1 00:00:05,106 --> 00:00:06,440 WELCOME. 2 00:00:06,440 --> 00:00:08,876 WELCOME, EVERYBODY, TO THIS 3 00:00:08,876 --> 00:00:19,287 ANNUAL EVENT AT OUR OWN 4 00:00:22,156 --> 00:00:22,523 WOMEN SCIENTISTS. 5 00:00:22,523 --> 00:00:25,493 MY NAME IS DORIS WU, I'M AN 6 00:00:25,493 --> 00:00:26,794 INVESTIGATOR AT NIDCD. 7 00:00:26,794 --> 00:00:28,663 I'LL BE THE MODERATOR FOR 8 00:00:28,663 --> 00:00:29,197 TODAY'S LECTURE. 9 00:00:29,197 --> 00:00:34,468 SO YOU CAN ENTER YOUR QUESTIONS 10 00:00:34,468 --> 00:00:35,736 AT THE BOX BELOW AND YOUR 11 00:00:35,736 --> 00:00:36,437 QUESTIONS WILL BE ANSWERED 12 00:00:36,437 --> 00:00:38,706 DURING THE Q & A SESSION. 13 00:00:38,706 --> 00:00:41,008 SO NOW I'D LIKE TO INTRODUCE OUR 14 00:00:41,008 --> 00:00:45,580 NEWLY ELECTED CHAIRPERSON OF THE 15 00:00:45,580 --> 00:00:51,853 WSA, DR. GIGI STORZ AT NICHD. 16 00:00:51,853 --> 00:00:53,354 >> THANK YOU, DORIS, AND ALSO 17 00:00:53,354 --> 00:00:55,022 THANK YOU, DORIS, FOR ALL THAT 18 00:00:55,022 --> 00:00:58,693 YOU'VE DONE TO ORGANIZE THE 2024 19 00:00:58,693 --> 00:01:01,262 LECTURE. 20 00:01:01,262 --> 00:01:05,833 SO AS DOOR DORIS MENTIONED, I M 21 00:01:05,833 --> 00:01:07,134 CURRENTLY SERVING AS CHAIR OF 22 00:01:07,134 --> 00:01:10,204 THE NIH WOMENS SCIENTISTS 23 00:01:10,204 --> 00:01:11,072 ADVISORS. 24 00:01:11,072 --> 00:01:13,274 THIS GROUP HAS BEEN AROUND FOR 25 00:01:13,274 --> 00:01:20,047 OVER 30 YEARS NOW ADVOCATING AND 26 00:01:20,047 --> 00:01:21,816 PROMOTING WOMEN SCIENTISTS AN 27 00:01:21,816 --> 00:01:23,451 THE RESEARCH THAT THEY ARE 28 00:01:23,451 --> 00:01:23,784 CONDUCTING. 29 00:01:23,784 --> 00:01:26,420 ONE OF THE MOST IMPORTANT 30 00:01:26,420 --> 00:01:28,789 EEFNLTS THAT IS CARRIED OUT 31 00:01:28,789 --> 00:01:32,727 EVERY YEAR IS THIS ANITA ROBERTS 32 00:01:32,727 --> 00:01:33,728 LECTURE, AND I THINK IT'S 33 00:01:33,728 --> 00:01:35,263 APPROPRIATE TO SAY A FEW WORDS 34 00:01:35,263 --> 00:01:41,168 ABOUT DR. ROBERTS. 35 00:01:41,168 --> 00:01:44,672 SO DR. ROBERTS CAME TO NIH IN 36 00:01:44,672 --> 00:01:48,276 1976 AND SPENT 30 YEARS AT NCI, 37 00:01:48,276 --> 00:01:51,112 RISING TO THE POSITION OF CHIEF 38 00:01:51,112 --> 00:01:52,980 OF THE LABORATORY OF CELL 39 00:01:52,980 --> 00:01:57,118 REGULATION AND CARCINOGENESIS AT 40 00:01:57,118 --> 00:01:59,320 A TIME WHEN NOT MANY WOMEN WERE 41 00:01:59,320 --> 00:02:00,755 THE CHIEFS OF LABORATORIES. 42 00:02:00,755 --> 00:02:04,458 SHE DID REALLY SEMINAL WORK 43 00:02:04,458 --> 00:02:07,428 FOCUSED PRIMARILY ON TGF BETA 44 00:02:07,428 --> 00:02:09,597 AND ITS ROLE IN THE GROWTH OF 45 00:02:09,597 --> 00:02:13,200 EPITHELIAL AND LYMPHOID CELLS. 46 00:02:13,200 --> 00:02:16,170 AND FOR QUITE A LONG PERIOD, SHE 47 00:02:16,170 --> 00:02:18,239 WAS ONE OF THE 50 MOST CITED 48 00:02:18,239 --> 00:02:20,474 SCIENTISTS. 49 00:02:20,474 --> 00:02:25,146 BUT IN ADDITION TO REALLY HAVING 50 00:02:25,146 --> 00:02:29,817 HER GROUP CONDUCT THIS 51 00:02:29,817 --> 00:02:31,085 GROUNDBREAKING WORK, ANITA WAS 52 00:02:31,085 --> 00:02:34,655 ALSO A SUPERSTAR MENTOR AND WAS 53 00:02:34,655 --> 00:02:38,059 REALLY RECOGNIZED FOR HER 54 00:02:38,059 --> 00:02:41,228 MENTORING TALENT, AND ALSO HER 55 00:02:41,228 --> 00:02:42,530 ABILITY TO BALANCE HER FAMILY 56 00:02:42,530 --> 00:02:46,067 AND PROMOTE HER FAMILY AND HER 57 00:02:46,067 --> 00:02:48,636 WORK LIFE. 58 00:02:48,636 --> 00:02:50,404 SO IT IS FOR THESE 59 00:02:50,404 --> 00:02:54,342 ACCOMPLISHMENTS THAT DR. ROBERTS 60 00:02:54,342 --> 00:02:56,177 IS CELEBRATED WITH THE ANITA 61 00:02:56,177 --> 00:02:56,744 ROBERTS LECTURE. 62 00:02:56,744 --> 00:02:59,246 I ALSO WANT TO POINT OUT THAT 63 00:02:59,246 --> 00:03:02,550 ONE OTHER RECOGNITION OF 64 00:03:02,550 --> 00:03:05,052 DR. ROBERTS' CONTRIBUTION CAN BE 65 00:03:05,052 --> 00:03:06,354 FOUND ON THE NIH CAMPUS. 66 00:03:06,354 --> 00:03:08,222 THIS IS ACTUALLY ONE OF MY 67 00:03:08,222 --> 00:03:10,858 FAVORITE PLACES ON THE NIH 68 00:03:10,858 --> 00:03:14,462 CAMPUS, AND THAT IS A FROG IN 69 00:03:14,462 --> 00:03:16,664 HONOR OF DR. ROBERTS. 70 00:03:16,664 --> 00:03:19,834 THIS FROG IS SITTING OUTSIDE OF 71 00:03:19,834 --> 00:03:23,337 BUILDING 35, OUTSIDE THE -- 72 00:03:23,337 --> 00:03:24,638 BUILDING 37, OUTSIDE OF THE 73 00:03:24,638 --> 00:03:25,639 BUILDING WHERE DR. ROBERTS USED 74 00:03:25,639 --> 00:03:28,342 TO WORK, AND IT'S FUN TO SEE 75 00:03:28,342 --> 00:03:30,978 EVERY ONCE IN A WHILE THE FROG 76 00:03:30,978 --> 00:03:32,880 GETS A NEW PIECE OF CLOTHING AND 77 00:03:32,880 --> 00:03:35,783 MOST RECENTLY, IT GOT DRESSED UP 78 00:03:35,783 --> 00:03:37,885 FOR HALLOWEEN. 79 00:03:37,885 --> 00:03:42,256 SO IN ADDITION TO REMEMBERS 80 00:03:42,256 --> 00:03:43,391 DR. ANITA ROBERTS WITH THIS 81 00:03:43,391 --> 00:03:45,326 FROG, THERE IS ALSO THIS LECTURE 82 00:03:45,326 --> 00:03:48,863 SERIES, WHICH WAS STARTED IN 83 00:03:48,863 --> 00:03:52,867 2006 WITH DR. ELIZABETH NABEL. 84 00:03:52,867 --> 00:03:56,470 TODAY, WE WILL HAVE THE 25TH 85 00:03:56,470 --> 00:04:02,576 LECTURE IN THIS SERIES WITH 86 00:04:02,576 --> 00:04:05,212 DR. CAROLINA BARILLAS, AND 87 00:04:05,212 --> 00:04:07,181 WITHOUT FURTHER ADO, I'M GOING 88 00:04:07,181 --> 00:04:08,949 TO HAVE TWO REPRESENTATIVES OF 89 00:04:08,949 --> 00:04:11,152 THE WOMEN'S FELLOW COMMITTEE 90 00:04:11,152 --> 00:04:13,421 ACTUALLY INTRODUCE TODAY'S 91 00:04:13,421 --> 00:04:17,792 SPEAKER, AND THOSE ARE 92 00:04:17,792 --> 00:04:25,766 DR. CARRIE LONG AND DR. MUNA 93 00:04:25,766 --> 00:04:27,635 FUYAL. 94 00:04:27,635 --> 00:04:28,836 CARRIE, DO YOU WANT TO TAKE 95 00:04:28,836 --> 00:04:29,036 OVER? 96 00:04:29,036 --> 00:04:31,906 >> GOOD AFTERNOON, EVERYONE. 97 00:04:31,906 --> 00:04:33,207 TODAY WE HAVE THE PRIVILEGE OF 98 00:04:33,207 --> 00:04:34,341 WELCOMING A VISIONARY LEADER TO 99 00:04:34,341 --> 00:04:34,742 THE STAGE. 100 00:04:34,742 --> 00:04:39,346 FOR THE 2024 ANITA ROBERTS 101 00:04:39,346 --> 00:04:41,215 LECTURE, DR. CAROLINA 102 00:04:41,215 --> 00:04:46,120 BARILLAS-MURY WILL BE PRESENTING 103 00:04:46,120 --> 00:04:53,461 AN IMPRESSIVE BODY OF WORK. 104 00:04:53,461 --> 00:04:55,763 SHE RECEIVED A PH.D. IN 105 00:04:55,763 --> 00:04:56,864 CHEMISTRY FROM THE UNIVERSITY OF 106 00:04:56,864 --> 00:04:57,932 ARIZONA TUCSON. 107 00:04:57,932 --> 00:04:59,366 IN 2003, DR. BARILLAS-MURY BEGAN 108 00:04:59,366 --> 00:05:00,901 HER TENURE AS AN INVESTIGATOR IN 109 00:05:00,901 --> 00:05:03,637 THE LABORATORY OF MALARIA AND 110 00:05:03,637 --> 00:05:04,305 VECTOR RESEARCH. 111 00:05:04,305 --> 00:05:05,539 THIS IS WITHIN THE NATIONAL 112 00:05:05,539 --> 00:05:06,907 INSTITUTE OF ALLERGY AND 113 00:05:06,907 --> 00:05:07,908 INFECTIOUS DISEASE. 114 00:05:07,908 --> 00:05:09,343 SHE HAS SERVED AS HEAD OF THE 115 00:05:09,343 --> 00:05:11,078 NIH MALARIA RESEARCH PROGRAM AND 116 00:05:11,078 --> 00:05:12,446 IS CURRENTLY BOTH A 117 00:05:12,446 --> 00:05:13,447 DISTINGUISHED INVESTIGATOR AND 118 00:05:13,447 --> 00:05:16,450 IS A LABORATORY CHIEF OF THE 119 00:05:16,450 --> 00:05:17,084 LNBR. 120 00:05:17,084 --> 00:05:19,920 DR. BARILLAS-MURY HAS AUTHORED 121 00:05:19,920 --> 00:05:20,688 124 PEER REVIEWED PUBLICATIONS 122 00:05:20,688 --> 00:05:21,689 HIGHLIGHTING HER EMINENCE IN THE 123 00:05:21,689 --> 00:05:23,424 FIELD OF MALARIA RESEARCH AND 124 00:05:23,424 --> 00:05:24,325 TROPICAL MEDICINE. 125 00:05:24,325 --> 00:05:25,726 HER ACCOLADES INCLUDE BUT ARE 126 00:05:25,726 --> 00:05:28,429 NOT LIMITED TO BEING ELECTED AS 127 00:05:28,429 --> 00:05:30,464 A FELLOW TO BOTH THE NATIONAL 128 00:05:30,464 --> 00:05:32,299 ACADEMIES OF MED SUN AND SCIENCE 129 00:05:32,299 --> 00:05:35,035 AND WINNING THE SANOFI PASTEUR 130 00:05:35,035 --> 00:05:36,270 AWARD. 131 00:05:36,270 --> 00:05:38,072 NOW I'LL HAND IT OFF TO MUNA. 132 00:05:38,072 --> 00:05:41,375 >> THANKS, CARRIE, HELLO, 133 00:05:41,375 --> 00:05:41,642 EVERYONE. 134 00:05:41,642 --> 00:05:44,211 TODAY WE ARE GATHERED NOT ONLY 135 00:05:44,211 --> 00:05:45,746 TO CELEBRATE DR. BARILLAS-MURY'S 136 00:05:45,746 --> 00:05:46,413 SCIENTIFIC CONTRIBUTIONS BUT 137 00:05:46,413 --> 00:05:48,449 ALSO IN THE SPIRIT OF ANITA 138 00:05:48,449 --> 00:05:50,818 ROBERTS TO LAUDE HER EXCELLENT 139 00:05:50,818 --> 00:05:52,353 MENTORSHIP. 140 00:05:52,353 --> 00:05:53,854 DR. BARILLAS-MURY HAS TRAINED 141 00:05:53,854 --> 00:05:55,789 OVER 50 YOUNG SCIENTISTS 142 00:05:55,789 --> 00:05:57,558 INCLUDING POSTBAC, GRADUATE 143 00:05:57,558 --> 00:05:58,859 STUDENTS AND POSTDOCTORAL 144 00:05:58,859 --> 00:05:59,426 FELLOWS. 145 00:05:59,426 --> 00:06:00,728 THESE TRAINEES HAVE GONE ON TO 146 00:06:00,728 --> 00:06:02,796 HAVE SUCCESSFUL CAREERS IN 147 00:06:02,796 --> 00:06:04,465 ACADEMIA, INDUSTRY, AND 148 00:06:04,465 --> 00:06:05,666 GOVERNMENT ROLES, BOTH WITHIN 149 00:06:05,666 --> 00:06:08,068 THE U.S. AND INTERNATIONALLY. 150 00:06:08,068 --> 00:06:09,603 IN RECOGNITION OF THE POSITIVE 151 00:06:09,603 --> 00:06:13,407 IMPACT ON THE PROFESSIONAL 152 00:06:13,407 --> 00:06:15,843 DEVELOPMENT OF POSTDOCTORAL 153 00:06:15,843 --> 00:06:21,415 FELLOWS, SHE WAS AWARDED THE 154 00:06:21,415 --> 00:06:24,985 2013 OUTSTANDING MENTOR AWARD. 155 00:06:24,985 --> 00:06:29,123 SHE ALSO MENTORS A GROUP OF FIVE 156 00:06:29,123 --> 00:06:31,025 TENURE TRACK INVESTIGATORS WITH 157 00:06:31,025 --> 00:06:32,760 THE AIM OF BUILDING A MORE 158 00:06:32,760 --> 00:06:35,296 INCLUSIVE COMMUNITY WITHIN THE 159 00:06:35,296 --> 00:06:35,896 INTRAMURAL RESEARCH PROGRAM. 160 00:06:35,896 --> 00:06:37,131 IT WAS NOT A SURPRISE TO ME WHEN 161 00:06:37,131 --> 00:06:40,100 I REACHED OUT TO HER PAST 162 00:06:40,100 --> 00:06:41,735 TRAINEES ABOUT HER MENTORSHIP 163 00:06:41,735 --> 00:06:43,370 AND THEY GOT BACK WITH THE 164 00:06:43,370 --> 00:06:43,871 WARMEST REPORTS ON HER. 165 00:06:43,871 --> 00:06:45,206 I'M GOING TO SHARE SOME OF THEIR 166 00:06:45,206 --> 00:06:46,874 WORDS HERE. 167 00:06:46,874 --> 00:06:48,509 DR. CAROLINA BARILLAS-MURY IS AN 168 00:06:48,509 --> 00:06:52,246 EXCEPTIONAL MENTOR AND 169 00:06:52,246 --> 00:06:53,881 SCIENTIST, ADMIRED FOR HUR 170 00:06:53,881 --> 00:06:54,748 UNWAVERING DEDICATION TO 171 00:06:54,748 --> 00:06:55,616 SCIENTIFIC EXCELLENCE AND HER 172 00:06:55,616 --> 00:06:59,887 GENERGENUINE COMMITMENT TO HER 173 00:06:59,887 --> 00:07:02,223 TRAINEES' GROWTH AND SUCCESS. 174 00:07:02,223 --> 00:07:03,624 SEEING THE SIGNIFICANT TIME AND 175 00:07:03,624 --> 00:07:05,593 EFFORT INTO UNDERSTANDING OUR 176 00:07:05,593 --> 00:07:06,894 INDIVIDUAL ASPIRATIONS AND 177 00:07:06,894 --> 00:07:08,395 PROVIDES GUIDANCE AND SUPPORT. 178 00:07:08,395 --> 00:07:09,296 WHETHER IT IS WRITING 179 00:07:09,296 --> 00:07:10,264 RECOMMENDATION LETTERS, 180 00:07:10,264 --> 00:07:11,465 CONNECTING US WITH THE KEY 181 00:07:11,465 --> 00:07:13,434 CONTACTS IN THE FIELD, OR 182 00:07:13,434 --> 00:07:14,868 PROVIDING STRATEGIC ADVICE FOR 183 00:07:14,868 --> 00:07:16,737 OUR CAREER DEVELOPMENT, SHE IS 184 00:07:16,737 --> 00:07:18,305 ALWAYS THERE TO HELP US NAVIGATE 185 00:07:18,305 --> 00:07:21,442 OUR PATHS TO SUCCESS. 186 00:07:21,442 --> 00:07:23,477 I JOINED CAROLINA'S LAB WHEN SHE 187 00:07:23,477 --> 00:07:26,914 FIRST STARTED AT THE NIH AND WAS 188 00:07:26,914 --> 00:07:27,448 HER FIRST PH.D. STUDENT. 189 00:07:27,448 --> 00:07:29,083 I HAD THE PRIVILEGE OF 190 00:07:29,083 --> 00:07:30,751 WITNESSING FIRSTHAND HER 191 00:07:30,751 --> 00:07:33,254 EXTRAORDINARY COMMITMENT TO 192 00:07:33,254 --> 00:07:35,889 SCIENTIFIC EXCELLENCE, HER 193 00:07:35,889 --> 00:07:36,857 INNOVATIVE APPROACH TO RESEARCH 194 00:07:36,857 --> 00:07:38,292 AND HER UNWAVERING DEDICATION TO 195 00:07:38,292 --> 00:07:40,694 THE GROWTH AND DEVELOPMENT OF 196 00:07:40,694 --> 00:07:43,430 HER RESEARCH GROUP MEMBERS. 197 00:07:43,430 --> 00:07:44,732 SHE CONSISTENTLY CHALLENGED ME 198 00:07:44,732 --> 00:07:46,600 TO THINK CRITICALLY AND 199 00:07:46,600 --> 00:07:47,368 CREATIVELY. 200 00:07:47,368 --> 00:07:48,736 HER PASSION FOR SCIENCE AND HER 201 00:07:48,736 --> 00:07:51,405 SENSE OF HUMOR ARE INFECTIOUS, 202 00:07:51,405 --> 00:07:53,474 AND IT HAS INSTILLED IN ME A 203 00:07:53,474 --> 00:07:56,310 DEEP SENSE OF PURPOSE AND 204 00:07:56,310 --> 00:07:59,613 ENTHUSIASM FOR MY RESEARCH. 205 00:07:59,613 --> 00:08:02,116 CAROLINA IS AN EXCELLENT MENTOR 206 00:08:02,116 --> 00:08:03,117 AND SCIENTIST, DISTINGUISHED BY 207 00:08:03,117 --> 00:08:04,985 HER UNWAVERING SCIENTIFIC RIGOR 208 00:08:04,985 --> 00:08:07,054 AND EXEMPLARY WORK ETHIC. 209 00:08:07,054 --> 00:08:09,456 MY TIME IN CAROLINA'S LAB WAS 210 00:08:09,456 --> 00:08:10,824 PIVOTAL IN SECURING A PERMANENT 211 00:08:10,824 --> 00:08:12,393 POSITION. 212 00:08:12,393 --> 00:08:13,927 HER MENTORSHIP LEFT A LASTING 213 00:08:13,927 --> 00:08:17,131 IMPACT ON MY CRITICAL THINKING 214 00:08:17,131 --> 00:08:18,299 SKILLS, ENABLING ME TO POSE 215 00:08:18,299 --> 00:08:19,633 SCIENTIFIC QUESTIONS WITH A 216 00:08:19,633 --> 00:08:20,934 LEVEL OF DEPTH AND PRECISION I 217 00:08:20,934 --> 00:08:22,136 WOULD NOT HAVE ACHIEVED 218 00:08:22,136 --> 00:08:25,306 OTHERWISE. 219 00:08:25,306 --> 00:08:26,307 DR. CAROLINA BARILLAS-MURY IS A 220 00:08:26,307 --> 00:08:28,375 BEACON OF SCIENTIFIC INTEGRITY 221 00:08:28,375 --> 00:08:29,677 AND MENTORSHIP. 222 00:08:29,677 --> 00:08:31,445 WITHOUT HER KIND GUIDANCE AND 223 00:08:31,445 --> 00:08:33,247 MORAL SUPPORT, I COULD NOT GIVE 224 00:08:33,247 --> 00:08:36,617 THE FAMOUS PAPER ON TIME BOMB 225 00:08:36,617 --> 00:08:39,119 THEORY, AND THE TENURE TRACK 226 00:08:39,119 --> 00:08:40,387 FACULTY AT MY CURRENT INSTITUTE. 227 00:08:40,387 --> 00:08:41,522 HER COMMITMENT TO ADVANCING 228 00:08:41,522 --> 00:08:43,357 SCIENCE WHILE NURTURING THE NEXT 229 00:08:43,357 --> 00:08:44,992 GENERATION OF SCIENTISTS 230 00:08:44,992 --> 00:08:48,395 INCLUDING MYSELF IS TRULY 231 00:08:48,395 --> 00:08:49,830 INSPIRING. 232 00:08:49,830 --> 00:08:51,031 HER WILLINGNESS TO INVEST TIME 233 00:08:51,031 --> 00:08:52,199 AND EFFORT INTO OUR GROWTH HAS 234 00:08:52,199 --> 00:08:54,501 HAD A LASTING IMPACT ON ALL OF 235 00:08:54,501 --> 00:08:54,935 US. 236 00:08:54,935 --> 00:08:57,037 I STILL REMEMBER WHEN SHE USED 237 00:08:57,037 --> 00:08:58,572 TO SING AND DANCE IN THE LAB 238 00:08:58,572 --> 00:09:00,974 WHEN WE GOT GREAT DATA AND 239 00:09:00,974 --> 00:09:02,710 DISCOVERY, AND I DO THE SAME 240 00:09:02,710 --> 00:09:07,114 WITH MY STUDENTS IN KOREA. 241 00:09:07,114 --> 00:09:08,749 A FEW OF THE THINGS I ADMIRE 242 00:09:08,749 --> 00:09:11,785 MOST ABOUT CAROLINA ARE HER 243 00:09:11,785 --> 00:09:12,553 UNPARALLELED SCIENTIFIC 244 00:09:12,553 --> 00:09:13,754 KNOWLEDGE COMBINED WITH GREAT 245 00:09:13,754 --> 00:09:14,154 SCIENTIFIC VISION. 