WEBVTT - Epstein-Barr Virus: The Fog of Discovery 0:00:00.560 --> 0:00:04.600 The epstein Bar virus infects almost everybody on Earth. For 0:00:04.640 --> 0:00:08.400 the most part, it's relatively minor. Occasionally it causes mono. 0:00:08.880 --> 0:00:12.360 You get sick, you get better. But it turns out 0:00:12.760 --> 0:00:17.000 the epstein Bar virus EBV stays in our bodies forever, 0:00:17.680 --> 0:00:21.800 and in some people, long after their initial infection, EBV 0:00:21.880 --> 0:00:26.680 winds up causing cancer. In other people it causes multiple sclerosis, 0:00:27.160 --> 0:00:31.560 which is not only scary, it's weird. When I think 0:00:31.600 --> 0:00:35.280 of viral illness, I think you get infected with the virus, 0:00:35.440 --> 0:00:39.040 maybe you get sick, your immune system responds, and most 0:00:39.080 --> 0:00:42.680 of the time you get better. That's it. But EBV 0:00:42.920 --> 0:00:48.160 isn't like that. And one lesson of EBV is maybe 0:00:48.200 --> 0:00:51.560 we need to think differently about how viruses make us sick, 0:00:52.800 --> 0:00:56.560 because sometimes they can hide out for decades and then 0:00:57.000 --> 0:01:00.520 through a complicated and unlucky series of events, they can 0:01:00.600 --> 0:01:05.440 do tremendous damage. I'm Jacob Goldstein, and this is Incubation, 0:01:05.720 --> 0:01:09.679 a show about viruses. Today on the show epstein Bar, 0:01:20.040 --> 0:01:22.280 let me just say a quick word about pronunciation. In 0:01:22.319 --> 0:01:26.120 the US we say epstein bar. In the UK they 0:01:26.160 --> 0:01:31.360 say epstein bar. You will hear both pronunciations in today's show. 0:01:31.720 --> 0:01:34.520 The show as usual is in two parts. In the 0:01:34.560 --> 0:01:37.640 second half of the show, we'll hear about this really 0:01:38.000 --> 0:01:42.640 major breakthrough just from the last few years linking EBV 0:01:42.959 --> 0:01:47.920 to multiple sclerosis and other autoimmune diseases. But first we're 0:01:47.920 --> 0:01:51.480 going to go back to the nineteen sixties. At that time, 0:01:51.840 --> 0:01:56.080 people knew that viruses could cause cancers in animals. In fact, 0:01:56.120 --> 0:01:59.400 we talked about that last season in our episode about HPV. 0:02:00.120 --> 0:02:03.560 In the sixties, no one had ever identified a virus 0:02:03.640 --> 0:02:08.000 that caused cancer in people. There were some researchers who 0:02:08.040 --> 0:02:11.519 thought such a thing might exist. One of those researchers 0:02:11.720 --> 0:02:15.200 was a young British pathologist named Anthony Epstein. 0:02:15.639 --> 0:02:18.400 He was extraordinary, a one off, i would say. 0:02:18.960 --> 0:02:22.400 Dorothy Crawford was a grad student in Epstein's lab later 0:02:22.639 --> 0:02:25.280 in the nineteen seventies, and she went on to co 0:02:25.360 --> 0:02:26.560 write a book about him. 0:02:26.840 --> 0:02:30.600 He was supremely self confident. He was highly intelligent, he 0:02:30.680 --> 0:02:34.000 was intuitive, he was persistent. He was somebody who's going 0:02:34.040 --> 0:02:35.560 to find the bloody virus if he's. 0:02:35.440 --> 0:02:39.680 There, Dorothy says Epstein needed more than intelligence, confidence and 0:02:39.720 --> 0:02:43.520 persistence to discover the link between viruses and cancer. She 0:02:43.600 --> 0:02:48.239 says he needed some lucky breaks. Epstein's first big break, 0:02:48.280 --> 0:02:51.760 according to Dorothy, was when a doctor named Dennis Burkett 0:02:51.880 --> 0:02:54.079 just happened to give a lecture at the hospital where 0:02:54.080 --> 0:02:55.000 Epstein worked. 