1 00:00:05,120 --> 00:00:06,920 >> WELCOME, EVERYBODY. 2 00:00:06,920 --> 00:00:08,960 TO TODAY'S SEMINAR. 3 00:00:08,960 --> 00:00:10,880 PRIVILEGED TO HAVE MARK DENNISON 4 00:00:10,880 --> 00:00:13,600 WORLD'S LEADER IN CORONAVIRUS 5 00:00:13,600 --> 00:00:15,320 VIROLOGY AND IMMUNOLOGY. 6 00:00:15,320 --> 00:00:16,440 MARK IS NOW THE 7 00:00:16,440 --> 00:00:18,120 DIRECTOR OF THE 8 00:00:18,120 --> 00:00:22,040 DIVISION OF PEDIATRIC INFECTIOUS 9 00:00:22,040 --> 00:00:24,800 DISEASES AT VANDERBILT 10 00:00:24,800 --> 00:00:25,280 UNIVERSITY. 11 00:00:25,280 --> 00:00:31,040 HE WAS AN UNDERGRADUATE FIRST AT 12 00:00:31,040 --> 00:00:33,360 THE UNIVERSITY OF KANSAS AND 13 00:00:33,360 --> 00:00:35,880 KANSAS IS CLEARLY DOING 14 00:00:35,880 --> 00:00:41,480 SOMETHING RIGHT. 15 00:00:41,480 --> 00:00:43,120 THEY'VE MADE HUGE CONTRIBUTIONS 16 00:00:43,120 --> 00:00:46,000 TO THE CORONAVIRUS. 17 00:00:46,000 --> 00:00:51,320 MARK HAD THE GOOD FORTUNE OF 18 00:00:51,320 --> 00:00:52,920 WORKING WITH STAN PERLMAN. 19 00:00:52,920 --> 00:00:55,800 ONE OF THE HEROES OF THE COVID 20 00:00:55,800 --> 00:00:56,360 EPIDEMIC. 21 00:00:56,360 --> 00:00:59,840 ONE OF THE FEW VIE LOCAL JUST 22 00:00:59,840 --> 00:01:02,240 WHO UNDERSTOOD THE IMPORTANCE OF 23 00:01:02,240 --> 00:01:04,080 IT EARLY ON. 24 00:01:04,080 --> 00:01:06,320 AND I'M SURE MARK DID VERY 25 00:01:06,320 --> 00:01:07,760 WELL BY TRAINING WITH HIM. 26 00:01:07,760 --> 00:01:10,320 I LOOKED UP SOME OF YOUR EARLY 27 00:01:10,320 --> 00:01:15,200 PAPERS AND I SAW THIS REMARKABLE 28 00:01:15,200 --> 00:01:19,040 PAPER, THE PROTOTYPE CORONAVIRUS 29 00:01:19,040 --> 00:01:22,280 THAT MOST OF THE FIELD WORKED ON 30 00:01:22,280 --> 00:01:24,640 AS A PROTOTYPE AND MARK WAS PUN 31 00:01:24,640 --> 00:01:30,360 U ONE OF THE FIRST PEOPLE -- HE 32 00:01:30,360 --> 00:01:32,240 WAS THE FIRST ONE TO SHOW THE 33 00:01:32,240 --> 00:01:35,200 POLLY PROTEIN CLEAVAGE. 34 00:01:35,200 --> 00:01:37,960 SO THAT WAS A LANDMARK THAT GOT 35 00:01:37,960 --> 00:01:39,200 MARK'S CAREER GOING. 36 00:01:39,200 --> 00:01:42,440 HE MOVED ON TO AN ASSISTANT 37 00:01:42,440 --> 00:01:44,240 PROFESSOR SHIP AT THOMAS 38 00:01:44,240 --> 00:01:45,560 JEFFERSON UNIVERSITY WHERE HE 39 00:01:45,560 --> 00:01:47,760 STARTED A FRUITFUL COLLABORATION 40 00:01:47,760 --> 00:01:52,560 WITH SUSAN WISE AND RALPH BARAK 41 00:01:52,560 --> 00:01:55,040 WAS IN YOUR LAB. 42 00:01:55,040 --> 00:01:55,640 >> NO. 43 00:01:55,640 --> 00:01:58,000 BUT WE'LL TALK ABOUT THAT LATER 44 00:01:58,000 --> 00:01:59,240 >> THEY PUBLISHED SOME OF THE 45 00:01:59,240 --> 00:02:02,320 MOST IMPORTANT EARLY PAPERS ON 46 00:02:02,320 --> 00:02:04,440 MOLECULAR VIROLOGY OF 47 00:02:04,440 --> 00:02:05,800 CORONAVIRUS. 48 00:02:05,800 --> 00:02:08,880 MANY OF THE ORIGINAL STUDIES -- 49 00:02:08,880 --> 00:02:12,080 DESCRIBING THE BASIC MOLECULAR 50 00:02:12,080 --> 00:02:12,640 VIROLOGY. 51 00:02:12,640 --> 00:02:15,320 HE MOVED ON TO VANDERBILT WHERE 52 00:02:15,320 --> 00:02:17,080 HE HAS HAD A FANTASTIC CAREER. 53 00:02:17,080 --> 00:02:19,120 ONE OF THE PIONEERS IN 54 00:02:19,120 --> 00:02:19,840 CORONAVIRUS. 55 00:02:19,840 --> 00:02:23,040 SOME NOTABLE FINDINGS 2004 HE 56 00:02:23,040 --> 00:02:25,760 ESTABLISHED THE EXPRESSION AND 57 00:02:25,760 --> 00:02:31,800 CHARACTERISTICS OF MANY OF THE 58 00:02:31,800 --> 00:02:45,200 SARS-CoV-SARS-CoV-2. 59 00:02:45,200 --> 00:02:47,240 2014 A BEAUTIFUL PAPER WITH CELL 60 00:02:47,240 --> 00:02:50,960 BIOLOGY SHOWING HOW IT'S 61 00:02:50,960 --> 00:02:53,880 EXPLORED TO GENERATE AND 62 00:02:53,880 --> 00:02:55,200 REPLICATE. 63 00:02:55,200 --> 00:02:57,520 2018 ANOTHER PRACTICAL 64 00:02:57,520 --> 00:02:58,520 DISCOVERY. 65 00:02:58,520 --> 00:03:00,200 DISCOVERED THAT THE REMDESIVIR 66 00:03:00,200 --> 00:03:03,120 ACTIVITY BETWEEN THE CORONAVIRUS 67 00:03:03,120 --> 00:03:05,240 -- SO MARK HAS HAD A REMARKABLE 68 00:03:05,240 --> 00:03:06,000 CAREER. 69 00:03:06,000 --> 00:03:06,840 HIGHLY PRODUCTIVE. 70 00:03:06,840 --> 00:03:08,640 A SUPERSTAR FOR THE LAST FEW 71 00:03:08,640 --> 00:03:11,640 YEARS AND MARK YOU MUST BE 72 00:03:11,640 --> 00:03:15,880 GIVING A SEMINAR A WEEK NOW. 73 00:03:15,880 --> 00:03:20,800 MAYBE HIS MOST UNIQUE CLAIM TO 74 00:03:20,800 --> 00:03:22,440 FAME, $1 MILLION FROM DOLLY 75 00:03:22,440 --> 00:03:23,840 PARTON. 76 00:03:23,840 --> 00:03:25,280 THAT MIGHT HAVE BEEN QUITE A 77 00:03:25,280 --> 00:03:25,800 THRILL. 78 00:03:25,800 --> 00:03:27,600 I'M SURE YOU DIDN'T GET THE 79 00:03:27,600 --> 00:03:31,800 WHOLE MILL BUT A GOOD CHUNK OF 80 00:03:31,800 --> 00:03:31,960 IT. 81 00:03:31,960 --> 00:03:33,840 THANK YOU FOR AGREEING TO 82 00:03:33,840 --> 00:03:36,200 PARTICIPATE AND WE'RE LOOKING 83 00:03:36,200 --> 00:03:36,280 FORWARD TO YOUR SEMINAR. 84 00:03:36,280 --> 00:03:38,080 >> JONATHAN, THAT IS ONE OF THE 85 00:03:38,080 --> 00:03:40,560 NICEST INTRODUCTIONS I'VE HAD. 86 00:03:40,560 --> 00:03:42,440 I'LL TRY TO LIVE UP TO THE 87 00:03:42,440 --> 00:03:45,960 IMAGE. 88 00:03:45,960 --> 00:03:53,000 IT'S AN HONOR TO BE INVITED. 89 00:03:53,000 --> 00:03:54,800 I THOUGHT ABOUT WHERE TO GO WITH 90 00:03:54,800 --> 00:03:58,080 THIS AND I TITLED IT ANTIVIRALS 91 00:03:58,080 --> 00:04:01,200 FOR CORONAVIRUS: MECHANISMS, 92 00:04:01,200 --> 00:04:05,320 RESISTANCE AND REGULATION. 93 00:04:05,320 --> 00:04:08,080 AND I HAVE SEVERAL GOALS. 94 00:04:08,080 --> 00:04:10,440 I WANT TO DESCRIBE SOME EXCITING 95 00:04:10,440 --> 00:04:15,080 WORK THAT WE'VE DONE WHICH GOES 96 00:04:15,080 --> 00:04:16,680 DEEP INTO THINKING AND HOW WE 97 00:04:16,680 --> 00:04:17,440 APPROACH IT. 98 00:04:17,440 --> 00:04:23,080 AND I ALSO WANT TO MAKE THIS -- 99 00:04:23,080 --> 00:04:25,840 AN RCR. 100 00:04:25,840 --> 00:04:27,400 HOW WE THINK ABOUT THE 101 00:04:27,400 --> 00:04:29,400 EXPERIMENTS AND THE TYPES OF 102 00:04:29,400 --> 00:04:33,240 EXPERIMENTS THAT WE CAN PERFORM 103 00:04:33,240 --> 00:04:37,080 WITH PANDEMIC VIRUSES. 104 00:04:37,080 --> 00:04:38,360 AND EXPECTATIONS AND 105 00:04:38,360 --> 00:04:39,080 REQUIREMENTS. 106 00:04:39,080 --> 00:04:41,760 FOR MOVING THINGS FORWARD IN 107 00:04:41,760 --> 00:04:43,320 DRUG DEVELOPMENT FOR HUMAN USE 108 00:04:43,320 --> 00:04:45,760 BUT ALSO FOR REGULATION OF 109 00:04:45,760 --> 00:04:47,200 BIOSAFETY AND BIOSECURITY. 110 00:04:47,200 --> 00:04:48,920 SO I HOPE THIS WILL BE 111 00:04:48,920 --> 00:04:51,320 INFORMATIVE AND USEFUL AND I'M 112 00:04:51,320 --> 00:04:52,760 HAPPY TO TAKE QUESTIONS. 113 00:04:52,760 --> 00:04:55,120 BECAUSE I'VE BEEN SPENDING A LOT 114 00:04:55,120 --> 00:04:56,480 OF TIME THINKING ABOUT THESE 115 00:04:56,480 --> 00:04:57,080 ISSUES. 116 00:04:57,080 --> 00:05:00,600 I WANT TO ACKNOWLEDGE THE 117 00:05:00,600 --> 00:05:04,480 SUPPORT AND POTENTIAL OR 118 00:05:04,480 --> 00:05:06,200 INTERACTIONS THAT I HAVE. 119 00:05:06,200 --> 00:05:18,640 FIRST THE SUPPORT OF -- AM I 120 00:05:18,640 --> 00:05:28,600 GETTING AN ECHO? 121 00:05:28,600 --> 00:05:30,560 SO, I WANT TO THANK THE FOLKS 122 00:05:30,560 --> 00:05:32,400 FROM MY LAB OF COURSE. 123 00:05:32,400 --> 00:05:43,560 AND THE LONG TIME INTERES -- TIME 124 00:05:43,560 --> 00:05:46,680 INTERACTIONS. 125 00:05:46,680 --> 00:05:49,800 AND THEN EMORY UNIVERSITY. 126 00:05:49,800 --> 00:05:53,120 AND THEN COLLABORATIONS AND 127 00:05:53,120 --> 00:05:57,480 CONSULTATIONS THAT I MAY HAVE 128 00:05:57,480 --> 00:06:03,920 ENGAGED IN. 129 00:06:03,920 --> 00:06:05,760 I ALSO WANT TO MENTION BECAUSE 130 00:06:05,760 --> 00:06:11,320 SOME OF MY OF COMES I'LL MAKE -- 131 00:06:11,320 --> 00:06:18,160 I'M A MEMBER OF NSABB. 132 00:06:18,160 --> 00:06:21,120 SO THE NEED FOR ANTIVIRALS I 133 00:06:21,120 --> 00:06:22,640 WISH WE DIDN'T OF COURSE. 134 00:06:22,640 --> 00:06:29,000 WHY DO WE NEED THEM? 135 00:06:29,000 --> 00:06:32,000 -- NOW WITH NEW CASES THIS VIRUS 136 00:06:32,000 --> 00:06:33,880 IS NOT DONE WITH US YET. 137 00:06:33,880 --> 00:06:39,840 IT DECIDES TO MUTATE TO A NEW 138 00:06:39,840 --> 00:06:46,480 CHESS BOARD. 139 00:06:46,480 --> 00:06:49,280 AND SO WE OF COURSE HAVE A LOT 140 00:06:49,280 --> 00:06:54,560 THAT WE NEED TO DEAL WITH. 141 00:06:54,560 --> 00:06:56,880 CONTINUED QUESTION EMERGENCE OF 142 00:06:56,880 --> 00:07:00,560 VARIANTS THAT CAN RENDER MONEY 143 00:07:00,560 --> 00:07:02,320 COLONIAL VACCINES THAT ARE 144 00:07:02,320 --> 00:07:05,880 INEFFICIENTIVE. 145 00:07:05,880 --> 00:07:07,200 AND BECAUSE EVERYBODY IS 146 00:07:07,200 --> 00:07:09,480 PREDICTING THIS VIRUS IS GOING 147 00:07:09,480 --> 00:07:16,040 TO BASKETBALL -- BECOME THE NEXT 148 00:07:16,040 --> 00:07:17,680 SEASONAL FLU BUT I HAVE 149 00:07:17,680 --> 00:07:19,960 SKEPTICISM ABOUT IT. 150 00:07:19,960 --> 00:07:24,480 THESE ALSO CONSIDERED SOMETHING 151 00:07:24,480 --> 00:07:27,480 -- PER USE. 152 00:07:27,480 --> 00:07:30,680 TARGETING MULTIPLE CONSERVATIVE 153 00:07:30,680 --> 00:07:32,760 FUNCTIONS AND ANYONE WHO HAS 154 00:07:32,760 --> 00:07:39,680 WORKED ON HIV AND INFLUENZA 155 00:07:39,680 --> 00:07:42,080 CERTAINLY RECOGNIZES -- THAT WE 156 00:07:42,080 --> 00:07:44,160 SHOULD TARGET MULTIPLE FUNCTIONS 157 00:07:44,160 --> 00:07:46,040 AND WORKING WITH COMBINATIONS 158 00:07:46,040 --> 00:07:49,120 FROM THE BEGINNING. 159 00:07:49,120 --> 00:07:52,680 THE RESISTANCE TESTING SHOULD BE 160 00:07:52,680 --> 00:07:54,200 INTEGRATED IN THE INITIAL 161 00:07:54,200 --> 00:07:56,040 DEVELOPMENT. 162 00:07:56,040 --> 00:08:01,800 THIS SHOULD BE IN INVITRO AND 163 00:08:01,800 --> 00:08:03,760 ENVY VOTE. 164 00:08:03,760 --> 00:08:05,480 ANTICIPATION. 