE WHERE SHE LIVES AND 1179 00:57:24,764 --> 00:57:26,832 WORKS AND FORMER POSTDOC AT 1180 00:57:26,832 --> 00:57:28,601 NIDDK WHO WENT BACK TO MARSEILLE 1181 00:57:28,601 --> 00:57:33,072 AND HAS BEEN INVOLVED FROM THE 1182 00:57:33,072 --> 00:57:35,574 BEGINNING IN STUDYING WHAT WE 1183 00:57:35,574 --> 00:57:39,278 ALL CALL GIANT VIRUSES, VIRUSES 1184 00:57:39,278 --> 00:57:44,250 FAR MORE COMPLEX THAN THE 1185 00:57:44,250 --> 00:57:49,255 VIRUSES YOU AND I STUDY AND THE 1186 00:57:49,255 --> 00:57:54,961 MYSTERY OF WHY THEY'RE SEEMINGLY 1187 00:57:54,961 --> 00:57:57,997 REDUNDANT WITH HOST FUNCTIONS. 1188 00:57:57,997 --> 00:57:59,198 CHANTAL, AARE YOU THERE? 1189 00:57:59,198 --> 00:58:01,367 I'M LOOKING FORWARD TO YOUR 1190 00:58:01,367 --> 00:58:01,567 TALK. 1191 00:58:01,567 --> 00:58:10,109 OVER TO YOU. 1192 00:58:10,109 --> 00:58:10,710 >> THANK YOU. 1193 00:58:10,710 --> 00:58:16,549 I'M PLEASED TO BE AT NIH. 1194 00:58:16,549 --> 00:58:22,188 I CHANGED A BIT MY FOCUS TO GIVE 1195 00:58:22,188 --> 00:58:30,196 FOCUS ON THE VIRUSES. 1196 00:58:30,196 --> 00:58:35,668 FIRST THE STUDY OF THE VIRUS. 1197 00:58:35,668 --> 00:58:43,409 SO THAT WAS THE FIRST VIRUS 1198 00:58:43,409 --> 00:58:53,953 DISCOVERED IN 2004 AND AND THIS 1199 00:58:59,959 --> 00:59:09,502 GENOME HAS 70% OF THE GENES AND 1200 00:59:09,502 --> 00:59:11,370 TO GIVE PERSPECTIVE IT'S A VIRUS 1201 00:59:11,370 --> 00:59:21,881 KNOWN AT THE TIME CD1 AND WE 1202 00:59:46,272 --> 00:59:49,408 DECIDE 1203 00:59:49,408 --> 00:59:55,114 DECIDED FROM WHAT WE LEARNED 1204 00:59:55,114 --> 01:00:05,624 FROM ME VIRUS WE WERE ABLE TO 1205 01:00:09,695 --> 01:00:15,067 SEE HOW SUCCESSFUL IT WAS NOT 1206 01:00:15,067 --> 01:00:25,611 ONLY MORE AND THERE IS NOW THE 1207 01:00:32,518 --> 01:00:42,995 VIRUS AND AND IT INCREASES THE 1208 01:01:03,649 --> 01:01:14,126 SIZE AND THERE WHAT IS HAPPENING 1209 01:01:37,383 --> 01:01:42,221 SO THIS PARTICLE IS OPEN WHERE 1210 01:01:42,221 --> 01:01:47,126 YOU SEE THE TRIANGLE OF THE 1211 01:01:47,126 --> 01:01:50,029 CAPSID AND WE HAVE THE 1212 01:01:50,029 --> 01:01:51,030 COMPARTMENT NOW WHICH IS 1213 01:01:51,030 --> 01:01:57,403 ACCOMPANIES THE GENOME. 1214 01:01:57,403 --> 01:02:02,575 THE 1215 01:02:02,575 --> 01:02:08,113 AS SOON AS THE TARGET IS OPEN IT 1216 01:02:08,113 --> 01:02:15,621 REACHED THE MEMBRANE AND IT'S 1217 01:02:15,621 --> 01:02:20,693 CREATED BY THE OPENING AND WE 1218 01:02:20,693 --> 01:02:25,364 HAVE THE COMPARTMENT INSIDE THE 1219 01:02:25,364 --> 01:02:31,003 TRANSCRIPTION OF THE GENES AND 1220 01:02:31,003 --> 01:02:36,141 YOU CAN SEE THE VIRAL FACTORY. 1221 01:02:36,141 --> 01:02:40,246 AND EXPANDS AND YOU CAN SEE BY 1222 01:02:40,246 --> 01:02:42,314 LIGHT MICROSCOPY WITH THE 1223 01:02:42,314 --> 01:02:45,451 NUCLEUS AND THE LATE STAGE OF 1224 01:02:45,451 --> 01:02:48,254 THE INFECTION WHERE THE VIRAL 1225 01:02:48,254 --> 01:02:52,157 FACTORY TAKING A HUGE AMOUNT OF 1226 01:02:52,157 --> 01:02:57,630 THE SPACE AND ALSO IT WILL BE 1227 01:02:57,630 --> 01:03:04,903 EXPELLED FROM THE CELL THROUGH 1228 01:03:04,903 --> 01:03:07,072 LYSASE OF THE CELL AND THERE WAS 1229 01:03:07,072 --> 01:03:12,077 EARLY EXPRESSION RATHER THAN 1230 01:03:12,077 --> 01:03:22,621 LATE AND THERE ARE AND FROM THE 1231 01:03:32,698 --> 01:03:34,566 TRANSCRIPTION THERE'S A SPECIFIC 1232 01:03:34,566 --> 01:03:38,203 STRUCTURE WHICH IS GOING TO BE 1233 01:03:38,203 --> 01:03:41,540 RECOGNIZED BY THE ENCODED 1234 01:03:41,540 --> 01:03:42,341 MACHINERY THAT WILL RECOGNIZE 1235 01:03:42,341 --> 01:03:46,011 AND GET INTO IT AND THEN THE 1236 01:03:46,011 --> 01:03:51,283 POLYMERASE OF THE VIRUS IS GOING 1237 01:03:51,283 --> 01:03:58,424 TO BE ABLE TO GET TO THE ENZYME 1238 01:03:58,424 --> 01:04:01,794 AND HAVE THIS TRANSCRIPTION. 1239 01:04:01,794 --> 01:04:10,102 AND NOW I WANT TO PRESENT TO YOU 1240 01:04:10,102 --> 01:04:15,107 THE VIRUS. 1241 01:04:15,107 --> 01:04:18,711 AND BY THE VIDEO AND INSIDE WE 1242 01:04:18,711 --> 01:04:24,049 HAVE THIS COMPARTMENT AND THE 1243 01:04:24,049 --> 01:04:26,485 CELL WAS SHOWING SOME STRUCTURE. 1244 01:04:26,485 --> 01:04:30,989 SO IN THE LAB WE MANAGED TO 1245 01:04:30,989 --> 01:04:37,396 DEVELOP AN OPENING THAT ALLOWED 1246 01:04:37,396 --> 01:04:42,201 US FOR THE STRUCTURE INSIDE THE 1247 01:04:42,201 --> 01:04:50,008 COMPARTMENT THAT CONTAIN DNA. 1248 01:04:50,008 --> 01:04:52,845 WE COLLECTED DETE OF THE 1249 01:04:52,845 --> 01:04:58,550 STRUCTURE AND WERE ABLE TO SOLVE 1250 01:04:58,550 --> 01:05:03,555 STRUCTURES. 1251 01:05:03,555 --> 01:05:13,399 AND THIS CONTAINS THE GENOME AND 1252 01:05:13,399 --> 01:05:17,202 THE FORM OF THE CELL STRUCTURE 1253 01:05:17,202 --> 01:05:25,611 AND THE DNA AND FINALLY THERE'S 1254 01:05:25,611 --> 01:05:35,954 STRANDS OF DNA SO WE HAVE IT 1255 01:05:35,954 --> 01:05:41,727 INSIDE THE CAPSID AND THE 1256 01:05:41,727 --> 01:05:47,966 CONTENT OF THIS FIBER AND THIS 1257 01:05:47,966 --> 01:05:58,343 IS ACTUALLY AN ENZYME. 1258 01:06:03,315 --> 01:06:08,187 AND THIS STRUCTURE HAS BEEN 1259 01:06:08,187 --> 01:06:17,095 SOLVED AND HERE WE LOOK AT THE 1260 01:06:17,095 --> 01:06:21,967 STRUCTURE. 1261 01:06:21,967 --> 01:06:32,511 THIS WAS TARGETED IN THE CAPSID. 1262 01:06:33,278 --> 01:06:38,517 AND THE DIFFERENCE BETWEEN THE 1263 01:06:38,517 --> 01:06:46,258 PROTEINS WAS THIS WAS PRESENTED 1264 01:06:46,258 --> 01:06:54,566 IN THE CAPSID AND THE SUB UNIT 1265 01:06:54,566 --> 01:06:57,302 OF THE RNA POLYMERASE WERE 1266 01:06:57,302 --> 01:07:07,746 PRESENTED WITH THE FIBER. 1267 01:07:15,854 --> 01:07:23,629 WE WERE OBSERVE IING OBSERVING D 1268 01:07:23,629 --> 01:07:33,972 THE RNA POLYMERASE. 1269 01:07:42,214 --> 01:07:48,020 AND LOOK AT HOW IT'S RELAXING 1270 01:07:48,020 --> 01:07:53,959 A 1271 01:07:53,959 --> 01:08:00,699 AND LOOK AT THE PROMOTER COULD 1272 01:08:00,699 --> 01:08:10,208 ACTUALLY BE RELAXED AND THEN 1273 01:08:10,208 --> 01:08:14,780 PROCEED AFTER. 1274 01:08:14,780 --> 01:08:23,889 SO SO AFTER SIX YEARS OF HARD 1275 01:08:23,889 --> 01:08:29,461 WORK AND THANKS TO A POSTDOC IN 1276 01:08:29,461 --> 01:08:37,302 OUR LAB WE KNOCKED OUT EACH OF 1277 01:08:37,302 --> 01:08:47,813 THE OXIDASE AND WE HAVE WILD 1278 01:08:50,282 --> 01:09:00,225 TYPE AND AND WHEN WE KNOCK OUT 1279 01:09:00,225 --> 01:09:05,998 THE WILD TYPE WE GET SURPRI 1280 01:09:05,998 --> 01:09:10,802 SURPRISINGLY STABLE FIBERS. 1281 01:09:10,802 --> 01:09:21,346 WHEN WE KNOCK OUT THE STRUCTURE 1282 01:09:23,715 --> 01:09:29,888 THE FIBER AND WE'RE ABLE TO SEE 1283 01:09:29,888 --> 01:09:35,560 WHAT WE SUSPECT AND MANY CHANGES 1284 01:09:35,560 --> 01:09:43,969 WHERE AND WE APPLY THE DIFFERENT 1285 01:09:43,969 --> 01:09:54,012 STRUCTURES DIDN'T WORK AND 1286 01:09:54,012 --> 01:09:57,215 COMPATIBLE FOR THE ANALYSIS AND 1287 01:09:57,215 --> 01:10:02,521 IF WE COMPARE THE VIRUS THAT HAS 1288 01:10:02,521 --> 01:10:12,964 BEEN KNOCKED OUT WE ONLY 1289 01:10:15,467 --> 01:10:15,967 INCREASE THE SECTION IN THE 1290 01:10:15,967 --> 01:10:23,408 MICE. 1291 01:10:23,408 --> 01:10:30,215 BUT WE TAKE THE STABLE 1292 01:10:30,215 --> 01:10:30,982 STRUCTURE. 1293 01:10:30,982 --> 01:10:36,788 IT'S NOT ONE PROTEIN OR ONE 1294 01:10:36,788 --> 01:10:44,296 STRUCTURE BUT AND IMAGINE A 1295 01:10:44,296 --> 01:10:47,666 REASON FOR THE TWO EXTREME 1296 01:10:47,666 --> 01:10:49,801 STRUCTURES BY DESTROYING AND THE 1297 01:10:49,801 --> 01:10:51,870 DNA IS ACTUALLY IN SIX STRAINS 1298 01:10:51,870 --> 01:10:53,939 THE SIX STRAINS DO NOT ALL HAVE 1299 01:10:53,939 --> 01:10:58,110 THE SAME LENGTHS. 1300 01:10:58,110 --> 01:11:06,218 THE FIRST IS GOING TO BE DONE 1301 01:11:06,218 --> 01:11:16,762 WITH THE FIRST AND YOU CAN SEE 1302 01:11:23,902 --> 01:11:24,202 HERE. 1303 01:11:24,202 --> 01:11:29,741 AND I TOLD YOU WE WERE WONDERING 1304 01:11:29,741 --> 01:11:33,345 WHY IT WAS PRESENTED AND NOT ON 1305 01:11:33,345 --> 01:11:36,948 THE GENOMIC SIDE. 1306 01:11:36,948 --> 01:11:47,492 WE DID DO THE FIRST AND REPLACED 1307 01:11:47,859 --> 01:11:55,500 TERMINAL WITH THE GFP AND ACTUAL 1308 01:11:55,500 --> 01:12:02,007 LY SHOWING THE PARTICLE AND THIS 1309 01:12:02,007 --> 01:12:06,611 IS ENRICHED. 1310 01:12:06,611 --> 01:12:17,189 WE SHAPE THE PARTICLE AND YOU 1311 01:12:17,189 --> 01:12:23,261 SEE THE DEGREES. 1312 01:12:23,261 --> 01:12:33,805 I'VE TOLD YOU FROM THE BEGINNING 1313 01:12:36,274 --> 01:12:41,513 AND THIS CAN BE TOTALLY 1314 01:12:41,513 --> 01:12:44,216 DIFFERENT AND GETS INSIDE THE 1315 01:12:44,216 --> 01:12:49,955 GENOME FOCUSSED FROM THE ENZYMES 1316 01:12:49,955 --> 01:13:00,465 INVOLVED IN MAKING THIS THIS 1317 01:13:00,966 --> 01:13:07,439 WORK WAS DONE AND THE TRUCK 1318 01:13:07,439 --> 01:13:14,946 STRUCTURE SHOWED AND THE 1319 01:13:14,946 --> 01:13:18,049 POLYSACCHARIDE AND THERE ARE 1320 01:13:18,049 --> 01:13:28,393 HUGE POLYSACCHARIDE. 1321 01:13:34,766 --> 01:13:40,639 THIS ADD INIMPACT ON THE 1322 01:13:40,639 --> 01:13:51,182 PARTICLE AND THE INDICATES WHERE 1323 01:13:52,417 --> 01:14:02,894 THE CONTROL VIRUS PRESENTED HERE 1324 01:14:07,799 --> 01:14:13,972 YOU CAN SEE THE CAPSIDS. 1325 01:14:13,972 --> 01:14:24,516 FINALLY, HAVE THE PROTEINS USED 1326 01:14:30,255 --> 01:14:32,924 AND YOU CAN SEE THIS IS THE SAME 1327 01:14:32,924 --> 01:14:38,596 PROTEIN AS COLLECTED. 1328 01:14:38,596 --> 01:14:49,074 OVER ALL IT APPEARS THE ONE 1329 01:14:50,008 --> 01:14:50,141 VIRUS. 1330 01:14:50,141 --> 01:15:00,685 THIS IS SHOWED SOME EQUIVALENCY 1331 01:15:02,253 --> 01:15:05,890 A 1332 01:15:05,890 --> 01:15:06,725 AND SECURE ESSENTIAL FUNCTION 1333 01:15:06,725 --> 01:15:17,235 SUCH AS GENOME PROTECTION AND 1334 01:15:18,269 --> 01:15:18,737 THE ENVIRONMENT. 1335 01:15:18,737 --> 01:15:20,638 I WILL NOW GO TO ANOTHER FAMILY 1336 01:15:20,638 --> 01:15:24,576 OF THE NOT SO GIANT VIRUSES WITH 1337 01:15:24,576 --> 01:15:28,613 PARTICLES AND GENOMES WHICH ARE 1338 01:15:28,613 --> 01:15:39,124 AROUND 400KV AND ONE QUESTION 1339 01:15:40,258 --> 01:15:48,666 WAS THE VIRUSES HAVE A 1340 01:15:48,666 --> 01:15:53,905 POLYMERASE AND LOOK AT THE 1341 01:15:53,905 --> 01:15:57,609 TRANSCRIPTION AND YOU NEED TO 1342 01:15:57,609 --> 01:16:03,214 WAIT TO TRANSCRIBE THE INFECTION 1343 01:16:03,214 --> 01:16:08,853 AND HERE'S THE PARTICLES THERE 1344 01:16:08,853 --> 01:16:13,425 IS NO POLYMERASE AND WE STARTED 1345 01:16:13,425 --> 01:16:15,460 FROM THE BEGINNING AND AT THE 1346 01:16:15,460 --> 01:16:22,200 END OF THE INFECTION WE WERE 1347 01:16:22,200 --> 01:16:28,773 SEEING THIS AND DECIDED TO GO 1348 01:16:28,773 --> 01:16:34,179 BACK TO THE TIME OF THE 1349 01:16:34,179 --> 01:16:34,446 INFECTION. 1350 01:16:34,446 --> 01:16:44,989 WE USED A TRICK PROTEIN AND WE 1351 01:16:45,890 --> 01:16:51,663 CAN SEE THE PROTEIN EXITING AND 1352 01:16:51,663 --> 01:16:58,703 GOING INTO THE CYTOBLAST BUT 1353 01:16:58,703 --> 01:17:04,943 POSTINFECTION WHEN THEY FULLY 1354 01:17:04,943 --> 01:17:15,487 MATURE WE CAN SEE THOSE VIRUSES 1355 01:17:16,354 --> 01:17:23,328 ARE A MISSING LINK BETWEEN THE 1356 01:17:23,328 --> 01:17:27,765 VIRUSES AND AT THE INITIATION OF 1357 01:17:27,765 --> 01:17:33,004 THE INFECTION CHANGE IT IN SUCH 1358 01:17:33,004 --> 01:17:43,448 A WAY THIS IS AFTER IF WE GO 1359 01:17:43,448 --> 01:17:53,558 BACK. 1360 01:18:01,366 --> 01:18:05,570 IF THERE IS A FUSION BETWEEN H4 1361 01:18:05,570 --> 01:18:14,145 AND H2B AND H2A. 1362 01:18:14,145 --> 01:18:19,617 IF WE OVEREXPRESS FROM THE 1363 01:18:19,617 --> 01:18:28,226 INFECTION YOU CAN SEE THE YAWN 1364 01:18:28,226 --> 01:18:34,199 -- NON INFECTED AND ALONG THE 1365 01:18:34,199 --> 01:18:39,737 NUCLEI AND THE NORMAL INFECTION 1366 01:18:39,737 --> 01:18:50,281 CYCLE WE CAN SEE THIS IS STILL 1367 01:18:59,857 --> 01:19:10,201 INFECTION IN THE CASE OF THE 1368 01:19:10,201 --> 01:19:20,745 INFECTION IS TAKING PLACE AND I 1369 01:19:34,092 --> 01:19:37,762 GUESS I SHOULD MAKE IT SMALLER. 1370 01:19:37,762 --> 01:19:48,072 THIS IS IN THE LAB THEY DID IN 1371 01:19:48,072 --> 01:19:58,616 VITRO AND ONE DIFFERENCE IS THAT 1372 01:20:07,992 --> 01:20:18,369 THEY WERE UNSTABLE AND WE 1373 01:20:21,272 --> 01:20:25,543 EXPRESSED INTO THE CELL. 1374 01:20:25,543 --> 01:20:29,147 THOSE MOST LIKELY INVOLVED IN 1375 01:20:29,147 --> 01:20:30,248 THE TRANSFER OF THE GENOME 1376 01:20:30,248 --> 01:20:36,587 INSIDE THE CAPSID AND THIS 1377 01:20:36,587 --> 01:20:42,560 TRANSFER ACTUALLY WILL MAKE IT 1378 01:20:42,560 --> 01:20:48,800 AND THEY NEED THE POLYMERASE TO 1379 01:20:48,800 --> 01:20:55,206 COME TO THE DNA AND AS SOON AS 1380 01:20:55,206 --> 01:21:03,147 THE PARTICLE STARTS OPENING THE 1381 01:21:03,147 --> 01:21:08,119 NUCLEOSOME WILL BE EXPOSED AND 1382 01:21:08,119 --> 01:21:14,425 START THE TRANSCRIPTION AND HERE 1383 01:21:14,425 --> 01:21:19,664 I PRESENT ALL THE FAMILIES IN 1384 01:21:19,664 --> 01:21:22,567 THE LAB AND THEY'RE INTERESTING 1385 01:21:22,567 --> 01:21:25,770 BECAUSE THEY DON'T HAVE THE SAME 1386 01:21:25,770 --> 01:21:35,847 GENOME SIDE AND THEY DO HAVE 1387 01:21:35,847 --> 01:21:38,649 GENOMES AND THEY'RE TOTALLY 1388 01:21:38,649 --> 01:21:38,916 DIFFERENT. 1389 01:21:38,916 --> 01:21:40,084 IN EACH THEY'RE 70% OF THE GENES 1390 01:21:40,084 --> 01:21:42,720 FOR WHICH WE HAVE NO IDEA OF 1391 01:21:42,720 --> 01:21:48,559 WHAT THEY ARE DOING AND DO NOT 1392 01:21:48,559 --> 01:21:52,096 RESEMBLE ANYTHING AND YOU CAN 1393 01:21:52,096 --> 01:21:53,398 ACCUMULATE AND THEY CORRESPOND 1394 01:21:53,398 --> 01:21:55,299 TO FUNCTION AND WE HAVE NO IDEA 1395 01:21:55,299 --> 01:22:00,071 WHAT THEY ARE YET OF THOSE GENES 1396 01:22:00,071 --> 01:22:02,507 AND PROTEINS MEANT TO DO THE 1397 01:22:02,507 --> 01:22:07,812 SAME THING IN THE FUNCTION 1398 01:22:07,812 --> 01:22:13,718 PROTEIN WHICH MEANS THUS WE 1399 01:22:13,718 --> 01:22:18,923 EXPECT TO DO DISCOVER AND 1400 01:22:18,923 --> 01:22:22,193 UNDERSTANDING THE STRATEGIES 1401 01:22:22,193 --> 01:22:23,628 DIFFERENT BUT IN BETWEEN THE 1402 01:22:23,628 --> 01:22:30,201 DIFFERENT FAMILIES OF VIRUSES. 1403 01:22:30,201 --> 01:22:32,804 HERE ARE THE PEOPLE IN THE LAB 1404 01:22:32,804 --> 01:22:37,475 WHO I'VE BEEN WORKING WITH IN 1405 01:22:37,475 --> 01:22:38,676 THE FIELD AND THIS IS THEY 1406 01:22:38,676 --> 01:22:44,482 DEVELOPED THE GENETICS IN THE 1407 01:22:44,482 --> 01:22:55,026 LAB AND WE WORKED ON THE LAB AND 1408 01:22:56,861 --> 01:23:01,165 I WANT TO THANK ALL THE PEOPLE 1409 01:23:01,165 --> 01:23:06,437 WITH WHICH WE'VE BEEN 1410 01:23:06,437 --> 01:23:16,948 COLLABORATING AND THE LAB AND 1411 01:23:18,716 --> 01:23:29,360 THE DETERMINATION AND BEING ABLE 1412 01:23:29,360 --> 01:23:30,061 TO LOOK AT THE DATA AND THANK 1413 01:23:30,061 --> 01:23:40,471 YOU FOR YOUR ATTENTION. 1414 01:23:43,641 --> 01:23:46,210 I THINK I WAS VERY FAST. 1415 01:23:46,210 --> 01:23:52,183 >> ANY QUESTIONS? 1416 01:23:52,183 --> 01:23:54,752 CHANTAL, I WAS WONDERING WHETHER 1417 01:23:54,752 --> 01:23:58,389 THE HISTONES ENCODED BY THE 1418 01:23:58,389 --> 01:24:02,760 VIRUSES ARE SIMILAR OR DIFFERENT 1419 01:24:02,760 --> 01:24:04,028 TO THE HISTONES. 1420 01:24:04,028 --> 01:24:04,962 >> VERY SIMILAR. 1421 01:24:04,962 --> 01:24:15,439 YOU CAN ALIGN THEM TOGETHER. 1422 01:24:16,140 --> 01:24:16,774 >> THANKS. 1423 01:24:16,774 --> 01:24:22,213 >> HI, CHANTAL. 1424 01:24:22,213 --> 01:24:22,647 >> HI. 1425 01:24:22,647 --> 01:24:26,183 >> WHAT ARE YOUR THOUGHTS ON HOW 1426 01:24:26,183 --> 01:24:27,718 THESE THINGS EVOLVED? 1427 01:24:27,718 --> 01:24:30,087 YOU MADE IT SOUND LIKE IT'S A 1428 01:24:30,087 --> 01:24:32,189 SEPARATE BRANCH OF LIFE OR THEY 1429 01:24:32,189 --> 01:24:34,058 DON'T HAVE ANY KIND OF -- DO 1430 01:24:34,058 --> 01:24:37,061 THEY INTERFACE AT ALL WITH THE 1431 01:24:37,061 --> 01:24:39,163 EUKARYOTIC GENOMES, DO THEY 1432 01:24:39,163 --> 01:24:40,064 INTEGRATE OR RECOMBINE? 1433 01:24:40,064 --> 01:24:45,937 WHAT ARE YOUR THOUGHTS ON THAT? 1434 01:24:45,937 --> 01:24:48,472 VERY PHILOSOPHICALLY. 1435 01:24:48,472 --> 01:24:49,974 >> THANK YOU FOR THE QUESTION. 1436 01:24:49,974 --> 01:25:00,518 WE CAN SEE PIECES OF THE GENOME 1437 01:25:05,356 --> 01:25:07,425 AND MANY WITH THE COST AND 1438 01:25:07,425 --> 01:25:12,997 THERE'S TWO PROCESSES THAT WORK. 1439 01:25:12,997 --> 01:25:23,541 ONE VIRUS AND OBVIOUSLY THERE'S 1440 01:25:32,316 --> 01:25:36,854 SOME ACQUISITION OF GENES BUT 1441 01:25:36,854 --> 01:25:43,995 ALSO SOME LOSS OF GENES AND THE 1442 01:25:43,995 --> 01:25:47,365 VIRUS WILL BE ABLE TO MOVE THE 1443 01:25:47,365 --> 01:25:49,667 POLYMERASE FROM THE HOST AND 1444 01:25:49,667 --> 01:25:52,403 THIS NEED FOR KEEPING THE 1445 01:25:52,403 --> 01:25:56,641 POLYMERASE WILL BE DECREASED. 1446 01:25:56,641 --> 01:26:01,445 THERE ARE TWO WAYS. 1447 01:26:01,445 --> 01:26:04,081 IN THE CASE OF THE FAMILIES 1448 01:26:04,081 --> 01:26:10,388 THEY'RE ABLE TO CREATE GENES AND 1449 01:26:10,388 --> 01:26:13,491 I CAN SEE AT SOME POINT THERE'S 1450 01:26:13,491 --> 01:26:17,328 TRANSCRIPTION AND TRANSLATION. 1451 01:26:17,328 --> 01:26:19,664 AND THIS IS POSSIBLE BECAUSE 1452 01:26:19,664 --> 01:26:22,633 THEY'RE PC RICH AND THEY'RE MORE 1453 01:26:22,633 --> 01:26:30,007 AWARE OF AP RICH GENOMES AND I 1454 01:26:30,007 --> 01:26:40,518 THINK THERE IS A STRONG AND SO 1455 01:26:40,518 --> 01:26:43,521 KEEP CHANGING TO WIN THE 1456 01:26:43,521 --> 01:26:49,427 COMPETITION AND THAT'S MOST 1457 01:26:49,427 --> 01:26:56,233 LIKELY WHY THEY HAVE THE 1458 01:26:56,233 --> 01:26:58,369 MACHINERY TO BE ABLE TO ADAPT TO 1459 01:26:58,369 --> 01:27:00,838 THE HOST ENVIRONMENT. 1460 01:27:00,838 --> 01:27:06,777 I HOPE I ANSWERED YOUR QUESTION. 1461 01:27:06,777 --> 01:27:07,912 >> ANYTHING ELSE? 1462 01:27:07,912 --> 01:27:08,612 THANK YOU, CHANTAL. 1463 01:27:08,612 --> 01:27:09,146 IT WAS FANTASTIC. 1464 01:27:09,146 --> 01:27:19,557 >> THANK YOU VERY MUCH. 1465 01:27:22,827 --> 01:27:24,528 >> LADIES AND GENTLEMEN, I'M 1466 01:27:24,528 --> 01:27:26,681 PLEASED TO ANNOUNCE A COFFEE BREAK. 1467 01:27:26,681 --> 01:27:30,251 SO OUR NEXT 1468 01:27:30,251 --> 01:27:33,121 SPEAKER NEEDS TO REAL 1469 01:27:33,121 --> 01:27:37,658 INTRODUCTION, DR. FAUCI WAS THE 1470 01:27:37,658 --> 01:27:44,999 DIRECTOR OF NIAID AND RETIRED 1471 01:27:44,999 --> 01:27:45,900 LAST DECEMBER FROM THE POSITION 1472 01:27:45,900 --> 01:27:47,068 AND CONTINUES TO HAVE AN 1473 01:27:47,068 --> 01:27:51,939 EXTREMELY BUSY SCHEDULE. 1474 01:27:51,939 --> 01:27:54,308 HE COULDN'T BE HERE TO PRESENT 1475 01:27:54,308 --> 01:27:58,513 THE TRIBUTE TO DR. SALZMAN BUT 1476 01:27:58,513 --> 01:28:08,923 AGREED TO HAVE A VIDEO. 1477 01:28:12,193 --> 01:28:13,928 >> THE IS TONY FAUCI. 1478 01:28:13,928 --> 01:28:19,534 I'M SORRY I CAN'T NOT BE THERE 1479 01:28:19,534 --> 01:28:24,639 BUT I HAVE THE HONOR OF PAYING 1480 01:28:24,639 --> 01:28:26,674 CONTRIBUTE TO NORMAN P. SALZMAN 1481 01:28:26,674 --> 01:28:28,743 THE NAMESAKE OF THE SYMPOSIUM. 1482 01:28:28,743 --> 01:28:30,311 IN THE NEXT FEW MINUTES I'LL 1483 01:28:30,311 --> 01:28:33,981 BRIEFLY SHARE HIGHLIGHTS OF THIS 1484 01:28:33,981 --> 01:28:34,749 EXTRAORDINARY 44-YEAR CAREER OF 1485 01:28:34,749 --> 01:28:40,321 NORMAN. 1486 01:28:40,321 --> 01:28:44,659 NORMAN WAS BORN IN MANHATTAN IN 1487 01:28:44,659 --> 01:28:46,627 AUGUST 1926 GRADUATED FROM THE 1488 01:28:46,627 --> 01:28:47,762 CITY COLLEGE OF NEW YORK AND 1489 01:28:47,762 --> 01:28:50,998 RECEIVED A MASTER'S IN BIO 1490 01:28:50,998 --> 01:28:53,401 CHEMISTRY FROM THE UNIVERSITY OF 1491 01:28:53,401 --> 01:28:53,668 MICHIGAN. 1492 01:28:53,668 --> 01:28:55,102 HE EARNED HIS DEGREE FROM 1493 01:28:55,102 --> 01:28:58,639 UNIVERSITY OF ILLINOIS IN 1953. 1494 01:28:58,639 --> 01:29:00,875 DIRECTLY AFTER RECEIVING HIS 1495 01:29:00,875 --> 01:29:03,110 Ph.D. HE CAME TO THE NIH WHERE 1496 01:29:03,110 --> 01:29:04,912 HE WOULD SPEND THE NEXT 33 1497 01:29:04,912 --> 01:29:05,112 YEARS. 1498 01:29:05,112 --> 01:29:07,582 HE FIRST JOINED WHAT WAS THEN AT 1499 01:29:07,582 --> 01:29:08,483 THE NATIONAL HEART INSTITUTE 1500 01:29:08,483 --> 01:29:13,588 WHERE HE WORKED IN THE 1501 01:29:13,588 --> 01:29:15,923 LABORATORY OF CHEMICAL 1502 01:29:15,923 --> 01:29:16,257 PHARMACOLOGY. 1503 01:29:16,257 --> 01:29:19,560 IN 1961 HE MOVED TO MY FORMER 1504 01:29:19,560 --> 01:29:20,094 INSTITUTE, THE NATIONAL 1505 01:29:20,094 --> 01:29:22,296 INSTITUTE OF ALLERGY AND IN 1506 01:29:22,296 --> 01:29:26,267 INFECTIOUS DISEASES TO HEAD THE 1507 01:29:26,267 --> 01:29:27,168 CELL BIOLOGY IN THE LABORATORY 1508 01:29:27,168 --> 01:29:28,870 OF THE VIRUSES AND SIX YEARS 1509 01:29:28,870 --> 01:29:31,138 LATER PROMOTED TO CHIEF OF THAT 1510 01:29:31,138 --> 01:29:31,439 LABORATORY. 1511 01:29:31,439 --> 01:29:33,441 DURING THE NEARLY TWO DECADES IN 1512 01:29:33,441 --> 01:29:39,080 THIS POSITION HE ATTRACTED MANY 1513 01:29:39,080 --> 01:29:41,115 INNOVATIVE SCIENTISTS TO WORK 1514 01:29:41,115 --> 01:29:42,149 WITH HIM. 1515 01:29:42,149 --> 01:29:46,521 WHEN I FIRST ARRIVED AS A 1516 01:29:46,521 --> 01:29:48,890 CLINICAL SOCIETY IN INTERNAL 1517 01:29:48,890 --> 01:29:50,558 MEDICINE HE WAS AN ICONIC FIGURE 1518 01:29:50,558 --> 01:29:52,927 IB VIROLOGY FOR THE WORK HE WAS 1519 01:29:52,927 --> 01:29:55,496 DOING AND WAS A GOOD FRIEND OF 1520 01:29:55,496 --> 01:29:59,967 MY MENTOR DR. SHELDON WOLF 1521 01:29:59,967 --> 01:30:07,441 CLINICAL DIRECTOR OF NIBIB. 1522 01:30:07,441 --> 01:30:10,611 IT'S IMPORTANT TO REMEMBER THE 1523 01:30:10,611 --> 01:30:11,779 SCIENTISTS ON WHOSE SHOULDERS 1524 01:30:11,779 --> 01:30:14,849 THE FIELD OF VIROLOGY STANDS 1525 01:30:14,849 --> 01:30:16,217 THOSE WHO LAID DOWN THE 1526 01:30:16,217 --> 01:30:18,719 FOUNDATION FOR VIROLOGY RESEARCH 1527 01:30:18,719 --> 01:30:22,590 AND SET NIAID ON THE PATH TO 1528 01:30:22,590 --> 01:30:25,059 BECOME THE RESEARCH POWERHOUSE 1529 01:30:25,059 --> 01:30:27,094 IN INFECTIOUS DISEASES IT IS 1530 01:30:27,094 --> 01:30:27,295 TODAY. 1531 01:30:27,295 --> 01:30:32,934 NORM IS ONE SUCH GIANT. 1532 01:30:32,934 --> 01:30:34,802 WHEN HE CAME TO THE NIH AFTER 1533 01:30:34,802 --> 01:30:37,438 DISCOVERING HOW TO GROW VIRUSES 1534 01:30:37,438 --> 01:30:39,106 IN THE LABORATORY AND AUTHORITY 1535 01:30:39,106 --> 01:30:40,508 IN THE CHEMISTRY OF VIRUSES HE 1536 01:30:40,508 --> 01:30:43,277 WAS INTERESTED IN UNDERSTANDING 1537 01:30:43,277 --> 01:30:46,013 THE GENETIC BASIS FOR ACUTE AND 1538 01:30:46,013 --> 01:30:47,181 VIRAL INFECTIONS AS WELL AS FOR 1539 01:30:47,181 --> 01:30:52,019 MALIGNANT FRANCE -- 1540 01:30:52,019 --> 01:30:52,687 TRANSFORMATION AND CONDUCTED 1541 01:30:52,687 --> 01:30:57,058 RESEARCH ON THE VIRUSES OF 1542 01:30:57,058 --> 01:30:57,558 VIRU 1543 01:30:57,558 --> 01:30:57,792 VIRUSES. 1544 01:30:57,792 --> 01:30:59,894 AND TO DETERMINE WHAT STEPS IN 1545 01:30:59,894 --> 01:31:02,296 THE LIFE CYCLE OF A VIRUS 1546 01:31:02,296 --> 01:31:09,070 SELECTED ANTIVIRONES MAY BE 1547 01:31:09,070 --> 01:31:11,138 TARGET AND INVESTIGATED SMALLPOX 1548 01:31:11,138 --> 01:31:11,505 VACCINES. 1549 01:31:11,505 --> 01:31:13,541 HE WAS AMONG THE FIRST 1550 01:31:13,541 --> 01:31:16,177 SCIENTISTS TO CAPTURE ELECTRONIC 1551 01:31:16,177 --> 01:31:19,947 MICROSCOPIC IMAGES OF REP 1552 01:31:19,947 --> 01:31:22,950 INDICATING VIRAL DNA MOLECULES 1553 01:31:22,950 --> 01:31:27,021 AND WORKED ON SD40 AND 1554 01:31:27,021 --> 01:31:28,422 INCREASINGLY FOCUSSED ON TUMOR 1555 01:31:28,422 --> 01:31:30,591 VIRUSES AND INVESTIGATING THE 1556 01:31:30,591 --> 01:31:31,525 MECHANISMS BY WHICH VIRUSES 1557 01:31:31,525 --> 01:31:32,460 CAUSE CANCER. 1558 01:31:32,460 --> 01:31:35,529 IN ADDITION TO HIS RESEARCH 1559 01:31:35,529 --> 01:31:36,464 ACCOMPLISHMENTS, NORM GAINED AN 1560 01:31:36,464 --> 01:31:38,099 INTERNATIONAL REPUTATION IN PART 1561 01:31:38,099 --> 01:31:44,905 BECAUSE IN 1966 AS SHOWN IN THIS 1562 01:31:44,905 --> 01:31:52,113 PHOTO, NORM DR. KOZLOF AND 1563 01:31:52,113 --> 01:31:54,882 OTHERS FOUND THE JOURNAL OF 1564 01:31:54,882 --> 01:31:55,149 VIROLOGY. 1565 01:31:55,149 --> 01:31:57,451 TO THIS DAY IT'S A TOP-RANKED 1566 01:31:57,451 --> 01:31:58,019 VIROLOGY JOURNAL. 1567 01:31:58,019 --> 01:32:00,788 AS RESULT OF HIS LEADERSHIP AND 1568 01:32:00,788 --> 01:32:01,889 THE INTERNATIONAL STATURE THAT 1569 01:32:01,889 --> 01:32:03,491 HIS LABORATORY ACHIEVED IN 1570 01:32:03,491 --> 01:32:08,496 VIROLOGY AND IN CELL BIOLOGY 1571 01:32:08,496 --> 01:32:15,069 RESEARCH FORM WAS SELECTED FOR 1572 01:32:15,069 --> 01:32:19,707 THE SUPERIOR SERVICE AWARD IN 1573 01:32:19,707 --> 01:32:19,907 1983. 1574 01:32:19,907 --> 01:32:25,946 SOON AFTER I BECAME CHIEF THIS 1575 01:32:25,946 --> 01:32:32,620 WAS THE FIRST CASE OF HIV/AIDS 1576 01:32:32,620 --> 01:32:35,990 OF MORBIDITY AND MORTALITY AND 1577 01:32:35,990 --> 01:32:38,125 AFFECTED NORM AND IN MY OWN 1578 01:32:38,125 --> 01:32:38,359 CAREER. 1579 01:32:38,359 --> 01:32:41,395 THIS PHOTO FROM THE MID 1980s 1580 01:32:41,395 --> 01:32:44,665 SHOWS THE NIAID LABORATORY 1581 01:32:44,665 --> 01:32:47,334 CHIEFS AT THE TIME WITH NORM 1582 01:32:47,334 --> 01:32:49,970 PICTURED SLIGHTLY TO THE RIGHT 1583 01:32:49,970 --> 01:32:52,506 OF CENTER NEXT TO BILL, PAUL AND 1584 01:32:52,506 --> 01:32:57,778 ME AT THE FAR LEFT. 1585 01:32:57,778 --> 01:33:00,014 GOING BACK TO THE PRIOR SLIDE NO 1586 01:33:00,014 --> 01:33:03,517 SURPRISE BUT GREAT LOSS TO 1587 01:33:03,517 --> 01:33:06,087 NIAAID IN 1986 GORGETOWN 1588 01:33:06,087 --> 01:33:07,588 UNIVERSITY SUCCESSFULLY 1589 01:33:07,588 --> 01:33:09,290 RECRUITED NORM TO MOVE HEADLONG 1590 01:33:09,290 --> 01:33:14,128 TO AIDS RESEARCH BY LEADING THE 1591 01:33:14,128 --> 01:33:16,130 MOLECULAR VIRAL LABORATORY THERE 1592 01:33:16,130 --> 01:33:18,265 AND HE AND HIS LABORATORY GROUP 1593 01:33:18,265 --> 01:33:20,434 FOCUSSED ON EVALUATING POTENTIAL 1594 01:33:20,434 --> 01:33:25,239 VACCINES FOR HIV/AIDS. 1595 01:33:25,239 --> 01:33:31,345 IN THE EARLY YEARS OF THE HIV 1596 01:33:31,345 --> 01:33:33,013 EPIDEMIC WE COLLABORATED WITH 1597 01:33:33,013 --> 01:33:35,149 NORM'S LAB AND SHOWN ARE TWO 1598 01:33:35,149 --> 01:33:37,318 PUBLICATIONS RESULT FROM THE 1599 01:33:37,318 --> 01:33:37,752 COLLABORATIONS. 1600 01:33:37,752 --> 01:33:42,623 THE FIRST PAPER THE FOURTH MOST 1601 01:33:42,623 --> 01:33:45,659 CITED AIDS RESEARCH PAPER IN 1602 01:33:45,659 --> 01:33:47,061 1989 DESCRIBED THE FIRST HIV 1603 01:33:47,061 --> 01:33:50,331 RESERVOIR IN THE BLOOD. 