WEBVTT NOTE duration:"01:06:07.3600000" NOTE recognizability:0.808 NOTE language:en-us NOTE Confidence: 0.919102911111111 00:00:00.000 --> 00:00:02.970 Thank you everyone for joining NOTE Confidence: 0.919102911111111 00:00:02.970 --> 00:00:05.346 our grand rounds today. NOTE Confidence: 0.919102911111111 00:00:05.350 --> 00:00:08.941 It is my honor and great pleasure NOTE Confidence: 0.919102911111111 00:00:08.941 --> 00:00:11.740 to introduce Doctor Jason Mills. NOTE Confidence: 0.919102911111111 00:00:11.740 --> 00:00:14.953 He is a Herman Brown endowed professor NOTE Confidence: 0.919102911111111 00:00:14.953 --> 00:00:17.400 at Baylor College of Medicine, NOTE Confidence: 0.919102911111111 00:00:17.400 --> 00:00:20.172 Chief of Research in the section NOTE Confidence: 0.919102911111111 00:00:20.172 --> 00:00:22.020 of gastroenterology and Hepatology, NOTE Confidence: 0.919102911111111 00:00:22.020 --> 00:00:24.515 and the Co director of Digestive Disease NOTE Confidence: 0.919102911111111 00:00:24.515 --> 00:00:27.500 Center at the Texas Medical Center. NOTE Confidence: 0.919102911111111 00:00:27.500 --> 00:00:31.066 So he graduated summa *** laude from NOTE Confidence: 0.919102911111111 00:00:31.066 --> 00:00:33.460 Washington University in Saint Louis with NOTE Confidence: 0.919102911111111 00:00:33.460 --> 00:00:38.140 double major in Russian and biology, right? NOTE Confidence: 0.919102911111111 00:00:38.140 --> 00:00:41.339 Then he received the MD and PhD NOTE Confidence: 0.919102911111111 00:00:41.340 --> 00:00:43.365 from University of Pennsylvania and NOTE Confidence: 0.919102911111111 00:00:43.365 --> 00:00:45.990 went back to Washu for his anatomic NOTE Confidence: 0.919102911111111 00:00:46.068 --> 00:00:49.990 pathology residency and postdoctoral. NOTE Confidence: 0.919102911111111 00:00:49.990 --> 00:00:50.994 Fellowship there. NOTE Confidence: 0.919102911111111 00:00:50.994 --> 00:00:54.508 And he mentioned that he had a NOTE Confidence: 0.919102911111111 00:00:54.508 --> 00:00:56.921 traumatizing experience with Doctor NOTE Confidence: 0.919102911111111 00:00:56.921 --> 00:01:00.840 Peter Humphrey as pathologist here at Yale. NOTE Confidence: 0.919102911111111 00:01:00.840 --> 00:01:03.000 Now when they were, you know, NOTE Confidence: 0.919102911111111 00:01:03.000 --> 00:01:05.499 signing out a big stack of the NOTE Confidence: 0.919102911111111 00:01:05.499 --> 00:01:07.618 Hershey Springs case in the middle, NOTE Confidence: 0.919102911111111 00:01:07.620 --> 00:01:08.860 they had a, you know, NOTE Confidence: 0.919102911111111 00:01:08.860 --> 00:01:10.696 frozen section and had to leave. NOTE Confidence: 0.919102911111111 00:01:10.700 --> 00:01:12.988 And then when they came back and they NOTE Confidence: 0.919102911111111 00:01:12.988 --> 00:01:15.040 didn't remember which stack half stack NOTE Confidence: 0.919102911111111 00:01:15.040 --> 00:01:17.497 they have reviewed versus they have not. NOTE Confidence: 0.919102911111111 00:01:17.500 --> 00:01:20.236 So they had to go over again the. NOTE Confidence: 0.919102911111111 00:01:20.240 --> 00:01:23.126 Except that's the entire case again. NOTE Confidence: 0.919102911111111 00:01:23.130 --> 00:01:25.482 So they will have a reunion NOTE Confidence: 0.919102911111111 00:01:25.482 --> 00:01:27.050 in the afternoon today. NOTE Confidence: 0.919102911111111 00:01:27.050 --> 00:01:30.336 So you can have some conversation on that, NOTE Confidence: 0.919102911111111 00:01:30.336 --> 00:01:31.069 right? NOTE Confidence: 0.919102911111111 00:01:31.070 --> 00:01:34.325 And actually Jason was my PhD thesis NOTE Confidence: 0.919102911111111 00:01:34.325 --> 00:01:36.920 mentor at Washu and so I have known NOTE Confidence: 0.919102911111111 00:01:36.920 --> 00:01:39.962 him for 18 years now and all my NOTE Confidence: 0.919102911111111 00:01:39.962 --> 00:01:42.170 interest in the GI research came NOTE Confidence: 0.919102911111111 00:01:42.170 --> 00:01:46.408 from him and and he was a positive NOTE Confidence: 0.919102911111111 00:01:46.410 --> 00:01:48.881 influence for me to pursue my career NOTE Confidence: 0.919102911111111 00:01:48.881 --> 00:01:50.960 in pathology on the first day. NOTE Confidence: 0.919102911111111 00:01:50.960 --> 00:01:53.350 When I joined this laboratory, NOTE Confidence: 0.919102911111111 00:01:53.350 --> 00:01:55.870 we sit down on the double headed NOTE Confidence: 0.919102911111111 00:01:55.870 --> 00:01:58.352 microscope and he went over mouse NOTE Confidence: 0.919102911111111 00:01:58.352 --> 00:02:00.552 and human stomach Histology and NOTE Confidence: 0.919102911111111 00:02:00.552 --> 00:02:03.239 encouraged me to become a pathologist. NOTE Confidence: 0.919102911111111 00:02:03.240 --> 00:02:06.768 And at that time I was very negative NOTE Confidence: 0.919102911111111 00:02:06.770 --> 00:02:09.605 because I never thought about becoming a NOTE Confidence: 0.919102911111111 00:02:09.605 --> 00:02:12.328 pathologist during my entire medical school. NOTE Confidence: 0.919102911111111 00:02:12.330 --> 00:02:15.710 But see now I'm a I became a pathologist. NOTE Confidence: 0.919102911111111 00:02:15.710 --> 00:02:17.850 That's how influence influential NOTE Confidence: 0.919102911111111 00:02:17.850 --> 00:02:20.980 he is and as pathologists. NOTE Confidence: 0.919102911111111 00:02:20.980 --> 00:02:22.940 And some researchers here, NOTE Confidence: 0.919102911111111 00:02:22.940 --> 00:02:26.572 we know well what metaplasia looks like, NOTE Confidence: 0.919102911111111 00:02:26.572 --> 00:02:28.148 but we do not know. NOTE Confidence: 0.919102911111111 00:02:28.148 --> 00:02:29.560 Well, you know, how it happens. NOTE Confidence: 0.919102911111111 00:02:29.560 --> 00:02:32.759 What's the process mechanism on the line? NOTE Confidence: 0.919102911111111 00:02:32.760 --> 00:02:34.766 So Doctor Miller says, NOTE Confidence: 0.919102911111111 00:02:34.766 --> 00:02:37.574 focused on his research in the NOTE Confidence: 0.919102911111111 00:02:37.574 --> 00:02:40.020 cellular and molecular process NOTE Confidence: 0.919102911111111 00:02:40.020 --> 00:02:42.048 changes during the metaplasia. NOTE Confidence: 0.919102911111111 00:02:42.048 --> 00:02:44.076 And published more than, NOTE Confidence: 0.919102911111111 00:02:44.080 --> 00:02:45.024 you know, NOTE Confidence: 0.919102911111111 00:02:45.024 --> 00:02:48.593 hundred papers on the metaplasia and in NOTE Confidence: 0.919102911111111 00:02:48.593 --> 00:02:51.560 addition to the seminal scientific works, NOTE Confidence: 0.919102911111111 00:02:51.560 --> 00:02:53.630 he is very talented as he told NOTE Confidence: 0.919102911111111 00:02:53.630 --> 00:02:55.240 you that he majored in Russian, NOTE Confidence: 0.919102911111111 00:02:55.240 --> 00:02:58.872 he is very fluent in Russian and French NOTE Confidence: 0.919102911111111 00:02:58.872 --> 00:03:01.770 and also he can speak some Chinese NOTE Confidence: 0.919102911111111 00:03:01.770 --> 00:03:04.395 and he knows many words in Korean. NOTE Confidence: 0.919102911111111 00:03:04.400 --> 00:03:08.978 So with his talents in language, NOTE Confidence: 0.919102911111111 00:03:08.980 --> 00:03:13.830 he recently coined terminology collagenosis. NOTE Confidence: 0.919102911111111 00:03:13.830 --> 00:03:16.826 Which describes a universal program NOTE Confidence: 0.919102911111111 00:03:16.826 --> 00:03:20.510 how mature cells reenter and change NOTE Confidence: 0.919102911111111 00:03:20.604 --> 00:03:23.655 their subcellular structure and NOTE Confidence: 0.919102911111111 00:03:23.655 --> 00:03:28.005 re-enter cell cycle and becoming a. NOTE Confidence: 0.919102911111111 00:03:28.010 --> 00:03:31.170 The regenerative cells which NOTE Confidence: 0.919102911111111 00:03:31.170 --> 00:03:32.830 happens during the metaplasia, NOTE Confidence: 0.919102911111111 00:03:32.830 --> 00:03:36.225 so he's on the title of his talk today NOTE Confidence: 0.919102911111111 00:03:36.225 --> 00:03:38.835 is the common features of metaplasia NOTE Confidence: 0.919102911111111 00:03:38.835 --> 00:03:41.708 and tumorigenesis in the GI track which NOTE Confidence: 0.919102911111111 00:03:41.710 --> 00:03:43.850 implies the polygenesis basically. NOTE Confidence: 0.919102911111111 00:03:43.850 --> 00:03:46.740 So please join me in welcoming Dr. NOTE Confidence: 0.919102911111111 00:03:46.750 --> 00:03:47.060 Mills. NOTE Confidence: 0.35584447 00:03:50.230 --> 00:03:50.510 That's. NOTE Confidence: 0.805820654166667 00:03:53.460 --> 00:03:55.350 Thanks. Thanks so much for the NOTE Confidence: 0.805820654166667 00:03:55.350 --> 00:03:57.190 invitation and thanks to Juan Jay. NOTE Confidence: 0.805820654166667 00:03:57.190 --> 00:03:59.068 I mean it's it's fantastic growth NOTE Confidence: 0.805820654166667 00:03:59.068 --> 00:04:01.148 obviously to come here and and see NOTE Confidence: 0.805820654166667 00:04:01.148 --> 00:04:02.690 people again and meet and meet NOTE Confidence: 0.805820654166667 00:04:02.690 --> 00:04:04.679 new people and but it it's really NOTE Confidence: 0.805820654166667 00:04:04.679 --> 00:04:06.576 fantastic to see you know somebody NOTE Confidence: 0.805820654166667 00:04:06.576 --> 00:04:09.292 that you saw kind of come immediately NOTE Confidence: 0.805820654166667 00:04:09.292 --> 00:04:11.712 can just over from in fact I picked NOTE Confidence: 0.805820654166667 00:04:11.712 --> 00:04:13.119 you up at the airport I think NOTE Confidence: 0.805820654166667 00:04:13.119 --> 00:04:15.310 when you were interviewing for a NOTE Confidence: 0.805820654166667 00:04:15.310 --> 00:04:17.685 Graduate School at Washington St. NOTE Confidence: 0.805820654166667 00:04:17.690 --> 00:04:19.104 Louis and then to have him come NOTE Confidence: 0.805820654166667 00:04:19.104 --> 00:04:21.127 to my lab and then not even be NOTE Confidence: 0.805820654166667 00:04:21.127 --> 00:04:22.487 interested in pathology and coming NOTE Confidence: 0.805820654166667 00:04:22.537 --> 00:04:24.112 to do a PhD and then to wind up. NOTE Confidence: 0.805820654166667 00:04:24.120 --> 00:04:26.262 A pathologist and then here is an NOTE Confidence: 0.805820654166667 00:04:26.262 --> 00:04:27.670 assistant professor and Andre is NOTE Confidence: 0.805820654166667 00:04:27.670 --> 00:04:29.390 the first out of my group to to NOTE Confidence: 0.805820654166667 00:04:29.446 --> 00:04:31.058 become an assistant professor. NOTE Confidence: 0.805820654166667 00:04:31.060 --> 00:04:33.664 So it's just you know it's fantastic NOTE Confidence: 0.805820654166667 00:04:33.664 --> 00:04:36.094 honor and and fun to see see how NOTE Confidence: 0.805820654166667 00:04:36.094 --> 00:04:37.576 things are things grow and and NOTE Confidence: 0.805820654166667 00:04:37.576 --> 00:04:39.200 it was a fantastic introduction NOTE Confidence: 0.805820654166667 00:04:39.200 --> 00:04:41.342 because you know essentially I just NOTE Confidence: 0.805820654166667 00:04:41.342 --> 00:04:43.590 want to I usually don't do a lot NOTE Confidence: 0.805820654166667 00:04:43.590 --> 00:04:45.188 of introduction for how I organize NOTE Confidence: 0.805820654166667 00:04:45.188 --> 00:04:47.425 the talk but because you know I am NOTE Confidence: 0.805820654166667 00:04:47.425 --> 00:04:49.448 a pathologist but also a cell and NOTE Confidence: 0.805820654166667 00:04:49.448 --> 00:04:50.546 developmental biologist my talk NOTE Confidence: 0.805820654166667 00:04:50.546 --> 00:04:52.500 kind of it will go back and forth. NOTE Confidence: 0.805820654166667 00:04:52.500 --> 00:04:54.300 The first part is all going to be sort NOTE Confidence: 0.805820654166667 00:04:54.349 --> 00:04:55.966 of human. Well, it's your background. NOTE Confidence: 0.805820654166667 00:04:55.966 --> 00:04:58.401 And then the middle part is gonna go NOTE Confidence: 0.805820654166667 00:04:58.401 --> 00:05:00.333 all the way down into ribosomes and, NOTE Confidence: 0.805820654166667 00:05:00.340 --> 00:05:02.560 you know, very cell biological. NOTE Confidence: 0.805820654166667 00:05:02.560 --> 00:05:04.604 But if you're interested in human pathology, NOTE Confidence: 0.805820654166667 00:05:04.610 --> 00:05:06.416 don't give up there because it'll NOTE Confidence: 0.805820654166667 00:05:06.416 --> 00:05:07.923 come back also to human pathology. NOTE Confidence: 0.805820654166667 00:05:07.923 --> 00:05:09.910 So that's on the sort of that organization. NOTE Confidence: 0.805820654166667 00:05:09.910 --> 00:05:11.954 And then just as one day said, NOTE Confidence: 0.805820654166667 00:05:11.960 --> 00:05:13.541 as a resident, NOTE Confidence: 0.805820654166667 00:05:13.541 --> 00:05:16.176 I became fascinated with metaplasia. NOTE Confidence: 0.805820654166667 00:05:16.180 --> 00:05:17.128 And, you know, NOTE Confidence: 0.805820654166667 00:05:17.128 --> 00:05:19.500 how do these cells that are sort of NOTE Confidence: 0.805820654166667 00:05:19.500 --> 00:05:21.536 normal cells show up in the wrong NOTE Confidence: 0.805820654166667 00:05:21.536 --> 00:05:23.198 place and how does that happen NOTE Confidence: 0.805820654166667 00:05:23.198 --> 00:05:24.810 at a cell biological? NOTE Confidence: 0.805820654166667 00:05:24.810 --> 00:05:25.593 Point of view, NOTE Confidence: 0.805820654166667 00:05:25.593 --> 00:05:26.898 so that's my clinical interest. NOTE Confidence: 0.805820654166667 00:05:26.900 --> 00:05:29.252 So we we're always doing sort of NOTE Confidence: 0.805820654166667 00:05:29.252 --> 00:05:30.949 translational work on that side, NOTE Confidence: 0.805820654166667 00:05:30.950 --> 00:05:32.588 but then on the research side, NOTE Confidence: 0.805820654166667 00:05:32.590 --> 00:05:38.170 my cell biologist always side says. NOTE Confidence: 0.805820654166667 00:05:38.170 --> 00:05:40.249 You know what what how does cells do that? NOTE Confidence: 0.805820654166667 00:05:40.250 --> 00:05:42.049 How can cells like make this happen? NOTE Confidence: 0.805820654166667 00:05:42.050 --> 00:05:43.210 So what are the mechanisms? NOTE Confidence: 0.805820654166667 00:05:43.210 --> 00:05:44.449 So that's what the talk is about. NOTE Confidence: 0.805820654166667 00:05:44.450 --> 00:05:47.060 So yes the cell biological NOTE Confidence: 0.805820654166667 00:05:47.060 --> 00:05:48.964 changes are the cell, NOTE Confidence: 0.805820654166667 00:05:48.964 --> 00:05:50.672 biological processes polygenesis and NOTE Confidence: 0.805820654166667 00:05:50.672 --> 00:05:55.998 then you know the the context for the. NOTE Confidence: 0.805820654166667 00:05:56.000 --> 00:05:58.469 Pathology is metaplasia. NOTE Confidence: 0.805820654166667 00:05:58.470 --> 00:06:01.320 So. NOTE Confidence: 0.805820654166667 00:06:01.320 --> 00:06:02.958 One just said why don't you put NOTE Confidence: 0.805820654166667 00:06:02.958 --> 00:06:04.283 prognosis in your title so I NOTE Confidence: 0.805820654166667 00:06:04.283 --> 00:06:05.429 I added it last night so. NOTE Confidence: 0.859913548333333 00:06:07.800 --> 00:06:09.156 OK. So you know as far NOTE Confidence: 0.859913548333333 00:06:09.156 --> 00:06:10.679 as I said it's like the, NOTE Confidence: 0.859913548333333 00:06:10.680 --> 00:06:12.402 the clinical drive for this is NOTE Confidence: 0.859913548333333 00:06:12.402 --> 00:06:13.980 how do these metaplasia happen, NOTE Confidence: 0.859913548333333 00:06:13.980 --> 00:06:15.500 how do precancerous lesions arise NOTE Confidence: 0.859913548333333 00:06:15.500 --> 00:06:17.620 along the GI tract and and how NOTE Confidence: 0.859913548333333 00:06:17.620 --> 00:06:18.975 do they progress to tumors. NOTE Confidence: 0.859913548333333 00:06:18.980 --> 00:06:22.172 So that's kind of what drives and NOTE Confidence: 0.859913548333333 00:06:22.172 --> 00:06:25.024 funds our work and lately you know NOTE Confidence: 0.859913548333333 00:06:25.024 --> 00:06:28.084 it's not just us but with the advent NOTE Confidence: 0.859913548333333 00:06:28.084 --> 00:06:31.228 of of single cell RNA seek in in NOTE Confidence: 0.859913548333333 00:06:31.228 --> 00:06:33.436 multiple organs I think you know NOTE Confidence: 0.859913548333333 00:06:33.436 --> 00:06:34.981 we're beginning to realize that NOTE Confidence: 0.859913548333333 00:06:34.981 --> 00:06:36.815 there's a lot more commonality NOTE Confidence: 0.859913548333333 00:06:36.815 --> 00:06:38.279 in metaplasia across multiple. NOTE Confidence: 0.859913548333333 00:06:38.280 --> 00:06:38.930 The Oregon. NOTE Confidence: 0.859913548333333 00:06:38.930 --> 00:06:41.205 So there might be commonality in in NOTE Confidence: 0.859913548333333 00:06:41.205 --> 00:06:43.013 these precancerous lesions that that NOTE Confidence: 0.859913548333333 00:06:43.013 --> 00:06:46.040 you know I was trained when I was an, NOTE Confidence: 0.859913548333333 00:06:46.040 --> 00:06:50.720 you know an AP resident to think it was. NOTE Confidence: 0.859913548333333 00:06:50.720 --> 00:06:51.686 Sort of process. NOTE Confidence: 0.859913548333333 00:06:51.686 --> 00:06:53.618 Interest on metaplasia in the stomach NOTE Confidence: 0.859913548333333 00:06:53.618 --> 00:06:55.470 and and certainly has nothing to NOTE Confidence: 0.859913548333333 00:06:55.470 --> 00:06:57.363 do with how colon cancer starts NOTE Confidence: 0.859913548333333 00:06:57.363 --> 00:06:59.168 or how pancreatic cancer starts. NOTE Confidence: 0.859913548333333 00:06:59.170 --> 00:07:01.159 On the other hand it's kind of like you NOTE Confidence: 0.859913548333333 00:07:01.159 --> 00:07:02.968 know it's kind of becoming clear that NOTE Confidence: 0.859913548333333 00:07:02.968 --> 00:07:04.850 that there's a lot of similarities. NOTE Confidence: 0.859913548333333 00:07:04.850 --> 00:07:06.570 So let's talk about that. NOTE Confidence: 0.859913548333333 00:07:06.570 --> 00:07:08.190 So you know with with Jim NOTE Confidence: 0.859913548333333 00:07:08.190 --> 00:07:09.270 Golden Ring at Vanderbilt, NOTE Confidence: 0.859913548333333 00:07:09.270 --> 00:07:11.455 we had this review recently NOTE Confidence: 0.859913548333333 00:07:11.455 --> 00:07:12.766 in gastroenterology talking NOTE Confidence: 0.859913548333333 00:07:12.766 --> 00:07:14.910 about some of these concepts. NOTE Confidence: 0.859913548333333 00:07:14.910 --> 00:07:17.046 In this one in particular we NOTE Confidence: 0.859913548333333 00:07:17.046 --> 00:07:18.470 focused on the similarities NOTE Confidence: 0.859913548333333 00:07:18.537 --> 00:07:20.665 between Barrett's metaplasia and NOTE Confidence: 0.859913548333333 00:07:20.665 --> 00:07:22.793 gastric and intestinal metaplasia. NOTE Confidence: 0.859913548333333 00:07:22.800 --> 00:07:23.696 And basically you know, NOTE Confidence: 0.859913548333333 00:07:23.696 --> 00:07:24.816 if you think of Barretts, NOTE Confidence: 0.859913548333333 00:07:24.820 --> 00:07:26.820 the ideology there is obviously NOTE Confidence: 0.859913548333333 00:07:26.820 --> 00:07:29.284 quite different from the way you NOTE Confidence: 0.859913548333333 00:07:29.284 --> 00:07:31.249 get intestinal metaplasia in the NOTE Confidence: 0.859913548333333 00:07:31.249 --> 00:07:33.430 stomach and and that's because, NOTE Confidence: 0.859913548333333 00:07:33.430 --> 00:07:34.950 you know, we know that. NOTE Confidence: 0.859913548333333 00:07:34.950 --> 00:07:37.560 Had a thing of of reflux of acid and NOTE Confidence: 0.859913548333333 00:07:37.560 --> 00:07:40.748 and probably also importantly bile as well. NOTE Confidence: 0.859913548333333 00:07:40.750 --> 00:07:42.742 And then that takes your squamous NOTE Confidence: 0.859913548333333 00:07:42.742 --> 00:07:44.568 epithelium right and turns it into NOTE Confidence: 0.859913548333333 00:07:44.568 --> 00:07:46.950 this what in Barretts is called, NOTE Confidence: 0.859913548333333 00:07:46.950 --> 00:07:47.926 you know, NOTE Confidence: 0.859913548333333 00:07:47.926 --> 00:07:51.342 a columnar mucosa at least at first, NOTE Confidence: 0.859913548333333 00:07:51.350 --> 00:07:53.270 which is basically organized NOTE Confidence: 0.859913548333333 00:07:53.270 --> 00:07:55.670 a pyloric gastric unit is. NOTE Confidence: 0.859913548333333 00:07:55.670 --> 00:07:56.975 So it's essentially just a NOTE Confidence: 0.859913548333333 00:07:56.975 --> 00:07:58.280 pyloric metaplasia or a pseudo NOTE Confidence: 0.859913548333333 00:07:58.334 --> 00:07:59.850 pyloric metaplasia from squamous, NOTE Confidence: 0.859913548333333 00:07:59.850 --> 00:08:01.450 although nobody ever calls it NOTE Confidence: 0.859913548333333 00:08:01.450 --> 00:08:02.610 that in the esophagus, NOTE Confidence: 0.859913548333333 00:08:02.610 --> 00:08:05.380 I want to point out that to researchers. NOTE Confidence: 0.859913548333333 00:08:05.380 --> 00:08:07.916 Jim being the one on golden Ring that NOTE Confidence: 0.859913548333333 00:08:07.916 --> 00:08:10.092 coined this term at Vanderbilt that NOTE Confidence: 0.859913548333333 00:08:10.092 --> 00:08:12.276 that that what that means is that NOTE Confidence: 0.859913548333333 00:08:12.276 --> 00:08:15.296 that the cells at the bottom are stem cells, NOTE Confidence: 0.859913548333333 00:08:15.300 --> 00:08:16.074 spasmolytic polypeptide NOTE Confidence: 0.859913548333333 00:08:16.074 --> 00:08:16.848 expressing metaplasia. NOTE Confidence: 0.859913548333333 00:08:16.848 --> 00:08:19.980 And so that's a term that was coined in, NOTE Confidence: 0.859913548333333 00:08:19.980 --> 00:08:22.758 in the stomach actually originally in NOTE Confidence: 0.859913548333333 00:08:22.758 --> 00:08:24.610 humans because spasmolytic polypeptide NOTE Confidence: 0.859913548333333 00:08:24.671 --> 00:08:26.589 is trefoil factor 2 and that shows NOTE Confidence: 0.859913548333333 00:08:26.589 --> 00:08:28.885 up only in these pyloric sort of NOTE Confidence: 0.859913548333333 00:08:28.885 --> 00:08:30.698 lesions in the body of the stomach. NOTE Confidence: 0.859913548333333 00:08:30.700 --> 00:08:33.316 So a lot of what we'll talk about NOTE Confidence: 0.859913548333333 00:08:33.316 --> 00:08:35.500 involves this transition into this. NOTE Confidence: 0.859913548333333 00:08:35.500 --> 00:08:38.332 Mucus secreting deep, antral, NOTE Confidence: 0.859913548333333 00:08:38.332 --> 00:08:40.590 deep pyloric TF2 positive NOTE Confidence: 0.859913548333333 00:08:40.590 --> 00:08:42.270 muck 6 positive lineage. NOTE Confidence: 0.859913548333333 00:08:42.270 --> 00:08:42.574 OK, NOTE Confidence: 0.859913548333333 00:08:42.574 --> 00:08:43.790 so in the stomach, NOTE Confidence: 0.859913548333333 00:08:43.790 --> 00:08:45.323 when H pylori get tired of being NOTE Confidence: 0.859913548333333 00:08:45.323 --> 00:08:45.980 in the Antrim, NOTE Confidence: 0.859913548333333 00:08:45.980 --> 00:08:47.564 they want to expand their knee and they NOTE Confidence: 0.859913548333333 00:08:47.564 --> 00:08:49.346 want to go into the body of the stomach. NOTE Confidence: 0.859913548333333 00:08:49.350 --> 00:08:51.390 And it turns out that the way they do this, NOTE Confidence: 0.859913548333333 00:08:51.390 --> 00:08:54.034 or we can model this with