1 00:00:05,901 --> 00:00:08,450 ALL RIGHT IT'S 2 PM. 2 00:00:08,450 --> 00:00:10,907 I'LL GO AHEAD AND LAUNCH INTO 3 00:00:10,907 --> 00:00:13,583 THE INTRODUCTION HERE, I'M ROSS 4 00:00:13,583 --> 00:00:15,744 TALOHA OF NATIONAL INSTITUTE OF 5 00:00:15,744 --> 00:00:18,018 DIABETES DIGESTIVE AND KIDNEY 6 00:00:18,018 --> 00:00:18,275 DISEASES. AND I'D LIKE TO 7 00:00:18,275 --> 00:00:20,587 WELCOME YOU ALL TO THE 2024 8 00:00:20,906 --> 00:00:22,274 JOHN DALY LECTURE, WE'VE HELD 9 00:00:22,274 --> 00:00:23,608 THIS ANNUAL LECTURE SINCE 2009, 10 00:00:23,608 --> 00:00:26,024 A YEAR AFTER THE PASS OF JOHN DALY. 11 00:00:26,024 --> 00:00:28,288 THE NIDDK, RESEARCH PROGRAM 12 00:00:28,288 --> 00:00:28,922 IN THE LABORATORY OF BIOORGANIC 13 00:00:28,922 --> 00:00:29,923 CHEMISTRY ARE PLEASED TO NOW 14 00:00:29,923 --> 00:00:30,557 PRESENT THE 12TH EDITION OF THIS 15 00:00:30,557 --> 00:00:32,759 AWARD TO DR' CAROL BOULEY. THIS 16 00:00:32,759 --> 00:00:33,360 EVENT SERVES TO HONOR JOHN'S 17 00:00:33,360 --> 00:00:37,864 MEMORY BY RECOGNIZING LEADING 18 00:00:37,864 --> 00:00:39,633 RECEPTOR NATURAL PROUKT RESEARCH 19 00:00:39,633 --> 00:00:42,102 SUCH A CAROLE ANN BEWLEY, WHO 20 00:00:42,102 --> 00:00:42,736 TYPIFIES JOHN DALY'S SCIENTIFIC 21 00:00:42,736 --> 00:00:47,274 IDEALS IN MORE WAY THAT ONE. 22 00:00:47,274 --> 00:00:49,876 J OHN DALY WAS A PIONEER IN 23 00:00:49,876 --> 00:00:50,343 NATURAL PRODUCTS AND 24 00:00:50,343 --> 00:00:51,945 PHARMACOLOGICAL AND FRIEND, 25 00:00:51,945 --> 00:00:52,546 DOMINI AND IDDK CHEMISTS. HE 26 00:00:52,546 --> 00:00:55,782 CAME TO NIH AS AN ORGANIC 27 00:00:55,782 --> 00:00:56,416 CHEMISTRY POSTDOC WORKING UNDER 28 00:00:56,416 --> 00:00:57,551 BERNARD WITCRRP DRUING THIS 29 00:00:57,551 --> 00:00:58,151 TIME. HE LEARNED PHARMACOLOGY 30 00:00:58,151 --> 00:01:00,754 FROM THE N., I. M. H. NOBEL 31 00:01:00,754 --> 00:01:01,388 LAUREATE JULIUS AXELROD. HE WAS 32 00:01:01,388 --> 00:01:02,389 WIDELY KNOWN FOR HIS WORK ON 33 00:01:02,389 --> 00:01:02,956 NATURAL PRODUCTS APPLIED TO 34 00:01:02,956 --> 00:01:04,024 MODULATE CELLULAR PROCESSES. HE 35 00:01:04,024 --> 00:01:04,658 INTRODUCED MANY ESSENTIAL TOOLS 36 00:01:04,658 --> 00:01:07,594 TO PERFORM ECOLOGICAL RESEARCH. 37 00:01:07,594 --> 00:01:08,228 SUCH AS SPORTS GLEN, WHICH WAS 38 00:01:08,228 --> 00:01:11,898 USED IN MY VERY OWN LABORATORY 39 00:01:11,898 --> 00:01:13,166 THIS WEEK, HE EXPLORED 40 00:01:13,166 --> 00:01:13,800 INTRACELLULAR SIGNALING INDUCED 41 00:01:13,800 --> 00:01:14,868 BY NATURAL SUBSTANCES FROM 42 00:01:14,868 --> 00:01:15,468 PLANTS AND ANIMALS, WHICH HE 43 00:01:15,468 --> 00:01:18,772 COLLECTED FROM JUNGLES IN S AND 44 00:01:18,772 --> 00:01:19,406 CENTRAL AMERICA, MADAGASCAR AND 45 00:01:19,406 --> 00:01:22,609 AUSTRALIA. THIS. YEERSZ 46 00:01:22,609 --> 00:01:23,476 RECIPIENT, DR. CAROLE ANN 47 00:01:23,476 --> 00:01:24,044 BEWLEY, IS WORLD LEADER IN 48 00:01:24,044 --> 00:01:25,645 NATIONAL PRODUCTS AND CHEMICAL 49 00:01:25,645 --> 00:01:26,179 BIOLOGY RESEARCH. SHE IS 50 00:01:26,179 --> 00:01:27,047 CURRENTLY THE CHIEF OF THE 51 00:01:27,047 --> 00:01:27,581 LABORATORY AT BIOORGANIC 52 00:01:27,581 --> 00:01:28,481 CHEMISTRY WITHIN THE NIDDK 53 00:01:28,481 --> 00:01:30,383 INTRAMURAL RESEARCH PROGRAM, 54 00:01:30,383 --> 00:01:31,017 WHERE SHE HAS SERVED SINCE 2019. 55 00:01:31,017 --> 00:01:31,618 NOTABLY, CAROL SERVES IN THIS 56 00:01:31,618 --> 00:01:32,152 ROLE THAT WAS PREVIOUSLY 57 00:01:32,152 --> 00:01:33,253 OCCUPIED BY JOHN DALY HIMSELF. 58 00:01:33,253 --> 00:01:35,589 CAROL. ... COMPLETED HER 59 00:01:35,589 --> 00:01:36,156 DOCTORAL STUDIES AT SCRIPPS 60 00:01:36,156 --> 00:01:42,996 INSTITUTION OF OCEANOGRAPHY AT 61 00:01:42,996 --> 00:01:47,167 UCSAN DIEGO1995 IN SUBSEQUENTLY 62 00:01:47,167 --> 00:01:47,734 TRAINED IN NMR ANALYSIS OF 63 00:01:47,734 --> 00:01:48,768 BIOMOLECULES USING NUCLEAR 64 00:01:48,768 --> 00:01:49,369 MAGNETIC RESONANCE METHODS IN 65 00:01:49,369 --> 00:01:50,370 THE LABORATORY OF METHODS IN 66 00:01:50,370 --> 00:01:50,937 THE LABORATORY OF CHEMICAL 67 00:01:50,937 --> 00:01:53,073 PHYSICS IN MR SECTION WITHIN 68 00:01:53,073 --> 00:01:53,640 NIDDK SHE BEGAN AS A TENURE 69 00:01:53,640 --> 00:01:54,774 TRACK INVESTIGATOR IN THE 70 00:01:54,774 --> 00:01:55,308 LABORATORY OF BIOORGANIC 71 00:01:55,308 --> 00:01:55,909 CHEMISTRY IN 1999 AND IN 2006 72 00:01:55,909 --> 00:01:57,877 INITIATED HER ROLE AS SECTION 73 00:01:57,877 --> 00:01:58,511 CHIEF OF THE NATIONAL PRODUCTS 74 00:01:58,511 --> 00:02:02,082 CHEMISTRY LABORATORY, HER 75 00:02:02,082 --> 00:02:02,549 INTERESTS INCLUDE THE 76 00:02:02,549 --> 00:02:03,183 IDENTIFICATION CHARACTERIZATION 77 00:02:03,183 --> 00:02:04,351 AND MECHANISTIC STUDIES OF 78 00:02:04,351 --> 00:02:04,951 NATURAL PRODUCTS, AS WELL AS 79 00:02:04,951 --> 00:02:10,190 STUDIES OF CARD HYDRATE BINDING 80 00:02:10,190 --> 00:02:10,757 PROTEINS, CAROLE HAS MADE 81 00:02:10,757 --> 00:02:12,792 IMMENSE, CONTRIBUTIONS TO THE 82 00:02:12,792 --> 00:02:13,426 SCIENTIFIC COMMUNITY THROUGH HER 83 00:02:13,426 --> 00:02:14,261 SERVICE ON JOURNAL EDITORIAL 84 00:02:14,261 --> 00:02:14,828 BOARDS, REVIEW PANELS, BOTH 85 00:02:14,828 --> 00:02:18,031 WITHIN THE NIH AND BEYOND WITHIN 86 00:02:18,031 --> 00:02:19,199 SCIENTIFIC SOCIETIES DR. BEWLEY 87 00:02:19,199 --> 00:02:21,935 HAS PUBLISHED ROUGHLY 75 88 00:02:21,935 --> 00:02:22,502 RESEARCH ARTICLES COVERING 89 00:02:22,502 --> 00:02:27,874 DIVERSE TOPICS AND NATURAL 90 00:02:27,874 --> 00:02:28,508 PRODUCT CHEMISTRY ASSESSMENTS OF 91 00:02:28,508 --> 00:02:29,409 PROTEIN STRUCTURE USING 92 00:02:29,409 --> 00:02:30,043 BIOPHYSICAL METHODS AND STUDIES 93 00:02:30,043 --> 00:02:34,547 OF HIV PROTEIN. CAROLE, HAS HAD 94 00:02:34,547 --> 00:02:35,181 A PROFOUND IMPACT ON MAKING THE 95 00:02:35,181 --> 00:02:36,449 SCIENTIFIC COMMUNITY A MORE 96 00:02:36,449 --> 00:02:37,083 COLLEGIAL AND INTERESTING PLACE 97 00:02:37,083 --> 00:02:38,351 ON A PERSONAL NOTE. I AM VERY 98 00:02:38,351 --> 00:02:38,985 PROUD TO SHARE WORKPLACE WITH A 99 00:02:38,985 --> 00:02:42,088 GOVERNMENT SCIENTIST, AS 100 00:02:42,088 --> 00:02:43,657 DEDICATED AND THOUGHTFUL AND 101 00:02:43,657 --> 00:02:48,295 DISTINGUISHED AS DR. BEWLEY, 102 00:02:48,295 --> 00:02:49,129 CAROLE'S MADE AN IMMENSELY 103 00:02:49,129 --> 00:02:50,463 POSITIVE IMPACT ON MY RESEARCH 104 00:02:50,463 --> 00:02:51,097 PROGRAM, AND I'VE HEARD SIMILAR 105 00:02:51,097 --> 00:02:52,532 STORIES FROM OTHER YOUNG, 106 00:02:52,532 --> 00:02:54,034 INDEPENDENT SCIENTISTS. CAROL'S 107 00:02:54,034 --> 00:02:54,668 LECTURE TODAY IS TITLED CHEMICAL 108 00:02:54,668 --> 00:02:55,201 DIVERSITY FROM NATURE AND 109 00:02:55,201 --> 00:02:55,735 ECOLOGICAL AND BIOLOGICAL 110 00:02:55,735 --> 00:02:56,336 SYSTEMS. QUESTIONS CAN BE 111 00:02:56,336 --> 00:02:56,936 SUBMITTED THROUGH THE SUBMIT 112 00:02:56,936 --> 00:02:57,604 LIVE FEEDBACK OPTION ON THE 113 00:02:57,604 --> 00:02:59,205 VIDEO CAST AFTER THE LECTURE IN 114 00:02:59,205 --> 00:02:59,839 A QUESTION AND ANSWER PERIOD. WE 115 00:02:59,839 --> 00:03:02,275 WILL HOLD A RECEPTION WITH 116 00:03:02,275 --> 00:03:08,481 CAROLE OUTSIDE THIS HALL, IT IS 117 00:03:08,481 --> 00:03:10,383 NOW ANY DISTINCT HONOR AND 118 00:03:10,383 --> 00:03:14,120 PRESSURE TO INVITE DR. CAROLE 119 00:03:14,120 --> 00:03:22,295 ANN BEWLEY TO RECEIVE THE PLAUE, 120 00:03:22,295 --> 00:03:27,567 AND DELIVER THE 2024 JOHN DALY 121 00:03:27,567 --> 00:03:27,834 LECTURE. 122 00:03:27,834 --> 00:03:38,044 [APPLAUSE] 123 00:03:51,224 --> 00:03:51,691 >> THANK YOU. 124 00:03:51,691 --> 00:04:29,744 [APPLAUSE] 125 00:04:29,744 --> 00:04:32,514 >> OKAY, THANKS EVERYONE FOR 126 00:04:32,514 --> 00:04:34,683 COMING AND THANK YOU ROSS FOR 127 00:04:34,683 --> 00:04:37,052 THE VERY NICE INTRODUCTION. 128 00:04:37,052 --> 00:04:39,087 AND IT'S REALLY AN HONOR TO BE 129 00:04:39,087 --> 00:04:41,256 ABLE TO GIVE THIS LECTURE IN 130 00:04:41,256 --> 00:04:42,257 HONOR OF JOHN DALY. 131 00:04:42,257 --> 00:04:45,293 I WAS LUCKY ENOUGH TO STILL 132 00:04:45,293 --> 00:04:47,696 OVERLAP WITH HIM FOR SEVERAL 133 00:04:47,696 --> 00:04:50,332 YEAR BEFORE HE PASSED AFTER I 134 00:04:50,332 --> 00:04:52,500 JOINED THE LAB OF ORGANIC 135 00:04:52,500 --> 00:04:52,901 CHEMISTRY. 136 00:04:52,901 --> 00:04:54,436 TODAY I'M GOING TO TALK ABOUT 137 00:04:54,436 --> 00:04:54,903 NATURAL PRODUCTS. 138 00:04:54,903 --> 00:04:57,305 FOR THOSE WHO DON'T KNOW THIS 139 00:04:57,305 --> 00:05:01,176 LECTURE SERIES ALTERNATES BACK 140 00:05:01,176 --> 00:05:04,512 AND FORTH FROM YEAR TO YEAR ON 141 00:05:04,512 --> 00:05:07,849 PHARMACOLOGY, AND THEN NATURAL 142 00:05:07,849 --> 00:05:08,116 PRODUCTS. 143 00:05:08,116 --> 00:05:10,819 SO I WAS SELECTED FOR NATURAL 144 00:05:10,819 --> 00:05:12,654 PRODUCTS. SO IT'S A LITTLE BIT 145 00:05:12,654 --> 00:05:13,288 OF AN UNCONVENTIONAL LECTURE FOR 146 00:05:13,288 --> 00:05:14,456 ME. I DON'T GET TO TALK ABOUT 147 00:05:14,456 --> 00:05:17,092 THESE AREAS MUCH, SO LOOKING 148 00:05:17,092 --> 00:05:18,660 FORWARD TO THIS TALK. 149 00:05:18,660 --> 00:05:19,794 OKAY, SO WHY NATURAL PRODUCTS? 150 00:05:19,794 --> 00:05:22,030 THIS IS CHART TAKEN FROM PIE 151 00:05:22,030 --> 00:05:24,165 CHART, THAT NEWMAN AND CRAIG 152 00:05:24,165 --> 00:05:24,733 FROM THE NCI PUBLISHED SOME 153 00:05:24,733 --> 00:05:28,570 YEARS AGO NOW, THEY CARRIED OUT 154 00:05:28,570 --> 00:05:30,538 THESE DECADE REVIEWS ON THE 155 00:05:30,538 --> 00:05:31,139 ROLE OF NATURAL PRODUCTS AND 156 00:05:31,139 --> 00:05:34,442 DRUG DEVELOPMENT AND DRUG DIS 157 00:05:34,442 --> 00:05:37,512 COVERRY, AND WE ALL KNOW NOW 158 00:05:37,512 --> 00:05:40,582 THAT PHARMACEUTICALS ARE BIASED, 159 00:05:40,582 --> 00:05:41,116 TOWARDS CONTAINING EITHER 160 00:05:41,116 --> 00:05:41,716 NATURAL THEY COME EITHER FROM 161 00:05:41,716 --> 00:05:42,684 NATURAL PRO DUCTS. THEY HAVE 162 00:05:42,684 --> 00:05:43,318 NATURAL PRODUCT SCAFFOLDS. THEY 163 00:05:43,318 --> 00:05:46,087 WERE THE SYNTHETIC COMPOUNDS 164 00:05:46,087 --> 00:05:48,456 THAT WERE INSPIRED BY STRUCTURES 165 00:05:48,456 --> 00:05:51,393 OF NATURAL PRODUCT, OR THEY 166 00:05:51,393 --> 00:05:51,993 MIGHT CONTAIN PHARMACOPHORES 167 00:05:51,993 --> 00:05:53,561 FROM NATURAL PRODUCTS. SO 168 00:05:53,561 --> 00:05:56,464 DEPENDING ON HOW YOU TALLY THIS 169 00:05:56,464 --> 00:05:59,501 OUR DRUGS TEND TO BE REPRESENTED 170 00:05:59,501 --> 00:06:04,839 AROUND 65% BY NATURAL PRODUCTS. 171 00:06:04,839 --> 00:06:09,044 AND HERE IS AN OVERVIEW OF... IS 172 00:06:09,044 --> 00:06:12,547 THIS SHOWING UP? 173 00:06:12,547 --> 00:06:15,583 OF ACTUAL DRUGS THAT WE USE IN 174 00:06:15,583 --> 00:06:18,420 THE CLINIC, AND THERE IT GOES. 175 00:06:18,420 --> 00:06:19,054 OKAY. 176 00:06:19,054 --> 00:06:20,955 SO AND COMING FROM DIVERSE 177 00:06:20,955 --> 00:06:23,258 SOURCES AND PLANTS AND FUNGI, 178 00:06:23,258 --> 00:06:25,760 AND MARINE, INVERTEBRATES, CONE 179 00:06:25,760 --> 00:06:28,930 SNAILS, ETCETERA. 