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>> ALL RIGHT. GOOD MORNING,

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00:00:07,273 --> 00:00:10,510
EVERYBODY.  ON BEHALF OF THE

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00:00:10,577 --> 00:00:14,714
ENTIRE NIH DYNAMICS AND

4
00:00:14,781 --> 00:00:16,683
REPLICATION I WOULD LIKE TO

5
00:00:16,750 --> 00:00:19,319
WELCOME YOU FOR VIRUSES AND

6
00:00:19,386 --> 00:00:20,754
RESEARCH AND MEDICINE.  BEFORE

7
00:00:20,820 --> 00:00:23,823
WE JUMP INTO THE PROGRAM I WOULD

8
00:00:23,890 --> 00:00:26,593
LIKE TO BRIEFLY MENTION A FEW

9
00:00:26,659 --> 00:00:29,396
UPCOMING EVENTS TO THIS

10
00:00:29,462 --> 00:00:31,998
AUDIENCE.  NOVEMBER 2ND WE WILL

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00:00:32,065 --> 00:00:37,771
HOLD THE 12TH DAVID DURSY AWARD

12
00:00:37,837 --> 00:00:42,008
AND SPEAKER IS FROM UNIVERSITY

13
00:00:42,075 --> 00:00:45,545
OF MINNESOTA -- THROUGH

14
00:00:45,612 --> 00:00:48,715
COMPARATIVE ANALYSIS NOVEMBER

15
00:00:48,782 --> 00:00:51,484
11TH UNIVERSITY OF MARYLAND

16
00:00:51,551 --> 00:00:54,654
COLLEGE PARK PROGRAM WILL HOLD

17
00:00:54,721 --> 00:00:57,957
THE FALL RESTRATES AND VERY

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00:00:58,024 --> 00:00:59,592
DISTINGUISHED GROUP OF SPEAKERS

19
00:00:59,659 --> 00:01:02,829
INCLUDING DANY AND OUR OWN ALEX

20
00:01:02,896 --> 00:01:05,532
COMPTON.  IF YOU WOULD LIKE TO

21
00:01:05,598 --> 00:01:07,300
ATTEND AND HAVEN'T ALREADY

22
00:01:07,367 --> 00:01:10,136
CONTACTED ME, REACH OUT AND WE

23
00:01:10,203 --> 00:01:12,572
WILL PUT YOU ON THE LIST.

24
00:01:12,639 --> 00:01:16,009
DECEMBER EIGHTH, NIH WILL HOLD

25
00:01:16,075 --> 00:01:19,312
THE 25TH SYMPOSIUM IN AWARDS AND

26
00:01:19,379 --> 00:01:20,980
BASIC AND CLINICAL VIROLOGY.

27
00:01:21,047 --> 00:01:23,183
YOU CAN CHECK OUT THE WEBSITE

28
00:01:23,249 --> 00:01:25,485
FOR MORE INFORMATION.  DECEMBER

29
00:01:25,552 --> 00:01:27,987
EIGHTH, THE NCI CRYPTER FOR

30
00:01:28,054 --> 00:01:30,457
EXCELLENCE AND HIV CANCER

31
00:01:30,523 --> 00:01:32,425
VIROLOGY WILL HOLD THE FALL

32
00:01:32,492 --> 00:01:34,661
THINK TANK AT NATURAL CONFERENCE

33
00:01:34,727 --> 00:01:37,297
CENTER IN BETHESDA AND CHAIRS

34
00:01:37,363 --> 00:01:38,531
FOR THIS CORRECTOR OF

35
00:01:38,598 --> 00:01:40,366
EXCELLENCE, YOU CAN CONTACT THEM

36
00:01:40,433 --> 00:01:42,535
AT U MASS FOR ADDITIONAL

37
00:01:42,602 --> 00:01:43,670
INFORMATION AND FINALLY WOULD

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00:01:43,736 --> 00:01:45,271
LIKE TO MAKE A PLUG FOR THE

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00:01:45,338 --> 00:01:48,041
FIFTH INSTALLMENT OF THE

40
00:01:48,107 --> 00:01:50,109
INTERNATIONAL VIRUSES CONFERENCE

41
00:01:50,176 --> 00:01:53,279
SPONSORED BY VIRUSES, VIRUSES

42
00:01:53,346 --> 00:01:58,284
2024 WORLD OF VIRUSES HOLD IN

43
00:01:58,351 --> 00:02:01,254
BARCELONA SPAIN FEBRUARY 14TH OR

44
00:02:01,321 --> 00:02:03,056
16TH AND GREAT GROUP OF SPEAKERS

45
00:02:03,122 --> 00:02:06,359
IS CHARLIE AND LOUIS AND LORDES

46
00:02:06,426 --> 00:02:08,161
AND CHECK OUT THE WEBSITE AND

47
00:02:08,228 --> 00:02:09,662
REGISTER AND THERE IS A PROGRAM

48
00:02:09,729 --> 00:02:14,667
FOR TALKS AND POSTERS DRIVEN BY

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00:02:14,734 --> 00:02:15,502
ABSTRACTS.

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00:02:15,568 --> 00:02:18,771
OKAY.  BACK TO THE FOCUS OF

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TODAY.

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00:02:19,105 --> 00:02:21,674
AS MEMBERS OF SOCIETY AND

53
00:02:21,741 --> 00:02:23,476
SCIENTISTS, WE ARE USED TO

54
00:02:23,543 --> 00:02:27,280
THINKING OF VIRUSES AS ENEMIES

55
00:02:27,347 --> 00:02:32,552
OR AT LEAST CYBER SERIES.

56
00:02:32,619 --> 00:02:34,454
WE HAVE SEEN A WAVE AFTER WAVE

57
00:02:34,521 --> 00:02:39,125
OF EPIDEMICS AND PANDEMICS

58
00:02:39,192 --> 00:02:41,461
EMERGING AND RE-EMERGING AND

59
00:02:41,528 --> 00:02:47,100
SARS V COVID 2 AND MERS AND

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00:02:47,166 --> 00:02:47,967
RESPIRATORY AND [INDISCERNIBLE]

61
00:02:48,034 --> 00:02:53,940
ZIKA EBOLA AND INFLUENZA POX

62
00:02:54,007 --> 00:02:55,375
REMAINING CONSTANT THREAT.

63
00:02:55,441 --> 00:02:59,479
VIRUSES HAVE A POSITIVE SIDE

64
00:02:59,546 --> 00:03:03,116
APART FROM ALL THIS.

65
00:03:03,182 --> 00:03:05,885
VIRUSES SERVE AS PLATFORMS FOR

66
00:03:05,952 --> 00:03:08,855
VIRUS BASED VACCINES

67
00:03:08,922 --> 00:03:10,924
IMMUNOTHERAPY AND VIRAL FACTORS

68
00:03:10,990 --> 00:03:17,263
AND FAMOUSLY PROBABLY CC1

69
00:03:17,330 --> 00:03:19,232
INVOLVED IN PRIMARY PLACENTA

70
00:03:19,299 --> 00:03:21,234
DEVELOPMENT AND USED IN

71
00:03:21,301 --> 00:03:22,969
RESTRICTION FACTORS TOWARDS THE

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00:03:23,036 --> 00:03:24,871
END OF THE DAY AND THOUGHT IT

73
00:03:24,938 --> 00:03:26,806
WOULD BE FUN TO EXPLORE TOPICS

74
00:03:26,873 --> 00:03:30,243
IN THIS YEAR'S CONTENTS AND

75
00:03:30,310 --> 00:03:31,744
ASSEMBLING AN ALL-STAR CAST TO

76
00:03:31,811 --> 00:03:34,514
TELL US ABOUT THEIR WORK IN THIS

77
00:03:34,581 --> 00:03:34,881
AREA.

78
00:03:34,948 --> 00:03:39,586
FROM DUKE, WE HAVE JEN FROM NCI

79
00:03:39,652 --> 00:03:43,623
AND SARAH WOOTON FROM ONTARIO

80
00:03:43,690 --> 00:03:46,426
VETERAN COLLEGE UP IN CANADA AND

81
00:03:46,492 --> 00:03:48,127
RECRUITING FROM BOSTON

82
00:03:48,194 --> 00:03:49,662
UNIVERSITY AND RECRUIT BACK TO

83
00:03:49,729 --> 00:03:51,664
HARVARD AND FROM OREGON HEALTH

84
00:03:51,731 --> 00:03:55,234
AND SCIENCES UNIVERSITY AND CHIP

85
00:03:55,301 --> 00:03:59,038
FROM UCSD AND DAVID FROM

86
00:03:59,105 --> 00:04:01,674
UNIVERSITY OF MINNESOTA AND FIN

87
00:04:01,741 --> 00:04:04,911
WILL I JOHN COUGHIN FROM TUFTS.

88
00:04:04,978 --> 00:04:06,279
WITHOUT FURTHER ADO, I WOULD

89
00:04:06,346 --> 00:04:10,416
LIKE TO INTRODUCE THE FIRST

90
00:04:10,483 --> 00:04:21,027
SPEAKER MATAIS FROM UNIVERSITY

91
00:04:22,996 --> 00:04:33,473
OF SDERM -- DISCONTINUED TO THE

92
00:04:36,376 --> 00:04:39,479
PRESENT AND THIS TALK IS

93
00:04:39,545 --> 00:04:40,747
ENTITLED CANCER AND NEW THERAPY

94
00:04:40,813 --> 00:04:46,686
WITH COMMON POLIO VIRUS.

95
00:04:46,753 --> 00:04:48,287
MATTIAS.

96
00:04:48,354 --> 00:04:48,955
>> AUDIENCE:  [APPLAUSE].

97
00:04:49,022 --> 00:04:53,760
>> THANK YOU VERY MUCH FOR THE

98
00:04:53,826 --> 00:04:54,093
INTRODUCTION.

99
00:04:54,160 --> 00:04:55,428
THANK YOU VERY MUCH FOR HAVING

100
00:04:55,495 --> 00:04:57,630
US FOR THIS IN-PERSON EVENT.  IT

101
00:04:57,697 --> 00:04:59,832
IS KIND OF EMOTIONAL TO ME THE

102
00:04:59,899 --> 00:05:02,502
VIRUS I WILL TALK YOU TO ABOUT

103
00:05:02,568 --> 00:05:06,072
WAS MANUFACTURED ACROSS THE

104
00:05:06,139 --> 00:05:07,407
STREET.  THE CLINIC IS GREAT.

105
00:05:07,473 --> 00:05:09,709
SO, I'M GOING TO UPDATE YOU

106
00:05:09,776 --> 00:05:13,112
WHERE WE ARE WITH CANCER

107
00:05:13,179 --> 00:05:17,617
IMMUNOTHERAPY AND BRAIN TUMORS

108
00:05:17,684 --> 00:05:20,153
COMBINO POLIO VIRUSES AND IN MY

109
00:05:20,219 --> 00:05:21,854
VIEW SCIENCE OF WHAT WE HAVE

110
00:05:21,921 --> 00:05:23,623
LEARNED IN THE PAST TWO YEARS.

111
00:05:23,690 --> 00:05:26,125
I'M CONFLICTED AND USED TO GET

112
00:05:26,192 --> 00:05:28,461
PAID BY A COMPANY AND HOLD

113
00:05:28,528 --> 00:05:29,996
EQUITY IN A COMPANY THAT

114
00:05:30,063 --> 00:05:31,064
DEVELOPS THIS THERAPY.

115
00:05:31,130 --> 00:05:33,966
SO, YOU ALL HAVE SEEN THIS.

116
00:05:34,033 --> 00:05:36,903
THIS IS HOW EVERYBODY, MORE OR

117
00:05:36,969 --> 00:05:39,672
LESS, AGREES ENTERTUMOR THERAPY

118
00:05:39,739 --> 00:05:42,608
WORKS AND WE HAVE DENDRITIC

119
00:05:42,675 --> 00:05:47,714
CELLS AND CDC ONES AND

120
00:05:47,780 --> 00:05:50,616
CROSS-[INDISCERNIBLE] 2

121
00:05:50,683 --> 00:05:52,518
ANTROEJENS AND T-CELL IMMUNITY

122
00:05:52,585 --> 00:05:54,787
AND HOPEFULLY T-CELL WILL ENTER

123
00:05:54,854 --> 00:05:56,823
THE TUMOR KILLING CELLS.

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00:05:56,889 --> 00:05:59,292
THOSE PATIENTS WHERE THIS IS

125
00:05:59,358 --> 00:06:00,727
SOMEWHAT WORKING HAVE BENEFIT TO

126
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RESPONDING TO IMMUNOCHECKPOINT

127
00:06:03,529 --> 00:06:05,631
BLOCKADE THAT WORKS HERE IN

128
00:06:05,698 --> 00:06:07,266
THESE STAGES AND VAST MAJORITY

129
00:06:07,333 --> 00:06:09,736
OF CANCER PATIENTS DON'T HAVE

130
00:06:09,802 --> 00:06:11,871
THIS WORKING.  THIS IS TRUE FOR

131
00:06:11,938 --> 00:06:14,340
BRAIN TUMORS AND CHECKPOINT

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00:06:14,407 --> 00:06:16,242
COMPLETELY FAILED IN BRAIN TUMOR

133
00:06:16,309 --> 00:06:17,810
PATIENTS THAT WE CAN SAFELY

134
00:06:17,877 --> 00:06:20,513
ASSUME THAT VIRTUALLY NO BRAIN

135
00:06:20,580 --> 00:06:23,216
TUMOR PATIENTS HAVE INTERTUMOR

136
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IMMUNITY.

137
00:06:23,549 --> 00:06:24,784
WHAT IS THE PROBLEM.

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00:06:24,851 --> 00:06:28,488
I AGREE WITH WHAT IS STATED BY

139
00:06:28,554 --> 00:06:30,823
IRA MELMAN AND MANY COLLEAGUES.

140
00:06:30,890 --> 00:06:33,392
THE PROBLEM IS HERE AND IT IS

141
00:06:33,459 --> 00:06:36,395
TUMOR ANTROEJEN TRAFFICKING

142
00:06:36,462 --> 00:06:37,830
CROSS-[INDISCERNIBLE] T-CELL

143
00:06:37,897 --> 00:06:42,201
PRIMING AND WAY TO FIX THIS IS I

144
00:06:42,268 --> 00:06:44,303
AGREE WITH MOST LEADING EXPERTS

145
00:06:44,370 --> 00:06:48,307
IS ENDOGENOUS SUSTAINED TYPE 1

146
00:06:48,374 --> 00:06:50,676
INTERFERON CDCS AND WILL TRY TO

147
00:06:50,743 --> 00:06:51,744
CONVINCE YOU THIS IS VERY

148
00:06:51,811 --> 00:06:54,180
DIFFICULT TO ACHIEVE.  WE GOT IT

149
00:06:54,247 --> 00:06:55,414
WITHOUT TRYING.

150
00:06:55,481 --> 00:06:57,517
THAT IS WHAT I WILL TELL YOU.

151
00:06:57,583 --> 00:07:01,187
THE VIRUS I WORK WITH IS PDS AND

152
00:07:01,254 --> 00:07:03,556
BRIEFLY EXPLAINED WHAT IT IS.

153
00:07:03,623 --> 00:07:07,827
WILD TYPE POLIO VIRUS MAHONEY

154
00:07:07,894 --> 00:07:09,929
AND LAB STRAIN USED AND TYPE 1

155
00:07:09,996 --> 00:07:12,532
VACCINE THAT IS A VACCINE THAT

156
00:07:12,598 --> 00:07:14,066
EVERYONE IN THIS ROOM GOT AND

157
00:07:14,133 --> 00:07:16,736
LIFE ATTENDED VACCINE IS A

158
00:07:16,803 --> 00:07:18,638
TISSUE CULTURE ADAPTIN OF THIS.

159
00:07:18,704 --> 00:07:21,374
WE TOOK THE TYPE 1 SALINE

160
00:07:21,440 --> 00:07:24,710
VACCINE AND REPLACED IT AND I

161
00:07:24,777 --> 00:07:26,412
WILL EXPLAIN BRIEFLY WHAT IT IS

162
00:07:26,479 --> 00:07:29,115
A LITTLE BIT LATER WITH

163
00:07:29,182 --> 00:07:30,783
CORRESPONDING ELEMENTS FROM

164
00:07:30,850 --> 00:07:32,952
HUMOON VIRUS TYPE 2.

165
00:07:33,019 --> 00:07:38,124
SO, I MADE THIS VIRUS MYSELF IN

166
00:07:38,191 --> 00:07:40,793
1996.

167
00:07:40,860 --> 00:07:43,596
IT IS EMBARRASSING.  WE FIGURED

168
00:07:43,663 --> 00:07:45,164
OUT NOW WHAT MAKES THIS

169
00:07:45,231 --> 00:07:46,265
INTERESTING.  IT IS WAY MORE

170
00:07:46,332 --> 00:07:48,301
INTERESTING THAN WE THOUGHT AND

171
00:07:48,367 --> 00:07:50,002
TOOK AN ETERNITY TO FIGURE THIS

172
00:07:50,069 --> 00:07:51,571
OUT.  I WILL TELL YOU.

173
00:07:51,637 --> 00:07:55,007
WHAT THIS VIRUS IS, WE HAVE

174
00:07:55,074 --> 00:07:57,176
THREE TYPES OF CELLS NATURALLY

175
00:07:57,243 --> 00:07:59,979
TARGETED BY POLIO VIRUS.

176
00:08:00,046 --> 00:08:02,815
THESE CELLS ARE KILLED

177
00:08:02,882 --> 00:08:04,383
EFFICIENTLY AND NEUR OWNIAL

178
00:08:04,450 --> 00:08:06,786
CELLS AND MYELOID CELLS AND

179
00:08:06,853 --> 00:08:09,422
CERTAIN EPITHELIAL CELLS SUBSET

180
00:08:09,488 --> 00:08:14,227
IN GI TRACT AND LYMPH NODES AND

181
00:08:14,293 --> 00:08:17,330
HIGHLY CRYTOPATHOGENIC IN CELLS

182
00:08:17,396 --> 00:08:20,099
AND NEUROLINEAGE PHENOTYPE AND

183
00:08:20,166 --> 00:08:22,735
NOT MUCH IN OTHER TYPE NONNEURAL

184
00:08:22,802 --> 00:08:24,704
CELLS AND SOMEWHAT OF A MYSTERY

185
00:08:24,770 --> 00:08:26,973
WHY IT WAS SAFE IN USE OF

186
00:08:27,039 --> 00:08:35,715
VACCINE AND VIRUS WE WORK WITH

187
00:08:35,781 --> 00:08:37,850
IS COMPLETELY DIFFERENT AND

188
00:08:37,917 --> 00:08:43,389
CRYTOPATHOGENIC AND WON'T EFFECT

189
00:08:43,456 --> 00:08:45,925
OR KILL THEM AND ONCHOLYTIC

190
00:08:45,992 --> 00:08:49,195
VIRUS THAT WORD IS NOT ALLOWED

191
00:08:49,262 --> 00:08:54,734
IN MY LAB NOT SURE IF CAN KILL

192
00:08:54,800 --> 00:08:55,968
MALIGNANT CELLS CAN KILL CELL

193
00:08:56,035 --> 00:08:59,205
LINES BUT IS A TISSUE ARTIFACT.

194
00:08:59,272 --> 00:09:03,542
REPORTING IN 2018 SUCCESSFUL

195
00:09:03,609 --> 00:09:05,378
CLINICAL TRIAL [INDISCERNIBLE]

196
00:09:05,444 --> 00:09:11,450
BLASTOMA COMMON BRAIN TUMOR THAT

197
00:09:11,517 --> 00:09:21,994
HAS NO ADEQUATE THERAPY --

198
00:09:28,267 --> 00:09:30,403
CHEMOAND RADIATION THAT THEY

199
00:09:30,469 --> 00:09:31,971
ALMOST INVARIABLY DO AND FOR

200
00:09:32,038 --> 00:09:34,006
THIS CONDITION IS NO APPROVED

201
00:09:34,073 --> 00:09:34,273
THERAPY.

202
00:09:34,340 --> 00:09:37,243
WE TREATED PATIENTS WITH A

203
00:09:37,310 --> 00:09:40,446
SINGLE INTERTUMOR INOCULATION OF

204
00:09:40,513 --> 00:09:42,782
PDS RIPO AND TUMOR WE INJECTED

205
00:09:42,848 --> 00:09:47,219
HERE AND SAW THE CLASSIC

206
00:09:47,286 --> 00:09:49,055
IMMUNOTHERAPY TAIL.

207
00:09:49,121 --> 00:09:52,758
YOU HAVE A SUBGROUP OF PATIENTS

208
00:09:52,825 --> 00:09:54,994
DOING EXTREMELY WELL AND

209
00:09:55,061 --> 00:09:56,862
BECOMING APPARENT LATE AFTER

210
00:09:56,929 --> 00:09:58,864
THERAPY AND PATIENT TAIL LOOKS

211
00:09:58,931 --> 00:10:01,200
LIKE THIS.  INJECT A TUMOR AND

212
00:10:01,267 --> 00:10:03,102
OVER A VERY LONG PERIOD,

213
00:10:03,169 --> 00:10:06,505
SOMETIMES CAN TAKE FIVE YEARS,

214
00:10:06,572 --> 00:10:11,777
THE TUMOR SLOW LY DISAPPEARS AS

215
00:10:11,844 --> 00:10:14,513
SEEN IN MRIS AND WHEN WE PUBLISH

216
00:10:14,580 --> 00:10:17,516
THIS WORK, WE GOT INVITED BY

217
00:10:17,583 --> 00:10:19,251
DIRECTOR OF SOOEBERITY OF PETER

218
00:10:19,318 --> 00:10:24,056
MARKS TO ASK FDA FOR ACCELERATED

219
00:10:24,123 --> 00:10:24,523
APPROVAL.

220
00:10:24,590 --> 00:10:26,892
THAT DID NOT GO OVER TOO WELL

221
00:10:26,959 --> 00:10:28,561
FOR SEVERAL REASONS AND POINT

222
00:10:28,627 --> 00:10:31,163
OUT MOST IMPORTANT ONE.  WE HAVE

223
00:10:31,230 --> 00:10:34,967
80% OR SO OF PATIENTS DERIVING

224
00:10:35,034 --> 00:10:36,836
ABSOLUTELY NO BENEFIT OF THIS.

225
00:10:36,902 --> 00:10:38,270
THAT IS THE PROBLEM.

226
00:10:38,337 --> 00:10:40,339
I WILL TELL YOU TODAY WHAT WE

227
00:10:40,406 --> 00:10:42,208
WILL DO TO FIX THAT AND STARTED

228
00:10:42,274 --> 00:10:44,076
A NEW TRIAL THAT IS COMPLETELY

229
00:10:44,143 --> 00:10:45,511
DIFFERENT AND REVOLUTIONARY FOR

230
00:10:45,578 --> 00:10:47,413
BRAIN TUMORS AND WILL EXPLAIN

231
00:10:47,480 --> 00:10:49,081
WHY WE DO THIS.

232
00:10:49,148 --> 00:10:51,217
THE MOST IMPORTANT EXPERIMENT IN

233
00:10:51,283 --> 00:10:54,053
MY CAREER IS THIS.

234
00:10:54,120 --> 00:10:57,723
SO, WHAT WE TRY TO DO HERE IS TO

235
00:10:57,790 --> 00:10:59,525
UNDERSTAND WHAT THE VIRUS DOES

236
00:10:59,592 --> 00:11:04,463
IN BRAIN TUMORS AND USE EX-VIVO

237
00:11:04,530 --> 00:11:06,699
TOMBO CITES ASSAY.  SUPER

238
00:11:06,766 --> 00:11:07,700
INTERESTING IF THINKING ABOUT

239
00:11:07,767 --> 00:11:11,070
DOING IT, DO IT.  WE TAKE TUMOR

240
00:11:11,137 --> 00:11:15,808
TISSUES FROM THE OR FRESH TUMOR

241
00:11:15,875 --> 00:11:20,312
TISSUES NOT PROCESSED BUT WE

242
00:11:20,379 --> 00:11:21,480
DISSECT IT AND [INDISCERNIBLE]

243
00:11:21,547 --> 00:11:31,090
THAT IS AN AGONIST FOR MDA5

244
00:11:31,157 --> 00:11:32,958
PATTERN RECEPTOR.  C GAS ALSO.

245
00:11:33,025 --> 00:11:35,027
WE PICK THESE AGONISTS BECAUSE

246
00:11:35,094 --> 00:11:37,296
THEY ARE THE CLASSIC TYPE 1

247
00:11:37,363 --> 00:11:39,632
INTERFERON GENERATING PATHWAYS

248
00:11:39,698 --> 00:11:43,502
IN THE INNATE IMMUNE SYSTEM.  WE

249
00:11:43,569 --> 00:11:45,471
TREAT THE SLICES AND MEASURE

250
00:11:45,538 --> 00:11:47,373
CYTOKINE RESPONSES AND SEE IN

251
00:11:47,440 --> 00:11:51,777
BLUE THE CYTOKINE RESPONSE TO

252
00:11:51,844 --> 00:11:53,512
PDSRIPO THAT STICKS OUT BECAUSE

253
00:11:53,579 --> 00:11:56,582
OF SOMETHING WE CALL TYPE 1

254
00:11:56,649 --> 00:12:00,486
INTERFERON DOMINANT INFLAMMATION

255
00:12:00,553 --> 00:12:06,392
POLO CANE TB1 SIGNATURE THAT IS

256
00:12:06,459 --> 00:12:08,661
STATE OF POINT HERE IS

257
00:12:08,727 --> 00:12:11,664
INTERFERON ALPHA THAT I WILL

258
00:12:11,730 --> 00:12:13,933
EXPLAIN IS VERY IMPORTANT

259
00:12:13,999 --> 00:12:16,168
EXPLAINING WHY THIS IS HAPPENING

260
00:12:16,235 --> 00:12:19,371
INCAPABLE OF INTERFERON RELEASE

261
00:12:19,438 --> 00:12:23,742
WITH INNATE AGONIST

262
00:12:23,809 --> 00:12:24,877
IMMUNOTHERAPY TESTED

263
00:12:24,944 --> 00:12:26,412
RIBOSTAND-OUT SIGNATURES

264
00:12:26,479 --> 00:12:28,848
SUSTAINED INTERFERON RELEASE AND

265
00:12:28,914 --> 00:12:32,184
SEE THAT TLRS PRODUCE SOMETHING

266
00:12:32,251 --> 00:12:33,586
COMPLETELY DIFFERENT AGONIST.

267
00:12:33,652 --> 00:12:38,057
IT IS MORE A CUP OF B CYTOKINE

268
00:12:38,124 --> 00:12:40,960
SIGNATURE TNF10 AND IT IS DEVOID

269
00:12:41,026 --> 00:12:44,763
OF CYTOKINE RELEASE SYNDROME

270
00:12:44,830 --> 00:12:46,699
CYTOKINES AND THIS INTERFERON

271
00:12:46,765 --> 00:12:51,337
RESPONSE STEMS FROM MACROPHAGES.

272
00:12:51,403 --> 00:12:54,907
SO, I THETA IS ISG AND SEE

273
00:12:54,974 --> 00:12:57,243
SIGNATURE IN MACROPHAGES AND

274
00:12:57,309 --> 00:13:00,146
TREATING TUMOR WITH PDS RIPO YOU

275
00:13:00,212 --> 00:13:02,815
DON'T KILL ANYTHING, NO

276
00:13:02,882 --> 00:13:05,451
ONCOLSIS.  YOU SEE INFECTION OF

277
00:13:05,518 --> 00:13:07,386
MYELOID CELLS AND SEE AN

278
00:13:07,453 --> 00:13:08,487
INTERFERON SIGNATURE.

279
00:13:08,554 --> 00:13:11,690
SO, I HAVE TO EXPLAIN TO YOU THE

280
00:13:11,757 --> 00:13:13,559
BRILLIANT STRATEGY THAT POLIO

281
00:13:13,626 --> 00:13:15,361
VIRUS USES THAT IS COMPLETELY

282
00:13:15,427 --> 00:13:17,763
DIFFERENT FROM RNA VIRUSES

283
00:13:17,830 --> 00:13:19,665
COMING TO THE INNATE RESPONSE

284
00:13:19,732 --> 00:13:23,502
AND IN CONTRAST TO MESSENGER RNA

285
00:13:23,569 --> 00:13:26,906
A 5 PRIME METHO GUAN ADEAN CAP

286
00:13:26,972 --> 00:13:30,075
USED FOR TRANSLATION AND EF

287
00:13:30,142 --> 00:13:32,111
TRANSLATION FACTOR TO THE CAP

288
00:13:32,178 --> 00:13:35,114
USED TO RECRUIT ERG FOR THE

289
00:13:35,181 --> 00:13:37,917
RIBOSOME AND RNA VIRUSES HAVE A

290
00:13:37,983 --> 00:13:40,052
PROBLEM.  THEY DON'T ACQUIRE A

291
00:13:40,119 --> 00:13:41,921
CAP STRUCTURE LIKE MESSENGER

292
00:13:41,987 --> 00:13:48,627
RNAS DO IN THE N NUCLEUS.

293
00:13:48,694 --> 00:13:50,896
THEY ACQUIRE CAP SOMEHOW ON

294
00:13:50,963 --> 00:13:52,464
THEIR OWN.

295
00:13:52,531 --> 00:13:55,234
POLIO VIRUS.  I USE THE WORD

296
00:13:55,301 --> 00:13:57,469
POLIO BUT MEAN ENTROE VIRUSES

297
00:13:57,536 --> 00:13:58,737
USE SOMETHING ENTIRELY

298
00:13:58,804 --> 00:14:01,006
DIFFERENT.  THEY HAVE A PROTEIN

299
00:14:01,073 --> 00:14:03,242
COVALENTLY LINKED TO THE 5 PRIME

300
00:14:03,309 --> 00:14:11,083
END AND POLIO VIRUS CAN'T U

301
00:14:11,150 --> 00:14:11,817
USE-DEPENDENT TRANSLATION LIKE

302
00:14:11,884 --> 00:14:15,354
MOST RNA VIRUSES DO.  IT HAS TO

303
00:14:15,421 --> 00:14:17,856
USE A METHOD OF TRANSLATION WITH

304
00:14:17,923 --> 00:14:20,859
INTERNAL ENTRY SITE THAT IS

305
00:14:20,926 --> 00:14:21,527
DISCOVERED NECKERITIES LAB AND

306
00:14:21,594 --> 00:14:25,030
ENTRY WORKS ABOUT I RECRUITING

307
00:14:25,097 --> 00:14:26,865
EFRG DIRECTLY TO THE VIRAL RNA

308
00:14:26,932 --> 00:14:29,034
THROUGH THE VIRUS WITHOUT THE

309
00:14:29,101 --> 00:14:30,803
NEED FOR E.

310
00:14:30,869 --> 00:14:32,738
WHAT POLIO VIRUS DOES THEN IS

311
00:14:32,805 --> 00:14:35,307
CLEAVES THE EFR G-PROTEIN SUCH

312
00:14:35,374 --> 00:14:40,546
THAT THE HOST CAN NO LONGER

313
00:14:40,613 --> 00:14:42,581
DIRECT PROTEIN SYNTHESIS LACKING

314
00:14:42,648 --> 00:14:45,551
PORTION OF EFRG THAT RECRUITS

315
00:14:45,618 --> 00:14:48,687
THE RIBOSOME BUT VIRUS CAN

316
00:14:48,754 --> 00:14:49,788
CONTINUE TRANSLATING BECAUSE C

317
00:14:49,855 --> 00:14:51,757
TERMINAL PORTION OF EFRG IS

318
00:14:51,824 --> 00:14:55,527
SUFFICIENT TO RECRUIT RIBOSOMES

319
00:14:55,594 --> 00:14:58,297
TO THE VIRAL GENOME.

320
00:14:58,364 --> 00:15:00,799
THIS STRATEGY HAS HUGE

321
00:15:00,866 --> 00:15:02,201
IMPLICATIONS FORINATE IN

322
00:15:02,268 --> 00:15:05,037
CONTRAST TO RNA VIRUSS THAT IS

323
00:15:05,104 --> 00:15:07,906
PREDOMINANTLY SENSED IN

324
00:15:07,973 --> 00:15:10,609
CYTOPLASM REGULARI POLIO VIRUS

325
00:15:10,676 --> 00:15:13,145
IS EXCLUSIVELY SENSED BY MDA5

326
00:15:13,212 --> 00:15:14,446
THAT IS VERY IMPORTANT FOR WHAT

327
00:15:14,513 --> 00:15:15,314
WE ARE DOING.

328
00:15:15,381 --> 00:15:18,350
YOU CAN SEE THIS PLAY OUT HERE.

329
00:15:18,417 --> 00:15:20,452
I WANT TO EXPLAIN WHAT RIPO IS

330
00:15:20,519 --> 00:15:24,056
AND WHY I'M SAYING IT IS NOT

331
00:15:24,123 --> 00:15:25,824
CRYTOPATHOGENIC AND NOT ALLOWED

332
00:15:25,891 --> 00:15:28,260
TO USE WILD-TYPE POLIO ANYMORE

333
00:15:28,327 --> 00:15:30,062
AND CLOSE RELATIVE TO JUST

334
00:15:30,129 --> 00:15:32,197
IGNORE THIS.

335
00:15:32,264 --> 00:15:34,667
IT IS WHAT WILD TYPE POLIO LOOKS

336
00:15:34,733 --> 00:15:38,203
LIKE AND PAIRING FOR EFRG

337
00:15:38,270 --> 00:15:40,873
CLEAVAGE THAT IS VERY RAPIDLY

338
00:15:40,939 --> 00:15:42,508
CLEAVED BY WILD TYPE INTRO

339
00:15:42,574 --> 00:15:45,611
VIRUSES TO CAP 21 AND SEEING

340
00:15:45,678 --> 00:15:46,412
CLEAVAGE PRODUCT HERE THAT IS

341
00:15:46,478 --> 00:15:47,780
VIRAL PROTEIN.

342
00:15:47,846 --> 00:15:49,615
AS A RESULT OF THIS CLEAVAGE,

343
00:15:49,682 --> 00:15:53,085
THE HOST CELL IS INCAPABLE OF

344
00:15:53,152 --> 00:15:55,187
MOUNTING INNATE INTERVIRAL

345
00:15:55,254 --> 00:15:55,454
RESPONSE.

346
00:15:55,521 --> 00:15:57,990
SO, WE REPRODUCE THE CLASSIC

347
00:15:58,057 --> 00:16:01,593
TYPE 1 INTERFERON RESPONSE THAT

348
00:16:01,660 --> 00:16:05,297
IS DESCRIBED BY [INDISCERNIBLE]

349
00:16:05,364 --> 00:16:08,167
ET AL 2000 AND EXPLICITLY

350
00:16:08,233 --> 00:16:11,403
EXPRESSED IRF3 AND SEE

351
00:16:11,470 --> 00:16:15,007
INTERFERON RELEASE AND IR3

352
00:16:15,074 --> 00:16:17,309
ACTIVATION AND PHOSPHOLATION 3

353
00:16:17,376 --> 00:16:19,645
DOES OCCUR AND DOESN'T RESULT IN

354
00:16:19,712 --> 00:16:21,847
A PRODUCTIVE INTERFERON RESPONSE

355
00:16:21,914 --> 00:16:24,049
WITH WILD TYPE VIRUS BECAUSE WE

356
00:16:24,116 --> 00:16:26,118
DON'T SEE PHOSPHO STAT 1.

357
00:16:26,185 --> 00:16:31,357
ENTROE VIRUSES FAMOUSLY AND OLD

358
00:16:31,423 --> 00:16:35,961
VIROLOGISTS AND MANY DECADES AGO

359
00:16:36,028 --> 00:16:37,896
KNEW THIS THEY DON'T MAKE

360
00:16:37,963 --> 00:16:39,865
INTERFERON RESPONSES.

361
00:16:39,932 --> 00:16:43,736
THIS RIPO VIRUS BECAUSE OF IRIS

362
00:16:43,802 --> 00:16:48,974
IS INCAPABLE OF CLEAVING EFRGS

363
00:16:49,041 --> 00:16:52,911
IN-TACT EFRG PREVAILS AND

364
00:16:52,978 --> 00:16:54,113
SURPRISINGLY IS VIRAL ARCTIC

365
00:16:54,179 --> 00:16:56,248
TRANSLATION IN THE CELLS AND

366
00:16:56,315 --> 00:16:59,985
LOOK AT UNOPPOSED TYPE 1

367
00:17:00,052 --> 00:17:01,453
INTERFERON RESPONSE.

368
00:17:01,520 --> 00:17:03,455
PHOSPHORYLATION 3 AND MASSIVE

369
00:17:03,522 --> 00:17:04,556
INTERFERON RELEASE AND INDUCTION

370
00:17:04,623 --> 00:17:06,892
OF STAT 1.  HERE IS INTERESTING

371
00:17:06,959 --> 00:17:09,762
PARTS OF THIS.  IT IS IRF7 AND

372
00:17:09,828 --> 00:17:13,432
THIS IS AN INTERFERON

373
00:17:13,499 --> 00:17:15,334
TRANSCRIPTION FACTOR THAT DRIVES

374
00:17:15,401 --> 00:17:17,169
TRANSCRIPTION OF INTERFERON

375
00:17:17,236 --> 00:17:19,872
ALPHA ISOFORMS.

376
00:17:19,938 --> 00:17:22,207
VERY LATE MD5 INDUCTION THAT

377
00:17:22,274 --> 00:17:24,376
HASN'T REACHED ITS PEAK BY 60

378
00:17:24,443 --> 00:17:25,077
HOURS.

379
00:17:25,144 --> 00:17:28,313
SO, WHY IS THIS SO SIGNIFICANT.

380
00:17:28,380 --> 00:17:31,316
THE LATE INTERFERON RESPONSE AND

381
00:17:31,383 --> 00:17:33,519
INTERFERON AUTHORED RELEASE AND

382
00:17:33,585 --> 00:17:35,654
PRIMATE EVOLUTION WE ACQUIRE

383
00:17:35,721 --> 00:17:38,457
APPLICATION OF INTERFERON ALPHA

384
00:17:38,524 --> 00:17:41,160
GENES OVER TIME AND 12 DIFFERENT

385
00:17:41,226 --> 00:17:42,461
INTERFERON ALPHA PROTEINS AND

386
00:17:42,528 --> 00:17:44,797
MOST PEOPLE AGREE IT IS UNKNOWN

387
00:17:44,863 --> 00:17:47,332
WHY WE HAVE THESE AND WHAT THE

388
00:17:47,399 --> 00:17:48,934
EVOLUTIONARY BENEFIT IS.  MOST

389
00:17:49,001 --> 00:17:51,570
PEOPLE AGREE WE HAVE THESE

390
00:17:51,637 --> 00:17:55,541
ISOFORMS TO BE ABLE TO EXTEND

391
00:17:55,607 --> 00:17:59,077
INTERFERON RESPONSES TIME-WISE.

392
00:17:59,144 --> 00:18:00,612
YOU CAN ACHIEVE DIFFERENT

393
00:18:00,679 --> 00:18:02,781
PATTERNS BY HAVING MULTIPLE

394
00:18:02,848 --> 00:18:04,283
TYPES OF INTERFERON A--LE FA

395
00:18:04,349 --> 00:18:04,516
GENES.

396
00:18:04,583 --> 00:18:06,285
THAT IS WHAT YOU SEE HERE.

397
00:18:06,351 --> 00:18:09,555
THIS IS SUPER LATE SUSTAINED

398
00:18:09,621 --> 00:18:12,658
INTERFERON ALPHA RESPONSE DUE TO

399
00:18:12,724 --> 00:18:16,728
UNOPPOSED MDA-5 ORCHESTRATED IN

400
00:18:16,795 --> 00:18:20,265
SENSING OF PDSRIPO THAT CAN'T

401
00:18:20,332 --> 00:18:22,201
OPPOSE THE INTERFERON RESPONSE.

402
00:18:22,267 --> 00:18:27,005
IT CAN'T CLEAVE THE EFRG.

403
00:18:27,072 --> 00:18:29,107
THIS IS REALLY INTERESTING IN

404
00:18:29,174 --> 00:18:31,977
THE NATURAL TARGET FOR FOLIO

405
00:18:32,044 --> 00:18:33,378
VIRUS THAT WE SEE IN THE SLIDES

406
00:18:33,445 --> 00:18:35,414
I WOULD SAY AND THOSE ARE

407
00:18:35,481 --> 00:18:36,648
MYELOID CELLS.

408
00:18:36,715 --> 00:18:38,317
THESE ARE MDMS.

409
00:18:38,383 --> 00:18:39,818
AGAIN WHAT I SHOWED YOU BEFORE

410
00:18:39,885 --> 00:18:43,021
IS IN THE CANCER CELL LINE AND

411
00:18:43,088 --> 00:18:46,358
MDM AND MONOCITE MACROPHAGES NOT

412
00:18:46,425 --> 00:18:49,795
INFECTED WITH PDS RIPO OR

413
00:18:49,862 --> 00:18:52,498
INFECTED WITH CLEAVAGE AND LOW

414
00:18:52,564 --> 00:18:53,799
VIRAL TRANSLATION AND MASSIVE

415
00:18:53,866 --> 00:18:59,204
TYPE 1 INTERFERON DEFENSE AND

416
00:18:59,271 --> 00:19:00,706
PHOSPHORYLATION ARE 3 AND FOR

417
00:19:00,772 --> 00:19:04,042
FORILATION OF 7 INDUCTION AND

418
00:19:04,109 --> 00:19:05,244
ESIG EXPRESSION AND THESE CELLS

419
00:19:05,310 --> 00:19:06,812
RESPOND BETTER THAN ANY OTHER

420
00:19:06,879 --> 00:19:08,881
TYPE OF CELL BECAUSE OF HIGHER

421
00:19:08,947 --> 00:19:12,150
LEVELS OF MDA5 AT BASELINE.

422
00:19:12,217 --> 00:19:15,521
AGAIN, HERE AT 48 HOURS IN MDMS,

423
00:19:15,587 --> 00:19:17,589
WE SEE INTERFERON THAT IS A

424
00:19:17,656 --> 00:19:22,094
DOMINANT RESPONSE WITH TYPE 13

425
00:19:22,160 --> 00:19:23,529
INTERFERONS LACKING

426
00:19:23,595 --> 00:19:24,830
[INDISCERNIBLE] CYTOKINES

427
00:19:24,897 --> 00:19:29,234
CONTRASTING TO TLR AGONISTS AND

428
00:19:29,301 --> 00:19:29,668
REALLY INTRIGUING.

429
00:19:29,735 --> 00:19:33,138
WHEN WE LET CELLS SIT IN THE

430
00:19:33,205 --> 00:19:35,541
INCUBATOR WE DON'T FEED THEM OR

431
00:19:35,607 --> 00:19:38,243
ANYTHING JUST LET THEM GO AND

432
00:19:38,310 --> 00:19:40,512
MDMS MIGHT NOT SURVIVE LONGER

433
00:19:40,579 --> 00:19:42,748
THAN FIVE DAYS.  THESE CELLS

434
00:19:42,814 --> 00:19:44,883
WILL LIVE AT LEAST A MONTH.

435
00:19:44,950 --> 00:19:47,052
TAKING THEM OUT AFTER 2 WEEKS

436
00:19:47,119 --> 00:19:51,123
RUNNING CRATO KIND ESSAYS SEE

437
00:19:51,189 --> 00:19:55,127
PDS RIPO MACROPHAGES SECRETE

438
00:19:55,193 --> 00:19:57,963
INTERFERON ALPHA AND NOTHING

439
00:19:58,030 --> 00:20:00,499
ELSE AND THESE MOCK INFECTED

440
00:20:00,566 --> 00:20:01,800
CELLS ARE DEAD.

441
00:20:01,867 --> 00:20:05,270
THIS IS WHAT WEIN DODGE NOWS

442
00:20:05,337 --> 00:20:07,839
SUSTAINED TYPE 1 INTERFERON

443
00:20:07,906 --> 00:20:10,042
BELIEFS MYELOID CELLS HOLY GRAIL

444
00:20:10,108 --> 00:20:14,012
IF YOU WANT IN CANCER

445
00:20:14,079 --> 00:20:17,182
IMMUNOTHERAPY AND PDRIPO THAT IS

446
00:20:17,249 --> 00:20:19,284
INTRIGUING AND A SUSTAINED

447
00:20:19,351 --> 00:20:19,718
SIGNATURE.

448
00:20:19,785 --> 00:20:21,386
WHY IS THIS HAPPENING?

449
00:20:21,453 --> 00:20:23,455
I WON'T GO INTO LOTS OF DETAILS

450
00:20:23,522 --> 00:20:25,324
AND DURATION OF THE RESPONSE

451
00:20:25,390 --> 00:20:28,860
THAT IS PATTERNS THAT DICTATE IT

452
00:20:28,927 --> 00:20:31,263
BY VIRAL RNA REPLICATION AND IF

453
00:20:31,330 --> 00:20:33,131
YOU SEE HERE FORGETTING THE

454
00:20:33,198 --> 00:20:34,533
TREATMENT THAT IS NOT IMPORTANT

455
00:20:34,600 --> 00:20:36,234
HERE AND SEE INNATE RESPONSE

456
00:20:36,301 --> 00:20:41,139
THAT IS INTERFERON SIGNALING

457
00:20:41,206 --> 00:20:43,709
CORRELATES WITH ABUNDANCE OF

458
00:20:43,775 --> 00:20:46,011
VIRAL RNA AND TRANSLATION IS

459
00:20:46,078 --> 00:20:50,549
ALMOST GONE BY 48 HOURS AND

460
00:20:50,616 --> 00:20:53,251
VIRAL RNA REPLICATION STARTS TO

461
00:20:53,318 --> 00:20:57,823
TAKE OFF AND VIRUS INCAPABLE OF

462
00:20:57,889 --> 00:20:59,124
DRIVING VIRAL TRANSLATION

463
00:20:59,191 --> 00:21:02,260
EFFICIENTLY AND CLEAVING FRG IS

464
00:21:02,327 --> 00:21:04,096
CAPABLE ENOUGH TO DIRECT VIRAL

465
00:21:04,162 --> 00:21:08,800
RNA REPLICATION THAT FUELS AN

466
00:21:08,867 --> 00:21:13,772
INTERFERON RESPONSE.

467
00:21:13,839 --> 00:21:17,609
SO, WE HAVE SHOWN THIS

468
00:21:17,676 --> 00:21:19,411
QUALITATIVELY SUPERIOR INNATE

469
00:21:19,478 --> 00:21:20,946
PATTERN THAT IS IMPORTANT IN

470
00:21:21,013 --> 00:21:23,048
CANCER IMMUNOTHERAPY.

471
00:21:23,115 --> 00:21:29,287
WHEN YOU TREAT B-16 MELANOMAS

472
00:21:29,354 --> 00:21:35,060
WITH POLY-RIPOCLS YOU SEE

473
00:21:35,127 --> 00:21:37,596
TRANSLATION -- YOU SEE WAY MORE

474
00:21:37,663 --> 00:21:39,464
CYTOKINES AND T-CELLS COMING IN

475
00:21:39,531 --> 00:21:41,533
WITH AGONISTS ARE STUPID T-CELLS

476
00:21:41,600 --> 00:21:43,702
AND ARE CONFUSED AND DON'T KNOW

477
00:21:43,769 --> 00:21:45,971
WHAT THEY ARE DOING.

478
00:21:46,038 --> 00:21:49,441
LOOK AT RIPO T-CELLS THAT ARE

479
00:21:49,508 --> 00:21:51,143
[INDISCERNIBLE] POSITIVE AND

480
00:21:51,209 --> 00:21:53,412
INTERFERON GAMMA POSITIVE AND

481
00:21:53,478 --> 00:21:55,414
QUALITATIVELY ARE BETTER T-CELLS

482
00:21:55,480 --> 00:21:59,284
THAT YOU CAN ACTUALLY SEE THIS

483
00:21:59,351 --> 00:22:01,987
IN THIS IN THE PICTURE YOU CAN

484
00:22:02,054 --> 00:22:04,656
SEE THEM AND IS QUITE

485
00:22:04,723 --> 00:22:07,893
IMPRESSIVE.  HUGE RIPO AND

486
00:22:07,959 --> 00:22:09,461
BIGGER THAN [INDISCERNIBLE] AND

487
00:22:09,528 --> 00:22:13,999
WE HAVE QUALITATIVELY BETTER

488
00:22:14,066 --> 00:22:21,006
INNATE PATTERN WITH PBSRIPO

489
00:22:21,073 --> 00:22:22,340
GENERATED T-CELLS ARE CAPABLE TO

490
00:22:22,407 --> 00:22:25,110
[INDISCERNIBLE] TUMOR AFTER A

491
00:22:25,177 --> 00:22:25,377
TRANSFER.

492
00:22:25,444 --> 00:22:26,845
OKAY.  MOVING, I EXPLAINED TO

493
00:22:26,912 --> 00:22:29,414
YOU INNATE PATTERN THAT WE ARE

494
00:22:29,481 --> 00:22:30,482
EXCITED ABOUT.

495
00:22:30,549 --> 00:22:32,484
NOW, WHAT ABOUT THE SPATIAL PART

496
00:22:32,551 --> 00:22:33,452
OF IT?

497
00:22:33,518 --> 00:22:35,420
WHICH CELLS ARE TARGETED?

498
00:22:35,487 --> 00:22:37,089
THIS IS THE MOST IMPORTANT SLIDE

499
00:22:37,155 --> 00:22:38,490
IN THE TALK.

500
00:22:38,557 --> 00:22:40,659
POLIO VIRUS WAS MISUNDERSTOOD

501
00:22:40,726 --> 00:22:42,594
FOR ALMOST A CENTURY.

502
00:22:42,661 --> 00:22:44,129
WHAT DO I MEAN BY THAT?

503
00:22:44,196 --> 00:22:47,265
IN THE 50S, THERE WAS INTRIGUING

504
00:22:47,332 --> 00:22:51,636
WORK IN CHIMPANZEES BY MULTIPLE

505
00:22:51,703 --> 00:22:54,873
PEOPLE AND THIS DAVID'S WORK AND

506
00:22:54,940 --> 00:22:57,976
IS EASY TO DETERMINE POLIO VIRUS

507
00:22:58,043 --> 00:22:59,711
DISTRIBUTION CAN TAKE UP ORGANS

508
00:22:59,778 --> 00:23:02,013
AND SAY THAT IS WHAT THEY DID.

509
00:23:02,080 --> 00:23:06,384
THEY SAW VIRUS IN LYMPHATIC

510
00:23:06,451 --> 00:23:15,327
STRUCTURES AND SO IT IS NOWHERE

511
00:23:15,393 --> 00:23:17,963
ELSE AND DON'T UNDERSTAND WHY IT

512
00:23:18,029 --> 00:23:20,732
HAPPENS AND MAIN SITE OF VIRUS

513
00:23:20,799 --> 00:23:22,067
REPLICATION IS THE LYMPHATIC

514
00:23:22,134 --> 00:23:24,102
SYSTEM AND INTERESTING STUDY IN

515
00:23:24,169 --> 00:23:27,472
PRIMATES PUBLISHED IN 2017 AND

516
00:23:27,539 --> 00:23:29,908
NIH A CO-SPONSOR OF THIS.  I SAW

517
00:23:29,975 --> 00:23:32,744
THIS AND ALMOST FELL OUT OF MY

518
00:23:32,811 --> 00:23:35,080
CHAIR.  WE HAD NEVER KNOWN --

519
00:23:35,147 --> 00:23:37,516
SO, THIS LYMPHATIC PRESENCE OF

520
00:23:37,582 --> 00:23:40,886
VIRUS WAS NEVER UNDERSTOOD BUT

521
00:23:40,952 --> 00:23:42,320
ACTUALLY MISINTERPRETED IN THE

522
00:23:42,387 --> 00:23:42,654
50S.

523
00:23:42,721 --> 00:23:44,156
PEOPLE DIDN'T KNOW WHAT TO MAKE

524
00:23:44,222 --> 00:23:44,756
OF IT.

525
00:23:44,823 --> 00:23:46,558
IN THE STUDY WE BEGAN TO

526
00:23:46,625 --> 00:23:48,627
UNDERSTAND WHAT IT IS ABOUT.

527
00:23:48,693 --> 00:23:50,061
THEY IDENTIFIED THE KEY TARGET

528
00:23:50,128 --> 00:23:54,366
FOR POLIO VIRUSES, WILD TYPE

529
00:23:54,432 --> 00:24:00,772
POLIO IN PRIMATE SYSTEM ARE CFRG

530
00:24:00,839 --> 00:24:03,542
MACROPHAGES AND LYMPHOCYOCYTES

531
00:24:03,608 --> 00:24:05,944
SPECULATE POLIO VIRUS IS LYMPHO

532
00:24:06,011 --> 00:24:12,384
TROPIC VIRUS TARGETING CDCS

533
00:24:12,450 --> 00:24:14,085
USING THEM TO HITCHHIKE A RIDE

534
00:24:14,152 --> 00:24:17,055
TO DRAGGING LYMPH NODES WHERE IT

535
00:24:17,122 --> 00:24:19,024
REPLICATES AND WE TESTED THIS

536
00:24:19,090 --> 00:24:22,027
WITH PBS RIPO AND IN THE BRAIN

537
00:24:22,093 --> 00:24:24,563
WE HAVE INTRIGUING LYMPHATIC

538
00:24:24,629 --> 00:24:28,133
DRAINAGE SYSTEMS IN 2015 SYSTEM

539
00:24:28,200 --> 00:24:32,037
OF LYMPHATIC DRAINAGE AND TRYING

540
00:24:32,103 --> 00:24:34,272
TO DRAIN DEEP CERVICAL LYMPH

541
00:24:34,339 --> 00:24:38,109
NODES AND INJECTING PEOPLE IN

542
00:24:38,176 --> 00:24:41,413
MOUSE GLEOMAS IN HEMISPHERES AND

543
00:24:41,479 --> 00:24:43,882
INJECTED HEMISPHERES WE SEE A

544
00:24:43,949 --> 00:24:47,819
STEADY DROP OF VIRUSES IN

545
00:24:47,886 --> 00:24:49,621
INJECTED HEMISPHERES AND NO

546
00:24:49,688 --> 00:24:50,856
INCREASE OF [INDISCERNIBLE] AND

547
00:24:50,922 --> 00:24:58,830
THIS VIRUS DOESN'T KILL ANYT

548
00:24:58,897 --> 00:24:59,197
ANYTHING.

549
00:24:59,264 --> 00:25:03,702
WE SAW IMPRESSIVE INCREASE OF

550
00:25:03,768 --> 00:25:07,138
VIRUS IN DEEP CERVICAL LYMPH

551
00:25:07,205 --> 00:25:10,542
NODES GOING ON SIX DAYS DROPPING

552
00:25:10,609 --> 00:25:13,879
PRECIPITOUSLY AND THIS IS TAKING

553
00:25:13,945 --> 00:25:17,015
OF INTERVIRION IMMUNE RESPONSE

554
00:25:17,082 --> 00:25:18,884
AND MICE TRANSGENIC POLIO

555
00:25:18,950 --> 00:25:21,219
RECEPTOR IN THE STUDIES AND

556
00:25:21,286 --> 00:25:23,088
REPEATING THE EXPERIMENT LOOKING

557
00:25:23,154 --> 00:25:30,228
AT DAY 5 AND COMPARING

558
00:25:30,295 --> 00:25:32,664
TRANSGENIC MICE WITH WILD TYPE

559
00:25:32,731 --> 00:25:41,740
MICE THIS ONLY HAPPENS IN MYOCIN

560
00:25:41,806 --> 00:25:45,043
TRANSGENIC AND WE -- THIS IS A

561
00:25:45,110 --> 00:25:47,779
WORK IN PROGRESS AND SHOWING

562
00:25:47,846 --> 00:25:50,849
THAT CELLS DO TRANSPORT VIRUS TO

563
00:25:50,916 --> 00:25:54,552
A CERVICAL LYMPH NODES ARE

564
00:25:54,619 --> 00:26:00,292
INDEED CDC1 POSITIVE CDC ONES

565
00:26:00,358 --> 00:26:03,428
AND INJECTING POLIO VIRUS IN

566
00:26:03,495 --> 00:26:09,968
TUMOR TARGETS CDCS AND LYMPH

567
00:26:10,035 --> 00:26:14,739
NODES CROSS-PRESENTING TUMOR

568
00:26:14,806 --> 00:26:16,641
[INDISCERNIBLE] AND LOTS HAVE

569
00:26:16,708 --> 00:26:18,443
NOT BEEN PROVEN YET AND LARGER

570
00:26:18,510 --> 00:26:21,246
SENSE BECOMING MORE AND MORE

571
00:26:21,313 --> 00:26:23,048
INTERESTED IN INNATE IMMUNE

572
00:26:23,114 --> 00:26:26,785
COMPARTMENTS IN CDS AND IN

573
00:26:26,851 --> 00:26:29,120
THERAPY AND SHOWING CHEMISTRY

574
00:26:29,187 --> 00:26:33,291
FOR CDC45 IMMUNE CELLS AND MOUSE

575
00:26:33,358 --> 00:26:35,860
GLEOMA AND SEE TUMORS ARE

576
00:26:35,927 --> 00:26:38,229
INTERLACED WITH MYELOID CELLS

577
00:26:38,296 --> 00:26:39,097
ALL THROUGHOUT.

578
00:26:39,164 --> 00:26:42,067
AND THIS IS KS67.

579
00:26:42,133 --> 00:26:44,202
PROLIFERATION STRAINS ARE

580
00:26:44,269 --> 00:26:46,237
PROLIFERATING TUMOR CELLS THAT

581
00:26:46,304 --> 00:26:50,608
WE GET A DOSE OF PDS RIPO.  THIS

582
00:26:50,675 --> 00:26:52,677
VIRUS DOESN'T KILL ANYTHING

583
00:26:52,744 --> 00:26:55,780
EFFECTING MYELOID CELLS AND

584
00:26:55,847 --> 00:26:57,916
MICROGLIA AND SEE THIS MYELOID

585
00:26:57,983 --> 00:27:05,991
EXPLOSION THAT IS A PROFOUND

586
00:27:06,057 --> 00:27:09,327
REACTION ENGULFING THE CNS AND

587
00:27:09,394 --> 00:27:10,862
MYELOID RESPONSE AND AS

588
00:27:10,929 --> 00:27:12,964
CONSEQUENCE SEE TUMOR REMAINING

589
00:27:13,031 --> 00:27:17,535
AND KS67 SIGNAL WE SEE HERE

590
00:27:17,602 --> 00:27:19,070
ACTUALLY PROLIFERATING

591
00:27:19,137 --> 00:27:19,504
MICROGLIA.

592
00:27:19,571 --> 00:27:24,976
I HAD A STUDENT IN MY LAB WHO

593
00:27:25,043 --> 00:27:28,580
GENERATED THESE WHO TREATED MICE

594
00:27:28,646 --> 00:27:31,416
WITH PDS RIPO AND SENT SLICES

595
00:27:31,483 --> 00:27:34,719
FROM BRAINS IN A BLINDED FASHION

596
00:27:34,786 --> 00:27:38,289
TO OUR CLINICAL BOARD CERTIFIED

597
00:27:38,356 --> 00:27:38,757
NEUROPATHOLOGIST.

598
00:27:38,823 --> 00:27:40,525
NOBODY IN MY FIELD DOES THAT.

599
00:27:40,592 --> 00:27:44,462
IT IS A DANGEROUS CAREER THAT HE

600
00:27:44,529 --> 00:27:46,264
DIDN'T ASK ME.

601
00:27:46,331 --> 00:27:51,669
I HAVE A CALL FROM A PATHOLOGIST

602
00:27:51,736 --> 00:27:53,471
AND NEVER SPOKE TO HER BEFORE.

603
00:27:53,538 --> 00:27:55,140
HE SAID I HAVE NEVER SEEN

604
00:27:55,206 --> 00:27:57,008
ANYTHING LIKE IT BEFORE.  HE IS

605
00:27:57,075 --> 00:28:00,011
AN HIV NEUROPATHOLOGY PERSON.

606
00:28:00,078 --> 00:28:02,514
HE SAID WHAT YOU HAVE IS A

607
00:28:02,580 --> 00:28:05,817
MASSIVE AND VERY UNUSUAL AND

608
00:28:05,884 --> 00:28:09,587
VERY WIDESPREAD MICROGLIA

609
00:28:09,654 --> 00:28:11,456
RESPONSE AND MAIN OUTCOME FOR

610
00:28:11,523 --> 00:28:14,325
ANALYSIS AND WAY THIS LOOKS LIKE

611
00:28:14,392 --> 00:28:18,063
IS SEEING EXTENSIVE PROFUSE

612
00:28:18,129 --> 00:28:21,466
MICROGLIA PROLIFERATION AND

613
00:28:21,533 --> 00:28:22,567
MICROGLIA ACTIVATION AND

614
00:28:22,634 --> 00:28:24,402
INTERESTING IT OCCURS IN THE

615
00:28:24,469 --> 00:28:27,105
ENTIRE CNS.  THIS IS NOT DRIVEN

616
00:28:27,172 --> 00:28:29,941
BY VIRAL DAMAGE TO NEURONAL OR

617
00:28:30,008 --> 00:28:32,877
GLIAL CELLS THAT IS DOGMA IN

618
00:28:32,944 --> 00:28:34,646
COLITIS BUT IS DRIVEN BY

619
00:28:34,712 --> 00:28:37,348
INFECTION OR DIRECT INFECTION OF

620
00:28:37,415 --> 00:28:39,584
MICROGLIA CELLS.

621
00:28:39,651 --> 00:28:43,922
SO, MICROGLIA ASSUMED PROFOUND

622
00:28:43,988 --> 00:28:44,956
MORPHOLOGICAL CHANGES SEEN HERE

623
00:28:45,023 --> 00:28:53,231
THAT IB1 POSITIVE AND TMM119

624
00:28:53,298 --> 00:28:56,935
CATEGORICAL MITOGLEEA MARKER AND

625
00:28:57,001 --> 00:29:00,438
CD11B PULLDOWNS AND MICROGLIA IN

626
00:29:00,505 --> 00:29:03,308
FACT ARE INFECTED BY PDS RIPO

627
00:29:03,374 --> 00:29:06,111
THAT IS A WORK IN PROGRESS AND

628
00:29:06,177 --> 00:29:08,213
WE DON'T QUITE HAVE A FULL GRASP

629
00:29:08,279 --> 00:29:09,080
ON THIS.

630
00:29:09,147 --> 00:29:11,883
WE BELIEVE THAT THIS DRAMATIC

631
00:29:11,950 --> 00:29:13,952
RESPONSE IS DUE TO INFECTION.

632
00:29:14,018 --> 00:29:16,154
SO, NOW, WHAT ARE WE GOING TO DO

633
00:29:16,221 --> 00:29:20,592
WITH ALL THIS IN A CLINIC?

634
00:29:20,658 --> 00:29:22,227
MY INTEREST HAS SHIFTED AWAY

635
00:29:22,293 --> 00:29:23,394
FROM THE TUMOR.

636
00:29:23,461 --> 00:29:25,830
I ACTUALLY HAVE ZERO CONFIDENCE

637
00:29:25,897 --> 00:29:27,765
THAT WE WILL EVER GET ANYTHING

638
00:29:27,832 --> 00:29:30,268
INTERESTING OR HELPFUL FROM THE

639
00:29:30,335 --> 00:29:33,138
TUMOR ITSELF AND EVEN DEPRESSED

640
00:29:33,204 --> 00:29:40,178
ABOUT MYELOID COMPARTMENTS IN

641
00:29:40,245 --> 00:29:43,381
TUMORS AND MYELOID COMPARTMENT

642
00:29:43,448 --> 00:29:47,986
IS ABUNDANT AND VICIOUS OF ALL

643
00:29:48,052 --> 00:29:53,191
CANCERS AND TUMORS ARE 80% OF A

644
00:29:53,258 --> 00:29:56,661
MACROPHAGE AND TUMOR ASSOCIATED

645
00:29:56,728 --> 00:29:59,964
MICROGLIA OR MACROPHAGES TO DO

646
00:30:00,031 --> 00:30:03,568
ANYTHING HELPFUL IS SINKING BY

647
00:30:03,635 --> 00:30:05,603
THE DAY AND IS ABCERTIFIED TO

648
00:30:05,670 --> 00:30:07,438
BELIEVE YOU CAN EVER GET

649
00:30:07,505 --> 00:30:10,742
IMMUNITY IN THE BRAIN WITHOUT

650
00:30:10,808 --> 00:30:15,747
ENGAGING TISSUE RESIDENT

651
00:30:15,813 --> 00:30:16,981
DEPARTMENT AND GLIM FATTIC

652
00:30:17,048 --> 00:30:19,784
SYSTEM AND THIS IS HOW WE

653
00:30:19,851 --> 00:30:22,453
APPROACH OUR CLINICAL STRATEGY.

654
00:30:22,520 --> 00:30:26,758
SO, THE NEW PROTOCOL THAT HAS

655
00:30:26,824 --> 00:30:35,567
BEEN  FDA APPROVED -- REAL TRIAL

656
00:30:35,633 --> 00:30:39,137
WON'T BEGIN UNTIL NEXT YEAR AND

657
00:30:39,204 --> 00:30:41,506
RECURRENT GBM AND RECURRENT

658
00:30:41,573 --> 00:30:44,409
SECTION AND WE TAKE OUT ALL THIS

659
00:30:44,475 --> 00:30:45,510
JUNK THAT IS IMPORTANT BECAUSE

660
00:30:45,577 --> 00:30:48,813
WE WANT TO GET RID OF

661
00:30:48,880 --> 00:30:49,948
IMMUNOSUPPRESSIVE EFFECT OF

662
00:30:50,014 --> 00:30:53,851
HAVING A TUMOR IN THERE AND MOST

663
00:30:53,918 --> 00:30:56,554
TUMORS HAVE HYPOXY AND NECROTIC

664
00:30:56,621 --> 00:30:58,423
AND WORST KIND OF MACROPHAGE YOU

665
00:30:58,489 --> 00:31:00,124
CAN THINK OF AND THINK IT IS

666
00:31:00,191 --> 00:31:04,162
BETTER TO GET RID OF IT RATHER

667
00:31:04,229 --> 00:31:07,131
THAN TO HOPE TO ENGAGE THIS

668
00:31:07,198 --> 00:31:09,500
STUFF AND WE INTERJECT PATIENTS

669
00:31:09,567 --> 00:31:11,903
AND GIVE TWO TANDEM INOCULATIONS

670
00:31:11,970 --> 00:31:16,708
AND FIVE DAYS APART AND INNATE

671
00:31:16,774 --> 00:31:20,378
PRIME

672
00:31:20,445 --> 00:31:23,348
PRIMING PHILOSOPHY AND TWO

673
00:31:23,414 --> 00:31:25,016
INJECTIONS INSTEAD OF ONE AND

674
00:31:25,083 --> 00:31:27,652
DON'T GIVE INSIDE OF THE TUMOR

675
00:31:27,719 --> 00:31:31,122
BUT FLAIR THAT IS A TYPE AND

676
00:31:31,189 --> 00:31:35,827
BRAIN SURROUNDING TUMOR THAT IS

677
00:31:35,893 --> 00:31:39,063
INFILL TRAYED IN IT AND

678
00:31:39,130 --> 00:31:40,898
COMPROMISED TUMOR ITSELF AND

679
00:31:40,965 --> 00:31:43,601
INJECT NEXT TO THE TUMOR SEEING

680
00:31:43,668 --> 00:31:45,603
PROFOUND CNS INFLAMMATORY

681
00:31:45,670 --> 00:31:48,506
CHANGES IN THE MOUSE AND TWO

682
00:31:48,573 --> 00:31:51,609
INJECTION GIVEN BACK-TO-BACK

683
00:31:51,676 --> 00:31:54,279
INTO FLAIR NOT TUMOR AND BACK IT

684
00:31:54,345 --> 00:31:56,714
UP WITH EVERY THREE WEEKS

685
00:31:56,781 --> 00:31:59,183
[INDISCERNIBLE] INOCULATION OF

686
00:31:59,250 --> 00:32:01,552
PDS RIPO AND INJECT PDS RIPO IN

687
00:32:01,619 --> 00:32:04,656
THE AREA OF THE SECOND FROM THE

688
00:32:04,722 --> 00:32:07,458
TOP DEEP CERVICAL LYMPH NODE.

689
00:32:07,525 --> 00:32:10,962
SO, A LOT OF POLIO VIRUS

690
00:32:11,029 --> 00:32:12,397
INJECTED ALL OVER THE PLACE IN

691
00:32:12,463 --> 00:32:16,901
THE BRAIN MULTIPLE TIMES AND FDA

692
00:32:16,968 --> 00:32:18,836
DID THIS WITHOUT COMMENT AND WAS

693
00:32:18,903 --> 00:32:20,905
SURPRISED.  THIS IS A RANDOMIZED

694
00:32:20,972 --> 00:32:23,074
TRIAL THAT WE HAD TO DO THIS AND

695
00:32:23,141 --> 00:32:25,843
WE DON'T LIKE IT.

696
00:32:25,910 --> 00:32:27,879
BUT, THIS IS THE TYPE OF

697
00:32:27,945 --> 00:32:30,281
SETTING THAT WE HOPE WILL GET US

698
00:32:30,348 --> 00:32:32,917
MORE RESPONSES, BETTER RESPONSES

699
00:32:32,984 --> 00:32:34,686
AND MORE DURABLE RESPONSES AND

700
00:32:34,752 --> 00:32:36,821
IN MORE PATIENTS AND ARE VERY

701
00:32:36,888 --> 00:32:39,857
EXCITED ABOUT KICKING THIS OFF.

702
00:32:39,924 --> 00:32:42,593
SO, THAT IS MY LAST SLIDE.

703
00:32:42,660 --> 00:32:44,729
AND I AM ACTUALLY DOING GOOD ON

704
00:32:44,796 --> 00:32:47,231
TIME AND WILL HAVE TIME FOR

705
00:32:47,298 --> 00:32:50,601
QUESTIONS IF YOU HAVE ANY.

706
00:32:50,668 --> 00:32:53,438
>> AUDIENCE:  [APPLAUSE].

707
00:32:53,504 --> 00:32:57,275
>> QUESTIONS FROM THE

708
00:32:57,342 --> 00:33:03,514
AUDITORIUM?

709
00:33:03,581 --> 00:33:10,254
>> I WONDER WHAT YOU WILL HAVE.

710
00:33:10,321 --> 00:33:17,328
>> IN VITRO AS I HAVE SHOWN WE

711
00:33:17,395 --> 00:33:21,699
USE MDMS DENDRITIC MOUSE CELLS.

712
00:33:21,766 --> 00:33:23,634
AS LONG AS WE CAN KEEP CELLS

713
00:33:23,701 --> 00:33:29,340
ALIVE, THEY HAVE THIS SIGNATURE.

714
00:33:29,407 --> 00:33:30,575
MY FORMER COLLABORATOR ALWAYS

715
00:33:30,641 --> 00:33:32,977
TELLS ME DON'T SAY THAT.  COULD

716
00:33:33,044 --> 00:33:37,615
BE A BAD THING; RIGHT?

717
00:33:37,682 --> 00:33:40,718
WE DON'T THINK OF RONIC CYTOKINE

718
00:33:40,785 --> 00:33:42,720
RESPONSES NECESSARILY AS A GOOD

719
00:33:42,787 --> 00:33:44,021
THING.

720
00:33:44,088 --> 00:33:46,657
IN VIVO, WE HAVE NO GOOD DATA

721
00:33:46,724 --> 00:33:48,826
FROM PATIENTS AND BRAIN TUMOR

722
00:33:48,893 --> 00:33:50,595
PATIENTS, YOU CAN'T DO A

723
00:33:50,661 --> 00:33:53,364
RESEARCH BY OPSY COMING FROM

724
00:33:53,431 --> 00:33:56,401
RISK OF DEATH THAT IS AN

725
00:33:56,467 --> 00:33:57,435
OPERATION AND YOU CAN'T JUST

726
00:33:57,502 --> 00:34:00,238
TAKE OUT TUMOR TO CHECK; RIGHT?

727
00:34:00,304 --> 00:34:03,574
WE DON'T KNOW IF DURABLE

728
00:34:03,641 --> 00:34:05,410
INTERFERON RESPONSE WE SEE IN

729
00:34:05,476 --> 00:34:09,313
VITRO ACTUALLY HAPPENS IN VIVO.

730
00:34:09,380 --> 00:34:11,816
CELLS THAT DO MOUNT THE

731
00:34:11,883 --> 00:34:12,650
PARTICULAR RESPONSE DON'T

732
00:34:12,717 --> 00:34:15,920
EXPRESS VIRAL ANTIGEN AND VIRAL

733
00:34:15,987 --> 00:34:17,522
TRANSLATION STOPS EARLY AND THEY

734
00:34:17,588 --> 00:34:19,657
DON'T REPLICATE VIRUS AND ARE

735
00:34:19,724 --> 00:34:21,626
NOT VISIBLE AS BEING INFECTED

736
00:34:21,692 --> 00:34:24,429
AND COULD GO ON FOR A WHILE AND

737
00:34:24,495 --> 00:34:25,696
WE JUST DON'T KNOW.

738
00:34:25,763 --> 00:34:27,398
>> FASCINATING TALK.

739
00:34:27,465 --> 00:34:29,567
I GUESS I'M WONDERING, YOU KNOW,

740
00:34:29,634 --> 00:34:32,370
HOW MUCH OF THE ANTITUMOR RISK

741
00:34:32,437 --> 00:34:33,838
EFFECT THAT YOU ARE SEEING WHEN

742
00:34:33,905 --> 00:34:37,708
IT WORKS IN PATIENTS AND ALSO

743
00:34:37,775 --> 00:34:41,512
MOUSE MODELS IS EFFECTIVE

744
00:34:41,579 --> 00:34:43,014
ADAPTIVE IMMUNE RESPONSE VERSUS

745
00:34:43,080 --> 00:34:46,417
ASPECTS OF INNATE IMMUNE CELLS

746
00:34:46,484 --> 00:34:48,820
SOMEHOW, YOU KNOW, DAMAGING

747
00:34:48,886 --> 00:34:52,723
TUMOR CELLS KILLING THEM.

748
00:34:52,790 --> 00:34:54,125
>> THE T-CELL RESPONSE.

749
00:34:54,192 --> 00:34:54,425
>> YEAH.

750
00:34:54,492 --> 00:34:56,527
>> YEAH, WE THINK THAT.

751
00:34:56,594 --> 00:35:01,299
>> WHAT IS THE EVIDENCE IN THE

752
00:35:01,365 --> 00:35:01,699
MICE?

753
00:35:01,766 --> 00:35:04,101
>> NONE.  OUR MOUSE WORK

754
00:35:04,168 --> 00:35:05,470
SUGGESTS THAT AND WHAT WE THINK

755
00:35:05,536 --> 00:35:07,104
AND THIS IS VERY DIFFICULT TO

756
00:35:07,171 --> 00:35:09,106
TEST.  WE DON'T HAVE TUMORS, AS

757
00:35:09,173 --> 00:35:10,541
I SAID; RIGHT?

758
00:35:10,608 --> 00:35:12,443
WE CAN'T JUST -- AS YOU SEE IN

759
00:35:12,510 --> 00:35:16,781
THE TRIAL.  SO, WE HAD A BY OPSY

760
00:35:16,848 --> 00:35:17,982
SOMEWHERE IN HERE THAT IS

761
00:35:18,049 --> 00:35:19,383
[INDISCERNIBLE] FOR OUR

762
00:35:19,450 --> 00:35:21,052
SURGEONS.

763
00:35:21,118 --> 00:35:25,223
SO, WE HAVE TUMOR MATERIALS AND

764
00:35:25,289 --> 00:35:27,492
TCS SEQUENCE MATERIALS AND IS A

765
00:35:27,558 --> 00:35:29,627
CHALLENGE THAT WE BELIEVE IS THE

766
00:35:29,694 --> 00:35:29,827
CASE.

767
00:35:29,894 --> 00:35:33,064
>> ARE YOU PLANNING ON

768
00:35:33,130 --> 00:35:33,498
[INDISCERNIBLE]?

769
00:35:33,564 --> 00:35:36,734
>> WE HAVE.  SO, WE HAVE A, I

770
00:35:36,801 --> 00:35:39,070
THINK, INTERESTING PAPER THAT I

771
00:35:39,136 --> 00:35:42,673
WILL IN 2021 COMMUNICATIONS

772
00:35:42,740 --> 00:35:46,244
STUDYING THIS VERY CLOSELY AND

773
00:35:46,310 --> 00:35:52,750
WE FOUND -- SO, ACTUALLY IT IS

774
00:35:52,817 --> 00:35:53,751
COUNTERINTUITIVE.

775
00:35:53,818 --> 00:35:59,724
SO, THESE PATIENTS HERE HAVE

776
00:35:59,790 --> 00:36:02,260
EXTREMELY LOW TUMOR MUTATIONAL

777
00:36:02,326 --> 00:36:05,196
BURDEN AND PUBLISHING OUR PAPER

778
00:36:05,263 --> 00:36:08,266
THERE IS MORE STUDIES IN BRAIN

779
00:36:08,332 --> 00:36:10,067
TUMOR PATIENTS AND CHECKPOINTS

780
00:36:10,134 --> 00:36:13,337
THAT CONFIRM THAT AND IN

781
00:36:13,404 --> 00:36:14,672
HYPOTHESIS, THERE IS ACTUALLY

782
00:36:14,739 --> 00:36:17,041
DATA THAT LOW TUMOR MUTATIONAL

783
00:36:17,108 --> 00:36:21,178
BURDEN TUMORS ARE MORE IMMUNE

784
00:36:21,245 --> 00:36:22,780
COMPETENT AND MORE IN-TACT

785
00:36:22,847 --> 00:36:25,349
IMMUNE ENVIRONMENT AND LOW TUMOR

786
00:36:25,416 --> 00:36:28,085
MUTATION IS SIGN OF ACTIVE

787
00:36:28,152 --> 00:36:30,555
IMMUNE EDITING AND IS ACTIVE

788
00:36:30,621 --> 00:36:37,395
PROCESS OF IMMUNOLOGIC REACTION

789
00:36:37,461 --> 00:36:41,999
IN TUMOR AND EVERYONE SEES THIS.

790
00:36:42,066 --> 00:36:46,704
IT PREDICTS IMMUNOTHERAPY IS TOO

791
00:36:46,771 --> 00:36:47,238
SIMPLISTIC; RIGHT?

792
00:36:47,305 --> 00:36:49,407
WE SEE THE OPPOSITE HERE.

793
00:36:49,473 --> 00:36:52,510
>> SO, THAT IS AN AMAZING TRIAL

794
00:36:52,577 --> 00:36:53,878
AT THE END.

795
00:36:53,945 --> 00:36:55,780
WHAT IS THE OUTCOME MEASURE?

796
00:36:55,846 --> 00:36:58,482
HOW ARE YOU FOLLOWING THE

797
00:36:58,549 --> 00:36:58,783
PATIENTS?

798
00:36:58,849 --> 00:37:01,852
>> YEAH.  GENOMES ARE ALWAYS

799
00:37:01,919 --> 00:37:03,955
SURVIVAL.  WE HAVE SOME

800
00:37:04,021 --> 00:37:06,257
BIOLOGICAL RESEARCH ENDPOINTS

801
00:37:06,324 --> 00:37:08,292
AND HAVE SOME VERY INTERESTING

802
00:37:08,359 --> 00:37:09,894
BLOOD MONITORING THAT WE ARE

803
00:37:09,961 --> 00:37:13,097
ALREADY DOING AND PARALYMPHATIC

804
00:37:13,164 --> 00:37:14,899
INJECTIONS WITH REPEAT EXPOSURES

805
00:37:14,966 --> 00:37:16,934
AND ARE VERY EXCITED ABOUT IT.

806
00:37:17,001 --> 00:37:18,336
IT WILL BE SURVIVAL.

807
00:37:18,402 --> 00:37:20,371
>> AND WITH RESPECT TO THE

808
00:37:20,438 --> 00:37:23,174
MARKERS, YOU WOULD EXPECT HOW WE

809
00:37:23,240 --> 00:37:26,344
THINK THE CD-14 MIGHT BE

810
00:37:26,410 --> 00:37:28,145
RELEASED FROM ACTIVATED

811
00:37:28,212 --> 00:37:28,679
MACROPHAGES.

812
00:37:28,746 --> 00:37:32,250
COULD YOU FOLLOW THAT MARKER?

813
00:37:32,316 --> 00:37:36,187
>> NO.  SO, I'M NOT AN

814
00:37:36,253 --> 00:37:36,520
IMMUNOLOGIST.

815
00:37:36,587 --> 00:37:38,155
I HAVE TO SAY THAT.

816
00:37:38,222 --> 00:37:40,758
WE MONITOR IN BLOOD WE GET

817
00:37:40,825 --> 00:37:41,993
REALLY EXCITING RESULTS AND

818
00:37:42,059 --> 00:37:43,561
CAN'T MONITOR THE BRAIN.  WE

819
00:37:43,628 --> 00:37:45,129
DON'T HAVE TISSUE.

820
00:37:45,196 --> 00:37:50,001
IN BLOOD, WE SEE A DECREASE IN

821
00:37:50,067 --> 00:37:52,169
T-CELL EXHAUSTION MARKERS AND

822
00:37:52,236 --> 00:37:57,541
INCREASE IN CDA NUMBERS AND CDA

823
00:37:57,608 --> 00:37:59,610
INTERFERON GAMMA AND WE SEE

824
00:37:59,677 --> 00:38:02,880
INCREASE IN CDC CIRCULATING IN

825
00:38:02,947 --> 00:38:05,950
CDC ONES IN BLOOD AND THINGS OF

826
00:38:06,017 --> 00:38:07,752
THAT NATURE AND EXCITED ABOUT

827
00:38:07,818 --> 00:38:10,254
THAT WE GET CEREAL BLOOD SAMPLES

828
00:38:10,321 --> 00:38:12,456
8 OR 9 NOW FROM THE FIRST TWO

829
00:38:12,523 --> 00:38:15,493
SUBJECTS WE ENROLLED AND MARKERS

830
00:38:15,559 --> 00:38:17,294
HAVE AN OUTWARD TREND OVERTIME

831
00:38:17,361 --> 00:38:19,764
AND HAVE A MORE SUSTAINED IMMUNE

832
00:38:19,830 --> 00:38:22,900
-- AT LEAST AS WE CAN TELL

833
00:38:22,967 --> 00:38:26,237
PERIFERL ENGAGEMENT AND

834
00:38:26,303 --> 00:38:28,072
PARALYMPHATIC INJECTIONS HE WE

835
00:38:28,139 --> 00:38:28,272
HAVE.

836
00:38:28,339 --> 00:38:30,174
>> HOW ABOUT IMAGING?  YOU

837
00:38:30,241 --> 00:38:31,108
INJECT THE FLAIRS.

838
00:38:31,175 --> 00:38:31,542
>> YEAH.

839
00:38:31,609 --> 00:38:33,077
>> HOW DOES THAT LOOK OVER TIME

840
00:38:33,144 --> 00:38:36,614
AND DO THE LYMPHATICS LIGHT UP

841
00:38:36,681 --> 00:38:38,849
WHEN THEY ARE IN PLAY IN THE

842
00:38:38,916 --> 00:38:41,385
VIRUS OR NOT ACTIVATED?

843
00:38:41,452 --> 00:38:44,288
>> IMAGING IS A HUGE PROBLEM;

844
00:38:44,355 --> 00:38:44,755
RIGHT?

845
00:38:44,822 --> 00:38:48,159
PEOPLE -- THIS IS NOT WHAT YOU

846
00:38:48,225 --> 00:38:52,430
THINK IT IS THIS IS A TUMOR

847
00:38:52,496 --> 00:38:54,098
GOING AWAY AND NOBODY KNOWS WHAT

848
00:38:54,165 --> 00:38:56,767
IT SHOWS BUT IT IS SIMPLY A

849
00:38:56,834 --> 00:38:58,469
MEASURE OF CONTRAST BEING ABLE

850
00:38:58,536 --> 00:39:00,871
TO ACCUMULATE SOMETHING NOT IN A

851
00:39:00,938 --> 00:39:03,407
NORMAL BRAIN AND WE HAVE THE

852
00:39:03,474 --> 00:39:06,110
PATIENT THAT IS A CR FOR SEVEN

853
00:39:06,177 --> 00:39:09,180
YEARS AND THINK THAT YOU WILL BE

854
00:39:09,246 --> 00:39:12,083
A CR FOREVER HOPEFULLY AND THIS

855
00:39:12,149 --> 00:39:13,584
PATIENT NEVER HAD ANYTHING.

856
00:39:13,651 --> 00:39:16,087
TUMOR WENT AWAY AND NO SIGNS ON

857
00:39:16,153 --> 00:39:18,789
MRI THAT ARE INDICATIVE OF ANY

858
00:39:18,856 --> 00:39:20,624
TROUBLE.  HE HAD NO CLINICAL --

859
00:39:20,691 --> 00:39:23,260
WE HAVE A LOT OF PROBLEMS WITH

860
00:39:23,327 --> 00:39:26,931
PERITUMOR INFLAMMATION AND EDEMA

861
00:39:26,997 --> 00:39:30,468
SEIZURES IN PATIENTS WITH

862
00:39:30,534 --> 00:39:31,936
INTERTUMORAL INOCULATIONS AND

863
00:39:32,002 --> 00:39:34,538
THIS PATIENT WITH A BIG HOLE

864
00:39:34,605 --> 00:39:36,774
HERE VIRUS DIDN'T END UP

865
00:39:36,841 --> 00:39:38,509
CONTRAST VIRUS END INOCULATION

866
00:39:38,576 --> 00:39:41,245
AND KNOW THAT INOCULATION DIDN'T

867
00:39:41,312 --> 00:39:43,080
PROPERLY TARGET THE TUMOR AND

868
00:39:43,147 --> 00:39:45,349
VIRUS IS VERY MUCH IN WAY WE

869
00:39:45,416 --> 00:39:47,952
INTEND NAIL AND VIRUS PROBABLY

870
00:39:48,018 --> 00:39:49,487
TARGETED AREAS AROUND THE TUMOR.

871
00:39:49,553 --> 00:39:53,157
THIS IS WHAT WE KIND OF HOPED

872
00:39:53,224 --> 00:39:54,792
FOR; RIGHT?

873
00:39:54,859 --> 00:39:56,527
NO BAD INFLAMMATION IN THE BRAIN

874
00:39:56,594 --> 00:39:59,697
WAS NOT A GOOD THING; RIGHT?

875
00:39:59,764 --> 00:40:02,600
WE CAN'T TOLERATE A LOT AND IN

876
00:40:02,666 --> 00:40:05,436
RESPONDERS, WE TYPICALLY SEE

877
00:40:05,503 --> 00:40:05,703
NOTHING.

878
00:40:05,770 --> 00:40:06,804
>> SCAN?

879
00:40:06,871 --> 00:40:08,239
>> WE HAVE DONE THAT.  IT IS

880
00:40:08,305 --> 00:40:12,877
VERY INTERESTING.

881
00:40:12,943 --> 00:40:14,912
WE HAVE DONE THIS ONCE.

882
00:40:14,979 --> 00:40:17,314
WE LOVE IT BUT INSURANCE WON'T

883
00:40:17,381 --> 00:40:21,585
PAY FOR IT FOR THESE PATIENTS SO

884
00:40:21,652 --> 00:40:25,222
--

885
00:40:25,289 --> 00:40:26,023
>> ONE LAST QUESTION.

886
00:40:26,090 --> 00:40:29,059
>> USING MD POLIO VIRUS IN HERE?

887
00:40:29,126 --> 00:40:30,594
>> OH, YEAH.  VERY MUCH.  THESE

888
00:40:30,661 --> 00:40:32,797
ARE PATIENTS THAT ARE ALL

889
00:40:32,863 --> 00:40:34,832
IMMUNE, OF COURSE.

890
00:40:34,899 --> 00:40:37,535
WE BOOST THEM.  THEY GET A

891
00:40:37,601 --> 00:40:41,572
BOOSTER WITH A PEDIATRIC VACCINE

892
00:40:41,639 --> 00:40:43,240
ON PURPOSE AND SUPER EXCITED

893
00:40:43,307 --> 00:40:45,743
ABOUT RECALL AND PUBLISHED A

894
00:40:45,810 --> 00:40:48,078
PAPER ON GYPSY ABOUT THIS THAT

895
00:40:48,145 --> 00:40:50,247
IS VERY COMPLICATED AND CAN'T

896
00:40:50,314 --> 00:40:52,349
PUT INTO MY TALK AND PART OF

897
00:40:52,416 --> 00:40:56,487
THIS AND LOVE IT AND IF DIDN'T

898
00:40:56,554 --> 00:40:58,055
HAVE VACCINE WOULDN'T BE ALLOWED

899
00:40:58,122 --> 00:41:01,625
TO DO THIS AND PATIENTS WITH

900
00:41:01,692 --> 00:41:02,560
PRE-EXISTING [INDISCERNIBLE] THE

901
00:41:02,626 --> 00:41:05,596
BETTER AND IN MOUSE MODELS WE DO

902
00:41:05,663 --> 00:41:07,131
BETTER IN VACCINATED MICE

903
00:41:07,198 --> 00:41:09,033
COMPARED TO UNVACCINATED MICE.

904
00:41:09,099 --> 00:41:11,101
WE ARE VERY EXCITED ABOUT

905
00:41:11,168 --> 00:41:11,335
RECALL.

906
00:41:11,402 --> 00:41:15,539
>> THANK YOU VERY MUCH.

907
00:41:15,606 --> 00:41:15,840
FANTASTIC.

908
00:41:15,906 --> 00:41:17,842
>> I WONDER IF I CAN GET A

909
00:41:17,908 --> 00:41:20,411
VOLUNTEER TO GO ON TO THE ZOOM

910
00:41:20,477 --> 00:41:22,046
LINK LOOKING FOR QUESTIONS IN

911
00:41:22,112 --> 00:41:24,882
THE CHAT AND WOULD LIKE TO

912
00:41:24,949 --> 00:41:27,284
ENGAGE THE VIRTUAL AUDIENCE THAT

913
00:41:27,351 --> 00:41:29,854
IS SEVERAL TIMES LARGER THAN

914
00:41:29,920 --> 00:41:31,555
IN-PERSON AUDIENCE AND RAISING

915
00:41:31,622 --> 00:41:32,790
HAND AND READING QUESTIONS

916
00:41:32,857 --> 00:41:34,892
SHOWING UP IN THE CHAT AND NOT

917
00:41:34,959 --> 00:41:36,894
SURE PEOPLE CAN VIRTUALLY UNMUTE

918
00:41:36,961 --> 00:41:42,466
THEM SFELVES ASKING QUESTIONS

919
00:41:42,533 --> 00:41:44,168
DIRECTLY AND WILL FIND OUT AND

920
00:41:44,235 --> 00:41:47,404
MOVING ALONG NEXT SPEAKER IS JEN

921
00:41:47,471 --> 00:41:50,574
RECEIVING DEGREE FROM EMORY

922
00:41:50,641 --> 00:41:51,976
UNIVERSITY SCHOOL OF MEDICINE

923
00:41:52,042 --> 00:41:59,250
AND DID FELLOWSHIP TRAINING IN

924
00:41:59,316 --> 00:41:59,750
MEDI

925
00:41:59,817 --> 00:42:01,852
MEDICAL ONCOLOGIST -- RESEARCH

926
00:42:01,919 --> 00:42:06,924
GROUP OF JAMES IN THE NCI

927
00:42:06,991 --> 00:42:09,293
ASSOCIATE RESEARCH POSITION.

928
00:42:09,360 --> 00:42:12,529
AND JEN USES CAR-T-CELL THERAPY

929
00:42:12,596 --> 00:42:17,568
TO INTRODUCE CANCERS IN THE

930
00:42:17,635 --> 00:42:23,207
BLOOD.

931
00:42:23,274 --> 00:42:26,443
>> [APPLAUSE].

932
00:42:26,510 --> 00:42:27,945
>> ALL RIGHT.  THANKS SO MUCH

933
00:42:28,012 --> 00:42:30,881
FOR HAVING ME.

934
00:42:30,948 --> 00:42:34,318
I GAVE A SIMILAR TALK AT

935
00:42:34,385 --> 00:42:38,555
WASHINGTON HOSPITAL CENTER FOR

936
00:42:38,622 --> 00:42:43,227
GRAND ROUNDS.

937
00:42:43,294 --> 00:42:47,564
I FEEL LUCKY TO HAVE WORKED AT

938
00:42:47,631 --> 00:42:50,701
BETHESDA CAMPUS AND NCI AND

939
00:42:50,768 --> 00:42:54,438
STEVE ROSENBERG AND I WILL TRY

940
00:42:54,505 --> 00:42:57,675
TO HIGHLIGHT THAT NOW IF YOU CAN

941
00:42:57,741 --> 00:43:01,478
INCLUDE MY TRAINED FELLOWSHIP 10

942
00:43:01,545 --> 00:43:03,480
YEARS OF CAR T-CELL THERAPY

943
00:43:03,547 --> 00:43:04,315
WORK.

944
00:43:04,381 --> 00:43:08,319
SO, DISCAN CLOSURE I'M ON

945
00:43:08,385 --> 00:43:11,388
SCIENTIFIC ADVISORY COMMITTEE A

946
00:43:11,455 --> 00:43:13,557
SMALL PHARMACEUTICAL COMPANY AND

947
00:43:13,624 --> 00:43:15,259
FEDERAL EMPLOYEE SO THAT IS AN

948
00:43:15,326 --> 00:43:15,793
UNPAID POSITION.

949
00:43:15,859 --> 00:43:17,962
ALL RIGHT.  I HAVE TWO CASE

950
00:43:18,028 --> 00:43:20,764
PRESENTATIONS TO TRY TO CENTER

951
00:43:20,831 --> 00:43:22,933
THE RESEARCH AROUND.

952
00:43:23,000 --> 00:43:25,436
MR. A, A GENTLEMAN I KNEW FOR A

953
00:43:25,502 --> 00:43:28,906
LONG TIME.  66-YEAR-OLD

954
00:43:28,973 --> 00:43:31,642
GENTLEMAN WITH NON-GERM NAL CELL

955
00:43:31,709 --> 00:43:34,311
TYPE LYMPHOMA AND MANY PRIOR

956
00:43:34,378 --> 00:43:35,512
RESIDENTS AND THEME PATIENTS

957
00:43:35,579 --> 00:43:39,149
COME TO US HAVING HAD MANY PRIOR

958
00:43:39,216 --> 00:43:42,453
[INDISCERNIBLE] MALIGNANCIES AND

959
00:43:42,519 --> 00:43:47,958
HAD VERY STANDARD UP-FRONT

960
00:43:48,025 --> 00:43:51,161
INTERCYCLING-BASED REGIMENT.

961
00:43:51,228 --> 00:43:54,698
COMBINING THAT WITH THE SMALL

962
00:43:54,765 --> 00:43:57,468
MOLECULE ORAL -- HE KEPT HAVING

963
00:43:57,534 --> 00:44:00,237
A LITTLE REMISSION BUT HAVING

964
00:44:00,304 --> 00:44:02,339
RESIDUAL LYMPHOMA AND THAT IS A

965
00:44:02,406 --> 00:44:05,442
VERY BAD INDICATOR.  HE HAD

966
00:44:05,509 --> 00:44:08,879
RADIATION THERAPY TO BIG

967
00:44:08,946 --> 00:44:12,249
ABDOMINAL MASS THAT BER AGED HIM

968
00:44:12,316 --> 00:44:14,151
AND STEM CELL TRANSPLANT MEANT

969
00:44:14,218 --> 00:44:18,088
TO BE CONSOLIDATIVE AND HAD

970
00:44:18,155 --> 00:44:20,557
COMPLETE REMISSION AND RELAPSED

971
00:44:20,624 --> 00:44:25,062
4 MONTHS LATER.  AGGRESSIVE

972
00:44:25,129 --> 00:44:26,397
B-CELL LYMPHOMA NOT RESPONSIVE

973
00:44:26,463 --> 00:44:28,565
TO TREATMENT AND 66 YEAR OLD

974
00:44:28,632 --> 00:44:32,336
VERY FIT HAD WELL CONTROLLED

975
00:44:32,403 --> 00:44:34,271
DEPRESSION GLAUCOMA AND

976
00:44:34,338 --> 00:44:38,609
ARTHRITIS AND BRINGING US TO

977
00:44:38,675 --> 00:44:41,512
OBLIGATORY BACKGROUND AND WHAT

978
00:44:41,578 --> 00:44:43,814
IS A CAR?

979
00:44:43,881 --> 00:44:45,215
HERE ARE COMPONENTS.

980
00:44:45,282 --> 00:44:48,218
HERE IS THE -- I SHOULD SAY THE

981
00:44:48,285 --> 00:44:49,586
[INDISCERNIBLE] FOR ANNE WHO

982
00:44:49,653 --> 00:44:52,256
PUBLISHED THIS NOW 10 YEARS AGO

983
00:44:52,322 --> 00:44:55,859
IN NATURE REVIEW OF CLINICAL

984
00:44:55,926 --> 00:44:57,828
ONCOLOGY AND STILL WORKS AND

985
00:44:57,895 --> 00:45:02,099
GREAT FIGURE AND THESE ARE THE

986
00:45:02,166 --> 00:45:02,733
ACTIVA

987
00:45:02,800 --> 00:45:04,201
ACTIVATION JUST AS YOU WOULD

988
00:45:04,268 --> 00:45:08,172
HAVE IN NORMAL ENDOGENOUS T-CELL

989
00:45:08,238 --> 00:45:10,674
AND COMPONENTS OF CHIMERA WHICH

990
00:45:10,741 --> 00:45:13,143
IS LIGHT AND HEAVY VARIABLE

991
00:45:13,210 --> 00:45:18,482
CHAINS THAT ARE CONNECTED BY A

992
00:45:18,549 --> 00:45:24,988
LINKER TYPICALLY AND THIS IS

993
00:45:25,055 --> 00:45:26,523
WHAT STANDARD CONSTRUCTS LOOK

994
00:45:26,590 --> 00:45:31,128
LIKE AND PROTEINS ARE CONNECTED

995
00:45:31,195 --> 00:45:33,430
BY HINGE AND TRANSMEMBRANE

996
00:45:33,497 --> 00:45:35,199
REGION AND WILL TALK LITTLE

997
00:45:35,265 --> 00:45:36,333
ABOUT OUR VIRAL VECTOR.

998
00:45:36,400 --> 00:45:39,570
I'M SORRY IT IS VERY, VERY

999
00:45:39,636 --> 00:45:42,339
IMPORTANT AND CAR GENES ARE

1000
00:45:42,406 --> 00:45:48,412
INCERTIFIED IN VECTOR AND GAMMA

1001
00:45:48,479 --> 00:45:49,646
RETROVIRAL VECTOR AND RESULT OF

1002
00:45:49,713 --> 00:45:51,982
THIS, GENES OF T-CELL AND NOW

1003
00:45:52,049 --> 00:45:55,152
CAR EXPRESSING T-CELL ARE

1004
00:45:55,219 --> 00:45:56,687
PERMANENTLY GENETICALLY MODIFIED

1005
00:45:56,753 --> 00:45:59,389
AND IT EXPRESSES CAR T-CELL

1006
00:45:59,456 --> 00:46:01,391
PROTEIN ON SURFACE AND GROSSLY

1007
00:46:01,458 --> 00:46:03,627
SIGNIFIED THERE ARE THOUSANDS OF

1008
00:46:03,694 --> 00:46:07,164
RECEPTORS ON T-CELL SURFACE AND

1009
00:46:07,231 --> 00:46:13,036
CLASSIC VERSION 1.0 IS TREATING

1010
00:46:13,103 --> 00:46:16,340
MALIGNANCY CDC CAR T-CELL --

1011
00:46:16,406 --> 00:46:18,842
MALIGNANT CANCER CELLS THAT ARE

1012
00:46:18,909 --> 00:46:20,744
DERIVED FROM B-CELLS AND SO NOW

1013
00:46:20,811 --> 00:46:24,281
THERE ARE VARIATIONS ON THIS

1014
00:46:24,348 --> 00:46:26,016
THEME AND DIFFERENT ANDROEJEN

1015
00:46:26,083 --> 00:46:27,718
TARGETS AND CARS I WILL TALK

1016
00:46:27,784 --> 00:46:30,587
ABOUT LATER AND IDEA IS I TOLD

1017
00:46:30,654 --> 00:46:32,156
THEM ONCOLOGY FELLOWS ARE

1018
00:46:32,222 --> 00:46:35,459
FINGERS COMING AND SENSING THE

1019
00:46:35,526 --> 00:46:39,429
ANTIGEN AND RESULT T-CELL IS

1020
00:46:39,496 --> 00:46:43,901
ACTIVATED INTERCYTOPLASMIC

1021
00:46:43,967 --> 00:46:44,735
[INDISCERNIBLE] AND IT IS A

1022
00:46:44,801 --> 00:46:46,236
FIGURE THAT WORKS AND GIVING

1023
00:46:46,303 --> 00:46:48,338
THIS I WILL SAY AGAIN THIS IS

1024
00:46:48,405 --> 00:46:50,474
STANDARD VERSION OF EVENTS AND

1025
00:46:50,541 --> 00:46:52,276
CLINICAL TRIALS ARE VARIATIONS

1026
00:46:52,342 --> 00:46:54,044
OF THIS I CAN TALK ABOUT LATER

1027
00:46:54,111 --> 00:46:59,650
IF DESIRED AND ESSENTIALLY

1028
00:46:59,716 --> 00:47:02,085
T-CELLS PDMC IS COLLECTED FROM

1029
00:47:02,152 --> 00:47:03,487
THE PATIENT AND TELL THEM THIS

1030
00:47:03,554 --> 00:47:05,756
IS A PROCESS AS IF DONATING

1031
00:47:05,822 --> 00:47:09,860
BLOOD THAT IS SIMPLE AND DONE

1032
00:47:09,927 --> 00:47:11,328
IN-HOUSE IN OUR CAN CELL

1033
00:47:11,395 --> 00:47:13,931
PROCESSING CENTER AND ARE TAKEN

1034
00:47:13,997 --> 00:47:16,934
FOR EX-VIVO PROCESSING AND

1035
00:47:17,000 --> 00:47:19,836
T-CELLS ACTIVATED AND TRANCE

1036
00:47:19,903 --> 00:47:23,774
DEUCED WITH THE GAMMA VIRAL

1037
00:47:23,840 --> 00:47:28,212
VECTOR -- CAN ALSO BE SUCCESSFUL

1038
00:47:28,278 --> 00:47:29,513
AND USUALLY A VIRAL VECTOR.

1039
00:47:29,580 --> 00:47:33,350
THE T-CELLS PROLIFERATE EX-VIVO

1040
00:47:33,417 --> 00:47:35,852
AND IN THE MEANTIME PATIENT GETS

1041
00:47:35,919 --> 00:47:38,522
CHEMOTHERAPY AND PATIENTS ASK ME

1042
00:47:38,589 --> 00:47:41,425
IF THIS IS CHEMOTHERAPY TO

1043
00:47:41,491 --> 00:47:42,926
DECREASE BURDEN OF MALIGNANCY

1044
00:47:42,993 --> 00:47:45,462
AND GREAT WHEN IT HAPPENS AND

1045
00:47:45,529 --> 00:47:47,030
FREQUENTLY HAPPENS AND THESE

1046
00:47:47,097 --> 00:47:48,966
FACTORS ARE RETREATING AND

1047
00:47:49,032 --> 00:47:51,535
PRIMARILY WE ARE DEPLETING WITH

1048
00:47:51,602 --> 00:47:55,706
THE SITES CALLED CONDITIONING

1049
00:47:55,772 --> 00:47:59,576
CHEMOTHERAPY OR LYMPHO DEPLETING

1050
00:47:59,643 --> 00:48:01,678
CHEMOTHERAPY AND TWO AGENTS

1051
00:48:01,745 --> 00:48:04,281
TOGETHER ARE TYPICAL REGIMENT

1052
00:48:04,348 --> 00:48:07,451
ENDOGENOUS LYMPHOOCYTES AND

1053
00:48:07,517 --> 00:48:08,852
LYMPHOCYTES ARE SYNC FOR

1054
00:48:08,919 --> 00:48:12,489
CYTOKINES THAT EFFECTIVELY MAKE

1055
00:48:12,556 --> 00:48:14,424
IT SO CYTOKINE BOILS IN BLOOD

1056
00:48:14,491 --> 00:48:19,329
AND IT PROMOTES CAR T-CELL

1057
00:48:19,396 --> 00:48:21,798
ACTIVITY IN VIVO WHEN THEY ARE

1058
00:48:21,865 --> 00:48:23,600
INFUSED INTO THE PATIENT THAT IS

1059
00:48:23,667 --> 00:48:27,170
A STANDARD THING WE DO TO TREAT

1060
00:48:27,237 --> 00:48:29,339
PATIENTS WITH CAR T-CELL THERAPY

1061
00:48:29,406 --> 00:48:31,675
AND MORE OFTEN THAN NOT --

1062
00:48:31,742 --> 00:48:35,579
INFUSION CENTER TO GET

1063
00:48:35,646 --> 00:48:37,214
LYMPHOCYTE DEPLETING

1064
00:48:37,281 --> 00:48:40,684
CHEMOTHERAPY AND CAR T-CELLS

1065
00:48:40,751 --> 00:48:42,419
IN-PATIENT AND OUT-PATIENT --

1066
00:48:42,486 --> 00:48:44,321
PHASE 1 TRIALS CURRENTLY IN OUR

1067
00:48:44,388 --> 00:48:47,758
GROUP WE ARE EXCLUSIVELY IN MANY

1068
00:48:47,824 --> 00:48:50,961
PATIENTS TO IN-PATIENT SERVICE

1069
00:48:51,028 --> 00:48:53,730
FOR NEEDS TO TOXICITY MONITORING

1070
00:48:53,797 --> 00:48:56,900
AND WHERE WERE WE JULY 1ST 2013

1071
00:48:56,967 --> 00:48:59,303
AND STARTED INTERNSHIPS AND

1072
00:48:59,369 --> 00:49:02,272
STARTING MEDICAL ONCOLOGY

1073
00:49:02,339 --> 00:49:04,241
HEMOTOLOGY FELLOWSHIP AND IN A

1074
00:49:04,308 --> 00:49:06,476
DIFFERENT PLACE THAN TODAY AND

1075
00:49:06,543 --> 00:49:08,345
NO APPROVED CAR-T CELL PRODUCTS

1076
00:49:08,412 --> 00:49:12,649
FOR MALIGNANCY AND SOME ANTI-C19

1077
00:49:12,716 --> 00:49:14,551
CAR T-CELL CLINICAL TRIALS AND

1078
00:49:14,618 --> 00:49:17,788
CAN SEE THERE ARE SOME REPORTS

1079
00:49:17,854 --> 00:49:19,089
HERE.

1080
00:49:19,156 --> 00:49:24,127
SO, THE -- MY MENTOR ARE FIRST 2

1081
00:49:24,194 --> 00:49:26,129
PUBLISH IN BLOOD AS BRIEF REPORT

1082
00:49:26,196 --> 00:49:29,700
ACTIVITY OF GIVING ANTI-C9

1083
00:49:29,766 --> 00:49:31,368
[INDISCERNIBLE] WHO IS NOW MORE

1084
00:49:31,435 --> 00:49:34,438
THAN A DECADE IN REMISSION AND

1085
00:49:34,504 --> 00:49:35,839
STARTED THAT STORY THIS IS A

1086
00:49:35,906 --> 00:49:37,407
REPORT IN THE JOURNAL FROM GROUP

1087
00:49:37,474 --> 00:49:41,178
OF UNIVERSITY OF PENNSYLVANIA

1088
00:49:41,244 --> 00:49:42,813
DR. PORTER KARL JUNE TALKING

1089
00:49:42,879 --> 00:49:45,415
ABOUT EARLY EXPERIENCE GIVING

1090
00:49:45,482 --> 00:49:48,518
CAR-T CELLS TO PATIENTS WITH

1091
00:49:48,585 --> 00:49:49,753
[INDISCERNIBLE] WITH REALLY

1092
00:49:49,820 --> 00:49:51,755
IMPRESSIVE REMISSIONS AND

1093
00:49:51,822 --> 00:49:55,425
IMPRESSIVE TOXICITIES CITTOKIND

1094
00:49:55,492 --> 00:49:57,861
RELEASE SYNDROME AND MEMORIAL

1095
00:49:57,928 --> 00:49:59,162
KETERRING BACK IN 2013 WITH

1096
00:49:59,229 --> 00:50:01,998
SERIES OF INDIVIDUALS WITH ACUTE

1097
00:50:02,065 --> 00:50:04,267
LYMPHO BLASTIC LEUKEMIA AND

1098
00:50:04,334 --> 00:50:06,636
IMPRESSIVE REMISSIONS INCLUDING

1099
00:50:06,703 --> 00:50:08,372
MRD NEGATIVE AND NEGATIVE

1100
00:50:08,438 --> 00:50:10,707
REMISSIONS AND ALSO I STARTED

1101
00:50:10,774 --> 00:50:14,111
FELLOWSHIP THAT ARE NO

1102
00:50:14,177 --> 00:50:16,880
ANTI-B-CELL MADE CAR-T CELL

1103
00:50:16,947 --> 00:50:18,315
PRODUCTS AND [INDISCERNIBLE]

1104
00:50:18,382 --> 00:50:23,687
ANTIGEN THAT IS WELL-EXPRESSED

1105
00:50:23,754 --> 00:50:25,922
ON PLASMA CELLS AND DIFFERENT

1106
00:50:25,989 --> 00:50:27,691
SITUATION THAN WHERE WE ARE NOW.

