The Self-Experimentation of Barry Marshall

Hi and welcome to meet the microbiologist, the podcast about the people who discover, innovate, and advance the field of microbiology. I'm your host Ashley Hagen, and today I'm joined by Dr. Robert Games, distinguished physician and professor of infectious diseases at Emory University. Welcome to the show Bob. Thank you. It's great to be here. You're the author of the book Derm Theory, Medical Pioneers and Infectious Diseases, which dives into the lives and discoveries of scientists at the heart of various paradigm shifts in scientific knowledge throughout history. Now this is the third and final episode in our three-part series featuring scientists who are highlighted in the upcoming second edition of your book. We've previously covered the life and work of Dr. Baraisanosi and Dr. Tony Fauci. Today we're discussing the life of Dr. Barry Marshall, the Australian physician who is best known for demonstrating in a rather unorthodox way that peptic ulcers are caused by the bacterium, helico-bacter pylory. We're fortunate to have audio clips from your interview and are excited to share them with our MTM listeners as we discuss Dr. Marshall's work. If you've enjoyed these interviews and want to learn more about the book Derm Theory, it will be available at asm.org/books. Be sure to check it out. Bob, before we jump into Marshall's life story, could you tell listeners about yourself? What does your day job entail and how did you become interested in writing this book? Well, as you mentioned, I am a physician in infectious diseases at Emory University School of Medicine. I have retired from my clinical duties, but I still do some teaching. The teaching that I do is now mostly on the history of medicine. I became interested in the history of medicine a number of years ago. It started when I was asked to give a talk on influenza to our house staff. I began to research for my own interests what happened a little over a hundred years ago with the influenza pandemic in 1918. I realized how little I knew about that pandemic. I began to question myself as to how we got the idea that these microorganisms actually can cause disease because in the long history of Western medicine that goes back some 2,500 years, the idea is that microorganisms cause human disease is comparatively recent. It's only about 150 to 170 years old. So I presented a seminar to my division in infectious diseases on how we got to the germ theory of disease and some of the people that made the most important contributions. I first would say surprised, but perhaps even shocked, at how many of even some of the professors that were my colleagues told me they didn't know anything about how that had happened. One of them suggested I should write a book and after a discussion with them that then head of the American Society of Microbiology Press, I wrote a book proposal which was accepted and I wrote the first edition of the book. And you are currently promoting the second edition of this book. So how did that second edition come about or what prompted you to consider writing another edition? Well, there were several reasons. First the book had done fairly well, but one of the comments I got in a reviewer of the book was that I had stopped in the first edition with the discovery of penicillin which really ended the book around the mid-1940s and I discussed the introduction of a modern antimicrobial therapy, but that's really where I stopped. And the reviewer said that there were some major shifts in thinking with organisms that were discovered in the 20th century and now the 21st century. And by adding the chapters that I have in, as you say, we have now done, we will be doing the podcast on Barry Marshall, but we've done two others. It allowed me to discuss some of the most important pathogens that humanity has had to deal with. One being HIV, perhaps the most important pathogen of the last half of the 20th century. And then with discussions with Dr. Fauci, we got into a number of other pathogens that have affected humanity in the now 21st century, including, of course, COVID. So then could you explain for listeners how Barry Marshall became a part of this roster? Well, as you'll hear, Barry Marshall did something in the 1980s, along with his colleague, Robin Warren, that really changed thinking as much about microorganisms and their effect on humans as the germ theory of disease itself. By the 1880s, the germ theory of disease had been fully accepted and for the next hundred years, medicine put diseases in two categories. They were either infectious diseases or chronic diseases. And what Barry Marshall and Robin Warren did is they began to blur the line between infectious diseases and chronic diseases. In addition, the story of what Barry Marshall really did is a golden opportunity to examine one of the central reasons for studying the history of medicine, which is to understand how does change occur in medicine. Because in my career, what I learned in medical school about peptic ulcer disease, totally wrong. And I've watched as Barry Marshall and Robin Warren tried to convince a very skeptical medical world that it had something to do with this funny shape bacteria called helical back to pylori. And that story is a fascinating one to hear. Oh, that's so amazing. I'm really fascinated to hear both from your perspective and from Dr. Marshall's how that paradigm shift occurred and how that change in scientific thinking progressed over time. So could you tell us a little bit about how you connected with