1604 01:33:50,331 --> 01:33:53,768 IN 1994, NORM WAS RECRUITED TO 1605 01:33:53,768 --> 01:33:56,837 HEAD THE LABORATORY OF MOLECULAR 1606 01:33:56,837 --> 01:34:00,875 RETRO VIROLOGY AT THE FREDERICK 1607 01:34:00,875 --> 01:34:05,412 CANCER RESEARCH CENTER FORT 1608 01:34:05,412 --> 01:34:07,348 DETRICK A POSITION HE HELD THE 1609 01:34:07,348 --> 01:34:09,416 LAST FOUR YEARS OF HIS CAREER. 1610 01:34:09,416 --> 01:34:10,751 HIS POSITIVE INFLUENCE ON THE 1611 01:34:10,751 --> 01:34:12,620 FIELD OF VIROLOGY REMAINS STRONG 1612 01:34:12,620 --> 01:34:13,420 TO THIS DAY. 1613 01:34:13,420 --> 01:34:16,724 AMONG THE LARGE NUMBER OF 1614 01:34:16,724 --> 01:34:17,658 SCIENTISTS AND PHYSICIAN 1615 01:34:17,658 --> 01:34:19,727 SCIENTISTS HE TRAINED AS LISTED 1616 01:34:19,727 --> 01:34:22,496 ON THE SLIDE AMONG THOSE WHO 1617 01:34:22,496 --> 01:34:24,965 BENEFIT FROM THE GENEROSITY AND 1618 01:34:24,965 --> 01:34:26,500 WISDOM OF HIS MENTORSHIP, MANY 1619 01:34:26,500 --> 01:34:29,436 HAVE GONE ON TO DISTINGUISHED 1620 01:34:29,436 --> 01:34:31,071 CAREERS AT NIH AND OTHER 1621 01:34:31,071 --> 01:34:35,342 RESEARCH INSTITUTIONS. 1622 01:34:35,342 --> 01:34:37,311 IN THE UNITED STATES AND ABROAD 1623 01:34:37,311 --> 01:34:39,914 IT'S A QUALITY AND STROKE OF HIS 1624 01:34:39,914 --> 01:34:41,382 MENTORSHIP ONE MENTEE RECEIVED A 1625 01:34:41,382 --> 01:34:43,083 NOBEL PRIZE AND SEVERAL HAVE 1626 01:34:43,083 --> 01:34:44,618 BEEN ELECTED TO THE NATIONAL 1627 01:34:44,618 --> 01:34:46,320 ACADEMY OF SCIENCES. 1628 01:34:46,320 --> 01:34:54,061 BEFORE I CKCONCLUDE I WANT TO 1629 01:34:54,061 --> 01:34:57,198 THANK LENNOR SALZMAN FOR SERVING 1630 01:34:57,198 --> 01:34:57,898 ON THE ORGANIZING COMMITTEE FOR 1631 01:34:57,898 --> 01:35:01,001 THE SIM POEM WAS FOR EACH OF THE 1632 01:35:01,001 --> 01:35:03,237 PAST 25 YEARS THAT IT HAS BEEN 1633 01:35:03,237 --> 01:35:03,871 HELD. 1634 01:35:03,871 --> 01:35:14,381 MY SINCERE THANKS, LINER AND 1635 01:35:15,349 --> 01:35:16,283 PLEASE ENJOY THE REST OF THE 1636 01:35:16,283 --> 01:35:16,517 MEETING. 1637 01:35:16,517 --> 01:35:26,861 THANK YOU VERY MUCH. 1638 01:35:27,561 --> 01:35:37,671 >> LENNOR. 1639 01:35:41,442 --> 01:35:44,078 >> GOOD MORNING AND WELCOME. 1640 01:35:44,078 --> 01:35:46,180 I'M HONORED TODAY TO BE HERE 1641 01:35:46,180 --> 01:35:50,684 WITH THIS ILLUSTRIOUS GROUP OF 1642 01:35:50,684 --> 01:35:54,021 SCIENTIST TO CELEBRATE THE 25th 1643 01:35:54,021 --> 01:35:56,123 ANNIVERSARY OF THE NORMAN P. 1644 01:35:56,123 --> 01:35:58,726 SALZMAN MEMORIAL AND SYMPOSIUM 1645 01:35:58,726 --> 01:36:02,763 IN BASIC AND CLINICAL VIROLOGY. 1646 01:36:02,763 --> 01:36:04,865 THIS IS THE FIRST TIME THE 1647 01:36:04,865 --> 01:36:06,567 SYMPOSIUM WILL BE LIVE HERE AT 1648 01:36:06,567 --> 01:36:15,676 THE LIPSETT AUDITORIUM. 1649 01:36:15,676 --> 01:36:18,078 200 REGISTERED AND EUROPE AND 1650 01:36:18,078 --> 01:36:19,113 180 REGISTERED. 1651 01:36:19,113 --> 01:36:27,054 THAT IS A BIG NUMBER. 1652 01:36:27,054 --> 01:36:29,957 FOR ME PERSONALLY THE EVENT IS A 1653 01:36:29,957 --> 01:36:32,426 TESTIMONY TO NORMAN'S DEVOTION 1654 01:36:32,426 --> 01:36:34,395 TO HIS SCIENTIFIC AND MENTORING 1655 01:36:34,395 --> 01:36:38,632 WORK AND TO OTHERS WHO WORK WITH 1656 01:36:38,632 --> 01:36:44,538 HIM TO CONTINUE THE HIGHEST 1657 01:36:44,538 --> 01:36:46,774 STANDARDS FOR ORIGINAL AND 1658 01:36:46,774 --> 01:36:47,308 MERITORIOUS WORK IN ALL 1659 01:36:47,308 --> 01:36:51,078 SCIENTIFIC EXPLORATION. 1660 01:36:51,078 --> 01:36:53,948 MORE ABOUT THAT IN A MINUTE. 1661 01:36:53,948 --> 01:36:59,486 THIS IS MY TIME TO SAY THANK YOU 1662 01:36:59,486 --> 01:37:03,490 TO DR. JULIE GERBERDING WHO IS 1663 01:37:03,490 --> 01:37:07,528 SITTING HERE WHEN SHE ARRIVED 1664 01:37:07,528 --> 01:37:09,630 EARLIER IN THE SYMPOSIUM. 1665 01:37:09,630 --> 01:37:10,764 OUR LONG ASSOCIATION AND SUPPORT 1666 01:37:10,764 --> 01:37:13,033 FOR THE SUPPORT FOR THE 1667 01:37:13,033 --> 01:37:15,069 FOUNDATION FOR NIH MADE THE 1668 01:37:15,069 --> 01:37:20,541 CONTINUATION OF THE NORMAN 1669 01:37:20,541 --> 01:37:22,710 SYMPOSIUM AND AWARD POSSIBLE FOR 1670 01:37:22,710 --> 01:37:25,179 THE LAST 25 YEARS. 1671 01:37:25,179 --> 01:37:26,513 OUR GRATITUDE. 1672 01:37:26,513 --> 01:37:33,921 TO THE EVENT STOP JENNEL LEWIS 1673 01:37:33,921 --> 01:37:37,524 AND ASHLEY SPOLEL AND TO 1674 01:37:37,524 --> 01:37:40,394 DR. ANTHONY FAUCI TO YOUR 1675 01:37:40,394 --> 01:37:42,162 CONTRIBUTE TO NORMAN WHEN HE WAS 1676 01:37:42,162 --> 01:37:44,798 CHIEF OF THE LABORATORY OF 1677 01:37:44,798 --> 01:37:45,366 VIRUSES. 1678 01:37:45,366 --> 01:37:50,738 REMEMBERING ALL HIS ACHIEVEMENTS 1679 01:37:50,738 --> 01:37:56,443 OVER THE YEARS. 1680 01:37:56,443 --> 01:37:59,680 THEY VISED ME AND HUGE THANK TO 1681 01:37:59,680 --> 01:38:01,548 THE ORGANIZING COMMITTEE AND 1682 01:38:01,548 --> 01:38:02,549 VIROLOGY INTEREST GROUP FOR 1683 01:38:02,549 --> 01:38:08,489 THEIR SUPPORT IN MAKE THE 1684 01:38:08,489 --> 01:38:10,557 SYMPOSIUM A SUCCESS CINCINNATI 1685 01:38:10,557 --> 01:38:14,528 1998. 1686 01:38:14,528 --> 01:38:16,697 -- SINCE 1998. 1687 01:38:16,697 --> 01:38:21,235 ON DECEMBER 11, 2023 IT WILL BE 1688 01:38:21,235 --> 01:38:26,940 26 YEARS SINCE THE DEATH OF 1689 01:38:26,940 --> 01:38:32,513 NORMAN SALZMAN. 1690 01:38:32,513 --> 01:38:35,082 SIX WEEKS AFTER HE WAS DIAGNOSED 1691 01:38:35,082 --> 01:38:39,086 WITH ASYMPTOMATIC PANCREATIC 1692 01:38:39,086 --> 01:38:41,188 CANCER. 1693 01:38:41,188 --> 01:38:42,990 DURING A BITTER COLD DECEMBER 1694 01:38:42,990 --> 01:38:46,827 DAY, NORMAN SAT OUTSIDE IN HIS 1695 01:38:46,827 --> 01:38:52,566 BELOVED GARDEN CONSIDERING HIS 1696 01:38:52,566 --> 01:38:54,535 LIFE AND CONTRIBUTION TO 1697 01:38:54,535 --> 01:38:59,373 VIROLOGY. 1698 01:38:59,373 --> 01:39:01,341 NOW, THERE ARE MORE THANK YOUS. 1699 01:39:01,341 --> 01:39:04,244 I WANT TO HAVE A SPECIAL THANK 1700 01:39:04,244 --> 01:39:08,215 YOU FOR DR. CHARLIE ROSE FOR HIS 1701 01:39:08,215 --> 01:39:09,750 TALK THIS MORNING. 1702 01:39:09,750 --> 01:39:14,121 I WISH I COULD UNDERSTAND A LOT 1703 01:39:14,121 --> 01:39:16,523 OF IT BUT I'M A SPEECH 1704 01:39:16,523 --> 01:39:21,628 PATHOLOGIST NOT A SCIENTIST. 1705 01:39:21,628 --> 01:39:27,234 FOR ALL THE TALKS TO COME, I 1706 01:39:27,234 --> 01:39:31,772 THANK YOU ALL FOR BEING HERE AND 1707 01:39:31,772 --> 01:39:34,741 MAKING THIS IS SYMPOSIUM ANOTHER 1708 01:39:34,741 --> 01:39:35,642 SUCCESS THIS YEAR. 1709 01:39:35,642 --> 01:39:39,079 26 YEARS LATER IT'S MY HONOR AND 1710 01:39:39,079 --> 01:39:43,117 PLEASURE TO PRESENT THE NORMAN 1711 01:39:43,117 --> 01:39:45,486 SALZMAN POST-DOCTORAL MEMORIAL 1712 01:39:45,486 --> 01:39:49,423 AWARD TO ALBERTO D. LOPEZ MUÑOZ, 1713 01:39:49,423 --> 01:39:55,062 Ph.D. AND HIS MENTOR, 1714 01:39:55,062 --> 01:39:56,163 DR. JONATHAN UDEL. 1715 01:39:56,163 --> 01:39:59,066 DO WE HAVE A SLIDE? 1716 01:39:59,066 --> 01:39:59,333 OH, GOOD. 1717 01:39:59,333 --> 01:40:06,573 THANK YOU. 1718 01:40:06,573 --> 01:40:10,144 WITH THIS CHECK COMES A CHECKS 1719 01:40:10,144 --> 01:40:19,052 OF $2,500 AND A PLAQUE FOR 1720 01:40:19,052 --> 01:40:29,263 DR. MUÑOZ AS WELL AS A PLAQUE 1721 01:40:29,263 --> 01:40:29,596 FOR DR. UDEL. 1722 01:40:29,596 --> 01:40:32,699 THE CHECK WILL BE SENT FROM THE 1723 01:40:32,699 --> 01:40:33,901 SALZMAN FUND FROM THE FOUNDATION 1724 01:40:33,901 --> 01:40:41,675 AT NIH AND I WAS TOLD THAT THE 1725 01:40:41,675 --> 01:40:51,985 PLAQUES WERE HERE. 1726 01:41:07,067 --> 01:41:10,604 THE FIRST SLIDE I'D LIKE TO HAVE 1727 01:41:10,604 --> 01:41:15,976 IS FOR DR. JONATHAN UDEL. 1728 01:41:15,976 --> 01:41:26,353 DO WE HAVE THAT SLIDE? 1729 01:41:29,489 --> 01:41:32,926 CHIEF CELLULAR BIOLOGY SECTION, 1730 01:41:32,926 --> 01:41:35,162 LABORATORY OF VIRAL DISEASES, 1731 01:41:35,162 --> 01:41:37,497 NATIONAL INSTITUTE OF ALLERGY 1732 01:41:37,497 --> 01:41:39,499 AND IN FEN HOUSE DISEASES, 1733 01:41:39,499 --> 01:41:41,435 NATIONAL INSTITUTES OF HEALTH -- 1734 01:41:41,435 --> 01:41:42,769 INFECTIOUS DISEASES AND NATIONAL 1735 01:41:42,769 --> 01:41:47,007 INSTITUTES OF HEALTH, DR. UDEL 1736 01:41:47,007 --> 01:41:55,649 M.D., Ph.D. MENTOR TO ALBE ALBE 1737 01:41:55,649 --> 01:41:59,419 MUNOZ FOR CAPSID PROTEIN 1738 01:41:59,419 --> 01:42:04,658 EXPRESSION A CORONAVIRUS VIRUS 1739 01:42:04,658 --> 01:42:13,066 FOR IMMUNOAND I'D LIKE TO 1740 01:42:13,066 --> 01:42:19,172 PRESENT THE PLAQUE TO DR 1741 01:42:19,172 --> 01:42:26,613 DR. YEWDELL. 1742 01:42:26,613 --> 01:42:28,348 I WAS GOING TO ASK YOU TO COME 1743 01:42:28,348 --> 01:42:28,682 TO THE PODIUM. 1744 01:42:28,682 --> 01:42:39,059 >> THANK YOU SO MUCH. 1745 01:43:06,119 --> 01:43:08,021 I'LL READ THIS AND PLEASE COME 1746 01:43:08,021 --> 01:43:12,426 TO THE PODIUM THE WINNER OF THE 1747 01:43:12,426 --> 01:43:18,899 SALZMAN AWARD, ALBERTO D. LOPEZ 1748 01:43:18,899 --> 01:43:22,636 MUÑOZ IN RECOGNITION FOR HIS 1749 01:43:22,636 --> 01:43:33,180 COULD, ENTITLED SURFACED CAPSID 1750 01:43:33,847 --> 01:43:34,648 NUCLEODILATION MENTORED BY 1751 01:43:34,648 --> 01:43:41,321 DR. YEWDELL AND CHIEF CELLULAR 1752 01:43:41,321 --> 01:43:43,156 BIOLOGY SECTION AND LABORATORY 1753 01:43:43,156 --> 01:43:49,563 OF VIRAL DISEASES AND NATIONAL 1754 01:43:49,563 --> 01:43:50,330 INSTITUTE OF INFECTIOUS 1755 01:43:50,330 --> 01:43:53,967 DISEASES, NIH. 1756 01:43:53,967 --> 01:44:04,311 HERE'S THIS PLAQUE. 1757 01:44:07,848 --> 01:44:18,058 CONGRATULATIONS. 1758 01:44:35,142 --> 01:44:40,313 WE HAVE A LOT OF BIO GRAPHICAL 1759 01:44:40,313 --> 01:44:46,019 DATA IN THE PROGRAM THAT'S 1760 01:44:46,019 --> 01:44:46,987 PRESENTED TO YOU TODAY SO I 1761 01:44:46,987 --> 01:44:57,531 WON'T GO INTO THAT EXCEPT TO SAY 1762 01:45:05,672 --> 01:45:16,149 THAT DR. ANTONIO LOPEZ MUNOZ IS 1763 01:45:16,716 --> 01:45:19,753 SERVING IN THE ASSOCIATION OF 1764 01:45:19,753 --> 01:45:21,855 SPANISH SCIENTISTS IN THE UNITED 1765 01:45:21,855 --> 01:45:26,259 STATES AND DR. MUÑOZ TOLD ME HIS 1766 01:45:26,259 --> 01:45:29,062 INSPIRATION TO BECOME A DOCTOR 1767 01:45:29,062 --> 01:45:30,464 CAME FROM THE NAME OF THE STREET 1768 01:45:30,464 --> 01:45:34,000 HE LIVED ON AS A YOUNG BOY. 1769 01:45:34,000 --> 01:45:35,068 THE STREET WAS NAMED DR. FLEMING 1770 01:45:35,068 --> 01:45:41,475 STREET. 1771 01:45:41,475 --> 01:45:44,411 IT'S MY PLEASURE TO PRESENT 1772 01:45:44,411 --> 01:45:54,888 DR. ANTONIO LOPEZ MUNOZ TO 1773 01:45:56,223 --> 01:45:57,958 PRESENT HIS LECTURE AND WE HAVE 1774 01:45:57,958 --> 01:45:58,391 THAT ON THE PLAQUE. 1775 01:45:58,391 --> 01:46:08,568 THANK YOU. 1776 01:46:19,145 --> 01:46:25,652 >> ALL RIGHT THEN. 1777 01:46:25,652 --> 01:46:28,355 THIRST, MRS. SALZMAN THANK YOU. 1778 01:46:28,355 --> 01:46:32,058 MY NAME IS ALBERTO LOPEZ AND 1779 01:46:32,058 --> 01:46:34,060 IT'S A PRIVILEGE TO ACKNOWLEDGE 1780 01:46:34,060 --> 01:46:39,666 THE MEMORY OF DR. SALZMAN BY 1781 01:46:39,666 --> 01:46:42,002 SHARING THE AMAZING SCIENCE FROM 1782 01:46:42,002 --> 01:46:47,073 THE LABORATORY OF DISEASES. 1783 01:46:47,073 --> 01:46:57,617 I'LL TALK ABOUT THE MODULATORY 1784 01:47:01,488 --> 01:47:03,690 ROLE OF THIS HAS FASCINATED ME 1785 01:47:03,690 --> 01:47:10,564 AS A STUDENT BACK IN SPAIN. 1786 01:47:10,564 --> 01:47:14,367 LARGE DNA VIRUSES AND HERPES 1787 01:47:14,367 --> 01:47:19,072 VIRUSES HAVE INVESTED A HUGE 1788 01:47:19,072 --> 01:47:27,047 DEAL IN DEVELOPING THE CYTOKINE 1789 01:47:27,047 --> 01:47:34,654 RECEPTORS AND KECHEMOKINES AND 1790 01:47:34,654 --> 01:47:40,060 INVADING THE FIRST STAGE OF THE 1791 01:47:40,060 --> 01:47:41,361 HUMAN RESPONSE WITH THIS IN MIND 1792 01:47:41,361 --> 01:47:46,633 I WONDERED IF THERE WAS A 1793 01:47:46,633 --> 01:47:48,735 CYTOKINE BINDING PROCESS 1794 01:47:48,735 --> 01:47:51,438 DESCRIBED TO STUDY THESE PROTEIN 1795 01:47:51,438 --> 01:47:53,740 AND SARS COV2 VIRUS. 1796 01:47:53,740 --> 01:47:59,379 AFTER EXTENSIVE RESEARCH I FOUND 1797 01:47:59,379 --> 01:48:09,889 THERE WAS NOT THESE KINDS OF 1798 01:48:10,724 --> 01:48:14,160 PROTEINS BUT IT WAS USED BY BOTH 1799 01:48:14,160 --> 01:48:15,862 HUMAN AND ANIMAL CORONAVIRUSES. 1800 01:48:15,862 --> 01:48:24,270 THE PROTEINS IS USUALLY 1801 01:48:24,270 --> 01:48:25,405 INTERINTRINT 1802 01:48:25,405 --> 01:48:28,842 INTERCELLULAR PATHWAYS BLOCKING 1803 01:48:28,842 --> 01:48:39,185 AT DIFFERENT LEVELS. 1804 01:48:44,290 --> 01:48:48,495 I WOULD LIKE TO STATE WHAT WE 1805 01:48:48,495 --> 01:48:51,097 KNOW ABOUT THE INFECTION AND THE 1806 01:48:51,097 --> 01:48:56,403 MOST ABUNDANTLY EXPRESSED DURING 1807 01:48:56,403 --> 01:49:03,343 THE INFECTION AND PROTEIN BINDS 1808 01:49:03,343 --> 01:49:07,080 TO THE DNA AND IN TERMS OF 1809 01:49:07,080 --> 01:49:09,015 IMMUNE RESPONSE IS A MAJOR 1810 01:49:09,015 --> 01:49:10,650 TARGET FOR ANTIBODY RESPONSES 1811 01:49:10,650 --> 01:49:17,857 AND CONTAINS NUMEROUS EPITOPES. 1812 01:49:17,857 --> 01:49:27,067 AND LATER THE VACCINATION 1813 01:49:27,067 --> 01:49:35,709 CONTRIBUTES TO THE N PROTEIN TO 1814 01:49:35,709 --> 01:49:37,343 THE IMMUNITY AND CLEAR UP THE 1815 01:49:37,343 --> 01:49:38,945 INFECTION FOR A BETTER 1816 01:49:38,945 --> 01:49:39,212 PROGNOSIS. 1817 01:49:39,212 --> 01:49:44,517 WITH THIS IN MIND WE STARTED 1818 01:49:44,517 --> 01:49:54,994 DOING BASIC EXPERIMENTS AND 1819 01:49:59,466 --> 01:50:06,005 STAINING WITH IN SITU VIRUSES 1820 01:50:06,005 --> 01:50:12,979 AND WE SHOW THE CELL SURFACE 1821 01:50:12,979 --> 01:50:14,881 SPIKES IN RED FOR VIRUSES AS 1822 01:50:14,881 --> 01:50:16,649 WELL AS IN BOTH CASES AND 1823 01:50:16,649 --> 01:50:19,352 CONSISTENTLY WITH ALL THE OTHER 1824 01:50:19,352 --> 01:50:21,788 CELL WE TESTED WE FOUND A 1825 01:50:21,788 --> 01:50:27,060 DISTRIBUTION PATTERN FOR LIKE 1826 01:50:27,060 --> 01:50:30,497 THE NUCLEIC ACID OR PROTEIN IN 1827 01:50:30,497 --> 01:50:30,697 GREEN. 1828 01:50:30,697 --> 01:50:36,336 WE CONFIRMED BY FORMING THE SAME 1829 01:50:36,336 --> 01:50:39,072 EXPERIMENT BY FLOW CYTOMETRY AND 1830 01:50:39,072 --> 01:50:46,679 WE POSTINFECTION WE STAIN WITH 1831 01:50:46,679 --> 01:50:57,223 MONOCLONAL ANTIBODIES AND FOUND 1832 01:51:03,496 --> 01:51:06,833 THE HISTO GRAM WE FOND THE SPIKE 1833 01:51:06,833 --> 01:51:09,736 AND THE NUCLEIC ACID AND 1834 01:51:09,736 --> 01:51:12,705 CONFIRMED WHEN WE QUANTIFY THE 1835 01:51:12,705 --> 01:51:14,507 FLUORESCENT INTENSITY AGAINST 1836 01:51:14,507 --> 01:51:25,051 LIKE A MOCK INFECTION CONDITION. 1837 01:51:28,454 --> 01:51:30,290 WHERE HE USED THE EPITHELIAL 1838 01:51:30,290 --> 01:51:32,392 CELLS AND INFECTED THEM AND 1839 01:51:32,392 --> 01:51:37,197 THREE DAYS POST INFECTION BOTH 1840 01:51:37,197 --> 01:51:40,667 FOR SARS WE FOUND THE SPIKE ON 1841 01:51:40,667 --> 01:51:43,536 THE SURFACE OF SOME OF THESE 1842 01:51:43,536 --> 01:51:44,804 EPITHELIAL CELLS FOR A SPIKE AS 1843 01:51:44,804 --> 01:51:47,907 WELL AS FOR THE NUCLEIC ACID 1844 01:51:47,907 --> 01:51:49,409 PROTEIN AND MORE DISCREET IN THE 1845 01:51:49,409 --> 01:51:54,147 INFECTION STILL SIGNIFICANT. 1846 01:51:54,147 --> 01:51:57,050 WE UNDERSTOOD THIS COULD BE 1847 01:51:57,050 --> 01:51:58,484 HAPPENING IN A BREAK-THROUGH 1848 01:51:58,484 --> 01:52:03,690 INFECTION IN HUMANS. 1849 01:52:03,690 --> 01:52:06,860 WE ALSO WANTED TO UNDERSTAND HOW 1850 01:52:06,860 --> 01:52:12,999 THE END IS BEING SECRETED AND WE 1851 01:52:12,999 --> 01:52:17,503 CLONED THE M PROTEIN AND 1852 01:52:17,503 --> 01:52:19,205 DETERMINE IF OTHER FACTORS WERE 1853 01:52:19,205 --> 01:52:22,675 REQUIRED LIKE FOR THE M PROTEIN 1854 01:52:22,675 --> 01:52:30,083 BEING EXPRESSED OUTSIDE. 1855 01:52:30,083 --> 01:52:32,418 AND POST TRANSFECTION I STAINED 1856 01:52:32,418 --> 01:52:37,790 WITH THE ANTIBODIES AND YOU CAN 1857 01:52:37,790 --> 01:52:40,326 SEE WE OBSERVE FOR THE M PROTEIN 1858 01:52:40,326 --> 01:52:46,666 COMPARED TO A CONTROL 1859 01:52:46,666 --> 01:52:48,167 TRANSFECTION NO OTHER VIRAL 1860 01:52:48,167 --> 01:52:53,273 FACTORS ARE REQUIRED FOR HUMAN 1861 01:52:53,273 --> 01:52:54,173 CORONAVIRUS AND VIRUS 1862 01:52:54,173 --> 01:52:55,074 EXPRESSION. 1863 01:52:55,074 --> 01:52:58,211 WE CAN UNDERSTAND THERE IS 1864 01:52:58,211 --> 01:53:00,580 EXPRESSION IN THE CELL SURFACE 1865 01:53:00,580 --> 01:53:03,049 AND HOW IT'S BIND IS IS THE NEXT 1866 01:53:03,049 --> 01:53:12,792 QUESTION I WONDER. 1867 01:53:12,792 --> 01:53:16,896 THESE ARE WELL KNOWN FOR BEING 1868 01:53:16,896 --> 01:53:20,867 USED AS PRECEPTORS FOR THE 1869 01:53:20,867 --> 01:53:22,468 CORECEPTOR OR ATTACHMENT 1870 01:53:22,468 --> 01:53:23,069 FACTORS. 1871 01:53:23,069 --> 01:53:29,943 THIS ALLOWS US TO PERFORM 1872 01:53:29,943 --> 01:53:34,414 INTERACTION ASSAYS AND HERE I 1873 01:53:34,414 --> 01:53:40,420 EMBEDDED THE BIO CENSOR -- 1874 01:53:40,420 --> 01:53:44,490 SENSOR WITH DIFFERENT GLYCANS 1875 01:53:44,490 --> 01:53:54,968 AND THE HEPARIN WAS FOUND AND 1876 01:53:54,968 --> 01:54:03,910 THIS IS AND I COMPLETED THE 1877 01:54:03,910 --> 01:54:06,579 TREATMENT AND WHEN WE INCUBATE 1878 01:54:06,579 --> 01:54:11,818 THE CELLS UNTREATED WITH THE 1879 01:54:11,818 --> 01:54:13,786 PROTEIN THIS PROTEIN STICKS TO 1880 01:54:13,786 --> 01:54:24,297 THE CELL SURFACE AND HERE WE 1881 01:54:24,931 --> 01:54:28,901 REMOVED THE CELLS AND THESE 1882 01:54:28,901 --> 01:54:31,070 TREATED LOST THE ABILITY TO BIND 1883 01:54:31,070 --> 01:54:36,109 AND RETAIN THE PROTEIN ON THE 1884 01:54:36,109 --> 01:54:37,710 CELL SURFACE. 1885 01:54:37,710 --> 01:54:40,646 FOR THOSE THAT LIKE FLOW 1886 01:54:40,646 --> 01:54:45,752 CYTOMETRY YOU'LL NOTICE THE 1887 01:54:45,752 --> 01:54:46,619 INTERESTING OBSERVATION WE 1888 01:54:46,619 --> 01:54:47,653 OBSERV 1889 01:54:47,653 --> 01:54:51,057 OBSERVED ACROSS ALL CELL LINES 1890 01:54:51,057 --> 01:54:54,761 AND INFECT THE POPULATION OF 1891 01:54:54,761 --> 01:54:56,496 CELLS EXPRESSING ONLY M PROTEIN 1892 01:54:56,496 --> 01:54:58,698 BUT NOT SPIKE PROTEIN. 1893 01:54:58,698 --> 01:55:02,668 I RECALL THE CONVERSATION AND WE 1894 01:55:02,668 --> 01:55:05,972 THOUGHT PERHAPS THIS M PROTEIN 1895 01:55:05,972 --> 01:55:07,607 COULD BE TRANSFERRED TO THE 1896 01:55:07,607 --> 01:55:08,541 SURROUNDING CELLS THAT WERE NOT 1897 01:55:08,541 --> 01:55:18,785 YET INFECTED. 1898 01:55:18,785 --> 01:55:23,856 AND ASSIGNED IT AND WELL TURE 1899 01:55:23,856 --> 01:55:32,598 WITH RECIPIENT CELL AND THE 1900 01:55:32,598 --> 01:55:34,667 INEFFECTIVE CELLS WOULD BE 1901 01:55:34,667 --> 01:55:42,642 SUSCEPTIBLE FOR INSECTION AND 1902 01:55:42,642 --> 01:55:52,051 THIS RECIPIENT CELL POPULATION 1903 01:55:52,051 --> 01:55:54,053 TO ALLOW FLOW CYTOMETRY 1904 01:55:54,053 --> 01:55:55,054 SEPARATION. 1905 01:55:55,054 --> 01:55:58,691 WE INFECTED THE CELLS AND 24 1906 01:55:58,691 --> 01:56:00,226 HOURS LATER WE ASKED IF THE 1907 01:56:00,226 --> 01:56:01,794 HYPOTHESIS WAS HAPPENING. 1908 01:56:01,794 --> 01:56:04,130 WE HAVE THE DONOR CELLS AND 1909 01:56:04,130 --> 01:56:08,668 HAVING THE M PROTEIN ON THE 1910 01:56:08,668 --> 01:56:10,603 SURFACE AND IF IT COULD BE 1911 01:56:10,603 --> 01:56:15,875 TRANSFERRED TO THE RECIPIENT 1912 01:56:15,875 --> 01:56:16,409 CELLS. 1913 01:56:16,409 --> 01:56:23,282 I'M SHOWING THE BASELINE WE SEE 1914 01:56:23,282 --> 01:56:27,053 NO SURFACE SIGNATURE FOR A SPIKE 1915 01:56:27,053 --> 01:56:30,656 AND CAPSID PROTEIN AND YOU CAN 1916 01:56:30,656 --> 01:56:34,093 SEE THE DONOR CELL SUSCEPTIBLE 1917 01:56:34,093 --> 01:56:36,195 FOR INFECTION AND GAINED 1918 01:56:36,195 --> 01:56:46,739 POSITIVE FOR SURFACE M PROTEIN 1919 01:56:46,973 --> 01:56:51,177 HOWEVER, THEY REMAIN NEGATIVE 1920 01:56:51,177 --> 01:56:54,780 AND HAVE PROTEIN ON THE SURFACE 1921 01:56:54,780 --> 01:56:56,582 TELLING US THE PRESENCE OF 1922 01:56:56,582 --> 01:56:59,118 GLYCANS ALLOWED THEM TO CATCH, 1923 01:56:59,118 --> 01:57:02,889 BIND AND RETAIN THE PROTEIN 1924 01:57:02,889 --> 01:57:04,590 AVAILABLE FROM THOSE DONOR 1925 01:57:04,590 --> 01:57:06,792 CELLS. 1926 01:57:06,792 --> 01:57:12,265 WE WONDERED IF THIS WAS TO 1927 01:57:12,265 --> 01:57:16,969 RECONFIRM THE GLYC AN GLYCAN ME 1928 01:57:16,969 --> 01:57:20,306 THE CELL AND WE REPLACED THE 1929 01:57:20,306 --> 01:57:24,243 RECIPIENT CELLS BY THE CELL 1930 01:57:24,243 --> 01:57:29,148 LINES AND YOU CAN SEE NOW THE 1931 01:57:29,148 --> 01:57:30,950 RECIPIENT CELL THE BLUE GUYS 1932 01:57:30,950 --> 01:57:33,486 REMAIN NEGATIVE FOR THE SPIKE 1933 01:57:33,486 --> 01:57:35,254 AND NUCLEIC ACID PROTEIN. 1934 01:57:35,254 --> 01:57:38,324 IN THE END THE ABSENCE OF 1935 01:57:38,324 --> 01:57:40,092 GLYCANS IN THE RECIPIENT CELLS 1936 01:57:40,092 --> 01:57:42,562 IS WHAT PREVENTED OR ALLOWED THE 1937 01:57:42,562 --> 01:57:48,167 CELLS TO CAPTURE, BIND OR RETAIN 1938 01:57:48,167 --> 01:57:51,070 WHAT WAS ON THE SURFACE OF THE 1939 01:57:51,070 --> 01:58:01,280 DONOR CELLS. 1940 01:58:07,853 --> 01:58:13,359 WE LOOK AT THE SURFACE OUTSIDE 1941 01:58:13,359 --> 01:58:15,094 THE CELL AND THE QUESTION I RAN 1942 01:58:15,094 --> 01:58:25,638 THE PROTEIN INTERACTION I USED 1943 01:58:25,972 --> 01:58:29,609 THE SARS COV2 STRUCTURE AND 1944 01:58:29,609 --> 01:58:31,010 ACCESSORY PROTEIN AGAINST THE 24 1945 01:58:31,010 --> 01:58:38,951 HUMAN CYTOKINES AND ETCETERA AND 1946 01:58:38,951 --> 01:58:40,886 YOU CAB SEE AMONG ALL ONLY THE M 1947 01:58:40,886 --> 01:58:45,024 PROTEIN WAS ABLE TO BIND AT THE 1948 01:58:45,024 --> 01:58:51,130 SPECIFIC SUBSET OF CHEMOKINES 1949 01:58:51,130 --> 01:59:01,607 AND WHERE I FOUND THE PARTICULAR 1950 01:59:01,607 --> 01:59:10,750 SET OF SIX CHEMOKINES HERE IN 1951 01:59:10,750 --> 01:59:13,686 YELLOW AND THE QUESTION IS THE 1952 01:59:13,686 --> 01:59:15,187 RELEVANCE BETWEEN PROTEIN AND 1953 01:59:15,187 --> 01:59:16,188 CHEMOKINES. 1954 01:59:16,188 --> 01:59:21,827 I CAME BACK TO THE ASSAY I 1955 01:59:21,827 --> 01:59:27,700 LEARNED TO USE IN GRAD SCHOOL 1956 01:59:27,700 --> 01:59:34,106 AND WE HAD A FIXED CONCENTRATION 1957 01:59:34,106 --> 01:59:37,843 OF CHEMOKINE AND WE HAVE 1958 01:59:37,843 --> 01:59:40,146 DIFFERENT CELLS FOR THE GIVEN 1959 01:59:40,146 --> 01:59:45,117 CHEMOKINE AND A POSITIVE BINDER 1960 01:59:45,117 --> 01:59:49,055 AND WE CAN PREINCUBATE THE 1961 01:59:49,055 --> 01:59:50,823 CHEMOKINE WITH A RECOMBINANT 1962 01:59:50,823 --> 01:59:54,827 PROTEIN AND SEAS IF THERE'S AN 1963 01:59:54,827 --> 01:59:58,731 ENHANCEMENT OR INHIBITION TO THE 1964 01:59:58,731 --> 02:00:00,566 LOWER CHAMBERS AND QUANTIFY HOW 1965 02:00:00,566 --> 02:00:06,872 MANY CELLS HAVE MY GRA-- MIGRAT 1966 02:00:06,872 --> 02:00:09,141 AND THERE'S THE INDUCTION OF THE 1967 02:00:09,141 --> 02:00:11,711 CHEMOKINE AND WHEN I PREINCUBATE 1968 02:00:11,711 --> 02:00:15,014 THE FIXED CONCENTRATION WITH 1969 02:00:15,014 --> 02:00:20,353 INCREASING CONCENTRATION OF THE 1970 02:00:20,353 --> 02:00:21,387 SARS COV2 PROTEIN I HAVE 1971 02:00:21,387 --> 02:00:23,589 MIGRATION FOR THE CELL LINES 1972 02:00:23,589 --> 02:00:27,927 EVEN FOR HUMAN PBMCCs. 1973 02:00:27,927 --> 02:00:34,767 IT WAS WORTHY TO BE REACHED OUT 1974 02:00:34,767 --> 02:00:40,740 AND THEY HAD THE INTERACTION 1975 02:00:40,740 --> 02:00:47,913 BETWEEN MUCK THE MONEY MERS AND 1976 02:00:47,913 --> 02:00:51,584 THEY OBSERVED THESE BETWEEN THE 1977 02:00:51,584 --> 02:00:58,724 SARS COV2 PROTEIN AND IT WAS 1978 02:00:58,724 --> 02:01:00,693 INTERESTING THE INTERACTION. 1979 02:01:00,693 --> 02:01:07,066 WE ALSO OBSERVED THE PHENOMENON 1980 02:01:07,066 --> 02:01:17,576 FOR THE PROTEIN AND IT'S HAD 1981 02:01:20,546 --> 02:01:25,551 GRATION AND TO HAVE THE 1982 02:01:25,551 --> 02:01:30,322 RECOMBINANT PROTEIN AND DURING 1983 02:01:30,322 --> 02:01:32,091 THE CORONAVIRUS AND THE OTHER 1984 02:01:32,091 --> 02:01:35,728 CORONAVIRUSES WHICH I BELIEVE IT 1985 02:01:35,728 --> 02:01:37,530 SUGGESTS THE MECHANISM IS 1986 02:01:37,530 --> 02:01:40,266 SOMETHING CONSERVED BETWEEN 1987 02:01:40,266 --> 02:01:40,866 HUMAN CORONAVIRUS DESPITE THE 1988 02:01:40,866 --> 02:01:43,169 SEQUENCE. 1989 02:01:43,169 --> 02:01:45,538 FINALLY, I WANT TO SHOW YOU WE 1990 02:01:45,538 --> 02:01:50,009 ARE ALSO WONDER ABOUT IF THE M 1991 02:01:50,009 --> 02:01:55,381 PROTEIN COULD BE A TARGET AND WE 1992 02:01:55,381 --> 02:01:59,151 OPTIMIZED IN THE LAB THE ADDC 1993 02:01:59,151 --> 02:02:01,420 BIO REPORT ASSAY AND REAL QUICK 1994 02:02:01,420 --> 02:02:04,023 WE INFECTED CELLS AND KNEW 24 1995 02:02:04,023 --> 02:02:05,658 HOURS LATER WE'D HAVE PROTEIN ON 1996 02:02:05,658 --> 02:02:08,360 THE SURFACE OF THE INFECTED 1997 02:02:08,360 --> 02:02:16,469 CELLS AND INCUBATED OVERNIGHT 1998 02:02:16,469 --> 02:02:21,941 WITH MICE IMMUNIZED WITH THE 1999 02:02:21,941 --> 02:02:31,050 EFFECTER CELLS PART WITH AND CAN 2000 02:02:31,050 --> 02:02:38,324 GO THIS IS THE CLEAR ACTIVATION 2001 02:02:38,324 --> 02:02:47,733 WE OBSERVED WHEN WE USED AN 2002 02:02:47,733 --> 02:02:55,774 ANANTIBIOTIC -- ANTIBODY AND 2003 02:02:55,774 --> 02:03:06,218 HERE WE USED THE AND SAW 2004 02:03:07,119 --> 02:03:15,060 ACTIVATION WHICH WAS HIGHER AND 2005 02:03:15,060 --> 02:03:22,234 THIS SUMMARY I WOULD LIKE TO 2006 02:03:22,234 --> 02:03:27,740 TAKEAWAY THE PROTEINS AND IT 2007 02:03:27,740 --> 02:03:30,109 COMBINED THROUGH THIS AND INFECT 2008 02:03:30,109 --> 02:03:32,444 TO NEIGHBORING CELLS AND 2009 02:03:32,444 --> 02:03:37,917 INHIBITS THE PROPERTIES WHICH WE 2010 02:03:37,917 --> 02:03:43,155 BELIEVE IT'S A TARGET FOR 2011 02:03:43,155 --> 02:03:44,623 ANTIBODY BASED IMMUNITY. 2012 02:03:44,623 --> 02:03:46,759 AND THE FUTURE DIRECTION RATHER 2013 02:03:46,759 --> 02:03:48,394 THAN SHOWING A LIST OF 2014 02:03:48,394 --> 02:03:50,696 EXPERIMENT I WANTED TO GIVE 2015 02:03:50,696 --> 02:03:55,134 CREDIT TO JOHN TO MY SUPERVISOR 2016 02:03:55,134 --> 02:04:00,940 AND CELL SURFACE EXPRESSION 2017 02:04:00,940 --> 02:04:07,046 SEEMS TO BE THE RULE AND SHOWN 2018 02:04:07,046 --> 02:04:17,590 THE VIRUS AN RNA BINDING PROTEIN 2019 02:04:24,063 --> 02:04:26,065 IS USED TO MODULATE THE IMMUNE 2020 02:04:26,065 --> 02:04:28,300 RESPONSE IN THE EARLY STAGE OF 2021 02:04:28,300 --> 02:04:28,701 INFECTION. 2022 02:04:28,701 --> 02:04:31,737 WITH THAT I WOULD LIKE TO THANK 2023 02:04:31,737 --> 02:04:37,643 THE INSTITUTE AND NIAID AND THE 2024 02:04:37,643 --> 02:04:40,579 LAB AND MY MENTOR AND I'M DEEPLY 2025 02:04:40,579 --> 02:04:43,048 GRATEFUL FOR THE OPPORTUNITY I 2026 02:04:43,048 --> 02:04:45,150 GOT FOR COMING HERE I'VE ENJOYED 2027 02:04:45,150 --> 02:04:46,719 EVERY DAY IN THE WILL BE AND 2028 02:04:46,719 --> 02:04:49,622 HAVING FUN AND LEARNING AND 2029 02:04:49,622 --> 02:04:50,689 MATURING AS A SCIENTIST. 