drugs. NOTE Confidence: 0.859913548333333 00:08:54.034 --> 00:08:56.008 And in fact Juan Jade pioneered this. NOTE Confidence: 0.859913548333333 00:08:56.010 --> 00:08:57.599 And there are hundreds of papers now NOTE Confidence: 0.859913548333333 00:08:57.599 --> 00:08:59.309 in the world using this technique, NOTE Confidence: 0.891849746666667 00:08:59.310 --> 00:09:03.078 which is using high doses of tamoxifen can NOTE Confidence: 0.891849746666667 00:09:03.078 --> 00:09:05.819 completely reprogram the stomach of a mouse. NOTE Confidence: 0.891849746666667 00:09:05.820 --> 00:09:07.844 The same way that H pylori can in NOTE Confidence: 0.891849746666667 00:09:07.844 --> 00:09:09.938 humans and actually H pylori and mouse NOTE Confidence: 0.891849746666667 00:09:09.938 --> 00:09:12.273 over a longer time course and what NOTE Confidence: 0.891849746666667 00:09:12.273 --> 00:09:14.143 happens during that reprogramming is NOTE Confidence: 0.891849746666667 00:09:14.143 --> 00:09:16.641 essentially what we talk about as NOTE Confidence: 0.891849746666667 00:09:16.641 --> 00:09:18.926 pathologist as chronic atrophic gastritis, NOTE Confidence: 0.891849746666667 00:09:18.930 --> 00:09:21.198 but is actually also a metaplasia NOTE Confidence: 0.891849746666667 00:09:21.198 --> 00:09:23.964 because it turns the corpus units away NOTE Confidence: 0.891849746666667 00:09:23.964 --> 00:09:26.708 from being oxyntic units with gas with NOTE Confidence: 0.891849746666667 00:09:26.785 --> 00:09:29.496 the parietal cells and chief cells into NOTE Confidence: 0.891849746666667 00:09:29.496 --> 00:09:31.126 basically a pyloric like structure NOTE Confidence: 0.891849746666667 00:09:31.126 --> 00:09:33.969 with MUC 5 AC positive foveolar cells, NOTE Confidence: 0.891849746666667 00:09:33.970 --> 00:09:35.446 a lower ismal. NOTE Confidence: 0.891849746666667 00:09:35.446 --> 00:09:37.906 Proliferative center and again these NOTE Confidence: 0.891849746666667 00:09:37.906 --> 00:09:40.814 deep antral like cells which are NOTE Confidence: 0.891849746666667 00:09:40.814 --> 00:09:43.784 characterized in the stomach as NOTE Confidence: 0.891849746666667 00:09:43.784 --> 00:09:45.566 spasmolytic polypeptide expressing NOTE Confidence: 0.891849746666667 00:09:45.566 --> 00:09:46.463 metaplasia. So. NOTE Confidence: 0.891849746666667 00:09:46.463 --> 00:09:47.069 You know, NOTE Confidence: 0.891849746666667 00:09:47.069 --> 00:09:49.190 the first step basically of H pylori NOTE Confidence: 0.891849746666667 00:09:49.256 --> 00:09:51.720 is to turn normal oxyntic glands into NOTE Confidence: 0.891849746666667 00:09:51.720 --> 00:09:53.929 these pseudo pyloric metaplasia glands, NOTE Confidence: 0.891849746666667 00:09:53.930 --> 00:09:55.256 which is much more what they're NOTE Confidence: 0.891849746666667 00:09:55.256 --> 00:09:56.480 accustomed to in the antrum, NOTE Confidence: 0.891849746666667 00:09:56.480 --> 00:09:59.864 and that's how they spread from the stomach. NOTE Confidence: 0.891849746666667 00:09:59.870 --> 00:10:01.562 So basically what that means is NOTE Confidence: 0.891849746666667 00:10:01.562 --> 00:10:03.833 that that you know as we kind of NOTE Confidence: 0.891849746666667 00:10:03.833 --> 00:10:05.459 learn more and more about Barretts NOTE Confidence: 0.891849746666667 00:10:05.515 --> 00:10:07.363 and we do the single cell RNA seek NOTE Confidence: 0.891849746666667 00:10:07.363 --> 00:10:09.450 and we do the genome studies and we NOTE Confidence: 0.891849746666667 00:10:09.450 --> 00:10:11.729 try to look at the clonal origin, NOTE Confidence: 0.891849746666667 00:10:11.730 --> 00:10:13.690 origin of the Barrett's lesions. NOTE Confidence: 0.891849746666667 00:10:13.690 --> 00:10:16.570 And you know the best consensus NOTE Confidence: 0.891849746666667 00:10:16.570 --> 00:10:19.649 is that these kind of columnar NOTE Confidence: 0.891849746666667 00:10:19.650 --> 00:10:21.378 lesions that look gastric are the NOTE Confidence: 0.891849746666667 00:10:21.378 --> 00:10:23.199 first ones that appear in Barretts. NOTE Confidence: 0.891849746666667 00:10:23.200 --> 00:10:25.958 But even these can be traced back NOTE Confidence: 0.891849746666667 00:10:25.958 --> 00:10:27.970 to roots in in oxyntic mucosa, NOTE Confidence: 0.891849746666667 00:10:27.970 --> 00:10:30.714 in other words, if you do clonal. NOTE Confidence: 0.891849746666667 00:10:30.714 --> 00:10:31.626 Genomic analysis, NOTE Confidence: 0.891849746666667 00:10:31.630 --> 00:10:34.303 you see that these often can be found in NOTE Confidence: 0.891849746666667 00:10:34.303 --> 00:10:37.388 a patient near where they're you know, NOTE Confidence: 0.891849746666667 00:10:37.388 --> 00:10:39.558 most proximal eccentric glands are. NOTE Confidence: 0.891849746666667 00:10:39.560 --> 00:10:41.696 So the idea then is that bile or NOTE Confidence: 0.891849746666667 00:10:41.696 --> 00:10:43.999 acid can turn these oxyntic glands NOTE Confidence: 0.891849746666667 00:10:43.999 --> 00:10:45.695 into these pyloric glands. NOTE Confidence: 0.891849746666667 00:10:45.700 --> 00:10:47.806 And then pretty clearly what happens NOTE Confidence: 0.891849746666667 00:10:47.806 --> 00:10:50.280 then is they become intestinal used. NOTE Confidence: 0.891849746666667 00:10:50.280 --> 00:10:51.496 And why do I say it's pretty clear? NOTE Confidence: 0.891849746666667 00:10:51.500 --> 00:10:53.908 It's because if you look at all Barrett NOTE Confidence: 0.891849746666667 00:10:53.908 --> 00:10:55.030 specimens, especially if you have, NOTE Confidence: 0.891849746666667 00:10:55.030 --> 00:10:56.150 you know, full thickness, NOTE Confidence: 0.891849746666667 00:10:56.150 --> 00:10:58.280 they almost always have bases that NOTE Confidence: 0.891849746666667 00:10:58.280 --> 00:11:00.379 are muck 6 positive or trefoil. NOTE Confidence: 0.891849746666667 00:11:00.380 --> 00:11:02.580 Factor 2 positive or look just like these, NOTE Confidence: 0.891849746666667 00:11:02.580 --> 00:11:04.184 you know spasmolytic polypeptide NOTE Confidence: 0.891849746666667 00:11:04.184 --> 00:11:06.189 expressing metaplasia cells and it's NOTE Confidence: 0.891849746666667 00:11:06.189 --> 00:11:08.182 only the surface at least until you NOTE Confidence: 0.891849746666667 00:11:08.182 --> 00:11:09.844 get a high grade dysplasia that NOTE Confidence: 0.891849746666667 00:11:09.844 --> 00:11:11.602 has a lot of intestinal lization NOTE Confidence: 0.891849746666667 00:11:11.602 --> 00:11:13.782 and of course then the progression NOTE Confidence: 0.891849746666667 00:11:13.782 --> 00:11:16.170 progression from here is into dysplasia. NOTE Confidence: 0.891849746666667 00:11:16.170 --> 00:11:19.586 So our research really is into you know, NOTE Confidence: 0.891849746666667 00:11:19.590 --> 00:11:21.014 how do you get from here to here, NOTE Confidence: 0.891849746666667 00:11:21.020 --> 00:11:22.436 how do you get from here to here NOTE Confidence: 0.891849746666667 00:11:22.436 --> 00:11:24.034 and how do you get from here to NOTE Confidence: 0.891849746666667 00:11:24.034 --> 00:11:25.370 here from a pathology standpoint, NOTE Confidence: 0.891849746666667 00:11:25.370 --> 00:11:27.470 you know then that gives you cancer. NOTE Confidence: 0.891849746666667 00:11:27.470 --> 00:11:29.297 One thing just as a take home NOTE Confidence: 0.891849746666667 00:11:29.297 --> 00:11:30.540 is that we think. NOTE Confidence: 0.891849746666667 00:11:30.540 --> 00:11:32.622 Critical event in all of these NOTE Confidence: 0.891849746666667 00:11:32.622 --> 00:11:34.670 transitions very early on is 53 NOTE Confidence: 0.891849746666667 00:11:34.670 --> 00:11:36.749 mutation and we're going to dig right NOTE Confidence: 0.891849746666667 00:11:36.749 --> 00:11:38.894 into the cell biology as we we you NOTE Confidence: 0.891849746666667 00:11:38.894 --> 00:11:41.240 know why we think that now clinically NOTE Confidence: 0.891849746666667 00:11:41.240 --> 00:11:43.215 and Barretts and molecularly we're NOTE Confidence: 0.891849746666667 00:11:43.215 --> 00:11:45.274 finding that that basically as soon as NOTE Confidence: 0.891849746666667 00:11:45.274 --> 00:11:47.398 you have a loss of heterozygosity for NOTE Confidence: 0.891849746666667 00:11:47.398 --> 00:11:49.715 people 53 and and and patients have NOTE Confidence: 0.695209716363636 00:11:49.720 --> 00:11:52.576 loss of function for PD3 then those NOTE Confidence: 0.695209716363636 00:11:52.576 --> 00:11:54.700 Barretts lesions behave differently. NOTE Confidence: 0.695209716363636 00:11:54.700 --> 00:11:56.324 They're almost always become NOTE Confidence: 0.695209716363636 00:11:56.324 --> 00:11:58.760 dysplastic and the rate of conversion NOTE Confidence: 0.695209716363636 00:11:58.822 --> 00:12:02.440 to neoplasms much higher. So. NOTE Confidence: 0.695209716363636 00:12:02.440 --> 00:12:04.358 What I'm saying is that I think, NOTE Confidence: 0.695209716363636 00:12:04.360 --> 00:12:05.660 you know, basically based on NOTE Confidence: 0.695209716363636 00:12:05.660 --> 00:12:07.271 the the lineage tracing and all NOTE Confidence: 0.695209716363636 00:12:07.271 --> 00:12:08.807 these sort of parallels and the NOTE Confidence: 0.695209716363636 00:12:08.807 --> 00:12:10.112 molecular work that we're doing NOTE Confidence: 0.695209716363636 00:12:10.112 --> 00:12:11.576 that what we think happens is, NOTE Confidence: 0.695209716363636 00:12:11.580 --> 00:12:13.278 you know, violent acid comes in, NOTE Confidence: 0.695209716363636 00:12:13.280 --> 00:12:14.975 Barretts and it. NOTE Confidence: 0.695209716363636 00:12:14.975 --> 00:12:17.800 Takes out the squamous epithelium NOTE Confidence: 0.695209716363636 00:12:17.800 --> 00:12:21.709 and then in the in the that sort NOTE Confidence: 0.695209716363636 00:12:21.709 --> 00:12:24.331 of damaged bedding and in that NOTE Confidence: 0.695209716363636 00:12:24.331 --> 00:12:26.466 reflex setting you get migration NOTE Confidence: 0.695209716363636 00:12:26.466 --> 00:12:29.629 of this kind of gastric epithelium. NOTE Confidence: 0.695209716363636 00:12:29.630 --> 00:12:32.780 And then the gastric epithelium NOTE Confidence: 0.695209716363636 00:12:32.780 --> 00:12:34.040 becomes intestinalis. NOTE Confidence: 0.695209716363636 00:12:34.040 --> 00:12:35.606 And so you can kind of see some of NOTE Confidence: 0.695209716363636 00:12:35.606 --> 00:12:36.930 these examples from and a lot of NOTE Confidence: 0.695209716363636 00:12:36.930 --> 00:12:38.410 the work that I was telling you, NOTE Confidence: 0.695209716363636 00:12:38.410 --> 00:12:40.786 the molecular work showing the origins NOTE Confidence: 0.695209716363636 00:12:40.786 --> 00:12:43.420 of the Barretts lesions in in, NOTE Confidence: 0.695209716363636 00:12:43.420 --> 00:12:44.340 you know, NOTE Confidence: 0.695209716363636 00:12:44.340 --> 00:12:46.404 way back at some point in a patient NOTE Confidence: 0.695209716363636 00:12:46.404 --> 00:12:48.278 in oxyntic mucosa is from Stuart NOTE Confidence: 0.695209716363636 00:12:48.278 --> 00:12:49.903 McDonald and Marnick Sanson and NOTE Confidence: 0.695209716363636 00:12:49.903 --> 00:12:51.665 Nick Wright who've been doing this NOTE Confidence: 0.695209716363636 00:12:51.665 --> 00:12:54.378 for a decade or two in in London. NOTE Confidence: 0.695209716363636 00:12:54.378 --> 00:12:57.366 So you can see like these oxyntic NOTE Confidence: 0.695209716363636 00:12:57.366 --> 00:12:58.896 lesions in in sometimes distal NOTE Confidence: 0.695209716363636 00:12:58.896 --> 00:13:00.945 Barretts and then you can see this NOTE Confidence: 0.695209716363636 00:13:00.945 --> 00:13:02.475 is just from their paper actually NOTE Confidence: 0.695209716363636 00:13:02.475 --> 00:13:04.169 and you see these more pyloric. NOTE Confidence: 0.695209716363636 00:13:04.170 --> 00:13:05.958 Regions where you have the spam NOTE Confidence: 0.695209716363636 00:13:05.958 --> 00:13:08.050 mucous cells at the bottom and then NOTE Confidence: 0.695209716363636 00:13:08.050 --> 00:13:10.010 you see spam mucous cells at the NOTE Confidence: 0.695209716363636 00:13:10.075 --> 00:13:12.247 bottom as the tops become intestinalis NOTE Confidence: 0.695209716363636 00:13:12.247 --> 00:13:15.930 used with goblet cells, so. NOTE Confidence: 0.695209716363636 00:13:15.930 --> 00:13:17.158 So we've been working, NOTE Confidence: 0.695209716363636 00:13:17.158 --> 00:13:19.000 we started working on Barretts five NOTE Confidence: 0.695209716363636 00:13:19.061 --> 00:13:21.098 or six years ago and started seeing NOTE Confidence: 0.695209716363636 00:13:21.098 --> 00:13:24.290 that all come together with our stomach work. NOTE Confidence: 0.695209716363636 00:13:24.290 --> 00:13:25.738 And then you know when you kind of NOTE Confidence: 0.695209716363636 00:13:25.738 --> 00:13:27.316 do this sort of thing then you go NOTE Confidence: 0.695209716363636 00:13:27.316 --> 00:13:29.008 back to the stomach and you think again, NOTE Confidence: 0.695209716363636 00:13:29.010 --> 00:13:31.392 well do we really understand how NOTE Confidence: 0.695209716363636 00:13:31.392 --> 00:13:32.980 the stomach metaplasia happens. NOTE Confidence: 0.695209716363636 00:13:32.980 --> 00:13:35.248 And so we started really kind of NOTE Confidence: 0.695209716363636 00:13:35.248 --> 00:13:37.298 digging into the different types NOTE Confidence: 0.695209716363636 00:13:37.298 --> 00:13:38.807 of stomach metaplasia. NOTE Confidence: 0.695209716363636 00:13:38.810 --> 00:13:40.637 You know that from a research side NOTE Confidence: 0.695209716363636 00:13:40.637 --> 00:13:42.782 and and actually in in Asia it's a NOTE Confidence: 0.695209716363636 00:13:42.782 --> 00:13:44.087 diagnostic thing where you really NOTE Confidence: 0.695209716363636 00:13:44.145 --> 00:13:45.529 make a distinction between. NOTE Confidence: 0.695209716363636 00:13:45.530 --> 00:13:47.156 Incomplete and test on that ablation, NOTE Confidence: 0.695209716363636 00:13:47.160 --> 00:13:49.070 complete and test on metaplasia. NOTE Confidence: 0.695209716363636 00:13:49.070 --> 00:13:49.630 In fact, NOTE Confidence: 0.695209716363636 00:13:49.630 --> 00:13:51.590 you know they're type ones and type NOTE Confidence: 0.695209716363636 00:13:51.590 --> 00:13:53.417 twos based on use and patterns. NOTE Confidence: 0.695209716363636 00:13:53.420 --> 00:13:55.298 But what does all that mean? NOTE Confidence: 0.695209716363636 00:13:55.300 --> 00:13:55.529 Well, NOTE Confidence: 0.695209716363636 00:13:55.529 --> 00:13:57.132 it turns out that really if you NOTE Confidence: 0.695209716363636 00:13:57.132 --> 00:13:59.120 go back in the in the stomach and NOTE Confidence: 0.695209716363636 00:13:59.120 --> 00:14:00.901 especially look at the borders of NOTE Confidence: 0.695209716363636 00:14:00.901 --> 00:14:02.397 patches of intestinal metaplasia, NOTE Confidence: 0.695209716363636 00:14:02.400 --> 00:14:04.472 a lot of the times they're they're NOTE Confidence: 0.695209716363636 00:14:04.472 --> 00:14:06.419 incomplete and they have the same NOTE Confidence: 0.695209716363636 00:14:06.419 --> 00:14:08.094 kind of organizations Barretts with NOTE Confidence: 0.695209716363636 00:14:08.100 --> 00:14:09.462 spasmolytic polypeptide expressing NOTE Confidence: 0.695209716363636 00:14:09.462 --> 00:14:12.186 metaplasia type deep pyloric cells at NOTE Confidence: 0.695209716363636 00:14:12.186 --> 00:14:14.226 the bottom and then internalization NOTE Confidence: 0.695209716363636 00:14:14.226 --> 00:14:15.750 of of goblet cells. NOTE Confidence: 0.695209716363636 00:14:15.750 --> 00:14:17.773 At the top and during COVID when NOTE Confidence: 0.695209716363636 00:14:17.773 --> 00:14:20.219 I had more time to kind of mess NOTE Confidence: 0.695209716363636 00:14:20.219 --> 00:14:22.391 around and and look into history of NOTE Confidence: 0.695209716363636 00:14:22.391 --> 00:14:24.751 stuff and I was trying to go back NOTE Confidence: 0.695209716363636 00:14:24.760 --> 00:14:27.329 and and try to figure out where NOTE Confidence: 0.695209716363636 00:14:27.329 --> 00:14:29.710 it was that everybody in the in NOTE Confidence: 0.695209716363636 00:14:29.710 --> 00:14:31.310 the stomach became obsessed with NOTE Confidence: 0.695209716363636 00:14:31.310 --> 00:14:32.240 intestinal metaplasia. NOTE Confidence: 0.695209716363636 00:14:32.240 --> 00:14:34.160 You know is this something that's NOTE Confidence: 0.695209716363636 00:14:34.160 --> 00:14:35.440 always happened because pretty NOTE Confidence: 0.695209716363636 00:14:35.490 --> 00:14:36.865 clearly the first thing that NOTE Confidence: 0.695209716363636 00:14:36.865 --> 00:14:38.240 happens in atrophy is this NOTE Confidence: 0.807014336521739 00:14:38.290 --> 00:14:39.490 more pyloric metaplasia. NOTE Confidence: 0.807014336521739 00:14:39.490 --> 00:14:40.726 Yet we never signed that out. NOTE Confidence: 0.807014336521739 00:14:40.730 --> 00:14:42.010 We never diagnosed that. NOTE Confidence: 0.807014336521739 00:14:42.010 --> 00:14:44.266 I started going back in history and NOTE Confidence: 0.807014336521739 00:14:44.266 --> 00:14:46.170 and you find that people you know. NOTE Confidence: 0.807014336521739 00:14:46.170 --> 00:14:48.395 Have been talking about pyloric NOTE Confidence: 0.807014336521739 00:14:48.395 --> 00:14:50.620 metaplasia actually since like the NOTE Confidence: 0.807014336521739 00:14:50.692 --> 00:14:53.239 1890s and it was only in the sort of NOTE Confidence: 0.807014336521739 00:14:53.239 --> 00:14:56.221 1960s or 70s that people became so NOTE Confidence: 0.807014336521739 00:14:56.221 --> 00:14:57.973 interested in intestinal medication. NOTE Confidence: 0.807014336521739 00:14:57.980 --> 00:15:00.206 It was about the time that endoscopic NOTE Confidence: 0.807014336521739 00:15:00.206 --> 00:15:01.937 biopsies came around and and NOTE Confidence: 0.807014336521739 00:15:01.937 --> 00:15:03.737 pathologists got only little snippets. NOTE Confidence: 0.807014336521739 00:15:03.740 --> 00:15:05.658 And you couldn't sort of tell the NOTE Confidence: 0.807014336521739 00:15:05.658 --> 00:15:07.777 orientation to tell whether there was basil, NOTE Confidence: 0.807014336521739 00:15:07.780 --> 00:15:10.420 you know, pyloric glands or not. NOTE Confidence: 0.807014336521739 00:15:10.420 --> 00:15:12.142 But even, you know in the 1890s NOTE Confidence: 0.807014336521739 00:15:12.142 --> 00:15:14.141 they kind of had this concept that NOTE Confidence: 0.807014336521739 00:15:14.141 --> 00:15:16.180 there were these sort of pyloric or. NOTE Confidence: 0.807014336521739 00:15:16.180 --> 00:15:18.007 Or acid or mucin cell like glance NOTE Confidence: 0.807014336521739 00:15:18.007 --> 00:15:20.053 at the bottom that these then might NOTE Confidence: 0.807014336521739 00:15:20.053 --> 00:15:22.416 have might be feeding these kind of NOTE Confidence: 0.807014336521739 00:15:22.416 --> 00:15:23.919 incomplete intestinal metaplasia. NOTE Confidence: 0.807014336521739 00:15:23.920 --> 00:15:27.441 This is from a textbook on gastric NOTE Confidence: 0.807014336521739 00:15:27.441 --> 00:15:29.838 pathology in 1897 just to kind NOTE Confidence: 0.807014336521739 00:15:29.838 --> 00:15:32.430 of show this diagram with sort of NOTE Confidence: 0.807014336521739 00:15:32.430 --> 00:15:35.034 spam metaplasia on the bottom and NOTE Confidence: 0.807014336521739 00:15:35.034 --> 00:15:36.989 then internalization on the top. NOTE Confidence: 0.807014336521739 00:15:36.990 --> 00:15:38.300 And then just you know, NOTE Confidence: 0.807014336521739 00:15:38.300 --> 00:15:40.370 I as I do a lot of sort of translational NOTE Confidence: 0.807014336521739 00:15:40.428 --> 00:15:41.989 work and I have slides about my NOTE Confidence: 0.807014336521739 00:15:41.989 --> 00:15:43.902 desk that I look at all the time NOTE Confidence: 0.807014336521739 00:15:43.902 --> 00:15:45.514 and you know bring people in like NOTE Confidence: 0.807014336521739 00:15:45.514 --> 00:15:46.963 Juan J and and sit and look. NOTE Confidence: 0.807014336521739 00:15:46.970 --> 00:15:48.842 You can actually see this pretty NOTE Confidence: 0.807014336521739 00:15:48.842 --> 00:15:50.888 frequently if you look for it where NOTE Confidence: 0.807014336521739 00:15:50.888 --> 00:15:52.596 you can see these kind of deep NOTE Confidence: 0.807014336521739 00:15:52.660 --> 00:15:54.765 pyloric glands erupting into more NOTE Confidence: 0.807014336521739 00:15:54.765 --> 00:15:56.449 superficial transitioning into this NOTE Confidence: 0.807014336521739 00:15:56.449 --> 00:15:58.742 kind of incomplete metaplasia. NOTE Confidence: 0.807014336521739 00:15:58.742 --> 00:16:02.486 OK, so that's stomach and esophagus. NOTE Confidence: 0.807014336521739 00:16:02.490 --> 00:16:04.394 But it turns out now with single NOTE Confidence: 0.807014336521739 00:16:04.394 --> 00:16:06.638 cell or in a site where you can NOTE Confidence: 0.807014336521739 00:16:06.638 --> 00:16:08.799 take apart each one of these cells NOTE Confidence: 0.807014336521739 00:16:08.799 --> 00:16:11.001 during progression to pan in lesions NOTE Confidence: 0.807014336521739 00:16:11.001 --> 00:16:12.905 again for some reason in you know NOTE Confidence: 0.807014336521739 00:16:12.905 --> 00:16:14.480 pathology we only talk about panning, NOTE Confidence: 0.807014336521739 00:16:14.480 --> 00:16:16.314 but in in the mouse where we NOTE Confidence: 0.807014336521739 00:16:16.314 --> 00:16:18.349 can sort of look at each step, NOTE Confidence: 0.807014336521739 00:16:18.350 --> 00:16:21.115 there's an intermediate step called NOTE Confidence: 0.807014336521739 00:16:21.115 --> 00:16:23.327 acinar ductal metaplasia where NOTE Confidence: 0.807014336521739 00:16:23.330 --> 00:16:26.084 the acinar cells shrink and become NOTE Confidence: 0.807014336521739 00:16:26.084 --> 00:16:28.530 more cuboidal columnar cells and NOTE Confidence: 0.807014336521739 00:16:28.530 --> 00:16:29.598 and proliferative. NOTE Confidence: 0.807014336521739 00:16:29.600 --> 00:16:31.622 In an acute or chronic pancreatitis NOTE Confidence: 0.807014336521739 00:16:31.622 --> 00:16:33.663 setting and when you start to NOTE Confidence: 0.807014336521739 00:16:33.663 --> 00:16:35.541 profile those cells by single cell NOTE Confidence: 0.807014336521739 00:16:35.541 --> 00:16:37.358 RNA seek what's interesting and NOTE Confidence: 0.807014336521739 00:16:37.358 --> 00:16:39.608 this was work done at Vanderbilt. NOTE Confidence: 0.807014336521739 00:16:39.610 --> 00:16:41.938 With a from Kathy Delgiorno's group NOTE Confidence: 0.807014336521739 00:16:41.938 --> 00:16:44.619 and and a number of collaborators NOTE Confidence: 0.807014336521739 00:16:44.619 --> 00:16:46.188 including Ken Lau. NOTE Confidence: 0.807014336521739 00:16:46.190 --> 00:16:47.534 I don't think you were on this paper NOTE Confidence: 0.807014336521739 00:16:47.534 --> 00:16:50.580 though on J while you were there, but. NOTE Confidence: 0.807014336521739 00:16:50.580 --> 00:16:53.788 But what you see in these early pancreatic NOTE Confidence: 0.807014336521739 