1107
00:50:27,758 --> 00:50:29,493
WHERE ARE WE NOW?

1108
00:50:29,559 --> 00:50:32,529
WE HAVE SIX FDA APPROVED CAR

1109
00:50:32,596 --> 00:50:35,799
T-CELL PRODUCTS FOR FOUR

1110
00:50:35,866 --> 00:50:38,869
HEMOLOGIC MALIGNANCIES AND WE

1111
00:50:38,935 --> 00:50:40,604
HAVE [INDISCERNIBLE] AND YOU

1112
00:50:40,670 --> 00:50:44,641
NOTICE WE HAVE CUTE LITTLE

1113
00:50:44,708 --> 00:50:47,544
NICKNAMES FOR THE PRODUCTS WITH

1114
00:50:47,611 --> 00:50:50,213
LONG AND CUMBERSOME NAMES

1115
00:50:50,280 --> 00:50:51,848
DIFFICULT TO ANNOUNCE AND THAT

1116
00:50:51,915 --> 00:50:55,485
WAS THE PRODUCT DEVELOPED BY MY

1117
00:50:55,552 --> 00:50:57,587
[INDISCERNIBLE] FOR STEVE

1118
00:50:57,654 --> 00:50:59,122
ROSENBERG STARTING BACK IN 2007

1119
00:50:59,189 --> 00:51:02,325
AND PRETTY GOOD TIMELINE; RIGHT?

1120
00:51:02,392 --> 00:51:05,095
FDA APPROVAL IN 2017 AND NOW

1121
00:51:05,162 --> 00:51:06,763
SECOND LINE AS WELL THAT IS

1122
00:51:06,830 --> 00:51:09,299
GREAT AND PATIENTS CAN GET

1123
00:51:09,366 --> 00:51:11,601
FIRST-LINE THERAPY AND IF

1124
00:51:11,668 --> 00:51:13,336
DOESN'T WORK CAN GET CAR-T CELL

1125
00:51:13,403 --> 00:51:15,872
THERAPY THAT IS EXCITING AND

1126
00:51:15,939 --> 00:51:19,409
APPROVED FOR LARGE B-CELL

1127
00:51:19,476 --> 00:51:21,378
LYMPHOMA AND ONE FOR MAN TELL

1128
00:51:21,445 --> 00:51:23,947
CELL LYMPHOMA AND ALL, IT IS THE

1129
00:51:24,014 --> 00:51:26,783
VERY FAMOUS UNIVERSITY OF

1130
00:51:26,850 --> 00:51:28,118
PENNSYLVANIA PRODUCT.

1131
00:51:28,185 --> 00:51:31,021
THIS IS THE FIRST FDA APPROVED

1132
00:51:31,087 --> 00:51:34,257
CAR-T CELL BACKED IN 27 TAENFOR

1133
00:51:34,324 --> 00:51:37,093
PEDIATRIC B-CELL ALL AND WE HAVE

1134
00:51:37,160 --> 00:51:40,564
ADULT B-CELL ALL PRODUCT AND

1135
00:51:40,630 --> 00:51:44,868
APPROVED AND TWO MULTIPLE

1136
00:51:44,935 --> 00:51:46,269
MYELOMA PRODUCTS TARGETED

1137
00:51:46,336 --> 00:51:47,304
AGAINST [INDISCERNIBLE] AND I

1138
00:51:47,370 --> 00:51:48,605
MENTIONED EARLIER.

1139
00:51:48,672 --> 00:51:50,507
THESE ARE EXCITING THERAPIES

1140
00:51:50,574 --> 00:51:52,309
THAT WORK WHEN CHEMOTHERAPY

1141
00:51:52,375 --> 00:51:52,742
DOESN'T.

1142
00:51:52,809 --> 00:51:58,181
IT IS A VERY -- THERE ARE NARROW

1143
00:51:58,248 --> 00:51:59,749
RANGE OF THERAPIES THAT CAN DO

1144
00:51:59,816 --> 00:52:03,320
THAT IN PATIENTS IN SOME CASES

1145
00:52:03,386 --> 00:52:06,356
AND INCURABLE -- LARGE B-CELL

1146
00:52:06,423 --> 00:52:08,158
LYMPHOMA AND WE ESTABLISHED AT

1147
00:52:08,225 --> 00:52:10,327
THIS POINT WE CAN CURE THOSE

1148
00:52:10,393 --> 00:52:12,562
PATIENTS AND LIKELY SUBSET OF

1149
00:52:12,629 --> 00:52:15,632
PATIENTS WITH INCURABLE B-CELL

1150
00:52:15,699 --> 00:52:18,235
MALIGNANCIES LYMPHOMAS AND

1151
00:52:18,301 --> 00:52:21,471
LEUKEMIAS WE CAN CURE.  BARRIER

1152
00:52:21,538 --> 00:52:23,273
I WILL TALK ABOUT IS PRICE

1153
00:52:23,340 --> 00:52:26,109
CELLULAR PRODUCTS COST HUNDREDS

1154
00:52:26,176 --> 00:52:28,445
OF THOUSANDS OF DOLLARS FOR

1155
00:52:28,512 --> 00:52:30,914
PRODUCT ITSELF AND NEEDS PATIENT

1156
00:52:30,981 --> 00:52:34,317
MIGHT NEED TO BE ADMITTED OR

1157
00:52:34,384 --> 00:52:35,385
POTENTIALLY HAVE LONG-TERM

1158
00:52:35,452 --> 00:52:39,155
EFFECTS IN TERMS OF CITTOPENIAS

1159
00:52:39,222 --> 00:52:41,992
AND B-CELL AMRASHIA THAT IS NOT

1160
00:52:42,058 --> 00:52:44,194
TRIVIAL AND COST BENEFIT

1161
00:52:44,261 --> 00:52:44,995
ANALYSIS ACTUALLY HAVE SHOWN IF

1162
00:52:45,061 --> 00:52:48,965
YOU ARE A PERSON WITH CURABLE

1163
00:52:49,032 --> 00:52:51,968
MALIGNANCY WITH ALL B-CELL

1164
00:52:52,035 --> 00:52:53,370
LYMPHOMA GETTING LOTS OF

1165
00:52:53,436 --> 00:52:55,171
THERAPIES AND DYING BECAUSE THEY

1166
00:52:55,238 --> 00:52:57,307
DON'T WORK IT IS PROBABLY COST

1167
00:52:57,374 --> 00:52:59,276
EFFECTIVE TO GET T-CELL THERAPY

1168
00:52:59,342 --> 00:53:01,378
AND HOPE IN FIELD IS VERSION 3.0

1169
00:53:01,444 --> 00:53:04,814
AND 5.0 WILL BE MUCH MORE

1170
00:53:04,881 --> 00:53:05,415
EFFECTIVE.

1171
00:53:05,482 --> 00:53:09,185
TALKING A LITTLE ABOUT THE STORY

1172
00:53:09,252 --> 00:53:11,855
OF WORKING WITH MENTOR STEVE

1173
00:53:11,922 --> 00:53:15,659
ROSENBERG WORKING ON 19 CAR --

1174
00:53:15,725 --> 00:53:17,027
AND TALKING ABOUT FUTURE

1175
00:53:17,093 --> 00:53:18,895
WORKABILITY ON THAT.  PATIENTS

1176
00:53:18,962 --> 00:53:22,365
WITH LARGE B-CELL LYMPHOMA HAVE

1177
00:53:22,432 --> 00:53:24,301
POOR OUTCOMES AND TRY TO BUILD

1178
00:53:24,367 --> 00:53:26,670
THIS STORY WITH ANECDOTE OF MR.

1179
00:53:26,736 --> 00:53:28,338
A THAT WILL COME BACK TO YOU IN

1180
00:53:28,405 --> 00:53:31,608
A LITTLE BIT.

1181
00:53:31,675 --> 00:53:34,511
PATIENTS WITH LARGE LYMPHOMA

1182
00:53:34,578 --> 00:53:36,546
GROUP CHEMOTHERAPY REFRACTORY

1183
00:53:36,613 --> 00:53:39,516
LASTING 12 MONTHS AFTER IN STEM

1184
00:53:39,583 --> 00:53:42,052
CELL TRANSPLANT THEY HAVE

1185
00:53:42,118 --> 00:53:44,955
PROGNOSIS AND PATIENTS ARE ALIVE

1186
00:53:45,021 --> 00:53:47,891
LONG-TERM AND IS VERY DIFFERENT

1187
00:53:47,958 --> 00:53:50,393
THAN IN THE FRONTLINE AND 60 OR

1188
00:53:50,460 --> 00:53:52,696
70% OF PATIENTS MIGHT BE CURED

1189
00:53:52,762 --> 00:53:55,832
WITH LARGE CELL LYMPHOMA WITH

1190
00:53:55,899 --> 00:53:58,201
CHEMOTHERAPY AND UP-FRONT IS NOT

1191
00:53:58,268 --> 00:54:02,505
CURATIVE AND LONG-TERM OUTLOOK

1192
00:54:02,572 --> 00:54:04,474
HISTORICALLY IS POOR AND STEVE

1193
00:54:04,541 --> 00:54:07,844
ROSENBERG WORKS ON CONSTRUCTING

1194
00:54:07,911 --> 00:54:09,946
ANTI-C9 CAR AND IT IS THE NAME

1195
00:54:10,013 --> 00:54:11,247
OF THE [INDISCERNIBLE] AND

1196
00:54:11,314 --> 00:54:15,352
REMEMBER THAT ANTIBODY DERIVED

1197
00:54:15,418 --> 00:54:17,721
RECOGNITION AND FINGERS EXTRA

1198
00:54:17,787 --> 00:54:20,323
CELLULARLY AND DOMAIN AND THIS

1199
00:54:20,390 --> 00:54:23,727
CONSTRUCT IS WHAT THEY DEVELOPED

1200
00:54:23,793 --> 00:54:25,962
AND STARTING BACK IN 2007 AND

1201
00:54:26,029 --> 00:54:28,031
RAN THE FIRST PHASE 1 CLINICAL

1202
00:54:28,098 --> 00:54:30,734
TRIAL LOOKING AT CAR-T CELL

1203
00:54:30,800 --> 00:54:32,736
THERAPY FOR NON-HODGE KINES

1204
00:54:32,802 --> 00:54:35,905
LYMPHOMA AND REPORTS IN JOURNAL

1205
00:54:35,972 --> 00:54:38,642
OF CLINICAL ONCOLOGY IN 2017

1206
00:54:38,708 --> 00:54:41,277
REPORTING EARLY PHASE 1 PATIENTS

1207
00:54:41,344 --> 00:54:44,848
AND OVERALL RESPONSE RATE LOVELY

1208
00:54:44,914 --> 00:54:49,519
73% WITH CR COMPLETION RATE OF

1209
00:54:49,586 --> 00:54:51,488
[INDISCERNIBLE] OCCURRING IN

1210
00:54:51,554 --> 00:54:55,625
HALF PATIENTS THAT IS PER

1211
00:54:55,692 --> 00:54:59,929
NCICTCA SYSTEM AND NEUROLOGIC

1212
00:54:59,996 --> 00:55:01,731
TOXICITY THEY ARE NOT FUNCTIONAL

1213
00:55:01,798 --> 00:55:04,267
AND DIVERSE TOXICITIES AND HAND

1214
00:55:04,334 --> 00:55:06,936
TREMORS APHASIAS AND MOTOR

1215
00:55:07,003 --> 00:55:08,772
DEFECTS SOMETIMES AND ATAXIA AND

1216
00:55:08,838 --> 00:55:10,774
APHASIA IS SOMETIMES VERY DENSE

1217
00:55:10,840 --> 00:55:13,476
AND PATIENT CAN'T SPEAK AND

1218
00:55:13,543 --> 00:55:16,479
INCREASED SAL MAN ILLA AND

1219
00:55:16,546 --> 00:55:18,948
PATIENT WANTS TO NAP A LOT AND

1220
00:55:19,015 --> 00:55:21,851
BE ON A VENTILATOR AND BE

1221
00:55:21,918 --> 00:55:23,720
INTUBATED FOR AIRWAY SUPPORT AND

1222
00:55:23,787 --> 00:55:26,589
GREAT BEGINNING WE ARE GIVING

1223
00:55:26,656 --> 00:55:29,959
INTERLEUKIN TWO INFUSIONS TO

1224
00:55:30,026 --> 00:55:31,995
CAR-T CELLS TO PROMOTE ACTIVITY

1225
00:55:32,062 --> 00:55:33,530
IN VIVO AND BECAUSE OF THAT

1226
00:55:33,596 --> 00:55:35,832
BECOMING CLEAR VERY SOON THIS IS

1227
00:55:35,899 --> 00:55:37,300
NOT IL2 EFFECT.

1228
00:55:37,367 --> 00:55:39,836
IT IS A DIFFERENT FLAVOR OF

1229
00:55:39,903 --> 00:55:42,972
NEUROLOGIC TOXICITY ON THE

1230
00:55:43,039 --> 00:55:46,142
SEVERE END WAS VERY COMMON.

1231
00:55:46,209 --> 00:55:48,344
CYTOTOXICITY AND RESULTS OF

1232
00:55:48,411 --> 00:55:50,280
EFFICACY IS EXCITING AND TAKEN

1233
00:55:50,346 --> 00:55:53,516
TO PHASE 2 MULTICENTERED TRIAL

1234
00:55:53,583 --> 00:55:56,753
AND CONSTRUCT USED IN EXTRA

1235
00:55:56,820 --> 00:55:58,755
CELLULAR PRODUCT AND AXY CELL

1236
00:55:58,822 --> 00:56:00,690
FOR SHORT AND DEDICATED TRIAL

1237
00:56:00,757 --> 00:56:03,026
FOR LARGE B-CELL LYMPHOMA AND

1238
00:56:03,093 --> 00:56:06,329
THEY ARE UP TO [INDISCERNIBLE]

1239
00:56:06,396 --> 00:56:10,433
23 AND HAVE CUTE AND GILLAD

1240
00:56:10,500 --> 00:56:12,068
TRIALS HAVE SHORT NAMES AND THIS

1241
00:56:12,135 --> 00:56:14,571
IS A TRIAL UNDER ONE PATIENTS

1242
00:56:14,637 --> 00:56:17,040
RETREATED GETTING FAIRLY

1243
00:56:17,107 --> 00:56:18,608
STANDARD CONDITIONED REGIMENT

1244
00:56:18,675 --> 00:56:20,977
WITH HIGH RESPONSE RATES YOU CAN

1245
00:56:21,044 --> 00:56:22,746
SEE HERE WITH OVERALL RESPONSE

1246
00:56:22,812 --> 00:56:25,782
RATE OF 0% AND 0 TO 54% AND

1247
00:56:25,849 --> 00:56:28,384
DURABLE IN MANY PATIENTS AND NOW

1248
00:56:28,451 --> 00:56:31,755
HAVE LONG-TERM FOLLOW UP DATA

1249
00:56:31,821 --> 00:56:33,723
PUBLISHED THIS YEAR IN BLOOD AND

1250
00:56:33,790 --> 00:56:35,959
30% OF PATIENTS ARE CURED

1251
00:56:36,025 --> 00:56:37,927
FOREVER FROM REFRACTORY LARGE

1252
00:56:37,994 --> 00:56:41,865
B-CELL LYMPHOMA AND HIGH GRADE

1253
00:56:41,931 --> 00:56:44,267
NEUROLOGIC TOXICITIES AND

1254
00:56:44,334 --> 00:56:46,870
DIVERSITIES CYTOKINE RELEASED

1255
00:56:46,936 --> 00:56:49,072
SYNDROME AND TOXICITIES ARE

1256
00:56:49,139 --> 00:56:51,508
MAJOR BARRIER TO USE IN PRODUCTS

1257
00:56:51,574 --> 00:56:53,276
TODAY AND KATIE WHO AT THE TIME

1258
00:56:53,343 --> 00:56:56,212
WAS A FELLOW WORKING WITH OUR

1259
00:56:56,279 --> 00:56:57,747
GROUP AND WENT INTO PRACTICE AND

1260
00:56:57,814 --> 00:56:59,249
CAME BACK AND IS WORKING IN THE

1261
00:56:59,315 --> 00:57:01,317
LAB AND WE ARE EXCITED ABOUT

1262
00:57:01,384 --> 00:57:03,920
THAT AND WENT BACK AND LOOKED

1263
00:57:03,987 --> 00:57:06,122
LONG-TERM AT PATIENTS TREATED

1264
00:57:06,189 --> 00:57:09,793
WITH AXY SILICON CONSTRUCT AND

1265
00:57:09,859 --> 00:57:12,428
PATIENTS GAINING 43 PATIENTS

1266
00:57:12,495 --> 00:57:13,863
GAINING 46 CELL INFUSIONS THAT

1267
00:57:13,930 --> 00:57:16,966
IS A MIX OF LARGE B-CELL

1268
00:57:17,033 --> 00:57:19,435
LYMPHOMA AND LOW GRADE NON-HODGE

1269
00:57:19,502 --> 00:57:22,038
KINES B LYMPHOMAS AND CLL AND

1270
00:57:22,105 --> 00:57:24,808
NICE DURABILITY YOU CAN SEE HERE

1271
00:57:24,874 --> 00:57:26,276
IN THIS CAP LYNNE MEYER PLOT

1272
00:57:26,342 --> 00:57:29,712
WITH HALF PATIENTS HAVING FAIRLY

1273
00:57:29,779 --> 00:57:30,814
DURABLE REMISSIONS OUT THREE

1274
00:57:30,880 --> 00:57:31,548
YEARS AND BEYOND.

1275
00:57:31,614 --> 00:57:33,983
I WANT TO TALK ABOUT THE

1276
00:57:34,050 --> 00:57:35,418
[INDISCERNIBLE] FOR LAB AND

1277
00:57:35,485 --> 00:57:37,287
CLINICAL RESEARCH TEAMS

1278
00:57:37,353 --> 00:57:39,355
EXPERIENCE TRYING TO DEVELOP

1279
00:57:39,422 --> 00:57:44,160
ESSENTIALLY VERSION 2.0 OF THE

1280
00:57:44,227 --> 00:57:46,062
AXY CELL CONSTRUCT FOR B-CELL

1281
00:57:46,129 --> 00:57:48,865
NON-HODGE KINES LYMPHOMA AND IS

1282
00:57:48,932 --> 00:57:51,501
WORK BY LEAH WITH LAB PUBLISHED

1283
00:57:51,568 --> 00:58:00,143
BACK IN 207  TAEN/* -- 2017 AND

1284
00:58:00,210 --> 00:58:03,580
T-CELL ACTIVATION COSTIMULATORY

1285
00:58:03,646 --> 00:58:05,748
DOMAIN TRANSMEMBRANE REGION AND

1286
00:58:05,815 --> 00:58:09,285
SINGLE CHAIN OF SINGLE CHAIN

1287
00:58:09,352 --> 00:58:12,655
VARIABLE FRAGMENTOR REGION HEAVY

1288
00:58:12,722 --> 00:58:16,159
CHAINS CONNECTED BY A LINKER AND

1289
00:58:16,226 --> 00:58:18,394
ON FIGURE AND TRANSMEMBRANE

1290
00:58:18,461 --> 00:58:20,330
REGIONS LOOK INACTIVE SKIPPING

1291
00:58:20,396 --> 00:58:22,332
THEM GIVING INITIAL CAR SCHEMA

1292
00:58:22,398 --> 00:58:25,301
AND HOW IT WORKS AND RECOGNIZED

1293
00:58:25,368 --> 00:58:28,805
EARLY ON BY LEAH FROM COLLEAGUES

1294
00:58:28,872 --> 00:58:33,309
THAT MEMBRANE DOMAINS OF CARS

1295
00:58:33,376 --> 00:58:37,947
CAN IMPACT FUNCTION AND

1296
00:58:38,014 --> 00:58:41,885
COMPARING CARS AND REGION DERIVE

1297
00:58:41,951 --> 00:58:43,186
FROM [INDISCERNIBLE] CONSTRUCTS

1298
00:58:43,253 --> 00:58:44,587
WITH DIFFERENT TRANSMEMBRANE

1299
00:58:44,654 --> 00:58:47,357
REGION DERIVED FROM CD8 AND

1300
00:58:47,423 --> 00:58:50,693
RATHER THAN CD28 AND CELLS ARE

1301
00:58:50,760 --> 00:58:52,195
DIFFERENT HINGE AND

1302
00:58:52,262 --> 00:58:53,730
TRANSMEMBRANE REGION DERIVED

1303
00:58:53,796 --> 00:58:58,301
FROM CD8 HAVE LOWER LEVELS OF

1304
00:58:58,368 --> 00:59:00,803
CYTOKINE [INDISCERNIBLE] STILL

1305
00:59:00,870 --> 00:59:03,339
WORKS AND STILL HAS CITTOLYTIC

1306
00:59:03,406 --> 00:59:04,107
PROPERTIES.

1307
00:59:04,173 --> 00:59:06,609
SO, THIS WAS VERY INTERESTING.

1308
00:59:06,676 --> 00:59:08,811
WE KNOW AND I REVIEW THIS BACK

1309
00:59:08,878 --> 00:59:11,714
IN 2016.

1310
00:59:11,781 --> 00:59:13,883
WE KNOW MOST CAR-T CELL

1311
00:59:13,950 --> 00:59:15,985
TOXICITIES ARE DUE TO CYTOKINES

1312
00:59:16,052 --> 00:59:20,123
BOTH PRODUCED BY T-CELLS

1313
00:59:20,189 --> 00:59:22,892
THEMSELVES AND DOWNSTREAM CAR-T

1314
00:59:22,959 --> 00:59:25,261
CELLS AND CAN WE IMPROVE INITIAL

1315
00:59:25,328 --> 00:59:27,297
CONSTRUCT DEVELOPED IN NCI WITH

1316
00:59:27,363 --> 00:59:29,732
INITIAL PUBLICATIONS BACK IN

1317
00:59:29,799 --> 00:59:30,133
2015?

1318
00:59:30,199 --> 00:59:33,636
LEAH AND OTHERS IN THE LAB FOR

1319
00:59:33,703 --> 00:59:35,838
NORRIS AS WELL DEVELOPED A NEW

1320
00:59:35,905 --> 00:59:37,974
CONSTRUCT THAT HAS A FULLY HUMAN

1321
00:59:38,041 --> 00:59:41,644
SINGLE CHAIN OF V AND CD8

1322
00:59:41,711 --> 00:59:44,380
MEMBRANE REGION AND WHAT ARE

1323
00:59:44,447 --> 00:59:46,482
POTENTIAL ADVANTAGES HERE?

1324
00:59:46,549 --> 00:59:48,518
HOPE WAS THAT THE FULLY HUMAN

1325
00:59:48,584 --> 00:59:52,488
AND ALL HUMAN PROTEINS AND

1326
00:59:52,555 --> 00:59:55,258
IMMUNOGENIC AND CAR CONSTRUCT

1327
00:59:55,325 --> 00:59:58,528
WITH CD8 HINGING TRANSMEMBRANE

1328
00:59:58,594 --> 01:00:01,030
REGION WOULD BE LESS TOXIC WITH

1329
01:00:01,097 --> 01:00:05,435
LOW CYTOKINE MODEL IN MOUSE

1330
01:00:05,501 --> 01:00:09,706
MODELS AND USING CONSTRUCT 28Z

1331
01:00:09,772 --> 01:00:14,043
CONSTRUCT IN A CLINICAL TRIAL

1332
01:00:14,110 --> 01:00:17,213
FOR PATIENTS THIS IS PHASE 1

1333
01:00:17,280 --> 01:00:20,049
FAIRLY STANDARD 3 + 3 AND

1334
01:00:20,116 --> 01:00:22,885
STARTING FAIRLY LOW DOSE CELL

1335
01:00:22,952 --> 01:00:25,054
DOSE LEVEL WORKING TO HIGH DOSE

1336
01:00:25,121 --> 01:00:27,357
LEVELS BASED ON TOXICITY PROFILE

1337
01:00:27,423 --> 01:00:30,626
AND 20 PATIENTS LARGE B-CELL

1338
01:00:30,693 --> 01:00:34,030
LYMPHOMA IS MOST KIND AND B-CELL

1339
01:00:34,097 --> 01:00:35,732
NON-HODGE KIN LYMPHOMA AND

1340
01:00:35,798 --> 01:00:37,967
POPULATIONS ARE ENRICHED IN

1341
01:00:38,034 --> 01:00:39,769
PATIENTS AND WE HAVE OTHER

1342
01:00:39,836 --> 01:00:41,571
LYMPHOMAS YOU CAN SEE HERE AND

1343
01:00:41,637 --> 01:00:43,373
OVERALL RESPONSE AND CR RATE IS

1344
01:00:43,439 --> 01:00:46,075
SIMILAR TO WHAT WE SEE IN OUR

1345
01:00:46,142 --> 01:00:48,444
CENTER AND IN AXY CELL PRODUCT

1346
01:00:48,511 --> 01:00:50,246
AND NOW WITH COMMERCIAL USE.

1347
01:00:50,313 --> 01:00:52,648
WE HAD -- VERY NICE RESPONSE

1348
01:00:52,715 --> 01:00:54,717
RATES AND FIVE PATIENTS WITH

1349
01:00:54,784 --> 01:00:56,152
COMPLETE REMISSION OVER FIVE

1350
01:00:56,219 --> 01:00:59,188
YEARS AND ABOUT PROBABLY ABOUT A

1351
01:00:59,255 --> 01:01:01,424
QUARTER OF PATIENTS THAT WE ARE

1352
01:01:01,491 --> 01:01:03,059
CURING.

1353
01:01:03,126 --> 01:01:07,363
ALSO, IT ENDS UP BEING FAIRLY

1354
01:01:07,430 --> 01:01:12,335
COMPARABLE TO CELL FOLLOW UP.

1355
01:01:12,402 --> 01:01:18,041
YOU SEE HERE FAIRLY SMALL DOSE.

1356
01:01:18,107 --> 01:01:21,778
WE HAD RESPONSES AND TOXICITIES

1357
01:01:21,844 --> 01:01:23,780
AND DURABLE RESPONSE LEVELS AND

1358
01:01:23,846 --> 01:01:25,448
MIDDLE LEVEL IS THE LOSER HERE

1359
01:01:25,515 --> 01:01:30,520
AND PATIENTS WITH LOW CAR-T CELL

1360
01:01:30,586 --> 01:01:33,523
LEVEL DID VERY WELL AND BACK TO

1361
01:01:33,589 --> 01:01:36,125
MR. A AND CASE I TALKED ABOUT

1362
01:01:36,192 --> 01:01:37,960
EARLIER AND HE RETRIEVED A

1363
01:01:38,027 --> 01:01:39,796
REMISSION AFTER FIVE YEARS OF

1364
01:01:39,862 --> 01:01:42,899
CAR T INFUSION AND FAIRLY LOW

1365
01:01:42,965 --> 01:01:45,134
DOSE AND PET SCAN AND MASSIVE WE

1366
01:01:45,201 --> 01:01:49,605
WILL SEE IN LIVER AND RETRO

1367
01:01:49,672 --> 01:01:52,375
PERITY ON EEL LESIONS AND VIDEO

1368
01:01:52,442 --> 01:01:54,010
ON PET SCAN AND WE CAN'T SEE

1369
01:01:54,077 --> 01:01:56,179
THIS IN REAL-TIME AND IT WASN'T

1370
01:01:56,245 --> 01:01:59,148
AN AREA THAT WAS AMENABLE AND

1371
01:01:59,215 --> 01:02:00,383
SEE A THEME THAT WE DON'T KNOW

1372
01:02:00,450 --> 01:02:02,218
WHAT IS GOING ON AND IS COMMON

1373
01:02:02,285 --> 01:02:05,321
IN OUR PATIENTS WE HAVE RESIDUAL

1374
01:02:05,388 --> 01:02:07,423
ACTIVITY ON A PET SCAN ABOUT A

1375
01:02:07,490 --> 01:02:08,991
MONTH AFTER TREATMENT AND

1376
01:02:09,058 --> 01:02:10,460
GRADUALLY ALL GOES AWAY AND

1377
01:02:10,526 --> 01:02:12,361
BECOMES CLEAR TO PATIENTS IN

1378
01:02:12,428 --> 01:02:14,097
COMPLETE REMISSION AND WHAT WE

1379
01:02:14,163 --> 01:02:15,965
SAW HERE AND HOW WE DO IN TERMS

1380
01:02:16,032 --> 01:02:24,073
OF TOXICITY PROFILE AMEEZED WIT

1381
01:02:24,140 --> 01:02:26,142
PROFILE AND PRIOR SINGLE CELL

1382
01:02:26,209 --> 01:02:27,243
EXPERIENCE USING AXY CELL

1383
01:02:27,310 --> 01:02:31,013
CONSTRUCT AND HIGH-GRADE

1384
01:02:31,080 --> 01:02:32,115
NEUROLOGIC TOXICITIES AND ALL

1385
01:02:32,181 --> 01:02:33,182
SIGNIFICANTLY LESS WITH LOW

1386
01:02:33,249 --> 01:02:36,252
NUMBER OF PATIENTS SIGNIFICANTLY

1387
01:02:36,319 --> 01:02:38,154
LESS WITH PHASE 1 TRIAL PRODUCT

1388
01:02:38,221 --> 01:02:40,089
THAT WAS GREAT AND EASY TO USE

1389
01:02:40,156 --> 01:02:43,359
PRODUCT AND CYTOKINE RELEASE

1390
01:02:43,426 --> 01:02:45,628
SYNDROME THAT IS MANAGEABLE AND

1391
01:02:45,695 --> 01:02:47,263
LOW RATES OF NEUROLOGIC TOXICITY

1392
01:02:47,330 --> 01:02:50,266
AND WHY IS THIS?

1393
01:02:50,333 --> 01:02:53,269
EXACTLY WHAT WE AS MOUSE MODELS

1394
01:02:53,336 --> 01:02:56,105
SHOWED AND CYTOKINES AND

1395
01:02:56,172 --> 01:02:58,441
PROTEINS IMPLICATED IN

1396
01:02:58,508 --> 01:03:01,544
NEUROLOGIC TOXICITY ARE LOWER IN

1397
01:03:01,611 --> 01:03:03,579
CAR-T CELLS THAN STANDARD AXY

1398
01:03:03,646 --> 01:03:06,249
CELL CONSTRUCT CAR-T CELLS

1399
01:03:06,315 --> 01:03:09,752
INCLUDING AIL2 AND PLAYERS

1400
01:03:09,819 --> 01:03:12,088
INTERFERON GAMMA KNOWN TO BE

1401
01:03:12,155 --> 01:03:13,923
NEUROLOGIC TOXICITY.

1402
01:03:13,990 --> 01:03:16,792
I WANT TO TALK BRIEFLY ABOUT SAM

1403
01:03:16,859 --> 01:03:18,427
A FELLOW WORKING WITH OUR TEAM

1404
01:03:18,494 --> 01:03:22,331
AND GOING BACK LOOKING AT OUR

1405
01:03:22,398 --> 01:03:25,635
EXPERIENCE TREATING BESHG ET

1406
01:03:25,701 --> 01:03:27,970
LYMPHOMA A RARE NON-HODGE KINES

1407
01:03:28,037 --> 01:03:29,805
LYMPHOMA WITH RAPID PROGRESSIVE

1408
01:03:29,872 --> 01:03:31,407
DISEASE AND REPRESENTED IN

1409
01:03:31,474 --> 01:03:34,544
CLINICAL TRIALS ANTI-C9 CAR-T

1410
01:03:34,610 --> 01:03:36,145
CELLS BECAUSE THEY PROGRESS SO

1411
01:03:36,212 --> 01:03:38,481
QUICKLY THEY CAN'T HANDLE THE

1412
01:03:38,548 --> 01:03:40,483
WAIT TIME FOR CELL PROCESSING IN

1413
01:03:40,550 --> 01:03:42,685
LARGE MULTI-CENTERED TRIALS WITH

1414
01:03:42,752 --> 01:03:44,720
CENTRAL CELL PROCESSING AND WE

1415
01:03:44,787 --> 01:03:46,589
HAD ON CAMPUS CELL PROCESSING

1416
01:03:46,656 --> 01:03:48,257
THAT IS RELATIVELY SHORT WE WERE

1417
01:03:48,324 --> 01:03:51,494
ABLE TO GET THESE PATIENTS IN

1418
01:03:51,561 --> 01:03:53,963
QUICKLY TREATING THEM WITH CAR-T

1419
01:03:54,030 --> 01:03:56,299
CELL THERAPY AND PATIENTS ARE

1420
01:03:56,365 --> 01:03:57,800
CURED IN COMPLETE REMISSION MORE

1421
01:03:57,867 --> 01:04:00,503
THAN FIVE YEARS AND ONE WITH

1422
01:04:00,570 --> 01:04:05,708
RISK OF STANDARD CELL MC63 CAR

1423
01:04:05,775 --> 01:04:07,076
CONSTRUCT AND ONE WITH OUR HUME

1424
01:04:07,143 --> 01:04:08,844
19 CONSTRUCT.

1425
01:04:08,911 --> 01:04:10,279
I WANT TO PIVOT A LITTLE BIT.

1426
01:04:10,346 --> 01:04:12,114
HOW ARE WE DOING ON TIME?  WE

1427
01:04:12,181 --> 01:04:16,118
CAN COVER IT TALKING ABOUT

1428
01:04:16,185 --> 01:04:22,225
EXPERIENCE AT NCI DEVELOPING

1429
01:04:22,291 --> 01:04:24,927
CAR-T CELLS FOR MULTIMYELOMA.

1430
01:04:24,994 --> 01:04:27,296
I WON'T GO THROUGH IT IN DETAIL.

1431
01:04:27,363 --> 01:04:29,932
HE HAD EVERY PRIOR REGIMENT THAT

1432
01:04:29,999 --> 01:04:32,702
WAS AVAILABLE FOR PATIENTS WITH

1433
01:04:32,768 --> 01:04:37,006
MULTIPLE MYELOMA AT THE TIME HE

1434
01:04:37,073 --> 01:04:40,376
ENTERED THE STUDY WE KNEW HE HAD

1435
01:04:40,443 --> 01:04:43,145
TO MANAGE THOSE GOING INTO THE

1436
01:04:43,212 --> 01:04:43,813
TRIAL.

1437
01:04:43,879 --> 01:04:48,117
WHY IS IT A GOOD TARGET?  STANDS

1438
01:04:48,184 --> 01:04:50,119
FOR B-CELL MATURATION ANTIGEN

1439
01:04:50,186 --> 01:04:52,555
AND IN LOW LEVELS MAJORITY OF

1440
01:04:52,622 --> 01:04:59,061
CASES MULTIPLE MYELOMA GREAT

1441
01:04:59,128 --> 01:05:02,031
CAR-T CELL ANTIGEN MILOMA AND

1442
01:05:02,098 --> 01:05:03,666
B-CELLS ARE EXPENDABLE AND CAR-T

1443
01:05:03,733 --> 01:05:07,336
CELLS DO A GREAT JOB ERADICATING

1444
01:05:07,403 --> 01:05:09,805
THE CELL IN THE BODY YOU WILL BE

1445
01:05:09,872 --> 01:05:12,575
OKAY YOU ARE IMMUNOCOMPROMISED

1446
01:05:12,642 --> 01:05:14,844
BUT PATIENTS CAN LIVE WITH THAT

1447
01:05:14,910 --> 01:05:17,580
LEVEL OF IMMUNOCOMPROMISED.  NOT

1448
01:05:17,647 --> 01:05:20,016
TISSUES THAT WE VITALLY NEED AND

1449
01:05:20,082 --> 01:05:24,186
MULTIPLE MYELOMA IS A TERRIBLE

1450
01:05:24,253 --> 01:05:25,421
MALIGNANCY CAUSING LESIONS IN

1451
01:05:25,488 --> 01:05:28,591
THE BONE CREATING BONY PAIN FOR

1452
01:05:28,658 --> 01:05:30,359
PATIENTS CAUSING ANEMIA AND

1453
01:05:30,426 --> 01:05:31,927
RENAL FAILURE AND ALL IS

1454
01:05:31,994 --> 01:05:33,763
RECOGNIZED FAIRLY LATE IN THE

1455
01:05:33,829 --> 01:05:36,399
DISEASE COURSE AND PATIENTS NO

1456
01:05:36,465 --> 01:05:39,235
ONE KNOWS WHY THEY ARE ANEMIC

1457
01:05:39,302 --> 01:05:41,504
AND GIVE IRON AND YEARS LATER

1458
01:05:41,570 --> 01:05:43,906
FIND OUT THEY HAVE MULTIPLE

1459
01:05:43,973 --> 01:05:47,310
MYELOMA THAT IS INCURABLE.

1460
01:05:47,376 --> 01:05:51,213
SO, THE LAB DEVELOPED THE FIRST

1461
01:05:51,280 --> 01:05:52,915
ANTI-B-CELL CAR CLINICAL RESULTS

1462
01:05:52,982 --> 01:05:55,618
PUBLISHING CANCER RESEARCH IN

1463
01:05:55,685 --> 01:06:00,956
2013 AND AS I ARRIVED AT NCI FOR

1464
01:06:01,023 --> 01:06:02,325
FELLOWSHIP AND MI VERY GOOD

1465
01:06:02,391 --> 01:06:04,026
COLLEAGUE A COUPLE YEARS AHEAD

1466
01:06:04,093 --> 01:06:06,128
OF ME IN FELLOWSHIP STARTED ON

1467
01:06:06,195 --> 01:06:08,898
THE GROUND WITH FIRST PHASE 1

1468
01:06:08,964 --> 01:06:11,434
TRIAL EVER OF CAR-T CELLS

1469
01:06:11,500 --> 01:06:14,937
MULTIPLE MYELOMA STARTING IN

1470
01:06:15,004 --> 01:06:17,273
2014 AND HE AND GYM AND GROUP

1471
01:06:17,340 --> 01:06:19,208
PUBLISHED FIRST REPORT OF FIRST

1472
01:06:19,275 --> 01:06:22,044
TWO PATIENTS WITH IMPRESSIVE

1473
01:06:22,111 --> 01:06:23,913
REMISSIONS IN BLOOD AND 24

1474
01:06:23,979 --> 01:06:25,548
PATIENTS WORK HEAVILY AND EVERY

1475
01:06:25,614 --> 01:06:27,516
LINE OF PRIOR THERAPY THAT WAS

1476
01:06:27,583 --> 01:06:29,318
AVAILABLE AND PATIENTS HAD

1477
01:06:29,385 --> 01:06:31,721
REALLY IMPRESSIVE MINIMAL

1478
01:06:31,787 --> 01:06:35,658
DISEASE NEGATIVE REMISSIONS AND

1479
01:06:35,725 --> 01:06:37,860
I FOLLOWED PATIENTS CREATING

1480
01:06:37,927 --> 01:06:40,262
MORE AT EFFECTIVE DOSE LEVEL AND

1481
01:06:40,329 --> 01:06:44,800
FINDING OVERALL RESPONSE RATE OF

1482
01:06:44,867 --> 01:06:49,138
63% BEING GOOD PARTIAL AND

1483
01:06:49,205 --> 01:06:52,174
COMPLETE REMISSION AND BONE

1484
01:06:52,241 --> 01:06:54,510
MARROW WAS CLEAR IN MULTIPLE

1485
01:06:54,577 --> 01:06:57,880
MYELOMA AND MARKERS GO DOWN AND

1486
01:06:57,947 --> 01:07:00,516
LIKE EVERY MYELOMA THERAPY

1487
01:07:00,583 --> 01:07:02,785
EVERYONE RELAPSED AND EVENT FOR

1488
01:07:02,852 --> 01:07:05,020
SURVIVAL IS 31 WEEKS SEVERAL

1489
01:07:05,087 --> 01:07:07,189
MONTHS OFF THERAPY THAT PATIENTS

1490
01:07:07,256 --> 01:07:10,760
HAD AMAZING QUALITY OF LIFE

1491
01:07:10,826 --> 01:07:14,530
AFTER SINGLE INFUSION OF CAR-T

1492
01:07:14,597 --> 01:07:17,600
CELLS AND LEARNING CURVE

1493
01:07:17,666 --> 01:07:20,202
MANAGING TOXICITY AND MR. B

1494
01:07:20,269 --> 01:07:24,573
RECEIVED ICU CARE AND DELIRIUM

1495
01:07:24,640 --> 01:07:28,411
THAT IS LOW-GRADE NEUROLOGIC

1496
01:07:28,477 --> 01:07:32,415
TOXICITY AND IL-6 RECEPTOR

1497
01:07:32,481 --> 01:07:34,717
ANTAGONIST AND STRESS REDUCED

1498
01:07:34,784 --> 01:07:36,719
STEROIDS AND MINIMAL RESIDUALS

1499
01:07:36,786 --> 01:07:39,155
OF NEGATIVE REMISSION LASTING 66

1500
01:07:39,221 --> 01:07:41,257
WEEKS AND AT RELAPSE HAD

1501
01:07:41,323 --> 01:07:43,292
[INDISCERNIBLE] A BC NEGATIVE

1502
01:07:43,359 --> 01:07:45,795
POPULATION AND YOU SEE FLOW AND

1503
01:07:45,861 --> 01:07:49,231
PRE-TREATMENT VERY HIGH BCMA

1504
01:07:49,298 --> 01:07:51,500
LEVELS OF MAZ MA CELL POPULATION

1505
01:07:51,567 --> 01:07:53,903
AND DEFINITELY PROPORTION OF

1506
01:07:53,969 --> 01:07:57,239
CELLS ARE NEGATIVE AND RELAPSE.

1507
01:07:57,306 --> 01:07:59,375
SO, I WILL GO THROUGH THIS

1508
01:07:59,442 --> 01:08:01,177
BRIEFLY SO WE HAVE TIME FOR

1509
01:08:01,243 --> 01:08:04,146
QUESTIONS AND FIRST COMMERCIALLY

1510
01:08:04,213 --> 01:08:07,983
AVAILABLE MADE B-CELL CAR-T CELL

1511
01:08:08,050 --> 01:08:11,821
THERAPY IS SDERM AND NICE SHORT

1512
01:08:11,887 --> 01:08:14,857
NICKNAME AND CONSTRUCT IS

1513
01:08:14,924 --> 01:08:16,392
DEVELOPED COLLABORATION WITH

1514
01:08:16,459 --> 01:08:19,061
BLUE BIOAND FIRST CENTER TO

1515
01:08:19,128 --> 01:08:22,398
ENROLL PATIENTS TREATED A

1516
01:08:22,465 --> 01:08:24,300
HANDFUL OF PATIENTS ON TRIAL

1517
01:08:24,366 --> 01:08:26,602
THAT IS EXCITING AND THEME THAT

1518
01:08:26,669 --> 01:08:29,305
IS HEAVILY PRETREATED PATIENTS

1519
01:08:29,371 --> 01:08:32,475
AND NICE OVERALL RESPONSERATE OF

1520
01:08:32,541 --> 01:08:35,678
88 TO 5% AND LESS THAN A YEAR IN

1521
01:08:35,744 --> 01:08:38,781
TERMS OF MEDIAN PROGRESSION FREE

1522
01:08:38,848 --> 01:08:41,851
SURVIVAL AND THERAPY AND DISEASE

1523
01:08:41,917 --> 01:08:43,285
THAT PASHIENTS ARE KNOWN TO

1524
01:08:43,352 --> 01:08:46,021
BEING TREATED AND GETTING

1525
01:08:46,088 --> 01:08:48,123
TREATMENT AND VERY FEW BREAKS

1526
01:08:48,190 --> 01:08:49,725
AND HAVING A YEAR OFF THERAPY

1527
01:08:49,792 --> 01:08:52,661
WAS AMAZING FOR PATIENTS SEEING

1528
01:08:52,728 --> 01:08:54,630
DAUGHTER GET MARRIED AND

1529
01:08:54,697 --> 01:08:56,065
GRANDCHILDREN BORN AND THIS

1530
01:08:56,131 --> 01:08:57,833
PRODUCT HAD A MANAGEABLE

1531
01:08:57,900 --> 01:09:00,803
TOXICITY PROFILE WITH 6% MORE

1532
01:09:00,870 --> 01:09:03,839
SEVERE CYTOKINE RELEASE

1533
01:09:03,906 --> 01:09:04,406
SYNDROME.

1534
01:09:04,473 --> 01:09:06,208
SO, DIFFERENT LAB WENT BACK AND

1535
01:09:06,275 --> 01:09:08,811
WHAT IS VERSION 2.0 OF THIS CELL

1536
01:09:08,878 --> 01:09:12,815
AND MAKING ANTI-BCMA CAR-T CELLS

1537
01:09:12,882 --> 01:09:14,583
BETTER AND WORKING HARD ON THIS

1538
01:09:14,650 --> 01:09:16,819
CONSTRUCT THAT YOU CAN SEE HERE

1539
01:09:16,886 --> 01:09:17,920
IS HEAVY SHADE ONLY.

1540
01:09:17,987 --> 01:09:22,458
NO LINKER MAKING POTENTIAL

1541
01:09:22,525 --> 01:09:24,827
IMMUNE RESPONSES AND SINGLE

1542
01:09:24,894 --> 01:09:27,997
CHAIN FV ARE DECREASED AND ONLY

1543
01:09:28,063 --> 01:09:29,665
AND FULLY HUMAN THAT IS VERY

1544
01:09:29,732 --> 01:09:32,034
SMALL AND HELPFUL.  IN THE

1545
01:09:32,101 --> 01:09:35,037
FUTURE OF CAR-T CELL WORLD WE

1546
01:09:35,104 --> 01:09:36,438
THINK PERHAPS WE CAN PACK MORE

1547
01:09:36,505 --> 01:09:38,974
CARS TO A SINGLE VECTOR AND

1548
01:09:39,041 --> 01:09:39,909
LIMITED ROOM OF COURSE AND

1549
01:09:39,975 --> 01:09:41,677
SMALLER COULD BE BETTER FOR

1550
01:09:41,744 --> 01:09:43,345
COMBINED THERAPY IN THE FUTURE

1551
01:09:43,412 --> 01:09:44,947
AND UNDERSTAND IT IS FULLY HUMAN

1552
01:09:45,014 --> 01:09:49,218
WITH IDEA WE COULD ELIMINATE

1553
01:09:49,285 --> 01:09:50,586
MASS IMMUNE RESPONSES AND FELLOW

1554
01:09:50,653 --> 01:09:53,355
WITH OUR GROUP THAT IS NOW

1555
01:09:53,422 --> 01:09:55,324
FACULTY AT STANFORD AND HITTING

1556
01:09:55,391 --> 01:09:57,359
UP PHASE 1 TRIAL AND BEAUTIFUL

1557
01:09:57,426 --> 01:10:00,062
OVERALL RESPONSE RATE OF 92%

1558
01:10:00,129 --> 01:10:02,631
WITH NICE MAJORITY OF PATIENTS

1559
01:10:02,698 --> 01:10:05,801
WITH CR AND VGPR AND 65 WEEKS

1560
01:10:05,868 --> 01:10:07,903
AND GETTING PATIENTS HERE BEYOND

1561
01:10:07,970 --> 01:10:10,673
A YEAR AND CS AND NEUROLOGIC

1562
01:10:10,739 --> 01:10:13,475
TOXICITY AND NUMBERS ARE BIG AND

1563
01:10:13,542 --> 01:10:14,610
IMPRESSED HOW MANAGEABLE AND

1564
01:10:14,677 --> 01:10:19,281
EASY PATIENTS ARE AND SHORT ICU

1565
01:10:19,348 --> 01:10:29,525
STAYS --

1566
01:10:32,828 --> 01:10:35,064
WE DID NOT SEE ANY OF THAT ON

1567
01:10:35,130 --> 01:10:35,965
THE TRIAL.

1568
01:10:36,031 --> 01:10:38,667
IT WAS A RELIEF AND VERY

1569
01:10:38,734 --> 01:10:41,670
REASSURING AND SAW

1570
01:10:41,737 --> 01:10:42,237
IMMUNORESPONSES THAT IS

1571
01:10:42,304 --> 01:10:43,806
SOMETHING THAT LAB IS LOOKING

1572
01:10:43,872 --> 01:10:48,911
INTO AND HOW WE CAN MAKE THIS

1573
01:10:48,978 --> 01:10:51,580
LESS IMMUNOGENIC THAT IS UP FOR

1574
01:10:51,647 --> 01:10:53,115
GRABS AT THIS POINT.

1575
01:10:53,182 --> 01:10:55,884
WHAT IS NEXT?  TARGETING THINGS

1576
01:10:55,951 --> 01:10:59,588
WE ARE DOING ON LONG NEXT LIST

1577
01:10:59,655 --> 01:11:04,793
AND TRIAL FOR SPECIFIC --

1578
01:11:04,860 --> 01:11:10,065
EXPRESSED ON B-CELLS AND I'M

1579
01:11:10,132 --> 01:11:13,135
HEARTENED BY NUMBER OF NOVEL

1580
01:11:13,202 --> 01:11:14,937
ANTIGENS WORKING AND KATIE THAT

1581
01:11:15,004 --> 01:11:19,241
I TOLD YOU EARLIER IS WORKING ON

1582
01:11:19,308 --> 01:11:23,412
THE LAB FOR T-CELL THERAPY AND

1583
01:11:23,479 --> 01:11:25,547
GAINING EXCITING RESULTS AND I

1584
01:11:25,614 --> 01:11:27,282
WON'T GET INTO THIS AND NOT

1585
01:11:27,349 --> 01:11:28,951
READY FOR PRIME TIME AND HAVE

1586
01:11:29,018 --> 01:11:31,754
POTENTIAL BENEFITS AND UPCOMING

1587
01:11:31,820 --> 01:11:34,523
TRIAL AND CONSTRUCT 19 CAR

1588
01:11:34,590 --> 01:11:37,126
T-CELLS CULTURE PROCESS THAT IS

1589
01:11:37,192 --> 01:11:40,462
DEVELOPING LVPI IN THE SPRING

1590
01:11:40,529 --> 01:11:44,099
AND JIM FOR AMAZING MENTORSHIP

1591
01:11:44,166 --> 01:11:45,334
AND SURGERY BRANCH AMAZING PLACE

1592
01:11:45,401 --> 01:11:47,169
TO WORK AND PROCESSING

1593
01:11:47,236 --> 01:11:48,337
DEPARTMENT TRANSFUSION OF

1594
01:11:48,404 --> 01:11:49,872
MEDICINE COULDN'T BE BETTER AND

1595
01:11:49,938 --> 01:11:53,475
HAVE AMAZING PATHOLOGISTS AS

1596
01:11:53,542 --> 01:11:58,414
WELL WORKING WITH FLOW CYTOMETRY

1597
01:11:58,480 --> 01:11:59,882
AND [INDISCERNIBLE].

1598
01:11:59,948 --> 01:12:03,419
THANK YOU FOR YOUR TIME.  I

1599
01:12:03,485 --> 01:12:10,693
REALLY APPRECIATE IT.

1600
01:12:10,759 --> 01:12:12,227
>> SO YOU TALKED ABOUT

1601
01:12:12,294 --> 01:12:13,896
[INDISCERNIBLE].  ARE THEY

1602
01:12:13,962 --> 01:12:15,364
SUSTAINED OR BRIEF AFTER.

1603
01:12:15,431 --> 01:12:19,168
>> YEAH.  THEY ARE CONSIDERED

1604
01:12:19,234 --> 01:12:20,302
REVERSIBLE.  THEY ARE ALMOST

1605
01:12:20,369 --> 01:12:21,904
ALWAYS REVERSIBLE IF YOU DON'T

1606
01:12:21,970 --> 01:12:24,440
HAVE ACUTE MORTALITY THAT IS NOW

1607
01:12:24,506 --> 01:12:27,342
REPORTED COMMERCIAL PRODUCTS

1608
01:12:27,409 --> 01:12:30,245
VARY INFREQUENT AND GETTING

1609
01:12:30,312 --> 01:12:31,980
PATIENT LAW IS REVERSIBLE IN

1610
01:12:32,047 --> 01:12:34,316
MOST CASES AND REPORTS HERE AND

1611
01:12:34,383 --> 01:12:36,051
THERE OF PATIENTS THAT ARE WEEKS

1612
01:12:36,118 --> 01:12:38,687
IN AND HAVING MAYBE PROLONGED

1613
01:12:38,754 --> 01:12:42,291
COGNITIVE DEFECTS AND DIE FROM

1614
01:12:42,357 --> 01:12:44,593
MALIGNANCY AND YOU ARE NOT

1615
01:12:44,660 --> 01:12:46,328
HEARING SO MUCH OF PATIENTS THAT

1616
01:12:46,395 --> 01:12:48,864
ARE CURED AND NOT KNOWN TO WHAT

1617
01:12:48,931 --> 01:12:50,833
EXTENT THERE IS A VERY, VERY

1618
01:12:50,899 --> 01:12:54,536
SMALL MINORITY OF PATIENTS WITH

1619
01:12:54,603 --> 01:12:57,539
LONG-TERM TOXICITIES AND

1620
01:12:57,606 --> 01:12:59,675
ANTI-BCMA CAR-T CELLS AND

1621
01:12:59,742 --> 01:13:02,845
DELAYED AFTER WEEKS OF CAR-T

1622
01:13:02,911 --> 01:13:04,713
CELL INFUSION.

1623
01:13:04,780 --> 01:13:07,116
>> HOW IS THIS ESCAPING?

1624
01:13:07,182 --> 01:13:09,251
>> YEAH.  LOTS OF PEOPLE NOT SO

1625
01:13:09,318 --> 01:13:11,086
MUCH OUR LAB BUT LOTS OF PEOPLE

1626
01:13:11,153 --> 01:13:13,255
PUBLISHED ON THIS AND MULTIPLE

1627
01:13:13,322 --> 01:13:15,691
MOLECULAR MECHANISMS BY WHICH

1628
01:13:15,758 --> 01:13:18,127
CAR ITSELF COULD BE

1629
01:13:18,193 --> 01:13:20,562
DOWNREGULATED OR I SHOULD SAY 20

1630
01:13:20,629 --> 01:13:22,297
[INDISCERNIBLE] ITSELF AND FOR

1631
01:13:22,364 --> 01:13:24,767
SURE AND TARGETS COULD BE

1632
01:13:24,833 --> 01:13:26,969
DOWNREGULATED AND ARE MULTIPLE

1633
01:13:27,035 --> 01:13:29,505
ESPECIALLY FOR C19 PRETTY WELL

1634
01:13:29,571 --> 01:13:31,607
DESCRIBED AND MULTIPLE GENETIC

1635
01:13:31,673 --> 01:13:34,143
CHANGES TO THE RECEPTOR TO

1636
01:13:34,209 --> 01:13:37,246
ANTIGEN TARGET I WOULD SAY THAT

1637
01:13:37,312 --> 01:13:38,514
STILL EXIST AND CAN'T COME IN

1638
01:13:38,580 --> 01:13:40,849
AND RECOGNIZE IT ESSENTIALLY.

1639
01:13:40,916 --> 01:13:42,551
>> SECOND CAR CD19.

1640
01:13:42,618 --> 01:13:43,952
>> EXACTLY.  RIGHT.

1641
01:13:44,019 --> 01:13:47,556
>> CHALLENGES TO THAT OR

1642
01:13:47,623 --> 01:13:47,990
STRAIGHTFORWARD?

1643
01:13:48,056 --> 01:13:49,158
>> GREAT QUESTION.

1644
01:13:49,224 --> 01:13:51,193
MULTIPLE MODELS AND SAYING MY

1645
01:13:51,260 --> 01:13:53,395
PATIENT ESCAPED AND WILL TARGET

1646
01:13:53,462 --> 01:13:56,198
AND EXPRESSING CD20 AND WILL

1647
01:13:56,265 --> 01:13:58,467
GIVE THEM THAT CAR AND GROUPS IN

1648
01:13:58,534 --> 01:14:00,202
CHINA HAVE DONE THAT A LOT AND

1649
01:14:00,269 --> 01:14:02,204
GOOD RESULTS I WILL SAY AND WHAT

1650
01:14:02,271 --> 01:14:05,307
SEEMS TO BE THE THEME IS WHEN

1651
01:14:05,374 --> 01:14:09,077
YOU COME IN AND CD19 IS

1652
01:14:09,144 --> 01:14:11,647
SUCCESSFUL AND VERY

1653
01:14:11,713 --> 01:14:13,315
SERENDIPITOUS AND ANTIGEN AND

1654
01:14:13,382 --> 01:14:16,618
GREAT TARGET ANTIGEN AND CASE OF

1655
01:14:16,685 --> 01:14:19,788
ALL AND CD20 AND PATIENTS

1656
01:14:19,855 --> 01:14:21,089
REMISSIONS DOESN'T SEEM LIKE A

1657
01:14:21,156 --> 01:14:23,792
TAIL OF CURE IS QUITE AS GOOD.

1658
01:14:23,859 --> 01:14:26,595
I THINK THAT IS NOT VERY WELL

1659
01:14:26,662 --> 01:14:26,895
UNDERSTOOD.

1660
01:14:26,962 --> 01:14:29,665
JIM THINKS THAT WELL YOU WEREN'T

1661
01:14:29,731 --> 01:14:34,336
HERE WITH CAR-T CELLS MALIGNANCY

1662
01:14:34,403 --> 01:14:36,872
IS WITH CAR-T CELLS ANTIGEN IS

1663
01:14:36,939 --> 01:14:38,740
BAD NECESSARILY AND HARD TO BE A

1664
01:14:38,807 --> 01:14:42,311
WAY FOR MALIGNANCY TO CURE YOU

1665
01:14:42,377 --> 01:14:44,279
AND EXPENSIVE FOR MULTIPLE

1666
01:14:44,346 --> 01:14:46,648
VECTORS AND PRODUCTS IN A KIND

1667
01:14:46,715 --> 01:14:48,917
OF INDUSTRY LEVEL AND WHY SO

1668
01:14:48,984 --> 01:14:50,752
MUCH INTEREST AND CAN WE PACK A

1669
01:14:50,819 --> 01:14:53,155
COUPLE OR THREE CARS INTO A

1670
01:14:53,222 --> 01:14:55,224
VECTOR AND HAVE A CELL EXPRESS

1671
01:14:55,290 --> 01:14:59,228
THOUSANDS OF ANTI-CD20 AND CD19

1672
01:14:59,294 --> 01:15:01,129
AND WILL IT BE EFFECTIVE AND

1673
01:15:01,196 --> 01:15:02,998
RESULTS ARE EARLY AND PATIENTS

1674
01:15:03,065 --> 01:15:04,867
CAN GO INTO REMISSION AND WILL

1675
01:15:04,933 --> 01:15:07,302
IT BE DURABLE AND BETTER OR LESS

1676
01:15:07,369 --> 01:15:08,604
TOXIC?

1677
01:15:08,670 --> 01:15:11,240
WE STILL DON'T KNOW ALL THAT.

1678
01:15:11,306 --> 01:15:12,074
>> OKAY.

1679
01:15:12,140 --> 01:15:14,810
>> YEAH.  SORRY.

1680
01:15:14,877 --> 01:15:15,777
>> HI.

1681
01:15:15,844 --> 01:15:18,146
>> GREAT TALK.  WE UNDERSTAND

1682
01:15:18,213 --> 01:15:20,616
CONSTRUCT OF THE CAR IS CRUCIAL

1683
01:15:20,682 --> 01:15:21,917
FOR SUCCESS OF THE GENE THERAPY

1684
01:15:21,984 --> 01:15:24,453
AND WHAT ABOUT THE VECTORS AND

1685
01:15:24,519 --> 01:15:26,622
DO THE VECTORS HAVE DOWNSTREAM

1686
01:15:26,688 --> 01:15:29,858
EFFECTS ON IT AND DO THEY CAUSE

1687
01:15:29,925 --> 01:15:31,693
INSERTION OF MUTOGENESIS?

1688
01:15:31,760 --> 01:15:33,962
>> YEAH.  SEEMS VERY, VERY

1689
01:15:34,029 --> 01:15:37,666
LITTLE THAT IT IS EXTREMELY,

1690
01:15:37,733 --> 01:15:39,334
EXTREMELY, EXTREMELY RARE.

1691
01:15:39,401 --> 01:15:42,271
>> CASE REPORTS AND RECENT ONE

1692
01:15:42,337 --> 01:15:46,208
USING TRANSPOISON SYSTEM AND

1693
01:15:46,275 --> 01:15:48,377
UNRELATED T-CELL LYMPHOMA THAT

1694
01:15:48,443 --> 01:15:51,079
IS A LITTLE MYSTERIOUS AND

1695
01:15:51,146 --> 01:15:53,248
DIFFERENT SYSTEM.

1696
01:15:53,315 --> 01:15:55,317
VECTORS SEEM TO BE VERY, VERY

1697
01:15:55,384 --> 01:15:56,652
SAFE AND TO THE EXTENT THAT

1698
01:15:56,718 --> 01:16:01,423
THERE IS A CASE REPORT BY PENN

1699
01:16:01,490 --> 01:16:04,226
ACTUALLY INSERTABLE MUTOGENESIS

1700
01:16:04,293 --> 01:16:05,961
IN TAP 2 GENE AND MIGHT BE BACK

1701
01:16:06,028 --> 01:16:10,465
IN 2018 AND CAR T-CELLS

1702
01:16:10,532 --> 01:16:12,968
DEFINITELY CHANGED CAR-T CELLS

1703
01:16:13,035 --> 01:16:14,136
AND ENDED UP BEING VERY

1704
01:16:14,202 --> 01:16:16,805
EFFECTIVE AND KILLING OFF THE

1705
01:16:16,872 --> 01:16:17,906
MALIGNANCY AND EVERYTHING THAT

1706
01:16:17,973 --> 01:16:21,043
IS WONDERFUL AND SHOWS THAT KIND

1707
01:16:21,109 --> 01:16:23,278
OF THING IS POSSIBLE, YES.

1708
01:16:23,345 --> 01:16:23,979
>> OKAY.

1709
01:16:24,046 --> 01:16:25,948
>> HOW ABOUT THE SUSTAINABILITY

1710
01:16:26,014 --> 01:16:29,251
OF THE EXPRESSION OF THE CAR?

1711
01:16:29,318 --> 01:16:32,654
DO YOU LOOK LONGITUDINALLY IN

1712
01:16:32,721 --> 01:16:33,622
PATIENTS SEEING IF LEVEL OF

1713
01:16:33,689 --> 01:16:35,991
EXPRESSION IS MAINTAINED?

1714
01:16:36,058 --> 01:16:38,760
>> SOMETIMES IT GOES DOWN, THE

1715
01:16:38,827 --> 01:16:39,194
CAR EXPRESSION IS.

1716
01:16:39,261 --> 01:16:42,130
>> DOES IT HAVE TO BE RELATED TO

1717
01:16:42,197 --> 01:16:42,564
INTEGRATION SITE?

1718
01:16:42,631 --> 01:16:43,398
>> I DON'T.

1719
01:16:43,465 --> 01:16:44,733
>> IS THAT STUDIED?

1720
01:16:44,800 --> 01:16:46,768
>> I DON'T KNOW.  IT DOESN'T

1721
01:16:46,835 --> 01:16:48,270
MEAN IT HASN'T BEEN STUDIED.

1722
01:16:48,337 --> 01:16:50,772
I HAVE TO LOOK FOR YOU AND THE

1723
01:16:50,839 --> 01:16:51,106
QUESTION.

1724
01:16:51,173 --> 01:16:52,174
>> INTEGRATE.

1725
01:16:52,240 --> 01:16:52,908
>> RIGHT.  RIGHT.

1726
01:16:52,975 --> 01:16:53,275
>> YEAH.

1727
01:16:53,342 --> 01:16:55,811
>> I DON'T KNOW.  I HAVE TO LOOK

1728
01:16:55,877 --> 01:16:56,645
IT UP HERE.

1729
01:16:56,712 --> 01:16:57,479
>> DELETIONS WITHIN --

1730
01:16:57,546 --> 01:17:01,249
>> I SEE WHAT YOU ARE SAYING.

1731
01:17:01,316 --> 01:17:03,352
>> HASN'T BEEN DONE, I DON'T

1732
01:17:03,418 --> 01:17:03,552
KNOW.

1733
01:17:03,618 --> 01:17:07,289
>> MIGHT HAVE BEEN.  I HAVE TO

1734
01:17:07,356 --> 01:17:07,990
LOOK.  YEAH.

1735
01:17:08,056 --> 01:17:10,525
>> HAVE YOU LOOKED AT

1736
01:17:10,592 --> 01:17:12,561
DISTRIBUTION AND BEFORE YOU PUT

1737
01:17:12,627 --> 01:17:14,563
IT INTO THE PATIENT AND TIMES

1738
01:17:14,629 --> 01:17:17,632
DOWN THE LINE AND CD ONES ARE

1739
01:17:17,699 --> 01:17:18,233
EXPANDING AND.

1740
01:17:18,300 --> 01:17:21,003
>> WE HAVE IT.  PEOPLE HAVE,

1741
01:17:21,069 --> 01:17:21,269
YEAH.

1742
01:17:21,336 --> 01:17:23,372
PEOPLE HAVE.  I JUST HAVE TO

1743
01:17:23,438 --> 01:17:25,674
LOOK AND I CAN'T HAVE A GREAT --

1744
01:17:25,741 --> 01:17:26,475
GO AHEAD.

1745
01:17:26,541 --> 01:17:29,111
>> HOW LOW OF AN ANTIGEN LEVEL

1746
01:17:29,177 --> 01:17:31,947
ON THE SURFACE DO YOU THINK?

1747
01:17:32,014 --> 01:17:33,448
CD19 AND HIGHER AND YOU KNOW YOU

1748
01:17:33,515 --> 01:17:34,416
HAVE NEGATIVES.

1749
01:17:34,483 --> 01:17:37,085
WHAT DO YOU THINK IS THE LIMIT?

1750
01:17:37,152 --> 01:17:40,522
>> VERY GOOD QUESTION AND

1751
01:17:40,589 --> 01:17:43,925
PRODUCT AND CONSTRUCT DEPENDENT

1752
01:17:43,992 --> 01:17:46,395
AND CONSTRUCTS WITH DIFFERENT

1753
01:17:46,461 --> 01:17:48,563
THRESHOLDS AND BC MAY CELLS FOR

1754
01:17:48,630 --> 01:17:50,365
INSTANCE AND PRODUCTS WE

1755
01:17:50,432 --> 01:17:53,168
DEVELOPED AND PART OF IT

1756
01:17:53,235 --> 01:17:55,437
HONESTLY IS DETECTION METHODS

1757
01:17:55,504 --> 01:17:57,839
AND YOU HAVE TO GET USED TO

1758
01:17:57,906 --> 01:18:00,175
CHEMISTRY AND FLOW CYTOMETRY AND

1759
01:18:00,242 --> 01:18:02,744
PCR IF YOU SET IT UP THAT WAY

1760
01:18:02,811 --> 01:18:05,280
AND BCMA EXPRESSION COULD BE

1761
01:18:05,347 --> 01:18:06,081
QUITE LOW.

1762
01:18:06,148 --> 01:18:10,752
IF UNIFORM, SOME CONSTRUCTS ARE

1763
01:18:10,819 --> 01:18:13,989
GOOD AND T-CELLS CAN GO AFTER

1764
01:18:14,056 --> 01:18:15,891
AND T-CELLS ARE RELATIVELY -- IN

1765
01:18:15,957 --> 01:18:18,493
THE LITERATURE, I SEE THERE IS

1766
01:18:18,560 --> 01:18:19,728
VARIATION IN WHAT YOUR CAR

1767
01:18:19,795 --> 01:18:23,231
CONSTRUCT CAN PICK UP AND WHAT

1768
01:18:23,298 --> 01:18:24,966
ANTIGEN DENSITY.

1769
01:18:25,033 --> 01:18:25,333
>> YES?

1770
01:18:25,400 --> 01:18:31,173
>> OKAY.  SO, FOR PATIENTS

1771
01:18:31,239 --> 01:18:33,108
PREVIOUSLY [INDISCERNIBLE].

1772
01:18:33,175 --> 01:18:34,242
COULD YOU USE [INDISCERNIBLE]?

1773
01:18:34,309 --> 01:18:35,610
>> GREAT QUESTION.  YEAH.  THIS

1774
01:18:35,677 --> 01:18:38,447
IS MOSTLY -- IT IS MOSTLY IN THE

1775
01:18:38,513 --> 01:18:40,182
LEUKEMIA LITERATURE THEY ARE

1776
01:18:40,248 --> 01:18:41,216
LOOKING AND THEY HAVE

1777
01:18:41,283 --> 01:18:42,484
[INDISCERNIBLE] WHICH IS -- AND

1778
01:18:42,551 --> 01:18:45,720
NOW THERE ARE SOME ANTI-C19

1779
01:18:45,787 --> 01:18:49,257
ANTIBODY THERAPIES IN B-CELL

1780
01:18:49,324 --> 01:18:51,393
NON-HODGE KINES LYMPHOMA AS

1781
01:18:51,460 --> 01:18:51,660
WELL.

1782
01:18:51,726 --> 01:18:54,196
SHORT ANSWER IS, YES.  IT CAN

1783
01:18:54,262 --> 01:18:54,729
SOMETIMES WORK.

1784
01:18:54,796 --> 01:18:57,032
THERE HAS BEEN A -- I WILL SAY

1785
01:18:57,099 --> 01:18:59,468
THIS IS A LITTLE VARIETY OF THIS

1786
01:18:59,534 --> 01:19:02,537
IN THE LITERATURE AND ARE

1787
01:19:02,604 --> 01:19:04,539
REPORTS PATIENTS WITH ALL AND

1788
01:19:04,606 --> 01:19:06,341
[INDISCERNIBLE] AND THEY HAVE

1789
01:19:06,408 --> 01:19:09,478
MORE OF THE -- SORRY.

1790
01:19:09,544 --> 01:19:09,744
FEEDBACK.

1791
01:19:09,811 --> 01:19:12,848
THESE CD19S THAT ARE LOW

1792
01:19:12,914 --> 01:19:15,450
EXPRESSING AND CD19 CLONES

1793
01:19:15,517 --> 01:19:19,154
WITHIN THE MALIGNANCY THAT COULD

1794
01:19:19,221 --> 01:19:23,391
MEAN YOUR PATIENT FAIRS POORLY

1795
01:19:23,458 --> 01:19:25,327
TO CAR-T CELLS SOME LEUKEMIA

1796
01:19:25,393 --> 01:19:26,161
PHYSICIANS WANT TO

1797
01:19:26,228 --> 01:19:28,430
[INDISCERNIBLE] AND GET CELLS

1798
01:19:28,497 --> 01:19:31,533
MANUFACTURED TO DO THAT FIRST

1799
01:19:31,600 --> 01:19:35,170
BEFORE THERE HAS FSH BEEN ANY CD

1800
01:19:35,237 --> 01:19:38,907
THERAPY AND THERE IS A LOT TO

1801
01:19:38,974 --> 01:19:39,241
LEARN THERE.

1802
01:19:39,307 --> 01:19:42,878
>> ANYBODY ONLINE?

1803
01:19:42,944 --> 01:19:48,083
ACTUALLY, ONLINE CAN UNMUTE AND

1804
01:19:48,150 --> 01:19:51,987
ASK THE QUESTION DIRECTLY.  CAN

1805
01:19:52,053 --> 01:19:53,522
THEY HEAR ME?

1806
01:19:53,588 --> 01:19:57,025
>> OKAY.  THANK YOU VERY MUCH.

1807
01:19:57,092 --> 01:19:58,560
>> THANK YOU.

1808
01:19:58,627 --> 01:19:59,060
>> [APPLAUSE].

1809
01:19:59,127 --> 01:20:01,396
>> NEXT SPEAKER IS SARAH WHO

1810
01:20:01,463 --> 01:20:05,800
RECEIVED PHD IN VIROLOGY UP IN

1811
01:20:05,867 --> 01:20:09,004
CANADA AND DID POST DOCTORAL

1812
01:20:09,070 --> 01:20:12,140
TRAINING WITH DUFTY MILLER AND

1813
01:20:12,207 --> 01:20:15,277
RECRUITED TO ONTARIO VEGETARIAN

1814
01:20:15,343 --> 01:20:17,445
COLLEGE AND IS A PROFESSOR AND

1815
01:20:17,512 --> 01:20:20,682
RESEARCH FOCUSES ON GENE THERAPY

1816
01:20:20,749 --> 01:20:22,684
AND VIRAL VECTOR VACCINES AND

1817
01:20:22,751 --> 01:20:29,391
VIRAL PATHOGENESIS TITLE OF THE

1818
01:20:29,457 --> 01:20:40,001
TALK AND MONO CLONAL ANTIBODIES

1819
01:20:44,272 --> 01:20:46,808
IS .

1820
01:20:46,875 --> 01:20:49,477
>> THANK YOU.  CAN EVERYONE HEAR

1821
01:20:49,544 --> 01:20:51,346
ME?

1822
01:20:51,413 --> 01:20:52,414
PROTECTIONS AGAINST INFECTIOUS

1823
01:20:52,480 --> 01:20:54,082
DISEASES AND POINTING OUT THIS

1824
01:20:54,149 --> 01:20:56,084
IS A COLLABORATIVE BODY OF WORK

1825
01:20:56,151 --> 01:21:03,091
BETWEEN MY LAB AT UNIVERSITY OF

1826
01:21:03,158 --> 01:21:04,626
GUELTH.

1827
01:21:04,693 --> 01:21:07,162
WE HAVE A LAB IN CANADA AND

1828
01:21:07,229 --> 01:21:08,563
STARTING WITH A BRIEF OVERVIEW

1829
01:21:08,630 --> 01:21:13,501
WHAT WE DO IN OUR LAB WE ARE

1830
01:21:13,568 --> 01:21:19,574
MOLECULAR WITH FOCUS ON MYOGENIC

1831
01:21:19,641 --> 01:21:23,211
DISEASES INFECTIOUS DISEASES AND

1832
01:21:23,278 --> 01:21:28,250
CANCER AND -- WHICH WILL BE

1833
01:21:28,316 --> 01:21:30,819
FOCUS OF MY TALK TODAY AND HAVE

1834
01:21:30,885 --> 01:21:33,255
A PROGRAM FOR LUNG GENE DELIVERY

1835
01:21:33,321 --> 01:21:36,791
FOCUS ON DELIVERING THERAPEUTIC

1836
01:21:36,858 --> 01:21:39,361
GENES AND CYSTIC FIBROSIS AND

1837
01:21:39,427 --> 01:21:44,132
USE A PEROMIXO VIRUS AND VIRAL

1838
01:21:44,199 --> 01:21:46,234
VECTOR VACCINE AND ONCO LYTIC

1839
01:21:46,301 --> 01:21:48,570
VIRUS AND WE HAVE ONE OR TWO

1840
01:21:48,637 --> 01:21:55,410
STUDENTS WORKING ON A POX VIRUS

1841
01:21:55,677 --> 01:21:58,480
SHEEP VIRUS.

1842
01:21:58,546 --> 01:21:59,714
OKAY.

1843
01:21:59,781 --> 01:22:01,549
SO IN CASE MANY ARE FAMILIAR

1844
01:22:01,616 --> 01:22:04,753
WITH AV AND THOUGHT I WOULD GIVE

1845
01:22:04,819 --> 01:22:08,189
A BRIEF INTRODUCTION AND AV IS A

1846
01:22:08,256 --> 01:22:12,294
SMALL AND NAKED DNA VIRUS.

1847
01:22:12,360 --> 01:22:17,899
IT IS IN THE FAMILY PIROVIRADAY.

1848
01:22:17,966 --> 01:22:20,502
IT IS REPLICATION DEFECTIVE

1849
01:22:20,568 --> 01:22:24,306
VIRUS AND DEPENDS ON IT TO

1850
01:22:24,372 --> 01:22:30,812
COMPLETE A LIFE CRYINGLE AND

1851
01:22:30,879 --> 01:22:34,749
OVER 200 -- AND OF COURSE THERE

1852
01:22:34,816 --> 01:22:38,653
ARE A NUMBER OF AVS RECEIVING

1853
01:22:38,720 --> 01:22:43,758
APPROVAL AND FDA WITH RECENT

1854
01:22:43,825 --> 01:22:45,126
BEING [INDISCERNIBLE] AND

1855
01:22:45,193 --> 01:22:49,030
MUSCULAR DISTROPHY AND JEN

1856
01:22:49,097 --> 01:22:50,398
MENTIONED THEY ARE MORE

1857
01:22:50,465 --> 01:22:51,800
EXPENSIVE AND DELIVERING MORE

1858
01:22:51,866 --> 01:22:53,935
VECTOR TO THE PATIENTS IN THIS

1859
01:22:54,002 --> 01:22:56,471
CASE AND NUMEROUS GENE THERAPIES

1860
01:22:56,538 --> 01:22:59,107
WAITING REGULATORY APPROVAL AND

1861
01:22:59,174 --> 01:23:03,378
40% ARE AD AND AD HAS A STRONG

1862
01:23:03,445 --> 01:23:04,979
SAFETY RECORD AND EFFICACY

1863
01:23:05,046 --> 01:23:06,915
RECORD IN CLINICAL TRIALS AND

1864
01:23:06,981 --> 01:23:09,984
TODAY I WILL TALK ABOUT THE

1865
01:23:10,051 --> 01:23:11,786
IMMUNOTHERAPY FOR INFECTIOUS

1866
01:23:11,853 --> 01:23:13,922
DISEASES AND KNOW THAT

1867
01:23:13,988 --> 01:23:15,924
MONOCLONAL ANTIBODY THERAPIES

1868
01:23:15,990 --> 01:23:18,560
ARE AN IMPORTANT TOOL IN OUR

1869
01:23:18,626 --> 01:23:20,862
[INDISCERNIBLE] TO PREVENT

1870
01:23:20,929 --> 01:23:22,564
INFECTIOUS DISEASES AND

1871
01:23:22,630 --> 01:23:25,266
ESPECIALLY FOR VIRUSES WE LACK

1872
01:23:25,333 --> 01:23:27,469
VACCINES AND EFFECTIVE THERAPIES

1873
01:23:27,535 --> 01:23:30,538
AND ISSUES WITH RECOMBINANT

1874
01:23:30,605 --> 01:23:33,475
THERAPY IS IT IS SHORT-LIVED

1875
01:23:33,541 --> 01:23:35,310
REQUIRING REPEAT DOSING AND

1876
01:23:35,377 --> 01:23:37,645
CIRCUMSTANCES ANTIBODIES HAVE TO

1877
01:23:37,712 --> 01:23:39,614
BE DELIVERED SYSTEMICALLY

1878
01:23:39,681 --> 01:23:42,550
PROBLEMATIC IN CASES AND MAPPING

1879
01:23:42,617 --> 01:23:45,487
COCKTAIL DELIVERED INTRAVENOUSLY

1880
01:23:45,553 --> 01:23:48,390
DURING A WEST AFRICA OUTBREAK

1881
01:23:48,456 --> 01:23:51,192
AND FRAGILE AND REQUIRE

1882
01:23:51,259 --> 01:23:51,860
[INDISCERNIBLE] AND DIFFER FROM

1883
01:23:51,926 --> 01:23:55,263
HOST DEPENDING HOW THEY ARE

1884
01:23:55,330 --> 01:23:58,600
PRODUCED SEEING WITH WEST AFRICA

1885
01:23:58,666 --> 01:23:59,734
OUTBREAK DIFFICULT TO SEE THESE

1886
01:23:59,801 --> 01:24:01,803
SCALE OUT AN OUTBREAK AND WE AND

1887
01:24:01,870 --> 01:24:03,405
OTHERS IN THE LAB HAVE EXPLORED

1888
01:24:03,471 --> 01:24:05,673
THIS ALTERNATIVE THAT IS VEKOR

1889
01:24:05,740 --> 01:24:09,978
EXPRESSION ANTIBODIES IN VIVO.

1890
01:24:10,044 --> 01:24:15,150
SO, PETER -- BALTIMORE AND BLAKE

1891
01:24:15,216 --> 01:24:17,786
COINED THE TERM AND AIVVP THAT I

1892
01:24:17,852 --> 01:24:20,989
WILL SAVE FROM HERE ON IN AND

1893
01:24:21,055 --> 01:24:23,024
USE OF GENE DELIVERY VECTOR THAT

1894
01:24:23,091 --> 01:24:27,896
IS AV VECTOR TO EXPRESS BROADLY

1895
01:24:27,962 --> 01:24:31,132
NEUTRALIZING MONOCLONAL -- SO,

1896
01:24:31,199 --> 01:24:33,568
IN A SENSE YOU TURN YOUR HOST

1897
01:24:33,635 --> 01:24:36,638
INTO THE VIRAL REACTOR.

1898
01:24:36,704 --> 01:24:39,541
THIS IN MOST CASES REQUIRES A

1899
01:24:39,607 --> 01:24:41,743
SINGLE INTRAMUSCULAR INJECTION

1900
01:24:41,810 --> 01:24:44,245
AND STUDIES IN LAB SUGGEST

1901
01:24:44,312 --> 01:24:46,948
SPRAYING DOSE OVER MULTIPLE

1902
01:24:47,015 --> 01:24:51,553
DOSES ENHANCES MONOCLONAL

1903
01:24:51,619 --> 01:24:53,521
ANTIBODY PRODUCTION AND

1904
01:24:53,588 --> 01:24:55,290
GLYCOSYLATION PATTERNS MATCH THE

1905
01:24:55,356 --> 01:24:58,693
HOST AND THIS CAN BE USED IN

1906
01:24:58,760 --> 01:24:59,394
IMMUNOCOMPROMISED INDIVIDUALS

1907
01:24:59,461 --> 01:25:00,995
AND WE AND OTHERS HAVE SHOWN

1908
01:25:01,062 --> 01:25:03,598
THIS LEADS TO VERY LONG AND

1909
01:25:03,665 --> 01:25:05,400
SUSTAINED ANTIBODY EXPRESSION IN

1910
01:25:05,467 --> 01:25:08,303
SOME SPECIES FOR THE LIFETIME OF

1911
01:25:08,369 --> 01:25:10,538
THE ANIMAL AND THIS APPROACH WAS

1912
01:25:10,605 --> 01:25:12,640
FIRST INVESTIGATED FOR TREATING

1913
01:25:12,707 --> 01:25:16,945
AND PREVENTING HIV AND ARE TWO

1914
01:25:17,011 --> 01:25:19,714
CL

1915
01:25:19,781 --> 01:25:22,016
CLINICAL TRIALS FOR PREVENTING

1916
01:25:22,083 --> 01:25:24,052
HIV INFECTIONS IN HUMANS AND

1917
01:25:24,118 --> 01:25:26,154
SHORT TIME I HAVE I WILL TRY TO

1918
01:25:26,221 --> 01:25:29,591
GO THROUGH WORK WE HAVE DONE FOR

1919
01:25:29,657 --> 01:25:31,626
VARIETY OF INFECTIOUS DISEASES

1920
01:25:31,693 --> 01:25:35,430
AND RECENTLY WORKING ON

1921
01:25:35,497 --> 01:25:36,798
BACTERIAL INFECTIONS AND GIVING

1922
01:25:36,865 --> 01:25:40,068
A LITTLE INTRODUCTION TO EBOLA

1923
01:25:40,134 --> 01:25:43,805
VIRUS AND NEGATIVE SENSE RNA

1924
01:25:43,872 --> 01:25:47,075
VIRUS IN FAMILY FILO VER ADAY

1925
01:25:47,141 --> 01:25:54,015
AND FOUR CCS OF EBOLA VIRUS AND

1926
01:25:54,082 --> 01:25:54,415
[INDISCERNIBLE].

1927
01:25:54,482 --> 01:25:57,519
THIS IS A ZOONOTIC INFECTION

1928
01:25:57,585 --> 01:25:59,220
TRANSMITTED FROM ANIMALS TO

1929
01:25:59,287 --> 01:26:01,856
HUMANS FROM BATS TO MONKEYS TO

1930
01:26:01,923 --> 01:26:03,858
HUMANS OR BATS DIRECTLY TO

1931
01:26:03,925 --> 01:26:06,694
HUMANS VIRUS ENTERS BODY TO

1932
01:26:06,761 --> 01:26:11,633
EXPOSURE TO CONTAMINATED BLOOD.

1933
01:26:11,699 --> 01:26:13,768
IT HAS A HIGH FATALITY RATE

1934
01:26:13,835 --> 01:26:15,937
BETWEEN 40 TO 90% AND AS MANY

1935
01:26:16,004 --> 01:26:19,107
WILL REMEMBER, WE HAVE LARGEST

1936
01:26:19,173 --> 01:26:22,410
OUTBREAK OF EBOLA VIRUS IN WEST

1937
01:26:22,477 --> 01:26:25,813
AFRICA BETWEEN 2014 AND 2016 AND

1938
01:26:25,880 --> 01:26:29,450
OVER 20,000 CONFIRMED CASES AND

1939
01:26:29,517 --> 01:26:31,286
11,000 DEATHS AND FATALITY RATE

1940
01:26:31,352 --> 01:26:33,655
AND DURING THE OUTBREAK A NUMBER

1941
01:26:33,721 --> 01:26:36,658
OF VACCINES AND THERAPIES WERE

1942
01:26:36,724 --> 01:26:39,694
TESTED AND WE HAVE A LICENSED

1943
01:26:39,761 --> 01:26:42,597
VACCINE RECOMBINANT VIRUS AND

1944
01:26:42,664 --> 01:26:45,333
VACCINE FOR EBOLA THAT ENCODES

1945
01:26:45,400 --> 01:26:47,802
PROTEIN ON THE SURFACE AND

1946
01:26:47,869 --> 01:26:49,203
ANTIBODY THERAPY THAT IS

1947
01:26:49,270 --> 01:26:51,172
PARTIALLY DEVELOPED HERE IS

1948
01:26:51,239 --> 01:26:53,708
APPROVED AND THEN IN SUBSEQUENT

1949
01:26:53,775 --> 01:26:57,178
OUTBREAKS ADDITIONAL MONOCLONAL

1950
01:26:57,245 --> 01:26:58,613
ANTIBODIES RECEIVED APPROVAL.

1951
01:26:58,680 --> 01:27:01,883
WHEN I FIRST STARTED TO WORK ON

1952
01:27:01,950 --> 01:27:03,952
THE VECTOR IMMUNOPROPHYLAXIS IS

1953
01:27:04,018 --> 01:27:06,087
AT THE BEGINNING OF THE WEST

1954
01:27:06,154 --> 01:27:08,022
AFRICA OUTBREAK AND GOING TO LAB

1955
01:27:08,089 --> 01:27:11,225
TO WORK ON ANTIBODIES THAT ARE

1956
01:27:11,292 --> 01:27:13,661
ISOLATED AND ARE MOUSE

1957
01:27:13,728 --> 01:27:15,096
ANTIBODIES STARTING WITH 2G4

1958
01:27:15,163 --> 01:27:18,433
THAT IS COMPONENT OF SAID MAP A

1959
01:27:18,499 --> 01:27:22,537
NEUTRALIZING ANTIBODY EVALUATING

1960
01:27:22,604 --> 01:27:22,737
5D2.

1961
01:27:22,804 --> 01:27:25,039
THESE WERE DERIVED FROM MICE

1962
01:27:25,106 --> 01:27:28,076
THAT WERE VACCINATED WITH THE

1963
01:27:28,142 --> 01:27:29,143
VACCINE.

1964
01:27:29,210 --> 01:27:31,012
SO, WE WERE NOT SURE THAT MICE

1965
01:27:31,079 --> 01:27:33,781
WERE MOUNTED IMMUNE RESPONSE TO

1966
01:27:33,848 --> 01:27:35,984
HUMAN CONSTANT DOMAIN AND

1967
01:27:36,050 --> 01:27:39,287
ENGINEERED AS IG2A ANTIBODIES

1968
01:27:39,354 --> 01:27:42,256
AND USED SAME CONSTRUCT DESIGN

1969
01:27:42,323 --> 01:27:48,262
AS ALEX BLAZE WITH A STRONG

1970
01:27:48,329 --> 01:27:51,332
MUSCLE SPECIFIC MOTOR AND

1971
01:27:51,399 --> 01:27:54,969
CLEAVAGE AND MICHAEL IS CRINGING

1972
01:27:55,036 --> 01:27:58,940
AT RIGHT NOW AND INCLUDING DP AS

1973
01:27:59,007 --> 01:28:01,843
WELL AND ANTIBODIES COULDN'T

1974
01:28:01,909 --> 01:28:03,678
QUANTIFY MOUSE OF AMOUNT OF

1975
01:28:03,745 --> 01:28:06,347
ANTIBODY PRODUCED IN MICE AND

1976
01:28:06,414 --> 01:28:08,616
USING EBOLA PROTILLIZES AND SEE

1977
01:28:08,683 --> 01:28:11,419
IN 7 DAYS WE HAD ANTIBODIES IN

1978
01:28:11,486 --> 01:28:14,522
THE BLOOD AND THEY INCREASE AND

1979
01:28:14,589 --> 01:28:16,791
PLATEAU AND THESE WERE JUST DATA

1980
01:28:16,858 --> 01:28:19,927
TO 125 DAYS AND LONG-TERM GENE

1981
01:28:19,994 --> 01:28:24,065
EXPRESSION AS WELL WE HAVE.

1982
01:28:24,132 --> 01:28:26,701
OKAY.  WE KNEW WE COULD EXPRESS

1983
01:28:26,768 --> 01:28:29,470
ANTIBODIES IN MICE AND MOVE TO

1984
01:28:29,537 --> 01:28:31,039
CHALLENGE STUDIES AND TYPICAL

1985
01:28:31,105 --> 01:28:34,108
REGIMENT IS TO ADMINISTER

1986
01:28:34,175 --> 01:28:37,011
GENOMES OF AV TO THE MUSCLE AND

1987
01:28:37,078 --> 01:28:39,180
28 DAYS LATER WE KNOW WE HAVE

1988
01:28:39,247 --> 01:28:41,215
HIGH LEVELS OF ANTIBODY

1989
01:28:41,282 --> 01:28:43,418
EXPRESSION AND CHALLENGE MICE

1990
01:28:43,484 --> 01:28:45,853
AND CHALLENGED WITH MOUSE

1991
01:28:45,920 --> 01:28:49,791
ADAPTED EBOLA VIRUS PERITONEAL

1992
01:28:49,857 --> 01:28:52,727
CHALLENGE AND THREE ANTIBODIES

1993
01:28:52,794 --> 01:28:54,529
VECTORIZED LED TO CASES COMPLETE

1994
01:28:54,595 --> 01:28:56,164
PROTECTION FROM CHALLENGE AND IN

1995
01:28:56,230 --> 01:28:59,367
CASE 2G4 WE LOST ONE OF THE

1996
01:28:59,434 --> 01:29:01,769
ANIMALS AND GENERALLY HIGH LEVEL

1997
01:29:01,836 --> 01:29:04,172
RATE OF SURVIVAL AND EVALUATING

1998
01:29:04,238 --> 01:29:06,007
THERAPEUTIC WINDOW AND I MEAN IT

1999
01:29:06,074 --> 01:29:08,276
IS 28 DAYS THAT IS IDEAL FROM

2000
01:29:08,342 --> 01:29:09,844
POINT OF VIEW FROM OUR

2001
01:29:09,911 --> 01:29:11,479
EXPERIMENTS THAT WE WANTED TO

2002
01:29:11,546 --> 01:29:14,048
SEE IF WE COULD SHORTEN THE

2003
01:29:14,115 --> 01:29:16,584
THERAPEUTIC WINDOW AND SAME DOSE

2004
01:29:16,651 --> 01:29:20,288
OF 1E11 AND CHALLENGED WITH

2005
01:29:20,354 --> 01:29:23,291
EBOLA VIRUS 2 WEEKS 7 DAYS 1 DAY

2006
01:29:23,357 --> 01:29:24,158
OR CHALLENGED THEM BEFORE WE

2007
01:29:24,225 --> 01:29:26,828
GAVE AV AND SEEING AT 7 DAYS

2008
01:29:26,894 --> 01:29:29,464
AFTER AV WAS ADMINISTERED 100%

2009
01:29:29,530 --> 01:29:31,699
OF MICE WERE PROTECTED REDUCING

2010
01:29:31,766 --> 01:29:35,103
TO THREE DAYS WE HAD 20%

2011
01:29:35,169 --> 01:29:36,037
SURVIVAL RATE AND SOMEWHERE

2012
01:29:36,104 --> 01:29:38,039
BETWEEN 3 AND 7 DAYS FOR

2013
01:29:38,106 --> 01:29:39,907
PARTICULAR ANTIBODIES WOULD BE

2014
01:29:39,974 --> 01:29:45,913
THE THERAPEUTIC WINDOW.

2015
01:29:45,980 --> 01:29:47,415
EVALUATED LONGEVITY OF

2016
01:29:47,482 --> 01:29:49,684
EXPRESSION AND ABILITY FOR

2017
01:29:49,751 --> 01:29:51,619
ANTIBODIES TO PROTECT LONG-TERM

2018
01:29:51,686 --> 01:29:54,522
AND IN CASE MICE RECEIVED TWO

2019
01:29:54,589 --> 01:29:57,625
DIFFERENT AVMABS ONE IN EITHER

2020
01:29:57,692 --> 01:29:59,761
LEG AND LET SIT IN ANIMAL

2021
01:29:59,827 --> 01:30:03,064
FACILITY FOR FIVE MONTHS AND

2022
01:30:03,131 --> 01:30:05,767
SHIPPED TO WINE PEG THAT WERE

2023
01:30:05,833 --> 01:30:07,835
CHALLENGED AND IN TERMS OF LONG

2024
01:30:07,902 --> 01:30:11,539
TERM MONITORING DELIVERING AV

2025
01:30:11,606 --> 01:30:13,307
INTRAMUSCULARLY SHOWN HERE OR

2026
01:30:13,374 --> 01:30:16,511
INTRANASALLY SUSTAINED ANTIBODY

2027
01:30:16,577 --> 01:30:18,780
EXPRESSION AND IN RECENT STUDIES

2028
01:30:18,846 --> 01:30:21,182
EXPRESSED HUMAN ANTIBODIES TO

2029
01:30:21,249 --> 01:30:23,251
QUANTIFY AMOUNT OF ANTIBODY IN

2030
01:30:23,317 --> 01:30:25,887
THE BLOOD AND SEE THAT

2031
01:30:25,953 --> 01:30:27,421
ANTIBODIES WERE EXPRESSED IN

2032
01:30:27,488 --> 01:30:29,223
LIFETIME OF ANIMAL AND NATURAL

2033
01:30:29,290 --> 01:30:33,027
AEBD POINT THEY HAVE 200

2034
01:30:33,094 --> 01:30:34,495
MICROMILLIGRAMS OF ANTIBODY AND

2035
01:30:34,562 --> 01:30:35,930
BLOOD AND QUESTION THAT IS ASKED

2036
01:30:35,997 --> 01:30:39,433
IF YOU HAVE SO MUCH ANTIBODY AND

2037
01:30:39,500 --> 01:30:40,802
CIRCULATION WILL IT IMPEDE

2038
01:30:40,868 --> 01:30:43,504
ABILITY OF ANIMAL TO RESPOND TO

2039
01:30:43,571 --> 01:30:45,306
ANALOGOUS CHALLENGE AND IN THIS

2040
01:30:45,373 --> 01:30:48,109
CASE DESIGNING AN EXPERIMENT

2041
01:30:48,176 --> 01:30:51,412
ADMINISTERING AVMABS AND TWO

2042
01:30:51,479 --> 01:30:53,881
WEEKS LATER VACCINATED AGAINST

2043
01:30:53,948 --> 01:30:55,516
INFLUENZA AND MICE WERE BOOSTED

2044
01:30:55,583 --> 01:31:01,756
70 DAYS LATER AND EVALUATED

2045
01:31:01,823 --> 01:31:02,423
ANTI-INFLUENZA ANTIBODY RESPONSE

2046
01:31:02,490 --> 01:31:05,760
AND MICE RECEIVING AV MABS ARE

2047
01:31:05,827 --> 01:31:08,329
EXPRESSING EBOLA-SPECIFIC

2048
01:31:08,396 --> 01:31:11,098
ANTIBODIES AND HERE ARE ANTI-HA

2049
01:31:11,165 --> 01:31:18,139
TIRES AND MICE GIVEN AV HAD HA

2050
01:31:18,206 --> 01:31:19,841
TIGHTERS DISTINGUISHABLE FROM

2051
01:31:19,907 --> 01:31:23,211
MICE GIVEN PDS AND HIGH

2052
01:31:23,277 --> 01:31:26,581
CONCENTRATION OF ANTIBODIES

2053
01:31:26,647 --> 01:31:30,151
CIRCULATING IN SIERRA MIST

2054
01:31:30,218 --> 01:31:32,153
DOESN'T IMPEDE ANIMAL FOR

2055
01:31:32,220 --> 01:31:34,455
RESPONDING TO THIS CHALLENGE AND

2056
01:31:34,522 --> 01:31:36,123
ANTIBODY CLONING THERAPIES AND

2057
01:31:36,190 --> 01:31:37,859
STRATEGIES OF DRAMATICALLY

2058
01:31:37,925 --> 01:31:39,427
IMPROVED OVER THE YEARS AND WE

2059
01:31:39,493 --> 01:31:41,762
HAVE A NUMBER OF VERY HIGHLY

2060
01:31:41,829 --> 01:31:44,866
POTENT HUMAN ANTIBODIES CLONED

2061
01:31:44,932 --> 01:31:46,934
FROM HUMAN SURVIVORS AND TWO

2062
01:31:47,001 --> 01:31:50,571
INCLUDED MAB100 AND 114 AND

2063
01:31:50,638 --> 01:31:53,274
ISOLATED FROM SURVIVOR OF EBOLA

2064
01:31:53,341 --> 01:31:57,511
VIRUS AND B-CELLS FROM N1995

2065
01:31:57,578 --> 01:32:00,514
OUTBREAK AND MOVED TO EXPRESSING

2066
01:32:00,581 --> 01:32:02,984
ANTIBODIES HUMAN IGG1 ANTIBODIES

2067
01:32:03,050 --> 01:32:05,753
WE CAN DETECT NOW IN THE SERUM

2068
01:32:05,820 --> 01:32:07,421
AND USING SAME CONSTRUCT

2069
01:32:07,488 --> 01:32:09,323
DESIGNED AND STUDIES MOST

2070
01:32:09,390 --> 01:32:12,593
EDAPTED TO EBOLA AND SEE AT

2071
01:32:12,660 --> 01:32:15,997
DOSES OF EBOLA DOSES 5 TIMES TO

2072
01:32:16,063 --> 01:32:20,101
THE 9 WE HAVE HIGH SURVIVAL AND

2073
01:32:20,167 --> 01:32:22,904
MAB114 WE START WITH LOWER DOSE

2074
01:32:22,970 --> 01:32:25,740
AND DOSE TO THE 10 WE HAVE HIGH

2075
01:32:25,806 --> 01:32:28,142
SURVIVAL IN ANIMALS LD50 DOSE

2076
01:32:28,209 --> 01:32:31,512
AND HIGH DOSE OF EBOLA WE HAVE.

2077
01:32:31,579 --> 01:32:33,814
AND SO WE STARTED TO, YOU KNOW,

2078
01:32:33,881 --> 01:32:36,484
WE HAVE A VACCINE FOR EBOLA.

2079
01:32:36,550 --> 01:32:39,754
AND WE DECIDED TO THEN FOCUS ON

2080
01:32:39,820 --> 01:32:41,889
A PATHOGEN WE DON'T HAVE A

2081
01:32:41,956 --> 01:32:44,225
VACCINE OR ANTIVIRALS AND

2082
01:32:44,292 --> 01:32:46,394
FOCUSED ON THE VIRUS AND VIRUSS

2083
01:32:46,460 --> 01:32:49,530
ARE SIMILAR TO EBOLA VIRUS AND

2084
01:32:49,597 --> 01:32:52,500
SIMILAR CASE FATALITY RATE AND

2085
01:32:52,566 --> 01:32:54,735
SIMILAR CLINICAL MANIFESTATION

2086
01:32:54,802 --> 01:32:57,705
AND WHO HIGH PRIORITY PATHOGEN

2087
01:32:57,772 --> 01:32:59,674
WITH EPIDEMIC POTENTIAL AND

2088
01:32:59,740 --> 01:33:01,642
CONTINUE TO BE OUTBREAKS OVER

2089
01:33:01,709 --> 01:33:03,945
THE YEARS AND RECENT OUTBREAKS

2090
01:33:04,011 --> 01:33:06,714
WERE IN FEBRUARY OF 2023 IN

2091
01:33:06,781 --> 01:33:08,015
NEWGUINEA AND REPORTS OF

2092
01:33:08,082 --> 01:33:10,117
OUTBREAKS STILL HAPPENING IN

2093
01:33:10,184 --> 01:33:16,123
JUNE AND NO LICENSE VACCINES OR

2094
01:33:16,190 --> 01:33:17,625
THERAPEUTICS AVAILABLE.

2095
01:33:17,692 --> 01:33:20,328
MAKING VERY GOOD ANTIBODIES

2096
01:33:20,394 --> 01:33:22,129
ISOLATED FROM HUMAN SURVIVOR

2097
01:33:22,196 --> 01:33:24,899
THAT IS MR191 AND NICE

2098
01:33:24,966 --> 01:33:27,635
EXPRESSION KINETICS DOSE OF 1

2099
01:33:27,702 --> 01:33:30,271
TIMES 1011 AND PEAK LEVELS OF

2100
01:33:30,338 --> 01:33:33,274
300 MICROGRAMS PER ML IN THE

2101
01:33:33,341 --> 01:33:36,944
BLOOD AND 1 x 10 TO THE 11 OR 10

2102
01:33:37,011 --> 01:33:42,283
TIMES 10 GENOMES 100% PROTECTION

2103
01:33:42,350 --> 01:33:44,352
FROM MOUSE ADAPTED VIRAL

2104
01:33:44,418 --> 01:33:46,153
CHALLENGE AND INTERESTED IN

2105
01:33:46,220 --> 01:33:49,724
MOVING AVV PLATFORM INTO HIGHER

2106
01:33:49,790 --> 01:33:51,926
ORDER SPECIES WE MOVE TO THE

2107
01:33:51,993 --> 01:33:54,462
GUINEA PIG MODEL AND ADAPTED

2108
01:33:54,528 --> 01:33:56,764
VIRUS AND IN CASE ANIMALS ARE

2109
01:33:56,831 --> 01:33:59,934
LARGER HIGH DOSES OF AV RANGING

2110
01:34:00,001 --> 01:34:03,037
FROM 5 x 12 TO THE VECTOR

2111
01:34:03,104 --> 01:34:04,839
GENOMES AND 5 x 11 AS A LOW DOSE

2112
01:34:04,905 --> 01:34:07,508
AND YOU CAN SEE AT MID AND HIGH

2113
01:34:07,575 --> 01:34:09,577
DOSE WE HAVE HIGH LEVELS OF

2114
01:34:09,643 --> 01:34:13,714
PROTECTION AND AGAIN 1,000 LD50

2115
01:34:13,781 --> 01:34:15,349
GUINEA PIG VIRUS CHALLENGE.

2116
01:34:15,416 --> 01:34:18,119
WE ARE SEEING EXPRESSION LEVELS

2117
01:34:18,185 --> 01:34:21,188
OF BETWEEN 50 TO 100 MICROGRAMS

2118
01:34:21,255 --> 01:34:25,192
PER MILL AND HUMAN ANTIBODIES IN

2119
01:34:25,259 --> 01:34:27,628
A GUINEA PIG AND GOAL IS TO

2120
01:34:27,695 --> 01:34:31,132
EVALUATE AVVIP IN NON-HUMAN

2121
01:34:31,198 --> 01:34:32,900
PRIMARY MODEL AND BEFORE MOVING

2122
01:34:32,967 --> 01:34:35,236
TO THE MODEL WE WANT TO EVALUATE

2123
01:34:35,302 --> 01:34:37,538
HOW THE VECTOR PERFORMED IN A

2124
01:34:37,605 --> 01:34:40,341
LARGE ANIMAL SPECIES AND I HAVE

2125
01:34:40,408 --> 01:34:43,010
ACCESS TO PRODUCTION ALMOST AND

2126
01:34:43,077 --> 01:34:45,646
ELECTED TO USE SHEEP AND

2127
01:34:45,713 --> 01:34:47,348
OBTAINED THREE LANDS TWO WEEKS

2128
01:34:47,415 --> 01:34:50,351
OF AGE ADMINISTERED AV

2129
01:34:50,418 --> 01:34:52,553
EXPRESSING ANTIBODY THAT IS A

2130
01:34:52,620 --> 01:34:57,658
HUMAN ANTIBODY DOSED 5 x 10 TO

2131
01:34:57,725 --> 01:35:03,397
THE 12 -- WE DID ADMINISTER IN

2132
01:35:03,464 --> 01:35:04,932
TWO DIFFERENT DOSES.

2133
01:35:04,999 --> 01:35:07,635
HERE ARE THE -- WE ARE ABLE TO

2134
01:35:07,701 --> 01:35:10,337
MONITOR SHEEP FOR THREE YEARS

2135
01:35:10,404 --> 01:35:12,373
AND ANTIBODY EXPRESSION LEVELS

2136
01:35:12,440 --> 01:35:13,874
OVER TIME WE HAVE AND SHEEP HAD

2137
01:35:13,941 --> 01:35:17,411
TO LEAVE THE STUDY.  HE WAS

2138
01:35:17,478 --> 01:35:18,312
PARTICULARLY ORNERY.

2139
01:35:18,379 --> 01:35:20,815
WE HAVE -- HE WAS NOT A NICE

2140
01:35:20,881 --> 01:35:21,082
ANIMAL.

2141
01:35:21,148 --> 01:35:23,017
WE WERE ABLE TO KEEP THE

2142
01:35:23,084 --> 01:35:24,718
REMAINING TWO FEMALES OUT TO

2143
01:35:24,785 --> 01:35:26,387
ALMOST THREE YEARS AND YOU CAN

2144
01:35:26,454 --> 01:35:28,255
SEE THERE IS A GRADUAL INCREASE

2145
01:35:28,322 --> 01:35:31,592
IN THE ANTIBODY EXPRESSION

2146
01:35:31,659 --> 01:35:35,229
LEVELS THAT STARTS TO SLOWLY

2147
01:35:35,296 --> 01:35:37,131
WAYNE AND AT AN ENDPOINT THEY

2148
01:35:37,198 --> 01:35:41,435
HAVE BETWEEN 20 TO 40 MICROGRAMS

2149
01:35:41,502 --> 01:35:47,274
PER ML OF HUMAN ANTIBODY IN THE

2150
01:35:47,341 --> 01:35:49,944
BLOOD AND 5 KILOGRAMS GROWING TO

2151
01:35:50,010 --> 01:35:55,149
80 KILOGRAMS AND LOTS OF CELL

2152
01:35:55,216 --> 01:35:57,251
TURNOVER AND MUSCLE MASS GREW

2153
01:35:57,318 --> 01:35:59,887
OBVIOUSLY AND ULTIMATELY DIDN'T

2154
01:35:59,954 --> 01:36:02,756
LEAD TO DILUTION OF VECTOR AND

2155
01:36:02,823 --> 01:36:06,227
AV INDUCED CELLS TO -- THIS IS

2156
01:36:06,293 --> 01:36:08,829
FIRST TIME WE DECIDED TO LOOK AT

2157
01:36:08,896 --> 01:36:14,435
RESPONSES THAT WE DID SEE

2158
01:36:14,502 --> 01:36:15,936
ANTI-CAPSIDATED VIRUS RESPONSES

2159
01:36:16,003 --> 01:36:25,946
THAT ARE UNEXPECTED.

