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NOKAY, GOOD AFTERNOON,
EVERYONE. CAN YOU HEAR ME OKAY.

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GREAT, WE'LL GIVE A COUPLE

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MINUTES FOR THE LAST FEW PEOPLE

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TO COME IN AND FIND THEIR SPOTS.

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WELL, GOOD AFTERNOON, EVERYONE,

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WELCOME TO THE CLOSE DATE OF

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SPRING, SOMETHING TO CELEBRATE

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AS WELL AS OUR WARK LS LECTURE

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00:00:27,062 --> 00:00:32,901
TODAY, I'M WITH THE HUMAN

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IMENETTIC BRANCHES AND I AM HERE

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TODAY TO BRUCE DR. CHRISTOPHER

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WALSH.

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HE'S AN INVESTIGATOR AT THE

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HOWARD HUGHES MEDICAL INSTITUTE

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AND AS WE WILL SEE TOGETHER,

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TODAY, THE WALSH LAB ACHIEVES A

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EXQUISITE LABORATORY SHEDDING

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LIGHT ON HOW OUR BRAINS EVOLVE

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AND AGE AND THROUGH THIS BETTER

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BED UNDERSTANDING NEUROLOGY AND

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PSYCHIATRY, AND HE'S RECEIVED

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NUMEROUS AWARDS SUCH AS THE

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AMERICAN NEUROLOGICAL

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ASSOCIATION, AMERICAN EPILEPSY

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ASSOCIATION AND THE ACADEMY OF

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MEDICINE, DR. WALSH COMPLETED

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HIS MD-Ph.D., AND AFTER A

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NEUROLOGY RESIDENCE HE COMPLETED

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RESEARCH FELLOWSHIP AT HARVARD

30
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GENETICS MEDICAL SCHOOL, HE HELD

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A BLOOD PROFESSORSHIP AT HARVARD

32
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SINCE 1999 AND YOINED CHILDREN'S

33
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AS CHIEF OF GENETICS IN 2006.

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DR. WALSH'S CLINICAL RESEARCH AT

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BOSTON CHILDREN'S IS DEEPLY

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ROOTED IN TEAM SCIENCE AND

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COLLABORATION WITH FAMILIES AND

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THIS WORK IS IDENTIFIED GENETIC

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CAUSES FOR HUNDREDS OF CONKIGZS

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IN NEUROLOGY AND PSYCHIATRY AND

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DEVELOPMENTAL DISORDERS AND AS

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WE HEAR ABOUT TODAY HAS EXTENDED

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INTO BRAIN AGING AS WELL EMPLOY

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AND IN SEEKING TO UNDERSTAND

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MECHANISMS OF GENETIC DEC,

46
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DR. WALSH AND HIS LAB HAVE

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TACKLED SOME OF THE DEEPEST

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BASIC QUESTIONS IN BRAIN

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DEVELOPMENT AND AGING.

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BODY EVOLUTIONARY AND

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DEVELOPMENT PROCESSES ACCOUNT

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FOR THE FOLD OF OUR CORTICALE

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SHEETS, WHAT ARE THE LINEAGE

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RELATIONSHIPS THAT CONNECT CELLS

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OVER THE COURSE OF BRAIN

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DEVELOPMENT AND HOW CAN WE USE

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THESE LINEAGES TO TELL US ABOUT

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THE PATTERN OF OF BRAIN

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ORGANIZATION IN THIS.

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AND THE TOOLS THE WALSH LAB USED

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TO ADDRESS THESE QUESTIONS OPENS

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UP NEW FIELDS OF BIOLOGY,

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RESEARCH AND THE REWRITING OF

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SOME TEXTBOOK PARAGRAPHS AS

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WELL.

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AND THE WALSH LAB HAS IMPACTED

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PAPERS AND THE FIELD BUT LARGE

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COHORTS WHO ARE INDIVIDUALLY

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TRAINED AND GO ON TO CONTINUE

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THE WORK IN THEIR OWN LABS.

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SO AS I'M SURE YOU CAN, WE'RE IN

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FOR A REAL TREAT TODAY, SO

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BEFORE I HAND IT OVER TO

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DR. WALSH, I WANT TO LET YOU

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KNOW ABOUT A FEW HOUSEKEEPING

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THINGINGS.

77
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YOU CAN SUBMIT QUESTIONS THROUGH

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THE SEND LIVE FEEDBACK OPTIONOT

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VIDEOCAST PAGE AND TODAY'S CME

80
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CODE IS 50117.

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50117.

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SO WITH THAT PLEASE JOIN ME IN

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WELCOMING OUR WALS SPEAKER TODAY

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DR. CHRIS WALSH.

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00:03:23,905 --> 00:03:24,205
[ APPLAUSE ]

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>> THANK YOU VERY MUCH AND
FOR

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THE INVITATION TO COME HERE AND

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IT'S A REAL THRILL WHEN I LOOK

89
00:03:30,345 --> 00:03:32,347
AT THE LIST OF OTHER PEOPLE WHO

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00:03:32,347 --> 00:03:35,650
HAVE GIVEN THE WALS LECTURES AND

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IT'S GREAT, OF COURSE TO VISIT

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WASHINGTON.

93
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I GOT A CHANCE TO SEE THE CHERRY

94
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BLOSSOMS, ALTHOUGH FROM THE BACK

95
00:03:46,828 --> 00:03:49,430
SEAT OF A SPEEDING TAXICAB, BUT

96
00:03:49,430 --> 00:03:51,099
ANYWAY, IT'S GREAT TO BE HERE.

97
00:03:51,099 --> 00:03:53,067
SO OUR LAB HAS BEEN INTERESTED

98
00:03:53,067 --> 00:03:57,939
FOR A LONG TIME IN USING --HUMAN

99
00:03:57,939 --> 00:03:59,007
GENETICS TO UNDERSTAND THE

100
00:03:59,007 --> 00:04:00,875
BIOLOGY OF HOW THE HUMAN BRAIN

101
00:04:00,875 --> 00:04:03,278
DEVELOPMENTS AND JUST FOR THOSE

102
00:04:03,278 --> 00:04:04,812
MIGHT NOT BE NEUROSCIENTISTS, I

103
00:04:04,812 --> 00:04:07,348
WANT TO REMIND YOU THAT THE

104
00:04:07,348 --> 00:04:10,018
CELLS IN THE CEREBRAL CORTEX,

105
00:04:10,018 --> 00:04:11,986
THE NEURONS ARE NONDIVIDING

106
00:04:11,986 --> 00:04:15,857
CELLS, AND SO THEY ARE FORMED

107
00:04:15,857 --> 00:04:16,791
DURING FETAL GUESTATION AND SO

108
00:04:16,791 --> 00:04:19,193
WE THINK OF THEM AS BEING BORN,

109
00:04:19,193 --> 00:04:23,898
ON A PARTICULAR DAY WHEN THEY

110
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UNDERGO THEIR CELL DIVISION AND

111
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BECOME PERTINENTLY POST MITOTIC

112
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FOR LONG.

113
00:04:30,271 --> 00:04:33,641
LET ME  WORK ON THE POINTER

114
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EMPLOY YOU CAN SEE THE THAT DNCH

115
00:04:35,843 --> 00:04:38,079
LAYERS ARE BORN IN SEQUENCE SO

116
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THESE ARE FIRST WORN 1S AND

117
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THESE ARE THE LAST  1S BORN GIVE

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THE PRECURSORS.

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SO THE 8 BILLION PEOPLE ON OUR

120
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PLANET IS A MUTE O GENESIS FOR

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EVERY REQUIRED YEEN THAT'S

122
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REQUIRED FOR THAT PROCESS, BUT

123
00:05:03,171 --> 00:05:05,239
TODAY I WILL TALK ABOUT

124
00:05:05,239 --> 00:05:06,307
MUTATIONS THAT OCCUR, THAT

125
00:05:06,307 --> 00:05:07,842
REGULATE THAT DEVELOPMENT BUT

126
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THAT OCCUR ACTUALLY DURING THAT

127
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DEVELOPMENT AS WELL, AND SO

128
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THESE ARE MUSEUM SWRAIIC

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MUTATIONS OR SOMATIC MUTATIONS

130
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AND THEY OCCUR ACTUALLY WITH

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EVERY CELL DIVISION THAT

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GENERATES THE EMBRYO.

133
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SO WHENEVER THE GENOME IS

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COPIED, THE COPY IS NEVER AS

135
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GOOD AS THE ORIGINAL AND THERE

136
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WERE ALWAYS A COUPLE POINT

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MUTATIONS INTRODUCED BY THAT AND

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OCCASIONALLY THINGS LIKE LINE

139
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ELEMENT TRANSPOSSESSIONS OR COPY

140
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NUMBER VARIANTS SO THESE OCCUR

141
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WITH EVERY CELL DIVISION THAT

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GENERATES THE EMBRYO THAT THEY

143
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CAN OCCUR EARLY LIKE THIS RED

144
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MUTATION BEFORE GASTROALATION,

145
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IN WHICH CASE THEY WOULD BE

146
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PRESENT IN ALL TISSUES BUT ONLY

147
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IN A FRACTION OF THE CELLS IN

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ANY TISSUE.

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THEY CAN OCCUR AFTER

150
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GASTRULATION, LIKE THIS YELLOW

151
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MUTATION AND TYPICALLY WOULD BE

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IN A SMALLER CELL IN THE BRAIN

153
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THAN IF IT HAD OCCURRED EARLIER

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OR THERE CAN ACTUALLY BE

155
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EXAMPLES OF MUTATIONS THAT ARE

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IN 1 HALF THE BRAIN AND NOT THE

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OTHER IN THE GREEN MUTATION OR

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EVEN A SMALL REGION OF THE

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BRAIN.

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SO AT THE END OF THE TALK, I

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WILL TELL YOU ABOUT SOMATIC

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MUTATIONS THAT CAN BE EMILY THED

163
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TO 1 SINGLE DIVIDING NEURON.

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AND I'M THRILLED THAT SOME OF

165
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THIS WORK HAS BEEN SUPPORTED

166
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NOW, BY THE COMMON FUND OF NIH

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THROUGH THE SMART CONSORTIUM,

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THE SOMATIC MUTATION ACROSS OR

169
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AS WE CALL IT IN BOSTON THE

170
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SMART CONSORTIUM.

171
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SO THESE MUTATIONS HAVE BEEN AN

172
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OBSESSION WITH US FOR THE LAST

173
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10 WREERS AND THEY CONTRIBUTE TO

174
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A GROWING NUMBER OF NEUROLOGICAL

175
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AND PSYCHIATRIC DECS AND I WILL

176
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TELL YOU ABOUT SOME OF THEM OVER

177
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THE COURSE OF THE NEXT 45

178
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MINUTES OR SO.

179
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I WILL TELL YOU BRIEFLY ABOUT

180
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SOMATIC ACTIVATING MUTATIONS IN

181
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THE PEDIATRIC EPILEPSY AND I

182
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WILL TALK ABOUT NEWER WORK, MOST

183
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OF IT UNPUBLISHED, ABOUT

184
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TEMPORAL LOBE EPILEPS EXPE THEN

185
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SOMATIC TUMOR SUPPRESSOR

186
00:07:01,255 --> 00:07:03,090
MUTATIONS OUT IN THE MICROGLIA

187
00:07:03,090 --> 00:07:04,459
AND THE ALZHEIMER BRAIN AND THEN

188
00:07:04,459 --> 00:07:07,228
AT THE END, I WILL TALK A BIT

189
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ABOUT THESE SOMATIC MUTATIONS

190
00:07:08,329 --> 00:07:11,766
THAT ARE LIMITED TO A SINGLE

191
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NEURON.

192
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SO REALLY A LOT OF OUR WORK ON

193
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THESE SOMATIC MUTATIONS STARTED

194
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BECAUSE OF THE INTEREST OF AMP

195
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DURANNIA, AND WANTED TO

196
00:07:23,211 --> 00:07:24,178
UNDERSTAND WHAT WAS GOING ON IN

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THE BRAIN OF THIS YOUNG BOY WHO

198
00:07:27,181 --> 00:07:30,818
HAD 1 HEMISPHERE, THE RIGHT

199
00:07:30,818 --> 00:07:31,419
HEMISPHERE, ALTHOUGH

200
00:07:31,419 --> 00:07:32,587
RADIOLOGISTS LIKE TO MESS US UP

201
00:07:32,587 --> 00:07:34,822
BY SHOWING IT ON THE LEFT SIDE,

202
00:07:34,822 --> 00:07:36,991
AND THAT ABNORMAL HEMISPHERE AND

203
00:07:36,991 --> 00:07:38,392
OVERGROWN AND DOESN'T SHOW GOOD

204
00:07:38,392 --> 00:07:40,228
DISTINCTION OF THE NORMAL GRAY

205
00:07:40,228 --> 00:07:42,964
MATTER AND WHITE MATTER AND IT'S

206
00:07:42,964 --> 00:07:44,899
INTENSELY EPILEPTIC SO THIS

207
00:07:44,899 --> 00:07:46,067
CHILD HAD INTRACTABLE EPILEPSY

208
00:07:46,067 --> 00:07:47,702
STARTING AT THE TIME OF BIRTH

209
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AND LEFT SIDED WEAKNESS BECAUSE

210
00:07:50,004 --> 00:07:50,571
THAT RIGHT HEMISPHERE EVEN

211
00:07:50,571 --> 00:07:52,507
THOUGH IT WAS BIG, IT WAS NOT

212
00:07:52,507 --> 00:07:53,441
DOING MUCH GOOD.

213
00:07:53,441 --> 00:07:58,412
SO IN A DESPERATE ATTEMPT TO

214
00:07:58,412 --> 00:08:00,681
CONTROL EPILEPSY, NEUROSERNLGONS

215
00:08:00,681 --> 00:08:02,149
REMOVED HIS ENTIRE RIGHT SPHERE,

216
00:08:02,149 --> 00:08:04,018
SO HERE YOU SEE SIGNERAL FLUID

217
00:08:04,018 --> 00:08:06,354
AND EVERYTHING DOWN THE THALAMUS

218
00:08:06,354 --> 00:08:07,288
HAS BEEN REMOVED.

219
00:08:07,288 --> 00:08:09,524
THIS WAS LIFE SAVING, HE HAD NO

220
00:08:09,524 --> 00:08:11,259
SEIZURES FOR 6 YEARS, THEY WERE

221
00:08:11,259 --> 00:08:12,793
CONTROLLED, HE LEARNED TO WALK,

222
00:08:12,793 --> 00:08:14,095
TALK, READS AT GRADE LEVEL AND

223
00:08:14,095 --> 00:08:16,397
SO, YOU KNOW HE REALLY GOT HIS

224
00:08:16,397 --> 00:08:19,767
LIFE BACK FROM THIS DRASTIC

225
00:08:19,767 --> 00:08:20,701
SURGERY.

226
00:08:20,701 --> 00:08:23,471
AND HIS NAME, HERE'S HIS

227
00:08:23,471 --> 00:08:26,541
PECTURE, HE THINKS OF HIMSELF,

228
00:08:26,541 --> 00:08:28,075
DANTE, I USE HIS NAME AND

229
00:08:28,075 --> 00:08:30,177
PICTURE WITH HIS PARENT'S  

230
00:08:30,177 --> 00:08:31,145
PERMISSION, HE REMAINS A LITTLE

231
00:08:31,145 --> 00:08:32,313
WEAK ON THE LEFT SIDE AND NEEDS

232
00:08:32,313 --> 00:08:34,248
A BRACE IT WALK BUT HE'S DOING

233
00:08:34,248 --> 00:08:36,817
AMAZINGLY WELL, AND SO, HE HAS

234
00:08:36,817 --> 00:08:37,652
A--SO WE POSTULATED THAT THIS

235
00:08:37,652 --> 00:08:40,254
MIGHT BE A MUTATION THAT'S ONLY

236
00:08:40,254 --> 00:08:41,155
PRESENT IN THAT 1 ABNORMAL HALF

237
00:08:41,155 --> 00:08:43,257
OF THE BRAIN AND SURE ENOUGH HIS

238
00:08:43,257 --> 00:08:44,825
MUTATION IS SHOWN HERE,OOSE A

239
00:08:44,825 --> 00:08:46,661
POINT MUTATION IN THE GENE

240
00:08:46,661 --> 00:08:50,097
CALLED AKT 3, IT CREATES A

241
00:08:50,097 --> 00:08:51,799
SPECIFIC AMINO ACID SUBSIDIARY

242
00:08:51,799 --> 00:08:52,633
CONSTITUTION, AT POSITION 17 AND

243
00:08:52,633 --> 00:08:54,502
YOU CAN SEE IN THIS OLD FASHION

244
00:08:54,502 --> 00:08:56,337
TD SANGER TRACE THAT THE BLOOD

245
00:08:56,337 --> 00:08:57,672
CELLS SHOW THE NORMAL SEQUENCE

246
00:08:57,672 --> 00:09:00,708
BUT THE BRAIN SHOWS A LITTLE

247
00:09:00,708 --> 00:09:03,477
EXTRA PEAK AND THAT REPRESENTS

248
00:09:03,477 --> 00:09:04,879
THIS MUTATION BEING PRESENT

249
00:09:04,879 --> 00:09:08,449
ABOUT ABOUT A THIRD OF THE CELLS

250
00:09:08,449 --> 00:09:11,319
FROM THE HEMISPHERE FROM THE

251
00:09:11,319 --> 00:09:12,486
NEUROSURGEONS AND STUDY IN THE

252
00:09:12,486 --> 00:09:14,455
LAB RATOREXPE IT'S ABNORMALITIES

253
00:09:14,455 --> 00:09:15,990
SEPTORS FROM REST OF HIS BODY.

254
00:09:15,990 --> 00:09:17,258
THIS WOULD BE LIMITED TO THE

255
00:09:17,258 --> 00:09:18,225
BRAIN AND HALF THE BRAIN EMPLOY

256
00:09:18,225 --> 00:09:20,461
SO THIS IS A XOAN CANCER

257
00:09:20,461 --> 00:09:21,596
ASSOCIATED MUTATION, ALTHOUGH

258
00:09:21,596 --> 00:09:23,864
AKT 3 IS AN ISOFORM OF AKT WHICH

259
00:09:23,864 --> 00:09:24,932
IS MOSTLY BRAIN SPECIFIC, SO

260
00:09:24,932 --> 00:09:30,137
THIS IS NOT A MAJOR ONCA GENE,

261
00:09:30,137 --> 00:09:32,173
ALTHOUGH THE EXACT PATHWAY

262
00:09:32,173 --> 00:09:35,610
GIVESERAL GUS MUTATION IS A

263
00:09:35,610 --> 00:09:37,211
MAJOR ONCA MUTATION, AND IT'S A

264
00:09:37,211 --> 00:09:38,579
GAIN OF FUNCTION MUTATION OF

265
00:09:38,579 --> 00:09:39,180
THIS KINASE.

266
00:09:39,180 --> 00:09:42,717
AND SO IN THE DECADE OR SO SINCE

267
00:09:42,717 --> 00:09:46,120
THAT, IT'S NOW CONVENTIONAL THAT

268
00:09:46,120 --> 00:09:47,088
THESE OVERGROWTH LESIONS OF THE

269
00:09:47,088 --> 00:09:48,689
BRAIN THAT ARE INTENSELY

270
00:09:48,689 --> 00:09:50,992
EPILEPTIC WHETHER THEY'RE BIG

271
00:09:50,992 --> 00:09:52,893
LIKE DANTE'S OR SMALLER LIKE

272
00:09:52,893 --> 00:09:54,061
THIS LESION, REPRESENT

273
00:09:54,061 --> 00:09:55,997
ACTIVATING MUTATIONS AND THE

274
00:09:55,997 --> 00:10:01,769
VAST MAJORITY OF THESE CASES OF

275
00:10:01,769 --> 00:10:03,738
ACTIVATING MUTATIONS IN THIS 1

276
00:10:03,738 --> 00:10:05,706
BIOCHEMICAL PATHWAY CALLED THE

277
00:10:05,706 --> 00:10:07,642
mTOR PATHWAY, TREATED

278
00:10:07,642 --> 00:10:09,944
SURGEICALLY AND IN FACT THESE

279
00:10:09,944 --> 00:10:11,045
KIDS GENERALLY RESPOND WELL TO

280
00:10:11,045 --> 00:10:12,780
SURGERY WITH MORE THAN HALF OF

281
00:10:12,780 --> 00:10:14,615
THEM BECOMES SEIZURE FREE.

282
00:10:14,615 --> 00:10:16,684
BUT THIS IS--EVEN THOUGH--THE

283
00:10:16,684 --> 00:10:18,986
MUTATIONS THAT CAUSE THIS

284
00:10:18,986 --> 00:10:20,955
CONDITION ARE CLASSIC ONCOGENIC

285
00:10:20,955 --> 00:10:22,490
MUTATIONS, ACTIVATING MUTATIONS

286
00:10:22,490 --> 00:10:25,326
IN PI3 KINASE, ACTIVATING

287
00:10:25,326 --> 00:10:28,095
MUTATIONS IN MTORE OR LOSS OF

288
00:10:28,095 --> 00:10:29,030
REGULATION IN REGULATORS AND

289
00:10:29,030 --> 00:10:34,235
DESPITE THE FACT THESE ARE

290
00:10:34,235 --> 00:10:35,536
ONCOGENIC MUTATIONS, THEY DO NOT

291
00:10:35,536 --> 00:10:36,837
GROW, THEY ARE STABLE AS FAR AS

292
00:10:36,837 --> 00:10:38,339
WE KNOW THROUGHOUT LIFE.

