1 00:00:08,221 --> 00:00:10,123 >> I'M FROM THE NATIONAL 2 00:00:10,123 --> 00:00:11,758 INSTITUTE ON AGING AND TODAY 3 00:00:11,758 --> 00:00:19,599 WITH ME IS DR. MOLLY WAXTER, WHO 4 00:00:19,599 --> 00:00:20,800 IS HEART AND MIND BEHIND THE 5 00:00:20,800 --> 00:00:21,401 WALS LECTURE. 6 00:00:21,401 --> 00:00:23,870 IT IS OUR PLEASURE TO INTRODUCE 7 00:00:23,870 --> 00:00:28,641 OUR SPEAKER FOR TODAY'S 8 00:00:28,641 --> 00:00:29,676 WEDNESDAY AFTERNOON LECTURE, DR. 9 00:00:29,676 --> 00:00:31,544 JONATHAN KIPNIS. 10 00:00:31,544 --> 00:00:37,517 DR. KIPNIS IS ALANA. AND EDITH 11 00:00:37,517 --> 00:00:40,220 L. WOLFF SH DISTINGUISHED 12 00:00:40,220 --> 00:00:40,787 PROFESSOR OF PATHOLOGY AND 13 00:00:40,787 --> 00:00:41,421 IMMUNOLOGY IN ST. LOUIS. 14 00:00:41,421 --> 00:00:44,624 HE IS PROFESSOR OF NEUROLOGY AND 15 00:00:44,624 --> 00:00:45,759 NEUROSCIENCE AND NEUROSURGERY 16 00:00:45,759 --> 00:00:48,128 AND DIRECTOR FOR THE CENTER OF 17 00:00:48,128 --> 00:00:50,330 BRAIN IMMUNOLOGY AND GLIA AT THE 18 00:00:50,330 --> 00:00:50,964 WASHINGTON UNIVERSITY SCHOOL OF 19 00:00:50,964 --> 00:00:52,632 MEDICINE. 20 00:00:52,632 --> 00:00:57,504 BEFORE I TELL YOU MORE ABOUT 21 00:00:57,504 --> 00:00:59,672 JONATHAN, IF YOU ARE ATTENDING 22 00:00:59,672 --> 00:01:03,243 THE LECTURE FOR CME CREDITS, THE 23 00:01:03,243 --> 00:01:06,146 CODE IS 57686. 24 00:01:06,146 --> 00:01:08,348 57686. 25 00:01:08,348 --> 00:01:10,450 IF YOU ARE WATCHING ONLINE AND 26 00:01:10,450 --> 00:01:16,389 WOULD LIKE TO SUBMIT A QUESTION, 27 00:01:16,389 --> 00:01:18,224 PLEASE USE THE SEND LIVE 28 00:01:18,224 --> 00:01:19,559 FEEDBACK BUTTON AND YOUR 29 00:01:19,559 --> 00:01:22,695 QUESTION WILL BE RELAID TO THE 30 00:01:22,695 --> 00:01:24,364 SPEAKER AT THE END OF THE 31 00:01:24,364 --> 00:01:24,597 LECTURE. 32 00:01:24,597 --> 00:01:28,635 WE ARE DELIGHTED TO HAVE DR. 33 00:01:28,635 --> 00:01:32,372 KIPNIS TO TALK ABOUT HIS STUDIES 34 00:01:32,372 --> 00:01:33,807 ON INTERACTION BETWEEN IMMUNE 35 00:01:33,807 --> 00:01:36,876 SYSTEM AND NERVOUS SYSTEM. 36 00:01:36,876 --> 00:01:40,213 HIS LAB DISCOVERED LYMPHATIC 37 00:01:40,213 --> 00:01:44,317 TISSUE SURROUNDING BRAIN THAT 38 00:01:44,317 --> 00:01:47,821 BROUGHT NEW PERSPECTIVE ON 39 00:01:47,821 --> 00:01:57,831 ALZHEIMER'S DISEASE, MULTIPLE 40 00:01:57,831 --> 00:02:02,101 SCLEROSIS AND DR. KIPNIS' LAB 41 00:02:02,101 --> 00:02:05,605 STUDIES THE COMPLEX RELATIONSHIP 42 00:02:05,605 --> 00:02:08,608 BETWEEN LYMPHATIC SYSTEM, 43 00:02:08,608 --> 00:02:10,043 GLYMPHATIC AND TRANSPORT BETWEEN 44 00:02:10,043 --> 00:02:15,682 BLOOD/BRAIN BARRIER. 45 00:02:15,682 --> 00:02:18,151 THEY HAVE RESEARCHED MAPPING THE 46 00:02:18,151 --> 00:02:22,121 IMMUNE RECEPTORS, THE PART OF 47 00:02:22,121 --> 00:02:24,290 THE BRAIN AND HE IS TRYING TO 48 00:02:24,290 --> 00:02:28,628 UNDERSTAND HOW CYTOKINES IMPACT 49 00:02:28,628 --> 00:02:29,429 BEHAVIOR. 50 00:02:29,429 --> 00:02:31,664 HIS LAB STUDIES NEUROIMMUNE 51 00:02:31,664 --> 00:02:37,503 INTERACTION IN THE CONTEXT OF 52 00:02:37,503 --> 00:02:42,942 SPINAL CORD INJURY AND BY 53 00:02:42,942 --> 00:02:44,944 UNRAVELLING THE CELLULAR 54 00:02:44,944 --> 00:02:48,281 MOLECULAR MECHANISMS WE HOPE TO 55 00:02:48,281 --> 00:02:50,550 MOVE FORWARD TO NOVEL 56 00:02:50,550 --> 00:02:51,751 THERAPEUTICS THAT EMPLOYEE THE 57 00:02:51,751 --> 00:02:52,886 HEALING POWER OF THE IMMUNE 58 00:02:52,886 --> 00:02:56,322 SYSTEM. 59 00:02:56,322 --> 00:03:00,627 DR. KIPNIS HAS BEEN A MEMBER OF 60 00:03:00,627 --> 00:03:02,295 THE NATIONAL ACADEMY OF MEDICINE 61 00:03:02,295 --> 00:03:03,963 SINCE 2022. 62 00:03:03,963 --> 00:03:05,899 HE HAS RECEIVED MANY AWARDS. 63 00:03:05,899 --> 00:03:11,437 HE HAS BEEN STUDYING INTERACTION 64 00:03:11,437 --> 00:03:15,408 IN THE CONTEXT OF HEALTH AND 65 00:03:15,408 --> 00:03:18,177 DISEASE SINCE HIS ELEMENTARY 66 00:03:18,177 --> 00:03:19,779 SCHOOL, ALMOST. 67 00:03:19,779 --> 00:03:21,214 SINCE HE GRADUATED SCHOOL WHEN 68 00:03:21,214 --> 00:03:23,583 HE DISCOVERED THE ROLE OF 69 00:03:23,583 --> 00:03:26,286 NATURALLY OCCURRING T-CELLS IN 70 00:03:26,286 --> 00:03:29,722 THE IMMUNE RESPONSE TO CENTRAL 71 00:03:29,722 --> 00:03:31,658 NERVOUS SYSTEM INJURIES. 72 00:03:31,658 --> 00:03:34,794 FOR HIS DOCTORAL STUDIES HE 73 00:03:34,794 --> 00:03:38,431 RECEIVED DISTINGUISHED PRIZE 74 00:03:38,431 --> 00:03:41,267 FROM THE ISRAELLY PARLIAMENT. 75 00:03:41,267 --> 00:03:43,036 HE RECEIVED A BACHELOR OF 76 00:03:43,036 --> 00:03:47,507 SCIENCE FROM TEL-AVIV AND PH.D. 77 00:03:47,507 --> 00:03:49,776 IN NEUROIMMUNOLOGY FROM THE -- 78 00:03:49,776 --> 00:03:50,643 INSTITUTE OF SCIENCE. 79 00:03:50,643 --> 00:03:53,046 HE WAS A FACULTY OF MEMBER FOR 80 00:03:53,046 --> 00:03:54,881 THE UNIVERSITY OF VIRGINIA FOR 81 00:03:54,881 --> 00:03:56,849 13 YEARS BEFORE MOVING TO 82 00:03:56,849 --> 00:03:57,483 WASHINGTON UNIVERSITY SCHOOL OF 83 00:03:57,483 --> 00:03:58,151 MEDICINE UNIVERSITY IN ST. LOUIS 84 00:03:58,151 --> 00:03:59,319 IN 2022. 85 00:03:59,319 --> 00:04:03,723 PLEASE JOIN ME IN WELCOMING DR. 86 00:04:03,723 --> 00:04:07,260 KIPNIS TO SPEAK ABOUT NAVIGATING 87 00:04:07,260 --> 00:04:09,062 UNCHARTED NEUROIMMUNE WATERS. 88 00:04:09,062 --> 00:04:19,305 >> THANK YOU. 89 00:04:21,941 --> 00:04:24,844 THANK YOU MACK AND MOLLY FOR 90 00:04:24,844 --> 00:04:25,478 INVITING ME. 91 00:04:25,478 --> 00:04:26,913 IT IS REALLY FUN. 92 00:04:26,913 --> 00:04:30,283 I DON'T SEE YOU AT ALL. 93 00:04:30,283 --> 00:04:32,618 I HAVE THE FOUR SOURCES OF LIGHT 94 00:04:32,618 --> 00:04:36,122 INTO MY EYES, AND IT IS NOT FUN 95 00:04:36,122 --> 00:04:38,091 AT ALL, BUT I GUESS IT IS A 96 00:04:38,091 --> 00:04:39,559 REQUIREMENT SO I HAVE TO GO WITH 97 00:04:39,559 --> 00:04:39,726 IT. 98 00:04:39,726 --> 00:04:41,728 I WAS TOLD THIS IS A BIG 99 00:04:41,728 --> 00:04:44,364 LECTURE, SO I SHOULD DO MORE. 100 00:04:44,364 --> 00:04:46,599 NORMALLY I PRESENT INTRODUCTION 101 00:04:46,599 --> 00:04:50,870 AND ONE OR TWO STORIES THAT ARE 102 00:04:50,870 --> 00:04:51,471 UNPUBLISHED. 103 00:04:51,471 --> 00:04:52,605 TOODS WILL BE A BUNCH OF 104 00:04:52,605 --> 00:04:54,007 DIFFERENT STORIES. 105 00:04:54,007 --> 00:04:55,541 IF YOU LOSE YOURSELF AT ONE 106 00:04:55,541 --> 00:04:57,710 POINT, DON'T WORRY, I PROBABLY 107 00:04:57,710 --> 00:04:58,911 LOST MYSELF THERE AS WELL. 108 00:04:58,911 --> 00:05:01,514 SO I WILL START THE LECTURE WITH 109 00:05:01,514 --> 00:05:04,484 THIS QUOTE IT SAYS IT IS WHAT WE 110 00:05:04,484 --> 00:05:05,518 KNOW ALREADY THAT OFTEN PREVENTS 111 00:05:05,518 --> 00:05:06,586 US FROM LEARNING. 112 00:05:06,586 --> 00:05:08,788 I THINK IT IS TRUE FOR EVERY 113 00:05:08,788 --> 00:05:08,988 FIELD. 114 00:05:08,988 --> 00:05:09,889 THINK ABOUT YOUR FIELD FOR A 115 00:05:09,889 --> 00:05:11,991 SECOND AND YOU WILL AGREE WITH 116 00:05:11,991 --> 00:05:13,726 ME, HOPEFULLY. 117 00:05:13,726 --> 00:05:16,262 IT IS VERY, VERY TRUE FOR THE 118 00:05:16,262 --> 00:05:18,197 FIELD OF NEUROIMMUNOLOGY, 119 00:05:18,197 --> 00:05:20,733 ANATOMY OF THE BRAIN AND HEAND 120 00:05:20,733 --> 00:05:25,038 FLOW OF CSF AND OLD CONCEPTS 121 00:05:25,038 --> 00:05:26,506 PEOPLE THOUGHT THEY FIGURED OUT 122 00:05:26,506 --> 00:05:28,608 WITH THE YUSZ OF EM AND NONE 123 00:05:28,608 --> 00:05:30,977 WANTS TO THINK IT TO BE 124 00:05:30,977 --> 00:05:34,614 DIFFERENT THAN WHAT THEY 125 00:05:34,614 --> 00:05:34,881 PROPOSED. 126 00:05:34,881 --> 00:05:36,049 THINGS MOVE FORWARD. 127 00:05:36,049 --> 00:05:37,884 IF YOU WERE TO BUY A HOUSE AND 128 00:05:37,884 --> 00:05:41,120 IT LOOKED LIKE THIS, YOU 129 00:05:41,120 --> 00:05:42,855 PROBABLY WOULD NOT WANT THAT 130 00:05:42,855 --> 00:05:43,656 PARTICULAR HOUSE. 131 00:05:43,656 --> 00:05:45,091 YOU PROBABLY WANT YOUR PIPING TO 132 00:05:45,091 --> 00:05:46,125 LOOK LIKE THIS. 133 00:05:46,125 --> 00:05:51,164 I THINK IT IS TRUE FOR OUR 134 00:05:51,164 --> 00:05:51,497 TISSUES. 135 00:05:51,497 --> 00:05:54,000 ALL OF OUR TISSUES HAVE TWO 136 00:05:54,000 --> 00:05:55,768 TYPES OF PIPES. 137 00:05:55,768 --> 00:05:58,337 BLOOD VESSELS, I THINK EVERYONE 138 00:05:58,337 --> 00:05:58,538 KNOWS. 139 00:05:58,538 --> 00:06:02,241 THE LYMPHATIC VESSELS, THAT MANY 140 00:06:02,241 --> 00:06:06,813 IN THE ROOM DON'T KNOW AND DON'T 141 00:06:06,813 --> 00:06:07,547 CARE ABOUT. 142 00:06:07,547 --> 00:06:09,816 BLOOD VESSELS ARE SIMILAR TO OUR 143 00:06:09,816 --> 00:06:14,353 WATER PIPES AND LYMPHATIC 144 00:06:14,353 --> 00:06:17,423 VESSELS ARE SIMILAR TO M SEWAGE 145 00:06:17,423 --> 00:06:18,624 PIPES. 146 00:06:18,624 --> 00:06:21,127 THE LYMPHATIC VESSELS REMOVE THE 147 00:06:21,127 --> 00:06:23,262 WASTE FROM THE TISSUE OUT INTO 148 00:06:23,262 --> 00:06:24,797 THE PERIPHERY. 149 00:06:24,797 --> 00:06:29,268 BEFORE IT GETS DETOXIFIED, IT 150 00:06:29,268 --> 00:06:37,110 GOES THROUGH THE LYMPH NODES. 151 00:06:37,110 --> 00:06:37,844 JUST THINK OF YOUR NEIGHBOR 152 00:06:37,844 --> 00:06:39,745 GOING THROUGH YOUR R TRASH CANS. 153 00:06:39,745 --> 00:06:43,416 IN TWO OR THREE WEEKS THEY KNOW 154 00:06:43,416 --> 00:06:45,184 EVERYTHING ABOUT YOU. 155 00:06:45,184 --> 00:06:47,987 IF THEY SEE SOMEBODY WEIRD IN 156 00:06:47,987 --> 00:06:50,323 YOUR TRASH CAN, BLOOD SOAKED 157 00:06:50,323 --> 00:06:52,425 TOWELS, THEY PROBABLY WILL CALL 158 00:06:52,425 --> 00:06:52,658 POLICE. 159 00:06:52,658 --> 00:06:54,760 SAME IMMUNE SYSTEM, NORMAL COMES 160 00:06:54,760 --> 00:06:57,563 WITH THE TISSUE, NOT COMING FROM 161 00:06:57,563 --> 00:06:59,465 NORMAL HEALTHY TISSUE, THEY 162 00:06:59,465 --> 00:07:01,200 WOULD GO AND EXPLORE WHAT IS 163 00:07:01,200 --> 00:07:02,635 HAPPENING IN THAT TISSUE. 164 00:07:02,635 --> 00:07:06,105 THAT IS VERY, VERY SIMPLISTIC 165 00:07:06,105 --> 00:07:07,907 WAY TO EXPLAIN IMMUNE 166 00:07:07,907 --> 00:07:10,243 SURVEILLANCE OF ORGANS WHAT THE 167 00:07:10,243 --> 00:07:11,811 IMMUNE SYSTEM DOES. 168 00:07:11,811 --> 00:07:13,613 THE NOTION WAS THE SECOND PART 169 00:07:13,613 --> 00:07:16,182 OF THE LYMPHATIC SYSTEM DOES NOT 170 00:07:16,182 --> 00:07:17,884 EXIST FOR THE BRAIN. 171 00:07:17,884 --> 00:07:21,954 OUR MOST IMPORTANT ORGAN WAS 172 00:07:21,954 --> 00:07:25,591 LEFT OUT OF IMMUNE SURVEILLANCE, 173 00:07:25,591 --> 00:07:26,826 OUR MOST IMPORTANT SURVEILLANCE 174 00:07:26,826 --> 00:07:30,496 AND TISSUE IN THE BODY. 175 00:07:30,496 --> 00:07:36,636 BRAIN IS EXTREMELY BUSY AND MET 176 00:07:36,636 --> 00:07:37,837 BOLICALLY PRODUCE WASTE. 177 00:07:37,837 --> 00:07:39,305 HOW DOES THE BRAIN CLEANSE 178 00:07:39,305 --> 00:07:41,941 ITSELF BECAUSE THERE ARE NO 179 00:07:41,941 --> 00:07:43,976 LYMPHATIC TISSUES IN THE BRAIN 180 00:07:43,976 --> 00:07:44,343 TISSUE. 181 00:07:44,343 --> 00:07:46,779 THERE IS ONE VERY POORLY DONE 182 00:07:46,779 --> 00:07:49,081 PAPER FROM NIH, MAYBE I 183 00:07:49,081 --> 00:07:50,816 SHOULDN'T MENTION IT, BUT IS 184 00:07:50,816 --> 00:07:53,352 WRONG, BUT THERE IS NO LYMPHATIC 185 00:07:53,352 --> 00:07:55,688 VESSELS IN THE BRAIN THAT IS 186 00:07:55,688 --> 00:07:56,589 AGREEABLE ON EVERYBODY. 187 00:07:56,589 --> 00:07:58,691 BUT THE BRAIN, AGAIN, LIKE I 188 00:07:58,691 --> 00:08:05,364 SAID, IT IS HIGHLY METABOLIC. 189 00:08:05,364 --> 00:08:14,307 SEVERAL YEARS AGO -- SHE CAME 190 00:08:14,307 --> 00:08:17,610 OUT WITH HOW IT SERVES, THE 191 00:08:17,610 --> 00:08:18,744 LYMPHATIC FUNCTION BEING ABLE TO 192 00:08:18,744 --> 00:08:20,346 GO THROUGH THE BRAIN TISSUE. 