1 00:00:06,975 --> 00:00:17,352 >> GOOD MORNING, EVERYONE. 2 00:00:09,607 --> 00:00:11,309 WELCOME TO THE SECOND TALK IN 3 00:00:11,309 --> 00:00:14,779 THE BIOWULF SEMINAR SERIES. 4 00:00:14,779 --> 00:00:17,548 THIS YEAR WE, THE HIGH 5 00:00:17,548 --> 00:00:19,217 PERFORMANCE COMPUTING GROUP ARE 6 00:00:19,217 --> 00:00:20,618 CELEBRATING 25 YEARS OF 7 00:00:20,618 --> 00:00:23,187 PROVIDING SCIENTIFIC, SUPER 8 00:00:23,187 --> 00:00:26,457 COMPUTING SERVICES TO THE NIH 9 00:00:26,457 --> 00:00:28,993 INTRAMURAL RESEARCHERS. 10 00:00:28,993 --> 00:00:32,830 STARTING 1999 WITH 40 BOXES AND 11 00:00:32,830 --> 00:00:36,134 SHELVES AND ONLY 14 USERS, 1-4, 12 00:00:36,134 --> 00:00:39,537 BIOWULF HAS GROWN NOW TO 4000 13 00:00:39,537 --> 00:00:44,008 USERS AND MORE THAN 2400 -- 14 00:00:44,008 --> 00:00:48,980 SORRY, COMPUTE NODES AND 2400 15 00:00:48,980 --> 00:00:49,547 ACTIVE USERS. 16 00:00:49,547 --> 00:00:53,084 TODAY WE ARE HONORED TO HAVE 17 00:00:53,084 --> 00:00:54,819 DR. RUTH NUSSINOV AS OUR 18 00:00:54,819 --> 00:00:55,053 SPEAKER. 19 00:00:55,053 --> 00:00:57,555 DR. NUSSINOV OBTAINED DEGREE 20 00:00:57,555 --> 00:00:59,123 FROM UNIVERSITY OF WASHINGTON 21 00:00:59,123 --> 00:01:01,993 AND RUTGERS, DISSERTATION 22 00:01:01,993 --> 00:01:04,462 DEVELOPED FIRST ALGORITHM FOR 23 00:01:04,462 --> 00:01:05,963 FOLDING OF RNA. 24 00:01:05,963 --> 00:01:07,532 THIS IS STILL TAUGHT IN 25 00:01:07,532 --> 00:01:09,801 BIOINFORM ATTICS CLASSES IN THE 26 00:01:09,801 --> 00:01:11,235 U.S. AND IN EUROPE. 27 00:01:11,235 --> 00:01:13,771 SHE WAS A POST-DOC RESEARCH 28 00:01:13,771 --> 00:01:16,507 ASSOCIATE IN THE WEISMAN 29 00:01:16,507 --> 00:01:20,712 INSTITUTE, BERKELEY, HARVARD AND 30 00:01:20,712 --> 00:01:22,013 TEL AVIV UNIVERSITY. 31 00:01:22,013 --> 00:01:24,415 SHE JOINED THE SCHOOL OF 32 00:01:24,415 --> 00:01:25,550 MEDICINE IN TEL AVIV UNIVERSITY 33 00:01:25,550 --> 00:01:27,719 WHERE SHE BECAME A FULL 34 00:01:27,719 --> 00:01:30,588 PROFESSOR AND LATER BECAME 35 00:01:30,588 --> 00:01:31,956 ASSOCIATED WITH NATIONAL CANCER 36 00:01:31,956 --> 00:01:33,558 INSTITUTE IN FREDERICK NATIONAL 37 00:01:33,558 --> 00:01:34,192 LABORATORY FOR CANCER RESEARCH. 38 00:01:34,192 --> 00:01:36,694 ELECTED FELLOW IN SEVERAL 39 00:01:36,694 --> 00:01:39,564 SOCIETIES, WON MULTIPLE NATIONAL 40 00:01:39,564 --> 00:01:42,266 AND INTERNATIONAL AWARDS AND HAS 41 00:01:42,266 --> 00:01:44,035 SERVED IN SEVERAL ROLES IN THE 42 00:01:44,035 --> 00:01:46,804 SCIENTIFIC COMMUNITY. 43 00:01:46,804 --> 00:01:49,841 DR. NUSSINOV'S LAB HAS MADE VERY 44 00:01:49,841 --> 00:01:51,943 EFFECTIVE USE OF BIOWULF. 45 00:01:51,943 --> 00:01:55,046 YEAR AFTER YEAR, GROUP 46 00:01:55,046 --> 00:01:57,115 CONSISTENTLY USING 10 TO 20% OF 47 00:01:57,115 --> 00:02:01,085 ALL PSYCH EMS IN THE HPC 48 00:02:01,085 --> 00:02:01,319 CLUSTER. 49 00:02:01,319 --> 00:02:03,154 JUST THIS YEAR, HER GROUP HAS 50 00:02:03,154 --> 00:02:07,091 USED 123 MILLION CPU HOURS. 51 00:02:07,091 --> 00:02:09,460 SO FAR IN 2024. 52 00:02:09,460 --> 00:02:13,131 THE YEAR HAS NOT ENDED YET, 53 00:02:13,131 --> 00:02:13,898 HOPEFULLY MORE. 54 00:02:13,898 --> 00:02:17,268 THIS NUMBER CORRESPONDS TO 40% 55 00:02:17,268 --> 00:02:22,774 OF USAGE OF NCIAS A WHOLE. 56 00:02:22,774 --> 00:02:27,845 USED GPU HOURS THIS YEAR AND 57 00:02:27,845 --> 00:02:30,314 JUST TO MENTION A FEW OF THE 58 00:02:30,314 --> 00:02:32,517 APPLICATIONS THAT THE GROUP USES 59 00:02:32,517 --> 00:02:36,487 ARE AMONG OTHERS MD, AMBER, 60 00:02:36,487 --> 00:02:40,291 BROMAX, CHARM, ROSETA, AMONG 61 00:02:40,291 --> 00:02:41,993 OTHER APPLICATIONS. 62 00:02:41,993 --> 00:02:45,563 DR. RUTH NUSSINOV TALK TODAY 63 00:02:45,563 --> 00:02:48,866 TITLED SCIENCE IS ABOUT 64 00:02:48,866 --> 00:02:50,968 CURIOSITY AND ASKING SIGNIFICANT 65 00:02:50,968 --> 00:02:51,469 QUESTIONS. 66 00:02:51,469 --> 00:02:51,702 WELCOME. 67 00:02:51,702 --> 00:02:53,671 [APPLAUSE] 68 00:02:53,671 --> 00:02:57,141 >> SO TO BEGIN WITH, OF COURSE, 69 00:02:57,141 --> 00:03:02,880 I WOULD LIKE TO THANK FIRST THE 70 00:03:02,880 --> 00:03:04,382 HELIX, WHICH IS WHERE WE STARTED 71 00:03:04,382 --> 00:03:07,151 AND THEN THE BIOWULF AND TO SAY 72 00:03:07,151 --> 00:03:10,054 THAT WITH ALL OF THIS TIME 73 00:03:10,054 --> 00:03:12,657 OBVIOUSLY, LIKE ANTONIO QUOTED, 74 00:03:12,657 --> 00:03:15,927 WITHOUT FIRST HELIX AND THEN THE 75 00:03:15,927 --> 00:03:17,528 BIOWULF, WE WOULDN'T BE WHERE WE 76 00:03:17,528 --> 00:03:17,695 ARE. 77 00:03:17,695 --> 00:03:19,197 I'M SPEAKING FOR EVERYBODY WHEN 78 00:03:19,197 --> 00:03:23,134 I SAY HOW GRATEFUL WE ALL ARE 79 00:03:23,134 --> 00:03:27,505 FOR THESE WONDERFUL FACILITIES, 80 00:03:27,505 --> 00:03:30,474 MAINTAINING THEM, GO IING FORWA 81 00:03:30,474 --> 00:03:34,445 WITH THEM, IMPLEMENTING NEW 82 00:03:34,445 --> 00:03:36,180 ADVANCES ALWAYS, NOT JUST 83 00:03:36,180 --> 00:03:38,082 SITTING, YOU KNOW, WHERE YOU 84 00:03:38,082 --> 00:03:41,352 ARE, BUT ALWAYS THE VERY LATEST 85 00:03:41,352 --> 00:03:43,654 AND FOR US, IT HAS BEEN A GOD 86 00:03:43,654 --> 00:03:47,124 SEND AND WE ARE VERY, VERY 87 00:03:47,124 --> 00:03:47,692 GRATEFUL. 88 00:03:47,692 --> 00:03:49,994 AND TODAY, I'LL DISCUSS SOME OF 89 00:03:49,994 --> 00:03:51,162 IT, OF COURSE, IT IS NOT 90 00:03:51,162 --> 00:03:54,432 POSSIBLE TO DISCUSS ALL. 91 00:03:54,432 --> 00:03:57,201 SO THE TITLE OF MY TALK IS A 92 00:03:57,201 --> 00:04:00,071 LITTLE UNUSUAL. 93 00:04:00,071 --> 00:04:03,875 AND IT CAME ABOUT -- LET ME SEE, 94 00:04:03,875 --> 00:04:08,813 IT CAME ABOUT FROM -- IT CAME 95 00:04:08,813 --> 00:04:09,213 ABO 96 00:04:09,213 --> 00:04:16,754 ABOUT, FROM THIS ISSUE, PHYSICS 97 00:04:16,754 --> 00:04:18,222 TODAY, I DON'T KNOW IF ANY OF 98 00:04:18,222 --> 00:04:19,457 YOU ARE FAMILIAR WITH THIS, IT 99 00:04:19,457 --> 00:04:21,626 IS ACTUALLY A VERY GOOD 100 00:04:21,626 --> 00:04:24,996 PUBLICATION, WHICH IS WE SHOULD 101 00:04:24,996 --> 00:04:26,497 PREPARE AND PUBLISHED BY 102 00:04:26,497 --> 00:04:28,299 AMERICAN INSTITUTE OF PHYSICS 103 00:04:28,299 --> 00:04:33,237 AND I GET IT BECAUSE I AM ON THE 104 00:04:33,237 --> 00:04:35,373 EDITORIAL BOARD OF PHYSICAL 105 00:04:35,373 --> 00:04:37,875 BIOLOGY FOR MANY YEARS. 106 00:04:37,875 --> 00:04:40,311 SO A FEW MONTHS AGO, YOU CAN 107 00:04:40,311 --> 00:04:43,147 SEE, JANUARY 2024, I RECEIVED 108 00:04:43,147 --> 00:04:47,051 THIS SPECIAL ISSUE AND I SEE 109 00:04:47,051 --> 00:04:48,753 GO 110 00:04:48,753 --> 00:04:50,855 GOODNESS, THEY SHOWED A 111 00:04:50,855 --> 00:04:52,089 WOODPECKER, SOMETHING FROM 112 00:04:52,089 --> 00:04:54,225 PHYSICS TODAY I DID NOT EXPECT. 113 00:04:54,225 --> 00:04:57,228 THEN I LOOK AND I SEE, OH, 114 00:04:57,228 --> 00:04:59,397 PECKING WITHOUT HEADACHES AND I 115 00:04:59,397 --> 00:05:02,700 THINK TO MYSELF, INDEED HOW COME 116 00:05:02,700 --> 00:05:04,769 I NEVER THOUGHT OF IT. 117 00:05:04,769 --> 00:05:10,174 HOW COME THE BIRD HITS THE TREE 118 00:05:10,174 --> 00:05:13,210 SO MUCH AND STILL DOES NOT GET 119 00:05:13,210 --> 00:05:13,477 HEADACHE? 120 00:05:13,477 --> 00:05:14,879 SURELY WE WOULD HAVE. 121 00:05:14,879 --> 00:05:18,049 AND YES, SO WHY WOODPECKERS 122 00:05:18,049 --> 00:05:20,518 DON'T GET CONCUSSIONS? 123 00:05:20,518 --> 00:05:22,286 I OPENED THE ISSUE AND I SEE 124 00:05:22,286 --> 00:05:28,125 THIS PIECE WRITTEN BY -- OH, OR 125 00:05:28,125 --> 00:05:30,428 DISCUSSING THE WORK OF OBVIOUSLY 126 00:05:30,428 --> 00:05:32,930 BY THE PAPER WRITTEN, BUT 127 00:05:32,930 --> 00:05:33,631 DISCUSS 128 00:05:33,631 --> 00:05:35,566 DISCUSSING THE WORK OF TWO 129 00:05:35,566 --> 00:05:40,905 SCIENTIFICS FROM BELGIUM, FROM 130 00:05:40,905 --> 00:05:43,140 UPENN UNIVERSITY, PROFESSOR AND 131 00:05:43,140 --> 00:05:45,009 HIS PhD STUDENT AND FROM WHAT I 132 00:05:45,009 --> 00:05:46,744 UNDERSTAND, THIS PARTICULAR 133 00:05:46,744 --> 00:05:49,947 QUESTION IS THE TOPIC OF THE PhD 134 00:05:49,947 --> 00:05:51,649 OF THE STUDENT. 135 00:05:51,649 --> 00:05:55,486 SO I LOOK AT IT AND THE STORY IS 136 00:05:55,486 --> 00:05:57,388 AS FOLLOWS. 137 00:05:57,388 --> 00:06:03,060 IN THE 1970S, PSYCHIATRIC MAY 138 00:06:03,060 --> 00:06:05,629 AND CO-WORKERS SAW POTENTIAL 139 00:06:05,629 --> 00:06:08,366 LEARNING FROM AN TOM CAL 140 00:06:08,366 --> 00:06:10,668 ADAPTION IN WOODPECKER TO 141 00:06:10,668 --> 00:06:13,537 WITHSTAND REPEATED BLOWS. 142 00:06:13,537 --> 00:06:15,272 BUT, OBVIOUSLY, THEY WERE A 143 00:06:15,272 --> 00:06:18,009 LITTLE SKEPTICAL. 144 00:06:18,009 --> 00:06:24,181 IN THE LANSET ARTICLE IN 1976, 145 00:06:24,181 --> 00:06:26,117 THEY QUESTIONED ONGOING 146 00:06:26,117 --> 00:06:29,120 HYPOTHESIS AT THE TIME AS TO THE 147 00:06:29,120 --> 00:06:32,456 CRANEIEL ABSORPTION OF SHOCK 148 00:06:32,456 --> 00:06:33,524 WHICH IS PART OF ADAPTION AND 149 00:06:33,524 --> 00:06:37,495 THEY WERE ASKING, IF THE BEAK 150 00:06:37,495 --> 00:06:40,031 ABSORBED MUCH OF ITS OWN IMPACT, 151 00:06:40,031 --> 00:06:41,699 THAT IS TO SAY COMING BACK FROM 152 00:06:41,699 --> 00:06:45,669 THE TREE TO THE BRAIN, THE 153 00:06:45,669 --> 00:06:46,270 UNFORT 154 00:06:46,270 --> 00:06:47,605 UNFORTUNATE BIRD WOULD HAVE TO 155 00:06:47,605 --> 00:06:49,073 POUND EVEN HARDER. 156 00:06:49,073 --> 00:06:51,375 SO HOW TO UNDERSTAND THIS? 157 00:06:51,375 --> 00:06:55,479 SO HOW DOES THE WOODPECKER DO 158 00:06:55,479 --> 00:06:55,646 IT? 159 00:06:55,646 --> 00:06:59,150 SOME THINK WOODPECKERS STRIKE 160 00:06:59,150 --> 00:07:01,719 TREES WITH THEIR BEAKS AT SPEEDS 161 00:07:01,719 --> 00:07:04,088 OF 20 KILOMETERS PER HOUR AND 162 00:07:04,088 --> 00:07:07,858 CAN REACH RATES OF 30 TIMES PER 163 00:07:07,858 --> 00:07:08,793 SECOND DURING DRUMMING. 