246 00:09:14,154 --> 00:09:15,856 HER ABILITY TO SEE BEYOND THE 247 00:09:15,856 --> 00:09:18,892 IMMEDIATE ROADBLOCKS AND COME UP 248 00:09:18,892 --> 00:09:22,196 WITH INNOVATIVE SOLUTION HAS 249 00:09:22,196 --> 00:09:23,397 PIONEERED NEW APPROACHES TO 250 00:09:23,397 --> 00:09:26,467 ENHANCE OUR UNDERSTANDING OF 251 00:09:26,467 --> 00:09:27,301 INTERACTIONS. 252 00:09:27,301 --> 00:09:28,869 ANOTHER ASPECT I ADMIRE MOST 253 00:09:28,869 --> 00:09:31,038 ABOUT CAROLINA IS HER REMARKABLE 254 00:09:31,038 --> 00:09:31,939 HUMILITY. 255 00:09:31,939 --> 00:09:32,806 DESPITE HER NUMEROUS 256 00:09:32,806 --> 00:09:34,541 ACHIEVEMENTS AND RECOGNITIONS, 257 00:09:34,541 --> 00:09:36,744 SHE REMAINS APPROACHABLE AND 258 00:09:36,744 --> 00:09:38,145 GENUINELY INTERESTED IN GIVING 259 00:09:38,145 --> 00:09:39,346 ADVICE ON ANY TOPIC OF 260 00:09:39,346 --> 00:09:40,881 DISCUSSION. 261 00:09:40,881 --> 00:09:42,983 ALWAYS OFFERING GUIDANCE WITH 262 00:09:42,983 --> 00:09:44,051 PATIENCE AND KINDNESS. 263 00:09:44,051 --> 00:09:45,919 THANK YOU, CAROLINA, FOR YOUR 264 00:09:45,919 --> 00:09:47,788 GUIDANCE AND SUPPORT, AND FOR 265 00:09:47,788 --> 00:09:49,289 BEING AN INSPIRING MENTOR TO ALL 266 00:09:49,289 --> 00:09:51,158 OF US. 267 00:09:51,158 --> 00:09:53,894 THESE WORDS HIGHLIGHT HOW 268 00:09:53,894 --> 00:09:54,895 DR. BARILLAS-MURY EXEMPLIFIES 269 00:09:54,895 --> 00:09:58,399 MANY OF THE SAME QUALITIES THAT 270 00:09:58,399 --> 00:10:00,234 MADE DR. ANITA B. ROBERTS SUCH A 271 00:10:00,234 --> 00:10:01,135 GREAT SCIENTIST AND MENTOR. 272 00:10:01,135 --> 00:10:04,304 IT IS A PLEASURE AND HONOR TO 273 00:10:04,304 --> 00:10:05,506 WELCOME DR. CAROLINA 274 00:10:05,506 --> 00:10:08,108 BARILLAS-MURY TODAY TO PRESENT 275 00:10:08,108 --> 00:10:11,745 THE 2024 AKN ANITA B. ROBERTS 276 00:10:11,745 --> 00:10:12,446 LECTURE. 277 00:10:12,446 --> 00:10:13,547 ALL YOURS, CAROLINA. 278 00:10:13,547 --> 00:10:14,047 >> THANK YOU. 279 00:10:14,047 --> 00:10:15,682 THANK YOU VERY MUCH. 280 00:10:15,682 --> 00:10:16,984 I WOULD LIKE TO START BY 281 00:10:16,984 --> 00:10:20,487 THANKING THE ORGANIZERS AND THE 282 00:10:20,487 --> 00:10:21,588 WOMEN SCIENTIST ADVISORS FOR THE 283 00:10:21,588 --> 00:10:22,656 OPPORTUNITY TO GIVE THIS 284 00:10:22,656 --> 00:10:25,626 LECTURE, I'M DEEPLY HONORED, AND 285 00:10:25,626 --> 00:10:27,261 ALSO I'M OVERWHELMED WITH 286 00:10:27,261 --> 00:10:30,764 EMOTION FROM THE COMMENTS 287 00:10:30,764 --> 00:10:31,865 RECEIVED BY THE PERSONS THAT 288 00:10:31,865 --> 00:10:32,733 HAVE BEEN IN MY LAB. 289 00:10:32,733 --> 00:10:34,368 SO I WOULD LIKE TO START BY 290 00:10:34,368 --> 00:10:39,840 SHARING THE SCREEN. 291 00:10:39,840 --> 00:10:50,150 PUT THE SLIDES ON. 292 00:10:50,517 --> 00:10:51,752 CAN EVERYONE SEE MY SLIDES? 293 00:10:51,752 --> 00:10:54,955 I JUST WANT TO MAKE SURE. 294 00:10:54,955 --> 00:10:55,355 WE'RE GOOD? 295 00:10:55,355 --> 00:10:56,023 >> YOU ARE GOOD. 296 00:10:56,023 --> 00:10:59,660 >> OKAY, GOOD. 297 00:10:59,660 --> 00:11:03,263 SO GOOD MORNING, EVERYBODY. 298 00:11:03,263 --> 00:11:04,565 MY LAB HAS BEEN WORKING FOR MANY 299 00:11:04,565 --> 00:11:15,075 YEARS IN TRYING TO UNDERSTAND -- 300 00:11:15,075 --> 00:11:16,577 SO MY LAB HAS BEEN INTERESTED 301 00:11:16,577 --> 00:11:19,012 FOR MANY YEARS IN UNDERSTANDING 302 00:11:19,012 --> 00:11:20,514 THE MOSQUITO-PARASITE 303 00:11:20,514 --> 00:11:21,548 INTERACTIONS THAT AFFECT MALARIA 304 00:11:21,548 --> 00:11:22,516 TRANSMISSION WITH THE ULTIMATE 305 00:11:22,516 --> 00:11:23,951 GOAL OF FINDING WAYS OF 306 00:11:23,951 --> 00:11:25,252 DISRUPTING THE TRANSMISSION 307 00:11:25,252 --> 00:11:29,490 CYCLE AND THEN PREVENT HUMAN 308 00:11:29,490 --> 00:11:30,057 DISEASE. 309 00:11:30,057 --> 00:11:31,158 WE WORK WITH THE ANOPHELES 310 00:11:31,158 --> 00:11:32,459 GAMBIAE BECAUSE IT'S A MAJOR 311 00:11:32,459 --> 00:11:34,528 VECTOR OF MALARIA IN AFRICA, AND 312 00:11:34,528 --> 00:11:36,830 THIS MOSQUITO IS EXTREMELY 313 00:11:36,830 --> 00:11:37,831 EFFICIENT IN TRANSMITTING THE 314 00:11:37,831 --> 00:11:39,233 DISEASE FROM ONE PERSON TO THE 315 00:11:39,233 --> 00:11:41,001 OTHER AND IT'S ONE OF THE 316 00:11:41,001 --> 00:11:45,138 REASONS WHY MALARIA, ANOPHELES 317 00:11:45,138 --> 00:11:46,874 GAMBIAE MALARIA, IS SUCH A 318 00:11:46,874 --> 00:11:47,908 DEVASTATING DISEASE, 319 00:11:47,908 --> 00:11:48,909 PARTICULARLY IN AFRICA. 320 00:11:48,909 --> 00:11:50,511 AND SO TODAY, I'M GOING TO SHARE 321 00:11:50,511 --> 00:11:52,679 WITH YOU ONE MAJOR PROJECT IN MY 322 00:11:52,679 --> 00:11:53,714 LAB, ONE OF THE MAIN PROJECTS, 323 00:11:53,714 --> 00:11:56,517 AND IT TRYING TO UNDERSTAND WHY 324 00:11:56,517 --> 00:11:57,484 IS THIS TRANSMISSION OF DISEASE 325 00:11:57,484 --> 00:12:00,587 SO EFFECTIVE? 326 00:12:00,587 --> 00:12:01,889 SO AT THE BEGINNING, I WILL 327 00:12:01,889 --> 00:12:04,625 SUMMARIZE HOW MOSQUITOES BECOME 328 00:12:04,625 --> 00:12:06,126 INFECTED WITH PLASMODIUM AND 329 00:12:06,126 --> 00:12:08,862 THEN WHAT KIND OF IMMUNE 330 00:12:08,862 --> 00:12:10,197 RESPONSES THEY MOUNT TO THE 331 00:12:10,197 --> 00:12:12,699 EARLY STAGES OF THE DISEASE. 332 00:12:12,699 --> 00:12:15,869 SO WE HAVE ON TOP THIS HAS TAKEN 333 00:12:15,869 --> 00:12:17,838 A BLOOD MEAL AND THE MOSQUITOES 334 00:12:17,838 --> 00:12:19,273 BECOME INFECTED WHEN THEY INGEST 335 00:12:19,273 --> 00:12:26,280 BLOOD FROM A VERTEBRATE HOST 336 00:12:26,280 --> 00:12:30,384 THAT CONTAIN GAMETOCYTES. 337 00:12:30,384 --> 00:12:32,719 THEY EMERGE FROM THE RED BLOOD 338 00:12:32,719 --> 00:12:38,525 CELLS AND MATURE INTO GR GAMETE, 339 00:12:38,525 --> 00:12:41,962 FERTATFERTILIZATION TAKES PLACED 340 00:12:41,962 --> 00:12:46,600 THE FOCUS TODAY IS THIS STAGE, 341 00:12:46,600 --> 00:12:49,336 THE BANANA SHAPED PARASITE, THE 342 00:12:49,336 --> 00:12:50,571 PARASITES THAT ARE SUCCESSFUL GO 343 00:12:50,571 --> 00:12:58,412 ON TO FORM AN OWE OOCYST, AND 344 00:12:58,412 --> 00:13:02,916 TWO WEEKS LATER IT WILL RELEASE 345 00:13:02,916 --> 00:13:05,319 THOUSANDS OF PAR SITES. 346 00:13:05,319 --> 00:13:09,122 THIS MOSQUITO OPENS CIRCULATORY 347 00:13:09,122 --> 00:13:12,025 SYSTEM, THEN WHEN THE MOSQUITO 348 00:13:12,025 --> 00:13:14,394 THAT IS INFECTED WITH THIS BITES 349 00:13:14,394 --> 00:13:15,696 THE NEXT PERSON, IT WILL 350 00:13:15,696 --> 00:13:18,098 TRANSMIT THE DISEASE. 351 00:13:18,098 --> 00:13:21,735 SO TODAY WE'RE GOING TO FOCUS ON 352 00:13:21,735 --> 00:13:24,571 THIS PART OF THE SQUARE, WHAT 353 00:13:24,571 --> 00:13:25,939 HAPPENS IN THESE EARLY STAGES. 354 00:13:25,939 --> 00:13:27,307 SO I WANT TO POINT OUT THAT MOST 355 00:13:27,307 --> 00:13:30,477 OF WHAT WE UNDERSTAND RIGHT NOW 356 00:13:30,477 --> 00:13:33,680 ABOUT THIS RESPONSE, THE INITIAL 357 00:13:33,680 --> 00:13:38,118 WORK, CAME FROM USING PLASMODIUM 358 00:13:38,118 --> 00:13:48,295 VERSION OF MALARIA AND THEY -- 359 00:13:48,295 --> 00:13:49,830 THEY BREAK THE BARRIERS THAT 360 00:13:49,830 --> 00:13:51,498 NORMALLY PREVENT THE GUT 361 00:13:51,498 --> 00:13:52,899 MICROBIOTA FROM COMING IN DIRECT 362 00:13:52,899 --> 00:13:54,301 CONTACT WITH EPITHELIAL CELLS 363 00:13:54,301 --> 00:13:56,770 AND THEY CAUSE EA IRREVERSIBLE 364 00:13:56,770 --> 00:13:58,905 DAMAGE TO THE CELL THEY INVADE. 365 00:13:58,905 --> 00:14:00,340 THIS CELL DIES, BUT IT DIES 366 00:14:00,340 --> 00:14:01,642 ASKING FOR HELP AND WHAT DO WE 367 00:14:01,642 --> 00:14:02,509 MEAN BY THAT? 368 00:14:02,509 --> 00:14:06,446 WHEN THIS CELL IS DYING, IT 369 00:14:06,446 --> 00:14:09,282 ACTIVATES -- THIS ACTIVATES 370 00:14:09,282 --> 00:14:10,183 CAASPP -- RESULTING IN THE 371 00:14:10,183 --> 00:14:11,385 INDUCTION OF ENZYMES THAT 372 00:14:11,385 --> 00:14:12,352 TRIGGER VERY STRONG NIGH 373 00:14:12,352 --> 00:14:20,460 TRAITION RESPONSE. 374 00:14:20,460 --> 00:14:20,727 NITRATION 375 00:14:20,727 --> 00:14:25,499 RESPONSE. 376 00:14:25,499 --> 00:14:29,336 PGE2 ATTRACTS HEMOCYTES, THEY'RE 377 00:14:29,336 --> 00:14:30,537 IN THE IMMUNE CELLS, THEY COME 378 00:14:30,537 --> 00:14:35,575 AND START PATROLLING THE BASAL 379 00:14:35,575 --> 00:14:38,278 LAMINA. 380 00:14:38,278 --> 00:14:40,147 THEY RELEASE MICRO VESICLES 381 00:14:40,147 --> 00:14:41,548 LOCALLY AND WE HAVE SHOWN THAT 382 00:14:41,548 --> 00:14:43,750 THIS RELEASE OF MICROVESICLES IS 383 00:14:43,750 --> 00:14:44,951 ESSENTIAL FOR EFFECTIVE 384 00:14:44,951 --> 00:14:45,986 ACTIVATION OF THE MOSQUITO 385 00:14:45,986 --> 00:14:48,689 COMPLEMENT SYSTEM. 386 00:14:48,689 --> 00:14:50,223 THE MOSQUITO COMPLEMENT SYSTEM 387 00:14:50,223 --> 00:14:52,959 HAS A PROTEIN TEP 1. 388 00:14:52,959 --> 00:14:53,927 THIS IS A FINAL -- OF THE 389 00:14:53,927 --> 00:14:56,129 PATHWAY VERY SIMILAR TO FACTOR 390 00:14:56,129 --> 00:14:57,631 C3 OF COMPLEMENT IN VERTEBRATES, 391 00:14:57,631 --> 00:14:59,066 AND WHEN ACTIVATED BY SOME 392 00:14:59,066 --> 00:15:01,501 FACTOR THAT IS NOT KNOWN YET 393 00:15:01,501 --> 00:15:03,704 PRESENT IN THE MICROVESICLE, 394 00:15:03,704 --> 00:15:06,106 THEN TEP1 DEPOSITS ON THE 395 00:15:06,106 --> 00:15:07,207 SURFACE OF THE PARASITE AND 396 00:15:07,207 --> 00:15:07,974 DESTROYS THE PARASITE. 397 00:15:07,974 --> 00:15:09,142 OKAY. 398 00:15:09,142 --> 00:15:12,446 SO HOW IMPORTANT IS THIS 399 00:15:12,446 --> 00:15:14,381 TEP1 MEDIATED KILLING? THIS WAS 400 00:15:14,381 --> 00:15:17,551 FIRST DESCRIBED BY A POSTDOC IN 401 00:15:17,551 --> 00:15:19,786 THE LAB WHERE I WILL DID MY 402 00:15:19,786 --> 00:15:22,522 POSTDOC, AND THE WAY THEY CAN 403 00:15:22,522 --> 00:15:25,892 SEE IF SOME FACTOR IN THE 404 00:15:25,892 --> 00:15:27,327 MOSQUITO IS IMPORTANT TO CONTAIN 405 00:15:27,327 --> 00:15:28,962 THE INFECTION, YOU ASK WHAT 406 00:15:28,962 --> 00:15:31,465 WOULD HAPPEN IF THAT GENE WAS NO 407 00:15:31,465 --> 00:15:33,233 LONGER THERE. 408 00:15:33,233 --> 00:15:34,000 MOSQUITOES, WE HAVE ONE TOOL 409 00:15:34,000 --> 00:15:38,371 THAT IS VERY USEFUL, WE CAN 410 00:15:38,371 --> 00:15:41,641 INJECTION STRANDED RNA GREATLY 411 00:15:41,641 --> 00:15:42,242 DECREASES EX-PEGS OF THE GENES 412 00:15:42,242 --> 00:15:43,410 THAT YOU WANT TO STUDY. 413 00:15:43,410 --> 00:15:45,378 SO IN THIS EXPERIMENT, EACH DOT 414 00:15:45,378 --> 00:15:46,346 REPRESENTS THE NUMBER OF 415 00:15:46,346 --> 00:15:48,215 PARASITES IN ONE MOSQUITO. 416 00:15:48,215 --> 00:15:56,356 SO THE NUMBER OF OOSEISTS THAT . 417 00:15:56,356 --> 00:15:59,059 WE HAVE THE CONTROL GROUP 418 00:15:59,059 --> 00:16:03,864 INJECTED WITH DOUBLE STRANDED 419 00:16:03,864 --> 00:16:05,599 LACZ THAT SHOULD HAVE A 420 00:16:05,599 --> 00:16:06,032 SILENCING EFFECT. 421 00:16:06,032 --> 00:16:08,668 WHEN WE SILENCE TEP1 WE CAN SEE 422 00:16:08,668 --> 00:16:10,537 INFECTION INCREASES, TYPICALLY 423 00:16:10,537 --> 00:16:11,938 IT INCREASES ABOUT FIVE FOLD 424 00:16:11,938 --> 00:16:14,241 WHEN TEP1 IS NO LONGER THERE. 425 00:16:14,241 --> 00:16:16,409 SO THIS TELLS US THAT ABOUT 80 426 00:16:16,409 --> 00:16:19,179 TO 85% OF PARASITES ARE 427 00:16:19,179 --> 00:16:25,218 ELIMINATED BY THIS SYSTEM. 428 00:16:25,218 --> 00:16:26,286 EVEN WHEN INFECTIONS ARE VERY 429 00:16:26,286 --> 00:16:26,720 HIGH. 430 00:16:26,720 --> 00:16:27,921 SO I'VE ONLY BEEN TALKING FOR A 431 00:16:27,921 --> 00:16:28,922 COUPLE OF MINUTES AND THERE'S 432 00:16:28,922 --> 00:16:30,223 ALREADY A CONTRADICTION IN WHAT 433 00:16:30,223 --> 00:16:32,926 I'M TELLING YOU. 434 00:16:32,926 --> 00:16:34,027 ONE, THAT THE MALARIA 435 00:16:34,027 --> 00:16:35,562 TRANSMISSION IS EXTREMELY 436 00:16:35,562 --> 00:16:36,096 EFFICIENT. 437 00:16:36,096 --> 00:16:36,997 NOW I'M TELLING YOU THAT THE 438 00:16:36,997 --> 00:16:39,065 MOSQUITO HAS A SYSTEM THAT CAN 439 00:16:39,065 --> 00:16:41,701 ELIMINATE 85% OF THE PARASITES. 440 00:16:41,701 --> 00:16:42,469 SO HOW IS THAT POSSIBLE? 441 00:16:42,469 --> 00:16:44,004 SO FOR THE REST OF THE LECTURE, 442 00:16:44,004 --> 00:16:45,739 I WILL HOPE TO CONVINCE YOU THAT 443 00:16:45,739 --> 00:16:50,544 THIS IS BECAUSE PLASMODIUM 444 00:16:50,544 --> 00:16:52,312 FALCIPARUM IS NOT A NORMAL 445 00:16:52,312 --> 00:16:53,180 PARASITE. 446 00:16:53,180 --> 00:16:54,915 IT HAS A MAGIC TRICK. 447 00:16:54,915 --> 00:16:58,118 IT HAS A GENOME ON ITS SURFACE 448 00:16:58,118 --> 00:17:01,154 THAT ALLOWS THIS TO BECOME 449 00:17:01,154 --> 00:17:01,922 UNDETECTED BY THE MOSQUITO 450 00:17:01,922 --> 00:17:03,590 IMMUNE SYSTEM SO IT CANNOT BE 451 00:17:03,590 --> 00:17:04,558 DESTROYED BY THE COMPLEMENT 452 00:17:04,558 --> 00:17:05,091 SYSTEM. 453 00:17:05,091 --> 00:17:06,626 SO THIS WORK FOR PLASMODIUM 454 00:17:06,626 --> 00:17:12,666 FALCIPARUM WAS DONE -- BUT NOW 455 00:17:12,666 --> 00:17:16,603 INFECT IT WITH A HUMAN MALARIA, 456 00:17:16,603 --> 00:17:17,637 PLASMODIUM FALCIPARUM, NOTHING 457 00:17:17,637 --> 00:17:18,839 HAPPENED. 458 00:17:18,839 --> 00:17:20,507 SO IT'S NOT KILLING THE 459 00:17:20,507 --> 00:17:23,276 PARASITE. 460 00:17:23,276 --> 00:17:25,345 WHEN THESE RESULTS CAME OUT IT 461 00:17:25,345 --> 00:17:27,514 CAUSED A BIG UPROAR IN THE 462 00:17:27,514 --> 00:17:28,949 FIELD, SOME INTERPRETED THAT 463 00:17:28,949 --> 00:17:30,150 THIS WAS AN EXAMPLE OF A BIG 464 00:17:30,150 --> 00:17:32,552 WASTE OF TIME, WHY USE THE MOUSE 465 00:17:32,552 --> 00:17:34,421 MODEL, INVEST ALL THIS TIME IN 466 00:17:34,421 --> 00:17:35,288 IMMUNE RESPONSE THAT IS 467 00:17:35,288 --> 00:17:40,126 IRRELEVANT TO HUMAN MALARIA. 468 00:17:40,126 --> 00:17:42,429 WE TACK A DIFFERENT PATH OR I 469 00:17:42,429 --> 00:17:43,196 INTERPRETED THINGS IN A 470 00:17:43,196 --> 00:17:45,365 DIFFERENT WAY, THE SAME DATA. 471 00:17:45,365 --> 00:17:47,234 MY APPROACH WAS OKAY, I THINK WE 472 00:17:47,234 --> 00:17:51,137 WERE VERY LUCKY THAT WE DID IT 473 00:17:51,137 --> 00:17:57,711 FIRST WITH P. BERGHEI. THEN YOU 474 00:17:57,711 --> 00:17:59,713 START -- THE LITERATURE -- 475 00:17:59,713 --> 00:18:01,014 ESCAPE OR THERE'S SOME CASES 476 00:18:01,014 --> 00:18:03,717 WHERE SOME MOSQUITOES CAN KILL 477 00:18:03,717 --> 00:18:04,284 SOME -- PARASITES. 478 00:18:04,284 --> 00:18:05,819 THIS BROUGHT US BACK TO SOME 479 00:18:05,819 --> 00:18:08,955 STUDIES IN THE 80s DONE HERE 480 00:18:08,955 --> 00:18:11,825 AT NIH, FRANCIS COLLINS AND -- 481 00:18:11,825 --> 00:18:15,095 IN WHICH THEY HAD SELECTED 482 00:18:15,095 --> 00:18:16,963 GENETICALLY A STRAIN OF 483 00:18:16,963 --> 00:18:18,765 MOSQUITOES CALLED THE REFACTORY 484 00:18:18,765 --> 00:18:20,033 STRAIN THAT KILLS ALL THE 485 00:18:20,033 --> 00:18:23,436 PARASITES PRETTY MUCH THAT 486 00:18:23,436 --> 00:18:25,105 INFECT THEM WITH ANY PARASITE. 487 00:18:25,105 --> 00:18:27,841 EVERYTHING LOOKS FINE, BUT AS 488 00:18:27,841 --> 00:18:30,443 SOON AS THE -- COMES IN CONTACT 489 00:18:30,443 --> 00:18:34,915 WITH THE MOSQUITO -- THE 490 00:18:34,915 --> 00:18:36,249 PARASITE IS DAMAGE AND AFTER 491 00:18:36,249 --> 00:18:37,584 IT'S KILLED IT'S COVERED WITH A 492 00:18:37,584 --> 00:18:38,351 BLACK PIGMENT. 