00:16:53.788 --> 00:16:57.098 lesions is the same sorts of gastric cells. NOTE Confidence: 0.807014336521739 00:16:57.100 --> 00:16:57.799 Now of course, NOTE Confidence: 0.807014336521739 00:16:57.799 --> 00:16:59.197 they're not organized into a gland, NOTE Confidence: 0.807014336521739 00:16:59.200 --> 00:17:00.726 you know, they're all on these asinine. NOTE Confidence: 0.807014336521739 00:17:00.730 --> 00:17:02.470 But by single cell RNA seek, NOTE Confidence: 0.807014336521739 00:17:02.470 --> 00:17:03.860 you see cells that look NOTE Confidence: 0.807014336521739 00:17:03.860 --> 00:17:04.972 like foveolar pit cells. NOTE Confidence: 0.807014336521739 00:17:04.980 --> 00:17:07.902 You see cells that look like NOTE Confidence: 0.807014336521739 00:17:07.902 --> 00:17:09.363 these spasmolytic polypeptide NOTE Confidence: 0.807014336521739 00:17:09.363 --> 00:17:11.189 pyloric metaplasia cells. NOTE Confidence: 0.807014336521739 00:17:11.190 --> 00:17:12.905 So and you see the same kinds NOTE Confidence: 0.807014336521739 00:17:12.905 --> 00:17:14.323 of cytokines that are starting NOTE Confidence: 0.807014336521739 00:17:14.323 --> 00:17:15.888 to emerge as being universal. NOTE Confidence: 0.807014336521739 00:17:15.890 --> 00:17:17.626 So I'm not going to talk about this, NOTE Confidence: 0.807014336521739 00:17:17.630 --> 00:17:19.694 but aisle 13, NOTE Confidence: 0.807014336521739 00:17:19.694 --> 00:17:22.982 aisle 33 shows up as mediating NOTE Confidence: 0.807014336521739 00:17:22.982 --> 00:17:25.850 these metaplasia as in the esophagus NOTE Confidence: 0.807014336521739 00:17:25.932 --> 00:17:28.434 and the stomach and even as we're NOTE Confidence: 0.807014336521739 00:17:28.434 --> 00:17:30.268 going to say now in the intestines. NOTE Confidence: 0.842524026842105 00:17:30.270 --> 00:17:32.286 And so the other thing I think NOTE Confidence: 0.842524026842105 00:17:32.286 --> 00:17:34.201 it's been really kind of exploding NOTE Confidence: 0.842524026842105 00:17:34.201 --> 00:17:36.163 in in from the pathology side. NOTE Confidence: 0.842524026842105 00:17:36.170 --> 00:17:38.070 Is that the right sided, NOTE Confidence: 0.842524026842105 00:17:38.070 --> 00:17:40.274 you know serrated sessile. NOTE Confidence: 0.842524026842105 00:17:40.274 --> 00:17:41.786 You know, polyps, NOTE Confidence: 0.842524026842105 00:17:41.786 --> 00:17:44.222 we used to call them serrated NOTE Confidence: 0.842524026842105 00:17:44.222 --> 00:17:46.195 sessile lesions also had this NOTE Confidence: 0.842524026842105 00:17:46.195 --> 00:17:48.120 same kind of basic format. NOTE Confidence: 0.842524026842105 00:17:48.120 --> 00:17:50.004 So in this case you're taking NOTE Confidence: 0.842524026842105 00:17:50.004 --> 00:17:51.563 things that were 100% intestinal NOTE Confidence: 0.842524026842105 00:17:51.563 --> 00:17:53.381 and then now they're moving towards NOTE Confidence: 0.842524026842105 00:17:53.381 --> 00:17:55.302 the gastric side and they wind up NOTE Confidence: 0.842524026842105 00:17:55.302 --> 00:17:57.083 somewhere in the middle with this kind NOTE Confidence: 0.842524026842105 00:17:57.083 --> 00:17:58.503 of pyloric morphology where again NOTE Confidence: 0.842524026842105 00:17:58.503 --> 00:18:00.080 single cell RNA seek shows that. NOTE Confidence: 0.842524026842105 00:18:00.080 --> 00:18:00.960 But then you know, NOTE Confidence: 0.842524026842105 00:18:00.960 --> 00:18:03.576 as I've been collecting these lesions NOTE Confidence: 0.842524026842105 00:18:03.576 --> 00:18:06.856 and we've been looking at them NOTE Confidence: 0.842524026842105 00:18:06.856 --> 00:18:09.040 morphologically and immunohistochemically, NOTE Confidence: 0.842524026842105 00:18:09.040 --> 00:18:10.816 you again see you know and. NOTE Confidence: 0.842524026842105 00:18:10.820 --> 00:18:13.004 And it's been described before too by NOTE Confidence: 0.842524026842105 00:18:13.004 --> 00:18:14.878 others that there's muck 6 positive, NOTE Confidence: 0.842524026842105 00:18:14.880 --> 00:18:16.794 which is exactly the same expression NOTE Confidence: 0.842524026842105 00:18:16.794 --> 00:18:18.444 pattern as spam cells that NOTE Confidence: 0.842524026842105 00:18:18.444 --> 00:18:19.720 emerge that are gastric, NOTE Confidence: 0.842524026842105 00:18:19.720 --> 00:18:20.538 you know, NOTE Confidence: 0.842524026842105 00:18:20.538 --> 00:18:22.583 that are characteristic deep sort NOTE Confidence: 0.842524026842105 00:18:22.583 --> 00:18:25.019 of acinar lesions within these SSL. NOTE Confidence: 0.842524026842105 00:18:25.020 --> 00:18:27.204 And then there's an ad mix sort NOTE Confidence: 0.842524026842105 00:18:27.204 --> 00:18:29.578 of muck 5 AC full Viola and NOTE Confidence: 0.842524026842105 00:18:29.578 --> 00:18:31.050 goblet cell surface lesions. NOTE Confidence: 0.842524026842105 00:18:31.050 --> 00:18:34.886 So at least on the right sided. NOTE Confidence: 0.842524026842105 00:18:34.890 --> 00:18:36.954 SSL type of lesion there seems to be NOTE Confidence: 0.842524026842105 00:18:36.954 --> 00:18:39.483 the same kind of metaplasia but sort of NOTE Confidence: 0.842524026842105 00:18:39.483 --> 00:18:41.769 coming from intestine back towards gastric. NOTE Confidence: 0.842524026842105 00:18:41.770 --> 00:18:43.300 Now that polyps and tubular adenoma NOTE Confidence: 0.842524026842105 00:18:43.300 --> 00:18:45.380 seem to take a different course that's NOTE Confidence: 0.842524026842105 00:18:45.380 --> 00:18:47.396 kind of more traditionally stem cell NOTE Confidence: 0.842524026842105 00:18:47.396 --> 00:18:49.729 based and doesn't fall within that category. NOTE Confidence: 0.842524026842105 00:18:49.730 --> 00:18:53.010 But still now we got four different organs NOTE Confidence: 0.842524026842105 00:18:53.010 --> 00:18:55.419 all converging towards this sort of, NOTE Confidence: 0.842524026842105 00:18:55.420 --> 00:18:57.919 you know pyloric like which is actually NOTE Confidence: 0.842524026842105 00:18:57.919 --> 00:19:00.162 probably maybe one of the primordial NOTE Confidence: 0.842524026842105 00:19:00.162 --> 00:19:02.376 embryonic states of the stomach and NOTE Confidence: 0.842524026842105 00:19:02.376 --> 00:19:04.812 that's probably why and repair the stomach. NOTE Confidence: 0.842524026842105 00:19:04.812 --> 00:19:06.558 Kind of chooses to go back NOTE Confidence: 0.842524026842105 00:19:06.558 --> 00:19:08.070 to this sort of lesion. NOTE Confidence: 0.842524026842105 00:19:08.070 --> 00:19:10.650 But once you have an established NOTE Confidence: 0.842524026842105 00:19:10.650 --> 00:19:13.379 lesion that's mixed lineage where it's, NOTE Confidence: 0.842524026842105 00:19:13.380 --> 00:19:14.670 you know, making both intestinal NOTE Confidence: 0.842524026842105 00:19:14.670 --> 00:19:16.459 and gastric cells at the same time, NOTE Confidence: 0.842524026842105 00:19:16.460 --> 00:19:18.294 you could see at least you know, NOTE Confidence: 0.842524026842105 00:19:18.300 --> 00:19:21.002 reason why that might be a risk NOTE Confidence: 0.842524026842105 00:19:21.002 --> 00:19:22.780 for progressing to cancer. NOTE Confidence: 0.842524026842105 00:19:22.780 --> 00:19:23.720 And so part of that, NOTE Confidence: 0.842524026842105 00:19:23.720 --> 00:19:24.522 you know, NOTE Confidence: 0.842524026842105 00:19:24.522 --> 00:19:26.857 manifest itself when you do genome NOTE Confidence: 0.842524026842105 00:19:26.857 --> 00:19:28.819 sequencing and you look for mutations. NOTE Confidence: 0.842524026842105 00:19:28.820 --> 00:19:30.220 And that's why this is kind of NOTE Confidence: 0.842524026842105 00:19:30.220 --> 00:19:31.963 some of the clinical data for why NOTE Confidence: 0.842524026842105 00:19:31.963 --> 00:19:33.595 people do 3 mutations so important, NOTE Confidence: 0.842524026842105 00:19:33.600 --> 00:19:34.110 which is that, NOTE Confidence: 0.842524026842105 00:19:34.110 --> 00:19:34.450 you know, NOTE Confidence: 0.842524026842105 00:19:34.450 --> 00:19:35.974 in these Barretts glands as they NOTE Confidence: 0.842524026842105 00:19:35.974 --> 00:19:37.268 start to progress and clones NOTE Confidence: 0.842524026842105 00:19:37.268 --> 00:19:38.878 emerge and they start to get the NOTE Confidence: 0.842524026842105 00:19:38.878 --> 00:19:40.379 ones that are mixed intestinal, NOTE Confidence: 0.842524026842105 00:19:40.380 --> 00:19:42.396 it seems like those are the ones that NOTE Confidence: 0.842524026842105 00:19:42.396 --> 00:19:44.348 are prone to developing P53 mutation. NOTE Confidence: 0.842524026842105 00:19:44.348 --> 00:19:46.756 It's those clones that then very rapidly, NOTE Confidence: 0.842524026842105 00:19:46.760 --> 00:19:48.200 you know, from a heterozygote, NOTE Confidence: 0.842524026842105 00:19:48.200 --> 00:19:50.186 once there's a loss of heterozygosity, NOTE Confidence: 0.842524026842105 00:19:50.190 --> 00:19:52.830 they almost immediately go into dysplasia. NOTE Confidence: 0.842524026842105 00:19:52.830 --> 00:19:56.148 And and neoplasia and then and NOTE Confidence: 0.842524026842105 00:19:56.148 --> 00:19:57.807 metastatic and metastasis. NOTE Confidence: 0.842524026842105 00:19:57.810 --> 00:19:58.177 OK. NOTE Confidence: 0.842524026842105 00:19:58.177 --> 00:20:01.480 So that's the like if my talks at sandwich, NOTE Confidence: 0.842524026842105 00:20:01.480 --> 00:20:02.914 that's this is the path introduction NOTE Confidence: 0.842524026842105 00:20:02.914 --> 00:20:04.574 that we're going to delve into what NOTE Confidence: 0.842524026842105 00:20:04.574 --> 00:20:06.100 we think some of the mechanisms are NOTE Confidence: 0.842524026842105 00:20:06.147 --> 00:20:07.673 for how we get these metaplasia and NOTE Confidence: 0.842524026842105 00:20:07.673 --> 00:20:09.350 then we'll come back out again to NOTE Confidence: 0.842524026842105 00:20:09.350 --> 00:20:11.194 see some of the clinical trial work NOTE Confidence: 0.842524026842105 00:20:11.194 --> 00:20:13.226 that we're doing to try to address it. NOTE Confidence: 0.842524026842105 00:20:13.230 --> 00:20:18.027 So the question is to where are all these? NOTE Confidence: 0.747923522 00:20:18.030 --> 00:20:19.470 Lesions coming from, you know, NOTE Confidence: 0.747923522 00:20:19.470 --> 00:20:21.222 in these four different organs and NOTE Confidence: 0.747923522 00:20:21.222 --> 00:20:23.573 you know the knee jerk response that I NOTE Confidence: 0.747923522 00:20:23.573 --> 00:20:25.831 would have given you 15 years ago when NOTE Confidence: 0.747923522 00:20:25.831 --> 00:20:27.895 Juan Jason the lab was the stem cell. NOTE Confidence: 0.747923522 00:20:27.900 --> 00:20:29.305 Everybody thinks stem cells are NOTE Confidence: 0.747923522 00:20:29.305 --> 00:20:31.046 what gives rise to, you know, NOTE Confidence: 0.747923522 00:20:31.046 --> 00:20:32.894 lesions and and that are proliferative NOTE Confidence: 0.747923522 00:20:32.894 --> 00:20:34.369 and gives rise to cancer. NOTE Confidence: 0.747923522 00:20:34.370 --> 00:20:35.916 Well, but it turns out, you know, NOTE Confidence: 0.747923522 00:20:35.916 --> 00:20:38.020 the stem cells are kind of tricky and NOTE Confidence: 0.747923522 00:20:38.084 --> 00:20:40.160 in the pyloric versus oxyntic mucosa. NOTE Confidence: 0.747923522 00:20:40.160 --> 00:20:41.840 So the, the professional stem cells NOTE Confidence: 0.747923522 00:20:41.840 --> 00:20:43.679 and the oxyntic costs are way up NOTE Confidence: 0.747923522 00:20:43.679 --> 00:20:45.005 here close to the surface and NOTE Confidence: 0.747923522 00:20:45.005 --> 00:20:46.607 then when you get this you know, NOTE Confidence: 0.747923522 00:20:46.610 --> 00:20:48.170 change into this more pyloric. NOTE Confidence: 0.747923522 00:20:48.170 --> 00:20:50.480 They're kind of down here. NOTE Confidence: 0.747923522 00:20:50.480 --> 00:20:52.345 So there's a change there NOTE Confidence: 0.747923522 00:20:52.345 --> 00:20:53.968 already work towards the base. NOTE Confidence: 0.747923522 00:20:53.968 --> 00:20:56.060 But then there's another thing that we, NOTE Confidence: 0.747923522 00:20:56.060 --> 00:20:56.440 you know, NOTE Confidence: 0.747923522 00:20:56.440 --> 00:20:57.580 have to think about which is NOTE Confidence: 0.747923522 00:20:57.580 --> 00:20:58.837 that say in the pancreas there NOTE Confidence: 0.747923522 00:20:58.837 --> 00:21:00.079 aren't any stem cells at all. NOTE Confidence: 0.747923522 00:21:00.080 --> 00:21:01.710 So where are those proliferative NOTE Confidence: 0.747923522 00:21:01.710 --> 00:21:02.688 cells coming from? NOTE Confidence: 0.747923522 00:21:02.690 --> 00:21:04.839 And and there's been a long strain, NOTE Confidence: 0.747923522 00:21:04.840 --> 00:21:06.778 relatively long for this kind of NOTE Confidence: 0.747923522 00:21:06.778 --> 00:21:08.803 cell plasticity field of maybe 10-15 NOTE Confidence: 0.747923522 00:21:08.803 --> 00:21:11.148 years of good mouse work with human NOTE Confidence: 0.747923522 00:21:11.148 --> 00:21:13.836 correlation showing that most of the NOTE Confidence: 0.747923522 00:21:13.836 --> 00:21:15.213 reparative metaplastic proliferating NOTE Confidence: 0.747923522 00:21:15.213 --> 00:21:17.184 proliferating cells in the pancreas NOTE Confidence: 0.747923522 00:21:17.184 --> 00:21:18.924 that come about during pancreatitis. NOTE Confidence: 0.747923522 00:21:18.930 --> 00:21:20.130 And pancreatic injuries actually NOTE Confidence: 0.747923522 00:21:20.130 --> 00:21:22.309 all come from the acinar cells that NOTE Confidence: 0.747923522 00:21:22.309 --> 00:21:23.929 are doing their digestive enzyme NOTE Confidence: 0.747923522 00:21:23.929 --> 00:21:25.225 secretion that that reprogram. NOTE Confidence: 0.747923522 00:21:25.230 --> 00:21:25.454 Well, NOTE Confidence: 0.747923522 00:21:25.454 --> 00:21:27.470 it turns out we have a ton of evidence NOTE Confidence: 0.747923522 00:21:27.521 --> 00:21:28.996 now that actually similar things NOTE Confidence: 0.747923522 00:21:28.996 --> 00:21:30.780 are happening down at the base. NOTE Confidence: 0.747923522 00:21:30.780 --> 00:21:32.964 And the reason probably why you get NOTE Confidence: 0.747923522 00:21:32.964 --> 00:21:35.040 this change from an oxyntic mucosa, NOTE Confidence: 0.747923522 00:21:35.040 --> 00:21:36.905 this kind of organization with NOTE Confidence: 0.747923522 00:21:36.905 --> 00:21:38.770 proliferative cells at the base NOTE Confidence: 0.747923522 00:21:38.836 --> 00:21:39.739 is because the, NOTE Confidence: 0.747923522 00:21:39.740 --> 00:21:41.707 the fuel for these changes in in NOTE Confidence: 0.747923522 00:21:41.707 --> 00:21:43.595 these lesions is actually at the NOTE Confidence: 0.747923522 00:21:43.595 --> 00:21:45.230 base and the differentiated cells NOTE Confidence: 0.747923522 00:21:45.230 --> 00:21:47.498 just as it happens in the pancreas, NOTE Confidence: 0.747923522 00:21:47.500 --> 00:21:48.664 in the acinar cells, NOTE Confidence: 0.747923522 00:21:48.664 --> 00:21:50.119 it's in the digestive enzymes. NOTE Confidence: 0.747923522 00:21:50.120 --> 00:21:52.286 Recruiting chief cells at the base. NOTE Confidence: 0.747923522 00:21:52.290 --> 00:21:54.924 So that brings up this concept NOTE Confidence: 0.747923522 00:21:54.924 --> 00:21:57.829 that how do you get from a, NOTE Confidence: 0.747923522 00:21:57.830 --> 00:21:59.626 a, a differentiated cell, NOTE Confidence: 0.747923522 00:21:59.626 --> 00:22:01.871 massive secretory cell like the NOTE Confidence: 0.747923522 00:22:01.871 --> 00:22:04.007 pancreatic acinar solar chief cell NOTE Confidence: 0.747923522 00:22:04.007 --> 00:22:06.425 to a much smaller proliferating cell. NOTE Confidence: 0.747923522 00:22:06.430 --> 00:22:08.370 And you know that actually, NOTE Confidence: 0.747923522 00:22:08.370 --> 00:22:10.218 you know stirred us to begin to NOTE Confidence: 0.747923522 00:22:10.218 --> 00:22:12.119 explore the idea of cell plasticity, NOTE Confidence: 0.747923522 00:22:12.120 --> 00:22:13.730 which is where this fits. NOTE Confidence: 0.747923522 00:22:13.730 --> 00:22:15.122 And you know this, NOTE Confidence: 0.747923522 00:22:15.122 --> 00:22:17.582 this concept has exploded in the last NOTE Confidence: 0.747923522 00:22:17.582 --> 00:22:20.228 five to 10 years and we had the first, NOTE Confidence: 0.747923522 00:22:20.230 --> 00:22:22.534 I think the first ever meeting that I helped. NOTE Confidence: 0.747923522 00:22:22.540 --> 00:22:22.939 Organized, NOTE Confidence: 0.747923522 00:22:22.939 --> 00:22:26.530 which is a keystone meeting in 2019 on it, NOTE Confidence: 0.747923522 00:22:26.530 --> 00:22:27.853 but then there was a follow up NOTE Confidence: 0.747923522 00:22:27.853 --> 00:22:29.420 and now there are a number of NOTE Confidence: 0.747923522 00:22:29.420 --> 00:22:30.368 meetings that are scheduled. NOTE Confidence: 0.747923522 00:22:30.370 --> 00:22:32.056 We had a paper on nomenclature, NOTE Confidence: 0.747923522 00:22:32.060 --> 00:22:34.020 but just to kind of put us all in the NOTE Confidence: 0.747923522 00:22:34.077 --> 00:22:35.802 same cell and developmental biology NOTE Confidence: 0.747923522 00:22:35.802 --> 00:22:38.270 page when we're talking about this lesions, NOTE Confidence: 0.747923522 00:22:38.270 --> 00:22:39.955 you know the canonical stem NOTE Confidence: 0.747923522 00:22:39.955 --> 00:22:42.000 cell idea of how you get. NOTE Confidence: 0.747923522 00:22:42.000 --> 00:22:43.730 Differentiation in a tissue is NOTE Confidence: 0.747923522 00:22:43.730 --> 00:22:45.907 that you have these stem cells NOTE Confidence: 0.747923522 00:22:45.907 --> 00:22:47.764 that make faith choices, right. NOTE Confidence: 0.747923522 00:22:47.764 --> 00:22:49.484 And as they differentiate and NOTE Confidence: 0.747923522 00:22:49.484 --> 00:22:50.860 they're basically like marbles NOTE Confidence: 0.747923522 00:22:50.918 --> 00:22:52.410 rolling down this Waddington, NOTE Confidence: 0.747923522 00:22:52.410 --> 00:22:53.786 this Conrad Waddington was NOTE Confidence: 0.747923522 00:22:53.786 --> 00:22:55.850 the person who came up with NOTE Confidence: 0.825815031333333 00:22:55.918 --> 00:22:58.683 this concept of a landscape of sort NOTE Confidence: 0.825815031333333 00:22:58.683 --> 00:23:00.522 of differentiation choices and then NOTE Confidence: 0.825815031333333 00:23:00.522 --> 00:23:02.573 the ball sort of slowly roll down NOTE Confidence: 0.825815031333333 00:23:02.573 --> 00:23:04.214 and then you get your chief cells and NOTE Confidence: 0.825815031333333 00:23:04.214 --> 00:23:05.519 parietal cells and acinar cells at the NOTE Confidence: 0.825815031333333 00:23:05.519 --> 00:23:06.820 base and then they just sit there. NOTE Confidence: 0.825815031333333 00:23:06.820 --> 00:23:08.514 You know, the idea inherent to this NOTE Confidence: 0.825815031333333 00:23:08.514 --> 00:23:10.050 concept is that it's a unidirectional NOTE Confidence: 0.825815031333333 00:23:10.050 --> 00:23:12.100 flow of the balls roll down the hill. NOTE Confidence: 0.825815031333333 00:23:12.100 --> 00:23:13.837 And so then if you need to get repair, NOTE Confidence: 0.825815031333333 00:23:13.840 --> 00:23:14.760 any kind of repair done, NOTE Confidence: 0.825815031333333 00:23:14.760 --> 00:23:16.335 then you need to take one of NOTE Confidence: 0.825815031333333 00:23:16.335 --> 00:23:17.380 these progenitors to repair. NOTE Confidence: 0.825815031333333 00:23:17.380 --> 00:23:19.306 But it's pretty clearly not the NOTE Confidence: 0.825815031333333 00:23:19.306 --> 00:23:21.540 case because now we all know that. NOTE Confidence: 0.825815031333333 00:23:21.540 --> 00:23:23.164 The balls can kind of go back up NOTE Confidence: 0.825815031333333 00:23:23.164 --> 00:23:24.662 the hill and you can get just NOTE Confidence: 0.825815031333333 00:23:24.662 --> 00:23:26.200 in the setting like I told you. NOTE Confidence: 0.825815031333333 00:23:26.200 --> 00:23:28.310 If acinar cells they can NOTE Confidence: 0.825815031333333 00:23:28.310 --> 00:23:29.154 become proliferative. NOTE Confidence: 0.825815031333333 00:23:29.160 --> 00:23:30.960 You can get sort of the balls going NOTE Confidence: 0.825815031333333 00:23:30.960 --> 00:23:32.717 over the grooves and being becoming NOTE Confidence: 0.825815031333333 00:23:32.717 --> 00:23:34.744 other cells like beta cells in the NOTE Confidence: 0.825815031333333 00:23:34.744 --> 00:23:36.370 pancreatic islets can become alpha cells. NOTE Confidence: 0.825815031333333 00:23:36.370 --> 00:23:39.070 So these are trans differentiation NOTE Confidence: 0.825815031333333 00:23:39.070 --> 00:23:40.690 and dedifferentiation events. NOTE Confidence: 0.825815031333333 00:23:40.690 --> 00:23:42.748 And in fact when you really think NOTE Confidence: 0.825815031333333 00:23:42.748 --> 00:23:44.943 where we care is pathologists and NOTE Confidence: 0.825815031333333 00:23:44.943 --> 00:23:47.013 and pathology researchers about the NOTE Confidence: 0.825815031333333 00:23:47.013 --> 00:23:49.410 injury and inflammation standpoint. NOTE Confidence: 0.825815031333333 00:23:49.410 --> 00:23:50.838 You know it's quite possible that NOTE Confidence: 0.825815031333333 00:23:50.838 --> 00:23:52.610 none of these grooves even stay the NOTE Confidence: 0.825815031333333 00:23:52.610 --> 00:23:53.890 same during inflammation in the NOTE Confidence: 0.825815031333333 00:23:53.890 --> 00:23:55.472 entire niches changing and all the NOTE Confidence: 0.825815031333333 00:23:55.472 --> 00:23:56.752 groups are changing the identities NOTE Confidence: 0.825815031333333 00:23:56.752 --> 00:23:58.781 may change you know and as we do NOTE Confidence: 0.825815031333333 00:23:58.781 --> 00:24:00.929 more single cell RNA seek we see that NOTE Confidence: 0.825815031333333 00:24:00.929 --> 00:24:02.873 you know I cell identities are all NOTE Confidence: 0.825815031333333 00:24:02.873 --> 00:24:04.840 kind of overlapping you know and and NOTE Confidence: 0.825815031333333 00:24:04.840 --> 00:24:09.176 these groups may not be so so clear. NOTE Confidence: 0.825815031333333 00:24:09.180 --> 00:24:11.630 So there's a lot of interest in NOTE Confidence: 0.825815031333333 00:24:11.630 --> 00:24:14.346 collagenosis and or in itself by in NOTE Confidence: 0.825815031333333 00:24:14.346 --> 00:24:16.336 plasticity and differentiation and in NOTE Confidence: 0.825815031333333 00:24:16.336 --> 00:24:18.560 fact that kind of got I was tickled NOTE Confidence: 0.825815031333333 00:24:18.560 --> 00:24:20.480 to see that there was a last month NOTE Confidence: 0.825815031333333 00:24:20.480 --> 00:24:22.295 the call for in scientific reports NOTE Confidence: 0.825815031333333 00:24:22.295 --> 00:24:24.431 for papers on on plasticity and NOTE Confidence: 0.825815031333333 00:24:24.431 --> 00:24:26.117 specifically specifically pathogenesis. NOTE Confidence: 0.825815031333333 00:24:26.120 --> 00:24:26.502 OK. NOTE Confidence: 0.825815031333333 00:24:26.502 --> 00:24:29.558 So the why do we have this term NOTE Confidence: 0.825815031333333 00:24:29.558 --> 00:24:31.933 pathogenesis and the reason is because NOTE Confidence: 