The Joe Walker Podcast - The Nobel Laureate Who Infected Himself for Science — Barry Marshall

Episode Date: August 26, 2025

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Today, it's my great honor to be speaking with Barry Marshall. Barry is a gastroenterologist, professor emeritus of clinical microbiology. And along with Robin Warren, he shared the 2005 Nobel Prize in Medicine and Physiology for their discovery of the bacterium H. Pylori and its role in causing gastritis and peptic ulcer disease. Just to put the scale of that in context as a humanitarian achievement, about 50% of the world's human population is infected with H. Pylori. It doesn't just cause gastritis and peptic ulcers. It also causes gastric cancer or stomach cancer. And stomach cancer is

the fifth most common cancer in the world. In recent years, it's been the fourth or fifth most common cause of cancer deaths, killing about 800,000 people per year. H. Pylori is responsible for approximately 90% of non-cardia stomach cancer cases. That's the more common form of stomach cancer. It can also cause some rare stomach cancers like M-A-L-T lymphoma. But that means that H. Pylori, this one bacterium, is responsible for about 5% of the total burden of all cancers globally. So one in 20 new cancers are caused by H. Pylori. It's the most cancer-causing pathogen that we know of, more so than even HPV or hepatitis B. And thanks to Barry's work, we're now able to prevent these cancer cases through simple eradication treatment of H. Pylori. So, Barry, welcome to the podcast.

Thanks very much, Joe. Good introduction. And thank you for doing obviously a lot of homework on that. Of course. My pleasure. So I've been, I've maybe spent about a week kind of reading up on H. Pylori in your work. And I'm going to try and unload as many of my questions on you now. But first question, it's well documented that poor old Charles Darry. and struggled with dyspepsia, most of his adult life. He had stomach pain, nausea. And if you read his letters or his diary, he complains about this a lot. He and his doctor put it down to nervous dyspepsia. So it also ruined his social life and turned him into a recluse. How good is the evidence that it was actually age pylori that was causing his problem?

So that is the subject of a rejected letter to nature that a friend of my. submitted. I don't know whether I was co-author, but I knew about it. And the epidemiology is that in the 19th century, the whole human race was infected with it. And there are many famous characters in the 19th century who died from stomach trouble or had it their whole life and made them particularly cranky and intolerant. So Charles Darwin, he would have had it, almost most people had it. And he had this issue, whether he was under stress or pressured, he would get in all these vomiting attacks. And there was all kinds of theories about why he had nervous dyspepsia. The fact that he was in the seminary school and later became an atheist, you see.

So there was this thing, he used to call himself the devil's chaplain because he didn't really believe it anymore. But so that was all the Freudians, came up with reasons why he had stomach trouble and he was conflicted, et cetera. But like anything that you don't understand in medicine and a lot of other areas, if we don't know the cause of it, we say it's caused by stress because every person on earth has got stress, so you can always blame it on the patients. And so everyone said it was stress. And in his biography, of course, even Alfred Nobel had the same diagnosis with stomach aches.

stress, so-called stress. But he went, Charles Darwin's an interesting one, though, because if you look at the details, his vomiting attacks started before his boat left Southampton on the voyage of the Beagle. So on the voyage of the Beagle, he got, in quote, seasickness all the time. But you used to have to go and sit on the boat for a few days while they were waiting for the right tide and they were loading it up. So he was in his cabin on the Beagle and had vomiting attacks then, even before he went on the voyage of the Beagle.

So the story of it being seasickness is pretty much bogus. Right. And then he, on the voyage of the Beagle, he had episodes where he would be laid up for days. And everyone said, oh, that was Shaga's disease in South America and some other things. And in his whole life, he was a member of like the Royal Society, but he couldn't really travel up to London except once every 10 years, give a speech because he would just go decompensate. He was always vomiting.

He's always taking health cures like icy cold water and things like that. He even was treated on one occasion with Bismuth treatment, which probably put him into remission because it does kill the H.Polri. So they snagged a good treatment at one point. And anyway, so when he died, he was always sitting there with this great beard plucking whiskers out of his beard and mucking around. So on his desk there were whiskers. and when he died, this is what I'm told third hand.

I don't have any proof. It's not published yet. But when he died, the housemaid swept up his desk and put all these whiskers in an envelope, all these loose whiskers. And then a friend of mine who shall remain nameless at the moment got hold of some of these whiskers from the Darwin family and ran a PCR on them and they're labelled with Helicobect. pylori. So yes, he did have helicobacter pylori, and that is certainly the most likely explanation for

Charles Darwin's lifelong gutsaches. That's amazing. This feels like a scoop, right? It is kind of a scoop, yeah. That's incredible. Can you just tell me a little bit about how that that works with the PCR and the genetics? Yeah, so the PCR is polymerase chain reaction, and the coincidence is that Carrie Mullis discovered that the same year that I and Robin Warren and discovered the importance of helicobacter pylori in 1983. So it was a bit of a landmark as the new biotech started to come in. So PCR, we can talk about that. So with all bacteria, all life forms and criminals, as you know,

everybody's got unique DNA and bacteria have got a unique DNA. And so with, for example, whiskers, you dissolve the DNA off them in a test tube and check it up, and then you would put it into a polymerase chain reaction set up in a machine. And if it finds the particular sequence of H. Pilari in there, you put a probe in, and we look for that. It will amplify that little piece of DNA a million times, or a thousand million times. And then you can take a bit of that fluid out of the test tube and put it on a gel, and you can see this little band of proteins appearing. And that won't happen unless you've got an exact match.

Right. So that's why PCR, it's an amazing thing. And of course, Carrie Mullis won the Nobel Prize for that in 1993, I think, 10 years later. Right. Sadly, he passed away about two years ago. But, you know, that is probably, you know, that in the last 100 years, a lot of important Nobel's. But that would be one of the best.

Right up there. Yeah. So I was trying to find examples of historical figures who'd suffered from stomach cancer. And one of the more famous ones was probably Napoleon. So I was reading a good study of his autopsy results. And when they opened his stomach up, so he died at the age of 51. When they opened his stomach up, it was just a cancerous mess.

But if that is, if stomach cancer was the cause of the, Napoleon's death, then you could say that there was probably a 90% chance that he was infected with H. Pylori as well, right? Yeah, yeah. So when you finally get the stomach cancer, in the last few years, as the stomach cancer is developing, the helicobacter may disappear, in fact. Once the cancer has started, well, you know, it's going to happen. Yeah.

But the idea is if you have helicobacter all your life, when did you catch it? You caught it two years of age or five years of age from your mother, probably. Yeah. And then it causes irritation in your stomach inflammation all your life. And so 50 years later, there's so much damage in your stomach that you can't make very much acid. So then the acid gradually declines and eventually other bacteria start living in your stomach, like bacteria from your mouth. And actually the stomach becomes just like your colon.

You know, there's stinky putrid bacteria living there. At that point, Helicobacter can't handle it anymore and disappears. And so most people with stomach cancer have got sort of putrid gastric contents for years before the stomach cancer develops and gets them. Right. And so that's the story. And so people with stomach cancer don't necessarily get a peptic ulcer because that's related to acid. So do it in ulcer and most peptic ulcers are acidic. And that wouldn't be much of a risk factor for stomach cancer.

But the final thing when the acid is gone. Now it's ready to get stomach cancer. Yeah, I have a question on the connection with duoden or ulcers. I'll come back to that in a moment. But imagine that you could tally up deaths from all of the different types of cancer through all of human history. Which one do you think would be responsible for the most deaths? Would it be gastric cancer?

Well, people didn't live long enough to get gastric cancer. So it wasn't really noticed until the 19th century, 20th century, I suppose. Yeah, okay. So if the average life spans 45, well, most people with gastric cancer would get it after that. Yeah. So you wouldn't notice. So it's in evolution, if you like, you know, obviously if gastric cancer killed you before you had any children, well then halicobacter would have been unsuccessful.

It would have just died out. But it's very chronic and you do pass it on to the next generations. And then probably between 2 and 5% of people with helicobacter would have got gastric cancer. but I'll be conservative. I'll say 2%. That would be like Japanese or Japanese Americans. Right. Good examples.

And years ago, as I was a kid, I remember my grandparents used to get the abbreviated books from Reader's Digest. And the history of the Mayo brothers, who started the Mayo Clinic. And when they were kids in about 1910, they used to operate on their dog. You know, if the dog, they would actually do surgery on the animals around the farm and I know they operated on their pet dog at some point. But when they started the Mayo Clinic in the 20s and 30s, stomach cancer was the number one cancer in America. So that's, Mayo Clinic would have the data on that.

They'd have the records of the patients even. And a lot of gastrointestinal stuff was actually first documented and studied at the Mayo Clinic. And it was a clinic for surgery into GI problems, cancer and esophageal disease. So you can find some originals. And behind you on the shelf, proceedings of the Mayo Clinic, 1929 to 1939 or 49, I think. And I bought that in Pitt Street in Pitt Street Bookshop in Melbourne many years ago. Oh, nice.

If you look through them, you can find original descriptions of various diseases that have been in the medical books for as long as I can remember. That's cool. Yep. So it's interesting that in the first half of the 20th century in the US and Europe, the leading cause of deaths from cancer was stomach cancer. Probably, yeah. And I think it was the incidence of stomach cancer was probably more common in the West

than it was in Japan at that stage. Yeah, maybe. But then since the second half of the 20th century, it's declined in the US and Europe. what explains that for well several things so the interesting thing is that even in the 60s they you can look at stored blood samples and you can see pretty much who had helicobacter or not by antibodies in the blood and when they looked at the Kaiser Permanente collection in California they could see that in 1966 60 percent of Americans

were infected with halicobacter. Wow. 50 or 60%. So there was still plenty of helicobacter around the place, but after 1930, there was this decline in stomach cancer in the US. And then we went so, well, helicobacter's going away. But in fact, helicobacter, the decline didn't explain the disappearance. Couldn't be explained by the disappearance of helicobacter

because there was still plenty of it. And so from going from number one, one down to number four cancer in those, in that 30, 40 year period, it wasn't just Helicobacter. And it might have been that it was refrigeration of food, more fresh vegetables. So that's really what happened. And everyone started drinking orange juice and got plenty of fresh vegetables. That was good.

And Americans, so, oh, yeah, so there's some. Some studies that show that having vitamin C in your stomach inhibits carcinogens. So there's helicobacter, and what we would say, helicobacter makes everything else worse. Anything you put in your mouth hits your stomach. And so if you've got a carcinogen in the water supply or bad food or something, then if you've got a helicobacter there, that helps set you up to get stomach cancer. So we would say the better diet, fresh fruit and vegetables, refrigeration, that protected a lot of people from stomach cancer.

I see. So the H. Pylori just amplifies any other carcinogens because it eats into the mucous. That's correct. If you don't have H. Pylori, you'll always have stomach acid. And stomach acid destroys carcinogens. They just get active molecules. So if you've got some acid there, they just get eaten up or destroyed or something. I see.

So it's also interesting that as there was this fall in the incidence of stomach cancer in the U.S. and Europe, there was a commensurate rise in the incidents of duodenal ulcers. That's right. And so I read this claim a couple of times when I was reading some papers and it seemed mysterious to me, but duodenal ulcers and stomach cancer are virtually, not totally, but more or less mutually exclusive. Yeah, I was waiting for you to say that.

Yeah, so if both are fundamentally caused by age pylori, I don't understand how one protects against the other. Is it what you were alluding to earlier with the stomach acid? It's related to stomach acid, yeah. And you had asked me a question earlier about ameprosol and acid blockers and things. So it's all wrapped up. Yeah.

So that's why Helicobacter was never discovered, you see, because the main acute disease that young people, working people would get would be do it in Lalsa. And let's worry about the important things and, you know, old people get, stomach cancer, there's just another cancer, so no one was focusing too much on that. Right. And everybody knew that if you had a duodenal ulcer, you never got stomach cancer.