180 00:06:28,930 --> 00:06:30,498 SO JOHN ACTUALLY STARTED 181 00:06:30,498 --> 00:06:31,633 WORKING ON NATURAL PRODUCTS 182 00:06:31,633 --> 00:06:34,803 AFTER HE CAME TO THE NIH HE WAS 183 00:06:34,803 --> 00:06:37,272 SYNTHETIC ORGANIC CHEMIST, AND 184 00:06:37,272 --> 00:06:38,707 AS ROSS MENTIONED IN THE 185 00:06:38,707 --> 00:06:41,876 INTRODUCTION, HE JOINED THE LAB 186 00:06:41,876 --> 00:06:45,146 OF BERNHARD WITKOP, WHO WAS 187 00:06:45,146 --> 00:06:48,149 WORKING ON TOXINS FROM FROGS. 188 00:06:48,149 --> 00:06:50,518 AND JOHN ACTUALLY CAME TO THE 189 00:06:50,518 --> 00:06:55,123 NIH TO WORK ON THIS COMPLEX 190 00:06:55,123 --> 00:07:00,261 ALKALOID, KNOWN AS BITRAKATOXIN 191 00:07:00,261 --> 00:07:04,866 IT'S ALKALOID THAT SOUTH 192 00:07:04,866 --> 00:07:07,035 AMERICANS USED IN POISON BLOW 193 00:07:07,035 --> 00:07:08,036 DARTS FOR HUNTING. 194 00:07:08,036 --> 00:07:09,537 WHEN THEY RAN OUT OF MATERIAL, 195 00:07:09,537 --> 00:07:12,974 JOHN WAS INVITED TO GO TO SOUTH 196 00:07:12,974 --> 00:07:14,776 AMERICA TO TRY AND FIND COLLECT 197 00:07:14,776 --> 00:07:15,944 MORE FROGS TO GET MORE MATERIAL. 198 00:07:15,944 --> 00:07:19,681 SO THIS IS A LITTLE BIT OF AN 199 00:07:19,681 --> 00:07:21,750 UNUSUAL FORAY INTO THE NATURAL 200 00:07:21,750 --> 00:07:22,016 PRODUCTS. 201 00:07:22,016 --> 00:07:23,418 AND I SORT OF TOOK A DIFFERENT 202 00:07:23,418 --> 00:07:28,757 TURN, I ACTUALLY WORKED AT THE 203 00:07:28,757 --> 00:07:32,127 SALK INSTITUTE AS POST BACK 204 00:07:32,127 --> 00:07:33,294 AFTER UNDER GRADUATES AND I 205 00:07:33,294 --> 00:07:35,730 LEARNED TO SCUBA DIVE, AND I'M 206 00:07:35,730 --> 00:07:37,599 GOING TO TAKE YOU ON A LITTLE 207 00:07:37,599 --> 00:07:40,769 BIT OF A... LET'S SEE. 208 00:07:40,769 --> 00:07:48,076 UNDER WATER EXCURSION. 209 00:07:48,076 --> 00:07:52,414 SO WHEN SCUBA DIVING ON CORAL 210 00:07:52,414 --> 00:07:54,949 REEFS YOU CAN QUICKLY SEE HOW 211 00:07:54,949 --> 00:07:55,583 MUCH DIVERSITY THERE IS IN THE 212 00:07:55,583 --> 00:07:56,117 SPECIES AND THE DIFFERENT 213 00:07:56,117 --> 00:07:58,753 ORGANISMS. SO HERE IS BARREL 214 00:07:58,753 --> 00:08:01,689 SPONGE, AND SOFT CORALS WAVING 215 00:08:01,689 --> 00:08:04,192 IN THE CURRENT, AND ALGAE ALL 216 00:08:04,192 --> 00:08:06,094 OVER THE SUBSTRATE. 217 00:08:06,094 --> 00:08:07,829 AND AS YOU ARE GOING TO SEE 218 00:08:07,829 --> 00:08:09,030 RIGHT HERE. 219 00:08:09,030 --> 00:08:11,533 LET ME SEE IF I CAN -- SOMETIMES 220 00:08:11,533 --> 00:08:14,369 SEE SPONGES, THIS IS ACTUALLY 221 00:08:14,369 --> 00:08:16,004 TWO DIFFERENT SPECIES OF 222 00:08:16,004 --> 00:08:17,238 SPONGESES THAT ARE LIVING IN 223 00:08:17,238 --> 00:08:18,973 CLOSE ASSOCIATION WITH ONE 224 00:08:18,973 --> 00:08:22,877 ANOTHER, AND SEE THESE TYPES OF 225 00:08:22,877 --> 00:08:24,646 MUTUALIST RELATIONSHIPS ALL OVER 226 00:08:24,646 --> 00:08:28,683 THE CORAL REEFS, AND IF YOU 227 00:08:28,683 --> 00:08:32,654 LOOK, SOMETIMES WE SEE SPONGES 228 00:08:32,654 --> 00:08:35,290 WHOSE SURFACES ARE COMPLETELY 229 00:08:35,290 --> 00:08:37,559 CLEAR, AND OTHERS THAT DARK RED 230 00:08:37,559 --> 00:08:39,761 ONES COVERED WITH DIFFERENT TYPE 231 00:08:39,761 --> 00:08:43,064 OF BACTERIA AND ALGAE, AND 232 00:08:43,064 --> 00:08:44,399 BIOFILMS ETC. 233 00:08:44,399 --> 00:08:47,902 AND ALSO WHEN SCUBA DIVING YOU 234 00:08:47,902 --> 00:08:49,504 CAN QUICKLY SEE IF YOU GO ON 235 00:08:49,504 --> 00:08:51,473 WALL OR REEF LIKE THIS, 236 00:08:51,473 --> 00:08:52,874 LITERALLY EVERY CM OF THE REEF 237 00:08:52,874 --> 00:08:55,944 IS COVERED WITH A LIVING 238 00:08:55,944 --> 00:08:58,480 ORGANISM, SOMEHOW THESE ALL LIVE 239 00:08:58,480 --> 00:09:00,348 TOGETHER, AND SUPPORT THIS WHOLE 240 00:09:00,348 --> 00:09:02,317 CORAL REEF COMMUNITY. 241 00:09:02,317 --> 00:09:04,719 SO IT'S THIS WHOLE COMMUNITY 242 00:09:04,719 --> 00:09:06,387 THAT I BECAME CONSIDERED IN 243 00:09:06,387 --> 00:09:13,895 BEFORE GOING TO GRAD SCHOOL. 244 00:09:13,895 --> 00:09:14,996 LET'S SEE -- OOPS, I DON'T WANT 245 00:09:14,996 --> 00:09:17,298 THAT. 246 00:09:17,298 --> 00:09:17,532 OKAY. 247 00:09:17,532 --> 00:09:21,703 AND SO, IF YOU... AS I MENTION 248 00:09:21,703 --> 00:09:23,938 IF YOU LOOK AT A LOT OF 249 00:09:23,938 --> 00:09:26,307 DIFFERENT MARINE SPONGES THAT 250 00:09:26,307 --> 00:09:28,710 ARE SHOWN OVER ON THE RIGHT 251 00:09:28,710 --> 00:09:33,748 SIDE, YOU CAN SEE THAT THESE 252 00:09:33,748 --> 00:09:35,550 SURFACES AGAIN ARE COMPLETELY 253 00:09:35,550 --> 00:09:36,851 UNFOULED, WHEN YOU TOUCH THEM 254 00:09:36,851 --> 00:09:38,419 THEY ARE ACTUALLY SMOOTH TO THE 255 00:09:38,419 --> 00:09:39,988 TOUCH, AND DON'T HAVE ANY KIND 256 00:09:39,988 --> 00:09:43,291 OF BIOFILM SO IF YOU ARE A 257 00:09:43,291 --> 00:09:44,993 CHEMIST, YOU THINK POSSIBLY 258 00:09:44,993 --> 00:09:46,127 COULD BE CHEMISTRY INSIDE OF 259 00:09:46,127 --> 00:09:48,930 THOSE ORGANISMS THAT ARE 260 00:09:48,930 --> 00:09:51,366 CONTROLLING EITHER 261 00:09:51,366 --> 00:09:56,237 ANTIBACTERIAL, ANTIFUNGAL, ETC 262 00:09:56,237 --> 00:09:59,507 THIS BECAME MOTIVATION FOR ME TO 263 00:09:59,507 --> 00:10:02,677 GRAD SCHOOL TORE DO MARINE 264 00:10:02,677 --> 00:10:05,013 NATURAL PRODUCT CHEMISTRY. 265 00:10:05,013 --> 00:10:07,248 FURTHER, IFFIC LOOK INSIDE 266 00:10:07,248 --> 00:10:09,317 SPONGES, NOT ALL SPONGESES BUT 267 00:10:09,317 --> 00:10:09,951 MANY THEY HAVE EXTREMELY COMPLEX 268 00:10:09,951 --> 00:10:11,553 MICROBIOMES. AND SO THIS IS A 269 00:10:11,553 --> 00:10:14,923 SPONGE CALLED ANALISOLI I WORKED 270 00:10:14,923 --> 00:10:17,725 ON YEARS AGO, AND IF FI‘EEZE IT 271 00:10:17,725 --> 00:10:18,359 AND CRACK IT OPEN, YOU SEE THAT 272 00:10:18,359 --> 00:10:20,228 IT IS JUST PACKED WITH THESE 273 00:10:20,228 --> 00:10:23,064 FILAMENTOUS BACTERIA. AND YEARS 274 00:10:23,064 --> 00:10:25,733 AND YEARS AGO I DID SOME FIELD 275 00:10:25,733 --> 00:10:29,270 WORK AND PULVERIZED THIS SPONGE 276 00:10:29,270 --> 00:10:32,240 IN AN OLD SCHOOL OMEGA MIXER 277 00:10:32,240 --> 00:10:34,142 THAT HAD A JUICER FILTER PAPER 278 00:10:34,142 --> 00:10:41,316 LIKE A CENTRIFUGE AND TAKE THE 279 00:10:41,316 --> 00:10:44,419 PULVERIZED TISSUE OUT TO DO SELL 280 00:10:44,419 --> 00:10:45,053 SEPARATIONS, IN THE FIELD IN A 281 00:10:45,053 --> 00:10:45,687 VERY PRIMITIVE CENTRIFUGE. AND I 282 00:10:45,687 --> 00:10:47,021 WAS ACTUALLY ABLE TO MAKE 283 00:10:47,021 --> 00:10:47,622 REALLY CLEAN PELLETS OF THESE 284 00:10:47,622 --> 00:10:49,857 FILAMENTOUS BACTERIA. AND AT THE 285 00:10:49,857 --> 00:10:51,759 TIME WE ALREADY SUSPECTED THAT 286 00:10:51,759 --> 00:10:54,395 THE CHEMISTRY WAS COMING FROM 287 00:10:54,395 --> 00:10:55,029 BACTERIAL SANDBION, NOT FROM THE 288 00:10:55,029 --> 00:10:57,265 SPONGE, BECAUSE WE WERE 289 00:10:57,265 --> 00:10:57,865 ISOLATING THE CYCLIC PEPTIDES 290 00:10:57,865 --> 00:10:59,100 THAT HAD ALL OF THESE NON 291 00:10:59,100 --> 00:10:59,734 PROTONACIOUS AMINO ACIDS. THEY 292 00:10:59,734 --> 00:11:05,273 HAD D AMINO ACIDS , BETA, AMINO 293 00:11:05,273 --> 00:11:09,611 GROUPS, AND HYDROXYLATIONS , 294 00:11:09,611 --> 00:11:10,178 AND AND UNUSUAL PLACES, 295 00:11:10,178 --> 00:11:10,812 ETCETERA, THAT SORT OF HINTED TO 296 00:11:10,812 --> 00:11:14,415 IT BEING BACTERIAL ORIGIN. 297 00:11:14,415 --> 00:11:17,485 SO WE'RE VERY LUCKY HERE AT NIH 298 00:11:17,485 --> 00:11:21,956 TO HAVE ACCESS TO THE NCI OPEN 299 00:11:21,956 --> 00:11:24,659 REPOSITORY UP IN FEDERICK THAT 300 00:11:24,659 --> 00:11:27,629 IS OPEN TO 10'S OF THOUSAND OF 301 00:11:27,629 --> 00:11:29,330 DIFFERENT MARINE EXTRACTS AS 302 00:11:29,330 --> 00:11:32,333 WELL AS PLANTS AND THAT 303 00:11:32,333 --> 00:11:36,137 REPOSITORY OF COURSE HAS BEEN 304 00:11:36,137 --> 00:11:39,407 MINED FOR YEARS, FOR ANTICANCER 305 00:11:39,407 --> 00:11:40,041 COMPOUNDS AND JUST A FEW OF THEM 306 00:11:40,041 --> 00:11:41,476 ARE THAT HAVE BEEN DISCOVERED 307 00:11:41,476 --> 00:11:42,076 OVER THE YEARS ARE SHOWN HERE 308 00:11:42,076 --> 00:11:44,045 AND YOU CAN SEE THE SPECIES AND 309 00:11:44,045 --> 00:11:46,381 KINGDOM DIVERSITY IN THE PIE 310 00:11:46,381 --> 00:11:46,614 CHART. 311 00:11:46,614 --> 00:11:49,550 SO WE WANTED TO SIMPLY DO A 312 00:11:49,550 --> 00:11:53,655 SCREEN FOR ANTIMICROBIAL 313 00:11:53,655 --> 00:11:57,325 COMPOUNDS USING NCI OPEN 314 00:11:57,325 --> 00:11:58,526 REPOSITORY, BECAUSE THAT HAD NOT 315 00:11:58,526 --> 00:11:59,961 BEEN DONE, SO WE JUST PICKED 316 00:11:59,961 --> 00:12:05,466 10,000 MARINE EXTRACTS AND A 317 00:12:05,466 --> 00:12:06,067 POST-DOC AND A FORMER SUMMER 318 00:12:06,067 --> 00:12:06,901 STUDENT CARRIED OUT THE SCR 319 00:12:06,901 --> 00:12:08,536 SCREENAND WE SIMPLY TESTED 320 00:12:08,536 --> 00:12:10,038 AGAINST GRAM-NEGATIVE AND 321 00:12:10,038 --> 00:12:12,306 GRAM-POSITIVE BACTERIA. 322 00:12:12,306 --> 00:12:14,475 AND GRAM POSITIVE HITS WERE VERY 323 00:12:14,475 --> 00:12:16,778 HIGH, WE GOT ABOUT 500 HITS, AND 324 00:12:16,778 --> 00:12:17,912 THAT'S NOT UNCOMMON, BUT 325 00:12:17,912 --> 00:12:27,922 SURPRISINGLY, AGAINST ECOLI, 326 00:12:27,922 --> 00:12:28,556 GRAMM NEGATIVE PATHOGEN WE ONLY 327 00:12:28,556 --> 00:12:31,192 GOT ABOUT 30 WHICH IS A 0.3% 328 00:12:31,192 --> 00:12:31,793 HIT RATE. SO THAT'S EXTREMELY 329 00:12:31,793 --> 00:12:32,860 LOW SO WE WENT ON TO DO 330 00:12:32,860 --> 00:12:33,494 ISOLATION STRUCTURE ELUCIDATION 331 00:12:33,494 --> 00:12:34,028 ETCETER‘A ON ALL OF THE 332 00:12:34,028 --> 00:12:36,664 COMPOUNDS THAT ALL THEIR 333 00:12:36,664 --> 00:12:37,865 EXTRACTS THAT HAD COMPOUND THAT 334 00:12:37,865 --> 00:12:39,567 IS WERE KILLING GRAM-NEGATIVE 335 00:12:39,567 --> 00:12:40,735 BACTERIA. 336 00:12:40,735 --> 00:12:42,804 AND FOUND, WITH THE EXCEPTION OF 337 00:12:42,804 --> 00:12:45,773 ONE SPONGE, AND ALL THESE WERE 338 00:12:45,773 --> 00:12:48,342 SPONGESES AS WELL, EVERY 339 00:12:48,342 --> 00:12:52,914 COMPOUND WAS RICH IN AMINE 340 00:12:52,914 --> 00:12:53,414 CONTAINING MOLECULES. 341 00:12:53,414 --> 00:12:55,416 IN A COUPLE OF SLIDES, DON'T 342 00:12:55,416 --> 00:12:57,885 WANT TO GO TO THIS PART OF OUR 343 00:12:57,885 --> 00:12:59,387 RESEARCH, BUT JUST WANT TO GIVE 344 00:12:59,387 --> 00:13:00,855 YOU ALL AN IMPRESSION OF WHAT'S 345 00:13:00,855 --> 00:13:01,355 OUT THERE. 346 00:13:01,355 --> 00:13:03,691 AND WHAT WE CAN LEARN FROM THE 347 00:13:03,691 --> 00:13:04,492 MARINE NATURAL PRODUCTS. 348 00:13:04,492 --> 00:13:06,561 SO I'M GOING TO TELL YOU THIS 349 00:13:06,561 --> 00:13:08,663 QUICKLY ABOUT THE WORK THAT WE 350 00:13:08,663 --> 00:13:10,198 DID ON THIS P-10. 