164 00:07:08,793 --> 00:07:11,495 A SUDDEN DECELERATION WHEN THEY 165 00:07:11,495 --> 00:07:14,698 HIT A TREE, RIGHT? WOULD EXCEED 166 00:07:14,698 --> 00:07:17,368 THE THRESHOLD THAT WOULD RENDER 167 00:07:17,368 --> 00:07:19,904 A CONCUSSIVE BLOW TO THE HUMAN 168 00:07:19,904 --> 00:07:21,539 BRAIN. 169 00:07:21,539 --> 00:07:24,909 BUT, THE BIRD'S BRAINS ARE 170 00:07:24,909 --> 00:07:26,610 UNHARMED, LEADING THE COMMUNITY 171 00:07:26,610 --> 00:07:30,848 TO BELIEVE IN THIS SPONGY BONE 172 00:07:30,848 --> 00:07:33,551 HYPOTHESIS. 173 00:07:33,551 --> 00:07:35,886 SO HERE IS OUR BIRD AND THAT 174 00:07:35,886 --> 00:07:42,293 SPONGY BONE OF CRANIAL ABS 175 00:07:42,293 --> 00:07:45,396 ABSORPTION OF THE SHOCK, SHOCK 176 00:07:45,396 --> 00:07:48,265 ABSORBERS AND HELMETS. 177 00:07:48,265 --> 00:07:51,435 BUT, YES, A SHOCKWAVE TROUBLING 178 00:07:51,435 --> 00:07:57,041 FROM THE BEAK WOULD BECOME 179 00:07:57,041 --> 00:08:00,978 CUSHION CUSSIONED EXCEPT BIRD 180 00:08:00,978 --> 00:08:02,680 WOULD LOSE PART 'VE BUILT-IN 181 00:08:02,680 --> 00:08:07,852 ENERGY BY BEAK SHOCK ABSORBER. 182 00:08:07,852 --> 00:08:13,190 SO THAT THEN READ 30 YEARS 183 00:08:13,190 --> 00:08:16,627 LATER, IN 2006, LAUREN GIBESON 184 00:08:16,627 --> 00:08:19,597 FROM THE PHYSICS DEPARTMENT AT 185 00:08:19,597 --> 00:08:22,500 MIT TO CARRY OUT SOME 186 00:08:22,500 --> 00:08:23,400 CALCULATIONS, LEADING HER TO 187 00:08:23,400 --> 00:08:25,236 SUGGEST THAT THE ANSWER LIES IN 188 00:08:25,236 --> 00:08:28,339 THE MASS DIFFERENCE BETWEEN THE 189 00:08:28,339 --> 00:08:30,407 HUMAN AND THE BRAIN AND THE 190 00:08:30,407 --> 00:08:32,476 BIRDS BRAINS. 191 00:08:32,476 --> 00:08:35,212 BIRDS CAN WITHSTAND THE 192 00:08:35,212 --> 00:08:36,413 DECELERATION BECAUSE OF THE 193 00:08:36,413 --> 00:08:38,315 SMALL SIZES OF THEIR BRAIN. 194 00:08:38,315 --> 00:08:41,952 WHICH DISTRESS THAT SHOWED 195 00:08:41,952 --> 00:08:44,555 DURINGATION OF THE IMPACT AND 196 00:08:44,555 --> 00:08:45,956 THE ORIENTATION OF THE SKULL. 197 00:08:45,956 --> 00:08:49,426 THE PRESSURE ON THE BRAIN IS 198 00:08:49,426 --> 00:08:50,461 PROPORTIONATE TO DECELERATION 199 00:08:50,461 --> 00:08:54,331 AND THE CT, BRAIN LENGTH IN 200 00:08:54,331 --> 00:08:56,367 DIRECTION OF IMPACT ALL TOGETHER 201 00:08:56,367 --> 00:09:00,137 IS ONE-SEVENTH OF THE HUMAN AND 202 00:09:00,137 --> 00:09:03,040 THIS IS THE EQUATION THAT SHE 203 00:09:03,040 --> 00:09:07,444 USED. 204 00:09:07,444 --> 00:09:09,113 SO STILL CONTINUING THE SAGA OF 205 00:09:09,113 --> 00:09:12,016 THE WOODPECK ERS AND THE TREES 206 00:09:12,016 --> 00:09:14,084 AND THE BRAIN CONCUSSIONS, TWO 207 00:09:14,084 --> 00:09:15,953 YEARS AGO, AN INTERNATIONAL TEAM 208 00:09:15,953 --> 00:09:20,457 FROM EUROPE AND CANADA TOOK IT 209 00:09:20,457 --> 00:09:24,261 UP AGAIN, ASKING SO HOW DOES THE 210 00:09:24,261 --> 00:09:28,566 BIRD AVOID INJURY? 211 00:09:28,566 --> 00:09:33,571 SO THEY LOOKED AT THREE SPECIES 212 00:09:33,571 --> 00:09:35,272 AND RECORDED HIGH-SPEED VIDEOS 213 00:09:35,272 --> 00:09:38,842 IN EUROPE AND CANADA, BUT NO 214 00:09:38,842 --> 00:09:40,244 CONSISTENT DECELERATION OF THE 215 00:09:40,244 --> 00:09:44,014 BRAIN VERSUS THE BEAK, THUS NO 216 00:09:44,014 --> 00:09:44,648 CUSS 217 00:09:44,648 --> 00:09:47,318 CUSSIONING AND THE MECH AN 218 00:09:47,318 --> 00:09:49,987 CALAMITY 219 00:09:49,987 --> 00:09:51,655 CALAMITY CALCULATION SHOWED IF 220 00:09:51,655 --> 00:09:54,491 THERE WAS THE ENERGY WOULD BE 221 00:09:54,491 --> 00:09:57,261 REDUCED, THUS THE TREE 222 00:09:57,261 --> 00:09:58,429 PENETRATION DIPPED. 223 00:09:58,429 --> 00:10:01,899 AND HERE THEY TOOK THE X-RAY 224 00:10:01,899 --> 00:10:04,368 COMPUTER TOMOGRAPHY, 225 00:10:04,368 --> 00:10:05,536 RECONSTRUCTIVE OF THE LEFT PART 226 00:10:05,536 --> 00:10:07,771 OF THE SKULL AND ENLARGED CIRCLE 227 00:10:07,771 --> 00:10:10,774 SHOWS THE SPONGY AND THE 228 00:10:10,774 --> 00:10:14,678 ENLARGED CIRCLE SHOWS THE SPONGY 229 00:10:14,678 --> 00:10:17,681 BRAIN LOCATED AT THE INTERFACE 230 00:10:17,681 --> 00:10:21,318 BETWEEN THE BEAK AND THE CRANIUM 231 00:10:21,318 --> 00:10:25,556 AS SUGGESTED THAT WHICH RELATES 232 00:10:25,556 --> 00:10:28,259 TO HYPOTHESIS FOR EACH SERVING 233 00:10:28,259 --> 00:10:32,463 AS SHOCK ABSORBERS. 234 00:10:32,463 --> 00:10:36,767 EXCEPT WHAT THE GROUP OBSERVED 235 00:10:36,767 --> 00:10:39,870 IS THE HEAD FUNCTIONS AS STIFF 236 00:10:39,870 --> 00:10:42,439 HAMMER. 237 00:10:42,439 --> 00:10:44,642 SO YES, THE SIZE OF THE BRAIN OF 238 00:10:44,642 --> 00:10:46,343 THE WOODPECKER IS MUCH SMALLER 239 00:10:46,343 --> 00:10:48,879 THAN THAT OF THE HUMAN AND THE 240 00:10:48,879 --> 00:10:53,017 ISSUE IS NEWTON SECOND LAW OF 241 00:10:53,017 --> 00:10:53,250 MOTION. 242 00:10:53,250 --> 00:10:57,254 WE KNOW THE NET FORCE EQUALS NOW 243 00:10:57,254 --> 00:11:00,024 TIMES ACCELERATION, A LARGE NET 244 00:11:00,024 --> 00:11:03,127 FORCE ACTING ON AN OBJECT HERE, 245 00:11:03,127 --> 00:11:06,530 THE BRAIN, CAUSES A LARGER 246 00:11:06,530 --> 00:11:08,766 ACCELERATION AND OBJECT WITH 247 00:11:08,766 --> 00:11:10,534 LARGER MASS REQUIRE MORE FORCE 248 00:11:10,534 --> 00:11:14,171 TO ACCELERATE. 249 00:11:14,171 --> 00:11:20,811 SO BIRDS CAN WITHSTRAND 250 00:11:20,811 --> 00:11:23,147 ACCELERATION BECAUSE OF SIZE OF 251 00:11:23,147 --> 00:11:25,516 BRAIN AND REDUCES STRES AND 252 00:11:25,516 --> 00:11:27,751 SHOWS DURATION OF THE IMPACT AND 253 00:11:27,751 --> 00:11:28,752 ORIENTATION OF THE SKULL. 254 00:11:28,752 --> 00:11:31,822 SO HERE IS OUR LITTLE 255 00:11:31,822 --> 00:11:33,924 WOODPECKER. 256 00:11:33,924 --> 00:11:37,294 THIS OF COURSE WE DON'T DO WITH 257 00:11:37,294 --> 00:11:39,963 THE BIOWULF. 258 00:11:39,963 --> 00:11:40,464 [LAUGHTER] 259 00:11:40,464 --> 00:11:43,067 >> BUT I THOUGHT I WOULD JUST 260 00:11:43,067 --> 00:11:44,802 BRING THE QUESTIONS HERE, THIS 261 00:11:44,802 --> 00:11:47,738 IS PHYSICS, THE QUESTIONS THAT 262 00:11:47,738 --> 00:11:51,308 PEOPLE ASK AND OVER SO MANY 263 00:11:51,308 --> 00:11:58,549 YEARS PRACTICALLY 50 YEARS, IN 264 00:11:58,549 --> 00:12:01,552 CANADA, AT MIT, STILL WANTING TO 265 00:12:01,552 --> 00:12:04,722 UNDERSTAND BASIC PROCESSES 266 00:12:04,722 --> 00:12:11,428 TAKING PLACE IN ANIMAL LIFE, 267 00:12:11,428 --> 00:12:14,064 RIGHT? OUR QUESTIONS ARE ON THE 268 00:12:14,064 --> 00:12:16,834 MOLECULAR AND CELLULAR LEVELS. 269 00:12:16,834 --> 00:12:18,736 SOME EXAMPLES, QUESTIONS THAT WE 270 00:12:18,736 --> 00:12:24,475 ASK USING ALSO THE BIOWULF IS 271 00:12:24,475 --> 00:12:26,443 EPIDEMIOLOGICAL SURVEYS OBSERVE 272 00:12:26,443 --> 00:12:28,979 THAT PEOPLE WITH AUTISM IS 273 00:12:28,979 --> 00:12:31,215 HIGHER RISK OF CANCER. 274 00:12:31,215 --> 00:12:35,819 THOSE WITH SCHIZOPHRENIA BY AS 275 00:12:35,819 --> 00:12:37,855 MUCH AS 50%. 276 00:12:37,855 --> 00:12:42,192 WE WERE WONDERING WHY THE HIGHER 277 00:12:42,192 --> 00:12:43,227 RISK. 278 00:12:43,227 --> 00:12:44,928 MUTATIONS CAN INVOLVE 279 00:12:44,928 --> 00:12:47,664 SUBSTITUTIONS OF SINGLE AMINO 280 00:12:47,664 --> 00:12:50,801 ACID IN PROTEIN SEQUENCE, THAT 281 00:12:50,801 --> 00:12:52,569 CHANGE CAN CAUSE CANCER. 282 00:12:52,569 --> 00:12:56,440 EXACTLY HOW? 283 00:12:56,440 --> 00:12:58,909 SOME OF THE MUTATIONS ARE MORE 284 00:12:58,909 --> 00:13:00,878 AGGRESSIVE THAN OTHERS. 285 00:13:00,878 --> 00:13:01,378 WHY? 286 00:13:01,378 --> 00:13:05,149 WHAT IS DIFFERENT ABOUT SUCH 287 00:13:05,149 --> 00:13:06,550 MUTATIONS? 288 00:13:06,550 --> 00:13:11,688 OUR AIM OVER THE YEARS HAS BEEN 289 00:13:11,688 --> 00:13:13,557 UNDERSTANDING THE MECHANISMS ON 290 00:13:13,557 --> 00:13:15,859 THE BASIC STRUCTURAL AND 291 00:13:15,859 --> 00:13:17,995 CELLULAR LEVEL AND WE DID THIS 292 00:13:17,995 --> 00:13:21,198 FRAMEWORK WE HAVE BEEN FOCUSING 293 00:13:21,198 --> 00:13:27,938 LARGELY ON THE ONCOGENIC 294 00:13:27,938 --> 00:13:29,940 CROSS-SECTIONING, WE STARTED ON 295 00:13:29,940 --> 00:13:32,743 SIGNALLING IN 2013, JUST A FEW 296 00:13:32,743 --> 00:13:36,346 MONTHS BEFORE VARMOS, THEN 297 00:13:36,346 --> 00:13:40,717 DIRECTOR OF NCI ANNOUNCED 298 00:13:40,717 --> 00:13:42,119 PROJECT OF NATIONAL INTEREST. 299 00:13:42,119 --> 00:13:45,122 WE SENSED THIS IS DIRECTION TO 300 00:13:45,122 --> 00:13:47,891 GO, RUSS IS SO CENTRAL, SO 301 00:13:47,891 --> 00:13:52,229 CRUCIAL IN CANCER AND THE SECOND 302 00:13:52,229 --> 00:13:54,631 THING WE REALIZE BECAUSE IT IS 303 00:13:54,631 --> 00:13:57,568 SO IMPORTANT, CHANCES ARE MANY 304 00:13:57,568 --> 00:13:59,736 EXPERI 305 00:13:59,736 --> 00:14:00,671 EXPERIMENTALISTS WOULD FOCUS ON 306 00:14:00,671 --> 00:14:02,840 IT AND EXPERIMENTAL DATA WOULD 307 00:14:02,840 --> 00:14:06,143 COME OUT, WHICH IS ESSENTIAL FOR 308 00:14:06,143 --> 00:14:07,444 COMPUTATIONAL BIOLOGY BECAUSE 309 00:14:07,444 --> 00:14:11,148 YOU BASE YOUR SIMULATIONS ON 310 00:14:11,148 --> 00:14:11,782 EXPERI 311 00:14:11,782 --> 00:14:13,350 EXPERIMENTAL DATA AND THEN YOU 312 00:14:13,350 --> 00:14:18,822 WANT TO TEST WHAT YOU GET AGAIN 313 00:14:18,822 --> 00:14:20,757 WITH EMERGING EXPERIMENTAL DATA. 314 00:14:20,757 --> 00:14:23,293 SO THIS IS CRUCIAL. 315 00:14:23,293 --> 00:14:25,929 ALL THE PROTEINS THAT YOU WILL 316 00:14:25,929 --> 00:14:29,533 SEE HERE ARE THOSE CIRCLED ONES 317 00:14:29,533 --> 00:14:32,336 ARE THOSE THAT WE HAVE EITHER 318 00:14:32,336 --> 00:14:35,739 WORKED ON DURING 10 OR 11 YEARS 319 00:14:35,739 --> 00:14:37,541 OR ARE WORKING ON. 320 00:14:37,541 --> 00:14:46,617 SO FIRST, ACT VAGSZ ACTIVATION 321 00:14:46,617 --> 00:14:52,022 OF RAS FROM GPT AND GPT 322 00:14:52,022 --> 00:14:52,322 ACTIVATION. 