293
00:10:38,339 --> 00:10:39,507
THEY SHOW OVERGROWTH O THEY

294
00:10:39,507 --> 00:10:41,008
SHOULD AN EFFECTIVE CLONAL

295
00:10:41,008 --> 00:10:42,276
SELECTION, A POSITIVE SLOANAL

296
00:10:42,276 --> 00:10:43,778
SELECTION OF THE MUTANT CELLS

297
00:10:43,778 --> 00:10:47,114
AND THEN THE DIFFERENCE IN THE

298
00:10:47,114 --> 00:10:48,983
SIZE OF THE LESION SEEMS TO

299
00:10:48,983 --> 00:10:50,317
REFLECT THE TIMESSA THE WHICH

300
00:10:50,317 --> 00:10:51,919
THE MUTATION OCCURS, THE EXACT

301
00:10:51,919 --> 00:10:53,487
SAME MUTATIONS CAN BE FOUND IN

302
00:10:53,487 --> 00:10:56,757
THESE SMALLER LESIONS CALLED

303
00:10:56,757 --> 00:10:58,526
FOLK O COTTERRAL DISPLASSIAS OR

304
00:10:58,526 --> 00:11:00,361
IN THE LARGER LESIONS AND SO WE

305
00:11:00,361 --> 00:11:01,996
PREE SIEWM IT'S ALL ABOUT TIMING

306
00:11:01,996 --> 00:11:03,998
AND IN FACT, MANY OF THESE SAME

307
00:11:03,998 --> 00:11:05,966
MUTATIONS CAN CAUSE OVERGROWTH

308
00:11:05,966 --> 00:11:08,436
OF NONCNS TISSUES AS DESCRIBED

309
00:11:08,436 --> 00:11:10,271
LIE LES BESECURITIZATION.ER AND

310
00:11:10,271 --> 00:11:12,573
OTHERS THAT CAN CAUSE VASCULAR

311
00:11:12,573 --> 00:11:14,241
OVERGROWTH FOR EXAMPLE.

312
00:11:14,241 --> 00:11:15,242
AND THEN THE OTHER THING TO NOTE

313
00:11:15,242 --> 00:11:17,244
IS THAT THE HIGHER THE VARIANT

314
00:11:17,244 --> 00:11:18,446
FREQUENCY AND THE LARGER THE

315
00:11:18,446 --> 00:11:20,948
LESION IN GENERAL AND THAT ALSO

316
00:11:20,948 --> 00:11:25,486
CORRELATES WITH THE MORE SEVERE

317
00:11:25,486 --> 00:11:27,054
NEUROLOGICAL DISABILITY, EARLIER

318
00:11:27,054 --> 00:11:30,558
ONSET OF SEIZURES AND GREATER

319
00:11:30,558 --> 00:11:30,925
DISABILITY.

320
00:11:30,925 --> 00:11:33,194
THEY ARE ONLY 1 OR 2-CENTIMETERS

321
00:11:33,194 --> 00:11:35,629
IN SIZE AND THEY RESPOND WELL TO

322
00:11:35,629 --> 00:11:36,897
SURGICAL REMOVAL AND THE

323
00:11:36,897 --> 00:11:37,998
MUTATION IS ONLY PRESENT IN

324
00:11:37,998 --> 00:11:39,734
ABOUT WOKNOW% OF THE CELLS SO

325
00:11:39,734 --> 00:11:41,969
IT'S REMARKABLE HOW IRRITATING

326
00:11:41,969 --> 00:11:44,105
THAT VERY, VERY SMALL POPULATION

327
00:11:44,105 --> 00:11:45,740
OF MUTANT CELLS CAN BE, AND

328
00:11:45,740 --> 00:11:47,141
AGAIN, ALSO THE DISCOVERY OF

329
00:11:47,141 --> 00:11:49,710
THESE MUTATIONS HAS PROMPTED THE

330
00:11:49,710 --> 00:11:51,045
REPURPOSING OF mTOR INHIBITORS

331
00:11:51,045 --> 00:11:52,179
DEVELOPED FOR THE TREATMENT OF

332
00:11:52,179 --> 00:11:55,950
CANCER FOR THE USE OF

333
00:11:55,950 --> 00:11:59,153
INTRACTABLE EPILEPSY ALL THE

334
00:11:59,153 --> 00:12:00,554
RESULTS HAVE NOT BEEN QUITE AS

335
00:12:00,554 --> 00:12:04,458
POSITIVE AS WE HOPED AND I ALSO

336
00:12:04,458 --> 00:12:07,828
WANT TO ACKNOWLEDGE ALISSA,

337
00:12:07,828 --> 00:12:10,131
DE'GAMA WHO WORKED ON MANY OF

338
00:12:10,131 --> 00:12:13,300
THESE, AND OTHERS WHO WORKED IN

339
00:12:13,300 --> 00:12:15,603
LABS IN PARIS AND KOREA HAVE

340
00:12:15,603 --> 00:12:17,838
DONE GREAT WORK ON THIS.

341
00:12:17,838 --> 00:12:18,973
SO THAT'S REALLY JUST AN

342
00:12:18,973 --> 00:12:19,306
INTRODUCTION.

343
00:12:19,306 --> 00:12:22,877
NOW I WANT TO TURN TO ADULT

344
00:12:22,877 --> 00:12:23,577
EPILEPSY.

345
00:12:23,577 --> 00:12:26,413
WHAT HAPPENS IN ADULT EPILEPSY?

346
00:12:26,413 --> 00:12:29,450
AND THE MOST COMMON FORM OF FOLK

347
00:12:29,450 --> 00:12:35,756
EPILEPSY IN ADULLS AND MESIAL

348
00:12:35,756 --> 00:12:38,058
TEMPORAL LOBE EPILEPSY, AND IT'S

349
00:12:38,058 --> 00:12:39,894
REFERRED TO AS MEDIAL, I WILL

350
00:12:39,894 --> 00:12:44,131
REFER TO IT AS MTLE, HIPIECE OF

351
00:12:44,131 --> 00:12:47,568
CONTENTERATEY WROTE DUN IT, A

352
00:12:47,568 --> 00:12:58,045
TREATUS CONTRIBUTED TO  HIP

353
00:12:58,045 --> 00:12:59,780
KRACTIES, PEOPLE WERE THOUGHT TO

354
00:12:59,780 --> 00:13:01,315
BE POSSESSED BY SPIRITS BECAUSE

355
00:13:01,315 --> 00:13:03,184
THE PRESENTATION OF EPILEPS

356
00:13:03,184 --> 00:13:05,386
SEYMOUR PSYCHIATRIC THAN SAID

357
00:13:05,386 --> 00:13:07,121
NEUROLOGICAL, THE AURAS CAN BE

358
00:13:07,121 --> 00:13:09,690
MEMORIES OR VOICES OR SMELLS,

359
00:13:09,690 --> 00:13:12,459
RATHER THAN CONVULINGSS.

360
00:13:12,459 --> 00:13:15,329
BUT THEA THE AGE OF ONSET IS

361
00:13:15,329 --> 00:13:17,164
TYPICALLY NOT IN CHILDHOOD BUT

362
00:13:17,164 --> 00:13:18,899
IN ADULTHOOD AFTER A LATENCY

363
00:13:18,899 --> 00:13:22,169
PERIOD THAT CAN BE MANY DECADES.

364
00:13:22,169 --> 00:13:24,471
AND THEN, AS I SAID, AFTER THE

365
00:13:24,471 --> 00:13:26,440
AURAS THERE CAN BE SPEECH

366
00:13:26,440 --> 00:13:28,008
ARREST, LOSS OF ATTENTION AND IF

367
00:13:28,008 --> 00:13:30,611
THERE ARE CONVULINGSS, THEY

368
00:13:30,611 --> 00:13:33,480
GENERALLY REFLECT GENERALIZATION

369
00:13:33,480 --> 00:13:35,416
EPILEPSY OR YAWPED THE TEMPORAL

370
00:13:35,416 --> 00:13:36,483
LOBE ITSELF.

371
00:13:36,483 --> 00:13:38,485
THIS ACCOUNTS FOR 2/3RDS OF

372
00:13:38,485 --> 00:13:40,421
ADULT EPILEPS EXPE IT'S NEVER

373
00:13:40,421 --> 00:13:41,922
BEEN EXPLAINED WHY THE TEMPORAL

374
00:13:41,922 --> 00:13:44,925
LOBE OF ALL THE PARTS OF THE

375
00:13:44,925 --> 00:13:45,960
BRAIN ARE PREFERENTIALLY

376
00:13:45,960 --> 00:13:47,962
ASHINGED EMPLOY THOSE POODIATRIC

377
00:13:47,962 --> 00:13:49,563
CONDITIONS I MENTIONED AFFECT

378
00:13:49,563 --> 00:13:50,965
THENY O CORTEX BUT NOT

379
00:13:50,965 --> 00:13:52,032
PARTICULARLY THE TEMPORAL LOBE,

380
00:13:52,032 --> 00:13:53,834
WHERE THE ADULT FORM,

381
00:13:53,834 --> 00:13:54,835
PREFERENTIALLY AFFECTS THE

382
00:13:54,835 --> 00:13:55,202
TEMPORAL LOBE.

383
00:13:55,202 --> 00:13:56,971
AND WE KNOW THAT IT AFFECTS THE

384
00:13:56,971 --> 00:14:00,107
TEMPORAL LOBE BECAUSE IT HAS A

385
00:14:00,107 --> 00:14:00,741
CHARACTERISTIC NEUROPATHOLOGICAL

386
00:14:00,741 --> 00:14:03,244
HALL WACKER, THIS IS CALLED

387
00:14:03,244 --> 00:14:05,079
MESIAL TEMPORAL SCLEROSIS, SO IF

388
00:14:05,079 --> 00:14:07,448
WE SLICE THAT TEMPORAL LOBE, THE

389
00:14:07,448 --> 00:14:09,283
MEDIATE STRUCTURES OF THE

390
00:14:09,283 --> 00:14:10,551
TEMPORAL LOBE REPRESENT THE

391
00:14:10,551 --> 00:14:13,320
HYPOCAMPUS AND THEN THE

392
00:14:13,320 --> 00:14:15,422
LASTERALATISMERAL LOBE

393
00:14:15,422 --> 00:14:16,390
REPRESENTS THE AUDITORY

394
00:14:16,390 --> 00:14:18,926
NEOCORTEX, AND WITHIN THE

395
00:14:18,926 --> 00:14:20,761
HIPPOCAMPUS, PATIENTS WITH

396
00:14:20,761 --> 00:14:23,163
MESIAL TEMPORAL LOBE EPILEPSY,

397
00:14:23,163 --> 00:14:24,331
CHARACTERISTICALLY SHOW A LOSS,

398
00:14:24,331 --> 00:14:25,766
IN THE HORN FIELD OR CA FIELDS

399
00:14:25,766 --> 00:14:28,168
AND YOU CAN SEE THAT NORMALLY

400
00:14:28,168 --> 00:14:30,938
THESE NEURONS STAIN BROWN, FOR

401
00:14:30,938 --> 00:14:32,673
IMMUNE RESILIENCE ACTIVITY AND A

402
00:14:32,673 --> 00:14:34,441
TYPICAL SPECIMEN AND NEURONS IN

403
00:14:34,441 --> 00:14:35,776
THESE REGIONS ARE COMPLOATLY

404
00:14:35,776 --> 00:14:38,846
LOST, AND THIS CAN BE SEEN RADIO

405
00:14:38,846 --> 00:14:40,681
GRAF GRAPHICALLY AS A BRIGHT

406
00:14:40,681 --> 00:14:43,250
SPOT AND IT'S KNOWN THAT

407
00:14:43,250 --> 00:14:44,351
PATIENTS WITH THIS PARTICULAR

408
00:14:44,351 --> 00:14:45,185
PATHOLOGY ASK RADIOLOGY RESPOND

409
00:14:45,185 --> 00:14:47,488
VERY WELL TO TEMPORAL LOBE

410
00:14:47,488 --> 00:14:47,721
REMOVAL.

411
00:14:47,721 --> 00:14:50,324
AND SO THIS IS THE CLASSIC

412
00:14:50,324 --> 00:14:51,392
COMPLEX EPILEPSY.

413
00:14:51,392 --> 00:14:58,265
THERE ARE NO MEN DEALIAN FORMS,

414
00:14:58,265 --> 00:15:00,801
2/3RDS OF PATES WILL HAVE HEAD

415
00:15:00,801 --> 00:15:03,604
TRAUMA OR A SINGLE SEIZURE IN

416
00:15:03,604 --> 00:15:04,038
CHILDHOOD.

417
00:15:04,038 --> 00:15:05,773
INHERITED GENES HAVE BEEN SHOWN

418
00:15:05,773 --> 00:15:07,274
WHETHER RARE OR COMMON HAVE BEEN

419
00:15:07,274 --> 00:15:10,110
SHOWN TO HAVE LITTLE OR NO ROLE

420
00:15:10,110 --> 00:15:11,745
AND YET TEMPORAL REMOVAL HAS

421
00:15:11,745 --> 00:15:13,714
BEEN KNOWN SINCE THE DAYS OF

422
00:15:13,714 --> 00:15:16,817
WIDER PEN FIELD TO PRODUCE

423
00:15:16,817 --> 00:15:18,419
DRAMATIC IMPROVEMENT SO THAT

424
00:15:18,419 --> 00:15:20,387
PROMPTED US TO CHECK WHETHER

425
00:15:20,387 --> 00:15:25,559
SOMATIC VARIANCE MIGHT BE

426
00:15:25,559 --> 00:15:29,196
IMPORTANT IN TEMPORAL LOBE

427
00:15:29,196 --> 00:15:29,663
COMPLEX.

428
00:15:29,663 --> 00:15:31,198
SO WE COLLECTED ALL THE

429
00:15:31,198 --> 00:15:32,466
SPECIMENS WE COULD FIND FROM

430
00:15:32,466 --> 00:15:33,534
BOSTON CHILDREN'S HOSPITAL AND

431
00:15:33,534 --> 00:15:35,803
THEN WE STARTED IN COLLABORATION

432
00:15:35,803 --> 00:15:36,437
WITH CHRIS [INDISCERNIBLE] WHO

433
00:15:36,437 --> 00:15:38,339
WAS IN THE PROCESS OF MOVING

434
00:15:38,339 --> 00:15:39,540
FROM YALE TO MASS GENERAL, AND

435
00:15:39,540 --> 00:15:41,308
HE HAD A LARGE COLLECTION OF

436
00:15:41,308 --> 00:15:42,609
SPECIMENS FROM DENNIS SPENCERS

437
00:15:42,609 --> 00:15:44,812
FROM HIS AND DENNIS SPENCER'S

438
00:15:44,812 --> 00:15:47,281
OPERATIONS THERE, AND WE  

439
00:15:47,281 --> 00:15:48,615
PERFORM DEEP WHOLE EXOHM

440
00:15:48,615 --> 00:15:50,551
SEQUENCING SO MUCH DEEPER, MORE

441
00:15:50,551 --> 00:15:52,353
THAN 10 TIMES DEEPER THAN A

442
00:15:52,353 --> 00:15:53,821
TYPICAL COVERAGE YOU WOULD DO TO

443
00:15:53,821 --> 00:15:56,223
LOOK FOR GERM LINE MUTATIONS

444
00:15:56,223 --> 00:15:57,992
BECAUSE THE MOSAIC MUTATIONS ARE

445
00:15:57,992 --> 00:15:59,059
HARDER TO DETECT, THEY'RE ONLY

446
00:15:59,059 --> 00:16:00,294
AT A FRACTION OF THE READS AND

447
00:16:00,294 --> 00:16:02,563
SO YOU HAVE TO GET A LOT DEEPER

448
00:16:02,563 --> 00:16:06,000
READ COVERAGE AND IN FACT, THIS

449
00:16:06,000 --> 00:16:08,502
500 EXOHM SEQUENCING HAS VERY

450
00:16:08,502 --> 00:16:09,103
POOR SENSITIVITY.

451
00:16:09,103 --> 00:16:11,338
EVEN AT THAT DEPTH TO DETECT

452
00:16:11,338 --> 00:16:13,607
SOMATIC MUTATIONS, SO IN THESE

453
00:16:13,607 --> 00:16:16,076
HUNDRED OR SO CASES WE FOUND A

454
00:16:16,076 --> 00:16:17,277
GRAND TOTAL OF 11 MUTATIONS THAT

455
00:16:17,277 --> 00:16:19,113
WERE PREDICTED TO HAVE A

456
00:16:19,113 --> 00:16:20,981
DELETERIOUS EFFECT ON THE

457
00:16:20,981 --> 00:16:21,815
PROTEIN AND YET 10 OF 11 OF

458
00:16:21,815 --> 00:16:28,255
THESE WERE IN THE RAS, RAF MAPK

459
00:16:28,255 --> 00:16:30,924
KINASE PATHWAY AND THEY'RE ALL

460
00:16:30,924 --> 00:16:33,660
ACTIVATING MUTATIONS THAT

461
00:16:33,660 --> 00:16:37,097
INCLUDES CANCER MUTATIONS, RAS,

462
00:16:37,097 --> 00:16:47,241
12, V-AT THE CLASSIC  ALLELE AND

463
00:16:47,241 --> 00:16:49,910
ACTIVATING IN NEURO11, THE

464
00:16:49,910 --> 00:16:50,811
NEGATIVE REGULATOR SUCH THAT

465
00:16:50,811 --> 00:16:53,180
THESE ARE ALL PREDICT TO BE

466
00:16:53,180 --> 00:16:53,480
ACTIVATING.

467
00:16:53,480 --> 00:16:54,815
SOPHISTICATEDY THAT SHOWS THAT

468
00:16:54,815 --> 00:16:56,083
RAS MUTATIONS MIGHT BE IMPORTANT

469
00:16:56,083 --> 00:16:57,751
OR IMPORTANT IN SOME CASES, BUT

470
00:16:57,751 --> 00:17:00,521
WE WANTED TO GET A BETTER SENSE

471
00:17:00,521 --> 00:17:04,291
OF JUST HOW FREQUENT THESE

472
00:17:04,291 --> 00:17:06,260
MUTATIONS ARE AND FOR THAT WE

473
00:17:06,260 --> 00:17:08,128
NEEDED MUCH MORE SENSITIVE

474
00:17:08,128 --> 00:17:09,863
SEQUENCING AND WE   PERFOR THE

475
00:17:09,863 --> 00:17:10,998
PURPOSED SEQUENCING GREATER THAN

476
00:17:10,998 --> 00:17:13,033
A THOUSAND AND WE DID AN AMAZING

477
00:17:13,033 --> 00:17:15,002
YOB FROM ALL OVER THE WORLD,

478
00:17:15,002 --> 00:17:18,772
FROM PARIS FROM TORONTO, AND

479
00:17:18,772 --> 00:17:20,407
SEQUENCING MORE THAN 500 CASES

480
00:17:20,407 --> 00:17:23,811
AND HERE, WE FIND THAT, ABOUT

481
00:17:23,811 --> 00:17:26,346
40% OF THE CASES HAVE ACTIVATING

482
00:17:26,346 --> 00:17:28,882
MUTATIONS IN THE RAS PATHWAY,

483
00:17:28,882 --> 00:17:32,086
MOST COMMONLY IN PTPN 11 WHICH

484
00:17:32,086 --> 00:17:34,922
ENCODES SHIP 2 WHERE WE SEE A

485
00:17:34,922 --> 00:17:36,790
DOZEN DIFFERENT PATIENTS AND

486
00:17:36,790 --> 00:17:38,792
ANOTHER DOZEN WITH MUTATIONS AT

487
00:17:38,792 --> 00:17:41,195
E76, ANOTHER DOZEN WITH

488
00:17:41,195 --> 00:17:41,695
SUBSTITUTIONS AT P498.

489
00:17:41,695 --> 00:17:43,964
SO MORE THAN A HUNDRED CASES

490
00:17:43,964 --> 00:17:45,399
WITH JUST PTPN MUTATIONS WHICH

491
00:17:45,399 --> 00:17:47,634
IS 15% OF ALL OF THE CASES, ALL

492
00:17:47,634 --> 00:17:49,937
OF THEM ARE MISSENSED, MANY OF

493
00:17:49,937 --> 00:17:51,338
THEM ARE RECURRENT AND MOST OF

494
00:17:51,338 --> 00:17:53,207
THEM ARE KNOWN TO BE ACTIVATING

495
00:17:53,207 --> 00:17:54,975
IN THE CONTEXT OF CANCER OR IN

496
00:17:54,975 --> 00:17:57,177
THE CONTEXT OF NOONAN SYNDROME

497
00:17:57,177 --> 00:18:00,080
WHERE ACTIVATION OF THE RAS

498
00:18:00,080 --> 00:18:01,115
PATHWAY IS IMPLICATED, ANOTHER

499
00:18:01,115 --> 00:18:02,516
HUNDRED CASES HAD ACTIVATED

500
00:18:02,516 --> 00:18:08,622
MUTATIONS IN THE RAS PATHWAY

501
00:18:08,622 --> 00:18:15,896
LIKE RAS ITSELF OR RAS ITSELF OR

502
00:18:15,896 --> 00:18:17,898
PTPN11 OR MAP ITSELF OR BRAF,

503
00:18:17,898 --> 00:18:20,000
AND THAT WAS UNIMON, THIS YIELD

504
00:18:20,000 --> 00:18:21,268
WAS COMPARABLE TO WHAT WE WOULD

505
00:18:21,268 --> 00:18:23,670
FIND IF WE DID A SINGLE

506
00:18:23,670 --> 00:18:26,340
SEQUENCING EXPERIMENT ON THESE

507
00:18:26,340 --> 00:18:27,641
SINGLE CORTICALE FOCUSING

508
00:18:27,641 --> 00:18:30,110
DISPLASSIA, AND YET WHEN THESE

509
00:18:30,110 --> 00:18:32,346
ARE APPLIED YOU CAN RECOVER

510
00:18:32,346 --> 00:18:33,413
ACTIVATING mTOR MUTATIONS IN

511
00:18:33,413 --> 00:18:36,316
80 OR 90% OF THE CASES.

