Barry Marshall and his colleague Robin Warren investigated stomach bacteria – a bizarre, wasteful activity said their critics citing the medical textbooks, which said micro-organisms could not survive in the stomach because of its high acidity.
Marshall and Warren theorized that a new species discovered in the stomach by Warren, Helicobacter pylori, was the unexpected cause of stomach ulcers, a condition that killed 500,000 people a year.
The researchers discovered that specific antibiotics killed the bacteria and cured ulcers permanently. Their evidence was largely ignored – perhaps because drug companies’ biggest profits at that time came from expensive ulcer medication taken twice daily.
In 1983, Australia’s Gastroenterological Society rejected Marshall’s request to present his research at their yearly conference. They rated his work, which would later merit a Nobel Prize, in the poorest 20 percent of papers submitted for the conference.
The following year, Marshall ingested Helicobacter pylori to deliberately infect his own stomach. Within days he was very ill, establishing a causal link between the bacteria and stomach disease.
Four decades after their discovery, Marshall and Warren were awarded the Nobel Prize in Physiology or Medicine.
Barry James Marshall was born in Kalgoorlie, Western Australia on September 30, 1951. His 19-year-old father was an apprentice fitter & turner who ended up running Kentucky Fried Chicken processing plants; his 18-year-old mother was a student nurse. Barry was the eldest of their four children.
At age eight, Barry moved with his family to Perth, the state capital. He was high-schooled at Newman College. In 1969, he began studying at the University of Western Australia School of Medicine, where in 1974, he received a Bachelor of Medicine and Bachelor of Surgery (MBBS).
In the not-so-distant past, stomach ulcers – holes in the stomach’s lining – were a major medical problem. Ulcers allowed highly acidic stomach fluid to burn into other tissues, causing severe pain and internal bleeding. All too often the condition had fatal consequences.
In the 1970s, James Black invented a new drug called cimetidine, marketed under the name Tagamet, which blocked the action of stomach acid, decreasing the stomach’s acidity. It became the most prescribed drug in the world and was the first drug in history to achieve sales of more than $1 billion a year. It did not cure ulcers, but, taken daily, stopped the worst of their effects.
This was the situation when the newly qualified Barry Marshall decided he would like to specialize in gastroenterology – stomachs and intestines. He made his choice because gastroenterologists were generally free in the evenings and at weekends!
Ulcers and Stress
Marshall found one or two patients a day arriving in his hospital with bleeding ulcers – many of them would need surgery in the shape of a partial gastrectomy, losing half of their stomachs.
The surgeons and the medical establishment believed stomach ulcers appeared in people whose lives were stressful, which made their stomachs more acidic.
Ulcers and Bacteria
In 1979, Marshall, now a junior hospital registrar, was in need of a research project. He met Robin Warren, a pathologist, who was talking to anyone who would listen – not many would – about bacteria in people’s stomachs.
Warren had seen bacteria in a sample of stomach lining – he had then used silver staining to confirm his observation.
The view that micro-organisms could not live in the stomach was so entrenched that gastroenterologists were often lax about hygiene, with the result that the bacteria Warren had observed were transferred from one patient to another by unsterilized instruments.
Marshall and Warren discovered that helicobacter pylori were present in the stomachs of 90 percent of people with stomach ulcers: they believed that, in most cases, stomach ulcers were caused by this bacteria.
Growing the Bacteria – Success by Accident
In order to further their case, Marshall and Warren took samples of bacteria from ulcerated stomachs and attempted to grow the bacteria in petri dishes. For months, nothing worked. Then, on the Easter weekend of 1982, their hospital was particularly busy. The petri dish samples, which were normally thrown out after two days, were kept longer, because no-one was available to dispose of them. It was Wednesday before anyone looked at the petri dishes. Abundant colonies of bacteria had grown. Marshall and Warren gave these bacteria the name Helicobacter pylori.
Marshall was dumbfounded and annoyed when he learned that his bacteria samples had always been given just two days to grow. If he had taken the trouble to learn about how samples were cultured at the hospital, his work would have advanced more rapidly.
Not Killing the Bacteria
Marshall decided that Helicobacter pylori ought to be vulnerable to treatment by antibiotics. He experimented with a few drugs, but none worked.
Puzzled, he began reviewing the history of ulcers and found that in the 1860s Adolf Kussmaul, a German doctor, had used bismuth compounds to treat ulcers. And Pepto-Bismol, an over-the-counter medication, was being used by some ulcer sufferers to lessen their symptoms.
When Marshall gave bismuth compounds to his patients, although their symptoms improved somewhat, and the Helicobacter pylori were temporarily suppressed, the patients always suffered relapses.
Killing the Bacteria – Another Happy Accident
Eventually, Marshall gave bismuth to an ulcer patient who was also suffering from another infection, which was being treated with metronidazole, an antibiotic.
Here was the breakthrough! The patient’s ulcers were cured.
Marshall realized that the twin attack of bismuth and metronidazole killed Helicobacter pylori and cured stomach ulcers.
In the first few months of 1984, Marshall tested bismuth and metronidazole on a few patients – the first four he treated were completely cured of stomach ulcers.
The medical establishment, however, remained stubbornly skeptical:
The Problem of Publishing
Marshall and Warren, believing that they had a cure for stomach ulcers, began presenting their work at conferences, which helped them find important scientific (but not medical) allies – particularly the microbiologist Martin Skirrow, who had chaired a conference in Belgium on Campylobacter bacteria. Skirrow invited Marshall to his hospital in Worcester, UK, and was impressed by what the young Australian doctor told him.
