1 00:00:06,994 --> 00:00:09,497 >> IT'S MY GREAT PLEASURE TO 2 00:00:09,497 --> 00:00:11,365 INTRODUCE DR. POLLY MATZINGER 3 00:00:11,365 --> 00:00:14,635 FOR THE IIG SEMINAR, CHIEF THE T 4 00:00:14,635 --> 00:00:19,273 CELL TOLERANCE AND MEMORY 5 00:00:19,273 --> 00:00:22,910 SECTION. 6 00:00:22,910 --> 00:00:25,379 7 00:00:25,379 --> 00:00:26,614 8 00:00:26,614 --> 00:00:31,385 IT'S JUST FITTING FOR THE WHOLE 9 00:00:31,385 --> 00:00:31,552 DAY. 10 00:00:31,552 --> 00:00:33,354 WITHOUT FURTHER ADO -- NO, WHAT 11 00:00:33,354 --> 00:00:36,424 I WANT TO SAY, WE KNOW HER 12 00:00:36,424 --> 00:00:39,961 DEGREE, B.S. IN BIOLOGY FROM 13 00:00:39,961 --> 00:00:41,562 UC-IRVINE, THREE YEARS LATER 14 00:00:41,562 --> 00:00:42,997 RECEIVED HER Ph.D., SO FOR 15 00:00:42,997 --> 00:00:46,200 SOME OF US THAT TOOK 30 YEARS, 16 00:00:46,200 --> 00:00:46,934 I'M IN AWE. 17 00:00:46,934 --> 00:00:50,004 SHE DID FOUR YEARS OF POSTDOC 18 00:00:50,004 --> 00:00:53,941 WORK AT CAMBRIDGE AND WAS A 19 00:00:53,941 --> 00:00:54,809 SCIENTIST AT THE BASEL INSTITUTE 20 00:00:54,809 --> 00:00:56,577 FOR SIX YEARS BEFORE COMING TO 21 00:00:56,577 --> 00:00:57,812 THE NIH. 22 00:00:57,812 --> 00:00:59,881 HER WORK ON T CELLS AND 23 00:00:59,881 --> 00:01:01,616 DENDRITIC CELLS IS FUNDAMENTAL 24 00:01:01,616 --> 00:01:05,553 TO UNDERSTANDING OF IMMUNOLOGY, 25 00:01:05,553 --> 00:01:10,892 SPECIFICALLY T CELLS LICENSE 26 00:01:10,892 --> 00:01:12,293 DENDRITIC CELLS AND TOLERIZEs 27 00:01:12,293 --> 00:01:14,061 FOR THE THYMUS, HAS OVER 100 28 00:01:14,061 --> 00:01:15,496 PUBLICATIONS, CHECKING BEFORE I 29 00:01:15,496 --> 00:01:19,200 CAME DOWN HERE HAS MORE THAN 30 00:01:19,200 --> 00:01:20,535 28,000 CITATIONS, AND COINED 31 00:01:20,535 --> 00:01:22,503 TERMS SUCH AS PROFESSIONAL 32 00:01:22,503 --> 00:01:25,973 ANTIGEN PRESENTING CELL, DANGER 33 00:01:25,973 --> 00:01:28,176 SIGNAL, DAMP, WON AWARDS 34 00:01:28,176 --> 00:01:30,244 INCLUDING AS A FILMMAKER FOR 35 00:01:30,244 --> 00:01:30,912 SPECIAL EXCELLENCE IN 36 00:01:30,912 --> 00:01:32,914 EDUCATIONAL FILMS FOR THE GERMAN 37 00:01:32,914 --> 00:01:35,550 TRANSLATION OF IMMUNITY, THE 38 00:01:35,550 --> 00:01:39,554 INSIDE STORY, AT THE 1986 FILM 39 00:01:39,554 --> 00:01:41,189 FESTIVAL, SHE WAS INDUCTED AS 40 00:01:41,189 --> 00:01:43,291 HONORARY LIFETIME MEMBER OF THE 41 00:01:43,291 --> 00:01:44,926 SCANDINAVIAN SOCIETY OF 42 00:01:44,926 --> 00:01:49,297 IMMUNOLOGY, IN 2002 DISCOVER 43 00:01:49,297 --> 00:01:50,631 MAGAZINE RECOGNIZED POLLY AS ONE 44 00:01:50,631 --> 00:01:52,466 OF THE 50 MOST IMPORTANT WOMEN 45 00:01:52,466 --> 00:01:55,970 IN SCIENCE AND RECEIVED AN 46 00:01:55,970 --> 00:01:56,871 HONORARY DOCTORATE, FOR THOSE 47 00:01:56,871 --> 00:01:59,240 WHO HAVEN'T HAD THE PLEASURE OF 48 00:01:59,240 --> 00:02:00,374 TALKING TO POLLY, WHAT I'LL TELL 49 00:02:00,374 --> 00:02:03,377 YOU IS IT'S NEVER A DULL MOMENT, 50 00:02:03,377 --> 00:02:04,378 SHE WILL CHALLENGE EVERY 51 00:02:04,378 --> 00:02:06,314 ASSUMPTION OUT OF YOUR MOUTH, 52 00:02:06,314 --> 00:02:08,282 AND MAKE YOU BACK THEM UP. 53 00:02:08,282 --> 00:02:12,954 SO, WITH THAT I'M SURE WE'RE IN 54 00:02:12,954 --> 00:02:14,822 STORE FOR A GREAT AND DIFFERENT 55 00:02:14,822 --> 00:02:17,358 TYPE OF TALK, AND I HOPE 56 00:02:17,358 --> 00:02:27,702 EVERYBODY ENJOYS IT. 57 00:02:27,969 --> 00:02:28,302 POLLY? 58 00:02:28,302 --> 00:02:28,803 [APPLAUSE] 59 00:02:28,803 --> 00:02:30,871 >> I GOT MY Ph.D. IN THREE 60 00:02:30,871 --> 00:02:33,608 YEARS BUT IT TOOK 11 TO GET A 61 00:02:33,608 --> 00:02:34,575 BACHELOR'S DEGREE. 62 00:02:34,575 --> 00:02:34,842 [LAUGHTER] 63 00:02:34,842 --> 00:02:37,712 SO, WHAT YOU MAKE -- YOU KNOW, 64 00:02:37,712 --> 00:02:43,517 THE BRITISH SAY STRAITS AND 65 00:02:43,517 --> 00:02:44,085 ROUNDABOUTS. 66 00:02:44,085 --> 00:02:47,655 THIS IS THE 30th YEAR, 30th 67 00:02:47,655 --> 00:02:49,690 ANNIVERSARY OF THE PUBLICATION 68 00:02:49,690 --> 00:02:52,193 OF THE DANGER MODEL. 69 00:02:52,193 --> 00:02:56,230 AND IT'S BEEN AN INTERESTING 30 70 00:02:56,230 --> 00:02:56,564 YEARS. 71 00:02:56,564 --> 00:02:58,866 WHAT HAS BEEN MOST INTERESTING 72 00:02:58,866 --> 00:03:04,338 TO ME IS HOW LONG IT IS TAKING 73 00:03:04,338 --> 00:03:06,307 FOR PEOPLE TO ACTUALLY APPLY THE 74 00:03:06,307 --> 00:03:06,807 MODEL. 75 00:03:06,807 --> 00:03:09,410 SO, PEOPLE TELL ME THEY TEACH 76 00:03:09,410 --> 00:03:10,011 DANGER. 77 00:03:10,011 --> 00:03:12,213 AND SO I ASK THEM, WHAT DO YOU 78 00:03:12,213 --> 00:03:13,447 TEACH? 79 00:03:13,447 --> 00:03:16,784 THEY SAY, WELL, YOU KNOW, IN THE 80 00:03:16,784 --> 00:03:18,552 CHAPTER ON ANTIGEN-PRESENTING 81 00:03:18,552 --> 00:03:19,754 CELLS AND ANTIGEN PROCESSING WE 82 00:03:19,754 --> 00:03:26,694 TALK ABOUT HOW YOU NEED TO 83 00:03:26,694 --> 00:03:31,499 ACTIVATE THEM, WITH PAMP AND 84 00:03:31,499 --> 00:03:32,266 DAMP, DAMAGE-ASSOCIATED 85 00:03:32,266 --> 00:03:33,234 MOLECULAR PATTERNS. 86 00:03:33,234 --> 00:03:36,737 I SAY, THAT'S GREAT, I'M GLAD 87 00:03:36,737 --> 00:03:37,271 SOMEBODY'S TEACHING THIS. 88 00:03:37,271 --> 00:03:40,041 WHAT DO YOU TEACH ABOUT WHY 89 00:03:40,041 --> 00:03:42,343 MOTHERS DON'T REJECT THEIR 90 00:03:42,343 --> 00:03:42,710 FETUSES? 91 00:03:42,710 --> 00:03:47,014 AND THEY SAY, WE KNOW PREGNANCY 92 00:03:47,014 --> 00:03:47,948 IS IMMUNOSUPPRESSIVE. 93 00:03:47,948 --> 00:03:52,320 I SAY, NO, NO, THAT'S NOT THE 94 00:03:52,320 --> 00:03:52,653 DANGER MODEL. 95 00:03:52,653 --> 00:03:54,855 WE'RE CUTTING OFF TOO SMALL A 96 00:03:54,855 --> 00:03:58,225 SLICE OF THE PIE, WHEN I WROTE 97 00:03:58,225 --> 00:03:59,927 THAT IS I MEAN PEOPLE ACCEPTED 98 00:03:59,927 --> 00:04:01,796 THE BASIC ASSUMPTION OF THE 99 00:04:01,796 --> 00:04:06,167 DANGER MODEL, WHICH IS THAT, A, 100 00:04:06,167 --> 00:04:08,035 YOU NEED TO ACTIVATE PRESENTING 101 00:04:08,035 --> 00:04:11,872 CELLS IN ORDER TO INITIATE AN 102 00:04:11,872 --> 00:04:13,107 IMMUNE RESPONSE, AND B, THAT ONE 103 00:04:13,107 --> 00:04:15,643 OF THE THINGS, OR MANY OF THE 104 00:04:15,643 --> 00:04:18,112 THINGS THAT ACTIVATE DENDRITIC 105 00:04:18,112 --> 00:04:19,980 CELLS ARE DANGER SIGNALS, 106 00:04:19,980 --> 00:04:20,348 ALARMIN 107 00:04:20,348 --> 00:04:22,483 WHATEVER YOU WANT TO CALL THEM, 108 00:04:22,483 --> 00:04:25,019 ALARM SIGNALS SENT BY INJURED OR 109 00:04:25,019 --> 00:04:28,656 STRESSED CELLS. 110 00:04:28,656 --> 00:04:30,358 YOU DON'T NEED A PATHOGEN. 111 00:04:30,358 --> 00:04:32,360 YOU NEED AN INJURED CELL. 112 00:04:32,360 --> 00:04:34,929 PEOPLE HAVE ACCEPTED THAT. 113 00:04:34,929 --> 00:04:36,330 AND IN THE TRANSPLANTATION 114 00:04:36,330 --> 00:04:42,136 FIELD, WE'RE TRYING TO APPLY IT. 115 00:04:42,136 --> 00:04:46,140 IN TUMOR IMMUNOTHERAPY, THEY ARE 116 00:04:46,140 --> 00:04:49,343 STILL STUCK WITH SELF, NON-SELF. 117 00:04:49,343 --> 00:04:51,512 IN PREGNANCY STUCK WITH SELF, 118 00:04:51,512 --> 00:04:51,912 NON-SELF. 119 00:04:51,912 --> 00:04:56,484 I'M GOING TO PICK A FEW THINGS 120 00:04:56,484 --> 00:04:57,651 THAT HAVE SOME NEW IDEAS THAT 121 00:04:57,651 --> 00:04:59,653 COME OUT OF THE DANGER MODEL, 122 00:04:59,653 --> 00:05:02,923 AND I'M NOT AN EXPERT IN ANY OF 123 00:05:02,923 --> 00:05:04,558 THESE FIELDS. 124 00:05:04,558 --> 00:05:10,398 I TEND TO THINK BROADLY, I DO 125 00:05:10,398 --> 00:05:13,434 THINK ABOUT DETAILS, I'M SURE 126 00:05:13,434 --> 00:05:14,969 EXPERTS WILL BE THROWING PIECES 127 00:05:14,969 --> 00:05:20,674 OF PIE AND ROTTEN TOMATOES, BUT 128 00:05:20,674 --> 00:05:21,976 I'M DO IT ANYWAY. 129 00:05:21,976 --> 00:05:25,780 MEL KOEN WAS THE GREATEST 130 00:05:25,780 --> 00:05:30,885 IMMUNOLOGY THEORYATICIAN, 131 00:05:30,885 --> 00:05:31,852 INVENTED HELP FOR T CELLS OUT OF 132 00:05:31,852 --> 00:05:32,286 THIN AIR. 133 00:05:32,286 --> 00:05:34,488 HE SAID IF YOU GO OUT AND YOU'RE 134 00:05:34,488 --> 00:05:36,424 CLEAR, IT'S IMPORTANT TO BE 135 00:05:36,424 --> 00:05:38,492 CLEAR, AND YOU'RE WRONG, IT'S 136 00:05:38,492 --> 00:05:39,326 OKAY. 137 00:05:39,326 --> 00:05:40,327 BECAUSE PEOPLE WILL DO THE 138 00:05:40,327 --> 00:05:42,730 EXPERIMENTS TO PROVE YOU WRONG. 139 00:05:42,730 --> 00:05:44,064 IT DOESN'T MATTER IF YOU'RE 140 00:05:44,064 --> 00:05:50,871 WRITE OR WRONG, SAY IT AND BE 141 00:05:50,871 --> 00:05:51,071 CLEAR. 142 00:05:51,071 --> 00:05:54,275 FIRST I'LL TALK ABOUT ALLERGY. 143 00:05:54,275 --> 00:06:04,752 WHAT MAKES AN ALLERGEN AND 144 00:06:12,827 --> 00:06:13,060 ALLERGEN. 145 00:06:13,060 --> 00:06:17,465 A NORWEGIAN ASKED A QUESTION, 146 00:06:17,465 --> 00:06:20,434 WHAT MAKES DUP P1 AND 2 147 00:06:20,434 --> 00:06:21,936 ALLERGENSES AND THE OTHERS NOT, 148 00:06:21,936 --> 00:06:27,475 THE PROTEINS A CAT CAN MAKE, AND 149 00:06:27,475 --> 00:06:30,177 ALL THE OTHER THOUSANDS OF 150 00:06:30,177 --> 00:06:34,048 PROTEINS THAT ARE NOT ALLERGENS. 151 00:06:34,048 --> 00:06:35,316 WHAT MAKES AN ALLERGEN AND 152 00:06:35,316 --> 00:06:35,883 ALLERGEN? 153 00:06:35,883 --> 00:06:39,887 THE SHORT ANSWER IS AN ALLERGEN 154 00:06:39,887 --> 00:06:40,988 IS AN IMMUNOGEN. 155 00:06:40,988 --> 00:06:42,423 WHAT MAKES AN IMMUNOGEN? 156 00:06:42,423 --> 00:06:43,958 THIS IS NOT NECESSARILY THE 157 00:06:43,958 --> 00:06:46,560 TARGET OF AN ANTIBODY RESPONSE. 158 00:06:46,560 --> 00:06:50,197 BUT SOMETHING THAT CAN INITIATE 159 00:06:50,197 --> 00:06:53,133 AN IMMUNE RESPONSE. 160 00:06:53,133 --> 00:06:53,701 ALLERGENS ARE IMMUNOGENS. 161 00:06:53,701 --> 00:06:59,173 THEY ARE KIND OF INTERESTING. 162 00:06:59,173 --> 00:07:02,243 SO DURP 1 IS A PROTEASE. 163 00:07:02,243 --> 00:07:04,345 AND IT'S A PROTEASE THAT ATTACKS 164 00:07:04,345 --> 00:07:06,981 THE SURFACE OF LUNG EPITHELIUM. 165 00:07:06,981 --> 00:07:14,054 AND ALSO OF B CELLS. 166 00:07:14,054 --> 00:07:18,259 DURP 2 LOOKS LIKE MD 2, AND 167 00:07:18,259 --> 00:07:19,593 ENHANCES LPS RESPONSES. 168 00:07:19,593 --> 00:07:23,464 SO THIS IS THE FIRST CATEGORY. 169 00:07:23,464 --> 00:07:29,937 THE ALLERGEN ITSELF CAUSES 170 00:07:29,937 --> 00:07:30,437 DAMAGE. 171 00:07:30,437 --> 00:07:31,338 CATEGORY 1. 172 00:07:31,338 --> 00:07:35,276 CATEGORY 2, THE ALLERGEN MIMICS 173 00:07:35,276 --> 00:07:40,147 OR HELPS AN ENDOGENOUS OR 174 00:07:40,147 --> 00:07:42,716 EXOGENOUS ALARM SIGNAL. 175 00:07:42,716 --> 00:07:44,652 CATEGORY 3, THE ALLERGEN IS 176 00:07:44,652 --> 00:07:48,322 PACKAGED WITH SOMETHING THAT 177 00:07:48,322 --> 00:07:50,357 CAUSES DAMAGE. 178 00:07:50,357 --> 00:08:00,901 HERE WE HAVE B VENOM, A MOLECULE 179 00:08:01,502 --> 00:08:03,504 CALLED MELOTIN, A PEPTIDE THAT 180 00:08:03,504 --> 00:08:04,972 INSERTS INTO MEMBRANE AND CAUSES 181 00:08:04,972 --> 00:08:06,774 PORES AND CAN DESTROY RED CELLS 182 00:08:06,774 --> 00:08:09,710 AND FOR NON-RED CELLS IT CAUSES 183 00:08:09,710 --> 00:08:16,283 A CYTOPLASM TO COME OUT, LIKE 184 00:08:16,283 --> 00:08:17,685 PYROPTOSIS. 185 00:08:17,685 --> 00:08:19,553 WHEN CYTOPLASM COMES OUT IT'S 186 00:08:19,553 --> 00:08:24,425 GOING TO ACTIVATE YOUR LOCAL 187 00:08:24,425 --> 00:08:30,431 APC. 3. 188 00:08:30,431 --> 00:08:34,735 CATEGORY 4, YOU'VE GIVEN AT THE 189 00:08:34,735 --> 00:08:39,306 SAME TIME AS DAMAGE. 190 00:08:39,306 --> 00:08:43,744 MY FAVORITE IS PEANUT. 191 00:08:43,744 --> 00:08:46,814 PEANUT ALLERGY DIDN'T EXIST IN 192 00:08:46,814 --> 00:08:50,918 AMERICA UNTIL THE 1990s AND 193 00:08:50,918 --> 00:08:52,553 DOESN'T EXIST WHERE PEOPLE EAT A 194 00:08:52,553 --> 00:08:54,922 LOT, VERY RARE IN INDONESIA, 195 00:08:54,922 --> 00:08:57,458 HOLLAND, I GREW UP UNTIL 7 IN 196 00:08:57,458 --> 00:08:57,891 HOLLAND. 197 00:08:57,891 --> 00:09:00,060 WE ATE PEANUT BUTTER EVERY 198 00:09:00,060 --> 00:09:00,861 MORNING. 199 00:09:00,861 --> 00:09:03,731 WE DIDN'T GET ALLERGIES. 200 00:09:03,731 --> 00:09:05,866 WHAT CAUSES PEANUT ALLERGY? 201 00:09:05,866 --> 00:09:09,169 TURNS OUT THAT PEANUT OIL IS A 202 00:09:09,169 --> 00:09:10,204 WONDERFUL EMOLLIENT, AND YOU 203 00:09:10,204 --> 00:09:13,574 FIND IT IN SKIN CREAMS. 204 00:09:13,574 --> 00:09:15,809 BECAUSE IT'S JUST GREAT AT 205 00:09:15,809 --> 00:09:23,651 MAKING SKIN SOFT AND HAPPY. 206 00:09:23,651 --> 00:09:24,518 CANADIANS BANNED PEANUT OIL 207 00:09:24,518 --> 00:09:32,493 RECENTLY IN BABY CREAMS. 208 00:09:32,493 --> 00:09:36,563 BABIES WHO HAVE RASHES, ECZEMA, 209 00:09:36,563 --> 00:09:38,298 BE ATOPIC VERY OFTEN, THEY 210 00:09:38,298 --> 00:09:40,067 BECOME ALLERGIC TO PEANUTS AND 211 00:09:40,067 --> 00:09:41,935 THEN OTHER NUTS. 212 00:09:41,935 --> 00:09:43,003 SO WHAT'S HAPPENING THERE? 213 00:09:43,003 --> 00:09:44,571 HERE'S WHAT I THINK IS 214 00:09:44,571 --> 00:09:44,905 HAPPENING. 215 00:09:44,905 --> 00:09:49,276 YOU'VE GOT SKIN THAT IS DAMAGED. 216 00:09:49,276 --> 00:09:52,646 YOU'VE GOT LOCAL 217 00:09:52,646 --> 00:09:53,647 ANTIGEN-PRESENTING CELLS 218 00:09:53,647 --> 00:09:56,917 ACTIVATED, AND YOU'RE SLATHERING 219 00:09:56,917 --> 00:09:58,552 IT WITH PEANUT OIL. 220 00:09:58,552 --> 00:10:02,356 IT'S A COMPLETE RECIPE FOR 221 00:10:02,356 --> 00:10:05,659 TURNING ON AN IMMUNE RESPONSE. 222 00:10:05,659 --> 00:10:08,095 SO, THE EXCEPTION THAT MIGHT 223 00:10:08,095 --> 00:10:13,300 PROVE THE RULE, MIGHT, ACTUALLY 224 00:10:13,300 --> 00:10:14,768 HAPPENED HERE, SO CAT AND DAN 225 00:10:14,768 --> 00:10:18,172 BARBER HAD A SON WITH ECZEMA, 226 00:10:18,172 --> 00:10:21,008 WERE CAREFUL NOT TO USE PEANUT 227 00:10:21,008 --> 00:10:21,842 OIL. 228 00:10:21,842 --> 00:10:24,178 AND SO THEY DIDN'T. 229 00:10:24,178 --> 00:10:28,282 AND WHEN HE WAS A YEAR AND A 230 00:10:28,282 --> 00:10:30,284 HALF OLD, HE ANAPHYLAXED IN DAY 231 00:10:30,284 --> 00:10:36,090 CARE WHEN THEY FED HIM HUMMUS, 232 00:10:36,090 --> 00:10:38,158 SESAME OIL USED IN HUMMUS IS 233 00:10:38,158 --> 00:10:39,593 ALSO USED IN CREAMS. 234 00:10:39,593 --> 00:10:44,531 SO, IF WE COULD STOP USING 235 00:10:44,531 --> 00:10:46,066 PEANUT OIL ON BABIES WITH BAD 236 00:10:46,066 --> 00:10:49,703 SKIN WE MIGHT BE ABLE TO STOP 237 00:10:49,703 --> 00:10:51,638 THIS EPIDEMIC OF PEANUT ALLERGY 238 00:10:51,638 --> 00:10:52,539 IN AMERICA. 239 00:10:52,539 --> 00:10:54,274 JOHNSON'S BABY OIL IS MINERAL 240 00:10:54,274 --> 00:10:54,908 OIL. 241 00:10:54,908 --> 00:10:56,343 WHY NOT USE THAT? 242 00:10:56,343 --> 00:10:59,546 IT'S EASIER TO STAY AWAY FROM 243 00:10:59,546 --> 00:11:07,321 MINERAL OIL THAN PEANUTS. 244 00:11:07,321 --> 00:11:08,622 SO, THE FIFTH CATEGORY IS IT'S 245 00:11:08,622 --> 00:11:13,961 GIVEN AT THE WRONG TIME. 246 00:11:13,961 --> 00:11:14,995 THESE ARE BOTH TIME. 247 00:11:14,995 --> 00:11:19,466 THIS ISN'T NECESSARILY A TIME 248 00:11:19,466 --> 00:11:20,467 WHEN THERE'S DAMAGE ALREADY. 249 00:11:20,467 --> 00:11:24,204 THOSE OF OF YOU AS OLD AS ME MAY 250 00:11:24,204 --> 00:11:26,340 REMEMBER THAT BEFORE WE GOT ALL 251 00:11:26,340 --> 00:11:28,976 EXCITED ABOUT LPS AND THOSE 252 00:11:28,976 --> 00:11:34,548 KINDS OF ADJUVANTS, PEOPLE WERE 253 00:11:34,548 --> 00:11:35,516 USING ANOTHER ADJUVANT, THERE 254 00:11:35,516 --> 00:11:43,123 WAS A PERIOD OF TIME WHEN PEOPLE 255 00:11:43,123 --> 00:11:45,259 WERE USING CASEIN, BOVINE, AN 256 00:11:45,259 --> 00:11:45,559 ADJUVANT. 257 00:11:45,559 --> 00:11:46,860 IF YOU INJECT IT INTO A MOUSE 258 00:11:46,860 --> 00:11:50,564 YOU'LL KILL THE MOUSE. 