512
00:18:36,316 --> 00:18:39,620
SO WE SUSPECTED THESE ACTIVATING

513
00:18:39,620 --> 00:18:40,787
RAS MUTATIONS MIGHT BE IMPORTANT

514
00:18:40,787 --> 00:18:42,556
IN A VERY LARGE FRACTION OF

515
00:18:42,556 --> 00:18:45,559
TEMPORAL LOBE OF EPILEPSY AND OF

516
00:18:45,559 --> 00:18:48,896
ALL CASES, 3-QUARTERS OF THE

517
00:18:48,896 --> 00:18:52,099
POSITIVE CASES SHOWED SCLEROSIS,

518
00:18:52,099 --> 00:18:53,567
SHOWED NO TUMOR, NO DISPLASSIA,

519
00:18:53,567 --> 00:18:55,502
AND THIS WAS HIGHER IN PATIENTS

520
00:18:55,502 --> 00:18:56,904
THAT HAD NO OTHER PATHOLOGY THAN

521
00:18:56,904 --> 00:18:58,672
IT WAS IN THOSE PATIENTS THAT

522
00:18:58,672 --> 00:19:00,073
ARE DUAL PATHOLOGY, THAT HAD

523
00:19:00,073 --> 00:19:03,710
ADDITIONAL THINGS LIKE A TUMOR

524
00:19:03,710 --> 00:19:04,311
OR DISPLASSIA.

525
00:19:04,311 --> 00:19:07,281
AND SO SOME OF THESE CASES WE

526
00:19:07,281 --> 00:19:08,715
HAVE MATCHED TISSUE FROM THE

527
00:19:08,715 --> 00:19:10,217
HIPPOCAMPUS AND FROM THE

528
00:19:10,217 --> 00:19:11,251
NEIGHBORING TEMPORAL LOBE AND

529
00:19:11,251 --> 00:19:14,488
WHAT WE NOTICED IS THAT IN ALL

530
00:19:14,488 --> 00:19:16,456
CASES, THE VARIANT IS PRESENT IN

531
00:19:16,456 --> 00:19:17,624
A HIGHER FRACTION OF CELLS AT

532
00:19:17,624 --> 00:19:21,094
WHAT WE CALL A HIGHER VARIANT

533
00:19:21,094 --> 00:19:22,696
ALLELE FREQUENCY IN THE

534
00:19:22,696 --> 00:19:24,831
HIPPOCAMPUS THAN IT IS IN THE

535
00:19:24,831 --> 00:19:26,900
NEIGHBORING CORTEX, SO IN THIS

536
00:19:26,900 --> 00:19:29,102
CASE IT'S PRESCRIBINGENT AT A

537
00:19:29,102 --> 00:19:31,071
VARIANTY FERENCEY OF 2 AND HALF

538
00:19:31,071 --> 00:19:34,074
THAT MEANS IT'S IN ABOUT HALF

539
00:19:34,074 --> 00:19:36,376
THE CELLS, DOUBLE THE THAT GIVES

540
00:19:36,376 --> 00:19:38,045
THE CELLS CARRYING THAT AND THEN

541
00:19:38,045 --> 00:19:41,248
IT'S UNDETECTABLE IN THE

542
00:19:41,248 --> 00:19:42,449
NEIGHBORING NEOCORTEX.

543
00:19:42,449 --> 00:19:43,617
AND THE OTHER THING WE NOTICE

544
00:19:43,617 --> 00:19:45,419
SIDE THAT THE WITH THE

545
00:19:45,419 --> 00:19:46,820
CORRELATION EARLIER AT THE TIME

546
00:19:46,820 --> 00:19:48,789
OF SURGERY, CAN YOU SEE HERE A

547
00:19:48,789 --> 00:19:50,591
50 YEAR-OLD FEMALE HAD A VARIANT

548
00:19:50,591 --> 00:19:52,593
ALLELE FREQUENCY OF 1, WE HAD A

549
00:19:52,593 --> 00:19:54,228
10 YEAR-OLD FEMALE, HAD A

550
00:19:54,228 --> 00:19:56,063
VARIANT ALLELE FREQUENCY THAT'S

551
00:19:56,063 --> 00:19:59,066
ABOUT 8, OR MALE, WHO IS

552
00:19:59,066 --> 00:20:01,068
OPERATED ON YOUNGER THAN 10 HAD

553
00:20:01,068 --> 00:20:02,369
A ALLELE FREQUENCY OF ABOUT 30

554
00:20:02,369 --> 00:20:05,706
AND SO ON, SO IT SEEPS JUST LIKE

555
00:20:05,706 --> 00:20:07,207
WITH mTOR, THE LARGER FRACTION

556
00:20:07,207 --> 00:20:08,775
OF CELLS THAT CARRY THE

557
00:20:08,775 --> 00:20:10,277
MUTATION, THE EARLIER THE ONSET

558
00:20:10,277 --> 00:20:11,712
OF THE EPILEPSY AND LIKELY THE

559
00:20:11,712 --> 00:20:14,881
MORE SEVERE THEY ARE.

560
00:20:14,881 --> 00:20:17,050
WELL THE INVOLVEMENT OF THESE

561
00:20:17,050 --> 00:20:20,587
MUTATIONS IN THE HIPPOCAMPUS

562
00:20:20,587 --> 00:20:21,688
CREATES A REMARKABLE SITUATION

563
00:20:21,688 --> 00:20:24,625
BECAUSE UNLIKE THE TEMPORAL,

564
00:20:24,625 --> 00:20:25,359
UNLIKE THE NEOCORTEX WHERE I

565
00:20:25,359 --> 00:20:28,595
TOLL YOU ALL OF THE NEURONS ARE

566
00:20:28,595 --> 00:20:31,565
POST MITOTIC, IN FACT IN THE

567
00:20:31,565 --> 00:20:33,000
HIPPOCAMPUS, SPECIAL OF COURSELY

568
00:20:33,000 --> 00:20:35,235
IN THE GYRUS OF THE HIPPOCAMPUS,

569
00:20:35,235 --> 00:20:37,404
THIS IS THE 1 PLACE IN THE

570
00:20:37,404 --> 00:20:40,574
CORTEX WHERE STEM CELLS PERSIST

571
00:20:40,574 --> 00:20:41,975
THROUGHOUT FETAL GUESTATION AND

572
00:20:41,975 --> 00:20:42,809
THROUGHOUT BIRTH, WHERE NEURONS

573
00:20:42,809 --> 00:20:44,344
CONTINUE TO BE FORMED AT LEAST

574
00:20:44,344 --> 00:20:47,347
FOR A FEW YEARS AFTER BIRTH.

575
00:20:47,347 --> 00:20:50,284
AND IN THE--AT THE PRESENT IN

576
00:20:50,284 --> 00:20:52,352
HUMANS IT'S CONTROVERSIAL

577
00:20:52,352 --> 00:20:54,288
WHETHER THIS POSTNATAL

578
00:20:54,288 --> 00:20:55,589
NEUROGENESIS IS LIFE LONG OR

579
00:20:55,589 --> 00:20:56,890
WHETHER IT PERSISTS FOR A FEW

580
00:20:56,890 --> 00:20:58,458
YEARS BUT THERE'S A CONSENSUS

581
00:20:58,458 --> 00:20:59,593
THAT THERE'S NO DOUBT IT

582
00:20:59,593 --> 00:21:00,894
CONTINUES AT LEAST FOR THE FIRST

583
00:21:00,894 --> 00:21:02,429
FEW YEARS OF LIFE.

584
00:21:02,429 --> 00:21:06,033
AND IN ANIMAL MODELS THIS

585
00:21:06,033 --> 00:21:07,200
HIPPOCAMPAL NEUROGENESIS HAS

586
00:21:07,200 --> 00:21:08,835
BEEN IMPLICATED IN MEMORY,

587
00:21:08,835 --> 00:21:10,337
FORMATION AND CONSOLIDATION, BUT

588
00:21:10,337 --> 00:21:11,972
IT'S ALSO MODULATED BY ALMOST

589
00:21:11,972 --> 00:21:14,841
EVERYTHING, THE ACTIVITY, THE

590
00:21:14,841 --> 00:21:18,078
TREADMILL, TOXINS, SEIZURES,

591
00:21:18,078 --> 00:21:22,683
WHICH INDUCE A WAVE OF WAVE OF

592
00:21:22,683 --> 00:21:24,551
NEUROGENESIS IN THE DENTATE

593
00:21:24,551 --> 00:21:26,219
GYRUS AND MANY OTHER THINGS AND

594
00:21:26,219 --> 00:21:28,588
SO THIS SUGGESTS THE POSSIBILITY

595
00:21:28,588 --> 00:21:30,624
THAT LIFE EVENTS MIGHT ACTUALLY

596
00:21:30,624 --> 00:21:32,259
MODULATE THE RISK OF THE

597
00:21:32,259 --> 00:21:33,660
TEMPORAL LOBE EPILEPSY BY

598
00:21:33,660 --> 00:21:35,529
MODUTING THE PROCESS OF

599
00:21:35,529 --> 00:21:36,363
NEUROGENESIS AND THIS CORTOON

600
00:21:36,363 --> 00:21:39,433
EXPLAINS THE WAY WE THINK ABOUT

601
00:21:39,433 --> 00:21:40,000
IT.

602
00:21:40,000 --> 00:21:41,668
SO CONGENITAL ACTIVATION OF THE

603
00:21:41,668 --> 00:21:44,471
RAS PATHWAY IN NEURONS IS KNOWN

604
00:21:44,471 --> 00:21:45,806
TO BE INHERENTLY EPILEPTIC, AS

605
00:21:45,806 --> 00:21:48,508
IT IS ACTIVATION OF THE PATHWAY

606
00:21:48,508 --> 00:21:49,710
NEURONS, BOTH OF THESE TEND TO

607
00:21:49,710 --> 00:21:51,945
MAKE THE NEURONS THAT CARRY THE

608
00:21:51,945 --> 00:21:53,747
VARIANT INTENSELY EPILEPTIC AND

609
00:21:53,747 --> 00:21:56,249
SO THAT--SO, NEURONS MIGHT BE--A

610
00:21:56,249 --> 00:21:58,452
SMALL CLONE OF NEURONS MIGHT

611
00:21:58,452 --> 00:22:01,121
CARRY AN ACTIVATING RAS MUTATION

612
00:22:01,121 --> 00:22:02,289
AND THIS REP SESENTSA I RISK

613
00:22:02,289 --> 00:22:03,924
FACTOR IN WHAT MIGHT BE PRESENT

614
00:22:03,924 --> 00:22:05,525
IN WHAT GOES ON TO HAVE SEIZURES

615
00:22:05,525 --> 00:22:07,361
BUT THEN IF THERE'S A RISK

616
00:22:07,361 --> 00:22:10,097
FACTOR, THAT WOULD STIMULATE A

617
00:22:10,097 --> 00:22:11,164
WAVE OF PROLIFERATION AND STEM

618
00:22:11,164 --> 00:22:12,332
CELLS THAT CARRY THIS VARIANT

619
00:22:12,332 --> 00:22:15,669
AND ANY SORT OF PROLIFERATION

620
00:22:15,669 --> 00:22:18,905
WILL FAVOR CLONES, THAT HAVE

621
00:22:18,905 --> 00:22:19,673
ACTIVATING CANCER MUTATIONS AND

622
00:22:19,673 --> 00:22:22,809
SO THAT WOULD CAUSE THE RAS

623
00:22:22,809 --> 00:22:24,444
ACTIVATED CLONES TO GROWTH

624
00:22:24,444 --> 00:22:29,049
FACTOR BIGGER THAN THE NORMAL

625
00:22:29,049 --> 00:22:29,282
CLONES.

626
00:22:29,282 --> 00:22:31,084
THAT CREATES A HIGHER GROUP OF

627
00:22:31,084 --> 00:22:32,519
CELLS THAT ARE NOW CARRYING THE

628
00:22:32,519 --> 00:22:34,287
MUTATION AND I JUST TOLD YOU THE

629
00:22:34,287 --> 00:22:35,355
HIGHER THE FRACTION OF CELLS

630
00:22:35,355 --> 00:22:37,090
THAT CARRY THE VARIANT, THE

631
00:22:37,090 --> 00:22:38,725
EARLIER THE ONSET OF SEIZURES

632
00:22:38,725 --> 00:22:41,128
AND THE GREATER THE RISK OF

633
00:22:41,128 --> 00:22:44,097
EPILEPSY, AND SO THIS MODEL CAN

634
00:22:44,097 --> 00:22:45,665
EXPLAIN THE

635
00:22:45,665 --> 00:22:46,199
PREDOMINANTLYLICATION OF

636
00:22:46,199 --> 00:22:47,300
EPILEPSY FOR THE LOBE IN THE

637
00:22:47,300 --> 00:22:49,269
FIRST PLACE BECAUSE OF THE

638
00:22:49,269 --> 00:22:50,504
PHENOMENON OF POST NEURONATAL

639
00:22:50,504 --> 00:22:52,172
GENESIS AND ALSO THE WELL KNOWN

640
00:22:52,172 --> 00:22:54,708
CLINICAL PEARL THAT SEIZURES

641
00:22:54,708 --> 00:22:56,109
BEGET SEIZURES, THAT THE PATIENT

642
00:22:56,109 --> 00:22:58,912
MIGHT HAVE HIS FIRST SEIZURE AT

643
00:22:58,912 --> 00:23:00,447
AGE 18, AND THE NEXT SEIZURE

644
00:23:00,447 --> 00:23:03,450
MIGHT BE 6 MONTHS LATER, OR 6

645
00:23:03,450 --> 00:23:05,619
YEARS LATER OR FOURTH SEIZURE

646
00:23:05,619 --> 00:23:07,354
MAY BE 6 YEARS LATER AND THERE

647
00:23:07,354 --> 00:23:10,657
ARE SOMETHING ABOUT SEIZURES

648
00:23:10,657 --> 00:23:12,826
THAT ARE EPILEAPT GENIC.

649
00:23:12,826 --> 00:23:14,561
WE CAN USE THE TOOLS THAT ARE

650
00:23:14,561 --> 00:23:16,563
DEVELOPED TO LOOK AT CANCER

651
00:23:16,563 --> 00:23:18,565
DRIVER MUTATIONS TO ASK WHETHER

652
00:23:18,565 --> 00:23:19,599
THESE ACTIVATING RAS

653
00:23:19,599 --> 00:23:20,534
MUTATIONINGS ARE UNDER CLONAL

654
00:23:20,534 --> 00:23:22,269
SELECTION IN THE TEMPORAL LOBE,

655
00:23:22,269 --> 00:23:24,704
AND SURE ENOUGH, IN THE

656
00:23:24,704 --> 00:23:28,041
EPILEPTIC BRAIN, THEY ARE AS

657
00:23:28,041 --> 00:23:34,047
SHOWN BY THESE THAT ARE ABOVE

658
00:23:34,047 --> 00:23:34,815
THIS PF.05 SIGNIFICANCE LINE

659
00:23:34,815 --> 00:23:37,484
WHEREAS IN THE NORMAL BREAN THEY

660
00:23:37,484 --> 00:23:39,419
DON'T SHOW STRONG EVIDENT OF THE

661
00:23:39,419 --> 00:23:41,488
POSITIVE SELECTION, WHERE WE'VE

662
00:23:41,488 --> 00:23:42,422
ALSO TAKEN ENGINEERED IPS LINES

663
00:23:42,422 --> 00:23:46,159
THAT HAVE 1 OF THE ACTIVATING

664
00:23:46,159 --> 00:23:47,894
PTPN LISTEN MUTATIONS, WE MIXED

665
00:23:47,894 --> 00:23:49,095
IT WITH THE WILD-TYPE CELLS AND

666
00:23:49,095 --> 00:23:50,964
YOU CAN SEE THAT THEY VERY

667
00:23:50,964 --> 00:23:52,265
QUICKLY OVERGROW THE CULTURE

668
00:23:52,265 --> 00:23:56,903
SOPHISTICATEDY THEY CLEARLY HAVE

669
00:23:56,903 --> 00:23:57,671
A PROLIFERATIVE ADVANTAGE.

670
00:23:57,671 --> 00:24:00,040
SO JUST TO SUMMARIZE, WE THINK

671
00:24:00,040 --> 00:24:01,608
THAT THIS IS--THIS HAS REALLY

672
00:24:01,608 --> 00:24:02,309
IMPORTANT THERAPEUTIC

673
00:24:02,309 --> 00:24:04,077
IMPLICATIONS BECAUSE JUST AS

674
00:24:04,077 --> 00:24:05,378
THEIR mTOR INHIBITORS, THERE

675
00:24:05,378 --> 00:24:07,147
ARE ALSO INHIBITORS OF THE MAP

676
00:24:07,147 --> 00:24:08,315
KINASE PATHWAY THAT HAVE BEEN

677
00:24:08,315 --> 00:24:09,516
DEVELOPED FOR CANCER BUT NOW

678
00:24:09,516 --> 00:24:11,485
THEY ACTUALLY ARE POTENTIAL

679
00:24:11,485 --> 00:24:13,420
APPLICABILITY TO AGAIN, A VERY

680
00:24:13,420 --> 00:24:15,522
COMMON FORM OF ADULT EPILEPSY.

681
00:24:15,522 --> 00:24:18,625
NOW, WE ALSO WANT TO KNOW WHY

682
00:24:18,625 --> 00:24:22,162
THESE NEURONS DIE, SO, TEMPORAL

683
00:24:22,162 --> 00:24:22,896
EPILEPSY IS A DEGENERATIVE

684
00:24:22,896 --> 00:24:23,997
CONDITION, IS THIS DUE TO THE

685
00:24:23,997 --> 00:24:25,832
MUTATION IN THE NEURONS OR DUE

686
00:24:25,832 --> 00:24:27,200
TO THE MUTATION IN THE DPLEEL

687
00:24:27,200 --> 00:24:29,069
CELLS THAT MIGHT KILL THE

688
00:24:29,069 --> 00:24:29,302
NEURONS?

689
00:24:29,302 --> 00:24:31,605
AND WE THINK WE HAVE SOME EFS

690
00:24:31,605 --> 00:24:33,006
THAT THE MUTATION IS--EVIDENCE

691
00:24:33,006 --> 00:24:35,242
THAT THE MUTATION IS ARISING IN

692
00:24:35,242 --> 00:24:37,511
THE NEUROEPITHELIUM BECAUSE IF

693
00:24:37,511 --> 00:24:38,712
WE SORT DIFFERENT SUBTYPES OF

694
00:24:38,712 --> 00:24:40,914
CELLS WE CAN FIND THEM IN THE

695
00:24:40,914 --> 00:24:42,849
NEURONS AND THE DENDRITES AND

696
00:24:42,849 --> 00:24:44,618
ASTRO SIGHTS SO IT'S CLEARLY

697
00:24:44,618 --> 00:24:45,886
PRESENT IN THE NEUROEPITHELIUM

698
00:24:45,886 --> 00:24:47,787
AND WE SUSPECTED THIS IS WHERE

699
00:24:47,787 --> 00:24:50,056
IT'S ORIGIN IS, BUT IT'S AGAIN

700
00:24:50,056 --> 00:24:51,224
PRESENT IN MULTIPLE CELL TYPES

701
00:24:51,224 --> 00:24:53,126
SO WE DON'T YET KNOW WHETHER THE

702
00:24:53,126 --> 00:24:54,528
NEURONS DIED BY SUICIDE OR

703
00:24:54,528 --> 00:24:55,896
WHETHER THEY GET MURDERED.

704
00:24:55,896 --> 00:24:57,964
WE ALSO WOULD LIKE TO FORMALLY

705
00:24:57,964 --> 00:25:01,301
TEST THE SITE THAT EPILEPSY

706
00:25:01,301 --> 00:25:03,270
INDUCES PROLIFERATION IN HUMAN

707
00:25:03,270 --> 00:25:04,538
TEMPORAL LOBE TISSUE AND WE

708
00:25:04,538 --> 00:25:06,273
THINK WE MIGHT BE ABLE TO DO

709
00:25:06,273 --> 00:25:07,541
THAT WITH SINGLE CELL METHODS

710
00:25:07,541 --> 00:25:12,279
THAT I WILL DESCRIBE LATER IN

711
00:25:12,279 --> 00:25:13,580
THE TALK.