493 00:18:38,351 --> 00:18:40,420 WE KNOW THIS IS -- RELATED 494 00:18:40,420 --> 00:18:44,224 BECAUSE IF YOU SILENCE TEP1 IT 495 00:18:44,224 --> 00:18:44,791 CAN RESCUE. 496 00:18:44,791 --> 00:18:48,528 THIS KILLS ALSO ANY PARASITE, BY 497 00:18:48,528 --> 00:18:51,898 THAT I MEAN MOUSE MALARIA, BIRD 498 00:18:51,898 --> 00:18:53,500 MALARIA, ALMOST ALL PLASMODIUM 499 00:18:53,500 --> 00:18:55,068 FALCIPARUM WITH ONE INTERESTING 500 00:18:55,068 --> 00:18:55,402 EXCEPTION. 501 00:18:55,402 --> 00:18:58,505 IF YOU INFECT IT WITH PLASMODIUM 502 00:18:58,505 --> 00:18:59,873 FALCIPARUM FROM A PATIENT FROM 503 00:18:59,873 --> 00:19:01,074 WEST AFRICA, THE SAME PLACE 504 00:19:01,074 --> 00:19:03,176 WHERE THIS MOSQUITO CAME FROM, 505 00:19:03,176 --> 00:19:06,680 YOU SEE A VERY DIFFERENT PICT 506 00:19:06,680 --> 00:19:06,980 PICTURE. 507 00:19:06,980 --> 00:19:08,648 IN THIS GRAPH I WANT TO SHOW YOU 508 00:19:08,648 --> 00:19:09,282 HOW DIFFERENT THIS IS. 509 00:19:09,282 --> 00:19:13,219 BECAUSE WE CAN HAVE EITHER -- IN 510 00:19:13,219 --> 00:19:14,554 A GIVEN MOSQUITO, IN THESE 511 00:19:14,554 --> 00:19:16,957 GRAPHS WE HAVE THE PARASITES IN 512 00:19:16,957 --> 00:19:19,159 THE X AXIS AND THE LIVE ONES IN 513 00:19:19,159 --> 00:19:19,926 THE Y AXIS. 514 00:19:19,926 --> 00:19:21,695 SO YOU SEE THAT IF THIS 515 00:19:21,695 --> 00:19:23,463 MOSQUITO, THE REFRACTORY 516 00:19:23,463 --> 00:19:25,098 MOSQUITO IS INFECTED WITH AN 517 00:19:25,098 --> 00:19:27,467 AFRICAN PARASITE, THEN NONE OF 518 00:19:27,467 --> 00:19:31,071 THE PARASITES ARE MELANIZED AND 519 00:19:31,071 --> 00:19:32,772 THEY ALL SURVIVE. 520 00:19:32,772 --> 00:19:35,442 IN CONTRAST, IF THIS CAME FROM 521 00:19:35,442 --> 00:19:37,711 BRAZIL, A BRAZILIAN INFECTION, 522 00:19:37,711 --> 00:19:38,912 AND THEN WHEN YOU LOOK THE A 523 00:19:38,912 --> 00:19:49,089 THIS, IN THIS CASE, 9 7% ARE 524 00:19:49,089 --> 00:19:51,825 MENONI SOO ED AND ABOUT 3% 525 00:19:51,825 --> 00:19:52,058 SURVIVE. 526 00:19:52,058 --> 00:19:53,193 SO THIS OPENS THE POSSIBILITY OF 527 00:19:53,193 --> 00:19:56,429 THE DEVELOPING GENETIC STRATEGY 528 00:19:56,429 --> 00:19:57,797 TO IDENTIFY THE PLASMODIUM 529 00:19:57,797 --> 00:19:58,631 FALCIPARUM INVISIBILITY GENE. 530 00:19:58,631 --> 00:20:00,266 SO WHAT IS DIFFERENT, WHAT DOES 531 00:20:00,266 --> 00:20:02,335 THE AFRICAN PARASITE HAVE THAT 532 00:20:02,335 --> 00:20:03,870 ALLOWS TO NOT BE DETECTED AND 533 00:20:03,870 --> 00:20:05,405 NOT BE DESTROYED BY THE SYSTEM 534 00:20:05,405 --> 00:20:07,907 THAT DESTROYS ALMOST ANY OTHER 535 00:20:07,907 --> 00:20:09,342 PARASITE? 536 00:20:09,342 --> 00:20:13,046 SO WE TOOK ADVANTAGE THAT -- 537 00:20:13,046 --> 00:20:15,248 WITH THESE TWO LINES THAT I SHOW 538 00:20:15,248 --> 00:20:23,356 YOU, 78 FROM BRAZIL AND GB4 FROM 539 00:20:23,356 --> 00:20:27,927 GHANA. 540 00:20:27,927 --> 00:20:35,602 THIS ALLOWS US TO IDENTIFY PFS47 541 00:20:35,602 --> 00:20:37,237 EXPRESSED ON THE SURFACE. 542 00:20:37,237 --> 00:20:41,941 SO THEN WE -- ANOTHER LAB IN THE 543 00:20:41,941 --> 00:20:43,143 NETHERLANDS HAD GENERATED A 544 00:20:43,143 --> 00:20:46,846 KNOCKOUT PARASITE FOR PFS47, 545 00:20:46,846 --> 00:20:49,682 SO -- FOR OTHER STUDIES, SO WE 546 00:20:49,682 --> 00:20:51,017 MADE A COLLABORATION WITH THEM, 547 00:20:51,017 --> 00:20:52,619 THEY SENT US THE PARASITE, AND 548 00:20:52,619 --> 00:20:56,056 THIS IS WHAT THE NF54 WILD TYPE 549 00:20:56,056 --> 00:20:57,257 PARASITE LOOKS LIKE IN THE 550 00:20:57,257 --> 00:20:58,324 REFRACTORY STRAIN. 551 00:20:58,324 --> 00:21:01,628 93% OF THE PARASITES SURVIVE AND 552 00:21:01,628 --> 00:21:03,029 7% ARE MEL NIEZED. 553 00:21:03,029 --> 00:21:07,834 BUT IF YOU DISRUPT NF54, YOU 554 00:21:07,834 --> 00:21:10,737 HAVE A KNOCKOUT AND THIS LOOKS 555 00:21:10,737 --> 00:21:12,705 VERY DIFFERENT AND 99% OF THE 556 00:21:12,705 --> 00:21:13,573 PARASITES ARE DESTROYED. 557 00:21:13,573 --> 00:21:15,642 IF YOU TAKE THESE KNOCKOUT 558 00:21:15,642 --> 00:21:18,611 PARASITES BUT NOW YOU SILENCE 559 00:21:18,611 --> 00:21:19,813 TEP, YOU CAN COMPLETELY REVERT 560 00:21:19,813 --> 00:21:22,115 ALL THE PARASITES SURVIVE, NO 561 00:21:22,115 --> 00:21:26,586 ONE IS MEL NIEZED. 562 00:21:26,586 --> 00:21:28,521 THIS TELLS THE PARASITE NEEDS 563 00:21:28,521 --> 00:21:30,090 THIS GENE TO EVADE BEING KILLED 564 00:21:30,090 --> 00:21:31,491 BY THE MOSQUITO IMMUNE SYSTEM. 565 00:21:31,491 --> 00:21:32,592 EVERYTHING ELSE APPEARS TO BE 566 00:21:32,592 --> 00:21:33,159 NORMAL. 567 00:21:33,159 --> 00:21:35,829 SO THIS GENE REALLY IS VERY 568 00:21:35,829 --> 00:21:38,898 IMPORTANT FOR THIS. 569 00:21:38,898 --> 00:21:40,266 SO IN SUMMARY FROM WHAT WE'VE 570 00:21:40,266 --> 00:21:44,270 SAID SO FAR, SO PARASITES THAT 571 00:21:44,270 --> 00:21:45,905 LACK PFS47 OR THEY HAVE THE 572 00:21:45,905 --> 00:21:49,309 WRONG PFS47, FOR EXAMPLE, THE 573 00:21:49,309 --> 00:21:51,377 BRAZILIAN PFS47 IN AN AFRICAN 574 00:21:51,377 --> 00:21:57,584 MOSQUITO, THEY ACTIVATE NOS 575 00:21:57,584 --> 00:22:00,453 CASPASE AND WE SEE THIS CAN 576 00:22:00,453 --> 00:22:02,155 ACTIVATE CASPASE, AND THEN THERE 577 00:22:02,155 --> 00:22:04,157 IS TEP 1 MEDIATED CLEARING. 578 00:22:04,157 --> 00:22:06,893 HOWEVER, IF THE PARASITE HAS THE 579 00:22:06,893 --> 00:22:08,128 RIGHT TYPE, THE AFRICAN 580 00:22:08,128 --> 00:22:10,396 PARASITES WITH THE AFRICAN 581 00:22:10,396 --> 00:22:12,165 MOSQUITO, THEN THERE'S INVASION 582 00:22:12,165 --> 00:22:14,033 OF -- BUT NO ACTIVATION OF 583 00:22:14,033 --> 00:22:14,367 CASPASE. 584 00:22:14,367 --> 00:22:15,768 SO WHAT WE SEE HERE IS THE 585 00:22:15,768 --> 00:22:18,738 PARASITE IS DYING BUT -- THE 586 00:22:18,738 --> 00:22:20,473 CELL IS DYING BUT THE CELL DIES 587 00:22:20,473 --> 00:22:21,241 WITHOUT BEING ABLE TO ASK FOR 588 00:22:21,241 --> 00:22:21,674 HELP. 589 00:22:21,674 --> 00:22:23,376 IT REALLY CANNOT NITRATE, AND IN 590 00:22:23,376 --> 00:22:26,179 THE ABSENCE OF THAT, THEN THINGS 591 00:22:26,179 --> 00:22:26,713 DON'T MOVE FORWARD. 592 00:22:26,713 --> 00:22:30,517 SO THAT WAS THE WORKING MODEL. 593 00:22:30,517 --> 00:22:34,354 SO WE CONCLUDED PLASMODIUM 594 00:22:34,354 --> 00:22:37,323 FALCIPARUM -- IMMUNE SYSTEM -- 595 00:22:37,323 --> 00:22:38,424 THE FIRST STEP IN THIS PROCESS. 596 00:22:38,424 --> 00:22:39,726 SO YOU SEE THIS IS THE SAME 597 00:22:39,726 --> 00:22:43,029 GRAPH I SHOW YOU, YOU SEE HOW 598 00:22:43,029 --> 00:22:43,863 DRASTICALLY DIFFERENT THESE 599 00:22:43,863 --> 00:22:45,398 PHENOTYPES ARE, AND ALTHOUGH 600 00:22:45,398 --> 00:22:46,399 THEY'RE SO DIFFERENT WHEN YOU 601 00:22:46,399 --> 00:22:50,370 LOOK AT THE PROTEIN, PFS47 602 00:22:50,370 --> 00:22:51,337 PROTEIN BETWEEN THESE TWO 603 00:22:51,337 --> 00:22:53,072 STRAINS, THEY'RE VERY SIMILAR. 604 00:22:53,072 --> 00:22:54,941 THEY'RE ALMOST IDENTICAL EXCEPT 605 00:22:54,941 --> 00:22:56,476 FOR FOUR AMINO ACIDS HERE IN THE 606 00:22:56,476 --> 00:23:02,015 CENTRAL DOMAIN, BETWEEN THESE 607 00:23:02,015 --> 00:23:04,450 TWO, THERE'S FOUR AMINO ACIDS. 608 00:23:04,450 --> 00:23:05,752 WE DID A SERIES OF EXPERIMENTS 609 00:23:05,752 --> 00:23:07,654 WHERE WE TOOK ONE AMINO ACID AT 610 00:23:07,654 --> 00:23:10,723 A TIME, WE TOOK THE GB4 AND 611 00:23:10,723 --> 00:23:13,126 CHANGED THIS AMINO ACID FOR ONE 612 00:23:13,126 --> 00:23:15,061 PERSON IN THE BRAZILIAN PARASITE 613 00:23:15,061 --> 00:23:16,663 ONE AT A TIME, AND THEN WE FEED 614 00:23:16,663 --> 00:23:17,997 THIS TO MOSQUITOES AND 615 00:23:17,997 --> 00:23:18,264 PHENOTYPE. 616 00:23:18,264 --> 00:23:22,035 AND WHAT WE FOUND IS THAT IF WE 617 00:23:22,035 --> 00:23:24,237 CHANGE ANY AMINO ACID IN THE 618 00:23:24,237 --> 00:23:25,572 AFRICAN STRAIN FOR A BRAZILIAN 619 00:23:25,572 --> 00:23:27,073 ONE, NOW THE TRICK DOESN'T WORK, 620 00:23:27,073 --> 00:23:28,708 THE PARASITE IS RECOGNIZED AND 621 00:23:28,708 --> 00:23:29,142 DESTROYED. 622 00:23:29,142 --> 00:23:30,343 SO FROM THESE, WE CONCLUDED THAT 623 00:23:30,343 --> 00:23:32,312 THE MOLECULAR INTERACTIONS 624 00:23:32,312 --> 00:23:34,214 BETWEEN PFS47 AND THE MOSQUITO 625 00:23:34,214 --> 00:23:35,815 VECTOR NEED TO BE VERY PRECISE 626 00:23:35,815 --> 00:23:39,219 AT LEAST IN SOME VECTOR PARASITE 627 00:23:39,219 --> 00:23:40,853 COMBINATIONS, AND LEAST IN THIS 628 00:23:40,853 --> 00:23:43,256 REFRACTORY STRAIN. 629 00:23:43,256 --> 00:23:45,758 ALSO WITH USE OF STUDIES, TRYING 630 00:23:45,758 --> 00:23:47,527 TO SEE IF ANTIBODIES TO SOME 631 00:23:47,527 --> 00:23:49,529 REGION OF THIS PROTEIN COULD BE 632 00:23:49,529 --> 00:23:53,866 PROTECTIVE, WE FOUND THAT DOMAIN 633 00:23:53,866 --> 00:23:56,469 1 AND 3 ARE VERY NEUROGENIC 634 00:23:56,469 --> 00:23:57,270 BUT -- DO NOT HAVE ANY EFFECT. 635 00:23:57,270 --> 00:23:58,271 HOWEVER, THERE'S A REGION SHOWN 636 00:23:58,271 --> 00:24:02,375 HERE IN RED IN DOMAIN 2 WHERE 637 00:24:02,375 --> 00:24:06,980 ANTIBODY BINDING POLYCLONAL 638 00:24:06,980 --> 00:24:10,383 OR -- ANTIBODIES GREATLY REDUCE 639 00:24:10,383 --> 00:24:10,717 TRANSMISSION. 640 00:24:10,717 --> 00:24:13,786 SO YOU ADD EITHER IGG OR YOUR 641 00:24:13,786 --> 00:24:21,694 SPECIFIC IGG TO PFS47 -- IGG OF 642 00:24:21,694 --> 00:24:25,098 PFS47 IN IMMUNIZED MICE AND WE 643 00:24:25,098 --> 00:24:29,135 FIND IT REDUCES THE INFECTION, 644 00:24:29,135 --> 00:24:40,113 BOTH IN -- AND T ANOPHELES GAMB- 645 00:24:46,152 --> 00:24:48,554 OKAY, SO NOW LET'S GET OUT OF 646 00:24:48,554 --> 00:24:49,822 THE LAB AND THINK OKAY, THAT'S 647 00:24:49,822 --> 00:24:51,991 ALL IN THE LAB, AND NOW WHAT ARE 648 00:24:51,991 --> 00:24:56,262 THE CONSEQUENCES OF THESE 649 00:24:56,262 --> 00:24:57,230 INTERACTIONS IN THE WORLD? 650 00:24:57,230 --> 00:25:00,199 HOW IMPORTANT HAS THIS ABILITY 651 00:25:00,199 --> 00:25:01,934 TO EVADE THE MOSQUITO IMMUNE 652 00:25:01,934 --> 00:25:03,703 SYSTEM, HOW IMPORTANT IS THIS 653 00:25:03,703 --> 00:25:05,038 FOR MALARIA TRANSMISSION AROUND 654 00:25:05,038 --> 00:25:05,471 THE WORLD? 655 00:25:05,471 --> 00:25:08,308 TO ANSWER THIS QUESTION THEN, WE 656 00:25:08,308 --> 00:25:09,742 TOOK A GENETIC APPROACH. 657 00:25:09,742 --> 00:25:13,246 SO WE ANALYZE -- SEVERAL YEARS 658 00:25:13,246 --> 00:25:17,617 AGO -- THE FIRST 364 SEQUENCES 659 00:25:17,617 --> 00:25:18,451 AVAILABLE OF PLASMODIUM 660 00:25:18,451 --> 00:25:19,919 FALCIPARUM FROM DIFFERENT HUMAN 661 00:25:19,919 --> 00:25:20,920 ISOLATES AROUND THE WORLD, AND 662 00:25:20,920 --> 00:25:23,189 THEN WHEN WE ANALYZED IT, WE 663 00:25:23,189 --> 00:25:24,824 FOUND 42 DIFFERENT HAPLOTYPES, 664 00:25:24,824 --> 00:25:28,428 AND WE DEFINE A HAPLOTYPE OF ANY 665 00:25:28,428 --> 00:25:29,629 AMINO ACID DIFFERENCE BETWEEN 666 00:25:29,629 --> 00:25:30,096 TWO PROTEINS. 667 00:25:30,096 --> 00:25:32,365 WHEN WE DID A PHYLOGENETIC TREE, 668 00:25:32,365 --> 00:25:33,833 WE CAN SEE IN GROUPS WE HAVE THE 669 00:25:33,833 --> 00:25:36,769 ORANGE GROUP, THE BLUE AND THE 670 00:25:36,769 --> 00:25:36,969 GREEN. 671 00:25:36,969 --> 00:25:38,604 OF COURSE THEY'RE CLOSER, THE 672 00:25:38,604 --> 00:25:39,806 THE ONES THAT ARE MORE SIMILAR 673 00:25:39,806 --> 00:25:40,707 ARE CLOSER TO EACH OTHER. 674 00:25:40,707 --> 00:25:44,844 WHEN WE PUT THESE IN A MAP, WE 675 00:25:44,844 --> 00:25:45,611 SEE THE DISTRIBUTION OF THESE 676 00:25:45,611 --> 00:25:49,682 COLORS IS NOT RANDOM. 677 00:25:49,682 --> 00:25:50,883 -- IN SOUTH AMERICA ARE BLUE, 678 00:25:50,883 --> 00:25:52,518 ORANGE IN AFRICA, AND GREEN 679 00:25:52,518 --> 00:25:55,955 DOMINATES IN ASIA. 680 00:25:55,955 --> 00:25:56,956 IN NEW GUINEA WE HAVE MOSTLY 681 00:25:56,956 --> 00:25:59,025 ASIAN BUT YOU FIND SOME OTHER 682 00:25:59,025 --> 00:26:00,126 HAPLOTYPES TO THIS REGION AND 683 00:26:00,126 --> 00:26:03,796 FROM OTHER CONTINENTS. 684 00:26:03,796 --> 00:26:03,996 OKAY. 685 00:26:03,996 --> 00:26:05,031 BUT THINKING ABOUT MALARIA, THIS 686 00:26:05,031 --> 00:26:06,532 IS VERY UNUSUAL BECAUSE WHY 687 00:26:06,532 --> 00:26:08,735 WOULD YOU HAVE GEOGRAPHIC 688 00:26:08,735 --> 00:26:09,502 DIFFERENCES, RIGHT? 689 00:26:09,502 --> 00:26:13,573 YOU HAVE HUMANS, WE ARE VERY 690 00:26:13,573 --> 00:26:17,610 SIMILAR, TO HAVE A HOST, THEN WE 691 00:26:17,610 --> 00:26:21,080 HAVE A SINGLE PARASITE, BUT WHAT 692 00:26:21,080 --> 00:26:21,981 IS VERY DIFFERENT IS THE 693 00:26:21,981 --> 00:26:22,515 MOSQUITOES. 694 00:26:22,515 --> 00:26:24,717 TO GIVE YOU AN IDEA, THIS IS A 695 00:26:24,717 --> 00:26:26,886 SIMPLIFIED MAP, WHAT YOU NEED TO 696 00:26:26,886 --> 00:26:27,987 REMEMBER FROM THIS MAP IS THAT 697 00:26:27,987 --> 00:26:30,156 ALL THESE COLORS REPRESENT THE 698 00:26:30,156 --> 00:26:31,190 DIFFERENT MOSQUITOES THAT ARE 699 00:26:31,190 --> 00:26:31,924 TRANSMITTING MALARIA IN 700 00:26:31,924 --> 00:26:33,126 DIFFERENT AREAS OF THE WORLD, 701 00:26:33,126 --> 00:26:36,863 AND THERE'S MORE THAN 40 MAJOR 702 00:26:36,863 --> 00:26:38,698 VECTORS OF MALARIA IN DIFFERENT 703 00:26:38,698 --> 00:26:39,132 PLACES. 704 00:26:39,132 --> 00:26:40,333 ANOTHER ASPECT TO REMEMBER IS 705 00:26:40,333 --> 00:26:41,868 SOME MOSQUITOES ARE 706 00:26:41,868 --> 00:26:42,969 EVOLUTIONARILY VERY DISTANT. 707 00:26:42,969 --> 00:26:43,936 FOR INSTANCE THOSE IN SOUTH 708 00:26:43,936 --> 00:26:48,307 AMERICA AND AFRICA SEPARATED 709 00:26:48,307 --> 00:26:49,876 100 MILLION YEARS AGO, WHEN 710 00:26:49,876 --> 00:26:51,277 THESE TWO CONTINENTS SEPARATED, 711 00:26:51,277 --> 00:26:56,115 THEN THESE TWO, AND OFTEN 712 00:26:56,115 --> 00:26:58,284 IT'S -- IN AFRICA BEGAN TO 713 00:26:58,284 --> 00:26:58,518 DIVERGE. 714 00:26:58,518 --> 00:27:02,088 SO BASICALLY THERE'S DIFFERENT 715 00:27:02,088 --> 00:27:02,655 MOSQUITOES TRANSMITTING IN 716 00:27:02,655 --> 00:27:03,956 DIFFERENT PLACES AND SOME OF 717 00:27:03,956 --> 00:27:12,498 THEM ARE EVE LEUT EVOLUTIONARILY 718 00:27:12,498 --> 00:27:15,101 DISTANT. 719 00:27:15,101 --> 00:27:16,269 SO DETERMINED BY PARASITE 720 00:27:16,269 --> 00:27:17,069 SELECTION BY THE MOSQUITO 721 00:27:17,069 --> 00:27:17,670 VECTORS. 722 00:27:17,670 --> 00:27:18,104 OKAY. 723 00:27:18,104 --> 00:27:20,840 SO HOW DO WE SHOW THAT? 724 00:27:20,840 --> 00:27:22,608 SO IN ORDER TO TEST THIS 725 00:27:22,608 --> 00:27:23,910 HYPOTHESIS, THIS IS VERY HARD TO 726 00:27:23,910 --> 00:27:26,612 DO IN THE FIELD BECAUSE YOU CAN 727 00:27:26,612 --> 00:27:27,914 MOVE MOSQUITOES AROUND, YOU 728 00:27:27,914 --> 00:27:32,418 DON'T WANT TO BE FAMOUS AND 729 00:27:32,418 --> 00:27:33,519 BRING AFRICAN MOSQUITOES IN 730 00:27:33,519 --> 00:27:37,690 OTHER PLACES AND CAUSE A 731 00:27:37,690 --> 00:27:39,192 PANDEMIC, SO WE BROUGHT THIS TO 732 00:27:39,192 --> 00:27:39,759 THE LAB. 733 00:27:39,759 --> 00:27:41,928 SO WE EXPANDED THE COLONIES TO 734 00:27:41,928 --> 00:27:47,300 HAVE AT THE SAME TIME, WE WOULD 735 00:27:47,300 --> 00:27:48,501 INFECT THE THREE MOSQUITOES AT 736 00:27:48,501 --> 00:27:49,502 THE SAME DAY, AT THE SAME TIME 737 00:27:49,502 --> 00:27:50,503 WITH PARASITES FROM DIFFERENT 738 00:27:50,503 --> 00:27:53,439 AREAS. 