Professor Barry Marshall
Professor Barry Marshall is an Australian physician, Professor of Clinical Microbiology at the University of Western Australia and the winner of the 2005 Nobel Prize for Physiology and Medicine for his discovery, along with Dr Robert Warren, of helicobacter pylori and its relationship to the cause of peptic ulcers. Their particular process of discovery has become something of science legend. As well as the Nobel Prize, Barry has been awarded countless prizes and accolades for his work, including the Buchanan Medal from the Royal Society and the Benjamin Franklin Medal (the longest awarded science prize in the US) and was made a Companion of the Order of Australia in 2007.
And so, I needed a guinea pig…
On earliest memories of science
My earliest memories of being interested in science are that my father was a fitter and turner and had a lot of trades tickets, so he always had technical books around the place. So he was doing diesel, electrical, refrigeration, and our house - and probably anyone in the 50s in Perth, Western Australia - didn’t really have a lot of books to read so you tended to read everything you could get your hands on, because I loved to read, so technical books is what I started off with.
The second part of it is my mother was an ex-nurse so then I had about four or five of her textbooks. So reading the 1950s style medical texts, which are pretty quirky if you look at them now, ah, very correct and sexual stuff was not really very important in them! And then in school, I was in a Catholic school where you had a limited repertoire, you couldn't actually do every single subject you were interested in, so I was not able to do any biology or life sciences either, it was chemistry, physics and maths, so that actually had the opposite effect on me. The one thing I wanted to do when I got out of high school was do some anatomy and biology, so medicine was the natural thing for me to go into.
Oh, and a little extra background story, (on medical advancements) at Pearl Harbor, the enlisted men that were taken to surgery all survived because they actually just got ether. The upper class officers and everybody that were injured, and got into surgery, a lot of them died from the chloroform, because they got the new product, the top product!
On the work that lead to winning the Nobel Prize
Well, my involvement with the discovery of Helicobacter pylori, the stomach bacteria that causes ulcers, is an example of how a bit of luck, and being in the right place at the right time, can really help your career. So I was training in internal medicine, so that’s everything except surgery, I suppose, and I was doing a gastroenterology term in the subsequent six months and I spoke to my boss and said, ‘What sort of research have you got on the go’, and he told me that he didn’t really have anything special but Dr Warren, who was a pathologist, had seen these bacteria on biopsies and was a bit excited and was trying to get people involved with it and he needed to have a person who could study the microscope appearance and then go and find those patients and find out what they had wrong with them or, if it was a new bacteria, where had they got it from? So with any new infectious disease, you’re immediately going to say, ‘Did you travel? Do you have any weird pets? Any strange countries? Do you eat any strange food or have funny habits or anything?’ So I then took the clinical part and started talking to the patients, and then sending material down to Dr Warren who’d look under the microscope and say, ‘Yes, he’s got it’, ‘No, he hasn’t’. And we were doing that for more than a year before we really started to get this inkling that these bacteria could be more important.
Dr Warren noticed that they caused inflammation, which means that white cells are kind of fighting the bacteria, so that was enough evidence for me that they were pathogens. They were harming the body and your body was actually recognising them as something that it needed to get rid of. And then it was only sort of a year or so later that we were first able to culture the bacteria and then it moved on to, ‘Hey, they might be causing ulcers’.
On testing the theory
Well, you see, I’m always terribly sceptical of other people’s discoveries because I say, ‘Aw, it’s just an association, you know. Those people have got these and they’ve got that, is it just a coincidence or is it cause and effect?’ You always have to ask this when you see a new medical discovery. Particularly when you’re going to say, ‘Hey, we think we’ve discovered the cause of ulcers because we saw these bacteria in some patients with ulcers’. So everyone was immediately extremely sceptical. They’ve heard ulcer cures hundreds of times in the past 20 years, probably. And so no-one believed it and they would say, ‘You have to prove it by giving those bacteria to a guinea pig and expecting to see the guinea pig develop ulcers, then maybe we’ll think about it, but until then it’s just airy fairy stuff’.
And so we did try and do that. In fact, I tried to infect various animals, guinea pigs included, and real pigs, and got nowhere because animals are quite resistant to a bacteria that comes from humans. So in the last resort I thought, ‘Aw, I’ve got to find out what the answer is. Are they really pathogens in humans?’
And so I needed a guinea pig.
Dr Warren says I asked him but he said he couldn’t do it because he’d already had helicobacter and I had treated him as a patient, you see, and so I said, ‘Oh well, it looks as though it’s going to have to be me’.
So then I did this experiment where I checked to make sure I didn’t have the bacteria and my stomach was healthy. And then I infected myself by drinking a pure culture of the bacteria from a patient who I’d seen a few months before with indigestion. And then I’ve got my fingers crossed. I said, ‘Well, let’s see what happens’. And I started vomiting for a week and at the end of that I had an endoscopy and, sure enough, the bacteria were there sticking right onto the cells that line the stomach, millions of the bacteria. My mother told me I had bad breath, my wife was worried about me - ‘What’s the matter with you!’ - so that went on for a couple of weeks. And the biopsies, when I showed them to Dr Warren, did show lots of the bacteria. So we had proved the bacteria could infect a healthy person and then you would get this inflammation in your stomach, although I didn’t actually get an ulcer.