712
00:25:13,580 --> 00:25:15,248
SO AFTER FINDING THESE

713
00:25:15,248 --> 00:25:17,384
ACTIVATING CANCER MUTATIONS IN

714
00:25:17,384 --> 00:25:18,585
THE TEMPORAL LOBE AND REALIZING

715
00:25:18,585 --> 00:25:19,619
THEY COULD BE SUCK YECT TO

716
00:25:19,619 --> 00:25:22,522
SELECTION IF THE CELLS UNDERGO

717
00:25:22,522 --> 00:25:23,223
PROLIFERATION, WE WONDERED

718
00:25:23,223 --> 00:25:24,925
WHETHER THIS IDEA OF CLONAL

719
00:25:24,925 --> 00:25:27,327
SELECTION MIGHT BE IMPORTANT IN

720
00:25:27,327 --> 00:25:28,929
OTHER DISEASES, THAT OCCUR LATE

721
00:25:28,929 --> 00:25:32,198
IN LIFE, AND WHERE WE KNOW THAT

722
00:25:32,198 --> 00:25:34,534
THERE IS INFLAMMATION WHICH ALSO

723
00:25:34,534 --> 00:25:35,535
STIMULATES PROLIFERATION, IN

724
00:25:35,535 --> 00:25:37,771
WHICH THEREFORE MIGHT ALSO SERVE

725
00:25:37,771 --> 00:25:42,342
AS A VEHICLE TO SELECT FOR

726
00:25:42,342 --> 00:25:43,843
MUTANT CLONES THAT MIGHT HAVE

727
00:25:43,843 --> 00:25:44,744
CANCER MUTATIONS.

728
00:25:44,744 --> 00:25:50,016
SO 2 BRAVE POST DOCS, AUGUST

729
00:25:50,016 --> 00:25:50,216
 CAN

730
00:25:50,216 --> 00:25:53,453
[INDISCERNIBLE] AND THEN

731
00:25:53,453 --> 00:25:55,255
[INDISCERNIBLE] A TALENTED POST

732
00:25:55,255 --> 00:25:56,456
DOCKERS WILL TAIGD A BRAND ANDEE

733
00:25:56,456 --> 00:25:57,991
IF THEY HAD ACTIVATING CANCER

734
00:25:57,991 --> 00:25:59,926
MUTATIONS IN THE CELLS OF

735
00:25:59,926 --> 00:26:01,361
ALZHEIMER BRAIN.

736
00:26:01,361 --> 00:26:03,530
WE TOOK PREFRONT WILL CORTEX

737
00:26:03,530 --> 00:26:04,898
FROM ALMOST 200 ALZHEIMER CASES

738
00:26:04,898 --> 00:26:06,333
AND OVER A HUNDRED AGED CONTROLS

739
00:26:06,333 --> 00:26:08,902
AND WE DID A CANCER PANEL OF 149

740
00:26:08,902 --> 00:26:10,637
CANCER YEENS WHERE WE COULD

741
00:26:10,637 --> 00:26:12,672
DETECT MUTATIONS EACH IF THEY'RE

742
00:26:12,672 --> 00:26:14,908
PRESENT OFTEN IN A FEW 1 OR 2%

743
00:26:14,908 --> 00:26:16,042
OF THE CELLS.

744
00:26:16,042 --> 00:26:18,244
SO WE SEQUENCED IT EVEN DEEPER,

745
00:26:18,244 --> 00:26:22,382
ALMOST 2000 X AVERAGE COVERAGE,

746
00:26:22,382 --> 00:26:23,817
SIMILAR IN AID ALZHEIMERS AND

747
00:26:23,817 --> 00:26:25,652
CONTROLS AND WE FOUND SURE

748
00:26:25,652 --> 00:26:26,620
ENOUGH, THE ALZHEIMER CASES

749
00:26:26,620 --> 00:26:29,489
ACTUALLY HAVE A HIGHER RATE OF

750
00:26:29,489 --> 00:26:32,826
MUTATIONS IN CANCER GENES, THAN

751
00:26:32,826 --> 00:26:33,627
AGE MATCHED CONTROLS.

752
00:26:33,627 --> 00:26:35,795
THE AGE MATCHED CONTROLS HAVE

753
00:26:35,795 --> 00:26:38,765
PLENTY OF THEM BUT ALZHEIMERS

754
00:26:38,765 --> 00:26:41,368
HAS THE STRINGENT PIPELINE WHICH

755
00:26:41,368 --> 00:26:42,302
ELIMINATES CURRENTLY MUTATED

756
00:26:42,302 --> 00:26:45,572
GENES, YOU SEE THAT THE

757
00:26:45,572 --> 00:26:46,940
DIFFERENCES IS THERE 30%

758
00:26:46,940 --> 00:26:48,475
INCREASE ANDOOSE A MORE MODEST

759
00:26:48,475 --> 00:26:49,909
INCREASE IF WE INCLUDE ALL

760
00:26:49,909 --> 00:26:52,012
MUTATED JEEPS ON THE PANEL BUT

761
00:26:52,012 --> 00:26:56,950
ACTUALLY A HIGHER P-VALUE.

762
00:26:56,950 --> 00:26:58,952
AND THIS DRVES IS ROBUST TO

763
00:26:58,952 --> 00:27:00,920
CONTROLLING FOR GENDER AND AGE,

764
00:27:00,920 --> 00:27:02,622
SEQUENCING COVERAGE AND

765
00:27:02,622 --> 00:27:04,691
POSTMORTEM INTERVAL AND TPEERS

766
00:27:04,691 --> 00:27:07,827
THAT ACCUMULATION OF CANCER

767
00:27:07,827 --> 00:27:08,695
DRIVER MUTATIONS IS SOMETHING

768
00:27:08,695 --> 00:27:10,664
THAT HAPPENS WITH AGE BUT IS

769
00:27:10,664 --> 00:27:13,400
ENHANCED IN THE ALZHEIMER BRAND

770
00:27:13,400 --> 00:27:14,134
AND MODALLY ALTHOUGH IT'S

771
00:27:14,134 --> 00:27:14,834
PARTICULARLY ENHANCE, I WANT TO

772
00:27:14,834 --> 00:27:16,970
YOU LOOK AT THE JEEPS THAT ARE

773
00:27:16,970 --> 00:27:17,804
RECURRENTLY MUTATED EMPLOY THOSE

774
00:27:17,804 --> 00:27:28,348
SHOW A MUCH STRONGER ENRICHMENT

775
00:27:30,016 --> 00:27:30,750
COMPARED TO CONTROL.

776
00:27:30,750 --> 00:27:32,385
ALTHOUGH THESE DIFFERENCES ARE

777
00:27:32,385 --> 00:27:33,119
NOT STATISTICALLY SIGNIFICANT

778
00:27:33,119 --> 00:27:34,921
BUT THIS MIGHT BE A WAY OF

779
00:27:34,921 --> 00:27:40,193
THINKING ABOUT HOW THE APOE4

780
00:27:40,193 --> 00:27:42,629
CREATES RISK BY STIMMULING THIS

781
00:27:42,629 --> 00:27:43,063
CLONAL COMPILATION.

782
00:27:43,063 --> 00:27:45,565
SO THIS IS A LIST OF THE MOST

783
00:27:45,565 --> 00:27:47,300
COMMONLY MUTATED JOONS, IT'S NOT

784
00:27:47,300 --> 00:27:51,638
RAS, IT'S NOT mTOR, IT'S GENES

785
00:27:51,638 --> 00:27:54,841
LIKE DNMT3 A AND XLS 1, THESE

786
00:27:54,841 --> 00:27:56,910
ARE YEENS THAT ARE VERY FAMILIAR

787
00:27:56,910 --> 00:27:58,578
BECAUSE THEY'RE CURRENTLY MUTATE

788
00:27:58,578 --> 00:28:00,213
INDEED BLOOD DISORDERS, CLONAL

789
00:28:00,213 --> 00:28:04,517
DISORDERS OF BLOOD, THINGS LIKE

790
00:28:04,517 --> 00:28:05,985
CLONAL HEMEAT O POETICESIS, AND

791
00:28:05,985 --> 00:28:08,054
THAT CONSIST WENT THE IDEA THAT

792
00:28:08,054 --> 00:28:11,424
IN CELLS PARTICULARLY THE

793
00:28:11,424 --> 00:28:13,293
MICROGLIA SHARE SOME COMMON

794
00:28:13,293 --> 00:28:15,562
PHENOTYPE AND LINEAGES WITH

795
00:28:15,562 --> 00:28:20,166
THESE MYELOID CELLS OF THE

796
00:28:20,166 --> 00:28:22,736
BLOOD, AND AND THESE YEENS ARE

797
00:28:22,736 --> 00:28:24,104
MUTATE INDEED ALZHEIMERS AND

798
00:28:24,104 --> 00:28:25,872
AGED CONTROLS BUT MORE COMMONLY

799
00:28:25,872 --> 00:28:27,841
IN ALZHEIMERS THERE ARE MORE

800
00:28:27,841 --> 00:28:29,008
YEENS THAT NOMINALLY HAVE

801
00:28:29,008 --> 00:28:31,111
GREATER NUMBERS OF MUTATIONS IN

802
00:28:31,111 --> 00:28:32,579
ALZHEIMER THAN CONTROL, THIS

803
00:28:32,579 --> 00:28:34,114
DOESN'T SURVIVE CORRECTION FROM

804
00:28:34,114 --> 00:28:35,949
149 DIFFERENT HYPOTHESIS AND IN

805
00:28:35,949 --> 00:28:38,051
ALZHEIMERS WE SEE INDIVIDUALS

806
00:28:38,051 --> 00:28:39,686
THAT ARE SIMULTANEOUS MUTATIONS

807
00:28:39,686 --> 00:28:41,321
OF YEEPS AT THE SAME TIME SHOWN

808
00:28:41,321 --> 00:28:42,388
BY THE ARROW HEADS AND WE HAVE

809
00:28:42,388 --> 00:28:44,057
NOT SEEN THAT IN A SINGLE AGE OF

810
00:28:44,057 --> 00:28:46,226
CONTROL. 

811
00:28:46,226 --> 00:28:47,393
AND SO THERE'S--THAT'S ANOTHER

812
00:28:47,393 --> 00:28:49,929
DIFFERENCE THAT IS STATISTICALLY

813
00:28:49,929 --> 00:28:50,263
SIGNIFICANT.

814
00:28:50,263 --> 00:28:52,031
AND THE--BUT WHAT WE FIND IN

815
00:28:52,031 --> 00:28:56,302
ALZHEIMER'S ALSO IS THAT THE

816
00:28:56,302 --> 00:28:59,172
GENES ARE PRESENT IN A LARGER

817
00:28:59,172 --> 00:29:01,307
MUTANT FRACTION SUGGESTING

818
00:29:01,307 --> 00:29:04,477
THEY'RE UNDER POSITIVE EVOLUTION

819
00:29:04,477 --> 00:29:05,712
AREA EXTENSION THAN IN CONTROLS

820
00:29:05,712 --> 00:29:08,882
THIS, IS PARTICULARLY TRUE FOR

821
00:29:08,882 --> 00:29:11,384
TUMOR SUPPRESSOR YEENS AND A

822
00:29:11,384 --> 00:29:12,919
PARTICULARLY FOR THESE 40%

823
00:29:12,919 --> 00:29:14,487
MUTATED YEENS AND I JUST SHOWED

824
00:29:14,487 --> 00:29:16,389
YOU ON THE PANEL AND YOU CAN

825
00:29:16,389 --> 00:29:17,991
DEMONSTRATE THAT THESE MUTATIONS

826
00:29:17,991 --> 00:29:19,192
ARE UNDER POSITIVE SELECTION

827
00:29:19,192 --> 00:29:21,795
UNDER BOTH NORMAL AGED CASES BUT

828
00:29:21,795 --> 00:29:23,596
TO A GREATER EXTEND IN

829
00:29:23,596 --> 00:29:24,764
ALZHEIMERS THAN IN NORMAL AGING

830
00:29:24,764 --> 00:29:26,766
BUT WE THINK OF THIS AS A

831
00:29:26,766 --> 00:29:27,834
PHENOMENON THAT HAPPENS, THIS

832
00:29:27,834 --> 00:29:28,902
CLONAL SELECTION HAPPENS IN

833
00:29:28,902 --> 00:29:34,574
NORMAL AGING BUT IS ENHANCED

834
00:29:34,574 --> 00:29:35,575
ABOUT SOMEBODY ABOUT THE BRAIN

835
00:29:35,575 --> 00:29:38,912
CAUSE ITS TO BE ENHANCED SO WHAT

836
00:29:38,912 --> 00:29:39,879
CARRYING THESE, AND THE YEENS

837
00:29:39,879 --> 00:29:42,749
AND WHAT WE KNEW ABOUT THE

838
00:29:42,749 --> 00:29:44,150
PATHOGENESIS OF ALZHEIMER'S DEC,

839
00:29:44,150 --> 00:29:46,119
OUR TOP SUSPECT WAS THE

840
00:29:46,119 --> 00:29:50,890
MICROGLIA CELLS WHICH ARE FORMED

841
00:29:50,890 --> 00:29:53,259
FROM A MOILOID LIKE PRECURSOR

842
00:29:53,259 --> 00:29:55,495
AND SEPARATES THEM EARLY AND

843
00:29:55,495 --> 00:30:00,834
CONTINUES TO DEVELOP IN THE

844
00:30:00,834 --> 00:30:04,037
BRAIN AND SO XENON TWEPPED A WAY

845
00:30:04,037 --> 00:30:05,772
TO PURIFY THEM OR ENRICH THEM SO

846
00:30:05,772 --> 00:30:08,107
THAT WE CAN GET PRIPERATION

847
00:30:08,107 --> 00:30:09,709
THAT'S 3-QUARTERS OR MORE

848
00:30:09,709 --> 00:30:11,211
MICROGLIAL CELLS AND THIS

849
00:30:11,211 --> 00:30:13,980
MICROGLIAL FRACTION FOR ALL OF

850
00:30:13,980 --> 00:30:14,881
THE PROLIFERATION STIMULATING

851
00:30:14,881 --> 00:30:18,117
MUTATIONS THAT WE TESTED, YOU

852
00:30:18,117 --> 00:30:20,453
CAN SEE THAT IT'S STRONGLY

853
00:30:20,453 --> 00:30:21,988
ENRICHED IN MICROGLIA COMPARED

854
00:30:21,988 --> 00:30:23,957
TO OTHER CELLS, WE CAN'T SAY

855
00:30:23,957 --> 00:30:24,891
THAT IT'S COMPLETELY ABSENT IN

856
00:30:24,891 --> 00:30:26,526
THE OTHER CELL TYPES BUT BECAUSE

857
00:30:26,526 --> 00:30:31,264
OUR SORTING IS NOT PERFECT BUT

858
00:30:31,264 --> 00:30:33,032
CLEARLY THEY SHOW ANYWHERE FROM

859
00:30:33,032 --> 00:30:34,234
HUNDRED FOLD ENRICHMENT AND YOU

860
00:30:34,234 --> 00:30:35,268
CAN SEE THESE MUTATIONS ARE

861
00:30:35,268 --> 00:30:37,237
PRESENT IN A VERY LARGE FRACTION

862
00:30:37,237 --> 00:30:40,740
OF THE MICROGLIA, SO THIS MUTANT

863
00:30:40,740 --> 00:30:42,675
ALLELE FRACTION OR VARIANT

864
00:30:42,675 --> 00:30:44,410
ALLELE FRACTION HERE OF 22%

865
00:30:44,410 --> 00:30:45,712
MEANS BASICALLY THAT MUTATION IS

866
00:30:45,712 --> 00:30:46,880
PRESCRIBING NEBT HALF THE

867
00:30:46,880 --> 00:30:48,514
MICRODPLIA OF THAT PERSON, THIS

868
00:30:48,514 --> 00:30:52,452
1'S PRESCRIBING NEBT 25% OF THEM

869
00:30:52,452 --> 00:30:53,987
AND AND THESE CLONES SEEM TO

870
00:30:53,987 --> 00:30:55,955
TAKE OVER A LARGE FRACTION OF

871
00:30:55,955 --> 00:30:58,458
THE MICROGLIA IN SOME CASES, WE

872
00:30:58,458 --> 00:30:59,959
TESTED WHETHER THESE ARE SHARED

873
00:30:59,959 --> 00:31:04,297
IN THE BLOOD, AND THE 1S WE

874
00:31:04,297 --> 00:31:05,932
TESTED ARE WERE ALL SHARED IN

875
00:31:05,932 --> 00:31:07,767
THE BLOOD ALTHOUGH WE THEN WORK

876
00:31:07,767 --> 00:31:09,068
WITH SID [INDISCERNIBLE] FROM

877
00:31:09,068 --> 00:31:10,803
STANFORD WHO ANALYZED A WHOLE

878
00:31:10,803 --> 00:31:11,871
EXOHM SEQUENCING OF THESE SAME

879
00:31:11,871 --> 00:31:15,875
CASES AND WHAT WE FIND BASICALLY

880
00:31:15,875 --> 00:31:17,477
IS THAT THE VARIANTS ARE SHARED

881
00:31:17,477 --> 00:31:19,812
IN BLOOD AND BRAIN BUT THEN THE

882
00:31:19,812 --> 00:31:26,386
VARIANTS THAT PRESUMABLY

883
00:31:26,386 --> 00:31:27,253
OCCURRED LATER BUT ARE NOT

884
00:31:27,253 --> 00:31:30,123
SHARED IN THE BLOOD, IT'S SHARED

885
00:31:30,123 --> 00:31:31,724
BETWEEN BRAIN AND BLOOD BUT THE

886
00:31:31,724 --> 00:31:32,926
CELLS LOOK LIKE ONCE THEY'RE IN

887
00:31:32,926 --> 00:31:35,895
THE BRAIN GO ON TO DEVELOP

888
00:31:35,895 --> 00:31:36,596
AADDITIONAL MUTATIONS THAT MIGHT

889
00:31:36,596 --> 00:31:37,764
CONTRIBUTE TO THE CLONAL

890
00:31:37,764 --> 00:31:38,865
SELECTION EMPLOY AND SO WHAT'S

891
00:31:38,865 --> 00:31:41,734
THE IMPACT OF THESE MUTATIONS.

892
00:31:41,734 --> 00:31:45,371
SO AGAIN, BY THE ANALOGY TO

893
00:31:45,371 --> 00:31:47,440
CLONAL HEMEAT O PORESIS, IS

894
00:31:47,440 --> 00:31:49,575
THESE SAME EXACT MUTATIONS

895
00:31:49,575 --> 00:31:50,510
DEVELOP IN THE HEMATOPOIETIC

896
00:31:50,510 --> 00:31:52,345
STEM CELLS AND THEY CREATE

897
00:31:52,345 --> 00:31:54,280
MUTANT PROGENY AND AS THOSE

898
00:31:54,280 --> 00:31:55,248
MUTANT PROGENY DEVELOP LARGER

899
00:31:55,248 --> 00:31:57,650
AND LARGER NUMBERS OF MUTATIONS,

900
00:31:57,650 --> 00:31:59,619
THEY DEVELOP AN INCREASINGLY

901
00:31:59,619 --> 00:32:00,453
ABNORMAL PATTERN OF

902
00:32:00,453 --> 00:32:02,655
TRANSCRIPTION EMPLOY THEY

903
00:32:02,655 --> 00:32:03,456
DEVELOP AN INFLAMMATORY SIGNAL

904
00:32:03,456 --> 00:32:04,657
WHICH IS THOUGHT THEN TO BE

905
00:32:04,657 --> 00:32:09,095
TOXIC TO OTHER CELLS AND THIS IS

906
00:32:09,095 --> 00:32:10,463
HOW CLONAL HEMEAT O POETICESIS

907
00:32:10,463 --> 00:32:11,864
IS THOUGHT TO BE THERE FOR

908
00:32:11,864 --> 00:32:12,932
CANCER BUT ALSO HEART DISEASE

909
00:32:12,932 --> 00:32:14,834
BECAUSE IT CREATES AN

910
00:32:14,834 --> 00:32:16,703
INFLAMMATORY ENVIRONMENT THAT

911
00:32:16,703 --> 00:32:17,537
CONTRIBUTES TO MANY--PERHAPS

912
00:32:17,537 --> 00:32:18,905
MANY DIFFERENT DISEASES AND SO,

913
00:32:18,905 --> 00:32:20,974
WE WANT WANTED TO KNOW THEN

914
00:32:20,974 --> 00:32:23,743
WHETHER THESE DRIVER MUTATIONS

915
00:32:23,743 --> 00:32:26,546
IN MICROGLIA ALSO MIGHT INDUCE

916
00:32:26,546 --> 00:32:27,714
AN INFLAMMATORY STATE AND WE

917
00:32:27,714 --> 00:32:28,848
APPROACH THAT IN 2 DIFFERENT

918
00:32:28,848 --> 00:32:31,918
WAYS, FIRST THEY THINKS TO BEN

919
00:32:31,918 --> 00:32:41,227
EBER, I WAS INTRODUCED TO SX

920
00:32:41,227 --> 00:32:42,428
HEAT THEY HAD ALREADY TARGETED

921
00:32:42,428 --> 00:32:50,169
OUR TOP THROW YEENS, DNMT3, AND

922
00:32:50,169 --> 00:32:52,105
TET2, AND ASXL1, AND WE SET TO

923
00:32:52,105 --> 00:32:53,406
COLLABORATE AND THEY

924
00:32:53,406 --> 00:32:54,907
DIFFERENTIATED THESE 2 TO A

925
00:32:54,907 --> 00:32:57,276
MICROTBLEEL STATE AND MEASURED

926
00:32:57,276 --> 00:32:58,644
TRANSCRIPT OME, AND WHAT WE FIND

927
00:32:58,644 --> 00:33:03,316
IS THAT ALL 3 OF THESE GENES

928
00:33:03,316 --> 00:33:06,119
CONTRIBUTE TO ABNORMAL

929
00:33:06,119 --> 00:33:07,253
INFLAMMATORY PATTERNS THAT HAVE

930
00:33:07,253 --> 00:33:08,454
BEEN DESCRIBED IN ALZHEIMER

931
00:33:08,454 --> 00:33:08,688
BRAIN.