Marshall and how you came to interview him? Well, as I say, I knew something about the story and I looked up Dr. Marshall. He is in Western Australia and I tried to find an email for him. And I had great difficulty in doing that. So I contacted a colleague of mine who actually works for the government of Australia. And he did some digging and eventually sent me the name or the email for Dr. Marshall as well as his assistant. And I sent an email to Dr. Marshall on several occasions and never really heard from him. And when I told my colleague, he said, did you try contacting his assistant? I said, no, he said, try that. That was the key. Because it was his assistant that made sure he saw my email. And that is when he responded. And we connected up to do an interview by Zoom, which is where I recorded it and got the audio clips that we're going to hear. That was in June of 2022. So let's talk about the early life of Dr. Marshall. Can you tell us a little bit about where he grew up and what was his educational background? So he was born in Western Australia in 1951. He was the oldest of four children. They moved around, but it was all pretty much on the Western part of Australia. His father was a tradesman. His mother had been a nurse until she had Barry. And then she was a stay-at-home mom at that point. He was a very bright student and had a boundless curiosity. One of the other aspects that I saw in his background was that his curiosity was also compounded with a certain tenacity. When he got on a subject, he was tenacious in learning about it. Eventually, he chose to go to medical school. And he graduated in the mid-70s. He did an internship again in Western Australia and decided that he wanted more of an academic career. So he moved to the Royal Perth Hospital, which is where he was when a lot of his work with Robin Warren began. So when he moved to Royal Perth Hospital, what was his specialty? He had chosen the specialty of internal medicine, and I think that fit with his personality, if you will. But he was still training. And part of the training that he was in, all of the individuals there in that program were encouraged to perform a research project each year. And he got connected up with a pathologist named Robin Warren. And who was Robin Warren? Well, as I mentioned, he was a pathologist who in early 1983 had been looking at gastric biopsies from patients who had a variety of GI illnesses, but mostly who had something that he diagnosed pathologically called gastritis. There was an inflammation in the lining of the stomach. And one of the things that Robin Warren had noted was an unusual curved bacteria that really no one had much commented on prior to that time. And it was in a series of patients. It wasn't just an isolated event. And he became rather interested, but he was a pathologist. He didn't really see patients. He only looked at the slides on the microscope at the time. So he really had no way of following up what was going on. So he was noticing these curved bacterium associated with sick patients who had gastric disease. What was the presumed cause of gastritis at that time? I know you mentioned that there has been a shift even during your time practicing medicine. What the cause was assumed to be. So what was it at that point? Well, as I mentioned, at that point in time, it was considered a chronic disease. The cause itself was not known. And there were a lot of theories about gastritis, about peptic ulcer disease, some of which were that it might be a genetic issue because it did tend to run in families. Cigarette smoking was considered an issue. And stress, by the way, people in textbooks, they wrote that stress was the cause of a lot of these symptoms. But there was no room to consider a bacteria might be involved. In fact, it was viewed at that time because of the acid that the stomach produced, that the stomach was not an area and environment that would allow the growth of any bacteria at all. Interesting. So when did scientists begin to consider that bacteria in the stomach might be the source of disease? Well, that's really the story we're about to tell because most gastroenterologists in particular just didn't think that they were just there. They were just colonizing the stomach if you saw them and that they really did not play any cause of role at all in a patient's symptoms or whatever was found on a biopsy. So Robin was fairly persistent, but he had developed a short list of patients that had had this funny shaped curved bacteria. Now, I'll also mention that if you look at the literature at the time, including Dr. Warren's first article, there are a variety of different names that were given to this bacteria, especially early on. It appeared like Campalobacter and there are reports, for example, that it's called Campalobacter Pylory, but to avoid any confusion and it took a while to sort this out. The bacteria that we're talking about is a different genus from Campalobacter and it is, I will now subsequently refer to it only as Helicobacter Pylory or H. Pylory. So Warren had this list of patients whose biopsies showed Helicobacter Pylory, but no way, as you mentioned, really, to track down the cause of their symptoms. I'm assuming this is where Marshall comes in. Can you tell us what happened next when the two partnered up? Well, Marshall was asked to do a research project and he took this list that Robin Warren had developed and I want to remind you that the bacteria that we're seeing were not at that point cultured. They were only observed on the biopsy. So