193 00:08:20,346 --> 00:08:23,950 OUR BRAINS ARE SWIMMING IN 194 00:08:23,950 --> 00:08:27,420 CEREBRAL SPINAL FLUID. 195 00:08:27,420 --> 00:08:37,263 CSF, WE HAVE A SPACE, PER 196 00:08:37,263 --> 00:08:37,763 PERIARTERAL SPACE. 197 00:08:37,763 --> 00:08:40,499 IT WILL GO THROUGH THE BRAIN 198 00:08:40,499 --> 00:08:44,003 TISSUE AND COLLECT THE 199 00:08:44,003 --> 00:08:45,304 METABOLITES AND COME OUT, HERE 200 00:08:45,304 --> 00:08:48,074 WE MADE A FANCY MOVIE AND I CAN 201 00:08:48,074 --> 00:08:49,041 SHOW IT TO YOU. 202 00:08:49,041 --> 00:08:55,248 WE PAID A LOT OF MONEY FOR IT. 203 00:08:55,248 --> 00:08:58,117 CSF GOES IN, WASHES THE SPACE. 204 00:08:58,117 --> 00:09:00,453 IT IS VERY SIMPLE UNDERSTANDING 205 00:09:00,453 --> 00:09:01,954 OF THE GLYMPHATIC SYSTEM. 206 00:09:01,954 --> 00:09:03,656 IT IS NOT VERY, VERY FAR AWAY 207 00:09:03,656 --> 00:09:05,458 FROM THAT MOVIE IF WE ARE 208 00:09:05,458 --> 00:09:06,025 LOOKING AT PARTICULAR BRAIN 209 00:09:06,025 --> 00:09:07,827 REGION. 210 00:09:07,827 --> 00:09:09,562 AND OF COURSE THE QUESTION IS 211 00:09:09,562 --> 00:09:12,064 WHERE ALL THIS JUNK GOES THEN? 212 00:09:12,064 --> 00:09:14,600 HOW DO YOU CLEAN THAT FROM NOT 213 00:09:14,600 --> 00:09:16,202 COMING BACK INTO THE BRAIN AND 214 00:09:16,202 --> 00:09:20,106 NOT CREATING A BRAIN SWAMP? 215 00:09:20,106 --> 00:09:22,008 SO WE TOTALLY INDEPENDENT OF 216 00:09:22,008 --> 00:09:25,678 THIS GLYMPHATIC STORY, WE WERE 217 00:09:25,678 --> 00:09:35,054 VERY INTERESTED IN BRAIN 218 00:09:35,054 --> 00:09:39,158 MNINGES, THREE LAYERS WITH THE P 219 00:09:39,158 --> 00:09:41,861 ATTACHED TO THE BRAIN, DURA 220 00:09:41,861 --> 00:09:45,131 ATTACHED TO THE SKULL, AND THE 221 00:09:45,131 --> 00:09:46,265 SPINAL FLUID FLOWS IN BETWEEN. 222 00:09:46,265 --> 00:09:49,769 THAT AREA IS VERY, VERY RICH IN 223 00:09:49,769 --> 00:09:53,606 ALL KINDS OF IMMUNE CELLS. 224 00:09:53,606 --> 00:09:55,775 MY LAB WAS STUDYING DIFFERENT 225 00:09:55,775 --> 00:09:59,078 IMMUNE CELLS IN THE DURA AND 226 00:09:59,078 --> 00:10:02,982 DERIVED CYTOKNES AND HOW THEY 227 00:10:02,982 --> 00:10:04,650 AFFECT BRAIN FUNCTION WITH A 228 00:10:04,650 --> 00:10:06,686 PARTICULAR INTEREST IN HOW 229 00:10:06,686 --> 00:10:10,022 THINGS ARE CHANGING IN AGES AND 230 00:10:10,022 --> 00:10:11,490 DISEASES LIKE ALZHEIMER'S AND 231 00:10:11,490 --> 00:10:12,925 HOW THAT MAY PLAY A ROLE. 232 00:10:12,925 --> 00:10:14,794 THAT WAS MY LAB. 233 00:10:14,794 --> 00:10:17,830 THAT WAS MY FIRST RO1, WHICH IS 234 00:10:17,830 --> 00:10:21,367 IN META PHASE THIS VERY 235 00:10:21,367 --> 00:10:22,635 EXCITING. 236 00:10:22,635 --> 00:10:25,237 WHICH IS HOW I GOT INTO IT IN 237 00:10:25,237 --> 00:10:26,906 THE VERY, VERY BEGINNING. 238 00:10:26,906 --> 00:10:29,442 I WILL NOT BE TALKING ABOUT THIS 239 00:10:29,442 --> 00:10:29,809 TODAY. 240 00:10:29,809 --> 00:10:31,277 I WILL MENTION IT AT THE END. 241 00:10:31,277 --> 00:10:33,379 A NEW STORY JUST CAME OUT. 242 00:10:33,379 --> 00:10:39,685 WE ARE VERY EXCITED ABOUT 243 00:10:39,685 --> 00:10:40,152 MENINGEAL IMMUNITY. 244 00:10:40,152 --> 00:10:42,655 HOW THE IMMUNE CELLS ARE COMING 245 00:10:42,655 --> 00:10:51,063 AND GOING TO INTO THE MENINGES. 246 00:10:51,063 --> 00:10:52,832 ANTWAN ESTABLISHED THIS WHOLE 247 00:10:52,832 --> 00:10:56,168 MOUNT OF THE MOUSE DURA. 248 00:10:56,168 --> 00:10:59,338 HE PEELS THE OUTMOST LAYER AND 249 00:10:59,338 --> 00:11:00,706 2-D ON A SLIDE. 250 00:11:00,706 --> 00:11:02,942 HERE THE LABELS THESE IN RED ARE 251 00:11:02,942 --> 00:11:06,345 BLOOD VESSELS. 252 00:11:06,345 --> 00:11:09,014 THIS IS THE SIGN, PEACE SIGN, 253 00:11:09,014 --> 00:11:11,717 WHATEVER YOU PREFER, THEY ARE 254 00:11:11,717 --> 00:11:16,655 VERY THICK STRUCTURES, THE SI 255 00:11:16,655 --> 00:11:16,889 SINUSES. 256 00:11:16,889 --> 00:11:20,359 THEY DRAIN THE CRANIAL, BRAIN 257 00:11:20,359 --> 00:11:22,094 BLOOD OUT INTO THE PERIPHERY. 258 00:11:22,094 --> 00:11:23,696 VERY IMPORTANT STRUCTURES. 259 00:11:23,696 --> 00:11:26,699 AND SO ALONG THESE STRUCTURES 260 00:11:26,699 --> 00:11:30,503 ANTWAN DID STAINS FOR MARKER FOR 261 00:11:30,503 --> 00:11:31,270 LYMPHATIC CELLS. 262 00:11:31,270 --> 00:11:33,539 IT IS A LONG STORY. 263 00:11:33,539 --> 00:11:35,307 THERE IS SOME STAINING WHICH 264 00:11:35,307 --> 00:11:36,275 LOOKED VASCULAR. 265 00:11:36,275 --> 00:11:38,711 IN THE EYE WE HAVE A VESSEL THAT 266 00:11:38,711 --> 00:11:41,213 DRAINS THE EYE, IT IS NOT MADE 267 00:11:41,213 --> 00:11:45,084 OF LYMPHATIC MATERIAL. 268 00:11:45,084 --> 00:11:49,822 HERE WE HAVE LYMPHATIC CELLS. 269 00:11:49,822 --> 00:11:54,493 CAN IT FUNCTION AS -- WILL IT 270 00:11:54,493 --> 00:11:55,561 DRAIN CSF? 271 00:11:55,561 --> 00:11:58,164 HERE IS A LIVE MOUSE WITH WINDOW 272 00:11:58,164 --> 00:11:59,965 IN SKULL. 273 00:11:59,965 --> 00:12:02,101 WE INJECT WITH GREEN AND RED 274 00:12:02,101 --> 00:12:02,935 INTO THE CSF. 275 00:12:02,935 --> 00:12:05,905 WE SEE THERE IS A GREEN TRACER 276 00:12:05,905 --> 00:12:07,940 FROM THE WLOOD IN THE SINUS AND 277 00:12:07,940 --> 00:12:11,911 THE TRACER FROM CSF IS IN THIS 278 00:12:11,911 --> 00:12:15,915 ONE VESSEL. 279 00:12:15,915 --> 00:12:19,251 IF WE TURN THE MOUSE UPSIDE DOWN 280 00:12:19,251 --> 00:12:21,620 AND THE CSF WILL CONTINUE TO 281 00:12:21,620 --> 00:12:23,088 FLOW INTO THE DRAINING. 282 00:12:23,088 --> 00:12:25,357 I LOVE THE MOUSE BECAUSE THEY 283 00:12:25,357 --> 00:12:27,526 ONLY HAVE ONE LUMP NODE ON EACH 284 00:12:27,526 --> 00:12:29,795 SIDE AND TWO ARE SUPERFICIAL. 285 00:12:29,795 --> 00:12:32,631 IN HUMANS WE HAVE OVER 100 ON 286 00:12:32,631 --> 00:12:34,233 EACH SIDE OF THE NECK. 287 00:12:34,233 --> 00:12:36,435 IT MAKES IT MUCH LESS FUN, BUT 288 00:12:36,435 --> 00:12:37,636 IT IS VERY IMPORTANT TO 289 00:12:37,636 --> 00:12:39,071 UNDERSTAND HOW THINGS ARE 290 00:12:39,071 --> 00:12:39,305 WORKING. 291 00:12:39,305 --> 00:12:41,874 WE PUBLISHED OUR PAPER, THERE 292 00:12:41,874 --> 00:12:44,310 WAS A SERIES OF LABS THAT WERE 293 00:12:44,310 --> 00:12:46,946 SHOWING VERY SIMILAR RESULTS. 294 00:12:46,946 --> 00:12:51,450 WE WERE TOLD WE WERE WRONG AND 295 00:12:51,450 --> 00:12:51,750 IRRELEVANT. 296 00:12:51,750 --> 00:12:52,818 IT DIDN'T LAST TOO LONG. 297 00:12:52,818 --> 00:12:55,521 THERE WAS A PAPER PUBLISHED THAT 298 00:12:55,521 --> 00:12:57,022 SHOWED WHAT WE SHOWED. 299 00:12:57,022 --> 00:13:01,460 THREE PAPERS, THIS IS EUROPEAN, 300 00:13:01,460 --> 00:13:02,495 THIS IS AMERICAN FROM NIH. 301 00:13:02,495 --> 00:13:04,497 THERE WAS A PAPER FROM 302 00:13:04,497 --> 00:13:04,763 AUSTRALIA. 303 00:13:04,763 --> 00:13:07,032 ALL THREE SHOWED THE PRESENCE OF 304 00:13:07,032 --> 00:13:10,936 THESE VESSELS IN FISH. 305 00:13:10,936 --> 00:13:14,306 THIS WAS NOW PRESENT IN RATS. 306 00:13:14,306 --> 00:13:17,142 AND AGAIN NIH HERE WITH A LITTLE 307 00:13:17,142 --> 00:13:19,144 BIT OF SUPPORT FROM US, NOT 308 00:13:19,144 --> 00:13:20,746 MUCH, EVEN THOUGH HE GAVE US 309 00:13:20,746 --> 00:13:22,848 AUTHORSHIP ON THE PAPER, WHICH 310 00:13:22,848 --> 00:13:26,819 WAS NICE OF HIM, SHOWED THE 311 00:13:26,819 --> 00:13:29,021 VESSELS EXIST IN PRIMATES AND 312 00:13:29,021 --> 00:13:29,388 HUMANS. 313 00:13:29,388 --> 00:13:32,591 HE SAID IT TOOK THEM TWO DAYS TO 314 00:13:32,591 --> 00:13:36,595 FIND THE VESSELS AND TWO YEARS 315 00:13:36,595 --> 00:13:38,631 TO CONVINCE HIMSELF THEY WERE 316 00:13:38,631 --> 00:13:38,831 REAL. 317 00:13:38,831 --> 00:13:40,599 THEY EXIST IN HUMANS AND FISH. 318 00:13:40,599 --> 00:13:41,867 THEY ARE PROBABLY REAL. 319 00:13:41,867 --> 00:13:43,035 NOW WE CAN UNDERSTAND WHAT THEY 320 00:13:43,035 --> 00:13:43,936 ARE DOING. 321 00:13:43,936 --> 00:13:46,038 BEFORE THEN, I KNOW MANY OF YOU 322 00:13:46,038 --> 00:13:47,139 MIGHT HAVE HEARD OF THIS. 323 00:13:47,139 --> 00:13:51,176 I WOULD LIKE TO SHOW YOU A BRIEF 324 00:13:51,176 --> 00:13:59,985 HISTORY OF CNS LYMPHATICS. 325 00:13:59,985 --> 00:14:07,393 JOSEPH II BELIEVED IN -- THERE 326 00:14:07,393 --> 00:14:10,563 WAS NO WAY TO PRESERVE ORGANS. 327 00:14:10,563 --> 00:14:12,898 THEY WERE MAKING REPLICAS OF 328 00:14:12,898 --> 00:14:15,167 HUMAN ORGANS AND PARTS OF HUMAN 329 00:14:15,167 --> 00:14:16,969 BODY USING WAX. 330 00:14:16,969 --> 00:14:18,470 THE PRECISION WAS INCREDIBLE. 331 00:14:18,470 --> 00:14:21,707 THIS IS A HUMAN BRAIN AND A FULL 332 00:14:21,707 --> 00:14:22,308 HUMAN HEAD. 333 00:14:22,308 --> 00:14:23,375 ALL FROM THE WAX. 334 00:14:23,375 --> 00:14:26,912 THEY WERE ABLE TO DO THIS FROM 335 00:14:26,912 --> 00:14:28,914 MARBLE SO WAX WAS PROBABLY EASY 336 00:14:28,914 --> 00:14:31,150 TO DO THESE AMAZING THINGS FROM. 337 00:14:31,150 --> 00:14:33,919 ALL THIS COMING FROM THE BRAIN, 338 00:14:33,919 --> 00:14:35,387 LYMPHATICS COMING FROM THE 339 00:14:35,387 --> 00:14:37,756 BRAIN, BASED ON THE WORK THERE 340 00:14:37,756 --> 00:14:42,061 IS LYMPHATICS, IT IS NOT AS 341 00:14:42,061 --> 00:14:43,662 INTENTION AS THEY WERE CLAIMING. 342 00:14:43,662 --> 00:14:51,403 HE GOT CRITICIZED SO REALLY 343 00:14:51,403 --> 00:14:52,738 CONTEMPORARIES KILLED THAT WHOLE 344 00:14:52,738 --> 00:14:56,642 THING AND HE DIED BASICALLY 345 00:14:56,642 --> 00:14:57,776 INFAMOUS, NOBODY EVEN KNOWS 346 00:14:57,776 --> 00:14:59,845 WHERE HE IS BURIED, 347 00:14:59,845 --> 00:15:00,479 UNFORTUNATELY. 348 00:15:00,479 --> 00:15:02,414 THERE WAS SOME TRUTH TO THAT. 349 00:15:02,414 --> 00:15:05,284 HE WAS EXAGGERATING OR VERY 350 00:15:05,284 --> 00:15:07,853 UNLUCKY OR LUCKY TO WORK WITH 351 00:15:07,853 --> 00:15:13,626 REALLY ABNORMAL HYPERLYMPHATIC 352 00:15:13,626 --> 00:15:13,859 PERSON. 353 00:15:13,859 --> 00:15:17,963 THERE WAS A PAPER IN 2003 THAT 354 00:15:17,963 --> 00:15:20,499 SAYS HERE TODAY THERE ARE 867 355 00:15:20,499 --> 00:15:22,935 MODELS ON DISPLAY IN THE MUSEUM. 356 00:15:22,935 --> 00:15:25,904 THE MUSEUM IN VIENNA, IF YOU 357 00:15:25,904 --> 00:15:29,475 HAPPEN TO BE THERE, MUST VISIT. 358 00:15:29,475 --> 00:15:32,211 COMPLEXITY OF MODELS REVEAL 359 00:15:32,211 --> 00:15:36,115 THEIR CREATORS AND ANATOMY. 360 00:15:36,115 --> 00:15:39,618 FOUR MODELS STAND OUT FOR 361 00:15:39,618 --> 00:15:45,190 ANATOMICAL MISCONCEPTIONS. 362 00:15:45,190 --> 00:15:46,091 LYMPHATIC ON BRAIN. 363 00:15:46,091 --> 00:15:48,293 IN 2003, I'M TOWARD THE END OF 364 00:15:48,293 --> 00:15:49,428 MY PH.D. 365 00:15:49,428 --> 00:15:51,530 I'M LEARNING ON THAT 366 00:15:51,530 --> 00:15:51,864 MISCONCEPTION. 367 00:15:51,864 --> 00:15:54,233 NO LYMPHATICS IN THE BRAIN. 368 00:15:54,233 --> 00:16:00,839 HERE IT SAYS LYMPHATIC SYSTEM 369 00:16:00,839 --> 00:16:04,109 WAS SO IMPRESSED THAT HE SAW 370 00:16:04,109 --> 00:16:06,145 LYMPH VESSELS EVEN WHERE THEY 371 00:16:06,145 --> 00:16:07,913 DIDN'T EXIST, IN THE BRAIN. 372 00:16:07,913 --> 00:16:10,849 IT WAS DESCRIBED IN DETAIL IN 373 00:16:10,849 --> 00:16:16,922 19th CENTURY. 374 00:16:16,922 --> 00:16:19,158 HOW DO YOU DESCRIBE SOMETHING 375 00:16:19,158 --> 00:16:21,560 THAT DOES NOT EXIST IN DETAIL. 376 00:16:21,560 --> 00:16:23,896 WE LIVE IN THAT MISCONCEPTION. 377 00:16:23,896 --> 00:16:28,067 ANYWAY, FUNNY ENOUGH, WE 378 00:16:28,067 --> 00:16:28,967 PUBLISHED COMMENTARY SAYING HE 379 00:16:28,967 --> 00:16:31,303 WAS RIGHT, BUT WE STILL HAVE NO 380 00:16:31,303 --> 00:16:33,706 CLUE WHERE HE IS BURIED. 