165 00:08:05,480 --> 00:08:08,240 TO DEFINE PATHWAYS THAT VIRUSES 166 00:08:08,240 --> 00:08:10,480 CAN USE TO ESCAPE FROM 167 00:08:10,480 --> 00:08:11,680 ANTIVIRALS AND THEN EDUCATION 168 00:08:11,680 --> 00:08:13,760 FOR USE AND HOW THEY WORK DURING 169 00:08:13,760 --> 00:08:15,240 THE INFECTION. 170 00:08:15,240 --> 00:08:18,200 MAYBE HALF OF THE CONVERSATIONS 171 00:08:18,200 --> 00:08:20,680 I HAD HAVE BEEN ABOUT TRYING TO 172 00:08:20,680 --> 00:08:23,040 GET PEOPLE TO UNDERSTAND TO USE 173 00:08:23,040 --> 00:08:24,680 SOMETHING EARLY AND EFFECTIVELY 174 00:08:24,680 --> 00:08:27,480 AND HOW ANTI VIRAL SHOULD WORK 175 00:08:27,480 --> 00:08:30,880 AND WHEN IT SHOULD BE USED. 176 00:08:30,880 --> 00:08:34,120 SO WHY SHOULD WE DETERMINE THE 177 00:08:34,120 --> 00:08:39,880 GENETICS AND MECHANISM? 178 00:08:39,880 --> 00:08:41,680 MONO THERAPY WILL FAIL. 179 00:08:41,680 --> 00:08:43,880 THERE IS NO QUESTION THAT WE CAN 180 00:08:43,880 --> 00:08:45,840 MAKE COMMENTS -- DIFFICULT TO 181 00:08:45,840 --> 00:08:48,480 ACQUIRE RESISTANCE BUT I'M NOT 182 00:08:48,480 --> 00:08:52,000 AS PATIENT AS THE VIRUS IS AND 183 00:08:52,000 --> 00:08:58,280 THE EMPHASIS -- CONTINUES IN THE 184 00:08:58,280 --> 00:09:02,640 UNVACCINATED POPULATIONS AND IN 185 00:09:02,640 --> 00:09:04,680 THAT SELECTION IT MAY BE RAPID. 186 00:09:04,680 --> 00:09:06,920 THERE MAY BE 100 TIMES LESS 187 00:09:06,920 --> 00:09:09,760 MUTATIONS BUT THAT STILL MEANS 188 00:09:09,760 --> 00:09:12,680 THEY HAVE A MILLION TIMES MORE 189 00:09:12,680 --> 00:09:15,240 MUTATIONS THAN HUMAN DNA. 190 00:09:15,240 --> 00:09:16,400 SLOW MUTATION IS A RELATIVE 191 00:09:16,400 --> 00:09:17,120 TERM. 192 00:09:17,120 --> 00:09:21,200 THE RAPID COMPARED TO -- 193 00:09:21,200 --> 00:09:24,080 ORGANISMS THEY MAY BE SLOW ERAS 194 00:09:24,080 --> 00:09:26,080 THEIR BASELINE IN TERMS -- BUT 195 00:09:26,080 --> 00:09:27,560 THEY CAN RAPIDLY ADAPT. 196 00:09:27,560 --> 00:09:30,480 SO PREDICTIONS OF RESISTANCE FOR 197 00:09:30,480 --> 00:09:31,600 SURVEILLANCE FROM NATURALLY 198 00:09:31,600 --> 00:09:33,480 OCCURRING MUTATIONS AND FROM 199 00:09:33,480 --> 00:09:35,360 TREATED PATIENTS. 200 00:09:35,360 --> 00:09:37,880 TO DEFINING NEW ANTIVIRAL 201 00:09:37,880 --> 00:09:40,080 TARGETS. 202 00:09:40,080 --> 00:09:45,040 WE'VE BEEN -- AMAZED -- AT THE 203 00:09:45,040 --> 00:09:46,080 FLEXIBILITY OF THE BIOLOGY THAT 204 00:09:46,080 --> 00:09:48,880 YOU CAN SEE ADAPTED MUTATIONS 205 00:09:48,880 --> 00:09:50,400 OCCURRING IN LOCATIONS THAT 206 00:09:50,400 --> 00:09:52,120 SHOULD MAKE NO SENSE IN TERMS OF 207 00:09:52,120 --> 00:09:54,320 A PROTEIN FUNCTION. 208 00:09:54,320 --> 00:10:00,320 IT MEANS WE DON'T HAVE A CLUE -- 209 00:10:00,320 --> 00:10:01,880 AND THEN I THINK THAT WE NEED TO 210 00:10:01,880 --> 00:10:05,120 BE MOVING TO A TERM ANTIVIRAL 211 00:10:05,120 --> 00:10:05,560 STEWARDSHIP. 212 00:10:05,560 --> 00:10:07,600 WE DON'T NEED TO WAIT UNTIL WE 213 00:10:07,600 --> 00:10:09,080 SEE MASSIVE RESISTANCE. 214 00:10:09,080 --> 00:10:11,080 WE NEED TO THINK ABOUT HOW WE 215 00:10:11,080 --> 00:10:13,480 MANAGE THESE COMPOUNDS BOTH FOR 216 00:10:13,480 --> 00:10:15,880 THEIR USE AND THE ADHERENCE OF 217 00:10:15,880 --> 00:10:17,960 INDIVIDUALS WHO GET THEM AND FOR 218 00:10:17,960 --> 00:10:19,720 HOW WE THINK SMART ABOUT 219 00:10:19,720 --> 00:10:21,120 DEVELOPMENT SO THAT WE DON'T GET 220 00:10:21,120 --> 00:10:24,680 IN A POSITION WHERE WE USE THE 221 00:10:24,680 --> 00:10:27,080 DRUGS ONE AT A TIME AND NONE OF 222 00:10:27,080 --> 00:10:28,400 THEM WORKING. 223 00:10:28,400 --> 00:10:30,840 I WANT TO SPEND A FEW MINUTES ON 224 00:10:30,840 --> 00:10:32,080 REPLICATION. 225 00:10:32,080 --> 00:10:34,760 I HAVE A LOT OF THINGS, WE'RE 226 00:10:34,760 --> 00:10:37,400 WORKING ON A NEW -- THE 227 00:10:37,400 --> 00:10:39,040 REPLICATION STRATEGY -- I WANT 228 00:10:39,040 --> 00:10:40,960 TO SAY OF COURSE EVERYBODY KNOWS 229 00:10:40,960 --> 00:10:43,280 IS A STRANGE STATEMENT FOR ME 230 00:10:43,280 --> 00:10:43,880 EVEN NOW. 231 00:10:43,880 --> 00:10:46,600 BUT THE CONCEPT OF THE VIRAL 232 00:10:46,600 --> 00:10:50,280 ENTRY AND WHERE IT'S TARGETING 233 00:10:50,280 --> 00:10:55,400 -- FOLLOWED BY THE TRANSLATION 234 00:10:55,400 --> 00:10:59,760 OF THE LARGE UP TO 30KB SINGLE 235 00:10:59,760 --> 00:11:02,880 STRAND RNA GENOME. 236 00:11:02,880 --> 00:11:05,440 IT'S TRANSLATED INTO TWO 237 00:11:05,440 --> 00:11:08,400 OVERLAPPING POLLY PROTEINS. 238 00:11:08,400 --> 00:11:10,760 THOSE ARE THEN PROCESSED IN THE 239 00:11:10,760 --> 00:11:13,080 CASE OF SARS-CoV-2. 240 00:11:13,080 --> 00:11:17,600 AND IN THE CASE OF SOME OF THE 241 00:11:17,600 --> 00:11:20,520 VIRUSES THEY HAVE THREE. 242 00:11:20,520 --> 00:11:26,240 PROCESS THESE 1 -- 16 PROTEINS. 243 00:11:26,240 --> 00:11:31,080 AND ALSO HAVE OTHER STEPS IN RNA 244 00:11:31,080 --> 00:11:32,640 MODIFICATION. 245 00:11:32,640 --> 00:11:36,160 THAT CAN LEAD TO THE FORMATION 246 00:11:36,160 --> 00:11:41,360 OF THE REPLICATION FACTORIES IN 247 00:11:41,360 --> 00:11:42,080 THE CELL. 248 00:11:42,080 --> 00:11:44,000 AND I COULD SPEND THE ENTIRE 249 00:11:44,000 --> 00:11:46,040 TIME TALKING ABOUT THE BEAUTIFUL 250 00:11:46,040 --> 00:11:50,000 COMPLEX DETAILS OF RNA VIRUS 251 00:11:50,000 --> 00:11:51,440 REPLICATION. 252 00:11:51,440 --> 00:11:53,000 ONE, THIS IS THE STAGE WHERE YOU 253 00:11:53,000 --> 00:11:55,960 COPY THE GENOME RNA. 254 00:11:55,960 --> 00:11:59,560 AND ALSO THE GENOMIC RNAs FOR 255 00:11:59,560 --> 00:12:02,000 SCENT PROTEINS THAT ARE USED FOR 256 00:12:02,000 --> 00:12:05,400 VIRUS REPLICATION. 257 00:12:05,400 --> 00:12:10,080 AND ALSO ENGAGE IN RELY 258 00:12:10,080 --> 00:12:12,040 COMBINATION OF LIFESTYLE. 259 00:12:12,040 --> 00:12:24,280 THEY ARE SURPRISINGLY ROBUST. 260 00:12:24,280 --> 00:12:31,040 NOW THE MAIN POINT, -- IS THAT 261 00:12:31,040 --> 00:12:33,720 LOOKING AT A NEW INHIBITOR AND 262 00:12:33,720 --> 00:12:37,440 THAT IS SUPPORTED THROUGH -- R19 263 00:12:37,440 --> 00:12:38,480 AS WELL. 264 00:12:38,480 --> 00:12:40,840 ONE THING THAT I GO BACK TO IS 265 00:12:40,840 --> 00:12:43,600 BACK IN THE DAY IN 1995 WE 266 00:12:43,600 --> 00:12:46,000 PERFORMED EXPERIMENTS 267 00:12:46,000 --> 00:12:52,760 DEMONSTRATING THAT THE INHIBITOR 268 00:12:52,760 --> 00:12:55,080 ABORTED AT ANY STAGE. 269 00:12:55,080 --> 00:12:56,960 IT STOPPED NO MATTER. 270 00:12:56,960 --> 00:12:59,280 SO THIS INDICATED THAT YOU WERE 271 00:12:59,280 --> 00:13:01,080 NOT JUST BLOCKING THE PROTEIN 272 00:13:01,080 --> 00:13:02,560 PROCESSING BUT THAT THE 273 00:13:02,560 --> 00:13:04,400 PROCESSING OF THE PROTEINS FOR 274 00:13:04,400 --> 00:13:05,880 REPLICATION WAS ACQUIRED 275 00:13:05,880 --> 00:13:07,680 THROUGHOUT THE ENTIRE 276 00:13:07,680 --> 00:13:11,160 REPLICATION CYCLE. 277 00:13:11,160 --> 00:13:14,880 SO THE INHIBITOR CAN BE 278 00:13:14,880 --> 00:13:15,920 PROFOUNDLY ACCURATE. 279 00:13:15,920 --> 00:13:19,880 I'M GOING TO SPEND MORE TIME 280 00:13:19,880 --> 00:13:23,080 TALKING ABOUT THE SYNTHESIS. 281 00:13:23,080 --> 00:13:25,120 AND WHERE WE ARE WITH REMDESIVIR 282 00:13:25,120 --> 00:13:28,160 AND RESISTANCE. 283 00:13:28,160 --> 00:13:30,480 CORONAVIRUSES TAKE MONEY OF 284 00:13:30,480 --> 00:13:32,240 THEIR NONSTRUCTURED PROTEINS TO 285 00:13:32,240 --> 00:13:36,760 FORM A MULTI-PROTEIN REPLICATE 286 00:13:36,760 --> 00:13:41,880 -- AND THEY ARE MEDIATED ON 287 00:13:41,880 --> 00:13:44,280 THESE LITTLE BLOG WALLS HERE 288 00:13:44,280 --> 00:13:45,720 THAT ARE WELL DESCRIBED. 289 00:13:45,720 --> 00:13:49,280 RICK SNYDER AND OTHERS TO FORM 290 00:13:49,280 --> 00:13:53,480 THESE -- THAT CAN BE MEMBRANE 291 00:13:53,480 --> 00:13:54,600 MODIFICATIONS. 292 00:13:54,600 --> 00:13:58,920 I AM GOING TO MOVE ON TO THAT 293 00:13:58,920 --> 00:13:59,480 DISCUSSION. 294 00:13:59,480 --> 00:14:02,720 SO ON THE UPPER LEFT IT'S SHOWN 295 00:14:02,720 --> 00:14:05,720 THE TWO REGIONS OF THE POLLY 296 00:14:05,720 --> 00:14:06,800 PROTEIN. 297 00:14:06,800 --> 00:14:08,320 ONE POLLY PROTEIN. 298 00:14:08,320 --> 00:14:11,040 THE TRANSLATION OCCURS AT THIS 299 00:14:11,040 --> 00:14:12,560 OF ENTIRE DOMAIN. 300 00:14:12,560 --> 00:14:17,480 THE WORK THAT I DID WAS SHOWING 301 00:14:17,480 --> 00:14:21,160 THAT IF YOU TRY TO INVITRO 302 00:14:21,160 --> 00:14:26,680 TRANSLATE THAT THE FIRST STARTED 303 00:14:26,680 --> 00:14:30,800 ALMOST IMMEDIATELY. 304 00:14:30,800 --> 00:14:35,520 IT TRANSLATES A STRING OF PEARLS 305 00:14:35,520 --> 00:14:36,720 AND THOSE INCLUDE IMPORTANT 306 00:14:36,720 --> 00:14:39,720 DOMAINS LINE THE RNA DEPENDENT 307 00:14:39,720 --> 00:14:52,680 -- AND CAPPING ENZYMES. 308 00:14:52,680 --> 00:14:56,080 AND THEN OTHER CO-FACTORS WHICH 309 00:14:56,080 --> 00:15:00,440 DON'T SEEM OVEN VIMMATIC 310 00:15:00,440 --> 00:15:19,200 FUNCTION. 311 00:15:19,200 --> 00:15:22,720 -- IT'S A SYMBOL AND LOOKS LIKE 312 00:15:22,720 --> 00:15:33,840 A DNA MULTI-PROTEIN ENZYME -- 313 00:15:33,840 --> 00:15:34,520 CO-FACTORS -- TYPE OF 314 00:15:34,520 --> 00:15:36,520 ACTIVITIES. 315 00:15:36,520 --> 00:15:39,280 STIMULATING FACTORS SUCH AS -- 316 00:15:39,280 --> 00:15:41,400 10 AND THEN OTHER ONES THAT MAY 317 00:15:41,400 --> 00:15:43,880 BE IMPORTANT FOR STABILIZING AND 318 00:15:43,880 --> 00:15:45,920 PROCESSING THE RNA STRAND 319 00:15:45,920 --> 00:15:47,120 THROUGH IT. 320 00:15:47,120 --> 00:15:49,880 SO CORONAVIRUS IS BIGGER AND 321 00:15:49,880 --> 00:15:52,680 BADDER IN MANY WAYS AND ARGUED 322 00:15:52,680 --> 00:15:55,280 FOR MANY YEARS THAT THIS COMPLEX 323 00:15:55,280 --> 00:15:57,560 -- WHAT I'M GOING TO TALK ABOUT 324 00:15:57,560 --> 00:15:59,520 NOW I'M GOING TO MOVE ON TO 325 00:15:59,520 --> 00:16:01,680 TALKING ABOUT WHERE WE'VE GONE 326 00:16:01,680 --> 00:16:04,120 WITH RESISTANCE AND I'M GOING TO 327 00:16:04,120 --> 00:16:05,680 SUMMARIZE BRIEFLY WITH WHAT IS 328 00:16:05,680 --> 00:16:07,280 HAPPENING WITH REMDESIVIR. 