My Track Record

Portrayals of science and scientists on television and in movies are often hilariously fanciful. In the generally wonderful BBC/PBS series “Sherlock,” for example, the title character sees the chemical structures of individual molecules through an ordinary light microscope. I guess peering into a ‘scope makes for more compelling and succinct visuals than, say, running samples through an HPLC and laboriously comparing them to standards. (“It’s UNCANNY, Watson! The retention time in THIS solvent is 9.72 minutes — HIGHLY suggestive of a halogen-substituted phenol!”)

Every so often, though, you come across a real-life science story that has an undeniably cinematic arc. Such is the tale of Australian physicians Barry J. Marshall and J. Robin Warren, who won the 2005 Nobel Prize in Medicine or Physiology for discovering the bacterium Helicobacter pylori and showing that it causes most cases of gastritis and peptic ulcers.

As recounted by Marshall (2001), his work with Warren drew upon four previously disparate strands of biomedical ideas and evidence. These strands, as of the late 1970s, were as follows. (1) Spiral-shaped bacteria had occasionally been found in the stomachs of various mammals, including humans. But these bacteria were not widely suspected of causing any particular disease. (2) Gastritis –- inflammation of the stomach -– was a well-known problem generally attributed to stress, which supposedly induced secretion of excessive acid into the stomach. But some patients developed gastritis despite an impaired ability to secrete acid. (3) An enzyme called urease, which breaks urea into carbon dioxide and ammonia, had been found in the stomach; some evidence suggested that it had been produced by bacteria. But urease’s importance, if any, was unclear. (4) Formulations containing bismuth, a heavy metal, had been used to successfully treat nonspecific gastrointestinal problems. But the mechanism of action and the importance of the bismuth itself were not clear either.

In pivotal studies conducted mostly in the early 1980s, Marshall and Warren synthesized these four strands into a coherent theory, as follows. Gastritis was not caused by acid secretion problems per se but by the spiral bacterium, H. pylori, which burrows into the mucus lining the stomach and causes inflammation. While most bacteria cannot survive the low pH of the stomach, H. pylori produces and secretes urease, which helps it weather the acidic environment by producing ammonia, which serves as a buffer. Finally, bismuth can cure gastric problems by serving as an antibiotic, killing H. pylori and ending the corresponding inflammation.

This was an exciting story in and of itself, but there was more. Not only does H. pylori cause the acute condition of gastritis, it turns out to be the main culprit in the chronic conditions of stomach ulcers and stomach cancer. Antibiotics were found to cure ulcers as well as gastritis (Marshall et al., 1988), and to drastically reduce the incidence of stomach cancer.

Marshall and Warren were initially ridiculed and dismissed. One can debate the extent to which this skepticism on the part of the scientific community was appropriate, because the preliminary evidence produced by Marshall and Warren was clear, but not overwhelming. A perfect example of this is the study in which Marshall et al. (1985) fulfilled Koch’s four postulates for identifying the causative agent of an infectious disease. Meeting the postulates is strong evidence that a disease’s cause has been found (Evans, 1976), so Marshall et al.’s (1985) study could be considered strong, yet — spoiler alert! — it was conducted on only one subject, Marshall himself, who gave himself gastritis by drinking a broth of H. pylori taken from another patient. Marshall believed this necessary because he had not been able to get H. pylori to cause disease in a healthy animal (Marshall & Adams, 2008), the usual way of fulfilling Koch’s third postulate. The study was not published in an elite journal but rather The Medical Journal of Australia, whose middling reputation may have also limited awareness and acceptance of the conclusions. Moreover, the idea that bacteria could cause disease in the stomach was considered implausible by many physicians, who assumed that the stomach’s high acidity kills essentially all microbes (Weintraub, 2010).

Another major, slightly comical step forward came during Marshall and Warren’s first big clinical study, in which they checked 100 gastritis patients for the possible presence of H. pylori in their stomachs (Marshall & Warren, 1984). They had no luck with the first 34 patients, but — spoiler alert! — sample #35 came back positive after incubating over a long holiday weekend, which gave the slow-growing H. pylori extra time to reveal itself. (It was actually during Easter. How perfect is that? On the third day, the bacteria appeared again. They were alive after all! Alive, I say!) After this, all samples were incubated for four days rather than two, and most were found to contain H. pylori.

It really is a great story. Why hasn’t it been turned into a movie?

REFERENCES

Evans, A. S. (1976). Causation and disease: the Henle-Koch postulates revisited. The Yale Journal of Biology and Medicine, 49(2), 175-195.

Marshall, B. J. (2001). One hundred years of discovery and rediscovery of Helicobacter pylori and its association with peptic ulcer disease. In H. L. T. Mobley, G. L. Mendz, & S. L. Hazell (Eds.), Helicobacter pylori: Physiology and Genetics. Washington (DC): ASM Press.

Marshall, B., & Adams, P. C. (2008). Helicobacter pylori: A Nobel pursuit? Canadian Journal of Gastroenterology, 22(11), 895.

Marshall, B. J., Armstrong, J. A., McGechie, D. B., & Glancy, R. J. (1985). Attempt to fulfil Koch’s postulates for pyloric Campylobacter. The Medical Journal of Australia, 142(8), 436-439.

Marshall, B. J., & Warren, J. R. (1984). Unidentified curved bacilli in the stomach of patients with gastritis and peptic ulceration. The Lancet, 323(8390), 1311-1315.

Marshall, B., Warren, J. R., Blincow, E., Phillips, M., Goodwin, C. S., Murray, R., … & Sanderson, C. (1988). Prospective double-blind trial of duodenal ulcer relapse after eradication of Campylobacter pylori. The Lancet, 332(8626), 1437-1442.

Weintraub, P. (2010). The Dr. who drank infectious broth, gave himself an ulcer, and solved a medical mystery. Discover Magazine, March 2010.