381 00:16:33,706 --> 00:16:40,646 HE IS THE RIGHT PERSON TO BECOME 382 00:16:40,646 --> 00:16:42,881 INFAMOUS, STUDYING LYMPHATICS. 383 00:16:42,881 --> 00:16:44,216 IT WAS A JOKE. 384 00:16:44,216 --> 00:16:50,522 I GUESS IT IS NOT FUNNY. 385 00:16:50,522 --> 00:16:52,124 THE ONE THAT IS VERY CLOSE TO 386 00:16:52,124 --> 00:16:59,231 OUR HEARTS IS THE 387 00:16:59,231 --> 00:17:01,500 NEUROINFLAMMATION, THE MODEL FOR 388 00:17:01,500 --> 00:17:03,135 MULTIPLE SCLEROSIS. 389 00:17:03,135 --> 00:17:06,638 WE JUST MADE A DISCOVERY OF 390 00:17:06,638 --> 00:17:09,074 LYMPHATICS I WAS INTERVIEWED BY 391 00:17:09,074 --> 00:17:09,541 NPR. 392 00:17:09,541 --> 00:17:14,513 WHAT DO YOU DREAM ABOUT THESE 393 00:17:14,513 --> 00:17:14,747 VESSELS? 394 00:17:14,747 --> 00:17:16,949 JUST A BLOB OF VESSELS. 395 00:17:16,949 --> 00:17:18,817 THAT DREAM CAME TRUE. 396 00:17:18,817 --> 00:17:21,353 A BUNCH OF LABS ARE WORKING ON 397 00:17:21,353 --> 00:17:21,653 LYMPHATICS. 398 00:17:21,653 --> 00:17:25,958 THIS IS A RECENT PAPER ON THE 399 00:17:25,958 --> 00:17:31,063 ROLE OF PCR SIGNALLING ON 400 00:17:31,063 --> 00:17:32,831 HEADACHES, WORK ON PARKINSON'S 401 00:17:32,831 --> 00:17:34,032 IN PATIENTS. 402 00:17:34,032 --> 00:17:44,476 A PAPER ON BRAIN INJURY AND 403 00:17:44,476 --> 00:17:45,677 HEMMORATIC STROKE, AND THE 404 00:17:45,677 --> 00:17:47,012 DIFFERENT SEXES IN MICE, THE 405 00:17:47,012 --> 00:17:50,282 WORK ON BRAIN TUMORS AND HOW 406 00:17:50,282 --> 00:17:51,884 THEY GUIDE IMMUNE RESPONSE 407 00:17:51,884 --> 00:17:53,252 AGAINST BRAIN TUMORS. 408 00:17:53,252 --> 00:17:59,024 THERE WERE A COUPLE OF PAPERED 409 00:17:59,024 --> 00:18:00,125 ASSOCIATED WITH -- BECAUSE OF 410 00:18:00,125 --> 00:18:02,594 THE LINK TO DYSFUNCTION BECAUSE 411 00:18:02,594 --> 00:18:04,630 OF THE ABNORMAL SKULL FORMATION. 412 00:18:04,630 --> 00:18:08,867 THIS IS A HANDFUL OF PAPERS I 413 00:18:08,867 --> 00:18:11,670 HAD ON MY COMPUTER AND I'M JUST 414 00:18:11,670 --> 00:18:14,673 LAZY TO PUT, I COULD PROBABLY A 415 00:18:14,673 --> 00:18:17,009 HUNDRED DIFFERENT PAPERS OF THE 416 00:18:17,009 --> 00:18:19,144 ROLE OF THESE VESSELS IN 417 00:18:19,144 --> 00:18:19,945 DIFFERENT DISEASES. 418 00:18:19,945 --> 00:18:22,181 I PAID A LOT OF MONEY FOR THIS 419 00:18:22,181 --> 00:18:24,449 MOVIE, SO I WILL BE PLAYING IT 420 00:18:24,449 --> 00:18:25,150 IS LOT. 421 00:18:25,150 --> 00:18:26,485 TO JUSTIFY CAN COST. 422 00:18:26,485 --> 00:18:28,220 I WILL SHOW YOU WHERE THE JUNK 423 00:18:28,220 --> 00:18:32,624 GOES OUT AND IT WILL GO INTO THE 424 00:18:32,624 --> 00:18:33,926 LYMPHATIC SYSTEM. 425 00:18:33,926 --> 00:18:35,828 I WILL SHOW YOU INTERESTING 426 00:18:35,828 --> 00:18:39,898 MECHANISMS THAT GOVERN THE FLOW 427 00:18:39,898 --> 00:18:42,634 ALONG THE VEINS AND THROUGH THE 428 00:18:42,634 --> 00:18:44,336 BRAIN AND WHY WE THINK IT IS 429 00:18:44,336 --> 00:18:45,871 IMPORTANT AND WHY I CARE ABOUT 430 00:18:45,871 --> 00:18:46,071 THIS. 431 00:18:46,071 --> 00:18:47,873 THAT WOULD BE THE STORY. 432 00:18:47,873 --> 00:18:49,708 IF YOU THOUGHT I'M SPEAKING FAST 433 00:18:49,708 --> 00:18:51,176 UNTIL NOW BECAUSE NOW I WILL 434 00:18:51,176 --> 00:18:52,578 START REALLY SPEAKING FAST. 435 00:18:52,578 --> 00:18:56,381 I HAVE A BUNCH OF SLIDES TO 436 00:18:56,381 --> 00:18:58,517 COVER. 437 00:18:58,517 --> 00:19:01,420 AFTER THIS DIRTY CSF GETS OUT OF 438 00:19:01,420 --> 00:19:04,923 THE BRAIN IT HAS TO REACH THE 439 00:19:04,923 --> 00:19:07,559 LYMPHATIC VESSELS, THE BRAIN'S 440 00:19:07,559 --> 00:19:09,695 SINK OR BRAIN'S TOILET. 441 00:19:09,695 --> 00:19:11,763 HOW DO YOU REACH THE TOILET, IF 442 00:19:11,763 --> 00:19:13,732 CSF IS HERE, IT GOES THROUGH THE 443 00:19:13,732 --> 00:19:15,868 BRAIN, HOW DO YOU GET TO THAT 444 00:19:15,868 --> 00:19:21,006 LAYER WHERE YOU HAVE TO CROSS 445 00:19:21,006 --> 00:19:21,273 ARACHNOID. 446 00:19:21,273 --> 00:19:23,742 IT IS PLACED THERE TO PREVENT 447 00:19:23,742 --> 00:19:28,146 CSF EXIT TO THE DURA. 448 00:19:28,146 --> 00:19:30,048 ARACHNOID SHOULD NOT ALLOW CSF 449 00:19:30,048 --> 00:19:36,788 TO ENTER THE DURA. 450 00:19:36,788 --> 00:19:39,958 IT HAPPENS IN HUMANS. 451 00:19:39,958 --> 00:19:43,528 THIS PAPER FROM NORWEGIAN, THEY 452 00:19:43,528 --> 00:19:45,264 INJECT PATIENTS AND SEE THE 453 00:19:45,264 --> 00:19:47,599 TRACE THAT APPEARED IN THE DURA. 454 00:19:47,599 --> 00:19:51,803 REMEMBER THAT IF YOU GO INTO 455 00:19:51,803 --> 00:19:54,006 TEXTBOOKS AND THERE ARE 456 00:19:54,006 --> 00:19:54,940 CLINICIANS IN THE ROOM THAT WILL 457 00:19:54,940 --> 00:19:58,076 THROW AT ME ROTTEN TOMATOES, 458 00:19:58,076 --> 00:19:58,844 WHICH IS FINE. 459 00:19:58,844 --> 00:20:00,145 I'M USED TO IT. 460 00:20:00,145 --> 00:20:03,682 THE TEXTBOOK SAYS THE ARACHNOID 461 00:20:03,682 --> 00:20:08,553 HAS THE UNIQUE STRUCTURES CALLED 462 00:20:08,553 --> 00:20:09,021 VILLI. 463 00:20:09,021 --> 00:20:10,856 THEY HAVE HOLES AND STICKING 464 00:20:10,856 --> 00:20:15,227 INTO THE SINUSES, INTO THE 465 00:20:15,227 --> 00:20:16,261 VENOUS STRUCTURES AND PUSHING 466 00:20:16,261 --> 00:20:16,929 CSF RIGHT THERE. 467 00:20:16,929 --> 00:20:19,364 I SEE YOU IN THE WHITE COAT, 468 00:20:19,364 --> 00:20:20,966 THAT IS HOW CLINICIANS ARE 469 00:20:20,966 --> 00:20:22,167 LEARNING IT, CORRECT? 470 00:20:22,167 --> 00:20:24,269 I WAS BOTHERED BY THIS IDEA 471 00:20:24,269 --> 00:20:27,072 BECAUSE MANY ANIMALS DON'T HAVE 472 00:20:27,072 --> 00:20:29,074 ARACHNOID RELATIONS AND CSF IS 473 00:20:29,074 --> 00:20:29,741 BEING PRODUCED. 474 00:20:29,741 --> 00:20:33,078 HOW IS CLEANING THERE? 475 00:20:33,078 --> 00:20:37,849 OUR BABIES DON'T HAVE 476 00:20:37,849 --> 00:20:40,052 GRANULATIONS UNTIL THEY BECOME 477 00:20:40,052 --> 00:20:40,786 MUCH OLDER. 478 00:20:40,786 --> 00:20:44,189 HOW DO YOU SEAL THE INTERFACE TO 479 00:20:44,189 --> 00:20:45,757 PREVENT THE BLOOD FROM FLOWING? 480 00:20:45,757 --> 00:20:47,159 IT MAKES NO SENSE. 481 00:20:47,159 --> 00:20:48,961 IF YOU REALLY LOOK CAREFULLY 482 00:20:48,961 --> 00:20:56,134 INTO THE ANATOMY, WHERE RICE 483 00:20:56,134 --> 00:20:57,402 UNIVERSITY DID AND SHOWED THEY 484 00:20:57,402 --> 00:20:59,137 ARE NOT GOING ALL THE WAY INTO 485 00:20:59,137 --> 00:21:00,906 THE SINUS, THEY ARE COMING INTO 486 00:21:00,906 --> 00:21:04,543 THE DURA WHICH SUPPORTS OUR 487 00:21:04,543 --> 00:21:06,578 FINDING IN MICE AND NOR WIE JOHN 488 00:21:06,578 --> 00:21:09,848 FINDINGS IN HUMANS. 489 00:21:09,848 --> 00:21:12,617 WE THINK THEY ARE BEING TAKEN BY 490 00:21:12,617 --> 00:21:14,353 THE LYMPHATIC VESSELS. 491 00:21:14,353 --> 00:21:19,157 HOW DOES CSF GET INTO THE DURA? 492 00:21:19,157 --> 00:21:20,659 BECAUSE IT HAS TO CROSS A 493 00:21:20,659 --> 00:21:31,203 BARRIER THAT IS SUPPOSED TO BE 494 00:21:33,605 --> 00:21:33,839 UNPERMEABLE. 495 00:21:33,839 --> 00:21:35,474 LEON IS HIS LAST DAY. 496 00:21:35,474 --> 00:21:43,482 THIS IS OUR OWN EM OF THE 497 00:21:43,482 --> 00:21:44,783 ARACHNOID BARRIER CELL. 498 00:21:44,783 --> 00:21:48,153 THEY CREATE THIS PERFECT BARRIER 499 00:21:48,153 --> 00:21:51,623 SO HOW DO YOU CROSS IT? 500 00:21:51,623 --> 00:21:58,463 THEY ARE VERY, VERY POOR IN 501 00:21:58,463 --> 00:21:58,797 TRANSCYTOSIS. 502 00:21:58,797 --> 00:22:01,633 WE INJECT AND THEY ALL ARRIVE IN 503 00:22:01,633 --> 00:22:04,469 THE DURA AT THE SAME TIME. 504 00:22:04,469 --> 00:22:05,771 SOMETHING ELSE IS HAPPENING. 505 00:22:05,771 --> 00:22:07,439 SOME PASSENGERS ARE MOVING CSF 506 00:22:07,439 --> 00:22:10,742 INTO THE BRAIN. 507 00:22:10,742 --> 00:22:14,179 I'M NOW DABBLING INTO MORE 508 00:22:14,179 --> 00:22:16,181 ANATOMY THAN ANY OF YOU WANT TO 509 00:22:16,181 --> 00:22:16,381 HEAR. 510 00:22:16,381 --> 00:22:18,817 I HAVE TO EXPLAIN IT. 511 00:22:18,817 --> 00:22:20,619 THIS IS UGLY WHOLE HEAD 512 00:22:20,619 --> 00:22:21,053 CLEARANCE. 513 00:22:21,053 --> 00:22:24,189 IT IS UGLY BECAUSE THE SCALA DID 514 00:22:24,189 --> 00:22:26,858 NOT SHRINK AS MUCH AS THE BRAIN 515 00:22:26,858 --> 00:22:27,059 DID. 516 00:22:27,059 --> 00:22:29,895 SO IT CREATED A SUB ARACHNOID 517 00:22:29,895 --> 00:22:30,095 SPACE. 518 00:22:30,095 --> 00:22:32,230 IT IS NICE FOR DEMONSTRATION 519 00:22:32,230 --> 00:22:33,698 BECAUSE YOU CAN SEE THESE 520 00:22:33,698 --> 00:22:37,536 VESSELS HERE, THESE ARE VEINS, 521 00:22:37,536 --> 00:22:40,405 BRIDGING VEINS OR CORTICAL 522 00:22:40,405 --> 00:22:41,506 BRAINS. 523 00:22:41,506 --> 00:22:44,676 BRINGING THE BLOOD FROM THE 524 00:22:44,676 --> 00:22:47,546 BRAIN INTO THE SINUSES. 525 00:22:47,546 --> 00:22:51,149 THEY GOW THERE THE ARACHNOID 526 00:22:51,149 --> 00:22:57,422 SPACE THROUGH THE MENINGES AND 527 00:22:57,422 --> 00:22:57,722 DURA. 528 00:22:57,722 --> 00:23:00,559 I WILL DO IT IN CARTOON FIRST. 529 00:23:00,559 --> 00:23:01,827 IT BRINGS THE BLOOD. 530 00:23:01,827 --> 00:23:04,362 AS IT GOES THROUGH THE 531 00:23:04,362 --> 00:23:05,831 ARACHNOID, THERE IS A OPENING 532 00:23:05,831 --> 00:23:06,498 AND TEAR. 533 00:23:06,498 --> 00:23:08,633 IF YOU LOOK AT THE ARACHNOID 534 00:23:08,633 --> 00:23:10,402 FROM THE ON THE, YOU SEE HOLES 535 00:23:10,402 --> 00:23:11,736 THAT ARE COMING. 536 00:23:11,736 --> 00:23:14,739 AS YOU SEE HERE, WE CALL THEM 537 00:23:14,739 --> 00:23:14,940 CUFFS. 538 00:23:14,940 --> 00:23:16,541 LIKE A CUFF ON A SHIRT. 539 00:23:16,541 --> 00:23:19,678 SO THE CSF, WHILE THE BLOOD 540 00:23:19,678 --> 00:23:21,513 FLOWS WITHIN, LET'S SAY, MY 541 00:23:21,513 --> 00:23:24,583 HAND, THE CSF WILL FLOW WITHIN 542 00:23:24,583 --> 00:23:25,217 MY SLEEVE. 543 00:23:25,217 --> 00:23:28,587 CSF FLOWS IN THE SLEEVE AND ENDS 544 00:23:28,587 --> 00:23:31,790 UP IN THE DUR AND CAN BE UPTAKEN 545 00:23:31,790 --> 00:23:33,959 BY IMMUNE CELLS. 546 00:23:33,959 --> 00:23:35,160 THE LYMPHATIC SYSTEM IS THERE 547 00:23:35,160 --> 00:23:36,695 AND WHATEVER IS LEFT WILL GET 548 00:23:36,695 --> 00:23:38,897 OUT OF THE LYMPHATIC SYSTEM. 549 00:23:38,897 --> 00:23:41,833 THE GREEN HERE IS THE ARACHNOID 550 00:23:41,833 --> 00:23:44,202 CUFF, ARACHNOID STRUCTURE THAT 551 00:23:44,202 --> 00:23:45,637 GOES ALONG THE VEIN. 552 00:23:45,637 --> 00:23:49,074 WITHIN THAT, THAT IS WHERE CSF 553 00:23:49,074 --> 00:23:49,274 FLOWS. 554 00:23:49,274 --> 00:23:51,443 IT GOES THERE BOTH WAYS FROM THE 555 00:23:51,443 --> 00:23:52,944 DURA TO THE BRAIN AND THE BRAIN 556 00:23:52,944 --> 00:23:54,779 TO THE DURA. 557 00:23:54,779 --> 00:23:56,047 THE COOL THINGS ABOUT THE 558 00:23:56,047 --> 00:23:59,484 STRUCTURE, THIS IS WHERE THE 559 00:23:59,484 --> 00:24:02,420 BLOOD/BRAIN BARRIERS ENDS OR 560 00:24:02,420 --> 00:24:03,054 STARTS, DEPENDING HOW YOU CALL 561 00:24:03,054 --> 00:24:04,289 IT. 562 00:24:04,289 --> 00:24:06,424 IT IS A UNIQUE STRUCTURE IN THE 563 00:24:06,424 --> 00:24:06,958 BRAIN. 564 00:24:06,958 --> 00:24:13,031 EXACTLY AT THE END OF THAT CUFF 565 00:24:13,031 --> 00:24:15,767 OF THE SLEEVE, THAT IS THE END 566 00:24:15,767 --> 00:24:19,070 OF MARKERS IN A NORMAL VESSEL. 567 00:24:19,070 --> 00:24:20,805 PERIPHERAL VESSEL STARTS. 568 00:24:20,805 --> 00:24:22,340 WHICH TELLS YOU HOW IMPORTANT 569 00:24:22,340 --> 00:24:25,076 THAT AREA IS TO CONTROL. 570 00:24:25,076 --> 00:24:28,180 NOW MOLECULES CAN COME OUT AND 571 00:24:28,180 --> 00:24:29,214 DIFFUSE THROUGH A SLEEVE INTO 572 00:24:29,214 --> 00:24:30,215 THE BRAIN. 