1
00:00:05,875 --> 00:00:06,643
GOOD MORNING.

2
00:00:06,643 --> 00:00:07,811
I ALSO WANT TO SAY GOOD

3
00:00:07,811 --> 00:00:08,612
AFTERNOON AND GOOD EVENING TO

4
00:00:08,612 --> 00:00:12,482
SOME OF YOU WHO LIVE IN THE

5
00:00:12,482 --> 00:00:13,650
DIFFERENT PART OF THE GLOBE.

6
00:00:13,650 --> 00:00:15,452
SO GOOD TO SEE YOU ALL HERE

7
00:00:15,452 --> 00:00:15,885
AGAIN.

8
00:00:15,885 --> 00:00:22,926
WELCOME TO DAY 2 OF THE WORKSHOP

9
00:00:22,926 --> 00:00:24,294
ON PROGENITOR RESILIENCE AND THE

10
00:00:24,294 --> 00:00:28,164
EARLY SO ONSET OF CHRONIC LUNG

11
00:00:28,164 --> 00:00:28,732
DISEASE.

12
00:00:28,732 --> 00:00:30,467
ON BEHALF OF THE ENTIRE WORKSHOP

13
00:00:30,467 --> 00:00:31,635
PLANNING TEAM, I WOULD LIKE TO

14
00:00:31,635 --> 00:00:32,802
WELCOME YOU AND THANK YOU FOR

15
00:00:32,802 --> 00:00:34,904
YOUR PARTICIPATION.

16
00:00:34,904 --> 00:00:38,141
I'M DR. QING LU, PROGRAM

17
00:00:38,141 --> 00:00:41,378
OFFICIAL IN THE DIVISION OF LUNG

18
00:00:41,378 --> 00:00:43,546
DISEASE.

19
00:00:43,546 --> 00:00:45,115
WHAT A GREAT MEETING WE HAD

20
00:00:45,115 --> 00:00:48,652
YESTERDAY, RIGHT?

21
00:00:48,652 --> 00:00:49,719
MANY PEOPLE HAVE SAID THAT.

22
00:00:49,719 --> 00:00:52,122
I'M VERY EXCITED AND HAPPY TO

23
00:00:52,122 --> 00:00:55,492
REPORT THAT IN THE AVERAGE

24
00:00:55,492 --> 00:00:58,528
YESTERDAY, WE HAD AROUND 200

25
00:00:58,528 --> 00:01:00,764
PEOPLE JOIN THE ZOOM ROOM AND

26
00:01:00,764 --> 00:01:03,566
ABOUT 20 PEOPLE JOINED THE NIH

27
00:01:03,566 --> 00:01:05,835
VIDEOCAST PLATFORM AT A GIVEN

28
00:01:05,835 --> 00:01:09,506
TIME.

29
00:01:09,506 --> 00:01:11,341
SO THAT SPEAKS THE INTEREST OF

30
00:01:11,341 --> 00:01:13,276
THE COMMUNITY TO THIS WORKSHOP.

31
00:01:13,276 --> 00:01:15,912
I WOULD LIKE TO THANK OUR

32
00:01:15,912 --> 00:01:17,414
CO-CHAIRS, ALL THE MODERATORS

33
00:01:17,414 --> 00:01:23,787
AND SPEAKERS, AND TH THE NIH

34
00:01:23,787 --> 00:01:24,354
WORKSHOP SUPPORT TEAM.

35
00:01:24,354 --> 00:01:25,622
BECAUSE OF YOU, THIS HAPPENED.

36
00:01:25,622 --> 00:01:28,124
WE WOULD LIKE TO LOOK FORWARD TO

37
00:01:28,124 --> 00:01:31,127
THE SUCCESSFUL DAY TWO OF THIS

38
00:01:31,127 --> 00:01:35,565
WORKSHOP, AND ALSO WELCOME YOU

39
00:01:35,565 --> 00:01:41,971
TO ACTIONABLE RECOMMENDATIONS.

40
00:01:41,971 --> 00:01:45,575
NOW LET ME WELCOME MYCO-LEAD,

41
00:01:45,575 --> 00:01:47,010
DR. CHRISTIAN GOMEZ, TO SAY A

42
00:01:47,010 --> 00:01:49,512
FEW WORDS BUT ALSO A RECAP FOR

43
00:01:49,512 --> 00:01:49,746
DAY ONE.

44
00:01:49,746 --> 00:01:50,647
THANK YOU.

45
00:01:50,647 --> 00:01:51,448
CHRISTIAN, TAKE IT OVER.

46
00:01:51,448 --> 00:01:51,848
>> THANK YOU.

47
00:01:51,848 --> 00:01:56,019
THANK YOU SO MUCH, QING LU.

48
00:01:56,019 --> 00:01:57,654
WELCOME AGAIN TO THIS EXCITING

49
00:01:57,654 --> 00:01:59,022
WORKSHOP.

50
00:01:59,022 --> 00:02:02,792
AS SHE SAID, WE HAVE A TERRIFIC

51
00:02:02,792 --> 00:02:04,327
DAY YESTERDAY, AND MANY THINGS

52
00:02:04,327 --> 00:02:10,366
HAPPENED, YOU KNOW, THAT NEED TO

53
00:02:10,366 --> 00:02:11,835
BE PUT BACK FOR THOSE THAT WERE

54
00:02:11,835 --> 00:02:13,036
PRESENT THERE AND FOAS JOINING

55
00:02:13,036 --> 00:02:15,038
US TODAY FOR THE FIRST TIME.

56
00:02:15,038 --> 00:02:16,740
SO WITHOUT FURTHER PREAMBLE, I

57
00:02:16,740 --> 00:02:24,180
WOULD LIKE TO INTRODUCE

58
00:02:24,180 --> 00:02:25,148
DR. SEUNGHYE HAN FROM

59
00:02:25,148 --> 00:02:27,150
NORTHWESTERNORTHWESTERN UNIVERS.

60
00:02:27,150 --> 00:02:28,251
SHE IS GOING TO PRESENT THE

61
00:02:28,251 --> 00:02:29,619
RECAP FOR DAY ONE.

62
00:02:29,619 --> 00:02:33,556
DR. HARNTION PLEAS HAN, PLEASE D

63
00:02:33,556 --> 00:02:34,424
ENJOY THIS EXCITING DAY.

64
00:02:34,424 --> 00:02:35,658
THANK YOU.

65
00:02:35,658 --> 00:02:36,559
>> HI, CHRISTIAN.

66
00:02:36,559 --> 00:02:38,228
THANK YOU FOR THE KIND

67
00:02:38,228 --> 00:02:38,695
INTRODUCTION.

68
00:02:38,695 --> 00:02:40,063
SO YESTERDAY WE HAD A VERY

69
00:02:40,063 --> 00:02:41,664
EXCITING WORKSHOP.

70
00:02:41,664 --> 00:02:45,335
OUR WORKSHOP WAS OPEN BY KEYNOTE

71
00:02:45,335 --> 00:02:47,170
SPEAKER DR. RAVI KALHAN WHO

72
00:02:47,170 --> 00:02:48,872
DISCUSSED HOW TO DEFINE

73
00:02:48,872 --> 00:02:50,006
RESPIRATORY RESILIENCE AND

74
00:02:50,006 --> 00:02:50,807
PROMOTE LUNG HEALTH.

75
00:02:50,807 --> 00:02:52,108
HE EMPHASIZED THAT WE NEED A

76
00:02:52,108 --> 00:02:54,577
FRAMEWORK FOR BIOMARKER

77
00:02:54,577 --> 00:02:56,679
DEVELOPMENT SIMILAR TO

78
00:02:56,679 --> 00:02:57,881
CHOLESTEROL-LIKE INDICATOR FORCE

79
00:02:57,881 --> 00:02:58,381
LUNG HEALTH.

80
00:02:58,381 --> 00:02:59,916
TO DO THIS, WE NEED TO SHIFT OUR

81
00:02:59,916 --> 00:03:01,985
FOCUS FROM DISEASE DEVELOPMENT

82
00:03:01,985 --> 00:03:03,219
TO UNDERSTANDING THE MECHANISMS

83
00:03:03,219 --> 00:03:06,422
OF RESPIRATORY HEALTH AND

84
00:03:06,422 --> 00:03:07,090
RESILIENCE.

85
00:03:07,090 --> 00:03:09,526
IN SESSION 1, WE HAD FOUR TALKS

86
00:03:09,526 --> 00:03:11,561
ON THE ROLE OF STEM PROGENITOR

87
00:03:11,561 --> 00:03:12,862
CELLS IN CHRONIC LUNG DISEASE.

88
00:03:12,862 --> 00:03:15,799
FIRST WE DISCUSSED THE

89
00:03:15,799 --> 00:03:17,033
MITOCHONDRIA INTEGRATED STRESS

90
00:03:17,033 --> 00:03:20,436
RESPONSE, ISR, THAT CONTROLS

91
00:03:20,436 --> 00:03:22,238
STEM CELL FATE.

92
00:03:22,238 --> 00:03:25,141
INDEPENDENT OF ATP SYNTHESIS,

93
00:03:25,141 --> 00:03:27,443
MITOCHONDRIAL DYSFUNCTIONS,

94
00:03:27,443 --> 00:03:29,979
SPECIFICALLY A HIGH RATIO,

95
00:03:29,979 --> 00:03:33,416
PREVENTS TRANS SIGGAL CELLS FROM

96
00:03:33,416 --> 00:03:37,220
DIFFERENTIATING INTO -- HOW THE

97
00:03:37,220 --> 00:03:42,325
ISR CONTROL THE CELL FATE AND

98
00:03:42,325 --> 00:03:43,626
WHETHER LEADS TO LUNG DISEASE

99
00:03:43,626 --> 00:03:45,228
NEEDS TO BE FURTHER INVESTIGATED

100
00:03:45,228 --> 00:03:46,629
WITH THE GOAL OF IDENTIFYING

101
00:03:46,629 --> 00:03:49,599
TARGETS TO IMPROVE THE WASTE AND

102
00:03:49,599 --> 00:03:50,533
PROGENITOR CELLS RESPONSE TO

103
00:03:50,533 --> 00:03:51,935
STRESS TO ENHANCE THEIR

104
00:03:51,935 --> 00:03:52,335
RESILIENCE.

105
00:03:52,335 --> 00:03:55,939
NEXT WE TALKED ABOUT DIGITAL

106
00:03:55,939 --> 00:03:59,542
AIRWAY PROGENITOR CELLS IN HUMAN

107
00:03:59,542 --> 00:04:02,846
LUNG DISEASE.

108
00:04:02,846 --> 00:04:04,848
THEY'VE BEEN IDENTIFIED IN HUMAN

109
00:04:04,848 --> 00:04:06,549
AND FERRET LUNGS.

110
00:04:06,549 --> 00:04:08,184
ALTERATION IN THIS CELL

111
00:04:08,184 --> 00:04:10,019
POPULATION ARE ASSOCIATED WITH

112
00:04:10,019 --> 00:04:10,553
COPD.

113
00:04:10,553 --> 00:04:13,256
FURTHER STUDIES ARE NECESSARY TO

114
00:04:13,256 --> 00:04:16,059
UNDERSTAND THE RESPIRATORY

115
00:04:16,059 --> 00:04:17,560
AIRWAY PATHOPHYSIOLOGY AND

116
00:04:17,560 --> 00:04:20,797
PROMOTE LUNG RESILIENCE.

117
00:04:20,797 --> 00:04:22,932
THE THIRD TALK WAS ABOUT A NEW

118
00:04:22,932 --> 00:04:32,041
AIRWAY CELL TYPE, HILLOCKS.

119
00:04:32,041 --> 00:04:34,310
FUTURE STUDIES SHOULD FURTHER

120
00:04:34,310 --> 00:04:37,547
CHARACTERIZE THE FUNCTION OF

121
00:04:37,547 --> 00:04:39,716
HILLOCK CELL AND THEIR

122
00:04:39,716 --> 00:04:40,817
CONTRIBUTIONS TO AIRWAY

123
00:04:40,817 --> 00:04:41,117
RESILIENCE.

124
00:04:41,117 --> 00:04:42,652
THE FINAL PRESENTATION IN

125
00:04:42,652 --> 00:04:49,726
SESSION ONE WAS ON DIFFIC

126
00:04:49,726 --> 00:04:51,527
DIFFERENTIATION AND IMPACT OF

127
00:04:51,527 --> 00:04:52,328
PERTURBING TRANSITIONAL CELL

128
00:04:52,328 --> 00:04:53,630
STATUS ON TISSUE REPAIR.

129
00:04:53,630 --> 00:04:56,032
COMMON INJURY REPAIR PROCESSES

130
00:04:56,032 --> 00:04:59,035
MAY UNDERLIE BOTH EMPHYSEMA AND

131
00:04:59,035 --> 00:05:00,103
FIBROSIS, REPRESENTING TWO

132
00:05:00,103 --> 00:05:02,438
EXTREMES OF THE SAME INJURY

133
00:05:02,438 --> 00:05:03,239
RESPONSE.

134
00:05:03,239 --> 00:05:05,508
FURTHER RESEARCH IS NEEDED FOR

135
00:05:05,508 --> 00:05:06,476
ELUCIDATE THE MOLECULAR

136
00:05:06,476 --> 00:05:09,746
MECHANISM AND THEIR ROLE IN

137
00:05:09,746 --> 00:05:13,383
RESILIENCE FOR DISEASE

138
00:05:13,383 --> 00:05:14,250
SUSCEPTIBILITY.

139
00:05:14,250 --> 00:05:15,885
SO NEXT SESSION TWO FOCUSES ON

140
00:05:15,885 --> 00:05:17,320
EMERGING TECHNOLOGIES AND MODEL

141
00:05:17,320 --> 00:05:19,389
SYSTEMS TO STUDY LUNG

142
00:05:19,389 --> 00:05:20,056
RESILIENCE.

143
00:05:20,056 --> 00:05:21,858
FIRST WE DISCUSSED THE RECENT

144
00:05:21,858 --> 00:05:25,628
ADVANCES IN ORGANOID SYSTEMS.

145
00:05:25,628 --> 00:05:36,072
VASCULARIZED ORGANOIDS --

146
00:05:37,540 --> 00:05:40,443
TRACING IS A VALUABLE TOOL TO

147
00:05:40,443 --> 00:05:42,278
PRECISELY LABEL BRONCHIAL STEM

148
00:05:42,278 --> 00:05:46,349
CELLS TO UNDERSTAND THE ORIGINS

149
00:05:46,349 --> 00:05:49,352
OF A T2 CELLS IN HOMEOSTASIS AND

150
00:05:49,352 --> 00:05:50,820
DISEASE STATE.

151
00:05:50,820 --> 00:05:53,456
ON AIRWAY CULTURE SYSTEM

152
00:05:53,456 --> 00:05:55,792
INCLUDES COMMON IN RARE AIRWAY

153
00:05:55,792 --> 00:05:57,894
CELL TYPES THAT MIMIC THE ION

154
00:05:57,894 --> 00:06:00,096
TRANSPORT DEFECTS OF CYSTIC

155
00:06:00,096 --> 00:06:00,496
FIBROSIS.

156
00:06:00,496 --> 00:06:03,933
PROVIDING A VALUABLE PLATFORM

157
00:06:03,933 --> 00:06:07,470
FOR PATHOGEN STUDIES --

158
00:06:07,470 --> 00:06:09,539
SCREENING AND UNDERSTANDING

159
00:06:09,539 --> 00:06:09,906
BIOPATHOLOGY.

160
00:06:09,906 --> 00:06:12,175
LASTLY WE DISCUSSED THE VALUE OF

161
00:06:12,175 --> 00:06:14,644
FERRET MODELS TO STUDY LUNG

162
00:06:14,644 --> 00:06:14,978
DISEASE.

163
00:06:14,978 --> 00:06:17,680
DUE TO THE ANATOMICAL AND

164
00:06:17,680 --> 00:06:19,015
CELLULAR DIFFERENCES BETWEEN

165
00:06:19,015 --> 00:06:21,951
HUMAN AND RODENT AIRWAY

166
00:06:21,951 --> 00:06:26,522
STRUCTURE, TRANSGENIC FERRETS

167
00:06:26,522 --> 00:06:28,091
ARE AN IDEAL MODEL TO STUDY

168
00:06:28,091 --> 00:06:29,625
HUMAN SPECIFIC LUNG DISEASE AND

169
00:06:29,625 --> 00:06:30,259
RESPIRATORY HELP.

170
00:06:30,259 --> 00:06:33,029
WE DISCUSSED THE LIMITATIONS OF

171
00:06:33,029 --> 00:06:33,830
EXISTING MODELS, EMPHASIZING THE

172
00:06:33,830 --> 00:06:36,099
NEED FOR LONGITUDAL HUMAN

173
00:06:36,099 --> 00:06:37,600
STUDIES AND ADVANCED MODELS THAT

174
00:06:37,600 --> 00:06:39,602
BETTER REFLECT HUMAN RESPIRATORY

175
00:06:39,602 --> 00:06:40,403
HEALTH AND TRAJECTORIES TO

176
00:06:40,403 --> 00:06:41,671
UNDERSTAND THE RESILIENCE

177
00:06:41,671 --> 00:06:44,374
MECHANISMS.

178
00:06:44,374 --> 00:06:45,942
IN SESSION THREE, WE DISCUSSED

179
00:06:45,942 --> 00:06:47,610
THE PROGENITOR BASED MARKERS

180
00:06:47,610 --> 00:06:53,349
THAT PREDICT EARLY ONSET OF

181
00:06:53,349 --> 00:07:03,493
CHRONIC

182
00:07:07,964 --> 00:07:08,664
DYNAMICS.

183
00:07:08,664 --> 00:07:11,768
A SPECIFIC PROTEIN MARKER WAS

184
00:07:11,768 --> 00:07:12,802
IDENTIFIED.

185
00:07:12,802 --> 00:07:14,337
THE SESSION CONCLUDED WITH A

186
00:07:14,337 --> 00:07:16,105
DISCUSSION ON A LARGER SCALE

187
00:07:16,105 --> 00:07:18,307
DATA APPLICATIONS IN PREDICTIVE

188
00:07:18,307 --> 00:07:21,911
MODELS AND THE VALUE OF

189
00:07:21,911 --> 00:07:23,413
LONGITUDAL DATA TO DEVELOP

190
00:07:23,413 --> 00:07:26,315
BIOMARMARKERS TO PREDICT LUNG

191
00:07:26,315 --> 00:07:27,316
HEALTH AND RESILIENCE.

192
00:07:27,316 --> 00:07:30,119
SO I TRIED TO CONCISE ALL THE

193
00:07:30,119 --> 00:07:33,990
WONDERFUL POINTS TO THIS VERY

194
00:07:33,990 --> 00:07:35,291
SHORT, CONCISE -- SO I MIGHT

195
00:07:35,291 --> 00:07:36,659
MISS SOME THINGS BUT I EXPECTED

196
00:07:36,659 --> 00:07:40,129
TO IS GOING TO BE MORE WONDERFUL

197
00:07:40,129 --> 00:07:41,364
DISCUSSION AND BY AMAZING

198
00:07:41,364 --> 00:07:41,864
SPEAKERS.

199
00:07:41,864 --> 00:07:50,907
SO WE CAN -- I'LL GO TO THE

200
00:07:50,907 --> 00:07:55,711
MODERATORS OF THE SESSION FOUR,

201
00:07:55,711 --> 00:07:58,414
DR. CHAPMAN AND DR. MAJKA.

202
00:07:58,414 --> 00:08:00,783
>> HI, GOOD MORNING.

203
00:08:00,783 --> 00:08:03,886
I'M SUE MAJKA, AND IT'S MY

204
00:08:03,886 --> 00:08:05,288
PLEASURE INTRODUCE DR. ANDREW

205
00:08:05,288 --> 00:08:06,889
WILSON AS OUR FIRST SPEAKER THIS

206
00:08:06,889 --> 00:08:07,323
MORNING.

207
00:08:07,323 --> 00:08:10,293
HE IS FROM BOSTON UNIVERSITY,

208
00:08:10,293 --> 00:08:11,461
THE CENTER FOR REGENERATIVE

209
00:08:11,461 --> 00:08:12,895
MEDICINE, AND THE SCIENTIFIC

210
00:08:12,895 --> 00:08:14,330
DIRECTOR OF THE ALPHA-1

211
00:08:14,330 --> 00:08:22,238
FOUNDATION.

212
00:08:22,238 --> 00:08:24,674
>> HELLO, THANK YOU VERY
MUCH,

213
00:08:24,674 --> 00:08:25,408
DR. MAJKA.

214
00:08:25,408 --> 00:08:27,243
I'M LOOKING FORWARD TO THE DAY.

215
00:08:27,243 --> 00:08:28,544
IT'S MY PLEASURE TO BE ABLE TO

216
00:08:28,544 --> 00:08:29,812
SPEAK TO YOU TODAY ABOUT THE

217
00:08:29,812 --> 00:08:32,348
APPLICATION OF PATIENT IPS CELLS

218
00:08:32,348 --> 00:08:33,850
TO MODEL INA VERY VO LUNG

219
00:08:33,850 --> 00:08:35,218
BIOLOGY AND SPECIFICALLY TO

220
00:08:35,218 --> 00:08:37,086
MODEL THAT BIOLOGY AS IT RELATES

221
00:08:37,086 --> 00:08:39,789
TO COPD AND EMPHYSEMA, THE

222
00:08:39,789 --> 00:08:41,224
DISEASES MY LAB PRIMARILY

223
00:08:41,224 --> 00:08:43,059
FOCUSES ON.

224
00:08:43,059 --> 00:08:44,360
SO I WANT TO START OFF JUST BY

225
00:08:44,360 --> 00:08:45,661
MAKING A COUPLE OF OBSERVATIONS

226
00:08:45,661 --> 00:08:46,896
THAT I THINK INDIVIDUALLY ARE

227
00:08:46,896 --> 00:08:48,131
NOT GOING TO BE A SURPRISE TO

228
00:08:48,131 --> 00:08:50,600
THIS AUDIENCE, BUT THAT

229
00:08:50,600 --> 00:08:51,367
COLLECTIVELY UNDERLIE THE

230
00:08:51,367 --> 00:08:52,468
RATIONALE FOR THE APPROACH THAT

231
00:08:52,468 --> 00:08:55,071
WE'VE TAKEN TO ADDRESS COPD AND

232
00:08:55,071 --> 00:08:56,105
EMPHYSEMA IN OUR WORK.

233
00:08:56,105 --> 00:08:57,740
THE FIRST OF THESE OBSERVATION

234
00:08:57,740 --> 00:08:59,475
WAS IN PART MADE PRETTY WELL

235
00:08:59,475 --> 00:09:00,977
YESTERDAY SO I WON'T BELABOR IT

236
00:09:00,977 --> 00:09:02,845
BUT JUST THE OBSERVATION THAT

237
00:09:02,845 --> 00:09:04,947
HUMAN LUNGS DIFFER STRUCTURALLY

238
00:09:04,947 --> 00:09:06,048
FROM RODENT LUNGS IN WAYS THAT

239
00:09:06,048 --> 00:09:08,117
CAN BE REALLY SALIENT AS RELATES

240
00:09:08,117 --> 00:09:14,257
TO MODELING COPD AND EMPHYSEMA.

241
00:09:14,257 --> 00:09:15,658
BUT I'D LIKE TO EXTEND THAT

242
00:09:15,658 --> 00:09:17,059
POINT TO THE GENETICS OF THE

243
00:09:17,059 --> 00:09:17,860
INDIVIDUAL CELL TYPES THAT MAKE

244
00:09:17,860 --> 00:09:22,298
UP THE LUNG AND THE DIFFERENCES

245
00:09:22,298 --> 00:09:24,066
BETWEEN HUMAN AND MOUSE LUNG AND

246
00:09:24,066 --> 00:09:25,468
GENETICALLY WERE VERY WELL MADE

247
00:09:25,468 --> 00:09:27,136
IN THIS PAPER PUBLISHED BACK IN

248
00:09:27,136 --> 00:09:29,071
2020 IN WHICH THEY LOOKED AT

249
00:09:29,071 --> 00:09:31,941
SINGLE CELL RES LAITION OF THE

250
00:09:31,941 --> 00:09:33,609
GENE EXPRESSION PROFILE OF THE

251
00:09:33,609 --> 00:09:34,844
CELLS THAT MAKE UP THE LUNG AND

252
00:09:34,844 --> 00:09:36,379
FOUND MINORITY OF GENES ARE

253
00:09:36,379 --> 00:09:38,047
ACTUALLY FAITHFULLY

254
00:09:38,047 --> 00:09:39,148
RECAPITULATED IN TERMS OF THEIR

255
00:09:39,148 --> 00:09:40,116
GENE EXPRESSION PATTERN IN THE

256
00:09:40,116 --> 00:09:40,983
MOUSE LUNG.

257
00:09:40,983 --> 00:09:45,021
FURTHERMORE, WHEN THEY LOOKED AT

258
00:09:45,021 --> 00:09:46,889
INDIVIDUAL GENES IDENTIFY BY

259
00:09:46,889 --> 00:09:48,090
GENOME WIDE ASSOCIATION STUDIES

260
00:09:48,090 --> 00:09:49,292
WITH RELEVANCE TO CHRONIC LUNG

261
00:09:49,292 --> 00:09:50,593
DISEASES, I'M SHOWING YOU DATA

262
00:09:50,593 --> 00:09:52,028
FROM ONE OF THEM HERE, BUT

263
00:09:52,028 --> 00:09:54,530
SIMILAR OBSERVATIONS WERE MADE

264
00:09:54,530 --> 00:09:56,632
FOR OTHER GWAS GENES RELATED TO

265
00:09:56,632 --> 00:09:59,202
COPD AND EMPHYSEMA SUCH AS HHIP,

266
00:09:59,202 --> 00:10:00,570
THE GENE EXPRESSION PROFILE

267
00:10:00,570 --> 00:10:03,139
DIFFERED IN WAYS NA COULD LIKELY

268
00:10:03,139 --> 00:10:04,140
BE BIOLOGICALLY SIGNIFICANT.

269
00:10:04,140 --> 00:10:07,910
SO THE POINT HERE IS SIMPLY THAT

270
00:10:07,910 --> 00:10:09,378
WE NEED TO BE VERY CAREFUL,

271
00:10:09,378 --> 00:10:11,214
THOUGHTFUL AND INTENTIONAL WHEN

272
00:10:11,214 --> 00:10:12,648
WE'RE DESIGNING EXPERIMENTS TO

273
00:10:12,648 --> 00:10:14,183
ADDRESS EXPERIMENTAL QUESTIONS

274
00:10:14,183 --> 00:10:15,918
TO BE COGNIZANT OF THE RELATIVE

275
00:10:15,918 --> 00:10:17,086
STRENGTHS AND WEAKNESSES OF THE

276
00:10:17,086 --> 00:10:19,255
VARIOUS MODELS WE APPLY TO ASK

277
00:10:19,255 --> 00:10:22,892
SPECIFIC QUESTIONS.

278
00:10:22,892 --> 00:10:23,559
THE SECOND OBSERVATION THAT I

279
00:10:23,559 --> 00:10:24,760
WOULD LIKE TO HIGHLIGHT THAT WE

280
00:10:24,760 --> 00:10:26,195
ALL KNOW TO BE TRUE BUT MAYBE

281
00:10:26,195 --> 00:10:27,496
DON'T THINK AS MUCH ABOUT IS

282
00:10:27,496 --> 00:10:29,165
THAT COPD SUSCEPTIBILITY IS, IN

283
00:10:29,165 --> 00:10:31,067
FACT, HERITABLE.

284
00:10:31,067 --> 00:10:35,271
SO ONLY AROUND 20% OF LONG TERM

285
00:10:35,271 --> 00:10:37,940
SMOKERS DEVELOP CLINICALLY

286
00:10:37,940 --> 00:10:40,576
SIGNIFICANT COPD OR EMPHYSEMA

287
00:10:40,576 --> 00:10:46,282
AND WE KNOW EITHER FROM GENETIC

288
00:10:46,282 --> 00:10:48,517
STUDIES OR -- THIS IS REALLY A

289
00:10:48,517 --> 00:10:49,986
GENETIC DISEASE AND WE KNOW THAT

290
00:10:49,986 --> 00:10:51,220
MANY INDIVIDUALS IN THE

291
00:10:51,220 --> 00:10:53,623
POPULATION DO NOT HARBOR THE

292
00:10:53,623 --> 00:10:55,091
SUSCEPTIBILITY GENES THAT MAKE

293
00:10:55,091 --> 00:10:57,059
THEM SUSCEPTIBLE TO THE SAME

294
00:10:57,059 --> 00:11:00,162
INJURY THAT OTHERS ARE TERRIBLY

295
00:11:00,162 --> 00:11:00,830
SUSCEPTIBLE TO AND I THINK THIS

296
00:11:00,830 --> 00:11:04,500
IS A REALLY IMPORTANT POINT THAT

297
00:11:04,500 --> 00:11:06,202
POTENTIALLY COULD BE A KEY TO

298
00:11:06,202 --> 00:11:06,902
UNDERSTANDING DISEASE

299
00:11:06,902 --> 00:11:09,805
PATHOGENESIS.

300
00:11:09,805 --> 00:11:11,107
THEN LASTLY, I JUST WANT TO

301
00:11:11,107 --> 00:11:12,308
HIGHLIGHT THE FACT THAT WE'VE

302
00:11:12,308 --> 00:11:13,843
LEARNED SO MUCH AS WE ALL KNOW

303
00:11:13,843 --> 00:11:15,444
FROM SINGLE CELL RNA SEQUENCING

304
00:11:15,444 --> 00:11:17,847
STUDIES PROFILING DISEASED LUNG

305
00:11:17,847 --> 00:11:18,814
FROM INDIVIDUALS WITH CHRONIC

306
00:11:18,814 --> 00:11:20,116
LUNG DISEASES IN RECENT YEARS

307
00:11:20,116 --> 00:11:22,418
AND THOSE INSIGHTS HAVE REALLY

308
00:11:22,418 --> 00:11:24,053
BEEN TRANSFORMATIVE, BUT FOR

309
00:11:24,053 --> 00:11:25,588
OBVIOUS REASONS, A LOT OF THE

310
00:11:25,588 --> 00:11:28,524
DATA THAT HAS EMERGED HAS

311
00:11:28,524 --> 00:11:29,725
FEATURED LUNGS THAT WERE SAMPLED

312
00:11:29,725 --> 00:11:31,394
AT THE END STAGE OF THE DISEASE,

313
00:11:31,394 --> 00:11:32,361
AND IT'S JUST IMPORTANT FOR US

314
00:11:32,361 --> 00:11:34,230
TO BE AWARE OF THE FACT THAT

315
00:11:34,230 --> 00:11:35,965
THAT DISEASE STATE MAY DIFFER

316
00:11:35,965 --> 00:11:36,766
SIGNIFICANTLY FROM THE EVENTS

317
00:11:36,766 --> 00:11:38,267
THAT ARE HAPPENING MOLECULARLY

318
00:11:38,267 --> 00:11:40,036
IN THE EARLIEST STAGES OF THE

319
00:11:40,036 --> 00:11:42,538
DISEASE, SO I THINK W IT WOULD E

320
00:11:42,538 --> 00:11:44,140
WISE FOR US TO ALSO TRY TO THINK

321
00:11:44,140 --> 00:11:45,474
CAREFULLY IN OUR FUTURE

322
00:11:45,474 --> 00:11:46,475
EXPERIMENTS ABOUT UNDERSTANDING

323
00:11:46,475 --> 00:11:48,244
THAT EARLY DISEASE STATE

324
00:11:48,244 --> 00:11:49,445
PARTICULARLY IF OUR GOAL WAS TO

325
00:11:49,445 --> 00:11:51,714
TRY TO DEVELOP NEW INTERVENTIONS

326
00:11:51,714 --> 00:11:54,583
THAT CAN BE APPLIED BEFORE THE

327
00:11:54,583 --> 00:11:56,319
LUNG HAS ADVANCED TO A VERY LATE

328
00:11:56,319 --> 00:11:57,720
STAGE OF DISEASE.

329
00:11:57,720 --> 00:12:00,189
AND SO WITH THESE OBSERVATIONS

330
00:12:00,189 --> 00:12:01,924
IN MIND, MY LAB WAS THINKING

331
00:12:01,924 --> 00:12:04,760
ABOUT HOW WE COULD APPLY MODEL

332
00:12:04,760 --> 00:12:06,962
SYSTEMS TO UNDERSTAND DISEASE

333
00:12:06,962 --> 00:12:08,264
PATHOGENESIS AND WE REALLY

334
00:12:08,264 --> 00:12:11,367
WANTED TO APPLY A MODEL THAT

335
00:12:11,367 --> 00:12:13,302
COULD FAITHFULLY RECAPITULATE

336
00:12:13,302 --> 00:12:14,570
THE GENETICS OF THE HUMAN LUNG

337
00:12:14,570 --> 00:12:16,305
THAT COULD CAPTURE THE

338
00:12:16,305 --> 00:12:18,107
HETEROGENEITY OF HUMAN PATIENT

339
00:12:18,107 --> 00:12:19,075
POPULATIONS AND THAT COULD BE

340
00:12:19,075 --> 00:12:20,976
USED TO STUDY THE INCEPTION OF

341
00:12:20,976 --> 00:12:22,845
DISEASE, THE EARLIEST DISEASE

342
00:12:22,845 --> 00:12:24,380
STATE WHERE WE MIGHT BE ABLE TO

343
00:12:24,380 --> 00:12:25,414
INTERVENE, AND SO WITH THOSE

344
00:12:25,414 --> 00:12:27,316
THINGS IN OUR MIND, WE DECIDED

345
00:12:27,316 --> 00:12:30,286
TO FOCUS ON HUMAN INDUCED

346
00:12:30,286 --> 00:12:33,089
PLURIPOTENT STEM CELLS AND APPLY

347
00:12:33,089 --> 00:12:35,891
THEM TO A MODEL OF COPD AND

348
00:12:35,891 --> 00:12:36,192
EMPHYSEMA.

349
00:12:36,192 --> 00:12:37,760
SO I WORK IN THE CENTER FOR

350
00:12:37,760 --> 00:12:39,929
REGENERATIVE MEDICINE AT BOSTON

351
00:12:39,929 --> 00:12:42,998
UNIVERSITY DI WITH DARRELL COTTN

352
00:12:42,998 --> 00:12:44,266
AND THE DIFFERENTIATION OF

353
00:12:44,266 --> 00:12:45,634
APPROACHES WE HAVE APPLIED HAVE

354
00:12:45,634 --> 00:12:48,270
BEEN APPLIED BY HIS LAB AND

355
00:12:48,270 --> 00:12:48,871
DEMONSTRATED IN THE LEFT-HAND

356
00:12:48,871 --> 00:12:49,638
PANEL OF THIS SLIDE.

357
00:12:49,638 --> 00:12:54,243
WE HAD A NICE DISCUSSION

358
00:12:54,243 --> 00:12:58,013
YESTERDAY OF IPS DIRECTED

359
00:12:58,013 --> 00:12:59,548
DIFFERENTIATION PROTOCOLS IN

360
00:12:59,548 --> 00:13:08,357
PROTOCOL.OVER ABOUT A 35-DAY PEN

361
00:13:08,357 --> 00:13:09,859
THIS CASE WE HAVE A SINGLE CELL

362
00:13:09,859 --> 00:13:11,560
TYPE THAT'S REPRESENTED IN OUR

363
00:13:11,560 --> 00:13:13,229
CULTURES AT THE END OF THE

364
00:13:13,229 --> 00:13:14,964
PROTOCOL, AND WE CAN PURIFY

365
00:13:14,964 --> 00:13:15,998
THOSE CELLS BASED ON THEIR

366
00:13:15,998 --> 00:13:17,266
EXPRESSION OF MARKER GENES, IN

367
00:13:17,266 --> 00:13:20,069
THIS CASE THERE'S A FLUORESCENT

368
00:13:20,069 --> 00:13:23,272
REPORTER GENE KNOCKED INTO THE

369
00:13:23,272 --> 00:13:24,306
SURFACTANT PROTEIN C LOCUS AND

370
00:13:24,306 --> 00:13:27,309
WE CAN GENERATE A PURE

371
00:13:27,309 --> 00:13:31,947
POPULATION CULTURED IN MATRIGEL

372
00:13:31,947 --> 00:13:35,117
AND CAN BE SERIALLY PASSAGED FOR

373
00:13:35,117 --> 00:13:36,619
ABOUT A YEAR.

374
00:13:36,619 --> 00:13:37,953
COMPARING THEM TO PRIMARY CELL

375
00:13:37,953 --> 00:13:39,355
TYPES AS IT WAS ILLUSTRATED IN

376
00:13:39,355 --> 00:13:42,958
THIS FIGURE FR FROM THE STEM CEL

377
00:13:42,958 --> 00:13:45,027
PAPER PUBLISHED IN 2017

378
00:13:45,027 --> 00:13:46,796
DEMONSTRATING THIS CELLULAR

379
00:13:46,796 --> 00:13:50,633
EXPRESSION PROFILE OF KEY TYPE T

380
00:13:50,633 --> 00:13:53,135
OF PRIMARY CELLS.

381
00:13:53,135 --> 00:13:54,336
THEN LASTLY IN THE PANEL OVER ON

382
00:13:54,336 --> 00:13:55,604
THE RIGHT WHAT IS BEING

383
00:13:55,604 --> 00:14:01,010
ILLUSTRATED HERE IS WHAT IA

384
00:14:01,010 --> 00:14:03,779
T2s NND LAMELLAR BODIES IN

385
00:14:03,779 --> 00:14:05,314
THOSE CELLS LOOK LIKE COMPARED

386
00:14:05,314 --> 00:14:06,749
TO THE SAME CELLS BUT AFTER

387
00:14:06,749 --> 00:14:08,851
CORRECTION OF THAT SINGLE

388
00:14:08,851 --> 00:14:10,519
MUTATION AND YOU CAN SEE THAT

389
00:14:10,519 --> 00:14:14,190
THE LAMELLAR BODIES IN THE TOP

390
00:14:14,190 --> 00:14:16,759
PANEL ARE MALFORMED, HAVE AN

391
00:14:16,759 --> 00:14:17,693
ABNORMAL APPEARANCE AND THEIR

392
00:14:17,693 --> 00:14:19,628
APPEARANCE IS RESTORED TO A

393
00:14:19,628 --> 00:14:21,230
NORMAL PATTERN FOLLOWING GENETIC

394
00:14:21,230 --> 00:14:21,831
CORRECTION.

395
00:14:21,831 --> 00:14:23,032
THE POINT HERE IS TWOFOLD, FIRST

396
00:14:23,032 --> 00:14:25,768
THAT THESE CELLS CAN BE USED TO

397
00:14:25,768 --> 00:14:27,169
MODEL FEATURES OF MONOGENIC

398
00:14:27,169 --> 00:14:28,604
DISEASES BUT I THINK YOU CAN

399
00:14:28,604 --> 00:14:29,472
EXTRAPOLATE THAT CONCEPT TO HOW

400
00:14:29,472 --> 00:14:31,140
WE THINK OF THE CELLS AS

401
00:14:31,140 --> 00:14:31,874
ESSENTIALLY BEING GENETIC

402
00:14:31,874 --> 00:14:33,008
SURROGATES FOR THE PATIENT FROM

403
00:14:33,008 --> 00:14:34,477
WHOM THEY WERE DERIVED AND IN

404
00:14:34,477 --> 00:14:36,278
THIS CASE THEY'RE BEING APPLIED

405
00:14:36,278 --> 00:14:40,115
TO UNDERSTAND THE CONSEQUENCES

406
00:14:40,115 --> 00:14:41,884
OF A MUTATION IN A SINGLE GENE

407
00:14:41,884 --> 00:14:43,352
BECAUSE THEY CONTAIN THE

408
00:14:43,352 --> 00:14:44,920
PATIENT'S ENTIRE GENOME.

409
00:14:44,920 --> 00:14:45,821
THEORETICALLY THEY CONTAIN ALL

410
00:14:45,821 --> 00:14:47,089
OF THE VARIANTS THAT AN

411
00:14:47,089 --> 00:14:48,390
INDIVIDUAL MIGHT HAVE THROUGHOUT

412
00:14:48,390 --> 00:14:51,026
THEIR GENOME AND CAN, THEREFORE,

413
00:14:51,026 --> 00:14:52,328
BE APPLIED TO UNDERSTAND THESE

414
00:14:52,328 --> 00:14:57,299
COMPLEX DISEASES AS WELL.

415
00:14:57,299 --> 00:14:58,133
SO WE KNOW OF COURSE THAT LIKE

416
00:14:58,133 --> 00:15:00,135
OTHER DISEASES, COPD AND

417
00:15:00,135 --> 00:15:03,506
EMPHYSEMA RESULT FROM A GENE BY

418
00:15:03,506 --> 00:15:04,206
ENVIRONMENT INTERACTION.

419
00:15:04,206 --> 00:15:05,341
MY LAB HAS TRIED TO DEVELOP

420
00:15:05,341 --> 00:15:07,042
APPROACHES TO UNDERSTAND BOTH

421
00:15:07,042 --> 00:15:08,210
THE GENETICS AND THE

422
00:15:08,210 --> 00:15:11,947
ENVIRONMENTAL CONSEQUENCES THAT

423
00:15:11,947 --> 00:15:13,782
ARE ASSOCIATED WITH THIS

424
00:15:13,782 --> 00:15:16,051
DISEASE.

425
00:15:16,051 --> 00:15:18,721
IMPLICIT IN OUR DECISION TO

426
00:15:18,721 --> 00:15:22,658
FOCUS ON TYPE 2, WE ARE GOING TO

427
00:15:22,658 --> 00:15:25,327
BE THINKING ABOUT EMPHYSEMA AS

428
00:15:25,327 --> 00:15:26,462
OUR OUTCOME IN THIS PARTICULAR

429
00:15:26,462 --> 00:15:27,730
SET OF STUDIES.

430
00:15:27,730 --> 00:15:29,164
WHILE WE TYPICALLY SEE

431
00:15:29,164 --> 00:15:31,333
CLINICALLY BOTH COPD AND

432
00:15:31,333 --> 00:15:32,201
EMPHYSEMA WITHIN THE SAME

433
00:15:32,201 --> 00:15:33,002
INDIVIDUALS BECAUSE THEY'RE ALL

434
00:15:33,002 --> 00:15:34,336
EXPOSED TO THE SAME

435
00:15:34,336 --> 00:15:35,337
ENVIRONMENTAL INJURY, THAT THOSE

436
00:15:35,337 --> 00:15:36,438
ARE, IN FACT, SEPARATE OUTCOMES

437
00:15:36,438 --> 00:15:37,873
THAT ARE DISTINCT TO THE

438
00:15:37,873 --> 00:15:39,375
COMPARTMENTS THAT ARE AFFECTED

439
00:15:39,375 --> 00:15:40,442
AND THOSE COMPARTMENTS OF COURSE

440
00:15:40,442 --> 00:15:41,577
ARE MADE UP BY DIFFERENT CELL

441
00:15:41,577 --> 00:15:42,545
TYPES THAT RESPOND DIFFERENTLY

442
00:15:42,545 --> 00:15:43,445
TO INJURY.

443
00:15:43,445 --> 00:15:45,948
BUT FOR THESE EXPERIMENTS, WE'RE

444
00:15:45,948 --> 00:15:48,951
THINKING ABOUT SPECIFICALLY

445
00:15:48,951 --> 00:15:52,955
EMPHYSEMA.

446
00:15:52,955 --> 00:15:56,025
SO IN ORDER TO EXPOSE IA T2s

447
00:15:56,025 --> 00:15:57,626
TO ENVIRONMENTAL INJURY, WE HAD

448
00:15:57,626 --> 00:15:58,761
TO FIRST EXPOSE THEM TO THE

449
00:15:58,761 --> 00:16:01,363
OUTSIDE STRIERMT ENVIRONMENT SOE

450
00:16:01,363 --> 00:16:03,265
ADAPTED THE 3D PROTOCOL I

451
00:16:03,265 --> 00:16:04,800
INTRODUCED YOU TO PREVIOUSLY TO

452
00:16:04,800 --> 00:16:05,968
ALLOW THESE CELLS TO BE CULTURED

453
00:16:05,968 --> 00:16:10,439
IN AN AIR LIQUID INTERFACE AS

454
00:16:10,439 --> 00:16:12,207
ILLUSTRATED IN THE SCHEMATIC

455
00:16:12,207 --> 00:16:12,508
HERE.

456
00:16:12,508 --> 00:16:14,276
ONCE WE HAD DONE SO, WE FIRST

457
00:16:14,276 --> 00:16:14,977
VALIDATED THE FACT THAT THESE

458
00:16:14,977 --> 00:16:16,412
CELLS WERE MAINTAINING THEIR

459
00:16:16,412 --> 00:16:17,813
IDENTITY AS TYPE 2 CELLS AND WE

460
00:16:17,813 --> 00:16:20,816
DID SO BY LOOKING AT CONTINUED

461
00:16:20,816 --> 00:16:24,386
EXPRESSION OF THE SURFACTANT

462
00:16:24,386 --> 00:16:25,821
PROTEIN RECORDER GENE YOU SEE IN

463
00:16:25,821 --> 00:16:30,693
THE BOTTOM PANEL RELATIVE TO THE

464
00:16:30,693 --> 00:16:33,529
CELLS IN THEIR STANDARD 3D

465
00:16:33,529 --> 00:16:34,964
CONDITIONS ON THE TOP.

466
00:16:34,964 --> 00:16:36,699
BY DOING SO WE'RE ABLE TO

467
00:16:36,699 --> 00:16:38,167
CONFIRM THESE CELLS MAINTAINED A

468
00:16:38,167 --> 00:16:41,604
TYPE 2 CELL IDENTITY WHEN

469
00:16:41,604 --> 00:16:42,938
CULTURED IN THE IDENTICAL

470
00:16:42,938 --> 00:16:43,372
CONDITIONS.

471
00:16:43,372 --> 00:16:46,342
WE WENT ON TO LOOK AT THE GENOME

472
00:16:46,342 --> 00:16:47,743
WIDE EXPRESSION PROFILE OF CELLS

473
00:16:47,743 --> 00:16:48,944
CULTURED IN THESE A.I.

474
00:16:48,944 --> 00:16:50,579
CONDITIONS RELATIVE TO THE

475
00:16:50,579 --> 00:16:54,450
STANDARD 3D CULTURE CONDITIONS

476
00:16:54,450 --> 00:16:58,087
OR TO CELLS CULTURES IN A

477
00:16:58,087 --> 00:16:59,722
TRANSWELL LABELED AS 2D, AND

478
00:16:59,722 --> 00:17:00,889
WHAT WE FOUND WAS THAT SIMILAR

479
00:17:00,889 --> 00:17:05,094
TO WHAT HAS BEEN PUBLISHED, THEY

480
00:17:05,094 --> 00:17:06,562
IN FACT ENHANCE THEIR MATURATION

481
00:17:06,562 --> 00:17:07,896
STATE AS READ OUT BY A PANEL OF

482
00:17:07,896 --> 00:17:09,198
GENES WE NO ARE ASSOCIATED WITH

483
00:17:09,198 --> 00:17:11,200
MATURATION OF TYPE 2 CELLS IN

484
00:17:11,200 --> 00:17:12,401
PRIMARY HUMAN SAMPLES AS WELL AS

485
00:17:12,401 --> 00:17:14,269
BY THE UPREGULATION OF A MODULE

486
00:17:14,269 --> 00:17:15,971
OF GENES ASSOCIATED WITH

487
00:17:15,971 --> 00:17:20,676
LAMELLAR BODY BIOGEN CYST.

488
00:17:20,676 --> 00:17:23,512
SO HAVING ESTABLISHED THIS

489
00:17:23,512 --> 00:17:24,847
CULTURE PLATFORM, WE WERE NEXT

490
00:17:24,847 --> 00:17:26,281
ABLE TO APPLY TO TRY TO

491
00:17:26,281 --> 00:17:28,717
UNDERSTAND THE CONSEQUENCES

492
00:17:28,717 --> 00:17:31,120
TRANSCRIPTIONALLY OF CIGARETTE

493
00:17:31,120 --> 00:17:33,389
SMOKE EXPOSURE AND TO DO SO WE

494
00:17:33,389 --> 00:17:34,390
INVESTED IN THE TREUMENT YOU SEE

495
00:17:34,390 --> 00:17:34,890
PICTURED HERE.

496
00:17:34,890 --> 00:17:36,191
I THINK IF YOU LOOK CAREFULLY,

497
00:17:36,191 --> 00:17:37,893
YOU CAN SEE THERE'S A CIGARETTE

498
00:17:37,893 --> 00:17:40,696
IN THE EXPOSURE SLOT OF THE

499
00:17:40,696 --> 00:17:41,830
UPPER LEFT-HAND -- OR OF THE

500
00:17:41,830 --> 00:17:43,032
INSTRUMENT THERE, AND IF YOU

501
00:17:43,032 --> 00:17:44,266
COULD CLICK ON THE PICTURE,

502
00:17:44,266 --> 00:17:49,972
PLEASE, WE'LL BE ABLE TO SEE A

503
00:17:49,972 --> 00:17:51,573
MOVIE OF THE SMOKING HAPPENING

504
00:17:51,573 --> 00:17:56,211
IN ACTION, AND TH IT PASSES OVER

505
00:17:56,211 --> 00:17:57,479
THE APICAL SURFACE OF THE CELLS

506
00:17:57,479 --> 00:17:59,815
THAT ARE CULTURED IN AN

507
00:17:59,815 --> 00:18:01,617
AIR-LIQUID INTERFACE AND THERE

508
00:18:01,617 --> 00:18:02,785
ARE CONTROL CELLS EXPOSED TO AIR

509
00:18:02,785 --> 00:18:04,620
IN THE SAME EXPERIMENT AND AFTER

510
00:18:04,620 --> 00:18:05,921
A PERIOD OF TIME, WE CAN SAMPLE

511
00:18:05,921 --> 00:18:07,489
THESE CELLS TO UNDERSTAND

512
00:18:07,489 --> 00:18:09,124
TRANSCRIPTIONALLY WHAT IS

513
00:18:09,124 --> 00:18:10,559
PERTURBED AS A CONSEQUENCE OF

514
00:18:10,559 --> 00:18:14,063
CIGARETTE SMOKE EXPOSURE.

515
00:18:14,063 --> 00:18:15,531
WHEN WE DO THAT, WE CAN GENERATE

516
00:18:15,531 --> 00:18:17,232
THE DATA THAT YOU SEE HERE AND

517
00:18:17,232 --> 00:18:19,868
THIS IS A SPRING PLOT SHOWING

518
00:18:19,868 --> 00:18:22,237
SINGLE CELL RNA SEQUENCING DATA

519
00:18:22,237 --> 00:18:23,138
FROM THESE CELLS IN FOUR

520
00:18:23,138 --> 00:18:24,440
DIFFERENT CONDITIONS, THEY'RE

521
00:18:24,440 --> 00:18:26,175
COLORED DIFFERENTLY BASED ON

522
00:18:26,175 --> 00:18:26,875
THEIR CONDITION AND THEY'RE

523
00:18:26,875 --> 00:18:28,043
LABELED TO IDENTIFY CELLS THAT

524
00:18:28,043 --> 00:18:32,214
WERE CULTURED JUST IN 3D AND

525
00:18:32,214 --> 00:18:33,115
SUBMERGED CULTURE AS WE

526
00:18:33,115 --> 00:18:34,383
TYPICALLY DO, CELLS THAT WERE

527
00:18:34,383 --> 00:18:36,251
CULTURED IN A TRANS WELL BUT

528
00:18:36,251 --> 00:18:37,486
SUBMERGED IN CULTURE THAT WE

529
00:18:37,486 --> 00:18:38,954
LABELED HERE IS 2D, CELLS THAT

530
00:18:38,954 --> 00:18:41,523
WERE CULTURED AT AIR LIQUID

531
00:18:41,523 --> 00:18:43,559
INTERFACE BUT EXPOSED TO AIR AS

532
00:18:43,559 --> 00:18:45,828
CONTROLS THAT ARE LABELED AS

533
00:18:45,828 --> 00:18:48,964
A.I. AND THEN THE -- THEN WE CAN

534
00:18:48,964 --> 00:18:50,065
IDENTIFY DIFFERENTIALLY

535
00:18:50,065 --> 00:18:51,567
EXPRESSED GENES COMPARING THE

536
00:18:51,567 --> 00:18:52,634
SMOKED CELLS TO THE AIR CONTROLS

537
00:18:52,634 --> 00:18:54,503
AND THEN LOOK AT PATHWAYS THAT

538
00:18:54,503 --> 00:18:56,438
WERE UPREGULATED OR

539
00:18:56,438 --> 00:18:57,639
DOWNREGULATED AS A CONSEQUENCE

540
00:18:57,639 --> 00:18:59,908
BY GENE SET ENRICHMENT ANALYSIS.

541
00:18:59,908 --> 00:19:01,643
I'M JUST SHOWING YOU THE

542
00:19:01,643 --> 00:19:02,811
HALLMARK DATA FOR THE

543
00:19:02,811 --> 00:19:03,712
UPREGULATED PATHWAYS HERE.

544
00:19:03,712 --> 00:19:05,547
SO THEN WE COULD USE THIS DATA

545
00:19:05,547 --> 00:19:10,052
TO TRY TO UNDERSTAND THE

546
00:19:10,052 --> 00:19:12,121
CONSEQUENCES OF ACUTE SMOKE

547
00:19:12,121 --> 00:19:13,222
EXPOSURE IN THIS PARTICULAR CELL

548
00:19:13,222 --> 00:19:14,656
TYPE THAT CAN BE HARD TO ACCESS

549
00:19:14,656 --> 00:19:17,493
FROM PATIENTS.

550
00:19:17,493 --> 00:19:18,160
OF COURSE IN ADDITION TO

551
00:19:18,160 --> 00:19:19,261
UNDERSTAND THE ENVIRONMENTAL

552
00:19:19,261 --> 00:19:21,096
EXPOSURE WE WANT TO BE ABLE TO

553
00:19:21,096 --> 00:19:25,801
UNDERSTAND THE GENE EXPRESSION

554
00:19:25,801 --> 00:19:29,738
AND THE CONSEQUENCES OF

555
00:19:29,738 --> 00:19:30,439
PERTURBATION -- GENOME WIDE

556
00:19:30,439 --> 00:19:32,040
ASSOCIATION STUDIES TO BE

557
00:19:32,040 --> 00:19:33,175
ASSOCIATED WITH COPD AND

558
00:19:33,175 --> 00:19:34,743
EMPHYSEMA AND TO DO THIS WORK WE

559
00:19:34,743 --> 00:19:38,680
TEAMED UP WITH THE CHANNING LAB

560
00:19:38,680 --> 00:19:40,182
AND WE THOUGHT WITH THEM ABOUT

561
00:19:40,182 --> 00:19:42,651
GENES IDENTIFIED BY GWAS THAT WE

562
00:19:42,651 --> 00:19:46,488
THOUGHT WOULD BE LIKELY TO BE

563
00:19:46,488 --> 00:19:47,556
BIOLOGICALLY RELEVANT IN TIP

564
00:19:47,556 --> 00:19:48,857
2 CELLS AND THAT WERE EXPRESSED

565
00:19:48,857 --> 00:19:50,793
IN HUMAN PRIMARY TIP 2 CELLS AS

566
00:19:50,793 --> 00:19:54,897
WELL AS IN OUR IPSC PLATFORM.

567
00:19:54,897 --> 00:19:56,765
AND TO TRY TO UNDERSTAND THE

568
00:19:56,765 --> 00:19:59,568
FUNCTIONAL CONSEQUENCES OF THESE

569
00:19:59,568 --> 00:20:01,236
GENES BOTH IN TERMS OF

570
00:20:01,236 --> 00:20:04,106
HOMEOSTASIS AND ALSO IN TERMS OF

571
00:20:04,106 --> 00:20:06,375
HAHOW THEY MIGHT CONTRIBUTE TO

572
00:20:06,375 --> 00:20:07,643
DISEASE SUSCEPTIBILITY OR

573
00:20:07,643 --> 00:20:10,512
PATHOGENESIS, WE MODIFIED OUR

574
00:20:10,512 --> 00:20:12,214
IPSC PLATFORM TO USE AN APPROACH

575
00:20:12,214 --> 00:20:14,216
CALLED CRISPR INTERFERENCE, AND

576
00:20:14,216 --> 00:20:18,053
SO TO DO THAT, WE KNOCKED A

577
00:20:18,053 --> 00:20:21,223
DCAS9 CRAB CONSTRUCT INTO THE

578
00:20:21,223 --> 00:20:22,157
AAVS1 HARBOR LOCUS OF OUR CELLS

579
00:20:22,157 --> 00:20:24,026
AND TOOK THEM TO THE NORMAL

580
00:20:24,026 --> 00:20:25,527
DIFFERENTIATION PROTOCOL TO

581
00:20:25,527 --> 00:20:28,363
GENERATE IA T2s AND INTRODUCED

582
00:20:28,363 --> 00:20:30,032
GUIDE RNAs TO KNOCK DOWN THE

583
00:20:30,032 --> 00:20:33,168
SPECIFIC GENES OF INTEREST IN A

584
00:20:33,168 --> 00:20:34,503
LENTIVIRUS AND THEN WE COULD

585
00:20:34,503 --> 00:20:36,471
SORT CELLS THAT WERE TRANSDUCED

586
00:20:36,471 --> 00:20:38,440
WITH THIS BFP REPORTER TO

587
00:20:38,440 --> 00:20:41,143
GENERATE PURE POPULATIONS OF IA

588
00:20:41,143 --> 00:20:42,144
T2s EXPRESSING THE GUIDE

589
00:20:42,144 --> 00:20:44,413
RNAs.

590
00:20:44,413 --> 00:20:48,250
THIS IS -- WE WERE ABLE TO

591
00:20:48,250 --> 00:20:49,618
TEMPORALLY CONTROL KNOCKDOWN BY

592
00:20:49,618 --> 00:20:51,353
THE INTRODUCTION OF DOXYCYCLINE

593
00:20:51,353 --> 00:20:52,754
TO THE TISSUE CULTURE MEDIA AND

594
00:20:52,754 --> 00:20:54,923
THEN WE APPLIED THIS TO THE

595
00:20:54,923 --> 00:20:56,825
APPROACH TO THAT NINE GENES WE

596
00:20:56,825 --> 00:20:59,027
HAD SELECTED.

597
00:20:59,027 --> 00:21:01,496
TO KNOCK THOSE GENES DOWN ONE AT

598
00:21:01,496 --> 00:21:04,333
A TIMEMENT I'M SHOWING YOU THE

599
00:21:04,333 --> 00:21:05,567
QPCR DATA FROM THAT EXPERIMENT

600
00:21:05,567 --> 00:21:07,236
HERE, SHOWING WE CAN LITERALLY

601
00:21:07,236 --> 00:21:08,704
KNOCK DOWN THESE GENES OF

602
00:21:08,704 --> 00:21:11,607
INTEREST FROM GWAS.

603
00:21:11,607 --> 00:21:13,308
SO BECAUSE TYPE 2 CELLS ARE

604
00:21:13,308 --> 00:21:15,944
PROGENITOR CELLS IN THE AL VEE

605
00:21:15,944 --> 00:21:17,479
ALVEOLUS, WE THOUGHT IT WOULD BE

606
00:21:17,479 --> 00:21:18,747
USEFUL TO LOOK AT CELL FUNCTION

607
00:21:18,747 --> 00:21:20,015
AND THE EFFECT OF KNOCKING DOWN

608
00:21:20,015 --> 00:21:22,417
THOSE GENES ON PROGENITOR CELL

609
00:21:22,417 --> 00:21:22,718
FUNCTION.

610
00:21:22,718 --> 00:21:24,019
I'M NOT SHOWING YOU THE DATA

611
00:21:24,019 --> 00:21:25,487
HERE BUT WE LOOKED AT PHENOTYPES

612
00:21:25,487 --> 00:21:27,289
THAT WE THOUGHT WERE RELEVANT

613
00:21:27,289 --> 00:21:28,957
FOR PROGENITOR CELLS THAT

614
00:21:28,957 --> 00:21:29,925
INCLUDED PROLIFERATION,

615
00:21:29,925 --> 00:21:31,493
MATURATION AND DIFFERENTIATION

616
00:21:31,493 --> 00:21:32,394
EFFICIENCY AND THEN FROM THAT

617
00:21:32,394 --> 00:21:34,529
PANEL OF NINE GENES, WE SELECTED

618
00:21:34,529 --> 00:21:36,732
ONE TO FOCUS ON AND DO A DEEP

619
00:21:36,732 --> 00:21:39,902
DIVE ON AND THAT GENE WAS DSP,

620
00:21:39,902 --> 00:21:41,103
AN INTERESTING GENE IN PART

621
00:21:41,103 --> 00:21:42,604
BECAUSE IT'S BEEN IDENTIFIED

622
00:21:42,604 --> 00:21:43,939
INDEPENDENTLY BY GENOME WIDE

623
00:21:43,939 --> 00:21:44,806
ASSOCIATION STUDIES TO BE

624
00:21:44,806 --> 00:21:46,441
ASSOCIATED WITH BOTH COPD BUT

625
00:21:46,441 --> 00:21:49,278
ALSO WITH PULMONARY FIBROSIS.

626
00:21:49,278 --> 00:21:50,545
THIS IS SORT OF AN OVERVIEW OF

627
00:21:50,545 --> 00:21:52,381
THE TYPE OF DATA THAT WE WERE

628
00:21:52,381 --> 00:21:53,615
ABLE TO GENERATE IN THESE

629
00:21:53,615 --> 00:21:55,317
STUDIES SO WE COULD LOOK

630
00:21:55,317 --> 00:21:56,385
TRANSCRIPTIONALLY BY SINGLE CELL

631
00:21:56,385 --> 00:21:57,886
RNA SEQUENCING ON THE LEFT AT

632
00:21:57,886 --> 00:22:00,022
THE GENE EXPRESSION PROFILE OF

633
00:22:00,022 --> 00:22:01,390
CELLS WITH DSP KNOCKDOWN

634
00:22:01,390 --> 00:22:02,724
COMPARED TO CONTROLS WITHOUT

635
00:22:02,724 --> 00:22:03,191
KNOCKDOWN.

636
00:22:03,191 --> 00:22:04,459
AND THEN FROM THAT GENE

637
00:22:04,459 --> 00:22:05,494
EXPRESSION DATA, WE COULD

638
00:22:05,494 --> 00:22:06,662
IDENTIFY MOLECULAR PROCESSES

639
00:22:06,662 --> 00:22:08,463
THAT WERE DYSREGULATED, IN THIS

640
00:22:08,463 --> 00:22:10,732
CASE METABOLISM, AND I'M SHOWING

641
00:22:10,732 --> 00:22:13,502
YOU A DATA FROM A SEAHORSE ASSAY

642
00:22:13,502 --> 00:22:15,971
TO INTERROGATE MITOCHONDRIAL

643
00:22:15,971 --> 00:22:17,572
FUNCTION IN THE CONTEXT OF DSP

644
00:22:17,572 --> 00:22:19,641
KNOCKDOWN AND WE LIKEWISE

645
00:22:19,641 --> 00:22:20,342
PERFORMED COMPLEMENTARY

646
00:22:20,342 --> 00:22:22,878
EXPERIMENTS TO OVEREXPRESS DSP

647
00:22:22,878 --> 00:22:24,413
USING AN APPROACH CALLED CRISPR

648
00:22:24,413 --> 00:22:25,314
ACTIVATION TO SEE THE RESULTS OF

649
00:22:25,314 --> 00:22:26,515
THAT WHICH IN THIS CASE WERE

650
00:22:26,515 --> 00:22:28,150
EXACTLY OPPOSITE OF WHAT YOU'RE

651
00:22:28,150 --> 00:22:28,817
SEEING HERE.

652
00:22:28,817 --> 00:22:31,620
THEN LASTLY, WE COULD

653
00:22:31,620 --> 00:22:33,388
INCORPORATE THE CIGARETTE SMOKE

654
00:22:33,388 --> 00:22:34,556
INJURY APPROACH THAT I

655
00:22:34,556 --> 00:22:38,026
INTRODUCED TO YOU PREVIOUSLY TO

656
00:22:38,026 --> 00:22:39,361
INTERROGATE GENE BY ENVIRONMENT

657
00:22:39,361 --> 00:22:40,629
INTERACTIONS AND UNDERSTAND IF

658
00:22:40,629 --> 00:22:43,365
THEY HAVE CONSEQUENCE OF THAT ON

659
00:22:43,365 --> 00:22:44,466
PROGENITOR CELL FUNCTION BY

660
00:22:44,466 --> 00:22:49,838
COLONY FORMING EFFICIENCY.

661
00:22:49,838 --> 00:22:51,039
WHILE I'VE JUST SHOWN YOU ALL OF

662
00:22:51,039 --> 00:22:53,108
THIS DATA AS IT APPLIES TO A

663
00:22:53,108 --> 00:22:54,209
SINGLE GENE AND A CELL TYPE, I

664
00:22:54,209 --> 00:22:55,744
THINK THIS IS A GENERALIZABLE

665
00:22:55,744 --> 00:22:58,647
APPROACH THAT COULD BE USED TO

666
00:22:58,647 --> 00:23:00,615
UNDERSTAND THE HOMEOSTATIC AND

667
00:23:00,615 --> 00:23:01,650
POTENTIALLY DISEASE RELEVANT

668
00:23:01,650 --> 00:23:03,285
CONSEQUENCES OF PERTURBING ANY

669
00:23:03,285 --> 00:23:04,686
GENE AND WHILE I'VE SHOWN TO YOU

670
00:23:04,686 --> 00:23:07,656
IN IA T2s, IT COULD ALSO BE

671
00:23:07,656 --> 00:23:08,623
PERFORMED IN AIRWAY CELLS AS

672
00:23:08,623 --> 00:23:08,857
WELL.

673
00:23:08,857 --> 00:23:10,258
WHEN I THINK ABOUT CURRENT GAPS

674
00:23:10,258 --> 00:23:12,160
IN UNDERSTANDING ASSOCIATED WITH

675
00:23:12,160 --> 00:23:14,029
THIS TYPE OF DATA, I THINK THAT

676
00:23:14,029 --> 00:23:15,998
IT'S IMPORTANT TO THINK ABOUT

677
00:23:15,998 --> 00:23:17,165
THE GENETIC CONTRIBUTIONS TO

678
00:23:17,165 --> 00:23:18,934
SUSCEPTIBILITY AND PATHOGENESIS

679
00:23:18,934 --> 00:23:20,702
TO UNDERSTAND BETTER THE

680
00:23:20,702 --> 00:23:22,270
HETEROGENEITY THAT EXISTS WITHIN

681
00:23:22,270 --> 00:23:23,939
PATIENTS WHO HAVE COPD AND

682
00:23:23,939 --> 00:23:24,706
EMPHYSEMA AND ALSO THE

683
00:23:24,706 --> 00:23:26,141
ASSOCIATED MOLECULAR PHENOTYPING

684
00:23:26,141 --> 00:23:27,309
DIFFERENCES THAT ARE ASSOCIATED

685
00:23:27,309 --> 00:23:29,511
WITH THOSE DIFFERENT PHENOTYPES.

686
00:23:29,511 --> 00:23:31,580
TO THINK ABOUT THE CELL TYPE AND

687
00:23:31,580 --> 00:23:32,414
COMPARTMENT SPECIFIC RESPONSES

688
00:23:32,414 --> 00:23:35,884
TO DISEASE RELEVANT INJURY AND

689
00:23:35,884 --> 00:23:38,053
AS I'VE MENTIONED ALREADY TO

690
00:23:38,053 --> 00:23:40,355
FOCUS ON PATHOGENESIS OF EARLY

691
00:23:40,355 --> 00:23:40,889
STAGE DISEASE.

692
00:23:40,889 --> 00:23:42,457
THEN LASTLY, SOME KEY RESEARCH

693
00:23:42,457 --> 00:23:43,125
OPPORTUNITIES THAT I THINK WOULD

694
00:23:43,125 --> 00:23:46,028
BE VALUABLE TO THINK ABOUT WOULD

695
00:23:46,028 --> 00:23:48,030
BE TO IDENTIFY LONGITUDAL COHORT

696
00:23:48,030 --> 00:23:49,898
STUDIES THAT HAVE ASSOCIATED

697
00:23:49,898 --> 00:23:51,066
BIOREPOSITORIES THAT WOULD ALLOW

698
00:23:51,066 --> 00:23:52,734
US TO LINK PRIMARY CELLS AND

699
00:23:52,734 --> 00:23:54,136
TISSUES WITH LONGITUDAL

700
00:23:54,136 --> 00:23:55,771
PHENOTYPING DATA.

701
00:23:55,771 --> 00:23:57,105
SECONDLY, TO THINK ABOUT

702
00:23:57,105 --> 00:23:58,540
EXPERIMENTAL VALIDATION OF GWAS

703
00:23:58,540 --> 00:24:00,042
VARIANT FUNCTION IN

704
00:24:00,042 --> 00:24:00,709
DISEASE-RELEVANT CELLS AND

705
00:24:00,709 --> 00:24:03,211
LASTLY TO FOCUS ON HUMAN MODEL

706
00:24:03,211 --> 00:24:04,646
SYSTEMS THAT CAN BE COUPLED

707
00:24:04,646 --> 00:24:06,481
TOGETHER WITH EITHER PCLS OR

708
00:24:06,481 --> 00:24:08,817
WITH ANIMAL MODELS THAT

709
00:24:08,817 --> 00:24:09,451
RECAPITULATE ESSENTIAL FEATURES

710
00:24:09,451 --> 00:24:11,753
OF THA HUMAN LUNG STRUCTURE.

711
00:24:11,753 --> 00:24:13,155
THANK YOU VUCH.

712
00:24:13,155 --> 00:24:15,991
 VVERY MUCH.

713
00:24:17,826 --> 00:24:18,860
I'D BE HAPPY TO TAKE ANY

714
00:24:18,860 --> 00:24:20,228
QUESTIONS AT THE END.

715
00:24:20,228 --> 00:24:26,101
>> QUESTIONS AT THE END.

716
00:24:26,101 --> 00:24:26,868
I'M HAROLD CHAPMAN.

717
00:24:26,868 --> 00:24:28,670
I JUST WANT TO INTRODUCE THE

718
00:24:28,670 --> 00:24:29,704
NEXT SPEAKER.

719
00:24:29,704 --> 00:24:33,675
THESE ARE ALL -- IN THIS

720
00:24:33,675 --> 00:24:36,478
SESSION, VERY HUMAN-ORIENTED

721
00:24:36,478 --> 00:24:37,679
PRESENTATIONS, AND THE ONE

722
00:24:37,679 --> 00:24:39,448
THAT'S COMING UP IS BY DAN

723
00:24:39,448 --> 00:24:40,182
WEISS.

724
00:24:40,182 --> 00:24:42,784
HE'S A PROFESSOR OF MEDICINE IN

725
00:24:42,784 --> 00:24:43,752
BIOENGINEERING AT THE UNIVERSITY

726
00:24:43,752 --> 00:24:44,286
OF VERMONT.

727
00:24:44,286 --> 00:24:45,887
HE'S BEEN INTERESTED IN THE

728
00:24:45,887 --> 00:24:49,257
POTENTIAL THERAPEUTIC POTENTIAL

729
00:24:49,257 --> 00:24:51,793
OF MESENCHYMAL STEM CELLS FOR A

730
00:24:51,793 --> 00:24:53,628
LONG TIME, AND I THINK HE'S

731
00:24:53,628 --> 00:24:55,297
GOING TO UPDATE US ON WHERE THIS

732
00:24:55,297 --> 00:24:56,364
FIELD STANDS.

733
00:24:56,364 --> 00:24:56,531
DAN?

734
00:24:56,531 --> 00:24:59,301
>> ALL RIGHT, THANK YOU
VERY

735
00:24:59,301 --> 00:25:02,938
MUCH, HAROLD, AND THANKS TO THE

736
00:25:02,938 --> 00:25:05,974
ORGANIZERS FOR INCLUDING THIS IN

737
00:25:05,974 --> 00:25:08,176
THE OVERALL SYMPOSIUM.

738
00:25:08,176 --> 00:25:12,013
THIS IS A LITTLE BIT DIFFERENT

739
00:25:12,013 --> 00:25:13,381
FROM ALL OF THE WORK YOU'VE SEEN

740
00:25:13,381 --> 00:25:14,883
SO FAR BUT I WANT TO HIGHLIGHT

741
00:25:14,883 --> 00:25:18,587
THE POTENTIAL OF CELL-BASED

742
00:25:18,587 --> 00:25:20,222
THERAPY USE CELLS THAT DON'T

743
00:25:20,222 --> 00:25:21,623
NECESSARILY GRAFT.

744
00:25:21,623 --> 00:25:22,891
SO WHAT WE'LL DO IS WE'LL GO

745
00:25:22,891 --> 00:25:27,696
OVER A LITTLE BIT OF THE

746
00:25:27,696 --> 00:25:28,663
RATIONALE BACKGROUND ON WHAT

747
00:25:28,663 --> 00:25:30,832
THESE MSCs ARE, KNOWN

748
00:25:30,832 --> 00:25:31,833
MECHANISMS OF ACTION AND A

749
00:25:31,833 --> 00:25:33,135
LITTLE BIT OF PRE-CLINICAL

750
00:25:33,135 --> 00:25:33,502
STUDIES.

751
00:25:33,502 --> 00:25:35,270
BUT WHAT I WANT TO DO IS FOCUS

752
00:25:35,270 --> 00:25:37,205
ON THE CLINICAL INVESTIGATIONS

753
00:25:37,205 --> 00:25:39,741
TO DATE IN COPD AND ONE OF THE

754
00:25:39,741 --> 00:25:40,909
THINGS WE'RE GOING TO HIGHLIGHT

755
00:25:40,909 --> 00:25:43,645
IS WHAT'S BEEN BROUGHT UP SO FAR

756
00:25:43,645 --> 00:25:45,480
THAT COPD LIKE SO MANY OTHER

757
00:25:45,480 --> 00:25:47,249
DISEASES IS A HETEROGENEOUS

758
00:25:47,249 --> 00:25:48,683
SYNDROME, AND SO IT'S NOT GOING

759
00:25:48,683 --> 00:25:50,152
TO BE ONE SIZE FITS ALL.

760
00:25:50,152 --> 00:25:54,256
AND WE'LL TALK A BIT ABOUT

761
00:25:54,256 --> 00:25:56,224
NON-COVID AND COVID RDS

762
00:25:56,224 --> 00:25:57,058
APPLICATIONS.

763
00:25:57,058 --> 00:25:57,859
BUT THE KEY THING IS, THERE'S

764
00:25:57,859 --> 00:25:59,027
BEEN A LOT OF WORK AND SOME OF

765
00:25:59,027 --> 00:26:00,595
THESE TRIALS WORK, SOME OF THEM

766
00:26:00,595 --> 00:26:03,999
DON'T, AND WE NEED TO UNDERSTAND

767
00:26:03,999 --> 00:26:05,467
BETTER ABOUT HOW WE CAN MAKE

768
00:26:05,467 --> 00:26:10,005
THEM ALL WORK.

769
00:26:10,005 --> 00:26:11,306
SO A LITTLE ABOUT MY LAB

770
00:26:11,306 --> 00:26:12,174
INTERESTS AND ALL THAT.

771
00:26:12,174 --> 00:26:14,643
WE'RE GOING TO TALK ABOUT THE

772
00:26:14,643 --> 00:26:15,677
UPPER RIGHT-HAND CORNER

773
00:26:15,677 --> 00:26:16,578
CELL-BASED THERAPIES BUT I WANT

774
00:26:16,578 --> 00:26:17,846
TO POINT OUT, WE'VE DONE A LOT

775
00:26:17,846 --> 00:26:19,047
OF WORK IN THE LOWER RIGHT-HAND

776
00:26:19,047 --> 00:26:21,249
CORNER THERE WITH HYDROGELS AND

777
00:26:21,249 --> 00:26:26,054
DEVELOPED A SERIES OF TOOLS WITH

778
00:26:26,054 --> 00:26:29,658
LUNG EXTRACELLULAR MATRIX

779
00:26:29,658 --> 00:26:32,160
DERIVED HYDROGELS FROM NORMAL

780
00:26:32,160 --> 00:26:35,697
AND DISEASED LUNGS, COPD, AND

781
00:26:35,697 --> 00:26:37,499
IPF THAT I THINK COULD BE

782
00:26:37,499 --> 00:26:39,734
VALUABLE ADDITIONS TO A LOT OF

783
00:26:39,734 --> 00:26:41,469
THE REALLY GREAT WORK THAT'S

784
00:26:41,469 --> 00:26:43,738
GONE ON SO FAR.

785
00:26:43,738 --> 00:26:49,010
SO WHAT ARE THESE M SCs?

786
00:26:49,010 --> 00:26:50,745
THESE ARE CELLS ORIGINALLY

787
00:26:50,745 --> 00:26:51,346
ISOLATED FROM THE BONE MARROW

788
00:26:51,346 --> 00:26:52,714
AND NOW HAVE BEEN FOUND TO BE

789
00:26:52,714 --> 00:26:54,449
PRESENT IN A RANGE OF TISSUES

790
00:26:54,449 --> 00:26:56,318
INCLUDING ADIPOSE, PLACENTAL,

791
00:26:56,318 --> 00:26:57,185
CORD BLOOD AND OTHERS.

792
00:26:57,185 --> 00:26:58,587
THEY DON'T LEAVE THESE TISSUES,

793
00:26:58,587 --> 00:27:00,488
THEY HAVE TO BE EXTRACTED AND

794
00:27:00,488 --> 00:27:02,457
FOR A VARIETY OF IN VITRO

795
00:27:02,457 --> 00:27:04,859
SYSTEMS, WHAT ONE CAN DO IS

796
00:27:04,859 --> 00:27:06,861
INCUBATE THE CELLS WITH A RANGE

797
00:27:06,861 --> 00:27:08,530
OF IMMUNE EFFECTOR CELLS

798
00:27:08,530 --> 00:27:09,931
INCLUDING T CELLS, B CELLS, ET

799
00:27:09,931 --> 00:27:11,967
CETERA, AS LISTED, AND IN

800
00:27:11,967 --> 00:27:13,168
VIRTUALLY EVERY CASE, THE

801
00:27:13,168 --> 00:27:15,904
PRESENCE OF THE MSC WILL INHIBIT

802
00:27:15,904 --> 00:27:18,974
BOTH PROLIFERATION AND THE

803
00:27:18,974 --> 00:27:19,708
PARTICULAR IMMUNE EFFECTOR

804
00:27:19,708 --> 00:27:20,642
FUNCTION OF THOSE CELLS.

805
00:27:20,642 --> 00:27:22,877
THE SCHEMATIC ON THE RIGHT SIDE

806
00:27:22,877 --> 00:27:24,613
SHOWS -- IT'S AN OLD SCHEMATIC,

807
00:27:24,613 --> 00:27:26,248
BUT RANGE OF SECRETED MEDIATORS

808
00:27:26,248 --> 00:27:28,183
THAT HAVE BEEN IMPLICATED IN

809
00:27:28,183 --> 00:27:28,850
THESE ACTIONS.

810
00:27:28,850 --> 00:27:31,820
THIS INCLUDES ALSO EXTRACELLULAR

811
00:27:31,820 --> 00:27:33,822
VESICLES AND THE EXTRACELLULAR

812
00:27:33,822 --> 00:27:36,191
VESICLE CONTENT.

813
00:27:36,191 --> 00:27:40,228
THE MSCs ALSO HAVE POOR

814
00:27:40,228 --> 00:27:41,396
INITIAL IMMUNOGENICITY WHICH

815
00:27:41,396 --> 00:27:44,266
MEANS ONE CAN UTILIZE NON-H LA.

816
00:27:44,266 --> 00:27:46,801
MATCHED ALLOGENEIC MSCs AND

817
00:27:46,801 --> 00:27:52,907
CLINICAL SCHEMES, IF YOU WILL.

818
00:27:52,907 --> 00:27:54,743
IN TERMS OF CLINICAL

819
00:27:54,743 --> 00:27:55,477
APPLICATIONS, THERE'S BEEN A

820
00:27:55,477 --> 00:27:56,511
WIDE RANGE OF INVESTIGATIONS

821
00:27:56,511 --> 00:27:59,014
BASED ON SOLID PRE-CLINICAL DATA

822
00:27:59,014 --> 00:28:02,584
IN DISEASES THAT ARE MOSTLY

823
00:28:02,584 --> 00:28:05,687
AUTOIMMUNE AND INFLAMMATORY AS

824
00:28:05,687 --> 00:28:06,655
LISTED, GRAFT-VERSUS-HOST

825
00:28:06,655 --> 00:28:09,024
DISEASE, CROHN'S, MULTIPLE

826
00:28:09,024 --> 00:28:10,592
SCLEROSIS, TYPE 1 AUTOIMMUNE

827
00:28:10,592 --> 00:28:14,129
DIABETES, ET CETERA.

828
00:28:14,129 --> 00:28:15,964
CARDIAC DISEASE AND OTHERS.

829
00:28:15,964 --> 00:28:18,600
AND TO DATE, THE MSC BASED

830
00:28:18,600 --> 00:28:19,968
CLINICAL THERAPIES ARE APPROVED

831
00:28:19,968 --> 00:28:24,606
FOR A LIMITED RANGE OF DISEASES.

832
00:28:24,606 --> 00:28:25,607
REFRACTORY PEDIATRIC GRAFT

833
00:28:25,607 --> 00:28:33,515
SWGRAFT-VERSUS-HOST DISEASE, MOT

834
00:28:33,515 --> 00:28:35,817
RECENTLY THIS FIRST IN THE U.S.

835
00:28:35,817 --> 00:28:38,687
ORPHAN DRUG DESIGNATION FOR

836
00:28:38,687 --> 00:28:40,288
HYPOPLASTIC LEFT HEART SYNDROME.

837
00:28:40,288 --> 00:28:42,691
IN THE WORLD OF -- WELL,

838
00:28:42,691 --> 00:28:43,992
ACTUALLY SO HOW DOES THIS WORK?

839
00:28:43,992 --> 00:28:46,628
SO AGAIN, THE CELLS DON'T LEAVE

840
00:28:46,628 --> 00:28:48,430
THEIR SOURCE OF ORIGIN, AND WHAT

841
00:28:48,430 --> 00:28:50,432
ONE HAS TO DO IS HARVEST THEM,

842
00:28:50,432 --> 00:28:51,766
EXPAND IN CULTURE AND THERE ARE

843
00:28:51,766 --> 00:28:53,301
MULTIPLE APPROACHES TO DOING

844
00:28:53,301 --> 00:28:57,939
THAT, AND THEN RE-ADMINISTER, OR

845
00:28:57,939 --> 00:28:59,007
ADMINISTER.

846
00:28:59,007 --> 00:29:00,208
MOSTLY SYSTEMICALLY, BUT FOR

847
00:29:00,208 --> 00:29:04,012
LUNG APPLICATIONS, THERE IS A

848
00:29:04,012 --> 00:29:06,414
RICH PRE-CLINICAL LITERATURE ON

849
00:29:06,414 --> 00:29:11,686
DIRECT INTRATRACH YE INTRATRACHY

850
00:29:11,686 --> 00:29:11,953
DELIVERY.

851
00:29:11,953 --> 00:29:13,455
WHAT HAPPENS IN SYSTEMIC

852
00:29:13,455 --> 00:29:14,122
ADMINISTRATION IS THAT THE CELLS

853
00:29:14,122 --> 00:29:15,357
WILL LODGE IN THE LUNGS MOSTLY

854
00:29:15,357 --> 00:29:18,259
ON THE FIRST PASS.

855
00:29:18,259 --> 00:29:19,127
THEY DON'T ENGRAFT.

856
00:29:19,127 --> 00:29:20,762
THIS IS CRITICALLY IMPORTANT.

857
00:29:20,762 --> 00:29:22,364
THEY SIT THERE FOR A FEW DAYS,

858
00:29:22,364 --> 00:29:24,666
THEY INTERACT WITH VARIOUS

859
00:29:24,666 --> 00:29:27,969
INTEGRINS ON THE CELL SURFACE

860
00:29:27,969 --> 00:29:29,838
AND THEY EXPRESS TOLL LIKE

861
00:29:29,838 --> 00:29:33,775
RECEPTORS AND OTHER DAMAGED

862
00:29:33,775 --> 00:29:34,442
ELECTROPATHOGEN ASSOCIATED

863
00:29:34,442 --> 00:29:35,610
RECEPTORS SUCH THAT THEY WILL

864
00:29:35,610 --> 00:29:37,045
RESPOND TO AND REACT ACCORDINGLY

865
00:29:37,045 --> 00:29:39,848
BY RELEASE OF A PORTFOLIO OF

866
00:29:39,848 --> 00:29:41,182
SUBSTANCES INCLUDING

867
00:29:41,182 --> 00:29:44,052
ANTI-INFLAMMATORY MOLECULES TO

868
00:29:44,052 --> 00:29:45,453
ANY GIVEN INFLAMMATORY

869
00:29:45,453 --> 00:29:47,655
SITUATION, AND THEN THEY'RE

870
00:29:47,655 --> 00:29:50,792
CLEAR, AND CLEARANCE MECHANISMS

871
00:29:50,792 --> 00:29:56,264
INCLUDE PHAGOCYTOSIS BY RESIDENT

872
00:29:56,264 --> 00:29:57,565
MACROPHAGES AND OTHERS.

873
00:29:57,565 --> 00:29:58,900
SO THESE CELLS ARE SHORT LIVED

874
00:29:58,900 --> 00:30:00,301
BUT DO HAVE A VERY POTENT

875
00:30:00,301 --> 00:30:03,204
EFFECT.

876
00:30:03,204 --> 00:30:05,006
SO IN THE WORLD OF LUNG AND

877
00:30:05,006 --> 00:30:07,342
RESPIRATORY ILLNESSES, THERE IS

878
00:30:07,342 --> 00:30:10,945
A VERY LARGE LITERATURE, OVER AT

879
00:30:10,945 --> 00:30:12,647
LEAST 500 PUBLICATIONS IN A

880
00:30:12,647 --> 00:30:17,352
VARIETY OF PRE-CLINICAL, THIS

881
00:30:17,352 --> 00:30:18,319
INCLUDES BOTH RODENT AS WELL AS

882
00:30:18,319 --> 00:30:20,355
LARGER ANIMALS SUCH AS PIGS,

883
00:30:20,355 --> 00:30:22,257
SHEEP AND ALL, THAT ONE CAN

884
00:30:22,257 --> 00:30:24,159
INDUCE A VARIETY OF DIFFERENT

885
00:30:24,159 --> 00:30:25,293
TYPES OF LUNG INJURIES.

886
00:30:25,293 --> 00:30:26,494
YOU CAN SEE IN THE RIGHT HAND

887
00:30:26,494 --> 00:30:27,829
GOING AROUND THE CIRCLE, THE

888
00:30:27,829 --> 00:30:30,665
RANGE OF DIFFERENT INJURY MODELS

889
00:30:30,665 --> 00:30:32,767
UTILIZED, AND IN VIRTUALLY EVERY

890
00:30:32,767 --> 00:30:33,868
CASE, SYSTEMIC ADMINISTRATION

891
00:30:33,868 --> 00:30:37,739
AND IN MANY CASES DIRECT

892
00:30:37,739 --> 00:30:38,473
INTRATRACHEAL ADMINISTRATION OF

893
00:30:38,473 --> 00:30:40,241
THE CELLS WILL AMELIORATE

894
00:30:40,241 --> 00:30:41,376
WHATEVER YOUR PARTICULAR

895
00:30:41,376 --> 00:30:42,377
INFLAMMATORY OR INJURY END

896
00:30:42,377 --> 00:30:42,877
POINTS ARE.

897
00:30:42,877 --> 00:30:44,946
AND AGAIN, THERE ARE A VARIETY

898
00:30:44,946 --> 00:30:46,881
OF POSTULATED MECHANISMS

899
00:30:46,881 --> 00:30:48,883
INCLUDING CELL CONTACT

900
00:30:48,883 --> 00:30:51,419
INDEPENDENT SOLUBLE MEDIATORS,

901
00:30:51,419 --> 00:30:53,354
INCLUDING A VARIETY OF

902
00:30:53,354 --> 00:30:55,256
CYTOKINES, ET CETERA, THE

903
00:30:55,256 --> 00:30:57,358
EXTRACELLULAR VESICLES, THERE'S

904
00:30:57,358 --> 00:30:58,860
SOME DEGREE POTENTIALLY OF CELL

905
00:30:58,860 --> 00:31:01,362
CONTACT DEPENDENT IN WHICH

906
00:31:01,362 --> 00:31:05,300
MITOCHONDRIA ARE TRANSFERRED

907
00:31:05,300 --> 00:31:06,734
THROUGH CONNECTION 43 BRIDGES

908
00:31:06,734 --> 00:31:08,470
FROM THE MSCs TO THE RESIP

909
00:31:08,470 --> 00:31:09,871
YEBT CELLS AND THERE'S SOME

910
00:31:09,871 --> 00:31:10,538
INDIRECT MECHANISMS.

911
00:31:10,538 --> 00:31:11,773
FOR EXAMPLE, WE'VE DONE A LOT OF

912
00:31:11,773 --> 00:31:14,175
WORK IN PRE-CLINICAL MODELS WITH

913
00:31:14,175 --> 00:31:16,311
ASTHMA AND THE MSCs ACTUALLY

914
00:31:16,311 --> 00:31:18,046
DON'T NECESSARILY DIRECTLY

915
00:31:18,046 --> 00:31:18,980
AFFECT THE LUNG BUT RATHER

916
00:31:18,980 --> 00:31:27,055
AFFECT THE I MU -- CELLS SO THIS

917
00:31:27,055 --> 00:31:28,256
HAS BEEN APPLIED INCREASINGLY SO

918
00:31:28,256 --> 00:31:29,891
OVER THE PAST NUMBER OF YEARS TO

919
00:31:29,891 --> 00:31:31,693
A VARIETY OF CLINICAL

920
00:31:31,693 --> 00:31:32,994
INVESTIGATIONS, AND TO GIVE YOU

921
00:31:32,994 --> 00:31:36,364
THE LANDSCAPE, MOST OF THESE ARE

922
00:31:36,364 --> 00:31:37,866
PHASE ONE SAFETY.

923
00:31:37,866 --> 00:31:39,434
DOSE ESCALATION.

924
00:31:39,434 --> 00:31:41,169
THERE'S A LIMITED BUT GROWING

925
00:31:41,169 --> 00:31:42,604
NUMBER OF PHASE 2 EFFICACY

926
00:31:42,604 --> 00:31:44,172
TRAILS BUT THERE IS STILL NO

927
00:31:44,172 --> 00:31:46,241
CONSENSUS ON APPROACH, AND THIS

928
00:31:46,241 --> 00:31:47,509
INCLUDES, WHERE DO YOU GET THE

929
00:31:47,509 --> 00:31:48,743
MSCs FROM?

930
00:31:48,743 --> 00:31:51,713
BONE MARROW, ADIPOSE, PLACENTAL,

931
00:31:51,713 --> 00:31:51,980
ET CETERA.