0.825815031333333 00:24:31.933 --> 00:24:34.723 all of those balls are rolling around NOTE Confidence: 0.825815031333333 00:24:34.723 --> 00:24:37.907 on the hill that that I was showing NOTE Confidence: 0.825815031333333 00:24:37.910 --> 00:24:39.494 you had to do sort of with the. NOTE Confidence: 0.825815031333333 00:24:39.500 --> 00:24:42.746 That, that tissue and developmental biology, NOTE Confidence: 0.825815031333333 00:24:42.750 --> 00:24:45.830 the idea that every cell has got its NOTE Confidence: 0.825815031333333 00:24:45.830 --> 00:24:47.982 own identity and that in plasticity NOTE Confidence: 0.825815031333333 00:24:47.982 --> 00:24:49.448 events the cells, you know, NOTE Confidence: 0.825815031333333 00:24:49.448 --> 00:24:50.822 change identity and it matters if NOTE Confidence: 0.825815031333333 00:24:50.822 --> 00:24:51.943 they become less differentiated NOTE Confidence: 0.825815031333333 00:24:51.943 --> 00:24:53.167 than they're rolling up. NOTE Confidence: 0.825815031333333 00:24:53.170 --> 00:24:54.580 And if they're trans differentiated, NOTE Confidence: 0.825815031333333 00:24:54.580 --> 00:24:55.690 they're, you know, NOTE Confidence: 0.825815031333333 00:24:55.690 --> 00:24:57.170 becoming another cell type. NOTE Confidence: 0.825815031333333 00:24:57.170 --> 00:24:59.096 But what if we're actually interested NOTE Confidence: 0.825815031333333 00:24:59.096 --> 00:25:01.660 in the process of how you take a NOTE Confidence: 0.825815031333333 00:25:01.660 --> 00:25:02.876 differentiated cell and convert NOTE Confidence: 0.825815031333333 00:25:02.876 --> 00:25:04.769 it to a proliferating cell? NOTE Confidence: 0.825815031333333 00:25:04.770 --> 00:25:05.406 You know, NOTE Confidence: 0.825815031333333 00:25:05.406 --> 00:25:07.632 that is not likely to be different NOTE Confidence: 0.825815031333333 00:25:07.632 --> 00:25:09.874 in every single organ, just like. NOTE Confidence: 0.825815031333333 00:25:09.874 --> 00:25:11.848 If you need a program cell death, NOTE Confidence: 0.825815031333333 00:25:11.850 --> 00:25:13.656 you have the apoptotic program and you NOTE Confidence: 0.825815031333333 00:25:13.656 --> 00:25:15.199 have apoptosis and that's the same. NOTE Confidence: 0.825815031333333 00:25:15.200 --> 00:25:17.230 And nobody thinks that apoptosis NOTE Confidence: 0.825815031333333 00:25:17.230 --> 00:25:19.680 is different in every cell type. NOTE Confidence: 0.825815031333333 00:25:19.680 --> 00:25:21.820 So this change in identity, NOTE Confidence: 0.825815031333333 00:25:21.820 --> 00:25:23.476 these dedifferentiation events are NOTE Confidence: 0.825815031333333 00:25:23.476 --> 00:25:26.380 likely to be similar across tissue types. NOTE Confidence: 0.825815031333333 00:25:26.380 --> 00:25:29.212 So there must be a cell biological process NOTE Confidence: 0.825815031333333 00:25:29.212 --> 00:25:32.358 or an osis that dictates these events. NOTE Confidence: 0.825815031333333 00:25:32.360 --> 00:25:35.070 And so we came up with this idea that if NOTE Confidence: 0.909255652083333 00:25:35.143 --> 00:25:37.527 we wanted to look at the cell biology NOTE Confidence: 0.909255652083333 00:25:37.527 --> 00:25:40.029 of how these cells rearrange then. NOTE Confidence: 0.909255652083333 00:25:40.030 --> 00:25:40.885 We should have a term NOTE Confidence: 0.909255652083333 00:25:40.885 --> 00:25:41.910 so we can talk about it. NOTE Confidence: 0.909255652083333 00:25:41.910 --> 00:25:43.866 And Paola is the Greek return, NOTE Confidence: 0.909255652083333 00:25:43.870 --> 00:25:45.290 like in palindromes, you know, NOTE Confidence: 0.909255652083333 00:25:45.290 --> 00:25:49.820 a site that goes back and forth. NOTE Confidence: 0.909255652083333 00:25:49.820 --> 00:25:51.878 Can be read both ways right. NOTE Confidence: 0.909255652083333 00:25:51.880 --> 00:25:54.645 And and and Jen is the general, NOTE Confidence: 0.909255652083333 00:25:54.650 --> 00:25:55.634 you know, generative. NOTE Confidence: 0.909255652083333 00:25:55.634 --> 00:25:57.930 So Palingenesis is the return to the NOTE Confidence: 0.909255652083333 00:25:57.996 --> 00:25:59.694 generative state, regenerative state. NOTE Confidence: 0.909255652083333 00:25:59.694 --> 00:26:02.630 So but when we're talking about this then NOTE Confidence: 0.909255652083333 00:26:02.692 --> 00:26:04.978 what we're talking about is basically. NOTE Confidence: 0.909255652083333 00:26:04.980 --> 00:26:07.176 How do you take these chief cells and make NOTE Confidence: 0.909255652083333 00:26:07.176 --> 00:26:09.098 these metaplastic proliferative cells? NOTE Confidence: 0.909255652083333 00:26:09.100 --> 00:26:11.002 So these are very Long live NOTE Confidence: 0.909255652083333 00:26:11.002 --> 00:26:12.400 cells that don't proliferate. NOTE Confidence: 0.909255652083333 00:26:12.400 --> 00:26:14.600 How do they become proliferative? NOTE Confidence: 0.909255652083333 00:26:14.600 --> 00:26:17.694 So the take home is that it? NOTE Confidence: 0.909255652083333 00:26:17.700 --> 00:26:19.110 It's a the. NOTE Confidence: 0.909255652083333 00:26:19.110 --> 00:26:19.580 Basic. NOTE Confidence: 0.909255652083333 00:26:19.580 --> 00:26:21.930 Like so biological change that NOTE Confidence: 0.909255652083333 00:26:21.930 --> 00:26:24.671 has to happen here is a change NOTE Confidence: 0.909255652083333 00:26:24.671 --> 00:26:27.730 in the way the cell uses energy. NOTE Confidence: 0.909255652083333 00:26:27.730 --> 00:26:30.264 When the cell is in the base NOTE Confidence: 0.909255652083333 00:26:30.264 --> 00:26:31.890 of a gastric unit, NOTE Confidence: 0.909255652083333 00:26:31.890 --> 00:26:33.846 then it uses energy to produce NOTE Confidence: 0.909255652083333 00:26:33.846 --> 00:26:35.150 digestive enzymes and secrete. NOTE Confidence: 0.909255652083333 00:26:35.150 --> 00:26:37.142 When it's in the base of a of NOTE Confidence: 0.909255652083333 00:26:37.142 --> 00:26:38.709 a reparative metaplastic unit, NOTE Confidence: 0.909255652083333 00:26:38.710 --> 00:26:41.308 then it uses energy to divide. NOTE Confidence: 0.909255652083333 00:26:41.310 --> 00:26:43.008 So all of the in between. NOTE Confidence: 0.909255652083333 00:26:43.010 --> 00:26:45.602 The Collagenosis part is how the NOTE Confidence: 0.909255652083333 00:26:45.602 --> 00:26:48.310 cell adapts itself to go from NOTE Confidence: 0.909255652083333 00:26:48.310 --> 00:26:50.102 a digestive enzyme secreting NOTE Confidence: 0.909255652083333 00:26:50.102 --> 00:26:53.100 energetic cell to a proliferating. NOTE Confidence: 0.909255652083333 00:26:53.100 --> 00:26:56.856 Non energetic but but non secretory. NOTE Confidence: 0.909255652083333 00:26:56.860 --> 00:26:59.247 So and basically this is the basic NOTE Confidence: 0.909255652083333 00:26:59.247 --> 00:27:01.818 scheme which seems to be conserved across, NOTE Confidence: 0.909255652083333 00:27:01.820 --> 00:27:04.676 you know, from fly guts to, you know, NOTE Confidence: 0.909255652083333 00:27:04.676 --> 00:27:06.416 pancreas to stomach to lung. NOTE Confidence: 0.909255652083333 00:27:06.420 --> 00:27:08.065 Every time you are calling NOTE Confidence: 0.909255652083333 00:27:08.065 --> 00:27:09.381 differentiated cells back into NOTE Confidence: 0.909255652083333 00:27:09.381 --> 00:27:11.650 the cell cycle and that is that NOTE Confidence: 0.909255652083333 00:27:11.650 --> 00:27:13.291 there's a massive upregulation of NOTE Confidence: 0.909255652083333 00:27:13.291 --> 00:27:15.265 autophagy and lysosome as the cell NOTE Confidence: 0.909255652083333 00:27:15.265 --> 00:27:16.694 reprograms its internal organs. NOTE Confidence: 0.909255652083333 00:27:16.694 --> 00:27:19.298 Followed by a second stage where NOTE Confidence: 0.909255652083333 00:27:19.298 --> 00:27:22.138 the genes that we recognize it NOTE Confidence: 0.909255652083333 00:27:22.138 --> 00:27:23.596 as being metaplastic. NOTE Confidence: 0.909255652083333 00:27:23.600 --> 00:27:25.679 And those are a lot of different NOTE Confidence: 0.909255652083333 00:27:25.679 --> 00:27:27.336 genes like trefoil factor or NOTE Confidence: 0.909255652083333 00:27:27.336 --> 00:27:28.736 spasmolytic polypeptide or some NOTE Confidence: 0.909255652083333 00:27:28.736 --> 00:27:30.840 of the socks genes like Sox 9. NOTE Confidence: 0.909255652083333 00:27:30.840 --> 00:27:33.378 Followed by this very important one, NOTE Confidence: 0.909255652083333 00:27:33.380 --> 00:27:35.095 which is the stage when the cell NOTE Confidence: 0.909255652083333 00:27:35.095 --> 00:27:36.135 decides whether to actually NOTE Confidence: 0.909255652083333 00:27:36.135 --> 00:27:37.659 enter the cell cycle or not. NOTE Confidence: 0.909255652083333 00:27:37.660 --> 00:27:39.788 And this is the key stage for cancer NOTE Confidence: 0.909255652083333 00:27:39.788 --> 00:27:41.288 because you're taking these old NOTE Confidence: 0.909255652083333 00:27:41.288 --> 00:27:43.106 long lived cells and you're bringing NOTE Confidence: 0.909255652083333 00:27:43.106 --> 00:27:44.768 them back into the cell cycle. NOTE Confidence: 0.909255652083333 00:27:44.770 --> 00:27:46.569 And so this is a checkpoint that NOTE Confidence: 0.909255652083333 00:27:46.569 --> 00:27:48.389 we'll talk about as being important. NOTE Confidence: 0.909255652083333 00:27:48.390 --> 00:27:50.094 And just to kind of put us on NOTE Confidence: 0.909255652083333 00:27:50.094 --> 00:27:50.920 an ultrastructural footing, NOTE Confidence: 0.909255652083333 00:27:50.920 --> 00:27:53.104 what we're talking about is a very NOTE Confidence: 0.909255652083333 00:27:53.104 --> 00:27:54.759 large pancreatic acinar cell or NOTE Confidence: 0.909255652083333 00:27:54.759 --> 00:27:56.424 digestive enzyme secreting chief cell NOTE Confidence: 0.909255652083333 00:27:56.424 --> 00:27:58.450 with layer after layer of rough ER, NOTE Confidence: 0.909255652083333 00:27:58.450 --> 00:28:00.860 all these secretory granules becoming NOTE Confidence: 0.909255652083333 00:28:00.860 --> 00:28:02.788 this much smaller proliferative NOTE Confidence: 0.909255652083333 00:28:02.788 --> 00:28:03.990 stem like cell. NOTE Confidence: 0.909255652083333 00:28:03.990 --> 00:28:06.302 And this can happen in the mouse and NOTE Confidence: 0.909255652083333 00:28:06.302 --> 00:28:09.940 you know about 42 hours basically. NOTE Confidence: 0.909255652083333 00:28:09.940 --> 00:28:11.613 So the kinds of things that are NOTE Confidence: 0.909255652083333 00:28:11.613 --> 00:28:13.132 going to happen and we're going NOTE Confidence: 0.909255652083333 00:28:13.132 --> 00:28:14.875 to talk about are modeled in this NOTE Confidence: 0.909255652083333 00:28:14.880 --> 00:28:17.750 little video that Jeff Brown is a NOTE Confidence: 0.909255652083333 00:28:17.750 --> 00:28:18.980 gastroenterologist and assistant NOTE Confidence: 0.909255652083333 00:28:19.042 --> 00:28:20.659 professor at Washu now. NOTE Confidence: 0.909255652083333 00:28:20.659 --> 00:28:21.158 Um, NOTE Confidence: 0.909255652083333 00:28:21.158 --> 00:28:24.152 basically all this rough ER turns NOTE Confidence: 0.909255652083333 00:28:24.152 --> 00:28:26.616 into autophagosomes and then starts NOTE Confidence: 0.909255652083333 00:28:26.616 --> 00:28:28.911 to digest all the secretory NOTE Confidence: 0.909255652083333 00:28:28.911 --> 00:28:31.794 apparatus and also gets rid of all NOTE Confidence: 0.909255652083333 00:28:31.794 --> 00:28:33.298 that extra ER itself. NOTE Confidence: 0.909255652083333 00:28:33.300 --> 00:28:34.772 The cell reshapes like NOTE Confidence: 0.909255652083333 00:28:34.772 --> 00:28:36.980 this and then the next step NOTE Confidence: 0.837158596315789 00:28:37.058 --> 00:28:40.298 is that's going to enter the the cell cycle. NOTE Confidence: 0.837158596315789 00:28:40.300 --> 00:28:43.090 So how do we study this? NOTE Confidence: 0.837158596315789 00:28:43.090 --> 00:28:46.114 So what we've taken to do doing is to NOTE Confidence: 0.837158596315789 00:28:46.114 --> 00:28:48.540 looking at these metaplasia models, NOTE Confidence: 0.837158596315789 00:28:48.540 --> 00:28:50.420 both of which involve collagenosis, NOTE Confidence: 0.837158596315789 00:28:50.420 --> 00:28:53.290 both of which are drug induced and NOTE Confidence: 0.837158596315789 00:28:53.290 --> 00:28:55.130 relatively short term like within days NOTE Confidence: 0.837158596315789 00:28:55.130 --> 00:28:57.414 we can get these changes in both the NOTE Confidence: 0.837158596315789 00:28:57.414 --> 00:28:59.600 stomach and the pancreas at the same time. NOTE Confidence: 0.837158596315789 00:28:59.600 --> 00:29:00.867 That way we can look at all NOTE Confidence: 0.837158596315789 00:29:00.867 --> 00:29:01.410 the conserved features, NOTE Confidence: 0.837158596315789 00:29:01.410 --> 00:29:03.776 not just what happens in the stomach. NOTE Confidence: 0.837158596315789 00:29:03.780 --> 00:29:06.130 And so we use two systems for the most part, NOTE Confidence: 0.837158596315789 00:29:06.130 --> 00:29:08.290 one of which. NOTE Confidence: 0.837158596315789 00:29:08.290 --> 00:29:10.922 Juan Jay invented which is our discovery, NOTE Confidence: 0.837158596315789 00:29:10.922 --> 00:29:12.504 which is that if you treat mice NOTE Confidence: 0.837158596315789 00:29:12.504 --> 00:29:13.847 with high doses of tamoxifen, NOTE Confidence: 0.837158596315789 00:29:13.850 --> 00:29:16.524 it has an estrogen and sex independent NOTE Confidence: 0.837158596315789 00:29:16.524 --> 00:29:18.550 toxicity effect on the stomach, NOTE Confidence: 0.837158596315789 00:29:18.550 --> 00:29:20.512 which kills all the parietal cells NOTE Confidence: 0.837158596315789 00:29:20.512 --> 00:29:22.810 within a couple of days basically, NOTE Confidence: 0.837158596315789 00:29:22.810 --> 00:29:24.905 and reprograms the chief cells NOTE Confidence: 0.837158596315789 00:29:24.905 --> 00:29:27.000 and the entire oxyntic mucosa NOTE Confidence: 0.837158596315789 00:29:27.073 --> 00:29:29.168 into this pyloric like mucosa. NOTE Confidence: 0.837158596315789 00:29:29.170 --> 00:29:31.354 And the other is an established NOTE Confidence: 0.837158596315789 00:29:31.354 --> 00:29:32.810 model of of Cerulean, NOTE Confidence: 0.837158596315789 00:29:32.810 --> 00:29:35.673 which is a CCK hormone analog treatment NOTE Confidence: 0.837158596315789 00:29:35.673 --> 00:29:38.338 that turns the pancreas into this. NOTE Confidence: 0.837158596315789 00:29:38.338 --> 00:29:39.810 Kind of duck like, NOTE Confidence: 0.837158596315789 00:29:39.810 --> 00:29:43.170 but it's really just more again NOTE Confidence: 0.837158596315789 00:29:43.170 --> 00:29:44.850 metaplastic proliferative phenotype. NOTE Confidence: 0.837158596315789 00:29:44.850 --> 00:29:46.824 So this is the dosing scheme for NOTE Confidence: 0.837158596315789 00:29:46.824 --> 00:29:48.666 high dose tamoxifen and this is NOTE Confidence: 0.837158596315789 00:29:48.666 --> 00:29:50.226 what it looks like pathologically. NOTE Confidence: 0.837158596315789 00:29:50.230 --> 00:29:51.445 Here's a normal mouse stomach NOTE Confidence: 0.837158596315789 00:29:51.445 --> 00:29:52.660 with parietal cells up here, NOTE Confidence: 0.837158596315789 00:29:52.660 --> 00:29:54.048 digestive enzyme secreting chief NOTE Confidence: 0.837158596315789 00:29:54.048 --> 00:29:56.546 cells here and within three days of NOTE Confidence: 0.837158596315789 00:29:56.546 --> 00:29:58.326 those tamoxifen injections the cells, NOTE Confidence: 0.837158596315789 00:29:58.330 --> 00:30:00.004 the units become like tubes with NOTE Confidence: 0.837158596315789 00:30:00.004 --> 00:30:01.792 just mucus cells on top and NOTE Confidence: 0.837158596315789 00:30:01.792 --> 00:30:03.628 mucous cells in the bottom and NOTE Confidence: 0.837158596315789 00:30:03.628 --> 00:30:04.890 then proliferation throughout, NOTE Confidence: 0.837158596315789 00:30:04.890 --> 00:30:06.135 whereas normally proliferation NOTE Confidence: 0.837158596315789 00:30:06.135 --> 00:30:09.040 is confined to this top area in. NOTE Confidence: 0.837158596315789 00:30:09.040 --> 00:30:12.120 The normal stomach and pancreas, NOTE Confidence: 0.837158596315789 00:30:12.120 --> 00:30:14.430 all of these acinar acini open up NOTE Confidence: 0.837158596315789 00:30:14.430 --> 00:30:17.057 and you get these kind of cuboidal NOTE Confidence: 0.837158596315789 00:30:17.057 --> 00:30:19.301 cyst like proliferative cells also NOTE Confidence: 0.837158596315789 00:30:19.301 --> 00:30:22.223 if we do the cerulean treatment NOTE Confidence: 0.837158596315789 00:30:22.223 --> 00:30:24.677 there just to give him a plug. NOTE Confidence: 0.837158596315789 00:30:24.680 --> 00:30:27.740 To embarrass him a little bit. NOTE Confidence: 0.837158596315789 00:30:27.740 --> 00:30:29.532 So with this system then we've been NOTE Confidence: 0.837158596315789 00:30:29.532 --> 00:30:31.727 able to and I'm just going to show NOTE Confidence: 0.837158596315789 00:30:31.727 --> 00:30:33.421 you some highlights but you know NOTE Confidence: 0.837158596315789 00:30:33.421 --> 00:30:35.332 because a lot of this is published NOTE Confidence: 0.837158596315789 00:30:35.332 --> 00:30:37.404 because it the the stomach system NOTE Confidence: 0.837158596315789 00:30:37.404 --> 00:30:40.240 is so synchronous and then we can NOTE Confidence: 0.837158596315789 00:30:40.240 --> 00:30:42.472 transmit translate that into lesions NOTE Confidence: 0.837158596315789 00:30:42.472 --> 00:30:44.936 in humans and and and then confirm NOTE Confidence: 0.837158596315789 00:30:44.936 --> 00:30:47.225 with the the pancreatic system we've NOTE Confidence: 0.837158596315789 00:30:47.225 --> 00:30:50.057 been really able to kind of pretty NOTE Confidence: 0.837158596315789 00:30:50.057 --> 00:30:52.256 quickly delineate us and others NOTE Confidence: 0.837158596315789 00:30:52.256 --> 00:30:55.363 the the the program that happens in NOTE Confidence: 0.837158596315789 00:30:55.363 --> 00:30:58.057 polygenesis and basically you take an. NOTE Confidence: 0.837158596315789 00:30:58.060 --> 00:30:59.944 A uninjured secretory cell and you NOTE Confidence: 0.837158596315789 00:30:59.944 --> 00:31:02.048 cause some kind of injury that's NOTE Confidence: 0.837158596315789 00:31:02.048 --> 00:31:03.998 going to induce some metaplasia. NOTE Confidence: 0.837158596315789 00:31:04.000 --> 00:31:05.568 And of course you know as we know NOTE Confidence: 0.837158596315789 00:31:05.568 --> 00:31:07.401 the whole point of that is to induce NOTE Confidence: 0.837158596315789 00:31:07.401 --> 00:31:09.250 proliferation so that it repairs the damage. NOTE Confidence: 0.837158596315789 00:31:09.250 --> 00:31:10.774 But the other thing that happens NOTE Confidence: 0.837158596315789 00:31:10.774 --> 00:31:12.678 is about this kind of time course NOTE Confidence: 0.837158596315789 00:31:12.678 --> 00:31:14.073 all the different the organelles NOTE Confidence: 0.837158596315789 00:31:14.073 --> 00:31:16.249 that are specifically tied to the NOTE Confidence: 0.837158596315789 00:31:16.249 --> 00:31:17.817 differentiated function are decreased. NOTE Confidence: 0.837158596315789 00:31:17.820 --> 00:31:18.256 You know, NOTE Confidence: 0.837158596315789 00:31:18.256 --> 00:31:20.000 so things like the rough ER and and NOTE Confidence: 0.837158596315789 00:31:20.050 --> 00:31:21.938 and and this is focused on the stomach, NOTE Confidence: 0.837158596315789 00:31:21.940 --> 00:31:23.905 but they're equivalents in in NOTE Confidence: 0.837158596315789 00:31:23.905 --> 00:31:25.477 pancreas and other organs, NOTE Confidence: 0.837158596315789 00:31:25.480 --> 00:31:29.048 but things like pepsinogen and and so on. NOTE Confidence: 0.837158596315789 00:31:29.050 --> 00:31:32.060 And that occurs across these three stages. NOTE Confidence: 0.837158596315789 00:31:32.060 --> 00:31:34.454 The first stage is this massive autophagy, NOTE Confidence: 0.855814773846154 00:31:34.460 --> 00:31:35.902 which is of course what's helping to NOTE Confidence: 0.855814773846154 00:31:35.902 --> 00:31:37.799 get rid of these differentiated organs. NOTE Confidence: 0.855814773846154 00:31:37.800 --> 00:31:40.146 The second stage is that METAPLASTIC NOTE Confidence: 0.855814773846154 00:31:40.146 --> 00:31:42.783 gene expression where you start to see NOTE Confidence: 0.855814773846154 00:31:42.783 --> 00:31:45.121 that the cells have rearranged how they. NOTE Confidence: 0.855814773846154 00:31:45.130 --> 00:31:47.510 Actually Mark and label and NOTE Confidence: 0.855814773846154 00:31:47.510 --> 00:31:50.450 then the final stage is this. NOTE Confidence: 0.855814773846154 00:31:50.450 --> 00:31:53.390 Mtorc increase, which is critical for NOTE Confidence: 0.855814773846154 00:31:53.390 --> 00:31:57.336 entering into the cell cycle and that is NOTE Confidence: 0.855814773846154 00:31:57.336 --> 00:31:59.522 immediately after a stage of induction NOTE Confidence: 0.855814773846154 00:31:59.522 --> 00:32:01.370 and then suppression of people 53. NOTE Confidence: 0.855814773846154 00:32:01.370 --> 00:32:03.498 So this crossing point is very important NOTE Confidence: 0.855814773846154 00:32:03.498 --> 00:32:05.489 because the main thing that P53 does NOTE Confidence: 0.855814773846154 00:32:05.489 --> 00:32:07.400 is I'll show you is suppress mtorc. NOTE Confidence: 0.855814773846154 00:32:07.400 --> 00:32:10.154 So CP3 has to decrease for these cells to NOTE Confidence: 0.855814773846154 00:32:10.154 --> 00:32:13.110 be licensed to read into the cell cycle. NOTE Confidence: 0.855814773846154 00:32:13.110 --> 00:32:14.265 So you know we're going to head NOTE Confidence: 0.855814773846154 00:32:14.265 --> 00:32:15.309 on this theme several times, NOTE Confidence: 0.855814773846154 00:32:15.310 --> 00:32:17.137 but I already hinted at it from NOTE Confidence: 0.855814773846154 00:32:17.137 --> 00:32:19.099 what we know about Barretts and NOTE Confidence: 0.855814773846154 00:32:19.099 --> 00:32:20.954 why this kind of reprogramming. NOTE Confidence: 0.855814773846154 00:32:20.960 --> 00:32:22.420 Is so important in NYPD. NOTE Confidence: 0.855814773846154 00:32:22.420 --> 00:32:23.599 Three is important. NOTE Confidence: 0.855814773846154 00:32:23.599 --> 00:32:25.957 It's important for this licensing step. NOTE Confidence: 0.855814773846154 00:32:25.960 --> 00:32:28.010 You don't let differentiated cells NOTE Confidence: 0.855814773846154 00:32:28.010 --> 00:32:30.600 back into the cell cycle unless NOTE Confidence: 0.855814773846154 00:32:30.600 --> 00:32:32.920 they've cleared up 53 checkpoint. NOTE Confidence: 0.855814773846154 00:32:32.920 --> 00:32:34.580 So thinking about mtorc one, NOTE Confidence: 0.855814773846154 00:32:34.580 --> 00:32:36.092 it's the central energy regulator and NOTE Confidence: 0.855814773846154 00:32:36.092 --> 00:32:38.338 this is a super simplistic version of it. NOTE Confidence: 0.855814773846154 00:32:38.340 --> 00:32:40.599 But just so that we're on the same page, NOTE Confidence: 0.855814773846154 00:32:40.600 --> 00:32:42.772 you know it's pretty much integrates NOTE Confidence: 0.855814773846154 00:32:42.772 --> 00:32:44.996 the vast majority of the cells NOTE Confidence: 0.855814773846154 00:32:44.996 --> 00:32:46.771 energetic inputs and outputs with NOTE Confidence: 0.855814773846154 00:32:46.771 --> 00:32:49.178 the two main wings being related, NOTE Confidence: 0.855814773846154 00:32:49.180 --> 00:32:50.820 wings being protein translation NOTE Confidence: 0.855814773846154 00:32:50.820 --> 00:32:53.280 and of course driving the cell NOTE Confidence: 0.855814773846154 00:32:53.347 --> 00:32:55.437 cycle via phosphorylation of the NOTE Confidence: 0.855814773846154 00:32:55.437 --> 00:32:56.805 small ribosomal subunit 6. NOTE Confidence: 0.855814773846154 00:32:56.805 --> 00:32:59.010 So this is going to be important NOTE Confidence: 0.855814773846154 00:32:59.073 --> 00:33:01.236 because this is a great marker for NOTE Confidence: 0.855814773846154 00:33:01.236 --> 00:33:03.120 Mturk activity by immunostaining. NOTE Confidence: 0.855814773846154 00:33:03.120 --> 00:33:04.968 Works great or an IF you can tell NOTE Confidence: 0.855814773846154 00:33:04.968 --> 00:33:07.009 how much import there is by how NOTE Confidence: 0.855814773846154 00:33:07.009 --> 00:33:08.524 much phosphorylated S6 there is, NOTE Confidence: 0.855814773846154 00:33:08.530 --> 00:33:09.781 so Amtrak increases. NOTE Confidence: 0.855814773846154 00:33:09.781 --> 00:33:12.283 This in itself is stimulated by NOTE Confidence: 0.855814773846154 00:33:12.283 --> 00:33:14.904 low energy and by autophagy and NOTE Confidence: 0.855814773846154 00:33:14.904 --> 00:33:17.029 all of the breakdown products NOTE Confidence: 0.855814773846154 00:33:17.103 --> 00:33:19.336 in in the lysosomes and a key. NOTE Confidence: 0.855814773846154 00:33:19.340 --> 00:33:21.948 Inhibitor of mtorc is this gene called before NOTE Confidence: 0.855814773846154 00:33:21.948 --> 00:33:24.667 or red one which we'll talk about also. NOTE Confidence: 0.855814773846154 00:33:24.670 --> 00:33:27.393 So let's look at some of how NOTE Confidence: 0.855814773846154 00:33:27.393 --> 00:33:29.704 what this looks like in actual NOTE Confidence: 0.855814773846154 00:33:29.704 --> 00:33:31.439 ultrastructure and you can see NOTE Confidence: 0.855814773846154 00:33:31.439 --> 00:33:33.834 that within 24 hours down now we're NOTE Confidence: 0.855814773846154 00:33:33.834 --> 00:33:36.310 looking in chief cells that we have NOTE Confidence: 0.855814773846154 00:33:36.310 --> 00:33:38.230 all these massive autophagosomes, NOTE Confidence: 0.855814773846154 00:33:38.230 --> 00:33:39.004 auto lysosomes, NOTE Confidence: 0.855814773846154 00:33:39.004 --> 00:33:40.939 all this auto degraded machinery NOTE Confidence: 0.855814773846154 00:33:40.939 --> 00:33:43.268 that these cells start to rearrange NOTE Confidence: 0.855814773846154 00:33:43.268 --> 00:33:44.744 their their entire architecture NOTE Confidence: 0.855814773846154 00:33:44.744 --> 00:33:47.519 and you can see just here this is NOTE Confidence: 0.855814773846154 00:33:47.519 --> 00:33:49.528 quantified by how much lysosomes there. NOTE Confidence: 0.855814773846154 00:33:49.528 --> 00:33:52.722 And then we use this 3D electron NOTE Confidence: 0.855814773846154 00:33:52.722 --> 00:33:55.126 microscopic tactic called focused NOTE Confidence: 0.855814773846154 00:33:55.126 --> 00:33:57.530 IMDb scanning electron microscopy NOTE Confidence: 0.855814773846154 00:33:57.611 --> 00:34:00.195 to kind of look at it more detail. NOTE Confidence: 0.855814773846154 00:34:00.200 --> 00:34:02.336 And you can see as we kind of NOTE Confidence: 0.855814773846154 00:34:02.340 --> 00:34:03.039 spin this around, NOTE Confidence: 0.855814773846154 00:34:03.039 --> 00:34:05.107 this is a single chief cell as this NOTE Confidence: 0.855814773846154 00:34:05.107 --> 00:34:07.047 polygenesis process that's happening early. NOTE Confidence: 0.855814773846154 00:34:07.050 --> 00:34:08.808 This is a capillary loop and NOTE Confidence: 0.855814773846154 00:34:08.808 --> 00:34:10.550 these are the secretory granules, NOTE Confidence: 0.855814773846154 00:34:10.550 --> 00:34:11.999 this is the nucleus and these are NOTE Confidence: 0.855814773846154 00:34:11.999 --> 00:34:13.280 all lysosomes and autophagosomes. NOTE Confidence: 0.855814773846154 00:34:13.280 --> 00:34:15.680 So like half the cell becomes NOTE Confidence: 0.855814773846154 00:34:15.680 --> 00:34:19.260 auto degradative as the. NOTE Confidence: 0.855814773846154 00:34:19.260 --> 00:34:23.054 As this early stage in Polygenesis happens, NOTE Confidence: 0.855814773846154 00:34:23.060 --> 00:34:26.520 so that's what's happening to NOTE Confidence: 0.855814773846154 00:34:26.520 --> 00:34:29.288 autophagosomes and and lysosomes. NOTE Confidence: 0.855814773846154 00:34:29.290 --> 00:34:31.298 For that to happen Mturk has to decrease NOTE Confidence: 0.855814773846154 00:34:31.298 --> 00:34:33.072 and here we're looking at mtorc NOTE Confidence: 0.855814773846154 00:34:33.072 --> 00:34:34.890 activity using this phosphorus 6 and NOTE Confidence: 0.796392662222222 00:34:34.944 --> 00:34:36.638 here we focus on the chief cells. NOTE Confidence: 0.796392662222222 00:34:36.640 --> 00:34:39.529 And here within 12 hours all all of this NOTE Confidence: 0.796392662222222 00:34:39.529 --> 00:34:41.728 phosphorus 6 or M torc activity is lost NOTE Confidence: 0.796392662222222 00:34:41.728 --> 00:34:44.272 in the chief cells and then by maximum NOTE Confidence: 0.796392662222222 00:34:44.272 --> 00:34:46.251 metaplasia it all comes back again. NOTE Confidence: 0.796392662222222 00:34:46.251 --> 00:34:47.877 So here it's working for secretion NOTE Confidence: 0.796392662222222 00:34:47.877 --> 00:34:49.460 and not for proliferation, NOTE Confidence: 0.796392662222222 00:34:49.460 --> 00:34:51.120 here it's working for proliferation. NOTE Confidence: 0.796392662222222 00:34:51.120 --> 00:34:53.464 And in between is when all that autophagy NOTE Confidence: 0.796392662222222 00:34:53.464 --> 00:34:55.611 is happening and you can see even on NOTE Confidence: 0.796392662222222 00:34:55.611 --> 00:34:57.498 Western blots of mouse stomach you can NOTE Confidence: 0.796392662222222 00:34:57.498 --> 00:34:59.437 see it happening on the other hand. NOTE Confidence: 0.796392662222222 00:34:59.440 --> 00:35:01.876 We knock out this suppressive ddit 4, NOTE Confidence: 0.796392662222222 00:35:01.880 --> 00:35:04.200 which I showed you in that cartoon with NOTE Confidence: 0.796392662222222 00:35:04.200 --> 00:35:06.937 it gets induced early to suppress network. NOTE Confidence: 0.796392662222222 00:35:06.940 --> 00:35:10.246 You don't have the same decrease NOTE Confidence: 0.796392662222222 00:35:10.246 --> 00:35:12.740 in mtorc activity and you don't NOTE Confidence: 0.796392662222222 00:35:12.740 --> 00:35:13.860 have the same autophagy. NOTE Confidence: 0.796392662222222 00:35:13.860 --> 00:35:14.838 So if you look at mtorc, NOTE Confidence: 0.796392662222222 00:35:14.840 --> 00:35:17.400 basically it's much, you know. NOTE Confidence: 0.796392662222222 00:35:17.400 --> 00:35:19.086 Normally it's like that and in NOTE Confidence: 0.796392662222222 00:35:19.086 --> 00:35:20.799 the four knockout it's like that. NOTE Confidence: 0.796392662222222 00:35:20.800 --> 00:35:23.500 So that leads to actually more, NOTE Confidence: 0.796392662222222 00:35:23.500 --> 00:35:24.972 more proliferation, NOTE Confidence: 0.796392662222222 00:35:24.972 --> 00:35:27.180 more metaplasia downstream. NOTE Confidence: 0.796392662222222 00:35:27.180 --> 00:35:28.736 And conversely, NOTE Confidence: 0.796392662222222 00:35:28.736 --> 00:35:31.848 when you inhibit mtorc. NOTE Confidence: 0.796392662222222 00:35:31.850 --> 00:35:34.682 That's how we know that the cell cycle NOTE Confidence: 0.796392662222222 00:35:34.682 --> 00:35:37.919 reentry is critical because taking rapamycin, NOTE Confidence: 0.796392662222222 00:35:37.920 --> 00:35:39.488 an M TORC inhibitor, NOTE Confidence: 0.796392662222222 00:35:39.488 --> 00:35:42.377 and treating mice with it does not block NOTE Confidence: 0.796392662222222 00:35:42.377 --> 00:35:44.231 the the metaplasia or the autophagy NOTE Confidence: 0.796392662222222 00:35:44.231 --> 00:35:46.228 or those first couple of steps, NOTE Confidence: 0.796392662222222 00:35:46.230 --> 00:35:49.440 but it it blocks the NOTE Confidence: 0.796392662222222 00:35:49.440 --> 00:35:50.724 proliferation completely. NOTE Confidence: 0.796392662222222 00:35:50.730 --> 00:35:53.634 So early on did it 4 suppresses mtorc. NOTE Confidence: 0.796392662222222 00:35:53.640 --> 00:35:56.268 We have all that autophagy but on NOTE Confidence: 0.796392662222222 00:35:56.268 --> 00:35:58.081 that last slide we also see that NOTE Confidence: 0.796392662222222 00:35:58.081 --> 00:36:00.244 did it four goes away within the NOTE Confidence: 0.796392662222222 00:36:00.244 --> 00:36:02.115 first couple of stages and that's NOTE Confidence: 0.796392662222222 00:36:02.115 --> 00:36:04.138 when 53 comes on and P53 continues NOTE Confidence: 0.796392662222222 00:36:04.138 --> 00:36:06.185 to suppress M torque until or NOTE Confidence: 0.796392662222222 00:36:06.185 --> 00:36:08.298 unless the cell then decides to NOTE Confidence: 0.796392662222222 00:36:08.298 --> 00:36:10.050 come back and the cell cycle. NOTE Confidence: 0.796392662222222 00:36:10.050 --> 00:36:12.498 So that part of the way we know that NOTE Confidence: 0.796392662222222 00:36:12.498 --> 00:36:15.327 is that in P53 knockouts we also don't NOTE Confidence: 0.796392662222222 00:36:15.327 --> 00:36:17.947 have this mtorc loss early on we NOTE Confidence: 0.796392662222222 00:36:17.947 --> 00:36:20.161 have more proliferation both in the. NOTE Confidence: 0.796392662222222 00:36:20.170 --> 00:36:22.414 The stomach and the pancreas and NOTE Confidence: 0.796392662222222 00:36:22.414 --> 00:36:25.339 then what we know that the critical NOTE Confidence: 0.796392662222222 00:36:25.339 --> 00:36:28.140 regulator of P53 that tells the cell NOTE Confidence: 0.796392662222222 00:36:28.140 --> 00:36:30.040 whether the cell should increase NOTE Confidence: 0.796392662222222 00:36:30.116 --> 00:36:32.412 M Turk and go back into the cell NOTE Confidence: 0.796392662222222 00:36:32.412 --> 00:36:34.356 cycle is a protein called ifrd one. NOTE Confidence: 0.796392662222222 00:36:34.360 --> 00:36:36.404 And we'll show you how that works NOTE Confidence: 0.796392662222222 00:36:36.404 --> 00:36:38.688 and how that P3 I 41 access works. NOTE Confidence: 0.796392662222222 00:36:38.690 --> 00:36:41.522 But you can see it's massively NOTE Confidence: 0.796392662222222 00:36:41.522 --> 00:36:42.642 upregulated during collagenosis NOTE Confidence: 0.796392662222222 00:36:42.642 --> 00:36:44.889 and then as the cells we enter NOTE Confidence: 0.796392662222222 00:36:44.889 --> 00:36:46.697 the cell cycle it goes away. NOTE Confidence: 0.796392662222222 00:36:46.700 --> 00:36:48.891 And in the absence of in the NOTE Confidence: 0.796392662222222 00:36:48.891 --> 00:36:50.112 absence of ID 11, NOTE Confidence: 0.796392662222222 00:36:50.112 --> 00:36:52.184 all the cells wind up dying and NOTE Confidence: 0.796392662222222 00:36:52.184 --> 00:36:54.179 not completing the process. NOTE Confidence: 0.796392662222222 00:36:54.180 --> 00:36:56.035 But if you knock out paid 53, NOTE Confidence: 0.796392662222222 00:36:56.040 --> 00:36:57.192 then they're rescued and NOTE Confidence: 0.796392662222222 00:36:57.192 --> 00:36:58.632 they reenter the cell cycle. NOTE Confidence: 0.796392662222222 00:36:58.640 --> 00:37:00.033 So that's how we know I pretty NOTE Confidence: 0.796392662222222 00:37:00.033 --> 00:37:00.920 when it's upstream of 53. NOTE Confidence: 0.796392662222222 00:37:00.920 --> 00:37:02.696 So we'll talk about how RD1 NOTE Confidence: 0.796392662222222 00:37:02.696 --> 00:37:05.069 dictates to P3 to dictate M torque. NOTE Confidence: 0.796392662222222 00:37:05.070 --> 00:37:07.920 A lot of this work was done by Max Yao, NOTE Confidence: 0.796392662222222 00:37:07.920 --> 00:37:12.480 who's in China now as an assistant professor. NOTE Confidence: 0.796392662222222 00:37:12.480 --> 00:37:15.104 So let's talk now about some of the NOTE Confidence: 0.796392662222222 00:37:15.104 --> 00:37:16.911 machinery that executes this process NOTE Confidence: 0.796392662222222 00:37:16.911 --> 00:37:20.029 and the way that we've started to do this. NOTE Confidence: 0.796392662222222 00:37:20.030 --> 00:37:20.788 Stepping back, NOTE Confidence: 0.796392662222222 00:37:20.788 --> 00:37:21.167 right, NOTE Confidence: 0.796392662222222 00:37:21.167 --> 00:37:23.441 like if this process of taking NOTE Confidence: 0.796392662222222 00:37:23.441 --> 00:37:25.490 a differentiated cell and bring NOTE Confidence: 0.796392662222222 00:37:25.490 --> 00:37:28.323 it back into the cell cycle is, NOTE Confidence: 0.796392662222222 00:37:28.323 --> 00:37:29.189 you know, NOTE Confidence: 0.796392662222222 00:37:29.189 --> 00:37:30.921 a conserve process across NOTE Confidence: 0.796392662222222 00:37:30.921 --> 00:37:32.220 multiple tissues just NOTE Confidence: 0.774541726666667 00:37:32.294 --> 00:37:34.460 like apoptosis, then there should be NOTE Confidence: 0.774541726666667 00:37:34.460 --> 00:37:36.590 genes that are dedicated to the process, NOTE Confidence: 0.774541726666667 00:37:36.590 --> 00:37:39.306 just as there are genes dedicated to NOTE Confidence: 0.774541726666667 00:37:39.306 --> 00:37:41.410 apoptosis like BCL's and caspases and so on. NOTE Confidence: 0.774541726666667 00:37:41.410 --> 00:37:45.322 So we started doing screens in NOTE Confidence: 0.774541726666667 00:37:45.322 --> 00:37:47.278 these regenerative metaplastic. NOTE Confidence: 0.774541726666667 00:37:47.280 --> 00:37:51.092 Organs after after you know during NOTE Confidence: 0.774541726666667 00:37:51.092 --> 00:37:52.670 the regenerative phase and look for NOTE Confidence: 0.774541726666667 00:37:52.722 --> 00:37:54.241 genes that are all ex Co expressed NOTE Confidence: 0.774541726666667 00:37:54.241 --> 00:37:56.130 and and from these I FD one indeed it NOTE Confidence: 0.774541726666667 00:37:56.130 --> 00:37:57.848 four came out I've already told you NOTE Confidence: 0.774541726666667 00:37:57.848 --> 00:37:59.684 about them need it for suppressing NOTE Confidence: 0.774541726666667 00:37:59.684 --> 00:38:01.881 mtorc I-41 suppressing P53 but we have NOTE Confidence: 0.774541726666667 00:38:01.881 --> 00:38:03.740 other targets that we've been working NOTE Confidence: 0.774541726666667 00:38:03.740 --> 00:38:05.770 on another really strong one is ATF NOTE Confidence: 0.774541726666667 00:38:05.770 --> 00:38:07.740 three which I want to talk about and NOTE Confidence: 0.774541726666667 00:38:07.740 --> 00:38:09.416 we're starting to piece together then NOTE Confidence: 0.774541726666667 00:38:09.416 --> 00:38:11.216 this architecture but this is what NOTE Confidence: 0.774541726666667 00:38:11.216 --> 00:38:13.114 we've learned so far in in this talk NOTE Confidence: 0.774541726666667 00:38:13.114 --> 00:38:15.140 do you injury happens the cell starts NOTE Confidence: 0.774541726666667 00:38:15.140 --> 00:38:17.510 to undergo a topology did it for. NOTE Confidence: 0.774541726666667 00:38:17.510 --> 00:38:19.250 Suppresses mtorc to turn it off NOTE Confidence: 0.774541726666667 00:38:19.250 --> 00:38:21.010 to allow the autophagy to happen. NOTE Confidence: 0.774541726666667 00:38:21.010 --> 00:38:23.593 I have heard one is induced that NOTE Confidence: 0.774541726666667 00:38:23.593 --> 00:38:25.390 eventually accumulates and suppresses NOTE Confidence: 0.774541726666667 00:38:25.390 --> 00:38:29.656 P53 which allows cell cycle entry. NOTE Confidence: 0.774541726666667 00:38:29.660 --> 00:38:33.258 So. Why then is mtorc so important? NOTE Confidence: 0.774541726666667 00:38:33.260 --> 00:38:34.130 Because, you know, NOTE Confidence: 0.774541726666667 00:38:34.130 --> 00:38:35.870 when we think about why Barretts NOTE Confidence: 0.774541726666667 00:38:35.870 --> 00:38:36.560 becomes cancer, NOTE Confidence: 0.774541726666667 00:38:36.560 --> 00:38:38.380 why gastric intestinal metaplasia NOTE Confidence: 0.774541726666667 00:38:38.380 --> 00:38:39.745 or you know, NOTE Confidence: 0.774541726666667 00:38:39.750 --> 00:38:41.630 pseudo pyloric metaplasia gives NOTE Confidence: 0.774541726666667 00:38:41.630 --> 00:38:44.660 rise to cancer and we think about NOTE Confidence: 0.774541726666667 00:38:44.660 --> 00:38:45.875 this pathogenesis process, NOTE Confidence: 0.774541726666667 00:38:45.880 --> 00:38:46.556 this conversion, NOTE Confidence: 0.774541726666667 00:38:46.556 --> 00:38:47.232 you know, NOTE Confidence: 0.774541726666667 00:38:47.232 --> 00:38:49.669 being critical for that and mtorc being NOTE Confidence: 0.774541726666667 00:38:49.669 --> 00:38:51.763 critical for that cell cycle reentry NOTE Confidence: 0.774541726666667 00:38:51.763 --> 00:38:54.000 because that's what you need for cancer. NOTE Confidence: 0.774541726666667 00:38:54.000 --> 00:38:55.360 Why is it so important? NOTE Confidence: 0.774541726666667 00:38:55.360 --> 00:38:55.619 Well, NOTE Confidence: 0.774541726666667 00:38:55.619 --> 00:38:57.432 here's what we delve like the deepest NOTE Confidence: 0.774541726666667 00:38:57.432 --> 00:38:58.842 into the structure and organelles NOTE Confidence: 0.774541726666667 00:38:58.842 --> 00:39:01.150 before we kind of come back out again. NOTE Confidence: 0.774541726666667 00:39:01.150 --> 00:39:04.734 Our thinking now is that it's all about NOTE Confidence: 0.774541726666667 00:39:04.734 --> 00:39:06.190 ribosomes when you're a chief cell. NOTE Confidence: 0.774541726666667 00:39:06.190 --> 00:39:08.662 I showed you that electron microscope NOTE Confidence: 0.774541726666667 00:39:08.662 --> 00:39:11.007 micrograph where it's just layer after NOTE Confidence: 0.774541726666667 00:39:11.007 --> 00:39:13.527 layer after layer of rough ER and all NOTE Confidence: 0.774541726666667 00:39:13.597 --> 00:39:17.098 that roughly RISER line by ribosomes. NOTE Confidence: 0.774541726666667 00:39:17.100 --> 00:39:19.916 That are making digestive enzymes to go into, NOTE Confidence: 0.774541726666667 00:39:19.920 --> 00:39:20.386 you know, NOTE Confidence: 0.774541726666667 00:39:20.386 --> 00:39:23.010 the lumen of the R and then to be secreted. NOTE Confidence: 0.774541726666667 00:39:23.010 --> 00:39:24.666 When you become a proliferative cell, NOTE Confidence: 0.774541726666667 00:39:24.670 --> 00:39:26.272 you don't need all that secretory NOTE Confidence: 0.774541726666667 00:39:26.272 --> 00:39:28.370 roufi R you need ribosomes in the NOTE Confidence: 0.774541726666667 00:39:28.370 --> 00:39:30.320 cytosol to make more ribosomes than NOTE Confidence: 0.774541726666667 00:39:30.320 --> 00:39:32.149 histones to make a copy of the cell. NOTE Confidence: 0.774541726666667 00:39:32.150 --> 00:39:35.174 And the key driver for ribosome NOTE Confidence: 0.774541726666667 00:39:35.174 --> 00:39:37.570 Biogenesis is M torque OK, NOTE Confidence: 0.774541726666667 00:39:37.570 --> 00:39:39.838 and the reason why ribosome Biogenesis NOTE Confidence: 0.774541726666667 00:39:39.838 --> 00:39:42.629 needs so much energy is because it's NOTE Confidence: 0.774541726666667 00:39:42.629 --> 00:39:44.649 an incredibly complex process of NOTE Confidence: 0.774541726666667 00:39:44.649 --> 00:39:46.835 assembling all of these ribosomal NOTE Confidence: 0.774541726666667 00:39:46.835 --> 00:39:49.112 proteins and ribosomal RNA's that NOTE Confidence: 0.774541726666667 00:39:49.112 --> 00:39:51.517 require all three RNA polymerases NOTE Confidence: 0.774541726666667 00:39:51.517 --> 00:39:53.480 and translation into these. NOTE Confidence: 0.774541726666667 00:39:53.480 --> 00:39:57.158 Large and small 1640 subunits which NOTE Confidence: 0.774541726666667 00:39:57.158 --> 00:39:59.594 come together as a single subunit, NOTE Confidence: 0.774541726666667 00:39:59.600 --> 00:40:01.075 multiple modifications happen and all NOTE Confidence: 0.774541726666667 00:40:01.075 --> 00:40:03.449 of its sort of starts in the nucleolus. NOTE Confidence: 0.774541726666667 00:40:03.450 --> 00:40:05.880 So that's our basic ribosome review. NOTE Confidence: 0.774541726666667 00:40:05.880 --> 00:40:06.978 And then as I talked about, NOTE Confidence: 0.774541726666667 00:40:06.980 --> 00:40:08.738 there's a big difference between this NOTE Confidence: 0.774541726666667 00:40:08.738 --> 00:40:10.698 pool and this side of solid pool, NOTE Confidence: 0.774541726666667 00:40:10.700 --> 00:40:11.040 right, NOTE Confidence: 0.774541726666667 00:40:11.040 --> 00:40:13.420 because this is for secretion and this NOTE Confidence: 0.774541726666667 00:40:13.420 --> 00:40:16.089 is more for division and housekeeping. NOTE Confidence: 0.774541726666667 00:40:16.090 --> 00:40:20.274 So to get from the ribosome to translation, NOTE Confidence: 0.774541726666667 00:40:20.280 --> 00:40:21.946 we have to realize that the M NOTE Confidence: 0.774541726666667 00:40:21.946 --> 00:40:24.146 RNA is going to be loaded up NOTE Confidence: 0.774541726666667 00:40:24.146 --> 00:40:25.214 the preinitiation complexes. NOTE Confidence: 0.774541726666667 00:40:25.220 --> 00:40:26.822 That's going to bring the two NOTE Confidence: 0.774541726666667 00:40:26.822 --> 00:40:27.356 subunits together. NOTE Confidence: 0.774541726666667 00:40:27.360 --> 00:40:28.685 So the two subunits only NOTE Confidence: 0.774541726666667 00:40:28.685 --> 00:40:30.010 come together with M RNA NOTE Confidence: 0.763685607272727 00:40:30.072 --> 00:40:32.950 normally, OK. So they're kept together NOTE Confidence: 0.763685607272727 00:40:32.950 --> 00:40:34.960 with M RNA as they translate. NOTE Confidence: 0.763685607272727 00:40:34.960 --> 00:40:36.864 And then the way most of our NOTE Confidence: 0.763685607272727 00:40:36.864 --> 00:40:38.356 translation happens is not with NOTE Confidence: 0.763685607272727 00:40:38.356 --> 00:40:39.901 single ribosomes but multiple ones NOTE Confidence: 0.763685607272727 00:40:39.901 --> 00:40:41.874 like pearls on a string, line up, NOTE Confidence: 0.763685607272727 00:40:41.874 --> 00:40:43.638 line up and those are called polysomes. NOTE Confidence: 0.763685607272727 00:40:43.640 --> 00:40:44.954 We're not going to go too much into this, NOTE Confidence: 0.763685607272727 00:40:44.960 --> 00:40:46.640 but you can tell the difference. NOTE Confidence: 0.763685607272727 00:40:46.640 --> 00:40:48.215 Between Monisms and polysomes by NOTE Confidence: 0.763685607272727 00:40:48.215 --> 00:40:50.128 spinning them down and the longer NOTE Confidence: 0.763685607272727 00:40:50.128 --> 00:40:52.074 you know ones or polysomes so they NOTE Confidence: 0.763685607272727 00:40:52.074 --> 00:40:53.966 take lower longer to spin spin out. NOTE Confidence: 0.763685607272727 00:40:53.970 --> 00:40:57.106 So the last review slide here on ribosomes. NOTE Confidence: 0.763685607272727 00:40:57.110 --> 00:40:59.406 The reason why they require so much, NOTE