351 00:13:10,198 --> 00:13:16,037 SIMPLY AN AMID VERSION OF 352 00:13:16,037 --> 00:13:21,109 BLASTOYTE AND S, AND ACCEPT 353 00:13:21,109 --> 00:13:28,750 TROTR EMITOZO 354 00:13:28,750 --> 00:13:30,485 ALKALOID THAT IS COMMON IN ONE 355 00:13:30,485 --> 00:13:32,987 GROUP OF MARINE SPONGES. SO TO 356 00:13:32,987 --> 00:13:33,621 GET AT THIS THIS AMID VERSION OF 357 00:13:33,621 --> 00:13:34,322 PLASTIC CYDEN WAS ACTUALLY 358 00:13:34,322 --> 00:13:34,956 ABOUT 20 TIMES MORE POTENT AND 359 00:13:34,956 --> 00:13:35,623 ACTUAL 360 00:13:35,623 --> 00:13:37,759 ACTUALLY.... GAVE US ACTIVITY 361 00:13:37,759 --> 00:13:38,392 AGAINST GRAM NEGATIVE BACTERIA 362 00:13:38,392 --> 00:13:41,863 WHEREAS THE OTHER ONE, THE THE 363 00:13:41,863 --> 00:13:43,931 NATURAL PRODUCT DID NOT. AND SO 364 00:13:43,931 --> 00:13:47,869 TO GET AT THIS KATHY H, IN THE 365 00:13:47,869 --> 00:13:48,503 LAB RAISED RESISTANT MUTANTS AND 366 00:13:48,503 --> 00:13:49,570 JUST BY YOU KNOW COMPETITION 367 00:13:49,570 --> 00:13:51,372 WITH INCREASING AMOUNT OF 368 00:13:51,372 --> 00:13:53,141 COMPOUND. 369 00:13:53,141 --> 00:13:56,277 AND THEN JACK DAVEISON DID 370 00:13:56,277 --> 00:13:58,679 COMPARATIVE GENOMICS ON THE 371 00:13:58,679 --> 00:14:00,715 MUTANT AND IS WHAT WE 372 00:14:00,715 --> 00:14:04,786 SURPRISINGLY FOUND IS THAT THE 373 00:14:04,786 --> 00:14:06,888 MUTANTS WERE ACTUALLY DELETING 374 00:14:06,888 --> 00:14:12,326 THE NOR-AGEING, NOR-A IS THE 375 00:14:12,326 --> 00:14:13,861 TRANSPORTER THAT GIVES 376 00:14:13,861 --> 00:14:16,631 RESISTANCE TO FLUOROQUINOLONE 377 00:14:16,631 --> 00:14:19,934 ANTIBIOTICS. THIS IS IN STA 378 00:14:19,934 --> 00:14:21,869 STAFFAUREUS BY THE WAY. 379 00:14:21,869 --> 00:14:26,240 AND STRANGELY WHEN THE 380 00:14:26,240 --> 00:14:28,309 STEPHORIOUS WERE SUBJECTED TO 381 00:14:28,309 --> 00:14:29,377 THIS COMPOUND THEY WERE DELETING 382 00:14:29,377 --> 00:14:33,181 THE EFFLEX PUMP, WHICH IS 383 00:14:33,181 --> 00:14:35,516 ACTUALLY WHAT MAKES THEM 384 00:14:35,516 --> 00:14:40,721 RESISTANT TO FLUOROQUINOLONES. 385 00:14:40,721 --> 00:14:42,023 SO IN THE STUDY WE ACTUALLY 386 00:14:42,023 --> 00:14:46,928 LEARNED THIS NOR-A TRANSPORTER 387 00:14:46,928 --> 00:14:47,562 IS ACTUALLY AN IMPORTER FOR THIS 388 00:14:47,562 --> 00:14:49,330 CLASS OF COMPOUNDS WHILE IT'S 389 00:14:49,330 --> 00:14:49,964 AN EXPORTER FOR FLUOROQUINOLONES 390 00:14:49,964 --> 00:14:54,902 AND THIS IS JUST ONE EXAMPLE OF 391 00:14:54,902 --> 00:14:56,737 MECHANICNISTIC STUDIES WE DONE 392 00:14:56,737 --> 00:14:57,605 IN OUR LAB. 393 00:14:57,605 --> 00:14:58,773 WE'VE ALSO BEEN VERY INTERESTED 394 00:14:58,773 --> 00:15:03,211 IN THIS GROUP OF POUNDS, SEPTRON 395 00:15:03,211 --> 00:15:05,680 IS A WELL KNOWN EXAMPLE. 396 00:15:05,680 --> 00:15:07,748 THIS IS WORK DONE IN LAB BY 397 00:15:07,748 --> 00:15:11,385 TORI KLEIN A CURRENT POST-DOC 398 00:15:11,385 --> 00:15:14,055 AND PREVIOUS WORK WE DONE IN 399 00:15:14,055 --> 00:15:16,490 COLLABORATION WITH CHRISTIAN 400 00:15:16,490 --> 00:15:19,260 MELANDERS LAB, WE SHOWED THAT 401 00:15:19,260 --> 00:15:22,964 WHEN DRUG RESISTANT BACTERIA ARE 402 00:15:22,964 --> 00:15:27,768 SUBJECTED TO SEPTRIN AND EXAMPLE 403 00:15:27,768 --> 00:15:30,638 METHICILLIN THE PRESENCE OF 404 00:15:30,638 --> 00:15:31,239 SEPTRIN WILL ACTUALLY RESTORE 405 00:15:31,239 --> 00:15:32,840 ANTIBODY BIOTIC SUSCEPTIBILITY 406 00:15:32,840 --> 00:15:33,441 TO THE DRUG THAT THE BACTERIA 407 00:15:33,441 --> 00:15:34,842 ARE RESISTANT TO. SO WE'VE BEEN 408 00:15:34,842 --> 00:15:35,443 VERY INTERESTED IN TRYING TO 409 00:15:35,443 --> 00:15:37,011 FIGURE OUT THE MECHANISM FOR HOW 410 00:15:37,011 --> 00:15:38,579 THIS COULD TAKE PLACE. 411 00:15:38,579 --> 00:15:41,148 SO TORI'S DONE AN AMAZING JOB 412 00:15:41,148 --> 00:15:44,118 WITH THIS PROJECT. 413 00:15:44,118 --> 00:15:48,556 PRIOR TO HER ARRIVAL WE DID A 414 00:15:48,556 --> 00:15:50,758 CHEMICAL GENETIC SCREEN WITH 415 00:15:50,758 --> 00:15:51,392 JEFF PIETROWSKI AND UNIVERSITY 416 00:15:51,392 --> 00:15:55,129 OF WISCONSIN AND FOUND THAT THE 417 00:15:55,129 --> 00:15:55,730 RESISTANT MUTANTS TO SCEPTRON 418 00:15:55,730 --> 00:15:56,697 WERE USUALLY DEFICIENT IN 419 00:15:56,697 --> 00:16:01,402 SOMETHINGTO DO WITH CELL WALL 420 00:16:01,402 --> 00:16:05,373 BIOSYNTHESIS, OR MEMBRANE, 421 00:16:05,373 --> 00:16:06,340 PERMEABILITY, AND SO TORY'S 422 00:16:06,340 --> 00:16:09,510 DONE A LOT OF MICROSCOPY AND 423 00:16:09,510 --> 00:16:10,244 T.TMETC, IF YOU WANT TO LEARN 424 00:16:10,244 --> 00:16:16,517 MORE ABOUT THIS STORY, AND HOW 425 00:16:16,517 --> 00:16:20,588 SCETPRON IS WORKING SHE'S 426 00:16:20,588 --> 00:16:28,062 SPEAKING AT L2L IN JANINE 2025. 427 00:16:28,062 --> 00:16:30,831 MORE ECOLOGICAL AREA OF FOCUS, 428 00:16:30,831 --> 00:16:33,501 WHEN WE ARE OUT DIVING WE LOOK 429 00:16:33,501 --> 00:16:36,771 FOR OUTLIERS, OR ORGANISMS OR 430 00:16:36,771 --> 00:16:38,372 THINGS THAT LOOK UNUSUAL, OR 431 00:16:38,372 --> 00:16:40,007 SHOULDN'T BE THERE. 432 00:16:40,007 --> 00:16:41,876 THIS IS WHAT HAPPENED WHEN WE 433 00:16:41,876 --> 00:16:43,544 FOUND THIS ALGAE. 434 00:16:43,544 --> 00:16:46,180 THIS IS IN US VIRGIN ISLANDS IN 435 00:16:46,180 --> 00:16:48,049 ROUND BAY. SO IT'S AT THE EAST 436 00:16:48,049 --> 00:16:49,684 END OF THE ISLAND. 437 00:16:49,684 --> 00:16:52,386 AND JUST SNORKELING, AND FOUND 438 00:16:52,386 --> 00:16:55,156 MOUNDS AND MOUNDS OF THIS ALGAE. 439 00:16:55,156 --> 00:17:00,328 THIS IS UNUSUAL, JUST A CORAL 440 00:17:00,328 --> 00:17:02,196 REBEL SUBSTRATE, AND HAS VERY 441 00:17:02,196 --> 00:17:04,565 HIGH CURRENT, VERY UNUSUAL FOR 442 00:17:04,565 --> 00:17:07,702 SOMETHING TO COME AND GROW TO 443 00:17:07,702 --> 00:17:11,339 THIS DENSITY ON THAT KIND OF 444 00:17:11,339 --> 00:17:12,039 SUBSTRATE. 445 00:17:12,039 --> 00:17:15,609 HMM... I HAVE A TIMER. 446 00:17:15,609 --> 00:17:18,913 OKAY. 447 00:17:18,913 --> 00:17:21,882 SO WE WERE INTERESTED IN THIS 448 00:17:21,882 --> 00:17:23,184 ORGANISM. 449 00:17:23,184 --> 00:17:33,594 IT'S NOT FORWARDING... 450 00:17:33,928 --> 00:17:44,171 SORRY ABOUT THIS. 451 00:18:03,858 --> 00:18:04,692 THANK YOU. 452 00:18:04,692 --> 00:18:07,928 OKAY, SO INTERESTED IN THE 453 00:18:07,928 --> 00:18:09,864 CHEMISTRY IN THIS ORGANISM. 454 00:18:09,864 --> 00:18:13,100 AND SO WE COLLECTED SOME, AND WE 455 00:18:13,100 --> 00:18:15,770 ENDED UP ISOLATING THESE 456 00:18:15,770 --> 00:18:17,805 MOLECULES, SO THESE ARE HIGHLY 457 00:18:17,805 --> 00:18:19,907 UNUSUAL, A NEW SCAFFOLD THAT HAS 458 00:18:19,907 --> 00:18:23,110 NOT BEEN SEEN BEFORE, OR SINCE. 459 00:18:23,110 --> 00:18:25,146 SO I DON'T SEEM TO HAVE A 460 00:18:25,146 --> 00:18:26,047 POINTER HERE. 461 00:18:26,047 --> 00:18:31,652 BUT, LET ME JUST SEE. 462 00:18:31,652 --> 00:18:33,854 THAT KIND OF WORKS. 463 00:18:33,854 --> 00:18:34,989 WANT TO POINT OUT A COUPLE 464 00:18:34,989 --> 00:18:36,924 THINGS HERE, THIS MOLECULE IS 465 00:18:36,924 --> 00:18:38,325 HIGHLY STRAINED AND THERE IS 466 00:18:38,325 --> 00:18:41,362 THIS ETHER RIGHT HERE, THAT'S 467 00:18:41,362 --> 00:18:43,931 ACTUALLY IN AN ORTHO POSITION 468 00:18:43,931 --> 00:18:45,633 THAT MAKES THE MOLECULE STRAINED 469 00:18:45,633 --> 00:18:51,405 AND ACTUALLY FOLDS INTO A BASKET 470 00:18:51,405 --> 00:18:57,878 SHAPE, AND ALSO HAS THIS 471 00:18:57,878 --> 00:18:59,680 2-CHLORU-BUTIN GROUP THAT 472 00:18:59,680 --> 00:19:00,214 ABSOLUTELY ESSENTIAL FOR 473 00:19:00,214 --> 00:19:01,882 ANTIBIOTIC ACTIVITY. SO WE ALSO 474 00:19:01,882 --> 00:19:02,516 WERE LUCKY IN THAT WE ISOLATED, 475 00:19:02,516 --> 00:19:05,119 I THINK EIGHT OR NINE DIFFERENT 476 00:19:05,119 --> 00:19:07,788 ANALOGS OF THIS CHRYSOPHANTINE 477 00:19:07,788 --> 00:19:11,158 FAMILY. SO THIS WAS THE MOST 478 00:19:11,158 --> 00:19:11,792 ABUNDANT AND THE MOST ACTIVE. WE 479 00:19:11,792 --> 00:19:13,394 ALSO ISOLATED LINEAR SO NON 480 00:19:13,394 --> 00:19:14,028 MACROCYCLIC COMPOUNDS AND ALSO 481 00:19:14,028 --> 00:19:17,498 ONES WHERE THIS STRAINED ETHER 482 00:19:17,498 --> 00:19:19,733 WAS NOT PRESENT, IT WAS ACTUALLY 483 00:19:19,733 --> 00:19:23,404 IN THE METAPOSITION. 484 00:19:23,404 --> 00:19:25,906 SO ANYONE ONE OF THOSE CHANGES, 485 00:19:25,906 --> 00:19:29,376 THE ACTIVITY, THE ANTI MICROBIAL 486 00:19:29,376 --> 00:19:34,381 ACTIVITY GOES WAY DOWN. 487 00:19:34,381 --> 00:19:40,888 SO... IN WORK WE WERE DOING 488 00:19:40,888 --> 00:19:45,860 MECHANICNISTICLY TO FIGURE OUT 489 00:19:45,860 --> 00:19:48,929 HOW THE ANTIBIOTICS MIGHT WORK, 490 00:19:48,929 --> 00:19:51,832 WE NOTICED MICROSCOPICALLY, 491 00:19:51,832 --> 00:19:52,399 THAT THESE COMPOUNDS WHERE 492 00:19:52,399 --> 00:19:52,967 BACTERIA AND THEY WERE ALSO 493 00:19:52,967 --> 00:19:56,070 CAUSING BALLOONING OF CELLS, SO 494 00:19:56,070 --> 00:19:57,605 THAT'S A HINT THEY COULD BE 495 00:19:57,605 --> 00:19:59,740 DISRUPTING MECHANISMS OF CELL 496 00:19:59,740 --> 00:20:01,175 DIVISION, SO WITH WE LOOKED AT 497 00:20:01,175 --> 00:20:03,043 VARIOUS COMPOUNDS THAT INHIBITED 498 00:20:03,043 --> 00:20:11,719 THE CYTOSKELETAL PROTEIN FIT-C, 499 00:20:11,719 --> 00:20:15,156 AND SO COMPOUNDS HERE AND 500 00:20:15,156 --> 00:20:15,723 HERE'S JUST A X-RAY CRYSTAL 501 00:20:15,723 --> 00:20:19,226 STRUCTURE OF FITZY. FIT-C, IS 502 00:20:19,226 --> 00:20:19,760 ACTUALLY PRECEDED. IT'S A 503 00:20:19,760 --> 00:20:21,896 TUBULIN HOMOLOG BUT SINCE IT'S 504 00:20:21,896 --> 00:20:22,530 BACTERIAL IT ACTUALLY PRECEDED 505 00:20:22,530 --> 00:20:23,130 TUBULIN. SO IT'S ALSO A G T P 506 00:20:23,130 --> 00:20:26,233 ACE AND WHEN G T P BINDS IT 507 00:20:26,233 --> 00:20:26,834 ACTUALLY INDUCES HEAD TO TAIL 508 00:20:26,834 --> 00:20:29,370 POLYMERIZATION AND 509 00:20:29,370 --> 00:20:33,007 PROTOFILAMENT FORMATION. AND SO 510 00:20:33,007 --> 00:20:35,442 WE WERE CURIOUS IF THEY WERE 511 00:20:35,442 --> 00:20:40,014 ACTUALLY FIT-C INHIBITORS. 