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THE BIOMEDICAL SCIENCE 20 SCIENTIST Cover feature

PROFESSOR MARSHALL ACCOLADES & AWARDS 1994: The Warren Alpert Prize 1995: The Australian Medical Association Award; The Albert Lasker Award for Clinical Medical Research 1996: The Gairdner Foundation International Award 1997: The and Ludwig Darmstaedter Prize 1998: The Dr AH Heineken Prize for Medicine; The Florey Medal; The Buchanan Medal of the Royal Society 1999: The Benjamin Franklin Medal for Life Sciences 2002: The Keio Medical Science Prize 2003: The Australian Centenary Medal; Medal 2005: in or Medicine

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In an exclusive interview, Professor tells George F Winter about his bold experiment, which led to acute gastritis and the Nobel prize.

n late July 1984, Dr Barry J Marshall in a stomach biopsy sample from a patient visible growth. But then came a four-day drank an unusual concoction that with non-ulcer dyspepsia, but further Easter weekend in April 1982. After fi ve would forever change his life, the investigation needed expertise in days incubation, on 14 April 1982, colonies lives of countless others and our . “I was not focusing on were seen for the fi rst time. understanding of medicine. The either gastroenterology or microbiology What was Professor Marshall’s reaction? 32-year-old Microbiology Registrar at the time I started my six-month “My recollection is the same as I always from Fremantle Hospital, Western gastroenterology assignment,” Professor feel whenever I see another medical , consumed beef broth Marshall tells The Biomedical Scientist. breakthrough: scepticism. ‘Where’s the Ilaced with 109 colony-forming units of “However, I knew that I had an aptitude proof? What else could it be? What haven’t Helicobacter pylori (H. pylori). and an interest in infectious disease, and we thought of?’ To discover why Dr Marshall took the had been off ered a job as an infectious “The microbiologist John Pearman had elixir and joined an elite club of medical disease trainee that year.” already seen two positive cultures by the self-experimenters (see box, overleaf), time he called me, and explained that the we have to go back three years, to 1979. Where’s the proof? trick was waiting the extra three days to At this time, Dr J Robin Warren, a Marshall and Warren’s challenge was to see what developed on the plate (we were Pathologist at the Royal Hospital, grow the organism. Their initial failure already using the right technique). So in Western Australia, was examining to do so was partly attributed to faulty some ways I was relieved but had seen too histological sections from gastritis incubators and to the routine discarding many disappointments with the project

PHOTOGRAPHY: RICHARD GLEED PHOTOGRAPHY: patients. He saw spiral-shaped of plates after 48 hours, if there was no so was not going to break open the

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Right. Dr Barry J Marshall and Dr J Robin Warren.

champagne just on that basis. Also, at vehicle, for example chicken soup or beef that point we did not know we were broth. In the lab on that occasion it was discovering the cause of peptic ulcers.” dissolved in beef broth, which is a culture By 1982 Marshall and Warren had medium for lots of diff erent bacteria.” begun a prospective investigation of After fi ve days, Marshall developed bad 100 consecutive patients undergoing This is the most breath, morning nausea and recurrent endoscopy. This was prompted after vomiting of acid-free gastric juice. A Dr Chris Sanderson, a Senior preposterous gastric biopsy after 10 days showed acute Gastroenterologist at the Royal Perth gastritis and many H. pylori. Hospital had advised Marshall: “Barry, thing I’d ever “This was one of the most exciting days you should stop buggerising around and for me,” enthuses Professor Marshall. do a proper study!” heard; I thought, “After I had the endoscopy, I did not know The results showed that 65% of patients for 48 hours what the result was.” The undergoing endoscopy had gastritis; there this guy is symptoms had spontaneously resolved was a strong association between spiral after a fortnight, but Professor Marshall’s bacteria and gastritis and all patients a madman wife, Adrienne, said she’d had enough with duodenal ulcers. And 80% of those and demandeddem that he immediately with gastric ulcers had the organism. commencecommen antibiotics or “be evicted from “I remember that 12 out of 13 patients thethe householdhous to sleep under a bridge”. with duodenal ulcer had the bacteria,” recalls Professor Marshall. “This prompted UnlockUnlo the puzzle me to review the charts of patient “The“The pathologist called to show me number 13 and I found that, although tthat the bacteria were causing Dr Warren had not seen the bacteria in infl ammation,” says Professor our current study, this patient did have Marshall.M “Since I had done this the bacteria seen on biopsy a year before, papartr of the experiment myself, I during an investigation for ulcers. knknewe the gram stain of gastric “This was the ‘exception which proved mucusmuc was already positive, although the rule’. I always tell people that thethe bbacteriaa hadn’t grown at that stage. anything in medicine which is 100% is “I wawass very excited after seeing the likely to be an artefact or ‘fake news’, so I organismm coucouldld histologyhistolog and could not wait to tell my didn’t want to fall into this trap myself. colonise histologically wife once I got home. She’d been in a car Ultimately, in many studies around the normal mucosa and induce gastritis. accident, resulting in moderate whiplash world, the percentage of duodenal ulcer This brings us back to Marshall’s famous and cracked ribs, so with four children positive for H. pylori was about 92%.” self-experiment in late July 1984. she was already busy and didn’t want Marshall and Warren were suggesting “The brew was cultured in the lab and I her to have to worry about a sick husband, not only that a bacterium caused stomach planned the experiment on the Monday so she was distressed when I told her the ulcers, but also that patients with ulcers after we saw that the cultures were infection had taken hold. could be treated with antibiotics. This growing. I drank it on the Tuesday morning “I knew then that I would have a off ended the medical establishment. Dr at 10am,” says Professor Marshall. publication out of it, but did not realise Martin Blaser of the Vanderbilt University “I pre-medicated myself with some the ultimate importance. Later on, when School of Medicine described the theory Tagamet, in case the gastric acid was too I was writing the paper and looking as “the most preposterous thing I’d ever strong for the H. pylori infection. At that through old reports of aetiology unknown heard; I thought, this guy is a madman”. point I did not involve Dr Warren in the infections, I could see that I had unlocked exact details of the experiment. the puzzle of .” Don’t ask, don’t tell “For my superiors in microbiology and Yet, despite showing a clear association gastroenterology, the situation was ‘don’t Recognition and acclaim between stomach ulcers and H. pylori, ask, don’t tell’,” he adds. After publication, there was a shift in Marshall and Warren had failed to establish “The taste of H. pylori is ‘no taste’. What medical thinking on the cause of stomach an animal model to demonstrate that the I mean is it acquires the taste of the ulcers. This culminated in 1994 at a