323 00:14:52,322 --> 00:14:56,693 WHEN I SAY MECHANISMS, THE TOP, 324 00:14:56,693 --> 00:14:59,496 THE TITLE, WHAT I MEAN IS AUTO 325 00:14:59,496 --> 00:15:02,199 INHIBITION OF THE PROTEIN AND 326 00:15:02,199 --> 00:15:04,434 ACTIVATION MECHANISM. 327 00:15:04,434 --> 00:15:06,470 ACTIVATION PHYSIOLOGICAL 328 00:15:06,470 --> 00:15:09,039 CONDITIONS AND IN CANCER 329 00:15:09,039 --> 00:15:11,675 MUTATIONS. 330 00:15:11,675 --> 00:15:17,147 SO YES, PROTEIN ARE INVOLVED IN 331 00:15:17,147 --> 00:15:20,117 RAS ACTIVATION WE HAVE LOOKED 332 00:15:20,117 --> 00:15:21,552 AT. 333 00:15:21,552 --> 00:15:25,255 RAS MAKE THE VASTLY IMPORTANT 334 00:15:25,255 --> 00:15:29,560 PATHWAY, MAPK LEADING TO CELL 335 00:15:29,560 --> 00:15:30,761 PROLIFERATION. 336 00:15:30,761 --> 00:15:37,501 HERE ALSO CASE ARE AND ERC, WE 337 00:15:37,501 --> 00:15:40,370 LOOKED AT THESE AND LEUKEMIA. 338 00:15:40,370 --> 00:15:47,144 BCRA ABL, A KINASE INVOLVED IN 339 00:15:47,144 --> 00:15:51,114 LEUKEMIA AND RELATES TO RAS. 340 00:15:51,114 --> 00:15:56,119 THE SECOND MAJOR PATHWAY, 341 00:15:56,119 --> 00:16:04,962 PI3KAKT, WE LOOKED AT LIPID 342 00:16:04,962 --> 00:16:09,466 KYNASE, TUMOR REPRESSAL. 343 00:16:09,466 --> 00:16:12,402 THIS PATHWAY LEADS TO 344 00:16:12,402 --> 00:16:14,271 CONTRIBUTES TO CELL GROWTH AND 345 00:16:14,271 --> 00:16:17,941 BOTH OF THESE, TWO PATHWAYS, 346 00:16:17,941 --> 00:16:22,946 MAPK AND PI3KAKT, LEAD TO THE 347 00:16:22,946 --> 00:16:26,650 CELL CYCLE, WHICH SEVERAL 348 00:16:26,650 --> 00:16:30,587 STAGES, AS YOU CAN SEE. 349 00:16:30,587 --> 00:16:33,890 AND IN EACH STAGE, THERE IS A 350 00:16:33,890 --> 00:16:43,600 KEY KINASE, CDK46 AND CDK2 WITH 351 00:16:43,600 --> 00:16:44,735 PARTNER CYCLINE. 352 00:16:44,735 --> 00:16:48,538 WE ARE FOCUSING ON ALSO THE CELL 353 00:16:48,538 --> 00:16:48,839 CYCLE. 354 00:16:48,839 --> 00:16:56,046 CELL CYCLE, ENTER ERK, AKT, PDK1 355 00:16:56,046 --> 00:17:01,418 AND NF1, ALSO, WHICH IS A GAP IN 356 00:17:01,418 --> 00:17:01,585 RAS. 357 00:17:01,585 --> 00:17:03,954 TO GIVE YOU A FLAVOR OF THE 358 00:17:03,954 --> 00:17:06,189 QUESTIONS THAT WE ASK, AND THAT 359 00:17:06,189 --> 00:17:10,661 THE BIOWULF NOW IS SORT OF 360 00:17:10,661 --> 00:17:12,362 CRUNCHING FOR THE CELL CYCLE, 361 00:17:12,362 --> 00:17:19,136 YOU CAN SEE THE LENGTH OF TIME 362 00:17:19,136 --> 00:17:21,304 SPENT IN THE CELL CYCLE ON THE 363 00:17:21,304 --> 00:17:24,608 DIFFERENT STAGES IS NOT THE SAME 364 00:17:24,608 --> 00:17:26,877 G1 IS MUCH LONGER THAN S. 365 00:17:26,877 --> 00:17:29,246 AND THEN THERE IS THE TRANSITION 366 00:17:29,246 --> 00:17:32,182 FROM G1 TO S. 367 00:17:32,182 --> 00:17:35,252 G1 ON AVERAGE IS ABOUT 12 HOURS 368 00:17:35,252 --> 00:17:39,222 IN HUMAN, THE TRANSITION IS 369 00:17:39,222 --> 00:17:40,557 ABOUT TWO ON AVERAGE. 370 00:17:40,557 --> 00:17:44,861 SO ONE OF THE QUESTIONS WE ASK, 371 00:17:44,861 --> 00:17:49,366 WHY IS THE MOTHER NATURE CHOOSE, 372 00:17:49,366 --> 00:17:54,671 HOW IS IT OPTIMIZE THE CDK4 AND 373 00:17:54,671 --> 00:17:58,842 CDK6, TO WORK OVER SUCH MUCH 374 00:17:58,842 --> 00:18:02,612 LONGER TIME SCALE AND THE CDK2, 375 00:18:02,612 --> 00:18:07,217 WITH CYCLINE A SPENDS HERE ABOUT 376 00:18:07,217 --> 00:18:09,352 TWO HOURS ON TRANSITION. 377 00:18:09,352 --> 00:18:12,956 WHAT IS DIFFERENT BETWEEN CDK4 378 00:18:12,956 --> 00:18:14,858 AND CDK2? 379 00:18:14,858 --> 00:18:18,428 I SHOULD SAY THESE QUESTIONS ARE 380 00:18:18,428 --> 00:18:19,162 VERY IMPORTANT. 381 00:18:19,162 --> 00:18:21,064 FIRST OF ALL, WE WANT TO 382 00:18:21,064 --> 00:18:23,133 UNDERSTAND, IT IS THE BASIC 383 00:18:23,133 --> 00:18:27,704 BIOLOGY OF THE CELL. 384 00:18:27,704 --> 00:18:31,007 SECOND, THESE CDK'S IS OTHER 385 00:18:31,007 --> 00:18:34,277 PROTEINS IN THE RAS SIGNALLING 386 00:18:34,277 --> 00:18:37,013 NETWORK, A MAJOR TARGETS IN DRUG 387 00:18:37,013 --> 00:18:37,547 DISCOVERY. 388 00:18:37,547 --> 00:18:40,884 SO AS I'LL SHOW IN A MINUTE, IF 389 00:18:40,884 --> 00:18:44,721 YOU HAVE CONFIRMATIONS THAT ARE 390 00:18:44,721 --> 00:18:47,157 GENERATED DURING ACTIVATION, IT 391 00:18:47,157 --> 00:18:50,861 CAN HELP YOU IN DESIGNING BETTER 392 00:18:50,861 --> 00:18:54,397 OR MORE OPTIMIZED DRUGS TO 393 00:18:54,397 --> 00:18:57,200 TARGET THESE CONFORMATIONS. 394 00:18:57,200 --> 00:18:59,069 SO HERE COMING BACK TO THE 395 00:18:59,069 --> 00:19:02,439 QUESTION ABOUT MUTATION, SO HERE 396 00:19:02,439 --> 00:19:07,310 FOR EXAMPLE, WE SEE K-RAS, THE 397 00:19:07,310 --> 00:19:10,947 MOST ONCOGENIC FORMATION OF THE 398 00:19:10,947 --> 00:19:13,784 RAS FAMILY AND HERE WE LOOK AT 399 00:19:13,784 --> 00:19:17,387 ITS MOST AGGRESSIVE MUTATIONS, 400 00:19:17,387 --> 00:19:20,524 RAS HAS MANY MUTATIONS, THE MOST 401 00:19:20,524 --> 00:19:25,529 AGGRESS ITCH IS G12V. 402 00:19:25,529 --> 00:19:36,072 G12V MEANS RESIDUE NUMBER 12 IS 403 00:19:36,907 --> 00:19:37,140 G 404 00:19:37,140 --> 00:19:37,440 G 405 00:19:37,440 --> 00:19:40,243 GLYCINE, WHY THIS MUTATION IS 406 00:19:40,243 --> 00:19:41,144 MOST AGGRESSIVE IN CANCER? 407 00:19:41,144 --> 00:19:45,215 WE CARRIED OUT SIMULATIONS, 408 00:19:45,215 --> 00:19:48,985 USING THE BIOWULF AND THE 409 00:19:48,985 --> 00:19:51,922 SIMULATION SHOWED THAT THE 410 00:19:51,922 --> 00:19:56,760 INACTIVE GDP K-RAS SPENDS MORE 411 00:19:56,760 --> 00:19:59,062 TIME IN THE ACTIVE-LIKE STATE 412 00:19:59,062 --> 00:20:00,864 THAN ANY OTHER MUTATIONS. 413 00:20:00,864 --> 00:20:05,135 OUR COLLEAGUES CARRIED OUT NMR 414 00:20:05,135 --> 00:20:08,839 EXPERIMENTS AND CONFIRMED OUR 415 00:20:08,839 --> 00:20:09,139 PREDICTIONS. 416 00:20:09,139 --> 00:20:12,776 THE LONGER TIME, THE LONGER THE 417 00:20:12,776 --> 00:20:15,545 TIME THE PROTEIN AND THIS IS -- 418 00:20:15,545 --> 00:20:18,882 THIS HOLDS FOR ALL PROTEINS, OF 419 00:20:18,882 --> 00:20:24,487 COURSE, ONCOGENES REPRESSOR ARE 420 00:20:24,487 --> 00:20:24,754 OPPOSITE. 421 00:20:24,754 --> 00:20:26,323 LONGER TIME THEY SPEND IN THE 422 00:20:26,323 --> 00:20:28,491 ACTIVE STATE, THE LONGER THE 423 00:20:28,491 --> 00:20:35,165 TIME THEY CAN ACTIVATE THE 424 00:20:35,165 --> 00:20:38,235 ONCOGENIC PATHWAY, FOR EXAMPLE, 425 00:20:38,235 --> 00:20:41,238 MAP-K, WHICH IS THE NUMBER ONE 426 00:20:41,238 --> 00:20:48,245 PROLIFERATION PATHWAY IN CANCER. 427 00:20:48,245 --> 00:20:54,284 WHY DOESN'T IT MOVE? 428 00:20:54,284 --> 00:20:54,451 OH. 429 00:20:54,451 --> 00:20:55,385 DID I SKIP ONE? 430 00:20:55,385 --> 00:20:56,953 I DON'T THINK SO. 431 00:20:56,953 --> 00:20:59,756 OKAY. 432 00:20:59,756 --> 00:21:00,924 HERE IS AN EXAMPLE. 433 00:21:00,924 --> 00:21:05,595 WHY WHAT WE CAN LEARN FROM 434 00:21:05,595 --> 00:21:08,198 KINASE ACTIVATION AND HERE WE 435 00:21:08,198 --> 00:21:15,071 CAN SEE THIS IS VERY IMPORTANT 436 00:21:15,071 --> 00:21:20,911 KINASE, IN PI3KAKT, PDK1 AND 437 00:21:20,911 --> 00:21:24,014 CELL GROWTH PATHWAY AND IS MAJOR 438 00:21:24,014 --> 00:21:27,317 TARGET IN DRUG DISCOVERY 439 00:21:27,317 --> 00:21:28,485 CONSEKWENTLY AND WHAT WE OBSERVE 440 00:21:28,485 --> 00:21:31,054 HERE, WHAT YOUR BE GLAND 441 00:21:31,054 --> 00:21:33,290 OBSERVED HERE IS THAT IN THE 442 00:21:33,290 --> 00:21:35,725 ACTIVATION, WHAT YOU OBSERVE, SO 443 00:21:35,725 --> 00:21:39,863 THE DRUG DESIGNERS USE CRYSTAL 444 00:21:39,863 --> 00:21:43,199 STRUCTURE TO DESIGN THE DRUGS, 445 00:21:43,199 --> 00:21:45,502 BUT IN THE SIMULATIONS, WE 446 00:21:45,502 --> 00:21:48,405 ACTUALLY SEE HERE OF THE MUTANT, 447 00:21:48,405 --> 00:21:52,242 WE ACTUALLY SEE THAT THE SPACE 448 00:21:52,242 --> 00:21:53,443 IS LARGER. 449 00:21:53,443 --> 00:21:56,913 HERE IT IS LONGER, THE ACCESS, 450 00:21:56,913 --> 00:21:59,049 SUGGESTING THAT THE DRUG COULD 451 00:21:59,349 --> 00:22:03,954 BE OPTIMIZED FURTH ER OPTIMIZED. 452 00:22:03,954 --> 00:22:08,558 SO HERE -- I DON'T KNOW IF I -- 453 00:22:08,558 --> 00:22:11,995 YES, I MISED THIS ONE. 454 00:22:11,995 --> 00:22:14,864 ACTIVATION, AFTER THE MUTATIONS. 455 00:22:14,864 --> 00:22:20,403 SO HERE IS I WONDER, YEAH, OKAY. 456 00:22:20,403 --> 00:22:25,942 HERE WE SEE ACTIVATION OF RAF, 457 00:22:25,942 --> 00:22:28,878 TOP OF MAP-K PATHWAY, SO WHAT WE 458 00:22:28,878 --> 00:22:32,716 SEE IS THE RAF, HERE, ACTIVATED 459 00:22:32,716 --> 00:22:38,521 BY RAS HERE TO RAS TO RAF 460 00:22:38,521 --> 00:22:41,157 MOLECULES, RAF HERE IS IN THE 461 00:22:41,157 --> 00:22:44,160 ACTIVE STATE BECAUSE IT IS BOUND 462 00:22:44,160 --> 00:22:47,030 TO RAS, AND THIS IS THE 463 00:22:47,030 --> 00:22:51,968 MEMBRANE, WHICH THIS BINDING 464 00:22:51,968 --> 00:22:56,506 PROMOTES OPENING OF RAF, 465 00:22:56,506 --> 00:22:58,641 TRANSITIONING IT FROM INACTIVE 466 00:22:58,641 --> 00:23:00,310 STATE TO THE ACTIVE STATE. 467 00:23:00,310 --> 00:23:02,212 SO WHAT WE SEE HERE, THIS IS AN 468 00:23:02,212 --> 00:23:06,816 EXAMPLE OF WHAT HAPPENS IN 469 00:23:06,816 --> 00:23:09,552 KINASE, AND OTHER PROTEIN 470 00:23:09,552 --> 00:23:09,853 ACTIVATION. 471 00:23:09,853 --> 00:23:12,655 NORMALLY AND PHYSIOLOGICAL 472 00:23:12,655 --> 00:23:17,160 CONDITIONS, MOST OF THE C 473 00:23:17,160 --> 00:23:18,928 CONFORMATIONS OF THE PROTEINS 474 00:23:18,928 --> 00:23:21,831 ARE IN THE INACTIVE STATE. 475 00:23:21,831 --> 00:23:25,301 THIS IS BECAUSE THE ENERGY IS 476 00:23:25,301 --> 00:23:25,568 LOWER. 