Confidence: 0.763685607272727 00:40:59.410 --> 00:41:01.664 they require 80% of the cells energy. NOTE Confidence: 0.763685607272727 00:41:01.670 --> 00:41:03.366 So that's why it's so important how you, NOTE Confidence: 0.763685607272727 00:41:03.370 --> 00:41:05.956 you know, regulate ribosome Biogenesis and NOTE Confidence: 0.763685607272727 00:41:05.956 --> 00:41:09.966 60% of your RNA in each cell is ribosomes. NOTE Confidence: 0.763685607272727 00:41:09.970 --> 00:41:12.088 So there's huge proportions of the NOTE Confidence: 0.763685607272727 00:41:12.088 --> 00:41:13.500 transcription and translation that NOTE Confidence: 0.763685607272727 00:41:13.554 --> 00:41:15.090 goes into ribosome Biogenesis. NOTE Confidence: 0.763685607272727 00:41:15.090 --> 00:41:17.430 So what happens to ribosomes NOTE Confidence: 0.763685607272727 00:41:17.430 --> 00:41:18.024 during palingenesis? NOTE Confidence: 0.763685607272727 00:41:18.024 --> 00:41:20.400 So we knew already that they had to NOTE Confidence: 0.763685607272727 00:41:20.462 --> 00:41:22.568 be coming off the rough ER and we saw NOTE Confidence: 0.763685607272727 00:41:22.568 --> 00:41:24.607 that's what all the autophagy was doing. NOTE Confidence: 0.763685607272727 00:41:24.610 --> 00:41:26.045 But you can also just document it, NOTE Confidence: 0.763685607272727 00:41:26.050 --> 00:41:27.151 there's many ways. NOTE Confidence: 0.763685607272727 00:41:27.151 --> 00:41:29.353 To to show that you're losing NOTE Confidence: 0.763685607272727 00:41:29.353 --> 00:41:30.898 both large and small. NOTE Confidence: 0.763685607272727 00:41:30.900 --> 00:41:32.706 Subunits of ribosomes are just Western NOTE Confidence: 0.763685607272727 00:41:32.706 --> 00:41:34.788 blots early on in the process and NOTE Confidence: 0.763685607272727 00:41:34.788 --> 00:41:36.706 then they come back on again later. NOTE Confidence: 0.763685607272727 00:41:36.710 --> 00:41:38.648 So there's a loss and then NOTE Confidence: 0.763685607272727 00:41:38.648 --> 00:41:39.294 regeneration process. NOTE Confidence: 0.763685607272727 00:41:39.300 --> 00:41:42.475 But you can also see some of the NOTE Confidence: 0.763685607272727 00:41:42.475 --> 00:41:43.800 ribosomes getting taken up into NOTE Confidence: 0.763685607272727 00:41:43.800 --> 00:41:45.697 the the rough ER and you can also NOTE Confidence: 0.763685607272727 00:41:45.697 --> 00:41:47.470 see them kind of spinning off the NOTE Confidence: 0.763685607272727 00:41:47.470 --> 00:41:48.870 ER here into the sideshow. NOTE Confidence: 0.763685607272727 00:41:48.870 --> 00:41:51.020 And in fact Juan J was one of the first NOTE Confidence: 0.763685607272727 00:41:51.085 --> 00:41:53.077 to show this by knocking out a gene NOTE Confidence: 0.763685607272727 00:41:53.077 --> 00:41:54.736 that that regulates all that rough NOTE Confidence: 0.763685607272727 00:41:54.736 --> 00:41:56.627 ER when he was a graduate student. NOTE Confidence: 0.763685607272727 00:41:56.627 --> 00:41:58.443 So this is kind of what we think NOTE Confidence: 0.763685607272727 00:41:58.443 --> 00:41:59.240 is happening. NOTE Confidence: 0.763685607272727 00:41:59.240 --> 00:42:01.858 In terms of stages of of pathogenesis, NOTE Confidence: 0.763685607272727 00:42:01.860 --> 00:42:05.528 normally you have all these rough ER. NOTE Confidence: 0.763685607272727 00:42:05.530 --> 00:42:08.170 Ribosomes making peptides and then, NOTE Confidence: 0.763685607272727 00:42:08.170 --> 00:42:08.812 you know, NOTE Confidence: 0.763685607272727 00:42:08.812 --> 00:42:10.738 there's an injury and these autophagosomes NOTE Confidence: 0.763685607272727 00:42:10.738 --> 00:42:12.975 start to take up the raffia and the NOTE Confidence: 0.763685607272727 00:42:12.975 --> 00:42:14.642 ribosomes all come off OK what's the NOTE Confidence: 0.763685607272727 00:42:14.642 --> 00:42:16.058 problem with the ribosomes coming off? NOTE Confidence: 0.763685607272727 00:42:16.060 --> 00:42:17.329 As soon as they come off the M RNA, NOTE Confidence: 0.763685607272727 00:42:17.330 --> 00:42:19.574 then they fall apart into their NOTE Confidence: 0.763685607272727 00:42:19.574 --> 00:42:21.710 subunits and into ribosomal proteins, NOTE Confidence: 0.763685607272727 00:42:21.710 --> 00:42:23.920 and those can stimulate P53. NOTE Confidence: 0.763685607272727 00:42:23.920 --> 00:42:25.033 I'm going to show you that again NOTE Confidence: 0.763685607272727 00:42:25.033 --> 00:42:26.130 a couple of different times, NOTE Confidence: 0.763685607272727 00:42:26.130 --> 00:42:28.629 but that's probably why this whole ribosome NOTE Confidence: 0.763685607272727 00:42:28.629 --> 00:42:31.208 is the center of this mtorc P53 axis. NOTE Confidence: 0.763685607272727 00:42:31.210 --> 00:42:32.983 But this is just to show you that we NOTE Confidence: 0.763685607272727 00:42:32.983 --> 00:42:34.827 also get a lot of ribosome Biogenesis, NOTE Confidence: 0.763685607272727 00:42:34.830 --> 00:42:35.664 so we're losing. NOTE Confidence: 0.763685607272727 00:42:35.664 --> 00:42:37.610 Have some and then later we see NOTE Confidence: 0.763685607272727 00:42:37.668 --> 00:42:39.578 huge increases in nucleolar size, NOTE Confidence: 0.763685607272727 00:42:39.580 --> 00:42:41.596 which you can see here in quantify NOTE Confidence: 0.763685607272727 00:42:41.596 --> 00:42:44.099 in both the stomach and the pancreas. NOTE Confidence: 0.763685607272727 00:42:44.100 --> 00:42:46.284 So what that means is we're losing NOTE Confidence: 0.763685607272727 00:42:46.284 --> 00:42:48.230 ribosomes here and then the nucleoli NOTE Confidence: 0.763685607272727 00:42:48.230 --> 00:42:50.132 are getting turned on or making NOTE Confidence: 0.763685607272727 00:42:50.132 --> 00:42:51.399 more ribosomes here. NOTE Confidence: 0.763685607272727 00:42:51.400 --> 00:42:54.484 But that's not the entire story as we see, NOTE Confidence: 0.763685607272727 00:42:54.484 --> 00:42:56.474 because I 41's going to play an important NOTE Confidence: 0.763685607272727 00:42:56.474 --> 00:42:58.478 part in between those two things. NOTE Confidence: 0.763685607272727 00:42:58.480 --> 00:43:00.160 So to be able to study these things, NOTE Confidence: 0.763685607272727 00:43:00.160 --> 00:43:01.714 we already have one tool which NOTE Confidence: 0.763685607272727 00:43:01.714 --> 00:43:02.750 is the ID one NOTE Confidence: 0.789456304545455 00:43:02.810 --> 00:43:05.560 knockout. But Charles Chow in the lab, NOTE Confidence: 0.789456304545455 00:43:05.560 --> 00:43:09.296 who's an instructor looking for a job soon, NOTE Confidence: 0.789456304545455 00:43:09.300 --> 00:43:10.980 also made a knockout of ribosome NOTE Confidence: 0.789456304545455 00:43:10.980 --> 00:43:12.400 Biogenesis for the first time, NOTE Confidence: 0.789456304545455 00:43:12.400 --> 00:43:14.008 surprisingly that he can. NOTE Confidence: 0.789456304545455 00:43:14.008 --> 00:43:16.018 Reduced ribosome Biogenesis knockout by NOTE Confidence: 0.789456304545455 00:43:16.018 --> 00:43:18.074 knocking out this key modifier that's NOTE Confidence: 0.789456304545455 00:43:18.074 --> 00:43:20.440 critical for the small subunit of ribosomes. NOTE Confidence: 0.789456304545455 00:43:20.440 --> 00:43:22.400 And when he does that you that you NOTE Confidence: 0.789456304545455 00:43:22.400 --> 00:43:24.153 can no longer make ribosomes and NOTE Confidence: 0.789456304545455 00:43:24.153 --> 00:43:26.355 when you do that and you induce NOTE Confidence: 0.789456304545455 00:43:26.355 --> 00:43:28.401 collagenosis all the cells die unless NOTE Confidence: 0.789456304545455 00:43:28.401 --> 00:43:30.740 you also put them on a P53 knockout. NOTE Confidence: 0.789456304545455 00:43:30.740 --> 00:43:33.434 So again PD3 knockout is critical NOTE Confidence: 0.789456304545455 00:43:33.434 --> 00:43:36.649 that's sensing the death of of cells NOTE Confidence: 0.789456304545455 00:43:36.649 --> 00:43:38.874 that don't make ribosomes anymore. NOTE Confidence: 0.789456304545455 00:43:38.880 --> 00:43:41.220 So this particular gene which is NOTE Confidence: 0.789456304545455 00:43:41.220 --> 00:43:43.610 involved in the ribosome Biogenesis. NOTE Confidence: 0.789456304545455 00:43:43.610 --> 00:43:45.522 Suppresses P53 presumably because NOTE Confidence: 0.789456304545455 00:43:45.522 --> 00:43:47.434 it makes both subunits. NOTE Confidence: 0.789456304545455 00:43:47.440 --> 00:43:48.736 So they're both subunits are there. NOTE Confidence: 0.789456304545455 00:43:48.740 --> 00:43:50.420 It stops the people to three NOTE Confidence: 0.789456304545455 00:43:50.420 --> 00:43:51.540 induction that happens with NOTE Confidence: 0.789456304545455 00:43:51.596 --> 00:43:53.248 ribosome will breakdown products, NOTE Confidence: 0.789456304545455 00:43:53.250 --> 00:43:56.256 but I have 41 is occurring here NOTE Confidence: 0.789456304545455 00:43:56.256 --> 00:43:58.678 earlier I showed you and it's also NOTE Confidence: 0.789456304545455 00:43:58.678 --> 00:44:00.449 responsible for suppressing P53. NOTE Confidence: 0.789456304545455 00:44:00.450 --> 00:44:01.714 How does that work? NOTE Confidence: 0.789456304545455 00:44:01.714 --> 00:44:03.710 Well, it turns out that it's in between. NOTE Confidence: 0.789456304545455 00:44:03.710 --> 00:44:05.138 That's just to remind you of NOTE Confidence: 0.789456304545455 00:44:05.138 --> 00:44:06.769 that and that NAP 10 is there, NOTE Confidence: 0.789456304545455 00:44:06.770 --> 00:44:08.121 but I heard you once turning on NOTE Confidence: 0.789456304545455 00:44:08.121 --> 00:44:09.370 earlier and doing the suppression. NOTE Confidence: 0.789456304545455 00:44:09.370 --> 00:44:11.570 So how does it work? NOTE Confidence: 0.789456304545455 00:44:11.570 --> 00:44:13.250 So it turns on it, you know, NOTE Confidence: 0.789456304545455 00:44:13.250 --> 00:44:14.250 it turns on here. NOTE Confidence: 0.789456304545455 00:44:14.250 --> 00:44:15.974 And what it does, NOTE Confidence: 0.789456304545455 00:44:15.974 --> 00:44:17.267 it turns out. NOTE Confidence: 0.789456304545455 00:44:17.270 --> 00:44:20.050 Is that I 41 fits right here right where the NOTE Confidence: 0.789456304545455 00:44:20.113 --> 00:44:22.633 M RNA would go between the two subunits. NOTE Confidence: 0.789456304545455 00:44:22.640 --> 00:44:24.344 So when I offered you one NOTE Confidence: 0.789456304545455 00:44:24.344 --> 00:44:25.790 attaches just like M RNA, NOTE Confidence: 0.789456304545455 00:44:25.790 --> 00:44:27.428 it can keep the two ribosomal NOTE Confidence: 0.789456304545455 00:44:27.428 --> 00:44:28.890 subunits together as a whole. NOTE Confidence: 0.789456304545455 00:44:28.890 --> 00:44:30.786 So instead of having this happen NOTE Confidence: 0.789456304545455 00:44:30.786 --> 00:44:32.050 during those early stages, NOTE Confidence: 0.789456304545455 00:44:32.050 --> 00:44:33.665 which then leads to breakdown NOTE Confidence: 0.789456304545455 00:44:33.665 --> 00:44:34.958 in P53 activation, NOTE Confidence: 0.789456304545455 00:44:34.958 --> 00:44:39.630 I 41 can come right there in that pocket. NOTE Confidence: 0.789456304545455 00:44:39.630 --> 00:44:41.275 And as they come off the ribosomes, NOTE Confidence: 0.789456304545455 00:44:41.280 --> 00:44:42.080 they're preserved. NOTE Confidence: 0.789456304545455 00:44:42.080 --> 00:44:44.480 So essentially 53 is blocked because NOTE Confidence: 0.789456304545455 00:44:44.480 --> 00:44:47.131 you don't get breakdown of all the NOTE Confidence: 0.789456304545455 00:44:47.131 --> 00:44:48.916 ribosomes during the first stage. NOTE Confidence: 0.789456304545455 00:44:48.920 --> 00:44:51.674 So on the one hand you could have this, NOTE Confidence: 0.789456304545455 00:44:51.680 --> 00:44:53.894 but when you have ribosome Biogenesis NOTE Confidence: 0.789456304545455 00:44:53.894 --> 00:44:57.079 you can stop P53 by making new ribosomes, NOTE Confidence: 0.789456304545455 00:44:57.080 --> 00:44:59.152 and if you have 41 then you salvage NOTE Confidence: 0.789456304545455 00:44:59.152 --> 00:45:00.605 the existing ribosomes so both NOTE Confidence: 0.789456304545455 00:45:00.605 --> 00:45:02.690 of those then converge on P53. NOTE Confidence: 0.789456304545455 00:45:02.690 --> 00:45:06.470 OK, so that is the ********. NOTE Confidence: 0.789456304545455 00:45:06.470 --> 00:45:07.730 Organellar and molecular stuff. NOTE Confidence: 0.789456304545455 00:45:07.730 --> 00:45:10.411 So now let's come kind of back out to NOTE Confidence: 0.789456304545455 00:45:10.411 --> 00:45:12.478 how this all comes out in tumors and NOTE Confidence: 0.789456304545455 00:45:12.478 --> 00:45:14.606 and come back out towards the pathology. NOTE Confidence: 0.789456304545455 00:45:14.610 --> 00:45:16.465 So with all this background NOTE Confidence: 0.789456304545455 00:45:16.465 --> 00:45:17.949 then it's pretty clear, NOTE Confidence: 0.789456304545455 00:45:17.950 --> 00:45:19.942 you know that the cells spent a lot NOTE Confidence: 0.789456304545455 00:45:19.942 --> 00:45:21.864 of time trying to regulate them to NOTE Confidence: 0.789456304545455 00:45:21.864 --> 00:45:24.091 work via PD3 and via this protein deed NOTE Confidence: 0.789456304545455 00:45:24.091 --> 00:45:26.211 at 4:00 to be able to ensure that NOTE Confidence: 0.789456304545455 00:45:26.211 --> 00:45:27.968 the there's no tumors that come out NOTE Confidence: 0.789456304545455 00:45:27.968 --> 00:45:29.911 of this taking these old cells and NOTE Confidence: 0.789456304545455 00:45:29.911 --> 00:45:31.930 driving them back into the cell cycle. NOTE Confidence: 0.789456304545455 00:45:31.930 --> 00:45:34.720 So what if we get rid of the ability to NOTE Confidence: 0.789456304545455 00:45:34.795 --> 00:45:37.658 stop mtorc and regulate this process so. NOTE Confidence: 0.789456304545455 00:45:37.660 --> 00:45:40.132 You know what if we take out them NOTE Confidence: 0.789456304545455 00:45:40.132 --> 00:45:41.599 torque regulation and then in NOTE Confidence: 0.789456304545455 00:45:41.599 --> 00:45:43.426 in a system where we can induce NOTE Confidence: 0.789456304545455 00:45:43.487 --> 00:45:45.337 metaplasia multiple times and the NOTE Confidence: 0.789456304545455 00:45:45.337 --> 00:45:47.453 thinking would be then that what's NOTE Confidence: 0.789456304545455 00:45:47.453 --> 00:45:49.294 going to happen is we kind of NOTE Confidence: 0.839834078 00:45:49.300 --> 00:45:50.836 injure each time and we don't NOTE Confidence: 0.839834078 00:45:50.836 --> 00:45:51.860 have much error checking. NOTE Confidence: 0.839834078 00:45:51.860 --> 00:45:53.680 Then you go through collagenosis, NOTE Confidence: 0.839834078 00:45:53.680 --> 00:45:55.192 then you heal, then you go through NOTE Confidence: 0.839834078 00:45:55.192 --> 00:45:56.080 pathogenesis and you heal. NOTE Confidence: 0.839834078 00:45:56.080 --> 00:45:58.264 But each time you can accumulate NOTE Confidence: 0.839834078 00:45:58.264 --> 00:46:00.442 mutations until finally you get to NOTE Confidence: 0.839834078 00:46:00.442 --> 00:46:02.410 the mutations like Karas or something NOTE Confidence: 0.839834078 00:46:02.410 --> 00:46:04.462 like that that drives a tumor and NOTE Confidence: 0.839834078 00:46:04.462 --> 00:46:06.268 then you know you no longer go NOTE Confidence: 0.839834078 00:46:06.268 --> 00:46:07.906 back to being a chief seller and. NOTE Confidence: 0.839834078 00:46:07.910 --> 00:46:08.750 Lesson or so. NOTE Confidence: 0.839834078 00:46:08.750 --> 00:46:11.068 So I already showed you how we kind NOTE Confidence: 0.839834078 00:46:11.068 --> 00:46:13.112 of we do these screens and coming NOTE Confidence: 0.839834078 00:46:13.112 --> 00:46:15.596 back to dead at 4 so that you know NOTE Confidence: 0.839834078 00:46:15.596 --> 00:46:17.380 knocks out the ability of the cell NOTE Confidence: 0.839834078 00:46:17.380 --> 00:46:19.177 to decrease M torque and it knocks NOTE Confidence: 0.839834078 00:46:19.177 --> 00:46:20.885 out its ability to be able to NOTE Confidence: 0.839834078 00:46:20.885 --> 00:46:22.922 sense the P53 damage and to be able NOTE Confidence: 0.839834078 00:46:22.922 --> 00:46:24.719 to stop cells from coming back. NOTE Confidence: 0.839834078 00:46:24.720 --> 00:46:26.645 And cell cycle basically just kind of NOTE Confidence: 0.839834078 00:46:26.645 --> 00:46:28.636 skips past all this error checking NOTE Confidence: 0.839834078 00:46:28.636 --> 00:46:30.116 right into the proliferation. NOTE Confidence: 0.839834078 00:46:30.120 --> 00:46:31.758 So you see a lot more proliferation NOTE Confidence: 0.839834078 00:46:31.758 --> 00:46:33.258 when you knock out deed it for. NOTE Confidence: 0.839834078 00:46:33.260 --> 00:46:35.006 And So what happens is essentially NOTE Confidence: 0.839834078 00:46:35.006 --> 00:46:36.849 you can take mutations and carry NOTE Confidence: 0.839834078 00:46:36.849 --> 00:46:38.414 them right into these dysplasias. NOTE Confidence: 0.839834078 00:46:38.420 --> 00:46:40.298 And so functionally what Max did NOTE Confidence: 0.839834078 00:46:40.298 --> 00:46:42.896 in the lab was do multiple rounds NOTE Confidence: 0.839834078 00:46:42.896 --> 00:46:45.026 of Immunogen which causes gastric NOTE Confidence: 0.839834078 00:46:45.026 --> 00:46:47.614 tumors kind of slowly in the stomach NOTE Confidence: 0.839834078 00:46:47.614 --> 00:46:49.876 in these cells that could no longer NOTE Confidence: 0.839834078 00:46:49.876 --> 00:46:51.962 in these mice that could no longer NOTE Confidence: 0.839834078 00:46:51.962 --> 00:46:53.805 regulate the the collagenosis and NOTE Confidence: 0.839834078 00:46:53.805 --> 00:46:55.660 that mtor checkpoint versus control NOTE Confidence: 0.839834078 00:46:55.660 --> 00:46:57.638 cells that could still did multiple NOTE Confidence: 0.839834078 00:46:57.638 --> 00:46:59.540 rounds of tamoxifen to do multiple NOTE Confidence: 0.839834078 00:46:59.540 --> 00:47:01.290 rounds of metaplasia and repair. NOTE Confidence: 0.839834078 00:47:01.290 --> 00:47:03.330 And what he saw as we predicted was NOTE Confidence: 0.839834078 00:47:03.330 --> 00:47:05.827 a lot more tumors in the deed at 4 NOTE Confidence: 0.839834078 00:47:05.827 --> 00:47:07.732 knockouts and a lot bigger tumors NOTE Confidence: 0.839834078 00:47:07.732 --> 00:47:09.766 in fact just for the pathology. NOTE Confidence: 0.839834078 00:47:09.770 --> 00:47:11.810 This is one that arose as a huge NOTE Confidence: 0.839834078 00:47:11.810 --> 00:47:13.999 sort of polypoid tumor that was NOTE Confidence: 0.839834078 00:47:13.999 --> 00:47:16.009 more intestinal type between the NOTE Confidence: 0.839834078 00:47:16.009 --> 00:47:17.438 Antrim and the corpus, NOTE Confidence: 0.839834078 00:47:17.440 --> 00:47:20.450 but then had a had a focus of the diffuse NOTE Confidence: 0.839834078 00:47:20.527 --> 00:47:23.096 signet ring cells that you can see. NOTE Confidence: 0.839834078 00:47:23.100 --> 00:47:24.668 And it's rare in the mouse to get NOTE Confidence: 0.839834078 00:47:24.668 --> 00:47:26.399 such an obviously metastatic tumor. NOTE Confidence: 0.839834078 00:47:26.400 --> 00:47:28.368 You can see them kind of in this NOTE Confidence: 0.839834078 00:47:28.368 --> 00:47:30.261 PAS stain going right through the NOTE Confidence: 0.839834078 00:47:30.261 --> 00:47:32.265 muscle area and into this aerosan NOTE Confidence: 0.839834078 00:47:32.331 --> 00:47:33.738 intelink vascular space. NOTE Confidence: 0.839834078 00:47:33.740 --> 00:47:36.440 So in other words, if you can't do this, NOTE Confidence: 0.839834078 00:47:36.440 --> 00:47:38.114 check here to make sure these NOTE Confidence: 0.839834078 00:47:38.114 --> 00:47:40.199 cells are OK and send them back, NOTE Confidence: 0.839834078 00:47:40.200 --> 00:47:41.310 you know, to repair them. NOTE Confidence: 0.839834078 00:47:41.310 --> 00:47:43.746 They come back to repair with mutations NOTE Confidence: 0.839834078 00:47:43.746 --> 00:47:45.860 and then eventually they form tumors. NOTE Confidence: 0.839834078 00:47:45.860 --> 00:47:50.256 OK, so last thing, the human thing. NOTE Confidence: 0.839834078 00:47:50.260 --> 00:47:53.140 You coming back all the way back to human, NOTE Confidence: 0.839834078 00:47:53.140 --> 00:47:56.020 the human part of the talk. NOTE Confidence: 0.839834078 00:47:56.020 --> 00:47:56.447 Again, NOTE Confidence: 0.839834078 00:47:56.447 --> 00:47:59.009 we've been again going back to NOTE Confidence: 0.839834078 00:47:59.009 --> 00:48:01.420 Barretts and trying to study this, NOTE Confidence: 0.839834078 00:48:01.420 --> 00:48:03.250 how these processes happen and how NOTE Confidence: 0.839834078 00:48:03.250 --> 00:48:05.060 people heal from these processes. NOTE Confidence: 0.839834078 00:48:05.060 --> 00:48:05.363 Unfortunately, NOTE Confidence: 0.839834078 00:48:05.363 --> 00:48:07.181 this great mouse models that we NOTE Confidence: 0.839834078 00:48:07.181 --> 00:48:08.891 can use for tumorigenesis and NOTE Confidence: 0.839834078 00:48:08.891 --> 00:48:10.746 metaplasia and stomach don't apply NOTE Confidence: 0.839834078 00:48:10.746 --> 00:48:12.599 because mice don't get variants, NOTE Confidence: 0.839834078 00:48:12.600 --> 00:48:13.800 they don't reflux at all, NOTE Confidence: 0.839834078 00:48:13.800 --> 00:48:15.204 they don't have any bile or NOTE Confidence: 0.839834078 00:48:15.204 --> 00:48:16.700 acid ever in their esophagus. NOTE Confidence: 0.839834078 00:48:16.700 --> 00:48:18.806 So there's no really good rodent NOTE Confidence: 0.839834078 00:48:18.806 --> 00:48:19.859 models for this. NOTE Confidence: 0.839834078 00:48:19.860 --> 00:48:21.606 So you know, you have to study the human. NOTE Confidence: 0.839834078 00:48:21.610 --> 00:48:24.208 And so I've been collaborating in NOTE Confidence: 0.839834078 00:48:24.208 --> 00:48:25.940 this amazing collaboration with. NOTE Confidence: 0.839834078 00:48:25.940 --> 00:48:28.175 Rhonda Souza and Stu Spechler's NOTE Confidence: 0.839834078 00:48:28.175 --> 00:48:29.963 group and Rob odds. NOTE Confidence: 0.702047116 00:48:29.970 --> 00:48:31.242 Also, you know, pathologist, NOTE Confidence: 0.702047116 00:48:31.242 --> 00:48:31.885 yeah, pathologist. NOTE Confidence: 0.702047116 00:48:31.885 --> 00:48:34.160 To look at, at their models of NOTE Confidence: 0.702047116 00:48:34.160 --> 00:48:36.088 Barretts and some clinical trials, NOTE Confidence: 0.702047116 00:48:36.090 --> 00:48:36.834 I'll just show you. NOTE Confidence: 0.702047116 00:48:36.834 --> 00:48:38.419 Here's where I had them down to Houston. NOTE Confidence: 0.702047116 00:48:38.420 --> 00:48:40.990 There's Rob and and me. NOTE Confidence: 0.702047116 00:48:40.990 --> 00:48:42.310 And there's actually, there's my. NOTE Confidence: 0.702047116 00:48:42.310 --> 00:48:44.542 There's the same microscope that Wanj NOTE Confidence: 0.702047116 00:48:44.542 --> 00:48:48.470 learned on, taken down to down to Houston. NOTE Confidence: 0.702047116 00:48:48.470 --> 00:48:50.171 And Rhonda like is fond of saying NOTE Confidence: 0.702047116 00:48:50.171 --> 00:48:52.048 that humans are the best model system. NOTE Confidence: 0.702047116 