2160
01:36:26,013 --> 01:36:26,280
PR

2161
01:36:26,347 --> 01:36:29,717
THIS ASSAY ONLY EVALUATED

2162
01:36:29,783 --> 01:36:32,353
RESPONSES THAT WE DIDN'T LOOK AT

2163
01:36:32,419 --> 01:36:34,188
RESPONSES AGAINST VARIABLE LIGHT

2164
01:36:34,255 --> 01:36:36,657
CHANGE ON NAMES AND TYPE OF

2165
01:36:36,724 --> 01:36:38,526
ANTIBODIES TO ACTUALLY QUANTIFY

2166
01:36:38,592 --> 01:36:40,227
THIS AND BOTTOM LINE LITTLE TO

2167
01:36:40,294 --> 01:36:42,129
NO DRUG ANTIBODY RESPONSE THAT

2168
01:36:42,196 --> 01:36:44,798
IS WHY WE WERE ABLE TO SEE

2169
01:36:44,865 --> 01:36:46,467
LONG-TERM ANTIBODY EXPRESSION.

2170
01:36:46,534 --> 01:36:48,636
WE ARE NOT SURE WHY THIS IS THE

2171
01:36:48,702 --> 01:36:49,270
CASE.

2172
01:36:49,336 --> 01:36:51,839
AGAIN WITH NON-HUMAN PRIMATE

2173
01:36:51,906 --> 01:36:54,441
STUDIES THAT IS NOT WHAT PEOPLE

2174
01:36:54,508 --> 01:36:56,043
SEE.  WE HAVE A NUMBER OF

2175
01:36:56,110 --> 01:36:58,212
EXPERIMENTS TO EVALUATE WHAT IS

2176
01:36:58,279 --> 01:37:00,414
GOING ON AND COULD BE BECAUSE OF

2177
01:37:00,481 --> 01:37:03,517
NATURE OF ANTIBODY AND NEXT

2178
01:37:03,584 --> 01:37:07,521
STEPS FOR AVPIP IS TO WRITE A

2179
01:37:07,588 --> 01:37:09,089
MONKEY STUDY THAT IS SCHEDULED

2180
01:37:09,156 --> 01:37:11,559
FOR THE SUMMER OF 2024 AND

2181
01:37:11,625 --> 01:37:15,196
REGARDING THE GENOME WE HAVE

2182
01:37:15,262 --> 01:37:20,301
MICCAC DOMAINS AND WE HAVE W2A

2183
01:37:20,367 --> 01:37:23,470
AND PRA AND NEED TO REVISE THE

2184
01:37:23,537 --> 01:37:26,040
CONSTRUCT DESIGN AND SO FAR WE

2185
01:37:26,106 --> 01:37:27,441
HAVE SEEN VERY GOOD EXPRESSION

2186
01:37:27,508 --> 01:37:31,779
OF THIS ANTIBODY IN MICE.

2187
01:37:31,845 --> 01:37:34,114
THE PLAN IS TO DOSE 5 x 10 TO

2188
01:37:34,181 --> 01:37:37,985
THE 12 VECTOR GENOMES PER KG AND

2189
01:37:38,052 --> 01:37:41,222
CHALLENGE 28 DAYS LATER WITH

2190
01:37:41,288 --> 01:37:48,862
WILD TYPE AUTHENTIC -- BIOLOGY

2191
01:37:48,929 --> 01:37:51,098
LAB IN CANADA AND WORKING ON

2192
01:37:51,165 --> 01:37:55,603
RESPECT TO AVIP FILO VIRUSES TO

2193
01:37:55,669 --> 01:38:01,508
DEVELOP A VIRUS AVVIP AND

2194
01:38:01,575 --> 01:38:02,243
PROTEINS DIFFER SIGNIFICANTLY

2195
01:38:02,309 --> 01:38:07,581
AND RANGE BETWEEN 55 AND 66 AM

2196
01:38:07,648 --> 01:38:10,351
EVENO ACID IDENTITY AND PROTEINS

2197
01:38:10,417 --> 01:38:15,723
IS MUCH LOWER AND 31% IMMUNOACID

2198
01:38:15,789 --> 01:38:18,058
IDENTITY AND WE DON'T HAVE PAN

2199
01:38:18,125 --> 01:38:21,428
FILO VIRUS ANTIBODIES AND WE

2200
01:38:21,495 --> 01:38:28,969
[INDISCERNIBLE] BISPECIFIC AN

2201
01:38:29,036 --> 01:38:31,438
ANTIBODY AND HEAVY CHAINS AND

2202
01:38:31,505 --> 01:38:37,411
INSERTED THE SCFV FOR A MODERN

2203
01:38:37,478 --> 01:38:39,647
VIRUS ANTIBODY MR1 AND WE HAVE

2204
01:38:39,713 --> 01:38:42,883
BEEN ABLE TO DETECT ANTIBODY

2205
01:38:42,950 --> 01:38:44,218
EXPRESSION IN VIVO.

2206
01:38:44,285 --> 01:38:46,654
THIS IS A LARGER CONSTRUCT THAT

2207
01:38:46,720 --> 01:38:49,523
IS A LITTLE OVERSIZED DIDN'T

2208
01:38:49,590 --> 01:38:52,192
HAVE WERPV BUT SEE EXPRESSION

2209
01:38:52,259 --> 01:38:53,694
STILL THAT IS VERY EXCITING AND

2210
01:38:53,761 --> 01:38:56,397
HAVE A POSTER TO TALK ABOUT

2211
01:38:56,463 --> 01:38:58,032
CHALLENGE RESULTS FROM THE

2212
01:38:58,098 --> 01:38:58,932
STUDY.

2213
01:38:58,999 --> 01:39:00,434
OKAY.  I STILL HAVE TIME AND WE

2214
01:39:00,501 --> 01:39:03,203
WILL MOVE ON TO RESPIRATORY

2215
01:39:03,270 --> 01:39:03,971
INFECTIONS.

2216
01:39:04,038 --> 01:39:05,873
OBVIOUSLY, YOU KNOW, FILO

2217
01:39:05,939 --> 01:39:07,174
VIRUSES ARE IMPORTANT AND

2218
01:39:07,241 --> 01:39:07,508
INTERESTING.

2219
01:39:07,574 --> 01:39:10,344
THIS IS NOT REALLY SOMETHING

2220
01:39:10,411 --> 01:39:11,979
THAT THE CAN AIDIAN GOVERNMENT

2221
01:39:12,046 --> 01:39:14,248
IS WORRIED ABOUT AND MOVING TO

2222
01:39:14,315 --> 01:39:17,251
WORKING ON RESPIRATORY PATHOGENS

2223
01:39:17,318 --> 01:39:19,720
AND ANYWAY WE DECIDED TO

2224
01:39:19,787 --> 01:39:21,522
EVALUATE WHETHER A PLATFORM

2225
01:39:21,588 --> 01:39:23,324
WOULD WORK FOR RESPIRATORY

2226
01:39:23,390 --> 01:39:26,627
INFECTIONS AND VIRUS AND

2227
01:39:26,694 --> 01:39:28,329
INFLUENZA VIRUS.

2228
01:39:28,395 --> 01:39:31,398
AS YOU KNOW RSVS ARE PROBLEMATIC

2229
01:39:31,465 --> 01:39:37,905
IN INFANTS AND ELDERLY

2230
01:39:37,971 --> 01:39:39,640
IMMUNOCOMPROMISED.

2231
01:39:39,707 --> 01:39:41,175
THIS REQUIRES MONTHLY

2232
01:39:41,241 --> 01:39:43,010
INTRAMUSCULAR INJECTIONS NOT TO

2233
01:39:43,077 --> 01:39:46,180
QUALIFY AT LEAST IN CANADA THERE

2234
01:39:46,246 --> 01:39:48,582
IS STRICT CRITERIA AND BABIES

2235
01:39:48,649 --> 01:39:52,186
ENTITLE TODAY HAVE ANTIBODY IN

2236
01:39:52,252 --> 01:39:56,357
FIRST YEAR OF LIFE AND WE KNOW

2237
01:39:56,423 --> 01:39:57,624
RESPONDING POORLY TO INFLUENCE

2238
01:39:57,691 --> 01:40:01,428
OF VACCINATION EVALUATING AVVIP

2239
01:40:01,495 --> 01:40:03,364
FOR THESE TWO RESPIRATORY

2240
01:40:03,430 --> 01:40:04,932
PATHOGENS AND DEALING WITH THEM

2241
01:40:04,998 --> 01:40:06,934
WE WANT TO INVESTIGATE WHETHER

2242
01:40:07,000 --> 01:40:09,770
OR NOT ANTIBODIES WOULD MAKE WAY

2243
01:40:09,837 --> 01:40:13,207
TO MUCOSAL SURFACES VERY GOOD

2244
01:40:13,273 --> 01:40:15,642
ANTIBODY EXPRESSION LEVELS THAT

2245
01:40:15,709 --> 01:40:20,581
WE USED ANTIBODY FROM JAMES

2246
01:40:20,647 --> 01:40:23,117
RSV90 AND ACTIVATED

2247
01:40:23,183 --> 01:40:25,953
[INDISCERNIBLE] AND EUTHANIZED

2248
01:40:26,019 --> 01:40:29,123
MICE WE COULD DETECT ANTIBODIES

2249
01:40:29,189 --> 01:40:33,560
IN LUNG AND INTESTINES AND

2250
01:40:33,627 --> 01:40:36,630
VAGINA AND ARE CONFIDENT THAT

2251
01:40:36,697 --> 01:40:39,266
ANTIBODIES ARE MAKING WAY TO

2252
01:40:39,333 --> 01:40:42,136
MUCOSAL SURFACES.

2253
01:40:42,202 --> 01:40:47,374
FIRST AGAIN IS STANDARD 1 x 1011

2254
01:40:47,441 --> 01:40:50,544
-- IN 28 DAYS LATER THEY WERE

2255
01:40:50,611 --> 01:40:54,748
CHALLENGED WITH RSVA2 STRAIN

2256
01:40:54,815 --> 01:40:58,752
INTERNASALLY DOSE OF 1 x 6PFU

2257
01:40:58,819 --> 01:41:01,755
AND DON'T DEVELOP CLINICAL SIGNS

2258
01:41:01,822 --> 01:41:03,190
VIRUS INFECTION AND CAN SEE

2259
01:41:03,257 --> 01:41:05,959
EVIDENCE OF VIRUS REPLICATION

2260
01:41:06,026 --> 01:41:07,961
AND FIVE DAYS POST CHALLENGE

2261
01:41:08,028 --> 01:41:09,363
QUANTIFYING AMOUNT OF VIRUS IN

2262
01:41:09,430 --> 01:41:12,699
THE LUNGS AND SEE IN MICE WE ARE

2263
01:41:12,766 --> 01:41:15,903
TREATED WITH VECTORIZED

2264
01:41:15,969 --> 01:41:16,937
[INDISCERNIBLE] AND NO EVIDENCE

2265
01:41:17,004 --> 01:41:18,839
OF REPLICATING VIRUS IN THE

2266
01:41:18,906 --> 01:41:21,775
LUNGS AND CONTROLLED AV AGAINST

2267
01:41:21,842 --> 01:41:24,111
EBOLA VIRUS THAT YOU CAN SEE

2268
01:41:24,178 --> 01:41:27,915
THERE IS A VIRUS REPLICATION IN

2269
01:41:27,981 --> 01:41:32,619
THE LUNGS AND PROBLEM FOR

2270
01:41:32,686 --> 01:41:35,155
INFANTS WANTING TO INVESTIGATE

2271
01:41:35,222 --> 01:41:39,259
IF THESE ANTIBODIES COULD BE

2272
01:41:39,326 --> 01:41:40,394
TRANSMITTED TO OFFSPRING.

2273
01:41:40,461 --> 01:41:43,831
28 DAYS LATER THEY WERE ALLOWED

2274
01:41:43,897 --> 01:41:45,666
TO AND DID IT WITH MICE AND

2275
01:41:45,732 --> 01:41:47,568
PREGNANT AND MOVED TO DIFFERENT

2276
01:41:47,634 --> 01:41:50,137
CAGES AND MONITORED ANTIBODY

2277
01:41:50,204 --> 01:41:51,205
EXPRESSION IN THEIR OFFSPRING.

2278
01:41:51,271 --> 01:41:54,341
YOU CAN SEE AT THE TIME WHEN THE

2279
01:41:54,408 --> 01:41:58,078
PUPS WERE BORN WE EUTHANIZED

2280
01:41:58,145 --> 01:42:00,714
PUPS AND EXTRACTED BLOOD AND

2281
01:42:00,781 --> 01:42:03,150
HIGH LEVELS OF ANTIBODY

2282
01:42:03,217 --> 01:42:05,586
EXPRESSION IN THE BLOOD AND

2283
01:42:05,652 --> 01:42:16,129
WANED OVER TIME AND BECAME

2284
01:42:25,506 --> 01:42:28,041
DETECTIBLE THE ANTIBODIES COULD

2285
01:42:28,108 --> 01:42:30,143
TRANSFER TO THE OFFSPRING AND

2286
01:42:30,210 --> 01:42:30,844
OFFER PROTECTION AND QUESTION WE

2287
01:42:30,911 --> 01:42:37,317
ARE ASKED IS CAN YOU TURN OFF

2288
01:42:37,384 --> 01:42:38,919
ANTIBODY EXPRESSION AND P SITES

2289
01:42:38,986 --> 01:42:41,855
ON EITHER SIDE OF CDNA FOR

2290
01:42:41,922 --> 01:42:46,693
ANTIBODY AND ADMINISTERED TO

2291
01:42:46,760 --> 01:42:51,565
MICE 28 DAYS LATER ADMINISTERED

2292
01:42:51,632 --> 01:42:58,071
VECTOR A STRONG MUSCLE SPECIFIC

2293
01:42:58,138 --> 01:42:59,806
CAPSID AND PROTEINS THAT IS

2294
01:42:59,873 --> 01:43:02,976
FUSED TO THE HIV TAP PROTEIN

2295
01:43:03,043 --> 01:43:06,346
THAT IS SELF-PENETRATING PEPTIDE

2296
01:43:06,413 --> 01:43:08,615
AND RESULTS THAT USE ANTIBODY

2297
01:43:08,682 --> 01:43:11,718
EXPRESSION DAY 28 AND

2298
01:43:11,785 --> 01:43:13,887
ADMINISTERED [INDISCERNIBLE] OR

2299
01:43:13,954 --> 01:43:16,290
RECOMBINANT TAT PROTEIN AT THIS

2300
01:43:16,356 --> 01:43:19,459
INITIAL CONCENTRATION DIDN'T

2301
01:43:19,526 --> 01:43:22,262
INTERFERE OR OBLATE ANTIBODY

2302
01:43:22,329 --> 01:43:25,032
EXPRESSION IN RED AND LOOKING AT

2303
01:43:25,098 --> 01:43:29,436
BLUE LINE AV DELIVERED WE SAW A

2304
01:43:29,503 --> 01:43:31,572
BLENDING OF ANTIBODY EXPRESSION

2305
01:43:31,638 --> 01:43:34,408
NOT ABLATION OF EXPRESSION BUT

2306
01:43:34,474 --> 01:43:36,476
HIGHER DOSES MIGHT HAVE BEEN

2307
01:43:36,543 --> 01:43:38,579
ABLE TO OBLATE IT AND

2308
01:43:38,645 --> 01:43:40,347
ADMINISTERED HIGHER DOSE CREATED

2309
01:43:40,414 --> 01:43:43,350
AT A LATER TIME POINT AND SAW A

2310
01:43:43,417 --> 01:43:45,085
REDUCTION AND POTENTIALLY HOPE

2311
01:43:45,152 --> 01:43:49,756
FOR ADMINISTERING RECOMBINATION

2312
01:43:49,823 --> 01:43:51,458
PROTEIN IF THIS WERE EVER TO

2313
01:43:51,525 --> 01:43:52,626
BECOME AN ISSUE.

2314
01:43:52,693 --> 01:44:01,234
MOVING ON TO INFLUENZA VIRUS WE

2315
01:44:01,301 --> 01:44:02,703
VECTORIZED ANOTHER ANTIBODY AND

2316
01:44:02,769 --> 01:44:05,906
THIS IS AN ANTIBODY EXPRESSING

2317
01:44:05,973 --> 01:44:10,210
ONE IN VIVO AGAIN 100 OR 150

2318
01:44:10,277 --> 01:44:12,546
MICROGRAMS PER ML AND STANDARD

2319
01:44:12,613 --> 01:44:15,515
VIRAL ANTIBODIES AND SAW FAIRLY

2320
01:44:15,582 --> 01:44:18,919
GOOD PROTECTION WITH MALE MICE

2321
01:44:18,986 --> 01:44:23,323
AND FEMALE MICE DIDN'T CONFER A

2322
01:44:23,390 --> 01:44:24,658
SIGNIFICANT AMOUNT OF

2323
01:44:24,725 --> 01:44:26,460
PROTECTION.

2324
01:44:26,526 --> 01:44:28,161
REVISING ANTIBODY AND SEQUENCE

2325
01:44:28,228 --> 01:44:31,698
TO INCLUDE A MICRO-RNA SCAFFOLD

2326
01:44:31,765 --> 01:44:32,966
DOWNSTREAM WITH CODING SEQUENCE

2327
01:44:33,033 --> 01:44:35,769
FOR THE ANTIBODY AND THIS

2328
01:44:35,836 --> 01:44:38,939
SCAFFOLD INCLUDES THREE SRNAS

2329
01:44:39,006 --> 01:44:41,608
AGAINST THREE GENE SEGMENTS.

2330
01:44:41,675 --> 01:44:43,744
WITHOUT -- THIS IS A BUSY GRAPH

2331
01:44:43,810 --> 01:44:46,580
THAT I WANTED TO POINT OUT BY

2332
01:44:46,647 --> 01:44:49,750
INCLUDING MICRO-RNA WE INCREASE

2333
01:44:49,816 --> 01:44:51,318
EFFICACY OF THIS PLATFORM AND

2334
01:44:51,385 --> 01:44:55,555
THIS IS THE ANTIBODY ON THE

2335
01:44:55,622 --> 01:44:58,191
[INDISCERNIBLE] AND HERE IS ANTI

2336
01:44:58,258 --> 01:45:00,927
BODY PLUS MICRON RNA AND HERE

2337
01:45:00,994 --> 01:45:03,030
THIS IS AGAIN MICRON RNA

2338
01:45:03,096 --> 01:45:04,564
EXPRESSING VECTOR AND IS A WAY

2339
01:45:04,631 --> 01:45:08,802
TO POTENTIALLY INCREASE THE

2340
01:45:08,869 --> 01:45:12,272
POTENCY OF VIP PLATFORM AND NOT

2341
01:45:12,339 --> 01:45:12,939
NECESSARILY INCREASING GHOSTS

2342
01:45:13,006 --> 01:45:16,810
AND NOW I WILL MOVE TO USE OF

2343
01:45:16,877 --> 01:45:21,648
AVVIP FOR BACTERIAL INFECTIONS

2344
01:45:21,715 --> 01:45:22,315
AND FOCUSING ON [INDISCERNIBLE]

2345
01:45:22,382 --> 01:45:24,418
AND HAVE INTEREST IN CYSTIC

2346
01:45:24,484 --> 01:45:27,721
FIBROSIS A CAUSE OF CHRONIC LUNG

2347
01:45:27,788 --> 01:45:30,023
INFECTION AND PEOPLE WITH CYSTIC

2348
01:45:30,090 --> 01:45:31,725
FIBROSIS AND RESPONSIBLE FOR 10

2349
01:45:31,792 --> 01:45:36,029
TO 15% OF INFECTIONS INHERENT

2350
01:45:36,096 --> 01:45:38,098
WORLDWIDE AND DRUG RESISTANT AND

2351
01:45:38,165 --> 01:45:41,168
NO VACCINES AVAILABLE AND TWO

2352
01:45:41,234 --> 01:45:45,238
PROMISING CANDIDATES THAT IS

2353
01:45:45,305 --> 01:45:48,575
POLYSACK ARIDE APSEUDOMOWNIS AND

2354
01:45:48,642 --> 01:45:51,778
COMPONENT OF TYPE 3 SECRETION

2355
01:45:51,845 --> 01:45:54,347
SYSTEM AND ALSO DEVELOPED

2356
01:45:54,414 --> 01:45:57,451
BISPECIFIC ANTIBODY COMBINING

2357
01:45:57,517 --> 01:46:01,021
CSFE FOR ANTIBODIES AND

2358
01:46:01,088 --> 01:46:04,891
VECTORIZE THE ANTIBODIES

2359
01:46:04,958 --> 01:46:06,059
EVALUATING EXPRESSION OF

2360
01:46:06,126 --> 01:46:09,496
KINETICS IN MICE AND SEE 100 TO

2361
01:46:09,563 --> 01:46:15,836
400 AND 8 MICROGRAMS PER ML WE

2362
01:46:15,902 --> 01:46:18,805
EVALUATED AND CONCENTRATIONS AT

2363
01:46:18,872 --> 01:46:19,639
11 VECTOR DOSE.

2364
01:46:19,706 --> 01:46:22,342
YOU KNOW, WE ARE GETTING ONE TO

2365
01:46:22,409 --> 01:46:28,715
2 UPWARDS OF THREE MLES AND

2366
01:46:28,782 --> 01:46:31,752
COULDN'T TELL YOU WHY IT

2367
01:46:31,818 --> 01:46:34,221
EXPRESSED 10 TIMES -- EVERYTHING

2368
01:46:34,287 --> 01:46:35,956
ELSE WAS THE SAME.

2369
01:46:36,022 --> 01:46:38,825
WE ALSO EXPRESSED BISPECIFIC

2370
01:46:38,892 --> 01:46:40,961
ANTIBODY AND WPRE WE THOUGHT

2371
01:46:41,027 --> 01:46:44,631
WOULD BE PROBLEMATIC AND HAD

2372
01:46:44,698 --> 01:46:46,933
REASONABLE EXPRESSION AND

2373
01:46:47,000 --> 01:46:49,469
EXPRESSION WANED FASTER THAT

2374
01:46:49,536 --> 01:46:52,005
CONVENTIONAL MONOCLONAL

2375
01:46:52,072 --> 01:46:54,274
ANTIBODIES AND PERFORMED ACUTE

2376
01:46:54,341 --> 01:46:57,644
CHALLENGE WITH APSEUDOMOWNIS

2377
01:46:57,711 --> 01:46:59,513
MODEL AND MICE WERE ADMINISTERED

2378
01:46:59,579 --> 01:47:03,183
AND ONE OF THREE VECTORS

2379
01:47:03,250 --> 01:47:06,353
INTRAMUSCULARLY AND 28 DAYS

2380
01:47:06,419 --> 01:47:10,190
LATER STANDARD PROTOCOL AND MICE

2381
01:47:10,257 --> 01:47:13,660
CHALLENGED WITH LETHAL DOSE OF

2382
01:47:13,727 --> 01:47:16,963
PA1 AND PA14 AND BISPECIFIC

2383
01:47:17,030 --> 01:47:19,099
ANTIBODY CONFERRED HIGH LEVELS

2384
01:47:19,166 --> 01:47:26,173
OF PROTECTION AGAINST A LETHAL

2385
01:47:26,239 --> 01:47:27,641
BACTERIAL CHALLENGE 18 TO 20

2386
01:47:27,707 --> 01:47:29,142
HOURS POSTED ADMINISTRATION.

2387
01:47:29,209 --> 01:47:34,981
WE WANTED TO INVESTIGATE IMPACT

2388
01:47:35,048 --> 01:47:37,083
OF BIODISTRIBUTION IN THE MODEL

2389
01:47:37,150 --> 01:47:38,919
AND MICE WERE CHALLENGED 28 DAYS

2390
01:47:38,985 --> 01:47:44,491
AFTER RECEIVING THE AV.

2391
01:47:44,558 --> 01:47:49,296
18 HOURS POST CHALLENGED MICE

2392
01:47:49,362 --> 01:47:53,066
WERE EUTHANIZED AND QUANTIFIED

2393
01:47:53,133 --> 01:47:57,237
AMOUNT OF COLOFTENIES IN VARIOUS

2394
01:47:57,304 --> 01:47:59,072
TISSUES DIRECTING GROUPS HERE

2395
01:47:59,139 --> 01:48:02,709
AND LIKE IN INFLUENZA WE SAW

2396
01:48:02,776 --> 01:48:04,144
DIFFERENCES AND SEX DIFFERENCES

2397
01:48:04,211 --> 01:48:06,646
IN TERMS OF THE CHALLENGE MODEL

2398
01:48:06,713 --> 01:48:09,482
AND YOU CAN SEE HERE BISPECIFIC

2399
01:48:09,549 --> 01:48:16,323
OR DOSE OF BOTH ANTI-PCRV AND

2400
01:48:16,389 --> 01:48:19,025
ANTI-PCRL YOU REDUCE BURDEN IN

2401
01:48:19,092 --> 01:48:21,328
TISSUES WE EXAMINED IN BOTH

2402
01:48:21,394 --> 01:48:22,929
CASES AND THESE ARE CONTROLS WE

2403
01:48:22,996 --> 01:48:25,031
WERE REPLACING THAT AND IN TERMS

2404
01:48:25,098 --> 01:48:27,067
OF FUTURE DIRECTIONS FOR THE

2405
01:48:27,133 --> 01:48:30,737
PROJECT WE HAVE SHOWN WE CAN

2406
01:48:30,804 --> 01:48:32,205
PREVENT AND USE PROPHYLACTICALLY

2407
01:48:32,272 --> 01:48:34,774
AND WOULD LOVE TO SEE IF WE CAN

2408
01:48:34,841 --> 01:48:36,776
USE THIS THERAPEUTICALLY AND WE

2409
01:48:36,843 --> 01:48:42,115
WILL EVALUATE COLONIZATION AND

2410
01:48:42,182 --> 01:48:44,751
BIOFILL FORMATION AND AVVP CAN

2411
01:48:44,818 --> 01:48:46,553
BE USED TO TREAT COLONIZATION

2412
01:48:46,620 --> 01:48:49,022
AND PREVENT IT AND HAVE INTEREST

2413
01:48:49,089 --> 01:48:52,192
IN CYSTIC FIBROSIS AND USING

2414
01:48:52,259 --> 01:48:55,896
CFTR CORRECTED MICE AND THESE

2415
01:48:55,962 --> 01:48:59,199
MICE WILL BE NATURALLY COLONIZED

2416
01:48:59,266 --> 01:49:01,701
PSEUDOMOWNIS THAT YOU CAN ADD TO

2417
01:49:01,768 --> 01:49:05,205
WATER AND NASAL CAVITIES CAN

2418
01:49:05,272 --> 01:49:07,374
BECOME THEM AND PE FORM NASAL

2419
01:49:07,440 --> 01:49:11,077
SWABS TO QUANTIFY THE NUMBER AND

2420
01:49:11,144 --> 01:49:12,879
ALSO INCIDENTALLY IN MODELS

2421
01:49:12,946 --> 01:49:15,949
EXPRESSING CFTR THIS PREVENTS

2422
01:49:16,016 --> 01:49:17,951
COLONIZATION AND NICE MODEL AND

2423
01:49:18,018 --> 01:49:21,054
EVALUATING WHETHER AVVIP CAN BE

2424
01:49:21,121 --> 01:49:26,459
USED TO TREAT COLONIZATION

2425
01:49:26,526 --> 01:49:26,860
THERAPEUTICALLY.

2426
01:49:26,927 --> 01:49:28,128
SUMMARY AND THIS IS ACTUALLY THE

2427
01:49:28,194 --> 01:49:31,097
CAP THAT WE ENGINEERED IN OUR

2428
01:49:31,164 --> 01:49:35,035
LAB NEGATES RAPID AND PROLONGED

2429
01:49:35,101 --> 01:49:37,337
SERUM ANTIBODY EXPRESSION AND WE

2430
01:49:37,404 --> 01:49:39,339
HAVE SHOWN THIS IS A GOOD

2431
01:49:39,406 --> 01:49:48,148
PLATFORM FOR PROPHYL ACTACTIVE

2432
01:49:48,214 --> 01:49:48,815
EFFICACY.

2433
01:49:48,882 --> 01:49:53,620
IF YOU ADMINISTER EXPRESSING

2434
01:49:53,687 --> 01:50:03,263
THESE -- THESE CAN BE

2435
01:50:03,330 --> 01:50:04,064
TRANSFERRED MATERNALLY AND

2436
01:50:04,130 --> 01:50:10,704
INCREASE POTENCY OF PLATFORM BY

2437
01:50:10,770 --> 01:50:13,206
INCLUDING CASSETTE -- OF COURSE

2438
01:50:13,273 --> 01:50:15,275
IN THIS SITUATION DELIVER THE AV

2439
01:50:15,342 --> 01:50:19,479
TO TARGET ORGAN AND COMBATING

2440
01:50:19,546 --> 01:50:21,481
INFLUENZA VIRUS INFECTIONS TO BE

2441
01:50:21,548 --> 01:50:24,417
DELIVERED TO THE NASAL CAVITY OR

2442
01:50:24,484 --> 01:50:24,684
LUNG.

2443
01:50:24,751 --> 01:50:34,227
WE BELIEVE AVVIP HOLES GREAT

2444
01:50:34,294 --> 01:50:35,929
POTENTIAL.

2445
01:50:35,996 --> 01:50:42,502
ALSO, FOR INDIVIDUALS THAT ARE

2446
01:50:42,569 --> 01:50:44,604
IMMUNODIFISHIENT AND COULD BE

2447
01:50:44,671 --> 01:50:48,708
USED IN OUTBREAK SCENARIOS FOR

2448
01:50:48,775 --> 01:50:50,076
PATHOGENS THAT DON'T HAVE

2449
01:50:50,143 --> 01:50:51,378
VACCINES BUT THERAPIES.

2450
01:50:51,444 --> 01:50:53,013
I WOULD LIKE TO THANK MEMBERS OF

2451
01:50:53,079 --> 01:50:57,584
MY LAB CONTRIBUTING TO WORK

2452
01:50:57,650 --> 01:50:59,652
INCLUDING ANNE WONG AND JORDAN

2453
01:50:59,719 --> 01:51:05,825
AND COLLABORATORS IN WINNIPEG.

2454
01:51:05,892 --> 01:51:09,095
I INITIALLY STARTED TO WORK ON

2455
01:51:09,162 --> 01:51:12,565
AVVIP WHEN I WENT TO WORK WITH

2456
01:51:12,632 --> 01:51:20,140
GARY AT UTMB AND COLLABORATORS.

2457
01:51:20,206 --> 01:51:21,441
I WOULD LIKE TO THANK THE

2458
01:51:21,508 --> 01:51:27,347
FUNDING AND THANKS FOR YOUR

2459
01:51:27,414 --> 01:51:28,715
ATTENT

2460
01:51:28,782 --> 01:51:29,015
ATTENTION.

2461
01:51:29,082 --> 01:51:31,684
>> YOU TOUCHED ON SEX-SPECIFIC

2462
01:51:31,751 --> 01:51:32,352
DIFFERENCES.  WHAT DO YOU THINK

2463
01:51:32,419 --> 01:51:33,787
IS GOING ON THERE?

2464
01:51:33,853 --> 01:51:36,489
>> PARTIALLY FEMALE MICE WEIGH 7

2465
01:51:36,556 --> 01:51:39,359
OR 8 GRABS LESS THAN MALE MICE

2466
01:51:39,426 --> 01:51:41,294
AND THOUGHT ABOUT IT AFTER THE

2467
01:51:41,361 --> 01:51:44,164
FACT AND DIDN'T TAILOR DOSE TO

2468
01:51:44,230 --> 01:51:45,298
INFLUENZA IN MALE AND FEMALE

2469
01:51:45,365 --> 01:51:48,201
MICE AND POTENTIALLY SHOULD DOSE

2470
01:51:48,268 --> 01:51:50,437
BASED ON WEIGHT AND WORKING WITH

2471
01:51:50,503 --> 01:51:52,572
INFLUENZA MODEL DOSING BASED ON

2472
01:51:52,639 --> 01:51:55,041
WEIGHT AND EASY TO DOSE AND WE

2473
01:51:55,108 --> 01:51:59,079
WILL GIVE A HIGH DOSE OF

2474
01:51:59,145 --> 01:51:59,379
INFLUENZA.

2475
01:51:59,446 --> 01:52:00,046
>> THANK YOU.

2476
01:52:00,113 --> 01:52:02,615
>> SO, DO YOU IN ANY OF THE

2477
01:52:02,682 --> 01:52:06,019
SITUATIONS, DO YOU THINK THAT IN

2478
01:52:06,086 --> 01:52:10,690
PEOPLE ANTIBODIES COULD BE

2479
01:52:10,757 --> 01:52:13,560
GENERATED?  IF SO ANY WAY TO

2480
01:52:13,626 --> 01:52:16,396
PREDICT WHICH MIGHT AND WHICH

2481
01:52:16,463 --> 01:52:18,998
MIGHT NOT GIVE IT?

2482
01:52:19,065 --> 01:52:20,967
>> VERY GOOD QUESTION AND

2483
01:52:21,034 --> 01:52:24,604
PRIMATE STUDIES EVALUATING AVVIP

2484
01:52:24,671 --> 01:52:27,774
AND MY UNDERSTANDING STUDIES

2485
01:52:27,841 --> 01:52:28,808
BROADLY INVOLVE [INDISCERNIBLE]

2486
01:52:28,875 --> 01:52:30,443
EXCEPTION OF WORK WHICH IS

2487
01:52:30,510 --> 01:52:32,245
SLIGHTLY DIFFERENT TYPE OF

2488
01:52:32,312 --> 01:52:32,612
ANTIBODY.

2489
01:52:32,679 --> 01:52:34,414
IT IS DIFFERENT.  YES.

2490
01:52:34,481 --> 01:52:37,817
IF YOU HAVE A BROADLY

2491
01:52:37,884 --> 01:52:39,385
NEUTRALIZING ANTIBODY DERIVED

2492
01:52:39,452 --> 01:52:42,455
AGAINST HIV THEY INDUCE

2493
01:52:42,522 --> 01:52:43,356
ANTIVIRAL DRUG RESPONSES AND

2494
01:52:43,423 --> 01:52:45,959
EXCITED TO DO NON-HUMAN PRIMATE

2495
01:52:46,025 --> 01:52:47,594
STUDY WITH THESE ANTIBODIES IS

2496
01:52:47,660 --> 01:52:50,296
THIS IS AN ANTIBODY HARVESTED

2497
01:52:50,363 --> 01:52:53,266
FROM B-CELLS IN PATIENT AFTER

2498
01:52:53,333 --> 01:52:56,636
ACUTE INFECTION AND NOT SOMATIC

2499
01:52:56,703 --> 01:52:58,204
HYPERMUTATION AND DIDN'T SEE

2500
01:52:58,271 --> 01:53:02,275
ANTIDRUG ANTIBODY RESPONSES IN

2501
01:53:02,342 --> 01:53:04,043
THE SHEEP BODES WELL FOR

2502
01:53:04,110 --> 01:53:06,246
NON-HUMAN PRIMATES AND ANSWERING

2503
01:53:06,312 --> 01:53:11,351
QUESTION ISSUE RELEVANT WITH HIV

2504
01:53:11,417 --> 01:53:13,953
ANTIBODY WITH THOSE DERIVED WITH

2505
01:53:14,020 --> 01:53:18,925
RSV ANTIBODY FOR EXAMPLE AND

2506
01:53:18,992 --> 01:53:19,325
INFECTIONS.

2507
01:53:19,392 --> 01:53:23,696
>> THAT IS THE PLATFORM COMPARED

2508
01:53:23,763 --> 01:53:27,467
TO MRNA PLATFORM TO EXPRESS

2509
01:53:27,534 --> 01:53:28,468
ANTIBODIES, YOU KNOW?

2510
01:53:28,535 --> 01:53:31,070
>> I HAVE SEEN PAPERS PEOPLE

2511
01:53:31,137 --> 01:53:33,640
EVALUATED DNA AND DAVID'S GROUP

2512
01:53:33,706 --> 01:53:35,375
IS SEEING MAYBE NOT THE SAME

2513
01:53:35,441 --> 01:53:37,944
LEVEL OF ANTIBODY EXPRESSION AND

2514
01:53:38,011 --> 01:53:39,479
DURATION OF THE EXPRESSION SEEMS

2515
01:53:39,546 --> 01:53:46,753
QUITE SIMILAR AND I HAVE NOT

2516
01:53:46,819 --> 01:53:50,657
FOLLOWED MRNA LITERATURE AND

2517
01:53:50,723 --> 01:53:55,428
IMPRESSION IS YOU WON'T HAVE

2518
01:53:55,495 --> 01:53:58,331
ANYWHERE NEAR SUSTAINED

2519
01:53:58,398 --> 01:54:01,467
EXPRESSION.  NOT SURE IF ANYONE

2520
01:54:01,534 --> 01:54:02,001
TRIED THAT.

2521
01:54:02,068 --> 01:54:06,039
>> I HAVE A FEELING IT WON'T

2522
01:54:06,105 --> 01:54:07,874
WORK FOR THIS PURPOSE.

2523
01:54:07,941 --> 01:54:15,515
>> MRNA DOESN'T ACHIEVE THE

2524
01:54:15,582 --> 01:54:21,354
LEVELS OF VECTOR OR ANTIBODY.

2525
01:54:21,421 --> 01:54:24,224
DURABLE IS FINE AND GETTING TO

2526
01:54:24,290 --> 01:54:24,958
THERAPEUTIC LEVELS.

2527
01:54:25,024 --> 01:54:25,458
>> INTERESTING.

2528
01:54:25,525 --> 01:54:27,727
>> [INDISCERNIBLE].

2529
01:54:27,794 --> 01:54:29,762
>> GO AHEAD.

2530
01:54:29,829 --> 01:54:31,998
>> INTERESTING EXPECTING THE

2531
01:54:32,065 --> 01:54:37,070
EXACT OPPOSITE THAT IS

2532
01:54:37,136 --> 01:54:37,403
INTERESTING.

2533
01:54:37,470 --> 01:54:37,670
>> YES.

2534
01:54:37,737 --> 01:54:39,339
>> A COUPLE OF NEGATIVES IN

2535
01:54:39,405 --> 01:54:41,140
THERE THAT IS GREAT.

2536
01:54:41,207 --> 01:54:43,076
BUT ONE QUESTION, YOU ARE

2537
01:54:43,142 --> 01:54:47,480
INTERPRETING THE SHEEP AS HAVING

2538
01:54:47,547 --> 01:54:48,915
CONFID

2539
01:54:48,982 --> 01:54:49,215
CONFIDENCE.

2540
01:54:49,282 --> 01:54:52,518
THEY WERE TALKING ABOUT EARLIER

2541
01:54:52,585 --> 01:54:54,654
SUCCESSFUL SUPPRESSION STUDY AND

2542
01:54:54,721 --> 01:54:55,488
YOU STARTED WITH LACK.

2543
01:54:55,555 --> 01:54:56,889
>> I DID, YES.

2544
01:54:56,956 --> 01:54:58,725
>> THAT MIGHT BE A KEY VARIABLE

2545
01:54:58,791 --> 01:55:03,396
THERE.  YOU ARE RIGHT.  NATURE

2546
01:55:03,463 --> 01:55:06,099
OF ANTIBODIES AND OTHER QUESTION

2547
01:55:06,165 --> 01:55:15,575
IS TARGETING THE VIRUS THAT IS

2548
01:55:15,642 --> 01:55:19,212
THE VIRUS AND CELLS AND HOW IS

2549
01:55:19,279 --> 01:55:19,746
THAT WORKING?

2550
01:55:19,812 --> 01:55:22,315
>> TECHNIQUE THAT GETS AV TO THE

2551
01:55:22,382 --> 01:55:22,515
LUNG.

2552
01:55:22,582 --> 01:55:24,384
I SHOULD -- I MEANT TO HIGHLIGHT

2553
01:55:24,450 --> 01:55:27,720
THAT AND FORGOT AND VECTOR WE

2554
01:55:27,787 --> 01:55:31,924
WILL USE IS A POTTIENT

2555
01:55:31,991 --> 01:55:35,328
TRANSDUCER OF LUNG AND MODEL AND

2556
01:55:35,395 --> 01:55:39,532
LUNG AND OTHER SPECIES AS WELL.

2557
01:55:39,599 --> 01:55:39,732
YEAH.

2558
01:55:39,799 --> 01:55:41,934
>> [INDISCERNIBLE].

2559
01:55:42,001 --> 01:55:44,304
>> ABOUT TO QUANTIFY ANTIBODY IN

2560
01:55:44,370 --> 01:55:46,572
THE LUNGS WITH A SORT OF RECENT

2561
01:55:46,639 --> 01:55:50,243
STUDY AND VECTORS WITH JUST

2562
01:55:50,310 --> 01:55:51,978
MICRO-RNA ON THEIR OWN

2563
01:55:52,045 --> 01:55:54,280
EXPRESSING GFP AND DIDN'T SEE A

2564
01:55:54,347 --> 01:55:55,915
LOT OF PROTECTION FROM THOSE.

2565
01:55:55,982 --> 01:55:57,583
HOWEVER, I THINK WE NEED TO

2566
01:55:57,650 --> 01:55:59,686
INCREASE THE DOSE AND HAVE TO DO

2567
01:55:59,752 --> 01:56:01,587
OPTIMIZATION AND HAVE DONE ONE

2568
01:56:01,654 --> 01:56:03,856
STUDY WITH MICRO-RNAS.

2569
01:56:03,923 --> 01:56:06,926
YOU HAVE TO HAVE ANTIBODY AND

2570
01:56:06,993 --> 01:56:08,428
EXPRESSED IN CELL TYPE VIRUS

2571
01:56:08,494 --> 01:56:11,798
WILL INFECT AND BE USEFUL

2572
01:56:11,864 --> 01:56:13,933
PACKAGED INTO EXOSOMES AND THE

2573
01:56:14,000 --> 01:56:14,500
OTHER THING.

2574
01:56:14,567 --> 01:56:16,736
>> TALKING ABOUT ENGINEERING AND

2575
01:56:16,803 --> 01:56:17,370
KILL SWITCH.

2576
01:56:17,437 --> 01:56:18,504
>> YES.

2577
01:56:18,571 --> 01:56:21,140
>> POTENTIAL DOWNSIDES OF

2578
01:56:21,207 --> 01:56:23,409
LONG-TERM ANTIBODY EXPRESSION,

2579
01:56:23,476 --> 01:56:26,479
WHY WOULD YOU --

2580
01:56:26,546 --> 01:56:28,548
>> [INDISCERNIBLE].  I MEAN I

2581
01:56:28,614 --> 01:56:30,450
THINK FOR STUDIES IN LARGE

2582
01:56:30,516 --> 01:56:33,286
ANIMALS LEVELS OF ANTIBODY

2583
01:56:33,353 --> 01:56:35,588
EXPRESSIONS ARE DESIRABLES AND

2584
01:56:35,655 --> 01:56:37,990
200 MICROGRAMS PER MILL IS A

2585
01:56:38,057 --> 01:56:39,759
NICE LEVEL OF ANTIBODY

2586
01:56:39,826 --> 01:56:41,594
EXPRESSION IS A THERAPEUTIC AND

2587
01:56:41,661 --> 01:56:47,033
NOT SEEING IN ONE STUDY GETTING

2588
01:56:47,100 --> 01:56:50,770
MGS PER MIL AND IF YOU USE AV TO

2589
01:56:50,837 --> 01:56:54,073
EXPRESS ANTIBODIES FOR

2590
01:56:54,140 --> 01:56:55,608
INDICATIONS LIKE CROHN'S DISEASE

2591
01:56:55,675 --> 01:57:01,614
OR LONG-TERM A ANTIBODY

2592
01:57:01,681 --> 01:57:02,482
EXPRESSION FOR A DISEASE WOULD

2593
01:57:02,548 --> 01:57:05,651
BE AN ISSUE AND FEEL THAT HAVING

2594
01:57:05,718 --> 01:57:07,687
ANTIBODIES AROUND ME PROTECT

2595
01:57:07,754 --> 01:57:08,855
AGAINST INFECTIONS.

2596
01:57:08,921 --> 01:57:10,857
IT IS GOOD.

2597
01:57:10,923 --> 01:57:11,557
>> YES, MA'AM.

2598
01:57:11,624 --> 01:57:13,659
>> VECTORS I COULD UNDERSTAND

2599
01:57:13,726 --> 01:57:17,397
HOW THEY WOULD BE EFFECTIVE FOR

2600
01:57:17,463 --> 01:57:19,699
RESPIRATORY VIRUSES MENTIONING

2601
01:57:19,766 --> 01:57:23,102
HIV FOR A FEW TIMES AND CAN YOU

2602
01:57:23,169 --> 01:57:24,470
MEASURE ANTIBODIES AND TISSUES

2603
01:57:24,537 --> 01:57:26,272
IN THE BODY AND HOW ABOUT

2604
01:57:26,339 --> 01:57:27,340
THROUGH THE BRAIN?

2605
01:57:27,407 --> 01:57:29,609
HOW IS THAT?

2606
01:57:29,675 --> 01:57:31,644
>> I HAVE NOT DONE WORK AND

2607
01:57:31,711 --> 01:57:33,980
STAYED AWAY FROM HIV AND MICHAEL

2608
01:57:34,046 --> 01:57:36,182
DID WORK AND PUT YOU ON THE HOT

2609
01:57:36,249 --> 01:57:37,250
SEAT AND QUANTIFIED.

2610
01:57:37,316 --> 01:57:39,385
>> RATE IS MUCH, MUCH LOWER AND

2611
01:57:39,452 --> 01:57:41,821
GOING ONE-TO-1,000.

2612
01:57:41,888 --> 01:57:46,893
>> HOW ABOUT IN OTHER TISSUES?

2613
01:57:46,959 --> 01:57:49,829
>> LESS IS ENOUGH AND POPULATED

2614
01:57:49,896 --> 01:57:51,531
AND WE SELL IT.

2615
01:57:51,597 --> 01:57:55,201
>> SO, FOR NON-HIV ANTIBODY WE

2616
01:57:55,268 --> 01:57:57,537
COULD SEE MUCOSAL SURFACES IN

2617
01:57:57,603 --> 01:57:59,338
THE INTESTINE.

2618
01:57:59,405 --> 01:58:01,274
>> DO YOU KNOW HOW LONG IS THE

2619
01:58:01,340 --> 01:58:04,277
EXPRESSION OR SUSTAINED IS IT?

2620
01:58:04,343 --> 01:58:04,744
>> MICE.

2621
01:58:04,811 --> 01:58:05,511
>> RIGHT.

2622
01:58:05,578 --> 01:58:07,046
>> SHEEP WE HAVE GONE OUT AS FAR

2623
01:58:07,113 --> 01:58:09,849
AS THREE YEARS FOR NON-HUMAN

2624
01:58:09,916 --> 01:58:12,485
PRIMATE STUDIES IS THE MONKEY

2625
01:58:12,552 --> 01:58:15,688
AND 10 YEARS NOW.

2626
01:58:15,755 --> 01:58:18,558
>> PROVIDING DRUG CELLS AND

2627
01:58:18,624 --> 01:58:21,861
SUSPECT THEY ARE VERY LONG AND

2628
01:58:21,928 --> 01:58:23,196
ESPECIALLY MUSCLES LONG-LIVED

2629
01:58:23,262 --> 01:58:25,398
AND PEOPLE ARE TARGETING MUSCLE

2630
01:58:25,465 --> 01:58:30,703
FOR GENE THERAPIES AND SUSPECT

2631
01:58:30,770 --> 01:58:32,104
QUITE LONG AND MADE

2632
01:58:32,171 --> 01:58:33,306
ADMINISTRATION STUDIES AND GOING

2633
01:58:33,372 --> 01:58:35,141
TO THE MUSCLE AND DIDN'T HAVE

2634
01:58:35,208 --> 01:58:36,309
TIME TO TALK ABOUT THAT.

2635
01:58:36,375 --> 01:58:38,644
>> WITH RESPECT TO THE QUESTION

2636
01:58:38,711 --> 01:58:43,883
FEMALE MICE WITH PR8 IS A

2637
01:58:43,950 --> 01:58:47,320
WIDESPREAD DISTRIBUTION AND WHAT

2638
01:58:47,386 --> 01:58:48,688
DID MICE DIE OF?  PULMONARY

2639
01:58:48,754 --> 01:58:49,021
DISEASE?

2640
01:58:49,088 --> 01:58:51,390
>> BOTH NUMBER OF CRITERIA

2641
01:58:51,457 --> 01:58:52,625
MEETING FOR ENDPOINT AND WAS

2642
01:58:52,692 --> 01:58:54,994
WEIGHT LOSS AND LOOKING AT

2643
01:58:55,061 --> 01:58:57,597
LUNGS, THEY WERE DECIMATED.  THE

2644
01:58:57,663 --> 01:58:57,797
LUNG.

2645
01:58:57,864 --> 01:59:00,099
>> LUNG AND SPLEEN AND WILL GO.

2646
01:59:00,166 --> 01:59:01,100
THAT ALSO?

2647
01:59:01,167 --> 01:59:03,803
>> LUNGS AND SECTIONS THAT LUNGS

2648
01:59:03,870 --> 01:59:06,072
WERE CONSOLIDATED AND HARD TO --

2649
01:59:06,138 --> 01:59:07,974
I'M SURPRISED THEY COULD

2650
01:59:08,040 --> 01:59:08,541
BREATHE, YEAH.

2651
01:59:08,608 --> 01:59:10,877
>> GOOD PLACE TO LOOK FOR

2652
01:59:10,943 --> 01:59:11,444
ANTIBODY LEVELS.

2653
01:59:11,511 --> 01:59:12,245
>> YEAH.

2654
01:59:12,311 --> 01:59:13,646
>> THAT IS THE NEXT THING THAT

2655
01:59:13,713 --> 01:59:15,114
WE ARE DOING.

2656
01:59:15,181 --> 01:59:15,414
THANKS.

2657
01:59:15,481 --> 01:59:17,183
>> ALL RIGHT.  THANK YOU VERY

2658
01:59:17,250 --> 01:59:17,383
MUCH.

2659
01:59:17,450 --> 01:59:19,719
>> THANK YOU.

2660
01:59:19,785 --> 01:59:20,520
>> AUDIENCE:  [APPLAUSE].

2661
01:59:20,586 --> 01:59:27,660
>> LAST TALK BEFORE LUNCH IS

2662
01:59:27,727 --> 01:59:30,229
NANCY SULLIVAN WHO DID PHD AT

2663
01:59:30,296 --> 01:59:32,565
HARVARD AND POST DOC WITH GARY

2664
01:59:32,632 --> 01:59:36,002
AT RESEARCH CENTER IN BETHESDA

2665
01:59:36,068 --> 01:59:39,705
AND TENURED AT BRC AND HEAD OF

2666
01:59:39,772 --> 01:59:41,407
DEFENSE RESEARCH SECTION AND

2667
01:59:41,474 --> 01:59:43,776
GROUNDWORK ON EBOLA VIRUS

2668
01:59:43,843 --> 01:59:45,478
VACCINE DEVELOPMENT AND HEARD

2669
01:59:45,545 --> 01:59:47,380
ABOUT IN PREVIOUS TALK AND

2670
01:59:47,446 --> 01:59:51,517
RECRUITED TO SERVE AS DIRECTOR

2671
01:59:51,584 --> 01:59:53,753
NATIONAL EMERGING INFECTIOUS

2672
01:59:53,819 --> 02:00:03,129
DISEASE LAB AT BOSTON UNIVE

2673
02:00:03,195 --> 02:00:03,429
UNIVERSITY.

2674
02:00:03,496 --> 02:00:05,131
>> THANK YOU, ERIC.

2675
02:00:05,197 --> 02:00:08,367
IT HAS BEEN A MINUTE SINCE I

2676
02:00:08,434 --> 02:00:10,770
HAVE BEEN TOGETHER WITH ALL MY

2677
02:00:10,836 --> 02:00:14,874
OLD HIV COLLEAGUES THAT I REALLY

2678
02:00:14,941 --> 02:00:19,612
APPRECIATE BEING HERE AND

2679
02:00:19,679 --> 02:00:23,015
STRIKES ME FRONT ROW LOOKS SAME

2680
02:00:23,082 --> 02:00:28,821
AS IT DID AT MEETINGS 30 YEARS

2681
02:00:28,888 --> 02:00:31,390
AGO.

2682
02:00:31,457 --> 02:00:31,791
OKAY.

2683
02:00:31,857 --> 02:00:34,260
I WILL TALK A LITTLE -- NOT SO

2684
02:00:34,327 --> 02:00:36,262
MUCH ABOUT VACCINES AND EFFICACY

2685
02:00:36,329 --> 02:00:40,566
AND USING EBOLA MODEL TO REALLY

2686
02:00:40,633 --> 02:00:42,902
UNDERSTAND HOW VACCINE VIRAL

2687
02:00:42,969 --> 02:00:45,237
VECTORS CAN WORK AND WHAT

2688
02:00:45,304 --> 02:00:49,475
ADVANTAGES ARE AND DISADVANTAGES

2689
02:00:49,542 --> 02:00:51,811
OVER OTHER PLATFORMS.

2690
02:00:51,877 --> 02:00:52,945
GOING BACK TO THE VERY BEGINNING

2691
02:00:53,012 --> 02:00:56,916
WHEN I FIRST STARTED TO WORK ON

2692
02:00:56,983 --> 02:01:00,519
EBOLA, THERE HAD BEEN MANY

2693
02:01:00,586 --> 02:01:03,923
VACCINES ELICITING STRONG

2694
02:01:03,990 --> 02:01:04,724
NEUTRALIZING ANTIBODY RESPONSES

2695
02:01:04,790 --> 02:01:07,660
KILLING VACCINES AND IN 90S

2696
02:01:07,727 --> 02:01:10,329
PROTEIN VACCINES BECOMING AN

2697
02:01:10,396 --> 02:01:13,332
ATTAINABLE APPROACH AND

2698
02:01:13,399 --> 02:01:15,501
NEUTRALIZING TIGHTERS WERE SUPER

2699
02:01:15,568 --> 02:01:18,704
HIGH AND ANIMALS DIED AND IN

2700
02:01:18,771 --> 02:01:20,806
SOME CASES GAVE ENHANCED DISEASE

2701
02:01:20,873 --> 02:01:23,843
LIKE IN GUINEA PIG MODEL AND GOT

2702
02:01:23,909 --> 02:01:26,545
ME THINKING DECIDING TO WORK ON

2703
02:01:26,612 --> 02:01:28,381
VACCINES EBOLA VIRUS THINKING

2704
02:01:28,447 --> 02:01:32,752
ABOUT WHAT WOULD BE NEEDED FOR

2705
02:01:32,818 --> 02:01:35,888
EFFECTIVE IMMUNE RESPONSE AND

2706
02:01:35,955 --> 02:01:37,223
EBOLA VIRUS CELLS AND STABLE

2707
02:01:37,289 --> 02:01:40,926
[INDISCERNIBLE] AND HIV AND

2708
02:01:40,993 --> 02:01:42,561
GLYCOE PROTEIN COVERS THE WHOLE

2709
02:01:42,628 --> 02:01:44,330
THING AND IS DENSE AND GIVEN

2710
02:01:44,397 --> 02:01:46,532
SIGN OF VARRION IT IS

2711
02:01:46,599 --> 02:01:46,999
[INDISCERNIBLE] AND

2712
02:01:47,066 --> 02:01:51,671
ACCESSIBILITY OF -- NEUTRALIZING

2713
02:01:51,737 --> 02:01:53,439
ANTIBODIES NEED A LITTLE HELP.

2714
02:01:53,506 --> 02:01:55,241
IT HAS A BROAD TROPHISM.

2715
02:01:55,307 --> 02:01:57,510
SO, WHEN YOU THINK ABOUT

2716
02:01:57,576 --> 02:01:59,111
ANTIBODIES THAT ARE MOSTLY

2717
02:01:59,178 --> 02:02:02,682
CIRCULATING AND HAVE A VIRUS

2718
02:02:02,748 --> 02:02:05,618
GETTING INTO EVERY TISSUE EXCEPT

2719
02:02:05,685 --> 02:02:08,521
T LYMPHOCYTES YOU NEED ANTIBODY

2720
02:02:08,587 --> 02:02:09,989
AND NEED IT EVERYWHERE.

2721
02:02:10,056 --> 02:02:12,091
OTHER THING THAT IS SO

2722
02:02:12,158 --> 02:02:14,493
SUCCESSFULLY THE SELECTED TO DO

2723
02:02:14,560 --> 02:02:17,196
IS RAPIDLY IS INTERNALIZED INTO

2724
02:02:17,263 --> 02:02:19,899
CELLS AND THE RECEPTOR BINDING

2725
02:02:19,965 --> 02:02:22,968
DOMAIN IS NOT ACCESSIBLE UNTIL

2726
02:02:23,035 --> 02:02:25,638
AFTER THE VIRUS IS

2727
02:02:25,705 --> 02:02:26,005
INTRACELLULAR.

2728
02:02:26,072 --> 02:02:27,640
I THOUGHT ABOUT WHAT WOULD BE A

2729
02:02:27,707 --> 02:02:29,942
BETTER APPROACH THAN PROTEIN AND

2730
02:02:30,009 --> 02:02:32,144
LIVE VIRUS THAT ARE ATTENUATED

2731
02:02:32,211 --> 02:02:34,513
VIRUS WOULD BE SOMETHING TO GIVE

2732
02:02:34,580 --> 02:02:37,116
US A POTENT T-CELL IMMUNE

2733
02:02:37,183 --> 02:02:39,185
RESPONSE TO AUGMENT ANTIBODIES.

2734
02:02:39,251 --> 02:02:43,456
I STARTED TO THINK ABOUT VIRAL

2735
02:02:43,522 --> 02:02:44,623
VECTORS BECAUSE MANY CAN

2736
02:02:44,690 --> 02:02:48,127
DIRECTLY TARGET DEN DRIDIC CELLS

2737
02:02:48,194 --> 02:02:50,329
THAT YOU GET BOTH

2738
02:02:50,396 --> 02:02:52,031
CROSS-PRESENTATION AND DIRECT

2739
02:02:52,098 --> 02:02:53,399
PRESENTATION RAMPING UP T-CELL

2740
02:02:53,466 --> 02:02:54,633
RESPONSE AND FIRST THING STARTED

2741
02:02:54,700 --> 02:02:56,502
WITH GOING BACK MANY YEARS AGO

2742
02:02:56,569 --> 02:02:58,504
WHEN PEOPLE JUST STARTED TO WORK

2743
02:02:58,571 --> 02:03:00,873
WITH PRIME BOOST APPROACHES THAT

2744
02:03:00,940 --> 02:03:02,374
HAVE VIRAL VECTORS.

2745
02:03:02,441 --> 02:03:06,045
SO, JUST TO DESCRIBE THE MODEL,

2746
02:03:06,112 --> 02:03:09,949
IT ALWAYS IS MACAQUES THAT ARE

2747
02:03:10,015 --> 02:03:11,150
SMALL STUDIES BECAUSE OF

2748
02:03:11,217 --> 02:03:12,785
LETHALITY AND HIGH CONTAINMENT

2749
02:03:12,852 --> 02:03:16,689
LEVEL NEEDED THAT IS HIGH

2750
02:03:16,756 --> 02:03:20,159
CHALLENGE DOSE AND UNIFORMLY IN

2751
02:03:20,226 --> 02:03:23,095
MACAQUE MODEL AND TARGETS

2752
02:03:23,162 --> 02:03:24,130
NUCLEOPROTEIN THOUGHT WOULD GIVE

2753
02:03:24,196 --> 02:03:27,433
BETTER T-CELL RESPONSES BECAUSE

2754
02:03:27,500 --> 02:03:30,936
OF HIGH AND ROWEN EXPRESSION AND

2755
02:03:31,003 --> 02:03:35,875
TRIED A HETEROL GAUS APPROACH

2756
02:03:35,941 --> 02:03:39,478
PRIMING WITH DNA AND WAS A LONG

2757
02:03:39,545 --> 02:03:41,647
REGIMENT AND FOUND WE GOT

2758
02:03:41,714 --> 02:03:43,082
UNIFORM PROTECTION IN MONKEYS

2759
02:03:43,149 --> 02:03:44,784
THAT FOR US WAS A BREAKTHROUGH

2760
02:03:44,850 --> 02:03:48,420
IN THINKING ABOUT HOW WE MIGHT

2761
02:03:48,487 --> 02:03:50,856
DEVELOP THIS FURTHER FOR

2762
02:03:50,923 --> 02:03:52,391
VACCINES AND MANY YEARS WE

2763
02:03:52,458 --> 02:03:55,327
MANAGED TO BREAK THIS DOWN TO A

2764
02:03:55,394 --> 02:03:58,397
SINGLE DOSE ADENO VIRUS

2765
02:03:58,464 --> 02:04:00,566
PROTECTING THAT GAVE ANTIBODY

2766
02:04:00,633 --> 02:04:02,568
AND T-CELL RESPONSES AND SEE

2767
02:04:02,635 --> 02:04:04,170
HERE A SINGLE SHOT PROTECTION

2768
02:04:04,236 --> 02:04:05,871
THAT IS GOOD AS THE PRIME BOOST

2769
02:04:05,938 --> 02:04:07,740
AND WE WANTED TO UNDERSTAND A

2770
02:04:07,807 --> 02:04:09,375
LITTLE MORE ABOUT WHAT VECTORS

2771
02:04:09,441 --> 02:04:10,743
WERE DOING.

2772
02:04:10,810 --> 02:04:12,344
AND WHAT WAS THE BALANCE OF

2773
02:04:12,411 --> 02:04:14,313
IMMUNE RESPONSES?

2774
02:04:14,380 --> 02:04:16,282
SO, TO GET AT THAT, WE DOSED

2775
02:04:16,348 --> 02:04:18,584
DOWN THE VACCINE TO A POINT WE

2776
02:04:18,651 --> 02:04:20,119
HAVE BREAKTHROUGH IN PROTECTION

2777
02:04:20,186 --> 02:04:22,755
TO START ASSOCIATING IMMUNE

2778
02:04:22,822 --> 02:04:24,123
RESPONSES AT THIS BREAKTHROUGH

2779
02:04:24,190 --> 02:04:26,125
DOSE BETWEEN 10 TO THE 9TH AND

2780
02:04:26,192 --> 02:04:28,627
10 TO THE 11TH AND LOOKING AT

2781
02:04:28,694 --> 02:04:32,665
T-CELLS WE DO BY INTRACELLULAR

2782
02:04:32,731 --> 02:04:34,433
CYTOKINE STAINING AND PBCS FROM

2783
02:04:34,500 --> 02:04:36,535
THE ANIMALS AND YOU CAN SEE WHAT

2784
02:04:36,602 --> 02:04:40,139
MIGHT BE A LITTLE BIT OF A TREND

2785
02:04:40,206 --> 02:04:42,441
FOR HIGHER CD8 T-CELL RESPONSES

2786
02:04:42,508 --> 02:04:45,144
IN SURVIVORS THAN FATALITIES AND

2787
02:04:45,211 --> 02:04:47,913
WHAT STOOD OUT WAS IN THE

2788
02:04:47,980 --> 02:04:49,548
BREAKTHROUGH DOSE WE HAD A CLEAR

2789
02:04:49,615 --> 02:04:51,951
DISTINCTION BETWEEN SURVIVORS

2790
02:04:52,017 --> 02:04:52,918
AND MORTALITIES AND WHOLE

2791
02:04:52,985 --> 02:04:54,653
PREMISE HAD BEEN THAT YOU NEEDED

2792
02:04:54,720 --> 02:04:57,823
MORE THAN AN ANTIBODY RESPONSE.

2793
02:04:57,890 --> 02:04:59,391
THIS WAS A LITTLE PERPLEXING WE

2794
02:04:59,458 --> 02:05:01,594
ARE USING VECTORS AND LOOKS LIKE

2795
02:05:01,660 --> 02:05:03,596
AN ANTIBODY RESPONSE DOING THE

2796
02:05:03,662 --> 02:05:06,298
WORK AND IS A SERIES OF STUDIES

2797
02:05:06,365 --> 02:05:08,400
TRYING TO OPTIMIZE THE ANTIGEN

2798
02:05:08,467 --> 02:05:10,936
AND NOTICE THAT A COUPLE

2799
02:05:11,003 --> 02:05:13,072
REGIMENTS AGAIN GAVE US

2800
02:05:13,138 --> 02:05:17,776
BREAKTHROUGH THAT WASN'T A DOSE

2801
02:05:17,843 --> 02:05:21,280
DIFFERENCE BUT CHANGE IN INSERT

2802
02:05:21,347 --> 02:05:24,149
AND FIRST TIME WE SAW NOT

2803
02:05:24,216 --> 02:05:25,517
ANTIBODIES BUT T-CELLS NOW THAT

2804
02:05:25,584 --> 02:05:27,720
WERE SEGREGATING WITH THE

2805
02:05:27,786 --> 02:05:30,089
ANIMALS THAT WERE PROTECTED IN

2806
02:05:30,155 --> 02:05:31,357
THE VACCINE REGIMENT.

2807
02:05:31,423 --> 02:05:33,192
WE WANTED TO TEST THIS MORE

2808
02:05:33,259 --> 02:05:34,460
DIRECTLY.

2809
02:05:34,526 --> 02:05:38,264
SO, WE LOOKED AT AFTER

2810
02:05:38,330 --> 02:05:39,598
VACCINATION, IN -- SORRY.

2811
02:05:39,665 --> 02:05:42,735
IN VACCINATING A CONTROL GROUP

2812
02:05:42,801 --> 02:05:45,704
AND HAVING ANOTHER GROUP WASN'T

2813
02:05:45,771 --> 02:05:47,172
VACCINATED WE TOOK

2814
02:05:47,239 --> 02:05:49,842
VACCINE-INDUCED ANTIBODIES FROM

2815
02:05:49,909 --> 02:05:54,146
A COHORT OF ANIMALS INFUSING

2816
02:05:54,213 --> 02:05:56,615
ANTIBODIES PRIOR TO INFECTIOUS

2817
02:05:56,682 --> 02:05:58,150
CHALLENGES AND DETERMINED A

2818
02:05:58,217 --> 02:06:03,355
CUTOFF FOR ANTIBODIES TO BE 1 IN

2819
02:06:03,422 --> 02:06:03,889
3,000.

2820
02:06:03,956 --> 02:06:05,491
WE SAW THE VACCINATED GROUP HAD

2821
02:06:05,557 --> 02:06:08,227
A CUTOFF FOR PROTECTION AND

2822
02:06:08,294 --> 02:06:12,164
INFUSED ANTIBODY WAS ORDERS OF

2823
02:06:12,231 --> 02:06:15,868
MAGNITUDE WE NEED FOR PROTECTION

2824
02:06:15,935 --> 02:06:17,870
AND UNVACCINATED ANIMALS DIDN'T

2825
02:06:17,937 --> 02:06:20,873
HAVE ANYTHING AND TO SURPRISE

2826
02:06:20,940 --> 02:06:26,045
HAD LITTLE PROTECTION OF ANIMALS

2827
02:06:26,111 --> 02:06:27,846
MASSIVE [INDISCERNIBLE] TO

2828
02:06:27,913 --> 02:06:30,049
ANTIBODIES AND POINTING OUT

2829
02:06:30,115 --> 02:06:31,517
T-CELL RESPONSE IS IMPORTANT

2830
02:06:31,583 --> 02:06:34,820
THAT IS NOW VERY CHALLENGING TO

2831
02:06:34,887 --> 02:06:37,523
TRY TO INFUSE T-CELLS AND WE

2832
02:06:37,589 --> 02:06:38,757
FLIPPED THE EXPERIMENT AROUND

2833
02:06:38,824 --> 02:06:41,493
AND VACCINATED AND DEPLETED THE

2834
02:06:41,560 --> 02:06:43,062
T-CELLS PRIOR TO INFECTION.

2835
02:06:43,128 --> 02:06:46,532
AND WHAT WE SAW HERE NOW WAS

2836
02:06:46,598 --> 02:06:48,834
THAT WE REALLY ELIMINATED

2837
02:06:48,901 --> 02:06:50,235
PROTECTION ON WHAT ANIMALS

2838
02:06:50,302 --> 02:06:52,805
DIDN'T HAVE A CD8 T-CELL

2839
02:06:52,871 --> 02:06:56,175
RESPONSE AND SUGGESTED THAT

2840
02:06:56,241 --> 02:06:57,476
OBVIOUSLY ANTIBODIES AND T-CELLS

2841
02:06:57,543 --> 02:07:00,479
ARE DOING SOMETHING AND

2842
02:07:00,546 --> 02:07:01,880
ANTIBODIES ARE NOT SUFFICIENT

2843
02:07:01,947 --> 02:07:04,750
AND CD8 T-CELLS ARE REQUIRED

2844
02:07:04,817 --> 02:07:06,085
TELLING US MORE ABOUT WHAT

2845
02:07:06,151 --> 02:07:08,287
VECTORS ARE DOG AND WE HAD

2846
02:07:08,354 --> 02:07:10,055
ANOTHER INDIRECT WAY OF SEEING

2847
02:07:10,122 --> 02:07:11,523
THIS THAT IS BY CHANCE.

2848
02:07:11,590 --> 02:07:13,625
SO, WE HAD VACCINATED A COHORT

2849
02:07:13,692 --> 02:07:15,661
OF ANIMALS WITH DNA WHEN WE

2850
02:07:15,728 --> 02:07:18,330
THOUGHT THAT WE PROABLE WILL I

2851
02:07:18,397 --> 02:07:26,038
WOULD END UP WITH

2852
02:07:26,105 --> 02:07:28,307
[INDISCERNIBLE] AND ABOUT THE

2853
02:07:28,374 --> 02:07:30,576
TIME THAT VIRUS WAS DISCOVERED

2854
02:07:30,642 --> 02:07:31,577
IN 2007.

2855
02:07:31,643 --> 02:07:34,813
WE THOUGHT COULD WE POSSIBLY GET

2856
02:07:34,880 --> 02:07:36,315
CROSS-PROTECTION IF WE HAVE A

2857
02:07:36,382 --> 02:07:39,351
GOOD CD8 RESPONSE AND

2858
02:07:39,418 --> 02:07:39,918
CROSS-PROTECTION AGAINST A

2859
02:07:39,985 --> 02:07:43,155
DIFFERENT SPECIES OF EBOLA

2860
02:07:43,222 --> 02:07:43,455
VIRUS?

2861
02:07:43,522 --> 02:07:46,191
ABOUT A YEAR AFTER ANIMALS WERE

2862
02:07:46,258 --> 02:07:49,528
PRIMED WITH DNA BOOSTED THEM

2863
02:07:49,595 --> 02:07:52,331
WITH SINGLE SHOT OF ADENOVIRUS

2864
02:07:52,398 --> 02:07:55,434
AND NOT SURPRISINGLY T-CELL

2865
02:07:55,501 --> 02:07:57,669
EPITOPES ARE MORE EASIER TO GET

2866
02:07:57,736 --> 02:08:00,439
CROSS -- ACROSS DIFFERENT

2867
02:08:00,506 --> 02:08:00,706
SPECIES.

2868
02:08:00,773 --> 02:08:03,042
THEY ARE SMALLER AND GOOD CD4

2869
02:08:03,108 --> 02:08:05,444
RESPONSE AND ALL ANIMALS AGAINST

2870
02:08:05,511 --> 02:08:07,613
[INDISCERNIBLE] OR CD4 AND 8.

2871
02:08:07,679 --> 02:08:15,921
WHAT WAS ENCOURAGING IS WE HAD A

2872
02:08:15,988 --> 02:08:19,825
NICE CD4 RESPONSE AND CD8

2873
02:08:19,892 --> 02:08:23,896
RESPONSES AND ANIMAL THAT WERE

2874
02:08:23,962 --> 02:08:26,865
FOR EBOLA EARLIER AND LOOKING AT

2875
02:08:26,932 --> 02:08:29,735
ANTIBODIES HAD NO

2876
02:08:29,802 --> 02:08:30,335
CROSS-REACTIVITY.

2877
02:08:30,402 --> 02:08:33,872
THAT IS BECAUSE FILO VIRUSS ARE

2878
02:08:33,939 --> 02:08:37,643
DIFFERENT AT GLYCOPROTEIN THREE

2879
02:08:37,709 --> 02:08:38,777
DIMENSIONAL LEVELS.

2880
02:08:38,844 --> 02:08:41,480
WE HAVE 100% SURVIVAL THAT SAYS

2881
02:08:41,547 --> 02:08:43,315
REALLY WHAT IS IMPORTANT HERE IS

2882
02:08:43,382 --> 02:08:46,051
T-CELL RESPONSE AND ONE ANIMAL

2883
02:08:46,118 --> 02:08:47,853
WITH VIREMIA LIVED AND TURNED

2884
02:08:47,920 --> 02:08:49,822
OUT TO BE THIS ANIMAL WITH

2885
02:08:49,888 --> 02:08:51,690
LOWEST CD8 RESPONSE AND AGAIN

2886
02:08:51,757 --> 02:08:53,859
POINTING IN A DIFFERENT WAY TO

2887
02:08:53,926 --> 02:08:55,661
THE IMPORTANCE OF THE ABILITY OF

2888
02:08:55,727 --> 02:08:58,397
THE VIRAL VECTORS TO GENERATE

2889
02:08:58,464 --> 02:09:00,532
T-CELL RESPONSES.

2890
02:09:00,599 --> 02:09:04,703
NOW, WE HAD BEEN BASICALLY OUR

2891
02:09:04,770 --> 02:09:08,841
PLATFORM ON AD5 BACK BEFORE HIV

2892
02:09:08,907 --> 02:09:10,642
STEP CROWD RESULT SHOWING IF

2893
02:09:10,709 --> 02:09:13,712
PEOPLE ARE AD5 IMMUNE BECAUSE OF

2894
02:09:13,779 --> 02:09:15,047
[INDISCERNIBLE] WITH ACTUAL

2895
02:09:15,114 --> 02:09:16,415
VIRUS THEY DON'T RESPOND TO

2896
02:09:16,482 --> 02:09:18,150
VACCINES AND IN CASES MIGHT BE

2897
02:09:18,217 --> 02:09:18,383
WORSE.

2898
02:09:18,450 --> 02:09:21,954
WE DECIDED TO LOOK AT THIS IN

2899
02:09:22,020 --> 02:09:24,556
MONKEYS AND HAD NAÏVE MONKEYS

2900
02:09:24,623 --> 02:09:28,427
AND ADD FIVE IMMUNE MONKEYS WE

2901
02:09:28,494 --> 02:09:30,729
VACCINATED WITH AD5 VECTOR AND

2902
02:09:30,796 --> 02:09:32,865
INTERESTING THAT WE WERE ABLE TO

2903
02:09:32,931 --> 02:09:37,369
GENERATE ANTIBODIES WITH AD5 IN

2904
02:09:37,436 --> 02:09:40,539
AD5 IMMUNE MONKEYS AND COULDN'T

2905
02:09:40,606 --> 02:09:42,674
GENERATE T-CELL RESPONSES AND IN

2906
02:09:42,741 --> 02:09:45,811
THE END WE COULD NOT PROTECT IN

2907
02:09:45,878 --> 02:09:50,983
THOSE ANIMALS LOSING CD8 T-CELL

2908
02:09:51,049 --> 02:09:52,151
RESPONSE.

2909
02:09:52,217 --> 02:09:53,418
INDEPENDENT EVIDENCE THAT T-CELL

2910
02:09:53,485 --> 02:09:55,220
RESPONSE IS IMPORTANT AND NICE

2911
02:09:55,287 --> 02:09:56,655
FOR UNDERSTANDING MECHANISMS AND

2912
02:09:56,722 --> 02:09:58,624
NOT SO NICE FOR VACCINE THAT WE

2913
02:09:58,690 --> 02:10:00,459
ARE TRYING TO DEVELOP THAT IS

2914
02:10:00,526 --> 02:10:02,261
BASED ON AD5.

2915
02:10:02,327 --> 02:10:03,996
WE LOOKED AT AND ARE WORKING

2916
02:10:04,062 --> 02:10:11,503
WITH CRUCEL AT THE TIME TO

2917
02:10:11,570 --> 02:10:14,640
MANUFACTURE AD5 AND AD26 AND

2918
02:10:14,706 --> 02:10:17,776
AD35 AND LOOKING AT ZERO

2919
02:10:17,843 --> 02:10:19,545
PREVALENCE RED IS HIGH AND BLUE

2920
02:10:19,611 --> 02:10:24,483
IS LOW AND ADD 26 AND ADD 35 AND

2921
02:10:24,550 --> 02:10:27,186
IN US HAD ALMOST ZERO PREVALENCE

2922
02:10:27,252 --> 02:10:31,657
IN AFRICA 35 AND OTHER PARTS OF

2923
02:10:31,723 --> 02:10:37,629
AFRICA AND WE DECIDED TO MOVE

2924
02:10:37,696 --> 02:10:40,933
FORWARD WITH AD26 AND AD35 AND

2925
02:10:40,999 --> 02:10:43,202
SET UP SAME EXPERIMENTS AND

2926
02:10:43,268 --> 02:10:44,937
MONKEYS IN SAME DOSE RANGE I'M

2927
02:10:45,003 --> 02:10:47,206
SHOWING HERE 10 TO THE 10TH AND

2928
02:10:47,272 --> 02:10:49,575
10 TO THE ELEVENTH AND REMEMBER

2929
02:10:49,641 --> 02:10:52,344
IS A NONREPLICATING VECTOR AND

2930
02:10:52,411 --> 02:10:55,113
DOSES SEEM HIGH BUT NOT WHEN YOU

2931
02:10:55,180 --> 02:10:57,416
CONSIDER IT IS NOT

2932
02:10:57,482 --> 02:10:59,318
NONREPLICATING AND SURPRISING AT

2933
02:10:59,384 --> 02:11:01,220
LOW DOSE DIDN'T GET GOOD

2934
02:11:01,286 --> 02:11:03,188
PROTECTION AND HIGH DOSE WE GET

2935
02:11:03,255 --> 02:11:04,756
NO PROTECTION AND WAS SO

2936
02:11:04,823 --> 02:11:06,992
STRANGE.  WE ARE THINKING ADENO

2937
02:11:07,059 --> 02:11:09,828
VIRUS IS AN ADENO VIRUS AND WHY

2938
02:11:09,895 --> 02:11:13,332
COULD THIS BE AND LOOKED AT AD26

2939
02:11:13,398 --> 02:11:15,234
AND FOUND SAME THING NOT GIVING

2940
02:11:15,300 --> 02:11:18,337
SAME RESULT THAT AD5 GAVE US AND

2941
02:11:18,403 --> 02:11:20,539
THOUGHT MAYBE T-CELLS ARE BETTER

2942
02:11:20,606 --> 02:11:24,810
AND LOOKING AT CD4 AND CD8 AND

2943
02:11:24,876 --> 02:11:27,279
STUNNING NO DIFFERENCES IN CD4

2944
02:11:27,346 --> 02:11:29,881
AND CD8 RESPONSES YET WE WERE

2945
02:11:29,948 --> 02:11:31,783
NOT GETTING PROTECTION AND

2946
02:11:31,850 --> 02:11:33,218
ANTIBODY RESPONSES WERE SIMILAR

2947
02:11:33,285 --> 02:11:34,953
AND T-CELL RESPONSES WERE

2948
02:11:35,020 --> 02:11:36,722
SIMILAR BUT NOT GETTING

2949
02:11:36,788 --> 02:11:39,491
PROTECTION AND AT TIME MARIO AT

2950
02:11:39,558 --> 02:11:42,461
VRC HAD DONE AN AWFUL LOT TO

2951
02:11:42,527 --> 02:11:44,796
DEFINE T-CELL PHENOTYPES BASED

2952
02:11:44,863 --> 02:11:47,833
ON INTRACELLULAR CYTOKINE

2953
02:11:47,899 --> 02:11:49,835
STAINING AND WAY WE DO THIS IS

2954
02:11:49,901 --> 02:11:53,071
IF YOU MEASURE IBT FEARON GAMMA

2955
02:11:53,138 --> 02:11:56,775
IN CRM OR CELLS IBT FEARON GAMMA

2956
02:11:56,842 --> 02:11:59,845
IS NOT COMING FROM SITE THAT

2957
02:11:59,911 --> 02:12:03,382
MAKES CYTOKINE COMING FROM GAMMA

2958
02:12:03,448 --> 02:12:06,618
WITH -- 3 AND 4 AND 5 CYTOKINES

2959
02:12:06,685 --> 02:12:09,321
AND TURNS OUT CHOOSING THREE

2960
02:12:09,388 --> 02:12:11,056
COMBINATIONS OF CYTOKINES YOU

2961
02:12:11,123 --> 02:12:13,392
CAN REALLY DISTINGUISH BETWEEN

2962
02:12:13,458 --> 02:12:16,595
TERMINAL EFFECTORS, EFFECTORS

2963
02:12:16,662 --> 02:12:18,497
AND MEMORY T-CELLS AND DECIDING

2964
02:12:18,563 --> 02:12:21,400
TO TAKE A LOOK AT THIS IN OUR

2965
02:12:21,466 --> 02:12:21,700
EXPERIMENT.

2966
02:12:21,767 --> 02:12:24,569
EACH OF THE SUBSETS IS

2967
02:12:24,636 --> 02:12:25,570
FUNCTIONALLY DISTINCT.

2968
02:12:25,637 --> 02:12:27,339
COULD WE SEE A DIFFERENCE?

2969
02:12:27,406 --> 02:12:30,342
FIRST THING THAT STRUCK US IS

2970
02:12:30,409 --> 02:12:32,511
PROTECTIVE VACCINE IS GENERATING

2971
02:12:32,577 --> 02:12:35,514
MORE CELLS PRODUCING TWO

2972
02:12:35,580 --> 02:12:36,248
CYTOKINES SIMULTANEOUSLY.

2973
02:12:36,315 --> 02:12:38,717
AND THAT IS NOT MISSING BUT MUCH

2974
02:12:38,784 --> 02:12:41,486
LOWER IN THE NONPROTECTIVE

2975
02:12:41,553 --> 02:12:44,389
VACCINE AND WHAT WAS MORE

2976
02:12:44,456 --> 02:12:45,757
STRIKING IS THAT WHICH

2977
02:12:45,824 --> 02:12:47,793
CATEGORIES THIS FELL INTO.

2978
02:12:47,859 --> 02:12:49,428
THE PROTECTIVE VACCINE WAS

2979
02:12:49,494 --> 02:12:53,965
GIVING INTERFERON GAMMA TNF

2980
02:12:54,032 --> 02:12:55,500
ALPHA DUAL SECRETING CELLS

2981
02:12:55,567 --> 02:12:58,437
BETTER ASSOCIATED WITH EFFECTOR

2982
02:12:58,503 --> 02:13:00,205
MECHANISMS AND HAVE SOME MEMORY

2983
02:13:00,272 --> 02:13:02,741
AND VACCINE THAT WASN'T

2984
02:13:02,808 --> 02:13:04,976
PROTECTIVE WASN'T GIVING US

2985
02:13:05,043 --> 02:13:08,146
THOSE BUT MORE OF A SINGLE

2986
02:13:08,213 --> 02:13:10,749
CYTOKINE IL2 THAT IS ASSOCIATED

2987
02:13:10,816 --> 02:13:13,318
WITH MEMORY AND NOT INITIAL

2988
02:13:13,385 --> 02:13:15,620
EFFECTOR RESPONSE THAT YOU WOULD

2989
02:13:15,687 --> 02:13:17,255
NEED FOR AN EBOLA INFECTION THAT

2990
02:13:17,322 --> 02:13:19,324
IS PRETTY AGGRESSIVE AND

2991
02:13:19,391 --> 02:13:20,826
SCRATCHING HEADS AGAIN ABOUT WHY

2992
02:13:20,892 --> 02:13:24,262
THIS IS.  TURNS OUT IT IS A

2993
02:13:24,329 --> 02:13:26,164
SIMPLE EXPLANATION AND DIFFERENT

2994
02:13:26,231 --> 02:13:28,567
ADENO VIRUS VECTORS TARGET

2995
02:13:28,633 --> 02:13:30,302
DIFFERENT DENDRITIC CELLS AND

2996
02:13:30,369 --> 02:13:32,270
I'M SURE OTHER CELLS ARE

2997
02:13:32,337 --> 02:13:34,306
DIFFERENT AND SEEN EVEN WHEN

2998
02:13:34,373 --> 02:13:36,842
DOING TISSUE BIOPSIES YOU CAN

2999
02:13:36,908 --> 02:13:39,478
SEE INFLUX OF IMMUNE CELLS TO

3000
02:13:39,544 --> 02:13:41,413
SITE OF INFECTION IS SPECIFIC TO

3001
02:13:41,480 --> 02:13:43,014
THE VECTOR AND EXPLAINED IT FOR

3002
02:13:43,081 --> 02:13:44,416
US AND DIDN'T SOLVE OUR PROBLEM

3003
02:13:44,483 --> 02:13:46,885
THAT IS NOT HAVING A VIRAL

3004
02:13:46,952 --> 02:13:49,521
VECTOR AS A VACCINE AND NEEDED A

3005
02:13:49,588 --> 02:13:51,757
SINGLE SHOT THAT WOULD ACT VERY

3006
02:13:51,823 --> 02:13:56,128
QUICKLY AND TURNED TO NON-HUMAN

3007
02:13:56,194 --> 02:14:00,732
DERIVED ADENOVIRAL VECTOR OR

3008
02:14:00,799 --> 02:14:04,102
VECTORS BEING DISCOVERED BY A

3009
02:14:04,169 --> 02:14:06,171
TINY COMPANY IN ITALY HAD DONE

3010
02:14:06,238 --> 02:14:10,175
THESE VIRUSES AND PICKED ONE IN

3011
02:14:10,242 --> 02:14:12,711
AD5 FAMILY THAT IS WORKING

3012
02:14:12,778 --> 02:14:14,813
THROUGH SAME RECEPTOR AND

3013
02:14:14,880 --> 02:14:17,416
ANOTHER FROM THE GROUP E.

3014
02:14:17,482 --> 02:14:19,518
WE WANTED A SECOND VACCINE AND

3015
02:14:19,584 --> 02:14:22,354
LOOKING AT T-CELL RESPONSES IS

3016
02:14:22,421 --> 02:14:25,724
SHOWING YOU HOW SIMILAR AD26 AND

3017
02:14:25,791 --> 02:14:27,692
AD35 ARE FOR PROFILES AND

3018
02:14:27,759 --> 02:14:30,962
LOOKING AT 5 AND CHIMP AD3 AND

3019
02:14:31,029 --> 02:14:32,664
POST DOC ACTUALLY THAT DID THIS

3020
02:14:32,731 --> 02:14:36,067
I ASKED HIM TO GO BACK AND REDO

3021
02:14:36,134 --> 02:14:36,701
IT.

3022
02:14:36,768 --> 02:14:39,171
I COULDN'T BELIEVE THAT CHIMP

3023
02:14:39,237 --> 02:14:41,406
AD3 LOOKED SIMILAR TO AD5 AND

3024
02:14:41,473 --> 02:14:43,909
QUALITIES BY INTRACELLULAR

3025
02:14:43,975 --> 02:14:46,011
CYTOKINE CAN BE TRICKY AND I

3026
02:14:46,077 --> 02:14:47,112
REALLY DIDN'T BELIEVE IT AT

3027
02:14:47,179 --> 02:14:47,679
FIRST.

3028
02:14:47,746 --> 02:14:49,581
TURNED OUT TO BE TRUE IT WAS

3029
02:14:49,648 --> 02:14:51,316
REALLY REPLICATING WHAT WE SAW

3030
02:14:51,383 --> 02:14:55,654
FOR AD5 THAT WAS SPECIFICALLY

3031
02:14:55,720 --> 02:14:58,089
TNF INTERFERON GAMMA A NICE

3032
02:14:58,156 --> 02:14:59,291
BALANCE BETWEEN EFFECTOR AND

3033
02:14:59,357 --> 02:15:01,660
MEMORY AND GIVES A REALLY GOOD

3034
02:15:01,726 --> 02:15:04,729
RESPONSE AND THEY DON'T BURN OUT

3035
02:15:04,796 --> 02:15:05,330
QUICKLY.

3036
02:15:05,397 --> 02:15:07,699
WE TESTED THESE IN MONKEYS AND

3037
02:15:07,766 --> 02:15:10,769
SHOWED IT WAS INTERESTING THAT

3038
02:15:10,836 --> 02:15:16,107
CHIMP AD PERFORMED WELL IN TERMS

3039
02:15:16,174 --> 02:15:19,010
OF ANTIBODY RESPONSES AND NEVER

3040
02:15:19,077 --> 02:15:21,012
PURSUED THAT TURNED OUT TO BE A

3041
02:15:21,079 --> 02:15:23,715
GREAT VECTOR ANYWAY AND CD4 AND

3042
02:15:23,782 --> 02:15:29,521
CD8 AND COMPARED TO 5 CHIMP AD5

3043
02:15:29,588 --> 02:15:31,089
VECTOR GAVE BETTER RESPONSES

3044
02:15:31,156 --> 02:15:34,559
THAN WHAT WE HAVE SEEN ON

3045
02:15:34,626 --> 02:15:38,196
AVERAGE AND FOR THE AD5 RESULT

3046
02:15:38,263 --> 02:15:39,331
AND WANTED TO ASK ABOUT

3047
02:15:39,397 --> 02:15:41,399
PROTECTION AND LOOKING AT ACUTE

3048
02:15:41,466 --> 02:15:42,567
PROTECTION THAT WE ARE DOING

3049
02:15:42,634 --> 02:15:44,669
MOST OF THE TIME FOR THE STUDIES

3050
02:15:44,736 --> 02:15:48,807
IS WE WANT A FAST-ACTING VACCINE

3051
02:15:48,874 --> 02:15:51,176
AND CHIMP AD3 GAVE SAME

3052
02:15:51,243 --> 02:15:54,179
PROTECTION AS CHIMP AD5 AND 63

3053
02:15:54,246 --> 02:15:56,281
IS PREDICTED FROM LOWER

3054
02:15:56,348 --> 02:15:58,750
RESPONSES ANTIBODY AND T-CELLS

3055
02:15:58,817 --> 02:16:00,118
DIDN'T AFFORD PROTECTION.

3056
02:16:00,185 --> 02:16:03,021
WHAT HAD NOT BEEN DONE TO THIS

3057
02:16:03,088 --> 02:16:05,123
POINT I THINK IS NOT STILL BEING

3058
02:16:05,190 --> 02:16:06,958
DONE FOR VACCINE PLATFORMS IS

3059
02:16:07,025 --> 02:16:08,360
TRYING TO UNDERSTAND WHAT IS

3060
02:16:08,426 --> 02:16:10,662
REQUIRED FOR DURABLE PROTECTION

3061
02:16:10,729 --> 02:16:12,864
AND WHEN YOU MAKE A VACCINE TO

3062
02:16:12,931 --> 02:16:14,799
GIVE YOU FAST PROTECTION YOU ARE

3063
02:16:14,866 --> 02:16:17,002
ASKING IT TO DO TWO DIFFERENT

3064
02:16:17,068 --> 02:16:19,004
THINGS, FAST AND LONG AND CAME

3065
02:16:19,070 --> 02:16:22,107
UP WHEN TALKING ABOUT MRNA.

3066
02:16:22,173 --> 02:16:23,842
YOU EXPECT TO PEAK AND CRASH

3067
02:16:23,909 --> 02:16:26,278
FAST AND LOOKING AT SINGLE SHOT

3068
02:16:26,344 --> 02:16:29,681
VACCINE FOR PROTECTION IN CHIMP

3069
02:16:29,748 --> 02:16:31,883
AD3 AND GAVE 50% PROTECTION AT A

3070
02:16:31,950 --> 02:16:34,653
YEAR THAT IS GOOD AND CHIMP AD63

3071
02:16:34,719 --> 02:16:36,555
DID NOT AND WAS DEPENDENT GOING

3072
02:16:36,621 --> 02:16:38,657
UP A LITTLE ON THE DOSE AND GOT

3073
02:16:38,723 --> 02:16:40,859
US THINKING ABOUT, YOU KNOW, HOW

3074
02:16:40,926 --> 02:16:42,761
CAN WE USE VIRAL VECTORS AND

3075
02:16:42,827 --> 02:16:45,030
SEEN WE CAN TUNE THEM NOW WITH

3076
02:16:45,096 --> 02:16:47,566
DNA AND ADENOVIRUS AND TUNE

3077
02:16:47,632 --> 02:16:49,668
IMMUNE RESPONSES AND CAN WE DO

3078
02:16:49,734 --> 02:16:51,937
THIS MORE AND EXTEND MEMORY AND

3079
02:16:52,003 --> 02:16:55,006
MBA IS KNOWN TO GENERATE VERY

3080
02:16:55,073 --> 02:16:56,575
POTENT CD4 RESPONSES THAT YOU

3081
02:16:56,641 --> 02:16:59,544
NEED FOR MEMORY AND GOOD CD8

3082
02:16:59,611 --> 02:17:01,379
RESPONSES AND GAVE YOU LONG-TERM

3083
02:17:01,446 --> 02:17:04,916
MEMORY AND DECIDED TO TRY PRIDE

3084
02:17:04,983 --> 02:17:07,752
BOOSTING WITH CHIMP 3 FOR FAST

3085
02:17:07,819 --> 02:17:09,621
RESPONSE AND MVA TO EXTEND

3086
02:17:09,688 --> 02:17:11,723
DURABILITY AND WILL SHOW YOU

3087
02:17:11,790 --> 02:17:13,858
IMMUNE RESPONSES IN BOOST THAT

3088
02:17:13,925 --> 02:17:15,827
WE WILL CALL PEAK RESPONSES AND

3089
02:17:15,894 --> 02:17:17,896
MEMORY RESPONSE AT TIME OF THE

3090
02:17:17,963 --> 02:17:21,366
CHALLENGE AND SO WHEN WE LOOK AT

3091
02:17:21,433 --> 02:17:24,302
ANTIBODY, THE CHIMP AD 3 BOOSTED

3092
02:17:24,369 --> 02:17:26,471
BY MVA GIVES MEMORY RESPONSES

3093
02:17:26,538 --> 02:17:30,208
THAT ARE HIGHER THAN THE PEAK

3094
02:17:30,275 --> 02:17:34,112
SINGLE SHOT SO THAT MVA IS

3095
02:17:34,179 --> 02:17:35,847
BOOSTING AND IS DURABLE WHEN WE

3096
02:17:35,914 --> 02:17:40,952
LOOK OUT AT A LONG TIME AND

3097
02:17:41,019 --> 02:17:45,957
MAGNITUDE AT PEAK PRIME BOOST IS

3098
02:17:46,024 --> 02:17:49,060
FOR -- LIKEWISE FOR CD4, MEMORY

3099
02:17:49,127 --> 02:17:51,296
RESPONSE AT A YEAR BOOSTED BY

3100
02:17:51,363 --> 02:17:53,331
MVA WAS AS HIGH AS PEAK RESPONSE

3101
02:17:53,398 --> 02:17:54,599
AFTER A SINGLE SHOT.

3102
02:17:54,666 --> 02:17:57,836
THAT WAS NOT THE CASE FOR CD8.

3103
02:17:57,902 --> 02:17:59,738
THIS WAS SOMEWHAT EXPECTED.

3104
02:17:59,804 --> 02:18:03,008
WE KNOW MVA IS GOOD AT BOOSTING

3105
02:18:03,074 --> 02:18:04,676
CD4 RESPONSES THAT TELLS YOU NOW

3106
02:18:04,743 --> 02:18:07,345
THAT WITH A DIFFERENT PRIMING

3107
02:18:07,412 --> 02:18:09,381
AND BOOSTING YOU CAN DIRECT

3108
02:18:09,447 --> 02:18:10,749
IMMUNE RESPONSE TO GO IN

3109
02:18:10,815 --> 02:18:13,818
WHATEVER DIRECTION YOU WANT AND

3110
02:18:13,885 --> 02:18:15,720
SO WHEN WE COMPARE I WANT TO GO

3111
02:18:15,787 --> 02:18:18,123
A LITTLE ABOUT THE PRIMING

3112
02:18:18,189 --> 02:18:18,923
MATTERS.

3113
02:18:18,990 --> 02:18:22,827
SO, WE ALSO BOOSTED CHIMP AD 63

3114
02:18:22,894 --> 02:18:25,296
AND SEE PEAK RESPONSES AFTER MVA

3115
02:18:25,363 --> 02:18:30,001
ARE LOWER AND MEMORY RESPONSES

3116
02:18:30,068 --> 02:18:33,004
ARE LOWER AND NOT BOOST THAT IS

3117
02:18:33,071 --> 02:18:36,207
DETERMINING WHAT YOU GET BUT IS

3118
02:18:36,274 --> 02:18:39,878
PRIME FOR MAGNITUDE AND TESTING

3119
02:18:39,944 --> 02:18:42,247
DURABLE PROTECTION WITH MVA

3120
02:18:42,313 --> 02:18:44,616
BOOST WE CAN EXTEND IT AND 50%

3121
02:18:44,683 --> 02:18:47,452
PROTECTION WE GET 100%

3122
02:18:47,519 --> 02:18:49,421
PROTECTION AND CD4 RESPONSE IS

3123
02:18:49,487 --> 02:18:53,024
GIVING LONGER TERM MEMORY AND

3124
02:18:53,091 --> 02:18:56,561
WANT TO GO IN A LITTLE MORE TO

3125
02:18:56,628 --> 02:18:58,163
THIS IDEA TUNE IMMUNE RESPONSE

3126
02:18:58,229 --> 02:19:00,832
AND GOING TO DNA PRIMED ANIMALS

3127
02:19:00,899 --> 02:19:04,602
WE HAD.  WE WANTED TO UNDERSTAND

3128
02:19:04,669 --> 02:19:06,438
HOW DOES THE NUMBER OF PRIMES

3129
02:19:06,504 --> 02:19:14,846
INFLUENCE WHAT YOU GET AFTER A

3130
02:19:14,913 --> 02:19:15,280
BOOST.

3131
02:19:15,346 --> 02:19:17,949
WE HAVE ANIMALS PRIMED 3 TIMES

3132
02:19:18,016 --> 02:19:21,252
OR 2 TIMES OR ONCE WITH DNA AND

3133
02:19:21,319 --> 02:19:23,154
RECEIVING ADENO VIRUS AND IN

3134
02:19:23,221 --> 02:19:25,857
CASE OF THE BOOST IT IS SAME

3135
02:19:25,924 --> 02:19:28,827
INTERVAL BETWEEN THE LAST PRIME

3136
02:19:28,893 --> 02:19:29,661
AND BOOST.

3137
02:19:29,728 --> 02:19:32,330
AND THIS WAS -- THIS IS ACTUALLY

3138
02:19:32,397 --> 02:19:32,997
INTERESTING.  SOME THAT WORK

3139
02:19:33,064 --> 02:19:36,468
WITH DNA VECTORS MIGHT NOT BE

3140
02:19:36,534 --> 02:19:37,168
SURPRISED.

3141
02:19:37,235 --> 02:19:38,636
YOU CAN CONSIDER THIS A PRIME

3142
02:19:38,703 --> 02:19:40,972
AND THIS A BOOST AND DON'T GET

3143
02:19:41,039 --> 02:19:46,344
MUCH BOOSTING OF ANTIBODIES WITH

3144
02:19:46,411 --> 02:19:46,644
DNA.

3145
02:19:46,711 --> 02:19:49,614
DNA IS NOT GOOD AT INDUCING

3146
02:19:49,681 --> 02:19:50,782
ANTIBODIES AND CD4 RESPONSE IS

3147
02:19:50,849 --> 02:19:53,384
GOOD AND YOU CAN SEE AFTER THREE

3148
02:19:53,451 --> 02:19:56,755
DNA INJECTIONS THAT ANTIBODY

3149
02:19:56,821 --> 02:19:57,789
RESPONSE IS MEASLY.

3150
02:19:57,856 --> 02:20:00,091
WHAT YOU CAN SEE NOW IS THAT THE

3151
02:20:00,158 --> 02:20:02,794
NUMBER OF PRIMES CAN INCREASE

3152
02:20:02,861 --> 02:20:04,329
THE EFFICACY OF THE BOOST.

3153
02:20:04,395 --> 02:20:07,866
SO, WITH MORE DNA PRIMES AND DNA

3154
02:20:07,932 --> 02:20:10,268
ITSELF IS NOT DOING IT WE ARE

3155
02:20:10,335 --> 02:20:12,871
GETTING BOOST WITH ADENO VIRUS

3156
02:20:12,937 --> 02:20:14,706
TUNING THAT IMMUNE RESPONSE AND

3157
02:20:14,773 --> 02:20:18,042
LOOKING AT CD4 AND CD8 RESPONSES

3158
02:20:18,109 --> 02:20:24,149
THIS IS QUITE INTERESTING

3159
02:20:24,215 --> 02:20:29,120
BECAUSE PREPONDERANCE OF CD4

3160
02:20:29,187 --> 02:20:34,559
CELLS INCREASED WITH DNA PRIMES.

3161
02:20:34,626 --> 02:20:39,130
YOU ARE REVERSING BIAS TOWARDS

3162
02:20:39,197 --> 02:20:44,769
CD4 OR CD8 DEPENDING HOW YOU

3163
02:20:44,836 --> 02:20:50,208
PRIME FOR CD8 AND QUALITY TO SEE

3164
02:20:50,275 --> 02:20:53,144
TRIPLE POSSIBILITY QUALITY THAT

3165
02:20:53,211 --> 02:20:57,448
IS LONG-TERM MEMORY THREE TIMES

3166
02:20:57,515 --> 02:21:00,118
PRIMING WITH DNA AND PHENOTYPES

3167
02:21:00,185 --> 02:21:02,353
STAYED THE SAME AND IS SELECTIVE

3168
02:21:02,420 --> 02:21:05,456
WITH WHAT IS BEING BOOSTED AND

3169
02:21:05,523 --> 02:21:08,026
HERE WITH CD8 WE SEE 1 TIMES

3170
02:21:08,092 --> 02:21:11,396
PRIME DOING GIVING MORE

3171
02:21:11,462 --> 02:21:12,363
DESIRABLE RESPONSE.

3172
02:21:12,430 --> 02:21:16,734
ONE TIME PRIME FOR T-CELL

3173
02:21:16,801 --> 02:21:24,475
QUALITY LOOKS LIKE ADENO VIRUS.

3174
02:21:24,542 --> 02:21:28,513
OKAY.  NOW WHEN WE LOOK AT

3175
02:21:28,580 --> 02:21:30,448
MEMORY AND LOOK THREE YEARS

3176
02:21:30,515 --> 02:21:33,117
LATER AT IMMUNE RESPONSES AND

3177
02:21:33,184 --> 02:21:36,588
GIVE ONE DNA BOOSTED BY AD5 OR

3178
02:21:36,654 --> 02:21:39,858
THREE DNAS BOOSTED BY AD5 WE ARE

3179
02:21:39,924 --> 02:21:42,961
NOT SEEING ONE DAY LOOK LIKE

3180
02:21:43,027 --> 02:21:45,830
ADENO VIRUS BUT DNA AND STRONG

3181
02:21:45,897 --> 02:21:48,233
CD4 RESPONSES CD8 RESPONSES

3182
02:21:48,299 --> 02:21:50,501
SUFFER AND CD8 RESPONSES ARE NOT

3183
02:21:50,568 --> 02:21:52,303
DURABLE AND NEED CD4 FOR THAT

3184
02:21:52,370 --> 02:21:54,672
AND SUSPECT IF WE BOOST ANIMALS

3185
02:21:54,739 --> 02:21:57,175
HERE WE GET GOOD CD8 RESPONSES

3186
02:21:57,242 --> 02:21:59,110
THAT TELLS YOU, YOU CAN SET UP

3187
02:21:59,177 --> 02:22:00,812
THE IMMUNE RESPONSE TO DO WHAT

3188
02:22:00,879 --> 02:22:02,881
YOU WANT WITH A DIAL DEPENDING

3189
02:22:02,947 --> 02:22:08,586
HOW YOU USE THESE VECTORS.

3190
02:22:08,653 --> 02:22:12,523
LIKEWISE DOWN HERE YOU EXPECT

3191
02:22:12,590 --> 02:22:14,792
MORE IS BETTER FOR ANTIBODY

3192
02:22:14,859 --> 02:22:18,830
RESPONSE AND IN FACT THAT IS NOT

3193
02:22:18,897 --> 02:22:20,164
THE CASE.

3194
02:22:20,231 --> 02:22:23,668
LOOKING AT INTERVAL WE HAVE A

3195
02:22:23,735 --> 02:22:25,603
GROUP WHERE WE PRIME AND BOOSTED

3196
02:22:25,670 --> 02:22:28,206
14 WEEKS LATER VERSUS PRIMING

3197
02:22:28,273 --> 02:22:30,942
AND BOOSTING A YEAR LATER.

3198
02:22:31,009 --> 02:22:33,912
WHAT WE SEE IS THAT WHEN WE

3199
02:22:33,978 --> 02:22:36,514
BOOST 8 WEEKS POST DNA PRIME, WE

3200
02:22:36,581 --> 02:22:43,488
ARE GETTING A SOLID CD4 RESPONSE

3201
02:22:43,554 --> 02:22:47,625
NOT SO MUCH CD8 RESPONSE AND

3202
02:22:47,692 --> 02:22:49,494
BOOSTING A YEAR AFTER THE PRIME

3203
02:22:49,560 --> 02:22:54,065
IT LOOKS LIKE ADENOVIRUS AND

3204
02:22:54,132 --> 02:23:00,805
WHAT HAPPENED IS AD RESPONSE IS

3205
02:23:00,872 --> 02:23:02,674
CONTRACTED AND DON'T HAVE CD4

3206
02:23:02,740 --> 02:23:05,009
THERE THAT YOU DO WITH DNA AND

3207
02:23:05,076 --> 02:23:06,945
IS BOOSTING WHAT IS SEEN

3208
02:23:07,011 --> 02:23:09,981
RECENTLY AND IS BOOSTING WHAT IS

3209
02:23:10,048 --> 02:23:13,251
THERE AND TUNING IT TOWARDS THE

3210
02:23:13,318 --> 02:23:16,821
VECTOR SEEMS MOST RECENTLY AND

3211
02:23:16,888 --> 02:23:18,790
THINK I WILL STOP THERE TO LEAVE

3212
02:23:18,856 --> 02:23:21,259
TIME FOR QUESTIONS.

3213
02:23:21,326 --> 02:23:25,263
HOW DOES THAT WORK?

3214
02:23:25,330 --> 02:23:26,664
BOTTOM LINE IS DIFFERENT VIRAL

3215
02:23:26,731 --> 02:23:28,333
VECTORS WORK IN DIFFERENT WAYS

3216
02:23:28,399 --> 02:23:33,271
AND VSV I DIDN'T TALK ABOUT IS

3217
02:23:33,338 --> 02:23:34,305
COMPLETELY DIFFERENT.

3218
02:23:34,372 --> 02:23:37,208
THAT VACCINE DESIGN IS SUCH THAT

3219
02:23:37,275 --> 02:23:40,712
IT IS DIRECTING THE VECTOR TO

3220
02:23:40,778 --> 02:23:44,315
EVERY TISSUE YOU WOULD SEE EBOLA

3221
02:23:44,382 --> 02:23:45,817
AND INTRAMUSCULAR RESPONSES GO

3222
02:23:45,883 --> 02:23:46,784
EVERYWHERE AND COMPLETELY

3223
02:23:46,851 --> 02:23:48,219
DIFFERENT STORY AND DIDN'T TALK

3224
02:23:48,286 --> 02:23:50,455
ABOUT INNATE RESPONSES WHICH IS

3225
02:23:50,521 --> 02:23:53,458
DIFFERENT AND IS USING VIRAL

3226
02:23:53,524 --> 02:23:55,927
VECTORS TO TUNE ADAPTIVE

3227
02:23:55,994 --> 02:23:58,463
IMMUNITY TO SEE CHOICE OF ADENO

3228
02:23:58,529 --> 02:24:00,932
VIRUS VECTOR TO DIRECT NEW ONE

3229
02:24:00,999 --> 02:24:02,300
DIRECTION OR ANOTHER.