329 00:16:07,280 --> 00:16:09,680 WHAT WE'RE TARGETING IS WITH THE 330 00:16:09,680 --> 00:16:15,880 PROCESS OF RNA SYNTHESIS. 331 00:16:15,880 --> 00:16:17,880 WHAT THEY FUNCTION AT THE LEVEL 332 00:16:17,880 --> 00:16:21,000 OF -- IS THE RNA SIN THUS. 333 00:16:21,000 --> 00:16:24,440 AND I'M GOING TO BE -- THIS IS 334 00:16:24,440 --> 00:16:26,400 ALSO NOW MATURED. 335 00:16:26,400 --> 00:16:29,360 THIS SCHEMATIC -- YOU CAN SEE 336 00:16:29,360 --> 00:16:32,080 IT'S LACKING TREMENDOUS NUMBER 337 00:16:32,080 --> 00:16:36,760 OF -- BUT IT'S ALWAYS WORTHWHILE 338 00:16:36,760 --> 00:16:40,400 TO DESCRIBE WHEN PEOPLE TALK 339 00:16:40,400 --> 00:16:43,480 ABOUT THE CORONAVIRUS THEY STILL 340 00:16:43,480 --> 00:16:45,240 REPRESENT THE MORE CLOSELY 341 00:16:45,240 --> 00:16:47,240 RELATED THAN THOSE OF THE ALPHA 342 00:16:47,240 --> 00:16:50,000 OR THE GAMMA OR DELTA OF 343 00:16:50,000 --> 00:16:52,040 CORONAVIRUS. 344 00:16:52,040 --> 00:16:54,760 THAT THERE IS A TREMENDOUS 345 00:16:54,760 --> 00:16:56,200 CONTRIBUTION OF BAT CORONAVIRUS 346 00:16:56,200 --> 00:17:00,280 IN OTHER ANIMAL SPECIES. 347 00:17:00,280 --> 00:17:03,160 I WANT TO BRING IT UP FOR A 348 00:17:03,160 --> 00:17:21,680 COUPLE OF REASONS. 349 00:17:21,680 --> 00:17:23,920 STILL AFTER 38 YEARS IT IS STILL 350 00:17:23,920 --> 00:17:27,400 A ROBUST AND POWERFUL MODEL AND 351 00:17:27,400 --> 00:17:28,720 MAYBE EVEN BECOMING MORE 352 00:17:28,720 --> 00:17:30,280 IMPORTANT AGAIN FOR REASONS THAT 353 00:17:30,280 --> 00:17:31,200 I'LL DESCRIBE. 354 00:17:31,200 --> 00:17:37,680 AND SO TO SUMMARIZE REMDESIVIR 355 00:17:37,680 --> 00:17:41,200 WHAT IT DOES ON THE LEFT IS -- 356 00:17:41,200 --> 00:17:42,720 SHOWING YOUR FIRST DOLLAR BILL 357 00:17:42,720 --> 00:17:43,480 IN THE RESTAURANT. 358 00:17:43,480 --> 00:17:47,160 THIS IS ONE OF THE FIRST FIGURES 359 00:17:47,160 --> 00:17:49,760 -- THAT A GRADUATE STUDENT IN MY 360 00:17:49,760 --> 00:17:54,160 LAB DESCRIBED AND SHOWED. 361 00:17:54,160 --> 00:17:58,200 THE TREMENDOUS AN VITRO 362 00:17:58,200 --> 00:17:58,760 ACTIVITY. 363 00:17:58,760 --> 00:18:00,800 AND THAT IS IF YOU LOOK AT THE 364 00:18:00,800 --> 00:18:05,680 CHANGE IN VIRUS CONCENTRATIONS 365 00:18:05,680 --> 00:18:07,920 -- YOU'RE GETTING REALLY SIX 366 00:18:07,920 --> 00:18:11,920 LOGS OF VIRUS INHIBITION OVER 367 00:18:11,920 --> 00:18:12,360 TIME. 368 00:18:12,360 --> 00:18:15,560 FULL LOG REDUCTION IN VIRUS 369 00:18:15,560 --> 00:18:16,880 REPLICATION AND WHEN WE LOOKED 370 00:18:16,880 --> 00:18:20,600 AT -- I WAS NOT A DRUG 371 00:18:20,600 --> 00:18:21,320 DEVELOPMENT PERSON. 372 00:18:21,320 --> 00:18:24,440 BUT WHEN WE STARTED AND I 373 00:18:24,440 --> 00:18:27,040 STARTED REALIZING -- THE 374 00:18:27,040 --> 00:18:28,760 EFFECTIVE CONCENTRATION. 375 00:18:28,760 --> 00:18:30,280 WHICH IS CALCULATED FROM 10 376 00:18:30,280 --> 00:18:32,600 POINT EXPERIMENTS FOR MORE WHICH 377 00:18:32,600 --> 00:18:37,440 ALLOWS YOU TO LOOK FROM 0-100%. 378 00:18:37,440 --> 00:18:39,880 SO WE'RE LOOKING AT SIX LOG 379 00:18:39,880 --> 00:18:40,280 SCALE. 380 00:18:40,280 --> 00:18:43,920 HERE WE'RE LOOKING AT 100 381 00:18:43,920 --> 00:18:46,000 PERCENTAGE. 382 00:18:46,000 --> 00:18:48,360 THIS IS THE CURVE. 383 00:18:48,360 --> 00:18:51,240 THIS DRUG WAS COOL IN BOTH. 384 00:18:51,240 --> 00:18:53,480 SO WHAT IS REMDESIVIR? 385 00:18:53,480 --> 00:19:03,480 IT'S CALLED A MONO -- 386 00:19:03,480 --> 00:19:12,760 PHOSPHORAMIDATE. 387 00:19:12,760 --> 00:19:19,280 IT FUNCTIONS AS A DELAYED OR 388 00:19:19,280 --> 00:19:23,840 NONOBLIGATE -- FOGGING INITIAL 389 00:19:23,840 --> 00:19:26,560 -- IT FUNCTIONS BY INCORPORATING 390 00:19:26,560 --> 00:19:30,560 AND BECAUSE OF WHAT THE FACTORS 391 00:19:30,560 --> 00:19:34,200 ARE WITHIN IT CAUSES A 392 00:19:34,200 --> 00:19:39,560 TERMINATION OF THE -- ONE TO 393 00:19:39,560 --> 00:19:41,960 THREE NUCLEOTIDES. 394 00:19:41,960 --> 00:19:50,320 IT CAN GET INCORPORATED. 395 00:19:50,320 --> 00:19:55,280 AND IT BYPASSES THE PROOFREADING 396 00:19:55,280 --> 00:19:55,720 FUNCTION. 397 00:19:55,720 --> 00:19:58,480 THIS IS WHAT PROFOUNDLY IMPACTED 398 00:19:58,480 --> 00:20:01,120 US THAT THIS DRUG COULD DO THIS. 399 00:20:01,120 --> 00:20:03,240 BECAUSE MOST TEST EDUCATED A 400 00:20:03,240 --> 00:20:05,680 FLAT LINE WHERE THEY HAD NO 401 00:20:05,680 --> 00:20:07,120 IMPACT. 402 00:20:07,120 --> 00:20:18,800 IT FUNSE FUNS -- FUNCTIONS -- 403 00:20:25,840 --> 00:20:25,960 -- 404 00:20:25,960 --> 00:20:26,680 [ INDISCERNIBLE ] 405 00:20:26,680 --> 00:20:29,560 AND NOT REALLY 100% CLEAR WHY 406 00:20:29,560 --> 00:20:34,320 IT'S ABLE TO ESCAPE THIS. 407 00:20:34,320 --> 00:20:37,080 SO OF COURSE IN THE INITIAL 408 00:20:37,080 --> 00:20:41,160 STUDY -- IT SHOWED SHORTENED 409 00:20:41,160 --> 00:20:43,280 HOSPITALIZATION EVEN IN SEVERELY 410 00:20:43,280 --> 00:20:45,400 ILL PATIENTS. 411 00:20:45,400 --> 00:20:48,880 IT STILL SHOWED A REDUCED 412 00:20:48,880 --> 00:20:50,440 HOSPITALIZATION WHICH SHOCKED ME 413 00:20:50,440 --> 00:20:52,520 THAT IT WAS ABLE TO BE EFFECTIVE 414 00:20:52,520 --> 00:20:54,080 THAT LATE. 415 00:20:54,080 --> 00:20:56,240 BUT A MORE RECENT STUDY WHICH 416 00:20:56,240 --> 00:21:02,000 GETS TO AN IMPORTANT POINT IS AN 417 00:21:02,000 --> 00:21:05,040 87% DECREASE IN HOSPITALIZATION 418 00:21:05,040 --> 00:21:06,280 AND DEATH. 419 00:21:06,280 --> 00:21:11,680 BUT AT A HIGH RISK PATIENT THAT 420 00:21:11,680 --> 00:21:14,760 BENEFIT IS SIGNIFICANT. 421 00:21:14,760 --> 00:21:17,360 AND SO IN ORAL FORMS OF 422 00:21:17,360 --> 00:21:18,840 REMDESIVIR HAVE BEEN DEVELOPED 423 00:21:18,840 --> 00:21:21,040 BY MULTIPLE AND STUDIED BY 424 00:21:21,040 --> 00:21:23,000 MULTIPLE GROUPS AND A RECENT 425 00:21:23,000 --> 00:21:29,960 STUDY LOOKED AT ITS EFFICACY -- 426 00:21:29,960 --> 00:21:37,880 SHOWING IT TO BE -- EFFICACIOUS. 427 00:21:37,880 --> 00:21:43,400 BECAUSE OF A LOT OF BIOLOGY OF 428 00:21:43,400 --> 00:21:44,240 HOW THAT WORKS. 429 00:21:44,240 --> 00:21:46,360 AS PART OF THOSE INITIAL STUDIES 430 00:21:46,360 --> 00:21:50,400 AND ALSO PUBLISHED -- IN 2018 WE 431 00:21:50,400 --> 00:21:52,360 DID DEVELOPMENT TESTING OF 432 00:21:52,360 --> 00:21:53,600 RESISTANCES. 433 00:21:53,600 --> 00:21:55,400 WE DISCOVERED THAT IT WAS VERY 434 00:21:55,400 --> 00:21:56,520 DIFFICULT TO GET. 435 00:21:56,520 --> 00:21:59,360 IT TOOK 23 PASSAGES. 436 00:21:59,360 --> 00:22:01,760 THIS IS OLD DATA AND WHAT WE 437 00:22:01,760 --> 00:22:04,760 FOUND IS THAT AFTER PASSAGE WE 438 00:22:04,760 --> 00:22:08,560 COULD SEE A SUM DIFFERENCE IN 439 00:22:08,560 --> 00:22:09,840 RESISTANCE IN LOG ORDER 440 00:22:09,840 --> 00:22:11,480 RESISTANCE. 441 00:22:11,480 --> 00:22:14,280 WHEN WE SEQUENCED THE PASSAGE 442 00:22:14,280 --> 00:22:15,880 POPULATION AT THE TIME WE WERE 443 00:22:15,880 --> 00:22:18,880 NOT DOING MULTIPLE LINEAGES. 444 00:22:18,880 --> 00:22:19,960 WE JUST DID ONE. 445 00:22:19,960 --> 00:22:22,760 WE IDENTIFIED TWO MUTATIONS. 446 00:22:22,760 --> 00:22:25,320 THERE ARE ONLY SIX IN THE WHOLE 447 00:22:25,320 --> 00:22:28,080 GENOME. 448 00:22:28,080 --> 00:22:34,480 SO IT WAS EASY TO DISCRIMINATE. 449 00:22:34,480 --> 00:22:36,800 WHAT WE SHOWED IS THERE ARE TWO 450 00:22:36,800 --> 00:22:39,240 MUTATIONS THAT OCCUR UP HERE AND 451 00:22:39,240 --> 00:22:41,000 HERE. 452 00:22:41,000 --> 00:22:44,520 AND THAT SIT IN REASONABLE 453 00:22:44,520 --> 00:22:47,440 PROXIMITY. 454 00:22:47,440 --> 00:22:49,600 AND THAT WHEN WE LOOK ON THE 455 00:22:49,600 --> 00:22:54,160 RIGHT PANEL THAT THIS IS WILD 456 00:22:54,160 --> 00:23:02,000 TYPE INHIBITIONS. 457 00:23:02,000 --> 00:23:04,520 STILL SOME SENSITIVITY TO HIGHER 458 00:23:04,520 --> 00:23:06,080 CONCENTRATIONS BUT DEFINITELY A 459 00:23:06,080 --> 00:23:08,000 DISTINCTION OF ABOUT TWO LOGS 460 00:23:08,000 --> 00:23:09,160 DIFFERENT. 461 00:23:09,160 --> 00:23:12,520 WHEN WE LOOKED AT THE INDIVIDUAL 462 00:23:12,520 --> 00:23:16,360 VIRAL MUTANTS -- WE SAW THAT 463 00:23:16,360 --> 00:23:18,680 THEY BOTH HAD A LITTLE 464 00:23:18,680 --> 00:23:20,880 INTERMEDIATE PHENOTYPE BUT WHEN 465 00:23:20,880 --> 00:23:24,160 WE PUT THEM TOGETHER WE SAW WHAT 466 00:23:24,160 --> 00:23:30,400 ALMOST LIKED LIKE PASSAGE 23. 467 00:23:30,400 --> 00:23:33,680 THIS TO ME IS AN UNCOMFORTABLE 468 00:23:33,680 --> 00:23:35,640 ZONE AND I WANT TO SEE IF THERE 469 00:23:35,640 --> 00:23:38,360 ARE ADDITIONAL MUTATIONS THAT 470 00:23:38,360 --> 00:23:41,440 CAN HAVE AFFECTS THAT ARE NOT IN 471 00:23:41,440 --> 00:23:43,680 THE -- AS MENTIONED BEFORE. 472 00:23:43,680 --> 00:23:59,240 THIS WAS THE MOST PROVOCATIVE. 473 00:23:59,240 --> 00:24:03,200 WE CAN FIND IT BUT IT'S 474 00:24:03,200 --> 00:24:04,600 ASSOCIATED WITH THE MUTATIONS 475 00:24:04,600 --> 00:24:09,160 AND IT CAUSES A LOSS OF FITNESS 476 00:24:09,160 --> 00:24:12,880 IN VITRO AND ATTENUATION IN 477 00:24:12,880 --> 00:24:23,440 VIVO. 478 00:24:23,440 --> 00:24:26,200 WE SAW A LOSS OF THE MUTANT 479 00:24:26,200 --> 00:24:29,720 VIRUS AND AN INCREASE IN THE 480 00:24:29,720 --> 00:24:30,960 WILD TYPE VIRUS. 481 00:24:30,960 --> 00:24:34,240 WHEN THEY WERE INTRODUCED INTO 482 00:24:34,240 --> 00:24:38,800 THE SARS-CoV -- THEY SAW THAT 483 00:24:38,800 --> 00:24:42,480 IT HAD THE SAME RESISTANCE 484 00:24:42,480 --> 00:24:42,720 PHENOTYPE. 485 00:24:42,720 --> 00:24:45,680 AND WHEN THEY PUT IT IN ANIMALS 486 00:24:45,680 --> 00:24:50,040 THEY SAW EVIDENCE THAT SUGGESTED 487 00:24:50,040 --> 00:24:52,400 ATTENUATION -- THAT IS A 488 00:24:52,400 --> 00:24:54,280 SIGNIFICANT CONCENTRATION. 