00:48:52.050 --> 00:48:53.607 So it with Barretts we have to do that. NOTE Confidence: 0.702047116 00:48:53.610 --> 00:48:56.965 So, So what in this model what NOTE Confidence: 0.702047116 00:48:56.965 --> 00:48:59.590 they've done is they you know with NOTE Confidence: 0.702047116 00:48:59.590 --> 00:49:02.005 the dysplastic Barretts you can treat NOTE Confidence: 0.702047116 00:49:02.005 --> 00:49:04.401 it by radiofrequency ablation just to NOTE Confidence: 0.702047116 00:49:04.401 --> 00:49:06.195 basically take out all the Barretts NOTE Confidence: 0.702047116 00:49:06.195 --> 00:49:09.058 and take it down to the ulcer bed and NOTE Confidence: 0.702047116 00:49:09.058 --> 00:49:10.894 granulation tissue and then for some NOTE Confidence: 0.702047116 00:49:10.894 --> 00:49:12.586 reason it heals back as squamous. NOTE Confidence: 0.702047116 00:49:12.590 --> 00:49:14.220 So basically what you're doing NOTE Confidence: 0.702047116 00:49:14.220 --> 00:49:15.198 is radiofrequency ablation, NOTE Confidence: 0.702047116 00:49:15.200 --> 00:49:15.730 the Barretts, NOTE Confidence: 0.702047116 00:49:15.730 --> 00:49:18.460 and it goes to this just ulcer bed basically. NOTE Confidence: 0.702047116 00:49:18.460 --> 00:49:20.910 What's leftover? NOTE Confidence: 0.702047116 00:49:20.910 --> 00:49:23.465 And then you know what happens though, NOTE Confidence: 0.702047116 00:49:23.470 --> 00:49:25.066 you know after this ulceration is it NOTE Confidence: 0.702047116 00:49:25.066 --> 00:49:26.655 comes back as a squamous and what NOTE Confidence: 0.702047116 00:49:26.655 --> 00:49:28.474 they did was they they took a bunch NOTE Confidence: 0.702047116 00:49:28.474 --> 00:49:29.926 of patients and enrolled them should NOTE Confidence: 0.702047116 00:49:29.926 --> 00:49:31.565 also say for the this study and NOTE Confidence: 0.702047116 00:49:31.565 --> 00:49:33.530 then did the pre and then one week, NOTE Confidence: 0.702047116 00:49:33.530 --> 00:49:35.246 two week and four week biopsies NOTE Confidence: 0.702047116 00:49:35.246 --> 00:49:36.953 all the way proximal to distal NOTE Confidence: 0.702047116 00:49:36.953 --> 00:49:38.724 from before the margin of RFA to NOTE Confidence: 0.702047116 00:49:38.724 --> 00:49:40.629 the gastric margin after the RFA. NOTE Confidence: 0.702047116 00:49:40.630 --> 00:49:42.454 And you know try to look at how NOTE Confidence: 0.702047116 00:49:42.454 --> 00:49:44.665 the healing process, how all this, NOTE Confidence: 0.702047116 00:49:44.665 --> 00:49:47.215 you know mucosa became squamous again. NOTE Confidence: 0.92109934625 00:49:49.370 --> 00:49:51.546 So that's kind of what it looks like. NOTE Confidence: 0.92109934625 00:49:51.550 --> 00:49:52.792 You know, the question is where NOTE Confidence: 0.92109934625 00:49:52.792 --> 00:49:54.049 does all that squamous come from? NOTE Confidence: 0.92109934625 00:49:54.050 --> 00:49:55.874 And the only source of squamous or even NOTE Confidence: 0.92109934625 00:49:55.874 --> 00:49:57.380 epithelial cells that you could think of NOTE Confidence: 0.92109934625 00:49:57.380 --> 00:49:58.968 would be at this proximal margin, right. NOTE Confidence: 0.92109934625 00:49:58.968 --> 00:50:00.258 But it turns out that's NOTE Confidence: 0.92109934625 00:50:00.258 --> 00:50:01.290 actually not what happens. NOTE Confidence: 0.92109934625 00:50:01.290 --> 00:50:03.125 What happens is it comes NOTE Confidence: 0.92109934625 00:50:03.125 --> 00:50:04.593 back as squamous throughout. NOTE Confidence: 0.92109934625 00:50:04.600 --> 00:50:07.132 So there's some source of squamous NOTE Confidence: 0.92109934625 00:50:07.132 --> 00:50:09.874 epithelium that's obviously trans or D or NOTE Confidence: 0.92109934625 00:50:09.874 --> 00:50:12.132 some kind of differentiating, you know, NOTE Confidence: 0.92109934625 00:50:12.132 --> 00:50:14.487 that's that's feeding the squamous. NOTE Confidence: 0.92109934625 00:50:14.490 --> 00:50:17.190 And you know we have a couple of clues, NOTE Confidence: 0.92109934625 00:50:17.190 --> 00:50:19.626 one of which well we talked about. NOTE Confidence: 0.92109934625 00:50:19.630 --> 00:50:21.597 But one of which I'll show you NOTE Confidence: 0.92109934625 00:50:21.597 --> 00:50:22.784 evidence for here, you know, NOTE Confidence: 0.92109934625 00:50:22.784 --> 00:50:23.988 so the idea is that coming from NOTE Confidence: 0.92109934625 00:50:23.988 --> 00:50:25.322 the proximal squamous, you know, NOTE Confidence: 0.92109934625 00:50:25.322 --> 00:50:26.834 there's a come from the distal gastric, NOTE Confidence: 0.92109934625 00:50:26.840 --> 00:50:28.436 but then why would that be squamous? NOTE Confidence: 0.92109934625 00:50:28.440 --> 00:50:29.800 But it turns out it just comes in NOTE Confidence: 0.92109934625 00:50:29.800 --> 00:50:31.169 all these little islands like this. NOTE Confidence: 0.92109934625 00:50:31.170 --> 00:50:32.060 And so if you focus, NOTE Confidence: 0.92109934625 00:50:32.060 --> 00:50:35.021 here's one of these islands of this NOTE Confidence: 0.92109934625 00:50:35.021 --> 00:50:37.200 NEO squamous healing epithelium. NOTE Confidence: 0.92109934625 00:50:37.200 --> 00:50:37.905 And, you know, NOTE Confidence: 0.92109934625 00:50:37.905 --> 00:50:39.840 where does this come from on either side? NOTE Confidence: 0.92109934625 00:50:39.840 --> 00:50:41.280 Basically it's going to go down NOTE Confidence: 0.92109934625 00:50:41.280 --> 00:50:42.540 to like a single cell. NOTE Confidence: 0.92109934625 00:50:42.540 --> 00:50:45.123 It turns out that there's pretty good NOTE Confidence: 0.92109934625 00:50:45.123 --> 00:50:46.900 evidence both morphologically and also NOTE Confidence: 0.92109934625 00:50:46.900 --> 00:50:48.415 with their advanced endoscopy that NOTE Confidence: 0.92109934625 00:50:48.415 --> 00:50:50.710 if you look under each of these new. NOTE Confidence: 0.92109934625 00:50:50.710 --> 00:50:52.642 Kind of ulcerated surface as a single NOTE Confidence: 0.92109934625 00:50:52.642 --> 00:50:54.610 cell layer of squamous is forming. NOTE Confidence: 0.92109934625 00:50:54.610 --> 00:50:57.010 They're all underneath ducts NOTE Confidence: 0.92109934625 00:50:57.010 --> 00:50:58.507 from submucosal glands. NOTE Confidence: 0.92109934625 00:50:58.507 --> 00:50:59.398 So you know, NOTE Confidence: 0.92109934625 00:50:59.398 --> 00:51:01.745 just for those of you don't remember NOTE Confidence: 0.92109934625 00:51:01.745 --> 00:51:03.729 your human esophageal theology. NOTE Confidence: 0.92109934625 00:51:03.730 --> 00:51:05.008 These are the 70 coastal glands, NOTE Confidence: 0.92109934625 00:51:05.010 --> 00:51:07.122 and they have ducts that reach NOTE Confidence: 0.92109934625 00:51:07.122 --> 00:51:08.796 up to the squamous epithelium. NOTE Confidence: 0.92109934625 00:51:08.796 --> 00:51:10.392 And normally like if you blade NOTE Confidence: 0.92109934625 00:51:10.392 --> 00:51:11.430 all this with RFA, NOTE Confidence: 0.92109934625 00:51:11.430 --> 00:51:13.019 then there's still a source of epithelium. NOTE Confidence: 0.92109934625 00:51:13.020 --> 00:51:15.330 At least you know distally for NOTE Confidence: 0.92109934625 00:51:15.330 --> 00:51:17.530 some of these squamous islands. NOTE Confidence: 0.92109934625 00:51:17.530 --> 00:51:19.378 But the other source is probably some of NOTE Confidence: 0.92109934625 00:51:19.378 --> 00:51:21.028 these deeper Barretts that escapes the. NOTE Confidence: 0.92109934625 00:51:21.030 --> 00:51:23.370 RFA as we have a lot of work showing NOTE Confidence: 0.92109934625 00:51:23.370 --> 00:51:25.538 that there's transitions in there. NOTE Confidence: 0.92109934625 00:51:25.540 --> 00:51:27.187 So like in fact that's what we're doing now. NOTE Confidence: 0.92109934625 00:51:27.190 --> 00:51:28.850 We're doing spatial transcriptomics, NOTE Confidence: 0.92109934625 00:51:28.850 --> 00:51:31.340 we're growing organoids and we're doing NOTE Confidence: 0.92109934625 00:51:31.402 --> 00:51:33.418 a lot of IHC and Multiplex IFF to kind NOTE Confidence: 0.92109934625 00:51:33.418 --> 00:51:35.560 of show how these transitions happen. NOTE Confidence: 0.92109934625 00:51:35.560 --> 00:51:38.930 So that's that. So summarizing. NOTE Confidence: 0.92109934625 00:51:38.930 --> 00:51:41.360 Take homes. NOTE Confidence: 0.92109934625 00:51:41.360 --> 00:51:42.925 This kind of pyloric metaplasia NOTE Confidence: 0.92109934625 00:51:42.925 --> 00:51:44.883 is some kind of like maybe NOTE Confidence: 0.92109934625 00:51:44.883 --> 00:51:46.538 or metaplasia that you see, NOTE Confidence: 0.92109934625 00:51:46.540 --> 00:51:47.330 you know, NOTE Confidence: 0.92109934625 00:51:47.330 --> 00:51:50.095 intestine in the cases of SL going NOTE Confidence: 0.92109934625 00:51:50.095 --> 00:51:52.465 towards that you see the body of. NOTE Confidence: 0.92109934625 00:51:52.470 --> 00:51:55.428 I don't mean gastritis and H NOTE Confidence: 0.92109934625 00:51:55.428 --> 00:51:57.400 pylori induced atrophic gastritis, NOTE Confidence: 0.92109934625 00:51:57.400 --> 00:52:00.382 it's the what seems to be NOTE Confidence: 0.92109934625 00:52:00.382 --> 00:52:01.873 happening in Barretts. NOTE Confidence: 0.92109934625 00:52:01.880 --> 00:52:04.240 And the root of this and although we NOTE Confidence: 0.92109934625 00:52:04.240 --> 00:52:06.507 don't know this yet in the SL how NOTE Confidence: 0.92109934625 00:52:06.507 --> 00:52:08.882 that happens but but at least in the NOTE Confidence: 0.92109934625 00:52:08.882 --> 00:52:10.724 pancreas and the stomach for sure NOTE Confidence: 0.92109934625 00:52:10.730 --> 00:52:13.187 and probably in Barretts is the cell NOTE Confidence: 0.92109934625 00:52:13.187 --> 00:52:15.039 biological process that's driving this, NOTE Confidence: 0.92109934625 00:52:15.040 --> 00:52:16.285 the palingenesis process. NOTE Confidence: 0.92109934625 00:52:16.285 --> 00:52:19.190 And that basically is about cells converting NOTE Confidence: 0.92109934625 00:52:19.253 --> 00:52:21.325 energy from one state to the other. NOTE Confidence: 0.92109934625 00:52:21.330 --> 00:52:23.594 Now you know this is a pathology grand NOTE Confidence: 0.92109934625 00:52:23.594 --> 00:52:25.538 rounds and I'll tell you that when NOTE Confidence: 0.92109934625 00:52:25.538 --> 00:52:27.682 I was doing a lot of this looking NOTE Confidence: 0.92109934625 00:52:27.682 --> 00:52:29.741 at where this metaplasia happened NOTE Confidence: 0.92109934625 00:52:29.741 --> 00:52:32.327 and where what people thought about NOTE Confidence: 0.84734664 00:52:32.398 --> 00:52:33.510 it 100 years ago. NOTE Confidence: 0.84734664 00:52:33.510 --> 00:52:34.810 Well, over 100 years ago, NOTE Confidence: 0.84734664 00:52:34.810 --> 00:52:36.694 George Adami was a famous pathologist NOTE Confidence: 0.84734664 00:52:36.694 --> 00:52:39.076 who at the time was at McGill said, NOTE Confidence: 0.84734664 00:52:39.076 --> 00:52:41.078 you know, it looks like in tissues NOTE Confidence: 0.84734664 00:52:41.078 --> 00:52:43.227 that are going to become cancerous, NOTE Confidence: 0.84734664 00:52:43.230 --> 00:52:45.030 there's all this reprogram, NOTE Confidence: 0.84734664 00:52:45.030 --> 00:52:48.230 you didn't use that term of cells NOTE Confidence: 0.84734664 00:52:48.230 --> 00:52:50.930 from mature cells to dividing cells, NOTE Confidence: 0.84734664 00:52:50.930 --> 00:52:52.204 and that seems to fuel the cancer. NOTE Confidence: 0.84734664 00:52:52.210 --> 00:52:54.106 So he kind of anticipated all of this. NOTE Confidence: 0.84734664 00:52:54.110 --> 00:52:56.112 And he said that what must happen NOTE Confidence: 0.84734664 00:52:56.112 --> 00:52:58.259 is the cell converts its energy NOTE Confidence: 0.84734664 00:52:58.259 --> 00:53:00.289 use from secretion to division. NOTE Confidence: 0.84734664 00:53:00.290 --> 00:53:01.606 So, you know, it's kind of funny. NOTE Confidence: 0.84734664 00:53:01.610 --> 00:53:03.461 Then we forgot that for like 9000. NOTE Confidence: 0.84734664 00:53:03.461 --> 00:53:03.672 Years. NOTE Confidence: 0.84734664 00:53:03.672 --> 00:53:04.516 And then, you know, NOTE Confidence: 0.84734664 00:53:04.520 --> 00:53:06.236 we've come back to that old NOTE Confidence: 0.84734664 00:53:06.236 --> 00:53:07.708 pathologists who just by looking NOTE Confidence: 0.84734664 00:53:07.708 --> 00:53:09.556 at a bunch of tissues made the NOTE Confidence: 0.84734664 00:53:09.556 --> 00:53:11.314 same kind of analysis that it NOTE Confidence: 0.84734664 00:53:11.314 --> 00:53:13.066 was the same in multiple tissues, NOTE Confidence: 0.84734664 00:53:13.070 --> 00:53:13.506 you know, NOTE Confidence: 0.84734664 00:53:13.506 --> 00:53:15.576 even as a picture of a liver cell with NOTE Confidence: 0.84734664 00:53:15.576 --> 00:53:17.190 its kind of autophagy before they NOTE Confidence: 0.84734664 00:53:17.190 --> 00:53:19.070 even knew what the organelles were. NOTE Confidence: 0.84734664 00:53:19.070 --> 00:53:21.102 So a lot of that depends on ribosomes NOTE Confidence: 0.84734664 00:53:21.102 --> 00:53:23.452 and and so the metaplasia depends on NOTE Confidence: 0.84734664 00:53:23.452 --> 00:53:25.800 this collagenosis which depends on ribosome. NOTE Confidence: 0.84734664 00:53:25.800 --> 00:53:28.047 So these are all areas where you NOTE Confidence: 0.84734664 00:53:28.047 --> 00:53:29.922 could target potentially both to. NOTE Confidence: 0.84734664 00:53:29.922 --> 00:53:30.834 First metaplasia, NOTE Confidence: 0.84734664 00:53:30.834 --> 00:53:33.570 but also if cancers emerge from NOTE Confidence: 0.84734664 00:53:33.656 --> 00:53:35.700 those this aberrant checking NOTE Confidence: 0.84734664 00:53:35.700 --> 00:53:37.744 of pathogenesis or P53, NOTE Confidence: 0.84734664 00:53:37.750 --> 00:53:39.140 then maybe with they proliferate NOTE Confidence: 0.84734664 00:53:39.140 --> 00:53:40.252 by going through that. NOTE Confidence: 0.74812823 00:53:48.360 --> 00:53:52.950 The city. Ohh, it's all the eye. NOTE Confidence: 0.74812823 00:53:52.950 --> 00:53:55.267 And where we got some of the NOTE Confidence: 0.74812823 00:53:55.267 --> 00:53:57.704 mice and this is our group down NOTE Confidence: 0.74812823 00:53:57.704 --> 00:53:59.806 in Texas with my wife's lab, NOTE Confidence: 0.74812823 00:53:59.806 --> 00:54:01.930 she's mysorekar and on the mills, NOTE Confidence: 0.74812823 00:54:01.930 --> 00:54:04.210 so we're the M&M labs together, so. NOTE Confidence: 0.87300657 00:54:10.950 --> 00:54:11.920 Yes, you know. And then. NOTE Confidence: 0.852713134 00:54:14.080 --> 00:54:16.220 So, so I don't know, NOTE Confidence: 0.852713134 00:54:16.220 --> 00:54:18.636 but I think there are papers already too. NOTE Confidence: 0.852713134 00:54:18.640 --> 00:54:21.220 But I'm, I I bet you it's the same aisle 13, NOTE Confidence: 0.852713134 00:54:21.220 --> 00:54:24.244 aisle 33 access which drives it NOTE Confidence: 0.852713134 00:54:24.244 --> 00:54:26.777 seemingly in in Barretts and NOTE Confidence: 0.852713134 00:54:26.777 --> 00:54:30.460 in pancreas and and in stomach. NOTE Confidence: 0.852713134 00:54:30.460 --> 00:54:32.770 The, the very idea Polygenist NOTE Confidence: 0.852713134 00:54:32.770 --> 00:54:34.156 is absolutely reversible. NOTE Confidence: 0.852713134 00:54:34.160 --> 00:54:35.189 Yeah, 100% it's, NOTE Confidence: 0.852713134 00:54:35.189 --> 00:54:38.070 it's a normal way to recruit stem cells, NOTE Confidence: 0.852713134 00:54:38.070 --> 00:54:39.200 especially for organs that don't NOTE Confidence: 0.852713134 00:54:39.200 --> 00:54:40.730 have stem cells like the pancreas. NOTE Confidence: 0.852713134 00:54:40.730 --> 00:54:42.158 That's the only way the pancreas NOTE Confidence: 0.852713134 00:54:42.158 --> 00:54:43.976 can kind of repair itself is by NOTE Confidence: 0.852713134 00:54:43.976 --> 00:54:45.068 recruiting the acinar cells. NOTE Confidence: 0.852713134 00:54:45.070 --> 00:54:46.988 And then normally they come right back. NOTE Confidence: 0.852713134 00:54:46.990 --> 00:54:49.090 It's only when you know they acquire NOTE Confidence: 0.852713134 00:54:49.090 --> 00:54:50.870 enough mutations that they don't read, NOTE Confidence: 0.852713134 00:54:50.870 --> 00:54:51.822 differentiate and they think NOTE Confidence: 0.852713134 00:54:51.822 --> 00:54:53.250 it's an idea to keep growing. NOTE Confidence: 0.852713134 00:54:53.250 --> 00:54:55.308 You know, that it becomes irreversible. NOTE Confidence: 0.852713134 00:54:55.310 --> 00:54:56.520 And that's why we think, NOTE Confidence: 0.852713134 00:54:56.520 --> 00:54:57.656 you know, chronic inflammation, NOTE Confidence: 0.852713134 00:54:57.656 --> 00:54:59.590 which is the first question you had, NOTE Confidence: 0.852713134 00:54:59.590 --> 00:55:00.946 is so important. NOTE Confidence: 0.852713134 00:55:00.946 --> 00:55:02.754 Because it keeps stimulating NOTE Confidence: 0.852713134 00:55:02.754 --> 00:55:04.770 this collagenosis until of these NOTE Confidence: 0.852713134 00:55:04.770 --> 00:55:05.950 kind of old cells. NOTE Confidence: 0.852713134 00:55:05.950 --> 00:55:07.056 You know, if you think about it, NOTE Confidence: 0.852713134 00:55:07.060 --> 00:55:08.782 they don't really do much error NOTE Confidence: 0.852713134 00:55:08.782 --> 00:55:10.316 checking of their chromatin under NOTE Confidence: 0.852713134 00:55:10.316 --> 00:55:11.309 normal circumstances because NOTE Confidence: 0.852713134 00:55:11.309 --> 00:55:13.295 they're just making a handful of, NOTE Confidence: 0.852713134 00:55:13.300 --> 00:55:13.820 you know, NOTE Confidence: 0.852713134 00:55:13.820 --> 00:55:15.380 digestive enzymes over and over again. NOTE Confidence: 0.852713134 00:55:15.380 --> 00:55:16.700 And most of their ribosomes NOTE Confidence: 0.852713134 00:55:16.700 --> 00:55:18.020 are already taken care of, NOTE Confidence: 0.852713134 00:55:18.020 --> 00:55:20.020 so they're most of their chromatin is inert. NOTE Confidence: 0.852713134 00:55:20.020 --> 00:55:22.036 So then you ask them to rearrange everything, NOTE Confidence: 0.852713134 00:55:22.040 --> 00:55:23.444 come back into cell cycle and NOTE Confidence: 0.852713134 00:55:23.444 --> 00:55:25.279 expose a bunch of cell cycle genes, NOTE Confidence: 0.852713134 00:55:25.280 --> 00:55:26.420 which is very dangerous. NOTE Confidence: 0.852713134 00:55:26.420 --> 00:55:28.690 So they need this error checking and it NOTE Confidence: 0.852713134 00:55:28.690 --> 00:55:30.475 just seems like we've evolved only one. NOTE Confidence: 0.852713134 00:55:30.480 --> 00:55:32.195 Protein which is P53 to do all NOTE Confidence: 0.852713134 00:55:32.195 --> 00:55:32.930 that error checking. NOTE Confidence: 0.852713134 00:55:32.930 --> 00:55:36.017 So each time you go through that cycle of NOTE Confidence: 0.852713134 00:55:36.017 --> 00:55:38.648 you're asking people to three to work. NOTE Confidence: 0.852713134 00:55:38.650 --> 00:55:40.432 And the more you do it the more chances NOTE Confidence: 0.852713134 00:55:40.432 --> 00:55:41.978 you're taking until you get a you NOTE Confidence: 0.852713134 00:55:41.978 --> 00:55:43.449 know clone that doesn't have it work. NOTE Confidence: 0.852713134 00:55:43.450 --> 00:55:45.538 And then you start having more NOTE Confidence: 0.852713134 00:55:45.538 --> 00:55:46.930 errors in each replication. NOTE Confidence: 0.852713134 00:55:46.930 --> 00:55:48.772 And then when that happens then NOTE Confidence: 0.852713134 00:55:48.772 --> 00:55:50.578 eventually you'll get a make or NOTE Confidence: 0.852713134 00:55:50.578 --> 00:55:52.377 a rass or you know something else NOTE Confidence: 0.852713134 00:55:52.377 --> 00:55:54.430 that drives it outside the geotrack. NOTE Confidence: 0.852713134 00:55:54.430 --> 00:55:54.701 Yeah. NOTE Confidence: 0.852713134 00:55:54.701 --> 00:55:56.598 Actually you know I 41 is conserved NOTE Confidence: 0.852713134 00:55:56.598 --> 00:55:58.248 all the way through plants. NOTE Confidence: 0.852713134 00:55:58.250 --> 00:56:00.590 It's the the the the it's. NOTE Confidence: 0.852713134 00:56:00.590 --> 00:56:01.202 Amazing protein. NOTE Confidence: 0.852713134 00:56:01.202 --> 00:56:03.038 It goes right between the ribosomes. NOTE Confidence: 0.852713134 00:56:03.040 --> 00:56:04.380 That's why it's so conserved. NOTE Confidence: 0.852713134 00:56:04.380 --> 00:56:07.476 And it has 0 phenotype in any Organism, NOTE Confidence: 0.852713134 00:56:07.480 --> 00:56:11.698 from plants to flies to yeast. NOTE Confidence: 0.852713134 00:56:11.700 --> 00:56:13.135 Even if it's not in all yeast. NOTE Confidence: 0.852713134 00:56:13.140 --> 00:56:15.384 Because I think it's more multicellular NOTE Confidence: 0.852713134 00:56:15.384 --> 00:56:17.314 thing when you knock it out until NOTE Confidence: 0.852713134 00:56:17.314 --> 00:56:19.612 you injure and ask them to kind of NOTE Confidence: 0.852713134 00:56:19.612 --> 00:56:21.112 reprogram and respond to injury. NOTE Confidence: 0.852713134 00:56:21.120 --> 00:56:22.912 So there's flying effort you want and NOTE Confidence: 0.852713134 00:56:22.912 --> 00:56:24.971 if you knock it out then you can't NOTE Confidence: 0.852713134 00:56:24.971 --> 00:56:26.669 recruit stem cells and the fly gut. NOTE Confidence: 0.567696278571429 00:56:28.760 --> 00:56:30.940 Deliver after partial hepatectomy NOTE Confidence: 0.567696278571429 00:56:30.940 --> 00:56:33.980 of you knockout I31 you screw up NOTE Confidence: 0.567696278571429 00:56:33.980 --> 00:56:37.144 the ability to to get all that GI NOTE Confidence: 0.567696278571429 00:56:37.144 --> 00:56:39.584 tract again and parasites kidney. NOTE Confidence: 0.567696278571429 00:56:39.590 --> 00:56:41.590 That's a non GI Oregon also and in NOTE Confidence: 0.567696278571429 00:56:41.590 --> 00:56:43.612 fact all this is tied to aging in NOTE Confidence: 0.567696278571429 00:56:43.612 --> 00:56:45.380 the sense that as you get older NOTE Confidence: 0.567696278571429 00:56:45.380 --> 00:56:47.088 you seem to be able to lose. NOTE Confidence: 0.567696278571429 00:56:47.090 --> 00:56:48.446 You lose these markers in these NOTE Confidence: 0.567696278571429 00:56:48.446 --> 00:56:50.167 genes and in in the bladder we NOTE Confidence: 0.567696278571429 00:56:50.167 --> 00:56:51.697 know that actually where each time NOTE Confidence: 0.567696278571429 00:56:51.697 --> 00:56:53.442 you go through UTI of shedding you NOTE Confidence: 0.567696278571429 00:56:53.442 --> 00:56:55.280 need to recruit new stem cells. NOTE Confidence: 0.567696278571429 00:56:55.280 --> 00:56:58.587 As you age you lose I 41 and NOTE Confidence: 0.567696278571429 00:56:58.587 --> 00:57:00.129 you're less able to do this. NOTE Confidence: 0.567696278571429 00:57:00.130 --> 00:57:02.994 That's work from the My wife side actually NOTE Confidence: 0.567696278571429 00:57:02.994 --> 00:57:04.987 because she's a a bladder expert. NOTE Confidence: 0.808378845625 00:57:14.930 --> 00:57:15.978 Yeah, right. So, yeah, NOTE Confidence: 0.808378845625 00:57:15.978 --> 00:57:17.923 the question is why are some metaplasia NOTE Confidence: 0.808378845625 00:57:17.923 --> 