932
00:31:51,980 --> 00:31:54,382
DO YOU USE AUTOLOGOUS,

933
00:31:54,382 --> 00:31:55,350
ALLOGENEIC, AND THERE ARE PROS

934
00:31:55,350 --> 00:31:56,117
AND CONS FOR BOTH.

935
00:31:56,117 --> 00:31:58,052
THE MANUFACTURING, IE, HOW YOU

936
00:31:58,052 --> 00:31:59,420
ISOLATE THE CELLS, HOW YOU

937
00:31:59,420 --> 00:32:02,690
EXPAND THEM IN TISSUE CULTURE IS

938
00:32:02,690 --> 00:32:04,959
A WIDE OPEN FIELD, IF YOU WILL.

939
00:32:04,959 --> 00:32:06,861
CELLS WERE MOSTLY UNMANIPULATED.

940
00:32:06,861 --> 00:32:09,597
ONE CAN ENGINEER, FOR EXAMPLE,

941
00:32:09,597 --> 00:32:12,333
MSC TO EXPRESS ANTITUMOR

942
00:32:12,333 --> 00:32:16,871
MOLECULES, FOR EXAMPLE, TRAIL,

943
00:32:16,871 --> 00:32:18,606
APOPTOSIS, INDUCING LIGAND AND

944
00:32:18,606 --> 00:32:22,143
THERE HAVE BEEN INTRIGUING

945
00:32:22,143 --> 00:32:25,580
STUDIES IN DISEASES SUCH AS

946
00:32:25,580 --> 00:32:27,048
MESOTHELIOMA AND LUNG CANCER

947
00:32:27,048 --> 00:32:27,849
UTILIZING THESE.

948
00:32:27,849 --> 00:32:32,120
THERE IS NO SET DOSE OR DOSING

949
00:32:32,120 --> 00:32:32,720
REGIMEN.

950
00:32:32,720 --> 00:32:37,392
WEEWE'LL COME BACK TO THAT IN A

951
00:32:37,392 --> 00:32:37,759
MINUTE.

952
00:32:37,759 --> 00:32:40,194
WE GOT INTO THIS A NUMBER OF

953
00:32:40,194 --> 00:32:41,396
YEARS AGO WORKING WITH A COMPANY

954
00:32:41,396 --> 00:32:43,264
AND I HAVE NO DISCLOSURE HERE, I

955
00:32:43,264 --> 00:32:46,334
WAS A P.I. FOR THIS COMPANY

956
00:32:46,334 --> 00:32:50,505
TRIAL, AND THIS WAS FOR COPD.

957
00:32:50,505 --> 00:32:52,607
IF YOU THINK ABOUT IT, COPD MAY

958
00:32:52,607 --> 00:32:54,075
NOT NECESSARILY BE THE BEST

959
00:32:54,075 --> 00:32:55,944
DISEASE TARGET FOR MSC-BASED

960
00:32:55,944 --> 00:32:58,146
CELL THERAPY AND THE RATIONALE

961
00:32:58,146 --> 00:33:02,083
HERE IS THAT THE MSCs WILL BE

962
00:33:02,083 --> 00:33:02,917
ADMINISTERED, STICK AROUND FOR A

963
00:33:02,917 --> 00:33:04,152
FEW DAYS AND THEN THEY'RE

964
00:33:04,152 --> 00:33:04,552
CLEARED.

965
00:33:04,552 --> 00:33:08,056
SO FOR ACUTE HIGH INTENSITY

966
00:33:08,056 --> 00:33:09,390
INFLAMMATORY SITUATION LIKE ARDS

967
00:33:09,390 --> 00:33:11,559
OR SEPTIC SHOCK, THIS WOULD BE A

968
00:33:11,559 --> 00:33:12,527
VERY GOOD STRATEGY.

969
00:33:12,527 --> 00:33:13,828
IT'S MORE ON THE TABLE AS TO

970
00:33:13,828 --> 00:33:16,230
WHETHER OR NOT A CHRONIC

971
00:33:16,230 --> 00:33:17,231
INFLAMMATORY SITUATION OR

972
00:33:17,231 --> 00:33:18,700
DESTRUCTIVE DISEASE LIKE COPD

973
00:33:18,700 --> 00:33:20,301
WOULD BE AMENABLE, BUT

974
00:33:20,301 --> 00:33:21,269
NONETHELESS, THIS IS AN

975
00:33:21,269 --> 00:33:22,937
OPPORTUNITY TO DO AN INITIAL

976
00:33:22,937 --> 00:33:24,238
SAFETY TRIAL IF NOTHING ELSE, SO

977
00:33:24,238 --> 00:33:28,643
THIS IS A PHASE TWO MULTICENTER

978
00:33:28,643 --> 00:33:31,913
RANDOMIZED DOUBLE BLIND

979
00:33:31,913 --> 00:33:34,415
CONTROLLED -- THE PLACEBO WAS

980
00:33:34,415 --> 00:33:35,750
THE VEHICLE -- NOT A DIFFERENT

981
00:33:35,750 --> 00:33:38,720
CELL AND YOU CAN SEE IN THE

982
00:33:38,720 --> 00:33:40,788
DIAGRAM, 65 PATIENTS, SIX SITES,

983
00:33:40,788 --> 00:33:41,789
FOUR INFUSIONS OVER THE COURSE

984
00:33:41,789 --> 00:33:42,256
OF FOUR MONTHS.

985
00:33:42,256 --> 00:33:43,658
THERE WAS NO RIGHT OR WRONG TO

986
00:33:43,658 --> 00:33:46,561
THIS, IT WAS JUST A STARTING

987
00:33:46,561 --> 00:33:47,095
POINT.

988
00:33:47,095 --> 00:33:49,364
SECONDARY OUTCOMES WERE

989
00:33:49,364 --> 00:33:50,264
PULMONARY FUNCTION, QUALITY OF

990
00:33:50,264 --> 00:33:51,466
LIFE, ET CETERA, BUT WE WERE

991
00:33:51,466 --> 00:33:52,767
ALSO ABLE TO BUILD IN AN

992
00:33:52,767 --> 00:33:53,568
INVESTIGATION TALL ARM IN WHICH

993
00:33:53,568 --> 00:33:55,403
WE LOOKED AT CIRCULATING

994
00:33:55,403 --> 00:33:57,772
INFLAMMATORY MEDIATORS.

995
00:33:57,772 --> 00:33:59,340
SO THE OUTCOME WAS THAT THERE

996
00:33:59,340 --> 00:34:02,076
WERE NO INFUSIONAL TOXICITIES,

997
00:34:02,076 --> 00:34:04,112
NO SIGNS, SYMPTOMS OF CELL

998
00:34:04,112 --> 00:34:07,148
EMBOLI, PULMONARY EMBOLI, NO

999
00:34:07,148 --> 00:34:08,583
SERIOUS ADVERSE EVENTS,

1000
00:34:08,583 --> 00:34:09,984
FOLLOW-UP USING THE OUTCOME

1001
00:34:09,984 --> 00:34:11,719
MEASURE AS LISTED.

1002
00:34:11,719 --> 00:34:13,921
THE STUDY AT 62 PATIENTS WARS

1003
00:34:13,921 --> 00:34:15,123
UNDERPOWERED TO ARE EFFICACY AND

1004
00:34:15,123 --> 00:34:17,959
THERE WAS NO EUREKA MOMENT, BUT

1005
00:34:17,959 --> 00:34:23,798
WE SAW NO CHANGE IN LUNG

1006
00:34:23,798 --> 00:34:26,367
VOLUMES, DLCO, SIX MINUTE WALK,

1007
00:34:26,367 --> 00:34:26,734
ET CETERA.

1008
00:34:26,734 --> 00:34:29,003
BUT WHAT WE DID FIND WAS THAT IN

1009
00:34:29,003 --> 00:34:31,439
PATIENTS WITH ELEVATED C

1010
00:34:31,439 --> 00:34:34,976
REACTIVE CIRCULATING PROTEIN, AT

1011
00:34:34,976 --> 00:34:36,811
STUDY ONSET THERE'S

1012
00:34:36,811 --> 00:34:37,545
STATISTICALLY SIGNIFICANT

1013
00:34:37,545 --> 00:34:39,414
DECREASE IN THE PATIENTS

1014
00:34:39,414 --> 00:34:41,015
RECEIVING THE CELLS AS OPPOSED

1015
00:34:41,015 --> 00:34:43,251
TO PLACEBO AND OVER THE COURSE

1016
00:34:43,251 --> 00:34:44,652
OF THE INFUSION PERIOD AND IT

1017
00:34:44,652 --> 00:34:46,220
REMAINED AS A TREND OVER THE

1018
00:34:46,220 --> 00:34:47,221
TWO-YEAR OBSERVATION PERIOD.

1019
00:34:47,221 --> 00:34:48,489
SO WE SAT ON THIS FOR A LONG

1020
00:34:48,489 --> 00:34:50,525
TIME AND THEN JUST REALIZED AS A

1021
00:34:50,525 --> 00:34:52,226
GROWING APPRECIATION ABOUT THE

1022
00:34:52,226 --> 00:34:57,932
HETEROGENEITY OF COPD -- WE WENT

1023
00:34:57,932 --> 00:34:58,933
BACK AND TOOK A LOOK AS TO

1024
00:34:58,933 --> 00:35:00,234
WHETHER OR NOT WE COULD STRATIFY

1025
00:35:00,234 --> 00:35:02,804
PATIENTS BASED ON INFLAMMATORY

1026
00:35:02,804 --> 00:35:03,137
PHENOTYPE.

1027
00:35:03,137 --> 00:35:05,139
SO WE WENT BACK AND DID A

1028
00:35:05,139 --> 00:35:06,407
RETROACTIVE STUDY FOCUSING ON

1029
00:35:06,407 --> 00:35:09,444
THE CRP.

1030
00:35:09,444 --> 00:35:11,979
CRP, WIDELY RECOGNIZED MARKER OF

1031
00:35:11,979 --> 00:35:13,181
INFLAMMATION IN COPD PATIENTS,

1032
00:35:13,181 --> 00:35:14,982
HIGHER MORTALITY, WORSE

1033
00:35:14,982 --> 00:35:16,684
EXACERBATION OUTCOMES, HIGHER

1034
00:35:16,684 --> 00:35:17,785
READMISSION RATE, ET CETERA.

1035
00:35:17,785 --> 00:35:20,621
SO WE SIMPLY JUST RESTRATIFIED

1036
00:35:20,621 --> 00:35:22,290
THE PATIENTS BASED ON LEVELS OF

1037
00:35:22,290 --> 00:35:24,125
CIRCULATING CRP STUDY ENTRY AS

1038
00:35:24,125 --> 00:35:29,197
LISTED.

1039
00:35:29,197 --> 00:35:30,765
WHAT WE SAW WAS THAT IN THE

1040
00:35:30,765 --> 00:35:33,434
PATIENTS IN THE HIGHEST QUARTILE

1041
00:35:33,434 --> 00:35:37,705
OF CRP GREATER THAN 4, THERE IS

1042
00:35:37,705 --> 00:35:39,540
BOTH STATISTICALLY SIGNIFICANT

1043
00:35:39,540 --> 00:35:41,309
AS WELL AS CLINICALLY MEANINGFUL

1044
00:35:41,309 --> 00:35:42,710
IMPROVEMENT IN OUTCOMES,

1045
00:35:42,710 --> 00:35:46,347
SPECIFICALLY FEV1, FEC, AND

1046
00:35:46,347 --> 00:35:47,381
6 MINUTE WALK DISTANCE AND YOU

1047
00:35:47,381 --> 00:35:48,950
CAN SEE IN THE GRAPHS OVER ON

1048
00:35:48,950 --> 00:35:52,553
THE RIGHT THAT THE TREND FOR

1049
00:35:52,553 --> 00:35:53,621
FEV1, 6 MINUTE WALK DISTANCE

1050
00:35:53,621 --> 00:35:57,125
LASTED OVER THE TWO-YEAR STUDY

1051
00:35:57,125 --> 00:35:58,192
PERIOD.

1052
00:35:58,192 --> 00:35:59,460
THIS IS OF COURSE WITH ALL THE

1053
00:35:59,460 --> 00:36:01,362
CAVEATS OF A RETROSPECTIVE POST

1054
00:36:01,362 --> 00:36:03,731
HOC LOOK AT A NUMBER OF --

1055
00:36:03,731 --> 00:36:04,665
LIMITED NUMBER OF PATIENTS BUT

1056
00:36:04,665 --> 00:36:06,601
IT OPENS DOOR THAT INFLAMMATORY

1057
00:36:06,601 --> 00:36:07,935
PHENOTYPE IS REALLY CRITICALLY

1058
00:36:07,935 --> 00:36:10,071
IMPORTANT WHEN YOU'RE TRYING TO

1059
00:36:10,071 --> 00:36:14,008
APPLY A CELL-BASED THERAPY.

1060
00:36:14,008 --> 00:36:16,244
SO THAT TAKING THIS OVER INTO TE

1061
00:36:16,244 --> 00:36:19,046
ACUTE INJURY WORLD WITH RESPECT

1062
00:36:19,046 --> 00:36:22,984
TO ARDS, AGAIN, THERE'S A FIRM

1063
00:36:22,984 --> 00:36:24,418
LARGE PRE-CLINICAL BACKGROUND IN

1064
00:36:24,418 --> 00:36:28,156
MODELS OF ACUTE LUNG INJURY OF

1065
00:36:28,156 --> 00:36:29,690
MSC ADMINISTRATION AS REALLY

1066
00:36:29,690 --> 00:36:31,058
QUITE EFFICACIOUS, AND THERE

1067
00:36:31,058 --> 00:36:35,530
WERE A FEW TRIALS IN NON-COVID

1068
00:36:35,530 --> 00:36:37,165
ARDS PRIOR TO THE PANDEMIC, BUT

1069
00:36:37,165 --> 00:36:39,100
ONCE THE PANDEMIC HIT, THERE WAS

1070
00:36:39,100 --> 00:36:42,870
A HUGE NUMBER WITH AT LEAST 75

1071
00:36:42,870 --> 00:36:43,838
DIFFERENT CLINICAL

1072
00:36:43,838 --> 00:36:44,972
INVESTIGATIONS LISTED ON

1073
00:36:44,972 --> 00:36:47,341
CLINICAL TRIAL.GOV AS WELL AS

1074
00:36:47,341 --> 00:36:49,544
THE WHO, WOR WORLD HEALTH

1075
00:36:49,544 --> 00:36:50,611
ORGANIZATION REGISTRY, AND THE

1076
00:36:50,611 --> 00:36:52,480
CHINESE CLINICAL TRIAL REGISTRY,

1077
00:36:52,480 --> 00:36:55,016
AND MOST OF THESE WERE PHASE ONE

1078
00:36:55,016 --> 00:36:58,052
UNBLINDED NON-RANDOMIZED AND ALL

1079
00:36:58,052 --> 00:36:59,353
THAT, BUT YOU CAN SEE HERE IN

1080
00:36:59,353 --> 00:37:02,390
THE SCHEMATICS WHICH ARE BASED

1081
00:37:02,390 --> 00:37:08,663
ON SOME WORK BY MICHAEL MATTAY

1082
00:37:08,663 --> 00:37:10,364
AND HIS GROUP, POTENTIAL

1083
00:37:10,364 --> 00:37:13,901
MECHANISMS OF MECHANISMS IN BOTH

1084
00:37:13,901 --> 00:37:18,206
COVID I!

1085
00:37:18,206 --> 00:37:20,141
SARS-COV-2 AND NON-COVID, SO A

1086
00:37:20,141 --> 00:37:21,843
LOT OF QUESTIONS TO PURSUE HERE.

1087
00:37:21,843 --> 00:37:24,011
THE SHORT STORY IS THAT SOME OF

1088
00:37:24,011 --> 00:37:24,846
THESE TRIALS WORKED.

1089
00:37:24,846 --> 00:37:26,280
THIS WAS A TRIAL FROM THE

1090
00:37:26,280 --> 00:37:30,051
UNIVERSITY OF MIAMI PUBLISHED IN

1091
00:37:30,051 --> 00:37:33,588
2021, AND IT WAS A DOUBLE BLIND

1092
00:37:33,588 --> 00:37:37,358
RANDOMIZED CONTROL TRIAL PLACEBO

1093
00:37:37,358 --> 00:37:38,793
HERE AND YOU CAN SEE THE DETAILS

1094
00:37:38,793 --> 00:37:42,230
OF THE TRIAL DIAGRAM HERE WAS

1095
00:37:42,230 --> 00:37:43,831
RELATIVELY SMALL, WITH 12

1096
00:37:43,831 --> 00:37:45,166
RECEIVING THE CELLS, 12

1097
00:37:45,166 --> 00:37:46,868
RECEIVING THE VEHICLE.

1098
00:37:46,868 --> 00:37:48,269
PRIMARY OUTCOMES WERE ADVERSE

1099
00:37:48,269 --> 00:37:52,740
EVENTS AND THE LIKE.

1100
00:37:52,740 --> 00:37:54,075
SHOWS THAT THIS TRIAL WORKED, SO

1101
00:37:54,075 --> 00:37:57,445
IF YOU LOOK AT THE SURVIVAL

1102
00:37:57,445 --> 00:37:59,680
CURVE ON THE LEFT, ADVERSE

1103
00:37:59,680 --> 00:38:00,815
EVENT, FREE TRIAL ON THE

1104
00:38:00,815 --> 00:38:01,682
RIGHT -- EXCUSE ME THE CENTER

1105
00:38:01,682 --> 00:38:03,084
AND THE TIME FOR RECOVERY.

1106
00:38:03,084 --> 00:38:05,553
THESE WERE ALL STATISTICALLY AND

1107
00:38:05,553 --> 00:38:06,587
CLINICALLY MEANINGFULLY IMPROVED

1108
00:38:06,587 --> 00:38:11,259
IN THESE PATIENTS.

1109
00:38:11,259 --> 00:38:14,061
SO SOME RECENT META-ANALYSES

1110
00:38:14,061 --> 00:38:15,696
SHOW THAT AMONGST THE DOUBLE

1111
00:38:15,696 --> 00:38:18,132
BLIND RANDOMIZED PLACEBO

1112
00:38:18,132 --> 00:38:19,133
CONTROLLED TRIALS, THERE'S A

1113
00:38:19,133 --> 00:38:20,568
CLEAR BENEFIT TO MSC

1114
00:38:20,568 --> 00:38:24,405
ADMINISTRATION.

1115
00:38:24,405 --> 00:38:26,774
THE QUESTION IS, WHY DON'T THEY

1116
00:38:26,774 --> 00:38:28,142
ALWAYS WORK?

1117
00:38:28,142 --> 00:38:31,979
SO TO PULL THIS ALL TOGETHER,

1118
00:38:31,979 --> 00:38:36,817
SOURCE MANUFACTURING DOSE DOSING

1119
00:38:36,817 --> 00:38:37,652
HAVE BEEN QUESTIONS FOR A LONG

1120
00:38:37,652 --> 00:38:38,452
TIME.

1121
00:38:38,452 --> 00:38:41,923
THE INFLAMMATORY -- OF THE

1122
00:38:41,923 --> 00:38:43,157
PATIENT IS REALLY WHERE I THINK

1123
00:38:43,157 --> 00:38:44,992
THE FOCUS SHOULD BE RIGHT NOW.

1124
00:38:44,992 --> 00:38:47,395
ONE OF THE THINGS WE'RE

1125
00:38:47,395 --> 00:38:48,629
SPEARHEADING, THIS IS THROUGH

1126
00:38:48,629 --> 00:38:49,597
THE INTERNATIONAL SOCIETY OF

1127
00:38:49,597 --> 00:38:50,831
CELL AND GENE THERAPY IS

1128
00:38:50,831 --> 00:38:51,899
COLLABORATIVE TRIAL WITH THE

1129
00:38:51,899 --> 00:38:52,800
INVESTIGATORS OF THOSE DOUBLE

1130
00:38:52,800 --> 00:38:54,602
BLIND RANDOMIZED PLACEBO

1131
00:38:54,602 --> 00:38:55,636
CONTROLLED TRIALS IN WHICH WE

1132
00:38:55,636 --> 00:38:59,040
WERE OBTAINING INDIVIDUAL

1133
00:38:59,040 --> 00:39:00,341
PATIENT DATA AND ASKING THE

1134
00:39:00,341 --> 00:39:04,278
QUESTION CO DOES THE INFLAMMATOY

1135
00:39:04,278 --> 00:39:05,980
PROFILE AS MEASURED BY

1136
00:39:05,980 --> 00:39:07,581
CIRCULATING INFLAMMATORY

1137
00:39:07,581 --> 00:39:09,283
MEDIATORS PREDICT OUTCOMES AS A

1138
00:39:09,283 --> 00:39:10,418
RESPONSE TO CELL-BASED THERAPY?

1139
00:39:10,418 --> 00:39:11,719
SO WE THINK THIS IS GOING TO

1140
00:39:11,719 --> 00:39:13,254
OPEN UP DOORS THAT WE'RE REALLY

1141
00:39:13,254 --> 00:39:14,655
FOCUSED MORE ON PERSONALIZED

1142
00:39:14,655 --> 00:39:15,823
MEDICINE IF YOU WANT TO USE THAT

1143
00:39:15,823 --> 00:39:19,727
TERM, BUT FINDING THE BEST

1144
00:39:19,727 --> 00:39:20,695
POPULATION MOST LIKELY TO

1145
00:39:20,695 --> 00:39:21,028
RESPOND.

1146
00:39:21,028 --> 00:39:24,665
SO WITH THAT, I'M GOING TO PUT

1147
00:39:24,665 --> 00:39:27,635
IN A PLUG, IF I MAY, FOR THE

1148
00:39:27,635 --> 00:39:30,738
CONFERENCE O, VERMONT STEM CELL

1149
00:39:30,738 --> 00:39:32,840
CONFERENCE THAT MANY OF YOU HAVE

1150
00:39:32,840 --> 00:39:34,008
BEEN TO.

1151
00:39:34,008 --> 00:39:38,512
NEXT JULY '25 IS OUR NEXT

1152
00:39:38,512 --> 00:39:39,246
ANNIVERSARY, INVITE EVERYBODY TO

1153
00:39:39,246 --> 00:39:42,583
PARTICIPATE IN THAT.

1154
00:39:42,583 --> 00:39:43,851
I WANT TO THANK, OF COURSE,

1155
00:39:43,851 --> 00:39:45,252
MANY, MANY, MANY PEOPLE I'VE HAD

1156
00:39:45,252 --> 00:39:46,220
THE PRIVILEGE OF BEING

1157
00:39:46,220 --> 00:39:46,988
ASSOCIATED WITH AND BEING ABLE

1158
00:39:46,988 --> 00:39:47,855
TO WORK WITH.

1159
00:39:47,855 --> 00:39:50,958
WITH THAT, THANK YOU, AND WE CAN

1160
00:39:50,958 --> 00:39:51,859
CONTINUE DISCUSSION IN THE

1161
00:39:51,859 --> 00:39:56,197
DISCUSSION PERIOD.

1162
00:39:56,197 --> 00:39:58,532
>> OKAY.

1163
00:39:58,532 --> 00:40:01,469
THANK YOU, DAN.

1164
00:40:01,469 --> 00:40:06,273
THE NEXT SPEAKER IS DIANHUA

1165
00:40:06,273 --> 00:40:08,142
JIANG, THAT'S MY BEST CHINESE,

1166
00:40:08,142 --> 00:40:11,812
SORRY, WHO IS GOING TO -- IS

1167
00:40:11,812 --> 00:40:13,047
FROM THE CEDARS-SINAI MEDICAL

1168
00:40:13,047 --> 00:40:14,882
CENTER IN L.A., AND HE'S BEEN

1169
00:40:14,882 --> 00:40:16,784
DEVELOPING A REALLY INTERESTING

1170
00:40:16,784 --> 00:40:18,486
STORY ON THE METABOLOMICS OF

1171
00:40:18,486 --> 00:40:21,389
STEM CELLS, AND A PARTICULAR

1172
00:40:21,389 --> 00:40:25,393
FOCUS IN, AS THE TITLE SAYS, ON

1173
00:40:25,393 --> 00:40:27,561
ZINC IN IPF, AND HE'S GOING TO

1174
00:40:27,561 --> 00:40:29,330
TAKE US WHERE HE THINK THAT'S

1175
00:40:29,330 --> 00:40:35,069
HEADED.  SO TAKE IT AWAY,

1176
00:40:35,069 --> 00:40:35,369
DIANHUA.

1177
00:40:35,369 --> 00:40:36,003
>> THANK YOU.

1178
00:40:36,003 --> 00:40:41,442
GOOD MORNING, EVERYBODY.

1179
00:40:41,442 --> 00:40:42,576
YES.

1180
00:40:42,576 --> 00:40:44,645
FIRST OF ALL I'D LIKE TO THANK

1181
00:40:44,645 --> 00:40:46,981
THE ORGANIZERS FOR INVITING ME

1182
00:40:46,981 --> 00:40:49,984
TO PRESENT MY RECENT WORK ON

1183
00:40:49,984 --> 00:40:58,793
ZINC METABOLISM IN IPF.

1184
00:40:58,793 --> 00:41:00,494
IPF PATHOGENESIS, SEVERAL

1185
00:41:00,494 --> 00:41:07,501
SPEAKERS HAVE TOUCHED ON.

1186
00:41:07,501 --> 00:41:09,036
I JUST WOULD LIKE TO BRIEFLY

1187
00:41:09,036 --> 00:41:13,808
HIGHLIGHT THE ROLE OF THE

1188
00:41:13,808 --> 00:41:15,342
IMPORTANCE CONCEPTUALLY IN THE

1189
00:41:15,342 --> 00:41:21,515
LAST 15 YEARS THAT

1190
00:41:21,515 --> 00:41:22,917
DIFFERENTIATION OF -- FUNCTION

1191
00:41:22,917 --> 00:41:25,986
AS STEM CELLS IN THE DISTAL

1192
00:41:25,986 --> 00:41:26,754
AIRIZED SPACE.

1193
00:41:26,754 --> 00:41:31,692
FOR THIS TALK, I WOULD LIKE TO

1194
00:41:31,692 --> 00:41:38,899
FOCUS ON THE INTRINSIC A T2 CELL

1195
00:41:38,899 --> 00:41:40,868
WHICH MIGHT BE THE KEY DRIVERS

1196
00:41:40,868 --> 00:41:50,077
FOR IPF PATHOGENESIS.

1197
00:41:50,077 --> 00:41:53,214
IT HAS LONG BEEN SUGGESTED

1198
00:41:53,214 --> 00:41:55,783
THAT -- STEM CELL EXHAUSTION IN

1199
00:41:55,783 --> 00:42:07,194
HIV LUNG AND SEVERAIPF LUNG, WEE

1200
00:42:10,064 --> 00:42:16,737
CAN SEE THE SIGNIFICANT LOSS OF

1201
00:42:16,737 --> 00:42:21,175
CELLS FROM IPF LUNG.

1202
00:42:21,175 --> 00:42:27,081
THIS LEADS TO -- CULTURE SYSTEM

1203
00:42:27,081 --> 00:42:28,182
FROM -- COLONY.

1204
00:42:28,182 --> 00:42:33,087
AND WE FURTHER SHOW THAT THE

1205
00:42:33,087 --> 00:42:34,088
INTERACTION BETWEEN

1206
00:42:34,088 --> 00:42:39,860
EXTRACELLULAR MATRIX -- AND THE

1207
00:42:39,860 --> 00:42:42,096
TR4 CAP 2 CELLS -- AS

1208
00:42:42,096 --> 00:42:48,569
ILLUSTRATED BY THE DIAGRAM FRO

1209
00:42:48,569 --> 00:42:53,641
FROM -- CHAMBERS PAPER.

1210
00:42:53,641 --> 00:42:55,142
AFTER THAT STUDY, WE HAVE

1211
00:42:55,142 --> 00:42:58,646
STUDIES TO LACK INTO WHAT ARE

1212
00:42:58,646 --> 00:43:05,119
THE -- HI IPF AND LOSS OF A T2 M

1213
00:43:05,119 --> 00:43:05,352
CELLS.

1214
00:43:05,352 --> 00:43:07,121
WE STARTED LOOKING AT SOME OF

1215
00:43:07,121 --> 00:43:11,358
THE CELLULAR METABOLISM

1216
00:43:11,358 --> 00:43:16,530
DISREGULATIONS IN IPF -- CELLS.

1217
00:43:16,530 --> 00:43:17,965
FOR THIS TALK I'LL MOSTLY TALK

1218
00:43:17,965 --> 00:43:20,834
ON ZINC AND I'LL TOUCH A LITTLE

1219
00:43:20,834 --> 00:43:27,942
BIT ON -- PLUS PLUS AND A LITTLE

1220
00:43:27,942 --> 00:43:30,144
ON THE IPF METABOLISM.

1221
00:43:30,144 --> 00:43:34,081
WE DID SINGLE CELL RNA

1222
00:43:34,081 --> 00:43:38,852
SEQUENCING WITH FRESHLY ISOLA 

1223
00:43:38,852 --> 00:43:41,555
ISOLATED -- CELLS FROM SIX

1224
00:43:41,555 --> 00:43:45,960
DONORS AND SIX HIV EXPLANTS, AND

1225
00:43:45,960 --> 00:43:51,498
WE CAN CLEARLY SEE THAT THE LOSS

1226
00:43:51,498 --> 00:43:59,173
OF -- CELLS -- CLUSTERS AND IN

1227
00:43:59,173 --> 00:44:01,075
STRIKING GENES LOST IN TYPE

1228
00:44:01,075 --> 00:44:05,746
2 CELLS CALLED THE -- 9AA AND

1229
00:44:05,746 --> 00:44:08,449
THIS GENE ENCODES A PROTEIN

1230
00:44:08,449 --> 00:44:10,551
CALLED THE ZINC A WHICH IS THE

1231
00:44:10,551 --> 00:44:13,320
ZINC -- YOU CAN SEE THE DIAGRAM

1232
00:44:13,320 --> 00:44:19,893
TO THE RIGHT AND THE -- CULTURE

1233
00:44:19,893 --> 00:44:25,266
BASICALLY TRANSPORT THE ZINC

1234
00:44:25,266 --> 00:44:28,702
FROM EXTRACELLULAR SPACE TO

1235
00:44:28,702 --> 00:44:30,037
THE -- ZINC CONCENTRATION INSIDE

1236
00:44:30,037 --> 00:44:32,640
THE CELL AND PERFORM BIOLOGICAL

1237
00:44:32,640 --> 00:44:34,675
FUNCTIONS.

1238
00:44:34,675 --> 00:44:39,980
I CAN CONFIRM THIS LOSS OF -- BY

1239
00:44:39,980 --> 00:44:42,383
RTP -- BY FLOW CYTOMETRY AND

1240
00:44:42,383 --> 00:44:51,358
ALSO CONFIRM FROM THE LGRC

1241
00:44:51,358 --> 00:44:53,060
DATASETS, AND THE LUNG TISSUE,

1242
00:44:53,060 --> 00:45:03,504
LOSS OF -- LUNG FUNCTION.

1243
00:45:05,406 --> 00:45:12,112
SO WITH TH THE SIGNIFICANT LOWER

1244
00:45:12,112 --> 00:45:15,449
ZINC EXPRESSION -- EXPECT THAT

1245
00:45:15,449 --> 00:45:20,120
THERE WOULD BE A SIGNIFICANT

1246
00:45:20,120 --> 00:45:23,090
LOWER ZINC INTRACELLULARLY AND

1247
00:45:23,090 --> 00:45:28,062
IF WE INDEED USE THE -- TO

1248
00:45:28,062 --> 00:45:29,530
MANAGE ZINC AND WE CAN SEE IN

1249
00:45:29,530 --> 00:45:34,668
PANEL A AND B AND WE SEE A

1250
00:45:34,668 --> 00:45:39,506
SIGNIFICANT LOWER ZINC -- IPF --

1251
00:45:39,506 --> 00:45:40,074
CELLS.

1252
00:45:40,074 --> 00:45:45,579
AND WE ALSO TAKE ADVANTAGE OF --

1253
00:45:45,579 --> 00:45:48,749
THE EXTRACELLULAR -- I MEAN THAT

1254
00:45:48,749 --> 00:45:54,955
IS ON THE CELL MEMBRANE AND --

1255
00:45:54,955 --> 00:45:58,058
HIGH AND LOW -- TYPE 2 CELLS WE

1256
00:45:58,058 --> 00:46:01,228
CAN CHARACTERIZE THAT -- TYPE

1257
00:46:01,228 --> 00:46:03,497
2 CELERY NEWELL CAPACITY IN

1258
00:46:03,497 --> 00:46:05,366
32 ORGANOID CULTURE SHOWING IN

1259
00:46:05,366 --> 00:46:12,072
PANEL D THAT -- LEAD TO --

1260
00:46:12,072 --> 00:46:12,840
COLONY WELL.

1261
00:46:12,840 --> 00:46:19,747
AND WHEN WE USE THAT -- ZINC IN

1262
00:46:19,747 --> 00:46:26,754
CULTURE, WE CAN SEE THE ZINC --

1263
00:46:26,754 --> 00:46:32,459
REMUABLE -- IPF TYPE 2 CELLS.

1264
00:46:32,459 --> 00:46:36,964
THAT'S SHOWING YOU PANEL F BU

1265
00:46:36,964 --> 00:46:44,538
BUT -- SHOWING IN PANEL G.

1266
00:46:44,538 --> 00:46:51,078
SO NEXT WE LACK INTO WHAT'S THE

1267
00:46:51,078 --> 00:46:55,849
MECHANISM RELATED TO THIS TYPE .

1268
00:46:55,849 --> 00:46:56,383
 2 CELL RENEWAL.

1269
00:46:56,383 --> 00:46:59,920
WE DID PATHWAY ANALYSIS, WE

1270
00:46:59,920 --> 00:47:07,194
FOUND THAT -- PATHWAYS IS

1271
00:47:07,194 --> 00:47:10,597
SIGNIFICANT DOWN REGULATED IPF

1272
00:47:10,597 --> 00:47:19,873
TYPE 2 CELLS, AND IT'S

1273
00:47:19,873 --> 00:47:25,846
INTERESTING -- THEY REQUIRE SOME

1274
00:47:25,846 --> 00:47:31,185
ZINC FOR THEIR ACTIVITY, AND AT

1275
00:47:31,185 --> 00:47:34,888
LEAST THERE ARE LOTS OF STUDIES

1276
00:47:34,888 --> 00:47:36,690
LACKING INTO THE -- AND STEM

1277
00:47:36,690 --> 00:47:41,728
CELL RENEWABLE AND ZINC IS THE

1278
00:47:41,728 --> 00:47:45,499
REQUIRED ELEMENT.

1279
00:47:45,499 --> 00:47:49,136
WE CAN SEE IN PANEL B, WE CAN

1280
00:47:49,136 --> 00:47:54,208
USE FRESH ISOLATE OF -- CELLS

1281
00:47:54,208 --> 00:47:57,911
CONFIRM THE THIRD ONE -- IN IPF

1282
00:47:57,911 --> 00:47:59,246
CELLS AND FURTHERMORE, IF WE

1283
00:47:59,246 --> 00:48:03,283
CAN -- IF WE USE SIRNG TREATMENT

1284
00:48:03,283 --> 00:48:12,259
AND WE CAN SEE -- TYPE 2 CELL

1285
00:48:12,259 --> 00:48:14,728
EXPRESS A CERTAIN ONE BUT NOT

1286
00:48:14,728 --> 00:48:20,400
MUCH IN IPF TYPE 2 CELLS PANEL

1287
00:48:20,400 --> 00:48:27,140
C, AND THEY ARE NOT -- SHOWN IN

1288
00:48:27,140 --> 00:48:32,312
PANEL D THERE H.

1289
00:48:32,312 --> 00:48:33,614
THERE HAVE BEEN LOTS OF

1290
00:48:33,614 --> 00:48:39,653
COMPOUNDS RELATED TO --

1291
00:48:39,653 --> 00:48:42,523
MANIPULATE -- A CERTAIN ONE

1292
00:48:42,523 --> 00:48:45,792
ACTIVITY, AND THE ONE FOR -- WE

1293
00:48:45,792 --> 00:48:52,566
HAVE -- WE USE IN ACTIVATOR

1294
00:48:52,566 --> 00:48:57,671
SRT1720 IN PANEL E, AND WE SEE

1295
00:48:57,671 --> 00:49:06,813
THAT -- ACTIVATOR ENHANCE TYPE T

1296
00:49:06,813 --> 00:49:09,016
THOSE PROCESS.

1297
00:49:09,016 --> 00:49:11,251
INTERESTING ENOUGH, SHOWING IN

1298
00:49:11,251 --> 00:49:19,660
PANEL H, IT LOOKS LIKE A ZINC

1299
00:49:19,660 --> 00:49:27,968
TREATMENT AND ACTIVATOR -- TYPE

1300
00:49:27,968 --> 00:49:32,973
2 CELERY NEWABLE.

1301
00:49:32,973 --> 00:49:40,480
SO WE FURTHER DID TARGET

1302
00:49:40,480 --> 00:49:43,884
DIVISION OF TYPE 2 CELLS AND WE

1303
00:49:43,884 --> 00:49:49,356
SEE THAT -- WE CAN ISOLATE THOSE

1304
00:49:49,356 --> 00:49:50,991
CELLS AN MEASURE THEIR CELLULAR

1305
00:49:50,991 --> 00:49:58,031
ZINC SHOWING PANEL D,

1306
00:49:58,031 --> 00:50:00,167
SIGNIFICANT LOWER ZINC

1307
00:50:00,167 --> 00:50:03,704
INTRACELLULARLY AND THOSE CELLS

1308
00:50:03,704 --> 00:50:06,673
DO NOT -- WELL BUT IF WE FURTHER

1309
00:50:06,673 --> 00:50:09,743
INJURE THOSE -- ISOLATE TYPE

1310
00:50:09,743 --> 00:50:11,812
2 CELLS AND WE CAN CLEARLY SEE

1311
00:50:11,812 --> 00:50:16,516
THOSE -- WE HAVE MUCH LOWER TYPE

1312
00:50:16,516 --> 00:50:20,587
2 CELERY C2 CELL RECOVERY AND TS

1313
00:50:20,587 --> 00:50:25,425
DO NOT FORM COLONY WELL AND

1314
00:50:25,425 --> 00:50:35,802
SHOWING PANEL I AND J.

1315
00:50:38,972 --> 00:50:43,644
SO IF WE LEAVE THOSE MICE LON 

1316
00:50:43,644 --> 00:50:47,981
LONGER -- LEAVE THEM ---YEA 

1317
00:50:47,981 --> 00:50:48,649
THEM ---YEAR-OLD -- PANEL B AND

1318
00:50:48,649 --> 00:50:55,155
PANEL C, AND FURTHERMORE, IF WE

1319
00:50:55,155 --> 00:51:03,697
GIVE ONE YEAR -- MICE -- -- LUNG

1320
00:51:03,697 --> 00:51:11,238
TISSUE -- AND WE CAN CLEARLY SEE

1321
00:51:11,238 --> 00:51:12,839
THAT -- MICE THEY HAVE A LOWER

1322
00:51:12,839 --> 00:51:16,643
SURVIVAL AND MUCH HIGHER --

1323
00:51:16,643 --> 00:51:23,617
SHOWING YOU IN PANEL F AS THE

1324
00:51:23,617 --> 00:51:24,117
HYDROXY -- COMPOUND.

1325
00:51:24,117 --> 00:51:26,653
WE ALSO TAKE ADVANTAGE OF

1326
00:51:26,653 --> 00:51:33,927
ZINC -- AVAILABLE AND WE GIVE

1327
00:51:33,927 --> 00:51:35,629
THEM ZINC AND WE SEE IT CAN

1328
00:51:35,629 --> 00:51:37,364
REDUCE LUNG FIBROSIS SHOWING IN

1329
00:51:37,364 --> 00:51:44,104
PANEL H.

1330
00:51:44,104 --> 00:51:47,507
LOWER -- WORSE.

1331
00:51:47,507 --> 00:51:52,946
AS WE STARTED THIS, WE ALSO

1332
00:51:52,946 --> 00:52:01,221
NOTED THAT -- IF YOU LACK AT --K

1333
00:52:01,221 --> 00:52:06,293
AT SIRT1 IT REQUIRES ZINC AND

1334
00:52:06,293 --> 00:52:11,665
ALSO REQUIRES NAD PLUS, PRODUCED

1335
00:52:11,665 --> 00:52:17,904
BY NAMPT AND SO IN THE OLD MICE,

1336
00:52:17,904 --> 00:52:21,508
AND WE DO SEE -- REDUCE

1337
00:52:21,508 --> 00:52:30,016
EVENTUALLY IN THE -- MICE.

1338
00:52:30,016 --> 00:52:35,922
AND WE CAN CONFIRM THE NAMPT --

1339
00:52:35,922 --> 00:52:39,159
CELLS ARE FRESHLY ISOLATED TYPE

1340
00:52:39,159 --> 00:52:43,363
2 CELLS AND ALSO WE CAN --

1341
00:52:43,363 --> 00:52:46,133
LOOKING -- CONFIRM BY SINGLE

1342
00:52:46,133 --> 00:52:49,770
CELL -- IN PANEL C AND ALSO BY

1343
00:52:49,770 --> 00:52:50,737
IMMUNOFLUORESCENT STAINING AS

1344
00:52:50,737 --> 00:52:57,844
SHOWN IN PANEL D AND E.

1345
00:52:57,844 --> 00:53:06,520
BUT UNFORTUNATELY THERE'S LOTS

1346
00:53:06,520 --> 00:53:17,063
OF -- COMPOUNDS AVAILABLE AND --

1347
00:53:19,633 --> 00:53:25,338
AAT AND  AT AND SIGNIFICANTLY EE

1348
00:53:25,338 --> 00:53:28,575
NAMPT ACTIVITY BUT WHEN WE

1349
00:53:28,575 --> 00:53:32,479
USE -- IN CULTURE AND --

1350
00:53:32,479 --> 00:53:35,615
SIGNIFICANTLY PROMOTES -- CELERY

1351
00:53:35,615 --> 00:53:38,585
NEWABLE AND SHOWING -- AS WELL

1352
00:53:38,585 --> 00:53:46,259
AS THE TYPE 2 -- -- THIS

1353
00:53:46,259 --> 00:53:50,463
PROCESS.

1354
00:53:50,463 --> 00:53:56,102
AND WE CAN ALSO TAKE ADVANT

1355
00:53:56,102 --> 00:54:00,874
ADVANTAGE -- ACTIVATION IN VIVO

1356
00:54:00,874 --> 00:54:05,145
AND WE TREAT THE MICE AND SAVING

1357
00:54:05,145 --> 00:54:07,881
THOSE AND HARVESTING -- FIVE

1358
00:54:07,881 --> 00:54:09,382
AND -- WE HAVE A MUCH BETTER

1359
00:54:09,382 --> 00:54:11,484
RECOVERY OF TYPE 2 CELLS, AND IF

1360
00:54:11,484 --> 00:54:16,590
WE LEAVE THEM 21 DAYS, WE CAN

1361
00:54:16,590 --> 00:54:18,658
SEE THAT -- SIGNIFICANTLY

1362
00:54:18,658 --> 00:54:22,429
REDUCED LUNG FIBROSIS.

1363
00:54:22,429 --> 00:54:26,099
SO THE LAST PIECE OF THIS

1364
00:54:26,099 --> 00:54:32,839
PRESENTATION, SO WE RECENTLY --

1365
00:54:32,839 --> 00:54:36,710
SUCH AS -- LIPIDS AFFECTING IPF

1366
00:54:36,710 --> 00:54:39,579
TYPE 2 CELLS, AND THE ONE WITH

1367
00:54:39,579 --> 00:54:45,385
THE GENES, THE LAST PANEL --

1368
00:54:45,385 --> 00:54:55,795
PANEL B AND THIS LPCAT1.

1369
00:55:00,734 --> 00:55:11,177
LPCAT1 LYSOPHOSPHATIDYLCHOLINE

1370
00:55:12,712 --> 00:55:18,218
ACYLTRANSFERASE 1, AND -- BODY

1371
00:55:18,218 --> 00:55:22,656
AND TO SECRETE EXTRACELLULAR

1372
00:55:22,656 --> 00:55:26,960
SPACE -- LPCAT 1 IS SPECIFICALLY

1373
00:55:26,960 --> 00:55:29,329
EXPRESSED IN TYPE 2 CELLS IN

1374
00:55:29,329 --> 00:55:35,035
LUNG TISSUE AND -- REDUCE THE

1375
00:55:35,035 --> 00:55:41,741
IPF TYPE 2 CELLS BY SINGLE CELL

1376
00:55:41,741 --> 00:55:45,779
RTPCR --.

1377
00:55:45,779 --> 00:55:50,984
WE GENERATED THE LPCAT1 DELETION

1378
00:55:50,984 --> 00:55:55,622
MICE, SO WE'RE LOOKING TO THOSE

1379
00:55:55,622 --> 00:55:58,625
CELLS AND -- ORGANELLE CULTURE.

1380
00:55:58,625 --> 00:56:03,830
THOSE TYPE 2 CELLS WITH --

1381
00:56:03,830 --> 00:56:06,967
DELETION -- WELL.

1382
00:56:06,967 --> 00:56:09,436
LASTLY, IF WE LEAVE THEM LONGER

1383
00:56:09,436 --> 00:56:12,472
AND THOSE MICE ARE SHOWING

1384
00:56:12,472 --> 00:56:17,944
REDUCED SURVIVAL, AND HAVE

1385
00:56:17,944 --> 00:56:24,317
SIGNIFICANT MORE FIBROSIS.

1386
00:56:24,317 --> 00:56:26,419
SO TO SUMMARIZE WHAT WE HAVE

1387
00:56:26,419 --> 00:56:30,090
RECENTLY WORKING ON DYSREGULATED

1388
00:56:30,090 --> 00:56:35,929
THE CELLULAR METABOLISM -- PLUS

1389
00:56:35,929 --> 00:56:40,033
PATHWAYS AS WELL AS -- AND WE

1390
00:56:40,033 --> 00:56:46,072
REALLY THINK THAT IT'S HARD TO

1391
00:56:46,072 --> 00:56:52,746
RECOVER TYPE 2 CELLS, POSSIBLE

1392
00:56:52,746 --> 00:56:54,447
TO RETORE TYPE 2 CELL PROGENITOR

1393
00:56:54,447 --> 00:56:55,882
CELL FUNCTION, WE PROBABLY NEED,

1394
00:56:55,882 --> 00:57:04,057
YOU KNOW, ZINC/SIRT1 AND

1395
00:57:04,057 --> 00:57:09,829
POSSIBLE OTHER REGULATORS --

1396
00:57:09,829 --> 00:57:10,330
OTHER COMPONENTS.

1397
00:57:10,330 --> 00:57:11,364
THANK YOU VERY MUCH.

1398
00:57:11,364 --> 00:57:11,831
LOOKING FORWARD TO THE

1399
00:57:11,831 --> 00:57:16,336
DISCUSSION.

1400
00:57:16,336 --> 00:57:17,737
>> THANK YOU SO MUCH.

1401
00:57:17,737 --> 00:57:19,539
SO JUST AS A RECAP, PLEASE POST

1402
00:57:19,539 --> 00:57:20,673
YOUR QUESTIONS IN THE CHAT AND

1403
00:57:20,673 --> 00:57:21,641
WE'LL ADDRESS THEM DURING THE

1404
00:57:21,641 --> 00:57:23,043
DISCUSSION PERIOD.

1405
00:57:23,043 --> 00:57:25,545
SO I'D LIKE TO INTRODUCE

1406
00:57:25,545 --> 00:57:28,114
DR. FRANK MCKEON FROM THE

1407
00:57:28,114 --> 00:57:33,553
UNIVERSITY OF HOUSTON, TE TEXAS

1408
00:57:33,553 --> 00:57:34,220
MEDICAL CENTER.

1409
00:57:34,220 --> 00:57:36,156
HE'S DIRECTOR OF THE SOMATIC

1410
00:57:36,156 --> 00:57:39,926
STEM CELL CENTER.

1411
00:57:39,926 --> 00:57:40,827
>> GOOD MORNING.

1412
00:57:40,827 --> 00:57:42,128
THANK YOU FOR INVITING ME.

1413
00:57:42,128 --> 00:57:44,230
I WILL BE TALKING ABOUT WORK

1414
00:57:44,230 --> 00:57:47,300
THAT I DO TOGETHER IN A SHARED

1415
00:57:47,300 --> 00:57:51,471
LAB WITH WA XIAN FOR THE ALMOST

1416
00:57:51,471 --> 00:57:52,672
LAST TWO DECADES NOW.

1417
00:57:52,672 --> 00:57:54,741
THE FOCUS OF THE LAB HAS BEEN

1418
00:57:54,741 --> 00:58:02,015
CLONING STEM CELLS.

1419
00:58:02,015 --> 00:58:03,383
WHAT WE'LL TALK ABOUT TODAY IS A

1420
00:58:03,383 --> 00:58:05,485
FRINGE AND SOME PEOPLE WILL

1421
00:58:05,485 --> 00:58:06,820
UNKINDLY CALL IT A LUNATIC

1422
00:58:06,820 --> 00:58:09,122
FRINGE AREA OF BIOLOGY OF THESE

1423
00:58:09,122 --> 00:58:10,090
PATHOGENIC STEM CELLS THAT ARE

1424
00:58:10,090 --> 00:58:12,725
SHOWING UP IN CHRONIC

1425
00:58:12,725 --> 00:58:14,127
INFLAMMATORY DISEASES IN THE

1426
00:58:14,127 --> 00:58:17,497
LUNG, BUT THEY'RE ALSO SHOWING

1427
00:58:17,497 --> 00:58:18,998
UP IN OTHER DISEASES AS WELL.

1428
00:58:18,998 --> 00:58:20,400
AND I THINK THIS IS PROBABLY A

1429
00:58:20,400 --> 00:58:24,971
MODEL FOR CHRONIC DISEASES IN

1430
00:58:24,971 --> 00:58:25,371
GENERAL.

1431
00:58:25,371 --> 00:58:27,540
I WILL TELL YOU THAT THESE CELLS

1432
00:58:27,540 --> 00:58:32,412
ARE PRE-EXISTING IN NORMAL LUNG.

1433
00:58:32,412 --> 00:58:34,080
AT LOW LEVELS, THEY'RE PRESENT

1434
00:58:34,080 --> 00:58:37,484
IN FETAL LUNG.

1435
00:58:37,484 --> 00:58:39,252
AND THEY'RE EPIGENETICALLY

1436
00:58:39,252 --> 00:58:39,652
FIXED.

1437
00:58:39,652 --> 00:58:41,221
SO IN THE NEXT SLIDE, IT'S JUST

1438
00:58:41,221 --> 00:58:43,623
MY DISCLOSURES.

1439
00:58:43,623 --> 00:58:45,091
AND THE NEXT SLIDE IS SOME WORK

1440
00:58:45,091 --> 00:58:47,760
THAT GOT US INTO THIS.

1441
00:58:47,760 --> 00:58:53,766
THIS IS WORK WE HAD SET UP A

1442
00:58:53,766 --> 00:58:56,202
MODEL OF OURS LARGELY BASED ON

1443
00:58:56,202 --> 00:59:00,573
THE WORK OF MARGARET HERAGE ON

1444
00:59:00,573 --> 00:59:04,444
RECOVERY OF PAISHEDZ FRR ARDS.

1445
00:59:04,444 --> 00:59:06,613
THAT TOGETHER WITH THE WORK WITH

1446
00:59:06,613 --> 00:59:07,780
PEDIATRIC NECROTIZING PNEUMONIA

1447
00:59:07,780 --> 00:59:09,115
SHOWED YOU COULD HAVE MASSIVE

1448
00:59:09,115 --> 00:59:09,816
LUNG DAMAGE AND YOU COULD

1449
00:59:09,816 --> 00:59:10,483
RECOVER FROM IT.

1450
00:59:10,483 --> 00:59:11,951
THE QUESTION IS WHAT WAS THE

1451
00:59:11,951 --> 00:59:12,585
MECHANISM OF THAT.

1452
00:59:12,585 --> 00:59:16,789
SO WE SET UP AN H1N1 INFLUENZA

1453
00:59:16,789 --> 00:59:20,293
MODEL IN SINGAPORE THAT WE COULD

1454
00:59:20,293 --> 00:59:21,394
DIAL IN THE AMOUNT OF DAMAGE.

1455
00:59:21,394 --> 00:59:23,029
SO WE COULD SHOW THAT THESE MICE

1456
00:59:23,029 --> 00:59:29,402
COULD RECOVER FROM 60% LUNG

1457
00:59:29,402 --> 00:59:31,538
DAMAGE TO A PRUS TEEN LUNG AT

1458
00:59:31,538 --> 00:59:32,338
THE END OF THE DAY.

1459
00:59:32,338 --> 00:59:34,274
I DON'T HAVE A POINTER, BUT WHAT

1460
00:59:34,274 --> 00:59:36,242
YOU SEE IS THE GREEN IS NORMAL

1461
00:59:36,242 --> 00:59:37,644
LUNG, AND YOU SEE THESE AREAS

1462
00:59:37,644 --> 00:59:39,546
THAT HAVE BEEN -- IN BLUE THAT

1463
00:59:39,546 --> 00:59:42,916
HAVE BEEN INFILTRATED, AND

1464
00:59:42,916 --> 00:59:46,719
LARGELY DENUDED OF ANY SORT OF

1465
00:59:46,719 --> 00:59:48,488
LUNG TISSUE REPLACED BY

1466
00:59:48,488 --> 00:59:49,589
NEUTROPHILS AND MACROPHAGES.

1467
00:59:49,589 --> 00:59:51,024
RIGHT IN THE 16 TESTIFY OF ALL

1468
00:59:51,024 --> 00:59:54,561
THAT WERE THESE KERATIN

1469
00:59:54,561 --> 00:59:55,395
5P63 CELLS, AND THEY ONLY SHOWED

1470
00:59:55,395 --> 00:59:57,096
UP IN THOSE REGIONS IN MASSIVE

1471
00:59:57,096 --> 01:00:00,033
AREAS.

1472
01:00:00,033 --> 01:00:01,301
IF YOU SEE THE BLOWUP OF THAT,

1473
01:00:01,301 --> 01:00:02,635
YOU CAN SEE THEY'RE FORMING

1474
01:00:02,635 --> 01:00:04,704
STRUCTURES THAT LOOK SIMILAR TO

1475
01:00:04,704 --> 01:00:05,338
ALVEOLI.

1476
01:00:05,338 --> 01:00:07,540
WE'VE ACTUALLY CHASED THOSE INTO

1477
01:00:07,540 --> 01:00:08,641
ALVEOLI, AND I'LL SHOW YOU THAT.

1478
01:00:08,641 --> 01:00:12,111
NOW IN BOSTON, WE WERE HEAVILY

1479
01:00:12,111 --> 01:00:13,846
INFLUENCED BY THE CLASSIC WORK

1480
01:00:13,846 --> 01:00:14,747
OF HOWARD GREEN.

1481
01:00:14,747 --> 01:00:18,117
HE WAS THE FIRST TO CLONE THE

1482
01:00:18,117 --> 01:00:19,352
EPIDERMAL STEM CELL THAT'S BEEN

1483
01:00:19,352 --> 01:00:23,056
HEAVILY USED IN REGENERATIVE

1484
01:00:23,056 --> 01:00:23,623
MEDICINE.

1485
01:00:23,623 --> 01:00:25,325
SO ON THE NEXT SLADE, YOU'LL SEE

1486
01:00:25,325 --> 01:00:26,826
WE ADAPTED THAT SAME TECHNOLOGY,

1487
01:00:26,826 --> 01:00:29,329
AND WE WERE ABLE TO CLONE THESE

1488
01:00:29,329 --> 01:00:32,365
P63 CELLS FROM ALL REGIONS OF

1489
01:00:32,365 --> 01:00:34,634
THE AIRWAY:  NASAL, TRACHEAL AND

1490
01:00:34,634 --> 01:00:35,068
LUNG.

1491
01:00:35,068 --> 01:00:41,040
AND EACH ONE OF THOSE DIFFERED.

1492
01:00:41,040 --> 01:00:41,574
 DIFFERED

1493
01:00:41,574 --> 01:00:42,809
SOMEWHAT, THEY HAD THEIR OWN

1494
01:00:42,809 --> 01:00:45,245
SIGNATURES, BUT THEY'RE LARGELY

1495
01:00:45,245 --> 01:00:47,981
P63 KERATIN 5 POSITIVE CELLS.

1496
01:00:47,981 --> 01:00:49,549
IN THE NEXT SLIDE, YOU CAN SEE

1497
01:00:49,549 --> 01:00:51,818
THAT -- YOU CAN DIFFERENTIATE

1498
01:00:51,818 --> 01:00:55,088
THEM, UPPER AIRWAY FORMS UPPER

1499
01:00:55,088 --> 01:00:56,589
AIRWAY EPITHELIUM UPON DIFFICULT

1500
01:00:56,589 --> 01:01:02,195
RENNIDIFFERENTIATION IN A 3D CU.

1501
01:01:02,195 --> 01:01:04,330
THE LUNG ONES GIVE RISE TO

1502
01:01:04,330 --> 01:01:05,398
DIFFERENT STRUCTURES.

1503
01:01:05,398 --> 01:01:08,134
THEY'RE ENRICHED IN TYPE 1 AND

1504
01:01:08,134 --> 01:01:09,936
TYPE 2 PNEUMOCYTE MARKERS.

1505
01:01:09,936 --> 01:01:11,904
THESE CELLS TURNED OUT TO BE

1506
01:01:11,904 --> 01:01:14,073
EXTREMELY VI VERSATILE.

1507
01:01:14,073 --> 01:01:15,174
ON THE NEXT SLIDE, YOU CAN SEE

1508
01:01:15,174 --> 01:01:16,909
WE CAN CLONE THESE, WE CAN PUT

1509
01:01:16,909 --> 01:01:21,014
THEM INTO -- BY SIMPLE

1510
01:01:21,014 --> 01:01:24,717
INTRATRACHEAL DELIVERY PUT THEM

1511
01:01:24,717 --> 01:01:25,551
DOWN THE TRACHEA.

1512
01:01:25,551 --> 01:01:26,853
IN THE NEXT SLIDE, YOU CAN SEE

1513
01:01:26,853 --> 01:01:31,024
THAT THEY, IN FACT, INCORPORATE

1514
01:01:31,024 --> 01:01:34,227
IT INTO H1N1 DAMAGED LUNG, AND

1515
01:01:34,227 --> 01:01:38,398
THEY DIDN'T INCORPORATE INTO ONE

1516
01:01:38,398 --> 01:01:39,432
THAT YOU DIDN'T DAMAGE.

1517
01:01:39,432 --> 01:01:43,002
SO THIS GAVE US A TREMENDOUS

1518
01:01:43,002 --> 01:01:44,270
SAFETY -- A SENSE OF SAFETY WE

1519
01:01:44,270 --> 01:01:45,004
COULD I THINK RATE.

1520
01:01:45,004 --> 01:01:49,575
INCORPORATE.IF YOU ZERO IN TO TY

1521
01:01:49,575 --> 01:01:56,549
FORMED LUNG, YOU CAN SEE THAT

1522
01:01:56,549 --> 01:01:59,585
THESE -- THE LACZ IS, IN FACT,

1523
01:01:59,585 --> 01:02:01,487
LABELING THOSE, THE ALVEOLI.

1524
01:02:01,487 --> 01:02:03,122
SO IT GAVE US THE OVERALL

1525
01:02:03,122 --> 01:02:04,590
IMPRESSION THAT P63 CELLS FROM

1526
01:02:04,590 --> 01:02:09,996
THE DISTAL AIRWAYS GIVE RISE TO

1527
01:02:09,996 --> 01:02:18,137
BONA FIDE ALVEOLI.

1528
01:02:18,137 --> 01:02:20,273
SO AT THIS POINT WE WERE GOING

1529
01:02:20,273 --> 01:02:23,042
WELL, MAYBE WE HAVE A CURE NOT

1530
01:02:23,042 --> 01:02:24,877
ONLY FOR ARDS BUT WE HAVE A CURE

1531
01:02:24,877 --> 01:02:25,845
FOR CHRONIC LUNG DISEASE.

1532
01:02:25,845 --> 01:02:28,281
BUT AT THE SAME TIME, WE WERE

1533
01:02:28,281 --> 01:02:31,751
HEAVILY INFLUENCED BY THE WORK

1534
01:02:31,751 --> 01:02:35,722
FROM CHILOSI AND WITSETT,

1535
01:02:35,722 --> 01:02:37,190
SCHWARTZ AND REYNOLDS, ALL OF

1536
01:02:37,190 --> 01:02:39,659
THEM SHOWING THAT THERE'S

1537
01:02:39,659 --> 01:02:41,294
P63 CELLS IN THESE LESIONS THAT

1538
01:02:41,294 --> 01:02:43,963
WERE SHOWING UP IN THESE CHRONIC

1539
01:02:43,963 --> 01:02:45,565
LUNG DISEASE.

1540
01:02:45,565 --> 01:02:46,966
JAY SHOWED US SOME VERY NICE

1541
01:02:46,966 --> 01:02:49,569
PICTURES YESTERDAY OF THESE

1542
01:02:49,569 --> 01:02:50,503
METAPLASIAS.

1543
01:02:50,503 --> 01:02:52,739
THOSE METAPLASIAS ARE ALL

1544
01:02:52,739 --> 01:02:54,974
SUBTENDED BY P63 POSITIVE CELLS.

1545
01:02:54,974 --> 01:02:59,379
SO ANYWAYS, WE DIDN'T THINK WE

1546
01:02:59,379 --> 01:03:03,282
COULD JUST SORT OF THROW NORMAL

1547
01:03:03,282 --> 01:03:05,585
LONG STEM CELLS DOWN INTO A

1548
01:03:05,585 --> 01:03:06,819
HIGHLY REMODELED COPD LUNG.

1549
01:03:06,819 --> 01:03:08,121
SO WE STARTED TO LOOK AT WHAT

1550
01:03:08,121 --> 01:03:10,590
WAS GOING ON IN THE COPD LUNG.

1551
01:03:10,590 --> 01:03:12,225
ON THE NEXT SLIDE, YOU CAN

1552
01:03:12,225 --> 01:03:13,726
SEE -- WE COULD READILY USE THE

1553
01:03:13,726 --> 01:03:15,328
SAME TECHNOLOGY, GENERATE

1554
01:03:15,328 --> 01:03:17,296
LIBRARIES FROM CONTROL PATIENTS,

1555
01:03:17,296 --> 01:03:18,965
CONTROL LUNGS, THESE ARE ALL

1556
01:03:18,965 --> 01:03:22,235
OBTAINED FROM THE TRANSPLANT

1557
01:03:22,235 --> 01:03:22,735
CENTERS.

1558
01:03:22,735 --> 01:03:25,772
AND COPD LUNGS.

1559
01:03:25,772 --> 01:03:27,607
THESE LIBRARIES ARE CLONES OF

1560
01:03:27,607 --> 01:03:28,274
P36 POSITIVE CELLS.

1561
01:03:28,274 --> 01:03:31,878
IF YOU DO THE SINGLE CELL

1562
01:03:31,878 --> 01:03:35,214
ANALYSIS, LOOK AT THE PIE CHART

1563
01:03:35,214 --> 01:03:36,315
AT THE BOTTOM LEFT.

1564
01:03:36,315 --> 01:03:42,989
IT DOMINATEIT'S DOMINATED BY A M

1565
01:03:42,989 --> 01:03:43,589
CELL IN BLUE.

1566
01:03:43,589 --> 01:03:45,491
THAT'S THE NORMAL STEM CELL THAT

1567
01:03:45,491 --> 01:03:47,427
GAVE RISE TO THIS REGENERATIVE

1568
01:03:47,427 --> 01:03:48,394
STEP.

1569
01:03:48,394 --> 01:03:51,164
IF YOU LOOK AT THE COPD, AND IT

1570
01:03:51,164 --> 01:03:52,999
DIDN'T MATTER WHICH PATIENTS FOR

1571
01:03:52,999 --> 01:03:54,467
COPD, WHICH TYPES, THEY ALL

1572
01:03:54,467 --> 01:03:56,035
LOOKED ALIKE, THEY WERE

1573
01:03:56,035 --> 01:03:57,937
DOMINATED BY THESE THREE WHICH

1574
01:03:57,937 --> 01:04:00,540
AT THE TIME WE CALLED VARIANTS.

1575
01:04:00,540 --> 01:04:03,176
AND IF YOU LOOK VERY CLOSELY ON

1576
01:04:03,176 --> 01:04:05,711
THE PIE CHARTS ON THE LEFT-HAND

1577
01:04:05,711 --> 01:04:08,247
SIDE, YOU SEE THAT EVEN THE

1578
01:04:08,247 --> 01:04:10,116
NORMAL PATIENTS HAVE SOME OF

1579
01:04:10,116 --> 01:04:12,084
THOSE CLONES THAT COME TO

1580
01:04:12,084 --> 01:04:13,719
DOMINATE THE COPD PATIENTS.

1581
01:04:13,719 --> 01:04:15,021
AND I SHOW YOU THIS SLIDE

1582
01:04:15,021 --> 01:04:16,756
BECAUSE THIS IS A PARADIGM FOR

1583
01:04:16,756 --> 01:04:19,091
EVERYTHING ELSE WE'VE SEEN, NOT

1584
01:04:19,091 --> 01:04:23,863
ONLY IN LUNG BUT ALSO IN

1585
01:04:23,863 --> 01:04:24,630
PEDIATRIC CROHN'S DISEASE AND

1586
01:04:24,630 --> 01:04:25,331
ULCERATIVE COLITIS.

1587
01:04:25,331 --> 01:04:27,333
YOU'RE GETTING THE SAME

1588
01:04:27,333 --> 01:04:28,401
EMERGENCE OF THESE VARIANTS.

1589
01:04:28,401 --> 01:04:30,203
SO THE QUESTION IS WHAT ARE

1590
01:04:30,203 --> 01:04:31,237
THESE VARIANTS DOING?

1591
01:04:31,237 --> 01:04:33,306
ON THE NEXT SLIDE, YOU CAN SEE

1592
01:04:33,306 --> 01:04:35,608
JUST A SIMPLE SHOTGUNNING OF

1593
01:04:35,608 --> 01:04:42,014
THOSE LIBRARIES INTO HIGHLY

1594
01:04:42,014 --> 01:04:42,582
IMMUNODEFICIENT MICE.

1595
01:04:42,582 --> 01:04:44,083
SO THESE MICE, THE ONLY THING

1596
01:04:44,083 --> 01:04:47,520
THEY HAVE IS NEUTROPHILS.

1597
01:04:47,520 --> 01:04:48,621
AND IF YOU LOOK AT THE CONTROL

1598
01:04:48,621 --> 01:04:50,156
ONES, THEY SELF-ASSEMBLE INTO

1599
01:04:50,156 --> 01:04:52,325
THESE LUMEN THAT ARE HOLLOW,

1600
01:04:52,325 --> 01:04:53,826
ESSENTIALLY CLEAR, WHEREAS THE

1601
01:04:53,826 --> 01:04:56,996
COPD, THEY'RE ALL FILLED WITH

1602
01:04:56,996 --> 01:04:58,197
NEUTROPHILS, AND THIS IS TRUE

1603
01:04:58,197 --> 01:04:59,365
ALL ACROSS THESE DIFFERENT

1604
01:04:59,365 --> 01:05:02,101
PATIENTS THAT WE LOOKED AT.

1605
01:05:02,101 --> 01:05:04,737
SO IT LOOKED AS IF THERE'S SOME

1606
01:05:04,737 --> 01:05:05,371
INFLAMMATORY COMPONENT OF THIS.

1607
01:05:05,371 --> 01:05:10,576
IF YOU LOOK IN THE NEXT SLIDE,

1608
01:05:10,576 --> 01:05:13,479
YOU GET MYOFIBROBLASTS

1609
01:05:13,479 --> 01:05:16,716
SURROUNDING THESE SAME LIBRARY

1610
01:05:16,716 --> 01:05:17,483
NODULES.

1611
01:05:17,483 --> 01:05:19,619
AND AGAIN, IT'S TRUE ACROSS ALL

1612
01:05:19,619 --> 01:05:22,421
THE COPD PATIENTS, IT'S NOT THE

1613
01:05:22,421 --> 01:05:24,957
CASE WITH CONTROL PATIENTS.

1614
01:05:24,957 --> 01:05:27,360
SO IN THE NEXT SLIDE, WE COULD

1615
01:05:27,360 --> 01:05:29,195
JUST USE SINGLE CELL SORTING TO

1616
01:05:29,195 --> 01:05:33,266
BREAK THESE LIBRARIES DOWN, AND

1617
01:05:33,266 --> 01:05:35,635
THEN CAN YOU FIND YOU COULD

1618
01:05:35,635 --> 01:05:37,904
MAKE -- CLUSTER ONE WAS THE

1619
01:05:37,904 --> 01:05:38,971
NORMAL STEM CELL.

1620
01:05:38,971 --> 01:05:40,873
CLUSTER TWO WAS A GOBLET CELL

1621
01:05:40,873 --> 01:05:41,374
METAPLASIA.

1622
01:05:41,374 --> 01:05:44,010
AND CLUSTERS THREE AND FOUR WERE

1623
01:05:44,010 --> 01:05:45,478
BOTH SQUAMOUS CELL METAPLASIA,

1624
01:05:45,478 --> 01:05:47,547
ONE OF WHICH IS FIBROTIC AND ONE

1625
01:05:47,547 --> 01:05:48,681
OF WHICH IS INFLAMMATORY.

1626
01:05:48,681 --> 01:05:51,017
AND THE GENE EXPRESSION PROFILES

1627
01:05:51,017 --> 01:05:52,418
EXACTLY MATCHED THESE PROFILES

1628
01:05:52,418 --> 01:05:53,553
HERE.

1629
01:05:53,553 --> 01:05:54,487
ON THE NEXT SLIDE, YOU CAN SEE

1630
01:05:54,487 --> 01:05:59,025
THAT WE'VE CARRIED THIS ON TO

1631
01:05:59,025 --> 01:06:02,261
IPF, AND TO CYSTIC FIBROSIS.

1632
01:06:02,261 --> 01:06:03,563
CYSTIC FIBROSIS IS ACTUALLY MORE

1633
01:06:03,563 --> 01:06:06,132
COMPLICATED.

1634
01:06:06,132 --> 01:06:07,934
IT'S GOT FIVE DIFFERENT

1635
01:06:07,934 --> 01:06:08,834
VARIANTS, THREE OF WHICH OVERLAP

1636
01:06:08,834 --> 01:06:13,673
WITH THOSE OF COPD.

1637
01:06:13,673 --> 01:06:17,143
FOR IPF, WE'RE STILL WORKING ON

1638
01:06:17,143 --> 01:06:19,579
THE HONEYCOMB -- WITH DAVID SH

1639
01:06:19,579 --> 01:06:24,450
WASCHWARTZ AND HIS COLLEAGUES BT

1640
01:06:24,450 --> 01:06:28,454
WE'VE PUBLISHED ON THE ONE THAT

1641
01:06:28,454 --> 01:06:31,891
CAN GIVE RISE TO CUBOIDAL

1642
01:06:31,891 --> 01:06:32,391
SYNDROME.

1643
01:06:32,391 --> 01:06:33,593
A THAT SAME TECHNOLOGY WE'VE

1644
01:06:33,593 --> 01:06:38,898
USED FOR SEVERE ASTHMA, FOR RA

1645
01:06:38,898 --> 01:06:40,700
AND COVID INTERSTITIAL LUNG

1646
01:06:40,700 --> 01:06:41,000
DISEASE.

1647
01:06:41,000 --> 01:06:43,069
WE DON'T KNOW HOW MANY OF THESE

1648
01:06:43,069 --> 01:06:44,437
VARIANT STEM CELLS EXIST BUT

1649
01:06:44,437 --> 01:06:46,205
WE'RE READY SURE AT THIS POINT

1650
01:06:46,205 --> 01:06:48,140
THAT THESE CELLS ARE PART OF

1651
01:06:48,140 --> 01:06:51,410
YOUR INNATE IMMUNE SYSTEM,

1652
01:06:51,410 --> 01:06:52,545
INNATE MUCOSAL IMMUNITY, AND

1653
01:06:52,545 --> 01:06:58,951
THEY HAVEN'T BENZENE BECAUSE BEE

1654
01:06:58,951 --> 01:07:00,319
THEY'RE PRESENT AT SUCH LOW

1655
01:07:00,319 --> 01:07:00,553
LEVELS.

1656
01:07:00,553 --> 01:07:02,355
BUT NEVERTHELESS, FROM OUR SIM

1657
01:07:02,355 --> 01:07:03,189
POLICE TI VIEW OF THE WORLD,

1658
01:07:03,189 --> 01:07:04,657
IT'S LIKE YOU HAVE GOOD GUYS AND

1659
01:07:04,657 --> 01:07:09,295
BAD GUYS, THE NORMAL LUNG STEM

1660
01:07:09,295 --> 01:07:11,163
CELL AND THEN YOU'VE GOT THESE

1661
01:07:11,163 --> 01:07:14,166
VARIANTS THAT ARE DRIVING THINGS

1662
01:07:14,166 --> 01:07:16,202
LIKE MUCOUS, HYPER NECROSIS AND

1663
01:07:16,202 --> 01:07:16,636
INFLAMMATION.

1664
01:07:16,636 --> 01:07:18,104
SO IT BECOMES A SIMPLE THING,

1665
01:07:18,104 --> 01:07:20,373
ALL OF THESE CELLS ARE

1666
01:07:20,373 --> 01:07:21,574
INTRINSICALLY IMMORTAL, SO YOU

1667
01:07:21,574 --> 01:07:24,043
CAN GROW THEM UP AT HIGH LEVELS

1668
01:07:24,043 --> 01:07:26,679
FOR HIGH THROUGHPUT SCREENS SUCH

1669
01:07:26,679 --> 01:07:28,280
AS 384 WELL SCREEN, SO ON THE

1670
01:07:28,280 --> 01:07:29,649
NEXT SLIDE, YOU CAN SEE WHAT

1671
01:07:29,649 --> 01:07:32,351
THOSE ARE LOOKING LIKE.

1672
01:07:32,351 --> 01:07:34,620
SO WE HAVE GENERATED SOME VERY

1673
01:07:34,620 --> 01:07:36,922
NICE AND VERY SPECIFIC, WORKING

1674
01:07:36,922 --> 01:07:39,191
TOGETHER WITH OUR CHEMISTRY

1675
01:07:39,191 --> 01:07:41,093
COLLEAGUES AT TUFTS, SOME

1676
01:07:41,093 --> 01:07:42,028
INCREDIBLY POWERFUL MOLECULES

1677
01:07:42,028 --> 01:07:44,997
THAT ARE PART OF A SYNTHETIC

1678
01:07:44,997 --> 01:07:46,799
LETHAL COMBINATION.

1679
01:07:46,799 --> 01:07:50,069
THE GOOD NEWS IS, THESE ARE

1680
01:07:50,069 --> 01:07:51,303
SHOWING BROAD EFFECTS ACROSS ALL

1681
01:07:51,303 --> 01:07:53,272
THESE VARIANT CELLS, AND WE CAN

1682
01:07:53,272 --> 01:07:55,341
GET INTO WHAT MAKES THESE

1683
01:07:55,341 --> 01:07:57,109
VARIANT CELLS EXPAND, BECAUSE I

1684
01:07:57,109 --> 01:07:58,944
THINK THAT'S THE KEY TO

1685
01:07:58,944 --> 01:07:59,912
UNDERSTANDING THEIR

1686
01:07:59,912 --> 01:08:00,780
VULNERABILITIES.

1687
01:08:00,780 --> 01:08:03,015
AND ON THE LAST SLIDE, I'LL JUST

1688
01:08:03,015 --> 01:08:04,150
SHOW YOU SOME OF THE KEY POINT

1689
01:08:04,150 --> 01:08:05,985
THAT I THINK ARE OUT THERE.

1690
01:08:05,985 --> 01:08:07,620
SO THERE'S CLEARLY A DOMINATION

1691
01:08:07,620 --> 01:08:11,190
BY THESE PATHOGENIC STEM CELLS

1692
01:08:11,190 --> 01:08:13,926
ACROSS ALL THESE CHRONIC LUNG

1693
01:08:13,926 --> 01:08:15,995
DISEASES, AND THAT EXTENDS INTO

1694
01:08:15,995 --> 01:08:18,164
CROHN'S AND UC, AND IT WOULDN'T

1695
01:08:18,164 --> 01:08:20,166
SHOCK ME THAT IT'S EXTENDING

1696
01:08:20,166 --> 01:08:22,001
INTO NASH AND CHRONIC KIDNEY

1697
01:08:22,001 --> 01:08:23,669
DISEASE.

1698
01:08:23,669 --> 01:08:25,304
THESE PATHOGENIC STEM CELLS

1699
01:08:25,304 --> 01:08:27,540
EXIST AT LOW LEVELS IN NORMAL

1700
01:08:27,540 --> 01:08:28,641
AND FETAL LUNG.

1701
01:08:28,641 --> 01:08:29,842
WE POSIT THEY REPRESENT

1702
01:08:29,842 --> 01:08:32,178
COMPONENTS OF THE INNATE

1703
01:08:32,178 --> 01:08:32,945
IMMUNITY.

1704
01:08:32,945 --> 01:08:36,716
WE'VE GOT TO DEMONSTRATE THIS.

1705
01:08:36,716 --> 01:08:37,883
AND THEN THE QUESTION IS, WHAT

1706
01:08:37,883 --> 01:08:39,518
CHANGES IN THE PATHOGENIC STEM

1707
01:08:39,518 --> 01:08:40,753
CELLS -- SO WE NORMALLY EXPECT

1708
01:08:40,753 --> 01:08:42,555
THESE THINGS TO SPIKE UP IN

1709
01:08:42,555 --> 01:08:44,623
RESPONSE TO A PATHOGEN AND THEN

1710
01:08:44,623 --> 01:08:48,661
DISAPPEAR, AND THEY DON'T.

1711
01:08:48,661 --> 01:08:50,062
WHAT WE CAN TELL FROM THE GENE

1712
01:08:50,062 --> 01:08:51,097
EXPRESSION PROFILES IS THERE'S

1713
01:08:51,097 --> 01:08:52,131
TWO THINGS THAT ARE GOING ON,

1714
01:08:52,131 --> 01:08:53,733
AND SOME OF THESE, DR. HAN

1715
01:08:53,733 --> 01:08:55,601
REFERRED TO EARLIER, THERE'S

1716
01:08:55,601 --> 01:08:58,637
SOMETHING TO DO WITH COMPLEX

1717
01:08:58,637 --> 01:08:59,705
1 IN THE MITOCHONDRIA AND THEN

1718
01:08:59,705 --> 01:09:01,140
THERE'S SOMETHING TO DO WITH

1719
01:09:01,140 --> 01:09:07,947
RESISTANCE TO FAST LIGAND --

1720
01:09:07,947 --> 01:09:08,414
CELL DEATH.

1721
01:09:08,414 --> 01:09:09,749
WE ALSO HAVE TO TRY TO CONNECT

1722
01:09:09,749 --> 01:09:11,183
UP THESE DATA WITH WHAT'S GOING

1723
01:09:11,183 --> 01:09:14,086
ON IN THESE REALLY BEAUTIFUL

1724
01:09:14,086 --> 01:09:17,423
SINGLE CELL RNA SEQ STUDIES OF

1725
01:09:17,423 --> 01:09:21,393
IPF, THESE SO CALLED ABNORMAL

1726
01:09:21,393 --> 01:09:22,461
BASALOID CELLS, AND I THINK

1727
01:09:22,461 --> 01:09:23,896
OTHERS HAVE MENTIONED THIS

1728
01:09:23,896 --> 01:09:26,532
ALREADY, THE VAST MAJORITY OF --

1729
01:09:26,532 --> 01:09:31,437
EVEN THOUGH 10 TO 20% OF HEAVY

1730
01:09:31,437 --> 01:09:32,538
SMOKERS DEVELOP COPD, THE VAST

1731
01:09:32,538 --> 01:09:34,039
MAJORITY OF CANCERS COME FROM

1732
01:09:34,039 --> 01:09:35,608
PATIENTS WITH PRE-EXISTING COPD.

1733
01:09:35,608 --> 01:09:37,243
SO ARE THESE PATHOGENIC STEM

1734
01:09:37,243 --> 01:09:39,812
CELLS SOMEHOW IN THAT TRACK TO

1735
01:09:39,812 --> 01:09:40,279
CANCER?

1736
01:09:40,279 --> 01:09:43,315
AND FINALLY, THIS DRUG

1737
01:09:43,315 --> 01:09:43,849
DEVELOPMENT.

1738
01:09:43,849 --> 01:09:46,252
WE REALLY NEED -- WE'VE GOT

1739
01:09:46,252 --> 01:09:47,286
100 MILLION PEOPLE JUST IN THIS

1740
01:09:47,286 --> 01:09:48,487
COUNTRY ALONE WITH CHRONIC LUNG

1741
01:09:48,487 --> 01:09:48,954
DISEASE.

1742
01:09:48,954 --> 01:09:51,490
WE REALLY NEED THERAPEUTICS.

1743
01:09:51,490 --> 01:09:53,225
WE'RE VERY EXCITED ABOUT WHERE

1744
01:09:53,225 --> 01:09:56,295
WE ARE NOW AND THERE'S A LOT OF

1745
01:09:56,295 --> 01:09:58,364
IND-ENABLING STUDIES GOING ON

1746
01:09:58,364 --> 01:09:58,697
NOW.

1747
01:09:58,697 --> 01:09:59,899
GOD WILLING, WEAR GOING TO GET

1748
01:09:59,899 --> 01:10:03,602
SOMETHING LIKE THIS INTO THE

1749
01:10:03,602 --> 01:10:05,204
NEXT -- AND I WANT TO THANK THE

1750
01:10:05,204 --> 01:10:06,505
PEOPLE ON THE NEXT SLIDE, SO A

1751
01:10:06,505 --> 01:10:08,307
WHOLE BUNCH OF GREAT

1752
01:10:08,307 --> 01:10:09,208
COLLABORATORS AND TALENTED

1753
01:10:09,208 --> 01:10:12,077
PEOPLE IN THE LABORATORY, AND

1754
01:10:12,077 --> 01:10:14,246
GREAT SUPPORT FROM THESE VARIOUS

1755
01:10:14,246 --> 01:10:14,814
PLACES.

1756
01:10:14,814 --> 01:10:19,919
THANKS VERY MUCH.

1757
01:10:19,919 --> 01:10:21,921
>> THANK YOU SO MUCH,
FRANK.

1758
01:10:21,921 --> 01:10:24,790
I THINK WE CAN NOW OPEN THE

1759
01:10:24,790 --> 01:10:30,429
DISCUSSION.

1760
01:10:30,429 --> 01:10:40,840
AND START WITH MINGXIA.

1761
01:10:42,274 --> 01:10:45,411
CAN YOU TURN ON YOUR CAMERA?

1762
01:10:45,411 --> 01:10:49,615
>> THE QUESTION IN THE
CHAT.

1763
01:10:49,615 --> 01:10:51,217
>> I WAS BASICALLY TRYING
TO

1764
01:10:51,217 --> 01:10:52,918
UNDERSTAND MORE ABOUT THE

1765
01:10:52,918 --> 01:10:56,889
FUNCTIONAL TESTING OF THE IPF --

1766
01:10:56,889 --> 01:10:59,859
WE'VE BEEN STRUGGLING A LITTLE

1767
01:10:59,859 --> 01:11:02,294
BIT ON SHOWING THE RELEVANT

1768
01:11:02,294 --> 01:11:04,763
FUNCTION OF THE -- AND OTHER

1769
01:11:04,763 --> 01:11:06,398
CELL TYPES AND LUNG ORGANOIDS

1770
01:11:06,398 --> 01:11:08,267
AND HOW PRECISELY THOSE

1771
01:11:08,267 --> 01:11:09,368
FUNCTIONS ARE RELATED TO THE

1772
01:11:09,368 --> 01:11:10,603
PHENOTYPES THAT WE'RE SEEING IN

1773
01:11:10,603 --> 01:11:13,205
PATIENTS.

1774
01:11:13,205 --> 01:11:16,675
SO THAT WAS MY QUESTION TO

1775
01:11:16,675 --> 01:11:18,510
DR. WILSON.

1776
01:11:18,510 --> 01:11:20,613
>> SO I READ IT IN THE
CHAT BUT

1777
01:11:20,613 --> 01:11:22,248
I CAN MAYBE JUST TRY TO EXPLAIN

1778
01:11:22,248 --> 01:11:24,316
VERBALLY AS WELL.

1779
01:11:24,316 --> 01:11:29,355
SO TRYING TO IDENTIFY FUNCTIONAL

1780
01:11:29,355 --> 01:11:30,789
BEHAVIORS OF PARTICULAR CELL

1781
01:11:30,789 --> 01:11:32,524
TYPES IN VITRO AND TRY TO RELATE

1782
01:11:32,524 --> 01:11:34,393
THEM TO IN VIVO BIOLOGY IS A

1783
01:11:34,393 --> 01:11:35,194
MAJOR CHALLENGE AND THAT WAS

1784
01:11:35,194 --> 01:11:36,562
SOMETHING WE HAD TO THINK A LOT

1785
01:11:36,562 --> 01:11:37,696
ABOUT WHEN WE WERE TRYING TO

1786
01:11:37,696 --> 01:11:39,999
UNDERSTAND THE CONSEQUENCES OF

1787
01:11:39,999 --> 01:11:40,833
PERTURBING INDIVIDUAL GENES IN

1788
01:11:40,833 --> 01:11:41,901
OUR SYSTEM, YOU KNOW, WE'RE

1789
01:11:41,901 --> 01:11:44,503
DEALING WITH A SINGLE IPSC

1790
01:11:44,503 --> 01:11:46,739
DERIVED CELL TYPE, IN THIS CASE

1791
01:11:46,739 --> 01:11:49,942
IA T2s, SO THE THINGS THAT WE

1792
01:11:49,942 --> 01:11:51,277
WERE LOOKING AT THAT WE THOUGHT

1793
01:11:51,277 --> 01:11:52,578
HAD SOME KIND OF FUNCTIONAL

1794
01:11:52,578 --> 01:11:54,713
RELEVANCE TO A PROGENITOR CELL

1795
01:11:54,713 --> 01:11:56,148
TYPE, AS I MENTIONED IN MY TALK,

1796
01:11:56,148 --> 01:11:58,751
WERE THINGS LIKE PROLIFERATION,

1797
01:11:58,751 --> 01:12:01,854
DIFFERENTIATION EFFICIENCY, AND

1798
01:12:01,854 --> 01:12:02,288
MATURATION.

1799
01:12:02,288 --> 01:12:03,555
WAND I SAID IN THE CHAT AND WHAT

1800
01:12:03,555 --> 01:12:06,058
WE DIDN'T LOOK AT AT THE TIME

1801
01:12:06,058 --> 01:12:07,126
WAS DIFFERENTIATION EFFICIENCY

1802
01:12:07,126 --> 01:12:09,261
IN TERMS OF GENERATING TYPE

1803
01:12:09,261 --> 01:12:12,998
1 CELLS, WOULD BE OBVIOUS

1804
01:12:12,998 --> 01:12:16,535
RELEVANT PHENOTYPE FOR A TYPE

1805
01:12:16,535 --> 01:12:16,769
2 CELL.

1806
01:12:16,769 --> 01:12:17,903
THE REASON WE DIDN'T DO SO AT

1807
01:12:17,903 --> 01:12:19,538
THE TIME WAS DARRELL'S LAB WAS

1808
01:12:19,538 --> 01:12:22,508
WORKING ON THAT TIME TO GENERATE

1809
01:12:22,508 --> 01:12:25,110
PROTOCOLS TO GENERATE IET1s

1810
01:12:25,110 --> 01:12:28,047
FROM IE T2s BUT THEY WEREN'T

1811
01:12:28,047 --> 01:12:28,948
REALLY PERFECTED YET.

1812
01:12:28,948 --> 01:12:30,249
BUT AT THIS POINT WE COULD DO

1813
01:12:30,249 --> 01:12:30,849
THAT NOW.

1814
01:12:30,849 --> 01:12:32,618
SO I THINK THAT WOULD BE ANOTHER

1815
01:12:32,618 --> 01:12:33,953
RELEVANT PHENOTYPE FOR A

1816
01:12:33,953 --> 01:12:35,154
PROGENITOR CELL LIKE A TYPE

1817
01:12:35,154 --> 01:12:35,988
2 CELL.

1818
01:12:35,988 --> 01:12:38,023
>> I GUESS I ASKED THAT
QUESTION

1819
01:12:38,023 --> 01:12:40,359
MOSTLY BECAUSE THESE FUNCTIONS

1820
01:12:40,359 --> 01:12:42,661
ARE MORE GENERAL STEM CELL

1821
01:12:42,661 --> 01:12:45,564
FUNCTIONS, SO I WAS WONDERING IF

1822
01:12:45,564 --> 01:12:48,667
THERE'S ANY SPECIFIC FUNCTION,

1823
01:12:48,667 --> 01:12:49,601
ESPECIALLY THE FUNCTIONAL

1824
01:12:49,601 --> 01:12:51,503
DEFECTS THAT WE WOULD SEE IN A

1825
01:12:51,503 --> 01:12:53,839
COPD LUNG.

1826
01:12:53,839 --> 01:12:56,909
BUT I GUESS THAT'S THE --

1827
01:12:56,909 --> 01:12:58,444
>> SO I THINK THAT'S THE
RIGHT

1828
01:12:58,444 --> 01:13:01,780
KIND OF QUESTION TO BE THINKING

1829
01:13:01,780 --> 01:13:03,082
ABOUT, AND OUR HYPOTHESIS WOULD

1830
01:13:03,082 --> 01:13:04,316
BE THAT THE PROGENITOR FUNCTION

1831
01:13:04,316 --> 01:13:06,218
WOULD BE SOMETHING THAT WOULD BE

1832
01:13:06,218 --> 01:13:07,886
IMPAIRED IN COPD OR EMPHYSEMA

1833
01:13:07,886 --> 01:13:09,188
BUT FOR SURE ALSO THINKING ABOUT

1834
01:13:09,188 --> 01:13:10,456
THE CROSSTALK BETWEEN DIFFERENT

1835
01:13:10,456 --> 01:13:11,290
CELL TYPES IS SOMETHING TO

1836
01:13:11,290 --> 01:13:12,825
CONSIDER AND WE HAVE THIS

1837
01:13:12,825 --> 01:13:13,859
REDUCTIONIST PLATFORM WHERE

1838
01:13:13,859 --> 01:13:15,294
WE'RE LOOKING AT ONE CELL TYPE.