489 00:24:54,280 --> 00:24:55,920 BUT THEY RECOVERED MORE RAPIDLY 490 00:24:55,920 --> 00:24:58,840 AND DID NOT GET AS SICK. 491 00:24:58,840 --> 00:25:00,880 AND HAD LESS VIRAL SHED. 492 00:25:00,880 --> 00:25:02,640 ONE OF THE IMPORTANT THINGS FOR 493 00:25:02,640 --> 00:25:07,080 US -- ONE OF THE POINTS -- ALSO 494 00:25:07,080 --> 00:25:09,640 WAS THE FACT THAT WE SAW WHEN WE 495 00:25:09,640 --> 00:25:12,640 WERE INTERESTED IN THIS TISSUE 496 00:25:12,640 --> 00:25:14,400 ACROSS RESISTANCE OR SENSITIVITY 497 00:25:14,400 --> 00:25:16,720 THIS WAS THE SLIDE I JUST 498 00:25:16,720 --> 00:25:17,520 SHOWED. 499 00:25:17,520 --> 00:25:20,200 WHAT WE SAW IS BASICALLY 500 00:25:20,200 --> 00:25:21,680 DECREASED SENSITIVITY WITH THE 501 00:25:21,680 --> 00:25:22,880 DRUG WITH THE MUTATIONS. 502 00:25:22,880 --> 00:25:26,440 IF WE TOOK THE SAME VIRUSES AND 503 00:25:26,440 --> 00:25:34,080 TESTED THEM WE SAW INCREASE. 504 00:25:34,080 --> 00:25:36,040 AND SO INTERESTINGLY THE 505 00:25:36,040 --> 00:25:40,680 INDIVIDUAL MUTATIONS CAUSE AN 506 00:25:40,680 --> 00:25:43,240 INTERMEDIATE LOSS OR INCREASED 507 00:25:43,240 --> 00:25:46,880 SENSITIVE AND COMBINED THEY HAD 508 00:25:46,880 --> 00:25:49,240 INCREASED SENSITIVITY. 509 00:25:51,800 --> 00:25:54,640 SO OF COURSE THIS IS THE KIND OF 510 00:25:54,640 --> 00:26:01,480 THING THAT ENCOURAGESES US. 511 00:26:01,480 --> 00:26:03,960 SO IF I WERE THERE AND I COULD 512 00:26:03,960 --> 00:26:08,000 SEE ALL OF YOU I WOULD PAUSE AND 513 00:26:08,000 --> 00:26:10,280 ASK IF YOU HAVE ANY QUESTIONS. 514 00:26:10,280 --> 00:26:12,600 I WANT TO DESCRIBE RECENT 515 00:26:12,600 --> 00:26:14,040 RESULTS. 516 00:26:14,040 --> 00:26:16,480 AND TAKE A CHANCE TO GO THROUGH 517 00:26:16,480 --> 00:26:19,920 THE COMPLICATED STORY THAT HAS 518 00:26:19,920 --> 00:26:20,760 TWO COMPONENTS. 519 00:26:20,760 --> 00:26:22,560 THE ISSUE OF SCIENCE AND 520 00:26:22,560 --> 00:26:25,200 DISCOVERY AND THE OTHER IS HOW 521 00:26:25,200 --> 00:26:27,080 WE GET THERE AND WHAT THIS MEANS 522 00:26:27,080 --> 00:26:29,600 WHEN WE THINK ABOUT RESISTANCE 523 00:26:29,600 --> 00:26:33,480 TESTING FOR SARS-CoV-2 AND 524 00:26:33,480 --> 00:26:41,760 OTHER PANDEMIC VIRUSES. 525 00:26:41,760 --> 00:26:45,080 AND THESE ARE THE TEAMS THAT 526 00:26:45,080 --> 00:26:47,480 PERFORMED THIS. 527 00:26:47,480 --> 00:26:49,400 VANDERBILT, BIOCHEMICAL STUDIES 528 00:26:49,400 --> 00:26:52,560 IN ALBERTA. 529 00:26:52,560 --> 00:26:54,320 ANIMAL STUDIES THAT ARE MOVING 530 00:26:54,320 --> 00:26:57,880 FORWARD WITH NOW IN DIRECTION OF 531 00:26:57,880 --> 00:27:03,840 THE GRANTS WITH UNC AND THEN 532 00:27:03,840 --> 00:27:05,280 GILLEAD. 533 00:27:05,280 --> 00:27:08,280 THE STRATEGY OF RESEARCH BASED 534 00:27:08,280 --> 00:27:10,120 ON THIS WE KNEW THAT THIS TOOK 535 00:27:10,120 --> 00:27:11,840 TIME AND WE WANTED TO GET 536 00:27:11,840 --> 00:27:15,000 STARTED IMMEDIATELY SO AS SOON 537 00:27:15,000 --> 00:27:18,120 AS THE VIRUS WAS AVAILABLE TO US 538 00:27:18,120 --> 00:27:19,640 WE WERE ONE OF THE FIRST PEOPLE 539 00:27:19,640 --> 00:27:22,480 TO GET FROM IT THE CDC. 540 00:27:22,480 --> 00:27:25,160 WE OBTAINED THE VIRUS AND WE DID 541 00:27:25,160 --> 00:27:26,800 THE ACTIVITY STUDIES AND THEY 542 00:27:26,800 --> 00:27:29,960 WERE DONE HERE IN VITRO AND ENVY 543 00:27:29,960 --> 00:27:33,240 VOTE AT UNC TO LOOK AT THE 544 00:27:33,240 --> 00:27:37,680 ACTIVITY OF REMDESIVIR AGAINST 545 00:27:37,680 --> 00:27:39,000 SARS-CoV-2. 546 00:27:39,000 --> 00:27:41,080 AT THE SAME TIME AS SOON AS WE 547 00:27:41,080 --> 00:27:42,960 IDENTIFIED WE WANTED TO BEGIN 548 00:27:42,960 --> 00:27:44,200 THE STUDIES. 549 00:27:44,200 --> 00:27:46,400 WITH IT REQUIRING MULTIPLE 550 00:27:46,400 --> 00:27:50,160 PASSAGES WE WANTED TO DO THAT 551 00:27:50,160 --> 00:27:56,280 IMMEDIATELY. 552 00:27:56,280 --> 00:27:59,560 TO DO EXACTLY WHAT WE DID WITH 553 00:27:59,560 --> 00:28:01,200 MHV. 554 00:28:01,200 --> 00:28:03,280 AND THEN LOOK AT THOSE AND 555 00:28:03,280 --> 00:28:06,680 IMMEDIATELY TAKE THOSE AND 556 00:28:06,680 --> 00:28:09,680 INTRODUCE THEM BACK INTO CLONES 557 00:28:09,680 --> 00:28:12,280 OF SARS-CoV-2. 558 00:28:12,280 --> 00:28:14,200 LIFE IN A PANDEMIC IS 559 00:28:14,200 --> 00:28:15,120 COMPLICATED. 560 00:28:15,120 --> 00:28:16,400 AND AS WE WERE PREPARING THIS 561 00:28:16,400 --> 00:28:18,440 AND DOING THIS WE WERE 562 00:28:18,440 --> 00:28:22,160 APPROACHING OCTOBER OF 2020 AND 563 00:28:22,160 --> 00:28:27,080 LOW AND BEHOLD REMDESIVIR 564 00:28:27,080 --> 00:28:33,160 RECEIVED EUA AND -- THE 565 00:28:33,160 --> 00:28:36,160 CONVERSATION THAT I HAD -- WE 566 00:28:36,160 --> 00:28:37,960 MAY HAVE SOME CHALLENGES. 567 00:28:37,960 --> 00:28:40,960 SO THE FDA APPROVAL REQUIRED 568 00:28:40,960 --> 00:28:43,920 DATA ON RESISTANCE AND AT THE 569 00:28:43,920 --> 00:28:47,560 SAME TIME NOW BECAUSE THIS IS AN 570 00:28:47,560 --> 00:28:48,800 APPROVED DRUG AND BECAUSE THIS 571 00:28:48,800 --> 00:28:51,800 IS A PANDEMIC VIRUS AND BECAUSE 572 00:28:51,800 --> 00:28:54,480 WE ARE DOING BOTH FORWARD 573 00:28:54,480 --> 00:28:56,920 GENETICS AND REVERSE GENETICS 574 00:28:56,920 --> 00:28:58,920 SUDDENLY WE HAVE ISSUES RELATED 575 00:28:58,920 --> 00:29:02,680 TO PC30. 576 00:29:02,680 --> 00:29:04,680 AND THE POTENTIAL FOR WHAT IS 577 00:29:04,680 --> 00:29:07,320 CALLED A MAJOR ACTION WHICH 578 00:29:07,320 --> 00:29:12,000 REQUIRES NIH APPROVAL WITH 579 00:29:12,000 --> 00:29:14,160 SARS-CoV-2 THAT MIGHT 580 00:29:14,160 --> 00:29:14,800 INTRODUCTION RESISTANCE. 581 00:29:14,800 --> 00:29:17,320 LET ME SUMMARIZE THE INTERESTING 582 00:29:17,320 --> 00:29:19,400 DILEMMA THAT WE FACED AT THIS 583 00:29:19,400 --> 00:29:21,560 TIME. 584 00:29:21,560 --> 00:29:24,720 YOU CAN CLAIM THIS IF YOU'RE A 585 00:29:24,720 --> 00:29:25,080 GRAD STUDENT. 586 00:29:25,080 --> 00:29:33,040 THIS IS FROM THE FDA -- NDA. 587 00:29:33,040 --> 00:29:35,400 THEREFORE BASED ON APPROPRIATE 588 00:29:35,400 --> 00:29:37,840 SCIENTIFIC DATA FDA HAS 589 00:29:37,840 --> 00:29:39,240 DETERMINED THAT YOU ARE REQUIRED 590 00:29:39,240 --> 00:29:42,760 TO CONDUCT THE FOLLOWING 591 00:29:42,760 --> 00:29:42,960 STUDIES: 592 00:29:51,160 --> 00:29:53,200 THAT IS EXACTLY WHAT WE WERE 593 00:29:53,200 --> 00:29:54,880 DOING. 594 00:29:54,880 --> 00:29:56,000 AT THE SAME TIME WE WERE MADE 595 00:29:56,000 --> 00:30:01,160 AWARE THAT THE NIH GUIDELINES 596 00:30:01,160 --> 00:30:04,560 INVOLVING MOLECULES -- HAVE A 597 00:30:04,560 --> 00:30:07,200 SECTION THAT -- EXPERIMENTS THAT 598 00:30:07,200 --> 00:30:10,720 REQUIRE APPROVAL. 599 00:30:10,720 --> 00:30:12,840 AND I WON'T GO THROUGH THE WHOLE 600 00:30:12,840 --> 00:30:14,280 THING BUT SOMETHING THAT 601 00:30:14,280 --> 00:30:16,920 DESCRIBED AS A MAJOR ACTION THAT 602 00:30:16,920 --> 00:30:19,560 CANNOT BE INITIATED WITHOUT -- 603 00:30:19,560 --> 00:30:21,960 THESE WERE THE THINGS -- IN LATE 604 00:30:21,960 --> 00:30:23,840 OCTOBER THAT WE PAUSED OUR WORK 605 00:30:23,840 --> 00:30:27,600 AND WE LOOKED AT THIS AND IT 606 00:30:27,600 --> 00:30:30,440 SAYS SUBMIT RELEVANT 607 00:30:30,440 --> 00:30:30,880 INFORMATION. 608 00:30:30,880 --> 00:30:36,080 THE PUBLICATION -- THE 609 00:30:36,080 --> 00:30:37,640 INFORMATION -- TO DO THE 610 00:30:37,640 --> 00:30:40,280 EXPERIMENTS IN THE FEDERAL 611 00:30:40,280 --> 00:30:42,880 REGISTER FOR 15 DAYS OF COMMENT 612 00:30:42,880 --> 00:30:47,520 AND SPECIFIC APPROVAL BY THE NIH 613 00:30:47,520 --> 00:30:50,600 -- SO ALTHOUGH THIS IS NOT THE 614 00:30:50,600 --> 00:30:53,080 ONLY LANGUAGE -- THIS IS SOME OF 615 00:30:53,080 --> 00:31:02,160 THE LANGUAGE. 616 00:31:02,160 --> 00:31:03,760 SO THIS IS WHERE WE WERE AT THE 617 00:31:03,760 --> 00:31:04,320 TIME. 618 00:31:04,320 --> 00:31:06,880 SO WHAT DID WE DO? 619 00:31:06,880 --> 00:31:08,720 WELL WE THOUGHT ABOUT THIS A LOT 620 00:31:08,720 --> 00:31:10,080 AND WE DETERMINED THAT WE NEEDED 621 00:31:10,080 --> 00:31:12,560 TO KEEP MOVING FORWARD WHILE WE 622 00:31:12,560 --> 00:31:14,560 TRY TO CONSIDER THIS IN THE 623 00:31:14,560 --> 00:31:16,880 CONTEXT OF A GREAT COMPLEXITIES 624 00:31:16,880 --> 00:31:18,680 OF THE PANDEMIC WHICH CONTINUE. 625 00:31:18,680 --> 00:31:21,120 SO HOW DID WE PURSUE OUR WORK? 626 00:31:21,120 --> 00:31:23,640 WE WENT AHEAD AND DID ANALYSIS. 627 00:31:23,640 --> 00:31:25,840 WE COMPLETED ANALYSIS AND 628 00:31:25,840 --> 00:31:28,000 COMPLETED PASSAGE VIRUSES. 629 00:31:28,000 --> 00:31:31,160 WE COMPLETED ALL OF OUR 630 00:31:31,160 --> 00:31:39,280 SEQUENCING AND HAD OBTAINED OUR 631 00:31:39,280 --> 00:31:50,560 PHENOTYPIC -- -- AND WE CHOSE TO 632 00:31:50,560 --> 00:31:56,320 MOVE TO REVERSE GENETICS. 633 00:31:56,320 --> 00:32:00,400 AND WE CAN DISCUSS ABOUT WHETHER 634 00:32:00,400 --> 00:32:01,960 THAT IS AN APPROPRIATE WAY TO 635 00:32:01,960 --> 00:32:03,600 LOOK AT THIS OR NOT. 636 00:32:03,600 --> 00:32:07,440 BUT THAT IS WHAT WE DID AND THEN 637 00:32:07,440 --> 00:32:09,120 BIOCHEMISTRY IN COLLABORATION 638 00:32:09,120 --> 00:32:10,760 AND STRUCTURAL MODELING. 639 00:32:10,760 --> 00:32:13,120 IT HAS HAD GOOD OUTCOMES BUT IT 640 00:32:13,120 --> 00:32:15,680 LED TO WHAT WOULD BE A TWO OR 641 00:32:15,680 --> 00:32:19,840 THREE MONTH PROCESS INTO A YEAR 642 00:32:19,840 --> 00:32:21,720 -- EXTRA TIME THAT WAS REQUIRED 643 00:32:21,720 --> 00:32:22,680 TO COMPLETE THIS WORK. 644 00:32:22,680 --> 00:32:24,360 HOW DID WE APPROACH THIS? 645 00:32:24,360 --> 00:32:25,560 BACK TO THE SCIENCE. 