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>> GREETINGS, EVERYONE. WE'RE

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GOING TO GET STARTED. TODAY

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(INAUDIBLE) ARE GOING TO THE

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HANG THE REIGNS TEMPORARILY TO

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WILL BOHR AND HE WILL INTRODUCE

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OUR SPEAKER. TAKE IT AWAY.

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>> THANK YOU, CAROLYN. IT IS A

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PLEA TOWER TO INTRODUCE

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SCHUMACHER, OLD FRIEND OF MINE.

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BEFORE I DO THAT I WANT TO

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REMIND EVERYONE THAT THE

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QUESTIONS ARE PUT IN THE CHAT

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AND THEN WE READ THEM FORBORNE

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AND HE WILL ANSWER QUESTIONS

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FOLLOWING THAT. BJORN IS VERY

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WELL KNOWN IN OUR FIELD OF AGING

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AND GENOME INSTABILITY. HE IS

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NOW PROFESSOR AND DIRECTOR OF

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THE INSTITUTE FOR GENOME

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STABILITY AND AGING DISEASES.

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AND CECAD CENTER THERE AS WELL.

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HE RECEIVED HIS Ph.D. FROM THE

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MAX PLANK INSTITUTE IN MUNCIEON.

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THEN A POST-DOCTORAL FELLOW IN

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ROTTERDAM WHERE HE DID IMPORTANT

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MOUSE WORK. HE'S CURRENTLY

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PRESIDENT OF GERMAN SOCIETY FOR

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DNA REPAIR, CO-DIRECTOR OF THE

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MINERVA CENTER OF BIOLOGICAL

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MECHANISMS OF HEALTHY AGING AT

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(INAUDIBLE) UNIVERSITY AND WAS

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ALSO THE PRESIDENT OF THE

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JOURNAL SOCIETY FOR AGING

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RESEARCH. AND IN ADDITION TO ALL

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HIS WORK ON GENOME INSTABILITY

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WHICH IS VERY IMPORTANT WORK HE

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HAS ALSO WRITTEN BOOKS ABOUT

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AGING RECENTLY A COUPLE OF YEARS

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AGO A VERY INTERESTING VERY

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COMPREHENSIVE BOOK ABOUT THE

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AGING PROCESS THAT WAS WIDELY

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REFERRED AND SOLD. HE HAS WORKED

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ON MAMMALIAN SYSTEMS AND

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CELLULAR SYSTEMS AND ON

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NEMATODES AND HAS RECENTLY

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DISCOVERED THE GENE COMPLEX

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IMPORTANT IN DNA REPAIR IN MANY

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OTHER VERY IMPORTANT ASPECTS OF

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DNA REPAIR RELATING TO THE VERY

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BROAD IMPLICATIONS OF DNA DAMAGE

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AND REPAIR.  SO WE ARE REALLY

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PLEASED TO HAVE YOU BJORN AND WE

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LOOK FORWARD TO YOUR

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PRESENTATION. THANK YOU.

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>> YOU ARE MUTED BJORN.

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>> NOW YOU SHOULD BE ABLE TO

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HEAR ME. SORRY. SO MUCH FOR THIS

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VERY KIND INTRODUCTIONS, THIS

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WONDERFUL WORDS. I'M VERY

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PLEASED TO SPEAK TO YOU TODAY

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ABOUT GENOME STABILITY AND HOW

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IT AFFECTS AGING. AND

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INHERITANCE AND HOW THESE TWO

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PROCESSES ARE REALLY

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INTERTWINED.  IN PARTICULAR WHAT

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WE CAN LEARN FROM SIMPLE MODEL

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ORGANISMS THAT WE BELIEVE HAS

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RELEVANCE FOR HUMAN HEALTH AND

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DISEASE. IS THIS NOT ADVANCING?

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USE THE ARROW.

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>> YOU ARE AWARE WE ARE LIVING

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IN THE MIDST OF THE DEMOGRAPHIC

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CHANGE THAT STARTED ABOUT 150

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YEARS AGO, SINCE THEN LIFE

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EXPECTANCY OF HUMANS HAS

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DOUBLED. AND THIS IS NOT ONLY

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RESTRICTED TO WESTERN EUROPE

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NORTH AMERICA BUT IT IS A REALLY

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WORLDWIDE PHENOMENON. WITH THE

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HIGH LIFE EXPECTANCY AND LOW

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MORTALITY OF MODERN SOCIETY WE

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REALLY HAVE ENTERED A PHASE

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WHERE THE PROPORTION OF ELDERLY

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HAS STEEPLY INCREASING AND WILL

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SOON BE 30% AND MORE OF OUR

86
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POPULATION WITH AGE ABOUT 60.

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AGING HOWEVER COMES INVARIABLY

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WITH DISEASE, WITH MULTIPLE

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CHRONIC DISORDERS RELATED FROM

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DEMENTIA WITH ALZHEIMER THE MOST

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PRESENT FORM, CARDIOVASCULAR

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DISEASE THAT STILL ARE THE

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NUMBER ONE KILLER ES. CHRONIC

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KIDNEY DISEASE, SEVERE CLINICAL

95
00:04:40,413 --> 00:04:42,048
PROBLEM, TYPE 2 DIABETES ON THE

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RISE, WITH MACULAR DEGENERATION

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IN LARGE PROPORTION OF THE

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POPULATION. A SINGLE BIGGEST

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RISK FACTOR FOR CANCER MORE THAN

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ANY GENETIC OR ENVIRONMENTAL

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FACTOR IS AGE. WHAT IS MORE IS

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THE DISEASES OF AGING SELDOM

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COME ALONE. IN FACT,

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MULTI-MORBIDITY IS THE TRUE

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DISEASE OF AGING. MULTI-MOSHED

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INCREASES AFTER THE FIFTH DECADE

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OF LIFE AND THAT MEANS WE HAVE

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AN EVER GROWING POPULATION THAT

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SUFFERS FROM MULTIPLE CHRONIC

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DISEASE. MORE THAN HALF THE

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ELDERLY SUFFER FROM THIS.

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ALREADY NOWADAYS WE ARE SPENDING

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50% OF HEALTHCARE COSTS ON THE

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ELDERLY AND BY 2050 WE HAVE 2

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BILLION PEOPLE ABOVE AGE 60. THE

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TRADITIONAL APPROACH THOSE

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DISEASES HAS BEEN DISEASE

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SPECIFIC THERAPIES. IN ORDER TO

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IMPROVE TREATMENT FOR DEDICATED

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CANCER RESEARCH TRYING TO

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UNDERSTAND THE BIOLOGY OF CANCER

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AS YOU ARE WELL AWARE, WE HAVE

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COME THROUGH PERSONALIZED

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MEDICINE TO PRECISION MEDICINE,

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TO ALWAYS MORE AND MORE

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SPECIFICALLY TREAT THE SPECIFIC

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CANCER TYPE. THIS IS ALSO

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INCREASINGLY TRUE FOR

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CARDIOVASCULAR DISEASE, DEMENTIA

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FORMS, SO ON. SPECIALIZED

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TREATMENTS. BUT IF YOU ARE NOW

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TAKE THESE CHRONIC DISEASE OF

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AGING TOGETHER WITH THE

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DEMOGRAPHIC CHANGE, THIS WOULD

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MEAN YOU WILL HAVE ONE

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HOSPITALIZATION OF THE OTHER,

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ONE TREATMENT AFTER THE OTHER,

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FOREVER INCREASING PROPORTION OF

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THE POPULATION.  MODERN AGING

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BIOLOGY HAS CHANGED THE PARADIGM

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AND IS POSTULATING THAT NOT ONLY

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CORRELATED TO THIS DISTINCT

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DISEASE TYPES BUT IN FACT IS THE

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ROOT CAUSE. INSTEAD OF TREATING

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DISEASE ONCE THEY OCCUR, AGING

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RESEARCH IS TRYING TO DIRECT

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GENERAL PROTECTIVE TREATMENT AT

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THE AGING PROCESS IN ORDER TO

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PREVENT AT LEAST DELAY ONSET OF

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AGE RELATED DISEASES.  THIS MOST

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CERTAINLY UNDERSTAND REQUIRES WE

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UNDERSTAND MECHANISMS THAT

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UNDERLIE THE AGING PROCESS.

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FUNDAMENTAL MECHANISM THAT

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DRIVES THE AGING PROCESS IS

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DAMAGE TO THE GENOME. WHILE THE

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GENOME CONTAINS ALL INFORMATION

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HOW TO BUILD AND MAINTAIN

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ITSELF, IT IS SURPRISINGLY

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UNSTABLE. IN FACT EXPOSED TO

161
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EXOGENOUS AND ENDOGENOUS DAMAGE

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TYPES, EVERY SINGLE DAY OF YOUR

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LIFE. EVERY SINGLE CELL IN YOUR

164
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BODY IS EXPOSED TO TENS OF

165
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THOUSANDS OF DAMAGING EVENTS.

166
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AND THEY CAN COME IN A DISTINCT

167
00:07:45,164 --> 00:07:47,934
DAMAGE TYPES DEPENDING ON THE

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GENOTOXIC INSIGHT AND HOW IT

169
00:07:49,769 --> 00:07:53,139
INTERACTS WITH SPECIFIC PARTS OF

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THE GENOME. THIS DIFFERENT

171
00:07:54,774 --> 00:07:58,578
DAMAGE TYPES HAS ESSENTIALLY TWO

172
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DISTINGUISHABLE MOLECULAR

173
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CONSEQUENCES. THE ONE WE

174
00:08:04,817 --> 00:08:08,521
UNDERSTAND WELL IS HOW DNA

175
00:08:08,588 --> 00:08:09,956
DAMAGE LEADS TO TRANSLOCATION

176
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MUTATIONS DELETIONS AND THEY ARE

177
00:08:11,824 --> 00:08:13,226
KNOWN MANY DECADES TO BE CAUSE

178
00:08:13,292 --> 00:08:16,963
FOR CANCER. BUT DNA DAMAGE

179
00:08:17,029 --> 00:08:19,532
CANNOT BLOCK TRANSCRIPTION

180
00:08:19,599 --> 00:08:21,567
REPLICATION, THIS LEADS TO CELL

181
00:08:21,634 --> 00:08:23,903
FATE ALTERATION. THE DNA DAMAGE

182
00:08:23,970 --> 00:08:27,406
RESPONSE THAT CAN INDUCE APOT

183
00:08:27,473 --> 00:08:31,510
POP TOTTIC CELL DEATH CELLULAR

184
00:08:31,577 --> 00:08:34,914
SENESCENCE THIS LEVERS TO STEM

185
00:08:34,981 --> 00:08:38,417
CELL COMPARTMENTS, ALL THESE

186
00:08:38,484 --> 00:08:43,856
CELL FATE ALTERATI ALTERATIONS O

187
00:08:43,923 --> 00:08:46,626
FUNCTIONAL DECLINE AND ATROPHIC

188
00:08:46,692 --> 00:08:48,628
AND SYSTEMIC O SO DNA DAMAGE IS

189
00:08:48,694 --> 00:08:49,862
A FUNDAMENTAL CAUSE THAT

190
00:08:49,929 --> 00:08:52,832
PROMOTES THE AGING PROCESS. DNA

191
00:08:52,899 --> 00:08:55,601
REPAIR MECHANISMS HAVE EVOLVED

192
00:08:55,668 --> 00:08:58,471
EARLY IN THE EVOLUTIONARY

193
00:08:58,537 --> 00:09:00,907
HISTORY BECAUSE THEY WERE

194
00:09:00,973 --> 00:09:02,341
ABSOLUTELY ESSENTIAL FOR

195
00:09:02,408 --> 00:09:04,977
ALLOWING STAGE REPLY KAY TORRS

196
00:09:05,044 --> 00:09:11,384
INITIALLY -- REPLICATORS AND

197
00:09:11,450 --> 00:09:12,652
PREVENTING MOLECULAR

198
00:09:12,718 --> 00:09:14,654
CONSEQUENCES.  HERE I SHOW

199
00:09:14,720 --> 00:09:15,288
EXAMPLES OF THE DISTINCT

200
00:09:15,354 --> 00:09:17,657
CONSEQUENCES OF DEFECTS IN DNA

201
00:09:17,723 --> 00:09:20,660
REPAIR. ON THE ONE SIDE YOU SEE

202
00:09:20,726 --> 00:09:24,096
HERE CHILD BORN WITH CONDITION

203
00:09:24,163 --> 00:09:30,369
CALLED PIG MEN TOE SUM AND --

204
00:09:30,436 --> 00:09:31,137
PIGMENTOSAM WITH SEVERAL

205
00:09:31,203 --> 00:09:33,372
THOUSAND FOLD INCREASE SKIN

206
00:09:33,439 --> 00:09:36,008
CANCER SUSCEPTIBILITY

207
00:09:36,075 --> 00:09:38,110
ILLUSTRATING THE MUTAGENIC

208
00:09:38,177 --> 00:09:40,212
CONSEQUENCE OF DNA DAMAGE. ON

209
00:09:40,279 --> 00:09:43,316
THE OTHER SIDE YOU SEW A BOY WHO

210
00:09:43,382 --> 00:09:46,252
SUFFERS FROM COCKAYNE SYNDROME,

211
00:09:46,319 --> 00:09:48,054
A PREMATURE AGING CONDITION

212
00:09:48,120 --> 00:09:51,891
WHERE INITIALLY SEVERE GROWTH

213
00:09:51,958 --> 00:09:54,860
DELAY IS DETECTED, AND FUNNELED

214
00:09:54,927 --> 00:10:00,433
BY MULTIPLE JOE GENERATIVE

215
00:10:00,499 --> 00:10:02,335
HISTONES LET LAR DEGENERATION,

216
00:10:02,401 --> 00:10:03,602
ATHEROSCLEROSIS, PATHOLOGIES

217
00:10:03,669 --> 00:10:06,038
THAT WE ARE EXPERIENCING ONLY AT

218
00:10:06,105 --> 00:10:07,974
VERY OLE AGE. HERE ALREADY

219
00:10:08,040 --> 00:10:12,111
WITHIN THE FIRST DECADE OF LIFE

220
00:10:12,178 --> 00:10:15,114
EXEMPLIFYING THE DEGENERATIVE

221
00:10:15,181 --> 00:10:17,249
CONSEQUENCES OF DNA DAMAGE. NOW

222
00:10:17,316 --> 00:10:19,919
WHEN WE WANT TO UNDERSTAND ANY

223
00:10:19,986 --> 00:10:25,558
PROCESS IN BIOLOGY, WE NEED TO

224
00:10:25,624 --> 00:10:29,362
UNDERSTAND HOW THIS PROCESS

225
00:10:29,428 --> 00:10:30,596
EVOLVED IN THE EVOLUTIONARY

226
00:10:30,663 --> 00:10:34,200
HISTORY. HERE A FUNDAMENTAL

227
00:10:34,266 --> 00:10:35,434
CONTRIBUTION TO UNDERSTANDING

228
00:10:35,501 --> 00:10:37,670
THE ULTIMATE CAUSES OF AGING

229
00:10:37,737 --> 00:10:42,308
CAME FROM A ZOOLOGIST WHO IN THE

230
00:10:42,375 --> 00:10:44,243
LATE 19TH CENTURY WAS ONE OF THE

231
00:10:44,310 --> 00:10:48,748
TOP EVOLUTIONARY BIOLOGISTS.

232
00:10:48,814 --> 00:10:51,650
WHAT WISEMANN PROPOSED WAS THE

233
00:10:51,717 --> 00:10:54,587
GERMPLASM THEORY, THE THEORY OF

234
00:10:54,653 --> 00:10:55,888
INHERITANCE WE HOLD TRUE UP TO

235
00:10:55,955 --> 00:11:01,260
THIS DAY. WHAT HE REALIZED IS

236
00:11:01,327 --> 00:11:03,796
INHERITABLE TRAITS EXCLUSIVELY

237
00:11:03,863 --> 00:11:08,134
PASSED ON BY GERM SETS. WHAT WAS

238
00:11:08,200 --> 00:11:11,437
LATER KNOWN AS THE WEISMANN

239
00:11:11,504 --> 00:11:13,939
BARRIER, DESCRIPTION OF THE

240
00:11:14,006 --> 00:11:14,940
PROTECTION OF HERITABLE GENOMES

241
00:11:15,007 --> 00:11:19,145
FROM SOMATIC ENVIRONMENT

242
00:11:19,211 --> 00:11:22,915
INFLUENCES. WHAT PASS ON GENETIC

243
00:11:22,982 --> 00:11:24,617
INFORMATION THROUGHOUT THE

244
00:11:24,683 --> 00:11:26,786
GENERATIONS. AND WHEN THEY

245
00:11:26,852 --> 00:11:29,288
DEFINITELY DO SO, THEY REQUIRE

246
00:11:29,355 --> 00:11:32,691
IN A DEFINITE GERM LINE

247
00:11:32,758 --> 00:11:35,394
MAINTENANCE. THE STOMA INSTEAD

248
00:11:35,461 --> 00:11:37,163
ONLY NEEDS TO BE MAINTAINED FOR

249
00:11:37,229 --> 00:11:39,932
AS LONG AS IT TOOK IN

250
00:11:39,999 --> 00:11:41,400
EVOLUTIONARY HISTORIC TIMES TO

251
00:11:41,467 --> 00:11:43,169
ESTABLISH THE NEXT GENERATION.

252
00:11:43,235 --> 00:11:46,505
ONCE THE GENES ARE SAFELY PASSED

253
00:11:46,572 --> 00:11:49,575
ON, THE STOMA CAN DECAY AGE AND

254
00:11:49,642 --> 00:11:52,244
DIE. THIS ULTIMATELY WHY WE AGE.

255
00:11:52,311 --> 00:11:54,346
WE ARE NOTHING MORE THAN THE

256
00:11:54,413 --> 00:12:00,152
MERE VEHICLES OF OUR GERM CELLS.

257
00:12:00,219 --> 00:12:02,054
THIS MEANS THE GENOME STABILITY

258
00:12:02,121 --> 00:12:05,357
IN GERM CELLS IS THE

259
00:12:05,424 --> 00:12:07,593
PREREQUISITE FOR FOR UNTILTY,

260
00:12:07,660 --> 00:12:09,895
GERM LINE AND SPECIES

261
00:12:09,962 --> 00:12:12,198
MAINTENANCE. FERTILITY. WHAT IS

262
00:12:12,264 --> 00:12:14,867
INTERESTING FOR US TO UNDERSTAND

263
00:12:14,934 --> 00:12:17,403
HOW GERM CELLS MANAGE TO

264
00:12:17,470 --> 00:12:18,971
INDEFINITELY MAINTAIN THEIR

265
00:12:19,038 --> 00:12:20,739
GENOMES THROUGHOUT THE

266
00:12:20,806 --> 00:12:22,942
GENERATIONS. BUT GERM CELLS COME

267
00:12:23,008 --> 00:12:25,511
IN DIFFERENT FLAVORS. AS Y'ALL

268
00:12:25,578 --> 00:12:27,413
KNOW, THE FEMALE GERM CELLS

269
00:12:27,480 --> 00:12:29,782
PROVIDE MORE CYTOPLASMIC

270
00:12:29,849 --> 00:12:31,550
COMPONENTS AND ORGANELLES AND

271
00:12:31,617 --> 00:12:34,320
THE FEMALE GERM CELLS

272
00:12:34,386 --> 00:12:37,790
PREDOMINANT SOURCE OF ANI PLOIDY

273
00:12:37,857 --> 00:12:42,194
ON THE GENOME CELL, AANYPLOIDY,

274
00:12:42,261 --> 00:12:43,996
TRISOMY 21, THE BIGGEST RISK

275
00:12:44,063 --> 00:12:48,834
FACTOR IS MATERNAL AGE. MANY

276
00:12:48,901 --> 00:12:50,903
GERM CELLS DO SOMETHING

277
00:12:50,970 --> 00:12:52,304
FUNDAMENTALLY DIFFERENT. MALE

278
00:12:52,371 --> 00:12:54,373
GERM CELLS ARE IN FACT THE

279
00:12:54,440 --> 00:12:56,075
PREDOMINANT SOURCE OF MUTATIONS.