2030 02:04:50,689 --> 02:04:51,290 THANK YOU EVERYBODY FOR YOUR 2031 02:04:51,290 --> 02:05:01,467 ATTENTION. 2032 02:05:09,375 --> 02:05:11,610 >> SO HOW DOES M GET OUT OF THE 2033 02:05:11,610 --> 02:05:12,711 CELL? 2034 02:05:12,711 --> 02:05:16,081 >> THAT'S THE MILLION-DOLLAR 2035 02:05:16,081 --> 02:05:18,484 QUESTION WE KNOW IT DOESN'T HAVE 2036 02:05:18,484 --> 02:05:24,023 A SINGLE PEPTIDE OR GO THROUGH 2037 02:05:24,023 --> 02:05:29,895 THE PATH WE AND HAS TO GO 2038 02:05:29,895 --> 02:05:33,098 OUTSIDE THROUGH THE PATHWAY AND 2039 02:05:33,098 --> 02:05:40,039 HAVE PLASTIC ENCODING FOR THE 2040 02:05:40,039 --> 02:05:43,509 PROTEIN AND WE BLOCKED THE 2041 02:05:43,509 --> 02:05:45,177 PATHWAY AND PROTEIN KEPT GOING 2042 02:05:45,177 --> 02:05:45,711 OUTSIDE. 2043 02:05:45,711 --> 02:05:51,083 >> IT SEEMS LIKE A COOL PATHWAY 2044 02:05:51,083 --> 02:05:57,756 TO FIGURE OUT. 2045 02:05:57,756 --> 02:06:03,429 AND IT'S BEEN ABLE TO REACH THE 2046 02:06:03,429 --> 02:06:10,402 CELL SURFACE BY INTERACTING WITH 2047 02:06:10,402 --> 02:06:13,739 GLYCANS INTERNALLY AND EXPOSED 2048 02:06:13,739 --> 02:06:15,140 OUTSIDE THE PROTEIN WILL BE 2049 02:06:15,140 --> 02:06:17,042 USING IN THAT PARTICULAR 2050 02:06:17,042 --> 02:06:17,309 SCENARIO. 2051 02:06:17,309 --> 02:06:25,084 I'M TRYING TO EXPLORE THAT WITH 2052 02:06:25,084 --> 02:06:27,653 DIFFERENT CELL LINES TO SEE THE 2053 02:06:27,653 --> 02:06:29,121 PROTEIN THAT STOPPED COMING OUT 2054 02:06:29,121 --> 02:06:30,456 BECAUSE THERE'S NO GLYCAN 2055 02:06:30,456 --> 02:06:32,558 EXPRESSION IN THE CELLS. 2056 02:06:32,558 --> 02:06:34,793 >> IN TERMS OF THE CHEMOKINE 2057 02:06:34,793 --> 02:06:38,130 BINDING SPECIFICITY IS THERE A 2058 02:06:38,130 --> 02:06:39,665 MUTATION TO KNOCK THAT OUT 2059 02:06:39,665 --> 02:06:41,400 CAPABILITY THAT WILL STILL ALLOW 2060 02:06:41,400 --> 02:06:43,669 FUNCTION IN TERMS OF REPLICATION 2061 02:06:43,669 --> 02:06:46,672 AND VIRUS PROTECTION? 2062 02:06:46,672 --> 02:06:48,040 >> TO THE CHARACTERIZATION OF 2063 02:06:48,040 --> 02:06:53,378 THE DOMAINS WE'RE WORKING ON 2064 02:06:53,378 --> 02:07:01,820 THAT AND USING ANTIBODIES IN THE 2065 02:07:01,820 --> 02:07:03,989 mRNA BINDING DOMAINS AND WHEN WE 2066 02:07:03,989 --> 02:07:06,358 BLOCK ONE OR THE OTHER WE LOSE 2067 02:07:06,358 --> 02:07:09,728 ABOUT 50% OF THE PROTEIN TO BIND 2068 02:07:09,728 --> 02:07:13,365 AND WHEN WE BLOCK BOTH WE NEARLY 2069 02:07:13,365 --> 02:07:15,033 LOST THE ABILITY OF THE PROTEIN 2070 02:07:15,033 --> 02:07:19,905 TO INTERACTION. 2071 02:07:19,905 --> 02:07:26,111 WE KNOW SEE THE RNA BINDING 2072 02:07:26,111 --> 02:07:28,213 DOMAINS WE MAIN WELCOME ACROSS 2073 02:07:28,213 --> 02:07:29,715 THE CONCERNS. 2074 02:07:29,715 --> 02:07:32,818 WE UNDERSTAND THIS NOT VERY 2075 02:07:32,818 --> 02:07:35,020 PERMISSIVE THE PERMUTATION BUT 2076 02:07:35,020 --> 02:07:39,625 FOR THE FINE TUBE -- TUNE WE 2077 02:07:39,625 --> 02:07:41,460 WOULD HAVE TO DO THIS GENESIS. 2078 02:07:41,460 --> 02:07:42,528 >> FASCINATING WORK. 2079 02:07:42,528 --> 02:07:51,136 CONGRATULATIONS. 2080 02:07:51,136 --> 02:07:55,274 >> DOES ANYONE HAVE ANY MORE 2081 02:07:55,274 --> 02:07:55,541 QUESTIONS. 2082 02:07:55,541 --> 02:08:01,947 >> ONE MORE QUESTION FOR YOU. 2083 02:08:01,947 --> 02:08:08,921 I ASSUME -- YOU ANSWERED MY 2084 02:08:08,921 --> 02:08:10,355 INITIAL QUESTION HOW 2085 02:08:10,355 --> 02:08:13,258 APPROACHABLE IT IS FOR OTHER 2086 02:08:13,258 --> 02:08:13,492 VIRUSES. 2087 02:08:13,492 --> 02:08:16,728 DID YOU TEST THE CAPSID PROTEIN 2088 02:08:16,728 --> 02:08:24,069 IF THEY BIND TO CYTOKINES? 2089 02:08:24,069 --> 02:08:31,743 >> BACK IN THE '80s INFLUENZA 2090 02:08:31,743 --> 02:08:34,713 PROTEINS AND I HAVEN'T RUN THE 2091 02:08:34,713 --> 02:08:38,016 WHOLE ASSAY WITH THE CYTOKINES 2092 02:08:38,016 --> 02:08:43,088 BUT I DO SEE THE 12B IN THE 2093 02:08:43,088 --> 02:08:48,293 ASSAY AND WITH THAT PARTICULAR 2094 02:08:48,293 --> 02:08:52,164 CHEMOKINE I SEE THE FLU M 2095 02:08:52,164 --> 02:08:55,100 PROTEIN AND WOULD LIKE TO KEEP 2096 02:08:55,100 --> 02:08:56,735 EXPLORING THAT. 2097 02:08:56,735 --> 02:08:58,437 >> WITH THAT, CONGRATULATIONS 2098 02:08:58,437 --> 02:09:03,075 AGAIN OR YOUR AWARD AND WE'RE 2099 02:09:03,075 --> 02:09:06,178 LOOKING FORWARD TO YOUR NEXT 2100 02:09:06,178 --> 02:09:10,649 RESEARCH. 2101 02:09:10,649 --> 02:09:21,193 NOW, I'M GOING TO INTRODUCE ANIS 2102 02:09:22,227 --> 02:09:23,262 LOWEN FROM EMORY UNIVERSITY 2103 02:09:23,262 --> 02:09:27,432 SCHOOL OF MEDICINE AND GOING NOT 2104 02:09:27,432 --> 02:09:31,069 BE ABLE TO BE IN PERSON BUT GIVE 2105 02:09:31,069 --> 02:09:37,376 HER PRESENTATION BY ZOOM. 2106 02:09:37,376 --> 02:09:43,916 THE TALK IS STOCHASTIC LOSS OF 2107 02:09:43,916 --> 02:09:46,051 DIVERSITY WITHIN THE NEW HOST IS 2108 02:09:46,051 --> 02:09:48,787 A MAJOR COMPONENT OF INFLUENZA A 2109 02:09:48,787 --> 02:09:51,023 VIRUS TRANSMISSION BOTTLENECKS. 2110 02:09:51,023 --> 02:09:52,524 WE LOOK FORWARD TO HEAR YOUR 2111 02:09:52,524 --> 02:09:52,858 PRESENTATION. 2112 02:09:52,858 --> 02:09:58,530 >> GOOD MORNING, EVERYONE. 2113 02:09:58,530 --> 02:10:01,867 THANK YOU FOR THE INVITATION TO 2114 02:10:01,867 --> 02:10:03,302 PARTICIPATE IN THE EXCELLENT 2115 02:10:03,302 --> 02:10:03,568 SYMPOSIUM. 2116 02:10:03,568 --> 02:10:05,170 I'M EXCITED FOR THE AFTERNOON. 2117 02:10:05,170 --> 02:10:07,039 IT'S BEEN GREAT SO FAR. 2118 02:10:07,039 --> 02:10:10,809 I CHANGED MY TITLE LATE TO 2119 02:10:10,809 --> 02:10:15,080 BROADEN IT AND TALK ABOUT 2120 02:10:15,080 --> 02:10:16,648 BOTTLENECKS AND INFLUENZA A 2121 02:10:16,648 --> 02:10:17,015 DYNAMICS. 2122 02:10:17,015 --> 02:10:19,017 THE A VIRUSES ARE CONSTANTLY 2123 02:10:19,017 --> 02:10:19,551 CHANGING. 2124 02:10:19,551 --> 02:10:22,854 THIS IS ILLUSTRATED HERE WITH 2125 02:10:22,854 --> 02:10:25,324 THE PHYLOGENETIC TREE SHOWING 2126 02:10:25,324 --> 02:10:29,761 THE HUMAN GENE THAT ENCODES THE 2127 02:10:29,761 --> 02:10:36,068 GLYCOPROTEIN AND LOOKING AT THE 2128 02:10:36,068 --> 02:10:39,905 H3N2 INFLUENZA VIRUSES THAT HAVE 2129 02:10:39,905 --> 02:10:41,740 CIRCULATED THE LAST YEARS AND 2130 02:10:41,740 --> 02:10:43,108 THIS SHOWS VARIANTS. 2131 02:10:43,108 --> 02:10:53,585 YOU CAN SEE A CLEAR AND THE 2132 02:10:58,423 --> 02:11:02,961 PATTERN IN WHICH IT'S REPLACED 2133 02:11:02,961 --> 02:11:06,064 BY A NOVEL CLAD IN THIS 2134 02:11:06,064 --> 02:11:08,767 SUCCESSIVE FASHION. 2135 02:11:08,767 --> 02:11:09,701 THE PROBLEM THIS PRESENTS IS 2136 02:11:09,701 --> 02:11:11,069 ILLUSTRATED ON THE TREE WITH THE 2137 02:11:11,069 --> 02:11:12,671 Xs. 2138 02:11:12,671 --> 02:11:16,274 SO THESE ARE IDENTIFYING STRAINS 2139 02:11:16,274 --> 02:11:18,110 CHOSEN TO BE INCLUDED IN THE 2140 02:11:18,110 --> 02:11:19,177 SEASONAL INFLUENZA VACCINE. 2141 02:11:19,177 --> 02:11:20,679 BECAUSE THE VIRUS CHANGES YEAR 2142 02:11:20,679 --> 02:11:22,748 ON YEAR, THE VACCINE NEEDS TO BE 2143 02:11:22,748 --> 02:11:27,786 UPDATED FROM ONE YEAR TO THE 2144 02:11:27,786 --> 02:11:28,453 NEXT. 2145 02:11:28,453 --> 02:11:34,259 AND THIS IS A MAJOR EFFORT FOR 2146 02:11:34,259 --> 02:11:36,228 BROAD SURVEILLANCE AND IN DEPTH 2147 02:11:36,228 --> 02:11:39,164 CHARACTERIZATION THAT FEEDS INTO 2148 02:11:39,164 --> 02:11:40,465 THAT STRAIN SELECTION PROCESS. 2149 02:11:40,465 --> 02:11:44,136 DESPITE THAT EFFORT THERE'S 2150 02:11:44,136 --> 02:11:45,404 GUESSWORK INVOLVED IN STRAIN 2151 02:11:45,404 --> 02:11:47,973 SELECTION BECAUSE THE VACCINE TO 2152 02:11:47,973 --> 02:11:51,109 BE PRODUCED OR THE STRAINS NEED 2153 02:11:51,109 --> 02:11:54,579 TO BE CHOSEN NINE MONTHS PRIOR 2154 02:11:54,579 --> 02:11:57,849 TO THE INFLUENZA SEASON. 2155 02:11:57,849 --> 02:12:01,453 IN OTHER WORDS IT REQUIRES 2156 02:12:01,453 --> 02:12:02,521 PREDICTING EVOLUTION. 2157 02:12:02,521 --> 02:12:07,125 THERE'S A STRONG PUBLIC HEALTH 2158 02:12:07,125 --> 02:12:09,428 MOTATION TO BETTER UNDERSTAND 2159 02:12:09,428 --> 02:12:12,531 VIRAL EVOLUTION. 2160 02:12:12,531 --> 02:12:14,566 WHEN THE FIELD DUG INTO THAT 2161 02:12:14,566 --> 02:12:20,572 PROBLEM AND WE SEE AT THE GLOBAL 2162 02:12:20,572 --> 02:12:22,874 POPULATION LEVEL EACH CLAD IS 2163 02:12:22,874 --> 02:12:24,109 REPLACED BY A NOVEL ONE OVER A 2164 02:12:24,109 --> 02:12:27,145 PERIOD OF A FEW YEARS. 2165 02:12:27,145 --> 02:12:30,482 AND IT'S A FASCINATING 2166 02:12:30,482 --> 02:12:31,083 EVOLUTIONARY DYNAMIC AND ONE 2167 02:12:31,083 --> 02:12:32,117 BEST DESCRIBED EXAMPLES OF 2168 02:12:32,117 --> 02:12:36,488 PUBLIC SELECTION IN BIOLOGY. 2169 02:12:36,488 --> 02:12:38,390 NONETHELESS, A SIMILAR DYNAMIC 2170 02:12:38,390 --> 02:12:43,929 IS NOT SEEING OCCURRING WITHIN 2171 02:12:43,929 --> 02:12:44,729 INDIVIDUALS. 2172 02:12:44,729 --> 02:12:47,065 SO WITHIN THE INFECTED PERSON 2173 02:12:47,065 --> 02:12:53,572 TENDS TO BE LOW DIVERSITY AND 2174 02:12:53,572 --> 02:12:55,640 RELATIVELY STATIC AND THEY 2175 02:12:55,640 --> 02:12:56,908 TYPICALLY REMAIN MINOR OVER THE 2176 02:12:56,908 --> 02:12:57,776 COURSE OF INFECTION. 2177 02:12:57,776 --> 02:13:03,081 WE'RE NOT SEEING A SIGNATURE OF 2178 02:13:03,081 --> 02:13:05,851 POSITIVE SELECTION OF ANTIGENIC 2179 02:13:05,851 --> 02:13:06,218 VARIANTS. 2180 02:13:06,218 --> 02:13:07,752 WHAT'S SEEN WITH INDIVIDUALS IS 2181 02:13:07,752 --> 02:13:10,222 A NEGATIVE SELECTION. 2182 02:13:10,222 --> 02:13:12,090 A PURGING OF MUTATION OBSERVED 2183 02:13:12,090 --> 02:13:14,092 AS WELL AS GENETIC DRIFT. 2184 02:13:14,092 --> 02:13:16,862 RANDOM CHANGES AND FREQUENCIES 2185 02:13:16,862 --> 02:13:18,663 ARE OBSERVED WITHIN INDIVIDUALS. 2186 02:13:18,663 --> 02:13:20,765 DESPITE PRE EXISTING IMMUNITY 2187 02:13:20,765 --> 02:13:22,868 AND MOST INFLUENZA CASES WE DID 2188 02:13:22,868 --> 02:13:31,409 NOT SEE ANTIGENICALLY INVOLVE 2189 02:13:31,409 --> 02:13:36,681 CASES SWEEP. 2190 02:13:36,681 --> 02:13:37,682 THIS CREATES AN INTERESTING 2191 02:13:37,682 --> 02:13:40,852 PUZZLE BECAUSE FOR A VARIANT TO 2192 02:13:40,852 --> 02:13:43,088 CIRCULATE GLOBALLY IT MUST ARISE 2193 02:13:43,088 --> 02:13:44,356 WITHIN INDIVIDUALS. 2194 02:13:44,356 --> 02:13:46,224 LEAVING US WITH THE QUESTION HOW 2195 02:13:46,224 --> 02:13:48,059 MUTANTS ARISE BEFORE GOING ON TO 2196 02:13:48,059 --> 02:13:58,403 CIRCULATE GLOBALLY. 2197 02:14:00,472 --> 02:14:07,746 THIS PRESENTS AN APPEALING MODEL 2198 02:14:07,746 --> 02:14:14,586 AND THE PROJECTS AND WE LOOK AT 2199 02:14:14,586 --> 02:14:19,090 THE INFLUENZA A VIRUS AND USING 2200 02:14:19,090 --> 02:14:29,467 THE VIRUS POPULATION. 2201 02:14:32,003 --> 02:14:35,974 THIS LEVERAGES LOOKING AT 2202 02:14:35,974 --> 02:14:36,908 SEASONAL INFLUENZA A VIRUS AND 2203 02:14:36,908 --> 02:14:38,643 IT'S A TEAM EFFORT AND WE HAVE 2204 02:14:38,643 --> 02:14:39,244 EXCELLENT WORKING TOGETHER ON 2205 02:14:39,244 --> 02:14:46,851 THIS. 2206 02:14:46,851 --> 02:14:54,426 OUR PARTICIPANTS ARE A MINIMAL 2207 02:14:54,426 --> 02:15:02,033 SEROLOGICAL RESPONSE AND THE 2208 02:15:02,033 --> 02:15:10,842 INOCULUM IS A SEASONAL STRAIN. 2209 02:15:10,842 --> 02:15:18,583 AND WE'RE USING THIS ATOM IZIZE. 2210 02:15:18,583 --> 02:15:21,186 WE CHALLENGED 18 PARTICIPANTS EN 2211 02:15:21,186 --> 02:15:23,855 THIS MANNER OF 18, 15 WERE 2212 02:15:23,855 --> 02:15:26,925 PRODUCTIVELY INFECTED. 2213 02:15:26,925 --> 02:15:30,195 WE SEE THE VIRAL LOAD IN THE 2214 02:15:30,195 --> 02:15:34,199 NASAL PHARYNGEAL SITE. 2215 02:15:34,199 --> 02:15:36,868 THE Y AXIS IS 45 MINUS THE CT 2216 02:15:36,868 --> 02:15:39,771 VALUE FROM THE PCR AND THE X 2217 02:15:39,771 --> 02:15:41,906 AXIS IS THE TIME OF INOCULATION 2218 02:15:41,906 --> 02:15:43,275 INDICATED HERE WITH THE YELLOW 2219 02:15:43,275 --> 02:15:53,385 ARROW. 2220 02:15:54,486 --> 02:16:00,258 AND THE DYNAMICS WITH INDIVIDUAL 2221 02:16:00,258 --> 02:16:01,726 I'LL SHOW DATA FROM THE ONGOING 2222 02:16:01,726 --> 02:16:05,163 EFFORT AND WE DON'T HAVE TO 2223 02:16:05,163 --> 02:16:06,998 UPDATE IT FROM EVERYONE JUST 2224 02:16:06,998 --> 02:16:07,165 YET. 2225 02:16:07,165 --> 02:16:09,301 THE FIRST THING WE SEQUENCED WAS 2226 02:16:09,301 --> 02:16:12,904 THE VIRAL INOCULUM. 2227 02:16:12,904 --> 02:16:15,640 I'M SHOWING THE DIVERSITY WITH 2228 02:16:15,640 --> 02:16:18,276 THE FREQUENCY OF SINGLE 2229 02:16:18,276 --> 02:16:21,413 NUCLEOTIDE VARIANTS WITH THE LOG 2230 02:16:21,413 --> 02:16:22,781 SCALE AND THE VIRAL GENOME ON 2231 02:16:22,781 --> 02:16:32,991 THE X AXIS. 2232 02:16:35,360 --> 02:16:43,468 ABOVE A THRESHOLD VEHICLE AND 2233 02:16:43,468 --> 02:16:46,671 THIS IS AMONG THE VARIANTS WE 2234 02:16:46,671 --> 02:16:48,106 DETECTED FOUR STOOD OUT IN 2235 02:16:48,106 --> 02:16:49,107 GREEN. 2236 02:16:49,107 --> 02:16:51,242 THE TWO IN THE PA SEGMENT AND 2237 02:16:51,242 --> 02:17:00,952 TWO IN NP RELATIVELY HIGH 2238 02:17:00,952 --> 02:17:02,921 FREQUENCY AND FOR THOSE WHO TAKE 2239 02:17:02,921 --> 02:17:05,657 A CLOSER LOOK AT THE FOUR 2240 02:17:05,657 --> 02:17:07,392 MUTATIONS, AND ASKED DO THEY 2241 02:17:07,392 --> 02:17:08,293 OCCUR IN NATURE? 2242 02:17:08,293 --> 02:17:12,230 ARE THEY SEEN IN CIRCULATING 2243 02:17:12,230 --> 02:17:13,998 H3N2 VIRUSES. 2244 02:17:13,998 --> 02:17:17,435 TO CUT TO THE CHASE A MAJOR 2245 02:17:17,435 --> 02:17:19,671 VARIANT IN THE INOCULUM ARE NOT 2246 02:17:19,671 --> 02:17:21,873 OCCURRING IN NATURE AND LIKELY 2247 02:17:21,873 --> 02:17:22,273 FROM PATIENTS. 2248 02:17:22,273 --> 02:17:23,475 THAT'S SHOWN DOWN HERE. 2249 02:17:23,475 --> 02:17:27,078 WHAT'S PLOTTED IN THE GRAPHS ARE 2250 02:17:27,078 --> 02:17:31,049 THE HAPLOTYPES OF THE PA AND NP 2251 02:17:31,049 --> 02:17:35,053 SEEN AMONG CIRCULATING VIRUSES 2252 02:17:35,053 --> 02:17:44,195 SINCE 1980. 2253 02:17:44,195 --> 02:17:46,898 THEY'RE VERY WELL CONSERVED AND 2254 02:17:46,898 --> 02:17:49,701 NONE MATCH THE MAJOR VARIANTS 2255 02:17:49,701 --> 02:17:50,268 SEEN IN THE STOCK. 2256 02:17:50,268 --> 02:17:52,871 THE MINOR VARIANTS IN OUR STOCK 2257 02:17:52,871 --> 02:17:53,772 ARE THE WILD TYPE. 2258 02:17:53,772 --> 02:17:58,877 THE MINOR PA IS THE MN AND THE 2259 02:17:58,877 --> 02:18:05,083 OTHER WAS CIRCULATED IN 2009. 2260 02:18:05,083 --> 02:18:09,187 THE MAJOR VARIANTS ARE WE 2261 02:18:09,187 --> 02:18:10,822 PRESUME ARE ADAPTATIONS. 2262 02:18:10,822 --> 02:18:14,826 I'LL SHOW THE DYNAMICS OF THE 2263 02:18:14,826 --> 02:18:16,861 HAPLOTYPES IN THE INOCULATED 2264 02:18:16,861 --> 02:18:18,930 INDIVIDUALS AND THE F026 AND 2265 02:18:18,930 --> 02:18:22,167 STARTING WITH THIS BECAUSE THE 2266 02:18:22,167 --> 02:18:23,935 DYNAMICS ARE SIMPLICISIMPLEST. 2267 02:18:23,935 --> 02:18:28,273 THE FREQUENCY ON THE Y AXIS OF 2268 02:18:28,273 --> 02:18:31,709 THE WILD TYPE HAPLOTYPES OVER 2269 02:18:31,709 --> 02:18:33,445 TIME WITH PA ON THE LEFT AND P 2270 02:18:33,445 --> 02:18:35,513 ON THE RIGHT. 2271 02:18:35,513 --> 02:18:37,982 YOU CAN SEE THE WILD TYPE 2272 02:18:37,982 --> 02:18:42,387 HAPLOTYPES STARTED AT LOW 2273 02:18:42,387 --> 02:18:43,388 FREQUENCY IN THE INDIVIDUAL THEN 2274 02:18:43,388 --> 02:18:46,191 INCREASED IN FREQUENCY. 2275 02:18:46,191 --> 02:18:51,095 THIS IS A VERY CLEAR SIGNATURE 2276 02:18:51,095 --> 02:18:53,998 OF POSITIVE SELECTION LEADING TO 2277 02:18:53,998 --> 02:18:59,370 ENRICHMENT OF THE WILD TYPES 2278 02:18:59,370 --> 02:19:03,107 WITHIN THE HOST AND SURPRISE 2279 02:19:03,107 --> 02:19:04,542 GIVEN THE VIRUS. 2280 02:19:04,542 --> 02:19:07,078 THE PATTERNS SEEN FOR PA AND NP 2281 02:19:07,078 --> 02:19:10,448 ARE SIMILAR. 2282 02:19:10,448 --> 02:19:12,383 THAT SUGGESTS THEIR LINKED 2283 02:19:12,383 --> 02:19:15,420 GENETICALLY AND THE REASSORTMENT 2284 02:19:15,420 --> 02:19:19,057 IS NOT SEPARATING THE WILD TYPE 2285 02:19:19,057 --> 02:19:21,793 GENE SEGMENTS BUT MOVING 2286 02:19:21,793 --> 02:19:22,160 IMPORTANTLY. 2287 02:19:22,160 --> 02:19:25,864 NOW LOCK AT ALL SIX INDIVIDUALS 2288 02:19:25,864 --> 02:19:27,065 THE ONE IN THE LOWER LEFT AND 2289 02:19:27,065 --> 02:19:29,667 THE OTHER PARTICIPANTS ARE 2290 02:19:29,667 --> 02:19:32,003 LABELLED HERE WITH THE RELEVANT 2291 02:19:32,003 --> 02:19:32,203 PLOTS. 2292 02:19:32,203 --> 02:19:34,339 YOU SEE THE DYNAMICS IN THE 2293 02:19:34,339 --> 02:19:39,077 OTHER FIVE INDIVIDUALS IS MORE 2294 02:19:39,077 --> 02:19:39,544 COMPLEX. 2295 02:19:39,544 --> 02:19:41,279 WE HAVE PA AND THEY'RE MOVING IN 2296 02:19:41,279 --> 02:19:41,880 DIFFERENT DIRECTIONS. 2297 02:19:41,880 --> 02:19:49,621 THE DYNAMICS ARE DISCORDANT 2298 02:19:49,621 --> 02:19:50,922 TELLING US ABOUT THE 2299 02:19:50,922 --> 02:19:51,322 REASSORTMENT. 2300 02:19:51,322 --> 02:19:54,425 IT WOULD ALLOW THE TWO GENOTYPES 2301 02:19:54,425 --> 02:19:56,261 PRESENT TO BECOME FOUR POSSIBLE 2302 02:19:56,261 --> 02:19:58,329 GENOTYPES AND THEREFORE YOU CAN 2303 02:19:58,329 --> 02:20:01,232 HAVE A SITUATION WHERE PA MAY BE 2304 02:20:01,232 --> 02:20:02,800 DECLINING IN FREQUENCY WHILE NP 2305 02:20:02,800 --> 02:20:05,069 IS INCREASING IN FREQUENCY. 2306 02:20:05,069 --> 02:20:07,071 CLEAR EVIDENCE OF REASSORTMENT 2307 02:20:07,071 --> 02:20:09,741 IN THE MAJORITY OF INDIVIDUALS. 2308 02:20:09,741 --> 02:20:12,710 SECONDLY, YOU HAVE A MESSIER 2309 02:20:12,710 --> 02:20:14,746 SITUATION OF THE OTHER FIVE 2310 02:20:14,746 --> 02:20:16,214 INDIVIDUALS AND THE FREQUENCY 2311 02:20:16,214 --> 02:20:19,751 CHANGES OF THE HAPLOTYPES IS NOT 2312 02:20:19,751 --> 02:20:24,289 AS DIRECTIONAL FOR F026 AND 2313 02:20:24,289 --> 02:20:27,859 RELEVANT TO NOTE IN EVERY CASE 2314 02:20:27,859 --> 02:20:35,700 AT LEAST ONE OF THE PA OR NP 2315 02:20:35,700 --> 02:20:36,768 HAPLOTYPE REACHES A FREQUENCY BY 2316 02:20:36,768 --> 02:20:39,604 THE END OF THE COURSE AND GIVING 2317 02:20:39,604 --> 02:20:41,573 A STRONG POSITIVE SELECTION 2318 02:20:41,573 --> 02:20:43,074 ACTING ACROSS THESE INDEPENDENT 2319 02:20:43,074 --> 02:20:47,679 INDIVIDUALS. 2320 02:20:47,679 --> 02:20:49,480 WE'LL COME BACK IN A MINUTE TO 2321 02:20:49,480 --> 02:20:51,182 WHY WE THINK IT HAPPENS IN THIS 2322 02:20:51,182 --> 02:20:52,150 CONTEXT AND ONE FURTHER PIECE OF 2323 02:20:52,150 --> 02:20:53,251 DATA FROM THE HUMAN. 2324 02:20:53,251 --> 02:20:58,923 I'VE SHOWN THE DATA FROM THE 2325 02:20:58,923 --> 02:21:03,061 NAVAL -- NASAL PHARYNGEAL SWABS 2326 02:21:03,061 --> 02:21:06,564 AND COLLECTING FROM 2327 02:21:06,564 --> 02:21:06,898 PARTICIPANTS. 2328 02:21:06,898 --> 02:21:14,072 THE NASAL PHARYNGEAL AND WE SEE 2329 02:21:14,072 --> 02:21:16,908 WHAT IS DETECTED AT THE 2330 02:21:16,908 --> 02:21:18,343 DIFFERENT SITES. 2331 02:21:18,343 --> 02:21:19,677 THE RESULTS ARE FROM ONE 2332 02:21:19,677 --> 02:21:21,346 PARTICIPANT AT 048. 2333 02:21:21,346 --> 02:21:22,180 WE PICKED THIS INDIVIDUAL 2334 02:21:22,180 --> 02:21:26,150 BECAUSE IT'S A PERSON WHO HAD 2335 02:21:26,150 --> 02:21:29,120 APPRECIABLE VIRAL LOADS AT ALL 2336 02:21:29,120 --> 02:21:32,323 FOUR SITES AND THE DYNAMICS ARE 2337 02:21:32,323 --> 02:21:33,958 SHOWN HERE IN PINK. 2338 02:21:33,958 --> 02:21:38,863 YOU CAN SEE DIFFERENT DYNAMICS 2339 02:21:38,863 --> 02:21:40,131 WITHIN THE ONE PARTICIPANT. 2340 02:21:40,131 --> 02:21:43,434 SO VERY STATIC SITUATION HERE 2341 02:21:43,434 --> 02:21:45,003 FOR EXAMPLE AND THE SWABS WE 2342 02:21:45,003 --> 02:21:48,706 HAVE SITUATIONS WHERE THE WILD 2343 02:21:48,706 --> 02:21:52,644 TYPE HAPLOTYPES ARE INCREASING 2344 02:21:52,644 --> 02:21:55,446 IN FREQUENCY IN THE NASAL 2345 02:21:55,446 --> 02:21:57,315 PHARYNGEAL LOCATION. 2346 02:21:57,315 --> 02:21:59,984 IT'S AN INTERESTING PICTURE AND 2347 02:21:59,984 --> 02:22:01,786 SUGGESTS THERE'S AT LEAST 2348 02:22:01,786 --> 02:22:02,520 PARTIALLY DIFFERENT 2349 02:22:02,520 --> 02:22:03,388 SUBPOPULATIONS AT THE DIFFERENT 2350 02:22:03,388 --> 02:22:05,089 LOCATIONS WITHIN A SINGLE 2351 02:22:05,089 --> 02:22:05,423 INDIVIDUAL. 2352 02:22:05,423 --> 02:22:10,662 THERE COULD BE MIGRATION BETWEEN 2353 02:22:10,662 --> 02:22:15,667 THEM HOWEVER THEY'RE NOT LEVEL 2354 02:22:15,667 --> 02:22:18,269 MIXED AND AN IMPORTANT 2355 02:22:18,269 --> 02:22:20,004 IMPLICATION IS WE COULD HAVE 2356 02:22:20,004 --> 02:22:21,572 DISTINCT NICHES FOR VIRAL 2357 02:22:21,572 --> 02:22:23,107 EVOLUTION AND DEEPER 2358 02:22:23,107 --> 02:22:24,842 TRANSMISSION WITHIN THE UPPER 2359 02:22:24,842 --> 02:22:27,078 ARE RESPIRATORY TRACT OF A 2360 02:22:27,078 --> 02:22:27,478 SINGLE INDIVIDUAL. 2361 02:22:27,478 --> 02:22:29,480 TO SUMMARIZE THAT PART WE'VE 2362 02:22:29,480 --> 02:22:31,916 SEEN IN THE CONTEXT OF 2363 02:22:31,916 --> 02:22:32,750 EXPERIMENTAL CHALLENGES POSITIVE 2364 02:22:32,750 --> 02:22:35,520 SELECTION IS ACTIVE DURING THE 2365 02:22:35,520 --> 02:22:37,055 BRIEF TIME COURSE OF ACUTE 2366 02:22:37,055 --> 02:22:37,522 INFECTION. 2367 02:22:37,522 --> 02:22:39,057 AND WHY DO WE THINK THIS IS 2368 02:22:39,057 --> 02:22:41,626 DIFFERENT FROM NATURAL ACUTE 2369 02:22:41,626 --> 02:22:43,494 INFECTIONS, I THINK THERE'S TWO 2370 02:22:43,494 --> 02:22:45,797 DISTINCT POSSIBILITIES. 2371 02:22:45,797 --> 02:22:47,665 ONE IS THE INITIAL POPULATION 2372 02:22:47,665 --> 02:22:53,671 SIZE IS QUITE LARGE AT 3.6 TEN 2373 02:22:53,671 --> 02:22:58,910 TIMES TO THE FIVE TIMES 50 IN 2374 02:22:58,910 --> 02:23:02,180 THE INOCULUM AND COULD GO TO THE 2375 02:23:02,180 --> 02:23:04,382 INITIAL POPULATION SIZE DIFFERS 2376 02:23:04,382 --> 02:23:08,753 FROM THE INOCULUM DOSE AND THE 2377 02:23:08,753 --> 02:23:10,788 MAGNITUDE OF EFFECTS BE 2378 02:23:10,788 --> 02:23:11,456 DIFFERENT. 2379 02:23:11,456 --> 02:23:15,059 IT COULD BE THE WILD TYPE AMINO 2380 02:23:15,059 --> 02:23:17,295 ACIDS ARE MORE FIT THAN THE 2381 02:23:17,295 --> 02:23:22,900 ALTERNATIVES IN HUMANS AND WOULD 2382 02:23:22,900 --> 02:23:30,074 DRIVE MORE EFFICIENT SELECTION. 2383 02:23:30,074 --> 02:23:31,542 AND THEY COMPRISE MULTIPLE 2384 02:23:31,542 --> 02:23:41,953 DISTINCT SUBPOPULATIONS. 2385 02:23:47,759 --> 02:23:50,495 WE KNOW FOR INFLUENZA A VIRUSES 2386 02:23:50,495 --> 02:23:51,229 TRANSMISSION ASSOCIATED WITH A 2387 02:23:51,229 --> 02:23:52,497 TIGHT BOTTLENECK. 2388 02:23:52,497 --> 02:23:54,799 THAT MEANS REGARDLESS OF THE 2389 02:23:54,799 --> 02:23:56,601 NUMBER OF VARIANTS PRESENT IN 2390 02:23:56,601 --> 02:23:58,436 THE DONOR INDIVIDUAL WE SEE THE 2391 02:23:58,436 --> 02:24:01,672 VERY FEW VARIANTS ESTABLISHED 2392 02:24:01,672 --> 02:24:03,574 INFECT 2393 02:24:03,574 --> 02:24:05,510 INFECTION IN AS FEW AS ONE 2394 02:24:05,510 --> 02:24:09,347 ESTABLISHED IN THE INDIVIDUAL AS 2395 02:24:09,347 --> 02:24:11,415 SEEN IN ANIMAL MODEL SYSTEMS AND 2396 02:24:11,415 --> 02:24:13,918 NATURALLY INFECTED HUMANS. 2397 02:24:13,918 --> 02:24:15,653 WE WANTED TO BETTER UNDERSTAND 2398 02:24:15,653 --> 02:24:20,658 THE POTENTIAL FOR SELECTION TO 2399 02:24:20,658 --> 02:24:22,760 ACT DURING TRANSMISSION. 2400 02:24:22,760 --> 02:24:25,096 WE QUESTION AT WHAT POINT DOES 2401 02:24:25,096 --> 02:24:26,898 THE BOTTLENECK ACT. 2402 02:24:26,898 --> 02:24:29,700 I'LL WALK YOU THROUGH 2403 02:24:29,700 --> 02:24:30,034 POSSIBILITIES. 2404 02:24:30,034 --> 02:24:35,206 IT COULD BE IN THE DONOR HOST 2405 02:24:35,206 --> 02:24:36,641 SUCH THAT FEW ARE SAID IN THE 2406 02:24:36,641 --> 02:24:37,108 ENVIRONMENT. 2407 02:24:37,108 --> 02:24:39,510 THE BOTTLENECK COULD OCCUR IN 2408 02:24:39,510 --> 02:24:42,013 THE ENVIRONMENT WHERE YOU HAVE 2409 02:24:42,013 --> 02:24:43,080 DILUTION OF VIRUS RELEASED IN 2410 02:24:43,080 --> 02:24:45,116 THE AREA OR ACTIVATION OF VIRUS 2411 02:24:45,116 --> 02:24:46,951 SUCH THAT IS NO LONGER 2412 02:24:46,951 --> 02:24:51,355 INFECTIOUS. 2413 02:24:51,355 --> 02:24:53,825 WE WOULD HAVE IT DURING THE 2414 02:24:53,825 --> 02:24:56,427 INITIAL INFECTION WHERE IT MEETS 2415 02:24:56,427 --> 02:24:58,329 MUCOSAL BARRIERS AND MAY NOT BE 2416 02:24:58,329 --> 02:25:04,202 ABLE TO PENETRATE EFFICIENTLY. 2417 02:25:04,202 --> 02:25:07,438 OR DURING WITHIN THE RECIPIENT 2418 02:25:07,438 --> 02:25:09,974 HOST AND DO VARIANTS INFECT IN 2419 02:25:09,974 --> 02:25:12,376 THE RECIPIENT BUT DURING THE 2420 02:25:12,376 --> 02:25:13,444 INITIAL EXPANSION OF THE VIRAL 2421 02:25:13,444 --> 02:25:14,145 POPULATIONS MANY LINEAGES ARE 2422 02:25:14,145 --> 02:25:17,415 LOST. 2423 02:25:17,415 --> 02:25:18,816 THE DISTINGUISHED THE 2424 02:25:18,816 --> 02:25:24,055 POSSIBILITIES WE DEVELOPED A 2425 02:25:24,055 --> 02:25:27,058 BAR-COD 2426 02:25:27,058 --> 02:25:28,993 BAR-CODED INFLUENZA VIRUS AND 2427 02:25:28,993 --> 02:25:36,234 WE'VE IDENTIFIED A REGION IN THE 2428 02:25:36,234 --> 02:25:42,440 GENOMES THE SITE OF DIVERSITY A 2429 02:25:42,440 --> 02:25:45,676 NATURAL OCCURRING BAR CODE AND 2430 02:25:45,676 --> 02:25:46,944 THIS IS ANOTHER SEASONAL 2431 02:25:46,944 --> 02:25:51,115 INFLUENZA VIRUS AND DIDN'T WANT 2432 02:25:51,115 --> 02:25:54,352 TO ATTENUATE THE VIRUS BUT 2433 02:25:54,352 --> 02:25:55,653 RATHER BUILD IN THE DIVERSITY 2434 02:25:55,653 --> 02:25:56,654 SEEN AT THE POPULATION LEVEL 2435 02:25:56,654 --> 02:26:00,291 INTO ONE VIRAL POPULATION. 2436 02:26:00,291 --> 02:26:08,399 WE FOUND 12 SITES OF VARIATION 2437 02:26:08,399 --> 02:26:13,337 AND ALLOWED EACH TO BE ONE OF 2438 02:26:13,337 --> 02:26:15,072 TWO NUCLEOTIDE IDENTITIES. 2439 02:26:15,072 --> 02:26:18,910 SINCE TWO TO THE 12 IS 4,096 THE 2440 02:26:18,910 --> 02:26:27,084 SYSTEM CREATES A LIBRARY WHERE 2441 02:26:27,084 --> 02:26:31,022 THERE ARE UP TO THOSE PRESENT 2442 02:26:31,022 --> 02:26:33,424 AND DETECTS CHANGES IN THE 2443 02:26:33,424 --> 02:26:34,759 GENETIC MAKEUP OF A VIRAL 2444 02:26:34,759 --> 02:26:35,059 POPULATION. 2445 02:26:35,059 --> 02:26:38,195 WE WORKED HARD TO MIKE SURE THE 2446 02:26:38,195 --> 02:26:42,566 BAR CODE WOULD BE FITNESS 2447 02:26:42,566 --> 02:26:44,902 NEUTRAL AND WILL DETECT RANDOM 2448 02:26:44,902 --> 02:26:48,639 CHANGES IN THE COMPOSITION. 2449 02:26:48,639 --> 02:26:51,776 IN OTHER WORDS, DETECT GENETIC 2450 02:26:51,776 --> 02:26:53,477 THROUGH AND WE USED THIS WITH 2451 02:26:53,477 --> 02:26:54,779 OUR FAVORITE ANIMAL MODEL WHICH 2452 02:26:54,779 --> 02:26:57,214 IS A GUINEA PIG. 2453 02:26:57,214 --> 02:26:59,450 WE USE THEM FOR INFLUENZA A 2454 02:26:59,450 --> 02:27:00,584 VIRUS FOR TRANSMISSION VIRUS 2455 02:27:00,584 --> 02:27:05,556 BECAUSE THEY'RE HIGHLY 2456 02:27:05,556 --> 02:27:10,995 SUSCEPTIBLE TO INFECTION AND WE 2457 02:27:10,995 --> 02:27:15,166 SEE TRANSMISSION FROM THE GUINEA 2458 02:27:15,166 --> 02:27:17,134 PIGS AND HAVE TWO WAYS TO MODEL 2459 02:27:17,134 --> 02:27:17,468 TRANSMISSION. 