259 00:11:50,564 --> 00:11:54,268 IF YOU INJECT YOU WILL BE ABLE 260 00:11:54,268 --> 00:11:55,669 TO ISOLATE HIGHLY INFLAMMATORY 261 00:11:55,669 --> 00:11:57,638 MICRO PHAGES OUT OF THE PER KNEE 262 00:11:57,638 --> 00:11:57,971 UM. 263 00:11:57,971 --> 00:12:03,210 IT IS NOT MEANT TO BE SYSTEMIC. 264 00:12:03,210 --> 00:12:06,814 AND YET WE FEED IT TO NEWBORN 265 00:12:06,814 --> 00:12:09,683 BABIES AT A TIME WHEN THEIR GUTS 266 00:12:09,683 --> 00:12:16,657 HAVE NOT COMPLETELY HEALED UP. 267 00:12:16,657 --> 00:12:22,963 FIRST 24, 48 HOURS OF BIRTH THE 268 00:12:22,963 --> 00:12:26,834 INTESTINAL EPITHELIUM IS LEAKY. 269 00:12:26,834 --> 00:12:28,602 YOU FEED MILK, CASEENI GETS INTO 270 00:12:28,602 --> 00:12:31,238 THE BLOOD AND YOU'VE JUST GIVEN 271 00:12:31,238 --> 00:12:32,539 A SYSTEMIC ADJUVANT WITH OTHER 272 00:12:32,539 --> 00:12:34,308 MILK PROTEINS. 273 00:12:34,308 --> 00:12:38,612 IS IT ANY SURPRISE THAT SOME 274 00:12:38,612 --> 00:12:40,314 BABIES GET MILK ALLERGIES? 275 00:12:40,314 --> 00:12:42,983 I WOULD LIKE TO SUGGEST THAT 276 00:12:42,983 --> 00:12:47,454 HOSPITALS SHOULD BANK HUMAN 277 00:12:47,454 --> 00:12:48,021 MILK. 278 00:12:48,021 --> 00:12:49,790 OBVIOUSLY IN HUMANS, HUMAN MILK 279 00:12:49,790 --> 00:12:54,328 GIVEN AT BIRTH DOES NOT DO THIS. 280 00:12:54,328 --> 00:12:56,063 SO, GET SOME DONORS, BANK SOME 281 00:12:56,063 --> 00:12:57,965 HUMAN MILK, GIVE IT TO YOUR 282 00:12:57,965 --> 00:12:59,499 PREEMIES AND THE OTHER BABIES 283 00:12:59,499 --> 00:13:02,135 WHO FOR SOME REASON CAN'T GET 284 00:13:02,135 --> 00:13:04,404 HUMAN MILK FROM THEIR MOTHERS. 285 00:13:04,404 --> 00:13:06,807 STOP GIVING COW'S MILK WHICH HAS 286 00:13:06,807 --> 00:13:09,643 THIS NATURAL ADJUVANT IN IT, TO 287 00:13:09,643 --> 00:13:16,516 A BABY WHOSE GUTS HAVEN'T YET 288 00:13:16,516 --> 00:13:17,117 LINKED UP. 289 00:13:17,117 --> 00:13:19,519 PROTEINS THAT DON'T DO ONE OF 290 00:13:19,519 --> 00:13:20,821 THESE THINGS, MOLECULES THAT 291 00:13:20,821 --> 00:13:22,522 DON'T DO ONE OF THESE THINGS 292 00:13:22,522 --> 00:13:25,325 TEND NOT TO BE ALLERGENS. 293 00:13:25,325 --> 00:13:27,761 YOU CAUSE DAMAGE, YOU MIMIC 294 00:13:27,761 --> 00:13:31,431 ENDOGENOUS OR EXOGENOUS ALARM 295 00:13:31,431 --> 00:13:32,866 SIGNAL, YOU'RE PACKAGED WITH 296 00:13:32,866 --> 00:13:40,807 SOMETHING THAT CAUSES DAMAGE, B 297 00:13:40,807 --> 00:13:42,009 VENOM ALSO HAS PHOSPHO-LIPAAST 298 00:13:42,009 --> 00:13:44,578 A2, YOU GIVE IT WHEN YOU ALREADY 299 00:13:44,578 --> 00:13:46,647 HAVE SOME DAMAGE. 300 00:13:46,647 --> 00:13:48,115 OR YOU'RE GIVING AT A TIME 301 00:13:48,115 --> 00:13:50,350 DAMAGING MOLECULE THAT GETS INTO 302 00:13:50,350 --> 00:13:51,952 THE WRONG PLACE. 303 00:13:51,952 --> 00:13:53,220 SO THAT'S WHAT MAKES AN ALLERGEN 304 00:13:53,220 --> 00:13:55,756 AN ALLERGEN, BY THE DANGER 305 00:13:55,756 --> 00:13:56,757 MODEL. 306 00:13:56,757 --> 00:14:03,530 SO THE SECOND QUESTION IN 307 00:14:03,530 --> 00:14:06,867 ALLERGY, WHICH IS REALLY A 308 00:14:06,867 --> 00:14:08,001 COMBINATION OF TWO QUESTIONS, IS 309 00:14:08,001 --> 00:14:10,103 WHY DO SOME PEOPLE RESPOND TO 310 00:14:10,103 --> 00:14:15,242 THESE ALLERGENS AND OTHER PEOPLE 311 00:14:15,242 --> 00:14:15,575 DON'T? 312 00:14:15,575 --> 00:14:19,346 WHY DO THESE INDUCE A Th2 313 00:14:19,346 --> 00:14:19,613 RESPONSE? 314 00:14:19,613 --> 00:14:21,014 I THINK THAT THAT'S NOT QUITE 315 00:14:21,014 --> 00:14:21,982 THE RIGHT QUESTION. 316 00:14:21,982 --> 00:14:22,983 WHEN YOU'RE ASKING THE WRONG 317 00:14:22,983 --> 00:14:25,485 QUESTION, YOU'RE GOING TO GET 318 00:14:25,485 --> 00:14:26,486 THE WRONG ANSWER. 319 00:14:26,486 --> 00:14:28,689 I THINK THE RIGHT QUESTION HERE 320 00:14:28,689 --> 00:14:31,391 ISN'T WHY DO SOME PEOPLE RESPOND 321 00:14:31,391 --> 00:14:33,427 AND OTHERS NOT. 322 00:14:33,427 --> 00:14:38,432 MOST PEOPLE WILL RESPOND TO 323 00:14:38,432 --> 00:14:40,901 THESE ALLERGENS. 324 00:14:40,901 --> 00:14:43,670 FREDERICKA SOLUSTO IN THE '90s 325 00:14:43,670 --> 00:14:48,875 SHOWED PEOPLE WHO ARE NOT 326 00:14:48,875 --> 00:14:50,777 ALLERGIC MAKE IgG OR IgA 327 00:14:50,777 --> 00:14:54,948 RESPONSES TO A POTENT ALLERGEN. 328 00:14:54,948 --> 00:14:56,249 I'VE BEEN ASKING ALLERGISTS FOR 329 00:14:56,249 --> 00:14:58,452 ABOUT A DECADE NOW TO DO THE 330 00:14:58,452 --> 00:15:00,887 FOLLOWING EXPERIMENT, IF THERE'S 331 00:15:00,887 --> 00:15:03,056 ANY ALLERGISTS OUT THERE THAT 332 00:15:03,056 --> 00:15:04,825 WILL DO IT, PLEASE DO IT. 333 00:15:04,825 --> 00:15:08,128 TAKE LARGE FAMILIES WERE SOME 334 00:15:08,128 --> 00:15:10,130 KIDS ARE ATOPIC AND ALLERGIC TO 335 00:15:10,130 --> 00:15:13,033 ANTIGENS, OTHER KIDS ARE NOT. 336 00:15:13,033 --> 00:15:14,468 IT HAS FAMILIES, IN THE SAME 337 00:15:14,468 --> 00:15:15,469 ENVIRONMENT. 338 00:15:15,469 --> 00:15:16,903 MY SISTER IS ALLERGIC TO SAGE 339 00:15:16,903 --> 00:15:19,006 BUT LIVES IN IDAHO AND BECAME 340 00:15:19,006 --> 00:15:20,974 ALLERGIC LATER. 341 00:15:20,974 --> 00:15:22,376 I'M NOT ALLERGIC TO SAGE BUT 342 00:15:22,376 --> 00:15:24,745 I'VE NEVER LIVED IN THE 343 00:15:24,745 --> 00:15:25,045 ENVIRONMENT. 344 00:15:25,045 --> 00:15:25,779 SAME ENVIRONMENT, KIDS AND 345 00:15:25,779 --> 00:15:26,646 FAMILY. 346 00:15:26,646 --> 00:15:28,715 PREDICTION IS THE ATOPIC KIDS 347 00:15:28,715 --> 00:15:29,783 ARE MAKING IGE TO WHATEVER 348 00:15:29,783 --> 00:15:32,586 ALLERGEN YOU TEST, THEY ARE 349 00:15:32,586 --> 00:15:35,422 ATOPIC TO, AND NON-ATOPIC KIDS 350 00:15:35,422 --> 00:15:39,059 WILL BE MAKING IgG OR IF IT'S 351 00:15:39,059 --> 00:15:41,762 A FOOD ALLERGEN, IgA. 352 00:15:41,762 --> 00:15:44,498 IT'S NOT THAT ATOPIC PEOPLE 353 00:15:44,498 --> 00:15:44,965 RESPOND. 354 00:15:44,965 --> 00:15:46,800 AND NON-ATOPIC PEOPLE DON'T 355 00:15:46,800 --> 00:15:47,100 RESPOND. 356 00:15:47,100 --> 00:15:53,740 IT'S THAT ATOPIC PEOPLE MAKE 357 00:15:53,740 --> 00:15:56,243 IGE, I'M JUST TALKING ABOUT THAT 358 00:15:56,243 --> 00:15:58,078 HERE, NON-ATOPIC MAKE THE NORMAL 359 00:15:58,078 --> 00:15:58,612 RESPONSE. 360 00:15:58,612 --> 00:16:00,013 AND I DON'T HAVE AN ANSWER TO 361 00:16:00,013 --> 00:16:03,884 WHY SOME PEOPLE MAKE IGE AND 362 00:16:03,884 --> 00:16:05,052 SOME PEOPLE DON'T. 363 00:16:05,052 --> 00:16:06,987 THAT'S-- THE DANGER MODEL IS HOW 364 00:16:06,987 --> 00:16:08,989 DO YOU INITIATE AN IMMUNE 365 00:16:08,989 --> 00:16:09,256 RESPONSE. 366 00:16:09,256 --> 00:16:10,690 IT'S NOT ABOUT HOW DO YOU 367 00:16:10,690 --> 00:16:12,159 DETERMINE WHAT CLASS OF RESPONSE 368 00:16:12,159 --> 00:16:13,627 YOU MAKE. 369 00:16:13,627 --> 00:16:15,929 I HAVE SOME IDEAS. 370 00:16:15,929 --> 00:16:18,865 ONE OF THEM COMES FROM A MAN 371 00:16:18,865 --> 00:16:20,967 NAMED FERNANDO MARTINEZ, WHO 372 00:16:20,967 --> 00:16:25,639 STUDIES ATOPIC PEOPLE, AND HE 373 00:16:25,639 --> 00:16:28,975 HAS THE FOLLOWING IDEA, SOUNDS 374 00:16:28,975 --> 00:16:32,746 LOGICAL AND COULD BE RIGHT THAT 375 00:16:32,746 --> 00:16:36,917 NEWBORNS, BECAUSE THEY JUST 376 00:16:36,917 --> 00:16:41,855 ENCOUNT ERRED OXYGEN HAD TO MAKE 377 00:16:41,855 --> 00:16:43,757 MUCOUS AND MOLECULES, ARE 378 00:16:43,757 --> 00:16:44,724 DEALING WITH NEWLY ARRIVED 379 00:16:44,724 --> 00:16:45,058 OXYGEN. 380 00:16:45,058 --> 00:16:46,426 WHEN THEY MAKE AN IMMUNE 381 00:16:46,426 --> 00:16:49,062 RESPONSE, YOU DON'T WANT TO MAKE 382 00:16:49,062 --> 00:16:50,330 AN IMMUNE RESPONSE THAT'S GOING 383 00:16:50,330 --> 00:16:51,965 TO GIVE YOU MORE OXYGEN 384 00:16:51,965 --> 00:16:52,866 RADICALS. 385 00:16:52,866 --> 00:16:56,036 YOU DON'T WANT TO MAKE A Th1 386 00:16:56,036 --> 00:16:56,303 RESPONSE. 387 00:16:56,303 --> 00:16:59,739 SO HE SUGGESTS THAT NEWBORNS ARE 388 00:16:59,739 --> 00:17:03,743 KIND OF BIASED TO MAKE 389 00:17:03,743 --> 00:17:05,846 NON-INFLAMMATORY POTENTIALLY IGE 390 00:17:05,846 --> 00:17:06,880 AND IgG 4 RESPONSES. 391 00:17:06,880 --> 00:17:10,050 THAT MAY BE TRUE, I DON'T KNOW 392 00:17:10,050 --> 00:17:13,253 HOW TO TEST IT. 393 00:17:13,253 --> 00:17:14,688 SO, IN SHORT, ALLERGY, DANGER 394 00:17:14,688 --> 00:17:16,623 MODEL CANNOT TELL YOU WHY SOME 395 00:17:16,623 --> 00:17:19,259 PEOPLE MAKE IGE AND OTHERS DON'T 396 00:17:19,259 --> 00:17:20,861 BUT PREDICTS THAT PEOPLE WILL 397 00:17:20,861 --> 00:17:22,896 RESPOND TO THE SAME ALLERGENS 398 00:17:22,896 --> 00:17:25,198 JUST IN A DIFFERENT WAY. 399 00:17:25,198 --> 00:17:27,934 IT SAYS AN ALLERGEN IS AN 400 00:17:27,934 --> 00:17:29,669 ALLERGEN BECAUSE IT RAISES ALARM 401 00:17:29,669 --> 00:17:34,941 SIGNALS IN ONE WAY OR THE OTHER. 402 00:17:34,941 --> 00:17:38,411 BY THE WAY, IF YOU HAVE 403 00:17:38,411 --> 00:17:39,446 QUESTIONS OR ARGUMENTS, IF 404 00:17:39,446 --> 00:17:44,885 SOMETHING I SAY DOESN'T FIT, 405 00:17:44,885 --> 00:17:46,853 RAISE YOUR HAND. 406 00:17:46,853 --> 00:17:47,888 DON'T WORRY ABOUT MICROPHONES, 407 00:17:47,888 --> 00:17:49,156 I'LL REPEAT FOR THE PEOPLE 408 00:17:49,156 --> 00:17:49,422 WATCHING. 409 00:17:49,422 --> 00:17:51,892 IF YOU HAVE A QUESTION IN THE 410 00:17:51,892 --> 00:17:52,993 MIDDLE, PLEASE ASK IT. 411 00:17:52,993 --> 00:17:54,995 I FOUND WHEN PEOPLE GET CONFUSED 412 00:17:54,995 --> 00:17:56,630 OR DISAGREE THEIR THOUGHTS GO 413 00:17:56,630 --> 00:17:58,398 SOMEWHERE ELSE AND EVENTUALLY 414 00:17:58,398 --> 00:18:00,367 THEY GO TO SLEEP. 415 00:18:00,367 --> 00:18:01,635 I THROW THINGS, I'M KNOWN FOR 416 00:18:01,635 --> 00:18:04,004 THROWING THINGS AT PEOPLE WHO GO 417 00:18:04,004 --> 00:18:04,771 TO SLEEP. 418 00:18:04,771 --> 00:18:05,038 [LAUGHTER] 419 00:18:05,038 --> 00:18:07,507 AND I HAVE A BAD AIM. 420 00:18:07,507 --> 00:18:07,841 [LAUGHTER] 421 00:18:07,841 --> 00:18:09,509 WHICH MEANS IF YOUR NEIGHBOR IS 422 00:18:09,509 --> 00:18:13,480 FALLING ASLEEP IT'S A GOOD IDEA 423 00:18:13,480 --> 00:18:15,415 TO WAKE THEM UP. 424 00:18:15,415 --> 00:18:19,186 OKAY, THAT'S ALLERGY. 425 00:18:19,186 --> 00:18:20,253 LET'S DO PREGNANCY. 426 00:18:20,253 --> 00:18:23,523 SO PREGNANCY WAS ONE OF THE 427 00:18:23,523 --> 00:18:25,825 FIRST PROBLEMS THAT THE SELF, 428 00:18:25,825 --> 00:18:27,494 NOT SELF-MODEL RAN INTO. 429 00:18:27,494 --> 00:18:29,996 IF YOU RESPOND TO THINGS THAT 430 00:18:29,996 --> 00:18:33,433 ARE FOREIGN, MOTHERS OUGHT TO 431 00:18:33,433 --> 00:18:35,001 REJECT THEIR FETUSES. 432 00:18:35,001 --> 00:18:38,004 PETER MEADOWAR WHO WON THE NOBEL 433 00:18:38,004 --> 00:18:39,472 PRIZE FOR THE EXPERIMENT THAT 434 00:18:39,472 --> 00:18:42,842 PUT THE MODEL ON THE MAP -- GO. 435 00:18:42,842 --> 00:18:53,153 >> (INAUDIBLE). 436 00:18:58,158 --> 00:19:02,596 >> THE QUESTION IS ABOUT THE 437 00:19:02,596 --> 00:19:04,030 HYGIENE HYPOTHESIS AND WHAT DO I 438 00:19:04,030 --> 00:19:06,366 THINK ABOUT IT. 439 00:19:06,366 --> 00:19:08,001 IT'S INTERESTING, YOU KNOW, FARM 440 00:19:08,001 --> 00:19:12,839 KIDS DON'T HAVE AS MANY 441 00:19:12,839 --> 00:19:13,540 ALLERGIES. 442 00:19:13,540 --> 00:19:17,744 I THINK THAT IS TRUE, IF YOU GET 443 00:19:17,744 --> 00:19:21,514 YOUR THINGS IN A NORMAL WAY, 444 00:19:21,514 --> 00:19:22,916 YOU'RE UNLIKELY TO GET ALLERGIC 445 00:19:22,916 --> 00:19:23,717 TO THEM. 446 00:19:23,717 --> 00:19:26,720 AGAIN, THE EXCEPTION IS MILK IN 447 00:19:26,720 --> 00:19:30,690 THE FIRST 24 OR 48 HOURS. 448 00:19:30,690 --> 00:19:32,759 FEED THEM PEANUTS. 449 00:19:32,759 --> 00:19:33,760 HERE'S ANOTHER THING PEOPLE 450 00:19:33,760 --> 00:19:35,095 DON'T THINK ABOUT. 451 00:19:35,095 --> 00:19:37,297 I HAVE A FARM, I HAVE A WELL, I 452 00:19:37,297 --> 00:19:40,000 DON'T HAVE CHLORINE IN MY WATER. 453 00:19:40,000 --> 00:19:44,037 AND WHEN YOU TAKE A SHOWER IN 454 00:19:44,037 --> 00:19:47,040 CHLORINE, CHLORINATED WATER, YOU 455 00:19:47,040 --> 00:19:48,875 ARE BREATHING HOT CHLORINE. 456 00:19:48,875 --> 00:19:50,944 WHAT IS THAT DOING TO YOUR 457 00:19:50,944 --> 00:19:51,278 LUNGS? 458 00:19:51,278 --> 00:19:52,946 WHEN YOU BATHE YOUR LITTLE BABY 459 00:19:52,946 --> 00:19:53,780 IN CHLORINATED WATER WHAT ARE 460 00:19:53,780 --> 00:19:57,317 YOU DOING TO ITS LUNGS? 461 00:19:57,317 --> 00:19:58,718 THAT WATER IS STEAMY. 462 00:19:58,718 --> 00:20:00,253 SO, THERE ARE THINGS THAT WE 463 00:20:00,253 --> 00:20:03,890 NEED TO THINK ABOUT IN THE 464 00:20:03,890 --> 00:20:04,758 HYGIENE HYPOTHESIS, NOT JUST 465 00:20:04,758 --> 00:20:07,460 ABOUT BEING EXPOSED TO LOTS OF 466 00:20:07,460 --> 00:20:08,094 DIRTY THINGS. 467 00:20:08,094 --> 00:20:10,230 AND THAT'S ALL WE HAVE TIME FOR 468 00:20:10,230 --> 00:20:11,298 ON THAT ONE. 469 00:20:11,298 --> 00:20:14,401 MAYBE AFTER I TALK WE CAN DO A 470 00:20:14,401 --> 00:20:15,302 LITTLE MORE. 471 00:20:15,302 --> 00:20:22,242 WHY DON'T MOTHERS REJECT THEIR 472 00:20:22,242 --> 00:20:22,475 FETUSES? 473 00:20:22,475 --> 00:20:23,576 MEADOWAR, KNOWING THIS WAS A 474 00:20:23,576 --> 00:20:28,081 PROBLEM AND BEING SMART AND ALSO 475 00:20:28,081 --> 00:20:29,549 AMAZINGLY STUPID, WROTE A PAPER 476 00:20:29,549 --> 00:20:34,020 WHERE HE SUGGESTED THREE THINGS. 477 00:20:34,020 --> 00:20:35,322 A, FETUSES IMMUNOSUPPRESS THEIR 478 00:20:35,322 --> 00:20:36,189 MOTHERS. 479 00:20:36,189 --> 00:20:37,090 THIS IS AN EVOLUTIONARILY SMART 480 00:20:37,090 --> 00:20:38,625 THING TO DO, TAKE THE 481 00:20:38,625 --> 00:20:39,726 INDIVIDUALS THAT ARE CARRYING 482 00:20:39,726 --> 00:20:44,564 THE NEXT GENERATION AND TURN 483 00:20:44,564 --> 00:20:45,532 THEM INTO AIDS PATIENTS. 484 00:20:45,532 --> 00:20:46,032 [LAUGHTER] 485 00:20:46,032 --> 00:20:50,403 SO, I'VE DISCOVERED IN MY CAREER 486 00:20:50,403 --> 00:20:52,472 MOST THINGS THAT ARE 487 00:20:52,472 --> 00:20:53,373 EVOLUTIONARILY DUMB GENERALLY 488 00:20:53,373 --> 00:20:57,510 TEND NOT TO BE TRUE AND IF NOT 489 00:20:57,510 --> 00:20:59,512 TRUE HOW MANY OF YOU CARRIED 490 00:20:59,512 --> 00:20:59,946 FETUSES? 491 00:20:59,946 --> 00:21:05,185 DID YOU HAVE TO LIVE IN A 492 00:21:05,185 --> 00:21:05,418 BUBBLE? 493 00:21:05,418 --> 00:21:05,585 NO! 494 00:21:05,585 --> 00:21:08,621 DO MY 200 SHEEP HAVE TO LIVE IN 495 00:21:08,621 --> 00:21:10,623 BUBBLES WHEN PREGNANT? 496 00:21:10,623 --> 00:21:10,824 NO. 497 00:21:10,824 --> 00:21:12,492 NOW, IT'S THROUGH THERE ARE SOME 498 00:21:12,492 --> 00:21:13,927 PARASITES THAT TAKE ADVANTAGE OF 499 00:21:13,927 --> 00:21:15,862 THE PREGNANT STATE, THE ONE THAT 500 00:21:15,862 --> 00:21:19,332 USED TO KEEP BEING THROWN IN MY 501 00:21:19,332 --> 00:21:22,202 FACE WAS MALARIA BECAUSE IN 502 00:21:22,202 --> 00:21:23,570 ENDIMMIC AREAS WOMEN IN FIRST 503 00:21:23,570 --> 00:21:25,271 PREGNANCIES IF THEY GET MALARIA 504 00:21:25,271 --> 00:21:27,040 DO VERY BADLY. 505 00:21:27,040 --> 00:21:28,441 FETUSES DIE, IF THEY DON'T DIE 506 00:21:28,441 --> 00:21:32,612 THEY GET LOW BIRTH WEIGHT. 507 00:21:32,612 --> 00:21:34,147 THE MOTHERS SOMETIMES DIE. 508 00:21:34,147 --> 00:21:36,683 IT TURNS OUT IT'S NOT BECAUSE 509 00:21:36,683 --> 00:21:37,817 THEY ARE IMMUNOSUPPRESSED. 510 00:21:37,817 --> 00:21:40,920 IT'S BECAUSE THERE'S A VARIANT 511 00:21:40,920 --> 00:21:44,457 OF MALARIA THAT ONLY GROWS IN 512 00:21:44,457 --> 00:21:46,359 PREGNANT WOMEN, IT HAS A 513 00:21:46,359 --> 00:21:50,897 PARTICULAR RECEPTOR THAT USES TO 514 00:21:50,897 --> 00:21:59,773 BIND ON THE PLACENTA. 515 00:21:59,773 --> 00:22:01,174 THIS PARTICULAR VARIANT GOES TO 516 00:22:01,174 --> 00:22:03,410 THE PLACENTA AND USES UP THE 517 00:22:03,410 --> 00:22:03,610 BLOOD. 