Professor Barry Marshall is an Australian Nobel Prize Laureate in the field of gastroenterology and microbiology. Early in his career, Professor Marshall went into internal medicine with a gastrointestinal emphasis, working with Dr J. Robin Warren to demonstrate that Helicobacter pylori is the cause of most peptic ulcers. In this conversation, Professor Marshall describes drinking a dose of the bacteria himself in order to prove causation amongst risk taking in medicine as well as future directions in his field.
I’d like to talk about the very famous story of how you drank a Petri dish containing cultured Helicobacter pylori to make the causal connection of the bacteria with peptic ulcers. Considering the resistance your findings faced by the medical and scientific community, what do you think the reasons were that people were unwilling to consider the connection? For example, do you think there was an economic motive?
What triggered me to do that experiment was a grand round that I did at Fremantle hospital, when I was a medical registrar there. I was in the senior registrar job in internal medicine, so I did a grand round about this bacterium. It became evident that normal non-specialists were just so entrenched with this stress idea – the brain/gut axis. I don’t believe in any of that. They were so entrenched; it was exactly like a religion at that point. You couldn’t move stuff that people knew. Even if you had facts, they just didn’t feel it was right. So the fallback position for everybody was ‘there’s only one person, there must be something he’s doing wrong, otherwise how come it’s not been discovered before?’. So there was that attitude, then the pathologist got up and said ‘well these changes in gastritis are extremely subtle, how can you really measure them objectively? Obviously people with ulcers have got a hole in their stomach and other bacteria can come and live in the ulcer, it’s probably just commensals, you’ve got a long way to go, where’s your animal model?’
At that point, I had been trying to infect rats and mice, guinea pigs and piglets for about six months and getting nowhere. It was kind of frustrating – I had no answer for that. I could not really do the next step. However, I did submit an MD thesis proposal and in that I said that if the animal work fails, then we would try to get a human volunteer experiment. So I had decided that I needed to go to that step. Looking back on it, it was riskier than I originally thought it was because I was pretty certain that I could eradicate it with antibiotics, but the ones I chose in fact probably wouldn’t have worked. I had an endoscopy to make sure I didn’t already have H. pylori. So I drank the bug thinking that I would just be asymptomatic. Most people I knew with H. pylori were infected blood donors. I found 40% of blood donors at Fremantle were infected and didn’t even know they had it. So obviously, it wasn’t killing them and no one could remember where they caught it from. There was no history involved with the infection so it was a bit of a puzzle.
Even Dr. Warren and a couple of other people thought it might have been sexually transmitted, close contact with somebody, because ladies who attended the STD clinic were more likely to be infected than everybody else. There were a whole slough of crazy little pilot studies trying to sort the epidemiology out, it was very confusing. However, I drank the bug and I did become unwell with a vomiting illness and there was no acid in the vomit. That triggered something that I had read in an old medical textbook, The Principles and Practices of Medicine by Sir William Osler in 1910. They described exactly the acute illness that I had. I suddenly realized that these old descriptions of vomiting without any acid in the vomit were probably H. pylori and it became less common and people forgot about it.
Putting it all together at that point, the endoscopy showed a very heavy infection with H. pylori, so it was lucky that I had chosen that strain because I could have chosen one that didn’t infect very well. However, I didn’t get an ulcer and the illness got better after two weeks – it was all over. Discussing it with a few colleagues enabled me to do this hypothesis article for the Medical Journal of Australia. I believe it is either the second or third most cited article in MJA with thousands of citations.
What changes occurred in your life after receiving the Nobel Prize?
I believe Nobel laureates develop a bit of an inferiority complex and maybe some paranoia. One of the things is that I’m always talking about things I know, I’m the font of knowledge for Helicobacter and I keep up in that field, but there are so many other topics that I don’t keep up with. If I pick up the Medical Journal of Australia, I’ll look at the headlines and think that I don’t have time to read certain articles. Similarly, I’m not going to have time to be able to read the journals that I used to read, so I get a bit paranoid about not keeping up.
The other thing is that you’re worried that you don’t have peer review as a Nobel laureate. If you say something, someone is happy to print it or put it up on the web. If I twitter about something and say “this is a load of rubbish” about the microbiome of the stomach, nobody else is saying that. So I think, am I nuts? I’m just looking for a little niche where I can fight the consensus. Anybody who says something is a consensus, I am immediately totally suspicious of it.
Moving on to some of your current research, increasing antibiotic resistance accounts for 15% of patients who are not cured of their H. pylori infections. When these patients are referred to you, you isolate their strain, they receive a ‘tailor-made’ combination of antibiotics. I was hoping you could discuss how much of a threat you believe antibiotic resistance is with respect to H. pylori?