2460 02:27:17,468 --> 02:27:21,105 WE HAVE INFECTED AND EXPOSED 2461 02:27:21,105 --> 02:27:22,940 ANIMALS TOGETHER WITHIN THE SAME 2462 02:27:22,940 --> 02:27:28,346 CAGE SO ALL MODES CAN OCCUR AND 2463 02:27:28,346 --> 02:27:30,147 HERE THE AEROSOL WITH ANIMALS IN 2464 02:27:30,147 --> 02:27:32,583 THE SAME CAGE BUT SEPARATE A 2465 02:27:32,583 --> 02:27:34,118 DIVIDER SUCH VIRUS CAN ONLY MOVE 2466 02:27:34,118 --> 02:27:35,219 THROUGH THE AIR TO THE EXPOSED 2467 02:27:35,219 --> 02:27:45,363 ANIMAL. 2468 02:27:47,431 --> 02:27:51,002 WE HAVE FOUR CONTACT 2469 02:27:51,002 --> 02:27:53,037 TRANSMISSION PAIRS AND THIS IS 2470 02:27:53,037 --> 02:27:54,772 SHOWING THE VIRAL LOAD DYNAMICS 2471 02:27:54,772 --> 02:27:57,308 IN THE ANIMALS AND THE 2472 02:27:57,308 --> 02:28:01,345 INOCULATED ANIMALS IN BLUE AND 2473 02:28:01,345 --> 02:28:07,118 EXPOSED ANIMALS ARE IN RED OR 2474 02:28:07,118 --> 02:28:10,554 YELLOW AND EVALUATE THE DYNAMICS 2475 02:28:10,554 --> 02:28:13,824 AND HAVE TAKEN THE NASAL WASH 2476 02:28:13,824 --> 02:28:15,659 SAMPLES AND APPLIED NEXT 2477 02:28:15,659 --> 02:28:17,194 GENERATION SEQUENCING TO THE BAR 2478 02:28:17,194 --> 02:28:18,329 CODE OF THE VIRUS. 2479 02:28:18,329 --> 02:28:24,935 LOOKING FIRST AT THE DIRECTLY 2480 02:28:24,935 --> 02:28:26,370 INOCULATED ANIMALS HERE WE HAVE 2481 02:28:26,370 --> 02:28:28,706 REPRESENTATIVE ANIMALS SHOWN AND 2482 02:28:28,706 --> 02:28:31,375 THE INOCULATION DOSE IS FIVE 2483 02:28:31,375 --> 02:28:33,811 TIMES TEN TO THE FOUR 2484 02:28:33,811 --> 02:28:34,912 PLATFORMING UNITS. 2485 02:28:34,912 --> 02:28:42,686 AND THE Y AXIS IS SHOWING THE 2486 02:28:42,686 --> 02:28:44,055 TITER AND NASAL WASHES ACROSS 2487 02:28:44,055 --> 02:28:44,789 TIME. 2488 02:28:44,789 --> 02:28:46,490 THE COLORS ARE SHOWING UNIQUE 2489 02:28:46,490 --> 02:28:47,024 BAR CODES. 2490 02:28:47,024 --> 02:28:54,298 EACH BAR CODE IS REPRESENTED AND 2491 02:28:54,298 --> 02:28:56,300 THE HEIGHT INDICATE THE 2492 02:28:56,300 --> 02:28:58,502 FREQUENCY IN THE POPULATION AND 2493 02:28:58,502 --> 02:29:01,772 YOU CAN SEE A LOT OF BAR CODES 2494 02:29:01,772 --> 02:29:03,074 WERE MAINTAINED OVER TIME. 2495 02:29:03,074 --> 02:29:04,875 IT'S A HIGH DIVERSITY SYSTEM. 2496 02:29:04,875 --> 02:29:07,078 THAT COULD BE SEEN MORE CLEARLY 2497 02:29:07,078 --> 02:29:12,450 HERE WITH A QUANTITATIVE 2498 02:29:12,450 --> 02:29:15,519 ANALYSIS OF DIVERSITY. 2499 02:29:15,519 --> 02:29:16,954 IT TAKES INTO ACCOUNT THE NUMBER 2500 02:29:16,954 --> 02:29:24,028 OF BAR COZE -- CODES DETECTED 2501 02:29:24,028 --> 02:29:33,771 AND SEE IN MOST ANIMALS A 2502 02:29:33,771 --> 02:29:34,805 GRADUAL DECLINE OVER TIME AND 2503 02:29:34,805 --> 02:29:36,440 YOU CAN SEE RIGHT AWAY THERE'S A 2504 02:29:36,440 --> 02:29:41,212 DIFFERENT DYNAMIC PLAYING OUT 2505 02:29:41,212 --> 02:29:42,746 AND FEW BAR CODES ESTABLISHED IN 2506 02:29:42,746 --> 02:29:44,181 THE EXPOSED ANIMALS. 2507 02:29:44,181 --> 02:29:46,650 THIS REPLICATES WELL WHAT HAS 2508 02:29:46,650 --> 02:29:48,385 BEEN SEEN PREVIOUSLY AS 2509 02:29:48,385 --> 02:29:53,858 DESCRIBED FROM BOTH ANIMAL 2510 02:29:53,858 --> 02:29:59,730 MODELS THERE'S A TIGHT 2511 02:29:59,730 --> 02:30:03,134 TRANSMISSION BOTTLENECK AND ONE 2512 02:30:03,134 --> 02:30:07,071 OR TWO FOR THESE AND IF YOU LOOK 2513 02:30:07,071 --> 02:30:13,010 AT THE TIME POINT POSITIVE IN 2514 02:30:13,010 --> 02:30:14,044 THE NASAL WATCHES WE HAVE A LOT 2515 02:30:14,044 --> 02:30:14,612 OF DETECTED. 2516 02:30:14,612 --> 02:30:16,647 THE FIRST IS HIGH DIVERSITY AND 2517 02:30:16,647 --> 02:30:22,753 IT'S IN THE ENSUING 24 HOURS THE 2518 02:30:22,753 --> 02:30:26,023 DIVERSITY COLLAPSES AND A COUPLE 2519 02:30:26,023 --> 02:30:26,891 LINEAGES PREVAIL AND IT'S 2520 02:30:26,891 --> 02:30:28,926 OBVIOUS WHEN WE LOOK AT THE 2521 02:30:28,926 --> 02:30:30,194 QUANTITATIVE ANALYSIS OF 2522 02:30:30,194 --> 02:30:30,861 DIVERSITY THE EXPOSED ANIMALS 2523 02:30:30,861 --> 02:30:32,363 ARE PLOTTED IN RED. 2524 02:30:32,363 --> 02:30:37,868 YOU CAN SEE THE SHARP DECLINE 2525 02:30:37,868 --> 02:30:41,138 EARLY ON IN THE DIVERSITY AND IT 2526 02:30:41,138 --> 02:30:43,073 APPEARS THERE'S A LOT OF BAR 2527 02:30:43,073 --> 02:30:44,375 CODES BEING TRANSFERRED FROM THE 2528 02:30:44,375 --> 02:30:48,846 ENVIRONMENT TO THE RECIPIENT 2529 02:30:48,846 --> 02:30:51,081 ANIMALS AND FEW THAT SUCCEED 2530 02:30:51,081 --> 02:30:53,984 WITHIN THE RECIPIENT HOST MOST 2531 02:30:53,984 --> 02:30:56,954 ARE LOST DESPITE THE BAR CODES 2532 02:30:56,954 --> 02:31:01,192 ARE FITNESS NULT NEUTRAL AND 2533 02:31:01,192 --> 02:31:03,093 THEY'RE LOST BECAUSE OF A 2534 02:31:03,093 --> 02:31:13,404 STOCHASTIC EVENT. 2535 02:31:16,607 --> 02:31:22,613 THESE THREE PAIRS WERE 2536 02:31:22,613 --> 02:31:23,781 INOCULATED AND EXPOSED PAIRS 2537 02:31:23,781 --> 02:31:25,482 SHOWN ON TOP AND BOTTOM. 2538 02:31:25,482 --> 02:31:27,818 AGAIN, VERY DIVERSE ON THE FIRST 2539 02:31:27,818 --> 02:31:28,986 POSITIVE DAY AND LOW DIVERSITY 2540 02:31:28,986 --> 02:31:39,330 ON SUBSEQUENT DAYS. 2541 02:31:46,437 --> 02:31:48,772 WE LOOK AT THESE TWO DAYS AFTER 2542 02:31:48,772 --> 02:31:50,641 THE POSITIVE SAMPLE. 2543 02:31:50,641 --> 02:31:53,010 SUCH THAT FEW LINEAGES ARE 2544 02:31:53,010 --> 02:31:54,011 SUSTAINED IN THE RECIPIENT OVER 2545 02:31:54,011 --> 02:31:57,481 THE COURSE OF INFECTION. 2546 02:31:57,481 --> 02:31:59,149 AND TO THINK ON THE IMPLICATIONS 2547 02:31:59,149 --> 02:32:01,452 OF THOSE RESULTS IT APPEARS THE 2548 02:32:01,452 --> 02:32:03,387 LOSS OF DIVERSITY IS PRIMARILY 2549 02:32:03,387 --> 02:32:05,055 DRIVEN BY EVENTS THAT OCCURRED 2550 02:32:05,055 --> 02:32:06,190 IN THE EXPANSION OF INFECTION 2551 02:32:06,190 --> 02:32:09,159 AND NOT AS WE MIGHT HAVE GUESSED 2552 02:32:09,159 --> 02:32:14,798 DURING THE DONOR RECIPIENT 2553 02:32:14,798 --> 02:32:16,967 TRANSFER ITSELF WE HAVE A 2554 02:32:16,967 --> 02:32:18,135 SITUATION AND IT'S HIGH 2555 02:32:18,135 --> 02:32:20,004 DIVERSITY OF EVENT INITIALLY AND 2556 02:32:20,004 --> 02:32:25,142 THE EXPANSION IS LOST DURING 2557 02:32:25,142 --> 02:32:35,519 POPULATION EXPANSION. 2558 02:32:39,356 --> 02:32:41,692 WE HAVE A HIGH DIVERSITY TIME 2559 02:32:41,692 --> 02:32:46,664 POINT WITHIN RECEPTING 2560 02:32:46,664 --> 02:32:57,174 INDIVIDUAL SO WE HAVE AND WE 2561 02:33:11,055 --> 02:33:12,423 HAVE INDIVIDUAL FOLKS WHO HAVE 2562 02:33:12,423 --> 02:33:13,223 BEEN EXAMINED. 2563 02:33:13,223 --> 02:33:18,762 TO FINISH I WANT TO ACKNOWLEDGE 2564 02:33:18,762 --> 02:33:26,937 THE GROUP WHO PERFORM THE WORK 2565 02:33:26,937 --> 02:33:31,075 AND THOSE WHO HAVE DONE THE 2566 02:33:31,075 --> 02:33:33,243 SEQUENCING ON THE DIRECTLY 2567 02:33:33,243 --> 02:33:34,278 CHALLENGED HUMANS AND IT'S A 2568 02:33:34,278 --> 02:33:36,647 GREAT TEAM EFFORT WITH THE 2569 02:33:36,647 --> 02:33:37,381 EXCELLENT COLLEAGUES AT EMORY 2570 02:33:37,381 --> 02:33:38,916 AND VIRGINIA TECH. 2571 02:33:38,916 --> 02:33:40,617 THE HUMAN CHALLENGE WORK GETS 2572 02:33:40,617 --> 02:33:42,853 FUNDED BY THE FOUNDATION FLU 2573 02:33:42,853 --> 02:33:43,554 LAB. 2574 02:33:43,554 --> 02:33:45,489 THE BAR CODE RELATED PUBLIC 2575 02:33:45,489 --> 02:33:46,990 HEALTH IS FUNDED BY NIH. 2576 02:33:46,990 --> 02:33:57,501 THANK YOU FOR YOUR ATTENTION. 2577 02:34:00,070 --> 02:34:01,305 >> GREAT TALK. 2578 02:34:01,305 --> 02:34:03,374 I WAS WONDERING IF THE 2579 02:34:03,374 --> 02:34:05,676 BOTTLENECK IS HAPPENING DURING 2580 02:34:05,676 --> 02:34:06,944 THE EXPANSION OF THE VIRUS WHY 2581 02:34:06,944 --> 02:34:08,812 ONLY IN THE RECIPIENT AND NOT 2582 02:34:08,812 --> 02:34:10,114 THE ORIGINAL INOCULATED ANIMALS? 2583 02:34:10,114 --> 02:34:11,882 >> GREAT POINT. 2584 02:34:11,882 --> 02:34:14,251 WE'RE VERY INTERESTED IN THE 2585 02:34:14,251 --> 02:34:17,488 DIFFERENCE WE SEE BETWEEN THE 2586 02:34:17,488 --> 02:34:19,089 NATURALLY EXPOSED ANIMALS AND 2587 02:34:19,089 --> 02:34:22,626 THE DYNAMIC. 2588 02:34:22,626 --> 02:34:24,461 THE KEY DIFFERENCE IN MY FIND IS 2589 02:34:24,461 --> 02:34:28,932 IS THE POPULATION SCIENCE 2590 02:34:28,932 --> 02:34:30,868 INITIALLY INTRODUCED AND WE KNOW 2591 02:34:30,868 --> 02:34:34,838 WE PUT FIVE TIMES TEN TO THE 2592 02:34:34,838 --> 02:34:37,474 FOUR INTRANASALLY IN THE 2593 02:34:37,474 --> 02:34:39,076 INOCULATED AND THE LARGE 2594 02:34:39,076 --> 02:34:43,747 POPULATION SIZE OVERCOMES THE 2595 02:34:43,747 --> 02:34:46,950 STOCHASTIC EFFECTS TO ALLOW 2596 02:34:46,950 --> 02:34:49,653 LINEAGES TO EXPAND AND TAKE HOLD 2597 02:34:49,653 --> 02:34:51,355 IN THE HOST AND THE SITE OF THE 2598 02:34:51,355 --> 02:34:52,489 INITIAL DEPOSITION FOR EXAMPLE 2599 02:34:52,489 --> 02:34:54,591 BUT I THINK THAT'S THE MOST 2600 02:34:54,591 --> 02:34:55,025 LIKELY EXPLANATION. 2601 02:34:55,025 --> 02:35:02,132 >> THANK YOU. 2602 02:35:02,132 --> 02:35:03,634 >> THANK YOU, NICE TALK AND 2603 02:35:03,634 --> 02:35:04,034 INTERESTING TOPIC. 2604 02:35:04,034 --> 02:35:09,373 THE FIRST PART OF YOUR TALK YOU 2605 02:35:09,373 --> 02:35:12,943 POINTED OUT THERE'S DISTINCT 2606 02:35:12,943 --> 02:35:14,044 NICHES IN PARTS OF THE 2607 02:35:14,044 --> 02:35:14,511 RESPIRATORY. 2608 02:35:14,511 --> 02:35:19,049 WHAT DO YOU THINK COULD BE 2609 02:35:19,049 --> 02:35:23,120 CONTRIBUTING TO THOSE. 2610 02:35:23,120 --> 02:35:26,924 IS IT IT IMMUNE INVOLVED? 2611 02:35:26,924 --> 02:35:27,524 I'M CURIOUS. 2612 02:35:27,524 --> 02:35:32,429 >> I AGREE. 2613 02:35:32,429 --> 02:35:37,100 IT'S INTERESTING WE HAVE SEEN 2614 02:35:37,100 --> 02:35:38,502 SPATIAL STRUCTURE AND IN THOSE 2615 02:35:38,502 --> 02:35:41,271 SYSTEMS WE'RE ABLE TO SAMPLE THE 2616 02:35:41,271 --> 02:35:44,908 LOWER RESPIRATORY TRACT. 2617 02:35:44,908 --> 02:35:47,978 SO WE SEE THESE VIRAL 2618 02:35:47,978 --> 02:35:49,379 SUBPOPULATIONS SET UP IN 2619 02:35:49,379 --> 02:35:51,248 DISTINCT POPULATION AND DON'T 2620 02:35:51,248 --> 02:35:52,216 NECESSARILY MIX WELL. 2621 02:35:52,216 --> 02:35:54,251 THE SIMPLE ANSWER IS VIRUSES ARE 2622 02:35:54,251 --> 02:35:55,953 MORE LIKELY TO SPREAD IN A 2623 02:35:55,953 --> 02:35:58,989 LOCALIZED MANNER TO INFECT 2624 02:35:58,989 --> 02:36:02,860 NEIGHBORING CELLS THAN TO 2625 02:36:02,860 --> 02:36:04,962 DISPERSE ALONG DISTANCE AND 2626 02:36:04,962 --> 02:36:06,730 CREATE STRUCTURE RATHER THAN A 2627 02:36:06,730 --> 02:36:07,598 PERFECTLY MIXED SYSTEM. 2628 02:36:07,598 --> 02:36:09,867 THE HUMAN RESPIRATORY TRACT, 2629 02:36:09,867 --> 02:36:12,069 EVERYTHING'S PRETTY CLOSE 2630 02:36:12,069 --> 02:36:16,773 TOGETHER. 2631 02:36:16,773 --> 02:36:19,042 WE WERE SURPRISED TO SEE A 2632 02:36:19,042 --> 02:36:23,046 SIMILAR SPATIAL STRUCTURE IN 2633 02:36:23,046 --> 02:36:33,056 THAT ANATOMICAL LOCATION. 2634 02:36:33,056 --> 02:36:36,293 IN THE MOUSE WE DON'T KNOW IT'S 2635 02:36:36,293 --> 02:36:36,693 REPLICATING THERE. 2636 02:36:36,693 --> 02:36:42,232 IT'S DETECTED THERE BUT COULD BE 2637 02:36:42,232 --> 02:36:47,170 MOVING INTO THE MOUSE FROM WHERE 2638 02:36:47,170 --> 02:36:49,706 IT'S REPLICATING AND IT'S 2639 02:36:49,706 --> 02:36:55,045 FEEDING INTO THE ORAL SITE NOT 2640 02:36:55,045 --> 02:36:58,549 JUST ANYWHERE AND NEEDS FURTHER 2641 02:36:58,549 --> 02:36:58,882 INVESTIGATION. 2642 02:36:58,882 --> 02:37:01,251 RIGHT NOW IT'S SIMPLY AN 2643 02:37:01,251 --> 02:37:01,552 OBSERVATION. 2644 02:37:01,552 --> 02:37:01,985 >> THANK YOU. 2645 02:37:01,985 --> 02:37:07,658 I HAVE A QUESTION ON MY OWN. 2646 02:37:07,658 --> 02:37:16,967 CAN YOU COMMENT ON THE HIGHLY 2647 02:37:16,967 --> 02:37:21,905 VARIABLE VIRUSES COULD BE 2648 02:37:21,905 --> 02:37:22,406 DETECTED PARTICLES? 2649 02:37:22,406 --> 02:37:27,044 >> THAT'S A GOOD POINT. 2650 02:37:27,044 --> 02:37:29,713 ONE POSSIBILITY WE SEE THEM LOST 2651 02:37:29,713 --> 02:37:35,018 EARLIER IS THE TRANSMITTED 2652 02:37:35,018 --> 02:37:39,056 GENOMES WHAT WE DETECT COULD BE 2653 02:37:39,056 --> 02:37:42,593 AC PACKAGED WITH A GENOME WITH 2654 02:37:42,593 --> 02:37:45,596 A DELETION OR NOT ALL THE GENE 2655 02:37:45,596 --> 02:37:46,129 SEGMENTS. 2656 02:37:46,129 --> 02:37:48,832 SUCH A VIRUS COULD INFECT CELLS 2657 02:37:48,832 --> 02:37:51,101 AND COULD START REPLICATION TO 2658 02:37:51,101 --> 02:37:52,903 SOME EXTENT BUT WOULDN'T MAKE 2659 02:37:52,903 --> 02:37:57,240 ANY PROGENY. 2660 02:37:57,240 --> 02:38:07,050 SO IT'S A POSSIBILITY I DON'T 2661 02:38:07,050 --> 02:38:16,093 HAVE EVIDENCE TO EXCLUDE IT AND 2662 02:38:16,093 --> 02:38:26,637 THIS IS LOOKING AT THE GEN EITY 2663 02:38:34,845 --> 02:38:36,513 AND IT COULD BE 12 OR 24 HOURS 2664 02:38:36,513 --> 02:38:44,855 BEFORE ANY PROGENY ARE MADE. 2665 02:38:44,855 --> 02:38:47,924 THEY WOULD HAVE A STRONG 2666 02:38:47,924 --> 02:38:49,760 TEMPORAL ADVANTAGE AND WOULD 2667 02:38:49,760 --> 02:38:52,029 TAKE OVER DUE TO THE 2668 02:38:52,029 --> 02:38:53,030 EXPERIMENTAL NATURE FOLLOWING 2669 02:38:53,030 --> 02:38:57,768 FROM THE FIRST GENERATION. 2670 02:38:57,768 --> 02:38:59,102 WE CANNOT EXCLUDE THE 2671 02:38:59,102 --> 02:39:01,138 POSSIBILITY OF INFECTED GENOMES. 2672 02:39:01,138 --> 02:39:07,044 >> OUT OF CURIOSITY, DO YOU HAVE 2673 02:39:07,044 --> 02:39:10,147 A NUMBER OF ALL THE BAR CODES 2674 02:39:10,147 --> 02:39:10,514 TRANSMITS? 2675 02:39:10,514 --> 02:39:14,351 OUT THEIR 4,000 IB AVERAGE IN 2676 02:39:14,351 --> 02:39:15,118 THOSE EXPERIMENTS, HOW MANY WERE 2677 02:39:15,118 --> 02:39:25,529 TRANSMITTED IN GENERAL? 2678 02:39:27,130 --> 02:39:30,434 >> I DON'T HAVE IT AT MY FIN 2679 02:39:30,434 --> 02:39:33,737 FINGER -- TIPS BUT LOOKS LIKE A 2680 02:39:33,737 --> 02:39:33,904 LOT. 2681 02:39:33,904 --> 02:39:40,210 >> WELL, THANK YOU SO MUCH. 2682 02:39:40,210 --> 02:39:42,913 >> WE DON'T HAVE ANY QUESTION 2683 02:39:42,913 --> 02:39:47,451 ONLINE SO ANICE THANK YOU SO 2684 02:39:47,451 --> 02:39:50,654 MUCH AND HOPEFULLY WE'LL GET YOU 2685 02:39:50,654 --> 02:39:52,155 TO THE D.C. AREA NEXT TIME WE 2686 02:39:52,155 --> 02:39:52,589 HAVE A MEETING HERE. 2687 02:39:52,589 --> 02:40:00,497 >> THANK YOU. 2688 02:40:00,497 --> 02:40:03,066 >> OKAY. 2689 02:40:03,066 --> 02:40:05,402 WE LITERALLY HAVE -- I'LL 2690 02:40:05,402 --> 02:40:10,674 FOLLOW-UP WITH THE QUESTION 2691 02:40:10,674 --> 02:40:11,074 ONLINE. 2692 02:40:11,074 --> 02:40:15,746 I HAVE A GREAT ANNOUNCEMENT NOW, 2693 02:40:15,746 --> 02:40:18,615 WHICH IS THE LUNCH BREAK. 2694 02:40:18,615 --> 02:40:21,451 FOR THOSE THAT DO NOT KNOW WHERE 2695 02:40:21,451 --> 02:40:24,254 THE FAS TERRACE IS, FOLLOW THE 2696 02:40:24,254 --> 02:40:24,454 CROWD. 2697 02:40:24,454 --> 02:40:27,390 TRUST ME, THE PEOPLE WILL GO 2698 02:40:27,390 --> 02:40:31,895 THERE. 2699 02:40:31,895 --> 02:40:33,430 WE'RE SUPPOSED TO COME BACK AT 2700 02:40:33,430 --> 02:40:34,812 1:00 SHARP, PLEASE. 2701 02:40:34,812 --> 02:40:38,749 GOOD AFTERNOON TO EVERYONE I 2702 02:40:38,749 --> 02:40:42,419 AM PATRICIA AND WELCOME TO THE 2703 02:40:42,419 --> 02:40:43,253 AFTERNOON SESSION. 2704 02:40:43,253 --> 02:40:45,222 IT'S A GREAT PLEASURE FOR ME TO 2705 02:40:45,222 --> 02:40:47,191 INTRODUCE THE FIRST SPEAKER OF 2706 02:40:47,191 --> 02:40:51,929 THE SESSION, DR. DANIEL CHERTOW. 2707 02:40:51,929 --> 02:40:54,364 HE IS THE HEAD OF THE EMERGING 2708 02:40:54,364 --> 02:40:57,601 PATHOGEN SECTION IN THE CRITICAL 2709 02:40:57,601 --> 02:41:03,140 CARE MEDICINE DEPARTMENT AT NIH 2710 02:41:03,140 --> 02:41:04,241 CLINICAL CENTER. 2711 02:41:04,241 --> 02:41:05,876 HIS RESEARCH INCLUDES 2712 02:41:05,876 --> 02:41:06,710 UNDERSTANDING THE PATHOGEN SINCE 2713 02:41:06,710 --> 02:41:11,114 OF SEVERE, EMERGING OR 2714 02:41:11,114 --> 02:41:15,485 RE-EMERGING INFECTIOUS DISEASES 2715 02:41:15,485 --> 02:41:19,656 INCLUDING EBOLA VIRUS, EBOLA 2716 02:41:19,656 --> 02:41:21,358 VIRUS WITH COVID-19 AND CARED 2717 02:41:21,358 --> 02:41:23,126 FOR PATIENTS WITH EBOLA IN WEST 2718 02:41:23,126 --> 02:41:27,865 AFRICA DURING THE OUTBREAK IN 2719 02:41:27,865 --> 02:41:34,605 2015 TO 2016 AND MA AS IT MADE 2720 02:41:34,605 --> 02:41:39,676 UNDERSTANDING OF THE PATHOGENIC 2721 02:41:39,676 --> 02:41:42,045 DISEASE AND HIS RESEARCH EFFORT 2722 02:41:42,045 --> 02:41:43,714 IS TOWARDS UNDERSTANDING THE 2723 02:41:43,714 --> 02:41:48,585 HOST PATHOGEN INTERACTION DURING 2724 02:41:48,585 --> 02:41:54,258 THE SEVERE COVID-19 AND 2725 02:41:54,258 --> 02:41:59,429 ESTABLISH A LANDMARK IN NATURE 2726 02:41:59,429 --> 02:42:01,164 DEMONSTRATING SARS COV2 IN AN 2727 02:42:01,164 --> 02:42:03,133 TOP CAL SITES INCLUDING THE 2728 02:42:03,133 --> 02:42:06,003 BRAIN ANATOMICAL SITES AND THE 2729 02:42:06,003 --> 02:42:07,037 PRESENTATION JUST TO SUMMARIZE 2730 02:42:07,037 --> 02:42:11,775 THE MOST IMPORTANT STUDIES ON 2731 02:42:11,775 --> 02:42:14,511 SEVERE COVID-19 AND THE TITLE IS 2732 02:42:14,511 --> 02:42:16,046 SARS COV2 INFECTION AND PER 2733 02:42:16,046 --> 02:42:21,218 SISSANCE IN THE HUMAN BODY AND 2734 02:42:21,218 --> 02:42:22,486 BRAIN -- PERSISTENCE IN THE 2735 02:42:22,486 --> 02:42:32,863 HUMAN BODY AND BRAIN. 2736 02:42:33,196 --> 02:42:38,568 THANK YOU PHOR THE INVITATION TO 2737 02:42:38,568 --> 02:42:47,477 THE ORGANIZERS AND MRS. SALZMAN 2738 02:42:47,477 --> 02:42:50,280 FOR CONTINUING THE AWARDS AND 2739 02:42:50,280 --> 02:42:52,215 I'LL STUDY THE FIRST YEAR OF THE 2740 02:42:52,215 --> 02:42:53,984 PANDEMIC IN THE NIH CLINICAL 2741 02:42:53,984 --> 02:43:01,024 CENTER AND I HAVE NO 2742 02:43:01,024 --> 02:43:01,325 DISCLOSURES. 2743 02:43:01,325 --> 02:43:04,761 AT THE ONSET NOT MUCH WAS GIVEN 2744 02:43:04,761 --> 02:43:05,929 OUTSIDE THE RESPIRATORY TRACT 2745 02:43:05,929 --> 02:43:13,637 AND MY GROUP DECIDED TO EMBARK 2746 02:43:13,637 --> 02:43:19,042 ON FATAL COVID-19 FIRST TO 2747 02:43:19,042 --> 02:43:21,611 DESCRIBE THE BURDEN OF COV2 AND 2748 02:43:21,611 --> 02:43:23,213 OUTSIDE THE RESPIRATORY TRACT 2749 02:43:23,213 --> 02:43:25,916 AND THE SECOND WAS TO DEFINE THE 2750 02:43:25,916 --> 02:43:27,351 CELLULAR TROPISM ACROSS THE 2751 02:43:27,351 --> 02:43:28,618 HUMAN BODY AND IMPORTANTLY THE 2752 02:43:28,618 --> 02:43:30,721 BRAIN. 2753 02:43:30,721 --> 02:43:33,323 THE THIRD IS TO DETERMINE IF 2754 02:43:33,323 --> 02:43:35,993 SARS COV2 PERSISTS IN WHAT 2755 02:43:35,993 --> 02:43:38,729 TISSUES AND INTERVALS AND TO DO 2756 02:43:38,729 --> 02:43:42,866 GOOD VIROLOGY AND DETERMINE THAT 2757 02:43:42,866 --> 02:43:44,968 SARS COV2 REPLICATES AND IS 2758 02:43:44,968 --> 02:43:49,072 THERE EVIDENCE AS THE EVOLVING 2759 02:43:49,072 --> 02:43:54,011 IN ANATOMIC COMPARTMENTS WE 2760 02:43:54,011 --> 02:43:58,148 COLLABORATED WITH A NUMBER OF 2761 02:43:58,148 --> 02:44:00,484 INVESTIGATORS AND VERY MUCH 2762 02:44:00,484 --> 02:44:02,486 REGIONAL HOSPITAL AND EASTERN 2763 02:44:02,486 --> 02:44:03,987 SHORE REGIONS OF MARYLAND AND 2764 02:44:03,987 --> 02:44:05,856 RECRUITMENT WAS INITIATED WITH 2765 02:44:05,856 --> 02:44:07,324 OUR UPSTREAM CLINICAL PARTNERS 2766 02:44:07,324 --> 02:44:09,526 AND WE HAD CONNECTION WITH THE 2767 02:44:09,526 --> 02:44:15,332 CRITICAL CARE DOCKS -- DOCTORS 2768 02:44:15,332 --> 02:44:18,869 WHO ALERTED US TO COVID-19 2769 02:44:18,869 --> 02:44:22,539 DEATHS AND THE REMAINS WERE 2770 02:44:22,539 --> 02:44:28,512 TRANSFERRED AND AUTOPSY WAS 2771 02:44:28,512 --> 02:44:30,614 PERFORMED IN COLLABORATION WITH 2772 02:44:30,614 --> 02:44:33,350 A POSTMORTEM INTERVAL OF LESS 2773 02:44:33,350 --> 02:44:35,752 THAN 24 HOURS TO PRESERVE TISSUE 2774 02:44:35,752 --> 02:44:38,088 AND PROTEIN AND NUCLEIC ACID 2775 02:44:38,088 --> 02:44:38,455 WITHIN TISSUE. 2776 02:44:38,455 --> 02:44:42,259 WE PERFORMED A TOTAL OF 44 2777 02:44:42,259 --> 02:44:44,161 AUTOPSIES BETWEEN MARCH AND 2020 2778 02:44:44,161 --> 02:44:45,095 AND MARCH 2021. 2779 02:44:45,095 --> 02:44:49,533 EACH AUTOPSY THAT WAS PERFORMED 2780 02:44:49,533 --> 02:44:54,137 IS DENOTED HERE ON THE MARYLAND 2781 02:44:54,137 --> 02:44:56,173 EPIDEMIOLOGY CURVE OF CASES 2782 02:44:56,173 --> 02:44:58,208 OUR CASES WERE WELL DISTRIBUTED 2783 02:44:58,208 --> 02:45:02,746 OVER THE FIRST YEAR OF THE 2784 02:45:02,746 --> 02:45:03,013 PANDEMIC. 2785 02:45:03,013 --> 02:45:04,047 IMPORTANTLY, NONE OF THESE 2786 02:45:04,047 --> 02:45:05,882 INDIVIDUALS WERE VACCINATED THIS 2787 02:45:05,882 --> 02:45:07,017 IS BEFORE VACCINATES WERE 2788 02:45:07,017 --> 02:45:10,454 AVAILABLE AND ALL INFECTED WITH 2789 02:45:10,454 --> 02:45:11,922 WILD TYPE AND THE VARIANT OF 2790 02:45:11,922 --> 02:45:14,357 CONCERNS HAS IMPLICATIONS FOR 2791 02:45:14,357 --> 02:45:16,426 THE GENERALIZABILITY OF OUR 2792 02:45:16,426 --> 02:45:16,693 FINDINGS. 2793 02:45:16,693 --> 02:45:18,728 WE PROCURED TISSUES FROM ALL 2794 02:45:18,728 --> 02:45:20,931 MAJOR ORGANS IN 44 CASE WITH 2795 02:45:20,931 --> 02:45:23,100 EXTENSIVE BRAIN SAMPLING IN A 2796 02:45:23,100 --> 02:45:24,801 SUBSET OF 11 CASES. 2797 02:45:24,801 --> 02:45:28,371 WE PRESERVED OVER 10,000 2798 02:45:28,371 --> 02:45:30,674 SPECIMENS ACROSS 85 ANATOMIC 2799 02:45:30,674 --> 02:45:33,610 SITES AND BODY FLUIDS IN THREE 2800 02:45:33,610 --> 02:45:34,177 WAYS. 2801 02:45:34,177 --> 02:45:41,985 FRESH TISSUE AND BODY FLUIDSES 2802 02:45:41,985 --> 02:45:45,856 -- FLUIDS FOR DROPLET PCR FOR 2803 02:45:45,856 --> 02:45:49,359 SARS COV2 AND PRESERVED ADJACENT 2804 02:45:49,359 --> 02:45:51,461 TISSUE FOR FLASH FROZEN SAMPLES 2805 02:45:51,461 --> 02:45:55,665 SO IN A SUBSET OF TISSUES WE CAN 2806 02:45:55,665 --> 02:45:58,535 PERFORM CULTURE AND LOOK FOR 2807 02:45:58,535 --> 02:46:00,670 REPLICATION IN OUR TISSUES AND 2808 02:46:00,670 --> 02:46:02,739 TISSUES WERE FIXED FOR 2809 02:46:02,739 --> 02:46:08,745 SUBSEQUENT HISTOLOGICAL AND 2810 02:46:08,745 --> 02:46:09,146 CHEMISTRY. 2811 02:46:09,146 --> 02:46:19,656 AND OUR COHORT WAS DIVERSE -- 2812 02:47:00,063 --> 02:47:00,497 [TECHNICAL DIFFICULTIES] 2813 02:47:00,497 --> 02:47:01,932 OF THE 11 ASSAYS ACROSS ALL 2814 02:47:01,932 --> 02:47:03,266 TISSUE GROUPS SAMPLED WITH THE 2815 02:47:03,266 --> 02:47:07,437 HIGHEST LEVELS DEPICTED IN RED, 2816 02:47:07,437 --> 02:47:09,372 DETECTED IN RESPIRATORY AND 2817 02:47:09,372 --> 02:47:13,009 CARDIOVASCULAR TISSUES EARLY IN 2818 02:47:13,009 --> 02:47:15,145 INFECTION AND AMONG THE LATE 2819 02:47:15,145 --> 02:47:17,747 CASES SARS RNA PERSISTED IN LOW 2820 02:47:17,747 --> 02:47:18,949 LEVELS DEPICTED IN THE BLUE 2821 02:47:18,949 --> 02:47:20,083 COLOR INCLUDING IN PATIENT 42 2822 02:47:20,083 --> 02:47:23,720 DENOTED AT THE TOP OF THE COLUMN 2823 02:47:23,720 --> 02:47:27,324 WHO DIED 230 DAYS AFTER INITIAL 2824 02:47:27,324 --> 02:47:29,893 COVID-19 ONSET THE TIME OF DEATH 2825 02:47:29,893 --> 02:47:32,696 RELATIVE TO ILLNESS ON SET IS AT 2826 02:47:32,696 --> 02:47:35,599 THE BOTTOM, EXCUSE ME, 230 DAYS 2827 02:47:35,599 --> 02:47:37,234 AFTER ILLNESS ONSET AND THEY 2828 02:47:37,234 --> 02:47:39,369 DIED OF CAUTIONS UNRELATED TO 2829 02:47:39,369 --> 02:47:43,506 THEIR INITIAL INFECTION. 2830 02:47:43,506 --> 02:47:46,710 SO DISPLAYED HERE ARE PCR 2831 02:47:46,710 --> 02:47:51,815 RESULTS FOR THE SAME 11 PATIENTS 2832 02:47:51,815 --> 02:47:53,683 ACROSS 10 ANATOMIC SITES IN THE 2833 02:47:53,683 --> 02:47:59,289 NERVOUS SYSTEM AND DETECTED IT 2834 02:47:59,289 --> 02:48:02,559 IN CNS TISSUES AND DETECTED 2835 02:48:02,559 --> 02:48:04,394 RESIDUAL RNA IN LATE CASES BOXED 2836 02:48:04,394 --> 02:48:05,295 THERE. 2837 02:48:05,295 --> 02:48:08,398 WE DEFINED LATE AS SOMEBODY THAT 2838 02:48:08,398 --> 02:48:09,966 DIED GREATER THAN OR EQUAL TO 31 2839 02:48:09,966 --> 02:48:12,902 DAYS AFTER THE INITIAL ILLNESS 2840 02:48:12,902 --> 02:48:16,139 ONSET AND IN THOSE LATE CASES WE 2841 02:48:16,139 --> 02:48:18,041 DETECTED RNA IN EACH OF AND 2842 02:48:18,041 --> 02:48:19,376 EVERY ONE OF THOSE IN AT LEAST 2843 02:48:19,376 --> 02:48:22,746 ONE REGION OF BRAIN AND 2844 02:48:22,746 --> 02:48:24,547 INCLUDING PATIENT NUMBER 42 WHO 2845 02:48:24,547 --> 02:48:26,883 DIED 230 DAYS AFTER ILLNESS 2846 02:48:26,883 --> 02:48:30,253 ONSET. 2847 02:48:30,253 --> 02:48:38,228 FROM OUR FROZEN SAMPLES WE HAD A 2848 02:48:38,228 --> 02:48:41,164 SUBSET OF TISSUES AND GREW VIRUS 2849 02:48:41,164 --> 02:48:43,433 FROM 25 FOCUSSING ON TISSUES 2850 02:48:43,433 --> 02:48:45,568 OUTSIDE THE RESPIRATORY TRACT 2851 02:48:45,568 --> 02:48:52,409 AND USING A VIROCELL CULTURE 2852 02:48:52,409 --> 02:48:56,646 THAT OVEREXPRESSED AND 2853 02:48:56,646 --> 02:49:01,851 SUCCESSFULLY GREW SARS COV2 FROM 2854 02:49:01,851 --> 02:49:07,957 NON-RESPIRATORY TISSUES THE E 2855 02:49:07,957 --> 02:49:09,993 EYEEY 2856 02:49:09,993 --> 02:49:18,268 EYEEYE, 2857 02:49:18,268 --> 02:49:24,207 DIFFERENT ORGANS AND ON THIS 2858 02:49:24,207 --> 02:49:26,376 FIGURE LOG TRANSFORMED RNA 2859 02:49:26,376 --> 02:49:28,511 LEVELS ARE SHOWN ON THE Y AXIS 2860 02:49:28,511 --> 02:49:31,948 AND ON THE LOG AXIS, LOG 2861 02:49:31,948 --> 02:49:34,250 TRANSFORM DAY OF ILLNESS ON THE 2862 02:49:34,250 --> 02:49:39,356 X AXIS LONG TRANSFORMED DAY OF 2863 02:49:39,356 --> 02:49:41,524 ILLNESS IS SHOWN AND SARS RNA 2864 02:49:41,524 --> 02:49:46,563 LEVELS WERE HIGHER IN 2865 02:49:46,563 --> 02:49:48,264 RESPIRATORY TISSUES SHOWN IN RED 2866 02:49:48,264 --> 02:49:52,202 COMPARED TO NON-RESPIRATORY IN 2867 02:49:52,202 --> 02:49:53,970 BLUE FOR MONTHS FOLLOWING 2868 02:49:53,970 --> 02:49:56,139 ILLNESS ONSET AND AYER RATE OF 2869 02:49:56,139 --> 02:49:58,508 DECLINE INVOLVED RNA LEVELS WAS 2870 02:49:58,508 --> 02:49:59,409 NOTED IN RESPIRATORY COMPARED 2871 02:49:59,409 --> 02:50:02,379 WITH NON-RESPIRATORY TISSUES 2872 02:50:02,379 --> 02:50:03,646 SUGGESTING A MORE RAPID 2873 02:50:03,646 --> 02:50:04,781 CLEARANCE FROM RESPIRATORY 2874 02:50:04,781 --> 02:50:05,849 COMPARED WITH NON-RESPIRATORY 2875 02:50:05,849 --> 02:50:14,224 TISSUES. 2876 02:50:14,224 --> 02:50:16,493 FINALLY WE EVALUATE THE 2877 02:50:16,493 --> 02:50:18,228 PROPORTION OF SARS COV2 SPIKE 2878 02:50:18,228 --> 02:50:19,729 GENE VARIANT POPULATIONS ACROSS 2879 02:50:19,729 --> 02:50:21,931 DIFFERENT TISSUES WITH THE SAME 2880 02:50:21,931 --> 02:50:32,075 PATIENT. 2881 02:50:34,577 --> 02:50:36,379 AND HAD BRAIN TISSUE BRACKET IN 2882 02:50:36,379 --> 02:50:37,647 RED NOT PRESENT IN THE LUNG 2883 02:50:37,647 --> 02:50:47,791 SAMPLE FROM THE SAME PATIENT. 