In 1984, Marshall and Warren sent a paper to the prestigious medical journal, The Lancet. The paper was rejected at the peer-review stage.
Martin Skirrow intervened and told the Lancet’s editors he had replicated Marshall and Warren’s findings. After months of delay, The Lancet published Marshall and Warren’s work.
In their paper, Marshall and Warren showed cases where they believed Helicobacter pylori had been seen by scientists in earlier times, but forgotten about.
The Australian scientists were the first to culture this new species, which they provisionally called pyloric campylobacter – it is now recognized as belonging to a new genus Helicobacter.
In a study of 100 patients who were referred for gastroscopy, they found a close association between these new bacteria and antral gastritis – an inflammation of part of the stomach lining.
“We know of no other disease state where, in the absence of complicating factors such as ulceration, bacteria and polymorphonuclear leucocytes are so intimately related without the bacteria being pathogenic… Although cause-and-effect cannot be proved in a study of this kind, we believe that pyloric campylobacter is aetiologically related to chronic antral gastritis and, probably, to peptic ulceration also.”
Barry J. Marshall and J. Robin Warren
Unidentified Curved Bacilli in the Stomach of Patients with Gastritis and Peptic Ulceration.
The Lancet 323(8390), pp. 1311–1315; June 16, 1984
Drinking Helicobacter pylori
To establish a causal link between Helicobacter pylori and illness, Marshall, who considered himself the only person who could give fully informed consent to the procedure, decided to infect himself with the bacteria. He told only a couple of trusted colleagues of his plan, fearing that an ethics committee would refuse him permission if word got out.
At Marshall’s request, Neil Noakes, a Fremantle Hospital microbiologist, made up a beaker containing a heavy suspension of the bacteria. Noakes could only watch in amazement when Marshall put the beaker to his lips and drank down 50 ml of cloudy brown bacterial fluid in a single gulp.
Five days later, Marshall began feeling ill, waking in the night with stomach pains and vomiting daily. Ten days after he drank the fluid, he was tested and Helicobacter pylori bacteria were found to be proliferating in his stomach.
With this experiment, Marshall proved that Helicobacter pylori was a pathogen.
And then his vomiting stopped. His stomach was tested again – this was 14 days after drinking the fluid. Helicobacter pylori were no longer present. In Marshall’s case, it seemed that Helicobacter pylori had been defeated by his body’s immune system.
Marshall and colleagues reported on this rather infamous experiment in the April 15, 1985 edition of The Medical Journal of Australia.
The Problem of Acceptance by the Medical Establishment
At first, the medical and pharmaceutical fields ignored Marshall and Warren’s discovery. Marshall observed that nobody could make a profit from of his discovery because his treatment worked using cheap, out-of-patent drugs.
In July 1984, Dr. Larry Altman, an American medical writer, spoke to Marshall by telephone and wrote an article for the New York Times: “New Bacterium Linked to Painful Stomach Ills”. Altman linked ulcers with Helicobacter pylori. He found it hard to get it past his editor and had to include skeptical voices from medical professors at Yale and Tufts telling readers that antibiotics were unlikely to help ulcers and it would take a decade to gather convincing evidence.
This article led to another article in The Star. The result was that readers who had suffered from stomach ulcers for years bypassed the medical establishment and started bombarding Marshall with letters asking for his advice on how to eradicate them.
It also meant ulcer sufferers were suddenly scrambling to take part in Marshall’s next clinical trial.
In 1985, Marshall conducted a double-blind placebo trial at the Royal Perth Hospital of a variety of treatments for ulcers.
He found that to cure 10 patients with the old treatment involving Tagamet, 104 patients needed to be treated. To cure 10 patients with Marshall’s treatment (bismuth and antibiotic) only 14 patients needed to be treated.
In the early 1990s other researchers began testing Marshall’s method.
Eventually, in 1994, the National Institute of Health in Washington concluded that in all cases of peptic ulcer, the essential first step was the identification and eradication of Helicobacter pylori.
Many of us are infected with Helicobacter pylori
About half of the world’s population is infected with Helicobacter pylori, mostly unaware of it. Marshall found that the bacteria are strongly associated with inflammation and stomach cancer – the first time a link between bacteria and cancer had been found. People infected with Helicobacter pylori are at least 10 times more likely to get stomach cancer than people who are not infected.
Marshall and Warren received the 2005 Nobel Prize in Physiology or Medicine for their “discovery of the bacterium Helicobacter pylori and its role in gastritis and peptic ulcer disease.”
Alfred Nobel would have approved – the founder of the famous prize suffered from stomach ulcers!
Other awards received by Marshall include:
1994: Warren Alpert Foundation Prize
1995: Lasker Prize
1997: Paul Ehrlich Prize
1998: Buchanan Medal
1999: Benjamin Franklin Medal for Life Sciences
2002: Keio Medical Science Prize
2003: Australian Centenary Medal
2003: Macfarlane Burnet Medal
2006: Western Australian of the Year
2007: Companion of the Order of Australia
Some Personal Details
Marshall married Adrienne Feldman, a psychology student, in 1972, while he was a medical student. They have four children. The family moved from Australia to America in 1986, when Marshall accepted a position at the University of Virginia. They returned to Australia in 1996.
In an interview with the Sydney Morning Herald in 1997, Adrienne said of her husband:
“He’s got a dreadful sense of humour. 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.”
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