So what they tell us then is, some of the things that lead up to ulcers were being caused by the bacteria. So of course after that we were incredibly excited and enthusiastic and started writing papers about it, and it took off at that point.
On the uniqueness of helicobacter
Helicobacter is very unique bacterium because it can survive in the stomach where there is a lot of acid. In fact the acid in your stomach is one tenth as concentrated as the acid in your car battery. So it’s still very, very strong. The pH is about 1.5. So how does it live there? Well, it utilises an enzyme called urea. So in your saliva - and all your body fluids, in fact - you have a bit of urea, which is a waste product, it’s just floating round in your body. So helicobacter can take that urea and split it into carbon dioxide and ammonia and the ammonia is an alkaline buffer. So around the bacteria you get this little bubble, or cloud, of ammonia keeping the pH of the bacteria above five. So every other bacteria you swallow is probably going to be killed by your stomach acid, in a healthy person, it stops us being sick. But the helicobacter, just for some reason, it was just a fluke that it had this mechanism from somewhere else, and, lo and behold, it can really stick in the stomach and live there.
And it’s very efficient. Once it got into the stomach underneath the acid, it was quite comfortable, it didn’t need to be fighting all the other bacteria or competing against them. No other bacteria could compete. So it got rid of all the superfluous genes out of its genome, it’s got quite a small genome, and it’s just a very efficient bacteria capsule designed for one thing: sticking in the stomach.
And it’s so hard to get rid of that you usually have it in your stomach for the rest of your life, unless we treat you with antibiotics. And if you’re a woman…so, humans have had it for hundreds of thousands of years, probably, so women then would pass it on then to their families and the children of the next generation by licking the spoon or kissing or things like that, so it’s a great strategy for helicobacter and it’s affected the whole human race. Luckily, they don’t all get ulcers but about 10% of people with helicobacter do get ulcers.
On a vaccine
We’ve been studying helicobacter now for 30 years so we know a lot about it and we’re very interested in the idea that helicobacter controls the immune system in some way because you can’t get rid of it. So if you had a normal bacterial infection, your immune activity would raise higher and higher and higher and then get rid of it, or the bacteria would multiply and kill you. But helicobacter sits somewhere in between. So if there’s too much immune reaction it’s going to dampen down the inflammatory cells, the white cells etc., and say, ‘There’s too many of you guys, go away and spray some toxin on the lining of the stomach or something’. So, utilising that mechanism and some other observations that people have made that if you have helicobacter you’re less likely to get asthma or some allergies. And this is this concept that has developed in the last 20 years or so about the hygiene hypothesis: humans in the 21st century are all so clean, we don’t get enough exposure to normal bacteria and infections and so our immune system becomes hyperactive and starts reacting to nuts and pollen and everything else.
So on that basis we said, ‘Well maybe helicobacter, because it’s disappearing out of the western world, it’s one of these things that sort of allowed the excessive immune activity to release or express itself. So the idea then would be to make some products out of helicobacter that keep your immune system down a little bit and so you’re back like humans were 100 years ago and you’re not actually having to have all those nasty infectious diseases, but by having a helicobacter product you could be only half hyperactive instead of 100% hyperactive on your immune system.
So how would we do that? We wanted to give live helicobacter, find a safe way, maybe people with severe immune conditions could take that, so we’ve done a lot of research on that. However, we still haven’t found the 100% safe helicobacter, so at the moment we’re going a bit quietly on that. But the future might be that we could brew up massive amounts of helicobacter and you could take it like a food product and add it to your food, or take it for breakfast, something like that. Maybe just a little bottle of it. But it’s the type of thing that hasn’t been tried before and really addresses the hygiene hypothesis and the hyperactivity that so many people have.
What happens when you get a stomach ulcer
Recently we’ve developed new insights as to why people get ulcers with helicobacter and why it all happened in the 20th century. The paradox is, you know, if you have a weak immune system, say you’re on chemotherapy or you’ve got AIDS or something, you will never get an ulcer from helicobacter, so that’s the clue. In fact, it’s not the helicobacter that causes the ulcer, it’s the white cells coming through the lining of your stomach to attack the helicobacter releasing superoxide radicals and everything. So what happened in the 20th century? People were healthier, stronger immune systems, and they were eating more protein so they had stronger acid levels, higher acid levels. And those things combined to make adults in the 20th century, firstly in the United States, in Chicago, maybe Berlin, New York City, where people were eating big steaks etc. and the businessmen were doing all this high living, and getting ulcers. So everyone says, ‘Oh, it must be stress’. But it wasn’t stress, it was just that humans had never been as healthy as they were in the 20th century, and so it’s the combination of the bacteria and the immune system that leads to ulcers.