646 00:32:25,560 --> 00:32:31,840 THE PASSAGE OF SARS-CoV-2 -- 647 00:32:31,840 --> 00:32:35,880 THIS IS THE RDV ACTIVE 648 00:32:35,880 --> 00:32:40,400 METABOLITE. 649 00:32:40,400 --> 00:32:45,680 WITH OUR MODEL WE CHOSE TO DO 650 00:32:45,680 --> 00:32:47,320 THREE LINEAGES. 651 00:32:47,320 --> 00:32:49,400 AND THE DRUG CONCENTRATION 652 00:32:49,400 --> 00:32:54,040 THAT'S WERE APPLIED. 653 00:32:54,040 --> 00:32:55,920 SO PLAYING ALONG WITH THE VIRUS 654 00:32:55,920 --> 00:32:58,120 TRYING TO GET THE DRUG HIGH 655 00:32:58,120 --> 00:33:00,680 ENOUGH TRYING NOT TO KILL IT 656 00:33:00,680 --> 00:33:04,880 COMPLETELY. 657 00:33:04,880 --> 00:33:07,960 AND SO YOU KEEP APPLYING DRUG 658 00:33:07,960 --> 00:33:13,440 AND YOU KEEP CODDLING IT ALONG. 659 00:33:13,440 --> 00:33:14,880 AND THAT IS WHAT WE DID. 660 00:33:14,880 --> 00:33:19,280 SO WE WERE ABLE TO SELECT 661 00:33:19,280 --> 00:33:21,120 RESISTANCE AND THEN AND 662 00:33:21,120 --> 00:33:26,600 DEMONSTRATED -- BY POTENCY AND 663 00:33:26,600 --> 00:33:28,480 EFFICACY. 664 00:33:28,480 --> 00:33:32,240 THE THREE ON THE BOTTOM ARE -- 665 00:33:32,240 --> 00:33:36,520 THREE PARALLEL PASSAGES IN DMSO 666 00:33:36,520 --> 00:33:38,880 WHICH IS THE CARRIER. 667 00:33:38,880 --> 00:33:40,840 THIS SHOWS SIGNIFICANT 668 00:33:40,840 --> 00:33:42,880 INHIBITION. 669 00:33:42,880 --> 00:33:46,240 ALL THREE OF THEM CLOSELY 670 00:33:46,240 --> 00:33:51,880 PARALLEL LINES. 671 00:33:51,880 --> 00:33:54,640 ALL THREE LINEAGES SHOW 672 00:33:54,640 --> 00:34:00,800 SIGNIFICANT LINK TO RESISTANCE. 673 00:34:00,800 --> 00:34:04,240 ONE OF THEM SHOWING SIGNIFICANT 674 00:34:04,240 --> 00:34:06,920 REDUCTION. 675 00:34:06,920 --> 00:34:10,240 SO WHEN WE USED THESE POINT TO 676 00:34:10,240 --> 00:34:11,440 CALCULATE ON THE RIGHT AND SHOWN 677 00:34:11,440 --> 00:34:13,920 IN THE SHADED BLUE YOU CAN SEE 678 00:34:13,920 --> 00:34:16,680 WHAT WE SAW WAS THAT ALL OF THE 679 00:34:16,680 --> 00:34:19,400 PASSAGES HAD SIMILAR CURVES AND 680 00:34:19,400 --> 00:34:20,280 VERY LITTLE CHANGE. 681 00:34:20,280 --> 00:34:26,760 THERE WAS NO CHANGE IN THE 682 00:34:26,760 --> 00:34:39,200 CONCENTRATION. 683 00:34:39,200 --> 00:34:40,840 SO THEN WE WANTED TO KNOW WHAT 684 00:34:40,840 --> 00:34:46,040 IS GOING ON IN THESE LINEAGES? 685 00:34:46,040 --> 00:34:48,000 AND WHAT WE SAW WAS SOMETHING 686 00:34:48,000 --> 00:34:54,160 THAT WAS VERY DIFFERENT. 687 00:34:54,160 --> 00:34:56,160 DIFFERENT PATTERNS AND THERE 688 00:34:56,160 --> 00:34:59,400 WERE THREE DIFFERENCES IN THREE 689 00:34:59,400 --> 00:35:03,440 LINEAGES. 690 00:35:03,440 --> 00:35:06,960 BY THE TIME WE PASSAGE THESE -- 691 00:35:06,960 --> 00:35:10,080 THIS IS PASSAGE 13 WE IDENTIFIED 692 00:35:10,080 --> 00:35:14,080 THAT THERE WERE MUTATIONS OCCUR 693 00:35:14,080 --> 00:35:17,040 OCCURRING -- AND RANGING FROM 694 00:35:17,040 --> 00:35:20,080 38% TO GREATER THAN 99%. 695 00:35:20,080 --> 00:35:21,760 FREQUENCY IN THE POPULATION. 696 00:35:21,760 --> 00:35:24,000 AND PARTICULARLY YOU CAN SEE -- 697 00:35:24,000 --> 00:35:25,320 I WON'T DESCRIBE WHAT THEY ARE 698 00:35:25,320 --> 00:35:27,000 NOW BECAUSE I'M GOING TO GO 699 00:35:27,000 --> 00:35:30,000 THROUGH THEM IN MORE DETAIL. 700 00:35:30,000 --> 00:35:35,640 BUT WE WANTED TO -- SAY WHAT WAS 701 00:35:35,640 --> 00:35:37,760 THE EVOLUTION OF THESE MUTATIONS 702 00:35:37,760 --> 00:35:40,320 AND HOW DID THEY OCCUR? 703 00:35:40,320 --> 00:35:42,200 WE DID THIS IN PART BECAUSE WE 704 00:35:42,200 --> 00:35:44,960 WERE FORCED TO DO THE MORE 705 00:35:44,960 --> 00:35:48,960 DETAILED ANALYSIS OF FORWARD 706 00:35:48,960 --> 00:35:50,920 GENETIC STUDIES, THE LIMITATIONS 707 00:35:50,920 --> 00:35:53,280 THAT WERE PLACED ON US AT THE 708 00:35:53,280 --> 00:35:55,480 TIME WITH THE EUA AND THE 709 00:35:55,480 --> 00:35:57,440 APPROVAL OF THE DRUG BUT IT LED 710 00:35:57,440 --> 00:35:59,600 TO SOME REAL INTERESTING 711 00:35:59,600 --> 00:36:01,520 UNDERSTANDING AND OBSERVATIONS. 712 00:36:01,520 --> 00:36:02,920 AND I WANT TO GO THROUGH A 713 00:36:02,920 --> 00:36:06,000 COUPLE OF THESE. 714 00:36:06,000 --> 00:36:15,080 LINEAGE 1 -- THEREOF WAS ONE 715 00:36:15,080 --> 00:36:19,840 LINEAGE 1 THERE WAS ONE 716 00:36:19,840 --> 00:36:21,200 SUBSTITUTION AND THAT STAYED AND 717 00:36:21,200 --> 00:36:22,880 THEN YOU SAW THE GRADUAL 718 00:36:22,880 --> 00:36:28,920 INCREASE IN THE OTHER MUTATIONS. 719 00:36:28,920 --> 00:36:31,280 AND THIS OTHER MUTATION WHICH 720 00:36:31,280 --> 00:36:34,240 WAS NOT PRESENT AT ALL CAME UP 721 00:36:34,240 --> 00:36:35,120 LATE. 722 00:36:35,120 --> 00:36:39,640 WHICH IS INTERESTING. 723 00:36:39,640 --> 00:36:42,840 LINEAGE 2 WAS -- ONLY A SINGLE 724 00:36:42,840 --> 00:36:45,120 MUTATION THAT CAME UP AND IT 725 00:36:45,120 --> 00:36:49,680 CAME TO DOMINANCE AT 799 BUT THE 726 00:36:49,680 --> 00:36:51,240 ONE THAT WAS THE MOST 727 00:36:51,240 --> 00:36:52,680 INTERESTING WAS THIS ONE. 728 00:36:52,680 --> 00:36:55,520 WE'RE FOLLOWING A MUTATION THAT 729 00:36:55,520 --> 00:37:03,240 BYPASS AGE 13 WAS AT 100%. 730 00:37:03,240 --> 00:37:07,120 759 AND 792. 731 00:37:07,120 --> 00:37:09,240 AND THAT THESE MUTATIONS AROSE 732 00:37:09,240 --> 00:37:11,480 AND CAME TO DOMINATE THE 733 00:37:11,480 --> 00:37:13,640 POPULATION AND THIS HAD A 734 00:37:13,640 --> 00:37:14,760 PATTERN WHICH SUGGESTED THAT YOU 735 00:37:14,760 --> 00:37:17,520 HAD ONE THAT AROSE FIRST 736 00:37:17,520 --> 00:37:19,080 FOLLOWED BY ANOTHER ONE THAT 737 00:37:19,080 --> 00:37:20,280 AROSE LATER. 738 00:37:20,280 --> 00:37:26,000 WE DID DIRECT RNA SEEK WITH 739 00:37:26,000 --> 00:37:31,160 NANOPORE SEQUENCING. 740 00:37:31,160 --> 00:37:34,040 WE CHOSE TO LOOK AT LINEAGES 1 741 00:37:34,040 --> 00:37:36,680 AND 3. 742 00:37:36,680 --> 00:37:39,080 IT HAD BETTER RESISTANCE 743 00:37:39,080 --> 00:37:41,520 PHENOTYPE AND THEY GAVE US 744 00:37:41,520 --> 00:37:44,800 EVOLUTIONARY PATTERNS. 745 00:37:44,800 --> 00:37:46,040 SO THIS IS JUST SHOWING IF YOU 746 00:37:46,040 --> 00:37:49,320 LOOK AT LINEAGE 1 IT'S EASY TO 747 00:37:49,320 --> 00:37:50,880 SHOW IT THIS WAY. 748 00:37:50,880 --> 00:37:54,400 FROM PASSAGE 6 TO PASSAGE 13. 749 00:37:54,400 --> 00:37:57,240 AND WHAT WE SAW WAS THIS ONE 750 00:37:57,240 --> 00:37:59,360 THAT CAME UP AT HIGH 751 00:37:59,360 --> 00:38:03,280 CONCENTRATION AND IN COMBINATION 752 00:38:03,280 --> 00:38:05,080 WE WERE ABLE TO TRACK. 753 00:38:05,080 --> 00:38:07,920 IF YOU LOOK AT THOSE THAT OH 754 00:38:07,920 --> 00:38:10,800 OCCURRED IN GENOMES YOU SEE THE 755 00:38:10,800 --> 00:38:12,480 TRACKING FOLLOWED BY ULTIMATELY 756 00:38:12,480 --> 00:38:18,080 THE STABILITY OF IT WITH THIS 757 00:38:18,080 --> 00:38:19,400 S759 MUTATION. 758 00:38:19,400 --> 00:38:25,240 IN LINEAGE 3 WE WENT FROM THIS 759 00:38:25,240 --> 00:38:27,280 DOWN TO A DOMINANT COMBINES OF 760 00:38:27,280 --> 00:38:29,680 THE TWO THAT WERE CO-OCCURRING. 761 00:38:29,680 --> 00:38:31,880 WE CHOSE TO STUDY THIS IN MORE 762 00:38:31,880 --> 00:38:33,880 DETAIL BECAUSE IT GAVE US A 763 00:38:33,880 --> 00:38:37,000 CLEAN GENOTYPE. 764 00:38:37,000 --> 00:38:39,760 WE WENT BACK AND LOOKED AT -- SO 765 00:38:39,760 --> 00:38:41,960 WE SAW THESE IN THE POPULATION. 766 00:38:41,960 --> 00:38:45,440 SINCE WE'RE DOING FORWARD 767 00:38:45,440 --> 00:38:48,920 GENETICS CAN WE ISOLATE VIRUSES 768 00:38:48,920 --> 00:38:50,600 AND LOOK AT THEM. 769 00:38:50,600 --> 00:38:52,720 AND WE HAD MULTIPLE ONES THAT WE 770 00:38:52,720 --> 00:38:54,840 DID. 771 00:38:54,840 --> 00:38:57,040 BUT THE PATTERNS WE SAW WERE 772 00:38:57,040 --> 00:39:00,040 EITHER THE 792 BY ITSELF OR THE 773 00:39:00,040 --> 00:39:01,840 COMBINES OF THE TWO SO THIS WAS 774 00:39:01,840 --> 00:39:03,680 THE REMAINDER OF THE WORK THAT 775 00:39:03,680 --> 00:39:08,480 WE DID. 776 00:39:08,480 --> 00:39:12,680 JASON PERRY AT GILEAD HAD DID 777 00:39:12,680 --> 00:39:14,400 SOME NICE MODELING FOR US. 778 00:39:14,400 --> 00:39:16,920 AND THEN LOOKING AT THE LOCATION 779 00:39:16,920 --> 00:39:19,120 OF THESE PARTICULAR MUTATIONS 780 00:39:19,120 --> 00:39:20,880 AND THIS IS SHOWING ALL OF THEM. 781 00:39:20,880 --> 00:39:23,080 I WANT TO MAKE A COUPLE OF 782 00:39:23,080 --> 00:39:25,680 IMPORTANT POINTS AND THAT IS THE 783 00:39:25,680 --> 00:39:29,760 LOCATION OF THE S759 AND THE 784 00:39:29,760 --> 00:39:30,160 792. 785 00:39:30,160 --> 00:39:33,000 THIS IS SHOWN IN THE -- OVER 786 00:39:33,000 --> 00:39:34,080 HERE. 787 00:39:34,080 --> 00:39:42,080 THIS IS THE CATALYTIC CLEFT OF 788 00:39:42,080 --> 00:39:47,960 THE POLYEERASE AND THEN THE 789 00:39:47,960 --> 00:39:50,720 COVID MOLECULE -- THIS IS 790 00:39:50,720 --> 00:39:53,840 SHOWING THE LOCATION OF 759. 791 00:39:53,840 --> 00:39:56,520 THIS IS UNIQUE AND VERY EXCITING 792 00:39:56,520 --> 00:40:00,400 IS BECAUSE IT OCCURS -- IN THE 793 00:40:00,400 --> 00:40:14,400 CATALYTIC TRIAL. 794 00:40:14,400 --> 00:40:18,080 IT WAS SURPRISING AND REALLY 795 00:40:18,080 --> 00:40:20,960 GAVE US FOCUS. 796 00:40:20,960 --> 00:40:24,360 IT DID NOT PREDICT ANY REAL 797 00:40:24,360 --> 00:40:27,000 INTERACTIONS ASSOCIATED. 798 00:40:27,000 --> 00:40:29,320 WHEN JASON WENT ON TO LOOK AT 799 00:40:29,320 --> 00:40:31,520 THE PREDICTIONS OF HOW THESE 800 00:40:31,520 --> 00:40:34,680 MIGHT INTERACT WITH REMDESIVIR 801 00:40:34,680 --> 00:40:38,320 IT DID SUGGEST OR PREDICT THAT 802 00:40:38,320 --> 00:40:40,120 S759 IN THE ACTIVE CORE MIGHT 803 00:40:40,120 --> 00:40:42,920 HAVE A DIFFERENT INTERACTION 804 00:40:42,920 --> 00:40:44,360 THAT MIGHT BE LOST. 805 00:40:44,360 --> 00:40:47,480 SO THIS WAS A REDUCTION BUT IT 806 00:40:47,480 --> 00:40:50,000 NEVERTHELESS GAVE US THE 807 00:40:50,000 --> 00:40:50,800 ENTHUSIASM. 