1839
01:13:15,294 --> 01:13:17,062
YOU KNOW, PLATFORMS LIKE YOURS

1840
01:13:17,062 --> 01:13:18,664
THAT INCLUDE MULTIPLE CELL TYPES

1841
01:13:18,664 --> 01:13:19,798
MIGHT BE REALLY INTERESTING TO

1842
01:13:19,798 --> 01:13:23,168
TRY TO ASK THAT KIND OF

1843
01:13:23,168 --> 01:13:24,336
QUESTION, AND OUR PLAN IS TO

1844
01:13:24,336 --> 01:13:25,838
SORT OF BUILD IN COMPLEXITY OVER

1845
01:13:25,838 --> 01:13:29,675
TIME AS WE'RE ABLE TO BUILD

1846
01:13:29,675 --> 01:13:30,843
COCULTURAL SYSTEMS.

1847
01:13:30,843 --> 01:13:38,784
>> THANK YOU.

1848
01:13:38,784 --> 01:13:39,818
>> SORRY.

1849
01:13:39,818 --> 01:13:41,186
THERE ARE SOME HANDS RAISED IN

1850
01:13:41,186 --> 01:13:45,657
THE CHAT TOO.

1851
01:13:45,657 --> 01:13:56,168
SO CAN WE START WITH JIANWEN.

1852
01:13:56,635 --> 01:14:02,908
>> I HAVE QUESTION FOR
DIANHUA,

1853
01:14:02,908 --> 01:14:04,276
MIXTURE OF MANY CELL TYPES, HAVE

1854
01:14:04,276 --> 01:14:06,678
YOU THINK ABOUT TO ISOLATE

1855
01:14:06,678 --> 01:14:10,449
PARTICULAR CELL TYPES INSTITUTE

1856
01:14:10,449 --> 01:14:15,054
INTO THE TRACHEA OR SYSTEMATIC

1857
01:14:15,054 --> 01:14:16,355
DELIVERY AND SEE WHETHER CERTAIN

1858
01:14:16,355 --> 01:14:18,824
TYPE OF MESENCHYMAL STEM CELLS

1859
01:14:18,824 --> 01:14:22,027
WOULD BE MORE CURATIVE, IF YOU

1860
01:14:22,027 --> 01:14:23,295
HAVE STRONG EVIDENCE TO SHOW

1861
01:14:23,295 --> 01:14:23,495
THAT.

1862
01:14:23,495 --> 01:14:25,998
>> SO THAT'S AN EXCELLENT

1863
01:14:25,998 --> 01:14:31,103
QUESTION.

1864
01:14:31,103 --> 01:14:33,238
AND LET ME EXPAND ON THAT

1865
01:14:33,238 --> 01:14:34,907
BECAUSE THE MSCs THAT ARE

1866
01:14:34,907 --> 01:14:36,742
ISOLATED FROM BONE MARROW VERSUS

1867
01:14:36,742 --> 01:14:38,143
PLACENTA VERSUS ADIPOSE ARE

1868
01:14:38,143 --> 01:14:39,478
SIMILAR BUT NOT COMPLETELY

1869
01:14:39,478 --> 01:14:41,246
IDENTICAL.

1870
01:14:41,246 --> 01:14:45,017
AND FURTHER, WHEN YOU, FOR

1871
01:14:45,017 --> 01:14:46,652
EXAMPLE, GET AN EXTRACTION,

1872
01:14:46,652 --> 01:14:49,188
LET'S SAY, A BONE MARROW ISOLATE

1873
01:14:49,188 --> 01:14:53,859
LIKE THAT IN A CULTURE SYSTEM,

1874
01:14:53,859 --> 01:14:54,793
THEN THERE CAN BE CLONES THAT

1875
01:14:54,793 --> 01:14:58,230
DEVELOP.

1876
01:14:58,230 --> 01:14:59,765
OF MSCs THAT WILL DEVELOP

1877
01:14:59,765 --> 01:15:01,733
DIFFERENT ATTRIBUTES, DIFFERENT

1878
01:15:01,733 --> 01:15:03,168
PROPERTIES AND THE LIKE TOO, SO

1879
01:15:03,168 --> 01:15:03,902
IT'S A DIFFICULT QUESTION, AND

1880
01:15:03,902 --> 01:15:05,838
THERE HAVE BEEN A NUMBER OF

1881
01:15:05,838 --> 01:15:08,640
COMPARATIVE STUDIES IN

1882
01:15:08,640 --> 01:15:09,775
PRE-CLINICAL MODELS, NOT JUST

1883
01:15:09,775 --> 01:15:11,677
LUNG DISEASE BUT A RANGE OF

1884
01:15:11,677 --> 01:15:13,378
OTHER INDICATIONS COMPARING, FOR

1885
01:15:13,378 --> 01:15:16,048
EXAMPLE, ADIPOSE VERSUS PLACENTA

1886
01:15:16,048 --> 01:15:17,449
ORIGIN.

1887
01:15:17,449 --> 01:15:20,119
AND THERE ARE SOME DIFFERENCES

1888
01:15:20,119 --> 01:15:23,722
IN THE OUTCOME, BUT THAT HASN'T

1889
01:15:23,722 --> 01:15:25,157
YET TRANSLATED INTO A RATIONAL

1890
01:15:25,157 --> 01:15:26,024
APPROACH TO CLINICAL

1891
01:15:26,024 --> 01:15:26,658
INVESTIGATION.

1892
01:15:26,658 --> 01:15:28,961
WHEN YOU LOOK AT IT

1893
01:15:28,961 --> 01:15:30,062
HISTORICALLY, THE MAJORITY OF

1894
01:15:30,062 --> 01:15:34,500
TRIALS HAVE UTILIZED BONE MARROW

1895
01:15:34,500 --> 01:15:38,904
ISOLATED MSCs CULTURED UNDER

1896
01:15:38,904 --> 01:15:39,872
NORMOX IC CONDITIONS WITH

1897
01:15:39,872 --> 01:15:41,573
CERTAIN GROWTH FACTORS IN THE

1898
01:15:41,573 --> 01:15:42,374
MEDIA AND THE LIKE TOO.

1899
01:15:42,374 --> 01:15:44,209
PART OF THAT IS PRACTICALITY,

1900
01:15:44,209 --> 01:15:49,148
PART OF THAT IS ACCESSIBILITY.

1901
01:15:49,148 --> 01:15:50,382
BUT WHEN YOU LOOK, FOR EXAMPLE,

1902
01:15:50,382 --> 01:15:51,383
AT THE LARGE NUMBER OF TRIALS

1903
01:15:51,383 --> 01:15:56,321
THAT STARTED IN THE PANDEMIC FOR

1904
01:15:56,321 --> 01:15:57,122
COVID-ASSOCIATED ARDS, THE

1905
01:15:57,122 --> 01:16:00,092
MAJORITY OF THOSE UTILIZE THE

1906
01:16:00,092 --> 01:16:01,727
UMBILICAL CORD ORIGIN MSCs,

1907
01:16:01,727 --> 01:16:04,296
AND THE REASON THERE IS THAT

1908
01:16:04,296 --> 01:16:06,131
THOSE ARE EASIER TO OBTAIN THAN

1909
01:16:06,131 --> 01:16:08,534
DOING AN ADIPOSE LIPOSUCTION OR

1910
01:16:08,534 --> 01:16:11,103
A BONE MARROW ASPIRATE.

1911
01:16:11,103 --> 01:16:13,238
AND SO IT'S THE SCIENCE VERSUS

1912
01:16:13,238 --> 01:16:15,140
THE PRACTICALITY VERSUS IF

1913
01:16:15,140 --> 01:16:19,545
YOU'REYOU'RE AN INDUSTRY PARTNE,

1914
01:16:19,545 --> 01:16:20,445
YOU'RE GOING TO WANT TO GO FOR

1915
01:16:20,445 --> 01:16:21,380
THE MOST DIRECT GROUP.

1916
01:16:21,380 --> 01:16:23,549
SO THERE'S STILL A LOT OF ROOM

1917
01:16:23,549 --> 01:16:25,184
TO IMPROVE UPON THAT, AND THERE

1918
01:16:25,184 --> 01:16:26,552
IS NO RIGHT -- THIS IS

1919
01:16:26,552 --> 01:16:27,853
IMPORTANT, THERE'S NO RIGHT,

1920
01:16:27,853 --> 01:16:29,588
THERE'S NO WRONG, BUT AT THE END

1921
01:16:29,588 --> 01:16:31,390
OF THE DAY, I STILL THINK THAT

1922
01:16:31,390 --> 01:16:32,724
THE INFLAMMATORY PHENOTYPE IS

1923
01:16:32,724 --> 01:16:34,126
REALLY GOING TO BE THE MAJOR

1924
01:16:34,126 --> 01:16:36,161
DETERMINING FACTOR AND WILL

1925
01:16:36,161 --> 01:16:37,729
OVERSHADOW, IF YOU WILL,

1926
01:16:37,729 --> 01:16:39,431
INDIVIDUAL DIFFERENCES BETWEEN

1927
01:16:39,431 --> 01:16:44,136
DIFFERENT ISOLATES OF CELLS.

1928
01:16:44,136 --> 01:16:48,373
>> THANK YOU.

1929
01:16:48,373 --> 01:16:49,975
>> WHILE WE'RE GOING
THROUGH THE

1930
01:16:49,975 --> 01:16:55,547
CHAT, COULD I ASK A QUESTION TO

1931
01:16:55,547 --> 01:16:55,781
DIANHUA?

1932
01:16:55,781 --> 01:16:56,448
>> YES.

1933
01:16:56,448 --> 01:16:58,317
>> I HAVE TWO QUESTIONS,
REALLY.

1934
01:16:58,317 --> 01:17:00,819
THE FIRST IS, YOU SAID ALL THIS

1935
01:17:00,819 --> 01:17:05,324
GREAT DATA ABOUT THE COLONY

1936
01:17:05,324 --> 01:17:06,692
FORMING EFFICIENCY AND GROWTH

1937
01:17:06,692 --> 01:17:08,460
POTENTIAL OF CELLS AS A FUNCTION

1938
01:17:08,460 --> 01:17:10,729
OF THE INTRACELLULAR ZINC, AND

1939
01:17:10,729 --> 01:17:13,165
I'M WONDERING WHETHER, SINCE IN

1940
01:17:13,165 --> 01:17:16,268
YOUR OWN EARLY STUDIES SHOWED

1941
01:17:16,268 --> 01:17:19,705
THE SORT OF LOSS OF INTEGRITY OF

1942
01:17:19,705 --> 01:17:22,007
IPF TYPE 2 CELLS, WHETHER THIS

1943
01:17:22,007 --> 01:17:24,676
GROWTH IS ACCOMPANIED BY CHANGES

1944
01:17:24,676 --> 01:17:30,382
IN DIFFERENTIATION OR THERE'S A

1945
01:17:30,382 --> 01:17:31,984
REVERSION TO A NORMAL TIP 2 CELL

1946
01:17:31,984 --> 01:17:35,654
OR IS IT A HETEROGENEOUS

1947
01:17:35,654 --> 01:17:36,521
POPULATION IN IPF AS IT IS TO

1948
01:17:36,521 --> 01:17:36,955
BEGIN WITH?

1949
01:17:36,955 --> 01:17:38,323
>> THAT'S A REALLY GOOD

1950
01:17:38,323 --> 01:17:40,192
QUESTION.

1951
01:17:40,192 --> 01:17:41,126
WE DO NOT KNOW.

1952
01:17:41,126 --> 01:17:47,332
I MEAN, YOU KNOW, SO WHAT I'M

1953
01:17:47,332 --> 01:17:51,169
GUESSING IS THAT -- IPF FOR

1954
01:17:51,169 --> 01:17:54,539
LUNGS YOU HAVE REALLY 10%, 15%

1955
01:17:54,539 --> 01:17:57,843
CELLS ARE REALLY -- POSITIVE --

1956
01:17:57,843 --> 01:18:02,514
SO WE CALL THEM -- WE DO NOT

1957
01:18:02,514 --> 01:18:06,151
KNOW IF -- IF THIS IS ZINC,

1958
01:18:06,151 --> 01:18:07,986
INCREASES POPULATION, VERY

1959
01:18:07,986 --> 01:18:12,257
LIKELY, AND WE HAVE ANOTHER

1960
01:18:12,257 --> 01:18:15,761
THING I THINK IS PROBABLY MORE

1961
01:18:15,761 --> 01:18:17,362
IMPORTANT IS THAT EVEN SOME

1962
01:18:17,362 --> 01:18:24,169
CELLS THAT LOOK NOT EXPRESS A

1963
01:18:24,169 --> 01:18:25,704
HIGH -- MAY RECOVER SOME OF

1964
01:18:25,704 --> 01:18:32,444
THEIR FUNCTIONALITY IN TERMS OF

1965
01:18:32,444 --> 01:18:37,649
3D -- MATRIGEL SYSTEM.

1966
01:18:37,649 --> 01:18:39,284
I MEAN, IT'S REALLY HARD TO

1967
01:18:39,284 --> 01:18:42,521
CHARACTERIZE THAT, AND WE

1968
01:18:42,521 --> 01:18:44,623
HAVE -- DON'T HAVE A GOOD MEANS

1969
01:18:44,623 --> 01:18:48,727
TO REALLY EXPLORE THAT.

1970
01:18:48,727 --> 01:18:50,629
I'M NOT SURE IF I ANSWERED YOUR

1971
01:18:50,629 --> 01:18:50,896
QUESTION.

1972
01:18:50,896 --> 01:18:54,633
>> YEAH, MAYBE SEND ME
SOME

1973
01:18:54,633 --> 01:18:57,235
ORGANOID OR PCS SYSTEM THAT

1974
01:18:57,235 --> 01:18:58,470
WOULD PROVIDE A CULTURE SYSTEM

1975
01:18:58,470 --> 01:19:01,673
WHERE YOU COULD SEE A CHANGE IN

1976
01:19:01,673 --> 01:19:02,374
TRANSCRIPTIONAL STATE MIGHT

1977
01:19:02,374 --> 01:19:02,574
HELP.

1978
01:19:02,574 --> 01:19:05,711
MY QUESTION IS, ZINC IS CHEAP.

1979
01:19:05,711 --> 01:19:09,014
ARE YOU PLANNING TO TAKE THIS TO

1980
01:19:09,014 --> 01:19:10,382
A CLINIC AND IF YOU'RE TRYING TO

1981
01:19:10,382 --> 01:19:12,517
DO THAT, COULD YOU HIGHLIGHT

1982
01:19:12,517 --> 01:19:14,286
WHERE THAT STAND?

1983
01:19:14,286 --> 01:19:19,624
>> RIGHT, THAT'S A
SIGNIFICANT

1984
01:19:19,624 --> 01:19:22,961
INTERESTING -- AFTER I PUBLISH

1985
01:19:22,961 --> 01:19:26,298
THE PAPER AND IT WAS A LOT OF --

1986
01:19:26,298 --> 01:19:32,003
CAN WE USE ZINC SUPPLEMENTS FROM

1987
01:19:32,003 --> 01:19:35,874
AMAZON OR SOMEWHERE -- CVS AND

1988
01:19:35,874 --> 01:19:39,711
WE CAN USE THEM FOR THE -- RIGHT

1989
01:19:39,711 --> 01:19:41,346
NOW OURSELF WE DO NOT HAVE ANY

1990
01:19:41,346 --> 01:19:44,783
PLANS TO DEVELOP.

1991
01:19:44,783 --> 01:19:50,922
IF WE LOOK AT A PAPER -- WHAT WE

1992
01:19:50,922 --> 01:19:54,059
REALLY THINK, YOU FEED SOME SORT

1993
01:19:54,059 --> 01:19:57,262
OF COMBINATION THERAPY, HOWEVER,

1994
01:19:57,262 --> 01:19:58,897
SOME TYPES OF FUNCTIONALITY, YOU

1995
01:19:58,897 --> 01:20:00,799
CAN USE A PROPER COMBINATION

1996
01:20:00,799 --> 01:20:09,207
WITH ZINC, WITH SOME OF THE

1997
01:20:09,207 --> 01:20:15,013
ACTUATORS OR -- SIRT1 -- A LOT

1998
01:20:15,013 --> 01:20:25,056
AVAILABLE FOR THAT -- SO -- IT

1999
01:20:25,056 --> 01:20:26,224
DEFINITELY WORTH IN CLINICAL

2000
01:20:26,224 --> 01:20:33,331
TRIAL TO LOOK INTO -- IF YOU CAN

2001
01:20:33,331 --> 01:20:35,467
RECOVER SOME OF THE -- FUNCTION

2002
01:20:35,467 --> 01:20:39,037
NOT JUST SOME OTHER --

2003
01:20:39,037 --> 01:20:41,273
>> SHOULD WE START WITH

2004
01:20:41,273 --> 01:20:41,873
WELLINGTON?

2005
01:20:41,873 --> 01:20:43,208
HIS HAND HAS BEEN UP FOR A

2006
01:20:43,208 --> 01:20:43,608
WHILE.

2007
01:20:43,608 --> 01:20:45,977
HIS ARM MUST BE VERY TIRED.

2008
01:20:45,977 --> 01:20:48,079
ELK TON?

2009
01:20:48,079 --> 01:20:56,254
WELLINGTON?

2010
01:20:56,254 --> 01:20:59,458
>> HE FELL ASLEEP WAITING.

2011
01:20:59,458 --> 01:21:09,634
>> XIAN --

2012
01:21:18,543 --> 01:21:20,378
>> WHATEVER YOU SHOW IS
QUITE

2013
01:21:20,378 --> 01:21:21,546
SURPRISING AND I WAS WONDERING,

2014
01:21:21,546 --> 01:21:25,350
WHEN YOU TALK ABOUT THESE

2015
01:21:25,350 --> 01:21:26,651
CLONES, AND YOU MENTIONED -- I

2016
01:21:26,651 --> 01:21:28,553
REMEMBER YOU HAVING -- YOU WERE

2017
01:21:28,553 --> 01:21:30,722
MENTIONING THAT THERE IS THE

2018
01:21:30,722 --> 01:21:32,057
CELL SURFACE MARKERS THAT YOU

2019
01:21:32,057 --> 01:21:36,161
ARE LOOKING FOR IN ORDER TO GET

2020
01:21:36,161 --> 01:21:42,100
SOME OF THIS EXTRACTED INTO THE

2021
01:21:42,100 --> 01:21:44,836
MADE ORGANOIDS AND EXPLORE

2022
01:21:44,836 --> 01:21:45,504
FURTHER.

2023
01:21:45,504 --> 01:21:46,905
SO DO YOU HAVE CELL SURFACE

2024
01:21:46,905 --> 01:21:51,676
MARKERS FOR AT LEAST SOME OF

2025
01:21:51,676 --> 01:21:54,746
THOSE THAT ONE CAN SEPARATE?

2026
01:21:54,746 --> 01:21:58,350
>> WE'VE UPLOADED THEM
INTO

2027
01:21:58,350 --> 01:21:58,550
THE --

2028
01:21:58,550 --> 01:21:59,217
>> YES, I SEE.

2029
01:21:59,217 --> 01:21:59,684
I SEE.

2030
01:21:59,684 --> 01:22:05,690
AND WHEN YOU TALK ABOUT THE

2031
01:22:05,690 --> 01:22:09,761
CLONE -- THESE ARE SOMEHOW CELL

2032
01:22:09,761 --> 01:22:10,629
AUTONOMOUS, HOW DO YOU THINK

2033
01:22:10,629 --> 01:22:11,830
THAT THIS WORKS, PARTICULARLY

2034
01:22:11,830 --> 01:22:16,668
WHEN WE THINK THAT THESE ARE

2035
01:22:16,668 --> 01:22:22,541
EARLY PRECURSORS OF THE COPD

2036
01:22:22,541 --> 01:22:26,111
LESIONS THAT AS ANDREW SAYS,

2037
01:22:26,111 --> 01:22:28,547
IT'S BETTER THAT WE FOCUS ON THE

2038
01:22:28,547 --> 01:22:30,549
EARLY STAGES THAN THE LATE.

2039
01:22:30,549 --> 01:22:31,850
>> RIGHT, RIGHT, RIGHT.

2040
01:22:31,850 --> 01:22:34,920
WELL, YOU KNOW, ONE THING WE

2041
01:22:34,920 --> 01:22:40,792
HAVEN'T QUITE DONE IT FOR THAT,

2042
01:22:40,792 --> 01:22:43,962
BUT -- LOOKED AT ADAPTING THE

2043
01:22:43,962 --> 01:22:47,933
SAME CLONING TECHNOLOGY FOR BOTH

2044
01:22:47,933 --> 01:22:49,301
BOWEL AND PLEURAL EFFUSIONS TO

2045
01:22:49,301 --> 01:22:51,369
LOOK ACTUALLY AT THE CANCER

2046
01:22:51,369 --> 01:22:52,771
REALM, AND IT TURNS OUT,

2047
01:22:52,771 --> 01:22:56,575
COMPARED TO WHAT THEY USUALLY

2048
01:22:56,575 --> 01:22:58,410
DO, WHICH IS GET THESE THINGS

2049
01:22:58,410 --> 01:22:59,578
CENTRIFUGED TO THE CELLS AND TRY

2050
01:22:59,578 --> 01:23:03,214
TO GET A PATHOLOGICAL READOUT ON

2051
01:23:03,214 --> 01:23:05,083
THEM, SIMPLY CLONING THE CELLS

2052
01:23:05,083 --> 01:23:09,387
WAS A MUCH BETTER APPROACH TO  

2053
01:23:09,387 --> 01:23:10,322
IT.

2054
01:23:10,322 --> 01:23:14,192
SO IT MAY BE THAT WE CAN TAKE --

2055
01:23:14,192 --> 01:23:15,827
AND USE THESE TYPES OF CELLS AS

2056
01:23:15,827 --> 01:23:17,662
A READOUT PERHAPS FOR EARLY

2057
01:23:17,662 --> 01:23:18,597
DISEASE.

2058
01:23:18,597 --> 01:23:20,298
AND I THINK WE SHOULD PROBABLY

2059
01:23:20,298 --> 01:23:24,336
PUT OUR HEADS TOGETHER ON THIS

2060
01:23:24,336 --> 01:23:26,004
AND FIGURE OUT HOW TO DO THIS

2061
01:23:26,004 --> 01:23:27,372
SYSTEMATICALLY.

2062
01:23:27,372 --> 01:23:29,274
BUT IT WORKED FOR THE CANCER.

2063
01:23:29,274 --> 01:23:31,242
THERE'S A WHOLE THING ON LUNG

2064
01:23:31,242 --> 01:23:35,113
CANCER THAT'S GOING ON, BUT WE

2065
01:23:35,113 --> 01:23:36,448
SHOULD -- SOMEHOW THIS GROUP

2066
01:23:36,448 --> 01:23:39,451
SHOULD FIGURE OUT HOW TO GET

2067
01:23:39,451 --> 01:23:42,921
THIS DONE IN A SYSTEMATIC WAY TO

2068
01:23:42,921 --> 01:23:46,358
SAY WHAT IS THE FREAK SEE OF

2069
01:23:46,358 --> 01:23:52,931
NFREQUENCY OFNORMAL CLONES VERSC

2070
01:23:52,931 --> 01:23:58,236
CLONES DERIVED FROM -- AS YOU

2071
01:23:58,236 --> 01:23:59,504
KNOW YOU'RE EXPLORING A LOT OF

2072
01:23:59,504 --> 01:24:00,805
REGIONS OF THE LUNG WITHOUT

2073
01:24:00,805 --> 01:24:03,274
HAVING TO -- WELL, I GUESS --

2074
01:24:03,274 --> 01:24:05,844
>> THANK YOU.

2075
01:24:05,844 --> 01:24:07,479
>> COULD I HAVE A
FOLLOW-UP

2076
01:24:07,479 --> 01:24:09,614
QUESTION ALONG THOSE LINES?

2077
01:24:09,614 --> 01:24:13,284
SO I'M TRAYING TO UNDERSTAND,

2078
01:24:13,284 --> 01:24:15,520
WHAT IS -- WHAT STEAMS UNIQUE

2079
01:24:15,520 --> 01:24:17,288
ABOUT THESE CELLS, AT LEAST ONE

2080
01:24:17,288 --> 01:24:19,658
THING, IS THAT YOU THINK THEY'RE

2081
01:24:19,658 --> 01:24:20,125
EPIGENETICALLY FIXED.

2082
01:24:20,125 --> 01:24:20,659
>> YES.

2083
01:24:20,659 --> 01:24:22,594
>> AND THAT'S A LITTLE
UNUSUAL

2084
01:24:22,594 --> 01:24:26,164
FOR STEM CELLS TO BEGIN WITH,

2085
01:24:26,164 --> 01:24:28,333
BUT I GUESS I'M WONDERING

2086
01:24:28,333 --> 01:24:32,237
WHETHER THAT SUCCESSION IMPLIES

2087
01:24:32,237 --> 01:24:33,571
SOME -- IT REALLY REFLECTS A

2088
01:24:33,571 --> 01:24:35,940
MEMORY FROM SOME FORMER STATE

2089
01:24:35,940 --> 01:24:37,242
THAT NOW --

2090
01:24:37,242 --> 01:24:41,312
>> ONE THING THAT WA IS
ABOUT TO

2091
01:24:41,312 --> 01:24:43,181
PUBLISH ON IS THE EPIGENETIC

2092
01:24:43,181 --> 01:24:44,816
PROFILES OF THE ENTIRE GI TRACT,

2093
01:24:44,816 --> 01:24:48,553
FROM STOMACH TO RECTUM, AND EACH

2094
01:24:48,553 --> 01:24:58,997
OF THOSE, CLONOGS ENIC AND

2095
01:24:59,297 --> 01:25:01,866
ABSOLUTELY FIXED -- I HAD THE

2096
01:25:01,866 --> 01:25:03,401
FEELING THAT THESE CELLS -- BUT

2097
01:25:03,401 --> 01:25:05,236
WE HAVEN'T DONE THE EXPERIMENTS

2098
01:25:05,236 --> 01:25:06,438
TO SHOW THIS.

2099
01:25:06,438 --> 01:25:08,673
BUT I HAVE THE FEELING THAT'S

2100
01:25:08,673 --> 01:25:10,542
CELLS ARE PART OF THIS INNATE

2101
01:25:10,542 --> 01:25:11,276
IMMUNE SYSTEM.

2102
01:25:11,276 --> 01:25:13,111
THEY COORDINATE INFLAMMATION,

2103
01:25:13,111 --> 01:25:15,780
THEY COORDINATE FIBROSIS TO WALL

2104
01:25:15,780 --> 01:25:21,553
OFF PATHOGENS, THEY GUM THEM UP

2105
01:25:21,553 --> 01:25:23,221
WITH -- I THINK THAT'S THEIR

2106
01:25:23,221 --> 01:25:23,655
NORMAL ROLE.

2107
01:25:23,655 --> 01:25:24,956
AND I THINK THEY'VE BEEN FIXED

2108
01:25:24,956 --> 01:25:26,357
TO BE THAT WAY, BUT WE'RE SEEING

2109
01:25:26,357 --> 01:25:28,526
THEM IN EVERY ORGAN THAT WE LOOK

2110
01:25:28,526 --> 01:25:29,360
AT.

2111
01:25:29,360 --> 01:25:35,066
FOR INSTANCE, FOR TERMINAL ILEUM

2112
01:25:35,066 --> 01:25:38,436
AND PEAD TR PEDIATRIC CROHN'S.

2113
01:25:38,436 --> 01:25:39,571
THEY'RE THERE AHEAD OF TIME

2114
01:25:39,571 --> 01:25:39,871
BUT --

2115
01:25:39,871 --> 01:25:41,439
>> DO YOU HAVE A WAY TO
IDENTIFY

2116
01:25:41,439 --> 01:25:45,643
THOSE IN SPACE, IN SITU, WITHOUT

2117
01:25:45,643 --> 01:25:48,213
PULLING THEM OUT AND SUBCLONING

2118
01:25:48,213 --> 01:25:48,413
THEM?

2119
01:25:48,413 --> 01:25:51,382
>> HERE'S THE THING, IT'S

2120
01:25:51,382 --> 01:25:51,950
COMPLICATED.

2121
01:25:51,950 --> 01:25:53,952
THESE CELLS REPRESENT ONE OUT OF

2122
01:25:53,952 --> 01:25:56,654
A THOUSAND OF ALL EPITHELIAL

2123
01:25:56,654 --> 01:25:57,922
CELLS ARE CLONOGENIC.

2124
01:25:57,922 --> 01:26:00,325
THAT NUMBER IS PRETTY FIXED

2125
01:26:00,325 --> 01:26:03,328
ACROSS TISSUES, WHETHER IT'S GI

2126
01:26:03,328 --> 01:26:04,729
TRACT, LUNG OR ANYTHING ELSE.

2127
01:26:04,729 --> 01:26:07,999
AND THEN, OF COURSE, WHEN YOU DO

2128
01:26:07,999 --> 01:26:10,401
A SINGLE CELL RNA SEQ FOR THE

2129
01:26:10,401 --> 01:26:12,570
WHOLE LUNG, IT MOSTLY IMMUNE AND

2130
01:26:12,570 --> 01:26:14,439
OTHER CELLS, SO YOU'RE LOOKING

2131
01:26:14,439 --> 01:26:16,307
AT A MAYBE ONE OUT OF 10,000

2132
01:26:16,307 --> 01:26:17,742
CELLS, IS THIS BASALOID

2133
01:26:17,742 --> 01:26:19,110
COMPONENT.

2134
01:26:19,110 --> 01:26:20,912
WHEREAS WE'RE AMPLIFYING THAT

2135
01:26:20,912 --> 01:26:22,647
REGION TO A GREAT -- THAT'S ALL

2136
01:26:22,647 --> 01:26:24,415
WE'RE CLONING.

2137
01:26:24,415 --> 01:26:28,453
SO I THINK THAT'S THE -- IT SORT

2138
01:26:28,453 --> 01:26:33,892
OF A -- MYOPIC IN THE SENSE YOU

2139
01:26:33,892 --> 01:26:35,059
DON'T HAVE ANY OTHER INFORMATION

2140
01:26:35,059 --> 01:26:39,697
THERE, BUT YOU DO HAVE THOSE

2141
01:26:39,697 --> 01:26:40,999
CLONOGENIC CELLS AND YOU'RE

2142
01:26:40,999 --> 01:26:41,866
AMPLIFYING THEM.

2143
01:26:41,866 --> 01:26:42,467
THEY BEHAVE VERY WELL.

2144
01:26:42,467 --> 01:26:44,302
I MEAN, THEY'RE IMMORTAL.

2145
01:26:44,302 --> 01:26:46,771
YOU CAN JUST GROW THEM FOREVER

2146
01:26:46,771 --> 01:26:49,707
AND AT THE END OF -- WE'VE DONE

2147
01:26:49,707 --> 01:26:51,109
SOME WE'VE GROWN CONTINUOUSLY IN

2148
01:26:51,109 --> 01:26:52,944
THE LAB FOR A YEAR, AND WHEN YOU

2149
01:26:52,944 --> 01:26:54,445
ASK THEM TO DO SOMETHING, THEY

2150
01:26:54,445 --> 01:26:55,713
ALWAYS DO THE RIGHT THING.

2151
01:26:55,713 --> 01:26:58,850
THEY DON'T FORGET.

2152
01:26:58,850 --> 01:27:00,418
WA IS DOING A LOT OF -- SHE'S

2153
01:27:00,418 --> 01:27:02,353
DONE ALL THE EPIGENETICS ON THE

2154
01:27:02,353 --> 01:27:03,788
GI TRACT BUT SHE'S NOW DOING

2155
01:27:03,788 --> 01:27:04,722
THAT WITH THE LUNG.

2156
01:27:04,722 --> 01:27:07,392
SO WE'LL BE ABLE TO SORT OF

2157
01:27:07,392 --> 01:27:08,359
FURTHER NAIL DOWN --

2158
01:27:08,359 --> 01:27:09,727
>> IT STILL SEEMS LIKE
IT'S A

2159
01:27:09,727 --> 01:27:11,029
CHALLENGE TO FIGURE OUT WHERE

2160
01:27:11,029 --> 01:27:13,364
THEY -- EXACTLY WHERE THEY ARE

2161
01:27:13,364 --> 01:27:15,366
IN SITU BECAUSE OF THE RARITY.

2162
01:27:15,366 --> 01:27:16,668
IS THAT FAIR?

2163
01:27:16,668 --> 01:27:18,002
>> THAT'S FAIR, BECAUSE
THEY'RE

2164
01:27:18,002 --> 01:27:24,409
RARE CELLS OF RARE CELLS.

2165
01:27:24,409 --> 01:27:26,978
BUT FROM FETAL TISSUE, FOR

2166
01:27:26,978 --> 01:27:28,112
INSTANCE, THEY'RE A LITTLE BIT

2167
01:27:28,112 --> 01:27:32,050
MORE COMMON THAN THEY ARE

2168
01:27:32,050 --> 01:27:33,985
FROM -- IN NORMAL LUNG.

2169
01:27:33,985 --> 01:27:35,820
IN FETAL TISSUE, THEY'RE

2170
01:27:35,820 --> 01:27:37,155
ACTUALLY, YOU KNOW, MAYBE

2171
01:27:37,155 --> 01:27:42,493
UPWARDS OF 10% AT 22 WEEKS.

2172
01:27:42,493 --> 01:27:44,128
>> IT WILL BE REALLY
INTERESTING

2173
01:27:44,128 --> 01:27:45,897
TO FIGURE OUT HOW IT IS THAT

2174
01:27:45,897 --> 01:27:46,931
THEY'RE EPIGENETICALLY FIXED.

2175
01:27:46,931 --> 01:27:48,299
>> YES, YES.

2176
01:27:48,299 --> 01:27:56,241
WELL, I KNOW SHE'S GOTTEN --

2177
01:27:56,241 --> 01:27:59,978
GOING -- ON THAT RIGHT NOW, IT

2178
01:27:59,978 --> 01:28:01,312
WOULD BE REALLY FUN TO SEE, I

2179
01:28:01,312 --> 01:28:01,846
AGREE WITH YOU.

2180
01:28:01,846 --> 01:28:04,849
>> SO I WANTED TO ASK AN
DRAW,

2181
01:28:04,849 --> 01:28:06,050
THEORETICALLY BASED ON SOME OF

2182
01:28:06,050 --> 01:28:07,952
THE CLINICAL TRIALS THAT DAN HAS

2183
01:28:07,952 --> 01:28:09,621
TALKED ABOUT AND SOME OF THE

2184
01:28:09,621 --> 01:28:10,288
BACKGROUND INFORMATION FROM

2185
01:28:10,288 --> 01:28:13,758
THAT, HOW WOULD YOU SEE

2186
01:28:13,758 --> 01:28:15,426
INTEGRATING IPSC AS A

2187
01:28:15,426 --> 01:28:16,661
THERAPEUTIC GIVEN HOW THE

2188
01:28:16,661 --> 01:28:18,263
CLINICAL TRIALS HAVE GONE WITH

2189
01:28:18,263 --> 01:28:23,768
CELL THERAPIES?

2190
01:28:23,768 --> 01:28:26,037
>> WELL, I GUESS I CAN
IMAGINE

2191
01:28:26,037 --> 01:28:26,738
SOME POSSIBILITIES.

2192
01:28:26,738 --> 01:28:27,839
SO FIRST OF ALL, I GUESS I

2193
01:28:27,839 --> 01:28:30,808
SHOULD JUST MENTION SPECIFICALLY

2194
01:28:30,808 --> 01:28:32,977
THAT IN TERMS OF TRYING TO

2195
01:28:32,977 --> 01:28:34,045
ENVISION IPSC CELLS AS A

2196
01:28:34,045 --> 01:28:34,879
THERAPY, NOT IN THE CONTEXT OF

2197
01:28:34,879 --> 01:28:36,381
WHAT DAN TALKED ABOUT, BUT I

2198
01:28:36,381 --> 01:28:37,982
THINK WHAT DARRELL'S GROUP HAS

2199
01:28:37,982 --> 01:28:41,686
SHOWN IN HIS RECENT PUBLICATIONS

2200
01:28:41,686 --> 01:28:44,555
IS THE POTENTIAL FOR IPSC

2201
01:28:44,555 --> 01:28:45,924
DERIVED EPITHELIAL CELLS TO

2202
01:28:45,924 --> 01:28:49,427
ENGRAFT EITHER IN THE TRACHEA OR

2203
01:28:49,427 --> 01:28:51,195
THE DISTAL LUNG SO THAT'S BEING

2204
01:28:51,195 --> 01:28:52,063
PERFORMED SPECIFICALLY WITH AN

2205
01:28:52,063 --> 01:28:54,732
EYE TOWARDS A FUTURE CELL-BASED

2206
01:28:54,732 --> 01:28:56,067
THERAPY FOR EPITHELIAL CELLS AND

2207
01:28:56,067 --> 01:28:57,602
I WOULD ENVISION HE WOULD TRY TO

2208
01:28:57,602 --> 01:28:58,703
APPLY SIMILAR TECHNIQUES TO

2209
01:28:58,703 --> 01:29:00,171
OTHER CELL TYPES AND I CERTAINLY

2210
01:29:00,171 --> 01:29:01,272
CAN IMAGINE IF ONE CAN

2211
01:29:01,272 --> 01:29:02,106
GENERATE -- I'M NOT SURE IF

2212
01:29:02,106 --> 01:29:04,409
THERE'S A NEED TO DO THAT SO

2213
01:29:04,409 --> 01:29:06,077
MUCH FOR MESENCHYMAL CELLS BUT I

2214
01:29:06,077 --> 01:29:07,845
CAN IMAGINE DEVELOPING

2215
01:29:07,845 --> 01:29:09,547
MESENCHYMAL CELLS SIMILAR TO THE

2216
01:29:09,547 --> 01:29:10,548
PROPERTIES THAT DAN HAS TALKED

2217
01:29:10,548 --> 01:29:12,116
ABOUT, ALTHOUGH WE CAN GET THOSE

2218
01:29:12,116 --> 01:29:13,751
PRIMARY CELLS RIGHT NOW, SO I

2219
01:29:13,751 --> 01:29:16,587
GUESS THE RATIONALE FOR THE IPSC

2220
01:29:16,587 --> 01:29:18,556
DERIVED VERSION MAYBE IS NOT

2221
01:29:18,556 --> 01:29:19,557
QUITE AS CLEAR TO ME.

2222
01:29:19,557 --> 01:29:21,225
BUT FOR EPITHELIAL CELLS, DAN,

2223
01:29:21,225 --> 01:29:22,527
YOU LOOK LIKE YOU HAVE SOMETHING

2224
01:29:22,527 --> 01:29:23,594
TO ADD TO THAT.

2225
01:29:23,594 --> 01:29:26,264
>> WELL, SO JUST TO GO OFF
ON

2226
01:29:26,264 --> 01:29:30,969
ONE POINT, ANDREW, THERE IS A

2227
01:29:30,969 --> 01:29:34,605
PUSH TOWARDS UTILIZING IPSC

2228
01:29:34,605 --> 01:29:36,975
DERIVED MSCs FOR THERAPEUTICS.

2229
01:29:36,975 --> 01:29:42,447
FOR THE PREVIOUS QUESTION,

2230
01:29:42,447 --> 01:29:43,114
CONTINUE TO HIGHLIGHT SOME OF

2231
01:29:43,114 --> 01:29:44,248
THE DIFFICULTIES IN THE FIELD OF

2232
01:29:44,248 --> 01:29:45,149
HETEROGENEITY OF THE PRODUCTS

2233
01:29:45,149 --> 01:29:46,417
THAT CAN BE ISOLATED FROM THE

2234
01:29:46,417 --> 01:29:49,520
DIFFERENT SOURCES, AND SO IPSC

2235
01:29:49,520 --> 01:29:53,191
DERIVED MSC HAS ALL THE

2236
01:29:53,191 --> 01:29:54,592
ATTRIBUTES OF BEING A UNIFORM

2237
01:29:54,592 --> 01:29:55,960
POPULATION, DOUBLING TIMES,

2238
01:29:55,960 --> 01:30:01,899
EXPANSION POTENTIAL, LACK OF

2239
01:30:01,899 --> 01:30:03,134
TERATOGEN IS IT, ET CETERA, SO

2240
01:30:03,134 --> 01:30:04,369
IT'S A REAL POSSIBILITY.

2241
01:30:04,369 --> 01:30:06,237
BUT THE GOAL -- TWO PARALLEL

2242
01:30:06,237 --> 01:30:08,239
GOALS AS YOU ARTICULATE, ONE IS

2243
01:30:08,239 --> 01:30:11,175
STRUCTURAL REPAIR, ONE IS

2244
01:30:11,175 --> 01:30:15,246
FUNCTIONAL MODULATION FOR AN

2245
01:30:15,246 --> 01:30:17,115
APPROACH FOR AN INFLAMMATORY OR

2246
01:30:17,115 --> 01:30:19,751
AN AUTOIMMUNE CONDITION IN WHICH

2247
01:30:19,751 --> 01:30:20,418
STRUCTURAL REPAIR ISN'T THE

2248
01:30:20,418 --> 01:30:21,719
PRIMARY GOAL.

2249
01:30:21,719 --> 01:30:24,389
SO APPLES AND ORANGES TO SOME

2250
01:30:24,389 --> 01:30:24,622
DEGREE.

2251
01:30:24,622 --> 01:30:29,494
>> NICELY STATED.

2252
01:30:29,494 --> 01:30:34,465
>> JOHANNS.

2253
01:30:34,465 --> 01:30:34,766
 JOHANNES.

2254
01:30:34,766 --> 01:30:35,867
>> THANK YOU FOR THE NICE

2255
01:30:35,867 --> 01:30:36,467
PRESENTATIONS.

2256
01:30:36,467 --> 01:30:40,438
MY QUESTIONS ARE FOR FRANK.

2257
01:30:40,438 --> 01:30:42,440
ALONG THOSE LINES, THAT WAS IN

2258
01:30:42,440 --> 01:30:44,575
DISCUSSION ALREADY.

2259
01:30:44,575 --> 01:30:46,044
SO WHEN THE CLONES ARE TAKEN,

2260
01:30:46,044 --> 01:30:48,679
SAY, FOR EXAMPLE, FROM THE SAME

2261
01:30:48,679 --> 01:30:50,848
LUNG, DIFFERENT REGIONS, DISEASE

2262
01:30:50,848 --> 01:30:52,750
REGION, NORMAL REGION OR LARGE

2263
01:30:52,750 --> 01:30:56,654
AIRWAY, SMALL AIRWAY, DO YOU SEE

2264
01:30:56,654 --> 01:30:58,423
THE CLUSTER DIFFERENCES WITHIN

2265
01:30:58,423 --> 01:31:00,558
THE SAME LUNG OR IS IT PRAIMLY

2266
01:31:00,558 --> 01:31:04,429
DRIVEN WITHIN ONE CLUSTER FOR

2267
01:31:04,429 --> 01:31:05,363
THOSE CLONES THAT HAVE COME FROM

2268
01:31:05,363 --> 01:31:06,330
THE LUNG?

2269
01:31:06,330 --> 01:31:09,667
>> WE HAVEN'T DONE THIS

2270
01:31:09,667 --> 01:31:10,701
RELIGIOUSLY.

2271
01:31:10,701 --> 01:31:14,539
AND YET WE'RE GETTING -- SOME

2272
01:31:14,539 --> 01:31:16,674
AREAS ARE EASY TO PICK OUT, THE

2273
01:31:16,674 --> 01:31:18,109
HONEYCOMB REGIONS ARE EASY TO

2274
01:31:18,109 --> 01:31:19,510
PICK OUT AND THE SCHWARTZ LAB

2275
01:31:19,510 --> 01:31:21,112
HAS DONE THAT.

2276
01:31:21,112 --> 01:31:23,114
AND SENT US THOSE TISSUES.

2277
01:31:23,114 --> 01:31:27,318
SO THOSE ARE THINGS THAT YOU CAN

2278
01:31:27,318 --> 01:31:30,688
RECOGNIZE.

2279
01:31:30,688 --> 01:31:32,056
IF WE GET THESE LUNGS AND WE'RE

2280
01:31:32,056 --> 01:31:33,724
SORT OF OVERWHELMED, WE'RE

2281
01:31:33,724 --> 01:31:35,059
TRYING TO FIND THE UPPER

2282
01:31:35,059 --> 01:31:36,661
REGIONS, FOR INSTANCE, IN A COPD

2283
01:31:36,661 --> 01:31:42,366
LUNG THAT ARE DAMAGED, AND --

2284
01:31:42,366 --> 01:31:43,768
BUT WE SHOULD BE DOING IT AS YOU

2285
01:31:43,768 --> 01:31:45,670
SAY IN A MORE SYSTEMATIC WAY.

2286
01:31:45,670 --> 01:31:46,871
WE JUST DON'T HAVE THE BANDWIDTH

2287
01:31:46,871 --> 01:31:48,639
FOR DOING IT, BUT IT WOULD BE

2288
01:31:48,639 --> 01:31:49,841
VERY INTERESTING TO SAY THIS

2289
01:31:49,841 --> 01:31:53,978
LOOKS NOMINALLY NORMAL, WHAT

2290
01:31:53,978 --> 01:31:55,413
DOES THE PROFILE LOOK LIKE.

2291
01:31:55,413 --> 01:31:59,817
AND CAN YOU SEE -- IT GETS NA

2292
01:31:59,817 --> 01:32:00,785
THESE OTHER QUESTIONS ABOUT

2293
01:32:00,785 --> 01:32:01,586
SPREADING THAT PEOPLE WERE

2294
01:32:01,586 --> 01:32:05,356
TALKING ABOUT IN YESTERDAY'S

2295
01:32:05,356 --> 01:32:05,656
SESSION.

2296
01:32:05,656 --> 01:32:06,424
>> THAT'S RIGHT.

2297
01:32:06,424 --> 01:32:07,758
ALONG THE LINES THAT WE HEARD

2298
01:32:07,758 --> 01:32:11,229
YESTERDAY AFTERNOON AS WELL,

2299
01:32:11,229 --> 01:32:12,597
EVEN THE LARGE AIRWAYS SEEM TO

2300
01:32:12,597 --> 01:32:15,133
BE KIND OF NOT LOOKING VERY GOOD

2301
01:32:15,133 --> 01:32:22,306
FOR PEOPLE PRE-COPD.

2302
01:32:22,306 --> 01:32:23,908
SO THERE SEEMS TO BE A MAJOR

2303
01:32:23,908 --> 01:32:25,042
ISSUE WITHIN THE ENTIRE LUNG

2304
01:32:25,042 --> 01:32:26,711
WHEN IT COMES TO THESE KIND OF

2305
01:32:26,711 --> 01:32:26,944
ISSUES.

2306
01:32:26,944 --> 01:32:28,613
>> YOU KNOW, YOU'RE
ABSOLUTELY

2307
01:32:28,613 --> 01:32:28,813
RIGHT.

2308
01:32:28,813 --> 01:32:29,780
IN FACT, ALL THE STUFF WE'VE

2309
01:32:29,780 --> 01:32:33,184
DONE WITH ASTHMA HAS BEEN

2310
01:32:33,184 --> 01:32:36,120
LARGELY WITH BRUSHINGS AND

2311
01:32:36,120 --> 01:32:36,854
BRONCHOSCOPY.

2312
01:32:36,854 --> 01:32:39,056
SO WE'RE GETTING JUST THE LARGE

2313
01:32:39,056 --> 01:32:39,323
AIRWAY.

2314
01:32:39,323 --> 01:32:42,059
SO IT'S A WHOLE AREA THAT WE

2315
01:32:42,059 --> 01:32:43,761
REALLY HAVEN'T TRIED TO MATCH UP

2316
01:32:43,761 --> 01:32:45,530
WITH WHAT'S GOING ON IN THE

2317
01:32:45,530 --> 01:32:46,330
LUNG, PER SE.

2318
01:32:46,330 --> 01:32:46,731
>> GREAT.

2319
01:32:46,731 --> 01:32:47,398
THANK YOU.

2320
01:32:47,398 --> 01:32:55,173
>> GREAT, THANK YOU.

2321
01:32:55,173 --> 01:32:56,941
>> OKAY, WE STILL HAVE
SOME

2322
01:32:56,941 --> 01:33:03,881
HANDS UP IN THE CHAT.

2323
01:33:03,881 --> 01:33:09,053
>

2324
01:33:09,053 --> 01:33:12,690
>> SEUNGHYE?

2325
01:33:12,690 --> 01:33:16,861
>> YOU PRESENTED NICE DATA
TODAY

2326
01:33:16,861 --> 01:33:19,730
ABOUT THE ZINC METABOLISM

2327
01:33:19,730 --> 01:33:23,467
RELATED TO THE NAD DEPLETION,

2328
01:33:23,467 --> 01:33:25,469
AND THAT ACTUALLY SOMEWHAT WAS

2329
01:33:25,469 --> 01:33:29,941
KIND OF CONSISTENT WITH I FIND

2330
01:33:29,941 --> 01:33:31,709
YESTERDAY, THAT THE LACK OF ANY

2331
01:33:31,709 --> 01:33:34,478
REGENERATION TRIGGERS PATHOLOGIC

2332
01:33:34,478 --> 01:33:36,414
ISR TO CHANGE THE STEM CELL

2333
01:33:36,414 --> 01:33:36,781
FATE.

2334
01:33:36,781 --> 01:33:38,416
SO I'M WONDERING IF YOU HAVE

2335
01:33:38,416 --> 01:33:43,221
LOOKED AT THE ISR ACTIVATION IN

2336
01:33:43,221 --> 01:33:48,259
YOUR -- -- TRY THE -- INHIBITOR

2337
01:33:48,259 --> 01:33:49,427
IN YOUR MICE.

2338
01:33:49,427 --> 01:33:54,031
>> RIGHT.

2339
01:33:54,031 --> 01:34:01,305
WELL, SO OUR STUDY, WE -- IF WE

2340
01:34:01,305 --> 01:34:09,614
LOOK INTO -- -- CELLS AND WE DO

2341
01:34:09,614 --> 01:34:19,423
SEE SOME OF THE STRESS RESPON 

2342
01:34:19,423 --> 01:34:20,524
RESPONSE, -- OXIDATIVE STRESS.

2343
01:34:20,524 --> 01:34:26,297
ESPECIALLY IF WE LOOK INTO --

2344
01:34:26,297 --> 01:34:27,398
POSITIVE AND NEGATIVE CELLS SO

2345
01:34:27,398 --> 01:34:33,738
DEFINITELY WE SEE -- REACTIVE

2346
01:34:33,738 --> 01:34:37,041
OXYGEN RELATED RESPONSE AND THE

2347
01:34:37,041 --> 01:34:39,777
MITOCHONDRIA DYSFUNCTION AND WE

2348
01:34:39,777 --> 01:34:45,483
HAVE NOT TRIED TO USE --

2349
01:34:45,483 --> 01:34:55,993
COMPOUND AND WE -- SO -- M --

2350
01:35:02,633 --> 01:35:06,704
NPT LOSS AND WHAT HAPPENED, SO

2351
01:35:06,704 --> 01:35:09,006
WHAT WE'RE THINKING IS THAT

2352
01:35:09,006 --> 01:35:11,742
WHERE POSSIBLE, YOUR SYSTEM

2353
01:35:11,742 --> 01:35:13,911
IS -- VERY ACUTE SYSTEM IF YOU

2354
01:35:13,911 --> 01:35:18,149
HAVE WIRING -- AND THAT VERY

2355
01:35:18,149 --> 01:35:22,520
POSSIBLE WILL -- ISR RESPONSE

2356
01:35:22,520 --> 01:35:26,791
THAT YOU HAVE -- SUDDENLY YOU

2357
01:35:26,791 --> 01:35:32,430
HAVE A SIGNIFICANT DEMAND OF ATP

2358
01:35:32,430 --> 01:35:42,973
AND -- IN THE -- OF IPF, WE ARE

2359
01:35:43,607 --> 01:35:44,575
THINKING THERE WOULD BE SOME

2360
01:35:44,575 --> 01:35:47,211
SORT OF STRESSOR, LIKE SMOKING

2361
01:35:47,211 --> 01:35:52,717
OR SOME ENVIRONMENTAL STRESSORS.

2362
01:35:52,717 --> 01:35:54,385
THAT ACCUMULATES PROBABLY A

2363
01:35:54,385 --> 01:35:58,723
VERY, VERY LONG TIME, LET'S SAY

2364
01:35:58,723 --> 01:36:01,625
SOMETIMES 15 YEARS AND YOU HAVE

2365
01:36:01,625 --> 01:36:05,363
SIGNIFICANT REDUCED FOR SOME OF

2366
01:36:05,363 --> 01:36:13,037
THE -- EXCHANGE WHILE -- PK1.

2367
01:36:13,037 --> 01:36:17,408
I THINK THAT STRESS RESPONSE IS

2368
01:36:17,408 --> 01:36:21,612
PROBABLY A REAL WORRY LONG TERM

2369
01:36:21,612 --> 01:36:23,481
AND THE LOSS OF THAT GENE

2370
01:36:23,481 --> 01:36:24,749
EXPRESSION AND EVENTUALLY YOU

2371
01:36:24,749 --> 01:36:27,084
HAVE LOSS OF TYPE 2 CELL

2372
01:36:27,084 --> 01:36:31,288
FUNCTIONALITY.

2373
01:36:31,288 --> 01:36:34,892
THAT'S -- SO -- SO DEFINITELY

2374
01:36:34,892 --> 01:36:36,494
THAT SHARES SIGNIFICANT

2375
01:36:36,494 --> 01:36:40,431
SIMILARITY BETWEEN ACUTE FIRING

2376
01:36:40,431 --> 01:36:44,602
FUNCTION AND -- IPF -- OVER KIND

2377
01:36:44,602 --> 01:36:48,572
OF 15 EVEN LONGER YEARS.

2378
01:36:48,572 --> 01:36:51,942
>> BECAUSE I WAS
WONDERING, YOU

2379
01:36:51,942 --> 01:36:55,045
MENTIONED WITH THE -- NAMP

2380
01:36:55,045 --> 01:36:56,981
KNOCKOUT MICE YOU BASICALLY

2381
01:36:56,981 --> 01:36:58,182
INDUCED MITOCHONDRIAL

2382
01:36:58,182 --> 01:37:00,584
DYSFUNCTION AND DEFINITELY

2383
01:37:00,584 --> 01:37:06,690
PROBLEM INDUCED THE HIGH RATIO,

2384
01:37:06,690 --> 01:37:09,427
SO I WAS WOULD BE WONDERING IF

2385
01:37:09,427 --> 01:37:13,397
THE ISR IS A DOWNSTREAM PATHWAY,

2386
01:37:13,397 --> 01:37:16,100
BECAUSE IN OUR MODEL, WE

2387
01:37:16,100 --> 01:37:18,369
ACTUALLY ADMINISTERED NMN WHICH

2388
01:37:18,369 --> 01:37:21,238
IS A PRECURSOR OF NAD AND WE

2389
01:37:21,238 --> 01:37:23,240
WERE ABLE TO RESCUE THE TOTALITY

2390
01:37:23,240 --> 01:37:27,978
AND THE MUSCLE WAS -- SO THAT'S

2391
01:37:27,978 --> 01:37:34,518
JUST MY THOUGHT.

2392
01:37:34,518 --> 01:37:37,755
>> WE THINK THAT WHERE
POSSIBLE

2393
01:37:37,755 --> 01:37:42,259
IS -- THEY ARE VERY, VERY

2394
01:37:42,259 --> 01:37:46,697
POSSIBLE -- OXIDATIVE STRESS,

2395
01:37:46,697 --> 01:37:53,938
OTHER VERY RESPONSE AND --

2396
01:37:53,938 --> 01:37:54,171
RELATED.

2397
01:37:54,171 --> 01:37:57,408
WE HAVEN'T TRIED YOUR SYSTEM

2398
01:37:57,408 --> 01:38:02,913
USING INHIBITORS --

2399
01:38:02,913 --> 01:38:04,081
>> MAYBE WE SHOULD GET TO
THE

2400
01:38:04,081 --> 01:38:08,219
OTHER HANDS IN THE CHAT.

2401
01:38:08,219 --> 01:38:13,224
YOU'VE BEEN WAITING A WHILE.

2402
01:38:13,224 --> 01:38:16,193
IF NOT, JOSE.

2403
01:38:16,193 --> 01:38:20,097
>> I'LL JUMP IN QUICKLY.

2404
01:38:20,097 --> 01:38:22,833
SO I THINK REALLY FASCINATING

2405
01:38:22,833 --> 01:38:23,501
DISCUSSION HERE.

2406
01:38:23,501 --> 01:38:26,770
JUST TO KIND OF JUMP ON THIS

2407
01:38:26,770 --> 01:38:30,407
IDEA OF THE CLONAL POTENTIAL OF

2408
01:38:30,407 --> 01:38:33,644
SOME OF THE STEM CELLS AND HOW

2409
01:38:33,644 --> 01:38:37,248
FIXED SOME OF THE -- COMMITMENT

2410
01:38:37,248 --> 01:38:37,548
MIGHT BE.

2411
01:38:37,548 --> 01:38:39,183
I WAS VERY CURIOUS FROM YOUR

2412
01:38:39,183 --> 01:38:40,417
TALK, FRANK, YOU'VE MENTIONED A

2413
01:38:40,417 --> 01:38:43,087
FEW TIMES THAT THESE CELLS MIGHT

2414
01:38:43,087 --> 01:38:48,526
BE PART OF SOME KIND OF INNATE

2415
01:38:48,526 --> 01:38:50,594
IMMUNE SYSTEM AND AS AN

2416
01:38:50,594 --> 01:38:51,729
IMMUNOLOGIST, IT KIND OF PIQUED

2417
01:38:51,729 --> 01:38:53,230
MY INTEREST IN TERMS OF HOWL

2418
01:38:53,230 --> 01:38:59,470
YOU'RE THINKING ABOUT THIS,

2419
01:38:59,470 --> 01:39:01,472
AND -- THEY MAY HAVE SOME

2420
01:39:01,472 --> 01:39:03,240
BENEFIT DURING AN ACUTE VIRAL

2421
01:39:03,240 --> 01:39:05,843
INFECTION OR DURING SOME KIND OF

2422
01:39:05,843 --> 01:39:07,378
BACTERIAL INFECTION, BUT THEN IN

2423
01:39:07,378 --> 01:39:08,946
THESE CHRONIC DISEASES, THEY'RE

2424
01:39:08,946 --> 01:39:12,049
BECOMING KIND OF COOPTED AND

2425
01:39:12,049 --> 01:39:13,317
EXPANDING TOO FAR OR KIND OF HOW

2426
01:39:13,317 --> 01:39:15,219
ARE YOU THINKING ABOUT THE

2427
01:39:15,219 --> 01:39:16,787
IMMUNOLOGICAL ROLE AND THEN THE

2428
01:39:16,787 --> 01:39:19,823
FUTURE DOWNSTREAM EXPANSION AND

2429
01:39:19,823 --> 01:39:20,457
PATHOGENESIS?

2430
01:39:20,457 --> 01:39:29,033
>> I THINK THE BEST --
WHAT'S

2431
01:39:29,033 --> 01:39:30,034
DIFFERENT BETWEEN THOSE WE DRAW

2432
01:39:30,034 --> 01:39:31,235
FROM FETAL AND NORMAL LUNG

2433
01:39:31,235 --> 01:39:32,636
VERSUS THOSE THAT ARE DOMINANT

2434
01:39:32,636 --> 01:39:36,173
IN THESE DISEASE STATES.

2435
01:39:36,173 --> 01:39:37,775
AND I BRIEFLY MENTIONED IT BUT

2436
01:39:37,775 --> 01:39:44,214
THERE'S A STRONG INHIBITION OF

2437
01:39:44,214 --> 01:39:48,185
FAST LIGAND INDUCED CELL DEATH,

2438
01:39:48,185 --> 01:39:49,620
AND AS YOU KNOW FROM YOUR

2439
01:39:49,620 --> 01:39:50,721
IMMUNOLOGY, THAT SEEMS TO BE A

2440
01:39:50,721 --> 01:39:52,756
BIG PLAYER IN GETTING RID OF T

2441
01:39:52,756 --> 01:39:57,861
CELLS YOU NO LONGER NEED.

2442
01:39:57,861 --> 01:39:59,463
SO I THINK THERE'S A LOT OF

2443
01:39:59,463 --> 01:40:00,297
SIMILARITIES THERE.

2444
01:40:00,297 --> 01:40:01,098
AND THERE'S SOMETHING ELSE

2445
01:40:01,098 --> 01:40:01,932
THAT'S GOING ON.

2446
01:40:01,932 --> 01:40:04,435
I'M TRYING TO WRAP MY HEAD

2447
01:40:04,435 --> 01:40:07,004
AROUND MITOCHONDRIA, WHICH IS

2448
01:40:07,004 --> 01:40:09,807
NOT A TRIVIAL THING, AND A LOT

2449
01:40:09,807 --> 01:40:11,442
OF THE GREAT TALKS IN THIS

2450
01:40:11,442 --> 01:40:15,779
SESSION WERE IN THIS MEETING ON

2451
01:40:15,779 --> 01:40:16,513
MITOCHONDRIA, BUT THERE'S

2452
01:40:16,513 --> 01:40:17,982
SOMETHING GOING ON WITH THE MY

2453
01:40:17,982 --> 01:40:19,817
TMITOCHONDRIA AND I THINK THOSE

2454
01:40:19,817 --> 01:40:21,018
ARE SOMEHOW ALSO PROTECTING

2455
01:40:21,018 --> 01:40:24,088
THESE CELLS FROM WHAT THEY --

2456
01:40:24,088 --> 01:40:26,757
INSTEAD OF SPIKING, THEY'RE JUST

2457
01:40:26,757 --> 01:40:28,158
PLATEAUING.

2458
01:40:28,158 --> 01:40:30,194
AND I THINK THAT PROBABLY -- I

2459
01:40:30,194 --> 01:40:31,595
DON'T KNOW, BUT THE GOOD NEWS

2460
01:40:31,595 --> 01:40:35,165
IS, IT'S THE SAME ACROSS ALL OF

2461
01:40:35,165 --> 01:40:38,402
THEM, WHETHER YOU LOOK IN IPF OR

2462
01:40:38,402 --> 01:40:43,874
CF OR COPD, THEY ALL SEEM TO

2463
01:40:43,874 --> 01:40:45,242
BE -- THIS CELL DEATH IN A

2464
01:40:45,242 --> 01:40:45,876
SIMILAR MECHANISM.

2465
01:40:45,876 --> 01:40:47,645
SO WE'RE REALLY EXCITED ABOUT

2466
01:40:47,645 --> 01:40:48,312
THAT TOO.

2467
01:40:48,312 --> 01:40:51,348
>> I GUESS ANY IDEA FOR
THEIR

2468
01:40:51,348 --> 01:40:52,783
EXPANSION OR SELECTION IN MORE

2469
01:40:52,783 --> 01:40:55,552
ACUTE FORMS OF LUNG INJURY?

2470
01:40:55,552 --> 01:40:57,354
I KNOW YOU KIND OF BEGAN THE

2471
01:40:57,354 --> 01:40:59,156
TALK WITH SOME OF THE CLASSIC

2472
01:40:59,156 --> 01:41:03,360
STUDIES WITH THE H1N1 DAMAGE

2473
01:41:03,360 --> 01:41:03,861
MODEL AND MICE.

2474
01:41:03,861 --> 01:41:06,630
I KNOW IT'S ALWAYS HARD TO

2475
01:41:06,630 --> 01:41:08,098
CORRECT THE MOUSE AND THE HUMAN,

2476
01:41:08,098 --> 01:41:09,066
BUT ANY OPPORTUNITY TO STUDY

2477
01:41:09,066 --> 01:41:12,202
THIS IN MORE ACUTE VIRAL

2478
01:41:12,202 --> 01:41:12,469
SETTINGS?

2479
01:41:12,469 --> 01:41:14,138
>> NO, BUT I'M HEARING
SOME

2480
01:41:14,138 --> 01:41:18,308
COLLEAGUES FROM M.D. ANDERSON

2481
01:41:18,308 --> 01:41:20,144
ARE DOING SORT OF CHRONIC

2482
01:41:20,144 --> 01:41:22,479
CHALLENGES WITH BACTERIA NA

2483
01:41:22,479 --> 01:41:24,214
LUNG, AND WITH TIME, THEY CAN

2484
01:41:24,214 --> 01:41:27,017
GET A CHRONIC DISEASE OUT OF

2485
01:41:27,017 --> 01:41:31,155
THAT, SIMILAR TO THIS SEQUENCES

2486
01:41:31,155 --> 01:41:33,824
OFBLY OWE MY 16 THAT RADANTE AND

2487
01:41:33,824 --> 01:41:34,758
OTHERS ARE TALKING ABOUT WHERE

2488
01:41:34,758 --> 01:41:38,529
YOU CAN GET A CHRONIC AND

2489
01:41:38,529 --> 01:41:38,962
PROGRESSIVE IPF.

2490
01:41:38,962 --> 01:41:40,564
THOSE ARE VERY INTRIGUING.

2491
01:41:40,564 --> 01:41:42,199
WHATEVER THEY'VE DONE, WE WOULD

2492
01:41:42,199 --> 01:41:45,102
IMAGINE THEY'VE GONE OVER THAT

2493
01:41:45,102 --> 01:41:49,406
HURDLE TO GIVE YOU STABLE CELLS

2494
01:41:49,406 --> 01:41:51,375
THAT ARE DRIVING DISEASE.

2495
01:41:51,375 --> 01:41:51,942
>> THANK YOU.

2496
01:41:51,942 --> 01:41:52,576
>> GREAT.

2497
01:41:52,576 --> 01:41:55,713
THANK YOU.

2498
01:41:55,713 --> 01:41:58,615
>> SO TALKING ABOUT
PROGENITORS

2499
01:41:58,615 --> 01:42:00,484
AS INNATE IMMUNE CELLS FROM A

2500
01:42:00,484 --> 01:42:01,785
VASCULAR PERSPECTIVE, WE SEE

2501
01:42:01,785 --> 01:42:05,689
SIMILAR CHANGES IN ENDOTHELIAL

2502
01:42:05,689 --> 01:42:07,424
CELLS IN THE CAB LEARS AND IN

2503
01:42:07,424 --> 01:42:08,625
RESPONSE TO INFLAMMATORY

2504
01:42:08,625 --> 01:42:10,260
SIGNALING, THEY ACTUALLY CHANGED

2505
01:42:10,260 --> 01:42:12,229
THEIR FATTY ACID BINDING

2506
01:42:12,229 --> 01:42:13,397
REPERTOIRE SO THINKING ABOUT

2507
01:42:13,397 --> 01:42:19,336
THAT WITH METABOLISM AND -- TO

2508
01:42:19,336 --> 01:42:24,942
INTEGRATE THE METABOLISM AND --

2509
01:42:24,942 --> 01:42:27,544
HAVE YOU LOOKED AT FATTY ACID

2510
01:42:27,544 --> 01:42:28,345
BINDING PROTEINS AS WELL?

2511
01:42:28,345 --> 01:42:29,146
>> WHO, ME?

2512
01:42:29,146 --> 01:42:30,147
>> OH, FRANK.

2513
01:42:30,147 --> 01:42:33,484
SORRY, YEAH.

2514
01:42:33,484 --> 01:42:35,719
>> WE ARE LOOKING AT WHAT
OTHER

2515
01:42:35,719 --> 01:42:39,723
THINGS THESE DO BESIDES EITHER

2516
01:42:39,723 --> 01:42:43,127
PRODUCING LARGE AMOUNTS OF MUCIN

2517
01:42:43,127 --> 01:42:48,098
OR DRIVING MYOFIBROBLASTS OR THE

2518
01:42:48,098 --> 01:42:48,432
IMMUNE CELLS.

2519
01:42:48,432 --> 01:42:52,503
THERE IS A LOT OF SIGNALING TO

2520
01:42:52,503 --> 01:42:53,237
ENDOTHELIAL CELLS.

2521
01:42:53,237 --> 01:42:54,671
AND SO WE'RE ESPECIALLY

2522
01:42:54,671 --> 01:43:00,711
INTERESTED IN THAT, YOU KNOW,

2523
01:43:00,711 --> 01:43:03,247
FOR PULMONARY HYPERTENSION AND

2524
01:43:03,247 --> 01:43:05,749
SUCH THINGS.

2525
01:43:05,749 --> 01:43:08,051
SO THAT, WE HAVE -- THAT WOULD

2526
01:43:08,051 --> 01:43:10,854
BE A REALLY FUN THING TO THROW

2527
01:43:10,854 --> 01:43:11,054
INTO.

2528
01:43:11,054 --> 01:43:12,589
BUT I THINK SOME OF THIS

2529
01:43:12,589 --> 01:43:13,791
PULMONARY HYPERTENSION MAY BE

2530
01:43:13,791 --> 01:43:15,993
GOING ON IN ALL OF THESE

2531
01:43:15,993 --> 01:43:19,129
CONDITIONS, SO HOW THEY INTERACT

2532
01:43:19,129 --> 01:43:20,798
WITH ENDOTHELIAL CELLS WOULD BE

2533
01:43:20,798 --> 01:43:21,865
SOMETHING WE'RE VERY INTERESTED

2534
01:43:21,865 --> 01:43:25,969
IN.

2535
01:43:25,969 --> 01:43:28,138
>>  -- HAD THEIR HAND UP
FOR A

2536
01:43:28,138 --> 01:43:30,808
LONG, LONG TIME.

2537
01:43:30,808 --> 01:43:33,977
XINWANG?

2538
01:43:33,977 --> 01:43:35,479
>> I THINK THEY MIGHT HAVE

2539
01:43:35,479 --> 01:43:36,146
STEPPED AWAY.

2540
01:43:36,146 --> 01:43:37,247
I'VE BEEN TEXTING THEM IN THE

2541
01:43:37,247 --> 01:43:41,385
CHAT.

2542
01:43:41,385 --> 01:43:43,053
SO MAYBE TOWARD THE END OF THIS

2543
01:43:43,053 --> 01:43:44,988
SESSION AND DISCUSSION, WE COULD

2544
01:43:44,988 --> 01:43:50,160
DISCUSS ADDITIONAL AREAS FOR

2545
01:43:50,160 --> 01:43:52,896
INVESTIGATION AND CURRENT

2546
01:43:52,896 --> 01:43:56,033
CHALLENGES, FUTURE STUDIES.

2547
01:43:56,033 --> 01:43:58,001
>> CAN I ASK ONE MORE
QUESTION?

2548
01:43:58,001 --> 01:43:58,902
>> OF COURSE.

2549
01:43:58,902 --> 01:44:02,239
SORRY.

2550
01:44:02,239 --> 01:44:02,673
[LAUGHTER]

2551
01:44:02,673 --> 01:44:07,778
SO THIS IS FOR DR. MCKEON.

2552
01:44:07,778 --> 01:44:08,779
I KNOW YOU MENTIONED

2553
01:44:08,779 --> 01:44:10,380
SPECIFICALLY THAT YOU SEE SOME

2554
01:44:10,380 --> 01:44:13,650
EVIDENCE OF THE MITOCHONDRIAL

2555
01:44:13,650 --> 01:44:17,120
COMPLEX 1 ON THIS THING.

2556
01:44:17,120 --> 01:44:18,388
CAN YOU JUST SHARE A LITTLE BIT

2557
01:44:18,388 --> 01:44:22,226
MORE ON THE WHY YOU THINK THE

2558
01:44:22,226 --> 01:44:22,593
COMPLEX 1?

2559
01:44:22,593 --> 01:44:23,627
BECAUSE THE OTHER THING IS THAT

2560
01:44:23,627 --> 01:44:30,000
WHAT I'M REALIZING IS THAT EACH

2561
01:44:30,000 --> 01:44:31,668
MITOCHONDRIAL ETC COMPLEXES

2562
01:44:31,668 --> 01:44:33,370
MIGHT HAVE DIFFERENT ROLE AND

2563
01:44:33,370 --> 01:44:34,338
DIFFERENT FUNCTION BECAUSE WHEN

2564
01:44:34,338 --> 01:44:40,043
I USE THE -- I DO SEE ALL

2565
01:44:40,043 --> 01:44:40,677
DIFFERENT PHENOTYPE.

2566
01:44:40,677 --> 01:44:44,281
SO I'M JUST WONDERING WHAT'S

2567
01:44:44,281 --> 01:44:46,550
YOUR -- TO SHARE A LOT OF IT

2568
01:44:46,550 --> 01:44:47,251
MORE ABOUT THAT.

2569
01:44:47,251 --> 01:44:49,186
>> I WAS ABOUT TO CALL YOU
AFTER

2570
01:44:49,186 --> 01:44:53,357
THIS SESSION, BECAUSE -- SO I

2571
01:44:53,357 --> 01:44:55,659
MEAN, THE ONE GENE -- ONE OF THE

2572
01:44:55,659 --> 01:44:59,329
GENES THAT'S SIGNIFICANTLY

2573
01:44:59,329 --> 01:45:02,366
UPREGULATED, AND AMONGST THE TOP

2574
01:45:02,366 --> 01:45:04,434
FEW, ACROSS THESE PATHOGENIC

2575
01:45:04,434 --> 01:45:09,439
CELLS IS A GENE CALLED NDUFA4L2.

2576
01:45:09,439 --> 01:45:11,842
AND YOU KNOW, ALREADY ITS NAME

2577
01:45:11,842 --> 01:45:14,912
ALONE IS ENOUGH TO BE ANNOYING,

2578
01:45:14,912 --> 01:45:22,419
BUT -- AND IT'S PART OF THE HIF.

2579
01:45:22,419 --> 01:45:30,427
AND IT HAS EFFECTS, AS YOU KNOW,

2580
01:45:30,427 --> 01:45:31,161
MITOCHONDRIAL RESPIRATION.

2581
01:45:31,161 --> 01:45:34,131
I HATE MITOCHONDRIA AND I HAVE

2582
01:45:34,131 --> 01:45:35,732
TO LEARN TO LOVE THEM AND THE

2583
01:45:35,732 --> 01:45:37,634
NOTION THAT YOU'VE GOT TO -- YOU

2584
01:45:37,634 --> 01:45:41,371
HAVE ALL THESE BEAUTIFUL SLIDE

2585
01:45:41,371 --> 01:45:43,774
AND -- YOU KNOW.

2586
01:45:43,774 --> 01:45:45,976
IT WOULD BE EMBARRASSING TO TALK

2587
01:45:45,976 --> 01:45:47,277
TO YOU BUT I WOULD LIKE TO SPEND

2588
01:45:47,277 --> 01:45:48,845
A LITTLE BIT OF TIME TO TRY TO

2589
01:45:48,845 --> 01:45:50,414
FIGURE OUT WHAT THAT GENE IS

2590
01:45:50,414 --> 01:45:51,248
DOING.

2591
01:45:51,248 --> 01:45:59,122
BUT IT'S VERY UPREGULATED, AND

2592
01:45:59,122 --> 01:46:00,390
IT'S -- OUR SUSPICION IS IT'S

2593
01:46:00,390 --> 01:46:01,491
PLAYING SOME ROLE IN THERE.

2594
01:46:01,491 --> 01:46:03,260
WE DON'T KNOW IF IT'S SHUTTING

2595
01:46:03,260 --> 01:46:07,097
DOWN RESPIRATION, IF IT'S --

2596
01:46:07,097 --> 01:46:07,798
MITOCHONDRIAL RESPIRATION AND

2597
01:46:07,798 --> 01:46:09,399
JUST EVERYTHING IS RUNNING ON

2598
01:46:09,399 --> 01:46:11,234
GLYCOLYSIS OR IF IT'S MORE

2599
01:46:11,234 --> 01:46:12,369
SOPHISTICATED THAN THAT AND

2600
01:46:12,369 --> 01:46:18,742
HAVING SOME ROLE IN OX PHOS FREA

2601
01:46:18,742 --> 01:46:19,376
RADICAL, WE DON'T KNOW.

2602
01:46:19,376 --> 01:46:21,578
>> WELL, HAPPY TO CHAT
AFTER

2603
01:46:21,578 --> 01:46:23,947
THIS MEETING.

2604
01:46:23,947 --> 01:46:25,749
>> IT'S A LITTLE BIT MORE

2605
01:46:25,749 --> 01:46:30,787
EMBARRASSING THAN IT IS ALREADY.

2606
01:46:30,787 --> 01:46:32,622
>> SO DAN, MAYBE YOU WANT
TO

2607
01:46:32,622 --> 01:46:34,891
COMMENT ON HOW YOU SEE CELL

2608
01:46:34,891 --> 01:46:36,126
THERAPEUTICS MOVING FORWARD FROM

2609
01:46:36,126 --> 01:46:37,227
HERE, WHERE WE ARE?

2610
01:46:37,227 --> 01:46:45,836
>> WELL, I THINK WHAT MOST

2611
01:46:45,836 --> 01:46:47,137
PEOPLE DON'T REALIZE IS SOME OF

2612
01:46:47,137 --> 01:46:50,440
THE TRIALS OF THE MSC BASED CELL

2613
01:46:50,440 --> 01:46:53,710
THERAPY FOR COVID ARDS WERE

2614
01:46:53,710 --> 01:46:54,011
SUCCESSFUL.

2615
01:46:54,011 --> 01:46:55,545
AND WHAT WE NEED TO DO IS

2616
01:46:55,545 --> 01:46:56,947
UNDERSTAND BETTER HOW THEY WERE

2617
01:46:56,947 --> 01:46:58,115
SUCCESSFUL AND THEN LEVERAGE

2618
01:46:58,115 --> 01:47:02,986
THAT TO A BROADER RANGE OF

2619
01:47:02,986 --> 01:47:03,453
INDICATIONS.

2620
01:47:03,453 --> 01:47:04,788
AND AGAIN TO COME BACK TO THE

2621
01:47:04,788 --> 01:47:09,026
PATIENT INFLAMMATORY PHENOTYPE

2622
01:47:09,026 --> 01:47:10,494
AS BEING A GUIDE.

2623
01:47:10,494 --> 01:47:11,661
SO WHAT WOULD YOU DO THERE?

2624
01:47:11,661 --> 01:47:14,698
YOU WOULD INCORPORATE POINT OF

2625
01:47:14,698 --> 01:47:18,668
CARE ASSESSMENTS, SO SOMEONE

2626
01:47:18,668 --> 01:47:21,004
COMES IN WITH ACUTE LUNG INJURY

2627
01:47:21,004 --> 01:47:23,106
OR SEPSIS, SEPTIC SHOCK OR ARDS

2628
01:47:23,106 --> 01:47:26,209
OR WHAT HAVE YOU, YOU DO A QUICK

2629
01:47:26,209 --> 01:47:27,544
DIAGNOSTIC AT THE BEDSIDE AND

2630
01:47:27,544 --> 01:47:30,247
SAY YOU ARE SOMEWHAT WHO IS MORE

2631
01:47:30,247 --> 01:47:33,950
LAKELY THAN NOT TO RESPOND TO AN

2632
01:47:33,950 --> 01:47:35,519
MSC-BASED SYSTEMIC

2633
01:47:35,519 --> 01:47:38,255
ADMINISTRATION, AND THEN GO FROM

2634
01:47:38,255 --> 01:47:38,855
THERE.

2635
01:47:38,855 --> 01:47:43,894
BUT IT ALSO HIGH LATE A DICTUM

2636
01:47:43,894 --> 01:47:45,062
THAT SAYS EVERY CLINICAL

2637
01:47:45,062 --> 01:47:46,430
INVESTIGATION NEEDS TO HAVE AS

2638
01:47:46,430 --> 01:47:47,497
MANY MECHANISTIC INVESTIGATIVE

2639
01:47:47,497 --> 01:47:48,498
ARMS AS POSSIBLE.

2640
01:47:48,498 --> 01:47:50,167
SO AS WE DESIGN THE FUTURE

2641
01:47:50,167 --> 01:47:51,601
TRIALS, WE NEED TO BE SMARTER

2642
01:47:51,601 --> 01:47:55,539
ABOUT BEING ABLE TO PULL MORE

2643
01:47:55,539 --> 01:47:57,107
INFORMATION OUT OF THE TRIALS

2644
01:47:57,107 --> 01:47:58,675
OVER AND ABOVE THE CLINICAL

2645
01:47:58,675 --> 01:48:00,410
OUTCOMES DATA.

2646
01:48:00,410 --> 01:48:01,711
I WANT TO ACTUALLY GO OFF A

2647
01:48:01,711 --> 01:48:03,080
LITTLE BIT ON WHAT FRANK WAS

2648
01:48:03,080 --> 01:48:06,650
SAYING, THOUGH, MITOCHONDRIAL

2649
01:48:06,650 --> 01:48:07,784
THERAPIES ARE A NEXT WAVE, IF

2650
01:48:07,784 --> 01:48:09,586
YOU WILL.

2651
01:48:09,586 --> 01:48:11,922
AND SO IT ONE THING TO

2652
01:48:11,922 --> 01:48:12,422
ADMINISTER CELLS.

2653
01:48:12,422 --> 01:48:15,459
IT ANOTHER THING TO ADMINISTER

2654
01:48:15,459 --> 01:48:17,961
THE EXTRACELLULAR VESICLES OR

2655
01:48:17,961 --> 01:48:19,596
THE SECRETOME FROM THE CELLS,

2656
01:48:19,596 --> 01:48:21,731
AND THERE'S A SUBSTANTIAL

2657
01:48:21,731 --> 01:48:23,934
LITERATURE THAT THOSE

2658
01:48:23,934 --> 01:48:26,570
PARTICULARLY EVs MIGHT BE AS

2659
01:48:26,570 --> 01:48:28,672
EFFICACIOUS AS THE PARENT CELL,

2660
01:48:28,672 --> 01:48:30,073
BUT AGAIN WE HAVE TO UNDERSTAND

2661
01:48:30,073 --> 01:48:31,041
HOW THEY'RE WORKING.

2662
01:48:31,041 --> 01:48:33,176
BUT THEN THE MITOCHONDRIA, I

2663
01:48:33,176 --> 01:48:34,377
MEAN, THERE'S A GROWING

2664
01:48:34,377 --> 01:48:37,514
LITERATURE THAT MITOCHONDRIAL

2665
01:48:37,514 --> 01:48:39,382
ADMINISTRATION, AND IF YOU THINK

2666
01:48:39,382 --> 01:48:42,452
ABOUT ARDS AND SOME OF THE

2667
01:48:42,452 --> 01:48:44,721
PATHOGENESIS IS ATP DEPLETION IN

2668
01:48:44,721 --> 01:48:48,191
THE TYPE 2 CELLS LEADING TO

2669
01:48:48,191 --> 01:48:49,359
SURFACTANT PRODUCTION DEPLETION,

2670
01:48:49,359 --> 01:48:51,394
ET CETERA.

2671
01:48:51,394 --> 01:48:52,896
AND HOW MITOCHONDRIAL TRANSFER

2672
01:48:52,896 --> 01:48:54,064
CAN POTENTIALLY RESCUE THAT.

2673
01:48:54,064 --> 01:48:56,399
IT'S ONE PIECE OF THE JIGSAW

2674
01:48:56,399 --> 01:48:58,535
PUZZLE, BUT IT AN INTRIGUING

2675
01:48:58,535 --> 01:49:01,171
PIECE THAT WHEN YOU'RE THINKING

2676
01:49:01,171 --> 01:49:05,041
OF FUTURE DIRECTIONS, IS ONE TO

2677
01:49:05,041 --> 01:49:07,978
INCORPORATE INTO THE OVERALL

2678
01:49:07,978 --> 01:49:09,679
PROGENITOR MINDSET, IF YOU WILL.

2679
01:49:09,679 --> 01:49:12,415
>> SO DAN, CAN I ASK A
QUESTION?

2680
01:49:12,415 --> 01:49:13,183
IT'S ALWAYS ANNOYED ME THAT

2681
01:49:13,183 --> 01:49:15,218
THERE HAVE BEEN SO MANY MSC

2682
01:49:15,218 --> 01:49:15,485
STUDIES.

2683
01:49:15,485 --> 01:49:17,187
AS YOU SAY, THEY DON'T

2684
01:49:17,187 --> 01:49:18,722
INCORPORATE BUT THEY HAVE

2685
01:49:18,722 --> 01:49:19,589
ANTI-INFLAMMATORY AND REPARATIVE

2686
01:49:19,589 --> 01:49:22,526
FUNCTIONS.

2687
01:49:22,526 --> 01:49:25,562
AND OF COURSE THE TIMING IS ALL

2688
01:49:25,562 --> 01:49:27,264
FOR AUTOLOGOUS TRANSPLANTS, YOU

2689
01:49:27,264 --> 01:49:30,534
KNOW, WE CAN SEE HOW EASY THAT

2690
01:49:30,534 --> 01:49:33,336
IS AND THOSE DO INCORPORATE AT

2691
01:49:33,336 --> 01:49:35,539
LEAST IN MICE, SO WE ALWAYS

2692
01:49:35,539 --> 01:49:36,606
THOUGHT THAT WOULD BE THE IDEAL

2693
01:49:36,606 --> 01:49:37,474
THING, BUT OF COURSE THE TIMING

2694
01:49:37,474 --> 01:49:40,744
IS SO BAD, PATIENTS SHOW UP IN

2695
01:49:40,744 --> 01:49:43,413
THE ICU WITH ARDS, AND YOU

2696
01:49:43,413 --> 01:49:44,648
CAN'T -- YOU CAN'T GROW THEM UP

2697
01:49:44,648 --> 01:49:47,017
FAST ENOUGH TO DO.

2698
01:49:47,017 --> 01:49:50,387
>> COUPLE THAT, FRANK,
WITH THE

2699
01:49:50,387 --> 01:49:52,022
LIKELIHOOD, AND THERE'S DATA IN

2700
01:49:52,022 --> 01:49:55,592
SOME CONDITIONS THAT MSCs

2701
01:49:55,592 --> 01:49:57,827
OBTAINED FROM AN ACUTE

2702
01:49:57,827 --> 01:50:00,730
INFLAMMATORY INJURY ARE NOT

2703
01:50:00,730 --> 01:50:01,698
NECESSARILY PROPERLY

2704
01:50:01,698 --> 01:50:03,633
FUNCTIONING, SO IT'S A DOUBLE

2705
01:50:03,633 --> 01:50:04,167
WHAMMY.

2706
01:50:04,167 --> 01:50:05,235
YOU CAN'T GET THEM, YOU CAN'T

2707
01:50:05,235 --> 01:50:07,003
EXPAND THEM, YOU CAN'T GET

2708
01:50:07,003 --> 01:50:08,538
ENOUGH, AND THEY MAY NOT WORK,

2709
01:50:08,538 --> 01:50:10,874
IF YOU WILL.

2710
01:50:10,874 --> 01:50:12,509
THIS GETS YOU BACK TO

2711
01:50:12,509 --> 01:50:14,177
ALLOGENEIC.

2712
01:50:14,177 --> 01:50:21,751
BUT ALLOGENEIC ARE STILL ALER JE

2713
01:50:21,751 --> 01:50:22,219
ALLOGENEIC.

2714
01:50:22,219 --> 01:50:23,820
IT WILL STILL PROVOKE A HOST

2715
01:50:23,820 --> 01:50:28,258
RESPONSE FAIRLY QUICKLY ONCE THE

2716
01:50:28,258 --> 01:50:29,226
EVENT, SPECIFICALLY WITH

2717
01:50:29,226 --> 01:50:29,826
SYSTEMIC ADMINISTRATION.

2718
01:50:29,826 --> 01:50:33,230
THERE'S A SKOLL SCHOOL OF THOUGT

2719
01:50:33,230 --> 01:50:34,464
IT'S NOT THE CELLS THAT ARE

2720
01:50:34,464 --> 01:50:35,999
ACTUALLY DOING ANYTHING,

2721
01:50:35,999 --> 01:50:38,702
ALTHOUGH THEY CAN DO THAT LONG

2722
01:50:38,702 --> 01:50:41,004
LIST OF THINGS, BUT IT'S THE

2723
01:50:41,004 --> 01:50:41,571
HOST-IMMUNE RESPONSE THAT'S

2724
01:50:41,571 --> 01:50:44,140
REALLY DRIVING THE HOPEFULLY

2725
01:50:44,140 --> 01:50:44,908
BENEFICIAL RESPONSE.

2726
01:50:44,908 --> 01:50:46,543
>> I SEE, I SEE.

2727
01:50:46,543 --> 01:50:48,245
THEN THE OTHER THING WAS, PEOPLE

2728
01:50:48,245 --> 01:50:51,615
WERE TALKING ABOUT -- IN THE

2729
01:50:51,615 --> 01:50:53,283
DAWN OF IPSCs, PEOPLE WERE

2730
01:50:53,283 --> 01:50:55,252
TALKING ABOUT WELL, LET'S GET A

2731
01:50:55,252 --> 01:50:58,655
WHOLE BUNCH OF IPSCs GOING

2732
01:50:58,655 --> 01:51:01,992
FROM ALL THE ALLO TYPES,

2733
01:51:01,992 --> 01:51:06,663
EVERYONE IS MHC, TO TRY TO FOCUS

2734
01:51:06,663 --> 01:51:07,864
ON AS MANY AS POSSIBLE.

2735
01:51:07,864 --> 01:51:11,968
>> IT'S KIND OF LIKE CORD
BLOOD

2736
01:51:11,968 --> 01:51:15,505
BLANKING.

2737
01:51:15,505 --> 01:51:15,939
BANKING.

2738
01:51:15,939 --> 01:51:17,140
THERE'S A WHOLE BUNCH OF HYPE

2739
01:51:17,140 --> 01:51:19,576
BUT WHAT DOES THAT EVER -- DO

2740
01:51:19,576 --> 01:51:20,777
NOT MISUNDERSTAND, I'M NOT

2741
01:51:20,777 --> 01:51:23,280
DISMISSING OR DOWNPLAYING, BUT

2742
01:51:23,280 --> 01:51:25,115
WHERE IS THE PROOF, WHERE IS THE

2743
01:51:25,115 --> 01:51:26,283
PUDDING HERE, IF YOU WILL?

2744
01:51:26,283 --> 01:51:26,983
>> RIGHT.

2745
01:51:26,983 --> 01:51:27,784
OKAY.

2746
01:51:27,784 --> 01:51:30,820
OKAY.

2747
01:51:30,820 --> 01:51:35,058
>> SO DAN, IF THESE CELLS
ARE

2748
01:51:35,058 --> 01:51:38,695
NOT IMMUNE PRIVILEGED -- CAN YOU

2749
01:51:38,695 --> 01:51:40,964
HEAR ME?

2750
01:51:40,964 --> 01:51:41,197
>> YES.

2751
01:51:41,197 --> 01:51:44,734
>> IF THESE CELLS ARE NOT
IMMUNE

2752
01:51:44,734 --> 01:51:46,202
PRIVILEGED AND ACT LIKE

2753
01:51:46,202 --> 01:51:48,305
ALLOGENEIC CELLS AND ARE

2754
01:51:48,305 --> 01:51:51,708
ULTIMATELY CLEARED, THAT'S

2755
01:51:51,708 --> 01:51:54,077
PRESUMABLY THEN HYPED UP THE

2756
01:51:54,077 --> 01:51:56,613
IMMUNE SYSTEM FOR THOSE CELLS.

2757
01:51:56,613 --> 01:51:59,115
WHAT HAPPENS -- IS THERE ANY

2758
01:51:59,115 --> 01:52:00,617
CONCERN OR ANY EXPERIENCE WITH

2759
01:52:00,617 --> 01:52:05,021
THE SECOND OR THIRD INFUSION OF

2760
01:52:05,021 --> 01:52:05,755
MESENCHYMAL STEM CELLS?