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was wonderful to see my family and friends having such a great time. Dr PIONEERS OF SELF-EXPERIMENTATION Warren and I spent the next few hours on the radio speaking to the various news Professor Marshall was a catastrophic effect on their Nicholas Senn and media groups around the world. At aware of self-experiments health. They were constantly the end of the evening we were the only after reading about the ill, tired and in pain, sober people remaining and I had to drive history of John Hunter’s however, their experiments everybody else home!” self-infection with did eventually pave the gonorrhoea and syphilis. way for the use of radium Still work to do Here, we look at three in medicine. In 1903, they Thirty-fi ve years after successfully other pioneers of medical jointly shared the Nobel growing the organism, H. pylori has self-experimentation. Prize in Physics. been established as the most common infection known to man and a major Marie Curie Stubbins Ffi rth cause of stomach cancer. Stubbins was a trainee H. pylori infects up to nine in 10 people doctor in the USA in the in developing countries, but with new early 19th century. He Nicholas was investigating combination therapies attaining cure conducted a experiments to whether cancer was rates of 90%, many lives (and much public prove that yellow fever was contagious. Among his money) have been saved. Professor Pentti not contagious. He started experiments was surgically Sipponen, Head of Pathology at Jorvi by rubbing the vomit of inserting a piece of Hospital in Finland, says: “Barry and those infected with yellow cancerous lymph node Robin’s discovery has meant enormous fever into incisions he had under his skin. In 1901, after savings in healthcare. I estimate this to be made on his body. an operation on a 60-year- billions and billions… Now practically all Ultimately, he moved on to old with lip cancer, he had gastric surgery, except that for cancer, is ingesting the vomit. He did the sample inserted under unnecessary and even unethical.” Along with her husband not catch yellow fever and the skin of his forearm. But for Professor Marshall, much work Pierre, Marie Curie routinely believed he had proven it Seven weeks later, just a red remains. “We still don’t know enough exposed herself to radiation. was not contagious. scar remained. Despite about the way H. pylori survives in the They hoped that radium’s However, another self- reporting his fi ndings in the stomach during a lifetime, obviously by burning effect might prove experimenter, army surgeon Journal of the American creating a balance between a pathogenic useful in the treatment of Jesse Lazear, proved yellow Medical Association, many surface organism and the attempts by the cancer. However, the fever was contagious if it scientists continued to body to eradicate it,” he says. radiation they routinely is directly transmitted into believe cancer was a “It seems to control the immune exposed themselves to had the bloodstream. communicable disease. system because in the stomach a fully- implemented immune reaction would probably bore holes in the mucosa, which Consensus Development Conference achievement with the 2005 Nobel Prize. would be opened up by the stomach acid in Washington DC convened by the US “Dr Warren and I were at the pub leading to dangerous haemorrhage.” National Institutes of Health (NIH). Most having a beer with fi sh and chips. It was Marshall and Warren’s achievement of the 22 researchers who attended pretty exciting, but it was the end of a was the product of a rigorous approach supported the claim that peptic ulcers are busy and stressful day and I had been to research, prepared minds that were caused by H. pylori. On 9 February 1994 up over the weekend preparing favoured by serendipity and – in the NIH panel concluded that ulcer slides and then giving a lecture Marshall’s case – a bold and patients with H. pylori infection should or two each day during the selfl ess approach towards be treated with antimicrobial agents. week before. I was overtired self-experimentation. A string of awards and honours and could not really participate followed (see box on p.20), including much in the celebrations after George F Winter is a journalist,

PHOTOGRAPHY: PUBLIC DOMAIN PHOTOGRAPHY: recognition of Marshall and Warren’s the announcement, although it author and Fellow of the IBMS.

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