477 00:23:25,568 --> 00:23:29,272 SO MOST OF THE CONFORMATIONS 478 00:23:29,272 --> 00:23:33,176 PREFER TO BE THIS HERE, IN 479 00:23:33,176 --> 00:23:34,711 ACTIVATION, IT SWITCHES, NOW 480 00:23:34,711 --> 00:23:37,480 MOST OF CONFORMATIONS ARE IN THE 481 00:23:37,480 --> 00:23:38,281 ACTIVE STATE. 482 00:23:38,281 --> 00:23:40,250 WHAT CAUSES THE SWITCH? 483 00:23:40,250 --> 00:23:46,589 THIS BY STABLE SWITCH IS BINDING 484 00:23:46,589 --> 00:23:48,625 TO THE MEM BRACE AND TO RAS 485 00:23:48,625 --> 00:23:53,196 BECAUSE IT STABILIZES THIS OPEN 486 00:23:53,196 --> 00:23:54,497 CONFORMATION, WHICH OTHERWISE IS 487 00:23:54,497 --> 00:23:58,201 VERY UNSTABLE, VERY UNSTABLE 488 00:23:58,201 --> 00:24:04,007 MEANS LOWER POPULATION TIME BUT 489 00:24:04,007 --> 00:24:05,175 STABILIZATION LEADS TO THE SHIFT 490 00:24:05,175 --> 00:24:06,409 BECAUSE IT IS MORE STABLE, 491 00:24:06,409 --> 00:24:09,579 HIGHER POPULATION TIME AND 492 00:24:09,579 --> 00:24:13,249 MUTATIONS MEAN PHYSIOLOGICAL 493 00:24:13,249 --> 00:24:13,550 ACTIVATION. 494 00:24:13,550 --> 00:24:16,186 THEY ALTER THE RELATIVE 495 00:24:16,186 --> 00:24:18,588 STABILITY OF THE ACTIVE VERSUS 496 00:24:18,588 --> 00:24:20,256 THE INACTIVE STATE. 497 00:24:20,256 --> 00:24:21,891 AND HERE, DISCUSS THIS MUTATION 498 00:24:21,891 --> 00:24:25,128 AND HERE THIS PARTICULAR 499 00:24:25,128 --> 00:24:32,569 MUTATION IS PRIMARY IN MELANOMA. 500 00:24:32,569 --> 00:24:32,769 YEAH. 501 00:24:32,769 --> 00:24:34,904 WE ALREADY SAW THIS ONE. 502 00:24:34,904 --> 00:24:37,874 SO WE ARE INTERESTED IN 503 00:24:37,874 --> 00:24:39,742 MECHANISMS OF ACTIVATION AND 504 00:24:39,742 --> 00:24:41,711 SIGNAL 505 00:24:41,711 --> 00:24:42,946 SIGNALLING, FIRST TO UNDERSTAND 506 00:24:42,946 --> 00:24:45,381 AND SECOND, THEY CAN HELP DRUG 507 00:24:45,381 --> 00:24:45,915 DISCO 508 00:24:45,915 --> 00:24:48,384 DISCOVERY AND REGIMEN OF THE 509 00:24:48,384 --> 00:24:49,586 DRUG DISCOVERY. 510 00:24:49,586 --> 00:24:53,556 MECHANISMS OF ACTIVATION CAN 511 00:24:53,556 --> 00:24:57,560 HELP DISCOVERY OF SINGLE DRUGS, 512 00:24:57,560 --> 00:25:01,431 HOWEVER, WE KNOW RESISTANCE IS 513 00:25:01,431 --> 00:25:02,832 EXPECTED. 514 00:25:02,832 --> 00:25:05,068 MECHANISMS ARE CELL SIGNALLING 515 00:25:05,068 --> 00:25:08,104 CAN HELP DECIDE DRUG 516 00:25:08,104 --> 00:25:11,174 COMBINATIONS, COMBINATIONS CAN 517 00:25:11,174 --> 00:25:13,676 LESSEN RESISTANCE FOR MOBILITY. 518 00:25:13,676 --> 00:25:17,981 SO HERE WE CAN SEE THE DRUG 519 00:25:17,981 --> 00:25:18,681 RESISTSANCE PROBLEM. 520 00:25:18,681 --> 00:25:21,851 ON THE LEFT-HAND SIDE HERE, THIS 521 00:25:21,851 --> 00:25:25,822 IS WHAT CAN HAPPEN IN A TUMOR IN 522 00:25:25,822 --> 00:25:26,589 CANCER. 523 00:25:26,589 --> 00:25:30,160 ALL CELLS, WHICH HAVE THIS RED 524 00:25:30,160 --> 00:25:35,198 DOT, HAVE A COMMON DRIVER 525 00:25:35,198 --> 00:25:35,999 MUTAT 526 00:25:35,999 --> 00:25:37,300 MUTATION. 527 00:25:37,300 --> 00:25:40,637 AND HERE ONE THAT HAS A 528 00:25:40,637 --> 00:25:43,072 DIFFERENT, RARE MUTATION, 529 00:25:43,072 --> 00:25:45,141 CHANCES ARE THAT WHEN THE TUMOR 530 00:25:45,141 --> 00:25:49,579 IS SEQUENCED TO FIND OUT WHICH 531 00:25:49,579 --> 00:25:50,713 MUTATION DOES THE INDIVIDUAL 532 00:25:50,713 --> 00:25:54,184 HAVE BECAUSE SO MANY ARE -- HAVE 533 00:25:54,184 --> 00:25:58,721 FREQUENT MUTATION, THEY WILL BE 534 00:25:58,721 --> 00:25:58,988 SEQUENCED. 535 00:25:58,988 --> 00:26:01,558 ONCE THEY -- THE DRUG IS 536 00:26:01,558 --> 00:26:04,093 ACCORDINGLY TARGETS THEM, THEN 537 00:26:04,093 --> 00:26:06,996 DRUG TREATMENT TARGETS THIS 538 00:26:06,996 --> 00:26:09,566 COMMON DRIVER MUTATION 539 00:26:09,566 --> 00:26:11,868 DECIMATING ALL OF THESE CELLS. 540 00:26:11,868 --> 00:26:14,103 WHAT HAPPENS NOW? 541 00:26:14,103 --> 00:26:18,007 NOW ONLY THESE CELL REMAINS 542 00:26:18,007 --> 00:26:21,678 BECAUSE EACH REAL MUTATION IS 543 00:26:21,678 --> 00:26:22,946 RESISTANT TO THAT SPECIFIC DRUG. 544 00:26:22,946 --> 00:26:26,115 SO NOW THAT THESE CELLS ARE 545 00:26:26,115 --> 00:26:27,784 DECIMATED, THESE PARTICULAR 546 00:26:27,784 --> 00:26:31,921 PROTEIN, A PARTICULAR CELL KEEPS 547 00:26:31,921 --> 00:26:35,725 DIVIDING AND NOW THE TUMOR IS 548 00:26:35,725 --> 00:26:37,427 RESISTANT TO THIS PARTICULAR 549 00:26:37,427 --> 00:26:37,627 DRUG. 550 00:26:37,627 --> 00:26:39,829 AND SO IT GROWS. 551 00:26:39,829 --> 00:26:42,465 NOW THIS, THESE PARTICULAR 552 00:26:42,465 --> 00:26:45,101 MUTATION WOULD BE TARGETED AND 553 00:26:45,101 --> 00:26:48,705 AGAIN, I -- WE DON'T SHOW HERE 554 00:26:48,705 --> 00:26:52,175 REPEATEDLY THIS, AND AGAIN, IT 555 00:26:52,175 --> 00:26:54,344 COULD HAPPEN THAT IT COULD, ONE 556 00:26:54,344 --> 00:26:56,846 WOULD EXPECT THAT THE TARGETED 557 00:26:56,846 --> 00:26:58,581 CELLS WITH TARGETED MUTATION 558 00:26:58,581 --> 00:27:01,651 WOULD BE DECIMATED AND ANOTHER 559 00:27:01,651 --> 00:27:06,189 CELL WITH RARE RESISTANT 560 00:27:06,189 --> 00:27:08,324 MUTATION WOULD REMAIN. 561 00:27:08,324 --> 00:27:10,793 UNTIL YOU CAN DO IT MULTIPLE 562 00:27:10,793 --> 00:27:13,563 TIMES AND HOPEFULLY EVENTUALLY 563 00:27:13,563 --> 00:27:18,301 YOU HAVE THE SET, THE TUMOR 564 00:27:18,301 --> 00:27:23,673 WITH, WITHOUT CANCER, WITHOUT 565 00:27:23,673 --> 00:27:25,041 ONCOGENIC MUTATIONS. 566 00:27:25,041 --> 00:27:26,776 SO THIS IS WHAT CAN HAPPEN IF 567 00:27:26,776 --> 00:27:31,581 YOU GIVE A DRUG TO A CANCER 568 00:27:31,581 --> 00:27:38,321 PATIENT AND WHY EVERY TIME 569 00:27:38,321 --> 00:27:39,122 RESISTANCE COMES UP AND THE 570 00:27:39,122 --> 00:27:40,823 CANCER RETURNS. 571 00:27:40,823 --> 00:27:44,861 INSTEAD YOU CAN DO SIMULTANEOUS 572 00:27:44,861 --> 00:27:46,929 TREATMENT, NOT JUST A DRUG THAT 573 00:27:46,929 --> 00:27:52,068 WOULD HIT THIS ONE, BUT A 574 00:27:52,068 --> 00:27:54,871 PRIORITY THIS ONE. 575 00:27:54,871 --> 00:27:57,206 SO THE POINT IS THE DRUG 576 00:27:57,206 --> 00:28:01,110 COMBINATION HAS A BETTER CHANCE. 577 00:28:01,110 --> 00:28:03,579 OF COURSE, THERE IS A PROBLEM 578 00:28:03,579 --> 00:28:04,647 HERE. 579 00:28:04,647 --> 00:28:08,217 HOW TO SELECT THE COMBINATION. 580 00:28:08,217 --> 00:28:12,322 HOW DOES THE ONCOLOGIST KNOW 581 00:28:12,322 --> 00:28:14,757 WHICH IS OPTIMAL COMBINATION, 582 00:28:14,757 --> 00:28:15,825 WHAT TO EXPECT? 583 00:28:15,825 --> 00:28:18,161 OKAY, ONCOLOGIST KNOWS WHICH IS 584 00:28:18,161 --> 00:28:23,032 THE FREQUENT MUTATION, BUT WHICH 585 00:28:23,032 --> 00:28:23,299 OTHERS? 586 00:28:23,299 --> 00:28:27,303 SO SMALL MOLECULES ARE AT THE 587 00:28:27,303 --> 00:28:27,637 FO 588 00:28:27,637 --> 00:28:29,872 FOREFRONT OF ANTI-CANCER 589 00:28:29,872 --> 00:28:31,908 THERAPIES, SUCCESSIVE TREATMENTS 590 00:28:31,908 --> 00:28:35,978 HAVE PROBLEMS WITH SINGLE 591 00:28:35,978 --> 00:28:39,115 MOLECULES IN CARRYING DRUG 592 00:28:39,115 --> 00:28:41,317 RESISTANCE. 593 00:28:41,317 --> 00:28:43,986 ONCOLOGISTS THEN FACE TOUGH 594 00:28:43,986 --> 00:28:47,924 CHOICES, NOT JUST WHICH DRUGS TO 595 00:28:47,924 --> 00:28:49,559 USE, BUT THE BEST TREATMENT 596 00:28:49,559 --> 00:28:52,962 PLANS BASED ON FACTORS LIKE 597 00:28:52,962 --> 00:28:54,997 TARGET PROTEINS, TARGET PATHWAY 598 00:28:54,997 --> 00:28:56,699 AND GENE EXPRESSION. 599 00:28:56,699 --> 00:29:00,336 SO WHAT THE ONCOLOGIST HAS 600 00:29:00,336 --> 00:29:02,004 ESSENTIALLY ALL OF THESE DRUGS, 601 00:29:02,004 --> 00:29:05,208 WHICH ONES TO CHOOSE. 602 00:29:05,208 --> 00:29:08,177 THE QUESTION THEN IS HOW TO 603 00:29:08,177 --> 00:29:11,080 SELECT SMALL MOLECULE 604 00:29:11,080 --> 00:29:11,814 COMBINATIONS. 605 00:29:11,814 --> 00:29:14,117 CONSIDERING THE REALITY OF 606 00:29:14,117 --> 00:29:17,220 CANCER'S DISRUPTION OF NORMAL 607 00:29:17,220 --> 00:29:20,790 CELLULAR PROCESSES, CLARIFIES 608 00:29:20,790 --> 00:29:23,059 WHY IT IS CRUCIAL TO UNDERSTAND 609 00:29:23,059 --> 00:29:25,561 THE INS AND OUTS OF CARE AND 610 00:29:25,561 --> 00:29:27,797 TREATMENT METHODS. 611 00:29:27,797 --> 00:29:30,400 FOR EXAMPLE, SMALL MOLECULE 612 00:29:30,400 --> 00:29:32,635 COMBINATIONS THAT TARGET 613 00:29:32,635 --> 00:29:34,837 MULTIPLE PATHWAYS APPEAR A 614 00:29:34,837 --> 00:29:38,141 PROMISING APPROACH, BUT HURDLES 615 00:29:38,141 --> 00:29:41,210 COME WITH IT, LIKE DEALING WITH 616 00:29:41,210 --> 00:29:42,879 PATHWAY CROSS TALK. 617 00:29:42,879 --> 00:29:45,748 IN OVER EXPRESSION, WHICH 618 00:29:45,748 --> 00:29:48,985 HAPPENS ALL THE TIME IN 619 00:29:48,985 --> 00:29:52,522 AGGRESSIVE CANCERS, SAME PATHWAY 620 00:29:52,522 --> 00:29:56,025 COMBINATION CAN ENCOUNTER 621 00:29:56,025 --> 00:30:00,963 ACTIVATION OF MULTIPLE ONCOGENIC 622 00:30:00,963 --> 00:30:03,232 PATHWAYS THROUGH CROSSTALKS, FOR 623 00:30:03,232 --> 00:30:03,566 EXAMPLE. 624 00:30:03,566 --> 00:30:06,169 SIMILARLY, STRONG ACTIVATING 625 00:30:06,169 --> 00:30:09,071 MUTATION, HAVE MANY ACTIVE 626 00:30:09,071 --> 00:30:10,740 CONFORMATIONS, SO HOW TO SELECT 627 00:30:10,740 --> 00:30:14,210 SMALL MOLECULE COMBINATIONS? 628 00:30:14,210 --> 00:30:17,213 DRUG COMBINATIONS CAN TARGET 629 00:30:17,213 --> 00:30:21,551 SAME PROTEIN, AUTOSTERIC ARE 630 00:30:21,551 --> 00:30:24,554 DRUGS THAT BIND AT THE ACTIVE 631 00:30:24,554 --> 00:30:25,922 SITE, THEY ARE COMPETITIVE WITH 632 00:30:25,922 --> 00:30:27,957 THE SUBSTRATE. 633 00:30:27,957 --> 00:30:31,794 SAME PATHWAY, UPSTREAM AND 634 00:30:31,794 --> 00:30:36,766 DOWNSTREAM PROTEIN, PROEN TOOS, 635 00:30:36,766 --> 00:30:38,501 REDUNDANT PATHWAY SIGNAL THROUGH 636 00:30:38,501 --> 00:30:41,370 SAME FAMILY PROTEINS, PARALLEL 637 00:30:41,370 --> 00:30:43,105 PATHWAYS, SIGNAL TO DIFFERENT 638 00:30:43,105 --> 00:30:47,243 FAMILY PROTEINS. 