512 00:20:40,014 --> 00:20:42,750 AND SO IN A SERIES OF 513 00:20:42,750 --> 00:20:45,786 DIFFERENT EXPERIMENTS, WE 514 00:20:45,786 --> 00:20:46,387 SHOWED THAT INDEED IF WE MAKE 515 00:20:46,387 --> 00:20:49,123 PROTOFILAMENTS AND ADD OUR 516 00:20:49,123 --> 00:20:53,661 COMPOUND IT DISCORRUPTS PROTOPY 517 00:20:53,661 --> 00:20:54,228 FILAMENT FORMATION. WE CAN 518 00:20:54,228 --> 00:20:55,529 INHIBIT GTPAS ACTIVITY AND 519 00:20:55,529 --> 00:21:00,267 REALLY. ... INTERESTINGLY, WE 520 00:21:00,267 --> 00:21:01,869 CARRIED OUT MOLECULAR DOCKING OF 521 00:21:01,869 --> 00:21:02,703 THIS. IS THE THREE DIMENSIONAL 522 00:21:02,703 --> 00:21:03,304 STRUCTURE SHOWN IN WHITE AND 523 00:21:03,304 --> 00:21:05,639 BLUE HERE. ACTUALLY JUST WHITE, 524 00:21:05,639 --> 00:21:08,409 THE BLUE IS GDP AND BINDING SITE 525 00:21:08,409 --> 00:21:11,111 IN THE BACK, AND CARRY OUT 526 00:21:11,111 --> 00:21:12,947 SOMETHING CALLED SATURATION 527 00:21:12,947 --> 00:21:15,449 TRANSFER DIFFERENCE NMR. 528 00:21:15,449 --> 00:21:17,384 SO WHAT WE'RE DOING IN THIS 529 00:21:17,384 --> 00:21:21,188 EXPERIMENT WE TAKE THE FIT-C 530 00:21:21,188 --> 00:21:24,158 PROTEIN IN NMR TUBE AND GDP 531 00:21:24,158 --> 00:21:28,729 BOUND TO IT IN GDP BINDING SITE 532 00:21:28,729 --> 00:21:34,969 AND TIE TRAIT IN THE 533 00:21:34,969 --> 00:21:37,404 CRESTOPHANTN AND FIND IT BINDS 534 00:21:37,404 --> 00:21:39,573 AND DISPLACE GDP IN THE BINDING 535 00:21:39,573 --> 00:21:40,874 SIGH, AND CAN ACTUALLY QUANTIFY 536 00:21:40,874 --> 00:21:47,381 THE DISTANCES, AND QUANTITY THE 537 00:21:47,381 --> 00:21:48,349 EFFECT, AND THAT'S DIRECTLY 538 00:21:48,349 --> 00:21:48,983 PROPORTIONAL TO THE DISTANCES OF 539 00:21:48,983 --> 00:21:50,184 ANY GIVEN PROTON THAT WE'RE 540 00:21:50,184 --> 00:21:52,086 OBSERVING FROM THE PROTEIN, AND 541 00:21:52,086 --> 00:21:54,788 THAT'S JUST SHOWN HERE IN THE 542 00:21:54,788 --> 00:21:56,690 MAGNITUDE OF THE LITTLE GRAY 543 00:21:56,690 --> 00:21:58,959 BALLS. AND IF WE WERE TO LOOK 544 00:21:58,959 --> 00:22:03,230 ON THE MAP THAT OUT ON TO THE 545 00:22:03,230 --> 00:22:04,898 MODEL IT FITS PERFECTLY WITH 546 00:22:04,898 --> 00:22:09,436 AREAS WHERE THERE IS NO SGD, 547 00:22:09,436 --> 00:22:12,139 SOLVENT EXPOSED AND THOSE WITH 548 00:22:12,139 --> 00:22:13,707 LARGEST ONE ARE BOUND DEEP IN 549 00:22:13,707 --> 00:22:24,018 THE BINDING SITE. 550 00:22:29,290 --> 00:22:29,857 SO JESSICA KEFFER POST A FORMER 551 00:22:29,857 --> 00:22:31,925 GRADUATE STUDENT IN THE LAB. 552 00:22:31,925 --> 00:22:32,559 WANTED TO SEE WHETHER THIS COULD 553 00:22:32,559 --> 00:22:33,861 ACTUALLY WORK INSIDE OF LIVE 554 00:22:33,861 --> 00:22:35,562 BACTERIA, THERE ARE MANY TIMES 555 00:22:35,562 --> 00:22:36,130 WHERE NATURAL PRODUCT MIGHT 556 00:22:36,130 --> 00:22:37,431 EXERT EFFECTS IN AN ENZYME 557 00:22:37,431 --> 00:22:38,065 ASSAY OR IN VITRO. BUT THEN THAT 558 00:22:38,065 --> 00:22:44,471 DOESN'T TRANSFER TO BACTERIA OR 559 00:22:44,471 --> 00:22:45,873 MAMMALIAN CELLS WHAT HAVE YOU. 560 00:22:45,873 --> 00:22:49,243 SO AN PERMEABLE E COLI CARRYING 561 00:22:49,243 --> 00:22:49,877 FITSY Y. F. P. AND YOU CAN JUST 562 00:22:49,877 --> 00:22:55,182 SEE HERE WHEN SHE ADDS NATURAL 563 00:22:55,182 --> 00:22:57,251 KRISOPLRANTINE A, OR EVEN THE 564 00:22:57,251 --> 00:22:57,885 SYNTHETIC HEMICRISOPHANTINE THAT 565 00:22:57,885 --> 00:23:00,521 WE GOT WITH A COLLABORATIONWITH 566 00:23:00,521 --> 00:23:03,824 PETER WIFF AT UNIVERSITY OF 567 00:23:03,824 --> 00:23:05,859 PITTSBURGH, BOTH OF THOSE 568 00:23:05,859 --> 00:23:08,495 COMPOUNDS DISRUPT THE Z-RING 569 00:23:08,495 --> 00:23:09,863 FORMATION IN BACTERIA IN LIVE 570 00:23:09,863 --> 00:23:11,999 CELLS. 571 00:23:11,999 --> 00:23:14,101 THIS WAS ESTABLISHED THAT IT IS 572 00:23:14,101 --> 00:23:18,072 INDEED AN ACTUAL FIT-C INHIBIT 573 00:23:18,072 --> 00:23:18,272 TORE. 574 00:23:18,272 --> 00:23:21,275 WE WANTED TO GET MORE OF THIS 575 00:23:21,275 --> 00:23:23,677 COMPOUND TO CARRY OUT ADDITIONAL 576 00:23:23,677 --> 00:23:25,346 STUDIES. 577 00:23:25,346 --> 00:23:26,513 IDEALLY ANIMAL STUDIES BUT WE 578 00:23:26,513 --> 00:23:29,850 WERE OUT OF COMPOUND, WHEN WE 579 00:23:29,850 --> 00:23:33,053 WENT TO BACK TO COLLECT THE 580 00:23:33,053 --> 00:23:35,322 ALGAE IT WASN'T THERE, SAID 581 00:23:35,322 --> 00:23:35,956 THIS HAPPENS A LOT WITH NATURAL 582 00:23:35,956 --> 00:23:37,458 PRODUCTS. AND SO WE STARTED TO 583 00:23:37,458 --> 00:23:41,795 LOOK IN THE LITERATURE, THIS 584 00:23:41,795 --> 00:23:44,264 CTAYLORI THIS STRANGE ALGAE HAD 585 00:23:44,264 --> 00:23:45,866 BEEN OBSERVED WORLDWIDE, BUT 586 00:23:45,866 --> 00:23:49,336 VERY SPOTTY, AND VERY 587 00:23:49,336 --> 00:23:49,670 SPORADICALLY. 588 00:23:49,670 --> 00:24:00,214 IN THE MORE POPULAR LITERATURE 589 00:24:01,915 --> 00:24:04,251 I CAME ACROSSHARMFUL ALGAE NEWSH 590 00:24:04,251 --> 00:24:04,885 THIS TITLE. WHAT IN THE WORLD IS 591 00:24:04,885 --> 00:24:06,587 C I CAME ACROSS I CAME ACROSS T 592 00:24:06,587 --> 00:24:08,355 DOING 593 00:24:08,355 --> 00:24:09,490 DOING SARDINIA AND THE TURIAN S 594 00:24:09,490 --> 00:24:13,160 DOING IN MEDITERRANEAN AND YOU 595 00:24:13,160 --> 00:24:15,996 CAN SEE THAT THE THE HUGE 596 00:24:15,996 --> 00:24:16,630 BLOOMS THAT IT'S MAKING BOTH YOU 597 00:24:16,630 --> 00:24:19,099 KNOW UNDERWATER THIS IS -- LET 598 00:24:19,099 --> 00:24:20,300 ME SEE, UNDERWATER EXACTLY LIKE 599 00:24:20,300 --> 00:24:21,468 I HAD SEEN. 600 00:24:21,468 --> 00:24:26,573 AND ALSO SHOULD SAY, WHEN THIS 601 00:24:26,573 --> 00:24:28,809 ALGAE STARTS TO GROW AND GAIN 602 00:24:28,809 --> 00:24:33,347 MASS, IT STARTS TO RESPIRATE AND 603 00:24:33,347 --> 00:24:35,749 MAKES BUBBLES OF AIR, TRAPPED IN 604 00:24:35,749 --> 00:24:40,754 THE M-SHEATHE THAT IT EXUDES AND 605 00:24:40,754 --> 00:24:41,622 WHAT HAPPENS THE AIR PRESSURE IS 606 00:24:41,622 --> 00:24:45,859 ENOUGH TO MAKE IT ACTUALLY RISE 607 00:24:45,859 --> 00:24:47,895 FROM THE BOTTOM OF THE SEA TO 608 00:24:47,895 --> 00:24:50,597 THE TOP JUST LIKE A BALLOON, AND 609 00:24:50,597 --> 00:24:54,067 WHAT WAS HAPPENING IN THE 610 00:24:54,067 --> 00:24:56,103 MEDITERRANEAN WAS GETTING THESE 611 00:24:56,103 --> 00:24:58,472 HUGE MASSES OF IT FLOATING UP, 612 00:24:58,472 --> 00:25:00,407 AND ALSO CAME ACROSS THIS... 613 00:25:00,407 --> 00:25:04,678 THESE SLIDES, THAT WHERE THIS 614 00:25:04,678 --> 00:25:07,014 WAS HAPPENING OFF THE COAST OF 615 00:25:07,014 --> 00:25:09,183 SARDINIA AND BECOMING A HUGE 616 00:25:09,183 --> 00:25:09,817 PROBLEM FOR TOURISM AS YOU COULD 617 00:25:09,817 --> 00:25:11,952 IMAGINE IF YOU GET IN THE WATER 618 00:25:11,952 --> 00:25:12,619 AND SEE THIS. 619 00:25:12,619 --> 00:25:13,754 SO THEY'VE BEEN TRYING TO CLEAN 620 00:25:13,754 --> 00:25:15,989 THIS UP, AND WE HAVE 621 00:25:15,989 --> 00:25:18,192 COLLABORATION TO MONITOR THESE 622 00:25:18,192 --> 00:25:21,228 ALGAE OUTBREAKS WITH RESEARCHER 623 00:25:21,228 --> 00:25:23,797 IN ITALY. 624 00:25:23,797 --> 00:25:27,067 BECAUSE WE WERE UNABLE TO GET 625 00:25:27,067 --> 00:25:32,539 MORE MATERIAL, JACK DAVISON 626 00:25:32,539 --> 00:25:33,874 FORMER POST-DOC IN THE LAB 627 00:25:33,874 --> 00:25:38,846 WANTED TO TAKE ON THE RISKY 628 00:25:38,846 --> 00:25:40,247 CHALLENGE OF ACTUALLY TRYING TO 629 00:25:40,247 --> 00:25:41,882 CULTURE THIS ALGAE IN THE LAB, 630 00:25:41,882 --> 00:25:46,520 AND A SUCCESSFUL IN DOING THIS 631 00:25:46,520 --> 00:25:47,721 AND ACTUALLY DID WHOLE GENOME 632 00:25:47,721 --> 00:25:48,322 SEQUENCING A TRANSCRIPTOMICS 633 00:25:48,322 --> 00:25:48,889 WITH THE GOAL OF TRYING TO 634 00:25:48,889 --> 00:25:50,157 FIGURE OUT IF WE COULD 635 00:25:50,157 --> 00:25:50,791 UNDERSTAND HOW THESE MOLECULES 636 00:25:50,791 --> 00:25:52,392 WERE BEING BIOSYNTHESIZED AND 637 00:25:52,392 --> 00:25:53,026 TO PRODUCE MORE IN VITRO IN THE 638 00:25:53,026 --> 00:25:56,463 LAB AND SO JACK WAS ABLE TO SHOW 639 00:25:56,463 --> 00:26:00,601 IN THE LAB THE ALGAE ACTUALLY 640 00:26:00,601 --> 00:26:07,875 DID MAKE DIFFERENT 641 00:26:07,875 --> 00:26:10,477 HEMICRESTOPHANTINE ANALOGS, AND 642 00:26:10,477 --> 00:26:13,847 NOW BROMINATED INSTEAD OF 643 00:26:13,847 --> 00:26:14,481 CHLORINATED AND HE COULD GET THE 644 00:26:14,481 --> 00:26:17,017 LINEAR MOLECULE BUT WE WERE 645 00:26:17,017 --> 00:26:17,484 NEVER ABLE TO GET THE 646 00:26:17,484 --> 00:26:18,085 CRISOPHANTINE A. THAT WE HAD 647 00:26:18,085 --> 00:26:21,522 WANTED TO SO WORK THAT'S 648 00:26:21,522 --> 00:26:22,155 CONTINUES TO THIS DAY BUT WHAT 649 00:26:22,155 --> 00:26:22,956 WAS REALLY INTERESTING IS THAT 650 00:26:22,956 --> 00:26:23,590 WHEN JACK DID THE WHOLE GENOME 651 00:26:23,590 --> 00:26:25,526 SEQUENCING HE'S ESSENTIALLY 652 00:26:25,526 --> 00:26:26,093 DOING META GENOMICS BECAUSE 653 00:26:26,093 --> 00:26:27,761 THERE ARE A LOT OF BACTERIA THAT 654 00:26:27,761 --> 00:26:29,663 COME WITH THE ALGAE COLLECTED IN 655 00:26:29,663 --> 00:26:37,871 THE FIELD, SO HE HAD THE CTALORI 656 00:26:37,871 --> 00:26:41,542 HE GOT FROM A JAPANESE CULTURE 657 00:26:41,542 --> 00:26:45,746 COLLECTION THAT IS AXENIC BE 658 00:26:45,746 --> 00:26:48,949 IT'S NOT, AND SOME THINGS WON'T 659 00:26:48,949 --> 00:26:51,652 GROW XENOGLY, AND THEN WE ALSO 660 00:26:51,652 --> 00:26:52,286 HE ALSO DID THE SAME SEQUENCING 661 00:26:52,286 --> 00:26:53,954 ON THE FIELD COLLECTED AND WHAT 662 00:26:53,954 --> 00:26:54,555 HE COULD SEE INTERESTINGLY IS 663 00:26:54,555 --> 00:26:55,155 THAT THERE IS ASTABILITY 664 00:26:55,155 --> 00:26:58,125 STABLE MICROBIOME ASSOCIATED 665 00:26:58,125 --> 00:27:03,297 WITH CTALORI AND WE HAVEN'T 666 00:27:03,297 --> 00:27:05,399 REALLY FOLLOWED UP WHETHER THOSE 667 00:27:05,399 --> 00:27:09,870 ASSOCIATED BACTERIA MIGHT HAVE 668 00:27:09,870 --> 00:27:11,271 FIT-C HOMOLOGS THAT ARE 669 00:27:11,271 --> 00:27:13,974 RESISTANT TO THESE KINDS OF 670 00:27:13,974 --> 00:27:14,608 COMPOUNDS ARE NOT SO ANYWAY THAT 671 00:27:14,608 --> 00:27:20,514 IS WORK FOR THE FUTURE. SO IF WE 672 00:27:20,514 --> 00:27:24,685 COME TO THE MORE MODERN AREA 673 00:27:24,685 --> 00:27:26,253 NATURAL PRODUCT RESEARCH, AND 674 00:27:26,253 --> 00:27:28,989 LIKE EVERY FIELD GENOMIC IS 675 00:27:28,989 --> 00:27:30,357 PLAYING A HUGE ROLE, NATURAL 676 00:27:30,357 --> 00:27:33,527 PRODUCTS ARE AMAZING, IN MY 677 00:27:33,527 --> 00:27:35,862 OPINION, SO IN EVERY ASPECT, BUT 678 00:27:35,862 --> 00:27:39,333 ALSO IF YOU LOOK AT THE BACTERIA 679 00:27:39,333 --> 00:27:40,634 THAT PRODUCE MOST OF THE NATURAL 680 00:27:40,634 --> 00:27:42,169 PRODUCTS WE'RE FAMILIAR WITH. 681 00:27:42,169 --> 00:27:45,872 SO WOULD BE ANTIBIOTICS AND DO 682 00:27:45,872 --> 00:27:49,876 WHOLE GENOME SEQUENCES, THIS IS 683 00:27:49,876 --> 00:27:52,546 A STRAIN FROM OUR LAB. 684 00:27:52,546 --> 00:27:57,384 EVERY ONE OF THESE COLORED 685 00:27:57,384 --> 00:27:58,018 RECTANGULAR BARS IS BIOSYNTHETIC 686 00:27:58,018 --> 00:28:02,589 GENE CLUSTER THAT ENCODES FOR 687 00:28:02,589 --> 00:28:03,223 A NATURAL PRODUCT. SO SOMETIMES 688 00:28:03,223 --> 00:28:09,863 THESE CAN ENCODE UP UP TO 30 OR 689 00:28:09,863 --> 00:28:11,431 EVEN 40, DIFFERENT COMPOUNDS IN 690 00:28:11,431 --> 00:28:11,999 A SINGLE GENOME. AND WHAT'S 691 00:28:11,999 --> 00:28:13,767 AMAZING IS THAT BACTERIA HAVE 692 00:28:13,767 --> 00:28:14,368 ACTUALLY ACQUIRED OR EVOLVED 693 00:28:14,368 --> 00:28:15,102 THESE BIOSYNTHETIC GENE 694 00:28:15,102 --> 00:28:15,736 CLUSTERS IN A CLUSTERED WAY. SO 695 00:28:15,736 --> 00:28:19,139 THE ENZYMES APPEAR CONSECUTIVELY 696 00:28:19,139 --> 00:28:23,076 