Or you never had stomach cancer and duodenal ulcer at the same time. Yeah. Because duodenalcer was a high acid level disease. Yeah. Stomach cancer was a low acid level disease. So why would you expect them to be connected? however so this is robin warren's insight right he's there like barry we don't let's not worry about ulcers let's just focus on this inflammation at the stomach in the stomach it's quite a puzzle

and you know i i sometimes see it even in people with juvenile ulcer so what's what's going on these bacteria are they related to it and i said okay well let's go and study that that sounds great we want to find how could bacteria live in the stomach? So this is our research. This is what you call curiosity-driven research. We're not trying to find the cause of ulcers because we could find these bacteria in plenty of people without ulcers. So he said, Barry, don't take biopsies from the edge of ulcers. There's too much healing and inflammation there anyway and means nothing. Take your biopsy five centimeters away from the ulcer, which we did. But of course we counted the ulcers and everything else we could see in the stomach at the same time but the biopsies

were not of ulcer borders and then so when the data came out the bacteria were an indicator of ulcer risk if you like and it was practically impossible to get a duodenal ulcer if you didn't have the bacteria so obviously if you ate enough aspirin you could get an ulcer anywhere and some of them would be in the duodenum so that was the other thing we found and you could get a cancer. If you had a cancer of the pancreas, sometimes it could bore a hole through the duodenum and you're like, well, there's a duodenal ulcer. So we had the exceptions that prove the rule, if you like, but, you know, high 90s was pretty normal. Yeah. The other mysterious thing is that they have noticed the toxin genes in helicobacter. And if you've got the toxin genes in

the helicobacter, you're more likely to get stomach cancer. Okay. Is that the card positive? Yeah. And you're also more likely to get duodenal ulcer. Yeah. So the Cag positive strain, which is the most virulent H. Pilari strain, that's great. That's correlated with both duodenal ulcers at stomach cancer. Yeah, so it increases your risk of both, but they're supposed to be mutually exclusive. Yeah, yeah, yeah, yeah.

So how do you work that out? Yeah. So the answer is that when you catch H.Pylori, you've got a high asset level. You're a young person. Yeah. and ultimately you get a duodenal ulcer, but there's acid in your stomachs which destroys the carcinogens and protects you from stomach cancer while you've got high acid level.

So the duodenal ulcer, if you like, is a marker for acid in the stomach and high acid probably. If you eat plenty of protein, you'll get a higher acid level. So it kind of, even though the germ itself has still got the toxin, it's causing a much stronger inflammation or, you know, statistically stronger inflammation and so you've got the inflammation means the white cells are going there trying to kill the H. Polari the white cells are the H. Pilari is not in your body, it's on your body if you're like, it's like dermatitis but it's dermatitis in the stomach or

it's like dandruff of your stomach if you could imagine that and it'll just be a bit annoying, not too bad, but over the years is gradually irritating the stomach. stomach. Now, the white cells then are trying to kill the H. Pilari to get to it, they have to separate the cells of the lining of the stomach. Now, those cells are protecting your body from the acid. And if you've got continually this process where white cells are burrowing up through and between the cells of the stomach wall to get to the H. Pilari and kill them, then it weakens the stomach wall, it weakens the acid barrier. And then, ultimately, if it's bad enough, the acid bores a hole in and you've got an ulcer.

So that's the situation. And that is why the toxin-producing H-Pylari is going to be more dangerous, more likely to cause ulcers. But with acid in the stomach, the ulcers don't necessarily lead to stomach cancer. Then as the years go by and acid level falls and you've got things happening in the stomach, at that point, there's not enough acid to create a duodenal ulcer. Because that usually means you have to be on the upper limit of, towards the upper limit or top 25% of the population to be getting a duodenal ulcer.

So people with duodenal ulcer do have higher assets than other people, but it's still within the normal range probably. Most of them don't exceed the normal distribution. Yeah. But being in the top 25% would be males and, you know, anybody could be there. Yeah. eating meat puts you up there if you have a low protein diet and you've got malnutrition or something you'll never get an ulcer because you're not far enough up the acid curve okay so then

okay so then what happens after your duodenal ulcer in quotes burns itself out because as you get older the damage acid went down a bit okay so you so i used to have an ulcer when i was 20 i was in university i was getting lots of study pressure pressure and but by the time i got to 30 i kind of didn't have to worry about it anymore, it seemed to have got better. And you're talking to a 60-year-old person. And that person has now, hasn't got enough acid to get significant ulcers, but it's becoming a cancer risk, you see. So the inflammation's there, the toxin is there, and the inflammation and the toxin, various things, damaging the stomach as you get older and leading to cancer. So that cancer is also associated with the toxin. And it's just this.

concept of inflammation for many, many years, even if it's not a malignant inflammation, can lead to cancer. And so that's been a big eye-opener. And halicobacter has been the example that got everybody excited about this. And it actually applies to three or four other, very common human diseases. Right. Yeah, H.PyLaur is, that's kind of like the textbook example now of that link between inflammation and cancer, right?

Yeah, yeah. So, okay, so in terms of resolving this paradox, of the inverse correlation between duodenal ulcers and gastritis, gastric cancer, sorry. It's really about the interaction between the H. Pylori and the host's acid secretion, yeah. So it's been known for years. See, people in China never used to get ulcers, but they would get stomach cancer. So you do have to have a reasonably nutritious diet, and so you think about it, well, not enough

protein so that means people with H. Pilari don't make enough acid. They don't make enough acid to get an ulcer. So if you study places that I've been like China, Japan, South America, Brazil, people who studied acid secretion when that was a pretty common test would find that in these countries the amount of acid produced was about 50% normal. So, for, For you and me, we might produce 28 or 30-milly equivalents per hour. If I stimulate your acid, that's a maximum. Some people would do 35, 40. So that's a healthy Western, if you like, diet male.

In Japan, when they did that study on healthy young males, it's like 17, 18, most Westerners would produce at least that. And then 20 years later, when Helicobacter was kind of on the way, in Japan, they repeated it, and in Japan they now had a bit more nutritious diet, a bit more protein. The acid secretion in Japanese males went up to like 25 or so. Right. Interesting. And so that was the 20th century, in quotes, ulcer epidemic, if you like, because Deutinole also started to get in the news because, oh, yeah, all those Wall Street guys,

these business guys in Chicago, you know, they're eating the big meals and under a lot of stress, they were getting ulcers, so obviously psychosomatic. But humans had never been so healthy as they were in the 20th century in the United States, and they're eating plenty of meat. They give you a higher acid level, and you've got H.Bolori, so, okay, you'll get ulcers. There's a lot of people wouldn't have a good enough diet to get ulcers. So the paradox is that when you get a duodenal ulcer is actually a sign of good health. because your immune system is very strong as hammering those helicobactors

are boring through the lining of the gut and then you've got an ulcer. So people used to say to me, oh yeah, well, when you have an ulcer, obviously your immune system's defective, the halicobacters are going crazy and you're losing the battle and you get an ulcer.

But it's very likely that it's the white cells fighting the H. Pilari that are doing all the damage and they're releasing all these superoxide radicals and things they used to kill bacteria. Right. And actually one of the first patients that I ever tested when I was working with Dr. Warren probably 1981, we had some smears of the mucus in the stomach and had white cells in it.

And you could see the engulfed bacteria inside the white cell. So we had a lot of evidence like that that got us a bit excited that, hey, these seem to be pathogenic. Your body hates these germs. Right, right. I just realized for people wondering what the duodenum is, it's the the first part of the small intestine that connects to the stomach. Yeah, so the lesson for stomach is that acid's incredibly toxic.

Yeah. So it needs to be in the stomach and nowhere else. And so at the top of your stomach, you've got your esophageal sphincter. And if that's working, that's great. If that's not working, well, you're going to get heart burn acid reflux, and that's another illness. At the bottom end of your stomach, you've got the pyloros, which means it's a Greek word meaning gatekeeper. So the pylorus, I think he might have been the guard at the city gates

because they had the guard, the gate there. They shut the gate at night. And the meantime, they would be taxing people coming in and out. That's why they changed the name to Helicobacter Pylori, which is the Greek possessive part of Pylorus, I think, something like that. So anyway, get back to that. So the bottom end is the pylorus. So when you're digesting your food, it's supposed to stay in your stomach and gets mixed up.

until all the food particles about less than three millimeters, and then your stomach will squirt it into the duodenum. The duodenum is right after the stomach. So the pylorus keeps the acid in. Now when the acid and food squirts into the duodenum is a little bit toxic. So at that point, you release bile, which has got bicarbonate into it, and the pH of bile is 8.5 or something. Okay.

into your intestines in the duodenum it's mixed with bile and all kinds of juice goes onto it and gets the pH neutral now so the other interesting about the stomach the the other reason you've got a stomach with acid in it is to kill bacteria and you can see so if you didn't have something in your stomach to kill all the germs when it goes into the duodenum and then starts percolating through your stomach, through your intestine over about six or eight hours, bacteria would already be there and be growing. And they'd start digesting your sugar and eat, digesting half of the nutrients in your food before you actually could digest them yourself.

You'd be filling up with gas and you'd be feeding this bacterial flora rather than yourself. So ideally, when it comes, when the food comes out of your stomach, you think it's neutralised, but it's pretty much sterile. Right. And then it has four or five hours to get to your colon. And by the time it gets to the colon, it's supposed to have all the good stuff taken out. And then it goes into colon.

It's a different process. But after that, you're sort of digesting goodies that are produced by the bacteria. But there's in medicine, in gastroenterology, if you have bacterial overgrowth, that means you've got bacteria in your small intestine, starting from the duodenum down. then you won't be able to eat sugar, you'll be lactose intolerant as well, and all kinds of

things could happen to you. So we would say that you want acid in the right place and not leaking too much up or down when you don't want it, and you want to have your bacteria in the right place as well, not in your small intestine. So in your small intestine, because you've got to absorb that food and the nutrients, you want that in intimate contact with actual cells lining the gut and they'll be taking up the fats and everything and absorbing them so only when that system when that barrier is broken down that makes you susceptible to other diseases like cholera and what have you so I'd say keep

don't get rid of all your acid if you can help it you know it's doing you good yeah good good good life advice so there's this set of observations known as the h pylori enigmas uh as you know the first of these was pointed out by holcomb in the early 1990s looking at africa so yeah the thing he observed was that there was a very high prevalence of h pylori infection yet a very low incidence of gastric cancer and since then other investigators have pointed out so-called enigmas in other regions like costa rica north Northern India, other parts of Asia. What do you make of these enigmas?

Are they actual enigmas or are they kind of illusions? It's a combination of things that you're right. It probably is correct that the African situation with Helicobacter is a bit interesting that people don't get as much stomach cancer. Now, I'd have to say that the data coming out of Africa is not really comprehensive. of, as you can imagine. And there are plenty of things in Africa that can kill you that are worse than H. Pilari,

so we're not too excited about it in Africa. However, what I can say is that I know people who worked in missionaries and things, Peace Corps in Africa and like Rwanda in different places. I think it was Rwanda. It might have been Uganda, but they reckon that one in three or one in four, African men had a scar on their abdomen where they'd had ulcer surgery because they

used to just open you up, do a bit of a few cuts in the stomach and cut the nerves to the stomach so you couldn't make much acid. So that was like anorectomy and vagotomy, those kinds of things. So you could actually end up as a bit of a gastrointestinal cripple, not able to digest your food, but a lot of the time that would stop you from bleeding to death from ulcers, if you like, can put you into remission. So ulcer surgery was very, very common in this hospital in Western Australia, Charles Gardner, where I was, we would do four or five a week on one surgeon. So a couple on Monday and a couple on Thursday or something every morning.

So they were very common to do those in Africa. So Helicobacter is not totally harmless. You used to produce a lot of due to analeses. So then what's the other situation? Well, maybe if they had access to meat in a high-protein diet in some areas, that would help, didn't collect much data, and a lot of people never lived long enough to get stomach cancer because that's going to happen after age 50 mostly.

So I'm a bit vague as to what the reason was, and people are still wondering about it. One other answer is that the original helicobacted, did not have the toxin gene. Oh, the one that you and Robin found in culture, it didn't? No, it probably did. I'm not sure about that. We didn't have genomics in those days.