2761
01:52:05,755 --> 01:52:07,757
>> THAT'S A GREAT
QUESTION, HAL.

2762
01:52:07,757 --> 01:52:09,526
IT GOES BACK TO THE QUESTION OF

2763
01:52:09,526 --> 01:52:10,560
DOSING REGIMEN, BECAUSE WHEN YOU

2764
01:52:10,560 --> 01:52:12,095
LOOK AT THE PRE-CLINICAL DATA,

2765
01:52:12,095 --> 01:52:14,497
MOST OF THOSE ARE SINGLE

2766
01:52:14,497 --> 01:52:16,499
ADMINISTRATION, IF YOU WILL.

2767
01:52:16,499 --> 01:52:17,967
BUT WHEN YOU GET INTO THE

2768
01:52:17,967 --> 01:52:19,836
CLINICAL TRIALS, SOME OF THEM

2769
01:52:19,836 --> 01:52:24,541
HAVE TWO OR THREE CELL

2770
01:52:24,541 --> 01:52:27,510
ADMINISTRATIONS SE SEPARATED

2771
01:52:27,510 --> 01:52:28,144
GENERALLY OVER A COUPLE OF DAYS

2772
01:52:28,144 --> 01:52:30,113
IF YOU WILL, BUT THERE'S BEEN NO

2773
01:52:30,113 --> 01:52:33,450
DATA FORTHCOMING AS TO WHETHER

2774
01:52:33,450 --> 01:52:36,653
OR NOT ONE HAS DEVELOPED LACK OF

2775
01:52:36,653 --> 01:52:42,692
TOLERANCE OR SOME SORT OF MORE

2776
01:52:42,692 --> 01:52:43,693
ROBUST IMMUNE RESPONSE.

2777
01:52:43,693 --> 01:52:47,564
>> LIKE HAN F ANAPHYLAXIS?

2778
01:52:47,564 --> 01:52:49,199
>> NO, NO, NO, HOPEFULLY
THAT

2779
01:52:49,199 --> 01:52:50,367
CAME THROUGH IN THE CHAT

2780
01:52:50,367 --> 01:52:53,069
RESPONSE TO AMANDA HILL AND ALL

2781
01:52:53,069 --> 01:52:53,970
THAT.

2782
01:52:53,970 --> 01:52:55,238
THE ONE THING THAT'S COME OUT OF

2783
01:52:55,238 --> 01:52:58,608
ALL THESE TRIALS IS SAFETY.

2784
01:52:58,608 --> 01:53:01,644
EVEN IN CRITICALLY ILL ARDS

2785
01:53:01,644 --> 01:53:04,347
PATIENTS ON THE VENTILATOR, ON

2786
01:53:04,347 --> 01:53:06,216
ECMO, THAT CLOSE TO DEATH AND

2787
01:53:06,216 --> 01:53:11,988
ALL THAT, NOBODY HAS FOUND ANY

2788
01:53:11,988 --> 01:53:12,956
ADVERSE EFFECT OF GIVING THE

2789
01:53:12,956 --> 01:53:13,523
MSC.

2790
01:53:13,523 --> 01:53:15,425
SO IN IMMUNE RESPONSE, THERE'S

2791
01:53:15,425 --> 01:53:16,259
THIS HUGE UMBRELLA.

2792
01:53:16,259 --> 01:53:18,561
WHAT DOES THAT MEAN?

2793
01:53:18,561 --> 01:53:21,531
SO IF IT MEANS THAT ONE IS

2794
01:53:21,531 --> 01:53:24,734
REVVING UP MACROPHAGES BECAUSE

2795
01:53:24,734 --> 01:53:32,742
THEY'RBECAUSE -- BUT THEY'RE THN

2796
01:53:32,742 --> 01:53:34,043
SECRETE IL10, I'M JUST GIVING

2797
01:53:34,043 --> 01:53:37,714
YOU SOME BROAD STROKE EXAMPLES,

2798
01:53:37,714 --> 01:53:40,116
AND THAT DOES SOMETHING TO RESET

2799
01:53:40,116 --> 01:53:41,418
THE HYPERINFLAMMATORY RESPONSE

2800
01:53:41,418 --> 01:53:42,619
THAT'S DETRIMENTAL IN ARDS, THEN

2801
01:53:42,619 --> 01:53:46,156
THAT'S A WIN-WIN SITUATION.

2802
01:53:46,156 --> 01:53:47,824
BUT HAL, SO FAR NOBODY HAS

2803
01:53:47,824 --> 01:53:49,993
DROPPED DEAD.

2804
01:53:49,993 --> 01:53:54,130
NOBODY HAS HAD ANAPHYLACTIC

2805
01:53:54,130 --> 01:53:54,397
RESPONSE.

2806
01:53:54,397 --> 01:53:57,167
>> IS ANYONE ENGINEERING
THESE

2807
01:53:57,167 --> 01:53:57,367
MSCs?

2808
01:53:57,367 --> 01:53:59,002
FOR INSTANCE, FOR SECRETE IL10

2809
01:53:59,002 --> 01:54:00,470
OR SOME OTHER --

2810
01:54:00,470 --> 01:54:03,840
>> SO THE ONE EXAMPLE I

2811
01:54:03,840 --> 01:54:13,116
MENTIONED IS STUDIES,

2812
01:54:13,116 --> 01:54:16,719
ENGINEERING MSCs TO SECRETE

2813
01:54:16,719 --> 01:54:20,490
TRAIL, TNF ALPHA RECEPTOR --

2814
01:54:20,490 --> 01:54:22,325
WITH TARGETING AN ANTITUMOR

2815
01:54:22,325 --> 01:54:22,525
AGENT.

2816
01:54:22,525 --> 01:54:23,960
SO THERE'S BEEN LESS WORK IN

2817
01:54:23,960 --> 01:54:27,030
TERMS OF MSCs SECRETE IL10,

2818
01:54:27,030 --> 01:54:29,566
BUT THERE HAS BEEN SOME WORK OR

2819
01:54:29,566 --> 01:54:33,403
OTHER THINGS WITH IL10 AS YOU

2820
01:54:33,403 --> 01:54:36,506
MENTIONED IN TRYING TO PRESERVE

2821
01:54:36,506 --> 01:54:39,976
LUNGS FOR TRANSPLANT.

2822
01:54:39,976 --> 01:54:41,511
SO A DONOR LUNG GETS TAKEN OUT,

2823
01:54:41,511 --> 01:54:44,080
CAN BE PUT ON AN EXTRA VASCULAR

2824
01:54:44,080 --> 01:54:48,918
LUNG PERFUSION DEVICE,

2825
01:54:48,918 --> 01:54:50,186
UNIVERSITY OF TORONTO HAS REALLY

2826
01:54:50,186 --> 01:54:54,123
PIONEERED THIS, AND MSCs,

2827
01:54:54,123 --> 01:54:56,259
ENGINEERING TO SECRETE IL10 THAT

2828
01:54:56,259 --> 01:54:57,560
POTENTIALLY COULD BE UTILIZED

2829
01:54:57,560 --> 01:54:59,963
INTO THAT CIRCUIT TO FURTHER

2830
01:54:59,963 --> 01:55:03,333
INCREASE THE VIABILITY OF THE

2831
01:55:03,333 --> 01:55:03,933
LUNGS.

2832
01:55:03,933 --> 01:55:05,768
IN A PARALLEL TYPE OF ENDEAVOR,

2833
01:55:05,768 --> 01:55:07,737
NOT WITH MSCs BUT WITH

2834
01:55:07,737 --> 01:55:10,373
ENDOTHELIAL PROGENITOR CELLS,

2835
01:55:10,373 --> 01:55:11,908
DUNCAN STEWART AT THE OTTAWA

2836
01:55:11,908 --> 01:55:13,743
HEALTH RESEARCH INSTITUTE HAS

2837
01:55:13,743 --> 01:55:20,216
ENGINEERED THE EPCs TO

2838
01:55:20,216 --> 01:55:23,686
OVEREXPERIENCE ANDRO POIETIN

2839
01:55:23,686 --> 01:55:25,288
WITH THE IDEA THAT THIS WOULD BE

2840
01:55:25,288 --> 01:55:28,658
BENEFICIAL FOR HYPERTENSION, HAS

2841
01:55:28,658 --> 01:55:30,927
HAD A CLINICAL TRIAL GOING ON

2842
01:55:30,927 --> 01:55:32,195
THAT AS WELL.

2843
01:55:32,195 --> 01:55:33,630
SO SHORT ANSWER, YES, IT'S AN

2844
01:55:33,630 --> 01:55:34,864
OPEN FIELD BUT LESS WELL

2845
01:55:34,864 --> 01:55:35,331
TRAVELED AT PRESENT.

2846
01:55:35,331 --> 01:55:38,868
>> THANK YOU.

2847
01:55:38,868 --> 01:55:40,603
>> I'M TOLD WE NEED TO
WRAP UP

2848
01:55:40,603 --> 01:55:45,008
FOR DINNER -- FOR LUNCH.

2849
01:55:45,008 --> 01:55:46,442
>> NO, FIVE MORE MINUTES.

2850
01:55:46,442 --> 01:55:48,845
WE CAN TAKE A 20-MINUTE BREAK.

2851
01:55:48,845 --> 01:55:49,412
CONTINUE.

2852
01:55:49,412 --> 01:55:49,846
FIVE MORE MINUTES.

2853
01:55:49,846 --> 01:55:51,948
THANK YOU.

2854
01:55:51,948 --> 01:55:56,886
>> IN TERMS OF ENDOTHELIAL

2855
01:55:56,886 --> 01:55:58,555
CELLS, WEILL CORNELL IS ALSO

2856
01:55:58,555 --> 01:56:01,124
ENGINEERING MICROVASCULAR

2857
01:56:01,124 --> 01:56:02,358
ENDOTHELIAL CELLS AS A

2858
01:56:02,358 --> 01:56:03,192
THERAPEUTIC.

2859
01:56:03,192 --> 01:56:04,027
SO I THINK THERE'S A LOT OF

2860
01:56:04,027 --> 01:56:06,296
OPPORTUNITY THERE.

2861
01:56:06,296 --> 01:56:07,330
>> I THINK SO.

2862
01:56:07,330 --> 01:56:11,067
BUT IT RAISES ANOTHER LEVEL OF

2863
01:56:11,067 --> 01:56:14,504
COMPLEXITY WITH THE FDA.

2864
01:56:14,504 --> 01:56:15,171
AND EUROPEAN UNION, FOR EXAMPLE,

2865
01:56:15,171 --> 01:56:17,106
AND ALL THAT.

2866
01:56:17,106 --> 01:56:21,811
SO FOR THE MSC, THE UMBRELLA

2867
01:56:21,811 --> 01:56:26,616
TERM MSC, THE REGIONAL

2868
01:56:26,616 --> 01:56:27,684
HEAVY-DUTY INVESTIGATIONS 10

2869
01:56:27,684 --> 01:56:29,385
YEARS AGO, FOR EXAMPLE, WERE IN

2870
01:56:29,385 --> 01:56:32,689
GRAFT VERSUS HOST DEEDS, AND THE

2871
01:56:32,689 --> 01:56:33,756
ENTITIES DOING THAT, EITHER

2872
01:56:33,756 --> 01:56:35,258
ACADEMIC OR INDUSTRY, HAD TO

2873
01:56:35,258 --> 01:56:36,593
JUMP THROUGH MANY, MANY, MANY

2874
01:56:36,593 --> 01:56:41,164
HOOPS WITH THE FDA FOR SAFETY

2875
01:56:41,164 --> 01:56:42,265
INDICATIONS IN PARTICULAR.

2876
01:56:42,265 --> 01:56:46,402
BUT BY AND LARGE, THE MSC

2877
01:56:46,402 --> 01:56:47,704
EXPERIENCE OF SAFETY, THE TRACK

2878
01:56:47,704 --> 01:56:52,208
RECORD OF SAFETY, IS SUCH THAT

2879
01:56:52,208 --> 01:56:57,513
IT'S LESS WORK TO PUT AN MSC

2880
01:56:57,513 --> 01:57:01,684
TRIAL FOR FDA APPROVAL.

2881
01:57:01,684 --> 01:57:02,952
ONCE YOU START ENGINEERING, IT'S

2882
01:57:02,952 --> 01:57:04,320
A WHOLE CAN OF WORMS AND YOU

2883
01:57:04,320 --> 01:57:05,788
HAVE TO REINVENT THE WHEEL

2884
01:57:05,788 --> 01:57:06,923
BECAUSE IT'S A NEW BEAST.

2885
01:57:06,923 --> 01:57:11,227
AND SO THAT'S WHETHER OR NOT ONE

2886
01:57:11,227 --> 01:57:14,964
AS AN ENTITY WANTS TO UNDERTAKE

2887
01:57:14,964 --> 01:57:17,834
EVERYTHING INVOLVED IN THAT IS A

2888
01:57:17,834 --> 01:57:18,701
SERIOUS DECISION TO MAKE.

2889
01:57:18,701 --> 01:57:23,039
AND SO THE PRE-CLINICAL DATA,

2890
01:57:23,039 --> 01:57:25,008
THE RATIONALE HAS GOT TO BE SO

2891
01:57:25,008 --> 01:57:26,009
SOLID AND CONVINCING FOR

2892
01:57:26,009 --> 01:57:36,552
SOMEBODY TO BE ABLE TO DO THAT.

2893
01:57:37,854 --> 01:57:39,589
>> I THINK WE CAN WRAP UP
FOR

2894
01:57:39,589 --> 01:57:42,492
DINNER NOW.

2895
01:57:42,492 --> 01:57:45,695
>> SO EVERYBODY COME TO
VERMONT

2896
01:57:45,695 --> 01:57:46,729
NEXT SUMMER FOR THAT CONFERENCE.

2897
01:57:46,729 --> 01:57:48,798
>> CAN I MAYBE -- JUST ONE

2898
01:57:48,798 --> 01:57:49,799
MINUTE BEFORE WE WRAP UP?

2899
01:57:49,799 --> 01:57:50,800
>> YES, WELLINGTON.

2900
01:57:50,800 --> 01:57:53,636
>> AGAIN TO FRANK, BECAUSE
I'M

2901
01:57:53,636 --> 01:57:57,340
VERY FASCINATED BY WHAT HE HAD

2902
01:57:57,340 --> 01:57:58,775
DESCRIBED AND PUBLISHED ON THIS.

2903
01:57:58,775 --> 01:58:01,978
FRANK, WHEN YOU TALK ABOUT THE

2904
01:58:01,978 --> 01:58:09,085
FETAL ORIGIN OF THE CELLS, I

2905
01:58:09,085 --> 01:58:11,187
SUPPOSE THIS MUST BE IN HUMANS

2906
01:58:11,187 --> 01:58:14,090
BECAUSE IN THE MOUSE, I CAN'T

2907
01:58:14,090 --> 01:58:15,925
REMEMBER WHEN I READ YOUR PAPER

2908
01:58:15,925 --> 01:58:18,227
WHETHER YOU HAVE DESCRIBED THEM

2909
01:58:18,227 --> 01:58:22,265
IN THE MOUSE AS WELL,

2910
01:58:22,265 --> 01:58:23,700
PARTICULARLY IN -- AIRWAYS.

2911
01:58:23,700 --> 01:58:25,068
>> THIS IS ALL IN HUMAN.

2912
01:58:25,068 --> 01:58:26,502
WHEN WE WERE IN BOSTON, WE

2913
01:58:26,502 --> 01:58:31,074
RECEIVED A NUMBER FROM CHRIS KRO

2914
01:58:31,074 --> 01:58:33,176
KROMM AT THE BRIGHAM, AND IT'S

2915
01:58:33,176 --> 01:58:34,744
NOT TRIVIAL TO -- WE LIVE IN

2916
01:58:34,744 --> 01:58:35,178
TEXAS NOW.

2917
01:58:35,178 --> 01:58:41,117
WE COULD BE -- FOR THIS KIND OF

2918
01:58:41,117 --> 01:58:42,985
STUFF, SO WE DID ALL THE

2919
01:58:42,985 --> 01:58:47,657
ANALYSIS AND CLONING FROM --

2920
01:58:47,657 --> 01:58:51,060
>> BUT FRANK, THOSE CELLS,
DO

2921
01:58:51,060 --> 01:58:55,898
YOU -- IN RESPONSE SOME OF THOSE

2922
01:58:55,898 --> 01:58:57,200
SIGNALS THAT WE HAVE BEEN

2923
01:58:57,200 --> 01:59:01,838
TALKING ABOUT, FOR EXAMPLE, --

2924
01:59:01,838 --> 01:59:03,072
ACID, FOR EXAMPLE, NOTCH

2925
01:59:03,072 --> 01:59:06,609
SIGNALING, FOR EXAMPLE, AND

2926
01:59:06,609 --> 01:59:08,244
FORGIVE ME, I MAY HAVE MISSED,

2927
01:59:08,244 --> 01:59:09,879
DID YOU NOTICE SOMETHING THAT

2928
01:59:09,879 --> 01:59:13,282
ACTUALLY MODULATE THIS EXPANSION

2929
01:59:13,282 --> 01:59:15,418
THAT HAS TO DO WITH SOME OF THIS

2930
01:59:15,418 --> 01:59:20,456
MORE CANONICAL SIGNALS, TGF

2931
01:59:20,456 --> 01:59:24,093
BETA, NOTCH --

2932
01:59:24,093 --> 01:59:26,295
>> WELLINGTON, ALL THOSE
THINGS

2933
01:59:26,295 --> 01:59:32,335
ARE IN THE COMPONENTS THAT --

2934
01:59:32,335 --> 01:59:34,704
HAS PUT TOGETHER IN THE MEDIA.

2935
01:59:34,704 --> 01:59:36,205
THE MEDIA ARE COMPLEX.

2936
01:59:36,205 --> 01:59:36,506
>> I SEE.

2937
01:59:36,506 --> 01:59:38,274
>> TO MAINTAIN THEM AS
STEM

2938
01:59:38,274 --> 01:59:40,343
CELLS.

2939
01:59:40,343 --> 01:59:41,511
BUT MANY OF THE PATHWAYS YOU

2940
01:59:41,511 --> 01:59:44,881
JUST MENTIONED ARE PART AND

2941
01:59:44,881 --> 01:59:46,048
PARCEL, BUT SHE'S PUBLISHED

2942
01:59:46,048 --> 01:59:46,682
THAT.

2943
01:59:46,682 --> 01:59:48,017
IF YOU ASK ME, I DON'T THINK I

2944
01:59:48,017 --> 01:59:50,319
COULD LIST THEM OFF FOR YOU, BUT

2945
01:59:50,319 --> 01:59:50,586
SHE COULD.

2946
01:59:50,586 --> 01:59:52,088
>> YEP, I UNDERSTAND.

2947
01:59:52,088 --> 01:59:54,490
WHAT I WAS JUST WANTING TO TRY

2948
01:59:54,490 --> 01:59:56,125
TO FIGURE OUT IS WHEN YOU

2949
01:59:56,125 --> 01:59:59,829
INHIBIT THE THINGS, IF ANY OF

2950
01:59:59,829 --> 02:00:02,799
THESE PATHWAYS INHIBIT YOU HAVE

2951
02:00:02,799 --> 02:00:04,734
A PREFERENTIAL EXPANSION OF A

2952
02:00:04,734 --> 02:00:07,103
PARTICULAR CLONE VERSUS ANOTHER,

2953
02:00:07,103 --> 02:00:08,304
AND MORE ABOUT RESPONSE --

2954
02:00:08,304 --> 02:00:11,474
>> IT'S A GOOD QUESTION,
AND

2955
02:00:11,474 --> 02:00:13,543
THIS HAS COME UP RECENTLY, SO

2956
02:00:13,543 --> 02:00:16,746
ONE THING WAS DOING WITH THIS IS

2957
02:00:16,746 --> 02:00:18,114
CLONING OUT THESE DIFFERENT

2958
02:00:18,114 --> 02:00:19,682
CELLS IN PANCREATIC CANCER.

2959
02:00:19,682 --> 02:00:23,452
SO IT SOUNDS WEIRD, BUT IT WAS

2960
02:00:23,452 --> 02:00:25,221
VERY CLEAR THAT THERE'S

2961
02:00:25,221 --> 02:00:27,456
HETEROGENEITY IN THOSE

2962
02:00:27,456 --> 02:00:28,457
INDIVIDUAL TUMOR PATIENTS OF

2963
02:00:28,457 --> 02:00:29,325
THEIR STEM CELLS.

2964
02:00:29,325 --> 02:00:33,396
SHE WAS NOT ABLE TO GET THE

2965
02:00:33,396 --> 02:00:36,165
BASAL VERSION OF PANCREATIC

2966
02:00:36,165 --> 02:00:36,532
CANCER.

2967
02:00:36,532 --> 02:00:39,769
SHE HAD SWITCHED TO ANOTHER

2968
02:00:39,769 --> 02:00:41,437
MEDIA AND WAS ABLE TO GET THAT.

2969
02:00:41,437 --> 02:00:42,872
SO THAT MAKES IT -- WE GET WHAT

2970
02:00:42,872 --> 02:00:45,741
WE GET, RIGHT?

2971
02:00:45,741 --> 02:00:47,410
SO ARE WE MISSING THINGS?

2972
02:00:47,410 --> 02:00:50,413
AND I THINK THAT'S A VERY REAL

2973
02:00:50,413 --> 02:00:52,415
POSSIBILITY, THAT IF WE HAD

2974
02:00:52,415 --> 02:00:54,050
SLIGHTLY DIFFERENT MEDIAS, WOULD

2975
02:00:54,050 --> 02:00:55,685
WE CAPTURE MORE.

2976
02:00:55,685 --> 02:00:57,587
BUT WE ARE CAPTURING THEM IN A

2977
02:00:57,587 --> 02:00:58,321
RECURRENT WAY.

2978
02:00:58,321 --> 02:01:01,190
SO FOR INSTANCE, COPD, ALL THE

2979
02:01:01,190 --> 02:01:04,994
CLONES THAT WE SEE IN COPD ARE

2980
02:01:04,994 --> 02:01:07,563
IN CYSTIC FIBROSIS.

2981
02:01:07,563 --> 02:01:08,631
CYSTIC FIBROSIS HAS TWO

2982
02:01:08,631 --> 02:01:09,699
ADDITIONAL ONES THAT ARE UNIQUE

2983
02:01:09,699 --> 02:01:09,999
TO IT.

2984
02:01:09,999 --> 02:01:10,566
>> I SEE.

2985
02:01:10,566 --> 02:01:14,203
>> BUT IT IS -- YOU GET
WHAT YOU

2986
02:01:14,203 --> 02:01:15,671
GET.

2987
02:01:15,671 --> 02:01:18,541
IF WE HAD UNLIMITED PATIENTS, WE

2988
02:01:18,541 --> 02:01:20,209
COULD MAKE A WHOLE SET OF MEDIAS

2989
02:01:20,209 --> 02:01:23,746
AND TRY TO CLONE OUT MORE.

2990
02:01:23,746 --> 02:01:24,881
BUT YOU KNOW --

2991
02:01:24,881 --> 02:01:26,849
>> WE HAVE AMANDA
HILLARYLY

2992
02:01:26,849 --> 02:01:31,153
QUHILL REALLYQUICKLY BEFORE THE.

2993
02:01:31,153 --> 02:01:31,888
>> HI.

2994
02:01:31,888 --> 02:01:33,222
THANK YOU VERY MUCH.

2995
02:01:33,222 --> 02:01:33,856
DANIEL, THANK YOU SO MUCH FOR

2996
02:01:33,856 --> 02:01:37,860
THE DISCUSSION.

2997
02:01:37,860 --> 02:01:42,431
I'M A VETERINARIAN, AND IN ORDER

2998
02:01:42,431 --> 02:01:43,833
TO HAVE A BETTER CLINICAL OUT

2999
02:01:43,833 --> 02:01:45,434
COME IN ALLOGENIC TRANSPLANTS,

3000
02:01:45,434 --> 02:01:47,536
IF THE PATIENT NEEDS MORE THAN

3001
02:01:47,536 --> 02:01:48,471
ONE APPLICATION WE USUALLY

3002
02:01:48,471 --> 02:01:50,139
CHANGE THE DONOR AND WE OBSERVE

3003
02:01:50,139 --> 02:01:51,641
THE CLINICAL OUTCOME IS BETTER

3004
02:01:51,641 --> 02:01:52,742
AS COMPARED TO USING THE SAME

3005
02:01:52,742 --> 02:01:52,975
DONOR.

3006
02:01:52,975 --> 02:01:54,911
IS THERE ANY STUDIES IN HUMANS

3007
02:01:54,911 --> 02:01:59,548
THAT SHOW THAT?

3008
02:01:59,548 --> 02:02:03,586
>> AMANDA, IF THE QUESTION
IS

3009
02:02:03,586 --> 02:02:05,354
TOWARDS ME, WHAT A FASCINATING

3010
02:02:05,354 --> 02:02:06,055
IDEA.

3011
02:02:06,055 --> 02:02:07,490
AND THE ANSWER IS, NO, NONE THAT

3012
02:02:07,490 --> 02:02:12,628
I'M AWARE.

3013
02:02:12,628 --> 02:02:15,164
WITBUT AGAIN, THERE ARE ONLY A

3014
02:02:15,164 --> 02:02:16,565
LIMITED NUMBER OF STUDIES WITH

3015
02:02:16,565 --> 02:02:20,436
MULTIPLE ADMINISTRATIONS, IF YOU

3016
02:02:20,436 --> 02:02:20,903
WILL.

3017
02:02:20,903 --> 02:02:23,306
BY AND LARGE, IT'S A SINGLE

3018
02:02:23,306 --> 02:02:24,206
ADMINISTRATION.

3019
02:02:24,206 --> 02:02:26,208
BUT THEN BACK TO HAL'S POINT, SO

3020
02:02:26,208 --> 02:02:27,777
FAR IN THOSE MULTIPLE

3021
02:02:27,777 --> 02:02:29,478
ADMINISTRATION STUDIES, THERE

3022
02:02:29,478 --> 02:02:31,981
HASN'T BEEN ANY OBVIOUS DOWNSIDE

3023
02:02:31,981 --> 02:02:35,384
TO USING THE SAME SOURCE.

3024
02:02:35,384 --> 02:02:36,385
>> OKAY, GREAT.

3025
02:02:36,385 --> 02:02:36,686
THANK YOU.

3026
02:02:36,686 --> 02:02:38,254
>> GOOD QUESTION.

3027
02:02:38,254 --> 02:02:47,496
REALLY INTERESTING QUESTION.

3028
02:02:47,496 --> 02:02:49,632
>> WELL, I THINK WE CAN
CONCLUDE

3029
02:02:49,632 --> 02:02:49,999
OUR DISCUSSION.

3030
02:02:49,999 --> 02:02:52,668
THANK YOU, EVERYBODY, FOR YOUR

3031
02:02:52,668 --> 02:02:54,570
PARTICIPATION, AND WHAT A LIVELY

3032
02:02:54,570 --> 02:02:56,706
DISCUSSION AND WONDERFUL TALKS.

3033
02:02:56,706 --> 02:02:59,108
>> WELL, THANK YOU BOTH
FOR

3034
02:02:59,108 --> 02:03:02,345
MODERATING, AND FOR DOING THIS.

3035
02:03:02,345 --> 02:03:02,545
GREAT.

3036
02:03:02,545 --> 02:03:04,480
>> THANK YOU ALL.

3037
02:03:04,480 --> 02:03:11,041
>> THANKS, EVERYONE.

3038
02:03:11,041 --> 02:03:13,843
SO I HAVE THE PLEASURE HERE TO

3039
02:03:13,843 --> 02:03:17,814
KICK OFF THIS SESSION, TOGETHER

3040
02:03:17,814 --> 02:03:21,318
WITH AMANDA JAMIESON.

3041
02:03:21,318 --> 02:03:22,919
AMANDA IS GOING TO GIVE A LITTLE

3042
02:03:22,919 --> 02:03:24,988
BIT OF A BRIEF OVERVIEW TO THE

3043
02:03:24,988 --> 02:03:26,956
SESSION AND THEN I THINK GOING

3044
02:03:26,956 --> 02:03:28,591
TO GO AHEAD AND INTRODUCE OUR

3045
02:03:28,591 --> 02:03:32,562
FIRST SPEAKER.

3046
02:03:32,562 --> 02:03:33,563
>> THANKS, JOSE.

3047
02:03:33,563 --> 02:03:34,831
SO THE OVERVIEW OF THIS SESSION

3048
02:03:34,831 --> 02:03:38,234
IS TO REALLY KIND OF PULL

3049
02:03:38,234 --> 02:03:40,136
INTEREST LOTS OF DIFFERENT

3050
02:03:40,136 --> 02:03:42,172
SYSTEMS BECAUSE THE LUNG IS NOT

3051
02:03:42,172 --> 02:03:44,474
AN ISOLATED ENVIRONMENT, CLEARLY

3052
02:03:44,474 --> 02:03:48,411
IT PART OF THE WHOLE BODY, AND

3053
02:03:48,411 --> 02:03:50,847
SO REALLY TO GET INSIGHTS FROM

3054
02:03:50,847 --> 02:03:52,982
OTHER FIELDS TO UNDERSTAND

3055
02:03:52,982 --> 02:03:54,117
MECHANISMS OF LUNG PROGENITOR

3056
02:03:54,117 --> 02:03:54,718
RESILIENCE.

3057
02:03:54,718 --> 02:03:55,552
THEN OF COURSE AS WE'VE BEEN

3058
02:03:55,552 --> 02:03:57,754
DOING FOR THESE LAST TWO DAYS IS

3059
02:03:57,754 --> 02:03:58,388
REALLY IDENTIFY CRITICAL GAPS

3060
02:03:58,388 --> 02:04:01,591
AND CHALLENGES AND OPPORTUNITIES

3061
02:04:01,591 --> 02:04:02,692
AND SOME NEW KEY RESEARCH

3062
02:04:02,692 --> 02:04:04,127
QUESTIONS ON HOW WE CAN PULL

3063
02:04:04,127 --> 02:04:06,496
FROM THESE MULTIDISCIPLINARY

3064
02:04:06,496 --> 02:04:09,666
AREAS.

3065
02:04:09,666 --> 02:04:12,869
SO CAN WE GET STARTED WITH OUR

3066
02:04:12,869 --> 02:04:14,904
FIRST SPEAKER, WHO IS HELEN C.

3067
02:04:14,904 --> 02:04:15,872
MIRANDA FROM CASEWESTERN

3068
02:04:15,872 --> 02:04:20,610
UNIVERSITY.

3069
02:04:20,610 --> 02:04:21,678
AS USUAL, WE'LL HAVE THE

3070
02:04:21,678 --> 02:04:22,545
DISCUSSION AT THE END, AND YOU

3071
02:04:22,545 --> 02:04:24,581
CAN PUT ANY SORT OF QUESTIONS IN

3072
02:04:24,581 --> 02:04:25,949
THE CHAT FOR CLARIFICATION

3073
02:04:25,949 --> 02:04:31,654
QUESTIONS.

3074
02:04:31,654 --> 02:04:32,255
>> HELLO.

3075
02:04:32,255 --> 02:04:34,557
CAN YOU ALL HEAR ME WELL?

3076
02:04:34,557 --> 02:04:35,558
YES?

3077
02:04:35,558 --> 02:04:35,925
OKAY.

3078
02:04:35,925 --> 02:04:36,860
>> YES, WE CAN HEAR YOU.

3079
02:04:36,860 --> 02:04:38,027
>> THANK YOU.

3080
02:04:38,027 --> 02:04:41,331
THANKS SO MUCH FOR THE

3081
02:04:41,331 --> 02:04:41,965
INVITATION.

3082
02:04:41,965 --> 02:04:42,999
I'VE BEEN THOROUGHLY ENJOYING

3083
02:04:42,999 --> 02:04:45,068
THIS MEETING, LEARNING A LOT

3084
02:04:45,068 --> 02:04:45,969
FROM DIFFERENT FIELDS BUT IT'S

3085
02:04:45,969 --> 02:04:48,071
VERY INTERESTING TO SEE HOW,

3086
02:04:48,071 --> 02:04:52,809
FROM DIFFERENT FEALDZ, FIELDS, N

3087
02:04:52,809 --> 02:04:53,777
FIND THIS INTERSECTION.

3088
02:04:53,777 --> 02:04:54,911
SO TODAY I'M GOING TO TALK ABOUT

3089
02:04:54,911 --> 02:04:57,680
IPINTEGRATED STRESS RESPONSE AND

3090
02:04:57,680 --> 02:05:00,450
HOW WE IDENTIFY PATHOGENS

3091
02:05:00,450 --> 02:05:01,818
ASSOCIATED TO THIS NEUROLOGICAL

3092
02:05:01,818 --> 02:05:07,123
DISEASE CALLED ALLS.

3093
02:05:07,123 --> 02:05:07,624
 ALS.

3094
02:05:07,624 --> 02:05:09,359
SO MY LAB FOCUSES ON THE STUDY

3095
02:05:09,359 --> 02:05:10,560
OF DIFFERENT TYPES OF

3096
02:05:10,560 --> 02:05:11,327
NEUROLOGICAL DISEASES.

3097
02:05:11,327 --> 02:05:13,296
WE HAVE A LARGER FOCUS ON

3098
02:05:13,296 --> 02:05:15,565
NEUROMUSCULAR DISEASES, BUT WE

3099
02:05:15,565 --> 02:05:17,267
HAVE ALSO DABBED IN THE FIELD OF

3100
02:05:17,267 --> 02:05:18,902
NEUROPEDIATRIC DISORDERS AS

3101
02:05:18,902 --> 02:05:19,202
WELL.

3102
02:05:19,202 --> 02:05:22,639
FOR THE PURPOSE OF THIS TALK

3103
02:05:22,639 --> 02:05:33,016
TODAY I'M GOING TO FOCUS ON ALS.

3104
02:05:33,016 --> 02:05:37,120
WE HAVE BEEN MODELING THIS

3105
02:05:37,120 --> 02:05:38,621
DISEASE USING THIS VERY SPECIFIC

3106
02:05:38,621 --> 02:05:39,989
SYSTEM THAT I WAS GLAD TO SEE

3107
02:05:39,989 --> 02:05:40,957
WAS REFERENCED TODAY AND

3108
02:05:40,957 --> 02:05:42,125
YESTERDAY BY DIFFERENT SPEAKERS.

3109
02:05:42,125 --> 02:05:44,894
SO WE ONLY DO STEM CELL MODELING

3110
02:05:44,894 --> 02:05:45,195
IN THE LAB.

3111
02:05:45,195 --> 02:05:47,063
THIS IS OUR EXPERTISE.

3112
02:05:47,063 --> 02:05:48,565
WE WORK WITH PEOPLE THAT USE

3113
02:05:48,565 --> 02:05:51,034
MOUSE MODELS, WITH HE WORK WITH

3114
02:05:51,034 --> 02:05:53,736
PEOPLE WITH FLY MODELS, WE HAVE

3115
02:05:53,736 --> 02:05:55,805
TONS OF COLLABORATIONS USING

3116
02:05:55,805 --> 02:05:57,106
OTHER MODELS BUT THIS IS OUR

3117
02:05:57,106 --> 02:05:57,507
EXPERTISE.

3118
02:05:57,507 --> 02:06:01,911
AS MANY SPEAKERS HAVE DISCUSSED

3119
02:06:01,911 --> 02:06:04,681
AND EMPHASIZED IN PREVIOUS

3120
02:06:04,681 --> 02:06:07,917
TALKS, BEFORE THE ADVENT OF

3121
02:06:07,917 --> 02:06:09,118
IPSCs, THE AVAILABLE

3122
02:06:09,118 --> 02:06:11,754
APPROACHES TO DIRECTLY STUDY IN

3123
02:06:11,754 --> 02:06:12,822
OUR CASE SPECIFICALLY

3124
02:06:12,822 --> 02:06:14,591
NEUROLOGICAL DISEASES WAS

3125
02:06:14,591 --> 02:06:20,563
POSTMORTEM HUMAN TISSUES,

3126
02:06:20,563 --> 02:06:22,799
IMMORTALIZED CELL LINES AND

3127
02:06:22,799 --> 02:06:25,468
ANIMAL MODELS AND POSTMORTEM

3128
02:06:25,468 --> 02:06:30,640
BRAIN TISSUES NOT ALWAYS

3129
02:06:30,640 --> 02:06:32,075
REPRESENT -- OFTEN REPRESENTS

3130
02:06:32,075 --> 02:06:33,343
THE END STAGE OF THE DISEASE AND

3131
02:06:33,343 --> 02:06:38,548
ARE OFTEN NOT WELL PRESERVED AND

3132
02:06:38,548 --> 02:06:42,886
WHILE MORE -- SPECIFICALLY

3133
02:06:42,886 --> 02:06:43,453
NEUROGENERATIVE DISEASE

3134
02:06:43,453 --> 02:06:44,020
PHENOTYPES.

3135
02:06:44,020 --> 02:06:45,355
MOST MOUSE MODELS ARE VERY

3136
02:06:45,355 --> 02:06:47,991
LIMITED TO SPECIFIC VARIANTS, SO

3137
02:06:47,991 --> 02:06:51,060
WE SELECT THIS MODEL WHERE WE

3138
02:06:51,060 --> 02:06:53,563
OBTAIN CELLS FROM PATIENTS, THE

3139
02:06:53,563 --> 02:06:56,399
FIBROBLASTS OR BLOOD CELLS, WE

3140
02:06:56,399 --> 02:06:58,902
THEN REPROGRAM THE CELLS IN

3141
02:06:58,902 --> 02:07:01,838
VITRO TO GENERATE STEM CELLS TO

3142
02:07:01,838 --> 02:07:03,573
BEHAVE AS IF THEY WERE EMBRYONIC

3143
02:07:03,573 --> 02:07:06,976
STEM CELLS IN THE DISH.

3144
02:07:06,976 --> 02:07:09,479
IN OUR LAB WE'RE EXPERT AT

3145
02:07:09,479 --> 02:07:10,113
DIFFERENTIATING CELLS INTO

3146
02:07:10,113 --> 02:07:13,116
DIFFERENT CELL TYPES SO WE MAKE

3147
02:07:13,116 --> 02:07:16,853
PROGENITOR CELLS, WE MAKE

3148
02:07:16,853 --> 02:07:18,221
SPECIFICALLY CORTICONEURONS,

3149
02:07:18,221 --> 02:07:21,190
ASTROCYTES AND OTHER GLIA SUCH

3150
02:07:21,190 --> 02:07:23,126
AS MICROGLIA AS WELL AS SKELETAL

3151
02:07:23,126 --> 02:07:23,793
MUSCLES.

3152
02:07:23,793 --> 02:07:24,694
BUT FOR THE PURPOSE OF THE TALK

3153
02:07:24,694 --> 02:07:26,696
TODAY, I'M GOING TO FOCUS ON HOW

3154
02:07:26,696 --> 02:07:27,497
WE'RE DIFFERENTIATING THESE

3155
02:07:27,497 --> 02:07:33,836
CELLS INTO MOTOR NEURONS.

3156
02:07:33,836 --> 02:07:37,473
SO WHAT IS AMYOTROPHIC LATERAL

3157
02:07:37,473 --> 02:07:38,575
SCLEROSIS DISEASE I'M GOING TO

3158
02:07:38,575 --> 02:07:41,110
FOCUS ON TODAY?

3159
02:07:41,110 --> 02:07:43,179
IT'S THE MOST COMMON ADULT ONSET

3160
02:07:43,179 --> 02:07:45,114
MOTOR NEURON DISEASE.

3161
02:07:45,114 --> 02:07:47,850
ITS PATHOPHYSIOLOGY HAS

3162
02:07:47,850 --> 02:07:49,752
INVOLVEMENT OF BOTH UPPER AND

3163
02:07:49,752 --> 02:07:50,553
LOWER MOTOR NEURON.

3164
02:07:50,553 --> 02:07:52,355
THIS IS TRULY A DEVASTATING

3165
02:07:52,355 --> 02:07:52,589
DISEASE.

3166
02:07:52,589 --> 02:07:54,591
THE PATIENTS SUFFER IN WHAT WE

3167
02:07:54,591 --> 02:07:56,259
CALL THE LOCKING SYNDROME, THEY

3168
02:07:56,259 --> 02:07:57,360
ESSENTIALLY LOSE THE ABILITY TO

3169
02:07:57,360 --> 02:07:58,761
MOVE, THEY BECOME WHEELCHAIR

3170
02:07:58,761 --> 02:08:00,997
BOUND, SOMETIMES BEDRIDDEN, AND

3171
02:08:00,997 --> 02:08:03,232
WHILE MOST OF THE PATIENTS DO

3172
02:08:03,232 --> 02:08:05,668
NOT SUFFER ANY COGNITIVE

3173
02:08:05,668 --> 02:08:06,803
IMPAIRMENT, SO THEY ARE FULLY

3174
02:08:06,803 --> 02:08:07,770
AWARE OF THEIR SURROUNDINGS BUT

3175
02:08:07,770 --> 02:08:08,905
THEY JUST CAN'T MOVE.

3176
02:08:08,905 --> 02:08:11,975
AND UNFORTUNATELY, THE LIFE

3177
02:08:11,975 --> 02:08:14,544
EXPECTANCY POST DIAGNOSIS IS

3178
02:08:14,544 --> 02:08:15,478
BETWEEN TWO TO FIVE YEARS.

3179
02:08:15,478 --> 02:08:17,180
AND IT'S IMPORTANT TO POINT OUT

3180
02:08:17,180 --> 02:08:18,982
THAT 90% OF THESE CASES ARE

3181
02:08:18,982 --> 02:08:21,684
CONSIDERED SPORADIC, WHERE

3182
02:08:21,684 --> 02:08:25,421
THERE'S NO -- PATTERN, BUT 10%

3183
02:08:25,421 --> 02:08:28,524
ARE KNOWN TO BE FAMILIAL WHEN WE

3184
02:08:28,524 --> 02:08:29,192
IDENTIFY THE DISEASE AND THIS

3185
02:08:29,192 --> 02:08:37,433
HAS A PATTERN OF HEREDITARY.

3186
02:08:37,433 --> 02:08:40,269
SO TO DATE, WE HAVE OVER 38

3187
02:08:40,269 --> 02:08:42,238
VARIANTS IN DIFFERENT GENES THAT

3188
02:08:42,238 --> 02:08:44,641
HAVE BEEN ASSOCIATED OR KNOWN TO

3189
02:08:44,641 --> 02:08:47,010
BE CAUSATIVE OF DIFFERENT TYPES

3190
02:08:47,010 --> 02:08:47,677
OF ALS.

3191
02:08:47,677 --> 02:08:50,213
HERE IN THIS GRAPH, WE HAVE IN

3192
02:08:50,213 --> 02:08:51,080
BLUE REPRESENTATION OF IMEENS

3193
02:08:51,080 --> 02:08:56,185
THATGENESWHICH HAVE BEEN ASSOCIH

3194
02:08:56,185 --> 02:08:58,054
ALS, IN RED WE HAVE GENES

3195
02:08:58,054 --> 02:08:59,022
ASSOCIATED WITH SPORADIC ALS.

3196
02:08:59,022 --> 02:09:00,790
SO THE MAJORITY OF THE GENES

3197
02:09:00,790 --> 02:09:02,158
HAVE BEEN IDENTIFIED IN BOTH

3198
02:09:02,158 --> 02:09:02,925
POPULATIONS BUT THE ONE I'M

3199
02:09:02,925 --> 02:09:04,927
GOING TO FOCUS ON TODAY IS THIS

3200
02:09:04,927 --> 02:09:07,497
GENE THAT IS CAUSATIVE OF A RARE

3201
02:09:07,497 --> 02:09:10,266
FORM OF ALS CALLED VAPB.

3202
02:09:10,266 --> 02:09:11,968
ALL THE WORK I'M GOING TO

3203
02:09:11,968 --> 02:09:14,637
DESCRIBE TODAY WAS IN MY LAB BY

3204
02:09:14,637 --> 02:09:22,912
MY PH.D. STUDENT, CURRAN LANDRY.

3205
02:09:22,912 --> 02:09:29,952
SO WHAT IS VAPB IS THIS HIGHLY

3206
02:09:29,952 --> 02:09:30,553
CONSERVED EXPRESSED PROTEIN.

3207
02:09:30,553 --> 02:09:32,622
IT'S A MEMBRANE PROTEIN ANCHORED

3208
02:09:32,622 --> 02:09:35,291
TO THE MEMBRANE OF THE AR AND IT

3209
02:09:35,291 --> 02:09:36,325
HAS THESE THREE DIFFERENT

3210
02:09:36,325 --> 02:09:36,859
DOMAINS.

3211
02:09:36,859 --> 02:09:44,567
THE TRTHE -- IS THE ONE THAT BIS

3212
02:09:44,567 --> 02:09:45,868
DIFFERENT ORGANELLES AND

3213
02:09:45,868 --> 02:09:46,936
PROTEINS TO THE MEMBRANE OF THE

3214
02:09:46,936 --> 02:09:54,544
AR AND THIS IS THOUGHT TO BE --

3215
02:09:54,544 --> 02:09:55,011
EASILY FUNCTION.

3216
02:09:55,011 --> 02:09:56,379
SO MUTATIONS THAT HAVE BEEN

3217
02:09:56,379 --> 02:09:57,580
ASSOCIATED TO -- MOSTLY

3218
02:09:57,580 --> 02:09:59,115
IDENTIFIED IN THAT DOMAIN SO IT

3219
02:09:59,115 --> 02:10:05,321
CAUSES A CHANGE FROM A PROLINE

3220
02:10:05,321 --> 02:10:09,959
TO A SERINE IN THE POSITION

3221
02:10:09,959 --> 02:10:11,260
OF -- 56, FIRST IDENTIFIED IN

3222
02:10:11,260 --> 02:10:12,295
THE BRAZILIAN POPULATION.

3223
02:10:12,295 --> 02:10:13,296
WE STILL ESTIMATE THE MAJORITY

3224
02:10:13,296 --> 02:10:15,631
OF THE PATIENTS WITH THIS

3225
02:10:15,631 --> 02:10:16,833
MUTATION ARE FROM BRAZIL BUT

3226
02:10:16,833 --> 02:10:17,800
DIFFERENT PATIENTS HAVE BEEN

3227
02:10:17,800 --> 02:10:19,702
IDENTIFIED IN OTHER PLACES, IN

3228
02:10:19,702 --> 02:10:28,544
OTHER COUNTRIES.

3229
02:10:28,544 --> 02:10:31,714
SO AS I MENTIONED, WE USE THESE

3230
02:10:31,714 --> 02:10:33,549
INDUCED PLURIPOTENT STEM CELLS

3231
02:10:33,549 --> 02:10:35,818
TO MODEL THE DISEASE AND WE'RE

3232
02:10:35,818 --> 02:10:37,553
GOING TO FOCUS ON THE MOLECULAR

3233
02:10:37,553 --> 02:10:39,856
MECHANISMS THAT ARE ASSOCIATED

3234
02:10:39,856 --> 02:10:44,727
WITH THE MUTANT VAPB AND IT'S

3235
02:10:44,727 --> 02:10:48,064
CAUSATIVE OF AMMO TROPHIC

3236
02:10:48,064 --> 02:10:48,698
LATERAL SCLEROSIS.

3237
02:10:48,698 --> 02:10:50,366
TO DO THAT WE ALSO RELY ON

3238
02:10:50,366 --> 02:10:56,906
CRISPR ENGINEERING SO THE FIRST

3239
02:10:56,906 --> 02:10:58,307
STEP FOR THIS PROJECT WAS TO

3240
02:10:58,307 --> 02:11:00,042
ACTUALLY KNOCK OUT VAPB FROM

3241
02:11:00,042 --> 02:11:01,878
THESE CELL LINES AND EITHER

3242
02:11:01,878 --> 02:11:03,946
EXPRESS THE VAPB WILD TYPE OR

3243
02:11:03,946 --> 02:11:06,449
THE MUTANT VAPB, SO WE THEN

3244
02:11:06,449 --> 02:11:09,252
GENERATE THIS PANEL THAT WE CALL

3245
02:11:09,252 --> 02:11:10,486
THESE ISOGENIC CELL LINES, SO

3246
02:11:10,486 --> 02:11:12,388
THEY HAVE ALL THE SAME GENETIC

3247
02:11:12,388 --> 02:11:13,289
BACKGROUND WITH THE DIFFERENCE

3248
02:11:13,289 --> 02:11:23,766
OF THESE SPECIFIC MUTATION.

3249
02:11:24,367 --> 02:11:25,668
SO FOR THIS SPECIFIC DISEASE

3250
02:11:25,668 --> 02:11:26,803
WE'RE GOING TO TALK ABOUT HOW

3251
02:11:26,803 --> 02:11:31,274
WE'RE GOING TO DIFFERENTIATE

3252
02:11:31,274 --> 02:11:32,275
THESE CELLS INTO MOTOR NEURONS.

3253
02:11:32,275 --> 02:11:34,777
THE PROTOCOL FOR ALTERNATIVE

3254
02:11:34,777 --> 02:11:35,945
DIFFERENTIATION IS REALLY WELL

3255
02:11:35,945 --> 02:11:37,513
ESTABLISHED.

3256
02:11:37,513 --> 02:11:38,514
WE DIFFERENTIATE THIS USING WHAT

3257
02:11:38,514 --> 02:11:42,585
WE CALL THE DUAL -- PROTOCOL.

3258
02:11:42,585 --> 02:11:43,686
WE DIFFERENTIATE THESE CELLS

3259
02:11:43,686 --> 02:11:46,756
INITIALLY FOR 15 DAYS TO

3260
02:11:46,756 --> 02:11:47,790
GENERATE MODERN PRO GENERAL

3261
02:11:47,790 --> 02:11:56,799
TORS PROGENITORS.

3262
02:11:56,799 --> 02:11:58,334
FURTHER MATURITY CELLS -- THESE

3263
02:11:58,334 --> 02:11:59,535
MOTOR NEURONS ARE CHARACTERIZED

3264
02:11:59,535 --> 02:12:05,875
BY POSITIVE STAINING OF --

3265
02:12:05,875 --> 02:12:06,209
1 AND -- 9.

3266
02:12:06,209 --> 02:12:10,847
THIS USES ABOUT 80 TO 90% OF --

3267
02:12:10,847 --> 02:12:12,615
NEURONS.

3268
02:12:12,615 --> 02:12:14,217
WE THEN -- THEN I'M GOING TO

3269
02:12:14,217 --> 02:12:16,252
DESCRIBE HOW WE ASSESS THESE

3270
02:12:16,252 --> 02:12:17,820
MOTOR NEURONS WE JUST

3271
02:12:17,820 --> 02:12:19,422
DIFFERENTIATED WITH EITHER THE

3272
02:12:19,422 --> 02:12:21,724
WILD TYPE VAPB OR THE MUTANT

3273
02:12:21,724 --> 02:12:23,226
VAPB SO WE FIRST ASSESS THEM FOR

3274
02:12:23,226 --> 02:12:23,993
THEIR FUNCTIONALITY.

3275
02:12:23,993 --> 02:12:25,127
IN THIS CASE, WE'RE GOING TO

3276
02:12:25,127 --> 02:12:26,729
TALK ABOUT ELECTROPHYSIOLOGY.

3277
02:12:26,729 --> 02:12:28,698
WE ALSO LOOK AT THEIR MOLECULAR

3278
02:12:28,698 --> 02:12:33,703
PROPERTIES, SO WE ASSESS

3279
02:12:33,703 --> 02:12:35,905
THEIR -- WE ALSO ANALYZED THEIR

3280
02:12:35,905 --> 02:12:36,939
MITOCHONDRIA AND I'M GOING TO

3281
02:12:36,939 --> 02:12:37,874
DESCRIBE THAT TOO, AND THEN AT

3282
02:12:37,874 --> 02:12:39,842
THE END, I'M GOING TO TALK ABOUT

3283
02:12:39,842 --> 02:12:42,545
HOW WE TIED ER EVERYTHING TOGETR

3284
02:12:42,545 --> 02:12:44,247
TO THIS INTEGRATIVE STRESS

3285
02:12:44,247 --> 02:12:45,381
RESPONSE MECHANISM THAT WE

3286
02:12:45,381 --> 02:12:46,182
IDENTIFIED.

3287
02:12:46,182 --> 02:12:47,016
AND ALL OF THE WORK THAT I'M

3288
02:12:47,016 --> 02:12:49,385
GOING TO DESCRIBE HERE IS

3289
02:12:49,385 --> 02:12:50,253
ACTUALLY AVAILABLE IN --

3290
02:12:50,253 --> 02:12:51,454
CURRENTLY AVAILABLE IN

3291
02:12:51,454 --> 02:12:54,257
BIOARCHIVES.

3292
02:12:54,257 --> 02:12:59,795
SO NEXT, FOR THE FIRST

3293
02:12:59,795 --> 02:13:00,463
ASSESSMENT WE WANTED TO LOOK AT

3294
02:13:00,463 --> 02:13:01,864
THE FUNCTIONALITY OF THESE MOTOR

3295
02:13:01,864 --> 02:13:02,231
NEURONS.

3296
02:13:02,231 --> 02:13:04,400
IN ORDER TO DO THAT, WE RELY ON

3297
02:13:04,400 --> 02:13:07,570
THIS MACHINE WE HAVE IN THE LAB

3298
02:13:07,570 --> 02:13:11,507
CALLED THE MYO STROBE MACHINE

3299
02:13:11,507 --> 02:13:12,408
FROM AXE YON.

3300
02:13:12,408 --> 02:13:14,644
THIS SYSTEM RELIES ON THESE

3301
02:13:14,644 --> 02:13:17,413
ARRAY OF ELECTRODES IN THE

3302
02:13:17,413 --> 02:13:20,049
BOTTOM OF WELLS IN A MOTOR WELL

3303
02:13:20,049 --> 02:13:22,652
PLATE, AND WE JUST PLATE THE

3304
02:13:22,652 --> 02:13:24,120
NEURONS ON TOP OF THESE

3305
02:13:24,120 --> 02:13:25,888
ELECTRODES AND THE ELECTRODES

3306
02:13:25,888 --> 02:13:27,757
PICK UP THESE CHANGES IN ION

3307
02:13:27,757 --> 02:13:31,894
CONCENTRATION AROUND THEM, AND

3308
02:13:31,894 --> 02:13:33,329
THAT'S A PROXY FOR THEIR FIRING

3309
02:13:33,329 --> 02:13:34,196
PROPERTIES.

3310
02:13:34,196 --> 02:13:37,767
SO HERE I BROUGHT TWO OF MANY OF

3311
02:13:37,767 --> 02:13:39,302
THE OUTPUTS THAT THIS MACHINE

3312
02:13:39,302 --> 02:13:43,406
GIVES US, BUT SHOW  BUT TWO OF M

3313
02:13:43,406 --> 02:13:44,407
GOING TO SHOW HERE ARE

3314
02:13:44,407 --> 02:13:46,142
REPRESENTATIVE OF THESE LOWER OR

3315
02:13:46,142 --> 02:13:50,513
DECREASED NEURONAL -- RATE WE

3316
02:13:50,513 --> 02:13:52,515
SAW IN THESE NEURONS.

3317
02:13:52,515 --> 02:13:54,550
SO WE SAW STATISTICAL

3318
02:13:54,550 --> 02:13:57,320
SIGNIFICANCE IN THE WAY THAT --

3319
02:13:57,320 --> 02:14:00,289
FIRING RATE AS WELL AS NEURONAL

3320
02:14:00,289 --> 02:14:08,030
OUTBURSTS.

3321
02:14:08,030 --> 02:14:10,700
SO SINCE THEIR FUNCTION WAS

3322
02:14:10,700 --> 02:14:12,134
CLEARLY DIFFERENT BETWEEN THE

3323
02:14:12,134 --> 02:14:14,971
TWO, SO WE HAVE THESE

3324
02:14:14,971 --> 02:14:15,404
ELECTROPHYSIOLOGICAL

3325
02:14:15,404 --> 02:14:16,572
DYSFUNCTION, WE THEN ASK WHAT

3326
02:14:16,572 --> 02:14:18,274
ARE THE MOLECULAR MECHANISMS

3327
02:14:18,274 --> 02:14:22,078
THAT COULD LEAD -- LEADS THIS

3328
02:14:22,078 --> 02:14:25,014
SPECIFIC MUTATION TO THESE

3329
02:14:25,014 --> 02:14:25,448
ELECTROPHYSIOLOGICAL

3330
02:14:25,448 --> 02:14:25,881
DYSFUNCTION.

3331
02:14:25,881 --> 02:14:29,919
IN ORDER TO DO THAT, WE WANTED

3332
02:14:29,919 --> 02:14:31,487
TO ASSESS THE VAPB BINDING

3333
02:14:31,487 --> 02:14:32,989
PARTNERS IN THE CONTEXT OF THE

3334
02:14:32,989 --> 02:14:34,490
MUTANT VERSUS THE WILD TYPE.

3335
02:14:34,490 --> 02:14:35,524
I DIDN'T MENTION THAT IN THE

3336
02:14:35,524 --> 02:14:36,926
BEGINNING, HOWEVER, THIS WAS

3337
02:14:36,926 --> 02:14:41,097
PRECISELY WHY WE DECIDED TO

3338
02:14:41,097 --> 02:14:42,064
CRISPR KNOCKOUT INITIALLY AND

3339
02:14:42,064 --> 02:14:43,232
THEN EXPRESS THE WILD TYPE OR

3340
02:14:43,232 --> 02:14:48,237
THE MUTANT BECAUSE THE PATIENTS

3341
02:14:48,237 --> 02:14:50,339
ACTUALLY ARE HETEROZYGOUS FOR

3342
02:14:50,339 --> 02:14:51,273
THE DEEDS SO THE PATIENT LINES

3343
02:14:51,273 --> 02:14:52,541
HAVE BOTH WILD TYPE AND MUTANT

3344
02:14:52,541 --> 02:14:55,177
VAVAPB.

3345
02:14:55,177 --> 02:14:56,512
WE REALLY WANTED TO SEPARATE

3346
02:14:56,512 --> 02:14:57,747
WHAT ARE THE PROTEINS BINDING

3347
02:14:57,747 --> 02:14:58,781
SPECIFICALLY TO THE MUTANT OR

3348
02:14:58,781 --> 02:15:02,585
THE WILD TYPE AND COMPARE THE

3349
02:15:02,585 --> 02:15:04,053
TWO, AND WHEN WE PERFORMED THIS

3350
02:15:04,053 --> 02:15:06,989
COMPARISON, WE NOTICED THAT

3351
02:15:06,989 --> 02:15:09,425
THERE WAS A DECREASE IN THE

3352
02:15:09,425 --> 02:15:10,926
NUMBER OF BINDING PARTNERS IN

3353
02:15:10,926 --> 02:15:13,696
THE MUTANT LINES COMPARED TO THE

3354
02:15:13,696 --> 02:15:14,864
WILD TYPE THAT WERE ASSOCIATED

3355
02:15:14,864 --> 02:15:16,966
TO THE MITOCHONDRIA.

3356
02:15:16,966 --> 02:15:19,068
THIS WAS NOT ENTIRELY TOO

3357
02:15:19,068 --> 02:15:19,835
SURPRISING.

3358
02:15:19,835 --> 02:15:21,537
THERE WAS ONE SPECIFIC PROTEIN

3359
02:15:21,537 --> 02:15:25,307
CALLED PTPIP51, A MITOCHONDRIAL

3360
02:15:25,307 --> 02:15:27,410
PROTEIN THAT HAS BEEN SHOWN TO

3361
02:15:27,410 --> 02:15:28,911
BIND TO VAPB, IT HAS BEEN SHOWN

3362
02:15:28,911 --> 02:15:30,446
TO PLAY IMPORTANT ROLES BETWEEN

3363
02:15:30,446 --> 02:15:33,249
THE MITOCHONDRIA AND THE AR, SO

3364
02:15:33,249 --> 02:15:34,750
WE VALIDATE THAT IN OUR

3365
02:15:34,750 --> 02:15:36,419
FINDINGS, IN OUR -- IN THE

3366
02:15:36,419 --> 02:15:38,187
CONTEXT OF THESE MOTOR NEURONS.

3367
02:15:38,187 --> 02:15:42,591
AND WE ALSO SEE A DECREASE

3368
02:15:42,591 --> 02:15:43,726
INTERACTION BETWEEN -- MUTANT

3369
02:15:43,726 --> 02:15:49,165
AND -- COMPARED TO THE WILD TY 

3370
02:15:49,165 --> 02:15:51,000
TYPE.

3371
02:15:51,000 --> 02:15:55,771
SO AS I MENTIONED, THESE

3372
02:15:55,771 --> 02:15:57,306
PROTEINS SPECIFICALLY ENSURES

3373
02:15:57,306 --> 02:15:58,307
THESE CONNECTION OR THESE

3374
02:15:58,307 --> 02:15:59,775
BINDING BETWEEN THE MITOCHONDRIA

3375
02:15:59,775 --> 02:16:00,042
AND THE.

3376
02:16:00,042 --> 02:16:00,509
A R.

3377
02:16:00,509 --> 02:16:02,611
SO WE THEN WANTED TO ASK IF WE

3378
02:16:02,611 --> 02:16:07,416
SEE LOSS OF BINDING PARTNERS TO

3379
02:16:07,416 --> 02:16:10,820
THE MITOCHONDRIA, WHAT WAS

3380
02:16:10,820 --> 02:16:12,221
HAPPENING TO THIS POINT OF

3381
02:16:12,221 --> 02:16:13,923
CONTACT BETWEEN THE ER AND

3382
02:16:13,923 --> 02:16:14,690
MITOCHONDRIA.

3383
02:16:14,690 --> 02:16:16,625
WE PERFORMED THIS ASSESSMENT

3384
02:16:16,625 --> 02:16:18,961
THROUGH EM AND WE DO SEE

3385
02:16:18,961 --> 02:16:19,728
STATISTICALLY SIGNIFICANT

3386
02:16:19,728 --> 02:16:22,565
DECREASE IN THESE ER

3387
02:16:22,565 --> 02:16:25,634
MITOCHONDRIAL CONTACT, AND WE

3388
02:16:25,634 --> 02:16:27,203
PERFORM THESE IN TWO TIME

3389
02:16:27,203 --> 02:16:27,903
POINTS.

3390
02:16:27,903 --> 02:16:33,409
THE FIRST ONE WAS -- 5 BECAUSE

3391
02:16:33,409 --> 02:16:34,844
WE WANTED A TIME POINT THAT

3392
02:16:34,844 --> 02:16:36,712
WOULD REPLICATE THE MATURATION

3393
02:16:36,712 --> 02:16:37,780
OF THE NEURON, SO THIS WAS THE

3394
02:16:37,780 --> 02:16:38,981
TIME POINT WHERE THE NEURONS

3395
02:16:38,981 --> 02:16:40,483
WERE CONSIDERED MATURE.

3396
02:16:40,483 --> 02:16:43,652
HOWEVER, THIS IS -- DISEASE SO

3397
02:16:43,652 --> 02:16:46,288
WE ALSO WANTED A VERSION OF AN

3398
02:16:46,288 --> 02:16:48,858
AGED MODERN NEURONS -- 60 OF

3399
02:16:48,858 --> 02:16:49,225
DIFFERENTIATION.

3400
02:16:49,225 --> 02:16:52,461
SO FOR THESE SPECIFIC MOLECULAR

3401
02:16:52,461 --> 02:16:53,295
PHENOTYPE, WE DIDN'T SEE ANY

3402
02:16:53,295 --> 02:16:54,163
DIFFERENCE.

3403
02:16:54,163 --> 02:16:57,199
WE SAW THE SIMILAR RESULTS

3404
02:16:57,199 --> 02:16:58,734
BETWEEN THE MATURE MOTOR NEURONS

3405
02:16:58,734 --> 02:17:00,569
AS WELL AS THE AGED MOTOR

3406
02:17:00,569 --> 02:17:03,939
NEURONS, HOWEVER, WHEN WE

3407
02:17:03,939 --> 02:17:05,241
DECIDED TO ASSESS THE FUNCTION

3408
02:17:05,241 --> 02:17:06,876
OF THE MITOCHONDRIA, WE DID THAT

3409
02:17:06,876 --> 02:17:11,080
BY PERFORMING A JC1 ASSAY, VERY

3410
02:17:11,080 --> 02:17:12,481
STANDARD MITOCHONDRIA MEMBRANE

3411
02:17:12,481 --> 02:17:13,249
POTENTIAL ASSESSMENT.

3412
02:17:13,249 --> 02:17:16,652
WE DID NOT SEE ANY CHANGES

3413
02:17:16,652 --> 02:17:17,920
INITIALLY WHEN THE NEURONS WERE

3414
02:17:17,920 --> 02:17:20,489
MATURE BUT WE SAW STATISTICALLY

3415
02:17:20,489 --> 02:17:25,060
SIGNIFICANT DECREASE IN MEMBRANE

3416
02:17:25,060 --> 02:17:27,096
POTENTIAL ON DAY 60 WHEN THESE

3417
02:17:27,096 --> 02:17:28,564
NEURONS ARE AGED WHICH WAS ALSO

3418
02:17:28,564 --> 02:17:32,434
VERY INTERESTING.

3419
02:17:32,434 --> 02:17:36,672
SO THEN WE DECIDED TO ASK THE

3420
02:17:36,672 --> 02:17:40,342
QUESTION WHAT WOULD BE THE

3421
02:17:40,342 --> 02:17:43,445
RESPONSE INTRACELLULARLY TO THIS

3422
02:17:43,445 --> 02:17:45,981
MITOCHONDRIAL DYSFUNCTION.

3423
02:17:45,981 --> 02:17:51,520
BASED ON THE KNOWLEDGE THAT THIS

3424
02:17:51,520 --> 02:17:53,656
CONTACT BETWEEN THE MITOCHONDRIA

3425
02:17:53,656 --> 02:17:55,324
AND ER IS VERY IMPORTANT FOR

3426
02:17:55,324 --> 02:18:00,095
HOMEOSHOMEOSTASIS, CALCIUM HAND,

3427
02:18:00,095 --> 02:18:03,499
AS WELL AS THE PRELIMINARY DATA

3428
02:18:03,499 --> 02:18:05,801
I'M NOT GOING TO SHOW TODAY, WE

3429
02:18:05,801 --> 02:18:07,369
DECIDED TO LOOK AT TRANSLATION,

3430
02:18:07,369 --> 02:18:09,772
A VERY ENERGETIC, INTENSIVE

3431
02:18:09,772 --> 02:18:10,072
PROCESS.

3432
02:18:10,072 --> 02:18:14,944
SO WE DECIDED TO LOOK INITIA

3433
02:18:14,944 --> 02:18:17,479
INITIALLY -- AND SAW INCREASE IN

3434
02:18:17,479 --> 02:18:19,648
PHOSPHORYLATION INDICATING THAT

3435
02:18:19,648 --> 02:18:21,951
MRNA TRANSLATION OR PROTEIN

3436
02:18:21,951 --> 02:18:26,522
SYNTHESIS MIGHT BE DEPLETED --

3437
02:18:26,522 --> 02:18:27,356
SO THEN WE ASSESS THE

3438
02:18:27,356 --> 02:18:30,292
TRANSLATION ITSELF BY USING

3439
02:18:30,292 --> 02:18:33,329
THE -- ASSAY THAT RELIES ON THE

3440
02:18:33,329 --> 02:18:36,532
POST OF PURE MY SEEN, IS

3441
02:18:36,532 --> 02:18:38,801
SUPPOSED TO BE INCORPORATED TO A

3442
02:18:38,801 --> 02:18:41,103
NASCENT PROTEIN AND THAT GIVES

3443
02:18:41,103 --> 02:18:45,174
YOU A PROXY TO HOW TRANSLATION

3444
02:18:45,174 --> 02:18:48,510
RATES ARE AT A GIVEN TIME.

3445
02:18:48,510 --> 02:18:53,349
OH IN SO IN THIS CASE WE THEN ET

3446
02:18:53,349 --> 02:18:54,583
THE PROTEIN, AND IN THE CONTEXT

3447
02:18:54,583 --> 02:18:56,852
OF THE WILD TYPE VERSUS THE

3448
02:18:56,852 --> 02:19:00,322
MUTANT, WE SEE CLEARLY A

3449
02:19:00,322 --> 02:19:01,657
DECREASE IN THIS PROTEIN,

3450
02:19:01,657 --> 02:19:03,525
INDICATING A DECREASE OR

3451
02:19:03,525 --> 02:19:06,662
SHUTDOWN IN MRNA TRANSLATION.

3452
02:19:06,662 --> 02:19:08,631
BUT THEN HOW DO WE TRY THESE

3453
02:19:08,631 --> 02:19:10,332
TRANSLATION DEFECTS TO THE

3454
02:19:10,332 --> 02:19:11,567
MITOCHONDRIAL DYSFUNCTION THAT

3455
02:19:11,567 --> 02:19:16,438
WE'VE SEEN BEFORE?

3456
02:19:16,438 --> 02:19:21,677
SO RECENTLY LITERATURE HAVE

3457
02:19:21,677 --> 02:19:28,484
POINTED TO THIS PROTEIN CALLED

3458
02:19:28,484 --> 02:19:30,119
DELE1, THE END OF A PROCESS

3459
02:19:30,119 --> 02:19:31,186
CALLED INTEGRATED STRESS

3460
02:19:31,186 --> 02:19:31,854
RESPONSE WHICH IN THIS CASE

3461
02:19:31,854 --> 02:19:34,023
WOULD BE THE PROTEIN SYNTHESIS.

3462
02:19:34,023 --> 02:19:37,326
SO MITOCHONDRIAL DYSFUNCTION

3463
02:19:37,326 --> 02:19:39,995
WOULD ACTIVATE DELE1 AND WOULD

3464
02:19:39,995 --> 02:19:43,165
CLEAVE IT INTO DELE1S THAT WOULD

3465
02:19:43,165 --> 02:19:45,367
THEN BE TRANSPORTED FROM THE

3466
02:19:45,367 --> 02:19:47,102
MITOCHONDRIA TO THE -- TO

3467
02:19:47,102 --> 02:19:50,939
ACTIVATE HRE, AND ACTIVATION OF

3468
02:19:50,939 --> 02:19:54,877
HRE -- ACTIVATE THIS PROCESS

3469
02:19:54,877 --> 02:19:56,078
CALLED INTEGRATED STRESS

3470
02:19:56,078 --> 02:19:58,314
RESPONSE THAT CULMINATES WITH

3471
02:19:58,314 --> 02:19:59,715
PHOSPHORYLATION TO -- ALPHA,

3472
02:19:59,715 --> 02:20:01,450
DECREASE OF PROTEIN SYNTHESIS

3473
02:20:01,450 --> 02:20:03,419
AND ACTIVATION OF ATF4.

3474
02:20:03,419 --> 02:20:05,988
SO IN THIS CASE, WE DECIDED TO

3475
02:20:05,988 --> 02:20:14,730
LOOK AT DELE1.

3476
02:20:14,730 --> 02:20:16,665
WE DO SEE AN INCREASE IN THE

3477
02:20:16,665 --> 02:20:21,470
LEVELS OF DELE1 S IN THE MOTOR

3478
02:20:21,470 --> 02:20:29,345
NEURONS COMPARED TO ITS CONTROL.

3479
02:20:29,345 --> 02:20:30,579
THEN THIS BECAME OUR PROPOSED

3480
02:20:30,579 --> 02:20:30,846
MECHANISM.

3481
02:20:30,846 --> 02:20:31,980
SO THERE'S A BREAK IN THE

3482
02:20:31,980 --> 02:20:33,916
CONTACT BETWEEN THE MITOCHONDRIA

3483
02:20:33,916 --> 02:20:35,150
AND ER SHOWN BY EM.

3484
02:20:35,150 --> 02:20:39,621
THIS WOULD THEN ACTIVATE DELE1

3485
02:20:39,621 --> 02:20:40,522
CLEAVAGE WHICH WOULD ACTIVATE

3486
02:20:40,522 --> 02:20:45,160
INTO A STRESS RESPONSE.

3487
02:20:45,160 --> 02:20:47,496
IT WILL BE RESPONSIBLE FOR ALL

3488
02:20:47,496 --> 02:20:48,797
THESE PHENOTYPES THAT I HAVE

3489
02:20:48,797 --> 02:20:55,938
DESCRIBED.

3490
02:20:55,938 --> 02:20:58,073
SO I HAVE SHOWN HERE THAT WE SEE

3491
02:20:58,073 --> 02:21:02,511
THIS INCREASE IN DELE1S.

3492
02:21:02,511 --> 02:21:08,517
I ALSO SHOW WE SEE AN INCREASE

3493
02:21:08,517 --> 02:21:10,819
IN PHOSPHO -- 2 ALPHA AS WELL AS

3494
02:21:10,819 --> 02:21:17,159
AN ACCOMPANIED DECREASE IN --

3495
02:21:17,159 --> 02:21:17,993
TRANSLATION IN THIS CASE.

3496
02:21:17,993 --> 02:21:19,561
SO THE QUESTION HERE WAS WHAT

3497
02:21:19,561 --> 02:21:20,863
HAPPENS IN WE INHIBIT THIS

3498
02:21:20,863 --> 02:21:21,630
PROCESS?

3499
02:21:21,630 --> 02:21:24,299
WHAT IF WE INHIBIT THE STRESS

3500
02:21:24,299 --> 02:21:26,235
RESPONSE USING THIS INHIBITOR

3501
02:21:26,235 --> 02:21:28,537
THAT HAS ALSO BEEN DESCRIBED

3502
02:21:28,537 --> 02:21:38,981
YESTERDAY IN HUNT'S TALK.

3503
02:21:39,481 --> 02:21:41,717
SO WE DECIDED TO TEST THIS DRUG

3504
02:21:41,717 --> 02:21:43,519
TO SEE IF IT COULD INHIBIT THE

3505
02:21:43,519 --> 02:21:44,153
PROCESS AND ASK THE QUESTION

3506
02:21:44,153 --> 02:21:46,755
COULD THIS DRUG THEN RESCUE ANY

3507
02:21:46,755 --> 02:21:48,123
OR ALL OF THESE PHENOTYPES THAT

3508
02:21:48,123 --> 02:21:55,464
I HAVE JUST DESCRIBED.

3509
02:21:55,464 --> 02:21:57,433
SO INITIALLY WE WANT TO ASSESS

3510
02:21:57,433 --> 02:22:05,207
THE INHIBITION OF ISR AND THE

3511
02:22:05,207 --> 02:22:06,842
RESCUE, AND THE FIRST WE

3512
02:22:06,842 --> 02:22:08,043
ASSESSED WAS THIS DECREASE IN

3513
02:22:08,043 --> 02:22:10,312
TRANSLATION BY RE-ASSESSING THE

3514
02:22:10,312 --> 02:22:11,613
SUNSET ASSAY, AND WE DO SEE A

3515
02:22:11,613 --> 02:22:13,415
COMPLETE RESCUE OF THE

3516
02:22:13,415 --> 02:22:18,454
PHENOTYPE, WE ZO SEE AN INCREASF

3517
02:22:18,454 --> 02:22:20,556
MRNA TRANSLATION PROTEIN

3518
02:22:20,556 --> 02:22:22,090
SYNTHESIS IN THIS CASE.

3519
02:22:22,090 --> 02:22:24,026
THIS WAS NOT TOO SURPRISING THIS

3520
02:22:24,026 --> 02:22:26,395
IS WHAT THESE DRUGS ARE SUPPOSED

3521
02:22:26,395 --> 02:22:27,596
TO DO, THESE ACTIVATORS ARE

3522
02:22:27,596 --> 02:22:29,164
SUPPOSED TO BYPASS THE

3523
02:22:29,164 --> 02:22:31,934
PHOSPHORYLATION OF THE ACTUAL

3524
02:22:31,934 --> 02:22:36,104
ALPHA AND INCREASE OR ACTIVATE

3525
02:22:36,104 --> 02:22:41,143
MRNA TRANSLATION.

3526
02:22:41,143 --> 02:22:47,015
HOWEVER, WE'VE ALSO SEEN THAT

3527
02:22:47,015 --> 02:22:51,887
THE TREATMENT WAS ALSO ABLE TO

3528
02:22:51,887 --> 02:22:53,055
RESCUE THE DEFECT WE SAW

3529
02:22:53,055 --> 02:22:53,555
INITIALLY.

3530
02:22:53,555 --> 02:23:02,164
SO THESE CELLS RESPONDED BY

3531
02:23:02,164 --> 02:23:02,931
INCREASING THE MITOCHONDRIAL

3532
02:23:02,931 --> 02:23:03,499
POTENTIALS.

3533
02:23:03,499 --> 02:23:04,833
SO BECAUSE THIS WAS A MORE

3534
02:23:04,833 --> 02:23:06,101
FUNCTIONAL ASSAY, WE THEN ASKED

3535
02:23:06,101 --> 02:23:09,471
CAN THAT BE SUFFICIENT TO THEN

3536
02:23:09,471 --> 02:23:12,541
RESCUE THE MOST BIOLOGICAL

3537
02:23:12,541 --> 02:23:14,676
RELEVANT PHENOTYPE THAT WE HAVE

3538
02:23:14,676 --> 02:23:16,845
IDENTIFIED INITIALLY WHICH

3539
02:23:16,845 --> 02:23:17,045
WAS --

3540
02:23:17,045 --> 02:23:19,381
>> DR. MIRANDA, WE'RE
GETTING

3541
02:23:19,381 --> 02:23:19,781
OVER TIME.

3542
02:23:19,781 --> 02:23:21,216
ARE YOU WRAPPING UP SOON?

3543
02:23:21,216 --> 02:23:24,052
>> YES.

3544
02:23:24,052 --> 02:23:24,486
LAST SLIDE.

3545
02:23:24,486 --> 02:23:24,953
SORRY.

3546
02:23:24,953 --> 02:23:25,921
I DIDN'T HEAR THE SOUND.

3547
02:23:25,921 --> 02:23:29,658
SORRY.

3548
02:23:29,658 --> 02:23:30,292
THE 2 MINUTES.

3549
02:23:30,292 --> 02:23:30,726
OKAY.

3550
02:23:30,726 --> 02:23:34,496
SO THIS IS -- NEXT.

3551
02:23:34,496 --> 02:23:36,698
SO IT DID RESCUE, AND THE NEXT

3552
02:23:36,698 --> 02:23:40,702
ONE WILL BE JUST A SUMMARY.

3553
02:23:40,702 --> 02:23:50,879
THANK YOU.

3554
02:23:56,351 --> 02:23:57,152
>> THANK YOU.

3555
02:23:57,152 --> 02:23:57,819
>> THANK YOU SO MUCH.

3556
02:23:57,819 --> 02:23:58,987
THE QUESTIONS WILL BE AT THE

3557
02:23:58,987 --> 02:23:59,154
END.

3558
02:23:59,154 --> 02:24:00,222
>> THANK YOU VERY MUCHMENT
I'D

3559
02:24:00,222 --> 02:24:04,459
LIKE TO HAND OVER THE PODIUM NOW

3560
02:24:04,459 --> 02:24:06,929
TO SAM RAREDON, WHO'S COMING TO

3561
02:24:06,929 --> 02:24:10,899
US TODAY FROM THE VASCULAR

3562
02:24:10,899 --> 02:24:14,002
BIOLOGY AND THERAPEUTICS

3563
02:24:14,002 --> 02:24:15,337
PROGRAM, SO PLEASE, SAM.

3564
02:24:15,337 --> 02:24:16,438
>> HI, EVERYONE.

3565
02:24:16,438 --> 02:24:18,106
SAM RAREDON, NEW SYSTEM

3566
02:24:18,106 --> 02:24:19,074
PROFESSOR AT YALE AND I'M GOING

3567
02:24:19,074 --> 02:24:20,909
TO TALK TODAY A LITTLE BIT ABOUT

3568
02:24:20,909 --> 02:24:22,244
CELL-TO-CELL CONNECTIVITY

3569
02:24:22,244 --> 02:24:22,511
ANALYSIS.

3570
02:24:22,511 --> 02:24:23,645
AND I'M GOING TO SPEND THE FIRST

3571
02:24:23,645 --> 02:24:25,080
CHUNK OF THE TALK JUST SORT OF

3572
02:24:25,080 --> 02:24:25,981
TALKING ABOUT THE DATA STRUCTURE

3573
02:24:25,981 --> 02:24:27,616
AND WHAT YOU CAN DO WITH IT AND

3574
02:24:27,616 --> 02:24:28,317
THEN THE SECOND HALF OF THE TALK

3575
02:24:28,317 --> 02:24:29,851
IS GOING TO BE A VARIETY OF

3576
02:24:29,851 --> 02:24:31,186
DIFFERENT APPLICATIONS BOTH IN

3577
02:24:31,186 --> 02:24:32,487
LUNG AND SOME OTHER ORGAN

3578
02:24:32,487 --> 02:24:33,155
SYSTEMS JUST SO YOU CAN SEE WHAT

3579
02:24:33,155 --> 02:24:34,756
YOU CAN DO AND WHAT YOU CAN

3580
02:24:34,756 --> 02:24:36,625
STUDY WHEN YOU STUDY

3581
02:24:36,625 --> 02:24:37,359
CELL-TO-CELL COMMUNICATION AS

3582
02:24:37,359 --> 02:24:41,463
SORT OF A PRIMARY FOCUS.

3583
02:24:41,463 --> 02:24:42,864
SO I JUST WANT TO START WITH

3584
02:24:42,864 --> 02:24:44,800
THIS SCHEMATIC, WHICH IS TO SORT

3585
02:24:44,800 --> 02:24:46,702
OF POINT OUT, IT'S A TRUISM BUT

3586
02:24:46,702 --> 02:24:48,470
THAT WHEN WE STUDY CELLS WITHIN

3587
02:24:48,470 --> 02:24:50,872
TISSUES, THEY ARE IN VERY

3588
02:24:50,872 --> 02:24:52,040
LOCALIZED SPECIALIZED MICRO

3589
02:24:52,040 --> 02:24:53,241
ENVIRONMENTS, AND WE OFTEN WILL

3590
02:24:53,241 --> 02:24:54,076
STUDY CELL BIOLOGY AND WE'LL

3591
02:24:54,076 --> 02:24:55,711
THINK ABOUT INTRINSIC EFFECTS OF

3592
02:24:55,711 --> 02:24:57,679
WHAT A CELL CAN AND CANNOT DO

3593
02:24:57,679 --> 02:24:59,114
AND HOW IT MIGHT CHANGE OR NOT

3594
02:24:59,114 --> 02:25:00,182
CHANGE AND DIFFERENT PROCESSES,

3595
02:25:00,182 --> 02:25:01,216
BUT THERE'S A WHOLE 'NOTHER

3596
02:25:01,216 --> 02:25:02,250
LAYER OF INFORMATION THAT WE ARE

3597
02:25:02,250 --> 02:25:03,652
SORT OF CUTTING OUT IF WE JUST

3598
02:25:03,652 --> 02:25:05,520
STUDY THE CELLS AS INDIVIDUAL

3599
02:25:05,520 --> 02:25:06,288
SYSTEMS.

3600
02:25:06,288 --> 02:25:07,522
AND THAT'S THE INCOMING

3601
02:25:07,522 --> 02:25:08,323
SIGNALING AND THE INFORMATION

3602
02:25:08,323 --> 02:25:10,125
THAT'S BEING PROVIDED TO THEM

3603
02:25:10,125 --> 02:25:10,792
LOCALLY, WHETHER OR NOT THEY ARE

3604
02:25:10,792 --> 02:25:13,395
HEARING IT, AND THE OUTGOING

3605
02:25:13,395 --> 02:25:13,929
SIGNALING WHICH IS THE

3606
02:25:13,929 --> 02:25:14,696
INFORMATION THERE THEN PROVIDING

3607
02:25:14,696 --> 02:25:16,765
TO THEIR LOCAL CONTEXT, WHICH

3608
02:25:16,765 --> 02:25:19,067
THEN GOES OUT TO THE OTHER CELLS

3609
02:25:19,067 --> 02:25:20,002
NEARBY.

3610
02:25:20,002 --> 02:25:21,503
AND WE REALLY STARTED

3611
02:25:21,503 --> 02:25:23,038
THINKING -- THIS DIAGRAM, I'VE

3612
02:25:23,038 --> 02:25:23,839
STARTED THINKING MORE AND MORE

3613
02:25:23,839 --> 02:25:24,940
ABOUT THIS BECAUSE IT'S ACTUALLY

3614
02:25:24,940 --> 02:25:26,541
A REALLY NICE WAY OF LOOKING AT

3615
02:25:26,541 --> 02:25:28,176
IT BECAUSE IT ALWAYS TREATS

3616
02:25:28,176 --> 02:25:29,645
EVERY INDIVIDUAL CELL WITHIN A

3617
02:25:29,645 --> 02:25:31,480
TISSUE AS A SINGLE DEDICATED

3618
02:25:31,480 --> 02:25:33,582
COMPUTE UNIT THAT'S TAKING IN

3619
02:25:33,582 --> 02:25:36,018
INFORMATION, PROCESSING IT AND

3620
02:25:36,018 --> 02:25:36,618
SPITTING DIFFERENT INFORMATION

3621
02:25:36,618 --> 02:25:38,186
BACK OUT AND ADAPTING EACH TIME

3622
02:25:38,186 --> 02:25:39,287
STEP, IT'S LIKE A LITTLE STATE

3623
02:25:39,287 --> 02:25:40,589
MACHINE THAT IS CHANGING OVER

3624
02:25:40,589 --> 02:25:41,156
TIME.

3625
02:25:41,156 --> 02:25:42,357
SO THIS IS SORT OF A FRAMEWORK

3626
02:25:42,357 --> 02:25:44,893
FOR THE WHOLE TALK, AND I THINK

3627
02:25:44,893 --> 02:25:46,128
SHOWS WHY THE SIGNALING

3628
02:25:46,128 --> 02:25:47,696
INFORMATION ITSELF CAN ACTUALLY

3629
02:25:47,696 --> 02:25:48,864
BE A VERY INTERESTING TARGET OF

3630
02:25:48,864 --> 02:25:52,467
STUDY.

3631
02:25:52,467 --> 02:25:53,869
SO THIS IS SORT OF ANOTHER

3632
02:25:53,869 --> 02:25:55,103
FRAMEWORK WHICH IS THAT WHEN WE

3633
02:25:55,103 --> 02:25:58,807
TALK ABOUT THINGS LIKE TISSUE

3634
02:25:58,807 --> 02:25:59,775
BEHAVIOR, MEANING HOW IT

3635
02:25:59,775 --> 02:26:01,343
RESPONDS TO AN INJURY OR HOW IT

3636
02:26:01,343 --> 02:26:02,878
BECOMES INFLAMED OR HOW IT

3637
02:26:02,878 --> 02:26:04,680
REGENERATES OR TISSUE MORPHOLOGY

3638
02:26:04,680 --> 02:26:07,149
IN TERMS OF HOW CELLS SELF

3639
02:26:07,149 --> 02:26:08,884
ASSEMBLE AND MIGRATE AND HOW

3640
02:26:08,884 --> 02:26:11,019
THEY SORT OF FORM THE STRUCTURE

3641
02:26:11,019 --> 02:26:12,387
OF TISSUES, AS WELL AS THINGS

3642
02:26:12,387 --> 02:26:13,722
LIKE TISSUE STABILITY WHICH I

3643
02:26:13,722 --> 02:26:15,590
THINK IS VERY APT FOR THIS

3644
02:26:15,590 --> 02:26:16,692
SEMINAR BECAUSE WHEN PEOPLE ARE

3645
02:26:16,692 --> 02:26:18,293
TALKING ABOUT RESILIENCE, THE

3646
02:26:18,293 --> 02:26:19,327
WAY MY BRAIN IS PROCESSING THIS

3647
02:26:19,327 --> 02:26:21,296
IS THINKING OH, THIS IS ABOUT

3648
02:26:21,296 --> 02:26:22,664
SYSTEM STABILITY, HOW MUCH IS A

3649
02:26:22,664 --> 02:26:23,932
SYSTEM OF CELLS OR INDIVIDUAL

3650
02:26:23,932 --> 02:26:25,267
CELLS WITHIN THAT TISSUE WILLING

3651
02:26:25,267 --> 02:26:28,103
TO STAY WITHIN HOMEOSTASIS OR

3652
02:26:28,103 --> 02:26:29,137
DEVIATE AND COME BACK.

3653
02:26:29,137 --> 02:26:33,075
BUT ALL OF THESE DIFFERENT

3654
02:26:33,075 --> 02:26:34,443
CONCEPTS, WHETHER WE'RE TALKING

3655
02:26:34,443 --> 02:26:36,978
ABOUT BEHAVIOR, MORPHOLOGY AND

3656
02:26:36,978 --> 02:26:37,546
SELF ASSEMBLY OR STABILITY,

3657
02:26:37,546 --> 02:26:39,648
THERE'S A ROLE TO BE PLAYED HERE

3658
02:26:39,648 --> 02:26:40,849
FOR CELL-TO-CELL COMMUNICATION

3659
02:26:40,849 --> 02:26:41,717
AND THERE'S A HUGE AMOUNT OF

3660
02:26:41,717 --> 02:26:43,351
INFORMATION PROCESSING THAT'S

3661
02:26:43,351 --> 02:26:44,352
GOING ON AT THAT LEVEL THAT

3662
02:26:44,352 --> 02:26:45,554
BECOMES VERY IMPORTANT FOR

3663
02:26:45,554 --> 02:26:46,688
REGENERATIVE MEDICINE

3664
02:26:46,688 --> 02:26:48,290
APPLICATIONS IN PARTICULAR.

3665
02:26:48,290 --> 02:26:51,259
LIKE DR. SHI LER TALKED ABOUT

3666
02:26:51,259 --> 02:26:53,128
YESTERDAY INFLUENCING TISSUE

3667
02:26:53,128 --> 02:26:57,399
STATE, PUSHING LARGE SETS FROM

3668
02:26:57,399 --> 02:27:01,803
AN ABERRANT PATHOLOGIC STATE,

3669
02:27:01,803 --> 02:27:03,972
THIS SHOULDING SOMEBODY WE

3670
02:27:03,972 --> 02:27:05,073
PROBABLY SHOULD BE STUDYING AND

3671
02:27:05,073 --> 02:27:05,974
THINKING ABOUT HOW WE MIGHT BE

3672
02:27:05,974 --> 02:27:07,042
ABLE TO INFLUENCE.