IN A CHAIN ON THE DNA OF THE 697 00:28:23,076 --> 00:28:24,077 ORGANISM 698 00:28:24,077 --> 00:28:28,115 SO THE WHOLE PROMISE OF 699 00:28:28,115 --> 00:28:30,517 GENOMICS IN NATURAL PRODUCTS HAS 700 00:28:30,517 --> 00:28:32,953 FEATURED THIS SCHEME, AND SO 701 00:28:32,953 --> 00:28:35,355 INSTEAD OF GOING OUT AND 702 00:28:35,355 --> 00:28:36,556 COLLECTING SOMETHING AND 703 00:28:36,556 --> 00:28:39,259 ISOLATING AND WORKING BACKWARDS 704 00:28:39,259 --> 00:28:41,361 WE WOULD LIKE TO WORK FORWARD TO 705 00:28:41,361 --> 00:28:45,866 TAKE AN ORGANISM AND HAVE IT'S 706 00:28:45,866 --> 00:28:47,300 GENOME AND LOOK AT BIOSYNTHETIC 707 00:28:47,300 --> 00:28:47,934 GENE CLUSTER OF INTEREST, THEN 708 00:28:47,934 --> 00:28:50,470 GO EXAMINE THE ENZYMATIC 709 00:28:50,470 --> 00:28:51,104 ASSEMBLY LINES WHICH I'VE SHOWN 710 00:28:51,104 --> 00:28:54,541 HERE. SO THIS IS THE 711 00:28:54,541 --> 00:28:55,175 BIOSYNTHETIC GENE CLRRSTER JUST 712 00:28:55,175 --> 00:28:57,310 SHOWED IN GENES. SOME OF THESE 713 00:28:57,310 --> 00:28:59,413 GENES ARE HUGE, AND MIGHT 714 00:28:59,413 --> 00:29:03,150 CONTAIN UPWARDS 10 OR 12 OR EVEN 715 00:29:03,150 --> 00:29:05,952 20 DIFFERENT ENZYMES, AND THOSE 716 00:29:05,952 --> 00:29:10,290 ENZYMES WORK AS A CHEMICAL 717 00:29:10,290 --> 00:29:13,060 ASSEMBLY LINE DEPICTED HERE, 718 00:29:13,060 --> 00:29:13,593 AND THEN WE WOULD GO TO A 719 00:29:13,593 --> 00:29:16,063 STRUCTURE BECAUSE SOMETIMES 720 00:29:16,063 --> 00:29:17,364 BIOINFORMATICALLY WE KNOW ENOUGH 721 00:29:17,364 --> 00:29:17,964 ABOUT THESE ENZYMES FUNCTION 722 00:29:17,964 --> 00:29:21,735 THAT WE CAN EVEN PREDICT STEREO 723 00:29:21,735 --> 00:29:25,672 CHEMISTRY OF ANY GIVEN CARBON, 724 00:29:25,672 --> 00:29:27,174 CHIRAL CARBON. 725 00:29:27,174 --> 00:29:29,309 SO THIS WHOLE PATHWAY HERE, IS 726 00:29:29,309 --> 00:29:30,444 JUST FROM A PROJECT IN OUR LAB 727 00:29:30,444 --> 00:29:36,349 THAT WHERE WE DISCOVERED THESE 728 00:29:36,349 --> 00:29:40,654 POTENT ANTIFUNGAL COMPOUNDS, 729 00:29:40,654 --> 00:29:41,288 CALLED THE ARIDOMISENSE AND I'M 730 00:29:41,288 --> 00:29:42,389 NOT GOING TO TALK ABOUT THOSE 731 00:29:42,389 --> 00:29:45,292 TODAY, BUT THAT WAS SORT OF THE 732 00:29:45,292 --> 00:29:47,494 PROMISE OF NATURAL PRODUCT 733 00:29:47,494 --> 00:29:52,766 DISCOVERY IN THE GENOMICERA. 734 00:29:52,766 --> 00:29:53,867 UNFORTUNATELY IT DOESN'T REALLY 735 00:29:53,867 --> 00:29:55,969 WORK LIKE THAT. 736 00:29:55,969 --> 00:29:58,438 BUT IT'S A NICE DIAGRAM. 737 00:29:58,438 --> 00:29:59,239 SOME YEARS AGO. 738 00:29:59,239 --> 00:30:02,843 WE WANTED TO TAKE ADVANTAGE OF 739 00:30:02,843 --> 00:30:07,647 POWER OF GENOMICS, AND MYSELF 740 00:30:07,647 --> 00:30:16,022 TOGETHER WITH CLIFF BARRY AND 741 00:30:16,022 --> 00:30:23,964 NIAID AND EUGENEK AND WERE 742 00:30:23,964 --> 00:30:29,369 AWARDED ONE OF TRANS-NIH 743 00:30:29,369 --> 00:30:32,038 INNOVATOR AWARDS, AND SO WHAT 744 00:30:32,038 --> 00:30:32,672 WE HAD PROPOSED TO DO WAS TO TO 745 00:30:32,672 --> 00:30:34,908 LOOK FOR ANTI MYCOBACTERALS 746 00:30:34,908 --> 00:30:35,542 ANTI TB DRUGS AND CLIFF HAD THE 747 00:30:35,542 --> 00:30:39,813 ECOLOGICAL IDEA THAT SINCE 748 00:30:39,813 --> 00:30:40,380 MYCOBACTERIA ORIGINATED ITS 749 00:30:40,380 --> 00:30:40,947 THOUGHT AT SORT OF AEROBIC 750 00:30:40,947 --> 00:30:42,149 ANAEROBIC INTERFACES. 751 00:30:42,149 --> 00:30:45,852 AND IF YOU LOOK DEEP INTO CORES 752 00:30:45,852 --> 00:30:47,988 IN BOGS FOR EXAMPLE, AND SO THEY 753 00:30:47,988 --> 00:30:50,757 WENT AND ISOLATED BACTERIA FROM 754 00:30:50,757 --> 00:30:54,628 THOSE BOG CORES FROM THAT 755 00:30:54,628 --> 00:30:54,995 INTERFACE. 756 00:30:54,995 --> 00:30:57,764 AND DID THE STANDARD CULTURE, 757 00:30:57,764 --> 00:31:02,769 AND BACTERIAL ISOLATES, AND 758 00:31:02,769 --> 00:31:07,941 EXTRACTING AND TESTING AGAINST 759 00:31:07,941 --> 00:31:10,010 MYCOBACTERIUM TUBERCULOSIS AND 760 00:31:10,010 --> 00:31:10,577 THEY FOUND THAT THESE THIS 761 00:31:10,577 --> 00:31:14,181 UNUSUAL STRAIN AS A GRAM 762 00:31:14,181 --> 00:31:16,950 NEGATIVE TRAIN, AND THEY 763 00:31:16,950 --> 00:31:23,490 ISOLATED CHRYSOBACTERIA, AND 764 00:31:23,490 --> 00:31:24,591 WERE SHOWING ANTI TB ACTIVITY. 765 00:31:24,591 --> 00:31:25,158 SO WE WERE OUR OUR ROLE WAS 766 00:31:25,158 --> 00:31:25,859 GOING TO BE TO LOOK AT THE 767 00:31:25,859 --> 00:31:26,493 CHEMISTRY AND TRY TO FIGURE OUT 768 00:31:26,493 --> 00:31:26,993 WHAT COMPOUNDS MIGHT BE 769 00:31:26,993 --> 00:31:29,095 PRESENTSO WITH A WE FOUND WITH 770 00:31:29,095 --> 00:31:32,065 THE BACTERIA IS THEY ALL 771 00:31:32,065 --> 00:31:35,902 CONTAINED BIOSYNTHETIC GENE 772 00:31:35,902 --> 00:31:38,872 CLUSTERS THAT ENCODED FOR THESE 773 00:31:38,872 --> 00:31:41,408 KNOWN MOLECULES, CALLED 774 00:31:41,408 --> 00:31:43,777 MICROVIRIDENS, SO MICROVIRIDENS 775 00:31:43,777 --> 00:31:46,980 ARE HISTORICALLY KNOWN FROM TO 776 00:31:46,980 --> 00:31:52,552 BE PRODUCED BY CYANOBACTERIA 777 00:31:52,552 --> 00:31:54,221 SHOWN HERE, AND THIS IS GENOME 778 00:31:54,221 --> 00:32:00,360 OF ANABINA SPECIES, AND AND SO 779 00:32:00,360 --> 00:32:00,994 THESE GRASPITIDES ARE KNOWN AS 780 00:32:00,994 --> 00:32:02,529 RIBOSOMALY ENCODED 781 00:32:02,529 --> 00:32:03,129 POST-RANSLATIONALLY MODIFIED 782 00:32:03,129 --> 00:32:04,831 PEPTIDES OR RIPS. 783 00:32:04,831 --> 00:32:07,400 AND RIPS ARE QUITE AMAZING, 784 00:32:07,400 --> 00:32:09,369 BECAUSE THEY ARE ACTUALLY, THEY 785 00:32:09,369 --> 00:32:13,306 START WITH A PEPTIDE PRECURSOR 786 00:32:13,306 --> 00:32:15,508 SYNTHESIZED BY THE RIBOSOME, SO 787 00:32:15,508 --> 00:32:18,879 THAT'S USUALLY THE A-GENE IN 788 00:32:18,879 --> 00:32:20,981 BIOSYNTHETIC GENE CLUSTER, AND 789 00:32:20,981 --> 00:32:23,683 THAT VERY SMALL BGC WILL HAVE 790 00:32:23,683 --> 00:32:26,419 TAILORING ENZYMES, SO OTHER 791 00:32:26,419 --> 00:32:28,455 ENZYMES THAT ARE GOING TO CARRY 792 00:32:28,455 --> 00:32:29,089 OUT CHEMISTRY ON THAT RIBOSOMALY 793 00:32:29,089 --> 00:32:30,657 ENCODED PEPTIDE. 794 00:32:30,657 --> 00:32:33,860 FOR THE GRASPITIDE FAMILY THEY 795 00:32:33,860 --> 00:32:42,168 ARE KNOWN FOR CONTAINING TWO 796 00:32:42,168 --> 00:32:43,703 ATPGRASPLIGASES, A HUGE SUPER 797 00:32:43,703 --> 00:32:46,473 FAMILY, AND BIND ATP AND CARRY 798 00:32:46,473 --> 00:32:49,976 OUT CHEMICAL REACTIONS OFTEN 799 00:32:49,976 --> 00:32:50,277 LIGATIONS. 800 00:32:50,277 --> 00:32:53,246 AND THESE BGC'S, USUALLY HAVE 801 00:32:53,246 --> 00:32:57,050 SOME KIND OF PROTEASE IN THEM, 802 00:32:57,050 --> 00:32:58,752 TO THE BGC TO CLEAVE THE PRODUCT 803 00:32:58,752 --> 00:33:01,955 AND THEN A TRANSPORTER TO 804 00:33:01,955 --> 00:33:04,124 SHUTTLE IT OUT OF THE CELL 805 00:33:04,124 --> 00:33:07,994 SO WHAT THIS LOOKS LIKE FOR THE 806 00:33:07,994 --> 00:33:09,329 CYANO BACTERIA IS SHOWN ON THE 807 00:33:09,329 --> 00:33:11,398 TYPE LINE HERE AND HERE. 808 00:33:11,398 --> 00:33:17,203 SO I JUST SPLIT UP THE WHOLE 809 00:33:17,203 --> 00:33:17,837 PRECURSOR PEPTIDE SEQUENCE. 810 00:33:17,837 --> 00:33:20,573 SO YOU GET LEADER, PEPTIDE, AND 811 00:33:20,573 --> 00:33:21,107 THEN A CORE. 812 00:33:21,107 --> 00:33:24,744 FOR THE CYANOBACTERIA THERE IS 813 00:33:24,744 --> 00:33:26,846 SIMPLE CORE RIGHT HERE, ACTUALLY 814 00:33:26,846 --> 00:33:28,281 ENCODING FOR THE NATURAL PRODUCT 815 00:33:28,281 --> 00:33:32,285 RIGHT HERE, TRICYCLIC SO 816 00:33:32,285 --> 00:33:35,789 CONTAINS TWO OMEBGA LACTONES 817 00:33:35,789 --> 00:33:36,423 AND ONE OMEGA LACTAM AND THEN. 818 00:33:36,423 --> 00:33:40,260 ... WHAT WE SAW IN THE 819 00:33:40,260 --> 00:33:42,796 CHRYSOBACTERIA THAT HAD ACTIVITY 820 00:33:42,796 --> 00:33:45,365 AGAINST MTB THIS VERY, VERY LONG 821 00:33:45,365 --> 00:33:47,500 CORE, THAT PEOPLE HAVE NEVER 822 00:33:47,500 --> 00:33:52,272 SEEN BEFORE IN A GRASPITIDE TYPE 823 00:33:52,272 --> 00:33:56,009 GENE CLUSTER, SO WE LOOK AT BGC 824 00:33:56,009 --> 00:34:01,681 WE AGAIN SEE THE GRASLIBASES AND 825 00:34:01,681 --> 00:34:02,248 STRANGELY WE DON'T SEE ANY 826 00:34:02,248 --> 00:34:03,783 TRANSPORTERS OR PROTEASES. 827 00:34:03,783 --> 00:34:05,485 SO WE SET OUT TO FIGURE OUT WHAT 828 00:34:05,485 --> 00:34:09,622 THE PRODUCTS MIGHT BE, AND JUST 829 00:34:09,622 --> 00:34:17,063 SO YOU KNOW THESE A 830 00:34:17,063 --> 00:34:20,166 ATP-GRASPLIGASES ARE MAKING AN 831 00:34:20,166 --> 00:34:24,871 LACTONE BOND BETWEEN SIR AND 832 00:34:24,871 --> 00:34:27,874 THRIANINIE NRRCLEOPHILE THE 833 00:34:27,874 --> 00:34:30,677 HYDROXYL IS A NUCLEOPHILE OR 834 00:34:30,677 --> 00:34:31,277 ASPARTATE OR GLUTAMATE AS THE 835 00:34:31,277 --> 00:34:31,845 ELECTROPHILE THAT HAS BEEN 836 00:34:31,845 --> 00:34:32,712 ACTIVATED BY A PHOSPHATE WITH 837 00:34:32,712 --> 00:34:38,485 THE ATP GRASP-LIGASE. 838 00:34:38,485 --> 00:34:40,954 SO JENNY IN OUR LAB, SOLVED ALL 839 00:34:40,954 --> 00:34:43,757 THESE QUESTIONS, BY MAKING 840 00:34:43,757 --> 00:34:45,225 SEVERAL DIFFERENT PEPTIDE 841 00:34:45,225 --> 00:34:46,893 CONSTRUCTS THESE WOULD ALL 842 00:34:46,893 --> 00:34:49,863 CONTAIN THE LEADER AND DIFFERENT 843 00:34:49,863 --> 00:34:51,931 VERSION OF THE CORE. 844 00:34:51,931 --> 00:34:57,003 AND HAVING INTRODUCING TEDPOTIER 845 00:34:57,003 --> 00:34:58,505 CLEAVAGE SITES, IN DIFFERENT 846 00:34:58,505 --> 00:35:00,440 AREAS ALONG THE PEPTIDE, AND WE 847 00:35:00,440 --> 00:35:03,510 GOT VERY LUCKY WITH THIS. 848 00:35:03,510 --> 00:35:06,112 HAPPEN TO BE IN GOOD PLACES. 849 00:35:06,112 --> 00:35:11,217 SO WHEN WE DID MSMS 850 00:35:11,217 --> 00:35:11,818 ECONSEQUENCES WE ARE WE WERE 851 00:35:11,818 --> 00:35:14,154 ABLE TO ELUCIDATE WHERE THOSE 852 00:35:14,154 --> 00:35:14,754 MACROCYCLES WERE FORMING. SO 853 00:35:14,754 --> 00:35:18,158 WHEN WE WOULD INCUBATE THAT 854 00:35:18,158 --> 00:35:18,758 PRECURSOR PEPTIDE WITH AN ATP 855 00:35:18,758 --> 00:35:22,228 GRASP GLYCASE. IN THIS CASE THE 856 00:35:22,228 --> 00:35:24,831 CDNC GENE, WHAT WE WOULD SEE IS 857 00:35:24,831 --> 00:35:28,835 LOSS OF 6 WATER MOLECULES, SO 858 00:35:28,835 --> 00:35:29,469 KNOW 6 DEHYDRATIONS HAD TO HAVE 859 00:35:29,469 --> 00:35:34,107 BEEN TAKING PLACE AND THAT SIX 860 00:35:34,107 --> 00:35:35,008 MACROLACTONES WERE PROBABLY 861 00:35:35,008 --> 00:35:37,677 BEING FORMED, AND THROUGH MSMS 862 00:35:37,677 --> 00:35:38,311 SEQUENCING OF EACH ONE OF THESE 863 00:35:38,311 --> 00:35:39,446 PRODUCTS. WE COULD ACTUALLY 864 00:35:39,446 --> 00:35:41,915 FIGURE OUT THIS WAS THE PRODUCT 865 00:35:41,915 --> 00:35:43,650 BGC WAS PRODUCING. 866 00:35:43,650 --> 00:35:45,318 SO THIS WAS UNUSUAL, THIS HAS 867 00:35:45,318 --> 00:35:46,753 NOT BEEN SEEN BEFORE IN ANY 868 00:35:46,753 --> 00:35:47,854 NATURAL PRODUCTS. 869 00:35:47,854 --> 00:35:49,055 IT'S A LITTLE BIT STRANGE. 