3230
02:24:02,367 --> 02:24:04,268
SEQUENCE OF PRIME BOOSTING WHAT

3231
02:24:04,335 --> 02:24:06,337
COMES FIRST OR SECOND AND HOW

3232
02:24:06,404 --> 02:24:11,509
MANY PRIMES YOU HAVE BEFORE THE

3233
02:24:11,576 --> 02:24:13,311
BOOST AND INTERVAL BETWEEN PRIME

3234
02:24:13,378 --> 02:24:16,280
AND BOOST ARE TOOLS TO USE WITH

3235
02:24:16,347 --> 02:24:17,448
VECTORS TO TUNE IMMUNE RESPONSE

3236
02:24:17,515 --> 02:24:19,417
TO WHAT YOU KNOW IS THE

3237
02:24:19,484 --> 02:24:22,153
MECHANISM OF IMMUNITY IN MOST

3238
02:24:22,220 --> 02:24:24,255
CASES HOPEFULLY BEFORE YOU START

3239
02:24:24,322 --> 02:24:24,622
STUDIES.

3240
02:24:24,689 --> 02:24:26,257
I WILL STOP WITH A SLIDE AND

3241
02:24:26,324 --> 02:24:30,128
LOTS OF YEARS AND PEOPLE.

3242
02:24:30,194 --> 02:24:32,163
THIS IS NOT ALL HANDS OF COURSE

3243
02:24:32,230 --> 02:24:35,299
AND APPRECIATE WHAT THEY DONE

3244
02:24:35,366 --> 02:24:38,803
AND APPRECIATE YOU FOR YOUR

3245
02:24:38,870 --> 02:24:39,437
ATTENTION.

3246
02:24:39,504 --> 02:24:39,971
THANK YOU.

3247
02:24:40,038 --> 02:24:44,709
>> AUDIENCE:  [APPLAUSE].

3248
02:24:44,776 --> 02:24:50,415
>> I WILL ASK A STUPID QUESTION.

3249
02:24:50,481 --> 02:24:50,815
[INDISCERNIBLE].

3250
02:24:50,882 --> 02:24:53,484
>> SO, DEPENDS ON WHEN YOU ARE

3251
02:24:53,551 --> 02:24:54,952
LOOKING; RIGHT?

3252
02:24:55,019 --> 02:24:56,454
IF YOU LOOK SHORT TERM THREE

3253
02:24:56,521 --> 02:24:59,924
TIMES IS ACTUALLY BETTER FOR

3254
02:24:59,991 --> 02:25:03,061
ANTIBODY RESPONSES.

3255
02:25:03,127 --> 02:25:05,063
DURABLE RESPONSE.

3256
02:25:05,129 --> 02:25:06,964
I THINK WHAT HAPPENS WHEN

3257
02:25:07,031 --> 02:25:10,001
LOOKING AT CONTRACTED RESPONSE

3258
02:25:10,068 --> 02:25:13,337
WHAT YOU BOOST WITH WILL TAKE

3259
02:25:13,404 --> 02:25:17,542
OVER PHENOTYPE YOU SEE AND IS

3260
02:25:17,608 --> 02:25:20,311
IMMUNOLOGICALLY BASED.

3261
02:25:20,378 --> 02:25:22,847
YOU COULD THINK OF SCENARIOS TO

3262
02:25:22,914 --> 02:25:24,248
PRIME TOO MUCH AND GET FEEDBACK

3263
02:25:24,315 --> 02:25:26,551
THAT REALLY -- THAT HAPPENS.  I

3264
02:25:26,617 --> 02:25:29,253
KNOW WITH THE VSV VACCINE YOU

3265
02:25:29,320 --> 02:25:33,958
GET A WHOPPING RESPONSE IN THE

3266
02:25:34,025 --> 02:25:34,926
BEGINNING.

3267
02:25:34,992 --> 02:25:38,062
BOTHINATE AND ADAPTIVE THAT IS

3268
02:25:38,129 --> 02:25:39,897
SHUT DOWN PRETTY QUICKLY AND

3269
02:25:39,964 --> 02:25:41,699
DURABILITY OF VACCINE IS NOT

3270
02:25:41,766 --> 02:25:44,268
GREAT AND MIGHT HAPPEN WITH MRNA

3271
02:25:44,335 --> 02:25:46,804
AND DON'T KNOW IF IT IS AN

3272
02:25:46,871 --> 02:25:48,639
EXPRESSION ISSUE OR FEEDBACK

3273
02:25:48,706 --> 02:25:52,743
FROM IMMUNOGENIC NATURE OF MRNA

3274
02:25:52,810 --> 02:25:55,113
AND CAN'T BE TOO MUCH IN THE

3275
02:25:55,179 --> 02:25:56,414
BEGINNING THAT SHUTS DOWN

3276
02:25:56,481 --> 02:25:57,515
DIFFERENT PATHWAYS.

3277
02:25:57,582 --> 02:26:00,151
>> WITH PRIMES, WHAT IS THE

3278
02:26:00,218 --> 02:26:03,054
LENGTH OF TIME BETWEEN FIRST AND

3279
02:26:03,121 --> 02:26:03,354
SECOND?

3280
02:26:03,421 --> 02:26:05,523
>> I DID TWO EXPERIMENTS.

3281
02:26:05,590 --> 02:26:07,692
FIRST IN THE SECOND PRIMES.

3282
02:26:07,759 --> 02:26:11,028
YEAH.  THOSE ARE ALL FOUR WEEKS.

3283
02:26:11,095 --> 02:26:12,130
YEAH.  YEAH.

3284
02:26:12,196 --> 02:26:16,033
>> CAN YOU TELL ME THE

3285
02:26:16,100 --> 02:26:16,767
[INDISCERNIBLE] BETWEEN

3286
02:26:16,834 --> 02:26:19,837
DIFFERENT ADENO TYPES

3287
02:26:19,904 --> 02:26:21,272
[INDISCERNIBLE] 25 TO SORT OF

3288
02:26:21,339 --> 02:26:23,407
SEE IF WE CAN GENETICALLY

3289
02:26:23,474 --> 02:26:25,576
PREDICT THE TARGET CELLS?

3290
02:26:25,643 --> 02:26:31,415
>> YEAH.  SO, DAN VARUKE 2R50ID

3291
02:26:31,482 --> 02:26:33,851
MAKING A CHIM ERIC VECTOR TO DO

3292
02:26:33,918 --> 02:26:35,486
JUST THAT.

3293
02:26:35,553 --> 02:26:38,055
IT WAS ADD 48 AND ADD 5.

3294
02:26:38,122 --> 02:26:39,223
IT DIDN'T WORK.

3295
02:26:39,290 --> 02:26:42,193
I THINK IT IS A LITTLE

3296
02:26:42,260 --> 02:26:43,928
COMPLICATED AND HEXON AND FIBER

3297
02:26:43,995 --> 02:26:46,264
ARE REALLY DICTATING WHAT

3298
02:26:46,330 --> 02:26:47,832
HAPPENS AT THE SURFACE OF THE

3299
02:26:47,899 --> 02:26:50,134
CELL.  WE ARE NOT QUITE THERE

3300
02:26:50,201 --> 02:26:52,370
YET WHERE YOU CAN PREDICT THE

3301
02:26:52,436 --> 02:26:54,572
RECEPTOR FROM THE SEQUENCE.

3302
02:26:54,639 --> 02:26:55,373
>> THANK YOU.

3303
02:26:55,439 --> 02:26:57,608
>> SOMETHING ABOUT THIS.  SO

3304
02:26:57,675 --> 02:26:57,975
INTERESTING.

3305
02:26:58,042 --> 02:27:01,179
AT THE VERY BEGINNING, I WAS

3306
02:27:01,245 --> 02:27:02,914
LOOKING AT 21 THOUSAND

3307
02:27:02,980 --> 02:27:05,149
DIGITALIZATION TIGHTERS AS DOING

3308
02:27:05,216 --> 02:27:05,850
[INDISCERNIBLE] AND THEN I

3309
02:27:05,917 --> 02:27:08,286
THOUGHT THAT IT IS EBOLA AND HOW

3310
02:27:08,352 --> 02:27:11,489
MUCH OF THAT IS NEUTRALIZED?

3311
02:27:11,556 --> 02:27:14,625
>> NEUTRALIZING RESPONSES, WELL,

3312
02:27:14,692 --> 02:27:16,594
I HAVE TO PARSE THIS NOW.

3313
02:27:16,661 --> 02:27:18,729
YOU CAN DO THE VIRUS

3314
02:27:18,796 --> 02:27:21,599
NEUTRALIZATION AND DO VSV

3315
02:27:21,666 --> 02:27:24,969
NEUTRALIZATION AND CAN DO WHOLE

3316
02:27:25,036 --> 02:27:27,538
VIRUS NEUTRALIZATION.

3317
02:27:27,605 --> 02:27:30,374
WHEN YOU LOOK IN INFECTED

3318
02:27:30,441 --> 02:27:34,078
MONKEYS, POST INFECTION

3319
02:27:34,145 --> 02:27:36,314
NEUTRALIZING RESPONSES BY PLAQUE

3320
02:27:36,380 --> 02:27:38,683
REDUCTION IS IMPRESSIVE AND MORE

3321
02:27:38,749 --> 02:27:41,485
TO DO WITH ASSAY AND DON'T THINK

3322
02:27:41,552 --> 02:27:43,120
IS NEUTRALIZATION, PER-SE, MIKE.

3323
02:27:43,187 --> 02:27:44,655
I DON'T KNOW.  YOU PROBABLY

3324
02:27:44,722 --> 02:27:49,193
REMEMBER THAT PAPER BY ERICA

3325
02:27:49,260 --> 02:27:54,599
SAPPHIRE WHERE SHE TESTED 50 OR

3326
02:27:54,665 --> 02:27:57,501
100 MONOCLONALS IN MICE THAT

3327
02:27:57,568 --> 02:27:59,103
GAVE BEAUTIFUL NEUTRALIZING

3328
02:27:59,170 --> 02:28:00,404
ACTIVITY NO MATTER HOW YOU

3329
02:28:00,471 --> 02:28:04,175
LOOKED THEY DIDN'T PROTECT.

3330
02:28:04,242 --> 02:28:04,976
[INDISCERNIBLE] THAT WE

3331
02:28:05,042 --> 02:28:06,377
DEVELOPED WAS DONE AND WASN'T

3332
02:28:06,444 --> 02:28:09,280
LOOKING FOR ANY ANTIBODIES.  I

3333
02:28:09,347 --> 02:28:11,716
WAS LOOKING FOR AN ANTIBODY THAT

3334
02:28:11,782 --> 02:28:14,452
WOULD BIND TO THE SURFACE

3335
02:28:14,518 --> 02:28:15,886
GLYCOPROTEIN AND BIND TO THE

3336
02:28:15,953 --> 02:28:17,121
CLEAVED PROTEIN ONCE IT IS

3337
02:28:17,188 --> 02:28:19,390
INSIDE OF THE CELL.  THAT WAS

3338
02:28:19,457 --> 02:28:23,027
THE ONLY ANTIBODY I COULD FIND

3339
02:28:23,094 --> 02:28:23,995
THAT DID THAT.

3340
02:28:24,061 --> 02:28:30,935
SAM DID ALL THAT WORK.  IT WAS

3341
02:28:31,002 --> 02:28:37,108
BEAUTI.

3342
02:28:37,408 --> 02:28:39,143
IT IS NOT NEUTRALIZATION HOW WE

3343
02:28:39,210 --> 02:28:42,380
THINK ABOUT IT AND FC AND IN

3344
02:28:42,446 --> 02:28:44,448
TERMS OF ANTIGEN PRESENTATION

3345
02:28:44,515 --> 02:28:47,952
FOR CD8 RESPONSES, FC WILL BE

3346
02:28:48,019 --> 02:28:50,121
HELPFUL AND ALL EXPERIMENTS

3347
02:28:50,187 --> 02:28:52,757
MUTATING FC SHOWING ROLE FOR FC

3348
02:28:52,823 --> 02:28:54,292
IN ANTIBODY RESPONSES WHEN YOU

3349
02:28:54,358 --> 02:28:55,793
MUTATE THE IF.  C YOU ARE DOING

3350
02:28:55,860 --> 02:28:59,463
A WHOLE ARRAY OF THINGS TO THE

3351
02:28:59,530 --> 02:29:01,465
IMMUNE RESPONSE.  IT IS NOT JUST

3352
02:29:01,532 --> 02:29:03,901
KNOCKING OUT THE FC EFFECTOR

3353
02:29:03,968 --> 02:29:05,603
FUNCTION THAT WE THINK ABOUT.

3354
02:29:05,670 --> 02:29:09,273
>> OTHER QUESTIONS HERE?  HOW

3355
02:29:09,340 --> 02:29:13,311
ABOUT ONLINE?  YOU HAVE BEEN

3356
02:29:13,377 --> 02:29:15,646
QUIET THIS MORNING.

3357
02:29:15,713 --> 02:29:18,582
OKAY.  IF NOT, THANK YOU VERY

3358
02:29:18,649 --> 02:29:19,650
MUCH.

3359
02:29:19,717 --> 02:29:21,619
>> THANK YOU!

3360
02:29:21,686 --> 02:29:22,153
>> AUDIENCE:  [APPLAUSE].

3361
02:29:22,219 --> 02:29:25,823
>> WE ARE ON TIME AND WILL BREAK

3362
02:29:25,890 --> 02:29:28,292
FOR LUNCH UNTIL 1:20.

3363
02:29:28,359 --> 02:29:31,028
THERE IS A CAFETERIA JUST TO THE

3364
02:29:31,095 --> 02:29:33,464
LEFT AS YOU LEAVE THE AUDITORIUM

3365
02:29:33,531 --> 02:29:37,335
AND WILL BE A POSTER SESSION.

3366
02:29:37,401 --> 02:29:40,037
PLEASE COME BACK AFTER LUNCH AND

3367
02:29:40,104 --> 02:29:40,838
JOIN US.

3368
02:29:40,905 --> 02:29:43,641
IT IS ABOUT TIME WE GET STARTED.

3369
02:29:43,708 --> 02:29:45,609
I AM NOT SURE PEOPLE OUT IN THE

3370
02:29:45,676 --> 02:29:47,411
LOBBY CAN HEAR ME.

3371
02:29:47,478 --> 02:29:53,751
TIME TO GET STARTED.

3372
02:30:15,906 --> 02:30:16,340
>>.

3373
02:30:16,407 --> 02:30:19,276
HI.  WELL, LET'S GET STARTED.

3374
02:30:19,343 --> 02:30:20,778
I'M HOPING MORE PEOPLE WILL JOIN

3375
02:30:20,845 --> 02:30:23,180
US FROM THE LOBBY AND THERE IS A

3376
02:30:23,247 --> 02:30:26,484
CHANGE IN PROGRAM AND SWITCHING

3377
02:30:26,550 --> 02:30:28,853
ORDERS AND TRULY WILL SWITCH

3378
02:30:28,919 --> 02:30:31,055
PLACES AND NEXT SPEAKER IS CHIP

3379
02:30:31,122 --> 02:30:35,126
WHO RECEIVED MD FROM JOHNS

3380
02:30:35,192 --> 02:30:36,360
HOPKINS UNIVERSITY DOING

3381
02:30:36,427 --> 02:30:40,164
INFECTIOUS DISEASE SCHOLARSHIPS

3382
02:30:40,231 --> 02:30:42,833
AT ANYAD MASS GENERAL JOINING IN

3383
02:30:42,900 --> 02:30:46,971
HARVARD MEDICAL SKIEN IN 1981

3384
02:30:47,037 --> 02:30:50,040
AND -- IN 1990 CHIP WAS

3385
02:30:50,107 --> 02:30:53,110
RECRUITED TO UNIVERSITY OF

3386
02:30:53,177 --> 02:30:55,045
COLORADO INSIDE OF THE DIVISION

3387
02:30:55,112 --> 02:30:56,547
OF INFECTIOUS DISEASES AND

3388
02:30:56,614 --> 02:30:58,649
SHARED NIH CLINICAL TRIALS GROUP

3389
02:30:58,716 --> 02:31:03,554
FROM 1985 TO 2002 TO REALLY

3390
02:31:03,621 --> 02:31:06,590
EXPAND THE SCOPE OF THAT GROUP.

3391
02:31:06,657 --> 02:31:09,493
2000 FIVE JOINED THE PATH OF

3392
02:31:09,560 --> 02:31:13,030
UCSD AND OTHER APPOINTMENTS AND

3393
02:31:13,097 --> 02:31:14,598
APPLICATIONS AND THERAPEUTICS

3394
02:31:14,665 --> 02:31:17,768
AND VERY ACTIVE IN HIV RESEARCH

3395
02:31:17,835 --> 02:31:20,838
AND IS A PIONEER IN FIELD OF AGE

3396
02:31:20,905 --> 02:31:24,975
THERAPY THAT IS TOPIC OF HIS

3397
02:31:25,042 --> 02:31:29,280
TALK TODAY.

3398
02:31:34,518 --> 02:31:34,652
>>.

3399
02:31:34,718 --> 02:31:36,921
>> THANK YOU.  PLEASURE TO BE

3400
02:31:36,987 --> 02:31:40,257
BACK HERE FREDERICK AND SEE JOHN

3401
02:31:40,324 --> 02:31:42,293
AND ALL OF STEVE AND ALL 12 FEET

3402
02:31:42,359 --> 02:31:42,960
OF HIM.

3403
02:31:43,027 --> 02:31:44,695
IT IS GREAT TO BE BACK HERE AND

3404
02:31:44,762 --> 02:31:46,063
I WILL TALK TODAY ABOUT

3405
02:31:46,130 --> 02:31:47,898
SOMETHING I STUMBLED INTO A

3406
02:31:47,965 --> 02:31:49,033
NUMBER OF YEARS AGO.

3407
02:31:49,099 --> 02:31:52,203
IT IS AN INFORMAL TALK IN THE

3408
02:31:52,269 --> 02:31:54,171
AFTERNOON BUT ONE THAT I PROMISE

3409
02:31:54,238 --> 02:31:56,106
IS IN A FIELD THAT IS MOVING

3410
02:31:56,173 --> 02:31:58,843
RELATIVELY RAPIDLY.  IF YOU

3411
02:31:58,909 --> 02:32:02,813
INDULGE ME IN A LITTLE BIT OF A

3412
02:32:02,880 --> 02:32:05,549
CULTURE SHOCK AND TALK ABOUT

3413
02:32:05,616 --> 02:32:07,485
WHERE THERAPEUTICS MIGHT GO IN

3414
02:32:07,551 --> 02:32:10,387
THE NEXT FEW YEARS AND THESE ARE

3415
02:32:10,454 --> 02:32:14,024
UNPAID DISCLOSURES AND SOMETHING

3416
02:32:14,091 --> 02:32:17,194
THAT IS KNOWN TO ALL OF YOU HERE

3417
02:32:17,261 --> 02:32:18,662
AND INFECTIONS BECOMING

3418
02:32:18,729 --> 02:32:19,964
INCREASING PROBLEM AROUND THE

3419
02:32:20,030 --> 02:32:22,933
WORLD AND IS A SLEEPER AND DON'T

3420
02:32:23,000 --> 02:32:24,301
REALIZE HOW MANY PEOPLE DIED

3421
02:32:24,368 --> 02:32:26,537
FROM THE INFECTIONS AND ONE AT A

3422
02:32:26,604 --> 02:32:30,407
TIME HERE AND THERE AND OPPOSED

3423
02:32:30,474 --> 02:32:34,778
TO OBVIOUS WAVES OF CORONAVIRUS

3424
02:32:34,845 --> 02:32:35,946
AND CUMULATIVE DEATH RATE AND

3425
02:32:36,013 --> 02:32:38,415
WHERE THEY ARE HEADED THIS IS

3426
02:32:38,482 --> 02:32:40,351
MAJOR INFECTIOUS DISEASE THREATS

3427
02:32:40,417 --> 02:32:42,152
OF THE ERA AND WE THOUGHT THAT

3428
02:32:42,219 --> 02:32:43,053
[INDISCERNIBLE] WITH ANSWER AND

3429
02:32:43,120 --> 02:32:45,389
AT TOP OF THE LINE YOU CAN SEE

3430
02:32:45,456 --> 02:32:47,157
THE DISCOVERY LINE OF

3431
02:32:47,224 --> 02:32:48,759
ANTI-BIOTICSES GOING BACK TO THE

3432
02:32:48,826 --> 02:32:52,696
EARLY PART OF THE LAST CENTURY

3433
02:32:52,763 --> 02:32:55,533
1930S AND STEADY SERIES OF NEW

3434
02:32:55,599 --> 02:32:57,535
ANTI-BIOTICS CLASSES DISCOVERED

3435
02:32:57,601 --> 02:33:01,672
IN THE NEXT 30 OR 40 YEARS AND

3436
02:33:01,739 --> 02:33:02,439
SEE SHORTLY AFTER EACH

3437
02:33:02,506 --> 02:33:05,643
ANTI-BIOTICS WAS INTRODUCED TO

3438
02:33:05,709 --> 02:33:07,278
THE CLINIC [INDISCERNIBLE] THERE

3439
02:33:07,344 --> 02:33:10,481
IS LONG DRY SPELL FROM 1970 TO

3440
02:33:10,548 --> 02:33:14,184
2000 WITH NO NEW ANTI-BIOTICS

3441
02:33:14,251 --> 02:33:16,754
DISCOVERED AND SENSE THEN YOU

3442
02:33:16,820 --> 02:33:19,757
HAVE TO CALL THEM SINGLES IF A

3443
02:33:19,823 --> 02:33:22,393
BASEBALL PLAYER AND TOP ITSELF

3444
02:33:22,459 --> 02:33:25,663
IS QUITE DRY AND BACTERIAL

3445
02:33:25,729 --> 02:33:26,864
PATHOGENS CONTINUE TO GO ALONG.

3446
02:33:26,931 --> 02:33:30,935
THIS IS WHERE THE STORY STARTS.

3447
02:33:31,001 --> 02:33:31,969
TOM PATTERSON A COLLEAGUE OF

3448
02:33:32,036 --> 02:33:37,942
MINE AT FACULTY OF UNIVERSITY OF

3449
02:33:38,008 --> 02:33:42,079
SAN DIEGO WAS IN EGYPT OVER THE

3450
02:33:42,146 --> 02:33:43,781
THANKSGIVING HOLIDAY AND HIPAA

3451
02:33:43,847 --> 02:33:45,316
POLICE ARE HERE THEY WROTE A

3452
02:33:45,382 --> 02:33:46,317
BOOK ABOUT THIS.

3453
02:33:46,383 --> 02:33:53,891
TOM IS A CO-AUTHOR AND THIS IS

3454
02:33:53,958 --> 02:33:55,626
PUBLIC DOMAIN AND THE BOOK GOES

3455
02:33:55,693 --> 02:33:57,394
INTO MORE DETAIL THAN I WILL

3456
02:33:57,461 --> 02:33:57,628
TODAY.

3457
02:33:57,695 --> 02:34:06,403
IT APPARENT WILLY HEADED FOR HO

3458
02:34:06,470 --> 02:34:12,076
WOD AND -- STEPHANIE TEXTED ME

3459
02:34:12,142 --> 02:34:13,844
AND THOUGHT HE DEVELOPED FOOD

3460
02:34:13,911 --> 02:34:15,579
POISONING AND TALKED TO HIM

3461
02:34:15,646 --> 02:34:18,048
MORE.  HE WAS DRINKING WATER

3462
02:34:18,115 --> 02:34:20,084
CONTINUOUSLY AND WAS FEBRUARY

3463
02:34:20,150 --> 02:34:22,820
RILE AND HAD LOTS OF ABDOMINAL

3464
02:34:22,886 --> 02:34:25,556
PAIN AND NO DIARRHEA AND

3465
02:34:25,623 --> 02:34:28,325
VOMITING AND WORRIED ABOUT

3466
02:34:28,392 --> 02:34:32,129
PANCREATITIS AND DIABETIC THAT

3467
02:34:32,196 --> 02:34:34,331
DRINKS A BIT AND TOOK HIM TO A

3468
02:34:34,398 --> 02:34:37,835
HOSPITAL AND FOUND A BIG

3469
02:34:37,901 --> 02:34:42,006
PSEUDOCYST AND GOT EVACUATED TO

3470
02:34:42,072 --> 02:34:46,010
FRANKFORT WHERE THE PSEUDOCYST

3471
02:34:46,076 --> 02:34:53,884
WASTURED  -- WAS PUNCTURED IN AN

3472
02:34:53,951 --> 02:34:56,153
ORGANISM THAT IS LARGE IN THAT

3473
02:34:56,220 --> 02:34:59,556
PART OF THE WORLD AND UC SAN

3474
02:34:59,623 --> 02:35:01,492
DIEGO DID EFFORT TO DRAIN THE

3475
02:35:01,558 --> 02:35:05,329
ABSCESS AND THE ABSCESS BEGAN TO

3476
02:35:05,396 --> 02:35:07,598
METASTASIZE AND TRYING TO GET

3477
02:35:07,665 --> 02:35:09,066
SURGEONS INVOLVED AND IS TOO

3478
02:35:09,133 --> 02:35:13,103
SICK TO OPERATE ON ONE OR TWO

3479
02:35:13,170 --> 02:35:14,872
DRAINING AND SAID HE IS GETTING

3480
02:35:14,938 --> 02:35:16,440
BETTER AND DON'T WANT TO OPERATE

3481
02:35:16,507 --> 02:35:19,376
ON HIM NOW AND WENT ON FOUR

3482
02:35:19,443 --> 02:35:23,080
MONTHS AND HE WAS OBTUNDED IN

3483
02:35:23,147 --> 02:35:25,949
SCU RENAL FAILING AND TALKING

3484
02:35:26,016 --> 02:35:28,519
ABOUT COMFORT CARE AND HIS WIFE

3485
02:35:28,585 --> 02:35:32,056
STEPHANIE IS A BULLDOG WHO RAN

3486
02:35:32,122 --> 02:35:37,327
ACROSS A PAPER FROM GEORGIA NOT

3487
02:35:37,394 --> 02:35:38,996
OURS BUT THEIR GEORGIA ABOUT

3488
02:35:39,063 --> 02:35:40,130
BACTERIOPHAGES THAT WERE FOUND

3489
02:35:40,197 --> 02:35:41,598
AND KILLED [INDISCERNIBLE] IN

3490
02:35:41,665 --> 02:35:42,900
THE LABORATORY AND GOT IN TOUCH

3491
02:35:42,966 --> 02:35:45,803
WITH ME AND ASKED IF WE COULD

3492
02:35:45,869 --> 02:35:47,671
USE THESE TO TREAT HER

3493
02:35:47,738 --> 02:35:50,974
HUSBANDED.  AUDIENCE KNOWS WELL

3494
02:35:51,041 --> 02:35:54,745
WHAT BACTERIOPHAGES ARE BACTERIA

3495
02:35:54,812 --> 02:35:58,549
OF VIRUSES AND FOUND IN 8 HOLES

3496
02:35:58,615 --> 02:36:01,518
IN [INDISCERNIBLE] OF BACTERIA

3497
02:36:01,585 --> 02:36:07,224
AND WERE EATING BACTERIA HENCE

3498
02:36:07,291 --> 02:36:08,358
BACTERIOPHAGES AND FOR A WHILE

3499
02:36:08,425 --> 02:36:11,962
WERE THOUGHT IT BE THE ANSWER TO

3500
02:36:12,029 --> 02:36:13,797
BACTERIAL INFECTIONS AND WERE

3501
02:36:13,864 --> 02:36:16,066
SOLD OVER THE COUNTER IN

3502
02:36:16,133 --> 02:36:18,035
MULTIPLE PARTS OF THE WORLD

3503
02:36:18,102 --> 02:36:20,304
MAINLY SYNDROMICALLY FOR EXAMPLE

3504
02:36:20,370 --> 02:36:26,043
FOR SPHERICALS OR DIARRHEA AND

3505
02:36:26,110 --> 02:36:30,047
HEALTHY BACTERIOLOGIC DECISION

3506
02:36:30,114 --> 02:36:31,915
AND WERE PARTICULARLY VIRUSS

3507
02:36:31,982 --> 02:36:34,051
WITH VERY NARROW HOST RANGE AND

3508
02:36:34,118 --> 02:36:36,687
WERE SOLD AS COCKTAILS

3509
02:36:36,754 --> 02:36:40,557
HOLEARIZED COCKTAILS THAT

3510
02:36:40,624 --> 02:36:44,495
SOMETIMES WORKED AND SOMETIMES

3511
02:36:44,561 --> 02:36:47,030
DIDN'T AND NOBODY KNEW WHY.

3512
02:36:47,097 --> 02:36:49,767
BEFORE LONG THEY FELL OUT OF

3513
02:36:49,833 --> 02:36:52,703
FAVOR IN THE WESTERN WORLD

3514
02:36:52,770 --> 02:36:54,438
PRIMARILY BECAUSE ANTI-BIOTICSES

3515
02:36:54,505 --> 02:36:57,775
CAME ALONG AND WERE EASY TO

3516
02:36:57,841 --> 02:36:58,075
MAKE.

3517
02:36:58,142 --> 02:36:59,476
WHEN YOU MADE THEM YOU COULD

3518
02:36:59,543 --> 02:37:02,412
SELL THEM TO KILL ALL KINDS OF

3519
02:37:02,479 --> 02:37:06,083
BACTERIA THAT WERE

3520
02:37:06,150 --> 02:37:07,985
STRAIGHTFORWARD AND ENTERED THE

3521
02:37:08,051 --> 02:37:11,688
LEXICON IN THE WESTERN WORLD AND

3522
02:37:11,755 --> 02:37:14,124
SUPPLANTED BACTERIOPHAGES AND

3523
02:37:14,191 --> 02:37:17,227
SOON BACTERIOPHAGES WERE

3524
02:37:17,294 --> 02:37:19,263
PRIMARILY USED IN SOVIET UNION

3525
02:37:19,329 --> 02:37:22,366
AND IN THE SOCIALIST REPUBLICS

3526
02:37:22,432 --> 02:37:30,107
PRIMARILY BECAUSE THEY WERE

3527
02:37:30,174 --> 02:37:33,076
CHEAP AND ANTI-BIOTICSES WEREN'T

3528
02:37:33,143 --> 02:37:35,946
AND WHEN BACTERIOPHAGES WERE

3529
02:37:36,013 --> 02:37:38,282
USED TOPICALLY ON WOUNDS AND

3530
02:37:38,348 --> 02:37:41,051
BURNS AND SOME GIVEN ORALLY FOR

3531
02:37:41,118 --> 02:37:43,787
DIE REAL DISEASE AND WERE NOT

3532
02:37:43,854 --> 02:37:45,622
GIVEN PERENNIAL AND PATIENT THAT

3533
02:37:45,689 --> 02:37:47,991
DISSEMINATED AND ASKED TO VECTOR

3534
02:37:48,058 --> 02:37:50,460
VIRAL ON INFECTION AND WASN'T

3535
02:37:50,527 --> 02:37:55,732
CLEAR TO FIND LYTICPHAGES FOR

3536
02:37:55,799 --> 02:37:57,467
INFECTION AND GETTING HIM TO

3537
02:37:57,534 --> 02:38:00,337
SITE OF INFECTION.  I WASN'T

3538
02:38:00,404 --> 02:38:02,339
CONFIDENT IT WOULD WORK AND FELT

3539
02:38:02,406 --> 02:38:04,708
IT WAS WORTH THE TRY GIVEN WE

3540
02:38:04,775 --> 02:38:06,376
HAD NOT MADE PROGRESS WITH

3541
02:38:06,443 --> 02:38:08,812
TRADITIONAL APPROACHES IN THE

3542
02:38:08,879 --> 02:38:12,416
LAST FEW MONTHS GETTING FDA

3543
02:38:12,482 --> 02:38:14,117
APPROVAL TO DO THIS TURNED OUT

3544
02:38:14,184 --> 02:38:16,453
TO BE EASIEST THING AROUND AND

3545
02:38:16,520 --> 02:38:19,356
WAS AN EASY PATHWAY FOR PATIENTS

3546
02:38:19,423 --> 02:38:21,592
WITH LIFE THREATENING INFECTIONS

3547
02:38:21,658 --> 02:38:25,162
WITH LICENSED PRODUCT EMERGENCY

3548
02:38:25,229 --> 02:38:26,230
IND PATHWAY REACH ON PHONE AND

3549
02:38:26,296 --> 02:38:28,165
TELL WHAT YOU WANT TO DO AND

3550
02:38:28,232 --> 02:38:29,900
DOESN'T SOUND TOO CRAZY CAN

3551
02:38:29,967 --> 02:38:35,505
GENERALLY GIVE APPROVAL THAT

3552
02:38:35,572 --> 02:38:35,772
DAY.

3553
02:38:35,839 --> 02:38:39,376
I WOULD EXPECT TO RUN INTO

3554
02:38:39,443 --> 02:38:41,378
PROBLEMS AND REGULATOR THERE

3555
02:38:41,445 --> 02:38:42,980
ANSWERED THE PHONE AND KNOW WHAT

3556
02:38:43,046 --> 02:38:44,615
I DO ALL DAY?

3557
02:38:44,681 --> 02:38:45,382
>> NO.

3558
02:38:45,449 --> 02:38:48,018
>> I DO FECAL TRANCE PLANTS AND

3559
02:38:48,085 --> 02:38:50,187
HATE IT.  THIS SOUNDS

3560
02:38:50,254 --> 02:38:52,723
INTERESTING.  WE SHOULD DO THIS.

3561
02:38:52,789 --> 02:38:54,258
ARE YOU FROM THE GOVERNMENT

3562
02:38:54,324 --> 02:38:56,460
TRYING TO HELP ME?  I ACTUALLY

3563
02:38:56,526 --> 02:38:58,629
AM AND KNOW WHERE YOU CAN GET

3564
02:38:58,695 --> 02:39:00,764
THEPHAGES AND DRD AND WHERE WE

3565
02:39:00,831 --> 02:39:02,900
GET BACK TO FREDERICK AND SHE

3566
02:39:02,966 --> 02:39:06,937
REFERRED ME TO PEOPLE WORKING IN

3567
02:39:07,004 --> 02:39:09,373
BIOMEDICAL DEFENSE RESEARCH

3568
02:39:09,439 --> 02:39:11,508
THEREIN HAMILTON AND

3569
02:39:11,575 --> 02:39:13,510
[INDISCERNIBLE] WHO HAD BEEN

3570
02:39:13,577 --> 02:39:14,945
WORKING ON [INDISCERNIBLE] FOR

3571
02:39:15,012 --> 02:39:18,048
PEOPLE COMING BACK FROM IRAQ AND

3572
02:39:18,115 --> 02:39:23,921
AFGHANISTAN WITH INJURIES AND

3573
02:39:23,987 --> 02:39:28,158
INJURIES FROM IMPROVISED

3574
02:39:28,225 --> 02:39:30,827
EXPLOSIVE DEVICES AND WORKING

3575
02:39:30,894 --> 02:39:32,129
WITH [INDISCERNIBLE] AND WITHIN

3576
02:39:32,195 --> 02:39:35,265
ABOUT 10 DAYS WE HAD FOURPHAGES

3577
02:39:35,332 --> 02:39:38,268
FROM EACH SOUR ACTIVE AGAINST

3578
02:39:38,335 --> 02:39:41,271
THE ORGANISM THAT IS SHOWN HERE.

3579
02:39:41,338 --> 02:39:44,641
THESE ARE NAVY PHAGES SHOWING

3580
02:39:44,708 --> 02:39:46,243
SUPPRESSION OF BACTERIAL

3581
02:39:46,310 --> 02:39:51,014
RESIDENT PRATION IN THIS LIQUID

3582
02:39:51,081 --> 02:39:55,218
ASSAY THAT CAN BE DONE IN 96

3583
02:39:55,285 --> 02:40:05,829
WELL PLATE AND SEE BLACK LINE IS

3584
02:40:06,229 --> 02:40:06,630
RESID

3585
02:40:06,697 --> 02:40:07,164
RESID

3586
02:40:07,230 --> 02:40:08,365
RESPIRATION UNIT AND CAUSING

3587
02:40:08,432 --> 02:40:10,300
SUPPRESSION OF THAT BACTERIA

3588
02:40:10,367 --> 02:40:12,636
OVER A 20-HOUR PERIOD.  WITHOUT

3589
02:40:12,703 --> 02:40:14,571
GOING INTO ALL OF THE DETAILS

3590
02:40:14,638 --> 02:40:16,506
TOM WAS LUCKY HE DID THIS WHEN

3591
02:40:16,573 --> 02:40:17,140
HE DID.

3592
02:40:17,207 --> 02:40:20,877
THIS IS ABOUT THE TIME IT IS

3593
02:40:20,944 --> 02:40:22,279
POSSIBLE TO CLEAR SUFFICIENTLY

3594
02:40:22,346 --> 02:40:25,716
TO BE ABLE TO GIVE THEM

3595
02:40:25,782 --> 02:40:29,486
PERENNIALLY AND USING CHLORA

3596
02:40:29,553 --> 02:40:33,557
KREN TROE FUGUATION AT THE NAVY

3597
02:40:33,623 --> 02:40:37,361
AND EXTRACTION PROGRAM AT SAN

3598
02:40:37,427 --> 02:40:39,329
DIEGO STATE PREPARATIONS WERE

3599
02:40:39,396 --> 02:40:41,631
CLEAN ENOUGH TO GIVE THEM

3600
02:40:41,698 --> 02:40:43,667
INITIALLY INTO HIS ABSCESSED

3601
02:40:43,734 --> 02:40:48,005
CAVITIES ON THE LEFT AS ANDREW

3602
02:40:48,071 --> 02:40:49,740
PICEL AND STUDYING PHAGES TO

3603
02:40:49,806 --> 02:40:52,843
DRAIN FROM ABSCESSED CAVITIES

3604
02:40:52,909 --> 02:40:59,316
FROM TEXAYNIMPHAGES AND MORE

3605
02:40:59,383 --> 02:41:00,584
CONSULTATION AND IN THINKING

3606
02:41:00,650 --> 02:41:02,719
MORE ABOUT IT TOM WAS AT THAT

3607
02:41:02,786 --> 02:41:06,656
POINT ON TWO PRESSERS AND

3608
02:41:06,723 --> 02:41:09,393
KIDNEYS WERE FAILING AND LIVER

3609
02:41:09,459 --> 02:41:11,261
WAS BEGINNING TO FAIL.

3610
02:41:11,328 --> 02:41:12,929
WE DECIDED WE NEEDED TO TRY TO

3611
02:41:12,996 --> 02:41:14,865
GO A LITTLE MORE SYSTEMICALLY

3612
02:41:14,931 --> 02:41:18,035
AND HE HAD ORGANISMS IN PERITY

3613
02:41:18,101 --> 02:41:21,271
ON EEL CAVITY AND DECIDED TO

3614
02:41:21,338 --> 02:41:23,173
TREAT THEM INTRAVENOUSLY AND

3615
02:41:23,240 --> 02:41:26,043
FELLOWS THAT ARE GIVING FIRST

3616
02:41:26,109 --> 02:41:27,944
DOSE OF FAITHS INTRAVENOUSLY AND

3617
02:41:28,011 --> 02:41:30,781
48 HOURS LATER HE WOKE UP AND

3618
02:41:30,847 --> 02:41:32,015
RECOGNIZED HIS DAUGHTER AND

3619
02:41:32,082 --> 02:41:34,351
FIRST TIME HE WAS AWAKE IN ABOUT

3620
02:41:34,418 --> 02:41:35,585
THREE MONTHS AND OVER THE NEXT

3621
02:41:35,652 --> 02:41:39,322
TWO OR THREE MONTHS MANAGED TO

3622
02:41:39,389 --> 02:41:40,290
GET OUT OF THE HOSPITAL.

3623
02:41:40,357 --> 02:41:41,958
I WILL SHOW YOU MORE ABOUT

3624
02:41:42,025 --> 02:41:45,929
REASONS WE THINK WE HAD IN VIVO

3625
02:41:45,996 --> 02:41:48,732
ACTIVITY IN A FEW MINUTES AND

3626
02:41:48,799 --> 02:41:50,434
FACULTY VISITING HIM IN 2018

3627
02:41:50,500 --> 02:41:52,436
BACK ON THE FACULTY AND WHEN

3628
02:41:52,502 --> 02:41:54,905
THEY CAME TO SAN DIEGO AND IN

3629
02:41:54,971 --> 02:41:57,541
THIS CASE, STEPHANIE, HER -- HIS

3630
02:41:57,607 --> 02:42:02,779
WIFE AND I, SHE IS AN INFECTIOUS

3631
02:42:02,846 --> 02:42:03,780
DISEASE EPIDEMIOLOGISTS DECIDED

3632
02:42:03,847 --> 02:42:06,149
TO DO TWO THINGS, ONE, PUT

3633
02:42:06,216 --> 02:42:09,653
TOGETHER A CENTER ALLOWING US TO

3634
02:42:09,719 --> 02:42:10,987
TAKE ADVANTAGE OF EXPERIENCE

3635
02:42:11,054 --> 02:42:13,690
WITH TOM AND MAKING AVAILABLE

3636
02:42:13,757 --> 02:42:16,460
FOR PEOPLE PROVIDING ADVICE

3637
02:42:16,526 --> 02:42:20,697
ANDPHAGES AND TO DEVELOP A BENCH

3638
02:42:20,764 --> 02:42:23,733
TO BENCH SIDE OR PHAGE RESEARCH

3639
02:42:23,800 --> 02:42:25,869
PROGRAM TO UNDERSTAND A MORE

3640
02:42:25,936 --> 02:42:27,537
RIGOROUS WAY HOW BEST TO

3641
02:42:27,604 --> 02:42:30,874
USEPHAGES IN THE CONTEXT OF

3642
02:42:30,941 --> 02:42:32,809
ANTI-MICROBIAL INFECTIONS AND

3643
02:42:32,876 --> 02:42:33,910
TREATMENT PROGRAM IS

3644
02:42:33,977 --> 02:42:34,411
STRAIGHTFORWARD.

3645
02:42:34,478 --> 02:42:36,079
WE HAVE A WEBSITE.

3646
02:42:36,146 --> 02:42:39,449
PEOPLE CONTACT US ABOUT PEOPLE

3647
02:42:39,516 --> 02:42:41,218
THAT MIGHT NEEDPHAGE THERAPY,

3648
02:42:41,284 --> 02:42:42,919
PHYSICIANS AND FAMILY MEMBERS

3649
02:42:42,986 --> 02:42:45,922
AND SO FORTH AND LAST FOUR YEARS

3650
02:42:45,989 --> 02:42:48,725
NOT QUITE 2,000 REQUESTS BUT

3651
02:42:48,792 --> 02:42:50,360
MANY TURN OUT TO BE PATIENTS

3652
02:42:50,427 --> 02:42:52,295
THAT ARE SENSITIVE TO

3653
02:42:52,362 --> 02:42:55,532
ANTI-BIOTICSES AND TALK TO

3654
02:42:55,599 --> 02:42:58,935
PHYSICIANS AND HELP THEM WITH

3655
02:42:59,002 --> 02:43:00,303
APPROACHES AND SOME HAVE BEEN --

3656
02:43:00,370 --> 02:43:05,075
I AM TRYING NOT TO BE BONAFIDE

3657
02:43:05,142 --> 02:43:07,677
CASES AND INITIATED HENCE ABOUT

3658
02:43:07,744 --> 02:43:09,045
3/4 OF THOSE.

3659
02:43:09,112 --> 02:43:14,451
FOR A WHILE WE HAD A LOT OF

3660
02:43:14,518 --> 02:43:16,653
TROUBLE FINDING PHAGES AND GOT

3661
02:43:16,720 --> 02:43:19,189
BETTER OVER TIME AND GMP ACCESS

3662
02:43:19,256 --> 02:43:22,058
TO PHAGES TO BEGIN PERENNIALLY

3663
02:43:22,125 --> 02:43:23,894
AND PROJECT WE ARE WORKING ON

3664
02:43:23,960 --> 02:43:27,230
AND ORGANISMS YOU MIGHT EXPECT

3665
02:43:27,297 --> 02:43:33,503
AND MULTIDRUG RESISTANT AND ESB

3666
02:43:33,570 --> 02:43:33,837
CHOLI.

3667
02:43:33,904 --> 02:43:36,606
AND STAFF IS THERE AND NOT --

3668
02:43:36,673 --> 02:43:39,976
HELLO JIM HOXY.

3669
02:43:40,043 --> 02:43:42,512
STAFF IS NOT A MULTIDRIVER

3670
02:43:42,579 --> 02:43:44,181
ORGANISM BUT ONE THAT HANGS OUT

3671
02:43:44,247 --> 02:43:46,149
ON AND PLANTED DEVICES BECAUSE

3672
02:43:46,216 --> 02:43:49,152
OF BIOFILMS.

3673
02:43:49,219 --> 02:43:53,356
PHAGES WILL BREAK UP BIOFILMS.

3674
02:43:53,423 --> 02:43:55,659
THEY ARE -- WE USEPHAGES TO

3675
02:43:55,725 --> 02:44:00,330
TREAT PEOPLE WITH INFECTED

3676
02:44:00,397 --> 02:44:02,465
CROSS-BCS AND CARDIAC DEVICES

3677
02:44:02,532 --> 02:44:04,267
WITH THOSE THAT PREEF YO USUALLY

3678
02:44:04,334 --> 02:44:08,672
FAILED ANTI-BIOTICSES AND

3679
02:44:08,738 --> 02:44:10,440
REQUESTS COME IN GETTING IN

3680
02:44:10,507 --> 02:44:12,042
TOUCH WITH NETWORK OF PEOPLE

3681
02:44:12,108 --> 02:44:14,878
THAT WORK IN DIFFERENT PLACES

3682
02:44:14,945 --> 02:44:17,347
AND WITH DIFFERENT ORGANISMS AND

3683
02:44:17,414 --> 02:44:25,555
GARY WORKS ON PSEUDOMOWNIS AND

3684
02:44:25,622 --> 02:44:28,325
AND SO FORTH.

3685
02:44:28,391 --> 02:44:31,161
AND WHEN WE HAVE DECIDED THAT A

3686
02:44:31,228 --> 02:44:34,531
PATIENT IS A GOOD CANDIDATE AND

3687
02:44:34,598 --> 02:44:35,432
PATIENT PHYSICIAN WANT TO

3688
02:44:35,498 --> 02:44:37,334
PROCEED WE GET THEM TO THE

3689
02:44:37,400 --> 02:44:43,106
LABORATORY AND THEY LOOK FOR

3690
02:44:43,173 --> 02:44:45,275
APHAGE AND WORK ON GETTING THEM

3691
02:44:45,342 --> 02:44:47,310
SENT AND OPPORTUNITY IN 2023 I

3692
02:44:47,377 --> 02:44:49,412
WILL TALK ABOUT BOTH OF THEM IN

3693
02:44:49,479 --> 02:44:50,680
RAPID FIRE AND PERHAPS WE WILL

3694
02:44:50,747 --> 02:44:54,117
HAVE A CHANCE TO TALK ABOUT SOME

3695
02:44:54,184 --> 02:44:55,552
OF THEM.

3696
02:44:55,619 --> 02:44:56,953
CHALLENGE IS RESISTANCE

3697
02:44:57,020 --> 02:44:59,923
DEVELOPED TOPHAGES AS THEY DO

3698
02:44:59,990 --> 02:45:01,324
ANTI-BIOTICSES WITH A NARROW

3699
02:45:01,391 --> 02:45:06,029
HOST RAGE AND CHALLENGING

3700
02:45:06,096 --> 02:45:07,631
SOMETIMES TO FIND ACTIVE PHAGE

3701
02:45:07,697 --> 02:45:12,035
OF AN ORGANISM AND LYSOGENIC

3702
02:45:12,102 --> 02:45:15,038
LIFESTYLE FOR NONPHAGEOLOGISTS

3703
02:45:15,105 --> 02:45:18,441
THAT INTEGRATE INTO DNA OF

3704
02:45:18,508 --> 02:45:20,510
BACTERIUM THEY ARE TRYING TO

3705
02:45:20,577 --> 02:45:25,482
TREAT AND JUMP AROUND AND CARRY

3706
02:45:25,548 --> 02:45:28,351
ANTI-BIOTICS RESISTANT GENES

3707
02:45:28,418 --> 02:45:33,390
WITH LYSOGENIZE.  YOU DON'T WANT

3708
02:45:33,456 --> 02:45:36,526
TO GIVE LYSOGENICPHAGES TO A

3709
02:45:36,593 --> 02:45:37,527
THERAPEUTIC SETTING.

3710
02:45:37,594 --> 02:45:40,430
WHAT ABOUT RESISTANCE?  BACK TO

3711
02:45:40,497 --> 02:45:42,766
PATIENT TOM PATTERSON.

3712
02:45:42,832 --> 02:45:44,200
UPPER RIGHT YOU HAVE SEEN

3713
02:45:44,267 --> 02:45:49,773
ALREADY, THIS IS THE NAVIPHAGES

3714
02:45:49,839 --> 02:45:51,574
SHOWING ACTIVITY AGAINST HIS

3715
02:45:51,641 --> 02:45:52,642
ORGANISM BEFORE TREATMENT AND

3716
02:45:52,709 --> 02:45:55,879
RIGHT PANEL YOU SEE IS FIXED

3717
02:45:55,945 --> 02:45:56,780
ANDPHAGES WERE NOT SUPPRESSING

3718
02:45:56,846 --> 02:46:02,018
HIS ORGANISM OVER THE SAME

3719
02:46:02,085 --> 02:46:02,619
TIMEFR

3720
02:46:02,686 --> 02:46:02,919
TIMEFRAME.

3721
02:46:02,986 --> 02:46:05,322
DAY 10 IS LITTLE EVIDENCE OF

3722
02:46:05,388 --> 02:46:09,059
PHAGE ACTIVITY AND SAME WITH ON

3723
02:46:09,125 --> 02:46:12,495
THE LEFT AND TEXAS AND A & M AND

3724
02:46:12,562 --> 02:46:14,698
NOT SURPRISING ANDPHAGES

3725
02:46:14,764 --> 02:46:18,034
INTERACTING WITH BACTERIA 300

3726
02:46:18,101 --> 02:46:19,135
MILLION YEARS AND TWO HAVE BEEN

3727
02:46:19,202 --> 02:46:26,710
ON A DANCE FOR A LONG TIME OF

3728
02:46:26,776 --> 02:46:28,712
EVOLUTION WITH PHAGES GOING ON

3729
02:46:28,778 --> 02:46:30,914
AND DEVELOPING SO ON AND SO

3730
02:46:30,980 --> 02:46:31,147
FORTH.

3731
02:46:31,214 --> 02:46:34,117
THERE IS DIVERSE INTERESTING

3732
02:46:34,184 --> 02:46:35,552
MECHANISMS FOR BACTERIA.  I'M

3733
02:46:35,618 --> 02:46:37,287
SORRY THEY HAVE DEVELOPED VERY

3734
02:46:37,354 --> 02:46:40,990
INTERESTING MECHANISMS TO AVOID

3735
02:46:41,057 --> 02:46:43,493
PHAGE PREDATION AND ENZYMES NOT

3736
02:46:43,560 --> 02:46:49,933
DEVELOPED FOR MOLECULAR OLOG

3737
02:46:49,999 --> 02:46:52,602
BIOLOGIST AND FOR DATA AND WERE

3738
02:46:52,669 --> 02:46:56,339
THINGS COMING OUT OF BATTLE

3739
02:46:56,406 --> 02:46:58,641
BETWEEN BACK TIERIANPHAGES AND

3740
02:46:58,708 --> 02:47:01,111
ADAPTING THINGS LIKE METHYLATING

3741
02:47:01,177 --> 02:47:03,413
GENOMES TO AVOID RESTRICTION

3742
02:47:03,480 --> 02:47:05,548
ENZYMES AND WAR WENT ON AND

3743
02:47:05,615 --> 02:47:08,184
THING THAT HAPPENS MOST OFTEN IN

3744
02:47:08,251 --> 02:47:11,187
VITRO STARTING WITH A PARTICULAR

3745
02:47:11,254 --> 02:47:12,522
ORGANISM AND IN A PARTICULAR

3746
02:47:12,589 --> 02:47:16,126
PHAGE IS EVOLUTION OF SURFACE

3747
02:47:16,192 --> 02:47:18,595
RECEPTOR AND INTRINSIC

3748
02:47:18,661 --> 02:47:20,196
MECHANISMS RESTRICTION ENZYMES

3749
02:47:20,263 --> 02:47:22,165
SO ON AND SO FORTH DON'T INVOLVE

3750
02:47:22,232 --> 02:47:24,701
A TREATMENT AND OFTEN ORGANISMS

3751
02:47:24,768 --> 02:47:31,941
WILL EVOLVE IN WAY THAT EFFECTS

3752
02:47:32,008 --> 02:47:34,043
ABILITY OF THE PHAGE TO BIND TO

3753
02:47:34,110 --> 02:47:37,147
THE SURFACE YOU CAN GET ORGANISM

3754
02:47:37,213 --> 02:47:40,116
AND LOOK ATPHAGE AND IN FACT BRD

3755
02:47:40,183 --> 02:47:42,619
AND TOM'S ORGANISM, THIS IS A --

3756
02:47:42,685 --> 02:47:44,754
THESE ARE NEWPHAGES THAT I WILL

3757
02:47:44,821 --> 02:47:47,056
NOW SUPPRESS AND YOU CAN SEE

3758
02:47:47,123 --> 02:47:50,727
BELOW THE TP3 AND ORGANISM THAT

3759
02:47:50,794 --> 02:47:53,730
IS RESISTANT TO ALL OTHER PHAGES

3760
02:47:53,797 --> 02:47:57,033
AT DAY 10 AND GO BACK AND TREAT

3761
02:47:57,100 --> 02:47:58,968
PATIENT WITH NEWPHAGES AND WHAT

3762
02:47:59,035 --> 02:48:00,870
WE DID WITH THIS PATIENT AND

3763
02:48:00,937 --> 02:48:04,908
ANOTHER THING TO DO TO PREVENT

3764
02:48:04,974 --> 02:48:07,477
PHAGE RESISTANCE IS DO

3765
02:48:07,544 --> 02:48:09,012
COMBINATION THERAPY LIKE WE HAVE

3766
02:48:09,078 --> 02:48:10,980
DONE WITH ANTI-BIOTICSES AND

3767
02:48:11,047 --> 02:48:13,183
VIRAL DRUGS AND WHAT WE LEARNED

3768
02:48:13,249 --> 02:48:17,520
IN THIS CASE IS WE STARTED WITH

3769
02:48:17,587 --> 02:48:20,857
FOUR PHAGES FROM AND IN THIS

3770
02:48:20,924 --> 02:48:24,060
CASE ON NAVY ON THE RIGHT AND

3771
02:48:24,127 --> 02:48:29,299
SEE THEY ARE MYOFAIPHAGES AND A

3772
02:48:29,365 --> 02:48:33,036
TIME NOT ABLE TO SEQUENCEPHAGES

3773
02:48:33,102 --> 02:48:36,039
USING COMMERCIAL KITS THAT WERE

3774
02:48:36,105 --> 02:48:37,440
HEAVILY MODERATED AND WERE

3775
02:48:37,507 --> 02:48:40,810
SIMILAR IN TERMS OF ESSENTIALLY

3776
02:48:40,877 --> 02:48:45,381
BEING ONEPHAGE WITH MINIMALED

3777
02:48:45,448 --> 02:48:47,650
GENETIC DIFFERENCES ALONG THEM

3778
02:48:47,717 --> 02:48:50,787
AND NEWPHAGE I SHOWED YOU A

3779
02:48:50,854 --> 02:48:52,655
MINUTE AGO WAS A DIFFERENT CLASS

3780
02:48:52,722 --> 02:48:57,193
OF PODOPHAGE THINKING ABOUT HOW

3781
02:48:57,260 --> 02:48:59,496
TO COMBINE THESE DIFFERENT

3782
02:48:59,562 --> 02:49:03,132
RECEPTORS AND RESISTANCE

3783
02:49:03,199 --> 02:49:05,268
PATHWAYS AND BEING PURSUED AND

3784
02:49:05,335 --> 02:49:07,770
OTHER THING TO BE DONE IS TO TRY

3785
02:49:07,837 --> 02:49:13,142
TO USE THEM IN CONCERT WITH

3786
02:49:13,209 --> 02:49:14,811
PAUL TURNER AT YALE HAS DONE

3787
02:49:14,878 --> 02:49:17,847
SOME VERY INTERESTING WORK USING

3788
02:49:17,914 --> 02:49:23,520
PHAGES THAT CAUSE BACTERIA TO

3789
02:49:23,586 --> 02:49:25,722
DOWNREGULATE THE B FLUX PUMP AND

3790
02:49:25,788 --> 02:49:27,457
BASICALLY CHOKE ON ANTIBIOTICS

3791
02:49:27,524 --> 02:49:28,892
TO WHICH THEY WERE RESISTANT

3792
02:49:28,958 --> 02:49:30,193
BEFORE, NO LONGER ABLE TO PUMP

3793
02:49:30,260 --> 02:49:31,294
THEM OUT.

3794
02:49:31,361 --> 02:49:33,162
THE OTHER THING THAT HAPPENS

3795
02:49:33,229 --> 02:49:37,033
WHEN THE PHAGE MODIFIES ITS

3796
02:49:37,100 --> 02:49:39,302
OUTER MEMBRANE PROTEINS IS THEY

3797
02:49:39,369 --> 02:49:41,404
CAN END UP LOSING THEIR CAPSULE.

3798
02:49:41,471 --> 02:49:43,273
IN TOM'S CASE THAT IS EXACTLY

3799
02:49:43,339 --> 02:49:45,642
WHAT HAPPENED.

3800
02:49:45,708 --> 02:49:47,510
PRE-TREATMENT, DAY 6, DAY 10,

3801
02:49:47,577 --> 02:49:53,416
YOU CAN SEE THAT BIG JUICY

3802
02:49:53,483 --> 02:49:54,717
CASSELL AT PRE-TREATMENT ON THE

3803
02:49:54,784 --> 02:49:56,252
LEFT, AND THE CAPSULE IS HARD TO

3804
02:49:56,319 --> 02:50:00,323
SEE THE THIRD TIME AROUND.

3805
02:50:00,390 --> 02:50:03,893
AT TEXAS A & M, THE BACTERIA

3806
02:50:03,960 --> 02:50:05,595
WERE SEQUENCED AND AGAIN TO MAKE

3807
02:50:05,662 --> 02:50:08,097
A LONG STORY SHORT, THE PRIMARY

3808
02:50:08,164 --> 02:50:11,367
DIFFERENCES WERE REALLY AT THE

3809
02:50:11,434 --> 02:50:13,469
SITE WHERE THE OUTER MEMBRANE

3810
02:50:13,536 --> 02:50:17,840
PROTEIN IS REGULATED.

3811
02:50:17,907 --> 02:50:18,942
IN THIS CASE AND OTHERS THAT

3812
02:50:19,008 --> 02:50:20,043
HAVE BEEN REPORTED SINCE THEN,

3813
02:50:20,109 --> 02:50:21,678
WHEN THIS HAPPENS, THE BACTERIUM

3814
02:50:21,744 --> 02:50:24,948
IS NO LONGER AS INVASIVE AND

3815
02:50:25,014 --> 02:50:31,988
IT'S NO LONGER AS RESILIENT, SO

3816
02:50:32,055 --> 02:50:34,924
WHAT IT GIVES UP TO THE PHAGE

3817
02:50:34,991 --> 02:50:36,993
MAKES IT MORE SUSCEPTIBLE TO

3818
02:50:37,060 --> 02:50:39,629
HOST IMMUNE RESPONSES, AND

3819
02:50:39,696 --> 02:50:41,497
AGAIN, MAYBE ONE OF THE

3820
02:50:41,564 --> 02:50:43,700
MECHANISMS BY WHICH PHAGE

3821
02:50:43,766 --> 02:50:45,001
THERAPEUTICS IT WORK DESPITE

3822
02:50:45,068 --> 02:50:45,535
RESISTANCE.

3823
02:50:45,602 --> 02:50:47,737
THE OTHER CHALLENGE IS -- AND

3824
02:50:47,804 --> 02:50:48,738
LIFESTYLE, I'VE ALREADY KIND OF

3825
02:50:48,805 --> 02:50:51,240
TALKED ABOUT WHY HOST RANGE --

3826
02:50:51,307 --> 02:50:52,675
WHY LIFESTYLE IS A PROBLEM, AND

3827
02:50:52,742 --> 02:50:54,310
HOST RANGE BEING VERY NARROW, IT

3828
02:50:54,377 --> 02:50:56,312
WOULD BE NICE TO BE ABLE TO

3829
02:50:56,379 --> 02:50:57,480
BROADEN THE HOST RANGE OR TO

3830
02:50:57,547 --> 02:50:59,782
MAKE PHAGES MORE RESILIENT TO

3831
02:50:59,849 --> 02:51:03,186
EVOLUTION OF THE CELL SURFACE.

3832
02:51:03,252 --> 02:51:05,054
PHAGE ENGINEERING CAN BE DONE.

3833
02:51:05,121 --> 02:51:08,625
THIS IS ANOTHER KIND OF ANECDOTE

3834
02:51:08,691 --> 02:51:11,928
WITH -- WORK WITH GRAHAM HATHEL,

3835
02:51:11,995 --> 02:51:15,765
WHO IS A MYCOBACTERIAL PHAGE

3836
02:51:15,832 --> 02:51:18,001
RESEARCHER AT THE UNIVERSITY OF

3837
02:51:18,067 --> 02:51:18,601
PITTSBURGH.

3838
02:51:18,668 --> 02:51:20,236
THIS IS A PATIENT HE AND I SAW

3839
02:51:20,303 --> 02:51:22,005
ABOUT SIX MONTHS AFTER TOM

3840
02:51:22,071 --> 02:51:25,842
PATTERSON, WHO WAS A YOUNG WOMAN

3841
02:51:25,908 --> 02:51:28,244
WHO HAD MYCOBACTERIUM INFECTION

3842
02:51:28,311 --> 02:51:29,712
STARTING WHEN SHE WAS 7 YEARS

3843
02:51:29,779 --> 02:51:31,414
OLD THAT PROGRESSED IN A CONTEXT

3844
02:51:31,481 --> 02:51:35,018
OF HER CYSTIC FIBROSIS,

3845
02:51:35,084 --> 02:51:36,586
TRANSPLANTATION WHEN SHE GOT TO

3846
02:51:36,653 --> 02:51:37,120
BE ABOUT 15.

3847
02:51:37,186 --> 02:51:38,888
SHE WAS INVOLVED FOR SEVERAL

3848
02:51:38,955 --> 02:51:40,823
WEEKS POST TRANSPLANT AND THE

3849
02:51:40,890 --> 02:51:41,491
INFECTION CAME BACK.

3850
02:51:41,557 --> 02:51:44,327
YOU CAN SEE THE NODULES ON HER

3851
02:51:44,394 --> 02:51:46,529
FOREARM ON THE LEFT, THE STERNAL

3852
02:51:46,596 --> 02:51:50,600
WOWPPEDWOUND ON THE RIGHT, PET S

3853
02:51:50,667 --> 02:51:51,768
SIGNS OF INFECTION ON THE LEFT

3854
02:51:51,834 --> 02:51:53,536
SIDE HERE.

3855
02:51:53,603 --> 02:51:56,506
NOW, THE PROBLEM WITH THE

3856
02:51:56,572 --> 02:51:58,041
MYCOBACTERIAL PHAGES THAT GRAHAM

3857
02:51:58,107 --> 02:52:00,443
HAD, HE HAS ABOUT 15,000 IN HIS

3858
02:52:00,510 --> 02:52:03,713
FREEZER FROM A VERY LARGE

3859
02:52:03,780 --> 02:52:05,448
NSF-SUPPORTED PROGRAM THAT HAS

3860
02:52:05,515 --> 02:52:06,249
UNDERGRADUATES LOOKING FOR

3861
02:52:06,315 --> 02:52:08,885
PHAGES ACTIVE AS PART OF A

3862
02:52:08,951 --> 02:52:10,119
COLLEGE COURSE, SOME OF THEM

3863
02:52:10,186 --> 02:52:12,689
TURNED OUT TO BE ACTIVE AGAINST

3864
02:52:12,755 --> 02:52:14,223
MYCOBACTERIAL INFECTION,

3865
02:52:14,290 --> 02:52:19,028
INCLUDING -- THE PROBLEM IS THEY

3866
02:52:19,095 --> 02:52:21,564
ALL ARE LYSOGENIC.

3867
02:52:21,631 --> 02:52:23,099
HOW DO YOU DO THAT?

3868
02:52:23,166 --> 02:52:26,069
GET RIT OF INTEGRATE STREAM OR

3869
02:52:26,135 --> 02:52:27,303
THE REPRESSOR GENE.

3870
02:52:27,370 --> 02:52:29,138
AND GRAHAM HAS A WAY TO DO THAT,

3871
02:52:29,205 --> 02:52:31,974
WHICH IS BASICALLY AN APPROACH

3872
02:52:32,041 --> 02:52:37,046
IN WHICH -- IS USED INTO A HOST

3873
02:52:37,113 --> 02:52:43,686
STRAIN OF NON-T -- JUST ELECTRO-

3874
02:52:43,753 --> 02:52:45,321
WHAT YOU WANT TO TAKE OUT WITH

3875
02:52:45,388 --> 02:52:47,523
STICKY ENDS AND SELECTING CLONES

3876
02:52:47,590 --> 02:52:52,028
THAT HAD -- THAT LACK THAT --

3877
02:52:52,095 --> 02:52:53,229
SHORTER, ESSENTIALLY, IN TERMS

3878
02:52:53,296 --> 02:52:54,864
OF DNA AND YOU END UP WITH

3879
02:52:54,931 --> 02:52:59,035
PLAQUES THAT YOU CAN THEN PUR

3880
02:52:59,102 --> 02:53:00,336
PURIFY, THEY'RE NOW JUST LYTIC

3881
02:53:00,403 --> 02:53:03,673
AND NO LONGER CAPABLE OF

3882
02:53:03,740 --> 02:53:04,040
INTEGRATING.

3883
02:53:04,107 --> 02:53:05,041
GOING BACK TO THE PATIENT, HE

3884
02:53:05,108 --> 02:53:06,242
WAS ABLE TO DO THAT AND WE WERE

3885
02:53:06,309 --> 02:53:08,544
ABLE TO US A SOME PHAGES THAT

3886
02:53:08,611 --> 02:53:10,513
WERE ACTIVE AGAINST YOUR

3887
02:53:10,580 --> 02:53:10,780
ORGANISM.

3888
02:53:10,847 --> 02:53:12,048
YOU CAN SEE ON THE LEFT, THE

3889
02:53:12,115 --> 02:53:18,721
SKIN LESIONS MELTING AWAY -- I'M

3890
02:53:18,788 --> 02:53:19,188
SORRY, ON THE RIGHT.

3891
02:53:19,255 --> 02:53:20,590
YOU CAN ALSO SEE THE PET SCAN

3892
02:53:20,656 --> 02:53:21,958
BEGINNING TO LOSE THE INTENSITY

3893
02:53:22,024 --> 02:53:23,793
SHE HAD AT THE ACUTE PHASE,

3894
02:53:23,860 --> 02:53:25,962
OBVIOUSLY YOU CAN STILL SEE HER

3895
02:53:26,028 --> 02:53:29,499
BLADDER, BUT SHE SHOWED BOTH

3896
02:53:29,565 --> 02:53:32,835
CLINICAL IMPROVEMENT AND

3897
02:53:32,902 --> 02:53:34,137
RADIOLOGIC IMPROVEMENT, FROM

3898
02:53:34,203 --> 02:53:36,339
WHAT WAS ESSENTIALLY PRE-HOSPICE

3899
02:53:36,405 --> 02:53:38,674
CARE, YOU CAN SEE HER PFTs

3900
02:53:38,741 --> 02:53:39,976
THRANS PLANT IMPROVE AND WITH

3901
02:53:40,042 --> 02:53:41,077
PHAGE THERAPY, IMPROVED FURTHER.

3902
02:53:41,144 --> 02:53:42,578
WE HAD A LITTLE BIT OF TROUBLE

3903
02:53:42,645 --> 02:53:42,845
WITH THIS.

3904
02:53:42,912 --> 02:53:44,480
THIS IS THE FIRST PATIENT

3905
02:53:44,547 --> 02:53:46,082
TREATED WITH GENETICALLY

3906
02:53:46,149 --> 02:53:47,216
MODIFIED PHAGE BECAUSE WE WERE

3907
02:53:47,283 --> 02:53:49,051
TRYING TO FIGURE IN THE U.K.

3908
02:53:49,118 --> 02:53:50,453
WHERE THEY DON'T EVEN LIKE

3909
02:53:50,520 --> 02:53:51,554
GENETICALLY MODIFIED CHEERIOS,

3910
02:53:51,621 --> 02:53:52,889
AND WE HAD TO ARGUE WITH THE

3911
02:53:52,955 --> 02:53:53,422
REGULATORS ABOUT THIS.

3912
02:53:53,489 --> 02:53:55,158
THEY SAID, WELL, YOU KNOW, THIS

3913
02:53:55,224 --> 02:53:59,228
IS A GMO AND WE SAID, WELL,

3914
02:53:59,295 --> 02:54:01,664
THERE ARE PERIODICALLY --

3915
02:54:01,731 --> 02:54:03,733
MUTATIONS IN LYSOGENIC PHAGES,

3916
02:54:03,800 --> 02:54:04,967
WHICH THEY THEN BECOME LYTIC,

3917
02:54:05,034 --> 02:54:07,570
AND THE PROBLEM IS THEY CAN

3918
02:54:07,637 --> 02:54:09,539
MUTATE -- THEY CAN -- MUTATE.

3919
02:54:09,605 --> 02:54:15,011
WE JUST DON'T -- THEY REALLY

3920
02:54:15,077 --> 02:54:16,012
ARE -- SOMETHING BETTER THAN

3921
02:54:16,078 --> 02:54:17,180
NATURE, WE DIDN'T ADD ANYTHING.

3922
02:54:17,246 --> 02:54:19,482
THEY BOUGHT THAT, SO GRAHAM WAS

3923
02:54:19,549 --> 02:54:23,619
ABLE TO USE THESE NOW IN ABOUT

3924
02:54:23,686 --> 02:54:24,153
40 PATIENTS.

3925
02:54:24,220 --> 02:54:27,490
WE REPORTED 20 OF THEM IN

3926
02:54:27,557 --> 02:54:28,958
CLINICAL -- DISEASES ABOUT A

3927
02:54:29,025 --> 02:54:30,426
YEAR AGO, AND TO MAKE A LONG

3928
02:54:30,493 --> 02:54:33,062
STORY SHORT, THE SUCCESS RATE IS

3929
02:54:33,129 --> 02:54:33,729
ABOUT 55%.

3930
02:54:33,796 --> 02:54:34,931
WE'VE LEARNED A LOT ABOUT

3931
02:54:34,997 --> 02:54:37,667
EVOLUTION OF ANTIBODIES TO

3932
02:54:37,733 --> 02:54:39,302
PHAGES IN THESE PATIENTS BECAUSE

3933
02:54:39,368 --> 02:54:42,505
THESE ARE PATIENTS THAT HAVE

3934
02:54:42,572 --> 02:54:43,706
BEEN TREATED FOR A LONG TIME

3935
02:54:43,773 --> 02:54:46,108
BECAUSE OF THEIR IMMUNE

3936
02:54:46,175 --> 02:54:46,976
SUPPRESSIVE CONDITION AND WE

3937
02:54:47,043 --> 02:54:49,812
LEARNED QUITE A BIT ABOUT PHAGE

3938
02:54:49,879 --> 02:54:50,479
RESISTANCE.

3939
02:54:50,546 --> 02:54:52,114
THESE PATIENTS GENERALLY DON'T

3940
02:54:52,181 --> 02:54:54,750
DEVELOP RESISTANCE, MYCOBACTERIA

3941
02:54:54,817 --> 02:54:56,385
ARE SLOW TO GROW AND HE HAS SOME

3942
02:54:56,452 --> 02:54:58,254
PHAGES THAT ARE QUITE ACTIVE

3943
02:54:58,321 --> 02:55:00,423
AGAINST A PRETTY IR VARIANT

3944
02:55:00,489 --> 02:55:01,657
SURFACE PROTEIN.

3945
02:55:01,724 --> 02:55:02,892
SO LET'S TALK ABOUT

3946
02:55:02,959 --> 02:55:03,492
OPPORTUNITIES.

3947
02:55:03,559 --> 02:55:04,594
WE'VE OBVIOUSLY TALKED ABOUT

3948
02:55:04,660 --> 02:55:05,361
INDIVIDUAL PATIENTS.

3949
02:55:05,428 --> 02:55:06,796
AGAIN I WON'T GO INTO ALL THE

3950
02:55:06,863 --> 02:55:07,029
DETAIL.

3951
02:55:07,096 --> 02:55:10,967
WE HAVE A SERIES WE PUBLISH FROM

3952
02:55:11,033 --> 02:55:15,204
UCSD, CASE REPORTS IN THE

3953
02:55:15,271 --> 02:55:16,339
LITERATURE KIND OF EVER SINCE,

3954
02:55:16,405 --> 02:55:17,740
AND WHEN YOU LOOK AT WHAT THESE

3955
02:55:17,807 --> 02:55:19,942
CASE REPORTS ARE ABOUT, THEY'RE

3956
02:55:20,009 --> 02:55:21,844
PRIMARILY PATIENTS WHO HAVE

3957
02:55:21,911 --> 02:55:23,779
IMPLANTED DEVICES AND PULMONARY

3958
02:55:23,846 --> 02:55:24,080
INFECTIONS.

3959
02:55:24,146 --> 02:55:26,182
NOW YOU SAY WELL, THIS IS -- OF

3960
02:55:26,249 --> 02:55:26,616
COURSE IT IS.

3961
02:55:26,682 --> 02:55:27,717
THAT'S WHAT CASE REPORTS ARE.

3962
02:55:27,783 --> 02:55:28,918
BUT IT ALSO TELLS YOU WHAT

3963
02:55:28,985 --> 02:55:30,286
PEOPLE THINK ARE WORKING.

3964
02:55:30,353 --> 02:55:31,220
AND IT GIVES YOU SOMETHING TO

3965
02:55:31,287 --> 02:55:34,590
THINK ABOUT IN TERMS OF HOW YOU

3966
02:55:34,657 --> 02:55:36,225
PRIORITIZE YOUR MORE STRUCTURED

3967
02:55:36,292 --> 02:55:37,193
RESEARCH STUDIES.

3968
02:55:37,260 --> 02:55:39,528
SO IN TERMS OF AREAS THAT PEOPLE

3969
02:55:39,595 --> 02:55:42,398
THINK MIGHT BE AMENABLE TO PHAGE

3970
02:55:42,465 --> 02:55:44,567
THERAPEUTICS, LIKE NOW THERE'S A

3971
02:55:44,634 --> 02:55:47,003
LOT OF -- INFECTIONS ASSOCIATED

3972
02:55:47,069 --> 02:55:49,372
WITH MEDICAL DEVICES.

3973
02:55:49,438 --> 02:55:50,673
THERE IS INTEREST IN -- THERE'S

3974
02:55:50,740 --> 02:55:54,510
A COMPANY IN DENMARK THAT IS

3975
02:55:54,577 --> 02:55:56,145
WORKING ON PHAGES THAT ARE

3976
02:55:56,212 --> 02:55:57,813
ACTIVE AGAINST ENTERIC

3977
02:55:57,880 --> 02:56:00,216
GRAM-NEGATIVE ORGANISMS TO TRY

3978
02:56:00,283 --> 02:56:02,518
TO TREAT PEOPLE WHO ARE ABOUT TO

3979
02:56:02,585 --> 02:56:07,456
UNDERGO CHEMOTHERAPY TO TRY TO

3980
02:56:07,523 --> 02:56:09,191
REDUCE MULTIDRUG RESISTANT

3981
02:56:09,258 --> 02:56:14,764
SEPSIS IN THE CONTEXT OF KNEW

3982
02:56:14,830 --> 02:56:15,031
NUTRAPENA.

3983
02:56:15,097 --> 02:56:17,433
THERE ARE THEORIES ABOUT MICRO

3984
02:56:17,500 --> 02:56:19,468
BIOMIBG DRIVERS OF INFLAMMATORY

3985
02:56:19,535 --> 02:56:20,236
BOWEL DISEASE AND SO FORTH.

3986
02:56:20,303 --> 02:56:26,275
SO THERE ARE A LOT OF POTENTIAL

3987
02:56:26,342 --> 02:56:27,944
MEDICAL -- AND STOP ACTING LIKE

3988
02:56:28,010 --> 02:56:30,680
THEY'RE SOME MAGICAL THING FROM

3989
02:56:30,746 --> 02:56:31,414
GEORGIA OR RUSSIA.

3990
02:56:31,480 --> 02:56:34,583
THEY REALLY ARE ANTIBIOTICS BUT

3991
02:56:34,650 --> 02:56:35,551
THEY'RE ANTIBIOTICS THAT HAPPEN

3992
02:56:35,618 --> 02:56:36,385
TO BE ALIVE.

3993
02:56:36,452 --> 02:56:37,753
SO OUR GOAL WITH THEM IS TO DO

3994
02:56:37,820 --> 02:56:39,956
THE SAME THING WE WOULD WITH A

3995
02:56:40,022 --> 02:56:42,725
SMALL MOLECULE, KILL ORGANISMS,

3996
02:56:42,792 --> 02:56:44,060
BUT THE MEANS BY WHICH YOU DO IT

3997
02:56:44,126 --> 02:56:45,528
IS A BIT DIFFERENT BECAUSE

3998
02:56:45,594 --> 02:56:46,862
UNLIKE ANTIBIOTICS, THEY'RE

3999
02:56:46,929 --> 02:56:47,763
REALLY QUITE LIMITED.

4000
02:56:47,830 --> 02:56:49,265
YOU GIVE THEM INTRAVENOUSLY AND

4001
02:56:49,332 --> 02:56:50,700
NEXT THING YOU KNOW, THEY'RE

4002
02:56:50,766 --> 02:56:53,669
BEING ELIMINATED BY THE KIDNEY,

4003
02:56:53,736 --> 02:56:55,938
ELIMINATED BY THE LIVER.

4004
02:56:56,005 --> 02:56:57,907
YOU GET A PHAGE, IT FINDS THE

4005
02:56:57,974 --> 02:56:59,208
ORGANISM AND AMPLIFIES ITSELF AT

4006
02:56:59,275 --> 02:57:00,543
THE SITE OF THE ORGANISM.

4007
02:57:00,609 --> 02:57:04,847
IT'S A MUCH SMARTER ANTIBUY

4008
02:57:04,914 --> 02:57:10,386
KROAB YAANTIMICROBIAL.

4009
02:57:10,453 --> 02:57:13,122
THE GOOD NEWS IS THERE ARE A LOT

4010
02:57:13,189 --> 02:57:14,390
OF CLINICAL TRIALS THAT HAVE

4011
02:57:14,457 --> 02:57:15,324
PICKED UP SINCE THAT TIME.

4012
02:57:15,391 --> 02:57:16,659
THEY'VE BEEN PICKING UP

4013
02:57:16,726 --> 02:57:18,127
INCREASINGLY SINCE THE LATE --

4014
02:57:18,194 --> 02:57:19,729
THE LAST HALF OF THE LAST

4015
02:57:19,795 --> 02:57:20,596
DECADE.

4016
02:57:20,663 --> 02:57:24,166
THE BLUE BARS HERE, THESE ARE

4017
02:57:24,233 --> 02:57:25,401
THERAPEUTIC INDICATIONS.

4018
02:57:25,468 --> 02:57:26,736
THE ORANGE ONES ARE PEOPLE

4019
02:57:26,802 --> 02:57:29,372
TRYING TO ASSESS -- USING PHAGES

4020
02:57:29,438 --> 02:57:32,074
AS A TOOL BUT THERAPEUTIC

4021
02:57:32,141 --> 02:57:34,176
RESEARCH IN BLUE BARS HAS BEEN

4022
02:57:34,243 --> 02:57:34,810
PICKING UP.

4023
02:57:34,877 --> 02:57:37,279
THE BAD NEWS ABOUT THESE PHAGE

4024
02:57:37,346 --> 02:57:38,647
TRIALS ARE MOST ARE BEING

4025
02:57:38,714 --> 02:57:39,882
UNDERTAKEN BY THE BIOTECH

4026
02:57:39,949 --> 02:57:45,087
INDUSTRY, TRYING TO FIND A QUICK

4027
02:57:45,154 --> 02:57:46,022
EDUCATION FOR SPECIFIC INFECTION

4028
02:57:46,088 --> 02:57:47,623
THAT CAN BE TAKEN TO THE FDA.

4029
02:57:47,690 --> 02:57:49,158
AND THEY'RE OFTEN DONE WITHOUT

4030
02:57:49,225 --> 02:57:50,693
DUE DILIGENCE BEFORE THEY'RE

4031
02:57:50,760 --> 02:57:54,397
STARTED IN TERMS OF WHAT DOSE,

4032
02:57:54,463 --> 02:57:56,165
WHAT FREQUENCY, WHAT ROUTE OF

4033
02:57:56,232 --> 02:57:57,033
ADMINISTRATION, AND NEEDLESS TO

4034
02:57:57,099 --> 02:57:58,334
SAY, MANY OF THEM HAVE NOT GONE

4035
02:57:58,401 --> 02:57:59,201
VERY WELL.

4036
02:57:59,268 --> 02:58:00,302
WOULD NEVER DEVELOP AN

4037
02:58:00,369 --> 02:58:01,937
ANTIBIOTIC THE SAME WAY.

4038
02:58:02,004 --> 02:58:03,472
WHAT WE I THINK IN MY VIEW NEED

4039
02:58:03,539 --> 02:58:07,309
TO BE DOING IS TAKING ADVANTAGE

4040
02:58:07,376 --> 02:58:08,711
OF WHAT WE LEARNED FROM HIV,

4041
02:58:08,778 --> 02:58:10,513
WHICH IS TO TAKE AN INTEGRATED

4042
02:58:10,579 --> 02:58:15,985
APPROACH AND ESSENTIALLY ITERATE

4043
02:58:16,052 --> 02:58:17,286
BETWEEN INNOVATION IN THE

4044
02:58:17,353 --> 02:58:19,255
LABORATORY WITH ENGINEERED

4045
02:58:19,321 --> 02:58:20,189
PHAGES, PHAGES OF DIFFERENT

4046
02:58:20,256 --> 02:58:24,393
TYPES THAT WE HAVE DISCOVERED,

4047
02:58:24,460 --> 02:58:26,262
COMBINED THEM WITH OTHER NOVEL

4048
02:58:26,328 --> 02:58:28,764
ANTIMICROBIAL APPROACHES, TAKE

4049
02:58:28,831 --> 02:58:33,269
THEM INTO CLINICAL TRIALS THAT

4050
02:58:33,335 --> 02:58:35,237
ARE WELL THOUGHT OUT TO DO

4051
02:58:35,304 --> 02:58:36,772
CLINICAL TRIALS BUT DON'T JUST

4052
02:58:36,839 --> 02:58:37,873
HAVE CLINICAL END POINTS BUT

4053
02:58:37,940 --> 02:58:40,276
WELL BACKED UP SO WHEN THINGS

4054
02:58:40,342 --> 02:58:41,410
WORK WE KNOW WHY, WHEN THEY

4055
02:58:41,477 --> 02:58:43,145
DON'T WORK, WE KNOW WHY, WE CAN

4056
02:58:43,212 --> 02:58:45,881
THEN TAKE THEM BACK AFTER DOING

4057
02:58:45,948 --> 02:58:48,050
SOME MATHEMATICAL MODELING AND

4058
02:58:48,117 --> 02:58:49,585
ITERATE, DO A BIT BETTER THE

4059
02:58:49,652 --> 02:58:50,152
NEXT TIME.

4060
02:58:50,219 --> 02:58:52,088
THIS IS THE TYPE OF RESEARCH

4061
02:58:52,154 --> 02:58:53,189
THAT NEEDS TO BE DONE.

4062
02:58:53,255 --> 02:58:54,323
UNFORTUNATELY THE BIOTECH

4063
02:58:54,390 --> 02:58:55,724
INDUSTRY IS NOT CAPITALIZED

4064
02:58:55,791 --> 02:58:56,592
ENOUGH TO DO THIS, AND THEY

4065
02:58:56,659 --> 02:58:58,360
CONTINUE TO KIND OF STAND UP TO

4066
02:58:58,427 --> 02:59:01,063
THE PLATE AND TRY TO HIT AN

4067
02:59:01,130 --> 02:59:02,498
INDICATION THAT WILL LET THEM

4068
02:59:02,565 --> 02:59:05,234
MOVE ON TO THE NEXT INVESTMENT.

4069
02:59:05,301 --> 02:59:06,435
NOW SOME STUDIES ARE BEING DONE

4070
02:59:06,502 --> 02:59:08,070
THAT ARE ACTUALLY QUITE

4071
02:59:08,137 --> 02:59:08,404
INTELLIGENT.

4072
02:59:08,471 --> 02:59:11,474
THIS IS A STUDY REPORTED WEEK

4073
02:59:11,540 --> 02:59:13,109
BEFORE LAST.

4074
02:59:13,175 --> 02:59:14,777
THIS ONE DONE BY A COMPANY

4075
02:59:14,844 --> 02:59:17,613
CALLED BIOMIX FROM ISRAEL.

4076
02:59:17,680 --> 02:59:20,583
THIS IS -- IN WHICH PEOPLE WHO

4077
02:59:20,649 --> 02:59:23,319
HAVE CYSTIC FIBROSIS AND ARE

4078
02:59:23,385 --> 02:59:24,120
SHEDDING PSEUDOMONAS AND DON'T

4079
02:59:24,186 --> 02:59:28,357
NEED TO BE TREATED ACUTELY

4080
02:59:28,424 --> 02:59:36,499
RECEIVE AI AI AEROSOLIZED -- ONN

4081
02:59:36,565 --> 02:59:39,802
THE LEFT, THE ACTIVE TREATMENT,

4082
02:59:39,869 --> 02:59:40,936
PATIENTS GENERALLY HAVE A

4083
02:59:41,003 --> 02:59:43,005
DECLINE IN THEIR PSEUDOMONAS

4084
02:59:43,072 --> 02:59:43,906
SHEDDING THERAPY LASTED A WEEK,

4085
02:59:43,973 --> 02:59:46,742
YOU CAN SEE THIS IS A WEEK POST

4086
02:59:46,809 --> 02:59:48,177
THERAPY.

4087
02:59:48,244 --> 02:59:49,211
COMPARED TO A COUPLE OF CONTROLS

4088
02:59:49,278 --> 02:59:50,112
ON THE RIGHT.

4089
02:59:50,179 --> 02:59:51,447
THEY HAVE ANOTHER 30 PATIENTS

4090
02:59:51,514 --> 02:59:53,249
THAT WILL BE UNBLINDED SOMETIME

4091
02:59:53,315 --> 02:59:54,450
IN THE NEXT MONTH OR SO, SO

4092
02:59:54,517 --> 02:59:55,851
WE'LL HAVE MORE NUMBERS.

4093
02:59:55,918 --> 02:59:58,554
BUT THE BOTTOM PANEL HERE, YOU

4094
02:59:58,621 --> 03:00:00,956
CAN SEE THEY DETECT PHAGES IN

4095
03:00:01,023 --> 03:00:02,625
THE SPUTUM AND CAN STILL DETECT

4096
03:00:02,691 --> 03:00:06,462
IT IN 2 OF THE 6 ACTIVE PATIENTS

4097
03:00:06,529 --> 03:00:07,229
A WEEK LATER.

4098
03:00:07,296 --> 03:00:08,297
THEY'RE GOING TO BE DOING SOME

4099
03:00:08,364 --> 03:00:09,298
MODELING TO TRY TO UNDERSTAND

4100
03:00:09,365 --> 03:00:11,700
THE RELATIONSHIPS BETWEEN

4101
03:00:11,767 --> 03:00:14,103
POPULATIONS HERE OF THE SORTS OF

4102
03:00:14,170 --> 03:00:17,706
THINGS THAT PEOPLE LIKE JOHN

4103
03:00:17,773 --> 03:00:19,909
KAUFMAN AND AL DID WITH HIV.

4104
03:00:19,975 --> 03:00:21,777
TRULY COME BACK AT THIS WITH A

4105
03:00:21,844 --> 03:00:23,946
MORE INTELLIGENT APPROACH NEXT

4106
03:00:24,013 --> 03:00:25,814
TIME AROUND.

4107
03:00:25,881 --> 03:00:28,117
ANOTHER OPPORTUNITY I'LL CLOSE

4108
03:00:28,184 --> 03:00:29,885
WITH IS THINKING ABOUT USING

4109
03:00:29,952 --> 03:00:33,923
PHAGES FOR OUTBREAK

4110
03:00:33,989 --> 03:00:35,024
INTERVENTIONS.

4111
03:00:35,090 --> 03:00:36,325
LAST FIVE OR 10 YEARS ARE

4112
03:00:36,392 --> 03:00:38,427
OUTBREAKS OF NDR INFECTIONS

4113
03:00:38,494 --> 03:00:39,962
AROUND THE WORLD, MOST RECENTLY

4114
03:00:40,029 --> 03:00:42,798
AN OUTBREAK OF HIGHLY DRUG

4115
03:00:42,865 --> 03:00:47,169
RESISTANT PSEUDOMONAS AERGENOSA

4116
03:00:47,236 --> 03:00:49,371
OF PRESIEVETIVE-FREE EYE DROPS.

4117
03:00:49,438 --> 03:00:51,340
PEOPLE WHO HAVE DRY EYE -- YOU

4118
03:00:51,407 --> 03:00:54,043
HAVE TO GIVE THEM FREQUENTLY FOR

4119
03:00:54,109 --> 03:00:55,945
DRY EYE, IT CAUSES

4120
03:00:56,011 --> 03:00:58,113
CONJUNCTIVITIS, CAN MAKE THINGS

4121
03:00:58,180 --> 03:00:59,114
WORSE.

4122
03:00:59,181 --> 03:01:00,983
PRESERVED DRUGS CAN GET

4123
03:01:01,050 --> 03:01:02,184
CONTAMINATED, DOESN'T TAKE MUCH

4124
03:01:02,251 --> 03:01:04,286
FOR PSEUDOMONAS TO GROW, AND TWO

4125
03:01:04,353 --> 03:01:06,222
PLANTS IN INDIA HAVE

4126
03:01:06,288 --> 03:01:07,856
CONTAMINATED THEIR EYE DROPS AND

4127
03:01:07,923 --> 03:01:09,491
CAUSED A LARGE OUTBREAK OF

4128
03:01:09,558 --> 03:01:10,326
ORGANISMS THAT YOU DON'T WANT TO

4129
03:01:10,392 --> 03:01:11,360
HAVE AROUND YOUR HOSPITAL.

4130
03:01:11,427 --> 03:01:17,466
THIS SHOWS YOU TH HOW THEY'RE DG

4131
03:01:17,533 --> 03:01:18,467
RESISTANT TO MOST OF THE

4132
03:01:18,534 --> 03:01:19,702
ANTIBIOTICS WE HAVE AVAILABLE TO

4133
03:01:19,768 --> 03:01:21,003
TREAT PATIENTS WITH.

4134
03:01:21,070 --> 03:01:22,972
AS OF MARCH, THERE HAVE BEEN 80

4135
03:01:23,038 --> 03:01:25,174
CASES IN 18 STATES IN THE U.S.,

4136
03:01:25,241 --> 03:01:26,375
14 PEOPLE HAVE LOST VISION,

4137
03:01:26,442 --> 03:01:32,281
THERE HAVE BEEN SOME

4138
03:01:32,348 --> 03:01:35,351
ENUCLEATIONS AND SOME DEATHS.

4139
03:01:35,417 --> 03:01:36,318
FROM THE CASE REPORTS, THIS KIND

4140
03:01:36,385 --> 03:01:37,720
OF SHOWS YOU WHAT THIS DOES TO

4141
03:01:37,786 --> 03:01:38,187
AN EYE.

4142
03:01:38,254 --> 03:01:39,922
THESE ARE VERY INVASIVE

4143
03:01:39,989 --> 03:01:40,589
INFECTIONS.

4144
03:01:40,656 --> 03:01:42,358
EYE IS NOT WELL VASCULARIZED,

4145
03:01:42,424 --> 03:01:45,828
AND ONCE THEY GET STARTED WITH

4146
03:01:45,894 --> 03:01:47,496
AN ABRADED CORNEA, THEY CAN BE

4147
03:01:47,563 --> 03:01:49,698
DIFFICULT TO ERADICATE.

4148
03:01:49,765 --> 03:01:52,101
NOW WE WERE ABLE TO GET THE

4149
03:01:52,167 --> 03:01:55,704
ORGANISMS FROM THE CDC AND THEN

4150
03:01:55,771 --> 03:01:58,774
DAVID PRIDE IN OUR GROUP FOUND

4151
03:01:58,841 --> 03:01:59,808
SOME PHAGES THAT HE'D BEEN

4152
03:01:59,875 --> 03:02:01,510
WORKING WITH ALREADY, SOME JUMBO

4153
03:02:01,577 --> 03:02:05,114
PHAGES ON A -- WITH SOME

4154
03:02:05,180 --> 03:02:07,950
COLLEAGUES AT UCSD WHO ARE

4155
03:02:08,017 --> 03:02:10,719
WORKING ON -- WITH THESE PHAGES

4156
03:02:10,786 --> 03:02:11,920
FOUND THREE PHAGES.

4157
03:02:11,987 --> 03:02:15,424
YOU CAN SEE DOWN THE Y AXIS,

4158
03:02:15,491 --> 03:02:19,161
THESE ARE VIJ PHA INDIVIDUAL PH,

4159
03:02:19,228 --> 03:02:20,663
THOSE ARE PSEUDOMONAS ISOLATES.

4160
03:02:20,729 --> 03:02:21,997
ONE IS FROM THE OUTBREAK.

4161
03:02:22,064 --> 03:02:24,500
YOU CAN SEE PHAGES THAT HAVE

4162
03:02:24,566 --> 03:02:30,306
ACTIVITY AGAINST EACH OF THESE

4163
03:02:30,372 --> 03:02:31,073
THREE ORGANISMS.

4164
03:02:31,140 --> 03:02:32,708
THE NICE THING ABOUT OUT DK

4165
03:02:32,775 --> 03:02:33,709
BREAK SITUATIONS, WHEN SOMEBODY

4166
03:02:33,776 --> 03:02:35,244
SHOWS UP IN A DIFFERENT TOWN

4167
03:02:35,311 --> 03:02:36,679
FROM THE SAME OUTBREAK, THOSE

4168
03:02:36,745 --> 03:02:37,980
PHAGES ARE VERY LIKELY TO BE

4169
03:02:38,047 --> 03:02:40,582
ACTIVE AS WELL.

4170
03:02:40,649 --> 03:02:42,584
SO WE'RE WORKING WITH THE CDC ON

4171
03:02:42,651 --> 03:02:43,786
TRYING TO DEVELOP A PROGRAM BY

4172
03:02:43,852 --> 03:02:46,288
WHICH THEY IDENTIFY IC ISOLATESF

4173
03:02:46,355 --> 03:02:47,723
CONCERN, WE FIND PHAGES THEN WE

4174
03:02:47,790 --> 03:02:50,559
START TRYING TO GROW THEM UP TO

4175
03:02:50,626 --> 03:02:55,397
BE USED IN OUTBREAK CONTROL.

4176
03:02:55,464 --> 03:02:59,201
SO I'LL FINISH -- PHAGES ARE

4177
03:02:59,268 --> 03:03:03,038
NARROW, ANTIBIOTICS ARE HOW THE

4178
03:03:03,105 --> 03:03:04,506
MICROBIOME DISRUPTING, PHAGES

4179
03:03:04,573 --> 03:03:05,441
ARE GENERALLY NOT.

4180
03:03:05,507 --> 03:03:08,544
YOU CAN DEVELOP A BACTERIOPHAGE

4181
03:03:08,610 --> 03:03:10,279
OR ISOLATE ONE RELATIVELY

4182
03:03:10,346 --> 03:03:10,512
QUICKLY.

4183
03:03:10,579 --> 03:03:14,116
THE COST OF PRODUCTION REALLY OF

4184
03:03:14,183 --> 03:03:16,952
AN INDIVIDUAL PHAGE IS QUITE

4185
03:03:17,019 --> 03:03:18,620
TRIFTRIVIAL.

4186
03:03:18,687 --> 03:03:20,489
THESE ARE ACTUALLY QUITE EASY TO

4187
03:03:20,556 --> 03:03:21,890
WORK WITH WITH THE SAME SORTS OF

4188
03:03:21,957 --> 03:03:26,595
APPROACHES USED FOR BIOLOGI

4189
03:03:26,662 --> 03:03:27,563
BIOLOGICAL -- THE SAME KIND OF A

4190
03:03:27,629 --> 03:03:29,565
PLANT COULD EASILY MAKE PHAGES

4191
03:03:29,631 --> 03:03:31,033
FOR THERAPY.

4192
03:03:31,100 --> 03:03:33,168
I TALKED TODAY PRIMARILY ABOUT

4193
03:03:33,235 --> 03:03:34,570
HUMAN MEDICINE BUT THERE ARE A

4194
03:03:34,636 --> 03:03:38,073
NUMBER OF OTHERS INCLUDING

4195
03:03:38,140 --> 03:03:38,841
BIODEFENSE, FOOD SAFETY.

4196
03:03:38,907 --> 03:03:41,043
THERE'S ALREADY A PHAGE APPROVED

4197
03:03:41,110 --> 03:03:42,778
FOR LISTERIA PREVENTION ON MEAT.

4198
03:03:42,845 --> 03:03:45,080
PEOPLE HAVE TALKED ABOUT

4199
03:03:45,147 --> 03:03:47,516
USING -- OR REPLACING

4200
03:03:47,583 --> 03:03:48,717
TETRACYCLINE IN CHICKENS WITH

4201
03:03:48,784 --> 03:03:49,585
PHAGES.

4202
03:03:49,651 --> 03:03:51,553
THERE'S SOME NICE WORK BEING

4203
03:03:51,620 --> 03:03:52,888
DONE ON THAT IN THE U.K. AND YOU

4204
03:03:52,955 --> 03:03:54,289
CAN THINK ABOUT OTHER

4205
03:03:54,356 --> 03:03:57,926
APPLICATIONS WITH PHAGES USED AS

4206
03:03:57,993 --> 03:04:00,229
VECTORS WITH SOME -- WE HEARD

4207
03:04:00,295 --> 03:04:01,096
ABOUT THIS MORNING.

4208
03:04:01,163 --> 03:04:02,498
SO I'LL STOP THERE AND THEN JUST

4209
03:04:02,564 --> 03:04:07,636
WANT TO DEDICATE THIS TO

4210
03:04:07,703 --> 03:04:10,038
CAPTAIN -- WHO IS A --

4211
03:04:10,105 --> 03:04:11,106
UNFORTUNATELY PASSED AWAY TWO

4212
03:04:11,173 --> 03:04:11,607
WEEKS AGO.

4213
03:04:11,673 --> 03:04:14,743
HE WAS THE COMMANDER OF THE --

4214
03:04:14,810 --> 03:04:18,347
HERE AT FORT DIETRICH UNTIL HE

4215
03:04:18,414 --> 03:04:21,550
RETIRED EARLIER THIS YEAR.

4216
03:04:21,617 --> 03:04:26,655
HE MA PLAYED A MAJOR ROLE FOR

4217
03:04:26,722 --> 03:04:27,923
LETTING TOM PATTERSON BE

4218
03:04:27,990 --> 03:04:28,223
TREATED.

4219
03:04:28,290 --> 03:04:28,824
THANKS VERY MUCH.

4220
03:04:28,891 --> 03:04:31,326
[APPLAUSE]

4221
03:04:31,393 --> 03:04:33,061
>> WE'RE GOING TO GO HOME AND

4222
03:04:33,128 --> 03:04:35,130
THROW OUR EYE DROPS AWAY.

4223
03:04:35,197 --> 03:04:35,397
QUESTIONS.

4224
03:04:35,464 --> 03:04:39,067
>> YOU BRIEFLY ALLUDED TO THE

4225
03:04:39,134 --> 03:04:44,006
HOST IMMUNE RESPONSE OF A PHAGE,

4226
03:04:44,072 --> 03:04:47,376
AND -- THAT WOULD SEEM TO ME TO

4227
03:04:47,443 --> 03:04:49,478
BE A SIGNIFICANT CONSIDERATION.

4228
03:04:49,545 --> 03:04:50,679
COULD YOU -- A LITTLE BIT?

4229
03:04:50,746 --> 03:04:51,213
>> SURE.

4230
03:04:51,280 --> 03:04:56,819
SO PHAGES WERE USED FOR A LONG

4231
03:04:56,885 --> 03:04:58,554
TIME AS A WAY TO STUDY HUMAN

4232
03:04:58,620 --> 03:05:00,622
IMMUNE RESPONSES IN -- CAUSING

4233
03:05:00,689 --> 03:05:00,956
ANTIBODIES.

4234
03:05:01,023 --> 03:05:06,228
YOU CAN INDUCE -- ANTIBODIES BY

4235
03:05:06,295 --> 03:05:07,663
THE -- ADMINISTRATION OF PHAGES.

4236
03:05:07,729 --> 03:05:10,933
WHAT ISN'T CLEAR IS WHAT IMPACT

4237
03:05:10,999 --> 03:05:13,001
THAT HAS ON THEIR EFFICACY FROM

4238
03:05:13,068 --> 03:05:14,336
TWO PERSPECTIVES.

4239
03:05:14,403 --> 03:05:15,871
FIRST, YOU'RE TREATING ACUTE

4240
03:05:15,938 --> 03:05:16,972
INFECTION, MOST OF WHAT YOU DO

4241
03:05:17,039 --> 03:05:19,475
WITH AN ANTIBIOTIC OR PHAGE IS

4242
03:05:19,541 --> 03:05:21,543
DONE IN THE FIRST WEEK.

4243
03:05:21,610 --> 03:05:22,845
SOME WITH CHRONIC INFECTIONS

4244
03:05:22,911 --> 03:05:27,149
LIKE PATIENTS WHO HAVE ORGAN

4245
03:05:27,216 --> 03:05:28,150
TRANSPLANTS AND -- ONLY ABOUT

4246
03:05:28,217 --> 03:05:33,155
HALF OF THEM DEVELOP ANTIBODIES,

4247
03:05:33,222 --> 03:05:35,224
AND WHEN GRAHAM AND -- HAVE

4248
03:05:35,290 --> 03:05:36,558
LOOKED AT THOSE PATIENTS, ONLY

4249
03:05:36,625 --> 03:05:37,759
ABOUT HALF OF THOSE SEEM TO HAVE

4250
03:05:37,826 --> 03:05:38,961
A CHANGE IN THE IMPACT OF THE

4251
03:05:39,027 --> 03:05:40,128
PHAGES WHEN THOSE ANTIBODIES

4252
03:05:40,195 --> 03:05:42,130
DEVELOP.

4253
03:05:42,197 --> 03:05:43,131
NOW WHY MIGHT THAT BE?

4254
03:05:43,198 --> 03:05:45,667
IT MIGHT BE WHEN YOU THINK

4255
03:05:45,734 --> 03:05:47,870
ABOUT -- WHEN YOU GIVE PHAGES

4256
03:05:47,936 --> 03:05:48,704
INTRAVENOUSLY, THEY'RE CLEARED

4257
03:05:48,770 --> 03:05:49,705
RAPIDLY FROM THE BLOODSTREAM,

4258
03:05:49,771 --> 03:05:51,006
AND THE GOAL IS TO BOLUS THE

4259
03:05:51,073 --> 03:05:52,207
PHAGES AND HOPE THAT THEY GET TO

4260
03:05:52,274 --> 03:05:55,711
THE SITE OF INFECTION BEFORE

4261
03:05:55,777 --> 03:05:57,246
THEY'RE CLEARED.

4262
03:05:57,312 --> 03:05:58,881
WHEN YOU HAVE ANTIBODIES, YOU

4263
03:05:58,947 --> 03:05:59,781
INCREASE THE RATE OF CLEARANCE

4264
03:05:59,848 --> 03:06:01,316
BUT IF THEY GET TO A SITE OF

4265
03:06:01,383 --> 03:06:06,989
INFECTION LIKE IN THE LUNG, THEY

4266
03:06:07,055 --> 03:06:09,291
CAN REPLICATE IN THE INFECTING

4267
03:06:09,358 --> 03:06:10,726
ORGANISM AND SPREAD LOCALLY.

4268
03:06:10,792 --> 03:06:15,297
TO JUST AS HIV CAN PERSIST IN

4269
03:06:15,364 --> 03:06:16,832
THE PRESENCE OF NEUTRALIZING

4270
03:06:16,899 --> 03:06:17,499
ANTIBODY, IT'S POSSIBLE THAT

4271
03:06:17,566 --> 03:06:19,568
PHASES ARE PERSISTING IN THEIR

4272
03:06:19,635 --> 03:06:20,903
PRESENCE OF NEUTRALIZING

4273
03:06:20,969 --> 03:06:22,538
ANTIBODIES BECAUSE OF THE

4274
03:06:22,604 --> 03:06:26,575
CONTINUITY OF THEIR TARGETS.

4275
03:06:26,642 --> 03:06:28,343
WAYS AROUND THAT INCLUDE USING

4276
03:06:28,410 --> 03:06:32,414
PHAGES OF DIFFERENT CLASSES.

4277
03:06:32,481 --> 03:06:33,615
BIOPHAGES AND -- VERY MUCH LIKE

4278
03:06:33,682 --> 03:06:35,050
THE APPROACH TO TRY TO PREVENT

4279
03:06:35,117 --> 03:06:38,420
PHAGE DEVELOPMENT COCKTAILS.

4280
03:06:38,487 --> 03:06:39,621
ANIMAL MODEL STUDIES HAVE LOOKED

4281
03:06:39,688 --> 03:06:41,356
AT THIS TOO AND LIKE MANY ANIMAL

4282
03:06:41,423 --> 03:06:43,458
MODEL STUDIES, YOU CAN SET THEM

4283
03:06:43,525 --> 03:06:45,093
OUT TO SHOW WHATEVER YOU WANT

4284
03:06:45,160 --> 03:06:46,862
TO.

4285
03:06:46,929 --> 03:06:50,399
WITH ABOLI APOLOGIES TO UNIVERSY

4286
03:06:50,465 --> 03:06:51,867
OF -- I'M JUST KIDDING.

4287
03:06:51,934 --> 03:06:53,535
BUT THERE IS AT LEAST ONE MODEL

4288
03:06:53,602 --> 03:06:56,939
IN WHICH THE PEOPLE AT WALTER

4289
03:06:57,005 --> 03:07:00,175
REED TOOK A -- IT WAS A -- MODEL

4290
03:07:00,242 --> 03:07:02,044
OF A WOUND INFECTION, AND I

4291
03:07:02,110 --> 03:07:04,580
IMMUNIZED HALF THE ANIMALS WITH

4292
03:07:04,646 --> 03:07:05,881
THE PHAGE WE WERE GOING TO USE,

4293
03:07:05,948 --> 03:07:07,316
THEN ESTABLISHED THE INFECTION,

4294
03:07:07,382 --> 03:07:10,085
AND TREATED A PARALLEL GROUP

4295
03:07:10,152 --> 03:07:12,287
THAT HADN'T BEEN IMMUNIZED AND

4296
03:07:12,354 --> 03:07:13,488
THERAPEUTIC RESPONSE WERE THE

4297
03:07:13,555 --> 03:07:13,956
SAME.

4298
03:07:14,022 --> 03:07:16,558
WE HAD OTHER ANIMAL MODELS WHICH

4299
03:07:16,625 --> 03:07:17,659
ANTIBODIES DO CAUSE A PROBLEM.

4300
03:07:17,726 --> 03:07:19,928
SO THE SHORT ANSWER IS, IT'S

4301
03:07:19,995 --> 03:07:20,529
WORK IN PROGRESS.

4302
03:07:20,596 --> 03:07:21,363
ONE OF THE THINGS THAT NEEDS TO

4303
03:07:21,430 --> 03:07:23,332
BE LOOKED AT IN SOME OF THE

4304
03:07:23,398 --> 03:07:24,166
CLINICAL TRIALS MOVING FORWARD,

4305
03:07:24,232 --> 03:07:25,968
SO WE UNDERSTAND WHAT ROLE THEY

4306
03:07:26,034 --> 03:07:27,035
ACTUALLY DO PLAY, RATHER THAN

4307
03:07:27,102 --> 03:07:28,270
HAVING SOMETHING NOT WORK AND

4308
03:07:28,337 --> 03:07:29,638
NOT REALIZE IT'S AN ANTIBODY

4309
03:07:29,705 --> 03:07:33,008
RESPONSE.