518 00:22:03,610 --> 00:22:07,180 THAT'S NOT GOOD FOR THE FETUS OR 519 00:22:07,180 --> 00:22:08,114 THE MOTHER. 520 00:22:08,114 --> 00:22:11,918 BUT IF THAT MOTHER MAKES IT, BY 521 00:22:11,918 --> 00:22:12,786 HER SECOND PREGNANCY, SHE'S 522 00:22:12,786 --> 00:22:23,329 BETTER, BY THE THIRD SHE'S FINE. 523 00:22:23,963 --> 00:22:27,867 AND LARS HAVID, LOOK HIM UP, 524 00:22:27,867 --> 00:22:34,874 HE'S COOL, BLED A BUNCH OF 525 00:22:34,874 --> 00:22:39,245 PEOPLE IN MALI, I THINK, AND 526 00:22:39,245 --> 00:22:42,148 FOUND THAT EVERY WOMAN EVER 527 00:22:42,148 --> 00:22:45,018 PREGNANT HAD ANTIBODIES TO THIS 528 00:22:45,018 --> 00:22:49,088 VARIANT, AND ALMOST NO MEN DID. 529 00:22:49,088 --> 00:22:51,658 WHAT THIS SAYS IS THAT THAT 530 00:22:51,658 --> 00:22:53,526 13-YEAR-OLD GIRL WHO HAS NEVER 531 00:22:53,526 --> 00:22:54,994 SEEN THIS VARIANT BEFORE BECAUSE 532 00:22:54,994 --> 00:22:56,763 SHE WASN'T PREGNANT, AND IS 533 00:22:56,763 --> 00:22:57,664 GOING THROUGH HER FIRST 534 00:22:57,664 --> 00:22:59,899 PREGNANCY, THE FIRST TIME SHE'S 535 00:22:59,899 --> 00:23:02,902 MAKING A PRIMARY RESPONSE. 536 00:23:02,902 --> 00:23:04,471 WHICH IS SLOW, NOT EFFECTIVE, 537 00:23:04,471 --> 00:23:06,239 BUT IF SHE MAKES IT BY THE 538 00:23:06,239 --> 00:23:07,574 SECOND PREGNANCY SHE'S MAKING A 539 00:23:07,574 --> 00:23:09,275 SECONDARY RESPONSE AND BY THE 540 00:23:09,275 --> 00:23:10,376 THIRD SHE'S FINE. 541 00:23:10,376 --> 00:23:14,013 WHICH SAYS YOU CAN MAKE A 542 00:23:14,013 --> 00:23:16,316 PRIMARY EFFECTIVE IMMUNE 543 00:23:16,316 --> 00:23:18,184 RESPONSE WHILE YOU'RE PREGNANT. 544 00:23:18,184 --> 00:23:19,052 PREGNANCY IS NOT 545 00:23:19,052 --> 00:23:20,587 IMMUNOSUPPRESSIVE. 546 00:23:20,587 --> 00:23:21,754 IT'S JUST THAT PARASITES ARE 547 00:23:21,754 --> 00:23:25,525 PRETTY GOOD AT TAKING ADVANTAGE 548 00:23:25,525 --> 00:23:26,259 OF IT. 549 00:23:26,259 --> 00:23:30,196 SO THAT WAS THE FIRST THING. 550 00:23:30,196 --> 00:23:33,166 THE SECOND, ALSO STILL WRITTEN 551 00:23:33,166 --> 00:23:37,437 IN TEXT BOOKS, I'M STILL HEARING 552 00:23:37,437 --> 00:23:38,271 PREGNANCY IS IMMUNOSUPPRESSIVE, 553 00:23:38,271 --> 00:23:40,974 IN TEXT BOOKS, IT'S IN THE 554 00:23:40,974 --> 00:23:44,310 NEWSPAPERS, IT'S ON NPR, SECOND 555 00:23:44,310 --> 00:23:46,613 ONE WAS THAT THE PLACENTA IS A 556 00:23:46,613 --> 00:23:47,514 PHYSICAL AND IMMUNOLOGICAL 557 00:23:47,514 --> 00:23:50,350 BARRIER BETWEEN MOTHER AND 558 00:23:50,350 --> 00:23:50,650 FETUS. 559 00:23:50,650 --> 00:23:51,551 ALSO PRETTY DUMB. 560 00:23:51,551 --> 00:23:53,086 MEANS IF YOUR FETUS GETS 561 00:23:53,086 --> 00:23:54,320 INFECTED, YOU AND IT ARE DEAD 562 00:23:54,320 --> 00:23:56,155 BECAUSE YOU CAN'T DO ANYTHING 563 00:23:56,155 --> 00:23:57,690 ABOUT IT. 564 00:23:57,690 --> 00:23:58,892 AND ALSO NOT TRUE. 565 00:23:58,892 --> 00:23:59,092 RIGHT? 566 00:23:59,092 --> 00:24:01,261 WE KNOW THERE'S TRAFFIC FROM 567 00:24:01,261 --> 00:24:03,596 FETUS TO MOTHER. 568 00:24:03,596 --> 00:24:04,797 PEOPLE ACTUALLY NOW ISOLATE 569 00:24:04,797 --> 00:24:06,866 THOSE CELLS OUT OF MATERNAL 570 00:24:06,866 --> 00:24:10,336 BLOOD, IN ORDER TO DO A 571 00:24:10,336 --> 00:24:11,771 NON-INVASIVE PRENATAL DIAGNOSIS. 572 00:24:11,771 --> 00:24:14,774 AND THERE'S TRAFFIC FROM MOTHER 573 00:24:14,774 --> 00:24:15,642 TO FETUS. 574 00:24:15,642 --> 00:24:18,878 SO 25% OF US SITTING IN THIS 575 00:24:18,878 --> 00:24:24,884 ROOM ARE MICROCHIMERIC FOR OUR 576 00:24:24,884 --> 00:24:26,119 MATERNAL HEMATOPOIETIC CELLS, 577 00:24:26,119 --> 00:24:27,153 FIRST DISCOVERED WHERE PEOPLE 578 00:24:27,153 --> 00:24:29,255 WERE WAITING FOR A KIDNEY, IN 579 00:24:29,255 --> 00:24:30,089 LIEDEN. 580 00:24:30,089 --> 00:24:32,358 WHEN THEY HAD A LIVING DONOR, 581 00:24:32,358 --> 00:24:34,127 THEY ALWAYS TEST THE IMMUNE 582 00:24:34,127 --> 00:24:35,361 RESPONSE OF THE RECIPIENT 583 00:24:35,361 --> 00:24:36,863 AGAINST THE DONOR BEFORE THEY DO 584 00:24:36,863 --> 00:24:37,697 THE TRANSPLANT BECAUSE IF 585 00:24:37,697 --> 00:24:38,898 THERE'S ALREADY A STRONG 586 00:24:38,898 --> 00:24:40,867 RESPONSE THAT TRANSPLANT IS GONE 587 00:24:40,867 --> 00:24:42,101 IN A WEEK. 588 00:24:42,101 --> 00:24:44,837 SO MOTHERS ARE OFTEN DONORS. 589 00:24:44,837 --> 00:24:48,575 IT TURNS OUT THAT 25% OF PEOPLE 590 00:24:48,575 --> 00:24:50,944 WAITING ON THESE KIDNEY LISTS 591 00:24:50,944 --> 00:24:54,180 WHEN TESTED DO NOT MAKE IMMUNE 592 00:24:54,180 --> 00:24:57,650 RESPONSES AGAINST THEIR MOTHERS' 593 00:24:57,650 --> 00:24:59,185 NON-INHERITED HLA ANTIGENS BUT 594 00:24:59,185 --> 00:25:02,589 AGAINST THEIR FATHER BUT NOT 595 00:25:02,589 --> 00:25:03,356 THEIR MOTHER. 596 00:25:03,356 --> 00:25:06,292 ZHANG AND MILLER FOLLOWED UP IN 597 00:25:06,292 --> 00:25:08,161 CANADA WITH MICE, MAKING 598 00:25:08,161 --> 00:25:09,562 CROSSES, FOLLOW MATERNAL AND 599 00:25:09,562 --> 00:25:13,299 FETAL CELLS AND SO ON AND 600 00:25:13,299 --> 00:25:20,473 DISCOVERED 25% OF ADULT MICE ARE 601 00:25:20,473 --> 00:25:22,542 MICROCHIMERIC FOR HUMAN CELLS. 602 00:25:22,542 --> 00:25:29,215 50% OF PEOPLE WITH SKIDs HAVE 603 00:25:29,215 --> 00:25:31,317 T CELLS FROM THEIR MOTHERS. 604 00:25:31,317 --> 00:25:33,353 THERE WAS A BANDWAGON WILL 605 00:25:33,353 --> 00:25:34,787 EXTRA-THYMIC T CELL PRODUCTION 606 00:25:34,787 --> 00:25:36,322 BECAUSE PEOPLE COULD FIND T 607 00:25:36,322 --> 00:25:42,629 CELLS IN NUDE MICE WHICH HAVE NO 608 00:25:42,629 --> 00:25:42,862 THYMUS. 609 00:25:42,862 --> 00:25:50,903 THEY FOUND T CELLS IN THE 610 00:25:50,903 --> 00:25:51,137 OMENTUM. 611 00:25:51,137 --> 00:25:52,538 THERE'S AN INTERESTING THING 612 00:25:52,538 --> 00:25:56,676 ABOUT BREEDING NUDE MICE, NEW 613 00:25:56,676 --> 00:25:59,412 THYMUS OR HAIR. 614 00:25:59,412 --> 00:26:01,547 THEY ARE PRETTY INEFFICIENT AT 615 00:26:01,547 --> 00:26:02,915 KEEPING UP BODY TEMPERATURE. 616 00:26:02,915 --> 00:26:06,319 SO IF YOU WANT TO BREED NUDE 617 00:26:06,319 --> 00:26:07,820 MICE WITH NUDE MOTHERS, YOU HAVE 618 00:26:07,820 --> 00:26:09,956 TO KEEP YOUR ANIMAL COLONY AT 619 00:26:09,956 --> 00:26:12,792 ABOUT 80 OR MORE DEGREES. 620 00:26:12,792 --> 00:26:13,926 WHICH IS EXPENSIVE AND 621 00:26:13,926 --> 00:26:18,431 UNCOMFORTABLE FOR PEOPLE WHO 622 00:26:18,431 --> 00:26:20,066 WORK THERE. 623 00:26:20,066 --> 00:26:21,134 PEOPLE TAKE HETEROZYGOUS MOTHERS 624 00:26:21,134 --> 00:26:23,770 AND BREED THEM TO NUDE FATHERS. 625 00:26:23,770 --> 00:26:27,206 AND NOW 50% OF YOUR PUPS ARE 626 00:26:27,206 --> 00:26:27,874 NUDE. 627 00:26:27,874 --> 00:26:29,709 SO THAT'S HOW THEY BREED. 628 00:26:29,709 --> 00:26:34,380 WELL, TURNS OUT IF YOU BREED 629 00:26:34,380 --> 00:26:34,881 NUDES 630 00:26:34,881 --> 00:26:36,849 USING HETEROZYGOUS T CELL 631 00:26:36,849 --> 00:26:37,650 SUFFICIENT MOTHERS YOU FIND T 632 00:26:37,650 --> 00:26:39,218 CELLS IN THE BABY. 633 00:26:39,218 --> 00:26:41,421 IF YOU BREED NUDES FROM NUDE 634 00:26:41,421 --> 00:26:43,056 MOTHERS, IN YOUR 80-DEGREE 635 00:26:43,056 --> 00:26:46,559 COLONY, YOU DON'T FIND T CELLS 636 00:26:46,559 --> 00:26:47,560 IN THE BABIES. 637 00:26:47,560 --> 00:26:48,995 THEY ARE MATERNAL. 638 00:26:48,995 --> 00:26:50,530 THERE'S TRAFFIC FROM FETUS TO 639 00:26:50,530 --> 00:26:53,533 MOTHER AND TRAFFIC FROM MOTHER 640 00:26:53,533 --> 00:26:54,267 TO FETUS. 641 00:26:54,267 --> 00:26:58,104 SO THAT IDEA WAS WRONG. 642 00:26:58,104 --> 00:27:00,606 SO WHY DON'T MOTHERS REJECT 643 00:27:00,606 --> 00:27:01,074 THEIR FETUSES? 644 00:27:01,074 --> 00:27:04,410 ACCORDING TO THE DANGER MODEL, 645 00:27:04,410 --> 00:27:06,746 IN ORDER TO INDUCE REJECTION 646 00:27:06,746 --> 00:27:09,949 RESPONSE, YOU NEED ALARM SIGNALS 647 00:27:09,949 --> 00:27:11,117 TO ACTIVATE APCs. 648 00:27:11,117 --> 00:27:14,387 SO FETUSES THAT ARE DEVELOPING 649 00:27:14,387 --> 00:27:16,055 NORMALLY HAVE A LOT OF CELL 650 00:27:16,055 --> 00:27:18,324 DEATH, WE KNOW THAT. 651 00:27:18,324 --> 00:27:25,231 YOU TURN THE PRIMITIVE INTO PAW 652 00:27:25,231 --> 00:27:28,601 INTO A HAND, THEY GET SCAVENGED, 653 00:27:28,601 --> 00:27:30,269 THEY DON'T RELEASE ALARM 654 00:27:30,269 --> 00:27:30,503 SIGNALS. 655 00:27:30,503 --> 00:27:35,274 AS LONG AS YOUR FETUS IS 656 00:27:35,274 --> 00:27:36,576 DEVELOPING NORMALLY, AND 657 00:27:36,576 --> 00:27:42,715 HEALTHILY, THERE'S NO IMMUNE 658 00:27:42,715 --> 00:27:44,851 RESPONSE INITIATED. 659 00:27:44,851 --> 00:27:46,919 >> HOW DO YOU RECONCILE THAT 660 00:27:46,919 --> 00:27:47,220 (INAUDIBLE). 661 00:27:47,220 --> 00:27:52,558 >> HOW DO I RECONCILE THAT WITH 662 00:27:52,558 --> 00:27:54,460 THE GENERATION OF FETAL SPECIFIC 663 00:27:54,460 --> 00:27:56,629 T REGS, SO IF YOU WANT ME TO 664 00:27:56,629 --> 00:27:58,164 TALK ABOUT TREGS YOU'LL HAVE TO 665 00:27:58,164 --> 00:28:01,334 ASK ME TO COME BACK. 666 00:28:01,334 --> 00:28:02,335 [LAUGHTER] 667 00:28:02,335 --> 00:28:05,505 BECAUSE THAT IS NOT A ONE-MINUTE 668 00:28:05,505 --> 00:28:05,805 ANSWER. 669 00:28:05,805 --> 00:28:07,173 HERE'S THE OTHER ONE PEOPLE 670 00:28:07,173 --> 00:28:08,374 MIGHT BE THINKING ABOUT. 671 00:28:08,374 --> 00:28:11,611 HOW DO I RECONCILE THAT WITH 672 00:28:11,611 --> 00:28:13,579 ANTIBODIES TO RH? 673 00:28:13,579 --> 00:28:14,046 RIGHT? 674 00:28:14,046 --> 00:28:15,681 A MOTHER RH NEGATIVE WILL MAKE 675 00:28:15,681 --> 00:28:18,417 ANTIBODIES TO HER FETUS WHO IS 676 00:28:18,417 --> 00:28:22,688 RH POSITIVE. 677 00:28:22,688 --> 00:28:24,190 WHAT'S INTERESTING, GOD IS IN 678 00:28:24,190 --> 00:28:26,325 THE DETAILS, IT'S A PROBLEM IN 679 00:28:26,325 --> 00:28:28,461 THE SECOND PREGNANCY, NOT THE 680 00:28:28,461 --> 00:28:28,661 FIRST. 681 00:28:28,661 --> 00:28:31,564 AND PEOPLE WHO -- THE MEDICAL 682 00:28:31,564 --> 00:28:36,302 FIELD KNOWS THIS BECAUSE THEY 683 00:28:36,302 --> 00:28:39,205 GIVE RHOGAM, GIVE ANTIBODIES 684 00:28:39,205 --> 00:28:40,640 WHEN SHE'S HAVING HER FIRST 685 00:28:40,640 --> 00:28:40,840 BIRTH. 686 00:28:40,840 --> 00:28:43,142 BIRTH IS DANGEROUS. 687 00:28:43,142 --> 00:28:46,045 RIPPING, BLEEDING, SURGEONS WITH 688 00:28:46,045 --> 00:28:46,345 KNIVES. 689 00:28:46,345 --> 00:28:47,246 IT'S DANGEROUS. 690 00:28:47,246 --> 00:28:49,615 THAT'S WHEN THEY GET PRIMED. 691 00:28:49,615 --> 00:28:52,151 NOT DURING THE PREGNANCY. 692 00:28:52,151 --> 00:28:58,424 NOW, A GYNECOLOGIST IN MY LAB 693 00:28:58,424 --> 00:28:59,859 FOR A WHILE, LIZ BONNIE, NOW AT 694 00:28:59,859 --> 00:29:02,862 UNIVERSITY OF VERMONT SAID 695 00:29:02,862 --> 00:29:06,499 THERE ARE A FEW WHO WILL MAKE 696 00:29:06,499 --> 00:29:09,902 ANTIBODIES EARLIER THAN THAT 697 00:29:09,902 --> 00:29:11,971 WITH A FRAGILE PLACENTA. 698 00:29:11,971 --> 00:29:14,273 PIECES BREAK OFF, THAT'S NOT 699 00:29:14,273 --> 00:29:15,908 PROGRAMMED CELL DEATH. 700 00:29:15,908 --> 00:29:17,977 I DON'T THINK YOU NEED TREGS. 701 00:29:17,977 --> 00:29:22,215 WE'LL TALK ABOUT WHAT THEY DO 702 00:29:22,215 --> 00:29:24,283 SOME OTHER TIME. 703 00:29:24,283 --> 00:29:24,483 OKAY. 704 00:29:24,483 --> 00:29:27,353 SO, MOTHERS DON'T REJECT FETUSES 705 00:29:27,353 --> 00:29:29,021 BECAUSE FETUSES DON'T LOOK 706 00:29:29,021 --> 00:29:30,256 DANGEROUS. 707 00:29:30,256 --> 00:29:33,459 BUT THERE IS ONE CONDITION WHERE 708 00:29:33,459 --> 00:29:36,796 FETUSES CAN LOOK DANGEROUS AND 709 00:29:36,796 --> 00:29:40,766 CAN ACTUALLY INDUCE A DISEASE IN 710 00:29:40,766 --> 00:29:41,000 MOM. 711 00:29:41,000 --> 00:29:44,070 SO, WE'RE MOVING TO 712 00:29:44,070 --> 00:29:44,604 AUTOIMMUNITY. 713 00:29:44,604 --> 00:29:46,372 THERE'S AN INTERESTING 714 00:29:46,372 --> 00:29:47,974 PHENOMENON IN LUPUS, THE ONLY 715 00:29:47,974 --> 00:29:48,641 AUTOIMMUNE DISEASE I'M GOING TO 716 00:29:48,641 --> 00:29:51,344 TALK ABOUT TODAY. 717 00:29:51,344 --> 00:29:53,279 I PUBLISHED A REVIEW IN 718 00:29:53,279 --> 00:29:54,313 FRONTIERS IN IMMUNOLOGY ON 719 00:29:54,313 --> 00:29:55,014 AUTOIMMUNITY, IF YOU WANT TO 720 00:29:55,014 --> 00:30:01,554 KNOW WHAT I THINK ABOUT OTHER 721 00:30:01,554 --> 00:30:02,588 AUTOIMMUNE DISEASES. 722 00:30:02,588 --> 00:30:05,024 SO, IN LUPUS, OFTEN WOMEN WHO 723 00:30:05,024 --> 00:30:09,762 HAVE LUPUS AND GET PREGNANT HAVE 724 00:30:09,762 --> 00:30:13,699 VERY FEW OR NO FLARES WHILE 725 00:30:13,699 --> 00:30:14,267 PREGNANT. 726 00:30:14,267 --> 00:30:15,234 HOWEVER, THERE'S AN OPPOSITE 727 00:30:15,234 --> 00:30:16,168 FINDING AS WELL. 728 00:30:16,168 --> 00:30:19,005 WOMEN WHO DON'T HAVE LUPUS 729 00:30:19,005 --> 00:30:21,674 SOMETIMES GET LUPUS WHEN THEY 730 00:30:21,674 --> 00:30:22,008 ARE PREGNANT. 731 00:30:22,008 --> 00:30:23,609 AND THEN IT GOES AWAY WHEN THEY 732 00:30:23,609 --> 00:30:25,444 ARE NO LONGER PREGNANT. 733 00:30:25,444 --> 00:30:28,281 THAT'S USUALLY A MISCARRIAGE, AN 734 00:30:28,281 --> 00:30:28,681 IMPORTANT DETAIL. 735 00:30:28,681 --> 00:30:33,786 SO, HOW DO DO YOU HAVE A MODEL 736 00:30:33,786 --> 00:30:35,755 THAT CAN EXPLAIN THAT? 737 00:30:35,755 --> 00:30:36,589 STAY TUNED. 738 00:30:36,589 --> 00:30:39,625 SO, BEFORE WE GET INTO THAT, LET 739 00:30:39,625 --> 00:30:43,262 ME TALK ABOUT WHAT I THINK ABOUT 740 00:30:43,262 --> 00:30:47,099 TOLERANCE AND AUTOIMMUNITY. 741 00:30:47,099 --> 00:30:47,767 VERY QUICKLY. 742 00:30:47,767 --> 00:30:49,769 OKAY. 743 00:30:49,769 --> 00:30:51,671 YOU HAVE A THYMUS. 744 00:30:51,671 --> 00:30:54,907 AND YOU HAVE THREE KINDS OF T 745 00:30:54,907 --> 00:30:57,410 CELLS THAT LEAVE, THAT ARE KIND 746 00:30:57,410 --> 00:30:58,978 OF IMPORTANT HERE, NOT 747 00:30:58,978 --> 00:31:00,446 NECESSARILY LEAVE. 748 00:31:00,446 --> 00:31:05,217 THE FIRST ONE IS HIGH AFFINITY 749 00:31:05,217 --> 00:31:05,484 ANTI-SELF. 750 00:31:05,484 --> 00:31:06,052 THAT GETS DELETED. 751 00:31:06,052 --> 00:31:08,821 WE WOULD ALL AGREE THAT GETS 752 00:31:08,821 --> 00:31:09,255 DELETED. 753 00:31:09,255 --> 00:31:12,892 ANYBODY WHO DOESN'T, RAISE THEIR 754 00:31:12,892 --> 00:31:13,459 HAND. 755 00:31:13,459 --> 00:31:14,160 >> I DARE YOU. 756 00:31:14,160 --> 00:31:15,828 >> I DARE YOU, NO, RAISE YOUR 757 00:31:15,828 --> 00:31:16,062 HAND. 758 00:31:16,062 --> 00:31:17,363 THERE MIGHT BE SOME PEOPLE WHO 759 00:31:17,363 --> 00:31:19,231 DON'T AGREE WITH THAT. 760 00:31:19,231 --> 00:31:24,570 MOST OF US DO. 761 00:31:24,570 --> 00:31:28,040 THE SECOND IS AN ANTI-PERIPHERAL 762 00:31:28,040 --> 00:31:30,476 ANTIGEN THAT IS ON SOME KIND OF 763 00:31:30,476 --> 00:31:33,212 LARGE ORGAN LIKE SKIN OR LIVER. 764 00:31:33,212 --> 00:31:36,248 THIS IS NUMBER TWO. 765 00:31:36,248 --> 00:31:40,853 AND THEN THE THIRD ONE IS AN 766 00:31:40,853 --> 00:31:41,654 ANTI-PERIPHERAL ANTIGEN, 767 00:31:41,654 --> 00:31:43,689 SPECIFIC FOR SOMETHING THAT'S 768 00:31:43,689 --> 00:31:44,957 BARRICADED OR SMALL. 769 00:31:44,957 --> 00:31:48,661 LIKE BRAIN. 770 00:31:48,661 --> 00:31:52,331 OR LET'S SAY ISLETS. 771 00:31:52,331 --> 00:31:56,702 FORGETTING TREGS FOR THE MOMENT. 772 00:31:56,702 --> 00:31:59,839 WHAT HAPPENS TO THESE CELLS? 773 00:31:59,839 --> 00:32:03,309 THAT ONE GETS DELETED. 774 00:32:03,309 --> 00:32:04,343 THAT ONE LEAVES. 775 00:32:04,343 --> 00:32:08,214 BECAUSE LIVER ANTIGENS, NOT ALL 776 00:32:08,214 --> 00:32:10,816 ARE PRESENTED IN THE THYMUS, AND 777 00:32:10,816 --> 00:32:11,317 IT CIRCULATES. 