0:02:55.360 --> 0:03:00.720 Dennis Burkett was a missionary doctor working in Uganda with children, 0:03:01.120 --> 0:03:06.000 and he described these large tumors of the jaw that 0:03:06.160 --> 0:03:09.040 was seemed to be very common among young children in 0:03:09.080 --> 0:03:12.760 this particular area. He'd never seen anything like it before, 0:03:12.760 --> 0:03:16.440 and neither had anybody else, and so he went on 0:03:16.480 --> 0:03:21.080 a jeep ride around Africa to look at the epidemiology 0:03:21.120 --> 0:03:24.320 of this tumor and tracking the geographical restriction of it. 0:03:24.919 --> 0:03:28.799 The tumor only occurred where malaria was what we call 0:03:28.880 --> 0:03:33.320 hyper endemic, so where malaria occurred all the year round 0:03:33.400 --> 0:03:37.840 at the same level. And he thought, and many people thought, 0:03:38.160 --> 0:03:40.960 that maybe it was caused by an infectious agent that 0:03:41.120 --> 0:03:46.440 was transmitted by mosquitoes, because malaria is transmitted by mosquitoes. 0:03:47.040 --> 0:03:51.640 And Burkett gives a lecture at the hospital where Epstein 0:03:51.720 --> 0:03:53.960 works talking about his work. That's right. 0:03:54.160 --> 0:03:57.080 It was the Middlesex hospital where Tony Epstein was working, 0:03:57.520 --> 0:04:01.760 and Burkett came in nineteen sixty one to give a lecture, 0:04:02.280 --> 0:04:05.040 and Tony Epstein just happened to see this notice on 0:04:05.080 --> 0:04:07.280 a noticeboard and went along. 0:04:08.080 --> 0:04:11.120 You read in your book that Epstein hears this lecture 0:04:11.240 --> 0:04:14.160 and he thinks, you know, this may be it, This 0:04:14.320 --> 0:04:17.400 may be the tumor that is caused by a virus. 0:04:17.880 --> 0:04:19.720 So what does he do next? What does he do 0:04:19.960 --> 0:04:21.160 after he hears this lecture? 0:04:21.560 --> 0:04:26.159 That very day he approached Burkett and asked him if 0:04:26.200 --> 0:04:29.760 he could send samples of the tumor to the Middlesex 0:04:29.800 --> 0:04:32.600 Hospital for him to study. And I mean, it's all 0:04:32.680 --> 0:04:34.360 very well to just say it like that, And they 0:04:34.400 --> 0:04:38.440 started arriving. But you know, getting a fresh tumor biopsy 0:04:38.600 --> 0:04:42.520 from Uganda to the Middlesex Hospital in time for it 0:04:42.640 --> 0:04:45.360 not to have died, the cells to have died, it's 0:04:45.400 --> 0:04:48.200 a mean feat on its own, despite everything else. In 0:04:48.640 --> 0:04:51.000 the mid sixties, exactly in the mid sixties. 0:04:51.080 --> 0:04:54.280 Yes, So they start arriving every week, Yes, and Tony 0:04:54.320 --> 0:04:57.400 Epstein starts looking at them, right, he wants to find 0:04:58.040 --> 0:05:03.040 some path that is causing this tumor. Right, So what 0:05:03.440 --> 0:05:04.359 does he start doing. 0:05:05.160 --> 0:05:09.920 Well, they were chunks of tumor and he straightway fixed 0:05:09.960 --> 0:05:12.480 them for the electron microscope. So that he could look 0:05:12.480 --> 0:05:15.039 at them under the electron microscope. And I just have 0:05:15.160 --> 0:05:17.480 to add that, I mean, it was dead lucky that 0:05:17.520 --> 0:05:21.080 the medal Sex had an electron microscope, but because at 0:05:21.080 --> 0:05:24.159 that time, you know, those machines were like gold dust 0:05:24.240 --> 0:05:28.040 and they're incredibly expensive. But pathology at the Middlesex Hospital 0:05:28.080 --> 0:05:31.359 had one and Tony had access to it, and so 0:05:31.520 --> 0:05:34.839 he started off preparing them and just looking at the 0:05:34.880 --> 0:05:37.040 cells and seeing if he could see any viruses in them. 0:05:37.480 --> 0:05:38.960 And the answer is he couldn't. 0:05:39.440 --> 0:05:43.200 He couldn't. Why not? What was going on? 0:05:43.560 --> 0:05:47.160 Because there weren't any no virus particles to see in 0:05:47.200 --> 0:05:50.800 the cells. And so he also put them into tissue 0:05:50.800 --> 0:05:54.720 culture to see if he could grow the cells, and 0:05:54.800 --> 0:05:55.279 he couldn't. 0:05:56.040 --> 0:05:58.520 Just to be clear, is the idea that like, maybe 0:05:58.560 --> 0:06:01.520 there were some very small number of virus particles in 0:06:01.560 --> 0:06:04.200 the tumor cells, and if you could you grow a 0:06:04.200 --> 0:06:07.120 bunch more cells, you could also get more virus particles 0:06:07.120 --> 0:06:08.479 so they'd be easier to see. 0:06:08.920 --> 0:06:12.239 Yes, that they might increase the number of virus carrying cells, 0:06:13.160 --> 0:06:16.760 but they didn't. He just basically spent three years getting 0:06:16.880 --> 0:06:18.520 native results all the way through. 