3673
02:27:07,042 --> 02:27:08,777
SO THIS IS ANOTHER VIEW OF THIS

3674
02:27:08,777 --> 02:27:09,611
WHICH IS THAT YOU CAN ACTUALLY

3675
02:27:09,611 --> 02:27:11,880
LOOK AT CONNECTIVITY DATA AS

3676
02:27:11,880 --> 02:27:12,948
NETWORK STRUCTURE, AND ALL OF

3677
02:27:12,948 --> 02:27:14,116
THE DATA SORT OF PROCESSING

3678
02:27:14,116 --> 02:27:15,717
THINGS I'M GOING TO SHOW TODAY

3679
02:27:15,717 --> 02:27:17,252
ARE DERIVED FROM THIS CENTRAL

3680
02:27:17,252 --> 02:27:18,386
CONCEPT, WHICH IS REGARDLESS OF

3681
02:27:18,386 --> 02:27:20,922
WHAT PROCESS YOU'RE STUDYING,

3682
02:27:20,922 --> 02:27:23,492
THERE'S A NETWORK ARCHITECTURE

3683
02:27:23,492 --> 02:27:27,229
ON THE CELL-TO-CELL SIGNALING

3684
02:27:27,229 --> 02:27:28,663
LEVEL, YOU GO FROM MULTIPLE

3685
02:27:28,663 --> 02:27:30,031
CELLS TO MULTIPLE KRIL TYPES,

3686
02:27:30,031 --> 02:27:31,533
YOU SEE AN INCREASING DIVERSITY

3687
02:27:31,533 --> 02:27:33,502
OF CELL TYPES BUT YOU ALSO SEE

3688
02:27:33,502 --> 02:27:34,569
INCREASING DIVERSITY OF

3689
02:27:34,569 --> 02:27:35,670
CELL-TO-CELL COMMUNICATION

3690
02:27:35,670 --> 02:27:36,638
STYLES THAT ARE PRESENT WITHIN A

3691
02:27:36,638 --> 02:27:37,339
TISSUE.

3692
02:27:37,339 --> 02:27:38,373
THIS EVENTUALLY OF COURSE LEADS

3693
02:27:38,373 --> 02:27:41,209
TO DEVELOPMENT OF HOMEOSTASIS.

3694
02:27:41,209 --> 02:27:42,911
WHEN WE SEE INFLAMMATION WHERE

3695
02:27:42,911 --> 02:27:44,412
WE MIGHT HAVE EX-TRAF JAITION OF

3696
02:27:44,412 --> 02:27:45,680
NEW CELLS INTO THE TISSUES THAT

3697
02:27:45,680 --> 02:27:47,249
ARE INFLAMED AND ACTIVATING THAT

3698
02:27:47,249 --> 02:27:48,650
TISSUE, WE ALMOST GET A NEW NODE

3699
02:27:48,650 --> 02:27:49,985
OR A NEW PRESENCE OF A NEW NODE

3700
02:27:49,985 --> 02:27:51,553
WITHIN THESE GRAPHS WHERE WE

3701
02:27:51,553 --> 02:27:56,758
HAVE HOMEOSTATIC SYSTEM AND THEN

3702
02:27:56,758 --> 02:27:58,393
THERE'S NEW CELLS BROUGHT IN AND

3703
02:27:58,393 --> 02:27:59,528
IT CHANGES THE GRAPH STRUCTURE

3704
02:27:59,528 --> 02:28:00,762
AND IF THE TISSUE HEALS, IT

3705
02:28:00,762 --> 02:28:02,230
COMES BACK TO HOMEOSTASIS.

3706
02:28:02,230 --> 02:28:04,566
BUT WE ALSO SEE THESE PATTERNS

3707
02:28:04,566 --> 02:28:07,235
IN PROGRESSIVE DISEASE, WHICH

3708
02:28:07,235 --> 02:28:10,372
I'VE DONE A LOT OF TRAINING IN

3709
02:28:10,372 --> 02:28:12,073
PULMONARY FIBROSIS AND WHAT WE

3710
02:28:12,073 --> 02:28:13,141
SEE ESSENTIALLY IS THE GRAPH ON

3711
02:28:13,141 --> 02:28:14,509
THE BOTTOM, YOU START TO GET

3712
02:28:14,509 --> 02:28:22,217
THESE AB BRANDT C ABERRANT CELLU

3713
02:28:22,217 --> 02:28:25,520
EVENTUALLY GET THIS SORT OF

3714
02:28:25,520 --> 02:28:26,488
PROGRESSIVE DIVERSION OR LOCKED

3715
02:28:26,488 --> 02:28:27,656
IN SYSTEM THAT'S NOT ABLE TO

3716
02:28:27,656 --> 02:28:28,156
COME BACK.

3717
02:28:28,156 --> 02:28:29,658
SO HOW DO WE STUDY THIS?

3718
02:28:29,658 --> 02:28:31,793
THERE'S A NUMBER OF STRENGTHS TO

3719
02:28:31,793 --> 02:28:33,595
THIS TYPE OF DATA BUT ONE OF

3720
02:28:33,595 --> 02:28:34,996
THEM IS WE'RE MEASURING MANY,

3721
02:28:34,996 --> 02:28:36,698
MANY CELLS AT ONCE FROM AN

3722
02:28:36,698 --> 02:28:37,499
INDIVIDUAL TIME POINT AND THIS

3723
02:28:37,499 --> 02:28:38,567
IS SOMETHING YOU WOULD REALLY

3724
02:28:38,567 --> 02:28:39,634
STRUG TOLL DO WITH OTHER

3725
02:28:39,634 --> 02:28:39,935
TECHNIQUES.

3726
02:28:39,935 --> 02:28:43,872
AT A SINGLE TIME POINT YOU CAN

3727
02:28:43,872 --> 02:28:46,208
GET SPATIAL DATA AND YOU GET

3728
02:28:46,208 --> 02:28:48,210
INFORMATION FROM AN ENTIRE

3729
02:28:48,210 --> 02:28:49,744
SYSTEM, YOU CAN SAY THESE CELLS

3730
02:28:49,744 --> 02:28:51,112
EITHER ARE INTERACTING OR HAVE

3731
02:28:51,112 --> 02:28:52,314
THE POTENTIAL TO INTERACT.

3732
02:28:52,314 --> 02:28:55,584
THIS IS JUST AN EXAMPLE OF A

3733
02:28:55,584 --> 02:28:58,220
NATIVE RAT THAT WE'VE GENERATED

3734
02:28:58,220 --> 02:29:00,689
WHICH I'LL USE SORT OF FOR SOME

3735
02:29:00,689 --> 02:29:04,459
DEMONSTRATIONS.

3736
02:29:04,459 --> 02:29:09,164
SO IN THESE DATA, ANYONE WHO'S

3737
02:29:09,164 --> 02:29:10,465
STUDYING CELL-TO-CELL SIGNAL

3738
02:29:10,465 --> 02:29:12,300
WILLING LOOK AT THE LIGAND AND

3739
02:29:12,300 --> 02:29:14,703
RECEPTOR EX-TRETION FOR

3740
02:29:14,703 --> 02:29:15,937
DIFFERENT CONNECTIVITY

3741
02:29:15,937 --> 02:29:16,504
COMMUNICATION MECHANISMS AND

3742
02:29:16,504 --> 02:29:18,406
VERY OFTEN THE PATTERNS IN THESE

3743
02:29:18,406 --> 02:29:19,975
DATA LOOK LIKE WHAT I'M SHOWING

3744
02:29:19,975 --> 02:29:21,309
HERE, WHICH IS THAT ONE CELL

3745
02:29:21,309 --> 02:29:24,079
TYPE WILL EXPRESS A LIGAND, THE

3746
02:29:24,079 --> 02:29:25,614
OTHER WILL EXPRESS A RECEPTOR,

3747
02:29:25,614 --> 02:29:26,915
AND THE FIRST GENERATION TOOLS

3748
02:29:26,915 --> 02:29:28,216
OF WHICH THERE ARE LIKE 40 OR 50

3749
02:29:28,216 --> 02:29:29,818
OF THEM NOW, WE BROKE ONE OF

3750
02:29:29,818 --> 02:29:32,254
THEM, BUT THERE'S CELL PHONE --

3751
02:29:32,254 --> 02:29:33,488
THERE'S A LOT OF THEM.

3752
02:29:33,488 --> 02:29:34,723
THEY WILL TEND TO AGGREGATE

3753
02:29:34,723 --> 02:29:35,023
INFORMING.

3754
02:29:35,023 --> 02:29:36,091
THEY WILL SAY WE'RE GOING TO

3755
02:29:36,091 --> 02:29:37,359
TAKE YOUR CELL TYPE LABELS AND

3756
02:29:37,359 --> 02:29:38,560
WE'RE GOING TO LOOK JUST AS A

3757
02:29:38,560 --> 02:29:39,861
WHOLE, WE'RE GOING TO SAY WHAT'S

3758
02:29:39,861 --> 02:29:41,630
THE LIGAND EXPRESSION FOR CELL

3759
02:29:41,630 --> 02:29:42,864
TYPE A THAT YOU PUT THOSE

3760
02:29:42,864 --> 02:29:45,400
ANNOTATIONS ON AND WHAT'S THE --

3761
02:29:45,400 --> 02:29:47,235
THEY'LL GIVE YOU A SINGLE IJ

3762
02:29:47,235 --> 02:29:48,570
HERE WHICH IS AN AGGREGATED

3763
02:29:48,570 --> 02:29:49,771
SCORED VALUE, AND YOU CAN DO A

3764
02:29:49,771 --> 02:29:50,305
LOT WITH THIS.

3765
02:29:50,305 --> 02:29:51,673
BUT IT LOSES A TON OF

3766
02:29:51,673 --> 02:29:55,377
INFORMATION.

3767
02:29:55,377 --> 02:29:56,678
SO THIS IS REALLY HOW WE SHOULD

3768
02:29:56,678 --> 02:29:57,812
BE DOING THIS IN ORDER TO

3769
02:29:57,812 --> 02:29:59,347
MAXIMIZE THE STATISTICAL POWER

3770
02:29:59,347 --> 02:29:59,814
OF THIS DATA.

3771
02:29:59,814 --> 02:30:01,316
THIS IS APPLICABLE TO LIKE ALL

3772
02:30:01,316 --> 02:30:03,852
SINGLE CELL DATA ANALYSIS, BUT

3773
02:30:03,852 --> 02:30:04,986
ONE THING THAT WE CAN DO THAT'S

3774
02:30:04,986 --> 02:30:06,421
VERY POWERFUL IS RATHER THAN

3775
02:30:06,421 --> 02:30:08,023
AGGREGATING, WE CAN GO IN AND

3776
02:30:08,023 --> 02:30:09,257
MAKE ONE TO ONE PAIRS OF A GIVEN

3777
02:30:09,257 --> 02:30:10,458
CELL AND ANOTHER CELL AND SAY

3778
02:30:10,458 --> 02:30:12,060
WE'RE GOING TO TREAT THESE AS

3779
02:30:12,060 --> 02:30:13,828
COMMUNICATING OR AGAIN, IF YOU

3780
02:30:13,828 --> 02:30:14,696
HAVE SPATIAL INFORMATION, YOU

3781
02:30:14,696 --> 02:30:15,830
ACTUALLY DO THIS WITHIN LOCAL

3782
02:30:15,830 --> 02:30:16,831
NEIGHBORHOODS, WHICH IS REALLY

3783
02:30:16,831 --> 02:30:17,666
POWERFUL.

3784
02:30:17,666 --> 02:30:18,733
AND YOU LOOK AT SINGLE EDGES,

3785
02:30:18,733 --> 02:30:20,035
YOU LITERALLY LOOK AT ONE CELL

3786
02:30:20,035 --> 02:30:21,870
TO ANOTHER CELL AND I IS A LET'S

3787
02:30:21,870 --> 02:30:22,938
CHARACTERIZE THAT EDGE AND IN

3788
02:30:22,938 --> 02:30:24,406
THIS CASE, WHAT I'M SHOWING ON

3789
02:30:24,406 --> 02:30:25,640
THE SCREEN HERE IS JUST ONE

3790
02:30:25,640 --> 02:30:26,107
MECHANISM.

3791
02:30:26,107 --> 02:30:28,910
WE COULD SAMPLE A HUNDRED PAIRS

3792
02:30:28,910 --> 02:30:31,813
OF CELLS FOR A GIVEN MECHANISM,

3793
02:30:31,813 --> 02:30:35,917
LIGAND X TO LIGAND Y -- BUT WE

3794
02:30:35,917 --> 02:30:37,185
ACTUALLY HAVE MANY THOUSANDS OF

3795
02:30:37,185 --> 02:30:39,387
MECHANISMS IN THESE DATA.

3796
02:30:39,387 --> 02:30:41,923
SO THIS IS HOW WE STRUCTURE OUR

3797
02:30:41,923 --> 02:30:43,091
CONNECTIVITY DATA, AND THERE'S A

3798
02:30:43,091 --> 02:30:43,959
COUPLE DIFFERENT PLATFORMS OUT

3799
02:30:43,959 --> 02:30:44,759
THERE THAT DO THIS.

3800
02:30:44,759 --> 02:30:48,096
FROM EAR ON, I'M GOING TO SHOW

3801
02:30:48,096 --> 02:30:51,766
YOU DATA AND ANALYSIS WITH A

3802
02:30:51,766 --> 02:30:54,869
PACKAGE WE WRITE AND MAINTAIN

3803
02:30:54,869 --> 02:30:57,539
CALLED NICHES, WE HAD TO FIGURE

3804
02:30:57,539 --> 02:30:58,740
OUT AN ACRONYM TO MAKE IT LOOK

3805
02:30:58,740 --> 02:30:59,641
PRETTY, BUT THIS IS THE

3806
02:30:59,641 --> 02:31:00,542
STRUCTURE OF THE DATA AND ONE

3807
02:31:00,542 --> 02:31:01,843
THING THAT I THINK IS REALLY

3808
02:31:01,843 --> 02:31:02,877
BEAUTIFUL ABOUT THIS IS THAT WE

3809
02:31:02,877 --> 02:31:04,579
FIGURED OUT A WAY TO TAKE

3810
02:31:04,579 --> 02:31:05,447
CELL-TO-CELL SIGNALING

3811
02:31:05,447 --> 02:31:09,751
INFORMATION AN OR REALLY

3812
02:31:09,751 --> 02:31:10,485
CELL-TO-CELL CONNECTIVITY DATA

3813
02:31:10,485 --> 02:31:12,120
AND FORMAT IT IN A WAY THAT'S

3814
02:31:12,120 --> 02:31:13,521
JUST THE SAME AS SINGLE CELL

3815
02:31:13,521 --> 02:31:14,622
DATA, WHERE SINGLE CELL DATA

3816
02:31:14,622 --> 02:31:16,791
WOULD HAVE A DIGITAL GENE

3817
02:31:16,791 --> 02:31:18,293
EXPRESSION MATRIX MEANING THE

3818
02:31:18,293 --> 02:31:19,461
ROWS ARE INDIVIDUAL GENES AND

3819
02:31:19,461 --> 02:31:20,428
THE COLUMBUS ARE INDIVIDUAL

3820
02:31:20,428 --> 02:31:21,696
CELLS, AND WHAT WE'VE DONE HERE

3821
02:31:21,696 --> 02:31:24,466
IS WE'VE CREATED A PARALLEL DATA

3822
02:31:24,466 --> 02:31:25,734
FRAMEWORK WHERE THE ROWS HERE

3823
02:31:25,734 --> 02:31:27,268
ARE SIGNALING MECHANISMS,

3824
02:31:27,268 --> 02:31:28,903
MEANING A LIGAND TO A RECEPTOR,

3825
02:31:28,903 --> 02:31:30,405
AND THE COLUMNS HERE ARE NOT

3826
02:31:30,405 --> 02:31:32,474
CELLS BUT THEY'RE EDGES, THEY'RE

3827
02:31:32,474 --> 02:31:34,809
A PAIR OF SENDING CELL TO A

3828
02:31:34,809 --> 02:31:35,910
RECEIVING CELL AND THEN WE

3829
02:31:35,910 --> 02:31:38,413
CHARACTERIZE ALL OF THESE EDGES

3830
02:31:38,413 --> 02:31:40,281
AND PUT THIS RIGHT BACK INTO

3831
02:31:40,281 --> 02:31:41,549
SINGLE CELL PLATFORMS AND DO

3832
02:31:41,549 --> 02:31:43,318
SOME REALLY COOL PROCESSING.

3833
02:31:43,318 --> 02:31:44,152
ONE THING THAT'S IMPORTANT ABOUT

3834
02:31:44,152 --> 02:31:46,554
THIS IS WE CARRY THE METADATA

3835
02:31:46,554 --> 02:31:47,188
WITH IT.

3836
02:31:47,188 --> 02:31:49,324
SO IF YOU HAVE LOCATION

3837
02:31:49,324 --> 02:31:51,226
INFORMATION, SAMPLE PATIENT

3838
02:31:51,226 --> 02:31:52,794
IDs, DISEASE, APPLICATION OF A

3839
02:31:52,794 --> 02:31:54,195
DRUG, THAT METADATA ALL COMES

3840
02:31:54,195 --> 02:31:56,297
OVER AND WE CAN SEE IT FROM OUR

3841
02:31:56,297 --> 02:31:57,332
SENDING AND RECEIVING CELLS AND

3842
02:31:57,332 --> 02:31:58,400
THAT BECOMES VERY IMPORTANT

3843
02:31:58,400 --> 02:32:00,835
LATER AND THIS MAKES US VERY

3844
02:32:00,835 --> 02:32:01,703
STATISTICALLY FLEXIBLE.

3845
02:32:01,703 --> 02:32:03,171
SO THIS IS JUST SORT OF THE

3846
02:32:03,171 --> 02:32:04,172
WORKFLOW THAT WE DO AND FROM

3847
02:32:04,172 --> 02:32:05,673
HERE ON, I'M GOING TO SHOW YOU

3848
02:32:05,673 --> 02:32:06,741
SOME APPLICATIONS.

3849
02:32:06,741 --> 02:32:10,345
SO YOU HAVE AN INPUT, A SINGLE

3850
02:32:10,345 --> 02:32:15,083
CELL GENE EXPRESSION MATRIX,

3851
02:32:15,083 --> 02:32:15,817
SPATIAL TRANSCRIPTOMICS

3852
02:32:15,817 --> 02:32:16,117
INFORMATION.

3853
02:32:16,117 --> 02:32:16,851
THERE ARE MANY THAT COME WITH

3854
02:32:16,851 --> 02:32:18,086
THE TOOL ALREADY BUT YOU CAN

3855
02:32:18,086 --> 02:32:19,054
ALSO DESIGN YOUR OWN AND THAT'S

3856
02:32:19,054 --> 02:32:20,622
JUST A LIST OF KNOWN OR

3857
02:32:20,622 --> 02:32:21,756
HYPOTHESIZED LIGAND RECEPTOR

3858
02:32:21,756 --> 02:32:22,891
MECHANISMS THAT YOU WANT TO

3859
02:32:22,891 --> 02:32:23,792
QUERY.

3860
02:32:23,792 --> 02:32:28,029
AND THE OUT PUME OUTPUTS FROM TA

3861
02:32:28,029 --> 02:32:28,630
CELL-TO-CELL OBJECT AS WELL AS

3862
02:32:28,630 --> 02:32:30,565
SOME SORT OF HIGHER DIMENSIONAL

3863
02:32:30,565 --> 02:32:31,733
SYSTEM CELL OBJECTS AND THEY

3864
02:32:31,733 --> 02:32:34,135
ALLOW YOU TO PUT THIS RIGHT INTO

3865
02:32:34,135 --> 02:32:36,704
ANY OTHER KIND OF SINGLE CELL

3866
02:32:36,704 --> 02:32:39,240
TOOL AND STUDYING IN PARALLEL

3867
02:32:39,240 --> 02:32:40,608
WHILE YOU'RE STUDYING TRANS

3868
02:32:40,608 --> 02:32:42,777
SCRIP TOE MIBG, OR THE OTHER

3869
02:32:42,777 --> 02:32:44,212
TYPES OF PROTEOMIC DATA.

3870
02:32:44,212 --> 02:32:45,680
SO THIS IS WHAT THIS LOOKS LIKE.

3871
02:32:45,680 --> 02:32:47,215
THIS IS JUST A DEMONSTRATION ON

3872
02:32:47,215 --> 02:32:49,951
A SMALL DEMONSTRATION -- YOU CAN

3873
02:32:49,951 --> 02:32:51,352
SEE THESE ARE FOUR DIFFERENT

3874
02:32:51,352 --> 02:32:53,188
CELL TYPES COLLECTED FROM THE

3875
02:32:53,188 --> 02:32:54,089
ALVEOLAR REGION OF THE LUNG.

3876
02:32:54,089 --> 02:32:55,857
THERE ARE 16 CELL TYPE TO CELL

3877
02:32:55,857 --> 02:32:57,592
TYPE CROSSES THAT YOU COULD

3878
02:32:57,592 --> 02:32:59,294
PREDICT SHOULD SHOW UP FROM THIS

3879
02:32:59,294 --> 02:33:00,095
IN PANEL I.

3880
02:33:00,095 --> 02:33:01,729
YOU CAN SEE UNDER PANEL J,

3881
02:33:01,729 --> 02:33:04,399
THERE'S AN EMBEDDING, NOT OF

3882
02:33:04,399 --> 02:33:05,133
CELLULAR INFORMATION BUT OF EDGE

3883
02:33:05,133 --> 02:33:07,635
INFORMATION, AND YOU CAN SEE THE

3884
02:33:07,635 --> 02:33:08,770
ANNOTATIONS HAVE CARRIED OVER SO

3885
02:33:08,770 --> 02:33:11,773
THERE ARE DISTINCT SIGNALING

3886
02:33:11,773 --> 02:33:14,642
STYLES OR WHAT WE CALL SIGNALING

3887
02:33:14,642 --> 02:33:15,677
ARCHETYPES ASSOCIATED WITH EACH

3888
02:33:15,677 --> 02:33:17,011
CELL TYPE TO CELL TYPE CROSS.

3889
02:33:17,011 --> 02:33:19,247
YOU CAN THEN RUN CELL

3890
02:33:19,247 --> 02:33:20,348
DIFFERENTIAL EXPRESSION AND YOU

3891
02:33:20,348 --> 02:33:21,182
CAN CHARACTERIZE EACH ONE OF

3892
02:33:21,182 --> 02:33:22,617
THOSE SIGNALING ARCHETYPES BASED

3893
02:33:22,617 --> 02:33:24,552
ON THE SIGNALING MECHANISMS

3894
02:33:24,552 --> 02:33:25,620
THEY'RE MOST LIKELY TO EMPLOY.

3895
02:33:25,620 --> 02:33:27,655
IF YOU LOOK CLOSELY AT THE ROWS,

3896
02:33:27,655 --> 02:33:29,724
THEY ARE NOT GENES BUT LIGAND

3897
02:33:29,724 --> 02:33:30,525
RECEPTOR PAIRS.

3898
02:33:30,525 --> 02:33:32,494
YOU CAN THINK OF THEM AS LIKE A

3899
02:33:32,494 --> 02:33:33,962
RADIO FREQUENCY, THAT DIFFERENT

3900
02:33:33,962 --> 02:33:35,563
CELL TYPES ARE UNIQUELY TUNED TO

3901
02:33:35,563 --> 02:33:37,031
WITHIN THIS GIVEN SYSTEM OF

3902
02:33:37,031 --> 02:33:39,334
STUDY.

3903
02:33:39,334 --> 02:33:42,137
SO THIS IS AN APPLICATION TO

3904
02:33:42,137 --> 02:33:47,008
PULMONARY FIBROSIS DATA FROM DR,

3905
02:33:47,008 --> 02:33:48,877
AND THIS DATA IS A VERY DENSE

3906
02:33:48,877 --> 02:33:49,844
SLIDE BUT EVERYTHING YOU'RE

3907
02:33:49,844 --> 02:33:51,513
SEEING HERE IS CONNECTIVITY

3908
02:33:51,513 --> 02:33:52,080
INFORMATION, IT'S NOT CELL

3909
02:33:52,080 --> 02:33:52,514
INFORMATION.

3910
02:33:52,514 --> 02:33:53,948
AND YOU CAN SEE ON THE LEFT SIDE

3911
02:33:53,948 --> 02:33:55,483
OF THE SCREEN THAT IT CARRIES

3912
02:33:55,483 --> 02:33:56,784
OVER DISEASE IDENTITY AND

3913
02:33:56,784 --> 02:33:57,719
SUBJECT IDENTITY, AND THEN WE

3914
02:33:57,719 --> 02:33:58,987
HAVE THESE TWO PIECES OF

3915
02:33:58,987 --> 02:34:00,054
INFORMATION, WHICH IS SENDING

3916
02:34:00,054 --> 02:34:01,823
CELL CLASS AND I'VE CLASSIFIED

3917
02:34:01,823 --> 02:34:04,993
THEM AS EPITHELIUM, ENDOTHELIUM,

3918
02:34:04,993 --> 02:34:06,761
AND RECEIVING SELL CLASS, AND IF

3919
02:34:06,761 --> 02:34:11,366
WE DON'T GO IN, BUT HIS

3920
02:34:11,366 --> 02:34:13,201
EPITHELIAL TO MESENCHYMAL

3921
02:34:13,201 --> 02:34:14,269
SIGNALING, JUST COMPUTATIONALLY

3922
02:34:14,269 --> 02:34:17,105
WE CAN GET A REALLY BEAUTIFUL

3923
02:34:17,105 --> 02:34:21,609
PORTRAIT IN CONTROL TISSUE AND

3924
02:34:21,609 --> 02:34:22,410
PULMONARY -- IS THAT WHY WHEN

3925
02:34:22,410 --> 02:34:23,678
YOU PULL OUT FEATURES YOU CAN

3926
02:34:23,678 --> 02:34:28,082
SEE THINGS LIKE CONNECTIVITY VIA

3927
02:34:28,082 --> 02:34:30,818
WIN7A AND THROUGH -- ARE REALLY

3928
02:34:30,818 --> 02:34:32,420
ENRICHED ALMOST SPECIFIC TO IPF

3929
02:34:32,420 --> 02:34:33,588
TISSUE, AND WHEN YOU THEN LOOK

3930
02:34:33,588 --> 02:34:34,756
AT THE BOTTOM PANEL HERE WHERE

3931
02:34:34,756 --> 02:34:35,924
YOU LOOK AT SENDING AND

3932
02:34:35,924 --> 02:34:37,859
RECEIVING CELL TYPE, YOU CAN

3933
02:34:37,859 --> 02:34:39,427
ACTUALLY SEE THIS IS SIGNALING

3934
02:34:39,427 --> 02:34:42,163
FROM THE ABERRANT BASAL CELLS

3935
02:34:42,163 --> 02:34:45,567
WE'VE HEARD SO MUCH ABOUT TO

3936
02:34:45,567 --> 02:34:49,170
FIBROBLAST AND MILD FIBROBLAST

3937
02:34:49,170 --> 02:34:51,406
CELLS, AND NO OTHER CELLS IN THE

3938
02:34:51,406 --> 02:34:52,840
NORMAL HEALTHY LUNG ARE REALLY

3939
02:34:52,840 --> 02:34:54,142
TUNED IN THIS WAY WHERE THEY

3940
02:34:54,142 --> 02:34:55,243
COULD PASS INFORMATION THROUGH

3941
02:34:55,243 --> 02:34:57,078
THESE PATHWAYS BUT WE SEE IT

3942
02:34:57,078 --> 02:34:59,280
VERY PROMINENTLY IN PULMONARY

3943
02:34:59,280 --> 02:34:59,781
FIBROSIS.

3944
02:34:59,781 --> 02:35:01,883
IF YOU'RE INTERESTED, YOU CAN

3945
02:35:01,883 --> 02:35:03,618
SEE A PRE-PRINT.

3946
02:35:03,618 --> 02:35:06,588
THESE ARE ENGINEERED LUNG

3947
02:35:06,588 --> 02:35:08,489
TISSUES WHERE DIFFERENT CELL

3948
02:35:08,489 --> 02:35:11,693
COMBINATIONS WITHIN A

3949
02:35:11,693 --> 02:35:12,694
BIOENGINEER SCAFFOLD.

3950
02:35:12,694 --> 02:35:14,596
ON THE RIGHT WE CAN SEE A QUAD

3951
02:35:14,596 --> 02:35:17,699
CULTURE SYSTEM WHERE WE'VE ADDED

3952
02:35:17,699 --> 02:35:18,900
IN ALVEOLAR MACROPHAGES.

3953
02:35:18,900 --> 02:35:19,801
WHAT'S IMPORTANT FOR THIS TALK

3954
02:35:19,801 --> 02:35:22,237
IS THE GRAPH STRUCTURE, WHEN WE

3955
02:35:22,237 --> 02:35:23,905
HAVE SINGLE EDGE DATA, WE CAN

3956
02:35:23,905 --> 02:35:25,974
ACTUALLY VISUALIZE THOSE IN

3957
02:35:25,974 --> 02:35:27,642
THESE U MAP EMBEDDINGS WHICH IS

3958
02:35:27,642 --> 02:35:30,945
A REALLY BEAUTIFUL WAY TO LOOK

3959
02:35:30,945 --> 02:35:32,880
AAT IT.

3960
02:35:32,880 --> 02:35:35,883
YOU CAN SEE HOW THE CONNECTIVITY

3961
02:35:35,883 --> 02:35:37,518
STRUCTURE HAS PHYSICALLY

3962
02:35:37,518 --> 02:35:37,752
CHANGED.

3963
02:35:37,752 --> 02:35:39,354
THIS IS A NICE OFF-TARGET EFFECT

3964
02:35:39,354 --> 02:35:41,990
BECAUSE WE'VE ADDED IMMUNE CELLS

3965
02:35:41,990 --> 02:35:45,059
BUT THE BIGGEST SEEN WE'RE

3966
02:35:45,059 --> 02:35:48,630
SEEING -- FROM EPITHELIUM TO

3967
02:35:48,630 --> 02:35:49,697
MESS -- IN THE PRESENCE OF

3968
02:35:49,697 --> 02:35:54,335
IMMUNE CELLS.

3969
02:35:54,335 --> 02:35:55,503
THIS IS A BUSY SLIDE, GIVEN THAT

3970
02:35:55,503 --> 02:35:57,872
I'M TIED ON TIME I'LL FOCUS ON

3971
02:35:57,872 --> 02:35:58,706
THE RIGHT SIDE OF THIS.

3972
02:35:58,706 --> 02:36:01,542
FOR THOSE INTERESTED IN STUDYING

3973
02:36:01,542 --> 02:36:04,612
DYNAMIC PROCESSES, NICHES LENDS

3974
02:36:04,612 --> 02:36:05,713
ITSELF REALLY, REALLY WELL TO

3975
02:36:05,713 --> 02:36:06,514
THIS BECAUSE YOU GO INTO EACH

3976
02:36:06,514 --> 02:36:08,049
ONE OF YOUR SAMPLES, TIME

3977
02:36:08,049 --> 02:36:11,419
POINTS, AND YOU CAN CA CALCULATE

3978
02:36:11,419 --> 02:36:12,787
CONNECTIVITY FOR EACH ONE AND

3979
02:36:12,787 --> 02:36:14,088
THEN MERGE THEM TOGETHER AND

3980
02:36:14,088 --> 02:36:18,059
LOOK FOR TRENDS, AND YOU CAN SEE

3981
02:36:18,059 --> 02:36:20,628
ACTUALLY CONNECTIVITY CURVES IN

3982
02:36:20,628 --> 02:36:25,500
PARTICULAR IN PANEL D, WINT4 --

3983
02:36:25,500 --> 02:36:27,435
YOU CAN ALSO SEE THE CELLS THAT

3984
02:36:27,435 --> 02:36:28,102
ARE ASSOCIATED WITH THAT CHANGE

3985
02:36:28,102 --> 02:36:30,071
AND IN THIS CASE, THE MESS THEEL

3986
02:36:30,071 --> 02:36:32,273
YELL TO SORT OF ALVEOLAR

3987
02:36:32,273 --> 02:36:33,908
PROGENITOR CELL TUNING IS REALLY

3988
02:36:33,908 --> 02:36:39,881
DYNAMIC IN THIS SYSTEM.

3989
02:36:39,881 --> 02:36:40,782
THIS IS A NICE -- I THINK

3990
02:36:40,782 --> 02:36:42,050
THERE'S A NUMBER OF PEOPLE AND I

3991
02:36:42,050 --> 02:36:43,217
THINK WE'RE HEARING A LOT ABOUT

3992
02:36:43,217 --> 02:36:44,986
THE DIFFICULTY OF TRANSLATING

3993
02:36:44,986 --> 02:36:46,954
ACROSS SPECIES AND THIS IS A

3994
02:36:46,954 --> 02:36:48,089
VERY REAL DIFFICULT HARD

3995
02:36:48,089 --> 02:36:48,356
PROBLEM.

3996
02:36:48,356 --> 02:36:49,657
I'VE GOT A LOT OF COLLEAGUES WHO

3997
02:36:49,657 --> 02:36:51,125
ARE ALSO STUDYING THIS, AND OR

3998
02:36:51,125 --> 02:36:52,727
THOLG IS NOT ALWAYS CLEAR

3999
02:36:52,727 --> 02:36:54,295
BETWEEN HUMANS AND MICE AND RATS

4000
02:36:54,295 --> 02:36:55,663
AND FERRETS AND MONKEYS AND

4001
02:36:55,663 --> 02:36:56,130
PIGS.

4002
02:36:56,130 --> 02:36:57,465
THEY'VE GOT DIFFERENT GENOMES

4003
02:36:57,465 --> 02:36:58,366
AND THOSE GENES ARE DISTRIBUTED

4004
02:36:58,366 --> 02:36:59,434
IN DIFFERENT WAYS WITHIN THE

4005
02:36:59,434 --> 02:36:59,867
DIFFERENT CELLS.

4006
02:36:59,867 --> 02:37:01,436
SO IT CAN BE A CHALLENGE.

4007
02:37:01,436 --> 02:37:03,871
WE HAVE STARTED TO SEE THAT

4008
02:37:03,871 --> 02:37:04,872
CONNECTIVITY STRUCTURE, HOWEVER,

4009
02:37:04,872 --> 02:37:06,874
IS A REALLY NICE WAY TO LOOK AT

4010
02:37:06,874 --> 02:37:08,343
GENETIC OR THOLG AND CELL TYPE

4011
02:37:08,343 --> 02:37:09,844
OR THOLG AND THIS IS JUST AN

4012
02:37:09,844 --> 02:37:11,779
EXAMPLE OF SOME DATA FROM RAT

4013
02:37:11,779 --> 02:37:15,983
LUNG, WHICH AGAIN I'VE GROUPED

4014
02:37:15,983 --> 02:37:17,185
INTO -- AND THEY'VE BEEN

4015
02:37:17,185 --> 02:37:18,119
CLUSTERED INDEPENDENTLY AND

4016
02:37:18,119 --> 02:37:18,953
LOOKING AT THE EDGE STRUCTURE

4017
02:37:18,953 --> 02:37:20,188
WITHIN THESE.

4018
02:37:20,188 --> 02:37:23,024
YOU'LL NOTE THAT IN -- WE'VE GOT

4019
02:37:23,024 --> 02:37:24,592
AN R -- VERY PRESENT AND

4020
02:37:24,592 --> 02:37:26,194
PROMINENT IN THE RAT AND PRETTY

4021
02:37:26,194 --> 02:37:29,230
MUCH ABSENT IN THE HUMAN, BUT WE

4022
02:37:29,230 --> 02:37:30,798
DO SEE -- CONNECTIVITY WITH A

4023
02:37:30,798 --> 02:37:32,266
VERY SIMILAR STRUCTURE IN THE

4024
02:37:32,266 --> 02:37:34,202
HUMAN DATA, SO IT STARTS ALLOW

4025
02:37:34,202 --> 02:37:35,803
YOU TO SAY MAYBE THESE ARE

4026
02:37:35,803 --> 02:37:39,507
FUNCTIONALLY ORTHOLOGUS AND

4027
02:37:39,507 --> 02:37:42,810
EVOLUTIONARILY THERE'S BEEN A

4028
02:37:42,810 --> 02:37:45,646
DIVERGENCE -- AND FINALLY, THIS

4029
02:37:45,646 --> 02:37:47,215
IS I THINK THE MOST EXCITING

4030
02:37:47,215 --> 02:37:49,550
THING ABOUT WHAT YOU CAN DO WITH

4031
02:37:49,550 --> 02:37:50,418
CONNECTIVITY DATA.

4032
02:37:50,418 --> 02:37:51,486
THIS IS A SORT OF A FRAMEWORK

4033
02:37:51,486 --> 02:37:52,820
WE'RE HOPING TO PUBLISH THIS

4034
02:37:52,820 --> 02:37:56,023
SOON BUT THE ACTUAL -- IF

4035
02:37:56,023 --> 02:37:56,991
ANYBODY IS INTERESTED IN DOING

4036
02:37:56,991 --> 02:37:58,893
THIS IT'S VERY EASY TO GENERATE

4037
02:37:58,893 --> 02:37:59,794
THIS ON YOUR DATA.

4038
02:37:59,794 --> 02:38:01,195
WE STARTED REALIZING YOU CAN

4039
02:38:01,195 --> 02:38:04,265
ACTUALLY USE CONNECTIVITY DATA

4040
02:38:04,265 --> 02:38:10,738
TO EXPLORE TISSUE MORPHOGEN --

4041
02:38:10,738 --> 02:38:13,608
YOU CAN SEE HERE HOW SPECIFIC

4042
02:38:13,608 --> 02:38:15,676
LIGAND TO RECEPTOR INTERACTIONS

4043
02:38:15,676 --> 02:38:17,278
WITH ARE VERY TIGHTLY ORGANIZED

4044
02:38:17,278 --> 02:38:22,417
IN THE TISSUE.

4045
02:38:22,417 --> 02:38:23,951
YOU CAN EVEN SEE ON THE BOTTOM

4046
02:38:23,951 --> 02:38:25,453
HERE THAT A SINGLE LIGAND, IN

4047
02:38:25,453 --> 02:38:27,989
THIS CASE, WINT5A BOTH LEFT AND

4048
02:38:27,989 --> 02:38:29,257
RIGHT, CAN BE SENSED VERY

4049
02:38:29,257 --> 02:38:30,958
DIFFERENTLY BASED ON SPECIFIC

4050
02:38:30,958 --> 02:38:38,599
REA ACCEPTOR PR ACCERECEPTOR PR.

4051
02:38:38,599 --> 02:38:40,168
I THINK THIS IS PROBABLY VERY

4052
02:38:40,168 --> 02:38:41,636
RELEVANT TO PULMONARY

4053
02:38:41,636 --> 02:38:42,970
REGENERATIVE MEDICINE, WE SEE A

4054
02:38:42,970 --> 02:38:43,905
STRUCTURAL REORGANIZATION OF THE

4055
02:38:43,905 --> 02:38:45,406
LUNG AND WE SEE THESE CELLULAR

4056
02:38:45,406 --> 02:38:46,607
CHANGES, AND I THINK THIS IS A

4057
02:38:46,607 --> 02:38:48,709
GREAT WAY TO LOOK AT AN

4058
02:38:48,709 --> 02:38:52,346
ADDITIONAL LAYER OF TISSUE

4059
02:38:52,346 --> 02:38:54,615
SECTIONS, BUT WE -- AND HOW

4060
02:38:54,615 --> 02:38:57,151
THOSE MIGHT CORRELATE.

4061
02:38:57,151 --> 02:38:58,853
SO THIS IS JUST MY CONCLUSIONS

4062
02:38:58,853 --> 02:39:00,154
HERE.

4063
02:39:00,154 --> 02:39:00,855
CELL-TO-CELL COMMUNICATION IS

4064
02:39:00,855 --> 02:39:01,989
REALLY OF HIGH IMPORTANCE TO

4065
02:39:01,989 --> 02:39:03,558
TISSUE BIOLOGY AND TISSUE

4066
02:39:03,558 --> 02:39:04,392
REGENERATIVE MEDICINE.

4067
02:39:04,392 --> 02:39:05,560
I THINK IT'S KIND OF

4068
02:39:05,560 --> 02:39:06,294
UNDERSTUDIED BUT IT DOESN'T HAVE

4069
02:39:06,294 --> 02:39:06,694
TO BE.

4070
02:39:06,694 --> 02:39:10,798
THERE'S AB A AN ENORMOUS AMOUNTF

4071
02:39:10,798 --> 02:39:11,232
INFORMATION THERE.

4072
02:39:11,232 --> 02:39:12,433
THERE'S A COUPLE OTHERS COMING

4073
02:39:12,433 --> 02:39:14,869
OUT NOW, WHERE YOU CAN REALLY

4074
02:39:14,869 --> 02:39:15,970
STATISTICALLY DO FLEXIBLE

4075
02:39:15,970 --> 02:39:16,704
ANALYSIS.

4076
02:39:16,704 --> 02:39:19,073
EVERYTHING I'VE SHOWN YOU, I'M

4077
02:39:19,073 --> 02:39:20,641
JUST CREATING A NEW DATA LAYER,

4078
02:39:20,641 --> 02:39:21,742
PUTTING IT BACK IN AND PLAYING

4079
02:39:21,742 --> 02:39:22,376
WITH IT.

4080
02:39:22,376 --> 02:39:24,212
THE SOFTWARE PAPER AND VIGNETTES

4081
02:39:24,212 --> 02:39:25,847
ARE HERE AND THEY'RE PUBLICLY

4082
02:39:25,847 --> 02:39:27,114
AVAILABLE, AND YOU CAN ALSO

4083
02:39:27,114 --> 02:39:29,250
EMAIL US IF YOU'RE INTERESTED IN

4084
02:39:29,250 --> 02:39:30,751
LEARNING HOW TO USE THESE.

4085
02:39:30,751 --> 02:39:32,286
AND I DON'T HAVE TIME SO WE CAN

4086
02:39:32,286 --> 02:39:33,221
TALK ABOUT THIS IN THE

4087
02:39:33,221 --> 02:39:34,455
DISCUSSION, BUT I THINK THERE

4088
02:39:34,455 --> 02:39:35,256
ARE MANY QUESTIONS THAT I

4089
02:39:35,256 --> 02:39:37,492
HAVEN'T ADDRESSED ABOUT

4090
02:39:37,492 --> 02:39:38,392
INTRACELLULAR TRANSDUCTION,

4091
02:39:38,392 --> 02:39:39,827
ABOUT CAUSAL INFERENCE IN THESE

4092
02:39:39,827 --> 02:39:41,762
DATA WHICH IS EXTREMELY TRICKY

4093
02:39:41,762 --> 02:39:43,564
AND I THINK WE NEED TO THINK

4094
02:39:43,564 --> 02:39:48,436
ABOUT IT WHEN WE -- AND THE

4095
02:39:48,436 --> 02:39:49,670
FINAL THING IS, THERE'S AN

4096
02:39:49,670 --> 02:39:50,738
OPPORTUNITY FOR SPAISH YOE

4097
02:39:50,738 --> 02:39:53,841
TEMPORAL MODELING AND REALLY

4098
02:39:53,841 --> 02:39:55,009
ADVANCED STATISTICAL METHODS AS

4099
02:39:55,009 --> 02:40:01,349
WELL AS -- THIS IS JUST MY

4100
02:40:01,349 --> 02:40:04,352
ACKNOWLEDGMENTS, I THANK MY LAB,

4101
02:40:04,352 --> 02:40:05,720
MY DEPARTMENT, FUNDING FOR DOING

4102
02:40:05,720 --> 02:40:06,554
THIS AND LOOKING FORWARD TO

4103
02:40:06,554 --> 02:40:07,154
TALKING AT THE END.

4104
02:40:07,154 --> 02:40:08,422
THANKS.

4105
02:40:08,422 --> 02:40:10,091
>> THANKS SO MUCH.

4106
02:40:10,091 --> 02:40:11,325
SO AS USUAL, YOU CAN PUT

4107
02:40:11,325 --> 02:40:14,328
QUESTIONS IN THE CHAT AND WE'LL

4108
02:40:14,328 --> 02:40:16,464
HAVE TIME FOR DISCUSSION AT THE

4109
02:40:16,464 --> 02:40:16,864
END.

4110
02:40:16,864 --> 02:40:22,870
AND SO NEXT WE HAVE SHAWN

4111
02:40:22,870 --> 02:40:24,138
DAVIDSON FROM NORTHWESTERN

4112
02:40:24,138 --> 02:40:25,439
UNIVERSITY, WHO WILL TALK ABOUT

4113
02:40:25,439 --> 02:40:30,611
SPECIAL METABOLOMICS.

4114
02:40:30,611 --> 02:40:32,880
>> THANKS TO THE
ORGANIZERS.

4115
02:40:32,880 --> 02:40:34,215
I'VE REALLY EP JOYED THESE TWO

4116
02:40:34,215 --> 02:40:34,849
DAYS.

4117
02:40:34,849 --> 02:40:35,850
IT'S EXCITING TO SEE ALL THE

4118
02:40:35,850 --> 02:40:37,351
INTEREST IN METABOLISM.

4119
02:40:37,351 --> 02:40:39,820
SO TODAY I'LL TALK ON OUR WORK

4120
02:40:39,820 --> 02:40:43,224
IN USING SPATIAL METABOLOMICS

4121
02:40:43,224 --> 02:40:45,927
AND FLEX OMICS TO GET

4122
02:40:45,927 --> 02:40:46,694
INFORMATION AND GET DOWN TO KIND

4123
02:40:46,694 --> 02:40:48,429
OF THE SINGLE CELL LAYER.

4124
02:40:48,429 --> 02:40:50,765
SO WE KNOW THERE ARE MANY

4125
02:40:50,765 --> 02:40:53,768
FACTORS THAT INFLUENCE CELL

4126
02:40:53,768 --> 02:40:54,769
METABOLISM AND I COME AT THIS

4127
02:40:54,769 --> 02:40:56,704
FROM A CANCER METABOLISM

4128
02:40:56,704 --> 02:40:57,638
BACKGROUND, BUT WHEN WE THINK

4129
02:40:57,638 --> 02:40:59,340
ABOUT THIS, WE THINK ABOUT CELL

4130
02:40:59,340 --> 02:41:01,208
INTRINSIC FACTORS, SUCH AS

4131
02:41:01,208 --> 02:41:04,679
GENETIC ALTERATIONS IN THE

4132
02:41:04,679 --> 02:41:07,348
CANCER WORLDS, TUMOR GRADE OR

4133
02:41:07,348 --> 02:41:08,316
ONCOGENOTYPE, BUT ALSO THINGS

4134
02:41:08,316 --> 02:41:10,384
LIKE CELL LINEAGE AND TISSUE OF

4135
02:41:10,384 --> 02:41:12,820
ORIGIN, AND THESE THINGS ARE

4136
02:41:12,820 --> 02:41:15,156
SOMEWHAT EASIER, MAYBE NOT TUMOR

4137
02:41:15,156 --> 02:41:16,657
GRADE BUT TO STUDY IN CELL

4138
02:41:16,657 --> 02:41:20,528
CULTURE.

4139
02:41:20,528 --> 02:41:25,766
BUT THEN THERE'S ALSO THESE

4140
02:41:25,766 --> 02:41:27,268
EXTRINSIC FACTORS, SUCH AS

4141
02:41:27,268 --> 02:41:28,836
ACCESS TO NUTRIENTS AND OXYGEN

4142
02:41:28,836 --> 02:41:30,004
AND HOW THESE CELLS ARE

4143
02:41:30,004 --> 02:41:31,172
INTERACTING WITH OTHER CELLS AS

4144
02:41:31,172 --> 02:41:32,306
WE JUST HEARD IN THE LAST TALK.

4145
02:41:32,306 --> 02:41:35,810
A LOT OF MICROBIAL INTERACTION,

4146
02:41:35,810 --> 02:41:37,144
FROM MICROBIOME AND DIFFERENT

4147
02:41:37,144 --> 02:41:40,247
DIET INPUTS THAT WE HAVE.

4148
02:41:40,247 --> 02:41:42,583
SO WE NEEDED TO DEVELOP SOME

4149
02:41:42,583 --> 02:41:44,318
TOOLS TO STUDY METABOLISM BETTER

4150
02:41:44,318 --> 02:41:45,419
AND TO REALLY ACCOUNT FOR SOME

4151
02:41:45,419 --> 02:41:47,989
OF THESE EXTRINSIC FACTORS, SO

4152
02:41:47,989 --> 02:41:49,790
WE BORROWED SOME OF THIS FROM

4153
02:41:49,790 --> 02:41:56,664
THE DIABETES FIELD USING THE

4154
02:41:56,664 --> 02:41:57,965
HYPER -- UTILIZING A CLAMP AND

4155
02:41:57,965 --> 02:42:00,701
WE PUT CHRONIC CATHETERS INTO

4156
02:42:00,701 --> 02:42:02,770
ANIMAL MODELS OF DISEASE, INTO

4157
02:42:02,770 --> 02:42:05,406
THE JUGULAR VEIN AND INTO THE

4158
02:42:05,406 --> 02:42:09,276
CAROTID ARTERY WHERE WE CAN THEN

4159
02:42:09,276 --> 02:42:11,779
INFUSE STABILIZED TO LABELED

4160
02:42:11,779 --> 02:42:13,848
NUTRIENTS BE, AND THESE ARE NICE

4161
02:42:13,848 --> 02:42:14,615
BECAUSE THESE ARE SAFE AND

4162
02:42:14,615 --> 02:42:15,816
THERE'S ACTUALLY A NUMBER OF

4163
02:42:15,816 --> 02:42:17,551
PEOPLE INFUSING IN HUMAN

4164
02:42:17,551 --> 02:42:20,554
CLINICAL TRIALS AND WE CAN

4165
02:42:20,554 --> 02:42:21,756
SIMULTANEOUSLY SAMPLE THE BLOOD,

4166
02:42:21,756 --> 02:42:22,957
AND IT'S IMPORTANT TO DELIVER IT

4167
02:42:22,957 --> 02:42:27,328
THIS WAY SO YOU CAN GET SOME

4168
02:42:27,328 --> 02:42:28,763
PSEUDOISOTO PICK STEADY STATE

4169
02:42:28,763 --> 02:42:30,164
WHICH WILL MAKE THE MODELING

4170
02:42:30,164 --> 02:42:31,966
DOWNSTREAM OF THESE REACTION

4171
02:42:31,966 --> 02:42:34,402
NETWORKS EASIER.

4172
02:42:34,402 --> 02:42:35,870
JUST ONE STRONG DRAMATIC EXAMPLE

4173
02:42:35,870 --> 02:42:38,973
IS WHEN WE DID THIS IN A KRAS

4174
02:42:38,973 --> 02:42:43,110
P53 MOUSE MODEL OF CANCER, WE

4175
02:42:43,110 --> 02:42:46,614
USED CELLS AND WE INFUSED MICE

4176
02:42:46,614 --> 02:42:48,349
WITH THAT CANCER AND THEN

4177
02:42:48,349 --> 02:42:49,150
ISOLATED CELLS FROM THOSE SAME

4178
02:42:49,150 --> 02:42:49,517
ANIMALS.

4179
02:42:49,517 --> 02:42:51,652
WHEN WE LOOKED AT THE METABOLISM

4180
02:42:51,652 --> 02:42:53,287
IN VITRO, YOU SEE WHAT YOU WOULD

4181
02:42:53,287 --> 02:42:54,889
EXPECT, YOU SEE THIS STRONG

4182
02:42:54,889 --> 02:42:59,493
CANONICAL WARBURG EFFECT OF ALL

4183
02:42:59,493 --> 02:43:00,828
GLUCOSE CONVERTED TO LACTATE AND

4184
02:43:00,828 --> 02:43:02,630
YOU START TO USE GLUTE MEAN TO

4185
02:43:02,630 --> 02:43:03,831
FILL A TCA CYCLE.

4186
02:43:03,831 --> 02:43:09,770
BUT WHEN WE LOOKED AT THOSE SAME

4187
02:43:09,770 --> 02:43:10,805
TUMORS IN VIVO BY BULK

4188
02:43:10,805 --> 02:43:12,973
METABOLOMICS, YOU CAN SEE THE

4189
02:43:12,973 --> 02:43:15,009
TUMOR WILL STILL TAKE UP A LOT

4190
02:43:15,009 --> 02:43:16,844
OF GLUCOSE AS WE WOULD KNOW AND

4191
02:43:16,844 --> 02:43:19,914
EXPECT FROM FTG PET BUT THE FATE

4192
02:43:19,914 --> 02:43:22,116
OF THAT GLUCOSE IS DIFFERENT AND

4193
02:43:22,116 --> 02:43:26,153
SENDS MORE OF A -- NOT AS

4194
02:43:26,153 --> 02:43:27,455
RELEVANT IN THE PHYSIOLOGICAL

4195
02:43:27,455 --> 02:43:28,823
SENSE SO WE THOUGHT THIS MIGHT

4196
02:43:28,823 --> 02:43:35,763
BE A GOOD APPROACH.

4197
02:43:35,763 --> 02:43:37,164
SO NOW WE CAN START DOING THIS

4198
02:43:37,164 --> 02:43:37,832
ACROSS SCALES.

4199
02:43:37,832 --> 02:43:39,967
SO USING THAT INFORMATION,

4200
02:43:39,967 --> 02:43:41,502
STARTING AT THE LEFT, YOU CAN

4201
02:43:41,502 --> 02:43:45,339
GET WHOLE BODY METABOLISM SO YOU

4202
02:43:45,339 --> 02:43:46,774
CAN INFUSE STABLE ISOTOPES, YOU

4203
02:43:46,774 --> 02:43:47,842
CAN THINK ABOUT HOW NUTRIENTS

4204
02:43:47,842 --> 02:43:49,043
ARE CLEARED IN DIFFERENT

4205
02:43:49,043 --> 02:43:52,880
SETTINGS, THE CLEARANCE RATES.

4206
02:43:52,880 --> 02:43:54,682
ONCE YOU KNOW A NUTRIENT IS

4207
02:43:54,682 --> 02:43:55,449
BEING METABOLIZED DIFFERENTLY IN

4208
02:43:55,449 --> 02:43:56,884
A MOUSE MODEL, YOU CAN FOCUS ON

4209
02:43:56,884 --> 02:44:00,154
A TISSUE THROUGH BULK

4210
02:44:00,154 --> 02:44:00,488
METABOLOMICS.

4211
02:44:00,488 --> 02:44:01,555
AND TODAY WHAT I WANT TO FOCUS

4212
02:44:01,555 --> 02:44:06,761
ON IS OUR USE OF MULTI-IMAGING

4213
02:44:06,761 --> 02:44:08,929
MASS -- TO GET PRETTY CLOSE TO

4214
02:44:08,929 --> 02:44:10,030
SINGLE CELL LEVEL WITHIN

4215
02:44:10,030 --> 02:44:10,798
INDIVIDUAL TISSUES.

4216
02:44:10,798 --> 02:44:13,267
WE'VE STARTED TO WORK ON AND

4217
02:44:13,267 --> 02:44:14,735
THERE'S SEVERAL PUBLICATIONS OUT

4218
02:44:14,735 --> 02:44:19,140
ON USING EXPANSION MICROSCOPY TO

4219
02:44:19,140 --> 02:44:22,209
INCREASE THE RESOLUTION DOWN TO

4220
02:44:22,209 --> 02:44:27,314
SUBCELLULAR AND EVEN ORGANELLE.

4221
02:44:27,314 --> 02:44:29,750
SO THIS IS MORE OR LESS AN FAQ

4222
02:44:29,750 --> 02:44:32,386
SLIDE THAT COMES UP, SO WE RELY

4223
02:44:32,386 --> 02:44:34,155
FOR METABOLISM WORK ON FRESH

4224
02:44:34,155 --> 02:44:34,855
FROZEN TISSUES.

4225
02:44:34,855 --> 02:44:38,359
WE CAN USE FFP FOR PEPTIDES AND

4226
02:44:38,359 --> 02:44:38,893
LIPIDS.

4227
02:44:38,893 --> 02:44:41,729
WE HAVE ABOUT A 10 TO 50-MICRON

4228
02:44:41,729 --> 02:44:42,263
LATERAL RESOLUTION.

4229
02:44:42,263 --> 02:44:45,332
WE CAN MAKE RELATIVE OR ABSOLUTE

4230
02:44:45,332 --> 02:44:48,936
MEASUREMENTS, YOU KNOW, GET REAL

4231
02:44:48,936 --> 02:44:50,304
QUANTITATIVE NUMBERS FOR THE

4232
02:44:50,304 --> 02:44:51,939
CONCENTRATION OF A DRUG IN A

4233
02:44:51,939 --> 02:44:53,274
CERTAIN CELL POPULATION, AND WE

4234
02:44:53,274 --> 02:44:55,342
CAN START TO FOCUS ON SPECIFIC

4235
02:44:55,342 --> 02:44:57,378
CELL SUBSETS.

4236
02:44:57,378 --> 02:44:59,880
SO MALDI STANDS FOR MATRIX

4237
02:44:59,880 --> 02:45:06,120
ASSISTED LASER DESORPTION

4238
02:45:06,120 --> 02:45:07,922
IONIZATION MASS SPECTROMETRY

4239
02:45:07,922 --> 02:45:08,389
IMAGING.

4240
02:45:08,389 --> 02:45:10,424
WHICH MATRIX YOU SEE WILL DEPEND

4241
02:45:10,424 --> 02:45:11,158
ON WHICH METABOLITES YOU ARE

4242
02:45:11,158 --> 02:45:12,426
ABLE TO DETECT.

4243
02:45:12,426 --> 02:45:13,794
IT'S AN EXCITING AREA BECAUSE I

4244
02:45:13,794 --> 02:45:15,062
THINK EACH WEEK AND MONTH

4245
02:45:15,062 --> 02:45:16,997
THERE'S A NUMBER OF NEW MATRICES

4246
02:45:16,997 --> 02:45:19,066
THAT ALLOW US TO SEE MORE OF THE

4247
02:45:19,066 --> 02:45:20,134
METABOLISM THAT WE COULD SEE

4248
02:45:20,134 --> 02:45:20,534
BEFORE.

4249
02:45:20,534 --> 02:45:21,969
AND THERE'S DIFFERENT CHEMICAL

4250
02:45:21,969 --> 02:45:26,240
STRATEGIES INCLUDING -- AND WE

4251
02:45:26,240 --> 02:45:28,642
ROUTINELY WORK WITH NUMEROUS

4252
02:45:28,642 --> 02:45:30,511
MATRICES IN THE LAB TO GET THE

4253
02:45:30,511 --> 02:45:32,980
COVERAGE THAT MIGHT COME CLOSE

4254
02:45:32,980 --> 02:45:35,683
BUT NOT QUITE TO LCMS AT THIS

4255
02:45:35,683 --> 02:45:39,887
POINT.

4256
02:45:39,887 --> 02:45:42,590
IMPORTANTLY, WE'VE OPTIMIZED

4257
02:45:42,590 --> 02:45:44,658
THIS FT-ICR TECHNOLOGY.

4258
02:45:44,658 --> 02:45:50,431
IN IS A 9.4 TESLA MRMS SYSTEM

4259
02:45:50,431 --> 02:45:51,999
FROM BRUKE.

4260
02:45:51,999 --> 02:45:57,104
R AND IF YOU -- I THINK IF YOU

4261
02:45:57,104 --> 02:46:00,140
CLICK, SO YOU CAN SEE THIS IS

4262
02:46:00,140 --> 02:46:01,976
ACQUISITION IN ACTION, YOU GET A

4263
02:46:01,976 --> 02:46:05,713
NEW MASS SPECTRUM, AND THIS IS

4264
02:46:05,713 --> 02:46:06,480
SPECIFICALLY UNTARGETED SO WE

4265
02:46:06,480 --> 02:46:08,449
HAVE A LOT OF FEATURES WE HAVE

4266
02:46:08,449 --> 02:46:10,751
AL GATED AND ANNOTATED AND WE

4267
02:46:10,751 --> 02:46:12,653
HAVE A LOT OF OTHERS WHERE WE

4268
02:46:12,653 --> 02:46:14,088
DIDN'T NECESSARILY KNOW WHAT THE

4269
02:46:14,088 --> 02:46:16,290
MESS OF THIS COMPOUND IS, AND

4270
02:46:16,290 --> 02:46:20,294
CRITICAL FOR ALL OF THIS IS THAT

4271
02:46:20,294 --> 02:46:23,230
THE MASS RESOLUTION OF ALL THESE

4272
02:46:23,230 --> 02:46:24,932
INSTRUMENTS IS QUITE HIGHER THAN

4273
02:46:24,932 --> 02:46:27,268
THE TIME OF FLIGHT IMAGING

4274
02:46:27,268 --> 02:46:30,104
ASPECTS AND ALLOWS US TO -- SO

4275
02:46:30,104 --> 02:46:34,008
YOU CAN ACTUALLY LABEL A 13C AND

4276
02:46:34,008 --> 02:46:37,444
13N AND THEN -- THE DIFFERENCE

4277
02:46:37,444 --> 02:46:39,546
BETWEEN THOSE TWO ATOMS IN THE

4278
02:46:39,546 --> 02:46:49,023
SAME RUN.

4279
02:46:49,023 --> 02:46:51,725
SO THIS IS JUST ONE EXAMPLE.

4280
02:46:51,725 --> 02:46:53,327
IF YOU INFAWS A FULLY LABELED

4281
02:46:53,327 --> 02:46:55,362
GLUCOSE AND IT GOES THROUGH

4282
02:46:55,362 --> 02:47:00,701
GLYCOLYSIS, YOU WOULD GET A SIX

4283
02:47:00,701 --> 02:47:02,970
LABEL UDP GLUCOSE.

4284
02:47:02,970 --> 02:47:03,904
ON THE OTHER HAND, IF YOU

4285
02:47:03,904 --> 02:47:05,506
INHUGHES A THREE LABELED

4286
02:47:05,506 --> 02:47:06,840
GLYCEROL, YOU WOULD BE ABLE TO

4287
02:47:06,840 --> 02:47:09,610
MONITOR A THREE LABEL GDP

4288
02:47:09,610 --> 02:47:12,646
GLUCOSE AND THAT WOULD INDICATE

4289
02:47:12,646 --> 02:47:13,414
THAT GLUCOMUTAGENESIS IS

4290
02:47:13,414 --> 02:47:16,150
HAPPENING IN THAT REGION.

4291
02:47:16,150 --> 02:47:18,552
SO YOU CAN SEE HERE IN THE

4292
02:47:18,552 --> 02:47:21,355
MEDULLA, THERE'S MUCH MORE

4293
02:47:21,355 --> 02:47:28,495
GLYCOLYSIS HAPPENING.

4294
02:47:28,495 --> 02:47:31,565
THEN THE CORTEX, THERE IS MUCH

4295
02:47:31,565 --> 02:47:38,205
MORE GLUCOGENESIS HAPPENING.

4296
02:47:38,205 --> 02:47:40,574
SO WE CAN START TO INFER

4297
02:47:40,574 --> 02:47:42,209
DIFFERENT METABOLIC PATHWAY

4298
02:47:42,209 --> 02:47:42,509
ACTIVITIES.

4299
02:47:42,509 --> 02:47:45,112
SO THIS ISN'T LIMITED TO GLYCOL

4300
02:47:45,112 --> 02:47:47,114
GIST AND GLUCOGENESIS, YOU JUST

4301
02:47:47,114 --> 02:47:48,315
HAVE TO DESIGN THE TRACERS THAT

4302
02:47:48,315 --> 02:47:51,118
YOU'RE TRACING INTO TO LAND ON

4303
02:47:51,118 --> 02:47:52,553
THE METABOLITES THAT ARE

4304
02:47:52,553 --> 02:47:53,687
IMPORTANT FOR THE PATHWAY OF

4305
02:47:53,687 --> 02:48:00,027
INTEREST.

4306
02:48:00,027 --> 02:48:03,897
YOU A 'NOANOTHER EXAMPLE, AND IK

4307
02:48:03,897 --> 02:48:05,566
THIS HIGHLIGHTS WHAT WE DO

4308
02:48:05,566 --> 02:48:06,867
DIFFERENT THAN MANY OTHERS AT

4309
02:48:06,867 --> 02:48:08,402
THIS POINT, IF YOU LOOK AT THE

4310
02:48:08,402 --> 02:48:12,006
FAR RIGHT WHERE YOU HAVE MALE

4311
02:48:12,006 --> 02:48:13,607
UNLABELED, IF YOU LOOKED AT MA

4312
02:48:13,607 --> 02:48:14,975
LATE LEVELS, YOU WOULD SAY THESE

4313
02:48:14,975 --> 02:48:17,344
ARE ROUGHLY THE SAME IN BOTH

4314
02:48:17,344 --> 02:48:20,347
REGIONS SEPARATED BY THAT DARK

4315
02:48:20,347 --> 02:48:21,515
OUTER STRIPE.

4316
02:48:21,515 --> 02:48:22,616
BUT WHAT'S MORE INTERESTING IS

4317
02:48:22,616 --> 02:48:25,152
IF YOU ASK WHERE DOES THAT MA

4318
02:48:25,152 --> 02:48:26,520
LATE COME FROM, AND SO WEE

4319
02:48:26,520 --> 02:48:31,859
LOOKED AT GLUCOSE, AS DATE AND

4320
02:48:31,859 --> 02:48:33,260
WE LOOK AT THE -- EACH ONE OF

4321
02:48:33,260 --> 02:48:37,364
THOSE TO THE -- YOU CAN SEE

4322
02:48:37,364 --> 02:48:38,799
THERE'S NO REAL DIFFERENCE.

4323
02:48:38,799 --> 02:48:40,167
OARCHED, THERE'S SOME REBINARY

4324
02:48:40,167 --> 02:48:41,735
DIFFERENCES SO IF YOU LOOK AT

4325
02:48:41,735 --> 02:48:44,171
CITRATE, SO CITRATE CONTRIBUTES

4326
02:48:44,171 --> 02:48:46,540
TO MA LATE UNIQUELY IN THE

4327
02:48:46,540 --> 02:48:50,277
QUARTILE OF THE KIDNEY, THERE'S

4328
02:48:50,277 --> 02:48:56,984
ACTUALLY A -- IN THE CORTEX OF

4329
02:48:56,984 --> 02:48:57,684
KIDNEY THAT ISN'T IN THE

4330
02:48:57,684 --> 02:48:58,318
MEDULLA.

4331
02:48:58,318 --> 02:48:58,952
THE POINT IS THAT EVEN THOUGH

4332
02:48:58,952 --> 02:49:00,788
THE LEVELS LOOK THE SAME, THE

4333
02:49:00,788 --> 02:49:02,156
SOURCE OF THOSE NUTRIENTS ARE

4334
02:49:02,156 --> 02:49:02,423
DIFFERENT.

4335
02:49:02,423 --> 02:49:04,191
SO IF YOU'RE THINKING ABOUT

4336
02:49:04,191 --> 02:49:05,125
TARGETING METABOLIC PATHWAYS,

4337
02:49:05,125 --> 02:49:06,293
IT'S IMPORTANT TO KNOW IF YOU

4338
02:49:06,293 --> 02:49:12,599
WANT TO DRIVE THE LEVEL -- AND

4339
02:49:12,599 --> 02:49:14,468
WE CAN GET MORE QUANTITATIVE

4340
02:49:14,468 --> 02:49:16,103
ABOUT THAT AND PRETTY MUCH

4341
02:49:16,103 --> 02:49:18,372
ACCOUNT FOR ALMOST ALL OF THE

4342
02:49:18,372 --> 02:49:20,107
CARBON CONTRIBUTION TO MA LATE,

4343
02:49:20,107 --> 02:49:21,075
FOR EXAMPLE, IN THESE TWO

4344
02:49:21,075 --> 02:49:23,177
RENALES SO IF YOU LOOK AT THE

4345
02:49:23,177 --> 02:49:27,381
CORTEX, WE'RE CLOSE TO 100%

4346
02:49:27,381 --> 02:49:28,749
THERE AND WITH HIGHER SPATIAL

4347
02:49:28,749 --> 02:49:29,883
RESOLUTION THAN WE HAVE NOW,

4348
02:49:29,883 --> 02:49:33,687
WE'RE GETTING CLOSER TO NOT JUST

4349
02:49:33,687 --> 02:49:36,256
CORTEX AND MEDULLA BUT T-CELL, B

4350
02:49:36,256 --> 02:49:40,427
CELL, CANCER CELL, STROMAL CELL,

4351
02:49:40,427 --> 02:49:41,528
THINGS LIKE THAT, SO THIS IS

4352
02:49:41,528 --> 02:49:43,997
VERY IMPORTANT FOR GETTING

4353
02:49:43,997 --> 02:49:48,035
QUANTITATIVE NUTRIENT -- IN

4354
02:49:48,035 --> 02:49:51,872
DIFFERENT CELL COMPARTMENTS.

4355
02:49:51,872 --> 02:49:52,773
SO THOSE WERE CARBON LABELED

4356
02:49:52,773 --> 02:49:55,309
EXAMPLES AND JUST AS ONE OTHER

4357
02:49:55,309 --> 02:49:56,743
INTERESTING EXAMPLE, LOOKING AT

4358
02:49:56,743 --> 02:49:59,046
WHERE DOES THE NEUROTRANSMITTER

4359
02:49:59,046 --> 02:50:01,115
GLUTAMATE COME FROM IN THE

4360
02:50:01,115 --> 02:50:01,615
BRAIN.

4361
02:50:01,615 --> 02:50:03,283
AND SO WHERE DOES IT GET THE

4362
02:50:03,283 --> 02:50:04,985
NITROGEN TO MAKE GLUTAMATE?

4363
02:50:04,985 --> 02:50:08,489
AND THIS IS JUST STRIKINGLY

4364
02:50:08,489 --> 02:50:11,058
HETEROGENEOUS THROUGHOUT.

4365
02:50:11,058 --> 02:50:12,259
SO -- AND EVEN THOUGH THE LEVELS

4366
02:50:12,259 --> 02:50:13,794
OF GLUTAMATE ARE RELATIVELY

4367
02:50:13,794 --> 02:50:15,229
CONSISTENT ACROSS THESE BRAIN

4368
02:50:15,229 --> 02:50:17,030
REGIONS, HOW IT ACTUALLY GETS

4369
02:50:17,030 --> 02:50:17,764
THAT NITROGEN OUT OF IT IS QUITE

4370
02:50:17,764 --> 02:50:25,439
DIFFERENT.

4371
02:50:25,439 --> 02:50:27,441
AS ANOTHER EXAMPLE, THERE'S A

4372
02:50:27,441 --> 02:50:31,445
LOT OF EXCITEMENT IN DIFFERENT

4373
02:50:31,445 --> 02:50:33,147
WAYS TO EXPAND THE METABALOME

4374
02:50:33,147 --> 02:50:35,616
COVERAGE, AND THIS WAS A SERIES

4375
02:50:35,616 --> 02:50:37,751
OF EFFORTS ON IMPROVING

4376
02:50:37,751 --> 02:50:40,621
DETECTION USING A WASHING

4377
02:50:40,621 --> 02:50:41,889
STRATEGY TO REMOVE THINGS THAT

4378
02:50:41,889 --> 02:50:44,024
MIGHT CAUSE ION EXPRESSION, SO

4379
02:50:44,024 --> 02:50:46,460
FOR THE FIRST TIME USING A

4380
02:50:46,460 --> 02:50:51,899
WASHING STRATEGY, WE'RE AGE TO

4381
02:50:51,899 --> 02:50:53,400
DETECT QUANTITATIVELY BY

4382
02:50:53,400 --> 02:50:56,036
SMAICIAL METABOLOMICS THE LEVEL

4383
02:50:56,036 --> 02:50:58,205
OF NAD AND NADH AND THIS ALSO

4384
02:50:58,205 --> 02:50:59,640
ENHANCES THE SIGNAL IN GENERAL

4385
02:50:59,640 --> 02:51:02,609
OF OTHER PHOSPHOTATE CONTAINING

4386
02:51:02,609 --> 02:51:03,610
METABOLITES, AND STRATEGIES LIKE

4387
02:51:03,610 --> 02:51:05,412
THIS CAN ACTUALLY BE USED TO SEE

4388
02:51:05,412 --> 02:51:07,881
A NUMBER OF DIFFERENT MOLECULES

4389
02:51:07,881 --> 02:51:11,518
AND THINKING IT'S AN EXCITING

4390
02:51:11,518 --> 02:51:12,886
AREA TO BE FOCUSING ON.

4391
02:51:12,886 --> 02:51:14,087
SO JUST TO THINK ABOUT SOME

4392
02:51:14,087 --> 02:51:15,589
CURRENT GAPS IN WHAT WE'RE DOING

4393
02:51:15,589 --> 02:51:16,990
HERE, WHEN WE HAVE STARTED TO

4394
02:51:16,990 --> 02:51:20,394
LOOK AT SOME PATIENT SAMPLES, I

4395
02:51:20,394 --> 02:51:21,595
THINK IT'S GOING TO BE IMPORTANT

4396
02:51:21,595 --> 02:51:25,732
TO FIND SOME WAYS TO DO BATCH

4397
02:51:25,732 --> 02:51:26,633
CORRECTION THAT ACCOUNT FOR BOTH

4398
02:51:26,633 --> 02:51:27,734
THE WAY THE SAMPLES ARE

4399
02:51:27,734 --> 02:51:29,703
COLLECTED AND THE TECHNICAL

4400
02:51:29,703 --> 02:51:31,672
VARIABILITY THAT HAPPENS RUN TO

4401
02:51:31,672 --> 02:51:33,440
RUN AND MONTH TO MONTH ON MASS

4402
02:51:33,440 --> 02:51:33,740
SPECS.

4403
02:51:33,740 --> 02:51:36,343
THIS IS NOT AN UNFAMILIAR

4404
02:51:36,343 --> 02:51:37,911
PROBLEM TO THE MASS SPEC WORLD,

4405
02:51:37,911 --> 02:51:39,880
SO WE'RE WORKING ON THIS AND

4406
02:51:39,880 --> 02:51:46,954
TRYING TO MAKE THIS WORK FOR

4407
02:51:46,954 --> 02:51:47,821
OUR -- AS WELL.

4408
02:51:47,821 --> 02:51:50,023
WE CONTINUE TO -- THIS IS

4409
02:51:50,023 --> 02:51:51,325
SOMEWHAT LABORIOUS BECAUSE WE

4410
02:51:51,325 --> 02:51:54,561
DON'T HAVE THE TEAM TOGRAPHY ON

4411
02:51:54,561 --> 02:51:57,431
THIS IMAGING PLATFORM YOU WOULD

4412
02:51:57,431 --> 02:51:59,833
HAVE WITH LCS SO WE RELY A LOT

4413
02:51:59,833 --> 02:52:02,469
ON MS2 AND ON TISSUE MS2, AND I

4414
02:52:02,469 --> 02:52:03,937
THINK THERE'S A LOT OF ROOM FOR

4415
02:52:03,937 --> 02:52:06,139
IMPROVEMENT IN KIND OF

4416
02:52:06,139 --> 02:52:06,940
TISSUE-SPECIFIC METABOLIC MODELS

4417
02:52:06,940 --> 02:52:09,543
AND WE'RE WORKING ON THAT

4418
02:52:09,543 --> 02:52:12,145
THROUGH A SERIES OF EXPERIMENTS

4419
02:52:12,145 --> 02:52:19,353
USING KINETIC TRACING IN THIS.

4420
02:52:19,353 --> 02:52:21,021
WITHIN MY LAB, WE'RE ESPECIALLY

4421
02:52:21,021 --> 02:52:23,090
INTERESTED IN UNDERSTANDING LUNG

4422
02:52:23,090 --> 02:52:28,061
CANCER HETEROGENEITY.

4423
02:52:28,061 --> 02:52:29,596
WE'VE STARTED TO DO SOME

4424
02:52:29,596 --> 02:52:31,131
EXPERIMENTS WITH CELL AUTONOMOUS

4425
02:52:31,131 --> 02:52:34,101
AND NON-CELL AUTONOMOUS RESPONSE

4426
02:52:34,101 --> 02:52:35,369
TO INFECTION IN COLLABORATION

4427
02:52:35,369 --> 02:52:36,703
WITH INVESTIGATORS HERE, AND

4428
02:52:36,703 --> 02:52:38,472
WE'RE GENERALLY JUST GETTING THE

4429
02:52:38,472 --> 02:52:41,174
DATA TO TALK TO EACH OTHER,

4430
02:52:41,174 --> 02:52:42,476
DOING SOME OF THESE ASSAYS ON

4431
02:52:42,476 --> 02:52:43,710
THE SAME SLIDE AND GETTING THE

4432
02:52:43,710 --> 02:52:46,647
CELL TYPE-SPECIFIC METABOLISM OF

4433
02:52:46,647 --> 02:52:48,615
DIFFERENT CELLS IN THE LUNG IN

4434
02:52:48,615 --> 02:52:50,050
DIFFERENT CONTEXTS.

4435
02:52:50,050 --> 02:52:54,621
SO I THINK THE FUTURE IS

4436
02:52:54,621 --> 02:52:56,523
BRIGHTER, I WAS INSPIRED BY A

4437
02:52:56,523 --> 02:52:59,326
LOT OF TALKS HERE AND SO I LOOK

4438
02:52:59,326 --> 02:53:00,360
TO DISCUSS FURTHER.

4439
02:53:00,360 --> 02:53:01,828
AND TO THANK THE LAB WHICH IS

4440
02:53:01,828 --> 02:53:04,064
JUST GETTING STARTED, AND IF

4441
02:53:04,064 --> 02:53:08,969
ANYONE IS INTERESTED MASS SPEC,

4442
02:53:08,969 --> 02:53:18,078
PLEASE FEEL FREE TO EMAIL ME.

4443
02:53:18,078 --> 02:53:19,980
I'D BE HAPPY TO CHAT MORE.

4444
02:53:19,980 --> 02:53:21,281
THANKS SO MUCH.

4445
02:53:21,281 --> 02:53:22,916
>> THANK YOU FOR THAT
TALK.

4446
02:53:22,916 --> 02:53:24,017
LACKING FORWARD TO DISCUSSION IN

4447
02:53:24,017 --> 02:53:24,551
A MOMENT.

4448
02:53:24,551 --> 02:53:26,186
WANTED TO GO AHEAD HERE AND

4449
02:53:26,186 --> 02:53:28,555
INTRODUCE OUR LAST SPEAKER FOR

4450
02:53:28,555 --> 02:53:34,528
THIS SESSION, PROFESSOR JIANWEN

4451
02:53:34,528 --> 02:53:36,930
QUE FROM COLUMBIA UNIVERSITY

4452
02:53:36,930 --> 02:53:37,297
MEDICAL CENTER.

4453
02:53:37,297 --> 02:53:40,167
>> YOU PRONOUNCED THE
CHINESE

4454
02:53:40,167 --> 02:53:41,835
VERY WELL, THANK YOU.

4455
02:53:41,835 --> 02:53:43,503
I'D ALSO LIKE TO THANK THE

4456
02:53:43,503 --> 02:53:45,238
ORGANIZING COMMITTEE FOR THIS

4457
02:53:45,238 --> 02:53:46,907
WONDERFUL WORKSHOP, AND I HAVE

4458
02:53:46,907 --> 02:53:48,175
BEEN LEARNING A LOT FOR THE PAST

4459
02:53:48,175 --> 02:53:49,076
TWO DAYS.

4460
02:53:49,076 --> 02:53:50,944
AND TODAY I WOULD LIKE TO TALK

4461
02:53:50,944 --> 02:53:52,746
ABOUT THIS POSSIBLE ROLE OF THE

4462
02:53:52,746 --> 02:53:55,315
NEURON IN LUNG REGENERATION, AND

4463
02:53:55,315 --> 02:53:57,284
HERE I USE POSSIBLE BECAUSE IT

4464
02:53:57,284 --> 02:53:59,686
REALLY IS.

4465
02:53:59,686 --> 02:54:02,522
NOT MANY SOLID DATA OUT THERE TO

4466
02:54:02,522 --> 02:54:04,558
SHOW THAT THERE'S A ROLE PLAYED

4467
02:54:04,558 --> 02:54:09,663
BY NEURON IN LUNG REGENERATION.

4468
02:54:09,663 --> 02:54:11,898
SO IN THIS SHORT TALK, I WOULD

4469
02:54:11,898 --> 02:54:13,433
LIKE TO DIVIDE MY TALK INTO

4470
02:54:13,433 --> 02:54:13,867
THREE PARTS.

4471
02:54:13,867 --> 02:54:15,302
FIRST I'M GOING TO TALK ABOUT

4472
02:54:15,302 --> 02:54:19,106
THIS INNOVATION OF THE TRACHEA

4473
02:54:19,106 --> 02:54:20,807
AND THE LUNG AND THEN TALK ABOUT

4474
02:54:20,807 --> 02:54:23,076
THIS POTENTIAL ASSOCIATION OF

4475
02:54:23,076 --> 02:54:24,411
INNERVATION WITH LUNG

4476
02:54:24,411 --> 02:54:26,947
REGENERATION BUT BASED -- MOSTLY

4477
02:54:26,947 --> 02:54:31,518
BASED ON DATA FROM OTHER ORGANS,

4478
02:54:31,518 --> 02:54:37,023
GUT AND INTESTINE, AND BUILD ON

4479
02:54:37,023 --> 02:54:39,226
THOSE FINDINGS IN THEIR TISSUES

4480
02:54:39,226 --> 02:54:40,761
AND I WAS THINKING ABOUT WHAT

4481
02:54:40,761 --> 02:54:43,230
POSSIBLE GAPS AND CHALLENGE THAT

4482
02:54:43,230 --> 02:54:44,531
WE WERE FACING WITH OUR TISSUE

4483
02:54:44,531 --> 02:54:47,367
AND LUNG.

4484
02:54:47,367 --> 02:54:50,871
SO THE -- SENSORY NEURONS

4485
02:54:50,871 --> 02:54:54,808
INCLUDE THIS VAGUS NEVER,

4486
02:54:54,808 --> 02:54:56,843
WHICH -- NEURON BODY LOCATED IN

4487
02:54:56,843 --> 02:55:02,082
THE BRAINSTEM SPECIFICALLY --

4488
02:55:02,082 --> 02:55:07,020
AND TUBULAR GANGLION, SEND

4489
02:55:07,020 --> 02:55:08,488
FIBERS T TO INNERVATE THE AIRWAS

4490
02:55:08,488 --> 02:55:09,356
AND THE LUNGS.

4491
02:55:09,356 --> 02:55:10,991
AND THE OTHER SIDE OF THE CENTER

4492
02:55:10,991 --> 02:55:13,794
OF THE NEURONS COMING FROM THIS

4493
02:55:13,794 --> 02:55:17,764
DORSAL ROOT GANGLION, THEY CAN

4494
02:55:17,764 --> 02:55:18,665
ALSO -- AIRWAYS.

4495
02:55:18,665 --> 02:55:22,002
THE MOTOR NEURONS ARE SENT BY

4496
02:55:22,002 --> 02:55:25,705
THIS SUR CAL THORACIC -- AN THEY

4497
02:55:25,705 --> 02:55:27,407
SEND THESE MOTOR NEURONS AND

4498
02:55:27,407 --> 02:55:30,811
NERVE FIBERS INNOVATE MUSCLES

4499
02:55:30,811 --> 02:55:38,985
AND BLOOD VESSELS IN THE LUNG.

4500
02:55:38,985 --> 02:55:41,822
THIS IS A VERY BEAUTIFUL PICTURE

4501
02:55:41,822 --> 02:55:45,058
TO SHOWN -- AT OREGON UNIVERSITY

4502
02:55:45,058 --> 02:55:46,460
HEALTH SCIENCE CENTER, HE USED

4503
02:55:46,460 --> 02:55:50,497
THIS PGP ANTIBODY, 9.5 ANTIBODY

4504
02:55:50,497 --> 02:55:53,066
TO LABEL NEURONS, NERVE FIBERS

4505
02:55:53,066 --> 02:55:56,670
IN THE LUNG AND YOU CAN SEE THIS

4506
02:55:56,670 --> 02:55:59,039
INTRICATE NERVE FIBERS

4507
02:55:59,039 --> 02:55:59,940
DISTRIBUTE ALONG THE TRACHEA BUT

4508
02:55:59,940 --> 02:56:04,110
ALSO THE AIRWAYS AND ALSO -- AND

4509
02:56:04,110 --> 02:56:08,815
RUN THROUGH THESE ALF VEE LIES.

4510
02:56:08,815 --> 02:56:17,657
AND THIS IS CREATING LABELED

4511
02:56:17,657 --> 02:56:19,292
TOMATO -- VIE GUS NERVE FIBERS

4512
02:56:19,292 --> 02:56:28,335
IN THVAGUS NERVE FIBERS INTHE L-

4513
02:56:28,335 --> 02:56:30,537
SOME OF THESE FIBERS SPREAD INTO

4514
02:56:30,537 --> 02:56:31,538
THE ALVEOLAR REGION, AND THE

4515
02:56:31,538 --> 02:56:36,076
PICTURE IN THE MIDDLE IS NA YOUN

4516
02:56:36,076 --> 02:56:42,983
SEE SOME OF THIS -- L STANDS FOR

4517
02:56:42,983 --> 02:56:44,918
LUMEN AND YOU CAN SEE THE

4518
02:56:44,918 --> 02:56:47,153
EPITHELIUM, LABELED WITH THIS E.

4519
02:56:47,153 --> 02:56:52,626
SHOWN BY THIS UNDERLYING NERVE

4520
02:56:52,626 --> 02:57:00,800
GUY PERT THIS IS ANOTHER -- THAT

4521
02:57:00,800 --> 02:57:04,070
STEPHN TO SHOW THAT THESE

4522
02:57:04,070 --> 02:57:06,106
LABELED NEURONS ARE LOCATED

4523
02:57:06,106 --> 02:57:11,111
RUNNING AROUND THE AL A V ALVEOD

4524
02:57:11,111 --> 02:57:12,345
AIRWAYS SHOWN BY THIS BRIGHT

4525
02:57:12,345 --> 02:57:18,285
STAINING WITH THIS GFP.

4526
02:57:18,285 --> 02:57:22,322
WOUWE ALL KNOW THIS IS ONE OF TE

4527
02:57:22,322 --> 02:57:28,428
OBVIOUS CELL WHICH IS NEURON --

4528
02:57:28,428 --> 02:57:30,230
THEY ARE INNERVATED ALSO BY

4529
02:57:30,230 --> 02:57:33,066
VAGUS NERVE AS WELL HERE, SHOWS

4530
02:57:33,066 --> 02:57:36,570
THIS NEURON SUBTYPE LABELED BY

4531
02:57:36,570 --> 02:57:41,875
P2RY1.

4532
02:57:41,875 --> 02:57:47,113
YOU CAN SEE THIS STAINING TO

4533
02:57:47,113 --> 02:57:49,516
SHOW THESE NERVE FIBERS

4534
02:57:49,516 --> 02:57:52,986
INNERVATE TO THE NEW

4535
02:57:52,986 --> 02:57:55,322
NEUROANTIBODY NEUROEPITHELIUM

4536
02:57:55,322 --> 02:57:56,256
BODIES.

4537
02:57:56,256 --> 02:57:57,424
THIS ARE ALSO INNERVATED BY

4538
02:57:57,424 --> 02:58:00,560
OTHER TYPES OF NEURONS, FOR

4539
02:58:00,560 --> 02:58:05,565
EXAMPLE, -- ALSO LABELED VAGUS

4540
02:58:05,565 --> 02:58:07,334
NERVE, AND YOU CAN SEE THAT THEY

4541
02:58:07,334 --> 02:58:12,706
ARE UNDERLYING THIS AND ANOTHER

4542
02:58:12,706 --> 02:58:15,575
PROTEIN CALLED CALCIUM BINDING

4543
02:58:15,575 --> 02:58:18,545
PROTEIN, YOU CAN SEE THAT THE

4544
02:58:18,545 --> 02:58:21,147
VAGUS NERVE CAN RUN THROUGH

4545
02:58:21,147 --> 02:58:28,989
THIS.

4546
02:58:28,989 --> 02:58:34,094
THOSE VAGUS NERVES CAN ALSO

4547
02:58:34,094 --> 02:58:35,662
INNERVATE ALL -- WHICH IS

4548
02:58:35,662 --> 02:58:38,665
GENERAL MARKER FOR VAGUS NERVE.

4549
02:58:38,665 --> 02:58:43,103
AND SENSE REA NERVE.

4550
02:58:43,103 --> 02:58:45,572
 SENSORY NERVE.

4551
02:58:45,572 --> 02:58:47,774
WE DON'T KNOW WHETHER THEY

4552
02:58:47,774 --> 02:58:48,541
CONTACT WITH TYPE 2 CELLS BUT

4553
02:58:48,541 --> 02:58:49,776
YOU CAN SEE THEY'RE VERY CLOSE

4554
02:58:49,776 --> 02:58:53,380
TO TYPE 2 CELLS AND TYPE

4555
02:58:53,380 --> 02:58:56,850
1 CELLS, AND SHOWN BY THE TYPE E

4556
02:58:56,850 --> 02:59:00,520
STAINING AND THEN TYPE 1 CELLS

4557
02:59:00,520 --> 02:59:03,056
SHOWN BY THIS GREEN STAINING.

4558
02:59:03,056 --> 02:59:12,098
AND THERE'S ANOTHER -- SHOULD BE

4559
02:59:12,098 --> 02:59:17,237
CRE MOS1 -- INNOVATE ALVEOLAR

4560
02:59:17,237 --> 02:59:18,371
REGION, ALTHOUGH WE DON'T KNOW

4561
02:59:18,371 --> 02:59:21,174
WHETHER IT CAN FORM SYNAPSE WITH

4562
02:59:21,174 --> 02:59:23,610
THESE EPITHELIAL CELLS OR WHAT

4563
02:59:23,610 --> 02:59:25,512
KIND OF THINGS ARE BEING

4564
02:59:25,512 --> 02:59:27,113
INNERVATED, IT JUST REMAINS

4565
02:59:27,113 --> 02:59:31,151
UNKNOWN.

4566
02:59:31,151 --> 02:59:35,689
SO WE KNOW THESE NERVES PLAY AN

4567
02:59:35,689 --> 02:59:36,923
IMPORTANT PART IN THE LUNGS AND

4568
02:59:36,923 --> 02:59:38,525
TRACHEA AND IT CAN REGULATE

4569
02:59:38,525 --> 02:59:41,161
BREATHING, IT CAN ALSO REGULATE

4570
02:59:41,161 --> 02:59:43,129
MUCUS SECRETION AND BRONCHOMOTOR

4571
02:59:43,129 --> 02:59:51,538
TONES AND ALSO REFLEX, ALSO

4572
02:59:51,538 --> 02:59:53,173
COUGH -- SO BOTH CAN CONTROL

4573
02:59:53,173 --> 02:59:57,911
BLOOD VESSELS TONES AND UPON

4574
02:59:57,911 --> 03:00:00,747
STIMULATION.

4575
03:00:00,747 --> 03:00:03,316
AND THEN -- HAS SHOWN VAGUS

4576
03:00:03,316 --> 03:00:04,684
NERVE, ALONG WITH OTHERS, HAS

4577
03:00:04,684 --> 03:00:07,821
SHOWN VAGUS NERVE CAN MODULATE

4578
03:00:07,821 --> 03:00:12,192
THESE IMMUNE FUNCTIONS, AIRWAY

4579
03:00:12,192 --> 03:00:16,029
HYPERACTIVITIES AS WELL, SHE HAS

4580
03:00:16,029 --> 03:00:21,034
A VERY NICE PAPER TO SHOW

4581
03:00:21,034 --> 03:00:21,801
CIRCULATE FROM THE LUNG TO THE

4582
03:00:21,801 --> 03:00:24,637
BRAIN TO MEDIATE THIS IMMUNE

4583
03:00:24,637 --> 03:00:27,140
FUNCTIONS AND TYPE OF ACTIVITY

4584
03:00:27,140 --> 03:00:30,844
FUNCTIONS OF THE LUNG.