280
00:12:56,142 --> 00:13:00,079
BOTH SINGLE NUCLEOTIDE STRUCTURE

281
00:13:00,146 --> 00:13:02,214
VARIANCE 80% WHICH ARE GENERATED

282
00:13:02,281 --> 00:13:03,616
IN H THE MALE GERM LINE, NOT THE

283
00:13:03,682 --> 00:13:05,417
FEMALE GERM LINE. SO THEY ARE

284
00:13:05,484 --> 00:13:08,988
FUNDAMENTAL DIFFERENCES.  WE ARE

285
00:13:09,054 --> 00:13:11,857
INTERESTED IN UNDERSTANDING THE

286
00:13:11,924 --> 00:13:13,826
CONSEQUENCES OF PATERNAL DNA

287
00:13:13,893 --> 00:13:17,229
DAMAGE BECAUSE THE PATERNAL

288
00:13:17,296 --> 00:13:18,497
GENOME IS SUCH AN IMPORTANT

289
00:13:18,564 --> 00:13:19,865
SOURCE FOR GENETIC ABOUT BEAR

290
00:13:19,932 --> 00:13:22,568
RATIONS. THIS PROJECT WAS

291
00:13:22,635 --> 00:13:25,738
PIONEERED BY CR 1 AND

292
00:13:25,804 --> 00:13:28,707
BIOINFORMATICS ANALYSIS WAS DONE

293
00:13:28,774 --> 00:13:31,710
BY DAVID (INAUDIBLE) IN THE LAB.

294
00:13:31,777 --> 00:13:33,546
THAT'S SOME HINTS THAT COULD BE

295
00:13:33,612 --> 00:13:35,080
CONSEQUENCES OF PATERNAL DNA

296
00:13:35,147 --> 00:13:37,950
DAMAGE. FOR EXAMPLE, THE RISK OF

297
00:13:38,017 --> 00:13:39,051
NEURODEVELOPMENTAL DISORDERS

298
00:13:39,118 --> 00:13:41,754
SUCH AS AUTISM AND SCHIZOPHRENIA

299
00:13:41,820 --> 00:13:44,356
IS LINKED TO CHROMOSOME

300
00:13:44,423 --> 00:13:45,558
STRUCTURE BOUNDS. THE LAST

301
00:13:45,624 --> 00:13:49,094
DECADES WE HAVE SEEN A STEEP

302
00:13:49,161 --> 00:13:53,632
INCREASE IN AUTISM CASES THAT

303
00:13:53,699 --> 00:13:55,534
ARE FOR WHICH THE BIGGEST RISK

304
00:13:55,601 --> 00:13:58,871
FACTOR IS THE PATERNAL AGE.

305
00:13:58,938 --> 00:14:03,375
THERE IS A LONG DEBATE A DECADE

306
00:14:03,442 --> 00:14:05,077
OLD DEBATE WHETHER THERE IS

307
00:14:05,144 --> 00:14:08,981
INCREASED LEUKEMIA RISK IN

308
00:14:09,048 --> 00:14:13,652
RADIATION EXPOSED PRODUCTS. MOST

309
00:14:13,719 --> 00:14:15,988
RECENTLY, THE UK GENOME PROJECT

310
00:14:16,055 --> 00:14:18,524
FOUND RARE CASES OF HYPERMUTATED

311
00:14:18,591 --> 00:14:21,927
GERM LINE GENOMES. ,

312
00:14:21,994 --> 00:14:22,861
HYPERMUTATED GERM LINE GENOMES

313
00:14:22,928 --> 00:14:26,498
IN HUMANS WERE ASSOCIATED WITH

314
00:14:26,565 --> 00:14:27,866
GENOTOXIC INFLUENCE OF THE

315
00:14:27,933 --> 00:14:29,401
FATHER, AT CLOSE TO CONCEPTION

316
00:14:29,468 --> 00:14:32,838
SO FOR EXAMPLE, WHEN THE FATHER

317
00:14:32,905 --> 00:14:34,840
UNDERWENT CHEMOTHERAPY.  SO

318
00:14:34,907 --> 00:14:37,810
THERE COULD BE SOMETHING TO IT.

319
00:14:37,876 --> 00:14:40,813
TO RESOLVE THIS ISSUE, WHAT

320
00:14:40,879 --> 00:14:43,282
CONSEQUENCES PATERNAL DNA DAMAGE

321
00:14:43,349 --> 00:14:44,683
COULD HAVE? WE TURN TO C

322
00:14:44,750 --> 00:14:46,485
ELEGANS.  THOSE FAMILIAR WITH

323
00:14:46,552 --> 00:14:47,720
THE C ELEGANS SYSTEM MIGHT BE

324
00:14:47,786 --> 00:14:51,624
SURPRISED THAT WE ARE STUDYING

325
00:14:51,690 --> 00:14:52,424
CONTRIBUTION OF DIFFERENT SEXES

326
00:14:52,491 --> 00:14:57,563
IN AN ANIMAL THAT IS NORMALLY

327
00:14:57,630 --> 00:14:58,163
HER HALF INDICT. WE CAN TAKE

328
00:14:58,230 --> 00:14:59,632
ADVANTAGE OF SEX DETERMINATION

329
00:14:59,698 --> 00:15:01,967
MUTANTS FEMALE ONLY GERM LINE

330
00:15:02,034 --> 00:15:06,038
MUTANTS, WHERE WE CAN HAVE

331
00:15:06,105 --> 00:15:07,506
SEPARATE SEX FEMALES WITH THE

332
00:15:07,573 --> 00:15:09,008
FEMALE GERM LINE AND NORMAL

333
00:15:09,074 --> 00:15:10,909
MALES WITH A MALE GERM LINE. WE

334
00:15:10,976 --> 00:15:14,446
DID A VERY SIMPLE EXPERIMENT. WE

335
00:15:14,513 --> 00:15:16,215
TREATED THE FEMALES WITH

336
00:15:16,282 --> 00:15:18,984
IONIZING RADIATION AND RIGHT

337
00:15:19,051 --> 00:15:21,120
AFTER THE MATE LET THEM MATE

338
00:15:21,186 --> 00:15:23,122
WITH HEALTHY MALES THEN WHEN HE

339
00:15:23,188 --> 00:15:25,257
ASK CALLED DELTA F FOR THE

340
00:15:25,324 --> 00:15:27,626
FEMALES IRRADIATED AND ASK HOW

341
00:15:27,693 --> 00:15:30,929
MUCH LETHALITY WOULD BE OBSERVED

342
00:15:30,996 --> 00:15:32,831
IN THE PROGENY? AS YOU CAN SEE

343
00:15:32,898 --> 00:15:35,467
HERE WITH INCREASES DOSESES OF

344
00:15:35,534 --> 00:15:39,438
IONIZING RADIATION THAT PROGENY

345
00:15:39,505 --> 00:15:41,240
SHOWS INCREASE LETHALITY, JUST

346
00:15:41,307 --> 00:15:43,609
AS EXPECTED. THE SURVIVES OF

347
00:15:43,676 --> 00:15:46,812
THESE ANIMALS WHICH WOULD BE THE

348
00:15:46,879 --> 00:15:49,648
DAUGHTERS, THEREFORE THE SONS WE

349
00:15:49,715 --> 00:15:51,550
THEN MADE GET HEALTHY OPPOSITE

350
00:15:51,617 --> 00:15:55,854
SEX AND AGAIN, THEN IT SAYS THE

351
00:15:55,921 --> 00:15:57,923
LETHALITY AMONG PROGENY, THEY

352
00:15:57,990 --> 00:16:03,262
WERE ON HEALTHY ENVIRONMENT. SO

353
00:16:03,329 --> 00:16:05,497
THIS IS ALL AS EXPECTED. BUT

354
00:16:05,564 --> 00:16:08,701
THEN WE IRRADIATED MALES AND

355
00:16:08,767 --> 00:16:12,905
DELTA M, WE IRRADIATED MALES AND

356
00:16:12,971 --> 00:16:15,307
MATED THEM WITH HEALTHY FEMALES,

357
00:16:15,374 --> 00:16:18,010
BUT IN THIS CASES WE OBSERVED

358
00:16:18,077 --> 00:16:20,579
NEARLY NO LETHALITY THEIR

359
00:16:20,646 --> 00:16:22,281
PROGENY THOUGH THE MALES HAD

360
00:16:22,348 --> 00:16:24,283
EXPERIENCED THE SAME DOSE OF

361
00:16:24,350 --> 00:16:30,723
RADIATION. WE THEN MADE A DOSE

362
00:16:30,789 --> 00:16:34,126
DAUGHTERS, OR SONS WITH HEALTHY

363
00:16:34,193 --> 00:16:36,662
OPPOSITE SEX. UNEXPECTEDLY WE

364
00:16:36,729 --> 00:16:40,332
THEN OBSERVE IN THEIR PROGENY

365
00:16:40,399 --> 00:16:42,434
ENORMOUSLY HIGH DEGREES OF

366
00:16:42,501 --> 00:16:45,204
LETHALITY, THIS WAS HIGHER IN

367
00:16:45,270 --> 00:16:47,906
THE OFFSPRING OF DAUGHTERS THAN

368
00:16:47,973 --> 00:16:50,476
THE OFFSPRING OF THE SONS BUT IN

369
00:16:50,542 --> 00:16:52,945
BOTH CASES WE OBSERVED IT. THE

370
00:16:53,011 --> 00:16:54,079
DIFFERENCE I CAN EXPLAIN TO YOU

371
00:16:54,146 --> 00:16:57,816
LATER ON. WE THEN ASKED WHETHER

372
00:16:57,883 --> 00:17:02,154
THERE WAS A SPECIFIC STATE IN

373
00:17:02,221 --> 00:17:03,055
SPERMATOGENESIS THAT WOULD BE

374
00:17:03,122 --> 00:17:04,323
VULNERABLE TO THE

375
00:17:04,390 --> 00:17:06,191
TRANSGENERATION OF LETHALITY. SO

376
00:17:06,258 --> 00:17:08,827
AGAIN, WE IRRADIATED THE MALES

377
00:17:08,894 --> 00:17:10,896
MATED IT DIRECTLY WITHIN THE

378
00:17:10,963 --> 00:17:13,031
HEALTHY FEMALE AND OBSERVE THE

379
00:17:13,098 --> 00:17:15,901
HIGH LEVEL OF PROGENY LETHALITY

380
00:17:15,968 --> 00:17:17,236
IN THE PROGENY OF THE DAUGHTER

381
00:17:17,302 --> 00:17:21,073
AND THE SONS.  WE CON TERMED

382
00:17:21,140 --> 00:17:25,411
THAT ALSO INDEPENDENT FEMINIZED

383
00:17:25,477 --> 00:17:27,613
MUTANTS THAT THE SAME OCCURS.

384
00:17:27,679 --> 00:17:31,250
THEN WE TOOK THIS MALE A DAY

385
00:17:31,316 --> 00:17:35,020
LATER AND MATED IT AGAIN. C

386
00:17:35,087 --> 00:17:38,123
ELEGANS LIKE HUMANS HAVE

387
00:17:38,190 --> 00:17:39,358
CONTINUOUSLY UNDERGONE

388
00:17:39,425 --> 00:17:41,827
SPERMATOGENESIS.  THEY STORE

389
00:17:41,894 --> 00:17:44,062
THEM IN EJACULATE 70% IN ONE

390
00:17:44,129 --> 00:17:46,465
MATING AND BY THIS TIME THEY

391
00:17:46,532 --> 00:17:48,634
WOULD HAVE NOW NEWLY GENERATED

392
00:17:48,700 --> 00:17:50,736
FROM STEM CELLS NEWLY GENERATED

393
00:17:50,803 --> 00:17:53,605
SPERM THEY USE ON THE SECOND DAY

394
00:17:53,672 --> 00:17:57,709
NOR THEIR MATING.  WE SEE NO

395
00:17:57,776 --> 00:17:59,044
LETHALITY IN THE OFFSPRING OF

396
00:17:59,111 --> 00:18:01,613
THE DAUGHTERS AND SONS

397
00:18:01,680 --> 00:18:03,315
SUGGESTING THAT ONLY THE MATURE

398
00:18:03,382 --> 00:18:05,684
SPERM IS VULNERABLE TO THE DNA

399
00:18:05,751 --> 00:18:11,089
DAMAGE BY THE NEWLY GENERATED.

400
00:18:11,156 --> 00:18:13,792
THEN WE ASK IF THIS ALSO HAPPENS

401
00:18:13,859 --> 00:18:18,530
IN THE HERMAPHODITE THEY SWITCH

402
00:18:18,597 --> 00:18:21,867
THE SEX OF GERM LINE, INITIALLY

403
00:18:21,934 --> 00:18:24,236
GENERATE SPERM WITH LAVA

404
00:18:24,303 --> 00:18:25,871
DEVELOPMENT, THIS THE THIRD

405
00:18:25,938 --> 00:18:27,806
STAGE THEY HAVE SPERMATOGENESIS,

406
00:18:27,873 --> 00:18:30,809
ALSO IN EARLY L 4 STAGE THE

407
00:18:30,876 --> 00:18:32,778
FINAL STAGE ONGOING

408
00:18:32,845 --> 00:18:35,347
SPERMATOGENESIS, ONE OF THE LATE

409
00:18:35,414 --> 00:18:38,584
STAGE ON SPERM MATURE NOW, WHILE

410
00:18:38,650 --> 00:18:41,553
GERM LINE NOW HAS SWITCHED TO

411
00:18:41,620 --> 00:18:45,390
PRODUCE OO CITES THAT ARE THEN

412
00:18:45,457 --> 00:18:48,827
FERTILIZED BY THE MATURE SPERM.

413
00:18:48,894 --> 00:18:51,463
ONLY IN THIS CASE WE SEE

414
00:18:51,530 --> 00:18:53,031
TRANSGENERATION LETHALITY

415
00:18:53,098 --> 00:18:56,168
FURTHER SUPPORTING ITS MATURE

416
00:18:56,235 --> 00:18:58,670
SPERM. THEN WE ASK HOW LONG

417
00:18:58,737 --> 00:19:00,906
WOULD IN BE MAINTAINED, THIS

418
00:19:00,973 --> 00:19:05,477
TRUNK GENERATION OF LETHALITY IN

419
00:19:05,544 --> 00:19:08,714
HALF INDICTS IN CONTRAST TO

420
00:19:08,780 --> 00:19:10,482
MATING OF EXPERIMENTS FROM

421
00:19:10,549 --> 00:19:11,717
HEALTHY GENOME OF OPPOSITE SEX

422
00:19:11,783 --> 00:19:15,354
BUT USING THE DAMAGED GENOME FOR

423
00:19:15,420 --> 00:19:15,954
SELF-FERTILIZATION AND

424
00:19:16,021 --> 00:19:17,956
ESSENTIALLY MAINTAINED FOREVER.

425
00:19:18,023 --> 00:19:19,525
THE FEW RARE SURVIVORS THEY GIVE

426
00:19:19,591 --> 00:19:23,161
RISE TO VERY HIGH LEVELS OF

427
00:19:23,228 --> 00:19:27,332
LETHALITY IN THE PROGENY AGAIN.

428
00:19:27,399 --> 00:19:28,700
NEXT, HAVE A LOOK WHAT HAPPENS

429
00:19:28,767 --> 00:19:30,102
TO THE DAMAGE GENOMES IN THE

430
00:19:30,168 --> 00:19:32,137
MATURE SPERM. NORMALLY MATURE

431
00:19:32,204 --> 00:19:33,005
SPERM MANY WORMS JUST LIKE

432
00:19:33,071 --> 00:19:35,974
HUMANS IS HIGHLY COMPACT. WE SEE

433
00:19:36,041 --> 00:19:38,410
THESE STRUCTURES HIGHLY

434
00:19:38,477 --> 00:19:41,013
COMPACTED DNA. AFTER IRRADIATION

435
00:19:41,079 --> 00:19:44,182
HOWEVER THE SHAPE OF THESE

436
00:19:44,249 --> 00:19:46,151
COMPACTED IS CHANGED AS IF THEY

437
00:19:46,218 --> 00:19:49,988
ARE DECOMPACTING DECONDENSING.

438
00:19:50,055 --> 00:19:50,956
NONETHELESS DESPITE THE DAMAGE

439
00:19:51,023 --> 00:19:54,893
WE INFLICT, THEY FERTILIZE AN

440
00:19:54,960 --> 00:19:56,495
EGG, FORM A ZYGOTE AND GROW UP

441
00:19:56,562 --> 00:19:58,931
TO EMBRYO OWE THEN GO TO RAPID

442
00:19:58,997 --> 00:20:01,199
ROUNDS OF CELL DIVISIONS BUT IN

443
00:20:01,266 --> 00:20:03,902
CONTRAST TO CONTROL WE SEE HERE

444
00:20:03,969 --> 00:20:06,572
FIGURES OF GENOME INSTABILITY.