But is that what you mean by the original? No, no, the original ones, you know, humans have been infected with Helicobacter for 100,000 years. No, than 100,000 years ago. Yeah, 150,000 years ago. Yeah, yeah. And so where did humans get it from? Well, they probably came out of the trees, started walking around on the ground

if I found a filthy, perfutriate animal lying there and ate it. Yeah. So, and it was probably a commensal organism of the ruminants. Ah, okay. Some kind of antelope that might now be extinct, you know, who don't know where it came from. But these bacteria that break down urea and make ammonia, they are common in the rumin of animals that eat grass.

It's one of the things that helps their digestion of the grass. so assuming that humans picked it up at that point so then when you look at helicobacter in Africa you find these African strains which seem to be ancestral strains and they don't have the toxin gene so then as you head from out of Africa to Europe you get up to 60% with the toxin gene you get to and then you get to Asia China's 99% or 95% something and so then you look around at different racial groups and migrations and you find there are some people who seem to have been separated off many years ago and don't have the toxin gene

and potentially would have less inflammation and less disease from helicobacter. Yeah, it's super interesting. So this is how we can say things like helicobacter has probably been traveling with our species for more than 100,000 years because they look at the genetic isolation of different human groups. And then they map that over the H. Pylori. And there's like a really good match. So there's a well-known model called Careers Cascade after a player career

with whom it was most associated that describes how gastritis progresses to gastric cancer. That's great. So you start with normal mucosa in the state. stomach that's the stomach lining and then you might get well so typically it's caused by an h pylori infection yep and that progresses to gastritis and then it can go in a few different directions but if you've got the um cag positive vaca s1m1 strain of h pylori you can get multifocal atrophic gastritis and then that progresses to as you know intestinal metaplasia then dysplasia then gastric cancer yep question to what extent

Is Korea's cascade reversible or is there, how likely is there that there's some sort of point of no return beyond which eradicating the H. Pylori won't cause you to heal? So I think if you have the careers cascade, if you like it, three-quarters away through it, you stop the H. Pylori and the inflammation. Most of the time the progression will stop. you're not going to get more of these islands of metaplasia in the stomach. That's my opinion, but I couldn't guarantee that there's a lot of data from it. So these are observations that I've made over the years looking down the microscopes with Warren.

And so the effect of helicobacter pylori on the gastric mucosar is very local. So you can see some helicobacter sitting on some cells and they're all toxic looking and sick. and then two or three cell widths away, cells are normal. So if you have a patch of helicobacter, you're sitting there for a few years, it could be damaging that area, and you could have normal cells nearby, if you like. So one of the problems,

when you get atrophic gastritis, the first thing that happens, helicobacter damages everything, you get the inflammation. And then I can tell you some stories about how the inflammation causes cancer. There's good data on that. But ultimately, the cells that are being damaged turn into intestinal cells. So that island is now Korea's intestinal metaplasia, a little island of it.

Once that happens, the helicopter can't live on it anymore because it doesn't stick to intestinal cells. So it's like you could say teleologically, the stomach says, or helicobacter is sticking on the gastric cells. Okay, let's replace them with intestinal cells and then helicobacter no more problem. Right. So, vocally, that is what happens. So it's an evolutionary thing, I suppose.

And so if, and once intestinal metapagia has formed, although people have tried to show that it goes away when you get rid of the helicobacter. I'm not sure it does. I just don't see the right experiments being done because you've got 250 little islands of metapalasia around in your stomach. So when Palaia, Palaio, Korea looks at a gastrectomy specimen and studies it carefully, he can find these islands of gastric metoplasia around in the stomach.

He says, oh, yeah, there's multifocal atrophic gastritis, or MAG, if you like, that's a risk factor for cancer. But if you tried to study out as a gastroenterologist and in life patients, you're going to go down, I think it might be there. you take a biopsy here, you take a biopsy there, and then you come back a year later, you try to take another biopsy in the same place, see what's happened, and you take a biopsy, and you might miss the metapleasure. It's not always an obvious which is metapleasure, and you say, oh, well, last year I biopsyed here and there was metaplasia,

and the biopsy this year doesn't show any metaplasia. So isn't that great? It's gone away since we eradicated the H. Pylori, and I say, well, you know, may have, but you haven't proven to me that has gone away because you have not taken out the whole stomach and counted it or something like he would do in a post-mortem sample. So there are some proponents. They reckon that it gets better and take probiotics in China. Someone will say take TCM, Chinese medicine. But I haven't seen, you know, it's not a proven if you like. And if I have, and if I have. I saw a medication on the market in the United States that the FDA has said, yes, gets rid of metapagia, I'd be tempted to believe it.

Yeah. Because the FDA wants to see data. They say, show us people who had 50 biopsies in 500 people followed for four years, that kind of thing. A million million dollar study. Those are the, that's the kind of evidence that would convince people that metaplaasure goes away. I don't think it does.

Okay, yeah, interesting. So you could... Prove me wrong. It's a challenge to people listening. So at the very least, around the sort of multifocal atrophic gastritis stage, you could reverse that. You can stop the gastritis and it's not going to progress as much or at all, perhaps. Yeah. And the data is that you will prevent 50% of future cancers at that point.

Yeah. But you can't get rid of the total risk of cancer once the people have got gastritis in metapalasia. One thing I was, we've talked about metapalasia briefly, is that they did a study in Stanford, no, in Harvard 20 years ago now, and they took an animal model of stomach cancer with helicobactors. So they had cat halicobactors or mouse halicobactors in gerbils. and so what they did was they took female mice and gave them a bone marrow transplant from a male mouse so that they had white chromosomes in their marrow

and then they gave them the bacteria so they developed stomach cancer and six months later they could sample the stomach cancer and say what can we find out about these cells that developed in stomach cancer and guess what they had Y chromosome in them so that means the stomach cancer comes because the inflammation triggers stem cells to migrate into your stomach.

Stem cells divide and turn into metaplasia, presumably, and the metaplasia is now the genealogy, the metaplasia, is from the stem cells. And that's what becomes malignant, if you're like. Because these are dividing cells, and they're susceptible to carcinogens. And then you can apply that model, if you like, to hepatitis B. You have it all your life, you've got inflammation,

maybe stem cells or something, and you've got liver cancer developing. So that's the cause of liver cancer. Cervical cancer, you've got papillomavirus sitting there all your life for many, many years, and maybe stem cells in the cervix lead on to different kinds of metapagia and cervical cancer. So Helicobacter is number one of all those three, but it does show that getting rid of these chronic infections, Yeah.

If you live long enough, it's going to save your life. Yeah. Yeah. So that's my understanding of it. There are all kinds of subtleties related to stomach cancer that we don't understand yet. And that's one of the areas that we would like to do fundamental research on, which related to cell biology and things like that. Interesting.

Well, at the end, I'll come back with some more questions on infectious diseases and chronic diseases. Okay. Go ahead. So can we do the urea breath test now? Okay, can I just, I just want to give you some context. Okay, yeah, I'm wondering about the personal story here. So I had never really heard of H. by Lory until last year. I'm sure I'd read it, read about it somewhere.

And I was aware of your story and the self-experiment where you drank, drank the H. Pylori. But I was in the US recording some podcast interviews last year. I was in Berkeley. Went out for a run one night and just had no fuel in the tank. So, was running much more slowly than my usual pace and got back, started feeling really nauseous. And then this developed into, I guess, some kind of gastrointestinal sickness over the next

maybe five days or something like that. And the main symptoms were, firstly, nausea. Secondly, a feeling of bloatedness, which I'd never experienced before. Thirdly, at nights a fever, a light fever. And then finally, kind of a strange, I described as like a gnawing feeling in the stomach. It wasn't pain, but especially when I hadn't eaten like a gnawing feeling, even after. You get up at midnight, open the fridge in the darkness, see the light and drink the milk. Yeah, exactly, exactly.

So I checked into a medical clinic in Berkeley. and the doctor said, I'm going to get you to do a breath test for H. Pylori. It's an incredible test. It's sublimely non-invasive. We'll demonstrate it in a moment. But anyway, I came back positive.

I don't know whether that was the cause of the symptoms or we just happened to catch it at the same time. But they put me on a quad therapy over there. So I had Bismuth-Subilisylate, metronisidol, ameprosol, and tetracycline. After about a week, I started noticing nominous and pins and needles in my fingers. Good, good blood level.

So I figured I was having some kind of side effect reaction and I stopped taking the quad treatment after the first week. But when I got back to Australia at the end of last year, I did two separate negative tests because I wanted to be extra sure, like a few weeks apart and, yeah, came back negative. So get me the name of that doctor, I'll write him a letter. Yeah, obviously on the ball. And yeah, very, very good initiative by that doctor.

But I love doing the breath test because it was so easy. And it's kind of genius how it works. So to save you having to... Thank you. I'll ask you about it in a moment, but to save you having to explain it, you can obviously interrupt me if I get any of this wrong. But H. Pylori, it feeds on the gastric urea. It uses urias to break down the urea into carbon dioxide and ammonia.

and if you feed the H. pylori, if you ingest urea, you can then measure the proportion of carbon dioxide in your breath to see whether you have HBilory in your stomach. It's breaking down that urea. But the breath test to be extra accurate labels the urea with an isotope in the case of your pie test at C-14. Other tests use, for example, C-13. And so then that gets tracked through to the carbon dioxide in your breath in your breath so you're measuring the C-14 and then that will tell you whether or not you're carrying H-Pilori so it's a cool it's cool thing well let's do the test and then I'll ask you a couple of questions so so what you have to be fasting for we say the stomach has to be empty effectively so we say fast

overnight and you don't miss your breakfast now I know you had a cup of coffee about two hours ago. It's probably okay. You still got acid in your stomach and there'll be no other bacteria. So the first thing you do is you have the pie test capsule, which is a capsule with just got sugar beads like hundreds and thousands. And on the surface of those beads, you've got a coating with a little bit of carbon 14 urea. And it's a beta emitter. So it's 100% safe and it's such a tiny amount that you don't have to worry about contamination or radiation or anything. So you're going to swallow that with a little drink of water and just enough to get it down, down your throat into your stomach and you start the timer at that point. So you want to try and swallow it

all down. So why don't you want too much water? Well, if you have a lot of water, you would dilute the urea. Oh, okay. You see, that's all. And theoretically, you might also, it might just go straight down into the duodenum and you've missed the stomach. The capsule goes surfing down and you get a low result so you wanted to just get into the stomach so right now it's probably sitting there in the top of your stomach okay and the gelatin capsules slowly dissolving yeah the little sugar beads are coming out and usually when we looked in the stomach when we were starting off this research we would find it on the greater on the outer aspect of this the stomach about halfway down the greater curve and we would find a little collection of these little beads and things probably

you're about five centimeters in diameter. And depending on what your stomach's doing, if it's just sitting there doing nothing, well, it won't be very much spread, but if you're feeling a bit hungry and you're getting a little bit of peristelsis in your stomach, that is good, because it'd be rolling those little beads around. So they now have urea on them,

which gets released into the, and it's sitting on top of the mucus layer in your stomach. Okay. So people think the stomach's like a football, but it's not. It's just like a wet, empty paper bag. You see, it's only like a football when you have a big meal. Right.

So usually the two sides of the two walls of the stomach, you're sort of contracting, moving a little bit as you do, and sort of rubbing together, and the bacteria and the urea and the capsule are all sort of rubbing around together. Oh, so that's why you want to be fasted. Yeah. And so it's a great, it's getting mixed. There's no way that Helicobacter can live there

and not be connected with the urea. Yeah. So how many minutes have you got? So we've got one half. Yeah. So years ago, I'm coming on, I'm playing talking to my boss, going from Brazil to the University of Virginia, I'm saying, it's a damn puzzle. How do those bacteria survive in acid? And I had already invented the breath this by then.

Yeah. And I think, oh, that's why it's got uriase. It's making ammonia, protects serum acid. And we went back to the lab and did an experiment. to prove this and got it published in the United States. So it's proven. And sorry, so the ammonia creates a little force field around the H-Py. Because ammonia, ammonia has a high pH.