Marshall took the list and began to look at over and he realized that one of the patients on the list was a woman he had actually taken care of and no one knew exactly what was wrong with her even though she had a variety of GI symptoms and he became quite intrigued and he began to look in the literature to see if anyone else had ever in medical literature going back 50 years had described this curve bacteria and much to his surprise. He found that this had been described before even though it had never been fully cultured. So he said, this isn't a completely new finding. There must be something going on with this. Oh, that's really interesting. So how was peptic ulcer disease diagnosed at the time? Well, as you mentioned, the way peptic ulcer disease was diagnosed was primarily by doing a what's called an endoscopy where a scope is put down into the stomach and often the first portion of the small intestine called the duodenum. And they would peer around and see if there was any abnormalities including an ulcer decay of the lining of a particular area of the digestive tract. And that's generally how it was diagnosed. The fact that there were these biopsies that showed the bacteria was really the new finding that he wanted to take notice of. So what they eventually did was put together all of the patients that had had issues and decided to do a study of 100 patients including the first few patients from that list and do in a pro observational if you will protocol where all the patients with gastrointestinal symptoms would be biopsy the biopsy would be looked that and importantly the biopsy would be cultured. So that really was the first step that he and Warren did in looking at whether or not this bacteria had any causal relationship to the symptoms that the patients were having. Were they able to find a causal relationship from this observational study? Well, they found a couple of things that every patient, every single patient that had a duodenum ulcer had evidence of this bacteria which we now know is H by Lori. Most of the patients that had ulcers or even gastritis on the biopsy had the bacteria as well. But a large portion of the people who had particularly gastric ulcers were on a medication or a really a class of medications that are called non-steroidal anti-inflammatory drugs or NSAIDs. A good example of that is ibuprofen and we do know and have known for a long time that that can cause a gastric ulcer. So when you eliminated patients that were on that class of medication virtually every one had this microorganism on the biopsy and the other interesting part about that is that in this first study they tried to culture the biopsy. And in the first 30 or so the microlab reported that nothing grew. Oh wow. But what happens is that H by Lori is a relatively slow growing bacteria. And when one particular plate had been mistakenly left in the incubator several extra days they found growth and they realized they realized that they weren't allowing the microorganism enough time. It was as Dr. Marshall said if nothing grew in two days the plate was thrown out and they stopped that in the protocol and allowed the plates to grow long enough to see that virtually everyone who had this organism on the biopsy if you give it enough time to grow in the lab all of them had this unusual bacteria growing up. And in their first paper on this study not only the day described the hundred patients but they also described some of the growth characteristics of H by Lori. Oh wow. You know I actually did a research project in grad school that involved H by Lori and I remember many days of waiting for our cultures to grow so now that you say that it brings back some memories but at least preliminarily this seems like pretty compelling evidence. I'm curious how the scientific community responded to this concept that the bacteria could cause ulcers. Well you might think that this is evidence for causation and it was very suggested but it didn't really tell you that this in fact was the cause. But in 1983 very Marshall decides he's going to present this association between H by Lori and Peptic ulcer disease at the Royal Australian College of Physicians meeting in Perth Australia in 1983. And I asked him about that experience. I did a presentation and the gastroenterologists didn't believe a bit of it. They sort of stood up and said, "Barry, you know people with duodenal ulcer don't have gastritis." I mean gastric ulcer has you know it's but I had done so much literature searching. I knew that they were wrong so it's difficult to tell your senior bosses trained at the Mayo clinic that. So he seemed pretty convinced, at least in the data that he was gathering, but why do you think people were so skeptical? Well, it was a really weird idea to all of the gastroenterologist present at the meeting. That it was just, he said in his Nobel speech that to the gastroenterologist, the concept of a germ causing ulcers was like saying the earth is flat. And he realized, after this meeting, that the data wasn't going to be enough, that he really had to have his ducks in a row, and that it was going to be difficult to get them to really rethink that what they thought they knew was wrong. It's so interesting because, you know, I'm coming from a perspective of now this is accepted knowledge. So when we dig into the idea of how the scientific thinking change, you know, I'm coming from it at hindsight is 2020, but we look at microbes that are flesh eating. You know, we know that this kind of pathogenesis is possible. So it's surprising