445
00:20:06,638 --> 00:20:10,042
WE SEE MICRONUCLEI, WE SEE

446
00:20:10,108 --> 00:20:11,610
NON-DESTRUCTION OF DNA HERE AND

447
00:20:11,677 --> 00:20:13,412
DESPITE ALL THESE GENOME

448
00:20:13,478 --> 00:20:15,447
INSTABILITY THESE EMBRYOS GROW

449
00:20:15,514 --> 00:20:17,616
UP TO ADULT WORMS. WE LOOK HERE

450
00:20:17,683 --> 00:20:22,087
NOW AT THE STOMA OF THE PROGENY

451
00:20:22,154 --> 00:20:25,724
AND WHEREAS INTESTINAL CELLS

452
00:20:25,791 --> 00:20:27,426
EASILY VISIBLE LARGE CELL TYPES

453
00:20:27,492 --> 00:20:28,927
THEY STILL SHOW SIGNS OF GENOME

454
00:20:28,994 --> 00:20:32,731
INSTABILITY. SO AFTER

455
00:20:32,798 --> 00:20:35,367
PERPETUATING -- PERPETUAL CYCLES

456
00:20:35,434 --> 00:20:36,501
OF CELL DIVISIONS STILL THEY

457
00:20:36,568 --> 00:20:38,103
HAVE EVER ONGOING GENOME

458
00:20:38,170 --> 00:20:43,542
INSTABILITY. NOW BELOOK AT GERM

459
00:20:43,609 --> 00:20:44,977
LINE OF DAUGHTER OF IRRADIATED

460
00:20:45,043 --> 00:20:48,981
MALE. WE LOOK AT THE GERM LINE

461
00:20:49,047 --> 00:20:53,652
AND WE SEE IN THE GERM CELLS

462
00:20:53,719 --> 00:20:55,654
AGAIN OVERT SIGNS OF GENOME

463
00:20:55,721 --> 00:20:56,955
INSTABILITY, YOU SEE

464
00:20:57,022 --> 00:21:01,293
MICRONUCLEI. IN THE OO CITES, WE

465
00:21:01,360 --> 00:21:05,163
SEE OBVIOUS SIGNS AGAIN

466
00:21:05,230 --> 00:21:08,433
FRAGMENTS OF DNA, SOME HAVE

467
00:21:08,500 --> 00:21:09,835
TELOMERE, OTHERS DON'T SO

468
00:21:09,901 --> 00:21:15,107
THERE'S ONE OOCITE AND YOU SEE

469
00:21:15,173 --> 00:21:16,842
ABERRANT FIGURES OF THE

470
00:21:16,908 --> 00:21:20,512
CHROMOSOMES.  THEN WE LOOK WHAT

471
00:21:20,579 --> 00:21:23,281
HAPPENED -- WHAT HAPPENS TO THE

472
00:21:23,348 --> 00:21:25,817
SEQUENCE OF THESE PROGENIES? SO

473
00:21:25,884 --> 00:21:29,054
WE DID WHOLE GENOME SEQUENCING

474
00:21:29,121 --> 00:21:30,756
OF THE FATHERS, THE MOTHERS, THE

475
00:21:30,822 --> 00:21:32,324
SONS AND DAUGHTERS AND THIS IS

476
00:21:32,391 --> 00:21:36,428
JUST ONE EXAMPLE WED MANY MORE

477
00:21:36,495 --> 00:21:37,796
AND OBSERVE THERE ARE FUSIONS

478
00:21:37,863 --> 00:21:39,731
BETWEEN THE CHROMOSOMES. HERE

479
00:21:39,798 --> 00:21:40,866
THESE ARE FUSION SITES, THESE

480
00:21:40,932 --> 00:21:44,302
ARE EXAMPLES OF THAT, THERE ARE

481
00:21:44,369 --> 00:21:46,738
ROUGHLY THE SAME NUMBERS IN

482
00:21:46,805 --> 00:21:48,740
DAUGHTERS AN SONS BUT ONLY ONE

483
00:21:48,807 --> 00:21:49,641
DIFFERENCE THAT ONLY THE

484
00:21:49,708 --> 00:21:53,211
DAUGHTERS HAVE FUSIONS THAT

485
00:21:53,278 --> 00:21:54,946
INVOLVE THE X CHROMOSOME. WHY IS

486
00:21:55,013 --> 00:21:58,917
THAT? BECAUSE ONLY THE DAUGHTERS

487
00:21:58,984 --> 00:22:01,153
FEMALES XX SO THEY HAVE ONE X

488
00:22:01,219 --> 00:22:02,154
CHROMOSOME FROM THE FATHER AND

489
00:22:02,220 --> 00:22:03,555
THE OTHER ONE FROM THE MOTHER

490
00:22:03,622 --> 00:22:08,193
WHILE THE MALES XO ONLY HAVE X

491
00:22:08,260 --> 00:22:10,295
CHROMOSOME FROM THE MOTHER. THIS

492
00:22:10,362 --> 00:22:13,999
TELLS US THE FUSIONS ARE

493
00:22:14,066 --> 00:22:15,567
GENERATED WITHIN THE PATERNAL

494
00:22:15,634 --> 00:22:17,703
GENOME. NOW WE LOOKED AT THE

495
00:22:17,769 --> 00:22:21,073
FUSION SITES AND ASKED IS THERE

496
00:22:21,139 --> 00:22:22,340
ANY CERTAIN SPECIFIC PROPERTY

497
00:22:22,407 --> 00:22:25,077
THAT WOULD TELL US WHAT IS GOING

498
00:22:25,143 --> 00:22:29,114
ON HERE? WE FIND THAT IN THIS

499
00:22:29,181 --> 00:22:31,083
FUSION SITE THERE IS A SPECIFIC

500
00:22:31,149 --> 00:22:33,385
ENRICHMENT OF ONE NUCLEOTIDE

501
00:22:33,452 --> 00:22:38,290
MICROHOMOLOGY. IN C ELEGANS ONE

502
00:22:38,356 --> 00:22:40,625
NUCLEOTIDE MICROHOMOLOGY AT HUGH

503
00:22:40,692 --> 00:22:44,129
SITE IS A TYPICAL HALLMARK OF

504
00:22:44,196 --> 00:22:45,363
REPAIR MECHANISM WHICH IS

505
00:22:45,430 --> 00:22:48,166
POLYMER RAISE MEDIATED ENJOINING

506
00:22:48,233 --> 00:22:49,735
T AND EJ. SO LET'S DO THE

507
00:22:49,801 --> 00:22:52,437
GENETICS AND FIND OUT WHETHER

508
00:22:52,504 --> 00:22:54,206
TMEJ IS INVOLVED IN GENERATING

509
00:22:54,272 --> 00:22:57,743
THESE FUSIONS. SO WHAT LOOKS

510
00:22:57,809 --> 00:22:59,644
VERY BUSY HERE I WILL TAKE YOU

511
00:22:59,711 --> 00:23:02,481
SLOWLY THROUGH. SO THESE ARE

512
00:23:02,547 --> 00:23:05,417
JUST TWO DIFFERENT 60 AND 90

513
00:23:05,484 --> 00:23:06,885
GRAY DIFFERENT IRRADIATION DOSE,

514
00:23:06,952 --> 00:23:10,255
USE THE GERM LINE SO WE CAN HAVE

515
00:23:10,322 --> 00:23:12,357
SEPARATE SEX. THEN WE

516
00:23:12,424 --> 00:23:15,160
INACTIVATED BRACA 1 TO

517
00:23:15,227 --> 00:23:17,129
INACTIVATE HOMOLOGOUS

518
00:23:17,195 --> 00:23:20,265
RECOMBINATION REPAIR, WE

519
00:23:20,332 --> 00:23:21,833
ACTIVATE NON-HOMOLOGOUS

520
00:23:21,900 --> 00:23:24,369
ENJOINING OR WE ELIMINATE TMEJ

521
00:23:24,436 --> 00:23:29,307
BY MUTATING THE POLYMERASE Q 1.

522
00:23:29,374 --> 00:23:33,879
THEN WE OBSERVED THESE Q 1 TMEJ

523
00:23:33,945 --> 00:23:36,348
DEFICIENT ANIMALS HAVE BEEN

524
00:23:36,414 --> 00:23:38,016
ENORMOUSLY HIGH SENSITIVITY TO

525
00:23:38,083 --> 00:23:40,318
IONIZING RADIATION. THE PROGENY

526
00:23:40,385 --> 00:23:43,955
DIRECTLY OF THIS MALE IS

527
00:23:44,022 --> 00:23:46,792
COMPLETELY LETHAL. FEW ANIMALS

528
00:23:46,858 --> 00:23:49,161
GROW UP THEY DON'T DEVELOP A

529
00:23:49,227 --> 00:23:51,963
GERM LINE SO IT IS TMEJ IS

530
00:23:52,030 --> 00:23:53,398
ABSOLUTELY ESSENTIAL TO REPAIR

531
00:23:53,465 --> 00:24:00,772
THE PATERNAL DNA DAMAGE. TMEJ

532
00:24:00,839 --> 00:24:02,374
HAS SOME CONTRIBUTION, THERE'S

533
00:24:02,440 --> 00:24:07,078
HERE YOU SEE INCREASED LETH

534
00:24:07,145 --> 00:24:09,614
LETHALITY, HERE IN THE PROGENY

535
00:24:09,681 --> 00:24:13,485
OF THE SON SO IT PLAYS SOME ROLE

536
00:24:13,552 --> 00:24:14,820
NOT AS PROM INNOCENT AS T

537
00:24:14,886 --> 00:24:16,955
MENTIONEREJ BUT HOMOLOGOUS

538
00:24:17,022 --> 00:24:19,958
RECOMBINATION REPAIR YOU WOULD

539
00:24:20,025 --> 00:24:22,427
EXPECT A MAJOR ROLE IN GERM

540
00:24:22,494 --> 00:24:26,164
LINE, IS DISPENSABLE. THEN WE

541
00:24:26,231 --> 00:24:30,068
ASKED WHO REPAIRS? IS IT FATHER

542
00:24:30,135 --> 00:24:31,636
THAT EXPERIENCE IT IS DNA DAMAGE

543
00:24:31,703 --> 00:24:40,345
OR THE MOTHER? WHERE SO WE SINCE

544
00:24:40,412 --> 00:24:43,415
SEPARATED THE POLYQ 1 MUTANT.

545
00:24:43,481 --> 00:24:46,084
BOTH PARENTS ARE HAVE A MUTATION

546
00:24:46,151 --> 00:24:48,520
IN -- WE OBSERVE THAT WHEN THE

547
00:24:48,587 --> 00:24:50,288
MALES ARE IRRADIATED AND MATED

548
00:24:50,355 --> 00:24:52,123
THAT THERE IS A VERY HIGH DEGREE

549
00:24:52,190 --> 00:24:57,028
OF LETHALITY. IN THE DIRECT

550
00:24:57,095 --> 00:24:58,897
PROGENY. WHEN HOWEVER THE FATHER

551
00:24:58,964 --> 00:25:03,635
WHO WE APPLIED THE DNA DAMAGE TO

552
00:25:03,702 --> 00:25:05,303
IS PARQ 1 MUTATED WE SEE NO

553
00:25:05,370 --> 00:25:08,240
EFFECT. WHENEVER HOWEVER THE

554
00:25:08,306 --> 00:25:11,676
MOTHER HAS NO TMEJ WE SEE THE

555
00:25:11,743 --> 00:25:13,612
SAME DEGREE OF LETHALITY IN THE

556
00:25:13,678 --> 00:25:16,314
PROGENY. SUGGESTING THAT THE

557
00:25:16,381 --> 00:25:19,251
MOTHER, MATERNALLY PROVIDED TMEJ

558
00:25:19,317 --> 00:25:24,522
IS REPAIRING THE PATERNAL DNA.

559
00:25:24,589 --> 00:25:27,058
NOW YOU MIGHT WONDER USING

560
00:25:27,125 --> 00:25:28,326
IONIZING RADIATION WORKING IN

561
00:25:28,393 --> 00:25:29,895
THE LAB DOES THIS HAPPEN IN

562
00:25:29,961 --> 00:25:33,565
NATURE? SO WE USE 540 NATURAL

563
00:25:33,632 --> 00:25:37,068
VARIANTS OF C ELEGANS THAT HAVE

564
00:25:37,135 --> 00:25:38,570
BEEN SEPARATEED FROM THE LEFT

565
00:25:38,637 --> 00:25:39,838
STRING FOR MILLIONS OF YEARS AND

566
00:25:39,905 --> 00:25:41,072
ASKED WHETHER IN THE STRUCTURE

567
00:25:41,139 --> 00:25:47,012
VARIANTS WE FINDS IN THESE MATES

568
00:25:47,078 --> 00:25:49,948
IS THERE THE SAME MICROHOMOLOGY

569
00:25:50,015 --> 00:25:52,450
PRESENTED, WE HAVE EXPECTED

570
00:25:52,517 --> 00:25:53,818
PERCENTAGE AND WE HAVE A MUCH

571
00:25:53,885 --> 00:25:56,688
HIGHER ENRICHMENT OF THE

572
00:25:56,755 --> 00:25:59,190
MICROHOMOLOHOMOLOGY. WE FIND AGE

573
00:25:59,257 --> 00:26:01,626
ONE NUCLEOTIDE MICROHOMOLOGY

574
00:26:01,693 --> 00:26:04,095
TYPICALLY HALLMARK OF TMEJ. THEN

575
00:26:04,162 --> 00:26:05,597
WE LOOK AT MUTATION ACCUMULATION

576
00:26:05,664 --> 00:26:07,699
LINES SO THIS IS IN THE LAB

577
00:26:07,766 --> 00:26:08,934
WHERE IN EACH GENERATION YOU

578
00:26:09,000 --> 00:26:11,136
PICK A WORM AND THEN LET IT

579
00:26:11,202 --> 00:26:12,604
ACCUMULATE RANDOM MUTATION

580
00:26:12,671 --> 00:26:14,739
STRUCTURE VARIANTS IN THIS CASE,

581
00:26:14,806 --> 00:26:17,075
OVER 40 GENERATIONS. AGAIN WE

582
00:26:17,142 --> 00:26:19,477
SEE A STRONG ENRICHMENT OF THE

583
00:26:19,544 --> 00:26:22,447
TMEJ AMONG THE STRUCTURE

584
00:26:22,514 --> 00:26:24,215
VARIANTS. NOW YOU MIGHT WONDER

585
00:26:24,282 --> 00:26:27,285
I'M NOT A WORM, DOES IT HAVE ANY

586
00:26:27,352 --> 00:26:28,853
RELEVANCE FOR ME AS HUMAN? WE

587
00:26:28,920 --> 00:26:33,625
TURN TO THE 1,000 GENOME PROJECT

588
00:26:33,692 --> 00:26:35,393
IN THE HUMAN GENOME SEQUENCES

589
00:26:35,460 --> 00:26:37,062
AND ASK WHETHER WE WOULD FIND

590
00:26:37,128 --> 00:26:40,031
HERE AGAIN THE TMEJ SIGNATURE

591
00:26:40,098 --> 00:26:42,567
AND WE DO, THERE IS AN OVERT

592
00:26:42,634 --> 00:26:45,704
PRESENTATION IN HUMAN IT IS TMEJ

593
00:26:45,770 --> 00:26:47,973
SIGNATURE IS 2 TO 6 NUCLEOTIDES

594
00:26:48,039 --> 00:26:50,041
IN CONTRAST TO THE ONE

595
00:26:50,108 --> 00:26:51,643
NUCLEOTIDE IN WORMS. SLIGHT

596
00:26:51,710 --> 00:26:52,410
MECHANISTIC DIFFERENCE.

597
00:26:52,477 --> 00:26:55,613
THEN WE ASKED WHETHER ALSO IN

598
00:26:55,680 --> 00:26:58,383
HUMAN THIS IS IS AN EFFECT OF

599
00:26:58,450 --> 00:27:00,919
THE PATERNAL GENOME. FOR THIS WE

600
00:27:00,986 --> 00:27:02,821
TURN TO THE TRIO STUDY WHERE IS

601
00:27:02,887 --> 00:27:05,023
THEY SEQUENCE MOTHER FATHER

602
00:27:05,090 --> 00:27:07,759
CHILD, AND WE SEE ONLY IN THE

603
00:27:07,826 --> 00:27:09,928
GENOMES THAT COME FROM THE

604
00:27:09,995 --> 00:27:12,530
FATHERS AN ENORMOUS ENRICHMENT

605
00:27:12,597 --> 00:27:15,233
OF THE MICROHOMOLOGY. THAT YOU

606
00:27:15,300 --> 00:27:19,537
CAN SEE HERE THIS IS THE TYPICAL

607
00:27:19,604 --> 00:27:20,638
TMEJ SIGNATURE, MICROHOMOLOGY

608
00:27:20,705 --> 00:27:23,074
DIRECTED REPAIR IN HUMANS.

609
00:27:23,141 --> 00:27:25,243
INDICATED THAT WHAT WE OBSERVE

610
00:27:25,310 --> 00:27:27,712
HERE C ELEGANS IS OCCURRING IN

611
00:27:27,779 --> 00:27:29,481
NATURE, AND IT IS OCCURRING

612
00:27:29,547 --> 00:27:32,350
NATURALLY IN THE HUMAN

613
00:27:32,417 --> 00:27:35,353
POPULATION, PARTICULAR --

614
00:27:35,420 --> 00:27:38,356
SPECIFICALLY IN THE FARMS. WHAT

615
00:27:38,423 --> 00:27:40,358
IS THE MECHANISM BEHIND THIS? WE

616
00:27:40,425 --> 00:27:42,327
TURN TO A DISCOVERY APPROACH

617
00:27:42,394 --> 00:27:44,996
WHERE WE JUST DID PROTEOMICS OF

618
00:27:45,063 --> 00:27:47,999
PROGENY IRRADIATED AND WE SEE

619
00:27:48,066 --> 00:27:50,869
STRONG INDUCTIONS OF THE PROTEIN

620
00:27:50,935 --> 00:27:55,273
DNA COMPLEXES NUCLEOSOME

621
00:27:55,340 --> 00:27:57,342
ASSEMBLY IN SHORT HISTONES.

622
00:27:57,409 --> 00:28:00,178
AMONG THE HISTOSTONES WE SEE

623
00:28:00,245 --> 00:28:03,181
ENORMOUS INDUCTIONS OF HISTONE H

624
00:28:03,248 --> 00:28:06,851
1, H 1 IS HISTONE AND HIGH

625
00:28:06,918 --> 00:28:10,455
LEVELS OF H 1 ASSOCIATED WITH

626
00:28:10,522 --> 00:28:11,990
HETERO CHROMETYIZATION BECAUSE

627
00:28:12,057 --> 00:28:14,225
THEY INCREASE THE COMPACTION OF

628
00:28:14,292 --> 00:28:21,066
THE THE DNA. HISTONE H 1

629
00:28:21,132 --> 00:28:22,834
RESPONSIBLE FOR THIS

630
00:28:22,901 --> 00:28:24,235
TRANSGENERATION OF LETHALITY?

631
00:28:24,302 --> 00:28:30,241
WHAT WE DO HERE IS WE NOW

632
00:28:30,308 --> 00:28:31,109
ELIMINATE NON-CERTAIN SUB UNIT

633
00:28:31,176 --> 00:28:35,146
OF HISTONE H 1 CALLED HIS 24 AND

634
00:28:35,213 --> 00:28:37,248
PROGENY OF DAUGHTERS AND SON WE

635
00:28:37,315 --> 00:28:39,084
SEE REVERSAL OF THE

636
00:28:39,150 --> 00:28:40,618
TRANSGENERATION LETHALITY.