It helps it to neutralize the stomach acid. Yeah, so H-Pylorri, it likes pH of six. Okay. Or more, six or seven, so neutral almost. Yeah. But acid is two. It's like battery acid that you normally have in your stomach. So H-Pylori is,

cranking out this urea's and urea is in your saliva and it's in your whole body in your blood it gets concentrated and excreted in your urine but it's a level of about two two and a half millimoles per litre in your blood or per hundred mils and um the helicobacter can survive as low as one milly mole and all the other bacteria will be killed in a few minutes but helicobacter is still there uh if there's urea present so that's the experiment we did so now we know why it is the only bacteria that lives in your stomach it doesn't have to have any competition from other bacteria it just lives there yeah and it doesn't have to have all these complicated enzymes and special mechanisms that e-coli has because that lives in the

colon it's really competitive there's no competition to h pylori's as i'm just a dumb little bacteria just make urea's pretty easy yeah it's got a monopoly on this yeah yeah so it's drinking time isn't it uh three and a half minutes yeah so oh i'm you're going to take your second drink of water now. Okay. So why do I do this? So if the bacteria was stuck in the, if the capsule was stuck in the esophagus for some reason,

if you hadn't swallowed it all the way down near the stomach, by now the capsule would have felt bits. Okay. And this will just make doubly sure that the bacteria is, the capsules in the stomach or the urea has gone in. Yeah. So the first ever urea breath test was Trimed's pie test, right? Yeah.

That was the work I did in the early 90s at the University of Virginia. Can you tell me the story of coming up with that? Yeah, so it started off. I was thinking about Helicobacter, as far back as 1984, and I developed a biopsy test, which is also based on urea's. The clothe test. The clot test. Yeah.

So I was working with that, and then I thought, well, it's a hell of a lot of work for me, actually. actually to do endoscopies on everybody all the time. If only I had a non-invasive test. So, okay, serology. So we started doing antibody tests. That was great, but it was not specific enough. I thought, oh, well, if I gave you some urea, I wonder if the bacteria would produce enough ammonia to be detected in your breath. Not ammonia in your breath, but what I did some studies, and we found that if you had helicobacter, you did not have any urea in your gastric juice.

It all been used up. So it comes in your saliva and it's in all your fluids. But if you had helicobacter and we sucked out some juice out of the stomach, there's no urea in it, just ammonia. And I found some ancient literature in the chemistry books about how some people had urea in their gastric juice, and some people had ammonia in their gastric juice, you see. and you didn't have both. So I said, oh, two and two makes four.

Okay, obviously these people had urea. So you could look at old chemistry books and you could see the people had H. Polari. It was a clue. And so I then got hold of some carbon-14 urea and I got a protocol at Royal Perth Hospital then. So that was 85. But I worked that out a few months before that.

And all the doctors, I worked with then, it all been, most of them were deceased, but Iva Surveyor was a great guy and he was the head of nuclear medicine. And his second in command was Professor Agatha van der Schaft, so she's retired and a little bit elderly now that I met her recently. So they're like, oh, Barry, we've looked at the books and it says that, you know, Uri-A's is present in people's stomachs and everybody has a raise the time, but all right, we'll try it out.

so we gave some isotope carbon-14 urea which which i had by then and i think the first person to do it was professor agatha vandersharf and we're one of those naughty things where we didn't do uh ethics committee or something because the ethics committee would have come back and said agatha what is should we approve this she says yeah it's me i'm the volunteer um anyway self-experiment yeah sort of a self-experiment anyway so she was negative um and And then we then did get approved, Dr. Fox was the head of nuclear isotopes then, and he approved it. We did about 20 people and 10 were positive and 10 were negative.

And it just worked like a dream. Yeah. And so we found out that equating it to the doses that we give now, so we were giving 10 times as much carbon 14 urea in those days because that was what they were used to using and even that's a tiny dose but compared with what we do now so the the negative people were giving a result of zero or five counts in the breath sample of radioactivity that's so close to background and if they took the pill the c14 urea was giving them accounts of about 2000 and so many times in medicine, you know, like, it's normal if it's like 3.6 and it's abnormal if it's

4.6. It's like 20% difference. That's the sort of thing we're worrying about. So to have a diagnostic test, which is potentially 10 counts or something and then 3,000 counts. If it's positive, everybody gets a bit excited about that. The patients, my God, 3,000, you know. So it was a good one for the doctors and the patients. It was pretty much black and wine. if you like, by that I mean is that if you were positive, it was up through the roof. And the beautiful thing is after you got rid of the helicobacter and went back to normal, it had come down to 10, it was zero. So it motivated the patients.

They said, boy, those antibiotics are really worth it. And so in those days, I used carbon 14 because we didn't have any carbon 13 technology at Royal Perth. It was a stable isotope, and you had to put it through a mass spec. right the technology really moved on and so by the time we commercialized the breath tests they were both were on the market and uh the carbon 14 was the easiest it still is the easiest and potentially least expensive i see so for developing countries and many countries they embraced the carbon 14 so right now um in china at least 20 million tests a year would be done using that i don't know what it is yeah several several people do it

so we're at nine minutes 30 here okay okay so what's been happening in your stomach is the capsule is like spreading around little granules the urea is reacting or not and you told me that your recent tests were negative so probably we'll get a result on you like 15 counts 20 counts something like that

but if we graph your carbon 14 excretion in your breath it will peak at about 15 minutes. So I don't care whether we did it at 10 minutes, 15 or 20. It's going to give the same result. We chose 10 minutes because that's as good as the other numbers because the results are already, if you're positive, the results are already sky high at 5 minutes. But the occasional outliers might take 10 minutes or so. So 10 minutes is a good time. And so that's routinely what we do. But if it was 15 minutes, it would be the same. Okay. so at this point you are going to give me a breath sample okay and if the helicobacter is there

some of that isotope urea has broken in half and released CO2 and it's only a tiny bit of CO2 but it means that the isotope will be coming out in your breath and a tiny bit of the CO2 you breathe out like a millionth of it will be an isotope one and that will give us a positive of result. So I've noticed with other breath tests I've done, the ones I did at the end of last year, they took a baseline sample as well. But you don't really need that. So the baseline on carbon 14 is zero. It's always zero. Yeah. But the baseline on carbon 13 is 1%. And so it's a naturally occurring isotope. And it's, if you eat a lot of corn, it might be 1.5% say. And so that would cloud, that's too much noise for the result. So you have to take a baseline.

line, it's not going to change in an hour from your baseline unless there's helicobacter. And it would go from 1.1% up to 1.12%. So that tiny difference is what you measure with carbon 13. So that means all the tests I've done have been C-13 tests. So this is my first pie test. Yeah. So the C-13 test, you would do 20 minutes at least. Yeah, so move the straw in and there is a self-sealing balloon.

So let's push it through the hole. Yeah, push it down there. It'll slip down into the... balloon, push it down. Okay, so now what you're going to do is, wait a minute, I'll give you some instructions. Yep. So we want lung ear, not mouth here. So I want you to take, say, two breaths in and out, and then one big breath in then and hold it.

Okay, this time breathe in, and you're going to hold this breath. Now hold it. Don't breathe, and we'll count for 10 seconds. 10, 9, 8, 7, 6, 5, 4. four, three, two, one. Now, blow that breath straight into the balloon until it's full. Okay, now at this point,

pinch it off at the bottom with your finger and pull the straw out. Okay, so a little bit of it leaked down. Is that saw or not? What you're going to do is tie that in or not. Okay. It's a simple granny's not. It is self-sealing.

So we need a leiter, and we probably got 1,500 mills. the 50 or something. Yeah, so when you hold your breath, that means you're getting lung air and we'll get a good concentration of CO2, 5% or so. If you were like taking several breaths, like ha ha ha, ha, like that,

a lot of the breath that you're breathing out is stuff you just breathed in and it's in your trachea or your mouth. So from that breath sample, we want one millimole of CO2. So we're going to take that breath, we'll bubble it through an alkali solution, like it could be sodium hydroxide, but it's something similar.

And that will suck up the CO2 out of it. And it'll collect the CO2 till we have one millymol of CO2. So if we had two millymoles of CO2 in that balloon, the test would only collect one of it. Right. And then we say in that one million mole of CO2, how many counts do we get? So that equivalent, everybody's the same at that point. Whether you're a little person or a big person, we collect one million mole of CO2. And in that millymol of CO2, we see how many counts we get per minute.

So it's hard to imagine how many atoms there are in a litre of anything or a gram of something. It's like 10 to the 20th numbers, possibly big numbers. So one in a trillion atoms in your body is carbon 14. So you have it naturally in your body. So now when we give you some carbon 14 there, we've effectively doubled the amount of radioactivity in your body and it passes out in your breath in the urine in 24 hours. So that's why it's safe because carbon 14 lasts for 5,000 years,

but it's continually passing through your body. And we're only measuring the occasional ones that liberate an electron. So that's called beta. Beta emission. It's not like gamma rays. it cannot penetrate your skin or paper or anything like that. That's why we need to collect a sample. And every single carbon 14 atom in that balloon is going to be detected by the breath.

So if we're counting a thousand, that's incredibly small amounts of carbon 14. Right. Because there's millions of them. So anyway, so the technique of counting carbon 14, you know what that was invented for. don't you carbon dating okay you know so if you dig up you know 10,000 year old bones from somewhere you carbon date them right because they're releasing a little bit of carbon 14 tiny amounts so that that's how sensitive the carbon 14 technology is so that's amazing and that's why when we put it through

the FDA there were some people a bit alarmed about radioactivity but when we when you do the calculations and you get down to the fact that it was a background and you get a breath test every time you go on a plane, every hour in a plane you get a breath test equivalent and no one worries about it. You get the same amount in a day of background. And the other funny thing is that the radioactivity in your body is not only carbon 14 as potassium.

And potassium in your body releases gamma rays. So if you sleep in the same bed as your partner, you're getting gamma rays from your partner, your whole life. Right. And that's about 15 breath tests a year. So you can't avoid it. Yeah.

And we, you know, we went into all this detail. And people who, the average person receives 300 in US units, that's mili-rams. So that's like a thousand breath tests a year equivalent, just from normal. If you live in Denver, it's twice as much. Right. because it's an altitude. So all those things, you can do the calculation. So the radioactivity and the breath test is much less than a dental x-ray.

Okay. So don't stress. We don't worry about children or pregnant women or anything like that. Okay. And the FDA has had a big meeting about it and signed off on it. So people, there are people who are still paranoid about it. But you can do quite a few tests. You could test a whole family in half an hour because it's only 10 minutes.

You do them all at once. It's completely safe. There's absolutely no side effects. You can send those balloons through the mail, everything. So if I give this to Alfred, will someone actually measure this for me? So try mid. You can on your way home, stop it on the way to the airport, if you like. Stop in and they'll suck the air out of it and run it through the machine, which only takes five minutes or so.

We'll organise that. But for people wondering what my results are, I'll post them in the comments. I'll give a guess. I'll say 15 counts. Okay. And that 50 is anything less than 50 is negative. Yeah. Be awkward if I'm positive. Well, if you're positive, that's a bit of a strange thing. I think that'll be unlikely after my... Are you married? I'd have to find your partner and test the partner because it's the only way you could catch it. Well, my girlfriend did a test after I did mine and she was negative. Okay, that's good. Yeah. So that's the chance of, you know, spreading to you. partner is over a few years is 50% as far as I can tell.

So I can have my second coffee now. Yeah, let's go for it. Cheers. This episode is sponsored by Eucalyptus, the Aussie startup providing digital healthcare clinics to help patients around the world take control of their quality of life. But this message isn't about Eucalyptus's products. You see, Australia stands at a crossroads. The world order is unraveling.