2884 02:50:47,791 --> 02:50:52,395 THESE SUGGEST COMPARTMENTIZING 2885 02:50:52,395 --> 02:50:57,000 AND WHERE WE SEQUENCED VIRUS THE 2886 02:50:57,000 --> 02:50:59,803 PREDOMINANT VARIANT AND WE WERE 2887 02:50:59,803 --> 02:51:02,472 ABLE TO DETECT MINOR VARIANTS IN 2888 02:51:02,472 --> 02:51:04,274 ONE ANATOMIC DEPARTMENT NOT 2889 02:51:04,274 --> 02:51:04,841 DETECTED IN THE RESPIRATORY 2890 02:51:04,841 --> 02:51:14,951 TRACT. 2891 02:51:18,955 --> 02:51:27,197 A SUBSET INCLUDE THYROID AND 2892 02:51:27,197 --> 02:51:30,200 ESOPHAGUS AND YOU CAN SEE THE 2893 02:51:30,200 --> 02:51:34,737 BROWN STAINING AND IN TOTAL WE 2894 02:51:34,737 --> 02:51:36,573 DETECTED SARS COV2 WITHIN MORE 2895 02:51:36,573 --> 02:51:39,042 THAN 30 CELL TYPES ACROSS 35 2896 02:51:39,042 --> 02:51:49,185 TISSUES. 2897 02:51:57,160 --> 02:52:00,096 SHOWN HERE IN THE BRAIN AND 2898 02:52:00,096 --> 02:52:02,732 FINAL CORD ON THE RIGHT AND WE 2899 02:52:02,732 --> 02:52:04,367 OBSERVED STRAINING WITH THE 2900 02:52:04,367 --> 02:52:06,369 MAGENTA AND THESE OBSERVATIONS 2901 02:52:06,369 --> 02:52:08,972 WERE ORTHOGONALLY VALIDATED 2902 02:52:08,972 --> 02:52:10,807 USING TWO DISTINCT PROBES ONE 2903 02:52:10,807 --> 02:52:16,179 WITH SPIKE AND CAPSID AND CHROME 2904 02:52:16,179 --> 02:52:21,384 GENIC IHC AND IN SUMMARY WE 2905 02:52:21,384 --> 02:52:23,887 OBSERVED SARS COV2 BURDEN IS 2906 02:52:23,887 --> 02:52:25,855 HIGHEST IN RESPIRATORY TISSUES 2907 02:52:25,855 --> 02:52:28,091 BUT WIDELY DISSEMINATED IN THE 2908 02:52:28,091 --> 02:52:31,027 BODY AND BRAIN AND RNA CAN EXIST 2909 02:52:31,027 --> 02:52:33,463 IN ANATOMICAL COMPARTMENTS OVER 2910 02:52:33,463 --> 02:52:36,165 SEVEN MONTHS AND THE VIRUS 2911 02:52:36,165 --> 02:52:39,936 INFECTS SEVERAL TYPE AND ABLE OF 2912 02:52:39,936 --> 02:52:42,705 EVOLVING IN MULTIPLE TISSUES 2913 02:52:42,705 --> 02:52:50,713 INCLUDING BRAIN AND WE OBSERVED 2914 02:52:50,713 --> 02:52:53,283 A PAUCITY OF INFLAMMATION AND 2915 02:52:53,283 --> 02:52:54,851 EFFECT OUTSIDE THE LUNGS IN 2916 02:52:54,851 --> 02:52:57,086 EARLY CASES AND AS LATE AS OUR 2917 02:52:57,086 --> 02:53:00,223 LATE CASES IF YOU LOOK AT 2918 02:53:00,223 --> 02:53:01,624 NON-RESPIRATORY ORGANS, THE 2919 02:53:01,624 --> 02:53:03,493 LIVER, KIDNEY, ETCETERA THERE 2920 02:53:03,493 --> 02:53:05,461 WAS AN ABSENCE OF HISTO PATH 2921 02:53:05,461 --> 02:53:09,465 LOGIC FINDINGS AND THERE WAS A 2922 02:53:09,465 --> 02:53:10,633 PREDOMINANTLY ABSENCE OF IMMUNE 2923 02:53:10,633 --> 02:53:12,635 CELL INFILTRATE IN THE TISSUES 2924 02:53:12,635 --> 02:53:17,740 WE CONFIRMED WERE INFECTED. 2925 02:53:17,740 --> 02:53:21,811 AND SO THIS WORK WAS TOOK A 2926 02:53:21,811 --> 02:53:23,580 YEOMAN'S EFFORT AND WAS TEAM 2927 02:53:23,580 --> 02:53:25,214 SCIENCE AND I WANT TO HIGHLIGHT 2928 02:53:25,214 --> 02:53:26,349 NAMES AND THE PRIMARY 2929 02:53:26,349 --> 02:53:28,851 COLLABORATORS AT THE UNIVERSITY 2930 02:53:28,851 --> 02:53:32,388 OF MARYLAND WERE ALLISON 2931 02:53:32,388 --> 02:53:34,724 GRAZIOLI A CRITICAL CARE AND 2932 02:53:34,724 --> 02:53:35,959 NEPHROLOGY DOCTOR WHO HELPED 2933 02:53:35,959 --> 02:53:38,728 FACILITATE THE BUILDING OF OUR 2934 02:53:38,728 --> 02:53:40,363 NETWORK AS WELL AS CAPPEL AND 2935 02:53:40,363 --> 02:53:42,732 OUR PHYSICIANS AT MARYLAND THAT 2936 02:53:42,732 --> 02:53:44,300 HAVE PARTICIPATED IN BOTH THESE 2937 02:53:44,300 --> 02:53:46,970 STUDIES AND ONGOING DOWN STREAM 2938 02:53:46,970 --> 02:53:48,838 WORK WE'RE DOING ON THE TISSUES. 2939 02:53:48,838 --> 02:53:50,740 SIDNEY STEIN AND MY GROUP WAS 2940 02:53:50,740 --> 02:53:54,277 THE POSTDOC THAT LED THE STUDY 2941 02:53:54,277 --> 02:53:55,712 AND THE FIRST AUTHOR ON THE 2942 02:53:55,712 --> 02:53:56,412 PAPER. 2943 02:53:56,412 --> 02:53:58,715 SIDNEY DID MORE OR LESS ALL THE 2944 02:53:58,715 --> 02:54:00,950 DROPLET DIGITAL PCR ACROSS 2945 02:54:00,950 --> 02:54:02,819 THOUSANDS OF THESE TISSUES AND 2946 02:54:02,819 --> 02:54:06,489 PARTICIPATED IN A GOOD MAJORITY 2947 02:54:06,489 --> 02:54:09,225 OF THE AUTOPSIES THEMSELVES AND 2948 02:54:09,225 --> 02:54:12,528 AMY DEWITT HELPED WITH THE 2949 02:54:12,528 --> 02:54:14,130 VIROLOGY WORK IN THE CONTAINMENT 2950 02:54:14,130 --> 02:54:17,667 LABS AND KAREN PETERSON AND 2951 02:54:17,667 --> 02:54:19,769 CLAYTON WINKLER DID THE 2952 02:54:19,769 --> 02:54:20,637 IMMUNOFLUORESCENCE IN THE BRAIN 2953 02:54:20,637 --> 02:54:26,709 AND ELI AND HIS GROUP DID THE 2954 02:54:26,709 --> 02:54:28,144 HIGH-SEQUENCING SINGLE CELL HIGH 2955 02:54:28,144 --> 02:54:29,779 THROUGHPUT SEQUENCING OF OUR 2956 02:54:29,779 --> 02:54:31,748 VARIANTS ACROSS THE DIFFERENT 2957 02:54:31,748 --> 02:54:33,549 TISSUES AND THEN OF COURSE OUR 2958 02:54:33,549 --> 02:54:34,484 NCI PARTNERS. 2959 02:54:34,484 --> 02:54:36,619 THIS WAS DONE AND IT'S 2960 02:54:36,619 --> 02:54:38,721 INTERESTING TO HISTORY TO NOTE 2961 02:54:38,721 --> 02:54:42,725 DR. KLINER WHO HEADS THE 2962 02:54:42,725 --> 02:54:43,926 ANATOMIC PATHOLOGY LAB HAS BEEN 2963 02:54:43,926 --> 02:54:46,062 HERE SINCE THE BEGINNING OF THE 2964 02:54:46,062 --> 02:54:47,163 AIDS EPIDEMIC AND WHEN THIS 2965 02:54:47,163 --> 02:54:50,733 STARSTAR 2966 02:54:50,733 --> 02:54:54,237 ED -- STARTED THEY HAD 2967 02:54:54,237 --> 02:54:56,673 FAMILIARITY WITH A NEW OUTBREAK 2968 02:54:56,673 --> 02:54:59,242 THOUGHT TO BE HIGHLY CONTAGIOUS 2969 02:54:59,242 --> 02:55:02,679 AND SHOWED GREAT FORTITUDE AND 2970 02:55:02,679 --> 02:55:05,014 SCIENTIFIC CURIOSITY TO DO THESE 2971 02:55:05,014 --> 02:55:09,552 STUDIES AND HAVE DONE THESE HAND 2972 02:55:09,552 --> 02:55:11,287 IN HAND WITH THEM AND THEY WOULD 2973 02:55:11,287 --> 02:55:16,125 GET CALLS FROM THE ADMISSIONS 2974 02:55:16,125 --> 02:55:21,197 TEAM SAYING WE NEED TO 2975 02:55:21,197 --> 02:55:23,766 FACILITATE A POSTMORTEM INTERVAL 2976 02:55:23,766 --> 02:55:26,369 OF 22 HOURS POST DEATH WHICH IS 2977 02:55:26,369 --> 02:55:27,603 ALMOST UNHEARD OF WITH THESE 2978 02:55:27,603 --> 02:55:29,038 TYPES OF STUDIES AND WITH THAT I 2979 02:55:29,038 --> 02:55:30,707 WILL CLOSE AND TAKE YOUR 2980 02:55:30,707 --> 02:55:39,382 QUESTIONS. 2981 02:55:39,382 --> 02:55:39,682 >> QUESTION? 2982 02:55:39,682 --> 02:55:47,724 CHARLIE? 2983 02:55:47,724 --> 02:55:51,127 >> AMAZING STUDY. 2984 02:55:51,127 --> 02:55:51,561 CONGRATULATIONS. 2985 02:55:51,561 --> 02:55:54,030 AND I WAS WONDERING, DO YOU HAVE 2986 02:55:54,030 --> 02:55:56,399 ANY INFORMATION ON PEOPLE THAT 2987 02:55:56,399 --> 02:56:00,870 HAVE HAD A MILDER NON-LETHAL 2988 02:56:00,870 --> 02:56:02,939 OUTCOME WHERE YOU KNOW SOMETHING 2989 02:56:02,939 --> 02:56:05,341 ABOUT THEIR HISTORY AND THEN 2990 02:56:05,341 --> 02:56:09,545 THEY SORT OF RAN INTO A WALL OR 2991 02:56:09,545 --> 02:56:10,480 SOMETHING LIKE THAT? 2992 02:56:10,480 --> 02:56:12,381 >> SO THIS WAS AN IMPORTANT 2993 02:56:12,381 --> 02:56:13,049 QUESTION. 2994 02:56:13,049 --> 02:56:14,751 THANK YOU FOR YOUR QUESTION, 2995 02:56:14,751 --> 02:56:16,385 DR. RICE AND FOR YOUR COMMENT OF 2996 02:56:16,385 --> 02:56:17,153 THE DAY. 2997 02:56:17,153 --> 02:56:19,188 THIS WAS A QUESTION THAT CAME UP 2998 02:56:19,188 --> 02:56:25,595 RIGHT FROM THE BEGINNING ABOUT 2999 02:56:25,595 --> 02:56:26,963 REALLY THE GENERALIZABILITY OF 3000 02:56:26,963 --> 02:56:32,201 OUR FINDINGS AND I MADE THE 3001 02:56:32,201 --> 02:56:33,469 COMMENTS ABOUT VACCINATIONS AND 3002 02:56:33,469 --> 02:56:36,439 THERE WERE PATIENTS THAT GAVE US 3003 02:56:36,439 --> 02:56:37,673 INSIGHT INTO PERHAPS THE ANSWER 3004 02:56:37,673 --> 02:56:38,708 TO YOUR QUESTION. 3005 02:56:38,708 --> 02:56:42,211 NOW, TRULY THE ANSWER TO YOUR 3006 02:56:42,211 --> 02:56:44,147 QUESTION REQUIRES MORE WORK AND 3007 02:56:44,147 --> 02:56:45,481 FIGURED WE'D SET THE EXAMPLE AND 3008 02:56:45,481 --> 02:56:46,716 OUR WORK WOULD BE DONE. 3009 02:56:46,716 --> 02:56:50,353 I THINK PERHAPS WE'LL PICK UP 3010 02:56:50,353 --> 02:56:51,554 THE GAUNTLET AND TRY TO ANSWER 3011 02:56:51,554 --> 02:56:52,755 THOSE QUESTIONS BUT I WILL SAY 3012 02:56:52,755 --> 02:56:56,893 THAT I ALLUDED TO THIS, THERE 3013 02:56:56,893 --> 02:57:02,732 WAS A 6-YEAR-OLD WHO CAME IN 3014 02:57:02,732 --> 02:57:05,868 WITH SHE HAD AN UNDERLYING 3015 02:57:05,868 --> 02:57:07,170 SEIZURE DISORDER AND WAS ON MEDS 3016 02:57:07,170 --> 02:57:08,571 AND DURING COVID THERE WERE 3017 02:57:08,571 --> 02:57:12,975 ISSUES AND WAS OFF HER MED AND 3018 02:57:12,975 --> 02:57:15,845 SHOWED UP IN THE HOSPITAL AND 3019 02:57:15,845 --> 02:57:18,047 WAS EPILEPTIC AND DOESN'T KNOW 3020 02:57:18,047 --> 02:57:20,983 SHE HAD COVID AND INCIDENTALLY 3021 02:57:20,983 --> 02:57:22,251 TESTED POSITIVE BUT AT THAT TIME 3022 02:57:22,251 --> 02:57:24,287 EVERYONE WAS BEING TESTED AND 3023 02:57:24,287 --> 02:57:27,256 HAD A COMPLICATION AND 3024 02:57:27,256 --> 02:57:29,125 UNFORTUNATELY DIED WITH 3025 02:57:29,125 --> 02:57:30,493 COMPLICATION FROM HER 3026 02:57:30,493 --> 02:57:31,928 NEUROLOGICAL ISSUES WITHIN 48 3027 02:57:31,928 --> 02:57:33,563 HOURS OF HOSPITALIZATION AND 3028 02:57:33,563 --> 02:57:35,131 BECAUSE SHE WAS COVID POSITIVE 3029 02:57:35,131 --> 02:57:39,368 SHE WAS PREFERRED TO US AND 3030 02:57:39,368 --> 02:57:40,670 FOUND VIRAL RNA IN VARIOUS 3031 02:57:40,670 --> 02:57:41,704 LEVELS THROUGHOUT HER BODY. 3032 02:57:41,704 --> 02:57:45,541 THIS IS A YOUNG HEALTHY BODY 3033 02:57:45,541 --> 02:57:47,109 THAT TYPICALLY DOESN'T HAVE 3034 02:57:47,109 --> 02:57:48,878 SEVERE ILLNESS AT LEAST NOT 3035 02:57:48,878 --> 02:57:52,481 ACUTE ILLNESS FROM COVID AND WE 3036 02:57:52,481 --> 02:57:55,218 FOUND VIRAL RNA IN MULTIPLE 3037 02:57:55,218 --> 02:57:56,786 ANATOMIC COMPARTMENTS. 3038 02:57:56,786 --> 02:57:59,922 >> FANTASTIC STUDY. 3039 02:57:59,922 --> 02:58:04,193 AS YOU KNOW, SYSTEMIC 3040 02:58:04,193 --> 02:58:09,565 MICROVASCULAR THROMBOSIS IS 3041 02:58:09,565 --> 02:58:11,200 DESCRIBED WIDELY IN POSTMORTEM 3042 02:58:11,200 --> 02:58:16,172 COVID-19 AND IT MAY BE ONE OF 3043 02:58:16,172 --> 02:58:18,341 THE UNDERLYING COMMON PATH LOGIC 3044 02:58:18,341 --> 02:58:18,641 MECHANISMS. 3045 02:58:18,641 --> 02:58:20,309 HOW FREQUENTLY DID YOU OBSERVE 3046 02:58:20,309 --> 02:58:22,245 IT AND WAS IT RELATED TO VIRAL 3047 02:58:22,245 --> 02:58:22,645 ACTIVITY? 3048 02:58:22,645 --> 02:58:25,948 >> SO WE DO DO SPECIAL STAINS 3049 02:58:25,948 --> 02:58:33,089 LOOKING FOR PRESENCE OF PLATELET 3050 02:58:33,089 --> 02:58:36,959 RICH THROMBINE AND IN THE LUNGS 3051 02:58:36,959 --> 02:58:39,929 IN THIS COHORT IT WAS EASILY 3052 02:58:39,929 --> 02:58:41,797 DETECTABLE AND PRETTY 3053 02:58:41,797 --> 02:58:42,098 WIDESPREAD. 3054 02:58:42,098 --> 02:58:45,301 IN OTHER ORGANS IT WAS PRESENT 3055 02:58:45,301 --> 02:58:49,171 BUT NOT AS PREDOMINANT AS MIGHT 3056 02:58:49,171 --> 02:58:49,472 THINK. 3057 02:58:49,472 --> 02:58:52,608 AND IT GETS BACK TO THE COMMENT 3058 02:58:52,608 --> 02:58:57,380 ABOUT OUR HISTO PATHOLOGIC 3059 02:58:57,380 --> 02:58:57,647 FINDINGS. 3060 02:58:57,647 --> 02:59:01,584 WHEN YOU LOOKED AT HISTO 3061 02:59:01,584 --> 02:59:09,091 PATHOLOGIC SAMPLES YOU SAW AN 3062 02:59:09,091 --> 02:59:19,635 APAUCITY -- AND IT'S NOT SAYING 3063 02:59:20,703 --> 02:59:26,709 IT'S NOT CONTRIBUTING TO 3064 02:59:26,709 --> 02:59:31,480 PATHOGENESIS. 3065 02:59:31,480 --> 02:59:35,651 AND THERE ARE WAYS TO BIAS YOUR 3066 02:59:35,651 --> 02:59:36,018 VIEW. 3067 02:59:36,018 --> 02:59:45,194 AND THERE'S THE CONCEPT OF WIDE 3068 02:59:45,194 --> 02:59:53,135 SPREAD ENDOTHELIAL ITIS AND SAW 3069 02:59:53,135 --> 02:59:55,037 A COBBLESTONING OF ENDOTHELIAL 3070 02:59:55,037 --> 02:59:57,573 CELLS AND ABSENT BOTH IN THE 3071 02:59:57,573 --> 02:59:59,542 LUNGS AND OUTSIDE THE LUNGS. 3072 02:59:59,542 --> 03:00:01,177 I THINK THERE'S MORE TO DO ON 3073 03:00:01,177 --> 03:00:03,713 THE HOST SIDE TO UNDERSTAND WHAT 3074 03:00:03,713 --> 03:00:06,716 THE DRIVERS OF THE ORGAN INJURY 3075 03:00:06,716 --> 03:00:13,356 AND DYSFUNCTION. 3076 03:00:13,356 --> 03:00:13,489 3077 03:00:13,489 --> 03:00:14,523 >> CONGRATULATIONS. 3078 03:00:14,523 --> 03:00:16,158 AMAZING JOB. 3079 03:00:16,158 --> 03:00:21,364 I'M WONDERING IF DID YOU OBSERVE 3080 03:00:21,364 --> 03:00:26,602 ANY CYTOTROPIC EFFECT OUTSIDE 3081 03:00:26,602 --> 03:00:27,803 THE RESPIRATORY TRACT OR DO YOU 3082 03:00:27,803 --> 03:00:31,574 THINK IT'S JUST A RESERVOIR FOR 3083 03:00:31,574 --> 03:00:32,708 REACTIVATION FOR THE VIRUS IN 3084 03:00:32,708 --> 03:00:33,109 THE FUTURE. 3085 03:00:33,109 --> 03:00:36,145 >> WE LOOKED CAREFULLY AND DID 3086 03:00:36,145 --> 03:00:38,647 NOT FIND EVIDENCE OF CYTOPATHIC 3087 03:00:38,647 --> 03:00:41,684 EFFECT OUTSIDE THE RESPIRATORY 3088 03:00:41,684 --> 03:00:42,084 TRACT. 3089 03:00:42,084 --> 03:00:43,619 IN PARTICULAR AND OBVIOUSLY 3090 03:00:43,619 --> 03:00:44,987 WE'RE WIDE INTERESTED IN THE 3091 03:00:44,987 --> 03:00:45,621 BRAIN AND PURSUING ADDITIONAL 3092 03:00:45,621 --> 03:00:51,694 STUDIES IN THE BRAIN. 3093 03:00:51,694 --> 03:00:54,730 AND AN ABSENCE OF PATHOLOGY IN 3094 03:00:54,730 --> 03:00:58,667 THE BRAIN AND AS YOU LOOK IN THE 3095 03:00:58,667 --> 03:01:02,438 VIRUS YOU MAY TAKE A VIRUS LIKE 3096 03:01:02,438 --> 03:01:02,671 RABIES. 3097 03:01:02,671 --> 03:01:05,775 RABIES CAN GET IN THE BRAIN BUT 3098 03:01:05,775 --> 03:01:09,879 THEY HAVE THESE NEURONS IN THE 3099 03:01:09,879 --> 03:01:12,181 BRAIN BUT ABSENCE OF THAT THERE 3100 03:01:12,181 --> 03:01:14,717 ISN'T REALLY CYTOPATHIC EFFECT 3101 03:01:14,717 --> 03:01:18,421 OF THE NEURONS BUT THE 3102 03:01:18,421 --> 03:01:21,257 TRANSCRIPTION FILE IS ALTERED. 3103 03:01:21,257 --> 03:01:24,727 BECAUSE YOU DON'T SEE HISTO 3104 03:01:24,727 --> 03:01:29,432 PATHOLOGIC INJURY DOESN'T MEAN 3105 03:01:29,432 --> 03:01:36,272 THERE'S NOT DYSFUNCTION. 3106 03:01:36,272 --> 03:01:44,213 >> CONGRATULATIONS. 3107 03:01:44,213 --> 03:01:47,083 AND THE VARIANTS YOU SEQUENCE ON 3108 03:01:47,083 --> 03:01:48,884 THE TISSUES PERSISTENTLY 3109 03:01:48,884 --> 03:01:49,718 AFFECTED CAN YOU COMMENT WHETHER 3110 03:01:49,718 --> 03:01:53,422 ANY OF THOSE MUTATIONS ARE FROM 3111 03:01:53,422 --> 03:01:57,593 VARIANTS YET TO BE EMERGING 2021 3112 03:01:57,593 --> 03:02:02,698 OR SO. 3113 03:02:02,698 --> 03:02:08,704 >> THE ANSWER IS NO. 3114 03:02:08,704 --> 03:02:12,007 MOST OFTEN THE PREDOMINANT 3115 03:02:12,007 --> 03:02:14,710 PATTERN IN THE INDIVIDUALS WHERE 3116 03:02:14,710 --> 03:02:16,412 WE SEQUENCE VIRUS ACROSS SITES 3117 03:02:16,412 --> 03:02:18,714 THE PREDOMINANT PATTERN IS THE 3118 03:02:18,714 --> 03:02:20,850 MAJOR VARIANT PREDOMINATED 3119 03:02:20,850 --> 03:02:22,718 ACROSS MOST TISSUES BUT THERE 3120 03:02:22,718 --> 03:02:24,587 WERE REPEATED EXAMPLES WHERE 3121 03:02:24,587 --> 03:02:29,024 MINOR VARIANTS WERE PRESENT 3122 03:02:29,024 --> 03:02:30,893 OUTSIDE THE LUNGS THAT WERE NOT 3123 03:02:30,893 --> 03:02:36,031 DETECTED IN THE LUNGS. 3124 03:02:36,031 --> 03:02:37,500 AND CLEARLY FROM SOME OF THE 3125 03:02:37,500 --> 03:02:38,634 WASTE WATER STUDIES THAT HAVE 3126 03:02:38,634 --> 03:02:42,538 BEEN DONE, THERE ARE SUGGESTIONS 3127 03:02:42,538 --> 03:02:45,508 THAT WE KNOW AND 3128 03:02:45,508 --> 03:02:46,108 IMMUNOCOMPROMISED INDIVIDUAL 3129 03:02:46,108 --> 03:02:47,409 WHERE'S THEY REPLICATE FOR A 3130 03:02:47,409 --> 03:02:50,212 LONG PERIOD OF TIME PERHAPS IN 3131 03:02:50,212 --> 03:02:52,014 THAT POPULATION THAT'S WHERE 3132 03:02:52,014 --> 03:02:57,353 SOME OF THE VIRAL EVOLUTION IS 3133 03:02:57,353 --> 03:02:58,687 TAKING PLACE. 3134 03:02:58,687 --> 03:02:59,855 >> CLEAR PRESENTATION. 3135 03:02:59,855 --> 03:03:00,623 VERY NICE. 3136 03:03:00,623 --> 03:03:02,525 I WAS WONDERING HOW YOU 3137 03:03:02,525 --> 03:03:04,193 EXTRAPOLATE ALL THIS INFORMATION 3138 03:03:04,193 --> 03:03:05,661 TO LONG COVID? 3139 03:03:05,661 --> 03:03:11,700 DOES THE VIRUS HAVE TO BE THERE 3140 03:03:11,700 --> 03:03:15,037 FOR LONG COVID? 3141 03:03:15,037 --> 03:03:17,072 >> THANK YOU FOR YOUR QUESTION 3142 03:03:17,072 --> 03:03:18,207 AND COMPLIMENT. 3143 03:03:18,207 --> 03:03:20,042 AS YOU KNOW AND AS WE DESCRIBED, 3144 03:03:20,042 --> 03:03:26,248 WE DID OBSERVATIONAL SCIENCE. 3145 03:03:26,248 --> 03:03:29,752 IN GETTING TO MECHANISM OF LONG 3146 03:03:29,752 --> 03:03:33,656 COVID OR EVEN UNDERLYING FACTORS 3147 03:03:33,656 --> 03:03:35,591 WITH LONG COVID IS CHALLENGING 3148 03:03:35,591 --> 03:03:38,494 AND WERE AIR FULL NOT TO 3149 03:03:38,494 --> 03:03:40,329 EXTRAPOLATE THE STUDY OF ACUTE 3150 03:03:40,329 --> 03:03:45,734 COVID FOLKS TO LONG COVID. 3151 03:03:45,734 --> 03:03:47,503 HAVING SAID THAT IT PUT A STAKE 3152 03:03:47,503 --> 03:03:49,505 IN THE GROUND AND HIGHLIGHT THE 3153 03:03:49,505 --> 03:03:51,407 POTENTIAL FOR VIRAL PERSISTENCE 3154 03:03:51,407 --> 03:03:54,777 AND THE POTENTIAL CONTRIBUTING 3155 03:03:54,777 --> 03:03:57,179 PERHAPS TO LONG COVID AS AN 3156 03:03:57,179 --> 03:03:58,647 UNDERLYING HYPOTHESIS THAT NEEDS 3157 03:03:58,647 --> 03:04:04,119 TO BE EVALUATED AN TED TESTED 3158 03:04:04,119 --> 03:04:04,653 FURTHER. 3159 03:04:04,653 --> 03:04:09,925 I WON'T COMMENT ON CAUSALITY BUT 3160 03:04:09,925 --> 03:04:12,962 THE FIELD HAS MOVED AND THE 3161 03:04:12,962 --> 03:04:15,097 PIECE OF LONG COVID HAS TO BE 3162 03:04:15,097 --> 03:04:15,364 EVALUATED. 3163 03:04:15,364 --> 03:04:19,101 >> ALSO, IN RELATIONSHIP TO THE 3164 03:04:19,101 --> 03:04:24,740 QUESTION THAT DR. ALTER RAISED, 3165 03:04:24,740 --> 03:04:27,443 DO YOU THINK AND THE TITER OF 3166 03:04:27,443 --> 03:04:29,311 THE VIRUS SINCE YOU HAVE 3167 03:04:29,311 --> 03:04:31,213 ANTIBIOTICS AFTER THE INITIAL 3168 03:04:31,213 --> 03:04:31,480 INFECTION. 3169 03:04:31,480 --> 03:04:38,387 LIKE A COLD INFECTION BUT STILL 3170 03:04:38,387 --> 03:04:46,128 OR SARS AFTER BECAUSE THE DATA 3171 03:04:46,128 --> 03:04:47,162 SHOWS ALMOST ALL ORGANS HAVE 3172 03:04:47,162 --> 03:04:48,430 SIGN OF REPLICATION OF THE 3173 03:04:48,430 --> 03:04:48,831 VIRUS. 3174 03:04:48,831 --> 03:04:49,932 WE DON'T KNOW ONCE THE 3175 03:04:49,932 --> 03:04:51,734 ANTIBODIES APPEAR MAYBE YOU HAVE 3176 03:04:51,734 --> 03:04:55,337 LOW LEVEL IN SOME ORGAN. 3177 03:04:55,337 --> 03:04:59,208 >> I THINK THE PREDOMINANT 3178 03:04:59,208 --> 03:05:02,244 HYPOTHESES AROUND LONG COVID IS 3179 03:05:02,244 --> 03:05:07,549 IS THERE VIRAL PERSISTENCE AND 3180 03:05:07,549 --> 03:05:09,685 THE HOST RESPONSE TO PERSISTENT 3181 03:05:09,685 --> 03:05:12,554 VIRUSES CONTRIBUTING TO SIGNS 3182 03:05:12,554 --> 03:05:14,823 AND SYMPTOMS. 3183 03:05:14,823 --> 03:05:20,229 THE PROTHROMBOTIC UNDNATURE, IS 3184 03:05:20,229 --> 03:05:22,598 THAT CONTRIBUTING TO CELL 3185 03:05:22,598 --> 03:05:24,833 DYSFUNCTION AND OTHERWISE HE'S 3186 03:05:24,833 --> 03:05:30,606 ARE ALL BEING EVALUATED BUT 3187 03:05:30,606 --> 03:05:30,939 CHALLENGING. 3188 03:05:30,939 --> 03:05:34,743 ONE OF THE STUDIES AND INCLUDING 3189 03:05:34,743 --> 03:05:41,884 DR. KNOPF OR BRINGING A COHORT 3190 03:05:41,884 --> 03:05:43,986 OF INDIVIDUALS CHARACTERIZED 3191 03:05:43,986 --> 03:05:45,187 WITH LONG COVID AND DO A 3192 03:05:45,187 --> 03:05:46,722 SAMPLING OF A SUBSET OF TISSUES 3193 03:05:46,722 --> 03:05:50,059 YOU CAN ACCESS AND TO SEE IF 3194 03:05:50,059 --> 03:05:53,028 THERE'S AN ASSOCIATION TO BEGIN 3195 03:05:53,028 --> 03:05:57,866 WITH BETWEEN VIRAL PERSISTENCE 3196 03:05:57,866 --> 03:05:59,535 AND GET CLOSER THERE TO TARGET 3197 03:05:59,535 --> 03:05:59,835 ASSOCIATION. 3198 03:05:59,835 --> 03:06:07,743 >> THANK YOU, DANIEL. 3199 03:06:07,743 --> 03:06:09,978 NOW LET'S MOVE TO THE NEXT 3200 03:06:09,978 --> 03:06:11,714 SPEAKER, AND IT'S A GREAT 3201 03:06:11,714 --> 03:06:15,584 PLEASURE FOR ME TO INTRODUCE 3202 03:06:15,584 --> 03:06:22,257 DR. URSULA BUCHOLZ ALSO KNOWN AS 3203 03:06:22,257 --> 03:06:23,158 ULA. 3204 03:06:23,158 --> 03:06:29,031 THE CHIEF OF THE -- NO? 3205 03:06:29,031 --> 03:06:38,707 THERE'S ANOTHER SLIDE? 3206 03:06:38,707 --> 03:06:38,874 NO? 3207 03:06:38,874 --> 03:06:40,175 OKAY. 3208 03:06:40,175 --> 03:06:43,746 LET ME GIVE YOU THE TITLE THEN. 3209 03:06:43,746 --> 03:06:45,481 ULA IS THE CHIEF OF THE RNA 3210 03:06:45,481 --> 03:06:48,884 VIRUS SECTION NOTICE LABORATORY 3211 03:06:48,884 --> 03:06:52,287 OF INFECTIOUS DISEASE AT THE 3212 03:06:52,287 --> 03:06:53,288 NIAID. 3213 03:06:53,288 --> 03:06:56,959 SHE COMPLETED HER Ph.D. IN 3214 03:06:56,959 --> 03:07:00,929 VIROLOGY AT THE UNIVERSITY OF 3215 03:07:00,929 --> 03:07:03,565 BERLIN IN GERMANY WHERE SHE 3216 03:07:03,565 --> 03:07:14,076 STUDIED ON HUMAN RESPIRATORY 3217 03:07:17,279 --> 03:07:22,684 STITIAL VIRUS AND FOLLOWED THE 3218 03:07:22,684 --> 03:07:31,794 LEAD FOCUSES ON THE SYNCYTIAL 3219 03:07:31,794 --> 03:07:34,062 VIRUS AND BECAME THE CHIEF OF 3220 03:07:34,062 --> 03:07:36,131 THE SECTION AND PRIMARY RESEARCH 3221 03:07:36,131 --> 03:07:40,035 INTEREST IS TO DEVELOP A LIVE 3222 03:07:40,035 --> 03:07:42,504 ATTENUATED PEDIATRIC VACCINE 3223 03:07:42,504 --> 03:07:47,309 AGAINST THE RCV WHICH CAUSES A 3224 03:07:47,309 --> 03:07:51,947 PRIMARY DISEASE IN INFANTS, THE 3225 03:07:51,947 --> 03:07:52,414 ELDERLY AND THE 3226 03:07:52,414 --> 03:07:54,883 IMMUNOCOMPROMISED INDIVIDUALS. 3227 03:07:54,883 --> 03:07:57,719 THE TITLE OF HER PRESENTATION 3228 03:07:57,719 --> 03:08:01,156 TODAY IS DEVELOPMENT OF LIVE 3229 03:08:01,156 --> 03:08:09,531 INTRANASAL VACCINES FOR ACTIVE 3230 03:08:09,531 --> 03:08:14,269 IMMUNIZATION AGAINST YOUNG 3231 03:08:14,269 --> 03:08:16,839 CHILDREN IN RESPIRATORY 3232 03:08:16,839 --> 03:08:18,173 SYNCYTIAL VIRUS DISEASE. 3233 03:08:18,173 --> 03:08:19,775 >> THANK YOU FOR THE KIND 3234 03:08:19,775 --> 03:08:26,715 INTRODUCTION AND THANK YOU TO 3235 03:08:26,715 --> 03:08:30,319 THE ORGANIZERS AND MRS. SALZMAN 3236 03:08:30,319 --> 03:08:31,653 FOR LETTING US TALK ABOUT OUR 3237 03:08:31,653 --> 03:08:32,120 WORK. 3238 03:08:32,120 --> 03:08:33,589 THIS IS GOING TO BE A 3239 03:08:33,589 --> 03:08:35,858 PRESENTATION ABOUT OUR CLINICAL 3240 03:08:35,858 --> 03:08:42,898 STUDY PROGRAMS WITH OUR CLINICAL 3241 03:08:42,898 --> 03:08:45,567 COLLABORAT 3242 03:08:45,567 --> 03:08:50,606 COLLABORATORS THE COMMUNICATION 3243 03:08:50,606 --> 03:08:52,741 RESEARCH AND WITH RODCHESTER 3244 03:08:52,741 --> 03:08:53,942 VANDERBILT AND LONG STANDING 3245 03:08:53,942 --> 03:09:02,384 COLLABORATION WITH THE IMPACT 3246 03:09:02,384 --> 03:09:06,088 NETWORK UP TO 18 CLINICAL SITES 3247 03:09:06,088 --> 03:09:12,227 AND THE RESPIRATORY SYNCYTIAL 3248 03:09:12,227 --> 03:09:16,398 VIRUS HAS AN RNA GENOME 3249 03:09:16,398 --> 03:09:17,833 COMPRISING 10 GENES AND 11 3250 03:09:17,833 --> 03:09:21,503 PROTEINS AND CAN BE MANIPULATED 3251 03:09:21,503 --> 03:09:24,039 BY THE SYSTEM PETER COLLINS SET 3252 03:09:24,039 --> 03:09:27,910 UP AT THE NIH. 3253 03:09:27,910 --> 03:09:30,913 RSV HAS TWO MAJOR PROTECTIVE 3254 03:09:30,913 --> 03:09:35,317 ANTIGENS OF FUSION GLYCOPROTEIN 3255 03:09:35,317 --> 03:09:37,819 F AND G AND THE PROTEINS THAT 3256 03:09:37,819 --> 03:09:41,790 INHIBIT THE INTERFERON RESPONSE 3257 03:09:41,790 --> 03:09:45,594 AND ANOTHER FACTOR OF THE RNA 3258 03:09:45,594 --> 03:09:48,730 REGULATORY FACTOR M2T. 3259 03:09:48,730 --> 03:09:50,532 RSV IS THE MOST IMPORTANT CAUSE 3260 03:09:50,532 --> 03:09:54,736 OF SEVERE LOWER RESPIRATORY 3261 03:09:54,736 --> 03:10:00,909 DISEASE IN INFANT DISEASE 3262 03:10:00,909 --> 03:10:03,579 CAUSING SEASONAL YEARLY 3263 03:10:03,579 --> 03:10:05,814 EPIDEMICS AND MOST THE BURDEN 3264 03:10:05,814 --> 03:10:06,715 OCCURS IN CHILDREN ABOVE SIX 3265 03:10:06,715 --> 03:10:07,816 MONTHS OF AGE. 3266 03:10:07,816 --> 03:10:13,755 THE MAJORITY IN CHILDREN ABOUT 3267 03:10:13,755 --> 03:10:17,893 SIX MONTHS OF AGE. 3268 03:10:17,893 --> 03:10:19,595 THIS YEAR TWO APPROACHES 3269 03:10:19,595 --> 03:10:25,300 RECEIVED APPROVAL IN '23. 3270 03:10:25,300 --> 03:10:33,275 ONE IS INDIRECT AND THIS DURING 3271 03:10:33,275 --> 03:10:36,578 WEEKS 32 TO 36 OF PREGNANCY AND 3272 03:10:36,578 --> 03:10:38,647 HALF LIFE MONOCLONAL SEVEN 3273 03:10:38,647 --> 03:10:41,717 MONTHS WHICH IS SUPPOSED TO BE 3274 03:10:41,717 --> 03:10:42,684 USED FOR SEASONAL IMMUNIZATION 3275 03:10:42,684 --> 03:10:46,855 OF NEONATES AND CHILDREN UNDER 8 3276 03:10:46,855 --> 03:10:49,424 MONTHS OF AGE BUT DUE TO 3277 03:10:49,424 --> 03:10:50,158 AVAILABILITY ISSUES THE 3278 03:10:50,158 --> 03:10:50,726 RECOMMENDATION THIS YEAR IS 3279 03:10:50,726 --> 03:11:00,035 UNDER SIX MONTHS OF AGE. 3280 03:11:00,035 --> 03:11:04,473 PROVIDING SHORT TERM PASSIVE 3281 03:11:04,473 --> 03:11:06,575 PROTECTION LEAVING OLD ER 3282 03:11:06,575 --> 03:11:07,776 INFANTS AND CHILDREN WITHOUT 3283 03:11:07,776 --> 03:11:12,147 ACTIVE IMMUNITY TO RSV AND A 3284 03:11:12,147 --> 03:11:15,317 VACCINE FOR THOSE STILL MUTED IN 3285 03:11:15,317 --> 03:11:16,718 THE POPULATION AND WOULD BE A 3286 03:11:16,718 --> 03:11:19,688 PART OF THE PEDIATRIC SCHEDULE. 3287 03:11:19,688 --> 03:11:24,292 RSV INFECTS THE RESPIRATORY 3288 03:11:24,292 --> 03:11:24,593 EPITHELIUM. 3289 03:11:24,593 --> 03:11:27,229 INFECTION IS RESTRICTED TO THE 3290 03:11:27,229 --> 03:11:28,063 RESPIRATORY TRACT AS FAR AS WE 3291 03:11:28,063 --> 03:11:31,500 KNOW AND I TALKED ON THIS SIDE 3292 03:11:31,500 --> 03:11:33,602 THE HIGH ATTACK RATE EARLY IN 3293 03:11:33,602 --> 03:11:37,039 LIFE AND BASICALLY EVERYBODY HAS 3294 03:11:37,039 --> 03:11:42,310 ANTIBODIES BY AGE TWO. 3295 03:11:42,310 --> 03:11:46,481 CAUSES THE RESPIRATORY DISEASE 3296 03:11:46,481 --> 03:11:49,785 FROM UPPER RESPIRATORY ILLNESS 3297 03:11:49,785 --> 03:11:50,819 WITH FREQUENT PERIODS OF 3298 03:11:50,819 --> 03:11:54,823 WHEEZING. 3299 03:11:54,823 --> 03:11:59,461 PRIMARY INFECTIONS ARE 3300 03:11:59,461 --> 03:12:06,435 ASYMPTOMATIC AND LET SEVERE OR 3301 03:12:06,435 --> 03:12:08,603 DURING THE SARS COV2 PANDEMIC WE 3302 03:12:08,603 --> 03:12:14,342 HAD A BIG CHANGE IN EPIDEMIOLOGY 3303 03:12:14,342 --> 03:12:22,751 WITH NO SIGNIFICANT WITH NO 3304 03:12:22,751 --> 03:12:24,319 CIRCULATION WITH LOCK DOWN 3305 03:12:24,319 --> 03:12:29,324 GUIDANCE IN EFFECT AND THIS LEFT 3306 03:12:29,324 --> 03:12:33,762 A HUGE POPULATION OF HIGHER AGE 3307 03:12:33,762 --> 03:12:36,998 GROUPS WITH A HIGHER LEVEL OF 3308 03:12:36,998 --> 03:12:45,107 SUSCEPTIBILITY TO RSV AND IN '22 3309 03:12:45,107 --> 03:12:50,278 WE OBSERVED WORLDWIDE O 3310 03:12:50,278 --> 03:12:51,546 HOSPITALIZATIONS IN OLDER 3311 03:12:51,546 --> 03:12:57,419 CHILDREN AND WE DO NEED ACTIVE 3312 03:12:57,419 --> 03:12:58,854 IMMUNITY TO INDUCE IMMUNITY IN 3313 03:12:58,854 --> 03:13:00,388 OLDER INFANTS AND YOUNG 3314 03:13:00,388 --> 03:13:00,655 CHILDREN. 