639 00:30:47,243 --> 00:30:47,543 C 640 00:30:47,543 --> 00:30:50,379 COMPENSATORY PATHWAYS AND THE 641 00:30:50,379 --> 00:30:52,248 COMBINATIONS OF TARGET PROTEINS 642 00:30:52,248 --> 00:30:56,219 IN REDUNDANT AND COMPENSATORY 643 00:30:56,219 --> 00:30:59,222 PATHWAYS CONSIDER MUTATIONS AND 644 00:30:59,222 --> 00:31:03,593 CROSS LINKAGES BETWEEN THEM. 645 00:31:03,593 --> 00:31:05,962 OVER EXPRESSION CONTRIBUTES 646 00:31:05,962 --> 00:31:07,864 DOMINANTLY TO THE NUMBER OF 647 00:31:07,864 --> 00:31:09,799 ACTIVE MOLECULES, COMBINATION 648 00:31:09,799 --> 00:31:12,802 SHOULD INCLUDE TRANS SCRIPTION 649 00:31:12,802 --> 00:31:17,139 FACTOR AND EPIGENETIC MODALATORS 650 00:31:17,139 --> 00:31:18,908 TO HELP IN OVER EXPRESSION. 651 00:31:18,908 --> 00:31:21,344 HERE IS AN EXAMPLE TO EXPLAIN 652 00:31:21,344 --> 00:31:24,380 THE ISSUE OF THE PATHWAYS 653 00:31:24,380 --> 00:31:28,451 BECAUSE DRUG RESISTANCE CAN 654 00:31:28,451 --> 00:31:33,289 BYPASS, CAN BYPASS DRUGS. 655 00:31:33,289 --> 00:31:38,461 SO HOW TO SELECT SMALL MOLECULE 656 00:31:38,461 --> 00:31:38,861 COMBINATIONS. 657 00:31:38,861 --> 00:31:45,568 SO HERE IS FOR EXAMPLE, MAPK 658 00:31:45,568 --> 00:31:50,540 EFGR KIND IS MAJOR RECEPTOR. 659 00:31:50,540 --> 00:31:53,442 HERE IS OUR MAPK, WHICH LEADS TO 660 00:31:53,442 --> 00:31:57,380 CELL SEPARATION AND THIS CELL 661 00:31:57,380 --> 00:31:57,613 GROWTH. 662 00:31:57,613 --> 00:32:00,149 WHAT THEN HAPPENS IS, WHAT CAN 663 00:32:00,149 --> 00:32:03,019 HAPPEN I SHOULD SAY, IS HERE, 664 00:32:03,019 --> 00:32:07,924 OKAY, EGFR. 665 00:32:07,924 --> 00:32:11,994 NOW EGFR HAS A MUTATION HERE 666 00:32:11,994 --> 00:32:13,062 NEXT TO IT. 667 00:32:13,062 --> 00:32:15,865 SO IT IS GOING TO KEEP WORKING 668 00:32:15,865 --> 00:32:22,572 ALL THE TIME, NOT ACTIVATED BY 669 00:32:22,572 --> 00:32:25,141 BINDS AT THE TOP. 670 00:32:25,141 --> 00:32:28,744 THEN THE ONCOLOGIST MAY TARGET 671 00:32:28,744 --> 00:32:31,280 IT HERE WITH ANTIBODY DRUG AND 672 00:32:31,280 --> 00:32:33,783 WITH DRUG, TARGET PROTEINS ONCE 673 00:32:33,783 --> 00:32:36,319 YOU TARGET PROTEIN, YOU ALSO 674 00:32:36,319 --> 00:32:38,888 BLOCK THE PATHWAY. 675 00:32:38,888 --> 00:32:41,757 THEN, HOWEVER, WHAT CAN HAPPEN, 676 00:32:41,757 --> 00:32:50,399 THERE ARE OTHER SAME FAMILY EGF 677 00:32:50,399 --> 00:32:52,735 KINASES, WHICH CAN BE ACTIVATED, 678 00:32:52,735 --> 00:32:56,906 TOO, NOT NECESSARILY NOW WITH 679 00:32:56,906 --> 00:32:59,241 LIGUNS, THEY CAN HAVE MUTATIONS. 680 00:32:59,241 --> 00:33:00,876 THIS IS WHAT HAPPENS. 681 00:33:00,876 --> 00:33:05,247 THEN THEY SUBSTITUTE FOR EGFR 682 00:33:05,247 --> 00:33:06,983 AND ACTIVATORS AND THESE 683 00:33:06,983 --> 00:33:07,850 PATHWAYS. 684 00:33:07,850 --> 00:33:12,088 IN ANOTHER CASE HERE WE SEE RAF 685 00:33:12,088 --> 00:33:16,025 HAS THIS MUTATION, NOW IT IS 686 00:33:16,025 --> 00:33:19,929 INHIBITED, THEN MAKE THIS HERE, 687 00:33:19,929 --> 00:33:25,568 SO THIS MAPK PATHWAY CAN MAP IS 688 00:33:25,568 --> 00:33:29,238 BLOCKED, BUT SIGNALLING CAN GO 689 00:33:29,238 --> 00:33:33,342 VIA MAKE FIVE SAME FAMILY. 690 00:33:33,342 --> 00:33:34,577 SO PATHWAYS. 691 00:33:34,577 --> 00:33:38,881 HOW TO SELECT SMALL MOLECULE 692 00:33:38,881 --> 00:33:40,483 COMBINATIONS, SO THESE ARE THE 693 00:33:40,483 --> 00:33:42,818 MAJOR POSSIBILITIES THAT I SAID 694 00:33:42,818 --> 00:33:44,854 BEFORE HERE. 695 00:33:44,854 --> 00:33:47,256 CAN STOP HERE, FOR EXAMPLE. 696 00:33:47,256 --> 00:33:52,094 SAME PROTEIN COMBINATION, TWO 697 00:33:52,094 --> 00:33:53,262 DRUGS. 698 00:33:53,262 --> 00:33:54,530 HERE, COMBINATION. 699 00:33:54,530 --> 00:33:57,233 STOPPING OR BLOCKING, SAME 700 00:33:57,233 --> 00:33:59,268 PATHWAY HERE AND HERE. 701 00:33:59,268 --> 00:34:02,738 HERE COMBINATION DIFFERENT 702 00:34:02,738 --> 00:34:08,577 PROTEINS ALSO BLOCKING. 703 00:34:08,577 --> 00:34:09,078 HE 704 00:34:09,078 --> 00:34:13,616 HERE, PARALLEL PATHWAYS OR I 705 00:34:13,616 --> 00:34:17,620 THINK HERE -- NO REDUNDANT 706 00:34:17,620 --> 00:34:20,189 PATHWAY, I'M SORRY AND HERE 707 00:34:20,189 --> 00:34:21,524 COMPENSATORY PATHWAY CAN HAPPEN. 708 00:34:21,524 --> 00:34:25,161 SO ALL OF THIS NEEDS WORKING 709 00:34:25,161 --> 00:34:28,164 OUT, WHICH IS BEST COMBINATION 710 00:34:28,164 --> 00:34:29,565 AND ULTIMATELY THE BEST WAY IS 711 00:34:29,565 --> 00:34:35,071 TO KEEP PROTATING SO NEW 712 00:34:35,071 --> 00:34:36,272 MUTATIONS DO NOT COME UP. 713 00:34:36,272 --> 00:34:38,741 OUR QUESTIONS ARE INDEED ON THE 714 00:34:38,741 --> 00:34:39,642 BIOPHYSICAL LEVEL. 715 00:34:39,642 --> 00:34:41,744 I DON'T KNOW IF I'M RUNNING OVER 716 00:34:41,744 --> 00:34:44,580 TIME. 717 00:34:44,580 --> 00:34:44,747 HUH? 718 00:34:44,747 --> 00:34:45,548 I'M FINE. 719 00:34:45,548 --> 00:34:48,517 THEN I WILL MENTION ALSO THAT 720 00:34:48,517 --> 00:34:50,953 OTHER QUESTION THAT I MENTIONED 721 00:34:50,953 --> 00:34:54,356 BEFORE ABOUT THE EPIDEMIOLOGICAL 722 00:34:54,356 --> 00:34:56,092 SURVEYS THAT OBSERVE THAT PEOPLE 723 00:34:56,092 --> 00:34:59,361 WILL AUTISM IS HIGHER RISK OF 724 00:34:59,361 --> 00:35:01,097 CANCER AND THOSE WITH 725 00:35:01,097 --> 00:35:05,701 SCHIZOPHRENIA BY AS MUCH AS 50%. 726 00:35:05,701 --> 00:35:08,370 WHEN WE SAW THIS, WE WERE JUST, 727 00:35:08,370 --> 00:35:09,672 WE DIDN'T KNOW THIS. 728 00:35:09,672 --> 00:35:14,510 THIS IS MEANT PEOPLE WORK ON IT 729 00:35:14,510 --> 00:35:18,514 AT THE NCI. 730 00:35:18,514 --> 00:35:20,216 HOW TO UNDERSTAND THIS. 731 00:35:20,216 --> 00:35:23,119 SO THIS IS WHAT WE HAVE. 732 00:35:23,119 --> 00:35:25,321 AUTISM IS NOT UNIQUE, AUTISM HAS 733 00:35:25,321 --> 00:35:28,424 BEEN ASSOCIATED 734 00:35:28,424 --> 00:35:30,459 EPIDEMIOLOGICALLY WITH THYROID 735 00:35:30,459 --> 00:35:33,796 CANCER, BREAST CANCER, BIPOLAR, 736 00:35:33,796 --> 00:35:36,031 BREAST AND LUNG, SCHIZOPHRENIA, 737 00:35:36,031 --> 00:35:38,400 COLON, LUNG, BREAST AND -- HOW 738 00:35:38,400 --> 00:35:41,303 TO UNDERSTAND THIS. 739 00:35:41,303 --> 00:35:44,206 THE POINT IS THAT THE SAME 740 00:35:44,206 --> 00:35:50,079 PATHWAYS ARE USED. 741 00:35:50,079 --> 00:35:56,118 AND THIS OF COURSE ARE 742 00:35:56,118 --> 00:35:58,888 NEURODEVELOPMENTAL DISORDERS AND 743 00:35:58,888 --> 00:35:59,121 CANCERS. 744 00:35:59,121 --> 00:36:02,458 WE ASK WHY THE INCREASED CANCER 745 00:36:02,458 --> 00:36:02,992 RISK. 746 00:36:02,992 --> 00:36:06,462 SO WE PUZZLED OVER THE 747 00:36:06,462 --> 00:36:07,830 TANTALIZING CROSSTALK BETWEEN 748 00:36:07,830 --> 00:36:10,733 CANCER AND NEURODEVELOPMENTAL 749 00:36:10,733 --> 00:36:11,000 DISORDERS. 750 00:36:11,000 --> 00:36:14,336 WE PUZZLED HOW MUTATIONS IN THE 751 00:36:14,336 --> 00:36:18,841 SAME GENE AND EVEN THE SAME 752 00:36:18,841 --> 00:36:21,577 MUTATIONS CAN LEAD TO SUCH 753 00:36:21,577 --> 00:36:23,979 DIFFERENT FETAL TYPE. 754 00:36:23,979 --> 00:36:28,384 CANCER VERSUS NEURODEVELOPMENTAL 755 00:36:28,384 --> 00:36:30,219 DISORDERS AND WHY PEOPLE WITH 756 00:36:30,219 --> 00:36:31,687 NEURODEVELOPMENTAL DISORDERS 757 00:36:31,687 --> 00:36:33,455 HAVE HIGHER RISK OF CANCER AND 758 00:36:33,455 --> 00:36:36,525 SCHIZOPHRENIA BY AS MUCH AS 50%. 759 00:36:36,525 --> 00:36:40,329 AND THE POINT FOR US, FOR MY 760 00:36:40,329 --> 00:36:44,733 GROUP PERSONALLY, WAS THAT 761 00:36:44,733 --> 00:36:48,003 PROTEINS THAT WE WERE ALREADY 762 00:36:48,003 --> 00:36:51,807 STUDYING, FOR EXAMPLE, RAS, RAF, 763 00:36:51,807 --> 00:36:57,646 ERK, AND P10 ARE AMONG THE 764 00:36:57,646 --> 00:36:59,381 ONCOGENIC PROTEINS THAT CAN 765 00:36:59,381 --> 00:37:01,483 HARBOR MUTATION THAT INCLUDE 766 00:37:01,483 --> 00:37:05,120 NEURODEVELOPMENTAL DISORDERS, 767 00:37:05,120 --> 00:37:10,659 SUCH AS AUTISM, SERB SER BRAL 768 00:37:10,659 --> 00:37:14,897 /* /* CEREBRAL PALSY. 769 00:37:14,897 --> 00:37:16,832 SO MANY WORK ON THIS BUT NOT AT 770 00:37:16,832 --> 00:37:18,200 THE DETAILED LEVEL. 771 00:37:18,200 --> 00:37:20,169 SO HERE WHAT HAPPENED AT THE 772 00:37:20,169 --> 00:37:22,271 TIME, WE WERE LOOKING AT THIS, 773 00:37:22,271 --> 00:37:26,976 WE WERE INVITED TO CONTRIBUTE TO 774 00:37:26,976 --> 00:37:29,511 ISSUE ON BIOPHYSICS OF IMMUNITY 775 00:37:29,511 --> 00:37:35,251 AND CANCER LEADING US TO LOOK 776 00:37:35,251 --> 00:37:37,219 INTO THE ORIGIN OF THE 777 00:37:37,219 --> 00:37:39,455 CONNECTION BETWEEN CANCER AND 778 00:37:39,455 --> 00:37:42,658 NEURODEVELOPMENTAL DISORDERS. 779 00:37:42,658 --> 00:37:44,960 WE SUGGESTED THAT IMMUNITY COULD 780 00:37:44,960 --> 00:37:47,696 BE VIEWED AS A KEY COMMON FACTOR 781 00:37:47,696 --> 00:37:50,366 AND IT IS NEURODEVELOPMENTAL 782 00:37:50,366 --> 00:37:51,734 DISORDERS AND CANCER WITH IMMUNE 783 00:37:51,734 --> 00:37:56,872 AND NERVOUS SYSTEMS EVOLVING AS 784 00:37:56,872 --> 00:37:57,539 EMBRYO DEVELOPS. 785 00:37:57,539 --> 00:38:03,245 SO HERE WE LOOKED, FOR EXAMPLE, 786 00:38:03,245 --> 00:38:07,383 RAS, SAME PROTEIN, SAME MOLECULE 787 00:38:07,383 --> 00:38:11,253 RAS, RAS CAN HAVE MUTATIONS 788 00:38:11,253 --> 00:38:14,089 ASSOCIATED WITH CANCER, FOR 789 00:38:14,089 --> 00:38:17,259 EXAMPLE, HERE ARE CANCER, 790 00:38:17,259 --> 00:38:20,062 MELANOMA, PANCREATIC CANCER, 791 00:38:20,062 --> 00:38:22,498 LUNG CANCER, ETCETERA. 792 00:38:22,498 --> 00:38:32,107 AND ALSO IN RASOOPATHY, ALSO 793 00:38:32,107 --> 00:38:32,775 ASSOCIATED WITH CANCER. 794 00:38:32,775 --> 00:38:37,479 SO HOW TO UNDERSTAND THIS. 795 00:38:37,479 --> 00:38:40,482 HERE WE LOOKED AT P10, THE 796 00:38:40,482 --> 00:38:44,520 PROTEIN IN THE GROUP WAS 797 00:38:44,520 --> 00:38:46,221 SIMULATING, WHERE WE SEE THAT 798 00:38:46,221 --> 00:38:51,460 SAME HERE EVEN SAME MUTATIONS 799 00:38:51,460 --> 00:38:56,165 CAN ENCODE NEURODEVELOPMENTAL 800 00:38:56,165 --> 00:38:57,333 DISORDERS AND CANCER. 