4310
03:07:33,075 --> 03:07:35,544
>> TWO QUICK QUESTIONS

4311
03:07:35,611 --> 03:07:43,151
ASSOCIATED WITH -- SO DO THEY --

4312
03:07:43,218 --> 03:07:45,387
TO THE PHAGE THAT OVERLAP --

4313
03:07:45,454 --> 03:07:46,488
ALSO WITH TUBERCULOSIS, AND THE

4314
03:07:46,555 --> 03:07:49,091
SECOND QUESTION IS, YOU MUST

4315
03:07:49,157 --> 03:07:50,826
HAVE THOUGHT OF THIS HARD ABOUT

4316
03:07:50,892 --> 03:07:52,894
SOME OF THE CHALLENGES WITH

4317
03:07:52,961 --> 03:07:54,963
TB -- EVERYTHING ELSE, IS THAT

4318
03:07:55,030 --> 03:08:01,436
REALLY A -- PROBLEM, A -- TAR

4319
03:08:01,503 --> 03:08:01,670
TARGET?

4320
03:08:01,737 --> 03:08:05,474
>> SO THE SHORT ANSWER IS THAT

4321
03:08:05,540 --> 03:08:07,876
SOME OF THE PHAGES THAT ARE

4322
03:08:07,943 --> 03:08:08,977
ACTIVE THAT ARE FROM THIS

4323
03:08:09,044 --> 03:08:10,312
COLLECTION ARE ACTIVE AGAINST

4324
03:08:10,379 --> 03:08:10,746
TB.

4325
03:08:10,812 --> 03:08:12,581
GRAHAM AND SOME IN VITRO

4326
03:08:12,648 --> 03:08:13,715
EXPERIMENTS THINKS HE HAS PHAGES

4327
03:08:13,782 --> 03:08:15,217
THAT ARE ACTIVE AGAINST ABOUT

4328
03:08:15,283 --> 03:08:18,820
85% OF TB THAT YOU ENCOUNTER

4329
03:08:18,887 --> 03:08:19,154
CLINICALLY.

4330
03:08:19,221 --> 03:08:20,689
NOT ALL OF THEM ARE ACTIVE.

4331
03:08:20,756 --> 03:08:23,659
THE PHAGES HAVE NOT BEEN USED IN

4332
03:08:23,725 --> 03:08:25,027
PEOPLE WITH TUBERCULOSIS YET.

4333
03:08:25,093 --> 03:08:27,929
THERE WAS A PATIENT WITH

4334
03:08:27,996 --> 03:08:29,531
ACTUALLY RTB IN GERMANY THAT WAS

4335
03:08:29,598 --> 03:08:32,534
BEING TEED UP TO BE TREATED,

4336
03:08:32,601 --> 03:08:33,602
UNFORTUNATELY DIED BEFORE THE

4337
03:08:33,669 --> 03:08:36,238
PHAGE COULD BE GOTTEN TO HIM.

4338
03:08:36,304 --> 03:08:37,673
THE CHALLENGE THAT PEOPLE KEEP

4339
03:08:37,739 --> 03:08:40,175
TALKING ABOUT IS, WELL, IT'S AN

4340
03:08:40,242 --> 03:08:40,809
INTRACELLULAR INFECTION, WILL

4341
03:08:40,876 --> 03:08:42,711
THE PHAGES GET THERE.

4342
03:08:42,778 --> 03:08:46,348
AND I -- SORRY?

4343
03:08:46,415 --> 03:08:49,951
>> ALSO CYST FORMATION.

4344
03:08:50,018 --> 03:08:53,088
>> YOU'VE GOT GRANULOMAS AND ALL

4345
03:08:53,155 --> 03:08:53,555
THIS.

4346
03:08:53,622 --> 03:08:54,523
MY VIEW HAS BEEN, YOU CAN SPEND

4347
03:08:54,589 --> 03:08:55,957
A LOT OF TIME TRYING TO FIGURE

4348
03:08:56,024 --> 03:08:57,592
THAT OUT IN MICE AND RATS, WHY

4349
03:08:57,659 --> 03:08:59,227
NOT GIVE TO HUMANS, JUST LIKE

4350
03:08:59,294 --> 03:09:06,902
YOU WOULD AN ANTITUBERCULOSE

4351
03:09:06,968 --> 03:09:09,404
DRUG, LOOK AT COLONIES IN THE

4352
03:09:09,471 --> 03:09:11,073
SPUTUM, YOU CAN SEE DECLINE IN

4353
03:09:11,139 --> 03:09:12,074
COLONY FORMATION WITHIN A WEEK

4354
03:09:12,140 --> 03:09:12,941
WHEN YOU DO THAT.

4355
03:09:13,008 --> 03:09:16,511
AND THEN PEOPLE -- THEN CAN YOU

4356
03:09:16,578 --> 03:09:19,915
DEVELOP CLINICALLY IN PEOPLE AND

4357
03:09:19,981 --> 03:09:21,116
MICE CAN FIGURE THAT OUT.

4358
03:09:21,183 --> 03:09:23,218
THIS KIND OF CYCLE OF WE HAVE TO

4359
03:09:23,285 --> 03:09:24,853
SEE IF IT GETS INTO THEM BEFORE

4360
03:09:24,920 --> 03:09:25,821
YOU GIVE TO PEOPLE.

4361
03:09:25,887 --> 03:09:28,156
I DON'T THINK THE ANIMAL MODELS

4362
03:09:28,223 --> 03:09:30,292
ARE THAT GOOD FOR HUMAN TB

4363
03:09:30,358 --> 03:09:30,525
ANYWAY.

4364
03:09:30,592 --> 03:09:31,626
SO IT'S A GREAT QUESTION, I'D

4365
03:09:31,693 --> 03:09:33,061
LOVE TO GET A LITTLE MORE

4366
03:09:33,128 --> 03:09:34,830
IMPATIENT WITH IT AND PUSH IT

4367
03:09:34,896 --> 03:09:37,566
FORWARD, AND I THINK SO WOULD

4368
03:09:37,632 --> 03:09:37,899
GRAHAM.

4369
03:09:37,966 --> 03:09:38,066
YES.

4370
03:09:38,133 --> 03:09:40,969
>> YOU MENTIONED THE -- AND

4371
03:09:41,036 --> 03:09:43,238
DIFFICULTY OF TARGETING SPECIFIC

4372
03:09:43,305 --> 03:09:43,705
BACTERIA.

4373
03:09:43,772 --> 03:09:47,642
MY QUESTION IS HOW OFTEN DO YOU

4374
03:09:47,709 --> 03:09:48,944
COME ACROSS A TARGET WHERE YOU

4375
03:09:49,010 --> 03:09:52,013
DON'T FIND A SUITABLE LYTIC

4376
03:09:52,080 --> 03:09:54,516
PHAGE, AND CAN YOU DO ANYTHING

4377
03:09:54,583 --> 03:09:56,485
BY ENGINEERING THE PHAGE TO

4378
03:09:56,551 --> 03:09:58,386
EXPAND ITS HOST RANGE?

4379
03:09:58,453 --> 03:09:59,654
>> THE ANSWER TO THE FIRST

4380
03:09:59,721 --> 03:10:01,523
QUESTION IS IT DEPENDS ON THE

4381
03:10:01,590 --> 03:10:05,694
ORGANISM YOU'RE TREATING.

4382
03:10:05,761 --> 03:10:08,997
SOME ORGANISMS LIKE STAPH AUREUS

4383
03:10:09,064 --> 03:10:11,299
HAVE ORGANISMS ACTIVE AGAINST A

4384
03:10:11,366 --> 03:10:13,468
PRETTY WIDE SWATH OF STAPH.

4385
03:10:13,535 --> 03:10:15,437
YOU CAN COME UP WITH A FIVE-PAGE

4386
03:10:15,504 --> 03:10:19,808
COCKTAIL THAT WOULD KNOCK OFF 8E

4387
03:10:19,875 --> 03:10:20,142
CLINICALLY.

4388
03:10:20,208 --> 03:10:21,476
-- TO HAVE THAT SAME COVERAGE,

4389
03:10:21,543 --> 03:10:28,483
YOU'D HAVE TO HAVE A LAY BREAR F

4390
03:10:28,550 --> 03:10:31,219
2- OR 300 PHASES.

4391
03:10:31,286 --> 03:10:33,655
-- TRYING TO USE THINGS IN THE

4392
03:10:33,722 --> 03:10:33,889
CLINIC.

4393
03:10:33,955 --> 03:10:36,591
YOU COULD HAVE A FIXED COCKTAIL

4394
03:10:36,658 --> 03:10:38,226
FOR STAPH, PROBABLY PSEUDOMONAS

4395
03:10:38,293 --> 03:10:43,565
AND PERHAPS FOR ENDO BACTERACIA

4396
03:10:43,632 --> 03:10:46,668
USED LIKE AN ANTIBIOTIC WHILE

4397
03:10:46,735 --> 03:10:47,836
YOU DO TESTING BUT YOU'D NEVER

4398
03:10:47,903 --> 03:10:49,471
DO THAT -- YOU'D HAVE TO HAVE A

4399
03:10:49,538 --> 03:10:50,705
LIBRARY OF CURATED PHAGES READY

4400
03:10:50,772 --> 03:10:52,107
TO GO, SCREEN AND THEN CHOOSE

4401
03:10:52,174 --> 03:10:55,544
THE ONES YOU WANT TO USE.

4402
03:10:55,610 --> 03:10:57,479
PEOPLE HAVE CHANGED HOST RANGE

4403
03:10:57,546 --> 03:11:01,516
BY CO-EVOLUTION OF PHAGES WITH

4404
03:11:01,583 --> 03:11:01,883
TARGETS.

4405
03:11:01,950 --> 03:11:03,919
PEOPLE HAVE ALSO -- THE -- BIOME

4406
03:11:03,985 --> 03:11:06,888
THAT HAS A CRISPR-BASED APPROACH

4407
03:11:06,955 --> 03:11:11,359
AND IS USING THAT APPROACH FOR

4408
03:11:11,426 --> 03:11:15,964
TRYING TO DECOLONIZE THE G.I.

4409
03:11:16,031 --> 03:11:19,401
TRACT AS MODIFIED -- HAS

4410
03:11:19,467 --> 03:11:22,003
MODIFIED SOME OF THE TAIL FIBERS

4411
03:11:22,070 --> 03:11:24,506
TO BE MORE INTERACTIVE WITH A

4412
03:11:24,573 --> 03:11:25,841
BROADER RANGE OF ORGANISMS.

4413
03:11:25,907 --> 03:11:27,142
I THINK IT'S ONE OF THE THINGS

4414
03:11:27,209 --> 03:11:28,143
THAT MAY MAKE IT POSSIBLE TO

4415
03:11:28,210 --> 03:11:32,113
EVEN GET AFTER -- BACTER A

4416
03:11:32,180 --> 03:11:32,647
LITTLE BIT BETTER.

4417
03:11:32,714 --> 03:11:35,116
YOU HAD A QUESTION.

4418
03:11:35,183 --> 03:11:35,817
SAME QUESTION?

4419
03:11:35,884 --> 03:11:36,885
OKAY, GOOD.

4420
03:11:36,952 --> 03:11:39,120
THINKING THE SAME WAY.

4421
03:11:39,187 --> 03:11:45,627
>> SO FOR THE -- PHAGE, THERE

4422
03:11:45,694 --> 03:11:48,830
MUST BE A HUGE NUMBER OF PHAGES.

4423
03:11:48,897 --> 03:11:50,565
HAS THERE BEEN ANY ML DONE, LIKE

4424
03:11:50,632 --> 03:11:53,368
WHAT ARE WE DOING -- ALL OF THE

4425
03:11:53,435 --> 03:11:54,970
PHAGES AND WHAT THEIR ACTIVITY

4426
03:11:55,036 --> 03:11:55,136
IS?

4427
03:11:55,203 --> 03:11:59,140
>> NO, THEY'RE 10 TO 31ST

4428
03:11:59,207 --> 03:12:00,108
PHAGES -- UNIQUE PHAGES, SO

4429
03:12:00,175 --> 03:12:01,309
THERE'S A LOT OF WORK TO DO

4430
03:12:01,376 --> 03:12:04,145
HERE.

4431
03:12:04,212 --> 03:12:06,014
THE PERSON WHO HAS DONE ALL

4432
03:12:06,081 --> 03:12:08,650
THIS, HE'S LOOKED AT THEM IN SEA

4433
03:12:08,717 --> 03:12:10,719
WATER, THE ESTIMATE IS THERE ARE

4434
03:12:10,785 --> 03:12:12,020
ABOUT 10 PHAGES FOR ANY

4435
03:12:12,087 --> 03:12:12,821
BACTERIUM IN THE WORLD RIGHT

4436
03:12:12,888 --> 03:12:13,588
NOW.

4437
03:12:13,655 --> 03:12:15,090
SO THE DIVERSITY IS REMARKABLE.

4438
03:12:15,156 --> 03:12:16,191
AND THAT'S ONE OF THE REASONS

4439
03:12:16,258 --> 03:12:18,460
WHY AT LEAST IT'S FEASIBLE TO

4440
03:12:18,526 --> 03:12:20,829
FIND A PHAGE FOR ANY ORGANISM

4441
03:12:20,896 --> 03:12:22,197
SOMEBODY MIGHT GET INFECTED

4442
03:12:22,264 --> 03:12:22,397
WITH.

4443
03:12:22,464 --> 03:12:25,967
>> IT SEEMS LIKE HIGH-THROUGHPUT

4444
03:12:26,034 --> 03:12:26,935
SCREENING, IT'S NOT A REACH,

4445
03:12:27,002 --> 03:12:27,135
RIGHT?

4446
03:12:27,202 --> 03:12:31,940
>> NO, IT'S NOT A REACH AT ALL.

4447
03:12:32,007 --> 03:12:33,909
IF YOU'RE LOOKING FOR PHAGES

4448
03:12:33,975 --> 03:12:35,343
ACTIVE AGAINST E. COLI, YOU GO

4449
03:12:35,410 --> 03:12:37,212
TO THE SEWAGE TREATMENT PLANT.

4450
03:12:37,279 --> 03:12:39,180
IF YOU LOOK AT THOSE ACTIVE

4451
03:12:39,247 --> 03:12:40,715
AGAINST STAPH, YOU TAKE KIND OF

4452
03:12:40,782 --> 03:12:45,654
A SOUPY PIECE OF GAUZE OFF A

4453
03:12:45,720 --> 03:12:47,088
WOUND THAT'S INFECT AND YOU

4454
03:12:47,155 --> 03:12:51,660
SCREEN THAT.

4455
03:12:51,726 --> 03:12:53,094
SO -- WATERING HOLE.

4456
03:12:53,161 --> 03:12:53,295
JOHN.

4457
03:12:53,361 --> 03:12:55,964
>> IS THERE ANY PROSPECT FOR

4458
03:12:56,031 --> 03:12:57,032
FINDING I WOULDN'T CALL THEM

4459
03:12:57,098 --> 03:12:58,566
PHAGES BUT VIRUSES ACTIVE

4460
03:12:58,633 --> 03:13:02,103
AGAINST PARASITIC ORGANISMS AND

4461
03:13:02,170 --> 03:13:02,304
FUNGI?

4462
03:13:02,370 --> 03:13:04,172
>> THERE ARE -- PEOPLE ARE

4463
03:13:04,239 --> 03:13:09,177
BEGINNING TO LOOK AT THAT.

4464
03:13:09,244 --> 03:13:10,178
THE MYCOBACTERIUM THAT PEOPLE

4465
03:13:10,245 --> 03:13:15,984
WOULD BE -- I MEAN THE FUNGUS --

4466
03:13:16,051 --> 03:13:17,252
WHICH IS GOING TO BE A BIGGER

4467
03:13:17,319 --> 03:13:18,520
AND BIGGER PROBLEM WITH DEVICES

4468
03:13:18,586 --> 03:13:21,923
AROUND THE WORLD, I WAS HAVING

4469
03:13:21,990 --> 03:13:24,292
DINNER WITH SOME COLLEAGUES FROM

4470
03:13:24,359 --> 03:13:27,028
HONG KONG LAST WEEK AND THEY

4471
03:13:27,095 --> 03:13:33,735
TOLD ME THAT KYU NHUN HAS SOME.

4472
03:13:33,802 --> 03:13:35,270
I SAID HAVE THEM CALL ME BECAUSE

4473
03:13:35,337 --> 03:13:36,671
WE'D LOVE TO LOOK AT THOSE.

4474
03:13:36,738 --> 03:13:37,772
PEOPLE ARE BEGINNING TO LOOK IN

4475
03:13:37,839 --> 03:13:38,640
THAT AREA AS WELL.

4476
03:13:38,707 --> 03:13:43,812
BUT GREAT QUESTION.

4477
03:13:43,878 --> 03:13:49,250
>> I WAS WONDERING, WHAT IS THE

4478
03:13:49,317 --> 03:13:52,320
SAFETY -- LOOK LIKE FOR PHAGE

4479
03:13:52,387 --> 03:13:54,289
THERAPIES?

4480
03:13:54,356 --> 03:13:58,026
DOES THAT CHANGE BASED ON THE --

4481
03:13:58,093 --> 03:14:01,062
OR DISEASE STATE OR --

4482
03:14:01,129 --> 03:14:02,297
>> WERE YOU ASKING WHAT THE

4483
03:14:02,364 --> 03:14:03,331
SUCCESS RATE IS?

4484
03:14:03,398 --> 03:14:06,267
>> SAFETY AND --

4485
03:14:06,334 --> 03:14:10,405
>> THE SAFETY RATE, OKAY.

4486
03:14:10,472 --> 03:14:11,272
SAFETY HAS ACTUALLY BEEN

4487
03:14:11,339 --> 03:14:12,374
SOMETHING THAT HAS BEEN WORKED

4488
03:14:12,440 --> 03:14:13,908
OUT OVER THE LAST FEW HUNDRED

4489
03:14:13,975 --> 03:14:14,976
THOUSAND YEARS.

4490
03:14:15,043 --> 03:14:17,178
THERE ARE MORE PHAGES IN US THAN

4491
03:14:17,245 --> 03:14:18,813
THERE ARE BACTERIA.

4492
03:14:18,880 --> 03:14:20,248
AND SO WE'RE JUST KIND OF --

4493
03:14:20,315 --> 03:14:22,650
WE'RE KIND OF A CORAL REEF ON

4494
03:14:22,717 --> 03:14:24,052
WHICH BACTERIA AND PHAGE LIVE.

4495
03:14:24,119 --> 03:14:28,023
WHEN YOU TALK TO THE FDA, THEIR

4496
03:14:28,089 --> 03:14:29,991
CONCERN IS NOT SAFETY.

4497
03:14:30,058 --> 03:14:32,594
THE FACT THAT THEY'VE SAID TO ME

4498
03:14:32,660 --> 03:14:34,362
AND OTHERS, WE DON'T WANT ANY

4499
03:14:34,429 --> 03:14:36,798
MORE STUDIES ABOUT SAFETY, WE

4500
03:14:36,865 --> 03:14:38,967
JUST WANT TO KNOW IF THEY WORK.

4501
03:14:39,034 --> 03:14:40,702
SO THEY DON'T ASK YOU TO DO ANY

4502
03:14:40,769 --> 03:14:42,103
TOXICITY STUDIES, THEY DON'T ASK

4503
03:14:42,170 --> 03:14:43,571
FOR STUDIES ON ANIMALS.

4504
03:14:43,638 --> 03:14:44,639
THEY JUST WANT YOU TO SHOW THEM

4505
03:14:44,706 --> 03:14:46,975
THE CMC DATA ABOUT HOW YOU GOT

4506
03:14:47,042 --> 03:14:48,476
RID OF THE ENDO TOXIN AND

4507
03:14:48,543 --> 03:14:50,245
PREAPED THEM, BUT SAFETY HAS NOT

4508
03:14:50,311 --> 03:14:51,646
BEEN AN ISSUE WITH THEM.

4509
03:14:51,713 --> 03:14:52,881
OBVIOUSLY I THINK WE'VE GOT TO

4510
03:14:52,947 --> 03:14:54,416
KEEP WATCHING, BUT RIGHT NOW

4511
03:14:54,482 --> 03:14:56,151
JUST GOT TO FIGURE OUT IF THEY

4512
03:14:56,217 --> 03:14:58,019
WORK AND, IF SO, HOW TO MOST

4513
03:14:58,086 --> 03:15:00,422
RIGOROUSLY USE THEM.

4514
03:15:00,488 --> 03:15:03,925
SO APPRECIATE YOUR PATIENCE FOR

4515
03:15:03,992 --> 03:15:04,859
A FREE ASSOCIATION TALK.

4516
03:15:04,926 --> 03:15:05,293
THANK YOU.

4517
03:15:05,360 --> 03:15:11,599
[APPLAUSE]

4518
03:15:11,666 --> 03:15:15,103
>> WE'RE GOING TO NOW MOVE ON TO

4519
03:15:15,170 --> 03:15:18,506
CLASS CREW.

4520
03:15:18,573 --> 03:15:19,707
POSTDOCTORAL WORK IN LA HOI

4521
03:15:19,774 --> 03:15:21,209
WHAT.

4522
03:15:21,276 --> 03:15:26,648
IN 1994, HE JOINED -- RESEARCH

4523
03:15:26,714 --> 03:15:27,482
PROGRAM THERE.

4524
03:15:27,549 --> 03:15:29,350
IN 2000 HE JOINED THE OREGON

4525
03:15:29,417 --> 03:15:31,786
HEALTH AND SCIENCES UNIVERSITY

4526
03:15:31,853 --> 03:15:35,123
VACCINE GENE THERAPY INSTITUTE.

4527
03:15:35,190 --> 03:15:37,459
RESEARCH FOCUS ON THE MOLECULAR

4528
03:15:37,525 --> 03:15:38,626
REACTION BETWEEN BIOPATHOGENS

4529
03:15:38,693 --> 03:15:39,928
AND THEIR HOST.

4530
03:15:39,994 --> 03:15:42,163
HIS TALK HAS PIONEERED THE

4531
03:15:42,230 --> 03:15:44,432
DEVELOPMENT OF DB VACCINES.

4532
03:15:44,499 --> 03:15:46,734
TIE IS UNIQUE BIOLOGY OF --

4533
03:15:46,801 --> 03:15:48,403
BASED VACCINES.

4534
03:15:48,470 --> 03:15:55,777
[APPLAUSE]

4535
03:15:55,844 --> 03:15:57,011
>> THANK YOU.

4536
03:15:57,078 --> 03:15:58,113
THANK YOU FOR THE INTRODUCTION

4537
03:15:58,179 --> 03:15:59,180
AND THANK YOU FOR A GREAT

4538
03:15:59,247 --> 03:16:02,050
MEETING.

4539
03:16:02,117 --> 03:16:04,886
SO WHILE WE WORK ON -- IT'S OF

4540
03:16:04,953 --> 03:16:06,187
COURSE A VIRUS THAT INFECTS A

4541
03:16:06,254 --> 03:16:08,723
LOT OF US, AND MOST OF US ARE

4542
03:16:08,790 --> 03:16:09,824
CHRONICALLY INFECTED AND THE

4543
03:16:09,891 --> 03:16:12,093
REASON IS THAT CME IS QUITE

4544
03:16:12,160 --> 03:16:13,862
UNIQUE IN ITS ABILITY TO ELICIT

4545
03:16:13,928 --> 03:16:15,497
AND MAINTAIN VERY STRONG EFFECT

4546
03:16:15,563 --> 03:16:17,165
ON MEMORY T-CELL RESPONSES.

4547
03:16:17,232 --> 03:16:19,567
THIS IS FROM A PAPER FROM

4548
03:16:19,634 --> 03:16:24,272
LEWIS -- FROM 2005 SHOWING

4549
03:16:24,339 --> 03:16:25,406
THAT -- CHRONICALLY INFECTED

4550
03:16:25,473 --> 03:16:29,944
WITH CME, 10% -- CD4 T-CELL

4551
03:16:30,011 --> 03:16:33,148
RESPONSES -- LEWIS HAD THIS IDEA

4552
03:16:33,214 --> 03:16:36,451
WHAT IF WE COULD USE THIS AND

4553
03:16:36,518 --> 03:16:37,752
REDIRECT THESE EFFECT ON MEMORY

4554
03:16:37,819 --> 03:16:39,387
T CELLS TO OTHER PATHOGENS.

4555
03:16:39,454 --> 03:16:40,255
WHAT THAT WOULD MEAN IS THAT YOU

4556
03:16:40,321 --> 03:16:42,123
HAVE A CONSTANT IMMUNE FIELD

4557
03:16:42,190 --> 03:16:44,192
AGAINST THESE PATHOGENS AND YOU

4558
03:16:44,259 --> 03:16:47,462
DON'T NEED THE RECALL RESPONSE

4559
03:16:47,529 --> 03:16:50,632
OR IN CASE OF PRIMARY INFECTION

4560
03:16:50,698 --> 03:16:51,699
FIRST TIME RESPONSE WHICH TAKES

4561
03:16:51,766 --> 03:16:53,701
TWO OR THREE WEEKS TO DEVELOP.

4562
03:16:53,768 --> 03:16:55,136
SO IN THE CASE OF SIV, FOR

4563
03:16:55,203 --> 03:16:56,871
INSTANCE, IN MONKEYS, YOU WILL

4564
03:16:56,938 --> 03:16:59,274
SEE DATA THAT WITHIN A WEEK, YOU

4565
03:16:59,340 --> 03:17:01,042
GO FROM VIRTUALLY NOTHING WITH

4566
03:17:01,109 --> 03:17:02,310
FAIRLY LOW DOSE INFECTION UP TO

4567
03:17:02,377 --> 03:17:05,079
10 TO THE 6TH, 10 TO THE 7TH

4568
03:17:05,146 --> 03:17:06,948
VIRUSES PER MILLILITER OF BLOOD.

4569
03:17:07,015 --> 03:17:08,716
SO BY TEAM EVEN IN THE

4570
03:17:08,783 --> 03:17:10,018
VACCINATED ANIMAL, YOUR IMMUNE

4571
03:17:10,084 --> 03:17:11,686
SYSTEM KICKS IN, YOUR T-CELL

4572
03:17:11,753 --> 03:17:16,357
RESPONSE KICKS IN, IT HAS TO

4573
03:17:16,424 --> 03:17:18,993
PLAY CATCH-UP FOR THE REST OF

4574
03:17:19,060 --> 03:17:20,995
THE TIME IN CONTROLLING THIS

4575
03:17:21,062 --> 03:17:21,262
INFECTION.

4576
03:17:21,329 --> 03:17:22,230
SO THE FIRST QUESTION IS OF

4577
03:17:22,297 --> 03:17:24,699
COURSE CAN WE USE CMV TO ELICIT

4578
03:17:24,766 --> 03:17:26,434
IMMUNE RESPONSES TO OTHER

4579
03:17:26,501 --> 03:17:28,336
ANTIGENS, DO THOSE HAVE THE SAME

4580
03:17:28,403 --> 03:17:28,636
PHENOTYPE.

4581
03:17:28,703 --> 03:17:30,038
THE ANSWER TO THAT IS YES.

4582
03:17:30,104 --> 03:17:35,443
IN THE MEANTIME, -- PROBABLY 50

4583
03:17:35,510 --> 03:17:37,478
OR EVEN MORE DIFFERENT ANTIGENS

4584
03:17:37,545 --> 03:17:38,980
INTO A RHESUS CME VECTOR AND

4585
03:17:39,047 --> 03:17:41,416
POINT OUT THAT THE WHOLE

4586
03:17:41,482 --> 03:17:42,517
STUDIES -- ARE NON-HUMAN

4587
03:17:42,584 --> 03:17:43,518
PRIMATES.

4588
03:17:43,585 --> 03:17:46,588
AND YOU ALWAYS GET THESE IMMUNE

4589
03:17:46,654 --> 03:17:48,890
RESPONSES SAME AS THE IMMUNE

4590
03:17:48,957 --> 03:17:51,993
RESPONSES TO THE CME ANTIGENS

4591
03:17:52,060 --> 03:17:55,263
AND THIS IS A VERY TYPICAL GRAPH

4592
03:17:55,330 --> 03:17:57,432
HERE, IF YOU VACCINATE AGAINST

4593
03:17:57,498 --> 03:18:00,702
SIV USING RHESUS -- OR --

4594
03:18:00,768 --> 03:18:02,904
ADENOVECTORS, THE T-CELL

4595
03:18:02,971 --> 03:18:04,205
RESPONSE IN THE PERIPHERY WILL

4596
03:18:04,272 --> 03:18:06,608
DISAPPEAR WITH THE OTHER VECTORS

4597
03:18:06,674 --> 03:18:07,875
BECAUSE THEY'RE CENTRAL MEMORY

4598
03:18:07,942 --> 03:18:10,111
RESPONSES AND THEY NEED TO BE

4599
03:18:10,178 --> 03:18:12,547
RECALLED.

4600
03:18:12,614 --> 03:18:15,416
WHEREAS IN THE CMV CASE, THESE

4601
03:18:15,483 --> 03:18:16,484
STAY AT A CERTAIN LEVEL IN THESE

4602
03:18:16,551 --> 03:18:18,019
ANIMALS FOR THE REST OF THE LIFE

4603
03:18:18,086 --> 03:18:19,887
OF THESE ANIMALS.

4604
03:18:19,954 --> 03:18:22,490
THEIR EFFECT ON MEMORY BIAS IS

4605
03:18:22,557 --> 03:18:24,058
SHOWN HERE BUT THE SURFACE MARK

4606
03:18:24,125 --> 03:18:24,926
STAINING, AND THEY ARE NOT JUST

4607
03:18:24,993 --> 03:18:27,228
IN THE BLOOD BUT ALSO IN THE

4608
03:18:27,295 --> 03:18:28,529
TISSUES, AND SOME OF THOSE

4609
03:18:28,596 --> 03:18:30,531
RESPONSES ARE REALLY HIGH, THIS

4610
03:18:30,598 --> 03:18:33,901
IS AN ANIMAL I THINK SEVEN YEARS

4611
03:18:33,968 --> 03:18:35,970
AFTER ORIGINAL INNOCULATION, 10,

4612
03:18:36,037 --> 03:18:37,272
20% OF THE T CELLS IN THE LIVER

4613
03:18:37,338 --> 03:18:41,876
AND SPLEEN ARE AGAINST THE

4614
03:18:41,943 --> 03:18:42,744
INSERTED ANTIGEN.

4615
03:18:42,810 --> 03:18:44,512
MOST IMPORTANTLY, THEY WORK.

4616
03:18:44,579 --> 03:18:47,782
SO USING THE SIV MODEL, LEWIS IN

4617
03:18:47,849 --> 03:18:48,883
SEVERAL STUDIES NOW HAS SHOWN

4618
03:18:48,950 --> 03:18:52,287
THAT WHEN YOU CHALLENGE ANIMALS

4619
03:18:52,353 --> 03:18:57,659
WITH SIV AND THIS IS A LOW DOSE

4620
03:18:57,725 --> 03:19:00,395
INTRARECTAL -- HIGHLY VIRULENT

4621
03:19:00,461 --> 03:19:04,699
IN RHESUS MACAQUES, ALL THE

4622
03:19:04,766 --> 03:19:06,668
ANIMALS IN THE CONTROL GROUP ARE

4623
03:19:06,734 --> 03:19:10,471
DEVELOP AIDS, THIS VERY

4624
03:19:10,538 --> 03:19:11,339
EXPLOSIVE INFECTION EARLY ON.

4625
03:19:11,406 --> 03:19:12,974
WHEN YOU VACCINATE WITH

4626
03:19:13,041 --> 03:19:14,609
ADENOVECTORS, WHAT YOU SEE IS

4627
03:19:14,676 --> 03:19:17,345
YOU REDUCE THE P VIRAL LOAD BUT

4628
03:19:17,412 --> 03:19:19,013
ULTIMATELY THESE VECTORS DON'T

4629
03:19:19,080 --> 03:19:19,247
PROTECT.

4630
03:19:19,314 --> 03:19:23,951
IN THE CASE OF CMV, WE SEE THIS

4631
03:19:24,018 --> 03:19:24,652
VERY INTERESTING -- ABOUT HALF

4632
03:19:24,719 --> 03:19:27,221
OF THE ANIMALS, THEY ARE

4633
03:19:27,288 --> 03:19:28,423
INFECTED AND THEN CONTROL THE

4634
03:19:28,489 --> 03:19:31,259
VIRUS, AND THE OTHER HAVE NO

4635
03:19:31,326 --> 03:19:32,694
PROTECTION, THERE'S NO

4636
03:19:32,760 --> 03:19:33,561
IMMUNOLOGICAL DIFFERENCE.

4637
03:19:33,628 --> 03:19:34,529
THE VACCINE WORKS IN BOTH

4638
03:19:34,595 --> 03:19:35,763
ANIMALS THE SAME WAY.

4639
03:19:35,830 --> 03:19:38,032
THE REASON WHY THIS IS A SUBJECT

4640
03:19:38,099 --> 03:19:39,801
OF A DIFFERENT TALK BUT WE HAVE

4641
03:19:39,867 --> 03:19:42,003
SOME INDICATION THAT IT'S THE

4642
03:19:42,070 --> 03:19:43,204
INNATE SET POINT OF THESE

4643
03:19:43,271 --> 03:19:45,506
ANIMALS THAT DICTATES THAT.

4644
03:19:45,573 --> 03:19:47,475
WHEN YOU MIX THE TWO, ADENOVIRUS

4645
03:19:47,542 --> 03:19:49,410
DOES THIS THING AND CMV DOES ITS

4646
03:19:49,477 --> 03:19:51,312
THING.

4647
03:19:51,379 --> 03:19:56,551
SO WE'VE SHOWN ALSO THAT SIV

4648
03:19:56,617 --> 03:19:57,985
IS -- CLEAR FROM THESE ANIMALS,

4649
03:19:58,052 --> 03:20:00,054
EARLY ON IN INFECTION YOU CAN

4650
03:20:00,121 --> 03:20:02,123
TRANSFER BONE MARROW FROM

4651
03:20:02,190 --> 03:20:04,859
CONTROL ANIMALS BUT YOU STILL

4652
03:20:04,926 --> 03:20:06,894
CAN TRANSFER SIV TO RECIPIENT

4653
03:20:06,961 --> 03:20:07,128
ANIMALS.

4654
03:20:07,195 --> 03:20:10,031
WHEN YOU DO THIS LATER, THERE'S

4655
03:20:10,098 --> 03:20:11,566
NO VIRUS IN THE RECIPIENT

4656
03:20:11,632 --> 03:20:12,533
ANIMALS, AND THIS IS VERY

4657
03:20:12,600 --> 03:20:16,170
DIFFERENT FROM ANIMALS THAT

4658
03:20:16,237 --> 03:20:19,807
ARE -- END UP ON ANTIRETROVIRAL

4659
03:20:19,874 --> 03:20:20,975
THERAPY, YOU CAN ALWAYS FIND

4660
03:20:21,042 --> 03:20:22,510
VIRUS AND ALWAYS TRANSFER VIRUS.

4661
03:20:22,577 --> 03:20:24,045
SO BASICALLY THEY'RE CURED OF

4662
03:20:24,112 --> 03:20:25,613
SIV BECAUSE OF THIS INTERSECTION

4663
03:20:25,680 --> 03:20:27,148
THAT HAPPENS VERY EARLY ON, AND

4664
03:20:27,215 --> 03:20:28,549
BY THE WAY, THIS IS VERY SIMILAR

4665
03:20:28,616 --> 03:20:32,587
TO WHAT YOU SEE IN ANIMALS THAT

4666
03:20:32,653 --> 03:20:36,457
ARE TREATED VERY EARLY ON WITH

4667
03:20:36,524 --> 03:20:37,258
ANTIRETROVIRAL THERAPY SO THERE

4668
03:20:37,325 --> 03:20:40,962
IS POSSIBILITY FOR A CURE EARLY

4669
03:20:41,028 --> 03:20:44,065
IN -- WE TRIED THERAPEUTIC

4670
03:20:44,132 --> 03:20:45,700
VACCINATION IN THE SIV MODEL

4671
03:20:45,767 --> 03:20:49,070
WITH -- AND THAT -- THIS REALLY

4672
03:20:49,137 --> 03:20:50,304
IS THE MODEL OF THIS EARLY

4673
03:20:50,371 --> 03:20:53,908
INTERCEPT.

4674
03:20:53,975 --> 03:21:00,415
SO IN ADDITION TO SIV, SHOWN IN

4675
03:21:00,481 --> 03:21:01,716
OTHER PATHOGEN MODELS, THERE WAS

4676
03:21:01,783 --> 03:21:06,521
A PAPER FROM -- AGAINST' BOW LA

4677
03:21:06,587 --> 03:21:08,289
VIRUS, THERE IS -- WE'VE SHOWN

4678
03:21:08,356 --> 03:21:10,258
IT PROTECTS AGAINST TB AND THEN

4679
03:21:10,324 --> 03:21:12,860
THERE'S SOME INDICATION IT MIGHT

4680
03:21:12,927 --> 03:21:14,495
WORK AGAINST MALARIA ALSO IN

4681
03:21:14,562 --> 03:21:18,566
THAT IT REDUCES THE LIVER STAGE

4682
03:21:18,633 --> 03:21:20,868
OF MALARIA PARASITES AND WORKS

4683
03:21:20,935 --> 03:21:24,806
AGAINST VIRUSES, BACTERIA AND

4684
03:21:24,872 --> 03:21:25,072
PARASITES.

4685
03:21:25,139 --> 03:21:26,541
SO I STARTED TO WORK WITH LEWIS

4686
03:21:26,607 --> 03:21:28,943
BECAUSE OF THESE DATA.

4687
03:21:29,010 --> 03:21:30,511
SO I WAS INTRIGUED BY THE FACT

4688
03:21:30,578 --> 03:21:34,115
THAT HE WAS USING RHESUS CMV IN

4689
03:21:34,182 --> 03:21:37,051
ANIMALS THAT ARE ALREADY CME

4690
03:21:37,118 --> 03:21:38,486
POSITIVE AND FOR ADENOVECTORS

4691
03:21:38,553 --> 03:21:41,989
AND SO ON, THIS IS A HUGE

4692
03:21:42,056 --> 03:21:43,090
PROBLEM WITH ASSOCIATED VECTORS.

4693
03:21:43,157 --> 03:21:45,827
WE CAN GO INTO -- AT ANY DOSE

4694
03:21:45,893 --> 03:21:47,361
AND WITH RESPECT TO THE T-CELL

4695
03:21:47,428 --> 03:21:48,563
RESPONSE, THERE'S NO DIFFERENCE.

4696
03:21:48,629 --> 03:21:52,834
EVEN AT VERY LOW DOSES IN CME

4697
03:21:52,900 --> 03:21:54,335
POSITIVE ANIMALS WE GET THE SAME

4698
03:21:54,402 --> 03:21:55,803
LEVEL OF RESPONSE T-CELL

4699
03:21:55,870 --> 03:21:58,506
RESPONSES AS WE DO WITH HIGHER

4700
03:21:58,573 --> 03:21:58,840
DOSE.

4701
03:21:58,906 --> 03:22:00,274
WE CAN USE THE SAME VECTORS OVER

4702
03:22:00,341 --> 03:22:03,444
AND OVER AGAIN IN INDUCING

4703
03:22:03,511 --> 03:22:04,979
IMMUNE RESPONSE TO NEW ANTIGENS

4704
03:22:05,046 --> 03:22:06,280
THAT WE INSERTED INTO THESE

4705
03:22:06,347 --> 03:22:07,482
ANIMALS.

4706
03:22:07,548 --> 03:22:08,816
SO LEWIS AND I TEAMED UP AND

4707
03:22:08,883 --> 03:22:11,552
WHAT WE'VE SHOWN IS THAT IT'S

4708
03:22:11,619 --> 03:22:14,722
THE ABILITY OF CMV TO

4709
03:22:14,789 --> 03:22:16,824
DOWNREGULATE CLASS ONE MOLECULES

4710
03:22:16,891 --> 03:22:18,559
AND BASICALLY HIDE FROM THE T

4711
03:22:18,626 --> 03:22:20,094
CELLS THAT USES -- THAT ENABLES

4712
03:22:20,161 --> 03:22:23,731
TO BE INDUCED, TO BE USED IN CMV

4713
03:22:23,798 --> 03:22:24,165
POSITIVE ANIMALS.

4714
03:22:24,232 --> 03:22:26,234
IF YOU KNOCK OUT THOSE DOWN

4715
03:22:26,300 --> 03:22:28,302
REGULATING GENES FROM CMV IT NO

4716
03:22:28,369 --> 03:22:31,706
LONGER ABLE TO DO THAT.

4717
03:22:31,772 --> 03:22:34,108
SO -- BOTH IN USING BUT ALSO

4718
03:22:34,175 --> 03:22:36,277
RELATING THE T-CELL RESPONSES IT

4719
03:22:36,344 --> 03:22:39,747
THEN USES.

4720
03:22:39,814 --> 03:22:42,383
SO THIS WORK THEN LED US TO

4721
03:22:42,450 --> 03:22:44,785
SOME -- WE FOUND THAT THE

4722
03:22:44,852 --> 03:22:45,620
EPITOPE SPECIFICITY WAS

4723
03:22:45,686 --> 03:22:47,755
DIFFERENT IN THESE ANIMALS, DOWN

4724
03:22:47,822 --> 03:22:49,156
DIAGNOSE REGULATING GENES, SO WE

4725
03:22:49,223 --> 03:22:52,894
STARTED MAPPING THE EPITOPES AND

4726
03:22:52,960 --> 03:22:55,963
C MOLECULES THAT REPRESENT THESE

4727
03:22:56,030 --> 03:22:58,032
EPITOPES AND THAT -- INTO A VERY

4728
03:22:58,099 --> 03:22:58,900
UNEXPECTED AND VERY INTERESTING

4729
03:22:58,966 --> 03:22:59,233
STORY.

4730
03:22:59,300 --> 03:23:02,737
BECAUSE WHAT WE FIND IS THAT THE

4731
03:23:02,803 --> 03:23:04,305
CD8 T-CELL RESPONSES INDUCED BY

4732
03:23:04,372 --> 03:23:06,674
THE RHESUS CMV VECTORS, THEY'RE

4733
03:23:06,741 --> 03:23:10,244
NOT RESTRICTED BY MHC CLASS 1.

4734
03:23:10,311 --> 03:23:15,116
SO THE PEPTIDES PRESENTED TO DCE

4735
03:23:15,182 --> 03:23:16,217
THAT WE'VE EVER HEARD UP,

4736
03:23:16,284 --> 03:23:18,019
THEY'RE NOT RECOGNIZED, DO NOT

4737
03:23:18,085 --> 03:23:19,487
RECOGNIZE THE PEPTIDES IN THE

4738
03:23:19,554 --> 03:23:23,324
CONTEXT OF MHC CLASS 1.

4739
03:23:23,391 --> 03:23:25,626
INSTEAD IN THE CONTEXT OF MHC IT

4740
03:23:25,693 --> 03:23:32,466
OR IN THE CONMHC2 OR A -- THE WW

4741
03:23:32,533 --> 03:23:33,868
THIS IS THESE ARE EACH

4742
03:23:33,935 --> 03:23:34,869
INDIVIDUAL ANIMALS.

4743
03:23:34,936 --> 03:23:37,605
EACH OF THESE SQUARES INDICATES

4744
03:23:37,672 --> 03:23:41,309
PEPTIDES THAT GIVE BACKGROUND

4745
03:23:41,375 --> 03:23:42,643
RESPONSE IN THESE ANIMALS, THEN

4746
03:23:42,710 --> 03:23:44,612
YOU CAN BLOCK THOSE T-CELL

4747
03:23:44,679 --> 03:23:48,683
RESPONSES WHICH ARE -- STAINING,

4748
03:23:48,749 --> 03:23:50,985
USING ANTIBODIES OR IN THE CASE

4749
03:23:51,052 --> 03:23:54,589
OF -- A PEPTIDE THAT BINDS TO

4750
03:23:54,655 --> 03:23:55,923
HMCE AND SHOWS THIS SPECIFICALLY

4751
03:23:55,990 --> 03:23:56,791
BLOCKS THOSE RESPONSES.

4752
03:23:56,857 --> 03:24:00,628
SO VERY SURPRISING FINDING.

4753
03:24:00,695 --> 03:24:02,697
SOME OF THE PEPTIDES, THEY GIVE

4754
03:24:02,763 --> 03:24:04,699
RESPONSES IN EVERY SINGLE ANIMAL

4755
03:24:04,765 --> 03:24:07,735
THAT WE EVER TESTED.

4756
03:24:07,802 --> 03:24:09,837
THAT'S NOT SO SURPRISING FOR

4757
03:24:09,904 --> 03:24:10,137
HMC.

4758
03:24:10,204 --> 03:24:12,673
BECAUSE IT'S A HIGHLY CONSERVED

4759
03:24:12,740 --> 03:24:14,742
MOLECULE, BUT MHC2, THESE ARE

4760
03:24:14,809 --> 03:24:18,913
ANIMALS THAT HAVE DIFFERENT MHCT

4761
03:24:18,980 --> 03:24:22,216
QUITE UNDERSTAND THE

4762
03:24:22,283 --> 03:24:23,651
BIOMECHANISMS FOR THIS, WE CAN

4763
03:24:23,718 --> 03:24:25,920
EASILY TEST ONE OF THESE --

4764
03:24:25,987 --> 03:24:26,921
WHETHER THESE RESPONSES ARE

4765
03:24:26,988 --> 03:24:28,456
THERE OR NOT LOOKING

4766
03:24:28,522 --> 03:24:31,759
SPECIFICALLY FOR THESE

4767
03:24:31,826 --> 03:24:32,526
SUPERTOPES.

4768
03:24:32,593 --> 03:24:34,261
SO SURPRISINGLY -- SO WHY HAS

4769
03:24:34,328 --> 03:24:36,330
THIS NEVER BEEN SEEN BEFORE IN

4770
03:24:36,397 --> 03:24:38,633
PEOPLE CME POSITIVE, THE T CELLS

4771
03:24:38,699 --> 03:24:42,069
RESPONSES ARE MHC1 RESTRICT.

4772
03:24:42,136 --> 03:24:44,205
THE SAME IS TRUE FOR MONKEYS --

4773
03:24:44,271 --> 03:24:45,106
INFECTED.

4774
03:24:45,172 --> 03:24:46,440
THE IMMUNE RESPONSE IN MONKEYS

4775
03:24:46,507 --> 03:24:49,310
NATURALLY INFECTED WITH CMV

4776
03:24:49,377 --> 03:24:51,345
AGAINST CMV PROTEINS, THEY ARE

4777
03:24:51,412 --> 03:24:52,680
CLASSICALLY RESTRICTED AS SHOWN

4778
03:24:52,747 --> 03:24:55,383
HERE IN RED.

4779
03:24:55,449 --> 03:24:59,120
IT'S ONLY THE ONES THAT GOT OUR

4780
03:24:59,186 --> 03:25:00,521
VECTORS THAT WERE -- RESTRICTED

4781
03:25:00,588 --> 03:25:02,089
EVEN TO THE CME PROTEINS AND

4782
03:25:02,156 --> 03:25:03,424
WHEN YOU GO INTO ANIMALS THAT

4783
03:25:03,491 --> 03:25:06,394
ARE CME POSITIVE WE HAVE ALL

4784
03:25:06,460 --> 03:25:07,428
THREE KINDS OF RESTRICTIONS.

4785
03:25:07,495 --> 03:25:10,398
SO WHAT'S GOING ON HERE?

4786
03:25:10,464 --> 03:25:14,001
THE SOLUTION WAS THAT WE USE

4787
03:25:14,068 --> 03:25:16,303
JUST BY SHEER COINCIDENCE THE

4788
03:25:16,370 --> 03:25:24,311
ONLY REI REI RE -- IT WAS ISOLAN

4789
03:25:24,378 --> 03:25:26,313
1968, 68-1, AND THAT VECTOR

4790
03:25:26,380 --> 03:25:29,283
LACKS TWO GENE REGIONS THAT ARE

4791
03:25:29,350 --> 03:25:32,420
PRESENT IN THE -- CMV, YOU HAVE

4792
03:25:32,486 --> 03:25:35,523
TO THIS FLIFOVER OF THIS GENE

4793
03:25:35,589 --> 03:25:36,624
REGION AND DELETION OF THESE TWO

4794
03:25:36,691 --> 03:25:39,760
GENE REGIONS AND IT TURNS OUT

4795
03:25:39,827 --> 03:25:41,529
BOTH OF THOSE REGIONS NEED TO BE

4796
03:25:41,595 --> 03:25:43,097
DELETED AND WE GET THESE

4797
03:25:43,164 --> 03:25:44,699
UNCONVENTIONAL T-CELL RESPONSES,

4798
03:25:44,765 --> 03:25:46,767
IF EITHER ONE OF THEM IS

4799
03:25:46,834 --> 03:25:49,203
REPAIRED, WE GET CONVENTIONAL

4800
03:25:49,270 --> 03:25:50,838
MHC CLASS 1 RESTRICTED CD8 T

4801
03:25:50,905 --> 03:25:52,039
CELLS.

4802
03:25:52,106 --> 03:25:54,275
SO THESE THREE REGIONS CONTAIN

4803
03:25:54,341 --> 03:25:55,242
CHEMOKINES, TO BE HONEST WE

4804
03:25:55,309 --> 03:25:57,211
DON'T KNOW HOW THEY PREVENT THE

4805
03:25:57,278 --> 03:25:59,513
CONDUCTION OF THESE

4806
03:25:59,580 --> 03:26:00,247
UNCONVENTIONAL RESPONSE BUT

4807
03:26:00,314 --> 03:26:04,185
THAT'S WHAT THEY DO.

4808
03:26:04,251 --> 03:26:07,321
THE OTHER TWO GENES ARE

4809
03:26:07,388 --> 03:26:09,757
HOMOLOGUES AND THEY ARE VERY

4810
03:26:09,824 --> 03:26:11,392
WELL-KNOWN ALTHOUGH THE

4811
03:26:11,459 --> 03:26:12,526
CHEMOKINE HOMOLOGUES, THEIR

4812
03:26:12,593 --> 03:26:14,462
FUNCTION IS TO BE PART OF A

4813
03:26:14,528 --> 03:26:19,834
RECEPTOR OF A PENT -- OMERE

4814
03:26:19,900 --> 03:26:21,402
COMPLEX.

4815
03:26:21,469 --> 03:26:23,137
SO -- CONTAIN THESE CHEMOKINE

4816
03:26:23,204 --> 03:26:24,572
GENES THAT PREVENT THE

4817
03:26:24,638 --> 03:26:25,873
UNCONVENTIONAL RESPONSES FROM

4818
03:26:25,940 --> 03:26:28,943
HAPPENING.

4819
03:26:29,009 --> 03:26:32,880
SO RHESUS AND HUMAN CMV HAS

4820
03:26:32,947 --> 03:26:35,449
HOMOLOGUES, SO THESE VIRUSES GO

4821
03:26:35,516 --> 03:26:36,917
AT GREAT LENGTHS TO PREVENT

4822
03:26:36,984 --> 03:26:38,152
THOSE RESPONSES FROM HAPPENING.

4823
03:26:38,219 --> 03:26:44,391
WE JUST ST STUMBLED ACROSS THEM.

4824
03:26:44,458 --> 03:26:45,826
THIS IS ALSO VERY

4825
03:26:45,893 --> 03:26:46,694
SPECIES-SPECIFIC.

4826
03:26:46,761 --> 03:26:49,096
WE JUST PUBLISHED A STUDY USING

4827
03:26:49,163 --> 03:26:50,765
PSEUDOMONAS MONKEYS AND WE

4828
03:26:50,831 --> 03:26:54,568
SHOWED SU PSEUDOMONAS MONKEY CMS

4829
03:26:54,635 --> 03:26:57,004
ALSO PROTECTED IN -- MACAQUE BUT

4830
03:26:57,071 --> 03:26:58,205
IT'S HIGHLY SPECIES-SPECIFIC.

4831
03:26:58,272 --> 03:27:00,941
SO IF WE HAVE RHESUS CMV AND

4832
03:27:01,008 --> 03:27:02,276
RHESUS -- WE GET THE

4833
03:27:02,343 --> 03:27:03,177
UNCONVENTIONAL RESPONSES.

4834
03:27:03,244 --> 03:27:07,181
IF WE PUT RHESUS CMV IN

4835
03:27:07,248 --> 03:27:08,716
PSEUDOMONAS MONKEYS, WE DON'T

4836
03:27:08,783 --> 03:27:11,352
GET THOSE UNCONVENTIONAL

4837
03:27:11,418 --> 03:27:12,486
RESPONSES.

4838
03:27:12,553 --> 03:27:14,288
-- DELETE THOSE TWO GENE

4839
03:27:14,355 --> 03:27:17,491
REGIONS, WE GET THE UNCONGRESS

4840
03:27:17,558 --> 03:27:18,692
UNCONVENTIONAL RESPONSES, IF YOU

4841
03:27:18,759 --> 03:27:21,462
PUT IT IN RHESUS, WE DON'T GET

4842
03:27:21,529 --> 03:27:22,997
IT, SO WE'RE CURRENTLY TRYING TO

4843
03:27:23,063 --> 03:27:27,668
FIGURE OUT IF THERE ARE --

4844
03:27:27,735 --> 03:27:28,602
SPECIES SPECIFICITY.

4845
03:27:28,669 --> 03:27:30,471
I'M THINKING ABOUT HUMAN CMV,

4846
03:27:30,538 --> 03:27:32,139
THAT ALSO MEANS WE CAN'T USE

4847
03:27:32,206 --> 03:27:35,176
RHESUS CMV, WE HAVE TO USE HUMAN

4848
03:27:35,242 --> 03:27:36,977
CMV TO GET THOSE UNCONVENTIONAL

4849
03:27:37,044 --> 03:27:37,244
RESPONSES.

4850
03:27:37,311 --> 03:27:39,513
YOU ALREADY KNOW IF WE PUT HUMAN

4851
03:27:39,580 --> 03:27:42,082
CMV IN MONKEYS, THEY ARE

4852
03:27:42,149 --> 03:27:43,384
CONVENTIONAL CD8 T-CELL

4853
03:27:43,450 --> 03:27:46,453
RESPONSES.

4854
03:27:46,520 --> 03:27:48,556
SO -- HAS HOMOLOGUES AND EACH

4855
03:27:48,622 --> 03:27:49,990
ONE OF THEM WHEN WE PUT THAT

4856
03:27:50,057 --> 03:27:55,496
INTO RHESUS CMV, IT ALSO ALSO

4857
03:27:55,563 --> 03:27:56,897
PREVENTS THE INDUCTION OF THESE

4858
03:27:56,964 --> 03:27:57,231
RESPONSES.

4859
03:27:57,298 --> 03:27:59,867
-- NOT TO SAME VIRUS AND CMV

4860
03:27:59,934 --> 03:28:01,936
HAS 250 GENES AS SOME OF THEM

4861
03:28:02,002 --> 03:28:03,537
ARE HOMOLOGOUS, SOME ARE NOT.

4862
03:28:03,604 --> 03:28:04,839
SO WE WERE WORRIED THAT THERE

4863
03:28:04,905 --> 03:28:07,575
ARE ADDITIONAL INHIBITORS IN

4864
03:28:07,641 --> 03:28:09,343
HUMAN CMV THAT ARE NOT CONSERVED

4865
03:28:09,410 --> 03:28:10,611
IN THE RHESUS CMV.

4866
03:28:10,678 --> 03:28:11,979
SO WHAT WE DID THEN IS WE

4867
03:28:12,046 --> 03:28:14,715
BASICALLY CLONED OUT -- WE

4868
03:28:14,782 --> 03:28:18,385
INSERTED ALL THE NON-C NON-CONSD

4869
03:28:18,452 --> 03:28:21,689
INTO RHESUS -- AND THEN TESTED

4870
03:28:21,755 --> 03:28:27,728
WHETHER WE GOT THOSE SUPERTOPE

4871
03:28:27,795 --> 03:28:29,897
RESPONSES.

4872
03:28:29,964 --> 03:28:32,867
INDEED THERE WAS ONE GENE CALLED

4873
03:28:32,933 --> 03:28:36,837
UL18 WHICH INHIBITED BOTH THE

4874
03:28:36,904 --> 03:28:43,611
MHC CLASS 1 -- AND THE -- SUP

4875
03:28:43,677 --> 03:28:45,179
SUPERTOPE RESPONSES.

4876
03:28:45,246 --> 03:28:46,914
IT'S BEEN STUDIED, CRYSTALLIZED

4877
03:28:46,981 --> 03:28:49,016
BECAUSE IT'S AN MHC CLASS

4878
03:28:49,083 --> 03:28:50,751
1 HOMOLOGUE THAT HUMAN CMV HAS

4879
03:28:50,818 --> 03:28:54,722
BUT THE RHESUS CMV DOES NOT HAVE

4880
03:28:54,788 --> 03:28:54,889
IT.

4881
03:28:54,955 --> 03:28:56,924
AND IT ASSOCIATES WITH -- AND IT

4882
03:28:56,991 --> 03:28:59,126
EVEN ASSOCIATES WITH PEPTIDE.

4883
03:28:59,193 --> 03:29:00,995
BUT IT DOESN'T PRESENT PEPTIDE

4884
03:29:01,061 --> 03:29:03,297
TO T CELLS BECAUSE IT'S HIGHLY

4885
03:29:03,364 --> 03:29:04,932
GLYCOSYLATED ON TOP OF THE

4886
03:29:04,999 --> 03:29:06,800
BINDING GROOVE, BUT UL18 IS,

4887
03:29:06,867 --> 03:29:13,574
IT'S A HIGHLY -- INHIBITOR

4888
03:29:13,641 --> 03:29:15,542
RECEPTOR AND IT BINDS TO -- WITH

4889
03:29:15,609 --> 03:29:19,947
A MUCH HIGHER AFFINITY THAN HOST

4890
03:29:20,014 --> 03:29:23,784
MHC MOLECULES SO IT'S REALLY

4891
03:29:23,851 --> 03:29:27,821
SENDING AN INHIBITORY SIGNAL --

4892
03:29:27,888 --> 03:29:30,858
EXPRESSED -- BUT ALSO ON T CEL

4893
03:29:30,925 --> 03:29:33,961
CELLS.

4894
03:29:34,028 --> 03:29:39,133
ZOUH1 EXPRESSES UL18 BECAUSE WE

4895
03:29:39,199 --> 03:29:41,235
GET CONVENTIONAL -- RESTRICTED

4896
03:29:41,302 --> 03:29:42,636
T-CELL RESPONSES AND ALSO SHOW

4897
03:29:42,703 --> 03:29:44,071
THIS DEPENDS ON THIS INTERACTION

4898
03:29:44,138 --> 03:29:46,507
WITH LEA1.

4899
03:29:46,573 --> 03:29:47,574
INTERESTINGLY, IT'S HIGHLY

4900
03:29:47,641 --> 03:29:50,110
EXPRESSED IN CME-SPECIFIC

4901
03:29:50,177 --> 03:29:51,312
T-CELLS THAT'S BEEN SHOWN IN

4902
03:29:51,378 --> 03:29:52,980
HUMANS AS WELL.

4903
03:29:53,047 --> 03:29:55,182
SO THE WAY YOU SHOWED THIS

4904
03:29:55,249 --> 03:29:56,116
BASICALLY POINT MUTATION NO

4905
03:29:56,183 --> 03:29:58,652
LONGER BINDS TO UL1 AND LOSE

4906
03:29:58,719 --> 03:29:59,887
THIS ABILITY TO INHIBIT THESE

4907
03:29:59,954 --> 03:30:03,057
RESPONSES.

4908
03:30:03,123 --> 03:30:04,525
SO THESE STUDIES DEMONSTRATE WE

4909
03:30:04,591 --> 03:30:06,193
HAVE A WHOLE RANGE OF GENES THAT

4910
03:30:06,260 --> 03:30:08,028
PREVENT INDUCTION OF THESE

4911
03:30:08,095 --> 03:30:09,663
UNCONVENTIONAL CD8 T-CELL

4912
03:30:09,730 --> 03:30:11,598
RESPONSES.

4913
03:30:11,665 --> 03:30:13,200
BUT WHY ARE THEY IN THE FIRST

4914
03:30:13,267 --> 03:30:14,735
PLACE, WHAT IS THE MECHANISM

4915
03:30:14,802 --> 03:30:16,270
THAT ENABLES THEM TO INDUCE

4916
03:30:16,337 --> 03:30:17,705
THESE RESPONSES AND NO OTHER

4917
03:30:17,771 --> 03:30:18,772
VECTOR HAS BEEN FOUND TO BE ABLE

4918
03:30:18,839 --> 03:30:20,674
TO DO THAT.

4919
03:30:20,741 --> 03:30:24,945
SO START WITH MHCE.

4920
03:30:25,012 --> 03:30:27,114
MHCE IS A CLASS 1 MOLECULE THAT

4921
03:30:27,181 --> 03:30:30,951
BINDS TO A PEPTIDE THAT IS IN

4922
03:30:31,018 --> 03:30:33,320
THE SINGLE PEPTIDE OF OTHER, OF

4923
03:30:33,387 --> 03:30:34,888
THE POLYMORPHIC CLASS

4924
03:30:34,955 --> 03:30:35,923
1 MOLECULES, AND OF COURSE THE

4925
03:30:35,990 --> 03:30:40,861
SINGLE PEPTIDE IS CLIPPED OFF IN

4926
03:30:40,928 --> 03:30:44,999
TRANSLOCATION AND LOADED ON TO

4927
03:30:45,065 --> 03:30:47,968
MHCE OR U -- TRANSPORTED TO THE

4928
03:30:48,035 --> 03:30:49,436
CELL SURFACE AND THIS PEPTIDE

4929
03:30:49,503 --> 03:30:51,138
THAT IS PRESENT IN ALL THE OTHER

4930
03:30:51,205 --> 03:30:53,240
CLASS 1 MOLECULES TOGETHER WITH

4931
03:30:53,307 --> 03:30:57,845
HLE BASICALLY INHIBITORY SIGNAL

4932
03:30:57,911 --> 03:31:00,814
FOR INHIBITORY AND K CELL

4933
03:31:00,881 --> 03:31:03,884
RECEPTOR CAN ALSO ACTIVATE IN

4934
03:31:03,951 --> 03:31:05,285
HUMANS WHO ARE -- POSITIVE OR

4935
03:31:05,352 --> 03:31:06,720
WELL-KNOWN TO HAVE AN EXPANSION

4936
03:31:06,787 --> 03:31:09,590
OF NK CELLS ACTIVATING -- AND

4937
03:31:09,656 --> 03:31:10,657
THIS IS PROBABLY ONE OF THE

4938
03:31:10,724 --> 03:31:14,495
REASONS WHY.

4939
03:31:14,561 --> 03:31:15,629
SO INTERESTINGLY, I TOLD YOU

4940
03:31:15,696 --> 03:31:18,499
THAT CMV IS VERY GOOD AT

4941
03:31:18,565 --> 03:31:20,334
ELIMINATING CLASS 1 MOLECULES SO

4942
03:31:20,401 --> 03:31:22,236
IT ELIMINATES THE NATURAL LIGAND

4943
03:31:22,302 --> 03:31:27,107
OF HLAE, AND THAT WOULD CREATE A

4944
03:31:27,174 --> 03:31:28,475
PROBLEM BECAUSE NO LONGER YOU

4945
03:31:28,542 --> 03:31:31,011
ARE INHIBITING THE NK CELLS.

4946
03:31:31,078 --> 03:31:34,548
BUT THOSE -- AND RHESUS CMV

4947
03:31:34,615 --> 03:31:42,122
ENCODE A GENE THAT HAS A DEPLOY

4948
03:31:42,189 --> 03:31:47,094
LOADED ON TO HLE BECAUSE IT ALSO

4949
03:31:47,161 --> 03:31:49,797
BLOCKS TAP AND THAT SERVES AS AN

4950
03:31:49,863 --> 03:31:53,267
INHIBITORY SIGNAL TO NK CELLS.

4951
03:31:53,333 --> 03:31:54,768
SO THE QUESTION WAS IS THIS IN

4952
03:31:54,835 --> 03:31:56,003
ANY WAY INVOLVED IN THE

4953
03:31:56,070 --> 03:31:58,539
INDUCTION OF THESE -- RESTRICTED

4954
03:31:58,605 --> 03:32:00,741
T CELLS AND THE ANSWER WAS YES.

4955
03:32:00,808 --> 03:32:02,543
POINT MUTATION -- SEQUENCE OF

4956
03:32:02,609 --> 03:32:06,013
THE VIRUS, WHEN WE GO INTO

4957
03:32:06,080 --> 03:32:08,215
MONKEYS NOW WITH THIS MODIFIED

4958
03:32:08,282 --> 03:32:11,185
VECTORS, WE LOSE ALL THE MHCE

4959
03:32:11,251 --> 03:32:13,253
RESPONSES AND NOW THE T-CELL

4960
03:32:13,320 --> 03:32:15,355
RESPONSES, THE CD8 T-CELL ROW

4961
03:32:15,422 --> 03:32:17,758
SPONSES ARE ALL RESTRICTED BY

4962
03:32:17,825 --> 03:32:18,959
MHT CLASS 2.

4963
03:32:19,026 --> 03:32:21,595
SO NOW WE HAVE A VECTOR THAT

4964
03:32:21,662 --> 03:32:23,831
MAKES EXCLUSIVELY MHC TO

4965
03:32:23,897 --> 03:32:25,232
RESTRICTED T CELLS, BOTH THE

4966
03:32:25,299 --> 03:32:26,867
CD4s AND THE CD8s.

4967
03:32:26,934 --> 03:32:28,769
THE CD4s ARE NOT AFFECTED AT

4968
03:32:28,836 --> 03:32:31,071
ALL BY ALL OF THE -- BY ALL OF

4969
03:32:31,138 --> 03:32:33,807
THIS T-CELL PROGRAMMING.

4970
03:32:33,874 --> 03:32:36,043
AND -- CAN REPLACE THE RHESUS --

4971
03:32:36,110 --> 03:32:40,848
BECAUSE IT HAS AN INTACT -- --

4972
03:32:40,914 --> 03:32:41,815
RESTRICTED T-CELL RESPONSES

4973
03:32:41,882 --> 03:32:45,018
BACK.

4974
03:32:45,085 --> 03:32:46,353
SO THAT WAS SOMEWHAT SURPRISING

4975
03:32:46,420 --> 03:32:47,821
BECAUSE THE WAY WE SHOW THAT OUR

4976
03:32:47,888 --> 03:32:50,390
IMMUNE RESPONSES ARE H LAE

4977
03:32:50,457 --> 03:32:53,594
RESTRICTED IS TO ADD THE

4978
03:32:53,660 --> 03:32:54,027
PEPTIDE -- CLASS.

4979
03:32:54,094 --> 03:32:56,130
SO WHY WOULD YOU NEED THE --

4980
03:32:56,196 --> 03:32:58,499
LINE PEPTIDE TO GET THE

4981
03:32:58,565 --> 03:32:59,933
RESPONSES TO NON- -- ALIGNED

4982
03:33:00,000 --> 03:33:00,300
SEQUENCES.

4983
03:33:00,367 --> 03:33:01,802
SO WHAT WE THINK IS HAPPENING IS

4984
03:33:01,869 --> 03:33:06,340
THAT THE VIRUS LOADS THIS VL9 ON

4985
03:33:06,406 --> 03:33:08,775
TO HLAE AND THAT DRIVES TO THE

4986
03:33:08,842 --> 03:33:09,943
CELL SURFACE BUT EVENTUALLY THIS

4987
03:33:10,010 --> 03:33:11,545
HAS TO BE EXCHANGED WITH OTHER

4988
03:33:11,612 --> 03:33:12,913
PEPTIDES WHICH ARE THEN

4989
03:33:12,980 --> 03:33:13,914
RECOGNIZED BY THE T CELLS.

4990
03:33:13,981 --> 03:33:15,916
BUT AT THIS POINT, SPECULATION,

4991
03:33:15,983 --> 03:33:17,551
WE'RE WORKING ON IT BUT WE DON'T

4992
03:33:17,618 --> 03:33:19,319
HAVE ACTUALLY SHOWN THIS.

4993
03:33:19,386 --> 03:33:24,458
THE KIND OF PEPTIDE EXCHANGE.

4994
03:33:24,525 --> 03:33:26,326
SO THEN WE ALSO LOOKED AT DOING

4995
03:33:26,393 --> 03:33:28,629
A BROAD SCREEN OF ANY OTHER

4996
03:33:28,695 --> 03:33:30,063
VIRAL GENE PRODUCTS THAT WE NEED

4997
03:33:30,130 --> 03:33:33,033
TO GET THOSE UNCONVENTIONAL

4998
03:33:33,100 --> 03:33:34,134
T-CELL RESPONSES.

4999
03:33:34,201 --> 03:33:35,802
SO WE DELETED LARGE CHUNKS OF

5000
03:33:35,869 --> 03:33:37,004
THE GENOME THAT ARE

5001
03:33:37,070 --> 03:33:38,005
NON-ESSENTIAL FOR GROWTH IN

5002
03:33:38,071 --> 03:33:41,508
VITRO, AND WE DID FIND ONE GENE

5003
03:33:41,575 --> 03:33:43,043
REGION WHICH IS A HOMOLOGUE OF

5004
03:33:43,110 --> 03:33:47,781
THE VIRAL T -- RESP RECEPTOR CAD

5005
03:33:47,848 --> 03:33:48,949
US28.

5006
03:33:49,016 --> 03:33:50,284
SO RHESUS -- IS FIVE HOMOLOGUES

5007
03:33:50,350 --> 03:33:51,952
AND TWO OF THOSE ARE REQUIRED TO

5008
03:33:52,019 --> 03:33:54,621
GET THE IMAGE -- RESTRICTED T

5009
03:33:54,688 --> 03:33:56,390
CELLS, SO THE PHENOTYPE OF THOSE

5010
03:33:56,456 --> 03:33:57,791
VIRUSES LOOKS EXACTLY LIKE THE

5011
03:33:57,858 --> 03:34:01,628
ONE I JUST SHOWED YOU, WITH ONLY

5012
03:34:01,695 --> 03:34:02,296
TWO RESPONSES.

5013
03:34:02,362 --> 03:34:04,731
WHAT WE HAVEN'T FOUND YET IS ANY

5014
03:34:04,798 --> 03:34:07,467
GENE PRODUCT THAT IS REQUIRED TO

5015
03:34:07,534 --> 03:34:10,571
GET THE MHC2 RESTRICTED

5016
03:34:10,637 --> 03:34:11,772
CD8 T-CELL RESPONSES SO WE DON'T

5017
03:34:11,838 --> 03:34:14,508
KNOW HOW AND WHY THOSE ARE BEING

5018
03:34:14,575 --> 03:34:18,345
INDUCED BY RHESUS CME.

5019
03:34:18,412 --> 03:34:20,314
BUT WHAT IT DOES INDICATE IS THE

5020
03:34:20,380 --> 03:34:21,748
FACT THAT YOU NEED THE

5021
03:34:21,815 --> 03:34:23,083
EXPRESSION OF VIRAL GENES TO GET

5022
03:34:23,150 --> 03:34:26,720
THOSE RESPONSES, THESE RESPONSES

5023
03:34:26,787 --> 03:34:28,288
HAVE TO BE PRIMED BY INFECTED

5024
03:34:28,355 --> 03:34:30,557
CELLS.

5025
03:34:30,624 --> 03:34:31,725
SO THEN THE NEXT QUESTION WAS

5026
03:34:31,792 --> 03:34:33,527
WHAT TYPES OF CELLS NEED TO BE

5027
03:34:33,594 --> 03:34:36,597
INFECTED TO GET THOSE TYPES OF

5028
03:34:36,663 --> 03:34:40,701
UNCOUNCONVENTIONAL T-CELL RESPO.

5029
03:34:40,767 --> 03:34:42,536
THE MHC1 RESPONSES THAT YOU

5030
03:34:42,603 --> 03:34:46,073
USUALLY GET AT ALL WAS CMV

5031
03:34:46,139 --> 03:34:47,374
POSITIVE MAKE, THEY'RE USUALLY

5032
03:34:47,441 --> 03:34:49,243
PRIMED NOT BY DIRECT

5033
03:34:49,309 --> 03:34:50,477
PRESENTATION BUT INDIRECT BY

5034
03:34:50,544 --> 03:34:54,114
CROSS PRESENTATION.

5035
03:34:54,181 --> 03:34:56,950
SO TO TEST THAT QUESTION, THEY

5036
03:34:57,017 --> 03:34:58,485
CAME UP WITH THIS CLEVER

5037
03:34:58,552 --> 03:35:00,587
STRATEGY THAT INTRODUCED

5038
03:35:00,654 --> 03:35:03,557
TARGETING SITE OF TISSUE OR

5039
03:35:03,624 --> 03:35:05,092
CELL-SPECIFIC MICRORNAs INTO

5040
03:35:05,158 --> 03:35:08,262
ESSENTIAL GENES OF EITHER -- OF

5041
03:35:08,328 --> 03:35:09,329
TRANSCRIPTION FACTORS, WE NEED

5042
03:35:09,396 --> 03:35:11,531
TWO OF THEM -- AND THE OTHER FOR

5043
03:35:11,598 --> 03:35:13,767
THE LATE GENE TRANSCRIPTION, AND

5044
03:35:13,834 --> 03:35:16,169
THEN IN CELLS THAT EXPRESS THOSE

5045
03:35:16,236 --> 03:35:17,738
MICRORNAs, THIS VIRUS CANNOT

5046
03:35:17,804 --> 03:35:18,171
REPLICATE.

5047
03:35:18,238 --> 03:35:21,875
BUT IN OTHER CELLS DON'T EXPRESS

5048
03:35:21,942 --> 03:35:23,677
THESE MICRORNAs, WHICH TARGET

5049
03:35:23,744 --> 03:35:26,613
THOSE ESSENTIAL GENES, THERE IS

5050
03:35:26,680 --> 03:35:32,119
REPLICATION, THIS IS SHOWING FOR

5051
03:35:32,185 --> 03:35:34,454
ENDOTHELIAL CELLS, NO GROWTH IN

5052
03:35:34,521 --> 03:35:35,756
ENDOTHELIAL CELLS BUT NORMAL

5053
03:35:35,822 --> 03:35:42,129
GROWTH IN MY B FIBROBLASTS.

5054
03:35:42,195 --> 03:35:43,330
IT TURNS OUT THIS WAS ACTUALLY

5055
03:35:43,397 --> 03:35:48,902
QUITE STRIKING IN THAT IF WE

5056
03:35:48,969 --> 03:35:51,371
TARGET -- IF WE INSERT

5057
03:35:51,438 --> 03:35:52,339
MICRORNAs THAT ARE

5058
03:35:52,406 --> 03:35:53,974
SPECIFICALLY EXPRESSED IN

5059
03:35:54,041 --> 03:35:57,744
MYELOID CELLS -- 142, WE LOSE

5060
03:35:57,811 --> 03:35:59,379
ALL THE T-CELL RESPONSES TO ALL

5061
03:35:59,446 --> 03:36:05,952
THE RESPONSES TO -- RESTRICTED,

5062
03:36:06,019 --> 03:36:07,721
WHICH MEANS TO GET THE IMAGE

5063
03:36:07,788 --> 03:36:09,389
TO -- RESPONSES WE NEED

5064
03:36:09,456 --> 03:36:11,091
INFECTION OF -- AND THIS, BY THE

5065
03:36:11,158 --> 03:36:13,226
WAY, MIGHT BE THE REASON WHY WE

5066
03:36:13,293 --> 03:36:14,995
NEED THESE GCPRs BECAUSE THEY

5067
03:36:15,062 --> 03:36:16,863
ARE IMPORTANT FOR LATENCY AND

5068
03:36:16,930 --> 03:36:20,634
REACTIVATION IN MYELOID CELLS.

5069
03:36:20,701 --> 03:36:21,968
WHAT WAS FASCINATING WAS THE

5070
03:36:22,035 --> 03:36:22,636
FLIP SIDE.

5071
03:36:22,703 --> 03:36:27,474
WHEN WE INTRODUCED ENDOTHELIAL

5072
03:36:27,541 --> 03:36:29,876
CELL MICRORNA TARGETING SITES WE

5073
03:36:29,943 --> 03:36:33,747
LOST ALL THE MHC2 RESPONSES AND

5074
03:36:33,814 --> 03:36:37,617
WE HAVE -- SO MHC2 RESPONSES

5075
03:36:37,684 --> 03:36:39,453
MUST BE PRIMED BY ENDOTHELIAL

5076
03:36:39,519 --> 03:36:42,089
CELLS INFECTED BY CMV,

5077
03:36:42,155 --> 03:36:43,323
ENDOTHELIAL CELLS ARE USUALLY

5078
03:36:43,390 --> 03:36:46,793
NOT EXPECTED TO INDUCE

5079
03:36:46,860 --> 03:36:47,694
MHC2 RESTRICTED RESPONSE BUT

5080
03:36:47,761 --> 03:36:50,030
KNOWN TO REGULATE UPON INFECTION

5081
03:36:50,097 --> 03:36:50,997
QUITE WELL ACTUALLY.

5082
03:36:51,064 --> 03:36:53,333
AND AS WE ALL RECEIVED -- SO IN

5083
03:36:53,400 --> 03:36:55,502
THIS CASE WHEN WE BLOCK

5084
03:36:55,569 --> 03:36:57,504
REPLICATION IN BOTH THE MYELOID

5085
03:36:57,571 --> 03:37:00,140
LINEAGE AND ENDOTHELIAL LINEAGE,

5086
03:37:00,207 --> 03:37:02,976
NOW WE'RE REVERTING BACK TO

5087
03:37:03,043 --> 03:37:04,878
MHC1A RESTRICT RESPONSES, WE

5088
03:37:04,945 --> 03:37:06,646
NEVER HAVE A VECTOR THAT DOESN'T

5089
03:37:06,713 --> 03:37:09,182
INDUCE CD8 T CELLS, SO THIS IS

5090
03:37:09,249 --> 03:37:10,584
ALWAYS ONE OF THE DEFAULT

5091
03:37:10,650 --> 03:37:11,918
PATHWAY AND THAT HAPPENS BY

5092
03:37:11,985 --> 03:37:13,019
CROSS PRESENTATION.

5093
03:37:13,086 --> 03:37:15,322
WHAT WE DON'T UNDERSTAND IS WHY

5094
03:37:15,389 --> 03:37:16,857
DID WE LOSE THESE RESPONSES WHEN

5095
03:37:16,923 --> 03:37:18,191
WE GET THE OTHER ONES?

5096
03:37:18,258 --> 03:37:23,029
WHY ARE THEY NOT ALWAYS THERE?

5097
03:37:23,096 --> 03:37:26,233
SO THERE MUST BE A MECHANISM FOR

5098
03:37:26,299 --> 03:37:27,868
DIRECT PRIMING.

5099
03:37:27,934 --> 03:37:29,736
IN A WAY WE CAN NOW -- WE HAVE

5100
03:37:29,803 --> 03:37:31,271
THIS WHOLE ZOO OF VECTORS, WE

5101
03:37:31,338 --> 03:37:32,606
CAN PRIME ALL OF THESE DIFFERENT

5102
03:37:32,672 --> 03:37:37,544
KINDS OF CD8 T CELLS, US11, IF

5103
03:37:37,611 --> 03:37:39,212
WE DELETE THAT GENE, YOU CAN

5104
03:37:39,279 --> 03:37:42,849
ALWAYS ADD MHC1A RESPONSES TO

5105
03:37:42,916 --> 03:37:44,384
IMMUNODOMINANT PEPTIDES TO ANY

5106
03:37:44,451 --> 03:37:47,454
OTHER VECTOR BACKBONE.

5107
03:37:47,521 --> 03:37:51,191
AND THIS ALLOWS US NOW TO

5108
03:37:51,258 --> 03:37:54,161
TEST -- THIS IS SO COOL IN

5109
03:37:54,227 --> 03:37:56,329
IMMUNOLOGY, ANY OF THOSE

5110
03:37:56,396 --> 03:37:57,130
PATHOGEN CHALLENGE EXPERIMENTS.

5111
03:37:57,197 --> 03:37:58,765
TO MAKE A VERY LONG STORY SHORT

5112
03:37:58,832 --> 03:38:04,571
IS FOR SIV, WE FIND THAT WE

5113
03:38:04,638 --> 03:38:06,373
COMPLETELY LOSE PROTECTION

5114
03:38:06,440 --> 03:38:09,109
AGAINST -- 9 IF WE DON'T HAVE

5115
03:38:09,176 --> 03:38:09,776
MHC-RESTRICTED T CELLS.

5116
03:38:09,843 --> 03:38:15,382
EITHER WE HAVE MHC-ONLY

5117
03:38:15,449 --> 03:38:16,716
VECTORS -- AND IN EACH CASE WE

5118
03:38:16,783 --> 03:38:20,086
HAVE PROTECTION IN ANY OF THE

5119
03:38:20,153 --> 03:38:21,988
CASES WHERE WE DON'T HAVE THE

5120
03:38:22,055 --> 03:38:23,190
MHC RESPONSES, WE DON'T HAVE

5121
03:38:23,256 --> 03:38:24,324
PROTECTION.

5122
03:38:24,391 --> 03:38:26,793
AND THE PROTECTION IS ALWAYS

5123
03:38:26,860 --> 03:38:31,331
THIS SORT OF BINARY PROTECTION,

5124
03:38:31,398 --> 03:38:32,632
HALF OF THE ANIMALS ARE

5125
03:38:32,699 --> 03:38:33,834
PROTECTED, THE OTHER HALF --

5126
03:38:33,900 --> 03:38:34,935
FROM EXPERIMENT TO EXPERIMENT

5127
03:38:35,001 --> 03:38:36,603
BUT NONE OF THESE VECTORS WE HAD

5128
03:38:36,670 --> 03:38:38,572
HIGH HOPES FOR THEIR MHC ONLY

5129
03:38:38,638 --> 03:38:40,207
THAT WILL PROTECT BETTER BUT IT

5130
03:38:40,273 --> 03:38:41,208
DOESN'T.

5131
03:38:41,274 --> 03:38:45,011
SO THAT IS A DIFFERENT REASON.

5132
03:38:45,078 --> 03:38:47,681
SO WHAT IT MEANS IS THAT THE

5133
03:38:47,747 --> 03:38:49,683
MHCE RESPONSES ARE QUIET BUT NOT

5134
03:38:49,749 --> 03:38:50,584
SUFFICIENT FOR PROTECTION IN

5135
03:38:50,650 --> 03:38:53,854
THESE CELLS.

5136
03:38:53,920 --> 03:38:55,622
BUT THEY HELP TO CONTROL SIV

5137
03:38:55,689 --> 03:38:58,558
INFECTION.

5138
03:38:58,625 --> 03:39:00,093
SO THE LAST COUPLE OF MINUTES,

5139
03:39:00,160 --> 03:39:01,695
SINCE THIS IS NCI, I THOUGHT I'D

5140
03:39:01,761 --> 03:39:03,530
TALK A LITTLE BIT ABOUT CANCER.

5141
03:39:03,597 --> 03:39:06,633
SO MHCE OR HLAE IN HUMANS IS

5142
03:39:06,700 --> 03:39:07,634
ACTUALLY A REALLY INTERESTING

5143
03:39:07,701 --> 03:39:09,503
TARGET FOR CANCER.

5144
03:39:09,569 --> 03:39:14,040
AND IT IS ALREADY USED AS A

5145
03:39:14,107 --> 03:39:17,444
CHECKPOINT BECAUSE MANY --

5146
03:39:17,511 --> 03:39:19,279
NORMAL CELLS DON'T EXPRESS A LOT

5147
03:39:19,346 --> 03:39:22,616
OF MHCE BUT IN CANCER CELLS YOU

5148
03:39:22,682 --> 03:39:24,551
OFTEN SEE IT BEING UPREGULATED.

5149
03:39:24,618 --> 03:39:26,419
IT TURNS OUT -- T CELLS OFTEN

5150
03:39:26,486 --> 03:39:32,025
EXPRESS A LOT OF -- CURRENTLY IN

5151
03:39:32,092 --> 03:39:33,260
CLINICAL TRIALS TO TRY TO BLOCK

5152
03:39:33,326 --> 03:39:34,995
THIS PATHWAY, THESE ARE

5153
03:39:35,061 --> 03:39:37,664
ANTIBODIES THAT TARGET -- AND

5154
03:39:37,731 --> 03:39:42,035
THAT'S BEEN NICE -- DATA SHOWING

5155
03:39:42,102 --> 03:39:43,570
ENHANCED EFFICACY OF VACCINES.

5156
03:39:43,637 --> 03:39:45,038
THEY PROBABLY DON'T WORK BY

5157
03:39:45,105 --> 03:39:46,473
THEMSELVES LIKE OTHER CHECKPOINT

5158
03:39:46,540 --> 03:39:48,975
INHIBITORS BUT THEY MAKE T CELLS

5159
03:39:49,042 --> 03:39:51,678
MORE EFFECTIVE -- T CELLS.

5160
03:39:51,745 --> 03:39:55,515
SO WE ASKED THE QUESTION, CAN WE

5161
03:39:55,582 --> 03:39:59,019
ELICIT -- AND THEN -- RESTRICTED

5162
03:39:59,085 --> 03:40:00,353
T CELLS TO RECOGNIZE TUMOR

5163
03:40:00,420 --> 03:40:00,687
CELLS.

5164
03:40:00,754 --> 03:40:02,556
AND THE ANSWER IS YES, WE GET

5165
03:40:02,622 --> 03:40:06,626
THE SAME TYPE OF UNCONVENTIONAL

5166
03:40:06,693 --> 03:40:08,495
T-CELL RESPONSE IF WE USE --

5167
03:40:08,562 --> 03:40:11,197
VECTORS TO VERY WELL DESCRIBE

5168
03:40:11,264 --> 03:40:14,568
TUMOR ANTIGENS LIKE -- OR -- AND

5169
03:40:14,634 --> 03:40:17,604
THEY HAVE THE SAME PHENOTYPE,

5170
03:40:17,671 --> 03:40:19,906
SAME FREQUENCY, LONGEVITY, ET

5171
03:40:19,973 --> 03:40:20,574
CETERA.

5172
03:40:20,640 --> 03:40:23,009
THE ONE DIFFERENCE WAS THESE

5173
03:40:23,076 --> 03:40:24,444
CANONICAL T CELLS THAT WE CANNOT

5174
03:40:24,511 --> 03:40:25,712
INDUCE THEM AGAINST CANCER

5175
03:40:25,779 --> 03:40:26,613
ANTIGENS BECAUSE THEY ARE

5176
03:40:26,680 --> 03:40:30,483
SUBJECT TO CENTRAL TOLERANCE.

5177
03:40:30,550 --> 03:40:35,088
SO WE GET A VERY NICE IMMUNE

5178
03:40:35,155 --> 03:40:38,758
RESPONSE, AND THEY DO RECOGNIZE

5179
03:40:38,825 --> 03:40:40,360
CANCER CELLS, SO THIS IS JUST

5180
03:40:40,427 --> 03:40:42,796
ONE PIECE OF DATA, THIS IS A

5181
03:40:42,862 --> 03:40:44,531
COLLABORATION WITH MOUNT SINAI

5182
03:40:44,598 --> 03:40:48,568
WHERE WE BASICALLY TOOK PROSTATE

5183
03:40:48,635 --> 03:40:54,240
CANCER CELLS, PUT THEM IN TISSUE

5184
03:40:54,307 --> 03:40:56,876
CULTURE, EXPOSED THEM TO MONKEYS

5185
03:40:56,943 --> 03:40:58,044
IMMUNIZED AGAINST PROSTATE

5186
03:40:58,111 --> 03:40:59,546
CANCER ANTIGEN AND SHOW THOSE T

5187
03:40:59,613 --> 03:41:01,848
CELLS GET STIMULATED BY THESE

5188
03:41:01,915 --> 03:41:04,517
PROSTATE CANCER CELLS AND THIS

5189
03:41:04,584 --> 03:41:06,152
IS MHCE RESTRICTED BECAUSE WE

5190
03:41:06,219 --> 03:41:09,222
CAN BLOCK IT WITH THE

5191
03:41:09,289 --> 03:41:13,259
VL9 PEPTIDE.

5192
03:41:13,326 --> 03:41:14,728
CONCLUSIONS AND QUESTIONS.

5193
03:41:14,794 --> 03:41:17,130
CME VECTORS IS REALLY THE FIRST

5194
03:41:17,197 --> 03:41:19,466
VACCINE MODALITY THAT CAN ELICIT

5195
03:41:19,532 --> 03:41:20,700
THESE UNCONVENTIONAL T-CELL

5196
03:41:20,767 --> 03:41:22,435
RESPONSES AND THEY'RE VERY

5197
03:41:22,502 --> 03:41:23,770
DISTINCT DEPENDING ON THE VECTOR

5198
03:41:23,837 --> 03:41:24,104
PHENOTYPE.

5199
03:41:24,170 --> 03:41:26,239
WE IDENTIFIED SOME OF THE VIRAL

5200
03:41:26,306 --> 03:41:27,641
GENOME PRODUCTS THAT ARE

5201
03:41:27,707 --> 03:41:29,075
RESPONSIBLE FOR THIS, BOTH

5202
03:41:29,142 --> 03:41:33,513
POSITIVE AND NEGATIVE REGULA

5203
03:41:33,580 --> 03:41:35,015
REGULATORS, AND MOST OF THEM ARE

5204
03:41:35,081 --> 03:41:36,549
CONSERVED BETWEEN HUMAN AND

5205
03:41:36,616 --> 03:41:39,919
RHESUS CMV BUT WE STILL DON'T

5206
03:41:39,986 --> 03:41:41,955
FULLY UNDERSTAND WHY CMV ARE

5207
03:41:42,022 --> 03:41:43,056
USING THOSE RESPONSES.

5208
03:41:43,123 --> 03:41:48,461
IT'S ALSO NOT CLEAR WHY SIV IS

5209
03:41:48,528 --> 03:41:49,562
SO SUSCEPTIBLE TO THESE

5210
03:41:49,629 --> 03:41:50,664
RESPONSES.

5211
03:41:50,730 --> 03:41:51,665
WE DINES NORMAL T-CELL

5212
03:41:51,731 --> 03:41:52,999
RESPONSES, WE HAVE NO

5213
03:41:53,066 --> 03:41:53,566
PROTECTION.

5214
03:41:53,633 --> 03:41:56,836
SO MAYBE IT'S SIV HASN'T LEARNED

5215
03:41:56,903 --> 03:41:58,705
RESPONSES AS WELL AS OTHER

5216
03:41:58,772 --> 03:42:00,473
RESPONSES BUT WE SIMPLY DON'T

5217
03:42:00,540 --> 03:42:04,678
KNOW SO WE'RE WORKING ON IT.

5218
03:42:04,744 --> 03:42:08,048
SO THIS STRICT DEPENDENCE ON

5219
03:42:08,114 --> 03:42:09,416
MHC-RESTRICTED T CELLS WEEFN

5220
03:42:09,482 --> 03:42:11,651
ONLY SEEN SO FAR FOR SIV.

5221
03:42:11,718 --> 03:42:14,688
SO IN TB, FOR INSTANCE, IT WORKS

5222
03:42:14,754 --> 03:42:17,490
BOTH WITH -- AND RESTRICTED T

5223
03:42:17,557 --> 03:42:19,693
CELLS, SAME FOR FLU.

5224
03:42:19,759 --> 03:42:22,295
SO WHAT WILL THESE STUDIES SHOW,

5225
03:42:22,362 --> 03:42:24,597
IT SEEMS MHCE, IN ADDITION TO

5226
03:42:24,664 --> 03:42:27,167
PRESENTING THIS PL9 PEPTIDE,

5227
03:42:27,233 --> 03:42:28,134
THERE'S ALWAYS BACKGROUND OF

5228
03:42:28,201 --> 03:42:30,437
OTHER PEPTIDES BEING PRESENTED

5229
03:42:30,503 --> 03:42:31,905
BY IMAGE -- THIS IS PROBABLY NOT

5230
03:42:31,971 --> 03:42:34,541
A DEDICATED MECHANISM, IT'S JUST

5231
03:42:34,607 --> 03:42:36,943
THE VL9 PEPTIDE GETS LOST AT

5232
03:42:37,010 --> 03:42:38,178
SOME POINT AND UNLIKE OTHER

5233
03:42:38,244 --> 03:42:40,613
CLASS 1 MOLECULES, MHCE IS QUITE

5234
03:42:40,680 --> 03:42:41,915
STABLE WITHOUT PEPTIDE AND

5235
03:42:41,981 --> 03:42:43,583
PROBABLY THAT'S WHY IT CAN PICK

5236
03:42:43,650 --> 03:42:46,352
UP SOME OTHER PEPTIDES EVEN LOW

5237
03:42:46,419 --> 03:42:48,588
AFFINITY ONES AND THEY CAN BE

5238
03:42:48,655 --> 03:42:50,090
TARGETED BY T CELLS BUT THEY'RE

5239
03:42:50,156 --> 03:42:51,324
NOT GOOD ENOUGH IN TERMS OF

5240
03:42:51,391 --> 03:42:54,194
BINDING AND HIGH AFFINITY AND

5241
03:42:54,260 --> 03:42:55,361
SURFACE FREQUENCY TO INDUCE

5242
03:42:55,428 --> 03:42:55,862
THOSE T CELLS.

5243
03:42:55,929 --> 03:42:58,598
SO THERE ARE SOME PARTICULAR

5244
03:42:58,665 --> 03:43:00,133
BACTERIAL PATHOGENS -- BUT

5245
03:43:00,200 --> 03:43:04,037
GENERALLY THEY'RE NOT INDUCED.

5246
03:43:04,104 --> 03:43:05,472
SO WHAT IT ALSO SUGGESTS IS TO

5247
03:43:05,538 --> 03:43:09,743
USE AN HCMV-BASED HIV VACCINE,

5248
03:43:09,809 --> 03:43:13,646
THE GOAL HAS TO BE TO ELICIT

5249
03:43:13,713 --> 03:43:15,982
HLE-RESTRICTED T-CELL RESPONSES

5250
03:43:16,049 --> 03:43:17,650
AND WE JUST STARTED THE CLINICAL

5251
03:43:17,717 --> 03:43:22,455
TRIAL WITH A VECTOR THAT LACKS

5252
03:43:22,522 --> 03:43:23,990
ALL THE GENES WE'VE IDENTIFIED

5253
03:43:24,057 --> 03:43:29,863
AS INHIBITORS INCLUDING UL18

5254
03:43:29,929 --> 03:43:31,698
AND -- LIF FUSION PROTEIN THAT'S

5255
03:43:31,765 --> 03:43:34,667
OPTIMIZED FOR T-CELL EPITOPE

5256
03:43:34,734 --> 03:43:35,001
COVERAGE.

5257
03:43:35,068 --> 03:43:38,104
THIS IS DONE BY THE COMPANY WE

5258
03:43:38,171 --> 03:43:40,173
STARTED A COUPLE YEARS AGO

5259
03:43:40,240 --> 03:43:43,042
FOR -- TECHNOLOGY, AND FOUNDED

5260
03:43:43,109 --> 03:43:45,278
BY THE -- FUNDED BY THE BILL AND

5261
03:43:45,345 --> 03:43:49,115
MELINDA GATES FOUNDATION AS

5262
03:43:49,182 --> 03:43:52,418
WELL -- WITH -- CLINICAL TRIALS.

5263
03:43:52,485 --> 03:43:54,087
SO THIS IS, OF COURSE, WORK OF

5264
03:43:54,154 --> 03:43:57,490
MANY PEOPLE OVER MANY YEARS, I

5265
03:43:57,557 --> 03:43:59,359
JUST WANT TO POINT OUT -- WHO'S

5266
03:43:59,425 --> 03:44:02,028
BEEN MAKING ALL THESE HUNDREDS,

5267
03:44:02,095 --> 03:44:03,229
THOUSANDS, ACTUALLY, OF

5268
03:44:03,296 --> 03:44:04,864
DIFFERENT VECTOR CONSTRUCTS,

5269
03:44:04,931 --> 03:44:08,635
SCOTT HANSEN IS RUNNING ALL THE

5270
03:44:08,701 --> 03:44:10,403
I MU NOLG EXPERIMENTS IN MONKEYS

5271
03:44:10,470 --> 03:44:11,704
AND MANY COLLABORATORS WHO HELP

5272
03:44:11,771 --> 03:44:14,707
US WITH THIS AND LOTS OF OUTSIDE

5273
03:44:14,774 --> 03:44:16,676
COLLABORATORS AS I MENTIONED,

5274
03:44:16,743 --> 03:44:21,247
STARTING WITH MOUNT SINAI, LEW'S

5275
03:44:21,314 --> 03:44:22,816
WORK WAS DONE WITH A GROUP AT

5276
03:44:22,882 --> 03:44:24,184
PITTSBURGH, AND THEN ALSO

5277
03:44:24,250 --> 03:44:25,919
WORKING, OF COURSE, HERE WITH

5278
03:44:25,985 --> 03:44:29,789
JEFF LITZEN, A LONG-TIME

5279
03:44:29,856 --> 03:44:32,759
COLLABORATOR, WE HAVE A GRANT TO

5280
03:44:32,826 --> 03:44:36,062
ACTUALLY GET TO THE QUESTION WHY

5281
03:44:36,129 --> 03:44:39,365
HLE RESPONSES ARE SO GOOD AT

5282
03:44:39,432 --> 03:44:40,400
CONTROLLING AND -- SO THANK YOU

5283
03:44:40,466 --> 03:44:40,667
VERY MUCH.

5284
03:44:40,733 --> 03:44:46,339
[APPLAUSE]

5285
03:44:46,406 --> 03:44:50,577
>> THANKS VERY MUCH, CLAUSE.

5286
03:44:50,643 --> 03:44:54,480
>> SO YOU RAISED THE ISSUE, I

5287
03:44:54,547 --> 03:44:55,315
REMEMBER FROM THE FIRST

5288
03:44:55,381 --> 03:44:56,349
PRESENTATION OF THIS, I DON'T

5289
03:44:56,416 --> 03:44:58,251
KNOW WHEN IT WAS 15 YEARS AGO OR

5290
03:44:58,318 --> 03:45:01,421
SOMETHING, AND THAT IS WHY --

5291
03:45:01,487 --> 03:45:03,723
THE ANIMALS.

5292
03:45:03,790 --> 03:45:05,158
ONE MIGHT IMAGINE THERE'S SOME

5293
03:45:05,225 --> 03:45:06,392
GENETIC DIFFERENCE, FOR EXAMPLE,

5294
03:45:06,459 --> 03:45:08,928
TO TRACK DOWN THE GENES.

5295
03:45:08,995 --> 03:45:09,195
THOUGHTS?

5296
03:45:09,262 --> 03:45:14,033
>> SO LOUIS AND MICHAEL --

5297
03:45:14,100 --> 03:45:15,768
TEAMED UP AND THEY DID BLOOD

5298
03:45:15,835 --> 03:45:16,669
TRANSCRIPTOMICS ON THESE

5299
03:45:16,736 --> 03:45:19,706
ANIMALS, AND IT SEEMS WITHIN THE

5300
03:45:19,772 --> 03:45:21,407
VERY FIRST COUPLE OF DAYS, THE

5301
03:45:21,474 --> 03:45:24,010
RESPONSE TO THE VACCINE IS

5302
03:45:24,077 --> 03:45:24,377
DIFFERENT.

5303
03:45:24,444 --> 03:45:25,879
IT'S NOT THE T-CELL RESPONSE,

5304
03:45:25,945 --> 03:45:27,180
NOT THE RESPONSES I TALKED

5305
03:45:27,247 --> 03:45:29,782
ABOUT, BUT IT'S THE INNATE

5306
03:45:29,849 --> 03:45:32,719
RESPONSE, PARTICULARLY IN IL15

5307
03:45:32,785 --> 03:45:35,722
SIGNATURE THAT IS SUSTAINED AND

5308
03:45:35,788 --> 03:45:39,792
HIGH IN THE ANIMALS THAT BOTH

5309
03:45:39,859 --> 03:45:41,327
WILL BE PROTECTED IN THE END

5310
03:45:41,394 --> 03:45:42,528
WHEREAS THE ONES THAT ARE NOT

5311
03:45:42,595 --> 03:45:43,897
PROTECTED, YOU DO NOT HAVE THIS

5312
03:45:43,963 --> 03:45:47,734
RESPONSE, AND IT SEEMS TO BE

5313
03:45:47,800 --> 03:45:49,802
PREDETERMINED EVEN BEFORE YOU

5314
03:45:49,869 --> 03:45:51,704
INJECT THE VACCINE, IT'S NOT THE

5315
03:45:51,771 --> 03:45:55,208
MAGNITUDE OF THE RESPONSE, IT'S

5316
03:45:55,275 --> 03:45:55,875
THE DELTA.

5317
03:45:55,942 --> 03:45:58,111
SO THE MONKEYS THAT HAVE LESS

5318
03:45:58,177 --> 03:45:59,579
IL15 RESPONSE AND THEN MAKE A

5319
03:45:59,646 --> 03:46:01,614
LOT OF IT, THOSE ARE THE ONES

5320
03:46:01,681 --> 03:46:02,482
THAT ARE PROTECTED.

5321
03:46:02,548 --> 03:46:06,920
SO WE'RE TRYING TO FIGURE OUT,

5322
03:46:06,986 --> 03:46:10,757
IL15 IS A VERY -- CYTOKINE

5323
03:46:10,823 --> 03:46:12,926
FOR -- AND K CELLS AND SO ON AND

5324
03:46:12,992 --> 03:46:14,093
TRY TO FIGURE OUT WHAT THAT

5325
03:46:14,160 --> 03:46:16,729
MEANS, BUT THAT CORRELATED QUITE

5326
03:46:16,796 --> 03:46:18,164
WELL WITH WHICH ANIMALS WILL BE

5327
03:46:18,231 --> 03:46:19,198
PROTECTED AND WHICH ANIMALS WILL

5328
03:46:19,265 --> 03:46:20,266
NOT BE PROTECTED.

5329
03:46:20,333 --> 03:46:24,003
>> SO HAVE THEY GONE DIGGING

5330
03:46:24,070 --> 03:46:26,039
THROUGH -- RESPONSE GENES AND --

5331
03:46:26,105 --> 03:46:26,372
INTERFERONS --

5332
03:46:26,439 --> 03:46:28,641
>> NOT YET.

5333
03:46:28,708 --> 03:46:32,278
ONE THING WE DID TR TRY IS WE DD

5334
03:46:32,345 --> 03:46:37,784
PUT IL15 INTO -- AND ACTUALLY WE

5335
03:46:37,850 --> 03:46:38,751
GOT PRETTY GOOD PROTECTION WITH

5336
03:46:38,818 --> 03:46:41,754
THOSE BUT IT WAS NOT 100%.

5337
03:46:41,821 --> 03:46:43,189
THERE WAS A LITTLE BIT OF A -- I

5338
03:46:43,256 --> 03:46:45,825
DON'T KNOW IF IT WAS

5339
03:46:45,892 --> 03:46:46,693
STATISTICALLY SIGNIFICANT.

5340
03:46:46,759 --> 03:46:48,161
>> I WANT TO JUST EXPRESS

5341
03:46:48,227 --> 03:46:52,365
CONFUSION ABOUT THE EDUCATION

5342
03:46:52,432 --> 03:46:53,866
OF -- RESPONSIVE T CELLS.

5343
03:46:53,933 --> 03:46:56,202
HOW IS THAT WORKING POSITIVE OR

5344
03:46:56,269 --> 03:46:57,971
NEGATIVE, OR AM I THINKING IN

5345
03:46:58,037 --> 03:47:02,909
THE RIGHT FRAMEWORK?

5346
03:47:02,976 --> 03:47:05,078
>> THESE ARE VERY WEIRD T CELLS.

5347
03:47:05,144 --> 03:47:07,447
SO ONE EXPERIMENT LOUIS DID

5348
03:47:07,513 --> 03:47:09,082
IS -- MONKEYS AND HE STILL GETS

5349
03:47:09,148 --> 03:47:12,018
THOSE RESPONSES.

5350
03:47:12,085 --> 03:47:14,053
WE ALSO HAVE IDENTIFIED SOME

5351
03:47:14,120 --> 03:47:18,124
T-CELL RECEPTORS THAT

5352
03:47:18,191 --> 03:47:20,326
CROSS-REACT WITH IMMUNODOMINANT

5353
03:47:20,393 --> 03:47:23,863
CLASSICALLY RESTRICTED MH

5354
03:47:23,930 --> 03:47:28,368
MHC1 PEPTIDES FROM RHESUS CMV.

5355
03:47:28,434 --> 03:47:29,669
SO WHAT WE THINK IS HAPPENING IS

5356
03:47:29,736 --> 03:47:33,039
THESE ARE NOT TWO PRIME EVENT,

5357
03:47:33,106 --> 03:47:35,441
IT'S NOT THAT YOU HAVE NAIVE T

5358
03:47:35,508 --> 03:47:37,176
CELLS THAT THEN GET PRIMED, BUT

5359
03:47:37,243 --> 03:47:38,611
IT'S A REPROGRAMMING.

5360
03:47:38,678 --> 03:47:40,580
ALSO A DE-PROGRAMMING OF THE

5361
03:47:40,646 --> 03:47:42,081
PRE-EXISTING MEMORY IN THE GIVEN

5362
03:47:42,148 --> 03:47:43,750
ANIMAL.

5363
03:47:43,816 --> 03:47:46,352
AND I'M SAYING DE-PROGRAMMING

5364
03:47:46,419 --> 03:47:49,355
BECAUSE WE ALSO FIND THAT WE GET

5365
03:47:49,422 --> 03:47:50,790
THESE VERY BROAD RESPONSES.

5366
03:47:50,857 --> 03:47:52,458
YOU NOTICE THERE'S HALF OF THE

5367
03:47:52,525 --> 03:47:55,795
PIP TIPEPTIDES SHOW UP POSITIVET

5368
03:47:55,862 --> 03:47:58,331
WE DON'T HAVE THE EQUIVALENT

5369
03:47:58,398 --> 03:48:02,769
BREADTH OF THE TCR USAGE.

5370
03:48:02,835 --> 03:48:04,737
SO FEW CLONAL TYPES GIVE YOU

5371
03:48:04,804 --> 03:48:06,572
THESE -- RESPONSES WHICH MEANS

5372
03:48:06,639 --> 03:48:08,808
EACH TCR IS HIGHLY REACTIVE EVEN

5373
03:48:08,875 --> 03:48:10,343
TO PEPTIDES THAT ARE NOT VERY

5374
03:48:10,410 --> 03:48:10,676
RELATED.

5375
03:48:10,743 --> 03:48:13,312
SO THAT'S WHY DE-PROGRAMMING, SO

5376
03:48:13,379 --> 03:48:14,680
I THINK -- AND WE DON'T KNOW HOW

5377
03:48:14,747 --> 03:48:16,215
IT WORKS.

5378
03:48:16,282 --> 03:48:19,285
SOMEHOW CMV ARE INDUCED IN THESE

5379
03:48:19,352 --> 03:48:20,653
T CELLS IN THE ABILITY TO

5380
03:48:20,720 --> 03:48:24,257
RESPOND TO THESE LOW AFFINITY

5381
03:48:24,323 --> 03:48:27,560
PEPTIDES PRESENTED BY MHCE AND

5382
03:48:27,627 --> 03:48:29,629
VERY TRANSIENTLY BECAUSE THEY

5383
03:48:29,695 --> 03:48:32,298
HAVE VERY LOW AFFINITY.

5384
03:48:32,365 --> 03:48:35,168
IT MIGHT EVEN BE -- IN THE

5385
03:48:35,234 --> 03:48:38,337
MOLECULE ITSELF THAN A TYPICAL

5386
03:48:38,404 --> 03:48:39,806
PEPTIDE MHC RECOGNITION.

5387
03:48:39,872 --> 03:48:43,643
SO THE TCRs ARE KRE CROSS

5388
03:48:43,709 --> 03:48:45,111
REACTIVE, THE T CELLS ARE VERY

5389
03:48:45,178 --> 03:48:47,113
CROSS REACTIVE, SO CMV IS THE

5390
03:48:47,180 --> 03:48:48,147
LOWEST THRESHOLD OF THESE T

5391
03:48:48,214 --> 03:48:49,515
CELLS TO BE ABLE TO RESPOND TO

5392
03:48:49,582 --> 03:48:50,016
THIS.