3315 03:13:00,655 --> 03:13:03,492 SO FOR US THE TARGET POPULATION 3316 03:13:03,492 --> 03:13:05,460 STARTING IN FOUR TO SIX MONTHS 3317 03:13:05,460 --> 03:13:08,730 OF AGE WE'RE DEVELOPING 3318 03:13:08,730 --> 03:13:13,902 INTRANASAL VACCINE FOR 3319 03:13:13,902 --> 03:13:15,570 ADMINISTRATION FOR ANTIBODIES 3320 03:13:15,570 --> 03:13:18,740 AND RESIDENT T CELLS AND B CELLS 3321 03:13:18,740 --> 03:13:23,578 TO INDUCE RAPID PROTECTION EARLY 3322 03:13:23,578 --> 03:13:27,382 IN LIFE LIVE VACCINES CAN BE 3323 03:13:27,382 --> 03:13:31,586 IMMUNOGENIC IN PASSIVE 3324 03:13:31,586 --> 03:13:31,887 ANTIBODIES. 3325 03:13:31,887 --> 03:13:38,693 THESE ARE ADJUVANTING AND AND 3326 03:13:38,693 --> 03:13:41,830 OUR RSV NON EXPERIENCE THAT 3327 03:13:41,830 --> 03:13:44,800 INCLUDES PASSIVE IMMUNITY BUT 3328 03:13:44,800 --> 03:13:50,739 NOT ACTIVELY ENCOUNTERED RSV AND 3329 03:13:50,739 --> 03:13:54,075 SUBUNIT VACCINES BECOME 3330 03:13:54,075 --> 03:13:55,544 CONTRAINDICATED BECAUSE INDUCED 3331 03:13:55,544 --> 03:13:58,880 MARKERS OF PRIMING FOR ENHANCED 3332 03:13:58,880 --> 03:13:59,815 RESPIRATORY DISEASE. 3333 03:13:59,815 --> 03:14:02,484 THE PRIME FOR ENHANCE DISEASE 3334 03:14:02,484 --> 03:14:06,121 WITH RSV INFECTION. 3335 03:14:06,121 --> 03:14:09,658 THIS IS TRUE EVEN FOR TH1 3336 03:14:09,658 --> 03:14:14,729 ADJUVANTS BUT NOT ASSOCIATED 3337 03:14:14,729 --> 03:14:15,163 WITH LIVE VACCINES. 3338 03:14:15,163 --> 03:14:18,233 THE PROB FOR US IS WE'RE DEALING 3339 03:14:18,233 --> 03:14:26,675 WITH AN INFECTION AGENT AND OUR 3340 03:14:26,675 --> 03:14:29,744 EFFICACY AND IT'S HARD TO 3341 03:14:29,744 --> 03:14:30,779 PROTECT EFFICACY AND PROTECTION 3342 03:14:30,779 --> 03:14:36,218 AGAINST RSV ASSOCIATED ILLNESS 3343 03:14:36,218 --> 03:14:36,918 WHILE STERILIZING IMMUNITY. 3344 03:14:36,918 --> 03:14:39,721 THE BIG CHALLENGES ATTENUATION 3345 03:14:39,721 --> 03:14:44,826 AND IMMUNOGENICITY ARE ADVERSELY 3346 03:14:44,826 --> 03:14:45,360 CORRELATE. 3347 03:14:45,360 --> 03:14:55,904 WE'RE USING REVERSE GENETICS TO 3348 03:14:57,739 --> 03:15:01,943 AND AND WE'RE DEALING WITH NOT 3349 03:15:01,943 --> 03:15:07,015 HAVING A FULLY PERMISSIVE ANIMAL 3350 03:15:07,015 --> 03:15:10,385 MODEL AND FOR THE LAST BIT OF 3351 03:15:10,385 --> 03:15:13,154 ATTENUATION WE RELY ON PHASED 1 3352 03:15:13,154 --> 03:15:14,656 STUDIES IN RSV NEGATIVE CHILDREN 3353 03:15:14,656 --> 03:15:16,758 BECAUSE POSITIVE CHILDREN WOULD 3354 03:15:16,758 --> 03:15:25,800 BE NOT AS ACCEPTABLE OR THE 3355 03:15:25,800 --> 03:15:29,804 VACCINE AND NEED TO STUDY THE 3356 03:15:29,804 --> 03:15:30,739 VACCINE CANDIDATES IN THE 3357 03:15:30,739 --> 03:15:32,874 SEASONS FREE FROM COMMUNITY RSV 3358 03:15:32,874 --> 03:15:36,645 ILLNESS AND ALSO DEALING WITH 3359 03:15:36,645 --> 03:15:38,446 THE INCIDENTS OF RESPIRATORY 3360 03:15:38,446 --> 03:15:41,449 ILLNESSES OF ALL CAUSES IN THE 3361 03:15:41,449 --> 03:15:42,584 YOUNG PEDIATRIC POPULATION EVERY 3362 03:15:42,584 --> 03:15:43,218 PARENT OF YOUNG CHILDREN KNOWS 3363 03:15:43,218 --> 03:15:53,395 VERY WELL. 3364 03:15:55,363 --> 03:15:56,831 AND THE LIVE VACCINES MAY BE 3365 03:15:56,831 --> 03:16:02,737 AFFECTED BY THE PRESENCE OF A 3366 03:16:02,737 --> 03:16:10,845 LONG LASTING ANTIBODY. 3367 03:16:10,845 --> 03:16:13,481 AND DESIGN THE ATTENUATING 3368 03:16:13,481 --> 03:16:18,753 MUTATION WE CAN DELETE CODONS 3369 03:16:18,753 --> 03:16:26,227 AND/OR STABILIZE PALPITATIONS 3370 03:16:26,227 --> 03:16:28,496 AND STABILIZE THESE AGAINST 3371 03:16:28,496 --> 03:16:29,164 ATTENUATION AS OTHERS IN THE LAB 3372 03:16:29,164 --> 03:16:39,341 HAVE DONE. 3373 03:16:39,741 --> 03:16:42,744 AND THE ANTAGONIST AND WE CAN 3374 03:16:42,744 --> 03:16:47,048 COMBINE MUTATIONS AND OTHERS IN 3375 03:16:47,048 --> 03:16:50,385 OUR LAB WORK WITH THE 3376 03:16:50,385 --> 03:16:52,988 OPTIMIZATION AND CAN OPTIMIZE 3377 03:16:52,988 --> 03:16:56,024 OPEN READING TO INCREASE ANTIGEN 3378 03:16:56,024 --> 03:16:57,692 EXPRESSION OR REORDER THE 3379 03:16:57,692 --> 03:17:00,161 GENOME. 3380 03:17:00,161 --> 03:17:03,898 I WANT IT TALK ABOUT THE LEAD 3381 03:17:03,898 --> 03:17:05,200 CANDIDATES THAT ARE CURRENTLY 3382 03:17:05,200 --> 03:17:08,236 THE MOST PROMISING AND HOPEFULLY 3383 03:17:08,236 --> 03:17:15,477 MAKING INTO EFFICACY STUDIES AND 3384 03:17:15,477 --> 03:17:18,346 THE LEAD CANDIDATE AND THIS IS 3385 03:17:18,346 --> 03:17:21,282 BASED ON A DELETION OF THE 3386 03:17:21,282 --> 03:17:25,086 INTERFERON AN TAG GIFT WHICH IS 3387 03:17:25,086 --> 03:17:28,623 PATHOGENICITY FACTOR BECAUSE IT 3388 03:17:28,623 --> 03:17:31,693 PROMOTES SHEDDING OF BRONCHIAL 3389 03:17:31,693 --> 03:17:32,660 EPITHELIAL CELLS AND IS 3390 03:17:32,660 --> 03:17:33,661 BENEFICIAL FROM THAT 3391 03:17:33,661 --> 03:17:34,062 PERSPECTIVE. 3392 03:17:34,062 --> 03:17:38,299 IN ADDITION, THIS CANDIDATE 3393 03:17:38,299 --> 03:17:42,837 CONTAINS A DELETION OF ONE COE 3394 03:17:42,837 --> 03:17:49,144 ON POLYMERASE PROTEIN THIS IS 3395 03:17:49,144 --> 03:17:51,179 GOOD FOR SAFETY IN THE LOWER 3396 03:17:51,179 --> 03:17:51,946 RESPIRATORY TRACT AND THE 3397 03:17:51,946 --> 03:17:53,214 VACCINE CANDIDATE LOWER THAN THE 3398 03:17:53,214 --> 03:17:54,482 UPPER TRACT. 3399 03:17:54,482 --> 03:17:56,651 AND IN ADDITION WITH THE 3400 03:17:56,651 --> 03:17:58,520 MUTATION TO STABILIZE THE VIRUS. 3401 03:17:58,520 --> 03:18:01,489 THIS CANDIDATE HAS BEEN 3402 03:18:01,489 --> 03:18:03,525 SEQUENTIALLY EVALUATES FOR 3403 03:18:03,525 --> 03:18:09,697 SAFETY AND CERTAINLY NEGATIVE 3404 03:18:09,697 --> 03:18:14,536 CHILDREN IN ORDER OF FIVE AND 3405 03:18:14,536 --> 03:18:18,006 TEN TO THE SIX DOSE IN 20 3406 03:18:18,006 --> 03:18:18,273 VACCINEES. 3407 03:18:18,273 --> 03:18:21,476 THE STUDY ESTABLISHED THE SAFETY 3408 03:18:21,476 --> 03:18:27,115 THAT WAS NO EXCESS RESPIRATORY 3409 03:18:27,115 --> 03:18:37,659 ILLNESS COMPARED TO THE PLACEBO 3410 03:18:41,896 --> 03:18:44,632 RECIPIENTS AND TITERS WERE 3411 03:18:44,632 --> 03:18:46,734 RELATIVELY LOW WITH LESS THAN 3412 03:18:46,734 --> 03:18:53,908 TWO LOGS PER MILLILITER OF THE 3413 03:18:53,908 --> 03:19:00,348 VACCINE AND WE AND WE SAW 3414 03:19:00,348 --> 03:19:02,450 ANTIBODY RESPONSE WITH 80% OF 3415 03:19:02,450 --> 03:19:05,320 THE VACCINES HAVING SERUM 3416 03:19:05,320 --> 03:19:06,588 ANTIBODIES WITH IMMUNIZATION AND 3417 03:19:06,588 --> 03:19:10,024 THE TITERS IS VERY LOW THIS IS 3418 03:19:10,024 --> 03:19:13,328 SIMILAR TO WHAT WILD TYPE IN 3419 03:19:13,328 --> 03:19:14,729 INDUCES IN THE FIRST INFECTION 3420 03:19:14,729 --> 03:19:19,134 IN YOUNG CHILDREN. 3421 03:19:19,134 --> 03:19:22,637 THE VACCINE TAKE OF 100% AND WE 3422 03:19:22,637 --> 03:19:25,840 FOLLOWED THE KIDS THROUGH THE 3423 03:19:25,840 --> 03:19:28,510 WINTER WE SAW SUBSTANTIAL RISE 3424 03:19:28,510 --> 03:19:30,245 IN NEUTRALIZING ANTIBODIES 3425 03:19:30,245 --> 03:19:31,946 DURING THE SEASON SO THESE 3426 03:19:31,946 --> 03:19:35,450 VACCINE CANDIDATES PRIME FOR A 3427 03:19:35,450 --> 03:19:36,851 STRONG RESPONSE AND SAW THE 3428 03:19:36,851 --> 03:19:38,286 RISES IN ABSENCE OF THE RSV 3429 03:19:38,286 --> 03:19:42,423 DISEASE IN MANY CASES. 3430 03:19:42,423 --> 03:19:45,593 THE SECOND LINE OF PHARMACY 3431 03:19:45,593 --> 03:19:47,395 CANDIDATES IS WITH OPEN READING 3432 03:19:47,395 --> 03:19:49,097 THAT'S A SMALL OVERLAPPING IN 3433 03:19:49,097 --> 03:19:52,567 THE M2 GENE WHICH EXPRESSES AN 3434 03:19:52,567 --> 03:19:54,969 RNA REGULATORY PROTEIN. 3435 03:19:54,969 --> 03:19:58,273 IF YOU DELETE TO THE OPEN 3436 03:19:58,273 --> 03:19:59,974 READING FRAME THERE'S LESS 3437 03:19:59,974 --> 03:20:02,043 REPLICATION AND HIGHER LEVEL OF 3438 03:20:02,043 --> 03:20:03,077 GENE TRANSCRIPTION AND THAT OF 3439 03:20:03,077 --> 03:20:05,880 COURSE RESULTS IN HIGHER PROTEIN 3440 03:20:05,880 --> 03:20:08,449 EXPRESSION AND IN THIS CASE 3441 03:20:08,449 --> 03:20:10,818 LOOKING AT BLOTS OF THE 3442 03:20:10,818 --> 03:20:15,690 PROTECTIVE ANTIGENS F AND G AND 3443 03:20:15,690 --> 03:20:18,893 YOU CAN SEE HOW MUCH MORE F AND 3444 03:20:18,893 --> 03:20:22,897 G IS SYNTHESIZED IN A VIRUS WITH 3445 03:20:22,897 --> 03:20:26,501 AN M2D DELETION AND HIGHLY 3446 03:20:26,501 --> 03:20:31,472 RESTRICTED IN CHIMPANZEES AND 3447 03:20:31,472 --> 03:20:32,974 GENE DELETION WAS HIGHLY STABLE. 3448 03:20:32,974 --> 03:20:35,076 THIS BLUE LINE RESULTS FROM A 3449 03:20:35,076 --> 03:20:38,813 PHASE 1 STUDY IN 6 TO 34 MONTHS 3450 03:20:38,813 --> 03:20:41,916 OLD WITH NASAL WASHES COLLECTED 3451 03:20:41,916 --> 03:20:43,518 OVER SEVEN SEQUENTIAL TIME 3452 03:20:43,518 --> 03:20:45,687 PERIODS OVER 17 DAYS AND SAW 3453 03:20:45,687 --> 03:20:47,422 SHEDDING IN OUR EXPERIENCE THAT 3454 03:20:47,422 --> 03:20:48,389 IS A LITTLE BIT ON THE HIGH 3455 03:20:48,389 --> 03:20:48,790 SIDE. 3456 03:20:48,790 --> 03:20:52,327 WE WENT BACK TO THE DRAWING 3457 03:20:52,327 --> 03:20:55,830 BOARD AND ADDED ANOTHER MUTATION 3458 03:20:55,830 --> 03:21:00,368 POLYMERASE WE KNOW FROM OTHER 3459 03:21:00,368 --> 03:21:02,704 VIRUSES AND CANDIDATES INDUCES 3460 03:21:02,704 --> 03:21:05,373 TEMPERATURE SENSITIVITY AND THIS 3461 03:21:05,373 --> 03:21:08,843 IS ALSO MUTATION THAT HAS BEEN 3462 03:21:08,843 --> 03:21:16,317 STABILIZED AGAINST D 3463 03:21:16,317 --> 03:21:17,151 DE-ATTENUATION OVER TIME AND 3464 03:21:17,151 --> 03:21:19,254 THIS YOU SEE ALL THE REDUCED 3465 03:21:19,254 --> 03:21:22,690 LEVEL OF SHEDDING AND ALSO MOVED 3466 03:21:22,690 --> 03:21:24,993 THE PEAK OF SHEDDING TO A LATER 3467 03:21:24,993 --> 03:21:27,929 TIME POINT WHICH IS ALSO A MARK 3468 03:21:27,929 --> 03:21:32,133 ER OF ATTENUATION OF THE VIRUS. 3469 03:21:32,133 --> 03:21:33,568 THIS CANDIDATE HAS BEEN 3470 03:21:33,568 --> 03:21:34,736 EVALUATED IN TWO STUDIES 3471 03:21:34,736 --> 03:21:40,074 MEANWHILE AND THE TEMPERATURE 3472 03:21:40,074 --> 03:21:41,442 SENSITIVITY AGAIN IS GOOD 3473 03:21:41,442 --> 03:21:42,744 ADDITIONAL SAFETY FEATURE TO 3474 03:21:42,744 --> 03:21:46,347 REDUCE AND PROTECT THE LOWER 3475 03:21:46,347 --> 03:21:47,515 RESPIRATORY TRACT FROM 3476 03:21:47,515 --> 03:21:47,815 REPLICATION. 3477 03:21:47,815 --> 03:21:50,785 WE AS YOU SAW IN THE LAST WE 3478 03:21:50,785 --> 03:21:54,756 LOOKED FOR SHEDDING BY THE ASSAY 3479 03:21:54,756 --> 03:22:04,666 ON THE X AXIS AND THE Y CHASMS 3480 03:22:04,666 --> 03:22:04,966 A 3481 03:22:04,966 --> 03:22:07,568 -- AXIS AND COMPARING THE 3482 03:22:07,568 --> 03:22:09,704 LINEAR CORRELATION SHOWS WE HAVE 3483 03:22:09,704 --> 03:22:15,076 ABOUT A TENFOLD HIGHER LEVEL OF 3484 03:22:15,076 --> 03:22:18,746 COPIES SO INDEED IN VITRO IT 3485 03:22:18,746 --> 03:22:20,581 SEEMS THE M2D DELETION DOES WHAT 3486 03:22:20,581 --> 03:22:27,722 WE PREDICTED RESULTING IN MORE 3487 03:22:27,722 --> 03:22:31,592 POSITIVE AND NEGATIVE SHED AND 3488 03:22:31,592 --> 03:22:35,263 MORE RNA SYNTHESIS PER PFU AND 3489 03:22:35,263 --> 03:22:38,833 HOLDS UP FOR THREE COMBINED DATA 3490 03:22:38,833 --> 03:22:44,372 FROM MANY STUDIES. 3491 03:22:44,372 --> 03:22:46,674 LOOKING WHETHER THIS TRANSLATES 3492 03:22:46,674 --> 03:22:50,111 TO BETTER IMMUNOGENICITY AMONG 3493 03:22:50,111 --> 03:22:53,448 PRIMARY INFECTION IN BOTH CASES 3494 03:22:53,448 --> 03:22:59,554 WE SAW LEVELS FROM PRE TO POST 3495 03:22:59,554 --> 03:23:02,390 IMMUNIZATIONS AND ANTIBODIES BUT 3496 03:23:02,390 --> 03:23:05,360 NO BIG DIFFERENCE IN THE IMMUNE 3497 03:23:05,360 --> 03:23:06,728 RESPONSE IN THE PRIMARY 3498 03:23:06,728 --> 03:23:09,697 RESPONSES IN YOUNG CHILDREN. 3499 03:23:09,697 --> 03:23:11,666 WE ALSO FOLLOWED THE CHILDREN 3500 03:23:11,666 --> 03:23:15,703 OVER THE RSV SEASON TAKING A 3501 03:23:15,703 --> 03:23:21,676 PRE-SEASON SAMPLE AND 3502 03:23:21,676 --> 03:23:26,347 POST-SAMPLE SEASON AND WE FOLLOW 3503 03:23:26,347 --> 03:23:30,151 THE KIDS OVER THE SEASON TO GET 3504 03:23:30,151 --> 03:23:32,520 REPORTED ON ATTENDED ACUTE 3505 03:23:32,520 --> 03:23:34,922 RESPIRATORY ILLNESS AND TAKE 3506 03:23:34,922 --> 03:23:37,658 SAMPLES TO IDENTIFY RSV 3507 03:23:37,658 --> 03:23:38,860 ASSOCIATED ILLNESS. 3508 03:23:38,860 --> 03:23:44,098 WE USUALLY SEE HERE IN THE GRAPH 3509 03:23:44,098 --> 03:23:48,903 THE RISES HERE AND YOU LOOK AT 3510 03:23:48,903 --> 03:23:51,672 THE RIGHT GRAPH SHOWING PLACEBO 3511 03:23:51,672 --> 03:23:52,373 RECIPIENTS GIVES THE COMPARISON 3512 03:23:52,373 --> 03:23:56,811 THIS SB WHAT WE SEE IN THE 3513 03:23:56,811 --> 03:23:58,212 WINTER SEASON WHEN SEEING RSV 3514 03:23:58,212 --> 03:24:04,385 FOR THE FIRST TIME AND THEN 3515 03:24:04,385 --> 03:24:07,789 SIMILAR LEVELS OF IMMUNOGENICITY 3516 03:24:07,789 --> 03:24:10,491 OF CANDIDATES AND TO WILD TYPE 3517 03:24:10,491 --> 03:24:10,858 RSV. 3518 03:24:10,858 --> 03:24:13,261 YOU CAN ALSO SEE SOME OF THE 3519 03:24:13,261 --> 03:24:14,162 VACCINEES HAVE THESE SUPER 3520 03:24:14,162 --> 03:24:18,266 STRONG RISES IN THE RSV SEASON 3521 03:24:18,266 --> 03:24:20,435 AND THE STAR IS THE ONE INCIDENT 3522 03:24:20,435 --> 03:24:26,741 WITH A REPORT ABOUT RSV ILLNESS 3523 03:24:26,741 --> 03:24:30,445 IN THE SEASON AND THAT WAS THE 3524 03:24:30,445 --> 03:24:31,712 PARTICIPANT THAT HAS NOT DONE 3525 03:24:31,712 --> 03:24:35,583 CONVERSIONS POST VACCINE AND SAW 3526 03:24:35,583 --> 03:24:39,821 TWO REPORTS IN THE RECIPIENTS. 3527 03:24:39,821 --> 03:24:41,155 AND PRIMING FOR STRONG RESPONSES 3528 03:24:41,155 --> 03:24:42,757 AND THAT IS SOMETHING WE SEE 3529 03:24:42,757 --> 03:24:46,394 GENERALLY IN THE STUDIES. 3530 03:24:46,394 --> 03:24:50,131 YOU CAN SEE THE SECOND RSV 3531 03:24:50,131 --> 03:24:50,965 INFECTION PROVIDES THE 3532 03:24:50,965 --> 03:24:53,367 SUBSTANTIAL TITER SIMILAR TO 3533 03:24:53,367 --> 03:24:54,936 WHAT THAT LEVEL OF SERUM 3534 03:24:54,936 --> 03:24:57,705 ANTIBODIES ARE AND THIS IS 3535 03:24:57,705 --> 03:24:58,773 ASOLID PROTECTION AGAINST 3536 03:24:58,773 --> 03:24:59,140 ILLNESS. 3537 03:24:59,140 --> 03:25:01,175 AND FOR US THE QUESTION IS HOW 3538 03:25:01,175 --> 03:25:04,212 CAN WE FOLLOW THE NICE IMMUNE 3539 03:25:04,212 --> 03:25:12,453 RESPONSES HOW CAN WE GET KIDS TO 3540 03:25:12,453 --> 03:25:12,854 FUL 3541 03:25:12,854 --> 03:25:16,424 BE FULLY PROTECTED LATER IN 3542 03:25:16,424 --> 03:25:16,924 LIFE. 3543 03:25:16,924 --> 03:25:18,726 GOOD VACCINE TAKE SHEDDING BY 3544 03:25:18,726 --> 03:25:20,928 CULTURE AND LOWERING THE NS2 3545 03:25:20,928 --> 03:25:22,663 CANDIDATE AND THAT WAS THE 3546 03:25:22,663 --> 03:25:24,832 BIGGEST ARGUMENT FOR MOVING -- 3547 03:25:24,832 --> 03:25:26,901 FOR THE GREATER COLLABORATIVES 3548 03:25:26,901 --> 03:25:29,136 MOVING THIS CANDIDATE FORWARD AS 3549 03:25:29,136 --> 03:25:33,140 THEY WANTED TO GO FORWARD WITH 3550 03:25:33,140 --> 03:25:38,713 THE MOST PROMISING SAFETY 3551 03:25:38,713 --> 03:25:39,046 PROFILE. 3552 03:25:39,046 --> 03:25:42,650 WE HAVE ALSO DONE A SMALL 3553 03:25:42,650 --> 03:25:44,285 POSTDOC RECENTLY LOOKING AT THE 3554 03:25:44,285 --> 03:25:50,291 MOST PROMISING CANDIDATES 3555 03:25:50,291 --> 03:25:58,733 DEVELOPMENT IN PHASE 1 POST 3556 03:25:58,733 --> 03:26:00,902 IMMUNIZATION AND WE LOOKED AT 3557 03:26:00,902 --> 03:26:02,737 COMBINED EFFICACY AND SHOWING IN 3558 03:26:02,737 --> 03:26:05,373 THE BLUE LINES AND ALL VACCINES 3559 03:26:05,373 --> 03:26:06,707 FROM THE SEVEN STUDIES ON THE 3560 03:26:06,707 --> 03:26:09,210 BLACK LINES AND LOOKING AT THE 3561 03:26:09,210 --> 03:26:15,816 MOST PROMISING WE DO SEE SOME 3562 03:26:15,816 --> 03:26:22,523 SUGGESTIVE DATA THAT SUGGESTS 3563 03:26:22,523 --> 03:26:27,795 EFFICACY WHEN YOU LOOK AT 3564 03:26:27,795 --> 03:26:29,964 VACCINE EFFICACY AND LOWER 3565 03:26:29,964 --> 03:26:34,135 ILLNESS OF UP TO 88% AND WE THEN 3566 03:26:34,135 --> 03:26:36,737 LOOK AT THE SUBSET OF KNOWN 3567 03:26:36,737 --> 03:26:41,776 RESPONDERS WE DID NOT SEE LOWER 3568 03:26:41,776 --> 03:26:42,743 RESPIRATORY TRACT ILLNESS IN 3569 03:26:42,743 --> 03:26:45,546 THAT GROUP AND GIVEN SMALL 3570 03:26:45,546 --> 03:26:47,949 NUMBERS AND IT'S JUST POSTDOC 3571 03:26:47,949 --> 03:26:49,050 ANALYSIS BUT JUST KIND OF 3572 03:26:49,050 --> 03:26:49,717 PROMISING. 3573 03:26:49,717 --> 03:26:56,324 LOOKING AT THE FOR THE POSTDOC 3574 03:26:56,324 --> 03:26:59,226 ANALYSIS ALL TOGETHER THE FIRST 3575 03:26:59,226 --> 03:27:02,163 IS VACCINEES WITH EVIDENCE OF OF 3576 03:27:02,163 --> 03:27:05,800 WILD TYPE DURING THE SURVEYED 3577 03:27:05,800 --> 03:27:07,702 SEASON AND YOU CAN SEE THE 3578 03:27:07,702 --> 03:27:10,404 PRIMING FOR THE STRONG RESPONSES 3579 03:27:10,404 --> 03:27:14,742 IF YOU SEE WILD TYPE DURING THE 3580 03:27:14,742 --> 03:27:19,213 SEASON WE ALSO SAW THE 3581 03:27:19,213 --> 03:27:23,751 DISABILITY TO ANTIBODY TITERS 3582 03:27:23,751 --> 03:27:25,753 AND THE POSTDOC ANALYSIS 3583 03:27:25,753 --> 03:27:27,788 CONFIRMATION THAT ANTIBODY 3584 03:27:27,788 --> 03:27:29,924 TITERS TO VACCINE ARE COMPARABLE 3585 03:27:29,924 --> 03:27:32,627 TO THOSE AND THE BIG QUESTION 3586 03:27:32,627 --> 03:27:35,596 HOW CAN WE HAVE VACCINES FROM 3587 03:27:35,596 --> 03:27:37,698 6.4 TO 10.2? 3588 03:27:37,698 --> 03:27:46,741 TO THAT END WE'RE WORKING ON THE 3589 03:27:46,741 --> 03:27:54,215 VIRE -- VIRUS F PROTEIN WITH 3590 03:27:54,215 --> 03:27:57,718 THE MOST POTENT STABILIZED FOR 3591 03:27:57,718 --> 03:28:03,791 EXPRESSION. 3592 03:28:03,791 --> 03:28:14,301 THE BOVINE INFLUENZA VIRUS IS 3593 03:28:21,108 --> 03:28:23,210 PROVIDE 3594 03:28:23,210 --> 03:28:26,547 PROVIDING PATHOGEN AND DOWN TO 3595 03:28:26,547 --> 03:28:28,382 TWO YEARS IN A DIFFERENT VERSION 3596 03:28:28,382 --> 03:28:30,718 OF THE RSV ANTIGEN AND LIKELY 3597 03:28:30,718 --> 03:28:31,452 DIFFERENT SET. 3598 03:28:31,452 --> 03:28:37,291 WE IMPROVED THIS VECTOR IN MANY 3599 03:28:37,291 --> 03:28:44,265 WAYS AND READY TO. 3600 03:28:44,265 --> 03:28:47,435 THE PREVACCINE STUDY HOPEFULLY 3601 03:28:47,435 --> 03:28:48,669 NEXT YEAR. 3602 03:28:48,669 --> 03:28:50,771 THE DISADVANTAGE IS IT'S A 3603 03:28:50,771 --> 03:28:57,378 SINGLE PROTEIN. 3604 03:28:57,378 --> 03:29:02,516 WE'RE LOOKING AT THE PRIMARY 3605 03:29:02,516 --> 03:29:03,551 IMMUNIZATION AFTER THE IMMUNITY 3606 03:29:03,551 --> 03:29:10,725 BY THE LONG LASTING ANTIBODIES 3607 03:29:10,725 --> 03:29:19,567 OR WITHOUT PRE F HAS WANED AND 3608 03:29:19,567 --> 03:29:22,036 LOOK AT THE PRE F VECTOR. 3609 03:29:22,036 --> 03:29:23,237 WE KNOW FROM MANY PRE CLINICAL 3610 03:29:23,237 --> 03:29:25,740 AND CLINICAL STUDIES THAT THE 3611 03:29:25,740 --> 03:29:33,714 SECOND TAME OF AN RSV VACCINE 3612 03:29:33,714 --> 03:29:40,588 VACCINE IS NOT GOING TO WITH THE 3613 03:29:40,588 --> 03:29:41,088 VICT 3614 03:29:41,088 --> 03:29:43,591 VECTOR INDUCED TO RSV BY THE 3615 03:29:43,591 --> 03:29:54,101 FIRST LAB ATTENUATED VACCINE. 3616 03:29:54,435 --> 03:29:59,940 WE HAVE TWO PROMISING 3617 03:29:59,940 --> 03:30:00,508 CANDIDATES. 3618 03:30:00,508 --> 03:30:06,347 THE CANDIDATE IN SANOFI WILL GO 3619 03:30:06,347 --> 03:30:07,948 POWERED FOR EFFICACY SCHEDULED 3620 03:30:07,948 --> 03:30:14,321 TO BEGIN EARLY IN 2024 AND THIS 3621 03:30:14,321 --> 03:30:24,799 IS OF COURSE SUPER EXCITING 3622 03:30:26,834 --> 03:30:27,668 ONGOING STUDIES. 3623 03:30:27,668 --> 03:30:32,306 WE FURTHER STUDIED LEAD 3624 03:30:32,306 --> 03:30:35,376 CANDIDATES INCLUDING THE 3625 03:30:35,376 --> 03:30:39,079 CANDIDATE IN SMALL PHASE 1/2 3626 03:30:39,079 --> 03:30:43,818 STUDIES AND CHARACTERIZE THE 3627 03:30:43,818 --> 03:30:45,286 PEDIATRIC IMMUNE RESPONSE 3628 03:30:45,286 --> 03:30:46,720 FOLLOWING INTRANASAL 3629 03:30:46,720 --> 03:30:49,990 IMMUNIZATION AND THIS IS AS MUCH 3630 03:30:49,990 --> 03:30:52,293 AS WE CAN BY SINGLE CELL 3631 03:30:52,293 --> 03:30:53,027 SEQUENCING GETTING FROM A SMALL 3632 03:30:53,027 --> 03:30:53,561 NUMBER OF CHILDREN IN THE 3633 03:30:53,561 --> 03:30:59,300 STUDIES. 3634 03:30:59,300 --> 03:31:05,439 IN ADDITION WE'RE MOVING FOR THE 3635 03:31:05,439 --> 03:31:15,382 VICTORY VACCINE CANDIDATES AND 3636 03:31:15,382 --> 03:31:18,385 LOOKING AT PRIME RICH FACTORS IN 3637 03:31:18,385 --> 03:31:20,221 LAB ATTENUATED RSV. 3638 03:31:20,221 --> 03:31:26,827 AND THIS IS WHERE WE ARE THIS 3639 03:31:26,827 --> 03:31:37,338 WAS A HUGE COLLABORATION AND 3640 03:31:44,845 --> 03:31:48,148 PETER COLLINS AND OUR STAFF 3641 03:31:48,148 --> 03:31:50,050 SCIENTISTS WHO CARRIED A BIG 3642 03:31:50,050 --> 03:31:51,719 LOAD AND OUR CLINICAL 3643 03:31:51,719 --> 03:31:52,853 COLLABORATORS I MENTIONED 3644 03:31:52,853 --> 03:31:55,756 EARLIER THE SANOFI TEAM AND ALL 3645 03:31:55,756 --> 03:31:57,358 THE STUDY PARTICIPANTS IN THIS 3646 03:31:57,358 --> 03:31:57,892 MANY PHASE 1 STUDIES. 3647 03:31:57,892 --> 03:32:08,235 THANK YOU VERY MUCH. 3648 03:32:09,403 --> 03:32:10,537 >> ANY QUESTIONS? 3649 03:32:10,537 --> 03:32:11,272 >> GREAT DATA. 3650 03:32:11,272 --> 03:32:13,941 ANY EVIDENCE FOR EMERGENCE OF 3651 03:32:13,941 --> 03:32:15,743 VACCINE ESCAPE VARIANTS 3652 03:32:15,743 --> 03:32:17,645 ESPECIALLY NOW THAT ELDERLY ARE 3653 03:32:17,645 --> 03:32:18,779 BEING RECOMMENDED TO RECEIVE THE 3654 03:32:18,779 --> 03:32:24,952 VACCINES AS WELL. 3655 03:32:24,952 --> 03:32:29,123 >> THERE ARE HUGE COLLABORATIVE 3656 03:32:29,123 --> 03:32:30,257 NETWORKS LOOKING AT THIS. 3657 03:32:30,257 --> 03:32:35,896 SO FAR RSV IS GENETICALLY STABLE 3658 03:32:35,896 --> 03:32:42,202 AND THERE'S A SUB GROUP A AND B 3659 03:32:42,202 --> 03:32:49,677 AND CHANGES BETWEEN SEASONS AND 3660 03:32:49,677 --> 03:32:51,278 THE IT'S REQUIRED ADDITIONAL 3661 03:32:51,278 --> 03:32:55,549 AMINO ACIDS LIKE 12 OR 18. 3662 03:32:55,549 --> 03:32:57,818 THEY'RE NOW FURTHER TEMPLATES 3663 03:32:57,818 --> 03:33:01,956 FOR ADDITIONAL MUTATIONS. 3664 03:33:01,956 --> 03:33:03,991 IF WE WOULD SEE VARIANTS THE F 3665 03:33:03,991 --> 03:33:06,727 IS ALSO FUNCTIONALLY CONSTRAINED 3666 03:33:06,727 --> 03:33:08,862 AND CAN'T ESCAPE FAR WITH 3667 03:33:08,862 --> 03:33:09,897 EPITOPES. 3668 03:33:09,897 --> 03:33:11,765 >> WE THOUGHT OF THE 3669 03:33:11,765 --> 03:33:12,366 CORONAVIRUS. 3670 03:33:12,366 --> 03:33:17,871 IT DOESN'T MUTATE AS MUCH AS. 3671 03:33:17,871 --> 03:33:20,874 >> WHAT DO YOU KNOW ABOUT THE 3672 03:33:20,874 --> 03:33:27,281 LOCAL MUCOSAL RESPONSES? 3673 03:33:27,281 --> 03:33:29,950 >> THE SARS COV2 PANDEMIC 3674 03:33:29,950 --> 03:33:30,851 IRONICALLY HAS BROUGHT OUT 3675 03:33:30,851 --> 03:33:33,954 CLOSER TO HAVING BETTER TOOLS IN 3676 03:33:33,954 --> 03:33:42,930 OUR GROUP. 3677 03:33:42,930 --> 03:33:44,965 THE BIG PROBLEM IS WITH THE 3678 03:33:44,965 --> 03:33:53,107 PEDIATRIC STUDIES THE TOOLS 3679 03:33:53,107 --> 03:33:54,174 YOUNG TODDLERS DON'T TOLERATE 3680 03:33:54,174 --> 03:33:57,411 THEM VERY WELL AND THE CLINICAL 3681 03:33:57,411 --> 03:33:58,645 TEAMS ASKED TO US REFRAIN FROM 3682 03:33:58,645 --> 03:34:01,081 USING THEM AND BACK TO NASAL 3683 03:34:01,081 --> 03:34:03,751 SWABS AND WASHES IT'S A 3684 03:34:03,751 --> 03:34:06,253 DIFFICULT SUBSTRATE BUT OUR 3685 03:34:06,253 --> 03:34:07,821 TOOLS HAVE IMPROVED A LOT AND 3686 03:34:07,821 --> 03:34:09,823 WE'RE RETROSPECTIVELY DOING THE 3687 03:34:09,823 --> 03:34:17,598 ANALYSIS AND HOPING TO GET MORE. 3688 03:34:17,598 --> 03:34:20,901 WE'RE LOOKING AT PBMCs AND 3689 03:34:20,901 --> 03:34:25,272 LOOKING AT THE LINEAGE 3690 03:34:25,272 --> 03:34:25,572 DEVELOPMENT. 3691 03:34:25,572 --> 03:34:28,042 >> GREAT WORK, ULA. 3692 03:34:28,042 --> 03:34:30,711 MODERNA IS DEVELOPING AN mRNA 3693 03:34:30,711 --> 03:34:35,482 VACCINE FOR RSV AND DO YOU 3694 03:34:35,482 --> 03:34:37,351 BELIEVE THE LIVE ATTENUATED TO 3695 03:34:37,351 --> 03:34:41,288 BE SUPERIOR TO mRNA AND WHY? 3696 03:34:41,288 --> 03:34:46,727 >> IT STILL REMAINS TO BE SEEN 3697 03:34:46,727 --> 03:34:48,562 IF LIKE I KNOW MODERNA AND 3698 03:34:48,562 --> 03:34:50,564 OTHERS ARE PLANNING TO GO TO 3699 03:34:50,564 --> 03:34:54,034 PEDIATRIC COHORTS WITH mRNA 3700 03:34:54,034 --> 03:34:54,835 VACCINES. 3701 03:34:54,835 --> 03:34:58,238 I MEAN WE'RE AT LID AND THERE'S 3702 03:34:58,238 --> 03:35:00,107 A HISTORY OF VACCINE ENHANCED 3703 03:35:00,107 --> 03:35:00,574 DISEASE. 3704 03:35:00,574 --> 03:35:02,709 FOR US WE'LL STAY WITH LAB 3705 03:35:02,709 --> 03:35:04,278 ATTENUATED VACCINES BECAUSE WE 3706 03:35:04,278 --> 03:35:06,480 KNOW THEY WILL PROVIDE A VERY 3707 03:35:06,480 --> 03:35:09,550 GOOD BASELINE ALL ANTIGENS OF 3708 03:35:09,550 --> 03:35:12,986 RSV AND GOOD MUCOSAL IMMUNITY. 3709 03:35:12,986 --> 03:35:17,024 THE HARD THING IS TO PROTECT THE 3710 03:35:17,024 --> 03:35:18,492 UPPER RESPIRATORY ATTRACT 3711 03:35:18,492 --> 03:35:23,097 AGAINST SUSCEPTIBILITY TO 3712 03:35:23,097 --> 03:35:25,099 INFECTION AND I THINK ALSO IN 3713 03:35:25,099 --> 03:35:27,501 OUR APPROACHES DURING THE 3714 03:35:27,501 --> 03:35:28,769 PANDEMIC WE FEEL MORE STRONGLY 3715 03:35:28,769 --> 03:35:31,438 THAN EVER IT'S A GOOD APPROACH 3716 03:35:31,438 --> 03:35:34,241 FOR A RESPIRATORY VIRUS, LIVE 3717 03:35:34,241 --> 03:35:40,214 ATTENUATED OVER mRNA INJECTABLE. 3718 03:35:42,683 --> 03:35:43,984 >> I'M CURIOUS ON THE DECISION 3719 03:35:43,984 --> 03:35:48,021 TO GO WITH THE BOOST WITH THE 3720 03:35:48,021 --> 03:35:51,758 BPRP AND GETTING THE DESCAB 3721 03:35:51,758 --> 03:35:51,992 SOLUBLE. 3722 03:35:51,992 --> 03:35:53,127 WHAT'S THE ADVANTAGE THERE? 3723 03:35:53,127 --> 03:35:57,631 >> ONE OF THE ADVANTAGES IS 3724 03:35:57,631 --> 03:36:01,668 WE'RE AGAIN GOING INTRANASALLY. 3725 03:36:01,668 --> 03:36:03,337 WE DO SEE SERUM IMMUNE RESPONSES 3726 03:36:03,337 --> 03:36:06,473 BUT WE KNOW EVERYTHING ELSE IN 3727 03:36:06,473 --> 03:36:11,311 BETWEEN AND THAT'S THE MUCOSAL 3728 03:36:11,311 --> 03:36:12,913 IMMUNE RESPONSE INITIATING FIRST 3729 03:36:12,913 --> 03:36:18,752 AND IT'S A BIVALENT VACCINE AND 3730 03:36:18,752 --> 03:36:19,820 PROTECT AGAINST ANOTHER MAJOR 3731 03:36:19,820 --> 03:36:21,989 PLAYER OF RESPIRATORY ILLNESS IN 3732 03:36:21,989 --> 03:36:24,291 CHILDREN AND GETTING THE SUPER 3733 03:36:24,291 --> 03:36:27,761 GOOD ANTIGEN. 3734 03:36:27,761 --> 03:36:30,397 THAT'S BASICALLY. 3735 03:36:30,397 --> 03:36:35,536 WE MIGHT PRE-CLINICALLY LOOK AT 3736 03:36:35,536 --> 03:36:37,404 OTHERS BUT THAT WILL BE OUR 3737 03:36:37,404 --> 03:36:38,205 AVENUE. 