932
00:33:08,688 --> 00:33:10,556
IT'S A SUBSET OF MICROGLIA THAT

933
00:33:10,556 --> 00:33:13,092
TAKE ON A VERY INFLAMMATORY

934
00:33:13,092 --> 00:33:15,461
PATTERN OF TRANSCRIPTION AND WE

935
00:33:15,461 --> 00:33:21,634
SEE THAT REPRODUCED NOTABLY BY

936
00:33:21,634 --> 00:33:22,735
DNMT3 AND ASXL1 PROLIFERATIONS

937
00:33:22,735 --> 00:33:26,806
AND WE SEE A SIGNAL STIMULATED

938
00:33:26,806 --> 00:33:31,144
BY ASXL1 AND TET2 AND MAYA IS A

939
00:33:31,144 --> 00:33:33,946
TALENTED POST DOC IN MY LAB WHO

940
00:33:33,946 --> 00:33:34,547
ANALYZED THESE DATA.

941
00:33:34,547 --> 00:33:38,384
AND THIS SHOWS THAT THE

942
00:33:38,384 --> 00:33:39,552
ENGINEERED MICROGLIAL CELLS HAVE

943
00:33:39,552 --> 00:33:41,554
UPREGULATION OF A HOST OF

944
00:33:41,554 --> 00:33:43,656
INFLAMMATORY GENES AND

945
00:33:43,656 --> 00:33:45,525
INFLAMMATORY SIGNATURES, AND

946
00:33:45,525 --> 00:33:46,726
ALSO PROLIFERATION SIGNATURES,

947
00:33:46,726 --> 00:33:47,860
SO THEY'RE VERY--SO THESE

948
00:33:47,860 --> 00:33:51,330
MUTATIONS CREATE A VERY ABNORMAL

949
00:33:51,330 --> 00:33:52,965
TRANSCREPT OHM IN THE MICROGLIA

950
00:33:52,965 --> 00:33:54,901
WHICH IS CONSISTENT WITH THE

951
00:33:54,901 --> 00:33:57,437
TRANSCRIPT OHM THAT'S SEEN IN

952
00:33:57,437 --> 00:33:59,405
LATE STAGE ALZHEIMER'S DEC.

953
00:33:59,405 --> 00:34:01,407
A SECOND APPROACH WE TOOK WAS

954
00:34:01,407 --> 00:34:04,010
ACTUALLY, FOCUSING ON THE BRAINS

955
00:34:04,010 --> 00:34:04,343
THEMSELVES.

956
00:34:04,343 --> 00:34:05,878
WE CAN'T CALL THE POINT

957
00:34:05,878 --> 00:34:08,114
MUTATIONS IN SINGLE CELL RNA SEQ

958
00:34:08,114 --> 00:34:12,552
DATA BUT WE CAN CALL COPY NUMBER

959
00:34:12,552 --> 00:34:14,187
VARIANTS SO MAYA

960
00:34:14,187 --> 00:34:15,354
BASICALLY--THERE ARE COPY NUMBER

961
00:34:15,354 --> 00:34:17,657
VARIANTS THAT CAN DRIVE THE

962
00:34:17,657 --> 00:34:27,366
HEMEAT ON POETICESIS THAT ARE

963
00:34:27,366 --> 00:34:29,469
RECURRENT MUTATED SO WE CAN CALL

964
00:34:29,469 --> 00:34:31,270
THESE MA SWRAIIC CHROMOSOME

965
00:34:31,270 --> 00:34:33,239
ALTERATIONS AND WE DID THIS IN A

966
00:34:33,239 --> 00:34:35,641
SMALL SAMPLE SIZE OF 30

967
00:34:35,641 --> 00:34:37,176
ALZHEIMER CASES AND 30 AGE

968
00:34:37,176 --> 00:34:37,910
CONTROLS.

969
00:34:37,910 --> 00:34:39,145
BUT WE AGAIN, SO WE FOUND THAT

970
00:34:39,145 --> 00:34:46,285
THERE ARE A HANDFUL OF MOSAIC

971
00:34:46,285 --> 00:34:47,487
NOMINALLY LARGER IN AGED

972
00:34:47,487 --> 00:34:49,922
CONTROLS ALTHOUGH THIS IS NOT

973
00:34:49,922 --> 00:34:50,690
STATISTICALLY SIGNIFICANT

974
00:34:50,690 --> 00:34:51,457
BECAUSE OF THE SMALL SAMPLE SIZE

975
00:34:51,457 --> 00:34:56,395
AND AGAIN YOU SEE A VERY LARGE

976
00:34:56,395 --> 00:34:58,397
NUMBER OF MICRODPLIA IN CELLS

977
00:34:58,397 --> 00:34:59,332
COMPARED TO CONTROL AND THE

978
00:34:59,332 --> 00:35:01,400
CELLS THAT CARRY THESE

979
00:35:01,400 --> 00:35:03,936
CHROMOSOME ALTERATIONS ARE AGAIN

980
00:35:03,936 --> 00:35:07,406
MICRODPLIA OR CAPILLARY

981
00:35:07,406 --> 00:35:09,308
ASSOCIATED MACROPHAGES.

982
00:35:09,308 --> 00:35:11,244
AND LESS CONPLEA OLIGO DENDRITIC

983
00:35:11,244 --> 00:35:14,113
CELLROCYTES BUT NOT OPCs OR

984
00:35:14,113 --> 00:35:14,347
NEURONS.

985
00:35:14,347 --> 00:35:16,215
AND AGAIN, THOSE CELLS THAT

986
00:35:16,215 --> 00:35:18,951
CARRY THESE MOSAIC CHROMOSOME

987
00:35:18,951 --> 00:35:20,720
OLTERATIONS AGAIN HAVE THIS

988
00:35:20,720 --> 00:35:22,088
ABNORMAL PATTERN OF

989
00:35:22,088 --> 00:35:23,723
TRANSCRIPTION THAT RESUMABLES

990
00:35:23,723 --> 00:35:25,024
THESE DISEASES ASSOCIATED

991
00:35:25,024 --> 00:35:26,359
MICROGLIA, WE SEE RUP REGULATION

992
00:35:26,359 --> 00:35:29,262
OF MANY YEENS THAT ARE A

993
00:35:29,262 --> 00:35:32,732
COMPONENT OF THE DAM SIGNATURE

994
00:35:32,732 --> 00:35:36,836
AND THEN WE SEE UPREGULATION OF

995
00:35:36,836 --> 00:35:39,472
REGULATORY PATHWAYS SUCH AS

996
00:35:39,472 --> 00:35:42,375
CYTOKINES AND SO ON OR CELL ARRA

997
00:35:42,375 --> 00:35:44,110
RESPONSE TO INTERLEUKIN 4.

998
00:35:44,110 --> 00:35:46,712
SO OUR WAY OF THINKING ABOUT

999
00:35:46,712 --> 00:35:49,782
THIS IS THAT I THINK IT'S

1000
00:35:49,782 --> 00:35:50,383
ACCEPTED THAT THE ALZHEIMER

1001
00:35:50,383 --> 00:35:53,219
BRAIN IS AN INFLAMMATORY

1002
00:35:53,219 --> 00:35:55,521
ENVIRONMENT AND THAT THERE IS

1003
00:35:55,521 --> 00:35:56,789
PROLIFERATION OF MICROGLIAL

1004
00:35:56,789 --> 00:35:59,325
CELLS AT A HIGHER RATE THAN

1005
00:35:59,325 --> 00:36:01,460
NORMAL AND WHENEVER WE SEE

1006
00:36:01,460 --> 00:36:03,596
INFLAMMATION AND PROLIFERATION,

1007
00:36:03,596 --> 00:36:05,164
THAT WILL DRIVE EVOLUTIONARY

1008
00:36:05,164 --> 00:36:07,266
SELECTION IN FAVOR OF CELLS THAT

1009
00:36:07,266 --> 00:36:08,668
CARRY ONCA YEENS BECAUSE THOSE

1010
00:36:08,668 --> 00:36:10,636
CELLS WERE SURVIVE BETTER AND

1011
00:36:10,636 --> 00:36:11,938
WILL PROLIFERATE BETTER THAN

1012
00:36:11,938 --> 00:36:14,640
WILD-TYPE CELLS AND SO THAT

1013
00:36:14,640 --> 00:36:16,542
PROLIFERATION WILL THEN

1014
00:36:16,542 --> 00:36:18,878
INVARIABLY SELECT FOR MUSEUM

1015
00:36:18,878 --> 00:36:20,246
ANT--FOR DRIVE MUTANT CLONES AND

1016
00:36:20,246 --> 00:36:23,015
THIS CREATES A PHENOMENON WE

1017
00:36:23,015 --> 00:36:28,721
CALL MICROGLIAL EXPANSION OR

1018
00:36:28,721 --> 00:36:30,790
MICE BUT AGAIN THAT COMES WITH A

1019
00:36:30,790 --> 00:36:32,892
COST BECAUSE THOSE HAVE

1020
00:36:32,892 --> 00:36:34,126
INFLAMMATORY SIGNATURES THAT

1021
00:36:34,126 --> 00:36:35,661
HAVE BEEN SHOWN IN BLOOD CELLS

1022
00:36:35,661 --> 00:36:38,764
TO PROMOTE THE DEATH OF THEIR

1023
00:36:38,764 --> 00:36:40,766
MAYBORRING CELLS BY SECRETION OF

1024
00:36:40,766 --> 00:36:41,934
INTERLEUKINS AND OTHER CYTOKINES

1025
00:36:41,934 --> 00:36:45,905
THAT ARE TOXIC TO OTHER CELLS.

1026
00:36:45,905 --> 00:36:47,573
SO IN THE LAST 10 MINUTES OR SO

1027
00:36:47,573 --> 00:36:49,308
I WILL TELL YOU ABOUT WHAT

1028
00:36:49,308 --> 00:36:51,310
HAPPENS TO A NEURON'S GENOME IN

1029
00:36:51,310 --> 00:36:52,712
HAD SOME OF THESE CONDITIONS

1030
00:36:52,712 --> 00:36:57,116
WITH AGING AND WITH DISEASE AND

1031
00:36:57,116 --> 00:36:58,985
PAISK BEE THIS DEVELOPING FROM

1032
00:36:58,985 --> 00:37:00,186
ISOLATING SINGLE NEURONS IN THE

1033
00:37:00,186 --> 00:37:02,488
BRAIN AND SEQUENCING THEIR

1034
00:37:02,488 --> 00:37:03,422
GENOMES AND COMPARING THEM.

1035
00:37:03,422 --> 00:37:05,658
WE HAD TO DO THIS BECAUSE THE

1036
00:37:05,658 --> 00:37:16,002
CLONAL STRUCTURE OF THE BRAIN

1037
00:37:16,002 --> 00:37:17,370
AND SO COMPLICATED THIS GOT US

1038
00:37:17,370 --> 00:37:20,373
INTO THE WHOLE AREA OF LOOKING

1039
00:37:20,373 --> 00:37:22,575
AT AGING OF SINGLE NEURONS.

1040
00:37:22,575 --> 00:37:25,244
SO BASICALLY TAKE SINGLE NUCLEI,

1041
00:37:25,244 --> 00:37:26,746
WE SEPARATE NEURONAL NUCLEI AND

1042
00:37:26,746 --> 00:37:28,981
PUT THEM INTO SINGLE WELLS YOU

1043
00:37:28,981 --> 00:37:31,484
AMPLIFY THE GENOME BY A VARIETY

1044
00:37:31,484 --> 00:37:32,785
OF DIFFERENT METHODS THE WAY YOU

1045
00:37:32,785 --> 00:37:35,421
MIGHT SEQUENCE YOUR GENOME FROM

1046
00:37:35,421 --> 00:37:37,857
YOUR BLOOD DNA AND MIKE AND

1047
00:37:37,857 --> 00:37:39,191
RACHEL LED A STUDY THAT WAS

1048
00:37:39,191 --> 00:37:40,426
PUBLISH INDEED 2018 WHERE THEY

1049
00:37:40,426 --> 00:37:42,261
LOOKED AT A SINGLE NEURONS FROM

1050
00:37:42,261 --> 00:37:44,964
A RANGE OF AGES, DWRP FROM

1051
00:37:44,964 --> 00:37:46,032
INFANT TO AGED INDIVIDUALS AND

1052
00:37:46,032 --> 00:37:48,367
WE WOULD TAKE LIKE 3 OR 4

1053
00:37:48,367 --> 00:37:49,402
NEURONS FROM THE PREFRONTAL

1054
00:37:49,402 --> 00:37:50,269
CORTEX OF AN INDIVIDUAL AND WHEN

1055
00:37:50,269 --> 00:37:51,837
YOU DO THAT TO A NEW BORN, YOU

1056
00:37:51,837 --> 00:37:55,508
FIND THAT THERE ARE ABOUT--THERE

1057
00:37:55,508 --> 00:37:57,910
ARE HUNDREDS OF SINGLE

1058
00:37:57,910 --> 00:37:59,345
NUCLEOTYPE VARIANTS AND POINT

1059
00:37:59,345 --> 00:38:00,413
MUTATION, 1 NUCLEOTYPE FOR

1060
00:38:00,413 --> 00:38:01,847
ANOTHER, IN THE SINGLE NEURON

1061
00:38:01,847 --> 00:38:03,582
COMPARED TO THE GERM LINE OF

1062
00:38:03,582 --> 00:38:05,451
THAT SAME PERSON, THEN

1063
00:38:05,451 --> 00:38:06,419
REMARKABLY, IN TEENAGERS IT'S

1064
00:38:06,419 --> 00:38:08,287
CLOSER TO A HUNDRED, AND IN

1065
00:38:08,287 --> 00:38:10,089
MIDDLE AGED INDIVIDUALS, IT'S

1066
00:38:10,089 --> 00:38:16,429
1500 AND IN ELDERLY INDIVIDUALS

1067
00:38:16,429 --> 00:38:17,596
IT'S MORE THAN 2000.

1068
00:38:17,596 --> 00:38:20,166
SO SINCE THEN, THERE ARE BETTER

1069
00:38:20,166 --> 00:38:22,401
WAYS AND MORE ACCURATE WAYS OF

1070
00:38:22,401 --> 00:38:25,171
AMPLIFYING THE SINGLE GENE OF

1071
00:38:25,171 --> 00:38:28,040
NEURONS, THE MDNA METHOD CREATES

1072
00:38:28,040 --> 00:38:30,142
AMPLIFICATION BUT RESULTS IN

1073
00:38:30,142 --> 00:38:31,844
UNEQUAL AMPLIFICATION IN THE

1074
00:38:31,844 --> 00:38:33,679
GENOME AND IN THE ARTIFACT.

1075
00:38:33,679 --> 00:38:35,448
CHUCK AT STANFORD DEVELOPED A

1076
00:38:35,448 --> 00:38:37,883
LINEAR METHOD CALLED PRIMARY

1077
00:38:37,883 --> 00:38:40,453
TEMPLATE AMPLIFICATION WHERE THE

1078
00:38:40,453 --> 00:38:42,688
PIECES ARE SHORTER AND GIVES YOU

1079
00:38:42,688 --> 00:38:43,823
AMPLIFICATION OF THE GENOME AND

1080
00:38:43,823 --> 00:38:46,625
WE FIND WITH THIS METHOD,

1081
00:38:46,625 --> 00:38:47,927
AGE-RELATED ACCUMULATION OF

1082
00:38:47,927 --> 00:38:49,328
MUTATIONS IS SLOWER INSTEAD OF

1083
00:38:49,328 --> 00:38:51,330
23 MUTATIONS PER YEAR, IT'S 17

1084
00:38:51,330 --> 00:38:52,965
MUTATIONS PER YEAR BUT IT'S

1085
00:38:52,965 --> 00:38:59,772
INKRE TINSIBLELY IBLE--INCREDIBY

1086
00:38:59,772 --> 00:39:02,241
LINEAR, AND YOU SEE 17 MUTATIONS

1087
00:39:02,241 --> 00:39:03,943
IN THE FIRST OF LIFE AND 17

1088
00:39:03,943 --> 00:39:05,611
MUTATIONS FROM THE END OF LIFE,

1089
00:39:05,611 --> 00:39:06,679
BUT THERE'S NORMAL VARIABILITY

1090
00:39:06,679 --> 00:39:08,147
IN THE INDIVIDUAL PERSON AND

1091
00:39:08,147 --> 00:39:09,982
THIS WAS WORK DONE BY JOE

1092
00:39:09,982 --> 00:39:11,617
[INDISCERNIBLE] AND MIKE MILLER

1093
00:39:11,617 --> 00:39:12,818
AND [INDISCERNIBLE] FROM MY LAB

1094
00:39:12,818 --> 00:39:14,920
AND JOE WHO'S IN PETER PARK'S

1095
00:39:14,920 --> 00:39:17,923
LAB WAS PUBLISHED A COUPLE YEARS

1096
00:39:17,923 --> 00:39:18,591
AGO.

1097
00:39:18,591 --> 00:39:21,093
AND THAT WORK HAS NOW BEEN

1098
00:39:21,093 --> 00:39:22,528
REPLICATED IN 4 DIFFERENT LABS

1099
00:39:22,528 --> 00:39:26,132
USING 5 DIFFERENT METHODS, THIS

1100
00:39:26,132 --> 00:39:30,403
ALL FIND JUST ABOUT 17 OR 18

1101
00:39:30,403 --> 00:39:32,571
SNVs PER YEAR, THIS IS WORK

1102
00:39:32,571 --> 00:39:34,673
THAT USES POST ACES, A STUDY

1103
00:39:34,673 --> 00:39:36,375
FROM [INDISCERNIBLE] AT THE

1104
00:39:36,375 --> 00:39:37,676
SANGER CENTER USING DUPLEX

1105
00:39:37,676 --> 00:39:42,014
SEQUENCING AND AN UNPUBLISHED 1

1106
00:39:42,014 --> 00:39:43,516
FROM [INDISCERNIBLE] LAB, I'VE

1107
00:39:43,516 --> 00:39:44,917
TAKEN THE LIBERTY OF TAKING THE

1108
00:39:44,917 --> 00:39:46,185
POINTS OF THE OTHER PAPER ANDS

1109
00:39:46,185 --> 00:39:48,521
PUTTING THEM ON THE SAME PLOT IT

1110
00:39:48,521 --> 00:39:49,588
SHOW HIGHWAY INCREDIBLE LOAMACYY

1111
00:39:49,588 --> 00:39:51,290
PRACTICESY CISE AND LINEAR THIS

1112
00:39:51,290 --> 00:39:52,224
IS WITH MULTIPLE DIFFERENT

1113
00:39:52,224 --> 00:39:55,494
METHODS AND HOW IN THE WORLD OF

1114
00:39:55,494 --> 00:39:56,395
NONCYCLING NEURONS DEVELOP

1115
00:39:56,395 --> 00:39:57,630
DOUBLE STRANDED POINT MUTATIONS,

1116
00:39:57,630 --> 00:40:01,000
AND I DON'T KNOW THE ANSWER TO

1117
00:40:01,000 --> 00:40:03,302
THAT BUTILE JUST PROPOSE A

1118
00:40:03,302 --> 00:40:04,036
PLAUSIBLE MECHANISM BECAUSE I

1119
00:40:04,036 --> 00:40:05,204
FIND IT EASIER TO THINK ABOUT IT

1120
00:40:05,204 --> 00:40:06,639
AND THAT STARS WITH THE FACT

1121
00:40:06,639 --> 00:40:10,075
THAT DNA DAMAGE IS UBIQUITOUS,

1122
00:40:10,075 --> 00:40:11,577
IT'S GENERALLY DAMAGED TO 1

1123
00:40:11,577 --> 00:40:13,379
STRAND OR THE RECOLLECT OR ELSE

1124
00:40:13,379 --> 00:40:15,047
THERE CAN BE DOUBLE STRANDED

1125
00:40:15,047 --> 00:40:16,015
BREAKS, AT ANY GIVEN MOMENT

1126
00:40:16,015 --> 00:40:17,750
THERE ARE MORE THAN A THOUSAND

1127
00:40:17,750 --> 00:40:18,617
SINGLE STRANDED LESIONS IN THE

1128
00:40:18,617 --> 00:40:19,718
GENOME, YOU CAN SEE THE

1129
00:40:19,718 --> 00:40:23,689
DIFFERENT TYPES HERE AND HOW

1130
00:40:23,689 --> 00:40:24,356
FREQUENT THEY ARE.

1131
00:40:24,356 --> 00:40:25,791
AND THESE ARE BY A VARIETY OF

1132
00:40:25,791 --> 00:40:27,660
DIFFERENT MECH NICHES BUT 1 OF

1133
00:40:27,660 --> 00:40:28,561
THE MECHANISMS IS ECCISION

1134
00:40:28,561 --> 00:40:31,497
REPAIR BUT THE WAY IT WORKS IS

1135
00:40:31,497 --> 00:40:33,232
BY ACTUALLY EXCISING 29 BASE

1136
00:40:33,232 --> 00:40:37,636
PAIRS BUT REPAIRING IT BY

1137
00:40:37,636 --> 00:40:38,270
REPLICATING THE UNDAMAGED TRAND

1138
00:40:38,270 --> 00:40:41,340
BUT IF A CELL HAS 2 LESIONS

1139
00:40:41,340 --> 00:40:45,511
WITHIN 29 BASE PAIRS OF EACH

1140
00:40:45,511 --> 00:40:48,714
OTHER, IT'S REPAIRING WITH A

1141
00:40:48,714 --> 00:40:50,583
BASE PLATE, IT WOULD CREATE 1.