637
00:28:40,685 --> 00:28:43,288
INDICATING INDEED THE HIGH H 1

638
00:28:43,354 --> 00:28:44,355
INDUCTION OF H 1 LINKER IS

639
00:28:44,422 --> 00:28:49,227
RESPONSIBLE.  I TOLD YOU THAT

640
00:28:49,294 --> 00:28:53,264
HIGH H 1 LINKER LEVELS WERE

641
00:28:53,331 --> 00:28:56,034
LINKED TO HETERO CHROMATIN

642
00:28:56,101 --> 00:28:57,502
FORMATION. WE LOOK HERE AT

643
00:28:57,569 --> 00:29:01,773
MARKER OF HETERO CHROMATIN

644
00:29:01,840 --> 00:29:04,642
DIMETHYLATION THAT IS NORMALLY

645
00:29:04,709 --> 00:29:05,877
VERY, VERY LOW PRESENT IN THE

646
00:29:05,944 --> 00:29:08,446
GERM LINE. HERE THE GERM LINE OF

647
00:29:08,513 --> 00:29:09,914
THE DAUGHTERS OF IRRADIATED

648
00:29:09,981 --> 00:29:12,317
FATHERS, WE SEE A STRONG

649
00:29:12,383 --> 00:29:13,785
INDUCTIONS OF THE HETERO

650
00:29:13,852 --> 00:29:16,154
CHROMATIN MARK. THIS IS A

651
00:29:16,221 --> 00:29:22,427
CONSEQUENCE OF H 1 LINKER, HS 24

652
00:29:22,494 --> 00:29:23,828
KNOCK DOWN, THAT PREVENTS

653
00:29:23,895 --> 00:29:25,830
FORMATION OF THE HETERO

654
00:29:25,897 --> 00:29:28,399
CHROMATIN AS WELL AS THE PROTEIN

655
00:29:28,466 --> 00:29:30,135
H 1 SAME EFFECT. THIS IS TRUE

656
00:29:30,201 --> 00:29:31,536
FOR THE DAUGHTERS AS WELL AS FOR

657
00:29:31,603 --> 00:29:34,205
THE SONS. NORMALLY IN THE MALE

658
00:29:34,272 --> 00:29:37,375
ONLY THE X CHROMOSOME IS HETERO

659
00:29:37,442 --> 00:29:39,911
CHROMETIZE, HERE YOU SEE HETERO

660
00:29:39,978 --> 00:29:41,479
CHROMATIN ALL OVER THE GENOMES.

661
00:29:41,546 --> 00:29:48,319
THIS IS REVERTED IN HIS 21. WHAT

662
00:29:48,386 --> 00:29:52,223
DOES HETERO CHROMATIN DO IN THE

663
00:29:52,290 --> 00:29:55,026
GENOME AND DNA REPAIR? HETERO --

664
00:29:55,093 --> 00:29:57,195
STRONG HETERO CHROMETYIZATION IS

665
00:29:57,262 --> 00:29:59,697
KNOWN TO PREVENT ACCESS TO

666
00:29:59,764 --> 00:30:00,932
HIGHLY EFFICIENT REPAIR

667
00:30:00,999 --> 00:30:02,934
MECHANISM SUCH AS HOMOLOGOUS

668
00:30:03,001 --> 00:30:06,070
RECOMBINATION REPAIR. NORMALLY

669
00:30:06,137 --> 00:30:08,740
IN THE GAMMA MUTAGENESIS IN THE

670
00:30:08,806 --> 00:30:10,141
ONGOING GERM LINE GENERATION IN

671
00:30:10,208 --> 00:30:14,712
FEMALES AND MALES, HOMOLOGOUS

672
00:30:14,779 --> 00:30:15,346
RECOMBINATION REPAIR IS

673
00:30:15,413 --> 00:30:18,917
IMPROVED.  DESPITE THE VERY HIGH

674
00:30:18,983 --> 00:30:21,819
LETHALITY OF THE PROGENIES OF

675
00:30:21,886 --> 00:30:23,521
THESE DAUGHTERS AND SONS OF

676
00:30:23,588 --> 00:30:27,192
IRRIDIATED FATHERS WE SEE LITTLE

677
00:30:27,258 --> 00:30:31,029
ENGAGEMENT OF RAD 51 MARKER FOR

678
00:30:31,095 --> 00:30:32,597
RECOMBINATION REPAIR.  WHEN WE

679
00:30:32,664 --> 00:30:35,567
KNOCK DOWN H ISHS 24 HPL 1 WE

680
00:30:35,633 --> 00:30:38,303
SEE STRONG ENGAGEMENT OF

681
00:30:38,369 --> 00:30:40,872
HOMOLOGOUS RECOMBINATION WE

682
00:30:40,939 --> 00:30:43,308
HYPOTHESIZE MIGHT RESOLVE THE

683
00:30:43,374 --> 00:30:45,310
TRANSGENERATION LETHALITY BY

684
00:30:45,376 --> 00:30:46,744
RESTORING STABLE GENOMES IN THE

685
00:30:46,811 --> 00:30:49,547
DAUGHTERS AND THE SONS. THIS IS

686
00:30:49,614 --> 00:30:51,849
INDEED THE CASE.  AGAIN, WE DO

687
00:30:51,916 --> 00:30:53,484
GENETICS. THE SLIDE LOOKS BUSY

688
00:30:53,551 --> 00:31:00,291
BUT I TAKE YOU THROUGH. MUTANTS

689
00:31:00,358 --> 00:31:02,193
MUTANT BACKGROUND, THEN WHAT WE

690
00:31:02,260 --> 00:31:04,762
DO HERE, WE LOOK AT THE PROGENY

691
00:31:04,829 --> 00:31:06,364
OF THE DAUGHTERS AND OF THE

692
00:31:06,431 --> 00:31:10,001
SONS. WE SEE AGAIN VERY HYPO

693
00:31:10,068 --> 00:31:13,104
LETHALITY IN THE PROGENIES HERE

694
00:31:13,171 --> 00:31:17,508
WHEN WE THEN TAKE OUT HIS 24 HPL

695
00:31:17,575 --> 00:31:19,177
1 WE SEE SIGNIFICANT REDUCTION

696
00:31:19,244 --> 00:31:23,748
OF THIS LETHALITY. WHEN WE THEN

697
00:31:23,815 --> 00:31:26,351
HOWEVER IN THE BACKGROUND OF

698
00:31:26,417 --> 00:31:30,088
THESE ELIMINATION OF THE HISTONE

699
00:31:30,154 --> 00:31:32,557
H 1 HETERO CHROMATIN PROTEIN,

700
00:31:32,624 --> 00:31:35,827
WHEN WE THEN TAKE OUT BRACA 1

701
00:31:35,893 --> 00:31:38,863
AND THUS PREVENT THE ENGAGEMENT

702
00:31:38,930 --> 00:31:42,066
OF HR AGAIN, THEN WE REVERT THE

703
00:31:42,133 --> 00:31:43,735
SUPPRESSION AND THEY ARE HIGHLY

704
00:31:43,801 --> 00:31:44,869
SENSITIVE AGAIN INDICATING THAT

705
00:31:44,936 --> 00:31:48,172
BY REDUCING HETERO CHROMATIN WE

706
00:31:48,239 --> 00:31:51,743
CAN GAIN ACCESS TO HR AND LET

707
00:31:51,809 --> 00:31:54,846
THEM FIX THE INHERITED GENOME

708
00:31:54,912 --> 00:31:56,047
DAMAGE. WHAT DID I SHOW YOU

709
00:31:56,114 --> 00:32:00,485
HERE? I SHOWED YOU THAT DAMAGE

710
00:32:00,551 --> 00:32:03,121
IN MATURE SPERM IS NOT REPAIRED

711
00:32:03,187 --> 00:32:06,457
LIKELY BECAUSE OF THE VERY HIGH

712
00:32:06,524 --> 00:32:08,893
COMPACTION OF CHROMATIN MANY THE

713
00:32:08,960 --> 00:32:11,429
MATURE SPERM, INSTEAD IT

714
00:32:11,496 --> 00:32:13,231
FERTILIZES AN EGG. IT IS EXPOSED

715
00:32:13,298 --> 00:32:17,335
TO MATERNALLY PROVIDED TMEJ THAT

716
00:32:17,402 --> 00:32:20,838
REPAIRS THE BRIGHT BUG PRODUCES

717
00:32:20,905 --> 00:32:23,007
STRUCTURE VARIANTS AND THEN THIS

718
00:32:23,074 --> 00:32:26,411
STRUCTURE VARIANTS GIVE RISE TO

719
00:32:26,477 --> 00:32:27,645
ONGOING GENOME STABILITY WE

720
00:32:27,712 --> 00:32:30,948
PROPOSE THIS IS DUE TO THE

721
00:32:31,015 --> 00:32:33,818
BREAKAGE CYCLE, EXACTLY WHAT

722
00:32:33,885 --> 00:32:35,520
(INAUDIBLE) OBSERVED IN MICE IN

723
00:32:35,586 --> 00:32:38,623
THE 1940s. ONGOING DNA DAMAGE

724
00:32:38,690 --> 00:32:40,558
IN THE DAUGHTERS AND THE SONS

725
00:32:40,625 --> 00:32:44,562
INCLUDING MANY THE GERM CELLS,

726
00:32:44,629 --> 00:32:47,098
WHERE THE DAMAGE DNA IS HEAVILY

727
00:32:47,165 --> 00:32:49,000
HETERO CHROMETIZED BY H 1

728
00:32:49,067 --> 00:32:50,835
LINKER. THIS PREVENTS ACCESS OF

729
00:32:50,902 --> 00:32:53,771
H -- HOMOLOGOUS RECOMBINATION

730
00:32:53,838 --> 00:32:56,741
REPAIR AND THEN GIVES RISE TO

731
00:32:56,808 --> 00:32:58,776
LETHALITY IN THE PROGENY WHICH

732
00:32:58,843 --> 00:33:02,947
CAN BE REVERTED BY RESOLVING THE

733
00:33:03,014 --> 00:33:05,516
HETERO CHROMETYIZATION AND

734
00:33:05,583 --> 00:33:08,152
ALLOWING HR. HERE WE FOUND THE

735
00:33:08,219 --> 00:33:09,821
INHERITANCE OF PATERNAL DNA

736
00:33:09,887 --> 00:33:13,991
DAMAGE BY HISTONE DNA REPAIR

737
00:33:14,058 --> 00:33:16,361
RESTRICTION THE DAMAGE SPERM

738
00:33:16,427 --> 00:33:18,830
GENOME INSTABILITY OFFSPRING AN

739
00:33:18,896 --> 00:33:19,897
TRANSGENERATIONALLY THAT WILLTY.

740
00:33:19,964 --> 00:33:22,633
MATERNAL TMEJ IS MAJOR REPAIR

741
00:33:22,700 --> 00:33:24,335
MECHANISM FOR PATERNAL DNA

742
00:33:24,402 --> 00:33:26,304
DAMAGE BUT LEADS TO CHROMOSOME

743
00:33:26,371 --> 00:33:28,873
REFUSION. PATERNALLY INHERITED

744
00:33:28,940 --> 00:33:30,108
STRUCTURE VARIANTS IN HUMANS

745
00:33:30,174 --> 00:33:32,443
CARRY THE SAME TMEJ SIGNATURE

746
00:33:32,510 --> 00:33:34,779
SUGGESTING THIS IS A HIGHLY

747
00:33:34,846 --> 00:33:37,215
CONSERVED MECHANISM. THE H 1

748
00:33:37,281 --> 00:33:38,983
LINKER MEDIATES HETERO CHROME

749
00:33:39,050 --> 00:33:41,853
TIP FORMATION AND PREVENTS

750
00:33:41,919 --> 00:33:43,755
ACCESS OF HOMOLOGOUS

751
00:33:43,821 --> 00:33:47,358
RECOMBINATION OF THE OFF

752
00:33:47,425 --> 00:33:47,959
SPRIEST. THE TRANSGENERATIONAL

753
00:33:48,025 --> 00:33:50,528
DNA DAMAGE CAN BE REPAIRED

754
00:33:50,595 --> 00:33:52,430
UPONNEDLY LESION OF H 1 LINKER

755
00:33:52,497 --> 00:33:55,500
HIS-24 THAT ALLOWS HOMOLOGOUS

756
00:33:55,566 --> 00:33:57,335
RECOMBINATION REPAIR ACCESS.

757
00:33:57,402 --> 00:33:59,537
THUS WE FIND UNDERPINNINGS OF

758
00:33:59,604 --> 00:34:02,740
GERM LINE HYPERMUTATION IN

759
00:34:02,807 --> 00:34:04,609
SPERM. NOW I WANT TO COME BACK

760
00:34:04,675 --> 00:34:08,679
FOR THE LAST FEW MINUTES OF THIS

761
00:34:08,746 --> 00:34:11,115
TALK TO OUR ORIGINAL THOUGHTS

762
00:34:11,182 --> 00:34:12,717
ABOUT THE DISTINCTIONS BETWEEN

763
00:34:12,784 --> 00:34:14,318
THE GERM LINE WITH THE

764
00:34:14,385 --> 00:34:15,753
INDEFINITE GERM LINE MAINTENANCE

765
00:34:15,820 --> 00:34:17,455
AND THE STOMA. DESPITE WHAT I

766
00:34:17,522 --> 00:34:19,457
JUST SHOWED YOU THAT THERE ARE

767
00:34:19,524 --> 00:34:23,561
GERM LINE MUTATIONS OTHERWISE WE

768
00:34:23,628 --> 00:34:24,695
WOULDN'T HAVE (INAUDIBLE) AS

769
00:34:24,762 --> 00:34:26,631
HUMANS THE SOMATIC MUTATION

770
00:34:26,697 --> 00:34:28,633
RATES ARE MORE THAN ORDER OF

771
00:34:28,699 --> 00:34:30,168
MAGNITUDE HIGHER THAN THE GERM

772
00:34:30,234 --> 00:34:32,603
LINE MUTATION RATES.  GENERALLY

773
00:34:32,670 --> 00:34:37,141
GERM LINES ARE FAR BETTER AT

774
00:34:37,208 --> 00:34:40,778
REPAIRING DNA THAN THE STOMA. SO

775
00:34:40,845 --> 00:34:42,647
ARE THERE MECHANISMS THAT

776
00:34:42,713 --> 00:34:47,218
RESTRICT SOMATIC DNA REPAIR?

777
00:34:47,285 --> 00:34:51,255
THIS COMES -- BRINGS US TO THE

778
00:34:51,322 --> 00:34:53,024
QUESTION WHETHER WE CAN ENHANCE

779
00:34:53,090 --> 00:34:55,660
CAPACITY TO DNA REPAIR BY FOR

780
00:34:55,726 --> 00:34:57,962
EXAMPLE, BRINGING THE SAME

781
00:34:58,029 --> 00:34:59,864
REPAIR CAPACITY OF A GERM LINE

782
00:34:59,931 --> 00:35:02,834
TO A SOMATIC CELL. THE PROBLEM

783
00:35:02,900 --> 00:35:04,769
SO FAR INCREASING DNA REPAIR HAS

784
00:35:04,836 --> 00:35:07,205
BEEN THAT HUNDREDS OF DISTINCT

785
00:35:07,271 --> 00:35:10,408
DAMAGE TYPES THAT SIX MAJOR DNA

786
00:35:10,475 --> 00:35:12,443
REPAIR SYSTEMS, AND MANY

787
00:35:12,510 --> 00:35:16,814
ADDITIONAL ONES ASSOCIATED FOR

788
00:35:16,881 --> 00:35:18,349
THESE DISTINCT DAMAGE TYPES AND

789
00:35:18,416 --> 00:35:20,918
THUS FAR HIGHLY SPECIFICALLY OR

790
00:35:20,985 --> 00:35:24,589
SINGLE REPAIR, GREATEST EXAMPLE

791
00:35:24,655 --> 00:35:26,123
PHOTO LYSIS COULD BE IMPROVED SO

792
00:35:26,190 --> 00:35:28,159
WE ASK THE QUESTION WHETHER

793
00:35:28,226 --> 00:35:30,027
THERE ARE MASS REGULATORS OF DNA

794
00:35:30,094 --> 00:35:34,532
REPAIR CAPACITIES.  AS I SHOWED

795
00:35:34,599 --> 00:35:38,169
YOU OUR PARADIGM THOUGHT WAS

796
00:35:38,236 --> 00:35:38,970
HERE THAT THERE COULD BE

797
00:35:39,036 --> 00:35:42,073
LIMITATION IN SOMATIC VERSUS

798
00:35:42,139 --> 00:35:43,975
GERM LINE REPAIR.  AS HUMANS A

799
00:35:44,041 --> 00:35:46,744
WAY TO COMPLICATE IT AGAIN TURN

800
00:35:46,811 --> 00:35:49,113
TO C ELEGANS WITH DISTINCT

801
00:35:49,180 --> 00:35:50,648
BETWEEN GERM LINE AT SOMA ARE

802
00:35:50,715 --> 00:35:52,583
EVIDENT AND SOME REPAIR

803
00:35:52,650 --> 00:35:55,686
MECHANISM SUCH AS HOMOLOGOUS

804
00:35:55,753 --> 00:35:59,123
RECOMBINATION GLOBAL GENOME

805
00:35:59,190 --> 00:36:00,191
NUCLEOTIDE EXCLUSIVELY PRESENT

806
00:36:00,258 --> 00:36:05,530
IN THE GERM LINE AND NOT THE

807
00:36:05,596 --> 00:36:08,866
SOMA. EXTRAORDINARY GRAD STUDENT

808
00:36:08,933 --> 00:36:10,968
(INDISCERNIBLE) IN THE LAB TOOK

809
00:36:11,035 --> 00:36:12,837
THE -- APPROACHED THIS ISSUE BY

810
00:36:12,904 --> 00:36:15,106
LOOKING NOW AT WHETHER WE COULD

811
00:36:15,172 --> 00:36:17,775
FIND COMMON REGULATORS OF DNA

812
00:36:17,842 --> 00:36:22,580
REPAIR GENES IN C ELEGANS. HE

813
00:36:22,647 --> 00:36:24,549
COMPILED ALL THE DNA DAMAGE

814
00:36:24,615 --> 00:36:26,350
RESPONSE STREAMS IN C ELEGANS

815
00:36:26,417 --> 00:36:28,252
AND ASK WHETHER IN THEIR

816
00:36:28,319 --> 00:36:30,021
PROMOTER SEQUENCE THERE COULD BE

817
00:36:30,087 --> 00:36:32,490
ANY SPECIFIC MOTIF OVER PERSON.