4585
03:00:30,844 --> 03:00:34,814
AND ALONG WITH OTHERS THEY'VE

4586
03:00:34,814 --> 03:00:35,815
SHOWN THIS HAS BEEN ASSOCIATED

4587
03:00:35,815 --> 03:00:38,985
WITH THIS CHRONIC DISEASE, FOR

4588
03:00:38,985 --> 03:00:42,822
EXAMPLE, HYPERREACTIVITIES AND

4589
03:00:42,822 --> 03:00:43,857
MUCUS OVERPROTECTION AS WELL,

4590
03:00:43,857 --> 03:00:48,361
BECAUSE THERE IS A CLOSE

4591
03:00:48,361 --> 03:00:50,697
INTERACTION BETWEEN GOBLET CELLS

4592
03:00:50,697 --> 03:00:58,471
AND NEURON FIBERS.

4593
03:00:58,471 --> 03:00:59,272
MY LAB IS STARTING TO GET INTO

4594
03:00:59,272 --> 03:01:00,707
THIS AREA MORE ON THE CANCER

4595
03:01:00,707 --> 03:01:04,944
SIDE AND IN PART IS MOTIVATED BY

4596
03:01:04,944 --> 03:01:07,080
MY COLLEAGUE, TIMOTHY WONG, WHO

4597
03:01:07,080 --> 03:01:09,048
HAS IDENTIFIED THAT IMPORTANT

4598
03:01:09,048 --> 03:01:11,518
ROLE OF THE VAGUS NERVE IN STO

4599
03:01:11,518 --> 03:01:13,720
MA'AM CANCER, AND WHAT HE FOUND

4600
03:01:13,720 --> 03:01:17,190
IS IF YOU CUT THE VAGUS NERVE,

4601
03:01:17,190 --> 03:01:19,726
YOU ACTUALLY COULD INHIBIT TUMOR

4602
03:01:19,726 --> 03:01:21,928
GROWTH IN THE STO MA'AM.

4603
03:01:21,928 --> 03:01:26,366
HE ALSO HAD OTHER PAPER AND SHOW

4604
03:01:26,366 --> 03:01:30,937
THAT VAGUS NERVE ALSO PLAYS AN

4605
03:01:30,937 --> 03:01:35,809
IMPORTANT ROLE IN -- CANCER.

4606
03:01:35,809 --> 03:01:40,013
SO WHAT WE FOUND IS THAT DURING

4607
03:01:40,013 --> 03:01:41,414
SMALL CELL LUNG CARCINOMA

4608
03:01:41,414 --> 03:01:42,949
DEVELOPMENT, AND YOU CAN SEE

4609
03:01:42,949 --> 03:01:46,452
GRADUALLY ACCUMULATION OF THIS

4610
03:01:46,452 --> 03:01:49,856
SYMPATHETIC NEURON NERVE FIBERS

4611
03:01:49,856 --> 03:01:52,458
IN DIFFERENT STAGE OF TUMOR

4612
03:01:52,458 --> 03:01:53,660
FORMATION, AND IN THE MIDDLE

4613
03:01:53,660 --> 03:01:59,165
PANEL, YOU CAN SEE THAT --

4614
03:01:59,165 --> 03:02:04,170
ACCUMULATED NEURON FIBERS,

4615
03:02:04,170 --> 03:02:06,472
NERVE -- IN A CLOSE RANGE OF

4616
03:02:06,472 --> 03:02:09,409
THOSE IN SITU LUNG CARCINOMA AND

4617
03:02:09,409 --> 03:02:11,211
WITH DISEASE PROGRESSION YOU CAN

4618
03:02:11,211 --> 03:02:14,147
SEE THOSE FIBERS NOW INFILTRATED

4619
03:02:14,147 --> 03:02:16,883
AND MIGRATE INTO THE TUMOR

4620
03:02:16,883 --> 03:02:18,484
TISSUE, WHICH IS SHOWN ON THE

4621
03:02:18,484 --> 03:02:26,993
RIGHT SIDE.

4622
03:02:26,993 --> 03:02:30,096
SO WE ASK CAN WE BLOCK THIS

4623
03:02:30,096 --> 03:02:33,600
TUMOR GROWTH BY JUST GET RID OF

4624
03:02:33,600 --> 03:02:34,033
THESE NEURONS.

4625
03:02:34,033 --> 03:02:43,109
HERE WE USE THIS 6-OHDA TO

4626
03:02:43,109 --> 03:02:45,511
ABLATE THOSE NERVE FIBERS IN

4627
03:02:45,511 --> 03:02:50,216
MOUSE TISSUE WITH THOSE

4628
03:02:50,216 --> 03:02:53,620
INJECTION -- WITH FOUR DOSES

4629
03:02:53,620 --> 03:02:56,489
INJECTION THEY CAN SEE NOW THIS

4630
03:02:56,489 --> 03:02:57,690
NERVE FIBER HAS BEEN ABLATED

4631
03:02:57,690 --> 03:03:03,663
WHICH IS SHOWN ON THE RIGHT SIDE

4632
03:03:03,663 --> 03:03:05,031
IN IN SITU TUMOR.

4633
03:03:05,031 --> 03:03:06,499
AND WHEN WE WAIT FOR A LONG

4634
03:03:06,499 --> 03:03:08,568
TIME, YOU CAN SEE THOSE TUMOR

4635
03:03:08,568 --> 03:03:15,942
NOW IS DISAPPEARED OR SHRINKED,

4636
03:03:15,942 --> 03:03:19,979
OHDA AND YOU CAN QUANTITATE THEM

4637
03:03:19,979 --> 03:03:22,482
AND YOU CAN SHOW THAT THERE'S

4638
03:03:22,482 --> 03:03:24,584
REDUCTION IN TUMOR SIZE ALSO IN

4639
03:03:24,584 --> 03:03:30,156
HUMOR NUMBERS IN A MOUSE TREATED

4640
03:03:30,156 --> 03:03:36,529
WITH 60.

4641
03:03:36,529 --> 03:03:37,230
 6-OHDA SUGGESTING THAT

4642
03:03:37,230 --> 03:03:39,632
THERE'S A NEUROAND CANCER CELL

4643
03:03:39,632 --> 03:03:40,667
INTERACTIONS DURING TUMOR

4644
03:03:40,667 --> 03:03:43,903
GROWTH.

4645
03:03:43,903 --> 03:03:45,305
BUT UNFORTUNATELY, REALLY RIGHT

4646
03:03:45,305 --> 03:03:47,140
NOW WE DON'T HAVE TOO MUCH DATA

4647
03:03:47,140 --> 03:03:51,711
ABOUT FOR THIS -- SO WE HAVE TO

4648
03:03:51,711 --> 03:03:52,946
LOOK INTO OTHER TISSUES.

4649
03:03:52,946 --> 03:03:54,380
IN THE INTESTINE, IT HAS BEEN

4650
03:03:54,380 --> 03:03:56,416
SHOWN BY FREDERICK AND

4651
03:03:56,416 --> 03:04:04,023
GENENTECH, HE SHOWS THAT

4652
03:04:04,023 --> 03:04:07,393
ADRENERGIC NERVES CAN PRODUCE

4653
03:04:07,393 --> 03:04:09,228
NEURAL TRANSMITTERS AND GROWTH

4654
03:04:09,228 --> 03:04:11,297
FACTORS WHICH IN TURN CAN

4655
03:04:11,297 --> 03:04:16,369
STIMULATE -- AND ALSO STEM

4656
03:04:16,369 --> 03:04:22,141
CELLS, THE IMMUNE CELLS, HERE HE

4657
03:04:22,141 --> 03:04:23,710
SHOWS THAT -- JUST

4658
03:04:23,710 --> 03:04:25,111
NEUROTRANSMITTERS OR GROWTH

4659
03:04:25,111 --> 03:04:27,146
FACTORS STIMULATE BY -- SE CITED

4660
03:04:27,146 --> 03:04:30,550
BY THE NEURONS CAN WORK ON TYPE

4661
03:04:30,550 --> 03:04:31,918
3 INNATE LYMPHOCYTE, WHICH IN

4662
03:04:31,918 --> 03:04:34,253
TURN CAN PRODUCE THIS

4663
03:04:34,253 --> 03:04:36,356
INTERLEUKIN 22, INTERLEUKIN 22

4664
03:04:36,356 --> 03:04:43,629
AND NOW CAN WORK ON THOSE STEM

4665
03:04:43,629 --> 03:04:45,431
CELLS TO -- EXPANSION AND ALSO

4666
03:04:45,431 --> 03:04:47,100
DIFFERENTIATE INVOLVED IN THIS

4667
03:04:47,100 --> 03:04:52,005
REGENERATION.

4668
03:04:52,005 --> 03:04:54,207
ANOTHER GROUP IN BEJING SHOWS

4669
03:04:54,207 --> 03:04:56,743
THAT ANOTHER TYPE OF NEURONS

4670
03:04:56,743 --> 03:05:06,886
WHICH IS 5HT,

4671
03:05:06,886 --> 03:05:08,154
5 HYDROXYTRYPTAMINE ALSO CAN

4672
03:05:08,154 --> 03:05:10,823
PROMOTE TUMOR GROWTH VIA THE

4673
03:05:10,823 --> 03:05:12,692
INTERACTION WITH THE CANCER STEM

4674
03:05:12,692 --> 03:05:17,330
CELLS, AND WHAT THEY SHOW IS

4675
03:05:17,330 --> 03:05:25,104
THAT MICROBIOTA CAN STIMULATE

4676
03:05:25,104 --> 03:05:26,039
NEURON -- NERVE ENDINGS TO

4677
03:05:26,039 --> 03:05:30,676
PRODUCE THIS 5HT.

4678
03:05:30,676 --> 03:05:32,812
SEROTONIN, TRANSMITTER WHICH IN

4679
03:05:32,812 --> 03:05:38,851
TURN CAN WORK ON -- STEM CELLS

4680
03:05:38,851 --> 03:05:43,189
AND DRIVE THE ACTIVATION OF --

4681
03:05:43,189 --> 03:05:44,524
WHICH IN TURN FURTHER PROMOTE

4682
03:05:44,524 --> 03:05:46,192
THE EXPANSION OF CANCER TEM

4683
03:05:46,192 --> 03:05:48,127
CELLS AND PROMOTE TUMOR

4684
03:05:48,127 --> 03:05:52,165
FORMATION.

4685
03:05:52,165 --> 03:06:00,873
NNT SAME GIN THE SAME GROUP THAE

4686
03:06:00,873 --> 03:06:03,209
PROLIFERATION VIA THE

4687
03:06:03,209 --> 03:06:04,410
MICROPHAGES IN THE MIDDLE THEY

4688
03:06:04,410 --> 03:06:08,748
USE THIS HE ENTERIC NEURONS THAT

4689
03:06:08,748 --> 03:06:15,188
AGAIN THOSE M -- CAN ACTD ARE

4690
03:06:15,188 --> 03:06:21,928
ATIONACTIVATENEURONS WHICH CAN T

4691
03:06:21,928 --> 03:06:25,498
WHICH IN TURN CAN PRODUCE

4692
03:06:25,498 --> 03:06:29,168
MICROPHAGE AND PGE2 LATER ON CAN

4693
03:06:29,168 --> 03:06:33,172
WORK ON THE STEM CELLS TO DRIVE

4694
03:06:33,172 --> 03:06:39,612
PROLIFERATION.

4695
03:06:39,612 --> 03:06:41,080
MANY OF YOU IN THE AUDIENCE IS

4696
03:06:41,080 --> 03:06:43,249
SHOWN THERE ARE MULTIPLE STEM

4697
03:06:43,249 --> 03:06:44,750
CELLS IN THE LUNG INCLUDING

4698
03:06:44,750 --> 03:06:48,020
BASAL CELLS, EPITHELIAL CELLS

4699
03:06:48,020 --> 03:06:53,960
AND ALSO WE HAVE SHOWN --

4700
03:06:53,960 --> 03:06:55,795
NEGATIVE POPULATIONS CAN DRIVE

4701
03:06:55,795 --> 03:07:01,234
LUNG REGENERATION.

4702
03:07:01,234 --> 03:07:03,569
BUT WE HAVE NO IDEA HOW THESE

4703
03:07:03,569 --> 03:07:05,738
NEURONS INTERACT WITH THESE STEM

4704
03:07:05,738 --> 03:07:10,977
CELLS, AND WHETHER IT IS

4705
03:07:10,977 --> 03:07:13,012
FLUID -- OR -- WHICH HAVE

4706
03:07:13,012 --> 03:07:15,047
BEHAVED LIKE A NEURON NETWORK

4707
03:07:15,047 --> 03:07:19,318
COMPONENT AND ALSO -- AND ALSO

4708
03:07:19,318 --> 03:07:20,720
IN ALVEOLI, WE DON'T KNOW

4709
03:07:20,720 --> 03:07:22,221
WHETHER -- WE DON'T KNOW WHETHER

4710
03:07:22,221 --> 03:07:24,724
THOSE NERVE ENDINGS CAN DIRECTLY

4711
03:07:24,724 --> 03:07:27,460
AFFECT THE ENDOTHELIAL CELLS OR

4712
03:07:27,460 --> 03:07:30,029
OTHER CELL TYPES AND WE DON'T

4713
03:07:30,029 --> 03:07:33,199
KNOW WHETHER THEY ARE DIRECT OR

4714
03:07:33,199 --> 03:07:35,268
INDIRECT THROUGH THESE -- IMMUNE

4715
03:07:35,268 --> 03:07:35,935
CELLS.

4716
03:07:35,935 --> 03:07:40,306
SO THERE ARE MANY GAPS, AND --

4717
03:07:40,306 --> 03:07:41,541
GAPS, AS I SAID WE DON'T KNOW

4718
03:07:41,541 --> 03:07:43,976
WHETHER NEURONS PLAY ANY ROLE IN

4719
03:07:43,976 --> 03:07:46,779
REGENERATION AND LACK OF

4720
03:07:46,779 --> 03:07:51,317
UNDERSTANDING THE NEURONS

4721
03:07:51,317 --> 03:07:53,519
SPECIFIC INNOVATING THESE

4722
03:07:53,519 --> 03:07:55,688
AIRWAYS AND WE DON'T KNOW

4723
03:07:55,688 --> 03:07:56,822
WHETHER THOSE -- WHAT TYPE OF

4724
03:07:56,822 --> 03:07:59,892
INCREASED NEURONS APPEARED IN

4725
03:07:59,892 --> 03:08:03,029
THE -- IN ASTHMA AND WE HAVE NO

4726
03:08:03,029 --> 03:08:07,233
IDEA HOW EXACTLY THIS

4727
03:08:07,233 --> 03:08:09,302
NEUROENDOCRINE CELLS INVOLVED IN

4728
03:08:09,302 --> 03:08:12,338
EPITHELIAL REGENERATION AT A

4729
03:08:12,338 --> 03:08:16,008
MOLECULAR LEVELS, AND THIS IS

4730
03:08:16,008 --> 03:08:18,444
LARGELY UNKNOWN AND ALSO LACK OF

4731
03:08:18,444 --> 03:08:20,346
IMAGING SYSTEM TO SHOW THE NERVE

4732
03:08:20,346 --> 03:08:25,785
ENDINGS IN EPITHELIAL CELLS.

4733
03:08:25,785 --> 03:08:26,852
SO WE HAVE MANY QUESTIONS WE

4734
03:08:26,852 --> 03:08:29,589
NEED TO ADDRESS AND CAN DISCUSS

4735
03:08:29,589 --> 03:08:36,229
LATER ON IN THE DISCUSSION PART.

4736
03:08:36,229 --> 03:08:37,897
WITH THAT, I WOULD LIKE TO THANK

4737
03:08:37,897 --> 03:08:41,167
MY PEOPLE IN THIS PICTURE

4738
03:08:41,167 --> 03:08:50,309
ESPECIALLY -- WHO GAVE ME LOTS

4739
03:08:50,309 --> 03:08:51,377
OF INPUT AND PREPARED THESE

4740
03:08:51,377 --> 03:08:51,677
SLIDES.

4741
03:08:51,677 --> 03:08:56,082
THANK YOU.

4742
03:08:56,082 --> 03:08:57,617
>> THANK YOU VERY MUCH.

4743
03:08:57,617 --> 03:09:07,126
SO NOW WE'D LIKE TO TRANSITION

4744
03:09:07,126 --> 03:09:07,793
INTO THE DISCUSSION OF GAPS AN

4745
03:09:07,793 --> 03:09:08,828
OPPORTUNITIES PARTICULARLY

4746
03:09:08,828 --> 03:09:10,496
FOCUSED ON Q & A SESSION
WITH

4747
03:09:10,496 --> 03:09:12,732
THE SPEAKERS THAT WE'VE HAD IN

4748
03:09:12,732 --> 03:09:14,100
THIS LAST SESSION.

4749
03:09:14,100 --> 03:09:15,334
JUST A HOUSEKEEPING NOTE, I KNOW

4750
03:09:15,334 --> 03:09:19,472
WE'RE A LITTLE BIT OVER TIME.

4751
03:09:19,472 --> 03:09:21,207
WE WILL HAVE A BRIEF BREAK JUST

4752
03:09:21,207 --> 03:09:25,077
TO HELP US TRANSITION AT 2:45 TO

4753
03:09:25,077 --> 03:09:28,080
OUR -- THAT'S 2:45 EASTERN TO

4754
03:09:28,080 --> 03:09:30,383
OUR STRATEGIC DISCUSSION, WHERE

4755
03:09:30,383 --> 03:09:34,920
WE'LL WRAP UP AND HAVE A FEW

4756
03:09:34,920 --> 03:09:36,622
FORWARD LOOKING POINT ON THE

4757
03:09:36,622 --> 03:09:37,156
ENTIRE WORKSHOP.

4758
03:09:37,156 --> 03:09:40,760
SO I'D LIKE TO OPEN THE FLOOR UP

4759
03:09:40,760 --> 03:09:42,695
TO ANY QUESTIONS FOR OUR

4760
03:09:42,695 --> 03:09:43,562
SPEAKERS IN THIS PARTICULAR

4761
03:09:43,562 --> 03:09:53,906
PANEL AT THIS POINT.

4762
03:10:02,682 --> 03:10:08,854
>> SOMEONE RAISED THEIR
HAND.

4763
03:10:08,854 --> 03:10:11,057
PLEASE.

4764
03:10:11,057 --> 03:10:11,691
>> HI.

4765
03:10:11,691 --> 03:10:13,459
THANKS FOR THE GREAT TALKS.

4766
03:10:13,459 --> 03:10:14,026
ALL.

4767
03:10:14,026 --> 03:10:16,862
PERHAPS MORE DIRECTED TOWARDS

4768
03:10:16,862 --> 03:10:17,697
MICHA BUT EVERYONE CAN RESPOND.

4769
03:10:17,697 --> 03:10:18,631
I'M CURIOUS HOW YOU THINK ABOUT

4770
03:10:18,631 --> 03:10:20,900
THE FUTURE OF COMPUTATIONALLY

4771
03:10:20,900 --> 03:10:23,569
MODELING COMPLEX DISEASES LIKE

4772
03:10:23,569 --> 03:10:25,237
THE VARIOUS FORMS OF LUNG

4773
03:10:25,237 --> 03:10:26,172
DISEASE YOU MENTIONED WHEN IT

4774
03:10:26,172 --> 03:10:28,074
FEELS LIKE EVERY DAY, WE END UP

4775
03:10:28,074 --> 03:10:29,942
DISCOVERING A NEW CELL STATE OR

4776
03:10:29,942 --> 03:10:35,815
TRANSITIONAL STATE, I MEAN, FROM

4777
03:10:35,815 --> 03:10:37,883
MY ENGINEERING BACKGROUND, YOU

4778
03:10:37,883 --> 03:10:38,684
CAN'T BUILD A MODEL IF THE

4779
03:10:38,684 --> 03:10:40,419
NUMBER OF VARIABLES JUST KEEPS

4780
03:10:40,419 --> 03:10:41,721
INCREASING AND CHANGING AND YET

4781
03:10:41,721 --> 03:10:42,922
THAT SEEMS TO BE THE SITUATION

4782
03:10:42,922 --> 03:10:43,856
WE'RE IN, SO HOW DO YOU SQUARE

4783
03:10:43,856 --> 03:10:45,691
THAT WITH EVERYONE'S DESIRE TO

4784
03:10:45,691 --> 03:10:48,127
BUILD MORE PREDICTIVE MODELS OR

4785
03:10:48,127 --> 03:10:49,228
STATISTICAL MODELS OF WHAT'S

4786
03:10:49,228 --> 03:10:53,366
GOING ON IN TISSUES?

4787
03:10:53,366 --> 03:10:55,000
>> I REALLY LIKE THIS
QUESTION.

4788
03:10:55,000 --> 03:10:58,003
I THINK IT'S A GREAT QUESTION,

4789
03:10:58,003 --> 03:11:00,106
HE'S SPOT-ON, IT'S AN ACTIVE

4790
03:11:00,106 --> 03:11:01,374
CHALLENGE AND PROBABLY ONE OF

4791
03:11:01,374 --> 03:11:02,375
THE FOREMOST CHALLENGES RIGHT

4792
03:11:02,375 --> 03:11:04,110
NOW BUT IT IS PROBABLY

4793
03:11:04,110 --> 03:11:04,810
SURMOUNTABLE.

4794
03:11:04,810 --> 03:11:06,879
THE KEY THING IS TO RELLIZE

4795
03:11:06,879 --> 03:11:08,247
THERE ARE THESE CATEGORIES OF

4796
03:11:08,247 --> 03:11:11,217
SCALE YOU CAN GO UP IN.

4797
03:11:11,217 --> 03:11:13,786
20, 30 YEARS AGO PEOPLE MIGHT

4798
03:11:13,786 --> 03:11:15,755
HAVE SAID OH IT'S TOO MUCH TO BE

4799
03:11:15,755 --> 03:11:16,989
STUDYING MULTIPLE MOLECULES

4800
03:11:16,989 --> 03:11:18,591
WITHIN A SINGLE CELL.

4801
03:11:18,591 --> 03:11:20,259
NOW WE'VE GOT OMICS LEVEL THINGS

4802
03:11:20,259 --> 03:11:21,727
WHERE THE PATTERNS THAT WE ARE

4803
03:11:21,727 --> 03:11:22,762
STUDYING AND WE'RE USED TO

4804
03:11:22,762 --> 03:11:25,097
STUDYING WHEN WE'RE LOOKING AT

4805
03:11:25,097 --> 03:11:26,399
MAPS OF CELL STATE AND YOU KNOW

4806
03:11:26,399 --> 03:11:27,833
EACH IS A VECTOR OF TENS OF

4807
03:11:27,833 --> 03:11:29,468
THOUSANDS OF NUMBERS AND WE'RE

4808
03:11:29,468 --> 03:11:31,504
SEEING HOW THOSE SELL STATES

4809
03:11:31,504 --> 03:11:33,439
CHANGE AND ARE REDISTRIBUTED.

4810
03:11:33,439 --> 03:11:36,041
WELL, THERE'S ANED AD LEVEL THAT

4811
03:11:36,041 --> 03:11:37,576
WE CAN GO UP WHEN WE START

4812
03:11:37,576 --> 03:11:39,278
TALKING ABOUT THINGS LIKE TISSUE

4813
03:11:39,278 --> 03:11:41,180
STATE, WE LOOK AT THE ACTUAL --

4814
03:11:41,180 --> 03:11:43,282
SO LIKE HOW MANY OF EVERY CELL

4815
03:11:43,282 --> 03:11:44,650
TYPE THERE IS WITHIN A TISSUE,

4816
03:11:44,650 --> 03:11:46,252
WITHIN A REGION, WE LOOK AT THE

4817
03:11:46,252 --> 03:11:47,586
INDIVIDUAL CELL STATE

4818
03:11:47,586 --> 03:11:48,087
THEMSELVES, WHAT'S THE

4819
03:11:48,087 --> 03:11:49,121
REPRESENTATION, AND THEN WE ALSO

4820
03:11:49,121 --> 03:11:51,223
LOOK AT THE CONNECTIVITY VALUES,

4821
03:11:51,223 --> 03:11:52,291
HOW THEY COMMUNICATE.

4822
03:11:52,291 --> 03:11:53,492
ALL OF THAT CAN BE CONDENSED OR

4823
03:11:53,492 --> 03:11:54,960
COMPRESSED DOWN INTO EMBEDDINGS

4824
03:11:54,960 --> 03:11:56,829
IN THE SAME WAY THAT WE NOW LOOK

4825
03:11:56,829 --> 03:11:58,030
AT CELL STATE, WE CAN START TO

4826
03:11:58,030 --> 03:11:59,131
LOOK AT THINGS LIKE TISSUE

4827
03:11:59,131 --> 03:11:59,498
STATE.

4828
03:11:59,498 --> 03:12:01,901
AND WHEN YOU HAVE THOSE KIND OF

4829
03:12:01,901 --> 03:12:04,136
A COMPUTATION -- THAT IS

4830
03:12:04,136 --> 03:12:05,337
COMPUTATIONAL TASK BUT ALSO SORT

4831
03:12:05,337 --> 03:12:06,939
OF A CONCEPTUAL ONE WHERE YOU

4832
03:12:06,939 --> 03:12:09,341
CAN SAY THIS IS CONTROL TISSUE,

4833
03:12:09,341 --> 03:12:11,610
IPF, COPD, REGENERATING TISSUE,

4834
03:12:11,610 --> 03:12:15,314
IF WE CAN START TO MAKE RELIABLE

4835
03:12:15,314 --> 03:12:16,148
EMBEDDINGS OF THE DATA, THEN WE

4836
03:12:16,148 --> 03:12:17,316
REALLY HAVE THE TOOLS NOT ONLY

4837
03:12:17,316 --> 03:12:19,985
TO DO PREDICTIVE MODELING BUT

4838
03:12:19,985 --> 03:12:20,920
ALSO JUST TO SORT OF OBSERVE OUR

4839
03:12:20,920 --> 03:12:24,323
DATA VERY CLEARLY AT THE END YOU

4840
03:12:24,323 --> 03:12:25,458
CAN SAY WHAT FEATURES ARE

4841
03:12:25,458 --> 03:12:27,626
DRIVING THAT, OH IT'S THE

4842
03:12:27,626 --> 03:12:29,328
EMERGENCE -- OR THE LOSS OF

4843
03:12:29,328 --> 03:12:31,197
THE -- IN THE LUNG OR THESE NEW

4844
03:12:31,197 --> 03:12:31,497
FIBROBLASTS.

4845
03:12:31,497 --> 03:12:32,331
BUT FIRST YOU CAN JUST SORT OF

4846
03:12:32,331 --> 03:12:35,434
SEE HOW THESE STATE TRANSITIONS

4847
03:12:35,434 --> 03:12:36,068
ARE OCCURRING AND HOW WE MIGHT

4848
03:12:36,068 --> 03:12:37,269
BE ABLE TO TARGET THEM

4849
03:12:37,269 --> 03:12:37,636
THERAPEUTICALLY.

4850
03:12:37,636 --> 03:12:38,771
SO THERE'S THIS BRIDGE THAT HAS

4851
03:12:38,771 --> 03:12:43,108
TO HAPPEN BETWEEN FEATURE LEVEL

4852
03:12:43,108 --> 03:12:44,844
INVESTIGATIONS AND MUCH MORE

4853
03:12:44,844 --> 03:12:46,412
HOLISTIC SYSTEMS LEVEL

4854
03:12:46,412 --> 03:12:48,214
COMPRESSION AND EMBEDDING AND

4855
03:12:48,214 --> 03:12:49,348
ARCHITECTURES THAT ALLOW US TO

4856
03:12:49,348 --> 03:12:50,316
OBSERVE OUR DATA.

4857
03:12:50,316 --> 03:12:51,484
WE'RE GETTING THERE, THOUGH.

4858
03:12:51,484 --> 03:12:52,618
THIS IS GOING TO HAPPEN SOON, I

4859
03:12:52,618 --> 03:12:56,121
THINK.

4860
03:12:56,121 --> 03:12:56,922
I DON'T KNOW IF OTHER PEOPLE

4861
03:12:56,922 --> 03:12:58,424
HAVE COMMENTS ABOUT THIS TOO.

4862
03:12:58,424 --> 03:13:01,327
IT'S A VERY GENERAL SUBJECT.

4863
03:13:01,327 --> 03:13:03,829
>> I THINK A RELATED
QUESTION,

4864
03:13:03,829 --> 03:13:06,866
SO WITH A LOT OF THE -- THIS IS

4865
03:13:06,866 --> 03:13:08,734
ALL VERY TRANSCRIPTOMIC BASED,

4866
03:13:08,734 --> 03:13:10,436
WHERE DO YOU THINK -- WHEN DO

4867
03:13:10,436 --> 03:13:11,337
YOU THINK OR WHERE ARE WE MOVING

4868
03:13:11,337 --> 03:13:13,138
TO ACTUALLY DO SIMILAR STUDIES

4869
03:13:13,138 --> 03:13:17,309
BUT AT THE PROTEOMIC LEVEL?

4870
03:13:17,309 --> 03:13:20,145
IS THAT LIKE A PIPE DREAM OR IS

4871
03:13:20,145 --> 03:13:21,347
THAT MORE OF A POSSIBILITY IN

4872
03:13:21,347 --> 03:13:26,619
THE COMING YEARS?

4873
03:13:26,619 --> 03:13:28,354
>> I THINK IT'S VERY
POSSIBLE.

4874
03:13:28,354 --> 03:13:29,121
I THINK THE TECHNOLOGIES ARE

4875
03:13:29,121 --> 03:13:31,957
IMPROVING.

4876
03:13:31,957 --> 03:13:35,828
YOU CAN ALREADY GET SOME REALLY

4877
03:13:35,828 --> 03:13:36,929
BEAUTIFUL MULTIPLEX SPATIAL

4878
03:13:36,929 --> 03:13:38,531
PROTEOMICS FROM LIKE CODEX

4879
03:13:38,531 --> 03:13:39,331
PLATFORMS AND OTHER THINGS LIKE

4880
03:13:39,331 --> 03:13:39,765
THAT.

4881
03:13:39,765 --> 03:13:41,867
YOU CAN USE EXISTING ANTIBODIES,

4882
03:13:41,867 --> 03:13:42,768
THERE'S A LOT OF DIFFERENT WAYS

4883
03:13:42,768 --> 03:13:43,335
OF DOING THIS.

4884
03:13:43,335 --> 03:13:45,404
I THINK IT HARDER -- JOSE MIGHT

4885
03:13:45,404 --> 03:13:47,673
KNOW MORE ABOUT IT, IT'S NOT AS

4886
03:13:47,673 --> 03:13:49,041
WELL DEVELOPED BUT IT IS

4887
03:13:49,041 --> 03:13:50,376
BEAUTIFUL DATA AND I THINK IT'S

4888
03:13:50,376 --> 03:13:52,344
VERY INTERESTING TO LOOK AT THE

4889
03:13:52,344 --> 03:13:53,312
TRANSCRIPTOMIC LAYER AND THE

4890
03:13:53,312 --> 03:13:54,079
PROTEOMICS LAYER BECAUSE THEY

4891
03:13:54,079 --> 03:13:55,047
ARE NOT ALWAYS THE SAME, AND

4892
03:13:55,047 --> 03:13:56,849
THEY'RE NOT THE SAME IN SOME

4893
03:13:56,849 --> 03:13:57,383
VERY INTERESTING WAYS.

4894
03:13:57,383 --> 03:13:58,884
WHEN YOU LOOK AT RNA, YOU'RE

4895
03:13:58,884 --> 03:14:01,687
LOOKING AT PROTEIN PRODUCTION --

4896
03:14:01,687 --> 03:14:03,956
IT LIKE A PROXY FOR FLUX, HOW

4897
03:14:03,956 --> 03:14:05,591
MUCH IS BEING SORT OF -- HOW

4898
03:14:05,591 --> 03:14:07,159
MUCH IS IT PATHWAY ACTIVATED?

4899
03:14:07,159 --> 03:14:09,495
THAT'S WHERE YOU GET THE RNA

4900
03:14:09,495 --> 03:14:09,929
LEVEL.

4901
03:14:09,929 --> 03:14:11,330
ON A PROTEIN LEVEL, IT MAY BE

4902
03:14:11,330 --> 03:14:12,431
BECAUSE YOU'RE DEGRADING THE

4903
03:14:12,431 --> 03:14:13,666
PROTEIN AND YOU'RE NOT SEEING IT

4904
03:14:13,666 --> 03:14:13,832
ALL.

4905
03:14:13,832 --> 03:14:15,367
SO IT'S VERY PATHWAY-SPECIFIC,

4906
03:14:15,367 --> 03:14:15,935
VERY PROCESS SPECIFIC.

4907
03:14:15,935 --> 03:14:18,203
I THINK WE DO NEED THESE

4908
03:14:18,203 --> 03:14:19,271
MULTIPLE LAYERS OF INFORMATION

4909
03:14:19,271 --> 03:14:20,272
TO REALLY UNDERSTAND WHAT'S

4910
03:14:20,272 --> 03:14:23,509
GOING ON.

4911
03:14:23,509 --> 03:14:26,879
>> MAYBE JUST TO KIND OF
SHIFT

4912
03:14:26,879 --> 03:14:30,115
THE CONVERSATION OVER TO SHAWN,

4913
03:14:30,115 --> 03:14:31,650
YOU KNOW, WE WERE JUST TALKING

4914
03:14:31,650 --> 03:14:34,153
ABOUT RNA AND PROTEIN METABOLISM

4915
03:14:34,153 --> 03:14:36,855
PROBABLY FITS IN THERE

4916
03:14:36,855 --> 03:14:37,122
SOMEWHERE.

4917
03:14:37,122 --> 03:14:40,025
HOW DO YOU FORESEE SOME OF THE

4918
03:14:40,025 --> 03:14:40,759
METABOLIC FLUX THINGS THAT

4919
03:14:40,759 --> 03:14:43,195
YOU'RE DOING IN TERMS OF

4920
03:14:43,195 --> 03:14:43,862
INFLUENCING OUR UNDERSTANDING OF

4921
03:14:43,862 --> 03:14:45,898
THESE POTENTIAL RECEPTOR LIGAND

4922
03:14:45,898 --> 03:14:46,732
INTERACTIONS REGARDLESS OF WHAT

4923
03:14:46,732 --> 03:14:52,538
WE'RE IB FERRING THEM FROM?

4924
03:14:52,538 --> 03:14:54,473
>> I THINK THERE'S A LOT
TO

4925
03:14:54,473 --> 03:14:54,974
LEARN HERE.

4926
03:14:54,974 --> 03:14:56,075
I THINK THE STRENGTH OF WHAT

4927
03:14:56,075 --> 03:14:57,610
WHICH DO IS THAT, YOU KNOW,

4928
03:14:57,610 --> 03:15:00,679
GETTING METABOLIC ACTIVITY

4929
03:15:00,679 --> 03:15:02,381
WILL -- THERE SHOULD BE A PRETTY

4930
03:15:02,381 --> 03:15:03,582
DECENT DISCONNECT FROM WHAT YOU

4931
03:15:03,582 --> 03:15:05,084
SEE FOR PROTEIN OR RNA LEVELS,

4932
03:15:05,084 --> 03:15:07,419
JUST BECAUSE OF DIFFERENT

4933
03:15:07,419 --> 03:15:08,253
ENZYMATIC ACTIVITIES THROUGH

4934
03:15:08,253 --> 03:15:11,156
THIS, AND SO I THINK IT ADDS A

4935
03:15:11,156 --> 03:15:13,959
VERY COMPLEMENTARY LAYER OF

4936
03:15:13,959 --> 03:15:14,760
INFORMATION AND HOW DIFFERENT IT

4937
03:15:14,760 --> 03:15:16,962
WILL BE FROM WHAT YOU SEE AT THE

4938
03:15:16,962 --> 03:15:18,063
PROTEOMIC LEVEL OR WHAT IT WILL

4939
03:15:18,063 --> 03:15:20,833
PREDICT OUTSIDE OF THAT, I'M NOT

4940
03:15:20,833 --> 03:15:22,534
SURE, BUT -- AND WE'RE REALLY

4941
03:15:22,534 --> 03:15:23,135
EXCITED TO INTEGRATE THESE

4942
03:15:23,135 --> 03:15:31,243
THINGS.

4943
03:15:31,243 --> 03:15:32,177
>> ABSOLUTELY.

4944
03:15:32,177 --> 03:15:36,181
I THINK ONE QUESTION THAT CAME

4945
03:15:36,181 --> 03:15:38,984
UP ACTUALLY BEFORE -- WE CAN

4946
03:15:38,984 --> 03:15:46,425
MOVE AHEAD TO YOHANNES, PLEASE.

4947
03:15:46,425 --> 03:15:48,227
>> THANK YOU.

4948
03:15:48,227 --> 03:15:49,828
THOSE WERE GREAT PRESENTATIONS.

4949
03:15:49,828 --> 03:15:52,331
MY QUESTION IS FOR SHAWN.

4950
03:15:52,331 --> 03:15:55,200
SHAWN, WHEN YOU LOOK AT SPECIAL

4951
03:15:55,200 --> 03:15:57,136
METABOLOMICS ON, SAY, INFLAMED

4952
03:15:57,136 --> 03:16:02,908
TISSUE, NOT HEAVILY INFLAMED BUT

4953
03:16:02,908 --> 03:16:04,343
SOME INFLAMMATION, WOULD YOU

4954
03:16:04,343 --> 03:16:06,879
REALLY SEE KIND OF COLOR CHANGES

4955
03:16:06,879 --> 03:16:08,914
OR REALLY CHANGES THAT ONE CAN

4956
03:16:08,914 --> 03:16:12,051
QUANTIFY, OR IS IT SOMETHING

4957
03:16:12,051 --> 03:16:15,554
THAT YOU NEED TO HAVE, LIKE A

4958
03:16:15,554 --> 03:16:17,022
DRASTIC RESPONSE TO SEE THESE

4959
03:16:17,022 --> 03:16:19,625
KIND OF METABOLOMICS CHANGES?

4960
03:16:19,625 --> 03:16:21,427
>> I DON'T THINK IT HAS TO
BE SO

4961
03:16:21,427 --> 03:16:21,660
DRASTIC.

4962
03:16:21,660 --> 03:16:22,828
I THINK IT DEPENDS ON WHAT THE

4963
03:16:22,828 --> 03:16:26,231
CAUSE OF INFLAMMATION IS.

4964
03:16:26,231 --> 03:16:28,467
WE HAVE SOME EARLY DATA ON

4965
03:16:28,467 --> 03:16:31,637
INFECTION MODELS AND SO WE HAVE

4966
03:16:31,637 --> 03:16:32,471
SOME LOCAL INFORMATION AROUND

4967
03:16:32,471 --> 03:16:32,938
THERE.

4968
03:16:32,938 --> 03:16:34,573
WE'VE DONE A LOT OF TUMOR WORK

4969
03:16:34,573 --> 03:16:35,607
AS WELL, SO I DON'T THINK THEY

4970
03:16:35,607 --> 03:16:38,077
HAVE TO BE DRAMA TI AND I THINK

4971
03:16:38,077 --> 03:16:41,246
THE OTHER STRENGTH OF

4972
03:16:41,246 --> 03:16:43,048
METABOLOMICS IS THAT THESE

4973
03:16:43,048 --> 03:16:45,350
CHANGES HAPPEN VERY QUICKLY.

4974
03:16:45,350 --> 03:16:48,020
WE'VE BEEN USING THIS

4975
03:16:48,020 --> 03:16:49,054
IMPLANTABLE MICRO DEVICE IN

4976
03:16:49,054 --> 03:16:51,290
CLINICAL TRIALS, AND THE DEVICE

4977
03:16:51,290 --> 03:16:53,125
IS IN THE TUMOR FOR ABOUT THREE

4978
03:16:53,125 --> 03:16:56,261
HOURS, AND WE CAN ACTUALLY GET

4979
03:16:56,261 --> 03:16:59,431
MEANININGFUL CELL RESPONSES IN

4980
03:16:59,431 --> 03:17:01,800
JUST THAT AMOUNT OF TIME, IT

4981
03:17:01,800 --> 03:17:04,203
MIGHT TAKE LONGER TO SEE

4982
03:17:04,203 --> 03:17:05,337
TRANSCRIPTIONAL CHANGES.

4983
03:17:05,337 --> 03:17:09,908
SO I THINK BOTH THE SPEED AND

4984
03:17:09,908 --> 03:17:13,979
THE CHANGE FROM THOSE DIFFERENT

4985
03:17:13,979 --> 03:17:16,715
INFLAMED AREAS COULD BE HELPFUL.

4986
03:17:16,715 --> 03:17:19,318
AND POSSIBLE.

4987
03:17:19,318 --> 03:17:21,787
>> VERY INTERESTING.

4988
03:17:21,787 --> 03:17:23,088
SO IN OTHER WORDS, LET'S SAY,

4989
03:17:23,088 --> 03:17:25,424
FOR EXAMPLE, IF YOU HAD A TIME

4990
03:17:25,424 --> 03:17:27,826
COURSE, AS YOU MENTIONED, LET'S

4991
03:17:27,826 --> 03:17:32,464
SAY, YOU KNOW -- EXPOSED SOMEHOW

4992
03:17:32,464 --> 03:17:38,337
SOMETHING AND LACKS OVER TIME.

4993
03:17:38,337 --> 03:17:40,572
AND ARE THERE DATA, THERE'S SOME

4994
03:17:40,572 --> 03:17:42,508
KIND OF CORRELATION DATA, SAY,

4995
03:17:42,508 --> 03:17:45,544
FOR EXAMPLE, IN TERMS OF LAVAGE

4996
03:17:45,544 --> 03:17:47,146
TO IT AND THIS KIND OF

4997
03:17:47,146 --> 03:17:48,213
METABOLOMICS OR SOMETHING LAKE

4998
03:17:48,213 --> 03:17:50,516
THAT, THOSE KIND OF DATA THAT

4999
03:17:50,516 --> 03:17:54,052
ARE GENERATED ALREADY OR NOT?

5000
03:17:54,052 --> 03:17:55,387
>> THAT MAY EXIST AT THE
BULK

5001
03:17:55,387 --> 03:17:56,722
LEVEL.

5002
03:17:56,722 --> 03:17:58,423
WE ARE ASKING SIMILAR QUESTIONS

5003
03:17:58,423 --> 03:18:01,860
ON THE SPATIAL LEVEL.

5004
03:18:01,860 --> 03:18:02,861
>> OKAY.

5005
03:18:02,861 --> 03:18:13,038
THANK YOU.

5006
03:18:14,439 --> 03:18:20,279
>> QUESTION FOR JIANWEN.

5007
03:18:20,279 --> 03:18:23,415
HAVE YOU STARTED LOOKING INTO

5008
03:18:23,415 --> 03:18:26,718
EITHER THE SEROTONIN OR OTHER

5009
03:18:26,718 --> 03:18:30,556
TRANSMITTER RECEPTORS -- CELLS?

5010
03:18:30,556 --> 03:18:33,091
>> THAT'S A GOOD QUESTION.

5011
03:18:33,091 --> 03:18:34,660
WE ARE JUST BEGINNING TO LOOK

5012
03:18:34,660 --> 03:18:39,698
INTO THIS, AND CREATE MODELS AND

5013
03:18:39,698 --> 03:18:40,999
THE FIRST THING WE'RE LOOKING AT

5014
03:18:40,999 --> 03:18:43,335
SINGLE CELL, I'M SURE YOU MAY

5015
03:18:43,335 --> 03:18:44,703
HAVE ACCESSED ALL THIS DATA AS

5016
03:18:44,703 --> 03:18:46,138
WELL, TO LOOK NE SINGLE CELL

5017
03:18:46,138 --> 03:18:48,540
DATA AND SEE WHAT ARE THE

5018
03:18:48,540 --> 03:18:50,642
POTENTIAL NEUROTRANSMITTERS

5019
03:18:50,642 --> 03:18:52,744
EXPRESSED OR RECEPTORS EXPRESSED

5020
03:18:52,744 --> 03:18:54,713
IN EPITHELIUM CELLS AND THE

5021
03:18:54,713 --> 03:18:58,350
MESENCHYMAL CELLS.

5022
03:18:58,350 --> 03:19:01,887
THE SEROTONIN, WE HAVE NOT

5023
03:19:01,887 --> 03:19:04,523
PARTICULARLY PAID ATTENTION TO.

5024
03:19:04,523 --> 03:19:07,125
WHY DO YOU ASK THE QUESTION?

5025
03:19:07,125 --> 03:19:07,893
WHY SEROTONIN IS IMPORTANT DO

5026
03:19:07,893 --> 03:19:11,330
YOU THINK?

5027
03:19:11,330 --> 03:19:15,634
>> THERE'S A FEW REPORTS

5028
03:19:15,634 --> 03:19:19,338
SUGGESTING SOME OF THE SEROTONIN

5029
03:19:19,338 --> 03:19:21,073
SUBTYPES -- RECEPTOR SUBTYPES

5030
03:19:21,073 --> 03:19:29,681
EXPRESSING TYPE 2 CELLS, AND --

5031
03:19:29,681 --> 03:19:31,083
SOME SHOWING MORE, SOME SHOWING

5032
03:19:31,083 --> 03:19:31,283
LESS.

5033
03:19:31,283 --> 03:19:32,551
>> I SEE.

5034
03:19:32,551 --> 03:19:37,756
INTERESTING.

5035
03:19:37,756 --> 03:19:38,724
>> I HAVE A QUESTION.

5036
03:19:38,724 --> 03:19:40,158
CAN I ASK A QUESTION?

5037
03:19:40,158 --> 03:19:41,360
>> OF COURSE.

5038
03:19:41,360 --> 03:19:45,397
>> SO THIS IS FOR JIANWEN
AS

5039
03:19:45,397 --> 03:19:46,465
WELL, I HAVE A QUESTION ABOUT

5040
03:19:46,465 --> 03:19:46,965
THE NEURON WORK.

5041
03:19:46,965 --> 03:19:48,934
DO YOU THINK THIS CAN BE USED --

5042
03:19:48,934 --> 03:19:50,569
THAT -- I MEAN, YOU'VE GOT

5043
03:19:50,569 --> 03:19:52,938
BEAUTIFUL PICTURES THERE, AND I

5044
03:19:52,938 --> 03:19:54,039
DON'T KNOW MUCH ABOUT THIS AND

5045
03:19:54,039 --> 03:19:55,874
I'M JUST SORT OF SEEING THIS

5046
03:19:55,874 --> 03:19:56,875
INCREDIBLE NEURON NETWORK IN THE

5047
03:19:56,875 --> 03:19:58,877
LUNG, AND IT BRINGS TO MIND, I

5048
03:19:58,877 --> 03:19:59,711
FORGET -- I'D HAVE TO DIG

5049
03:19:59,711 --> 03:20:01,079
THROUGH LITERATURE BUT I KNOW

5050
03:20:01,079 --> 03:20:02,214
THERE'S SOME STUDIES WHERE CAN

5051
03:20:02,214 --> 03:20:04,816
YOU ESSENTIALLY DOSE NEURONS INA

5052
03:20:04,816 --> 03:20:11,623
VERY VO WITHINVIVO AND THEY'LL T

5053
03:20:11,623 --> 03:20:13,058
DELIVERED AT THE SYNAPSES.

5054
03:20:13,058 --> 03:20:14,860
CAN YOU USE THIS AS A DELIVERY

5055
03:20:14,860 --> 03:20:15,661
MECHANISM TO TRIGGER

5056
03:20:15,661 --> 03:20:17,629
REGENERATION IN THESE TISSUES OR

5057
03:20:17,629 --> 03:20:20,866
TO MANIPULATE THE CELLS WHEREVER

5058
03:20:20,866 --> 03:20:21,800
THE END PROCESSES ARE?

5059
03:20:21,800 --> 03:20:23,268
>> THAT IS A VERY GOOD
QUESTION.

5060
03:20:23,268 --> 03:20:24,836
I WOULD JUST SAY, THOSE

5061
03:20:24,836 --> 03:20:25,437
BEAUTIFUL PICTURES ARE COMING

5062
03:20:25,437 --> 03:20:30,075
FROM OTHER LABS AND FROM --

5063
03:20:30,075 --> 03:20:31,009
OTHER LABS AS WELL.

5064
03:20:31,009 --> 03:20:36,815
MY LAB, WE JUST -- THE PAPER WAS

5065
03:20:36,815 --> 03:20:38,317
JUST ACCEPTED YESTERDAY I THINK

5066
03:20:38,317 --> 03:20:41,620
BY CANCER DISCOVERY AND WE DO

5067
03:20:41,620 --> 03:20:44,489
SEE THAT NERVE ENDINGS

5068
03:20:44,489 --> 03:20:45,657
INTERACTING WITH CANCER CELL,

5069
03:20:45,657 --> 03:20:46,792
BUT TO COME BACK TO YOUR

5070
03:20:46,792 --> 03:20:51,964
QUESTION, YES, YOU CAN USE THAT

5071
03:20:51,964 --> 03:20:53,031
TOOL TO DELIVER DRUGS THROUGH

5072
03:20:53,031 --> 03:20:55,901
THE NERVE FIBERS AND TO THE --

5073
03:20:55,901 --> 03:20:58,437
FROM GANGLIA INTO THE BRAIN.

5074
03:20:58,437 --> 03:21:04,843
AND THOSE COULD BE USE THE AND A

5075
03:21:04,843 --> 03:21:06,778
VIRUS AND AS A CARRIER TO DRIVE

5076
03:21:06,778 --> 03:21:07,546
ALL THOSE AGENTS.

5077
03:21:07,546 --> 03:21:10,983
THAT'S INTERESTING.

5078
03:21:10,983 --> 03:21:14,052
>> I HAD A QUESTION FOR
HELEN.

5079
03:21:14,052 --> 03:21:15,354
I WAS WONDERING, WE HEARD A

5080
03:21:15,354 --> 03:21:18,056
LITTLE BIT, I'M BY NO MEANS AN

5081
03:21:18,056 --> 03:21:19,558
EXPERT MYSELF IN THE INTEGRATED

5082
03:21:19,558 --> 03:21:22,294
STRESS RESPONSE, BUT WE HEARD

5083
03:21:22,294 --> 03:21:25,630
YESTERDAY IN ONE OF THE FIRST

5084
03:21:25,630 --> 03:21:26,331
TALKS ABOUT THE IMPORTANCE OF

5085
03:21:26,331 --> 03:21:29,101
THE INTEGRATED STRESS RESPONSE

5086
03:21:29,101 --> 03:21:30,235
KIND OF DOWNSTREAM OF

5087
03:21:30,235 --> 03:21:32,004
MANIPULATING THE ELECTRON

5088
03:21:32,004 --> 03:21:33,805
TRANSPORT CHAIN IN MITOCHONDRIA

5089
03:21:33,805 --> 03:21:35,607
AND THEN LEADING TO PARTICULAR

5090
03:21:35,607 --> 03:21:38,243
SUSCEPTIBILITY IN TERMS OF LOSS

5091
03:21:38,243 --> 03:21:43,048
OF AL VE ALVEOLAR EPITHELIAL CE.

5092
03:21:43,048 --> 03:21:44,383
I DON'T KNOW IF YOU WERE IN

5093
03:21:44,383 --> 03:21:45,384
ATTENDANCE FOR THIS TALK OR IF

5094
03:21:45,384 --> 03:21:47,452
YOU HAD ANY REFLECTIONS ON YOUR

5095
03:21:47,452 --> 03:21:49,421
WORK BASED ON THIS ISR MECHANISM

5096
03:21:49,421 --> 03:21:52,024
AND SIMILARITIES OR DIFFERENCES

5097
03:21:52,024 --> 03:21:53,158
BETWEEN LUNG PARENCHYMA AND WHAT

5098
03:21:53,158 --> 03:21:55,861
YOU'RE SEEING IN PERIPHERAL

5099
03:21:55,861 --> 03:21:57,029
NEURONS.

5100
03:21:57,029 --> 03:21:58,430
>> YEAH, I MEAN, IT'S

5101
03:21:58,430 --> 03:21:59,031
INTERESTING, BECAUSE I THINK

5102
03:21:59,031 --> 03:22:01,033
PEOPLE ARE JUST STARTING TO --

5103
03:22:01,033 --> 03:22:04,302
PEOPLE HAVE STUDIED IT FOR MANY

5104
03:22:04,302 --> 03:22:07,172
YEARS IN CANCER, CANCER-LIKE

5105
03:22:07,172 --> 03:22:10,008
CELLS, BUT I THINK IMPLICATIONS

5106
03:22:10,008 --> 03:22:12,310
IN OTHER DISEASES AS WELL AS

5107
03:22:12,310 --> 03:22:14,546
DEVELOPMENT AS IT WAS EMPHASIZED

5108
03:22:14,546 --> 03:22:15,614
YESTERDAY, WE'RE JUST STARTING

5109
03:22:15,614 --> 03:22:16,648
TO WORK ON.

5110
03:22:16,648 --> 03:22:18,283
I THINK ONE OF THE POINTS

5111
03:22:18,283 --> 03:22:20,152
THAT -- I THINK IT WAS DR. HAN

5112
03:22:20,152 --> 03:22:21,887
THAT GAVE THAT TALK THAT SHE

5113
03:22:21,887 --> 03:22:24,990
ALSO RAISED THAT WE ALSO DON'T

5114
03:22:24,990 --> 03:22:27,259
KNOW THE SEPARATION BETWEEN --

5115
03:22:27,259 --> 03:22:32,164
WE KNOW ONCE YOU ACTIVATE STRESS

5116
03:22:32,164 --> 03:22:34,332
RESPONSE YOU HAVE THESE

5117
03:22:34,332 --> 03:22:35,867
SIMULTANEOUSLY ACTIVATION OF

5118
03:22:35,867 --> 03:22:39,337
SPECIFIC TARGETED GENES, AS WELL

5119
03:22:39,337 --> 03:22:42,340
AS YOU HAVE A SHUTDOWN IN GLOBAL

5120
03:22:42,340 --> 03:22:44,543
TRANSLATION SO YOU HAVE A

5121
03:22:44,543 --> 03:22:46,178
DEPLETED PROTEIN SYNTHESIS.

5122
03:22:46,178 --> 03:22:48,346
AND WE DON'T KNOW WHICH ONE IS

5123
03:22:48,346 --> 03:22:50,715
ACTUALLY -- WE DON'T EVEN KNOW

5124
03:22:50,715 --> 03:22:52,417
WHICH ONE IS RESPONSIBLE FOR THE

5125
03:22:52,417 --> 03:22:53,418
PHENOTYPES WE'RE SEEING AND I

5126
03:22:53,418 --> 03:22:54,953
THINK SHE ALLUDED TO THAT, AND

5127
03:22:54,953 --> 03:22:58,323
WE DON'T KNOW WHICH ONE OF THOSE

5128
03:22:58,323 --> 03:23:00,058
ARMS IS ACTUALLY RESPONSIBLE FOR

5129
03:23:00,058 --> 03:23:01,193
THAT EITHER.

5130
03:23:01,193 --> 03:23:02,861
SO I MEAN, I DON'T HAVE A

5131
03:23:02,861 --> 03:23:04,196
STRAIGHT ANSWER FOR THAT.

5132
03:23:04,196 --> 03:23:07,199
YOU KNOW, JUST TO SAY THAT WE

5133
03:23:07,199 --> 03:23:08,834
STILL HAVE A LOT TO UNDERSTAND

5134
03:23:08,834 --> 03:23:09,801
AND STUDY.

5135
03:23:09,801 --> 03:23:14,439
THERE IS ONE OF THE FOCUS OF OUR

5136
03:23:14,439 --> 03:23:15,574
LAB, NOW I TRY TO SEPARATE THESE

5137
03:23:15,574 --> 03:23:16,975
ARMS AND TRY TO UNDERSTAND HOW

5138
03:23:16,975 --> 03:23:22,080
EACH ONE OF THEM AFFECT IN OUR

5139
03:23:22,080 --> 03:23:22,848
CASE THE --

5140
03:23:22,848 --> 03:23:24,449
>> AND I GUESS RELATED
MORE

5141
03:23:24,449 --> 03:23:29,154
GLOBALLY TO THE USE OF IN VITRO

5142
03:23:29,154 --> 03:23:31,389
MODELS FOR STUDYING ALS

5143
03:23:31,389 --> 03:23:34,759
PATHOGENESIS, I WAS WONDERING IF

5144
03:23:34,759 --> 03:23:35,727
YOU COULD COMMENT A LITTLE BIT

5145
03:23:35,727 --> 03:23:38,497
IN TERMS OF YOUR PERSPECTIVE ON

5146
03:23:38,497 --> 03:23:39,831
HOW THE NEUROSCIENCE COMMUNITY

5147
03:23:39,831 --> 03:23:45,103
HAS KIND OF BEEN PUSHING FORWARD

5148
03:23:45,103 --> 03:23:46,371
ON THE DEVELOPMENT OF THESE

5149
03:23:46,371 --> 03:23:46,838
MODELS.

5150
03:23:46,838 --> 03:23:48,240
WE HEARD A VERY NICE TALK IN THE

5151
03:23:48,240 --> 03:23:50,876
PRIOR SESSION THIS MORNING ABOUT

5152
03:23:50,876 --> 03:23:54,045
THE USE OF MODELS TO STUDY KIND

5153
03:23:54,045 --> 03:23:56,248
OF MONOGENIC CASES OF DISEASE.

5154
03:23:56,248 --> 03:23:57,949
ARE WE STILL LIMITED TO

5155
03:23:57,949 --> 03:23:58,984
MONOGENIC CASES?

5156
03:23:58,984 --> 03:24:05,490
DO WE SEE -- SHINING THROUGH IN

5157
03:24:05,490 --> 03:24:07,325
THESE CULTURES, WHAT'S YOUR

5158
03:24:07,325 --> 03:24:07,792
FEELING ON THIS?

5159
03:24:07,792 --> 03:24:10,996
>> I MEAN, WE'RE MOSTLY
USING

5160
03:24:10,996 --> 03:24:12,097
MONOGENIC, JUST BECAUSE WE HAVE

5161
03:24:12,097 --> 03:24:13,565
AT LEAST 38 DIFFERENT GENES

5162
03:24:13,565 --> 03:24:15,300
ASSOCIATED TO ALS THAT WE KNOW

5163
03:24:15,300 --> 03:24:15,734
ARE CAUSATIVE.

5164
03:24:15,734 --> 03:24:20,105
BUT WE HAVE MOVED SORT OF TO TRY

5165
03:24:20,105 --> 03:24:22,073
AND INCREASE THE NUMBER OF

5166
03:24:22,073 --> 03:24:23,241
SPORADIC PATIENTS, AND SOMETIMES

5167
03:24:23,241 --> 03:24:26,645
I DO GET ASKED WHEN I GIVE THIS

5168
03:24:26,645 --> 03:24:28,180
TALK, LIKE ARE YOU INCLUDING

5169
03:24:28,180 --> 03:24:28,780
SPORADIC PATIENTS.

5170
03:24:28,780 --> 03:24:30,282
IN ORDER TO INCLUDE THOSE CELLS,

5171
03:24:30,282 --> 03:24:32,417
WE NEED A LARGER NUMBER.

5172
03:24:32,417 --> 03:24:33,451
SO ONE PERSON THAT HAS BEEN

5173
03:24:33,451 --> 03:24:37,622
WORKING A LOT ON THAT IS CLIVE

5174
03:24:37,622 --> 03:24:39,191
SWENSON AT CEDARS-SINAI, SO HE

5175
03:24:39,191 --> 03:24:43,161
DOES HAVE A GOOD REPOS TRIF, SO

5176
03:24:43,161 --> 03:24:48,400
YOU JUST HAVE TO INCREED BUT

5177
03:24:48,400 --> 03:24:50,168
WHAT WE SAW IS THAT A LOT OF

5178
03:24:50,168 --> 03:24:53,438
THESE PHENOTYPES THAT WE SEE

5179
03:24:53,438 --> 03:24:57,209
MODELS, WE CAN OFTEN

5180
03:24:57,209 --> 03:24:58,376
RECAPITULATE AT LEAST PARTIALLY,

5181
03:24:58,376 --> 03:25:01,046
SO ANOTHER LINE OF STUDY SINCE

5182
03:25:01,046 --> 03:25:11,623
WE'VE IDENTIFIED THE I - --

5183
03:25:12,324 --> 03:25:17,095
BECAUSE OF TIME, SO THESE TWO

5184
03:25:17,095 --> 03:25:21,099
ACTIVATORS ARE CURRENTLY IN

5185
03:25:21,099 --> 03:25:23,034
CLINICAL TRIAL FOR SPORADIC AND

5186
03:25:23,034 --> 03:25:25,103
FOR FAMILIAL ALS CASES.

5187
03:25:25,103 --> 03:25:29,341
THEY'RE ALSO IN CLINICAL TRIAL

5188
03:25:29,341 --> 03:25:30,842
FOR VANISHING WHITE MATTER

5189
03:25:30,842 --> 03:25:31,076
DISEASE.

5190
03:25:31,076 --> 03:25:32,911
SO EVEN IF YOU START FROM

5191
03:25:32,911 --> 03:25:34,312
DIFFERENT MONOGENIC OR EVEN IF

5192
03:25:34,312 --> 03:25:38,550
YOU START FROM DIFFERENT

5193
03:25:38,550 --> 03:25:39,451
MOLECULAR EVENTS YOU CAN END UP

5194
03:25:39,451 --> 03:25:41,419
WITH THE SAME SORT OF PATHWAY IF

5195
03:25:41,419 --> 03:25:42,254
YOU ACTIVATE ISR.

5196
03:25:42,254 --> 03:25:43,888
SO WE ARE TRYING NOW TO IDENTIFY

5197
03:25:43,888 --> 03:25:47,492
WHICH ONES ARE ACTUALLY BEING --

5198
03:25:47,492 --> 03:25:52,197
WHICH OF THESE GENES CAN BE

5199
03:25:52,197 --> 03:25:54,866
ASSOCIATED TO THIS ACTIVATION OF

5200
03:25:54,866 --> 03:25:55,400
ISR.

5201
03:25:55,400 --> 03:25:58,136
WE HAVE STUDIED FIVE OF THEM AND

5202
03:25:58,136 --> 03:26:02,374
HALF OF THEM DOES -- DIFFERENT

5203
03:26:02,374 --> 03:26:03,675
MUTATIONS, DIFFERENT VARIANTS.

5204
03:26:03,675 --> 03:26:05,010
SO I THINK THAT'S HOW WE ARE

5205
03:26:05,010 --> 03:26:05,610
PROGRESSING.

5206
03:26:05,610 --> 03:26:07,212
ANOTHER THING THAT WE'RE DOING

5207
03:26:07,212 --> 03:26:08,813
IS A LOT OF PEOPLE HERE ALSO

5208
03:26:08,813 --> 03:26:10,915
MENTIONED THE USE OF ORGANOIDS

5209
03:26:10,915 --> 03:26:13,084
AND OTHER SYSTEMS, SO IN OUR LAB

5210
03:26:13,084 --> 03:26:15,287
WE DO A CO-CULTURE SYSTEM,

5211
03:26:15,287 --> 03:26:16,955
BETWEEN THE MOTOR NEURONS AND

5212
03:26:16,955 --> 03:26:17,455
SKELETAL MUSCLE.

5213
03:26:17,455 --> 03:26:20,892
WE HAVE BEEN ABLE TO

5214
03:26:20,892 --> 03:26:23,595
SPONTANEOUSLY GENERATE THESE

5215
03:26:23,595 --> 03:26:24,696
NEUROMUSCULAR JUNCTIONS, THE

5216
03:26:24,696 --> 03:26:25,797
SYNAPSES BETWEEN THE TWO, AND I

5217
03:26:25,797 --> 03:26:27,932
THINK THAT'S WHAT WE'RE

5218
03:26:27,932 --> 03:26:28,967
PROGRESSING TOWARDS, SO NOT JUST

5219
03:26:28,967 --> 03:26:31,469
USING THESE SILOED SPECIFIC CELL

5220
03:26:31,469 --> 03:26:33,772
TYPES, BUT ALSO INCORPORATING

5221
03:26:33,772 --> 03:26:37,642
OTHER CELLS TO THE SYSTEM.

5222
03:26:37,642 --> 03:26:41,513
>> IN TERMS OF
INCORPORATING

5223
03:26:41,513 --> 03:26:44,816
OTHER CELLS, I KNOW, AMANDA, NOT

5224
03:26:44,816 --> 03:26:46,951
ONE OF THE WEEKERS, BUT HERE IN

5225
03:26:46,951 --> 03:26:48,386
THIS SESSION, I WANTED TO KIND

5226
03:26:48,386 --> 03:26:50,388
OF PULL YOU INTO THE DISCUSSION

5227
03:26:50,388 --> 03:26:50,655
HERE.

5228
03:26:50,655 --> 03:26:52,424
WE'VE HEARD A LITTLE BIT ABOUT

5229
03:26:52,424 --> 03:26:53,591
IMMUNE CELLS IN A FEW OF THE

5230
03:26:53,591 --> 03:26:54,459
DIFFERENT TALKS BUT ALWAYS

5231
03:26:54,459 --> 03:26:58,530
PLAYING QUITE A PERIPHERAL ROLE

5232
03:26:58,530 --> 03:26:58,730
HERE.

5233
03:26:58,730 --> 03:27:00,365
I KNOW YOUR LAB IS THINKING A

5234
03:27:00,365 --> 03:27:02,133
LOT ABOUT IMMUNE CELL

5235
03:27:02,133 --> 03:27:05,170
CONTRIBUTIONS AND HELPING TO --

5236
03:27:05,170 --> 03:27:08,173
I WAS JUST WONDERING, YOUR

5237
03:27:08,173 --> 03:27:09,474
GENERAL VIEW IN TERMS OF HOW YOU

5238
03:27:09,474 --> 03:27:15,613
SEE THE IMMUNE SYSTEM, IN TERMS

5239
03:27:15,613 --> 03:27:17,816
OF BEING ABLE TO DRIVE TISSUE

5240
03:27:17,816 --> 03:27:18,116
RESILIENCE?

5241
03:27:18,116 --> 03:27:19,651
>> THAT'S SOMETHING I WAS
KIND

5242
03:27:19,651 --> 03:27:21,753
OF THINKING ABOUT THROUGHOUT THE

5243
03:27:21,753 --> 03:27:25,924
PAST COUPLE DAYS, AND SOME

5244
03:27:25,924 --> 03:27:27,592
CONNECTIONS HERE AND THERE BUT

5245
03:27:27,592 --> 03:27:29,394
TALLLY THAT WAS A GOOD QUESTION

5246
03:27:29,394 --> 03:27:36,468
I HAD FOR -- MAYBE SPECIFICALLY

5247
03:27:36,468 --> 03:27:36,868
JIANWEN.

5248
03:27:36,868 --> 03:27:38,169
SO IN TERMS OF WHAT THE NEURONS

5249
03:27:38,169 --> 03:27:40,672
ARE DOING IN CANCER, DO YOU KNOW

5250
03:27:40,672 --> 03:27:42,140
SPECIFICALLY WHAT CELLS THEY'RE

5251
03:27:42,140 --> 03:27:46,678
INTERACTING WITH AND WOULD THAT

5252
03:27:46,678 --> 03:27:48,313
HAVE -- ARE THEY INTERACTING

5253
03:27:48,313 --> 03:27:48,747
WITH IMMUNE CELLS?

5254
03:27:48,747 --> 03:27:49,881
I THINK THAT WAS ONE OF THE OPEN

5255
03:27:49,881 --> 03:27:51,850
QUESTIONS, BUT CAN YOU SORT OF

5256
03:27:51,850 --> 03:27:53,017
SPECULATE ON WHAT YOU'RE SEEING

5257
03:27:53,017 --> 03:27:54,085
IN CANCER AND HOW THAT COULD

5258
03:27:54,085 --> 03:27:55,320
INTERACT OR HOW THAT COULD

5259
03:27:55,320 --> 03:27:58,089
REFLECT ON WHAT COULD BE

5260
03:27:58,089 --> 03:28:00,225
HAPPENING IN MORE PROGRESSIVE

5261
03:28:00,225 --> 03:28:01,426
LUNG DISEASES THAT -- AND WHAT

5262
03:28:01,426 --> 03:28:02,994
CELLS ARE REALLY INTERACTING

5263
03:28:02,994 --> 03:28:05,397
WITH AND WHAT THEIR CELLS

5264
03:28:05,397 --> 03:28:06,598
THEY'RE CONTROLLING.

5265
03:28:06,598 --> 03:28:07,799
THAT'S A VERY OPEN-ENDED

5266
03:28:07,799 --> 03:28:12,337
QUESTION, I THINK, BUT THIS IS

5267
03:28:12,337 --> 03:28:13,772
THE TIME TO SPECULATE, HOW WOULD

5268
03:28:13,772 --> 03:28:15,273
YOU GO ABOUT TRYING TO FIGURE

5269
03:28:15,273 --> 03:28:19,811
THAT OUT AS WELL.

5270
03:28:19,811 --> 03:28:21,212
 -- FOR ALL THE SPEAKERS, HOW

5271
03:28:21,212 --> 03:28:24,282
DOES IT INTERACT WITH THE IMMUNE

5272
03:28:24,282 --> 03:28:25,016
SYSTEM.

5273
03:28:25,016 --> 03:28:26,217
I GUESS ALSO IN TEMPLES BEING

5274
03:28:26,217 --> 03:28:27,385
ABLE TO -- YOU SEE THESE

5275
03:28:27,385 --> 03:28:28,887
SNAPSHOTS IN TIME, THE IMMUNE

5276
03:28:28,887 --> 03:28:29,788
CELLS ARE COMING IN AND OUT, SO

5277
03:28:29,788 --> 03:28:31,823
I THINK THAT'S ANOTHER

5278
03:28:31,823 --> 03:28:32,857
COMPLICATION IN THESE SYSTEMS

5279
03:28:32,857 --> 03:28:36,494
WHEN YOU'RE LOOKING AT THINGS.

5280
03:28:36,494 --> 03:28:40,698
>> THAT'S A VERY GOOD
QUESTION,

5281
03:28:40,698 --> 03:28:41,699
ONE CHALLENGE I WAS THINKING I

5282
03:28:41,699 --> 03:28:46,504
WANT TO PUT ON IS HOW WOULD THAT

5283
03:28:46,504 --> 03:28:55,980
REGENERATION -- IMMUNE CELLS, WE

5284
03:28:55,980 --> 03:28:58,983
KNOW THEY ARE COMING VERY

5285
03:28:58,983 --> 03:29:03,822
QUICKLY.

5286
03:29:03,822 --> 03:29:06,524
VIRUS INFECTIONS, THE NEURONS

5287
03:29:06,524 --> 03:29:10,328
ARE ACUTELY INJURED.

5288
03:29:10,328 --> 03:29:12,096
THEY ARE NOT QUIESCENT, THEY

5289
03:29:12,096 --> 03:29:15,066
QUICKLY COME OUT OF THIS

5290
03:29:15,066 --> 03:29:16,534
QUIESCENT STATE AND FIRE SIGNALS

5291
03:29:16,534 --> 03:29:20,171
AND IN THE FIRST INTERACT

5292
03:29:20,171 --> 03:29:22,073
MESENCHYMAL CELLS AROUND THEM

5293
03:29:22,073 --> 03:29:23,241
AND BLOOD VESSELS WHICH CAN

5294
03:29:23,241 --> 03:29:25,743
CONTROL THE BLOOD VESSELS AND

5295
03:29:25,743 --> 03:29:30,381
ALSO MAY POTENTIALLY INTERACT

5296
03:29:30,381 --> 03:29:34,686
WITH PATROLLING MICROPHAGES OR

5297
03:29:34,686 --> 03:29:38,189
TYPE 2 INNATE LYMPHOID CELLS AS

5298
03:29:38,189 --> 03:29:41,025
WELL, AND RIGHT NOW I HAVE NO

5299
03:29:41,025 --> 03:29:42,861
EVIDENCE BUT AS I JUST MENTIONED

5300
03:29:42,861 --> 03:29:45,330
IN THE INTESTINE, THOSE NERVE

5301
03:29:45,330 --> 03:29:50,568
FIBERS CAN INTERACT WITH

5302
03:29:50,568 --> 03:29:51,169
MICROPHAGES BUT ALSO INTERACT

5303
03:29:51,169 --> 03:29:53,471
WITH THE ROC2 CELLS.

5304
03:29:53,471 --> 03:29:56,107
WE RECENTLY IDENTIFIED THIS IN

5305
03:29:56,107 --> 03:29:58,576
ANOTHER POPULATION,

5306
03:29:58,576 --> 03:29:59,611
RIC3 POPULATION, SPECIFICALLY

5307
03:29:59,611 --> 03:30:06,284
LOCALIZED TO THE BIG BLOOD

5308
03:30:06,284 --> 03:30:07,252
VESSELS.

5309
03:30:07,252 --> 03:30:08,720
WE DON'T KNOW WHETHER THEY ARE

5310
03:30:08,720 --> 03:30:09,587
INVOLVED IN CONNECTION WITH

5311
03:30:09,587 --> 03:30:12,423
THESE NERVE FIBERS AND MY

5312
03:30:12,423 --> 03:30:14,425
COLLABORATOR HAS A VERY

5313
03:30:14,425 --> 03:30:20,899
INTERESTING DATA TO THOUGH

5314
03:30:20,899 --> 03:30:23,268
THESE, AND ALSO SURVEY IMMUNE

5315
03:30:23,268 --> 03:30:24,502
RESPONSE ENVIRONMENT TO --

5316
03:30:24,502 --> 03:30:26,871
>> I THINK ONE OF MY
FAVORITE

5317
03:30:26,871 --> 03:30:28,139
EXAMPLES OF THIS, I REMEMBER

5318
03:30:28,139 --> 03:30:29,741
NOW, HEARING QUITE A LONG TIME

5319
03:30:29,741 --> 03:30:33,044
AGO FROM SOME WORK THAT RICH

5320
03:30:33,044 --> 03:30:34,746
LOCKSEED'S GROUP WAS DOING IN

5321
03:30:34,746 --> 03:30:36,381
TERMS OF THE POSITIONING OF

5322
03:30:36,381 --> 03:30:40,184
ILC2s AT THESE CRITICAL BRANCH

5323
03:30:40,184 --> 03:30:45,757
IF WAVES, POSITIONING -- NEURONS

5324
03:30:45,757 --> 03:30:47,492
AS WELL KIND OF CONTROLLING THIS

5325
03:30:47,492 --> 03:30:48,359
OVERALL COMMUNITY.

5326
03:30:48,359 --> 03:30:53,398
THE HYPOTHESIS YOU COULD ALMOST

5327
03:30:53,398 --> 03:30:55,066
ENVISION CLOSING OFF CERTAIN

5328
03:30:55,066 --> 03:30:56,501
REGIONS OF THE LUNG IN CASE THAT

5329
03:30:56,501 --> 03:30:57,802
CERTAIN DANGER WAS DETECTED TO

5330
03:30:57,802 --> 03:31:01,005
SHIFT FLOW FROM ONE DIRECTION OR

5331
03:31:01,005 --> 03:31:02,407
ANOTHER.

5332
03:31:02,407 --> 03:31:03,775
I DON'T KNOW IF THIS STILL

5333
03:31:03,775 --> 03:31:04,676
REMAINS PURELY SPECULATIVE, BUT

5334
03:31:04,676 --> 03:31:05,810
SINCE WE TALKED ABOUT

5335
03:31:05,810 --> 03:31:07,111
REGIONALITY, I WAS WONDERING IF

5336
03:31:07,111 --> 03:31:08,680
THE PANELISTS HERE HAVE HAD ANY

5337
03:31:08,680 --> 03:31:11,849
THOUGHTS ON THIS IF

5338
03:31:11,849 --> 03:31:17,722
>> I NOTICED YOU HAD SOME
IMMUNE

5339
03:31:17,722 --> 03:31:19,490
CELLS -- NEURONS IN YOUR

5340
03:31:19,490 --> 03:31:19,724
DATASET?

5341
03:31:19,724 --> 03:31:23,061
>> I DO NOT IN MY DATA.

5342
03:31:23,061 --> 03:31:27,198
I WISH I DID.

5343
03:31:27,198 --> 03:31:28,733
IF ANYONE HERE HAS DATA FROM THE

5344
03:31:28,733 --> 03:31:30,268
LUNG THAT HAS A CLEAR NEURON

5345
03:31:30,268 --> 03:31:31,703
POPULATION IN IT, I THINK IT

5346
03:31:31,703 --> 03:31:32,303
WOULD BE VERY INTERESTING TO

5347
03:31:32,303 --> 03:31:35,840
LOOK AT THIS, AND I STRONGLY

5348
03:31:35,840 --> 03:31:37,842
SUSPECT THEY HAVE A UNIQUE

5349
03:31:37,842 --> 03:31:41,379
LIGAND AND RECEPTOR PRO T PROFID

5350
03:31:41,379 --> 03:31:43,881
WE COULD DOPE IN

5351
03:31:43,881 --> 03:31:45,450
NEUROTRANSMITTERS SO YOU COULD

5352
03:31:45,450 --> 03:31:46,951
SEE WHO'S LISTENING OR CAPABLE

5353
03:31:46,951 --> 03:31:48,987
OF LISTENING.

5354
03:31:48,987 --> 03:31:51,623
THE DATA I HAVE DOES NOT HAVE

5355
03:31:51,623 --> 03:31:55,994
NEURONS IN IT AND I -- BUT

5356
03:31:55,994 --> 03:31:57,695
DEFINITELY WITH THE RIGHT DATA

5357
03:31:57,695 --> 03:31:58,696
YOU COULD LOOK AT THIS.

5358
03:31:58,696 --> 03:32:03,368
>> ONE QUESTION I HAD IS
RELATED

5359
03:32:03,368 --> 03:32:05,436
TO THE TIME COMPONENT.

5360
03:32:05,436 --> 03:32:08,873
THIS MAY COME UP MORE OF AN

5361
03:32:08,873 --> 03:32:09,741
EPIDEMIOLOGICAL LEVEL OVER THE

5362
03:32:09,741 --> 03:32:12,777
THEME OVER THE PAST FEW

5363
03:32:12,777 --> 03:32:15,647
SESSIONS.

5364
03:32:15,647 --> 03:32:17,982
BUT IN TERMS OF GENERATING TIME

5365
03:32:17,982 --> 03:32:19,350
SERIES DATA THAT IS AMENABLE FOR

5366
03:32:19,350 --> 03:32:20,652
THE TYPES OF COMPUTATIONAL

5367
03:32:20,652 --> 03:32:24,689
METHODS THAT YOU'VE DEVELOPED,

5368
03:32:24,689 --> 03:32:26,357
HOW REFINED DO WE NEED TO BE?

5369
03:32:26,357 --> 03:32:27,592
BECAUSE I FEEL LIKE IF WE DO A

5370
03:32:27,592 --> 03:32:36,634
TIME SEARS EASE SOMETIME SERIES,

5371
03:32:36,634 --> 03:32:40,004
JUST BECAUSE OF REALITIES, OF

5372
03:32:40,004 --> 03:32:41,072
FUNDING, THREE OR FOUR TIME

5373
03:32:41,072 --> 03:32:42,473
POINTS IN BETWEEN.

5374
03:32:42,473 --> 03:32:47,078
THEN YOU WERE LIKE MAN, HEY, I

5375
03:32:47,078 --> 03:32:53,484
THINK IF I'D PROFILED EIGHT

5376
03:32:53,484 --> 03:32:55,687
HOURS I WOULD HAVE KNOWN EVEN

5377
03:32:55,687 --> 03:32:56,020
MORE.

5378
03:32:56,020 --> 03:32:59,724
HOW MUCH TIME RESOLUTION DO WE

5379
03:32:59,724 --> 03:32:59,924
NEED?

5380
03:32:59,924 --> 03:33:03,461
>> THE FUNDING -- PEOPLE
WANT TO

5381
03:33:03,461 --> 03:33:05,063
SEE TIME POINTS, THEY DON'T WANT

5382
03:33:05,063 --> 03:33:07,165
TO SEE REPLICATES.

5383
03:33:07,165 --> 03:33:08,232
WE MAKE THOSE DATASET AND THAT'S

5384
03:33:08,232 --> 03:33:09,100
SORT OF THE STANDARD HERE AND

5385
03:33:09,100 --> 03:33:10,935
YOU CAN SEE VERY STRONG

5386
03:33:10,935 --> 03:33:12,570
SIGNALING, BUT AS I THINK YOU'RE

5387
03:33:12,570 --> 03:33:16,441
POINTING OUT, IT IS MUCH, MUCH

5388
03:33:16,441 --> 03:33:17,508
MORE BEAUTIFUL AND FUN TO PLAY

5389
03:33:17,508 --> 03:33:19,377
WITH THE DATA IF YOU -- LIKE I

5390
03:33:19,377 --> 03:33:20,778
WOULD RATHER HAVE FEWER

5391
03:33:20,778 --> 03:33:21,746
REPLICATES AND A TIGHTER TIME

5392
03:33:21,746 --> 03:33:23,314
COURSE, BECAUSE EACH INDIVIDUAL

5393
03:33:23,314 --> 03:33:26,117
TIME POINT HAS ENORMOUS BLEED A

5394
03:33:26,117 --> 03:33:28,086
IN PHENOTYPE SPACE.

5395
03:33:28,086 --> 03:33:32,090
IT'S LIKE A FRACTION OF THE

5396
03:33:32,090 --> 03:33:34,959
SHELLS HAVE -- SO THAT ONE TIME

5397
03:33:34,959 --> 03:33:37,061
POINT YOU GET AT DAY 3 ACTUALLY

5398
03:33:37,061 --> 03:33:38,329
HAS SOME CELLS THAT ARE VERY

5399
03:33:38,329 --> 03:33:42,166
SIMILAR TO WHAT YOU SEE AT DAY

5400
03:33:42,166 --> 03:33:42,767
ONE AND DAY 7 MAYBE.

5401
03:33:42,767 --> 03:33:43,668
SO YOU GET A DISTRIBUTION.

5402
03:33:43,668 --> 03:33:45,303
SO THAT MEANS YOUR STATISTICAL

5403
03:33:45,303 --> 03:33:47,905
POWER IS MUCH, MUCH STRONGER.

5404
03:33:47,905 --> 03:33:50,208
IF WE WERE DOING TIGHT TIME

5405
03:33:50,208 --> 03:33:51,542
SERIES OF THESE KINDS OF

5406
03:33:51,542 --> 03:33:52,710
PROCESSES, THE DATA QUALITY IS

5407
03:33:52,710 --> 03:33:53,277
BETTER.

5408
03:33:53,277 --> 03:33:54,779
BUT YOU END UP HAVING TO WRITE

5409
03:33:54,779 --> 03:33:55,747
THESE GRANTS THAT ARE SAYING I'M

5410
03:33:55,747 --> 03:33:57,415
GOING TO DEVOTE ALL MY RESOURCES

5411
03:33:57,415 --> 03:34:00,084
TO DOING A SINGLE TIME POINT OR

5412
03:34:00,084 --> 03:34:04,188
N OF 2 TIGHT TIME COURSE, SO YOU

5413
03:34:04,188 --> 03:34:05,156
END UP REDISTRIBUTING AND SAY

5414
03:34:05,156 --> 03:34:09,861
I'M GOING TO DO AN N OF 6, SO I

5415
03:34:09,861 --> 03:34:12,196
HAVE A STRONG ANSWER TO THAT

5416
03:34:12,196 --> 03:34:14,098
ABOUT WHAT WE SHOULD BE DOING

5417
03:34:14,098 --> 03:34:16,334
SCIENTIFICALLY, BUT IT CAN BE

5418
03:34:16,334 --> 03:34:18,636
CHALLENGING TO -- THIS IS

5419
03:34:18,636 --> 03:34:20,271
EXPENSIVE DATA TO MAKE.

5420
03:34:20,271 --> 03:34:21,706
TIME COURSE DATA IS BEAUTIFUL.

5421
03:34:21,706 --> 03:34:23,274
>> SO IT LOOKS LIKE WE'RE

5422
03:34:23,274 --> 03:34:23,875
GETTING SOME QUESTIONS COMING

5423
03:34:23,875 --> 03:34:25,076
THROUGH THE CHAT, SO MAYBE LAST

5424
03:34:25,076 --> 03:34:29,280
10 MINUTES, WE CAN START GOING

5425
03:34:29,280 --> 03:34:32,083
THROUGH THIS.

5426
03:34:32,083 --> 03:34:34,018
SAM, HAVE YOU COMPARED NICHES

5427
03:34:34,018 --> 03:34:36,354
WITH CELL PHONE DB OR CELL CHAT

5428
03:34:36,354 --> 03:34:38,122
D ABOUT ARE THESE TOOLS FOCUSED

5429
03:34:38,122 --> 03:34:39,357
ON NODES OR EDGES?

5430
03:34:39,357 --> 03:34:41,425
>> ANYONE WHO'S GOING TO
START

5431
03:34:41,425 --> 03:34:43,928
DOING CONNECTIVITY ANALYSIS, YOU

5432
03:34:43,928 --> 03:34:45,463
LITERALLY HAVE LIKE 40 OR 50

5433
03:34:45,463 --> 03:34:46,697
DIFFERENT TOOLS TO PULL FROM.

5434
03:34:46,697 --> 03:34:47,965
THOSE BEING MENTIONED ARE SOME

5435
03:34:47,965 --> 03:34:49,534
OF THE EARLIEST ONES AND THEY'RE

5436
03:34:49,534 --> 03:34:50,735
SORT OF THE GOLD STANDARD,

5437
03:34:50,735 --> 03:34:52,036
THEY'RE EASY TO PULL OFF THE

5438
03:34:52,036 --> 03:34:52,336
SHELF.

5439
03:34:52,336 --> 03:34:54,305
WE'VE DONE THIS COMPARISON

5440
03:34:54,305 --> 03:34:54,605
EXTENSIVELY.

5441
03:34:54,605 --> 03:34:56,474
THE BASIC ANSWER IS THAT ALL OF

5442
03:34:56,474 --> 03:34:57,275
THESE DIFFERENT TOOLS ARE GOING

5443
03:34:57,275 --> 03:34:58,810
TO GIVE YOU KIND OF SORT OF

5444
03:34:58,810 --> 03:35:00,411
SIMILAR ANSWERS BUT THEY'RE

5445
03:35:00,411 --> 03:35:02,013
DIFFERENT IN TERMS OF HOW EASY

5446
03:35:02,013 --> 03:35:04,182
OR HARD THEY ARE TO USE AND HOW

5447
03:35:04,182 --> 03:35:04,949
STATISTICALLY ADAPTABLE THEY

5448
03:35:04,949 --> 03:35:05,650
ARE.

5449
03:35:05,650 --> 03:35:07,118
AND THAT'S THE BIG DIFFERENCE.

5450
03:35:07,118 --> 03:35:08,753
IF YOU USE THE SAME GROUND

5451
03:35:08,753 --> 03:35:10,721
TRUTH, YOU QUERY THE SAME

5452
03:35:10,721 --> 03:35:11,956
MECHANISMS, THESE TOOLS ARE ALL

5453
03:35:11,956 --> 03:35:14,325
GOING TO GIVE YOU MORE OR LESS A

5454
03:35:14,325 --> 03:35:15,593
PRETTY SIMILAR PORTRAIT OF

5455
03:35:15,593 --> 03:35:18,296
WHAT'S GOING ON.

5456
03:35:18,296 --> 03:35:20,865
BUT IF YOU -- NICHES, THERE'S A

5457
03:35:20,865 --> 03:35:25,036
NEW ONE CAME OUT CALLED DEEP

5458
03:35:25,036 --> 03:35:27,104
TOK, THOSE ARE ALL GOING TO GIVE

5459
03:35:27,104 --> 03:35:30,541
YOU SINGLE EDGE DAY, I FIND OUT

5460
03:35:30,541 --> 03:35:31,843
WOW, IT'S NOT FROM OUR TIME

5461
03:35:31,843 --> 03:35:33,644
COURSE BUT FROM OUR DRUG EFFECT

5462
03:35:33,644 --> 03:35:33,978
OR SOMETHING.

5463
03:35:33,978 --> 03:35:35,580
YOU CAN REALLY QUICKLY PIVOT AND

5464
03:35:35,580 --> 03:35:37,448
CHASE THAT PATTERN IN THE DATA.

5465
03:35:37,448 --> 03:35:39,050
WITH THE NODE BASED ONES LIKE

5466
03:35:39,050 --> 03:35:40,918
CELL CHAT AND CELL PHONE DB THAT

5467
03:35:40,918 --> 03:35:43,087
HAVE BEEN MENTIONED HERE, YOU

5468
03:35:43,087 --> 03:35:47,992
PUT HANDCUFFS ON AT THE BEG

5469
03:35:47,992 --> 03:35:48,759
BEGINNING -- REALLY THE

5470
03:35:48,759 --> 03:35:50,695
DIFFERENCE COMES WITH HOW

5471
03:35:50,695 --> 03:35:51,696
STATISTICALLY FLEXIBLE THEY ARE

5472
03:35:51,696 --> 03:35:53,464
AND HOW EASY THE DATA ANALYSIS

5473
03:35:53,464 --> 03:35:54,098
IS.

5474
03:35:54,098 --> 03:35:56,300
BUT AT THE END OF THE DAY, IF

5475
03:35:56,300 --> 03:35:58,202
YOU DO ALL THESE THINGS RIGHT

5476
03:35:58,202 --> 03:36:00,371
YOU CAN GET THESE TOOLS TO AGREE

5477
03:36:00,371 --> 03:36:01,205
WITH ONE ANOTHER.

5478
03:36:01,205 --> 03:36:02,707
>> DR. MIRANDA, CAN YOU
PLEASE

5479
03:36:02,707 --> 03:36:04,642
COMMENT ON WHAT THE FIELD THINKS

5480
03:36:04,642 --> 03:36:10,948
ABOUT HOW RSRIB IMPROVES -- I

5481
03:36:10,948 --> 03:36:13,451
WONDER WHAT IS THE PROPOSED

5482
03:36:13,451 --> 03:36:16,420
MODEL IN THE NEUROFIELD?

5483
03:36:16,420 --> 03:36:17,188
>> THAT'S INTERESTING.

5484
03:36:17,188 --> 03:36:18,389
THAT'S A GREAT QUESTION.

5485
03:36:18,389 --> 03:36:21,559
THE SHORT ANSWER IS THAT I DON'T

5486
03:36:21,559 --> 03:36:25,997
HAVE A PROPOSED MECHANISM.