from that standpoint that this was such a novel idea. Well, the gastroenterologist just thought that this H. Pylori organism was just colonizing the stomach, even though that alone was an odd idea, considering the view that the stomach with his acid was not an environment for bacteria. So it was just an idea that it was colonizing had nothing to do with with the symptoms or any of the findings that caused ulcers, et cetera. Well, in 1983, Barry Marshall made two important observations, really discoveries in many ways that would really strengthen this association. The first was showing that it was a real pathogen that just colonizing the stomach would be made more possible by show plausible rather by showing that if you treated the bacteria that it would alter peptic ulcer disease. So that was one thing. The other thing that he wanted to show and did was that instead of just colonizing the stomach, the body was making specific antibodies to H. Pylori. Meaning that the body was reacting to the bacteria's presence as a pathogen and he this idea, this finding would lead to a serologic test rather than actually having to to grow the bacteria out of a stomach biopsy from an endoscopy. You could at least see that someone had been exposed to the bacteria by a serologic test. So those two things came, came next, but I want to get back to the treatment for a moment. I've been known for a couple of centuries, really, that bismuth salts, such as bismis citrate or what we now know as bismuth subcellicilase subcellicitor BSS, which all of us know as pepto bismol had been used as a treatment in stomach disorders. Now at the same time, there were medications on the market that suppressed acid secretion in the stomach. The first really widely marketed one was a drug called simedity. And simedity, and then others, would reduce the patient's symptoms immediately, but if you stop the medication even for like a day, the symptoms would recur immediately. Whereas bismuth, not every time, in fact it was maybe only a third of the time, but if you treated someone with, as I say, pepto bismol, the symptoms would often be inexplicably eradicated, and permanently the patient would be essentially cured. And this was a conundrum that Barry Marshall was really surprised at. And he decided he would do something thinking that this was a real pathogen. He did something that is familiar to all clinical microbiologists. He had the microlab develop a lawn of H. Pylori, and then he impregnated a disc with bismuth. And he put the bismuth disc directly on the culture plate, and he did this in March of 1983. And he wanted to see what happened. So this is what he told me. I was busy in a clinical job in total medicine, and right at the end of the day before I went home, I went up to the microlab, and with the lab tech there, we opened the incubator and got that petri dish out. And there was this crisp zone, you know, about a 15 millimeter, 20 millimeter radius around the bismuth disc. And I knew that, you know, if you drink pepto bismol, you must have thousands of micrograms per mil. That's pretty effective probably. You have a hypothesis. We should be able to test it by doing this experiment, and you've predicted it, and nobody ever thought of even doing that experiment at that point. So now, Marshall is armed with the evidence that the reason that pepto bismol worked in many of these patients is that it had an antimicrobial effect of strong one, apparently, on H. Pylori. And I had asked him at one point what personally convinced him that he was really on the right track, and he told me it was seeing that zone of inhibition around the bismuth disc that told him this is the right way to consider. Now, the next thing he did was develop a test to look for these specific antibodies to H. Pylori. And as I mentioned, it ended up as a serologic test. One of the ironies of this was he began to see that a lot of people who did not necessarily have gastrointestinal symptoms had antibodies, so they had been exposed to the organism. And he was still trying to work out what the natural history of this particular disease and its relationship to H. Pylori really was. So how did he go about working that natural history out? Well, you know, when you have a putative organism that causes a disease, we'd known for over a hundred years that one of the ways to prove that this organism causes this disease is to prove Cox postulates. And to remind everyone what Cox postulates are, this was of course developed by Robert Cox, he had the idea that the putative organism must be constantly present in disease tissue that you can isolate the organism in pure culture from that disease tissue. Number three is that you take the organism from a pure culture and you induce disease when you injected into experimental animals. And number four is from those experimental animals, you must get back the same organism. So number one and two he had covered it sounds like yes, they were very clear from his his work and Robin Warren's work. The problem was they could not develop an animal model for H. Pylori. He tried many different ways, many different animals with any number of different types of anoculums and he could not develop one. He was quite frustrated in doing this. And so with that frustration, he took really quite a brave step. I got him to do the endoscopy on me one morning. He says Barry, I don't know why you're asking me to do this and I don't want you to tell me. So that was his exact words. So I had a biopsy that I was normal, no bugs or anything. The following