Saturday, August 2, 1997
Smug as a bug
He was so sure he was right and conventional medical wisdom wrong about the cause of stomach ulcers that he swallowed bacteria to prove his point. Now once-sceptical peers are talking about a possible Nobel prize. MELISSA SWEET reports.
BARRY is back. He's burnt out, mellowed out and glad to have some time to just hang out, now that he is home in Perth and far from the frenzy of 10 years in the United States limelight. He may not be a household name in Australia, at least not yet, but there is no doubt that Barry Marshall is a star. In the conservative world of medicine, Marshall has achieved international celebrity status for helping to revolutionise understanding and treatment of ulcers, not traditionally a subject high on sex appeal. Just consider his publication record: he has been splashed by the New Yorker, Time magazine, Reader's Digest, The New York Times, The Wall Street Journal and The Washington Post, to name just a few. Don't mention the recent Fortune magazine piece, though. He didn't like that; didn't like its theme of Brash Barry As Underdog Wins Out. A shame, because that is one of the many interesting aspects to the Barry Marshall story which is compelling at several levels: single discovery sets young WA doctor from not especially privileged background on road to fame, fortune and maybe even a Nobel prize; entrenched attitudes and interests in the health industry impede the march of knowledge and patient care; and why hard slog, serendipity and, perhaps most importantly, salesmanship are so important to science.
There is no doubt that Marshall, 46, has been one hell of a salesman. That helps explain why he is so well known for a discovery which stemmed from the observations of a colleague, Dr Robin Warren. In the early 1980s, Warren, a pathologist at Royal Perth Hospital, had become resigned to unkind jokes from his peers about his theory that an unusual bug he was seeing down his microscope had some role in causing stomach inflammation. No-one had taken much notice because it was such an outlandish notion. Everyone knew that bacteria couldn't survive in the stomach's acid environment. They'd been taught so at medical school. Marshall was in the final stages of training to become a physician, having dropped earlier plans to become a GP because, he explains: "When I was in medical school I was given the impression that everything had already been discovered in medicine. It must have been the way it was taught. "So I never thought that medical research would be interesting, but as I did my internship ... I realised there were a lot of people who had things wrong with them that you couldn't do anything about particularly." So Marshall, who had not been known at med school as an especially conscientious type, was casting around for a research project to complete his evolution into physician. His boss suggested he check out Warren, who "was always carrying on about seeing bacteria in [stomach] biopsies". The rest, as they say, is medical history.
The pair spent several months trying to culture the bugs, succeeding only accidentally when the culture was left longer than usual because of a lack of lab staff over an Easter break. Once able to grow the bug, they could show it was a "new" organism. It was initially thought to belong to the Campylobacter family but was later declared part of a new genus, Helicobacter, which is now known to have members also infecting animals other than humans. Most importantly, however, Marshall and Warren began to gather evidence to support their medical heresy that Helicobacter pylori were contributing to many ulcers. The establishment was difficult to persuade - everyone accepted that ulcers were caused by acid, stress, spicy foods, and should be treated by drugs blocking acid production. This led to Marshall's rather dramatic decision to swallow a solution containing the bug to prove it caused disease. About a week later, he started vomiting and suffering other painful symptoms of gastritis, or inflammation of the stomach, which is now recognised as being caused by H pylori. His wife, Adrienne, was not impressed. "That's a very Barry thing to have done," she recalls. They had four young children, Marshall was working 14-hour days, seeing patients all day and doing research at night, and now he was "dreadfully ill". "I told him he had to stop it and get some treatment." He did. But his point had been made.
IT WOULD be easy enough to portray Marshall as the poor country lad made good. His father was a boilermaker, his mother a nurse. They lived in Perth until he was about four, then moved north to Carnarvon and a house with a dirt floor and outdoor toilet. A few years later, they moved inland to the tough mining town of Kalgoorlie, of which he remembers tin roofs, night-cart toilets, and their "fridge", a Coolgardie safe. Then it was back to Perth, where his father worked as a cray fisherman and later ran chicken processing plants for Kentucky Fried. "For many years we didn't have a car," says Marshall, the eldest of four children. "We weren't the first ones in the street to get a TV or any of those things that happened in the '50s and '60s. We never had any money but we had a pretty good life." Engineering was his first love and remains a hobby. His first scientific paper on H pylori was written on a homebuilt word processor. He has to be one of the few professors to have established an Internet site on his field of research (http://www.helico.com/index.html). It includes everything you may ever want to know about ulcers and H pylori, and links to Marshall's personal home page, complete with pictures of him feeding black swans. Adrienne says Barry has never quite outgrown his love of play. "He's got a dreadful sense of humour," she says. "He's always being stupid, bad jokes, puns, that sort of thing. He really enjoys everything he does. He's a 150 per cent person; whatever he's doing he throws himself into. He's probably a bit more of a boy than a man; a lot of the researchers are like that."