801 00:38:57,333 --> 00:39:01,303 SO HERE FOR EXAMPLE, COWDEN 802 00:39:01,303 --> 00:39:03,238 SYNDROME, A NEURODEVELOPMENTAL 803 00:39:03,238 --> 00:39:07,810 DISORDER, WE SEE FOR EXAMPLE, 804 00:39:07,810 --> 00:39:10,746 HY68 IS BOTH HERE AND IN ANOTHER 805 00:39:10,746 --> 00:39:17,453 ONE AND IN GLYOBLASTOMA, VERY 806 00:39:17,453 --> 00:39:19,922 SERIOUS BRAIN CANCER, BRAIN 807 00:39:19,922 --> 00:39:23,225 TUMORS, HERE THIS ONE, H93, 808 00:39:23,225 --> 00:39:27,029 AGAIN, IN COWDEN SYNDROME, IS 809 00:39:27,029 --> 00:39:34,503 ALSO IN ENDOMETRIAL CARCINOMA. 810 00:39:34,503 --> 00:39:37,606 HOW TO UNDERSTAND THIS. 811 00:39:37,606 --> 00:39:40,376 SO DECIPHERING THE CONNECTION 812 00:39:40,376 --> 00:39:41,577 BETWEEN CANCER AND 813 00:39:41,577 --> 00:39:44,279 NEURODEVELOPMENTAL DISORDERS. 814 00:39:44,279 --> 00:39:47,549 OUR GOALS ARE TO FIGURE OUT HOW 815 00:39:47,549 --> 00:39:51,720 SHOULD MUTATIONS LEAD TO THE 816 00:39:51,720 --> 00:39:53,255 TRANSITION OF CELL FROM 817 00:39:53,255 --> 00:39:56,158 NEURODEVELOPMENTAL DISORDERS TO 818 00:39:56,158 --> 00:39:57,893 CANCERS AND TO DEVELOP A 819 00:39:57,893 --> 00:39:59,628 STRATEGY TO PREDICT 820 00:39:59,628 --> 00:40:02,531 NEURODEVELOPMENTAL DISORDER 821 00:40:02,531 --> 00:40:05,267 RELATED MUTATIONS THUS THE RISK 822 00:40:05,267 --> 00:40:09,071 FOR CARRIERS, EVEN IN THE 823 00:40:09,071 --> 00:40:10,572 ABSENCE OF CLINICAL 824 00:40:10,572 --> 00:40:12,007 PRESENTATION, IF WE'RE ABLE TO 825 00:40:12,007 --> 00:40:15,244 DO THIS, IT WOULD HELP IN EARLY 826 00:40:15,244 --> 00:40:19,581 DETECTION AND CARE. 827 00:40:19,581 --> 00:40:21,116 TOWARD THIS AIM WE TEST, HAVE 828 00:40:21,116 --> 00:40:24,386 BEEN TESTING OUR CONCEPT THAT 829 00:40:24,386 --> 00:40:25,721 NEURODEVELOPMENTAL DISORDER 830 00:40:25,721 --> 00:40:28,023 PROMOTING MUTATIONS TEND TO BE 831 00:40:28,023 --> 00:40:32,094 WEAKER THAN THOSE OF CANCERS. 832 00:40:32,094 --> 00:40:33,495 MUSIC ALSO THE BIOWULF. 833 00:40:33,495 --> 00:40:35,764 YEAH. 834 00:40:35,764 --> 00:40:38,434 SIMULATIONS, WE EXPECT CANCER 835 00:40:38,434 --> 00:40:40,035 RELATED BUT NOT INDEED 836 00:40:40,035 --> 00:40:42,571 NEURODEVELOPMENTAL DISORDER 837 00:40:42,571 --> 00:40:45,574 RELATED MUTATIONS WOULD TEND TO 838 00:40:45,574 --> 00:40:51,080 FAVOR CONFORMATIONS SO WE LOOKED 839 00:40:51,080 --> 00:40:55,551 AT ENSEMBLES, THE PROPENSITY OF 840 00:40:55,551 --> 00:40:59,088 THE ENSEMBLE GENOMIC ANALYSIS, 841 00:40:59,088 --> 00:41:01,156 DONE THAT, AS WELL, THIS IS 842 00:41:01,156 --> 00:41:03,792 BIOINFORM ATTICS AND EXPECT 843 00:41:03,792 --> 00:41:06,328 HIGHER LEVELS FOR CERTAIN 844 00:41:06,328 --> 00:41:08,597 ISOFORMS IN EMBRYONIC BRAIN, 845 00:41:08,597 --> 00:41:13,001 CARRIER OF ISOFORM HARBORING 846 00:41:13,001 --> 00:41:15,938 MUTATIONS MAY FACE HIGHER RISK 847 00:41:15,938 --> 00:41:18,273 LATER IN LIFE. 848 00:41:18,273 --> 00:41:22,511 AND THE FREQUENCIES, STRONGER 849 00:41:22,511 --> 00:41:24,546 MUTATIONS TEND TO HAVE HIGHER 850 00:41:24,546 --> 00:41:25,180 FREQUENCIES. 851 00:41:25,180 --> 00:41:27,349 SO I DON'T KNOW IF I SHOULD, LET 852 00:41:27,349 --> 00:41:30,452 ME KNOW WHEN I SHOULD STOP. 853 00:41:30,452 --> 00:41:34,223 SO WHY ARE CANCERS AND 854 00:41:34,223 --> 00:41:37,459 NEURODEVELOPMENTAL DISORDERS 855 00:41:37,459 --> 00:41:40,229 CONNECTED AND WHY IS SIGNALLING 856 00:41:40,229 --> 00:41:44,166 STRONGER IN CANCER AND WEAKER IN 857 00:41:44,166 --> 00:41:47,136 NEURODEVELOPMENTAL DISORDERS? 858 00:41:47,136 --> 00:41:48,837 SO WHY ARE CANCER AND 859 00:41:48,837 --> 00:41:52,274 NEURODEVELOPMENTAL DISORDERS 860 00:41:52,274 --> 00:41:52,508 RELATED? 861 00:41:52,508 --> 00:41:56,845 BOTH ARE DEVELOPMENTAL 862 00:41:56,845 --> 00:41:58,413 DISEASES,ING PROLIFERATION AND 863 00:41:58,413 --> 00:41:59,982 DIFFERENTIATION, DIFFERENTIATION 864 00:41:59,982 --> 00:42:02,818 IS KEY IN NEURODEVELOPMENTAL 865 00:42:02,818 --> 00:42:03,785 DISORDERS. 866 00:42:03,785 --> 00:42:05,554 PROLIFERATION IS THE KEY IN 867 00:42:05,554 --> 00:42:06,054 CANCER. 868 00:42:06,054 --> 00:42:08,590 OF COURSE, BOTH PATHWAYS ARE 869 00:42:08,590 --> 00:42:11,260 NEEDED IN BOTH. 870 00:42:11,260 --> 00:42:13,262 WHY STRONGER SIGNALLING IN 871 00:42:13,262 --> 00:42:15,464 CANCER? 872 00:42:15,464 --> 00:42:19,067 PROLIFERATION IS A HALLMARK OF 873 00:42:19,067 --> 00:42:21,203 CANCER WITH MAP K AND MAJOR 874 00:42:21,203 --> 00:42:23,038 PATHWAY DIFFERENTIATION IS 875 00:42:23,038 --> 00:42:25,274 HALLMARK OF NEURODEVELOPMENTAL 876 00:42:25,274 --> 00:42:30,279 DISORDERS, WITH PIK3, AND MAJOR 877 00:42:30,279 --> 00:42:31,880 PROLIFERATION AND PATHWAY IN 878 00:42:31,880 --> 00:42:33,549 CELL GROWTH, WE HAVE SEEN THIS. 879 00:42:33,549 --> 00:42:37,119 BOTH ASSOCIATED WITH CELL CYCLE 880 00:42:37,119 --> 00:42:38,620 POPULATION, SIGNALLING IN 881 00:42:38,620 --> 00:42:40,289 PROSECUTE LIFERATION IS EXPECTED 882 00:42:40,289 --> 00:42:42,524 TO BE STRONGER, WE HAVE TO LOOK 883 00:42:42,524 --> 00:42:46,695 ALSO AT CHROMA TIN ACCESSIBILITY 884 00:42:46,695 --> 00:42:50,365 AND BECAUSE IT RELATES TO 885 00:42:50,365 --> 00:42:54,469 DIFFERENTIATION CHROMETIN MAKING 886 00:42:54,469 --> 00:43:01,276 MUTATION MORE HIGHLY LIKELY IN 887 00:43:01,276 --> 00:43:02,077 THE AGENT. 888 00:43:02,077 --> 00:43:09,051 AND I'M SORRY, I -- I PRESSED 889 00:43:09,051 --> 00:43:13,422 END SIGNAL STRENGTH DETERMINES 890 00:43:13,422 --> 00:43:16,225 THE DURATION DETERMINES CELL, 891 00:43:16,225 --> 00:43:19,294 THAT WAS OUR CONCLUSION OR 892 00:43:19,294 --> 00:43:19,828 SUGGESTION. 893 00:43:19,828 --> 00:43:21,863 AND FINALLY, JUST TO SAY AGAIN 894 00:43:21,863 --> 00:43:29,071 HERE WHAT I MENTIONED BEFORE, 895 00:43:29,071 --> 00:43:31,640 UNDERSTANDING MECHANISMS ON THE 896 00:43:31,640 --> 00:43:34,743 BASIC STRUCTURAL AND CELLULAR 897 00:43:34,743 --> 00:43:35,277 LEVELS. 898 00:43:35,277 --> 00:43:39,081 I WILL KEEP THE NEXT TWO SLIDES 899 00:43:39,081 --> 00:43:42,751 OF THE PI3K MECHANISM SO THAT I 900 00:43:42,751 --> 00:43:49,224 AM NOT OVER TIME AND JUST 901 00:43:49,224 --> 00:43:50,792 ACKNOWLEDGE MY COLLEAGUES. 902 00:43:50,792 --> 00:43:52,494 THANK YOU VERY MUCH. 903 00:43:52,494 --> 00:44:00,902 [APPLAUSE] 904 00:44:00,902 --> 00:44:02,504 >> ALL RIGHT, SO WE HAVE SOME 905 00:44:02,504 --> 00:44:04,539 TIME FOR QUESTIONS. 906 00:44:04,539 --> 00:44:06,942 THOSE PEOPLE IN THE VIDEOCAST 907 00:44:06,942 --> 00:44:11,046 CAN PRESS THE FEEDBACK BUTTON TO 908 00:44:11,046 --> 00:44:14,116 SEND US QUESTIONS AND YES, WE 909 00:44:14,116 --> 00:44:15,550 HAVE A MICROPHONE IN THE CENTER, 910 00:44:15,550 --> 00:44:17,753 IF YOU WANT TO LINEUP FOR THE 911 00:44:17,753 --> 00:44:19,655 QUESTIONS, PLEASE. 912 00:44:19,655 --> 00:44:20,956 >> I HAVE A QUESTION. 913 00:44:20,956 --> 00:44:25,560 SO WE KNOW THAT AND I HAVE 914 00:44:25,560 --> 00:44:27,596 EXPERIENCED THIS THAT CERTAIN 915 00:44:27,596 --> 00:44:30,732 DRUGS THAT TARGET CANCER CAUSE 916 00:44:30,732 --> 00:44:34,503 LIKE PROBLEMS LIKE CENTRAL 917 00:44:34,503 --> 00:44:36,672 NERVOUS SYSTEM, RIGHT? 918 00:44:36,672 --> 00:44:39,041 LIKE PROBLEMS AND LIKE MOVEMENT 919 00:44:39,041 --> 00:44:40,575 AND MANY, MANY DIFFERENT 920 00:44:40,575 --> 00:44:40,942 PROBLEMS. 921 00:44:40,942 --> 00:44:42,511 I WONDER IF YOU INVESTIGATED 922 00:44:42,511 --> 00:44:47,182 THAT LIKE RESEPTIN, WHAT TYPE OF 923 00:44:47,182 --> 00:44:47,783 INTERACTION HAPPENING THERE? 924 00:44:47,783 --> 00:44:51,286 >> NOT GOING TO -- SO MANY, MANY 925 00:44:51,286 --> 00:44:54,690 QUESTI 926 00:44:54,690 --> 00:44:56,692 QUESTIONS, THERE ARE NO 927 00:44:56,692 --> 00:44:59,561 SIMULATIONS OF SIMULATIONS OF 928 00:44:59,561 --> 00:45:04,066 (AWAY FROM MIC) -- SIMULATION OF 929 00:45:04,433 --> 00:45:06,435 RECEPTORS INVOLVE VERY LARGE, 930 00:45:06,435 --> 00:45:11,239 THERE IS THE MEMBRANE, RIGHT, SO 931 00:45:11,239 --> 00:45:15,410 WE SIMULATE SO MUCH SO WE FOCUS, 932 00:45:15,410 --> 00:45:17,679 WE LOOK AT THEM, WE CONSIDER 933 00:45:17,679 --> 00:45:20,148 THEM, WE ACCOUNT FOR THE ROLES 934 00:45:20,148 --> 00:45:23,251 AND WE LOOK AT CLINICAL AND 935 00:45:23,251 --> 00:45:23,885 EXPERI 936 00:45:23,885 --> 00:45:25,220 EXPERIMENTAL DATA RELATING TO 937 00:45:25,220 --> 00:45:27,656 THEM AND ALWAYS THERE IN OUR 938 00:45:27,656 --> 00:45:35,130 MINDS, LIKE FOR EXAMPLE, 939 00:45:35,130 --> 00:45:36,565 FREQUENTLY MUTATED IN CANCER, WE 940 00:45:36,565 --> 00:45:38,433 DO NOT SIMULATE IT. 941 00:45:38,433 --> 00:45:41,303 I CANNOT FROM OUR WORK, CANNOT 942 00:45:41,303 --> 00:45:41,503 SAY. 943 00:45:41,503 --> 00:45:43,939 >> NO WORRIES. 944 00:45:43,939 --> 00:45:45,540 >> HELLO. 945 00:45:45,540 --> 00:45:48,443 SO WHEN YOU WERE DISCUSSING THE 946 00:45:48,443 --> 00:45:51,346 RISKS OF NEURODEVELOPMENTAL 947 00:45:51,346 --> 00:45:53,749 DISORDERS AND NEUROLOGICAL 948 00:45:53,749 --> 00:45:57,119 MENTAL DISORDERS VERSUS CANCER. 949 00:45:57,119 --> 00:45:58,887 YOU MENTIONED LINK BETWEEN 950 00:45:58,887 --> 00:46:00,489 NEURODEVELOPMENTAL DISORDERS AND 951 00:46:00,489 --> 00:46:02,190 CANCER RISK. 952 00:46:02,190 --> 00:46:03,992 YOU SHOWED I SAW FOR 953 00:46:03,992 --> 00:46:04,793 SCHIZOPHRENIA LINK BETWEEN THAT 954 00:46:04,793 --> 00:46:07,195 AND LUNG CANCER AND COLON 955 00:46:07,195 --> 00:46:07,429 CANCER. 