0:06:18.960 --> 0:06:22.160 So three years three years is a long time it 0:06:22.200 --> 0:06:25.040 is to look and not see. I mean, it would 0:06:25.040 --> 0:06:30.640 be reasonable to conclude, oh, my hypothesis was incorrect, this 0:06:30.800 --> 0:06:34.320 tumor is not caused by a virus. Like, why doesn't 0:06:34.360 --> 0:06:35.560 he come to that conclusion? 0:06:35.760 --> 0:06:38.880 He would never do that to Every time you asked 0:06:38.960 --> 0:06:42.359 him why he did it, he said, because I just 0:06:42.440 --> 0:06:45.720 knew it was right. That's what he always said. It 0:06:45.760 --> 0:06:46.520 had to be right. 0:06:47.240 --> 0:06:52.039 So it's during this period, right that Yvonne Barr comes 0:06:52.080 --> 0:06:54.360 to work with Tony Epstein, and she of course becomes 0:06:54.400 --> 0:06:57.320 the other half of Epstein Bar. So tell me about her. 0:06:57.760 --> 0:07:00.560 Well, she joined a bit later, I mean as the 0:07:00.560 --> 0:07:02.640 three years were coming to an end, so she was 0:07:03.040 --> 0:07:08.200 virtually there when the breakthrough came. She was a scientist 0:07:08.360 --> 0:07:13.040 from Ireland and her job was to set these cells 0:07:13.120 --> 0:07:16.120 up in culture. So he looked at them under the 0:07:16.160 --> 0:07:19.360 electron microscope and he also put them into culture, and 0:07:19.440 --> 0:07:22.480 as I've already said, nothing grew. But that was her 0:07:22.560 --> 0:07:23.200 job anyway. 0:07:23.560 --> 0:07:29.160 Huh So three years in nothing, nothing, nothing? Then what happened? Then? 0:07:29.240 --> 0:07:32.840 What happened was fog fog fog. 0:07:33.240 --> 0:07:35.400 A common occurrence in London. 0:07:35.640 --> 0:07:38.360 I'm told fog fog? 0:07:38.680 --> 0:07:42.360 Yes, why is fog? Why is fog important. 0:07:42.000 --> 0:07:45.200 Why, because it delayed the flight that the sample was 0:07:45.240 --> 0:07:49.760 coming in on. And he throw is particularly low lying 0:07:49.840 --> 0:07:53.320 and particularly prone to fog, and so they diverted the 0:07:53.320 --> 0:07:57.080 plane to Manchester. Obviously, it arrived late. It was a 0:07:57.120 --> 0:08:01.080 Friday afternoon. Everybody had gone home except on He waited 0:08:01.120 --> 0:08:04.160 for it, and when he got it into the lab, 0:08:04.440 --> 0:08:07.320 it came in a bottle of transport medium, as we 0:08:07.360 --> 0:08:09.400 call it, and he held it up to the light 0:08:09.760 --> 0:08:12.920 and it was all cloudy, and that means to everybody 0:08:13.240 --> 0:08:17.760 that it was contaminated with bacteria. And because the temple 0:08:17.800 --> 0:08:21.240 had been delayed, these bacteria had grown in the culture 0:08:21.880 --> 0:08:23.000 and it would be useless. 0:08:23.560 --> 0:08:26.000 An urmal person would throw it out and wait for 0:08:26.040 --> 0:08:27.160 the sample next week. 0:08:27.400 --> 0:08:31.160 Yes, but Tony didn't do that. He'd got some of 0:08:31.160 --> 0:08:34.000 the sample out, looked at it under the microscope and 0:08:34.080 --> 0:08:39.120 did not see any bacteria. He saw free floating tumor cells. 0:08:40.520 --> 0:08:43.240 And so for the first time ever, he put the 0:08:43.280 --> 0:08:47.240 free floating cells into a culture. Previously, he'd been putting 0:08:47.320 --> 0:08:51.280 lumps of tumor into the culture, but there weren't any 0:08:51.360 --> 0:08:53.480 lumps this time. They'd all shape, the cells had all 0:08:53.520 --> 0:08:54.840 shaken free on the journey. 0:08:55.240 --> 0:08:58.040 So okay, so he finally now can see the cells, 0:08:58.040 --> 0:09:00.320 he can culture the cells, which he's been on able 0:09:00.360 --> 0:09:00.960 to do before. 