808 00:40:50,800 --> 00:40:52,400 SO WHAT DID WE DO? 809 00:40:52,400 --> 00:40:58,880 WE TOOK THE LINEAGES AND THE -- 810 00:40:58,880 --> 00:41:00,800 PLAQUE ISOLATES. 811 00:41:00,800 --> 00:41:02,960 THESE WERE IN THE BACKGROUND OF 812 00:41:02,960 --> 00:41:04,080 POPULATION VIRUSES. 813 00:41:04,080 --> 00:41:06,560 SO WE HAD TO COMPARE THOSE. 814 00:41:06,560 --> 00:41:09,880 WHAT WE SAW WAS -- IF WE LOOKED 815 00:41:09,880 --> 00:41:18,000 AT THE DSMO -- WHEN WE TOOK THE 816 00:41:18,000 --> 00:41:21,280 792 ALONE WE SAW AN INTERMEDIATE 817 00:41:21,280 --> 00:41:21,840 PHENOTYPE. 818 00:41:21,840 --> 00:41:25,200 WHEN WE LOOKED AT EITHER THE 819 00:41:25,200 --> 00:41:33,360 COMBINES OF 759 PLUS 792 WE 820 00:41:33,360 --> 00:41:46,080 CAPITULATES THE LINEAGE. 821 00:41:46,080 --> 00:41:48,080 SO COULD NOT PROVE IT BECAUSE WE 822 00:41:48,080 --> 00:41:50,720 DID NOT ISOLATE IT. 823 00:41:50,720 --> 00:41:53,120 AND WHEN WE TOOK THAT SAME DATA 824 00:41:53,120 --> 00:41:57,160 AND CONVERTED IT -- -- WE SAW 825 00:41:57,160 --> 00:41:58,400 SIGNIFICANT DIFFERENCES 826 00:41:58,400 --> 00:42:02,760 ASSOCIATED WITH THOSE ISOLATED 827 00:42:02,760 --> 00:42:07,080 VIRUSES WITH A SHIFT OF 2.6X 828 00:42:07,080 --> 00:42:09,440 INCREASE COMPARED TO WILD TYPE 829 00:42:09,440 --> 00:42:11,280 UP TO 8X. 830 00:42:11,280 --> 00:42:14,480 WITH THE LINEAGE AND THE SIMILAR 831 00:42:14,480 --> 00:42:18,320 ALMOST IDENTICAL CURVES BUT THE 832 00:42:18,320 --> 00:42:21,160 VALUE IS ALMOST IDENTICAL WITH 833 00:42:21,160 --> 00:42:29,720 THE TWO MUTATIONS. 834 00:42:29,720 --> 00:42:31,480 SO AGAIN REMEMBER WE FELT WE 835 00:42:31,480 --> 00:42:33,920 WERE NOT IN A POSITION TO DO 836 00:42:33,920 --> 00:42:36,560 REVERSE GENETICS WITH 837 00:42:36,560 --> 00:42:38,320 SARS-CoV-2 BASED ON THE DATA 838 00:42:38,320 --> 00:42:40,200 THAT I PRESENTED AT THE TIME SO 839 00:42:40,200 --> 00:42:43,400 WE MOVED TO DO THIS IN ANOTHER 840 00:42:43,400 --> 00:42:49,040 BETA CORONAVIRUS -- AND MOUSE 841 00:42:49,040 --> 00:42:52,000 HEPATITIS VIRUS. 842 00:42:52,000 --> 00:43:00,320 IT'S ABOUT 75% 85%. 843 00:43:00,320 --> 00:43:03,040 POLYMER AS. 844 00:43:08,680 --> 00:43:13,040 WHAT WE SAW WAS A SIGNIFICANT 845 00:43:13,040 --> 00:43:14,880 CONS FIR MAKINGS. 846 00:43:14,880 --> 00:43:16,560 -- CONFIRMATION. 847 00:43:16,560 --> 00:43:21,600 *. 848 00:43:21,600 --> 00:43:25,480 WHAT WE SAW WAS ICE GENETIC WILD 849 00:43:25,480 --> 00:43:30,000 TYPE -- WITH SIGNIFICANT 850 00:43:30,000 --> 00:43:31,080 INHIBITION. 851 00:43:31,080 --> 00:43:34,240 -- AND INTERMEDIARY PHENOTYPE 852 00:43:34,240 --> 00:43:37,600 WITH THE ACTIVE RESIDUE AND THEN 853 00:43:37,600 --> 00:43:39,280 ALMOST COMPLETE RESISTANCE 854 00:43:39,280 --> 00:43:40,600 PHENOTYPE. 855 00:43:40,600 --> 00:43:43,200 SO THIS TO US PROVIDED 856 00:43:43,200 --> 00:43:44,920 SIGNIFICANT CONFIRMATION. 857 00:43:44,920 --> 00:43:48,080 ONE, THAT THE MUTATIONS COULD 858 00:43:48,080 --> 00:43:49,800 REMEDIATE RESISTANCE BY 859 00:43:49,800 --> 00:43:52,440 THEMSELVES AND TWO, THIS IS 860 00:43:52,440 --> 00:43:54,880 TRANSFERABLE BROADLY ACROSS 861 00:43:54,880 --> 00:43:57,680 DIFFERENT -- GROUPS OF 862 00:43:57,680 --> 00:43:58,280 CORONAVIRUSs. 863 00:43:58,280 --> 00:44:01,200 SO THIS WAS AN IMPORTANT 864 00:44:01,200 --> 00:44:02,160 OBSERVATION FOR US. 865 00:44:02,160 --> 00:44:04,480 AND WHEN WE LOOKED AT THAT THAT 866 00:44:04,480 --> 00:44:18,960 ALSO WA -- RECAPITULATES. 867 00:44:18,960 --> 00:44:21,200 SO THE DATA WE HAD SEEN IN TERMS 868 00:44:21,200 --> 00:44:24,040 OF THE CO-EVOLUTION AND THE 869 00:44:24,040 --> 00:44:27,920 SEPARATE ADDITION OF THE 7th 870 00:44:27,920 --> 00:44:30,200 MUTATION -- THIS REALLY SUPPORTS 871 00:44:30,200 --> 00:44:33,080 HOW THAT EVOLUTION AND WHY THAT 872 00:44:33,080 --> 00:44:35,680 EVOLUTION MIGHT HAVE OCCURRED. 873 00:44:35,680 --> 00:44:37,520 SO NEXT QUESTION WAS ABOUT WHAT 874 00:44:37,520 --> 00:44:40,760 WAS THE IMPACT ON VIRUS 875 00:44:40,760 --> 00:44:42,880 REPLICATION AND FITNESS OF THE 876 00:44:42,880 --> 00:44:43,400 VIRUS. 877 00:44:43,400 --> 00:44:46,080 WE DEFINE IT AS COMPETITIVELY 878 00:44:46,080 --> 00:44:48,600 BUT WE WERE NOT YET IN THE 879 00:44:48,600 --> 00:44:50,680 POSITION OF DOING COMPETITIVE 880 00:44:50,680 --> 00:44:52,800 EXPERIMENT. 881 00:44:52,800 --> 00:45:03,960 -- COMPARING REGULAR REPLICATION 882 00:45:03,960 --> 00:45:04,280 REPLICATION. 883 00:45:04,280 --> 00:45:07,800 THOSE MAY BE REAL AND WE'LL KNOW 884 00:45:07,800 --> 00:45:10,520 THAT BY DOING COMPUTATION. 885 00:45:10,520 --> 00:45:12,640 BUT REMEMBER THESE WERE ALL FROM 886 00:45:12,640 --> 00:45:16,720 GROWTH ADAPTATION. 887 00:45:16,720 --> 00:45:19,120 SO THERE IS A LOT OF GROWTH 888 00:45:19,120 --> 00:45:21,000 ADAPTATION THAT MAY GO ON TO 889 00:45:21,000 --> 00:45:22,760 CHANGE THAT BUT WHEN WE ISOLATED 890 00:45:22,760 --> 00:45:25,000 IT AND LOOKED AT THEM WE SAW A 891 00:45:25,000 --> 00:45:26,480 DIFFERENT STORY. 892 00:45:26,480 --> 00:45:30,480 WILD TYPE -- THESE HAD AN 893 00:45:30,480 --> 00:45:32,120 IMMEDIATE DEFECT WITH 894 00:45:32,120 --> 00:45:35,800 SIGNIFICANT DELAY. 895 00:45:35,800 --> 00:45:37,880 WHEREAS IN THE DOUBLE MUTANT HAD 896 00:45:37,880 --> 00:45:40,480 A SIGNIFICANT ALTERATIONS AND 897 00:45:40,480 --> 00:45:42,840 DELAY IN ITS REPLICATION 898 00:45:42,840 --> 00:45:44,680 SUGGESTING A FITNESS COST THAT 899 00:45:44,680 --> 00:45:45,760 WAS ASSOCIATED WITH THE 900 00:45:45,760 --> 00:45:49,160 INDEPENDENT MUTATIONS WHICH WAS 901 00:45:49,160 --> 00:45:51,040 ENCOURAGING. 902 00:45:51,040 --> 00:45:55,000 SO NEXT WE WANTED TO LOOK AT THE 903 00:45:55,000 --> 00:45:58,160 BIOCHEMISTRY AND THIS WAS A 904 00:45:58,160 --> 00:46:02,800 BEAUTIFUL WORK DONE IN THE LAB. 905 00:46:02,800 --> 00:46:04,800 I WANT TO SUMMARIZE. 906 00:46:04,800 --> 00:46:08,280 THIS IS IMPORTANT AND IT IS 907 00:46:08,280 --> 00:46:10,280 AVAILABLE TO THOSE WHO WANT TO 908 00:46:10,280 --> 00:46:12,920 REVIEW IT. 909 00:46:12,920 --> 00:46:19,360 LOOKING AT S759A AND 792A IN THE 910 00:46:19,360 --> 00:46:26,480 COMPLEX. 911 00:46:26,480 --> 00:46:29,480 WILD TYPE VIRUS FAVORED 912 00:46:29,480 --> 00:46:30,920 INCORPORATION OF REMDESIVIR. 913 00:46:30,920 --> 00:46:39,160 YOU SUE TH ---IN CONTRACT YOU SAW THE 914 00:46:39,160 --> 00:46:40,720 SIGNIFICANT SHIFT TO THE OTHER 915 00:46:40,720 --> 00:46:44,040 SIDE WHERE NOW ATP IS FAVORED 916 00:46:44,040 --> 00:46:46,280 OVER REMDESIVIR. 917 00:46:46,280 --> 00:46:50,080 AND S792A HAD NO DIFFERENCE. 918 00:46:50,080 --> 00:46:52,080 THIS WAS EXCITING TO SEE. 919 00:46:52,080 --> 00:46:54,680 IT WAS VERY ENCOURAGING AND 920 00:46:54,680 --> 00:46:56,200 SUPPORTING OF THE RESULTS THAT 921 00:46:56,200 --> 00:46:57,760 WE HAD SEEN THAT WE WERE SEEING 922 00:46:57,760 --> 00:46:59,920 THE SIGNIFICANT DIFFERENCE WITH 923 00:46:59,920 --> 00:47:01,520 759 ALONE AND THEN WITH THE 924 00:47:01,520 --> 00:47:04,640 COMBINES. 925 00:47:04,640 --> 00:47:07,000 -- COMBINATION. 926 00:47:07,000 --> 00:47:09,760 WHEN WE LOOKED -- THE BASIC 927 00:47:09,760 --> 00:47:12,120 THING IS THAT WHEN YOU LOOKED AT 928 00:47:12,120 --> 00:47:14,800 WILD TYPE THIS IS SHOWING THE 929 00:47:14,800 --> 00:47:18,680 SAME DATA IS THAT THIS IS ATP 930 00:47:18,680 --> 00:47:20,880 INCORPORATION VERSUS REMDESIVIR 931 00:47:20,880 --> 00:47:22,400 INCORPORATION SO THE EFFICIENCY 932 00:47:22,400 --> 00:47:24,840 WAS SIGNIFICANTLY HIGHER. 933 00:47:24,840 --> 00:47:26,040 TWO AND A HALF FOLD HIGHER. 934 00:47:26,040 --> 00:47:30,920 IN THE SETTINGS OF THE 759 935 00:47:30,920 --> 00:47:33,760 MUTATION IT HAD SIGNIFICANT 936 00:47:33,760 --> 00:47:36,800 DECREASE -- BUT THE DIFFERENTIAL 937 00:47:36,800 --> 00:47:40,200 DIFFERENCE THE DELTA DELTA WAS 938 00:47:40,200 --> 00:47:42,320 THAT IT FAVORED ATP OVER 939 00:47:42,320 --> 00:47:42,880 REMDESIVIR. 940 00:47:42,880 --> 00:47:48,600 AND 792 HAD NO CHANGE. 941 00:47:48,600 --> 00:47:51,560 SURPRISINGLY IT INCREASED ATP 942 00:47:51,560 --> 00:47:53,840 INCORPORATION BUT IT DID NOT 943 00:47:53,840 --> 00:47:55,360 ALTER REMDESIVIR IN CORPORATION. 944 00:47:55,360 --> 00:47:59,280 SO IT WAS A WASH IN THAT REGARD. 945 00:47:59,280 --> 00:48:02,680 SO THIS RESULTED IN NUMBERS AND 946 00:48:02,680 --> 00:48:05,240 -- MANY OF YOU MAY UNDERSTAND 947 00:48:05,240 --> 00:48:06,440 THESE BETTER THAN I DO. 948 00:48:06,440 --> 00:48:09,520 BUT THE ISSUE OF SELECTIVITY 949 00:48:09,520 --> 00:48:14,080 WHICH REPRESENTS THE V MAX OVER 950 00:48:14,080 --> 00:48:16,880 KM DIFFERENCE BETWEEN ATP AND 951 00:48:16,880 --> 00:48:19,200 REMDESIVIR AND IT WAS LIKE FOUR 952 00:48:19,200 --> 00:48:21,960 FOLD INCREASE FOR ATP OR 953 00:48:21,960 --> 00:48:24,080 DECREASE FOR REMDESIVIR AND 954 00:48:24,080 --> 00:48:25,480 DISCRIMINATION IS LOOKING AT 955 00:48:25,480 --> 00:48:27,280 THIS NUMBER COMPARED TO THAT OF 956 00:48:27,280 --> 00:48:28,800 WILD TYPE. 957 00:48:28,800 --> 00:48:30,120 COMPARING THAT WITH WILD TYPE 958 00:48:30,120 --> 00:48:31,880 AND THAT WAS ABOUT 10 TIMES MORE 959 00:48:31,880 --> 00:48:33,440 AND THESE NUMBER WERE ALL 960 00:48:33,440 --> 00:48:35,000 CONSISTENT AND BEAUTIFULLY 961 00:48:35,000 --> 00:48:36,080 RESOLVED. 962 00:48:36,080 --> 00:48:38,080 SUGGESTING THIS REAL SHIFT IN 963 00:48:38,080 --> 00:48:42,800 HOW THIS DRUG WORKS. 964 00:48:42,800 --> 00:48:45,480 SO SINCE 792 DIDN'T DO THIS THE 965 00:48:45,480 --> 00:48:47,160 QUESTION WAS WHAT DID IT DO? 966 00:48:47,160 --> 00:48:49,760 AND THE GROUP HAD SOME IDEA FROM 967 00:48:49,760 --> 00:48:52,480 OTHER WORK THAT THERE MAY BE 968 00:48:52,480 --> 00:48:55,760 OTHER MECHANISMS AND ONE WAS HOW 969 00:48:55,760 --> 00:48:59,000 MUCH ATP DOES IT TAKE. 970 00:48:59,000 --> 00:49:01,240 THAT MEANS IS WE NEED TWO 971 00:49:01,240 --> 00:49:02,560 DIFFERENT TEMPLATES. 