739 00:27:53,439 --> 00:27:58,678 SHOWN HERE BY THE AS TR ASTERISM 740 00:27:58,678 --> 00:28:00,012 AFRICA, AMERICA OR ASIA. 741 00:28:00,012 --> 00:28:01,981 SO WHEN WE DID THESE EXPERIMENTS 742 00:28:01,981 --> 00:28:02,949 WE FOUND SOME VERY STRIKING 743 00:28:02,949 --> 00:28:03,282 RESULTS. 744 00:28:03,282 --> 00:28:04,917 SO IN THE FIRST ONE, YOU TAKE AN 745 00:28:04,917 --> 00:28:08,421 AFRICAN PARASITE, THIS IS NF54, 746 00:28:08,421 --> 00:28:11,057 INFECTING ANOPHELES GAMBIAE FROM 747 00:28:11,057 --> 00:28:13,459 AFRICA, VIRUS FROM ASIA OR THE 748 00:28:13,459 --> 00:28:14,360 AMERICAS, AND WHAT YOU SEE IS 749 00:28:14,360 --> 00:28:15,928 THAT THE AFRICAN PARASITES 750 00:28:15,928 --> 00:28:17,263 INFECT THE AFRICAN MOSQUITOES 751 00:28:17,263 --> 00:28:18,564 BETTER THAN THOSE OF OTHER 752 00:28:18,564 --> 00:28:20,867 CONTINENTS. 753 00:28:20,867 --> 00:28:21,868 SO NOW WHAT WOULD HAPPEN IF WE 754 00:28:21,868 --> 00:28:25,671 TAKE THE SAME MOSQUITOES BUT NOW 755 00:28:25,671 --> 00:28:28,007 THE PARASITE CAME FROM ASIA. 756 00:28:28,007 --> 00:28:30,309 IF YOU DO THAT, THIS IS FROM A 757 00:28:30,309 --> 00:28:33,980 PATIENT FROM ASIA, NOW THIS 758 00:28:33,980 --> 00:28:37,583 ASIAN PARASITE INFECT THE 759 00:28:37,583 --> 00:28:38,251 MOSQUITOES -- IN THE NEW WORLD 760 00:28:38,251 --> 00:28:39,552 THEY REALLY DON'T DO WELL. 761 00:28:39,552 --> 00:28:41,554 WHAT IF THIS WAS A PARASITE THAT 762 00:28:41,554 --> 00:28:43,489 CAME FROM SOUTH AMERICA, FROM 763 00:28:43,489 --> 00:28:45,291 BRAZIL? 764 00:28:45,291 --> 00:28:48,027 THEN THIS ONE DOES BETTER IN 765 00:28:48,027 --> 00:28:48,694 THIS AMERICAN VECTOR THAN WITH 766 00:28:48,694 --> 00:28:52,498 THOSE FROM AFRICA OR -- SO THIS 767 00:28:52,498 --> 00:28:54,066 TELLS US THERE IS SELECTION THAT 768 00:28:54,066 --> 00:28:55,701 THE PARASITES IN A GIVEN 769 00:28:55,701 --> 00:28:57,870 CONTINENT DO BETTER. 770 00:28:57,870 --> 00:28:59,205 IF THEY'RE INFECTED WITH 771 00:28:59,205 --> 00:29:00,373 MOSQUITOES FROM THE SAME PLACE, 772 00:29:00,373 --> 00:29:04,110 THAT MAKES SENSE BECAUSE FOR 773 00:29:04,110 --> 00:29:05,511 THE -- THEY HAD TO SURVIVE IN 774 00:29:05,511 --> 00:29:05,978 THE VECTOR. 775 00:29:05,978 --> 00:29:07,280 IT'S THE ONLY WAY THEY CAN MOVE 776 00:29:07,280 --> 00:29:08,481 FROM ONE PERSON TO ANOTHER. 777 00:29:08,481 --> 00:29:09,348 THEY MUST PASS THROUGH A 778 00:29:09,348 --> 00:29:12,218 MOSQUITO. 779 00:29:12,218 --> 00:29:15,922 SO NOW TO WHAT EXTENT IS THIS 780 00:29:15,922 --> 00:29:17,356 SELECTION -- COULD BE BY MANY 781 00:29:17,356 --> 00:29:18,424 FACTORS BUT DO THIS HAVE 782 00:29:18,424 --> 00:29:19,959 ANYTHING TO DO WITH THE MOSQUITO 783 00:29:19,959 --> 00:29:20,526 IMMUNE SYSTEM? 784 00:29:20,526 --> 00:29:23,596 THE WAY WE CAN ADDRESS THAT IS 785 00:29:23,596 --> 00:29:25,431 THAT TEP1 THAT I TALKED ABOUT 786 00:29:25,431 --> 00:29:28,401 HAVE A STABILIZER THAT IS VERY 787 00:29:28,401 --> 00:29:30,369 WELL CONSERVED AND THERE'S A 788 00:29:30,369 --> 00:29:37,043 CLEAR OR THE LCLEAR ORTHO LOG SN 789 00:29:37,043 --> 00:29:38,244 DISRUPT THE MOSQUITO IMMUNE 790 00:29:38,244 --> 00:29:39,979 SYSTEM BY SILENCING THE 791 00:29:39,979 --> 00:29:41,080 STABILIZER AND THEN ASK WHEN WE 792 00:29:41,080 --> 00:29:44,817 DO THAT CAN WE REVERT -- SO WE 793 00:29:44,817 --> 00:29:45,785 DID THOSE EXPERIMENTS AND I'LL 794 00:29:45,785 --> 00:29:46,519 SHOW YOU SOME EXAMPLES. 795 00:29:46,519 --> 00:29:48,521 THIS IS THE ASIAN MOSQUITO WITH 796 00:29:48,521 --> 00:29:49,689 AN AFRICAN PARASITE. 797 00:29:49,689 --> 00:29:51,257 NORMALLY IT DOESN'T DO SO WELL, 798 00:29:51,257 --> 00:29:55,094 BUT IF YOU SILENCE LRIM1 THEN 799 00:29:55,094 --> 00:29:55,795 INFECTIONS INCREASE 800 00:29:55,795 --> 00:29:56,128 SIGNIFICANTLY. 801 00:29:56,128 --> 00:29:58,364 NOW WE GO TO MOSQUITOES FROM THE 802 00:29:58,364 --> 00:30:03,002 NEW WORLD, THIS IS ALBIMANUS 803 00:30:03,002 --> 00:30:06,105 WITH AN AFRICAN PARASITE, REALLY 804 00:30:06,105 --> 00:30:07,974 BAD, BUT IF YOU SILENCE, YOU GET 805 00:30:07,974 --> 00:30:09,709 THIS STRIKING INCREASE. 806 00:30:09,709 --> 00:30:11,210 AND THE SAME THING HAPPENS WITH 807 00:30:11,210 --> 00:30:11,777 THE ASIAN PARASITES. 808 00:30:11,777 --> 00:30:13,613 SO WHAT DOES THIS MEAN, THAT IF 809 00:30:13,613 --> 00:30:15,414 YOU TURN OFF OR DISRUPT THE 810 00:30:15,414 --> 00:30:17,149 MOSQUITO IMMUNE SYSTEM, ALL THE 811 00:30:17,149 --> 00:30:18,551 PARASITES CAN INFECT ALL THE 812 00:30:18,551 --> 00:30:21,420 DIFFERENT MOSQUITOES. 813 00:30:21,420 --> 00:30:22,955 THIS TELLS US IS THE MOSQUITO 814 00:30:22,955 --> 00:30:24,323 IMMUNE SYSTEM THE ONE EXERTING 815 00:30:24,323 --> 00:30:25,791 THIS SELECTED PRESSURE. 816 00:30:25,791 --> 00:30:27,660 WE DID SOME OTHER EXPERIMENTS 817 00:30:27,660 --> 00:30:28,527 THAT I'M JUST GOING TO 818 00:30:28,527 --> 00:30:28,961 SUMMARIZE. 819 00:30:28,961 --> 00:30:31,564 WE ALSO TOOK THE N TB. 54 820 00:30:31,564 --> 00:30:34,333 KNOCKOUT PARASITES AND REPLACED 821 00:30:34,333 --> 00:30:37,703 THE PF47 FROM AFRICA -- FROM THE 822 00:30:37,703 --> 00:30:39,805 NEW WORLD AND CHANGING THAT ALSO 823 00:30:39,805 --> 00:30:40,506 CHANGED THE COMPATIBILITY. 824 00:30:40,506 --> 00:30:41,774 SO BASED ON THIS, THE PICTURE 825 00:30:41,774 --> 00:30:45,845 THAT WE HAVE IS THAT MALARIA IS 826 00:30:45,845 --> 00:30:49,215 KNOWN TO HAVE ORIGINATED IN 827 00:30:49,215 --> 00:30:51,417 AFRICA AND THE -- REGIONS IN 828 00:30:51,417 --> 00:30:52,451 AFRICA, AND IT'S THOUGHT TO HAVE 829 00:30:52,451 --> 00:30:56,922 BEEN A SINGLE TRANSFER FROM A 830 00:30:56,922 --> 00:30:59,458 GORILLA, PARASITE, TO A HUMAN. 831 00:30:59,458 --> 00:31:04,397 ONE THE INFECTIONCE THE INFECTIS 832 00:31:04,397 --> 00:31:06,866 ESTABLISHED IN HUMANS, GORILLAS 833 00:31:06,866 --> 00:31:11,804 GORILLAS -- SEVERAL CENTURIES 834 00:31:11,804 --> 00:31:13,172 MOVED TO ASIA, BUT THE 835 00:31:13,172 --> 00:31:14,907 MOSQUITOES WERE LEFT BEHIND, SO 836 00:31:14,907 --> 00:31:16,442 NOW THESE PARASITES HAD TO ADAPT 837 00:31:16,442 --> 00:31:18,944 TO A NEW MOSQUITO IN ORDER TO 838 00:31:18,944 --> 00:31:22,381 ESTABLISH LOCAL CYCLES OF 839 00:31:22,381 --> 00:31:24,483 TRANSMISSION. 840 00:31:24,483 --> 00:31:29,855 THE OTHER ADAPTATION WAS FROM -- 841 00:31:29,855 --> 00:31:31,891 REGIONS TO ASIA AND THEN ANOTHER 842 00:31:31,891 --> 00:31:34,493 ADAPTATION WITHIN AFRICA WAS 843 00:31:34,493 --> 00:31:35,928 HUMAN CIVIC REGIONS WHERE IT 844 00:31:35,928 --> 00:31:38,431 ORIGINATED TO THE REGION WHERE 845 00:31:38,431 --> 00:31:39,965 IT ORIGINATED -- SO ALSO MORE 846 00:31:39,965 --> 00:31:41,067 RECENTLY THIS HAPPENED OVER 847 00:31:41,067 --> 00:31:43,469 THOUSANDS OF YEARS, BUT MORE 848 00:31:43,469 --> 00:31:44,670 RECENTLY WITH THE DISCOVERY OF 849 00:31:44,670 --> 00:31:46,005 THE NEW WORLD, IT'S ESTIMATED 850 00:31:46,005 --> 00:31:48,407 ABOUT 8 TO 10 MILLION AFRICAN 851 00:31:48,407 --> 00:31:49,608 SLAVES WERE BROUGHT TO THE 852 00:31:49,608 --> 00:31:52,645 AMERICAS AND MANY OF THEM WERE 853 00:31:52,645 --> 00:31:53,512 INFECTED WITH PLASMODIUM 854 00:31:53,512 --> 00:31:53,879 FALCIPARUM. 855 00:31:53,879 --> 00:31:55,181 THIS PARASITE NOW FINDS ITSELF 856 00:31:55,181 --> 00:31:57,049 IN A DIFFERENT CONTINENT WITH 857 00:31:57,049 --> 00:31:58,684 MOSQUITOES THAT WERE REALLY, 858 00:31:58,684 --> 00:31:59,685 REALLY DIFFERENT, AND SO THIS 859 00:31:59,685 --> 00:32:01,654 WAS ANOTHER BIG SELECTION 860 00:32:01,654 --> 00:32:04,056 BECAUSE ONLY THOSE, MOST 861 00:32:04,056 --> 00:32:05,024 PARASITES -- TODAY IN AFRICA 862 00:32:05,024 --> 00:32:07,760 HAVE NEVER BEEN ABLE TO 863 00:32:07,760 --> 00:32:08,627 ESTABLISH -- HAVE NOT BEEN ABLE 864 00:32:08,627 --> 00:32:09,862 TO ESTABLISH IN THE NEW WORLD, 865 00:32:09,862 --> 00:32:11,997 ONLY THE ONES THAT HAVE THOSE 866 00:32:11,997 --> 00:32:12,932 FOUR AMINO ACID DIFFERENCES THAT 867 00:32:12,932 --> 00:32:14,366 I SHOW YOU ARE ABLE TO BE 868 00:32:14,366 --> 00:32:16,001 TRANSMITTED AND THAT SELECTION 869 00:32:16,001 --> 00:32:17,436 IS STILL HAPPENING TODAY. 870 00:32:17,436 --> 00:32:19,638 OKAY. 871 00:32:19,638 --> 00:32:21,040 SO BASED ON THIS, NOW WE GO BACK 872 00:32:21,040 --> 00:32:22,641 TO THE LAB, WE GET OUT OF THE 873 00:32:22,641 --> 00:32:23,709 FIELD, WE GO BACK INTO THE LAB. 874 00:32:23,709 --> 00:32:25,244 SO BASED ON THIS, WE PROPOSE A 875 00:32:25,244 --> 00:32:27,413 MODEL THAT WE CALL THE LOCK AND 876 00:32:27,413 --> 00:32:28,280 KEY THEORY. 877 00:32:28,280 --> 00:32:30,816 WITH THESE, WE CAN THINK OF 878 00:32:30,816 --> 00:32:31,917 PFS47 AS A KEY AND THERE'S 879 00:32:31,917 --> 00:32:34,320 DIFFERENT VERSIONS OF THE KEY OR 880 00:32:34,320 --> 00:32:37,156 HAPLOTYPES, AND THEN HERE 881 00:32:37,156 --> 00:32:39,125 HAPLOTYPES 1, 2 AND 3, AND THIS 882 00:32:39,125 --> 00:32:40,359 KEY INTERACTS WITH THE LOCK IN 883 00:32:40,359 --> 00:32:42,428 THE MOSQUITO, A RECEPTOR, AND 884 00:32:42,428 --> 00:32:43,395 THE INTERACTION OF THE KEY WITH 885 00:32:43,395 --> 00:32:45,464 THE LOCK ALLOWS THE PARASITE TO 886 00:32:45,464 --> 00:32:50,669 TURN OFF THE NITRATION RESPONSE 887 00:32:50,669 --> 00:32:51,937 IN THE EPITHELIAL CELL. 888 00:32:51,937 --> 00:32:53,906 THE KEY YOU NEED DEPENDS WHICH 889 00:32:53,906 --> 00:32:56,075 LOCK YOU'RE TRYING TO OPEN, SO 890 00:32:56,075 --> 00:32:57,743 WHAT WORKS GREAT FOR AFRICA 891 00:32:57,743 --> 00:32:59,178 DOESN'T WORK SO WELL IN THE NEW 892 00:32:59,178 --> 00:33:00,579 WORLD AND SO FORTH. 893 00:33:00,579 --> 00:33:01,914 SO THERE HAS TO BE A MATCH 894 00:33:01,914 --> 00:33:02,982 BETWEEN THE KEY AND THE LOCK FOR 895 00:33:02,982 --> 00:33:03,783 THIS SYSTEM TO WORK. 896 00:33:03,783 --> 00:33:05,985 SO THE KEY TO THIS THEORY IS TO 897 00:33:05,985 --> 00:33:07,386 IDENTIFY WHAT IS THE LOCK, WHAT 898 00:33:07,386 --> 00:33:10,556 IS THE MOSQUITO RECEPTOR OF 899 00:33:10,556 --> 00:33:10,956 PFS47. 900 00:33:10,956 --> 00:33:13,292 SO IN ORDER TO DO THAT, FIRST WE 901 00:33:13,292 --> 00:33:19,398 MOBILIZED SOME -- WE TOOK -- 902 00:33:19,398 --> 00:33:23,502 THEN WE REMOVED THE CYTOPLASM 903 00:33:23,502 --> 00:33:25,137 PART AND TOOK THE INSOLUBLE PART 904 00:33:25,137 --> 00:33:28,274 THAT HAS THE MEMBRANES AND 905 00:33:28,274 --> 00:33:30,376 PROTEINS. 906 00:33:30,376 --> 00:33:34,780 WE RUN THOSE, WERE DISSECTED AND 907 00:33:34,780 --> 00:33:36,348 CLEANED EITHER 24 OR 48 HOURS 908 00:33:36,348 --> 00:33:38,717 AFTER FEEDING THEM ON HUMAN 909 00:33:38,717 --> 00:33:40,452 SERUM, AND THEN WE TRANSFERRED 910 00:33:40,452 --> 00:33:43,956 THESE PROTEINS TO A MEMBRANE AND 911 00:33:43,956 --> 00:33:45,825 THEN THE MEMBRANE IS INCUBATED 912 00:33:45,825 --> 00:33:48,527 WITH WHAT WE CALL A BAIT, WHICH 913 00:33:48,527 --> 00:33:51,564 IS RECOMBINANT PFS47 AND THERE'S 914 00:33:51,564 --> 00:33:53,399 NO BAIT CONTROL, AND THEN WE ASK 915 00:33:53,399 --> 00:33:57,102 DID THIS PFS47, THIS RECOMBINANT 916 00:33:57,102 --> 00:33:59,939 PROTEIN BIND TO ANY SPECIFIC 917 00:33:59,939 --> 00:34:05,511 BAND AND WE FIND IT DOES. 918 00:34:05,511 --> 00:34:08,380 WE CUT THE SPOT, DID A MASS SPEC 919 00:34:08,380 --> 00:34:09,949 AND IDENTIFIED A PUTATIVE 920 00:34:09,949 --> 00:34:10,382 RECEPTOR. 921 00:34:10,382 --> 00:34:12,818 WE TOOK THIS PUTATIVE RECEPTOR, 922 00:34:12,818 --> 00:34:14,119 WE SILENCED EXPRESSION WITH 923 00:34:14,119 --> 00:34:15,421 DOUBLE STRANDED RNA AND WE SHOW 924 00:34:15,421 --> 00:34:20,192 THAT THE SIGNALING IS GREATLY 925 00:34:20,192 --> 00:34:22,027 REDUCED WHEN WE SILENCE THE 926 00:34:22,027 --> 00:34:22,361 EXPRESSION. 927 00:34:22,361 --> 00:34:24,129 TO MAKE SURE WE HAVE THE RIGHT 928 00:34:24,129 --> 00:34:26,699 PROTEIN, WE ALSO EXPRESS REIMI 929 00:34:26,699 --> 00:34:30,169 NENT RECEPTOR AND BINDING -- YOU 930 00:34:30,169 --> 00:34:32,838 SEE PLASMA RESONANCE 931 00:34:32,838 --> 00:34:36,075 RESPONSES -- AND THEN EITHER 932 00:34:36,075 --> 00:34:38,244 WHEN WE IMMOBILIZE THE RECEPTOR 933 00:34:38,244 --> 00:34:42,147 AND THEN BOUND SOLUBLE PFS47 OR 934 00:34:42,147 --> 00:34:44,817 IMMOBILIZE PFS47 AND INCUBATE 935 00:34:44,817 --> 00:34:46,619 WITH SOLUBLE RECEPTOR, IN BOTH 936 00:34:46,619 --> 00:34:48,854 CASES WE GET HIGH AFFINITY 937 00:34:48,854 --> 00:34:49,088 BINDING. 938 00:34:49,088 --> 00:34:51,390 SO THIS IS A HIGH AFFINITY 939 00:34:51,390 --> 00:34:51,790 INTERACTION. 940 00:34:51,790 --> 00:34:53,425 WE ALSO MADE ANTIBODIES TO IT, 941 00:34:53,425 --> 00:34:56,061 AND IN THIS PICTURE HERE ON THE 942 00:34:56,061 --> 00:34:57,630 LEFT SIDE, WE CAN SEE IN RED, 943 00:34:57,630 --> 00:35:00,466 THIS IS THE ACTIN IN THE MICRO 944 00:35:00,466 --> 00:35:02,968 VILLI, THIS IS THE LUMEN SIDE OF 945 00:35:02,968 --> 00:35:06,038 THE MOSQUITO --, HERE IS WHERE 946 00:35:06,038 --> 00:35:12,878 WE SEE THE STRONGEST THINNING 947 00:35:12,878 --> 00:35:16,615 FOR THE PFS47 RECEPTOR, AND 948 00:35:16,615 --> 00:35:17,816 BOUNDARIES IN THE INTERCELLULAR 949 00:35:17,816 --> 00:35:18,317 JUNCTIONS. 950 00:35:18,317 --> 00:35:20,386 NOW ON THE RIGHT SIDE, WE HAVE A 951 00:35:20,386 --> 00:35:22,054 PARASITE IN THE PROCESS OF -- 952 00:35:22,054 --> 00:35:25,424 THAT HAS JUST INVADED THIS -- 953 00:35:25,424 --> 00:35:25,958 CELL. 954 00:35:25,958 --> 00:35:28,127 SEW WITH HAVE THE PARASITE IN 955 00:35:28,127 --> 00:35:29,561 GREEN, HERE YOU SEE THIS RED 956 00:35:29,561 --> 00:35:30,629 SPOT, THIS IS A RECEPTOR. 957 00:35:30,629 --> 00:35:34,199 THIS IS LOOKING FROM THE TOP AND 958 00:35:34,199 --> 00:35:37,169 THIS IS LACKING SIDEWAYS. 959 00:35:37,169 --> 00:35:37,703 LOOKING SIDEWAYS. 960 00:35:37,703 --> 00:35:39,571 AT THE POINT WHERE THE PAWR SITE 961 00:35:39,571 --> 00:35:40,773 INVADES THE CELL, THERE'S 962 00:35:40,773 --> 00:35:42,074 AGGREGATION OF THE RECEPTOR. 963 00:35:42,074 --> 00:35:43,842 SO THERE'S CLEAR CLOSE 964 00:35:43,842 --> 00:35:45,311 INTERACTION OF THE SURFACE OF 965 00:35:45,311 --> 00:35:48,781 THE PARASITE WITH THIS RECEPTOR. 966 00:35:48,781 --> 00:35:51,283 ALSO WHAT IS THIS PUTATIVE 967 00:35:51,283 --> 00:35:51,917 RECEPTOR? 968 00:35:51,917 --> 00:35:55,254 IT'S A DEEP PROTEIN THAT HAS NO 969 00:35:55,254 --> 00:35:58,457 OR THE LOGS, NONE FUNCTIONING IN 970 00:35:58,457 --> 00:36:00,159 ANY OTHER SYSTEM. 971 00:36:00,159 --> 00:36:08,701 IT WAS CLEAR -- -- PROTEINS WITH 972 00:36:08,701 --> 00:36:10,769 THESE -- DOMAINS HAVE STRUCTURAL 973 00:36:10,769 --> 00:36:12,638 HOMOLOGY TO OTHER PROTEINS THAT 974 00:36:12,638 --> 00:36:15,040 ARE INTERACTING PROTEINS, AND 975 00:36:15,040 --> 00:36:18,744 ALSO SOME MORE RECENTLY -- 976 00:36:18,744 --> 00:36:19,979 CONTAINING PROTEINS HAVE BEEN 977 00:36:19,979 --> 00:36:21,480 PROPOSED TO BE PATHOGEN 978 00:36:21,480 --> 00:36:24,883 REGULATION RECEPTORS, IN OTHER 979 00:36:24,883 --> 00:36:27,653 SYSTEMS. 