818
00:36:32,557 --> 00:36:34,792
T THIS APPROACH WAS MUCH EASIER

819
00:36:34,859 --> 00:36:37,795
IN C ELEGANS THAN MAMMALS

820
00:36:37,862 --> 00:36:39,163
BECAUSE PROMOTER STRUCTURE IS

821
00:36:39,230 --> 00:36:43,167
SIMPLE. HE FOUND A SEQUENCE THAT

822
00:36:43,234 --> 00:36:46,771
CDE CHR, THEY ARE BOUND BY A

823
00:36:46,837 --> 00:36:49,807
TRANSCRIPTION REPRESSER COMPLEX,

824
00:36:49,874 --> 00:36:53,444
SO CALLED DREAM COMPLEX THAT

825
00:36:53,511 --> 00:36:57,915
STANDS FOR DIMERIZATION R

826
00:36:57,982 --> 00:37:01,319
DROSOPHILA AND THEN ALSO IN C

827
00:37:01,385 --> 00:37:04,989
ELEGANS. WHERE IT IS KNOWN IN C

828
00:37:05,056 --> 00:37:06,657
ELEGANS THIS DREAM COMPLEX IS

829
00:37:06,724 --> 00:37:08,225
SPECIFICALLY IN SOMATIC CELLS

830
00:37:08,292 --> 00:37:10,861
BUT NOT IN THE GERM LINE. SO

831
00:37:10,928 --> 00:37:12,830
HYPOTHESIS WAS THAT THIS DREAM

832
00:37:12,897 --> 00:37:14,298
COMPLEX COULD BIND PROMOTER OF

833
00:37:14,365 --> 00:37:17,001
DNA REPAIR GENES AND REPRESS

834
00:37:17,068 --> 00:37:21,172
EXPRESSION.  TO TEST WHETHER

835
00:37:21,238 --> 00:37:24,742
DREAM MUTANTS COULD THEN CHANGE

836
00:37:24,809 --> 00:37:26,811
RESISTANCE TO DNA DAMAGE, WE

837
00:37:26,877 --> 00:37:28,879
PERFORMED DEVELOPMENTAL ASSAY.

838
00:37:28,946 --> 00:37:31,182
WE TOOK NOW, WE ARE IN THE SOMA

839
00:37:31,248 --> 00:37:33,784
NOW, WE ARE LOOKING AT L 1 WORMS

840
00:37:33,851 --> 00:37:37,254
THIS IS THE FIRST LARVA STATE

841
00:37:37,321 --> 00:37:39,190
WHERE 90% CELLS ALREADY

842
00:37:39,256 --> 00:37:40,324
TERMINALLY DIFFERENTIATED AND

843
00:37:40,391 --> 00:37:43,794
THEN JUST GROW IN SIZE TO FORM

844
00:37:43,861 --> 00:37:46,731
ADULT ELEMENTS THROUGH THE L 1 L

845
00:37:46,797 --> 00:37:51,602
2, L 3 L 4 LARVA STAGES. SO WE

846
00:37:51,669 --> 00:37:54,038
SAID 48 HOURS LATER THE WORMS

847
00:37:54,105 --> 00:37:58,242
HAVE GROWN UP TO YOUNG ADULTS,

848
00:37:58,309 --> 00:38:00,811
ALL TREATED THE ANIMALS WITH DNA

849
00:38:00,878 --> 00:38:01,779
DAMAGE WITH (INAUDIBLE) IN THIS

850
00:38:01,846 --> 00:38:03,881
CASE AND ASK HOW MUCH DELAY

851
00:38:03,948 --> 00:38:05,082
WOULD THERE BE BY THE DNA

852
00:38:05,149 --> 00:38:09,453
DAMAGE. SO HERE WE SEE ABOUT IN

853
00:38:09,520 --> 00:38:10,888
WILD TYPE ALMOST ALL THE ANIMALS

854
00:38:10,955 --> 00:38:15,259
ARE STILL IN THE L 1 OR L 2

855
00:38:15,326 --> 00:38:18,262
LARVA STAGE, DELAYED BUT

856
00:38:18,329 --> 00:38:21,365
MUTATIONS THAT ABROGATE DREAM

857
00:38:21,432 --> 00:38:26,671
FUNCTION IN 52 DPR 1 DIFFERENT

858
00:38:26,737 --> 00:38:28,906
SUBUNITS, OR CONFIRM RESISTANCE

859
00:38:28,973 --> 00:38:30,908
TO DNA DAMAGE, NOW THE ANIMALS

860
00:38:30,975 --> 00:38:32,543
CAN GROW BETTER THAN WILD TYPE.

861
00:38:32,610 --> 00:38:35,513
THIS IS A BONA FIDE FUNCTION OF

862
00:38:35,579 --> 00:38:36,847
DREAM BECAUSE WHEN WE TAKE

863
00:38:36,914 --> 00:38:39,850
SINGLE MUTANTS, THEIR RESISTANCE

864
00:38:39,917 --> 00:38:41,752
HERE PROFICIENCY IN GROWING IN

865
00:38:41,819 --> 00:38:44,121
CONTRAST TO WILD TYPE IS THE

866
00:38:44,188 --> 00:38:48,926
SAME IN THE GENETIC -- IN

867
00:38:48,993 --> 00:38:51,729
ADULTHOOD THERE IS ONE BIG

868
00:38:51,796 --> 00:38:52,496
IMPORTANT DIFFERENCE BETWEEN

869
00:38:52,563 --> 00:38:54,965
WORMS AND HUMANS, I SHOWED YOU A

870
00:38:55,032 --> 00:38:56,867
HUMAN, ONE DNA REPAIR IS

871
00:38:56,934 --> 00:38:58,969
SUFFICIENT TO ACCELERATE AGENING

872
00:38:59,036 --> 00:39:01,205
THE SIMPLE NEMATODE, ONLY THREE

873
00:39:01,272 --> 00:39:02,673
WEEKS WE NEED TO APPLY DNA

874
00:39:02,740 --> 00:39:05,342
DAMAGE TO ACCELERATE AGE, WE DO

875
00:39:05,409 --> 00:39:06,777
THIS HERE IN THE SOLID LINES

876
00:39:06,844 --> 00:39:10,181
WHERE WE APPLY IN YOUNG

877
00:39:10,247 --> 00:39:12,283
ADULTHOOD AND THEY ARE SHORT

878
00:39:12,349 --> 00:39:14,852
LIVED BUT LIFE SPAN CONDITIONS

879
00:39:14,919 --> 00:39:16,320
OF DNA DAMAGE SIGNIFICANTLY

880
00:39:16,387 --> 00:39:18,189
EXTENDED BY DIFFERENT MUTATIONS

881
00:39:18,255 --> 00:39:23,294
OF THE DREAM COMPLEX.  DO THEY

882
00:39:23,360 --> 00:39:27,264
REPAIR? IF YOU REINDUCE DIMER

883
00:39:27,331 --> 00:39:29,200
PYRIMIDINE DIMERS WE HAVE

884
00:39:29,266 --> 00:39:30,568
SIGNIFICANT ADVANTAGE THAT WE

885
00:39:30,634 --> 00:39:34,171
CAN MEASURE THE DIMERS THE

886
00:39:34,238 --> 00:39:36,340
DAMAGE WITH SPECIFIC MONOCLONAL

887
00:39:36,407 --> 00:39:38,542
ANTIBODY. WE DO THIS HERE IN THE

888
00:39:38,609 --> 00:39:42,446
SLOT PLOT WHERE YOU SEE VERY

889
00:39:42,513 --> 00:39:45,349
INFLECTION IMMEDIATELY AFTER AND

890
00:39:45,416 --> 00:39:47,384
THEY GET SLOWLY REPAIRED IN WILD

891
00:39:47,451 --> 00:39:50,254
TYPE BUT MORE READILY REPAIRED

892
00:39:50,321 --> 00:39:52,723
DPR 1 SO THEY REPAIR GENETICS

893
00:39:52,790 --> 00:39:57,294
ARE IMPROVED.  THIS IS IN 1

894
00:39:57,361 --> 00:39:59,330
ANIMALS WE HERE LOOK AT ADULTS

895
00:39:59,396 --> 00:40:01,465
LOOK AT THE HEAD REGION OF A

896
00:40:01,532 --> 00:40:04,502
WORM, MOST CELLS ARE NEURONS IN

897
00:40:04,568 --> 00:40:06,303
FACT. AND THEY ARE VERY, VERY

898
00:40:06,370 --> 00:40:09,607
SLOW AT REPAIRING THE CPTs. WE

899
00:40:09,673 --> 00:40:13,210
DO STAINING FOR CPTs AND LIMB

900
00:40:13,277 --> 00:40:15,780
52 MUTANTS ARE REPAIRING FAR

901
00:40:15,846 --> 00:40:20,251
SUPERIOR THAN THE WILD TYPE.

902
00:40:20,317 --> 00:40:24,622
THEN WE ASK WE FOUND THIS DREAM

903
00:40:24,688 --> 00:40:26,690
TARGET SEQUENCE IN SO MANY DNA

904
00:40:26,757 --> 00:40:30,761
REPAIR GENES, DO THEY ALSO

905
00:40:30,828 --> 00:40:32,663
REPRESS DNA REPAIR GENES IN

906
00:40:32,730 --> 00:40:36,300
GENERAL? SO HERE WE COMPARE 52

907
00:40:36,367 --> 00:40:38,202
MUTANTS WITH WILD TYPE IN RNA

908
00:40:38,269 --> 00:40:40,538
SEQ AND WE SEE CONSISTENT WITH

909
00:40:40,604 --> 00:40:42,072
MUTATING ACTIVATING

910
00:40:42,139 --> 00:40:43,707
TRANSCRIPTION REPRESSER, MANY

911
00:40:43,774 --> 00:40:46,110
GENES ARE INDUCED AND

912
00:40:46,177 --> 00:40:49,013
DEREPRESSED, AMONG THOSE REPAIR

913
00:40:49,079 --> 00:40:52,049
GENES.  WHAT IS MORE IS WE FIND

914
00:40:52,116 --> 00:40:54,785
REPAIR GENES NOW INDUCE THAT

915
00:40:54,852 --> 00:40:58,656
OPERATE IN NUCLEOTIDE REPAIR IN

916
00:40:58,722 --> 00:41:02,626
BASE SIBLING REPAIR HOMOLOGOUS

917
00:41:02,693 --> 00:41:03,894
RECOMBINATION, NON-HOMOLOGOUS

918
00:41:03,961 --> 00:41:05,996
ENJOINING SO A TRUE MASTER

919
00:41:06,063 --> 00:41:09,533
REGULATOR OF DNA REPAIR

920
00:41:09,600 --> 00:41:10,568
EXPRESSION THEN WE THOUGHT IF

921
00:41:10,634 --> 00:41:12,670
THAT IS SO ANIMALS SHOULD BE

922
00:41:12,736 --> 00:41:16,740
RESISTANT TO UV DAMAGE BUT ALL

923
00:41:16,807 --> 00:41:18,375
TYPES OF DAMAGE. THIS IS WHAT WE

924
00:41:18,442 --> 00:41:21,178
DESCRIBE HERE. WE USE IONIZING

925
00:41:21,245 --> 00:41:22,179
RADIATION HIGH DOSE BECAUSE IT

926
00:41:22,246 --> 00:41:24,315
IS POST MITOTIC CELLS GROWING IN

927
00:41:24,381 --> 00:41:26,684
SIZE AND DEVELOPMENT AND WE SEE

928
00:41:26,750 --> 00:41:28,519
THAT THERE IS A SIGNIFICANT

929
00:41:28,586 --> 00:41:31,655
IMPROVEMENT RESISTANT IONIZING

930
00:41:31,722 --> 00:41:32,656
RADIATION THAT IN THIS CASE IS

931
00:41:32,723 --> 00:41:34,992
TOTALLY DEPENDENT ON

932
00:41:35,059 --> 00:41:38,262
NON-HOMOLOGOUS ENJOINING. WE

933
00:41:38,329 --> 00:41:40,531
ELIMINATE NON-HOMOLOGOUS

934
00:41:40,598 --> 00:41:42,566
ENJOINING, NO SUCH DEFECT. WHEN

935
00:41:42,633 --> 00:41:45,469
WE TEST ISOLATING LESIONS FOR

936
00:41:45,536 --> 00:41:47,638
MMS WE SEE SIGNIFICANT

937
00:41:47,705 --> 00:41:49,840
RESISTANCE CONFER IL 52. WHAT IS

938
00:41:49,907 --> 00:41:52,376
INTERESTING IS WHEN WE TAKE A

939
00:41:52,443 --> 00:41:56,080
HYPERSENSITIVE POLYMERASE MUTANT

940
00:41:56,146 --> 00:41:58,582
THEN POLYH 1 MUTANTS ARE

941
00:41:58,649 --> 00:41:59,850
HYPERSENSITIVE TO ISOLATING

942
00:41:59,917 --> 00:42:01,619
LESION AND WE CAN SUPPRESS

943
00:42:01,685 --> 00:42:04,321
BECAUSE OTHER REPAIR MECHANISMS

944
00:42:04,388 --> 00:42:07,091
ARE -- CAN TAKE OVER BECAUSE

945
00:42:07,157 --> 00:42:10,461
THEY ARE MORE ACTIVE. ALSO

946
00:42:10,527 --> 00:42:11,629
CISPLATIN STILL IMPORTANT IN

947
00:42:11,695 --> 00:42:15,833
CHEMOTHERAPY INDUCING AN

948
00:42:15,900 --> 00:42:17,501
INTERESTING CROSS LINK IN 52

949
00:42:17,568 --> 00:42:22,373
MUTANTS SHOW RESISTANCE. HERE IS

950
00:42:22,439 --> 00:42:24,408
AN EXPERIMENT THAT GOT US REALLY

951
00:42:24,475 --> 00:42:27,211
EXCITED.  HERE INSTEAD OF THE

952
00:42:27,278 --> 00:42:30,581
POST MITOTIC L 1 LAB THEY GROW

953
00:42:30,648 --> 00:42:32,917
IN SIMILAR SIZE WE TAKE EARLY

954
00:42:32,983 --> 00:42:34,818
EMBRYOS THAT WILL ONS GO THE

955
00:42:34,885 --> 00:42:37,621
MOST RAPID ROUNDS OF REPLICATION

956
00:42:37,688 --> 00:42:41,058
AT CELL CYCLE TO FORM THEN THE L

957
00:42:41,125 --> 00:42:43,160
1 LAB.  WHEN WE HOWEVER TREAT

958
00:42:43,227 --> 00:42:45,296
THIS EARLY EMBRYO WITH IONIZING

959
00:42:45,362 --> 00:42:46,764
RADIATION THE ANIMALS DIE. SO

960
00:42:46,830 --> 00:42:50,100
WITH INCREASING ION, THE EMBRYOS

961
00:42:50,167 --> 00:42:55,306
ARE DEAD. WHEN WE HAVE A 52

962
00:42:55,372 --> 00:42:57,441
MUTANT THIS SENSITIVITY IS

963
00:42:57,508 --> 00:43:00,311
REVERSED.  THEY BECOME

964
00:43:00,377 --> 00:43:02,646
RESISTANT. THE EARLY REPAIR

965
00:43:02,713 --> 00:43:04,915
EARLY EMBRYOS IS EXECUTED BY

966
00:43:04,982 --> 00:43:06,817
HOMOLOGOUS RECOMBINATION REPAIR.

967
00:43:06,884 --> 00:43:11,055
WE ACTIVATE BRAC BARD THEN GET A

968
00:43:11,121 --> 00:43:14,124
HYPERSENSITIVITY TO IONIZING

969
00:43:14,191 --> 00:43:15,259
RADIATION JUST LIKE HUMAN

970
00:43:15,326 --> 00:43:17,394
CARRIER CELLS BUT WE CAN REVERT

971
00:43:17,461 --> 00:43:23,534
THE SENSITIVITY BY MUTATING LIN

972
00:43:23,600 --> 00:43:25,869
52. OTHERS FROM MECHANISMS CAN

973
00:43:25,936 --> 00:43:27,304
TAKE OVER, IN THIS CASE

974
00:43:27,371 --> 00:43:28,672
NON-HOMOLOGOUS ENJOYING THAT

975
00:43:28,739 --> 00:43:31,709
TAKES OVER BUT VICE VERSA, ALSO

976
00:43:31,775 --> 00:43:33,043
HOMOLOGOUS RECOMBINATION REPAIR

977
00:43:33,110 --> 00:43:36,080
IS MORE ACTIVE AND COMPENSATE

978
00:43:36,146 --> 00:43:39,917
HERE FOR HOMOLOGOUS EFFECTS. NOW

979
00:43:39,984 --> 00:43:43,921
AGAIN, YOU MIGHT ARGUE WORMS AND

980
00:43:43,988 --> 00:43:47,157
HUMAN IS RELEVANT. THE DREAM

981
00:43:47,224 --> 00:43:49,727
COMPLEX IS HIGHLY CONSERVED FROM

982
00:43:49,793 --> 00:43:52,029
WORMS TO HUMANS.  WE ASK WHETHER

983
00:43:52,096 --> 00:43:54,832
IN THE TARGETS DEMONSTRATED TO

984
00:43:54,898 --> 00:43:57,234
BE DIRECTLY TARGETED IN THE

985
00:43:57,301 --> 00:44:00,504
PROMOTERS BY THE DREAM COMPLEX

986
00:44:00,571 --> 00:44:02,172
REGULATED BY THE DREAM COMPLEX

987
00:44:02,239 --> 00:44:03,841
WE ASK WHETHER AMONG THOSE GENES

988
00:44:03,907 --> 00:44:05,476
THERE ARE DNA REPAIR JEANS AND

989
00:44:05,542 --> 00:44:09,046
WE FIND SIGNIFICANT DNA REPAIR

990
00:44:09,113 --> 00:44:13,017
GENE JUST LIKE IN C ELEGANS.

991
00:44:13,083 --> 00:44:15,652
HUMANS ARE MORE COMPLICATED

992
00:44:15,719 --> 00:44:17,154
DIFFERENT SUBUNITS CAN FUNCTION

993
00:44:17,221 --> 00:44:19,123
AT OTHER COMPLEXES BUT THERE ARE

994
00:44:19,189 --> 00:44:21,058
ALSO SOME ADVANTAGES IN HUMANS.