778 00:32:11,317 --> 00:32:12,752 THE LIVER IS BIG, NOT 779 00:32:12,752 --> 00:32:13,886 BARRICADED, SOON IT WILL GO 780 00:32:13,886 --> 00:32:14,787 THROUGH THE LIVER. 781 00:32:14,787 --> 00:32:17,690 IT'S GOING TO SEE LIVER ANTIGENS 782 00:32:17,690 --> 00:32:20,826 ON LIVER APCs IN THE ABSENCE 783 00:32:20,826 --> 00:32:26,632 OF ALARM SIGNALS, ABSENCE OF 784 00:32:26,632 --> 00:32:27,500 CO-STIMULATION, AND IT DIES. 785 00:32:27,500 --> 00:32:30,069 BECAUSE THE LIVER IS BIG AND NOT 786 00:32:30,069 --> 00:32:33,406 VERY BARRICADED THAT T CELL 787 00:32:33,406 --> 00:32:35,241 DOESN'T LAST VERY LONG. 788 00:32:35,241 --> 00:32:37,376 LET'S LOOK AT T CELL NUMBER 789 00:32:37,376 --> 00:32:39,211 THREE AGAINST BRAIN OR ISLET. 790 00:32:39,211 --> 00:32:40,379 THERE'S NOT A LOT OF TRAFFIC 791 00:32:40,379 --> 00:32:41,080 THROUGH THE BRAIN. 792 00:32:41,080 --> 00:32:44,550 THERE IS TRAFFIC BUT NOT A LOT. 793 00:32:44,550 --> 00:32:46,185 AND THERE ISN'T A LOT OF TRAFFIC 794 00:32:46,185 --> 00:32:51,457 THROUGH HIGH LET'S OF LANGERHANS 795 00:32:51,457 --> 00:32:52,792 EITHER, THEY ARE GOING TO 796 00:32:52,792 --> 00:32:53,893 CIRCULATE A WHILE BEFORE THEY 797 00:32:53,893 --> 00:32:56,128 SEE THEIR ANTIGEN. 798 00:32:56,128 --> 00:32:59,698 IF BOTH CASES, SHOULD THE T CELL 799 00:32:59,698 --> 00:33:05,771 GET ACTIVATED BEFORE IT GETS 800 00:33:05,771 --> 00:33:06,138 TOLERIZED? 801 00:33:06,138 --> 00:33:06,472 WHAT HAPPENS? 802 00:33:06,472 --> 00:33:07,873 LET'S LOOK AT THE LIVER T CELL 803 00:33:07,873 --> 00:33:09,075 AND SAY IT'S OUT THERE, IT'S 804 00:33:09,075 --> 00:33:10,976 COME OUT OF THE THYMUS 805 00:33:10,976 --> 00:33:11,944 YESTERDAY, HASN'T GONE THROUGH 806 00:33:11,944 --> 00:33:15,247 THE LIVER YET, AND YOU GET AN 807 00:33:15,247 --> 00:33:18,150 INFECTION, EITHER IN THE LIVER 808 00:33:18,150 --> 00:33:19,718 OR CROSS-REACTS WITH THE LIVER. 809 00:33:19,718 --> 00:33:26,025 THAT T CELL GETS ACTIVATED. 810 00:33:26,025 --> 00:33:27,560 IT EXPANDS ITS POPULATION, LET'S 811 00:33:27,560 --> 00:33:30,429 SAY IT'S A CD8, GOES OUT AND 812 00:33:30,429 --> 00:33:31,664 AMONG OTHER THINGS WIPES OUT 813 00:33:31,664 --> 00:33:34,366 PART OF THE LIVER. 814 00:33:34,366 --> 00:33:37,203 EACH CD8 IS ESTIMATED TO KILL 815 00:33:37,203 --> 00:33:39,438 BETWEEN THREE AND 30 OR A 816 00:33:39,438 --> 00:33:40,940 HUNDRED TARGETS AND NEEDS TO BE 817 00:33:40,940 --> 00:33:41,273 RESTIMULATED. 818 00:33:41,273 --> 00:33:46,912 WE'LL COME BACK IF I HAVE TIME 819 00:33:46,912 --> 00:33:48,714 FOR TUMORS. 820 00:33:48,714 --> 00:33:51,684 REMEMBER THAT, THREE TO A 821 00:33:51,684 --> 00:33:52,651 HUNDRED TARGETS. 822 00:33:52,651 --> 00:33:56,755 WHEN IT KILLS THREE OR A HUNDRED 823 00:33:56,755 --> 00:33:57,590 LIVER CELLS, IT RESTS. 824 00:33:57,590 --> 00:34:00,126 IF THE INFECTION IS OVER, IT NOW 825 00:34:00,126 --> 00:34:01,660 CIRCULATES AND WILL AGAIN 826 00:34:01,660 --> 00:34:02,394 CIRCULATE THROUGH THE LIVER IN 827 00:34:02,394 --> 00:34:08,434 THE ABSENCE OF ALARM SIGNALS AND 828 00:34:08,434 --> 00:34:08,767 GET TOLERIZED. 829 00:34:08,767 --> 00:34:10,503 PEOPLE FORGET MEMORY CELLS CAN 830 00:34:10,503 --> 00:34:13,572 ALSO BE DELETED BY LACK OF 831 00:34:13,572 --> 00:34:14,106 CO-STIMULATION. 832 00:34:14,106 --> 00:34:16,375 THIS WAS FIRST DISCOVERED WITH T 833 00:34:16,375 --> 00:34:18,110 CELL CLONES. 834 00:34:18,110 --> 00:34:19,245 WHICH ARE MEMORY CELLS. 835 00:34:19,245 --> 00:34:20,946 NOT ONLY THE NAIVE CELL THAT CAN 836 00:34:20,946 --> 00:34:23,182 GET DELETED IN THE PERIPHERY, 837 00:34:23,182 --> 00:34:23,983 ABSENCE OF CO-STIMULATION, IT'S 838 00:34:23,983 --> 00:34:25,718 ALSO THE MEMORY CELL. 839 00:34:25,718 --> 00:34:28,487 YOU ALWAYS HAVE THIS CHANCE TO 840 00:34:28,487 --> 00:34:29,989 KEEP DELETING YOUR AUTOREACTIVE 841 00:34:29,989 --> 00:34:34,059 CELLS IN THE PERIPHERY, IF IT'S 842 00:34:34,059 --> 00:34:35,127 A HEALTHY PERIPHERY. 843 00:34:35,127 --> 00:34:37,763 WHAT ABOUT THE BRAIN T CELL? 844 00:34:37,763 --> 00:34:40,499 SO, IT LASTS A BIT LONGER. 845 00:34:40,499 --> 00:34:42,535 IT MIGHT LAST A LOT LONGER. 846 00:34:42,535 --> 00:34:45,104 AND SO IT HAS A HIGHER 847 00:34:45,104 --> 00:34:48,107 PROBABILITY OF GETTING ACTIVATED 848 00:34:48,107 --> 00:34:49,575 BEFORE IT BECOMES TOLERIZED. 849 00:34:49,575 --> 00:34:56,515 SO, I'M NO LONGER SURPRISED THAT 850 00:34:56,515 --> 00:34:57,616 MUCH AUTOIMMUNITY, 851 00:34:57,616 --> 00:35:01,120 TISSUE-SPECIFIC AUTOIMMUNITY, IS 852 00:35:01,120 --> 00:35:03,789 TO SMALL OR BARRICADED ORGANS. 853 00:35:03,789 --> 00:35:04,657 BRAIN, ISLETS, EYE, WE'LL COME 854 00:35:04,657 --> 00:35:07,259 BACK TO THE EYE. 855 00:35:07,259 --> 00:35:12,598 GO AHEAD. 856 00:35:12,598 --> 00:35:12,798 SHOUT. 857 00:35:12,798 --> 00:35:13,032 LOUDER. 858 00:35:13,032 --> 00:35:23,342 >> (INAUDIBLE). 859 00:35:25,177 --> 00:35:27,680 >> THE QUESTION IS, DO I THINK 860 00:35:27,680 --> 00:35:29,148 THAT ORGANS THAT HAVE MORE DEATH 861 00:35:29,148 --> 00:35:32,618 LIKE THE LIVER AS OPPOSED TO THE 862 00:35:32,618 --> 00:35:35,354 BRAIN, DEPENDS ON HOW MUCH 863 00:35:35,354 --> 00:35:36,088 ALCOHOL YOU DRINK, RIGHT? 864 00:35:36,088 --> 00:35:37,890 THAT I WOULD HAVE A HIGHER 865 00:35:37,890 --> 00:35:43,662 PROBABILITY OF HAVING AN 866 00:35:43,662 --> 00:35:44,430 AUTOIMMUNE RESPONSE. 867 00:35:44,430 --> 00:35:46,465 SHORT ANSWER, I DON'T KNOW. 868 00:35:46,465 --> 00:35:49,268 SLIGHTLY LONGER ANSWER, I THINK 869 00:35:49,268 --> 00:35:49,435 NOT. 870 00:35:49,435 --> 00:35:51,003 BECAUSE IN ORGANS WHERE YOU HAVE 871 00:35:51,003 --> 00:35:52,738 A LOT OF DEATH, LIKE GERMINAL 872 00:35:52,738 --> 00:35:57,776 CENTERS, WE'LL GET TO THAT, YOU 873 00:35:57,776 --> 00:36:01,080 ALSO HAVE SPECIAL SCAVENGERS AND 874 00:36:01,080 --> 00:36:02,581 GOOD SCAVENGING TO PICK UP DYING 875 00:36:02,581 --> 00:36:03,682 CELLS. 876 00:36:03,682 --> 00:36:05,017 IF THEY ARE DYING BY PROGRAMMED 877 00:36:05,017 --> 00:36:06,285 CELL DEATH, THEN NO. 878 00:36:06,285 --> 00:36:07,286 IF YOU'RE DOING DAMAGE, IF I 879 00:36:07,286 --> 00:36:08,954 BEAT YOU OVER THE HEAD WITH A 880 00:36:08,954 --> 00:36:10,022 BASEBALL BAT EVERY DAY FROM THE 881 00:36:10,022 --> 00:36:11,557 DAY YOU WERE BORN, YOU WOULD 882 00:36:11,557 --> 00:36:13,525 PROBABLY NOT ONLY BE KIND OF 883 00:36:13,525 --> 00:36:19,365 GAGA, BUT YOU MIGHT HAVE AN 884 00:36:19,365 --> 00:36:20,032 AUTOIMMUNE DISEASE AGAINST 885 00:36:20,032 --> 00:36:21,634 SOMETHING IN YOUR HEAD. 886 00:36:21,634 --> 00:36:24,803 WHEN DEATH IS NORMAL PROCESS YOU 887 00:36:24,803 --> 00:36:25,404 HAVE SPECIAL SCAVENGERS. 888 00:36:25,404 --> 00:36:26,472 THANK YOU FOR ASKING THE 889 00:36:26,472 --> 00:36:27,006 QUESTION. 890 00:36:27,006 --> 00:36:29,241 LET'S USE THAT. 891 00:36:29,241 --> 00:36:31,710 SO MANY MANY YEARS AGO, I WAS IN 892 00:36:31,710 --> 00:36:33,345 GERMANY TALKING TO MEDICAL 893 00:36:33,345 --> 00:36:35,381 STUDENTS. 894 00:36:35,381 --> 00:36:37,516 I GAVE THEM A TOTAL FAIRY TALE 895 00:36:37,516 --> 00:36:40,152 ABOUT ONE WAY OF GETTING LUPUS. 896 00:36:40,152 --> 00:36:42,821 IT TURNED OUT ONE OF THOSE 897 00:36:42,821 --> 00:36:44,256 MEDICAL STUDENTS GREW UP TO 898 00:36:44,256 --> 00:36:47,326 BECOME A RHEUMATOLOGIST AND 899 00:36:47,326 --> 00:36:48,360 TESTED THAT FAIRY TALE AND IT 900 00:36:48,360 --> 00:36:49,628 TURNED OUT TO BE TRUE. 901 00:36:49,628 --> 00:36:52,965 HERE IS THE FAIRY TALE. 902 00:36:52,965 --> 00:36:57,303 IN GERMINAL CENTERS, SO A 903 00:36:57,303 --> 00:36:59,838 GERMINAL CENTER, WHAT IS A 904 00:36:59,838 --> 00:37:00,706 GERMINAL CENTER? 905 00:37:00,706 --> 00:37:06,578 IT'S PART OF A LYMPH NODE OR 906 00:37:06,578 --> 00:37:09,848 SPLEEN WHERE B CELLS PLUS T, 907 00:37:09,848 --> 00:37:13,485 FHs, WORK TOGETHER TO MAKE AN 908 00:37:13,485 --> 00:37:14,653 ANTIBODY RESPONSE. 909 00:37:14,653 --> 00:37:16,455 THEY B CELLS PROLIFERATE. 910 00:37:16,455 --> 00:37:22,461 IN THE PROLIFERATION THEY NOT 911 00:37:22,461 --> 00:37:22,928 ONLY PROLIFERATE THEY 912 00:37:22,928 --> 00:37:24,797 HYPERMUTATE, GETTING B CELLS 913 00:37:24,797 --> 00:37:28,367 WITH HIGHER AFFINITY BUT IN THAT 914 00:37:28,367 --> 00:37:29,601 PROCESS OF RANDOM HYPERMUTATION 915 00:37:29,601 --> 00:37:31,270 A LOT OF B CELLS GET LOWER 916 00:37:31,270 --> 00:37:35,274 AFFINITY, SOME MAKE NO ANTIBODY 917 00:37:35,274 --> 00:37:37,309 AT ALL, THEY DIE BY PROGRAMMED 918 00:37:37,309 --> 00:37:38,010 CELL DEATH. 919 00:37:38,010 --> 00:37:40,879 THERE'S SO MUCH DEATH IN 920 00:37:40,879 --> 00:37:43,782 GERMINAL CENTERS THAT THERE ARE 921 00:37:43,782 --> 00:37:46,118 SPECIAL SCAVENGERS TO PICK THEM 922 00:37:46,118 --> 00:37:47,286 UP, MACROPHAGES. 923 00:37:47,286 --> 00:37:48,721 HERE WAS MY FAIRY TALE. 924 00:37:48,721 --> 00:37:56,028 SUPPOSE YOU HAD A TINGIBLE BODY 925 00:37:56,028 --> 00:37:57,663 MACROPHAGE, SO IT NO LONGER 926 00:37:57,663 --> 00:38:00,799 SAWING THE DYING B CELLS, B 927 00:38:00,799 --> 00:38:03,202 CELLS WOULD STILL DIE BY NORMAL 928 00:38:03,202 --> 00:38:05,571 PROGRAMMED CELL DEATH BUT 929 00:38:05,571 --> 00:38:08,640 WOULDN'T GET SCAVENGED, WOULD 930 00:38:08,640 --> 00:38:09,408 FALL APART. 931 00:38:09,408 --> 00:38:11,477 AND WHAT HAPPENS WHEN YOU FALL 932 00:38:11,477 --> 00:38:11,844 APART? 933 00:38:11,844 --> 00:38:13,045 YOU RELEASE ALARM SIGNALS. 934 00:38:13,045 --> 00:38:15,214 THIS IS A PERSON WHO WOULD HAVE 935 00:38:15,214 --> 00:38:19,518 A LUPUS FLARE EVERY TIME THEY 936 00:38:19,518 --> 00:38:22,121 GOT AN INFECTION THAT GAVE THEM 937 00:38:22,121 --> 00:38:22,888 GERMINAL CENTERS. 938 00:38:22,888 --> 00:38:27,393 MOST OF THE ANTIBODIES, NOT ALL, 939 00:38:27,393 --> 00:38:30,596 MOST ARE AGAINST INTRACELLULAR 940 00:38:30,596 --> 00:38:32,030 COMPONENTS, DNA, RNA, TUBULIN, 941 00:38:32,030 --> 00:38:35,634 SO ON, CELLS ARE FALLING APART. 942 00:38:35,634 --> 00:38:44,977 YOU DON'T GET ANTIBODIES TO M 943 00:38:44,977 --> 00:38:48,747 HC LUPUS BUT INTRACELLULAR 944 00:38:48,747 --> 00:38:49,047 COMPONENTS. 945 00:38:49,047 --> 00:38:52,084 MARTIN HERMAN, I'LL WRITE HIS 946 00:38:52,084 --> 00:38:56,555 NAME DOWN, HERRMAN, LOOK HIM UP, 947 00:38:56,555 --> 00:38:56,889 THERE. 948 00:38:56,889 --> 00:39:00,559 I'M NOT GOOD AT THIS. 949 00:39:00,559 --> 00:39:04,096 WHEN HE LOOKED AT HIS LUPUS 950 00:39:04,096 --> 00:39:08,700 PATIENTS HE FOUND ABOUT 5% OF 951 00:39:08,700 --> 00:39:12,504 THEM HAD INDEED MUTATIONS IN THE 952 00:39:12,504 --> 00:39:13,372 SCAVENGE RECEPTOR OF TINGIBLE 953 00:39:13,372 --> 00:39:14,573 BODY MACROPHAGES. 954 00:39:14,573 --> 00:39:15,707 HOW ABOUT THAT? 955 00:39:15,707 --> 00:39:15,941 OKAY. 956 00:39:15,941 --> 00:39:19,144 YOU'LL SAY, YEAH, BUT LUPUS IS 957 00:39:19,144 --> 00:39:20,746 PREDOMINANTLY A FEMALE DISEASE. 958 00:39:20,746 --> 00:39:23,649 WELL, TRUE. 959 00:39:23,649 --> 00:39:24,716 AND NOT. 960 00:39:24,716 --> 00:39:29,354 SO, POST PUBERTY ONSET LUPUS IS 961 00:39:29,354 --> 00:39:30,889 PREDOMINANTLY FEMALE. 962 00:39:30,889 --> 00:39:32,057 PRE-PUBERTY ONSET LUPUS, WHICH 963 00:39:32,057 --> 00:39:35,961 IS RARE, HAS NO SEX BIAS. 964 00:39:35,961 --> 00:39:39,465 SO WHY IS IT THAT POST PUBERTY 965 00:39:39,465 --> 00:39:41,533 ONSET LUPUS IS MOSTLY FEMALE? 966 00:39:41,533 --> 00:39:43,368 I THINK IT'S BECAUSE THERE IS 967 00:39:43,368 --> 00:39:44,403 DEATH THAT GOES ON IN FEMALE 968 00:39:44,403 --> 00:39:47,005 BODIES THAT DOESN'T GO ON IN 969 00:39:47,005 --> 00:39:49,308 MALE BODIES, WE POP AN OVARY 970 00:39:49,308 --> 00:39:52,578 EVERY MONTH, KILL OFF, CLEAN UP, 971 00:39:52,578 --> 00:39:53,912 REGENERATE AN ENTIRE UTERINE 972 00:39:53,912 --> 00:39:54,813 LINING EVERY MONTH. 973 00:39:54,813 --> 00:39:55,747 THAT'S A LOT OF DEATH. 974 00:39:55,747 --> 00:39:58,050 IT'S A LOT OF SCAVENGING, IT'S A 975 00:39:58,050 --> 00:39:59,985 LOT OF WOUND HEALING AND SO ON. 976 00:39:59,985 --> 00:40:04,289 IT'S A LOT OF GENES INVOLVED, A 977 00:40:04,289 --> 00:40:07,993 LOT OF POTENTIAL FOR MUTATIONS. 978 00:40:07,993 --> 00:40:12,264 AND A LOT OF POTENTIAL FOR 979 00:40:12,264 --> 00:40:14,800 ENVIRONMENTAL INSULT. 980 00:40:14,800 --> 00:40:18,971 SO, I TELL RHEUMATOLOGISTS WHO 981 00:40:18,971 --> 00:40:20,906 GET YOUNG LUPUS PATIENTS THEY 982 00:40:20,906 --> 00:40:22,908 USUALLY ARE DIAGNOSED IN THEIR 983 00:40:22,908 --> 00:40:23,976 TEENS AND EARLY 20s, TO PUT 984 00:40:23,976 --> 00:40:26,845 THEM ON THE PILL AND DON'T LET 985 00:40:26,845 --> 00:40:28,614 THEM CYCLE. 986 00:40:28,614 --> 00:40:31,016 AND SEE WHAT HAPPENS. 987 00:40:31,016 --> 00:40:33,986 IT'S CALLED DIAGNOSIS BY 988 00:40:33,986 --> 00:40:34,753 TREATMENT. 989 00:40:34,753 --> 00:40:36,154 I WOULD BET THAT A GOOD 990 00:40:36,154 --> 00:40:38,257 PROPORTION OF THOSE PEOPLE WILL 991 00:40:38,257 --> 00:40:39,224 STOP HAVING THEIR LUPUS 992 00:40:39,224 --> 00:40:39,691 SYMPTOMS. 993 00:40:39,691 --> 00:40:41,159 I GAVE THIS TALK MANY YEARS AGO 994 00:40:41,159 --> 00:40:44,029 AND A VERY OLD LADY, OLDER THAN 995 00:40:44,029 --> 00:40:45,531 I AM, CERTAINLY OLDER THAN I WAS 996 00:40:45,531 --> 00:40:47,132 THEN, CAME UP TO ME LATER AND 997 00:40:47,132 --> 00:40:49,735 SAID SHE GOT LUPUS WHEN SHE WAS 998 00:40:49,735 --> 00:40:51,937 14, AND HER FAMILY PHYSICIAN, A 999 00:40:51,937 --> 00:40:53,872 LONG TIME AGO, FAMILY PHYSICIAN 1000 00:40:53,872 --> 00:40:55,641 TOLD HER IF SHE MADE IT TO 1001 00:40:55,641 --> 00:40:58,143 MENOPAUSE IT MIGHT GO AWAY. 1002 00:40:58,143 --> 00:41:01,914 SHE MADE IT TO MENOPAUSE, IT 1003 00:41:01,914 --> 00:41:03,315 WENT AWAY. 1004 00:41:03,315 --> 00:41:04,750 AND THIS ACTUALLY HAPPENS TO 1005 00:41:04,750 --> 00:41:06,885 SOME PROPORTION OF PEOPLE WHO 1006 00:41:06,885 --> 00:41:09,988 HAVE LUPUS. 1007 00:41:09,988 --> 00:41:12,190 IT'S A REPRODUCTIVE-AGE PROBLEM. 1008 00:41:12,190 --> 00:41:13,559 SO WHEN I TELL RHEUMATOLOGISTS 1009 00:41:13,559 --> 00:41:15,227 PUT THEM ON THE PILL AND DON'T 1010 00:41:15,227 --> 00:41:17,162 LET THEM CYCLE THEY SAY THAT'S 1011 00:41:17,162 --> 00:41:18,196 NOT NORMAL, WE'RE NOT DOING 1012 00:41:18,196 --> 00:41:18,830 THAT. 1013 00:41:18,830 --> 00:41:20,132 YOU KNOW WHAT? 1014 00:41:20,132 --> 00:41:22,568 CYCLING EVERY MONTH ISN'T NORMAL 1015 00:41:22,568 --> 00:41:22,935 EITHER. 1016 00:41:22,935 --> 00:41:24,836 WE WERE NOT MEANT TO CYCLE EVERY 1017 00:41:24,836 --> 00:41:25,037 MONTH. 1018 00:41:25,037 --> 00:41:29,041 UNTIL THE PILL WE TENDED TO BE 1019 00:41:29,041 --> 00:41:30,008 PREGNANT OR LACTATING. 1020 00:41:30,008 --> 00:41:33,612 CYCLING EVERY MONTH IS NOT 1021 00:41:33,612 --> 00:41:35,013 NORMAL. 1022 00:41:35,013 --> 00:41:37,583 NO WONDER, MAYBE, LUPUS 1023 00:41:37,583 --> 00:41:38,984 INCIDENCE HAS RISEN SINCE THE 1024 00:41:38,984 --> 00:41:43,255 1960 IT'S WHEN THE PILL WAS 1025 00:41:43,255 --> 00:41:44,323 FIRST MADE. 1026 00:41:44,323 --> 00:41:45,857 SO, OKAY, I TOLD YOU THAT I 1027 00:41:45,857 --> 00:41:48,026 WOULD TELL YOU ABOUT THESE TWO 1028 00:41:48,026 --> 00:41:49,728 PREGNANCY THINGS. 1029 00:41:49,728 --> 00:41:55,100 THE WOMAN WHO HAS LUPUS, GETS 1030 00:41:55,100 --> 00:41:56,368 PREGNANT, NO LONGER CYCLING. 1031 00:41:56,368 --> 00:41:58,036 WHATEVER IS GOING WRONG WITH 1032 00:41:58,036 --> 00:42:00,973 CYCLES IS GIVING HER THIS ALARM 1033 00:42:00,973 --> 00:42:02,307 SIGNAL AND RESPONSES, IS NO 1034 00:42:02,307 --> 00:42:05,677 LONGER HAPPENING. 