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bonds with colleagues. So if you're an ambitious young person, wondering what to do with your career, while your decision is a deeply personal one, let this message plant a seed in your mind. Consider joining a well-funded startup like Eucalyptus or any other excellent startup. You can check out Eucalyptus's open roles at eucalyptus.comhealth slash careers. That's E-U-C-A-L-Y-T-U-T-U-S. dot health slash careers so you mentioned the clow test which was the earlier test you developed clow meaning yeah campbellabacter like organism yeah which that was the original name for hpilor until 89 yep and the clow test was was for testing for uriase and gastric biopsy samples yeah um so i was reading that when trimed u.s.a eventually bought the manufacturing rights to the

flow test. You wanted to try and keep the manufacturing in Perth to build up the industry here, but that effort ultimately founded. And I was curious what that experience taught you about either the difficulties of manufacturing generally or the difficulties of trying to manufacture in Australia or Perth specifically. So it was great. We had good support in Western Australia. And at that point, Technology Park near Curtin University was starting up. And that was a biotech incubator, if you like, and a company there, Delta West, who mainly made transfusion water and things like that, plus a few creams. But they did have some good equipment and some smart chemists.

They actually optimized this test. So it was a little test, a little bit of gel. And you take a biopsy sample at endoscopy, and you stick the biopsy in this gel. And if ammonia is produced, it's like litmus, if you like, goes red from yellow to red. So the beauty of that test was the gastroenterologist who believed in H. Pilari. At that point, nobody believed it except a few fishinados, if you like. But if I was interested in it, but my hospital microbiology didn't believe it or my hospital pathologist didn't believe it, they wouldn't give me the diagnosis. But if I was a gastroenterologist with this

little test, I could just put the test in my pocket after putting the biopsy in and look at it 10 minutes later, and if it went red, I've made the diagnosis very accurately, you see. So the positive predictive value, which means if the test goes positive in, say, 20 minutes or so, it's 100% certain that you've got the germ. Right. And patients like to look at the nice red color developing. Oh, my God, I've got a lot of helicobactors there. So it helps motivation.

And so it really took off. And so the beauty of it was you didn't need a lab or anything. other people to treat, diagnose and treat helicobacter. But to see if you were cured, I had to do another endoscopy on you, which is a lot of extra manpower, if you like. But of course, if I'm a private gastroenterologist, there's money in the bank. So gastroenterologist thought it was good. But obviously question about that was the first test and it was made.

I know what you mean. Yeah, so what did it teach you about manufacturing? Yeah, so the story about manufacturing and that. So I remember that I had, I was excited about it and nobody else was. But I showed it to my good friend, Rod, has been my business manager in Australia since the year dot. And I said, you know, Rod, I reckon we could make this test for five cents and probably get 25 cents for it. And he looked at it and he said, well, Barry, I think you could probably get $2.50 for it. so together we then connect up with Delta West and they did the patenting and did that hard work

and so after a few years the issue with this product was it was a refrigerated product and when we shipped it to America we would have a refrigerated box which would effectively double the manufacturing price to fly you know 100 kilos of these tests maybe We do 50,000 tests in a box, but it had to be a refrigerated box, and that would go out maybe once a month. And then if the flight was delayed, it might end up in the summer in Chicago on the tarmac and the refrigerator failed or something, and 50,000 tests went up in smoke. They would deteriorate.

So we used to fly them to Chicago, so they arrived at midnight, and they would straight away. get onto a truck. And if you drove them down to St. Louis, which was our distribution center, it was Kansas City, I think, actually. You'd drive them down in the night. They'd arrive at 6 o'clock in the morning. It was still nice and cool, and then they go into the fridge. So that's how we solved it.

Yeah. But it was a bit of a hassle, and the people who were our distributors in the United States said, well, Barry, I've got a big company. ultimately it was Kimberley Clark who makes all the world's tissues Kleenex and the problem was that I would by then I was I had a little company that I was a shareholder in that was doing the distribution doing pretty well and the problem was if Delta West sold it to somebody else I would no longer be connected to the distribution

and so my mates would you know all that hard work that they'd put in into releasing it in the US, it'd be lost. And so we said we should buy it. So my mates in America got some money and bought it. And then ultimately resold it to Kimberley Clark. And so straightaway they had the pie test and the Clow test and all the investors got their money back at that point. And the West Australian investors got seven.

million US for selling a machine that makes them, which is a robot manufacturing robot built in Perth by a guy Peter Clark. He often works for the government. Now he's pretty senior, but he's sort of a government advisor on technology. So thank you, Peter. So built a good machine that could produce a million of them a month or something and shipped that all over. to the United States and then it was made in the U.S. That's where most of the sales were at that point. So that was good. So at that point I actually returned with my family back from the U.S.

I had a bit of a bankroll and paid for my house and all that kind of stuff and started working in HMRC funding. So it got to the U.S., but it's not like they snuck it away from us. They paid through the nose to Delta West. to get that money. Yeah. To get that facility moved to the US. Yeah.

And that was so, it wasn't that we couldn't produce it, produce it or create the technology because they just bought the machine, shipped the machine out. So whenever I see this story about poor Aussies, they've been rorted again by the new discovery is now being made in tech, in the US. You need to delve a bit deeply and say, well, who owned it? And what did they pay for it? Right. And were Australians prepared to pay that for it?

And they were not. To get $7 million out of Perth investors, be pretty hard. Yeah, that's not bad. I suppose you could have floated it on the stock market, maybe. People, people did that. But there's a bit or a lot of rorting goes on with that kind of thing and overhyping. And that also happened with CLO test over the years, various ownerships and things. in Australia and there's I I felt that there was a bit of rorting that went on but I was not

party to it I used to read about how fabulous it was and I said wow did I do that when did I do that that's funny so it sounds like the main constraint on manufacturing in Perth was just the geographic isolation of Australia it's like any time you need to transport things cause a huge difficulties yeah so one of one of the reasons I was one of the many reasons I was very excited to talk with you is I think there are so many meta-scientific lessons from your and Robin's story

and one question I was asking myself was why wasn't H-Py-Lory discovered earlier than 1979? And I was reading through the book you edited Helica Back to Pioneers, which it's actually an excellent

just case study in how science works Because you have, like for about a century in different places around the world, you have, it's kind of like research is feeling the elephant from different angles. Exactly right. Putting the story. Exactly right. And you get that in this because each chapter's a different, a different story and the larger story of discovering. So I kept meeting people all around the world who told me that their father had discovered H. Pi Lorry or whatever.

It's funny that the chapter titles are like, H. Pylori was discovered here. H. Pylori was discovered here, and you get all or most of the heavy hitters who are still alive to write chapters. But so I was using this book, and I was trying to, so there were four clues to the existence of H. Pylori, which if you put them all together, you could have deduced the existence of the bug without laying eyes on it like Robin did. And the first clue was endemic hyperchloridria. Then there was the presence of, the existence of gastric uriase.

and then there was this kind of strange result that we could treat gastro we could treat peptic ulcer disease with antibiotics and then and then the fourth clue was that there were spiral bacteria in the stomach yeah in different mammals but but then by about 1940 we'd seen we'd forgotten about them we'd seen them in humans but so I was trying I was trying to work out how big was the window in which all these clues were overlapping? Looking back on it, what I would say is that there's new technologies continually being invented. And they might be invented for problem A. A good example would be cell phones, right?

Okay, you need to talk to people when you're away from home. Okay, cell phone. But of course, 90% of the use of a cell phone is for everything else. You know, it's an alarm, it's a body monitor, it's getting information on the internet, watch your movies, you know, all that sort of stuff. When I've got my first a Motorola flip phone, 1993 or something, I said, this is great. I can make phone calls from my car. Yeah, so that was about it.

So now, so that also happened in gastroenterology. Yeah. And so, and also there's things that happen like there's World War I, there's World War II, And scientists pushed hither and thither, kicked out of the U.S., for example, and now they're somewhere else, and they changed. So all these things were happening. So if you look back on it, you talked about antibiotics. Well, Bismuth, which is one of my patents as well, I discovered that Bismuth kills how like a back down a lot of other bacteria. Right.

That had been used as a component of antacid mixtures for 200 years. So people in England were taking it in 1850. for stomach aches. We don't know what causes stomach aches. Including Charles Darwin, right? Okay, Charles Darwin sometimes was taking Vismuth. Yeah, yeah. But because it was not scientific.

Nobody knew that it was a good for bacteria. But in fact, it used to be used to treat syphilis. It was painful. You get these Bismuth injections with black stains on your buttocks. But Bismuth was sort of a recognized antibiotic, but why would you want to use it in the stomach? Why would it be important to the stomach? No, it's an ant acid as well.

So that was that one. The next one was spiral bacteria in the stomachs of animals. Yeah. So that was published in different places in German literature. So if you went and told me that bacteria can't live in the stomach, I would say, well, acid there, obviously. But I haven't read that German literature from 1890 showing pictures of all these bacteria in dog stomachs. So that was business error. Yeah, so it was like the inflammation didn't flow very easily in those days.

Yeah. They would be held up by the different languages. Right, right. So we talked about the bacteria. The next one was the urease. Neurias had a fabulous history in chemistry. It was the first enzyme that was purified. And it was shown to be a protein.

Before that, they didn't know what enzymes were. And it was found in the dog's stomach also. And there was a guy called Murray Luck. we did all kinds of urea's experiments. It was discovered in 1925. Yeah, Luck and Seth. Yeah. And they did a book about uriads in the dog's stomach.

And they said, oh, you know, we think that it makes ammonia, protects you from acid. Because we find all the dogs have got this ammonia thing in their stomach. And then in Oliver and Fitzgerald wrote a thesis on uriase in human stomachs. This is the Irish group. Yeah. And they said, oh, obviously it protects you from acid. have the urea's that's produced by your cells and the ammonia protects you from acid. Yeah.

And they even developed an ulcer treatment where they were feeding people urea to generate ammonia and neutralize the acid. So it's like an antacet. They said, we'll take urea. You've got the urea's enzyme. But, of course, they would throw up. Urea is like eating, chewing tinfoil. It's horrible stuff.

So it sometimes healed fearful, but it was toxic to take. So that was Oliver Fitzgerald. He ultimately became the president of the British Society of Gastroenterology. So he was, like, famous. But that was his thesis. And then in America, these guys, Lieber and Lafever, actually they were Belgians, I think. They studied urea and urea's and ammonia in the stomach. And they showed that if you took tetracycline, it went away.

Right. Which is an antibiotic. Yeah. So they said, oh, it's probably caused by bacteria. End of story, blah, blah, blah. Let's go on and do something else. And I actually met Dr. Leva years ago. He's since passed away and had this discussion with him.

And a lot of Belgians used to do this. They would stick a tube down your throat and suck the acid out. How much are you making? So they could do these kinds of experiments. But nobody picked up on this. So what's the thing that happened? Oh, and then endoscopy started. Yeah.

So the story is that wouldn't be great. great if we could look in the stomach, see if you've got an ulcer or something. So everybody used to have barium meals and you would swallow the chalky medicine and they would tip you this way and that way and they would see like a very primitive kind of low resolution black and white negative image of your stomach. And they could say the wall of the stomach's got a hole. It looks like I've got a hole in it. So that's probably an ulcer or the duodenal ulcer. So that was the diagnosis of ulcers in those days. If you had less than an ulcer just gastritis, where we couldn't diagnose it very well.

So then to look in your stomach, you used to have to use a straight tube, like a sword swallower. Oh, God. And they would, like, poke this tube down. So this is the technology from the 30s onwards. And we used to do that at Charles Gardner Hospital when I was a thoracics registrar,

and you'd look down this tube and you'd have a bit of a mirror on the end, you'd move it this way and that way. It was pretty difficult to do. So the patient would be strong. struggling and gagging. People holding them face, holding them down. Anyway, so that was that.

So when you had flexible endoscopy, everyone says, hooray, now we can just look in the stomach and you don't have to have an anesthetic and you just gag a couple of times and we'll look with this fibro optic gadget and we can see you've got an ulcer. So there's a technology. It's now invented to find ulcers, but they don't realize there's a hundred other things you can do with that. technology and Robin Warren's there. Why don't you take a biopsy? We'll have a look at the inflammation

and we're, what do you know? We found bacteria. So Warren and I, we were the only gastroenterologists in the world who were taking a biopsy off every single patient we ever saw. And so by the time, you know, we put the whole thing together. We had 1,000 patients, 2,000 patients, 3,000 patients in our repertoire to, you know, test it out. And everyone, when we were, you know, we started talking about it, everyone said, well, how can you be so certain? You know, it's just a new thing, and you seem like you really know it. What's been going on in time? Well, we've been doing it now for three years on thousands of people and treating them

with antibiotics. Yeah. So we got pretty cocky about it at that point. So what I'm saying is there's a convergence of different technologies that made us realize it. Now, the fourth one that is really fabulous is that I think it was like 19, In 1979, Jimmy Carter and the National Library of Medicine put the index medicus. That's all the medical journals every month went on the internet.