870 00:35:49,055 --> 00:35:54,127 AND I CAN JUST SAY, AND WORK 871 00:35:54,127 --> 00:35:55,795 I... WON'T TALK ABOUT, IF WE GO 872 00:35:55,795 --> 00:36:00,800 ON AND FORM THE THIRD RING, 873 00:36:00,800 --> 00:36:02,535 PROTEAE, INHIBITION, GOES DOWN, 874 00:36:02,535 --> 00:36:04,571 THEY CONTINUE TO GET 875 00:36:04,571 --> 00:36:07,640 INCREASINGLY MORE POTENT. 876 00:36:07,640 --> 00:36:10,910 SO, TO UNDERSTAND THIS, SO HOW 877 00:36:10,910 --> 00:36:16,049 HOW MIGHT THIS ATPGRALIGASE, A 878 00:36:16,049 --> 00:36:21,354 SINGING ATPGRASLIGE IN THE 879 00:36:21,354 --> 00:36:23,857 BIOSYNTHETIC GENE CLUSTER YET 880 00:36:23,857 --> 00:36:24,491 WE CAN GET THIS REALLY COMPLEX 881 00:36:24,491 --> 00:36:30,630 CHEMISTRY HAPPENING ON SINGLE 882 00:36:30,630 --> 00:36:31,264 RIBOSOMAL PEPTIDE. SO TO FIGURE 883 00:36:31,264 --> 00:36:35,401 THIS OUT JENNY SOLVED THE 884 00:36:35,401 --> 00:36:36,002 CRYSTAL STRUCTURE OF THE CDNC 885 00:36:36,002 --> 00:36:37,670 THAT ATP GRASP LIKE ACE IN THE 886 00:36:37,670 --> 00:36:38,304 PRESENCE OF ADP AND WHAT I DID 887 00:36:38,304 --> 00:36:41,708 NOT MENTION EARLIER IS ENCODE IN 888 00:36:41,708 --> 00:36:48,281 PRECURSOR PEPTIDE, SEQUENCE 889 00:36:48,281 --> 00:36:48,915 LEADER PART THE N TERMINAL PART 890 00:36:48,915 --> 00:36:50,316 OF THE PRECURSOR PEPTIDE. 891 00:36:50,316 --> 00:36:50,884 THERE'S A CONSERVED LEADER 892 00:36:50,884 --> 00:36:51,985 SEQUENCE THAT'S COMMON TO THIS 893 00:36:51,985 --> 00:36:54,354 WHOLE GRASPIDE FAMILY AND THIS 894 00:36:54,354 --> 00:36:56,122 WAS THE FIRST STRUCTURE WHERE WE 895 00:36:56,122 --> 00:36:59,492 HAD LEADER-BOUND, AS WELL AS ADP 896 00:36:59,492 --> 00:37:01,661 AND THE PEPTIDE SUBSTRATE THAT'S 897 00:37:01,661 --> 00:37:03,730 GOING TO BECOME THAT CORE. 898 00:37:03,730 --> 00:37:07,934 AND SO WE WERE LUCKY IN THAT THE 899 00:37:07,934 --> 00:37:10,470 STRUCTURE THAT SHE SOLVED WAS 900 00:37:10,470 --> 00:37:19,078 ACTUALLY ASYMMETRIC HOMODIMER SO 901 00:37:19,078 --> 00:37:21,614 MOLECULE WAS INACTIVE AND SO IT 902 00:37:21,614 --> 00:37:22,215 WAS JUST OPEN WITH THE LEADER 903 00:37:22,215 --> 00:37:25,385 BOUND AND A DP. BUT NO SUBSTRATE 904 00:37:25,385 --> 00:37:27,353 BOUND, AND OTHER MOLECULE, 905 00:37:27,353 --> 00:37:29,455 ACTUALLY CORE BOUND, WHERE THE 906 00:37:29,455 --> 00:37:31,791 CHEMISTRY, THE MACROLUCTUM 907 00:37:31,791 --> 00:37:32,392 CYCLIZATIONS ARE TAKING PLACE 908 00:37:32,392 --> 00:37:35,428 AND THOSE ARE JUST SHOWN HERE 909 00:37:35,428 --> 00:37:39,232 AND HERE RESPECTIVELY. 910 00:37:39,232 --> 00:37:42,602 SO THIS ENZYME UNDER GOES A HUGE 911 00:37:42,602 --> 00:37:46,272 CONFIRMATIONAL CHANGE, WHEN THAT 912 00:37:46,272 --> 00:37:48,107 CORE PEPTIDE, THE SUBSTRATE IS 913 00:37:48,107 --> 00:37:51,110 BOUND, THAT SORT OF LOOP AND 914 00:37:51,110 --> 00:37:54,013 HELICAL REGION ACTUALLY TRAVELS 915 00:37:54,013 --> 00:37:57,083 A FULL 90 DEGREES, ACROSS TO 916 00:37:57,083 --> 00:37:57,650 GRAB THE SUBSTRATE. 917 00:37:57,650 --> 00:38:02,322 AND... THE CHANGE IS SO DRAMATIC 918 00:38:02,322 --> 00:38:03,456 THE SECONDARY STRUCTURAL 919 00:38:03,456 --> 00:38:05,258 ELEMENTS IN THAT REGION, 920 00:38:05,258 --> 00:38:09,862 ACTUALLY CHANGE AS WELL. 921 00:38:09,862 --> 00:38:11,431 AS SHOWN DOWN HERE. 922 00:38:11,431 --> 00:38:15,802 SO THIS IS JUST A CLOSE UP OF 923 00:38:15,802 --> 00:38:19,405 THE ACTIVE SITE, AND WHAT'S VERY 924 00:38:19,405 --> 00:38:22,342 NICE, AS WELL, IS THAT THE 925 00:38:22,342 --> 00:38:24,010 RESOLUTION WAS GREAT IN THIS 926 00:38:24,010 --> 00:38:26,379 CRYSTAL STRUCTURE, WE COULD 927 00:38:26,379 --> 00:38:29,983 ACTUALLY SEE THE N-TERMINAL 928 00:38:29,983 --> 00:38:36,656 REGION OF THAT CORE, THE 3-ANE, 929 00:38:36,656 --> 00:38:41,527 TOWARDS US, AND C-TERMINUS WHICH 930 00:38:41,527 --> 00:38:43,096 IS DIRECTED BACK INTO THE 931 00:38:43,096 --> 00:38:43,329 SLIDES. 932 00:38:43,329 --> 00:38:46,032 AND THE LEADER, WHICH WOULD BE 933 00:38:46,032 --> 00:38:48,134 UP HERE WAS BOUND AS WELL, SO WE 934 00:38:48,134 --> 00:38:51,704 COULD SEE, ORIENTATION OF HOW 935 00:38:51,704 --> 00:38:54,307 THAT ENTIRE PRECURSOR PEPTIDE 936 00:38:54,307 --> 00:39:03,449 WOULD BE BOUND TO THE 937 00:39:03,449 --> 00:39:05,518 ATBGRASPLYGASE. 938 00:39:05,518 --> 00:39:08,321 AND SO WHAT WE ALSO LEARNED 939 00:39:08,321 --> 00:39:10,156 FROM THIS AND ALSO MUCH MANY 940 00:39:10,156 --> 00:39:10,790 MRRTAGENESIS EXPERIMENTS THAT I 941 00:39:10,790 --> 00:39:11,391 WON'T TALK ABOUT IS THAT THIS 942 00:39:11,391 --> 00:39:12,692 ONE RESIDUE ARGININE 123 MAKES 943 00:39:12,692 --> 00:39:15,161 THESE TWO HYDROGEN BONDS TO THIS 944 00:39:15,161 --> 00:39:15,662 CONSERVED ASPARTATE AND 945 00:39:15,662 --> 00:39:16,296 GLUTAMATE. AND SO THIS ASPARTATE 946 00:39:16,296 --> 00:39:19,999 IS GOINGTO BECOME ONE OF THE 947 00:39:19,999 --> 00:39:21,367 MACROLACTONE BONDS IF YOU LOOK 948 00:39:21,367 --> 00:39:24,837 AT ARGININE OVER... SEE IF I CAN 949 00:39:24,837 --> 00:39:26,239 FIND IT. 950 00:39:26,239 --> 00:39:28,308 HERE, JUST A SEQUENCE ALIGNMENT 951 00:39:28,308 --> 00:39:37,784 OF THE CRYSLER BACTERIA VERSUS 952 00:39:37,784 --> 00:39:40,687 CYANOBACTERIA, ARGININE ONLY 953 00:39:40,687 --> 00:39:41,287 OCCURS IN THE CARCIO BACTERIA 954 00:39:41,287 --> 00:39:42,422 AND IT'S REPLACED BY AN ACIDIC 955 00:39:42,422 --> 00:39:43,056 RESIDUE IN THE CYANOBACTERIA. SO 956 00:39:43,056 --> 00:39:45,425 JENNY'S DONE ALL OF THE SWAPPING 957 00:39:45,425 --> 00:39:49,862 YOU MIGHT IMAGINE, AND THE 958 00:39:49,862 --> 00:39:55,001 SINGLE ARGININE IS RESPONSIBLE 959 00:39:55,001 --> 00:39:55,635 FOR THE SPECIES SPECIFICITY AND 960 00:39:55,635 --> 00:39:57,804 THE MACRO LACTONE FORMATION IN 961 00:39:57,804 --> 00:39:58,438 THE CHRYSOBACTERIA. SO IT'S SORT 962 00:39:58,438 --> 00:40:03,276 OF ACTUALLY. ... ACTING AS AN 963 00:40:03,276 --> 00:40:05,111 ANCHOR FOR THE SUBSTRATES TO 964 00:40:05,111 --> 00:40:05,311 BIND. 965 00:40:05,311 --> 00:40:08,214 SO WE HAVE THIS MODEL NOW, IN 966 00:40:08,214 --> 00:40:11,517 THE KINETIC EXPERIMENTS I WON'T 967 00:40:11,517 --> 00:40:13,453 SHOW YOU, WE HAVE THIS MODEL 968 00:40:13,453 --> 00:40:17,523 WHERE THE ARGININE AND SUBSTRATE 969 00:40:17,523 --> 00:40:19,359 COMES IN, THE ARGININE SORT OF 970 00:40:19,359 --> 00:40:19,992 ANCHORS THROUGH THOSE TWO ACIDIC 971 00:40:19,992 --> 00:40:21,861 RESID 972 00:40:21,861 --> 00:40:25,865 RESIDUESAND ATP BINDS, ATP AND 973 00:40:25,865 --> 00:40:27,900 ENZYME CLOSE AND IS MAKES IT 974 00:40:27,900 --> 00:40:28,534 MACROCYCLE OPENS MOVES ETCETERA 975 00:40:28,534 --> 00:40:29,102 AND JUST GOES DOWN THE LINE 976 00:40:29,102 --> 00:40:32,472 INTHIS ITERATIVE PROCESS. 977 00:40:32,472 --> 00:40:35,308 AND BELIEVE THIS OR SHOULD SAY 978 00:40:35,308 --> 00:40:36,676 KNOW THIS TO BE TRUE. 979 00:40:36,676 --> 00:40:39,112 IN KINETIC STUDIES WE'VE SHOWN 980 00:40:39,112 --> 00:40:43,349 YOU NEVER GET AN MACROCYCLE ON 981 00:40:43,349 --> 00:40:45,852 THE C TERMINAL REGION OF THE 982 00:40:45,852 --> 00:40:46,686 PEPTIDE BEING FORMED BEFORE THE 983 00:40:46,686 --> 00:40:47,320 N TERMINAL. SO IT'S ABSOLUTELY 984 00:40:47,320 --> 00:40:49,856 ITERATIVE AND JUST GOES DOWN THE 985 00:40:49,856 --> 00:40:52,992 CHAIN. 986 00:40:52,992 --> 00:40:55,895 SO, A LONG TERM GOAL IN OUR LAB 987 00:40:55,895 --> 00:40:59,799 IS TO SOLVE STRUCTURES AND TO 988 00:40:59,799 --> 00:41:01,434 UNDERSTAND AND DEFINE THIS 989 00:41:01,434 --> 00:41:02,702 ENTIRE PATH WAY. 990 00:41:02,702 --> 00:41:06,005 IT'S STILL EARLY DAYS, ACTUALLY 991 00:41:06,005 --> 00:41:08,307 IN THIS AREA, IN NATURAL 992 00:41:08,307 --> 00:41:10,843 PRODUCTS, SO WE DON'T KNOW... WE 993 00:41:10,843 --> 00:41:12,912 DON'T HAVE A STRUCTURAL PICTURE 994 00:41:12,912 --> 00:41:16,349 OF ANY BIOSYNTHETIC GENE CLUSTER 995 00:41:16,349 --> 00:41:19,285 WORKING THROUGH THE ENTIRE PATH 996 00:41:19,285 --> 00:41:21,187 WAY, AND THAT'S WHAT WE'RE 997 00:41:21,187 --> 00:41:21,721 WORKING ON NOW. 998 00:41:21,721 --> 00:41:25,825 SO JENNY WAS ABLE TO SOLVE THE 999 00:41:25,825 --> 00:41:33,166 CRYSTAL STRUCTURE OF THE SECOND 1000 00:41:33,166 --> 00:41:40,106 ATBGRASLIGSE THAT INSTALLS THAT 1001 00:41:40,106 --> 00:41:40,673 MACRO LACTAM AND MAKES WHAT 1002 00:41:40,673 --> 00:41:44,710 WE'LL CALL THE MATURE , OF IN 1003 00:41:44,710 --> 00:41:49,215 THE CORE, AND JUST RECENTLY, 1004 00:41:49,215 --> 00:41:49,849 WE'RE LOOKING FOR THE PROTEASE 1005 00:41:49,849 --> 00:41:54,687 TO ACTUALLY MAKE THE PREASSUMED 1006 00:41:54,687 --> 00:42:00,393 PROTEAES THAT SHOW CLEAVE, 1007 00:42:00,393 --> 00:42:01,027 CONSERVED GG MOTIF. AND THAT'S 1008 00:42:01,027 --> 00:42:04,096 VERY COMMON IN A CROSS BIOLOGY. 1009 00:42:04,096 --> 00:42:04,597 IT'S NOT JUST IN THESE 1010 00:42:04,597 --> 00:42:05,865 BIOSYNTHETIC GENE CLUSTERS, BUT 1011 00:42:05,865 --> 00:42:06,466 THERE IS NO PROTEASE IN THIS 1012 00:42:06,466 --> 00:42:08,134 GENE CLUSTER. SO WE'VE BEEN VERY 1013 00:42:08,134 --> 00:42:08,768 INTERESTED IN TRYING TO FIGURE 1014 00:42:08,768 --> 00:42:09,402 OUT HOW THIS THIS FINAL PRODUCT 1015 00:42:09,402 --> 00:42:11,737 MIGHT BE CLEAVED, EXPORTED FROM 1016 00:42:11,737 --> 00:42:12,305 THE CELL TO GIVE THE MATURE 1017 00:42:12,305 --> 00:42:16,075 PRODUCT AND THAT'S JUST WORK ON 1018 00:42:16,075 --> 00:42:17,743 GOING, IN THE MEANTIME, JENNY 1019 00:42:17,743 --> 00:42:20,746 SOLVED THE STRUCTURE OF THIS 1020 00:42:20,746 --> 00:42:24,484 ALPHA BETA HYDROLASE WHICH IS 1021 00:42:24,484 --> 00:42:26,719 HIGHLY UNUSUAL. THOSE NEVER 1022 00:42:26,719 --> 00:42:27,353 OCCUR IN THE CYANOBACTER‘IAL 1023 00:42:27,353 --> 00:42:30,523 BIOSYNTHETIC GENE CLUSTERS ONLY 1024 00:42:30,523 --> 00:42:31,123 IN THESE CARCIO BACTERIA. AND 1025 00:42:31,123 --> 00:42:33,292 WHAT SHE FOUND IS RATHER THAN 1026 00:42:33,292 --> 00:42:36,395 CLEAVING THIS GGMOTIF IT'S 1027 00:42:36,395 --> 00:42:39,599 ACTUALLY CLEAVING THIS CONSERVED 1028 00:42:39,599 --> 00:42:41,567 LEADER, AND VERY INTERESTING 1029 00:42:41,567 --> 00:42:44,337 BECAUSE THAT THAT LEADER IS 1030 00:42:44,337 --> 00:42:53,579 CENTRAL TO ACTIVATE THE 1031 00:42:53,579 --> 00:42:54,180 ATPGRASPLIGASE SO IT THERE'S 1032 00:42:54,180 --> 00:42:56,182 SOME REGULATION GOING ON, WITH 1033 00:42:56,182 --> 00:42:56,649 THIS ACTIVITY IN THIS 1034 00:42:56,649 --> 00:42:57,283 BIOSYNTHETIC GENE CLUSTER. AND 1035 00:42:57,283 --> 00:42:59,552 THAT'S, THAT WORK THAT'S GOING 1036 00:42:59,552 --> 00:43:00,686 ON IN THE LAB. 1037 00:43:00,686 --> 00:43:04,690 SO COMING BACK TO JOHN DALY'S 1038 00:43:04,690 --> 00:43:06,692 CAREER AND INTEREST, I THINK 1039 00:43:06,692 --> 00:43:07,860 PEOPLE PROBABLY KNOW, AT LEAST 1040 00:43:07,860 --> 00:43:09,662 THE OLDER PEOPLE KNOW, THAT JOHN 1041 00:43:09,662 --> 00:43:12,031 WAS A GREAT EXPLORER. 