1035 00:42:05,677 --> 00:42:07,012 SHE DOESN'T FLARE. 1036 00:42:07,012 --> 00:42:10,882 AND VERY OFTEN THEY FLARE WITH A 1037 00:42:10,882 --> 00:42:12,084 VENGEANCE AFTER BIRTH. 1038 00:42:12,084 --> 00:42:12,784 THAT'S A DANGER MODEL 1039 00:42:12,784 --> 00:42:14,686 EXPLANATION FOR WHY THEY DON'T 1040 00:42:14,686 --> 00:42:14,886 FLARE. 1041 00:42:14,886 --> 00:42:16,088 HERE'S THE DANGER MODEL 1042 00:42:16,088 --> 00:42:18,256 EXPLANATION FOR THOSE WOMEN WHO 1043 00:42:18,256 --> 00:42:19,391 DON'T HAVE LUPUS, WHO NOW 1044 00:42:19,391 --> 00:42:22,828 SOMETIMES GET IT WHILE THEY ARE 1045 00:42:22,828 --> 00:42:23,128 PREGNANT. 1046 00:42:23,128 --> 00:42:24,763 THAT IS THERE'S SOMETHING WRONG 1047 00:42:24,763 --> 00:42:25,464 WITH THE FETUS. 1048 00:42:25,464 --> 00:42:27,966 THERE'S A LOT OF DEATH IN THE 1049 00:42:27,966 --> 00:42:28,500 FETUS. 1050 00:42:28,500 --> 00:42:30,068 A LOT OF PROGRAMMED CELL DEATH, 1051 00:42:30,068 --> 00:42:32,204 A LOT OF GENES. 1052 00:42:32,204 --> 00:42:35,240 A LOT OF SCAVENGING. 1053 00:42:35,240 --> 00:42:35,841 MORE GENES. 1054 00:42:35,841 --> 00:42:37,709 IMAGINE YOU HAVE A FETUS THAT 1055 00:42:37,709 --> 00:42:40,312 HAS SOMETHING GOING WRONG WITH 1056 00:42:40,312 --> 00:42:42,180 ITS DEATH PROCESS. 1057 00:42:42,180 --> 00:42:44,583 SO IT'S RELEASING ALARM SIGNALS. 1058 00:42:44,583 --> 00:42:46,018 CELLS ARE FALLING APART. 1059 00:42:46,018 --> 00:42:47,319 THE MOTHER, BECAUSE WE KNOW 1060 00:42:47,319 --> 00:42:49,955 THERE'S TRAFFIC IN BOTH 1061 00:42:49,955 --> 00:42:51,923 DIRECTIONS, THE MOTHER RESPONDS 1062 00:42:51,923 --> 00:42:52,891 TO THAT. 1063 00:42:52,891 --> 00:42:55,861 AND WHILE SHE'S PREGNANT WITH 1064 00:42:55,861 --> 00:42:57,396 THIS SLIGHTLY DAMAGED WHATEVER, 1065 00:42:57,396 --> 00:43:02,401 FETUS, SHE WILL HAVE LUPUS. 1066 00:43:02,401 --> 00:43:03,035 THESE FETUSES, MOSTLY MISCARRY, 1067 00:43:03,035 --> 00:43:04,503 WHAT YOU'D EXPECT FROM A FETUS 1068 00:43:04,503 --> 00:43:08,006 WHO HAS A PROBLEM WITH DEATH 1069 00:43:08,006 --> 00:43:08,507 PROCESSES. 1070 00:43:08,507 --> 00:43:11,176 ONCE THEY LEAVE, THE MOTHER'S 1071 00:43:11,176 --> 00:43:11,843 LUPUS GOES AWAY. 1072 00:43:11,843 --> 00:43:19,151 THAT'S HOW THE DANGER MODEL CAN 1073 00:43:19,151 --> 00:43:21,453 EXPLAIN. 1074 00:43:21,453 --> 00:43:21,653 OKAY. 1075 00:43:21,653 --> 00:43:24,322 THAT'S AUTOIMMUNITY IN A VERY 1076 00:43:24,322 --> 00:43:26,291 SMALL NUTSHELL. 1077 00:43:26,291 --> 00:43:34,266 TUMORS. 1078 00:43:34,266 --> 00:43:35,233 SO, IMMUNOTHERAPY OF TUMORS IS 1079 00:43:35,233 --> 00:43:39,638 AT LEAST FOR SOME PEOPLE THE 1080 00:43:39,638 --> 00:43:44,076 BANDWAGON OF THE DAY. 1081 00:43:44,076 --> 00:43:46,611 WAS IT 2018, 17, CAR-T CELLS, 1082 00:43:46,611 --> 00:43:49,147 CAR T CELL RECEPTOR WAS THE 1083 00:43:49,147 --> 00:43:50,882 MOLECULE OF THE YEAR? 1084 00:43:50,882 --> 00:43:52,951 IT'S WONDERFUL. 1085 00:43:52,951 --> 00:43:55,854 PEOPLE ARE MAKING NEW VACCINES. 1086 00:43:55,854 --> 00:43:57,789 USING CAR-T CELLS, USING 1087 00:43:57,789 --> 00:43:58,657 CHECKPOINT INHIBITORS. 1088 00:43:58,657 --> 00:44:03,161 AND THEY ARE GETTING A LOT OF 1089 00:44:03,161 --> 00:44:03,595 RESULTS. 1090 00:44:03,595 --> 00:44:06,598 IN 30 TO 40% OF TUMOR-BEARING 1091 00:44:06,598 --> 00:44:06,898 PEOPLE. 1092 00:44:06,898 --> 00:44:11,670 WHAT'S GOING ON IN THE OTHER 60 1093 00:44:11,670 --> 00:44:12,671 TO 70%? 1094 00:44:12,671 --> 00:44:15,741 HERE'S A DANGER MODEL POINT OF 1095 00:44:15,741 --> 00:44:18,543 VIEW ON THIS. 1096 00:44:18,543 --> 00:44:21,546 WHAT'S WRONG WITH THE TUMOR? 1097 00:44:21,546 --> 00:44:23,181 SOMEBODY, WHAT'S WRONG WITH A 1098 00:44:23,181 --> 00:44:23,515 TUMOR? 1099 00:44:23,515 --> 00:44:30,322 WHAT MAKES A TUMOR A TUMOR? 1100 00:44:30,322 --> 00:44:30,455 1101 00:44:30,455 --> 00:44:31,957 LOSS OF GROWTH INHIBITION, 1102 00:44:31,957 --> 00:44:32,891 UNCONTROLLED GROWTH. 1103 00:44:32,891 --> 00:44:34,126 WHEN A CELL STARTS UNCONTROLLED 1104 00:44:34,126 --> 00:44:35,961 GROWING IT DOES LOTS OF OTHER 1105 00:44:35,961 --> 00:44:36,461 THINGS. 1106 00:44:36,461 --> 00:44:39,598 BUT IT'S THAT LOSS OF GROWTH 1107 00:44:39,598 --> 00:44:43,401 CONTROL WHICH IS REALLY THE 1108 00:44:43,401 --> 00:44:45,871 UNIVERSAL ASPECT OF TUMORS. 1109 00:44:45,871 --> 00:44:47,038 THE IMMUNE SYSTEM CANNOT 1110 00:44:47,038 --> 00:44:47,806 DISCRIMINATE BETWEEN RAPID CELL 1111 00:44:47,806 --> 00:44:49,875 DIVISION IN THE BONE MARROW, IN 1112 00:44:49,875 --> 00:44:51,843 THE GUT, RAPID CELL DIVISION IN 1113 00:44:51,843 --> 00:44:53,278 THYMUS, RAPID CELL DIVISION IN 1114 00:44:53,278 --> 00:44:56,248 SKIN, AND RAPID CELL DIVISION IN 1115 00:44:56,248 --> 00:44:57,449 A TUMOR. 1116 00:44:57,449 --> 00:44:59,551 THAT'S NOT SENDING ALARM 1117 00:44:59,551 --> 00:45:00,152 SIGNALS. 1118 00:45:00,152 --> 00:45:03,155 SO, AT LEAST IN THE EARLY STAGES 1119 00:45:03,155 --> 00:45:05,991 OF TUMORS, YOU KNOW, THEY ARE 1120 00:45:05,991 --> 00:45:08,293 GROWING, DIVIDING. 1121 00:45:08,293 --> 00:45:09,694 OR MULTIPLYING. 1122 00:45:09,694 --> 00:45:13,331 BECAUSE DIVISION AND 1123 00:45:13,331 --> 00:45:14,833 MULTIPLICATION IN BIOLOGY ARE 1124 00:45:14,833 --> 00:45:16,668 THE SAME. 1125 00:45:16,668 --> 00:45:18,036 WHILE THEY ARE GROWING, YOU 1126 00:45:18,036 --> 00:45:20,672 KNOW, THEY ARE NOT SENDING ALARM 1127 00:45:20,672 --> 00:45:22,240 SIGNALS. 1128 00:45:22,240 --> 00:45:24,709 SO, WHAT HAPPENS TO A T CELL 1129 00:45:24,709 --> 00:45:28,780 THAT IS CIRCULATING THAT CAN SEE 1130 00:45:28,780 --> 00:45:31,983 A TUMOR ANTIGEN IN A C MOLECULE? 1131 00:45:31,983 --> 00:45:34,186 IT WILL GET SIGNALED. 1132 00:45:34,186 --> 00:45:37,255 IT WON'T GET CO-STIMULATED. 1133 00:45:37,255 --> 00:45:39,191 AND SO IT DIES. 1134 00:45:39,191 --> 00:45:41,459 SO, WHILE THIS TUMOR IS GROWING, 1135 00:45:41,459 --> 00:45:43,795 IT'S INDUCING TOLERANCE OF 1136 00:45:43,795 --> 00:45:44,629 ITSELF. 1137 00:45:44,629 --> 00:45:46,498 NOW WHEN IT GETS -- IF IT'S A 1138 00:45:46,498 --> 00:45:50,235 SOLID TUMOR AND GETS BIG ENOUGH, 1139 00:45:50,235 --> 00:45:51,469 AND IF IT'S POORLY VASCULARIZED 1140 00:45:51,469 --> 00:45:57,209 IT WILL START TO STARVE IN THE 1141 00:45:57,209 --> 00:45:57,776 MIDDLE. 1142 00:45:57,776 --> 00:46:00,946 AND TUMOR PATHOLOGISTS TELL ME, 1143 00:46:00,946 --> 00:46:03,982 THEY CALL THIS STERILE NECROSIS, 1144 00:46:03,982 --> 00:46:04,916 BECAUSE STARVATION IS PROGRAMMED 1145 00:46:04,916 --> 00:46:05,217 CELL DEATH. 1146 00:46:05,217 --> 00:46:08,887 AND SO THESE CELLS ARE GOING TO 1147 00:46:08,887 --> 00:46:09,721 GET SCAVENGED. 1148 00:46:09,721 --> 00:46:11,590 SO YOU STILL DON'T GET 1149 00:46:11,590 --> 00:46:12,390 ACTIVATION OF T CELLS. 1150 00:46:12,390 --> 00:46:17,429 AND THEY CONTINUE TO BE 1151 00:46:17,429 --> 00:46:17,896 TOLERIZED. 1152 00:46:17,896 --> 00:46:21,132 WHEN THE DEATH GETS SO BIG THAT 1153 00:46:21,132 --> 00:46:23,602 THE SCAVENGING CAPACITY IS 1154 00:46:23,602 --> 00:46:26,104 OVERLOADED, NOW YOU WILL GET 1155 00:46:26,104 --> 00:46:29,407 SOME ALARM SIGNALS, SOME CELLS 1156 00:46:29,407 --> 00:46:39,885 DIE AND DON'T GET SCAVENGED, 1157 00:46:49,895 --> 00:46:50,495 TUMOR INFILTRATING LYMPHOCYTES, 1158 00:46:50,495 --> 00:46:51,997 TILs, TAKE THEM OUT, GROW THEM 1159 00:46:51,997 --> 00:46:55,400 IN BATHTUBS FULL OF IL-2, AND 1160 00:46:55,400 --> 00:46:56,835 STICK THEM BACK IN. 1161 00:46:56,835 --> 00:46:58,770 IF YOU'D HEARD STEVE GIVE A 1162 00:46:58,770 --> 00:47:00,939 TALK, I DON'T KNOW, 15 YEARS AGO 1163 00:47:00,939 --> 00:47:04,743 OR SO, HE ALWAYS HAD THREE 1164 00:47:04,743 --> 00:47:06,111 SLIDES HE GAVE. 1165 00:47:06,111 --> 00:47:09,547 ONE, FIRST ONE, A GUY WHO HAD A 1166 00:47:09,547 --> 00:47:10,649 MELANOMA METASTASIS IN HIS LUNG 1167 00:47:10,649 --> 00:47:14,119 THE SIZE OF A SOFTBALL. 1168 00:47:14,119 --> 00:47:15,220 HE ISOLATED TILs, PUT THEM 1169 00:47:15,220 --> 00:47:18,356 BACK IN, IT WENT DOWN TO THE 1170 00:47:18,356 --> 00:47:19,524 SIZE OF A BASEBALL. 1171 00:47:19,524 --> 00:47:20,625 HE DID IT AGAIN. 1172 00:47:20,625 --> 00:47:24,362 IT WENT DOWN TO THE SIZE OF A 1173 00:47:24,362 --> 00:47:25,130 GOLF BALL. 1174 00:47:25,130 --> 00:47:28,400 THEN IT GREW OUT AND KILLED THE 1175 00:47:28,400 --> 00:47:29,234 PATIENT. 1176 00:47:29,234 --> 00:47:31,469 WHAT IS WRONG WITH THIS PROCESS? 1177 00:47:31,469 --> 00:47:36,408 ANYBODY? 1178 00:47:36,408 --> 00:47:38,743 WHAT'S WRONG, HE STOPPED. 1179 00:47:38,743 --> 00:47:40,312 HE STOPPED. 1180 00:47:40,312 --> 00:47:44,249 AND PEOPLE WHO DO TUMOR VACCINES 1181 00:47:44,249 --> 00:47:44,916 ALSO STOP. 1182 00:47:44,916 --> 00:47:48,353 THEY GIVE A VACCINE ONCE, TWICE, 1183 00:47:48,353 --> 00:47:52,290 THREE TIMES, FIVE TIMES, THEY 1184 00:47:52,290 --> 00:47:52,490 STOP. 1185 00:47:52,490 --> 00:47:56,094 WHAT HAPPENS IS YOU'VE GOT A 1186 00:47:56,094 --> 00:48:00,365 TUMOR, AND IT'S GROWING. 1187 00:48:00,365 --> 00:48:01,366 YOU DO SOMETHING. 1188 00:48:01,366 --> 00:48:03,335 YOU VACCINATE, YOU PUT IN 1189 00:48:03,335 --> 00:48:05,270 TILs, YOU DO SOMETHING, IT 1190 00:48:05,270 --> 00:48:05,637 GETS SMALLER. 1191 00:48:05,637 --> 00:48:09,140 IF YOU GOT THE LAST TUMOR CELL, 1192 00:48:09,140 --> 00:48:09,341 GREAT. 1193 00:48:09,341 --> 00:48:11,109 IF YOU HAVEN'T, WHAT'S GOING ON 1194 00:48:11,109 --> 00:48:12,777 WITH THE IMMUNE RESPONSE, LET'S 1195 00:48:12,777 --> 00:48:15,880 SAY CD8, IS IT'S GOING UP, PEAKS 1196 00:48:15,880 --> 00:48:20,051 AT DAY 8 OR SO AND COMES DOWN. 1197 00:48:20,051 --> 00:48:20,685 RIGHT? 1198 00:48:20,685 --> 00:48:23,922 TUMOR STARTS TO GROW OUT AGAIN. 1199 00:48:23,922 --> 00:48:25,857 YOU DO IT AGAIN. 1200 00:48:25,857 --> 00:48:26,624 TUMOR GETS SMALLER. 1201 00:48:26,624 --> 00:48:33,531 YOU'RE IMMUNE RESPONSE GOES UP 1202 00:48:33,531 --> 00:48:34,099 AND COMES DOWN. 1203 00:48:34,099 --> 00:48:37,469 THEY STOP. 1204 00:48:37,469 --> 00:48:40,638 GIVING ONE OR TWO SHOTS OF A 1205 00:48:40,638 --> 00:48:45,610 VACCINE AGAINST A VIRUS OR 1206 00:48:45,610 --> 00:48:46,678 BACTERIUM OR WHATEVER, PATHOGEN, 1207 00:48:46,678 --> 00:48:48,446 WORKS, BECAUSE YOU GIVE THE 1208 00:48:48,446 --> 00:48:49,547 VACCINE, EXPAND YOUR T CELLS 1209 00:48:49,547 --> 00:48:52,617 THAT CAN SEE IT, BOOST, THAT'S 1210 00:48:52,617 --> 00:48:54,452 AS GOOD AS IT'S GOING TO GET 1211 00:48:54,452 --> 00:48:55,653 BECAUSE THERE ARE LIMITS TO HOW 1212 00:48:55,653 --> 00:48:57,288 MUCH YOU CAN EXPAND THEM. 1213 00:48:57,288 --> 00:48:58,623 THEY REST. 1214 00:48:58,623 --> 00:49:01,192 THEY GO INTO RESTING MEMORY 1215 00:49:01,192 --> 00:49:01,760 STATE. 1216 00:49:01,760 --> 00:49:04,162 WHEN THE PATHOGEN COMES, IT DOES 1217 00:49:04,162 --> 00:49:07,799 THE DAMAGE THAT REINITIATES THE 1218 00:49:07,799 --> 00:49:08,500 RESPONSE. 1219 00:49:08,500 --> 00:49:10,435 BUT KILLING OF TUMORS BY A 1220 00:49:10,435 --> 00:49:14,439 KILLER IS PROGRAMMED CELL DEATH. 1221 00:49:14,439 --> 00:49:15,507 IMMUNE SYSTEM DOES NOT THROW 1222 00:49:15,507 --> 00:49:16,741 FUEL ON THE FIRE. 1223 00:49:16,741 --> 00:49:18,977 KILLERS DON'T INDUCE A KIND OF 1224 00:49:18,977 --> 00:49:19,811 DEATH THAT'S IMMUNOGENIC. 1225 00:49:19,811 --> 00:49:21,980 MANY TUMOR PEOPLE TALK ABOUT 1226 00:49:21,980 --> 00:49:25,083 THIS, IMMUNOGENIC CELL DEATH AND 1227 00:49:25,083 --> 00:49:26,084 NON-IMMUNOGENIC CELL DEATH. 1228 00:49:26,084 --> 00:49:30,255 BUT THEY DON'T PUT IT TO WORK. 1229 00:49:30,255 --> 00:49:33,725 SO, STEVE ROSENBERG GAVE A TALK, 1230 00:49:33,725 --> 00:49:36,127 BEFORE COVID, SO SAY THREE YEARS 1231 00:49:36,127 --> 00:49:37,695 AGO, WHERE HE HAPPENED TO LET 1232 00:49:37,695 --> 00:49:42,000 SLIP THAT HE HAD GIVEN TWO 1233 00:49:42,000 --> 00:49:43,601 PATIENTS TILs, THREE TIMES. 1234 00:49:43,601 --> 00:49:47,138 BOTH OF THEM WENT INTO LONG-TERM 1235 00:49:47,138 --> 00:49:47,472 REMISSION. 1236 00:49:47,472 --> 00:49:50,108 SO I ASKED HIM WHY HE DOESN'T DO 1237 00:49:50,108 --> 00:49:51,309 THAT MORE OFTEN. 1238 00:49:51,309 --> 00:49:53,511 HIS ANSWER WAS INTERESTING. 1239 00:49:53,511 --> 00:49:55,313 HE SAID, I ONLY HAVE SO MUCH 1240 00:49:55,313 --> 00:49:55,780 MONEY. 1241 00:49:55,780 --> 00:49:57,549 I ONLY HAVE SO MANY CLINICAL 1242 00:49:57,549 --> 00:49:57,849 FELLOWS. 1243 00:49:57,849 --> 00:49:59,184 I ONLY HAVE SO MANY PATIENTS 1244 00:49:59,184 --> 00:50:00,618 THAT ARE WILLING TO GIVE THEIR 1245 00:50:00,618 --> 00:50:01,352 BODIES TO SCIENCE. 1246 00:50:01,352 --> 00:50:03,555 I WANT SOMETHING THAT'S GOING TO 1247 00:50:03,555 --> 00:50:06,858 WORK IN TWO SHOTS. 1248 00:50:06,858 --> 00:50:11,896 I SAID, AIN'T GONNA HAPPEN. 1249 00:50:11,896 --> 00:50:12,597 IF YOU'RE REALLY LUCKY, AND IT 1250 00:50:12,597 --> 00:50:14,399 WAS SMALL OR YOU GOT A REALLY 1251 00:50:14,399 --> 00:50:15,800 GREAT IMMUNE RESPONSE OR IT 1252 00:50:15,800 --> 00:50:17,902 HADN'T TOLERIZED COMPLETELY AND 1253 00:50:17,902 --> 00:50:19,237 YOU HAD A HIGHER FREQUENCY OF 1254 00:50:19,237 --> 00:50:22,040 CELLS TO START WITH, YEAH. 1255 00:50:22,040 --> 00:50:28,046 MOST OF THE TIME, NO. 1256 00:50:28,046 --> 00:50:29,247 KEEP BOOSTING. 1257 00:50:29,247 --> 00:50:32,050 IT'S A REALLY SIMPLE ANSWER. 1258 00:50:32,050 --> 00:50:36,054 IF YOU HAVE A VACCINE THAT MAKES 1259 00:50:36,054 --> 00:50:46,598 A TUMOR GET SMALLER, DON'T STOP. 1260 00:50:48,066 --> 00:50:52,704 NOW, WE PUT IN CAR-T CELLS, THEY 1261 00:50:52,704 --> 00:50:53,771 KILL, 30 TO 100 TARGETS, AND 1262 00:50:53,771 --> 00:50:55,073 THEN THEY REST. 1263 00:50:55,073 --> 00:51:00,011 YOU NEED TO RESTIMULATE THEM. 1264 00:51:00,011 --> 00:51:01,846 I'VE HAD FELLOWS TELL ME NO, NO, 1265 00:51:01,846 --> 00:51:02,881 NO, THEY ARE THERE, THEY ARE 1266 00:51:02,881 --> 00:51:04,282 ACTIVE, I CAN PULL THEM OUT OF 1267 00:51:04,282 --> 00:51:06,351 THE ARM, PUT THEM IN CULTURE, 1268 00:51:06,351 --> 00:51:08,887 TURN THEM INTO KILLERS. 1269 00:51:08,887 --> 00:51:10,955 THAT TAKES FIVE-DAY CULTURE, 1270 00:51:10,955 --> 00:51:12,123 ACTIVATED APCs. 1271 00:51:12,123 --> 00:51:14,459 PULLING THEM OUT OF THE ARM, 1272 00:51:14,459 --> 00:51:16,828 THEY ARE RESTING CD8s. 1273 00:51:16,828 --> 00:51:17,595 YES, THEY ARE THERE. 1274 00:51:17,595 --> 00:51:22,667 BUT YOU NEED TO BOOST THEM. 1275 00:51:22,667 --> 00:51:24,702 SO, MAYBE THEY COULD DO THAT 1276 00:51:24,702 --> 00:51:27,906 MORE OFTEN. 1277 00:51:27,906 --> 00:51:29,774 WHAT ABOUT CHECKPOINT 1278 00:51:29,774 --> 00:51:30,375 INHIBITORS? 1279 00:51:30,375 --> 00:51:32,410 SO TOM WALDEMANN ASKED ME SOME 1280 00:51:32,410 --> 00:51:35,547 TIME AGO DID I HAVE ANY THOUGHTS 1281 00:51:35,547 --> 00:51:36,748 ABOUT MAKING CHECKPOINT 1282 00:51:36,748 --> 00:51:38,716 INHIBITOR THERAPY A LITTLE MORE 1283 00:51:38,716 --> 00:51:41,553 UNIVERSAL. 1284 00:51:41,553 --> 00:51:43,188 A LITTLE MORE EFFECTIVE. 1285 00:51:43,188 --> 00:51:45,056 I ASKED HIM, IF HE KNEW IN THE 1286 00:51:45,056 --> 00:51:50,094 TUMORS WHERE HE WAS GIVING THIS 1287 00:51:50,094 --> 00:51:52,630 TO PEOPLE, DID HE KNOW IF THIS 1288 00:51:52,630 --> 00:51:58,770 WAS AN IMMUNOLOGICALLY COLD OR 1289 00:51:58,770 --> 00:51:59,437 IMMUNOLOGICALLY HOT TUMOR? 