So they had primitive internet by 1980. At that point, Robin Warren and I are getting together, 1980, 81. The Royal Perth Hospital Medical Library got a telex machine, and we could query the international literature, month looking for things about stomach and bacteria and gastritis and cancer and we would send off a request and a day later we'd get a printout with different publications so we started to see what was going on in the world so it was medline medline medline yeah and then uh in and sorry that's um it would only tell you the it would only give you the citation and then you would have to

go find the physical so we would say here's a citation and we would send back give us the abstract And then if we wanted to actually see the whole paper, the Australian National Library would have it. Oh, okay. And they would photocopy it and send copies. So we were like doing internet research remotely. So it delayed the period. It was like two or three weeks before you got anything back.

Okay. But overnight you would get the abstracts. You might get the brief abstracts and you might get the title. From the computer. Yeah. Yeah. And you'd say, oh, you'd say, number 26, give me that. And then they would, Royal Path Hospital Library, would get through their connections and then get it back.

And they would sometimes get faxes from America or Switzerland or someplace. So we started doing proper research at that point. And the thing is that I think eventually might have been Clinton said it's free. Previously, everyone was getting a subscription to this thing because they were getting these like big telephone books every three months full of all the literature citations in medicine. And you would have to troll through that. Eventually it was online, and then they said, and it's free. So you still have to pay your telephone bill,

but you could download 100 references if you like, and you could actually see text on your little screen by the 80s. So that really helped. But early on when we were just doing it by TALIX, that's how Robin Warren and I found all these things in the literature by helicobacter pioneers. So you'd say, well, I wonder if dogs have it. And then you'd find the report in dogs. And we found several doctors over the years who got excited briefly about helicobacter

but really couldn't get the traction, if you like, to do further research on it. And the surgical PhD in Oxford that I spoke to, I can't remember his name, but he applied for a research fellowships to do more study on these bacteria that they had seen and he was knocked back. So he went off and did something else. But by the time we found it, it was starting to rise up from the ashes, if you're like, you could see little seedlings of the discovery popping up around the world. And if we hadn't done it maybe by five years later,

it would have been exposed by somebody in England probably. Yeah, you often see that in the history of science. So it's a convergence of these technologies, the Internet, pulling back all these other bits of information into one place. I see. And there's some fantastic examples of stuff that we dug up. Yeah. And one of them was a post-mortem study in Minnesota,

where this nerdy pathologist had studied, done post-mortems on traffic accidents. Now, in Minnesota, if you're driving to your farm and you have a traffic accident, you just freeze to death in your car. And so that when they do the post-mortem, you're frozen solid so that you kind of thore out. And it's just like doing a post-mortem on a fresh specimen. if you like. So they actually saw all the inflammation and reported it. And they reported that whenever they found in a young person a duodenal ulcer, they always found gastritis. We don't understand this. The ulcer's in the duodenum and the gastritis is in the stomach.

So what's going on here? So when people came along to me and said, Barry, you know, people with duodenal ulcer don't have gastritis, the lesions in the duodenum stomach is normal. I'd say, well I know something you don't know there's this study from Minnesota 1952 that people have forgotten about and they'll say 100% of people with duodenal ulcer have gastritis right so I got pretty cock cocky and pretty annoying I suppose to everybody else you have the data yeah yeah so that's the answer get more data and I often get that question you know Dr. Marshall what can I do to I get this thing accepted or whatever or get this

drug through the FDA, I said, just get more data. They are only interested in data, those people. They're not human beings at all. If you go broke, commit suicide because you've failed, they don't care. It's such an interesting, such an interesting case study and just how science works. Because just to circle back to my earlier question when I was wondering to myself, why didn't we discover it earlier? and maybe of those four different clues,

maybe the latest one was the presence of gastric urias. So, I mean, obviously luck discovered it in 25, but then it's not connected to ulcers until the late 40s. Yeah, and bacteria in the stomach, they proved it in the 50s. Yeah, yeah, exactly. So if you take, say, say you say, okay, from the late 40s to 79 is the window where all these clues are coextensive, it's about three

three decades give or take you know why wasn't it what were the constraints operating in that period that prevented scientists from joining the dots it sounds like correct me if I'm wrong

but the literature the literatures were just so disconnected you didn't have a unifying hypothesis you had four or five different divergent bits of information yeah and the librarian

of Congress was this guy Joseph, I forget his name wasn't Joseph, but his name was Boston, Daniel Boston, I think. And he was the librarian in the US Congress and he wrote a lot of books and everything. So he said the delay in the discovery, the reason we don't make these discoveries is not ignorance. It's the illusion of knowledge. So the overriding thing is everybody knew ulcers were caused by stress. End off story, take you, tranquilizers. And so I'd say, well, in retrospect, if you get pain in the stomach every time you eat a meal,

you know, we rely on food to actually calm us down and make us feel better. If you haven't, if you don't have that, you could feel pretty stressed. I know I would be. So that's one thing. So the other thing is that once you have a unifying hypothesis, you can test it in 20 different ways by looking for information in the literature. And so we were able to do this. And so by 86, 85, if you like, we had pulled all this literature together and see how it fits.

And a lot of that literature was never, ever online. We might have found it in a veterinary book. I found this a lot of stuff about urea's and urea in cybergagi scientific tables, which is a book of tables, you know, how much sodium is in your blood, how much sodium's in your urine, is in women and men and children. And so one of the things they had there is how much urea is in gastric juice. I could look at that. And looking at that data, I'd say, right, I'm going to make a breath test now.

And it's going to work because I can see this. But it confirmed what we had found. Maybe I saw the cybergigia urea data first and then went out and tested for patients. Yeah. So once you've got a unifying hypothesis, you can test it in the literature just from information. And I say there's quite a few Nobel laureates who won their Nobel Prize from reading other people's scientific data.

Like Carrie Mullis made the discovery just, you know, with a thought bubble when he was driving his girlfriend up to the ski resort on the weekend. Yeah. So he was the discoverer of PCR. He discovered it in his brain. Yeah. And went and did like one afternoon, one afternoon research to test it out.

Yeah. So Warren and I were kind of like that. Yeah. So I said, why don't, I've talked to Robin, why don't we try treating this patient with tetracycline? Okay, so that was our first patient. And then it was like, I said, you know, I've been looking at this literature and this guy in England.

He's done this study and chose that if you take, bismuth treatment for your ulcers, the recurrence rate is only about 50% versus 90% if you're taking acid blockers. I said, you know, it could be our bacteria there and bismuth might be an antibiotic. That's interesting. So of course, then I got some bismuth and tested it. It was the best thing for killing helicobacter pylori. It was like penicillin. And it was an ulcer treatment already on the market. So it actually accelerated things. So that was, The eureka moment, right, in 1983 at Fremantle Hospital, we grew the Helicobacter, and I got hold of some bismuth medicine. And I actually had Pepto-Bismol, which is a pink stomach medicine

that's been on the market in the supermarkets for 100 years in America. So I got hold of some. We made a disc of peptobosmal, put it on this culture of helicobacter, and put it in the incubator. And Monday morning after work, it was like 4.30 in the after. noon. I said, oh, yeah, I better check those culture plates I've got in there. And there was the disc in the middle of the plate was covered in helicobacter. And the disc in the middle with the bismuth on it was there. And there was like a five centimeter diameter zone around that disc where all the helicobacters have been killed. Yeah, wow. So I said, right, you know, get me some of this. We're going to test it out on a few patients. And that was, that was

just, you know, probably called Robin Warren, spoke to the pathologist, look, I want to test this and extremely exciting after that. That was more exciting, I think, well, equally exciting of the self-experiment result. Oh, interesting. Yeah, so that would, that, that happened a few months before I did the self-experiment, but I got a bit cheeky then started publishing. Yeah. I just want to pick up on one other interesting lesson in something you said. You mentioned And like the new technology of endoscopes. It's interesting because often in the history of science, it's actually technology that becomes the platform for new scientific discoveries.

And it sounds like, so we didn't, fiber optic endoscopes didn't become common until the 1970s. And it sounds like that was a big enabling factor for you and Warren. So it was pretty much established. you know, I was seeing endoscopies from 75 onwards, and it was tricky technology. It wasn't very bright, you know, but we'd have a darkened room to look down. And, of course, we never used to wear gloves,

and these things would be splashing stomach juice on all the gastroenterologists who caught halicobacter. So we did some studies on gastroenterologists. They had twice as much halicobacter as any other medical profession, yeah. That makes sense. Yeah. The 1954 study by Palmer, who was this kind of sort of titan of American gastroenterology, they looked at over 1,100 sub-gastric samples and couldn't find spiral bacteria in any of them.

And that sort of solidified the consensus around the idea that the stomach was sterile and probably reduced a lot of the enthusiasm for researching, looking for bacteria in the stomach. How did he miss H. Pylori with that many subjects? There was someone in his leg was cheating. That's the only thing you can think of. Oh, really? So Palmer, he was a great pathologist

and he used to run Walter Reed Hospital Pathology Department. Okay. And so you can imagine World War II, you know, there's all kinds of body tissue turning up in different places, tropical diseases. So they were actually the doyans of pathos of in the United States. If they said something, you believed it.

So Parma was great. But I met Stone Friedberg when I was in Boston. Years later, he was in his 90s. He was about 96, still seeing patients. But he was a cardiologist and a general physician. But he published a paper in 1937 or so, finding bacteria in the stomach of patients, who had gastrectomy mostly for ulcers.

So I think he found it in 46% of his samples, and he presented it. And then it was like World War II, and there was diabetes had just been discovered or insulin had been discovered. So there's all kinds of fancy stuff going on in medicine. And he became a general physician and a cardiologist, I think. So he did okay. But a few years later, after the war, the Palmer and his friends decided, to check the bacteria issue.

And so he said to his registrar or research fellow, he said, look, there's 1,100 samples in our biopsy collection. Go down and have a look at those and see if any of them got these bacteria. And so then he gets this report back a few months later. So we looked at them. We really couldn't see them. Couldn't see any. And so he says, okay, you know, he's something.

off on the paper he was the senior author and um i don't know who was who was on the paper besides him because you know you just remember him you remember when famous people make horrible mistakes and so everybody believed it and never bothered to look so the only way you could miss these bacteria was by not doing proper research not staining them properly or just faking totally faking it Yeah. So it was inexplainable, but he was deceased by the time I started asking this question. So either someone got lazy and said, oh, look, if we said there's no bacteria, that fits with the paradigm. It's a pretty safe thing to say.

Yeah, yeah. Or there was some sort of malicious. So Palmer might have said to him, look, this is, this is rubbish. Bacteria can't live in the stomach. Go ahead and look at these things and then publish a paper and then we'll give you a PhD and off you go. Right. So that was it. I don't think, he never went and looked at them.

Yeah, yeah. So that gets on to fraud in scientific research and how important it can be not to do it. So if he had seen the bacteria and started doing what we did, the literature was available. You know, the tetracycline treatment study, bismuth, you know, he could have done a lot of that. Yeah. And maybe ulcers and helicobacter could have been worked out before 1960. And since 1960, you know, half a million people or a million people a year would have been dying around the world from ulcers.

Millions of people were having their stomach removed and, you know, never enjoying their food ever again, losing weight and, you know, having a horrible life. Yeah. And that was because of that screw up in Palmer in Walter Reed. That's crazy. One of the other interesting lessons from your story is just this theme of scientific, how scientific knowledge diffuses.

And people might think that it's sort of like a light switch where you come up with a new discovery and everyone just instantly updates their knowledge. But it can take years for acceptance of the discovery to roll out. And you could take the NIH Consensus Conference in 9. 1994 as the date at which H. Pylori and its link to... It was stamped. Gastrides got the stamp of approval. So that's about 10 years after the definitive paper that Ewan-Woran published.