980 00:36:27,653 --> 00:36:30,556 SO HERE WE HAVE THE PREDICTED 981 00:36:30,556 --> 00:36:34,393 STRUCTURE OF THIS RECEPTOR IN 982 00:36:34,393 --> 00:36:37,730 ANOPHELES GAMBIAE, DIRUS AND 983 00:36:37,730 --> 00:36:38,597 ALBIMANUS. 984 00:36:38,597 --> 00:36:39,598 SO WHAT HAPPENS IF WE REDUCE 985 00:36:39,598 --> 00:36:40,833 EXPRESSION OF THIS RECEPTOR? 986 00:36:40,833 --> 00:36:43,335 THIS IS HARD TO DO BUT WHEN WE 987 00:36:43,335 --> 00:36:44,903 DO THAT, WE SEE THERE'S A 988 00:36:44,903 --> 00:36:46,839 SIGNIFICANT REDUCTION IN THE 989 00:36:46,839 --> 00:36:48,173 LEVEL OF INFECTION. 990 00:36:48,173 --> 00:36:50,609 SO THE INTERACTION OF PFS47 WITH 991 00:36:50,609 --> 00:36:51,710 THIS RECEPTOR IS IMPORTANT FOR 992 00:36:51,710 --> 00:36:54,880 THE PARASITE TO SURVIVE. 993 00:36:54,880 --> 00:36:57,282 WE ALSO WANTED TO SEE MORE 994 00:36:57,282 --> 00:37:00,919 DETAIL, WE HAD DETERMINED THAT 995 00:37:00,919 --> 00:37:02,755 CASPASE ACTIVATION WAS IMPORTANT 996 00:37:02,755 --> 00:37:07,793 BASED ON MRNA EXPRESSION AND 997 00:37:07,793 --> 00:37:08,994 ON -- ACTIVITY BUT WE WANTED TO 998 00:37:08,994 --> 00:37:10,429 SEE THE CELL BIOLOGY IN MORE 999 00:37:10,429 --> 00:37:10,662 DETAIL. 1000 00:37:10,662 --> 00:37:12,297 SO WHAT IS THE DIFFERENCE OF HOW 1001 00:37:12,297 --> 00:37:14,166 A CELERY SPONDZ WHEN IT'S 1002 00:37:14,166 --> 00:37:16,268 INVADED BY EITHER WILD TYPE OR 1003 00:37:16,268 --> 00:37:18,737 KNOCKOUT PARASITE? 1004 00:37:18,737 --> 00:37:21,907 SO IN THE WILD TYPE -- LOOK 1005 00:37:21,907 --> 00:37:22,875 REALLY NICE WHEN THEY COMPLETE 1006 00:37:22,875 --> 00:37:24,109 INVASION, THEY LOOK LIKE THIS, 1007 00:37:24,109 --> 00:37:25,377 WHILE IN THE KNOCKOUT, THEY'RE 1008 00:37:25,377 --> 00:37:26,378 ALL FRAGMENTED. 1009 00:37:26,378 --> 00:37:32,384 THEY'RE TORN APART. 1010 00:37:32,384 --> 00:37:33,385 HERE'S THE QUANTITATION. 1011 00:37:33,385 --> 00:37:36,655 IN THE KNOCKOUT WE HAVE MORE -- 1012 00:37:36,655 --> 00:37:37,823 PARASITES AND BECAUSE MORE OF 1013 00:37:37,823 --> 00:37:40,726 THEM DIE, WE SEE ALSO HIGHER 1014 00:37:40,726 --> 00:37:43,228 CASPASE ACTIVATION, AND WE 1015 00:37:43,228 --> 00:37:45,297 ALSO -- EITHER BY ENZYMATIC 1016 00:37:45,297 --> 00:37:46,498 ASSAY OR COUNTING WHAT IS THE 1017 00:37:46,498 --> 00:37:48,133 PERCENT OF INVADED CELLS THAT 1018 00:37:48,133 --> 00:37:52,404 ARE CASPASE H-POSITIVE. 1019 00:37:52,404 --> 00:37:53,605 TO GIVE YOU AN IDEA OF WHAT THIS 1020 00:37:53,605 --> 00:37:55,307 LOOKS LIKE IN THE MICROSCOPE, SO 1021 00:37:55,307 --> 00:37:57,409 IN THE KNOCKOUT, WE SEE HIGH 1022 00:37:57,409 --> 00:37:58,410 ACTIVATION OF CASPASE IN THE 1023 00:37:58,410 --> 00:37:59,878 CELL AND THIS IS AN ANTIBODY 1024 00:37:59,878 --> 00:38:01,647 THAT DETECTS ACTIVATED CASPASE. 1025 00:38:01,647 --> 00:38:03,182 SO WE HAVE A BIG DIFFERENCE IN 1026 00:38:03,182 --> 00:38:04,383 HOW THESE TWO SYSTEMS ARE 1027 00:38:04,383 --> 00:38:05,050 WORKING. 1028 00:38:05,050 --> 00:38:06,685 THIS ONE IS VERY ACTIVE, WHILE 1029 00:38:06,685 --> 00:38:09,221 IN THE WILD TYPE, THIS IS A 1030 00:38:09,221 --> 00:38:10,756 QUIET CELL ON WHICH NIGH 1031 00:38:10,756 --> 00:38:12,491 TRAITION AN CASPASE ACTIVATION 1032 00:38:12,491 --> 00:38:13,926 DON'T TAKE PLACE. 1033 00:38:13,926 --> 00:38:17,296 ALSO WHEN WE LOOK AT -- TO LOOK 1034 00:38:17,296 --> 00:38:19,131 AT DNA FRAGMENTATION, WE SEE A 1035 00:38:19,131 --> 00:38:22,334 LOT OF DNA FRAGMENTATION IN THE 1036 00:38:22,334 --> 00:38:24,570 KNOCKOUT BUT NOT IN THE WILD 1037 00:38:24,570 --> 00:38:25,637 TYPE. 1038 00:38:25,637 --> 00:38:25,938 OKAY. 1039 00:38:25,938 --> 00:38:26,939 HOW DOES THIS WORK? 1040 00:38:26,939 --> 00:38:30,342 WE HAVE THIS PROTEIN WITH NO -- 1041 00:38:30,342 --> 00:38:33,078 TO ANYTHING, NO FUNCTION, SO HOW 1042 00:38:33,078 --> 00:38:34,880 IS THIS AFFECTING APOPTOSIS? 1043 00:38:34,880 --> 00:38:38,283 SO WE DECIDED OKAY, LET'S TRY TO 1044 00:38:38,283 --> 00:38:42,121 SEEK OR FIND A PARTNER THAT 1045 00:38:42,121 --> 00:38:43,956 INTERACTS THAT MAYBE CAN GIVE US 1046 00:38:43,956 --> 00:38:46,058 A HINT OF HOW THIS COULD WORK. 1047 00:38:46,058 --> 00:38:48,127 SO WE DID A SIMILAR EXPERIMENT 1048 00:38:48,127 --> 00:38:50,329 TO WHAT WE USED TO DETECT THE 1049 00:38:50,329 --> 00:38:51,530 RECEPTOR, BUT FIRST WE WANTED TO 1050 00:38:51,530 --> 00:38:54,333 SEE IN WHICH FRACTION IS MOST OF 1051 00:38:54,333 --> 00:38:55,534 THE RECEPTOR IN THE MOSQUITO 1052 00:38:55,534 --> 00:38:56,468 WHEN WITH HE DO THIS. 1053 00:38:56,468 --> 00:39:00,405 SO TO DO THIS WE TOOK AGAIN -- 1054 00:39:00,405 --> 00:39:03,809 GOT A READ OF THE CYTOPLASMIC 1055 00:39:03,809 --> 00:39:06,778 FRACTION, THEN WE EXTRACTED -- 1056 00:39:06,778 --> 00:39:11,817 TO REMOVE MEMBRANE AND THEN WE 1057 00:39:11,817 --> 00:39:13,785 HAVE INSOLUBLE PART. 1058 00:39:13,785 --> 00:39:16,788 HERE WE FIND THIS IS WHERE MOST 1059 00:39:16,788 --> 00:39:17,789 OF THE RECEPTOR IS. 1060 00:39:17,789 --> 00:39:21,827 SO THEN WE PREPARED THE 1061 00:39:21,827 --> 00:39:23,862 HOMOGENEOUS FROM THIS FRACTION 1062 00:39:23,862 --> 00:39:26,665 TO SEE -- SO WE PREPARED NEW 1063 00:39:26,665 --> 00:39:28,300 GELS, WE RUN THE GEL, THEN 1064 00:39:28,300 --> 00:39:29,501 TRANSFER THE PROTEIN TO A 1065 00:39:29,501 --> 00:39:31,770 MEMBRANE AND THEN WE PROBE THIS 1066 00:39:31,770 --> 00:39:39,945 WITH A P47 BAIT, MEANING WE AS 1067 00:39:39,945 --> 00:39:43,582 ASKED P47 RECEPTOR BIND ANYWHERE 1068 00:39:43,582 --> 00:39:45,217 AND WE FOUND THERE'S STRONG 1069 00:39:45,217 --> 00:39:46,084 BINDING TO PROTEINS AND 1070 00:39:46,084 --> 00:39:48,187 SOMETIMES WE SEE A SECOND 1071 00:39:48,187 --> 00:39:51,056 BINDING APPEARS TO BE THE 1072 00:39:51,056 --> 00:39:55,093 DIMER -- PROTEIN IS A DIMER. 1073 00:39:55,093 --> 00:40:02,201 WHEN WE WENT AHEAD AND RAN IT 1074 00:40:02,201 --> 00:40:07,206 THROUGH THE GEL AND -- PROTEIN 1075 00:40:07,206 --> 00:40:11,577 70-3, AND WHEN WE REDUCE -- WHEN 1076 00:40:11,577 --> 00:40:13,679 WE SIGN THIS EXPRESSION OF THIS 1077 00:40:13,679 --> 00:40:15,080 PROTEIN WE GREATLY REDUCE THE 1078 00:40:15,080 --> 00:40:17,249 SIGNAL IN THE FAR WEST. 1079 00:40:17,249 --> 00:40:18,984 THERE'S VERY LITTLE BINDING WITH 1080 00:40:18,984 --> 00:40:20,319 THE RECOMBINANT RECEPTOR WITH 1081 00:40:20,319 --> 00:40:21,386 THE MEMORY AND THIS IS THE 1082 00:40:21,386 --> 00:40:22,487 ACTING CONTROL TO SHOW THAT IT 1083 00:40:22,487 --> 00:40:25,257 WAS PROTEIN. 1084 00:40:25,257 --> 00:40:29,828 OKAY. 1085 00:40:29,828 --> 00:40:32,898 SO WE WANTED TO CONFIRM THESE 1086 00:40:32,898 --> 00:40:35,767 PROTEINS INTERACT SO WE MAKE THE 1087 00:40:35,767 --> 00:40:36,735 TWO PROTEINS RECOMBINANT SO IF 1088 00:40:36,735 --> 00:40:39,004 WE RUN THE P47 RECEPTOR IN A 1089 00:40:39,004 --> 00:40:42,507 MEMBRANE, THEN THE BAIT, THE 1090 00:40:42,507 --> 00:40:43,842 RECOMBINANT HSC70 PROTEIN BINDS 1091 00:40:43,842 --> 00:40:44,743 TO IT. 1092 00:40:44,743 --> 00:40:46,378 WE CAN ALSO DO BINDING 1093 00:40:46,378 --> 00:40:49,548 INTERACTIONS WITH THE LYSIS -- 1094 00:40:49,548 --> 00:40:53,852 IN BOTH CASES WE GET SATURABLE 1095 00:40:53,852 --> 00:40:54,086 BINDING. 1096 00:40:54,086 --> 00:40:57,256 SO WHAT IS THE EFFECT OF 1097 00:40:57,256 --> 00:40:58,657 REDUCING EXPRESSION OF PROTEIN 1098 00:40:58,657 --> 00:41:05,130 IN WILD TYPE PLASMODIUM 1099 00:41:05,130 --> 00:41:05,464 FALCIPARUM. 1100 00:41:05,464 --> 00:41:07,099 IT'S ABLE TO INTERACT WITH THE 1101 00:41:07,099 --> 00:41:09,968 RECEPTOR, THEN THE RECEPTOR 1102 00:41:09,968 --> 00:41:11,270 INTERACTS WITH EACH PROTEIN. 1103 00:41:11,270 --> 00:41:12,704 SO IF YOU REMOVE IT FROM THE 1104 00:41:12,704 --> 00:41:14,006 SYSTEM, THIS SHOULD AFFECT THE 1105 00:41:14,006 --> 00:41:15,007 PARASITE, THE PARASITE SHOULD 1106 00:41:15,007 --> 00:41:16,208 NOT DO SO WELL BECAUSE WE'RE 1107 00:41:16,208 --> 00:41:19,077 SAYING THAT EACH PROTEIN IN THIS 1108 00:41:19,077 --> 00:41:20,145 INTERACTION IS IMPORTANT. 1109 00:41:20,145 --> 00:41:22,547 IT WILL BE AFFECTED WHEN WE 1110 00:41:22,547 --> 00:41:23,682 REDUCE EXPRESSION. 1111 00:41:23,682 --> 00:41:25,250 AND THIS IS INDEED WHAT WE SEE 1112 00:41:25,250 --> 00:41:28,186 WHEN WE SILENCE REDUCED 1113 00:41:28,186 --> 00:41:29,955 EXPRESSION -- WE BEGIN TO SEE 1114 00:41:29,955 --> 00:41:33,725 INCREASING FRAGMENTED PARASITES, 1115 00:41:33,725 --> 00:41:35,127 REDUCTION IN THE NUMBER OF LIVE 1116 00:41:35,127 --> 00:41:39,331 PARASITES, AND INCREASE IN -- 1117 00:41:39,331 --> 00:41:40,799 ACTIVITY. 1118 00:41:40,799 --> 00:41:43,035 SO IF YOU -- THE PICTURE NEEDS 1119 00:41:43,035 --> 00:41:44,903 TO LOOK LIKE A KNOCKOUT 1120 00:41:44,903 --> 00:41:47,539 PARASITE, LIKE PFS47 IS NO 1121 00:41:47,539 --> 00:41:49,308 LONGER WORKING IF THE INITIAL 1122 00:41:49,308 --> 00:41:53,011 PROTEIN IS NOT THERE. 1123 00:41:53,011 --> 00:41:54,546 SO THERE'S -- THAT IS VERY 1124 00:41:54,546 --> 00:41:55,347 IMPORTANT TO KILL THE PARASITE, 1125 00:41:55,347 --> 00:41:57,949 SO WE ASKED IS THIS DEATH THAT 1126 00:41:57,949 --> 00:42:00,852 WE'RE SEEING WHEN WE ASSIGN EACH 1127 00:42:00,852 --> 00:42:01,953 PROTEIN MEDIATED BY CASPASE? 1128 00:42:01,953 --> 00:42:03,722 TO DO THAT EXPERIMENT, THIS IS A 1129 00:42:03,722 --> 00:42:05,023 REPEAT OF WHAT I JUST TOLD YOU, 1130 00:42:05,023 --> 00:42:06,625 THAT THE NUMBER OF LIVE 1131 00:42:06,625 --> 00:42:09,361 PARASITES REDUCES WHEN YOU -- 1132 00:42:09,361 --> 00:42:13,598 PROTEIN 70 THIS IS IN WILD TYPE 1133 00:42:13,598 --> 00:42:17,102 PARASITES THAT HAVE PFS47. 1134 00:42:17,102 --> 00:42:18,637 IN THE WILD TYPE THIS SYSTEM IS 1135 00:42:18,637 --> 00:42:20,138 NO LONGER ACTIVE. 1136 00:42:20,138 --> 00:42:24,409 WHEN WE DO -- EACH OF PROTEIN 1137 00:42:24,409 --> 00:42:28,113 17 -- YOU CAN RESCUE THIS. 1138 00:42:28,113 --> 00:42:30,415 SO WHEN YOU RESCUE THIS, THIS IS 1139 00:42:30,415 --> 00:42:33,352 TELLING US THE KILLING IS 1140 00:42:33,352 --> 00:42:37,189 MEDIATED BY CASPASE -- 2. 1141 00:42:37,189 --> 00:42:38,156 SO ALL TOGETHER SUMMARY OF WHAT 1142 00:42:38,156 --> 00:42:39,491 WE'VE SAID SO FAR, WHAT WE KNOW 1143 00:42:39,491 --> 00:42:42,160 SO FAR HOW THIS IS WORKING, SO 1144 00:42:42,160 --> 00:42:43,528 PLASMODIUM FALCIPARUM HAS A 1145 00:42:43,528 --> 00:42:45,964 MAGIC PROTEIN CALLED PFS47 ON 1146 00:42:45,964 --> 00:42:47,165 ITS SURFACE, AND THIS PROTEIN 1147 00:42:47,165 --> 00:42:48,934 HAS DIFFERENT HAPLOTYPES, IT IND 1148 00:42:48,934 --> 00:42:50,335 ACTS WITH THE MOSQUITO RECEPTOR 1149 00:42:50,335 --> 00:42:53,538 THAT IS DIFFERENT IN DIFFERENT 1150 00:42:53,538 --> 00:42:56,041 MOSQUITOES, AND THIS RECEPTOR 1151 00:42:56,041 --> 00:42:59,211 INTERACTS WITH PROTEIN HSC70 AND 1152 00:42:59,211 --> 00:43:00,579 THROUGH SOME MECHANISM 1153 00:43:00,579 --> 00:43:02,080 SUPPRESSES CASPASE AND IT HAS 1154 00:43:02,080 --> 00:43:03,715 SHOWN IN OTHER SYSTEMS IN 1155 00:43:03,715 --> 00:43:05,784 VERTEBRATES THAT THERE'S SOME 1156 00:43:05,784 --> 00:43:10,455 EXAMPLES OF -- PROTEIN HAVING AN 1157 00:43:10,455 --> 00:43:12,491 ANTIPIPE TO TICK EFFECT, THE 1158 00:43:12,491 --> 00:43:13,825 PRECISE MECHANISM, WE STILL 1159 00:43:13,825 --> 00:43:16,561 DON'T KNOW. 1160 00:43:16,561 --> 00:43:19,765 -- MODELS FOR THESE THREE 1161 00:43:19,765 --> 00:43:20,499 PROTEINS, AND WE HAVE BEEN 1162 00:43:20,499 --> 00:43:22,834 TRYING FOR MANY YEARS TO 1163 00:43:22,834 --> 00:43:23,902 CRYSTALLIZE AND SOLVE THE 1164 00:43:23,902 --> 00:43:26,805 STRUCTURE F OF THESE PROTEIN, TS 1165 00:43:26,805 --> 00:43:28,340 HAS PROVED TO BE VERY 1166 00:43:28,340 --> 00:43:28,774 CHALLENGING. 1167 00:43:28,774 --> 00:43:30,409 VERY RECENTLY WE HAVE BEEN ABLE 1168 00:43:30,409 --> 00:43:34,279 TO PRODUCE LARGE AMOUNTS OF 1169 00:43:34,279 --> 00:43:35,380 PFS47 RECEPTOR OF EACH PROTEIN 1170 00:43:35,380 --> 00:43:36,948 AND WE ARE IN THE PROCESS OF 1171 00:43:36,948 --> 00:43:41,219 FORMING A STABLE DIMER, AND 1172 00:43:41,219 --> 00:43:43,088 BECAUSE -- PROTEIN IS BIG, THE 1173 00:43:43,088 --> 00:43:45,424 TWO TOGETHER HAVE ALMOST 100 -- 1174 00:43:45,424 --> 00:43:49,227 AND THAT PUTS US IN A SIZE -- TO 1175 00:43:49,227 --> 00:43:50,228 SOLVE THE STRUCTURE. 1176 00:43:50,228 --> 00:43:53,799 OUR DREAM IS TO BE ABLE TO PUT 1177 00:43:53,799 --> 00:43:55,100 THESE THREE INTERACT, AND WHAT 1178 00:43:55,100 --> 00:43:56,334 ARE THE MOLECULAR INTERACTIONS. 1179 00:43:56,334 --> 00:44:00,472 THIS IS PARTICULARLY 1180 00:44:00,472 --> 00:44:02,574 IMPORTANT -- PFS47 AND THE 1181 00:44:02,574 --> 00:44:04,009 RECEPTOR BECAUSE THIS WILL BE A 1182 00:44:04,009 --> 00:44:04,776 MOLECULAR LANGUAGE OF 1183 00:44:04,776 --> 00:44:05,110 COMPATIBILITY. 1184 00:44:05,110 --> 00:44:06,745 WE KNOW THE SEQUENCES OF 1185 00:44:06,745 --> 00:44:07,579 PARASITES ALL OVER THE WORLD AND 1186 00:44:07,579 --> 00:44:09,181 WE KNOW THE SEQUENCES OF THE 1187 00:44:09,181 --> 00:44:10,148 RECEPTORS IN THE MOSQUITO, SO IF 1188 00:44:10,148 --> 00:44:12,050 WE KNEW HOW THEY INTERACT, WE 1189 00:44:12,050 --> 00:44:14,419 COULD PREDICT HOW LIKELY IS A 1190 00:44:14,419 --> 00:44:16,288 PARASITE TO BE TRANSMITTED BY A 1191 00:44:16,288 --> 00:44:17,656 GIVEN VECTOR IN A DIFFERENT 1192 00:44:17,656 --> 00:44:22,994 PLACE, AT LEAST IN TERMS OF THE 1193 00:44:22,994 --> 00:44:24,663 MOSQUITO ANALYSIS. 1194 00:44:24,663 --> 00:44:26,431 INDEED THIS -- DOMAIN 2, THERE'S 1195 00:44:26,431 --> 00:44:30,335 TWO OF THEM THAT ARE FIXED, TWO 1196 00:44:30,335 --> 00:44:30,969 NUCLEOTIDES -- COMBINATION THAT 1197 00:44:30,969 --> 00:44:32,304 ARE ALMOST FIXED IN DIFFERENT 1198 00:44:32,304 --> 00:44:34,239 CONTINENTS, PACEICALLY FOR THESE 1199 00:44:34,239 --> 00:44:37,209 TWO POSITIONS, 98% OF PARASITES 1200 00:44:37,209 --> 00:44:40,145 ARE T-T IN THE AMERICAS, C-C IN 1201 00:44:40,145 --> 00:44:41,880 AFRICA, AND T-C IN ASIA. 1202 00:44:41,880 --> 00:44:45,350 SO THIS ALLOWS US TO GENERATE -- 1203 00:44:45,350 --> 00:44:49,287 TO DEVELOP A HIGH RESOLUTION 1204 00:44:49,287 --> 00:44:51,256 MELTING GENOTYPE ASSAY, 1205 00:44:51,256 --> 00:44:52,858 BASICALLY YOU RUN A PCR, YOU 1206 00:44:52,858 --> 00:44:53,925 MELT THE PRODUCTS AND THEN YOU 1207 00:44:53,925 --> 00:44:56,862 CAN TELL IF THE PARASITE -- 1208 00:44:56,862 --> 00:44:57,629 WHERE IT'S LIKELY THAT IT CAME 1209 00:44:57,629 --> 00:44:58,063 FROM. 1210 00:44:58,063 --> 00:45:00,298 THIS IS VERY USEFUL BECAUSE NOW 1211 00:45:00,298 --> 00:45:01,733 WITH -- MANY PEOPLE ARE MOVING A 1212 00:45:01,733 --> 00:45:04,469 LOT, SO SOMETIMES YOU ENCOUNTER 1213 00:45:04,469 --> 00:45:10,408 PLACES WHERE MALARIA HAS BEEN 1214 00:45:10,408 --> 00:45:12,043 ERADICATED, YOU NEED TO KNOW 1215 00:45:12,043 --> 00:45:15,213 WHERE IT CAME FROM, WHAT ARE THE 1216 00:45:15,213 --> 00:45:16,648 CHANCE OF AN EPIDEMIC. 