1042 00:43:12,031 --> 00:43:14,133 I ALREADY TOLD YOU HE STARTED 1043 00:43:14,133 --> 00:43:16,802 HIS FORAY IN NATURAL PRODUCTS, 1044 00:43:16,802 --> 00:43:18,237 GOING TO THE JUNGLES AND 1045 00:43:18,237 --> 00:43:23,175 COLLECTING THESE DENDROBATED 1046 00:43:23,175 --> 00:43:25,845 FROGS. AND HE KEPT THE FI‘OGS. 1047 00:43:25,845 --> 00:43:26,479 HE BROUGHT THEM BACK TO THE LAB, 1048 00:43:26,479 --> 00:43:28,881 NIH AND BUILDING EIGHT. HIS 1049 00:43:28,881 --> 00:43:31,484 OFFICE HAD A CHEMICAL FUME HOOD 1050 00:43:31,484 --> 00:43:32,051 IN IT. 1051 00:43:32,051 --> 00:43:33,886 WASN'T REALLY EVEN AN OFFICE, 1052 00:43:33,886 --> 00:43:38,324 AND HAD THIS TERRARIA IN HIS 1053 00:43:38,324 --> 00:43:39,825 OFFICE WHERE HE KEPT THE FROGS, 1054 00:43:39,825 --> 00:43:42,361 AND FIND OVER THE YEARS, THE 1055 00:43:42,361 --> 00:43:46,632 FROGS WOULD LOSE THEIR POISONS 1056 00:43:46,632 --> 00:43:53,306 IN THE SKIN, SO ALWAYS SUSPECTED 1057 00:43:53,306 --> 00:43:57,076 THAT AT LEAST FOR SOME FROGS, 1058 00:43:57,076 --> 00:43:57,643 CLEARLY ARE ABLE TO DE NOVO 1059 00:43:57,643 --> 00:43:58,277 SYNTHESIZE THESE ALKALOIDS. BUT 1060 00:43:58,277 --> 00:43:59,278 OTHERS ARE PROBABLY GETTING 1061 00:43:59,278 --> 00:43:59,812 THEM FROM THEIR DIET. AND 1062 00:43:59,812 --> 00:44:03,015 THERE'S EXAMPLES OF THAT THROUGH 1063 00:44:03,015 --> 00:44:05,551 OUT BIOLOGY AND ECOLOGY. 1064 00:44:05,551 --> 00:44:08,120 IN THE LATER YEARS OF HIS 1065 00:44:08,120 --> 00:44:11,357 CAREER, HE WAS VERY FIXATED ON 1066 00:44:11,357 --> 00:44:13,893 WHAT COULD BE THE SOURCES OF 1067 00:44:13,893 --> 00:44:16,062 THESE TOXINS, AND HE ACTUALLY 1068 00:44:16,062 --> 00:44:18,864 WAS GOING BACK TO THE RAINFOREST 1069 00:44:18,864 --> 00:44:21,867 WHERE HE WOULD FIND THE HIGHEST 1070 00:44:21,867 --> 00:44:29,575 NUMBER OF FROGS, AND WOULD CRAWL 1071 00:44:29,575 --> 00:44:30,543 ON THE GROUND, AND BRINGS TARPS 1072 00:44:30,543 --> 00:44:34,947 AND VIALS AND WOULD LITERALLY 1073 00:44:34,947 --> 00:44:40,186 COLLECT EVERY SINGLE ANT OR 1074 00:44:40,186 --> 00:44:41,320 ARTHROPOD, AND WHATEVER INSECT 1075 00:44:41,320 --> 00:44:42,888 HE COULD FIND, AND BRING BACK TO 1076 00:44:42,888 --> 00:44:49,328 THE LAB AT THAT TIME, THE 1077 00:44:49,328 --> 00:44:50,763 MASSSPECTROMETERS WERE NOT SO 1078 00:44:50,763 --> 00:44:51,797 SENSITIVE, YOU COULD RUN A 1079 00:44:51,797 --> 00:44:56,135 SAMPLE ON THAT SMALL OF A RUN OF 1080 00:44:56,135 --> 00:44:58,270 MASSSPEC ON THAT SMALL OF 1081 00:44:58,270 --> 00:44:59,872 SAMPLE, SO HE WAS DOING WHAT 1082 00:44:59,872 --> 00:45:04,377 CALL, COMBINATORIAL 1083 00:45:04,377 --> 00:45:04,910 BIOPROSPECTING. SO HE WAS 1084 00:45:04,910 --> 00:45:05,511 ACTUALLY COMBINING DOZENS OR 1085 00:45:05,511 --> 00:45:08,447 HUNDREDS OF LITTLE INSECTS AND 1086 00:45:08,447 --> 00:45:09,882 RUNNING MASS SPEC ON THEM, AND 1087 00:45:09,882 --> 00:45:14,820 LOOKING FOR ALKALOIDS, HE SUE 1088 00:45:14,820 --> 00:45:18,457 EXPECTED MIGHT BE PRESENT BASED 1089 00:45:18,457 --> 00:45:20,459 ON WHAT FROGS LIVE THERE. 1090 00:45:20,459 --> 00:45:22,862 AND WHAT ALKALOIDS HE ALREADY 1091 00:45:22,862 --> 00:45:24,563 DISCOVERED FROM THOSE FROGS. 1092 00:45:24,563 --> 00:45:26,232 KIND OF REMARKABLE TO THINK 1093 00:45:26,232 --> 00:45:27,566 BACK, THAT HE WAS THINKING ALONG 1094 00:45:27,566 --> 00:45:29,735 THOSE LINES, BECAUSE TODAY, THE 1095 00:45:29,735 --> 00:45:33,205 MASS SPECTROMETRS WOULD BE 1096 00:45:33,205 --> 00:45:34,940 SENSITIVE ENOUGH, PROBABLY TO 1097 00:45:34,940 --> 00:45:38,310 TELL THE ALKALOID IN A SINGLE 1098 00:45:38,310 --> 00:45:39,311 INSECT. 1099 00:45:39,311 --> 00:45:41,547 AND WHAT MANY NATURAL PRODUCTS 1100 00:45:41,547 --> 00:45:45,017 PEOPLE DO TODAY, IS NONE OF THIS 1101 00:45:45,017 --> 00:45:49,221 ECOLOGY OR COLLECTING ETC, 1102 00:45:49,221 --> 00:45:50,189 CULTURALING TAKES PLACE, IT'S 1103 00:45:50,189 --> 00:45:54,860 ALL DONE ON THE COMPUTER THROUGH 1104 00:45:54,860 --> 00:45:57,029 BIOINFORMATICS AND GENOME 1105 00:45:57,029 --> 00:45:58,531 MINING, SO KIND OF LOSING THAT 1106 00:45:58,531 --> 00:46:02,268 CONNECTION WITH NATURE. 1107 00:46:02,268 --> 00:46:03,769 SO TODAY IF SOMEONE WERE 1108 00:46:03,769 --> 00:46:06,772 TACKLING THIS PROBLEM, I SUSPECT 1109 00:46:06,772 --> 00:46:09,275 THEY TAKE ALL THE ORGANISM AND 1110 00:46:09,275 --> 00:46:15,581 IS DO GENOME SEQUENCING, AND 1111 00:46:15,581 --> 00:46:17,550 SHOTGUN SEQUENCES ON THEM SXO 1112 00:46:17,550 --> 00:46:20,319 HOPE THEY COULD MAYBE FIND SOME 1113 00:46:20,319 --> 00:46:20,920 KIND OF CHEMICAL CUES IN THE 1114 00:46:20,920 --> 00:46:26,392 ENZYMES THAT ARE ENCODED IN THE 1115 00:46:26,392 --> 00:46:27,259 GENOMES, I WILL SAY PLANTS AND 1116 00:46:27,259 --> 00:46:36,001 INSECTS ARE THE NO EASY, THEY 1117 00:46:36,001 --> 00:46:38,337 DON'T GIVE THE WHAT BACTERIA 1118 00:46:38,337 --> 00:46:38,971 DO. BUT IT'S REALLY FUN TO THINK 1119 00:46:38,971 --> 00:46:41,373 BACK ON HOW WHAT JOHN WOULD BE 1120 00:46:41,373 --> 00:46:42,007 DOING TODAY, IF YOU WERE STILL 1121 00:46:42,007 --> 00:46:42,641 DOING RESEARCH. SO WITH THAT, I 1122 00:46:42,641 --> 00:46:45,478 JUST WANT TO THANK THIS IS NOT 1123 00:46:45,478 --> 00:46:47,546 ALL THE COMPREHENSIVE SLIDE, OF 1124 00:46:47,546 --> 00:46:50,449 CURRENT, BUT MENTIONED PEOPLE 1125 00:46:50,449 --> 00:46:51,050 OR HOW THEIR NAMES ON SLIDES 1126 00:46:51,050 --> 00:46:52,251 ALONG THE WAY AND I'VE HAD A 1127 00:46:52,251 --> 00:46:52,818 GREAT GROUP OF STUDENTS AND 1128 00:46:52,818 --> 00:46:57,556 POST-DOCS ALL THROUGH MY CAREER 1129 00:46:57,556 --> 00:46:58,190 HERE, AND UNDERGRADS AND THEN 1130 00:46:58,190 --> 00:46:58,824 THANKS SOME OF MY COLLABORATORS 1131 00:46:58,824 --> 00:47:03,062 THAT AYE MENTIONED AND DURING 1132 00:47:03,062 --> 00:47:05,598 THE TALK AND LONG TIME SUPPORT, 1133 00:47:05,598 --> 00:47:08,167 AND LBC, AND BENEFICIARIES 1134 00:47:08,167 --> 00:47:10,736 ACROSS NIH, FUNDING PERMITS 1135 00:47:10,736 --> 00:47:11,370 THAT WHERE PARK SERVICES LET US 1136 00:47:11,370 --> 00:47:13,172 GO ON DO THIS WORK IN THEIR 1137 00:47:13,172 --> 00:47:15,141 WATERS, AND THEIR LANDS AND 1138 00:47:15,141 --> 00:47:17,009 FUNDING OF COURSE, AND I OF 1139 00:47:17,009 --> 00:47:19,712 COURSE HAVE TO THANK NIDDK FOR 1140 00:47:19,712 --> 00:47:20,346 SUPPORTING NATURAL PRODUCT AND 1141 00:47:20,346 --> 00:47:22,114 IS CHEMISTRY IN A VERY BIG WAY 1142 00:47:22,114 --> 00:47:26,786 FOR ALL THESE DECADES AND ALL OF 1143 00:47:26,786 --> 00:47:27,586 YOU FOR YOUR ATTENTION. 1144 00:47:27,586 --> 00:47:32,591 [APPLAUSE] 1145 00:47:32,591 --> 00:47:34,326 >> ALL RIGHT, ANY QUESTIONS 1146 00:47:34,326 --> 00:47:40,633 FROM THE AUDIENCE FOR CAROLE? 1147 00:47:40,633 --> 00:47:42,568 I'LL START OUT WITH ONE. 1148 00:47:42,568 --> 00:47:45,704 THE SOURCES YOU ISOLATE THESE 1149 00:47:45,704 --> 00:47:48,073 NATURAL PRODUCTS FROM ARE SO 1150 00:47:48,073 --> 00:47:48,274 COOL. 1151 00:47:48,274 --> 00:47:50,709 AND WHEN I LOOK AT VIDEO YOU 1152 00:47:50,709 --> 00:47:52,878 SHOW IN THE PICTURES IT JUST 1153 00:47:52,878 --> 00:47:55,147 SEEMS SO OVERWHELMING TO ME, DO 1154 00:47:55,147 --> 00:47:56,549 YOU HAVE A SENSE OF WHETHER, 1155 00:47:56,549 --> 00:47:59,585 LIKE, IS THERE A WAY TO 1156 00:47:59,585 --> 00:48:02,454 PRIORITIZE WHERE YOU THINK 1157 00:48:02,454 --> 00:48:03,322 UNEXPECTED NATURAL PRODUCTS 1158 00:48:03,322 --> 00:48:04,490 MIGHT COME FROM. 1159 00:48:04,490 --> 00:48:05,591 YOU MENTIONED THINGS THAT 1160 00:48:05,591 --> 00:48:06,091 SHOULDN'T BE THERE. 1161 00:48:06,091 --> 00:48:09,094 DO YOU HAVE THOUGHTS ON THAT? 1162 00:48:09,094 --> 00:48:12,164 >> M-HM, I HAVE A LOT OF 1163 00:48:12,164 --> 00:48:12,431 THOUGHTS. 1164 00:48:12,431 --> 00:48:13,265 [LAUGHTER] >> THAT'S SORT OF 1165 00:48:13,265 --> 00:48:17,002 HOW WE STARTED WHEN I STARTED MY 1166 00:48:17,002 --> 00:48:17,336 LAB. 1167 00:48:17,336 --> 00:48:21,607 SO WE PRETTY MUCH FOCUSED ON 2 1168 00:48:21,607 --> 00:48:23,142 THINGS, ONE COLLECT ORGANISMS -- 1169 00:48:23,142 --> 00:48:26,846 IN THE CASE OF THE ALGAE, I 1170 00:48:26,846 --> 00:48:31,283 NEVER SEEN ANY ALGAE THAT LOOKED 1171 00:48:31,283 --> 00:48:32,484 LIKE THAT YEARS AND YEARS OF 1172 00:48:32,484 --> 00:48:36,021 DIVING, AND SPONGES WE CAN LOOK 1173 00:48:36,021 --> 00:48:36,655 FOR THINGS WITH SMOOTH SURFACES 1174 00:48:36,655 --> 00:48:38,657 THAT ARE LOOKED AT LIKE THEY'RE 1175 00:48:38,657 --> 00:48:39,291 CHEMICALLY DEFENDED. SO WHY IS 1176 00:48:39,291 --> 00:48:43,896 THIS SPONGE RIGHT NEXT TO IT 1177 00:48:43,896 --> 00:48:47,600 COMPLETELY BIOFELT AND IT'S NOT 1178 00:48:47,600 --> 00:48:52,638 I WILL SAY THAT BECAUSE I HAD 1179 00:48:52,638 --> 00:48:53,272 DONE SO MUCH WORK WITH SYMBIOSIS 1180 00:48:53,272 --> 00:48:53,906 AND I KNEW WHAT SPECIES ARE EVEN 1181 00:48:53,906 --> 00:48:54,907 AT THE LEVEL OF ORDER OF SPONGES 1182 00:48:54,907 --> 00:48:57,476 CONTAINED HUGE POPULATIONS OF 1183 00:48:57,476 --> 00:48:58,110 BACTERIAL SYMBIOTES. THAT'S WHAT 1184 00:48:58,110 --> 00:49:00,946 WE STAR GETTED EARLY ON IN ANY 1185 00:49:00,946 --> 00:49:01,146 LAB. 1186 00:49:01,146 --> 00:49:02,281 >> VERY COOL. 1187 00:49:02,281 --> 00:49:04,650 >> CONGRATULATIONS, CAROLE, SO 1188 00:49:04,650 --> 00:49:06,652 WELL DESERVED, AND I KNOW THAT 1189 00:49:06,652 --> 00:49:08,554 JOHN WOULD HAVE BEEN GLOWING TO 1190 00:49:08,554 --> 00:49:10,856 WATCH YOUR LECTURE. 1191 00:49:10,856 --> 00:49:13,626 I'M WONDERING ABOUT THE 1192 00:49:13,626 --> 00:49:14,693 TRANSLATIONAL ROLE OF NATURAL 1193 00:49:14,693 --> 00:49:15,027 PRODUCTS. 1194 00:49:15,027 --> 00:49:17,897 SO FOR A WHILE, THE 1195 00:49:17,897 --> 00:49:20,900 PHARMACEUTICAL INDUSTRY WAS VERY 1196 00:49:20,900 --> 00:49:22,134 EXCITED ABOUT NATURAL PRODUCT 1197 00:49:22,134 --> 00:49:23,903 AND THEN WANED. 1198 00:49:23,903 --> 00:49:25,437 IS IT COMING BACK, AND DO YOU 1199 00:49:25,437 --> 00:49:27,239 HAVE ANY THOUGHT ABOUT HOW TO 1200 00:49:27,239 --> 00:49:28,707 ENHANCE THE ROLE OF NATURAL 1201 00:49:28,707 --> 00:49:30,976 PRODUCTS IN DRUG DISCOVERY? 1202 00:49:30,976 --> 00:49:33,512 >> YEAH, WHAT KEN IS REFERRING 1203 00:49:33,512 --> 00:49:35,547 TO, ALL OF THE DRUGS THAT ARE 1204 00:49:35,547 --> 00:49:37,349 ACTUALLY, WELL, MOST, THAT CAME 1205 00:49:37,349 --> 00:49:39,118 FROM NATURAL PRODUCTS, MOST OF 1206 00:49:39,118 --> 00:49:41,387 THEM CAME FROM THE 1207 00:49:41,387 --> 00:49:45,157 PHARMACEUTICAL INDUSTRY, SO 1208 00:49:45,157 --> 00:49:47,293 PHARMA -- EVERY SINGLE LARGE 1209 00:49:47,293 --> 00:49:49,561 PHARMA COMPANY USED TO HAVE VERY 1210 00:49:49,561 --> 00:49:50,996 LARGE NATURAL PRODUCTS DIVISION, 1211 00:49:50,996 --> 00:49:54,433 AND HAVE COLLECTIONS AND 1212 00:49:54,433 --> 00:49:55,401 MICROBIAL COLLECTIONS, SOME OF 1213 00:49:55,401 --> 00:49:59,571 THE WORK WE DID EARLIER WOULD BE 1214 00:49:59,571 --> 00:50:02,708 THROUGH THESE COOPERATIV GRANTS 1215 00:50:02,708 --> 00:50:05,577 BETWEEN NIH AND EXTRAMURAL 1216 00:50:05,577 --> 00:50:07,446 RESEARCHERS AND PHARMA COMPANY 1217 00:50:07,446 --> 00:50:09,815 HAD TO BE INVOLVED TO DO THE 1218 00:50:09,815 --> 00:50:10,115 SCREENING. 