5393
03:48:50,083 --> 03:48:52,585
BUT AGAIN, IT'S ONE OF THOSE

5394
03:48:52,652 --> 03:48:55,388
AREAS WHERE WE'RE ACTIVELY

5395
03:48:55,455 --> 03:48:57,023
WORKING ON IT BUT IT'S BEEN VERY

5396
03:48:57,090 --> 03:48:57,356
DIFFICULT.

5397
03:48:57,423 --> 03:48:58,291
ALSO THAT'S WHAT WE'RE WORKING

5398
03:48:58,357 --> 03:48:59,492
ON WITH JEFF HERE.

5399
03:48:59,559 --> 03:49:00,793
IT'S BEEN REALLY HARD TO CLONE

5400
03:49:00,860 --> 03:49:02,595
ALL THESE TCRs AND THEN GET

5401
03:49:02,662 --> 03:49:02,995
THEM TO FIRE.

5402
03:49:03,062 --> 03:49:04,697
WHEN YOU PET THEM INTO JUST ANY

5403
03:49:04,764 --> 03:49:06,332
RANDOM T-CELL.

5404
03:49:06,399 --> 03:49:09,669
SO THAT ALSO TELLS US THERE IS

5405
03:49:09,735 --> 03:49:11,304
SOMETHING IN THE EPIGENETIC

5406
03:49:11,370 --> 03:49:14,607
LANDSCAPE OF THESE T CELLS THAT

5407
03:49:14,674 --> 03:49:17,376
CHANGES WHEN THEY BECOME

5408
03:49:17,443 --> 03:49:19,078
HLE-RESTRICTED.

5409
03:49:19,145 --> 03:49:19,345
>> GREAT.

5410
03:49:19,412 --> 03:49:22,682
>> I HAVE A VERY -- QUESTION.

5411
03:49:22,748 --> 03:49:28,321
I KNOW -- THE -- WILL ACTUALLY

5412
03:49:28,387 --> 03:49:30,523
DICTATE A NEW RESPONSE.

5413
03:49:30,590 --> 03:49:33,593
-- SO I JUST WONDER WHAT --

5414
03:49:33,659 --> 03:49:35,328
WHETHER YOU CONSIDER ALL OF

5415
03:49:35,394 --> 03:49:36,596
THESE IN THE NEXT WORK

5416
03:49:36,662 --> 03:49:39,232
ESPECIALLY THE -- OF THE

5417
03:49:39,298 --> 03:49:40,766
SUPERTOPE IN THAT NETWORK AND

5418
03:49:40,833 --> 03:49:43,035
HOW IT WILL CORRESPOND TO THE --

5419
03:49:43,102 --> 03:49:44,737
>> I'M NOT SURE I QUITE

5420
03:49:44,804 --> 03:49:45,638
UNDERSTAND YOUR QUESTION.

5421
03:49:45,705 --> 03:49:47,373
THE NETWORK IN THE HIV WORLD

5422
03:49:47,440 --> 03:49:50,276
MEANS THAT YOU HAVE THESE HIGHLY

5423
03:49:50,343 --> 03:49:52,478
CONSERVED EPITOPES OR THESE --

5424
03:49:52,545 --> 03:49:53,913
SOME ARE MORE IMPORTANT FOR THE

5425
03:49:53,980 --> 03:49:57,350
VIRUS THAN OTHERS THAT ARE LESS

5426
03:49:57,416 --> 03:49:58,684
IMPORTANT.

5427
03:49:58,751 --> 03:49:59,685
IF THAT'S WHAT YOU'RE GETTING

5428
03:49:59,752 --> 03:49:59,952
AT.

5429
03:50:00,019 --> 03:50:02,188
WHAT I CAN SAY IS, WHAT I JUST

5430
03:50:02,255 --> 03:50:04,891
SAID TO MIKE, EVERY TCR WE

5431
03:50:04,957 --> 03:50:08,261
IDENTIFIED SO FAR RESPONDS TO A

5432
03:50:08,327 --> 03:50:08,728
SUPERTOPE.

5433
03:50:08,794 --> 03:50:13,166
AND THEN TO SOME UNIQUE OTHER

5434
03:50:13,232 --> 03:50:15,334
EPITOPES THAT ONLY THIS TCR

5435
03:50:15,401 --> 03:50:16,335
RECOGNIZES IN A WAY.

5436
03:50:16,402 --> 03:50:19,372
BUT THE SUPERTOPES FOR SOME

5437
03:50:19,438 --> 03:50:21,541
REASON SEEM TO BE THE -- OF

5438
03:50:21,607 --> 03:50:22,108
THESE IMMUNE RESPONSES.

5439
03:50:22,175 --> 03:50:23,809
I DON'T KNOW IF THAT'S A NETWORK

5440
03:50:23,876 --> 03:50:24,544
IN THE CLASSICAL SENSE.

5441
03:50:24,610 --> 03:50:29,382
I THINK IT'S MORE OF A --

5442
03:50:29,448 --> 03:50:30,850
REACTIVITY VERY SENSITIVE TO A

5443
03:50:30,917 --> 03:50:31,617
GIVEN TCR.

5444
03:50:31,684 --> 03:50:35,988
AGAIN, WHY THOSE ARE SUPERTOPES,

5445
03:50:36,055 --> 03:50:39,258
IS IT THEY'RE MOST ABUNDANTLY

5446
03:50:39,325 --> 03:50:40,259
MADE, HIGH AFFINITY, WE DON'T

5447
03:50:40,326 --> 03:50:41,227
KNOW AT THIS POINT.

5448
03:50:41,294 --> 03:50:42,562
THERE'S NO OBVIOUS REASON.

5449
03:50:42,628 --> 03:50:44,263
ALSO THERE IS NO HOMOLOGY IN

5450
03:50:44,330 --> 03:50:47,733
MOST CASES BETWEEN ANY OF THOSE

5451
03:50:47,800 --> 03:50:51,704
PEPTIDES AND THE EL9 SEQUENCE

5452
03:50:51,771 --> 03:50:53,072
WHICH IS EVENTUALLY WHICH HAS

5453
03:50:53,139 --> 03:50:54,740
EVOLVED TO BIND.

5454
03:50:54,807 --> 03:50:57,777
SO THESE BIND SOME OF THEM WITH

5455
03:50:57,843 --> 03:51:00,146
AFFINITY TO MHC.

5456
03:51:00,213 --> 03:51:01,280
I DON'T KNOW IF THIS ANSWERS

5457
03:51:01,347 --> 03:51:02,048
YOUR QUESTION.

5458
03:51:02,114 --> 03:51:05,284
OTHERWISE WE'LL TALK LATER.

5459
03:51:05,351 --> 03:51:05,851
THANK YOU.

5460
03:51:05,918 --> 03:51:13,859
[APPLAUSE]

5461
03:51:13,926 --> 03:51:15,595
>> SO WE'RE GOING TO GO BACK IN

5462
03:51:15,661 --> 03:51:19,599
THE PROGRAM TO MICHAEL FARZAN.

5463
03:51:19,665 --> 03:51:21,634
MICHAEL DOES PH.D. RESEARCH

5464
03:51:21,701 --> 03:51:23,636
IMMUNOLOGY AT HARVARD MEDICAL

5465
03:51:23,703 --> 03:51:24,470
SCHOOL, JUST LIKE NANCY DID.

5466
03:51:24,537 --> 03:51:26,272
HE STAYED ON AT HARVARD,

5467
03:51:26,339 --> 03:51:27,807
EVENTUALLY SERVING AS PROFESSOR

5468
03:51:27,873 --> 03:51:28,808
IN THE DEPARTMENT OF

5469
03:51:28,874 --> 03:51:30,209
MICROBIOLOGY AND IMMUNOLOGY.

5470
03:51:30,276 --> 03:51:31,911
HE THEN SPENT A DECADE AS

5471
03:51:31,978 --> 03:51:33,412
CO-CHAIR AND THEN CHAIR OF THE

5472
03:51:33,479 --> 03:51:35,214
DEPARTMENT OF IMMUNOLOGY AND

5473
03:51:35,281 --> 03:51:36,482
MICROBIOLOGY AT SCRIPPS,

5474
03:51:36,549 --> 03:51:36,749
FLORIDA.

5475
03:51:36,816 --> 03:51:38,384
HE RETURNED TO HARVARD MEDICAL

5476
03:51:38,451 --> 03:51:40,253
SCHOOL EARLIER THIS YEAR, AS

5477
03:51:40,319 --> 03:51:41,954
DIRECTOR OF VIROLOGY RESEARCH AT

5478
03:51:42,021 --> 03:51:43,589
BOSTON CHILDREN'S.

5479
03:51:43,656 --> 03:51:45,558
HE'S WORKED EXTENSIVELY ON HIV

5480
03:51:45,625 --> 03:51:56,369
AND MORE RECENTLY ON SA SARS-CO.

5481
03:52:01,407 --> 03:52:01,540
[APPLAUSE]

5482
03:52:01,607 --> 03:52:03,676
>> SO THIS IS GOING TO BE --

5483
03:52:03,743 --> 03:52:05,544
THIS IS NEW WORK AND RELATIVELY

5484
03:52:05,611 --> 03:52:06,345
SIMPLER WORK SO EVERYBODY CAN

5485
03:52:06,412 --> 03:52:08,347
SORT OF RELAX A LITTLE BIT.

5486
03:52:08,414 --> 03:52:09,482
EVERYTHING I'M GOING TO EXPLAIN

5487
03:52:09,548 --> 03:52:10,983
IS ACTUALLY REASONABLY

5488
03:52:11,050 --> 03:52:11,951
UNDERSTANDABLE, I HOPE.

5489
03:52:12,018 --> 03:52:14,020
MAYBE EXCEPT FOR THE LAST PART,

5490
03:52:14,086 --> 03:52:15,655
BUT LET'S GO THROUGH THE EASY

5491
03:52:15,721 --> 03:52:16,088
PART 1ST OF ALL.

5492
03:52:16,155 --> 03:52:21,060
SO WHAT WE'RE DOING IS, WE'RE

5493
03:52:21,127 --> 03:52:23,129
EDITING PRIMARILY MURINE CELLS,

5494
03:52:23,195 --> 03:52:26,766
EDITING THEM IN SUCH A WAY,

5495
03:52:26,832 --> 03:52:28,367
VARIABLE CHANGE, THEY'RE NOW

5496
03:52:28,434 --> 03:52:30,569
TYPICALLY A HUMAN ANTIBODY,

5497
03:52:30,636 --> 03:52:32,972
BROADLY NEUTRALIZING ANTIBODY

5498
03:52:33,039 --> 03:52:35,308
AGAINST EITHER HIV OR SARS.

5499
03:52:35,374 --> 03:52:37,643
AND SO THE STRUCTURE OF THIS

5500
03:52:37,710 --> 03:52:39,512
TALK IS WHAT WE DO, WHY WE DO

5501
03:52:39,578 --> 03:52:41,113
IT, HOW WE DO IT, HARD WORK AND

5502
03:52:41,180 --> 03:52:41,447
WHAT'S NEXT.

5503
03:52:41,514 --> 03:52:42,615
I SHOULD MENTION THAT SOME OF

5504
03:52:42,682 --> 03:52:45,151
THESE SLIDES WERE A LITTLE

5505
03:52:45,217 --> 03:52:48,220
GEARED TOWARDS GRADUATE

5506
03:52:48,287 --> 03:52:49,622
STUDENTS, SO I'LL GO BY THEM

5507
03:52:49,689 --> 03:52:52,892
QUICKLY BUT I DON'T NEED TO

5508
03:52:52,958 --> 03:52:53,993
CONSULT ANYBODY, THERE'S A LOT

5509
03:52:54,060 --> 03:52:55,294
OF THINGS I'M SURE YOU

5510
03:52:55,361 --> 03:52:55,828
UNDERSTAND.

5511
03:52:55,895 --> 03:52:58,798
BUT THE BASIC GOAL HERE IS THAT

5512
03:52:58,864 --> 03:53:00,866
WE MIGHT FIND A B CELL RECEPTOR

5513
03:53:00,933 --> 03:53:03,269
AND WE DO SO BY EDITING IT WITH

5514
03:53:03,336 --> 03:53:03,569
CRISPR.

5515
03:53:03,636 --> 03:53:06,439
AGAIN YOU PUT IN THE HEAVY LIGHT

5516
03:53:06,505 --> 03:53:07,406
CHAIN -- WE GRAFT THOSE CELLS

5517
03:53:07,473 --> 03:53:09,342
BACK INTO MICE, AND THEN WE

5518
03:53:09,408 --> 03:53:10,776
MEASURE A BUNCH OF THINGS.

5519
03:53:10,843 --> 03:53:13,512
THE ACTIVITY THAT -- REPERTOIRE

5520
03:53:13,579 --> 03:53:19,985
BY DEEP SEQUENCING -- TOLERANCE,

5521
03:53:20,052 --> 03:53:22,455
BLAH, BLAH, BLAH.

5522
03:53:22,521 --> 03:53:23,856
AND SO WE DO THAT FOR A NUMBER

5523
03:53:23,923 --> 03:53:25,191
OF REASONS, BUT BEFORE I GET

5524
03:53:25,257 --> 03:53:28,894
THERE, I WANT TO SNEAK IN TWO

5525
03:53:28,961 --> 03:53:30,062
SORT OF TECHNICAL POINTS.

5526
03:53:30,129 --> 03:53:31,497
THE FIRST IS WHEN WE DO THIS IN

5527
03:53:31,564 --> 03:53:36,836
MICE, WE CAN DISTINGUISH BETWEEN

5528
03:53:36,902 --> 03:53:40,973
THE CELLS THAT WE EDITED AND THE

5529
03:53:41,040 --> 03:53:43,642
HOST BECAUSE THEY'RE MARKED

5530
03:53:43,709 --> 03:53:47,847
WITH -- OR TWO MARKERS, SO THE

5531
03:53:47,913 --> 03:53:53,619
ORIGIN MICE ARE CD4 -- .1 AND --

5532
03:53:53,686 --> 03:53:54,186
.2.

5533
03:53:54,253 --> 03:53:56,355
SO THAT SORT OF PINKISH BOX IN

5534
03:53:56,422 --> 03:53:57,823
THE CORNER IS REALLY OUR SECRET

5535
03:53:57,890 --> 03:53:58,124
SAUCE.

5536
03:53:58,190 --> 03:53:59,525
SO I'M GOING TO SAY WE DO THIS A

5537
03:53:59,592 --> 03:54:00,726
LITTLE BETTER THAN MOST PEOPLE

5538
03:54:00,793 --> 03:54:01,927
IN THIS FIELD BECAUSE WE HAVE A

5539
03:54:01,994 --> 03:54:04,530
COUPLE OF EFFICIENCY BONUSES.

5540
03:54:04,597 --> 03:54:07,867
ONE BONUS IS WE'RE NOT USING

5541
03:54:07,933 --> 03:54:14,907
CONVENTIONAL CAS9, WE'RE USING

5542
03:54:14,974 --> 03:54:16,208
CAS12A.

5543
03:54:16,275 --> 03:54:17,810
-- THAT WE DON'T OWN BUT SORT

5544
03:54:17,877 --> 03:54:19,245
OF DEVELOPED ITS USE.

5545
03:54:19,311 --> 03:54:20,980
AND THEN THE SECOND THING WE'RE

5546
03:54:21,046 --> 03:54:23,649
USING IS AAV, AND THIS IS KIND

5547
03:54:23,716 --> 03:54:26,085
OF THE HOOK INTO THE MEASURE OF

5548
03:54:26,152 --> 03:54:27,653
THESE -- WHICH IS WHEN ARE

5549
03:54:27,720 --> 03:54:29,388
VIRUSES USEFUL.

5550
03:54:29,455 --> 03:54:31,357
A, THESE EXTREMELY -- FOR A

5551
03:54:31,424 --> 03:54:33,392
NUMBER OF REASONS, BUT ONE OF

5552
03:54:33,459 --> 03:54:35,494
ITS BEST USES, IT SERVES AS A

5553
03:54:35,561 --> 03:54:39,231
WONDERFUL WAY TO DELIVER A

5554
03:54:39,298 --> 03:54:41,801
HOMOLOGY -- REPAIR TEMPLATE.

5555
03:54:41,867 --> 03:54:44,036
THAT'S THE ONE PLACE WHERE THE

5556
03:54:44,103 --> 03:54:45,938
VIRUS CAN BE ESPECIALLY USEFUL.

5557
03:54:46,005 --> 03:54:49,141
IN THIS TALK.

5558
03:54:49,208 --> 03:54:49,475
OKAY.

5559
03:54:49,542 --> 03:54:50,976
SO WHY ARE WE DOING THIS IN THE

5560
03:54:51,043 --> 03:54:52,411
FIRST PLACE?

5561
03:54:52,478 --> 03:54:54,980
WELL, THERE'S FOUR REASONS.

5562
03:54:55,047 --> 03:54:55,981
THE FIRST THING I'LL SPEND A

5563
03:54:56,048 --> 03:54:57,516
LITTLE TIME IS, WE'RE HARNESSING

5564
03:54:57,583 --> 03:54:59,885
A MAMMALIAN LYMPH NODE TO

5565
03:54:59,952 --> 03:55:02,721
DEVELOP ANTIBODIES, TO AFFINITY

5566
03:55:02,788 --> 03:55:03,522
MATURE ANTIBODIES.

5567
03:55:03,589 --> 03:55:05,691
OUR PREMISE IS THAT THE

5568
03:55:05,758 --> 03:55:07,960
EVOLUTION SELECTS MUCH BETTER

5569
03:55:08,027 --> 03:55:09,829
THAN PHAGE DISPLAY OR OTHER

5570
03:55:09,895 --> 03:55:12,198
TECHNIQUES FOR IMPROVING

5571
03:55:12,264 --> 03:55:15,167
ANTIBODIES IN VITRO AND SHOWS

5572
03:55:15,234 --> 03:55:16,101
SOME EVIDENCE FOR THAT.

5573
03:55:16,168 --> 03:55:18,771
IT'S MORE THEORY THAN IT IS

5574
03:55:18,838 --> 03:55:20,172
PROOF, BUT I SHOW SOMETHING IN

5575
03:55:20,239 --> 03:55:21,040
SUPPORT OF THAT.

5576
03:55:21,106 --> 03:55:22,441
THE SECOND THING IS WE WANT TO

5577
03:55:22,508 --> 03:55:24,443
CREATE MORE RELEVANT VACCINE

5578
03:55:24,510 --> 03:55:24,844
MODELS.

5579
03:55:24,910 --> 03:55:26,545
THIS IS ESPECIALLY IMPORTANT FOR

5580
03:55:26,612 --> 03:55:30,516
CLASS OF VACCINE -- THE HIV

5581
03:55:30,583 --> 03:55:32,151
FIELD WHICH RELIES ON A UNIQUE

5582
03:55:32,218 --> 03:55:35,287
PROPERTY OF THE KI DIVERSITY CHS

5583
03:55:35,354 --> 03:55:37,289
OF THE HUMAN REPERTOIRE, NOT

5584
03:55:37,356 --> 03:55:38,591
FOUND IN MONKEYS, NOT FOUND IN

5585
03:55:38,657 --> 03:55:39,024
MICE.

5586
03:55:39,091 --> 03:55:40,092
SO IN ORDER TO REPLICATE THAT

5587
03:55:40,159 --> 03:55:41,627
AND TO MAKE A MOUSE MODEL OF

5588
03:55:41,694 --> 03:55:43,696
THAT, WE HAVE TO ENGINEER THE B

5589
03:55:43,762 --> 03:55:50,236
CELLS TO THOSE -- CHAINS.

5590
03:55:50,302 --> 03:55:51,971
SOME DAY WE CAN THINK ABOUT CAR

5591
03:55:52,037 --> 03:55:53,205
B CELLS IN THE SAME MANNER WE

5592
03:55:53,272 --> 03:55:55,541
THINK OF CAR-T-CELLS, ALTHOUGH I

5593
03:55:55,608 --> 03:55:56,542
CHALLENGE YOU TO THINK OF THE

5594
03:55:56,609 --> 03:55:58,177
USE CASES IN CAR B CELLS.

5595
03:55:58,244 --> 03:55:59,578
THE ONE I CAN THINK OF

5596
03:55:59,645 --> 03:56:01,680
IMMEDIATELY IS SUPPRESSING THE

5597
03:56:01,747 --> 03:56:02,848
ESTABLISHED HIV INFECTION WITH

5598
03:56:02,915 --> 03:56:05,818
ANTIBODIES.

5599
03:56:05,885 --> 03:56:07,486
SO I THINK THIS IS THE POINT

5600
03:56:07,553 --> 03:56:08,754
WHERE I'M KIND OF INTRODUCING

5601
03:56:08,821 --> 03:56:10,389
EVERYBODY TO THINGS THEY KNOW,

5602
03:56:10,456 --> 03:56:13,659
JUST TO REMIND YOU AN ANTIBODY

5603
03:56:13,726 --> 03:56:15,094
IS AN SC REGION, VARIABLE

5604
03:56:15,160 --> 03:56:15,594
REGIONS.

5605
03:56:15,661 --> 03:56:16,929
WE'RE ONLY INTERESTED IN

5606
03:56:16,996 --> 03:56:18,364
MODIFYING THOSE VARIABLE

5607
03:56:18,430 --> 03:56:20,165
REGIONS -- THE ONES THAT CONTACT

5608
03:56:20,232 --> 03:56:22,568
ANTIGEN, OF COURSE, THEY HAVE

5609
03:56:22,635 --> 03:56:24,537
CDLs 1, 2 AND 3s.

5610
03:56:24,603 --> 03:56:27,573
THEY CAN BE SHORT OR LONG, AND

5611
03:56:27,640 --> 03:56:28,541
ESPECIALLY GENERALLY PROVIDES A

5612
03:56:28,607 --> 03:56:30,843
LOT OF BINDING AND -- MOST

5613
03:56:30,910 --> 03:56:32,177
DIVERSE ELEMENT OF ANTIBODIES.

5614
03:56:32,244 --> 03:56:35,648
SO WE'RE VERY FOCUSED ON THAT.

5615
03:56:35,714 --> 03:56:37,082
YOU CAN SEE IN PART WHY IT IS,

5616
03:56:37,149 --> 03:56:38,217
BECAUSE IT'S AT THE JUNCTION OF

5617
03:56:38,284 --> 03:56:43,989
THE V, D AND J REGIONS, AND ALL

5618
03:56:44,056 --> 03:56:45,858
THE -- DIVERSITY AND ALL THOSE

5619
03:56:45,925 --> 03:56:47,293
GOOD THINGS YOU LEARN IN YOUR

5620
03:56:47,359 --> 03:56:48,260
IMMUNOLOGY TEXT, THAT'S WHERE

5621
03:56:48,327 --> 03:56:49,828
MOST OF THAT HAPPENS OR A HUGE

5622
03:56:49,895 --> 03:56:50,696
AMOUNT OF DIVERSITY.

5623
03:56:50,763 --> 03:56:53,098
AND IT CAN THEY CAN BE SHORT AND

5624
03:56:53,165 --> 03:56:54,266
THEY CAN BE LONG.

5625
03:56:54,333 --> 03:56:55,935
THERE'S AN EXAMPLE OF THE LONG

5626
03:56:56,001 --> 03:56:56,569
OVER THERE.

5627
03:56:56,635 --> 03:57:00,940
IT'S AN APEX -- HIV NEUTRALIZING

5628
03:57:01,006 --> 03:57:05,411
ANTIBODIES AND THAT LONG -- VERY

5629
03:57:05,477 --> 03:57:06,445
IMPORTANT TO TALK ABOUT THE

5630
03:57:06,512 --> 03:57:12,217
SECOND PART OF THE TALK.

5631
03:57:12,284 --> 03:57:13,519
BASICALLY I WANTED TO REMIND YOU

5632
03:57:13,586 --> 03:57:15,154
WHAT OUR TROUBLE IS -- PRIMARY B

5633
03:57:15,220 --> 03:57:16,121
CELLS.

5634
03:57:16,188 --> 03:57:18,290
BIG PROBLEM IS IT'S A RELATIVELY

5635
03:57:18,357 --> 03:57:21,226
RANDOM PROCESS WHERE -- V, D AND

5636
03:57:21,293 --> 03:57:27,132
J RECOMBINES, WE COMBINE IN A

5637
03:57:27,199 --> 03:57:29,201
RANDOM WAY, CREATE -- THERE'S

5638
03:57:29,268 --> 03:57:32,404
OTHER FORMS OF RANDOMIZATION AND

5639
03:57:32,471 --> 03:57:33,172
DIVERSIFICATION, BUT WE DON'T

5640
03:57:33,238 --> 03:57:33,606
KNOW WHAT'S THERE.

5641
03:57:33,672 --> 03:57:35,240
SO WE HAVE TO TRY TO SOLVE THE

5642
03:57:35,307 --> 03:57:36,175
PROBLEM OF TRYING TO ADD

5643
03:57:36,241 --> 03:57:37,076
SOMETHING, WHICH WE DON'T KNOW

5644
03:57:37,142 --> 03:57:39,912
WHAT IT IS REALLY.

5645
03:57:39,979 --> 03:57:41,180
SO WHAT DOES THAT REALLY COME

5646
03:57:41,246 --> 03:57:41,747
DOWN TO?

5647
03:57:41,814 --> 03:57:45,584
THE HOMOLOGY ARM, SO HOMOLOGY

5648
03:57:45,651 --> 03:57:47,653
DIRECTED REPAIR TEMPLATE.

5649
03:57:47,720 --> 03:57:49,488
SOMETHING THAT GUIDES THE DNA

5650
03:57:49,555 --> 03:57:50,789
REPAIR PROCESS, IT'S WHAT'S

5651
03:57:50,856 --> 03:57:53,125
NORMALLY GOING ON IN YOUR BODY,

5652
03:57:53,192 --> 03:57:55,461
IS THAT WHEN THERE'S SAY A

5653
03:57:55,527 --> 03:57:56,695
DOUBLE STRANDED BREAK ON ONE

5654
03:57:56,762 --> 03:57:57,997
CHROMOSOME BUT LOOKS OVER TO THE

5655
03:57:58,063 --> 03:57:58,964
OTHER CHROMOSOME AND FIXES IT.

5656
03:57:59,031 --> 03:58:02,568
WE FOOL THE SYSTEM, FIX IT WITH

5657
03:58:02,635 --> 03:58:05,504
SOME DOUBLE STRANDED DNA THAT WE

5658
03:58:05,571 --> 03:58:08,374
OURSELVES PROVIDE AND AS I'LL

5659
03:58:08,440 --> 03:58:10,943
MENTION AAV IS A VERY GOOD WAY

5660
03:58:11,010 --> 03:58:11,510
TO DO THAT.

5661
03:58:11,577 --> 03:58:16,215
OUR PROBLEM IS THAT WE REQUIRE

5662
03:58:16,281 --> 03:58:17,082
SOMETHING THAT'S THERE AND AGAIN

5663
03:58:17,149 --> 03:58:19,785
WE DON'T KNOW WHAT'S THERE

5664
03:58:19,852 --> 03:58:22,087
ESPECIALLY ON THE -- PRIME END.

5665
03:58:22,154 --> 03:58:23,355
LET ME PAUSE FOR A SECOND AND

5666
03:58:23,422 --> 03:58:24,923
TELL YOU A SPECULATIVE REASON

5667
03:58:24,990 --> 03:58:26,325
WHY AAV IS PROBABLY A VERY GOOD

5668
03:58:26,392 --> 03:58:29,395
WAY TO EDIT THINGS, AND ALSO WHY

5669
03:58:29,461 --> 03:58:31,330
IT'S A LITTLE BIT OF A PROBLEM

5670
03:58:31,397 --> 03:58:36,502
WHEN WE THINK ABOUT AAV USING AS

5671
03:58:36,568 --> 03:58:37,603
PAIRP IN PARTICULARLY IN CELLS

5672
03:58:37,670 --> 03:58:39,772
THAT ARE NOT DIFFERENTIATED.

5673
03:58:39,838 --> 03:58:45,411
THAT REALLY SOOMS IN  ZOOMS IN E

5674
03:58:45,477 --> 03:58:47,279
STRANDED BREAK.

5675
03:58:47,346 --> 03:58:49,481
A SPECULATIVE HYPOTHESIS I TELL

5676
03:58:49,548 --> 03:58:50,649
PEOPLE SO THEY REMEMBER IS THAT

5677
03:58:50,716 --> 03:58:52,718
THE AAV REPLICATION CYCLE ALSO

5678
03:58:52,785 --> 03:58:56,588
REQUIRES THE SAME REPAIR ENZYMES

5679
03:58:56,655 --> 03:59:02,027
TO GO THROUGH ITS PROCESS OF

5680
03:59:02,094 --> 03:59:04,363
SECOND STRAND SYNTHESIS,

5681
03:59:04,430 --> 03:59:06,832
CIRCLIZATION, ALL OF THESE

5682
03:59:06,899 --> 03:59:08,734
REQUIRE -- USED BY THE CELL, THE

5683
03:59:08,801 --> 03:59:11,070
PRESUMPTION IS THAT THE

5684
03:59:11,136 --> 03:59:15,007
COLOCALIZATION -- WHAT'S

5685
03:59:15,074 --> 03:59:18,410
BRINGING THE AAV EPSOME TO THE

5686
03:59:18,477 --> 03:59:20,145
DOUBLE STRANDED BREAK.

5687
03:59:20,212 --> 03:59:21,647
NOW YOU REMEMBER THAT AAV LIKES

5688
03:59:21,714 --> 03:59:24,583
TO GO TO A DOUBLE STRANDED BRE

5689
03:59:24,650 --> 03:59:24,850
BREAK.

5690
03:59:24,917 --> 03:59:27,453
WEAVES IN EXTENSIVELY, PART OF

5691
03:59:27,519 --> 03:59:29,588
THE SECRET SAUCE THAT GIVES US

5692
03:59:29,655 --> 03:59:31,490
EFFICIENCY TO ACCOMPLISH WHAT

5693
03:59:31,557 --> 03:59:32,691
WE'RE DOING.

5694
03:59:32,758 --> 03:59:35,394
ANYWAY, THAT WAS AN ASIDE STORY

5695
03:59:35,461 --> 03:59:36,528
BECAUSE OF THE NATURE OF THESE

5696
03:59:36,595 --> 03:59:37,696
TALKS, BUT THE MAIN STORY IS,

5697
03:59:37,763 --> 03:59:38,864
HOW DO WE SOLVE THE PROBLEM OF

5698
03:59:38,931 --> 03:59:40,332
NOT KNOWING WHAT'S THERE?

5699
03:59:40,399 --> 03:59:45,137
SO THE FIELD DOES IT BY IGNORING

5700
03:59:45,204 --> 03:59:46,438
THE DIVERSE REGION AND HITTING

5701
03:59:46,505 --> 03:59:47,740
WHERE THOSE BLUE ARROWS ARE

5702
03:59:47,806 --> 03:59:49,842
GOING, WHICH IS AN INTRON

5703
03:59:49,908 --> 03:59:52,111
BETWEEN THE LAST J REGION AND

5704
03:59:52,177 --> 03:59:55,848
THE FIRST REGION -- WHICH IT'S

5705
03:59:55,914 --> 03:59:59,251
TYPICALLY SPLICED INTO.

5706
03:59:59,318 --> 04:00:00,319
THAT COMES WITH PROBLEMS AS I

5707
04:00:00,385 --> 04:00:02,187
SHOW YOU.

5708
04:00:02,254 --> 04:00:03,489
DIFFERENT HARDER APPROACH IN

5709
04:00:03,555 --> 04:00:05,424
WHICH WE EDIT -- WE MAKE A

5710
04:00:05,491 --> 04:00:07,893
SINGLE CUT AND THEN REACH TO A

5711
04:00:07,960 --> 04:00:09,828
VERY DISTANT 5 PRIME REGION,

5712
04:00:09,895 --> 04:00:11,396
VARIABLE REGION, AND BRIDGE

5713
04:00:11,463 --> 04:00:12,498
THOSE TWO AND SURPRISINGLY IT

5714
04:00:12,564 --> 04:00:12,765
WORKS.

5715
04:00:12,831 --> 04:00:15,400
ONE THING TO SAY IS THAT WE

5716
04:00:15,467 --> 04:00:17,202
DON'T NEED A TON OF EFFICIENCY

5717
04:00:17,269 --> 04:00:18,237
BECAUSE WHAT ARE WE GOING TO DO?

5718
04:00:18,303 --> 04:00:20,339
WE'RE GOING TO PUT THE CELL BACK

5719
04:00:20,405 --> 04:00:24,276
INTO AN ANIMAL, YOU DON'T NEED

5720
04:00:24,343 --> 04:00:25,911
80% EFFICIENCY, YOU DON'T NEED

5721
04:00:25,978 --> 04:00:26,945
EVEN 10% EFFICIENCY.

5722
04:00:27,012 --> 04:00:28,313
WE THINK YOU JUST NEED SOMETHING

5723
04:00:28,380 --> 04:00:34,153
ON THE ORDER OF .8% EFFICIENCY.

5724
04:00:34,219 --> 04:00:36,455
THAT'S 15,000 CELLS -- SO

5725
04:00:36,522 --> 04:00:40,626
SOMETHING ON THAT ORDER.

5726
04:00:40,692 --> 04:00:42,127
SO THERE ARE SEVERAL WAYS TO

5727
04:00:42,194 --> 04:00:43,562
EDIT THE B CELL RECEPTOR.

5728
04:00:43,629 --> 04:00:46,632
THIS IS THE WAY THAT IT'S

5729
04:00:46,698 --> 04:00:47,833
COMMONLY DONE.

5730
04:00:47,900 --> 04:00:52,004
THIS IS SORT OF OUR EXAMPLE OF

5731
04:00:52,070 --> 04:00:53,839
HOW WE SHOULDN'T DO THAT.

5732
04:00:53,906 --> 04:00:54,807
I HAVE TO GIVE PROPS TO THE

5733
04:00:54,873 --> 04:00:56,775
PEOPLE THAT DEVELOPED IT.

5734
04:00:56,842 --> 04:01:00,612
I'M USING ESPECIALLY MICHELLE'S

5735
04:01:00,679 --> 04:01:01,346
MODEL HERE, BRILLIANT WORK, ET

5736
04:01:01,413 --> 04:01:02,548
CETERA, BUT I'M GOING TO USE IT

5737
04:01:02,614 --> 04:01:08,654
AS SORT OF A COUNTER EXAMPLE.

5738
04:01:08,720 --> 04:01:10,389
WE ARE GOING TO DO IT IN FAVOR

5739
04:01:10,455 --> 04:01:12,257
OF THE REPLACING THE GENES

5740
04:01:12,324 --> 04:01:13,559
DIRECTLY OVERRIDING THE ORIGINAL

5741
04:01:13,625 --> 04:01:14,693
MURINE GENES WITH THE HUMAN

5742
04:01:14,760 --> 04:01:15,961
VERSION OF THOSE GENES.

5743
04:01:16,028 --> 04:01:19,731
AND NOT MESSING WITH THE

5744
04:01:19,798 --> 04:01:20,499
REGULATORY MECHANISM THAT YOU DO

5745
04:01:20,566 --> 04:01:22,100
WHEN YOU USE THAT CONSTRUCT OF

5746
04:01:22,167 --> 04:01:25,270
THERE, AND I WON'T COUNT THROUGH

5747
04:01:25,337 --> 04:01:26,872
ALL THE WAYS THAT IS A NATURAL

5748
04:01:26,939 --> 04:01:28,941
CONSTRUCT THAT LEADS TO

5749
04:01:29,007 --> 04:01:30,175
DYSREGULATION OF THE B CELL, I

5750
04:01:30,242 --> 04:01:31,577
WILL JUST SHOW YOU THAT IT

5751
04:01:31,643 --> 04:01:33,512
DISREGULATES THE B CELL.

5752
04:01:33,579 --> 04:01:34,947
THERE'S A THIRD TRICK WE DO

5753
04:01:35,013 --> 04:01:37,049
MOSTLY FOR VACCINE, WHERE WE

5754
04:01:37,115 --> 04:01:38,550
OVERWRITE JUST THE CDR, AND WE

5755
04:01:38,617 --> 04:01:40,619
DO SO BY RELYING ON SMALL

5756
04:01:40,686 --> 04:01:42,287
CONSENSUS REGIONS IN THE

5757
04:01:42,354 --> 04:01:43,255
VARIABLE REGION AS WELL AS

5758
04:01:43,322 --> 04:01:44,456
CUTTING THE SAME J REGION WE

5759
04:01:44,523 --> 04:01:53,632
ALWAYS CUT.

5760
04:01:53,699 --> 04:01:55,534
WHAT WE'RE TRYING TO DO IS

5761
04:01:55,601 --> 04:01:58,804
REPLACE HIV NEUTRALIZING

5762
04:01:58,871 --> 04:01:59,671
ANTIBODIES -- THE VARIABLE GENES

5763
04:01:59,738 --> 04:02:01,306
OF MURINE B CELLS WITH THE

5764
04:02:01,373 --> 04:02:02,841
VARIABLE DOSE OF HIV

5765
04:02:02,908 --> 04:02:05,377
NEUTRALIZING AND BODIES.

5766
04:02:05,444 --> 04:02:11,250
ON THE LEFT, OVER HERE, YOU CAN

5767
04:02:11,316 --> 04:02:14,219
SEE WHAT WE'RE DOING IS WE'RE

5768
04:02:14,286 --> 04:02:15,854
REPLACING WHAT'S KNOWN AS

5769
04:02:15,921 --> 04:02:19,558
CAPTIVE 56 OR VR62625 APEX

5770
04:02:19,625 --> 04:02:21,960
ANTIBODY, AND THEN OVER HERE,

5771
04:02:22,027 --> 04:02:22,661
101074.

5772
04:02:22,728 --> 04:02:24,396
THE DIFFERENCE IN EFFICIENCIES

5773
04:02:24,463 --> 04:02:26,231
ARE PROBABLY TRACEABLE TO THE

5774
04:02:26,298 --> 04:02:28,066
FOLLOWING FACT.

5775
04:02:28,133 --> 04:02:36,608
VRC2625 ONLY REQUIRES HEAVY

5776
04:02:36,675 --> 04:02:40,212
CHAIN.

5777
04:02:40,279 --> 04:02:42,381
-- WE'RE GETTING ESSENTIALLY

5778
04:02:42,447 --> 04:02:43,882
HALF OF THE EFFICIENCY OF

5779
04:02:43,949 --> 04:02:44,583
101074.

5780
04:02:44,650 --> 04:02:45,417
IT'S JUST IMPORTANT TO REMEMBER

5781
04:02:45,484 --> 04:02:48,654
THAT A SUBSET OF THE VRC2625

5782
04:02:48,720 --> 04:02:50,188
CELLS ARE CARRYING THE MURINE

5783
04:02:50,255 --> 04:02:50,622
LIGHT CHAIN.

5784
04:02:50,689 --> 04:02:51,857
IT DOESN'T REALLY MATTER, WHEN

5785
04:02:51,924 --> 04:02:53,358
YOU ENGRAFT THOSE CELLS BACK IN

5786
04:02:53,425 --> 04:02:56,561
TO ANIMALS AND THEN -- ONE, TWO

5787
04:02:56,628 --> 04:02:57,496
AND THREE TIMES, YOU GET BETTER

5788
04:02:57,562 --> 04:03:00,332
AND BETTER NEUTRALIZING --

5789
04:03:00,399 --> 04:03:02,734
PASSING A BENCHMARK HERE OF

5790
04:03:02,801 --> 04:03:06,705
2-MICROGRAM PER ML, PROTECTIVE

5791
04:03:06,772 --> 04:03:09,608
IN A MONKEY MODEL.

5792
04:03:09,675 --> 04:03:10,776
SIMILAR, 101074, ONE

5793
04:03:10,842 --> 04:03:12,010
VACCINATION, TWO VACCINATION AND

5794
04:03:12,077 --> 04:03:12,878
THESE THREE MUST KIND OF SPLIT

5795
04:03:12,945 --> 04:03:14,980
UP TOURING THAT SECOND

5796
04:03:15,047 --> 04:03:15,280
VACCINATION.

5797
04:03:15,347 --> 04:03:18,483
THIS WAS A 20-MICROGRAM PER ML

5798
04:03:18,550 --> 04:03:21,653
DOPED IN TO THE SAME NAIVE SERA

5799
04:03:21,720 --> 04:03:23,388
SERVING AS OUR BENCHMARK HERE.

5800
04:03:23,455 --> 04:03:24,456
WHAT'S INTERESTING I THINK AND

5801
04:03:24,523 --> 04:03:26,792
WORTH NOTING IS THAT MICE --

5802
04:03:26,858 --> 04:03:28,860
IT'S KIND OF WELL-KNOWN, MOST

5803
04:03:28,927 --> 04:03:32,331
MICE DO NOT RAISE NEUTRALIZING

5804
04:03:32,397 --> 04:03:34,533
ANTIBODIES IF THERE ARE NO -- IF

5805
04:03:34,599 --> 04:03:37,069
WE DON'T ADD THESE MODIFIED B

5806
04:03:37,135 --> 04:03:39,771
CELLS INTO THEM.

5807
04:03:39,838 --> 04:03:41,073
SO THOSE ARE THE CONTROLS.

5808
04:03:41,139 --> 04:03:42,741
SAME NUMBER OF VACCINATIONS BUT

5809
04:03:42,808 --> 04:03:45,677
NO ENGRAFTED B CELLS.

5810
04:03:45,744 --> 04:03:49,514
THIS IS JUST TO MAKE THE SIMPLE

5811
04:03:49,581 --> 04:03:50,248
POINT THAT IF YOU DO IT THE

5812
04:03:50,315 --> 04:03:51,683
OTHER WAY, WHAT WE CALL THE

5813
04:03:51,750 --> 04:03:53,986
INTRON EDITED WAY, YOU PUT HEAVY

5814
04:03:54,052 --> 04:03:55,954
AND LIGHT CHAIN BOTH IN THAT

5815
04:03:56,021 --> 04:03:58,357
INTRON, YOU DISRUPT THE

5816
04:03:58,423 --> 04:04:00,225
MECHANISM -- THE UNDERLYING

5817
04:04:00,292 --> 04:04:01,660
MECHANISM AS INDICATED HERE IN

5818
04:04:01,727 --> 04:04:05,364
GREEN LINES BY THE FACT THAT THE

5819
04:04:05,430 --> 04:04:06,331
NEUTRALIZING RESPONSES ARE MUCH

5820
04:04:06,398 --> 04:04:08,667
LOWER WHEN YOU DO SO.

5821
04:04:08,734 --> 04:04:10,502
SAME NUMBER OF -- CELLS GOING

5822
04:04:10,569 --> 04:04:12,504
INTO THE MICE, MUCH LOWER

5823
04:04:12,571 --> 04:04:18,410
NEUTRALIZING SERA.

5824
04:04:18,477 --> 04:04:19,778
ANOTHER WAY TO LOOK AT THIS IS

5825
04:04:19,845 --> 04:04:22,981
LOOK AT THE RATES OF SOMATIC

5826
04:04:23,048 --> 04:04:28,920
HYPERMUTATION IN THESE MICE.

5827
04:04:28,987 --> 04:04:30,555
THE BLUE ARE A COUPLE MICE THAT

5828
04:04:30,622 --> 04:04:32,424
HAVE BEEN EDITED IN THIS OTHER

5829
04:04:32,491 --> 04:04:34,493
WAY, BY INTRODUCING THE INTRON.

5830
04:04:34,559 --> 04:04:35,927
SO WE'RE KIND OF KICKING A DEAD

5831
04:04:35,994 --> 04:04:37,229
HORSE HERE.

5832
04:04:37,295 --> 04:04:39,097
YOU ABSOLUTELY WANT TO HAVE YOUR

5833
04:04:39,164 --> 04:04:41,266
HEAVY LIGHT CHAIN PROPERLY

5834
04:04:41,333 --> 04:04:42,401
PLACED WHERE THE MURINE OR THE

5835
04:04:42,467 --> 04:04:45,337
OTHER ANIMALS HEAVY LIGHT CHAIN

5836
04:04:45,404 --> 04:04:50,108
ARE, DON'T DO IT THE OTHER WAY.

5837
04:04:50,175 --> 04:04:51,777
BUT YOU CAN SEE ONE OF THE

5838
04:04:51,843 --> 04:04:52,844
REASONS WHY IT'S NOT VERY

5839
04:04:52,911 --> 04:04:56,014
GOOD -- I THINK IT'S MORE OF AN

5840
04:04:56,081 --> 04:04:57,115
EFFECT THAN ANYTHING ELSE.

5841
04:04:57,182 --> 04:04:59,751
BUT RATES OF SOMATIC

5842
04:04:59,818 --> 04:05:01,053
HYPERMUTATION ARE POOR, AND AS A

5843
04:05:01,119 --> 04:05:03,255
CONSEQUENCE OF THAT, YOU DON'T

5844
04:05:03,321 --> 04:05:05,223
GET WITH INTRON -- BUT YOU DO

5845
04:05:05,290 --> 04:05:06,958
GET UNIQUELY WITH NATIVE --

5846
04:05:07,025 --> 04:05:07,826
AFFINITY MATURATION OF THESE B

5847
04:05:07,893 --> 04:05:08,393
CELLS.

5848
04:05:08,460 --> 04:05:10,328
SO WE LIKE THIS.

5849
04:05:10,395 --> 04:05:12,431
THIS IS A BIG MILESTONE FOR US.

5850
04:05:12,497 --> 04:05:14,066
AND THE WAY WE DID THIS, WE

5851
04:05:14,132 --> 04:05:15,834
PULLED OUT A BUNCH OF ACTUALLY

5852
04:05:15,901 --> 04:05:16,935
ONLY HEAVY CHAINS HERE.

5853
04:05:17,002 --> 04:05:18,670
MORE OR LESS RANDOM, AND THOSE

5854
04:05:18,737 --> 04:05:20,005
ARE SHOWN IN PINK AND RED, THE

5855
04:05:20,072 --> 04:05:21,473
ONES THAT WE PICKED OUT OF THESE

5856
04:05:21,540 --> 04:05:22,808
THREE MICE THAT ARE ENGRAFTED.

5857
04:05:22,874 --> 04:05:25,310
THESE ARE JUST INDIVIDUAL

5858
04:05:25,377 --> 04:05:28,513
SEQUENCES, AND THEN WE

5859
04:05:28,580 --> 04:05:30,148
CHARACTERIZED THEM AGAINST THE

5860
04:05:30,215 --> 04:05:31,316
WILD TYPE ANTIBODY.

5861
04:05:31,383 --> 04:05:33,852
THESE ARE THE CHAINS AGAINST THE

5862
04:05:33,919 --> 04:05:36,388
WILD TYPE HEAVY CHAIN ALL IN THE

5863
04:05:36,455 --> 04:05:37,823
CONTEXT OF THE WILD TYPE LIGHT

5864
04:05:37,889 --> 04:05:42,828
CHAIN, AND YOU CAN SEE THAT ALL

5865
04:05:42,894 --> 04:05:45,130
OF THESE OUTPERFORMED THE WILD

5866
04:05:45,197 --> 04:05:48,633
TYPE ANTIBODY, FOUR OF THESE

5867
04:05:48,700 --> 04:05:50,936
VERY CONSISTENTLY ACROSS ALL

5868
04:05:51,002 --> 04:05:57,008
ASSAYS WE USED.

5869
04:05:57,075 --> 04:05:57,943
THESE FOUR ALWAYS WORKED OUT AND

5870
04:05:58,009 --> 04:05:58,977
THOSE FOUR, WHEN IT CAME RIGHT

5871
04:05:59,044 --> 04:06:02,047
DOWN TO IT, THEY SHARED A COMMON

5872
04:06:02,114 --> 04:06:04,916
ELEMENT, TWO MUTATION IN THE

5873
04:06:04,983 --> 04:06:07,552
CDR3 AS IT TURNED OUT, AND THESE

5874
04:06:07,619 --> 04:06:08,620
WERE BASICALLY DOING ALL THE

5875
04:06:08,687 --> 04:06:10,789
WORK TO IMPROVE THE POTENCY OF

5876
04:06:10,856 --> 04:06:16,061
THESE ANTIBODIES.

5877
04:06:16,128 --> 04:06:17,596
I DON'T HAVE THE GLOBAL PANEL

5878
04:06:17,662 --> 04:06:19,831
BUT THERE'S ANOTHER FIGURE IN

5879
04:06:19,898 --> 04:06:22,167
THE PUBLISHED PAPER THAT SHOWS

5880
04:06:22,234 --> 04:06:26,471
THE GLOBAL PANEL.

5881
04:06:26,538 --> 04:06:27,906
THE REASON WE IN PART WANT TO DO

5882
04:06:27,973 --> 04:06:29,508
THIS IS WE KNOW VERY WELL THAT

5883
04:06:29,574 --> 04:06:31,843
WHEN YOU TRY TO IMPROVE AN

5884
04:06:31,910 --> 04:06:34,946
ANTIBODY USING A CELL CULTURE

5885
04:06:35,013 --> 04:06:39,818
SYSTEM, YOU USE MAMMALIAN -- OR

5886
04:06:39,885 --> 04:06:41,219
INTELLIGENT DESIGN OF SOME SORT,

5887
04:06:41,286 --> 04:06:44,689
YOU ALWAYS GET BETTER AFFINITY.

5888
04:06:44,756 --> 04:06:45,657
THAT'S ALL YOU GO.

5889
04:06:45,724 --> 04:06:47,859
AND ALMOST INVARIABLY, YOU

5890
04:06:47,926 --> 04:06:49,494
UNDERMINE OTHER ELEMENTS,

5891
04:06:49,561 --> 04:06:50,795
IMPORTANT ELEMENTS OF THESE

5892
04:06:50,862 --> 04:06:52,097
ANTIBODIES, INCLUDING ESPECIALLY

5893
04:06:52,164 --> 04:06:53,532
THE HALF-LIFE AND THE

5894
04:06:53,598 --> 04:06:54,199
BIOAVAILABILITY.

5895
04:06:54,266 --> 04:06:59,004
AND WE'VE KNOWN THAT, I REMEMBER

5896
04:06:59,070 --> 04:07:01,406
BEAUTIFUL WORK BY PUTTING THE W

5897
04:07:01,473 --> 04:07:02,240
TRYPTOPHAN RIGHT IN THE MIDDLE

5898
04:07:02,307 --> 04:07:02,774
OF THAT.

5899
04:07:02,841 --> 04:07:05,143
AND THAT JUST CRASHED AND BURNED

5900
04:07:05,210 --> 04:07:07,445
ON BIOAVAILABILITY.

5901
04:07:07,512 --> 04:07:08,647
THIS ANTIBODY HERE, THIS IS

5902
04:07:08,713 --> 04:07:10,615
ANOTHER EXAMPLE OF SOMEBODY

5903
04:07:10,682 --> 04:07:12,584
INTELLIGENTLY COMBINING 101074

5904
04:07:12,651 --> 04:07:14,753
WITH ANOTHER ANTIBODY -- WITH

5905
04:07:14,819 --> 04:07:17,722
ELEMENTS OF ANOTHER ANTIBODY

5906
04:07:17,789 --> 04:07:18,924
MAKING IT MORE POTENT BUT IT

5907
04:07:18,990 --> 04:07:20,492
TURNS OUT TO BE A WORSE

5908
04:07:20,559 --> 04:07:22,327
ANTIBODY.

5909
04:07:22,394 --> 04:07:24,196
SO 101074 WAS KIND OF A GOLD

5910
04:07:24,262 --> 04:07:24,462
STANDARD.

5911
04:07:24,529 --> 04:07:26,932
IT'S A LOVELY, BEAUTIFUL, BEST

5912
04:07:26,998 --> 04:07:27,899
BEHAVED ANTIBODY THAT I'VE EVER

5913
04:07:27,966 --> 04:07:30,135
WORKED WITH, AND IT'S KIND OF A

5914
04:07:30,202 --> 04:07:31,870
GO-TO, IT'S A GOLD STANDARD FOR

5915
04:07:31,937 --> 04:07:32,871
EVERYBODY WORKING WITH THESE

5916
04:07:32,938 --> 04:07:35,040
ANTIANTIBODIES.

5917
04:07:35,106 --> 04:07:38,210
WE DID A COUPLE OF ASSAYS.

5918
04:07:38,276 --> 04:07:40,512
ONE POLYREACTIVITY.

5919
04:07:40,579 --> 04:07:43,348
AS YOU CAN SEE WE DIDN'T HARM

5920
04:07:43,415 --> 04:07:44,449
THE POLYREACTIVITY BY

5921
04:07:44,516 --> 04:07:45,450
INTRODUCING THE CHANGES THAT WE

5922
04:07:45,517 --> 04:07:47,219
DID, WHEREAS THE INTELLIGENTLY

5923
04:07:47,285 --> 04:07:48,520
DESIGNED FORM OF THE SAME

5924
04:07:48,587 --> 04:07:50,255
ANTIBODY DID INDEED IN THIS

5925
04:07:50,322 --> 04:07:52,591
PARTICULAR CASE HARM THE

5926
04:07:52,657 --> 04:07:53,158
POLYREACTIVITY.

5927
04:07:53,225 --> 04:07:58,363
BY THE WAY, THIS IS BJORKMAN'S

5928
04:07:58,430 --> 04:07:59,998
ANTIBODY AND SORT OF ANOTHER BAD

5929
04:08:00,065 --> 04:08:02,634
ACTOR IN THE HIV FIELD.

5930
04:08:02,701 --> 04:08:08,440
SIMILARLY, WHAT HAPPENS WHEN YOU

5931
04:08:08,506 --> 04:08:11,509
SEE THIS MAJOR POLL

5932
04:08:11,576 --> 04:08:14,045
REREACTIVITY, WE DID MANAGE TO

5933
04:08:14,112 --> 04:08:15,981
SQUEEZE SOME -- I WON'T MAKE TOO

5934
04:08:16,047 --> 04:08:17,682
MUCH OF IT BUT BASICALLY NO HARM

5935
04:08:17,749 --> 04:08:19,751
DONE TO THE BIOAVAILABILITY WHEN

5936
04:08:19,818 --> 04:08:21,052
YOU'RE IMPROVING THE POTENCY OF

5937
04:08:21,119 --> 04:08:24,322
THE ANTIBODY.

5938
04:08:24,389 --> 04:08:25,790
SAME SOURCE.

5939
04:08:25,857 --> 04:08:27,692
SO WHAT WE DID WAS WE STARTED

5940
04:08:27,759 --> 04:08:34,466
WITH SOME ANTIBODIES, WUHAN

5941
04:08:34,532 --> 04:08:35,834
STRAIN, ANCESTRAL STRAIN AND DID

5942
04:08:35,900 --> 04:08:42,073
NOT WORK AGAINST A COUPLE OF

5943
04:08:42,140 --> 04:08:44,042
OMICRON, SO WE PUT THEM INTO

5944
04:08:44,109 --> 04:08:45,744
MICE, DROVE THEM WITH VARIOUS

5945
04:08:45,810 --> 04:08:46,745
OMICRON ISOLATES AND TRIED TO

5946
04:08:46,811 --> 04:08:50,915
IMPROVE THEM IN VARIOUS WAYS.

5947
04:08:50,982 --> 04:08:51,983
INTERESTING FACT IS OF COURSE

5948
04:08:52,050 --> 04:08:54,519
MICE DO MAKE GOOD ANTIBODIES

5949
04:08:54,586 --> 04:09:02,327
AGAINST SARS.

5950
04:09:02,394 --> 04:09:03,061
ONE OR THE OTHER.

5951
04:09:03,128 --> 04:09:04,162
SO OUR ABILITY TO SEE A

5952
04:09:04,229 --> 04:09:07,766
DIFFERENCE BETWEEN THE WILD TYPE

5953
04:09:07,832 --> 04:09:09,868
AND THE B CELL ENGRAFTED MICE

5954
04:09:09,934 --> 04:09:14,105
WAS NOT VERY STRONG.

5955
04:09:14,172 --> 04:09:17,309
IT DIDN'T MATTER.

5956
04:09:17,375 --> 04:09:20,512
WE PRAY PLAYED THE SAME GAME AG.

5957
04:09:20,578 --> 04:09:22,580
THIS IS JUST STRAIGHT OUT

5958
04:09:22,647 --> 04:09:25,116
AFFINITY OUT OF -- WE WERE IN A

5959
04:09:25,183 --> 04:09:26,518
HURRY SO WE JUST CHARACTERIZED

5960
04:09:26,584 --> 04:09:28,486
THAT GUY THERE, WHICH IS OUR

5961
04:09:28,553 --> 04:09:31,122
BEST BINDER OF THE SET OF

5962
04:09:31,189 --> 04:09:33,958
VARIANTS THAT WE TRIED.

5963
04:09:34,025 --> 04:09:38,229
WE GOT A 61 FOLD, THIS IS OUR

5964
04:09:38,296 --> 04:09:40,865
BEST -- INCREASE IN AFFINITY

5965
04:09:40,932 --> 04:09:43,501
AGAINST THE -- BUT IT ALSO

5966
04:09:43,568 --> 04:09:44,903
EXTENDED TO SOME OF THE OTHER

5967
04:09:44,969 --> 04:09:46,004
OMICRONS AS WELL.

5968
04:09:46,071 --> 04:09:47,739
WE GOT THIS INTERESTING ON ONE

5969
04:09:47,806 --> 04:09:49,708
OF THE OMICRONS, WE GOT A GAIN

5970
04:09:49,774 --> 04:09:51,242
OF NEUTRALIZATION, AND THEN BACK

5971
04:09:51,309 --> 04:09:57,382
TO THE ANCESTRAL, WHICH IS --

5972
04:09:57,449 --> 04:09:57,782
BA.5 IMPROVEMENT.

5973
04:09:57,849 --> 04:09:59,017
THAT COLLATED WITH AFFINITY, AND

5974
04:09:59,084 --> 04:10:00,885
THIS IS WHAT THAT CHANGE LOOKED

5975
04:10:00,952 --> 04:10:02,754
LIKE ACROSS A BUNCH OF THESE

5976
04:10:02,821 --> 04:10:06,925
DIFFERENT VIRUSES, AND IN

5977
04:10:06,991 --> 04:10:10,428
CONTRAST, THIS GUY OVER HERE,

5978
04:10:10,495 --> 04:10:13,498
AND IT DID GREAT AGAINST THE --

5979
04:10:13,565 --> 04:10:14,699
BUT OF COURSE IT'S NOT A

5980
04:10:14,766 --> 04:10:16,167
GUARANTEE HERE AND WE DIDN'T GET

5981
04:10:16,234 --> 04:10:17,736
THE SAME KIND OF BREADTH WE SAW

5982
04:10:17,802 --> 04:10:21,806
THE FIRST TIME.

5983
04:10:21,873 --> 04:10:23,341
VERY QUICKLY SAME STORY WITH

5984
04:10:23,408 --> 04:10:23,875
BIOLOGICS.

5985
04:10:23,942 --> 04:10:25,977
DON'T PUT IN AN ANTIBODY, PUT IN

5986
04:10:26,044 --> 04:10:27,278
A BIOLOGIC, WE HAD BEEN

5987
04:10:27,345 --> 04:10:28,580
INTERESTED IN THE CD4, WORKING

5988
04:10:28,646 --> 04:10:33,318
WITH A MOLECULE CALLED EDC4,

5989
04:10:33,385 --> 04:10:34,619
THIS IS A COMPANY I'M CO-FOUNDER

5990
04:10:34,686 --> 04:10:39,557
OF THAT DEVELOPS CD4.

5991
04:10:39,624 --> 04:10:41,393
AT THIS POINT WE'RE MAKING A

5992
04:10:41,459 --> 04:10:43,361
BETTER CD4 OUT OF THEIR CD4,

5993
04:10:43,428 --> 04:10:45,230
PLAYING THE EXACT SAME GAME WE

5994
04:10:45,296 --> 04:10:48,867
DID BEFORE, ONLY WITH AN

5995
04:10:48,933 --> 04:10:50,068
UNGAMELY CONSTRUCT, IT HAS TO DO

5996
04:10:50,135 --> 04:10:52,604
WITH THE PRESENCE OF THE

5997
04:10:52,670 --> 04:10:56,274
C1 BINDER OF THE LIGHT CHAIN.

5998
04:10:56,341 --> 04:10:58,810
AGAIN, THE AFFINITY MATURATION,

5999
04:10:58,877 --> 04:11:00,412
WE CHARACTERIZE BOTH SILENT AND

6000
04:11:00,478 --> 04:11:03,515
NON-SILENT MUTATION.

6001
04:11:03,581 --> 04:11:06,151
TWO VERY ROBUST MUTATIONS CAME

6002
04:11:06,217 --> 04:11:08,219
OUT AND ALL 10 OF THE MICE WE

6003
04:11:08,286 --> 04:11:09,421
INOCULATED, THIS WAS VERY

6004
04:11:09,487 --> 04:11:10,522
CONSISTENT, EVERY ONE OF THESE

6005
04:11:10,588 --> 04:11:12,090
MICE SHOWED UP, SHOWED UP

6006
04:11:12,157 --> 04:11:13,625
SOMEWHERE BETWEEN 30 AND 90% OF

6007
04:11:13,691 --> 04:11:16,661
ALL THE CLONES WE SEQUENCED, AND

6008
04:11:16,728 --> 04:11:19,431
THEN SOME OF THESE OTHER

6009
04:11:19,497 --> 04:11:20,732
MUTATIONS AS WELL AS -- THE

6010
04:11:20,799 --> 04:11:22,066
INTERESTING THING IS THE SILENT

6011
04:11:22,133 --> 04:11:23,401
MUTATIONS SHOWED UP IN WHAT ARE

6012
04:11:23,468 --> 04:11:26,438
CALLED AID HOT SPOTS, SO --

6013
04:11:26,504 --> 04:11:28,106
SITES OF MUTATION WHERE IT'S THE

6014
04:11:28,173 --> 04:11:29,207
NON-CODING MUTATIONS DID NOT

6015
04:11:29,274 --> 04:11:32,043
SHOW UP ON NID HOT SPOTS, IN

6016
04:11:32,110 --> 04:11:33,378
PARTICULAR, THESE TWO.

6017
04:11:33,445 --> 04:11:34,813
SO SOMEHOW OR ANOTHER, THE

6018
04:11:34,879 --> 04:11:35,880
IMMUNE SYSTEM HAD TO WORK HARDER

6019
04:11:35,947 --> 04:11:40,385
TO GET THERE.

6020
04:11:40,452 --> 04:11:41,586
LONG STORY SHORT, WE

6021
04:11:41,653 --> 04:11:43,421
CHARACTERIZE THESE MUTATIONS,

6022
04:11:43,488 --> 04:11:45,523
MANY SHOWED UP DIRECTLY IN THE

6023
04:11:45,590 --> 04:11:48,159
BINDING SITE.

6024
04:11:48,226 --> 04:11:53,364
WE DID DEVELOP A PANEL AND THIS

6025
04:11:53,431 --> 04:11:54,199
IS CONFUSING YOU HERE PAUSE THIS

6026
04:11:54,265 --> 04:11:55,834
OVER HERE IS ORIGINAL CD4,

6027
04:11:55,900 --> 04:11:56,968
THAT'S NOT WHAT WE STARTED WITH.

6028
04:11:57,035 --> 04:11:58,703
THIS IS THE CD4 WE STARTED WITH.

6029
04:11:58,770 --> 04:12:00,505
THIS IS AN IMPROVED CD4 WE'VE

6030
04:12:00,572 --> 04:12:02,006
BEEN WORKING WITH FOR SOME TIME,

6031
04:12:02,073 --> 04:12:05,176
AND THIS IS THE CONSEQUENCES OF

6032
04:12:05,243 --> 04:12:08,346
OUR VARIOUS CONSTRUCTS THAT HAD

6033
04:12:08,413 --> 04:12:10,682
THESE VARIOUS MUTATIONS AND

6034
04:12:10,748 --> 04:12:11,483
COMBINATIONS.

6035
04:12:11,549 --> 04:12:12,750
AGAIN, THIS MUTATION AND THIS

6036
04:12:12,817 --> 04:12:14,085
MUTATION ARE DOING ALL THE

6037
04:12:14,152 --> 04:12:16,154
LIFTING, REALLY.

6038
04:12:16,221 --> 04:12:17,255
AND THERE'S AN INTERESTING STORY

6039
04:12:17,322 --> 04:12:21,726
ABOUT THE FIRST ONE.

6040
04:12:21,793 --> 04:12:24,462
AGAIN SAME GAME, NO REAL CHANGE

6041
04:12:24,529 --> 04:12:25,430
IN POLYREACTIVITY.

6042
04:12:25,497 --> 04:12:26,998
TWO OUT OF THREE THAT WE

6043
04:12:27,065 --> 04:12:27,999
CHARACTERIZED IN VITRO RETAINED

6044
04:12:28,066 --> 04:12:30,401
THE HALF-LIFE OF OUR HALF-LIFE

6045
04:12:30,468 --> 04:12:31,269
IMPROVED CD4.

6046
04:12:31,336 --> 04:12:33,671
ONE DID NOT, AND THE ORIGINAL

6047
04:12:33,738 --> 04:12:37,709
CD4, WE KNEW TO BE A DISASTER.

6048
04:12:37,775 --> 04:12:40,345
SO THAT'S WHAT WE'VE DONE WITH

6049
04:12:40,411 --> 04:12:42,247
BIOLOGICS.

6050
04:12:42,313 --> 04:12:43,414
I'M GOING TO DO THIS VERY

6051
04:12:43,481 --> 04:12:47,018
QUICKLY NOW FOR VACCINES.

6052
04:12:47,085 --> 04:12:48,219
THOFS MORE DEVELOPED WORK.

6053
04:12:48,286 --> 04:12:49,454
THERE WILL BE SOME SPECULATION

6054
04:12:49,521 --> 04:12:51,890
HERE AND SOME PREACHING I THINK

6055
04:12:51,956 --> 04:12:52,490
TO SOME EXTENT.

6056
04:12:52,557 --> 04:12:54,592
SO THIS IS A GOOD PICTURE

6057
04:12:54,659 --> 04:12:56,995
PROVIDED BY DENNIS BURTON, WHO

6058
04:12:57,061 --> 04:12:59,397
GENERATED A LOT OF THE DATA

6059
04:12:59,464 --> 04:13:00,398
UNDERLYING THIS PICTURE, WHICH

6060
04:13:00,465 --> 04:13:02,033
IS THE MAIN NEUTRALIZING

6061
04:13:02,100 --> 04:13:03,268
EPITOPES, I WOULD PROBABLY ARGUE

6062
04:13:03,334 --> 04:13:03,935
THAT THE THREE MOST IMPORTANT

6063
04:13:04,002 --> 04:13:07,405
WERE THE CD4 BINDING SITE.

6064
04:13:07,472 --> 04:13:09,607
SURELY THE V3 GLYCAN, KIND OF A

6065
04:13:09,674 --> 04:13:11,976
SUBSTITUTE FOR THE CORECEPTOR IN

6066
04:13:12,043 --> 04:13:14,746
THE UNCD4 BOUND STATE AND THEN

6067
04:13:14,812 --> 04:13:16,080
THE APEX, AND WE CAN ARGUE ABOUT

6068
04:13:16,147 --> 04:13:17,916
WHETHER THESE ARE USEFUL OR

6069
04:13:17,982 --> 04:13:18,583
NON-USEFUL EPITOPES.

6070
04:13:18,650 --> 04:13:20,051
BUT WHAT I'M GOING TO TELL YOU

6071
04:13:20,118 --> 04:13:21,452
IS, WE'RE GOING TO FOCUS ON THE

6072
04:13:21,519 --> 04:13:22,620
APEX AND THE REASON WE'RE GOING

6073
04:13:22,687 --> 04:13:25,823
TO FOCUS ON THE APEX, THIS IS

6074
04:13:25,890 --> 04:13:27,292
PREACHING, THIS IS THE SHORTETH

6075
04:13:27,358 --> 04:13:29,427
PATH BETWEEN THE IMMUNE REP

6076
04:13:29,494 --> 04:13:31,195
REPERTOIRE, THE ANTIBODY

6077
04:13:31,262 --> 04:13:33,064
REPERTOIRE THAT'S IN EACH OF US,

6078
04:13:33,131 --> 04:13:34,232
AND REASONABLY GOOD PROTECTION

6079
04:13:34,299 --> 04:13:38,303
AGAINST THE VIRUS.

6080
04:13:38,369 --> 04:13:40,505
THAT'S PREACHING, THAT'S NOT

6081
04:13:40,572 --> 04:13:41,406
SCIENTIFICALLY STATING THAT.

6082
04:13:41,472 --> 04:13:43,174
BUT LET ME TELL YOU ABOUT THESE

6083
04:13:43,241 --> 04:13:44,142
ANTIBODIES AND TELL YOU WHY I

6084
04:13:44,208 --> 04:13:44,576
THINK THAT.

6085
04:13:44,642 --> 04:13:46,678
FIRST THING TO SAY IS THEY BIND

6086
04:13:46,744 --> 04:13:47,445
THE APEX REGION.

6087
04:13:47,512 --> 04:13:50,615
YOU ONLY NEED ONE TO BIND.

6088
04:13:50,682 --> 04:13:52,584
THEY BIND -- THEY INTERFACE AT

6089
04:13:52,650 --> 04:13:53,384
THE TOP.

6090
04:13:53,451 --> 04:13:59,691
LONG TYROSINE SULFATED H

6091
04:13:59,757 --> 04:14:00,391
CDR3s.

6092
04:14:00,458 --> 04:14:01,826
THEY'RE VERY POTENT, IN TIGHT

6093
04:14:01,893 --> 04:14:02,994
BECAUSE THEY NEUTRALIZE THE

6094
04:14:03,061 --> 04:14:04,762
ENTIRE SPIKE WITH ONE ANTIBODY

6095
04:14:04,829 --> 04:14:05,630
RATHER THAN MAYBE TWO OR THREE

6096
04:14:05,697 --> 04:14:07,065
FOR THE OTHER CLASSES OF

6097
04:14:07,131 --> 04:14:07,832
ANTIBODIES.

6098
04:14:07,899 --> 04:14:11,002
VERY LITTLE SOMATOHYPERMUTATION

6099
04:14:11,069 --> 04:14:13,071
IS NEEDED.

6100
04:14:13,137 --> 04:14:16,374
THAT'S IN STRONG CONTRAST, WHERE

6101
04:14:16,441 --> 04:14:18,009
A GOOD DEAL OF HEROIC CHANGES

6102
04:14:18,076 --> 04:14:21,212
ARE NECESSARY TO MAKE THESE

6103
04:14:21,279 --> 04:14:22,080
ANTIBODIES.

6104
04:14:22,146 --> 04:14:23,181
THESE ANTIBODIES ARE VERY

6105
04:14:23,247 --> 04:14:24,916
SIMILAR TO WHAT'S CIRCULATING IN

6106
04:14:24,983 --> 04:14:28,119
YOUR BODY RIGHT NOW.

6107
04:14:28,186 --> 04:14:31,789
SO LET ME -- THEY'RE THERE NOT

6108
04:14:31,856 --> 04:14:38,963
FOR THE RETHE EPITOPE ISRARELY D

6109
04:14:39,030 --> 04:14:40,064
INDIVIDUALS IN ITS WHOLE --

6110
04:14:40,131 --> 04:14:40,298
FORM.

6111
04:14:40,365 --> 04:14:41,933
SO THE GAIN IS TO FOCUS THE

6112
04:14:42,000 --> 04:14:43,601
IMMUNE SYSTEM IN ON THAT CLASS

6113
04:14:43,668 --> 04:14:44,569
OF ANTIBODIES.

6114
04:14:44,636 --> 04:14:47,972
SO NOW KNOWING THAT I'M SHORT OF

6115
04:14:48,039 --> 04:14:49,540
TIME, I'M GOING TO TELL YOU MY

6116
04:14:49,607 --> 04:14:50,241
PUNCH LINE FIRST.

6117
04:14:50,308 --> 04:14:51,909
THE SORT OF ORGANIZING

6118
04:14:51,976 --> 04:14:54,445
HYPOTHESIS THAT IS DRIVING OUR

6119
04:14:54,512 --> 04:14:55,980
CURRENT VACCINE WORK.

6120
04:14:56,047 --> 04:14:58,816
THE FIRST THING IS THAT WE

6121
04:14:58,883 --> 04:15:03,021
PUBLISHED RECENTLY THAT THE CDRS

6122
04:15:03,087 --> 04:15:04,122
SUFFICIENT TO DEVELOP A

6123
04:15:04,188 --> 04:15:06,057
PROTECTIVE RESPONSE.

6124
04:15:06,124 --> 04:15:09,594
SO THESE ANTIBODIES AND OF THEIR

6125
04:15:09,661 --> 04:15:12,430
PROGENITORS, THEIR PRESUMED

6126
04:15:12,497 --> 04:15:13,665
UNMUTATED PRECURSORS.

6127
04:15:13,731 --> 04:15:16,834
THIS MEANS TO ME THAT THE

6128
04:15:16,901 --> 04:15:18,369
PROBLEM WITH AN HIV VACCINE CAN

6129
04:15:18,436 --> 04:15:21,939
BE DISTILLED DOWN TO ELICITING

6130
04:15:22,006 --> 04:15:23,741
THESE 25 TO 30 AMINO ACID

6131
04:15:23,808 --> 04:15:24,742
SEQUENCES.

6132
04:15:24,809 --> 04:15:27,679
WE KNOW VERY MUCH ABOUT WHAT

6133
04:15:27,745 --> 04:15:29,447
THESE 25 TO 30 AMINO ACID

6134
04:15:29,514 --> 04:15:30,682
SEQUENCES SHOULD LOOK LIKE.

6135
04:15:30,748 --> 04:15:33,084
WE KNOW WHICH DIVERSITY CHAINS

6136
04:15:33,151 --> 04:15:34,385
THEY SHOULD COME FROM, THEY KNOW

6137
04:15:34,452 --> 04:15:37,055
HOW TO BE POSITIONED, WE KNOW

6138
04:15:37,121 --> 04:15:39,557
EXACTLY AND WE KNOW THEIR

6139
04:15:39,624 --> 04:15:39,824
FREQUENCY.

6140
04:15:39,891 --> 04:15:41,959
SO THIS IS GOOD, BECAUSE THESE

6141
04:15:42,026 --> 04:15:43,628
PRECURSORS AS WE DEFINED THEM UP

6142
04:15:43,695 --> 04:15:46,364
TO THIS POINT ARE VERY COMMON IN

6143
04:15:46,431 --> 04:15:47,532
US.

6144
04:15:47,598 --> 04:15:50,968
SECOND GOOD POINT.

6145
04:15:51,035 --> 04:15:56,908
CURRENT SOSIP TRANSAMERICA TRANC

6146
04:15:56,974 --> 04:16:00,411
VACCINES ARE CLOSE TO ELICITING

6147
04:16:00,478 --> 04:16:01,512
THESE.

6148
04:16:01,579 --> 04:16:04,348
THIRD, WE CAN BRING THE SOSIP

6149
04:16:04,415 --> 04:16:05,717
CLOSER TO OUR CURRENT REPERTOIRE

6150
04:16:05,783 --> 04:16:06,451
AND THEN OF COURSE MOVE THEM

6151
04:16:06,517 --> 04:16:08,519
WITH A MUCH SMALLER STEP THAN

6152
04:16:08,586 --> 04:16:10,655
FOR EXAMPLE THE CD4 BINDING SITE

6153
04:16:10,722 --> 04:16:12,390
TO WHERE THEY NEED TO BE TO MAKE

6154
04:16:12,457 --> 04:16:16,694
A NEUTRALIZING ANTIBODY.

6155
04:16:16,761 --> 04:16:17,562
OKAY.

6156
04:16:17,628 --> 04:16:19,964
LET'S SEE.

6157
04:16:20,031 --> 04:16:21,933
OKAY.

6158
04:16:21,999 --> 04:16:24,102
THIS IS BASICALLY TALKING ABOUT

6159
04:16:24,168 --> 04:16:25,336
HOW WE DEVELOPED OUR SYSTEM.

6160
04:16:25,403 --> 04:16:28,406
AGAIN WE'RE JUST CHANGING THE

6161
04:16:28,473 --> 04:16:30,475
CDR3s IN AN OTHERWISE KIE

6162
04:16:30,541 --> 04:16:32,577
VERSE BACKGROUND OF MURINE

6163
04:16:32,643 --> 04:16:33,010
VARIABLE CHAIN.

6164
04:16:33,077 --> 04:16:36,647
SO AGAIN, HUMAN CDR3s, MURINE

6165
04:16:36,714 --> 04:16:40,017
B CELLS, MURINE B CELL RECEPTOR,

6166
04:16:40,084 --> 04:16:40,685
MURINE B CELLS.

6167
04:16:40,752 --> 04:16:42,787
SO THE ONLY THING WE'RE

6168
04:16:42,854 --> 04:16:45,289
INTERDEUTING NOW IS JUST A CDR3.

6169
04:16:45,356 --> 04:16:46,457
THE CDR3 IS THERE.

6170
04:16:46,524 --> 04:16:47,692
AND THIS IS AN EXAMPLE.

6171
04:16:47,759 --> 04:16:51,095
SO NOW WE PUT IN THE

6172
04:16:51,162 --> 04:16:51,429
VRC2625CDR3.

6173
04:16:51,496 --> 04:16:56,234
IT'S A BIG LONG CDR3 --

6174
04:16:56,300 --> 04:16:58,870
SULFATES, INTO THE BACKGROUND OF

6175
04:16:58,936 --> 04:17:00,738
MURINE B CELLS AND THEN WE

6176
04:17:00,805 --> 04:17:01,072
IMMUNIZE.

6177
04:17:01,139 --> 04:17:04,475
THIS IS IMMUNIZATION WITH

6178
04:17:04,542 --> 04:17:05,109
PROTEIN.

6179
04:17:05,176 --> 04:17:07,779
AGAIN WHAT YOU CAN SEE IS WE DO

6180
04:17:07,845 --> 04:17:09,747
GET NEUTRALIZATION HERE.

6181
04:17:09,814 --> 04:17:12,717
AGAIN -- AND THIS POSITIVE

6182
04:17:12,784 --> 04:17:15,119
CONTROL IS 2-MICROGRAM PER ML

6183
04:17:15,186 --> 04:17:15,787
LEVEL HERE.

6184
04:17:15,853 --> 04:17:17,989
SO JUST FOR THE CVR3, WE CAN

6185
04:17:18,055 --> 04:17:20,324
DRIVE THAT TO A 2-MICROGRAM PER

6186
04:17:20,391 --> 04:17:24,896
ML LEVEL OF THIS VERY POTENT

6187
04:17:24,962 --> 04:17:25,396
ANTIBODY.

6188
04:17:25,463 --> 04:17:27,732
AS YOU WOULD EXPECT, IT'S A GOOD

6189
04:17:27,799 --> 04:17:29,333
DEAL OF HYPERSOMATIC MUTATION

6190
04:17:29,400 --> 04:17:31,135
WITHIN THE CDR3, AND WE KNEW

6191
04:17:31,202 --> 04:17:32,770
THIS WAS ACTUALLY A MUTATION

6192
04:17:32,837 --> 04:17:35,740
THAT EMERGED AND CHANGES THE

6193
04:17:35,807 --> 04:17:37,708
PROPERTY OF THE ANTIBODY SO IT'S

6194
04:17:37,775 --> 04:17:39,210
ACTUALLY -- THAN THE ORIGINAL

6195
04:17:39,277 --> 04:17:39,477
ANTIBODY.

6196
04:17:39,544 --> 04:17:42,213
SO SOME OF THESE CHANGES, WE'RE

6197
04:17:42,280 --> 04:17:43,548
AGAIN ABLE TO PLAY THE GAME OF

6198
04:17:43,614 --> 04:17:45,516
IMPROVING THE ANTIBODY, WHICH

6199
04:17:45,583 --> 04:17:48,486
DERIVES TO IN VIVO SELECTION.

6200
04:17:48,553 --> 04:17:49,787
BUT WHAT WAS IMPORTANT TO US, I

6201
04:17:49,854 --> 04:17:51,889
THINK, WAS THE IDEA THAT THE

6202
04:17:51,956 --> 04:17:53,191
UNDERLYING BACKGROUND OF

6203
04:17:53,257 --> 04:17:54,759
VARIABLE CHAINS THAT ARE BURYING

6204
04:17:54,826 --> 04:17:59,897
THE CDR3, THEY ARE VERY DIVERSE.

6205
04:17:59,964 --> 04:18:02,300
SO AFTER THIRD IMMUNIZATION, WE

6206
04:18:02,366 --> 04:18:03,968
GOT SOME THAT POPPED UP MORE

6207
04:18:04,035 --> 04:18:06,237
FREQUENTLY, BUT WE WERE ABLE

6208
04:18:06,304 --> 04:18:07,471
TO -- IN BOTH OF THE GERMINAL

6209
04:18:07,538 --> 04:18:10,875
CENTERS AND THE FULL PBMC, SEE A

6210
04:18:10,942 --> 04:18:12,577
LOT OF VARIABLE CHAINS PRESENTED

6211
04:18:12,643 --> 04:18:16,147
IN THE CDR3.

6212
04:18:16,214 --> 04:18:19,217
SO -- IT IS THE CDR3 AS IS

6213
04:18:19,283 --> 04:18:20,751
WELL-KNOWN FOR -- WE PLAY THIS

6214
04:18:20,818 --> 04:18:23,154
SAME GAME WITH OTHER CDR3s,

6215
04:18:23,221 --> 04:18:23,487
OKAY?

6216
04:18:23,554 --> 04:18:26,224
SO THESE ARE THE CDR3s OF TWO

6217
04:18:26,290 --> 04:18:28,993
WELL-KNOWN AND RELATED ANTIBODY,

6218
04:18:29,060 --> 04:18:32,697
PG9 AND PG16 AGAIN AT THIS

6219
04:18:32,763 --> 04:18:34,799
APACKS CLASS, AGAIN LONG,

6220
04:18:34,866 --> 04:18:36,968
HYDROGEN SULFATED.

6221
04:18:37,034 --> 04:18:40,705
THIS IS THE SAME ORIGINAL

6222
04:18:40,771 --> 04:18:42,907
ANTIBODY, BUT IT'S UNMUTATED

6223
04:18:42,974 --> 04:18:43,341
COMMON ANCESTOR.

6224
04:18:43,407 --> 04:18:46,077
THE WAY IT WAS CALCULATED TO

6225
04:18:46,143 --> 04:18:49,080
EMERGE DURING THE -- BE ABLE TO

6226
04:18:49,146 --> 04:18:51,382
DRIVE UP ANTIBODY RESPONSES

6227
04:18:51,449 --> 04:18:51,816
THERE.

6228
04:18:51,883 --> 04:18:53,050
BY THE WAY, THESE CONTROLS ARE

6229
04:18:53,117 --> 04:18:57,321
COMING UP BECAUSE THAT'S AN MRNA

6230
04:18:57,388 --> 04:19:02,994
VACCINE, NOT A PROTEIN VACCINE.

6231
04:19:03,060 --> 04:19:04,195
BUT ANYWAY, BOTTOM LINE IS,

6232
04:19:04,262 --> 04:19:06,464
WE'RE VERY INTERESTED IN A

6233
04:19:06,530 --> 04:19:09,767
SUBSET OF APEX ANTIBODIES, IN

6234
04:19:09,834 --> 04:19:13,905
PARTICULAR THIS DOUBLE TYROSINE

6235
04:19:13,971 --> 04:19:16,908
YYDF MOTIF.

6236
04:19:16,974 --> 04:19:18,209
EVERYTHING WE'VE BEEN ABLE TO DO

6237
04:19:18,276 --> 04:19:20,077
THAT BINDS THE SOSIP THAT WE'VE

6238
04:19:20,144 --> 04:19:20,845
BEEN WORKING WITH.

6239
04:19:20,912 --> 04:19:22,079
AND THIS IS JUST TO SHOW YOU

6240
04:19:22,146 --> 04:19:22,747
THAT.

6241
04:19:22,813 --> 04:19:25,816
AND THEN THE ORIGIN OF THAT.

6242
04:19:25,883 --> 04:19:28,986
WHICH IS THIS PARTICULAR

6243
04:19:29,053 --> 04:19:33,257
DIVERSITY CHAIN, 1 IN 24 THAT

6244
04:19:33,324 --> 04:19:34,825
WE'RE CARRYING IN OUR BODY,

6245
04:19:34,892 --> 04:19:36,928
WE'VE ALL GOT THIS DIVERSITY

6246
04:19:36,994 --> 04:19:38,095
CHAIN, READ IT IN DOM NAPT

6247
04:19:38,162 --> 04:19:41,565
FRAMEDOMINANTFRAME, THIS IS IT,S

6248
04:19:41,632 --> 04:19:45,136
WHAT WE THINK WE NEED TO ELICIT

6249
04:19:45,202 --> 04:19:49,307
WITH OUR NEW ANTIGENS.

6250
04:19:49,373 --> 04:19:51,108
ONE QUESTION COULD BE -- AND

6251
04:19:51,175 --> 04:19:52,310
YOUR FINAL SLIDE, WHAT IS THE

6252
04:19:52,376 --> 04:19:55,246
FREQUENCY OF THESE ANTIBODIES IN

6253
04:19:55,313 --> 04:19:57,348
UNAFFECTED PATIENTS.

6254
04:19:57,415 --> 04:19:59,417
REPERTOIRES OF TIME -- BOTTOM

6255
04:19:59,483 --> 04:20:02,153
LINE, THE YYDF MOTIF SHOWS UP IN

6256
04:20:02,219 --> 04:20:04,055
ABOUT 1 OF 2,000 OF YOUR

6257
04:20:04,121 --> 04:20:04,922
ANTIBODIES, AND THEN IF YOU

6258
04:20:04,989 --> 04:20:05,923
BROADEN THAT A LITTLE BIT, YOU

6259
04:20:05,990 --> 04:20:08,592
CAN ADD SOME MORE IN THERE, BUT

6260
04:20:08,659 --> 04:20:11,662
THAT'S THE BOTTOM LINE, AND SO

6261
04:20:11,729 --> 04:20:12,563
WHAT'S NEXT FOR US?

6262
04:20:12,630 --> 04:20:15,032
WE WANT TO KNOW CAN THESE -- CAN

6263
04:20:15,099 --> 04:20:16,934
MODIFIED SOSIPs, THE ONES

6264
04:20:17,001 --> 04:20:22,406
WE'RE SELECTING FOR, ENRICH FOR

6265
04:20:22,473 --> 04:20:23,774
BCRs FROM PROPERTIES FROM

6266
04:20:23,841 --> 04:20:23,975
PBMC.

6267
04:20:24,041 --> 04:20:26,043
CAN I JUST SORT OUT THE

6268
04:20:26,110 --> 04:20:27,178
ANTIBODIES THAT I CARED ABOUT

6269
04:20:27,244 --> 04:20:29,914
USING THE SOSIPs THAT I'M

6270
04:20:29,981 --> 04:20:30,147
MAKING.

6271
04:20:30,214 --> 04:20:32,350
NOW THE SECOND THING IS, CAN I

6272
04:20:32,416 --> 04:20:35,720
MAKE A NEUTRALIZING ANTIBODY

6273
04:20:35,786 --> 04:20:36,754
FROM USING THE SYSTEM I JUST

6274
04:20:36,821 --> 04:20:38,856
SHOWED YOU, WHERE I PUT IN THE

6275
04:20:38,923 --> 04:20:40,024
HEAVY AND THE LIGHT CHAIN.

6276
04:20:40,091 --> 04:20:42,159
CAN I TURN AN ANTIBODY THAT I

6277
04:20:42,226 --> 04:20:44,128
PULL OUT OF A REGULAR HIV

6278
04:20:44,195 --> 04:20:47,431
NEGATIVE PERSON AND TURN IT INTO

6279
04:20:47,498 --> 04:20:48,866
A NEUTRALIZING ANTIBODY.

6280
04:20:48,933 --> 04:20:50,267
AND CAN WE DO SOMETHING

6281
04:20:50,334 --> 04:20:52,036
ANALOGOUS IN A NON-HUMAN PRIMATE

6282
04:20:52,103 --> 04:20:55,906
WITH A RELATED DIVERSITY CHAIN.

6283
04:20:55,973 --> 04:20:58,409
SO THOSE ARE -- AND THEN SIMPLY

6284
04:20:58,476 --> 04:21:01,379
TO ACKNOWLEDGE THE PEOPLE WHO

6285
04:21:01,445 --> 04:21:05,783
HAVE BEEN INVOLVED IN THIS.

6286
04:21:05,850 --> 04:21:07,985
BASICALLY INVENTED -- EDITING.

6287
04:21:08,052 --> 04:21:08,853
THERE SHE IS THERE.

6288
04:21:08,919 --> 04:21:10,721
AND THEN OUR VACCINE WORK IS

6289
04:21:10,788 --> 04:21:13,624
BEING LED BY THIS GREAT TEAM AT

6290
04:21:13,691 --> 04:21:16,961
THE BROAD, COMPOSED OF -- WITH

6291
04:21:17,028 --> 04:21:18,062
HELP FROM SOME OF THESE OTHER

6292
04:21:18,129 --> 04:21:19,530
PEOPLE TOO.

6293
04:21:19,597 --> 04:21:20,865
THANKS.

6294
04:21:20,931 --> 04:21:27,004
[APPLAUSE]

6295
04:21:27,071 --> 04:21:37,314
>> QUESTIONS?

6296
04:21:40,251 --> 04:21:41,318
OKAY.

6297
04:21:41,385 --> 04:21:43,888
WE'RE GOING TO TAKE A BREAK

6298
04:21:43,954 --> 04:21:47,391
UNTIL 3:50.

6299
04:21:47,458 --> 04:21:50,895
POSTERS ARE OUT THERE.

6300
04:21:50,961 --> 04:21:52,029
SEE THE WORK, AND PLEASE COME

6301
04:21:52,096 --> 04:21:56,901
BACK.

6302
04:21:56,967 --> 04:21:58,736
>> ALL RIGHT, LET'S GET STARTED

6303
04:21:58,803 --> 04:22:01,238
AGAIN.

6304
04:22:01,305 --> 04:22:02,773
WE'RE COMING IN THE HOME STRETCH

6305
04:22:02,840 --> 04:22:03,774
HERE, TWO MORE TALKS.

6306
04:22:03,841 --> 04:22:08,179
SO OUR NEXT SPEAKER IS DAVID,

6307
04:22:08,245 --> 04:22:12,016
WHO RECEIVED HIS PH.D. IN

6308
04:22:12,083 --> 04:22:14,485
MOLECULAR BIOLOGY AT UW-MADISON.

6309
04:22:14,552 --> 04:22:15,519
DAVE AND I WERE GRADUATE

6310
04:22:15,586 --> 04:22:17,655
STUDENTS TOGETHER IN THAT LAB.

6311
04:22:17,721 --> 04:22:19,323
HOW MANY DECADES AGO.

6312
04:22:19,390 --> 04:22:21,058
LOST TRACK.

6313
04:22:21,125 --> 04:22:22,493
DAVE LOOKS A LOT YOUNGER THAN I

6314
04:22:22,560 --> 04:22:25,596
DO, BUT ANYWAY.

6315
04:22:25,663 --> 04:22:28,099
HE THEN CAME TO THE NCI

6316
04:22:28,165 --> 04:22:29,633
FREDERICK TO DO A POSTDOC WITH

6317
04:22:29,700 --> 04:22:32,937
NANCY JENKINS AND NEIL COPELAND.

6318
04:22:33,003 --> 04:22:34,605
IN 1996, HE WAS RECRUITED TO THE

6319
04:22:34,672 --> 04:22:35,372
FACULTY OF UNIVERSITY OF

6320
04:22:35,439 --> 04:22:36,507
MINNESOTA.

6321
04:22:36,574 --> 04:22:40,311
AMONG MANY OTHER THINGS, DAVE IS

6322
04:22:40,377 --> 04:22:42,746
WORKING TO EXPLORE MUTAGENESIS

6323
04:22:42,813 --> 04:22:44,115
TO IDENTIFY AND UNDERSTAND GENES

6324
04:22:44,181 --> 04:22:46,150
AND PATHWAYS THAT GOVERN CANCER

6325
04:22:46,217 --> 04:22:46,784
CELL BEHAVIOR.

6326
04:22:46,851 --> 04:22:49,453
HIS GROUP PIONEERED THE USE OF

6327
04:22:49,520 --> 04:22:52,089
AN ACTIVE SYSTEM KNOWN AS

6328
04:22:52,156 --> 04:22:55,126
SLEEPING BEAUTY FOR --

6329
04:22:55,192 --> 04:22:55,793
MUTAGENESIS.

6330
04:22:55,860 --> 04:22:58,262
HIS TALK IS ENTITLED THE ENEMY

6331
04:22:58,329 --> 04:22:59,930
WITHIN, TURNING TRANSPOSONS FROM

6332
04:22:59,997 --> 04:23:00,531
FOES TO FRIENDS.

6333
04:23:00,598 --> 04:23:01,565
THANK YOU.

6334
04:23:01,632 --> 04:23:05,269
[APPLAUSE]

6335
04:23:05,336 --> 04:23:05,936
>> THANK YOU.

6336
04:23:06,003 --> 04:23:07,805
IT'S GREAT TO BE BACK FOR

6337
04:23:07,872 --> 04:23:10,241
FREDERICK, WHICH I CAN CALL HOME

6338
04:23:10,307 --> 04:23:12,476
FOR FIVE YEARS AS I WAS HERE AS

6339
04:23:12,543 --> 04:23:14,011
A POSTDOC TORE FELLOW WITH NEIL

6340
04:23:14,078 --> 04:23:14,578
AND NANCY.

6341
04:23:14,645 --> 04:23:18,115
SO THESE ARE MY DISCLOSURES.

6342
04:23:18,182 --> 04:23:20,050
SOME OF THE WORK I'LL DISCUSS IS

6343
04:23:20,117 --> 04:23:21,485
FUNDED BY GENENTECH.

6344
04:23:21,552 --> 04:23:23,554
I'M GOING TO TALK ABOUT

6345
04:23:23,621 --> 04:23:25,556
TRANSPOSONS IN HUMAN BIOLOGY, IN

6346
04:23:25,623 --> 04:23:27,958
PARTICULAR HOW WE USE THEM AS A

6347
04:23:28,025 --> 04:23:29,293
TOOL IN CANCER AND IF THERE'S

6348
04:23:29,360 --> 04:23:31,061
TIME, I'LL TALK ABOUT IT. CELL

6349
04:23:31,128 --> 04:23:32,596
PHENOTYPE, WHICH IS SOMETHING

6350
04:23:32,663 --> 04:23:35,132
NEW WE'RE DOING WITH SLEEPING

6351
04:23:35,199 --> 04:23:37,034
BEAUTY TRANSPOSON MUTAGENESIS.

6352
04:23:37,101 --> 04:23:38,235
SO EVERYONE HAS BEEN TALKING

6353
04:23:38,302 --> 04:23:38,569
ABOUT VIRUSES.

6354
04:23:38,636 --> 04:23:40,237
I'M GOING TO TALK ABOUT

6355
04:23:40,304 --> 04:23:41,372
TRANSPOSON, BUT WHAT WE'RE DOING

6356
04:23:41,438 --> 04:23:45,075
WITH TRANSPOSONS HAS REALLY BEEN

6357
04:23:45,142 --> 04:23:46,177
INSPIRED BY PRIOR WORK WITH

6358
04:23:46,243 --> 04:23:47,278
VIRUS, I WOULD SAY.

6359
04:23:47,344 --> 04:23:49,180
SO TRANSPOSONS ARE TRANS --

6360
04:23:49,246 --> 04:23:50,447
TRANS POE SAL ELEMENTS ARE

6361
04:23:50,514 --> 04:23:51,916
SEQUENCES OF DNA THAT CAN JUMP

6362
04:23:51,982 --> 04:23:53,017
FROM ONE PLACE TO ANOTHER WITHIN

6363
04:23:53,083 --> 04:23:56,020
A CELL, SO THEY'RE CALLED

6364
04:23:56,086 --> 04:23:57,655
JUMPING GENES OR MOBILE GENETIC

6365
04:23:57,721 --> 04:23:58,422
ELEMENTS.

6366
04:23:58,489 --> 04:24:01,058
BASICALLY THERE'S TWO TYPES.

6367
04:24:01,125 --> 04:24:04,562
CLASS 1 THAT MOVES TO AN --

6368
04:24:04,628 --> 04:24:06,797
INTERMEDIATE, AND CLASS II,

6369
04:24:06,864 --> 04:24:07,464
PHYSICALLY MOVED FROM ONE

6370
04:24:07,531 --> 04:24:10,868
LOCATION TO ANOTHER IN THE

6371
04:24:10,935 --> 04:24:12,203
TRANSPOSITION PROCESS.

6372
04:24:12,269 --> 04:24:14,471
USUALLY THEY'LL EXPRESS THE

6373
04:24:14,538 --> 04:24:15,039
PROTEINS NECESSARY FOR

6374
04:24:15,105 --> 04:24:15,773
MOBILIZATION.

6375
04:24:15,839 --> 04:24:19,777
SO FOR EXAMPLE, TRANSPOSONS WERE

6376
04:24:19,843 --> 04:24:21,946
DEVELOPED IN 1952, WHICH IS

6377
04:24:22,012 --> 04:24:24,181
BEFORE THE STRUCTURE OF DNA WAS

6378
04:24:24,248 --> 04:24:25,282
KNOWN, SO HOW DID SHE DO THAT?

6379
04:24:25,349 --> 04:24:29,420
SHE SHOWED USING GENETIC MEANS

6380
04:24:29,486 --> 04:24:31,989
THAT A GENE SHE HAD DEFINED

6381
04:24:32,056 --> 04:24:33,290
WHICH TURNED OUT TO BE A

6382
04:24:33,357 --> 04:24:34,425
TRANSPOSON COULD CHANGE POSITION

6383
04:24:34,491 --> 04:24:36,126
WITHIN A SINGLE GENERATION, AND

6384
04:24:36,193 --> 04:24:37,828
SHE RECEIVED THE NOBEL PRIZE FOR

6385
04:24:37,895 --> 04:24:41,432
THAT IN 1983.

6386
04:24:41,498 --> 04:24:42,967
BUT TRANSPOSONS ACTUALLY GO BACK

6387
04:24:43,033 --> 04:24:45,436
TO THE BEGINNING OF MODERN

6388
04:24:45,502 --> 04:24:46,003
GENETICS.

6389
04:24:46,070 --> 04:24:47,972
-- NOW KNOWN TO BE CAUSED BY A

6390
04:24:48,038 --> 04:24:53,043
TRANSPOSON INSERTION, ENCODING

6391
04:24:53,110 --> 04:24:54,011
STARCH -- ENZYME.

6392
04:24:54,078 --> 04:24:54,979
TRANSPOSONS ARE EVERYWHERE, SO

6393
04:24:55,045 --> 04:24:56,313
THERE'S AN UNCOUNTED NUMBER OF

6394
04:24:56,380 --> 04:24:56,680
THEM.

6395
04:24:56,747 --> 04:24:59,283
THEY'RE FOUND IN NEARLY ALL

6396
04:24:59,350 --> 04:24:59,717
GENOMES.

6397
04:24:59,783 --> 04:25:01,051
THEY HAVE INTERESTING DIVERSE

6398
04:25:01,118 --> 04:25:03,954
MODES OF REPLICATION, AND

6399
04:25:04,021 --> 04:25:05,356
THEY'RE A SOURCE OF USEFUL

6400
04:25:05,422 --> 04:25:08,325
TOOLS.

6401
04:25:08,392 --> 04:25:09,426
THE HUMAN GENOME ISN'T ANY

6402
04:25:09,493 --> 04:25:10,261
DIFFERENT.

6403
04:25:10,327 --> 04:25:12,296
IT'S ACTUALLY ABOUT 45% COMPOSED

6404
04:25:12,363 --> 04:25:13,631
OF TRANSPOSABLE ELEMENTS.

6405
04:25:13,697 --> 04:25:17,568
THE VAST MAJORITY OF THESE ARE

6406
04:25:17,635 --> 04:25:19,370
INACTIVE FOSSIL REMNANTS

6407
04:25:19,436 --> 04:25:22,206
ALTHOUGH IN ALL PEOPLE, THEY'RE

6408
04:25:22,273 --> 04:25:26,677
STILL UNDERGOING TRANSPOSITION.

6409
04:25:26,744 --> 04:25:28,078
TRANSPOSONS HAVE HAD A MASSIVE

6410
04:25:28,145 --> 04:25:29,580
INFLUENCE ON OUR EVOLUTIONARY

6411
04:25:29,647 --> 04:25:31,415
HISTORY, SO MANY SEQUENCES HAVE

6412
04:25:31,482 --> 04:25:33,083
BEEN DOMESTICATED FOR USE BY

6413
04:25:33,150 --> 04:25:35,185
THEIR HOST SPECIES.

6414
04:25:35,252 --> 04:25:38,155
ONE FAMOUS COMPACT IS THE RAD

6415
04:25:38,222 --> 04:25:40,424
1 AND 2 ENVIEMS INVOLVED IN

6416
04:25:40,491 --> 04:25:42,326
RECOMBINATION, ACTUALLY DERIVED

6417
04:25:42,393 --> 04:25:46,363
FROM ANCIENT TRANSPOSES.

6418
04:25:46,430 --> 04:25:48,265
-- CAN ALSO BE DOMESTICATED FOR

6419
04:25:48,332 --> 04:25:51,368
USE OF REGULATORY ELEMENTS.

6420
04:25:51,435 --> 04:25:51,535
IN

6421
04:25:51,602 --> 04:25:55,306
GENE EXPRESSION.

6422
04:25:55,372 --> 04:25:56,774
BUT THEY CAN ALSO CAUSE DISEASE.

6423
04:25:56,840 --> 04:25:58,642
SO GERMLINE AND SOMATIC CELERY

6424
04:25:58,709 --> 04:26:00,044
ARRANGEMENTS, DELETIONS AND

6425
04:26:00,110 --> 04:26:04,548
INSERTIONS, AND IT'S NOW KNOWN

6426
04:26:04,615 --> 04:26:07,651
THAT CRYPTIC PROMOTERS BECOME

6427
04:26:07,718 --> 04:26:11,288
ACTIVATED.

6428
04:26:11,355 --> 04:26:13,791
THESE CRYPTIC PROMOTERS BECOME

6429
04:26:13,857 --> 04:26:14,925
ACTIVATED DURING CANCER

6430
04:26:14,992 --> 04:26:16,026
DEVELOPMENT AND DRIVE EXPRESSION

6431
04:26:16,093 --> 04:26:19,196
OF NOVEL TRANSCRIPTS ENCODING

6432
04:26:19,263 --> 04:26:21,165
NEW PROTEIN ISOFORMS THAT CAN

6433
04:26:21,231 --> 04:26:22,800
DRIVE CANCER.

6434
04:26:22,866 --> 04:26:23,734
AND IT WAS OBSERVATIONS LIKE

6435
04:26:23,801 --> 04:26:25,969
THIS THAT MOTIVATED ME TO LOOK

6436
04:26:26,036 --> 04:26:27,771
TO TRANSPOSONS AS TOOLS FOR

6437
04:26:27,838 --> 04:26:29,907
MAMMALIAN GENETICS, AND SINCE I

6438
04:26:29,973 --> 04:26:32,509
WAS IN NEIL AND NANCY'S LAB HERE

6439
04:26:32,576 --> 04:26:33,644
IN FREDERICK, I WAS ALWAYS

6440
04:26:33,711 --> 04:26:36,413
INTERESTED IN THE IDEA OF DOING

6441
04:26:36,480 --> 04:26:37,381
FORWARD GENETICS IN THE MOUSE

6442
04:26:37,448 --> 04:26:37,948
MODEL.

6443
04:26:38,015 --> 04:26:40,150
SO REVERSE -- THIS IS IN

6444
04:26:40,217 --> 04:26:41,485
CONTRAST TO REVERSE GENETICS,

6445
04:26:41,552 --> 04:26:43,120
WHERE YOU START WITH A GENE AND

6446
04:26:43,187 --> 04:26:44,988
YOU ALTER IT AND SEE WHAT

6447
04:26:45,055 --> 04:26:46,890
PHENOTYPE YOU'LL GET, IN FORWARD

6448
04:26:46,957 --> 04:26:49,426
GENETICS, YOU USE RANDOM

6449
04:26:49,493 --> 04:26:51,195
MUTAGENESIS TO ISOLATE CELLS OR

6450
04:26:51,261 --> 04:26:52,496
ORGANISMS THAT HAVE A PHENOTYPE

6451
04:26:52,563 --> 04:26:54,732
YOU'RE INTERESTED IN AND THEN

6452
04:26:54,798 --> 04:26:56,266
YOU FIGURE OUT WHAT GENE GOT

6453
04:26:56,333 --> 04:26:57,334
ALTERED IN THE PROCESS.

6454
04:26:57,401 --> 04:27:00,237
AND SO THAT WAS REALLY THE

6455
04:27:00,304 --> 04:27:01,972
MOTIVATION FOR DEVELOPING

6456
04:27:02,039 --> 04:27:06,477
TRANSPOSON MUTAGENESIS IN MICE.

6457
04:27:06,543 --> 04:27:08,178
MORE SO ALSO WAS THE STUDY OF

6458
04:27:08,245 --> 04:27:11,014
SLOW TRANSFORMING RETROVIRUSES.

6459
04:27:11,081 --> 04:27:13,117
WHEN I WAS IN NEIL AND NANCY'S

6460
04:27:13,183 --> 04:27:15,219
LAB, THAT'S WHAT I WAS WORKING

6461
04:27:15,285 --> 04:27:15,386
ON.

6462
04:27:15,452 --> 04:27:20,691
I WANTED, WHEN STA -- THAT WOULE

6463
04:27:20,758 --> 04:27:24,995
SIMILAR TO HUMAN TE TUMORS BUT

6464
04:27:25,062 --> 04:27:25,996
ALTERED DURING TUMOR

6465
04:27:26,063 --> 04:27:26,630
DEVELOPMENT.

6466
04:27:26,697 --> 04:27:27,564
THE EXPERIENCE I HAD WORKING

6467
04:27:27,631 --> 04:27:30,300
WITH NEIL AND NANCY WAS GREAT,

6468
04:27:30,367 --> 04:27:36,407
BECAUSE WORKING WITH OTHERS, THE

6469
04:27:36,473 --> 04:27:37,808
THREE OF US FOUND SOME REALLY

6470
04:27:37,875 --> 04:27:38,776
THINGS THAT I THOUGHT WERE

6471
04:27:38,842 --> 04:27:41,779
REALLY COOL, IN TERMS OF ACUTE

6472
04:27:41,845 --> 04:27:48,352
MYELOID LOU KEEM LEUKEMIA INDUCA

6473
04:27:48,419 --> 04:27:51,422
RETROVIRUS, WE FOUND THAT HOXA

6474
04:27:51,488 --> 04:27:55,225
GENES -- IF HUMAN HOXA-9 GENE

6475
04:27:55,292 --> 04:27:58,162
WAS ACTIVATED BY FUSIONS TO A

6476
04:27:58,228 --> 04:28:05,903
NUCLEAR PORIN PROTEIN GENE TO

6477
04:28:05,969 --> 04:28:07,971
CAUSE LO LEUKEMIA.

6478
04:28:08,038 --> 04:28:08,972
WE THOUGHT WOULDN'T IT BE

6479
04:28:09,039 --> 04:28:10,207
AWESOME IF WE COULD DO THE SAME

6480
04:28:10,274 --> 04:28:11,742
THING BUT FOR OTHER TISSUES?

6481
04:28:11,809 --> 04:28:14,411
THE PROBLEM WITH RETROVIRUS IS

6482
04:28:14,478 --> 04:28:18,916
WE HAVE STUDIES -- FOR MAMMARY

6483
04:28:18,982 --> 04:28:21,084
TUMORS, BUT THESE VIRUSES DON'T

6484
04:28:21,151 --> 04:28:24,321
REPLICATE WELL AND INFECT POORLY

6485
04:28:24,388 --> 04:28:26,156
REPLICATING TISSUES VERY WELL

6486
04:28:26,223 --> 04:28:28,158
THAT ARE HOSTING CELL TYPE

6487
04:28:28,225 --> 04:28:29,092
RESTRICTIONS AND THEY ALSO HAVE

6488
04:28:29,159 --> 04:28:30,727
VERY BIASED INSERTION

6489
04:28:30,794 --> 04:28:31,061
PREFERENCE.