0:09:01.320 --> 0:09:05.400 What happened, well, very soon he had enough cells to 0:09:05.640 --> 0:09:08.600 look at them under the electron microscope, and he looked 0:09:08.600 --> 0:09:11.440 down the microscope and in the very first grid that 0:09:11.520 --> 0:09:13.640 he looked at, he saw viruses. 0:09:13.760 --> 0:09:15.640 He saw a virus, this thing that he's been looking 0:09:15.679 --> 0:09:19.320 for and not seeing for three years. Yes, there it is. 0:09:19.600 --> 0:09:23.320 In the very first grid square he saw viruses. And 0:09:23.400 --> 0:09:27.200 he knew immediately that they were herpes viruses by the 0:09:27.240 --> 0:09:30.680 shape of the virus particles. And he says that he 0:09:30.760 --> 0:09:33.679 was so excited. He was afraid, you know, he's going 0:09:33.760 --> 0:09:37.240 to do something wrong, very unusual for Tony, I might say. 0:09:37.320 --> 0:09:40.080 So he switched the microscope off, went for a walk 0:09:40.080 --> 0:09:43.199 around the block in the snow, and then came back 0:09:43.320 --> 0:09:45.160 and turned it on again and made sure that they 0:09:45.160 --> 0:09:46.560 were still there, and they were. 0:09:47.080 --> 0:09:49.600 Wow. You imagine like his hands are shaking or something. 0:09:49.640 --> 0:09:52.320 He's afraid he's going to knock it down or something. 0:09:52.760 --> 0:09:56.200 I suppose, yes, or that he's seeing things. And I 0:09:56.200 --> 0:09:59.160 can tell you that we now know that only about 0:09:59.200 --> 0:10:02.959 one percent at most of cells in those cell lines 0:10:03.000 --> 0:10:04.240 contain virus particles. 0:10:04.640 --> 0:10:07.000 You're telling me there's a one in one hundred chants 0:10:07.000 --> 0:10:08.400 that he would see it in the first grid. 0:10:08.679 --> 0:10:11.760 Yes, I am telling you that. Yes, I mean, you know, 0:10:11.920 --> 0:10:13.679 it's ridiculous, but that's what happened. 0:10:14.000 --> 0:10:16.000 So, I mean, this is this is a big moment, right, 0:10:16.200 --> 0:10:19.320 This is him seeming to find the link between a 0:10:19.400 --> 0:10:20.600 virus and a tumor. 0:10:20.960 --> 0:10:25.480 Yes, but nobody believed it. I mean, I don't suppose 0:10:25.480 --> 0:10:27.480 I would have believed it either, to be honest. 0:10:27.480 --> 0:10:30.000 Why not? Why wouldn't you have believed it? 0:10:30.559 --> 0:10:32.360 Because it's so ridiculous? 0:10:32.920 --> 0:10:35.400 Tell me more what I don't why why ridiculous? 0:10:35.760 --> 0:10:38.640 Well, because at that time, viruses were known to cause 0:10:38.679 --> 0:10:42.800 things like flu and measles and mumps, you know, and 0:10:43.320 --> 0:10:46.880 not tumors. I mean it just I can understand why 0:10:46.920 --> 0:10:48.840 people just did not believe it. 0:10:48.840 --> 0:10:52.120 It does feel that way, right, And I guess also 0:10:52.240 --> 0:10:56.800 the fact that there can be, certainly with some viruses 0:10:56.800 --> 0:11:02.040 and tumors, a long latency period between infection and the 0:11:02.080 --> 0:11:04.800 development of the tumor also, I guess makes it harder 0:11:04.840 --> 0:11:07.080 to believe, right, I mean, harder to prove causality, Like 0:11:07.120 --> 0:11:09.840 if you know, if you got spots all over your 0:11:09.840 --> 0:11:12.880 body and then suddenly developed a tumor and be like, oh, okay, 0:11:12.920 --> 0:11:15.080 I get it, that's the virus. But this doesn't work 0:11:15.120 --> 0:11:15.679 that way. 0:11:15.559 --> 0:11:19.840 Right, Oh, no, it definitely doesn't. And I mean, okay, 0:11:20.040 --> 0:11:24.079 in berkelnfoma, there's a long incubation period. And what that 0:11:24.160 --> 0:11:27.400 means is that there must be other factors. The virus 0:11:27.440 --> 0:11:30.440 is not the only thing needed to cause the tumor. 