I was wondering, would there be some meaningful percentage of GPs and gastroenterologists who, even today in 2025, still ascribe ulcers and gastritis to stress? or do you think that's hardly any yeah okay so so by this point it's yeah yeah okay interesting however if you could walk down the street and ask 10 people what causes ulcers they all say stress yeah so it's still in the in the in the media you know Tom Cruz his poor e-type jaggs are stuck on the in in rain man you know the e-type jags couldn't get brought into the country they didn't have the documents or something he's there drinking Pepto-Bismol because he's got an ulcer so you still see it yeah so maybe a few more decades

until the punters yeah yeah get diffused but um so the medical book on ulcers used to be 114 pages and now it's like two pages so saved all that waste of time all the midstudent could go down the beach so if you hadn't made the discovery until say 2015 do you think it still would have taken 10 years to gain acceptance? Um, yep. Well, I suppose with the internet and me doing a podcast or two about it and everything and then maybe if you, it helps if you have a commercial product that someone's going to sponsor and so that happens a lot faster these days. But if you had, if I discovered that something that was out of patent and was just generic.

It's a bit harder because who's going to spend the money? They're never going to get their money back on it. Yeah. So what I discovered is that the US system, the capitalistic system actually works very well if you can connect into the people who are going to spend $100 million and promulgate this new treatment. Yeah.

So that on the one hand, if you couldn't get the financing, nothing would happen very hard. So we had both of those. So in Australia, there wasn't anybody selling anything related to helicobacter treatment or doing big clinical trials until I did one in Australia. So NH and MRC had to fund it and it took a few years. and then it kind of leaked out and diffused out. And then we had to wait until there was a treatment before anybody really had conferences about it

and approved it in other countries. So you have to do that work. So all you can do as a scientist is focus on the data. You may get a patent or two, but I'd say don't let it ruin your life. Let the university do it because you'll get a percentage of it in the end and the university is not going to give it away for free.

So other people can do that. They've got professionals to do that. So that's a mistake I made that I tried to do it all myself a little bit. Now, slowed it down a little bit, but the connection I made was with Proctrine Gamble, who made Peptobismal, and they realized they had an ulcer product there. So then, okay, money started coming out for research to an extent.

And then finally, AstraZeneca had ameprosol, which with the moxacillin was really going to cure a lot of it and it's going to be easy to take and say if they already got the product. So then in the 90s, they spread the word on it. And so that finally in 2005, the Nobel Committee didn't have any scary doubts about it. It was totally proven. Yeah. Okay.

A couple of questions on the concept of self-experimentation, because your self-experiment in 1984, where you drank the H. Pyloria to try and prove the link between the infection and gastritis. Probably one of the most famous self-experiments in the history of science. Yep. I live to tell the tale. And I was curious, given your famous self-experiment, do many scientists confide in you about self-experiments of their own?

Some. Okay. And so I think I said a good example in some way in the, it, if somebody is in an early stage and they can plan a reasonable self-experiment, it's not going to be too dangerous, ethics committees will approve it these days. Okay. So, ethics, it's likely that the ethics committee at Fremantle Hospital would have approved mine, but things were moving pretty fast for me at that time, and I was just getting frustrated

that I could not break this barrier, is it commensal or is it a pathogen. Right. So the pathology data was proof as far as I was concerned, but we didn't have an animal model, so you couldn't do that. Yeah. And most gastroenterologists and normal people, they, you know, show them a pathology slide. They don't actually see the importance of white cells. And it doesn't resonate with them, if you like.

And so it was a stumbling block for me, and I thought I need to do it. And can I risk getting it knocked back? Well, no. and can I risk that, you know, it's going to take months before they sign off on it and give me all kinds of hassles with it. So I decided, right, like I need to find out. And so maybe I'll do it.

In fact, I had submitted a MD thesis a couple of years before and Animal Studies was part of it. And the last line was, if I can't infect animals, I'll get a human volunteer. So at that point, nobody, was shocked or anything so it had kind of passed muster yeah at that level yeah so i read a paper saying that a lot of self-experimentation happens behind the scenes but it's just not documented because of potential worries about ethics committees i don't know if you had a dramatic experiment

like mine uh you would probably document it but actually my paper was written in the third person you know yeah so i volunteered did this or that and it wasn't for a couple of years until you revealed who that was right yeah So people kind of knew, I think. But these days, if you tried to get that paper published without an ethics committee, the journal wouldn't look at it. Okay. They'd be criticised too much.

Yeah, okay. So these days, you have to cross the T's dot the I's as far as ethics committee because there's a lot of stuff that's been criticised over the years. There's a lot of important good stuff that's come out before, the strict oversight was there. But it's a bit too risky for journals to start publishing it. If they say, oh, there's an ethics committee, they signed off on it. Well, then the responsibility for all that is the ethics committee.

Yeah. So recently there was a professor who was trying out new treatments for COVID in Barcelona, I recall. And, you know, I know that guy peripherally. He was a great microbiologist, but of course they found out that he was using one ethics committee application for the last 10 years for all these different research and just putting the same number on things. So he was severely criticized. So you can't do it these days. Actually, it's good in some ways because quite often only studies that are successful can get published. So if you've got a great result, everyone wants us to publish it.

if you tested something and it made no difference, well, it's still science, but nobody wants to publish it in a good journal, you see. So what happened over the last 20 years, all the studies that were getting positive results were published. And the fact that there was 10 times as many that got negative results, you didn't see them, so you thought, okay, this usually works. So it might be, I love giving you the answer of the thing about acupuncture, where acupuncture works well you know it's not it's not easily testable and so there's thousands of or maybe there be dozens or hundreds of papers showing that it works but the ones where it didn't work were not really published or no one knew about it so nowadays you have to before you start

your research you have to show that it's approved by the ethics and you've you've registered it in the clinical trials database and so that when I say okay treatment X works the reviewers can look in that database of studies and they say well hang on I mean there's 30 other published this 30 other papers that have been started but never got published right so we can assume that they didn't work yeah so therefore you're just a lucky it's just lucky fluke with you yeah and they won't publish it you see so it's better it's safer as it is but it does delay things a little bit one of the basic critiques of self-experiments is that there's just an n of one do you think that that critique is overrated uh no i'd say end of one it's a starting

point um but you want to have some objective evidence that can't be subject so if you said barry do you think helicobectis cause uh bloating i'd say oh yeah i got bloating and and they I said, well, how do you know you're bloating? Well, I feel bloated. But what is that? Well, say, if you've got a photograph, or is your stomach bigger? No, I just looked the same. So I didn't really have any evidence from what I said, what I felt.

So that's the trouble with the end of one. Say I had something that stopped me from feeling nervous. Echinacea. I'll give you some kind of therapy, which I think is probably bogus. So I'd say, when I take this, I feel better. Okay, well, that's the end of one. one and it's so subjective, you wouldn't believe it. However, if I said, you have took the echinacea and I've had an MRI scan and these funny little wiggly bits

in my frontal lobe have all gone straight, just like normal. I'd say, well, hang on a minute. That's something interesting. That is objective data. So with my experiment, Warren could look at the biopsy and you say, look, no white cells anymore or the white cells have come. they've gone. And the electron micrograph show all the cells is damaged exactly like and do it in lots of patients. Okay, let's publish. So that's the end of one. But you can't get away with it always. But so that, in retrospect, there was lots of data that I could have collected in that experiment that would have been other objective data, but I didn't know it was happening until it's happening.

So when I was vomiting, you know, why didn't you catch a glass full of that vomit and run through the chemistry department? They would have found so much data in there. But of course, six o'clock in the morning when you're throwing your guts out in the toilet,

you don't really think about science. You're not thinking about the pH level of the vomiters. That's right, yeah. So that was another thing, you know, a bit of a serendipity that I discovered that helicobacter ruined your stomach acid. In the acute infection, you don't have any acid. So why would you think it causes ulcers?

So quite a paradox. Yeah. So there's a phenomenon I've noticed in the history of science, which is that partnerships of two people seem to be unusually productive. Many famous examples, Marien P.O. Curie, Colin Gertie, Watson and Crick, many, many others. if I try to model what makes those partnerships unusually effective the first sort of starting point is just to note

that there's usually some kind of complementarity and I think the complementary skill sets for you and Robin were he sort of brought the pathology side and you brought the clinical side but when I was reading about your collaborator so some of these partnerships feel like marriages so I a couple of years ago I interviewed Daniel Kahneman who won the Nobel Prize in economic sciences in, like, 2002 or 2003,

because the Israeli psychologist hit a famous partnership with Amos Diverski. And when you read about their partnership, so they kind of pioneered our understanding of biases and heuristics in psychology, and then that fed into behavioral economics. If you read about their partnership, it sounds a lot like a marriage. It was like platonic, but incredibly intense. And if I read about your own Warren's partnership, it seemed like a little more complicated, maybe not so much like a marriage that was the sort of the individual letters in 1983.

And then the 1984 paper was like a very difficult process of drafting that. I think eventually your wife's got involved one night at your house. And they wouldn't let you leave the room until you'd settled on a final draft, which then was accepted without any. changes, which is impressive. But I wanted to hear how, in your words, how you would describe the character of your collaboration with Warren. Well, Warren was pretty obsessional,

and people would say he was a bit pedantic on focusing on fine details of pathology. Yeah. But I respected him because he actually taught me the pathology and you know although it was a fine detail i say i believe it you know those cells should not be like that and this one over here is definitely abnormal so this kind of detail people who are interested in pathology you know like is it cancer is it not cancer move on dr warren what's the next case you know that kind of thing so that that in a busy a pathology department that would be the uh the usual interaction with dr warren yeah and it's like look

this meeting finishes in two minutes. We've got eight more cases, Dr. Warren. Could you stop talking about that one? Get on to the next three or something. So that would happen with Robin. But Robin had this, you know, you could complain and do the same complaint to him every week. It would make no difference to him.

Water off a duck's back. That was Robin. He was in stone as far as that was concerned. So that was good for him as a pathologist and actually in his life because nobody, a lot of people don't know that he had epilepsy. So he had this occasional epileptic attacks. So he needed to be pretty rigid in what he did. Otherwise, you know, he could fall off the rails and he did break his hip at one point, falling off his bike. So, you know, I respected that.

He used to smoke little cigars. And I used to sit down there with him and also like an next. smoker or I'd have a cigar with him. So we, but we, the, the interaction was that every week we would do a few hours together looking down the microscope at these cases. Is that side by side at the bench? Yeah, yes, both looking down the same microscope or the two-headed microscope. Yeah.

And so to, to, you don't realize what a pathologist does. So in the middle of one of these sessions, a call, someone comes in and gives him a slide. And he says, hang on to Barry, looks at it on a microscope. And then five minutes later, the phone rings from the theatre. And a surgeon says, what do you think, Robin? Is this cancer? He says, yes, definitely a sarcoma. Take the leg off.

Hit, click. You know, like, so making decisions like that, you have to be exact and meticulous. And if you like, pedantic or obsessional. So that was Robin. But I'd be there like, Robin, okay, I'm going to go and treat. somebody, you know, or they've got this patient, he's still waiting in the emergency and I think we could use the patient, he might feel better. So, or Robin, I've got to get some samples from cats, where can I get them? So I had 20 different research projects going

on at once. Yeah. And, but Robin was a bit, he was focused on the results of pathology. And I could say, right, let's go and look at the cats and, dogs. So I was all over the place and it was good for him to pull me back in focus. Look, you can't publish all that. And our wife said the same thing. There says, it's 10 papers here. Why? And it's just published one of them. And focus down. And so we were, and I'd be writing a paper with 20 different ideas in it. And he was, there's one idea here. Germs cause bacteria. Germs cause gastritis and that was also. So, Eventually, we became compatible.

I knew what Robin was like, and I accepted the deficiencies in my own personality and maybe vice versa. So it was a good partnership. And I think because also I liked talking people and studying things like that. So the fact that Robin would run overtime on a lot of these sessions

didn't really worry to me too much but of course my wife is like how come you're not home at 530 Barry I had a session with Robin so that used to go on so you're right we were different I was looking at

diverse sources of information and Robin was focusing on the statistics and the biopsies and inflammation so the great story is in 1983 1982 we could not do the statistics on gastritis and helicobacter to show the association because the P value was always 0.0,000, 0,000, 5 digits.