5487
03:36:25,997 --> 03:36:27,531
I ENDED UP HAVING A MEETING WITH

5488
03:36:27,531 --> 03:36:32,336
THE PERS PERSON LEADING THE CLIL

5489
03:36:32,336 --> 03:36:33,704
TRIALS, AND THE DATA WAS

5490
03:36:33,704 --> 03:36:37,808
COLLECTED BASED ON THESE MOUSE

5491
03:36:37,808 --> 03:36:41,045
MODELS, I THINK IT SHOULD BE

5492
03:36:41,045 --> 03:36:43,080
KNOCKOUT MOUSE MODELS, KIND

5493
03:36:43,080 --> 03:36:45,483
OF -- THE MECHANISM OF ALS, BUT

5494
03:36:45,483 --> 03:36:48,252
THE ONLY DATA FROM AN ALS MODEL

5495
03:36:48,252 --> 03:36:51,455
WHICH IS FROM THE SOD1, THIS IS

5496
03:36:51,455 --> 03:36:52,556
THE -- I GUESS THE BEST MODEL

5497
03:36:52,556 --> 03:36:54,959
THAT WE HAVE SO FAR, THE BEST

5498
03:36:54,959 --> 03:36:57,995
MOUSE MODEL THAT WE HAVE, DID

5499
03:36:57,995 --> 03:37:00,398
NOT ENCOURAGE THE USE OF ISRID.

5500
03:37:00,398 --> 03:37:02,099
SO WHEN I HAD THAT CONVERSATION

5501
03:37:02,099 --> 03:37:06,037
HER INITIALLY, SHE SAID THEIR

5502
03:37:06,037 --> 03:37:09,273
INVETO DATA WERE SHOWING VITRO

5503
03:37:09,273 --> 03:37:11,275
JUST LIKE OURS DID, AND THEY

5504
03:37:11,275 --> 03:37:16,047
WERE THINKING ABOUT PROPOSING A

5505
03:37:16,047 --> 03:37:17,848
MISLOCALIZATION OF THIS PROTEIN

5506
03:37:17,848 --> 03:37:20,952
THAT GOT PHOSPHORYLATED AND THIS

5507
03:37:20,952 --> 03:37:22,253
LOCALIZES AND IT'S COMMON TO

5508
03:37:22,253 --> 03:37:24,388
MOST OF THE ALS, IT'S A PA

5509
03:37:24,388 --> 03:37:30,494
WILLING TO THAT IS SEEN MOST

5510
03:37:30,494 --> 03:37:34,031
WITH -- BUT IN OUR MODEL

5511
03:37:34,031 --> 03:37:36,500
SPECIFICALLY, THE FACT IT

5512
03:37:36,500 --> 03:37:40,972
DOESN'T HAVE THAT PATHOLOGY.

5513
03:37:40,972 --> 03:37:42,173
SO IN THIS CONVERSATION WITH

5514
03:37:42,173 --> 03:37:43,541
HER, SHE'S LIKE OH MAYBE WE

5515
03:37:43,541 --> 03:37:48,145
SHOULD LINK THAT TO A

5516
03:37:48,145 --> 03:37:48,846
MITOCHONDRIA DYSREGULATION.

5517
03:37:48,846 --> 03:37:50,548
SO I THINK -- OUR WORK IS THE

5518
03:37:50,548 --> 03:37:53,551
FIRST ONE THAT SHOWS A SPECIFIC

5519
03:37:53,551 --> 03:37:56,887
VARIANT THAT IS LINKED TOLL

5520
03:37:56,887 --> 03:37:58,189
PHENOTYPE THROUGH ACTIVATION OF

5521
03:37:58,189 --> 03:38:00,958
ISL.

5522
03:38:00,958 --> 03:38:03,561
SO THE FIELD DOESN'T HAVE THAT

5523
03:38:03,561 --> 03:38:05,429
YET.

5524
03:38:05,429 --> 03:38:09,200
>> SO IT MORE OF LIKE THE
NEURAL

5525
03:38:09,200 --> 03:38:11,869
FIELD MORE OF THE ISSUE OF --

5526
03:38:11,869 --> 03:38:12,837
ACTUALLY IMPROVED THE FUNCTION

5527
03:38:12,837 --> 03:38:14,939
OF WHATEVER THE CALL FOR CELL

5528
03:38:14,939 --> 03:38:15,973
TYPE.

5529
03:38:15,973 --> 03:38:18,075
WHAT WE SHOWED IS THE CHANGE FOR

5530
03:38:18,075 --> 03:38:21,012
DIFFERENTIATION POTENTIAL BUT

5531
03:38:21,012 --> 03:38:23,414
IT'S NOT NECESSARILY FUNCTION UR

5532
03:38:23,414 --> 03:38:27,785
ABOUT FOR IMPROVED FUNCTION OF

5533
03:38:27,785 --> 03:38:28,953
THE CELL.

5534
03:38:28,953 --> 03:38:29,253
THANK YOU.

5535
03:38:29,253 --> 03:38:30,554
>> THERE'S ONE LAST
QUESTION

5536
03:38:30,554 --> 03:38:32,790
BEFORE WE WRAP UP.

5537
03:38:32,790 --> 03:38:34,025
OR MAYBE WE'LL HAVE TIME FOR A

5538
03:38:34,025 --> 03:38:35,593
COUPLE MORE BUT JUST A COUPLE

5539
03:38:35,593 --> 03:38:36,827
MORE MINUTES HERE AND ACTUALLY I

5540
03:38:36,827 --> 03:38:38,362
HAD THIS QUESTION AS WELL, SO

5541
03:38:38,362 --> 03:38:41,132
THIS IS FOR -- DO YOU OBSERVE

5542
03:38:41,132 --> 03:38:42,033
ANY COLOCALIZATION OF NEURONS

5543
03:38:42,033 --> 03:38:43,100
AND BLOOD VESSELS IN THE LUNG?

5544
03:38:43,100 --> 03:38:45,069
DO YOU THINK NEURONS MIGHT PLAY

5545
03:38:45,069 --> 03:38:47,071
A ROLE IN REPAIRING BLOOD

5546
03:38:47,071 --> 03:38:47,938
VESSELS AFTER INJURY?

5547
03:38:47,938 --> 03:38:48,806
>> YES.

5548
03:38:48,806 --> 03:38:52,610
BLOOD VESSELS CONTROLLED MAJORLY

5549
03:38:52,610 --> 03:38:55,913
BY SYMPATHETIC NEURONS AND IF

5550
03:38:55,913 --> 03:39:01,152
YOU STAIN WITH TH, YOU CAN SEE

5551
03:39:01,152 --> 03:39:03,387
THERE'S SMOOTH MUSCLE CELLS IN

5552
03:39:03,387 --> 03:39:12,963
THE BLOOD VESSELS, AND ALSO I --

5553
03:39:12,963 --> 03:39:16,500
ALSO SEND NERVE ENDING.

5554
03:39:16,500 --> 03:39:19,970
TOLS, THESE TWO -- CONSTRICTION,

5555
03:39:19,970 --> 03:39:24,241
THINGS LIKE THAT.

5556
03:39:24,241 --> 03:39:27,078
>> THANKS.

5557
03:39:27,078 --> 03:39:28,913
WELLINGTON CARDOSA HAS A

5558
03:39:28,913 --> 03:39:31,315
QUESTION.

5559
03:39:31,315 --> 03:39:32,149
RAISED HAND.

5560
03:39:32,149 --> 03:39:37,154
>> YES.

5561
03:39:37,154 --> 03:39:39,190
THIS QUESTION WAS FORMICA.

5562
03:39:39,190 --> 03:39:50,434
FOFOR MICHA.YOUR IDEA OF ACTUAL 

5563
03:39:50,901 --> 03:39:51,569
EXPLORING -- IT'S NOT

5564
03:39:51,569 --> 03:39:53,671
CONTROVERSIAL BUT IT IS SUCH A

5565
03:39:53,671 --> 03:39:57,007
COMPLEX THING BECAUSE WHEN WE

5566
03:39:57,007 --> 03:40:02,213
HAVE A TISSUE MORPHOGEN IT

5567
03:40:02,213 --> 03:40:04,048
DEPENDS ON SO MANY DIFFERENT

5568
03:40:04,048 --> 03:40:05,516
THINGS.

5569
03:40:05,516 --> 03:40:07,451
THERE IS -- BETWEEN

5570
03:40:07,451 --> 03:40:08,319
EXTRACELLULAR MATRIX.

5571
03:40:08,319 --> 03:40:11,589
THERE ARE CORE RECEPTORS, AND I

5572
03:40:11,589 --> 03:40:17,895
WONDER WHAT IT IS INSIDE THIS

5573
03:40:17,895 --> 03:40:18,162
PAMMAGE --

5574
03:40:18,162 --> 03:40:20,197
>> THIS IS JUST GETTING
STARTED.

5575
03:40:20,197 --> 03:40:23,601
SO I WOULD BE HAPPY TO TALK WITH

5576
03:40:23,601 --> 03:40:24,368
YOU ABOUT THIS MORE BECAUSE

5577
03:40:24,368 --> 03:40:25,636
YOU'RE PUTTING YOUR FINGER RIGHT

5578
03:40:25,636 --> 03:40:26,203
ON THE ISSUES.

5579
03:40:26,203 --> 03:40:29,540
WHAT IS VEABL NOW  AVAILABLE NOE

5580
03:40:29,540 --> 03:40:30,975
PACK SJ IS VERY SIMPLE AND

5581
03:40:30,975 --> 03:40:33,577
YOU'RE RIGHT, CAN I CALL THAT A

5582
03:40:33,577 --> 03:40:34,445
TISSUE MORPHOGEN?

5583
03:40:34,445 --> 03:40:35,946
NO, I CAN CALL THAT A SIGNALING

5584
03:40:35,946 --> 03:40:38,883
FIELD OR COLOCATION OF -- AND

5585
03:40:38,883 --> 03:40:40,651
YOU CAN SEPA TESHES.

5586
03:40:40,651 --> 03:40:43,053
THAT'S REALLY WHAT WE CAN STUDY

5587
03:40:43,053 --> 03:40:43,954
CURRENTLY.

5588
03:40:43,954 --> 03:40:45,022
I WILL SAY I'VE GOT

5589
03:40:45,022 --> 03:40:47,358
CONVERSATIONS GOING ON WITH

5590
03:40:47,358 --> 03:40:48,125
STATISTICIANS WHICH ARE TRYING

5591
03:40:48,125 --> 03:40:49,326
TO ANSWER WHAT YOU'RE BRINGING

5592
03:40:49,326 --> 03:40:51,562
UP, WHICH IS FOR EACH -- WE NEED

5593
03:40:51,562 --> 03:40:52,830
TO THINK ABOUT INTERACTIONS WITH

5594
03:40:52,830 --> 03:40:54,965
OTHER MECHANISMS, AND WE HAVE TO

5595
03:40:54,965 --> 03:40:56,100
THINK VERY CAREFULLY ABOUT WHAT

5596
03:40:56,100 --> 03:40:57,334
WE CAN PULL OUT OF IT.

5597
03:40:57,334 --> 03:40:58,402
BUT THE INFORMATION IS THERE.

5598
03:40:58,402 --> 03:41:01,238
IT'S A MATTER OF THEN MAKING THE

5599
03:41:01,238 --> 03:41:02,239
RIGHT STATISTICAL MODELS THAT

5600
03:41:02,239 --> 03:41:03,841
ARE REALLY BIOLOGICALLY

5601
03:41:03,841 --> 03:41:04,241
INFORMED.

5602
03:41:04,241 --> 03:41:06,143
SO I THINK THERE'S ENORMOUS

5603
03:41:06,143 --> 03:41:08,179
POTENTIAL THERE IN THE COMING

5604
03:41:08,179 --> 03:41:11,649
DECADES TO DO THIS TO LIBRARIES

5605
03:41:11,649 --> 03:41:13,984
OF TISSUES IN PARAFFIN RIGHT

5606
03:41:13,984 --> 03:41:15,719
NOW, BUT WE DO HAVE TO DO IT

5607
03:41:15,719 --> 03:41:15,986
CAREFULLY.

5608
03:41:15,986 --> 03:41:16,820
>> I'D LOVE TO LEARN MORE
ABOUT

5609
03:41:16,820 --> 03:41:17,021
THAT.

5610
03:41:17,021 --> 03:41:21,926
THANK YOU.

5611
03:41:21,926 --> 03:41:23,394
>> SO I THINK WHAT WE'RE
GOING

5612
03:41:23,394 --> 03:41:26,997
TO DO IS I WON'T CALL IT A BREAK

5613
03:41:26,997 --> 03:41:28,999
BUT JUST SO PEOPLE CAN STAND UP

5614
03:41:28,999 --> 03:41:32,636
AND SIT BACK DOWN IN 2 1/2 TO 3

5615
03:41:32,636 --> 03:41:33,571
MINUTES.

5616
03:41:33,571 --> 03:41:34,838
WHY DON'T WE ALL GO AHEAD AND DO

5617
03:41:34,838 --> 03:41:36,574
THIS AND THEN WE'LL START AGAIN

5618
03:41:36,574 --> 03:41:40,110
SHARP AT 2:45 WITH THE STRATEGIC

5619
03:41:40,110 --> 03:41:40,477
DISCUSSION.

5620
03:41:40,477 --> 03:41:42,046
SO THANK YOU VERY MUCH TO THE

5621
03:41:42,046 --> 03:41:43,247
PANELISTS AND EVERYWITHIN FOR

5622
03:41:43,247 --> 03:41:46,462
EVERYONE FOR YOURQUESTIONS.

5623
03:41:46,462 --> 03:41:48,063
SO WHAT I WANTED TO DO IS

5624
03:41:48,063 --> 03:41:55,738
JUST SHOW A COUPLE OF SLIDES TO

5625
03:41:55,738 --> 03:41:58,607
FRAME THE DISCUSSION AND WRAP-UP

5626
03:41:58,607 --> 03:41:58,841
HERE.

5627
03:41:58,841 --> 03:42:00,109
SO HERE ARE SOME OF THE OVERALL

5628
03:42:00,109 --> 03:42:01,277
GOALS FOR THE WORKSHOP THAT WE

5629
03:42:01,277 --> 03:42:02,878
HAD AS WE WERE PUTTING THIS

5630
03:42:02,878 --> 03:42:05,014
TOGETHER.

5631
03:42:05,014 --> 03:42:06,849
FIRST AND FOREMOST TO REALLY

5632
03:42:06,849 --> 03:42:09,885
HELP FACILITATE COLLABORATIONS

5633
03:42:09,885 --> 03:42:11,520
AMONGST BASIC SCIENCE

5634
03:42:11,520 --> 03:42:12,488
RESEARCHES, CLINICIANS, INDUSTRY

5635
03:42:12,488 --> 03:42:13,823
EXPERTS AND REACHING SOME OF

5636
03:42:13,823 --> 03:42:15,224
THESE KNOWLEDGE GAPS IN OUR

5637
03:42:15,224 --> 03:42:16,826
UNDERSTANDING OF REGENERATIVE

5638
03:42:16,826 --> 03:42:18,627
STEM CELL RESILIENCE WITH

5639
03:42:18,627 --> 03:42:19,528
CHRONIC LUNG DISEASES.

5640
03:42:19,528 --> 03:42:21,797
WE ALSO NEED TO CONNECT RESEARCH

5641
03:42:21,797 --> 03:42:23,999
ON BASIC MECHANISMS TO WHAT

5642
03:42:23,999 --> 03:42:25,668
THERAPEUTIC NEEDS ARE ES PISHLY

5643
03:42:25,668 --> 03:42:27,937
AS THEY RELATE TO LUNG

5644
03:42:27,937 --> 03:42:29,004
PROGENITORS, RESILIENCE AND

5645
03:42:29,004 --> 03:42:29,905
CHRONIC LUNG DISEASE AND LASTLY

5646
03:42:29,905 --> 03:42:31,941
TRY TO PRIORITIZE WHAT THE

5647
03:42:31,941 --> 03:42:32,775
CRITICAL RESEARCH GAPS,

5648
03:42:32,775 --> 03:42:33,976
CHALLENGES AND OPPORTUNITIES ARE

5649
03:42:33,976 --> 03:42:42,218
AS THEY PERTAIN TO THESE TOPICS.

5650
03:42:42,218 --> 03:42:43,953
SO THE OVERALL WORKSHOP

5651
03:42:43,953 --> 03:42:45,087
OBJECTIVES PUT INTO A LITTLE

5652
03:42:45,087 --> 03:42:47,523
MORE GRANULARITY ARE TO HELP

5653
03:42:47,523 --> 03:42:49,758
DEFINE PROGENITOR CELL

5654
03:42:49,758 --> 03:42:53,696
RESILIENCE AND SOME OF THEIR

5655
03:42:53,696 --> 03:42:54,563
REGULATORY FACTORS TO UNDERSTAND

5656
03:42:54,563 --> 03:43:00,035
THE ROLE OF F OF PROGENITOR CELN

5657
03:43:00,035 --> 03:43:02,104
EARLY ONSET OF CHRONIC DISEASE,

5658
03:43:02,104 --> 03:43:03,873
DISCUSS EMERGING TECHNOLOGIES

5659
03:43:03,873 --> 03:43:05,708
AND MODEL SYSTEMS, IDENTIFY GAPS

5660
03:43:05,708 --> 03:43:07,343
IN RESEARCH ON PROGENITOR BASED

5661
03:43:07,343 --> 03:43:08,644
MARKERS PREDIBTING EARLY

5662
03:43:08,644 --> 03:43:09,879
DISEASE, DISCUSS THERAPEUTIC

5663
03:43:09,879 --> 03:43:11,013
INTERVENTIONS TARGETING

5664
03:43:11,013 --> 03:43:12,147
PROGENITORS TO PREVENT AND TREAT

5665
03:43:12,147 --> 03:43:12,982
THEM, LEVERAGE INSIGHTS FROM

5666
03:43:12,982 --> 03:43:14,884
OTHER DISCIPLINES AND AGAIN TO

5667
03:43:14,884 --> 03:43:16,919
FACILITATE COLLABORATION AMONG

5668
03:43:16,919 --> 03:43:18,087
BASIC SCIENCE CLINICIANS AND

5669
03:43:18,087 --> 03:43:25,527
INDUSTRY EXPERTS.

5670
03:43:25,527 --> 03:43:27,963
WHAT I THINK WE'VE BEEN ABLE TO

5671
03:43:27,963 --> 03:43:29,431
DO IS CERTAINLY OVER THE PAST

5672
03:43:29,431 --> 03:43:31,867
FEW YEARS, ENABLED BY BOTH A LOT

5673
03:43:31,867 --> 03:43:33,369
OF HYPOTHESIS-DRIVEN WORK AND

5674
03:43:33,369 --> 03:43:37,039
ALSO NEW AND EMERGING UNBIASED

5675
03:43:37,039 --> 03:43:38,140
PROFILING TECHNIQUES, WE'VE

5676
03:43:38,140 --> 03:43:40,542
BECOME QUITE GOOD AND DEFINING

5677
03:43:40,542 --> 03:43:42,811
PROGENITOR CELL STATES AND

5678
03:43:42,811 --> 03:43:45,748
SUBSETS, AND I THINK WE'VE HEARD

5679
03:43:45,748 --> 03:43:46,148
A LOT ABOUT THIS.

5680
03:43:46,148 --> 03:43:47,883
I THINK THAT THERE'S STILL THE

5681
03:43:47,883 --> 03:43:49,919
CHALLENGE OF CONNECTING THESE

5682
03:43:49,919 --> 03:43:52,655
PROGENITOR CELLS WITH RESILIENT

5683
03:43:52,655 --> 03:43:53,455
FUNCTIONS, AND SOME OF THIS MAY

5684
03:43:53,455 --> 03:43:55,724
BE DUE TO THE NEEDS OF BETTER

5685
03:43:55,724 --> 03:43:56,959
DEFINED RESILIENCE AND IN DOING

5686
03:43:56,959 --> 03:43:58,494
SO, HELP TO UNDERSTAND THE

5687
03:43:58,494 --> 03:43:59,662
REGULATORY FACTORS THAT HELP TO

5688
03:43:59,662 --> 03:44:03,632
PUSH AND PULL ON THE SYSTEM.

5689
03:44:03,632 --> 03:44:04,967
LIKEWISE, ONE OF THE TASKS, ONE

5690
03:44:04,967 --> 03:44:06,035
OF THE MANDATES THAT WE HAD WAS

5691
03:44:06,035 --> 03:44:08,237
TO TRY TO UNDERSTAND THE ROLE OF

5692
03:44:08,237 --> 03:44:09,471
PROGENITOR CELLS AND THE EARLY

5693
03:44:09,471 --> 03:44:10,839
ONSET OF CHRONIC DISEASE.

5694
03:44:10,839 --> 03:44:11,740
I THINK THIS IS WHERE A LOT OF

5695
03:44:11,740 --> 03:44:13,242
US ARE THINKING IN TERMS OF

5696
03:44:13,242 --> 03:44:14,777
BETTER PREVENTION AND EARLY

5697
03:44:14,777 --> 03:44:16,278
INTERVENTION AND INTERCEPTION OF

5698
03:44:16,278 --> 03:44:17,446
DISEASE.

5699
03:44:17,446 --> 03:44:20,749
HOWEVER, BY NECESSITY OF THE

5700
03:44:20,749 --> 03:44:23,385
TYPES OF DISEASE MODELS OR HUMAN

5701
03:44:23,385 --> 03:44:25,187
SYSTEMS THAT WE WORK IN, WE'VE

5702
03:44:25,187 --> 03:44:26,155
GAINED A LOT OF UNDERSTANDING OF

5703
03:44:26,155 --> 03:44:30,859
SOME OF THESE FEATURES IN REALLY

5704
03:44:30,859 --> 03:44:32,494
EXTREME CHRONIC DISEASE SO

5705
03:44:32,494 --> 03:44:33,729
TRYING TO WALK THAT BACK

5706
03:44:33,729 --> 03:44:35,030
EARLIER, GOING BACK TO THE VERY

5707
03:44:35,030 --> 03:44:36,932
BEGINNING IN RAVI'S VERY

5708
03:44:36,932 --> 03:44:38,067
BEAUTIFUL KEYNOTE TALK I THINK

5709
03:44:38,067 --> 03:44:40,269
IS SOMETHING OF UTMOST

5710
03:44:40,269 --> 03:44:41,103
IMPORTANCE.

5711
03:44:41,103 --> 03:44:42,071
THE NEXT THING WE'VE BEEN ABLE

5712
03:44:42,071 --> 03:44:45,240
TO DO IS WE CERTAINLY HAVE NOW

5713
03:44:45,240 --> 03:44:47,476
MUCH MORE ADVANCED MODEL SYSTEMS

5714
03:44:47,476 --> 03:44:50,179
THAN WE DID 10 OR 20 YEARS AGO,

5715
03:44:50,179 --> 03:44:51,880
BUT I THINK THERE'S STILL GAPS

5716
03:44:51,880 --> 03:44:53,349
IN A LOT OF THESE MODEL SYSTEMS,

5717
03:44:53,349 --> 03:44:54,817
AND THIS IS HIGHLIGHTED BY SOME

5718
03:44:54,817 --> 03:44:58,153
OF THE TALKS AND THEY MIGHT BE

5719
03:44:58,153 --> 03:45:01,056
GOOD FOR PERHAPS EARLY FETAL OR

5720
03:45:01,056 --> 03:45:03,192
KIND OF NEONATAL TISSUE

5721
03:45:03,192 --> 03:45:04,693
UNDERSTANDING, BUT REALLY THAT

5722
03:45:04,693 --> 03:45:06,028
ROBUST ADULT UNDERSTANDING IS

5723
03:45:06,028 --> 03:45:08,831
CHALLENGING AND OF COURSE

5724
03:45:08,831 --> 03:45:11,133
MULTISYSTEM MODELS CAN BE QUITE

5725
03:45:11,133 --> 03:45:12,267
COMPLEX TO DEVELOP.

5726
03:45:12,267 --> 03:45:13,435
WHILE WE HEARD SOME I THINK VERY

5727
03:45:13,435 --> 03:45:16,839
FASCINATING TALKS IN TERMS OF

5728
03:45:16,839 --> 03:45:18,440
BIOMARKERS CONNECTING THEM TO

5729
03:45:18,440 --> 03:45:19,842
PROGENITOR BASED BIOMARKERS IS

5730
03:45:19,842 --> 03:45:21,643
STILL A CHALLENGE, ESPECIALLY AS

5731
03:45:21,643 --> 03:45:23,645
THESE PROGENITOR CELLS ARE BEING

5732
03:45:23,645 --> 03:45:24,279
ACTIVELY DEFINED.

5733
03:45:24,279 --> 03:45:25,748
WE'VE HEARD ABOUT DEFINITIONS

5734
03:45:25,748 --> 03:45:28,117
THAT OFTENTIMES ARE IN RNA SPACE

5735
03:45:28,117 --> 03:45:31,887
OR PERHAPS VALIDATED THROUGH A

5736
03:45:31,887 --> 03:45:33,288
COUPLE OF KEY MARKERS THAT COULD

5737
03:45:33,288 --> 03:45:35,691
BE STAINED FOR OR USED FOR

5738
03:45:35,691 --> 03:45:36,959
LINEAGE TRACING, BUT HOW THAT

5739
03:45:36,959 --> 03:45:38,527
TIES TO PERIPHERAL CIRCULATING

5740
03:45:38,527 --> 03:45:39,695
BIOMARCS AND IF THOSE, IN FACT,

5741
03:45:39,695 --> 03:45:40,996
ARE COMING FROM THE PROGENITORS

5742
03:45:40,996 --> 03:45:42,097
OR LINKED TO THEIR FUNCTION, I

5743
03:45:42,097 --> 03:45:43,198
THINK IT'S STILL VERY MUCH AN

5744
03:45:43,198 --> 03:45:45,501
OPEN QUESTION.

5745
03:45:45,501 --> 03:45:52,775
THE NECK THING THAT WE HAVE OF F

5746
03:45:52,775 --> 03:45:54,476
COURSE THERAPEUTIC

5747
03:45:54,476 --> 03:45:55,377
INTERVENTIONS, WE OF COURSE NEED

5748
03:45:55,377 --> 03:45:58,313
MUCH MORE WORK DONE HERE.

5749
03:45:58,313 --> 03:46:01,350
IN OUR LAST SESSION, WE'RE

5750
03:46:01,350 --> 03:46:02,985
CERTAINLY ABLE TO CAPTURE SOME

5751
03:46:02,985 --> 03:46:03,986
INTERESTING THOUGHTS FROM OTHER

5752
03:46:03,986 --> 03:46:05,320
DISCIPLINES, BUT THERE'S MUCH

5753
03:46:05,320 --> 03:46:08,223
MORE TERRITORY TO BE EXPLORED

5754
03:46:08,223 --> 03:46:09,158
HERE.

5755
03:46:09,158 --> 03:46:11,026
AND WHILE WE HAD A VERY NICE

5756
03:46:11,026 --> 03:46:12,761
REPRESENTATION OF PANELISTS FROM

5757
03:46:12,761 --> 03:46:14,396
BASIC SCIENTISTS AND CLINICIAN

5758
03:46:14,396 --> 03:46:15,898
FIELD, I REALLY WANT TO MAKE

5759
03:46:15,898 --> 03:46:18,000
SURE IF THERE'S ANY BIOTECH OR

5760
03:46:18,000 --> 03:46:19,068
INDUSTRY REPRESENTATIVES IN THE

5761
03:46:19,068 --> 03:46:20,769
AUDIENCE TO REALLY HEAR YOUR

5762
03:46:20,769 --> 03:46:22,738
VOICE IN TERMS OF HOW WE CAN BE

5763
03:46:22,738 --> 03:46:23,972
BETTER FACILITATING

5764
03:46:23,972 --> 03:46:30,846
COLLABORATION.

5765
03:46:30,846 --> 03:46:32,481
SO RESILIENCE.

5766
03:46:32,481 --> 03:46:33,882
A WORD THAT WAS RIGHT IN THE

5767
03:46:33,882 --> 03:46:36,085
TITLE OF THIS WORKSHOP ON

5768
03:46:36,085 --> 03:46:36,952
PROGENITOR RESILIENCE IN THE

5769
03:46:36,952 --> 03:46:38,954
EARLY ONSET OF CHRONIC LUNG

5770
03:46:38,954 --> 03:46:39,755
DISEASES.

5771
03:46:39,755 --> 03:46:40,989
AND THE MORE I THINK ABOUT IT, I

5772
03:46:40,989 --> 03:46:45,060
THINK IT'S ACTUALLY REALLY A

5773
03:46:45,060 --> 03:46:46,762
PERFECT WORD TO CAPTURE THE

5774
03:46:46,762 --> 03:46:47,830
CHALLENGE OF WHAT WE NEED TO DO

5775
03:46:47,830 --> 03:46:48,097
HERE.

5776
03:46:48,097 --> 03:46:49,131
THE REASON FOR THIS IS BECAUSE

5777
03:46:49,131 --> 03:46:50,899
THERE ARE TWO DEFINITIONS FOR

5778
03:46:50,899 --> 03:46:52,634
THIS WORD.

5779
03:46:52,634 --> 03:46:54,970
THE FIRST ONE IS THIS CAPACITY

5780
03:46:54,970 --> 03:46:58,040
TO WITHSTAND OR RECOVER QUICKLY

5781
03:46:58,040 --> 03:46:59,575
FROM DIFFICULTIES AND A CERTAIN

5782
03:46:59,575 --> 03:47:00,943
TOUGHNESS, THAT PERHAPS THE

5783
03:47:00,943 --> 03:47:04,580
IMAGE ON THE LEFT OF THIS REALLY

5784
03:47:04,580 --> 03:47:05,881
BEAUTIFUL ART FORM OF POTTERY

5785
03:47:05,881 --> 03:47:10,886
WHERE CERAMIC IS SOMETHING THAT

5786
03:47:10,886 --> 03:47:12,454
IS QUITE DURABLE AND HARD UNTIL

5787
03:47:12,454 --> 03:47:13,755
IT BREAKS AND ONE KIND OF

5788
03:47:13,755 --> 03:47:15,591
PATCHES IT UP OR PUTS IT BACK

5789
03:47:15,591 --> 03:47:16,358
TOGETHER.

5790
03:47:16,358 --> 03:47:17,025
WE'VE HEARD A LOT OF TALKS ABOUT

5791
03:47:17,025 --> 03:47:17,759
TYPES OF PROGENITOR CELLS THAT

5792
03:47:17,759 --> 03:47:19,394
MAY ACT IN THIS WAY, TO HELP

5793
03:47:19,394 --> 03:47:21,330
PROVIDE THE LUNG WITH A CERTAIN

5794
03:47:21,330 --> 03:47:22,865
TOUGHNESS OR RAPID RESPONSE

5795
03:47:22,865 --> 03:47:24,933
MECHANISM, BUT THEN THESE

5796
03:47:24,933 --> 03:47:26,335
MECHANISMS COULD BE COOPTED IN

5797
03:47:26,335 --> 03:47:26,768
CHRONIC DISEASE.

5798
03:47:26,768 --> 03:47:27,970
THE OTHER ONE, AND I THINK THIS

5799
03:47:27,970 --> 03:47:30,105
IS SOMETHING THAT WE HEARD LESS

5800
03:47:30,105 --> 03:47:31,473
ABOUT, BUT SOMETHING THAT WE

5801
03:47:31,473 --> 03:47:32,975
REALLY NEED TO THINK CAREFULLY

5802
03:47:32,975 --> 03:47:35,544
ABOUT IS THIS ABILITY OF AN

5803
03:47:35,544 --> 03:47:38,147
OBJECT TO SPRING BACK INTO SHAPE

5804
03:47:38,147 --> 03:47:39,848
OR ELASTICITY.

5805
03:47:39,848 --> 03:47:40,449
THIS OF COURSE IS FUNDAMENTAL

5806
03:47:40,449 --> 03:47:41,550
WITH EVERY SINGLE BREATH THAT

5807
03:47:41,550 --> 03:47:42,151
WE'RE TAKING.

5808
03:47:42,151 --> 03:47:43,485
SO I THINK NOT JUST THINKING

5809
03:47:43,485 --> 03:47:45,420
ABOUT RESILIENCE AS KIND OF A

5810
03:47:45,420 --> 03:47:47,823
TOUGHNESS OF THE SYSTEM, BUT

5811
03:47:47,823 --> 03:47:50,592
ALSO THE PARTICULAR SHAPE OR

5812
03:47:50,592 --> 03:47:51,960
ELASTICITY IT CAN KEEP IS

5813
03:47:51,960 --> 03:47:52,528
SOMETHING THAT WILL BE VERY

5814
03:47:52,528 --> 03:47:53,829
IMPORTANT AS WE FRAME OUR

5815
03:47:53,829 --> 03:47:55,330
DISCUSSION AND THE CHALLENGES

5816
03:47:55,330 --> 03:48:01,103
GOING FORWARD.

5817
03:48:01,103 --> 03:48:02,804
SO WHAT I'D LIKE TO DO HERE IS

5818
03:48:02,804 --> 03:48:06,942
POSE A FEW QUESTIONS JUST TO

5819
03:48:06,942 --> 03:48:08,043
KIND OF OPEN UP DISCUSSION AND

5820
03:48:08,043 --> 03:48:11,880
WE CAN CERTAINLY BOUNCE BACK AND

5821
03:48:11,880 --> 03:48:15,050
FORTH BETWEEN THESE, AND I HOPE

5822
03:48:15,050 --> 03:48:16,351
AS MANY OF THE PANELISTS THAT

5823
03:48:16,351 --> 03:48:18,253
ARE ABLE TO STAY ON ARE ABLE TO

5824
03:48:18,253 --> 03:48:19,821
PARTICIPATE IN THIS STRATEGIC

5825
03:48:19,821 --> 03:48:22,824
DISCUSSION SECTION.

5826
03:48:22,824 --> 03:48:24,660
SO AS SOME THINGS COME UP,

5827
03:48:24,660 --> 03:48:25,994
PLEASE FEEL FREE TO CHIME IN.

5828
03:48:25,994 --> 03:48:27,362
WE'LL TRY TO USE THE RAISE HAND

5829
03:48:27,362 --> 03:48:28,463
FUNCTION JUST TO KEEP THINGS IN

5830
03:48:28,463 --> 03:48:31,700
GOOD ORDER.

5831
03:48:31,700 --> 03:48:32,968
BUT I THINK A FEW QUESTIONS AT

5832
03:48:32,968 --> 03:48:34,403
LEAST CAME TO MIND AS I WAS

5833
03:48:34,403 --> 03:48:35,337
LISTENING AND TRYING TO

5834
03:48:35,337 --> 03:48:36,705
INTEGRATE ALL THESE TALKS ARE,

5835
03:48:36,705 --> 03:48:38,407
IS RESILIENCE JUST THE ABSENCE

5836
03:48:38,407 --> 03:48:40,209
OF DISEASE OR IS IT REALLY THE

5837
03:48:40,209 --> 03:48:45,047
PRESENCE OF A SPECIAL STATE?

5838
03:48:45,047 --> 03:48:47,015
SO HOW DO WE BEGIN TO QUANTIFY

5839
03:48:47,015 --> 03:48:47,649
SOMETHING THAT WE MAY NOT EVEN

5840
03:48:47,649 --> 03:48:50,419
KNOW HOW TO MEASURE.

5841
03:48:50,419 --> 03:48:51,687
THIS IS SOMETHING THAT'S REALLY,

5842
03:48:51,687 --> 03:48:52,988
REALLY IMPORTANT TO TRY TO

5843
03:48:52,988 --> 03:48:54,990
UNDERSTAND.

5844
03:48:54,990 --> 03:48:56,725
I THINK MOST PEOPLE MAY THINK OF

5845
03:48:56,725 --> 03:48:58,527
STEM AND PROGENITOR CELL AS A

5846
03:48:58,527 --> 03:49:00,429
GOOD THING, BUT WE'VE ALSO HEARD

5847
03:49:00,429 --> 03:49:01,763
ABOUT SOME PLACES WHERE THERE

5848
03:49:01,763 --> 03:49:03,031
MIGHT BE INDIVIDUAL STATES WHICH

5849
03:49:03,031 --> 03:49:04,266
COULD BE POTENTIALLY

5850
03:49:04,266 --> 03:49:05,767
DETRIMENTAL, AND FURTHERMORE, WE

5851
03:49:05,767 --> 03:49:06,902
NEED TO UNDERSTAND THE

5852
03:49:06,902 --> 03:49:09,871
REGIONALITY OF WHERE THOSE CELLS

5853
03:49:09,871 --> 03:49:11,306
ARE LOCALIZED WITHIN THE LUNG.

5854
03:49:11,306 --> 03:49:12,674
THE NEXT QUESTION THAT COMES TO

5855
03:49:12,674 --> 03:49:13,976
MIND IS HOW WE BALANCE THE

5856
03:49:13,976 --> 03:49:15,744
COMPLEXITY AND THE PHYSIOLOGICAL

5857
03:49:15,744 --> 03:49:17,312
RELEVANCE WITH THE SCALABILITY

5858
03:49:17,312 --> 03:49:21,650
OF OUR SYSTEMS, AND SO ONE COULD

5859
03:49:21,650 --> 03:49:23,385
THINK ABOUT THIS IN TERMS OF

5860
03:49:23,385 --> 03:49:26,088
SOME OF THE EX VIVO MODELS OR IN

5861
03:49:26,088 --> 03:49:27,489
VIVO REDUCTIONIST MODELS THAT WE

5862
03:49:27,489 --> 03:49:28,590
USE TO STUDY HUMAN DISEASE BUT

5863
03:49:28,590 --> 03:49:29,725
ALSO THE TYPES OF MEASUREMENTS

5864
03:49:29,725 --> 03:49:31,627
THAT WE'RE TAKING IN HUMAN

5865
03:49:31,627 --> 03:49:33,629
TRIALS AS WELL.

5866
03:49:33,629 --> 03:49:34,863
THE NEXT QUESTION THAT COMES TO

5867
03:49:34,863 --> 03:49:37,766
MIND IS HOW WE CONNECT EARLY

5868
03:49:37,766 --> 03:49:39,101
KNOWLEDGE ON PROGENITOR

5869
03:49:39,101 --> 03:49:41,570
HETEROGENEITY TO NON-LUNG

5870
03:49:41,570 --> 03:49:42,838
PARENCHYMAL BIOMARKERS TO REALLY

5871
03:49:42,838 --> 03:49:44,339
ACCESS THIS EARLY ONSET OF

5872
03:49:44,339 --> 03:49:44,573
DISEASE.

5873
03:49:44,573 --> 03:49:45,574
SO SOME DISCUSSION THAT CAME UP

5874
03:49:45,574 --> 03:49:48,944
OF, YOU KNOW, DOES THE NOSE

5875
03:49:48,944 --> 03:49:49,845
REFLECT WHAT'S HAPPENING IN THE

5876
03:49:49,845 --> 03:49:52,180
DEEPER LUNG PARENCHYMA, CAN WE

5877
03:49:52,180 --> 03:49:55,050
ACTUALLY GO INTO THE BLOOD TO

5878
03:49:55,050 --> 03:49:56,918
PROFILE WHAT IS GOING ON AND SO

5879
03:49:56,918 --> 03:49:57,986
FORTH.

5880
03:49:57,986 --> 03:50:00,389
NEXT, WHAT KIND OF THERAPEUTIC

5881
03:50:00,389 --> 03:50:01,456
INTERVENTIONS ARE CURRENTLY

5882
03:50:01,456 --> 03:50:03,425
FUNCTIONING THROUGH TARGETING

5883
03:50:03,425 --> 03:50:04,059
PROGENITORS OR RESILIENCE.

5884
03:50:04,059 --> 03:50:04,960
WE'VE HEARD ABOUT SOME THINGS

5885
03:50:04,960 --> 03:50:06,361
THAT ARE REALLY ON THE CUTTING

5886
03:50:06,361 --> 03:50:07,829
EDGE, BUT JUST TAKING A STEP

5887
03:50:07,829 --> 03:50:09,331
BACK, ARE THERE THINGS THAT WE

5888
03:50:09,331 --> 03:50:10,432
REALLY ARE CURRENTLY DOING THAT

5889
03:50:10,432 --> 03:50:11,933
MAY ACTUALLY WORK ON THIS LEVEL

5890
03:50:11,933 --> 03:50:13,368
AND WE DON'T EVEN UNDERSTAND

5891
03:50:13,368 --> 03:50:16,505
JUST YET.

5892
03:50:16,505 --> 03:50:18,507
I THINK THAT RAVI'S INITIAL

5893
03:50:18,507 --> 03:50:20,776
POINT ON GENERATING AN ANALOGOUS

5894
03:50:20,776 --> 03:50:22,611
VIEW TO CARDIOVASCULAR HEALTH IS

5895
03:50:22,611 --> 03:50:24,313
SOMETHING THAT IS VERY IMPORTANT

5896
03:50:24,313 --> 03:50:24,913
TO DO.

5897
03:50:24,913 --> 03:50:26,748
TRYING TO DERIVE SOME OF THESE

5898
03:50:26,748 --> 03:50:28,650
EARLY BIOMARKERS THAT WE MAY BE

5899
03:50:28,650 --> 03:50:30,585
ABLE TO MEASURE THROUGH A SIMPLE

5900
03:50:30,585 --> 03:50:32,954
BLOOD DRAW OR PERHAPS AN EVEN

5901
03:50:32,954 --> 03:50:34,289
SIMPLER NASAL SWAB WOULD BE FON

5902
03:50:34,289 --> 03:50:41,496
TAS TICFANTASTIC IN TERMS OF TRG

5903
03:50:41,496 --> 03:50:44,232
THINGS REALLY ON A POPULATION

5904
03:50:44,232 --> 03:50:45,500
SCALE AND LASTLY I COME BACK TO

5905
03:50:45,500 --> 03:50:47,769
THE QUESTION OF -- WE'VE HAD A

5906
03:50:47,769 --> 03:50:50,038
LOT OF NIGHTS TALKS FROM BASIC

5907
03:50:50,038 --> 03:50:51,773
SCIENTISTS AND CLINICIANS BUT AT

5908
03:50:51,773 --> 03:50:54,743
THE END OF THE DAY THE

5909
03:50:54,743 --> 03:50:55,377
TRANSLATION INTO THE CLINIC

5910
03:50:55,377 --> 03:50:57,312
REALLY RELIES A LOT ON BIOTECH

5911
03:50:57,312 --> 03:50:58,647
AND INDUSTRY LAYER AND CLOSE

5912
03:50:58,647 --> 03:51:00,482
COLLABORATION BETWEEN ALL OF US

5913
03:51:00,482 --> 03:51:01,650
AND SO AGAIN JUST PROMPTING HERE

5914
03:51:01,650 --> 03:51:02,517
FOR ADDITIONAL DISCUSSION.

5915
03:51:02,517 --> 03:51:03,652
SO WITH THAT, I'LL PAUSE ON

5916
03:51:03,652 --> 03:51:04,019
THIS.

5917
03:51:04,019 --> 03:51:05,987
I KNOW I'VE ONLY HAD A BRIEF

5918
03:51:05,987 --> 03:51:07,456
CHANCE TO SUMMARIZE A LOT OF

5919
03:51:07,456 --> 03:51:08,490
BEAUTIFUL WORK THAT WAS

5920
03:51:08,490 --> 03:51:09,124
PRESENTED OVER THE PAST COUPLE

5921
03:51:09,124 --> 03:51:11,360
OF DAYS, BUT I HOPE THAT WE HAVE

5922
03:51:11,360 --> 03:51:15,764
SOME OPPORTUNITY TO DISCUSS SOME

5923
03:51:15,764 --> 03:51:26,241
FORWARD THINKING IDEAS HERE.

5924
03:51:27,709 --> 03:51:28,110
YOHANNES, PLEASE.

5925
03:51:28,110 --> 03:51:29,678
>> THANK YOU FOR PUTTING

5926
03:51:29,678 --> 03:51:33,448
TOGETHER THESE POINTS, JOSE.

5927
03:51:33,448 --> 03:51:34,816
THE ONE THING THAT I WOULD LIKE

5928
03:51:34,816 --> 03:51:36,385
TO MENTION IS OBVIOUSLY THERE

5929
03:51:36,385 --> 03:51:40,522
WERE A FEW DISCUSSIONS GOING ON

5930
03:51:40,522 --> 03:51:42,591
ABOUT POLYMORPHISMS OR

5931
03:51:42,591 --> 03:51:46,962
SUSCEPTIBILITY, AND I THINK THAT

5932
03:51:46,962 --> 03:51:48,764
IS, TO YOUR FIRST QUESTION, IS

5933
03:51:48,764 --> 03:51:50,165
RESILIENCE ABSENCE OF DISEASE OR

5934
03:51:50,165 --> 03:51:54,870
PRESENCE OF A SPECIAL STATE.

5935
03:51:54,870 --> 03:51:56,238
OR PROGENITOR CELLS, WHAT ARE

5936
03:51:56,238 --> 03:52:00,075
THEY DOING AND DO THEY HAVE

5937
03:52:00,075 --> 03:52:01,910
SUSCEPTIBILITY SOMEHOW WHEN THEY

5938
03:52:01,910 --> 03:52:03,612
ARE TRANSITIONING TO A STATE

5939
03:52:03,612 --> 03:52:08,049
THAT IS ACTUALLY REGENERATING

5940
03:52:08,049 --> 03:52:10,185
THE NORMAL LUNG.

5941
03:52:10,185 --> 03:52:15,724
I THINK THESE ISSUES ARE KIND OF

5942
03:52:15,724 --> 03:52:17,025
DIFFICULT FOR US TO CAPTURE AT

5943
03:52:17,025 --> 03:52:18,360
THIS POINT BECAUSE WE DON'T

5944
03:52:18,360 --> 03:52:18,927
UNDERSTAND THE BIOLOGY VERY

5945
03:52:18,927 --> 03:52:20,395
WELL, AND THERE IS A LOT OF WORK

5946
03:52:20,395 --> 03:52:26,234
BEING DONE THAT IS IMPRESSIVE.

5947
03:52:26,234 --> 03:52:27,969
AND IT'S GREAT, BUT I THINK

5948
03:52:27,969 --> 03:52:33,208
POLYMORPHISM IS ONE THAT SHOULD

5949
03:52:33,208 --> 03:52:35,043
BE CLEARLY PUT INTO THIS

5950
03:52:35,043 --> 03:52:35,310
EQUATION.

5951
03:52:35,310 --> 03:52:37,846
AND THE OTHER THING OBVIOUSLY IS

5952
03:52:37,846 --> 03:52:38,914
ALSO EXPOSURE, AND THAT'S

5953
03:52:38,914 --> 03:52:42,417
SOMETHING THAT IS VERY DIFFIC 

5954
03:52:42,417 --> 03:52:48,557
DIFFICULT.

5955
03:52:48,557 --> 03:52:49,991
DATA ANALYSIS LIKE SAM SHOWED US

5956
03:52:49,991 --> 03:52:51,993
IS AN IMPORTANT ONE BUT DAVID

5957
03:52:51,993 --> 03:52:53,195
MENTIONED FOR EXAMPLE THAT

5958
03:52:53,195 --> 03:52:59,034
EXPOSURE NOT ONLY TO POLLUTION

5959
03:52:59,034 --> 03:53:00,035
PM2.5 WHICH IS BECOMING

5960
03:53:00,035 --> 03:53:02,137
EXTREMELY IMPORTANT NOW WITH

5961
03:53:02,137 --> 03:53:03,104
WILDFIRES RAGING ALL OVER THE

5962
03:53:03,104 --> 03:53:04,372
U.S. AND EVERYWHERE IN THE WORLD

5963
03:53:04,372 --> 03:53:05,674
REALLY, AND HOW TO CAPTURE THAT

5964
03:53:05,674 --> 03:53:09,177
NOT ONLY NOW FROM THE PM 2.5. OF

5965
03:53:09,177 --> 03:53:11,346
VIEW, BUT WE'VE SHOWN, FOR

5966
03:53:11,346 --> 03:53:12,781
EXAMPLE, PM2.5 IS NOT THE SAME

5967
03:53:12,781 --> 03:53:15,817
LIKE PM2.5 FROM WOOD SMOKE OR

5968
03:53:15,817 --> 03:53:16,885
FROM CIGARETTE SMOKE.

5969
03:53:16,885 --> 03:53:19,955
THEY CAN BE SYNERGISTIC, IN

5970
03:53:19,955 --> 03:53:21,523
FACT, IN CAUSING DISEASE.

5971
03:53:21,523 --> 03:53:26,328
SO THEY  THERE ARE IN FACT A LOF

5972
03:53:26,328 --> 03:53:27,729
FACTORS THAT NEED TO BE PUT INTO

5973
03:53:27,729 --> 03:53:28,997
THE EQUATION TO START

5974
03:53:28,997 --> 03:53:33,134
UNDERSTANDING HOW TO GO FORWARD

5975
03:53:33,134 --> 03:53:34,936
AND DISENTANGLE, IF YOU WILL,

5976
03:53:34,936 --> 03:53:36,505
THE UNDERSTANDING OF THIS

5977
03:53:36,505 --> 03:53:38,874
RESILIENCE ISSUE.

5978
03:53:38,874 --> 03:53:43,078
BUT THE WORD ITSELF IS, I THINK,

5979
03:53:43,078 --> 03:53:44,112
APPROPRIATE AND CORRECT.

5980
03:53:44,112 --> 03:53:47,182
BUT THESE ARE JUST THE

5981
03:53:47,182 --> 03:53:50,418
COMPLEXITYS THAT JUST MAKE IT AT

5982
03:53:50,418 --> 03:53:51,887
THIS POINT REALLY DIFFICULT FOR

5983
03:53:51,887 --> 03:53:52,821
US TO CAPTURE EVERYTHING.

5984
03:53:52,821 --> 03:53:58,226
>> SO PERHAPS IF I CAN
KIND OF

5985
03:53:58,226 --> 03:54:00,662
TIE WHAT YOUR COMMENT WAS AROUND

5986
03:54:00,662 --> 03:54:02,497
THE IDEA OF RESILIENCE, YOU'RE

5987
03:54:02,497 --> 03:54:03,932
PROPOSING, OF COURSE, THERE'S

5988
03:54:03,932 --> 03:54:05,000
DIFFICULTIES IN MEASURING WHAT

5989
03:54:05,000 --> 03:54:06,468
SOME OF THESE ENVIRONMENTAL

5990
03:54:06,468 --> 03:54:08,403
CHALLENGES ARE IN QUITE A

5991
03:54:08,403 --> 03:54:11,239
HOLISTIC WAY, BUT ALSO AT THE

5992
03:54:11,239 --> 03:54:12,274
SAME TIME, WE MAY WANT TO THINK

5993
03:54:12,274 --> 03:54:15,644
ABOUT DIFFERENCES IN ENVIRONMENT

5994
03:54:15,644 --> 03:54:17,078
THAT PEOPLE MAY NEED TO BE

5995
03:54:17,078 --> 03:54:18,680
RESILIENT FOR, AND IN ESSENCE,

5996
03:54:18,680 --> 03:54:20,015
THINKING ABOUT DISTINCT

5997
03:54:20,015 --> 03:54:23,518
ENVIRONMENTAL EXPOSURES, WE

5998
03:54:23,518 --> 03:54:24,986
THINK A LOT IN OUR LABORATORY

5999
03:54:24,986 --> 03:54:27,022
ABOUT VIRAL CHALLENGES, FOR

6000
03:54:27,022 --> 03:54:30,725
EXAMPLE, WE THINK LESS IS A

6001
03:54:30,725 --> 03:54:33,295
BLIND SPOT FOR US ABOUT

6002
03:54:33,295 --> 03:54:33,662
PM2.5 EXPOSURE.

6003
03:54:33,662 --> 03:54:35,931
SO I THINK THAT THINKING IF THIS

6004
03:54:35,931 --> 03:54:37,666
SAME MECHANISMS OR WHICH

6005
03:54:37,666 --> 03:54:41,436
MECHANISMS APLAY  APPLY FOR WHIH

6006
03:54:41,436 --> 03:54:42,571
ENVIRONMENTAL CHALLENGES BROADLY

6007
03:54:42,571 --> 03:54:43,471
SPEAKING IS CERTAINLY SOMETHING

6008
03:54:43,471 --> 03:54:45,507
THAT WE NEED TO THINK A LOT

6009
03:54:45,507 --> 03:54:48,310
ABOUT GOING FORWARD.

6010
03:54:48,310 --> 03:54:50,912
>> YES, AND I MENTIONED
PM2.5,

6011
03:54:50,912 --> 03:54:52,414
BUT CLEARLY ENVIRONMENT IS NOT

6012
03:54:52,414 --> 03:54:53,381
ONLY POLLUTION, RIGHT?

6013
03:54:53,381 --> 03:54:56,217
I MEAN, THERE IS FITNESS THAT

6014
03:54:56,217 --> 03:54:59,621
RAVI MENTIONED, FOR EXAMPLE, AND

6015
03:54:59,621 --> 03:55:00,689
SOCIAL STRESS.

6016
03:55:00,689 --> 03:55:01,756
I MEAN, THESE ARE ISSUES THAT WE

6017
03:55:01,756 --> 03:55:04,526
DON'T EVEN HAVE A FOOD HANDLE

6018
03:55:04,526 --> 03:55:08,563
ON, HOW TO QUANTIFY AND PUT INTO

6019
03:55:08,563 --> 03:55:10,999
THE EQUATION.

6020
03:55:10,999 --> 03:55:11,566
BUT ESSENTIALLY THIS

6021
03:55:11,566 --> 03:55:12,767
ENVIRONMENTAL ISSUE IS A VERY

6022
03:55:12,767 --> 03:55:15,570
DIFFICULT ISSUE AND SHOULD BE

6023
03:55:15,570 --> 03:55:16,605
CONSIDERED.

6024
03:55:16,605 --> 03:55:18,440
WE DIDN'T HEAR MUCH ABOUT

6025
03:55:18,440 --> 03:55:21,042
OXIDATIVE STRESS, WHICH IS ALSO

6026
03:55:21,042 --> 03:55:28,383
VERY DIFFICULT TO STUDY AND AS A

6027
03:55:28,383 --> 03:55:30,986
BASIC SCIENTIST WE KNOW STRESS

6028
03:55:30,986 --> 03:55:33,521
IS REALLY A COMPLICATED ISSUE AS

6029
03:55:33,521 --> 03:55:34,289
WELL.

6030
03:55:34,289 --> 03:55:35,957
SO THERE ARE THINGS LIKE THAT

6031
03:55:35,957 --> 03:55:37,425
THAT WE DIDN'T EVEN TOUCH UPON

6032
03:55:37,425 --> 03:55:38,360
IN THIS SESSION.

6033
03:55:38,360 --> 03:55:39,427
>> I THINK AS SOME OF THE

6034
03:55:39,427 --> 03:55:41,062
CAMERAS TURN ON HERE, I KNOW

6035
03:55:41,062 --> 03:55:44,399
THAT DOING THIS KIND OF VIRTUAL

6036
03:55:44,399 --> 03:55:46,935
ROUNDTABLE IS NOT AS NATURAL AS

6037
03:55:46,935 --> 03:55:50,772
DOING SO IN PERSON, BUT PLEASE,

6038
03:55:50,772 --> 03:55:52,874
I CERTAINLY DON'T NEED TO BE THE

6039
03:55:52,874 --> 03:55:54,609
NEXUS IN COMMUNICATION HERE.

6040
03:55:54,609 --> 03:55:56,344
SO SAM, IF YOU WANT TO CALL OUT

6041
03:55:56,344 --> 03:55:58,513
ON SOMEONE ELSE, OR DAVID I SEE

6042
03:55:58,513 --> 03:56:00,615
YOUR HANDS ARE UP, LET'S TRY TO

6043
03:56:00,615 --> 03:56:02,550
STIMULATE SOME INTERACTIONS HERE

6044
03:56:02,550 --> 03:56:03,318
JUST LIKE THE DIAGRAMS THAT YOU

6045
03:56:03,318 --> 03:56:05,053
WERE SHOWING, SAM, AS WE START

6046
03:56:05,053 --> 03:56:07,188
TO LAYER IN SOME ADDITIONAL

6047
03:56:07,188 --> 03:56:11,126
COMPLEXITY.

6048
03:56:11,126 --> 03:56:12,093
SAM, I THINK YOU WERE NEXT.

6049
03:56:12,093 --> 03:56:12,560
>> SURE.

6050
03:56:12,560 --> 03:56:16,798
AND DAVID, YOU CAN GO AFTER ME.

6051
03:56:16,798 --> 03:56:17,499
I THINK IT'S A GOOD FRAMING TOO.

6052
03:56:17,499 --> 03:56:19,134
I JUST WANT TO TALK ABOUT THIS,

6053
03:56:19,134 --> 03:56:20,735
I'VE BEEN THINKING ABOUT THIS, I

6054
03:56:20,735 --> 03:56:21,469
DIDN'T REALIZE HOW MUCH THERE

6055
03:56:21,469 --> 03:56:23,304
WAS GOING TO BE A THESIS ABOUT

6056
03:56:23,304 --> 03:56:24,105
RESILIENCE HERE, AND I THINK IT

6057
03:56:24,105 --> 03:56:25,640
IS VERY INTERESTING AND I THINK

6058
03:56:25,640 --> 03:56:26,708
THE WAY YOU'RE FRAMING IT

6059
03:56:26,708 --> 03:56:27,942
ACTUALLY WITH THESE TWO

6060
03:56:27,942 --> 03:56:28,943
DIFFERENT DEFINITIONS IS QUITE

6061
03:56:28,943 --> 03:56:29,244
APPROPRIATE.

6062
03:56:29,244 --> 03:56:30,378
IN MY HEAD WHEN I STARTED

6063
03:56:30,378 --> 03:56:31,880
HEARING IT, I WAS THINKING

6064
03:56:31,880 --> 03:56:32,580
SYSTEM STABILITY.

6065
03:56:32,580 --> 03:56:34,916
LIKE IN DYNAMICAL SYSTEMS THEORY

6066
03:56:34,916 --> 03:56:36,418
AND SYSTEMS BIOLOGY, PEOPLE TALK

6067
03:56:36,418 --> 03:56:37,786
A LOT ABOUT STABLE POINTS OF A

6068
03:56:37,786 --> 03:56:39,921
SYSTEM.

6069
03:56:39,921 --> 03:56:41,389
AND THEY'LL THINK ABOUT, IS

6070
03:56:41,389 --> 03:56:42,323
THERE A STABLE POINT IN A

6071
03:56:42,323 --> 03:56:43,091
CERTAIN CONFIGURATION OR ISN'T

6072
03:56:43,091 --> 03:56:43,425
THERE?

6073
03:56:43,425 --> 03:56:45,827
WHEN YOU BRING IN THIS CONCEPT

6074
03:56:45,827 --> 03:56:46,728
OF RESILIENCE, I THINK IT'S

6075
03:56:46,728 --> 03:56:47,696
QUITE MATHEMATICALLY

6076
03:56:47,696 --> 03:56:48,897
WELL-DEFINED BECAUSE YOU CAN SAY

6077
03:56:48,897 --> 03:56:50,131
SORT OF HOW DEEP IS THAT ENERGY

6078
03:56:50,131 --> 03:56:51,700
WELL, HOW STABLE IS IT, HOW

6079
03:56:51,700 --> 03:56:53,368
MUCH -- HOW HARD IS TO KICK IT

6080
03:56:53,368 --> 03:56:55,503
OUT OF HOMEOSTASIS OR TO MOVE

6081
03:56:55,503 --> 03:56:58,640
THAT SYSTEM.

6082
03:56:58,640 --> 03:57:01,443
YOU CAN ALSO TALK ABOUT THAT

6083
03:57:01,443 --> 03:57:01,910
ELASTICITY.

6084
03:57:01,910 --> 03:57:03,478
HOW FAR AWAY FROM A GIVEN STABLE

6085
03:57:03,478 --> 03:57:04,846
POINT, HOW MUCH DO YOU HAVE TO

6086
03:57:04,846 --> 03:57:05,914
PERTURB THE SYSTEM AWAY FROM

6087
03:57:05,914 --> 03:57:07,215
THAT PLACE BEFORE YOU GO OVER A

6088
03:57:07,215 --> 03:57:09,984
SADDLE AND YOU'RE INTO A

6089
03:57:09,984 --> 03:57:11,619
DIFFERENT ENERGY WELL WHICH WE

6090
03:57:11,619 --> 03:57:13,288
CAN THINK ABOUT TRANSITION TO

6091
03:57:13,288 --> 03:57:15,657
FIBROSIS.

6092
03:57:15,657 --> 03:57:16,291
HOMEOSTASIS INFLAMMATION OR ALL

6093
03:57:16,291 --> 03:57:17,425
THE WAY TO FIBROSIS.

6094
03:57:17,425 --> 03:57:20,628
SO I DO THINK THE WORD HAS THE

6095
03:57:20,628 --> 03:57:22,163
NECESSARY MEANINGS WITHIN IT AND

6096
03:57:22,163 --> 03:57:24,499
I THINK IT IS QUITE APPROPRIATE.

6097
03:57:24,499 --> 03:57:34,609
DAVID.

6098
03:57:39,881 --> 03:57:41,616
>> I HAVE A COUPLE OF
COMMENTS,

6099
03:57:41,616 --> 03:57:43,618
BUT I'LL RESERVE MAY COMMENTS

6100
03:57:43,618 --> 03:57:45,353
ABOUT THE ENVIRONMENT FOR LATER

6101
03:57:45,353 --> 03:57:46,888
BECAUSE I THINK THAT THEY MAY

6102
03:57:46,888 --> 03:57:51,726
LEAD INTO SORT OF FUTURE

6103
03:57:51,726 --> 03:57:52,360
OPPORTUNITIES.

6104
03:57:52,360 --> 03:57:57,398
IN TERMS OF THE CONCEPT OF

6105
03:57:57,398 --> 03:57:58,166
RESILIENCE, I'VE BEEN THINKING

6106
03:57:58,166 --> 03:57:59,400
FOR THE PAST TWO DAYS ABOUT IT

6107
03:57:59,400 --> 03:58:03,571
BEING SO CONTEXT-DEPENDENT.

6108
03:58:03,571 --> 03:58:05,607
CONTEXT DEPENDENT IN TERMS OF

6109
03:58:05,607 --> 03:58:11,312
AGE, STAGE OF DISEASE, A VARIETY

6110
03:58:11,312 --> 03:58:12,747
OF DIFFERENT FACTORS THAT ARE

6111
03:58:12,747 --> 03:58:16,818
GOING TO AFFECT THE INHERENT

6112
03:58:16,818 --> 03:58:22,223
RESILIENCE AND THE INHERENT

6113
03:58:22,223 --> 03:58:22,891
RESILIENT STATES WHEN CHALLENGED

6114
03:58:22,891 --> 03:58:23,858
AND STRESSED IN CERTAIN WAYS.

6115
03:58:23,858 --> 03:58:34,402
SO I THINK I AGREE WITH WHAT SAM

6116
03:58:35,436 --> 03:58:38,173
IS STAYING, IT'S COMPLEX AND THE

6117
03:58:38,173 --> 03:58:39,374
TRANSITION STATES ARE REALLY

6118
03:58:39,374 --> 03:58:44,412
SOMEWHAT DEPENDENT ON THE POINT

6119
03:58:44,412 --> 03:58:46,080
IN TIME THAT THEY'RE BEING

6120
03:58:46,080 --> 03:58:50,985
ASSESSED, AND IN THAT CONTEXT, I

6121
03:58:50,985 --> 03:58:57,559
THINK IT'S VERY DANGEROUS TO

6122
03:58:57,559 --> 03:59:00,895
GENERALIZE BEYOND THAT POINT AND

6123
03:59:00,895 --> 03:59:01,329
CONTEXT.

6124
03:59:01,329 --> 03:59:08,102
SO I THINK THAT WE NEED TO SORT

6125
03:59:08,102 --> 03:59:09,737
OF BEGIN TO THINK ABOUT HOW TO

6126
03:59:09,737 --> 03:59:11,406
INTEGRATE THESE FINDINGS ACROSS

6127
03:59:11,406 --> 03:59:16,911
THESE DIFFERENT CONTEXTUAL

6128
03:59:16,911 --> 03:59:19,881
DISEASE AND DEMOGRAPHIC AND

6129
03:59:19,881 --> 03:59:23,051
EXPOSURE STATES AS A WAY OF

6130
03:59:23,051 --> 03:59:29,057
UNDERSTANDING THE PLASTICITY OF

6131
03:59:29,057 --> 03:59:37,031
RESILIENCE.

6132
03:59:37,031 --> 03:59:41,102
>> CAN I ADD ONE SENTENCE
TO ADD

6133
03:59:41,102 --> 03:59:45,406
TO WHAT YOHANNES MENTIONED

6134
03:59:45,406 --> 03:59:45,840
EARLIER.

6135
03:59:45,840 --> 03:59:50,545
THE GENE ENVIRONMENT, THE GWAS

6136
03:59:50,545 --> 03:59:54,215
FIND DIFFERENT VARIANTS OF --

6137
03:59:54,215 --> 03:59:56,417
IPF BUT THOSE VARIANTS THEY HAVE

6138
03:59:56,417 --> 04:00:00,321
TO KIND OF DETERMINE DIFFERENT

6139
04:00:00,321 --> 04:00:01,856
VARIANCES -- WHEN THEY SEE THE

6140
04:00:01,856 --> 04:00:03,124
SMOKER THAT DEVELOPS COPD.

6141
04:00:03,124 --> 04:00:06,661
SO WHEN WE TALK ABOUT RESILIENCE

6142
04:00:06,661 --> 04:00:10,765
OF CELL TYPE, I THINK THESE

6143
04:00:10,765 --> 04:00:11,900
GENETIC COMPONENTS HAVE TO BE

6144
04:00:11,900 --> 04:00:13,034
CONSIDERED CAREFULLY, ESPECIALLY

6145
04:00:13,034 --> 04:00:14,269
IN RESPONSE TO THE ENVIRONMENT

6146
04:00:14,269 --> 04:00:15,003
OF CHALLENGE.

6147
04:00:15,003 --> 04:00:18,973
THAT'S WHERE THE GENETIC

6148
04:00:18,973 --> 04:00:20,275
DETERMINANTS ACTUALLY PLAY A

6149
04:00:20,275 --> 04:00:23,378
ROLE, HOW TO STRESS THE -- WHEN

6150
04:00:23,378 --> 04:00:26,714
YOU SEE BIG DIFFERENCE BETWEEN

6151
04:00:26,714 --> 04:00:29,717
THESE TWO GROUPS OF ALLELE

6152
04:00:29,717 --> 04:00:31,019
CARRIER.

6153
04:00:31,019 --> 04:00:33,388
ABOUT THIS GENETIC -- SO THE

6154
04:00:33,388 --> 04:00:34,856
GENE PROBABLY PLAYS A ROLE IN

6155
04:00:34,856 --> 04:00:37,859
DIFFERENT CELL TYPE AS WE HAVE

6156
04:00:37,859 --> 04:00:39,560
HEARD IN THE DIFFERENT -- LIKE

6157
04:00:39,560 --> 04:00:41,062
FIBROBLASTS AND IMMUNE CELL

6158
04:00:41,062 --> 04:00:51,172
TYPE.

6159
04:00:52,573 --> 04:00:56,110
>> RAVI, I KNOW PERHAPS
YOU HAD

6160
04:00:56,110 --> 04:00:56,744
SOME THOUGHT, I THINK YOU MIGHT

6161
04:00:56,744 --> 04:00:59,514
HAVE USED EVEN THE WORD TIPPING

6162
04:00:59,514 --> 04:01:00,782
POINT INSTEAD OF SADDLE OR

6163
04:01:00,782 --> 04:01:02,684
SOMETHING LIKE THIS IN TERMS

6164
04:01:02,684 --> 04:01:04,719
OF -- BUT PERHAPS IF WE CAN KIND

6165
04:01:04,719 --> 04:01:08,923
OF SCALE BACK OUT TO THE PATIENT

6166
04:01:08,923 --> 04:01:10,224
OR EPI LEVEL RATHER THAN THE

6167
04:01:10,224 --> 04:01:14,028
KIND OF PURE SYSTEMS DATA LEVEL,

6168
04:01:14,028 --> 04:01:15,463
AS WHAT SAM WAS MENTIONING, HOW

6169
04:01:15,463 --> 04:01:18,333
ARE YOU KIND OF VIEWING THIS OR

6170
04:01:18,333 --> 04:01:19,634
INTERPRETING THIS PROBLEM?

6171
04:01:19,634 --> 04:01:21,936
>> YEAH, I MEAN, I THINK
THIS IS

6172
04:01:21,936 --> 04:01:23,771
KIND OF THE CHALLENGE THAT WE'RE

6173
04:01:23,771 --> 04:01:27,675
FACED WITH, IS THAT WE ARE

6174
04:01:27,675 --> 04:01:31,779
PRECONDITIONED BY OUR TRAINING,

6175
04:01:31,779 --> 04:01:32,981
FUNDING MECHANISMS AND

6176
04:01:32,981 --> 04:01:38,953
MOTIVATIONS TO STUDY DISEASE.

6177
04:01:38,953 --> 04:01:40,088
THAT'S OUR BUSINESS MODEL.

6178
04:01:40,088 --> 04:01:42,190
AND YET, IF WE WANT TO CONFRONT

6179
04:01:42,190 --> 04:01:42,824
PUBLIC HEALTH PROBLEMS, WE HAVE

6180
04:01:42,824 --> 04:01:45,526
TO STUDY HEALTH.

6181
04:01:45,526 --> 04:01:49,597
NOT JUST DISEASE.

6182
04:01:49,597 --> 04:01:50,732
THE MINORITY OF PEOPLE DEVELOP

6183
04:01:50,732 --> 04:01:52,467
DISEASE BUT ALSO THE MINORITY OF

6184
04:01:52,467 --> 04:01:53,768
PEOPLE REMAIN HEALTHY THROUGHOUT

6185
04:01:53,768 --> 04:01:58,239
THEIR LIFESPAN.

6186
04:01:58,239 --> 04:01:59,674
THAT'S SORT OF ALL THESE IN

6187
04:01:59,674 --> 04:02:00,141
BETWEEN POINTS.

6188
04:02:00,141 --> 04:02:04,178
IN THE RESPIRATORY SYSTEM, THERE

6189
04:02:04,178 --> 04:02:06,147
ARE AN ENDLESS POINT OF INJURY,

6190
04:02:06,147 --> 04:02:09,117
LIKE YOHANNES WAS SAYING.

6191
04:02:09,117 --> 04:02:10,752
SOME PEOPLE HAVE AIR POLLUTION,

6192
04:02:10,752 --> 04:02:12,487
SOME PEOPLE SMOKE, SOME PEOPLE

6193
04:02:12,487 --> 04:02:14,422
LIVE IN MOLDY HOMES, SOME PEOPLE

6194
04:02:14,422 --> 04:02:18,126
ARE SENSITIVE TO ALLERGENS, SOME

6195
04:02:18,126 --> 04:02:19,494
PEOPLE GET VIRAL INFECTION OVER

6196
04:02:19,494 --> 04:02:20,895
AND OVER AGAIN AND RECOVER, SOME

6197
04:02:20,895 --> 04:02:22,096
PEOPLE GET VIRAL INFECTIONS THAT

6198
04:02:22,096 --> 04:02:24,799
SEEM TO HAVE UNRELENTING DECLINE

6199
04:02:24,799 --> 04:02:25,400
AFTERWARDS.

6200
04:02:25,400 --> 04:02:27,035
AND THAT HETEROGENEITY OF WHO

6201
04:02:27,035 --> 04:02:28,736
CONFRONTS VARIOUS TIPPING POINTS

6202
04:02:28,736 --> 04:02:29,704
ADVAIR JUST TIMES, SORT OF WHAT

6203
04:02:29,704 --> 04:02:32,640
DAVID WAS JUST SAYING, AND TIP

6204
04:02:32,640 --> 04:02:35,977
TOWARDS AN UNRELENTING DECLINE,

6205
04:02:35,977 --> 04:02:39,180
VERSUS HAVE AN IMPAIRMENT FOR A

6206
04:02:39,180 --> 04:02:39,947
SHORT PERIOD OF TIME, THEN ARE

6207
04:02:39,947 --> 04:02:41,849
ABLE TO HEAL, RECOVER, VERSUS

6208
04:02:41,849 --> 04:02:43,618
THOSE WHO SEEM UNAFFECTED BY ALL

6209
04:02:43,618 --> 04:02:45,253
OF THESE THINGS NO MATTER WHAT

6210
04:02:45,253 --> 04:02:49,724
THEY DO THROUGHOUT THEIR LIFE,

6211
04:02:49,724 --> 04:02:51,192
ARE REALLY IMPORTANT QUESTIONS

6212
04:02:51,192 --> 04:02:53,161
TO UNDERSTAND HEALTH.

6213
04:02:53,161 --> 04:02:55,329
SO I UNDERSTAND THE VEDZ WHO

6214
04:02:55,329 --> 04:03:00,201
HAVE IDEAL RESPIRATORY HEALTH

6215
04:03:00,201 --> 04:03:01,936
AND WHY THEY DO OR DON'T RESPOND

6216
04:03:01,936 --> 04:03:02,804
TO INJURY.

6217
04:03:02,804 --> 04:03:03,805
UNDERSTANDING THOSE WHO DEVIATE

6218
04:03:03,805 --> 04:03:05,039
FROM HEALTH BUT ARE ABLE TO GET

6219
04:03:05,039 --> 04:03:07,608
BACK TO HEALTH IS REALLY

6220
04:03:07,608 --> 04:03:09,310
IMPORTANT, AND I THINK WE'VE

6221
04:03:09,310 --> 04:03:10,945
HEARD A LOT OF INFORMATION ABOUT

6222
04:03:10,945 --> 04:03:13,047
PEOPLE WHO DESEND INTO SORT OF

6223
04:03:13,047 --> 04:03:14,749
DISEASE AND VARIOUS MECHANISMS

6224
04:03:14,749 --> 04:03:16,017
AROUND IT, BUT I THINK I WOULD

6225
04:03:16,017 --> 04:03:18,152
ENCOURAGE US TO SORT OF

6226
04:03:18,152 --> 04:03:23,224
CHALLENGE THE THINKING A LITTLE

6227
04:03:23,224 --> 04:03:24,926
BIT AROUND HOW TO STUDY AND

6228
04:03:24,926 --> 04:03:26,861
PROMOTE HEALTH VERSUS SORT OF

6229
04:03:26,861 --> 04:03:28,996
THIS UNRELENTING DECLINE TOWARDS

6230
04:03:28,996 --> 04:03:30,198
DISEASE.

6231
04:03:30,198 --> 04:03:30,932
NOW OF COURSE I DON'T KNOW HOW

6232
04:03:30,932 --> 04:03:32,166
TO DO ANY OF THAT, BUT THAT'S

6233
04:03:32,166 --> 04:03:33,634
SORT OF, I THINK, THE CHALLENGE

6234
04:03:33,634 --> 04:03:37,505
WE'RE FACED WITH.

6235
04:03:37,505 --> 04:03:38,573
WELLINGTON, PLEASE, YOUR

6236
04:03:38,573 --> 04:03:39,841
INSIGHTS ARE ALWAYS GOOD SO GO

6237
04:03:39,841 --> 04:03:40,041
AHEAD.

6238
04:03:40,041 --> 04:03:45,246
>> THANK YOU.

6239
04:03:45,246 --> 04:03:46,347
TALKING ABOUT RESILIENCE, THERE

6240
04:03:46,347 --> 04:03:47,915
IS ONE FACTOR THAT WE PROBABLY

6241
04:03:47,915 --> 04:03:51,819
VHAVE TALKED ABOUT A LITTLE BIT,

6242
04:03:51,819 --> 04:03:53,354
BUT I'D LIKE TO EMPHASIZE THAT

6243
04:03:53,354 --> 04:03:57,859
IT IS THE FACTOR AGE, AGING,

6244
04:03:57,859 --> 04:04:02,497
BECAUSE RESILIENCE HAS A LOT TO

6245
04:04:02,497 --> 04:04:06,400
DO WITH AGE AND ONE OF THE

6246
04:04:06,400 --> 04:04:08,503
THINGS THAT ARE ACTUALLY EVEN

6247
04:04:08,503 --> 04:04:10,037
MORE COMPLICATED IS TO DEFINE

6248
04:04:10,037 --> 04:04:11,672
WHAT IT IS ENVIRONMENT VERSUS

6249
04:04:11,672 --> 04:04:18,179
WHAT IT IS AGING, AND I THINK IT

6250
04:04:18,179 --> 04:04:19,580
IS PERHAPS WORTH AT LEAST

6251
04:04:19,580 --> 04:04:20,481
GETTING A LITTLE BIT INTO THIS,

6252
04:04:20,481 --> 04:04:22,350
ALTHOUGH THIS IS A VERY, VERY

6253
04:04:22,350 --> 04:04:26,921
COMPLEX SUBJECT.

6254
04:04:26,921 --> 04:04:29,590
>> YEAH, I CAN'T AGREE
WITH YOU

6255
04:04:29,590 --> 04:04:30,391
MORE, WELLINGTON.

6256
04:04:30,391 --> 04:04:35,396
I THINK AGE IS A HUGE ISSUE, AND

6257
04:04:35,396 --> 04:04:37,031
THE DYNAMICS THAT OCCUR IN TERMS

6258
04:04:37,031 --> 04:04:39,167
OF AGING, IN TERMS OF RESILIENCE

6259
04:04:39,167 --> 04:04:40,568
WILL TEACH US SO MUCH ABOUT

6260
04:04:40,568 --> 04:04:46,174
RESILIENCE.

6261
04:04:46,174 --> 04:04:48,242
>> ANDREW AND SUSAN ARE
HAVING A

6262
04:04:48,242 --> 04:04:50,044
CONVERSATION IN THE CHAT WITHOUT

6263
04:04:50,044 --> 04:04:52,680
US, BUT I WOULD ENCOURAGE TO YOU

6264
04:04:52,680 --> 04:04:57,618
SHARE, ANDREW OR SUSAN.

6265
04:04:57,618 --> 04:04:59,520
>> SUSAN, DO YOU WANT TO
GO

6266
04:04:59,520 --> 04:05:03,858
FIRST?

6267
04:05:03,858 --> 04:05:04,892
SORRY, GO AHEAD.

6268
04:05:04,892 --> 04:05:06,894
>> SORRY.

6269
04:05:06,894 --> 04:05:08,362
JUST TRYING TO WEIGH IN A LITTLE

6270
04:05:08,362 --> 04:05:10,598
BIT.

6271
04:05:10,598 --> 04:05:12,200
THERE ARE SOME GOOD

6272
04:05:12,200 --> 04:05:17,772
EPIDEMIOLOGIC STUDIES OUT THERE

6273
04:05:17,772 --> 04:05:18,639
ABOUT NOT NECESSARILY IN THE

6274
04:05:18,639 --> 04:05:20,408
LUNG FIELD ABOUT HE EXTREME

6275
04:05:20,408 --> 04:05:22,109
PHENOTYPES, AND I JUST WONDER IF

6276
04:05:22,109 --> 04:05:27,515
WE NEED TO FOSTER WAYS OF DOING

6277
04:05:27,515 --> 04:05:29,417
THOSE KINDS OF STUDIES, WHETHER

6278
04:05:29,417 --> 04:05:34,455
IT'S ON A GWAS SCALE OR WHAT, TO

6279
04:05:34,455 --> 04:05:40,161
BE ABLE TO IDENTIFY THOSE

6280
04:05:40,161 --> 04:05:43,531
INDIVIDUALS WHO ARE 40 PACK A

6281
04:05:43,531 --> 04:05:45,466
YEAR SMOKERS BUT STILL HAVE

6282
04:05:45,466 --> 04:05:48,002
REALLY GOOD LUNG FUNCTION.

6283
04:05:48,002 --> 04:05:51,405
WHAT ARE THOSE EXTREME

6284
04:05:51,405 --> 04:05:54,475
PHENOTYPES THAT REALLY MAKE YOU

6285
04:05:54,475 --> 04:05:57,411
THINK ABOUT THIS INDIVIDUAL HAS

6286
04:05:57,411 --> 04:06:01,816
SOME SORT OF GENETIC BACKGROUND

6287
04:06:01,816 --> 04:06:06,420
THAT PROMOTES RESILIENCE.

6288
04:06:06,420 --> 04:06:09,390
>> I CAN JUST ADD ON TO
THAT

6289
04:06:09,390 --> 04:06:09,590
MAYBE.

6290
04:06:09,590 --> 04:06:10,625
I TOTALLY AGREE WITH THAT

6291
04:06:10,625 --> 04:06:12,593
COMMENT, AND IT MAKES ME THINK

6292
04:06:12,593 --> 04:06:14,595
ABOUT LONGITUDAL COHORT IN WHICH

6293
04:06:14,595 --> 04:06:16,764
THE PARTICIPANTS HAVE BEEN

6294
04:06:16,764 --> 04:06:20,334
CAREFULLY PHENOTYPES AND WE KNOW

6295
04:06:20,334 --> 04:06:21,335
THEIR GENETIC BACKGROUND AS WELL

6296
04:06:21,335 --> 04:06:23,004
AS WHAT EXPOSURES THEY HAD.

6297
04:06:23,004 --> 04:06:24,305
AN EXAMPLE I HAD IN MIND

6298
04:06:24,305 --> 04:06:25,640
ALTHOUGH THERE ARE CERTAINLY

6299
04:06:25,640 --> 04:06:27,875
OTHERS IS THE FRAMINGHAM HEART

6300
04:06:27,875 --> 04:06:30,811
STUDY WHERE INDIVIDUALS HAVE

6301
04:06:30,811 --> 04:06:32,980
BEEN CHARACTERIZED GENETICALLY,

6302
04:06:32,980 --> 04:06:34,181
POLYGENIC RISK SCORES TO THINK

6303
04:06:34,181 --> 04:06:35,750
ABOUT THEIR RISK FOR VARIOUS

6304
04:06:35,750 --> 04:06:36,751
DISEASES AND THEN SPECIFICALLY

6305
04:06:36,751 --> 04:06:38,719
IN THE CASE OF FRAMINGHAM, WE

6306
04:06:38,719 --> 04:06:39,854
COLLECTED REPROGRAMMABLE BLOOD

6307
04:06:39,854 --> 04:06:42,023
CELLS ON THE ENTIRE EXISTING

6308
04:06:42,023 --> 04:06:44,358
COHORT SO WE HAVE THE PRECURSOR

6309
04:06:44,358 --> 04:06:46,294
CELLS TO MAKE THE IPSC CELLS IF

6310
04:06:46,294 --> 04:06:49,030
WE WANT TO ON OVER 6500

6311
04:06:49,030 --> 04:06:50,064
FRAMINGHAM PARTICIPANTS AND YOU

6312
04:06:50,064 --> 04:06:50,998
CAN ALSO IMAGINE COLLECTING

6313
04:06:50,998 --> 04:06:52,566
OTHER TISSUES FROM THOSE

6314
04:06:52,566 --> 04:06:53,567
PARTICIPANTS, AND I THINK YOU

6315
04:06:53,567 --> 04:06:55,102
COULD SIMILARLY APLAY THAT

6316
04:06:55,102 --> 04:06:56,437
PARADIGM TO THE LUNG HEALTH

6317
04:06:56,437 --> 04:06:58,606
STUDY, FOR INSTANCE, THAT'S

6318
04:06:58,606 --> 04:07:00,207
CURRENTLY ENROLLING OR TO OTHER

6319
04:07:00,207 --> 04:07:01,242
LONGITUDAL COHORT THAT WOULD

6320
04:07:01,242 --> 04:07:03,678
ALLOW YOU TO IDENTIFY THESE

6321
04:07:03,678 --> 04:07:06,814
EXTREME -- LIKE SUSAN MENTIONS.

6322
04:07:06,814 --> 04:07:09,850
>> THIS IDEA, ANDREW,
OBVIOUSLY

6323
04:07:09,850 --> 04:07:11,485
WE WERE EMAILING ABOUT THIS

6324
04:07:11,485 --> 04:07:12,586
EARLIER THIS WEEK SO IT'S

6325
04:07:12,586 --> 04:07:14,455
TIMELY, THIS IDEA OF TAKING

6326
04:07:14,455 --> 04:07:16,457
ADVANTAGE OF THE

6327
04:07:16,457 --> 04:07:18,659
POPULATION-BASED COHORTS, THE

6328
04:07:18,659 --> 04:07:22,930
EPI STUDIES LIKE FRAMINGHAM OR

6329
04:07:22,930 --> 04:07:23,831
CARDIA, NOT JUST BECAUSE I WORK

6330
04:07:23,831 --> 04:07:25,599
WITH IT BUT BECAUSE IT'S

6331
04:07:25,599 --> 04:07:26,367
ACTUALLY A GOOD EXAMPLE, BUT

6332
04:07:26,367 --> 04:07:31,405
WHERE WE COULD CREATE IPSC

6333
04:07:31,405 --> 04:07:32,306
LIBRARIES FROM INDIVIDUAL

6334
04:07:32,306 --> 04:07:37,111
PEOPLE, RIGHT, WHO WE KNOW THEIR

6335
04:07:37,111 --> 04:07:37,912
LIFECOURSE ALREADY.

6336
04:07:37,912 --> 04:07:40,548
IT DOES AFFORD A HUGE

6337
04:07:40,548 --> 04:07:42,049
OPPORTUNITY, I THINK, TO

6338
04:07:42,049 --> 04:07:43,584
UNDERSTAND THESE MECHANISMS AND

6339
04:07:43,584 --> 04:07:47,388
LINK THEM BACK TO SORT OF WHAT

6340
04:07:47,388 --> 04:07:48,322
WE ALREADY KNOW ABOUT THE

6341
04:07:48,322 --> 04:07:49,156
LIFECOURSE OF THESE INDIVIDUALS

6342
04:07:49,156 --> 04:07:51,992
AND SORT OF THE AIRWAY CELLS AND

6343
04:07:51,992 --> 04:07:53,394
THE ALVEOLAR CELLS AND SORT OF

6344
04:07:53,394 --> 04:07:56,430
ALL THESE THINGS, IT SEEMS LIKE

6345
04:07:56,430 --> 04:07:58,499
A VERY, VERY COMPELLING

6346
04:07:58,499 --> 04:08:00,935
OPPORTUNITY TO ME.

6347
04:08:00,935 --> 04:08:03,304
>> JUST TO ELABORATE A
TINY BIT

6348
04:08:03,304 --> 04:08:04,438
FURTHER, YOU CAN FIND

6349
04:08:04,438 --> 04:08:06,040
INDIVIDUALS WITHIN FRAMINGHAM,

6350
04:08:06,040 --> 04:08:07,942
FOR EXAMPLE, WHO HAVE 30 PACK A

6351
04:08:07,942 --> 04:08:09,610
YEAR HISTORY OF SMOKING AND HAVE

6352
04:08:09,610 --> 04:08:11,445
NORMAL PFTs AND DON'T HAVE

6353
04:08:11,445 --> 04:08:13,114
SIGNIFICANT EMPHYSEMA ON A CT

6354
04:08:13,114 --> 04:08:14,815
SCAN SO I WOULD HYPOTHESIZE

6355
04:08:14,815 --> 04:08:18,185
THOSE WOULD BE THE GENETICALLY

6356
04:08:18,185 --> 04:08:19,286
RESILIENT INDIVIDUALS WHO CAN

6357
04:08:19,286 --> 04:08:20,755
UNDERGO THESE ENORMOUS EXPOSURES

6358
04:08:20,755 --> 04:08:22,189
AND NOT DEVELOP DISEASE.

6359
04:08:22,189 --> 04:08:24,024
>> AND IMPORTANTLY IN
FRAMINGHAM

6360
04:08:24,024 --> 04:08:25,893
AND CARDIA, IT'S NOT JUST

6361
04:08:25,893 --> 04:08:27,528
DEVELOPING EMPHYSEMA.

6362
04:08:27,528 --> 04:08:29,363
WITH CT TECHNOLOGY WE CAN

6363
04:08:29,363 --> 04:08:32,933
MEASURE EVEN INTERMEDIATE --

6364
04:08:32,933 --> 04:08:34,869
WHAT LOOKS LIKE INJURED LUNG AND

6365
04:08:34,869 --> 04:08:36,170
FIVE YEARS LATER, IT'S PRISTINE

6366
04:08:36,170 --> 04:08:36,470
AGAIN.

6367
04:08:36,470 --> 04:08:37,538
I THINK THESE ARE REALLY

6368
04:08:37,538 --> 04:08:38,572
IMPORTANT THINGS TO CONSIDER.

6369
04:08:38,572 --> 04:08:40,941
>> I WOULD LIKE TO
ACTUALLY -- I

6370
04:08:40,941 --> 04:08:44,345
FIND THIS VERY, VERY, VERY

6371
04:08:44,345 --> 04:08:46,414
IMPORTANT, RAVI, WHAT YOU HAVE

6372
04:08:46,414 --> 04:08:48,616
ACTUALLY MENTIONED, AS A WAY TO

6373
04:08:48,616 --> 04:08:51,318
APPROACH THIS QUESTION, WHICH IS

6374
04:08:51,318 --> 04:08:52,253
VERY DIFFICULT AS I HAVE

6375
04:08:52,253 --> 04:08:52,787
MENTIONED.

6376
04:08:52,787 --> 04:08:53,988
NOW I WOULD LIKE TO INTRODUCE

6377
04:08:53,988 --> 04:08:58,058
ANOTHER QUESTION THATS IS R. IT-

6378
04:08:58,058 --> 04:08:59,326
WHEN YOU TALK ABOUT RESILL

6379
04:08:59,326 --> 04:09:01,695
YERNTION THIS IS A LUNG

6380
04:09:01,695 --> 04:09:03,898
WORKSHOP, BUT IS RESILIENCE THE

6381
04:09:03,898 --> 04:09:06,333
SAME IN ALL ORGANS OF AN

6382
04:09:06,333 --> 04:09:06,634
INDIVIDUAL?

6383
04:09:06,634 --> 04:09:09,770
SO HERE WE CAN ACTUALLY HAVE

6384
04:09:09,770 --> 04:09:11,939
SOMETHING THAT IT IS -- WOW,

6385
04:09:11,939 --> 04:09:14,608
THIS PERSON LIVED FOR 103 YEARS

6386
04:09:14,608 --> 04:09:18,879
OLD OR 90-SOMETHING, IS THIS A

6387
04:09:18,879 --> 04:09:20,080
CONJUNCTION OF THINGS, IN FACT,

6388
04:09:20,080 --> 04:09:26,253
THAT WHAT WE HAVE IS A

6389
04:09:26,253 --> 04:09:27,555
RESILIENCE OF EACH INDIVIDUAL

6390
04:09:27,555 --> 04:09:30,391
ORGAN ALL TOGETHER OR IS THERE

6391
04:09:30,391 --> 04:09:32,059
SOMETHING THAT BIASED US

6392
04:09:32,059 --> 04:09:34,595
TOWARDS -- AGAIN, PERHAPS THE

6393
04:09:34,595 --> 04:09:35,996
IPSC AS AN APPROACH TO GO OVER

6394
04:09:35,996 --> 04:09:39,099
THIS IS AN INTERESTING ONE,

6395
04:09:39,099 --> 04:09:41,502
BECAUSE IT WOULD DEPEND ON YOU

6396
04:09:41,502 --> 04:09:48,342
OF COURSE DERIVE ALL OF THESE

6397
04:09:48,342 --> 04:09:51,712
DIFFERENT -- FROM HIM OR HER.

6398
04:09:51,712 --> 04:09:53,347
>> I THINK THAT'S A VERY

6399
04:09:53,347 --> 04:09:54,014
INTERESTING POINT THAT YOU'RE

6400
04:09:54,014 --> 04:09:54,548
RAISING.