972 00:49:02,560 --> 00:49:08,360 ONE THAT BASICALLY HAD -- IN THE 973 00:49:08,360 --> 00:49:10,480 RUN OF TEMPLATE THAT WOULD 974 00:49:10,480 --> 00:49:15,680 NORMALLY INCORPORATED -- 975 00:49:15,680 --> 00:49:17,160 REMDESIVIR AND THAT THIS WOULD 976 00:49:17,160 --> 00:49:20,760 REPRESENT A PLACE WHERE YOU 977 00:49:20,760 --> 00:49:24,000 WOULD HAVE POTENTIAL 978 00:49:24,000 --> 00:49:25,280 INCORPORATION AND YOU CAN SEE 979 00:49:25,280 --> 00:49:26,240 HOW THAT WORKS. 980 00:49:26,240 --> 00:49:29,280 IN CONTRAST TO REMDESIVIR IT 981 00:49:29,280 --> 00:49:31,880 INCORPORATED INTO THE STRAND SO 982 00:49:31,880 --> 00:49:35,640 WITH WILD TYPE VIRUS IT DOES 983 00:49:35,640 --> 00:49:39,480 JUST FINE ACROSS THE TEMPLATE A. 984 00:49:39,480 --> 00:49:42,680 WITH UTP AS IT IS SUPPOSED TO 985 00:49:42,680 --> 00:49:44,840 INCORPORATING HERE BUT WITH 986 00:49:44,840 --> 00:49:47,440 TEMPLATE R INCORPORATED IT TAKES 987 00:49:47,440 --> 00:49:53,400 HIGH CONCENTRATIONS TO GET UP TO 988 00:49:53,400 --> 00:49:55,840 -- A HIGHER CONCENTRATION TO 989 00:49:55,840 --> 00:49:57,840 OVERCOME THE INHIBITION. 990 00:49:57,840 --> 00:50:00,840 SO WHEN THEY LOOKED AT THAT WITH 991 00:50:00,840 --> 00:50:03,800 THE 792 MUTANT THEY SAW WITH 992 00:50:03,800 --> 00:50:05,880 WILD TYPE THIS IS ESSENTIALLY 993 00:50:05,880 --> 00:50:10,160 REPRESENTS THE CURVE SEEP OVER 994 00:50:10,160 --> 00:50:13,080 HERE IN READ. 995 00:50:13,080 --> 00:50:17,320 IT DIDN'T -- WAS NOT ABLE TO USE 996 00:50:17,320 --> 00:50:19,120 UTP TO OVERCOME. 997 00:50:19,120 --> 00:50:22,960 IN CONTRAST THE 792 MUTATION WAS 998 00:50:22,960 --> 00:50:26,400 MUCH MORE PROFOUNDLY AT VERY LOW 999 00:50:26,400 --> 00:50:28,280 CONCENTRATIONS OF UTP TO 1000 00:50:28,280 --> 00:50:35,960 OVERCOME. 1001 00:50:35,960 --> 00:50:38,280 SO THESE TWO THINGS TOGETHER 1002 00:50:38,280 --> 00:50:40,360 SUGGESTED THAT THERE ARE TWO 1003 00:50:40,360 --> 00:50:40,800 MECHANISMS. 1004 00:50:40,800 --> 00:50:44,480 ONE BUT IS FAVORING ATP OVER 1005 00:50:44,480 --> 00:50:47,880 REMDESIVIR AND THE OTHER IS 1006 00:50:47,880 --> 00:50:50,280 FAVORING LOW CONCENTRATIONS OF 1007 00:50:50,280 --> 00:50:53,600 ATP TO OVERCOME -- -- ALREADY IN 1008 00:50:53,600 --> 00:50:55,480 THE TEMPLATE. 1009 00:50:55,480 --> 00:50:59,320 THEN NEXT I WANT TO FINISH UP -- 1010 00:50:59,320 --> 00:51:01,960 LOOKED AT THIS OF COURSE. 1011 00:51:01,960 --> 00:51:03,120 WHAT IS HAPPENING IN THE 1012 00:51:03,120 --> 00:51:04,280 POPULATION? 1013 00:51:04,280 --> 00:51:06,400 AT THE TIME WHICH WAS ABOUT A 1014 00:51:06,400 --> 00:51:11,880 MONTH AGO -- WE HAD LOOKED AT 1015 00:51:11,880 --> 00:51:14,280 ABOUT 7 MILLION GENOMES IN THE 1016 00:51:14,280 --> 00:51:16,600 DATABASE AND YOU CAN SEE THE 1017 00:51:16,600 --> 00:51:19,280 MUTATIONS THAT WE'VE IDENTIFIED 1018 00:51:19,280 --> 00:51:21,280 AND SELECTED AND THERE ARE 1019 00:51:21,280 --> 00:51:24,640 PROFOUNDLY LOW CONCENTRATIONS. 1020 00:51:24,640 --> 00:51:27,280 759A WAS SEEN IN ONE. 1021 00:51:27,280 --> 00:51:29,440 SEQUENCE OUT OF 6 OR 7 MILLION. 1022 00:51:29,440 --> 00:51:34,080 AND THERE WERE MANY 759 1023 00:51:34,080 --> 00:51:38,120 SUBSTITUTIONS -- OF ALL OF THESE 1024 00:51:38,120 --> 00:51:42,320 RESIDUES AND THE MOST FREQUENT 1025 00:51:42,320 --> 00:51:47,080 WAS IN 189S. 1026 00:51:47,080 --> 00:51:48,720 REALLY NATURALLY OCCURRING ONES 1027 00:51:48,720 --> 00:51:51,000 ARE VERY FEW. 1028 00:51:51,000 --> 00:51:53,040 WHICH IS ENCOURAGINGS ALSO. 1029 00:51:53,040 --> 00:51:54,880 BUT IT ALSO SUGGEST THAT WE NEED 1030 00:51:54,880 --> 00:51:56,880 TO UNDERSTAND THIS BECAUSE THIS 1031 00:51:56,880 --> 00:52:00,840 IS NATIVE SUBSTITUTIONS. 1032 00:52:00,840 --> 00:52:05,080 THIS IS A REPLICATED PROTEIN. 1033 00:52:05,080 --> 00:52:06,680 HIGH LEVEL OF SELECTION WITH A 1034 00:52:06,680 --> 00:52:08,680 HIGHLY EFFECTIVE DRUG LEADS TO 1035 00:52:08,680 --> 00:52:18,680 HIGH GENETIC BOTTLENECK THERE -- 1036 00:52:18,680 --> 00:52:22,000 THAT ARE THERE. 1037 00:52:22,000 --> 00:52:25,080 759 WAS PRESENT IN THE VIRUS 1038 00:52:25,080 --> 00:52:29,560 STOCK THAT WE HAD WHICH WAS A P3 1039 00:52:29,560 --> 00:52:32,400 STOCK. 1040 00:52:32,400 --> 00:52:33,000 .046%. 1041 00:52:33,000 --> 00:52:36,640 SO WAS THAT A PASSAGE ADAPTATION 1042 00:52:36,640 --> 00:52:38,080 FROM THEM OR SOMETHING THAT 1043 00:52:38,080 --> 00:52:40,040 ACTUALLY DID COME FROM THE 1044 00:52:40,040 --> 00:52:42,240 ORIGINAL STRAIN? 1045 00:52:42,240 --> 00:52:43,640 SO IT WAS PRESENT. 1046 00:52:43,640 --> 00:52:45,920 AND IT DID POTENTIALLY HAVE THAT 1047 00:52:45,920 --> 00:52:46,360 ADVANTAGE. 1048 00:52:46,360 --> 00:52:49,400 WE DID NOT SELECT IT OR FURTHER 1049 00:52:49,400 --> 00:52:51,240 PASSAGE THE VIRUS TO GET THAT. 1050 00:52:51,240 --> 00:52:53,080 SO I DON'T KNOW WHAT THIS MEANS 1051 00:52:53,080 --> 00:52:55,000 BUT WE HAVE A LOT TO LOOK AT. 1052 00:52:55,000 --> 00:52:59,640 TO SUMMARIZE -- PASSAGE OF 1053 00:52:59,640 --> 00:53:02,720 SARS-CoV-2 IS IN MULTIPLE 1054 00:53:02,720 --> 00:53:09,040 POTENTIAL GENETIC PATHWAYS TO 1055 00:53:09,040 --> 00:53:13,320 RDV RESISTANCE WITH HIGH GENETIC 1056 00:53:13,320 --> 00:53:16,120 BARRIER. 1057 00:53:16,120 --> 00:53:22,080 MUTATIONS AT 759 -- -- 1058 00:53:40,000 --> 00:53:42,200 THIS WAS BOTH INTERESTING AND 1059 00:53:42,200 --> 00:53:46,520 NOT SURPRISINGS BUT THE CURRENT 1060 00:53:46,520 --> 00:53:50,080 VIRUSES CAN DO THIS. 1061 00:54:08,480 --> 00:54:11,440 SO I THINK THIS IS THE SORT OF 1062 00:54:11,440 --> 00:54:13,280 BROAD VIEW WE WANT TO HAVE OF 1063 00:54:13,280 --> 00:54:15,160 THIS KIND OF RESISTANCE STUFF. 1064 00:54:15,160 --> 00:54:17,400 THE QUESTION IS WHAT TO WE DO 1065 00:54:17,400 --> 00:54:17,920 NOW? 1066 00:54:17,920 --> 00:54:21,360 WHAT IS OUR IDEAL TO-DO LIST? 1067 00:54:21,360 --> 00:54:28,240 TO DO DIRECT CO-IN FIBS 1068 00:54:28,240 --> 00:54:34,040 COMPETITION FITNESS AND. 1069 00:54:34,040 --> 00:54:36,480 AND OF COURSE SO THEN TESTING 1070 00:54:36,480 --> 00:54:43,080 CROSS RESISTANCE -- 1071 00:55:02,280 --> 00:55:04,360 HOW DO WE GO ABOUT THAT AND 1072 00:55:04,360 --> 00:55:09,760 WHERE DO WE GO FROM HERE? 1073 00:55:09,760 --> 00:55:15,240 EUA AND NDA, WE'RE AT THE 1074 00:55:15,240 --> 00:55:17,480 BARRIER AND SO WHERE DO WE GO? 1075 00:55:17,480 --> 00:55:19,320 SO I HAVE BEEN THINKING ABOUT 1076 00:55:19,320 --> 00:55:21,280 THIS A LOT. 1077 00:55:21,280 --> 00:55:24,080 AND I THINK THAT THIS IS 1078 00:55:24,080 --> 00:55:32,160 SOMETHING THAT WHEN I -- MENTION 1079 00:55:32,160 --> 00:55:34,480 THIS WE HAVE WHAT APPEAR TO BE 1080 00:55:34,480 --> 00:55:44,200 DIFFERENTIAL REQUIREMENTS AND 1081 00:55:44,200 --> 00:55:46,960 ARE VALID PUBLIC HEALTH NEEDS 1082 00:55:46,960 --> 00:55:48,680 WITH PUBLIC HEALTH CONCERNS CAN 1083 00:55:48,680 --> 00:55:51,360 WE DO GENETIC STUDIES. 1084 00:55:51,360 --> 00:55:55,280 IF IT HASN'T BEEN PROVEN TO BE A 1085 00:55:55,280 --> 00:55:57,640 RESISTANCE WE CANNOT TEST IT. 1086 00:55:57,640 --> 00:55:58,720 BECAUSE IT IS NOT PROVEN. 1087 00:55:58,720 --> 00:56:01,600 IF IT'S PROVEN -- BUT WE CANNOT 1088 00:56:01,600 --> 00:56:03,280 PROVE IT UNLESS IT'S BEEN TESTED 1089 00:56:03,280 --> 00:56:05,360 SO, THAT IS THE QUESTION. 1090 00:56:05,360 --> 00:56:28,600 OR DO WE WAIT UNTIL THEY EMERGE. 1091 00:56:28,600 --> 00:56:30,720 SO WITH THAT WITH THOSE TWO 1092 00:56:30,720 --> 00:56:33,120 DIFFERENT ASPECTS I'LL STOP. 1093 00:56:33,120 --> 00:56:35,280 I WANT TO THANK AGAIN ALL OF THE 1094 00:56:35,280 --> 00:56:37,160 PEOPLE THAT DID ALL OF THIS WORK 1095 00:56:37,160 --> 00:56:39,360 OVER THE LAST COUPLE OF YEARS. 1096 00:56:39,360 --> 00:56:43,440 I'M GRATEFUL TO BE PART OF THE 1097 00:56:43,440 --> 00:56:44,720 TEAM. 1098 00:56:44,720 --> 00:56:46,880 I CAN LEAVE MY SLIDES UP OR STOP 1099 00:56:46,880 --> 00:56:48,080 THEM AND HAPPY TO TAKE 1100 00:56:48,080 --> 00:56:48,680 QUESTIONS. 1101 00:56:48,680 --> 00:56:50,280 >> THANK YOU, MARK. 1102 00:56:50,280 --> 00:56:53,080 THIS WAS A WONDERFUL TALK. 1103 00:56:53,080 --> 00:56:54,480 VERY THOUGHT PROVOKING AND WE 1104 00:56:54,480 --> 00:56:55,960 HAVE A LOT OF QUESTIONS. 1105 00:56:55,960 --> 00:57:02,200 SO I'M GOING TO -- GROUP THEM. 1106 00:57:02,200 --> 00:57:04,040 >> I CAN END MY SHARING. 1107 00:57:04,040 --> 00:57:06,440 >> OKAY. 1108 00:57:06,440 --> 00:57:09,640 SO GIVEN WHAT YOU'VE SHOWN TODAY 1109 00:57:09,640 --> 00:57:15,040 -- AND THE LEVEL OF INFECTIOUS 1110 00:57:15,040 --> 00:57:18,240 AROUND THE GLOBE DO YOU FEEL 1111 00:57:18,240 --> 00:57:21,880 THAT GIVING ONE DRUG REMDESIVIR 1112 00:57:21,880 --> 00:57:26,720 IS STILL -- OR SHOULD PHYSICIANS 1113 00:57:26,720 --> 00:57:31,360 GO WITH GIVING A GROUP OF DRUGS 1114 00:57:31,360 --> 00:57:33,440 SO THAT TO MINIMIZE THE 1115 00:57:33,440 --> 00:57:36,480 POTENTIAL FORGETTING RESISTANCE. 1116 00:57:36,480 --> 00:57:39,640 >> THANK YOU FOR THAT QUESTION. 1117 00:57:39,640 --> 00:57:43,840 AS A PHYSICIAN AND A INFECTIOUS 1118 00:57:43,840 --> 00:57:47,280 DISEASE PERSON -- I THINK I SAID 1119 00:57:47,280 --> 00:57:50,560 IT LAST YEAR AT THE NIH 1120 00:57:50,560 --> 00:57:53,560 ANTIVIRAL -- WE SHOULD BE 1121 00:57:53,560 --> 00:57:54,360 DEVELOPING COMBINATIONS. 1122 00:57:54,360 --> 00:57:56,280 THERE ARE SO MANY THINGS I'M NOT 1123 00:57:56,280 --> 00:57:58,800 AN EXPERT IN SO I'M WITH PEOPLE 1124 00:57:58,800 --> 00:58:03,240 WITH THE FDA AND OTHERS I'M 1125 00:58:03,240 --> 00:58:08,160 GOING TO TREAD ON THIN ICE. 1126 00:58:08,160 --> 00:58:11,440 AN EUA DOES NOT ALLOW YOU TO GO 1127 00:58:11,440 --> 00:58:12,160 OFF LABEL. 