And we wanted to find out exactly. So then the H. Hewlett-Packard 11C calculator came on the market, which could do factorial 64. So Robin and I got, he bought one and we did it and it was p equals 0.10 noughts 1. which was very satisfying. Yeah, okay, that's one of the best P values you'll find. I've never seen anything like that. Was there over a moment where the collaboration seemed at risk? When we wanted to publish letters to the Lancet,

Robin sort of said, well, you know, when you walked in the door barrier, I already had the association with gastritis pretty much worked out, and I had enough data, I could have published that, and I had some drawings of bacteria, so I could have done that. And I said, fair enough, but since I had been working with him for 18 months, that stated, I said, but now you want to publish in the Lancet instead of an obscure pathology journal, maybe not obscure, but I said, if you want to publish in the Lancet,

that is because you've got the next chapter, which is the clinical data and although we are going to publish about gastritis this is our letters to the Lancet we've got the whole picture here now because we've got bacteria and we've got we know that they cause ulcers

even though it's not present in these letters and it could cause cancer and so we had we knew that this observation under the microscope of a bit of pathology really was translational into an important disease. And so at that point, I sort of put my foot down and I said, well, you can't publish any of it. Since I walked in the door in your office, your publication has to stop that point.

And then we can be joint authors on the second half. But the reason it'll go in the Lancet is not because it's a bit of pathology. it's because it's an important clinical thing. Yeah. And so, okay, so we agreed to, we then agreed to publish separate letters. And so that if you read Robin's letter, you can see, I could ask pathology.

And then if you read my letter, it's everything else that we knew at that point. But the key word that I was the one that worked out that it was likely to cause stomach cancer because I've read the literature on gastritis and cancer. And so the last sentence of our first two letters was it could also be, you know, you weren't allowed to say it caused anything as to preliminary, but we already knew at that point. And we said this could also cause gastritis associated diseases, for example,

peptic ulcer and gastric cancer. That sentence won us the Nobel Prize. It was a little taser. And Robin sort of said, well, at that point, if we stopped doing research and then became motor mechanics or something, we still would have won it. That's great. This episode is sponsored by Vanta. Trust isn't just earned, it's demanded. Whether you're a startup founder navigating your first audit or a seasoned security professional scaling your GRC program, proving your commitment to security has never been more critical or more complex.

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For a limited time, get $1,000 off Vanta at vanta.com slash Joe. That's V-A-T-A-com slash joe for $1,000 off. Earlier we mentioned that H. Pylori has been with us for at least 100,000 years, probably. If it's co-evolved with our species, there's good reason to think there could be benefits to it. What do you think is most likely to be the most important benefit? So the only one that they've identified is that it seems to suppress the immune system a little bit so you are less likely to get allergies. And so kids in countries where everyone's got H. Pilari tend not to get asthma, less of it.

And in New York City, kids who had H. Pilari had a 45% reduction in their need for allergy medicines, asthma, things like that. So it does have to stay in your body, it has to do something to the immune system. So suppress it a little bit. I see. And so it probably takes the edge. If you're one of these people, it's a bit of a hyperreactor. If you've got H. Pilari, you might come down a bit. There's a conflicting data and we can argue about it.

But I've got a company called On Deck, it's sort of doing research continuously on this idea of having a probiotic that's actually related to killed helicobacter. And so that we could take the edge off your immune system and perhaps modify or reduce any tendency to be allergic and get asthma or hay fever, eczema. We don't know. But it might be quite a good sort of almost a probiotic, but it would be killed helicobacter. So in terms of the benefits of infection, what do you make of the seeming inverse correlation between H-Pylaria infection, esophical cancer? Okay, so if you have helicobacter in a lot of people that keeps the acid lower, makes the acid lower ultimately at a time when you're starting to get esophagitis and higher

disson as you get older. So you can see that if you have a helicobacter, you might not get the expression of those disorders as much. and it appears that chronic acid in the esophagus is the risk factor for adenocarcinoma of the esophagus. So on that basis, okay, I can see that it could help protect you from acid-induced cancers, if you like, because the acid is lower. But the risk that you, on the other side of it would be

that the risk of Helicobacter itself causing stomach cancer is people have calculated as 4x the esophageal benefit. So these days, don't worry, treat the helicobacter and take an acid blocker and you're sweet. So the net benefit still makes sense to eradicate. How plausible is it that we could eradicate H.Pioreg globally like we did with smallpox? 90% of it is going to be just hygiene and knowledge.

It's not all that easy to catch helicobacter. You catch it off your mother, of it these days, you know, people clean their teeth every morning and they don't chew up the food, feed it to the babies like everybody used to do in the past century. So it's not super easy to catch halicobacter. You've got to be in pretty intimate contact with family member usually or have dirty water, you know, feces contamination of your water.

So those things, as the standard of living around the world and understanding infectious disease happens, Helicobacter is having a hard time going, keeping on. Ultimately, I think probably there will be like a vaccine. So I've actually, I'm connected with groups around the world who are working on vaccines for helicobacter. So it's not easy enough yet and not certain enough to make it worthwhile. But there are vaccines for helicobacter that are, or at least one.

It'd be a traveller's vaccine. You could take it and it would cut down your risk of catching it if you're in Africa or South America or somewhere. What seems to you like the most promising delivery platform? I would say it has to be oral. Oral recombin. Yeah, yeah. Because then it would go into the stomach.

That's right. Yeah. So you need to have your immune system that's carrying out some kind of surveillance in your gut and making antibodies which stick to the proteins on H. Polari, stop it from attaching to your stomach. That would be the thing. Yeah. When do you predict we'll have an H. Pylori vaccine?

I would say, you know, to roll out for every week in 15 or 20 years. So we might actually have it now, but of course we have to test it in animals and thousands of people and then how long do you have to have it before you helicobacter goes away or you get protected? And as soon as you have a trial, the knowledge about helicobacter goes up in the community and they stop catching it from general public health. what happened western countries tried to eradicate it already with vaccine or just to just eradicate it through the quad or triple therapy oh it was a bit it is a bit more difficult than normal infections okay and you have to do a certain preliminary test and then

you've got to do a follow-up test as well yeah so whether you're in retract infection i'd say well just dipstick your urine or something so yeah we're not quite there with h polari um Also, there was always a bit of argument as to whether or not it's good or bad. So people who didn't really feel like treating it would say, oh, it's probably good for you in some reason in some way. So in evolution, you know, all the humans had it. So you could easily say it has a benefit. But what we think is that it only had a benefit in childhood related to allergies. That would be the thing.

I see. After that, you've lived too long. Time for you to go. and helicobacter will help you on your way. Is Japan still the country to beat when it comes to screening and eradication programs? Well, probably. I think the children in Japan

are only 2% infected as far as the data I've seen. So that means the next generation is not going to have it. And if you've been to Japan a few times, you know they are extremely clean in Japan. I mean, anybody who eats raw fish all the time needs to make sure there's no germs around. Is there something they do really well in screening and eradication

that Western countries like Australia could easily copy? No. They just test for it. So they have numerous tests on the market and they actually had a feces test, urine test, breath tests and endoscopy. And actually they already had universal

endoscopic cancer screening. And I think they still have it. From the age of 40 onwards, you can have an endoscopy every two years and they'll take some biopsies and look for it so they they already had awareness of stomach cancer and protection and half the population used to do that which was endoscopy and i think they i'm not sure whether they still do probably still do so helicobacter kind of got caught up in that and was going to be half of people in japan already had a way of finding it and

treating it because it happened pretty quick once the government signed off on the treatment and started paying for it everybody wanted it right okay last question barry okay so one one way of describing the paradigm shift that you and dr warren initiated is that you blurred the long held distinction between infectious diseases and chronic diseases because we discovered what we thought was a chronic disease was actually caused by a pathogen are there any other chronic conditions arthritis alzheimer is ibs schizophrenia, diabetes, obesity, that you think will eventually come to discover are actually caused by microbes? Which ones are the most?

That's a pretty good list. So I'm interested in all of those. So since PCRs come out, any kind of chronic disease people have been looking for germs, viruses with using molecular probes and things like that. So recently one of these probably bogus papers was finding. genomes of bacteria and viruses in bits of brain and in bits of tumors, things like that. So it's a situation of early reports and positive results getting reported and everybody's excited and hyped up.

So that's been going on a lot, but pretty lean pickings for most of it. So I would say, you know, certainly, I would say almost certainly types of Alzheimer's. Alzheimer's are probably a viral illness, whether it's chronic or whether damage was done years ago and something leads on. So, for instance, polio, I was just talking about this the other day, that people who have polio as children are more likely to get motor neurone disease when they're adults. Now, they're more likely than another group that never had polio, but nevertheless, most motor neurone disease is not polio, is not related to that.

So that's the kind of evidence that's exciting. And a lot of these autoimmune diseases like Crohn's disease and colitis, for example, they look like infections. You know, if Warren had seen bacteria on colitis, these say those white cells are doing something, fighting the bacteria. But it's not obvious at the moment about that. So I say keep looking.

But what we have to do is look in early life. And my thought is that if little children from the day they're born, we should be looking at their microbiome and documenting they had a cold, they had a runny nose, they had diarrhea, they vomited, just like that each time something happens, we collect a bit of it and put it in the fridge. And then 20 years later, someone will discover a virus. We've got a probe for it.

I thought, let's go and look at all those samples that we stored. So that kind of data and bio-banking is going to unlock a few of these. I don't know how many. And I see data, there's tantalizing data out there. So, you know, nuns with Alzheimer's, you could look at their application letter when they were 18 years old to get into the nunnery. This is a study in Ireland. and you could get a linguist to look at the language and you could say this person's less intelligent than that one.

This person's not as good at writing letters than that one. So the ones who didn't write a great letter, they got Alzheimer's more so. So this ability to look longitudinally at illnesses and just normal people and notice aberrations or trends is going to be important, that'll give us clues. And so all this stuff about big data

and all this different kind of data we're collecting about ourselves, it's going to be, we're all going to have monitors on ourselves. All my labs, my hemoglobin and everything that I ever had taken in the last 20 years, I've got it on my computer. So it might not be easy to grab it all at the moment. But, you know, the health record, for example,

I think the privacy stuff is, we should think about it, maybe have a privacy ombudsman, but it's not front and center in most people and you don't really care too much about it mostly. So that is going to be an advantage. So five years or ten years from now, things will be coming out of it, and then they already are.

So in San Francisco, where they've got, as I said, bio-banking Kaiser Permanente serum since 1960 or something, every 20 years or every 10 years, they do a massive randomized study around the United States and collect blood and data from everybody and it's in a public database. That kind of thing is going to find out a few causes of these diseases. And we're getting new biologic therapies

working out what autoimmune disease is triggered by, hopefully. And we can say something's an autoimmune disease. We know you're reacting, but at the moment we can't tell what started it. But this idea of finding the 3D structure of every antibody that's floating around in your blood and looking at everything else in the environment, we might be able to tell that it's really coming from dandelions or whatever. So I'm very optimistic, but it's going to take some skilled smart PhDs, looking at a lot of numbers and graphs on the screen.

And I think we're really into the biological century, if you like, and all that information will eventually be obvious to us, just as some information became obvious to me once we started to be able to query the online databases. Absolutely. Well, I've got through almost all of my questions, been really fun talking with you. Thanks so much. well thank you for obviously spending a lot of time preparing the questions and it was fun answering because they were slightly different questions than I usually answer amazing all right

thanks so much barry okay appreciate it very much joe i hope you enjoyed this episode if you did you can support the show by leaving a five-star rating on apple podcasts or Spotify or by subscribing on youtube thanks to this episode sponsors you can find them in the episode description and thanks to Bill Manos and the Manos Foundation for their generous patronage of the show. If you'd like to become a sponsor or patron, you can go to jnwpod.com slash sponsor or email me at joe at jnwpod.com. That's joe at jnwpod.com. Thanks for listening.

Until next time, chow.