956 00:46:07,429 --> 00:46:09,598 I READ THAT SCHIZOPHRENICS HAVE 957 00:46:09,598 --> 00:46:12,634 HIGHER RISKS OF SMOKING AND 958 00:46:12,634 --> 00:46:14,035 POORER DIETS, HOW DO YOU CONTROL 959 00:46:14,035 --> 00:46:17,105 FOR LIFESTYLE RISK VERSUS 960 00:46:17,105 --> 00:46:17,539 MUTATIONAL RISK? 961 00:46:17,539 --> 00:46:21,476 >> I CANNOT SAY (AWAY FROM 962 00:46:21,476 --> 00:46:32,020 MIC) -- WHAT WE ARE SHOWING AND 963 00:46:33,622 --> 00:46:44,065 HAS DIRECT -- (INAUDIBLE) -- 964 00:46:49,538 --> 00:46:55,143 HYPOTHESIS AND THEN AFTER WE 965 00:46:55,143 --> 00:46:57,245 FORMULATE THE HYPOTHESIS, WE GO 966 00:46:57,245 --> 00:46:59,481 BACK AND WE CHECK AGAINST THE 967 00:46:59,481 --> 00:47:01,516 LITERATURE, ALWAYS, ALWAYS, 968 00:47:01,516 --> 00:47:02,384 ALWAYS WE CHECK. 969 00:47:02,384 --> 00:47:04,286 YOU KNOW, THERE IS BARELY A DAY 970 00:47:04,286 --> 00:47:07,422 THAT I DON'T CHECK LITERATURE, 971 00:47:07,422 --> 00:47:09,291 ALWAYS WE'RE VERY AND 972 00:47:09,291 --> 00:47:12,127 LITERATURE, I MEAN, YES, OTHER 973 00:47:12,127 --> 00:47:13,428 COMPUTATIONS FOR SURE, WE WANT 974 00:47:13,428 --> 00:47:15,096 TO KNOW WHAT OTHER PEOPLE ARE 975 00:47:15,096 --> 00:47:16,131 DOING. 976 00:47:16,131 --> 00:47:17,799 EXPERIMENTAL WORK VERY CRITICAL 977 00:47:17,799 --> 00:47:21,336 SO SIMULATIONS ARE EXTREMELY 978 00:47:21,336 --> 00:47:21,937 IMPORT 979 00:47:21,937 --> 00:47:22,204 IMPORTANT. 980 00:47:22,204 --> 00:47:24,606 I MEAN, THIS IS WHAT WE'RE DOING 981 00:47:24,606 --> 00:47:26,708 OTHERWISE WE WOULDN'T BE 982 00:47:26,708 --> 00:47:32,347 SPENDING SO MUCH OF THE BIOWULF 983 00:47:32,347 --> 00:47:34,583 MONEY BUDGET, SAME TIME ONE HAS 984 00:47:34,583 --> 00:47:36,985 TO BEAR IN MIND, THESE ARE 985 00:47:36,985 --> 00:47:41,289 SIMULATIONS AND THEY NEED ALSO 986 00:47:41,289 --> 00:47:42,691 EXPERIMENTAL VALIDATION, 987 00:47:42,691 --> 00:47:43,992 EXPERIMENTAL AND CLINICAL IN 988 00:47:43,992 --> 00:47:44,593 THIS CASE. 989 00:47:44,593 --> 00:47:45,961 >> GOT YOU. 990 00:47:45,961 --> 00:47:50,866 THANK YOU. 991 00:47:50,866 --> 00:47:53,301 >> SO TO GO ALONG WITH THE TITLE 992 00:47:53,301 --> 00:47:57,105 OF YOUR TALK, I'M JUST CURIOUS, 993 00:47:57,105 --> 00:47:58,673 WHY DO YOU THINK THERE IS NOT 994 00:47:58,673 --> 00:48:03,545 MORE CONTROL MECHANISMS SINCE 995 00:48:03,545 --> 00:48:08,483 RAS MUTATION HAVE DELIRUOUS 996 00:48:08,483 --> 00:48:08,817 EFFECT. 997 00:48:08,817 --> 00:48:10,218 >> I DID NOT UNDERSTAND 998 00:48:10,218 --> 00:48:10,519 QUESTION. 999 00:48:10,519 --> 00:48:14,856 >> I DID NOT FINISH YET, SO WHY 1000 00:48:14,856 --> 00:48:21,363 IS IT THAT THE CIRCUITRY IS NOT 1001 00:48:21,363 --> 00:48:23,431 TRYING TO ACCOUNT FOR THE FACT 1002 00:48:23,431 --> 00:48:30,005 THAT RAS IS SO MUTOGENIC OR WHY 1003 00:48:30,005 --> 00:48:32,741 HAS RAS NOT BECOME EVOLUTIONARY 1004 00:48:32,741 --> 00:48:37,345 WISE LESS MUTOGENIC OR LESS 1005 00:48:37,345 --> 00:48:37,612 MUTATABLE. 1006 00:48:37,612 --> 00:48:40,148 >> THE ISSUE IS AS FOLLOWS, 1007 00:48:40,148 --> 00:48:43,752 CANCER IS VERY, IS BYPASS, 1008 00:48:43,752 --> 00:48:45,487 RIGHT, OF EVOLUTION. 1009 00:48:45,487 --> 00:48:50,425 SAME PATHWAYS, SAME PROTEINS. 1010 00:48:50,425 --> 00:48:53,295 WE ALSO KNOW AND MANY PAPERS 1011 00:48:53,295 --> 00:48:56,298 ABOUT THIS, WE ALSO WITH DEBATE, 1012 00:48:56,298 --> 00:49:01,102 WHAT IS THE MINIMUM NUMBER OF 1013 00:49:01,102 --> 00:49:02,137 MUTATIONS NEEDED FOR CANCER? 1014 00:49:02,137 --> 00:49:04,706 SOME PEOPLE SAY EVERYBODY AGREES 1015 00:49:04,706 --> 00:49:06,341 ONE IS NOT ENOUGH. 1016 00:49:06,341 --> 00:49:10,912 IF ONE WERE ENOUGH, I THINK SO 1017 00:49:10,912 --> 00:49:13,682 VERY MANY PEOPLE WOULD HAVE 1018 00:49:13,682 --> 00:49:13,949 CANCER. 1019 00:49:13,949 --> 00:49:16,017 THINK OF THE PROBABILITY, YOU 1020 00:49:16,017 --> 00:49:17,919 HAVE ALL OF THESE GENES, WHICH 1021 00:49:17,919 --> 00:49:23,959 HAVE SO MANY RESIDUES OR 1022 00:49:23,959 --> 00:49:25,493 NUCLEOTIDES, SO THE CHANCE THAT 1023 00:49:25,493 --> 00:49:28,597 A MUTATION WOULD COME UP IS VERY 1024 00:49:28,597 --> 00:49:28,797 HIGH. 1025 00:49:28,797 --> 00:49:31,032 SO THE QUESTION IS, SO WE KNOW, 1026 00:49:31,032 --> 00:49:32,934 WE NEED MORE THAN ONE MUTATION. 1027 00:49:32,934 --> 00:49:34,769 THE QUESTION IS, WHAT IS THE 1028 00:49:34,769 --> 00:49:36,871 MINIMUM NUMBER. 1029 00:49:36,871 --> 00:49:39,608 SOME PEOPLE FROM JOHNS HOPKINS, 1030 00:49:39,608 --> 00:49:41,376 THEY SUGGESTED THREE, OTHERS 1031 00:49:41,376 --> 00:49:42,577 SUGGESTED MORE. 1032 00:49:42,577 --> 00:49:42,844 ETCETERA. 1033 00:49:42,844 --> 00:49:45,547 I DON'T KNOW, OBVIOUSLY AND 1034 00:49:45,547 --> 00:49:48,683 PROBABLY DEPENDS ON CONTEXT, 1035 00:49:48,683 --> 00:49:50,652 PROBABLY MORE. 1036 00:49:50,652 --> 00:49:54,422 WHAT MY FEELING IS THAT JUST 1037 00:49:54,422 --> 00:49:56,257 LIKE CANCER REQUIRES MORE THAN 1038 00:49:56,257 --> 00:50:00,228 ONE DRIVER MUTATION, 1039 00:50:00,228 --> 00:50:01,830 NEURODEVELOPMENTAL DISORDERS 1040 00:50:01,830 --> 00:50:05,333 ALSO REQUIRE MORE THAN ONE 1041 00:50:05,333 --> 00:50:05,600 MUTATION. 1042 00:50:05,600 --> 00:50:10,171 AND SOME MUTATIONS ARE NOT KNOWN 1043 00:50:10,171 --> 00:50:16,378 TO BE HARBORED BY CERTAIN 1044 00:50:16,378 --> 00:50:19,214 INDIVIDUALS BECAUSE THEY DON'T 1045 00:50:19,214 --> 00:50:21,016 HAVE -- THEY HAVE SAY ONE 1046 00:50:21,016 --> 00:50:23,318 MUTATION OR TWO MUTATIONS, IT 1047 00:50:23,318 --> 00:50:27,022 STILL DOESN'T SHOW, BUT NO 1048 00:50:27,022 --> 00:50:28,456 SYMPTOMS. 1049 00:50:28,456 --> 00:50:28,657 RIGHT? 1050 00:50:28,657 --> 00:50:30,959 BUT WHAT -- AND I THINK THIS IS 1051 00:50:30,959 --> 00:50:35,497 THE KEY HERE, HOWEVER, SINCE IT 1052 00:50:35,497 --> 00:50:38,767 IS THE SAME PROTEIN AND THE SAME 1053 00:50:38,767 --> 00:50:42,170 MUTATIONS, THE CHANCE, THE 1054 00:50:42,170 --> 00:50:45,240 PROBABILITY OF THAT INDIVIDUAL 1055 00:50:45,240 --> 00:50:48,510 HAVING ANOTHER MUTATION WHICH 1056 00:50:48,510 --> 00:50:50,578 WOULD ENHANCE THESE IS HIGHER 1057 00:50:50,578 --> 00:50:53,548 THAN IF YOU DON'T HAVE THESE 1058 00:50:53,548 --> 00:50:54,182 MUTATIONS. 1059 00:50:54,182 --> 00:50:57,185 THESE MUTATIONS ARE OFTEN 1060 00:50:57,185 --> 00:50:58,820 INHERITED, SO THEY CAN COME FROM 1061 00:50:58,820 --> 00:51:02,457 BOTH PARENTS, FROM ONE OF THE 1062 00:51:02,457 --> 00:51:05,326 PARENTS, BUT THE PARENTS DOESN'T 1063 00:51:05,326 --> 00:51:08,096 SHOW ANY FOR EXAMPLE, AUTISM, NO 1064 00:51:08,096 --> 00:51:13,568 AUTISM SYMPTOMS. 1065 00:51:13,568 --> 00:51:13,968 RIGHT? 1066 00:51:13,968 --> 00:51:17,439 BUT MAYBE THE CHILD, THE 1067 00:51:17,439 --> 00:51:22,043 OFFSPRING, IF HE INHERITS MORE 1068 00:51:22,043 --> 00:51:24,579 MUTATIONS, IT CAN -- OR OTHER 1069 00:51:24,579 --> 00:51:26,347 MUTATION DURING DEVELOPMENT 1070 00:51:26,347 --> 00:51:28,616 COMES EMBRYO DEVELOPMENT COMES 1071 00:51:28,616 --> 00:51:32,320 UP, THEN IT WILL SHOW AND THEN 1072 00:51:32,320 --> 00:51:37,058 SIMILARLY FOR CANCER, SEEMS 1073 00:51:37,058 --> 00:51:39,761 MUTANT, WHICH I SHOWED, SEEMS 1074 00:51:39,761 --> 00:51:41,329 MUTATIONS ARE THE SAME, THEY 1075 00:51:41,329 --> 00:51:48,903 ALWAYS HAVE SOME MUTATIONS THAT 1076 00:51:48,903 --> 00:51:50,638 ENCAPSULATE CANCER SO 1077 00:51:50,638 --> 00:51:52,307 PROBABILITY OF HAVING ANOTHER 1078 00:51:52,307 --> 00:51:55,110 MUTATION IS HIGHER THAN 1079 00:51:55,110 --> 00:51:59,013 ACQUIRING THREE, FOUR, FIVE NEW 1080 00:51:59,013 --> 00:52:00,582 MUTATIONS, RIGHT? 1081 00:52:00,582 --> 00:52:04,686 OUR VIEW IS THE PROTEINS ARE THE 1082 00:52:04,686 --> 00:52:07,255 SAME, MUTATIONS ARE THE SAME, 1083 00:52:07,255 --> 00:52:08,490 PATHWAYS ARE THE SAME. 1084 00:52:08,490 --> 00:52:11,226 SO IT IS A QUESTION OF THE 1085 00:52:11,226 --> 00:52:15,330 PROBABILITY, THE INHERITED, YOU 1086 00:52:15,330 --> 00:52:17,932 KNOW, MUTATIONS AND THEN THE 1087 00:52:17,932 --> 00:52:20,168 PROBABILITY AND THE SAME RELATED 1088 00:52:20,168 --> 00:52:22,070 TO WHAT YOU WERE ASKING. 1089 00:52:22,070 --> 00:52:23,304 >> RIGHT. 1090 00:52:23,304 --> 00:52:25,874 SO THE NUMBER OF MUTATIONS, ONE 1091 00:52:25,874 --> 00:52:29,144 IN CANCER, AT LEAST, 1092 00:52:29,144 --> 00:52:31,412 EPIDEMIOLOGICAL CURVES SHOW A 1093 00:52:31,412 --> 00:52:33,581 CERTAIN GROWTH, RIGHT? AND THAT 1094 00:52:33,581 --> 00:52:37,385 GROWTH USUALLY HINTS AT FIVE OR 1095 00:52:37,385 --> 00:52:40,622 SIX MUTATIONS IN TERMS OF ADULT 1096 00:52:40,622 --> 00:52:42,757 CANCERS, NOT CHILDHOOD CANCERS. 1097 00:52:42,757 --> 00:52:45,160 IS THERE ANY SIMILAR 1098 00:52:45,160 --> 00:52:46,928 EPIDEMIOLOGY ON 1099 00:52:46,928 --> 00:52:48,530 NEURODEVELOPMENTAL DISORDERS? 1100 00:52:48,530 --> 00:52:51,666 >> EPIDEMIOLOGY, WE SHOULD 1101 00:52:51,666 --> 00:52:53,668 ALWAYS, OR AT LEAST I 1102 00:52:53,668 --> 00:52:56,271 PERSONALLY, THERE IS SOME -- YOU 1103 00:52:56,271 --> 00:52:58,973 TAKE IT WITH A GRAIN OF SALT, 1104 00:52:58,973 --> 00:52:59,174 RIGHT? 1105 00:52:59,174 --> 00:53:02,644 BECAUSE HOW DO YOU -- SOME 1106 00:53:02,644 --> 00:53:05,313 PEOPLE FOR EXAMPLE, SOCIAL, DOES 1107 00:53:05,313 --> 00:53:09,884 IT MEAN THEY HAVE AUTISM? 1108 00:53:09,884 --> 00:53:11,252 I DON'T KNOW. 1109 00:53:11,252 --> 00:53:17,025 IT THEN DEPENDS HOW EXACTLY YOU 1110 00:53:17,025 --> 00:53:18,493 DEFINE, RIGHT? SO YOU DON'T 1111 00:53:18,493 --> 00:53:19,994 KNOW, THIS IS NUMBER ONE. 1112 00:53:19,994 --> 00:53:23,231 AND NUMBER TWO, OVER THE YEARS, 1113 00:53:23,231 --> 00:53:28,036 THERE WAS NO AWARENESS, 1114 00:53:28,036 --> 00:53:29,571 EPIDEMIOLOGICAL STUDIES, I DON'T 1115 00:53:29,571 --> 00:53:31,673 KNOW, PEOPLE COMPLAIN LESS, THEY 1116 00:53:31,673 --> 00:53:35,777 WENT LESS TO MAYBE YOU KNOW 1117 00:53:35,777 --> 00:53:37,145 PHYSICIANS, DOCTORS, ETCETERA. 