It’s a moderate threat, once you know how to get around it. You learn these principles of microbial therapy in medical school and it’s not going to change. Always, if you find the resistance pattern of the organism, you navigate around it with your antibiotics. The tricky part is that many of the antibiotics I like to use are active in the stomach and are often old. The best example is tetracycline. Everyone says “don’t use that, it’s not very well absorbed, it stays there in the lumen of the gut, it passes out in the stool.” Hang on a minute – that’s great for H. pylori.
There is need for further studies to work out the pharmacology of antibiotics in the gastric mucosa because when amoxicillin fails, we have no idea why it fails. All Helicobacter are always sensitive to amoxicillin. So you should be able to just give people amoxicillin and a PPI (proton pump inhibitor), and expect a cure. We’re not seeing that. So you have to add the third drug, there are different ones.
So I’m not too worried about it with Helicobacter, it’s a bit like a Streptococcus. It’s got a limited repertoire. However, it mutates extremely fast. It’s almost like a virus. According to a paper we did, its right on the top of the list for mutation. The reason is because it doesn’t have to protect its genome. There’s nothing else floating around much except other Helicobacters. So they’re all moving genes around, sucking them in and out as they divide. It doesn’t check the accuracy of its copying. So it’s continuously disabling its ribosomes or changing its ribosomes, so it very easily becomes resistant to macrolides or metronidazole. So it becomes interesting; there’s so many Helicobacter in your stomach – 1010 organisms. So for the stomach, it doesn’t matter that its doing bad copies of itself because it will just continue to have an evolution in the gastric mucosa. That’s why it becomes resistant to these things that require some interaction between an antibiotic and a functional protein, because they disable the protein in some way and then it’s resistant. So I think in the future, we need to do more studies on the pharmacology of the gastric mucosa and immunology. I’m optimistic that we’ll figure it out eventually. But, at the moment we haven’t made much progress in the last 10 years. That said, we still kill 99% of H. pylori that is referred to us.
The Marshall Centre for Infectious Diseases Research and Training has a principle goal in facilitating the development of new vaccines for H. pylori. Given that the bacterium is part of the normal flora as you mentioned before, for approximately 50% of people, do you believe that non-pathogenic H. pylori should be eradicated?
This is the question that I had trouble with. So, statistically it is normal because half the people in the world have it, so they’re not at the two standard deviations from the mean to have H. pylori. However, it is a pathogen even in the normal flora. It’s been normal in stone age Man, ever since humans left Africa 70,000 years ago they’ve been carrying H. pylori – maybe even hundreds of thousands of years before that. So in that respect, you could say it is normal flora and it may have had a beneficial effect. The ones that get the press are due to the fact that it downregulates the immune system a little. The beauty of this might be that if you had H. pylori you were less allergic and everybody’s a little bit allergic so that’s okay. But there are these kids that are outliers in their allergy response who are way up high in their responsiveness. They’re the ones that get anaphylaxis. So maybe if you had H. pylori, you would be less likely to be up in that group, you’d be more down in the middle of the range. As humans migrated out of Africa and visited all these other continents, with different plants and animals, it’s possible that having H. pylori was a bit beneficial. You’re hiding in the bushes from a lion, all of a sudden you start sneezing, that would not be good. Being less allergic might have helped human migrations.
Nowadays, Helicobacter has been disappearing by about 50% every generation in the last 50 years. So since about 1960, in Western countries it’s just been declining. It’s not antibiotics. It’s better hygiene, smaller families and it’s not terribly infectious. If you have both parents infected, each child has about a 50% chance of picking it up from an Australian parent. It’s in the next generation, but not a lot. So you can’t blame me if Helicobacter disappears. I’m killing it, I’m doing my best, but in fact 90% of the work is just done by modern living in 21st century life.
Are there any other medical issues that you would like to see gaining the same attention as the microbiome?
I think the immune system of the gut is important. We can put things into the stomach and into the colon, but the small intestine we can’t really investigate. As far as I’m concerned, there’s only two causes of anything: genetic and environmental, in particular all the viruses that you catch in the first few years of life. I think we’ve got a long way to go but we are on the threshold of cheap sequencing. So what we’re going to see is a lot of cheap sequencing during the lifetimes of lots of people. Then maybe 10 years from now, we will have computers big enough to figure out what it all means. We will probably be able to see that a lot of it is viral triggers – who knows.
Image 1: SHKP and CUHK Present Distinguished Lecture by Nobel Laureate in Physiology or Medicine [Barry Marshall]. Communications and Public Relations Office. 2013 [cited 30 May 2018]. Available from: https://www.cpr.cuhk.edu.hk/en/press_detail.php?id=1649
Image 2: public domain, accessed from https://pixabay.com/en/bacteria-black-health-microbiology-359956/
Conflicts of interest