0:11:30.760 --> 0:11:34.080 You need other things. And of course the obvious thing 0:11:34.280 --> 0:11:39.000 in this case is malaria, which immuno suppresses the children 0:11:39.440 --> 0:11:42.200 and causes them to be you know, more susceptible to 0:11:42.280 --> 0:11:42.920 this virus. 0:11:43.400 --> 0:11:48.280 Aha. So that explains that original link between the tumor 0:11:48.559 --> 0:11:55.480 and the geographic areas where malaria is especially prevalent. Yes, 0:11:56.320 --> 0:12:00.760 So tell me about the rest of Tony Epstein's he 0:12:00.840 --> 0:12:04.439 makes this big discovery, people don't believe him. Eventually they 0:12:04.440 --> 0:12:06.640 do believe him. How does his career play out? 0:12:07.559 --> 0:12:10.120 Well, he was nothing if not single minded. 0:12:10.600 --> 0:12:11.280 You know, he was. 0:12:12.880 --> 0:12:16.040 Persistent in what he did. He never gave up. He 0:12:16.120 --> 0:12:20.679 was highly self confident, and he was also an obsessional worker. 0:12:21.200 --> 0:12:24.800 And so you know, as soon as he in his 0:12:24.840 --> 0:12:28.040 own mind believed that this was a tumor virus. He 0:12:28.520 --> 0:12:30.640 knew that what he had to do was make a 0:12:30.720 --> 0:12:32.640 vaccine to stop the tumor. 0:12:33.200 --> 0:12:36.160 Right, it follows, right, Oh my god, we can prevent 0:12:36.280 --> 0:12:38.080 cancer with the vaccine, yep. 0:12:38.520 --> 0:12:41.480 So it's a totally direct way of thinking, and he 0:12:41.559 --> 0:12:43.800 just went for it. So you know, we're still on 0:12:43.840 --> 0:12:47.800 a learning curve, frankly, and Tony was part of the 0:12:47.880 --> 0:12:51.520 learning curve and had a huge, huge impact. 0:12:54.440 --> 0:12:57.880 I really appreciate your time of truly fascinating conversation. Thank 0:12:57.880 --> 0:13:02.160 you so much, No problem. Dorothy Crawford is a retired 0:13:02.200 --> 0:13:05.640 professor of medical microbiology and co author of the book 0:13:06.040 --> 0:13:10.559 Cancer Virus, The Story of Epstein Barr Virus. Today, there 0:13:10.600 --> 0:13:13.480 is still no vaccine for EBV, but people are working 0:13:13.520 --> 0:13:17.199 on it. Since Epstein's original discovery, EBV has also been 0:13:17.240 --> 0:13:20.880 linked to other forms of cancer, including Hodgkin's disease and 0:13:21.000 --> 0:13:25.000 cancers of the nose, throat, and stomach. Epstein died earlier 0:13:25.000 --> 0:13:27.119 this year at the age of one hundred and two. 0:13:27.800 --> 0:13:31.000 As for Yvon Barr, she moved to Australia in nineteen 0:13:31.080 --> 0:13:34.000 sixty six and became a high school math and science teacher. 0:13:34.520 --> 0:13:39.080 She died in twenty sixteen, at age eighty three. We'll 0:13:39.080 --> 0:13:41.440 be back in a minute to discuss new research linking 0:13:41.480 --> 0:13:56.040 EBV to multiple sclerosis. It's been clear for decades now 0:13:56.120 --> 0:14:00.800 that EBV causes certain cancers, and there's been speculation that 0:14:00.880 --> 0:14:04.080 the virus may also be linked to multiple sclerosis and 0:14:04.200 --> 0:14:09.199 other autoimmune diseases, but until recently, that's all it was speculation. 0:14:10.320 --> 0:14:13.600 Bill Robinson is a professor of medicine and chief of 0:14:13.640 --> 0:14:18.400 the Division of Immunology and Rheumatology at Stanford. He specializes 0:14:18.440 --> 0:14:21.800 in autoimmune diseases, and he says for a long time 0:14:21.920 --> 0:14:24.720 he and his colleagues didn't really buy the idea that 0:14:24.840 --> 0:14:26.600 EBV causes MS. 0:14:27.120 --> 0:14:32.080 We had dismissed it as epiphenomena, meaning ninety four percent 0:14:32.160 --> 0:14:36.720 of all humans are infected with EBV, and how could 0:14:36.760 --> 0:14:39.480 it actually be the cause of MASS given only about 0:14:39.520 --> 0:14:41.640 one in nine hundred people developed mass. 0:14:42.400 --> 0:14:43.400 Was that your own view? 0:14:43.960 --> 0:14:45.160 That was definitely my view. 0:14:45.880 --> 0:14:51.720 Basically, almost everybody has EBV, almost