1290 00:51:59,437 --> 00:52:00,872 HIS ANSWER WAS NO. 1291 00:52:00,872 --> 00:52:02,040 SOMETIMES YOU CAN'T KNOW. 1292 00:52:02,040 --> 00:52:06,578 BECAUSE YOU CAN'T GET TO IT. 1293 00:52:06,578 --> 00:52:08,980 YOU CAN'T BIOPSY AND ASK IF 1294 00:52:08,980 --> 00:52:10,014 THERE ARE ACTIVATED FEW TILs 1295 00:52:10,014 --> 00:52:12,217 IN THERE. 1296 00:52:12,217 --> 00:52:13,651 GIVE YOUR CHECKPOINT INHIBITORS 1297 00:52:13,651 --> 00:52:14,719 TO PEOPLE WHO DON'T HAVE AN 1298 00:52:14,719 --> 00:52:15,887 IMMUNE RESPONSE GOING. 1299 00:52:15,887 --> 00:52:16,688 WELL, IT DOESN'T HELP. 1300 00:52:16,688 --> 00:52:19,324 YOU NEED TO GET THAT IMMUNE 1301 00:52:19,324 --> 00:52:20,225 RESPONSE GOING FIRST. 1302 00:52:20,225 --> 00:52:24,896 AND THEN GIVE YOUR CHECKPOINT 1303 00:52:24,896 --> 00:52:25,163 INHIBITOR. 1304 00:52:25,163 --> 00:52:27,131 SO HOW DO YOU DO THAT? 1305 00:52:27,131 --> 00:52:29,100 WELL, IF YOU KNOW WHAT THE 1306 00:52:29,100 --> 00:52:32,337 ANTIGEN IS YOU CAN VACCINATE. 1307 00:52:32,337 --> 00:52:34,205 IF THE TUMOR IS SURFACE OR CLOSE 1308 00:52:34,205 --> 00:52:36,841 TO THE SURFACE, YOU CAN DO 1309 00:52:36,841 --> 00:52:37,976 DAMAGE IN IT. 1310 00:52:37,976 --> 00:52:46,584 YOU KNOW, STICK A PIN IN IT. 1311 00:52:46,584 --> 00:52:51,556 INJECT IT, ALUM DOES AMAZING 1312 00:52:51,556 --> 00:52:53,524 AMAZING DAMAGE. 1313 00:52:53,524 --> 00:52:56,160 DO WHAT RON GERMAIN'S LAB DOES, 1314 00:52:56,160 --> 00:52:57,462 USE TWO TUNED LASERS, NEITHER 1315 00:52:57,462 --> 00:52:59,130 LASER ALONE IS ENOUGH TO DAMAGE 1316 00:52:59,130 --> 00:53:01,399 TISSUE SO YOU DON'T DAMAGE THE 1317 00:53:01,399 --> 00:53:02,066 TISSUE IN BETWEEN. 1318 00:53:02,066 --> 00:53:05,169 WHERE YOU PUT THE TWO LASERS, 1319 00:53:05,169 --> 00:53:05,937 YOU DAMAGE. 1320 00:53:05,937 --> 00:53:09,274 THAT'S A WAY, ONE WAY AT LEAST, 1321 00:53:09,274 --> 00:53:12,710 TO TURN A COLD TUMOR INTO A HOT 1322 00:53:12,710 --> 00:53:13,177 TUMOR. 1323 00:53:13,177 --> 00:53:15,313 LET THE T CELLS EXPAND. 1324 00:53:15,313 --> 00:53:18,583 THEN GIVE YOUR CHECKPOINT 1325 00:53:18,583 --> 00:53:18,883 INHIBITORS. 1326 00:53:18,883 --> 00:53:21,653 SO I THINK WHAT'S WRONG WITH A 1327 00:53:21,653 --> 00:53:24,756 LOT OF TUMOR IMMUNOTHERAPY IS 1328 00:53:24,756 --> 00:53:26,524 NOT IT'S BAD THERAPY. 1329 00:53:26,524 --> 00:53:32,130 IT'S JUST BEING USED INCORRECTLY 1330 00:53:32,130 --> 00:53:34,799 BECAUSE PEOPLE BASE USE ON AN 1331 00:53:34,799 --> 00:53:37,435 OLD MODEL, AND THAT IS -- SAYS 1332 00:53:37,435 --> 00:53:39,203 THAT ONCE YOU GET AN IMMUNE 1333 00:53:39,203 --> 00:53:40,505 RESPONSE GOING, THE MERE 1334 00:53:40,505 --> 00:53:43,908 PRESENCE OF THE ANTIGEN IS 1335 00:53:43,908 --> 00:53:44,809 ENOUGH TO MAINTAIN IT. 1336 00:53:44,809 --> 00:53:45,877 THE MERE PRESENCE OF THAT 1337 00:53:45,877 --> 00:53:48,446 ANTIGEN IS NOT ENOUGH TO 1338 00:53:48,446 --> 00:53:49,147 MAINTAIN IT. 1339 00:53:49,147 --> 00:53:50,648 THOSE CELLS GO INTO RESTING 1340 00:53:50,648 --> 00:53:53,618 STATE, YOU NEED TO REACTIVATE 1341 00:53:53,618 --> 00:53:56,154 AND REACTIVATE APCs IN ORDER 1342 00:53:56,154 --> 00:53:57,722 TO REACTIVATE IT. 1343 00:53:57,722 --> 00:54:00,224 WE NEED TO STOP THINKING IN THE 1344 00:54:00,224 --> 00:54:02,627 OLD WAY AND USE THESE QUITE 1345 00:54:02,627 --> 00:54:05,296 AMAZING THERAPIES IN THE WAY 1346 00:54:05,296 --> 00:54:06,364 THEY SHOULD BE USED. 1347 00:54:06,364 --> 00:54:08,366 MAYBE IF WE DID THAT, STOPPED 1348 00:54:08,366 --> 00:54:11,969 THINKING THE OLD WAY, WE COULD 1349 00:54:11,969 --> 00:54:14,172 ACTUALLY CURE MORE PEOPLE. 1350 00:54:14,172 --> 00:54:14,906 THANK YOU FOR LISTENING. 1351 00:54:14,906 --> 00:54:17,075 [APPLAUSE] 1352 00:54:17,075 --> 00:54:25,750 1353 00:54:25,750 --> 00:54:26,184 QUESTIONS? 1354 00:54:26,184 --> 00:54:26,551 ARGUMENTS? 1355 00:54:26,551 --> 00:54:28,486 CRITICISMS? 1356 00:54:28,486 --> 00:54:34,592 1357 00:54:34,592 --> 00:54:36,861 1358 00:54:36,861 --> 00:54:36,994 1359 00:54:36,994 --> 00:54:42,033 >> (INAUDIBLE). 1360 00:54:42,033 --> 00:54:44,202 >> CAN I TELL YOU WHAT I THINK 1361 00:54:44,202 --> 00:54:45,803 IS DIFFERENT BETWEEN 20% WHO 1362 00:54:45,803 --> 00:54:48,139 RESPOND AND 70 WHO DON'T? 1363 00:54:48,139 --> 00:54:50,842 >> WHAT IS THE DIFFERENCE? 1364 00:54:50,842 --> 00:54:52,944 I JUST TOLD YOU. 1365 00:54:52,944 --> 00:54:53,177 OKAY. 1366 00:54:53,177 --> 00:54:56,614 SO, ACTUALLY I FORGOT ONE 1367 00:54:56,614 --> 00:54:57,081 CATEGORY. 1368 00:54:57,081 --> 00:55:01,686 SO, IN A TUMOR THAT HAS NO ALARM 1369 00:55:01,686 --> 00:55:04,989 SIGNALS, YOU CAN GIVE YOUR 1370 00:55:04,989 --> 00:55:05,623 CHECKPOINT INHIBITORS, IT 1371 00:55:05,623 --> 00:55:06,958 DOESN'T HELP BECAUSE YOU DON'T 1372 00:55:06,958 --> 00:55:08,993 HAVE IMMUNE RESPONSE TO CHECK. 1373 00:55:08,993 --> 00:55:12,330 YOU NEED TO GET THAT IMMUNE 1374 00:55:12,330 --> 00:55:12,797 RESPONSE GOING FIRST. 1375 00:55:12,797 --> 00:55:15,166 SO THAT WOULD BE A DIFFERENCE 1376 00:55:15,166 --> 00:55:17,301 BETWEEN ONE KIND OF COLD 1377 00:55:17,301 --> 00:55:20,671 TUMOR -- WAIT, I'M NOT DONE. 1378 00:55:20,671 --> 00:55:22,306 THERE'S ALSO THE POSSIBILITY AND 1379 00:55:22,306 --> 00:55:26,043 PROBABILITY OF TUMORS THAT HAVE 1380 00:55:26,043 --> 00:55:27,345 ALREADY TOLERIZED. 1381 00:55:27,345 --> 00:55:30,515 ESPECIALLY IN -- I'M ALMOST 77, 1382 00:55:30,515 --> 00:55:31,816 MY THYMUS ISN'T PUTTING OUT A 1383 00:55:31,816 --> 00:55:32,250 LOT. 1384 00:55:32,250 --> 00:55:32,750 T CELL ANYMORE. 1385 00:55:32,750 --> 00:55:35,086 IF I GET A TUMOR AND IT'S GOING 1386 00:55:35,086 --> 00:55:37,188 TOLERANCE, I HAVEN'T GOT A LOT 1387 00:55:37,188 --> 00:55:38,122 OF NEW REPLACEMENTS. 1388 00:55:38,122 --> 00:55:42,427 SO THEN YOU CAN DO SOMETHING 1389 00:55:42,427 --> 00:55:46,030 LIKE WHAT EPHRAIM FUCHS DOES, 1390 00:55:46,030 --> 00:55:47,265 YOU SHOULD HAVE SOME T CELLS 1391 00:55:47,265 --> 00:55:50,902 THAT CAN SEE THAT TUMOR. 1392 00:55:50,902 --> 00:55:53,604 THAT PLUS CHECKPOINT INHIBITORS 1393 00:55:53,604 --> 00:55:56,707 COULD BE REALLY FUN. 1394 00:55:56,707 --> 00:56:01,412 YOU DON'T LIKE IT? 1395 00:56:01,412 --> 00:56:02,346 1396 00:56:02,346 --> 00:56:03,881 IT'S OKAY. 1397 00:56:03,881 --> 00:56:04,282 >> (INAUDIBLE). 1398 00:56:04,282 --> 00:56:05,850 >> 30% RESPOND, 70% THAT DON'T, 1399 00:56:05,850 --> 00:56:07,084 COLDER, HOTTER? 1400 00:56:07,084 --> 00:56:08,686 >> ARE THE 20% THAT RESPOND 1401 00:56:08,686 --> 00:56:08,953 SMALLER? 1402 00:56:08,953 --> 00:56:13,424 YES, SOME OF THEM. 1403 00:56:13,424 --> 00:56:18,129 YES, SOME OF THEM. 1404 00:56:18,129 --> 00:56:19,831 >> OLDER OR NOT TOLERIZED. 1405 00:56:19,831 --> 00:56:21,232 >> NOT TOLERIZED OR THEY ARE 1406 00:56:21,232 --> 00:56:24,368 BIGGER, REMEMBER I SAID YOU GET 1407 00:56:24,368 --> 00:56:25,436 REALLY BIG IN SOLID TUMOR YOU 1408 00:56:25,436 --> 00:56:29,040 GET ENOUGH DEATH IN THE MIDDLE 1409 00:56:29,040 --> 00:56:31,175 YOU START ACTIVATING -- YOUR 1410 00:56:31,175 --> 00:56:32,810 SCAVENGERS CAN'T KEEP UP AND 1411 00:56:32,810 --> 00:56:33,845 YOU'LL BE EXPANDING T CELLS. 1412 00:56:33,845 --> 00:56:35,913 EACH ONE OF THE T CELLS CAN KILL 1413 00:56:35,913 --> 00:56:36,848 THREE TO A HUNDRED TARGETS AND 1414 00:56:36,848 --> 00:56:38,015 THEY HAVE TO GO BACK TO THE 1415 00:56:38,015 --> 00:56:40,318 LYMPH NODE AND GET RESTIMULATED, 1416 00:56:40,318 --> 00:56:42,820 THAT TAKES TWO DAYS, EVEN FOR A 1417 00:56:42,820 --> 00:56:43,955 SECONDARY, WHAT'S THE TUMOR 1418 00:56:43,955 --> 00:56:44,589 DOING? 1419 00:56:44,589 --> 00:56:45,189 THE MEANTIME? 1420 00:56:45,189 --> 00:56:47,091 MAKING MILLIONS MORE. 1421 00:56:47,091 --> 00:56:47,992 YOU LOST THE RACE. 1422 00:56:47,992 --> 00:56:51,162 THAT WOULD BE A GOOD ONE TO 1423 00:56:51,162 --> 00:56:52,096 TREAT. 1424 00:56:52,096 --> 00:56:53,664 GO AHEAD. 1425 00:56:53,664 --> 00:56:55,533 >> SO HOW DO YOU ALSO RECONCILE 1426 00:56:55,533 --> 00:56:58,903 THIS WITH THE CONCEPT OF 1427 00:56:58,903 --> 00:57:00,404 IMMUNOSURVEILLANCE, CD8 T CELLS 1428 00:57:00,404 --> 00:57:01,472 THAT ARE ELIMINATING -- 1429 00:57:01,472 --> 00:57:06,978 >> OKAY, HOW DO I RECOGNIZE WITH 1430 00:57:06,978 --> 00:57:12,116 THE CONCEPT OF IMFLOW KNOW OF 1431 00:57:12,116 --> 00:57:12,884 OF -- IMMUNOSURVEILLANCE. 1432 00:57:12,884 --> 00:57:16,787 WE USED TO THINK WE GOT A TUMOR 1433 00:57:16,787 --> 00:57:18,523 MIGHT HAVE FINISHES AND THE ONES 1434 00:57:18,523 --> 00:57:20,057 THAT GREW YOU THE THE IMMUNE 1435 00:57:20,057 --> 00:57:21,526 SYSTEM COULDN'T DEAL WITH. 1436 00:57:21,526 --> 00:57:25,096 NOW WE KNOW BECAUSE OF P53 AND 1437 00:57:25,096 --> 00:57:25,730 CHECKPOINTS, DIFFERENT 1438 00:57:25,730 --> 00:57:28,900 CHECKPOINTS, WE DON'T GET TUMORS 1439 00:57:28,900 --> 00:57:29,367 THAT OFTEN. 1440 00:57:29,367 --> 00:57:30,668 SO I THINK THAT WHAT'S GOING ON 1441 00:57:30,668 --> 00:57:34,038 HERE IS WE DON'T GET TUMORS VERY 1442 00:57:34,038 --> 00:57:34,539 OFTEN. 1443 00:57:34,539 --> 00:57:36,274 THEY ARE JUST ALSO SENDING ALARM 1444 00:57:36,274 --> 00:57:40,578 SIGNALS WHEN WE GET THEM. 1445 00:57:40,578 --> 00:57:42,813 NOW, THERE WAS BILL CULLY, LONG 1446 00:57:42,813 --> 00:57:45,116 TIME AGO, WHO NOTICED THAT ONE 1447 00:57:45,116 --> 00:57:47,418 OF THE SARCOMAS ON A PATIENT GOT 1448 00:57:47,418 --> 00:57:51,923 A BACTERIAL INFECTION AND 1449 00:57:51,923 --> 00:57:52,924 DISAPPEARED. 1450 00:57:52,924 --> 00:57:53,491 SO, TUMORS DO SPONTANEOUSLY 1451 00:57:53,491 --> 00:57:54,425 SOMETIMES GO AWAY. 1452 00:57:54,425 --> 00:57:59,030 IF I HAD A MEDICAL NO, MA'AM -- 1453 00:57:59,030 --> 00:58:00,264 MELANOMA ON THE HAND I WOULD BE 1454 00:58:00,264 --> 00:58:02,266 STICKING PINS IN IT OR BANGING 1455 00:58:02,266 --> 00:58:04,936 IT ON THE PIANO, RIGHT? 1456 00:58:04,936 --> 00:58:05,102 JAY. 1457 00:58:05,102 --> 00:58:09,707 >> I HAD A QUESTION. 1458 00:58:09,707 --> 00:58:11,976 THERE'S BEEN DEBATE FOR MANY 1459 00:58:11,976 --> 00:58:12,743 YEARS WHETHER IMMUNOSURVEILLANCE 1460 00:58:12,743 --> 00:58:17,582 WAS REAL OR NOT. 1461 00:58:17,582 --> 00:58:21,152 BOB SHRIVER HAD EXPERIMENTS THAT 1462 00:58:21,152 --> 00:58:27,692 MADE IT CLEAR THAT IF YOU INDUCE 1463 00:58:27,692 --> 00:58:30,962 A SARCOMA WITH CARCINOGEN IN AN 1464 00:58:30,962 --> 00:58:33,464 IMMUNODEFICIENT MOUSE, YOU GET 1465 00:58:33,464 --> 00:58:35,199 TUMORS THAT HAVE REJECTION 1466 00:58:35,199 --> 00:58:37,802 ANTIGENS THAT WILL BE REJECTED 1467 00:58:37,802 --> 00:58:40,104 IN AN IMMUNOCOMPETENT MOUSE, 1468 00:58:40,104 --> 00:58:46,210 WHEREAS THE ONES THAT ARISE, IF 1469 00:58:46,210 --> 00:58:48,112 YOU GIVE THE METHCOLANTHERE IN 1470 00:58:48,112 --> 00:58:50,348 YOU IMMUNOCOMPETENT MOUSE THEY 1471 00:58:50,348 --> 00:58:52,283 DON'T HAVE REJECTION ANTIGENS 1472 00:58:52,283 --> 00:58:53,884 PRESUMABLY BECAUSE TUMORS THAT 1473 00:58:53,884 --> 00:58:55,953 HAD THEM GOT ELIMINATED BEFORE 1474 00:58:55,953 --> 00:58:59,790 THEY EVER BECAME CLINICALLY 1475 00:58:59,790 --> 00:59:00,024 EVIDENT. 1476 00:59:00,024 --> 00:59:04,428 >> IT'S A REALLY BAD MODEL, 1477 00:59:04,428 --> 00:59:04,962 METHCOLANTHERE. 1478 00:59:04,962 --> 00:59:07,398 IT CAUSES DAMAGE. 1479 00:59:07,398 --> 00:59:12,269 TRANSPLANTING TUMORS ALSO CAUSES 1480 00:59:12,269 --> 00:59:12,536 DAMAGE. 1481 00:59:12,536 --> 00:59:14,438 THERE WERE THOSE DATA AND DATA 1482 00:59:14,438 --> 00:59:17,074 SAYING NUDE MICE DON'T GET MORE 1483 00:59:17,074 --> 00:59:18,843 TUMORS THAN OTHER MICE. 1484 00:59:18,843 --> 00:59:20,811 RAG KNOCKOUT MICE DON'T GET MORE 1485 00:59:20,811 --> 00:59:22,880 TUMORS THAN OTHER MICE. 1486 00:59:22,880 --> 00:59:24,782 T CELL KNOCKOUT MICE DON'T GET 1487 00:59:24,782 --> 00:59:27,151 MORE TUMORS THAN OTHER MICE. 1488 00:59:27,151 --> 00:59:30,921 I THINK THE SHRIVER DATA WITH 1489 00:59:30,921 --> 00:59:31,555 METHCOLANTHERE-INDUCED TUMOR IS 1490 00:59:31,555 --> 00:59:35,793 ONE WE NEED TO IGNORE. 1491 00:59:35,793 --> 00:59:37,094 [LAUGHTER] 1492 00:59:37,094 --> 00:59:38,729 SOMETIMES YOUR MODEL TELLS YOU 1493 00:59:38,729 --> 00:59:39,897 WHAT DATA TO IGNORE. 1494 00:59:39,897 --> 00:59:41,699 >> OKAY. 1495 00:59:41,699 --> 00:59:43,134 >> YOU COULD BE WRONG. 1496 00:59:43,134 --> 00:59:43,968 >> ANOTHER QUESTION. 1497 00:59:43,968 --> 00:59:45,269 >> MY OTHER QUESTION THOUGH THAT 1498 00:59:45,269 --> 00:59:53,377 I CAME UP HERE TO ASK IS, I 1499 00:59:53,377 --> 00:59:57,314 THINK IN 2022, WHATEVER, A 1500 00:59:57,314 --> 01:00:06,223 COUPLE YEARS AGO, SAMIR KALAF 1501 01:00:06,223 --> 01:00:07,658 PUBLISHED A PAPER IN WHICH THEY 1502 01:00:07,658 --> 01:00:10,628 LOOKED AT THE TIMING OF GIVING A 1503 01:00:10,628 --> 01:00:12,463 CANCER VACCINE AND CHECKPOINT 1504 01:00:12,463 --> 01:00:16,867 INHIBITORS, I THINK IT WAS 1505 01:00:16,867 --> 01:00:17,802 ANTI-PD-1 AND FOUND SURPRISINGLY 1506 01:00:17,802 --> 01:00:21,005 THAT IF THEY GIVE THE CHECKPOINT 1507 01:00:21,005 --> 01:00:23,374 INHIBITOR FIRST AND GAVE THE 1508 01:00:23,374 --> 01:00:24,475 VACCINE LATER, THE VACCINE 1509 01:00:24,475 --> 01:00:27,011 DIDN'T WORK NEARLY AS WELL AS IF 1510 01:00:27,011 --> 01:00:28,779 THEY GAVE THE VACCINE AND 1511 01:00:28,779 --> 01:00:32,583 CHECKPOINT INHIBITOR AT THE SAME 1512 01:00:32,583 --> 01:00:35,386 TIME OR THE -- OR GAVE THE 1513 01:00:35,386 --> 01:00:36,654 CHECKPOINT INHIBITOR LATER. 1514 01:00:36,654 --> 01:00:39,590 AND WE -- OUR LAB, WILL BECKER 1515 01:00:39,590 --> 01:00:41,192 IN OUR LAB COULD REPRODUCE THOSE 1516 01:00:41,192 --> 01:00:41,792 FINDINGS. 1517 01:00:41,792 --> 01:00:46,497 >> I DON'T FIND THAT SURPRISING. 1518 01:00:46,497 --> 01:00:48,866 >> SO, IT'S IMPORTANT BECAUSE 1519 01:00:48,866 --> 01:00:50,935 WITH A LOT OF THESE CUSTOM 1520 01:00:50,935 --> 01:00:53,537 CANCER VACCINES THAT PEOPLE ARE 1521 01:00:53,537 --> 01:00:58,075 TRYING TO MAKE TO NEOEPITOPES 1522 01:00:58,075 --> 01:00:59,577 AND SO FORTH IT TAKES TIME TO 1523 01:00:59,577 --> 01:01:00,945 MAKE THE CUSTOM VACCINE, AND 1524 01:01:00,945 --> 01:01:03,714 THERE'S A TENDENCY TO SAY, WELL, 1525 01:01:03,714 --> 01:01:05,149 WE DON'T WANT TO LEAVE THE 1526 01:01:05,149 --> 01:01:06,383 PATIENT UNTREATED WHILE DOING 1527 01:01:06,383 --> 01:01:09,420 THAT SO WE'LL START CHECKPOINT 1528 01:01:09,420 --> 01:01:11,322 INHIBITORS FIRST AND THEN WHEN 1529 01:01:11,322 --> 01:01:13,724 THE VACCINE IS READY WE'LL GIVE 1530 01:01:13,724 --> 01:01:14,125 THE VACCINE. 1531 01:01:14,125 --> 01:01:16,660 IF SAMIR'S DATA ARE CORRECT -- 1532 01:01:16,660 --> 01:01:17,862 >> THAT'S A BAD IDEA. 1533 01:01:17,862 --> 01:01:19,497 >> THAT'S THE WRONG THING TO DO. 1534 01:01:19,497 --> 01:01:22,867 SO BUT I WANT TO KNOW WHETHER 1535 01:01:22,867 --> 01:01:29,607 YOU HAVE A HYPOTHESIS TO EXPLAIN 1536 01:01:29,607 --> 01:01:30,574 THAT FINDING. 1537 01:01:30,574 --> 01:01:34,378 >> WELL, WHEN T CELLS GET 1538 01:01:34,378 --> 01:01:36,180 ACTIVATED, THEY UPREGULATE 1539 01:01:36,180 --> 01:01:37,148 THINGS. 1540 01:01:37,148 --> 01:01:38,115 OKAY? 1541 01:01:38,115 --> 01:01:39,083 >> TRUE. 1542 01:01:39,083 --> 01:01:42,520 >> THAT WHOLE PD-1, PD-L1 AXIS 1543 01:01:42,520 --> 01:01:44,755 NOW BECOMES MORE SENSITIVE. 1544 01:01:44,755 --> 01:01:45,756 THERE'S MORE OF IT. 1545 01:01:45,756 --> 01:01:47,858 SO I WOULD THINK WHEN YOU'VE GOT 1546 01:01:47,858 --> 01:01:51,162 RESTING T CELLS GIVING 1547 01:01:51,162 --> 01:01:54,131 CHECKPOINT INHIBITORS IS 1548 01:01:54,131 --> 01:01:54,398 USELESS. 