Marshall studied medicine at the University of Western Australia from 1969-74 and worked on the wheat bins during holidays. He and Adrienne married while still studying (she did psychology) so they could get a Commonwealth scholarship. "We wanted to get away from our parents, basically," he laughs, "but we used to eat quite a few meals at our parents' houses because we couldn't afford food." Finances are not a problem these days, of course. Marshall doesn't spell out exactly how much the discovery has earned him - he has shares in a company which makes tests and other products related to H pylori - but notes that all his children have had expensive US college educations. It seems he is in the fortunate position of seeing patients out of choice rather than necessity, with enough funds left over to pursue his research interests. He adds that he has no inclination to be a businessman full-time but is enjoying his lab at Sir Charles Gairdner Hospital and hopes to establish a biotech industry in Perth: "I can now do what I like and I don't have to do something if I don't like it." BUT the road to this point was long and hard, which brings us back to Marshall's brashness. Associate Professor Stuart Hazell, a microbiologist at the University of NSW, recalls that many medical feathers were ruffled when Marshall first began his campaign to rewrite the textbooks. "When Barry spoke he was very brash, "... that I've discovered this and that you people are going to have to relearn all your medicine because we've now worked out what is really going on'," Hazell remembers. "The vast majority of the medical profession, not only in Australia but worldwide, considered Barry to be a quack and really were extremely dismissive for a number of years." Adrienne says her husband's aggressiveness in selling his message - unlike many doctors, he has never been media-shy - was simply a reflection of extreme frustration. "It was a tremendous struggle to get his work presented and published," she says. "It was really tough to hang in there."
Dr Tom Borody, a Sydney gastroenterologist who has treated thousands of ulcer patients with antibiotics after becoming an early convert, says: "He was changing the world and the world wasn't seeing it." Marshall himself underplays the underdog image. "I used to have a pretty good following. Robin Hood and his merry men - we used to think of it as a guerilla warfare. There were a lot of people who didn't believe what we said but they couldn't keep us quiet. I was very thick-skinned." Robin Warren believes that if Marshall hadn't tried to push their discovery so hard, "I suspect I'd still be trying to convince people of it. He's a much better salesman than I am. If you make a big discovery, if you don't sell it, it's not going to be heard by anyone else." But Marshall took at least a decade longer than he expected to persuade colleagues that ulcer patients with H pylori should be treated with antibiotics. (This treatment is not recommended for the estimated 15 per cent of peptic ulcers caused by aspirin and other non-steroidal anti-inflammatory drugs). Indeed, Australia only recently licensed the first antibiotic combination therapy for H pylori. The time-lag reflects, as Professor William Doe of the Australian National University comments, "how difficult it is to change medical paradigms because everyone has a vested interest in the status quo". The pharmaceutical industry held the biggest vested interest in ulcers. Two of its biggest all-time earners have been the acid suppressing drugs cimetidine (Tagamet) and ranitidine (Zantac), and Astra had just launched the first of a new, even more potent type of acid suppressant. These drugs did not cure ulcers, meaning patients often needed lifelong therapy. The notion that common garden varieties of antibiotics (many of which were out of patent and so did not hold the lure of vast profits) might cure ulcers was, unsurprisingly, not high on the industry's priorities. The pharmaceutical industry is the main source of information for doctors, which helps explain why Tagamet and Zantac are still big sellers. But, to be fair, knowledge rarely advances in a single bound. Many painstaking studies are needed to prove a new hypothesis, especially one so challenging to the previous paradigm. As well, H pylori proved more difficult to eradicate than initially expected, and the drug combinations now recommended often cause side effects. Even so, they have brought great benefit to many thousands. Marshall recalls that during his decade at the University of Virginia, patients came from all over to have their ulcers cured. And H pylori is having ramifications way beyond ulcers. It is now accepted by the World Health Organisation as contributing to many gastric cancers, an enormous problem in many Asian and developing countries, and an international race is under way to develop vaccines against the bug. Professor Doe says the discovery has also contributed to a "renaissance" of interest in the concept that many chronic diseases may be caused by persisting unrecognised infections.
It's also been a job creation scheme to make the Employment Minister, Amanda Vanstone, jealous. Dr Neville Hoffman, Marshall's boss at Sir Charles Gairdner Hospital, says that the discovery has created an industry and the bug has now reached the stage where there are more people living off it than dying from it. Borody notes that there is now an entire journal devoted to Helicobacter, which is the subject of almost 3,000 new scientific papers annually. Stuart Hazell says: "It's made Barry's career, it's made my career, and it's made plenty of other people's careers." NOT surprisingly, whispers about a possible Nobel prize have grown so loud that there are even rumours that the Swedes have asked for Marshall's US supporters to tone down their lobbying. Borody says: "It is one of the major breakthroughs in this century, basically, and that is why I believe he will end up getting the big prize; they should both get it." The discovery has already attracted several lucrative, coveted gongs. The Harvard Medical School gave the two researchers the $US25,000 (about $32,500) Warren Alpert prize, which recognises work that has most benefited clinical practice. This year the pair won Germany's Paul Ehrlich prize, and Marshall has also received the Lasker prize in the US. But Stuart Hazell says their lack of recognition in Australia is "pathetic" and a comment on the status of Australian science and technology generally. "I was talking to [Federal Science Minister] Peter McGauran the other day, saying it's about time someone organised for these guys to get an Order of Australia."
But you get the feeling that Marshall, who is officially on sabbatical leave from the University of Virginia, is enjoying a break from the jet-setting whirl of conferences and media interviews that had become his lot in the US. After working seven-day weeks for years, he is trying now to have at least one day a week free of H pylori, which his wife describes as "like our fifth child". "I had my midlife crisis last year, I think," he laughs. "I'm trying to become less famous for a while and get back into the lab."
Melissa Sweet is the Herald's Medical Writer.
Dr Barry Marshall ... In the background are H pylori, curved S-shaped black bacteria. The dark brown are the mucus cells that line the stomach. Photograph by TONY McDONOUGH