995
00:44:21,125 --> 00:44:22,626
ONE BIG ADVANTAGE IS THAT WE

996
00:44:22,693 --> 00:44:26,597
KNOW THAT THE DREAM COMPLEX IS

997
00:44:26,663 --> 00:44:28,532
ASSEMBLED VIA THE CROSS

998
00:44:28,599 --> 00:44:32,436
CORRELATION OF LIN 52 BY THE

999
00:44:32,503 --> 00:44:34,938
JERC 1A KINASE.  WHEN THAT IS

1000
00:44:35,005 --> 00:44:38,342
ABSENTS AND LIN 52 IS NOT

1001
00:44:38,409 --> 00:44:40,144
PHOSPHORYLATED THE DREAM COMPLEX

1002
00:44:40,210 --> 00:44:41,378
DISASSEMBLES AND NO LONGER

1003
00:44:41,445 --> 00:44:44,748
REPRESSES.  FOR THE DIRK 1A

1004
00:44:44,815 --> 00:44:47,484
STUDIED IN MANY, MANY DIFFERENT

1005
00:44:47,551 --> 00:44:49,086
CIRCUMSTANCES, AND THERE ARE

1006
00:44:49,153 --> 00:44:51,622
INHIBITORS AVAILABLE. MOST

1007
00:44:51,688 --> 00:44:53,524
ESTABLISH THE NATURAL COMPONENT

1008
00:44:53,590 --> 00:44:56,326
WE USE IN ADDITION INDEPENDENT

1009
00:44:56,393 --> 00:44:58,095
CHEMICAL INHIBITOR. THE

1010
00:44:58,162 --> 00:44:59,863
HYPOTHESIS WAS THAT WHEN WE

1011
00:44:59,930 --> 00:45:03,967
INHIBIT DIRK 1A WE ALLEVIATE THE

1012
00:45:04,034 --> 00:45:08,439
DREAM FUNCTION AND THEN COULD

1013
00:45:08,505 --> 00:45:11,375
DEREPRESS AND MAYBE THIS IS A

1014
00:45:11,442 --> 00:45:14,211
STRATEGY TO PREVENT DEVELOPMENT

1015
00:45:14,278 --> 00:45:15,546
BY REDUCING ACCUMULATION OF

1016
00:45:15,612 --> 00:45:18,248
SOMATIC MUTATION AND PROMOTE

1017
00:45:18,315 --> 00:45:21,318
LONGEVITY BY KEEPING GENOMES

1018
00:45:21,385 --> 00:45:23,654
MORE STABLE. THIS IS WORK. SO

1019
00:45:23,720 --> 00:45:27,124
INITIALLY WE TOOK NOW QUIESCENT

1020
00:45:27,191 --> 00:45:28,158
HUMAN CELLS BECAUSE THE DREAM

1021
00:45:28,225 --> 00:45:31,495
COMPLEX IS ASSEMBLED IN G1 AND G

1022
00:45:31,562 --> 00:45:34,231
0 PHASES OF THE CELL CYCLE SO WE

1023
00:45:34,298 --> 00:45:36,033
TOOK QUIESCENT HUMAN CELLS AND

1024
00:45:36,100 --> 00:45:38,702
TREATED THEM WITH HARMINE SAND

1025
00:45:38,769 --> 00:45:41,705
FIRST ASKED IS BY INHIBITING

1026
00:45:41,772 --> 00:45:46,610
DREAM DYRK 1A THE DREAM

1027
00:45:46,677 --> 00:45:48,245
COMPLEXIN HINT? WE SEE

1028
00:45:48,312 --> 00:45:49,279
DEREPRESSION OF DREAM TARGET

1029
00:45:49,346 --> 00:45:53,217
GENES SO THEY ARE NOW IN USE.

1030
00:45:53,283 --> 00:45:57,121
MANY OF THESE ARE AFFECTIVE

1031
00:45:57,187 --> 00:46:00,124
REPAIR. THAT HYPOTHESIZES

1032
00:46:00,190 --> 00:46:01,358
LEADING TO DNA DAMAGE IS EXACTLY

1033
00:46:01,425 --> 00:46:05,429
WHAT HAPPENS.  WE SEE LEAGUES

1034
00:46:05,496 --> 00:46:06,897
ISOLATING LESIONS, DIFFERENT

1035
00:46:06,964 --> 00:46:09,266
LESION TYPES NORMALLY WE SEE IN

1036
00:46:09,333 --> 00:46:11,735
QUIESCENT CELLS HIGH DEGREE OF

1037
00:46:11,802 --> 00:46:13,504
APOPTOSIS. BUT IT IS SUFFICIENT

1038
00:46:13,570 --> 00:46:15,973
TO TREAT THEM WITH HARMINE OR

1039
00:46:16,039 --> 00:46:20,077
THE SIGNIFICANTLY REDUCED

1040
00:46:20,144 --> 00:46:22,279
SENSITIVITY TO DNA DAMAGE. THE

1041
00:46:22,346 --> 00:46:25,649
VERY SAME WE OBSERVED IN C

1042
00:46:25,716 --> 00:46:29,920
ELEGANS. WE IMPLEMENT THAT IN

1043
00:46:29,987 --> 00:46:33,090
VIVO. SO THE PHENOTYPE THE

1044
00:46:33,157 --> 00:46:34,591
PATHOLOGY WE INITIALLY TOOK AS

1045
00:46:34,658 --> 00:46:37,094
PROOF OF CONCEPT WAS RETINAL

1046
00:46:37,161 --> 00:46:40,297
DEGENERATION. WHY? BECAUSE WE

1047
00:46:40,364 --> 00:46:47,271
KNEW THAT COCKAYNE SYNDROME, HAS

1048
00:46:47,337 --> 00:46:49,072
RETINAL DEGENERATION BY LOSS OF

1049
00:46:49,139 --> 00:46:50,874
PHOTO RECEPTOR CELLS, THIS

1050
00:46:50,941 --> 00:46:52,009
EQUIVALENT MOUSE WITH SAME

1051
00:46:52,075 --> 00:46:53,477
MUTATION MUCH MILDER THAN THE

1052
00:46:53,544 --> 00:46:55,412
HUMAN, THAT'S MOUSE SPECIFIC

1053
00:46:55,479 --> 00:46:58,215
THAT WE SEE THEY ARE SLOWER, BUT

1054
00:46:58,282 --> 00:47:03,787
WE SEE DEGENERATION. WE THEN ASK

1055
00:47:03,854 --> 00:47:07,457
WHETHER WE FIND IN ANY LINK IN

1056
00:47:07,524 --> 00:47:09,927
THE SPORADICALLY OCCURRING AGE

1057
00:47:09,993 --> 00:47:11,395
RELATED MACULAR DEGENERATION,

1058
00:47:11,461 --> 00:47:13,864
THESE ARE NORMAL PEOPLE THAT

1059
00:47:13,931 --> 00:47:15,699
DEVELOP AGE RELATED MACULAR

1060
00:47:15,766 --> 00:47:18,135
DEGENERATION WITH AGE AND WE

1061
00:47:18,202 --> 00:47:22,439
COMPARE THEIR RNA SEQ PROFILE

1062
00:47:22,506 --> 00:47:25,442
WITH AGE MATCH NON-HEALTHY

1063
00:47:25,509 --> 00:47:28,045
PEOPLE, RETINAS, AND ASK WHICH

1064
00:47:28,111 --> 00:47:30,647
TYPE OF GENES ARE UNDEREXPRESS

1065
00:47:30,714 --> 00:47:33,450
AND DOWN REGULATED AND WE FIND

1066
00:47:33,517 --> 00:47:35,652
HERE THAT TRANSCRIPTION COVERED

1067
00:47:35,719 --> 00:47:37,054
NUCLEOTIDE EXCISION REPAIR GENES

1068
00:47:37,120 --> 00:47:40,190
ARE DOWN-REGULATED IN THESE

1069
00:47:40,257 --> 00:47:42,726
HUMAN AMD PATIENTS AND IT IS THE

1070
00:47:42,793 --> 00:47:44,561
SAME PROCESS THAT IS INDUCED BY

1071
00:47:44,628 --> 00:47:46,930
CSB SUGGESTING THAT THE VERY

1072
00:47:46,997 --> 00:47:50,534
SAME MECHANISM DRIVE AGE RELATED

1073
00:47:50,601 --> 00:47:53,570
MACULAR DEGENERATION, AS DRIVES

1074
00:47:53,637 --> 00:47:55,005
RETINAL DEGENERATION IN CS

1075
00:47:55,072 --> 00:47:57,341
PATIENT. WE USED A MOUSE MODEL

1076
00:47:57,407 --> 00:47:59,376
HERE THAT IS AS SEVERE AS THE

1077
00:47:59,443 --> 00:48:02,779
HUMANS WHICH IS ESCC 1, FOR THIS

1078
00:48:02,846 --> 00:48:06,650
WE WORK TOGETHER WITH

1079
00:48:06,717 --> 00:48:08,352
(INAUDIBLE) AND THAT DID THE

1080
00:48:08,418 --> 00:48:10,921
EXPERIMENTS HERE. WHERE WE

1081
00:48:10,988 --> 00:48:13,423
TREATED THE PRODROID NER

1082
00:48:13,490 --> 00:48:16,326
DEFICIENT ANIMAL WITH HARMINE

1083
00:48:16,393 --> 00:48:18,829
AND WE KNEW THAT THE ERCC ONE

1084
00:48:18,895 --> 00:48:21,865
KNOCK OUT IN THE RETINA NUCLEAR

1085
00:48:21,932 --> 00:48:24,501
LAYER SHOWS APOPTOSIS IN PHOTO

1086
00:48:24,568 --> 00:48:27,371
RECEPTOR CELLS WHICH IS A DRIVER

1087
00:48:27,437 --> 00:48:31,008
OF MACULAR DEGENERATION. AND

1088
00:48:31,074 --> 00:48:33,810
THIS DEGENERATION THIS TUNNEL

1089
00:48:33,877 --> 00:48:35,746
POSITIVE CELLS ARE SIGNIFICANTLY

1090
00:48:35,812 --> 00:48:38,181
REDUCED BY THE HARMINE TREATMENT

1091
00:48:38,248 --> 00:48:40,384
SUGGESTING WE CAN CONFER

1092
00:48:40,450 --> 00:48:42,486
RESISTANCE TO DNA DAMAGE IN

1093
00:48:42,552 --> 00:48:45,289
VIVO. IS IT REALLY DNA DAMAGE?

1094
00:48:45,355 --> 00:48:48,358
SO HERE WE LOOK AT GAMMA H 2AX

1095
00:48:48,425 --> 00:48:50,294
IN RETINA YOU CAN REGULARLY SEE

1096
00:48:50,360 --> 00:48:53,297
IN A NUCLEAR LAYER, IT IS

1097
00:48:53,363 --> 00:48:56,633
ACCUMULATED IN THE SCC 1

1098
00:48:56,700 --> 00:48:57,934
ENDOGENOUS DNA DAMAGE, THIS IS

1099
00:48:58,001 --> 00:49:01,772
PREVENTED BY THE TREATMENT OF

1100
00:49:01,838 --> 00:49:05,842
HEARMINE INDICATING INDEED DNA

1101
00:49:05,909 --> 00:49:10,013
REPAIR IS INEPT. SO WE FOUND

1102
00:49:10,080 --> 00:49:12,916
HERE DREAM FUNCTION MASTER

1103
00:49:12,983 --> 00:49:16,887
REGULATOR OF DNA C ELEGANS

1104
00:49:16,953 --> 00:49:17,654
ELEVATE RESCISSION TANS TO DNA

1105
00:49:17,721 --> 00:49:20,891
DAMAGE BY IMPROVING SOMATIC

1106
00:49:20,957 --> 00:49:23,560
REPRESSION OF DNA REPAIR GENE

1107
00:49:23,627 --> 00:49:25,295
AND COMPARE GERM LION, THE DREAM

1108
00:49:25,362 --> 00:49:28,098
COMPLEXES INHIBITION AND

1109
00:49:28,165 --> 00:49:28,999
QUIESCENT HUMAN CELLS ELSE

1110
00:49:29,066 --> 00:49:31,601
INVESTIGATES RESISTANCE TO DNA

1111
00:49:31,668 --> 00:49:35,639
DAMAGE TYPES, THE DREAM IN VIVO

1112
00:49:35,706 --> 00:49:36,907
PROTECT IT IS RETINAL

1113
00:49:36,973 --> 00:49:39,576
DEGENERATION IN ERCC 1 MICE,

1114
00:49:39,643 --> 00:49:41,178
DREAM INHIBITION OFFERS

1115
00:49:41,244 --> 00:49:42,312
PHARMACOLOGICAL ROUTE FOR

1116
00:49:42,379 --> 00:49:44,514
ENHANCED GENOME MAINTENANCE TO

1117
00:49:44,581 --> 00:49:47,050
PREVENT REQUEST DNA DAMAGE

1118
00:49:47,117 --> 00:49:47,718
DRIVEN CANCER IN DEVELOPMENT AND

1119
00:49:47,784 --> 00:49:49,820
AGINAGING. I ACKNOWLEDGED THE PE

1120
00:49:49,886 --> 00:49:51,955
THAT DID THE WORK. WE ARE HIRING

1121
00:49:52,022 --> 00:49:57,227
POST DOCS AND REALLY HAPPY TO

1122
00:49:57,294 --> 00:49:57,828
TAKE ANY QUESTIONS. THANK YOU

1123
00:49:57,894 --> 00:50:03,066
VERY MUCH FOR YOUR ATTENTION.

1124
00:50:03,133 --> 00:50:05,035
I'M AVAILABLE FOR ANY QUESTIONS

1125
00:50:05,102 --> 00:50:10,607
YOU MAY HAVE. THANK YOU.

1126
00:50:10,674 --> 00:50:12,876
>> WONDERFUL LECTURE, REALLY

1127
00:50:12,943 --> 00:50:16,747
INTERESTING, GREAT WORK.  DO WE

1128
00:50:16,813 --> 00:50:18,315
HAVE QUESTIONS IN THE -- AMONG

1129
00:50:18,382 --> 00:50:28,892
THE ATTENDEES HERE? KYNA ASKS,

1130
00:50:34,698 --> 00:50:37,667
GREAT DATA AND TALK. DOES

1131
00:50:37,734 --> 00:50:39,836
IRRADIATION OF MALES AFFECT THE

1132
00:50:39,903 --> 00:50:43,373
EXPECTANCY OF OFFSPRING?

1133
00:50:43,440 --> 00:50:47,577
>> WE HAVEN'T OBSERVED THAT IN C

1134
00:50:47,644 --> 00:50:49,679
ELEGANS. WHAT WE HAVE OBSERVED

1135
00:50:49,746 --> 00:50:54,618
IS THAT THE OFFSPRING SHOW SLIDE

1136
00:50:54,684 --> 00:50:56,286
DEVELOPMENTAL DELAY SO THERE ARE

1137
00:50:56,353 --> 00:50:58,588
PHENOTYPIC ALTERATIONS. SO FAR

1138
00:50:58,655 --> 00:51:01,358
WE HAVE NOT OBSERVED HOWEVER

1139
00:51:01,425 --> 00:51:09,833
THAT IT IS LIFE SPAN REDUCTION.

1140
00:51:09,900 --> 00:51:14,738
>> (INDISCERNIBLE)

1141
00:51:14,805 --> 00:51:18,642
>> WE HAVE A COMMENT BY

1142
00:51:18,708 --> 00:51:22,112
(INDISCERNIBLE) SAYING AMAZING

1143
00:51:22,179 --> 00:51:26,283
PRESENTATION. MICHAEL SAYS GREAT

1144
00:51:26,349 --> 00:51:27,050
TALK BJORN, DO YOU KNOW THE

1145
00:51:27,117 --> 00:51:29,419
TARGETS OF THE DYRK 1A ON HUMAN

1146
00:51:29,486 --> 00:51:32,222
CELLS CONTROLLED H EXPRESSION OF

1147
00:51:32,289 --> 00:51:34,224
DNA REPAIR GENES?

1148
00:51:34,291 --> 00:51:39,229
>> YEAH, SO IN DYRK 1A ACROSS

1149
00:51:39,296 --> 00:51:42,299
MULTIPLE TARGETS WE FIND IT

1150
00:51:42,365 --> 00:51:43,800
AFFECTIVELY INHIBITS INHIBITION

1151
00:51:43,867 --> 00:51:48,472
OF DYRK 1A EFFECTIVELY INHIBITS

1152
00:51:48,538 --> 00:51:49,906
THE DREAM COMPLEX, IT IS KNOWN

1153
00:51:49,973 --> 00:51:54,878
THAT DYRK 1A PHOSPHORYLATES LIN

1154
00:51:54,945 --> 00:51:59,916
52 IN A SPECIFIC SITE SERENE 1A,

1155
00:51:59,983 --> 00:52:03,453
SO THAT IS THE MECHANISM OF HOW

1156
00:52:03,520 --> 00:52:06,122
DYRK 1A AFFECTS DNA REPAIR

1157
00:52:06,189 --> 00:52:10,794
FUNCTION. AND OF COURSE DYR 1A

1158
00:52:10,861 --> 00:52:14,965
ITSELF ANY KINASE HAS ADDITIONAL

1159
00:52:15,031 --> 00:52:17,901
TARGETS, AND WE ARE CURRENTLY

1160
00:52:17,968 --> 00:52:19,369
EXPLORING HOW WE CAN

1161
00:52:19,436 --> 00:52:21,037
SUFFICIENTLY SPECIFICALLY

1162
00:52:21,104 --> 00:52:23,607
INHIBIT DYRK 1A TO BRING ABOUT

1163
00:52:23,673 --> 00:52:26,710
THE EFFECTS OF DREAM INHIBITION

1164
00:52:26,776 --> 00:52:28,845
TO INCREASE THE EXPRESSION OF

1165
00:52:28,912 --> 00:52:31,648
DNA REPAIR GENES.

1166
00:52:31,715 --> 00:52:33,817
>> OKAY. WE HAVE ANOTHER

1167
00:52:33,884 --> 00:52:39,789
QUESTION FROM MICHAEL. HE ASKS

1168
00:52:39,856 --> 00:52:41,958
DOES CISPLATIN CANCER HAVE

1169
00:52:42,025 --> 00:52:43,226
MUTATIONS IN DREAM COMPLEX?

1170
00:52:43,293 --> 00:52:45,195
>> THAT IS A VERY INTERESTING

1171
00:52:45,262 --> 00:52:45,962
QUESTION. .

1172
00:52:46,029 --> 00:52:47,397
WE DON'T KNOW, WE HAVEN'T LOOKED

1173
00:52:47,464 --> 00:52:50,834
AT THAT. T BUT I THINK THIS IS A

1174
00:52:50,901 --> 00:52:54,504
VERY EXCITING QUESTION TO ASK

1175
00:52:54,571 --> 00:52:56,373
BECAUSE THAT WOULD CERTAINLY

1176
00:52:56,439 --> 00:52:59,476
ALLOW CANCER CELLS TO BECOME

1177
00:52:59,543 --> 00:53:00,777
RESISTANTS IF THEY COULD

1178
00:53:00,844 --> 00:53:03,013
INCREASE DNA REPAIR FUNCTIONS.

1179
00:53:03,079 --> 00:53:05,815
THIS IS SOMETHING WE DEFINITELY

1180
00:53:05,882 --> 00:53:12,188
SHOULD LOOK AT.

1181
00:53:12,255 --> 00:53:13,990
>> PHILLIP SAYS BASED ON THE

1182
00:53:14,057 --> 00:53:16,159
MODEL I DON'T QUITE UNDERSTAND

1183
00:53:16,226 --> 00:53:18,395
WHY SECOND GENERATION IRRADIATED

1184
00:53:18,461 --> 00:53:21,698
FEMALES ARE HEALTHY.

1185
00:53:21,765 --> 00:53:28,204
>> SO FOR THE FEMALE, THEY CAN

1186
00:53:28,271 --> 00:53:31,741
DIRECTLY REPAIR AND THEN BE

1187
00:53:31,808 --> 00:53:35,378
HEALTHY, BUT DO NOT -- THEY USE

1188
00:53:35,445 --> 00:53:38,315
ACCURATE REPAIR MECHANISMS,

1189
00:53:38,381 --> 00:53:40,517
HOMOLOGOUS RECOMBINATION REPAIR.