573 00:24:30,215 --> 00:24:31,483 LOTS OF INTERESTING CONTROL 574 00:24:31,483 --> 00:24:32,617 HAPPENING HERE AND SOME OF THE 575 00:24:32,617 --> 00:24:34,519 NEW WORKS WE ARE WORKING ON. 576 00:24:34,519 --> 00:24:37,155 IN MICE WE SHOWED BOTH WAYS, UP 577 00:24:37,155 --> 00:24:44,462 AND DOWN, BUT IN COLLABORATION 578 00:24:44,462 --> 00:24:46,364 WITH THE LAB, THEY SHOW THE 579 00:24:46,364 --> 00:24:48,633 MOVEMENT OF THE TRACER FROM THE 580 00:24:48,633 --> 00:24:51,102 DURA INTO THE CSF AGAIN THROUGH 581 00:24:51,102 --> 00:24:53,038 THOSE BRIDGING VEINS. 582 00:24:53,038 --> 00:24:55,574 I'M NOT OPPOSED TO WORK IN MICE 583 00:24:55,574 --> 00:24:57,209 FOR THE SAKE OF A MOUSE. 584 00:24:57,209 --> 00:24:59,177 IT IS VERY FUN WHEN OUR MOUSE 585 00:24:59,177 --> 00:25:03,748 WORK TRANSLATES TO HUMAN ANATOMY 586 00:25:03,748 --> 00:25:04,149 AND BIOLOGY. 587 00:25:04,149 --> 00:25:06,985 WE HAVE AMAZING COLLABORATION 588 00:25:06,985 --> 00:25:08,954 WITH DANNY HOPEFULLY WE WILL 589 00:25:08,954 --> 00:25:11,723 CONTINUE IN THE FUTURE. 590 00:25:11,723 --> 00:25:13,258 I'M NOT QUESTIONING -- IN THE 591 00:25:13,258 --> 00:25:16,194 FIELD OF ALZHEIMER'S, THE 592 00:25:16,194 --> 00:25:18,763 CURRENT STATE OF THE FIELD IS 593 00:25:18,763 --> 00:25:24,736 THAT AMYLOID BETA IS BEING 594 00:25:24,736 --> 00:25:29,007 REMOVED ACROSS THE BLOOD/BRAIN 595 00:25:29,007 --> 00:25:29,274 BARRIER. 596 00:25:29,274 --> 00:25:32,110 IT USED TO BE THE ONLY WAY, WE 597 00:25:32,110 --> 00:25:34,646 ARE SAYING THERE ARE OTHER WAYS. 598 00:25:34,646 --> 00:25:37,382 THE LYMPHATIC ROUTE IS A WAY TO 599 00:25:37,382 --> 00:25:42,387 REMOVE AMYLOID FROM THE BRAIN. 600 00:25:42,387 --> 00:25:44,689 A MOUSE, KILLING LYMPHATIC 601 00:25:44,689 --> 00:25:48,360 VESSELS IN THAT MOUSE, WE SEE 602 00:25:48,360 --> 00:25:50,695 AMYLOID IN THE DURA MATTER AND 603 00:25:50,695 --> 00:25:52,264 INSIDE THE BRAIN, THE BLOCKS ARE 604 00:25:52,264 --> 00:25:54,165 MORE OF THEM AND THEY ARE 605 00:25:54,165 --> 00:25:54,399 LARGER. 606 00:25:54,399 --> 00:26:01,072 IF YOU REMOVE THAT ROUTE OF 607 00:26:01,072 --> 00:26:03,608 EXCISION OR WASTE REMOVAL, IT 608 00:26:03,608 --> 00:26:07,145 BUILDS UP MORE AMYLOID WAIST IN 609 00:26:07,145 --> 00:26:08,179 THE BRAIN. 610 00:26:08,179 --> 00:26:11,082 IF WE ENHANCE THOSE ROUTES AND 611 00:26:11,082 --> 00:26:14,886 COMBINE WITH ANTI-AMYLOID 612 00:26:14,886 --> 00:26:17,922 THERAPY, WE GET SYNERGISTIC 613 00:26:17,922 --> 00:26:18,189 EFFECT. 614 00:26:18,189 --> 00:26:21,660 THERE WAS A GROUP FROM MAYO I 615 00:26:21,660 --> 00:26:22,927 CLINIC SHOWED SOME ALZHEIMER'S 616 00:26:22,927 --> 00:26:25,163 MARKERS WILL APPEAR IN THE 617 00:26:25,163 --> 00:26:27,165 DRAINING LYMPH NODES, MUCH 618 00:26:27,165 --> 00:26:29,200 HIGHER THAN IN PERIPHERAL BLOOD 619 00:26:29,200 --> 00:26:31,269 AND MORE PREDICTIVE OF THE 620 00:26:31,269 --> 00:26:32,304 DEVELOPMENTS. 621 00:26:32,304 --> 00:26:35,373 AGAIN, SUPPORTING THIS LYMPHATIC 622 00:26:35,373 --> 00:26:38,410 ROUTE OF REMOVAL IN ALZHEIMER'S 623 00:26:38,410 --> 00:26:41,346 PATIENTS TO THE BLOOD VESSELS. 624 00:26:41,346 --> 00:26:43,615 IF THAT IS TRUE OUR SLEEVES, OUR 625 00:26:43,615 --> 00:26:45,216 POINTS WHICH WE BELIEVE ARE THE 626 00:26:45,216 --> 00:26:52,123 EXIT POINT FROM THE BRAIN, 627 00:26:52,123 --> 00:26:56,428 SHOULD SHOW SOME DEGREE OF 628 00:26:56,428 --> 00:26:56,695 CLOGGING. 629 00:26:56,695 --> 00:27:00,031 IN UNPUBLISHED DATA, WE ARE 630 00:27:00,031 --> 00:27:04,836 SEEING THESE AREAS CLOGGED BY 631 00:27:04,836 --> 00:27:05,070 AMYLOID. 632 00:27:05,070 --> 00:27:06,705 WE COLLABORATED ON THIS AS WELL 633 00:27:06,705 --> 00:27:10,108 BUT NOW WE HAVE FIRST IMAGING 634 00:27:10,108 --> 00:27:14,346 FROM HUMANS IN COLLABORATION 635 00:27:14,346 --> 00:27:20,685 WITH PAUL MARRA, THE ACE POINTS 636 00:27:20,685 --> 00:27:24,022 ARE CLOGGED WITH AMYLOID IN 637 00:27:24,022 --> 00:27:26,291 ALZHEIMER'S PATIENTS. 638 00:27:26,291 --> 00:27:28,526 SOME OF WASTE REMOVAL IS 639 00:27:28,526 --> 00:27:29,527 HAPPENING ACROSS THE ROUTE. 640 00:27:29,527 --> 00:27:32,831 THIS IS THE WAY OUT. 641 00:27:32,831 --> 00:27:34,599 WHAT ABOUT THE WAY IN? 642 00:27:34,599 --> 00:27:37,469 WE SHOWED THAT VASCULAR 643 00:27:37,469 --> 00:27:38,737 PULSATION IS IMPORTANT TO 644 00:27:38,737 --> 00:27:40,271 PROPAGATE THE FLOW ALONG THE 645 00:27:40,271 --> 00:27:43,308 VESSEL AND INSIDE THE VESSEL. 646 00:27:43,308 --> 00:27:45,443 -- USED TO BE IN THE LAB, HE IS 647 00:27:45,443 --> 00:27:48,012 NOW A PI IN PARIS, HE WAS REALLY 648 00:27:48,012 --> 00:27:48,813 INTERESTED IN THIS FUNCTION OF 649 00:27:48,813 --> 00:27:50,982 THE VESSELS. 650 00:27:50,982 --> 00:27:55,787 AND MANY OF YOU HERE KNOW ABOUT 651 00:27:55,787 --> 00:27:56,054 MICROGLIA. 652 00:27:56,054 --> 00:27:57,622 YOU FIND THIS LABELING 653 00:27:57,622 --> 00:27:59,524 THROUGHOUT THE WHOLE BRAIN. 654 00:27:59,524 --> 00:28:02,827 THERE IS ANOTHER MYLOID CELL 655 00:28:02,827 --> 00:28:05,864 THAT SITS INSIDE THE BRAIN, LESS 656 00:28:05,864 --> 00:28:16,474 KNOWN TO NEUROSCIENTISTS. 657 00:28:16,474 --> 00:28:16,941 PERIVASCULAR MACROPHAGES. 658 00:28:16,941 --> 00:28:19,144 IT IS COVERED BY THE CELLS HERE 659 00:28:19,144 --> 00:28:20,311 IN TEAL. 660 00:28:20,311 --> 00:28:22,981 IF YOU LOOK AT THE BLOOD/BRAIN 661 00:28:22,981 --> 00:28:27,986 BARRIER NICHE, SO FROM INSIDE, 662 00:28:27,986 --> 00:28:30,622 OF COURSE, WE HAVE THE CELLS OF 663 00:28:30,622 --> 00:28:34,692 THE BLOOD VESSELS, INSIDE WE 664 00:28:34,692 --> 00:28:37,595 HAVE THE SMOOTH MUSCLE, 665 00:28:37,595 --> 00:28:43,701 PERISITES AND MACROPHAGES IN THE 666 00:28:43,701 --> 00:28:46,638 PUR 667 00:28:46,638 --> 00:28:51,176 PURPLE. 668 00:28:51,176 --> 00:28:53,011 MACROPHAAGES ARE CONSTANTLY 669 00:28:53,011 --> 00:28:56,481 TRACING WHAT IS HAPPENING. 670 00:28:56,481 --> 00:29:00,084 THEY ARE PHAGOCYTES AND IN TOUCH 671 00:29:00,084 --> 00:29:03,621 WITH CSF AND IN THE BRAIN. 672 00:29:03,621 --> 00:29:06,658 ANTWOINE HAD A COOL IDEA, THEY 673 00:29:06,658 --> 00:29:07,592 TAKE UP SPACE. 674 00:29:07,592 --> 00:29:09,894 IF WE REMOVE THOSE CELLS WE WILL 675 00:29:09,894 --> 00:29:11,863 INCREASE THE SPACE AND MORE CSF 676 00:29:11,863 --> 00:29:16,734 WILL BE ABLE TO GO THROUGH AND 677 00:29:16,734 --> 00:29:18,102 IMPROVE CSF MOVEMENT. 678 00:29:18,102 --> 00:29:19,137 ESPECIALLY IN OLD MICE. 679 00:29:19,137 --> 00:29:20,205 IT IS A COOL IDEA. 680 00:29:20,205 --> 00:29:21,239 LET'S DO IT. 681 00:29:21,239 --> 00:29:25,376 HERE HE INJECTED THIS MICE WITH 682 00:29:25,376 --> 00:29:28,880 BUBBLES OF FAT LOADED WITH TOXIC 683 00:29:28,880 --> 00:29:31,382 MATERIAL, MACROPHAGES BECAUSE 684 00:29:31,382 --> 00:29:33,718 THE UPTAKE IS IN THE CSF, THEY 685 00:29:33,718 --> 00:29:36,454 WILL SWALLOW, THE MATERIAL WILL 686 00:29:36,454 --> 00:29:39,991 BURST INSIDE AND KILL THE CELL. 687 00:29:39,991 --> 00:29:42,660 60%, 70% OF CELLS WILL BE 688 00:29:42,660 --> 00:29:42,961 ELIMINATED. 689 00:29:42,961 --> 00:29:45,430 WHAT IS HAPPENING WITH CSF FLOW 690 00:29:45,430 --> 00:29:47,665 IN THIS MICE? 691 00:29:47,665 --> 00:29:50,335 IT WAS STUNNING BECAUSE WE FOUND 692 00:29:50,335 --> 00:29:51,603 THE OPPOSITE. 693 00:29:51,603 --> 00:29:53,137 THERE WAS LESS CSF GOING AROUND 694 00:29:53,137 --> 00:29:54,639 THE BRAIN, GOING INTO THE BRAIN. 695 00:29:54,639 --> 00:29:57,675 IT IS ALWAYS FUN TO GET RESULTS 696 00:29:57,675 --> 00:30:00,144 OPPOSITE OF WHAT YOU EXPECTED 697 00:30:00,144 --> 00:30:02,080 UNLESS YOU SWITCH THE GROUPS, IT 698 00:30:02,080 --> 00:30:04,816 IS A COOL FINDING WHICH I DIDN'T 699 00:30:04,816 --> 00:30:07,252 EXPECT WHICH IS PROBABLY TRUE. 700 00:30:07,252 --> 00:30:08,987 LET'S TRY TO UNDERSTAND WHAT IS 701 00:30:08,987 --> 00:30:09,954 HAPPENING HERE. 702 00:30:09,954 --> 00:30:11,890 ANTWOINE DID -- WE REALIZED 703 00:30:11,890 --> 00:30:14,192 THERE IS NO REAL GOOD METHOD TO 704 00:30:14,192 --> 00:30:17,295 MEASURE CSF FLOW IN A LIVE 705 00:30:17,295 --> 00:30:17,729 MOUSE. 706 00:30:17,729 --> 00:30:20,932 HE DEVELOPED SUCH ASSAYS. 707 00:30:20,932 --> 00:30:23,301 THIS IS A MEWS, THIS IS THE EYE 708 00:30:23,301 --> 00:30:25,169 AND THE EAR, NOW YOU SEE THE 709 00:30:25,169 --> 00:30:28,072 MOUSE ON THE SCREEN. 710 00:30:28,072 --> 00:30:28,773 ANTWOINE LIFTS THAT PIECE OF 711 00:30:28,773 --> 00:30:30,074 SKIN AND THE MUSCLE WHICH COVERS 712 00:30:30,074 --> 00:30:33,211 THE BEGINNING OF MIDDLE 713 00:30:33,211 --> 00:30:33,511 ARTERIES. 714 00:30:33,511 --> 00:30:37,849 WE INJECT TRACERS, IT WILL GO 715 00:30:37,849 --> 00:30:40,151 UNDER AND FOLLOW THE MCA AND DIE 716 00:30:40,151 --> 00:30:40,785 INSIDE THE BRAIN. 717 00:30:40,785 --> 00:30:43,154 WE ARE LOOKING AT THE BEGINNING 718 00:30:43,154 --> 00:30:46,057 OF THE ARTERY AND YOU CAN 719 00:30:46,057 --> 00:30:48,226 SEE.JEX THAT IS THE TREE OF MCA 720 00:30:48,226 --> 00:30:51,729 IS BEING FILLED WITH THE TRACER. 721 00:30:51,729 --> 00:30:55,333 NOW WE CAN COMPARE THE NORMAL 722 00:30:55,333 --> 00:30:58,937 MICE AND MICE WITH NO 723 00:30:58,937 --> 00:30:59,237 MACROPHAGES. 724 00:30:59,237 --> 00:31:00,471 THE DIFFERENCE WAS ROBUST. 725 00:31:00,471 --> 00:31:03,074 IT IS VERY FUN BECAUSE WHEN YOU 726 00:31:03,074 --> 00:31:04,876 HAVE SUCH A BIG DIFFERENCE, YOU 727 00:31:04,876 --> 00:31:06,010 CAN UNDERSTAND WHAT REALLY IS 728 00:31:06,010 --> 00:31:11,382 HAPPENING THERE, AT LEAST 729 00:31:11,382 --> 00:31:11,649 PARTIALLY. 730 00:31:11,649 --> 00:31:14,218 LONG STORY SHORT, WHEN WE PUT 731 00:31:14,218 --> 00:31:17,555 MICE IN A HIGH CO2 ENVIRONMENT 732 00:31:17,555 --> 00:31:21,759 AND THEY NEED TO VASO DILATE 733 00:31:21,759 --> 00:31:29,267 MORE, THOSE THAT DID NOT HAVE 734 00:31:29,267 --> 00:31:30,835 MACROPHAGES COULD NOT DILATE. 735 00:31:30,835 --> 00:31:34,539 THEY ARE CONSTANTLY EATING THE 736 00:31:34,539 --> 00:31:37,175 DEBRIS THAT OTHER CELLS DEPOSIT. 737 00:31:37,175 --> 00:31:42,013 IF YOU REMOVE MACROPHAGES YOU 738 00:31:42,013 --> 00:31:44,816 START SEEING BUILD UP OF ECM 739 00:31:44,816 --> 00:31:46,451 AROUND THE VESSELS. 740 00:31:46,451 --> 00:31:48,586 F WE THINK THIS PREVENTS VESSELS 741 00:31:48,586 --> 00:31:53,091 TO FULLY DILATE BECAUSE IT IS 742 00:31:53,091 --> 00:31:56,561 BUILT UP WITH GUNK ALONG THE 743 00:31:56,561 --> 00:31:57,328 VESSELS. 744 00:31:57,328 --> 00:31:59,063 OLD MICE HAVE PROBLEMS WITH CSF 745 00:31:59,063 --> 00:31:59,263 FLOW. 746 00:31:59,263 --> 00:32:01,599 THIS IS LIVE IMAGING. 747 00:32:01,599 --> 00:32:09,874 THIS IS A NORMAL YOUNG MOUSE TWO 748 00:32:09,874 --> 00:32:12,610 MONTHS AND THIS ONE IS 24 749 00:32:12,610 --> 00:32:12,844 MONTHS. 750 00:32:12,844 --> 00:32:15,980 IT IS NOT NEW AND WE ALSO 751 00:32:15,980 --> 00:32:19,050 REALIZED THAT THE TYPES OF 752 00:32:19,050 --> 00:32:21,919 PERIVASCULAR MACROPHAGES ARE 753 00:32:21,919 --> 00:32:23,087 CHANGING IN OLD MICE. 754 00:32:23,087 --> 00:32:27,291 WE GIVE THEM MCSF INFUSION, A 755 00:32:27,291 --> 00:32:28,026 GROWTH FACTOR. 756 00:32:28,026 --> 00:32:31,729 IN A COUPLE OF HOURS, SIX, SEVEN 757 00:32:31,729 --> 00:32:37,135 HOURS, WE GET REDUCTION OF 758 00:32:37,135 --> 00:32:42,106 PERIVASCULAR AND MORE CSF CAN GO 759 00:32:42,106 --> 00:32:48,279 THROUGH THE VASCULARTURE. 