week in July, I mixed up some petri dishes and soup, the beef soup and drank it. And then I didn't think anything was going to happen for a few years. Obviously it's a chronic infection, gastritis, you might get ulcers. But I had this acute illness. I was going crazy with this project. I was a bit over tired, I wasn't sleeping well. And I was as you've got a bad breath, you don't look well. And then I was getting up and vomiting in the mornings. I said, well, you know, I wonder if this is something to do with the bacterias on day change. I had a helicopter everywhere in there. So I was pretty excited. Yeah, he had mixed up a slurry of a h pylori bacteria and drank it, knowing that he had a normal biopsy of his stomach on, you know, before he did this. And then 10 days later, he got the same endoscopist to do a biopsy. And as he said, he had bacteria everywhere. He had done the self experimentation. So he actually got very, very sick from this also. Was he able to treat himself? Yeah, he did. He was, he was armed with the knowledge from that experiment. We talked about earlier about the zone of inhibition around the bismuth disc that he knew he could treat himself if he got sick with a pepto bismol. And he added in actually an antibiotic that he knew h pylori was susceptible to. But amazingly, he hadn't told anybody that he was going to do it. to do this that may be the person in the lab that saw him drink the slurry and told his wife, hadn't told Robin. Warren, no one. And as you mentioned, he got quite sick. And as he got quite sick, he eventually told his wife. When I'm told my wife about it, and of course she was like, oh my god, you're going to inflict the whole family. That's why you've got such a bad breath. This is disaster. So he treated himself and was very quickly cured and was fine. Do you think the severity of symptoms and also the efficiency of treatment were in line with his expectations? Or do you think either of these was surprising in any way? Well, I think he was surprised that he got this cute illness. And as I describe in the book chapter, it's probably a little too detailed to go into right here. But it helped him develop the natural history of what happens when someone gets H. Pylori often, particularly in developing world, often as a very young child, that they will get this cute illness with some vomiting. And then things will die down for a while. But he was very sick and he was able to treat himself and cure himself. This is obviously a very bold experimental approach. How common is physician self-experimentation throughout history? Well, it's been described. There are Dr. Larry Altman, who had been the medical reporter for The New York Times, actually wrote a book called Who Goes First about physicians that had experimented on themselves. But that was only about a dozen or so. And it was very detailed stories about what had happened. The major article that I saw on physician self-experimentation was published in 2012 in the journal called the Texas Heart Institute by a Dr. Weiss, who found in the last two centuries about 465 examples of physician self-experimentation. About two-thirds of which were in the area of infectious diseases, which I'd include vaccine administration, SOC actually administered his vaccine before it was licensed for use, for example. But there have been other areas such as anesthesiology, pharmacology, radiology, oncology. There are a number of examples of physician self-experimentation. And the conclusion from Dr. Weiss's study showed that despite that a lot of these were pretty unwise decisions, including a few deaths, many of the self-experiments were invaluable to the medical community and actually helped in understanding disease. And it seems that in this case, at least, we now have a quote-unquote animal model. We have a model that shows that H. Pylori is causing disease in very martial himself. Well, he did prove the Cox postulates with his work. Now, from that, however, he developed along with some other work and published in around '85 what he considered to be. And it's still probably correct the natural history of H. Pylori. And it began to put together some of the information that he had gotten from serologic studies that many patients will get it and have no symptoms or if they have symptoms, it will be noisy and vomiting, such as he got. And many times this occurs in a child who is too young to even explain what they're experiencing, that parents see vomiting, but that's really about all. Now, the organism, again, can persist and cause inflammation, either in the lining of the stomach, or as we'll see, it can produce problems in the first portion of the small intestine called the duodenum, but it will also affect acid secretion. First, it'll shut off acid secretion, but if the inflammation continues, acid secretion can actually rise. And that's when we start to see some of the symptoms that started this whole process for very martial in that first hundred patients that he was seeing. But as I say, I go into the natural history in a little more detail in the book chapter. So he's proved Cox postulates, and he has also begun to demonstrate the natural history of disease here. How did the scientific community respond to this time? Are they on board? Well, again, particularly in '85, he said that this was a particularly difficult year. Most of the time, the presentations that he made, his results were disputed or believed, and he said often not because of science, but people, even in the folklore said that no one could replicate his