Albert Lasker
Clinical Medical Research Award

Award Description

Barry Marshall
For the visionary discovery that Helicobacter pylori causes peptic ulcer disease.

A half-century of entrenched ideas about the causes of gastritis and peptic ulcer disease were challenged by the iconoclastic Dr. Marshall, whose belief in the accuracy of his clinical observations led him to experiment on his own body, and embarked him upon a worldwide crusade to convince colleagues that a bacterium, Helicobacter pylori, was the real culprit causing ulcers. Enduring skepticism and derision for his unorthodox idea, Dr. Marshall nonetheless prevailed as researchers, bent on demolishing his hypothesis, ironically ended up confirming it.

Peptic ulcer disease is a painful inflammation of the gastric and duodenal epithelium that leads to erosive cratering. Twenty-five million Americans and countless millions of others around the world are plagued with this condition. Its chronic, life-disrupting pain was relieved only by acid-reducing medications. The paradigm-shattering hypothesis promulgated by Dr. Marshall proposed that peptic ulcer disease could actually be cured through the use of comparatively inexpensive antibiotic therapy.

In this century, theories about the cause of ulcers have taken two forms—the psychosomatic and the dysregulatory. Stress induced by modern life was believed to turn the body against itself in a theory still prevalent today. Rest, anxiety reduction and special diets are the cornerstones of therapy in the psychosomatic model. In the dysregulatory model, hypersecretion of stomach acid caused injury to the gastric and duodenal lining. Antacids became the standard ulcer therapy, and when the gastric H₂ receptor that regulates acid secretion was identified, the acid theory gained credence in the minds of physicians armed with safe and effective acid-suppressing drugs. Although ulcers could be managed with increasing sophistication, their high rates of recurrence remained a vexing clinical problem.

That problem was destined to be solved in the paradigm shift Dr. Marshall would initiate as a result of work he began in 1982, with J. Robin Warren, a pathologist at Royal Perth Hospital in Australia where Dr. Marshall was training in gastroenterology. Dr. Warren had first noticed the presence of bacteria in biopsy specimens of stomach tissue taken from ulcer patients. Dr. Marshall biopsied 100 gastritis and ulcer patients and found a strong correlation between morbidity and the microbes. Presenting these observations at a 1983 infectious disease workshop in Brussels, the young Dr. Marshall created a sensation when he put persuasion before proof, and declared that people free of bacteria were free of peptic ulcers.

In a joint 1984 paper published in The Lancet, Dr. Marshall and Dr. Warren described isolating and growing a previously unidentified bacillus from biopsies of the gastritis and ulcer patients. The pyloric campylobacter, as they called it, survived the extreme acidity of the stomach by penetrating the thick mucus lining of the stomach walls and growing in the grooves between cells. Since the deeper mucus layers are slightly alkaline, the bacteria thrived in a neutral environment protected from gastric acid. The paper contained a discussion of the inability of acid-suppressing H₂ receptor antagonists to prevent ulcer recurrences, while noting that bismuth-containing compounds did improve rates of relapse. Bismuth is bactericidal, and in patients treated with it, bacteria disappeared and gastritis improved. Their paper also contained the hypothesis which Dr. Marshall would go to great lengths to prove: Bacteria could be the cause of chronic gastritis and peptic ulcer disease.

Proving that a bacterium is the cause of a disease requires a researcher to perform a set of experiments known as Koch's Postulates. The four experiments: Isolate the organism from the diseased animal; grow the organism in vitro; introduce the organism into a healthy animal so that it gets the disease; and finally isolate the same organism again. Scientists use animal models for these proofs, but Dr. Marshall faced an enormous obstacle: No animal model existed for chronic gastritis. Rats and pigs, fed his bacterial stew, ate the microbes like a main course. Then in 1984, on the 100th anniversary of Koch's original publication, Dr. Marshall made a courageous decision: He would perform the experiments on himself.

The April 15, 1985 issue of the Medical Journal of Australia contained a cool clinical description of the dramatic experiment:

"A volunteer (Dr. Marshall) with normal gastric mucosa received pyloric campylobacter by mouth. A mild illness developed which lasted 14 days. Gastritis (proven by biopsy) was present on the tenth day after ingestion of the bacteria, but this had largely resolved by the fourteenth day. The syndrome of acute pyloric campylobacter gastritis is described. It is proposed that this disorder may progress to a chronic infection which predisposes to peptic ulceration."

Following publication of Dr. Marshall's auto-infection paper, interest in the bacterial cause of ulcer disease increased worldwide. Working with Ivor Surveyor, Dr. Marshall developed a simple test to confirm the presence or absence of the bacteria without endoscopic biopsy. Based upon the bacteria's release of urease, an enzyme not found in the stomach, the test measures increased carbon dioxide in the breath resulting from the enzyme's ability to break down urea.

In 1986, Dr. Marshall accepted an appointment at the University of Virginia to continue his work, publishing in 1988 the first double-blind study of duodenal ulcer relapse rates after eradication of H. pylori. The study found that 92 percent of ulcers healed after the bacteria disappeared and only 21 percent relapsed within the following year. When the bacteria persisted, only 61 percent of ulcers healed, and, once healed, 84 percent recurred.

Armed with new diagnostic tests for the bacterium, epidemiologists looking at populations on all continents began to see the truth: Everywhere gastritis and peptic ulcer disease struck, the bacteria could be found. So widely spread was the bacteria in humans, it appeared to be the world's most common chronic infection. But even more startling were reports that the bacterium, now officially named Helicobacter pylori, was associated with the occurrence of stomach cancer. Decreased prevalence of H. pylori was strongly associated with declining incidence of the cancer. Starting out to create one revolution, Dr. Marshall had inadvertently created another—the idea that a bacterial infection could cause a cancer.

As Dr. Marshall propounded his testable hypothesis, investigators attempting to disprove it began, instead, to report confirmation. In 1994, the National Institutes of Health convened a Consensus Panel on Helicobacter pylori in Peptic Ulcer Disease. The published report supported Dr. Marshall's theory while noting that most people infected with H. pylori do not develop duodenal or gastric ulcers, implying that factors including the particular strain of bacteria and individual susceptibility play a role in peptic ulcer disease. The Consensus Report recommended that patients with H. pylori ulcers be treated with antibiotics to eradicate the infection, as well as acid-suppressing agents to relieve the symptoms.

Flying solo against the winds of orthodoxy, Dr. Marshall put the infection theory of ulcers on the map of medical discoveries. The gratitude of untold millions of ulcer patients is embodied in his 1995 Albert Lasker Clinical Medical Research Award.