760 00:32:48,279 --> 00:32:51,916 IT ONLY LASTED 24 HOURS AND WENT 761 00:32:51,916 --> 00:32:54,352 BACK TO NORMAL I GAVE US HOPE 762 00:32:54,352 --> 00:32:55,653 AND WE HAVE SEVERAL 763 00:32:55,653 --> 00:32:57,221 COLLABORATIONS GOING ON TO MAKE 764 00:32:57,221 --> 00:32:59,957 THIS EFFECT GO MUCH LONGER AND 765 00:32:59,957 --> 00:33:02,927 GET SUBSTANTIAL BENEFITS TO THE 766 00:33:02,927 --> 00:33:03,127 BRAIN. 767 00:33:03,127 --> 00:33:04,696 I TELL MY KIDS THE BEAUTY OF 768 00:33:04,696 --> 00:33:07,699 BEING A SCIENTIST, YOU CAN STILL 769 00:33:07,699 --> 00:33:09,400 DESTROY THINGS AND IT IS VALID 770 00:33:09,400 --> 00:33:11,035 AND EXCITING. 771 00:33:11,035 --> 00:33:13,538 IF WE CAN'T FIX THEM IN 772 00:33:13,538 --> 00:33:16,507 PERPETUITY, WE CAN DESTROY THEM. 773 00:33:16,507 --> 00:33:20,878 WE GO INTO OUR AMYLOID MOUSE 774 00:33:20,878 --> 00:33:22,914 MODEL, WE SEE AGAIN 775 00:33:22,914 --> 00:33:24,549 ACCUMULATION, MORE ACCUMULATION 776 00:33:24,549 --> 00:33:28,019 OF AMYLOID PLAQUES INSIDE THE 777 00:33:28,019 --> 00:33:28,219 BRAIN. 778 00:33:28,219 --> 00:33:32,256 WE ARE PREVENTING CSF FLOW IN 779 00:33:32,256 --> 00:33:33,791 THE BRAIN WHICH LEADS TO PLAQUES 780 00:33:33,791 --> 00:33:35,426 IN THE BRAIN. 781 00:33:35,426 --> 00:33:39,397 WHAT ALLOWS THE FLOW OF CSF? 782 00:33:39,397 --> 00:33:42,200 YOU SEE THERE IS A LOT OF BLANK 783 00:33:42,200 --> 00:33:43,067 SPACE. 784 00:33:43,067 --> 00:33:44,435 SOMETIMES YOU LOOK AT 785 00:33:44,435 --> 00:33:46,404 COMMERCIALS FROM COMPANIES HOW 786 00:33:46,404 --> 00:33:49,640 DRUGS WORK, EMPTY SPACE, ONE 787 00:33:49,640 --> 00:33:52,276 NEURON, THE MOLECULE ARRIVES AND 788 00:33:52,276 --> 00:33:53,478 ANOTHER ONE ARRIVES. 789 00:33:53,478 --> 00:33:53,745 NO. 790 00:33:53,745 --> 00:33:57,215 THIS IS NOT HOW A BRAIN LOOKS 791 00:33:57,215 --> 00:33:57,415 LIKE. 792 00:33:57,415 --> 00:34:04,822 IT HAS LOTS OF CELLS, EXTRA 793 00:34:04,822 --> 00:34:06,657 CELLULAR DENSE TISSUE. 794 00:34:06,657 --> 00:34:12,764 THAT IS SOMETHING WE FOUND -- IN 795 00:34:12,764 --> 00:34:13,564 THE LAB. 796 00:34:13,564 --> 00:34:15,867 HE CAME FROM SLEEP LAB. 797 00:34:15,867 --> 00:34:17,969 HE OPENED HIS LAB AT YOU PEN. 798 00:34:17,969 --> 00:34:21,105 WHAT PROPAGATES THE FLOW FROM 799 00:34:21,105 --> 00:34:24,375 THE DENSE --. 800 00:34:24,375 --> 00:34:27,044 HE SAID, NO, AS A SLEEP 801 00:34:27,044 --> 00:34:29,781 BIOLOGIST. 802 00:34:29,781 --> 00:34:31,949 I'M AN IMMUNEOLOGIST. 803 00:34:31,949 --> 00:34:33,217 THE SLEEP WORLD IS WHY DO WE 804 00:34:33,217 --> 00:34:33,851 SLEEP? 805 00:34:33,851 --> 00:34:35,419 ONE OF THE NEW EXCITING THEORYS 806 00:34:35,419 --> 00:34:37,822 IS WHEN WE SLEEP, WE CLEANSE OUR 807 00:34:37,822 --> 00:34:39,023 BRAIN MORE EFFICIENTLY. 808 00:34:39,023 --> 00:34:41,392 WE KNOW THAT SOME OF THE, FOR 809 00:34:41,392 --> 00:34:42,927 EXAMPLE, OUR TRACER EXPERIMENTS 810 00:34:42,927 --> 00:34:45,563 ARE WORKING WAY MORE EFFICIENTLY 811 00:34:45,563 --> 00:34:47,365 IN A SLEEPING MOUSE THAN A 812 00:34:47,365 --> 00:34:47,832 WAKEFUL MOUSE. 813 00:34:47,832 --> 00:34:49,400 NO QUESTION ABOUT IT. 814 00:34:49,400 --> 00:34:50,301 I WILL GO THROUGH THIS. 815 00:34:50,301 --> 00:34:52,837 THIS IS A VERY COMPLICATED PAPER 816 00:34:52,837 --> 00:34:54,672 AND IT IS PUBLISHED LAST YEAR. 817 00:34:54,672 --> 00:34:56,674 I WILL DO IT VERY, VERY QUICKLY. 818 00:34:56,674 --> 00:34:59,744 I WILL SUMMARIZE THE WHOLE THING 819 00:34:59,744 --> 00:35:01,946 BECAUSE THE CONCEPT IS EXCITING. 820 00:35:01,946 --> 00:35:03,915 WHEN WE SLEEP WE EMIT WAVES. 821 00:35:03,915 --> 00:35:05,416 YOU CAN RECORD WAVES. 822 00:35:05,416 --> 00:35:09,921 BY THE TYPE OF WAVES YOU EMIT, 823 00:35:09,921 --> 00:35:14,559 I'M SURE YOU HAVE THE OURA RING, 824 00:35:14,559 --> 00:35:19,230 DEEP LEAP OR REM SLEEP? 825 00:35:19,230 --> 00:35:21,399 SO IT WAS SUGGESTED WHEN NEURONS 826 00:35:21,399 --> 00:35:24,335 ARE FIRING, DURING SLEEP NEURONS 827 00:35:24,335 --> 00:35:27,772 ARE FIRING TOGETHER, 828 00:35:27,772 --> 00:35:30,408 SYNCHRONIZED ACTIVITY. 829 00:35:30,408 --> 00:35:33,778 WE GENERATE SUBSTANTIAL SURGES 830 00:35:33,778 --> 00:35:37,081 OF FLOW THIS IS THE WAY WE ARE 831 00:35:37,081 --> 00:35:37,348 RECORDING. 832 00:35:37,348 --> 00:35:40,384 IN DEEP SLEEP WE HAVE VE SLOW 833 00:35:40,384 --> 00:35:42,954 WAVES WITH VERY HIGH MAGNITUDE. 834 00:35:42,954 --> 00:35:48,292 HE SUGGEST MAYBE THIS POWER OF 835 00:35:48,292 --> 00:35:51,429 PUSHING THIS INTO THE 836 00:35:51,429 --> 00:35:52,063 INTERSTITIAL SPACE WILL BE 837 00:35:52,063 --> 00:35:54,265 SUFFICIENT TO CARRY THE WATER 838 00:35:54,265 --> 00:35:56,367 MOLECULES WITH THEM, WHICH WILL 839 00:35:56,367 --> 00:35:59,403 CARRY THE METABOLITES AGAIN. 840 00:35:59,403 --> 00:36:00,771 HE DID RECORDING. 841 00:36:00,771 --> 00:36:05,142 THIS IS A 32-CHANNEL RECORDING. 842 00:36:05,142 --> 00:36:08,346 WE RECORD THE MUSCLES IN THE 843 00:36:08,346 --> 00:36:11,582 NECK AND 28 CHANNELS IN THE 844 00:36:11,582 --> 00:36:12,617 HIPPO CAMPUS. 845 00:36:12,617 --> 00:36:20,992 YOU SEE APPEARANCE OF THIS 846 00:36:20,992 --> 00:36:22,593 MACROWAVES AND SYNCHRONIZED 847 00:36:22,593 --> 00:36:24,028 ACTIVITY DURING SLEEP. 848 00:36:24,028 --> 00:36:27,798 WE CAN SILENCE NEURAL ACTIVITY 849 00:36:27,798 --> 00:36:31,235 USING CHEMOGENETIC APPROACH. 850 00:36:31,235 --> 00:36:34,238 EXPRESS MODIFIED RECEPTOR. 851 00:36:34,238 --> 00:36:41,512 SO WE GIVE THE MICE LIGANDS, WE 852 00:36:41,512 --> 00:36:42,980 INTERFERE WITH ACTIVITY. 853 00:36:42,980 --> 00:36:45,783 ALL THE WAVES ARE BEING 854 00:36:45,783 --> 00:36:47,952 SUPPRESSED IN THE HIPPOCAMPUS. 855 00:36:47,952 --> 00:36:49,654 IF YOU LOOK AT GLOBAL BRAIN, 856 00:36:49,654 --> 00:36:50,755 THERE IS NO EFFECT. 857 00:36:50,755 --> 00:36:53,324 WE ARE AFFECTING A SMALL AREA OF 858 00:36:53,324 --> 00:36:55,393 THE HIP POECAMPUS. 859 00:36:55,393 --> 00:36:56,861 WILL THIS BE SUFFICIENT TO 860 00:36:56,861 --> 00:36:58,963 AFFECT THE CSF FLOW FROM THAT 861 00:36:58,963 --> 00:37:00,164 BRAIN REGION? 862 00:37:00,164 --> 00:37:01,799 HERE IS AN EXPERIMENT, 863 00:37:01,799 --> 00:37:03,501 EXPRESSING THE P SUMS ON THE ONE 864 00:37:03,501 --> 00:37:06,470 SIDE OF THE HIP POECAMPUS, 865 00:37:06,470 --> 00:37:09,173 CONTROL OR GFP. 866 00:37:09,173 --> 00:37:11,108 THEN AFTER THREE WEEKS WE INJECT 867 00:37:11,108 --> 00:37:13,611 THEM WITH A DRUG, WITHIN A 868 00:37:13,611 --> 00:37:16,948 COUPLE OF HOURS WILL SILENCE 869 00:37:16,948 --> 00:37:19,116 ACTIVI 870 00:37:19,116 --> 00:37:19,383 ACTIVITY. 871 00:37:19,383 --> 00:37:22,954 WE INJECT WITH TRACER AND DURING 872 00:37:22,954 --> 00:37:26,691 THE DAYTIME THE MICE WILL FALL 873 00:37:26,691 --> 00:37:29,927 ASLEEP AND WE WILL BOTHER THEM. 874 00:37:29,927 --> 00:37:31,996 THERE IS SOMETHING THAT GOES 875 00:37:31,996 --> 00:37:34,065 THROUGH THE CAGE AND MAKE SURE 876 00:37:34,065 --> 00:37:36,567 THE MOUSE IS GENTLY BOTHERED AND 877 00:37:36,567 --> 00:37:37,201 NOT SLEEP. 878 00:37:37,201 --> 00:37:39,837 WE TAKE THE BRAIN OUT. 879 00:37:39,837 --> 00:37:43,074 HOW MUCH FLOW, HOW MUCH CSF 880 00:37:43,074 --> 00:37:44,108 ENTERS, GOES THROUGH THE 881 00:37:44,108 --> 00:37:46,477 PARTICULAR AREA OF THE BRAIN 882 00:37:46,477 --> 00:37:50,047 WITH OR WITHOUT NEURAL ACTIVITY. 883 00:37:50,047 --> 00:37:52,917 WHEN WE SUPPRESS NEURAL 884 00:37:52,917 --> 00:37:54,618 ACTIVITY, IN SLEEPING MOUSE MORE 885 00:37:54,618 --> 00:37:56,620 FLOW GOES THROUGH THAT AREA FOR 886 00:37:56,620 --> 00:37:59,290 THE WHOLE BRAIN, BUT HIP 887 00:37:59,290 --> 00:37:59,557 POECAMPUS. 888 00:37:59,557 --> 00:38:06,464 WHEN MOUSE IS SLEEPING THERE IS 889 00:38:06,464 --> 00:38:11,635 MORE TRAFFIC AND WE REDUCE CSF 890 00:38:11,635 --> 00:38:14,372 GOING THROUGH THE AREA WITHOUT 891 00:38:14,372 --> 00:38:14,939 AFFECTING OTHER THING GOING 892 00:38:14,939 --> 00:38:19,143 AROUND. 893 00:38:19,143 --> 00:38:24,782 40 HERTZ, FAST WAVES, AFFECTED 894 00:38:24,782 --> 00:38:35,292 AMYLOID REMOVAL IN THE BRAIN. 895 00:38:36,360 --> 00:38:38,362 WE CAN INCREASE THE FLOW. 896 00:38:38,362 --> 00:38:41,632 IT IS A COMPLICATED PAPER, BUT 897 00:38:41,632 --> 00:38:46,804 IT IS QUITE EXCITING. 898 00:38:46,804 --> 00:38:52,843 WE ARE PROPOSED IS DURING 899 00:38:52,843 --> 00:38:57,681 DAYTIME WE IN THE NIGHT TIME 900 00:38:57,681 --> 00:38:59,784 WHEN OUR BRAIN IS FULL OF JUNK, 901 00:38:59,784 --> 00:39:01,652 THEY FIRE TOGETHER AND IT 902 00:39:01,652 --> 00:39:03,487 CREATES WAVES WHICH ALLOWS 903 00:39:03,487 --> 00:39:13,898 REMOVAL OF THE WASTE OR 904 00:39:15,800 --> 00:39:16,000 MOVEMENT. 905 00:39:16,000 --> 00:39:21,839 NEURONS THAT FIRE TOGETHER WIRE 906 00:39:21,839 --> 00:39:22,306 TOGETHER. 907 00:39:22,306 --> 00:39:24,775 SO THEN SUGGESTED NEURONS THAT 908 00:39:24,775 --> 00:39:26,577 FIRE TOGETHER SHOWER TOGETHER. 909 00:39:26,577 --> 00:39:28,312 THAT IS THE IDEA. 910 00:39:28,312 --> 00:39:36,987 IMPLICATIONS ARE EXCITING. 911 00:39:36,987 --> 00:39:39,757 ONE OF THE PHENO TYPES OF OLD 912 00:39:39,757 --> 00:39:44,562 MICE IS THEY DON'T SLEEP WELL. 913 00:39:44,562 --> 00:39:45,863 SO IMPROVEMENT OF SLEEP. 914 00:39:45,863 --> 00:39:50,267 THAT IS SUPER EXCITING. 915 00:39:50,267 --> 00:39:52,770 IF I HAVE ONE GOAL, REDUCE MY 916 00:39:52,770 --> 00:39:55,339 SLEEP TO ONE HOUR. 917 00:39:55,339 --> 00:39:56,841 CAN YOU MAKE YOUR CLEANING AT 918 00:39:56,841 --> 00:39:58,275 NIGHT IN A SHORT TIME AND WAKE 919 00:39:58,275 --> 00:39:59,910 UP AND GO BACK TO YOUR STUFF. 920 00:39:59,910 --> 00:40:03,247 THAT IS A VERY EXCITING STUFF. 921 00:40:03,247 --> 00:40:05,683 IF I'M INVITED FOR A SMALLER 922 00:40:05,683 --> 00:40:07,985 TALK AND I WILL BRING ALL THE 923 00:40:07,985 --> 00:40:09,253 UNPUBLISHED RESULTS. 924 00:40:09,253 --> 00:40:12,022 ANYWAY, WHY DO WE CARE? 925 00:40:12,022 --> 00:40:15,459 WHAT HAPPENS IN THE BRAIN WHEN 926 00:40:15,459 --> 00:40:17,027 LYMPHATICS ARE IMPAIRED? 927 00:40:17,027 --> 00:40:19,897 THIS IS THE WORK OK.D. 928 00:40:19,897 --> 00:40:24,135 JUST GOT PUBLISHED AND I'M NOT 929 00:40:24,135 --> 00:40:26,770 GOING TO ELAP RATE. 930 00:40:26,770 --> 00:40:29,607 KD FOUND IF YOU TAKE YOUNG MICE 931 00:40:29,607 --> 00:40:31,175 AND INTERFERE WITH THEIR 932 00:40:31,175 --> 00:40:34,712 LYMPHATIC VESSELS WE HAVE 933 00:40:34,712 --> 00:40:35,212 COGNITIVE DYSFUNCTIONS. 934 00:40:35,212 --> 00:40:36,947 WE DIDN'T UNDERSTAND HOW THIS IS 935 00:40:36,947 --> 00:40:39,049 ALL HAPPENS. 936 00:40:39,049 --> 00:40:46,123 HE SAID LET ME CHECK FOR MYSELF. 937 00:40:46,123 --> 00:40:47,791 HE DID SEVERAL ESSAYS, YOU 938 00:40:47,791 --> 00:40:51,729 INTRODUCE THE MOUSE IN THE WATER 939 00:40:51,729 --> 00:40:54,131 AND OPEN A SECOND ARM. 940 00:40:54,131 --> 00:40:58,502 IN NORMAL, HEALTHY MOUSE WILL GO 941 00:40:58,502 --> 00:41:00,604 INTO THE NEW ARM THAN THE OLD 942 00:41:00,604 --> 00:41:01,071 ARM. 943 00:41:01,071 --> 00:41:02,206 THEY ARE CURIOUS. 944 00:41:02,206 --> 00:41:04,041 THEY REMEMBER THE OLD ARM AND 945 00:41:04,041 --> 00:41:07,411 ARE PREFERRING THE NEW ARM. 946 00:41:07,411 --> 00:41:09,413 MICE THAT HAVE LYMPHATIC 947 00:41:09,413 --> 00:41:11,815 DYSFUNCTION, WE DID TWO WAYS OF 948 00:41:11,815 --> 00:41:13,417 LYMPHATIC DYSFUNCTION IN THIS 949 00:41:13,417 --> 00:41:15,186 PAPER, THEY DON'T HAVE A 950 00:41:15,186 --> 00:41:15,486 PREFERENCE. 