1217 00:45:16,648 --> 00:45:18,617 I THINK YOU HEARD IN MARYLAND, 1218 00:45:18,617 --> 00:45:22,454 EVERY YEAR THERE'S A FEW MALARIA 1219 00:45:22,454 --> 00:45:24,789 CASES, SOMETIMES CASES OF LOCAL 1220 00:45:24,789 --> 00:45:25,891 TRANSMISSION AND THEY REALLY 1221 00:45:25,891 --> 00:45:27,192 NEED TO KNOW WHERE THESE 1222 00:45:27,192 --> 00:45:28,960 PARASITES ARE COMING FROM, SO 1223 00:45:28,960 --> 00:45:31,062 THIS IS EXTREMELY HELPFUL FOR 1224 00:45:31,062 --> 00:45:31,596 THAT. 1225 00:45:31,596 --> 00:45:33,965 EVERYTHING I'VE TOLD YOU SO FAR 1226 00:45:33,965 --> 00:45:41,206 IS A MAJOR DETERMINANT -- VERY 1227 00:45:41,206 --> 00:45:45,510 HIGH MORTALITY, PARTICULARLY IN 1228 00:45:45,510 --> 00:45:49,581 CHILDREN. 1229 00:45:49,581 --> 00:45:55,587 P.VIVAX IS A MAJOR PROBLEM -- SO 1230 00:45:55,587 --> 00:45:58,690 THEY ARE RESISTANT TO INFECTION 1231 00:45:58,690 --> 00:45:59,324 WITH THE VIRUS. 1232 00:45:59,324 --> 00:46:02,928 SO WE ASK WAS THIS COMPATIBILITY 1233 00:46:02,928 --> 00:46:07,198 AND PV47 WHICH IS THE ORTHO LOG 1234 00:46:07,198 --> 00:46:08,800 IN VIRUS, WOULD THIS ALSO BE 1235 00:46:08,800 --> 00:46:11,636 GOING THROUGH A SIMILAR PROCESS? 1236 00:46:11,636 --> 00:46:18,743 SO HERE AGAIN ALL THE VAWR VARI, 1237 00:46:18,743 --> 00:46:23,415 THERE'S NOR GENETIC DIVERSITY, 1238 00:46:23,415 --> 00:46:27,052 THE HIGHEST LEVELS ARE IN ASIA 1239 00:46:27,052 --> 00:46:28,587 AND NEW GUINEA, AND MOST 1240 00:46:28,587 --> 00:46:31,656 PARASITES ARE SEGREGATED BY 1241 00:46:31,656 --> 00:46:32,624 CONTINENT. 1242 00:46:32,624 --> 00:46:34,159 ALTHOUGH THE PARASITE ORIGINATED 1243 00:46:34,159 --> 00:46:37,529 IN AFRICA, THERE'S LESS 1244 00:46:37,529 --> 00:46:40,065 DIVERSITY AND LESS PARASITES IN 1245 00:46:40,065 --> 00:46:43,034 AFRICA BECAUSE ALMOST EVERY -- 1246 00:46:43,034 --> 00:46:45,370 MOST PEOPLE IN AFRICA RECEIVE 1247 00:46:45,370 --> 00:46:47,739 SOME INFECTION WITH VIVEX. 1248 00:46:47,739 --> 00:46:49,841 NEW CASES ARE APPEARING AND IT'S 1249 00:46:49,841 --> 00:46:50,609 NOT CLEAR WHERE EXACTLY THEY 1250 00:46:50,609 --> 00:46:51,209 CAME FROM. 1251 00:46:51,209 --> 00:46:55,780 NOW I IF WE LOOK AT THE 1252 00:46:55,780 --> 00:46:58,817 DIFFERENCES, THEY ARE NOT 1253 00:46:58,817 --> 00:46:59,050 RANDOM. 1254 00:46:59,050 --> 00:47:01,019 IN THIS THE PINK AREA IS THE 1255 00:47:01,019 --> 00:47:02,120 DOMAIN BETWEEN THE TWO SYSTEMS 1256 00:47:02,120 --> 00:47:03,221 THAT WE TALKED ABOUT THAT IS 1257 00:47:03,221 --> 00:47:05,624 ALSO VERY IMPORTANT, I WANT TO 1258 00:47:05,624 --> 00:47:07,926 CALL YOUR ATTENTION TO A 1259 00:47:07,926 --> 00:47:10,061 DIFFERENCE HERE CLOSE TO THE END 1260 00:47:10,061 --> 00:47:11,296 TERMINUS, AND HERE FOR 1261 00:47:11,296 --> 00:47:12,931 COMPARISON, WE HAVE PFS47 AND 1262 00:47:12,931 --> 00:47:14,432 AGAIN THE NUCLEOTIDES ARE HERE 1263 00:47:14,432 --> 00:47:20,138 IN DOMAIN 2, BETWEEN THESE TWO 1264 00:47:20,138 --> 00:47:21,006 SYSTEMS AND THAT'S TRUE HERE. 1265 00:47:21,006 --> 00:47:23,108 THIS IS JUST A NETWORK ANALYSIS 1266 00:47:23,108 --> 00:47:24,976 TO STUDY ALL THE HAPLOTYPES AND 1267 00:47:24,976 --> 00:47:26,845 HOW THEY'RE CONNECTED, THE 1268 00:47:26,845 --> 00:47:28,680 CLOSER THEY ARE, THE LESS 1269 00:47:28,680 --> 00:47:30,348 DISTANCE THERE ARE BETWEEN THEM. 1270 00:47:30,348 --> 00:47:32,417 AND WE CAN SEE THAT THE ONCE IN 1271 00:47:32,417 --> 00:47:34,119 THE NEW WORLD ARE MORE SEPARATED 1272 00:47:34,119 --> 00:47:35,220 FROM THE REST. 1273 00:47:35,220 --> 00:47:36,855 IF WE LOOK AT THIS IN A 1274 00:47:36,855 --> 00:47:41,459 QUANTITATIVE WAY WITH THIS 1275 00:47:41,459 --> 00:47:43,461 HEAT -- MAP, AND FST IS THE 1276 00:47:43,461 --> 00:47:46,197 HIGHEST, BETWEEN .6 AND .86 1277 00:47:46,197 --> 00:47:46,865 BETWEEN THE SOUTH AMERICAN 1278 00:47:46,865 --> 00:47:47,966 CONTINENT AND THE REST OF THE 1279 00:47:47,966 --> 00:47:50,402 WORLD, AND THIS IS REFLECTED 1280 00:47:50,402 --> 00:47:50,602 HERE. 1281 00:47:50,602 --> 00:47:57,242 TO GIVE YOU AN IDEA, IF IT MORE 1282 00:47:57,242 --> 00:47:59,978 THAN 7.05, WE'LL HAVE EXTREMELY 1283 00:47:59,978 --> 00:48:02,414 HIGH POPULATION DIVERSITY, THIS 1284 00:48:02,414 --> 00:48:03,948 SELECTION BY GEOGRAPHIC AREA AND 1285 00:48:03,948 --> 00:48:07,886 THAT WE THINK IS CREATED BY THE 1286 00:48:07,886 --> 00:48:08,420 MOSQUITOES. 1287 00:48:08,420 --> 00:48:09,954 THEN IN CONTRAST, THERE'S SOME 1288 00:48:09,954 --> 00:48:13,658 OTHER REGIONS LIKE THOSE IN 1289 00:48:13,658 --> 00:48:15,860 AFRICA AND NEW GUINEA ARE NOT SO 1290 00:48:15,860 --> 00:48:17,395 WELL DIFFERENTIATED, THERE'S 1291 00:48:17,395 --> 00:48:19,297 ACTUALLY SOME OVERLAP, SO THE 1292 00:48:19,297 --> 00:48:26,171 FST VALUE IS NOT SO HIGH. 1293 00:48:26,171 --> 00:48:29,874 LAST PART OF THE TALK, THIS IS 1294 00:48:29,874 --> 00:48:30,475 SOMETHING FASCINATING. 1295 00:48:30,475 --> 00:48:35,313 THIS IS PLASMODIUM VIVEX IN 1296 00:48:35,313 --> 00:48:36,614 MEXICO, TRANSMITTED BY TWO 1297 00:48:36,614 --> 00:48:37,182 DIFFERENT VECTORS. 1298 00:48:37,182 --> 00:48:39,217 IN THE HIGHLANDS IN GREEN AND 1299 00:48:39,217 --> 00:48:41,186 THEN THE COASTAL AREA IS THE 1300 00:48:41,186 --> 00:48:44,456 MAIN VECTOR. 1301 00:48:44,456 --> 00:48:46,224 THIS STUDY WAS DONE HERE IN THE 1302 00:48:46,224 --> 00:48:47,525 BORDER BETWEEN MEXICO IN THE 1303 00:48:47,525 --> 00:48:48,860 BORDER BETWEEN MEXICO AND 1304 00:48:48,860 --> 00:48:53,765 GUATEMALA. 1305 00:48:53,765 --> 00:48:56,501 SO IN THAT AREA, WE SEE SEVERAL 1306 00:48:56,501 --> 00:49:01,406 YEARS AGO, XIN ZHUAN SU IN 1307 00:49:01,406 --> 00:49:03,041 COLLABORATION WITH THE GROUP, 1308 00:49:03,041 --> 00:49:04,342 THEY DID A VERY INTERESTING 1309 00:49:04,342 --> 00:49:06,611 STUDY ON WHICH THEY GENOTYPED 1310 00:49:06,611 --> 00:49:07,579 PARASITES FROM THE HIGHLANDS AND 1311 00:49:07,579 --> 00:49:10,215 THOSE FROM THE COASTAL AREAS, 1312 00:49:10,215 --> 00:49:12,717 AND THEY FOUND THERE WERE THREE 1313 00:49:12,717 --> 00:49:16,888 GENOTYPES TOO IN THE HIGHLAND 1314 00:49:16,888 --> 00:49:18,323 AND ONE MAJOR HERE. 1315 00:49:18,323 --> 00:49:19,758 THEY TOOK TWO SPECIES OF THE 1316 00:49:19,758 --> 00:49:21,059 MOSQUITOES IN THE LAB AND THEN, 1317 00:49:21,059 --> 00:49:22,727 AGAIN, THE SAME DAY A AT THE SAE 1318 00:49:22,727 --> 00:49:24,395 TIME, THEY TOOK BLOOD FROM AN 1319 00:49:24,395 --> 00:49:25,697 INFECTED PATIENT AND YOU HAVE TO 1320 00:49:25,697 --> 00:49:28,666 DO IT WITH PATIENTS WITH VIRUS 1321 00:49:28,666 --> 00:49:29,868 BECAUSE -- SO THEY TOOK BLOOD 1322 00:49:29,868 --> 00:49:30,902 FROM THE INFECTED PATIENT AND 1323 00:49:30,902 --> 00:49:32,103 GAVE TO THE TWO MOSQUITOES AT 1324 00:49:32,103 --> 00:49:32,971 THE SAME TIME AND THEY ASKED HOW 1325 00:49:32,971 --> 00:49:34,405 WELL ARE THEY INFECTED. 1326 00:49:34,405 --> 00:49:36,007 AND THEY FOUND SOMETHING 1327 00:49:36,007 --> 00:49:36,307 INTERESTING. 1328 00:49:36,307 --> 00:49:38,309 THOSE PAIR SITES WITH THE RED 1329 00:49:38,309 --> 00:49:40,111 GENOTYPE THAT THEY CALL C1, THEY 1330 00:49:40,111 --> 00:49:43,948 INFECT VERY WELL AND -- THEY 1331 00:49:43,948 --> 00:49:46,351 DON'T INFECT VERY WELL, SO IT'S 1332 00:49:46,351 --> 00:49:48,520 THE OPPOSITE FOR THOSE IN THE 1333 00:49:48,520 --> 00:49:49,320 HIGHLANDS. 1334 00:49:49,320 --> 00:49:51,890 AGAIN THE ONE IN THE HIGHLANDS 1335 00:49:51,890 --> 00:49:55,226 AFFECT THE MOSQUITO PRESSING IN 1336 00:49:55,226 --> 00:49:58,129 THE HIGH LATES -- THE COASTAL 1337 00:49:58,129 --> 00:49:59,998 AREA. 1338 00:49:59,998 --> 00:50:01,232 SO THEY KEPT IT FOR MANY YEARS, 1339 00:50:01,232 --> 00:50:02,433 THIS WAS PUBLISHED MANY YEARS 1340 00:50:02,433 --> 00:50:06,738 AGO, SO NOW WE WENT BABBL BACK D 1341 00:50:06,738 --> 00:50:08,106 SEQUENCED PFS47 FROM THESE 1342 00:50:08,106 --> 00:50:10,275 SAMPLES AND ASKED IS THERE ANY 1343 00:50:10,275 --> 00:50:11,142 AMINO ACID THAT CORRELATES WITH 1344 00:50:11,142 --> 00:50:12,944 THE ABILITY OF THE PARASITE TO 1345 00:50:12,944 --> 00:50:14,779 INFECT ONE MOSQUITO OR THE 1346 00:50:14,779 --> 00:50:16,080 OTHER? 1347 00:50:16,080 --> 00:50:20,919 AND WE TOOK THE MOST CLEARLY 1348 00:50:20,919 --> 00:50:21,953 DIFFERENT INFECTIONS THAT WERE 1349 00:50:21,953 --> 00:50:22,821 DIFFERENT BETWEEN THE TWO 1350 00:50:22,821 --> 00:50:24,122 VECTORS, SO BASICALLY WE 1351 00:50:24,122 --> 00:50:26,758 CONSIDER THOSE PARASITE -- THOSE 1352 00:50:26,758 --> 00:50:28,560 INFECTIONS WHERE THERE WAS A 1353 00:50:28,560 --> 00:50:29,561 SIGNIFICANT -- IN THE PREVALENCE 1354 00:50:29,561 --> 00:50:31,796 OF INFECTION BETWEEN THE TWO 1355 00:50:31,796 --> 00:50:32,397 MOSQUITOES -- SPECIES. 1356 00:50:32,397 --> 00:50:34,499 SO WHEN WE DID THAT, WE FOUND 1357 00:50:34,499 --> 00:50:35,400 SOMETHING VERY STRIKING. 1358 00:50:35,400 --> 00:50:39,771 IF YOU HAVE A POSITIVELY 1359 00:50:39,771 --> 00:50:42,373 CHARGED -- IN POSITION 27 THEN 1360 00:50:42,373 --> 00:50:45,743 YOUR VECTOR OF REFERENCE DOSH DO 1361 00:50:45,743 --> 00:50:47,979 REALLY WELL THERE BUT -- SO IF 1362 00:50:47,979 --> 00:50:51,449 YOU HAVE A NEGATIVELY CHARGED 1363 00:50:51,449 --> 00:50:54,385 RESIDUE, IT'S THE OPPOSITE. 1364 00:50:54,385 --> 00:50:55,587 IT'S A VERY GOOD VECTOR FOR YOU 1365 00:50:55,587 --> 00:50:59,958 BUT NOT MUCH LUCK IF YOU TRY TO 1366 00:50:59,958 --> 00:51:04,896 INFECTOINFECT ALBIMANUS. 1367 00:51:04,896 --> 00:51:07,632 IN RED ARE THE AMINO ACIDS IN 1368 00:51:07,632 --> 00:51:10,268 THE D2 DOMAIN, THIS IS IN THE 1369 00:51:10,268 --> 00:51:11,135 END TERMINUS, THEY'RE ALL IN THE 1370 00:51:11,135 --> 00:51:13,872 SAME PHASE OF PV47, THE SAME 1371 00:51:13,872 --> 00:51:17,041 THING IS FOUND IN PFS47, SO WE 1372 00:51:17,041 --> 00:51:18,776 THINK THIS MIGHT BE THE PHASE 1373 00:51:18,776 --> 00:51:20,778 WHERE P47 INTERACTS WITH THE 1374 00:51:20,778 --> 00:51:21,880 MOSQUITO RECEPTOR. 1375 00:51:21,880 --> 00:51:24,182 AND AGAIN, WE'RE HOPING -- WE'RE 1376 00:51:24,182 --> 00:51:25,717 LOOKING FORWARD TO HAVING THIS 1377 00:51:25,717 --> 00:51:28,286 STRUCTURE SO WE CAN REALLY MODEL 1378 00:51:28,286 --> 00:51:31,589 THESE INTERACTIONS AND PREDICT 1379 00:51:31,589 --> 00:51:32,690 COMPATIBILITY. 1380 00:51:32,690 --> 00:51:34,492 SO IN SHORT, WE HAVE SHOWN THE 1381 00:51:34,492 --> 00:51:35,660 MOSQUITO HAS AN IMMUNE SYSTEM 1382 00:51:35,660 --> 00:51:39,063 AND IT CAN BE EFFECTIVE IN 1383 00:51:39,063 --> 00:51:39,731 ELIMINATING PLASMODIUM 1384 00:51:39,731 --> 00:51:40,632 PARASITES. 1385 00:51:40,632 --> 00:51:44,335 IT'S A COMPLEX CYST THEAM 1386 00:51:44,335 --> 00:51:50,308 INVOLVES EPITHELIAL NITRATION, 1387 00:51:50,308 --> 00:51:52,277 ACTIVATION OF TEP1. 1388 00:51:52,277 --> 00:51:53,678 IF ANYTHING FAILS THEN THE 1389 00:51:53,678 --> 00:51:54,812 PARASITE CAN ESCAPE. 1390 00:51:54,812 --> 00:51:56,948 WE HOPE THAT THIS NEW 1391 00:51:56,948 --> 00:51:58,783 UNDERSTANDING WILL HELP US TO 1392 00:51:58,783 --> 00:52:03,922 DEVELOP NEW WAYS OF DISRUPTING 1393 00:52:03,922 --> 00:52:04,689 THE -- TRANSMISSION AND 1394 00:52:04,689 --> 00:52:05,290 PREVENTING DISEASE. 1395 00:52:05,290 --> 00:52:08,226 I WOULD LIKE TO FINISH BY 1396 00:52:08,226 --> 00:52:09,427 INTRODUCING THE PEOPLE THAT DID 1397 00:52:09,427 --> 00:52:16,701 THE WORK I PRESENTED TODAY. 1398 00:52:16,701 --> 00:52:19,671 GISELE DEMONSTRATED THAT 1399 00:52:19,671 --> 00:52:21,506 EPITHELIAL NITRATION WAS 1400 00:52:21,506 --> 00:52:23,908 ESSENTIAL FOR EFFECTIVE 1401 00:52:23,908 --> 00:52:25,944 ACTIVATION, HER STUDIES CLEARLY 1402 00:52:25,944 --> 00:52:26,711 DEMONSTRATED THAT. 1403 00:52:26,711 --> 00:52:30,648 LINDSAY GARVER SHOWED -- 1404 00:52:30,648 --> 00:52:32,650 SIGNALING IS CLEARLY A KEY 1405 00:52:32,650 --> 00:52:34,719 PLAYER AND IS CREATING 1406 00:52:34,719 --> 00:52:39,223 ACTIVATION OF CASPASE. 1407 00:52:39,223 --> 00:52:45,163 URVASHI RAMPHUL DID A SCREEN AND 1408 00:52:45,163 --> 00:52:47,799 DEMONSTRATED IF YOU'RE -- 1409 00:52:47,799 --> 00:52:49,100 SILENCING CASPASE HAS NO EFFECT 1410 00:52:49,100 --> 00:52:52,236 IN THE WILD TYPE PARASITE. 1411 00:52:52,236 --> 00:52:58,409 FOR A LONG TIME WE KNEW -- TO 1412 00:52:58,409 --> 00:52:59,811 ACTIVATE TEP1, HE FOUND THE 1413 00:52:59,811 --> 00:53:02,313 MISSING LINK IS HEMOCYTE, AND 1414 00:53:02,313 --> 00:53:07,318 THE RELEASE OF HEMOCYTES AND 1415 00:53:07,318 --> 00:53:07,952 MICROVESICLES, THAT'S AN 1416 00:53:07,952 --> 00:53:08,619 ESSENTIAL STEP. 1417 00:53:08,619 --> 00:53:11,789 IF YOU DISRUPT THE STEP, THEN 1418 00:53:11,789 --> 00:53:13,458 STEP ONE ACTIVATION DOESN'T 1419 00:53:13,458 --> 00:53:14,225 HAPPEN. 1420 00:53:14,225 --> 00:53:20,365 ANA PEATRIZ DISCOVERED -- SHE 1421 00:53:20,365 --> 00:53:22,700 IDENTIFIED THE ENZYMES THAT MAKE 1422 00:53:22,700 --> 00:53:23,901 THE PROSTAGLANDIN AND THEN SHOW 1423 00:53:23,901 --> 00:53:26,537 THAT WHEN HEMOCYTES TOUCH ON 1424 00:53:26,537 --> 00:53:29,640 A -- SURFACE, THEY RELEASE MICRO 1425 00:53:29,640 --> 00:53:34,412 VESICLES AND ARE ATTRACTED IF 1426 00:53:34,412 --> 00:53:37,081 YOU -- -- IS A MAJOR PLAYER, 1427 00:53:37,081 --> 00:53:39,050 WE'VE BEEN WORKING TOGETHER FOR 1428 00:53:39,050 --> 00:53:40,418 21 YEARS NOW. 1429 00:53:40,418 --> 00:53:44,822 HE MAPPED THE PFS47 GENE, IT WAS 1430 00:53:44,822 --> 00:53:46,991 A VERY CHALLENGING PROJECT THAT 1431 00:53:46,991 --> 00:53:48,126 TOOK ALMOST SEVEN YEARS AND A 1432 00:53:48,126 --> 00:53:50,762 LOT OF EFFORT, AND SOME POINT WE 1433 00:53:50,762 --> 00:53:52,430 WERE THINKING WE WOULD RETIRE 1434 00:53:52,430 --> 00:53:53,498 BEFORE WE FOUND WHAT THE GENE 1435 00:53:53,498 --> 00:53:54,766 WAS, BUT WE LOCKED OUT THAT 1436 00:53:54,766 --> 00:53:56,834 SOMEONE HAD A KNOCKOUT AND -- 1437 00:53:56,834 --> 00:53:59,103 THAT BECAME A MAJOR CANDIDATE, 1438 00:53:59,103 --> 00:54:00,271 AND IT TURNED OUT TO BE THE 1439 00:54:00,271 --> 00:54:06,511 RIGHT THING, SO THE OTHER LAB 1440 00:54:06,511 --> 00:54:10,114 THAT -- SAVED US 12 YEARS OF OUR 1441 00:54:10,114 --> 00:54:12,250 LIVES HAVING TO DO A KNOCKOUT 1442 00:54:12,250 --> 00:54:13,885 FOR 40 GENES. 1443 00:54:13,885 --> 00:54:21,292 ALSO I WANT HE IDENTIFIED THE R, 1444 00:54:21,292 --> 00:54:23,528 HE DID SOME OTHER ONES LOOKING 1445 00:54:23,528 --> 00:54:26,964 AT THE ROLE OF EARLY TRANSITION 1446 00:54:26,964 --> 00:54:28,066 BETWEEN -- AND HUMANS THAT I DID 1447 00:54:28,066 --> 00:54:29,700 NOT PRESENT FOR THE SAKE OF 1448 00:54:29,700 --> 00:54:32,336 TIME. 1449 00:54:32,336 --> 00:54:34,872 GASPAR CANEPA WAS OUR PARASITE 1450 00:54:34,872 --> 00:54:36,841 ENGINEER, DETHE KNOCKOUTS AND 1451 00:54:36,841 --> 00:54:38,409 REPLACEMENTS, FIRST REPLACING 1452 00:54:38,409 --> 00:54:40,578 INDIVIDUAL AMINO ACIDS AND -- 1453 00:54:40,578 --> 00:54:42,246 FROM DIFFERENT CONTINENTS AND 1454 00:54:42,246 --> 00:54:50,221 NOT SHOW IT TODAY BUT ALSO THE 1455 00:54:50,221 --> 00:54:53,191 HUMAN -- 47, THE PARASITE THAT 1456 00:54:53,191 --> 00:54:54,826 INFECTS CHIMPANZEES OR 1457 00:54:54,826 --> 00:54:55,259 GUERILLAS. 1458 00:54:55,259 --> 00:54:57,762 THEN ALSO HEE AND ALVARO WORKED 1459 00:54:57,762 --> 00:54:59,597 TOGETHER IN MAPPING THE REGION 1460 00:54:59,597 --> 00:55:00,998 WHERE ANTIBODY BINDING BLOCKED 1461 00:55:00,998 --> 00:55:01,566 TRANSMISSION. 