1142
00:40:50,583 --> 00:40:57,756
SO EVEN THE NONREPLICATING GENES

1143
00:40:57,756 --> 00:40:58,757
ARE REPLICATING.

1144
00:40:58,757 --> 00:40:59,959
AND GIIVE THE FREQUENCY OF THE

1145
00:40:59,959 --> 00:41:01,460
EVENTS AND THE LOW RATE OF 15 OR

1146
00:41:01,460 --> 00:41:02,895
18 PER YEAR, THERE ARE MORE THAN

1147
00:41:02,895 --> 00:41:04,263
ENOUGH, YOU CAN PREDICT THERE

1148
00:41:04,263 --> 00:41:06,398
ARE MORE THAN ENOUGH TIMES WHEN

1149
00:41:06,398 --> 00:41:08,033
YOU WOULD HAVE 2 DIFFERENT

1150
00:41:08,033 --> 00:41:10,302
LESIONS WITHIN 29 BASE PAIRS TO

1151
00:41:10,302 --> 00:41:12,304
ACCOUNT FOR 1 ANOTHER AND

1152
00:41:12,304 --> 00:41:13,506
ACCOUNT FOR WHAT WE SEE.

1153
00:41:13,506 --> 00:41:15,474
SO WHAT HAPPENS THEN IN DISEASE,

1154
00:41:15,474 --> 00:41:19,778
AND SO MIKE MILLER AND MIKE

1155
00:41:19,778 --> 00:41:21,180
[INDISCERNIBLE] WE COLLABORATE

1156
00:41:21,180 --> 00:41:22,815
WIDE ALICE LEE'S LAB TO STUDY

1157
00:41:22,815 --> 00:41:25,351
SINGLE NEURONS FROM A POSTMORTEM

1158
00:41:25,351 --> 00:41:26,785
ALZHEIMER BRAIN EMPLOY WE

1159
00:41:26,785 --> 00:41:28,721
FOCUSED ON LARGE NEURONIAL

1160
00:41:28,721 --> 00:41:31,023
NUCLEI AND THESE ARE PARAMETRAL

1161
00:41:31,023 --> 00:41:32,458
NEURONS WHICH ARE AFFECTED BY

1162
00:41:32,458 --> 00:41:34,793
THE KEEZ, AND WE FIND THAT THESE

1163
00:41:34,793 --> 00:41:35,895
NEURONS HAVE ABOUT 200 EXTRA

1164
00:41:35,895 --> 00:41:38,163
MUSEUM TAIGS COMPARED TO AGE

1165
00:41:38,163 --> 00:41:39,899
MATCHED CONTROLS AND THAT'S MORE

1166
00:41:39,899 --> 00:41:41,333
OR LESS EQUIVALENT TO THE 10

1167
00:41:41,333 --> 00:41:43,435
YEARS OF LIFE, THAT YOU LOSE TO

1168
00:41:43,435 --> 00:41:45,404
ALZHEIMER DEC IF YOU FIGURE THAT

1169
00:41:45,404 --> 00:41:47,239
YOU ACCUMULATE ABOUT 17 OR 18

1170
00:41:47,239 --> 00:41:49,909
MUTATIONS PER YEAR, FOR 10

1171
00:41:49,909 --> 00:41:50,109
YEARS.

1172
00:41:50,109 --> 00:41:52,745
AND SO WHAT CAUSES THEM.

1173
00:41:52,745 --> 00:41:55,014
SO TO DO THAT, WE CAN AGAIN USE

1174
00:41:55,014 --> 00:41:58,384
TOOLS TWEPPED FOR THE STUDY OF

1175
00:41:58,384 --> 00:42:00,719
CANCER, THAT LOOK AT BASE

1176
00:42:00,719 --> 00:42:03,188
SUBSTITUTIONS AND LOOK AT THE 3

1177
00:42:03,188 --> 00:42:04,823
BASE PAIR CONTEXT, THE 2

1178
00:42:04,823 --> 00:42:06,559
NEIGHBORS BASES WHERE THE

1179
00:42:06,559 --> 00:42:09,061
SUBSIDIARY CONSTITUTION OCCURS

1180
00:42:09,061 --> 00:42:10,829
SO HERE'S A C TO A CHAIMPLE AND

1181
00:42:10,829 --> 00:42:12,031
THERE MIGHT BE AN AOT OTHER SIDE

1182
00:42:12,031 --> 00:42:14,833
OF IT SO THIS CREATES 16

1183
00:42:14,833 --> 00:42:16,168
DIFFERENT C TO A CHANGES AND

1184
00:42:16,168 --> 00:42:18,137
THEN IT LOOKS FOR RECURRENT

1185
00:42:18,137 --> 00:42:19,772
PATTERNS OF SUBSTITUTION AND IT

1186
00:42:19,772 --> 00:42:21,273
TURNS OUT THAT THINGS THAT

1187
00:42:21,273 --> 00:42:23,375
DAMAGE THE GENOME NEVER DO IT IN

1188
00:42:23,375 --> 00:42:25,678
A RANDOM WAY, THEY ALWAYS

1189
00:42:25,678 --> 00:42:26,412
PREFERENTIALLY AFFECT SOME BASES

1190
00:42:26,412 --> 00:42:28,514
AND NOT OTHERS SO THIS IS A

1191
00:42:28,514 --> 00:42:29,582
SIMULATED LUNG CANCER GENOME

1192
00:42:29,582 --> 00:42:32,451
WHERE YOU SEQUENCING IT AND ALL

1193
00:42:32,451 --> 00:42:33,419
THE SOMATIC MUTATION ANDS THEN

1194
00:42:33,419 --> 00:42:38,057
YOU SORT THEM INTO RECURRENT

1195
00:42:38,057 --> 00:42:39,391
BUCKYS USING NONNEGATIVE MATRIX

1196
00:42:39,391 --> 00:42:41,093
FACTORS, SO IN THE SIMULATED

1197
00:42:41,093 --> 00:42:42,928
LUNG CANCER THERE ARE SEVERAL

1198
00:42:42,928 --> 00:42:45,698
PATTERNS 1 HAS RED C TO T

1199
00:42:45,698 --> 00:42:49,234
CHAIMPLES, AND THIS IS CALLED

1200
00:42:49,234 --> 00:42:50,736
SINGLE BASE SIGNATURE 1 AND THIS

1201
00:42:50,736 --> 00:42:54,073
IS SEEN IN ALL DIVIDING CELLS

1202
00:42:54,073 --> 00:42:55,307
AND THIS REPRESENTS EXAMINATION

1203
00:42:55,307 --> 00:42:57,710
DURING THE CELL CYCLE.

1204
00:42:57,710 --> 00:42:58,744
WELL'S 1 CALLED SIGNATURE 4

1205
00:42:58,744 --> 00:43:00,713
WHICH HAS THE PLURIBU C TO A

1206
00:43:00,713 --> 00:43:02,448
CHANGES WHICH IS ONLY SEEN SEEN

1207
00:43:02,448 --> 00:43:06,418
IN LUNG CANCERS OF SMOKERS, THIS

1208
00:43:06,418 --> 00:43:16,862
IS DUE TO DIRECT TOXICITY.

1209
00:43:17,963 --> 00:43:19,164
THIS REPRESENTS JUST AGING, IT'S

1210
00:43:19,164 --> 00:43:22,835
SEEN IN ALL TUMORS AND IN ALL

1211
00:43:22,835 --> 00:43:23,636
TISSUES, AND PROPORTIONAL TO

1212
00:43:23,636 --> 00:43:25,070
NOTHING BUT THE AGE OF THE

1213
00:43:25,070 --> 00:43:32,344
PATIENT AT THE TIME OF

1214
00:43:32,344 --> 00:43:33,078
DIAGNOSIS.

1215
00:43:33,078 --> 00:43:35,247
SOPHISTICATED IN NEURONS, WE USE

1216
00:43:35,247 --> 00:43:36,982
LETTERS TO REFER TO THEM RATHER

1217
00:43:36,982 --> 00:43:38,384
THAN NUMBERS AND AFTER THE FACT,

1218
00:43:38,384 --> 00:43:39,852
SAW HOW THEY COMPARED TO THE

1219
00:43:39,852 --> 00:43:41,854
CANCER SIGNATURES AND THE AGE

1220
00:43:41,854 --> 00:43:43,155
RELATED ACCUMULATION IN NEURONS

1221
00:43:43,155 --> 00:43:44,923
IS MAINLY DRIVEN BY A SIGNATURE

1222
00:43:44,923 --> 00:43:47,626
A, BUT THIS RESEMBLES VERY

1223
00:43:47,626 --> 00:43:49,461
CLOSELY THE SIGNATURE SBS 5

1224
00:43:49,461 --> 00:43:50,796
WHICH IS A MYSTERIOUS AGE

1225
00:43:50,796 --> 00:43:51,964
RELATED SIGNATURE WHICH IS AGAIN

1226
00:43:51,964 --> 00:43:53,232
AS I SAID PROPORTIONAL TO

1227
00:43:53,232 --> 00:43:54,633
NOTHING ELSE OTHER THAN THE AGE

1228
00:43:54,633 --> 00:43:56,502
OF PATIENT, AT THE TIME OF

1229
00:43:56,502 --> 00:43:59,004
DIAGNOSE BUT HERE WE SHOW THAT

1230
00:43:59,004 --> 00:44:01,440
THIS IS ACTUALLY COMPLETELY

1231
00:44:01,440 --> 00:44:04,343
UCIBOLITTOUS, IT HAPPENS CELLS

1232
00:44:04,343 --> 00:44:05,844
THAT UNDER GO CELL DIVISION, AND

1233
00:44:05,844 --> 00:44:09,982
WE DID A PAPER ON CARDIO MY O

1234
00:44:09,982 --> 00:44:12,184
SITES ALSO ACCUMULATE THIS SBS 5

1235
00:44:12,184 --> 00:44:14,053
SIGNATURE AND SO AGAIN, IT MAY

1236
00:44:14,053 --> 00:44:17,623
BE CONSIST WENT SOME SORT OF

1237
00:44:17,623 --> 00:44:19,525
FAULTY NUCLEOTIDE EXCISION

1238
00:44:19,525 --> 00:44:19,758
REPAIR.

1239
00:44:19,758 --> 00:44:21,660
AND SO, THEN WHAT HAPPENS IN

1240
00:44:21,660 --> 00:44:22,961
ALZHEIMER'S DISEASE, WHAT ABOUT

1241
00:44:22,961 --> 00:44:24,363
THESE EXTRA MUTATIONS, WELL, WE

1242
00:44:24,363 --> 00:44:28,333
FIND THAT THESE EXTRA MUTATIONS

1243
00:44:28,333 --> 00:44:29,401
ACTUALLY REPRESENT A MUTATION

1244
00:44:29,401 --> 00:44:30,469
PATTERN WHICH IS RARE IN THE

1245
00:44:30,469 --> 00:44:32,071
NORMAL BRAIN WHICH WE CALL

1246
00:44:32,071 --> 00:44:36,875
SIGNATURE C AND HAS THE CTO A

1247
00:44:36,875 --> 00:44:38,177
CHANGES WHICH ARE RARE IN NORMAL

1248
00:44:38,177 --> 00:44:40,746
BRAIN AND WE FIND THAT IN FACT

1249
00:44:40,746 --> 00:44:41,480
THE SIGNATURE BEHAVES VERY

1250
00:44:41,480 --> 00:44:43,449
DIFFERENTLY THEN THE NORMAL

1251
00:44:43,449 --> 00:44:45,350
NEURONAL SIGNATURE, THE NORMAL

1252
00:44:45,350 --> 00:44:47,186
NEURONAL SIGNATURE AND VERY

1253
00:44:47,186 --> 00:44:48,220
PROPORTIONAL TO GENE EXPRESSION.

1254
00:44:48,220 --> 00:44:50,389
IT HAPPENS MORE COMMONLY AND

1255
00:44:50,389 --> 00:44:52,157
HIGHY EXPRESSED GENES AND IS

1256
00:44:52,157 --> 00:44:53,659
UNCOMMON IN YEENS THAT HAVE LOW

1257
00:44:53,659 --> 00:44:56,095
EXPRESSION BUT THIS EXTRA

1258
00:44:56,095 --> 00:44:57,730
SIGNATURE IN ALZHEIMERS DOES NOT

1259
00:44:57,730 --> 00:44:58,897
SHOW THE SAME RELATIONSHIP AT

1260
00:44:58,897 --> 00:44:59,431
ALL.

1261
00:44:59,431 --> 00:45:02,401
IT'S NOT PROPORTIONAL TO GENE

1262
00:45:02,401 --> 00:45:02,968
EXPRESSION.

1263
00:45:02,968 --> 00:45:05,938
AND SO THESE SIGNATURE CANS

1264
00:45:05,938 --> 00:45:07,406
IMPLICATE MECHANISMS OF

1265
00:45:07,406 --> 00:45:10,409
TOXICITY, WE EXPECT THE C TO A

1266
00:45:10,409 --> 00:45:11,343
CHEANCHS MIGHT REPRESENTOX

1267
00:45:11,343 --> 00:45:12,611
ILLEGALS GAUNINE BECAUSE THAT

1268
00:45:12,611 --> 00:45:13,345
HAPPENS IN CIGARETTE SMOKE AND

1269
00:45:13,345 --> 00:45:18,450
YOU CAN SEE THAT THERE'S AN

1270
00:45:18,450 --> 00:45:21,120
EXCESS OFOX O GAUNINE, AND IT

1271
00:45:21,120 --> 00:45:23,222
INCREASES NORMALLY IN AGE BUT

1272
00:45:23,222 --> 00:45:28,260
FURTHER INCREASE INDEED

1273
00:45:28,260 --> 00:45:29,328
ALZHEIMER'S DISEASE.

1274
00:45:29,328 --> 00:45:30,896
MORE RECENTLY [INDISCERNIBLE]

1275
00:45:30,896 --> 00:45:33,098
LOOKED AT FRONTAL TEMPORAL

1276
00:45:33,098 --> 00:45:33,799
DEMENTIA AND SPECIFICALLY DO YOU

1277
00:45:33,799 --> 00:45:35,901
TO CASES WHERE THERE'S

1278
00:45:35,901 --> 00:45:37,703
AMPLIFICATION OF THE C9 RFP3,

1279
00:45:37,703 --> 00:45:41,140
AND THAT SHOWS A SIMILAR

1280
00:45:41,140 --> 00:45:42,541
PHENOMENON TO ALZHEIMERS, ABOUT

1281
00:45:42,541 --> 00:45:43,509
WOHUNDRED EXTRA MUTATIONS AND

1282
00:45:43,509 --> 00:45:46,178
WHAT THE SIMILAR PATTERN OF

1283
00:45:46,178 --> 00:45:46,812
NUCLEOTIDE SUBSTITUTION EMPLOY

1284
00:45:46,812 --> 00:45:49,348
NOW AT THE BETTER TECHNIQUES WE

1285
00:45:49,348 --> 00:45:51,483
CAN ANALYZE A SECOND TYPE OF

1286
00:45:51,483 --> 00:45:53,018
MUTATION IN NEURONS CALLED

1287
00:45:53,018 --> 00:45:56,088
INDELATWALS, SO INDELATWALS ARE

1288
00:45:56,088 --> 00:45:57,389
INSERTION OF BASES, TYPICALLY

1289
00:45:57,389 --> 00:46:00,225
SHORT A FEW BASE PAIRS OR THE

1290
00:46:00,225 --> 00:46:02,327
DELETION OF A COUPLE OF BASES SO

1291
00:46:02,327 --> 00:46:05,464
I JUST REFER TO THEM AS

1292
00:46:05,464 --> 00:46:09,468
INDELATWALS, OR SOMATIC

1293
00:46:09,468 --> 00:46:11,537
INDELATWALS, S-INDELs, AND

1294
00:46:11,537 --> 00:46:14,473
THESE ACCUMULATE BUT ALMOST 10

1295
00:46:14,473 --> 00:46:16,809
TIMES SLOWER THAN SNVs, ONLY 2

1296
00:46:16,809 --> 00:46:19,011
OR 3 PER YEAR AND THEY HAVE AN

1297
00:46:19,011 --> 00:46:20,946
EVEN STRONGER RELATIONSHIP TO

1298
00:46:20,946 --> 00:46:23,582
TRANSCRIPTION THAN THE SNVs,

1299
00:46:23,582 --> 00:46:26,151
SO BOTH INDELs AND SNVs ARE

1300
00:46:26,151 --> 00:46:28,353
ENRICHED IN HIGHLY EXPRESSED

1301
00:46:28,353 --> 00:46:29,855
YEENS THAT'S AGAIN SHOWN HERE

1302
00:46:29,855 --> 00:46:33,826
FOR SNVs AND HERE FOR INDELs

1303
00:46:33,826 --> 00:46:36,395
BUT THEY SHOW A STRONGER

1304
00:46:36,395 --> 00:46:38,597
ENRICHMENT AND AGAIN, THEY'RE

1305
00:46:38,597 --> 00:46:40,399
BOTH STRONGLY ENRICHED AT NEURAL

1306
00:46:40,399 --> 00:46:42,701
PROMOTERS AND ENHANCERS BUT

1307
00:46:42,701 --> 00:46:44,469
PARTICULARLY THE INDELs,

1308
00:46:44,469 --> 00:46:46,872
AGAIN, THE SNVs SHOW

1309
00:46:46,872 --> 00:46:49,274
ENRICHMENT AT H3 K27 ACETYLATION

1310
00:46:49,274 --> 00:46:53,278
PEAKS. 

1311
00:46:53,278 --> 00:46:56,849
THE INDELs SHOW A STRONGER

1312
00:46:56,849 --> 00:46:58,717
ENRICHMENT, THE SNVs SHOW A

1313
00:46:58,717 --> 00:47:01,019
LITTLE ENRICHMENT BUT THE

1314
00:47:01,019 --> 00:47:02,988
INDELs ARE VERY, VERY HIGH LE

1315
00:47:02,988 --> 00:47:05,657
ENRICHED SO THE INDELS, HAPPEN

1316
00:47:05,657 --> 00:47:06,959
WHERE YOU DON'T WANT THEM, THEY

1317
00:47:06,959 --> 00:47:09,661
HAPPEN IN INN HANSERS, THEY ARE

1318
00:47:09,661 --> 00:47:10,829
ENRICHED IN ENHANCERS AND ENRICH

1319
00:47:10,829 --> 00:47:12,364
INDEED ANY FORM OF OPEN

1320
00:47:12,364 --> 00:47:14,766
CHROMATIN, SO THEY ARE VERY

1321
00:47:14,766 --> 00:47:17,302
DAMAGING AND THESE 2 OR 3

1322
00:47:17,302 --> 00:47:18,804
INDELs PER YEAR ARE MORE

1323
00:47:18,804 --> 00:47:21,440
DAMAGING THAN THE 15 OR 20

1324
00:47:21,440 --> 00:47:22,374
SNVs, ONCE YOU FIGURE WHERE

1325
00:47:22,374 --> 00:47:23,775
THEY OCCUR IN THE GENE, WHETHER

1326
00:47:23,775 --> 00:47:25,277
THEY OCCUR IN A GENE OR OUTSIDE

1327
00:47:25,277 --> 00:47:26,712
OF A YEEN AND WHETHER THEY

1328
00:47:26,712 --> 00:47:28,080
ACTUALLY ARE LIKELY TO IMPAIR

1329
00:47:28,080 --> 00:47:32,484
THE FUNCTION OF THAT GENE.

1330
00:47:32,484 --> 00:47:35,888
SO RECENTLY WORK THAT'S NOT

1331
00:47:35,888 --> 00:47:41,760
PUBLISHED YET, WE  DISCOVERED, E

1332
00:47:41,760 --> 00:47:44,196
FOUND IT BUT DIDN'T KNOW WHAT TO

1333
00:47:44,196 --> 00:47:44,963
DO WITH IT.

1334
00:47:44,963 --> 00:47:47,933
BOTH ALZHEIMER HYMER AND STD

1335
00:47:47,933 --> 00:47:51,270
HAVE A LARGE INCREASE IN THE

1336
00:47:51,270 --> 00:47:52,905
INDELs, SO THIS SHOWS AGE

1337
00:47:52,905 --> 00:47:55,474
MATCHED CONTROLS AND ALZHEIMER

1338
00:47:55,474 --> 00:47:58,110
SINGLE NEURONS AND ALS, FOOTWORK

1339
00:47:58,110 --> 00:47:59,511
TD NEURONS AND SOME LOOK NORMAL

1340
00:47:59,511 --> 00:48:01,613
AND THIS IS THE LOG PLOT SO THIS

1341
00:48:01,613 --> 00:48:03,448
IS 5000 HERE AND THIS IS 500,

1342
00:48:03,448 --> 00:48:06,451
BUT YOU SEE SOME NEURONS HAVE

1343
00:48:06,451 --> 00:48:08,687
THOUSANDS OF THESE INDELs,

1344
00:48:08,687 --> 00:48:13,792
WHICH WOULD BE INCREDIBLY COURT

1345
00:48:13,792 --> 00:48:20,299
AND  -

1346
00:48:20,299 --> 00:48:21,133
-DAMAGING FOR THE PAT

1347
00:48:21,133 --> 00:48:21,533
E-PRESCRIBINGS.