1549 01:01:54,398 --> 01:01:55,366 DEPENDING ON HALF-LIFE OF THE 1550 01:01:55,366 --> 01:01:59,470 ANTIBODY, I DON'T KNOW WHAT THE 1551 01:01:59,470 --> 01:02:00,671 HALF-LIFE IS, DEPENDING HOW LATE 1552 01:02:00,671 --> 01:02:02,640 YOU WAIT TO GIVE THE VACCINE, 1553 01:02:02,640 --> 01:02:04,809 YOU MAY STILL HAVE IT. 1554 01:02:04,809 --> 01:02:05,810 OR YOU MAY NOT. 1555 01:02:05,810 --> 01:02:07,711 I WOULD GIVE THE VACCINE, I 1556 01:02:07,711 --> 01:02:09,613 WOULDN'T DO IT AT THE SAME TIME. 1557 01:02:09,613 --> 01:02:11,148 GIVE THE VACCINE, WAIT A COUPLE 1558 01:02:11,148 --> 01:02:13,651 DAYS AND THEN GIVE THE 1559 01:02:13,651 --> 01:02:14,118 CHECKPOINT INHIBITOR. 1560 01:02:14,118 --> 01:02:16,120 >> THAT'S WHAT SAMIR FOUND WAS 1561 01:02:16,120 --> 01:02:16,821 BETTER EMPIRICALLY. 1562 01:02:16,821 --> 01:02:17,221 >> GREAT. 1563 01:02:17,221 --> 01:02:19,990 >> AND HE FOUND THAT THE T CELLS 1564 01:02:19,990 --> 01:02:23,661 THAT WERE ACTIVATED, IF YOU GAVE 1565 01:02:23,661 --> 01:02:27,064 CHECKPOINT INHIBITOR FIRST WERE 1566 01:02:27,064 --> 01:02:32,069 CD38 POSITIVE, HE CALLED THEM 1567 01:02:32,069 --> 01:02:33,404 SUBPRIMED OR SOMETHING LIKE 1568 01:02:33,404 --> 01:02:39,643 THAT, POORLY PRIMED, NOT CLEAR 1569 01:02:39,643 --> 01:02:40,711 WHAT THE MECHANISM IS AND I 1570 01:02:40,711 --> 01:02:41,745 THOUGHT YOU MIGHT HAVE IDEAS. 1571 01:02:41,745 --> 01:02:46,684 >> WELL, THAT WAS THE IDEA. 1572 01:02:46,684 --> 01:02:47,051 ANYBODY ELSE? 1573 01:02:47,051 --> 01:02:47,551 >> FURTHER QUESTION -- 1574 01:02:47,551 --> 01:02:57,761 (INAUDIBLE). 1575 01:03:10,641 --> 01:03:15,312 >> SO THIS IS A LOT TO REPEAT. 1576 01:03:15,312 --> 01:03:17,581 SO, THIS MAN IS HAVING A 1577 01:03:17,581 --> 01:03:18,649 PROBLEM. 1578 01:03:18,649 --> 01:03:22,987 WITH THE IDEA TUMORS DON'T SEND 1579 01:03:22,987 --> 01:03:23,854 ALARM SIGNALS. 1580 01:03:23,854 --> 01:03:29,059 SMOKERS GET MORE LUNG CANCER 1581 01:03:29,059 --> 01:03:30,094 THAN NONSMOKERS, WE THINK SMOKE 1582 01:03:30,094 --> 01:03:31,495 IS DAMAGING TO THE LUNG. 1583 01:03:31,495 --> 01:03:34,331 LARGE TUMORS KILL PEOPLE. 1584 01:03:34,331 --> 01:03:35,132 THAT'S PRETTY DAMAGING. 1585 01:03:35,132 --> 01:03:37,001 LET'S DO THE LARGE TUMOR FIRST. 1586 01:03:37,001 --> 01:03:40,204 IT'S HAD A LONG TIME TO TOLERIZE 1587 01:03:40,204 --> 01:03:41,872 FOR ITSELF. 1588 01:03:41,872 --> 01:03:44,942 BEFORE IT ACTUALLY STARTS DOING 1589 01:03:44,942 --> 01:03:45,175 DAMAGE. 1590 01:03:45,175 --> 01:03:46,911 AND THEN ONE CAN ASK WHAT KIND 1591 01:03:46,911 --> 01:03:49,647 OF DAMAGE IS IT DOING? 1592 01:03:49,647 --> 01:03:52,016 IS THAT A KIND OF DAMAGE THAT 1593 01:03:52,016 --> 01:03:54,685 GIVES YOU ALARM SIGNALS? 1594 01:03:54,685 --> 01:03:58,155 THERE'S ALL KINDS OF DEATHS THAT 1595 01:03:58,155 --> 01:03:59,056 DON'T. 1596 01:03:59,056 --> 01:04:00,024 PYROPTOSIS DOES. 1597 01:04:00,024 --> 01:04:00,824 APOPTOSIS DOESN'T. 1598 01:04:00,824 --> 01:04:02,993 SO I THINK THE LARGE TUMOR, THE 1599 01:04:02,993 --> 01:04:05,262 VERY LARGE TUMOR, HAS ALREADY 1600 01:04:05,262 --> 01:04:06,497 TOLERIZED ENOUGH FOR ITSELF THAT 1601 01:04:06,497 --> 01:04:07,531 EVEN WHEN IT DOES A LITTLE 1602 01:04:07,531 --> 01:04:09,166 DAMAGE, YOU GET THE TILs, A 1603 01:04:09,166 --> 01:04:13,037 LITTLE BIT OF DAMAGE, THREE T 1604 01:04:13,037 --> 01:04:14,405 CELLS, THEY EXPAND, KILL 300 1605 01:04:14,405 --> 01:04:15,906 TARGETS, HAVE TO BE 1606 01:04:15,906 --> 01:04:17,174 RESTIMULATED, THE TUMOR IS 1607 01:04:17,174 --> 01:04:19,710 GETTING THAT MUCH BIGGER. 1608 01:04:19,710 --> 01:04:25,382 YOU'VE LOST THE RACE. 1609 01:04:25,382 --> 01:04:29,119 NOW, UV-INDUCED DEATH IN THE 1610 01:04:29,119 --> 01:04:29,653 SKIN, UV-INDUCED DEATH IS 1611 01:04:29,653 --> 01:04:31,555 PROGRAMMED CELL DEATH. 1612 01:04:31,555 --> 01:04:33,424 IRRADIATION DEATH OF A TUMOR IS 1613 01:04:33,424 --> 01:04:34,358 PROGRAMMED CELL DEATH. 1614 01:04:34,358 --> 01:04:35,492 WE'VE GOT TO THINK ABOUT WHAT 1615 01:04:35,492 --> 01:04:39,830 KIND OF DEATH WE'RE DOING HERE. 1616 01:04:39,830 --> 01:04:42,566 LUNG, I DON'T THINK I KNOW 1617 01:04:42,566 --> 01:04:43,667 ENOUGH ABOUT WHAT CIGARETTE 1618 01:04:43,667 --> 01:04:45,035 SMOKE DOES AND HOW IT DAMAGES TO 1619 01:04:45,035 --> 01:04:47,805 BE ABLE TO ANSWER THAT PART OF 1620 01:04:47,805 --> 01:04:47,972 IT. 1621 01:04:47,972 --> 01:04:50,374 I THINK ONE OF THE THINGS I TELL 1622 01:04:50,374 --> 01:04:51,575 MY POSTDOCS IS THAT ONE OF THE 1623 01:04:51,575 --> 01:04:53,777 REALLY NICE THINGS ABOUT BEING A 1624 01:04:53,777 --> 01:04:55,279 SCIENTIST IS THAT IT'S REALLY 1625 01:04:55,279 --> 01:04:58,782 OKAY TO SAY YOU DON'T KNOW. 1626 01:04:58,782 --> 01:05:00,651 AND ABOUT THAT, I DON'T KNOW 1627 01:05:00,651 --> 01:05:04,088 ENOUGH ABOUT CIGARETTE SMOKE. 1628 01:05:04,088 --> 01:05:04,488 >> (INAUDIBLE). 1629 01:05:04,488 --> 01:05:06,690 >> I CAN'T HEAR YOU. 1630 01:05:06,690 --> 01:05:08,859 >> (INAUDIBLE). 1631 01:05:08,859 --> 01:05:13,897 1632 01:05:13,897 --> 01:05:14,932 >> MIGHT CAUSE AUTOIMMUNITY. 1633 01:05:14,932 --> 01:05:22,673 >> NO, THE IDEA OF THE TUMOR, IT 1634 01:05:22,673 --> 01:05:33,083 COMES -- (INAUDIBLE) -- 1635 01:05:41,692 --> 01:05:43,460 >> OKAY. 1636 01:05:43,460 --> 01:05:44,661 YEAH, YEAH. 1637 01:05:44,661 --> 01:05:46,063 >> INDUCING MORE RESISTANT TUMOR 1638 01:05:46,063 --> 01:05:46,463 CELLS. 1639 01:05:46,463 --> 01:05:48,098 >> LET'S DEAL WITH THAT. 1640 01:05:48,098 --> 01:05:51,201 THE IDEA IS IF YOU VACCINATE, 1641 01:05:51,201 --> 01:05:53,270 AND YOU GET YOUR TUMORS TO GO 1642 01:05:53,270 --> 01:05:57,474 DOWN, YOU GET A FEW CELLS LEFT, 1643 01:05:57,474 --> 01:05:59,777 GROW OUT, DO IT AGAIN, SOME MAY 1644 01:05:59,777 --> 01:06:02,179 NO LONGER HAVE THE ANTIGEN 1645 01:06:02,179 --> 01:06:04,048 YOU'RE VACCINATING TO, THEY 1646 01:06:04,048 --> 01:06:06,016 BECOME RESISTANT. 1647 01:06:06,016 --> 01:06:09,653 YES, ABSOLUTELY, AND THAT'S BEEN 1648 01:06:09,653 --> 01:06:11,221 SHOWN IMMUNOLOGIC ESCAPE, TUMOR 1649 01:06:11,221 --> 01:06:11,455 ESCAPE. 1650 01:06:11,455 --> 01:06:12,856 THE VACCINE SHOULD NOT BE 1651 01:06:12,856 --> 01:06:14,124 AGAINST ONE ANTIGEN UNLESS IT'S 1652 01:06:14,124 --> 01:06:15,426 AGAINST THE MUTATION THAT IS 1653 01:06:15,426 --> 01:06:18,462 MAKING THAT TUMOR A TUMOR. 1654 01:06:18,462 --> 01:06:20,798 IF YOU CAN GET THAT ONE, RIGHT, 1655 01:06:20,798 --> 01:06:25,069 WHEN THE TUMORS NO LONGER HAVE 1656 01:06:25,069 --> 01:06:27,538 THAT THEY ARE NO LONGER TUMOR 1657 01:06:27,538 --> 01:06:29,073 CELLS, NO LONGER NON-GROWTH 1658 01:06:29,073 --> 01:06:29,373 CONTROLLED. 1659 01:06:29,373 --> 01:06:29,973 YOU'RE RIGHT. 1660 01:06:29,973 --> 01:06:31,175 VACCINE SHOULD BE AGAINST MORE 1661 01:06:31,175 --> 01:06:32,142 THAN ONE ANTIGEN. 1662 01:06:32,142 --> 01:06:35,779 I COULD DO AT LEAST THREE. 1663 01:06:35,779 --> 01:06:37,714 THE CHANCES OF GETTING IMMUNE TO 1664 01:06:37,714 --> 01:06:39,817 ALL THREE ARE PRETTY LOW. 1665 01:06:39,817 --> 01:06:40,551 I KNOW THIS. 1666 01:06:40,551 --> 01:06:43,420 I HAVE A BUNCH OF SHEEP. 1667 01:06:43,420 --> 01:06:45,722 THEY GET WORMS. 1668 01:06:45,722 --> 01:06:47,391 THEY DIE FROM WORMS ACTUALLY. 1669 01:06:47,391 --> 01:06:50,327 I USE THREE WORMERS THAT WORK BY 1670 01:06:50,327 --> 01:06:53,397 THREE DIFFERENT WAYS. 1671 01:06:53,397 --> 01:06:54,498 WITH THE IDEA THAT, YOU KNOW, 1672 01:06:54,498 --> 01:06:56,133 ONE IN 100,000 TO A MILLION 1673 01:06:56,133 --> 01:06:57,634 MIGHT HAVE A MUTANT AGAINST ONE, 1674 01:06:57,634 --> 01:06:59,203 ONE IN A MILLION AGAINST 1675 01:06:59,203 --> 01:07:00,170 ANOTHER, ONE IN A MILLION 1676 01:07:00,170 --> 01:07:01,171 AGAINST A THIRD. 1677 01:07:01,171 --> 01:07:05,476 CHANCE OF ONE WORM HAVING ALL 1678 01:07:05,476 --> 01:07:08,212 THREE IS 1 IN 10 TO THE 18th. 1679 01:07:08,212 --> 01:07:10,881 I DON'T KNOW THERE'S THAT MANY 1680 01:07:10,881 --> 01:07:11,849 WORMS ON THE PLANET. 1681 01:07:11,849 --> 01:07:13,684 SO IT'S THE SAME. 1682 01:07:13,684 --> 01:07:13,984 GIVE THREE. 1683 01:07:13,984 --> 01:07:16,653 WE KNOW THIS FROM AIDS. 1684 01:07:16,653 --> 01:07:18,722 PEOPLE USED TO GIVE ONE DRUG 1685 01:07:18,722 --> 01:07:19,823 UNTIL THE VIRUS MUTATION, GIVE 1686 01:07:19,823 --> 01:07:20,557 ANOTHER ONE. 1687 01:07:20,557 --> 01:07:21,892 NOW THEY GIVE FOUR. 1688 01:07:21,892 --> 01:07:23,026 ALL AT ONCE. 1689 01:07:23,026 --> 01:07:23,961 AND IT WORKS. 1690 01:07:23,961 --> 01:07:27,264 SO I WOULD USE AT LEAST THREE. 1691 01:07:27,264 --> 01:07:29,299 AND THEN YOUR CHANCE OF TUMOR 1692 01:07:29,299 --> 01:07:33,070 ESCAPE IS MUCH, MUCH LOWER. 1693 01:07:33,070 --> 01:07:35,272 1694 01:07:35,272 --> 01:07:38,375 WE'RE GOING TO HAVE A HALF HOUR 1695 01:07:38,375 --> 01:07:38,876 TOGETHER. 1696 01:07:38,876 --> 01:07:41,812 >> YES, I KNOW. 1697 01:07:41,812 --> 01:07:42,112 >> SHORT. 1698 01:07:42,112 --> 01:07:43,747 >> ANSWER THIS PART OF THE 1699 01:07:43,747 --> 01:07:46,283 QUESTION ABOUT CIGARETTE SMOKE. 1700 01:07:46,283 --> 01:07:46,550 >> OKAY. 1701 01:07:46,550 --> 01:07:49,386 GO TO THE MICROPHONE. 1702 01:07:49,386 --> 01:07:50,454 HERE. 1703 01:07:50,454 --> 01:07:53,223 NO, NO, HERE, IT'S QUICKER. 1704 01:07:53,223 --> 01:07:56,360 1705 01:07:56,360 --> 01:07:59,029 >> YEAH, SO FIRST OF ALL, THERE 1706 01:07:59,029 --> 01:08:00,664 ARE CARCINOGENS IN CIGARETTE 1707 01:08:00,664 --> 01:08:02,199 SMOKE, I CAN'T NAME ALL OF THEM, 1708 01:08:02,199 --> 01:08:03,867 BUT IT'S KNOWN THAT LUNG CANCER 1709 01:08:03,867 --> 01:08:07,104 IS ONE OF THE CANCERS THAT HAS 1710 01:08:07,104 --> 01:08:10,707 GENERALLY HAS A HIGH TUMOR 1711 01:08:10,707 --> 01:08:12,709 MUTATIONAL BURDEN, MEANING THERE 1712 01:08:12,709 --> 01:08:17,247 ARE LOTS OF MUTATIONS THAT COULD 1713 01:08:17,247 --> 01:08:21,718 BE TARGETS FOR IMMUNOTHERAPY. 1714 01:08:21,718 --> 01:08:23,787 SO, AT LEAST THAT'S BECAUSE OF 1715 01:08:23,787 --> 01:08:25,822 THE CARCINOGENS IN THE CIGARETTE 1716 01:08:25,822 --> 01:08:26,223 SMOKE. 1717 01:08:26,223 --> 01:08:28,759 BUT THE OTHER THING I WANT TO 1718 01:08:28,759 --> 01:08:31,929 POINT OUT IS THAT STUDIES HAVE 1719 01:08:31,929 --> 01:08:34,998 BEEN DONE TO SHOW NICOTINE 1720 01:08:34,998 --> 01:08:36,600 ITSELF IS CARCINOGENIC. 1721 01:08:36,600 --> 01:08:38,302 >> THE QUESTION WAS ABOUT CELL 1722 01:08:38,302 --> 01:08:39,269 DEATH. 1723 01:08:39,269 --> 01:08:39,703 >> YEAH. 1724 01:08:39,703 --> 01:08:40,704 >> ARE THEY CARCINOGENIC BECAUSE 1725 01:08:40,704 --> 01:08:43,540 THEY CAUSE DEATH? 1726 01:08:43,540 --> 01:08:45,842 >> I'M SORRY, THE COMPONENTS IN 1727 01:08:45,842 --> 01:08:51,648 CIGARETTE SMOKE THAT ARE 1728 01:08:51,648 --> 01:08:53,050 CARCINOGENIC ARE MUTAGENS, IF 1729 01:08:53,050 --> 01:08:55,252 THEY HIT THE WRONG GENE YOU CAN 1730 01:08:55,252 --> 01:08:56,753 GET A MALIGNANCY. 1731 01:08:56,753 --> 01:08:57,020 >> RIGHT. 1732 01:08:57,020 --> 01:08:58,488 >> WHAT I WANTED TO MAKE -- 1733 01:08:58,488 --> 01:09:00,691 >> THAT'S THE ANSWER TO THAT 1734 01:09:00,691 --> 01:09:03,026 ONE, RIGHT? 1735 01:09:03,026 --> 01:09:03,293 >> YEAH. 1736 01:09:03,293 --> 01:09:03,794 >> CELL-CAUSING DEATH. 1737 01:09:03,794 --> 01:09:05,829 >> WHAT I WANTED TO MAKE PEOPLE 1738 01:09:05,829 --> 01:09:07,898 AWARE OF, THAT MANY PEOPLE ARE 1739 01:09:07,898 --> 01:09:11,235 NOT AWARE OF, IS THAT NICOTINE 1740 01:09:11,235 --> 01:09:15,572 ITSELF CAN CAUSE TUMORS IN MICE, 1741 01:09:15,572 --> 01:09:16,673 FOR EXAMPLE. 1742 01:09:16,673 --> 01:09:23,180 AND THAT THEREFORE THE IDEA THAT 1743 01:09:23,180 --> 01:09:25,983 VAPING, INHALING NICOTINE 1744 01:09:25,983 --> 01:09:27,985 WITHOUT ALL OF THOSE CARCINOGENS 1745 01:09:27,985 --> 01:09:29,453 FROM TOBACCO SMOKE DOESN'T 1746 01:09:29,453 --> 01:09:31,488 COMPLETELY PROTECT YOU BECAUSE 1747 01:09:31,488 --> 01:09:35,626 THE NICOTINE ITSELF, BESIDES 1748 01:09:35,626 --> 01:09:37,761 BEING ADDICTIVE, IS ALSO 1749 01:09:37,761 --> 01:09:38,195 CARCINOGEN. 1750 01:09:38,195 --> 01:09:41,064 >> AN ADVERTISEMENT TO STOP 1751 01:09:41,064 --> 01:09:42,299 VAPING; THERE YOU GO. 1752 01:09:42,299 --> 01:09:44,234 >> YOU'VE BEEN IGNORING ME 1753 01:09:44,234 --> 01:09:44,434 THERE. 1754 01:09:44,434 --> 01:09:49,373 >> I'M SO SORRY. 1755 01:09:49,373 --> 01:09:52,709 I'M BLIND. 1756 01:09:52,709 --> 01:09:54,511 >> ANYWAY, VERY INTERESTING 1757 01:09:54,511 --> 01:09:54,711 TALK. 1758 01:09:54,711 --> 01:09:55,912 >> BUT. 1759 01:09:55,912 --> 01:09:57,147 [LAUGHTER] 1760 01:09:57,147 --> 01:09:59,049 >> WELL, SO THEN WHAT IS 1761 01:09:59,049 --> 01:10:00,083 AUTOIMMUNITY, WHAT IS SOMETHING 1762 01:10:00,083 --> 01:10:01,652 LIKE M.S., RIGHT? 1763 01:10:01,652 --> 01:10:06,657 IF I'M HEARING YOU CORRECTLY, 1764 01:10:06,657 --> 01:10:12,396 YOU CONSTANTLY HAVE TO HAVE THIS 1765 01:10:12,396 --> 01:10:13,997 IMMUNOGENIC CELL DEATH 1766 01:10:13,997 --> 01:10:18,435 HAPPENING, IN ORDER TO SUSTAIN 1767 01:10:18,435 --> 01:10:19,603 THESE BOUNDS COMING BACK AGAIN 1768 01:10:19,603 --> 01:10:20,704 AND AGAIN. 1769 01:10:20,704 --> 01:10:22,539 >> YES, VERY IMPORTANT POINT. 1770 01:10:22,539 --> 01:10:24,875 BECAUSE MANY PEOPLE -- HANG ON. 1771 01:10:24,875 --> 01:10:27,711 MANY PEOPLE SUGGESTED, MY 1772 01:10:27,711 --> 01:10:29,313 CATEGORY TWO, AUTOIMMUNITY, LIKE 1773 01:10:29,313 --> 01:10:31,815 WITH RHEUMATIC FEVER, RIGHT, YOU 1774 01:10:31,815 --> 01:10:33,483 CAN INITIATE AND AUTOIMMUNE 1775 01:10:33,483 --> 01:10:35,419 RESPONSE WITH CROSS-REACTION TO 1776 01:10:35,419 --> 01:10:36,453 SOME PATHOGEN. 1777 01:10:36,453 --> 01:10:37,854 BUT THE NICE THING ABOUT 1778 01:10:37,854 --> 01:10:39,056 RHEUMATIC FEVER, IT TELLS YOU 1779 01:10:39,056 --> 01:10:41,558 THAT YOU NEED TO KEEP DOING THAT 1780 01:10:41,558 --> 01:10:44,027 BECAUSE WHEN THEY PUT KIDS ON 1781 01:10:44,027 --> 01:10:45,162 PENICILLIN FOR 20 YEARS, AND 1782 01:10:45,162 --> 01:10:48,465 THEY DON'T HAVE THAT, IT GOES 1783 01:10:48,465 --> 01:10:48,665 AWAY. 1784 01:10:48,665 --> 01:10:51,735 YES, YOU HAVE TO KEEP DOING IT. 1785 01:10:51,735 --> 01:10:52,703 >> YEAH, SO WE HAVE, YOU KNOW, 1786 01:10:52,703 --> 01:10:54,471 TODAY I SAW IN THE CLINIC, 1787 01:10:54,471 --> 01:11:00,944 RIGHT, WE HAVE PEOPLE WHO HAVE 1788 01:11:00,944 --> 01:11:03,313 THIS TRANSVERSE MYELITIS, 1789 01:11:03,313 --> 01:11:04,081 ONE-TIME ATTACK, IMMUNE 1790 01:11:04,081 --> 01:11:07,517 MEDIATED, WE CAN'T FIND 1791 01:11:07,517 --> 01:11:09,486 PATHOGENS, THEORETICALLY IT'S 1792 01:11:09,486 --> 01:11:09,786 AUTOIMMUNE. 1793 01:11:09,786 --> 01:11:13,056 IT NEVER HAPPENS AGAIN. 1794 01:11:13,056 --> 01:11:14,224 RIGHT? 1795 01:11:14,224 --> 01:11:14,558 >> UH-HUH. 1796 01:11:14,558 --> 01:11:18,328 >> SO, THEN BASED ON DANGER 1797 01:11:18,328 --> 01:11:23,033 MODEL, IN ORDER TO HAVE CHRONIC 1798 01:11:23,033 --> 01:11:26,770 AUTOIMMUNE DISEASE, 1799 01:11:26,770 --> 01:11:29,940 ORGAN-SPECIFIC AUTOIMMUNE 1800 01:11:29,940 --> 01:11:32,042 DISEASE, THAT ORGAN MUST HAVE 1801 01:11:32,042 --> 01:11:33,677 PERIODS OF THIS IMMUNOGENIC CELL 1802 01:11:33,677 --> 01:11:35,979 DEATH BECAUSE OTHERWISE EVEN THE 1803 01:11:35,979 --> 01:11:39,349 CELLS THAT HAVE BEEN AUTOIMMUNE, 1804 01:11:39,349 --> 01:11:40,117 RIGHT, EVENTUALLY THEY WOULD 1805 01:11:40,117 --> 01:11:41,485 BECOME ALLERGIC, WOULD BE 1806 01:11:41,485 --> 01:11:42,219 DELETED. 