1190
00:53:40,584 --> 00:53:45,121
SO WHATEVER IS BROKEN FROM

1191
00:53:45,188 --> 00:53:48,692
PROVIDED AS BROKEN DNA FROM AN

1192
00:53:48,758 --> 00:53:50,393
OOCITE THAT LEADS TO NOT

1193
00:53:50,460 --> 00:53:53,330
REPAIRED LEADS TO MITOTIC

1194
00:53:53,396 --> 00:53:54,698
CATASTROPHE DIRECTLY IN THE

1195
00:53:54,764 --> 00:53:57,233
EMBRYOS SO THE ONES THAT HAVE

1196
00:53:57,300 --> 00:53:59,002
UNRESOLVED DNA DAMAGE MAY JUST

1197
00:53:59,069 --> 00:54:01,771
DIE IMMEDIATELY OFF SO THEY DO

1198
00:54:01,838 --> 00:54:07,177
NOT GIVE RISE TO ANIMALS AT ALL.

1199
00:54:07,243 --> 00:54:11,114
WHILE IT IS ONLY THE FUSION

1200
00:54:11,181 --> 00:54:14,384
EVENTS THAT ARE GENERATED IN THE

1201
00:54:14,451 --> 00:54:16,453
PATERNAL DNA DAMAGE, DNA THAT

1202
00:54:16,519 --> 00:54:20,323
GIVES RISE TO THIS ONGOING DNA

1203
00:54:20,390 --> 00:54:22,592
DAMAGE BUT THEY DO NOT LEAD TO

1204
00:54:22,659 --> 00:54:26,162
MITOTIC CATASTROPHE DESPITE THE

1205
00:54:26,229 --> 00:54:28,932
ABERRANT MITOTIC FIGURES WE SEE

1206
00:54:28,999 --> 00:54:31,034
WITH NON-DISJUNCTION OF

1207
00:54:31,101 --> 00:54:31,935
CHROMOSOMES AND THINGS LIKE THAT

1208
00:54:32,002 --> 00:54:33,536
SO THAT IS THE MAJOR DIFFERENCE

1209
00:54:33,603 --> 00:54:35,939
SO FEMALES EITHER REPAIR OR THEY

1210
00:54:36,006 --> 00:54:37,641
ARE EMBRYONICALLY LETHAL

1211
00:54:37,707 --> 00:54:43,713
DIRECTLY.

1212
00:54:43,780 --> 00:54:44,948
>> WE HAVE A QUESTION FROM

1213
00:54:45,015 --> 00:54:46,783
(INAUDIBLE). HE SAYS I ADMIRE

1214
00:54:46,850 --> 00:54:48,518
YOUR BEAUTIFUL WORK. HE SAID

1215
00:54:48,585 --> 00:54:51,388
THAT THE DEFECTS IN HOMOLOGOUS

1216
00:54:51,454 --> 00:54:53,356
RECOMBINATION CAUSES CELL DEATH

1217
00:54:53,423 --> 00:54:58,294
DUE TO RADIATION AS A RESULT OF

1218
00:54:58,361 --> 00:55:00,196
NEGLECTING C ELEGANS. IS

1219
00:55:00,263 --> 00:55:01,431
NON-HOMOLOGOUS ENJOINING

1220
00:55:01,498 --> 00:55:05,468
ACTIVATED BY DSB IN C ELEGANS,

1221
00:55:05,535 --> 00:55:07,337
DOES IT NOT CONTRIBUTE TO

1222
00:55:07,404 --> 00:55:08,038
CHROMOSOME FUSION?

1223
00:55:08,104 --> 00:55:11,608
>> SO THAT IS SOME CONTRIBUTION

1224
00:55:11,675 --> 00:55:13,610
OF (INAUDIBLE) AS WELL SO WE DO

1225
00:55:13,677 --> 00:55:19,082
FIND NHJJ MUTANTS INCREASE LEVEL

1226
00:55:19,149 --> 00:55:22,519
OF TRANSGENERATION LETHALITY SO

1227
00:55:22,585 --> 00:55:26,956
THERE IS SOME FUNCTION OF NATJ

1228
00:55:27,023 --> 00:55:28,558
AS WELL BUT IT IS THE

1229
00:55:28,625 --> 00:55:30,160
PREDOMINANT REPAIR MECHANISM

1230
00:55:30,226 --> 00:55:35,465
APPEARS TO BE TMEJ.

1231
00:55:35,532 --> 00:55:40,737
>> (INDISCERNIBLE) SORRY IF I'M

1232
00:55:40,804 --> 00:55:42,539
MISPRONOUNCING YOUR NAME, SAYS

1233
00:55:42,605 --> 00:55:45,709
OVEREXPRESSION OR DISREGULATION

1234
00:55:45,775 --> 00:55:47,277
MAY OF MANY DNA REPAIR GENES

1235
00:55:47,343 --> 00:55:49,045
LEADS TO INCREASE GENOME

1236
00:55:49,112 --> 00:55:50,747
INSTABILITY DUE TO TOXICITY OF

1237
00:55:50,814 --> 00:55:52,782
DNA LESIONS GENERATING DURING

1238
00:55:52,849 --> 00:55:56,786
DNA REPAIR. DID YOU OBSERVE ANY

1239
00:55:56,853 --> 00:55:57,954
INSTABILITY IN MUTANT?

1240
00:55:58,021 --> 00:56:01,491
>> VERY INTERESTING QUESTION. WE

1241
00:56:01,558 --> 00:56:05,695
DO NOT. THE REASON WE BELIEVE IS

1242
00:56:05,762 --> 00:56:08,465
THAT WITH THE DREAM INHIBITION

1243
00:56:08,531 --> 00:56:10,700
OR ABROGATION WE SEE A

1244
00:56:10,767 --> 00:56:13,570
RELATIVELY MILD INCREASE IN

1245
00:56:13,636 --> 00:56:14,871
EXPRESSION OF DNA REPAIR GENE.

1246
00:56:14,938 --> 00:56:16,539
IT IS NOT HUGELY OVEREXPRESSED.

1247
00:56:16,606 --> 00:56:20,977
IT IS A RELATIVELY MILD BUT SO

1248
00:56:21,044 --> 00:56:23,079
MANY THE STOICHIOMETRY OF NORMAL

1249
00:56:23,146 --> 00:56:24,547
REPAIR MECHANISMS ARE STILL

1250
00:56:24,614 --> 00:56:26,883
MAINTAINED.  IT APPEARS THAT WE

1251
00:56:26,950 --> 00:56:30,053
ARE REALLY HITTING A SWEET SPOT

1252
00:56:30,120 --> 00:56:31,254
THERE WHERE IT IS FUNCTIONING

1253
00:56:31,321 --> 00:56:34,057
BETTER BUT IT DOES NOT LEAD TO

1254
00:56:34,124 --> 00:56:37,260
ABERRANT REPAIR EVENTS THAT

1255
00:56:37,327 --> 00:56:41,631
WOULD BE DETRIMENTAL. THE -- SO

1256
00:56:41,698 --> 00:56:43,266
THE COORDINATION OF REPAIR

1257
00:56:43,333 --> 00:56:44,601
MECHANISMS SEEM TO BE REALLY

1258
00:56:44,667 --> 00:56:47,170
VERY WELL MAINTAINED. SO WE DO

1259
00:56:47,237 --> 00:56:50,673
NOT -- WE DON'T REALLY SEE

1260
00:56:50,740 --> 00:56:52,742
ADVERSE EFFECTS IN RELATION TO

1261
00:56:52,809 --> 00:56:56,846
THE DNA REPAIR CAPACITY.

1262
00:56:56,913 --> 00:57:00,950
>> WE HAVE A QUESTION FROM KYNA

1263
00:57:01,017 --> 00:57:03,186
ASKING MMS LESIONS ARE REPAIRED

1264
00:57:03,253 --> 00:57:07,891
BY BER, ARE DREAM MUTANTS BER

1265
00:57:07,957 --> 00:57:12,095
GENES ENZYMES UPREGULATED OR

1266
00:57:12,162 --> 00:57:13,429
ONLY SOME FOR EXAMPLE RATE

1267
00:57:13,496 --> 00:57:14,097
LIMITING STEP?

1268
00:57:14,164 --> 00:57:18,968
>> WE FIND SOME R GENES

1269
00:57:19,035 --> 00:57:21,805
DEREPRESS SO INDUCED IN THE

1270
00:57:21,871 --> 00:57:23,673
DREAM MUTANTS SO IT WOULD

1271
00:57:23,740 --> 00:57:26,109
SUGGEST THAT THAT INDEED IS

1272
00:57:26,176 --> 00:57:28,778
EXPLAINING THE ELEVATED

1273
00:57:28,845 --> 00:57:33,483
RESISTANCE TO MMS. WE HAVEN'T

1274
00:57:33,550 --> 00:57:36,519
REALLY VALIDATED WHICH OF THOSE

1275
00:57:36,586 --> 00:57:39,322
IS THE RATE LIMITING FACTOR IN

1276
00:57:39,389 --> 00:57:40,657
BR BUT THIS IS CERTAINLY

1277
00:57:40,723 --> 00:57:41,224
SOMETHING INTERESTING TO GO

1278
00:57:41,291 --> 00:57:44,194
AFTER.

1279
00:57:44,260 --> 00:57:49,032
>> IN THE HUMAN CELLS, MALE OR

1280
00:57:49,098 --> 00:57:50,800
FEMALE DO YOU SEE THIS

1281
00:57:50,867 --> 00:57:53,803
DIFFERENCE IN TMEJ PATHWAY?

1282
00:57:53,870 --> 00:57:57,040
>> VERY GOOD QUESTION. WE SEE IT

1283
00:57:57,106 --> 00:57:59,676
IN THE HUMAN GENOMES SO THAT

1284
00:57:59,742 --> 00:58:01,044
WOULD SUGGEST THAT ALSO IN

1285
00:58:01,110 --> 00:58:04,647
HUMANS IT IS REALLY THE TMEJ.

1286
00:58:04,714 --> 00:58:06,649
THIS HAS NOT HOWEVER YET BEEN

1287
00:58:06,716 --> 00:58:11,254
EXPLORED TMEJ IS ONLY BEEN

1288
00:58:11,321 --> 00:58:12,455
AROUND FOR ABOUT TEN YEARS

1289
00:58:12,522 --> 00:58:16,392
MAYBE. I THINK IT IS REALLY

1290
00:58:16,459 --> 00:58:18,027
UNDERINVESTIGATED. AND TURNS OUT

1291
00:58:18,094 --> 00:58:21,064
TO BE REALLY A MAJOR REPAIR

1292
00:58:21,130 --> 00:58:24,067
MECHANISM. NATURALLY OCCURRING

1293
00:58:24,133 --> 00:58:25,902
PATERNAL STRUCTURE VARIANCE IN

1294
00:58:25,969 --> 00:58:27,370
HUMANS WOULD SUGGEST EXACTLY

1295
00:58:27,437 --> 00:58:28,538
THAT THIS HAPPENS IN HUMANS AS

1296
00:58:28,605 --> 00:58:30,273
WELL.

1297
00:58:30,340 --> 00:58:36,446
>> THANK YOU.

1298
00:58:36,512 --> 00:58:40,250
>> BILL.

1299
00:58:40,316 --> 00:58:43,786
>> GREAT TALK. DO YOU KNOW HOW

1300
00:58:43,853 --> 00:58:47,323
GENES, 1A IS REGULATED WITH AGE?

1301
00:58:47,390 --> 00:58:48,892
>> GOOD QUESTION. WE DON'T KNOW

1302
00:58:48,958 --> 00:58:51,661
YET. WE GENERATED ACTUALLY NOW

1303
00:58:51,728 --> 00:58:54,764
NEW MOUSE MODELS FOR DREAM AND

1304
00:58:54,831 --> 00:58:57,567
THERE WE WILL EXPLORE THIS NOW

1305
00:58:57,634 --> 00:59:00,036
MUCH NOR THE MAMMALIAN SYSTEM AS

1306
00:59:00,103 --> 00:59:02,305
WELL. IT CERTAINLY IS VERY

1307
00:59:02,372 --> 00:59:04,140
INTERESTING QUESTION. ONE

1308
00:59:04,207 --> 00:59:05,241
INTERESTING RESULT, ACTUALLY

1309
00:59:05,308 --> 00:59:09,545
VERY EXCITING RESULT WE GOT NOW

1310
00:59:09,612 --> 00:59:12,682
FROM SUPER LONG LIVED MAMMALS,

1311
00:59:12,749 --> 00:59:14,017
SOME OF THE BAT SPECIESES THAT

1312
00:59:14,083 --> 00:59:16,119
ARE VERY LONG LIVED, THERE WE

1313
00:59:16,185 --> 00:59:20,523
FIND EXACTLY THAT DREAM TARGET

1314
00:59:20,590 --> 00:59:23,493
GENES ARE INDUCED THROUGH AGING,

1315
00:59:23,559 --> 00:59:25,728
THAT IS NOT HAPPENING IN HUMAN

1316
00:59:25,795 --> 00:59:29,299
AND MIC MICE. SO IT MIGHT VERY L

1317
00:59:29,365 --> 00:59:32,101
BE THAT CURBING DREAM FUNCTION

1318
00:59:32,168 --> 00:59:33,369
COULD HAVE BEEN A NATURALLY

1319
00:59:33,436 --> 00:59:34,871
EVOLVING MECHANISM FROM

1320
00:59:34,938 --> 00:59:36,105
MAMMALIAN LONGEVITY, THAT

1321
00:59:36,172 --> 00:59:37,807
SOMETHING WE ARE NOW

1322
00:59:37,874 --> 00:59:38,708
INVESTIGATING AND THINK WE ARE

1323
00:59:38,775 --> 00:59:40,376
VERY EXCITED ABOUT IT THAT IT

1324
00:59:40,443 --> 00:59:42,478
COULD BE REALLY SOMETHING THAT

1325
00:59:42,545 --> 00:59:43,913
NATURE HAS DONE IN THOSE

1326
00:59:43,980 --> 00:59:47,817
SPECIESES THAT ARE REALLY

1327
00:59:47,884 --> 00:59:48,384
EXCEPTIONALLY LONG LIVED.

1328
00:59:48,451 --> 00:59:51,721
>> IF YOU TREATED MOUSE WITH

1329
00:59:51,788 --> 00:59:54,090
HARMINE WITH INHIBITOR DOES THAT

1330
00:59:54,157 --> 00:59:55,992
GET PREMATURE AGING OR ANYTHING?

1331
00:59:56,059 --> 00:59:58,394
>> WE HAVE DONE THAT ONLY IN THE

1332
00:59:58,461 --> 00:59:59,862
SEC 1 MODEL BECAUSE IT IS

1333
00:59:59,929 --> 01:00:01,064
RAPIDLY DEGENERATING MODEL.

1334
01:00:01,130 --> 01:00:03,232
THERE WE CAN PREVENT THE

1335
01:00:03,299 --> 01:00:04,767
DEGENERATION SO SUGGESTING THIS

1336
01:00:04,834 --> 01:00:07,103
COULD WORK. HARMINE HAS BEEN

1337
01:00:07,170 --> 01:00:09,539
INDUCED IN PHASE 2 CLINICAL

1338
01:00:09,605 --> 01:00:17,347
TRIALS FOR TREATING TR TRISOMY ,

1339
01:00:17,413 --> 01:00:20,016
DYRK 1A IS LOCATED ON CHROMOSOME

1340
01:00:20,083 --> 01:00:23,419
21, OVEREXPRESSED IN DOWN'S

1341
01:00:23,486 --> 01:00:29,258
SYNDROME. SO MIGHT VERY WELL BE

1342
01:00:29,325 --> 01:00:32,762
THAT THE ELEVATED DYRK 1A

1343
01:00:32,829 --> 01:00:33,696
ACTIVITY COULD EXPLAIN SOME OF

1344
01:00:33,763 --> 01:00:36,399
THE PREMATURE AGING AND

1345
01:00:36,466 --> 01:00:37,600
NEURODEGENERATION IN DOWN'S

1346
01:00:37,667 --> 01:00:40,603
SYNDROME PATIENTS BECAUSE THEY

1347
01:00:40,670 --> 01:00:42,538
MIGHT THEN BECOME DEFISH IN

1348
01:00:42,605 --> 01:00:46,442
MULTIPLE DNA REPAIR MECHANISMS.

1349
01:00:46,509 --> 01:00:48,444
IN THESE TRIALS HARMINE DOESN'T

1350
01:00:48,511 --> 01:00:49,645
HAVE A SUFFICIENT SECURITY

1351
01:00:49,712 --> 01:00:51,748
OFFICERTY PROFILE. SO LIKELY

1352
01:00:51,814 --> 01:00:53,783
BECAUSE THEY ARE OFF TARGET

1353
01:00:53,850 --> 01:00:57,453
EFFECTS WITH RELATED KINASES

1354
01:00:57,520 --> 01:01:01,524
THAT HAVE SIMILAR ACTIVE SITES

1355
01:01:01,591 --> 01:01:05,628
AS DYRK 1A SO THAT IS WHY I

1356
01:01:05,695 --> 01:01:08,531
THINK THERE'S REALLY A LOT OF

1357
01:01:08,598 --> 01:01:09,932
IMPETUS NOW TO DEVELOP MORE

1358
01:01:09,999 --> 01:01:12,602
SPECIFIC INHIBITORS IN HARMINE.

1359
01:01:12,668 --> 01:01:13,936
>> SAFETY THING.

1360
01:01:14,003 --> 01:01:16,906
>> THERE IS A QUESTION FROM

1361
01:01:16,973 --> 01:01:18,741
(INDISCERNIBLE).  WOULD YOU

1362
01:01:18,808 --> 01:01:22,211
EXPECT NON-DNA STRUCTURES SUCH

1363
01:01:22,278 --> 01:01:25,982
AS QUO TRIPLEXES TO BE A SIG DNA

1364
01:01:26,049 --> 01:01:28,551
DAMAGE? DOES IT CONTAIN DNA

1365
01:01:28,618 --> 01:01:31,354
REPAIR MECHANISM ACTING ON THIS

1366
01:01:31,421 --> 01:01:33,556
THESE, IF NOT EXTENDING

1367
01:01:33,623 --> 01:01:35,324
POLYMERASES SPECIALIZING IN

1368
01:01:35,391 --> 01:01:37,193
NON-DNA STRUCTURES ALSO PROTECT

1369
01:01:37,260 --> 01:01:38,127
AGAINST AGE SOMETHING

1370
01:01:38,194 --> 01:01:41,364
>> WE HAVEN'T YET LOOKED AT

1371
01:01:41,431 --> 01:01:43,466
THOSE STRUCTURE, VERY GOOD IDEA

1372
01:01:43,533 --> 01:01:45,134
WE KNOW HOWEVER YES INDEED

1373
01:01:45,201 --> 01:01:47,737
ALTERNATIVE POLYMERASES ARE

1374
01:01:47,804 --> 01:01:50,273
INDUCE IN THE DREAM MUTANTS. SO

1375
01:01:50,339 --> 01:01:51,474
SUGGESTING THAT THEY COULD

1376
01:01:51,541 --> 01:01:54,110
PROMOTE RESOLVING (INAUDIBLE)

1377
01:01:54,177 --> 01:01:56,646
THERE'S I THINK INCREASING

1378
01:01:56,712 --> 01:01:57,680
EVIDENCE THAT (INAUDIBLE) ARE

1379
01:01:57,747 --> 01:01:59,816
NATURALLY -- THEY ARE NATURALLY

1380
01:01:59,882 --> 01:02:02,218
OCCURRING. AND THEY MIGHT BE A

1381
01:02:02,285 --> 01:02:05,421
DRIVER OF GENOME INSTABILITY FOR

1382
01:02:05,488 --> 01:02:08,024
EXAMPLE, THEY CAN PROMOTE

1383
01:02:08,091 --> 01:02:09,859
FORMATION OF RNA TRANSCRIPTION

1384
01:02:09,926 --> 01:02:16,332
WHICH IS A SIGNIFICANT SOURCE OF

1385
01:02:16,399 --> 01:02:18,701
ABERRANT GENOMIC STRUCTURE. SO

1386
01:02:18,768 --> 01:02:21,971
IT IS VERY INTERESTING TO

1387
01:02:22,038 --> 01:02:23,973
EXPLORE THIS FURTHER. IN

1388
01:02:24,040 --> 01:02:24,874
PARTICULAR THE INVOLVEMENT OF

1389
01:02:24,941 --> 01:02:30,313
THE INDUCED TLS THAT WE DO SEE.