3738 03:36:38,205 --> 03:36:42,709 >> FOLLOWING THAT QUESTION, WHY 3739 03:36:42,709 --> 03:36:45,779 DO YOU THINK CAN YOU SPECULATE 3740 03:36:45,779 --> 03:36:54,721 IF THE BOOST IS AS SUPERIOR AS 3741 03:36:54,721 --> 03:36:55,789 THE IMMUNOMODIFICATION? 3742 03:36:55,789 --> 03:36:57,758 >> IT'S MADE IT STABLE. 3743 03:36:57,758 --> 03:37:00,227 THE F PROTEIN IS FIRST SECRETED 3744 03:37:00,227 --> 03:37:06,633 AS A PRE-FUSION AND GETS 3745 03:37:06,633 --> 03:37:11,972 TRIGGERED AND FALLS TO POST-F 3746 03:37:11,972 --> 03:37:16,577 AND A GROUP HAVE SHOWED IF YOU 3747 03:37:16,577 --> 03:37:18,745 ABSORB HUMAN SERA WITH POST F 3748 03:37:18,745 --> 03:37:21,782 THE NEUTRALIZATION ACTIVITY OF 3749 03:37:21,782 --> 03:37:26,286 THE CELL IS STILL THERE AND 3750 03:37:26,286 --> 03:37:31,091 NEUTRALIZING ANTIBODIED ARE NOT 3751 03:37:31,091 --> 03:37:38,365 CAPTURED WITH POSTS F AND 3752 03:37:38,365 --> 03:37:45,806 BASICALLY WE KNOW THAT THE SITE 3753 03:37:45,806 --> 03:37:52,412 0 MOST CRITICAL EPITOPE FOR 3754 03:37:52,412 --> 03:37:55,649 NEUTRALIZING ANTIBODY -- 3755 03:37:55,649 --> 03:37:57,184 >> SO WHY NOT IMMUNIZE FROM THE 3756 03:37:57,184 --> 03:38:02,823 VERY BEGINNING WITH PRE F THEN? 3757 03:38:02,823 --> 03:38:04,491 >> BECAUSE THERE WAS ONE ANIMAL 3758 03:38:04,491 --> 03:38:07,828 MODEL IF YOU DO THAT YOU STILL 3759 03:38:07,828 --> 03:38:10,797 TRIGGER MARKERS THAT PREDICT 3760 03:38:10,797 --> 03:38:13,300 SUSCEPTIBILITY FOR ENHANCED 3761 03:38:13,300 --> 03:38:13,934 RESPIRATORY DISEASE. 3762 03:38:13,934 --> 03:38:17,638 THE NEXT TIME YOU WOULD GET 3763 03:38:17,638 --> 03:38:19,273 INFECTED WITH WILD TYPE RSV IT 3764 03:38:19,273 --> 03:38:22,709 MAY NOT BE THE ENTIRE POPULATION 3765 03:38:22,709 --> 03:38:25,045 BUT IT MIGHT BE IN SOME 3766 03:38:25,045 --> 03:38:27,781 INDIVIDUALS YOU SEE THE ENHANCED 3767 03:38:27,781 --> 03:38:31,652 RESPIRATORY DISEASE THAT WAS 3768 03:38:31,652 --> 03:38:33,920 OBSERVED WHEN IT INACTIVATED IN 3769 03:38:33,920 --> 03:38:36,790 THE EARLY DAYS OF RSV. 3770 03:38:36,790 --> 03:38:37,791 >> LAST QUESTION. 3771 03:38:37,791 --> 03:38:38,992 >> THANKS FOR YOUR TALK. 3772 03:38:38,992 --> 03:38:44,197 I WAS CURIOUS, WHAT CAUSES THIS 3773 03:38:44,197 --> 03:38:45,432 ENHANCED -- I FORGOT WHAT TO 3774 03:38:45,432 --> 03:38:46,133 CALL IT. 3775 03:38:46,133 --> 03:38:51,772 >> ENHANCED RESPIRATORY DISEASE. 3776 03:38:51,772 --> 03:38:54,241 THE WAS OBSERVE ED LIKE TRYING 3777 03:38:54,241 --> 03:38:57,177 TO DO WORK THROUGH ACTIVATE AND 3778 03:38:57,177 --> 03:38:58,445 THEN IMMUNIZED CHILDREN AND IT 3779 03:38:58,445 --> 03:39:01,682 WAS ALL GOOD UNTIL YOU GOT TO 3780 03:39:01,682 --> 03:39:06,320 RSV NAIVE POPULATIONS WHERE THE 3781 03:39:06,320 --> 03:39:10,223 PRIMARY IMMUNIZATION WAS WITH 3782 03:39:10,223 --> 03:39:14,261 LOTS OF SOON YOU ARE IMMUNOGENIC 3783 03:39:14,261 --> 03:39:18,098 EPITOPES AND LOOKED AT THE 3784 03:39:18,098 --> 03:39:19,266 STRONG NEUTRALIZING EPITOPES AND 3785 03:39:19,266 --> 03:39:23,003 STRONG INDUCTION OF ANTIBODIES 3786 03:39:23,003 --> 03:39:30,844 BUT NOT NEUTRALIZING AND INDUCED 3787 03:39:30,844 --> 03:39:34,014 RESPONSE AND LIKE A HUGE 3788 03:39:34,014 --> 03:39:35,515 OVERREACTION ENHANCED 3789 03:39:35,515 --> 03:39:36,683 RESPIRATORY DISEASE AGAINST THE 3790 03:39:36,683 --> 03:39:39,853 RSV ANTIGEN THAT CAME FROM THE 3791 03:39:39,853 --> 03:39:44,157 COMMUNITY SO UNINHIBITED RSV 3792 03:39:44,157 --> 03:39:45,892 APPLICATION, ABSENCE OF 3793 03:39:45,892 --> 03:39:47,894 NEUTRALIZATION WITH A STRONG 3794 03:39:47,894 --> 03:39:50,364 IMMUNE RESPONSE AND IN THE EARLY 3795 03:39:50,364 --> 03:39:55,369 STUDY TWO TODDLERS PASSED AWAY. 3796 03:39:55,369 --> 03:40:00,540 YOU CAN RING KING ET AL. 3797 03:40:00,540 --> 03:40:09,850 >> THANK YOU, ULA FOR YOUR GREAT 3798 03:40:09,850 --> 03:40:11,518 PRESENTATION. 3799 03:40:11,518 --> 03:40:14,121 >> ALL RIGHT. 3800 03:40:14,121 --> 03:40:17,591 THE LAST PRESENTATION OF THE DAY 3801 03:40:17,591 --> 03:40:20,994 IS DR. TIJANA IVANOVIC. 3802 03:40:20,994 --> 03:40:23,630 SHE WAS BORN IN SERBIA BUT CAME 3803 03:40:23,630 --> 03:40:26,233 TO THE UNIVERSITY OF CALIFORNIA, 3804 03:40:26,233 --> 03:40:28,368 LOS ANGELES TO DO HER UNDER 3805 03:40:28,368 --> 03:40:30,570 GRADUATE DEGREE AND GOT A Ph.D. 3806 03:40:30,570 --> 03:40:34,608 FROM HARVARD AND POST DOCKED 3807 03:40:34,608 --> 03:40:37,544 WITH STEVE HARRISON AN 3808 03:40:37,544 --> 03:40:39,813 OUTSTANDING VIROLOGIST OF VIRAL 3809 03:40:39,813 --> 03:40:41,915 AND CELLULAR FACTORS OVER MANY 3810 03:40:41,915 --> 03:40:42,115 YEARS. 3811 03:40:42,115 --> 03:40:47,387 WHILE POSTDOC IN STEVE'S LAB SHE 3812 03:40:47,387 --> 03:40:50,857 DEVELOPED SINGLE PARTICLE 3813 03:40:50,857 --> 03:40:52,826 METHODS FOR STUDYING VIRAL 3814 03:40:52,826 --> 03:40:53,059 FUSION. 3815 03:40:53,059 --> 03:40:56,830 AFTER HER POSTDOC SHE WENT TO 3816 03:40:56,830 --> 03:40:58,064 BRANDEIS UNIVERSITY AS AN 3817 03:40:58,064 --> 03:41:00,801 ASSISTANT PROFESSOR AND HER 3818 03:41:00,801 --> 03:41:02,702 PROGRAM WAS MOSTLY ON VIRUS 3819 03:41:02,702 --> 03:41:07,441 ASSEMBLY AND HOST INTERACTION 3820 03:41:07,441 --> 03:41:10,343 AND ADAPTATION SHE WAS SUPPORT 3821 03:41:10,343 --> 03:41:16,049 THE NIH'S NEW INNOVATOR AWARD 3822 03:41:16,049 --> 03:41:21,221 AND G. HERALD AND LEAH MATHERS 3823 03:41:21,221 --> 03:41:22,789 CHARITABLE FOUNDATION AND WAS 3824 03:41:22,789 --> 03:41:26,693 RECRUITED TO COME TO NIH AND 3825 03:41:26,693 --> 03:41:28,995 NIAID IN THE LABORATORY OF VIRAL 3826 03:41:28,995 --> 03:41:30,964 DISEASES AND STARTED IN MAY THIS 3827 03:41:30,964 --> 03:41:31,164 YEAR. 3828 03:41:31,164 --> 03:41:35,268 SO WITH THAT, I WILL INVITE 3829 03:41:35,268 --> 03:41:38,705 TIJANA TO COME UP AND TELL US 3830 03:41:38,705 --> 03:41:40,974 WHAT SHE'S BEEN DOING. 3831 03:41:40,974 --> 03:41:43,343 >> THANK YOU, JOE FOR THE KIND 3832 03:41:43,343 --> 03:41:44,244 INTRODUCTION. 3833 03:41:44,244 --> 03:41:54,788 THANK YOU SO THE ORGANIZERS AND 3834 03:41:55,388 --> 03:41:58,058 MRS. SALZMAN FOR THE INVITATION 3835 03:41:58,058 --> 03:42:00,160 AND A NICE DAY OF TALKS 3836 03:42:00,160 --> 03:42:04,331 INCLUDING BY TO THE AWARDEE. 3837 03:42:04,331 --> 03:42:06,700 I'D LIKE TO SHARE WORK FROM MY 3838 03:42:06,700 --> 03:42:08,034 LAB BRANDEIS AND HERE. 3839 03:42:08,034 --> 03:42:10,670 WE'RE INTERESTED IN 3840 03:42:10,670 --> 03:42:12,539 UNDERSTANDING HOW PHENOTYPIC 3841 03:42:12,539 --> 03:42:15,876 PROCESSES SO THOSE NOT ROOTED IN 3842 03:42:15,876 --> 03:42:17,477 GENETIC CHANGE CAN INFLUENCE AND 3843 03:42:17,477 --> 03:42:22,582 CHANGE VIRAL EVOLUTION. 3844 03:42:22,582 --> 03:42:30,257 THIS STORY WILL BE ABOUT VIRUS 3845 03:42:30,257 --> 03:42:31,591 SHAPE AND STRUCTURE. 3846 03:42:31,591 --> 03:42:36,429 SHAPE IN VIROLOGY CONFERS 3847 03:42:36,429 --> 03:42:38,698 IMPORTANT FUNCTION AND UNDER 3848 03:42:38,698 --> 03:42:41,434 SELECTIVE PRESSURE AND DEFINING 3849 03:42:41,434 --> 03:42:45,872 THE PRESSURES AND PROCESSES IS 3850 03:42:45,872 --> 03:42:46,439 DIFFICULT ESPECIALLY WHEN 3851 03:42:46,439 --> 03:42:48,875 DEALING WITH ONLY SNAPSHOTS IN 3852 03:42:48,875 --> 03:42:49,876 TIME. 3853 03:42:49,876 --> 03:42:51,711 SO VIRUSES HERE PRESENT UNIQUE 3854 03:42:51,711 --> 03:42:54,748 OPPORTUNITY BECAUSE OF THEIR 3855 03:42:54,748 --> 03:42:58,385 RAPID VIRAL REPLICATION, THE 3856 03:42:58,385 --> 03:42:59,486 RAPID EVOLUTION AND PRESENT 3857 03:42:59,486 --> 03:43:01,454 THEIR OWN CHALLENGES AND THIS IS 3858 03:43:01,454 --> 03:43:11,765 THEIR SMALL SIZE. 3859 03:43:17,871 --> 03:43:21,007 HOW DO WE STUDY THESE AND THIS 3860 03:43:21,007 --> 03:43:29,683 IS WHAT WE EMBRACE IN OUR LAB WE 3861 03:43:29,683 --> 03:43:32,619 STARTED WITH THE MOST EXTREME 3862 03:43:32,619 --> 03:43:36,056 EXAMPLES AND POLY MORPHIC 3863 03:43:36,056 --> 03:43:41,928 VIRUSES AND THEY GENERATE A 3864 03:43:41,928 --> 03:43:45,599 MIXTURE OF SHAPES THEY INCLUDE 3865 03:43:45,599 --> 03:43:49,769 PARTICLES AND FILAMENTS OF 3866 03:43:49,769 --> 03:43:55,308 VARIOUS LENGTHS AND IT 3867 03:43:55,308 --> 03:44:01,815 REPRESENTS A SINGLE VIRUS 3868 03:44:01,815 --> 03:44:04,084 PARTICLES AND SPHERES AND 3869 03:44:04,084 --> 03:44:06,920 NOODLES ENCODE THE GENOME AND 3870 03:44:06,920 --> 03:44:08,555 SHAPE IS A PHENOTYPIC TRAIT AND 3871 03:44:08,555 --> 03:44:10,657 WE FOCUSSED ON THE INFLUENZA 3872 03:44:10,657 --> 03:44:18,832 VIRUS BUT I HAVE EXAMPLES OF SO 3873 03:44:18,832 --> 03:44:19,799 MEMBERS FROM DIFFERS FAMILIES 3874 03:44:19,799 --> 03:44:25,639 HERE LISTED ON THE LEFT 3875 03:44:25,639 --> 03:44:28,575 INCLUDING DANGEROUS PATHOGENS 3876 03:44:28,575 --> 03:44:33,546 AND EMERGING VIRUS AND SEEMS 3877 03:44:33,546 --> 03:44:35,348 IMPORTANT TO UNDERSTAND. 3878 03:44:35,348 --> 03:44:37,183 THIS TALK I'LL LEAD YOU THE OUR 3879 03:44:37,183 --> 03:44:38,752 DISCOVERY OF THE FUNCTION OF 3880 03:44:38,752 --> 03:44:40,920 VARIANT SHAPE AND GROWING 3881 03:44:40,920 --> 03:44:41,788 UNDERSTANDING OF THE REGULATION 3882 03:44:41,788 --> 03:44:43,056 OF VARIANT SHAPE. 3883 03:44:43,056 --> 03:44:48,662 AND BOTH OF THESE STUDIES WERE 3884 03:44:48,662 --> 03:44:58,238 ENABLED BY EMPLOYING SINGLE 3885 03:44:58,238 --> 03:45:03,810 VIRION AND THE HAVE THE ABILITY 3886 03:45:03,810 --> 03:45:05,145 TO STUDY AND CHARACTERIZE THE 3887 03:45:05,145 --> 03:45:07,180 FULL DIVERSITY OF A POPULATION 3888 03:45:07,180 --> 03:45:09,749 RATHER THAN MEASURING AN AVERAGE 3889 03:45:09,749 --> 03:45:10,717 INHERENT IN THE BULK OF 3890 03:45:10,717 --> 03:45:12,485 APPROACHES. 3891 03:45:12,485 --> 03:45:14,621 AND SO THE FIRST PART OF MY TALK 3892 03:45:14,621 --> 03:45:18,425 WILL BE ON THE FUNCTION OF 3893 03:45:18,425 --> 03:45:19,559 VARIANT SHAPE AND THIS WORK WAS 3894 03:45:19,559 --> 03:45:21,895 LED BY A FORMER POSTDOC IN THE 3895 03:45:21,895 --> 03:45:30,437 LAB. 3896 03:45:30,437 --> 03:45:33,573 SOME FUNCTION OF THE SHAPE 3897 03:45:33,573 --> 03:45:36,910 DERIVE FROM OBSERVATIONS 3898 03:45:36,910 --> 03:45:39,112 DOMINATE IN ANIMAL INFECTIONS 3899 03:45:39,112 --> 03:45:41,448 AND A FEW PATHOGENS IN VITRO ARE 3900 03:45:41,448 --> 03:45:43,083 FOR SPHERICAL FORMS. 3901 03:45:43,083 --> 03:45:45,719 I SUGGESTED SOME UNIQUE IN VIVO 3902 03:45:45,719 --> 03:45:51,758 PRESSURE THAT FAVORED FILAMENTS. 3903 03:45:51,758 --> 03:45:56,596 THEY ENCODE THE SAME GENOME AND 3904 03:45:56,596 --> 03:45:58,131 ALSO THE SAME COPY NUMBER. 3905 03:45:58,131 --> 03:46:01,534 SO REALLY THE ONLY THING THEY 3906 03:46:01,534 --> 03:46:02,869 DIFFER IN IS WHAT'S DISPLAYED ON 3907 03:46:02,869 --> 03:46:04,003 THE SURFACES. 3908 03:46:04,003 --> 03:46:07,040 AND THESE PROTEINS ARE GENERALLY 3909 03:46:07,040 --> 03:46:11,077 INVOLVING ANTIGENS AND WE 3910 03:46:11,077 --> 03:46:16,516 HYPOTHESIZED THEY MAY COME FROM 3911 03:46:16,516 --> 03:46:19,419 THE MEDIATING CELL ENTRY. 3912 03:46:19,419 --> 03:46:22,889 I'M SHOWING AN ELECTROMICROGRAPH 3913 03:46:22,889 --> 03:46:24,290 OF A FLU PARTICLE. 3914 03:46:24,290 --> 03:46:34,801 YOU CAN SEE A DENSE ARRAY OF 3915 03:46:42,642 --> 03:46:46,045 GLUTAMATE AND THIS BINDS TO 3916 03:46:46,045 --> 03:46:50,183 RECEPTORS WHICH COMBINE TO THE 3917 03:46:50,183 --> 03:46:54,754 ENTIRE PARTICLE AND THE 3918 03:46:54,754 --> 03:46:56,322 ENDOSOMES TRIGGER FUSION BY THE 3919 03:46:56,322 --> 03:46:58,424 BASE DOMAIN PORTION OF THE 3920 03:46:58,424 --> 03:47:00,593 MOLECULE WHICH UNDER GOES A 3921 03:47:00,593 --> 03:47:03,563 SERIES OF FUNCTIONAL REARRA 3922 03:47:03,563 --> 03:47:06,032 REARRANGEMENTS AND BRINGS THEM 3923 03:47:06,032 --> 03:47:11,871 TOGETHER ALLOWING THEM TO FUSE. 3924 03:47:11,871 --> 03:47:15,008 BOTH FUNCTION UNDER THE ANTIBODY 3925 03:47:15,008 --> 03:47:16,242 PRESSURE AND SO YOU HAVE 3926 03:47:16,242 --> 03:47:17,977 ANTIBIOTICS THAT BIND TO THE 3927 03:47:17,977 --> 03:47:20,413 HEAD OF HA AND BLOCK ATTACHMENT 3928 03:47:20,413 --> 03:47:26,719 OR THE BASE OF HA AND PREVENT HA 3929 03:47:26,719 --> 03:47:30,723 CONFIRMAT 3930 03:47:30,723 --> 03:47:33,293 CONFIRMATIONAL CHANGES AND 3931 03:47:33,293 --> 03:47:37,063 THOUGHT THEY MAY NEUTRALIZE 3932 03:47:37,063 --> 03:47:38,932 ANTIBODIES WITH MORE SPIKE 3933 03:47:38,932 --> 03:47:44,470 PROTEINS ON THE SURFACES AND THE 3934 03:47:44,470 --> 03:47:45,972 FRACTIONATED VIRUSES HAVE 3935 03:47:45,972 --> 03:47:50,343 SPHERES OR FILAMENTS IN TWO 3936 03:47:50,343 --> 03:47:54,747 PREPS AND IN THE PRESENCE OF 3937 03:47:54,747 --> 03:47:55,181 INCREASING ANTIBODY 3938 03:47:55,181 --> 03:48:00,920 CONCENTRATIONS AND WITHOUT 3939 03:48:00,920 --> 03:48:02,722 ADDING INHIBITORS BUT WITH 3940 03:48:02,722 --> 03:48:04,991 EITHER TYPE OF ANTIBODY 3941 03:48:04,991 --> 03:48:07,527 FILAMENTS WERE LESS ATTENUATED 3942 03:48:07,527 --> 03:48:09,295 FOR THE SAME ANTIBODY 3943 03:48:09,295 --> 03:48:09,629 CONCENTRATION. 3944 03:48:09,629 --> 03:48:14,133 HERE WHAT IS PLOTTED IS THE FULL 3945 03:48:14,133 --> 03:48:19,172 INHIBITION FOR THE PREPS IN 3946 03:48:19,172 --> 03:48:22,709 THEIR SPHERES OR FILAMENTS AND 3947 03:48:22,709 --> 03:48:25,144 TAKES THE SAME IN THE CONTEXT OF 3948 03:48:25,144 --> 03:48:26,980 FILAMENTS AND SPHERES. 3949 03:48:26,980 --> 03:48:30,717 WHAT IS THE MECHANISM THAT LEADS 3950 03:48:30,717 --> 03:48:32,385 TO THIS RESISTANCE. 3951 03:48:32,385 --> 03:48:35,154 WE STARTED ADDRESSING THE 3952 03:48:35,154 --> 03:48:37,390 DISCUSSION IN THE CONTEXT OF 3953 03:48:37,390 --> 03:48:39,759 ANTIBODIES THOSE THAT BIND EHA 3954 03:48:39,759 --> 03:48:43,663 DO NOT INTERFERE WITH ATTACHMENT 3955 03:48:43,663 --> 03:48:48,468 BUT PREVENT CONFIRMATIONAL 3956 03:48:48,468 --> 03:48:51,104 CHANGES IN THE ENDOSOME. 3957 03:48:51,104 --> 03:48:54,073 WE HAD A NICE ASSAY WE DEVELOPED 3958 03:48:54,073 --> 03:48:57,076 DURING MY POSTDOC JOE MENTIONED. 3959 03:48:57,076 --> 03:48:59,078 THIS IS HERE WE CAN OBSERVE 3960 03:48:59,078 --> 03:49:02,348 VIRUS FUSION AT THE LEVEL OF 3961 03:49:02,348 --> 03:49:04,918 SINGLE VIRIONS. 3962 03:49:04,918 --> 03:49:08,154 AND YOU'RE SEEINGS FUFG AND 3963 03:49:08,154 --> 03:49:10,657 MERGING THEIR ENVELOPES WITH A 3964 03:49:10,657 --> 03:49:14,894 SINGLE LAYER ON THE MICROSCOPE 3965 03:49:14,894 --> 03:49:18,197 COVER SLIP AND DEPOSITING THE 3966 03:49:18,197 --> 03:49:19,766 DYE TO THE TARGET MEMBRANE. 3967 03:49:19,766 --> 03:49:22,502 YOU SEE THIS AS FLASHES AND 3968 03:49:22,502 --> 03:49:25,171 FLUORESCENCE AND THE DYE 3969 03:49:25,171 --> 03:49:26,372 DISSIPATE FROM THE SITE OF 3970 03:49:26,372 --> 03:49:28,041 FUSION AND YOU SEE MANY HERE IN 3971 03:49:28,041 --> 03:49:36,749 THE MOVIE. 3972 03:49:36,749 --> 03:49:45,892 THIS INCLUDES FLUORESCEIN AND 3973 03:49:45,892 --> 03:49:56,369 THIS WE EMPLOY MICROSCOPES. 3974 03:50:03,109 --> 03:50:06,312 YOU GET THE PROCESS AND WE COULD 3975 03:50:06,312 --> 03:50:10,783 DERIVE OR EXTRACT FROM THE 3976 03:50:10,783 --> 03:50:13,152 INFORMATION FOR FILAMENT VIRUSES 3977 03:50:13,152 --> 03:50:15,722 IN A SORT OF MORE MIXED 3978 03:50:15,722 --> 03:50:17,490 POPULATION I DESCRIBED EARLIER. 3979 03:50:17,490 --> 03:50:21,294 AND EXTRACT THE DATA FROM THE 3980 03:50:21,294 --> 03:50:23,963 EXPERIMENTS PERFORMED WITH THE 3981 03:50:23,963 --> 03:50:26,699 MORE SPHERICAL OR MOMENTOUS 3982 03:50:26,699 --> 03:50:29,535 PREPS WE CAN GET IDEA FOR LONG 3983 03:50:29,535 --> 03:50:31,437 VERSUS SHORT PARTICLES IN THE 3984 03:50:31,437 --> 03:50:32,772 FUSION ASSAY AND IN THE 3985 03:50:32,772 --> 03:50:35,475 PRESENTATION OF THE BASE BINDING 3986 03:50:35,475 --> 03:50:38,544 ANTIBODY WITH CONFIRMATIONAL 3987 03:50:38,544 --> 03:50:39,012 CHANGES. 3988 03:50:39,012 --> 03:50:43,416 THE PROBABILITY OF THE FUSION OR 3989 03:50:43,416 --> 03:50:46,152 FUSION EFFICIENCY OR THE END OF 3990 03:50:46,152 --> 03:50:48,521 THE REACTION GOES DOWN WITH 3991 03:50:48,521 --> 03:50:49,589 DECREASING ANTIBODY 3992 03:50:49,589 --> 03:50:51,858 CONCENTRATION AND THAT EFFECT 3993 03:50:51,858 --> 03:50:54,727 OCCURS FOR HIGHER ANTIBODY 3994 03:50:54,727 --> 03:50:55,762 CONCENTRATION FOR THE 3995 03:50:55,762 --> 03:50:58,765 FILAMENTOUS PARTICLE ARE FASTER 3996 03:50:58,765 --> 03:51:03,069 AT FUSING AND BOTH PARTICLE 3997 03:51:03,069 --> 03:51:04,971 TYPES HOLD THE SAME VALUE. 3998 03:51:04,971 --> 03:51:07,774 WHAT DOES IT TELL US ABOUT THE 3999 03:51:07,774 --> 03:51:12,712 UNDERLYING MECHANISM? 4000 03:51:12,712 --> 03:51:23,222 SO THIS COMES FROM THE FUSION 4001 03:51:26,793 --> 03:51:30,696 AND HERE'S A MORE INTENSE 4002 03:51:30,696 --> 03:51:34,400 DEPICTION FROM MY POST DOCTORAL 4003 03:51:34,400 --> 03:51:35,101 WORK. 4004 03:51:35,101 --> 03:51:39,472 HERE YOU CAN SEE THE AGE OF 4005 03:51:39,472 --> 03:51:41,774 FUSION IS INDEPENDENT OF EACH 4006 03:51:41,774 --> 03:51:42,141 OTHER. 4007 03:51:42,141 --> 03:51:45,111 ALL EVENTS TAKE PLACE AT THE 4008 03:51:45,111 --> 03:51:47,980 SURFACE OF PARTICLES AND HERE IN 4009 03:51:47,980 --> 03:51:51,250 GREEN IS THAT REGION OF THE 4010 03:51:51,250 --> 03:51:54,454 VIRION WHICH INTERFACES THE 4011 03:51:54,454 --> 03:51:57,457 TARGET BIO LAYER. 4012 03:51:57,457 --> 03:52:00,226 AND IT'S TRIGGERED AND THIS 4013 03:52:00,226 --> 03:52:03,563 HAPPENS ANYWHERE AT RANDOM IN 4014 03:52:03,563 --> 03:52:04,831 THE INTERFACE AND INDIVIDUALS 4015 03:52:04,831 --> 03:52:06,899 CANNOT BRING TWO MEMBRANES 4016 03:52:06,899 --> 03:52:17,076 TOGETHER. 4017 03:52:17,076 --> 03:52:21,380 SOME HAs ARE LOST AS 4018 03:52:21,380 --> 03:52:21,914 PARTICIPANTS AND THERE'S 4019 03:52:21,914 --> 03:52:23,249 REDUNDANCIES AND YOU'LL HAVE 4020 03:52:23,249 --> 03:52:25,451 SOME NEXT TO EACH OTHER AND THEY 4021 03:52:25,451 --> 03:52:27,286 CAN COLLAPSE AND BRING THE 4022 03:52:27,286 --> 03:52:28,554 MEMBRANES TOGETHER. 4023 03:52:28,554 --> 03:52:30,056 THE TRANSITION IS FAST. 4024 03:52:30,056 --> 03:52:31,557 AND THE EARLY TRANSITION OF 4025 03:52:31,557 --> 03:52:33,459 EXTENSION IS SLOW. 4026 03:52:33,459 --> 03:52:35,862 SO THE OVER ALL RATE OF FUSION 4027 03:52:35,862 --> 03:52:39,932 IS DETERMINED BY THE RATE OF 4028 03:52:39,932 --> 03:52:41,601 EXTENSION AND HUMAN CLUSTERS 4029 03:52:41,601 --> 03:52:45,938 WITH THE GROUP THAT CAN COLLAPSE 4030 03:52:45,938 --> 03:52:46,639 TOGETHER. 4031 03:52:46,639 --> 03:52:50,042 WHICH IS IN TURN RELATED TO THE 4032 03:52:50,042 --> 03:52:50,343 ACTIVATION. 4033 03:52:50,343 --> 03:52:51,344 AND NOW YOU CAN IMAGINE WHAT 4034 03:52:51,344 --> 03:52:54,881 WOULD HAPPEN IF YOU HAD ADDED 4035 03:52:54,881 --> 03:52:56,115 ANTIBODIES TO THE MIX. 4036 03:52:56,115 --> 03:52:58,251 YOU INCREASE THE FRACTION THAT 4037 03:52:58,251 --> 03:53:01,621 CANNOT PARTICIPATE AND RESTRICT 4038 03:53:01,621 --> 03:53:02,788 POSSIBLE PROFUSION CLUSTERS 4039 03:53:02,788 --> 03:53:03,189 FORMING. 4040 03:53:03,189 --> 03:53:06,726 YOU HAVE FEWER WAYS OF FORMING 4041 03:53:06,726 --> 03:53:12,131 THE CLUSTERS AND YOU MIGHT 4042 03:53:12,131 --> 03:53:13,633 DERIVE IT'S IMPOSSIBLE TO 4043 03:53:13,633 --> 03:53:15,735 ASSEMBLE A FUSION CLUSTER. 4044 03:53:15,735 --> 03:53:18,104 SO THIS LED TO ME PREDICTION 4045 03:53:18,104 --> 03:53:20,706 LARGER PARTICLES MIGHT HAVE MORE 4046 03:53:20,706 --> 03:53:22,508 OPPORTUNITIES FOR FUSION CLUSTER 4047 03:53:22,508 --> 03:53:29,115 FORMATION FOR THE SAME EXTENT OF 4048 03:53:29,115 --> 03:53:33,920 ENACT VASION FOR THE HA FOR THE 4049 03:53:33,920 --> 03:53:36,389 SPHERICAL PARTICLES. 4050 03:53:36,389 --> 03:53:40,259 THIS WAS TESTED AND WE COULD 4051 03:53:40,259 --> 03:53:45,164 MAKE PREDICTIONS ON A COMPUTER. 4052 03:53:45,164 --> 03:53:49,468 THESE ARE FROM COMPUTER 4053 03:53:49,468 --> 03:53:49,769 SIMULATIONS. 4054 03:53:49,769 --> 03:53:51,304 YOU CAN SEE THE LARGER PARTICLES 4055 03:53:51,304 --> 03:54:01,847 ARE FASTER AT FUSING AND TAKES 4056 03:54:02,815 --> 03:54:08,287 MORE ACTIVATION FOR FLOW OF 4057 03:54:08,287 --> 03:54:11,924 FUSION AND ALL PARTICLE SIZES 4058 03:54:11,924 --> 03:54:13,759 HERE INCLUDING THE PATCHES ARE 4059 03:54:13,759 --> 03:54:15,828 HAs FOR GIVEN PARTICLE TYPE AND 4060 03:54:15,828 --> 03:54:18,731 THE RANGE OF PARTICLE SIZES 4061 03:54:18,731 --> 03:54:21,934 REPRESENT NATURAL VARIATION OF 4062 03:54:21,934 --> 03:54:24,704 FLU PARTICLES. 4063 03:54:24,704 --> 03:54:29,375 ALL PARTICLE TYPES HAVE A NEAR 4064 03:54:29,375 --> 03:54:32,111 PERFECT CHANCE OF INFUSION BY 4065 03:54:32,111 --> 03:54:34,380 THE SMALLEST FUSION OF 4066 03:54:34,380 --> 03:54:36,215 ACTIVATION OF HA AND GREATER 4067 03:54:36,215 --> 03:54:38,484 THAN 90% IN ACTIVATION FOR ANY 4068 03:54:38,484 --> 03:54:43,756 EFFECT OF THE FUSION YIELD TO 4069 03:54:43,756 --> 03:54:45,891 SUGGEST THAT FILAMENTS MAY 4070 03:54:45,891 --> 03:54:50,730 RESIST THE SLOW DOWN OF FUSION 4071 03:54:50,730 --> 03:54:51,897 AND REDUCTION OF FUSION 4072 03:54:51,897 --> 03:54:53,532 EFFICIENCY BY ANTIBODIES. 4073 03:54:53,532 --> 03:54:55,968 I'M PULLING OUT THE 4074 03:54:55,968 --> 03:54:57,970 REPRESENTATIVE DATA FOR THE 4075 03:54:57,970 --> 03:55:00,673 PATCHES THAT REPRESENT THE 4076 03:55:00,673 --> 03:55:03,709 POPULATIONS THAT WERE DERIVED BY 4077 03:55:03,709 --> 03:55:05,678 FRACTIONATION AND HERE I ENABLED 4078 03:55:05,678 --> 03:55:07,847 DIRECT COMPARISON OF SIMULATION 4079 03:55:07,847 --> 03:55:09,915 AND THEORY AND HIGHLIGHTING THE 4080 03:55:09,915 --> 03:55:18,591 PARTS OF THE INACTIVATION CURVES 4081 03:55:18,591 --> 03:55:21,927 AND THE SINGLE PARTICLE 4082 03:55:21,927 --> 03:55:23,129 EXPERIMENTS SIMULATE THE MODEL 4083 03:55:23,129 --> 03:55:26,098 AND SHOWED FILAMENTS CAN RESIST 4084 03:55:26,098 --> 03:55:27,466 THE SLOW DOWN OF FUSION PRODUCED 4085 03:55:27,466 --> 03:55:31,170 BY ANTIBODIES AND THERE'S ACTION 4086 03:55:31,170 --> 03:55:36,242 INFUSION PROBABILITY. 4087 03:55:36,242 --> 03:55:38,711 SO WE'RE IN THE PROCESS OF 4088 03:55:38,711 --> 03:55:39,378 GENERATING QUANTITATIVE MODELS 4089 03:55:39,378 --> 03:55:42,481 WITH ANTIBODIES THAT INHIBIT 4090 03:55:42,481 --> 03:55:43,382 ATTACHMENT AND INCLUDE OTHER 4091 03:55:43,382 --> 03:55:46,352 TYPES OF ACTIVATION SUCH AS THE 4092 03:55:46,352 --> 03:55:49,455 OBSERVATION FOR THE ADVANTAGE OF 4093 03:55:49,455 --> 03:55:51,924 FILAMENTS NOT LIMITED TO THE 4094 03:55:51,924 --> 03:55:53,993 SOLUBLE INHIBITORS AND FLU AND 4095 03:55:53,993 --> 03:56:04,537 IF YOU TAKE PROTEINS FOR OTHER 4096 03:56:05,004 --> 03:56:08,107 FILAMENT VIRUSES AND YOU SEE 4097 03:56:08,107 --> 03:56:13,746 EBOLA ANTIBODIES AND RE SIST TH 4098 03:56:13,746 --> 03:56:14,747 ACTIVATION AND IT'S IMPORTANT 4099 03:56:14,747 --> 03:56:17,316 FOR ADAPTATION. 4100 03:56:17,316 --> 03:56:19,585 THIS LED TO THIS MODEL. 4101 03:56:19,585 --> 03:56:21,454 BY ALWAYS ASSEMBLING A MIXTURE 4102 03:56:21,454 --> 03:56:27,526 OF PARTICLE SHAPES AND VIRUSES 4103 03:56:27,526 --> 03:56:30,062 HAVE READY PARTICLE TYPES WITH 4104 03:56:30,062 --> 03:56:30,730 ROUNDS OF INFECTION UNDER 4105 03:56:30,730 --> 03:56:34,734 PRESSURE. 4106 03:56:34,734 --> 03:56:36,068 BY ALWAYS HAVING A SUB 4107 03:56:36,068 --> 03:56:38,204 POPULATION OF FILAMENTS YOU WILL 4108 03:56:38,204 --> 03:56:42,775 BE ABLE TO INITIATE AND 4109 03:56:42,775 --> 03:56:44,877 REPLICATE IN THE PRESENCE OF 4110 03:56:44,877 --> 03:56:46,479 INHIBITERS AND LEAD TO MUTATIONS 4111 03:56:46,479 --> 03:56:51,917 WHEN AND WHERE THEY'RE NEEDED. 4112 03:56:51,917 --> 03:57:02,428 AND SPHERES MAY DOMINATE MORE 4113 03:57:04,463 --> 03:57:06,732 ECONOMICALLY EFFICIENT IN 4114 03:57:06,732 --> 03:57:15,908 ASSEMBLY AND ENTRY. 4115 03:57:15,908 --> 03:57:21,247 HOW POTENT WOULD A STRATEGY BE 4116 03:57:21,247 --> 03:57:28,687 AND WE ENCOUNTER AN INITIAL 4117 03:57:28,687 --> 03:57:30,122 INFECTION STARTING WITH A SINGLE 4118 03:57:30,122 --> 03:57:31,023 VIRUS PARTICLE. 4119 03:57:31,023 --> 03:57:34,660 AND YOU'RE TALKING ABOUT 4120 03:57:34,660 --> 03:57:35,194 PROVIDING ADVANTAGE IN 4121 03:57:35,194 --> 03:57:39,398 CONDITIONS OF ATTENUATION. 4122 03:57:39,398 --> 03:57:42,968 WE WANTED TO ASK IF THE 4123 03:57:42,968 --> 03:57:45,438 POPULATION DISTRIBUTION IS A 4124 03:57:45,438 --> 03:57:46,739 FIXED FEATURE OF THE VIRAL 4125 03:57:46,739 --> 03:57:48,541 GENOME OR EXPECT TO INCREASE THE 4126 03:57:48,541 --> 03:57:49,809 PROPORTION OF BENEFICIAL TYPES 4127 03:57:49,809 --> 03:57:51,377 AS NEEDED. 4128 03:57:51,377 --> 03:57:56,282 BECAUSE YOU CAN IMAGINE IF YOU 4129 03:57:56,282 --> 03:57:57,683 REQUIRE GENETIC CHANGE FOR SUCH 4130 03:57:57,683 --> 03:58:02,721 A SHIFT IT WOULDN'T BE SUCH AN 4131 03:58:02,721 --> 03:58:05,591 EFFICIENT METHOD UNDER PRESSURE. 4132 03:58:05,591 --> 03:58:10,729 AND THE FORMER IS ASSUMED BY THE 4133 03:58:10,729 --> 03:58:11,030 LITERATURE. 4134 03:58:11,030 --> 03:58:13,666 THE DISTRIBUTIONS ARE FIXED. 4135 03:58:13,666 --> 03:58:15,501 BUT TO PROPERLY ADDRESS THE 4136 03:58:15,501 --> 03:58:16,368 QUESTION WE NEEDED A NOVEL 4137 03:58:16,368 --> 03:58:23,476 METHOD TO STUDY SHAPE. 4138 03:58:23,476 --> 03:58:27,546 THIS WORK WAS LED BY A TALENTED 4139 03:58:27,546 --> 03:58:30,082 POST DOC IN THE LAB AND JOINED A 4140 03:58:30,082 --> 03:58:31,016 YEAR AGO AND I'LL SHARE SOME OF 4141 03:58:31,016 --> 03:58:41,260 THE WORK HERE. 4142 03:58:52,605 --> 03:58:55,307 THE CHALLENGE WAS TO STUDY SHAPE 4143 03:58:55,307 --> 03:58:57,877 AND WE USED MICROSCOPY AND IT'S 4144 03:58:57,877 --> 03:59:03,816 INHERENTLY LOW THROUGHPUT. 4145 03:59:03,816 --> 03:59:08,087 WE CAN MEASURE SAME BY MEASURING 4146 03:59:08,087 --> 03:59:12,691 THE SCATTERED INTENSITY OF THE 4147 03:59:12,691 --> 03:59:14,994 VIRUS PARTICLE SMALL PARTICLES 4148 03:59:14,994 --> 03:59:17,696 WILL SCATTER LIGHT LESS THAN 4149 03:59:17,696 --> 03:59:18,130 LARGER PARTICLES. 4150 03:59:18,130 --> 03:59:20,799 THIS IS ILLUSTRATED HERE. 4151 03:59:20,799 --> 03:59:24,637 WE VALIDATED THIS APPROACH BY 4152 03:59:24,637 --> 03:59:28,641 COMPARING PURIFIED SAMPLES 4153 03:59:28,641 --> 03:59:31,544 DERIVED FROM ELECTROMICROSCOPY 4154 03:59:31,544 --> 03:59:35,548 AND YOU'LL SEE THE NOISE PEAK 4155 03:59:35,548 --> 03:59:38,717 INHERENT IN THE BUFFER AND FOR 4156 03:59:38,717 --> 03:59:41,921 SPHERICAL PARTICLES A SINGLE 4157 03:59:41,921 --> 03:59:42,955 FIRST HERE. 4158 03:59:42,955 --> 03:59:45,791 YOU'LL SEE THE SECOND BUMP UP 4159 03:59:45,791 --> 03:59:47,293 HERE IN THE FILAMENTOUS 4160 03:59:47,293 --> 03:59:47,560 PARTICLES. 4161 03:59:47,560 --> 03:59:49,528 TO INCREASE THE SENSITIVITY OF 4162 03:59:49,528 --> 03:59:51,964 THE APPROACH WE INCLUDED A 4163 03:59:51,964 --> 03:59:53,299 SECOND DIMENSION. 