1807 01:11:42,219 --> 01:11:45,322 >> THEY WOULD BE MEMORY CELLS. 1808 01:11:45,322 --> 01:11:46,289 >> SEEMS LIKE A CANCER -- RIGHT, 1809 01:11:46,289 --> 01:11:50,861 A A COUNTERPART TO YOUR CANCER 1810 01:11:50,861 --> 01:11:51,061 STORY. 1811 01:11:51,061 --> 01:11:52,829 >> YES AND NO. 1812 01:11:52,829 --> 01:11:54,231 QUICKLY, YES AND NO. 1813 01:11:54,231 --> 01:11:56,967 YOU WON'T BE DISAPPOINTED. 1814 01:11:56,967 --> 01:11:57,734 I PROMISE YOU. 1815 01:11:57,734 --> 01:11:58,368 >> OKAY. 1816 01:11:58,368 --> 01:11:58,635 [LAUGHTER] 1817 01:11:58,635 --> 01:12:01,972 >> YOU GUYS ARE STILL HERE? 1818 01:12:01,972 --> 01:12:04,641 SO, THERE'S FOUR CATEGORIES OF 1819 01:12:04,641 --> 01:12:07,244 AUTOIMMUNE DISEASE, VERY 1820 01:12:07,244 --> 01:12:07,577 QUICKLY. 1821 01:12:07,577 --> 01:12:08,678 ONE, BORING, YOU HAVE AN 1822 01:12:08,678 --> 01:12:11,181 INFECTION AND DON'T KNOW IT AND 1823 01:12:11,181 --> 01:12:14,851 MY FAVORITE POSTER CHILD HERE IS 1824 01:12:14,851 --> 01:12:19,423 LYME, FIRST DIAGNOSED AS 1825 01:12:19,423 --> 01:12:24,761 JUVENILE RHEUMATOID ARTHRITIS. 1826 01:12:24,761 --> 01:12:28,265 HOW MANY OTHER ARTHRITIES ARE 1827 01:12:28,265 --> 01:12:29,166 INFECTION WITH SOMETHING WE 1828 01:12:29,166 --> 01:12:30,567 DON'T KNOW. 1829 01:12:30,567 --> 01:12:31,435 YOU'RE DESTROYING THE ORGAN AS 1830 01:12:31,435 --> 01:12:34,204 TRYING TO GET RID OF THE 1831 01:12:34,204 --> 01:12:35,005 PATHOGEN. 1832 01:12:35,005 --> 01:12:35,205 TWO -- 1833 01:12:35,205 --> 01:12:37,574 >> M.S. CAN BE THAT. 1834 01:12:37,574 --> 01:12:38,141 >> HANG ON. 1835 01:12:38,141 --> 01:12:42,846 I THINK M.S. COULD BE ANY ONE OF 1836 01:12:42,846 --> 01:12:43,713 THESE CATEGORIES, PROBABLY IS 1837 01:12:43,713 --> 01:12:45,482 MORE THAN ONE DISEASE. 1838 01:12:45,482 --> 01:12:47,684 SOME PEOPLE RESPOND TO 1839 01:12:47,684 --> 01:12:49,319 INTERFERON BETA, SOME DON'T, 1840 01:12:49,319 --> 01:12:51,254 SOME TO PAXLOVID, SOME DON'T, 1841 01:12:51,254 --> 01:12:51,955 IT'S DIFFERENT DISEASES. 1842 01:12:51,955 --> 01:12:54,391 SECOND IS ALSO AN INFECTION, 1843 01:12:54,391 --> 01:12:57,160 KNOWN AS MOLECULAR MIMICRY FOR 1844 01:12:57,160 --> 01:12:58,795 VERY LONG TIME. 1845 01:12:58,795 --> 01:13:00,530 YOU HAVE AN INFECTION, WITH 1846 01:13:00,530 --> 01:13:02,766 SOMETHING NOT NECESSARILY IN THE 1847 01:13:02,766 --> 01:13:04,468 TARGET ORGAN. 1848 01:13:04,468 --> 01:13:06,236 HERE'S RHEUMATIC FEVER. 1849 01:13:06,236 --> 01:13:08,772 YOU GET STREP. 1850 01:13:08,772 --> 01:13:11,475 YOU RESPOND TO STREP. 1851 01:13:11,475 --> 01:13:14,044 >> THAT CANNOT BE SUSTAINED 1852 01:13:14,044 --> 01:13:14,811 AUTOIMMUNITY, RIGHT? 1853 01:13:14,811 --> 01:13:16,847 >> IT CAN BE IF YOU DON'T GIVE 1854 01:13:16,847 --> 01:13:17,180 PENICILLIN. 1855 01:13:17,180 --> 01:13:19,416 THEY GIVE IT BECAUSE THE FIRST 1856 01:13:19,416 --> 01:13:20,116 RESPONSE STARTS DESTROYING THE 1857 01:13:20,116 --> 01:13:21,184 HEART VALVE AND THEY KNOW IF 1858 01:13:21,184 --> 01:13:22,619 THEY NOW DO A SECONDARY 1859 01:13:22,619 --> 01:13:24,387 RESPONSE, IT'S GOING TO BE EVEN 1860 01:13:24,387 --> 01:13:24,855 WORSE. 1861 01:13:24,855 --> 01:13:28,124 SO THEY KEEP THE STREP OUT. 1862 01:13:28,124 --> 01:13:31,528 SO, IMAGINE YOU'VE GOT AN 1863 01:13:31,528 --> 01:13:34,898 INFECTION IN THE GUT. 1864 01:13:34,898 --> 01:13:37,534 AND IT'S GOT A CROSS-REACTIVE 1865 01:13:37,534 --> 01:13:39,269 PEPTIDE WITH SOMETHING IN THE 1866 01:13:39,269 --> 01:13:40,937 BRAIN, AND IT'S A CHRONIC 1867 01:13:40,937 --> 01:13:42,105 INFECTION. 1868 01:13:42,105 --> 01:13:43,573 YOU NOW HAVE LONG-LASTING M.S. 1869 01:13:43,573 --> 01:13:46,776 >> NO, NO, NO, NO, NO. 1870 01:13:46,776 --> 01:13:48,678 YOU HAVE ATTACK OF M.S., FIND 1871 01:13:48,678 --> 01:13:50,914 THESE LESIONS IN THE BRAIN. 1872 01:13:50,914 --> 01:13:52,983 YOU DON'T HAVE TO DO ANYTHING. 1873 01:13:52,983 --> 01:13:56,820 >> NO, YOU DON'T HAVE TO -- 1874 01:13:56,820 --> 01:13:58,688 >> NO, NO, NO, YOU DON'T DO 1875 01:13:58,688 --> 01:13:59,389 ANYTHING AND LESIONS WILL HEAL. 1876 01:13:59,389 --> 01:14:02,259 >> IT'S THAT THE OTHER KIND OF 1877 01:14:02,259 --> 01:14:04,494 M.S., RELAPSING REMITTING AND 1878 01:14:04,494 --> 01:14:06,062 PROGRESSIVE, RIGHT? 1879 01:14:06,062 --> 01:14:07,731 SO, RELAPSING REMITTING, TO ME 1880 01:14:07,731 --> 01:14:07,864 -- 1881 01:14:07,864 --> 01:14:11,167 >> NO, WE THINK IT'S ONE M.S. 1882 01:14:11,167 --> 01:14:12,669 >> WELL, MAYBE. 1883 01:14:12,669 --> 01:14:16,006 IT'S THE DIFFERENT STAGE OF THE 1884 01:14:16,006 --> 01:14:16,373 DISEASE. 1885 01:14:16,373 --> 01:14:17,741 [LAUGHTER] 1886 01:14:17,741 --> 01:14:19,776 >> CAN I SPEAK? 1887 01:14:19,776 --> 01:14:20,176 >> YEAH. 1888 01:14:20,176 --> 01:14:21,545 >> THANK YOU. 1889 01:14:21,545 --> 01:14:23,747 YOU'VE GOT AN ENVIRONMENTAL 1890 01:14:23,747 --> 01:14:25,482 PATHOGEN. 1891 01:14:25,482 --> 01:14:27,484 IT COMES EVERY SPRING, MAYBE. 1892 01:14:27,484 --> 01:14:28,785 IT'S OUT THERE AND YOU RUN INTO 1893 01:14:28,785 --> 01:14:32,522 IT WHEN YOU GO RUNNING, MAYBE. 1894 01:14:32,522 --> 01:14:35,158 YOU GET IT, YOU CLEAR IT. 1895 01:14:35,158 --> 01:14:36,593 BUT IT'S OUT THERE. 1896 01:14:36,593 --> 01:14:38,094 YOU GET IT AGAIN. 1897 01:14:38,094 --> 01:14:39,596 YOU CLEAR IT. 1898 01:14:39,596 --> 01:14:41,097 AND IT HAPPENS TO CROSS-REACT 1899 01:14:41,097 --> 01:14:42,666 WITH SOMETHING IN THE BRAIN. 1900 01:14:42,666 --> 01:14:44,668 EVERY SINGLE TIME YOU CLEAR IT 1901 01:14:44,668 --> 01:14:45,936 YOU'LL GET A FLARE. 1902 01:14:45,936 --> 01:14:47,737 ONE OF THE QUESTIONS THAT AT 1903 01:14:47,737 --> 01:14:50,674 LEAST SOME M.S. PEOPLE HAVE 1904 01:14:50,674 --> 01:14:54,978 GIVEN ME IS HOW CAN I EXPLAIN 1905 01:14:54,978 --> 01:14:56,446 WHY THE LESIONS -- IT'S HARD TO 1906 01:14:56,446 --> 01:14:59,749 PREDICT WHERE THEY ARE GOING TO 1907 01:14:59,749 --> 01:14:59,983 BE. 1908 01:14:59,983 --> 01:15:02,652 I HAVE AN ANSWER FOR THAT. 1909 01:15:02,652 --> 01:15:03,720 IT'S HAND WAVING. 1910 01:15:03,720 --> 01:15:06,122 PEOPLE ASK IF MY WRISTS GET 1911 01:15:06,122 --> 01:15:08,091 TIRED OF HAND WAVING. 1912 01:15:08,091 --> 01:15:08,358 [LAUGHTER] 1913 01:15:08,358 --> 01:15:08,959 HERE'S THE SUGGESTION. 1914 01:15:08,959 --> 01:15:10,226 BECAUSE WE SEE THAT. 1915 01:15:10,226 --> 01:15:13,296 YOU GET A LESION, A LESION HERE, 1916 01:15:13,296 --> 01:15:16,700 A LESION THERE, ANOTHER ONE 1917 01:15:16,700 --> 01:15:16,900 HERE. 1918 01:15:16,900 --> 01:15:19,369 WE KNOW THAT IF YOU CUT -- CAN'T 1919 01:15:19,369 --> 01:15:21,304 REMEMBER WHAT IT'S CALLED, A 1920 01:15:21,304 --> 01:15:23,907 NERVE HERE, IF YOU CUT IT, THE 1921 01:15:23,907 --> 01:15:26,610 MICROGLIA AT THE OTHER END OF 1922 01:15:26,610 --> 01:15:28,745 THE NERVE GET ACTIVATED, IN A 1923 01:15:28,745 --> 01:15:30,647 WAY THAT ANY DENDRITIC CELL OR 1924 01:15:30,647 --> 01:15:33,750 MACROPHAGE TRYING TO PRESENT TO 1925 01:15:33,750 --> 01:15:38,088 A T CELL WOULD GET UPREGULATED, 1926 01:15:38,088 --> 01:15:39,789 CLASS 1, CLASS 2, CD40 AND SO 1927 01:15:39,789 --> 01:15:41,024 ON, AND THEN THEY REST. 1928 01:15:41,024 --> 01:15:43,226 IF YOU'VE DONE DAMAGE TO A 1929 01:15:43,226 --> 01:15:44,294 NERVE, NO MATTER HOW FAR AWAY, 1930 01:15:44,294 --> 01:15:46,930 AS LONG AS IT'S CONNECTED TO THE 1931 01:15:46,930 --> 01:15:50,333 BRAIN, YOU COULD GET TEMPORARY 1932 01:15:50,333 --> 01:15:50,800 MICROGLIA ACTIVATION. 1933 01:15:50,800 --> 01:15:52,202 THERE IS T CELL TRAFFIC THROUGH 1934 01:15:52,202 --> 01:15:54,838 THE BRAIN. 1935 01:15:54,838 --> 01:15:56,706 NOW LET'S SAY YOU ARE IN THE 1936 01:15:56,706 --> 01:16:01,311 PROCESS OF CLEARING THIS 1937 01:16:01,311 --> 01:16:01,911 CROSS-REACTIVE INFECTION, AND 1938 01:16:01,911 --> 01:16:03,146 YOU GOT A LITTLE DRUNK AND 1939 01:16:03,146 --> 01:16:05,448 YOU'RE DRIVING HOME AND YOU WEAR 1940 01:16:05,448 --> 01:16:07,817 CONTACTS, AND YOU RUN INTO THIS 1941 01:16:07,817 --> 01:16:11,788 TRUCK WITH HUGE HEADLIGHTS, 1942 01:16:11,788 --> 01:16:13,657 WHICH DOES DAMAGE TO YOUR 1943 01:16:13,657 --> 01:16:13,890 RETINA. 1944 01:16:13,890 --> 01:16:15,759 NOW YOU'VE GOT AN AREA OF THE 1945 01:16:15,759 --> 01:16:19,229 BRAIN, A LITTLE BIT DAMAGED, 1946 01:16:19,229 --> 01:16:20,030 ACTIVATED MICROGLIA AND 1947 01:16:20,030 --> 01:16:20,897 CROSS-REACTIVE PEPTIDE AND T 1948 01:16:20,897 --> 01:16:22,365 CELLS WILL GO THERE AND THAT'S 1949 01:16:22,365 --> 01:16:24,934 WHERE YOUR LESION IS GOING TO 1950 01:16:24,934 --> 01:16:25,802 BE. 1951 01:16:25,802 --> 01:16:27,570 WELL, WE DON'T HAVE A GOOD MODEL 1952 01:16:27,570 --> 01:16:29,539 IN MICE. 1953 01:16:29,539 --> 01:16:31,341 IF WE HAD -- THERE'S SOME KIND 1954 01:16:31,341 --> 01:16:37,280 OF MONKEY YOU CAN DO A MODEL FOR 1955 01:16:37,280 --> 01:16:38,581 M.S. 1956 01:16:38,581 --> 01:16:39,683 GIVE IT EAE. 1957 01:16:39,683 --> 01:16:42,118 PUT A PAPER CLIP ON ITS TAIL. 1958 01:16:42,118 --> 01:16:44,387 SEE WHERE THE LESION GOES. 1959 01:16:44,387 --> 01:16:46,956 WE CAN'T DO IT IN MICE BECAUSE 1960 01:16:46,956 --> 01:16:48,758 IT'S NOT A CEREBELLAR DISEASE IN 1961 01:16:48,758 --> 01:16:48,958 MICE. 1962 01:16:48,958 --> 01:16:52,829 YOU COULD DO IT IN THIS MONKEY. 1963 01:16:52,829 --> 01:16:55,765 I THINK RELAPSING REMITTING CAN 1964 01:16:55,765 --> 01:16:56,766 BE A CROSS-REACTION WITH 1965 01:16:56,766 --> 01:16:58,068 ENVIRONMENTAL ANTIGEN. 1966 01:16:58,068 --> 01:17:00,970 THAT'S THE SECOND CATEGORY HERE. 1967 01:17:00,970 --> 01:17:01,805 IT'S STILL INFECTION BUT DOESN'T 1968 01:17:01,805 --> 01:17:03,440 HAVE TO BE THE TARGET ORGAN 1969 01:17:03,440 --> 01:17:06,910 BECAUSE YOU HAVE AN AUTOIMMUNE 1970 01:17:06,910 --> 01:17:07,510 COMPONENT. 1971 01:17:07,510 --> 01:17:10,547 THANK YOU FOR STAYING SO LONG. 1972 01:17:10,547 --> 01:17:15,852 THREE MORE MINUTES AND I'M DONE. 1973 01:17:15,852 --> 01:17:17,787 THIRD CATEGORY IS DEATH, THAT'S 1974 01:17:17,787 --> 01:17:17,987 LUPUS. 1975 01:17:17,987 --> 01:17:20,557 I'VE ALREADY TALKED ABOUT THAT. 1976 01:17:20,557 --> 01:17:22,292 THAT'S DEATH. 1977 01:17:22,292 --> 01:17:23,793 I THINK IN ALL THESE THREE 1978 01:17:23,793 --> 01:17:26,062 CATEGORIES THERE'S NOTHING WRONG 1979 01:17:26,062 --> 01:17:30,166 WITH THE IMMUNE SYSTEM. 1980 01:17:30,166 --> 01:17:33,470 THERE IS ONE FOURTH, ALSO GIVES 1981 01:17:33,470 --> 01:17:33,803 YOU LUPUS. 1982 01:17:33,803 --> 01:17:38,308 BAD DEATH AND BED SCAVENGING. 1983 01:17:38,308 --> 01:17:40,176 BAD, MMM, RECOGNITION OF DEATH, 1984 01:17:40,176 --> 01:17:42,679 IF YOU LIKE, OR BAD RECOGNITION 1985 01:17:42,679 --> 01:17:42,979 IN GENERAL. 1986 01:17:42,979 --> 01:17:47,617 THERE'S A FORM OF LUPUS IN MICE, 1987 01:17:47,617 --> 01:17:49,452 WHERE THERE'S BEEN A 1988 01:17:49,452 --> 01:17:52,522 DUPLICATION, AND YOU HAVE A HIGH 1989 01:17:52,522 --> 01:17:55,992 LEVEL OF AN RNA RECOGNIZER. 1990 01:17:55,992 --> 01:17:59,229 AND IT RESPONDS TO THE NORMAL 1991 01:17:59,229 --> 01:18:00,363 LEVELS OF SYSTEMIC RNA. 1992 01:18:00,363 --> 01:18:05,535 SO NOW YOU GET ACTIVATION SIG 1993 01:18:05,535 --> 01:18:06,870 SIGNALS AND LUPUS. 1994 01:18:06,870 --> 01:18:08,938 I THINK M.S. IS EITHER GOING TO 1995 01:18:08,938 --> 01:18:12,108 BE HERE, WITH INFECTION IN THE 1996 01:18:12,108 --> 01:18:14,210 BRAIN, OR HERE, WITH MOLECULAR 1997 01:18:14,210 --> 01:18:17,447 MIMICRY, WHERE YOU HAVE AN 1998 01:18:17,447 --> 01:18:18,882 INFECTION SOMEWHERE ELSE. 1999 01:18:18,882 --> 01:18:22,786 AND IF IT'S CHRONIC, YOU'LL GET 2000 01:18:22,786 --> 01:18:24,287 PROGRESSIVE. 2001 01:18:24,287 --> 01:18:25,021 IF IT'S RELAPSING REMITTING, 2002 01:18:25,021 --> 01:18:29,125 THEN I WOULD SAY IT'S NOT 2003 01:18:29,125 --> 01:18:29,993 CHRONIC INFECTION. 2004 01:18:29,993 --> 01:18:32,095 THAT'S THE BEST I CAN DO. 2005 01:18:32,095 --> 01:18:33,496 DOESN'T LIKE IT. 2006 01:18:33,496 --> 01:18:33,763 IT'S OKAY. 2007 01:18:33,763 --> 01:18:35,899 I TOLD YOU I'M NOT AN EXPERT IN 2008 01:18:35,899 --> 01:18:37,867 ANY OF THESE FIELDS, AND THE 2009 01:18:37,867 --> 01:18:43,439 EXPERTS WILL GET UP AND SAY UGH. 2010 01:18:43,439 --> 01:18:45,642 >> I'M THINKING YOUR FINGER 2011 01:18:45,642 --> 01:18:52,649 SHOWING LIKE THE TUMOR GROWTH 2012 01:18:52,649 --> 01:18:54,951 AND TUMOR DEATH, THE THIRD TUMOR 2013 01:18:54,951 --> 01:18:59,155 GROW, GROW, BUT T CELL RESTS, 2014 01:18:59,155 --> 01:19:02,959 I'M THINKING LIKE THE THIRD TIME 2015 01:19:02,959 --> 01:19:04,260 TUMOR GROWTH IS ALSO ORIGINAL 2016 01:19:04,260 --> 01:19:08,998 ONE, ALSO THE FIRST ONE, TWO 2017 01:19:08,998 --> 01:19:12,468 MORE, THE THIRD ONE TUMOR GROWTH 2018 01:19:12,468 --> 01:19:15,972 THEY CHANGE, THEY LIKE TO BECOME 2019 01:19:15,972 --> 01:19:16,739 THE -- 2020 01:19:16,739 --> 01:19:17,073 >> RIGHT. 2021 01:19:17,073 --> 01:19:18,508 SO THAT WAS ALSO SUGGESTED. 2022 01:19:18,508 --> 01:19:21,244 AND I THINK THERE WILL BE TIMES 2023 01:19:21,244 --> 01:19:21,544 LIKE THAT. 2024 01:19:21,544 --> 01:19:22,979 IF YOU VACCINATE AGAINST ONLY 2025 01:19:22,979 --> 01:19:25,915 ONE ANTIGEN ON THE TUMOR, THEN 2026 01:19:25,915 --> 01:19:28,651 IT CAN MUTATE, SO THE T CELLS 2027 01:19:28,651 --> 01:19:29,853 CAN'T FEED ANYMORE. 2028 01:19:29,853 --> 01:19:33,590 BUT YOU STILL NEED TO KEEP THAT 2029 01:19:33,590 --> 01:19:36,192 IMMUNE RESPONSE GOING. 2030 01:19:36,192 --> 01:19:38,428 >> YES, BUT LIKE MAYBE NOT THE 2031 01:19:38,428 --> 01:19:40,797 RIGHT EXAMPLE, LIKE THE 2032 01:19:40,797 --> 01:19:43,633 MELANOMA, DOING THE PD-L1 2033 01:19:43,633 --> 01:19:46,469 THERAPY, AND SOME PATIENT MAYBE 2034 01:19:46,469 --> 01:19:49,405 THEY HAVE MORE, MORE T CELL, 2035 01:19:49,405 --> 01:19:53,610 AFTER LIKE THREE MONTHS OR SIX 2036 01:19:53,610 --> 01:19:55,245 MONTHS THERAPY, THOSE TYPES, 2037 01:19:55,245 --> 01:20:00,583 THEY ARE RESPONSE, BUT AFTER 2038 01:20:00,583 --> 01:20:02,118 MAYBE SEVERAL MONTHS MAYBE THE 2039 01:20:02,118 --> 01:20:03,353 TUMOR -- 2040 01:20:03,353 --> 01:20:04,354 >> THE TUMOR MUTATED. 2041 01:20:04,354 --> 01:20:05,221 THEY WILL DO THAT. 2042 01:20:05,221 --> 01:20:05,655 >> YEAH. 2043 01:20:05,655 --> 01:20:05,922 YEAH. 2044 01:20:05,922 --> 01:20:06,956 >> THEY WILL DO THAT. 2045 01:20:06,956 --> 01:20:09,359 I THINK THAT'S A SMALL SUBSET. 2046 01:20:09,359 --> 01:20:09,959 >> OKAY. 2047 01:20:09,959 --> 01:20:11,761 >> ESPECIALLY IF YOU HAVE A 2048 01:20:11,761 --> 01:20:12,962 POLYCLONAL RESPONSE. 2049 01:20:12,962 --> 01:20:14,964 AND THAT MOST OF THEM, I'M NOT 2050 01:20:14,964 --> 01:20:16,599 SAYING IT'S ALL, I TELL MY 2051 01:20:16,599 --> 01:20:20,970 POSTDOCS EVERY TIME YOU SAY 2052 01:20:20,970 --> 01:20:22,405 "ALL" OR "NEVER" IN BIOLOGY IT'S 2053 01:20:22,405 --> 01:20:23,072 A LIE. 2054 01:20:23,072 --> 01:20:23,339 >> OKAY. 2055 01:20:23,339 --> 01:20:24,140 THANK YOU. 2056 01:20:24,140 --> 01:20:25,775 >> THERE ARE EXCEPTIONS. 2057 01:20:25,775 --> 01:20:27,677 BUT THERE WILL BE THOSE, YES, 2058 01:20:27,677 --> 01:20:28,678 ABSOLUTELY, AND THOSE WILL BE 2059 01:20:28,678 --> 01:20:29,612 HARD TO DEAL WITH. 2060 01:20:29,612 --> 01:20:30,713 >> THANK YOU. 2061 01:20:30,713 --> 01:20:32,081 YOU'RE WELCOME. 2062 01:20:32,081 --> 01:20:34,884 I THINK I'M DONE. 2063 01:20:34,884 --> 01:20:38,321 [APPLAUSE] 2064 01:20:38,321 --> 01:20:40,924 2065 01:20:40,924 --> 01:20:50,967