951 00:41:15,486 --> 00:41:18,556 THEY ARE IMPAIRED IN NOVEL 952 00:41:18,556 --> 00:41:19,290 EXPLORATION BEHAVIOR AS WELL AS 953 00:41:19,290 --> 00:41:23,694 OTHER BEHAVIORS. 954 00:41:23,694 --> 00:41:25,930 KD WAS RECORDING AND WHILE THERE 955 00:41:25,930 --> 00:41:36,407 WAS NO AFFECT ON EXCITATORY 956 00:41:42,046 --> 00:41:42,947 INPUTS. 957 00:41:42,947 --> 00:41:44,582 THE NUMBER OF NEURONS IS NOT A 958 00:41:44,582 --> 00:41:44,815 PROBLEM. 959 00:41:44,815 --> 00:41:52,623 THE INPUTS WERE REDUCED WE 960 00:41:52,623 --> 00:41:56,160 THOUGHT MICROGLIA, FIRE MICE 961 00:41:56,160 --> 00:41:58,529 PROMOTER OF CSF RECEPTOR. 962 00:41:58,529 --> 00:42:04,335 THE MOUSE IS BORN WITH 963 00:42:04,335 --> 00:42:10,474 MACROPHAGES BUT NOT MICROGLIA. 964 00:42:10,474 --> 00:42:13,644 WE DON'T GET THE INHIBITORY 965 00:42:13,644 --> 00:42:16,046 SYNAPSE DYSFUNCTION. 966 00:42:16,046 --> 00:42:22,886 THEY ARE PLAYING A KEY ROLE. 967 00:42:22,886 --> 00:42:25,956 THEY ARE PROBABLY EATING THOSE 968 00:42:25,956 --> 00:42:26,223 SYNAPSES. 969 00:42:26,223 --> 00:42:27,024 WE DID NOT SEE THAT. 970 00:42:27,024 --> 00:42:29,793 WE SEE THE EATING, BUT THERE WAS 971 00:42:29,793 --> 00:42:33,163 NO CHANGE IN THE AMOUNT OF 972 00:42:33,163 --> 00:42:33,530 EATING. 973 00:42:33,530 --> 00:42:37,735 WHAT WE DID DETECT IS UP 974 00:42:37,735 --> 00:42:40,237 REGULATION IN AISLE 6 PRODUCED 975 00:42:40,237 --> 00:42:43,407 BY MICROGLIA. 976 00:42:43,407 --> 00:42:45,142 I'M SUMMARIZING FOUR YEARS OF 977 00:42:45,142 --> 00:42:46,977 WORK IN ONE SLIDE. 978 00:42:46,977 --> 00:42:50,481 I'M DOING A DISSERVICE TO K.D., 979 00:42:50,481 --> 00:42:52,883 BUT IT IS PUBLISHED SO IT WILL 980 00:42:52,883 --> 00:42:54,318 BE EVI TO FOLLOW. 981 00:42:54,318 --> 00:42:57,721 THESE ARE MICE THAT HAVE NO ISLE 982 00:42:57,721 --> 00:43:00,457 6 RECEPTOR. 983 00:43:00,457 --> 00:43:03,994 IT IS PRODUCED BY MICRODPLEEA 984 00:43:03,994 --> 00:43:11,602 AND SIGNAL ON TO NEURONS. 985 00:43:11,602 --> 00:43:19,977 WE MICROGLIALIL-6. 986 00:43:19,977 --> 00:43:23,347 ABOUT WHAT IS HAPPENING WITHIN 987 00:43:23,347 --> 00:43:23,614 THE CELL. 988 00:43:23,614 --> 00:43:26,550 SO AGED MICE, IT IS A PATTERN 989 00:43:26,550 --> 00:43:30,087 YOU HAVE PROBABLY SEEN. 990 00:43:30,087 --> 00:43:31,221 STUDYING BASIC PHYSIOLOGY AND 991 00:43:31,221 --> 00:43:35,125 APPLYING IT TO AGES AND LOOK AT 992 00:43:35,125 --> 00:43:38,429 WHAT IS GOING WRONG WHERE 993 00:43:38,429 --> 00:43:38,662 MODELS. 994 00:43:38,662 --> 00:43:40,364 WE ARE STUDYING WHAT IS 995 00:43:40,364 --> 00:43:42,633 HAPPENING IN YOUNG MICE AND HOW 996 00:43:42,633 --> 00:43:44,735 THESE THINGS ARE GOING WRONG IN 997 00:43:44,735 --> 00:43:45,569 AGING. 998 00:43:45,569 --> 00:43:48,772 IN AGING WE SEE REDUCTION OF 999 00:43:48,772 --> 00:43:51,075 INHIBITORY INPUTS IN THE SAME 1000 00:43:51,075 --> 00:43:51,975 REGION. 1001 00:43:51,975 --> 00:43:54,778 LYMPHATIC VESSELS ARE SEVERELY 1002 00:43:54,778 --> 00:43:56,313 DETERIORATED IN AGED MICE. 1003 00:43:56,313 --> 00:43:57,247 THAT IS NOT NEW. 1004 00:43:57,247 --> 00:43:59,083 WE SHOWED THIS BEFORE. 1005 00:43:59,083 --> 00:44:01,585 WE DON'T KNOW HOW TO IMPROVE 1006 00:44:01,585 --> 00:44:03,520 SYNAPSES, BUT WE KNOW HOW TO 1007 00:44:03,520 --> 00:44:05,756 IMPROVE LYMPHATIC VESSELS. 1008 00:44:05,756 --> 00:44:10,327 WE INFECT MICE WITH VIRUS THAT 1009 00:44:10,327 --> 00:44:13,063 WILL SHOW VEGFC. 1010 00:44:13,063 --> 00:44:16,200 AND LYMPHATIC VESSELS ARE 1011 00:44:16,200 --> 00:44:20,738 EXPANDING SUBSTANTIALLY AND NO 1012 00:44:20,738 --> 00:44:21,805 DIFFERENT FROM YOUNG MICE. 1013 00:44:21,805 --> 00:44:31,248 WE SEE INCREASE IN INHIBITORY 1014 00:44:31,248 --> 00:44:32,616 SYNAPSE. 1015 00:44:32,616 --> 00:44:34,051 EXCITE SYNAPSES WERE NOT 1016 00:44:34,051 --> 00:44:34,518 AFFECTED. 1017 00:44:34,518 --> 00:44:40,624 SUPER EXCITING WORK, GIVES US A 1018 00:44:40,624 --> 00:44:42,659 GLIMPSE OF MOLECULAR. 1019 00:44:42,659 --> 00:44:46,363 WHAT SIGNALS MICROGLIA RECEIVE 1020 00:44:46,363 --> 00:44:48,465 TO PRODUCE NEED YEA TOR AND HOW 1021 00:44:48,465 --> 00:44:52,770 THE MEDIATORS ARE AFFECTING THE 1022 00:44:52,770 --> 00:44:54,838 SYNAPTIC INPUT INTO NEURONS. 1023 00:44:54,838 --> 00:44:56,840 FINALLY, IF YOU WILL ALLOW ME 1024 00:44:56,840 --> 00:44:58,475 FIVE MORE MINUTES. 1025 00:44:58,475 --> 00:45:01,278 WHY DO I CARE? 1026 00:45:01,278 --> 00:45:08,118 I'M AN IMMUNOLOGIST, WHAT I CARE 1027 00:45:08,118 --> 00:45:09,253 IS UNDERSTANDING HOW THE IMMUNE 1028 00:45:09,253 --> 00:45:11,021 SYSTEM SEES WHAT IS HAPPENING IN 1029 00:45:11,021 --> 00:45:13,056 THE BRAIN AND HOW THIS PROCESS 1030 00:45:13,056 --> 00:45:15,092 IS IMPAIRED IN DIFFERENT 1031 00:45:15,092 --> 00:45:16,660 DISEASES AND, OF COURSE, IN 1032 00:45:16,660 --> 00:45:16,860 AGING. 1033 00:45:16,860 --> 00:45:18,195 WE MAKE CLEAN CSF. 1034 00:45:18,195 --> 00:45:19,997 IT IS GOING THROUGH THE BRAIN 1035 00:45:19,997 --> 00:45:23,267 TISSUE AND COMES OUT OF DIRTY 1036 00:45:23,267 --> 00:45:26,437 CSF, CARRY METABOLITES AND 1037 00:45:26,437 --> 00:45:28,539 PROTEINS AND PEPTIDES FROM THE 1038 00:45:28,539 --> 00:45:28,739 BRAIN. 1039 00:45:28,739 --> 00:45:31,408 IT GOES INTO THE DURA AND 1040 00:45:31,408 --> 00:45:34,044 BECOMES THE CSF LYMPH. 1041 00:45:34,044 --> 00:45:36,079 THE MOLECULES ARE COMING INTO 1042 00:45:36,079 --> 00:45:40,150 THE DURA, THEY ARE BEING UPTAKEN 1043 00:45:40,150 --> 00:45:42,286 BY A LOT OF IMMUNE CELLS. 1044 00:45:42,286 --> 00:45:51,328 IT WILL BE UPTAKING BY APCs AND 1045 00:45:51,328 --> 00:45:55,165 PRESENTED TO PATROLING CELLS. 1046 00:45:55,165 --> 00:45:57,601 THEY LEAVE BY NEARBY LYMPHATIC 1047 00:45:57,601 --> 00:45:57,835 VESSEL. 1048 00:45:57,835 --> 00:45:59,803 THIS IS PRESENTATION OF THE 1049 00:45:59,803 --> 00:46:00,637 BRAIN IMMUNE CODE. 1050 00:46:00,637 --> 00:46:02,406 WE THOUGHT, OKAY, FROEBL THERE 1051 00:46:02,406 --> 00:46:05,576 IS A PROBLEM IN THE BRAIN, THEN 1052 00:46:05,576 --> 00:46:06,743 THIS IMMUNE CODE WILL CHANGE 1053 00:46:06,743 --> 00:46:08,812 BECAUSE YOU WILL START 1054 00:46:08,812 --> 00:46:12,716 EXPRESSING NEW PROTEINS. 1055 00:46:12,716 --> 00:46:15,352 THIS BAR CODE HERE PROBABLY WILL 1056 00:46:15,352 --> 00:46:16,620 CHANGE WAY WAY BEFORE DISEASE 1057 00:46:16,620 --> 00:46:17,688 REALLY STARTS. 1058 00:46:17,688 --> 00:46:20,123 SO WE WERE VERY EXCITED TO 1059 00:46:20,123 --> 00:46:21,558 UNDERSTAND WHAT IS BEING 1060 00:46:21,558 --> 00:46:23,627 PRESENTED IN THE BORDERS OF THE 1061 00:46:23,627 --> 00:46:30,701 BRAIN AND HOW THIS IS RELEVANT. 1062 00:46:30,701 --> 00:46:31,602 REALLY BRILLIANT PH.D. STUDENT 1063 00:46:31,602 --> 00:46:33,337 IN THE LAB. 1064 00:46:33,337 --> 00:46:35,239 IN COLLABORATION WITH -- WHO 1065 00:46:35,239 --> 00:46:38,675 PASSED AWAY TWO YEARS AGO, WE 1066 00:46:38,675 --> 00:46:43,013 TOOK ALL THESE BODER CELLS THAT 1067 00:46:43,013 --> 00:46:45,249 PRESENT THE PEPTIDES AND LOOKED 1068 00:46:45,249 --> 00:46:47,017 AT WHAT IS BEING PRESENTED. 1069 00:46:47,017 --> 00:46:48,685 I'M DOING IT VERY QUICKLY. 1070 00:46:48,685 --> 00:46:50,654 IT WAS JUST PUBLISHED A COUPLE 1071 00:46:50,654 --> 00:46:51,154 OF MONT AGO. 1072 00:46:51,154 --> 00:46:53,657 IT IS ONLINE. 1073 00:46:53,657 --> 00:46:56,627 MITCH SAW LOTS OF INTERESTING 1074 00:46:56,627 --> 00:47:02,633 CELL PROTEINS. 1075 00:47:02,633 --> 00:47:09,373 ONE IS MIRKS YLINE. 1076 00:47:09,373 --> 00:47:10,641 PEPTIDES WERE FOUND THAT WERE 1077 00:47:10,641 --> 00:47:12,609 NOT PREDICTED. 1078 00:47:12,609 --> 00:47:15,145 THESE PEPTIDES WE FOUND THEM IN 1079 00:47:15,145 --> 00:47:16,413 THIS STRAIN AND IN DIFFERENT 1080 00:47:16,413 --> 00:47:18,715 STRAINS OF MICE AND ALSO IN 1081 00:47:18,715 --> 00:47:19,616 HUMANS. 1082 00:47:19,616 --> 00:47:21,685 THEY WERE PRESENT IN HUMAN 1083 00:47:21,685 --> 00:47:21,952 SUBJECTS. 1084 00:47:21,952 --> 00:47:24,621 WHAT ARE THE PEPTIDES DOING? 1085 00:47:24,621 --> 00:47:25,956 THEY MAY HAVE YOU YEEK 1086 00:47:25,956 --> 00:47:26,590 REGULATORY ROLE. 1087 00:47:26,590 --> 00:47:28,759 IF THIS IS INDUCTION OF DISEASE 1088 00:47:28,759 --> 00:47:32,796 IN THE MOUSE WHEN WE IMMUNE 1089 00:47:32,796 --> 00:47:36,533 NICE, CELLS WITH GO INTO THE 1090 00:47:36,533 --> 00:47:41,939 BRAIN AND CAUSE PARALYSIS. 1091 00:47:41,939 --> 00:47:44,841 MULTIPLE SLER ROW SIS. 1092 00:47:44,841 --> 00:47:47,277 WE SEE SUBSTANTIAL REDUCTION AND 1093 00:47:47,277 --> 00:47:48,712 SEVERITY OF THE DISEASE. 1094 00:47:48,712 --> 00:47:51,415 IF WE MODIFY THE PEPTIDE IT 1095 00:47:51,415 --> 00:47:52,916 LOSES ITS EFFECT. 1096 00:47:52,916 --> 00:47:54,718 THIS PEPTIDE IS DRIVING 1097 00:47:54,718 --> 00:47:56,086 SOMETHING VERY, VERY SPECIFIC. 1098 00:47:56,086 --> 00:47:58,522 I WILL NOT BOTHER YOU WITH 1099 00:47:58,522 --> 00:47:58,755 DETAILS. 1100 00:47:58,755 --> 00:48:02,926 THIS PEPTIDE INDUCES AN DODGE 1101 00:48:02,926 --> 00:48:09,766 NOUS CELLS, THE SUPPRESSER 1102 00:48:09,766 --> 00:48:10,033 CELLS. 1103 00:48:10,033 --> 00:48:16,607 THEY SUPPRESS INDOGENO SURKS 1104 00:48:16,607 --> 00:48:18,175 RESPONSES IN THE BRAIN. 1105 00:48:18,175 --> 00:48:19,076 IN DISEASE CONDITIONS WHAT 1106 00:48:19,076 --> 00:48:21,712 HAPPENS IS THE PROTECTIVE 1107 00:48:21,712 --> 00:48:23,013 PEPTIDES ARE DISAPPEARING. 1108 00:48:23,013 --> 00:48:24,481 I THOUGHT THEY WOULD GO UP, BUT 1109 00:48:24,481 --> 00:48:26,049 THEY ARE GOING DOWN. 1110 00:48:26,049 --> 00:48:27,851 AND THAT IS POTENTIALLY ANOTHER 1111 00:48:27,851 --> 00:48:31,321 LAYER THAT ALLOWS MORE SEVERE 1112 00:48:31,321 --> 00:48:32,789 INFLAMMATION TO GO ON. 1113 00:48:32,789 --> 00:48:33,924 CAN WE REPLENISH. 1114 00:48:33,924 --> 00:48:36,193 IF YOU THINK OF A BAR CODE 1115 00:48:36,193 --> 00:48:38,895 AGAIN, LOSING SOME OF THE BARS 1116 00:48:38,895 --> 00:48:40,063 GETTING WIPED OUT. 1117 00:48:40,063 --> 00:48:41,898 CAN WE REINSTATE THEM? 1118 00:48:41,898 --> 00:48:43,400 CAN WE BRING THEM BACK? 1119 00:48:43,400 --> 00:48:47,904 WE PACKAGED OUR PEPTIDE IN THE 1120 00:48:47,904 --> 00:48:50,407 EXTRA CELLULAR VESICLES SO 1121 00:48:50,407 --> 00:48:52,743 INJECT IN THE CSF AND UPTAKEN 1122 00:48:52,743 --> 00:48:55,412 AND PRESENTED IN THE BORDERS 1123 00:48:55,412 --> 00:48:57,280 THAT SUPPRESSES THE DISEASE 1124 00:48:57,280 --> 00:48:58,181 VERY, VERY NICELY. 1125 00:48:58,181 --> 00:48:59,216 BASICALLY WHAT WE ARE SUGGESTING 1126 00:48:59,216 --> 00:49:01,752 IS THE BRAIN IS CONSTANTLY BEING 1127 00:49:01,752 --> 00:49:02,753 WASHED. 1128 00:49:02,753 --> 00:49:05,555 THE BRAIN'S SIGNATURE IS BEING 1129 00:49:05,555 --> 00:49:07,958 BROUGHT OUT INTO THE DURA AND 1130 00:49:07,958 --> 00:49:10,427 PRESENTED THERE AND SURVEYED BY 1131 00:49:10,427 --> 00:49:11,962 THE IMMUNE CELLS. 1132 00:49:11,962 --> 00:49:13,630 THE SIGNATURE WHEN IT CHANGES, 1133 00:49:13,630 --> 00:49:16,433 THAT IS WHEN IMMUNE RESPONSE IS 1134 00:49:16,433 --> 00:49:17,167 CHANGING. 1135 00:49:17,167 --> 00:49:19,836 WE HAVE THE NORMAL SCANNING OF 1136 00:49:19,836 --> 00:49:21,838 THE BRAIN LIKE A BAR CODE, IN 1137 00:49:21,838 --> 00:49:23,573 DISEASE CONDITIONS, IN THIS CASE 1138 00:49:23,573 --> 00:49:25,642 THE MOLECULES, ONE OF THE MAJOR 1139 00:49:25,642 --> 00:49:27,077 CELLS ARE MISSING. 