1348
00:48:21,533 --> 00:48:23,468
SO IF YOU LOOK AT THESE, YOU SEE

1349
00:48:23,468 --> 00:48:25,404
A FAIRLY WIDE DISTRIBUTION OF

1350
00:48:25,404 --> 00:48:27,439
DIFFERENT TYPES, THESE ORANGE 1S

1351
00:48:27,439 --> 00:48:31,810
ARE 1 BASE PAIR DELETIONS, THESE

1352
00:48:31,810 --> 00:48:33,512
GREEN PAIRS ARE 1 BASE PAIR,

1353
00:48:33,512 --> 00:48:35,080
HAVE YOU 2 BASE PAIR DELETIONS,

1354
00:48:35,080 --> 00:48:37,582
AND 2 BASE PAIR IN BLUE AND SO

1355
00:48:37,582 --> 00:48:37,883
ON.

1356
00:48:37,883 --> 00:48:40,585
IN THESE ABNORMAL 1S, ARE ALMOST

1357
00:48:40,585 --> 00:48:42,087
EXCLUSIVELY 2 BASE PAIR

1358
00:48:42,087 --> 00:48:44,222
DELETIONS THIS, SHOWS AGAIN THE

1359
00:48:44,222 --> 00:48:45,057
REDUCED NORMAL BECAUSE YOU SEE

1360
00:48:45,057 --> 00:48:46,825
IN IS THE NORMAL PATTERN AND

1361
00:48:46,825 --> 00:48:48,226
THEN SUPER IMPOSED ON THIS IS

1362
00:48:48,226 --> 00:48:50,595
THE HUGE SPIKES IN ALS AND IN

1363
00:48:50,595 --> 00:48:52,664
ALZHEIMER'S DEC, OF THESE 2 BASE

1364
00:48:52,664 --> 00:48:55,434
PAIR DELETIONS THAT OCCUR AT

1365
00:48:55,434 --> 00:48:57,269
HAWAIILY RECURRENT PATTERN IN

1366
00:48:57,269 --> 00:49:00,439
BOTH--AND A VERY SIMILAR PATTERN

1367
00:49:00,439 --> 00:49:01,373
OF ESSENTIA WILYAIN

1368
00:49:01,373 --> 00:49:02,207
INDISTINGUISHABLE PATTERN AND

1369
00:49:02,207 --> 00:49:03,442
THESE 2 VERY, VERY DIFFERENT

1370
00:49:03,442 --> 00:49:03,709
DISEASES.

1371
00:49:03,709 --> 00:49:04,676
FOURTH APPEARANCE WE DIDN'T KNOW

1372
00:49:04,676 --> 00:49:05,510
WHETHER THESE WERE SINGLE

1373
00:49:05,510 --> 00:49:07,045
STRANDED EVENTS THAT WERE JUST A

1374
00:49:07,045 --> 00:49:08,647
LESION ON 1 STRAND AND NOT THE

1375
00:49:08,647 --> 00:49:10,949
OTHER, OR DOUBLE STRANDED EVENT.

1376
00:49:10,949 --> 00:49:12,551
WE SUSPECTED THEY MIGHT BE

1377
00:49:12,551 --> 00:49:13,518
SINGLE STRANDED BECAUSE

1378
00:49:13,518 --> 00:49:16,688
[INDISCERNIBLE] HAD ALSO STUDIED

1379
00:49:16,688 --> 00:49:18,657
ALZHEIMER NEURONS AND HE HAD

1380
00:49:18,657 --> 00:49:20,859
SEEN MANY SIMILAR PATTERNS

1381
00:49:20,859 --> 00:49:23,862
INDELs BUT HAD NOT SEEN THE

1382
00:49:23,862 --> 00:49:25,397
LARGE ACCUMULATION IN INDELs

1383
00:49:25,397 --> 00:49:26,965
IN ALZHEIMER DEC EMPLOY HE

1384
00:49:26,965 --> 00:49:28,033
THOUGHT THEY MUST BE SINGLE

1385
00:49:28,033 --> 00:49:32,237
STRAND BUT IN FACT, DIANE CHOW

1386
00:49:32,237 --> 00:49:35,240
ADAPTED THIS METHOD OF TAGGING

1387
00:49:35,240 --> 00:49:40,846
THE 2 DIFFERENT STRANDS OF DNA,

1388
00:49:40,846 --> 00:49:43,248
WHERE YOU USE TRANSPOSES TO

1389
00:49:43,248 --> 00:49:46,184
LABEL THE STRAND, SO IF A

1390
00:49:46,184 --> 00:49:47,819
VARIANT IS DOUBLE STRANDED, IT'S

1391
00:49:47,819 --> 00:49:50,255
THROUGH ON THE WATSON AND YOU

1392
00:49:50,255 --> 00:49:51,990
CAN DO COMPLEMENT, AND YOU CAN

1393
00:49:51,990 --> 00:49:54,226
BE SRN THIS IS A TRUE DOUBLE

1394
00:49:54,226 --> 00:49:55,160
STRANDED MUTATION, WHEREAS IF

1395
00:49:55,160 --> 00:49:57,029
THERE'S ANY SORT OF

1396
00:49:57,029 --> 00:49:59,431
AMPLIFICATION ARTIFACT OR ANY

1397
00:49:59,431 --> 00:50:00,499
SORT OF POSTMORTEM CHANGE, THIS

1398
00:50:00,499 --> 00:50:01,800
WILL BE PRESENT ON 1 STRAND AND

1399
00:50:01,800 --> 00:50:03,268
NOT THE OTHER SO CAN YOU FILTER

1400
00:50:03,268 --> 00:50:04,036
THESE OUT.

1401
00:50:04,036 --> 00:50:06,872
SO WE FIND THESE 2 BASE PAIR

1402
00:50:06,872 --> 00:50:07,973
INSERTIONS ARE MOST COMMONLY

1403
00:50:07,973 --> 00:50:09,908
SINGLE STRAND BUT THEY ARE

1404
00:50:09,908 --> 00:50:10,709
DEFINITELY FREQUENCY DOUBLE

1405
00:50:10,709 --> 00:50:14,913
STRANDED AS WELL, SO THIS MAKES

1406
00:50:14,913 --> 00:50:16,548
US SO CLEARLY THEY ARE REAL BUT

1407
00:50:16,548 --> 00:50:18,550
IN FACT, THIS MAKES US BELIEVE

1408
00:50:18,550 --> 00:50:19,618
THAT SINGLE STRANDED EVENTS ARE

1409
00:50:19,618 --> 00:50:22,354
LIKELY TO BE A BIOLOGICAL PHENOM

1410
00:50:22,354 --> 00:50:24,823
BECAUSE OF THEIR SPECISSITY AND

1411
00:50:24,823 --> 00:50:26,858
THE RESEMBLANCE OF THE DOUBLE

1412
00:50:26,858 --> 00:50:27,292
STRANDED SIGNATURE.

1413
00:50:27,292 --> 00:50:30,662
SO I WILL JUST WRAP UP HERE, THE

1414
00:50:30,662 --> 00:50:34,232
NEURONAL GENOME IS INHERENTLY

1415
00:50:34,232 --> 00:50:36,835
CHANGING, THE NEURONS GAIN AN

1416
00:50:36,835 --> 00:50:38,570
SNV EVERY FEW WEEKS THROUGHOUT

1417
00:50:38,570 --> 00:50:41,339
YOUR LIFE AND 2 TO 3 INDELs

1418
00:50:41,339 --> 00:50:44,109
PER YEAR IN A LINEAR FASHION

1419
00:50:44,109 --> 00:50:48,413
NORMALLY, THE MUTATIONS ARE

1420
00:50:48,413 --> 00:50:50,015
ENRICHED IN EXACTLY THE MOST

1421
00:50:50,015 --> 00:50:51,917
TRANSCRIBED PARTS OF THE GENOME

1422
00:50:51,917 --> 00:50:54,719
AND THEN AD AND ALS BOTH SHOW

1423
00:50:54,719 --> 00:50:59,024
INCREASED NUMBERS OF SINGLE

1424
00:50:59,024 --> 00:50:59,991
NUCLEOTIDE VARIANTS ABOUT 200

1425
00:50:59,991 --> 00:51:01,760
EQUIVALENT TO THE 10 YEARS OF SO

1426
00:51:01,760 --> 00:51:04,196
OF AGING THAT IS LOST TO EITHER

1427
00:51:04,196 --> 00:51:06,398
OF THESE CONDITIONS BUT PERHAPS

1428
00:51:06,398 --> 00:51:08,033
MORE REMARKABLY THEY SHOW LARGE

1429
00:51:08,033 --> 00:51:11,002
INCREASES OF HUNDREDS TO EVEN

1430
00:51:11,002 --> 00:51:12,971
SOMETIMES THOUSANDS OF INDELs,

1431
00:51:12,971 --> 00:51:16,074
AND THESE AGAIN ARE HIGHLY

1432
00:51:16,074 --> 00:51:18,110
ENRICHED IN GENES AND THE

1433
00:51:18,110 --> 00:51:18,910
MECHANISM WE DON'T YET

1434
00:51:18,910 --> 00:51:20,679
UNDERSTAND BUT WE'RE VERY, VERY

1435
00:51:20,679 --> 00:51:22,314
ACTIVELY TRYING TO FIGURE OUT

1436
00:51:22,314 --> 00:51:24,382
WHAT THE MECHANISM OF THERE ARE

1437
00:51:24,382 --> 00:51:25,884
BECAUSE THIS COULD POTENTIALLY

1438
00:51:25,884 --> 00:51:27,352
CAUSE WIDE SPREAD CHANGES IN

1439
00:51:27,352 --> 00:51:29,187
GENE EXPRESSION THAT MIGHT

1440
00:51:29,187 --> 00:51:29,788
ULTIMATELY HAVE SOME

1441
00:51:29,788 --> 00:51:35,127
RELATIONSHIP TO THE DEATH OF

1442
00:51:35,127 --> 00:51:35,794
THOSE NEURONS.

1443
00:51:35,794 --> 00:51:38,763
SO I'LL JUST CONCLUDE THAT THE

1444
00:51:38,763 --> 00:51:49,307
WORK BY SOMATIC  MOSWRRK ZAIC, I

1445
00:51:54,846 --> 00:51:56,414
WILL ILTRAIT THIS WITH

1446
00:51:56,414 --> 00:51:57,682
ILITRATIONS WE HAVE 80 BILLION

1447
00:51:57,682 --> 00:51:58,950
NEURONS AND GLIAL CELLS

1448
00:51:58,950 --> 00:51:59,684
APPROXIMATELILY AND EACH OF

1449
00:51:59,684 --> 00:52:01,920
THESE ARE BORN WITH A ABOUT A

1450
00:52:01,920 --> 00:52:04,789
HUNDRED SOMATIC SNVs THAT ARE

1451
00:52:04,789 --> 00:52:07,425
DEVELOPMENTAL CLONAL 1S FROM THE

1452
00:52:07,425 --> 00:52:09,528
CELL THAT OCCURS DURING THE CELL

1453
00:52:09,528 --> 00:52:11,429
DIVISIONS THAT GENERATED AND SO

1454
00:52:11,429 --> 00:52:12,564
THAT GIVES YOU 8 TRILLION

1455
00:52:12,564 --> 00:52:14,633
SOMATIC MUTATIONS JUST IN YOUR

1456
00:52:14,633 --> 00:52:15,033
BRAIN NEURONS.

1457
00:52:15,033 --> 00:52:18,136
AND OF COURSE, NOW THE GENOME

1458
00:52:18,136 --> 00:52:19,871
STARTS LOOKING PRETTY SMALL,

1459
00:52:19,871 --> 00:52:22,274
IT'S A MERE 3 BILLION BASE PAIRS

1460
00:52:22,274 --> 00:52:24,376
SO 8 TRILLION DIVIDED BY 3

1461
00:52:24,376 --> 00:52:26,244
BILLION 2000 TIMES THE AVERAGE

1462
00:52:26,244 --> 00:52:29,447
SPOT IN YOUR GENOME IS MUTATED 3

1463
00:52:29,447 --> 00:52:30,982
TAMES JUST IN YOUR NEURONS JUST

1464
00:52:30,982 --> 00:52:32,651
AT BIRTH TO SAY NOTHING OF THE

1465
00:52:32,651 --> 00:52:34,219
AGE RELATED 1S I WAS JUST

1466
00:52:34,219 --> 00:52:35,654
TELLING YOU ABOUT.

1467
00:52:35,654 --> 00:52:36,955
AND THEN, A SIMILAR CALCULATION

1468
00:52:36,955 --> 00:52:38,323
WILL HOLD FOR WHATEVER YOUR

1469
00:52:38,323 --> 00:52:40,725
FAVORITE CELL TYPE IS, THE SAME

1470
00:52:40,725 --> 00:52:42,160
CALCULATION, HOLD FORS GLIAL

1471
00:52:42,160 --> 00:52:43,195
CELLS, TBLEEL CELLS ALREADY HAVE

1472
00:52:43,195 --> 00:52:45,297
A MUTATION IN EVERY SINGLE--NOT

1473
00:52:45,297 --> 00:52:47,165
JUST EVERY YEEN IN THE GENOME

1474
00:52:47,165 --> 00:52:47,766
BUT EVERY NUCLEOTIDE IN THE

1475
00:52:47,766 --> 00:52:48,433
GERONTOLOGYSTS MEMORY CLONE AND

1476
00:52:48,433 --> 00:52:49,734
IT'S JUST A QUESTION THEN OF

1477
00:52:49,734 --> 00:52:51,002
WHETHER THEY'RE UNDER THE RIGHT

1478
00:52:51,002 --> 00:52:53,104
SORT OF CLONAL SELECTION, TO

1479
00:52:53,104 --> 00:52:57,509
CAUSE THOSE MUTATIONS TO HAVE AN

1480
00:52:57,509 --> 00:52:57,976
EFFECT.

1481
00:52:57,976 --> 00:53:00,879
AND THIS SIMULATION IS COPIED

1482
00:53:00,879 --> 00:53:02,714
FROM BEN EBBER 2 DESCRIBED THIS

1483
00:53:02,714 --> 00:53:04,049
FOR 10 BILLION T-CELLS EMPLOY SO

1484
00:53:04,049 --> 00:53:06,551
I BELIEVE THAT ANY INFLAMMATION

1485
00:53:06,551 --> 00:53:08,186
WILL BREED PROLIFERATION AND ANY

1486
00:53:08,186 --> 00:53:09,588
PROLIFERATION WILL BREED A

1487
00:53:09,588 --> 00:53:12,190
COMITITION, A CLONAL SELECTION

1488
00:53:12,190 --> 00:53:13,725
OF THOSE CELLS THAT THAT HAPPEN

1489
00:53:13,725 --> 00:53:15,360
TO HAVE ACTIVATING MUTATIONS

1490
00:53:15,360 --> 00:53:18,263
THAT ARE ESSENTIALLY CANCER LIKE

1491
00:53:18,263 --> 00:53:19,564
MUTATIONS, BUT, OFTEN TIMES,

1492
00:53:19,564 --> 00:53:20,966
THESE CANCER MUTATIONS OCCUR IN

1493
00:53:20,966 --> 00:53:22,734
CELLS LIKE NEURONS AND MICROGLIA

1494
00:53:22,734 --> 00:53:26,571
THAT DON'T FORM TUMORS, BUT THEY

1495
00:53:26,571 --> 00:53:28,173
CREATE ALTERNATE DISEASE STATES

1496
00:53:28,173 --> 00:53:30,242
THAT DON'T LOOK LIKE MASSES THAT

1497
00:53:30,242 --> 00:53:32,210
YOU CAN TAKE OUT.

1498
00:53:32,210 --> 00:53:34,879
SO AGAIN, OTHER MYSTERIOUS

1499
00:53:34,879 --> 00:53:36,348
NONNEUROLOGIC DISEASES ARE

1500
00:53:36,348 --> 00:53:38,550
LIKELY TO REFLECT OTHER KINDS OF

1501
00:53:38,550 --> 00:53:40,752
ROLES OF SOMATIC MUTATION, SO I

1502
00:53:40,752 --> 00:53:43,488
TRIED TO ACKNOWLEDGE EVERYONE AS

1503
00:53:43,488 --> 00:53:44,089
I WENT.

1504
00:53:44,089 --> 00:53:45,957
THE SINGLE AGING NEWON WAS

1505
00:53:45,957 --> 00:53:47,926
STARTED BY MIKE MILLER AND THEN

1506
00:53:47,926 --> 00:53:51,763
[INDISCERNIBLE] MAYED A MAJOR

1507
00:53:51,763 --> 00:53:53,365
ROLE, AND WE'VE BEEN REALLY

1508
00:53:53,365 --> 00:53:55,133
LUCKY TO COLLABORATE WITH BRAD

1509
00:53:55,133 --> 00:53:57,335
FROM THE MGHAL JEIMER CENTER,

1510
00:53:57,335 --> 00:53:59,604
THE TEMPORAL EPILEPSY WORK IS

1511
00:53:59,604 --> 00:54:01,339
THE WORK OF [INDISCERNIBLE], AND

1512
00:54:01,339 --> 00:54:05,110
I DIDN'T MENTION [INDISCERNIBLE]

1513
00:54:05,110 --> 00:54:06,378
IS THE BIOINFORMATICIAN FROM THE

1514
00:54:06,378 --> 00:54:07,679
LAB HAD IN WHICH WE DID THIS

1515
00:54:07,679 --> 00:54:08,980
WORK, I THINK WE'VE MENINGED ALL

1516
00:54:08,980 --> 00:54:10,715
THESE PEOPLE HERE BUT WE'VE BEEN

1517
00:54:10,715 --> 00:54:12,450
AGAIN LUCKY TO HAVE THE

1518
00:54:12,450 --> 00:54:15,186
COOPERATION FOR THE ROSE MAP

1519
00:54:15,186 --> 00:54:19,291
PROJECT AND THEN AS THE FTD ALS,

1520
00:54:19,291 --> 00:54:22,394
AND WE WOULD BE NO PLACE WITHOUT

1521
00:54:22,394 --> 00:54:24,296
PETER PARK, I WANT SHORTENED

1522
00:54:24,296 --> 00:54:25,764
SHOW OUTIO, IN MANY OF THESE

1523
00:54:25,764 --> 00:54:30,969
PROGECS AND HE'S LIKE A GENIUS

1524
00:54:30,969 --> 00:54:35,273
WHEN IT COMES TO ANALYZING THESE

1525
00:54:35,273 --> 00:54:38,243
THINGS, AND LEE, AS WELL,

1526
00:54:38,243 --> 00:54:39,244
BRILLIANT PEOPLE IN HER LAB,

1527
00:54:39,244 --> 00:54:40,345
THANK YOU VERY MUCH AND I WILL

1528
00:54:40,345 --> 00:54:48,253
BE HAPPY TO ANSWER QUESTIONS.

1529
00:54:48,253 --> 00:54:50,221
MWE MIGHT HAVE TO REPEAT

1530
00:54:50,221 --> 00:54:55,293
THIS--THERE WE GO, OKAY, SO AS

1531
00:54:55,293 --> 00:54:57,495
WE'RE WAITING EARLIER QUESTION,

1532
00:54:57,495 --> 00:54:58,430
ANY INFORMATION ABOUT THE

1533
00:54:58,430 --> 00:55:00,365
EXISTENCE OF THESE MUTATIONS IN

1534
00:55:00,365 --> 00:55:03,768
THE POPULATION OF CHILDREN WHO

1535
00:55:03,768 --> 00:55:07,939
HAVE EXPERIENCED FIBERAL

1536
00:55:07,939 --> 00:55:09,074
SEIZURE?

1537
00:55:09,074 --> 00:55:11,009
>> NO, WE DON'T HAVE ANY
SPA

1538
00:55:11,009 --> 00:55:12,043
SPECIFIC INFORMATION AGAIN WE

1539
00:55:12,043 --> 00:55:14,079
CAN ONLY WORK WITH A POSTMORTEM

1540
00:55:14,079 --> 00:55:17,182
BRAIN OR A TEMPORAL LOBE

1541
00:55:17,182 --> 00:55:17,449
RESECTION.

1542
00:55:17,449 --> 00:55:18,583
WHAT WE'RE TRYING TO DO THOUGH

1543
00:55:18,583 --> 00:55:20,452
IS TO FIGURE OUT IF THOSE, YOU

1544
00:55:20,452 --> 00:55:22,854
KNOW IF OUR PATIENTS THAT HAVE A

1545
00:55:22,854 --> 00:55:24,622
HISTORY OF FEB RILE SEIZURES, IF

1546
00:55:24,622 --> 00:55:28,493
WHAT I'M SAYING IS TRUE, WE

1547
00:55:28,493 --> 00:55:29,461
HYPOTHESIZE THAT SEIZURE WOULD

1548
00:55:29,461 --> 00:55:30,795
HAVE INDUCED A WAVE OF NUR O

1549
00:55:30,795 --> 00:55:33,498
GENESIS IN THE TEMPORAL LOBE AND

1550
00:55:33,498 --> 00:55:37,469
YOU KNOW I MENTIONED THAT THESE

1551
00:55:37,469 --> 00:55:39,204
CANCERS ARE VERY SPECIFIC.

