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Barry James Marshall—Discovery of Helicobacter pylori as a Cause of Peptic Ulcer

      Barry James Marshall was born September 30, 1951, in Kalgoorlie, a mining town about 400 miles east of Perth, Western Australia. Two years later his father, a pipefitter, drove 1,000 miles north to Carnarvon where he found employment at a whaling station. His mother moved the family to Perth 5 years later because she wanted their 4 children to obtain a university education. Although Marshall was a good student, he did not excel, but he had a boundless curiosity and many interests. He attended Newman College (University of Melbourne), where it was felt that his mathematical ability was insufficient to study his initial preference of electrical engineering. Subsequently, he chose medical school and attended the University of Western Australia in Perth.
      During medical school, he met and married Adrienne, a psychology student. His internship and residency in internal medicine were completed at Queen Elizabeth II Medical Centre (Sir Charles Gairdner Hospital) in Perth. He began his training as a specialist in 1978 and the following year moved to the Royal Perth Hospital to study cardiology. In 1981, he rotated to the gastroenterology division where he met J. Robin Warren, a pathologist. Marshall was looking for a research topic and learned that Warren had a list of patients whose gastric biopsies showed “curved” bacteria. Warren needed a clinician to follow the patients to see what diagnoses they had and their subsequent progress. Marshall had treated a patient with severe abdominal pain but no apparent diagnosis; the only abnormal finding in the patient at endoscopy was erythema of the stomach and curved bacteria in the stomach biopsy. He referred her to a psychiatrist who gave an antidepressant.
      In their first meeting, Warren showed slides of the curved bacteria and the histologic features of the gastric mucosa. Marshall was aware of the finding of Campylobacter jejuni as a cause of food-borne gastroenteritis. He noted that the Campylobacter organisms appeared very similar to the curved bacilli that Warren had reported in his gastric biopsies. In reviewing the literature, Marshall found that these curved spiral bacteria had been reported but had been ignored, thought to be an artifact. His gastroenterology rotation ended and in 1982 he became a hematology registrar providing care for bone marrow transplant patients. During the last 6 months of the rotation year he was assigned to Port Hedland Hospital, 1,200 miles north of Perth.
      He took his records and notes and continued to study the approximately 100 patients that he and Warren had collected. While at the Port Hedland Hospital, he presented his work to the local College of Physicians Meeting at which it received a mixed response, because at the time emotional stress and spicy food were thought to be the major causes of gastritis and ulcers. His wife, Adrienne, was most helpful in editing his early papers because of her writing skills. She continued to play a major role in his published papers, presentations, and books.
      Marshall learned that his contract at the Royal Perth Hospital would not be renewed at the completion of his training as no consultant positions were available. Fortunately, he was approached by the Fremantle Hospital, the smallest teaching hospital in Perth. He accepted a position and developed an enthusiastic group of co-workers, as well as support from the hospital. Further research revealed that the majority of patients with peptic ulcer at the hospital had the curved bacteria in their gastric biopsies, which became known as Campylobacter pylori in 1982. In early 1983, he contacted Dr Martin Skirrow, a gastroenterologist at the Worcester Infirmary in England, who subsequently invited him to present his work at the European Campylobacter Meeting in Brussels. Marshall visited Skirrow in England, where he saw that peptic ulcer patients there had the spiral organism in their biopsies, just as he had seen in Australia. Cliodna McNulty, a registrar at Worcester, successfully isolated the spiral organism.
      During the succeeding months, a number of other investigators in Australia and Europe also recognized the presence of bacteria in gastric biopsies of peptic ulcer patients. Marshall and Warren reported in The Lancet in 1984 the presence of the curved bacteria in 77% of 22 patients with gastric ulcer and in 100% of 13 patients with duodenal ulcer. No spiral bacteria were grown from the first 34 cases, presumably because the cultures were discarded too soon; on Easter weekend 1982, a more prolonged culture grew the organism. In 1989 the organism was renamed Helicobacter pylori after ribosomal sequencing showed it was distinct from Camplyobacter.
      Marshall was unsuccessful in developing an animal model, so he decided to experiment upon himself. In 1984, following a baseline endoscopy which showed a normal gastric mucosa, he drank a culture of the organism. Three days later he developed nausea and achlorhydria. Vomiting occurred and on day 8 a repeat endoscopy and biopsy showed marked gastritis and a positive H. pylori culture. At day 14, a third endoscopy was performed and he then began treatment with antibiotics and bismuth. He recovered promptly and thus had fulfilled Koch’s postulates for the role of H. pylori in gastritis.
      Late in 1984, Marshall obtained funding from the Australian Medical Research Council to conduct a prospective double-blind trial to determine if antibiotics could cure duodenal ulcer. He moved from Fremantle to the Royal Perth Hospital because more patients would be available for the trial. He then began to work closely with Warren again; they had met only periodically while Marshall was at the Fremantle Hospital.
      Marshall was contacted by Procter & Gamble, Co. (P&G) who patented much of his work with treatment using bismuth and antibiotics to treat the gastric bacteria. P&G set up a laboratory at the University of Virginia, Charlottesville, where Marshall and his family moved in order to continue his research. In 1994, the National Institutes of Health had a consensus meeting in Washington, DC, that ended with a statement to the effect that the key to treatment of gastric and duodenal ulcers was the detection and eradication of H. pylori. In 1994, he took a leave of absence and worked to get the breath test approved by the Food and Drug Administration. He and his family returned to Perth in 1996, when he was awarded a McFarlane Burnet Fellowship, which funded a laboratory at the University of Western Australia. He continues to live in Perth and practices at the University, where he sees patients in the gastroenterology department of the Sir Charles Gairdner Hospital.
      He was the recipient of the Lasker Award in 1995 and the Benjamin Franklin medal in 1999. He shared the Nobel Prize for Medicine or Physiology in 2005 with J. Robin Warren. He was honored by a stamp issued by the Solomon Islands in 2014, in a sheet that also depicted penicillin co-discoverer Alexander Fleming. Scott Number 1551.