1462 00:55:01,566 --> 00:55:05,436 AND THIAGO SILVA DID THE CELL 1463 00:55:05,436 --> 00:55:06,637 BIOLOGY, REALLY SHOWING WHAT ARE 1464 00:55:06,637 --> 00:55:09,140 THE DIFFERENCES BETWEEN WILD 1465 00:55:09,140 --> 00:55:14,779 TYPE AND KNOCKOUT PARASITE, AND 1466 00:55:14,779 --> 00:55:18,483 HE -- DOWNSTREAM FACTOR THAT IS 1467 00:55:18,483 --> 00:55:20,351 KEY -- BESIDES THEM, THERE WERE 1468 00:55:20,351 --> 00:55:21,552 MANY POSTDOCS AND STUDENTS OVER 1469 00:55:21,552 --> 00:55:22,587 THE YEARS THAT WERE INVOLVED IN 1470 00:55:22,587 --> 00:55:25,756 THESE PROJECTS, ALSO 1471 00:55:25,756 --> 00:55:31,629 COLLABORATORS WITHIN NMVR -- AND 1472 00:55:31,629 --> 00:55:31,963 RTB. 1473 00:55:31,963 --> 00:55:33,064 ALSO I MENTIONED FOR THE 1474 00:55:33,064 --> 00:55:34,232 KNOCKOUT THE GROUP IN THE 1475 00:55:34,232 --> 00:55:36,968 NETHERLANDS THAT GAVE US THE 54 1476 00:55:36,968 --> 00:55:38,269 KNOCKOUT PARASITE, AND THEN MANY 1477 00:55:38,269 --> 00:55:40,671 OTHER GROUPS THAT HAVE 1478 00:55:40,671 --> 00:55:42,940 COLLABORATED IN THE FIELD 1479 00:55:42,940 --> 00:55:44,342 STUDIES PROVIDING SEQUENCES FOR 1480 00:55:44,342 --> 00:55:45,877 THIS IN-DEPTH ANALYSIS AT A 1481 00:55:45,877 --> 00:55:46,310 POPULATION LEVEL. 1482 00:55:46,310 --> 00:55:48,379 AND FINALLY, I LOVE THIS SLIDE. 1483 00:55:48,379 --> 00:55:49,914 THIS IS THE PEOPLE THAT HAVE 1484 00:55:49,914 --> 00:55:53,417 TRAINED IN MY LAB OVER THE 1485 00:55:53,417 --> 00:55:54,185 YEARS, STUDENTS, POSTBAC 1486 00:55:54,185 --> 00:55:55,653 STUDENTS, GRADUATE STUDENTS, AND 1487 00:55:55,653 --> 00:56:01,025 POSTDOCS. 1488 00:56:01,025 --> 00:56:02,760 AND THEIR ENERGY, TALENT AND 1489 00:56:02,760 --> 00:56:05,196 DEDICATION IS WHAT REJUVENATES 1490 00:56:05,196 --> 00:56:06,531 AND ENERGIZES OUR LAB 1491 00:56:06,531 --> 00:56:09,267 CONSTANTLY. 1492 00:56:09,267 --> 00:56:10,468 ALSO THE TIME I SPEND WITH THEM 1493 00:56:10,468 --> 00:56:11,936 EVERY DAY IS MY FAVORITE TIME OF 1494 00:56:11,936 --> 00:56:17,108 THE DAY. 1495 00:56:17,108 --> 00:56:18,476 ALSO BEING THEIR MENTOR HAS BEEN 1496 00:56:18,476 --> 00:56:19,377 ONE OF THE MOST REWARDING 1497 00:56:19,377 --> 00:56:20,611 EXPERIENCES OF WORKING AS A 1498 00:56:20,611 --> 00:56:22,246 SCIENTIST. 1499 00:56:22,246 --> 00:56:26,317 AND ALSO I THINK THAT AS 1500 00:56:26,317 --> 00:56:27,818 SCIENTISTS, WE BECOME PART OF 1501 00:56:27,818 --> 00:56:29,520 THE LEGACY OF INDIVIDUALS WITH 1502 00:56:29,520 --> 00:56:30,922 STRONG CRITICAL THINKING, 1503 00:56:30,922 --> 00:56:31,856 BECAUSE WE UNDERSTAND THE 1504 00:56:31,856 --> 00:56:33,591 IMPORTANCE OF SEEKING AND 1505 00:56:33,591 --> 00:56:35,126 PROMOTING TRUTH AND 1506 00:56:35,126 --> 00:56:35,459 TRANSPARENCY. 1507 00:56:35,459 --> 00:56:37,662 AND I DO THINK THAT THIS IS 1508 00:56:37,662 --> 00:56:39,797 SOMETHING THAT IS NOW MORE 1509 00:56:39,797 --> 00:56:41,632 CRITICAL THAN EVER, BECAUSE WE 1510 00:56:41,632 --> 00:56:44,168 ARE CONSTANTLY NAVIGATING A SEA 1511 00:56:44,168 --> 00:56:46,971 OF INFORMATION AND 1512 00:56:46,971 --> 00:56:48,639 MISINFORMATION, AND PEOPLE 1513 00:56:48,639 --> 00:56:49,807 SOMETIMES HAVE A HARD TIME, WE 1514 00:56:49,807 --> 00:56:52,343 ALL HAVE A HARD TIME FINDING OUT 1515 00:56:52,343 --> 00:56:54,679 WHAT IS TRUE, AND WE NEED TO 1516 00:56:54,679 --> 00:56:56,547 DISTINGUISH WHAT IS TRUE AND 1517 00:56:56,547 --> 00:57:00,351 WHAT IS FAKE. 1518 00:57:00,351 --> 00:57:01,485 I THINK CRITICAL THINK SOMETHING 1519 00:57:01,485 --> 00:57:02,787 A TRAINING THAT IS GOING TO BE 1520 00:57:02,787 --> 00:57:06,791 VERY VALUABLE. 1521 00:57:06,791 --> 00:57:15,433 FINALLY, THIS WORK WAS DONE AT 1522 00:57:15,433 --> 00:57:15,600 NBR. 1523 00:57:15,600 --> 00:57:15,900 THANK YOU. 1524 00:57:15,900 --> 00:57:18,970 >> THANK YOU, DR. BARILLAS. 1525 00:57:18,970 --> 00:57:20,204 IT'S SO WELL PUT AND I REALLY 1526 00:57:20,204 --> 00:57:23,474 THANK YOU FOR A WONDERFUL 1527 00:57:23,474 --> 00:57:25,209 SEMINAR, JUST INVESTIGATIVE 1528 00:57:25,209 --> 00:57:27,812 RESEARCH IN EVERY POSSIBLE WAY, 1529 00:57:27,812 --> 00:57:31,415 CELL BIOLOGY, GEOGRAPHIC, 1530 00:57:31,415 --> 00:57:37,989 GENOMICS, HATS OFF TO YOU. 1531 00:57:37,989 --> 00:57:39,257 SO THE FLOOR IS OPEN TO 1532 00:57:39,257 --> 00:57:39,557 QUESTIONS. 1533 00:57:39,557 --> 00:57:44,161 I WILL START BY -- I'M JUST 1534 00:57:44,161 --> 00:57:46,564 CURIOUS, WHAT IS THE FUNCTION 1535 00:57:46,564 --> 00:57:50,901 FOR THIS PFS47 PROTEIN IN THE 1536 00:57:50,901 --> 00:57:53,838 PARASITE ITSELF? 1537 00:57:53,838 --> 00:57:54,071 LIKE -- 1538 00:57:54,071 --> 00:57:58,342 >> THAT'S AN EXCELLENT QUESTION. 1539 00:57:58,342 --> 00:58:00,745 SO WHAT IS EMERGING IS THAT 1540 00:58:00,745 --> 00:58:03,514 PFS47 IS IMPORTANT TO HAVE 1541 00:58:03,514 --> 00:58:05,950 OPTIMAL FERTILIZATION. 1542 00:58:05,950 --> 00:58:08,986 IF YOU HAVE -- FOR INSTANCE, A 1543 00:58:08,986 --> 00:58:10,354 KNOCKOUT PARASITE, EVEN IF IT'S 1544 00:58:10,354 --> 00:58:11,789 INEFFICIENT AND THERE'S NO 1545 00:58:11,789 --> 00:58:12,757 COMPETITION, THEY STILL CAN 1546 00:58:12,757 --> 00:58:13,524 REPRO DAWES AND EVERYTHING IS 1547 00:58:13,524 --> 00:58:14,525 FINE. 1548 00:58:14,525 --> 00:58:16,160 BUT IF YOU HAVE A WILD TYPE AND 1549 00:58:16,160 --> 00:58:19,263 A KNOCKOUT PARASITE, THE WILD 1550 00:58:19,263 --> 00:58:20,831 TYPE WILL FERTILIZE MUCH BETTER. 1551 00:58:20,831 --> 00:58:21,899 >> I SEE. 1552 00:58:21,899 --> 00:58:22,967 >> DOES THAT MAKE SENSE? 1553 00:58:22,967 --> 00:58:24,268 SO WE DON'T SEE IT IN THE LAB 1554 00:58:24,268 --> 00:58:25,503 BECAUSE THEY'RE NOT COMPETING 1555 00:58:25,503 --> 00:58:27,872 WITH ANYBODY. 1556 00:58:27,872 --> 00:58:30,007 BUT PFS47, SO IT'S NOT AN 1557 00:58:30,007 --> 00:58:32,977 ABSOLUTE REQUIREMENT, BUT WHAT 1558 00:58:32,977 --> 00:58:34,512 IS EMERGING IS THAT IT 1559 00:58:34,512 --> 00:58:35,613 FACILITATES OR ENHANCES 1560 00:58:35,613 --> 00:58:40,885 FERTILIZATION. 1561 00:58:40,885 --> 00:58:43,087 >> SO THEN THE OTHER SIDE OF THE 1562 00:58:43,087 --> 00:58:44,055 STORY IS THE RECEPTOR. 1563 00:58:44,055 --> 00:58:46,090 WHAT DOES THE RECEPTOR DO 1564 00:58:46,090 --> 00:58:47,325 NORMALLY IN THE INSECT? 1565 00:58:47,325 --> 00:58:48,626 >> THAT'S A MILLION DOLLAR 1566 00:58:48,626 --> 00:58:49,060 QUELL. 1567 00:58:49,060 --> 00:58:51,462 WE DON'T KNOW WHAT IT DOES. 1568 00:58:51,462 --> 00:58:53,597 WE KNOW IT ESSENTIAL BECAUSE -- 1569 00:58:53,597 --> 00:58:54,899 WELL, SO SOMETHING I DID NOT 1570 00:58:54,899 --> 00:58:56,100 MENTION, THAT WE HAD A 1571 00:58:56,100 --> 00:58:56,867 COMPLETELY DIFFERENT PROJECT 1572 00:58:56,867 --> 00:59:00,638 LOOKING AT WHAT IS THE RECEPTOR 1573 00:59:00,638 --> 00:59:04,942 THAT THE VIRUS INTERACTS WITH IN 1574 00:59:04,942 --> 00:59:06,243 VARIOUS MOSQUITOES AND WE DID 1575 00:59:06,243 --> 00:59:08,713 THE WHOLE PROJECT. 1576 00:59:08,713 --> 00:59:10,448 WE CHARACTERIZE THE PROTEIN -- 1577 00:59:10,448 --> 00:59:11,615 DIFFERENT PROJECT, NOTHING TO DO 1578 00:59:11,615 --> 00:59:12,983 ONE WITH THE OTHER. 1579 00:59:12,983 --> 00:59:15,319 SO -- AND ALSO WE SHOWED THAT 1580 00:59:15,319 --> 00:59:16,654 EACH PROTEIN IS VERY IMPORTANT, 1581 00:59:16,654 --> 00:59:18,222 SO THE PICTURE THAT IS EMERGING 1582 00:59:18,222 --> 00:59:20,758 IS THAT YOU MAY HAVE -- TO 1583 00:59:20,758 --> 00:59:23,394 PATHOGENS ARE EXPLOITING THIS 1584 00:59:23,394 --> 00:59:26,997 MECHANISM THAT ALLOWINGS ALLOWO 1585 00:59:26,997 --> 00:59:28,899 SHUT DOWN CASPASES BECAUSE YOU 1586 00:59:28,899 --> 00:59:30,234 WANT TO INVADE THE CELL, IP FECT 1587 00:59:30,234 --> 00:59:32,036 THE CELL, YOU DON'T WANT THE 1588 00:59:32,036 --> 00:59:34,004 CELL TO DIE FROM A VIRUS WHILE 1589 00:59:34,004 --> 00:59:35,106 YOU'RE MULTIPLYING OR FOR A 1590 00:59:35,106 --> 00:59:37,274 MOSQUITO, YOU DON'T WANT TO ASK 1591 00:59:37,274 --> 00:59:39,977 FOR HELP AND CALL FOR THE IMMUNE 1592 00:59:39,977 --> 00:59:41,278 SYSTEM TO KILL YOU. 1593 00:59:41,278 --> 00:59:43,948 NOW WHAT IS THE FUNG FUNCTION OS 1594 00:59:43,948 --> 00:59:44,315 RECEPTOR? 1595 00:59:44,315 --> 00:59:45,516 WE DON'T KNOW, BUT WHEN WE TRIED 1596 00:59:45,516 --> 00:59:50,888 TO DO WITH THE KNOCKOUT,, WE 1597 00:59:50,888 --> 00:59:52,256 COULD NEVER GET HOMOZYGOUS 1598 00:59:52,256 --> 00:59:53,057 KNOCKOUTS. 1599 00:59:53,057 --> 00:59:54,358 IT'S ESSENTIAL. 1600 00:59:54,358 --> 00:59:55,793 SO IT PLAYED SOME ESSENTIAL ROLE 1601 00:59:55,793 --> 00:59:57,495 AND I THINK EVOLUTION OF THE 1602 00:59:57,495 --> 00:59:58,562 RECEPTOR HAS NOTHING TO DO WITH 1603 00:59:58,562 --> 00:59:59,764 THE MOSQUITOES. 1604 00:59:59,764 --> 01:00:00,865 BASICALLY THESE MOSQUITOES WERE 1605 01:00:00,865 --> 01:00:04,568 AROUND BEFORE TH THERE WERE HUM, 1606 01:00:04,568 --> 01:00:05,669 THEY WERE BITING DINOSAURS 1607 01:00:05,669 --> 01:00:05,970 ALREADY. 1608 01:00:05,970 --> 01:00:08,072 BUT WE CAME MUCH LATER, RIGHT? 1609 01:00:08,072 --> 01:00:10,975 SO THEY EMERGED IN SOUTH AMERICA 1610 01:00:10,975 --> 01:00:13,043 WHERE THE COLONIES WERE STILL 1611 01:00:13,043 --> 01:00:15,780 TOGETHER, AND WHERE DINOSAURS 1612 01:00:15,780 --> 01:00:17,915 WERE THEIR MAIN MEAL. 1613 01:00:17,915 --> 01:00:24,155 THEN EFFICIENTLY, WE -- FROM A 1614 01:00:24,155 --> 01:00:28,292 BARILLAS TRANSFER TODRED TO A HN 1615 01:00:28,292 --> 01:00:29,693 ABOUT 50,000 YEARS AGO AND THEN 1616 01:00:29,693 --> 01:00:30,327 MALARIA STARTED. 1617 01:00:30,327 --> 01:00:31,529 SO MOSQUITOES KILL ALMOST ALL 1618 01:00:31,529 --> 01:00:32,863 THE PARASITES, BUT ONCE IN A 1619 01:00:32,863 --> 01:00:35,332 WHILE, THERE'S A LUCKY PARASITE 1620 01:00:35,332 --> 01:00:36,333 THAT HAPPENS A PROTEIN WITH A 1621 01:00:36,333 --> 01:00:37,301 DIFFERENT FUNCTION THAT ALLOWS 1622 01:00:37,301 --> 01:00:39,336 TO TURN ON THE MOSQUITO IMMUNE 1623 01:00:39,336 --> 01:00:40,871 SYSTEM, AND WHEN THAT 1624 01:00:40,871 --> 01:00:42,306 COINCIDENCE HAPPENS, THIS MAKES 1625 01:00:42,306 --> 01:00:43,908 A BIG WINNER PARASITE, BECAUSE 1626 01:00:43,908 --> 01:00:45,876 IT NOW CAN JUMP FROM FLY FROM 1627 01:00:45,876 --> 01:00:49,280 PERSON TO PERSON, AND ONCE IT'S 1628 01:00:49,280 --> 01:00:50,147 INFECTED, ONE MOSQUITO CAN 1629 01:00:50,147 --> 01:00:50,681 INFECT MANY PEOPLE. 1630 01:00:50,681 --> 01:00:52,450 >> AND THAT BECOMES BAD NEWS FOR 1631 01:00:52,450 --> 01:00:52,683 US. 1632 01:00:52,683 --> 01:00:54,051 >> GOOD NEWS FOR THE MOSQUITO, 1633 01:00:54,051 --> 01:00:55,453 GOOD NEWS FOR THE PARASITE, VERY 1634 01:00:55,453 --> 01:00:55,953 BAD NEWS FOR US. 1635 01:00:55,953 --> 01:00:57,555 >> EXACTLY. 1636 01:00:57,555 --> 01:01:02,126 SO I WAS JUST IMPRESSED BY THE 1637 01:01:02,126 --> 01:01:05,396 WAY THESE RECEPTOR CLUSTERED, 1638 01:01:05,396 --> 01:01:09,433 AND SO IS IT A TRANSMEMBRANE 1639 01:01:09,433 --> 01:01:11,936 PROTEIN, AND IF THAT CLUSTERING 1640 01:01:11,936 --> 01:01:15,206 SOMEHOW IS REQUIRED FOR ITS 1641 01:01:15,206 --> 01:01:16,507 FUNCTION, IT'S JUST A LOT OF -- 1642 01:01:16,507 --> 01:01:18,242 >> INITIALLY WE THOUGHT WE WILL 1643 01:01:18,242 --> 01:01:24,915 HAVE LIKE A MEMBRANE RECEPTOR 1644 01:01:24,915 --> 01:01:26,584 BUT IT DOESN'T SEEM TO BE THE 1645 01:01:26,584 --> 01:01:29,053 CASE, BUT WHEN THE PARASITE 1646 01:01:29,053 --> 01:01:30,488 INVADES, IT REALLY HAS TO MAKE A 1647 01:01:30,488 --> 01:01:31,789 PORE IN THE CELL AND THEN IT 1648 01:01:31,789 --> 01:01:32,890 BREAKS SITE TOE SKELETON. 1649 01:01:32,890 --> 01:01:34,925 IT DOESN'T FORM LIKE A VESICLE. 1650 01:01:34,925 --> 01:01:38,295 IT'S A VERY AGGRESSIVE INVASION. 1651 01:01:38,295 --> 01:01:40,331 SO ONE INTERPRETATION IS THAT 1652 01:01:40,331 --> 01:01:42,766 THIS MAY SEAL THE WOUND SO THAT 1653 01:01:42,766 --> 01:01:43,868 IMMEDIATELY, WHEN THE CELL -- 1654 01:01:43,868 --> 01:01:48,772 BECAUSE THE PARASITE FORMS A 1655 01:01:48,772 --> 01:01:51,575 MEMBRANE ATTACK PROTEIN COMPLEX 1656 01:01:51,575 --> 01:01:53,210 AND AT SOME POINT IT START 1657 01:01:53,210 --> 01:01:55,713 BREAKING THE CYTOSKELETON. 1658 01:01:55,713 --> 01:01:57,314 AND IT TAKES THE PARASITE ABOUT 1659 01:01:57,314 --> 01:02:00,951 A MINUTE, A MINUTE AND A HALF 1660 01:02:00,951 --> 01:02:03,120 TO -- WE'VE DONE LIVE VIDEO, WE 1661 01:02:03,120 --> 01:02:04,255 CAN VIDEO MOSQUITOES INFEBTED 1662 01:02:04,255 --> 01:02:07,892 WITH A PARASITE AND WE CAN VIDEO 1663 01:02:07,892 --> 01:02:10,728 THE PARASITE INVADING THE RED 1664 01:02:10,728 --> 01:02:11,362 BLOOD CELL. 1665 01:02:11,362 --> 01:02:13,430 SO IT TAKES LIKE 60 TO 1666 01:02:13,430 --> 01:02:14,431 90 SECONDS FOR THE PARASITE TO 1667 01:02:14,431 --> 01:02:14,999 CROSS. 1668 01:02:14,999 --> 01:02:16,700 SO THAT'S VERY FAST FOR THE 1669 01:02:16,700 --> 01:02:18,235 CELL, THE CELL IS SLOW TO REACT, 1670 01:02:18,235 --> 01:02:19,303 BUT THEN YOU CAN SEND THE 1671 01:02:19,303 --> 01:02:20,404 SIGNALS AND CALL FOR HELP. 1672 01:02:20,404 --> 01:02:22,339 THE PARASITE HAS CROSSED THE 1673 01:02:22,339 --> 01:02:23,874 CELL, BUT THEN THE HEMOSITES 1674 01:02:23,874 --> 01:02:26,810 WILL COME AND THE COMPLEMENT 1675 01:02:26,810 --> 01:02:28,979 SYSTEM WILL COME AND THEY TAKE 1676 01:02:28,979 --> 01:02:30,648 CARE OF THE PARASITE. 1677 01:02:30,648 --> 01:02:33,250 IT CALLS FOR HELP, RIGHT? 1678 01:02:33,250 --> 01:02:33,784 ASKING FOR HELP. 1679 01:02:33,784 --> 01:02:34,752 >> I SEE. 1680 01:02:34,752 --> 01:02:35,486 ANY OTHER QUESTIONS? 1681 01:02:35,486 --> 01:02:41,692 >> SO THERE WAS APPRECIATION 1682 01:02:41,692 --> 01:02:46,297 FROM NIKKI, MY APOLOGIES IF I 1683 01:02:46,297 --> 01:02:46,931 MISPRONOUNCED THE NAME, THANK 1684 01:02:46,931 --> 01:02:48,499 YOU FOR AN INSPIRATIONAL TALK. 1685 01:02:48,499 --> 01:02:50,334 AND I COMPLETELY AGREE, 1686 01:02:50,334 --> 01:02:51,735 COMPLETELY INSPIRATIONAL. 1687 01:02:51,735 --> 01:02:54,371 CAN I ASK ONE QUESTION SINCE I 1688 01:02:54,371 --> 01:02:58,409 STARTED TALKING? 1689 01:02:58,409 --> 01:03:04,381 I FULLY APPRECIATE THE DESIRE TO 1690 01:03:04,381 --> 01:03:07,551 HAVE A COSTRUCTURE OF THE PFS47 1691 01:03:07,551 --> 01:03:11,288 PROTEIN AND ITS RECEPTOR. 1692 01:03:11,288 --> 01:03:12,690 AND HOW FRUSTRATING IT MUST BE 1693 01:03:12,690 --> 01:03:13,991 TO WANT TO KNOW WHAT THAT 1694 01:03:13,991 --> 01:03:16,393 STRUCTURE LOOKS LIKE. 1695 01:03:16,393 --> 01:03:20,664 GIVEN THAT YOU HAVE THESE GROUPS 1696 01:03:20,664 --> 01:03:22,399 OF THE AFRICAN VERSIONS, THE 1697 01:03:22,399 --> 01:03:26,971 BRAZILIAN VERSIONS OF BOTH THE 1698 01:03:26,971 --> 01:03:29,607 RECEPTOR AND THE 47 PROTEIN, 1699 01:03:29,607 --> 01:03:34,044 HAVE YOU DONE ANY MODELING OR 1700 01:03:34,044 --> 01:03:41,819 SORT OF PREDICTIONS, EVEN ALPHA 1701 01:03:41,819 --> 01:03:42,686 FOLD PREDICTIONS TO TRY AND GET 1702 01:03:42,686 --> 01:03:43,887 AT WHAT THE INTERACTION IS, 1703 01:03:43,887 --> 01:03:45,055 BECAUSE YOU HAVE SOME 1704 01:03:45,055 --> 01:03:46,457 DETERMINANTS OF SPECIFICITY 1705 01:03:46,457 --> 01:03:46,690 ALREADY. 