1128 00:58:12,160 --> 00:58:13,640 SHOULD TRIALS BE DONE AND I 1129 00:58:13,640 --> 00:58:14,840 BELIEVE THEY SHOULD. 1130 00:58:14,840 --> 00:58:20,440 WHEN WE LOOK AT THE EUAs -- 1131 00:58:20,440 --> 00:58:23,520 THERE ARE CONSTRAINING IN MANY 1132 00:58:23,520 --> 00:58:25,840 WAYS AND MANY QUESTIONS ARISE. 1133 00:58:25,840 --> 00:58:28,040 HOW CAN WE USE THESE 1134 00:58:28,040 --> 00:58:29,880 INDIVIDUALLY AND HOW CAN WE FIND 1135 00:58:29,880 --> 00:58:31,560 THEM INDIVIDUALLY AND USE THEM. 1136 00:58:31,560 --> 00:58:33,280 BUT THE ANSWER IS I BELIEVE ONE 1137 00:58:33,280 --> 00:58:35,840 OF THE THINGS THAT HASN'T COME 1138 00:58:35,840 --> 00:58:38,200 UP IS THAT WE SHOULD ONLY BE 1139 00:58:38,200 --> 00:58:42,240 LOOKING AT COMBINATIONS. 1140 00:58:42,240 --> 00:58:44,240 ABSOLUTELY FOR PREVENTION. 1141 00:58:44,240 --> 00:58:49,480 CAN PEOPLE JUST GO AND DO THAT? 1142 00:58:49,480 --> 00:58:50,800 NO. 1143 00:58:50,800 --> 00:58:54,000 THERE WOULD NEED TO BE AN 1144 00:58:54,000 --> 00:58:56,080 ENCOURAGEMENT -- TO WORK ACROSS 1145 00:58:56,080 --> 00:58:57,600 COMPANIES TO TEST THESE THINGS 1146 00:58:57,600 --> 00:59:00,880 TOGETHER BECAUSE I THINK -- ONE 1147 00:59:00,880 --> 00:59:02,760 PLUS ONE EQUALS 4. 1148 00:59:02,760 --> 00:59:06,000 ONE ALONE IS GOING TO EQUAL ZERO 1149 00:59:06,000 --> 00:59:07,680 IF YOU'RE NOT CAREFUL 1150 00:59:07,680 --> 00:59:08,840 >> THERE WAS A QUESTION 1151 00:59:08,840 --> 00:59:15,480 REGARDING LIFE-THERE IS ANY DATA 1152 00:59:15,480 --> 00:59:17,840 ON THE EFFECTIVENESS OF 1153 00:59:17,840 --> 00:59:22,000 REMDESIVIR IN VAXED VERSUS 1154 00:59:22,000 --> 00:59:23,640 UNHAVE BEENED INDIVIDUALS? 1155 00:59:23,640 --> 00:59:25,560 >> I ALWAYS RETREAT BACK TO THE 1156 00:59:25,560 --> 00:59:27,200 LAB. 1157 00:59:27,200 --> 00:59:29,200 WHEN THIS HAPPENS. 1158 00:59:29,200 --> 00:59:31,600 THE DRUG IS GOING TO WORK 1159 00:59:31,600 --> 00:59:34,400 AGAINST ANY VIRUS AND EARLY ON 1160 00:59:34,400 --> 00:59:37,960 IT'S GOING TO -- VIRUS 1161 00:59:37,960 --> 00:59:38,480 REPLICATION. 1162 00:59:38,480 --> 00:59:40,680 WHAT WE DON'T KNOW IF YOU'RE 1163 00:59:40,680 --> 00:59:44,240 ONLY REPLICATED 10 TO THE 5th 1164 00:59:44,240 --> 00:59:46,800 INSTEAD OF 10 TO THE 8th DOES 1165 00:59:46,800 --> 00:59:48,360 IT MATTER. 1166 00:59:48,360 --> 00:59:53,920 IF YOUR DURING RACE I -- DURATION 1167 00:59:53,920 --> 00:59:55,840 IS SHORTER. 1168 00:59:55,840 --> 00:59:57,880 THEY NEED TO BE USED EARLY. 1169 00:59:57,880 --> 01:00:00,600 AND THE LIMITATIONS ON TESTING 1170 01:00:00,600 --> 01:00:02,680 AND DIAGNOSTICS AND DOCTORS 1171 01:00:02,680 --> 01:00:05,080 SAYING YOU'RE NOT SO BAD. 1172 01:00:05,080 --> 01:00:06,400 LET'S SEE HOW DO YOU. 1173 01:00:06,400 --> 01:00:08,960 SO I THINK TO GET THESE IN AN 1174 01:00:08,960 --> 01:00:10,600 ORGANIZED WAY IS GOING TO BE ONE 1175 01:00:10,600 --> 01:00:12,480 OF THE CHALLENGES. 1176 01:00:12,480 --> 01:00:16,080 ALSO IF THEY ARE USED PARTIALLY. 1177 01:00:16,080 --> 01:00:17,880 YOU HAVE LOTS OF PEOPLE AROUND 1178 01:00:17,880 --> 01:00:19,200 THEM. 1179 01:00:19,200 --> 01:00:21,720 THE PEOPLE THAT ARE AT RISK ARE 1180 01:00:21,720 --> 01:00:24,880 THOSE THAT ARE NOT VACCINATED 1181 01:00:24,880 --> 01:00:27,960 AND THEN THEY START TAKING THE 1182 01:00:27,960 --> 01:00:30,080 DRUG AND START FEELING BETTER 1183 01:00:30,080 --> 01:00:33,240 AND THEN STOP TAKING THE DRUG. 1184 01:00:33,240 --> 01:00:34,880 >> TRACK WHERE THE DRUGS ARE 1185 01:00:34,880 --> 01:00:36,520 GOING AND HOW MANY PEOPLE ARE 1186 01:00:36,520 --> 01:00:38,360 USING IT AND HOW LONG? 1187 01:00:38,360 --> 01:00:41,400 >> I'M NOT PRIVY TO THAT BUT IF 1188 01:00:41,400 --> 01:00:45,040 YOU READ THE NDA AND THE 1189 01:00:45,040 --> 01:00:46,520 EXPECTATIONS FROM THE FDA TO 1190 01:00:46,520 --> 01:00:50,200 PROVIDE A LOT OF DATA ON 1191 01:00:50,200 --> 01:00:52,840 INFORMATION. 1192 01:00:52,840 --> 01:00:57,680 I THINK THAT IS ALL DATA THAT -- 1193 01:00:57,680 --> 01:01:00,520 THEY ARE ASKED OR ENCOURAGED TO 1194 01:01:00,520 --> 01:01:01,000 PROVIDE. 1195 01:01:01,000 --> 01:01:05,320 THAT IS PART OF THE EUAs IS TO 1196 01:01:05,320 --> 01:01:07,600 LOOK FOR RESISTANCE ISSUES. 1197 01:01:07,600 --> 01:01:09,120 >> ONE QUESTION IS MIGHT THERE 1198 01:01:09,120 --> 01:01:11,680 BE AN INDEPENDENT REVIEW PROCESS 1199 01:01:11,680 --> 01:01:13,600 THAT CAN SPEED THIS APPROVAL 1200 01:01:13,600 --> 01:01:15,080 PROCESS? 1201 01:01:15,080 --> 01:01:18,680 >> I SUPPOSE. 1202 01:01:18,680 --> 01:01:20,880 I'VE SEEN INCENTIVES THAT APPEAR 1203 01:01:20,880 --> 01:01:23,600 TO GO -- I'LL COMMENT THAT 1204 01:01:23,600 --> 01:01:25,680 RECENTLY A THING CAME OUT -- 1205 01:01:25,680 --> 01:01:27,040 WITHOUT A PUBLIC COMMENT. 1206 01:01:27,040 --> 01:01:28,920 THIS IS SO IMPORTANT THAT WE'RE 1207 01:01:28,920 --> 01:01:31,120 NOT DOING PUBLIC COMMENT. 1208 01:01:31,120 --> 01:01:37,880 ANY INTRODUCTION OF A -- ACID -- 1209 01:01:37,880 --> 01:01:41,240 FROM SARS-CoV IS NOW SELECT 1210 01:01:41,240 --> 01:01:41,880 AGENT. 1211 01:01:41,880 --> 01:01:46,960 SO WHAT CONSTITUTES A VIRULENCE 1212 01:01:46,960 --> 01:01:47,880 DETERMINANT? 1213 01:01:47,880 --> 01:01:52,120 WOULD A SINGLE MUTATION FROM 1214 01:01:52,120 --> 01:01:55,200 SARS CORKS V2 DO THAT? 1215 01:01:55,200 --> 01:01:57,080 THAT WOULD BE INTERESTING. 1216 01:01:57,080 --> 01:01:59,280 I WOULD LIKE TO SO THIS 1217 01:01:59,280 --> 01:02:01,480 RECONCILED OR PUT IN A WAY THAT 1218 01:02:01,480 --> 01:02:03,400 DOESN'T REQUIRE ME TO GO IN THE 1219 01:02:03,400 --> 01:02:05,560 FEDERAL REGISTER FOR 15 DAYS 1220 01:02:05,560 --> 01:02:08,960 EVERY TIME I WANT TO INTRODUCE A 1221 01:02:08,960 --> 01:02:11,080 MUTATION INTO SARS-CoV-2. 1222 01:02:11,080 --> 01:02:15,280 THERE ARE STRATEGIES TORAH 1223 01:02:15,280 --> 01:02:19,280 ALLOWING SURVEILLANCE -- * THERE 1224 01:02:19,280 --> 01:02:20,840 NEEDS TO BE SOME MECHANISM FOR 1225 01:02:20,840 --> 01:02:23,040 BEING ABLE TO ALLOW WORK LIKE 1226 01:02:23,040 --> 01:02:26,120 THIS TO GO FORWARD WITHOUT THE 1227 01:02:26,120 --> 01:02:26,520 DATA. 1228 01:02:26,520 --> 01:02:28,680 THE DAY THAT YOU'VE GOT THE DATA 1229 01:02:28,680 --> 01:02:30,480 THE DAY THAT THE DRUG IS 1230 01:02:30,480 --> 01:02:32,000 APPROVED NOW YOU CAN -- NOW YOU 1231 01:02:32,000 --> 01:02:35,080 HAVE TO PAUSE AT LEAST ANY 1232 01:02:35,080 --> 01:02:38,560 FORWARD OR REVERSE GENETIC 1233 01:02:38,560 --> 01:02:40,480 STUDIES WITH RESISTANCE. 1234 01:02:40,480 --> 01:02:42,080 IT SURPRISES A LOT OF PEOPLE 1235 01:02:42,080 --> 01:02:43,960 WHEN I BRING IT UP SO I THINK 1236 01:02:43,960 --> 01:02:46,040 THERE SHOULD BE SOME REVIEW 1237 01:02:46,040 --> 01:02:49,000 PROCESS THAT POTENTIALLY 1238 01:02:49,000 --> 01:02:50,200 RECOGNIZES THE IMPORTANCE OF 1239 01:02:50,200 --> 01:02:53,560 THIS PROCESS. 1240 01:02:53,560 --> 01:02:55,320 >> ONE QUESTION ASKED -- I 1241 01:02:55,320 --> 01:02:57,200 MENTIONED YOU ARE SKEPTICAL OF 1242 01:02:57,200 --> 01:03:04,920 COVID BECOMING A NEW SEASONAL 1243 01:03:04,920 --> 01:03:06,560 VIRUS LIKE FLU? 1244 01:03:06,560 --> 01:03:10,240 >> IT'S GOING TO GO WHERE IT 1245 01:03:10,240 --> 01:03:12,240 GOES A. REMEMBER FOR ALL OF THE 1246 01:03:12,240 --> 01:03:14,040 YEARS I'VE BEEN DOING SELECTION 1247 01:03:14,040 --> 01:03:17,200 IN THE LAB BECAUSE OF COURSE -- 1248 01:03:17,200 --> 01:03:20,480 IT'S WHAT I DO. 1249 01:03:20,480 --> 01:03:22,120 I ALWAYS FIND OUT WHAT MY 1250 01:03:22,120 --> 01:03:24,320 SELECTION PROCESS WAS ONCE I SEE 1251 01:03:24,320 --> 01:03:25,000 THE VIRUS. 1252 01:03:25,000 --> 01:03:27,480 I THINK I KNOW WHAT IT WAS AND 1253 01:03:27,480 --> 01:03:38,200 THEN THE VIRUS DEMONSTRATES -- 1254 01:03:38,200 --> 01:03:41,120 -- AND SO I THINK WE DON'T KNOW. 1255 01:03:41,120 --> 01:03:43,440 PEOPLE WOULD LIKE TO EXPECT THAT 1256 01:03:43,440 --> 01:03:46,080 IT WILL BE LESS AND LESS 1257 01:03:46,080 --> 01:03:46,840 VIRULENT. 1258 01:03:46,840 --> 01:03:49,480 THAT WILL HAPPEN AND ONE OF THE 1259 01:03:49,480 --> 01:03:52,120 REASONS IS IF THAT VIRUS HAS 1260 01:03:52,120 --> 01:03:54,120 INCREASED FITNESS FOR MANY OTHER 1261 01:03:54,120 --> 01:03:55,640 REASONS. 1262 01:03:55,640 --> 01:04:00,360 INCREASED TRANSMISSIBILITY. 1263 01:04:00,360 --> 01:04:03,360 CAPACITY -- THE ONLY THICK THAT 1264 01:04:03,360 --> 01:04:05,600 MATTERS -- THE VIRUS THAT IS 1265 01:04:05,600 --> 01:04:07,080 HERE TOMORROW IS THE ONE THAT IS 1266 01:04:07,080 --> 01:04:08,720 SUCCESSFUL TODAY AND WE DON'T 1267 01:04:08,720 --> 01:04:11,040 HAVE ENOUGH NATURAL HISTORY 1268 01:04:11,040 --> 01:04:12,000 EXPERIMENTS. 1269 01:04:12,000 --> 01:04:13,920 IT'S LIKE PREDICTING THE STOCK 1270 01:04:13,920 --> 01:04:14,800 MARKETS. 1271 01:04:14,800 --> 01:04:16,920 YESTERDAY'S RETURNS ARE NO 1272 01:04:16,920 --> 01:04:18,200 INDICATION OF FUTURE NEEDS. 1273 01:04:18,200 --> 01:04:18,720 >> THANK YOU. 1274 01:04:18,720 --> 01:04:19,760 THANK YOU SO MUCH. 1275 01:04:19,760 --> 01:04:21,880 I HAVE A FEW OTHER QUESTIONS BUT 1276 01:04:21,880 --> 01:04:25,160 I'M GOING TO E-MAIL THEM TO YOU. 1277 01:04:25,160 --> 01:04:27,480 >> I'M FINE WITH EITHER WAY. 1278 01:04:27,480 --> 01:04:29,800 >> AND SOME ARE VERY TECHNICAL 1279 01:04:29,800 --> 01:04:31,200 DETAILED. 1280 01:04:31,200 --> 01:04:33,960 >> I WOULD BE HAPPY FOR YOU TO 1281 01:04:33,960 --> 01:04:36,880 PUT ME IN TOUCH WITH ANYONE. 1282 01:04:36,880 --> 01:04:37,880 >> THANK YOU SO MUCH 1283 01:04:37,880 --> 01:04:41,440 AND THIS ENDS TODAY'S COVID-19 1284 01:04:41,440 --> 01:04:43,280 SEMINAR INTEREST GROUP 1285 01:04:43,280 --> 01:06:53,000 SESSION.