00:57:19.838 is dangerous and some not, right? NOTE Confidence: 0.808378845625 00:57:19.838 --> 00:57:22.462 You know, I have no idea because that's NOTE Confidence: 0.808378845625 00:57:22.462 --> 00:57:24.783 the same thing with stomach, right? NOTE Confidence: 0.808378845625 00:57:24.783 --> 00:57:26.195 I mean, autoimmune gastritis NOTE Confidence: 0.808378845625 00:57:26.195 --> 00:57:27.254 causes massive metaplasia. NOTE Confidence: 0.808378845625 00:57:27.260 --> 00:57:29.549 And you know, there's a huge controversy NOTE Confidence: 0.808378845625 00:57:29.549 --> 00:57:31.520 about whether it increases risk of NOTE Confidence: 0.808378845625 00:57:31.520 --> 00:57:33.690 gastric cancer or not in the absence NOTE Confidence: 0.808378845625 00:57:33.748 --> 00:57:35.470 of Co infection with H pylori. NOTE Confidence: 0.808378845625 00:57:35.470 --> 00:57:36.890 And I think probably the NOTE Confidence: 0.808378845625 00:57:36.890 --> 00:57:38.026 consensus is it doesn't. NOTE Confidence: 0.808378845625 00:57:38.030 --> 00:57:40.352 So even the very same metaplasia NOTE Confidence: 0.808378845625 00:57:40.352 --> 00:57:41.900 and H pylori context. NOTE Confidence: 0.808378845625 00:57:41.900 --> 00:57:44.258 You know it's risky, but but it's not in NOTE Confidence: 0.808378845625 00:57:44.258 --> 00:57:48.720 the autoimmune gastritis context, so. NOTE Confidence: 0.808378845625 00:57:48.720 --> 00:57:51.936 I, I, I don't know, uh, I, you know, NOTE Confidence: 0.808378845625 00:57:51.936 --> 00:57:54.209 I think 1 aspect would be the NOTE Confidence: 0.808378845625 00:57:54.209 --> 00:57:56.559 repetitive nature and the chronicity. NOTE Confidence: 0.808378845625 00:57:56.560 --> 00:57:58.324 Another aspect, you know, NOTE Confidence: 0.808378845625 00:57:58.324 --> 00:57:59.647 in the stomach, NOTE Confidence: 0.808378845625 00:57:59.650 --> 00:58:01.338 I've always thought of that H pylori is NOTE Confidence: 0.808378845625 00:58:01.338 --> 00:58:03.240 also got oncogenes that it, you know, NOTE Confidence: 0.808378845625 00:58:03.240 --> 00:58:04.840 pretty much injects into cells. NOTE Confidence: 0.808378845625 00:58:04.840 --> 00:58:08.557 And also there's this sense of kind NOTE Confidence: 0.808378845625 00:58:08.557 --> 00:58:11.764 of progression and that that that NOTE Confidence: 0.808378845625 00:58:11.764 --> 00:58:13.605 that glands on the border between NOTE Confidence: 0.808378845625 00:58:13.605 --> 00:58:15.644 the Antrim and the corpus going to go NOTE Confidence: 0.808378845625 00:58:15.644 --> 00:58:17.233 through this more and more and more NOTE Confidence: 0.808378845625 00:58:17.288 --> 00:58:19.096 as autoimmune gastritis, I think. NOTE Confidence: 0.808378845625 00:58:19.096 --> 00:58:19.742 You know, NOTE Confidence: 0.808378845625 00:58:19.742 --> 00:58:21.034 kind of happens sporadically, NOTE Confidence: 0.808378845625 00:58:21.040 --> 00:58:21.670 hits an area, NOTE Confidence: 0.808378845625 00:58:21.670 --> 00:58:23.658 then comes back and it's kind of back and NOTE Confidence: 0.808378845625 00:58:23.658 --> 00:58:25.289 forth in different areas as opposed to NOTE Confidence: 0.808378845625 00:58:25.289 --> 00:58:27.217 the same area going over and over again, NOTE Confidence: 0.808378845625 00:58:27.220 --> 00:58:29.090 but. NOTE Confidence: 0.808378845625 00:58:29.090 --> 00:58:30.308 I've never been asked that question. NOTE Confidence: 0.808378845625 00:58:30.310 --> 00:58:31.626 It's a really good about the cervix, NOTE Confidence: 0.808378845625 00:58:31.630 --> 00:58:33.898 you know like in areas where you NOTE Confidence: 0.808378845625 00:58:33.898 --> 00:58:35.602 get metaplasia that don't that NOTE Confidence: 0.808378845625 00:58:35.602 --> 00:58:37.010 may even be protective. NOTE Confidence: 0.808378845625 00:58:37.010 --> 00:58:39.034 I mean you know in the stomach a NOTE Confidence: 0.808378845625 00:58:39.034 --> 00:58:40.394 complete intestinal metaplasia seems NOTE Confidence: 0.808378845625 00:58:40.394 --> 00:58:42.409 almost protective against gastric cancer. NOTE Confidence: 0.808378845625 00:58:42.410 --> 00:58:45.690 So that's another interesting fact. NOTE Confidence: 0.808378845625 00:58:45.690 --> 00:58:48.108 And and I think in autoimmune NOTE Confidence: 0.808378845625 00:58:48.108 --> 00:58:49.720 gastritis there's more complete NOTE Confidence: 0.808378845625 00:58:49.795 --> 00:58:51.447 than there is incomplete. NOTE Confidence: 0.808378845625 00:58:51.450 --> 00:58:53.112 But I think it's definitely risky NOTE Confidence: 0.808378845625 00:58:53.112 --> 00:58:55.128 to have the kind of metaplasia where NOTE Confidence: 0.808378845625 00:58:55.128 --> 00:58:57.326 you have a mixed phenotype where it's NOTE Confidence: 0.808378845625 00:58:57.326 --> 00:58:59.790 both gastric and intestinal and it keeps. NOTE Confidence: 0.808378845625 00:58:59.790 --> 00:59:02.090 Happening it almost, you know, NOTE Confidence: 0.808378845625 00:59:02.090 --> 00:59:03.410 is asking for trouble. NOTE Confidence: 0.808378845625 00:59:03.410 --> 00:59:05.390 So maybe pure metaplasia are better. NOTE Confidence: 0.808378845625 00:59:05.390 --> 00:59:06.446 I don't know. NOTE Confidence: 0.808378845625 00:59:06.446 --> 00:59:07.854 It's a good question. NOTE Confidence: 0.808378845625 00:59:07.860 --> 00:59:08.240 Haven't. NOTE Confidence: 0.559212765 00:59:10.510 --> 00:59:11.160 Haven't asked. NOTE Confidence: 0.70453817 00:59:13.220 --> 00:59:15.690 OK. Question on the. NOTE Confidence: 0.25466174 00:59:18.090 --> 00:59:22.780 Building. And you describe. NOTE Confidence: 0.25466174 00:59:22.780 --> 00:59:23.780 But when you look at. NOTE Confidence: 0.56233963 00:59:26.390 --> 00:59:27.749 Or the before. NOTE Confidence: 0.9236553 00:59:30.990 --> 00:59:33.800 Yeah, yeah. He. NOTE Confidence: 0.56206702125 00:59:36.560 --> 00:59:40.172 Your life experiences that are known NOTE Confidence: 0.56206702125 00:59:40.172 --> 00:59:42.680 to alters. So the question is, drew, NOTE Confidence: 0.56206702125 00:59:42.680 --> 00:59:44.948 are there germline variants of genes NOTE Confidence: 0.56206702125 00:59:44.948 --> 00:59:49.040 like D at 4 the AG is the autophagy NOTE Confidence: 0.56206702125 00:59:49.040 --> 00:59:51.036 genes that affect susceptibility? NOTE Confidence: 0.56206702125 00:59:51.040 --> 00:59:53.620 I. That's a good question. NOTE Confidence: 0.56206702125 00:59:53.620 --> 00:59:54.890 I don't know did it. NOTE Confidence: 0.56206702125 00:59:54.890 --> 00:59:56.725 Four is very controversial also NOTE Confidence: 0.56206702125 00:59:56.725 --> 00:59:58.193 from the cancer standpoint, NOTE Confidence: 0.56206702125 00:59:58.200 --> 00:59:59.994 it seems like half the literature NOTE Confidence: 0.56206702125 00:59:59.994 --> 01:00:01.855 says that mutations are variants or NOTE Confidence: 0.56206702125 01:00:01.855 --> 01:00:03.667 pro tumorigenic and half are anti. NOTE Confidence: 0.56206702125 01:00:03.670 --> 01:00:05.930 But the issue with pathogenesis NOTE Confidence: 0.56206702125 01:00:05.930 --> 01:00:08.618 and tumorigenesis is you know it's NOTE Confidence: 0.56206702125 01:00:08.618 --> 01:00:10.880 a cycle normally so umm and it's NOTE Confidence: 0.56206702125 01:00:10.880 --> 01:00:12.470 sort of aberration in the cycling NOTE Confidence: 0.56206702125 01:00:12.470 --> 01:00:14.487 that we think is giving the tumors. NOTE Confidence: 0.56206702125 01:00:14.490 --> 01:00:17.010 So just kind of completely knocking NOTE Confidence: 0.56206702125 01:00:17.010 --> 01:00:19.140 it down might not would probably NOTE Confidence: 0.56206702125 01:00:19.140 --> 01:00:20.490 give you a premature aging thing NOTE Confidence: 0.56206702125 01:00:20.490 --> 01:00:22.008 if in fact that's what I said, NOTE Confidence: 0.56206702125 01:00:22.010 --> 01:00:23.132 I pretty one has no phenotype NOTE Confidence: 0.56206702125 01:00:23.132 --> 01:00:24.269 but actually it has an aging. NOTE Confidence: 0.56206702125 01:00:24.270 --> 01:00:27.721 Genotype so as you age then and NOTE Confidence: 0.56206702125 01:00:27.721 --> 01:00:30.449 you get inability to regenerate NOTE Confidence: 0.56206702125 01:00:30.449 --> 01:00:33.360 the that tends to be where you NOTE Confidence: 0.56206702125 01:00:33.360 --> 01:00:34.920 manifest your pathogenesis defects NOTE Confidence: 0.56206702125 01:00:34.987 --> 01:00:37.062 because you probably wouldn't be NOTE Confidence: 0.56206702125 01:00:37.062 --> 01:00:39.137 able to necessarily you've never NOTE Confidence: 0.56206702125 01:00:39.209 --> 01:00:41.243 traced people that don't get tumors NOTE Confidence: 0.56206702125 01:00:41.243 --> 01:00:43.497 based on you know lacking that but NOTE Confidence: 0.56206702125 01:00:43.497 --> 01:00:45.590 obviously people do three is a key NOTE Confidence: 0.56206702125 01:00:45.652 --> 01:00:47.948 checkpoint and that is the you know NOTE Confidence: 0.56206702125 01:00:47.948 --> 01:00:49.759 incredibly tight the tumor genesis NOTE Confidence: 0.56206702125 01:00:49.760 --> 01:00:52.520 the in terms I'll be a little bit NOTE Confidence: 0.56206702125 01:00:52.520 --> 01:00:54.978 more specific though about autophagy. NOTE Confidence: 0.56206702125 01:00:54.980 --> 01:00:58.326 Which is that we have tried with a NOTE Confidence: 0.56206702125 01:00:58.326 --> 01:01:00.902 G57 and 1601 variant to show effects NOTE Confidence: 0.56206702125 01:01:00.902 --> 01:01:03.789 and haven't really been successful. NOTE Confidence: 0.56206702125 01:01:03.790 --> 01:01:05.698 Where we have genetically been able NOTE Confidence: 0.56206702125 01:01:05.698 --> 01:01:06.970 to completely shut palingenesis NOTE Confidence: 0.56206702125 01:01:07.020 --> 01:01:08.581 down both in the pancreas and the NOTE Confidence: 0.56206702125 01:01:08.581 --> 01:01:10.250 stomach is by affecting lysosomes. NOTE Confidence: 0.56206702125 01:01:10.250 --> 01:01:11.858 So if you want to really get dive NOTE Confidence: 0.56206702125 01:01:11.858 --> 01:01:13.409 into the autophagy aspect of it, NOTE Confidence: 0.56206702125 01:01:13.410 --> 01:01:14.370 we actually think it. NOTE Confidence: 0.56206702125 01:01:14.370 --> 01:01:16.490 It's from the EPG 5 which is the NOTE Confidence: 0.56206702125 01:01:16.490 --> 01:01:17.738 fusion of autophagosomes and NOTE Confidence: 0.56206702125 01:01:17.738 --> 01:01:19.489 lysosome steps down there are the NOTE Confidence: 0.56206702125 01:01:19.489 --> 01:01:21.064 most important and a lot of it NOTE Confidence: 0.56206702125 01:01:21.064 --> 01:01:22.460 maybe non canonical autophagy. NOTE Confidence: 0.56206702125 01:01:22.460 --> 01:01:25.190 So a knockout the the best knockout. NOTE Confidence: 0.56206702125 01:01:25.190 --> 01:01:26.382 They had to stop. NOTE Confidence: 0.56206702125 01:01:26.382 --> 01:01:28.766 The whole process is as in the NOTE Confidence: 0.56206702125 01:01:28.766 --> 01:01:31.406 phosphorylation that phosphorylase that puts NOTE Confidence: 0.56206702125 01:01:31.406 --> 01:01:34.200 phosphate phosphate groups on Mano six, NOTE Confidence: 0.56206702125 01:01:34.200 --> 01:01:35.635 you know to make Manor 6 phosphate. NOTE Confidence: 0.56206702125 01:01:35.640 --> 01:01:37.120 So none of the digestive, NOTE Confidence: 0.56206702125 01:01:37.120 --> 01:01:39.360 the license only enzymes go to the lysosome. NOTE Confidence: 0.56206702125 01:01:39.360 --> 01:01:40.785 Those mice are completely resistant NOTE Confidence: 0.56206702125 01:01:40.785 --> 01:01:42.834 to you know which is not necessarily NOTE Confidence: 0.56206702125 01:01:42.834 --> 01:01:44.544 a good thing because it means NOTE Confidence: 0.56206702125 01:01:44.544 --> 01:01:46.084 they can't repair in the pancreas NOTE Confidence: 0.56206702125 01:01:46.084 --> 01:01:47.891 is kind of if you keep forcing NOTE Confidence: 0.56206702125 01:01:47.891 --> 01:01:50.046 pancreatitis or pancreas is turned NOTE Confidence: 0.56206702125 01:01:50.046 --> 01:01:52.504 to snot basically because they can't NOTE Confidence: 0.56206702125 01:01:52.504 --> 01:01:54.575 you know repair the damage so. NOTE Confidence: 0.56206702125 01:01:54.575 --> 01:01:55.760 In our experience, NOTE Confidence: 0.56206702125 01:01:55.760 --> 01:01:58.130 it's really lysosomes I you know, NOTE Confidence: 0.56206702125 01:01:58.130 --> 01:01:59.294 it's massive autophagy. NOTE Confidence: 0.56206702125 01:01:59.294 --> 01:02:00.070 Clearly LC3, NOTE Confidence: 0.56206702125 01:02:00.070 --> 01:02:02.870 it's all the classic but the the main. NOTE Confidence: 0.56206702125 01:02:02.870 --> 01:02:04.641 The thing seems to be required is NOTE Confidence: 0.56206702125 01:02:04.641 --> 01:02:06.169 the flux through the lysosomes. NOTE Confidence: 0.480954455 01:02:08.800 --> 01:02:09.470 Short question. NOTE Confidence: 0.6431545 01:02:11.550 --> 01:02:11.850 Cheap. NOTE Confidence: 0.823314832142857 01:02:17.630 --> 01:02:19.674 Yeah. So, so the question is whether NOTE Confidence: 0.823314832142857 01:02:19.674 --> 01:02:21.568 parietal cells can do the same thing. NOTE Confidence: 0.823314832142857 01:02:21.570 --> 01:02:23.793 And in fact, as part of the more general NOTE Confidence: 0.823314832142857 01:02:23.793 --> 01:02:25.609 question of is it like universal and NOTE Confidence: 0.823314832142857 01:02:25.609 --> 01:02:27.415 the parietal cells are great test case NOTE Confidence: 0.823314832142857 01:02:27.415 --> 01:02:29.570 of the only cell that we've never seen NOTE Confidence: 0.823314832142857 01:02:29.570 --> 01:02:32.090 couldn't do any kind of plasticity. NOTE Confidence: 0.823314832142857 01:02:32.090 --> 01:02:33.674 And actually Juan Jay also did NOTE Confidence: 0.823314832142857 01:02:33.674 --> 01:02:35.230 the that the experiment early on. NOTE Confidence: 0.823314832142857 01:02:35.230 --> 01:02:37.374 So if he did when he was doing NOTE Confidence: 0.823314832142857 01:02:37.374 --> 01:02:39.609 the the tamoxifen to be marked, NOTE Confidence: 0.823314832142857 01:02:39.610 --> 01:02:41.418 all the parietal cells, NOTE Confidence: 0.823314832142857 01:02:41.418 --> 01:02:45.179 they all died basically and they they didn't, NOTE Confidence: 0.823314832142857 01:02:45.180 --> 01:02:47.916 they never seem to. D differentiate. NOTE Confidence: 0.823314832142857 01:02:47.920 --> 01:02:49.397 Actually we have a pretty good idea NOTE Confidence: 0.823314832142857 01:02:49.397 --> 01:02:51.362 because some of our work is just on NOTE Confidence: 0.823314832142857 01:02:51.362 --> 01:02:52.390 the regular differentiation parietal NOTE Confidence: 0.823314832142857 01:02:52.390 --> 01:02:54.208 cells and there seems to be a NOTE Confidence: 0.823314832142857 01:02:54.208 --> 01:02:55.220 checkpoint and their differentiation, NOTE Confidence: 0.823314832142857 01:02:55.220 --> 01:02:57.056 after which they are no longer NOTE Confidence: 0.823314832142857 01:02:57.056 --> 01:02:59.188 plastic at all, but up to about NOTE Confidence: 0.823314832142857 01:02:59.188 --> 01:03:00.698 halfway into becoming a parietal, NOTE Confidence: 0.823314832142857 01:03:00.700 --> 01:03:03.040 so then they can take detours. NOTE Confidence: 0.823314832142857 01:03:03.040 --> 01:03:04.660 And in fact, NOTE Confidence: 0.823314832142857 01:03:04.660 --> 01:03:07.900 working with Shilpa Jane at Baylor, NOTE Confidence: 0.823314832142857 01:03:07.900 --> 01:03:09.442 we've been collecting some of the NOTE Confidence: 0.823314832142857 01:03:09.442 --> 01:03:10.803 interesting sort of parietal hyperplasia NOTE Confidence: 0.823314832142857 01:03:10.803 --> 01:03:12.495 that happen in a neuroendocrine setting NOTE Confidence: 0.823314832142857 01:03:12.495 --> 01:03:14.139 or an autoimmune gastritis setting, NOTE Confidence: 0.823314832142857 01:03:14.140 --> 01:03:16.030 and you can definitely see some pretty NOTE Confidence: 0.823314832142857 01:03:16.030 --> 01:03:17.660 odd using markers that we know of. NOTE Confidence: 0.823314832142857 01:03:17.660 --> 01:03:19.495 Pre parietal cells some odd NOTE Confidence: 0.823314832142857 01:03:19.495 --> 01:03:21.330 sort of parietal cell variance, NOTE Confidence: 0.823314832142857 01:03:21.330 --> 01:03:23.010 but I don't think those are coming backwards. NOTE Confidence: 0.823314832142857 01:03:23.010 --> 01:03:24.702 I think those are actually coming NOTE Confidence: 0.823314832142857 01:03:24.702 --> 01:03:26.808 from the stem cell and then in NOTE Confidence: 0.823314832142857 01:03:26.808 --> 01:03:28.333 the setting bottom you gastritis. NOTE Confidence: 0.823314832142857 01:03:28.340 --> 01:03:30.224 They take a detour because they're NOTE Confidence: 0.823314832142857 01:03:30.224 --> 01:03:32.295 going to be destroyed basically by NOTE Confidence: 0.823314832142857 01:03:32.295 --> 01:03:34.180 the anti parietal cell antibodies. NOTE Confidence: 0.823314832142857 01:03:34.180 --> 01:03:36.244 So yeah, not all cells can do it. NOTE Confidence: 0.823314832142857 01:03:36.250 --> 01:03:39.538 Seems like protocells are quite resistant. NOTE Confidence: 0.823314832142857 01:03:39.540 --> 01:03:40.368 A lot of questions. NOTE Confidence: 0.8811298 01:03:45.310 --> 01:03:45.890 Yeah. NOTE Confidence: 0.72511107 01:03:51.070 --> 01:03:53.520 He said great. It's great to like, NOTE Confidence: 0.72511107 01:03:53.520 --> 01:03:56.340 you know, don't present that often, NOTE Confidence: 0.72511107 01:03:56.340 --> 01:04:01.020 but before a bunch of pathologists, so. NOTE Confidence: 0.72511107 01:04:01.020 --> 01:04:04.240 Yeah, is the neuroendocrine proliferation, NOTE Confidence: 0.72511107 01:04:04.240 --> 01:04:05.997 you know those little tumors or little NOTE Confidence: 0.72511107 01:04:05.997 --> 01:04:07.991 growths or you know that you get with NOTE Confidence: 0.72511107 01:04:07.991 --> 01:04:09.610 chronic bridal cell loss or chronic, NOTE Confidence: 0.72511107 01:04:09.610 --> 01:04:11.054 you know, PPI's and. NOTE Confidence: 0.72511107 01:04:11.054 --> 01:04:13.308 You know, is are those metaplastic? NOTE Confidence: 0.72511107 01:04:13.308 --> 01:04:15.034 They sure look funny, right? NOTE Confidence: 0.72511107 01:04:15.034 --> 01:04:15.810 I mean, you know, NOTE Confidence: 0.72511107 01:04:15.810 --> 01:04:18.612 they don't look like they're normal NOTE Confidence: 0.72511107 01:04:18.612 --> 01:04:20.820 endocrine cells sitting lining up NOTE Confidence: 0.72511107 01:04:20.820 --> 01:04:23.432 with the rest of the epithelium, NOTE Confidence: 0.72511107 01:04:23.432 --> 01:04:25.001 because normally integrins NOTE Confidence: 0.72511107 01:04:25.001 --> 01:04:27.750 cells are always surrounded by. NOTE Confidence: 0.72511107 01:04:27.750 --> 01:04:28.990 Other non neuroendocrine epithelial NOTE Confidence: 0.72511107 01:04:28.990 --> 01:04:31.191 cells and then you know in these NOTE Confidence: 0.72511107 01:04:31.191 --> 01:04:32.646 lesions you get these little, NOTE Confidence: 0.72511107 01:04:32.650 --> 01:04:36.049 you know, expansions. NOTE Confidence: 0.72511107 01:04:36.050 --> 01:04:39.566 And I yeah great great question. NOTE Confidence: 0.72511107 01:04:39.570 --> 01:04:41.481 How would they you know the the NOTE Confidence: 0.72511107 01:04:41.481 --> 01:04:43.491 only the one thing that that might NOTE Confidence: 0.72511107 01:04:43.491 --> 01:04:45.880 speak to that is one of the detours NOTE Confidence: 0.72511107 01:04:45.880 --> 01:04:47.818 it seems like those riddles can NOTE Confidence: 0.72511107 01:04:47.818 --> 01:04:49.695 make but I just said is towards NOTE Confidence: 0.72511107 01:04:49.695 --> 01:04:50.920 more of an endocrine lineage. NOTE Confidence: 0.72511107 01:04:50.920 --> 01:04:53.412 So you know maybe maybe that's why NOTE Confidence: 0.72511107 01:04:53.412 --> 01:04:55.790 I never really thought about it. NOTE Confidence: 0.72511107 01:04:55.790 --> 01:04:57.742 We had a mouse model where we drove NOTE Confidence: 0.72511107 01:04:57.742 --> 01:04:59.730 large tea energen you know to drive NOTE Confidence: 0.72511107 01:04:59.730 --> 01:05:01.712 proliferation and to to try to get NOTE Confidence: 0.72511107 01:05:01.712 --> 01:05:03.420 a bunch of pre parietal cells but NOTE Confidence: 0.72511107 01:05:03.420 --> 01:05:04.685 what happened with time this is NOTE Confidence: 0.72511107 01:05:04.685 --> 01:05:06.340 when I was in Jeff Gordon's lab. NOTE Confidence: 0.72511107 01:05:06.340 --> 01:05:08.884 What happened with time was they all NOTE Confidence: 0.72511107 01:05:08.884 --> 01:05:10.858 turned into endocrine tumors in the stomach. NOTE Confidence: 0.72511107 01:05:10.860 --> 01:05:12.610 So they actually went through. NOTE Confidence: 0.72511107 01:05:12.610 --> 01:05:15.090 So it's like they hit a certain wall NOTE Confidence: 0.72511107 01:05:15.090 --> 01:05:17.110 of parietal cell differentiation and NOTE Confidence: 0.72511107 01:05:17.110 --> 01:05:19.780 then took a detour towards endocrine. NOTE Confidence: 0.72511107 01:05:19.780 --> 01:05:21.360 Then it became endocrine proliferations, NOTE Confidence: 0.72511107 01:05:21.360 --> 01:05:23.520 and then they became metastatic NOTE Confidence: 0.72511107 01:05:23.520 --> 01:05:24.306 neuroendocrine tumors. NOTE Confidence: 0.72511107 01:05:24.306 --> 01:05:25.878 So I don't know, NOTE Confidence: 0.72511107 01:05:25.880 --> 01:05:27.800 maybe we just solved a mystery. NOTE Confidence: 0.72511107 01:05:27.800 --> 01:05:29.928 Maybe it's because the reason why they NOTE Confidence: 0.72511107 01:05:29.928 --> 01:05:32.456 happen so much is not just because of NOTE Confidence: 0.72511107 01:05:32.456 --> 01:05:34.760 hypergastrinemia and the G cell stimulation, NOTE Confidence: 0.72511107 01:05:34.760 --> 01:05:36.146 but also because. NOTE Confidence: 0.72511107 01:05:36.146 --> 01:05:38.918 The pre parietal cells themselves can NOTE Confidence: 0.72511107 01:05:38.918 --> 01:05:41.928 fuel endocrine cells in that setting. NOTE Confidence: 0.72511107 01:05:41.930 --> 01:05:43.530 Yeah, and take a detour. NOTE Confidence: 0.72511107 01:05:43.530 --> 01:05:46.032 They clearly can in the mouse we showed. NOTE Confidence: 0.72511107 01:05:46.032 --> 01:05:46.796 That means it's hard, NOTE Confidence: 0.72511107 01:05:46.800 --> 01:05:48.104 it's artificial because we're NOTE Confidence: 0.72511107 01:05:48.104 --> 01:05:50.060 expressing large T but but still, NOTE Confidence: 0.72511107 01:05:50.060 --> 01:05:51.716 they start off as pre parietal cells and NOTE Confidence: 0.72511107 01:05:51.716 --> 01:05:53.410 then you could watch them even become, NOTE Confidence: 0.72511107 01:05:53.410 --> 01:05:54.156 you know, NOTE Confidence: 0.72511107 01:05:54.156 --> 01:05:56.767 through EM and and staining become endocrine. NOTE Confidence: 0.72511107 01:05:56.770 --> 01:05:57.460 So yeah, NOTE Confidence: 0.72511107 01:05:57.460 --> 01:05:57.805 maybe, NOTE Confidence: 0.72511107 01:05:57.805 --> 01:05:59.530 maybe that's maybe your two NOTE Confidence: 0.72511107 01:05:59.530 --> 01:06:00.710 questions are linked. NOTE Confidence: 0.890194292 01:06:06.090 --> 01:06:07.360 All right. Thank you, everybody. Yeah.