Thursday, May 19, 2022

Part I

Some stories in cancer discovery really need a movie—this is one of them. Let us start by reflecting that it is estimated that 20% of cancer is caused by infectious agents. By and large, this mainly refers to viruses. OK, there is a schistosome or two that causes cancer. But today’s article revolves around a bacterium that causes cancer.

Why is it noteworthy that bacteria are involved? Because that brings into play the possibility of treatment or prevention with antibiotics, which is not true with other microorganisms.

Helicobacter pylori are spiral-shaped gram-negative bacteria resident in the distal part of the stomach (the part closer to the small intestine). In some parts of the developing world and Far East, they are present in over 50% of the population. Nonetheless, this was not recognized or “discovered” until after 1980. This seems to stem from the fact that it burrows under the mucosal layer of the stomach in order to protect itself from the stomach’s strong acidic environment.

In the early 1980s, the causes of gastritis and ulcers were thought to be understood to occur as a result of hyperacidity stemming from stress and other physiologic causes. New, effective acid-suppressant drugs had recently made their appearance on the market and greatly improved treatment of these conditions. Thus, when two young Australian gastroenterologists, Barry Marshall and Robin Warren, recognized the presence of these bacteria on biopsy specimens from endoscopies at that time, there was not much interest by the medical community—the bacteria were thought to be commensal—the H. pylori could survive in that climate but had no pathologic impact on the environment.

Marshall and Warren managed to obtain a grant for a one-year study of 100 gastric endoscopies in which biopsies were taken and cultured for the presence of the bacteria with the aim of correlating the presence of the bacteria with abnormal diagnoses. As it turned out, the first 30 biopsies were negative for any bacterial growth. Only on the 31st culture was H. pylori grown out in the petri dish. What had happened? The lab technicians were disposing of the plates after 48 hours as was normal for the usual cultures. The last plate, the 31st, was left in the incubator over the weekend—H. pylori is a slow-growing microorganism and requires more than 48 hours to appear. So six months of work was wasted (on a 12-month grant). but ultimately they obtained their data. It turned out that H. pylori grew out of the vast majority of the biopsies from patients with gastritis or duodenal ulcers.

When this was written up and submitted for publication, the journal reviewers did not believe the data or think it significant, so the initial papers were rejected—the same skepticism was present when Marshall presented these findings at gastroenterology meetings. Bacteria could not possibly be responsible for gastritis/ulcers. This led to a remarkable undertaking in 1983—self-experimentation. Marshall, after a normal gastroscopy, personally swallowed a broth containing H. pylori. The expectation was that it would take weeks/months for illness to develop. Instead, he had symptoms after a few days and within 10 days had severe gastritis on endoscopy as well as very positive biopsies for the bacterium. He terminated the experiment at 14 days by taking an antibiotic. (It is of note that this is one of several stories of self-experimentation in medical history that have become the stuff of legend.)

This was a fulfillment of Koch’s postulates, a set of rules promulgated by Robert Koch in 1890 for establishing causation between an infectious agent and a disease. It is very rare that we are able to fulfill these postulates in humans—most ethics committees would be unwilling to allow such experiments to be undertaken.

Nonetheless, the success of this self-experimentation led to further acceptance of the role of H. pylori in gastritis and ulcer disease. Marshall and Warren went on to conduct randomized trials with various antibiotic regimens to demonstrate that the bacterium could be eradicated and that eradication of the bacterium would prevent the associated diseases. The long-term impact is that patients with persistent hyperacidity symptoms are routinely screened and, if H. pylori is cultured or detected, they are treated and the bacteria eliminated.

The mode of transmission of this bacterium is still unknown. It is the most widespread chronic infection in the world, with over half of the world’s population harboring the bacterium, 70% in Africa. However, in the United States and the West, the infection rate is much lower. The overall rate is about 30% in the U.S. but seems to be declining, and is race/ethnicity dependent—15-20% among whites, 40-50% among blacks, 60% in Hispanics.

Marshall and Warren shared the 2005 Nobel Prize in Medicine for their work on H. pylori and gastritis/ulcers. But important for us is that H. pylori has important etiologic connections to cancer—it is a major cause of gastric cancer and to other cancers as well. We will explore these issues in the next episode of Thoughts on Cancer.

Alfred I. Neugut, MD, PhD, is a medical oncologist and cancer epidemiologist at Columbia University Irving Medical Center/New York Presbyterian and Mailman School of Public Health in New York.

This article is for educational purposes only and is not intended to be a substitute for professional medical advice, diagnosis, or treatment, and does not constitute medical or other professional advice. Always seek the advice of your qualified health provider with any questions you may have regarding a medical condition or treatment.

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