1140 00:49:27,077 --> 00:49:29,746 SO THE IMMUNE RESPONSE BECOMES 1141 00:49:29,746 --> 00:49:32,215 ABNORMAL AND INSTEAD OF 1142 00:49:32,215 --> 00:49:34,818 SUPPRESSING THE RESPONSE BECOMES 1143 00:49:34,818 --> 00:49:36,853 MORE OF AN ACTIVATOR TYPE. 1144 00:49:36,853 --> 00:49:39,856 IF WE LOOK INTO THE AGED MICE, 1145 00:49:39,856 --> 00:49:42,292 AGAIN, THE SIGNATURE OF PROTEINS 1146 00:49:42,292 --> 00:49:43,493 IS COME LEADLY DIFFERENT. 1147 00:49:43,493 --> 00:49:46,363 IN A.D., THIS IS MY FAVORITE 1148 00:49:46,363 --> 00:49:47,064 SLIDE. 1149 00:49:47,064 --> 00:49:49,166 THIS IS ONLY THREE MONTHS OLD 1150 00:49:49,166 --> 00:49:50,834 MOUSE AND FOUR MONTHS OLD MOUSE. 1151 00:49:50,834 --> 00:49:58,275 IF YOU LOOK INSIDE THE CIRCLE, 1152 00:49:58,275 --> 00:50:00,077 THIS IS THE IN YELLOW IS THE 1153 00:50:00,077 --> 00:50:02,546 AMOUNT OF SUPPRESSIVE PEPTIDE, 1154 00:50:02,546 --> 00:50:05,716 IN FOUR MONTHS IT DISAPPEARS 1155 00:50:05,716 --> 00:50:06,016 COMPLETELY. 1156 00:50:06,016 --> 00:50:07,718 WE CANNOT FIND IT. 1157 00:50:07,718 --> 00:50:10,687 WHAT HAPPENS TO AD INSIDE THE 1158 00:50:10,687 --> 00:50:13,924 PEPTIDE AND HOW IMMUNE CELLS ARE 1159 00:50:13,924 --> 00:50:14,191 CHANGING? 1160 00:50:14,191 --> 00:50:16,560 MAYBE THE FLASH OF THE BRAIN IS 1161 00:50:16,560 --> 00:50:18,261 NOT GOOD AND WE DON'T GET THE 1162 00:50:18,261 --> 00:50:19,463 PEPTIDE COMING OUT. 1163 00:50:19,463 --> 00:50:21,932 LOTS OF EXCITING QUESTIONS. 1164 00:50:21,932 --> 00:50:24,401 CAN WE MAYBE DETECT THAT IMMUNE 1165 00:50:24,401 --> 00:50:27,437 BAR CODE, IMMUNE SIGNATURE OF 1166 00:50:27,437 --> 00:50:28,839 DISEASE IN PATIENTS. 1167 00:50:28,839 --> 00:50:30,607 THIS IS SMALL PREP. 1168 00:50:30,607 --> 00:50:32,109 FIVE AND FIVE. 1169 00:50:32,109 --> 00:50:35,445 WE HAVE A NICE AMOUNT OF 1170 00:50:35,445 --> 00:50:35,712 PARTIALS. 1171 00:50:35,712 --> 00:50:38,381 WE HAVE SAMPLES FOR OVER SIX 1172 00:50:38,381 --> 00:50:39,082 MONTHS. 1173 00:50:39,082 --> 00:50:43,920 WE JUST BOUGHT A NEW FANCY MASS 1174 00:50:43,920 --> 00:50:48,191 SPEC TO GIVE US BETTER READS ON 1175 00:50:48,191 --> 00:50:49,192 THE SAMPLE. 1176 00:50:49,192 --> 00:50:53,797 EVEN WITH A SMALL SAMPLE, WE 1177 00:50:53,797 --> 00:50:56,266 ALREADY SEE THERE ARE SOME 1178 00:50:56,266 --> 00:50:58,335 PEPTIDES ONLY APPEARING IN AD 1179 00:50:58,335 --> 00:51:00,971 AND OTHERS IN PD. 1180 00:51:00,971 --> 00:51:03,173 MY STUDENT TELLS ME IF I GET A 1181 00:51:03,173 --> 00:51:05,976 SAMPLE AD OR PD HE WILL BE ABLE 1182 00:51:05,976 --> 00:51:08,912 TO TELL WHICH ONE IT IS BECAUSE 1183 00:51:08,912 --> 00:51:11,314 SOME PEPTIDES ARE EITHER/OR. 1184 00:51:11,314 --> 00:51:12,849 THIS IS A DREAM THAT MAYBE ONE 1185 00:51:12,849 --> 00:51:15,452 DAY WE CAN DO THIS, I MEAN, IT 1186 00:51:15,452 --> 00:51:17,954 IS MORE INVASIVE THAN BLOOD 1187 00:51:17,954 --> 00:51:21,057 TEST, CSF TEST, IF WE GET ENOUGH 1188 00:51:21,057 --> 00:51:22,225 MATERIAL FROM CSF. 1189 00:51:22,225 --> 00:51:25,095 THIS IS ALL DONE FROM DURA. 1190 00:51:25,095 --> 00:51:28,365 POTENTIALLY WE COULD DEVELOP 1191 00:51:28,365 --> 00:51:30,767 REALLY EXCITING DIAGNOSTIC TOOLS 1192 00:51:30,767 --> 00:51:33,270 TO PREDICT DISEASES OF THE 1193 00:51:33,270 --> 00:51:33,770 BRAIN. 1194 00:51:33,770 --> 00:51:35,972 THIS IS WISHFUL THINKING. 1195 00:51:35,972 --> 00:51:38,909 I HOPE ONE DAY IT WILL BECOME 1196 00:51:38,909 --> 00:51:39,176 REALITY. 1197 00:51:39,176 --> 00:51:41,144 I SHOW THE DATA AND THANKED THEM 1198 00:51:41,144 --> 00:51:42,012 ALONG THE WAY. 1199 00:51:42,012 --> 00:51:44,347 MANY PEOPLE IN THE LAB, WHO I 1200 00:51:44,347 --> 00:51:49,653 WAS NOT ABLE TO PRESENT, MANY 1201 00:51:49,653 --> 00:51:49,986 COLLABORATORS. 1202 00:51:49,986 --> 00:51:52,355 AND MANY FUNDING SOURCES, I 1203 00:51:52,355 --> 00:51:55,625 WOULD LIKE TO EMPHASIZE NIA 1204 00:51:55,625 --> 00:51:57,360 BECAUSE THEY BELIEVED IN MY 1205 00:51:57,360 --> 00:51:59,963 THINGS VERY EARLY IN LIFE. 1206 00:51:59,963 --> 00:52:02,699 WHEN IMMUNOLOGY WAS NOT A FIANCE 1207 00:52:02,699 --> 00:52:04,835 THING AND NO ONE WANTED TO DEAL 1208 00:52:04,835 --> 00:52:07,771 WITH THE IMMUNE EFFECTS ON THE 1209 00:52:07,771 --> 00:52:08,638 BRAIN. 1210 00:52:08,638 --> 00:52:09,706 I WAS LUCKILY TO GET SUPPORT 1211 00:52:09,706 --> 00:52:15,278 FROM NIA, THE ALZHEIMER'S FUND. 1212 00:52:15,278 --> 00:52:16,646 AND MANY OTHER SOURCES. 1213 00:52:16,646 --> 00:52:18,849 AND I GUESS I WILL STOP HERE. 1214 00:52:18,849 --> 00:52:28,358 THANK YOU. 1215 00:52:28,358 --> 00:52:30,727 >> WE HAVE A FEW QUESTIONS BUT 1216 00:52:30,727 --> 00:52:37,667 THE MIC IS NOT WORKING. 1217 00:52:37,667 --> 00:52:40,170 CUP YOUR HANDS. 1218 00:52:40,170 --> 00:52:43,073 >> SO ONE QUESTION. 1219 00:52:43,073 --> 00:52:47,310 DID YOU CHECK THE MYELOID 1220 00:52:47,310 --> 00:52:52,649 COMPARTMENT AND THIS CHANGE IN 1221 00:52:52,649 --> 00:52:54,217 PEPTIDE CONCENTRATION COULD BE 1222 00:52:54,217 --> 00:52:56,686 RELATED TO TYPE OF -- THAT 1223 00:52:56,686 --> 00:52:57,387 PROCESSED IT? 1224 00:52:57,387 --> 00:53:05,428 >> BRILLIANT QUESTION. 1225 00:53:05,428 --> 00:53:07,230 IN A VERY SIMPLE EXPERIMENT, 1226 00:53:07,230 --> 00:53:15,438 FIRST OF ALL, IF YOU TAKE 1227 00:53:15,438 --> 00:53:17,641 MYELODAPC AND LOAD THEM, YOU SEE 1228 00:53:17,641 --> 00:53:21,945 WHAT HAS BEEN PRESENTED, WE 1229 00:53:21,945 --> 00:53:25,715 CANNOT FIND OUR SUPPRESSIVE 1230 00:53:25,715 --> 00:53:28,051 PEPTIDES PRESENTED BY B CELLS. 1231 00:53:28,051 --> 00:53:28,418 NEVER. 1232 00:53:28,418 --> 00:53:32,656 THAT IS WHY ANTI-B CELL THERAPY 1233 00:53:32,656 --> 00:53:34,658 IS WORKING IN ALS. 1234 00:53:34,658 --> 00:53:36,960 IT IS HYPOTHESIS, WHICH IS 1235 00:53:36,960 --> 00:53:38,061 EXCITING, BUT WE NEED TO PROVE 1236 00:53:38,061 --> 00:53:39,329 IT IS THE CASE. 1237 00:53:39,329 --> 00:53:43,967 WE ALSO KNOW WHEN YOU ACTIVATE 1238 00:53:43,967 --> 00:53:51,641 MICROFWLEEA OR MYELOID CELLS, 1239 00:53:51,641 --> 00:53:57,681 YOU ACTIVATE PRO TEASES. 1240 00:53:57,681 --> 00:54:00,283 WE DON'T KNOW IF THE CLEAVAGE 1241 00:54:00,283 --> 00:54:02,352 HAPPENS IN APC OR THE CELL OF 1242 00:54:02,352 --> 00:54:02,852 ORIGIN? 1243 00:54:02,852 --> 00:54:04,587 IS IT PREPACKED THAT WAY OR 1244 00:54:04,587 --> 00:54:08,091 CHOPPED BY APCs. 1245 00:54:08,091 --> 00:54:10,160 IF YOU TAKE CULTURES, IT IS 1246 00:54:10,160 --> 00:54:16,333 COMING FROM -- AND TREAT THEM 1247 00:54:16,333 --> 00:54:18,935 WITH DIFFERENT LPS AND CRAZY ACT 1248 00:54:18,935 --> 00:54:22,472 VASE, YOU SEE THE RELEASE OF 1249 00:54:22,472 --> 00:54:24,040 VESICLES WILL CONTAIN DIFFERENT 1250 00:54:24,040 --> 00:54:24,708 PEPTIDES. 1251 00:54:24,708 --> 00:54:27,310 THIS IS PROBABLY A COMBINATION. 1252 00:54:27,310 --> 00:54:28,945 >> GOING BACK TO THE LAST POINT, 1253 00:54:28,945 --> 00:54:33,483 WHEN CROWE HAVE AN INFECTION OR 1254 00:54:33,483 --> 00:54:35,352 MENINGEAL INFECTION, DO YOU SEE 1255 00:54:35,352 --> 00:54:37,754 THE SWITCH AND REDUCTION OF THE 1256 00:54:37,754 --> 00:54:38,421 SUPPRESSION MECHANISM? 1257 00:54:38,421 --> 00:54:39,322 >> YES. 1258 00:54:39,322 --> 00:54:41,091 SO WHAT WE THINK IS HAPPENING. 1259 00:54:41,091 --> 00:54:44,060 I WAS TALKING WITH KEN, I SAID, 1260 00:54:44,060 --> 00:54:51,368 KEN, OUR SUPPRESSER PEPTIDES IS 1261 00:54:51,368 --> 00:54:52,335 GOING UP. 1262 00:54:52,335 --> 00:54:54,404 YOU INTRODUCE SEVERE 1263 00:54:54,404 --> 00:54:54,771 INFLAMMATION. 1264 00:54:54,771 --> 00:54:56,973 THE BODILY TISSUE RESPONDS. 1265 00:54:56,973 --> 00:55:00,010 THERE IS A PROBLEM, WE NEED TO 1266 00:55:00,010 --> 00:55:03,279 ALLOW IMMUNE RESPONSE TO FIGHT 1267 00:55:03,279 --> 00:55:04,280 INFECTION. 1268 00:55:04,280 --> 00:55:06,883 IT IS BEING SENSED AROUND THE 1269 00:55:06,883 --> 00:55:10,020 BRAIN AND DON'T PRESENT ANY MORE 1270 00:55:10,020 --> 00:55:11,454 SUPPRESSIVE PEPTIDES. 1271 00:55:11,454 --> 00:55:12,622 >> IS IT TYPE 1? 1272 00:55:12,622 --> 00:55:14,290 >> YES. 1273 00:55:14,290 --> 00:55:14,891 IT IS. 1274 00:55:14,891 --> 00:55:16,960 >> LET'S GO OVER HERE. 1275 00:55:16,960 --> 00:55:19,129 >> HI. 1276 00:55:19,129 --> 00:55:22,399 IF YOU HAVE SHOWN THE PEPS THERE 1277 00:55:22,399 --> 00:55:25,769 TIDES ARE RESTRICTED -- 1278 00:55:25,769 --> 00:55:27,871 >> I KIND OF GLANCED THROUGH IT. 1279 00:55:27,871 --> 00:55:29,005 I DIDN'T SHOW YOU. 1280 00:55:29,005 --> 00:55:34,210 T SO WHEN WE IMMUNIZE WITH OUR 1281 00:55:34,210 --> 00:55:38,615 PEPTIDE WE VIE DUCTION IN THE 1282 00:55:38,615 --> 00:55:38,782 RES. 1283 00:55:38,782 --> 00:55:42,285 THESE ARE CTLA POSITIVE. 1284 00:55:42,285 --> 00:55:45,789 IF THE YOU WISH LIKE TR1 TYPE OF 1285 00:55:45,789 --> 00:55:45,989 CELLS. 1286 00:55:45,989 --> 00:55:48,558 IF YOU INHIBIT THE BETA, YOU 1287 00:55:48,558 --> 00:55:51,294 LOSE THE INHIBITORY EFFECT. 1288 00:55:51,294 --> 00:55:55,999 IT IS NOT CLASSICAL T-RES. 1289 00:55:55,999 --> 00:55:58,668 YOU DO SEE THEM AS WELL. 1290 00:55:58,668 --> 00:56:03,106 YOU CAN DETECT THOSE ENDOGENOUS 1291 00:56:03,106 --> 00:56:03,306 CELLS. 1292 00:56:03,306 --> 00:56:07,410 IN NORMAL MOUSE, YOU SEE THEM IN 1293 00:56:07,410 --> 00:56:11,281 THE AROUND THE BRAIN AND NOWHERE 1294 00:56:11,281 --> 00:56:11,915 ELSE. 1295 00:56:11,915 --> 00:56:18,288 THEY ARE C T LA POSITIVE, YOU DO 1296 00:56:18,288 --> 00:56:19,889 SEE SOME. 1297 00:56:19,889 --> 00:56:22,459 >> DR. CASPE. 1298 00:56:22,459 --> 00:56:24,127 >> THAT WAS FANTASTIC. 1299 00:56:24,127 --> 00:56:28,631 MHC CONNECTION. 1300 00:56:28,631 --> 00:56:33,470 IF YOU POSTULATE THE TYPE OF 1301 00:56:33,470 --> 00:56:35,338 PROCESSING AND PRESENTATION THAT 1302 00:56:35,338 --> 00:56:37,273 OCCURS FOR THE PEPTIDES YOU SEE 1303 00:56:37,273 --> 00:56:39,876 THERE, HAS A MAJOR EFFECT ON 1304 00:56:39,876 --> 00:56:45,315 DISEASE AND PHYSIOLOGY. 1305 00:56:45,315 --> 00:56:48,251 YOU SHOULD SEE STRONG MHC 1306 00:56:48,251 --> 00:56:48,585 ASSOCIATIONS. 1307 00:56:48,585 --> 00:56:49,752 COULD YOU TALK ABOUT THAT? 1308 00:56:49,752 --> 00:56:56,092 >> WHICH YOU DO WITH ALZHEIMER'S 1309 00:56:56,092 --> 00:57:01,798 AND MS. 1310 00:57:01,798 --> 00:57:05,635 AD IS STRONG FOR SURE. 1311 00:57:05,635 --> 00:57:05,869 YEAH. 1312 00:57:05,869 --> 00:57:07,170 I DON'T KNOW IF I ANSWERED YOUR 1313 00:57:07,170 --> 00:57:07,470 QUESTION. 1314 00:57:07,470 --> 00:57:10,340 YOU KNOW, I'M NOT NECESSARILY 1315 00:57:10,340 --> 00:57:12,442 SAYING THAT THESE THINGS ARE THE 1316 00:57:12,442 --> 00:57:17,514 DRIVING FORCE OF THE DISEASE. 1317 00:57:17,514 --> 00:57:19,682 SO BUT IT'S VERY POSSIBLE THAT 1318 00:57:19,682 --> 00:57:21,184 THIS WILL JUST END UP MAYBE 1319 00:57:21,184 --> 00:57:23,019 BEING A DIAGNOSTIC TOOL. 1320 00:57:23,019 --> 00:57:25,088 YOU SEE CHANGES ARE HAPPENING. 1321 00:57:25,088 --> 00:57:27,223 MAYBE THE OUTCOME TO THE CHANGES 1322 00:57:27,223 --> 00:57:29,959 IS NOT AFFECTING PROGRESSION OF 1323 00:57:29,959 --> 00:57:31,127 BUNCH OF DIFFERENT DISEASES. 1324 00:57:31,127 --> 00:57:34,998 I DO THINK IT AFFECTS 1325 00:57:34,998 --> 00:57:37,066 PROGRESSION OF AD AND 1326 00:57:37,066 --> 00:57:38,434 NEUROINFLAMMATORY CONDITIONS. 1327 00:57:38,434 --> 00:57:40,637 BUT STILL I DO BELIEVE WHEN 1328 00:57:40,637 --> 00:57:42,639 DISEASE STARTS IN THE BRAIN AND 1329 00:57:42,639 --> 00:57:44,574 YOU START MAKING OR PRODUCING 1330 00:57:44,574 --> 00:57:46,276 DIFFERENT PROTEINS, THE FLOW 1331 00:57:46,276 --> 00:57:48,211 THING IS REAL AND REALLY THE 1332 00:57:48,211 --> 00:57:50,947 BRAIN WASTE IS BEING WASHED INTO 1333 00:57:50,947 --> 00:57:54,117 THE CSF INTO THE DURA AND THE 1334 00:57:54,117 --> 00:57:55,919 CELLS ARE PRESENTING THESE 1335 00:57:55,919 --> 00:57:57,387 PEPTIDES YOU WILL START SEEING A 1336 00:57:57,387 --> 00:57:58,821 CHANGE IN THAT SIGNATURE. 