The Medscape Awards in Infectious Diseases: Bacterium

1980-2012

John G. Bartlett, MD

June 01, 2012

The Most Important Discovery of a New Bacterium (1980-2012)

My choice for the greatest achievement in the discovery of a new bacterium is Helicobacter pylori. The story of this organism and its etiologic roles in peptic ulcer disease and gastric cancer is a prime example of a relationship that was long suspected but resisted bitterly by the medical establishment, with eventual victory and a Nobel Prize.

Early history relevant to the role of H pylori in peptic ulcer disease includes the 1868 recommendation by Kussmaul to use bismuth agents to treat peptic ulcer disease, although the antibacterial properties of bismuth were yet to be discovered.¹ In 1939, A. Stone Freedberg reported H pylori in the human stomach but abandoned this research when he was ordered to move on to other subjects.^2,3 Barry Marshall later speculated that Freedberg would have won the Nobel Prize for his discovery in 1951 if his mentor had allowed him to continue his work.⁴ In 1964, John Lykoudis⁵ recommended antibiotic treatment for peptic ulcer disease at a meeting of the Medico-Surgical Society of Greece, but the manuscript was rejected and Lykoudis was subsequently fined 4000 drachmas for administering this treatment.

The roles of Robin Warren (Figure 1) and Barry Marshall (Figure 2) in the discovery of H pylori began in 1981, when Dr. Marshall, a young gastroenterologist, joined Dr. Warren, a pathologist, in the Royal Perth Hospital in Australia.⁶

Figure 1. Dr. Robin Warren, self-portrait. Used with permission.

Figure 2. Dr. Barry Marshall. Courtesy of The Office of the Nobel Laureates, University of Western Australia, Perth.

Dr. Warren had observed the bacterium in gastric biopsies and autopsies, and Dr. Marshall advocated antibiotic therapy, which proved successful.⁶ Despite the early successes of these 2 eventual Nobel laureates, the road they traveled was not always smooth. Marshall and Warren reported "unidentified curved bacilli on gastric epithelium in active chronic gastritis" in The Lancet in 1983⁷ and a more comprehensive description of this association based on a review of 100 gastric biopsies in 1984.⁸ The field of gastroenterology, however, was not ready for this challenge to long-held beliefs about peptic ulcer disease and its treatment.

The backlash was brutal.¹ Dr. Larry Altman, medical correspondent for The New York Times, who reported these results, later wrote, "I have never seen the medical community more defensive or critical of a story."⁹ I spoke with Dr. Altman about these events, and to this day, he recalls that "this was the review that got me the most heat for misleading the public" (Personal communication. May 16, 2012).

To defend his thesis, in 1984 Marshall intentionally drank cultured H pylori and developed gastric symptoms, which were relieved with antibiotics.¹⁰ Another health professional who was similarly frustrated by the rejection of the theory of an association between H pylori and gastritis leading to peptic ulcer disease also consumed the putative agent. Multiple gastric biopsies before and after ingestion nicely demonstrated the resulting disease; however, Marshall's colleague was less fortunate because antibiotics were unsuccessful in eradicating his disease, and he had debilitating symptoms for 3 years.^11,12

My experience with this disease was brief but telling. In 1986, I was invited to present a summary of the science of a bacterial cause of peptic ulcer disease at the annual meeting of the American Gastroenterology Association in San Francisco. I reviewed the data and submitted my abstract, but was somewhat shocked by the response from those who had invited me because they insisted on an editorial rebuttal. Their concern was that some attendees listening to my talk "might actually believe a bacterial cause." The "Editor's Note" for the program read:

Dr. Bartlett has summarized results from a number of reports dealing with gastric campylobacter-like organisms (GCLO) and gastritis. While intriguing, these reports (most of which are letters or abstracts) have done no more than call attention to an association between gastritis and GCLO. What remains completely unsettled, in our opinion, is whether GCLO are the cause of gastritis or present as a result of gastritis (ie, organisms colonize only in the presence of inflamed mucosa of some other etiology).

Despite this relatively rude treatment of an invited guest, I braced for the encounter and showed slides of the gastric biopsies from before and after self-ingestion of H pylori by Arthur Morris.¹¹ I then placed a glass of water (that I claimed to have seeded with H pylori but which was actually plain water) on the podium and invited skeptics to drink after my presentation. There were skeptical comments, but no one drank from the chalice.

It is not possible to identify a specific data set or a particular report that changed conventional teaching about peptic ulcer disease to a recognition that it was a bacterial infection rather than a consequence of gastric acidity. The period between 1987 and 1990 was particularly important because during this time, antibiotics to eradicate H pylori resulted in high rates of cure and prevention of relapses.¹³ Subsequent work implicated H pylori as a cause of gastric cancer¹⁴and gastric lymphoma.¹⁵

The citation at the presentation of the Nobel Prize in 2005 is particularly important in terms of recognizing the importance of both the pathogen and the disease it causes:

Against prevailing dogmas, you [Drs. Warren and Marshall] discovered that one of the most common and important diseases of mankind, peptic ulcer disease, is caused by a bacterial infection of the stomach. Your discovery has meant that this frequently chronic and disabling condition can now be permanently cured by antibiotics, to the benefit of millions of patients. Your pioneering work has also stimulated research all around the world to better understand the link between chronic infections and diseases such as cancer.

The rationale for this selection as the most important discovery of a bacterium and its role in human disease is based on several observations that contribute to the weight of H pylori as an important and unusual pathogen.

It is one of the most common infections, on the basis of serology studies that imply not simply colonization but an immune response to microbial infection. Most serologic studies show prevalence rates of 20%-90%; which vary substantially by age (with rates greater than 50% in persons older than 50 years) and by social class or national patterns of hygiene.¹⁶ In the United States, approximately 30% of people are colonized with H pylori, and colonization persists unless the person takes antibiotics directed against H pylori.
H pylori is the major cause of peptic ulcer disease, which affects 15%-20% of those colonized or approximately 10% of the population at a cost of approximately $3.4 billion per year for healthcare in the United States.¹⁷
H pylori is an unusual infection because it causes a chronic inflammatory response without the usual findings to suggest infection, such as elevation of C-reactive protein level, erythrocyte sedimentation rate, or procalcitonin level.¹⁸ As a traditional infectious disease model, H pylori violates all the rules.
H pylori is a recognized carcinogen, presumably by its association with chronic inflammation (chronic gastritis).¹⁴ Thus, it is the only bacterium listed as a class 1 carcinogen,¹⁹ and it is also implicated in gastric lymphoma.¹⁵

The long battle to legitimize H pylori as a human pathogen was the classic example of the difficulty our profession has with unconventional theories. For this and the other reasons cited above, the discovery of H pylori receives my vote for the greatest achievement in discovery of a bacterium in the past 30 years.