1118 00:53:37,145 --> 00:53:41,015 SO IT WAS LESS NOW THERE IS 1119 00:53:41,015 --> 00:53:42,317 INCREASING AWARENESS, RIGHT? 1120 00:53:42,317 --> 00:53:45,420 SO I THINK IT IS THE DEFINITION 1121 00:53:45,420 --> 00:53:48,056 OF THE SYMPTOMS, ETCETERA, AND I 1122 00:53:48,056 --> 00:53:49,657 DON'T KNOW THAT THERE IS A CL 1123 00:53:49,657 --> 00:53:52,160 CLEAR -- YEAH. 1124 00:53:52,160 --> 00:53:57,298 THIS IS ALL VERY -- SO WE DON'T 1125 00:53:57,298 --> 00:54:00,702 GO INTO THIS, WE JUST, THIS IS 1126 00:54:00,702 --> 00:54:03,271 JUST OUR THINKING, WE DO 1127 00:54:03,271 --> 00:54:04,772 SIMULATIONS. 1128 00:54:04,772 --> 00:54:05,039 CURIOSITY. 1129 00:54:05,039 --> 00:54:06,774 >> WHAT WE OBSERVE IS THAT IN 1130 00:54:06,774 --> 00:54:09,177 CAN 1131 00:54:09,177 --> 00:54:13,448 CANCER, THE MUTATIONS PROMOTE A 1132 00:54:13,448 --> 00:54:19,020 HIGHER PROPENSITY OF THE ACTIVE 1133 00:54:19,020 --> 00:54:19,320 C 1134 00:54:19,320 --> 00:54:20,855 CONFORMATION AS COMPARED TO THAT 1135 00:54:20,855 --> 00:54:24,692 OF OTHERS FOR EXAMPLE, THERE IS 1136 00:54:24,692 --> 00:54:25,994 STILL A RANGE FOR SURE. 1137 00:54:25,994 --> 00:54:29,530 YEAH. 1138 00:54:29,530 --> 00:54:32,233 >> EXCELLENT TALK, THANK YOU, I 1139 00:54:32,233 --> 00:54:33,401 LEARNED A LOT. 1140 00:54:33,401 --> 00:54:36,838 ONE EARLIER SLIDE, YOU SHOWED 1141 00:54:36,838 --> 00:54:38,072 DISTANCE BETWEEN TWO -- 1142 00:54:38,072 --> 00:54:40,975 >> CAN YOU SPEAK LOUDER? 1143 00:54:40,975 --> 00:54:43,578 >> MEASURED IN EXTREMES FROM THE 1144 00:54:43,578 --> 00:54:46,147 CRYSTAL STRUCTURE AS COMPARED TO 1145 00:54:46,147 --> 00:54:47,215 MAGNITUDE OF MEASUREMENT FROM 1146 00:54:47,215 --> 00:54:49,384 YOUR SIMULATION, WHAT GAVE YOU 1147 00:54:49,384 --> 00:54:50,818 MORE CONFIDENCE IN -- 1148 00:54:50,818 --> 00:54:51,953 >> WHAT, WHAT? 1149 00:54:51,953 --> 00:54:54,155 >> WHAT GAVE YOU MORE CONFIDENCE 1150 00:54:54,155 --> 00:54:56,491 IN THE MAGNITUDE OF THE 1151 00:54:56,491 --> 00:54:57,358 MEASUREMENT OF THE GAP? 1152 00:54:57,358 --> 00:54:59,360 >> I DON'T KNOW, WHAT I'M SAYING 1153 00:54:59,360 --> 00:55:02,196 IS ONE HAS TO CONSIDER AND ONE 1154 00:55:02,196 --> 00:55:04,565 HAS TO CHECK SIMULATIONS IS 1155 00:55:04,565 --> 00:55:08,336 DEFINITELY ONE WAY AND NMR IS 1156 00:55:08,336 --> 00:55:08,569 ANOTHER. 1157 00:55:08,569 --> 00:55:09,003 YEAH. 1158 00:55:09,003 --> 00:55:12,774 WE KNOW CRYSTAL STRUCTURES 1159 00:55:12,774 --> 00:55:16,878 AFTERALL WE, DO SIMULATIONS, WE 1160 00:55:16,878 --> 00:55:20,114 KNOW ALL OF THESE PROTEINS ARE 1161 00:55:20,114 --> 00:55:21,716 HIGHLY DYNAMIC, CRYSTAL 1162 00:55:21,716 --> 00:55:26,387 STRUCTURE EVENTUAL LY CAPTURE OE 1163 00:55:26,387 --> 00:55:27,422 STATE, RIGHT? THAT PARTICULAR 1164 00:55:27,422 --> 00:55:30,558 STATE IS THE ONE THAT'S FAVORED 1165 00:55:30,558 --> 00:55:33,261 UNDER THE CRYSTALLIZATION 1166 00:55:33,261 --> 00:55:34,829 CONDITIONS, PERIOD. 1167 00:55:34,829 --> 00:55:37,298 FOR MANY YEARS PEOPLE, WE HAD 1168 00:55:37,298 --> 00:55:39,067 ISSUES WITH THAT THINKING, 1169 00:55:39,067 --> 00:55:40,668 CRYSTAL STRUCTURE IS THIS 1170 00:55:40,668 --> 00:55:41,102 STRUCTURE. 1171 00:55:41,102 --> 00:55:43,338 NO SUCH THING AS THIS STRUCTURE. 1172 00:55:43,338 --> 00:55:45,940 IT IS A SNAPSHOT. 1173 00:55:45,940 --> 00:55:46,841 >> THANK YOU VERY MUCH. 1174 00:55:46,841 --> 00:55:49,410 >> WE KNOW THIS AND CRYSTAL 1175 00:55:49,410 --> 00:55:51,512 STRUCTURE DO NOT EXPLAIN, YOU 1176 00:55:51,512 --> 00:55:59,320 KNOW, THOSE FOR EXAMPLE, WHAT I 1177 00:55:59,320 --> 00:56:04,892 SKIPPED OVER HERE, HERE FOR 1178 00:56:04,892 --> 00:56:07,996 EXAMPLE, THE DIFFERENCE HERE 1179 00:56:07,996 --> 00:56:11,899 BETWEEN THE ACTIVE CRYSTAL 1180 00:56:11,899 --> 00:56:14,836 STRUCTURE AND WHAT NEEDS TO BE 1181 00:56:14,836 --> 00:56:18,306 IS VERY LARGE. 1182 00:56:18,306 --> 00:56:20,842 THIS IS THE PI3K, YEAH. 1183 00:56:20,842 --> 00:56:24,312 SO THIS IS, YEAH, I MEAN, WE 1184 00:56:24,312 --> 00:56:29,350 WERE ASKING HERE, THE DISTANCE 1185 00:56:29,350 --> 00:56:31,686 IS NOT THAT DISTANCE. 1186 00:56:31,686 --> 00:56:32,053 OKAY. 1187 00:56:32,053 --> 00:56:36,457 THIS IS DURING CATA LYSIS, THIS 1188 00:56:36,457 --> 00:56:40,628 IS KRI CRYSTAL STRUCTURE AND 1189 00:56:40,628 --> 00:56:43,064 CRYSTAL STRUCTURE DID NOT 1190 00:56:43,064 --> 00:56:43,364 EXPLAIN. 1191 00:56:43,364 --> 00:56:47,035 THIS IS LIPID LIP2. 1192 00:56:47,035 --> 00:56:47,335 YEAH. 1193 00:56:47,335 --> 00:56:47,835 ANYWAY. 1194 00:56:47,835 --> 00:56:49,537 >> THANK YOU FOR THE TALK, IT 1195 00:56:49,537 --> 00:56:50,938 WAS VERY INTERESTING. 1196 00:56:50,938 --> 00:56:52,306 I ACTUALLY HAVE A VERY SIMILAR 1197 00:56:52,306 --> 00:56:55,710 QUESTION REGARDING CRYSTAL 1198 00:56:55,710 --> 00:56:58,012 STRUCTURE VERSUS SIMULATIONS. 1199 00:56:58,012 --> 00:57:00,214 I UNDERSTAND YOU USE -- 1200 00:57:00,214 --> 00:57:00,948 SOMETHING LIKE THAT? 1201 00:57:00,948 --> 00:57:01,949 >> YES. 1202 00:57:01,949 --> 00:57:04,118 MY QUESTION IS, CAN YOU ACTUALLY 1203 00:57:04,118 --> 00:57:06,854 REPRODUCE THE CRYSTAL STRUCTURES 1204 00:57:06,854 --> 00:57:10,591 AND THE CONDITIONS WHICH ARE 1205 00:57:10,591 --> 00:57:12,693 PRESENT WHEN YOU DO 1206 00:57:12,693 --> 00:57:13,061 CRYSTALLIZATION? 1207 00:57:13,061 --> 00:57:15,963 CAN YOU FIRST PROVE YOU CAN 1208 00:57:15,963 --> 00:57:17,665 REPRODUCE CRYSTAL STRUCTURE IN 1209 00:57:17,665 --> 00:57:19,100 CONCERN CONDITIONS AND MOVE ON 1210 00:57:19,100 --> 00:57:23,171 TO CONDITIONS IN REAL LIFE CELL? 1211 00:57:23,171 --> 00:57:26,941 >> SO THIS IS A FANTASTIC 1212 00:57:26,941 --> 00:57:28,476 QUESTION, BUT WHAT WE DO USUALLY 1213 00:57:28,476 --> 00:57:30,411 IS OTHER WAY AROUND, WE START 1214 00:57:30,411 --> 00:57:32,080 WITH THE CRYSTAL STRUCTURE, 1215 00:57:32,080 --> 00:57:32,280 RIGHT? 1216 00:57:32,280 --> 00:57:37,885 WE CAN START WITH A MODEL 1217 00:57:37,885 --> 00:57:39,320 STRUCTURE, RIGHT? THERE ARE 1218 00:57:39,320 --> 00:57:43,791 MANY, DEPENDING ON ACCURACY OF 1219 00:57:43,791 --> 00:57:46,727 THE MODELING AND AS WE KNOW, 1220 00:57:46,727 --> 00:57:49,564 THERE WOULD BE SOME BARRIERS, 1221 00:57:49,564 --> 00:57:49,764 RIGHT? 1222 00:57:49,764 --> 00:57:53,101 THE QUESTION OF SIMULATION TIME, 1223 00:57:53,101 --> 00:57:56,137 MULTIPLE TRAJECTORIES, ETCETERA, 1224 00:57:56,137 --> 00:57:56,537 ETCETERA. 1225 00:57:56,537 --> 00:57:58,739 BUT THERE ARE CASES WE HAVE 1226 00:57:58,739 --> 00:58:04,779 LOOKED AND WE HAVE CAPTURED OVER 1227 00:58:04,779 --> 00:58:07,482 THE YEARS, WE STARTED FOR 1228 00:58:07,482 --> 00:58:11,786 EXAMPLE MODELING BASED ON CRY-OM 1229 00:58:11,786 --> 00:58:14,956 OR VICE VERSA, I CAN'T REMEMBER 1230 00:58:14,956 --> 00:58:16,424 FOR SURE, QUITE A NUMBER OF 1231 00:58:16,424 --> 00:58:17,358 YEARS AGO. 1232 00:58:17,358 --> 00:58:17,558 YEAH. 1233 00:58:17,558 --> 00:58:20,228 >> YOU USUALLY TREAT WATER AS 1234 00:58:20,228 --> 00:58:21,762 EXPLICIT OR IMPLICIT? 1235 00:58:21,762 --> 00:58:24,699 >> EXPLICIT, ALWAYS EXPLICIT. 1236 00:58:24,699 --> 00:58:29,337 >> HOW ABOUT IONS PRESENT? 1237 00:58:29,337 --> 00:58:31,072 >> ALWAYS, WE ARE PARTICULAR 1238 00:58:31,072 --> 00:58:33,975 ABOUT EXPERIMENTAL, SIMULATION 1239 00:58:33,975 --> 00:58:36,744 CONDITION, ALWAYS EXPLICIT. 1240 00:58:36,744 --> 00:58:38,746 YES, I GUESS THAT IS WHAT YOU 1241 00:58:38,746 --> 00:58:41,182 ARE INTO. 1242 00:58:41,182 --> 00:58:41,482 [LAUGHTER] 1243 00:58:41,482 --> 00:58:42,517 >> WE SHARE THIS. 1244 00:58:42,517 --> 00:58:46,854 IT IS FASTER IF IT IS NOT 1245 00:58:46,854 --> 00:58:50,525 EXPLICIT, RIGHT? BUT, USING THE 1246 00:58:50,525 --> 00:58:57,565 BIOWULF, WE ARE ABLE TO DO THIS. 1247 00:58:57,565 --> 00:58:58,566 YES. 1248 00:58:58,566 --> 00:59:02,036 >> LAST QUESTION FROM THE 1249 00:59:02,036 --> 00:59:02,537 VIDEOCAST. 1250 00:59:02,537 --> 00:59:05,106 RAS AND GRAPH MUTATIONS THAT 1251 00:59:05,106 --> 00:59:09,076 OCCUR IN EMBRYONIC SITES DO NOT 1252 00:59:09,076 --> 00:59:14,115 CAUSE MELANOMA IN ADULT CYTES DO 1253 00:59:14,115 --> 00:59:18,019 LEAD TO MELANOMA, WHAT IS 1254 00:59:18,019 --> 00:59:21,355 DIFFERENCE IN EMBRYO AND ADULT 1255 00:59:21,355 --> 00:59:21,822 CELLS? 1256 00:59:21,822 --> 00:59:24,125 >> I DON'T EXACTLY KNOW WHAT IS 1257 00:59:24,125 --> 00:59:26,661 THE DIFFERENCE BETWEEN THE 1258 00:59:26,661 --> 00:59:29,330 EMBRYO AND THE ADULT AS FAR AS 1259 00:59:29,330 --> 00:59:31,132 CELL CYCLE, IT IS ACTUALLY VERY 1260 00:59:31,132 --> 00:59:32,333 IMPORTANT QUESTION. 1261 00:59:32,333 --> 00:59:34,235 I DON'T EXACTLY KNOW. 1262 00:59:34,235 --> 00:59:39,073 BUT WE KNOW THAT AS I SAY 1263 00:59:39,073 --> 00:59:41,342 DIFFERENTIATION IS VERY 1264 00:59:41,342 --> 00:59:41,842 IMPORTANT. 1265 00:59:41,842 --> 00:59:45,546 THIS IS IN THE EMBRYO CELLS HAVE 1266 00:59:45,546 --> 00:59:47,949 TO DIFFERENTIATE, RIGHT? COMING 1267 00:59:47,949 --> 00:59:52,253 BACK TO CANCER, IN CANCER, IN 1268 00:59:52,253 --> 00:59:54,555 TUMORS, CELLS DIFFERENTIATE AND 1269 00:59:54,555 --> 00:59:56,190 GO BACK. 1270 00:59:56,190 --> 00:59:56,490 RIGHT? 1271 00:59:56,490 --> 00:59:59,327 THEY GO BACK IN EVOLUTION. 1272 00:59:59,327 --> 01:00:00,861 YEAH. 1273 01:00:00,861 --> 01:00:03,164 SO -- 1274 01:00:03,164 --> 01:00:04,165 >> THANK YOU. 1275 01:00:04,165 --> 01:00:06,867 >> AND THANK YOU VERY MUCH. 1276 01:00:06,867 --> 01:00:13,007 [APPLAUSE] 1277 01:00:13,007 --> 01:00:15,076 >> SO I GUESS I CLOSE.