results, but turned out that wasn't true. He started working with physicians first in England, and then the Netherlands, and then because Perth is fairly close to Asia, he made some trips and gave some talks, and people started to try and replicate his results. The other problem that he realized was that he was bucking against a system that was really the pharmaceutical companies who made things like SIMEDADIN, or TAGAMET as its trade name is, or ZANTEC, that didn't feel there was any reason to do anything. They were making a lot of money, and they could make a patient feel better even though they couldn't cure them. But because they couldn't cure them, that meant they had to stay on the drug, and there was really no incentive for them to find a cure. In fact, in the 1980s in the United States, it's estimated that somewhere between two and four percent of our entire population was on TAGAMET. Wow, so he had difficulty gaining credibility and funding for his work, but what really changed the trajectory of his research? Well, this was a real boost from a totally unexpected source. Not long after this self-experimentation that Barry Marshall did, his friend and colleague Robin Warren had gotten a call from a journalist from a tabloid called The Star. And the journalist had read a little bit about this funny bacteria that Warren had described, and they were talking about it, but Warren then told him the journalist about Marshall's self-experimentation. And lo and behold, The Star ran a story, and I'll quote the headline, quote, "Ginney Pig Doctor discovers new cause for ulcers and the cure." Oh my gosh. Wow. Well, the story was picked up by multiple news outlets, including The New York Times. Wow. And so this was beneficial, then, to the research trajectory? Well, it did. It did a number of things. First of all, one of the things that it did was it go to the Australian Research Association, a local organization to give him some funding, which he had been really lacking. It was really a difficult thing for him to do anything, because no one really believed him. And this is what he said about his situation at the time. I had no support, no funding for a secretary or a research fellow, and it's just me. And so then The Star came out, and Robin Warren and I were getting letters from America. The word kind of got out in America that we could cure ulcers. So he ended up really doing a lot of really experimental work in curing ulcers and telling people about the regimens that in fact he had used on himself. But he still had the question, is H. Pylori really the cause of the problem? While he had proven Cox postulates, he needed to do this in a larger scale. And he needed to do it in a study that, as I say, the medical research foundation in Australia had given him a limited but some funding to do, to do a double-blinded placebo-controlled study. I had to do the double-blind study. No matter how much data I've got until I do the double-blind study, it's worth nothing. So I then spent the next two or three years doing that double-blind study. Everyone thinks you've died, because you don't publish. It's all secret and blinded. But at the end of the three years, when you get a good publication in the Lancet, everyone says you're the conquering hero. So that study took several years to do. But that star article had another boost from that source. And so what was that other unexpected source? Well, the star article had another connection, which is is that a man named Michael Mannhardt, who was a microbiologist at Procter and Gamble, saw the article and began to examine Marshall's publications. Guess what Procter and Gamble makes? - A lot of things, actually. - Well, they do. - What do they make in this case? - Peptobysmal. So he became very intrigued by all of the work that Marshall was doing. And by this point, he had moved, Marshall had moved to a hospital called Fremantle. And well, here's what he had to say about his call. - Mike Mannhardt called me a midday in Fremant. So that was midnight in Cincinnati. And I had this long discussion and a few days later I was on a plane to Cincinnati. - And Dr. Marshall said that that changed his life. - Wow. - Because in 1985 Procter and Gamble funded a fellowship and a laboratory at the University of Virginia in the United States for Marshall to further his research. And while he expected to be in the US for maybe two-three years, he ended up staying in America for about 10 years. And his research at the University of Virginia, at this point, centered around diagnostic tests for H. Pylory and Procter and Gamble with their business relationships help Marshall get patents for these diagnostic tests. - Interesting. And what were some of the particular contributions to the field in terms of diagnostics for H. Pylory? - Well, the main thing that they worked on in that time was a breath test. And the breath test used a very minute amount of radioactive carbon, carbon 13 actually, that was in a material called urea. And if H. Pylory were in the stomach of a patient, the urea would be broken down by the bacteria's urea as enzyme. And it would produce radioactive, very small amounts, but radioactive carbon dioxide, which could be detected in a patient's exhaled breath within minutes. And what that did is it eliminated the need to study H. Pylory by using endoscopy by looking at slides of stomach or ulcer biopsies and it eliminated the need to have to culture this to see if H. Pylory was present in the stomach. Now this was a game changer. - Right, so much less invasive, obviously. Breath