nobody has MS. There's 0:14:51.760 --> 0:14:53.200 no way there can be a cause of link. The 0:14:53.280 --> 0:14:56.840 numbers just don't make sense exactly. So this idea is 0:14:56.880 --> 0:15:01.000 out there for decades really, and only just in the 0:15:01.040 --> 0:15:04.680 last couple of years, right in twenty twenty two, there 0:15:04.720 --> 0:15:10.960 were two studies that really seemed compellingly to demonstrate a 0:15:11.080 --> 0:15:16.280 link between epstein barvirus and multiple sclerosis. And I want 0:15:16.320 --> 0:15:18.040 to talk about both studies. Of course, I want to 0:15:18.040 --> 0:15:20.360 talk about the study you did, but before we get 0:15:20.400 --> 0:15:23.200 to that, let's talk about the other study. Let's talk 0:15:23.240 --> 0:15:27.080 about the epidemiological study. Tell me about that work. 0:15:27.840 --> 0:15:30.680 Yes, so, in the military, people are getting tested every 0:15:30.720 --> 0:15:35.480 several years for HIV disease and other things, and the 0:15:35.480 --> 0:15:41.320 military has banked samples from those collections. And Alberto Asherio 0:15:41.480 --> 0:15:44.880 at Harvard School of Public Health, who's been a leader 0:15:44.880 --> 0:15:49.160 in the field on the association of epstein bar virus 0:15:50.000 --> 0:15:54.000 with multiple scrosis, completed a lot of paperwork and went 0:15:54.040 --> 0:15:57.640 through a lot of regulatory requirements and with that received 0:15:58.040 --> 0:16:04.160 blood samples that were did from individuals who developed multiple scrosis, 0:16:04.320 --> 0:16:09.160 either in the military or following service, and basically use 0:16:09.240 --> 0:16:14.880 these to show that essentially everybody who developed MS was 0:16:14.920 --> 0:16:20.520 infected with EBV prior to developing MS. Huh More, specifically, 0:16:20.600 --> 0:16:24.800 they had eight hundred one patients total, and eight hundred 0:16:25.440 --> 0:16:28.040 out of the eight hundred and one, so ninety nine 0:16:28.360 --> 0:16:34.120 point nine percent were infected with EBV before they developed 0:16:34.200 --> 0:16:35.880 clinical multiple scrosis. 0:16:36.600 --> 0:16:40.040 So that study shows very elegantly and very compellingly that 0:16:40.640 --> 0:16:44.040 EBV is basically necessary but not sufficient to get MS. 0:16:44.080 --> 0:16:48.240 It doesn't tell us anything about why, about the mechanism, 0:16:48.320 --> 0:16:51.960 about what's going on, and that's what your work tells us, 0:16:51.960 --> 0:16:53.720 and I want to get to that, but before we do, 0:16:53.880 --> 0:16:57.880 let's just talk briefly about multiple sclerosis as a disease, 0:16:57.960 --> 0:17:00.800 both what happens to patients and also so well what 0:17:00.840 --> 0:17:03.000 happens to patients sort of clinically and then what happens 0:17:03.000 --> 0:17:05.840 at the cellular level tell me about multiple sclerosis. 0:17:06.080 --> 0:17:11.000 Yeah, so, in MS, the immune system attacks the milin sheath, 0:17:11.520 --> 0:17:17.080 which is the insulating coating on neurons, and it's essential 0:17:17.240 --> 0:17:22.399 for effective nerve conduction and thus sensation and you know, 0:17:22.520 --> 0:17:26.399 muscle movement. I think of the milin sheath as you know, 0:17:26.440 --> 0:17:29.919 the equivalent of the insulation around a wire. If you 0:17:30.320 --> 0:17:33.520 cut the insulation on a wire, it's short circuits and 0:17:33.600 --> 0:17:37.199 doesn't conduct. And likewise, if the immune system attacks and 0:17:37.280 --> 0:17:42.200 damages the milin sheath on individual nerves, those nerves also 0:17:42.320 --> 0:17:45.639 won't conduct. In us won't receive sensory signals or be 0:17:45.680 --> 0:17:49.040 able to transmit signals to activate muscles in thus move. 0:17:50.160 --> 0:17:54.840 So okay, so this is what goes wrong in patients 0:17:54.840 --> 0:17:58.760 who have multiple sclerosis. Their own immune system attacks the 0:17:58.840 --> 0:18:05.119 milin sheath that's for their nerves. When you set out 0:18:05.200 --> 0:18:09.320 to study the role of EBV and MS, what are 0:18:09.359 --> 0:18:10.879 you what's your hypothesis? 