1706 01:03:46,690 --> 01:03:49,159 >> YES, SO WE'VE BEEN HAVING BIG 1707 01:03:49,159 --> 01:03:50,227 DISCUSSION, WELL FIRST, WE ARE 1708 01:03:50,227 --> 01:03:58,936 NOT, YOU KNOW, MY PH.D. IS IN 1709 01:03:58,936 --> 01:03:59,503 BIOCHEMISTRY AND WE'VE BEEN 1710 01:03:59,503 --> 01:04:01,572 PLAYING AROUND WITH ALPHA FOLD. 1711 01:04:01,572 --> 01:04:02,906 SO WE'RE NOT SURE THAT THE 1712 01:04:02,906 --> 01:04:04,408 STRUCTURES THEY'RE GIVING US ARE 1713 01:04:04,408 --> 01:04:05,175 100%. 1714 01:04:05,175 --> 01:04:07,011 AND HONESTLY, WE'VE BEEN 1715 01:04:07,011 --> 01:04:10,214 DISCUSSING WITH ALVERO, IF YOU 1716 01:04:10,214 --> 01:04:11,682 KNOW SOMEONE WHO CAN HELP US, 1717 01:04:11,682 --> 01:04:12,783 BECAUSE WHAT WE NEED TO PUT IS 1718 01:04:12,783 --> 01:04:14,385 TO -- WHEN YOU TRY TO MAKE THE 1719 01:04:14,385 --> 01:04:16,353 COMPLEX USING ALPHA FOLD, WE 1720 01:04:16,353 --> 01:04:17,755 DON'T KNOW HOW TO PROVIDE THE 1721 01:04:17,755 --> 01:04:19,223 INFORMATION WE HAVE. 1722 01:04:19,223 --> 01:04:21,592 BASICALLY WE WOULD LIKE TO TELL, 1723 01:04:21,592 --> 01:04:22,793 THIS IS THE FACE OF THE PROTEIN 1724 01:04:22,793 --> 01:04:25,095 THAT SHOULD BE BINDING, BECAUSE 1725 01:04:25,095 --> 01:04:29,466 THAT'S WHERE ALL THE IMPORTANT 1726 01:04:29,466 --> 01:04:30,801 POLYMORPHISMS ARE, AND IF WE 1727 01:04:30,801 --> 01:04:32,503 HAVE THE MODEL WHERE THE 1728 01:04:32,503 --> 01:04:34,471 DIFFERENCES IN THE RECEPTORS -- 1729 01:04:34,471 --> 01:04:35,239 HAVE MANY DIFFERENCES. 1730 01:04:35,239 --> 01:04:38,475 SO THE RECEPTORS ARE LIKE MUCH 1731 01:04:38,475 --> 01:04:41,011 MORE -- LIKE 80% IDENTICAL, 1732 01:04:41,011 --> 01:04:43,047 THEY'RE NOT AS SIMILAR AS PFS47. 1733 01:04:43,047 --> 01:04:44,448 SO FOR THE RECEPTOR, WE DON'T 1734 01:04:44,448 --> 01:04:46,116 KNOW HOW TO PREDICT HOW IT WILL 1735 01:04:46,116 --> 01:04:47,418 BIND. 1736 01:04:47,418 --> 01:04:49,353 SO PFS47, IT'S PRETTY CLEAR BUT 1737 01:04:49,353 --> 01:04:51,455 THE RECEPTOR IS ABOUT 1738 01:04:51,455 --> 01:04:53,290 80-SOMETHING% SO IT HAS LAKE 20% 1739 01:04:53,290 --> 01:05:00,097 DIFFERENCE IN AMINO -- IT NOT SO 1740 01:05:00,097 --> 01:05:01,565 OBVIOUS HOW THEY FIT TOGETHER, 1741 01:05:01,565 --> 01:05:03,667 PARTICULARLY THE ONES FROM NEW 1742 01:05:03,667 --> 01:05:04,935 WORLD AND AFRICA BECAUSE THEY 1743 01:05:04,935 --> 01:05:06,370 ARE SO DISTANT, BUT IF YOU 1744 01:05:06,370 --> 01:05:07,104 REMEMBER, THEY'RE ALSO THE ONES 1745 01:05:07,104 --> 01:05:09,506 THAT HAVE THE MOST EXTREME 1746 01:05:09,506 --> 01:05:09,807 PHENOTYPES. 1747 01:05:09,807 --> 01:05:14,978 SO THE JUMP -- SO MANY PEOPLE 1748 01:05:14,978 --> 01:05:17,247 HAVE ASIA NO THE NEW WORLD, NONE 1749 01:05:17,247 --> 01:05:19,550 OF THESE PARASITES ARE ABLE TO 1750 01:05:19,550 --> 01:05:22,286 ESTABLISH A TRANSMISSION CYCLE 1751 01:05:22,286 --> 01:05:23,387 IN THE NEW WORLD. 1752 01:05:23,387 --> 01:05:24,688 SO THIS IS A VERY STRONG 1753 01:05:24,688 --> 01:05:25,422 NEGATIVE SELECTION. 1754 01:05:25,422 --> 01:05:26,890 BUT WE HOPE TO GET AT LEAST ONE 1755 01:05:26,890 --> 01:05:28,058 PAIR TO WORK BECAUSE ONCE I 1756 01:05:28,058 --> 01:05:29,159 THINK WE GET ONE PAIR WORKING 1757 01:05:29,159 --> 01:05:31,528 THEN WE CAN MODEL ALL THE REST. 1758 01:05:31,528 --> 01:05:32,629 THAT'S OUR HOPE. 1759 01:05:32,629 --> 01:05:33,597 BUT WE'RE VERY CLOSE. 1760 01:05:33,597 --> 01:05:36,900 WE'RE NOW BEGINNING -- WE HAVE 1761 01:05:36,900 --> 01:05:40,137 ALMOST ENOUGH, WE'RE OPTIMIZING 1762 01:05:40,137 --> 01:05:41,405 THE PREPS TO REALLY STABILIZE 1763 01:05:41,405 --> 01:05:41,905 THE COMPLEX. 1764 01:05:41,905 --> 01:05:44,208 ALSO THE RECEPTOR IS 1765 01:05:44,208 --> 01:05:45,609 CHALLENGING, BECAUSE WE THINK IT 1766 01:05:45,609 --> 01:05:47,444 NORMALLY INTERACTS WITH OTHER 1767 01:05:47,444 --> 01:05:49,847 PROTEINS, SO IT DOESN'T HAVE TO 1768 01:05:49,847 --> 01:05:51,215 BE ALONE IN SOLUTION, IT FALLS 1769 01:05:51,215 --> 01:05:52,216 OUT OF SOLUTION IF YOU LACK AT 1770 01:05:52,216 --> 01:05:52,716 IT SIDEWAYS. 1771 01:05:52,716 --> 01:05:56,787 SO WE HAVE TO STABILIZE IT, BIND 1772 01:05:56,787 --> 01:05:58,122 THE COMPLEX AND WE HAVE TO -- 1773 01:05:58,122 --> 01:06:00,057 IT'S ONLY STABLE UNDER VERY HIGH 1774 01:06:00,057 --> 01:06:06,263 SALT, SO WE HAVE TO FIND -- ONCE 1775 01:06:06,263 --> 01:06:07,264 IT'S BOUND TO SOMETHING, IT'S 1776 01:06:07,264 --> 01:06:07,598 STABLE. 1777 01:06:07,598 --> 01:06:08,599 BUT THE STABILITY OF THE 1778 01:06:08,599 --> 01:06:10,200 RECEPTOR HAS BEEN A BIG 1779 01:06:10,200 --> 01:06:12,603 CHALLENGE. 1780 01:06:12,603 --> 01:06:15,639 >> WELL, THANK YOU. 1781 01:06:15,639 --> 01:06:19,376 SO YOU KNOW, DR. BARILLAS, YOU 1782 01:06:19,376 --> 01:06:26,016 ARE SOMEONE WHO HAS TRAVELED FAR 1783 01:06:26,016 --> 01:06:27,217 BY DISTANCE, CAREER, 1784 01:06:27,217 --> 01:06:28,085 SCIENTIFICALLY IN SPEAKING. 1785 01:06:28,085 --> 01:06:30,687 SO FOR THE AUDIENCE, THERE'S A 1786 01:06:30,687 --> 01:06:32,089 QUESTION FROM THE FELLOWS THAT 1787 01:06:32,089 --> 01:06:34,424 WHAT WOULD BE THE ONE ADVICE YOU 1788 01:06:34,424 --> 01:06:37,694 WOULD GIVE TO THE NEW GENERATION 1789 01:06:37,694 --> 01:06:41,031 OF WOMEN OR ANY SCIENTIST FOR 1790 01:06:41,031 --> 01:06:43,133 THAT MATTER, BUT ESPECIALLY 1791 01:06:43,133 --> 01:06:46,770 MINORITY SCIENTISTS? 1792 01:06:46,770 --> 01:06:49,106 >> WELL, I THINK IN GENERAL, I 1793 01:06:49,106 --> 01:06:50,641 WOULD SAY YOU NEED TO LOVE WHAT 1794 01:06:50,641 --> 01:06:52,409 YOU DO, THAT'S ONE THING. 1795 01:06:52,409 --> 01:06:53,377 ENJOY WHAT YOU'RE DOING. 1796 01:06:53,377 --> 01:06:54,745 PEOPLE TELL ME OH, YOU WENT TO 1797 01:06:54,745 --> 01:06:56,346 SCAL LIKE 20-SOMETHING YEARS. 1798 01:06:56,346 --> 01:06:57,714 YEAH, BUT I ENJOY EVERY DAY OF 1799 01:06:57,714 --> 01:06:58,582 IT, YOU KNOW? 1800 01:06:58,582 --> 01:06:59,349 I'M A NERD. 1801 01:06:59,349 --> 01:07:01,952 SO I ENJOY BEING A NERD, RIGHT? 1802 01:07:01,952 --> 01:07:06,323 AS LONG AS YOU ENJOY THE PATH, 1803 01:07:06,323 --> 01:07:07,291 NO? 1804 01:07:07,291 --> 01:07:08,292 THE SECOND ONE IS DON'T BE 1805 01:07:08,292 --> 01:07:10,561 AFRAID TO TRY THINGS. 1806 01:07:10,561 --> 01:07:12,296 WHEN I STARTED MY PH.D., I 1807 01:07:12,296 --> 01:07:13,497 JOINED A LAB AND IT TURNED OUT 1808 01:07:13,497 --> 01:07:15,199 TO BE A DISASTER AND AFTER TWO 1809 01:07:15,199 --> 01:07:17,401 YEARS, I HAD TO DROP THE PH.D. 1810 01:07:17,401 --> 01:07:18,302 THESIS AND START AGAIN. 1811 01:07:18,302 --> 01:07:20,771 BUT THEN, YOU KNOW, THREE YEARS 1812 01:07:20,771 --> 01:07:22,639 LATER, 2 1/2 YEARS LATER, LESS 1813 01:07:22,639 --> 01:07:23,841 THAN THREE YEARS LATER, I 1814 01:07:23,841 --> 01:07:24,274 GRADUATED. 1815 01:07:24,274 --> 01:07:25,542 I DID A WHOLE NEW PROJECT 1816 01:07:25,542 --> 01:07:26,743 STARTING FROM SCRATCH. 1817 01:07:26,743 --> 01:07:28,378 BUT I HAD LEARNED SO MUCH IN 1818 01:07:28,378 --> 01:07:31,348 THOSE TWO YEARS THAT I HAD 1819 01:07:31,348 --> 01:07:33,417 MATURED SCIENTIFICALLY. 1820 01:07:33,417 --> 01:07:34,718 SO SOMETIMES THERE'S SETBACKS 1821 01:07:34,718 --> 01:07:36,587 BUT I KNEW I WAS IN THE WRONG 1822 01:07:36,587 --> 01:07:37,588 PLACE AND HAD TO CHANGE. 1823 01:07:37,588 --> 01:07:39,089 SO DON'T BE AFRAID, EVEN IF THE 1824 01:07:39,089 --> 01:07:40,390 COST IS HIGH, IF YOU SEE THERE'S 1825 01:07:40,390 --> 01:07:43,360 SOMETHING THAT IS REALLY NOT 1826 01:07:43,360 --> 01:07:44,428 GOING -- DON'T BE AFRAID. 1827 01:07:44,428 --> 01:07:46,263 DON'T BE AFRAID TO ASK. 1828 01:07:46,263 --> 01:07:49,466 WHEN I DID MY -- I HAVE AN 1829 01:07:49,466 --> 01:07:51,168 ANECDOTE, WHEN I WAS DOING MY 1830 01:07:51,168 --> 01:07:53,804 PH.D. IN ARIZONA, THEY HAD A 1831 01:07:53,804 --> 01:07:55,606 MEETING WITH THE PEOPLE FROM THE 1832 01:07:55,606 --> 01:08:00,878 MA CAR TUR FOUNMCARTHUR FOUNDATD 1833 01:08:00,878 --> 01:08:03,046 TO SWITCH TO MOSQUITOES SO THERE 1834 01:08:03,046 --> 01:08:04,147 WERE VERY FEW PEOPLE IN THE 1835 01:08:04,147 --> 01:08:07,985 MOLECULAR TOOLS, WE CLONED THE 1836 01:08:07,985 --> 01:08:10,921 FIRST EVER IN MOSQUITO, SO THEY 1837 01:08:10,921 --> 01:08:12,222 INVITED ALL THE MAIN SCIENTIST, 1838 01:08:12,222 --> 01:08:15,392 AND MY PH.D. ADVISOR, HE WAS 1839 01:08:15,392 --> 01:08:18,328 SUPERVISOR GENEROUS, TOM 1840 01:08:18,328 --> 01:08:19,630 WELLAMS, HE TOLD ME FRIDAY, 1841 01:08:19,630 --> 01:08:21,832 DON'T SCHEDULE ANYTHING, I 1842 01:08:21,832 --> 01:08:23,800 VOLUNTEER, YOU'RE GOING TO BE 1843 01:08:23,800 --> 01:08:26,837 CHANGING -- THEY HAD CAROUSELS 1844 01:08:26,837 --> 01:08:28,739 WITH SLIDES, HE SAID NO, NO, 1845 01:08:28,739 --> 01:08:29,907 YOU'RE GOING TO THANK ME BECAUSE 1846 01:08:29,907 --> 01:08:31,308 THE BEST PEOPLE WORKING WITH 1847 01:08:31,308 --> 01:08:32,609 VECTORS AND THE FUTURE OF WHERE 1848 01:08:32,609 --> 01:08:34,478 THIS FIELD IS GOING IS GOING TO 1849 01:08:34,478 --> 01:08:36,680 BE -- IT'S A CLOSED MEETING, YOU 1850 01:08:36,680 --> 01:08:37,781 ARE GOING TO BE THE ONLY STUDENT 1851 01:08:37,781 --> 01:08:38,782 THAT WILL GET IN BECAUSE YOU'RE 1852 01:08:38,782 --> 01:08:39,850 GOING TO BE CHANGING SLIDES. 1853 01:08:39,850 --> 01:08:41,184 SO YOU LISTEN TO ALL THE TALKS 1854 01:08:41,184 --> 01:08:42,920 AND THEN -- SO I WENT THERE, AND 1855 01:08:42,920 --> 01:08:49,226 I LISTENED TO THE TALK OF -- 1856 01:08:49,226 --> 01:08:49,726 FROM HARVARD. 1857 01:08:49,726 --> 01:08:51,261 HE BLEW MY MIND AWAY AND I WAS 1858 01:08:51,261 --> 01:08:55,098 SO AFRAID OF APPROACHING HIM. 1859 01:08:55,098 --> 01:08:58,402 BECAUSE I WAS LIKE -- TALKING TO 1860 01:08:58,402 --> 01:09:00,103 PROFESSOR -- FROM HARVARD. 1861 01:09:00,103 --> 01:09:01,438 I THOUGHT I WAS TOTALLY OUT OF 1862 01:09:01,438 --> 01:09:02,072 MY LEAGUE. 1863 01:09:02,072 --> 01:09:03,573 BUT THEN I REMEMBERED, I HAD A 1864 01:09:03,573 --> 01:09:04,808 PROFESSOR THAT TOLD ME, AS A 1865 01:09:04,808 --> 01:09:05,909 STUDENT YOU HAVE ONE BIG THING 1866 01:09:05,909 --> 01:09:07,411 GOING FOR YOU. 1867 01:09:07,411 --> 01:09:08,812 YOU HAVE NOTHING, AND THEN YOU 1868 01:09:08,812 --> 01:09:12,382 HAVE NOTHING TO LOSE. 1869 01:09:12,382 --> 01:09:13,984 SO DON'T FORGET THAT, RIGHT? 1870 01:09:13,984 --> 01:09:15,919 SO WHAT IS THE WORST THING THAT 1871 01:09:15,919 --> 01:09:16,353 CAN HAPPEN? 1872 01:09:16,353 --> 01:09:17,354 YOU STAY EXACTLY WHERE YOU ARE, 1873 01:09:17,354 --> 01:09:18,755 SO YOU HAVE NOTHING TO LOSE AND 1874 01:09:18,755 --> 01:09:19,389 MUCH TO GAIN. 1875 01:09:19,389 --> 01:09:22,159 SO I WENT AND TALKED TO HIM, 1876 01:09:22,159 --> 01:09:23,226 LONG STORY SHORT AFTER HE 1877 01:09:23,226 --> 01:09:24,861 INVITED ME TO GIVE A TALK AND WE 1878 01:09:24,861 --> 01:09:26,730 DISCUSSED, I ENDED UP DOING MY 1879 01:09:26,730 --> 01:09:28,432 POSTDOC WITH HIM AT HARVARD AND 1880 01:09:28,432 --> 01:09:30,133 THEN AT EMBL, AND I THINK IN 1881 01:09:30,133 --> 01:09:31,835 TERMS OF TRAINING, THAT PUT ME 1882 01:09:31,835 --> 01:09:33,804 IN A VERY GOOD POSITION WITH TOP 1883 01:09:33,804 --> 01:09:37,741 LEVEL TRAINING, RIGHT? 1884 01:09:37,741 --> 01:09:40,377 WE WERE THE GENERATION THAT 1885 01:09:40,377 --> 01:09:42,346 BUILT THE TOOLS, AND THAT WAS 1886 01:09:42,346 --> 01:09:44,581 ALSO FRUSTRATING AS POSTDOCS 1887 01:09:44,581 --> 01:09:46,049 BECAUSE THEY HAD ALL THE TOOLS 1888 01:09:46,049 --> 01:09:47,584 AND WE HAVE NOTHING, WE HAVE TO 1889 01:09:47,584 --> 01:09:48,251 BUILD EVERYTHING FROM SCRATCH. 1890 01:09:48,251 --> 01:09:50,320 BUT I THINK THAT NOW WE ARE 20 1891 01:09:50,320 --> 01:09:51,488 YEARS, 25 YEARS LATER, WE'RE AT 1892 01:09:51,488 --> 01:09:53,357 A POINT WHERE WE HAVE ENOUGH 1893 01:09:53,357 --> 01:09:54,691 TOOLS TO ASK GOOD QUESTIONS, 1894 01:09:54,691 --> 01:09:55,759 RIGHT? 1895 01:09:55,759 --> 01:09:58,595 AND DO INTERESTING WORK. 1896 01:09:58,595 --> 01:10:01,231 >> THAT'S GREAT. 1897 01:10:01,231 --> 01:10:04,067 THE STORY ALSO TELLS US TO TRY 1898 01:10:04,067 --> 01:10:07,471 TO ISAIAS THE OPPORTUNITY WHEN 1899 01:10:07,471 --> 01:10:08,005 IT AVAILABLE. 1900 01:10:08,005 --> 01:10:11,808 AND YES, I THINK THAT'S REALLY A 1901 01:10:11,808 --> 01:10:15,746 GREAT BOTTOM LINE. 1902 01:10:15,746 --> 01:10:17,280 ENJOY, AND NOT BE AFRAID OF 1903 01:10:17,280 --> 01:10:17,948 FAILURES. 1904 01:10:17,948 --> 01:10:18,849 >> AND CHANGE, RIGHT? 1905 01:10:18,849 --> 01:10:20,250 >> AND CHANGE. 1906 01:10:20,250 --> 01:10:22,419 RIGHT. 1907 01:10:22,419 --> 01:10:23,954 >> AND ALSO I HAVE BEEN VERY 1908 01:10:23,954 --> 01:10:27,958 LUCKY BECAUSE EVERYWHERE W WHERE 1909 01:10:27,958 --> 01:10:29,593 I'VE BEEN, THIS IS AN ACTIVITY 1910 01:10:29,593 --> 01:10:31,261 TO PROMOTE WOMEN SCIENTIST, BUT 1911 01:10:31,261 --> 01:10:36,033 I'VE HAD AMAZING MALE 1912 01:10:36,033 --> 01:10:36,833 SCIENTISTS, COLLEAGUES, MENTORS 1913 01:10:36,833 --> 01:10:38,668 THAT HAVE BEEN JUST SUPER 1914 01:10:38,668 --> 01:10:39,970 HELPFUL. 1915 01:10:39,970 --> 01:10:42,806 SO I THINK THAT YOU KNOW, IF YOU 1916 01:10:42,806 --> 01:10:45,108 LOOK CAREFULLY, THEY'RE ALWAYS 1917 01:10:45,108 --> 01:10:46,410 IN EACH DEPARTMENT, YOU WILL 1918 01:10:46,410 --> 01:10:48,578 FIND, YOU KNOW, COLLEAGUES THAT 1919 01:10:48,578 --> 01:10:54,284 ARE SUPPORTIVE, THAT ARE OPEN, 1920 01:10:54,284 --> 01:10:56,353 MIKE MENTORS, I GIVE YOU THIS 1921 01:10:56,353 --> 01:10:57,187 EXAMPLE OF GIVING THIS 1922 01:10:57,187 --> 01:10:58,088 OPPORTUNITY TO BE IN THE FIELD, 1923 01:10:58,088 --> 01:10:59,623 THAT WAS MIKE WELLS, AND SECOND 1924 01:10:59,623 --> 01:11:01,358 ONE WAS FOR -- BOTH OF THEM 1925 01:11:01,358 --> 01:11:06,063 PASSED AWAY SOME YEARS AGO, BUT 1926 01:11:06,063 --> 01:11:07,464 THEY LEFT -- THEY WERE SUCH 1927 01:11:07,464 --> 01:11:08,765 EXCELLENT MENTORS THAT YOU FEEL 1928 01:11:08,765 --> 01:11:12,169 THAT IT IS YOUR DUTY TO FOLLOW 1929 01:11:12,169 --> 01:11:13,703 THEIR STEPS AND CONTRIBUTE FROM 1930 01:11:13,703 --> 01:11:14,704 THE NEXT GENERATION, BECAUSE 1931 01:11:14,704 --> 01:11:18,975 THEY LEFT A LEGACY WITH YOU. 1932 01:11:18,975 --> 01:11:22,112 >> THAT'S WONDERFUL. 1933 01:11:22,112 --> 01:11:23,213 SO I DON'T SEE ANY OTHER 1934 01:11:23,213 --> 01:11:23,980 QUESTIONS IN THE CHAT. 1935 01:11:23,980 --> 01:11:27,250 SO IF THERE'S NO OTHER QUESTIONS 1936 01:11:27,250 --> 01:11:29,453 THAT I CAN SEE, I'D LIKE TO 1937 01:11:29,453 --> 01:11:31,621 CLOSE THE SEMINAR AND THANK YOU 1938 01:11:31,621 --> 01:11:33,390 AGAIN, DR. BARILLAS, FOR YOUR 1939 01:11:33,390 --> 01:11:34,057 WONDERFUL PRESENTATION. 1940 01:11:34,057 --> 01:11:36,460 >> THANK YOU VERY MUCH. 1941 01:11:36,460 --> 01:11:37,627 >> YES, THANK YOU. 1942 01:11:37,627 --> 01:11:37,894 EXCELLENT. 1943 01:11:37,894 --> 01:11:48,038 >> BYE.