test seems to be much more pleasant for the patient and more direct for the physician. - And what it did, I think, was it allowed multiple investigators at multiple sites around the world, really, to start looking into H. Pylory. And not only could they detect whether it was present, but they could detect the cure and the aftermath of the cure. And if the tide began to turn in 1991. Now Barry Marshall had published that double blinded controlled trial in 1988. And shortly thereafter had done the work to get the breath test out there. So there was a period from about 89 to 91 where there was a flurry of activity around the world looking at this. And as I say, the tide really, the first convincing study in the United States came out in 1991 in the annals of internal medicine. And that one stated that combined therapy, 'cause you usually need multiple agents to deal with H. Pylory, along with a acid suppressing medication called Renididine, was superior to Renididine alone in causing Duodno ulcer healing. And they said, and I'm quoting here, our results indicate that H. Pylory plays a central role in Duodno ulcer disease. And this is when things really started to change. - So this seems to be a very exciting turn of the tide. It's recognized by a large group of the scientific community. What happens next for Dr. Marshall? - Well, I asked him, when did he really feel this change? He said the tide began to turn in 1981, but when it really changed was in 1993. A BBC team began to shoot a documentary about Marshall's efforts. And he went to, with the team, he went to the American Gastroenterology Association meeting in New Orleans in '93. And with the team following him, Dr. Marshall explains what happened. - In that meeting, they were rows and rows of helicopter posters. But I guarantee there was 250 helicopter back to posters. Just follow, they put a mic on me, I think. And then I just walked around looked at the posters. And this guy said, "Oh, this is great, Dr. Marshall. You know, I really think you should win the Nobel Prize." And this is on air. I said, "Never mention the Nobel Prize, that would juke me." - So this seems like it has to be a bit surreal for Marshall to go kind of, you know, I'm thinking about this heading in the star talking about him as a guinea pig doctor to now people are talking about, you know, doing a documentary on him following him around and discussing possibilities of a Nobel Prize. Did he come in on that? Did, you know, this shift seem to impact him? - It did. And in fact, he said, again, in his Nobel speech, that 1994 was the real watershed year. In February of that year, the National Institutes of Health held a consensus meeting in Washington, DC, which after a couple of days had a statement to the effect that the key to treating Diwaddon on gastroal ulcers was detection and eradication of H. Pylori. He said, "I had been waiting 10 years for this day "and I felt a combination of relief and satisfaction "that I had achieved what I set out to do. "Years before, I had developed a hypothesis, tested, "and proved it, and now it had reached official acceptance. "So it took him 10 years "from when he personally was convinced "that he was on the right track "to really get this kind of consensus statement." - Wow, that's really incredible. - And again, we're not talking, you know, you can look back in history in the 1700s and see how long a major advance took to be fully accepted, but you could say, "Oh, well, that's 'cause people "really didn't have access to the information." It was, you know, not that long ago and people had plenty of access to that information and yet it took 10 years to get people to fully believe it. - Yeah, I think that's a really interesting point because as we're going through it, you know, and talking through this with you at each step, I'm kind of like so then did people believe. I'm sure then everyone was convinced, you know, and it's true, 10 years in the scope of scientific history is not that long, but when we're talking about this chronologically and looking at the steps and the different evidence and data to support this claim, it feels like a very long time and that's for those of us who are just hearing it not personally invested and sacrificing for that kind of change in scientific thinking. - Yeah, and I suspect Dr. Marshall felt it felt a lot more than 10 years. - I'm sure. So when was he fully recognized for his contributions? He did indeed win the Nobel Prize, correct? - Yes, that came out in 2005 and he had an interesting experience with that. In a podcast we did a little while ago with Francois Baucassineuxi, I asked her about her experience in winning the Nobel Prize and she had mentioned that there was a lot of pressure on her after that, particularly in the first year. People wanted a lot of her time, she had to learn how to devote her time to various things and there was a great deal of pressure on her to deal with AIDS and other things. And she described, especially after that first year from the Nobel Prize, it to be a nightmare. Dr. Marshall had a very different experience. - It's fantastic because you get this great publicity and it's a great publicity for your hospital and university, that sort of thing happens. All of a sudden you're right up there and everybody is getting a bit of the Nobel charisma. You're getting all this media attention. So people then appreciate you and value you. So that's great. All of a sudden you've got an easy life as far as getting things done. - Interesting. Thoughts about why they're