4164 03:59:53,299 --> 03:59:57,703 IF YOU USED FLUORESCENT ANTIBODY 4165 03:59:57,703 --> 04:00:00,439 COMBINED TO SURFACE OF VIRUS 4166 04:00:00,439 --> 04:00:03,375 PARTICLES YOU CAN PULL THE 4167 04:00:03,375 --> 04:00:04,877 PARTICLE POPULATION IN THE 4168 04:00:04,877 --> 04:00:06,011 FLUORESCENT DIMENSION AND YOU 4169 04:00:06,011 --> 04:00:10,182 CAN SEE THE CLOUDS ON THE RIGHT 4170 04:00:10,182 --> 04:00:13,519 SEPARATE FROM THE BUFFER NOISE 4171 04:00:13,519 --> 04:00:15,821 AND SO GREATLY EXTENDED THE 4172 04:00:15,821 --> 04:00:17,256 DYNAMIC RANGE OF WHAT CAN BE 4173 04:00:17,256 --> 04:00:19,625 MEASURED AND INCREASING THE 4174 04:00:19,625 --> 04:00:22,261 SENSITIVITY TO HUNDRED THOUSANDS 4175 04:00:22,261 --> 04:00:24,396 TIMES OF MICROSCOPY AND WE WERE 4176 04:00:24,396 --> 04:00:26,699 IN A GREAT POSITION TO START 4177 04:00:26,699 --> 04:00:28,667 ASKING QUESTIONS ABOUT PARTICLE 4178 04:00:28,667 --> 04:00:31,203 SHAPE IN ATTENUATED INFECTIONS. 4179 04:00:31,203 --> 04:00:41,747 AND THE BEAUTY IS WE CAN MEASURE 4180 04:00:45,451 --> 04:00:47,620 MANY SAMPLES AUTOMATICALLY. 4181 04:00:47,620 --> 04:00:49,154 IT'S A GREAT OPPORTUNITY FOR 4182 04:00:49,154 --> 04:00:51,624 ANALYZING SHAPE IN DYNAMIC 4183 04:00:51,624 --> 04:00:51,857 SYSTEMS. 4184 04:00:51,857 --> 04:00:56,061 AND WE STARTED WITH A VERY BASIC 4185 04:00:56,061 --> 04:00:57,930 EXPERT IN VIROLOGY THE TIME 4186 04:00:57,930 --> 04:00:59,098 COURSE OF INFECTION. 4187 04:00:59,098 --> 04:01:01,400 AND NOW THERE WAS A NEW LENS TO 4188 04:01:01,400 --> 04:01:04,603 INTERROGATE THE DATA WITH AND 4189 04:01:04,603 --> 04:01:08,440 THIS IS THE ABILITY TO COUNT 4190 04:01:08,440 --> 04:01:09,575 PARTICLES AND MEASURE SHAPE. 4191 04:01:09,575 --> 04:01:11,176 AND TO THE INCREASED SENSITIVITY 4192 04:01:11,176 --> 04:01:15,014 HE WAS ABLE TO DO IT IN TWO 4193 04:01:15,014 --> 04:01:15,280 EXTREMES. 4194 04:01:15,280 --> 04:01:25,724 HE INFECTED CELLS AT HIGH 4195 04:01:26,158 --> 04:01:27,459 MULTIPLICITY AND LESS THAN 1% OF 4196 04:01:27,459 --> 04:01:29,528 CELLS WERE INFECTED AND THE 4197 04:01:29,528 --> 04:01:32,564 INFECTED CELLS RECEIVED AT MOST 4198 04:01:32,564 --> 04:01:38,737 THE SINGLE INFECTIOUS UNIT. 4199 04:01:38,737 --> 04:01:45,344 SO THE YIELD IN THE LATTER CASE 4200 04:01:45,344 --> 04:01:48,781 ESPECIALLY WAS INHIBITED VIRUS 4201 04:01:48,781 --> 04:01:50,416 PREP AND ONLY LOOKED AT THE 4202 04:01:50,416 --> 04:01:52,685 FIRST ROUND AND NOT NEWLY 4203 04:01:52,685 --> 04:01:53,318 INFECTED CELLS. 4204 04:01:53,318 --> 04:01:54,753 WHAT YOU OBSERVE YOU GET MORE 4205 04:01:54,753 --> 04:01:58,524 PARTICLES PRODUCED AND EVEN THE 4206 04:01:58,524 --> 04:02:00,693 PARTICLES ARE MEASURABLE AND 4207 04:02:00,693 --> 04:02:06,231 COUNTABLE AND WE COULD DERIVE 4208 04:02:06,231 --> 04:02:08,901 PARTICLE SHAPE AND THE FIRST 4209 04:02:08,901 --> 04:02:10,169 SURPRISE IS SHAPE NOT GOING TO 4210 04:02:10,169 --> 04:02:14,006 BE FIXED SO THE VERY SAME VIRUS 4211 04:02:14,006 --> 04:02:15,441 HOW MUCH WENT INTO CELLS IN THE 4212 04:02:15,441 --> 04:02:18,143 FIRST PLACE PRODUCED PARTICLES 4213 04:02:18,143 --> 04:02:19,812 OF DIFFERENT SHAPES AND LESS 4214 04:02:19,812 --> 04:02:22,748 VIRUS INPUT PRODUCED MORE 4215 04:02:22,748 --> 04:02:26,719 FILAMENT AND PRODUCED MORE 4216 04:02:26,719 --> 04:02:27,219 SPHERES. 4217 04:02:27,219 --> 04:02:28,253 THE SHAPE IS NOT CONSTANT 4218 04:02:28,253 --> 04:02:30,489 THROUGHOUT INFECTION. 4219 04:02:30,489 --> 04:02:33,058 THERE'S MORE FILAMENTS INITIALLY 4220 04:02:33,058 --> 04:02:34,126 PRODUCED AND MORE SPHERES AND 4221 04:02:34,126 --> 04:02:34,860 LATER YOU GET MORE FILAMENTS 4222 04:02:34,860 --> 04:02:38,097 AGAIN. 4223 04:02:38,097 --> 04:02:40,899 SO SHAPE IS NOT UNIQUELY 4224 04:02:40,899 --> 04:02:42,067 SPECIFIED BY THE GENOME AND 4225 04:02:42,067 --> 04:02:44,737 SIMPLY CHANGING HOW MUCH YOU PUT 4226 04:02:44,737 --> 04:02:48,574 INTO A CELL CAN SHAPE OUTCOMES. 4227 04:02:48,574 --> 04:02:51,977 INFECTIONS OF DIFFERENT CELL 4228 04:02:51,977 --> 04:02:54,012 TYPES SHOW THERE'S ALSO 4229 04:02:54,012 --> 04:02:56,315 CELL-BASED DIFFERENCES THAT CAN 4230 04:02:56,315 --> 04:02:57,282 INFLUENCE SHAPE. 4231 04:02:57,282 --> 04:02:59,118 BUT WHAT ABOUT THE ANTIBODIES I 4232 04:02:59,118 --> 04:03:02,921 TOLD YOU FILAMENTS CAN RESIST 4233 04:03:02,921 --> 04:03:04,890 ANTIBODY PRESSURE? 4234 04:03:04,890 --> 04:03:06,725 CAN THE PRESENCE OF ANTIBODIES 4235 04:03:06,725 --> 04:03:11,630 OR VIRUS REPLICATION BY 4236 04:03:11,630 --> 04:03:13,298 ANTIBODIES INFLUENCE THE 4237 04:03:13,298 --> 04:03:14,233 RESULTING PARTICLE SHAPE? 4238 04:03:14,233 --> 04:03:21,840 THIS WOULD BE IMPORTANT TO HELP 4239 04:03:21,840 --> 04:03:31,850 VIRUSES INFECT NEURONS OF CELLS 4240 04:03:31,850 --> 04:03:38,257 AND THIS IS SPECIFIC FOR TWO 4241 04:03:38,257 --> 04:03:39,525 VIRUS STRAINS AND EXPERIMENTS IN 4242 04:03:39,525 --> 04:03:41,160 TWO CELL TYPES. 4243 04:03:41,160 --> 04:03:43,762 I'LL ILLUSTRATE RESULT FOR A 4244 04:03:43,762 --> 04:03:49,268 SINGLE NEUTRALIZING AND 4245 04:03:49,268 --> 04:03:51,036 NON-NEUTRALIZING ANTIBODY AND 4246 04:03:51,036 --> 04:03:54,740 THIS IS BEFORE THE VIRUS BOUND 4247 04:03:54,740 --> 04:04:01,046 TO CELLS DURING ENTRY AND YOU 4248 04:04:01,046 --> 04:04:05,117 SEE REDUCTION IN VIRUS YIELD AND 4249 04:04:05,117 --> 04:04:06,118 STRIKINGLY INCREASE PROPORTION 4250 04:04:06,118 --> 04:04:08,253 OF FILAMENTS. 4251 04:04:08,253 --> 04:04:10,722 IT SEEMS VIRUS CAN RESPOND TO 4252 04:04:10,722 --> 04:04:14,726 ANTIBODY PRESSURE BY PRODUCING 4253 04:04:14,726 --> 04:04:16,895 MORE FILAMENTS. 4254 04:04:16,895 --> 04:04:19,665 NEXT WE ASKED WHERE BASICALLY 4255 04:04:19,665 --> 04:04:23,802 HOW DOES THE NEUTRALIZATION OR 4256 04:04:23,802 --> 04:04:25,370 WHEN THE ANTIBODY WAS PRESENT 4257 04:04:25,370 --> 04:04:28,740 RELATES TO THIS SHAPE OUTCOME. 4258 04:04:28,740 --> 04:04:29,908 WE HAD VARIATION OF THE 4259 04:04:29,908 --> 04:04:31,543 EXPERIMENT WHERE THE ANTIBODY 4260 04:04:31,543 --> 04:04:36,248 WAS PRESENT BEFORE ENTRY AND 4261 04:04:36,248 --> 04:04:39,384 DURING THE FIRST FOUR HOURS 4262 04:04:39,384 --> 04:04:40,152 ENTRY OR AFTER THEY WERE 4263 04:04:40,152 --> 04:04:46,091 COMPLETED. 4264 04:04:46,091 --> 04:04:48,460 I SEE MOST ANTIBODIES TO AN 4265 04:04:48,460 --> 04:04:58,904 EXTENT INHIBITED ASSEMBLY. 4266 04:05:02,808 --> 04:05:04,476 THE EFFECT OF ANTIBODY PRESENCE 4267 04:05:04,476 --> 04:05:11,683 WAS MORE POTENT ON SHAPE DESPITE 4268 04:05:11,683 --> 04:05:19,157 THE INHIBITION OF VIRUS 4269 04:05:19,157 --> 04:05:26,598 PRODUCTION. 4270 04:05:26,598 --> 04:05:30,736 YOU STILL SEE INCREASED 4271 04:05:30,736 --> 04:05:38,744 FILAMENTS WHEN THE ANTIBODY WAS 4272 04:05:38,744 --> 04:05:41,546 PRESENT AND BINDING TO AN 4273 04:05:41,546 --> 04:05:42,781 ANTIBODY WITHOUT INFECTING VIRUS 4274 04:05:42,781 --> 04:05:45,584 PRODUCTION CAN TRIGGER INFECTION 4275 04:05:45,584 --> 04:05:50,722 TO START PRODUCING MORE 4276 04:05:50,722 --> 04:05:52,658 FILAMENTS. 4277 04:05:52,658 --> 04:05:54,192 NEUTRALIZATION WAS REQUIRED AND 4278 04:05:54,192 --> 04:05:57,562 YOU HAD TO INHIBIT THE 4279 04:05:57,562 --> 04:05:58,397 NEUTRALIZING. 4280 04:05:58,397 --> 04:06:02,901 AND THERE MAY BE TWO MECHANISMS 4281 04:06:02,901 --> 04:06:06,171 BY WHICH A VIRUS CAN RESPOND TO 4282 04:06:06,171 --> 04:06:08,273 SHAPE BUT INFECTED CELLS CAN 4283 04:06:08,273 --> 04:06:13,145 SENSE THE PRESENCE OF 4284 04:06:13,145 --> 04:06:14,112 ATTENUATING PRESSURE AND LEADS 4285 04:06:14,112 --> 04:06:15,948 TO THE RESPONSE THAT WOULD BE 4286 04:06:15,948 --> 04:06:17,950 BENEFICIAL IN THE NEXT CYCLE. 4287 04:06:17,950 --> 04:06:24,790 THE RESPONSES TO ANTIBODIES ARE 4288 04:06:24,790 --> 04:06:28,160 FAST. 4289 04:06:28,160 --> 04:06:30,162 AND YOU START TO SEE INCREASED 4290 04:06:30,162 --> 04:06:38,136 IN FILAMENTS WITH NO EFFECT ON 4291 04:06:38,136 --> 04:06:43,742 THESE AND THIS CONVINCED US THE 4292 04:06:43,742 --> 04:06:44,676 INFECTION IS SENSING THE 4293 04:06:44,676 --> 04:06:46,345 PRESENCE OF ANTIBODIES AND DO 4294 04:06:46,345 --> 04:06:51,950 NOT REQUIRE GENETIC CHANGE TO 4295 04:06:51,950 --> 04:06:54,753 START CHANGING THE ASSEMBLY 4296 04:06:54,753 --> 04:07:00,225 CHARACTERISTICS. 4297 04:07:00,225 --> 04:07:05,497 AND WE'VE SHOWN TRANSIENT 4298 04:07:05,497 --> 04:07:08,266 CHANGES IN SURFACE TENSION CAN 4299 04:07:08,266 --> 04:07:17,376 TRIGGER SHAPE CHANGES. 4300 04:07:17,376 --> 04:07:27,919 AND THERE'S BEEN A SERIES OF C 4301 04:07:34,226 --> 04:07:36,728 ELEGANS AND IT'S SHAPED TO 4302 04:07:36,728 --> 04:07:38,330 EXTERNAL CONDITIONS IF IT'S NOT 4303 04:07:38,330 --> 04:07:39,931 A FIXED FEATURE OF THE VIRAL 4304 04:07:39,931 --> 04:07:44,669 GENOME SO VIRUSES ARE MORE 4305 04:07:44,669 --> 04:07:46,738 POWERFUL OPPONENTS THAN 4306 04:07:46,738 --> 04:07:47,572 PREVIOUSLY ANTICIPATED. 4307 04:07:47,572 --> 04:07:49,408 SIMPLY CHANGING THE VIRUS AMOUNT 4308 04:07:49,408 --> 04:07:51,810 AND EXTENT OF REPLICATION AND 4309 04:07:51,810 --> 04:07:54,880 CHANGES OF REPLICATION INHI 4310 04:07:54,880 --> 04:08:05,390 INHIBITORS AND CHANGES AND SO 4311 04:08:06,291 --> 04:08:12,864 THIS LED TO COMBINING TO THIS 4312 04:08:12,864 --> 04:08:19,805 MODEL AND INCREASE PROPORTION OF 4313 04:08:19,805 --> 04:08:21,940 FILAMENTS BOUND BY ANTIBODIES 4314 04:08:21,940 --> 04:08:23,975 CAN STILL MEDIATE ENTRY AND 4315 04:08:23,975 --> 04:08:32,551 ALLOW SOME LEVEL OF REPLICATION 4316 04:08:32,551 --> 04:08:34,319 EVEN IF SOME COULD BE BENEFICIAL 4317 04:08:34,319 --> 04:08:37,522 AND THE VIRUSES CAN ACQUIRE TRUE 4318 04:08:37,522 --> 04:08:40,425 RESISTANCE AND INFECT NEURONS OF 4319 04:08:40,425 --> 04:08:42,894 CELLS IN OUR SPHERES CAN 4320 04:08:42,894 --> 04:08:45,931 DOMINATE AGAIN AND MORE QUICKLY 4321 04:08:45,931 --> 04:08:53,538 SPREAD THROUGH POPULATION. 4322 04:08:53,538 --> 04:08:57,109 I MENTIONED KEY PLAYERS IN THE 4323 04:08:57,109 --> 04:08:58,243 WORK AND IT'S GROUP EFFORT AND 4324 04:08:58,243 --> 04:09:02,714 STUDENTS WHO CONTRIBUTED TO THE 4325 04:09:02,714 --> 04:09:13,225 WORK ARE STEVEN AND NICK AND 4326 04:09:15,994 --> 04:09:20,031 SPECIAL THANKS TO COLLABORATORS 4327 04:09:20,031 --> 04:09:22,067 WHO PROVIDED WORK AND I DIDN'T 4328 04:09:22,067 --> 04:09:26,738 INCLUDE SOME WORK ON 4329 04:09:26,738 --> 04:09:28,840 QUANTITATING VIRUS ATTACHMENT 4330 04:09:28,840 --> 04:09:30,075 AND BOSTON COLLEGE. 4331 04:09:30,075 --> 04:09:31,977 A LOT OF THE FUND IS EXTRAMURAL 4332 04:09:31,977 --> 04:09:34,412 FUNDING LISTED HERE FROM MY TIME 4333 04:09:34,412 --> 04:09:40,252 AT BRANDEIS BUT NOW HERE AT THE 4334 04:09:40,252 --> 04:09:50,395 DIR AND COLLABORATE IN THIS 4335 04:09:50,395 --> 04:10:00,605 ENVIRONMENT. 4336 04:10:07,546 --> 04:10:10,649 >> TAKE A PERSPECTIVE ON VIRUSES 4337 04:10:10,649 --> 04:10:11,983 WITH REGARD TO SHAPE. 4338 04:10:11,983 --> 04:10:17,956 MY QUESTION RELATES TO IN VIVO 4339 04:10:17,956 --> 04:10:25,030 VALIDATION. 4340 04:10:25,030 --> 04:10:26,498 AND CAN YOU VALIDATE OR HAVE YOU 4341 04:10:26,498 --> 04:10:30,435 TRIED TO VALIDATE IT IN A MOUSE 4342 04:10:30,435 --> 04:10:32,871 MODEL OF SUB LETHAL INFECTION? 4343 04:10:32,871 --> 04:10:33,505 >> GREAT QUESTION. 4344 04:10:33,505 --> 04:10:35,173 WE'RE STARTING THAT WORK AND 4345 04:10:35,173 --> 04:10:37,909 THIS IS ONE OF THE 4346 04:10:37,909 --> 04:10:40,679 COLLABORATIONS WE STARTED AND WE 4347 04:10:40,679 --> 04:10:42,314 HAVE SOME MOUSE SAMPLES. 4348 04:10:42,314 --> 04:10:47,118 IT WILL WORK IT'S JUST NOT A 4349 04:10:47,118 --> 04:10:49,020 TRIVIAL TRANSITION BECAUSE WE 4350 04:10:49,020 --> 04:10:54,759 WANT TO BASICALLY HAVE A WAY OF 4351 04:10:54,759 --> 04:11:02,767 STUDYING ANALYZING VIRUS SHAPE 4352 04:11:02,767 --> 04:11:05,036 WITHOUT MUCH MANIPULATION AND 4353 04:11:05,036 --> 04:11:06,938 YOU WANT THE DIRTIEST ANIMAL 4354 04:11:06,938 --> 04:11:08,907 SAMPLES AND HAVE A WAY OF THE 4355 04:11:08,907 --> 04:11:11,509 SHAPE OUT AND WE'RE MAKING 4356 04:11:11,509 --> 04:11:12,377 PROGRESS BUT THE ASSAY REQUIRES 4357 04:11:12,377 --> 04:11:14,079 FINE TUNING BUT WE'LL THERE BE. 4358 04:11:14,079 --> 04:11:15,947 >> AND FOLLOW ON TO THAT IS IF 4359 04:11:15,947 --> 04:11:19,985 THE ASSAY CAN BE FINE TUNED IT 4360 04:11:19,985 --> 04:11:21,720 WOULD BE FINE TO COLLABORATE TO 4361 04:11:21,720 --> 04:11:24,990 SEE IF THERE'S ANATOMICAL IMPACT 4362 04:11:24,990 --> 04:11:29,060 OF EVEN WITHIN THE UPPER 4363 04:11:29,060 --> 04:11:29,694 RESPIRATORY TRACT WITH VIRUS 4364 04:11:29,694 --> 04:11:35,233 SHAPE AND REAPPLY THAT. 4365 04:11:35,233 --> 04:11:36,234 >> THANK YOU. 4366 04:11:36,234 --> 04:11:41,906 THAT'S WHERE WE'RE HEADING WITH 4367 04:11:41,906 --> 04:11:43,441 THE ANIMAL SAMPLES AND WE DON'T 4368 04:11:43,441 --> 04:11:44,175 NEED A LOT AND THAT'S THE POWER 4369 04:11:44,175 --> 04:11:45,477 OF THIS METHOD. 4370 04:11:45,477 --> 04:11:46,845 I THINK IT'S REALISTIC TO GET 4371 04:11:46,845 --> 04:11:50,715 THERE. 4372 04:11:50,715 --> 04:11:58,723 I'M HOPEFUL. 4373 04:11:58,723 --> 04:12:00,625 DOES IT DIFFER BETWEEN THE TWO 4374 04:12:00,625 --> 04:12:01,126 FORMS? 4375 04:12:01,126 --> 04:12:02,627 YOU COULD IMAGINE IT WOULD 4376 04:12:02,627 --> 04:12:08,166 INFLUENCE THE ABILITY TO INDUCE 4377 04:12:08,166 --> 04:12:08,767 NEUTRALIZING ANTIBODIES AT 4378 04:12:08,767 --> 04:12:10,502 VARIOUS DOSES. 4379 04:12:10,502 --> 04:12:20,979 >> THE DENSITY IS VERY HIGH. 4380 04:12:37,329 --> 04:12:37,996 >> INTERESTING TOPIC. 4381 04:12:37,996 --> 04:12:45,403 IT'S FASCINATING THE FACT THAT 4382 04:12:45,403 --> 04:12:46,705 IN SPHERICAL AND FILAMENTOUS YOU 4383 04:12:46,705 --> 04:12:51,209 GET THE SAME COPY OF GENOME BUT 4384 04:12:51,209 --> 04:12:52,977 IS IT POSSIBLE TO LOOK THE OTHER 4385 04:12:52,977 --> 04:12:56,881 WAY WIN VIRIONS AND COULD THAT 4386 04:12:56,881 --> 04:13:02,954 IMPACT THE SHAPE OF THE VIRUS? 4387 04:13:02,954 --> 04:13:10,729 >> I SEE. 4388 04:13:10,729 --> 04:13:12,097 AND THIS WAS A CONVENIENT SYSTEM 4389 04:13:12,097 --> 04:13:14,733 TO ASK THE QUESTIONS OF THE 4390 04:13:14,733 --> 04:13:21,206 ADVANTAGE OF EVERYTHING ELSE. 4391 04:13:21,206 --> 04:13:24,409 OTHERWISE LIKE RESPIRATORY 4392 04:13:24,409 --> 04:13:25,677 SYNCYTIAL VIRUS WOULD HAVE 4393 04:13:25,677 --> 04:13:29,047 MULTIPLE COPIES AND WOULD HAVE 4394 04:13:29,047 --> 04:13:31,750 THEN ADDITION TO THE ADVANTAGES 4395 04:13:31,750 --> 04:13:33,985 THE ADVANTAGE OF DELIVERING 4396 04:13:33,985 --> 04:13:35,053 MULTIPLES FROM A SINGLE 4397 04:13:35,053 --> 04:13:43,194 INFECTION EVENT. 4398 04:13:43,194 --> 04:13:47,399 AND LOOK EIGHT AT IT IN THE 4399 04:13:47,399 --> 04:13:49,300 CONTEXT OF NO GENOME. 4400 04:13:49,300 --> 04:13:51,169 WOULD IT AFFECT THE SHAPE? 4401 04:13:51,169 --> 04:13:53,972 >> THE NO GENOME PARTICLES WOULD 4402 04:13:53,972 --> 04:13:55,707 NOT YIELD AN INFECTION. 4403 04:13:55,707 --> 04:13:57,642 THAT WOULD NOT BE ADVANTAGEOUS. 4404 04:13:57,642 --> 04:14:02,714 FLU IS KNOWN TO GENERATE EMPTY 4405 04:14:02,714 --> 04:14:05,216 PARTICLES TOO. 4406 04:14:05,216 --> 04:14:06,484 WE DON'T THINK SO BASICALLY IN 4407 04:14:06,484 --> 04:14:09,521 OUR EXPERIMENTS WE DON'T SEE 4408 04:14:09,521 --> 04:14:11,356 EVIDENCE OF EMPTY PARTICLES 4409 04:14:11,356 --> 04:14:14,726 BEING MORE PROMINENT IN EITHER 4410 04:14:14,726 --> 04:14:18,463 PARTICLE FORM. 4411 04:14:18,463 --> 04:14:19,497 SOO UNDER THE CONDITIONS WHERE 4412 04:14:19,497 --> 04:14:21,566 YOU GET MORE SPHERES OR 4413 04:14:21,566 --> 04:14:25,703 FILAMENTS THE SAME NUMBER OF 4414 04:14:25,703 --> 04:14:26,738 PARTICLES YIELDS THE SAME OUTPUT 4415 04:14:26,738 --> 04:14:31,276 AGAIN. 4416 04:14:31,276 --> 04:14:33,945 SO IT SEEMS THE NUMBERS DON'T 4417 04:14:33,945 --> 04:14:38,483 CHANGE BETWEEN THE TWO PARTICLE 4418 04:14:38,483 --> 04:14:38,683 FORMS. 4419 04:14:38,683 --> 04:14:41,319 GOOD I'M WONDERING IF THE GENOME 4420 04:14:41,319 --> 04:14:45,690 HAS INVOLVEMENT IN THE SHAPE OF 4421 04:14:45,690 --> 04:14:45,924 VIRIONS. 4422 04:14:45,924 --> 04:14:46,157 >> YEAH. 4423 04:14:46,157 --> 04:14:48,393 I DON'T KNOW. 4424 04:14:48,393 --> 04:14:48,927 YEAH. 4425 04:14:48,927 --> 04:14:50,795 >> THAT WOULD BE REALLY 4426 04:14:50,795 --> 04:14:51,095 INTERESTING. 4427 04:14:51,095 --> 04:14:51,362 THANK YOU. 4428 04:14:51,362 --> 04:14:55,467 >> THANKS. 4429 04:14:55,467 --> 04:14:58,303 >> THANK YOU FOR THE 4430 04:14:58,303 --> 04:14:58,736 PRESENTATION. 4431 04:14:58,736 --> 04:15:01,506 I'M WONDERING IF THE 4432 04:15:01,506 --> 04:15:02,974 DISTRIBUTION AND SHAPE IS BINARY 4433 04:15:02,974 --> 04:15:06,010 OR ONLY SEE LONGER FILAMENTS OR 4434 04:15:06,010 --> 04:15:08,680 IF YOU'VE OBSERVED PARTICLES IN 4435 04:15:08,680 --> 04:15:08,913 BETWEEN. 4436 04:15:08,913 --> 04:15:10,715 >> IT'S NOT BINARY. 4437 04:15:10,715 --> 04:15:12,116 THERE'S A WHOLE DISTRIBUTION OF 4438 04:15:12,116 --> 04:15:14,419 SHAPES I THINK I SHOWED EARLIER 4439 04:15:14,419 --> 04:15:15,954 IN MICROGRAPHS. 4440 04:15:15,954 --> 04:15:19,591 YOU HAVE EVERYTHING TWICE THE 4441 04:15:19,591 --> 04:15:21,125 LENGTH OF THE SPHERE TO ALMOST A 4442 04:15:21,125 --> 04:15:23,094 THOUSAND TIMES THE LENGTH OF A 4443 04:15:23,094 --> 04:15:25,096 SPHERE AND ANYTHING IN BETWEEN 4444 04:15:25,096 --> 04:15:29,033 AND SO I THINK WITH MORE 4445 04:15:29,033 --> 04:15:30,535 MATERIAL WITH THE LARGER PART OF 4446 04:15:30,535 --> 04:15:32,070 MATERIAL YOU HAVE MORE 4447 04:15:32,070 --> 04:15:35,440 OPPORTUNITIES OF ENTRY UNDER 4448 04:15:35,440 --> 04:15:35,874 EXTENSIVE PRESSURE. 4449 04:15:35,874 --> 04:15:37,008 THE DISTRIBUTION OF PARTICLE AND 4450 04:15:37,008 --> 04:15:39,944 THE WAY WE PRESSURE THIS WE'RE 4451 04:15:39,944 --> 04:15:42,046 NOT MEASURING THE SIZE PRECISELY 4452 04:15:42,046 --> 04:15:44,816 BUT YOU DO SEE TWO DISTINCT 4453 04:15:44,816 --> 04:15:45,250 PEAKS. 4454 04:15:45,250 --> 04:15:46,317 THERE'S A DISTRIBUTION AROUND 4455 04:15:46,317 --> 04:15:48,453 EACH. 4456 04:15:48,453 --> 04:15:50,722 SO THERE'S SOMETHING BINARY 4457 04:15:50,722 --> 04:15:51,556 ABOUT IT. 4458 04:15:51,556 --> 04:15:53,291 EITHER THE FIRST OR SECOND 4459 04:15:53,291 --> 04:15:54,759 POPULATION BUT WITHIN THE 4460 04:15:54,759 --> 04:15:55,326 POPULATIONS THERE'S A HUGE 4461 04:15:55,326 --> 04:15:55,627 VARIABILITY. 4462 04:15:55,627 --> 04:15:57,929 >> THANK YOU. 4463 04:15:57,929 --> 04:16:02,767 >> I HAD A QUESTION. 4464 04:16:02,767 --> 04:16:08,573 IN WERE ONE SLIDE YOU HAD A 4465 04:16:08,573 --> 04:16:09,941 VIRION WITH A GREEN SURFACE AS 4466 04:16:09,941 --> 04:16:14,679 THE CONTACT SURFACE, DOES THAT 4467 04:16:14,679 --> 04:16:16,748 CHANGE BETWEEN SINGLE PARTICLES 4468 04:16:16,748 --> 04:16:19,017 OR THE ELONGATED PARTICLE? 4469 04:16:19,017 --> 04:16:23,655 ARE YOU JUST ENGAGING A LARGER 4470 04:16:23,655 --> 04:16:24,389 SURFACE? 4471 04:16:24,389 --> 04:16:27,025 >> THAT'S THE ASSUMPTION IN THE 4472 04:16:27,025 --> 04:16:29,727 SIMULATION MODEL THAT WOULD BE 4473 04:16:29,727 --> 04:16:33,731 THE CONTACT AREA OF THE SMALL 4474 04:16:33,731 --> 04:16:35,800 SPHERICAL PARTICLE AND THE 4475 04:16:35,800 --> 04:16:37,535 CONTACT AREA WOULD INCREASE IN 4476 04:16:37,535 --> 04:16:39,737 LENGTH BECAUSE THE FILAMENTS 4477 04:16:39,737 --> 04:16:41,506 HAVE THE SAME DIAMETER OF THE 4478 04:16:41,506 --> 04:16:43,007 SPHERE JUST LONGER. 4479 04:16:43,007 --> 04:16:45,843 YOU WOULD HAVE MORE -- 4480 04:16:45,843 --> 04:16:47,545 >> YOU WOULD BE FUSING THROUGH 4481 04:16:47,545 --> 04:16:49,013 THE LENGTH OF THE FILAMENT NOT 4482 04:16:49,013 --> 04:16:50,548 THE TIP? 4483 04:16:50,548 --> 04:16:53,651 >> THAT'S THE ASSUMPTION BUT IT 4484 04:16:53,651 --> 04:16:55,687 SEEMS THE DATA QUANTITATIVELY 4485 04:16:55,687 --> 04:16:57,956 WITH THE ASSUMPTION. 4486 04:16:57,956 --> 04:17:01,125 >> OKAY. 4487 04:17:01,125 --> 04:17:04,295 ALSO YOU WOULD EXPECT -- BECAUSE 4488 04:17:04,295 --> 04:17:10,268 YOU HAVE THE IF SURFACE AND SO I 4489 04:17:10,268 --> 04:17:14,706 CAN'T IMAGINE IT'S A FLIMSY 4490 04:17:14,706 --> 04:17:15,807 PARTICLE AND YOU'D HAVE TO 4491 04:17:15,807 --> 04:17:16,841 ENGAGE THE LENGTH. 4492 04:17:16,841 --> 04:17:18,276 >> LAST QUESTION. 4493 04:17:18,276 --> 04:17:19,811 ARE THERE OTHER ANTIBODIES 4494 04:17:19,811 --> 04:17:21,946 SPECIFICALLY RECOGNIZE ONE FORM 4495 04:17:21,946 --> 04:17:24,816 OR THE OTHER FORM AND HAVE THOSE 4496 04:17:24,816 --> 04:17:25,550 BEEN -- 4497 04:17:25,550 --> 04:17:28,786 >> IT'S THE EXACT SAME HA. 4498 04:17:28,786 --> 04:17:35,793 THE SAME GLYCOPROTEINS 4499 04:17:35,793 --> 04:17:39,964 DISPLAYED. 4500 04:17:39,964 --> 04:17:50,141 >> SORRY. 4501 04:17:51,709 --> 04:17:53,578 >> THAT'S THE CHALLENGE THE SAME 4502 04:17:53,578 --> 04:17:55,480 HAs AND DENSITY ON THE SURFACE 4503 04:17:55,480 --> 04:18:01,552 AND MOST ANTIBODIES AS WE KNOW 4504 04:18:01,552 --> 04:18:06,758 THEN BIND TO -- SO THEY WOULD 4505 04:18:06,758 --> 04:18:07,859 NOT BE DIFFERENT. 4506 04:18:07,859 --> 04:18:09,661 >> BECAUSE NEUTRALIZING BY 4507 04:18:09,661 --> 04:18:12,096 DEFINITION MAY PROBABLY WORK BUT 4508 04:18:12,096 --> 04:18:17,635 NOTE NEUTRALIZING MAY BE HIDDEN 4509 04:18:17,635 --> 04:18:20,438 IN ONE FORM AND NOT ANOTHER OR 4510 04:18:20,438 --> 04:18:21,539 VICE VERSA. 4511 04:18:21,539 --> 04:18:23,541 >> IT'S THE SAME HAs. 4512 04:18:23,541 --> 04:18:25,977 >> I'M JUST TALKING ABOUT 4513 04:18:25,977 --> 04:18:31,382 EXPOSURE OF THE EPITOPE? 4514 04:18:31,382 --> 04:18:31,816 >> RIGHT. 4515 04:18:31,816 --> 04:18:33,284 >> IN THE FILAMENT YOU HAVE THE 4516 04:18:33,284 --> 04:18:36,087 ENDS WHICH IS A PORTION OF THE 4517 04:18:36,087 --> 04:18:37,321 SPHERE. 4518 04:18:37,321 --> 04:18:39,123 SO IF THERE'S ANY DIFFERENCE 4519 04:18:39,123 --> 04:18:48,032 YOUR DISPLAYING THE FILAMENT AND 4520 04:18:48,032 --> 04:18:50,001 HOW DO YOU TARGET ONE VERSUS THE 4521 04:18:50,001 --> 04:18:50,201 OTHER? 4522 04:18:50,201 --> 04:18:52,270 WE'RE THINKING OF METHODS THAT 4523 04:18:52,270 --> 04:18:57,975 ARE SO A STUDENT IN THE LAB IS 4524 04:18:57,975 --> 04:18:59,911 WORKING ON BUILDING THE ORGANIC 4525 04:18:59,911 --> 04:19:04,615 CONSTRUCT THAT CAN BE CODED WITH 4526 04:19:04,615 --> 04:19:06,884 VIRUS PARTICLES AND ASSEMBLED 4527 04:19:06,884 --> 04:19:08,553 INTO SHELLS TO AN INDIVIDUAL 4528 04:19:08,553 --> 04:19:11,656 COMPONENT CAN HAVE ANTIBODIES 4529 04:19:11,656 --> 04:19:19,130 AGAINST HA AND THEN STIMULATE 4530 04:19:19,130 --> 04:19:26,003 THE CELL AND HAVE COOPERATIE IV 4531 04:19:26,003 --> 04:19:27,338 ENCLOSURE AND SHAPE AND THIS IS 4532 04:19:27,338 --> 04:19:28,473 ONE DIRECTION WE'RE THINKING IN 4533 04:19:28,473 --> 04:19:29,640 THOSE TERMS. 4534 04:19:29,640 --> 04:19:31,109 HOW DO YOU TARGET NOT ONE VERSUS 4535 04:19:31,109 --> 04:19:33,544 THE OTHER BUT HOW DO YOU ENSURE 4536 04:19:33,544 --> 04:19:34,078 YOU TARGET ALL THE SHAPES? 4537 04:19:34,078 --> 04:19:40,852 RIGHT. 4538 04:19:40,852 --> 04:19:45,957 >> I'M WONDERING WHETHER YOU 4539 04:19:45,957 --> 04:19:51,162 THINK MORPHOGENESIS HAS AN 4540 04:19:51,162 --> 04:19:52,530 INFLUENCE IN THE SHAPE AND HOW 4541 04:19:52,530 --> 04:19:55,600 MUCH MATRIX THERE IS OPPOSED TO 4542 04:19:55,600 --> 04:20:01,239 OTHER VIRUSES AND THE CURVATURE 4543 04:20:01,239 --> 04:20:05,777 OF THE MEMBRANE AND IF YOU THINK 4544 04:20:05,777 --> 04:20:06,477 OF THE ABUNDANCE HAS AN 4545 04:20:06,477 --> 04:20:10,047 INFLUENCE AND WHETHER YOU CAN 4546 04:20:10,047 --> 04:20:20,258 PROBE THAT. 4547 04:20:22,360 --> 04:20:27,965 >> WE TRIED TO ASK THAT 4548 04:20:27,965 --> 04:20:36,741 PARTICULAR QUESTION AND WE WENT 4549 04:20:36,741 --> 04:20:41,846 INTO THE DIRECTION OF THESE 4550 04:20:41,846 --> 04:20:44,782 EFFECTS AND ANY PROTEIN 4551 04:20:44,782 --> 04:20:49,754 EXPRESSION WILL TAKE TIME AND I 4552 04:20:49,754 --> 04:20:52,590 DIDN'T SHOW THE BACK UP SLIDE 4553 04:20:52,590 --> 04:20:55,593 BUT YOU CAN TAKE THE INFECTION 4554 04:20:55,593 --> 04:20:57,461 AND CHANGE IT INTO HYPERTONIC 4555 04:20:57,461 --> 04:20:59,230 AND MEASURE SHAPE OR WHAT'S 4556 04:20:59,230 --> 04:21:02,733 PRODUCED AFTER 30 MINUTES TO 4557 04:21:02,733 --> 04:21:07,305 INCREASE OR DECREASE TENSION. 4558 04:21:07,305 --> 04:21:11,275 AND WITHIN 30 MINUTES HAVE YOU 4559 04:21:11,275 --> 04:21:18,149 SPHERES VERSUS FILMIMENTSS -- 4560 04:21:18,149 --> 04:21:20,284 FILAMENTS AND PROTEINS AND WE 4561 04:21:20,284 --> 04:21:23,254 DON'T HAVE ANY EVIDENCE OF THE 4562 04:21:23,254 --> 04:21:23,821 ADDITIONAL COMPONENT. 4563 04:21:23,821 --> 04:21:25,656 THE A LITTLE BIT WE LOOKED WE 4564 04:21:25,656 --> 04:21:27,058 DIDN'T FIND ANYTHING BUT SHOULD 4565 04:21:27,058 --> 04:21:28,159 LOOK INTO THAT MORE CAREFULLY. 4566 04:21:28,159 --> 04:21:34,699 THANK YOU. 4567 04:21:34,699 --> 04:21:38,302 >> CAN YOU FOLLOW UP DURING THE 4568 04:21:38,302 --> 04:21:38,569 RECEPTION? 4569 04:21:38,569 --> 04:21:38,836 THANK YOU. 4570 04:21:38,836 --> 04:21:49,180 WE NEED TO WRAP UP. 4571 04:21:50,314 --> 04:21:52,917 WELL, THAT CONCLUDES OUR 4572 04:21:52,917 --> 04:21:57,555 MEETING. 4573 04:21:57,555 --> 04:22:01,826 FIRST I'D LIKE TO THANK LENNOR 4574 04:22:01,826 --> 04:22:02,727 COMING DOWN HERE. 4575 04:22:02,727 --> 04:22:06,998 WITHOUT YOU THIS IS IMPOSSIBLE. 4576 04:22:06,998 --> 04:22:10,635 ALSO SO TO THE SPEAKERS. 4577 04:22:10,635 --> 04:22:14,705 THANK YOU FOR ACCEPTING THE 4578 04:22:14,705 --> 04:22:15,006 INVITATION. 4579 04:22:15,006 --> 04:22:21,112 THANK YOU SO MUCH. 4580 04:22:21,112 --> 04:22:22,680 OF COURSE THE NIH FOR ALL YOUR 4581 04:22:22,680 --> 04:22:27,685 SUPPORT AND THEY'RE BEHIND THE 4582 04:22:27,685 --> 04:22:27,919 SCENES. 4583 04:22:27,919 --> 04:22:30,054 WITHOUT THEM NONE OF THIS WOULD 4584 04:22:30,054 --> 04:22:32,924 WORK SO THANK YOU SO MUCH ALL 4585 04:22:32,924 --> 04:22:38,729 THE TEAM AND ESPECIALLY ASHLEY 4586 04:22:38,729 --> 04:22:43,134 AND JENNELLE. 4587 04:22:43,134 --> 04:22:44,035 THANK YOU SO MUCH. 4588 04:22:44,035 --> 04:22:48,306 IT'S BEEN A FANTASTIC MEETING 4589 04:22:48,306 --> 04:22:52,043 AND LENNOR DECIDED TO HAVE THE 4590 04:22:52,043 --> 04:22:57,048 SPECIAL 25 ANNIVERSARY A 4591 04:22:57,048 --> 04:23:00,952 RECEPTION FOLLOWING IN THE 4592 04:23:00,952 --> 04:23:01,152 FOYER. 4593 04:23:01,152 --> 04:23:03,587 PLEASE STICK AROUND OUTSIDE THE 4594 04:23:03,587 --> 04:23:06,257 LIPSETT AND WE CAN CONTINUE WITH 4595 04:23:06,257 --> 04:23:09,961 SCIENTIFIC CONVERSATIONS OR NOT. 4596 04:23:09,961 --> 04:23:10,828 THANK YOU SO MUCH. 4597 04:23:10,828 --> 04:23:21,138 SEE YOU NEXT YEAR.