1219 00:50:10,115 --> 00:50:12,384 THAT WAS THE OLD DAYS, AND THEN 1220 00:50:12,384 --> 00:50:15,788 IT BECOMES VERY EXPENSIVE. 1221 00:50:15,788 --> 00:50:18,657 AND THE OTHER PROBLEM IS YOU 1222 00:50:18,657 --> 00:50:20,893 START TO REISOLATE COMPOUND THAT 1223 00:50:20,893 --> 00:50:22,361 ARE ARE ALREADY KNOWN, AND OF 1224 00:50:22,361 --> 00:50:25,364 COURSE PHARMA DOESN'T WANT TO 1225 00:50:25,364 --> 00:50:25,864 DO. 1226 00:50:25,864 --> 00:50:28,167 WHAT'S HAPPENED IN THE LAST 1227 00:50:28,167 --> 00:50:31,070 DECADE MAYBE 7 OR 8 YEARS, 1228 00:50:31,070 --> 00:50:33,572 PHARMA HAS BEEN DONATING THEIR 1229 00:50:33,572 --> 00:50:36,742 COLLECTIONS TO ACADEMIC LABS OR 1230 00:50:36,742 --> 00:50:38,911 CENTERS, AND TRYING TO MAKE 1231 00:50:38,911 --> 00:50:40,512 THOSE AVAILABLE, SIMILAR TO HOW 1232 00:50:40,512 --> 00:50:45,351 THE NCI OPEN REPOSITORY DOES. 1233 00:50:45,351 --> 00:50:47,419 AND THERE'S REALLY BEEN A MOVE 1234 00:50:47,419 --> 00:50:52,491 TO I ALLUDED TO, TO DO SHOTGUN 1235 00:50:52,491 --> 00:50:56,095 SEQUENCING ON SAY 1236 00:50:56,095 --> 00:50:57,296 50,000MICROBIAL STRAINS AND TRY 1237 00:50:57,296 --> 00:50:59,665 TO ASSEMBLE THOSE AND LOOK FOR 1238 00:50:59,665 --> 00:51:02,901 NEW MOLECULES, SO THEY ARE OFTEN 1239 00:51:02,901 --> 00:51:06,338 REFERRED TO AS ORPHAN GENE 1240 00:51:06,338 --> 00:51:11,844 STRUCTURES OR CRYPITIC 1241 00:51:11,844 --> 00:51:12,678 COMPOUNDS, AND IDENTIFY THOSE, 1242 00:51:12,678 --> 00:51:13,879 AND USE SYNTHETIC BIOLOGY TO 1243 00:51:13,879 --> 00:51:15,714 MAKE THEM IN THE LAB. 1244 00:51:15,714 --> 00:51:18,150 ONE THING I DID NOT MENTION IN 1245 00:51:18,150 --> 00:51:20,019 MY TALK IS THAT THE REASON THAT 1246 00:51:20,019 --> 00:51:25,491 WE CAN DO THAT... SIMILAR TO THE 1247 00:51:25,491 --> 00:51:29,595 GRASPATIDES IF WE WANTED TO LOOK 1248 00:51:29,595 --> 00:51:35,401 FOR MORE MORE GRASPATIDES IN 1249 00:51:35,401 --> 00:51:36,035 FACT THAT'S WHAT WE DID WITH THE 1250 00:51:36,035 --> 00:51:37,569 KRRNIN LAB IS YOU CAN DO A 1251 00:51:37,569 --> 00:51:38,170 BIOINFORMATIC SEARCH ON THAT 1252 00:51:38,170 --> 00:51:43,475 PRECURSOR PEPTIDE AND AN ATP, 1253 00:51:43,475 --> 00:51:47,713 GLASPITIDE, THE COULD OCCURRENCE 1254 00:51:47,713 --> 00:51:49,882 OF THOSE TWO THINGS, IF GENOME 1255 00:51:49,882 --> 00:51:50,449 AND IF YOU GET A HIT WITH A 1256 00:51:50,449 --> 00:51:53,118 BIOSYNTHETIC GENE CLUSTER YOU 1257 00:51:53,118 --> 00:51:54,953 CAN GO AFTER THAT EXACTLY WHAT 1258 00:51:54,953 --> 00:51:57,923 WE'VE BEEN DOING FOR THAT 1259 00:51:57,923 --> 00:51:58,590 FAMILY, SO LIKEWISE YOU CAN DO 1260 00:51:58,590 --> 00:52:01,994 IT FOR OTHER CLASSES AS WELL AND 1261 00:52:01,994 --> 00:52:03,862 THAT'S THE FORMS THAT TECHNOLOGY 1262 00:52:03,862 --> 00:52:07,866 THAT MANY STARTUPS ARE USING, SO 1263 00:52:07,866 --> 00:52:08,500 WOULD SAY IT'S GOING FROM PHARMA 1264 00:52:08,500 --> 00:52:10,035 TO STARTUPS NOW. YEAH. AND 1265 00:52:10,035 --> 00:52:10,602 THERE ARE SOME THAT ARE ARE 1266 00:52:10,602 --> 00:52:11,570 HAVING GREAT SUCCESS WITH THAT. 1267 00:52:11,570 --> 00:52:12,738 YEAH. SO JACK DAVISON THE 1268 00:52:12,738 --> 00:52:13,338 FORMER POSTDOC IN MY LAB GOT 1269 00:52:13,338 --> 00:52:21,580 SWALLOWED UP IN A HEARTBEAT ONCE 1270 00:52:21,580 --> 00:52:24,783 LIFEMINE PHARMACEUTICALS STARTED 1271 00:52:24,783 --> 00:52:26,318 UP, AND THEY WERE GOING TO WORK 1272 00:52:26,318 --> 00:52:31,723 ON FUNGIA AND ALGAE AND JACK HAD 1273 00:52:31,723 --> 00:52:34,460 THAT EXPERIENCE AND HE WAS GONE. 1274 00:52:34,460 --> 00:52:36,128 >> HI, CAROLE, THAT WAS 1275 00:52:36,128 --> 00:52:38,730 BEAUTIFUL, I HAD A QUESTION 1276 00:52:38,730 --> 00:52:42,534 ABOUT THE STRUCTURE ELUCIDATION 1277 00:52:42,534 --> 00:52:45,304 OF NATURAL PRODUCTS AND PLEASE 1278 00:52:45,304 --> 00:52:46,305 EDUCATE ME THERE. 1279 00:52:46,305 --> 00:52:49,208 UNLESS PUREFIED TO CERTAIN 1280 00:52:49,208 --> 00:52:49,842 EXTENT STRUCTURAL ELUCIDATION BY 1281 00:52:49,842 --> 00:52:52,010 NMR OR SOME SORT OF THINGS LIKE 1282 00:52:52,010 --> 00:52:54,680 THAT NOT SO STRAIGHTFORWARD, DO 1283 00:52:54,680 --> 00:53:01,987 YOU THINK ANALYTIC CHEMICAL 1284 00:53:01,987 --> 00:53:02,588 WOULD GET TO A STAGE WHERE WE 1285 00:53:02,588 --> 00:53:04,556 WOULD BE ABLE TO LECDATE 1286 00:53:04,556 --> 00:53:05,190 STRUCTURES OF NATURAL PRODUCTS 1287 00:53:05,190 --> 00:53:09,895 IN MORE COMPLEX MIXTURE WITHOUT 1288 00:53:09,895 --> 00:53:11,396 NECESSARILY HAVING TO THEM TO 1289 00:53:11,396 --> 00:53:11,997 ALMOST HOMOGENEITY. I'M JUST 1290 00:53:11,997 --> 00:53:13,866 CURIOUS TO KNOW YOUR THOUGHT ON 1291 00:53:13,866 --> 00:53:14,433 THAT 1292 00:53:14,433 --> 00:53:16,335 >> SO ONE THING I DID MENTION, 1293 00:53:16,335 --> 00:53:19,938 I WANTED TO MENTION TOO, THE 1294 00:53:19,938 --> 00:53:20,572 POSTDOCS SPENT HUNDREDS OF HOURS 1295 00:53:20,572 --> 00:53:24,710 SLOWLY SITTING IN THE MORE 1296 00:53:24,710 --> 00:53:25,611 COMPLEX POUND, AND NEVER GOES ON 1297 00:53:25,611 --> 00:53:25,911 TO A SLIDE. 1298 00:53:25,911 --> 00:53:29,214 THERE IS START TO GO BE ENOUGH 1299 00:53:29,214 --> 00:53:32,217 NMR LIBRARIES OUT THERE, SMALL 1300 00:53:32,217 --> 00:53:33,552 MOLECULE ONES, THAT YOU CAN 1301 00:53:33,552 --> 00:53:37,489 START TO DO SOME MATCHING, 1302 00:53:37,489 --> 00:53:40,259 >> SO ARE THERE AI-BASED 1303 00:53:40,259 --> 00:53:41,026 METHODS BEING DEVELOPED. 1304 00:53:41,026 --> 00:53:42,394 >> YEAH, PEOPLE ARE TRYING TO 1305 00:53:42,394 --> 00:53:42,895 DO THAT. 1306 00:53:42,895 --> 00:53:43,829 >> I SEE, FASCINATING. 1307 00:53:43,829 --> 00:53:52,738 THANK YOU. 1308 00:53:52,738 --> 00:53:54,373 >> I WAS GOING TO ASK, THIS 1309 00:53:54,373 --> 00:53:59,611 QUESTION, RELATED, BUT, THEN 1310 00:53:59,611 --> 00:54:02,080 ASKED. 1311 00:54:02,080 --> 00:54:04,283 THE COMPLEX FORMATION OF WHAT 1312 00:54:04,283 --> 00:54:07,219 YOU SAW A AND B UNITS COMBINING, 1313 00:54:07,219 --> 00:54:08,921 USUALLY, IT IS YOU MUST CHANGE 1314 00:54:08,921 --> 00:54:14,393 THE CONFIRMATION OF AN A UNIT OR 1315 00:54:14,393 --> 00:54:16,328 B UNIT SO THEY CAN INTERACT WITH 1316 00:54:16,328 --> 00:54:19,031 SMALL MOLECULES. 1317 00:54:19,031 --> 00:54:21,867 AND I THINK YOU NOTICE THERE 1318 00:54:21,867 --> 00:54:26,438 WAS ATP BINDING, AND THAT IS 1319 00:54:26,438 --> 00:54:29,875 IMPORTANT TO KNOW, IF IT WAS THE 1320 00:54:29,875 --> 00:54:32,411 CONFIRMATION CHANGE. 1321 00:54:32,411 --> 00:54:35,147 AND THE TWO WERE BINDING 1322 00:54:35,147 --> 00:54:35,781 TOGETHER, IS THERE INFORMATION 1323 00:54:35,781 --> 00:54:36,848 ABOUT THAT? 1324 00:54:36,848 --> 00:54:39,251 >> I THINK WHAT YOU ARE ASKING 1325 00:54:39,251 --> 00:54:41,520 IS WHETHER WE SEE PART OF... IF 1326 00:54:41,520 --> 00:54:45,691 THE ADP BINDING OR ATP BINDING 1327 00:54:45,691 --> 00:54:48,827 IS WHAT IS INDUCING THE LARGE 1328 00:54:48,827 --> 00:54:50,128 CONFIRMATION CHANGE. 1329 00:54:50,128 --> 00:54:51,997 >> YES. 1330 00:54:51,997 --> 00:54:54,666 >> SO THAT'S TRUE, SMELL, BUT 1331 00:54:54,666 --> 00:54:59,004 DEPENDS ON THE ATPLIGASE. 1332 00:54:59,004 --> 00:55:02,674 SOME YOU GET QUITE A DRAMATIC 1333 00:55:02,674 --> 00:55:06,044 CHANGE, SIMPLY BY COMBINING ATP, 1334 00:55:06,044 --> 00:55:06,478 AND IN FACT IN THE 1335 00:55:06,478 --> 00:55:07,079 CYANOBACTERIAL ENZYME THERE'S 1336 00:55:07,079 --> 00:55:09,648 ONE CRYSTAL STRUCTURE OF THE 1337 00:55:09,648 --> 00:55:10,282 ASSIGN A BACTERIAL ENZYME BUT IT 1338 00:55:10,282 --> 00:55:14,286 DOESN'T HAVE A T P I THINK THEY 1339 00:55:14,286 --> 00:55:15,787 SIMPLY... THEY DON'T UNDERGO 1340 00:55:15,787 --> 00:55:18,257 HUGE CONFIRMATIONAL CHANGE JUST 1341 00:55:18,257 --> 00:55:20,926 BINDING ATP, AND EVEN BINDING 1342 00:55:20,926 --> 00:55:22,928 THE LEADER THEY STILL HAVE 1343 00:55:22,928 --> 00:55:29,468 THAT... WHATEVER PALM OF THE 1344 00:55:29,468 --> 00:55:29,868 LIGASE THERE. 1345 00:55:29,868 --> 00:55:32,704 IT'S NOT UNTIL THE CORE, WHERE 1346 00:55:32,704 --> 00:55:36,475 THE CHEMISTRY TAKE PLACE, DOES 1347 00:55:36,475 --> 00:55:37,075 THE ENZYME CLOSE. 1348 00:55:37,075 --> 00:55:39,211 SO I THINK QUITE UNUSUAL, FOR 1349 00:55:39,211 --> 00:55:43,181 THIS FAMILY OF ENZYMES, AT LEAST 1350 00:55:43,181 --> 00:55:43,815 WHAT OUR CRYSTAL STRUCTURES TELL 1351 00:55:43,815 --> 00:55:45,550 US. 1352 00:55:45,550 --> 00:55:46,151 >> LIKE THE SYNTHESIS IS A 1353 00:55:46,151 --> 00:55:46,652 VERY BASIC EXAMPLE OF A 1354 00:55:46,652 --> 00:55:49,521 CONFIRMATION CHANGE INDUCED BY 1355 00:55:49,521 --> 00:55:50,055 SUBSTRATE SO THAT THEY'RE 1356 00:55:50,055 --> 00:55:51,657 BINDING OF AN OTHER . 1357 00:55:51,657 --> 00:55:53,625 >> CAROLE, GREAT TALK, THE 1358 00:55:53,625 --> 00:55:56,461 SECOND STORY WHEN YOU WENT BACK 1359 00:55:56,461 --> 00:55:57,329 AND REISOLATED AND COULDN'T FIND 1360 00:55:57,329 --> 00:55:58,430 THE PRODUCT. 1361 00:55:58,430 --> 00:56:00,499 DO YOU HAVE A SENSE IF THAT'S... 1362 00:56:00,499 --> 00:56:03,135 WERE MISSING THE BACTERIA THAT 1363 00:56:03,135 --> 00:56:08,940 HAD THE CYCLIZATION OR MULTIPLE 1364 00:56:08,940 --> 00:56:14,646 BACTERIA ARE REQUIRED TO MAKE 1365 00:56:14,646 --> 00:56:17,449 THE STRUCTURE, OR IS THAT 1366 00:56:17,449 --> 00:56:18,116 ANSWERABLE QUESTION, 1367 00:56:18,116 --> 00:56:21,353 >> IN THE ALGAE, SO I THINK 1368 00:56:21,353 --> 00:56:22,954 JACK AND I WOULD AGREE, WE THINK 1369 00:56:22,954 --> 00:56:25,157 THE ALGAE IS MAKING IT. 1370 00:56:25,157 --> 00:56:28,193 WE DON'T THINK THE BACTERIA 1371 00:56:28,193 --> 00:56:28,727 MAKING IT. 1372 00:56:28,727 --> 00:56:31,396 >> WELL IT COULD BE BACTERIAL 1373 00:56:31,396 --> 00:56:31,963 SYRNBIOTE THAT'S PROVIDING 1374 00:56:31,963 --> 00:56:32,898 SOMETHING YEAH WE JUST DON'T 1375 00:56:32,898 --> 00:56:35,701 KNOW ENOUGH ABOUT IT. 1376 00:56:35,701 --> 00:56:36,702 >> ALL RIGHT. 1377 00:56:36,702 --> 00:56:38,904 IF THERE ARE NO MORE QUESTIONS, 1378 00:56:38,904 --> 00:56:40,605 JOIN ME IN THANKING CAROLE ONCE 1379 00:56:40,605 --> 00:56:43,742 AGAIN FOR A FANTASTIC DAILY 1380 00:56:43,742 --> 00:56:45,877 LECTURE. 1381 00:56:45,877 --> 00:56:48,146 [APPLAUSE] 1382 00:56:48,146 --> 00:56:49,381 FANTASTIC DALY LECTURE. 1383 00:56:49,381 --> 00:56:50,749 WE'LL HAVE RECEPTION OUTSIDE IN 1384 00:56:50,749 --> 00:56:53,151 THE SEMINAR HALL, SO PLEASE JOIN 1385 00:56:53,151 --> 00:57:03,428 US, THANK YOU!