6401
04:09:54,548 --> 04:09:56,217
THE OTHER THING THAT COMES TO

6402
04:09:56,217 --> 04:09:58,085
MIND IS OF COURSE PRIMARY

6403
04:09:58,085 --> 04:10:00,821
CELL-BASED MODELING RELATIVE TO

6404
04:10:00,821 --> 04:10:03,791
IPS, I MEAN, VERY DIFFERENT

6405
04:10:03,791 --> 04:10:05,459
CHALLENGE BUT ONE COULD ALSO

6406
04:10:05,459 --> 04:10:07,428
IMAGINE THAT THE LIFE HISTORY OF

6407
04:10:07,428 --> 04:10:09,530
ENVIRONMENTAL EXPOSURES, NOW WE

6408
04:10:09,530 --> 04:10:10,631
HAVE OVER THE PAST FOUR OR FIVE

6409
04:10:10,631 --> 04:10:12,366
YEARS INDIVIDUALS WILL BE

6410
04:10:12,366 --> 04:10:13,901
RECOVERING FROM VERY SEVERE

6411
04:10:13,901 --> 04:10:17,004
COVID INFECTIONS IN A WAY THAT

6412
04:10:17,004 --> 04:10:19,940
PERHAPS OTHER RESPIRATORY

6413
04:10:19,940 --> 04:10:21,308
VIRAL -- IS THIS GENETICS, YOU

6414
04:10:21,308 --> 04:10:22,610
KNOW, OR IS THIS IS NOT?

6415
04:10:22,610 --> 04:10:26,514
WE UNDERSTAND NOW, FOR EXAMPLE,

6416
04:10:26,514 --> 04:10:28,349
IT'S SUCH A HARD EXAMPLE TO WRAP

6417
04:10:28,349 --> 04:10:29,817
MY MIND AROUND BUT YOU WOULD

6418
04:10:29,817 --> 04:10:31,418
THINK HIGH LEVELS OF ACE 2 IS A

6419
04:10:31,418 --> 04:10:32,953
GOOD THING BECAUSE IT'S

6420
04:10:32,953 --> 04:10:33,621
TISSUE-PROTECTIVE IN STERILE

6421
04:10:33,621 --> 04:10:34,421
LUNG INJURY.

6422
04:10:34,421 --> 04:10:36,490
IT'S TISSUE-PROTECTIVE IN FLU

6423
04:10:36,490 --> 04:10:37,992
INFECTION.

6424
04:10:37,992 --> 04:10:39,026
HOWEVER, THIS MAY NOT BE THE

6425
04:10:39,026 --> 04:10:42,563
BEST THING IN TERMS OF

6426
04:10:42,563 --> 04:10:44,231
SARS-COV-2 AND COVID-19, SO I

6427
04:10:44,231 --> 04:10:44,999
THINK THAT, DAVID, YOU WERE THE

6428
04:10:44,999 --> 04:10:45,966
ONE WHO I THINK MENTIONED

6429
04:10:45,966 --> 04:10:47,501
SOMETHING ABOUT CONTEXT

6430
04:10:47,501 --> 04:10:50,704
DEPENDENCY OF RESILIENCY AND THE

6431
04:10:50,704 --> 04:10:53,007
THINK CHERRY PICKING ONE GENE

6432
04:10:53,007 --> 04:10:54,208
AND ONE TISSUE, HERE'S ONE

6433
04:10:54,208 --> 04:10:55,309
EXAMPLE WHERE IT COULD GO

6434
04:10:55,309 --> 04:10:58,979
MULTIPLE WAYS.

6435
04:10:58,979 --> 04:11:00,447
BUT THE THINK THE IDEA OF THE

6436
04:11:00,447 --> 04:11:04,952
I.IPSC KIND OF BIOBANK APPROACHS

6437
04:11:04,952 --> 04:11:06,487
IS QUITE INTERESTING TO GET AT

6438
04:11:06,487 --> 04:11:07,588
THE HEART OF SOME OF THESE

6439
04:11:07,588 --> 04:11:08,889
GENETICALLY GROUNDED IDEAS, BUT

6440
04:11:08,889 --> 04:11:09,857
BRINGING IN THE ENVIRONMENT IS

6441
04:11:09,857 --> 04:11:13,427
ALWAYS THE TENSION THERE.

6442
04:11:13,427 --> 04:11:14,995
>> JUST TO BUILD ON WHAT
YOU

6443
04:11:14,995 --> 04:11:17,031
SAID, I THINK WE KNOW QUITE A

6444
04:11:17,031 --> 04:11:18,899
BIT ABOUT THE GENETICS OF

6445
04:11:18,899 --> 04:11:21,635
DISEASE.

6446
04:11:21,635 --> 04:11:22,770
WE DON'T KNOW NEARLY ENOUGH

6447
04:11:22,770 --> 04:11:24,004
ABOUT THE GENETICS OF

6448
04:11:24,004 --> 04:11:25,272
ENVIRONMENTAL SUSCEPTIBILITY.

6449
04:11:25,272 --> 04:11:27,408
AND WHEN YOU THINK ABOUT HOW

6450
04:11:27,408 --> 04:11:30,778
THAT RELATES TO RESILIENCE, IT'S

6451
04:11:30,778 --> 04:11:34,915
ABSOLUTELY CRITICAL.

6452
04:11:34,915 --> 04:11:37,484
AND SO I THINK THAT'S AN AREA

6453
04:11:37,484 --> 04:11:42,089
THAT REALLY DESERVES A LOT MORE

6454
04:11:42,089 --> 04:11:42,990
EMPHASIS OVER THE NEXT SEVERAL

6455
04:11:42,990 --> 04:11:49,964
YEARS TO FIGURE OUT WHAT MAKES

6456
04:11:49,964 --> 04:11:54,735
THOSE INDIVIDUALS RESILIENT TO

6457
04:11:54,735 --> 04:11:56,704
ENVIRONMENTAL STRESS, OR THE

6458
04:11:56,704 --> 04:11:58,906
FLIP SIDE IS WHY ARE SOME PEOPLE

6459
04:11:58,906 --> 04:12:01,809
SO SUSCEPTIBLE TO ENVIRONMENTAL

6460
04:12:01,809 --> 04:12:02,810
STRESS.

6461
04:12:02,810 --> 04:12:04,878
SEPARATE FROM DISEASE.

6462
04:12:04,878 --> 04:12:07,514
SEPARATE FROM DEVELOPMENTAL

6463
04:12:07,514 --> 04:12:08,449
DISEASE.

6464
04:12:08,449 --> 04:12:09,984
>> AND THIS IS ACTUALLY --
I

6465
04:12:09,984 --> 04:12:12,553
WANT TO CHIME IN, IS THAT MAYBE

6466
04:12:12,553 --> 04:12:17,391
NEURON PLAY A ROLE IN THIS

6467
04:12:17,391 --> 04:12:22,396
ADAPTATION COULD SOME WAY IN THE

6468
04:12:22,396 --> 04:12:23,864
FUTURE WOULD DEVELOP TOOLS TO

6469
04:12:23,864 --> 04:12:25,833
JUST STIMULATE THE CERTAIN TYPE

6470
04:12:25,833 --> 04:12:27,901
OF NEURONS IN VAGUS NERVE TO

6471
04:12:27,901 --> 04:12:32,272
TREAT, FOR EXAMPLE, ASTHMAS OR

6472
04:12:32,272 --> 04:12:36,243
EVEN PROMOTE -- BECAUSE IN THE

6473
04:12:36,243 --> 04:12:37,711
VEGAS NERVE THERE'S SO MANY

6474
04:12:37,711 --> 04:12:42,116
NEURONS BUT IF WE COMBINE WITH

6475
04:12:42,116 --> 04:12:45,152
SINGLE CELL -- IDENTIFY

6476
04:12:45,152 --> 04:12:49,623
INDIVIDUAL NEURONS AND THEN

6477
04:12:49,623 --> 04:12:50,824
INTERFERE CERTAIN TYPES OF

6478
04:12:50,824 --> 04:12:52,126
NEURONS FOR TREATMENT AND ALSO

6479
04:12:52,126 --> 04:12:54,595
FOR ADAPTATIONS, AND I THINK

6480
04:12:54,595 --> 04:12:56,497
THAT WOULD IMPROVE RESILIENCE

6481
04:12:56,497 --> 04:12:57,564
FOR HUMANS AS WELL IN THE

6482
04:12:57,564 --> 04:13:05,506
FUTURE.

6483
04:13:05,506 --> 04:13:07,508
>> I JUST WANT TO TAKE A
MINUTE

6484
04:13:07,508 --> 04:13:08,575
TO CHIME IN ABOUT THE VALUE OF

6485
04:13:08,575 --> 04:13:11,178
USING THE FULL EXTENT OF THE

6486
04:13:11,178 --> 04:13:13,247
LIFECOURSE FOR THESE SORTS OF

6487
04:13:13,247 --> 04:13:15,949
STUDIES, BECAUSE WE'RE FACED IN

6488
04:13:15,949 --> 04:13:18,285
THE NEONATAL INTENSIVE CARE UNIT

6489
04:13:18,285 --> 04:13:24,491
WITH A DELLS OF PAT OODLES OF PT

6490
04:13:24,491 --> 04:13:25,993
UNDERGO THE SAME ENVIRONMENTAL

6491
04:13:25,993 --> 04:13:26,960
EXPOSURES AND YET HAVE VERY

6492
04:13:26,960 --> 04:13:30,364
DIFFERENT OUTCOMES THAT ALSO

6493
04:13:30,364 --> 04:13:31,432
IMPAIRED THEIR ABILITY TO

6494
04:13:31,432 --> 04:13:34,034
ACHIEVE MAXIMUM LUNG GROWTH

6495
04:13:34,034 --> 04:13:35,803
POTENTIAL.

6496
04:13:35,803 --> 04:13:37,738
AND I THINK DOING SOME OF THESE

6497
04:13:37,738 --> 04:13:39,606
STUDIES IN THOSE POPULATIONS IS

6498
04:13:39,606 --> 04:13:45,145
CRITICAL.

6499
04:13:45,145 --> 04:13:48,315
>> PICKING OUT THE
POPULATIONS

6500
04:13:48,315 --> 04:13:51,218
WHERE YOU HAVE THOSE EXTREME

6501
04:13:51,218 --> 04:13:52,519
EXPOSURES IS A GREAT WAY OF

6502
04:13:52,519 --> 04:14:02,796
DOING THE WORK.

6503
04:14:04,531 --> 04:14:07,134
>> I THINK ONE CHALLENGE
THAT

6504
04:14:07,134 --> 04:14:09,803
CAME TO MIND IS THIS QUESTION OF

6505
04:14:09,803 --> 04:14:13,474
HOW REGIONALIZED SOME OF THESE

6506
04:14:13,474 --> 04:14:14,508
RESPONSES ARE.

6507
04:14:14,508 --> 04:14:18,078
WE SAW SOME VERY BEAUTIFUL

6508
04:14:18,078 --> 04:14:20,514
IMAGES EITHER OF JUST ONE

6509
04:14:20,514 --> 04:14:24,985
EPITHELIAL LAYER AND ALVEOLUS,

6510
04:14:24,985 --> 04:14:26,687
CLUSTER OF DIFFERENT ALVEOLI,

6511
04:14:26,687 --> 04:14:29,523
THE WHOLE LUNG, AND THERE'S

6512
04:14:29,523 --> 04:14:30,124
REGIONALITY IN ALL OF THE

6513
04:14:30,124 --> 04:14:31,191
DIFFERENT RESPONSES.

6514
04:14:31,191 --> 04:14:32,392
THERE'S EVEN SOME AREAS OF THE

6515
04:14:32,392 --> 04:14:35,996
LUNG AND OTHER AREAS THAT LOOK

6516
04:14:35,996 --> 04:14:37,197
TOTALLY FINE OR TWO DISEASES IN

6517
04:14:37,197 --> 04:14:39,566
THE SAME LUNG IN SOME CASES, SO

6518
04:14:39,566 --> 04:14:44,404
I'M WONDERING, GIVEN THAT'S

6519
04:14:44,404 --> 04:14:45,639
CHALLENGES, HOW DO WE THINK

6520
04:14:45,639 --> 04:14:46,740
ABOUT REGIONALITY IN TERMS OF

6521
04:14:46,740 --> 04:14:49,243
KIND OF NEXT GENERATION

6522
04:14:49,243 --> 04:14:59,486
THERAPEUTICS.

6523
04:15:03,957 --> 04:15:07,127
>> ARE YOU TALKING ABOUT
THE

6524
04:15:07,127 --> 04:15:08,796
STEM CELLS IN DIFFERENT REGIONS?

6525
04:15:08,796 --> 04:15:09,963
>> STEM CELLS IN DIFFERENT

6526
04:15:09,963 --> 04:15:12,199
REGIONS OR JUST EVEN WITHOUT

6527
04:15:12,199 --> 04:15:13,534
NECESSARILY NEEDING TO INVOKE

6528
04:15:13,534 --> 04:15:16,503
THE STEM CELLS, I THINK WE SEE

6529
04:15:16,503 --> 04:15:18,005
IN MANY OF THE DISEASES THAT

6530
04:15:18,005 --> 04:15:19,406
THERE'S CERTAIN AREAS OF THE

6531
04:15:19,406 --> 04:15:20,908
LUNG THAT WILL BE QUITE HIGHLY

6532
04:15:20,908 --> 04:15:22,009
AFFECTED AND OTHER ONES WHICH

6533
04:15:22,009 --> 04:15:25,179
SEEM TO BE COMPLETELY NORMAL IN

6534
04:15:25,179 --> 04:15:28,682
TERMS OF ARCHITECTURE.

6535
04:15:28,682 --> 04:15:30,517
AND SO OBVIOUSLY THIS POSES A

6536
04:15:30,517 --> 04:15:32,219
CERTAIN CHALLENGE IN A WAY, YOU

6537
04:15:32,219 --> 04:15:34,855
KNOW, IT'S NOT LIKE THE WHOLE

6538
04:15:34,855 --> 04:15:36,423
TISSUE IS DISEASED, SOME OF IT

6539
04:15:36,423 --> 04:15:39,793
IS OKAY, SOME OF IT IS NOT, SO

6540
04:15:39,793 --> 04:15:41,962
THIS IS A CHALLENGE IN BOTH

6541
04:15:41,962 --> 04:15:42,663
UNDERSTANDING THE SYSTEM BUT

6542
04:15:42,663 --> 04:15:46,166
ALSO WHEN IT COMES TO THINKING

6543
04:15:46,166 --> 04:15:56,944
ABOUT THE THERAPEUTIC OPPORTUNI.

6544
04:15:58,278 --> 04:15:59,279
CARLA, DID YOU WANT TO MENTION

6545
04:15:59,279 --> 04:15:59,546
SOMETHING?

6546
04:15:59,546 --> 04:16:01,014
>> YES, THANK YOU.

6547
04:16:01,014 --> 04:16:01,748
THIS IS CARLA KIM.

6548
04:16:01,748 --> 04:16:03,317
FIRST THANK YOU ALL FOR

6549
04:16:03,317 --> 04:16:05,919
ORGANIZING THIS AND IT'S A

6550
04:16:05,919 --> 04:16:07,821
PLEASURE TO BE INCLUDED.

6551
04:16:07,821 --> 04:16:11,425
I WAS WANTING TO POTENTIALLY

6552
04:16:11,425 --> 04:16:14,261
HAVE US THINKING ABOUT SYSTEMIC

6553
04:16:14,261 --> 04:16:15,562
INFLUENCES AND MAYBE A LITTLE AT

6554
04:16:15,562 --> 04:16:19,533
WHAT YOU'RE TOUCHING ON OF HOW

6555
04:16:19,533 --> 04:16:21,034
MEASURING CHANGES IN ONE PART OF

6556
04:16:21,034 --> 04:16:22,536
THE PULMONARY SYSTEM COULD BE

6557
04:16:22,536 --> 04:16:25,372
REFLECTIVE OF OTHER CHANGES.

6558
04:16:25,372 --> 04:16:29,009
WE'VE BEEN STUDYING HOW AIRWAY

6559
04:16:29,009 --> 04:16:30,477
INJURY IMPACTS THE ALVEOLAR

6560
04:16:30,477 --> 04:16:33,046
CELLS AND HOW THAT COULD BE

6561
04:16:33,046 --> 04:16:34,548
MEDIATED THROUGH IMMUNE CELL

6562
04:16:34,548 --> 04:16:34,848
SIGNALING.

6563
04:16:34,848 --> 04:16:38,652
SO I WAS THINKING ABOUT THIS

6564
04:16:38,652 --> 04:16:40,487
YESTERDAY, MAYBE IT WAS EARLIER

6565
04:16:40,487 --> 04:16:43,290
TODAY WHEN DR. GOCHE WAS TALKING

6566
04:16:43,290 --> 04:16:44,958
ABOUT CAN THE NASAL CELLS TELL

6567
04:16:44,958 --> 04:16:46,827
US WHAT'S GOING ON DEEPER IN THE

6568
04:16:46,827 --> 04:16:48,028
LUNG.

6569
04:16:48,028 --> 04:16:49,563
WE DON'T KNOW MUCH ABOUT THAT.

6570
04:16:49,563 --> 04:16:51,298
SO THE KIND OF STUDIES WHERE WE

6571
04:16:51,298 --> 04:16:54,434
CAN PURPOSELY COMPARE CELLS FROM

6572
04:16:54,434 --> 04:16:55,936
DIFFERENT REGIONS, FROM THE SAME

6573
04:16:55,936 --> 04:16:59,873
PERSON OR SYSTEM, AND GET A

6574
04:16:59,873 --> 04:17:01,842
HANDLE ON A MUCH BROADER SCALE

6575
04:17:01,842 --> 04:17:05,512
OF WHAT ARE THE CHANGES GOING

6576
04:17:05,512 --> 04:17:06,747
ON.

6577
04:17:06,747 --> 04:17:09,449
THAT COULD REVEAL OPPORTUNITIES

6578
04:17:09,449 --> 04:17:12,119
WHERE -- FOR DETECTION AND ALSO

6579
04:17:12,119 --> 04:17:14,554
FOR TREATMENT.

6580
04:17:14,554 --> 04:17:17,591
I'M ALSO SITTING HERE AT AN

6581
04:17:17,591 --> 04:17:20,627
EARLY STAGE LUNG CANCER

6582
04:17:20,627 --> 04:17:21,762
DETECTION CONFERENCE, AND I

6583
04:17:21,762 --> 04:17:26,433
THINK THERE'S A LOT OF ROOM

6584
04:17:26,433 --> 04:17:28,769
WHERE OUR FIELD, YOU KNOW, OFTEN

6585
04:17:28,769 --> 04:17:31,939
THROUGH FUNDING MECHANISMS WE

6586
04:17:31,939 --> 04:17:33,807
DON'T HAVE A PROJECT THAT

6587
04:17:33,807 --> 04:17:36,376
INVOLVES CANCER WHEN IT'S NHLBI,

6588
04:17:36,376 --> 04:17:38,979
BUT I THINK THERE'S A LOT OF

6589
04:17:38,979 --> 04:17:40,080
PRECANCEROUS SITUATIONS THAT

6590
04:17:40,080 --> 04:17:43,717
WE'RE ALL VERY CURIOUS OF HOW

6591
04:17:43,717 --> 04:17:47,020
MUTATION OR EXPOSURE MIGHT ALTER

6592
04:17:47,020 --> 04:17:47,788
SUSCEPTIBILITY FOR A LUNG

6593
04:17:47,788 --> 04:17:52,726
DISEASE OR LUNG HEALTH AGING

6594
04:17:52,726 --> 04:17:54,661
THAT PERHAPS IS POTENTIALLY

6595
04:17:54,661 --> 04:17:56,496
GOING ALONG WITH PRECANCEROUS

6596
04:17:56,496 --> 04:17:57,431
CONDITIONS.

6597
04:17:57,431 --> 04:17:59,666
SO MAYBE WAYS OF CONNECTING

6598
04:17:59,666 --> 04:18:04,705
ACROSS AGENCIES ALSO, SUCH AS A

6599
04:18:04,705 --> 04:18:07,274
JOINT EFFORT BETWEEN NIA, NCI

6600
04:18:07,274 --> 04:18:11,511
AND NHLBI SO WE CAN ASK SOME OF

6601
04:18:11,511 --> 04:18:12,379
THESE TYPES OF QUESTIONS.

6602
04:18:12,379 --> 04:18:13,880
SO THAT WAS A LOT, BUT JUST SOME

6603
04:18:13,880 --> 04:18:24,157
THOUGHTS THERE.

6604
04:18:25,225 --> 04:18:27,394
>> THIS IS MOUMITA.

6605
04:18:27,394 --> 04:18:29,396
I THINK CARLA WAS JUST TALKING

6606
04:18:29,396 --> 04:18:32,399
ABOUT THE PRESENTATION THAT I

6607
04:18:32,399 --> 04:18:34,034
DID YESTERDAY, AND WE DO SATISFY

6608
04:18:34,034 --> 04:18:35,702
UPPER AIRWAY PROGENITORS

6609
04:18:35,702 --> 04:18:41,074
ACTUALLY CORRELATED WITH BOTH

6610
04:18:41,074 --> 04:18:42,342
LUNG FUNCTION DECLINE AND

6611
04:18:42,342 --> 04:18:42,843
DIFFUSION ISSUE.

6612
04:18:42,843 --> 04:18:49,616
WE DO SEE THAT SAME WITH NASAL

6613
04:18:49,616 --> 04:18:50,584
BRUSHINGS, SO ARE THESE FOR

6614
04:18:50,584 --> 04:18:52,652
IMMUNE CELLS, FOR SOME KIND OF

6615
04:18:52,652 --> 04:18:55,455
NEURONAL CONNECTION WE HEARD

6616
04:18:55,455 --> 04:18:56,957
TODAY, HOW ARE CELLS

6617
04:18:56,957 --> 04:18:57,657
COMMUNICATING.

6618
04:18:57,657 --> 04:19:00,127
WE KNOW THAT THERE ARE REGIONAL

6619
04:19:00,127 --> 04:19:01,228
PROGENITORS BUT CLEARLY THERE IS

6620
04:19:01,228 --> 04:19:03,196
SOME KIND OF A UNIFIED THEME.

6621
04:19:03,196 --> 04:19:05,665
COULD THAT BE THAT THIS

6622
04:19:05,665 --> 04:19:06,933
COMMUNICATION IS VIA IMMUNE

6623
04:19:06,933 --> 04:19:08,735
SYSTEM, COULD THAT BE VIA SOME

6624
04:19:08,735 --> 04:19:11,571
KIND OF COMMUNICATION WITH

6625
04:19:11,571 --> 04:19:12,806
NEURON SYSTEM?

6626
04:19:12,806 --> 04:19:20,180
AND I CANNOT, LIKE, YOU KNOW, --

6627
04:19:20,180 --> 04:19:20,814
PREMALIGNANCY, PRECANCER

6628
04:19:20,814 --> 04:19:22,249
STANDPOINT BECAUSE WHEN WE FIRST

6629
04:19:22,249 --> 04:19:23,183
STARTED LOOKING AT IT, THAT

6630
04:19:23,183 --> 04:19:25,419
PRETTY MUCH THE PREMALIGNANCY

6631
04:19:25,419 --> 04:19:27,988
POPULATION IS ABOUT 30 TO 40% OF

6632
04:19:27,988 --> 04:19:30,190
PEOPLE ALREADY HAVE COPD.

6633
04:19:30,190 --> 04:19:31,525
THEY'RE HEAVY SMOKERS.

6634
04:19:31,525 --> 04:19:32,859
ALSO WE FOUND PEOPLE, THEY ARE

6635
04:19:32,859 --> 04:19:35,829
LIKE IN THEIR 70s, WITH

6636
04:19:35,829 --> 04:19:37,030
HUNDRED PACK YEARS SMOKING

6637
04:19:37,030 --> 04:19:38,065
HISTORY, BUT THEY DON'T HAVE

6638
04:19:38,065 --> 04:19:38,999
COPD.

6639
04:19:38,999 --> 04:19:43,136
THEY MAY HAVE THAT PRE-COPD

6640
04:19:43,136 --> 04:19:47,908
PHENOTYPE WHICH HAS -- WHICH

6641
04:19:47,908 --> 04:19:49,042
DOESN'T EXIST ANYMORE SO YES,

6642
04:19:49,042 --> 04:19:50,877
THEY COULD BE AT RISK, BUT AT

6643
04:19:50,877 --> 04:19:53,647
THIS POINT THEY'RE REALLY A

6644
04:19:53,647 --> 04:19:55,215
RESILIENT POPULATION RATHER THAN

6645
04:19:55,215 --> 04:19:56,716
A SUSCEPTIBLE POPULATION.

6646
04:19:56,716 --> 04:19:59,519
SO HOW ARE THEY DIFFERENT WITH A

6647
04:19:59,519 --> 04:20:01,822
45-YEAR-OLD HAVING MUCH LESS

6648
04:20:01,822 --> 04:20:08,195
SMOKING HISTORY WITH LOW

6649
04:20:08,195 --> 04:20:08,862
NORMAL -- 76 BUT 100 PACK YEARS,

6650
04:20:08,862 --> 04:20:10,397
SO THE HETEROGENEITY BETWEEN

6651
04:20:10,397 --> 04:20:12,933
PATIENTS IS JUST SO DIVERSE,

6652
04:20:12,933 --> 04:20:15,268
THAT IT'S HARD TO MODULATE.

6653
04:20:15,268 --> 04:20:20,240
LIKE ANY MODEL SYSTEM, UNLESS WE

6654
04:20:20,240 --> 04:20:22,642
GO AND TRY TO MAKE IPC THAT WE

6655
04:20:22,642 --> 04:20:33,053
WERE DISCUSSING BEFORE.

6656
04:20:36,089 --> 04:20:37,424
>> DANIEL, WOULD YOU LIKE
TO

6657
04:20:37,424 --> 04:20:39,726
ADD?

6658
04:20:39,726 --> 04:20:44,197
>> SO THIS IS JUST A
FASCINATING

6659
04:20:44,197 --> 04:20:44,731
DISCUSSION.

6660
04:20:44,731 --> 04:20:46,066
BUT I WANTED TO GO BACK AND HAY

6661
04:20:46,066 --> 04:20:47,634
LIGHT SOMETHING ABOUT THE

6662
04:20:47,634 --> 04:20:49,503
ENVIRONMENT.

6663
04:20:49,503 --> 04:20:51,238
BECAUSE IF WE'RE TRYING TO STUDY

6664
04:20:51,238 --> 04:20:54,541
THE BEHAVIOR OF ANY GIVEN

6665
04:20:54,541 --> 04:21:01,081
PROGENITOR CELL, ITS HOME IS

6666
04:21:01,081 --> 04:21:02,115
CRITICALLY IMPORTANT.

6667
04:21:02,115 --> 04:21:03,216
SO THIS BECOMES A QUESTION OF

6668
04:21:03,216 --> 04:21:03,984
TOOLS.

6669
04:21:03,984 --> 04:21:06,186
AND SO IF YOU'RE TRYING TO STUDY

6670
04:21:06,186 --> 04:21:08,221
SOMETHING ON ALI OR ROUTINE

6671
04:21:08,221 --> 04:21:12,058
TISSUE CULTURE OR IN A GEL, A

6672
04:21:12,058 --> 04:21:15,228
GOOD STRATEGY IS TO TRY AND

6673
04:21:15,228 --> 04:21:17,330
MIMIC AS BEST POSSIBLE WHAT THIS

6674
04:21:17,330 --> 04:21:19,232
CELL IS GOING TO SEE IN REAL

6675
04:21:19,232 --> 04:21:20,634
LIFE.

6676
04:21:20,634 --> 04:21:22,903
AND SO YOU CAN TAKE THAT AND

6677
04:21:22,903 --> 04:21:28,208
SAY, WELL, IF I HAVE BASAL

6678
04:21:28,208 --> 04:21:29,142
EPITHELIAL CELLS OR WHATEVER

6679
04:21:29,142 --> 04:21:34,247
TYPE FROM A COPD PATIENT AND TO

6680
04:21:34,247 --> 04:21:36,016
HIGHLIGHT WHAT WAS SAID FOR

6681
04:21:36,016 --> 04:21:37,217
MULTIPLE COPD PATIENTS BECAUSE

6682
04:21:37,217 --> 04:21:39,252
YOU NEED THAT INDIVIDUAL

6683
04:21:39,252 --> 04:21:42,856
HETEROGENEITY AND VARIABILITY,

6684
04:21:42,856 --> 04:21:43,957
WHO ARE YOU GOING TO CULTURE

6685
04:21:43,957 --> 04:21:46,993
THEM ON?

6686
04:21:46,993 --> 04:21:48,428
MATRI GEL OR EXTRACELLULAR

6687
04:21:48,428 --> 04:21:50,597
MATRIX DERIVED FROM A NORMAL

6688
04:21:50,597 --> 04:21:52,165
LUNG OR A LUNG WITH EMPHYSEMA?

6689
04:21:52,165 --> 04:21:53,300
WHAT PART OF THAT LUNG ARE YOU

6690
04:21:53,300 --> 04:21:54,534
GOING TO CULTURE IT ON?

6691
04:21:54,534 --> 04:21:56,169
BECAUSE THE AIRWAYS ARE

6692
04:21:56,169 --> 04:21:57,804
DIFFERENT FROM THE ALVEOLI,

6693
04:21:57,804 --> 04:21:59,072
DIFFERENT FROM THE VASCULATURE.

6694
04:21:59,072 --> 04:22:02,042
THEY HAVE DIFFERENT MATRIX

6695
04:22:02,042 --> 04:22:08,548
PROTEIN COMPOSITION, DIFFERENT

6696
04:22:08,548 --> 04:22:10,116
GLYCO -- MATRIX ASSOCIATED

6697
04:22:10,116 --> 04:22:10,951
GROWTH FACTOR AND SO ON.

6698
04:22:10,951 --> 04:22:12,452
THIS ISN'T REALLY THAT DIFFICULT

6699
04:22:12,452 --> 04:22:16,156
A CONCEPT, BUT IF WE CAN

6700
04:22:16,156 --> 04:22:16,790
INCORPORATE THAT TYPE OF

6701
04:22:16,790 --> 04:22:19,459
THINKING INTO THE TOOLS THAT WE

6702
04:22:19,459 --> 04:22:24,998
UTILIZE, AND THEN YOU CAN GET

6703
04:22:24,998 --> 04:22:27,033
MORE USEFUL INFORMATION, THROW

6704
04:22:27,033 --> 04:22:31,771
IN OTHER FACTORS LIKE SICKLY CYC

6705
04:22:31,771 --> 04:22:33,873
MECHANICAL STRAIGHT, SO THROWING

6706
04:22:33,873 --> 04:22:35,475
STRETCH, HAVE YOUR CALL FOR

6707
04:22:35,475 --> 04:22:36,243
SYSTEM, STRETCH SOMEHOW.

6708
04:22:36,243 --> 04:22:38,211
AND YOU CAN HAVE VERY FREQUENCY

6709
04:22:38,211 --> 04:22:40,680
AND AMPLITUDE AND MIMIC NORMAL

6710
04:22:40,680 --> 04:22:42,048
VENTILATION THAT 8 TO 12, 12 TO

6711
04:22:42,048 --> 04:22:46,286
16 BREATHS A MINUTE VERSUS A BAD

6712
04:22:46,286 --> 04:22:47,854
EMPHYSEMA, 4 TO 6 BREATHS A

6713
04:22:47,854 --> 04:22:48,888
MINUTE OR WHATEVER.

6714
04:22:48,888 --> 04:22:56,763
SO AGAIN, THINKING MORE IN A

6715
04:22:56,763 --> 04:22:58,064
GRANULAR WAY IS GOING TO BUY US

6716
04:22:58,064 --> 04:22:59,833
A LOT MORE INFORMATION AND IT

6717
04:22:59,833 --> 04:23:00,600
WILL HELP DEVICE THEN I THINK

6718
04:23:00,600 --> 04:23:04,537
MORE TARGETED STRATEGIES.

6719
04:23:04,537 --> 04:23:06,606
IF YOU HAVE A PROGENITOR CELL,

6720
04:23:06,606 --> 04:23:07,907
TAKE FRANK AND SIMILAR WORK AND

6721
04:23:07,907 --> 04:23:09,843
YOU WANT TO PUT A PROGENITOR

6722
04:23:09,843 --> 04:23:15,482
CELL INTO A LUNG WITH EMPHYSEMA

6723
04:23:15,482 --> 04:23:17,384
FOR EXAMPLE WITH THE GOAL OF

6724
04:23:17,384 --> 04:23:19,486
STRUCTURALLY REGENERATING DISTAL

6725
04:23:19,486 --> 04:23:21,755
ARRAYS AND ALVEOLI, THAT CELL

6726
04:23:21,755 --> 04:23:22,956
NEEDS TO RESPOND TO WHAT IT'S

6727
04:23:22,956 --> 04:23:25,425
GOING TO SEE IN THAT DISEASED

6728
04:23:25,425 --> 04:23:26,726
LUNG WITH EMPHYSEMA AND

6729
04:23:26,726 --> 04:23:28,628
HOPEFULLY UTILIZE THOSE CUES TO

6730
04:23:28,628 --> 04:23:33,199
DO WHAT YOU HOPE IT GOING TO DO.

6731
04:23:33,199 --> 04:23:35,835
SO WHEN YOU LOOK IN FORWARD

6732
04:23:35,835 --> 04:23:37,671
LOOKING DIRECTIONS, THIS IS, I

6733
04:23:37,671 --> 04:23:44,144
THINK, AN IMPORTANT PLATFORM.

6734
04:23:44,144 --> 04:23:47,047
>> YOU THINK THAT'S A
GREAT

6735
04:23:47,047 --> 04:23:47,447
POINT.

6736
04:23:47,447 --> 04:23:49,115
JUST FOLLOWING UP THE POINT THAT

6737
04:23:49,115 --> 04:23:51,217
WAS BROUGHT UP BY MULTIPLE

6738
04:23:51,217 --> 04:23:52,752
PEOPLE ABOUT THE GENE

6739
04:23:52,752 --> 04:23:54,821
ENVIRONMENTAL INTERACTION, THE

6740
04:23:54,821 --> 04:23:57,190
WAY I WANT TO -- ONE THING I

6741
04:23:57,190 --> 04:24:00,427
WANT TO ADD ON THAT POINT IS

6742
04:24:00,427 --> 04:24:03,330
THAT AS YOU SAID, MULTIPLE --

6743
04:24:03,330 --> 04:24:07,100
IT'S ALL ABOUT THE KIND OF THE

6744
04:24:07,100 --> 04:24:10,603
CONTEST DEPENDING ON THE STATE

6745
04:24:10,603 --> 04:24:13,506
OF YOUR LIFE AND THEN AGE AND

6746
04:24:13,506 --> 04:24:15,475
SOME CONDITIONS AND HOW YOU

6747
04:24:15,475 --> 04:24:16,810
REACT TO THE ENVIRONMENT

6748
04:24:16,810 --> 04:24:18,311
CONDITION AND THEN HOW YOU REACT

6749
04:24:18,311 --> 04:24:23,783
COULD BE ALREADY WIRED BY

6750
04:24:23,783 --> 04:24:24,684
GENETIC CONDITION THAT YOU

6751
04:24:24,684 --> 04:24:25,752
ALREADY HAVE BUT AT THE SAME

6752
04:24:25,752 --> 04:24:28,688
TIME, IT COULD BE THROUGH THE

6753
04:24:28,688 --> 04:24:29,789
METABOLISM, BECAUSE METABOLISM

6754
04:24:29,789 --> 04:24:32,425
COULD BE SOMETHING THAT YOU --

6755
04:24:32,425 --> 04:24:35,362
LIKE REACT TO THE EXTERNAL OR

6756
04:24:35,362 --> 04:24:39,833
INTERNAL STIMULI AS SHAWN DAVIS

6757
04:24:39,833 --> 04:24:41,134
SHOWED IN HIS FIRST TALK.

6758
04:24:41,134 --> 04:24:42,335
SO LIKE PREVIOUSLY PEOPLE

6759
04:24:42,335 --> 04:24:43,937
THOUGHT THAT LIKE A

6760
04:24:43,937 --> 04:24:45,939
TRANSCRIPTION FACTOR IE GENE

6761
04:24:45,939 --> 04:24:48,341
CONTROLLED THE M METABOLISM AND

6762
04:24:48,341 --> 04:24:50,343
DICTATE WHAT CELLS TO DO, BUT

6763
04:24:50,343 --> 04:24:52,746
THE WAY THE RECENT THEME KIND OF

6764
04:24:52,746 --> 04:24:56,649
THINKING IS THAT THE METABOLISM

6765
04:24:56,649 --> 04:24:59,152
ACTUALLY DICTATES THE

6766
04:24:59,152 --> 04:25:01,221
TRANSCRIPTION FACTORS, AND THEN

6767
04:25:01,221 --> 04:25:03,022
THE CONTROL, THE CELL BEHAVIOR.

6768
04:25:03,022 --> 04:25:05,291
SO IT KIND OF MAKES SENSE

6769
04:25:05,291 --> 04:25:07,460
BECAUSE LIKE THE METABOLISM CAN

6770
04:25:07,460 --> 04:25:08,628
BE INFLUENCED BY A LOT OF

6771
04:25:08,628 --> 04:25:12,198
EXTERNAL STIMULI, IE ENVIRONMENT

6772
04:25:12,198 --> 04:25:15,568
LIKE NUTRIENT AND STRESS AND ET

6773
04:25:15,568 --> 04:25:16,836
CETERA, AND JUST TELL THE CELL

6774
04:25:16,836 --> 04:25:17,837
THIS IS NOT THE TIME THAT YOU

6775
04:25:17,837 --> 04:25:20,473
REACT IN A CERTAIN WAY OR NOT.

6776
04:25:20,473 --> 04:25:23,443
AND THEN BASED ON THAT CELL

6777
04:25:23,443 --> 04:25:26,079
BEHAVES AND THEN UNTIL THOSE

6778
04:25:26,079 --> 04:25:28,114
STRESS OR EXTERNAL STIMULI KIND

6779
04:25:28,114 --> 04:25:29,315
OF SETTLE DOWN, THAT'S SORT OF

6780
04:25:29,315 --> 04:25:31,050
LIKE A CHECK-IN POINT, AND THE

6781
04:25:31,050 --> 04:25:33,686
SAME WAY, THAT'S HOW I ALSO

6782
04:25:33,686 --> 04:25:38,024
THINK ABOUT THE STRESS RESPONSE.

6783
04:25:38,024 --> 04:25:40,727
LIKE THE CHANGES.

6784
04:25:40,727 --> 04:25:41,995
THE CELLS HAVE TO HAVE A

6785
04:25:41,995 --> 04:25:45,765
CHECKPOINT BEFORE YOU COMMIT IT

6786
04:25:45,765 --> 04:25:47,734
INTO CERTAIN CELL BEHAVIOR SUCH

6787
04:25:47,734 --> 04:25:49,202
AS PROLIFERATION, WHATEVER, AND

6788
04:25:49,202 --> 04:25:50,570
THEN YOU JUST WAIT AND MAKE SURE

6789
04:25:50,570 --> 04:25:54,274
THAT YOU HAVE ALL THE CONDITION

6790
04:25:54,274 --> 04:25:55,809
APPROPRIATELY OR AT LEAST IN

6791
04:25:55,809 --> 04:25:58,344
CERTAIN CONTEXTS, THAT SHOULD --

6792
04:25:58,344 --> 04:26:03,550
WHATEVER THE APPROPRIATE

6793
04:26:03,550 --> 04:26:04,584
RESPONSE THAT THE CELL IS

6794
04:26:04,584 --> 04:26:04,951
COMMITTED.

6795
04:26:04,951 --> 04:26:06,986
AND UNTIL THOSE SETTLE DOWN,

6796
04:26:06,986 --> 04:26:11,991
THEN YOU JUST COMMITTED IN THE

6797
04:26:11,991 --> 04:26:12,525
RIGHT PATHWAY.

6798
04:26:12,525 --> 04:26:14,127
SO FROM THAT ASPECT, I THINK THE

6799
04:26:14,127 --> 04:26:15,829
ONE THING THAT WE NEED TO THINK

6800
04:26:15,829 --> 04:26:18,998
ABOUT IS THAT WE HAVE A VERY

6801
04:26:18,998 --> 04:26:23,203
WONDERFUL, VERY -- 3D CULTURE

6802
04:26:23,203 --> 04:26:25,672
SYSTEM AND A LOT OF -- VERY

6803
04:26:25,672 --> 04:26:26,840
VALUABLE IN VITRO SYSTEM, BUT AS

6804
04:26:26,840 --> 04:26:29,242
WE LEARN FROM THE CANCER

6805
04:26:29,242 --> 04:26:31,077
METABOLISM FIELD, THE INDIVIDUAL

6806
04:26:31,077 --> 04:26:32,979
METABOLISM IS VERY DIFFERENT

6807
04:26:32,979 --> 04:26:33,847
FROM IN VIVO METABOLISM, AND

6808
04:26:33,847 --> 04:26:35,482
SOME OF THE DISCREPANCY BETWEEN

6809
04:26:35,482 --> 04:26:37,417
THE ANIMAL STUDIES VERSUS THE

6810
04:26:37,417 --> 04:26:38,518
HUMAN CLINICAL TRIAL, I'M NOT

6811
04:26:38,518 --> 04:26:42,689
SAYING THIS IS ALL BUT PARTLY

6812
04:26:42,689 --> 04:26:45,725
COMING FROM THE STUDY FINDING,

6813
04:26:45,725 --> 04:26:50,930
IN VITRO STUDY FINDING AND W WE

6814
04:26:50,930 --> 04:26:52,432
KNOW IT'S VERY DIFFERENT, SO

6815
04:26:52,432 --> 04:26:53,800
THIS IS SOMETHING THAT WE NEED

6816
04:26:53,800 --> 04:26:57,170
TO JUST KEEP IN MIND, THAT THE

6817
04:26:57,170 --> 04:26:59,105
IN VITRO METABOLISM ITSELF IS

6818
04:26:59,105 --> 04:27:01,875
VERY DIFFERENT FROM IN VIVO, AND

6819
04:27:01,875 --> 04:27:04,744
IT COULD MAKE THE CELLS BEHAVE

6820
04:27:04,744 --> 04:27:07,180
DIFFERENTLY FROM WHAT ACTUALLY

6821
04:27:07,180 --> 04:27:08,381
CELLS BEHAVE INA VERY VO, WHICH

6822
04:27:08,381 --> 04:27:10,650
WE ACTUALLY CARE ABOUT.

6823
04:27:10,650 --> 04:27:12,285
SO THAT'S JUST THE ONE THING

6824
04:27:12,285 --> 04:27:13,820
THAT I'D WANT PEOPLE TO THINK

6825
04:27:13,820 --> 04:27:17,323
ABOUT.

6826
04:27:17,323 --> 04:27:19,192
>> I THINK IT TOOK A WHILE
TO

6827
04:27:19,192 --> 04:27:20,793
LEARN THAT IN CANCER METABOLISM.

6828
04:27:20,793 --> 04:27:23,429
IT STARTED OFF AS ONE ONCOGENE,

6829
04:27:23,429 --> 04:27:24,430
ONE METABOLIC PHENOTYPE.

6830
04:27:24,430 --> 04:27:28,535
A LOT OF NICE WORK DONE EARLY IN

6831
04:27:28,535 --> 04:27:30,236
2010, MARIA BEING ONE OF THEM,

6832
04:27:30,236 --> 04:27:30,970
SHOWING YOU HAVE THE SAME

6833
04:27:30,970 --> 04:27:32,138
MUTATION IN TWO DIFFERENT PLACES

6834
04:27:32,138 --> 04:27:33,873
AND YOU HAVE COMPLETELY

6835
04:27:33,873 --> 04:27:36,376
DIFFERENT METABOLIC PHENOTYPES,

6836
04:27:36,376 --> 04:27:37,343
METABOLIC DEPENDENCIES, SO I

6837
04:27:37,343 --> 04:27:39,078
COMPLETELY AGREE, I THINK THAT

6838
04:27:39,078 --> 04:27:42,248
IS A -- METABOLISM ISN'T A

6839
04:27:42,248 --> 04:27:42,982
TWO-WAY STREET, IT'S NOT A

6840
04:27:42,982 --> 04:27:44,651
RESULT OF AN UPSTREAM SIGNALING

6841
04:27:44,651 --> 04:27:45,318
PATHWAY.

6842
04:27:45,318 --> 04:27:48,922
IT'S A RECIPROCAL PROCESS.

6843
04:27:48,922 --> 04:27:51,324
I HOPE THAT OUR TECHNOLOGY GETS

6844
04:27:51,324 --> 04:27:52,859
TO ANSWER SOME OF THOSE

6845
04:27:52,859 --> 04:28:03,369
QUESTIONS IN THE RIGHT MODELS.

6846
04:28:04,270 --> 04:28:05,738
>> I THINK WE CAN'T HEAR
YOU AT

6847
04:28:05,738 --> 04:28:15,748
THE MOMENT.

6848
04:28:15,748 --> 04:28:17,850
>> I WANTED TO BRING UP A
LITTLE

6849
04:28:17,850 --> 04:28:20,753
DIFFERENT TAKE ON RESILIENCE,

6850
04:28:20,753 --> 04:28:22,188
NOT A POPULATION LEVEL OR PERSON

6851
04:28:22,188 --> 04:28:23,423
LEVEL BUT AT A MOLECULAR LEVEL

6852
04:28:23,423 --> 04:28:25,058
AS TO WHERE I THINK YOU COULD

6853
04:28:25,058 --> 04:28:27,160
ARGUE FOR SOME MAYBE

6854
04:28:27,160 --> 04:28:30,129
ASPIRATIONALLY FOR HOW WE COULD

6855
04:28:30,129 --> 04:28:31,364
IMPROVE RESILIENCE.

6856
04:28:31,364 --> 04:28:34,734
ONE WOULD BE ABLE TO REGULATE

6857
04:28:34,734 --> 04:28:36,669
AND STABILIZE CONTROL AND TO

6858
04:28:36,669 --> 04:28:37,337
SOME DEGREE EP GENETIC STATES.

6859
04:28:37,337 --> 04:28:42,675
I MEAN, THE WHOLE FIELD OF

6860
04:28:42,675 --> 04:28:46,512
IPSLs IS HINGED ON THE GETTING

6861
04:28:46,512 --> 04:28:47,814
THE CELL RIGHT, BUT WE DON'T

6862
04:28:47,814 --> 04:28:49,315
REALLY CONTROL THE EPIGENETICS

6863
04:28:49,315 --> 04:28:53,152
AND IT'S SO EASY TO GO WRONG

6864
04:28:53,152 --> 04:28:57,256
THAT I THINK IN NATURAL --

6865
04:28:57,256 --> 04:29:00,693
NORMAL CELLS AND AN ORGANISM BUT

6866
04:29:00,693 --> 04:29:03,296
ALSO IN A CULTURE SYSTEM, I

6867
04:29:03,296 --> 04:29:07,100
THINK THERE SHOULD BE A LITTLE

6868
04:29:07,100 --> 04:29:08,234
MORE ATTENTION FROM MY

6869
04:29:08,234 --> 04:29:09,035
PERSPECTIVE AND TRYING TO

6870
04:29:09,035 --> 04:29:11,237
UNDERSTAND HOW TO REGULATE THE

6871
04:29:11,237 --> 04:29:12,538
RESILIENCE BASED ON REGULATING

6872
04:29:12,538 --> 04:29:14,007
AN EPIGENETIC STATE.

6873
04:29:14,007 --> 04:29:16,342
AND THE OTHER IS A LOT OF CELLS

6874
04:29:16,342 --> 04:29:17,644
ARE -- AS WE'VE HEARD A LOT

6875
04:29:17,644 --> 04:29:19,012
ABOUT, GO DOWN A PATHOLOGICAL

6876
04:29:19,012 --> 04:29:20,813
PATH, BUT WE HAVEN'T TALKED TOO

6877
04:29:20,813 --> 04:29:21,414
MUCH ABOUT HOW THERE'S AN

6878
04:29:21,414 --> 04:29:22,749
OPPORTUNITY FOR RESILIENCE

6879
04:29:22,749 --> 04:29:22,982
THERE.

6880
04:29:22,982 --> 04:29:24,550
AND IN THAT CASE, THE RESILIENCE

6881
04:29:24,550 --> 04:29:29,088
IS BASED ON REVERSING THE SPRING

6882
04:29:29,088 --> 04:29:30,390
THAT WENT -- THE SPRING THAT

6883
04:29:30,390 --> 04:29:32,892
SPRUNG TOO FAR IN THE FIRST

6884
04:29:32,892 --> 04:29:33,893
IMAGE THAT I THINK WAS

6885
04:29:33,893 --> 04:29:34,827
PRESENTED.

6886
04:29:34,827 --> 04:29:37,497
I WOULD SAY RESILIENCE IS AN

6887
04:29:37,497 --> 04:29:42,168
OPPORTUNITY FOR REVERSING AT A

6888
04:29:42,168 --> 04:29:42,902
CELLULAR LEVEL AND MOLECULAR

6889
04:29:42,902 --> 04:29:44,871
LEVEL SOME OF THE THINGS THAT

6890
04:29:44,871 --> 04:29:45,972
WE'VE LEARNED HAVE GONE WRONG

6891
04:29:45,972 --> 04:29:47,073
AND TO THE EXTENT THAT WE CAN

6892
04:29:47,073 --> 04:29:48,541
TAKE ADVANTAGE OF THE KNOWLEDGE

6893
04:29:48,541 --> 04:29:50,710
ABOUT HOW THINGS HAPPENED, TO

6894
04:29:50,710 --> 04:29:53,112
REVERSE IT, THEN THAT'S APLAYING

6895
04:29:53,112 --> 04:29:59,419
AAPPLYINGA NEW LEVEL OF RESILIEE

6896
04:29:59,419 --> 04:29:59,619
FIELD.

6897
04:29:59,619 --> 04:30:01,821
FROM MY PERSPECTIVE, THESE ARE

6898
04:30:01,821 --> 04:30:03,122
THE TWO THINGS THAT I WOULD DO

6899
04:30:03,122 --> 04:30:03,389
THE MOST.

6900
04:30:03,389 --> 04:30:05,191
>> CAN YOU RESPOND TO THAT
REAL

6901
04:30:05,191 --> 04:30:06,826
QUICK, JUST SHORT?

6902
04:30:06,826 --> 04:30:08,361
I THINK THAT'S VERY RIGHT, I

6903
04:30:08,361 --> 04:30:09,429
THINK THERE'S SOME VERY

6904
04:30:09,429 --> 04:30:12,231
INTERESTING LITERATURE OUT THERE

6905
04:30:12,231 --> 04:30:14,100
FROM THE LUNG FIELD BUT ALSO

6906
04:30:14,100 --> 04:30:16,069
BEYOND ABOUT THIS EXACT SORT OF

6907
04:30:16,069 --> 04:30:18,738
FUNDAMENTAL CONCEPT OF EP

6908
04:30:18,738 --> 04:30:20,039
GENETIC STATE AND VERY COOL

6909
04:30:20,039 --> 04:30:21,641
BECAUSE AS YOU GET MORE AND MORE

6910
04:30:21,641 --> 04:30:25,678
OPEN CHROMATIN, YOUR SORT OF

6911
04:30:25,678 --> 04:30:27,747
ACCESSIBLE STATE SPACE BROADENS.

6912
04:30:27,747 --> 04:30:29,282
THE CELL STATES THAT ARE ALLOWED

6913
04:30:29,282 --> 04:30:29,515
BROADEN.

6914
04:30:29,515 --> 04:30:31,818
SO EVEN IF YOU PUT A CELL WITHIN

6915
04:30:31,818 --> 04:30:33,286
A VERY FOCUSED MICROENVIRONMENT

6916
04:30:33,286 --> 04:30:35,254
AND YOU GET REALLY GOOD CELLULAR

6917
04:30:35,254 --> 04:30:36,122
DIFFERENTIATION, YOU'RE GOING TO

6918
04:30:36,122 --> 04:30:37,790
GET A DIFFERENT -- THAT CELL HAS

6919
04:30:37,790 --> 04:30:39,392
A DIFFERENT ABILITY TO RESPOND

6920
04:30:39,392 --> 04:30:41,694
BASED ON ITS EP GENETIC STATE.

6921
04:30:41,694 --> 04:30:44,497
IF CHROMATIN IS ONLY ALLOWING

6922
04:30:44,497 --> 04:30:45,164
THOSE CERTAIN GENES, THEN IT'S

6923
04:30:45,164 --> 04:30:46,699
STUCK THERE, BUT IF IT HAS A

6924
04:30:46,699 --> 04:30:47,867
BROADER CHROMATIN ACCESSIBILITY,

6925
04:30:47,867 --> 04:30:49,435
THEN IT CAN GET PUSHED AROUND

6926
04:30:49,435 --> 04:30:49,736
MORE EASILY.

6927
04:30:49,736 --> 04:30:51,804
SO I THINK IT PROBABLY IS VERY

6928
04:30:51,804 --> 04:30:52,672
DEEPLY RELATED TO WHAT WE'RE

6929
04:30:52,672 --> 04:30:54,507
TALKING ABOUT AND WE SEE IT IN

6930
04:30:54,507 --> 04:30:56,409
AGING AS WELL, WHERE THERE'S

6931
04:30:56,409 --> 04:30:57,844
THIS SORT OF PROGRESSIVE

6932
04:30:57,844 --> 04:30:59,245
EPIGENETIC CHANGE IN A LOT OF

6933
04:30:59,245 --> 04:30:59,746
DIFFERENT CELL SYSTEMS.

6934
04:30:59,746 --> 04:31:01,280
>> I THINK WE SHOULD BE
PAYING

6935
04:31:01,280 --> 04:31:02,115
MORE ATTENTION TO THIS.

6936
04:31:02,115 --> 04:31:04,684
IN TERMS OF RECOMMENDATIONS FOR

6937
04:31:04,684 --> 04:31:08,121
THE NHLBI, THAT WOULD BE ONE OF

6938
04:31:08,121 --> 04:31:08,588
MINE.

6939
04:31:08,588 --> 04:31:11,057
THE OTHER WOULD BE REVERSING THE

6940
04:31:11,057 --> 04:31:16,896
PATHOLOGICAL CELL STATE.

6941
04:31:16,896 --> 04:31:17,864
BOTH VERY DIFFERENT THAN TALKING

6942
04:31:17,864 --> 04:31:21,667
ABOUT PEOPLE.

6943
04:31:21,667 --> 04:31:27,140
>> WE ALSO PROBABLY NEED
TO LOOK

6944
04:31:27,140 --> 04:31:28,541
AT EARLY DISEASE BECAUSE MOST OF

6945
04:31:28,541 --> 04:31:30,943
THE TIME THAT WE ARE JUST

6946
04:31:30,943 --> 04:31:32,678
LOOKING AT IN DISEASE JUST

6947
04:31:32,678 --> 04:31:34,046
BECAUSE WHERE TISSUES ARE

6948
04:31:34,046 --> 04:31:35,314
AVAILABLE, SO RESILIENCE IS

6949
04:31:35,314 --> 04:31:37,216
PROBABLY LIKE NOT WHERE WE ARE

6950
04:31:37,216 --> 04:31:38,818
LOOKING AT MAYBE IT'S NOT

6951
04:31:38,818 --> 04:31:39,685
RESIDENT ANYMORE BECAUSE THEY

6952
04:31:39,685 --> 04:31:41,654
HAVE COMMITTED TO GO TO THIS

6953
04:31:41,654 --> 04:31:42,522
DISEASE PATHWAY.

6954
04:31:42,522 --> 04:31:44,557
ESPECIALLY FOR THE HUMAN CELLS,

6955
04:31:44,557 --> 04:31:46,025
HUMAN TISSUES, BECAUSE THAT'S

6956
04:31:46,025 --> 04:31:48,828
WHAT IS AVAILABLE, HOW TO GET

6957
04:31:48,828 --> 04:31:52,932
MONORMAL, DURING THE PROCESS OF

6958
04:31:52,932 --> 04:32:00,339
DISEASE DEVELOPMENT.

6959
04:32:00,339 --> 04:32:05,111
>> I HATE TO ACTUALLY
BREAK THE

6960
04:32:05,111 --> 04:32:07,180
LINE BECAUSE OF THE EPIGENETIC

6961
04:32:07,180 --> 04:32:10,716
CHANGES ARE VERY INTERESTING,

6962
04:32:10,716 --> 04:32:12,351
BUT SOME MINUTES AGO, WHAT CAME

6963
04:32:12,351 --> 04:32:16,189
UP TO MY MIND WAS SOMETHING THAT

6964
04:32:16,189 --> 04:32:20,126
COULD BE A POTENTIAL WAY OF

6965
04:32:20,126 --> 04:32:24,931
EXPLORING THE QUESTIONS THAT WAS

6966
04:32:24,931 --> 04:32:25,932
POSED IN TERMS OF HOW WE CAN

6967
04:32:25,932 --> 04:32:29,135
UNDERSTAND A LITTLE BIT MORE

6968
04:32:29,135 --> 04:32:34,307
ABOUT THE NEURAL.

6969
04:32:34,307 --> 04:32:37,310
AND COMES UP TO MY MIND ALWAYS

6970
04:32:37,310 --> 04:32:38,110
SOME THINK THAT IT'S KIND OF

6971
04:32:38,110 --> 04:32:39,512
LIKE READILY AVAILABLE.

6972
04:32:39,512 --> 04:32:42,648
BUT I DON'T KNOW -- WHEN I SAY

6973
04:32:42,648 --> 04:32:44,183
MODEL, ESSENTIALLY THE HUMANS,

6974
04:32:44,183 --> 04:32:46,752
PATIENTS WHO HAVE UNDERGONE LUNG

6975
04:32:46,752 --> 04:32:49,455
TRANSPLANTATION IN WHICH YOU

6976
04:32:49,455 --> 04:32:52,658
HAVE ALL OF THE CONNECTIONS

6977
04:32:52,658 --> 04:32:55,361
BETWEEN THE NEURONS, SO I WAS

6978
04:32:55,361 --> 04:32:59,198
WONDERING IF -- HAS ANYBODY

6979
04:32:59,198 --> 04:33:01,234
THOUGHT ABOUT WHAT ARE THE

6980
04:33:01,234 --> 04:33:02,301
DIFFERENCES?

6981
04:33:02,301 --> 04:33:04,570
THIS IS A VERY DIRTY SYSTEM TO

6982
04:33:04,570 --> 04:33:10,142
ACTUALLY WORK IF WE CAN SAY SO,

6983
04:33:10,142 --> 04:33:13,145
BECAUSE THERE IS ALL OF THE

6984
04:33:13,145 --> 04:33:13,946
SUPPRESSION AND ALL OF THE

6985
04:33:13,946 --> 04:33:16,983
THINGS THAT MAKE THINKS VERY

6986
04:33:16,983 --> 04:33:18,150
COMPLICATED, BUT TO MY MIND, ONE

6987
04:33:18,150 --> 04:33:21,254
OF THE FEW WAYS OF ADDRESSING

6988
04:33:21,254 --> 04:33:24,457
POTENTIAL QUESTIONS LIKE THOSE

6989
04:33:24,457 --> 04:33:33,766
THAT WERE RAISED.

6990
04:33:33,766 --> 04:33:38,304
>> I WANT TO RAISE ANOTHER

6991
04:33:38,304 --> 04:33:39,205
POINT, I MEAN CHALLENGES IN

6992
04:33:39,205 --> 04:33:47,079
TERMS OF HOW WE STUDY THIS

6993
04:33:47,079 --> 04:33:47,613
RESILIENCE.

6994
04:33:47,613 --> 04:33:49,582
ONE THING, SYSTEMS DIFFERENCES

6995
04:33:49,582 --> 04:33:53,152
BETWEEN MOUSE AND HUMAN, ANOTHER

6996
04:33:53,152 --> 04:33:56,222
IS A DOSE EFFECT RKT AND IT'S A

6997
04:33:56,222 --> 04:33:57,723
WHOLE DURATION THAT THE UNIVERSE

6998
04:33:57,723 --> 04:34:08,267
WILL GET TO -- TREATED IN CELLS

6999
04:34:08,968 --> 04:34:10,269
OF MICE, AND THEY USE THAT, YOU

7000
04:34:10,269 --> 04:34:11,971
CAN ALSO TREAT A WEEK, A MOUSE

7001
04:34:11,971 --> 04:34:15,141
OR WHAT KIND OF CRITERIA, THE

7002
04:34:15,141 --> 04:34:18,311
HALLMARKS OF RESILIENCE, SO

7003
04:34:18,311 --> 04:34:23,783
EXACTLY WHAT KIND OF -- I MEAN,

7004
04:34:23,783 --> 04:34:27,687
CURIOUS, WILL LOOK AT --

7005
04:34:27,687 --> 04:34:28,921
RESILIENCY THAT'S MOLECULAR

7006
04:34:28,921 --> 04:34:30,790
MARKER OF SOME FUNCTIONALITY OR

7007
04:34:30,790 --> 04:34:36,529
EXPRESSION PROFILES, AND I THINK

7008
04:34:36,529 --> 04:34:41,667
IT'S -- HAVE TO THINK ABOUT --

7009
04:34:41,667 --> 04:34:47,473
AND WHAT KIND OF CRITERIA WE

7010
04:34:47,473 --> 04:34:50,776
LOOK AT IS THE WHOLE EXPRESSION

7011
04:34:50,776 --> 04:35:01,020
FUNCTIONALITY.

7012
04:35:08,127 --> 04:35:11,230
>> I ACTUALLY WANT TO
BRING UP

7013
04:35:11,230 --> 04:35:13,666
ANOTHER CRAZY -- I WAS THINKING

7014
04:35:13,666 --> 04:35:14,266
YOU KNOW WHEN YOU TERRITORY

7015
04:35:14,266 --> 04:35:16,635
CANCERS, YOU DO HAVE A

7016
04:35:16,635 --> 04:35:19,438
RESISTANCE IN THE LABS, AND I

7017
04:35:19,438 --> 04:35:22,875
DON'T WORK IN CLINICS ANYMORE,

7018
04:35:22,875 --> 04:35:29,015
BUT I WONDER, SAY YOU HAVE THAT

7019
04:35:29,015 --> 04:35:31,317
FIBROSIS, ASTHMA, CHRONIC

7020
04:35:31,317 --> 04:35:34,487
DISEASE, COPD, THE SYSTEM WOULD

7021
04:35:34,487 --> 04:35:39,158
DEVELOP A RESISTANCE BY --

7022
04:35:39,158 --> 04:35:40,793
DIFFERENT CELL TYPES AND HAVE

7023
04:35:40,793 --> 04:35:42,261
ANYBODY THINK ABOUT THAT WAY?

7024
04:35:42,261 --> 04:35:45,297
CAN WE USE SYSTEMATIC BIOLOGIES

7025
04:35:45,297 --> 04:35:55,708
TO ADDRESS THOSE ISSUES?

7026
04:35:58,444 --> 04:36:08,888
MAYBE CLINICIANS HAVE AN IDEA?

7027
04:36:20,900 --> 04:36:21,834
>> CAN YOU REPEAT THE
QUESTION

7028
04:36:21,834 --> 04:36:22,668
AGAIN?

7029
04:36:22,668 --> 04:36:26,739
>> THE QUESTION WOULD BE,
YOU

7030
04:36:26,739 --> 04:36:28,674
KNOW, WHEN YOU TREAT CANCER,

7031
04:36:28,674 --> 04:36:36,649
THEY DEVELOP THE SYSTEMS O RECYR

7032
04:36:36,649 --> 04:36:40,386
RELAPSE AFTER TREATMENT IF YOU

7033
04:36:40,386 --> 04:36:42,021
TREAT PATIENTS WITH FIBROSIS AND

7034
04:36:42,021 --> 04:36:45,491
CHRONIC DISEASE LIKE ASTHMA THE

7035
04:36:45,491 --> 04:36:47,460
SYSTEM NOW WILL ALSO DEVELOP A

7036
04:36:47,460 --> 04:36:49,562
LITTLE RESISTANCE IN SOME WAY,

7037
04:36:49,562 --> 04:36:51,297
MOBILIZE DIFFERENT TYPE OF CELL

7038
04:36:51,297 --> 04:36:52,164
TYPES.

7039
04:36:52,164 --> 04:36:53,599
WOULD YOU CONSIDER THIS

7040
04:36:53,599 --> 04:36:55,067
POSSIBILITY IN CLINICS?

7041
04:36:55,067 --> 04:36:58,404
>> WELL, I MEAN, THIS CAME
UP --

7042
04:36:58,404 --> 04:37:02,308
HALL ASKED US -- WELL, NO, NOT

7043
04:37:02,308 --> 04:37:03,409
HAL BUT AMANDA I THINK ASKED

7044
04:37:03,409 --> 04:37:05,644
ABOUT WITH RESPECT TO

7045
04:37:05,644 --> 04:37:07,880
MESENCHYMAL STROMAL CELL-BASED

7046
04:37:07,880 --> 04:37:08,681
THERAPY, MULTIPLE

7047
04:37:08,681 --> 04:37:10,182
ADMINISTRATIONS WITH DIFFERENT

7048
04:37:10,182 --> 04:37:10,616
SOURCES.

7049
04:37:10,616 --> 04:37:12,384
CELLS OF DIFFERENT ORIGIN.

7050
04:37:12,384 --> 04:37:17,823
THAT ARGUABLY COULD MITIGATE ANY

7051
04:37:17,823 --> 04:37:19,925
POTENTIAL IMMUNE RESPONSE TO A

7052
04:37:19,925 --> 04:37:21,427
GIVEN EPITOPE ON ANY ONE GIVEN

7053
04:37:21,427 --> 04:37:25,664
SOURCE.

7054
04:37:25,664 --> 04:37:27,967
I DON'T KNOW HOW TO ANSWER THAT.

7055
04:37:27,967 --> 04:37:30,503
MY GUT WOULD BE THAT IF YOU CAN

7056
04:37:30,503 --> 04:37:32,571
GET STRUCTURAL REPAIR WITH

7057
04:37:32,571 --> 04:37:38,344
WHATEVER PROGENITOR CELL OR I

7058
04:37:38,344 --> 04:37:39,612
IPSC, THE HALF-LIFE IS QUITE

7059
04:37:39,612 --> 04:37:42,281
LONG OF TURNOVERS PRESUMABLY

7060
04:37:42,281 --> 04:37:44,717
LIKE THE NATIVE EPITHELIUM, THEN

7061
04:37:44,717 --> 04:37:46,285
YOU WOULDN'T NEED TO NECESSARILY

7062
04:37:46,285 --> 04:37:46,719
DO THAT.

7063
04:37:46,719 --> 04:37:47,887
IT WOULD TAKE YEARS AND YEARS

7064
04:37:47,887 --> 04:37:51,590
AND YEARS AND YEARS TO REDEVELOP

7065
04:37:51,590 --> 04:37:53,492
A PATHOLOGY.

7066
04:37:53,492 --> 04:37:58,430
SO CONCEPTUALLY INTERESTING,

7067
04:37:58,430 --> 04:38:00,566
CLINICALLY PROBABLY NOT

7068
04:38:00,566 --> 04:38:01,800
NECESSARY, NOT UNTIL WE CAN FIX

7069
04:38:01,800 --> 04:38:03,068
IT THE FIRST TIME AROUND AT

7070
04:38:03,068 --> 04:38:06,739
LEAST.

7071
04:38:06,739 --> 04:38:08,674
>> TO ME, A LOT OF CHRONIC
LUNG

7072
04:38:08,674 --> 04:38:10,009
DISEASE ACTUALLY WE DON'T EVEN

7073
04:38:10,009 --> 04:38:12,945
HAVE TREATMENT IS I THINK IN

7074
04:38:12,945 --> 04:38:15,114
MEDICINE, THE REAL, LIKE, GOOD

7075
04:38:15,114 --> 04:38:16,649
EXAMPLE OF THE REAL TREATMENT IS

7076
04:38:16,649 --> 04:38:19,919
USUALLY THE ANTIBODY FOR THE

7077
04:38:19,919 --> 04:38:21,554
INFECTION, SO IN THAT CASE,

7078
04:38:21,554 --> 04:38:24,790
USUALLY YOU DEVELOP RESISTANCE

7079
04:38:24,790 --> 04:38:26,025
SOMETIMES BUT I DON'T THINK IN

7080
04:38:26,025 --> 04:38:27,459
CHRONIC LUNG DISEASE, WE DON'T

7081
04:38:27,459 --> 04:38:32,364
HAVE THOSE KIND OF ANTIBIOTIC

7082
04:38:32,364 --> 04:38:35,034
HRB LIKE THE TREATMENT FOR

7083
04:38:35,034 --> 04:38:38,704
PULMONARY FIBROSIS OR EMPHYSEMA,

7084
04:38:38,704 --> 04:38:40,906
COPD, SO I THINK THAT'S AN

7085
04:38:40,906 --> 04:38:41,974
INTERESTING CONCEPT BUT I DON'T

7086
04:38:41,974 --> 04:38:46,145
THINK WE CAN THINK ABOUT THAT

7087
04:38:46,145 --> 04:38:48,781
LEVEL YET AT THIS POINT.

7088
04:38:48,781 --> 04:38:59,325
>> I WANT TO BOUNCE THIS
TO JOHN

7089
04:39:02,728 --> 04:39:02,928
ENGELHART.

7090
04:39:02,928 --> 04:39:03,996
ONE OF THE ISSUES WITH

7091
04:39:03,996 --> 04:39:05,898
CELL-BASED THERAPY FOR CYSTIC

7092
04:39:05,898 --> 04:39:06,966
FIBROSIS IS THAT IT COULD BE THE

7093
04:39:06,966 --> 04:39:09,134
CASE IN WHICH THE BODY AND LET'S

7094
04:39:09,134 --> 04:39:13,339
SAY A PATIENT WILL RECOGNIZE AN

7095
04:39:13,339 --> 04:39:15,207
ATTACK SEQ PROTEIN AS A FOREIGN

7096
04:39:15,207 --> 04:39:16,709
EPITOPE BECAUSE THEY DIDN'T GROW

7097
04:39:16,709 --> 04:39:19,311
UP WITH IF THE IMMUNE SYSTEM

7098
04:39:19,311 --> 04:39:19,678
DIDN'T DEVELOP.

7099
04:39:19,678 --> 04:39:23,549
I'M NOT SURE IF THE CFTR

7100
04:39:23,549 --> 04:39:24,583
MODULATOR DATA HAS ADDRESSED

7101
04:39:24,583 --> 04:39:26,252
THAT, BUT IT RAISES THE

7102
04:39:26,252 --> 04:39:32,324
POSSIBILITY THAT IF YOU HAVE A

7103
04:39:32,324 --> 04:39:38,564
GENETIC DISEASE, MISFOLD FOLDEDR

7104
04:39:38,564 --> 04:39:39,565
POORLY EXPRESSED OR WHATEVER

7105
04:39:39,565 --> 04:39:41,433
PROTEIN AND NOW YOU HAVE IT,

7106
04:39:41,433 --> 04:39:45,304
DOES THAT BRING IN, IN RESPONSE,

7107
04:39:45,304 --> 04:39:46,739
A SHORTENED HALF LIFE OF YOUR

7108
04:39:46,739 --> 04:39:47,172
THERAPY?

7109
04:39:47,172 --> 04:39:49,041
SO JOHN, ARE YOU HERE?

7110
04:39:49,041 --> 04:39:53,078
OR ANYONE ELSE WOULD LIKE TO

7111
04:39:53,078 --> 04:39:56,148
ADDRESS THAT QUESTION?

7112
04:39:56,148 --> 04:39:58,384
>> I'M NOT SURE IF JOHN
WAS

7113
04:39:58,384 --> 04:40:00,352
STILL HERE, BUT I WANTED TO

7114
04:40:00,352 --> 04:40:04,890
CHECK WITH OUR NHLBI COLLEAGUES,

7115
04:40:04,890 --> 04:40:12,665
AS WE'RE UP AT 3:45 TO SEE IF WE

7116
04:40:12,665 --> 04:40:16,135
SHOULD MOVE ON TO THE CLOSING

7117
04:40:16,135 --> 04:40:16,368
REMARKS.

7118
04:40:16,368 --> 04:40:17,569
>> YEAH, WE CAN.

7119
04:40:17,569 --> 04:40:23,075
I'D ALSO LIKE TO ASK THE PANEL

7120
04:40:23,075 --> 04:40:23,609
ONE QUESTION.

7121
04:40:23,609 --> 04:40:25,544
I KNOW THIS WORKSHOP, WE KIND OF

7122
04:40:25,544 --> 04:40:30,215
FOCUS ON THE PROGENITOR CELLS

7123
04:40:30,215 --> 04:40:32,451
AND THE ROLE IN LUNG RESILIENCE,

7124
04:40:32,451 --> 04:40:35,521
BUT I'M SURE THERE ARE A LOT OF

7125
04:40:35,521 --> 04:40:40,092
CELLS IN THE LUNG AND OTHER --

7126
04:40:40,092 --> 04:40:41,627
CELL PROBABLY VERY IMPORTANT TOO

7127
04:40:41,627 --> 04:40:44,330
IN THE PRESERVED LUNG OR LOSS OF

7128
04:40:44,330 --> 04:40:45,831
LUNG FUNCTION TRAJECTORY, SO

7129
04:40:45,831 --> 04:40:49,368
JUST WANTED TO KNOW, YOU KNOW,

7130
04:40:49,368 --> 04:40:50,969
THE BIG PICTURE OF LUNG

7131
04:40:50,969 --> 04:40:52,404
RESILIENCE, WE HAVEN'T DISCUSSED

7132
04:40:52,404 --> 04:40:56,809
OTHER CELLS, SO THE NEURON, WE

7133
04:40:56,809 --> 04:41:00,512
DIDN'T REALLY DISCOVER DISCOVER

7134
04:41:00,512 --> 04:41:03,015
MUCH OTHER CELL TYPES.

7135
04:41:03,015 --> 04:41:04,416
THE CRITICAL ROLE OF OTHER CELL

7136
04:41:04,416 --> 04:41:09,388
TYPE IN THE LUNG RESILIENCE.

7137
04:41:09,388 --> 04:41:11,757
>> I THINK SAM AND I MIGHT
BE

7138
04:41:11,757 --> 04:41:14,326
ABLE TO BE HERE MANY MORE HOURS

7139
04:41:14,326 --> 04:41:16,528
DISCUSSING THIS TOPIC HERE.

7140
04:41:16,528 --> 04:41:19,164
I MEAN, THERE'S OBVIOUSLY -- WE

7141
04:41:19,164 --> 04:41:21,133
DIDN'T GET INTO FIBROBLASTS OR

7142
04:41:21,133 --> 04:41:22,101
FIBROBLASTS SUBSETS OR WHAT

7143
04:41:22,101 --> 04:41:23,001
NAMES FOR THEM COULD BE.

7144
04:41:23,001 --> 04:41:25,504
I THINK THIS IS PROBABLY THE

7145
04:41:25,504 --> 04:41:26,372
TOPIC FOR ANOTHER MEETING

7146
04:41:26,372 --> 04:41:27,840
POTENTIALLY.

7147
04:41:27,840 --> 04:41:30,376
IN ADDITION TO THE REST OF THE

7148
04:41:30,376 --> 04:41:33,479
EPITHELIAL CELLS THAT FOLKS ARE

7149
04:41:33,479 --> 04:41:34,313
CATALOGING.

7150
04:41:34,313 --> 04:41:37,516
I KNOW THAT ON THAT TOPIC, I SAW

7151
04:41:37,516 --> 04:41:38,917
THAT JACKIE, I BELIEVE, HAD SENT

7152
04:41:38,917 --> 04:41:41,653
OUT AN EMAIL EARLIER TODAY ON

7153
04:41:41,653 --> 04:41:45,257
KIND OF MAPPING A LUNG CELL

7154
04:41:45,257 --> 04:41:48,560
ATLAS AS PART OF THE HUBMAP

7155
04:41:48,560 --> 04:41:49,795
PROJECT SO I'M SURE THERE WILL

7156
04:41:49,795 --> 04:41:51,363
BE MORE DISCUSSION ON THESE

7157
04:41:51,363 --> 04:41:53,665
POINTS THERE.

7158
04:41:53,665 --> 04:41:56,368
I THINK AT LEAST FROM WHERE --

7159
04:41:56,368 --> 04:41:58,070
AT LEAST SOME OF OUR LAB SITS IN

7160
04:41:58,070 --> 04:42:01,874
TERMS OF THE SINGLE CELL SPACE,

7161
04:42:01,874 --> 04:42:06,145
WE ARE VERY MUCH STILL KIND OF

7162
04:42:06,145 --> 04:42:08,213
IDENTIFYING AND ENUMERATING THE

7163
04:42:08,213 --> 04:42:09,982
DIFFERENT CELL SUBSET THAT ARE

7164
04:42:09,982 --> 04:42:10,349
POSSIBLE, RIGHT?

7165
04:42:10,349 --> 04:42:11,150
ONE OF THE THINGS THAT THEY'VE

7166
04:42:11,150 --> 04:42:12,384
GOTTEN TO THE BOTTOM OF

7167
04:42:12,384 --> 04:42:15,487
EVERYTHING, AND THEN YOU LEARN

7168
04:42:15,487 --> 04:42:18,257
ABOUT THE IONOCYTE, YOU LEARN

7169
04:42:18,257 --> 04:42:19,825
ABOUT OTHER KIND OF UNIQUE

7170
04:42:19,825 --> 04:42:21,693
CELLS, OUR GROUP HAS FOUND ONE

7171
04:42:21,693 --> 04:42:22,961
IN THE NOSE RECENTLY AND SO

7172
04:42:22,961 --> 04:42:23,295
FORTH.

7173
04:42:23,295 --> 04:42:24,830
SO AS YOU START TO BUILD OUT

7174
04:42:24,830 --> 04:42:28,333
THAT PARTS LIST, YOU RAPIDLY

7175
04:42:28,333 --> 04:42:30,002
SCALE ON THE POTENTIAL

7176
04:42:30,002 --> 04:42:31,470
INTERACTIONS THAT MAY BE PRESENT

7177
04:42:31,470 --> 04:42:33,906
ACROSS THESE SYSTEMS, NOT TO

7178
04:42:33,906 --> 04:42:35,574
MENTION THE IMPORTANCE OF THE

7179
04:42:35,574 --> 04:42:36,742
ENVIRONMENTAL LAYER ON TOP OF

7180
04:42:36,742 --> 04:42:40,312
THIS, AND SO I THINK THAT

7181
04:42:40,312 --> 04:42:41,980
CLEARLY FOOD FOR THOUGHT GOING

7182
04:42:41,980 --> 04:42:44,416
FORWARD, BUT IN KEEPING THE

7183
04:42:44,416 --> 04:42:47,553
CONCEPT OF RESILIENCE AND

7184
04:42:47,553 --> 04:42:48,787
RESILIENCE IS ANCHORED WITHIN

7185
04:42:48,787 --> 04:42:50,389
THE PLASTICITY OF THESE

7186
04:42:50,389 --> 04:42:52,024
PROGENITOR CELLS DEPENDING ON

7187
04:42:52,024 --> 04:42:53,792
HOW FIXED OR UNFIXED THEY MIGHT

7188
04:42:53,792 --> 04:42:55,527
BE IS CERTAINLY SOMETHING

7189
04:42:55,527 --> 04:42:58,030
INTERESTING TO THINK ABOUT

7190
04:42:58,030 --> 04:43:00,632
MOVING FORWARD.

7191
04:43:00,632 --> 04:43:02,835
>> THANK YOU.

7192
04:43:02,835 --> 04:43:04,870
IF YOU DON'T HAVE ANY OTHER

7193
04:43:04,870 --> 04:43:08,273
COMMENTS, YES, WE CAN CLOSE THIS

7194
04:43:08,273 --> 04:43:08,640
WORKSHOP.

7195
04:43:08,640 --> 04:43:12,511
I JUST WANTED TO SAY, THIS IS A

7196
04:43:12,511 --> 04:43:17,182
VERY, VERY SUCCESSFUL WORKSHOP,

7197
04:43:17,182 --> 04:43:19,051
I HAVE SEEN -- I HAVE

7198
04:43:19,051 --> 04:43:20,819
EXPERIENCED, I THINK, I

7199
04:43:20,819 --> 04:43:22,254
DEFINITELY MYSELF LEARNED A LOT

7200
04:43:22,254 --> 04:43:23,322
IN THE LAST TWO DAYS.

7201
04:43:23,322 --> 04:43:25,591
AGAIN, I JUST WANT TO THANK OUR

7202
04:43:25,591 --> 04:43:26,792
EXTRAORDINARY CO-CHAIRS,

7203
04:43:26,792 --> 04:43:33,031
MODERATORS, ALL THE SPEAKERS,

7204
04:43:33,031 --> 04:43:36,735
FOR YOUR EFFORT AND CONTRIBUTION

7205
04:43:36,735 --> 04:43:39,104
OF YOUR WISDOM TO THIS WORKSHOP.

7206
04:43:39,104 --> 04:43:41,240
I ALSO WANT TO THANK ALL THE

7207
04:43:41,240 --> 04:43:42,374
PARTICIPANTS TO STICK AROUND TO

7208
04:43:42,374 --> 04:43:44,476
THE END OF THE WORKSHOP, BY

7209
04:43:44,476 --> 04:43:47,579
LOOKING AT THE SCREEN TO SEE HOW

7210
04:43:47,579 --> 04:43:49,214
MANY PEOPLE AT THIS TIME, AND

7211
04:43:49,214 --> 04:43:52,084
IT'S REALLY HARD, TWO DAYS IT

7212
04:43:52,084 --> 04:43:54,019
WAS A WORKSHOP, SO I REALLY -- I

7213
04:43:54,019 --> 04:43:55,420
PROBABLY MENTIONED AT THE

7214
04:43:55,420 --> 04:43:57,155
BEGINNING OF THE WORKSHOPS, WE

7215
04:43:57,155 --> 04:44:04,530
PLAN TO PUBLISH EXECUTIVE

7216
04:44:04,530 --> 04:44:05,631
SUMMARY, ON THE WEBSITE

7217
04:44:05,631 --> 04:44:07,132
HOPEFULLY IN A FEW MONTHS.

7218
04:44:07,132 --> 04:44:08,767
WE ALSO PLAN TO PUBLISH A WHITE

7219
04:44:08,767 --> 04:44:12,170
PAPER TO SUMMARIZE THIS

7220
04:44:12,170 --> 04:44:12,871
WORKSHOP.

7221
04:44:12,871 --> 04:44:14,940
WE'RE HOPING PROBABLY WITHIN A

7222
04:44:14,940 --> 04:44:17,175
YEAR BUT DEFINITELY WITH YOUR

7223
04:44:17,175 --> 04:44:19,711
GUYS' HELP, WE HAVE SOME

7224
04:44:19,711 --> 04:44:20,812
DISCUSSION WITH THE CO-CHAIRS

7225
04:44:20,812 --> 04:44:26,184
AND WE ACTUALLY HAVE TWO

7226
04:44:26,184 --> 04:44:28,987
SCIENTIFIC -- IT'S TWO, DR. HAN

7227
04:44:28,987 --> 04:44:33,625
AND DR. -- THEY ALSO --

7228
04:44:33,625 --> 04:44:35,294
LEADERSHIP SO STAY TUNED.

7229
04:44:35,294 --> 04:44:38,497
ALSO JUST WANTED TO REMIND, THIS

7230
04:44:38,497 --> 04:44:42,534
WORKSHOP HA HAS BEEN VIDEOCASTED

7231
04:44:42,534 --> 04:44:43,468
AND THE RECORDING WILL BE

7232
04:44:43,468 --> 04:44:45,871
AVAILABLE, I THINK ON NIH

7233
04:44:45,871 --> 04:44:46,939
VIDEOCAST PAST EVENTS ONE WEEK

7234
04:44:46,939 --> 04:44:50,309
FROM TODAY.

7235
04:44:50,309 --> 04:44:51,410
SO IF YOUR COLLEAGUES,

7236
04:44:51,410 --> 04:44:53,478
ESPECIALLY IF YOUR TRAINEES HAVE

7237
04:44:53,478 --> 04:44:54,813
NOT GOT AN OPPORTUNITY TO

7238
04:44:54,813 --> 04:44:56,615
PARTICIPATE IN THIS WORKSHOP, IF

7239
04:44:56,615 --> 04:44:57,983
THEY'RE INTERESTED, I WOULD

7240
04:44:57,983 --> 04:45:00,719
ENCOURAGE THEM TO DO SO, TO LOOK

7241
04:45:00,719 --> 04:45:05,057
AT THOSE RECORDINGS A WEEK FROM

7242
04:45:05,057 --> 04:45:10,896
TODAY JUST BY THE TITLE, THEY

7243
04:45:10,896 --> 04:45:12,364
WILL BE ABLE TO FIND IT A WEEK

7244
04:45:12,364 --> 04:45:13,198
FROM TODAY.

7245
04:45:13,198 --> 04:45:15,601
WE WILL BRING ALL THE GREAT

7246
04:45:15,601 --> 04:45:18,403
IDEAS AND RECOMMENDATIONS FOR

7247
04:45:18,403 --> 04:45:20,572
THE DISCUSSION INTERNALLY.

7248
04:45:20,572 --> 04:45:21,974
WE HOPE SOME RECOMMENDATIONS

7249
04:45:21,974 --> 04:45:24,209
WILL BE IMPLEMENTED IN THE NEXT

7250
04:45:24,209 --> 04:45:25,344
FEW YEARS.

7251
04:45:25,344 --> 04:45:27,112
I THINK THAT'S WHAT I HAVE.

7252
04:45:27,112 --> 04:45:34,286
I'D LIKE TO BRING MYCOLEAD DR

7253
04:45:34,286 --> 04:45:44,830
DR. CHRISTINE CHRISTIAN GOMEZ TO

7254
04:45:50,836 --> 04:45:51,770
SAY A FEW WORDS.

7255
04:45:51,770 --> 04:45:52,971
>> I JUST WANT TO TAKE THE

7256
04:45:52,971 --> 04:45:58,844
OPPORTUNITY TO ALSO THANK YOU,

7257
04:45:58,844 --> 04:46:00,012
DR. LIU AND DR. GOMEZ FOR

7258
04:46:00,012 --> 04:46:01,313
LEADING THIS AND REALLY

7259
04:46:01,313 --> 04:46:01,980
SPEARHEADING THIS EFFORT.

7260
04:46:01,980 --> 04:46:03,515
NONE OF THIS WOULD HAVE BEEN

7261
04:46:03,515 --> 04:46:08,854
POSSIBLE WITH EITHER OF YOU, AND

7262
04:46:08,854 --> 04:46:10,355
ALSO TO SHAWN AND JACKIE TO

7263
04:46:10,355 --> 04:46:14,793
PROVIDING SUPPORT AS WELL, IT

7264
04:46:14,793 --> 04:46:16,528
MAKES OUR PROCESS QUITE EASY AND

7265
04:46:16,528 --> 04:46:18,030
LETS US FOCUS ON THE SCIENCE AND

7266
04:46:18,030 --> 04:46:19,398
THE DISCUSSION AND THEN

7267
04:46:19,398 --> 04:46:21,533
EVERYTHING HAPPENS SEAMLESSLY IN

7268
04:46:21,533 --> 04:46:21,900
THE BACKGROUND.

7269
04:46:21,900 --> 04:46:23,068
SO I JUST WANT TO MAKE SURE THAT

7270
04:46:23,068 --> 04:46:25,771
WE CAN ALL PUT OUR KIND OF

7271
04:46:25,771 --> 04:46:28,106
VIRTUAL HAND TOGETHER FOR THEIR

7272
04:46:28,106 --> 04:46:30,876
INCREDIBLE SUPPORT OF THIS

7273
04:46:30,876 --> 04:46:32,177
WORKSHOP, AND THEN CHRISTIAN, I

7274
04:46:32,177 --> 04:46:33,278
MIGHT HAVE HEARD YOU COME

7275
04:46:33,278 --> 04:46:36,682
THROUGH, SO I WILL HAND TO YOU.

7276
04:46:36,682 --> 04:46:37,849
>> CAN YOU HEAR ME NOW?

7277
04:46:37,849 --> 04:46:38,950
>> YES.

7278
04:46:38,950 --> 04:46:44,723
>> PERFECT.

7279
04:46:44,723 --> 04:46:47,292
SO I GUESS TO STAY WITHIN THE

7280
04:46:47,292 --> 04:46:48,126
END OF THE WORKSHOP, I JUST WANT

7281
04:46:48,126 --> 04:46:49,461
TO THANK EVERYONE FOR YOUR

7282
04:46:49,461 --> 04:46:50,796
PARTICIPATION AND CONTRIBUTIONS.

7283
04:46:50,796 --> 04:46:55,934
WE HAD A LOT OF GOOD INSIGHT

7284
04:46:55,934 --> 04:46:57,836
COME IN THESE TWO DAYS, AND WE

7285
04:46:57,836 --> 04:47:00,439
EXPECT THAT THIS WILL PAVE THE

7286
04:47:00,439 --> 04:47:01,773
WAY FOR ADVANCES THAT WILL

7287
04:47:01,773 --> 04:47:03,508
INCREASE OUR UNDERSTANDING OF

7288
04:47:03,508 --> 04:47:09,014
PROGENITOR RESILIENCE AND ALSO

7289
04:47:09,014 --> 04:47:10,015
CHRONIC DISEASES.

7290
04:47:10,015 --> 04:47:10,716
WE LOOK FORWARD TO CONTINUING

7291
04:47:10,716 --> 04:47:11,316
THAT DIALOGUE.

7292
04:47:11,316 --> 04:47:13,719
WE MAY BE SETTING THE GROUND, I

7293
04:47:13,719 --> 04:47:16,154
THINK, TO BE WHAT I CALL -- I

7294
04:47:16,154 --> 04:47:20,192
WOULD LIKE TO CALL THE PILOTS OF

7295
04:47:20,192 --> 04:47:21,493
LUNG HEALTH, AND HOW THIS CAN

7296
04:47:21,493 --> 04:47:25,497
HELP TO DEFINE A MORE RESILIENT

7297
04:47:25,497 --> 04:47:27,199
FUTURE FOR LUNG HEALTH IS STILL

7298
04:47:27,199 --> 04:47:28,600
AHEAD OF US, YOU KNOW.

7299
04:47:28,600 --> 04:47:30,235
SO PLEASE STAY ENGAGED AND

7300
04:47:30,235 --> 04:47:32,838
CONNECTED AS WE MOVE FORWARD.

7301
04:47:32,838 --> 04:47:34,172
AND THANK YOU ALL FOR MAKING

7302
04:47:34,172 --> 04:47:36,742
THIS WORKSHOP A REMARKABLE

7303
04:47:36,742 --> 04:47:37,809
SUCCESS, AND WITH THAT, I CLOSE.

7304
04:47:37,809 --> 04:47:39,911
THANK YOU SO MUCH.

7305
04:47:39,911 --> 04:47:40,679
>> THANK YOU.

7306
04:47:40,679 --> 04:47:41,847
HAVE A GREAT DAY.

7307
04:47:41,847 --> 04:47:51,847
A GREAT EVENING.