1337 00:57:58,821 --> 00:58:01,724 WHICH IF YOU CAN DETECT EARLY 1338 00:58:01,724 --> 00:58:03,293 ENOUGH, THAT BY ITSELF COULD BE 1339 00:58:03,293 --> 00:58:04,627 VERY, VERY EXCITING THING. 1340 00:58:04,627 --> 00:58:05,862 >> OVER HERE, PLEASE. 1341 00:58:05,862 --> 00:58:09,165 >> VERY NICE TALK. 1342 00:58:09,165 --> 00:58:14,571 YOU SHOWED WHAT AGE THE CSF FLOW 1343 00:58:14,571 --> 00:58:16,406 DECREASES AND WHAT FIRES 1344 00:58:16,406 --> 00:58:18,174 TOGETHER SHOWERS TOGETHER. 1345 00:58:18,174 --> 00:58:20,577 DURING EARLY DEVELOPMENT, DO YOU 1346 00:58:20,577 --> 00:58:23,079 SEE UNIQUE PATTERNS OF CSF 1347 00:58:23,079 --> 00:58:23,279 NODES? 1348 00:58:23,279 --> 00:58:24,981 >> VERY, VERY INTERESTING 1349 00:58:24,981 --> 00:58:25,248 QUESTION. 1350 00:58:25,248 --> 00:58:26,849 ONE THING WE ARE NOT DOING IN 1351 00:58:26,849 --> 00:58:27,984 THE LAB 1352 00:58:27,984 --> 00:58:28,651 >> OKAY. 1353 00:58:28,651 --> 00:58:31,688 >> IS DEVELOPMENTAL ASPECTS OF 1354 00:58:31,688 --> 00:58:31,988 MS. 1355 00:58:31,988 --> 00:58:37,427 WE DON'T DO NEURODEVELOPMENT AT 1356 00:58:37,427 --> 00:58:37,860 ALL. 1357 00:58:37,860 --> 00:58:39,128 >> OKAY. 1358 00:58:39,128 --> 00:58:42,665 >> MENINGEAL LYMPHATICS, FOR 1359 00:58:42,665 --> 00:58:44,634 EXAMPLE, THEY DEVELOP AFTER 1360 00:58:44,634 --> 00:58:45,902 EVERY OTHER LYMPHATIC BED. 1361 00:58:45,902 --> 00:58:49,372 THE MOUSE IS BORN WITH ALL THE 1362 00:58:49,372 --> 00:58:52,041 LYMPHATICS, BUT DOES NOT HAVE 1363 00:58:52,041 --> 00:58:54,777 MENINGEAL LIMB FAT IGS. 1364 00:58:54,777 --> 00:58:56,346 THEY APPEAR AFTER THREE WEEKS. 1365 00:58:56,346 --> 00:58:56,946 >> OH, WOW. 1366 00:58:56,946 --> 00:58:58,381 >> THERE IS A LOT OF THEM AND 1367 00:58:58,381 --> 00:59:00,149 THERE IS A PRUNING AND THERE ARE 1368 00:59:00,149 --> 00:59:03,152 LESS OF THEM. 1369 00:59:03,152 --> 00:59:06,723 ONE OF MY POST DOCS IS STUDYING. 1370 00:59:06,723 --> 00:59:09,459 HIS PAPER MAY BE COMING OUT. 1371 00:59:09,459 --> 00:59:11,961 I DON'T KNOW WHAT IS HAPPENING 1372 00:59:11,961 --> 00:59:14,530 IN -- WITH CSF, PATTERNS OF CSF 1373 00:59:14,530 --> 00:59:16,666 FLOW IN EHLY DEVELOPMENT. 1374 00:59:16,666 --> 00:59:18,201 VERY INTERESTING QUESTION. 1375 00:59:18,201 --> 00:59:21,537 >> ESPECIALLY WITH SPONTANEOUS 1376 00:59:21,537 --> 00:59:22,205 ACTIVITY. 1377 00:59:22,205 --> 00:59:25,875 >> REMEMBER ALSO MICROGLIA 1378 00:59:25,875 --> 00:59:27,243 ARRIVE IN THE BRAIN, THE ARRIVAL 1379 00:59:27,243 --> 00:59:29,512 OF THE CELLS AND DISPERSAL 1380 00:59:29,512 --> 00:59:30,513 THROUGHOUT THE BRAIN, FIRST 1381 00:59:30,513 --> 00:59:33,182 ALONG THE ARTERIES AND THE BRAIN 1382 00:59:33,182 --> 00:59:35,985 TISSUE, FOLLOWS THE PATTERNS OF 1383 00:59:35,985 --> 00:59:36,819 THE FLOW. 1384 00:59:36,819 --> 00:59:40,590 SO IT IS PROBABLY THERE WAY 1385 00:59:40,590 --> 00:59:42,692 BEFORE -- IT PROBABLY 1386 00:59:42,692 --> 00:59:44,460 ESTABLISHES ITSELF. 1387 00:59:44,460 --> 00:59:46,129 I DON'T KNOW WHEN CSF STARTS 1388 00:59:46,129 --> 00:59:47,330 BEING PRODUCED IN MICE. 1389 00:59:47,330 --> 00:59:47,830 I DON'T KNOW. 1390 00:59:47,830 --> 00:59:49,432 I SHOULD KNOW THAT. 1391 00:59:49,432 --> 00:59:52,135 THAT PATTERN IS WHAT FLOW WILL 1392 00:59:52,135 --> 00:59:53,269 LOOK LIKE WITH APPEARANCE OF 1393 00:59:53,269 --> 00:59:54,203 CELLS IN THE BRAIN. 1394 00:59:54,203 --> 00:59:54,437 >> OKAY. 1395 00:59:54,437 --> 00:59:55,972 THANK YOU. 1396 00:59:55,972 --> 00:59:57,874 >> MAYBE TWO MORE QUESTIONS THEN 1397 00:59:57,874 --> 00:59:59,976 WE HAVE A RECEPTION. 1398 00:59:59,976 --> 01:00:00,343 OKAY. 1399 01:00:00,343 --> 01:00:00,977 >> HI. 1400 01:00:00,977 --> 01:00:02,078 I APPRECIATE THE MENTION OF 1401 01:00:02,078 --> 01:00:04,180 SLEEP AS WE START TO LEARN IT IS 1402 01:00:04,180 --> 01:00:06,616 MORE OF AN ACTIVE PROCESS. 1403 01:00:06,616 --> 01:00:10,086 AND I CAN IMAGINE IT BRINGS ITS 1404 01:00:10,086 --> 01:00:12,422 OWN CHALLENGES WHEN DEVELOPING 1405 01:00:12,422 --> 01:00:13,990 YOUR EXPERIMENTAL DESIGNS. 1406 01:00:13,990 --> 01:00:15,858 MY QUESTION IS HOW DO YOU 1407 01:00:15,858 --> 01:00:24,467 ANTICIPATE THE TIE OF AGING 1408 01:00:24,467 --> 01:00:30,139 IMMUNAL -- SYSTEMICALLY AND ROOT 1409 01:00:30,139 --> 01:00:30,440 MICROBIOTA. 1410 01:00:30,440 --> 01:00:34,677 >> IT IS A SUPER COMPLICATED 1411 01:00:34,677 --> 01:00:34,944 QUESTION. 1412 01:00:34,944 --> 01:00:36,646 MY NEIGHBOR THREE FLOORS ABOVE 1413 01:00:36,646 --> 01:00:38,414 ME IS JEFF GORDON. 1414 01:00:38,414 --> 01:00:40,950 EVERY TIME WE DO IT, WE TRY TO 1415 01:00:40,950 --> 01:00:44,153 MAKE SURE WE KNOW WHAT WE ARE 1416 01:00:44,153 --> 01:00:44,354 DOING. 1417 01:00:44,354 --> 01:00:47,023 WE JUST GOT IRB TO DO SOMETHING 1418 01:00:47,023 --> 01:00:48,558 THE ALZHEIMER'S PATIENTS. 1419 01:00:48,558 --> 01:00:50,626 I CANNOT TALK ABOUT IT RIGHT 1420 01:00:50,626 --> 01:00:50,827 NOW. 1421 01:00:50,827 --> 01:00:53,730 IT IS JUST THE BEGINNING OF THE 1422 01:00:53,730 --> 01:00:54,063 PROJECT. 1423 01:00:54,063 --> 01:00:58,134 DEFINITELY ALL SYSTEMS ARE 1424 01:00:58,134 --> 01:00:59,035 COOPERATING AND PLAYING TOGETHER 1425 01:00:59,035 --> 01:01:01,170 AND I CANNOT REALLY TELL YOU 1426 01:01:01,170 --> 01:01:03,506 EXACTLY WHAT IS HAPPENING WITH 1427 01:01:03,506 --> 01:01:09,178 THIS PARTICULAR PATHWAY. 1428 01:01:09,178 --> 01:01:10,880 MICROBIOTICS ARE CHANGING, 1429 01:01:10,880 --> 01:01:12,949 BARRIERS IN THE BRAIN ARE 1430 01:01:12,949 --> 01:01:15,685 CHANGING, LYMPHATIC VESSELS ARE 1431 01:01:15,685 --> 01:01:15,952 CHANGING. 1432 01:01:15,952 --> 01:01:20,189 THE AMOUNT OF LYMPHATIC VESSELS 1433 01:01:20,189 --> 01:01:21,657 IS CHANGING. 1434 01:01:21,657 --> 01:01:24,861 TOTALLY OFF TOPIC OF THE 1435 01:01:24,861 --> 01:01:26,129 QUESTION, BUT I DON'T KNOW IF 1436 01:01:26,129 --> 01:01:28,030 YOU HEARD OF THIS NEW SURGICAL 1437 01:01:28,030 --> 01:01:32,902 APPROACH IN CHINA ALL OVER THE 1438 01:01:32,902 --> 01:01:36,806 NEWS, THEY DO STENOSIS OF 1439 01:01:36,806 --> 01:01:43,179 LYMPHATIC VESSELS IN THE NECK OF 1440 01:01:43,179 --> 01:01:45,114 ALZHEIMER'S PATIENTS. 1441 01:01:45,114 --> 01:01:46,616 FROM WHAT IS BEING SHOWN IN THE 1442 01:01:46,616 --> 01:01:48,351 MEDIA AND WHAT THEY CAN REPORT 1443 01:01:48,351 --> 01:01:54,824 IN LECTURINGS, , I HOPE IT IS 1444 01:01:54,824 --> 01:01:55,091 TRUE. 1445 01:01:55,091 --> 01:01:57,093 REMEMBER ALSO WHILE I DO BELIEVE 1446 01:01:57,093 --> 01:01:59,595 IN SLEEP THE BRAIN CLEARANCE IS 1447 01:01:59,595 --> 01:02:03,433 AT ITS MAXIMUM CAPACITY, I AM 1448 01:02:03,433 --> 01:02:05,268 NOT SAYING THERE IS NO BRAIN 1449 01:02:05,268 --> 01:02:06,369 CLEARANCE DURING WAKEFULNESS. 1450 01:02:06,369 --> 01:02:09,338 THERE ARE A LOT OF ARGUMENTS 1451 01:02:09,338 --> 01:02:10,940 BETWEEN SOME GROUPS. 1452 01:02:10,940 --> 01:02:13,676 WE REMAIN NEUTRALITY BECAUSE IT 1453 01:02:13,676 --> 01:02:16,879 IS DEFINITELY HAPPENING IN 1454 01:02:16,879 --> 01:02:20,349 DAYTIME, BUT ENHANCED IN NIGHT 1455 01:02:20,349 --> 01:02:20,550 TIME. 1456 01:02:20,550 --> 01:02:23,352 DIFFERENT TYPES OF WASTE MAY 1457 01:02:23,352 --> 01:02:25,021 REQUIRE DIFFERENT APPROACHES TO 1458 01:02:25,021 --> 01:02:25,655 REMOVE IT. 1459 01:02:25,655 --> 01:02:28,391 SOME MAY BE MOVING DURING 1460 01:02:28,391 --> 01:02:30,793 DAYTIME AND SLEEP TIME. 1461 01:02:30,793 --> 01:02:33,095 NOT SURE IF I ANSWERED YOUR 1462 01:02:33,095 --> 01:02:33,362 QUESTION. 1463 01:02:33,362 --> 01:02:35,298 BUT I CERTAINLY ANSWERED 1464 01:02:35,298 --> 01:02:37,567 SOMEBODY'S QUESTION. 1465 01:02:37,567 --> 01:02:40,770 >> LAST QUESTION. 1466 01:02:40,770 --> 01:02:43,673 THANK YOU SO MUCH FOR THE 1467 01:02:43,673 --> 01:02:45,074 PHENOMENAL STORY. 1468 01:02:45,074 --> 01:02:52,081 BASED OND ALL YOU DISCOVERED, 1469 01:02:52,081 --> 01:02:56,419 WHAT IS YOUR -- GLYMPHATIC IN 1470 01:02:56,419 --> 01:03:00,623 ORDER TO IMPROVE AGING 1471 01:03:00,623 --> 01:03:00,890 DISORDERS. 1472 01:03:00,890 --> 01:03:03,659 >> I USED TO BE AT UNIVERSITY OF 1473 01:03:03,659 --> 01:03:06,963 VIRGINIA TWO HOURS ODOWN THE 1474 01:03:06,963 --> 01:03:07,363 ROAD. 1475 01:03:07,363 --> 01:03:09,365 I WAS INVITED TO GIVE A TALK 1476 01:03:09,365 --> 01:03:12,635 ABOUT BLACKSBURG, IT IS NOT AN 1477 01:03:12,635 --> 01:03:17,340 MD SCHOOL, THE OTHER. 1478 01:03:17,340 --> 01:03:19,308 SOMEBODY ASKED ME WHAT DO YOU 1479 01:03:19,308 --> 01:03:22,278 THINK A BRAIN MASSAGE WILL DO TO 1480 01:03:22,278 --> 01:03:22,578 LYMPHATICS. 1481 01:03:22,578 --> 01:03:25,081 I SAID, I HAVE NO CLUE, BUT SIGN 1482 01:03:25,081 --> 01:03:25,915 ME UP. 1483 01:03:25,915 --> 01:03:33,823 WE JUST RECENTLY PROPOSED TO 1484 01:03:33,823 --> 01:03:36,526 ARPAH, BRAIN MASSAGE, MANUAL 1485 01:03:36,526 --> 01:03:38,361 THERAPY FOR LYMPHATICS ALONG 1486 01:03:38,361 --> 01:03:41,497 WITH THE NECK TO IMPROVE THE 1487 01:03:41,497 --> 01:03:41,731 SUCTION. 1488 01:03:41,731 --> 01:03:43,666 IT DID NOT GO VERY WELL. 1489 01:03:43,666 --> 01:03:45,635 I DO BELIEVE THERE IS SOMETHING 1490 01:03:45,635 --> 01:03:45,902 THERE. 1491 01:03:45,902 --> 01:03:48,571 IF YOU TALK TO MANUAL THERAPISTS 1492 01:03:48,571 --> 01:03:51,040 THEY TELL YOU BEAUTIFUL AMAZING 1493 01:03:51,040 --> 01:03:51,274 STORIES. 1494 01:03:51,274 --> 01:03:54,377 THERE IS SOMETHING THERE. 1495 01:03:54,377 --> 01:03:55,778 >> THIS IS VERY PROMISING. 1496 01:03:55,778 --> 01:03:59,048 ALSO WE HAVE A COUPLE OF STUDIES 1497 01:03:59,048 --> 01:04:02,585 WE FOUND FOR SOUND BASED 1498 01:04:02,585 --> 01:04:05,121 MANIPULATIONS AND FOR MAYBE 1499 01:04:05,121 --> 01:04:05,421 ACUPUNCTURE. 1500 01:04:05,421 --> 01:04:07,590 >> ARE YOU ENA? 1501 01:04:07,590 --> 01:04:08,624 >> YES. 1502 01:04:08,624 --> 01:04:11,093 >> YOU KNOW OUR WORK. 1503 01:04:11,093 --> 01:04:12,194 >> VERY MUCH. 1504 01:04:12,194 --> 01:04:13,563 WHAT YOU ARE DOING. 1505 01:04:13,563 --> 01:04:15,431 >> I ALWAYS THOUGHT THAT 1506 01:04:15,431 --> 01:04:17,166 STANDING ON MY HEAD IS A GOOD 1507 01:04:17,166 --> 01:04:19,468 THING SO I BOUGHT THIS THING AND 1508 01:04:19,468 --> 01:04:20,002 STAND UP. 1509 01:04:20,002 --> 01:04:23,306 NOW THROUGH YOUR FUNDING, WE SAW 1510 01:04:23,306 --> 01:04:25,942 THAT WHEN YOU PUT THE MICE TILT 1511 01:04:25,942 --> 01:04:28,511 UP AND TILT DOWN, THE FLOW OF 1512 01:04:28,511 --> 01:04:30,079 CSF IS COMPLETELY DIFFERENT AND 1513 01:04:30,079 --> 01:04:32,615 I'M NOT SURE ANYMORE I WANT TO 1514 01:04:32,615 --> 01:04:33,583 STAND ON MY HEAD NOW. 1515 01:04:33,583 --> 01:04:35,251 NOT TO SAY YOU SHOULD DO IT. 1516 01:04:35,251 --> 01:04:36,619 I DON'T KNOW WHAT IT DOES TO 1517 01:04:36,619 --> 01:04:37,553 YOUR SF SF DRAINAGE OUT OF THE 1518 01:04:37,553 --> 01:04:38,487 HEAD. 1519 01:04:38,487 --> 01:04:41,991 >> THANK YOU SO MUCH. 1520 01:04:41,991 --> 01:04:44,360 -- CSF DRAINAGE OUT OF THE HEAD. 1521 01:04:44,360 --> 01:04:46,395 >> THANK YOU SO MUCH. 1522 01:04:46,395 --> 01:04:51,233 >> CME CODE 57686. 1523 01:04:51,233 --> 01:04:53,102 THERE IS A RECEPTION OUTSIDE. 1524 01:04:53,102 --> 01:05:03,145 SEE YOU OUT THERE.