0:18:11.520 --> 0:18:15.520 We were very focused on taking the B cells from 0:18:15.600 --> 0:18:21.920 human multiple scrosis patients and then isolating the specific individual 0:18:21.960 --> 0:18:24.280 antibodies produced by each B cell. 0:18:24.920 --> 0:18:26.560 A B cell is a cell that's part of the 0:18:26.560 --> 0:18:30.520 immune system, right, So you're looking at the antibodies produced 0:18:30.520 --> 0:18:33.280 by the B cells in a multiple sclerosis patient. 0:18:33.720 --> 0:18:38.040 Yes, And to our great surprise, many of the antibodies 0:18:38.119 --> 0:18:44.240 were antibodies against viruses, of which EBV was a prominent virus. 0:18:44.760 --> 0:18:49.000 Huh. So, in a sense, these are immune cells doing 0:18:49.040 --> 0:18:52.240 what immune cells are supposed to do. They're creating antibodies 0:18:52.280 --> 0:18:54.080 to attack pathogens. 0:18:54.160 --> 0:18:59.480 And protect that individual against you know, viral pathogens such 0:18:59.480 --> 0:19:02.160 as E as well as other herpes viruses. 0:19:02.520 --> 0:19:05.399 When you put it that way, seems good, right, Oh great, 0:19:05.440 --> 0:19:09.399 there's a virus has infected my body. My immune cells 0:19:09.440 --> 0:19:14.080 are creating antibodies to attack that virus. That's what's supposed 0:19:14.080 --> 0:19:16.359 to happen. Where does it go wrong? 0:19:17.320 --> 0:19:22.000 So we discovered that some B cells made antibodies that 0:19:22.200 --> 0:19:26.439 not only bound to EBV, but they cross bound to 0:19:26.880 --> 0:19:29.040 human milin, meaning that. 0:19:28.960 --> 0:19:34.200 The same antibody could essentially attack both the epstein bar 0:19:34.400 --> 0:19:38.240 virus and the patient's own the person's own milin. 0:19:38.840 --> 0:19:39.520 That's correct. 0:19:40.080 --> 0:19:43.480 So was there like a specific moment when you realize 0:19:43.560 --> 0:19:48.199 that MS patients have these antibodies that attack both EBV 0:19:48.320 --> 0:19:49.560 and their own milin. 0:19:50.080 --> 0:19:55.840 The lead author, Toby Lance on our Nature paper emailed 0:19:55.880 --> 0:20:00.440 and called when he first found that these antibodies that 0:20:00.480 --> 0:20:03.800 we had isolated from human MS patients spinal fluid B 0:20:03.880 --> 0:20:06.879 cells when he found that they bound EBV. The email 0:20:06.960 --> 0:20:10.280 may call me and they're like, Bill, they're reactive with EBV, 0:20:11.560 --> 0:20:13.320 and I think we were both shocked. 0:20:13.960 --> 0:20:16.080 Yeah, what'd you say? What'd you think when you got 0:20:16.080 --> 0:20:16.440 that call? 0:20:17.160 --> 0:20:21.000 I was floored. I couldn't believe it, and I was like, wow, 0:20:22.119 --> 0:20:27.520 this is real. Because it's one thing to be statistically 0:20:28.200 --> 0:20:33.800 or epidemiologically associated, and a second component is to have 0:20:33.840 --> 0:20:38.800 a mechanistic basis, And our work provided the mechanistic basis 0:20:39.080 --> 0:20:43.040 by which EBV was causing a subset of MS and 0:20:43.080 --> 0:20:47.320 thus enables people to further believe the statistical finding that 0:20:47.400 --> 0:20:48.639 it's strongly associated. 0:20:49.440 --> 0:20:53.359 So I know that your study applies to something like 0:20:53.640 --> 0:20:57.240 a quarter of MS patients. And then, as I understand it, 0:20:58.000 --> 0:21:02.240 there's other researchers that shows similar things, quite similar things 0:21:02.280 --> 0:21:06.560 going on in other patients, essentially antibodies that bind you know, 0:21:06.640 --> 0:21:09.440 both the EBV and tamiolin. Is that right? 