1390
01:02:30,379 --> 01:02:33,449
>> WE HAVE A QUESTION FROM WILL

1391
01:02:33,516 --> 01:02:35,818
NATHAN. DO YOU SEE LONG TERM

1392
01:02:35,885 --> 01:02:37,086
TOXICITIES ASSOCIATED WITH

1393
01:02:37,153 --> 01:02:41,190
STREAM INHIBITION IN MICE?

1394
01:02:41,257 --> 01:02:47,130
>> NOT YET. WE HAVE JUST

1395
01:02:47,196 --> 01:02:49,765
GENERATED THE PHOSPHOMUTANT MICE

1396
01:02:49,832 --> 01:02:54,537
AND WE HAVE GENERATED PHLOX

1397
01:02:54,604 --> 01:02:58,641
MICE. SO THERE IS -- THERE ARE

1398
01:02:58,708 --> 01:03:02,011
SEVERAL MUTANTS OF SUBUNITS OF

1399
01:03:02,078 --> 01:03:04,313
DREAM. SOME OF THEM DOUBLE

1400
01:03:04,380 --> 01:03:06,549
MUTANT COMBINATIONS ARE

1401
01:03:06,616 --> 01:03:07,583
EMBRYONIC LETHAL BECAUSE THEY

1402
01:03:07,650 --> 01:03:08,718
ARE FUNCTIONING OTHER COMPLEXES

1403
01:03:08,784 --> 01:03:10,219
THAT ARE REQUIRED FOR PROMOTING

1404
01:03:10,286 --> 01:03:14,123
CELL CYCLE.  THAT'S WHY WE

1405
01:03:14,190 --> 01:03:15,658
GENERATED NOW DREAM SPECIFIC

1406
01:03:15,725 --> 01:03:17,560
MOUSE MUTANTS, BECAUSE THAT

1407
01:03:17,627 --> 01:03:19,595
HASN'T BEEN ACCOMPLISHED YET. WE

1408
01:03:19,662 --> 01:03:20,496
ARE CURRENTLY INVESTIGATING

1409
01:03:20,563 --> 01:03:23,032
THEM. IN PARTICULAR WE ARE

1410
01:03:23,099 --> 01:03:27,770
INTERESTING IN HOW THIS ACTS IN

1411
01:03:27,837 --> 01:03:29,238
TERMINALLY DIFFERENTIATED CELL

1412
01:03:29,305 --> 01:03:32,208
TYPES SO THE FIRST CELL TYPE WE

1413
01:03:32,275 --> 01:03:34,544
LOOK AT NEURONS BECAUSE THEY

1414
01:03:34,610 --> 01:03:36,746
DON'T HAVE ANY OF THE

1415
01:03:36,812 --> 01:03:38,648
PROBLEMATIC OF CYCLING AND

1416
01:03:38,714 --> 01:03:43,252
WHETHER SOME SUB UNIT IS THEN

1417
01:03:43,319 --> 01:03:44,820
FOR INSTANCE POLYCOMPLEX THAT

1418
01:03:44,887 --> 01:03:47,390
DRIVES S PHASE SO THAT'S QUITE

1419
01:03:47,456 --> 01:03:48,524
SOME COMPLEXITY AREN'T THE

1420
01:03:48,591 --> 01:03:50,726
SUBUNITS THERE. BUT WE BELIEVE

1421
01:03:50,793 --> 01:03:55,031
WE CAN LEARN MUCH MORE NOW WITH

1422
01:03:55,097 --> 01:03:56,332
HAVING DREAM SPECIFIC MUTANTS

1423
01:03:56,399 --> 01:03:58,334
AND CELL TYPE SPECIFIC

1424
01:03:58,401 --> 01:04:04,740
ABROGATION OF DREAM IN PLACE.

1425
01:04:04,807 --> 01:04:10,813
>> PHILLIP ASKS WHY DON'T

1426
01:04:10,880 --> 01:04:12,415
FEMALES USE TMEJ ON THEIR OWN

1427
01:04:12,481 --> 01:04:14,317
DAMAGE?

1428
01:04:14,383 --> 01:04:18,321
>> SO THEY SEEM TO REALLY

1429
01:04:18,387 --> 01:04:21,157
PROTECT THEIR OWN GENOME SO WE

1430
01:04:21,224 --> 01:04:22,959
SEE IN FEMALES ALSO SOME

1431
01:04:23,025 --> 01:04:28,598
SENSITIVITY WHEN THEY ARE TMEJ

1432
01:04:28,664 --> 01:04:32,468
DEFICIENT, LIKE IN

1433
01:04:32,535 --> 01:04:33,636
HERMAPHRODITES BUT IN

1434
01:04:33,703 --> 01:04:38,007
(INAUDIBLE) THEY PREVENT TMEJ TO

1435
01:04:38,074 --> 01:04:40,243
ACT UPON THE MATERNAL GENOME SO

1436
01:04:40,309 --> 01:04:42,478
IT IS PROBABLY SOMETHING THAT

1437
01:04:42,545 --> 01:04:46,349
HAPPENS PRIOR TO THE FUSION OF

1438
01:04:46,415 --> 01:04:48,818
THE PATERNAL AND MATERNAL

1439
01:04:48,884 --> 01:04:50,386
NUCLEI. IT IS LIKELY THAT IT

1440
01:04:50,453 --> 01:04:56,559
OCCURS IN THE CYTOSOL SO WE

1441
01:04:56,626 --> 01:04:58,361
GENERATED STUDIES FOR TMEJ AND

1442
01:04:58,427 --> 01:05:00,997
WHERE IT ACT AND WHICH LOCATION

1443
01:05:01,063 --> 01:05:02,698
IT ACTS TO FIGURE THIS OUT

1444
01:05:02,765 --> 01:05:04,300
BETTER. THERE SEEMS TO BE REALLY

1445
01:05:04,367 --> 01:05:08,638
A SELECTIVE USAGE ON THE

1446
01:05:08,704 --> 01:05:10,273
PATERNAL GENOME BUT NOT THE

1447
01:05:10,339 --> 01:05:11,841
MATERNAL, AT LEAST NOT IN THE

1448
01:05:11,907 --> 01:05:16,912
ZYGOTE.

1449
01:05:16,979 --> 01:05:19,749
>> QUESTION, WHAT IS THE

1450
01:05:19,815 --> 01:05:21,984
EVOLUTIONARY ADVANTAGE TO HAVING

1451
01:05:22,051 --> 01:05:23,619
GAINED RELATED TO DNA REPAIR

1452
01:05:23,686 --> 01:05:27,156
SUPPRESSION IN HUMANS?

1453
01:05:27,223 --> 01:05:30,159
>> YES. SO THAT QUESTION I GET

1454
01:05:30,226 --> 01:05:33,362
ALL THE TIME. IF SOMETHING

1455
01:05:33,429 --> 01:05:35,231
WORSENED DNA WHY ON EARTH WOULD

1456
01:05:35,298 --> 01:05:37,033
YOU HAVE IT? I THINK THERE ARE A

1457
01:05:37,099 --> 01:05:39,702
COUPLE OF ANSWERS TO THAT. ONE

1458
01:05:39,769 --> 01:05:43,406
ANSWER IS THAT WHEN WE LOOK AT

1459
01:05:43,472 --> 01:05:45,541
LIN 52 MUTANTS OTHERWISE VERY

1460
01:05:45,608 --> 01:05:50,212
HEALTHY, WE DO SEE A SLIGHT

1461
01:05:50,279 --> 01:05:52,181
DECREASE. SO IT IS POSSIBLE

1462
01:05:52,248 --> 01:05:53,582
THERE IS A CERTAIN COST TO

1463
01:05:53,649 --> 01:05:55,885
IMPROVING SOMATIC REPAIR THAT

1464
01:05:55,951 --> 01:05:57,987
COULD THEN GO AT THE EXPENSE OF

1465
01:05:58,054 --> 01:06:01,090
THE GERM LINE. AND THIS WOULD

1466
01:06:01,157 --> 01:06:02,892
CERTAINLY PARTICULAR IN C

1467
01:06:02,958 --> 01:06:05,094
ELEGANS BE SELECTED AGAINST

1468
01:06:05,161 --> 01:06:06,329
IMMEDIATELY, SUCH A TRAIT

1469
01:06:06,395 --> 01:06:09,498
BECAUSE IT IS ALL ABOUT RAPID

1470
01:06:09,565 --> 01:06:11,100
REPRODUCTION. THAT MIGHT BE PART

1471
01:06:11,167 --> 01:06:12,868
OF THE ANSWER. THE OTHER ANSWER

1472
01:06:12,935 --> 01:06:15,805
COULD BE THAT IT MIGHT HAVE

1473
01:06:15,871 --> 01:06:17,273
CO-EVOLVED WITH CELL CYCLE

1474
01:06:17,340 --> 01:06:18,874
BECAUSE THE DREAM CONTROL CELL

1475
01:06:18,941 --> 01:06:21,243
CYCLE GENES.  WE KNOW DREAM

1476
01:06:21,310 --> 01:06:23,112
ABROGATION ITSELF IS

1477
01:06:23,179 --> 01:06:25,047
INSUFFICIENT TO DRIVE CELLS INTO

1478
01:06:25,114 --> 01:06:27,049
CYCLING, ADDITIONAL STRONG

1479
01:06:27,116 --> 01:06:30,286
ONCOGENE FOR THAT. BUT IT

1480
01:06:30,353 --> 01:06:31,654
CONTROLS GENES BECAUSE UPON

1481
01:06:31,721 --> 01:06:34,490
ENTRY INTO S PHASE, MANY DNA

1482
01:06:34,557 --> 01:06:36,592
REPAIR MECHANISMS ARE INDUCED.

1483
01:06:36,659 --> 01:06:41,664
THAT ARE NOT PRESENT IN G1. THE

1484
01:06:41,731 --> 01:06:44,867
DREAM IS THE MECHANISM THAT

1485
01:06:44,934 --> 01:06:46,502
CONTROLS THIS INDUCTION OF

1486
01:06:46,569 --> 01:06:48,604
REPAIR GENE SO THERE COULD BE A

1487
01:06:48,671 --> 01:06:50,539
CO-EVOLUTION OF THE REQUIREMENT

1488
01:06:50,606 --> 01:06:53,309
OF S PHASE ENTRY AND THE

1489
01:06:53,376 --> 01:06:57,113
RESTRICTION AND THE ACTIVATION

1490
01:06:57,179 --> 01:06:59,782
OF DNA REPAIR GENES. SO THAT

1491
01:06:59,849 --> 01:07:01,851
COULD BE A SECOND ANSWER. THIRD

1492
01:07:01,917 --> 01:07:04,186
ANSWER COULD BE, IT IS JUST NOT

1493
01:07:04,253 --> 01:07:07,089
-- IT IS JUST NO REASON TO

1494
01:07:07,156 --> 01:07:10,292
MAINTAIN SOMATIC GENOMES, THERE

1495
01:07:10,359 --> 01:07:13,295
IS NO REASON NOT RESTRICTING IT.

1496
01:07:13,362 --> 01:07:15,197
BUT GIVEN THIS IS SO CONSERVED

1497
01:07:15,264 --> 01:07:17,666
THIS PHENOMENA FROM WORMS TO

1498
01:07:17,733 --> 01:07:20,636
HUMANS THERE IS -- THERE MUST BE

1499
01:07:20,703 --> 01:07:22,538
SELECTIVE ADVANTAGE OF CURBING

1500
01:07:22,605 --> 01:07:27,610
SOMATIC DNA REPAIR.

1501
01:07:27,676 --> 01:07:29,545
>> LOOKS LIKE (INAUDIBLE) HAS A

1502
01:07:29,612 --> 01:07:29,845
QUESTION.

1503
01:07:29,912 --> 01:07:32,281
>> WONDERFUL TALK. REALLY

1504
01:07:32,348 --> 01:07:35,117
ENJOYED IT. I UNDERSTAND

1505
01:07:35,184 --> 01:07:37,019
FUNCTIONING FOCUSING MOSTLY ON

1506
01:07:37,086 --> 01:07:39,255
AGING. SO YOU ARE DOING STUDIES

1507
01:07:39,321 --> 01:07:41,891
IN QUIESCENT CELLS.  HAVE YOU

1508
01:07:41,957 --> 01:07:46,595
CONSIDERED USING DIVIDING CELLS?

1509
01:07:46,662 --> 01:07:48,264
OR GET MORE INFORMATION ABOUT

1510
01:07:48,330 --> 01:07:51,767
CANCER? SO WHEN WE TREAT

1511
01:07:51,834 --> 01:07:54,236
DIVIDING CELLS WITH HARMINE, WE

1512
01:07:54,303 --> 01:07:55,938
SEE NO BENEFIT BECAUSE IN

1513
01:07:56,005 --> 01:07:57,706
DIVIDING CELLS IN EVERY S PHASE

1514
01:07:57,773 --> 01:08:00,142
YOU GET ANY WAY THE DISASSEMBLY

1515
01:08:00,209 --> 01:08:02,878
OF THE DREAM COMPLEX. SO THIS

1516
01:08:02,945 --> 01:08:07,316
SEEM TO BE PREDOMINANTLY

1517
01:08:07,383 --> 01:08:09,685
BENEFICIAL FOR NON-DIVIDING

1518
01:08:09,752 --> 01:08:11,887
CELLS BUT IF YOU THINK ABOUT

1519
01:08:11,954 --> 01:08:13,756
STEM CELLS, MANY OF THE STEM

1520
01:08:13,823 --> 01:08:16,258
CELLS COMPARTMENTS ARE MOSTLY

1521
01:08:16,325 --> 01:08:19,094
QUIESCENT. THINK ABOUT

1522
01:08:19,161 --> 01:08:20,996
HEMATOPOIETIC STEM CELLS MOST

1523
01:08:21,063 --> 01:08:23,399
ALMOST ALL ENTIRE LIFE IN

1524
01:08:23,466 --> 01:08:25,134
QUIESCENT STATE, THEY HAVE

1525
01:08:25,201 --> 01:08:28,003
RESTRICTIONS IN REPAIR SO WHAT U

1526
01:08:28,070 --> 01:08:31,207
YOU FIND IN STEM CELL AGING ARE

1527
01:08:31,273 --> 01:08:35,177
NHEJ MEDIATED REPAIR FUSIONS.

1528
01:08:35,244 --> 01:08:38,347
THAT -- AND YOU FIND THAT WITH

1529
01:08:38,414 --> 01:08:41,116
AGING THOSE THAT ARE SELECTED

1530
01:08:41,183 --> 01:08:42,785
FOR ARE THEN FUSION ASSOCIATED

1531
01:08:42,852 --> 01:08:45,888
TO AGE DEPENDENT LEUKEMIA. SO WE

1532
01:08:45,955 --> 01:08:48,023
THINK THIS COULD BE VERY

1533
01:08:48,090 --> 01:08:51,093
BENEFICIAL IN THIS QUIESCENT

1534
01:08:51,160 --> 01:08:53,329
STEM CELLS TO PREVENT

1535
01:08:53,395 --> 01:08:56,265
ACCUMULATING GENOME ABERRATIONS

1536
01:08:56,332 --> 01:08:57,700
THAT DRIVE CANCER IN THE OLD

1537
01:08:57,766 --> 01:09:01,403
AGE. SO THIS COMES I THINK TO

1538
01:09:01,470 --> 01:09:04,273
QUITE EXTENT FROM DORMANT CELLS,

1539
01:09:04,340 --> 01:09:06,775
DORMANT CELLS WHICH HAVE ALL THE

1540
01:09:06,842 --> 01:09:09,144
REPLY KAYTIVE POTENTIAL OF STEM

1541
01:09:09,211 --> 01:09:13,349
CELL SO THERE WE THINK WHERE

1542
01:09:13,415 --> 01:09:14,550
THIS COULD HAVE HAVE VERY

1543
01:09:14,617 --> 01:09:19,188
IMPORTANT IMPLICATIONS.

1544
01:09:19,255 --> 01:09:26,795
>> THANK YOU.

1545
01:09:26,862 --> 01:09:28,597
>> DO YOU WANT TO CLOSE IT OUT?

1546
01:09:28,664 --> 01:09:30,499
LOOKS LIKE WE HAVE NO MORE

1547
01:09:30,566 --> 01:09:31,000
QUESTIONS IN THE CHAT.

1548
01:09:31,066 --> 01:09:36,238
>> WE ONLY HAVE ONE COMMENT FROM

1549
01:09:36,305 --> 01:09:37,706
THE VILHELM, THANK YOU FOR ALL

1550
01:09:37,773 --> 01:09:40,009
YOUR ANSWERS VERY STIMULATING. I

1551
01:09:40,075 --> 01:09:43,913
WOULD LIKE TO ADD THANK YOU FOR

1552
01:09:43,979 --> 01:09:46,348
DR. SCHUMACHER'S WONDERFUL TALK

1553
01:09:46,415 --> 01:09:49,084
AND REALLY APPRECIATE SHARING

1554
01:09:49,151 --> 01:09:49,985
THESE FINDINGS. THANK YOU SO

1555
01:09:50,052 --> 01:09:50,619
MUCH.

1556
01:09:50,686 --> 01:09:52,288
>> GOOD TO SEE YOU.

1557
01:09:52,354 --> 01:09:54,990
>> THANK YOU.

1558
01:09:55,057 --> 01:09:56,458
>> THANK YOU SO MUCH. IT WAS AN

1559
01:09:56,525 --> 01:09:58,494
HONOR.

1560
01:09:58,561 --> 01:09:59,061
>> THANK YOU.

1561
01:09:59,128
>> THANK YOU. TAKE CARE.