in pression of this experience differed so much. Now that we have gone through both of their stories in detail, there are similarities in the amount of effort it took to convince the scientific community that their discovery was valid and credible. And both of these carry a certain degree of I just think personal challenge. So there's some vindication I would assume in being recognized, but I'm curious if you have any thoughts about why the impression here. Here's different. - Well, I think there were a couple of things with the discovery of HIV. There was quite a controversy as to who discovered it. And that was something that was not interlaced in Dr. Marshall's situation. But I think after she won the Nobel Prize, there were still a lot of controversies, even still are around the world about how to handle things with HIV/AIDS. And because she had been the Nobel Laureate for this discovery, there was a lot of pressure on Dr. Francois Puype's new C to intercede in places, particularly political areas, that a Nobel Prize might open a door that no one else could go through. And she felt that pressure. I don't think the same was true for Dr. Marshall. In fact, as you heard, in many ways, things became easier for him. And I think that's part of the reason why. - Yeah, and you know, this is getting a little bit granular, but as a microbiologist, I wonder how much of that is intrinsic to the fact that we're talking about a virus with out of cure, you know, bacteria, that is almost fully treatable if managed correctly. You know, there's an ongoing disease burden that's a little bit different. And so this pressure, as you mentioned, for continued research and what are the next steps and how do we eliminate this really devastating disease. However, H. Puylori does carry with it some significant complications if not treated appropriately and efficiently. So what do we know about the progression of gastric disease caused by H. Puylori today? - Well, as I, we've mentioned before, the natural history of H. Puylori can produce a variety of gastrointestinal issues. But in some patients with chronic gastritis, there are lymphoid follicles that will develop in the stomach and actually progress into a low grade cancer that is called mucosa associated lymphoid tissue lymphoma or malt lymphoma. And while this association with H. Puylori and gastric ulcers do I know ulcers and gastritis was being made a close association between this organism and malt lymphoma was noticed at about the same time. And most interestingly, in patients where H. Puylori was eradicated with treatment and several of these patients repeat. And I mean repeated biopsies showed no evidence of the lymphoma. And in one article again published in The Lancet, and I'll quote the conclusion of the article it says these results suggest a eradication of H. Puylori causes regression of low grade malt lymphoma and that anti H. Puylori treatment should be given for this lymphoma. Now this idea, along with the idea that H. Puylori causes a chronic disease led to an avalanche of looking for microorganisms that could be causing chronic diseases including numerous cancers, arthritis, type 1 diabetes, atherosclerosis, multiple sclerosis, schizophrenia, and even Alzheimer's disease. So this concept that was developed by Dr. Marshall and Warren in the early 1980s has been a true paradigm shift about how microorganisms can be the trigger for a variety of different types of diseases. - And what challenges remain when it comes to H. Puylori research? - Well, one of the things that all researchers who are even physicians that are treating H. Puylori have found that there are regimens usually of multiple drugs that can eradicate it, but it doesn't necessarily eradicate it in a 100% of patients. Some of these are pharmacological issues and unfortunately some of the reasons that the eradication doesn't occur is antibiotic resistance seems to be developing in H. Puylori. So no treatment regimen is effective 100% of a time and it would be great if we could find one that is. The other thing that people have tried to do is develop a vaccine against H. Puylori and as far as I am aware, all the attempts to make a vaccine for that organism have been unsuccessful. - So how did Marshall reflect on the process of proving misparadigm shifting hypothesis? - Well, he had a lot of people that simply would not accept it, particularly in the first 10 years of his efforts and it was rather discouraging that it was almost like people were voting. So I asked him about his thinking on the process of getting people to accept his idea. - We couldn't knock down our own hypothesis. That's the thing, be critical of your own data and then go with the data. And once you've got a pathway and you're getting facts, then it doesn't matter how many people there are out there who don't believe you. Science is not a democracy. - Oh, that's powerful. That science is not a democracy. Bob, thank you so much for speaking with me today and thank you for taking the time to share Marshall's story with us. - It was a pleasure to be here and share this rather amazing story. - That's it for today's show. If you enjoy this episode, please share it with someone who might also enjoy it. And if you're interested in reading germ theory, the second edition will be out in the spring and you can access the first edition of the book at asm.org/books right now. I'd like to thank Ray Ortega for our podcast production. I'm Ashley Hagen and I'll be with you next time with a new microbiologist for you to meet. (upbeat music)