6490
04:28:31,128 --> 04:28:32,396
SO THIS IS WHY I STARTED TO

6491
04:28:32,463 --> 04:28:34,798
THINK ABOUT OTHER OPTIONS, AND

6492
04:28:34,865 --> 04:28:36,600
IN PARTICULAR, TRANSPOSONS.

6493
04:28:36,667 --> 04:28:38,769
NOW SOMETIMES IN SCIENCE YOU

6494
04:28:38,836 --> 04:28:40,337
JUST GET LUCKY, SO I RETURNED TO

6495
04:28:40,404 --> 04:28:41,872
MINNESOTA WHERE I'M FROM, AND I

6496
04:28:41,939 --> 04:28:45,409
STARTED MY LAB, AND I WAS GOING

6497
04:28:45,476 --> 04:28:48,078
FOR A WALK WITH ANOTHER

6498
04:28:48,145 --> 04:28:49,046
PROFESSOR, PERIHACKETT, AND HE

6499
04:28:49,112 --> 04:28:52,683
TOLD ME ABOUT THE PAPER THAT HE

6500
04:28:52,749 --> 04:28:55,519
HAD UNDER REVIEW AT CELL THAT

6501
04:28:55,586 --> 04:28:57,321
DESCRIBED SLEEPING BEAUTY, WHICH

6502
04:28:57,387 --> 04:29:00,591
PAVED THE WAY FOR

6503
04:29:00,657 --> 04:29:01,492
TRANSPOSON-BASED TOOLS.

6504
04:29:01,558 --> 04:29:02,960
THEY CALL IT SLEEPING BEAUTY

6505
04:29:03,026 --> 04:29:04,495
BECAUSE HE AND THE PEOPLE IN HIS

6506
04:29:04,561 --> 04:29:06,997
LAB CLONED A BUNCH OF COPIES OF

6507
04:29:07,064 --> 04:29:10,434
A TC1 TRANSPOSEASE FROM

6508
04:29:10,501 --> 04:29:11,768
DIFFERENT SPECIES OF FISH.

6509
04:29:11,835 --> 04:29:12,970
THEY DOESN'T KOANT FIND ANY

6510
04:29:13,036 --> 04:29:14,371
ACTIVE VERSIONS BUT THEY LINED

6511
04:29:14,438 --> 04:29:17,708
UP ALL THE INACTIVE COPIES AND

6512
04:29:17,774 --> 04:29:19,643
THEY DEDUCED THE SEQUENCE, IT

6513
04:29:19,710 --> 04:29:21,211
MUST HAVE BEEN ACTIVE MILLIONS

6514
04:29:21,278 --> 04:29:23,914
OF YEARS AGO, IN ANCESTORS TO

6515
04:29:23,981 --> 04:29:25,115
THESE FISH AND THEY FIXED ALL

6516
04:29:25,182 --> 04:29:26,783
THE MUTATIONS THAT OCCURRED AND

6517
04:29:26,850 --> 04:29:28,785
THEY GOT, IN THE END, AN EB SIEM

6518
04:29:28,852 --> 04:29:31,388
THEY CALLED SB10 WHICH WOULD

6519
04:29:31,455 --> 04:29:32,856
CATALYZE THE CUT AND PASTE

6520
04:29:32,923 --> 04:29:33,123
REACTION.

6521
04:29:33,190 --> 04:29:37,194
SO IT WAS THE FIRST VER --

6522
04:29:37,261 --> 04:29:38,695
ALTHOUGH MANY HAVE BEEN FOUND

6523
04:29:38,762 --> 04:29:42,032
SINCE THEN OR CREATED.

6524
04:29:42,099 --> 04:29:44,501
I STARTED WORKING WITH PERIAS

6525
04:29:44,568 --> 04:29:48,071
WELL AS STEVE AND SCOTT OVER

6526
04:29:48,138 --> 04:29:50,207
THERE ON KIND OF IMPROVING THE

6527
04:29:50,274 --> 04:29:51,308
SLEEPING BEAUTY SYSTEM AND USING

6528
04:29:51,375 --> 04:29:56,346
IT FOR A VARIETY OF THINGS.

6529
04:29:56,413 --> 04:29:58,582
SO YOU CAN THINK OF IT AS A

6530
04:29:58,649 --> 04:30:00,984
TWO-PART SYSTEM, THE TRANS POE

6531
04:30:01,051 --> 04:30:04,421
SAYS AND TRANSPOSON VECTOR THAT

6532
04:30:04,488 --> 04:30:07,291
YOU PROVIDE TO A CELL, FLANKED

6533
04:30:07,357 --> 04:30:09,693
BY REPEATS THAT CAN BE BOUND BY

6534
04:30:09,760 --> 04:30:12,062
THE TRANSPOSE ACE, IT EXCISING

6535
04:30:12,129 --> 04:30:17,901
FROM THE DONOR LOCUS, THAT TA IS

6536
04:30:17,968 --> 04:30:19,403
DUPLICATED, EXCISION SITE IS

6537
04:30:19,469 --> 04:30:21,705
REPAIRED BY THE HOST SELL

6538
04:30:21,772 --> 04:30:24,942
MACHINERY.

6539
04:30:25,008 --> 04:30:26,577
SO WHAT CAN YOU DO WITH IT?

6540
04:30:26,643 --> 04:30:27,778
YOU CAN DELIVER -- TO CELLS OR

6541
04:30:27,844 --> 04:30:31,915
YOU CAN USE TO DAMAGE CELLS BY

6542
04:30:31,982 --> 04:30:33,216
INSERTIONAL MUTAGENESIS, SO TWO

6543
04:30:33,283 --> 04:30:33,817
VERY DIFFERENT THINGS.

6544
04:30:33,884 --> 04:30:36,620
YOU CAN ALSO IMAGINE SEPARATING

6545
04:30:36,687 --> 04:30:39,189
THOSE INTO -- SO FOR EXAMPLE, WE

6546
04:30:39,256 --> 04:30:40,624
SHOWED YOU IT COULD BE USED TO

6547
04:30:40,691 --> 04:30:43,260
ENHANCE THE WAY THE GERMLINE

6548
04:30:43,327 --> 04:30:45,596
TRANS GENESIS DRAMATICALLY.

6549
04:30:45,662 --> 04:30:47,397
CAN YOU ALSO DELIVER GENES TO

6550
04:30:47,464 --> 04:30:48,932
SOMATIC CELLS FOR LONG TERM GENE

6551
04:30:48,999 --> 04:30:52,302
TRANSFER AND EXPRESSION AND --

6552
04:30:52,369 --> 04:30:53,770
GENE THERAPY, FOR EXAMPLE, AND

6553
04:30:53,837 --> 04:30:55,205
SLEEPING BEAUTY HAS BEEN USED TO

6554
04:30:55,272 --> 04:30:56,740
DELIVER CHIMERIC ANTIGEN

6555
04:30:56,807 --> 04:30:58,475
RECEPTOR TRANS GENES TO HUMAN T

6556
04:30:58,542 --> 04:31:02,479
CELLS IN CLINICAL TRIALS, SO

6557
04:31:02,546 --> 04:31:03,480
THAT'S SOME THINGS YOU COULD DO

6558
04:31:03,547 --> 04:31:05,449
WITH IT.

6559
04:31:05,515 --> 04:31:06,783
WE WERE MORE INTERESTED IN USING

6560
04:31:06,850 --> 04:31:09,920
IT AS A GENETIC TOOL FOR FORWARD

6561
04:31:09,987 --> 04:31:11,622
GENETICS, SO WE SHOWED WE COULD

6562
04:31:11,688 --> 04:31:13,323
ACHIEVE GERMLINE MUTAGENESIS AND

6563
04:31:13,390 --> 04:31:15,859
CREATE MICE WITH HERITABLE

6564
04:31:15,926 --> 04:31:17,194
MUTATIONS, BUT MOST OF OUR WORK

6565
04:31:17,260 --> 04:31:20,397
HAS BEEN TO USE THE TRANSPOSON

6566
04:31:20,464 --> 04:31:21,598
TO -- BY MOBILIZING IT IN

6567
04:31:21,665 --> 04:31:23,600
SPECIFIC TISSUES OF TRANS GENG

6568
04:31:23,667 --> 04:31:25,769
MICE.

6569
04:31:25,836 --> 04:31:26,003
GENIC

6570
04:31:26,069 --> 04:31:26,503
MICE.

6571
04:31:26,570 --> 04:31:27,371
I'LL TALK ABOUT THESE

6572
04:31:27,437 --> 04:31:30,107
APPLICATIONS FOR CANCER.

6573
04:31:30,173 --> 04:31:33,610
I MENTIONED SLEEPING BEAUTY CAN

6574
04:31:33,677 --> 04:31:35,212
MEDIATE STABLE -- IN THE CONTEXT

6575
04:31:35,278 --> 04:31:36,513
OF GENETICALLY INJURED MOUSE

6576
04:31:36,580 --> 04:31:43,153
MODEL THMMODEL OF CANCER -- TO T

6577
04:31:43,220 --> 04:31:46,423
TISSUES OF MICE.

6578
04:31:46,490 --> 04:31:48,191
OFTENTIMES WE ALSO DELIVER

6579
04:31:48,258 --> 04:31:50,260
CRISPR REAGENTS TO KNOCK OUT

6580
04:31:50,327 --> 04:31:51,662
TUMOR SUPPRESSORS AND WE CAN

6581
04:31:51,728 --> 04:31:52,729
CREATE VARIOUS TYPES OF CANCER

6582
04:31:52,796 --> 04:31:53,497
BY DOING THAT.

6583
04:31:53,563 --> 04:31:55,666
THAT'S USEFUL BECAUSE US CAN

6584
04:31:55,732 --> 04:31:57,167
CREATE DIVERSE GENETICALLY

6585
04:31:57,234 --> 04:31:58,268
DISTINCT MODELS OF CANCER

6586
04:31:58,335 --> 04:32:03,373
WITHOUT HAVING TO MAKE GERM

6587
04:32:03,440 --> 04:32:04,474
LINES TRANSGENIC MICE.

6588
04:32:04,541 --> 04:32:06,043
SO FOR EXAMPLE, WE SHOWED WE CAN

6589
04:32:06,109 --> 04:32:07,177
INDUCE VARIOUS TYPES OF BRAIN

6590
04:32:07,244 --> 04:32:09,012
TEU NORS OVER THE YEARS IN MICE

6591
04:32:09,079 --> 04:32:12,749
BY DELIVERING SB TRANSPOSON

6592
04:32:12,816 --> 04:32:14,618
ENCODED ONCOGENES TO THE MICE

6593
04:32:14,685 --> 04:32:16,386
OF -- TO THE BRAINS OF NEONATAL

6594
04:32:16,453 --> 04:32:17,320
MICE TO MAKE THESE DIFFERENT

6595
04:32:17,387 --> 04:32:19,823
FORMS OF BRAIN TUMORS.

6596
04:32:19,890 --> 04:32:21,158
WE SHOWED THAT WE COULD USE

6597
04:32:21,224 --> 04:32:25,262
SLEEPING BEAUTY TO DLI DELIVER S

6598
04:32:25,328 --> 04:32:29,766
TO CELLS IN THE LIVER FOR

6599
04:32:29,833 --> 04:32:30,200
CHOLANGIOCARCINOMA.

6600
04:32:30,267 --> 04:32:31,635
THESE ARE USEFUL FOR LOTS OF

6601
04:32:31,702 --> 04:32:32,836
OTHER CLEVER PEOPLE WHO DID MORE

6602
04:32:32,903 --> 04:32:35,439
IMPORTANT WORK THAN WE DID TO

6603
04:32:35,505 --> 04:32:37,407
STUDY THE ROLE OF INNATE

6604
04:32:37,474 --> 04:32:39,576
ADAPTIVE IMMUNE SYSTEM IN GLIOMA

6605
04:32:39,643 --> 04:32:40,977
GENESIS, FIND GLIOMA

6606
04:32:41,044 --> 04:32:42,379
VULNERABILITIES AND TEST NEW

6607
04:32:42,446 --> 04:32:43,380
PRE-CLINICAL THERAPIES, AND LOTS

6608
04:32:43,447 --> 04:32:45,649
OF INTERESTING WORK HAS ALSO

6609
04:32:45,716 --> 04:32:47,384
BEEN DONE ON MODELS OF LIVER

6610
04:32:47,451 --> 04:32:49,686
TUMORS USING THIS BASIC

6611
04:32:49,753 --> 04:32:58,662
APPROACH.

6612
04:32:58,729 --> 04:33:00,497
THEY CREATED THE WORLD'S FIRST

6613
04:33:00,564 --> 04:33:02,432
PORCINE MODEL OF GLIOGLASS THOMA

6614
04:33:02,499 --> 04:33:03,533
WHERE THEY USE APPROACHES

6615
04:33:03,600 --> 04:33:05,469
SIMILAR TO WHAT I DESCRIBED TO

6616
04:33:05,535 --> 04:33:07,104
DELIVER TRANSPOSONS AS WELL AS

6617
04:33:07,170 --> 04:33:09,840
CRISPR AGENTS TO THE BRAINS OF

6618
04:33:09,906 --> 04:33:12,843
NEONATAL PIGS, AND THEY CAN

6619
04:33:12,909 --> 04:33:15,479
INDUCE CLASSICAL GDM IN THESE

6620
04:33:15,545 --> 04:33:20,083
PIGS.

6621
04:33:20,150 --> 04:33:21,518
AND HAVE DEVELOPED REPORTERS

6622
04:33:21,585 --> 04:33:23,420
THEY CAN USE IN SERUM AND HOPE

6623
04:33:23,487 --> 04:33:24,855
TO USE IT FOR TESTING NEW

6624
04:33:24,921 --> 04:33:28,825
THERAPIES FOR GVMs.

6625
04:33:28,892 --> 04:33:30,627
NOW I'M GOING TO TALK FOR THE

6626
04:33:30,694 --> 04:33:35,465
REST OF THE TIME ABOUT USING --

6627
04:33:35,532 --> 04:33:36,433
IT'S PRETTY SIMPLE.

6628
04:33:36,500 --> 04:33:38,268
WE MADE ONE LINE OF MICE THAT

6629
04:33:38,335 --> 04:33:40,137
CARRY THE TRANSPOSON SO PART 1

6630
04:33:40,203 --> 04:33:45,208
OF THE SB SYSTEM.

6631
04:33:45,275 --> 04:33:46,710
IN ALL THESE EXPERIMENTS IT'S

6632
04:33:46,777 --> 04:33:51,715
PRESENT AS A MULTICOPY

6633
04:33:51,782 --> 04:33:53,450
CONCATAMER IN THE MOUSE GENOME.

6634
04:33:53,517 --> 04:33:54,584
THE REASON FOR THAT, WE DIDN'T

6635
04:33:54,651 --> 04:33:57,354
THINK WE COULD INDUCE CANCER BY

6636
04:33:57,420 --> 04:34:00,190
MOBILIZING A SINGLE TRANSPOSON.

6637
04:34:00,257 --> 04:34:02,459
CANCER TAKES THE -- WITHIN A

6638
04:34:02,526 --> 04:34:03,560
CELL OR CLONE OF CELLS, SO

6639
04:34:03,627 --> 04:34:05,629
THAT'S WHY THERE'S MULTIPLE

6640
04:34:05,695 --> 04:34:08,565
COPIES OF THE TRANSPOSON.

6641
04:34:08,632 --> 04:34:10,333
THAT'S THE LAUNCH PAD FOR THESE

6642
04:34:10,400 --> 04:34:14,204
TRANS POE SO

6643
04:34:14,271 --> 04:34:14,504
TRANSPOSONS.

6644
04:34:14,571 --> 04:34:16,173
NOW YOU HAVE A MOUSE THAT HAS

6645
04:34:16,239 --> 04:34:17,274
BOTH PARTS OF THE SLEEPING

6646
04:34:17,340 --> 04:34:17,841
BEAUTY SYSTEM.

6647
04:34:17,908 --> 04:34:20,310
WE SHOWED MANY, MANY SOMATIC

6648
04:34:20,377 --> 04:34:21,378
MUTATION INSERTIONS THAT WERE

6649
04:34:21,444 --> 04:34:24,581
OCCURRING AND WE HOPE THAT THIS

6650
04:34:24,648 --> 04:34:25,949
COULD RESULT IN CANCER.

6651
04:34:26,016 --> 04:34:29,820
IN MY VERY FIRST GRADUATE

6652
04:34:29,886 --> 04:34:32,422
STUDENT WHO THEN WENT TO

6653
04:34:32,489 --> 04:34:35,425
POSTDOC, HE AND MY LAB DESIGNED

6654
04:34:35,492 --> 04:34:37,194
THIS TRANSPOSON, WE HOPE THAT

6655
04:34:37,260 --> 04:34:40,463
COULD INDUCE CANCER, CALLED IT

6656
04:34:40,530 --> 04:34:41,431
T2 ONC.

6657
04:34:41,498 --> 04:34:43,066
WE INCLUDED ELEMENTS THAT WERE

6658
04:34:43,133 --> 04:34:45,168
REALLY INFORMED BY PRIOR STUDIES

6659
04:34:45,235 --> 04:34:47,537
ON SLOW TRANSFORMING RETROVIRAL

6660
04:34:47,604 --> 04:34:49,506
AND HOW THOSE COULD CAUSE

6661
04:34:49,573 --> 04:34:49,739
CANCER.

6662
04:34:49,806 --> 04:34:51,675
IN FACT, THE VERY FIRST VERSION

6663
04:34:51,741 --> 04:34:57,247
OF THE T2 ONC MADE HAS A PORTION

6664
04:34:57,314 --> 04:35:07,824
FROM THE MARINE STEM REUR EEN S.

6665
04:35:07,891 --> 04:35:08,959
WE INCLUDED COUNCIL STREAM OF

6666
04:35:09,025 --> 04:35:10,660
THAT AN ARTIFICIAL EXON WITH A

6667
04:35:10,727 --> 04:35:11,528
SPLICED DONOR.

6668
04:35:11,595 --> 04:35:14,097
SUPPLIES ACCEPTORS IN BOTH

6669
04:35:14,164 --> 04:35:15,966
ORIENTATIONS AND A

6670
04:35:16,032 --> 04:35:18,702
BI-DIRECTIONAL POLYA WITH VIRUS

6671
04:35:18,768 --> 04:35:19,769
FROM SB40.

6672
04:35:19,836 --> 04:35:21,938
THE IDEA WAS THIS COULD CAUSE

6673
04:35:22,005 --> 04:35:26,543
GAIN OF FUNCTION -- OR LOST

6674
04:35:26,610 --> 04:35:28,845
MUTATIONS IN TUMOR SUPPRESSOR

6675
04:35:28,912 --> 04:35:29,112
GENES.

6676
04:35:29,179 --> 04:35:31,681
REMEMBER WE'RE MOBILIZING FROM A

6677
04:35:31,748 --> 04:35:33,817
DONOR CHROMOSOME SITE WHERE

6678
04:35:33,884 --> 04:35:36,686
THERE'S MULTIPLE TRANSPOSON

6679
04:35:36,753 --> 04:35:41,892
VECTORS.

6680
04:35:41,958 --> 04:35:44,427
PERRY HACKETT, HE SAID I'M

6681
04:35:44,494 --> 04:35:45,295
TRYING TO DO GENE THERAPY AND

6682
04:35:45,362 --> 04:35:46,897
YOU JUST MADE THE TRANSPOSON

6683
04:35:46,963 --> 04:35:47,464
FROM HELL.

6684
04:35:47,530 --> 04:35:48,932
ACTUALLY IT DID CONFUSE

6685
04:35:48,999 --> 04:35:49,532
REGULATORS IN WASHINGTON.

6686
04:35:49,599 --> 04:35:50,967
THEY'RE LIKE, YOU WANT TO USE

6687
04:35:51,034 --> 04:35:52,903
THIS THING THAT CAUSES CANCER

6688
04:35:52,969 --> 04:35:54,070
FOR GENE THERAPY?

6689
04:35:54,137 --> 04:35:57,507
BUT YOU KNOW, WE MADE LIKE THE

6690
04:35:57,574 --> 04:35:58,708
WORST CASE GENE THERAPY VECTOR.

6691
04:35:58,775 --> 04:36:00,410
IT'S GOT NO GENE AND ALL IT DOES

6692
04:36:00,477 --> 04:36:05,148
IS DAMAGE ENDOGENOUS GENES.

6693
04:36:05,215 --> 04:36:08,785
SO THE WHOLE THING WORKS, AND TO

6694
04:36:08,852 --> 04:36:10,053
CARRY OUT A SLEEPING BEAUTY

6695
04:36:10,120 --> 04:36:11,788
TRANSPOSON SCREEN, YOU CROSS THE

6696
04:36:11,855 --> 04:36:13,223
TRANSPOSON LINE TO A TRANS POE

6697
04:36:13,290 --> 04:36:20,597
SAYS -- YOU AGE THE MICE,

6698
04:36:20,664 --> 04:36:21,932
OFTENTIMES THESE MICE HAVE A

6699
04:36:21,998 --> 04:36:24,734
CANCER PRED PREDISPOSING MUTATIN

6700
04:36:24,801 --> 04:36:25,602
THE BACKGROUND.

6701
04:36:25,669 --> 04:36:26,603
YOU AGE THEM.

6702
04:36:26,670 --> 04:36:28,338
THE GRADUATE STUDENT OR POSTDOC

6703
04:36:28,405 --> 04:36:30,006
STARTS TO GET STRESH STRESSED

6704
04:36:30,073 --> 04:36:32,676
OUT AFTER ABOUT A YEAR.

6705
04:36:32,742 --> 04:36:34,010
MOST OF THESE EXPERIMENTS, WE

6706
04:36:34,077 --> 04:36:36,713
AGED THE MICE UP TO TWO YEARS,

6707
04:36:36,780 --> 04:36:38,915
COLLECTED THE TUMORS, THEN

6708
04:36:38,982 --> 04:36:40,450
SEQUENCED THE TRANSPOSON

6709
04:36:40,517 --> 04:36:41,084
INSERTION SITES.

6710
04:36:41,151 --> 04:36:42,452
SO HERE'S AN EXAMPLE WHERE WE

6711
04:36:42,519 --> 04:36:43,787
DID THIS IN LIVER, THE LIVER

6712
04:36:43,853 --> 04:36:45,522
WOULD HAVE MULTIPLE TUMORS IN

6713
04:36:45,588 --> 04:36:49,225
IT, YOU COLLECT THE TUMORS, PCR

6714
04:36:49,292 --> 04:36:52,162
TO AMPLIFY THE INTERGR INTEGRATE

6715
04:36:52,228 --> 04:36:55,665
SO A PIECE OF DNA INTEGRATED IN

6716
04:36:55,732 --> 04:36:56,533
ADJACENT GENOMIC DNA FROM A

6717
04:36:56,599 --> 04:36:57,300
CELL.

6718
04:36:57,367 --> 04:37:02,272
AND DO NEXT GEN SEQUENCING.

6719
04:37:02,339 --> 04:37:04,107
WE DID IT IN A BARCODED FASHION

6720
04:37:04,174 --> 04:37:05,308
SO YOU COULD HAVE A DIFFERENT

6721
04:37:05,375 --> 04:37:07,610
BARCODE FOR EACH TUMOR AND

6722
04:37:07,677 --> 04:37:08,878
SEQUENCE IN BULK.

6723
04:37:08,945 --> 04:37:12,615
THEN WORK WITH THE

6724
04:37:12,682 --> 04:37:16,119
BIOINFORMATICIANS, YOU RECOVERED

6725
04:37:16,186 --> 04:37:16,853
THOUSANDS PER TUMOR.

6726
04:37:16,920 --> 04:37:18,621
YOU MAKE THE GOOD STUFF, DISTILL

6727
04:37:18,688 --> 04:37:20,023
THAT DOWN, IT'S LIKE MAKING

6728
04:37:20,090 --> 04:37:20,790
WHISKEY.

6729
04:37:20,857 --> 04:37:22,826
WHAT WE'RE LOOKING FOR ARE THE

6730
04:37:22,892 --> 04:37:24,527
CANCER-CAUSING INSERTIONS, AND

6731
04:37:24,594 --> 04:37:26,663
TO DO THAT, WE CLONE A BUNCH OF

6732
04:37:26,730 --> 04:37:28,064
INSERTIONS FROM MULTIPLE

6733
04:37:28,131 --> 04:37:30,800
INDEPENDENT TE TUMOR, AND WE'RE

6734
04:37:30,867 --> 04:37:32,268
LOOKING FOR REGIONS CALLED

6735
04:37:32,335 --> 04:37:33,503
COMMON INSERTION SITES, WHICH IS

6736
04:37:33,570 --> 04:37:35,505
THE SAME TERMINOLOGY USED IN

6737
04:37:35,572 --> 04:37:41,878
SLOW TRANSFORMING PRE TROA VIRUS

6738
04:37:41,945 --> 04:37:42,212
RESEARCH.

6739
04:37:42,278 --> 04:37:43,513
AFFECTING THE SAME GENE IN THE

6740
04:37:43,580 --> 04:37:44,848
SAME WAY SO AS TO GIVE THAT CELL

6741
04:37:44,914 --> 04:37:50,153
A SELECTIVE ADVANTAGE.

6742
04:37:50,220 --> 04:37:52,222
AND WHEN WE DID THESE SCREENS,

6743
04:37:52,288 --> 04:37:53,223
IT BECAME CLEAR THAT THE WHOLE

6744
04:37:53,289 --> 04:37:56,159
THING WAS WORKING BECAUSE WE SAW

6745
04:37:56,226 --> 04:37:58,495
ACTIVATION OF KNOWN AND NOVEL --

6746
04:37:58,561 --> 04:38:01,965
OF MANY KNOWN CANCER GENES LIKE

6747
04:38:02,032 --> 04:38:03,733
NOTCH 1 OR BRAF, AS WELL AS LOSS

6748
04:38:03,800 --> 04:38:05,468
OF FUNCTION INSERTION IN KNOWN

6749
04:38:05,535 --> 04:38:09,739
TUMOR SUPPRESSOR GENES LIKE NF1,

6750
04:38:09,806 --> 04:38:10,707
NF2.

6751
04:38:10,774 --> 04:38:12,575
IN FACT IF WE HAD DONE THIS 20

6752
04:38:12,642 --> 04:38:13,777
OR 30 YEARS EARLIER, I WOULD

6753
04:38:13,843 --> 04:38:14,844
HAVE DISCOVERED ALL OF THESE

6754
04:38:14,911 --> 04:38:15,512
CANCER GENES.

6755
04:38:15,578 --> 04:38:16,880
BUT OF COURSE SLEEPING BEAUTY

6756
04:38:16,946 --> 04:38:18,214
DIDN'T EXIST THEN EITHER.

6757
04:38:18,281 --> 04:38:22,719
SO ANYWAY.

6758
04:38:22,786 --> 04:38:26,656
SO YOU CAN ACTIVATE ONCOGENES

6759
04:38:26,723 --> 04:38:28,591
WHERE AN INTERNALLY TRUNK ATED

6760
04:38:28,658 --> 04:38:30,326
ACTIVATED FORM OR C TERMINALLY

6761
04:38:30,393 --> 04:38:32,695
TRUNK ATED ACTIVATED FORMS, OR

6762
04:38:32,762 --> 04:38:34,998
YOU JUST GET KNOCKOUT OF THE

6763
04:38:35,065 --> 04:38:35,865
TUMOR SUPPRESSOR GENE.

6764
04:38:35,932 --> 04:38:37,300
IF IT'S A GENE THAT DOESN'T HAVE

6765
04:38:37,367 --> 04:38:38,735
A KNOWN ROLE IN CANCER, YOU

6766
04:38:38,802 --> 04:38:41,938
COULD GUESS WHETHER IT WAS A TEU

6767
04:38:42,005 --> 04:38:43,740
TUMOR SUPPRESSOR GENE OR

6768
04:38:43,807 --> 04:38:45,241
ONCOGENE BY LOOKING AT THE

6769
04:38:45,308 --> 04:38:46,109
PATTERN AND ORIENTATION

6770
04:38:46,176 --> 04:38:46,976
PREFERENCES OF THE INSERTION.

6771
04:38:47,043 --> 04:38:48,845
SO IF IT LOOKS LIKE THIS WHERE

6772
04:38:48,912 --> 04:38:50,380
IT SPREAD THROUGHOUT THE GENE

6773
04:38:50,447 --> 04:38:51,981
WITHOUT A STRONG ORIENTATION

6774
04:38:52,048 --> 04:38:53,650
BIAS, MAYBE THAT'S A TUMOR

6775
04:38:53,716 --> 04:38:54,184
SUPPRESSOR GENE.

6776
04:38:54,250 --> 04:38:56,686
BUT THEY'RE ALL LINED UP IN THE

6777
04:38:56,753 --> 04:38:59,589
SAME PLACE AND THE SAME

6778
04:38:59,656 --> 04:39:00,623
TRANSCRIPTIONAL ORIENTATION,

6779
04:39:00,690 --> 04:39:02,792
YOU'RE PROBABLY CREATING A

6780
04:39:02,859 --> 04:39:03,793
FUSION TRANSCRIPT THAT'S

6781
04:39:03,860 --> 04:39:04,227
OVEREXPRESSED.

6782
04:39:04,294 --> 04:39:06,830
SO WE FIRST REPORTED ON THIS

6783
04:39:06,896 --> 04:39:08,264
DOING MUTAGENESIS SCREENS IN

6784
04:39:08,331 --> 04:39:09,799
2005 AND SOME OF THAT WORK WAS

6785
04:39:09,866 --> 04:39:11,835
WITH NEIL AND NANCY.

6786
04:39:11,901 --> 04:39:13,970
AND BY 2009, WE WERE DOING THESE

6787
04:39:14,037 --> 04:39:16,306
SCREENS IN TISSUE-SPECIFIC

6788
04:39:16,372 --> 04:39:18,308
MANNER.

6789
04:39:18,374 --> 04:39:19,576
AND ADAM CAME HERE TO FREDERICK

6790
04:39:19,642 --> 04:39:21,778
TO WORK WITH NEIL, NANCY AND

6791
04:39:21,845 --> 04:39:24,914
LINO AND MADE THIS CRE ROCKS

6792
04:39:24,981 --> 04:39:26,116
REGULATED OF THE TRANS POE SAYS

6793
04:39:26,182 --> 04:39:27,550
TRANS GENE WHICH HAS BEEN VERY

6794
04:39:27,617 --> 04:39:29,819
USEFUL, SO YOU CAN JUST COMBINE

6795
04:39:29,886 --> 04:39:33,323
IT WITH DIFFERENT TISSUE

6796
04:39:33,389 --> 04:39:35,158
SPECIFIC CRES TO MODEL DIFFERENT

6797
04:39:35,225 --> 04:39:36,593
FORMS OF CANCER JUST LIKE WE

6798
04:39:36,659 --> 04:39:37,694
HOPED IN THE BEGINNING.

6799
04:39:37,760 --> 04:39:40,196
AT THIS POINT THERE'S OVER 80

6800
04:39:40,263 --> 04:39:41,831
PUBLICATIONS OR ANOTHER TRANS

6801
04:39:41,898 --> 04:39:45,869
POE SAL ELEMENT, SCREENS FOR

6802
04:39:45,935 --> 04:39:46,970
CARCINOMAS, SARCOMAS, LOTS OF

6803
04:39:47,036 --> 04:39:48,071
DIFFERENT TYPES OF CANCER.

6804
04:39:48,138 --> 04:39:50,440
AS I SAID OFTEN ON A

6805
04:39:50,507 --> 04:39:51,641
PREDISPOSING BACKGROUND OR

6806
04:39:51,708 --> 04:39:54,144
CANCER PROMOTING ENVIRONMENT.

6807
04:39:54,210 --> 04:39:57,247
AND NOW WE'RE TRYING TO USE THE

6808
04:39:57,313 --> 04:39:58,515
TECHNOLOGY TO ASK MORE

6809
04:39:58,581 --> 04:39:58,982
INTERESTING QUESTIONS.

6810
04:39:59,048 --> 04:40:02,018
WHAT ABOUT CANCER EVOLUTION,

6811
04:40:02,085 --> 04:40:03,119
EVOLUTION OF DRUG RESISTANCE OR

6812
04:40:03,186 --> 04:40:08,258
METASTASIS?

6813
04:40:08,324 --> 04:40:10,860
SO ONE THING I WANT TO EMPHASIZE

6814
04:40:10,927 --> 04:40:12,495
ABOUT THE NATURE OF THESE

6815
04:40:12,562 --> 04:40:14,964
GENETIC EVENTS INTRODUCED BY THE

6816
04:40:15,031 --> 04:40:16,299
TRANSPOSON IS THEY CREATE FUSION

6817
04:40:16,366 --> 04:40:17,267
TRANSCRIPTS THAT CAN BE

6818
04:40:17,333 --> 04:40:18,168
RECOVERED BY RNA SEQ.

6819
04:40:18,234 --> 04:40:20,904
SO WHEN A TRANSCRIPT INITIATES

6820
04:40:20,970 --> 04:40:22,839
WITHIN THE TRANSPOSON AND FUSES

6821
04:40:22,906 --> 04:40:27,777
TO DOWNSTREAM EXONS, YOU

6822
04:40:27,844 --> 04:40:29,379
COULD -- OR THE SUPPLIES

6823
04:40:29,445 --> 04:40:30,713
ACCEPTORS INTERRUPT

6824
04:40:30,780 --> 04:40:31,948
TRANSCRIPTION INITIATED AT THE

6825
04:40:32,015 --> 04:40:33,016
CELLULAR PROMOTOR, YOU SHOULD BE

6826
04:40:33,082 --> 04:40:34,884
ABLE TO SEE ALL THOSE EVENTS IN

6827
04:40:34,951 --> 04:40:36,052
RNA SEQUENCING DATA.

6828
04:40:36,119 --> 04:40:37,921
SO IF YOU DO THAT WITH SLEEPING

6829
04:40:37,987 --> 04:40:39,355
BEAUTY ACCELERATED TUMORS, YOU

6830
04:40:39,422 --> 04:40:41,157
CAN ALSO GET THE GENE EXPRESSION

6831
04:40:41,224 --> 04:40:43,026
PROFILE OF THAT TUMOR, AND

6832
04:40:43,092 --> 04:40:45,295
WORKING WITH AN INFORMATACIST

6833
04:40:45,361 --> 04:40:47,597
NAMED AARON SARVER, WE TRIED TO

6834
04:40:47,664 --> 04:40:49,999
SIMPLIFY THE GENE EXPRESSION

6835
04:40:50,066 --> 04:40:53,269
PROFILES BY LOOK FORKING FOR

6836
04:40:53,336 --> 04:40:58,208
CLUSTERS OF GENESES THAT ARE

6837
04:40:58,274 --> 04:41:01,211
CO-REGULATED.

6838
04:41:01,277 --> 04:41:05,548
YOU CAN TAKE THAT CLUSTER AND --

6839
04:41:05,615 --> 04:41:06,749
CLUSTER TO GIVE US A CERTAIN

6840
04:41:06,816 --> 04:41:08,952
SCORE AND AARON CALLS THOSE GENE

6841
04:41:09,018 --> 04:41:11,554
CLUSTER EXPRESSION SUMMARY

6842
04:41:11,621 --> 04:41:15,525
SCORES, OR GCESS.

6843
04:41:15,592 --> 04:41:16,292
WHAT'S BEEN INTERESTING ABOUT

6844
04:41:16,359 --> 04:41:19,729
THIS IS IF WE DO THIS RNA SEQ ON

6845
04:41:19,796 --> 04:41:24,500
TRANS POE ZONE INDUCED -- AND

6846
04:41:24,567 --> 04:41:26,536
THEN LOOK AT THE FUSION

6847
04:41:26,603 --> 04:41:28,404
TRANSCRIPTS TO GET THE GENOTYPE

6848
04:41:28,471 --> 04:41:32,008
AND MAKE GENOTYPE PHENOTYPE

6849
04:41:32,075 --> 04:41:33,176
CORRELATIONS, AND WE'VE DONE

6850
04:41:33,243 --> 04:41:34,811
THIS WITH A NUMBER OF DIFFERENT

6851
04:41:34,877 --> 04:41:36,112
MODEL SYSTEMS, AND I'LL TALK A

6852
04:41:36,179 --> 04:41:38,948
LITTLE BIT ABOUT THE MAMMARY

6853
04:41:39,015 --> 04:41:41,551
TUMORS ACCELERATED ON A

6854
04:41:41,618 --> 04:41:43,853
PI3 KINASE MUTANT BACKGROUND AND

6855
04:41:43,920 --> 04:41:45,288
OSTEOSARCOMAS ACCELERATED ON A

6856
04:41:45,355 --> 04:41:47,156
P53 MUTANT BACKGROUND.

6857
04:41:47,223 --> 04:41:52,729
SO WE USED -- TO ACCELERATE

6858
04:41:52,795 --> 04:41:53,930
OSTEOSARCOMA GENESIS ON WILD

6859
04:41:53,997 --> 04:41:57,166
PIPE OR P53 MUTANT BACKGROUND ON

6860
04:41:57,233 --> 04:41:58,034
MICE.

6861
04:41:58,101 --> 04:42:02,872
AND THIS FEELS -- VERSUS AGE IN

6862
04:42:02,939 --> 04:42:04,240
MONTHS, YOU CAN SEE HOW LONG

6863
04:42:04,307 --> 04:42:06,909
THESE EXPERIMENTS TAKE.

6864
04:42:06,976 --> 04:42:08,645
AND P53 MUTATION ALONE WAS KNOWN

6865
04:42:08,711 --> 04:42:12,248
TO CAUSE OSTEOSARCOMA.

6866
04:42:12,315 --> 04:42:13,316
OSTEOSARCOMA COULD BE INDUCED ON

6867
04:42:13,383 --> 04:42:14,884
A WILD TYPE BACKGROUND WITH

6868
04:42:14,951 --> 04:42:16,552
SLEEPING BEAUTY MUTAGENESIS, BUT

6869
04:42:16,619 --> 04:42:17,920
IF YOU COMBINE THE TWO, YOU GET

6870
04:42:17,987 --> 04:42:21,524
THE FASTEST DEVELOPING AS YOE

6871
04:42:21,591 --> 04:42:22,925
SARCOMAS, AND YOU ALSO TEND TO

6872
04:42:22,992 --> 04:42:24,160
SEE MORE PER MOUSE.

6873
04:42:24,227 --> 04:42:26,229
IF IT WAS SLEEPING BEAUTY EXCEL

6874
04:42:26,296 --> 04:42:27,830
BRAITED ON A P53 MUTANT

6875
04:42:27,897 --> 04:42:28,364
BACKGROUND.

6876
04:42:28,431 --> 04:42:30,900
SO THESE ARE THE RECURRENT

6877
04:42:30,967 --> 04:42:33,836
TRANSPOSON GENE FUSIONS THAT WE

6878
04:42:33,903 --> 04:42:36,606
SEE.

6879
04:42:36,673 --> 04:42:38,007
SO EACH OF THE COLUMNS HERE IS A

6880
04:42:38,074 --> 04:42:44,113
GIVEN AS Y OSTEOSARCOMA, YOU CAE

6881
04:42:44,180 --> 04:42:45,548
GENE FUSIONS.

6882
04:42:45,615 --> 04:42:48,718
IT GOES DOWN FROM THERE.

6883
04:42:48,785 --> 04:42:50,253
, FROM PTEN.

6884
04:42:50,320 --> 04:42:52,188
SO THE LIST IS COULD BE SPIC

6885
04:42:52,255 --> 04:42:53,856
WITH US FOR CAMPAIGNING MANY

6886
04:42:53,923 --> 04:43:00,963
KNOWN OR SUSPECTED -- SO THAT'S

6887
04:43:01,030 --> 04:43:03,166
ALL -- THAT'S GOOD.

6888
04:43:03,232 --> 04:43:07,537
WHAT ABOUT THE OTHER GENES?

6889
04:43:07,603 --> 04:43:09,305
WELL, MANY OF THEM DO SHOW

6890
04:43:09,372 --> 04:43:11,674
RECURRENT COPY NUMBER

6891
04:43:11,741 --> 04:43:15,712
ALTERATIONS IN OSTEOSARCOMA, BUT

6892
04:43:15,778 --> 04:43:17,547
BUT -- HAVE A LOT OF GENE COPY

6893
04:43:17,613 --> 04:43:18,581
NUMBER CHANGES SO MAYBE THESE

6894
04:43:18,648 --> 04:43:19,115
AREN'T IMPORTANT.

6895
04:43:19,182 --> 04:43:21,084
BUT ALSO MANY OF THESE GENES

6896
04:43:21,150 --> 04:43:22,719
SHOWED RECURRENT COPY

6897
04:43:22,785 --> 04:43:24,887
ALTERATIONS IN CANINE AS YOE

6898
04:43:24,954 --> 04:43:26,189
SARCOMA AS WELL, SO WE THINK A

6899
04:43:26,255 --> 04:43:29,158
LOT OF THEM ARE MEANINGFUL,

6900
04:43:29,225 --> 04:43:32,428
BECAUSE THE GENE COPY -- IN THE

6901
04:43:32,495 --> 04:43:34,197
SAME DIRECTION AS HUMAN

6902
04:43:34,263 --> 04:43:34,530
OSTEOSARCOMA.

6903
04:43:34,597 --> 04:43:35,932
BUT DO ANY OF THEM CORRELATE

6904
04:43:35,998 --> 04:43:37,633
WITH CLINICALLY RELEVANT

6905
04:43:37,700 --> 04:43:38,201
PHENOTYPES?

6906
04:43:38,267 --> 04:43:44,073
SO IT TURNS OUT THAT THE SB

6907
04:43:44,140 --> 04:43:46,709
ACCELERATED OSTEOSARCOMAS --

6908
04:43:46,776 --> 04:43:49,679
IMMUNE CELL INFILTRATION.

6909
04:43:49,746 --> 04:43:51,647
SO FOR EXAMPLE, THIS CLUSTER OF

6910
04:43:51,714 --> 04:43:56,119
COVARIANT GENES DOWN HERE IS --

6911
04:43:56,185 --> 04:43:59,188
OUR CELL CYCLE GENES.

6912
04:43:59,255 --> 04:44:03,126
IT'S REALLY -- THESE ARE

6913
04:44:03,192 --> 04:44:04,127
OSTEOSARCOMA CELL LINES WE

6914
04:44:04,193 --> 04:44:05,862
ISOLATED FROM THE TUMORS BUT IT

6915
04:44:05,928 --> 04:44:07,597
ALSO VARIES IN THE TUMORS.

6916
04:44:07,663 --> 04:44:09,232
SIMILAR FOR THE IMMUNE CELL

6917
04:44:09,298 --> 04:44:09,665
INFILL TAITION.

6918
04:44:09,732 --> 04:44:11,734
SOME OF THE SAMPLES ARE

6919
04:44:11,801 --> 04:44:15,338
IMMUNE-COLD AND OTHERS ARE MORE

6920
04:44:15,405 --> 04:44:15,671
IMMUNE-HOT.

6921
04:44:15,738 --> 04:44:16,773
SO WE CAN USE INFORMATION LIKE

6922
04:44:16,839 --> 04:44:18,207
THIS TO GENERATE GRAPHS LIKE

6923
04:44:18,274 --> 04:44:20,476
THIS ONE, WHERE YOU CAN LOOK AT

6924
04:44:20,543 --> 04:44:28,117
THE TOTAL -- THE GCESS SCHOR,

6925
04:44:28,184 --> 04:44:32,722
SCORE.EACH DOT IS A TUMOR, AND E

6926
04:44:32,789 --> 04:44:34,490
SIZE OF THE DOT REFLECTS THE

6927
04:44:34,557 --> 04:44:36,526
TOTAL NUMBER OF TRANSPOSON GENE

6928
04:44:36,592 --> 04:44:38,961
FUSIONS, IN THIS CASE D WHAT YOU

6929
04:44:39,028 --> 04:44:40,630
CAN SEE FROM THIS IS SOMETHING

6930
04:44:40,696 --> 04:44:42,331
THAT YOU ALL WOULD HAVE

6931
04:44:42,398 --> 04:44:46,469
PREDICTED, WHICH IS THAT MYC

6932
04:44:46,536 --> 04:44:48,004
LEVELS ARE HIGH IN SAMPLES WHERE

6933
04:44:48,070 --> 04:44:52,041
THERE'S A TRANSPOSON ACTIVATED

6934
04:44:52,108 --> 04:44:53,109
FUSION, AND THAT ALSO TENDS TO

6935
04:44:53,176 --> 04:44:56,979
BE THE SAMPLES WITH THE HIGHEST

6936
04:44:57,046 --> 04:45:02,018
GCESS SCORE, SO NICK IS DRIVING

6937
04:45:02,084 --> 04:45:05,154
A -- THERE'S A FEW CANDIDATE,

6938
04:45:05,221 --> 04:45:06,823
ONE OF WHICH IS ACTIVATION OF

6939
04:45:06,889 --> 04:45:10,760
THE COLONY STIMULATING FACTOR

6940
04:45:10,827 --> 04:45:11,461
1 RECEPTOR.

6941
04:45:11,527 --> 04:45:12,929
SO TUMORS WITH HIGH LEVELS OF

6942
04:45:12,995 --> 04:45:15,631
THIS CAUSED BY TRANSPOSON

6943
04:45:15,698 --> 04:45:18,501
ACTIVATION ARE LOW IN IMMUNE

6944
04:45:18,568 --> 04:45:18,968
CELL INFILTRATION.

6945
04:45:19,035 --> 04:45:28,578
SO WE WENT AND AHEAD AND -- ON A

6946
04:45:28,644 --> 04:45:30,046
P53 MUTANT BACKGROUND.

6947
04:45:30,112 --> 04:45:31,647
THIS IS THE CURVE RIGHT HERE AND

6948
04:45:31,714 --> 04:45:34,484
THESE MICE DEVELOP OSTEOSARCOMAS

6949
04:45:34,550 --> 04:45:35,051
FASTEST.

6950
04:45:35,117 --> 04:45:37,019
WHEN YOU LOOK AT THESE

6951
04:45:37,086 --> 04:45:40,957
OSTEOSARCOMAS, THEY HAVE LOWER

6952
04:45:41,023 --> 04:45:42,725
IMMUNE INFILTRATION THAN

6953
04:45:42,792 --> 04:45:44,594
OSTEOSARCOMAS WITH P53 ALONE.

6954
04:45:44,660 --> 04:45:47,997
SO THIS LEADS US TO BELIEVE THAT

6955
04:45:48,064 --> 04:45:53,302
CSF 1 RECEPTOR EXPRESSION CAN

6956
04:45:53,369 --> 04:45:57,240
APPROPRIATE AND/OR THAT SHEDS

6957
04:45:57,306 --> 04:45:59,108
CSF 1 RECEPTOR SOMEHOW IS

6958
04:45:59,175 --> 04:46:02,278
SEQUESTERING LIGANDS AND

6959
04:46:02,345 --> 04:46:04,447
PREVENTING IMMUNE CELL

6960
04:46:04,514 --> 04:46:07,183
INFILTRATION.

6961
04:46:07,250 --> 04:46:09,485
NOW, YOU MIGHT WONDER IF IT'S

6962
04:46:09,552 --> 04:46:11,120
EVEN IMPORTANT IN HUMAN

6963
04:46:11,187 --> 04:46:11,454
OSTEOSARCOMA.

6964
04:46:11,521 --> 04:46:12,255
IT TURNS OUT IT IS.

6965
04:46:12,321 --> 04:46:13,523
THIS IS THE SAME KIND OF YOU AAL

6966
04:46:13,589 --> 04:46:16,692
CYST WITH HUMAN OSTEOSAR COMA

6967
04:46:16,759 --> 04:46:20,396
LOOKING AT CELL CYCLE AND IMMUNE

6968
04:46:20,463 --> 04:46:25,635
ILL FILTRATION.

6969
04:46:25,701 --> 04:46:27,737
HIGH IMMUNE CELL INFILTRATION OF

6970
04:46:27,803 --> 04:46:29,272
THE PRIMARY TUMOR, A BETTER

6971
04:46:29,338 --> 04:46:29,705
OUTCOME.

6972
04:46:29,772 --> 04:46:32,141
SO WE SHOULD CARE ABOUT THESE

6973
04:46:32,208 --> 04:46:34,944
PHENOTYPES IN OSTEOSARCOMA.

6974
04:46:35,011 --> 04:46:39,882
NOW WE HAVE VERY SIMILAR DATA

6975
04:46:39,949 --> 04:46:51,227
WSH WE AK EL --ON A -- THIS KNOE

6976
04:46:51,294 --> 04:46:52,461
LOX REGULATED EXPRESSION OF THE

6977
04:46:52,528 --> 04:46:53,996
THIS ACTIVATED FORM.

6978
04:46:54,063 --> 04:46:56,399
THIS MUTATION IS COMMON IN HUMAN

6979
04:46:56,465 --> 04:46:58,601
MAMMARY TUMORS.

6980
04:46:58,668 --> 04:47:03,172
AND WE COMBINE THAT WITH -- THAT

6981
04:47:03,239 --> 04:47:05,575
EXPRESSED IN DIFFERENT

6982
04:47:05,641 --> 04:47:10,046
COMARTMENTS OF THE MAMMARY GLAND

6983
04:47:10,112 --> 04:47:11,447
EPITHELIAL TISSUES AND USED A

6984
04:47:11,514 --> 04:47:13,316
DIFFERENT TRANSPOSON THAT'S MORE

6985
04:47:13,382 --> 04:47:15,284
ACTIVE IN EPITHELIAL CELLS, AND

6986
04:47:15,351 --> 04:47:16,852
THEN THE SAME CONDITIONAL

6987
04:47:16,919 --> 04:47:23,025
SLEEPING BEAUTY TRANS  TRANSPOSE

6988
04:47:23,092 --> 04:47:23,459
GENE.

6989
04:47:23,526 --> 04:47:25,461
I WON'T GO INTO THE DETAILS ON

6990
04:47:25,528 --> 04:47:27,797
THIS, BUT IT DID ACCELERATE

6991
04:47:27,863 --> 04:47:30,433
MAMMARY TUMORS ON A PICK

6992
04:47:30,499 --> 04:47:31,734
3 RELATED TO BACKGROUND WITH

6993
04:47:31,801 --> 04:47:36,672
BOTH LOCK OR MTB -- THE

6994
04:47:36,739 --> 04:47:39,508
ACCELERATED TUMORS WERE MOSTLY

6995
04:47:39,575 --> 04:47:39,942
ADENOCARCINOMAS, BUT

6996
04:47:40,009 --> 04:47:41,043
INTERESTINGLY, WE COULD GET SOME

6997
04:47:41,110 --> 04:47:42,678
THAT WERE ER POSITIVE AND SOME

6998
04:47:42,745 --> 04:47:45,081
THAT WERE ER NEGATIVE.

6999
04:47:45,147 --> 04:47:47,049
THAT WAS INFLUENCED BY THE

7000
04:47:47,116 --> 04:47:48,384
TARGET CELL TRANSFORMATION,

7001
04:47:48,451 --> 04:47:51,253
WHERE THEY TENDED TO BE NEGATIVE

7002
04:47:51,320 --> 04:47:52,955
IF WE USE THE THE GENE.

7003
04:47:53,022 --> 04:47:54,256
WE FOREMANNED WHOLE EXOME

7004
04:47:54,323 --> 04:47:55,925
SEQUENCING AND RECOVERY OF THE

7005
04:47:55,992 --> 04:47:57,126
TRANSPOSON INSERTION SITES FROM

7006
04:47:57,193 --> 04:47:58,894
TUMORS AND MATCHED NORMAL

7007
04:47:58,961 --> 04:48:01,063
EPITHELIAL TISSUES FROM THESE

7008
04:48:01,130 --> 04:48:02,498
MICE.

7009
04:48:02,565 --> 04:48:06,335
ON 164 TUMORS AND MATCHED NORMAL

7010
04:48:06,402 --> 04:48:06,636
TISSUE.

7011
04:48:06,702 --> 04:48:10,239
WE NOW RECOVER THESE BY A

7012
04:48:10,306 --> 04:48:11,474
HYBRIDDATION APPROACH, WHICH

7013
04:48:11,540 --> 04:48:14,110
GIVES US A BETTER REPRESENTATION

7014
04:48:14,176 --> 04:48:18,447
OF THE CLONALITY OF EVERY

7015
04:48:18,514 --> 04:48:21,083
INSERTION SITE.

7016
04:48:21,150 --> 04:48:23,819
THERE WERE ONLY 34 CODING

7017
04:48:23,886 --> 04:48:25,454
MUTATION FROM 24 OF THESE

7018
04:48:25,521 --> 04:48:27,757
TUMORS, AND THEY WERE IN SOME

7019
04:48:27,823 --> 04:48:28,624
INTERESTING GENES BUT IT DOES

7020
04:48:28,691 --> 04:48:29,925
SHOW YOU THAT THE MAJORITY OF

7021
04:48:29,992 --> 04:48:32,228
THE GENETIC DAMAGE BEING DONE IN

7022
04:48:32,294 --> 04:48:34,096
THESE MODEL SYSTEMS IS BY THE

7023
04:48:34,163 --> 04:48:34,764
TRANSPOSON.

7024
04:48:34,830 --> 04:48:36,265
AND THERE WERE MANY THOUSANDS OF

7025
04:48:36,332 --> 04:48:37,600
INSERTION SITES RECOVERED WITH

7026
04:48:37,667 --> 04:48:39,769
STRONG EVIDENCE FOR CLONAL

7027
04:48:39,835 --> 04:48:42,371
EXPANSION OF INSERTIONS WITHIN

7028
04:48:42,438 --> 04:48:42,705
TUMORS.

7029
04:48:42,772 --> 04:48:44,774
IT'S ALLOWED US TO DEFINE WHAT

7030
04:48:44,840 --> 04:48:46,108
ARE THE LIKELY INITIATORS AND

7031
04:48:46,175 --> 04:48:49,412
WHAT CAUSES PROGRESSION IN THIS

7032
04:48:49,478 --> 04:48:52,782
MODEL.

7033
04:48:52,848 --> 04:48:56,385
WE ALSO DID RNA SEQUENCING IN

7034
04:48:56,452 --> 04:48:59,255
THESE MAMMARY TUMORS COMPARED TO

7035
04:48:59,321 --> 04:49:01,223
HUMAN AND SOUGHT NEW TUMOR

7036
04:49:01,290 --> 04:49:02,224
PHENOTYPES AND DISCOVERED

7037
04:49:02,291 --> 04:49:03,292
DRIVERS.

7038
04:49:03,359 --> 04:49:05,828
AND THIS IS THE KIND OF DATA WE

7039
04:49:05,895 --> 04:49:07,329
HAVE FROM THIS MODEL WHERE EACH

7040
04:49:07,396 --> 04:49:08,731
DOT IS A TUMOR.

7041
04:49:08,798 --> 04:49:10,499
THESE ARE U MAP PROJECTIONS

7042
04:49:10,566 --> 04:49:11,801
SHOWING DIFFERENT CLUSTERS.

7043
04:49:11,867 --> 04:49:13,402
SO WE DON'T GET ALL ONE

7044
04:49:13,469 --> 04:49:14,036
PHENOTYPE.

7045
04:49:14,103 --> 04:49:15,337
WE GET DIFFERENT TYPES OF

7046
04:49:15,404 --> 04:49:16,706
MAMMARY TUMORS.

7047
04:49:16,772 --> 04:49:18,074
AND THEY'RE SIMILAR TO DIFFERENT

7048
04:49:18,140 --> 04:49:21,711
TYPES OF HUMAN BREAST CANCER.

7049
04:49:21,777 --> 04:49:24,346
THEY ALSO TEND TO HAVE DIFFERENT

7050
04:49:24,413 --> 04:49:27,416
MUTATIONS, SO THIS CLUSTER OVER

7051
04:49:27,483 --> 04:49:30,653
HERE IS THE ONE WITH THE P10

7052
04:49:30,720 --> 04:49:32,188
INSERTIONS.

7053
04:49:32,254 --> 04:49:35,157
THIS ONE IS WITH ACTIVATION OF A

7054
04:49:35,224 --> 04:49:36,892
GENE -- THEN WHEN YOU LOOK AT

7055
04:49:36,959 --> 04:49:39,161
THE GCESS CLUSTERS, YOU CAN SEE

7056
04:49:39,228 --> 04:49:42,164
INTERESTING THINGS LIKE THIS IS

7057
04:49:42,231 --> 04:49:44,133
THE TUMORS THAT ARE ER POSITIVE

7058
04:49:44,200 --> 04:49:45,668
AND HAVE HIGH LEVELS OF

7059
04:49:45,735 --> 04:49:49,171
EXPRESSION OF ER-DEPENDENT GENE

7060
04:49:49,238 --> 04:49:50,039
EXPRESSION.

7061
04:49:50,106 --> 04:49:53,342
THESE TUMORS ARE VERY I MAWN

7062
04:49:53,409 --> 04:49:56,579
COLD AND HIGH CELL CYCLE, SO YOU

7063
04:49:56,645 --> 04:49:57,780
CAN CORRELATE THESE MUTATIONS

7064
04:49:57,847 --> 04:49:59,882
WITH A GIVEN CANCER PHENOTYPE.

7065
04:49:59,949 --> 04:50:02,251
AND SO WE'VE DONE THAT TO

7066
04:50:02,318 --> 04:50:05,921
DEVELOP A BUNCH OF

7067
04:50:05,988 --> 04:50:07,056
GENOTYPE/PHENOTYPE CORRELATIONS.

7068
04:50:07,123 --> 04:50:09,658
ONE THAT INTERESTS US, BECAUSE

7069
04:50:09,725 --> 04:50:13,295
OF THE IMMUNE CELL -- PHENOTYPE

7070
04:50:13,362 --> 04:50:18,634
IS -- SO THERE'S A SUBSET OF

7071
04:50:18,701 --> 04:50:22,438
HYPOMETHYLATED JUP HIGH TUMORS,

7072
04:50:22,505 --> 04:50:31,680
AND AS I SAID, THIS JEAN ENCODES

7073
04:50:31,747 --> 04:50:33,315
PLACHYCOBAN, THEREFORE IT'S

7074
04:50:33,382 --> 04:50:34,950
CONFUSING WHETHER IT'S A TUMOR

7075
04:50:35,017 --> 04:50:36,051
SUPPRESSOR OR AN ONCOGENE.

7076
04:50:36,118 --> 04:50:39,221
IT CAN INCREASE 2D AND 3D GROWTH

7077
04:50:39,288 --> 04:50:41,690
IN MODEL SYSTEMS, INCREASES --

7078
04:50:41,757 --> 04:50:45,461
SIGNALING AND ENHANCED -- GENE

7079
04:50:45,528 --> 04:50:45,761
EXPRESSION.

7080
04:50:45,828 --> 04:50:47,429
IF YOU LOOK IN HUMAN BASAL

7081
04:50:47,496 --> 04:50:51,700
BREAST CANCERS, HIGH JUMP IS

7082
04:50:51,767 --> 04:50:54,036
ASSOCIATED WITH THE WORST OUT

7083
04:50:54,103 --> 04:50:56,305
COME, AND IMMUNE SELL -- AS

7084
04:50:56,372 --> 04:50:58,140
MEASURED BY T CELLS IN IHC

7085
04:50:58,207 --> 04:50:59,141
EXPERIMENTS IN HUMAN BREAST

7086
04:50:59,208 --> 04:51:01,243
CANCER.

7087
04:51:01,310 --> 04:51:03,412
SO I SHOWED HOW YOU COULD USE

7088
04:51:03,479 --> 04:51:07,116
RNA SEQ TO GENERATE GENOTYPE

7089
04:51:07,183 --> 04:51:08,117
PHENOTYPE CORRELATIONS AND THAT

7090
04:51:08,184 --> 04:51:10,419
ARE SHOWN HERE.

7091
04:51:10,486 --> 04:51:11,854
AND WE THINK THESE ARE

7092
04:51:11,921 --> 04:51:14,190
CLINICALLY RELEVANT ASSOCIATIONS

7093
04:51:14,256 --> 04:51:17,560
THAT NEED TO BE EXPLORED.

7094
04:51:17,626 --> 04:51:20,329
SO IT MAKES US THINK, IMMUNE

7095
04:51:20,396 --> 04:51:22,331
CELL INFILTRATION AND ACTIVITY

7096
04:51:22,398 --> 04:51:23,666
SYNERGIZE WITH NEW ADJUVANT

7097
04:51:23,732 --> 04:51:25,801
CHEMOTHERAPY TO ALLOW SOME

7098
04:51:25,868 --> 04:51:26,368
OSTEOSARCOMA PATIENTS TO BE

7099
04:51:26,435 --> 04:51:28,270
CURED AND MAY IMPROVE BREAST

7100
04:51:28,337 --> 04:51:29,471
CANCER OUTCOMES AS WELL.

7101
04:51:29,538 --> 04:51:31,440
SO MAYBE IF WE COULD MODULATE

7102
04:51:31,507 --> 04:51:34,176
THE PATHWAYS WE TALKED ABOUT

7103
04:51:34,243 --> 04:51:35,578
EARLIER IN THOSE DISEASES, BUT

7104
04:51:35,644 --> 04:51:38,781
IT ALSO MADE US WONDER WHAT

7105
04:51:38,848 --> 04:51:40,382
IMMUNE CELL AUTONOMOUS

7106
04:51:40,449 --> 04:51:42,384
MECHANISMS COULD BE MODULATED TO

7107
04:51:42,451 --> 04:51:46,989
IMPROVE T-CELL -- INTO THE TUMOR

7108
04:51:47,056 --> 04:51:48,090
AND ACTIVITY.

7109
04:51:48,157 --> 04:51:50,125
NOW INSPIRED BY WORK FROM

7110
04:51:50,192 --> 04:51:51,894
UNIVERSITY OF IOWA, WE'VE BEEN

7111
04:51:51,961 --> 04:51:54,396
DOING SCREENING FOR T-CELL

7112
04:51:54,463 --> 04:51:57,633
AUTONOMOUS GENES AND PATHWAY TO

7113
04:51:57,700 --> 04:51:59,134
REGULATE INFILTRATION INTO

7114
04:51:59,201 --> 04:51:59,368
TUMORS.

7115
04:51:59,435 --> 04:52:01,971
TO DO THIS, WE BUILT A NEW TYPE

7116
04:52:02,037 --> 04:52:03,939
OF TRANS GENE WHERE WE COULD

7117
04:52:04,006 --> 04:52:06,809
TURN SLEEPING BEAUTY, IN THIS

7118
04:52:06,876 --> 04:52:08,277
CASE AN IMPROVED VERSION, WE

7119
04:52:08,344 --> 04:52:09,645
COULD TURN IT ON AND OFF.

7120
04:52:09,712 --> 04:52:13,482
SO THIS IS BOTH PREREGULATED

7121
04:52:13,549 --> 04:52:16,452
AND -- AND DOX REGULATED.

7122
04:52:16,518 --> 04:52:18,287
THE IDEA IS WE CAN HAVE ENOUGH

7123
04:52:18,354 --> 04:52:19,922
TRANSPOSITION TO GET NEW CELL

7124
04:52:19,989 --> 04:52:21,223
PHENOTYPES BUT NOT SUCH

7125
04:52:21,290 --> 04:52:22,992
TRANSPOSITION THAT YOU INDUCE

7126
04:52:23,058 --> 04:52:23,859
CANCER.

7127
04:52:23,926 --> 04:52:28,397
SO WE DID THIS WITH CD2 CRE AND

7128
04:52:28,464 --> 04:52:29,999
CREATED MICE WITH DOXYCYCLINE

7129
04:52:30,065 --> 04:52:31,767
AND I DUED T-CELL MUTAGENESIS.

7130
04:52:31,834 --> 04:52:36,105
WE TOOK THOSE MICE AND OR THE

7131
04:52:36,171 --> 04:52:38,207
TOPICALLY INJECTED A CANCER, SO

7132
04:52:38,274 --> 04:52:40,309
IN THIS CASE, A MOUSE MODEL OF

7133
04:52:40,376 --> 04:52:42,044
PANCREATIC DUCTAL

7134
04:52:42,111 --> 04:52:45,648
ADENOCARCINOMA, CALLED KPC MAU,

7135
04:52:45,714 --> 04:52:47,583
IN COLLABORATION WITH UNIVERSITY

7136
04:52:47,650 --> 04:52:48,050
OF MINNESOTA.

7137
04:52:48,117 --> 04:52:49,885
WE LET TUMOR GROW FOR THREE

7138
04:52:49,952 --> 04:52:53,422
WEEKS OR SO, HARVESTED TUMOR AND

7139
04:52:53,489 --> 04:52:57,826
SPLEEN AND THEN LOOK AT THE --

7140
04:52:57,893 --> 04:52:59,228
IN THE SPLEEN AS A CONTROL OR

7141
04:52:59,295 --> 04:52:59,428
TUMOR.

7142
04:52:59,495 --> 04:53:02,865
A AND WHAT WE'RE LOOKING FOR ARE

7143
04:53:02,932 --> 04:53:05,200
MUTATIONS AND T-CELLS IN TUMORS

7144
04:53:05,267 --> 04:53:08,103
THAT ARE NOT PRESENT OR ENRICHED

7145
04:53:08,170 --> 04:53:11,206
GREATLY ABOVE WHAT YOU'D SEE IN

7146
04:53:11,273 --> 04:53:13,943
THE SPLEEN FROM THE SAME MOUSE.

7147
04:53:14,009 --> 04:53:15,244
SOME EVENTS OCCUR SPECIFICALLY

7148
04:53:15,311 --> 04:53:16,745
IN T CELLS THAT ARE PRESENT IN

7149
04:53:16,812 --> 04:53:20,482
TUMOR AND NOT SPLEEN.

7150
04:53:20,549 --> 04:53:21,717
THE NUMBER ONE CANDIDATE WE GOT

7151
04:53:21,784 --> 04:53:23,218
FROM THAT, ALTHOUGH WE GOT A

7152
04:53:23,285 --> 04:53:26,455
NUMBER OF CANDIDATES, IS CALLED

7153
04:53:26,522 --> 04:53:27,122
O27B.

7154
04:53:27,189 --> 04:53:29,058
THIS GENE IS ALREADY IMPLICATED

7155
04:53:29,124 --> 04:53:33,262
IN T-CELL BIOLOGY, WHERE IT --

7156
04:53:33,329 --> 04:53:41,136
IT'S A DEUBIQUITIN ASE, AND FUSE

7157
04:53:41,203 --> 04:53:45,007
THEM INTO KPC DUE MORE BEARING

7158
04:53:45,074 --> 04:53:45,841
MICE.

7159
04:53:45,908 --> 04:53:47,576
THE MICE WERE TREATED WITH

7160
04:53:47,643 --> 04:53:48,811
IL2 EVERY OTHER DAY.

7161
04:53:48,877 --> 04:53:55,851
AT INPUT -- BUT LATER, IN TUMOR,

7162
04:53:55,918 --> 04:54:00,956
YOU SEE DOUBLE THAT NUMBER OF

7163
04:54:01,023 --> 04:54:03,025
O27B POSITIVE CELLS, SO THEY'RE

7164
04:54:03,092 --> 04:54:04,159
ENRICHED IN THE TUMOR, NOT IN

7165
04:54:04,226 --> 04:54:04,893
THE LYMPH NODE.

7166
04:54:04,960 --> 04:54:06,195
NOW THEY'RE ALSO ENRICHED IN

7167
04:54:06,261 --> 04:54:07,496
SPLEEN AND BLOOD, AND THAT MIGHT

7168
04:54:07,563 --> 04:54:10,265
BE BECAUSE OF THE IL-2 WE'RE

7169
04:54:10,332 --> 04:54:12,668
GIVING.  SO WE THINK THIS IS THE

7170
04:54:12,735 --> 04:54:14,203
TBINNING OF MAYBE A VALIDATION

7171
04:54:14,269 --> 04:54:19,942
OF THIS GENE AS A GENE WHO COULD

7172
04:54:20,009 --> 04:54:20,576
IMPROVE -- IN THE INTEREST OF

7173
04:54:20,643 --> 04:54:22,044
TIME I WON'T GO THROUGH THIS BUT

7174
04:54:22,111 --> 04:54:25,280
WE DID THE SAME KIND OF SCREEN

7175
04:54:25,347 --> 04:54:30,619
BUT FOR -- EXHAUSTION.

7176
04:54:30,686 --> 04:54:34,690
WE GOT -- SEEMS TO CONFER, DRK

7177
04:54:34,757 --> 04:54:35,891
INCLUDING SOME GENES THAT HAVE

7178
04:54:35,958 --> 04:54:37,426
ALREADY BEEN IMPLICATED IN

7179
04:54:37,493 --> 04:54:38,360
T-CELL EXHAUSTION.

7180
04:54:38,427 --> 04:54:40,896
SO I THINK THE IDEA HERE IS WE

7181
04:54:40,963 --> 04:54:42,398
HAVE CANDIDATE GENES THAT MIGHT

7182
04:54:42,464 --> 04:54:43,799
CHANGE T-CELL PHENOTYPE WITH

7183
04:54:43,866 --> 04:54:46,101
REGARD TO ANTITUMOR ACTIVITY.

7184
04:54:46,168 --> 04:54:48,103
WE'D LIKE TO TAKE THOSE

7185
04:54:48,170 --> 04:54:50,839
CANDIDATES, TEST THEM IN

7186
04:54:50,906 --> 04:54:54,676
TUMOR-REACTIVE T CELLS OR TILs

7187
04:54:54,743 --> 04:54:56,612
OR IN FUTURE, WE'RE THINKING

7188
04:54:56,678 --> 04:54:57,913
ABOUT BROADENING THIS IDEA OF

7189
04:54:57,980 --> 04:54:59,648
SCREENS TO OTHER IMMUNE CELL

7190
04:54:59,715 --> 04:55:01,617
TYPES OR OTHER CELL TYPES THAT

7191
04:55:01,683 --> 04:55:05,220
HAVE POTENTIAL FOR REGENERATIVE

7192
04:55:05,287 --> 04:55:10,926
REGENERAL --WE ALSO HOPE SINGLEL

7193
04:55:10,993 --> 04:55:11,860
INSERTION ANALYSIS WILL HELP US

7194
04:55:11,927 --> 04:55:12,928
IN OUR GOALS.

7195
04:55:12,995 --> 04:55:18,700
WHEN WE THINK ABOUT IT, CA CANCR

7196
04:55:18,767 --> 04:55:21,236
CELLS -- HAVE EXTENDED

7197
04:55:21,303 --> 04:55:23,005
LONGEVITY, AND A COMPETITIVE

7198
04:55:23,072 --> 04:55:23,972
ADVANTAGE OVER HOST CELLS SO

7199
04:55:24,039 --> 04:55:25,307
THAT YOU DON'T HAVE TO -- THEY

7200
04:55:25,374 --> 04:55:28,577
CAN MAKE THEIR OWN ROOM.

7201
04:55:28,644 --> 04:55:29,912
BUT WHAT YOU DON'T WANT THEM TO

7202
04:55:29,978 --> 04:55:31,680
DO IS PROLIFERATE WITHOUT NORMAL

7203
04:55:31,747 --> 04:55:33,949
CONTROL OR LOSE THEIR

7204
04:55:34,016 --> 04:55:35,651
DIFFERENTIATION POTENTIAL.

7205
04:55:35,717 --> 04:55:37,519
SO -- AND I THINK THIS SB SYSTEM

7206
04:55:37,586 --> 04:55:40,222
WILL HELP US FIND GENES THAT

7207
04:55:40,289 --> 04:55:42,958
COULD HELP SALES DO THIS AND TRY

7208
04:55:43,025 --> 04:55:44,359
TO AVOID THIS.

7209
04:55:44,426 --> 04:55:47,096
AND THAT'S REALLY WHAT -- KIND

7210
04:55:47,162 --> 04:55:48,397
OF WHAT WE'RE THINKING ABOUT

7211
04:55:48,464 --> 04:55:49,965
WITH THIS LAST BIT OF WORK.

7212
04:55:50,032 --> 04:55:51,300
SO THESE WERE THE PEOPLE THAT

7213
04:55:51,366 --> 04:55:54,336
WERE INVOLVED, AND SOME OF OUR

7214
04:55:54,403 --> 04:55:55,037
FUNDING, AND I'M HAPPY TO TAKE

7215
04:55:55,104 --> 04:55:56,572
ANY QUESTIONS YOU HAVE NOW.

7216
04:55:56,638 --> 04:56:03,879
[APPLAUSE]

7217
04:56:03,946 --> 04:56:05,747
>> SO IT'S A FASCINATING SYSTEM.

7218
04:56:05,814 --> 04:56:08,717
IS THERE ANY BIAS, ARE THERE HOT

7219
04:56:08,784 --> 04:56:13,856
SPOTS OR REFRACTIVE SEQUENCES OR

7220
04:56:13,922 --> 04:56:14,056
SITES?

7221
04:56:14,123 --> 04:56:16,191
>> I GLOSSED OVER ONE MAJOR

7222
04:56:16,258 --> 04:56:17,593
THING, SOURCE OF BIAS, WHICH IS

7223
04:56:17,659 --> 04:56:20,462
MANY OF THE INSERTIONS LAND

7224
04:56:20,529 --> 04:56:22,197
WITHIN -- THEY JUMP AND THEY

7225
04:56:22,264 --> 04:56:24,600
LAND LOCALLY.

7226
04:56:24,666 --> 04:56:25,934
SO WE TRY TO IGNORE THE LOCAL

7227
04:56:26,001 --> 04:56:27,336
HOPS AND DO EVERY SCREEN WITH

7228
04:56:27,402 --> 04:56:29,638
TWO DIFFERENT DONORS, ONE WHERE

7229
04:56:29,705 --> 04:56:31,507
IT'S ON ONE CHROMOSOME AND

7230
04:56:31,573 --> 04:56:33,709
WITHIN WHERE THE TRONS POE SONS

7231
04:56:33,775 --> 04:56:34,476
ON ANOTHER.

7232
04:56:34,543 --> 04:56:36,345
WE ALSO THINK THE RNA SEQ

7233
04:56:36,411 --> 04:56:37,646
ANALYSIS OF THESE POPULATIONS

7234
04:56:37,713 --> 04:56:39,414
HELPS CLARIFY WHAT'S BEING

7235
04:56:39,481 --> 04:56:41,150
SELECTED FOR, BY SEEING THE SAME

7236
04:56:41,216 --> 04:56:42,584
KIND OF FUSION TRANSCRIPTS.

7237
04:56:42,651 --> 04:56:45,888
>> SO YOU SHOULD BE ABLE TO SEEP

7238
04:56:45,954 --> 04:56:50,125
THAT WITH SOME BIOINFORMATICS.

7239
04:56:50,192 --> 04:56:51,927
>> YEAH.

7240
04:56:51,994 --> 04:56:53,562
WITH REGARD TO OTHER GENOMIC

7241
04:56:53,629 --> 04:56:54,863
FEATURES, IT'S RELATIVELY

7242
04:56:54,930 --> 04:56:57,533
NEUTRAL, SO SB TRANSPOSON

7243
04:56:57,599 --> 04:57:01,003
INSERTION IS AFFECTED A LOT LESS

7244
04:57:01,069 --> 04:57:03,105
BY GENOMIC CONTEXT THAN BY

7245
04:57:03,172 --> 04:57:06,408
VIRUSES OR OTHER TRANSPOSONS IN

7246
04:57:06,475 --> 04:57:06,575
USE.

7247
04:57:06,642 --> 04:57:08,911
>> SO YOU THINK ABOUT LOOKING AT

7248
04:57:08,977 --> 04:57:12,214
ALSO EPIGENETIC CHANGES COMPARED

7249
04:57:12,281 --> 04:57:12,714
TO GENETIC CHANGES?

7250
04:57:12,781 --> 04:57:14,716
>> THAT'S A GREAT QUESTION.

7251
04:57:14,783 --> 04:57:16,785
WE HAVE -- YOU KNOW, I THINK IF

7252
04:57:16,852 --> 04:57:18,820
WE CAN DO THE SINGLE CELL

7253
04:57:18,887 --> 04:57:21,423
ANALYSES, YOU KNOW, THAT I

7254
04:57:21,490 --> 04:57:23,158
ALLUDED TO AT THE END, WE COULD

7255
04:57:23,225 --> 04:57:24,927
SEE FOR ANY GIVEN INSERTION HOW

7256
04:57:24,993 --> 04:57:27,129
FAR IS THE EFFECT, YOU KNOW, ON

7257
04:57:27,196 --> 04:57:32,234
NEIGHBORING GENES.

7258
04:57:32,301 --> 04:57:34,236
A MORE CREATIVE THING, INSTEAD

7259
04:57:34,303 --> 04:57:39,241
OF MOBILIZING A PROMOTOR,

7260
04:57:39,308 --> 04:57:42,644
MOBILIZE SIS REGULATORY

7261
04:57:42,711 --> 04:57:44,246
SEQUENCES, LIKE BORDER ELEMENTS

7262
04:57:44,313 --> 04:57:47,149
AND SEE WHAT YOU COULD LEARN BY

7263
04:57:47,216 --> 04:57:48,383
PERTURBING THE GENOME IN THAT

7264
04:57:48,450 --> 04:57:49,051
WAY.

7265
04:57:49,117 --> 04:57:52,020
I WOULD SAY THE CANCER SCREENS

7266
04:57:52,087 --> 04:57:57,392
THAT WE DO, THEY DO REVEAL

7267
04:57:57,459 --> 04:57:58,994
RECURRENT MUTATIONS IN READERS

7268
04:57:59,061 --> 04:58:00,529
AND WRITERS FOR SURE, JUST LIKE

7269
04:58:00,596 --> 04:58:08,136
IN HUMAN CANCER.

7270
04:58:08,203 --> 04:58:09,037
>> OTHER QUESTIONS?

7271
04:58:09,104 --> 04:58:10,405
>> GREAT TALK.

7272
04:58:10,472 --> 04:58:12,841
IN THE TUMOR SUPPRESSOR GENE

7273
04:58:12,908 --> 04:58:17,212
KNOCKOUT, DO YOU NEED BOTH

7274
04:58:17,279 --> 04:58:18,647
COPIES TO BE INACTIVATED?

7275
04:58:18,714 --> 04:58:19,414
>> GOOD QUESTION.

7276
04:58:19,481 --> 04:58:21,950
WHEN WE FIRST DID THIS, WE

7277
04:58:22,017 --> 04:58:23,585
THOUGHT WE WON'T GET ANY TUMOR

7278
04:58:23,652 --> 04:58:24,453
SUPPRESSORS BECAUSE IT HAS TO

7279
04:58:24,519 --> 04:58:26,088
HIT BOTH COPIES AND THAT'S NOT

7280
04:58:26,154 --> 04:58:27,089
GOING TO HAPPEN LIKELY BY

7281
04:58:27,155 --> 04:58:27,322
CHANCE.

7282
04:58:27,389 --> 04:58:29,658
BUT INSTEAD WE RECOVER A LOT OF

7283
04:58:29,725 --> 04:58:31,059
TUMOR SUPPRESSOR GENE INSERTIONS

7284
04:58:31,126 --> 04:58:34,529
AND IN SOME TUMORS, IT'S ONE

7285
04:58:34,596 --> 04:58:35,764
INSERTION IN EACH ALLELE.

7286
04:58:35,831 --> 04:58:38,667
IN OTHER CASES, WE THINK WHAT'S

7287
04:58:38,734 --> 04:58:40,435
HAPPENED IS HAPLOINSUFFICIENCY,

7288
04:58:40,502 --> 04:58:41,903
SO IN THE RIGHT GENETIC CONTEXT,

7289
04:58:41,970 --> 04:58:43,405
YOU ONLY NEED TO LOSE ONE COPY

7290
04:58:43,472 --> 04:58:43,905
OF P10.

7291
04:58:43,972 --> 04:58:45,140
AND WE HAVE SOME EVIDENCE FOR

7292
04:58:45,207 --> 04:58:47,276
THAT IN TUMORS WHERE WE TOOK THE

7293
04:58:47,342 --> 04:58:48,543
TUMOR, WE MADE CLONAL CELL LINES

7294
04:58:48,610 --> 04:58:51,780
AND YOU CAN SEE THAT EXACT KIND

7295
04:58:51,847 --> 04:58:53,582
OF DIVERSITY WHERE SOME SELLS IN

7296
04:58:53,649 --> 04:58:56,752
THE TUMOR HAD THOSE INSERTION

7297
04:58:56,818 --> 04:58:58,954
AND THEN -- IN OTHERS THEY

7298
04:58:59,021 --> 04:59:01,823
RETAIN A WILD TYPE ALLELE.

7299
04:59:01,890 --> 04:59:04,960
>> ANYBODY ELSE?

7300
04:59:05,027 --> 04:59:07,863
ANYBODY ONLINE?

7301
04:59:07,929 --> 04:59:12,134
>> THE CSF R HAD EXPRESSION --

7302
04:59:12,200 --> 04:59:21,943
MEANS OF IMMUNE SILENCING.

7303
04:59:22,010 --> 04:59:22,577
YOU WEREN'T SURE WHETHER THAT

7304
04:59:22,644 --> 04:59:23,812
WAS WORKING THROUGH DECOY OR

7305
04:59:23,879 --> 04:59:24,313
SOME OTHER PROGRAM.

7306
04:59:24,379 --> 04:59:27,115
SO I GUESS I MIGHT HAVE THROWN

7307
04:59:27,182 --> 04:59:29,251
CSF ON TO THAT OR USED A DECOY

7308
04:59:29,318 --> 04:59:31,119
TO TRY TO RECAPITULATE IT OR

7309
04:59:31,186 --> 04:59:31,653
SOMETHING LIKE THAT?

7310
04:59:31,720 --> 04:59:33,055
>> THAT'S WHAT WE WANT TO DO

7311
04:59:33,121 --> 04:59:33,355
NOW.

7312
04:59:33,422 --> 04:59:34,956
SO WHEN WE LOOKED AT THE SERUM

7313
04:59:35,023 --> 04:59:36,258
OF THESE MICE, INDEED THEY HAD

7314
04:59:36,325 --> 04:59:38,794
HIGH LEVELS OF SHED CSF 1R,

7315
04:59:38,860 --> 04:59:44,066
COMING FROM THE TUMOR.

7316
04:59:44,132 --> 04:59:46,468
AND THEY HAD LOWER LEVELS IN

7317
04:59:46,535 --> 04:59:50,539
CIRCULATION, SO THERE IS A DECOY

7318
04:59:50,605 --> 04:59:51,506
EFFECT, BUT WHETHER THAT'S

7319
04:59:51,573 --> 04:59:52,708
RESPONSIBLE FOR THE IMMUNE COLD

7320
04:59:52,774 --> 04:59:53,875
ENVIRONMENT OR NOT, WE'RE NOT

7321
04:59:53,942 --> 04:59:57,079
SURE.

7322
04:59:57,145 --> 05:00:00,749
SO IT'S WEIRD BECAUSE -- BECAUSE

7323
05:00:00,816 --> 05:00:02,384
PEOPLE THINK -- SO THIS WOULD

7324
05:00:02,451 --> 05:00:04,720
SUGGEST WE SHOULD PUT CSF 1 IN

7325
05:00:04,786 --> 05:00:05,854
THE TUMOR AND GET THE IMMUNE

7326
05:00:05,921 --> 05:00:08,223
CELLS BACK, BUT GENERALLY CSF

7327
05:00:08,290 --> 05:00:09,291
1 EXPRESSION IN TUMORS IS

7328
05:00:09,358 --> 05:00:09,991
THOUGHT OF AS A BAD THING

7329
05:00:10,058 --> 05:00:11,860
BECAUSE IT RECRUITS

7330
05:00:11,927 --> 05:00:15,364
IMMUNOSUPPRESSIVE MACROPHAGE.

7331
05:00:15,430 --> 05:00:17,432
BUT I THINK THAT REMAINS TO BE

7332
05:00:17,499 --> 05:00:19,501
SEEN.

7333
05:00:19,568 --> 05:00:20,602
>> THANKS.

7334
05:00:20,669 --> 05:00:28,877
[APPLAUSE]

7335
05:00:28,944 --> 05:00:33,682
>> LAST BUT NOT LEAST, JOHN

7336
05:00:33,749 --> 05:00:34,449
KAFFIN.

7337
05:00:34,516 --> 05:00:35,917
ONE MORE UW-MADISON GRADUATE

7338
05:00:35,984 --> 05:00:36,518
HERE.

7339
05:00:36,585 --> 05:00:38,587
WORKING WITH HOWARD TENMAN.

7340
05:00:38,653 --> 05:00:42,023
HE DID A POSTDOC AND IN 1975 WAS

7341
05:00:42,090 --> 05:00:43,158
RECRUITED TO THE FACULTY AT

7342
05:00:43,225 --> 05:00:43,992
TUFTS.

7343
05:00:44,059 --> 05:00:49,097
MOST NOTABLY FOR SPHOD TODAY'S ,

7344
05:00:49,164 --> 05:00:51,600
HE SERVED AS DIRECTOR FROM 1997

7345
05:00:51,666 --> 05:00:51,900
UNTIL 2005.

7346
05:00:51,967 --> 05:00:53,301
IN ADDITION TO HIS FACULTY

7347
05:00:53,368 --> 05:00:54,870
APPOINTMENT AT TUFTS, JOHN HAS

7348
05:00:54,936 --> 05:00:56,438
MAINTAINED HIS CLOSE TIES TO THE

7349
05:00:56,505 --> 05:00:59,708
DRP AND THE NCI SERVING AS A

7350
05:00:59,775 --> 05:01:00,976
SPECIAL ADVISER TO THE DIRECTOR

7351
05:01:01,042 --> 05:01:03,245
OF NCI CENTER FOR CANCER

7352
05:01:03,311 --> 05:01:05,180
RESEARCH.

7353
05:01:05,247 --> 05:01:06,648
JOHN'S RESEARCH FOCUS ON GETTING

7354
05:01:06,715 --> 05:01:08,183
A BETTER UNDERSTANDING OF THE

7355
05:01:08,250 --> 05:01:10,318
REACTION OF RETROVIRUSES AND

7356
05:01:10,385 --> 05:01:12,020
HOST CELLS AND ORGANISMS, HE'S A

7357
05:01:12,087 --> 05:01:13,021
LEADING AUTHORITY IN THIS AREA.

7358
05:01:13,088 --> 05:01:14,656
THE TITLE OF JOHN'S TALK TODAY

7359
05:01:14,723 --> 05:01:17,726
IS VIRUS VERSUS VIRUS, HUMAN

7360
05:01:17,793 --> 05:01:20,796
ENDOGENOUS RETROVIRUSES AS

7361
05:01:20,862 --> 05:01:21,463
ANTIRETROVIRAL RESTRICTION

7362
05:01:21,530 --> 05:01:21,696
FACTORS.

7363
05:01:21,763 --> 05:01:31,940
[APPLAUSE]

7364
05:01:32,140 --> 05:01:32,874
>> THANK YOU, ERIC.

7365
05:01:32,941 --> 05:01:34,176
THIS HAS BEEN A REALLY FUN DAY

7366
05:01:34,242 --> 05:01:34,609
FOR ME.

7367
05:01:34,676 --> 05:01:38,447
I HAVE TO SAY, IT'S BEEN A

7368
05:01:38,513 --> 05:01:39,981
REALLY WONDERFUL SERIES OF TALKS

7369
05:01:40,048 --> 05:01:41,016
PRECEDING THIS.

7370
05:01:41,082 --> 05:01:44,486
ON ALL OF THE TALKS I NOTE IT

7371
05:01:44,553 --> 05:01:47,556
INVOLVED VERY ELEGANT GENETIC

7372
05:01:47,622 --> 05:01:53,128
ENGINEERING TO ACCOMPLISH GOALS

7373
05:01:53,195 --> 05:01:54,896
PARTICULARLY USING VIRUSES AND

7374
05:01:54,963 --> 05:01:59,301
FOR VARIOUS PURPOSES.

7375
05:01:59,367 --> 05:02:00,402
I WANT TO CHANGE THE SUBJECT A

7376
05:02:00,469 --> 05:02:02,704
LITTLE BIT.

7377
05:02:02,771 --> 05:02:04,339
THE THING -- ENGINEERING A VIRUS

7378
05:02:04,406 --> 05:02:06,875
TO DO THINGS THAT ARE USEFUL FOR

7379
05:02:06,942 --> 05:02:15,183
YOU, BUT WITHOUT A HUMAN TOUCH,

7380
05:02:15,250 --> 05:02:17,419
ENTIRELY BY NATURE OVER THE

7381
05:02:17,486 --> 05:02:19,254
COURSE OF THE LAST 10 MILLION

7382
05:02:19,321 --> 05:02:21,122
YEARS OR SO IS THE RANGE WE'RE

7383
05:02:21,189 --> 05:02:26,194
GOING TO SPAN IN THIS TALK.

7384
05:02:26,261 --> 05:02:32,534
SO I'LL FIRST SHOW YOU MY VIEW

7385
05:02:32,601 --> 05:02:35,136
OF SORT OF THE PROCESS OF HOST

7386
05:02:35,203 --> 05:02:35,804
RETROVIRUS EVOLUTION.

7387
05:02:35,871 --> 05:02:37,005
THE THING TO REMEMBER ABOUT

7388
05:02:37,072 --> 05:02:39,441
VECTOR VIRUSES, UNLIKE ALMOST

7389
05:02:39,508 --> 05:02:41,009
ALL OTHER VIRUSES WITH A VERY

7390
05:02:41,076 --> 05:02:42,410
FEW RARE EXCEPTIONS, THEY'VE

7391
05:02:42,477 --> 05:02:43,545
LEFT BEHIND A FOSSIL RECORD THAT

7392
05:02:43,612 --> 05:02:44,646
WE CAN LOOK AT.

7393
05:02:44,713 --> 05:02:47,282
THIS HAS BEEN ALLUDED TO BEFORE,

7394
05:02:47,349 --> 05:02:48,917
AND IT'S IN THIS FOSSIL RECORD

7395
05:02:48,984 --> 05:02:53,655
WE'RE USING TO TRY TO CARVE OUT

7396
05:02:53,722 --> 05:02:54,789
IMPORTANT FEATURES.

7397
05:02:54,856 --> 05:02:58,360
YOU CAN VISUALIZE, WITH MY

7398
05:02:58,426 --> 05:03:02,297
ELEGANT COMPUTER GRAPHICS, THE

7399
05:03:02,364 --> 05:03:04,933
PROCESS OF HOST-VIRUS EVOLUTION

7400
05:03:05,000 --> 05:03:06,368
IN VERY BROAD TERMS.

7401
05:03:06,434 --> 05:03:09,371
IN GENERAL, THE -- REVOLUTION OF

7402
05:03:09,437 --> 05:03:16,778
THE VIRUS AND HOST IS OFTEN THE

7403
05:03:16,845 --> 05:03:19,314
RELATIVELY BENIGN RELATIONSHIP.

7404
05:03:19,381 --> 05:03:22,817
SO LIKE COMMON COLD VIRUSES AND

7405
05:03:22,884 --> 05:03:23,885
OTHER VIRUSES THAT CIRCULATE

7406
05:03:23,952 --> 05:03:25,253
WITHOUT KILLING US, THE VIRUSES

7407
05:03:25,320 --> 05:03:27,255
DO OKAY, WE MAY GET A LITTLE

7408
05:03:27,322 --> 05:03:28,557
UNCOMFORTABLE BUT WE DO OKAY IN

7409
05:03:28,623 --> 05:03:32,727
GENERAL, THAT'S THE USUAL

7410
05:03:32,794 --> 05:03:33,361
CIRCUMSTANCE.

7411
05:03:33,428 --> 05:03:35,497
BUT WHEN WE GO TO ANOTHER

7412
05:03:35,564 --> 05:03:36,998
SPECIES, ALL OF THE CONTROLS

7413
05:03:37,065 --> 05:03:38,099
THAT ARE BUILT INTO THAT OR A

7414
05:03:38,166 --> 05:03:40,735
LOT OF THEM ON THE HOST SIDE

7415
05:03:40,802 --> 05:03:42,103
HAVE GONE AWAY, AND YOU GET A

7416
05:03:42,170 --> 05:03:44,039
SITUATION WHERE THE VIRUS CAN BE

7417
05:03:44,105 --> 05:03:48,076
QUITE LETHAL ACTUALLY, OR CAUSE

7418
05:03:48,143 --> 05:03:48,843
CONSIDERABLE MORTALITY.

7419
05:03:48,910 --> 05:03:49,778
THAT CAN'T GO ON.

7420
05:03:49,844 --> 05:03:52,080
THERE'S GOT TO BE ONE OR ANOTHER

7421
05:03:52,147 --> 05:03:53,815
END POINT OF THIS, ONE OF WHICH

7422
05:03:53,882 --> 05:03:58,553
IS THE HOST CAN'T RECOVER -- CAN

7423
05:03:58,620 --> 05:04:00,889
REBOUND, THOSE EXTINCT, THOSE --

7424
05:04:00,956 --> 05:04:03,625
THE VIRUS GOES EXTINCT, AND THE

7425
05:04:03,692 --> 05:04:04,859
OTHERS, THEY RE-ESTABLISH A NICE

7426
05:04:04,926 --> 05:04:06,161
WORKING RELATIONSHIP LIKE YOU

7427
05:04:06,227 --> 05:04:11,399
SEE IN THE BEGINNING.

7428
05:04:11,466 --> 05:04:13,168
WE CAN'T TELL WHAT HAPPENED

7429
05:04:13,234 --> 05:04:14,603
BECAUSE WE HAD NO TRACES LEFT OF

7430
05:04:14,669 --> 05:04:16,271
THIS PROCESS, EXCEPT IN THE CASE

7431
05:04:16,338 --> 05:04:18,340
OF RETROVIRUSES, WHERE THEY

7432
05:04:18,406 --> 05:04:21,276
OFTEN, NOT ALWAYS BUT OFTEN CAN

7433
05:04:21,343 --> 05:04:23,211
GET INTO THE GERMLINE AND LEAVE

7434
05:04:23,278 --> 05:04:25,080
BEHIND A PROVIRUS THAT CAN LAST

7435
05:04:25,146 --> 05:04:26,715
FOREVER ESSENTIALLY THROUGH MANY

7436
05:04:26,781 --> 05:04:29,351
MILLIONS OF YEARS OF SUBSEQUENT

7437
05:04:29,417 --> 05:04:31,019
EVOLUTION AND LEAVE US WITH A

7438
05:04:31,086 --> 05:04:38,226
FOSSIL RECORD OF THIS PROCESS.

7439
05:04:38,293 --> 05:04:40,729
IN ADDITION THE VIRUS CAN

7440
05:04:40,795 --> 05:04:41,529
SOMETIMES PARTICIPATE IN THE

7441
05:04:41,596 --> 05:04:42,163
EXTINCTION AND THAT'S WHAT I

7442
05:04:42,230 --> 05:04:44,265
WANT TO TALK ABOUT TODAY.

7443
05:04:44,332 --> 05:04:46,234
SO AS THE COURSE OF EVOLUTION

7444
05:04:46,301 --> 05:04:47,335
GOES ALONG, YOU EFFICIENTLY END

7445
05:04:47,402 --> 05:04:55,810
EEFNTEVENTUALLY ENDUP WITH HUMAS

7446
05:04:55,877 --> 05:04:58,580
RETROVIRUS, AFFECT NATTILY CAL

7447
05:04:58,647 --> 05:05:02,717
CALLED HRS, AND THE FOSSIL

7448
05:05:02,784 --> 05:05:13,061
RECORD WE STUDY.

7449
05:05:16,431 --> 05:05:19,801
THE BLUE SQUARES, SUBSPECIES,

7450
05:05:19,868 --> 05:05:21,703
ALL OF WHICH ARE VISIBLY RELATED

7451
05:05:21,770 --> 05:05:26,975
TO EXTANT EXOGENOUS VIRUSES,

7452
05:05:27,042 --> 05:05:29,044
INFECTIOUS VIRUSES AND OTHER

7453
05:05:29,110 --> 05:05:34,983
SPECIES, AND THEY TELL US THAT

7454
05:05:35,050 --> 05:05:36,618
THROUGHOUT OUR EVOLUTIONARY

7455
05:05:36,685 --> 05:05:38,086
HISTORY, LOOKING BACK MAYBE

7456
05:05:38,153 --> 05:05:40,789
20 MILLION YEARS OR SO, MAYBE

7457
05:05:40,855 --> 05:05:45,427
EVEN A LITTLE MORE, WE CAN SEE

7458
05:05:45,493 --> 05:05:51,666
EVIDENCE FOR AT LEAST 30

7459
05:05:51,733 --> 05:05:54,936
PREVIOUS PANDEMICS THAT HAVE

7460
05:05:55,003 --> 05:05:57,839
AFFECTED OUR DISTANT ANCESTORS.

7461
05:05:57,906 --> 05:05:59,340
AND I'M GOING TO FOCUS ON ONE

7462
05:05:59,407 --> 05:06:02,210
GROUP IN PARTICULAR, WHICH IT'S

7463
05:06:02,277 --> 05:06:12,620
CALLED HERV-K HML-2.

7464
05:06:13,955 --> 05:06:15,356
IT'S THE ONE THAT LOOKS MOST

7465
05:06:15,423 --> 05:06:17,158
LIKE THE MAMMARY TUMOR VIRUS OF

7466
05:06:17,225 --> 05:06:20,195
MICE, AND THAT SITS WAY IN THE

7467
05:06:20,261 --> 05:06:21,296
RETROVIRUS GENUS WAY OVER IN THE

7468
05:06:21,362 --> 05:06:26,101
CORNER THERE, AND THIS IS A MOST

7469
05:06:26,167 --> 05:06:28,903
RECENT VIRUS.

7470
05:06:28,970 --> 05:06:33,241
EVEN TODAY, I SAW THE ENDOGENOUS

7471
05:06:33,308 --> 05:06:35,543
RETROVIRUSES REFERRED TO AS --

7472
05:06:35,610 --> 05:06:36,845
RETRO TRANSPOSONS.

7473
05:06:36,911 --> 05:06:37,812
THESE ARE NOT TRANSPOSONS.

7474
05:06:37,879 --> 05:06:39,347
ONCE THEY'RE IN THE GERMLINE,

7475
05:06:39,414 --> 05:06:41,316
THERE'S NO EVIDENCE, ALTHOUGH

7476
05:06:41,382 --> 05:06:42,984
PEOPLE OFTEN SAY IT, THERE'S NO

7477
05:06:43,051 --> 05:06:44,519
EVIDENCE THAT THESE CAN

7478
05:06:44,586 --> 05:06:47,622
TRANSPOSE WITHIN THE SINGLE CE

7479
05:06:47,689 --> 05:06:53,394
CELL.

7480
05:06:53,461 --> 05:06:55,063
THEY CAN MOVE SOMEWHERE ELSE IN

7481
05:06:55,130 --> 05:06:57,165
THE BODY, BUT IT GETS INTO THE

7482
05:06:57,232 --> 05:06:59,100
GERMLINE -- THAT'S THE ONLY

7483
05:06:59,167 --> 05:07:00,635
MECHANISM WE KNOW FOR ALMOST ALL

7484
05:07:00,702 --> 05:07:01,669
OF THESE VIRUSES.

7485
05:07:01,736 --> 05:07:03,071
VERY OCCASIONALLY THEY WILL

7486
05:07:03,138 --> 05:07:09,778
EVOLVE INTO A TRANSPOSON.

7487
05:07:09,844 --> 05:07:11,880
MORE RECENT ONES HAVE DONE THIS.

7488
05:07:11,946 --> 05:07:14,082
SO I THINK I DARE TO THE GENOME

7489
05:07:14,149 --> 05:07:15,517
NOT AS THE BATTLEGROUND BUT AS

7490
05:07:15,583 --> 05:07:20,321
THE GRAVEYARD FOR THESE VIRUSES.

7491
05:07:20,388 --> 05:07:22,423
BUT THE REMAINS THAT ARE IN

7492
05:07:22,490 --> 05:07:23,191
THESE GRAVES, LOOKING AT THEM

7493
05:07:23,258 --> 05:07:26,161
CAN TELL US A LOT, AND ALSO, OF

7494
05:07:26,227 --> 05:07:28,029
COURSE, OCCASIONALLY THESE

7495
05:07:28,096 --> 05:07:29,164
VIRUSES ARE DOING SOMETHING

7496
05:07:29,230 --> 05:07:33,301
USEFUL FOR US.

7497
05:07:33,368 --> 05:07:39,874
SO IN BROAD TERMS, THEY CAN DO

7498
05:07:39,941 --> 05:07:41,342
THINGS LIKE INDUCING A NEW OR

7499
05:07:41,409 --> 05:07:44,846
VIRAL GENE THAT CAN BE COOPTED

7500
05:07:44,913 --> 05:07:46,247
LIKE SIN SIGH DIN WHICH WAS

7501
05:07:46,314 --> 05:07:49,684
MENTIONED ALREADY TODAY TO PLAY

7502
05:07:49,751 --> 05:07:51,553
AN IMPORTANT ROLE IN FETAL

7503
05:07:51,619 --> 05:07:51,986
DEVELOPMENT.

7504
05:07:52,053 --> 05:07:54,189
THEY CAN LEAD TO INSERTIONAL

7505
05:07:54,255 --> 05:07:55,256
INACTIVATION OR ACTIVATION OF

7506
05:07:55,323 --> 05:08:00,128
GENES.

7507
05:08:00,195 --> 05:08:02,864
INTRODUCTION OF THE

7508
05:08:02,931 --> 05:08:04,399
TRANSCRIPTIONAL MACHINE -- THEY

7509
05:08:04,465 --> 05:08:08,803
CAN MODIFY GENE EXPRESSION, BY

7510
05:08:08,870 --> 05:08:10,171
TURNING IT ON IN CELL TYPES

7511
05:08:10,238 --> 05:08:11,840
WHERE IT'S NOT ALWAYS PRESENT,

7512
05:08:11,906 --> 05:08:14,809
THEY CAN BECOME PARTS OF -- YOU

7513
05:08:14,876 --> 05:08:16,277
CAN STILL SEE THEM AS EXPRESSED

7514
05:08:16,344 --> 05:08:23,585
THAT WAY.

7515
05:08:23,651 --> 05:08:29,490
THEY CAN ALSO DO PATHOGENESIS,

7516
05:08:29,557 --> 05:08:32,026
BY REPLICATION OF PROGENY OF

7517
05:08:32,093 --> 05:08:33,528
INTACT PROVIRUS, THIS IS NOT

7518
05:08:33,595 --> 05:08:35,797
POSSIBLE IN HUMANS AS FAR AS WE

7519
05:08:35,864 --> 05:08:37,966
KNOW, THEY PROVIDE A FOSSIL

7520
05:08:38,032 --> 05:08:39,167
RECORD, BUT MOST IMPORTANT THING

7521
05:08:39,234 --> 05:08:40,869
THAT THESE CAN DO IS THEY CAN

7522
05:08:40,935 --> 05:08:41,736
PROVIDE PROTECTION FROM

7523
05:08:41,803 --> 05:08:44,806
INFECTION BY RELATED VIRUS,

7524
05:08:44,873 --> 05:08:47,108
WHICH IS ITSELF QUITE

7525
05:08:47,175 --> 05:08:47,942
PATHOGENIC.

7526
05:08:48,009 --> 05:08:49,677
AND I POSTULATE AND WE THINK ONE

7527
05:08:49,744 --> 05:08:50,445
OF THE IMPORTANT THINGS IF YOU

7528
05:08:50,511 --> 05:08:51,980
THINK BACK TO THAT TREE, ONE

7529
05:08:52,046 --> 05:08:53,147
CHARACTERISTIC THAT'S SHARED BY

7530
05:08:53,214 --> 05:08:58,253
ALL OF THE VIRUSES, THEY'RE ALL

7531
05:08:58,319 --> 05:08:59,053
EXTINCT.

7532
05:08:59,120 --> 05:09:03,858
ALL OF THE INFECTIOUS VIRUSES --

7533
05:09:03,925 --> 05:09:04,092
EXTINCT.

7534
05:09:04,158 --> 05:09:07,729
I THINK THIS MAY BE DUE IN PART

7535
05:09:07,795 --> 05:09:10,598
TO THIS PHENOMENON, SO THAT'S

7536
05:09:10,665 --> 05:09:14,535
WHAT I WANT TO TALK ABOUT.

7537
05:09:14,602 --> 05:09:16,638
THERE ARE SEVERAL MECHANISMS

7538
05:09:16,704 --> 05:09:18,172
THAT HAVE BEEN AROUND A LONG

7539
05:09:18,239 --> 05:09:21,175
TIME, PARTICULARLY IN ANIMAL

7540
05:09:21,242 --> 05:09:23,011
MODELS, IT'S EASY TO VISUALIZE

7541
05:09:23,077 --> 05:09:25,079
HOW AN EXOGENOUS PROTEIN CAN

7542
05:09:25,146 --> 05:09:26,180
PREVENT INFECTION OF THE SAME

7543
05:09:26,247 --> 05:09:27,215
VIRUS FROM OUTSIDE.

7544
05:09:27,282 --> 05:09:30,785
FOR EXAMPLE, IN THE TOP DIE

7545
05:09:30,852 --> 05:09:35,823
GRAND CANYONDIAGRAMTHERE, IT CAR

7546
05:09:35,890 --> 05:09:38,226
FOR THAT PARTICULAR VIRUS AND

7547
05:09:38,293 --> 05:09:39,427
THAT CAN OF COURSE BLOCK

7548
05:09:39,494 --> 05:09:40,862
INFECTION FROM OUTSIDE, AND THAT

7549
05:09:40,929 --> 05:09:42,297
COULD BE EITHER A FULL LENGTH --

7550
05:09:42,363 --> 05:09:44,499
GENE IN SOME CASES, THERE IS A

7551
05:09:44,565 --> 05:09:48,703
PROTEIN CA WHICH IS JUST A FRAGT

7552
05:09:48,770 --> 05:09:50,305
THAT CONTAINS RECEPTOR-BINDING

7553
05:09:50,371 --> 05:09:52,607
DOMAIN, AND THEY BOTH DO THE

7554
05:09:52,674 --> 05:09:53,541
SAME THING.

7555
05:09:53,608 --> 05:09:55,176
ANOTHER CASE, THIS IS WHAT WE'LL

7556
05:09:55,243 --> 05:09:58,579
GET TO THIS WITH THU THIS ONE, E

7557
05:09:58,646 --> 05:10:02,150
YOU HAVE A SELF ASSEMBLING

7558
05:10:02,216 --> 05:10:04,652
PROTEIN THAT CONSISTS OF -- A

7559
05:10:04,719 --> 05:10:06,454
VUK TOUR THAT CONSISTS OF MANY

7560
05:10:06,521 --> 05:10:09,390
COPIES OF THE SAME MOLECULE.

7561
05:10:09,457 --> 05:10:10,892
THAT OCCASIONALLY CAN BE.SOINED

7562
05:10:10,959 --> 05:10:16,798
BEPOISONED BY A MUTANT BUT THAT

7563
05:10:16,864 --> 05:10:18,700
CANNOT BE ADDED ON TO, OR OTHER

7564
05:10:18,766 --> 05:10:20,068
WAYS TO DISRUPT THE STRUCTURE

7565
05:10:20,134 --> 05:10:22,437
AND FUNCTION OF THAT STRUCTURE.

7566
05:10:22,503 --> 05:10:24,539
VERY STRONG DOMINANT FASHION.

7567
05:10:24,605 --> 05:10:26,708
SO YOU GET A TRANS DOMINANT GENE

7568
05:10:26,774 --> 05:10:29,277
THAT CAN BLOCK THAT KIND OF

7569
05:10:29,344 --> 05:10:39,520
ASSEMBLY.

7570
05:10:40,054 --> 05:10:42,156
ONE CASE THAT'S KNOWN, THE

7571
05:10:42,223 --> 05:10:43,257
INCOMING VIRUS BLOCKS INFECTION

7572
05:10:43,324 --> 05:10:45,293
AND ANOTHER NOAB CASE IS A CASE

7573
05:10:45,360 --> 05:10:47,261
OF A VIRUS ACTUALLY RELATED TO

7574
05:10:47,328 --> 05:10:51,599
THE ONES I'M GOING TO TALK ABO

7575
05:10:51,666 --> 05:10:55,336
ABOUT, THERE'S AN ENDOGENOUS

7576
05:10:55,403 --> 05:10:57,772
VIRUS THERE THAT CAUSES THE

7577
05:10:57,839 --> 05:11:00,408
ASSEMBLING GAG GENE TO GO TO THE

7578
05:11:00,475 --> 05:11:03,144
WRONG PLACE IN THE CELL AND GET

7579
05:11:03,211 --> 05:11:13,388
DEGRADED.