1552
00:55:39,204 --> 00:55:41,139
AND SON 1 OF THEM IS SPECTACULAR

1553
00:55:41,139 --> 00:55:42,240
FOR CELL DIVISION, WHEN I GO

1554
00:55:42,240 --> 00:55:44,876
BACK TO THIS LUNG CANCER, THIS

1555
00:55:44,876 --> 00:55:46,845
SBS 1, IT'S SEEN ONLY IN

1556
00:55:46,845 --> 00:55:49,180
DIVIDING CELLS AND NOT PRESENT

1557
00:55:49,180 --> 00:55:50,248
IN NEURONS ISSUES THE NEURONS

1558
00:55:50,248 --> 00:55:51,783
HAVE A FEW OF THESE MUTATIONS

1559
00:55:51,783 --> 00:55:53,284
FROM THE DEVELOPMENT BUT THEN

1560
00:55:53,284 --> 00:55:55,520
THEY DON'T ACCUMULATE THEM WITH

1561
00:55:55,520 --> 00:55:55,687
AGE.

1562
00:55:55,687 --> 00:55:57,455
HAY ACCUMULATE OTHER THINGS

1563
00:55:57,455 --> 00:55:59,858
HOWEVER, WE CAN LOOK IN THE

1564
00:55:59,858 --> 00:56:00,792
TEMPORAL LOBE SPECIMENS TO SEE

1565
00:56:00,792 --> 00:56:02,694
IF THEY HAVE MORE OF THE NORMAL

1566
00:56:02,694 --> 00:56:05,764
NEURONS AND THAT WOULD BE

1567
00:56:05,764 --> 00:56:07,198
INDICATOR THEY WOULD GO ARK

1568
00:56:07,198 --> 00:56:09,033
DIGGAL ROUNDS OF PROLIFERATION

1569
00:56:09,033 --> 00:56:11,436
AND CORRELATE WITH THE HISTORY

1570
00:56:11,436 --> 00:56:12,137
OF REFRESHING FACTORS.

1571
00:56:12,137 --> 00:56:13,671
>> OKAY, I WILL MOVE ON TO
1

1572
00:56:13,671 --> 00:56:15,573
MORE.

1573
00:56:15,573 --> 00:56:18,410
IN THE CASES OF CLONAL

1574
00:56:18,410 --> 00:56:19,778
PROLIFERATIONS, IN THESE

1575
00:56:19,778 --> 00:56:21,980
NEUROLOGICAL DECS DUE TO SOMATIC

1576
00:56:21,980 --> 00:56:23,915
VARIANTS, SHOULD THESE CASES

1577
00:56:23,915 --> 00:56:30,588
ALSO BE DRIEBED AS BENIGN

1578
00:56:30,588 --> 00:56:31,423
NEOPLAZ MIDSISMS.

1579
00:56:31,423 --> 00:56:33,291
LET'S SEE IT DEPENDS ON THE

1580
00:56:33,291 --> 00:56:36,327
PRECISE DEFINITION OF THE TERMNY

1581
00:56:36,327 --> 00:56:37,729
O PLASM, I'M TRYING TO RECALL

1582
00:56:37,729 --> 00:56:39,764
WHAT WAS TAUGHT IN PATHOLOGY BUT

1583
00:56:39,764 --> 00:56:41,900
THAT WAS 40 YEARS AGO OR 35

1584
00:56:41,900 --> 00:56:43,635
YEARS AGO, MY UNDERSTANDING OF A

1585
00:56:43,635 --> 00:56:47,572
NEOPLASM IS THAT THEY GROW.

1586
00:56:47,572 --> 00:56:50,742
AND SO BY THAT DEFINITION, NO,

1587
00:56:50,742 --> 00:56:52,377
BECAUSE AGAIN, PEDIATRIC 1S ARE

1588
00:56:52,377 --> 00:56:54,679
FIXED DISORDERS AS FAR AS WE

1589
00:56:54,679 --> 00:56:55,947
KNOW DON'T GROW, PROBABLY WILL

1590
00:56:55,947 --> 00:56:57,148
FIND OUT SOME DAY THEY ARE

1591
00:56:57,148 --> 00:57:01,252
GROWING IN SOME WAYS WHERE THE

1592
00:57:01,252 --> 00:57:02,353
OVERALL MASS OR APPEARANCE

1593
00:57:02,353 --> 00:57:03,721
DOESN'T CHANGE, PROBABLY A LOT

1594
00:57:03,721 --> 00:57:04,989
MORE DYNAMIC THAN I GIVE THEM

1595
00:57:04,989 --> 00:57:06,057
CREDIT FAR BUT THEY DON'T

1596
00:57:06,057 --> 00:57:07,358
OBVIOUSLY GROW IN THE WAY I

1597
00:57:07,358 --> 00:57:12,163
THINK OF AS A NEOPLASM.

1598
00:57:12,163 --> 00:57:13,531
>> HI, VERY NICE TALK.

1599
00:57:13,531 --> 00:57:17,602
I THINK YOUR EPILEPSY DATA

1600
00:57:17,602 --> 00:57:19,938
SUGGESTS BECAUSE OF THE NETWORK

1601
00:57:19,938 --> 00:57:21,673
NATURE OF NEURONS, A VERY SMALL

1602
00:57:21,673 --> 00:57:23,975
PROPORTION OF AFFECTED NEURONS

1603
00:57:23,975 --> 00:57:24,909
CAN HAVE AN OUTSIDE EFFECT

1604
00:57:24,909 --> 00:57:26,010
EMPLOY SO I'M WONDER FIGURE YOU

1605
00:57:26,010 --> 00:57:27,512
HAVE THOUGHTS AS TO HOW OR

1606
00:57:27,512 --> 00:57:29,147
WHETHER THESE SOMATIC MUTATIONS

1607
00:57:29,147 --> 00:57:31,115
MAY CONTRIBUTE TO NORMAL HUMAN

1608
00:57:31,115 --> 00:57:33,451
DIVERSITY IN EMERGING ITS OF

1609
00:57:33,451 --> 00:57:41,693
NEUROCOGNITIVE FUNCTION AND

1610
00:57:41,693 --> 00:57:41,960
BEHAVIOR?

1611
00:57:41,960 --> 00:57:43,495
>> THANK YOU VERY MUCH FOR
THAT

1612
00:57:43,495 --> 00:57:43,862
QUESTION.

1613
00:57:43,862 --> 00:57:45,163
I THINK VERY LIKELY THEY DO.

1614
00:57:45,163 --> 00:57:46,364
IT'S A LITTLE HARD TO KNOW HOW

1615
00:57:46,364 --> 00:57:47,665
TO MAKE THAT ARGUMENT, AND THE

1616
00:57:47,665 --> 00:57:50,602
REASON I THINK IT'S LIKELY THAT

1617
00:57:50,602 --> 00:57:53,404
THEY DO, IS THAT SOMATIC

1618
00:57:53,404 --> 00:57:54,772
DEVELOPMENTAL MUTATIONS THAT ARE

1619
00:57:54,772 --> 00:57:56,307
CLONEALLY SHARED ARE COMMON

1620
00:57:56,307 --> 00:57:58,510
ENOUGH SO THAT A TYPICAL PERSON,

1621
00:57:58,510 --> 00:58:01,479
IF WE GO THROUGH THE MAP, A

1622
00:58:01,479 --> 00:58:04,682
TYPICAL PERSON WILL CONTAIN A

1623
00:58:04,682 --> 00:58:07,418
FUNCTION ALTERING EXONIC SOMATIC

1624
00:58:07,418 --> 00:58:08,953
MUTATION IN LIKE ABOUT 2% OF

1625
00:58:08,953 --> 00:58:09,888
THEIR CELLS OR MORE.

1626
00:58:09,888 --> 00:58:13,558
SO BASIC LYE ALL OF US HAVE A

1627
00:58:13,558 --> 00:58:14,292
FUNCTION ALTERING EXONIC

1628
00:58:14,292 --> 00:58:15,560
MUTATION AND SOME CLONE IN OUR

1629
00:58:15,560 --> 00:58:16,628
BRAIN SOMEWHERE, TO SAY NOTHING

1630
00:58:16,628 --> 00:58:19,264
OF 1S THAT MIGHT BE ALSO

1631
00:58:19,264 --> 00:58:20,698
FUNCTION ALTERING AND NONCODING

1632
00:58:20,698 --> 00:58:22,200
SO, YOU KNOW THERE ARE SO MANY

1633
00:58:22,200 --> 00:58:23,501
OF THEM THAT THEY ARE VERY

1634
00:58:23,501 --> 00:58:25,336
COMMON AND AS I SAY, ONCE YOU

1635
00:58:25,336 --> 00:58:32,644
GET DOWN TO SMALL CLONES, WE ALL

1636
00:58:32,644 --> 00:58:34,712
HAVE EVERYTHING, SO I DO BELIEVE

1637
00:58:34,712 --> 00:58:35,914
THAT--BUT AGAIN HOW TO CORRELATE

1638
00:58:35,914 --> 00:58:37,081
THEM WITH DIFFERENCES IN

1639
00:58:37,081 --> 00:58:39,951
BEHAVIOR OR UNIQUE ASPECTS OF

1640
00:58:39,951 --> 00:58:40,184
PEOPLE.

1641
00:58:40,184 --> 00:58:44,856
AND WHAT'S REALLY COOL IS THAT

1642
00:58:44,856 --> 00:58:48,693
THE DEVELOPMENTAL 1S ACTUALLY

1643
00:58:48,693 --> 00:58:53,698
ARE ENRICHED IN NONCODING

1644
00:58:53,698 --> 00:58:55,099
REGULATORY ELEMENTS, ENHANCERS

1645
00:58:55,099 --> 00:58:55,466
AND PROMOTERS.

1646
00:58:55,466 --> 00:58:58,236
WHAT'S INTERESTING ABOUT THAT IS

1647
00:58:58,236 --> 00:59:00,405
THAT EXONIC MUTATIONS ARE PRETTY

1648
00:59:00,405 --> 00:59:02,941
MUCH ALL BAD THE PROTEIN

1649
00:59:02,941 --> 00:59:05,910
SEQUENCE OF OF ALL PROTEIN

1650
00:59:05,910 --> 00:59:06,945
SYSTEM OPTIMIZED FOR PERFECT

1651
00:59:06,945 --> 00:59:09,113
FUNCTION, A MUTATION IS NOT

1652
00:59:09,113 --> 00:59:10,481
LIKELY TO TO IMPROVE THE

1653
00:59:10,481 --> 00:59:13,351
FUNCTION OF A PROTEIN, ON THE

1654
00:59:13,351 --> 00:59:19,624
OTHER HAND IS MUTATION AND AND

1655
00:59:19,624 --> 00:59:21,125
SO THEY MIGHT SHIFT THE

1656
00:59:21,125 --> 00:59:22,493
EXPRESSION, SORE THEY MIGHT TURN

1657
00:59:22,493 --> 00:59:24,028
IT ON SOME PLACE WHERE IT'S NOT

1658
00:59:24,028 --> 00:59:25,797
TURNED ON SO THOSE ARE JUST THE

1659
00:59:25,797 --> 00:59:28,333
KIND OF MUTATIONS THAT MIGHT

1660
00:59:28,333 --> 00:59:29,300
GENERATE FUNCTIONAL DIVERSITY

1661
00:59:29,300 --> 00:59:30,802
WITHOUT CREATING DISEASE.

1662
00:59:30,802 --> 00:59:31,803
SOIME INTERESTED WHETHERRINE

1663
00:59:31,803 --> 00:59:33,004
TIEN'S BRAIN HAD SOME

1664
00:59:33,004 --> 00:59:35,506
INTERESTING ENHANCER IN

1665
00:59:35,506 --> 00:59:36,541
YOUITATION, AND SOME--SO HAD

1666
00:59:36,541 --> 00:59:38,576
SOME GENE TURNED ON, PLACE WHERE

1667
00:59:38,576 --> 00:59:46,951
IT MIGHT NOT NORMALLY BE.

1668
00:59:46,951 --> 00:59:48,920
>> SURE, SO 2 QUESTIONS.

1669
00:59:48,920 --> 00:59:50,822
THE FIRST 1 IS:  YESTERDAY I

1670
00:59:50,822 --> 00:59:53,891
WENT FOR A 2-MILE WALK WITH A

1671
00:59:53,891 --> 00:59:57,495
FRIEND OF MINE, SHE'S ALMOST 98

1672
00:59:57,495 --> 01:00:01,432
YEARS OLD, ALMOST NEVER SICK,

1673
01:00:01,432 --> 01:00:02,600
SHE EXERCISES AT 8 IN THE

1674
01:00:02,600 --> 01:00:03,768
MORNING, ALL THESE GOOD THINGS

1675
01:00:03,768 --> 01:00:06,771
AND WHEN I LOOK AT THESE

1676
01:00:06,771 --> 01:00:08,172
HORRENDOUS NUMBERS, I ASK

1677
01:00:08,172 --> 01:00:11,776
MYSELF, HOW CAN SHE POSSIBLY

1678
01:00:11,776 --> 01:00:21,686
AVOID ALL OF THESE DEBILITATING

1679
01:00:21,686 --> 01:00:21,919
ITATING

1680
01:00:21,919 --> 01:00:24,689
MUTATIONS, REALLY. 

1681
01:00:24,689 --> 01:00:26,658
SHE'S AMAZING, HOW DOES THAT

1682
01:00:26,658 --> 01:00:26,891
HAPPEN.

1683
01:00:26,891 --> 01:00:27,625
>> THAT'S A GREAT
QUESTION.

1684
01:00:27,625 --> 01:00:29,594
I WOULD LIKE TO LEARN THE ANSWER

1685
01:00:29,594 --> 01:00:32,030
RIGHT AWAY BEFORE I GET 1 DAY

1686
01:00:32,030 --> 01:00:32,497
OLDER.

1687
01:00:32,497 --> 01:00:34,799
WHAT FASCINATES ME IN THESE

1688
01:00:34,799 --> 01:00:35,967
MUTATIONS IN MICROGLIA, IT'S A

1689
01:00:35,967 --> 01:00:38,069
WAY OF INTEGRATING OUR INHERITED

1690
01:00:38,069 --> 01:00:41,873
GENOME WITH OUR LIFESTYLE.

1691
01:00:41,873 --> 01:00:46,110
SO BECAUSE, YOU KNOW THESE--MANY

1692
01:00:46,110 --> 01:00:48,012
THINGS MIGHT, SO WE'RE DOING A

1693
01:00:48,012 --> 01:00:49,781
PARALLEL STUDY OF CHRONIC

1694
01:00:49,781 --> 01:00:51,883
INSEVERE MITRAL LOP RAGHTY AND

1695
01:00:51,883 --> 01:00:52,684
AMERICAN FOOTBALL PLAYERS AND

1696
01:00:52,684 --> 01:00:55,019
WITH Mc KEY IN BOSTON ANALYZED

1697
01:00:55,019 --> 01:00:56,688
THE BRAINING OF MANY FAMOUS

1698
01:00:56,688 --> 01:01:00,758
FOOTBALL PLAYERS, AND SO, WE SEE

1699
01:01:00,758 --> 01:01:02,427
SIMILAR PATTERNS OF MUTATION IN

1700
01:01:02,427 --> 01:01:04,162
THE GENOMES OF SINGLE NEURONS,

1701
01:01:04,162 --> 01:01:06,464
AND WE HAVE IN EVIDENT THAT THEY

1702
01:01:06,464 --> 01:01:08,666
ALSO HAVE THESE CLONAL

1703
01:01:08,666 --> 01:01:09,367
SOPHISTICATED MOTTIC EVOLUTION

1704
01:01:09,367 --> 01:01:15,907
AS WELL, AND SO, YOU CAN IMAGINE

1705
01:01:15,907 --> 01:01:16,974
THAT--SO LIFESTYLE CHANGES OR

1706
01:01:16,974 --> 01:01:18,376
HEAD TRAUMA MIGHT INDUCE

1707
01:01:18,376 --> 01:01:19,877
IMFLAMMATION IN THE BRAIN AND

1708
01:01:19,877 --> 01:01:21,779
AGAIN, THAT WOULD THEN STIMULATE

1709
01:01:21,779 --> 01:01:24,015
PROLIFERATION OF THESE CELLS SO

1710
01:01:24,015 --> 01:01:25,950
THAT'S A MECHANISM, HOW THESE

1711
01:01:25,950 --> 01:01:29,353
LIFE TILE EVENTS MIGHT INTEGRATE

1712
01:01:29,353 --> 01:01:31,322
THEMSELVES BY PROMOTING

1713
01:01:31,322 --> 01:01:32,256
POTENTIALLY PROMOTING IN THE

1714
01:01:32,256 --> 01:01:34,125
CASE OF DISEASE, YOU KNOW

1715
01:01:34,125 --> 01:01:35,026
PROLIFERATION AND CLONAL

1716
01:01:35,026 --> 01:01:41,566
SELECTION OF CELLS THAT HAVE

1717
01:01:41,566 --> 01:01:42,033
DAMAGING MUTATIONS.

1718
01:01:42,033 --> 01:01:43,434
>> WHICH SORT OF RELATES
TO THE

1719
01:01:43,434 --> 01:01:44,836
LESSER QUESTION, EARLY ON YOU

1720
01:01:44,836 --> 01:01:46,671
MENTIONED SOMETHING VERY, VERY

1721
01:01:46,671 --> 01:01:47,972
BRIEFLY ABOUT TREADMILL ACTIVITY

1722
01:01:47,972 --> 01:01:49,707
AND I WAS WONDERING HOW DOES

1723
01:01:49,707 --> 01:01:51,576
THAT RELATE TO A MUTATION IN THE

1724
01:01:51,576 --> 01:01:52,276
BRAIN IN.

1725
01:01:52,276 --> 01:01:53,778
>> SO AS FAR AS WE KNOW IT

1726
01:01:53,778 --> 01:01:54,846
DOESN'T CREATE MUTATIONS IN THE

1727
01:01:54,846 --> 01:01:58,950
BRAIN BUT IT CREATES A ROUND OF

1728
01:01:58,950 --> 01:02:04,722
PROLIFERATION IN THE DENTEGYRUS.

1729
01:02:04,722 --> 01:02:06,624
AND THEY'VE SHOWN THAT WITH

1730
01:02:06,624 --> 01:02:08,493
ANIMALS, SO IF THEY TAKE THEM TO

1731
01:02:08,493 --> 01:02:10,128
THE TREADMILL THEY GET A WAVE IN

1732
01:02:10,128 --> 01:02:11,429
THE HIPPOCAMPUS AND IT HELPS

1733
01:02:11,429 --> 01:02:12,263
THEM LEARN.

1734
01:02:12,263 --> 01:02:13,564
THAT'S GENERALLY THOUGHT OF AS A

1735
01:02:13,564 --> 01:02:18,503
POSITIVE THING, I DON'T KNOW I

1736
01:02:18,503 --> 01:02:20,138
DON'T KNOW THIS IS SOPHISTICATED

1737
01:02:20,138 --> 01:02:22,673
I HAVEN'T TOTALLY FIGURED OUT

1738
01:02:22,673 --> 01:02:26,344
HOW THE POSITIVE ASPECTS OF

1739
01:02:26,344 --> 01:02:26,944
HYPOCAMPAL NEUROGENESIS MIGHT

1740
01:02:26,944 --> 01:02:28,813
INTEGRATE WITH THE POTENTIAL FOR

1741
01:02:28,813 --> 01:02:32,817
IT TO INDUCE CLONAL SELECTION OF

1742
01:02:32,817 --> 01:02:36,654
DAMAGING VARIANTS EMPLOY N1 MORE

1743
01:02:36,654 --> 01:02:38,322
QUESTION AT LOWS, THE I WANT TO

1744
01:02:38,322 --> 01:02:42,393
REPEAT THE CME CODE THAT PEOPLE

1745
01:02:42,393 --> 01:02:45,930
CAN'T QUITE SEE.

1746
01:02:45,930 --> 01:02:47,999
510113 EMPLOY SO COULD THE

1747
01:02:47,999 --> 01:02:50,067
TRANSCRIPTION GENES BE A RESULT

1748
01:02:50,067 --> 01:02:51,402
OF TRANSCRIPTION COMPLEX

1749
01:02:51,402 --> 01:02:53,638
CREATING THE MUTATIONS?

1750
01:02:53,638 --> 01:02:57,508
>> YES, IT'S POSSIBLE THAT
IF I

1751
01:02:57,508 --> 01:02:58,976
UNDERSTAND CORRECT 3 THAT

1752
01:02:58,976 --> 01:03:00,611
COMPLEX MIGHT INDUCE THE

1753
01:03:00,611 --> 01:03:02,446
MUTATION, THE WAY WE THINK ABOUT

1754
01:03:02,446 --> 01:03:05,183
IT IS SOMETHING THAT THE PROCESS

1755
01:03:05,183 --> 01:03:14,759
OF TRANSSCRIKS AND IT NEED TO BE

1756
01:03:14,759 --> 01:03:19,297
ABLE AND EXPOSING THE AND THEY

1757
01:03:19,297 --> 01:03:29,807
HAVE TO OPEN UP TO BE HELPFUL

1758
01:03:32,977 --> 01:03:38,516
EMPLOY NTHANK 

1759
01:03:38,516 --> 01:03:38,950
>> BIG THANK YOU.

1760
01:03:38,950 --> 01:03:40,785
>> THANK YOU VERY MUCH.

1761
01:03:40,785 --> 01:03:51,095
>> [ APPLAUSE ]