0:21:10.160 --> 0:21:14.000 Yes, there's several groups studying other antigens that are mimicked 0:21:14.000 --> 0:21:18.679 by EBV, including our own. And it turns out that 0:21:18.840 --> 0:21:23.840 EBV infections also associated with other diseases such as systemic 0:21:23.920 --> 0:21:29.199 loopus or SL and it's also associated with rheumatoid arthritis. 0:21:29.760 --> 0:21:32.879 So these are all autoimmune disease, these diseases where the 0:21:32.920 --> 0:21:37.520 body's immune system is attacking itself. Basically, yes, I mean 0:21:37.840 --> 0:21:41.480 is this like, are we right now? Are you right 0:21:41.560 --> 0:21:44.600 now finding the answer to this question that people have 0:21:44.680 --> 0:21:48.560 been asking for whatever fifty years, eighty years, like, are 0:21:48.560 --> 0:21:52.840 you finding the virus that is causing autoimmune diseases? 0:21:54.000 --> 0:21:58.840 We believe we are, and we are performing experiments to 0:21:58.960 --> 0:22:03.119 further bear out the mechanisms that would encompass one hundred 0:22:03.160 --> 0:22:07.200 percent of MS and as well as of lupus and 0:22:07.760 --> 0:22:10.360 other autoimmune diseases that are EBV associated. 0:22:10.960 --> 0:22:15.040 And just to be clear, in these other autoimmune diseases, 0:22:15.880 --> 0:22:19.679 what are the immune cells? What are the antibodies attacking? 0:22:20.480 --> 0:22:23.920 In the other autoimmune diseases, They're not attacking myelin' They're 0:22:23.920 --> 0:22:29.520 attacking their corresponding tissue anogens. So in loopus, the immune 0:22:29.520 --> 0:22:33.640 system attacks the nucleus of cells and also the kidney. 0:22:34.240 --> 0:22:37.640 In rheumatoid arthritis it attacks the joints. 0:22:38.080 --> 0:22:42.240 So I mean, why does this one virus, EBV, Why 0:22:42.280 --> 0:22:46.520 does this one virus cause us to make antibodies that 0:22:46.600 --> 0:22:50.120 attack so many different parts of the body, Like, what's 0:22:50.160 --> 0:22:50.639 going on? 0:22:51.560 --> 0:22:55.080 You know? I think we don't know. We only you know, 0:22:55.200 --> 0:23:01.159 hypothesize and speculate. My sense is that given EBV as 0:23:01.200 --> 0:23:05.359 a herpes virus that's present in a person's B cells 0:23:05.400 --> 0:23:08.440 as well as epithelial cells for life, and that it's 0:23:08.560 --> 0:23:13.560 transiently reactivating on a periodic basis, that those properties make 0:23:13.600 --> 0:23:19.320 it reimmunize the individual multiple times repeatedly over the courses 0:23:19.359 --> 0:23:20.000 of their life. 0:23:20.680 --> 0:23:23.600 So basically, most people get this virus when they're a kid. Right, 0:23:23.680 --> 0:23:27.040 So you have this virus not just in your body 0:23:27.080 --> 0:23:29.399 for your whole life, but in your B cells, in 0:23:29.480 --> 0:23:33.960 your immune cells, and it periodically sort of turns back 0:23:34.040 --> 0:23:37.080 on basically and causes an immune response. And it's the 0:23:37.080 --> 0:23:41.040 idea that it's happening again and again and again. That's 0:23:41.119 --> 0:23:42.520 fundamentally the problem. 0:23:42.920 --> 0:23:45.760 I think that that's contributing to the problem. 0:23:46.880 --> 0:23:52.840 Almost everybody gets EBV, has EBV. Very few people get 0:23:52.880 --> 0:23:55.880 autoimmune diseases, certainly relative to the share of people who 0:23:55.880 --> 0:23:59.520 get EBV. What's going on there? Like, why do only 0:23:59.560 --> 0:24:02.280 some people get autoimmune diseases if we all have EBV. 0:24:03.119 --> 0:24:07.640 Yeah, that's the big question, and that's why more than 0:24:07.680 --> 0:24:11.000 five years ago we were skeptics that there was any 0:24:11.080 --> 0:24:15.920 relationship between EBV and MS or these other autoimmune diseases 0:24:15.960 --> 0:24:16.560 like lupus. 0:24:16.920 --> 0:24:21.000 Well, so presumably it's sort of necessary but not sufficient, right, 0:24:21.080 --> 0:24:25.399 Like you need to have EBV and something else or 0:24:25.440 --> 0:24:30.000 in some other set of phenomenon, characteristics, risk factors, whatever 0:24:30.760 --> 0:24:34.320