7580
05:11:13,688 --> 05:11:14,956
THE RETROVIRUSES OVERALL,

7581
05:11:15,023 --> 05:11:15,790
THERE'S SOMETHING LIKE EIGHT'

7582
05:11:15,857 --> 05:11:17,091
THOUSAND DIFFERENT BITS AND

7583
05:11:17,158 --> 05:11:18,626
PIECES OF -- 80,000 DIFFERENT

7584
05:11:18,693 --> 05:11:20,762
BITS AND PIECES OF DNA THAT

7585
05:11:20,828 --> 05:11:23,064
COMES FROM OUR GENOME FROM THE

7586
05:11:23,131 --> 05:11:30,004
PROCESS OF ENDOGENOUS PR

7587
05:11:30,071 --> 05:11:30,872
PROVIRUSES, NOT IN OUR DNA, FOR

7588
05:11:30,938 --> 05:11:33,408
THE MOST PART THEIR EXPRESSION

7589
05:11:33,474 --> 05:11:36,811
IS HIGHLY REGULATED BY BOTH

7590
05:11:36,878 --> 05:11:39,447
EPIGENETIC CELL-SPECIFIC

7591
05:11:39,514 --> 05:11:40,548
EFFECTS, TRANS EFFECTS, AND SOME

7592
05:11:40,615 --> 05:11:48,122
OF THAT PROBABLY REFLECTS TO

7593
05:11:48,189 --> 05:11:51,526
SOME EXTENT PRESERVATION, SO IF

7594
05:11:51,592 --> 05:11:52,760
YOU CAN LOOK AT THAT, CAN YOU

7595
05:11:52,827 --> 05:11:54,062
GET SOME INFORMATION FROM THAT,

7596
05:11:54,128 --> 05:11:55,063
ALTHOUGH I'M NOT GOING TO TALK

7597
05:11:55,129 --> 05:11:56,764
ABOUT THAT RIGHT NOW.

7598
05:11:56,831 --> 05:11:58,366
AT THE TIME OF INTEGRATION OF

7599
05:11:58,433 --> 05:12:01,469
THE GENOME, ALL BUT A FEW,

7600
05:12:01,536 --> 05:12:03,638
HOWEVER, WERE VIRUS, NOT

7601
05:12:03,704 --> 05:12:04,072
TRANSPOSONS.

7602
05:12:04,138 --> 05:12:14,482
SO WE ACTUALLY KNOW THAT FOR

7603
05:12:14,549 --> 05:12:18,853
SOME VIRUSES BECAUSE IT'S BEEN

7604
05:12:18,920 --> 05:12:20,755
SHOWN -- STRONG PURIFYING

7605
05:12:20,822 --> 05:12:21,856
SELECTION, MEANING IT'S NEEDED

7606
05:12:21,923 --> 05:12:25,126
TO OFFER ALL THE -- THE VIRUS

7607
05:12:25,193 --> 05:12:26,127
HAS BEEN GOING BACK AND FORTH

7608
05:12:26,194 --> 05:12:26,794
AROUND THE GENOME.

7609
05:12:26,861 --> 05:12:28,763
AS FAR AS WE KNOW, THE MOST

7610
05:12:28,830 --> 05:12:32,200
RECENT ACQUISITION OF ANY HERV

7611
05:12:32,266 --> 05:12:38,039
WAS BY -- OF HML-2s WAS OVER

7612
05:12:38,106 --> 05:12:38,573
300,000 YEARS AGO.

7613
05:12:38,639 --> 05:12:42,076
THIS IS THE ONLY ONE THAT'S

7614
05:12:42,143 --> 05:12:44,612
POLYMORPHIC IN THE GENOME OF

7615
05:12:44,679 --> 05:12:48,416
HUMANS.

7616
05:12:48,483 --> 05:12:50,017
A LOT OF THE PROVIRUSES STILL

7617
05:12:50,084 --> 05:12:52,854
ARE CAPABLE OF BEING EXPRESSED

7618
05:12:52,920 --> 05:12:55,423
AND EVEN EXPRESSING PROTEINS AND

7619
05:12:55,490 --> 05:12:56,958
EVEN EXPRESSING DEFECTIVE

7620
05:12:57,024 --> 05:12:57,425
VIRULENCE.

7621
05:12:57,492 --> 05:12:58,726
AND THAT'S OFTEN SEEN IN CANCER

7622
05:12:58,793 --> 05:13:00,294
AND VARIOUS OTHER DISEASES.

7623
05:13:00,361 --> 05:13:04,465
SOME CANCERS, FOR EXAMPLE, ARE

7624
05:13:04,532 --> 05:13:08,936
CHARACTERIZED BY THE COPIOUS

7625
05:13:09,003 --> 05:13:11,606
PRODUCTION.

7626
05:13:11,672 --> 05:13:13,074
-- ONE SPECIFIC PROVIRUS THAT

7627
05:13:13,141 --> 05:13:15,009
HAPPENS TO HAVE A GOOD GAG GENE.

7628
05:13:15,076 --> 05:13:16,344
IT'S NOT LIKE ALL OF THEM ARE

7629
05:13:16,410 --> 05:13:17,545
BEING EXPRESSED IN ONE DIFFERENT

7630
05:13:17,612 --> 05:13:17,745
WAY.

7631
05:13:17,812 --> 05:13:19,313
ONE OF THEM HAPPENS TO BE

7632
05:13:19,380 --> 05:13:20,781
EXPRESSED BECAUSE OF ITS

7633
05:13:20,848 --> 05:13:24,252
LOCATION OR ITS LTR COMPOSITION

7634
05:13:24,318 --> 05:13:26,287
TO BE EXPRESSED IN THIS KIND OF

7635
05:13:26,354 --> 05:13:28,923
CANCER CELL, AND MAKE COPIOUS

7636
05:13:28,990 --> 05:13:30,424
PARTICLES.

7637
05:13:30,491 --> 05:13:33,961
THE NOMENCLATURE IS VERY MESSY.

7638
05:13:34,028 --> 05:13:36,364
WE REFER TO THEM BY THEIR

7639
05:13:36,430 --> 05:13:37,932
CHROMOSOMAL -- ROUGHLY

7640
05:13:37,999 --> 05:13:41,369
CHROMOSOMAL LOCATION, I.E., THE

7641
05:13:41,435 --> 05:13:44,105
CHROMOSOME BAND THAT THEY'RE IN.

7642
05:13:44,172 --> 05:13:45,740
SO THE ONE I WANT TO TALK ABOUT

7643
05:13:45,806 --> 05:13:53,114
PARTICULARLY IS ONE AT 38Q12.3,

7644
05:13:53,181 --> 05:13:55,316
CHROMOSOME 3 -- 12.3, AND THAT

7645
05:13:55,383 --> 05:13:56,784
IS ONE THAT'S REALLY GOING TO BE

7646
05:13:56,851 --> 05:13:59,086
THE FOCUS OF THE REST OF THE

7647
05:13:59,153 --> 05:14:00,821
TALK.

7648
05:14:00,888 --> 05:14:02,690
THIS CHART WAS PUT TOGETHER IN

7649
05:14:02,757 --> 05:14:03,791
MY LAB SOME YEARS AGO.

7650
05:14:03,858 --> 05:14:07,361
HE WENT THROUGH THE WHOLE HUMAN

7651
05:14:07,428 --> 05:14:08,996
GENOME AS A SEQUENCE OF WHAT WAS

7652
05:14:09,063 --> 05:14:12,200
KNOWN AT THAT TIME.

7653
05:14:12,266 --> 05:14:14,168
AND PULLED OUT ALL THE

7654
05:14:14,235 --> 05:14:17,371
PROVIRUSES OF THIS GROUP.

7655
05:14:17,438 --> 05:14:19,240
AND THEN LOOKED AT THEM, YOU SEE

7656
05:14:19,307 --> 05:14:21,342
A LITTLE BIT OF MARKS ON THE

7657
05:14:21,409 --> 05:14:21,842
PROVIRUSES.

7658
05:14:21,909 --> 05:14:23,778
THAT'S A MUTATION THAT CAUSES

7659
05:14:23,844 --> 05:14:25,046
DEFECTIVENESS OF A PARTICULAR

7660
05:14:25,112 --> 05:14:25,513
GENE.

7661
05:14:25,580 --> 05:14:27,315
YOU CAN SEE ALMOST ALL OF THESE

7662
05:14:27,381 --> 05:14:28,716
ARE AFFECTED ONE WAY OR THE

7663
05:14:28,783 --> 05:14:29,317
OTHER.

7664
05:14:29,383 --> 05:14:32,186
WITH VERY FEW EXCEPTIONS.

7665
05:14:32,253 --> 05:14:34,388
ONE POWERFUL THING HERE IS THAT

7666
05:14:34,455 --> 05:14:36,357
WHEN YOU KNOW THIS, YOU KNOW THE

7667
05:14:36,424 --> 05:14:38,926
CODING CAPACITY, YOU JUST LOOK

7668
05:14:38,993 --> 05:14:40,361
AT THE DATA UNDERLYING IT AND

7669
05:14:40,428 --> 05:14:42,663
SEE WHAT THE CODING CAPACITY OF

7670
05:14:42,730 --> 05:14:44,432
THIS IS, THEN YOU LOOK AT THE

7671
05:14:44,498 --> 05:14:46,434
TUMOR OR SOMETHING, PULL OUT

7672
05:14:46,500 --> 05:14:48,169
JUST DO RNA SEQ AND PULL OUT

7673
05:14:48,236 --> 05:14:49,403
FRAGMENTS OF RNA TO COME FROM

7674
05:14:49,470 --> 05:14:52,807
ANY OF THESE, JUST FROM A FRAG

7675
05:14:52,873 --> 05:14:53,941
FRAGMENT OF RNA, YOU CAN TELL

7676
05:14:54,008 --> 05:14:55,109
EXACTLY WHAT THE CODING CAPACITY

7677
05:14:55,176 --> 05:14:56,177
OF THAT PROVIRUS IS.

7678
05:14:56,244 --> 05:14:57,612
IT'S A VERY POWER TESTIMONY TOOL

7679
05:14:57,678 --> 05:15:02,350
POWERFUL TOOL TO USETO STUDY EXN

7680
05:15:02,416 --> 05:15:03,117
TUMORS AND SO ON.

7681
05:15:03,184 --> 05:15:05,786
SO THE PROVIRUS IN PARTICULAR

7682
05:15:05,853 --> 05:15:08,956
MARKED BY THE BLUE CIRCLE, I HAD

7683
05:15:09,023 --> 05:15:11,259
TO GET A BIT OF NOMENCLATURE,

7684
05:15:11,325 --> 05:15:12,360
I'LL SHOW YOU MORE ABOUT THIS IN

7685
05:15:12,426 --> 05:15:13,527
A MINUTE, YOU CAN SUBDIVIDE

7686
05:15:13,594 --> 05:15:18,366
THESE INTO THREE GROUPS,

7687
05:15:18,432 --> 05:15:28,109
TREE IS THAT THESE ARE

7688
05:15:28,175 --> 05:15:29,543
INTEGRATED INTO -- THESE

7689
05:15:29,610 --> 05:15:31,178
APPEARED IN THE TREE AT A TIME

7690
05:15:31,245 --> 05:15:34,915
THAT'S CONSISTENT WITH BEING

7691
05:15:34,982 --> 05:15:36,284
INTEGRATED INTO COMMON ANCESTOR

7692
05:15:36,350 --> 05:15:37,585
HUMANS AND GORILLAS.

7693
05:15:37,652 --> 05:15:40,087
SO THAT'S ON THE ORDER OF

7694
05:15:40,154 --> 05:15:42,256
MILLIONS OF YEARS AGO.

7695
05:15:42,323 --> 05:15:51,365
THE OTHER ONE, THE 22Q11.3 IS IN

7696
05:15:51,432 --> 05:15:58,839
PART ANCESTRAL TO THE -- THIS ON

7697
05:15:58,906 --> 05:16:00,474
THE LEFT SHOWS YOU ANALYSIS OF

7698
05:16:00,541 --> 05:16:03,010
ALL OF THESE WITH THE SAME COLOR

7699
05:16:03,077 --> 05:16:04,312
CODING AS BEFORE, AND YOU CAN

7700
05:16:04,378 --> 05:16:07,014
SEE THAT THE PICK ONES, THE

7701
05:16:07,081 --> 05:16:08,949
LTR5V, ARE ANCESTRAL TO THE

7702
05:16:09,016 --> 05:16:16,490
OTHER TWO GROUPS, THE 5HS IN

7703
05:16:16,557 --> 05:16:18,559
BLUE, AND SOMETHING ELSE I HAVE

7704
05:16:18,626 --> 05:16:24,699
TO TELL YOU IS THAT PAUL

7705
05:16:24,765 --> 05:16:26,600
BIENIASZ'S LAB SOME YEARS AGO

7706
05:16:26,667 --> 05:16:27,802
DID A VERY CLEVER EXPERIMENT,

7707
05:16:27,868 --> 05:16:30,204
THE VERY, VERY SHORT BRANCHES,

7708
05:16:30,271 --> 05:16:31,939
THOSE ARE THE MOST RECENT

7709
05:16:32,006 --> 05:16:34,008
INTEGRATED IN OUR DNA.

7710
05:16:34,075 --> 05:16:35,443
ON THE PRINCIPLE THAT THESE WERE

7711
05:16:35,509 --> 05:16:37,845
ALL INFECTIOUS AT THE TIME THEY

7712
05:16:37,912 --> 05:16:39,213
WERE INTEGRATED, SO THEY

7713
05:16:39,280 --> 05:16:40,514
PROBABLY ARE ALL VERY CLOSELY

7714
05:16:40,581 --> 05:16:41,782
RELATED TO ONE ANOTHER, VERY

7715
05:16:41,849 --> 05:16:43,384
SIMILAR TO ONE ANOTHER, AND WITH

7716
05:16:43,451 --> 05:16:44,585
ALL THE MUTATIONS THAT MAKE THEM

7717
05:16:44,652 --> 05:16:46,220
DIFFERENT HAVE OCCURRED SINCE,

7718
05:16:46,287 --> 05:16:48,356
SO THE CONSENSUS SEQUENCE FROM

7719
05:16:48,422 --> 05:16:50,291
ALL OF THOSE PROVIRUSES, AND

7720
05:16:50,358 --> 05:16:52,460
THEY'RE ABLE TO RECONSTRUCT AN

7721
05:16:52,526 --> 05:16:53,561
INFECTIOUS VIRUS FROM THAT,

7722
05:16:53,627 --> 05:16:58,933
WHICH IS CALLED HERV KCON, FOR

7723
05:16:58,999 --> 05:17:02,236
CONSENSUS, AND THIS IS INDEED

7724
05:17:02,303 --> 05:17:03,270
INFECTIOUS PROVIRUS, SO WE'VE

7725
05:17:03,337 --> 05:17:04,472
USED THIS FOR QUITE A NUMBER OF

7726
05:17:04,538 --> 05:17:04,905
OUR EXPERIMENTS.

7727
05:17:04,972 --> 05:17:08,776
WE USE IT IN A WAY THAT OFTEN

7728
05:17:08,843 --> 05:17:09,810
HAS IN THE PLACE OF THE ENVELOPE

7729
05:17:09,877 --> 05:17:11,112
GENE, THERE'S ACTUALLY BEEN PUT

7730
05:17:11,178 --> 05:17:15,583
A GFP OR SOME OTHER MARKER, AND

7731
05:17:15,649 --> 05:17:18,819
IT'S MADE BY TRANSFECTING CELLS

7732
05:17:18,886 --> 05:17:21,789
WITH THIS CLONE AND BY

7733
05:17:21,856 --> 05:17:24,291
TRANSFECTING VSVG ENVELOPE SO IT

7734
05:17:24,358 --> 05:17:26,327
CAN BE EASILY USED TO INFECT

7735
05:17:26,394 --> 05:17:27,862
CELLS.

7736
05:17:27,928 --> 05:17:29,864
SO THIS PARTICULAR PROVIRUS NOW,

7737
05:17:29,930 --> 05:17:34,835
WE'RE BACK TO 3Q12.3, HAS A MORE

7738
05:17:34,902 --> 05:17:37,004
INTERESTING CHARACTERISTIC.

7739
05:17:37,071 --> 05:17:38,973
8 TO 12 MILLION YEARS OLD,

7740
05:17:39,039 --> 05:17:41,776
AND -- A COMPLETE GAG PROTEIN,

7741
05:17:41,842 --> 05:17:42,977
BUT -- ARE ALL DISRUPTED.

7742
05:17:43,043 --> 05:17:44,278
BUT IT HAS GAG.

7743
05:17:44,345 --> 05:17:48,048
AND GAG FOR THE NON-RETRO

7744
05:17:48,115 --> 05:17:51,218
VIEROLOGISTS, EC EXPRESSION ALOE

7745
05:17:51,285 --> 05:17:53,454
IS ENOUGH TO MAKE GOOD LOOKING

7746
05:17:53,521 --> 05:17:57,892
VIRUS PARTICLES.

7747
05:17:57,958 --> 05:18:00,394
REMARKABLY, THERE IS A FOUR-BASE

7748
05:18:00,461 --> 05:18:02,263
PAIR DUPLICATION IN THE 5 PRIME

7749
05:18:02,329 --> 05:18:05,299
LTR BUT NOT IN THE 3 PRIME LTR.

7750
05:18:05,366 --> 05:18:08,669
THE GOOD RETROVIROLOGISTS WILL

7751
05:18:08,736 --> 05:18:09,770
IMMEDIATELY RECOGNIZE THAT

7752
05:18:09,837 --> 05:18:11,138
DUPLICATION MUST HAVE OCCURRED

7753
05:18:11,205 --> 05:18:13,107
AFTER THE LTRs WERE MADE, MOST

7754
05:18:13,174 --> 05:18:15,643
LIKELY AFTER INTEGRATION.

7755
05:18:15,709 --> 05:18:18,846
WE DON'T YET HAVE GOOD EVIDENCE

7756
05:18:18,913 --> 05:18:20,414
FOR REASONS I DON'T WANT TO GET

7757
05:18:20,481 --> 05:18:21,715
INTO, THAT THIS ACTUALLY

7758
05:18:21,782 --> 05:18:24,218
HAPPENED RELATIVELY RECENTLY,

7759
05:18:24,285 --> 05:18:28,656
PROBABLY WITHIN THE LAST 5 1/2

7760
05:18:28,722 --> 05:18:29,857
MILLION YEARS OR SO BUT WE DON'T

7761
05:18:29,924 --> 05:18:30,858
KNOW THAT FOR SURE.

7762
05:18:30,925 --> 05:18:32,560
IT'S SOMETHING I REALLY WANT TO

7763
05:18:32,626 --> 05:18:33,627
KNOW AND SHOULD BE ABLE TO KNOW

7764
05:18:33,694 --> 05:18:34,728
BUT WE DON'T KNOW IT YET.

7765
05:18:34,795 --> 05:18:36,730
BUT THE OTHER THING, REMARKABLE

7766
05:18:36,797 --> 05:18:38,766
THING ABOUT THIS DUPLICATION,

7767
05:18:38,833 --> 05:18:43,537
IT'S A DUPLICATION OF A --

7768
05:18:43,604 --> 05:18:44,004
SEQUENCE.

7769
05:18:44,071 --> 05:18:48,742
THE GATTGATT IS A BINDING SITE

7770
05:18:48,809 --> 05:18:55,082
FOR A FAMILY OF TRANS KRIPTION N

7771
05:18:55,149 --> 05:18:58,552
FACTORS. TRANSCRIPTION

7772
05:18:58,619 --> 05:18:58,986
FACTOR.

7773
05:18:59,053 --> 05:19:04,091
IF YOU TAKE AN LTR, SORT OF --

7774
05:19:04,158 --> 05:19:08,696
ASSAY, TACK ON LUCIFERASE AND

7775
05:19:08,762 --> 05:19:11,765
LOOK FOR LUCIFERASE ACTIVITY AND

7776
05:19:11,832 --> 05:19:13,667
YOU THEN REVERT THAT -- YOU TAKE

7777
05:19:13,734 --> 05:19:16,070
OUT THE DUPLICATION BASICALLY,

7778
05:19:16,136 --> 05:19:19,807
SO THAT GOES BACK TO WHAT --

7779
05:19:19,874 --> 05:19:24,378
ALMOST THE ANCESTRAL TYPE IN THE

7780
05:19:24,445 --> 05:19:25,980
3 -- YOU SEE THAT GREATLY

7781
05:19:26,046 --> 05:19:26,680
REDUCES ACTIVITY.

7782
05:19:26,747 --> 05:19:31,452
SO THIS CREATION OF THIS

7783
05:19:31,519 --> 05:19:37,958
REDUPLICATION WAS CLEARLY

7784
05:19:38,025 --> 05:19:39,660
IMPORTANT IN -- THE EXPRESSION

7785
05:19:39,727 --> 05:19:40,528
OF THIS PROVIRUS.

7786
05:19:40,594 --> 05:19:41,862
YOU CAN SEE THAT REALLY HERE.

7787
05:19:41,929 --> 05:19:43,697
THIS IS A STUDY THAT WAS DONE

7788
05:19:43,764 --> 05:19:47,401
PUBLISHED ABOUT A YEAR AGO WHERE

7789
05:19:47,468 --> 05:19:49,336
TOP TO BOTTOM ARE ALL THE

7790
05:19:49,403 --> 05:19:52,273
DIFFERENT PROVIRUSES,

7791
05:19:52,339 --> 05:19:54,108
COLOR-CODED, AND ACROSS ARE ALL

7792
05:19:54,174 --> 05:19:55,342
HUMAN TISSUES.

7793
05:19:55,409 --> 05:20:00,681
THIS IS A VERY LARGE DATASET OF

7794
05:20:00,748 --> 05:20:02,349
EXPRESSION -- OF RNA SEQ

7795
05:20:02,416 --> 05:20:03,484
ANALYSIS FROM DIFFERENT HUMAN

7796
05:20:03,551 --> 05:20:04,351
TISSUES.

7797
05:20:04,418 --> 05:20:07,087
AND WHAT CAN IMMEDIATELY CATCH

7798
05:20:07,154 --> 05:20:11,525
YOUR EYE IS 3Q12.3 IS EXPRESSED

7799
05:20:11,592 --> 05:20:13,394
IN EVERY SINGLE SOLID TISSUE IN

7800
05:20:13,460 --> 05:20:13,861
THE BODY.

7801
05:20:13,928 --> 05:20:15,329
IT'S NOT EXPRESSED,

7802
05:20:15,396 --> 05:20:16,764
INTERESTINGLY, IN WHOLE BLOOD --

7803
05:20:16,830 --> 05:20:18,899
ACTUALLY IS A LITTLE BIT, WE'VE

7804
05:20:18,966 --> 05:20:21,001
LOOKED MORE SPECIFICALLY AT

7805
05:20:21,068 --> 05:20:22,269
PBMCs, THERE'S A VERY LOW

7806
05:20:22,336 --> 05:20:24,171
EXPRESSION BUT YOU DON'T SEE IT

7807
05:20:24,238 --> 05:20:26,073
IN WHOLE BLOOD, BUT EVERY OTHER

7808
05:20:26,140 --> 05:20:28,509
TISSUE IS EXPRESSED -- THIS IS

7809
05:20:28,576 --> 05:20:31,712
THE SAME PROVIRUS WITH THE

7810
05:20:31,779 --> 05:20:32,446
INTACT GAG GENE.

7811
05:20:32,513 --> 05:20:34,148
IT'S A TINY FRAGMENT, ACTUALLY

7812
05:20:34,214 --> 05:20:37,217
NOT EXPRESSED FROM THE LTR, IT'S

7813
05:20:37,284 --> 05:20:38,319
EXPRESSED AS PART OF ANOTHER

7814
05:20:38,385 --> 05:20:44,058
GENE.

7815
05:20:44,124 --> 05:20:45,092
SO THAT'S ONE INTERESTING

7816
05:20:45,159 --> 05:20:49,530
FEATURE OF THIS PROVIRUS.

7817
05:20:49,597 --> 05:20:53,734
THE SUPPRESSION OF THE GAG GENE

7818
05:20:53,801 --> 05:20:58,172
OF EVOLUTION, IF YOU LIKE,

7819
05:20:58,238 --> 05:20:59,006
ANCESTRAL -- THERE'S STILL MORE

7820
05:20:59,073 --> 05:21:01,308
YET TO COME.

7821
05:21:01,375 --> 05:21:03,377
SO IF WE HAVE A LOOK AT THE

7822
05:21:03,444 --> 05:21:04,945
TREES THAT RELATE, I SHOWED YOU

7823
05:21:05,012 --> 05:21:07,915
ONE OF THESE BEFORE BUT THIS NOW

7824
05:21:07,982 --> 05:21:09,683
IS SEPARATED BY GENES.

7825
05:21:09,750 --> 05:21:13,587
IF WE NOW RELATE GAG, RT AND

7826
05:21:13,654 --> 05:21:15,389
ENVELOPE GENES, WE ALSO SEE

7827
05:21:15,456 --> 05:21:18,092
ABOUT THE SAME GENERAL PATTERN,

7828
05:21:18,158 --> 05:21:19,793
AND EVERYTHING IS ABOUT THE SAME

7829
05:21:19,860 --> 05:21:21,462
PLACE AS YOU MIGHT EXPECT, AND

7830
05:21:21,528 --> 05:21:24,698
YOU CAN SEE HOW THE 5B

7831
05:21:24,765 --> 05:21:27,701
PROVIRUSES ARE ANCESTRAL IN BOTH

7832
05:21:27,768 --> 05:21:30,437
THE 5HS AND 5A.

7833
05:21:30,504 --> 05:21:36,577
THE BLUE EARMARKS THE 3Q12.3.

7834
05:21:36,644 --> 05:21:38,312
THERE'S A VERY LONG BRANCH LIKE

7835
05:21:38,379 --> 05:21:39,847
WITHIN THE GAG GENE, BUT

7836
05:21:39,913 --> 05:21:42,683
EVERYTHING ELSE -- BUT -- AND

7837
05:21:42,750 --> 05:21:46,153
THAT THE PAL GENE ACTUALLY GOES

7838
05:21:46,220 --> 05:21:47,388
WITH 5B PROVIRUSES.

7839
05:21:47,454 --> 05:21:49,490
IT'S ACTUALLY RIGHT NEXT TO THE

7840
05:21:49,556 --> 05:21:53,460
ONE I SORT OF MENTIONED BEFORE,

7841
05:21:53,527 --> 05:21:54,028
22Q11.23.

7842
05:21:54,094 --> 05:21:56,296
BUT WHEN YOU GO BACK TO END, YOU

7843
05:21:56,363 --> 05:22:00,934
COME BACK TO -- YOU COME BACK UP

7844
05:22:01,001 --> 05:22:04,672
TO BEING NESTLED IN WITH THE

7845
05:22:04,738 --> 05:22:06,540
OTHER 5HS PROVIRUSES.

7846
05:22:06,607 --> 05:22:12,579
YOU'LL NOTICE ALSO THE RED ARROW

7847
05:22:12,646 --> 05:22:15,149
POINTS TO 22Q11.3 AND THOSE ARE

7848
05:22:15,215 --> 05:22:17,217
RIGHT NEXT TO EACH OTHER, SO IT

7849
05:22:17,284 --> 05:22:18,385
SUGGESTS THERE'S BEEN A

7850
05:22:18,452 --> 05:22:19,787
RECOMBINATION OF THAT.

7851
05:22:19,853 --> 05:22:21,989
THERE WAS AN HISTORICAL

7852
05:22:22,056 --> 05:22:23,090
RECOMBINATION EVENT THAT JOINED

7853
05:22:23,157 --> 05:22:26,894
THESE TWO PRO VICE PROVIRUSES.

7854
05:22:26,960 --> 05:22:27,861
YOU CAN SEE THAT IN THE SEQUENCE

7855
05:22:27,928 --> 05:22:29,430
OF THESE TWO, YOU CAN SEE THE

7856
05:22:29,496 --> 05:22:30,564
CROSSOVER PATTERN DOWN BELOW AND

7857
05:22:30,631 --> 05:22:31,765
YOU CAN SEE THE POINTS OF THE

7858
05:22:31,832 --> 05:22:32,332
CROSSOVER.

7859
05:22:32,399 --> 05:22:34,468
ABOUT IN THE MIDDLE OF THE GAG

7860
05:22:34,535 --> 05:22:36,970
GENE, GO THROUGH 5HS TO MIDDLE

7861
05:22:37,037 --> 05:22:40,708
OF THE GAG GENE TO 22Q11.23 AND

7862
05:22:40,774 --> 05:22:43,377
BACK TO A 5HS PROVIRUS IN THE

7863
05:22:43,444 --> 05:22:45,412
MIDDLE OF THE POL GENE.

7864
05:22:45,479 --> 05:22:46,847
THE POSITION IS TURNS OUT THAT

7865
05:22:46,914 --> 05:22:48,882
CROSSOVER IN GAG IS ACTUALLY

7866
05:22:48,949 --> 05:22:50,517
QUITE IMPORTANT IN THE PHENOTYPE

7867
05:22:50,584 --> 05:22:55,122
OF THIS PROVIRUS.

7868
05:22:55,189 --> 05:23:05,666
SO IT'S AN OLD PROVIRUS, AND

7869
05:23:07,367 --> 05:23:12,740
3 IM. 12-POINT #AND WE'VE GOT AN

7870
05:23:12,806 --> 05:23:15,142
HERE FOR DOING SOMETHING

7871
05:23:15,209 --> 05:23:15,743
INTERESTING.

7872
05:23:15,809 --> 05:23:20,981
SO AGAIN, WE HI HYPOTHESIZE, THS

7873
05:23:21,048 --> 05:23:24,418
HAS TURNED INTO A TRANSCRIPTION

7874
05:23:24,485 --> 05:23:25,085
FACTOR.

7875
05:23:25,152 --> 05:23:26,286
YOU SEE EXACTLY THIS KIND OF

7876
05:23:26,353 --> 05:23:27,554
THING HAPPEN, THERE ARE SEVERAL

7877
05:23:27,621 --> 05:23:33,827
MECHANISMS I ALREADY DISCUSSED.

7878
05:23:33,894 --> 05:23:36,163
AND SO IS THIS, IN FACT -- IS

7879
05:23:36,230 --> 05:23:37,631
EXPRESSION OF THIS GAG GENE IN

7880
05:23:37,698 --> 05:23:39,366
SOME WAY SUPPRESSIVE OR

7881
05:23:39,433 --> 05:23:43,170
REPLICATION OF THE ANCESTRAL

7882
05:23:43,237 --> 05:23:46,740
HML-2 VIRUS, WHICH IS NOW

7883
05:23:46,807 --> 05:23:51,779
REPRESENTED -- AND WHAT -- IF IT

7884
05:23:51,845 --> 05:23:56,049
IS, WHAT STAGE DOES IT WORK, AND

7885
05:23:56,116 --> 05:23:57,484
WHAT DOMAINS IN GAG ARE

7886
05:23:57,551 --> 05:23:58,085
IMPORTANT AND SO ON.

7887
05:23:58,152 --> 05:23:59,620
AND IS IT EVIDENCE, FOR EXAMPLE,

7888
05:23:59,686 --> 05:24:01,455
FOR PURIFYING SELECTION OF THIS,

7889
05:24:01,522 --> 05:24:02,623
WHICH WOULD BE A CHARACTERISTIC

7890
05:24:02,689 --> 05:24:03,924
YOU WOULD EXPECT TO SEE FOR

7891
05:24:03,991 --> 05:24:04,825
SOMETHING THAT WAS BEING

7892
05:24:04,892 --> 05:24:06,260
STRONGLY SELECTED IN THIS WAY.

7893
05:24:06,326 --> 05:24:12,800
SO WE'LL START WITH -- DOESN'T

7894
05:24:12,866 --> 05:24:13,801
DO ANYTHING AS FAR AS WE KNOW

7895
05:24:13,867 --> 05:24:15,669
BUT IT'S ABOUT THE SAME AGE.

7896
05:24:15,736 --> 05:24:20,707
AND ON THE LEFT, ON THE TOP IS

7897
05:24:20,774 --> 05:24:24,511
THE WHOLE PROVIRUS, 3Q12.3, AND

7898
05:24:24,578 --> 05:24:26,113
YOU CAN SEE ABOVE GAG, THERE'S

7899
05:24:26,180 --> 05:24:27,881
ACTUALLY A SPOT.

7900
05:24:27,948 --> 05:24:34,121
SO THE PA BARS HERE, WE SCANNEDE

7901
05:24:34,188 --> 05:24:38,525
GTEX -- WE SCANNED THE THOUSAND

7902
05:24:38,592 --> 05:24:39,793
GENOMES PROJECT WHICH IS

7903
05:24:39,860 --> 05:24:43,030
ACTUALLY ABOUT 2500 HUMAN GENOME

7904
05:24:43,096 --> 05:24:44,498
SEQUENCES, ABOUT 5,000 SEQUENCES

7905
05:24:44,565 --> 05:24:48,569
ACTUALLY, IF YOU THINK EVERYBODY

7906
05:24:48,635 --> 05:24:52,272
IS DUPLICATING, AND ON THE -- IS

7907
05:24:52,339 --> 05:24:57,010
THE FREQUENCY OF THE -- ALLELE

7908
05:24:57,077 --> 05:25:00,247
OF ALL THESE PEOPLE.

7909
05:25:00,314 --> 05:25:02,416
SO THESE 5,000 SEQUENCES, LOOK

7910
05:25:02,482 --> 05:25:03,483
FOR SEQUENCES THAT ARE DIFFERENT

7911
05:25:03,550 --> 05:25:04,484
FROM THE MAJORITY.

7912
05:25:04,551 --> 05:25:08,222
THE FREQUENCY OF THOSE, IT GOES

7913
05:25:08,288 --> 05:25:11,158
UP -- IT NEVER GOES ABOVE 50%

7914
05:25:11,225 --> 05:25:12,993
OTHERWISE THEN IT BECOMES A

7915
05:25:13,060 --> 05:25:13,994
MAJOR ALLELE, BUT IT GOES UP

7916
05:25:14,061 --> 05:25:16,930
PRETTY CLOSE IN SOME OF THESE.

7917
05:25:16,997 --> 05:25:18,465
BUT YOU'LL NOTICE PARTICULARLY

7918
05:25:18,532 --> 05:25:21,702
IN THE CAPSID REGION, THE GAG

7919
05:25:21,768 --> 05:25:23,804
GENE AT THE BOTTOM, THERE IS NOT

7920
05:25:23,871 --> 05:25:29,977
A SY SINGLE DIFFERENT NUCLEOTIDE

7921
05:25:30,043 --> 05:25:31,245
AMONG ANYBODY IN THE WORLD AS

7922
05:25:31,311 --> 05:25:32,512
FAR AS WE CAN TELL FROM THIS.

7923
05:25:32,579 --> 05:25:35,716
LESS THAN 5,000 MUTATIONS HAVE

7924
05:25:35,782 --> 05:25:38,418
OCCURRED SINCE THIS WAS LAST

7925
05:25:38,485 --> 05:25:40,921
COALESCED, IF YOU LIKE.

7926
05:25:40,988 --> 05:25:42,456
SINCE EVERY GENE COMES FROM ONE

7927
05:25:42,522 --> 05:25:45,158
PERSON AND AT SOME POINT IN THE

7928
05:25:45,225 --> 05:25:47,361
DISTANT PAST, WHICH IS CALLED

7929
05:25:47,427 --> 05:25:47,794
COALESCENCE POINT.

7930
05:25:47,861 --> 05:25:49,763
SINCE THAT POINT, THERE HASN'T

7931
05:25:49,830 --> 05:25:52,566
BEEN A SINGLE CHANGE.

7932
05:25:52,633 --> 05:25:55,435
WHICH -- QUITE RECENT.

7933
05:25:55,502 --> 05:25:57,871
AND SIMILARLY THE SAME THING IS

7934
05:25:57,938 --> 05:25:59,740
TRUE OF THE MATRIX PROTEIN, ALL

7935
05:25:59,806 --> 05:26:00,874
THOSE THAT'S FAIRLY SMALL SO

7936
05:26:00,941 --> 05:26:02,209
IT'S NOT QUITE AS SIGNIFICANT,

7937
05:26:02,276 --> 05:26:03,510
THEN BY COMPARISON, YOU CAN SEE

7938
05:26:03,577 --> 05:26:07,014
THIS NON-CODING PROVIRUS OVER --

7939
05:26:07,080 --> 05:26:09,182
ON THE RIGHT THAT SHOWS LOTS OF

7940
05:26:09,249 --> 05:26:11,585
ACCUMULATION CHANGE.

7941
05:26:11,652 --> 05:26:12,352
ALL RIGHT.

7942
05:26:12,419 --> 05:26:19,092
SO TO SEE HOW RESEARCH -- FACTOR

7943
05:26:19,159 --> 05:26:22,729
WORK, WE'LL TAKE THE FOLLOWING

7944
05:26:22,796 --> 05:26:24,932
EXPERIMENTAL APPROACH.

7945
05:26:24,998 --> 05:26:30,771
IF YOU -- TRANS FEX WITH THE --

7946
05:26:30,837 --> 05:26:37,611
AND AL also you make pseudovirus

7947
05:26:37,678 --> 05:26:41,515
with various gag genes, cores of

7948
05:26:41,581 --> 05:26:43,417
interest or just gag genes as

7949
05:26:43,483 --> 05:26:47,854
the case may be with gag --

7950
05:26:47,921 --> 05:26:53,527
and -- and then often with a --

7951
05:26:53,593 --> 05:26:57,364
you get infectious voi R virus d

7952
05:26:57,431 --> 05:27:07,040
assay, so you do the cotrans --d

7953
05:27:07,107 --> 05:27:09,576
do western blots and electron

7954
05:27:09,643 --> 05:27:10,544
microscopy and so on in the

7955
05:27:10,610 --> 05:27:11,912
cells to see what the proteins

7956
05:27:11,979 --> 05:27:13,246
and what the cells look like.

7957
05:27:13,313 --> 05:27:14,348
SO THE REST OF THE DATA WILL

7958
05:27:14,414 --> 05:27:16,616
SHOW YOU THAT.

7959
05:27:16,683 --> 05:27:20,787
SO THIS SHOWS INCREASING AMOUNTS

7960
05:27:20,854 --> 05:27:25,859
OF THE WILD TYPE CORE TO THE

7961
05:27:25,926 --> 05:27:29,463
MUTANT GAG 3Q12.3 GAG, AND SO

7962
05:27:29,529 --> 05:27:33,667
WHERE YOU HAVE -- AND SO WHAT IT

7963
05:27:33,734 --> 05:27:39,373
SHOWS IS THAT LOW LEVELS, LIKE G

7964
05:27:39,439 --> 05:27:41,808
SUPPRESSION OF THE NOW

7965
05:27:41,875 --> 05:27:44,411
INFECTIOUS VIRUS RELEASE, WHEN

7966
05:27:44,478 --> 05:27:48,548
YOU COTRANSFECT THOSE UP TO

7967
05:27:48,615 --> 05:27:51,051
ABOUT -- A RATIO OF 1 TO 16, I

7968
05:27:51,118 --> 05:27:52,586
THINK IT WAS HERE, WHERE WE GET

7969
05:27:52,652 --> 05:27:53,754
ABOUT 50% REDUCTION.

7970
05:27:53,820 --> 05:27:56,023
SO IT'S VERY STRONG SUPPRESSION

7971
05:27:56,089 --> 05:27:58,692
OF RELEASE OF PARTICLES, REVERSE

7972
05:27:58,759 --> 05:28:09,136
TRANS SCRIP TRANSCRIPTASE PARTI.

7973
05:28:09,202 --> 05:28:13,006
I STOLE ONE OF HIS MOST FAMOUS

7974
05:28:13,073 --> 05:28:13,840
DRAWINGS, I WOULD SAY.

7975
05:28:13,907 --> 05:28:16,009
FROM THE NON-RETRO VIROLOGISTS

7976
05:28:16,076 --> 05:28:19,312
IN THE AUDIENCE, I WANT TO POINT

7977
05:28:19,379 --> 05:28:23,750
OUT  THE GAG PROTEIN IS ALL

7978
05:28:23,817 --> 05:28:24,551
THAT'S IMPORTANT RIGHT HERE AS

7979
05:28:24,618 --> 05:28:25,619
FAR AS I'M CONCERNED AT THE

7980
05:28:25,685 --> 05:28:26,286
MOMENT.

7981
05:28:26,353 --> 05:28:28,555
AND THE GAG PROTEIN CONSISTS

7982
05:28:28,622 --> 05:28:29,423
PRINCIPALLY, THERE'S SOME OTHER

7983
05:28:29,489 --> 05:28:30,624
BITS AND PIECES I'M NOT GOING TO

7984
05:28:30,690 --> 05:28:32,793
TALK ABOUT, OF THREE DOMAINS:

7985
05:28:32,859 --> 05:28:35,529
MATRIX MA, CAPSID CA, AND KNEW

7986
05:28:35,595 --> 05:28:37,931
CLEE CAPSID NC.

7987
05:28:37,998 --> 05:28:39,866
MATRIX INTERACTS WITH THE CELL

7988
05:28:39,933 --> 05:28:43,804
MEMBRANE USUALLY.

7989
05:28:43,870 --> 05:28:44,938
CAPSID INTERACTS ONE TO ANOTHER

7990
05:28:45,005 --> 05:28:48,375
TO FORM THE STRUCTURE -- THE

7991
05:28:48,442 --> 05:28:50,677
INTERNAL STRUCTURE -- TO BRING

7992
05:28:50,744 --> 05:28:53,747
THE VIRUS RNA -- WHEN IT'S THERE

7993
05:28:53,814 --> 05:28:58,018
AND FORMS A CODING ON THE RNA

7994
05:28:58,085 --> 05:28:59,286
BASICALLY.

7995
05:28:59,352 --> 05:29:02,489
ONE MORE PIECE OF NOMENCLATURE,

7996
05:29:02,556 --> 05:29:05,192
THE CAPSID DOMAIN IS DIVIDED --

7997
05:29:05,258 --> 05:29:08,895
YOU CAN DIVIDE IT INTO THREE

7998
05:29:08,962 --> 05:29:13,834
REGIONS.

7999
05:29:13,900 --> 05:29:20,307
NTD --, CTD.

8000
05:29:20,373 --> 05:29:21,875
SO THE REGION RESPONSIBLE FOR

8001
05:29:21,942 --> 05:29:27,914
THIS PHENOTYPE, HE MADE MADE HYD

8002
05:29:27,981 --> 05:29:29,883
STRUCTURES BETWEEN THE WILD TYPE

8003
05:29:29,950 --> 05:29:33,053
AND THE 3Q12.3 GAG, AND THEN

8004
05:29:33,120 --> 05:29:38,525
LOOKED AT THE ABILITY OF THESE

8005
05:29:38,592 --> 05:29:41,862
TO FORM PARTICLES ON THE

8006
05:29:41,928 --> 05:29:47,567
COTRA -- THECAPSID DOMAIN IN THS

8007
05:29:47,634 --> 05:29:52,973
VERY -- WAS THE SUPPRESSIVE --

8008
05:29:53,039 --> 05:29:54,241
DOMINANT SUPPRESSIVE DOMAIN AND

8009
05:29:54,307 --> 05:29:59,846
IN PARTICULAR, THE END TERMINAL

8010
05:29:59,913 --> 05:30:01,481
HALF OF THE CAPSID DOMAIN, IN

8011
05:30:01,548 --> 05:30:04,551
THIS STUDY INCLUDED THE LINGER.

8012
05:30:04,618 --> 05:30:09,523
SO THIS REGION FOR THE

8013
05:30:09,589 --> 05:30:11,825
SUPPRESSIVE EVENT -- DEFINE THAT

8014
05:30:11,892 --> 05:30:13,493
DOWN A LITTLE BIT, THIS NOW

8015
05:30:13,560 --> 05:30:19,466
SHOWS THE STRUCTURE OF THE -- OF

8016
05:30:19,533 --> 05:30:21,268
CAPSID, AND AGAIN THE INTERNAL

8017
05:30:21,334 --> 05:30:23,236
DOMAIN IS IN DARK GREY, THE Y

8018
05:30:23,303 --> 05:30:25,038
TERMINAL DOMAIN IS IN LIGHT GREY

8019
05:30:25,105 --> 05:30:26,806
AND YOU CAN SEE THE LINGER KIND

8020
05:30:26,873 --> 05:30:27,941
OF WINDING IN BETWEEN THEM.

8021
05:30:28,008 --> 05:30:29,876
WHEN HE LOOKED AT THAT, JUST

8022
05:30:29,943 --> 05:30:31,278
LOOKING AT THE SEQUENCE, THE

8023
05:30:31,344 --> 05:30:32,479
BIGGEST DIFFERENCE IS IN THE

8024
05:30:32,546 --> 05:30:38,151
MIDDLE OF THE LINGER IN THE

8025
05:30:38,218 --> 05:30:41,855
3Q12.3, THERE'S -- OF THE SER

8026
05:30:41,922 --> 05:30:42,189
SERINE.

8027
05:30:42,255 --> 05:30:44,024
IT'S WHAT ALLOWS THE FLEXIBILITY

8028
05:30:44,090 --> 05:30:47,327
OF THE CAPSID PROTEIN TO

8029
05:30:47,394 --> 05:30:48,395
ASSEMBLE AND THAT'S WHAT ALLOWS

8030
05:30:48,461 --> 05:30:51,598
THE VIRUS TO FORM THIS RATHER

8031
05:30:51,665 --> 05:30:53,567
INTERESTING SORT OF SPACE

8032
05:30:53,633 --> 05:30:55,635
CAPSULE-LIKE STRUCTURE WHERE

8033
05:30:55,702 --> 05:30:57,604
EVERY SINGLE HEXAMER, WHICH IS

8034
05:30:57,671 --> 05:30:58,972
THE -- SIX OF THESE IS A

8035
05:30:59,039 --> 05:31:00,707
FUNDAMENTAL UNIT, HAS TO BE AT A

8036
05:31:00,774 --> 05:31:01,675
SLIGHTLY DIFFERENT ANGLE WITH

8037
05:31:01,741 --> 05:31:03,043
RESPECT TO ONE ANOTHER.

8038
05:31:03,109 --> 05:31:04,144
SO THERE HAS TO BE SOME

8039
05:31:04,211 --> 05:31:05,345
FLEXIBILITY IN THE WAY THEY

8040
05:31:05,412 --> 05:31:06,913
INTERACT.

8041
05:31:06,980 --> 05:31:08,548
I THINK -- I BELIEVE AND I THINK

8042
05:31:08,615 --> 05:31:10,483
MOST PEOPLE BELIEVE THAT'S

8043
05:31:10,550 --> 05:31:11,418
ALLOWED BY THE PRESENCE OF THIS

8044
05:31:11,484 --> 05:31:13,253
LINGER SCWEANS.

8045
05:31:13,320 --> 05:31:14,487
SEQUENCE.

8046
05:31:14,554 --> 05:31:17,724
SO THE DELETION -- MIGHT WELL

8047
05:31:17,791 --> 05:31:18,925
CHANGE THE WAY THE CAPSID IS

8048
05:31:18,992 --> 05:31:24,998
ALLOWED TO FORM.

8049
05:31:25,065 --> 05:31:29,903
SO TH THIS EXPERIMENT SHOWS

8050
05:31:29,970 --> 05:31:33,640
DIRECTLY THAT IF YOU SUBSTITUTE

8051
05:31:33,707 --> 05:31:34,674
EITHER THE WHOLE LINGER THAT'S

8052
05:31:34,741 --> 05:31:37,944
THE THIRD BAR FROM THE LEFT, YOU

8053
05:31:38,011 --> 05:31:43,950
GET A VERY -- YOU GET A STRONG F

8054
05:31:44,017 --> 05:31:45,952
YOU JUST TAKE THE WILD TYPE GAG

8055
05:31:46,019 --> 05:31:48,788
GENE AND JUST DELETE THAT ONE

8056
05:31:48,855 --> 05:31:51,524
SERINE, YOU ALSO GET IN THIS

8057
05:31:51,591 --> 05:31:54,894
EXPERIMENT ABOUT A 54 OR SO

8058
05:31:54,961 --> 05:32:01,034
SUPPRESSION OF EXPRESSION.

8059
05:32:01,101 --> 05:32:05,572
SO THAT -- IT TURNS OUT IF YOU

8060
05:32:05,639 --> 05:32:08,475
TAKE THAT -- IF YOU REPAIR THE

8061
05:32:08,541 --> 05:32:13,246
SERINE DOMAIN IN 3Q12.3, THAT

8062
05:32:13,313 --> 05:32:16,216
ACTUALLY DOES NOT COMPLETELY

8063
05:32:16,283 --> 05:32:17,417
RECALL THE DEFECT SO THERE'S

8064
05:32:17,484 --> 05:32:19,452
SOMETHING ELSE GOING ON BUT THIS

8065
05:32:19,519 --> 05:32:21,488
IS CERTAINLY THE PRINCIPAL

8066
05:32:21,554 --> 05:32:22,255
REASON FOR THIS.

8067
05:32:22,322 --> 05:32:25,525
GIVEN THAT, WE TOOK ADVANTAGE OF

8068
05:32:25,592 --> 05:32:28,128
OUR ASSOCIATION WITH DRP AND

8069
05:32:28,194 --> 05:32:30,797
WITH OUR VERY GOOD FRIEND ALLAN

8070
05:32:30,864 --> 05:32:33,033
WHO'S ASSOCIATED WITH A VERY

8071
05:32:33,099 --> 05:32:37,437
GOOD ELECTRON MY CR MICROSCOPISE

8072
05:32:37,504 --> 05:32:43,209
PASSED THEM ON TO FERRI AND TOOK

8073
05:32:43,276 --> 05:32:43,543
SOME PICTURES.

8074
05:32:43,610 --> 05:32:47,180
SO THE TOP LINE HERE IS JUST THE

8075
05:32:47,247 --> 05:32:48,782
WILD TYPE, IT ACTUALLY MAKES

8076
05:32:48,848 --> 05:32:49,883
VERY NICE PARTICLES.

8077
05:32:49,949 --> 05:32:52,919
THIS IS JUST THE GAG PROTEIN, SO

8078
05:32:52,986 --> 05:32:54,454
THERE'S NO PROTEASE, SO YOU'RE

8079
05:32:54,521 --> 05:32:56,656
JUST GETTING MATURE PARTICLES IN

8080
05:32:56,723 --> 05:32:58,391
THE ABSENCE OF PROTEASE.

8081
05:32:58,458 --> 05:33:00,126
THEY'RE VERY NICE LOOKING

8082
05:33:00,193 --> 05:33:03,530
IMMATURE PARTICLE, TRUST ME.

8083
05:33:03,596 --> 05:33:04,497
S, TRUST ME.

8084
05:33:04,564 --> 05:33:06,066
THE SECOND LINE HAPPENS IF YOU

8085
05:33:06,132 --> 05:33:09,302
TRY AND COTRANSFECT IT WITH

8086
05:33:09,369 --> 05:33:09,636
ITSELF.

8087
05:33:09,703 --> 05:33:11,171
SO YOU SEE AGAIN, IT WORKS VERY

8088
05:33:11,237 --> 05:33:14,874
WELL.

8089
05:33:14,941 --> 05:33:18,378
SO NOW WHAT HAPPENS IF -- WHAT

8090
05:33:18,445 --> 05:33:22,115
HAPPENS NOW WITH THE 3Q12.3 GAG

8091
05:33:22,182 --> 05:33:24,050
ALONE, AND WHEREAS YOU DON'T SEE

8092
05:33:24,117 --> 05:33:25,051
ANY OF THOSE NICE BUDDING

8093
05:33:25,118 --> 05:33:27,754
PARTICLE, ALL YOU SEE ARE ONE OF

8094
05:33:27,821 --> 05:33:30,857
THE ARROWS THERE, YOU JUST SEE

8095
05:33:30,924 --> 05:33:32,158
THICKENINGS IN THE CELL

8096
05:33:32,225 --> 05:33:34,561
MEMBRANE, SO SORT OF TRYING TO

8097
05:33:34,627 --> 05:33:36,863
ASSEMBLE AND COULD ASSEMBLE BUT

8098
05:33:36,930 --> 05:33:40,700
IT COULDN'T CURVE ITSELF AROUND.

8099
05:33:40,767 --> 05:33:41,801
THEN ON THE SECOND LINE, YOU SEE

8100
05:33:41,868 --> 05:33:43,436
WHAT HAPPENS IF YOU NOW

8101
05:33:43,503 --> 05:33:44,604
COTRANSFECT WITH THE WILD TYPE,

8102
05:33:44,671 --> 05:33:47,474
AND NOT ONLY YOU GET ITSELF

8103
05:33:47,540 --> 05:33:49,642
AROUND, BUT NOW YOU FORM SOME

8104
05:33:49,709 --> 05:33:51,711
VERY ABERRANT LOOKING

8105
05:33:51,778 --> 05:33:52,011
STRUCTURES.

8106
05:33:52,078 --> 05:33:53,646
THESE ARE WHAT WE LIKE TO CALL

8107
05:33:53,713 --> 05:33:55,815
VIRAL UNLIKE PARTICLE, VUPs,

8108
05:33:55,882 --> 05:33:57,350
AS OPPOSED TO VIRAL LIKE

8109
05:33:57,417 --> 05:34:02,922
PARTICLES OR VLPs.

8110
05:34:02,989 --> 05:34:08,194
AND SO -- AND NOW IF YOU NOW

8111
05:34:08,261 --> 05:34:12,132
TAKE THE HS GAG AND PUT IN THE

8112
05:34:12,198 --> 05:34:14,434
CAPSID FROM 3Q12.3, AGAIN YOU

8113
05:34:14,501 --> 05:34:16,736
GET THE SAME COLLECTION OF

8114
05:34:16,803 --> 05:34:17,537
PHENOTYPES, AND THEN HOW IT

8115
05:34:17,604 --> 05:34:21,841
LEADS AGAIN TO THESE VUPs IN

8116
05:34:21,908 --> 05:34:30,216
THE C COTRANSFECTION EXPERIMENT.

8117
05:34:30,283 --> 05:34:30,750
>> [INAUDIBLE]

8118
05:34:30,817 --> 05:34:35,955
>> THE ANSWER IS NO.

8119
05:34:36,022 --> 05:34:38,158
BECAUSE OTHER MUTATIONS THAT ARE

8120
05:34:38,224 --> 05:34:41,294
ALSO INVOLVED IN THIS THAT WE

8121
05:34:41,361 --> 05:34:45,465
HAVEN'T TRACKED DOWN YET.

8122
05:34:45,532 --> 05:34:47,434
BUT IF YOU MUTATE THE WILD TYPE

8123
05:34:47,500 --> 05:34:48,435
SERINE, YES, IT DOES BUT WE

8124
05:34:48,501 --> 05:34:55,442
DON'T HAVE PICTURE OF THAT.

8125
05:34:55,508 --> 05:34:56,876
SO WHATEVER THE OTHER DEFECT IS,

8126
05:34:56,943 --> 05:34:58,178
IT'S STILL IN CAPSID BECAUSE YOU

8127
05:34:58,244 --> 05:35:00,814
PUT THE WILD TYPE CAPSID BACK

8128
05:35:00,880 --> 05:35:03,550
INTO 3Q12.3, NOW YOU GET WILD

8129
05:35:03,616 --> 05:35:09,656
TYPE BUDDING AGAIN.

8130
05:35:09,722 --> 05:35:11,191
SO NOW WHAT I SAID BEFORE IS THE

8131
05:35:11,257 --> 05:35:18,832
CAPSID DOMAIN OF 3Q12.3 IS

8132
05:35:18,898 --> 05:35:20,800
IDENTICAL EXCEPT FOR ONE AMINO

8133
05:35:20,867 --> 05:35:22,335
ACID THAT'S ALMOST CERTAINLY

8134
05:35:22,402 --> 05:35:23,736
IRRELEVANT, ANOTHER PART THAT'S

8135
05:35:23,803 --> 05:35:24,971
NOT PARTICULARLY INTERESTING TO

8136
05:35:25,038 --> 05:35:27,173
US RIGHT NOW, SO THE QUESTION

8137
05:35:27,240 --> 05:35:33,613
IS, DOES 22Q11.23 HAVE THE SAM

8138
05:35:33,680 --> 05:35:40,386
SAME -- CAN THAT ALSO SUPPRESS

8139
05:35:40,453 --> 05:35:41,054
KKAN.

8140
05:35:41,120 --> 05:35:42,388
I SHOWED YOU THIS BEFORE.

8141
05:35:42,455 --> 05:35:46,860
THE ANSWER, IF YOU LACK, IS NO.

8142
05:35:46,926 --> 05:35:53,700
THIS DOES NOT -- THE ANSWER IS

8143
05:35:53,766 --> 05:35:55,969
IF YOU PUT GAG CAPSID PROTEIN --

8144
05:35:56,035 --> 05:35:57,871
I'M SORRY, IF YOU PUT THE CAPSID

8145
05:35:57,937 --> 05:36:05,078
PROTEIN INTO HS GAG THEY'RE

8146
05:36:05,144 --> 05:36:08,581
MOVING CAPSID PROTEIN HAS THE

8147
05:36:08,648 --> 05:36:09,215
SAME PHENOTYPE.

8148
05:36:09,282 --> 05:36:13,353
IT'S BASICALLY THE SAME PROTEIN.

8149
05:36:13,419 --> 05:36:17,624
HOWEVER, IF YOU TAKE 22Q11.23

8150
05:36:17,690 --> 05:36:21,694
ITSELF AND EXPRESS GAG AND

8151
05:36:21,761 --> 05:36:25,431
EXPRESS IT, IT DOES NOT SUPPR

8152
05:36:25,498 --> 05:36:28,201
SUPPRESS.

8153
05:36:28,268 --> 05:36:29,569
SO WHAT'S GOING ON HERE?

8154
05:36:29,636 --> 05:36:32,972
WHAT'S GOING ON HERE IS REVEALED

8155
05:36:33,039 --> 05:36:35,174
IN ANOTHER ELECTRON MICROGRAPH,

8156
05:36:35,241 --> 05:36:38,545
AND THAT IS THAT IF YOU LOOK ON

8157
05:36:38,611 --> 05:36:39,512
THAT -- I KNOW I DON'T HAVE A

8158
05:36:39,579 --> 05:36:40,914
GOOD PICTURE OF IT, BUT IF YOU

8159
05:36:40,980 --> 05:36:41,814
LOOK AT THE CELL MEMBRANE, YOU

8160
05:36:41,881 --> 05:36:44,884
DON'T SEE ANYTHING.

8161
05:36:44,951 --> 05:36:49,055
IN HOW WE'RE EXPRESSING THIS

8162
05:36:49,122 --> 05:36:52,859
ANCESTRAL PROVIRUS FOR THE GAG

8163
05:36:52,926 --> 05:36:55,428
GENE IN 3Q12.3.

8164
05:36:55,495 --> 05:36:58,064
WHAT YOU DO SEE INSIDE THE CELL

8165
05:36:58,131 --> 05:37:01,367
ARE LOTS AND LOTS OF CAPSIDS,

8166
05:37:01,434 --> 05:37:03,136
IMMATURE CAPSIDS.

8167
05:37:03,202 --> 05:37:04,837
THESE -- AS SOME OF YOU OLD TIME

8168
05:37:04,904 --> 05:37:06,339
VIROLOGISTS REMEMBER, THESE ARE

8169
05:37:06,406 --> 05:37:07,206
CALLED A PARTICLES.

8170
05:37:07,273 --> 05:37:10,810
AND IT IS A KNOWN ROOT OF -- IN

8171
05:37:10,877 --> 05:37:12,579
FACT MOUSE MEMORY TUMOR VIRUS,

8172
05:37:12,645 --> 05:37:16,916
FOR EXAMPLE, OR MASON PFIZER

8173
05:37:16,983 --> 05:37:19,352
MONKEY VIRUS, ASSEMBLY AT THE

8174
05:37:19,419 --> 05:37:21,554
CELL MEMBRANE, INTRACELLULARLY

8175
05:37:21,621 --> 05:37:23,156
INTO THESE A PARTICLES, MAKE

8176
05:37:23,222 --> 05:37:24,591
THEIR WAY TO THE CELL MEMBRANE

8177
05:37:24,657 --> 05:37:28,861
AND BUD OUT AND GET PROCESSED.

8178
05:37:28,928 --> 05:37:32,131
SO THIS IS ACTUALLY A BIG

8179
05:37:32,198 --> 05:37:34,067
SURPRISE, WE'VE KNOWN ABOUT THE

8180
05:37:34,133 --> 05:37:35,001
DIVISION OF SOME OF THESE

8181
05:37:35,068 --> 05:37:36,703
VIRUSES FOR YEARS AND YEARS AND

8182
05:37:36,769 --> 05:37:38,504
YEARS, NOBODY LOOKED TO SEE WHAT

8183
05:37:38,571 --> 05:37:41,341
THE GAG PROTEIN ACTUALLY MADE

8184
05:37:41,407 --> 05:37:42,508
AND WHERE THEY WERE.

8185
05:37:42,575 --> 05:37:43,509
AND WHY IS THAT?

8186
05:37:43,576 --> 05:37:44,944
WELL, NOW WE LOOK AT THE MATRIX

8187
05:37:45,011 --> 05:37:45,511
PROTEIN.

8188
05:37:45,578 --> 05:37:54,120
THE MATRIX PROTEIN COMES FROM

8189
05:37:54,187 --> 05:37:59,959
THE 22Q11.23 TYPE B PARENT.

8190
05:38:00,026 --> 05:38:02,528
WE CAN SEE A VERY BIG DIFFERENCE

8191
05:38:02,595 --> 05:38:05,898
IN THE NUMBER OF BASIC AMINO

8192
05:38:05,965 --> 05:38:07,266
ACID RES KNEWS.

8193
05:38:07,333 --> 05:38:10,436
THE BASE NUMBER -- NUMBER OF

8194
05:38:10,503 --> 05:38:16,175
BASIC AMINO ACID RESIDUES.

8195
05:38:16,242 --> 05:38:18,778
THERE ARE MANY FEWER, A FEW NOR

8196
05:38:18,845 --> 05:38:23,716
ACIDIC RESIDUES, AS COMPARED TO

8197
05:38:23,783 --> 05:38:26,586
THE 5HS.

8198
05:38:26,653 --> 05:38:29,122
DOWN A BOTTOM YOU CAN SEE THE

8199
05:38:29,188 --> 05:38:31,591
CALCULATED PI OF THESE PROTEINS.

8200
05:38:31,658 --> 05:38:39,599
FOR THE MATRIX IS LTR5A -- L

8201
05:38:39,666 --> 05:38:43,636
LTR -- I GOT THEM REVERSED.

8202
05:38:43,703 --> 05:38:47,907
DO A LITTLE RECOMBINATION THERE.

8203
05:38:47,974 --> 05:38:50,843
IT'S 9.122 ROUGHLY AND FOR 5A OR

8204
05:38:50,910 --> 05:38:51,944
B -- I'M SORRY, THEY'RE RIGHT.

8205
05:38:52,011 --> 05:38:54,480
THEY'RE RIGHT.

8206
05:38:54,547 --> 05:39:00,153
IT'S -- NO, THEY'RE WRONG.

8207
05:39:00,219 --> 05:39:00,486
IT'S 4.8.

8208
05:39:00,553 --> 05:39:01,954
IT GOES FROM BEING BASIC TO

8209
05:39:02,021 --> 05:39:04,624
BEING ACIDIC BASICALLY.

8210
05:39:04,691 --> 05:39:06,392
SO THESE BASIC RESIDUES INTERACT

8211
05:39:06,459 --> 05:39:09,228
WITH THE ACIDIC PHOSPHATE HEAD

8212
05:39:09,295 --> 05:39:11,664
GROUPS OF PET 2 AT THE CELL

8213
05:39:11,731 --> 05:39:13,733
MEMBRANE AND ARE WHAT DRIVE THE

8214
05:39:13,800 --> 05:39:16,002
CELL MEMBRANE ASSOCIATION.

8215
05:39:16,069 --> 05:39:22,675
ERICA COULD LECTUI COULD LECTURR

8216
05:39:22,742 --> 05:39:23,242
HOURS.

8217
05:39:23,309 --> 05:39:28,581
SO THIS CERTAINLY IS TH THE

8218
05:39:28,648 --> 05:39:32,719
REASON -- THE FACT THEY ASEMI AE

8219
05:39:32,785 --> 05:39:33,953
IN THE CYTOPLASM MEANS THEY

8220
05:39:34,020 --> 05:39:35,688
NEVER GET TO INTERACT WITH THE

8221
05:39:35,755 --> 05:39:37,990
GAG PROTEIN, BUT THEY PROBABLY

8222
05:39:38,057 --> 05:39:39,092
DID RESTRICT -- I'LL COME BACK

8223
05:39:39,158 --> 05:39:40,526
TO THAT IN A MINUTE -- IT

8224
05:39:40,593 --> 05:39:42,595
PROBABLY WILL RESTRICT A VIRUS

8225
05:39:42,662 --> 05:39:44,897
THAT REPLICATED THROUGH THE SAME

8226
05:39:44,964 --> 05:39:48,134
MECHANISM AS MANY --

8227
05:39:48,201 --> 05:39:48,735
RETROVIRUSES DO, FOR EXAMPLE,

8228
05:39:48,801 --> 05:39:59,479
MAMMARY TAU M TUMOR VIRUS.

8229
05:40:00,012 --> 05:40:01,514
SO, FINALLY, LET'S LOOK AND

8230
05:40:01,581 --> 05:40:06,786
SATISFY SEEWHAT VIRUSES THESE D.

8231
05:40:06,853 --> 05:40:11,257
YOU CAN SEE HERE WHAT HAPPENS,

8232
05:40:11,324 --> 05:40:14,660
THE EMPTY VECTOR EXPRESSION OF

8233
05:40:14,727 --> 05:40:24,137
3Q12.3 GAG HS, THE 5HS GAG,

8234
05:40:24,203 --> 05:40:30,443
22Q11.23 GAG, AND YOU CAN SEE

8235
05:40:30,510 --> 05:40:32,745
THAT -- MLV AND ALV ARE NOT

8236
05:40:32,812 --> 05:40:35,148
TOUCHED BY ANY OF THAT'S,

8237
05:40:35,214 --> 05:40:37,350
THEY'RE OBVIOUSLY BUDDING

8238
05:40:37,416 --> 05:40:38,885
INDEPENDENTLY SO YOU DON'T

8239
05:40:38,951 --> 05:40:42,288
INTERACT WITH THIS PROTEIN.

8240
05:40:42,355 --> 05:40:44,891
HOWEVER, MASON -- MONKEY VIRUS

8241
05:40:44,957 --> 05:40:47,260
WHICH ALSO -- IS SUPPRESSED BY

8242
05:40:47,326 --> 05:40:49,061
THE 3Q12.3.

8243
05:40:49,128 --> 05:40:51,464
IN FACT, WE POSTULATE THAT THIS

8244
05:40:51,531 --> 05:40:52,732
SUPPRESSIVE GENE EVOLVED OR AT

8245
05:40:52,799 --> 05:40:55,201
LEAST WAS STRONGLY SELECTED BY

8246
05:40:55,268 --> 05:40:57,470
ITS RESISTANCE TO THE VIRUS AS

8247
05:40:57,537 --> 05:41:01,741
REREPLICATED IN THIS WAY.

8248
05:41:01,808 --> 05:41:05,378
SO -- BUT THEN NOW OF COURSE --

8249
05:41:05,444 --> 05:41:11,284
FOW LOOK AT THE GUERILLA IN THEE

8250
05:41:11,350 --> 05:41:13,186
ROOM HERE, HIV WHICH I AVOIDED

8251
05:41:13,252 --> 05:41:14,987
TALKING ABOUT UNTIL NOW, HIV IS

8252
05:41:15,054 --> 05:41:19,625
ALSO STRONGLY SUPPRESSED BY

8253
05:41:19,692 --> 05:41:23,062
THIS -- BY THE

8254
05:41:23,129 --> 05:41:23,996
3Q12.3 COEXPRESSION.

8255
05:41:24,063 --> 05:41:24,997
OKAY?

8256
05:41:25,064 --> 05:41:27,633
AND HERE'S JUST ANOTHER PLOT

8257
05:41:27,700 --> 05:41:31,170
THAT SHOWS THE DOSE-RESPONSE TO

8258
05:41:31,237 --> 05:41:32,138
THAT.

8259
05:41:32,205 --> 05:41:36,409
ON THE LEFT-HAND PLOT.

8260
05:41:36,475 --> 05:41:36,742
ALV, I THINK.

8261
05:41:36,809 --> 05:41:41,981
>> YOU SAID THIS WAS

8262
05:41:42,048 --> 05:41:45,751
UBIQUITOUSLY -- NOT T CELLS?

8263
05:41:45,818 --> 05:41:48,020
>> QUITE A LOW LEVEL.

8264
05:41:48,087 --> 05:41:51,090
IT WASN'T SEEN AT ALL IN WHOLE

8265
05:41:51,157 --> 05:41:52,625
BLOOD IN GTEX.

8266
05:41:52,692 --> 05:41:55,461
SO YES, GOOD POINT.

8267
05:41:55,528 --> 05:41:58,965
SO WHY ARE WE INFECTED BY HIV?

8268
05:41:59,031 --> 05:42:00,833
I COULD ARGUE THAT THE

8269
05:42:00,900 --> 05:42:02,168
EXPRESSION IN T CELLS IS JUST

8270
05:42:02,235 --> 05:42:05,438
TOO LOW FOR THAT TO HAPPEN.

8271
05:42:05,504 --> 05:42:10,743
>> [INAUDIBLE]

8272
05:42:10,810 --> 05:42:12,678
>> WE HAVEN'T LOOKED AT THE

8273
05:42:12,745 --> 05:42:13,312
EXPRESSION.

8274
05:42:13,379 --> 05:42:14,347
THAT'S A VERY GOOD QUESTION BUT

8275
05:42:14,413 --> 05:42:15,781
WE HAVEN'T LOOKED AT THE

8276
05:42:15,848 --> 05:42:20,019
EXPRESSION LEVEL IN -- CELLS.

8277
05:42:20,086 --> 05:42:22,788
THOSE ARE, OF COURSE -- I DON'T

8278
05:42:22,855 --> 05:42:23,089
KNOW.

8279
05:42:23,155 --> 05:42:24,957
IS THE ANSWER TO THAT.

8280
05:42:25,024 --> 05:42:26,292
WE DON'T KNOW, WE'RE IN THE

8281
05:42:26,359 --> 05:42:28,895
PROCESS ACTUALLY OF PUTTING THIS

8282
05:42:28,961 --> 05:42:31,397
IN FRONT OF A TUNEABLE PROMOTER

8283
05:42:31,464 --> 05:42:32,765
SO WE CAN SEE WHAT LEVEL OF

8284
05:42:32,832 --> 05:42:34,467
EXPRESSION IS NECESSARY.

8285
05:42:34,533 --> 05:42:39,505
THESE ARE WAY -- CMV LINK

8286
05:42:39,572 --> 05:42:41,173
PROMOTER.

8287
05:42:41,240 --> 05:42:51,784
SO, AGAIN YOU CAN SEE THE HRV ON

8288
05:42:59,625 --> 05:43:02,728
THE RIGHT-HAND PANEL, THERE YOU

8289
05:43:02,795 --> 05:43:07,867
GET THE MESSY PUV PHENOMENON

8290
05:43:07,934 --> 05:43:08,801
THEN, SUGGESTING THE MECHANISM

8291
05:43:08,868 --> 05:43:09,602
OF SAME.

8292
05:43:09,669 --> 05:43:11,003
AND QUITE STRIKINGLY, THIS IS A

8293
05:43:11,070 --> 05:43:17,043
PAPER THAT APPEARED FROM JENG'S

8294
05:43:17,109 --> 05:43:24,417
LAB RECENTLY, AND THIS IS THE

8295
05:43:24,483 --> 05:43:25,818
C-TERMINUS OF GAG AND THIS IS

8296
05:43:25,885 --> 05:43:28,988
THE ASSEMBLY OF THE IMMATURE GAG

8297
05:43:29,055 --> 05:43:33,159
PROTEINS FORMS, ERIC CAN TALK TO

8298
05:43:33,225 --> 05:43:34,627
YOU FOR HOURS ABOUT THIS ONE

8299
05:43:34,694 --> 05:43:38,297
TOO.

8300
05:43:38,364 --> 05:43:42,935
AND IN ORANGE IS THE HML-2 AND

8301
05:43:43,002 --> 05:43:46,339
GREY IS THE HIV1, AND LOOK HOW

8302
05:43:46,405 --> 05:43:46,973
THOSE OVERLAY.

8303
05:43:47,039 --> 05:43:48,674
SO LOOKING AT THIS, THIS

8304
05:43:48,741 --> 05:43:50,476
REALLY -- I MEAN, IT'S NOT --

8305
05:43:50,543 --> 05:43:52,078
IT'S EASY TO HYPOTHESIZE, WE'RE

8306
05:43:52,144 --> 05:43:55,915
NOT PROVING IT BUT IT'S EASY TO

8307
05:43:55,982 --> 05:43:57,450
HYPOTHESIZE THESE MIGHT

8308
05:43:57,516 --> 05:44:01,053
COASSEMBLE VERY WELL.

8309
05:44:01,120 --> 05:44:03,789
EVEN THOUGH -- THERE ARE SOME

8310
05:44:03,856 --> 05:44:05,057
CONSERVED AMINO ACID SEQUENCES

8311
05:44:05,124 --> 05:44:06,158
BETWEEN THEM AND MAYBE IN THE

8312
05:44:06,225 --> 05:44:06,859
IMPORTANT PLACES WE HAVEN'T DONE

8313
05:44:06,926 --> 05:44:11,330
A REALLY DETAILED ANALYSIS, BUT

8314
05:44:11,397 --> 05:44:13,165
CERTAINLY WORKING HYPOTHESIS IS

8315
05:44:13,232 --> 05:44:14,333
WHAT HAPPENS HERE, THESE

8316
05:44:14,400 --> 05:44:15,434
COASSEMBLE BECAUSE OF THIS VERY

8317
05:44:15,501 --> 05:44:18,904
STRONG SIMILARITY IN WHAT HAVE

8318
05:44:18,971 --> 05:44:20,306
THE IMPORTANT -- I THINK WE'LL

8319
05:44:20,373 --> 05:44:21,874
ALL AGREE IS THE IMPORTANT

8320
05:44:21,941 --> 05:44:22,742
COASSEMBLY POINT, ASSEMBLY POINT

8321
05:44:22,808 --> 05:44:30,449
FOR IMMATURE VIRUS PARTICLES.

8322
05:44:30,516 --> 05:44:31,951
AND I THINK THIS IS MY LAST

8323
05:44:32,018 --> 05:44:33,285
SLIDE, JUST TO SHOW YOU, SO FROM

8324
05:44:33,352 --> 05:44:36,856
THIS, WE CAN INFER QUITE A BIT

8325
05:44:36,922 --> 05:44:37,423
AND HYPOTHESIZE QUITE A BIT

8326
05:44:37,490 --> 05:44:39,191
ABOUT HOW THE EVOLUTION OF THIS,

8327
05:44:39,258 --> 05:44:42,628
WHAT CLEARLY HAS TO BE A

8328
05:44:42,695 --> 05:44:43,129
RESTRICTION FACTOR.

8329
05:44:43,195 --> 05:44:44,230
THERE'S NOTHING ELSE THAT CAN

8330
05:44:44,296 --> 05:44:46,899
REALLY EXPLAIN ALL THAT WE HAVE,

8331
05:44:46,966 --> 05:44:47,233
I THINK.

8332
05:44:47,299 --> 05:44:52,505
WHAT HAPPENED IS YOU STARTED OUT

8333
05:44:52,571 --> 05:45:01,914
WITH BOTH POINTS 22Q23.3 AND

8334
05:45:01,981 --> 05:45:03,115
3Q12.3 WERE INTEGRATED AT SOME

8335
05:45:03,182 --> 05:45:06,519
TIME WITHIN THIS 4 MILLION

8336
05:45:06,585 --> 05:45:08,587
YEAR -- OF COURSE THEY COULD

8337
05:45:08,654 --> 05:45:11,223
HAVE BEEN 2 MILLION YEARS APART,

8338
05:45:11,290 --> 05:45:11,857
3 MILLION YEARS APART, WE CAN'T

8339
05:45:11,924 --> 05:45:14,527
TELL THAT, BUT OUR WORKING

8340
05:45:14,593 --> 05:45:17,063
HYPOTHESIS IS THAT THE MUTATION,

8341
05:45:17,129 --> 05:45:22,735
THE KEY GAG MUTATION AROSE IN

8342
05:45:22,802 --> 05:45:27,773
THE 22Q11.23 AND WAS STRONGLY

8343
05:45:27,840 --> 05:45:29,475
SELECTED SO BY GIVING RESISTANCE

8344
05:45:29,542 --> 05:45:33,579
TO A VIRUS LIKE THE 5A OR 5B

8345
05:45:33,646 --> 05:45:34,680
TYPES THEY'RE REPLICATING

8346
05:45:34,747 --> 05:45:36,515
THROUGH THIS INTRACELLULAR

8347
05:45:36,582 --> 05:45:37,349
ASSEMBLY.

8348
05:45:37,416 --> 05:45:38,884
AND THAT PERHAPS IN RESPONSE TO

8349
05:45:38,951 --> 05:45:41,854
THAT, I CAN REALLY SPECULATE

8350
05:45:41,921 --> 05:45:43,689
LIKE CRAZY NOW BECAUSE THIS IS

8351
05:45:43,756 --> 05:45:46,125
THE SPECULATION PART OF THE

8352
05:45:46,192 --> 05:45:48,961
TALK, AS A RESPONSE TO THAT TO

8353
05:45:49,028 --> 05:45:50,830
FIND HS TYPE, NOW FOUND A WAY

8354
05:45:50,896 --> 05:45:52,932
AROUND IT BY PUTTING IN ALL

8355
05:45:52,998 --> 05:45:54,567
THOSE BASIC AMINO ACIDS WHICH

8356
05:45:54,633 --> 05:45:56,836
GAVE IT THE PLASMA MEMBRANE

8357
05:45:56,902 --> 05:45:58,370
INTERACTION, SO IT SNEAKED ITS

8358
05:45:58,437 --> 05:45:59,905
WAY AROUND WHAT WAS NOW THIS

8359
05:45:59,972 --> 05:46:00,339
RESTRICTION FACTOR.

8360
05:46:00,406 --> 05:46:03,109
SO THIS IS A HOST OF -- THIS IS

8361
05:46:03,175 --> 05:46:04,944
SORT OF THE HOST-VIRUS -- IT

8362
05:46:05,010 --> 05:46:06,712
TOOK PLACE LIKE 10 MILLION YEARS

8363
05:46:06,779 --> 05:46:09,582
AGO.

8364
05:46:09,648 --> 05:46:15,354
AND THEN 3Q12.3 IS THE ONLY

8365
05:46:15,421 --> 05:46:16,989
REIMI NENT -- IN OUR BODY, IN

8366
05:46:17,056 --> 05:46:19,959
OUR GENOME, PICKED UP THAT GAG

8367
05:46:20,025 --> 05:46:21,527
GENE AND THAT THEN WAS SELECTED

8368
05:46:21,594 --> 05:46:24,130
BECAUSE NOW THAT WAS ABLE TO

8369
05:46:24,196 --> 05:46:30,269
RESIST INFECTION BY -- THAT WAS

8370
05:46:30,336 --> 05:46:35,341
ABLE TO RESIST INFECTION BY THE

8371
05:46:35,407 --> 05:46:44,683
HML-2 TYPE AND 5HS TYPE AND --

8372
05:46:44,750 --> 05:46:48,721
BUT ONLY ACTUALLY WHO'S

8373
05:46:48,787 --> 05:46:50,356
EXPRESSED WELL ENOUGH, AND SO AT

8374
05:46:50,422 --> 05:46:52,992
SOME POINT, WHICH I THINK

8375
05:46:53,058 --> 05:46:54,960
ACTUALLY -- OUR INITIAL DATA

8376
05:46:55,027 --> 05:46:58,898
SUGGESTED THAT THE FOUR BASE

8377
05:46:58,964 --> 05:46:59,999
DUPLICATION THAT CREATES THIS

8378
05:47:00,065 --> 05:47:07,239
VERY STRONG PROMOTOR FOR THE OX

8379
05:47:07,306 --> 05:47:09,608
PBX FACTOR -- SITE HAPPENED IN

8380
05:47:09,675 --> 05:47:10,976
THE HUMAN LINEAGE.

8381
05:47:11,043 --> 05:47:14,146
AND I THINK -- WHAT I WOULD LOVE

8382
05:47:14,213 --> 05:47:16,782
TO THINK, THIS IS NOW REAL

8383
05:47:16,849 --> 05:47:17,716
SPECULATION, IS THAT HAPPENED

8384
05:47:17,783 --> 05:47:19,985
ONLY QUITE RECENTLY, AND IT WAS

8385
05:47:20,052 --> 05:47:20,953
THE OCCURRENCE OF THAT MUTATION

8386
05:47:21,020 --> 05:47:23,622
THAT GAVE THIS VIRUS ENOUGH

8387
05:47:23,689 --> 05:47:26,258
RESISTANCE POWERS, WE BOOSTED

8388
05:47:26,325 --> 05:47:27,426
THE LEVEL OF EXPRESSION HIGH

8389
05:47:27,493 --> 05:47:31,030
ENOUGH SO THAT IT WAS NOW -- IT

8390
05:47:31,096 --> 05:47:32,565
NOW HAD THE PATTERN THAT YOU SEE

8391
05:47:32,631 --> 05:47:33,732
IN VIRTUALLY EVERY CELL IN THE

8392
05:47:33,799 --> 05:47:34,366
BODY.

8393
05:47:34,433 --> 05:47:39,138
VERY INTERESTINGLY, NOT IN

8394
05:47:39,205 --> 05:47:39,638
LYMPHOCYTES APPARENTLY.

8395
05:47:39,705 --> 05:47:44,143
AND THAT'S WHAT -- ACTUALLY ONE

8396
05:47:44,210 --> 05:47:45,244
REASON BECAUSE HIV IS SENSITIVE

8397
05:47:45,311 --> 05:47:49,014
TO IT, THAT SORT OF DIRECTED THE

8398
05:47:49,081 --> 05:47:50,115
INFECTION LEVEL OF HIV BUT

8399
05:47:50,182 --> 05:47:51,884
THAT'S GETTING A LITTLE TOO FAR

8400
05:47:51,951 --> 05:47:53,852
AFOOT, BECAUSE HIV HAD THAT

8401
05:47:53,919 --> 05:47:59,558
BEFORE IT SAW HUMANS, OF COURSE.

8402
05:47:59,625 --> 05:48:02,061
SO THAT I THINK IS THE END OF MY

8403
05:48:02,127 --> 05:48:04,930
STORY, AND I WILL THANK ALL OF

8404
05:48:04,997 --> 05:48:08,234
THESE PEOPLE VERY MUCH.

8405
05:48:08,300 --> 05:48:09,101
PARTICULARLY MIKE FREEMAN,

8406
05:48:09,168 --> 05:48:10,970
REALLY DID ESSENTIALLY --

8407
05:48:11,036 --> 05:48:13,072
VIRTUALLY ALL OF THE WORK EXCEPT

8408
05:48:13,138 --> 05:48:17,443
FOR THE ELECTRON MICROGRAPHS,

8409
05:48:17,509 --> 05:48:18,844
AND I WILL THANK YOU FOR YOUR

8410
05:48:18,911 --> 05:48:19,612
ATTENTION, I'LL THANK EVERYBODY

8411
05:48:19,678 --> 05:48:21,080
FOR A REALLY WONDERFUL DAY.

8412
05:48:21,146 --> 05:48:29,221
[APPLAUSE]

8413
05:48:29,288 --> 05:48:35,694
>> SO -- MATRIX HAS A --

8414
05:48:35,761 --> 05:48:36,328
RETENTION SIGNAL.

8415
05:48:36,395 --> 05:48:37,763
I'M WONDERING IF THERE'S ANY

8416
05:48:37,830 --> 05:48:41,200
ELEMENT IN THIS --

8417
05:48:41,267 --> 05:48:43,168
>> THEY'RE PROBABLY IS.

8418
05:48:43,235 --> 05:48:47,840
WE HAVEN'T DONE -- IT COULD --

8419
05:48:47,906 --> 05:48:49,275
INCLUDES THAT, WE HAVEN'T DONE

8420
05:48:49,341 --> 05:48:52,278
ANYTHING -- IT'S A GOOD POINT.

8421
05:48:52,344 --> 05:48:54,113
AS I RECALL IT WAS VERY EASY TO

8422
05:48:54,179 --> 05:48:56,949
CONVERT IT BACK TO -- RIGHT.

8423
05:48:57,016 --> 05:49:00,152
ALTHOUGH THIS ONE, WITH ALL OF

8424
05:49:00,219 --> 05:49:02,888
THOSE -- ON THAT VERY HIGH LOW

8425
05:49:02,955 --> 05:49:05,758
P.I., IT VERY HARD TO SEE HOW IT

8426
05:49:05,824 --> 05:49:09,161
COULD GET BACK TO THE PLASMA

8427
05:49:09,228 --> 05:49:09,795
MEMBRANE.

8428
05:49:09,862 --> 05:49:09,995
MARY.

8429
05:49:10,062 --> 05:49:13,032
>> SO PRESUMABLY, WE HAVE HIV

8430
05:49:13,098 --> 05:49:15,801
BECAUSE IT'S NOT EXPRESSED IN

8431
05:49:15,868 --> 05:49:16,268
LYMPHOCYTES AND --

8432
05:49:16,335 --> 05:49:18,203
>> IT COULD BE DRK CERTAINLY

8433
05:49:18,270 --> 05:49:20,739
COULD BE ONE THING THAT ALLOWED

8434
05:49:20,806 --> 05:49:22,041
HIV TO --

8435
05:49:22,107 --> 05:49:23,676
>> THERE'S OTHER RETROVIRUSES

8436
05:49:23,742 --> 05:49:25,144
WHICH MAY HAVE JUMP AS MANY

8437
05:49:25,210 --> 05:49:26,679
TIMES BUT NOT BEEN ABLE TO CAUSE

8438
05:49:26,745 --> 05:49:28,047
A PANDEMIC.

8439
05:49:28,113 --> 05:49:29,948
>> MIGHT WANT TO THINK ABOUT

8440
05:49:30,015 --> 05:49:31,150
WHAT WOULD HAPPEN IF WE COULD

8441
05:49:31,216 --> 05:49:31,817
EXPRESS IT.

8442
05:49:31,884 --> 05:49:33,986
>> KIND OF GOING ON MARY'S

8443
05:49:34,053 --> 05:49:36,522
QUESTION, SO A LOT OF

8444
05:49:36,588 --> 05:49:38,157
RETROVIRUSES INFECT AND

8445
05:49:38,223 --> 05:49:39,825
REPLICATE IN --

8446
05:49:39,892 --> 05:49:41,827
>> NOT THAT MANY.

8447
05:49:41,894 --> 05:49:43,962
THEY'RE MOSTLY --

8448
05:49:44,029 --> 05:49:45,030
>>  --

8449
05:49:45,097 --> 05:49:49,268
>> MLV -- I DON'T -- REPLICATE

8450
05:49:49,335 --> 05:49:49,902
IN T CELLS?

8451
05:49:49,968 --> 05:49:51,136
OH, YEAH.

8452
05:49:51,203 --> 05:49:53,539
IN LYMPHOCYTES.

8453
05:49:53,605 --> 05:49:55,407
NLCs, IT IMMUNE TO THIS.

8454
05:49:55,474 --> 05:49:55,808
I SHOWED YOU THAT.

8455
05:49:55,874 --> 05:49:56,809
>> OH, OKAY.

8456
05:49:56,875 --> 05:50:01,647
>> ANY VIRUS THAT -- WHERE THE

8457
05:50:01,714 --> 05:50:05,217
GAG GENE IS CAPABLE OF ASSEMBLY.

8458
05:50:05,284 --> 05:50:07,052
>> THERE SHOULD HAVE BEEN AT

8459
05:50:07,119 --> 05:50:09,221
SOME POINT -- MAYBE THERE'S NOT

8460
05:50:09,288 --> 05:50:11,657
ENOUGH TIME TO MAYBE TURN ON

8461
05:50:11,724 --> 05:50:13,859
EXPRESSION OF LYMPHOCYTES.

8462
05:50:13,926 --> 05:50:19,598
>> WELL, HIV HAS NOT PUT -- FOR

8463
05:50:19,665 --> 05:50:21,300
A HUNDRED AND SOME YEARS.

8464
05:50:21,367 --> 05:50:23,235
>>  -- AND VIRUSES LIKE THAT.

8465
05:50:23,302 --> 05:50:25,771
>> WE HAVE OTHER MECHANISMS TO

8466
05:50:25,838 --> 05:50:30,609
PROTECT US AGAINST -- WE DIDN'T

8467
05:50:30,676 --> 05:50:31,477
HAVE AGOVEK, WE'D PROBABLY ALL

8468
05:50:31,543 --> 05:50:40,519
BE DEAD FROM IT BY NOW.

8469
05:50:40,586 --> 05:50:44,022
>> YOU'RE FOCUSED ON RESTRICTION

8470
05:50:44,089 --> 05:50:45,758
FACTORS BUT -- SPHERICAL BALLS

8471
05:50:45,824 --> 05:50:48,327
IN THE CELL -- DO A HECK OF A

8472
05:50:48,394 --> 05:50:49,862
LOT OF OTHER THINGS.

8473
05:50:49,928 --> 05:50:52,931
SO NOT OTHER -- MAYBE 22?

8474
05:50:52,998 --> 05:50:56,402
>> WELL, PERHAPS.

8475
05:50:56,468 --> 05:50:58,871
THAT COULD BE.

8476
05:50:58,937 --> 05:51:01,607
>> FROM YOUR PERSPECTIVE --

8477
05:51:01,673 --> 05:51:03,008
>> WHEN WE LACK CLOSELY AT

8478
05:51:03,075 --> 05:51:06,845
THOSE, YOU PROBABLY COULDN'T --

8479
05:51:06,912 --> 05:51:11,316
VEVERY EASILY -- THERE'S AN

8480
05:51:11,383 --> 05:51:12,718
OPENING AT THE END.

8481
05:51:12,785 --> 05:51:13,419
BECAUSE THEY STILL HAVE THAT

8482
05:51:13,485 --> 05:51:16,188
SAME MUTATION, THAT SERINE

8483
05:51:16,255 --> 05:51:18,690
DELETION IN THEM, SO MY GUESS IS

8484
05:51:18,757 --> 05:51:21,293
THEY CAN FORM A SPHERE IF

8485
05:51:21,360 --> 05:51:22,828
THEY'RE SORT OF UNIMPEDED BUT

8486
05:51:22,895 --> 05:51:24,363
WHEN THEY HAVE TO PULL THE CELL

8487
05:51:24,430 --> 05:51:26,098
MEMBRANE AROUND WITH THEM, IT'S

8488
05:51:26,165 --> 05:51:26,799
JUST NOT A STRONG ENOUGH

8489
05:51:26,865 --> 05:51:27,800
ASSOCIATION TO DO THAT.

8490
05:51:27,866 --> 05:51:29,101
THERE'S SOME INTERACTION

8491
05:51:29,168 --> 05:51:31,837
PROBABLY THAT SERINE -- THAT IT

8492
05:51:31,904 --> 05:51:36,208
NEEDS TO FORM THE -- SOME EFFORT

8493
05:51:36,275 --> 05:51:38,977
NEEDED IF YOU LIKE ON THE PART

8494
05:51:39,044 --> 05:51:40,279
OF -- TO ACTUALLY FORM THAT

8495
05:51:40,345 --> 05:51:42,581
SCWEER.

8496
05:51:42,648 --> 05:51:43,582
FRANK, I THINK?

8497
05:51:43,649 --> 05:51:45,317
>> JUST REAL QUICK, YOU SAID IT

8498
05:51:45,384 --> 05:51:48,053
WASN'T EXPRESSED IN HUMAN --

8499
05:51:48,120 --> 05:51:49,788
WHAT ABOUT IN THE GORILLA OR --

8500
05:51:49,855 --> 05:51:51,323
>> WE HAVEN'T LOOKED AT THAT.

8501
05:51:51,390 --> 05:51:54,860
>> IS IT POSSIBLE IT'S

8502
05:51:54,927 --> 05:51:57,362
PREVENTING TRANSMISSION FROM

8503
05:51:57,429 --> 05:52:00,699
OTHER MAYBE LOWER PRIMATES?

8504
05:52:00,766 --> 05:52:03,402
>> THIS DOESN'T GO VERY LOW.

8505
05:52:03,469 --> 05:52:06,572
THESE PARTICULAR -- THESE PLR

8506
05:52:06,638 --> 05:52:12,177
PROVIRUSES ARE IN GORILLAS,

8507
05:52:12,244 --> 05:52:14,780
HUMANS, CHIMPANZEES, AND -- BUT

8508
05:52:14,847 --> 05:52:15,180
THAT'S IT.

8509
05:52:15,247 --> 05:52:17,015
>> BUT WOULD IT PREVENT IT

8510
05:52:17,082 --> 05:52:18,317
FROM -- BUT WHO IT PREVENT

8511
05:52:18,383 --> 05:52:19,518
THINGS COMING OVER FROM RHESUS?

8512
05:52:19,585 --> 05:52:21,620
>> POSSIBLY.

8513
05:52:21,687 --> 05:52:24,223
OH, IT WOULD PREVENT THINGS

8514
05:52:24,289 --> 05:52:26,425
THAT -- THINGS THAT WERE CAPABLE

8515
05:52:26,492 --> 05:52:28,093
OF COASSEMBLY WOULD BE BLOCKED.

8516
05:52:28,160 --> 05:52:30,028
>> SO THEY WOULD BE UNDER A GAG?

8517
05:52:30,095 --> 05:52:34,233
>> SO IF THEY WERE -- OTHER

8518
05:52:34,299 --> 05:52:38,937
RELATIVES OF HERV-K, AND THERE

8519
05:52:39,004 --> 05:52:44,643
ARE -- LOWER PRIMATES IF YOU

8520
05:52:44,710 --> 05:52:45,811
LIKE, MONKEYS AND SO ON, THAT

8521
05:52:45,878 --> 05:52:48,247
PROBABLY WOULD COASSEMBLE AND IT

8522
05:52:48,313 --> 05:52:50,883
PROBABLY WOULD BE --.

8523
05:52:50,949 --> 05:52:54,620
>> SO -- HAS A QUESTION ONLINE.

8524
05:52:54,686 --> 05:52:58,957
CAN YOU JUST UNMUTE AND ASK?

8525
05:52:59,024 --> 05:52:59,691
>> SURE.

8526
05:52:59,758 --> 05:53:02,327
I WAS JUST WONDERING, DOES THIS

8527
05:53:02,394 --> 05:53:04,296
MEAN THAT IF YOU HAVE

8528
05:53:04,363 --> 05:53:05,864
COINFECTION FROM -- RETROVIRUSES

8529
05:53:05,931 --> 05:53:07,399
A CELL THAT THEY WOULD RESTRICT

8530
05:53:07,466 --> 05:53:08,901
EACH OTHER IF THEIR GAG PROTEINS

8531
05:53:08,967 --> 05:53:17,242
ARE CLOSE ENOUGH?

8532
05:53:17,309 --> 05:53:20,212
>> IT'S UNLIKELY THE TWO

8533
05:53:20,279 --> 05:53:21,613
RETROVIRUSES JUST INDIVIDUAL

8534
05:53:21,680 --> 05:53:23,248
PARTICLES INFECTING THE SAME

8535
05:53:23,315 --> 05:53:24,483
CELL WOULD EVER MEET.

8536
05:53:24,550 --> 05:53:27,853
THEY'RE VERY -- THE CELL IS VERY

8537
05:53:27,920 --> 05:53:29,821
BIG, THE -- ARE QUITE SMALL.

8538
05:53:29,888 --> 05:53:33,358
WHAT WE DON'T KNOW, WE JUST

8539
05:53:33,425 --> 05:53:35,027
HAVEN'T DONE IT YET, IS WHETHER

8540
05:53:35,093 --> 05:53:37,563
IT IS ACTUALLY -- THE EXPRESSION

8541
05:53:37,629 --> 05:53:39,164
OF THIS GAG PROTEIN HAS AN

8542
05:53:39,231 --> 05:53:41,400
EFFECT ON INCOMING VIRUS.

8543
05:53:41,466 --> 05:53:45,537
BECAUSE THERE'S POSSIBLE.

8544
05:53:45,604 --> 05:53:47,172
PROTEIN FRAGMENT THAT DOES HAVE

8545
05:53:47,239 --> 05:53:50,142
AN IMPACT ON ONCOMING VIRUS.

8546
05:53:50,208 --> 05:53:51,810
SO WE JUST DON'T KNOW THAT.

8547
05:53:51,877 --> 05:53:52,611
WE'LL TRY TO GET THE EXPERIMENT

8548
05:53:52,678 --> 05:53:52,978
DONE SOON.

8549
05:53:53,045 --> 05:53:57,015
>> YOU SAID THE NTD IS HAVING AN

8550
05:53:57,082 --> 05:53:57,249
EFFECT?

8551
05:53:57,316 --> 05:54:01,486
>> THAT WAS NTD PLUS LEAKER IN

8552
05:54:01,553 --> 05:54:05,023
THAT EXPERIMENT.

8553
05:54:05,090 --> 05:54:07,092
THE DATA SUGGESTS THAT THERE IS

8554
05:54:07,159 --> 05:54:08,460
SOME OTHER -- THERE ARE SOME

8555
05:54:08,527 --> 05:54:10,262
OTHER MUTATIONS INVOLVED AS

8556
05:54:10,329 --> 05:54:10,596
WELL.

8557
05:54:10,662 --> 05:54:13,131
WE DON'T HAVE THOSE SORTED OUT

8558
05:54:13,198 --> 05:54:13,298
YET.

8559
05:54:13,365 --> 05:54:19,838
>> TO DECEMBER TE THAO T THESE A

8560
05:54:19,905 --> 05:54:23,508
LOT OF HOST FACTORS.

8561
05:54:23,575 --> 05:54:25,077
>> [INAUDIBLE]

8562
05:54:25,143 --> 05:54:27,312
>> RIGHT.

8563
05:54:27,379 --> 05:54:33,552
>> SO WILL THEY -- DONE

8564
05:54:33,619 --> 05:54:34,519
ENDOGENOUS RETROVIRUSES ARE

8565
05:54:34,586 --> 05:54:35,320
EASIER TO INFECT?

8566
05:54:35,387 --> 05:54:39,791
>> THAT'S ACTUALLY -- THERE'S A

8567
05:54:39,858 --> 05:54:41,560
HISTORY -- BLAME IT ON CHICKENS.

8568
05:54:41,627 --> 05:54:43,328
WHERE THE EXPRESSION OF

8569
05:54:43,395 --> 05:54:47,532
ENDOGENOUS RETROVIRUSES DOESN'T

8570
05:54:47,599 --> 05:54:49,301
LOSE TOLERANCE, BUT IT ACTUALLY

8571
05:54:49,368 --> 05:54:51,703
MAKES INCOMING VIRUSES -- IT

8572
05:54:51,770 --> 05:54:53,005
OBVIOUSLY HELPS THE REPLICATION

8573
05:54:53,071 --> 05:54:55,107
OF INCOMING VIRUSES, BUT IN THAT

8574
05:54:55,173 --> 05:54:58,310
PARTICULAR CASE, IT MAKES THE

8575
05:54:58,377 --> 05:55:00,379
MOST PATHOGENIC, BECAUSE THE

8576
05:55:00,445 --> 05:55:02,347
MAJOR PATHOGENIC EFFECT OF THIS

8577
05:55:02,414 --> 05:55:06,551
PARTICULAR VIRUS IS -- MEDIATED,

8578
05:55:06,618 --> 05:55:08,487
SO YOU GET IMMUNE RESPONSE

8579
05:55:08,553 --> 05:55:10,355
AGAINST VIRUS, THAT KILLS OFF

8580
05:55:10,422 --> 05:55:11,790
IMPORTANT CELLS WHEN YOU GET

8581
05:55:11,857 --> 05:55:12,691
SICK.

8582
05:55:12,758 --> 05:55:18,397
SO IT CAN WORK BOTH WAYS.

8583
05:55:18,463 --> 05:55:19,865
IN THIS CASE, I JUST DON'T KNOW.

8584
05:55:19,931 --> 05:55:25,871
>> THE FINAL LAST QUESTION?

8585
05:55:25,937 --> 05:55:28,473
>> HAVE YOU KNOCKED DOWN THE

8586
05:55:28,540 --> 05:55:29,741
EXPRESSION IN DIFFERENT CELLS

8587
05:55:29,808 --> 05:55:31,677
AND TRIED TO INFECT HIV?

8588
05:55:31,743 --> 05:55:33,812
DOES IT CHANGE THE TROPISM?

8589
05:55:33,879 --> 05:55:35,013
>> WE'RE AT THE VERY BEGINNING

8590
05:55:35,080 --> 05:55:36,314
ON THAT KIND OF EXPERIMENT.

8591
05:55:36,381 --> 05:55:37,983
YOU SEE MOST ALL THE DATA WE

8592
05:55:38,050 --> 05:55:41,286
HAVE ON THAT.

8593
05:55:41,353 --> 05:55:42,821
THOSE ARE ALL ON THE DRAWING

8594
05:55:42,888 --> 05:55:43,355
BOARD.

8595
05:55:43,422 --> 05:55:45,157
TURNING IT DOWN, TURNING IT UP,

8596
05:55:45,223 --> 05:55:46,358
SO ON, SO FORTH.

8597
05:55:46,425 --> 05:55:49,094
>> CAN I ASK ONE LAST?

8598
05:55:49,161 --> 05:55:49,728
>> THANK YOU.

8599
05:55:49,795 --> 05:55:51,296
>> THERE'S SOMEONE ONLINE.

8600
05:55:51,363 --> 05:55:52,364
>> GOT ANOTHER ONE.

8601
05:55:52,431 --> 05:55:53,331
>> ONLINE, GO FOR IT.

8602
05:55:53,398 --> 05:55:56,768
>> I JUST -- YOU MENTIONED

8603
05:55:56,835 --> 05:55:58,970
LYMPHOCYTES AND YOU SAID THEY'RE

8604
05:55:59,037 --> 05:56:01,039
NOT EXPRESSED IN T-CELLS.

8605
05:56:01,106 --> 05:56:03,375
WHAT ABOUT MACROPHAGES?

8606
05:56:03,442 --> 05:56:04,276
>> WE DON'T KNOW.

8607
05:56:04,342 --> 05:56:09,314
WE'VE LOOKED AT -- THERE'S WHOLE

8608
05:56:09,381 --> 05:56:11,283
BLOOD IN GTEX AND THEN WE'VE

8609
05:56:11,349 --> 05:56:14,186
LOOKED AT PDMCs, TOTAL

8610
05:56:14,252 --> 05:56:16,521
PDMCs, WE LOOKED AT THAT

8611
05:56:16,588 --> 05:56:19,791
PURIFIED CD4 CELLS, JUST -- I

8612
05:56:19,858 --> 05:56:21,393
THINK JUST NAIVE CELLS IS WHAT

8613
05:56:21,460 --> 05:56:22,327
WE HAPPENED TO HAVE AROUND IN

8614
05:56:22,394 --> 05:56:23,595
THE LAB AT THE TIME WE DID THAT.

8615
05:56:23,662 --> 05:56:25,363
SO WE HAVEN'T DONE AN EXHAUSTIVE

8616
05:56:25,430 --> 05:56:26,131
SEARCH ON THAT.

8617
05:56:26,198 --> 05:56:27,799
WE HAVEN'T LOOKED AT MACROPHAGES

8618
05:56:27,866 --> 05:56:29,000
OR OTHER CELL TYPES.

8619
05:56:29,067 --> 05:56:29,901
THAT, WE WILL CERTAINLY DO, BUT

8620
05:56:29,968 --> 05:56:30,969
WE HAVEN'T DONE THAT YET.

8621
05:56:31,036 --> 05:56:31,536
>> OKAY.

8622
05:56:31,603 --> 05:56:32,304
THANK YOU.

8623
05:56:32,370 --> 05:56:33,405
BECAUSE A LOT OF THE --

8624
05:56:33,472 --> 05:56:35,440
>> WHERE DO WE PICK UP OUR GIFT

8625
05:56:35,507 --> 05:56:40,812
BAGS OF CRANBERRIES?

8626
05:56:40,879 --> 05:56:45,150
>> IT'S ABOUT 400 MILES NORTH OF

8627
05:56:45,217 --> 05:56:54,459
HERE.

8628
05:56:54,526 --> 05:56:55,193
>> ALL RIGHT.

8629
05:56:55,260 --> 05:56:56,161
I THINK WE'RE AT THE END OF THE

8630
05:56:56,228 --> 05:56:56,328
DAY.

8631
05:56:56,394 --> 05:56:56,928
THANK YOU VERY MUCH.

8632
05:56:56,995 --> 05:57:05,403
[APPLAUSE]

8633
05:57:05,470 --> 05:57:07,272
>> SO I'LL BE VERY BRIEF.

8634
05:57:07,339 --> 05:57:09,775
IT BEEN A REALLY FANTASTIC DAY.

8635
05:57:09,841 --> 05:57:11,643
I HOPE EVERYBODY ENJOYED IT AS

8636
05:57:11,710 --> 05:57:12,410
MUCH AS I DID.

8637
05:57:12,477 --> 05:57:13,445
I THINK A FEW THANKS ARE IN

8638
05:57:13,512 --> 05:57:13,879
ORDER.

8639
05:57:13,945 --> 05:57:15,013
I'D LIKE TO THANK ALL THE

8640
05:57:15,080 --> 05:57:17,749
SPEAKERS FOR FANTASTIC TALKS.

8641
05:57:17,816 --> 05:57:21,553
[APPLAUSE]

8642
05:57:21,620 --> 05:57:23,655
AND ALL OF YOU FOR A GREAT

8643
05:57:23,722 --> 05:57:24,756
DISCUSSION AND STAYING UNTIL THE

8644
05:57:24,823 --> 05:57:24,956
END.

8645
05:57:25,023 --> 05:57:26,725
THANK YOU FOR OUR ONLINE

8646
05:57:26,792 --> 05:57:27,692
AUDIENCE.

8647
05:57:27,759 --> 05:57:31,229
I'D LIKE TO THANK OUR

8648
05:57:31,296 --> 05:57:36,601
ADMINISTRATIVE STAFF FOR

8649
05:57:36,668 --> 05:57:37,469
LOGISTICS AS WELL AS THE

8650
05:57:37,536 --> 05:57:38,303
CONFERENCE PLANNERS.

8651
05:57:38,370 --> 05:57:39,404
I THINK A LOT OF YOU PROBABLY

8652
05:57:39,471 --> 05:57:41,106
GOT EMAILS FROM TERRY AT SOME

8653
05:57:41,173 --> 05:57:42,307
POINT ALONG THE WAY.

8654
05:57:42,374 --> 05:57:43,341
WE APPRECIATE THAT HELP.

8655
05:57:43,408 --> 05:57:46,611
[APPLAUSE]

8656
05:57:46,678 --> 05:57:49,014
AND I HOPE YOU'LL JOIN US FOR

8657
05:57:49,080 --> 05:57:53,852
UPCOMING AND FUTURE DRP EVENTS.

8658
05:57:53,919 --> 05:57:59,024
NEXT UP IS THE DERSEY MEMORIAL

8659
05:57:59,090 --> 05:57:59,858
SYMPOSIUM WHICH WILL BE NEXT

8660
05:57:59,925 --> 05:58:00,125
THURSDAY.

8661
05:58:00,192 --> 05:58:01,793
YOU CAN ATTEND IF YOU'RE LOCAL

8662
05:58:01,860 --> 05:58:03,128
IN PERSON OR ONLINE IF YOU'RE

8663
05:58:03,195 --> 05:58:04,095
NOT LOCAL.

8664
05:58:04,162 --> 05:58:07,265
SO AGAIN, THANKS VERY MUCH, AND

8665
05:58:07,332 --> 05:58:08,500
ENJOY THE REST OF YOUR DAY.

8666
05:58:08,567
[APPLAUSE]