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The newspaper of The Johns Hopkins University November 6, 2006 | Vol. 36 No. 10
Thinking Out Loud

William R. Brody

By William R. Brody


I recently attended the awards ceremony where Carol Greider received the 2006 Lasker Award for Basic Medical Research for her co-discovery of the telomerase enzyme. It was a wonderful event, and the chair of the Lasker Awards committee, Joseph Goldstein, presented the trail of studies that eventually led to the discovery of telomeres and telomerase.

At the ceremony, I heard a wonderful quote attributed to Albert Szent-Giorgyi, who received the Nobel Prize in 1937:

"Discovery consists of seeing what everyone else has seen and thinking what no one else has thought."

This is one of the best descriptions of the process of discovery, and it is a succinct yet profound way to characterize what Hopkins faculty members, postdoctoral fellows and students attempt to do during their tenure here.

When a fundamental breakthrough occurs in science, that field of investigation looks entirely different post-discovery than it did pre-discovery. And yet, looking back, we can note two interesting things about these discoveries. First, they are based upon observations made before by many people, but only one or a few had had the courage or insight or creativity to draw a new conclusion from the evidence. And second, the insight appears "obvious" once the data are conclusive, even though prior to that time the new hypothesis had been very controversial.

Nothing illustrates these points better than the work of Dr. Barry T. Marshall. Until 1983, the established dogma — based upon years of observation by thousands of investigators — was that ulcers in the upper gastrointestinal tract resulted from excess acid secretion in the stomach and, therefore, were aptly named peptic ulcers. It all made perfect sense. I recall long discussions about them in my medical school pathology class, and subsequently having to prepare a background paper for my internal medicine rotation, discussing the etiology of peptic ulcer disease, when one of my assigned patients had a peptic ulcer. All of the treatment regimes, pharmacological or surgical, were based on mechanisms to reduce the secretion of acid in the stomach.

Along came Dr. Marshall, who speculated that the same observed phenomena might be explained rather differently: that the etiology of peptic ulcers was inflammation from bacteria or other infectious agents that thrive in high-acid environments. "Impossible," said many of his colleagues. "Everyone knows bacteria can't survive in high-acid environments." His ideas were felt to be prerequisites for committing him to an institution for patients with refractory insanity. But Marshall persisted nonetheless.

I frequently comment that a fine line exists between perseverance, a trait generally held in very high esteem, and perseveration, a term that a psychiatrist is more likely to utter in the discussion of a patient's abnormally repetitive behavior. Fortunately for the world of medical science and for thousands who suffer from peptic ulcer disease, Marshall persevered. He discovered that certain strains of helicobacteria thrive in high-acid environments found in the stomach and duodenum and, in fact, can create gastritis and ulcers. He was awarded the Lasker Prize in 1995 and the Nobel Prize in 2005, and his work has completely changed the landscape for understanding and treating patients with "peptic" ulcer disease.

Marshall methodically investigated 100 patients with (noncancerous) duodenal and gastric ulcers and found that he could culture bacteria in 17 of those affected. By serendipity, he discovered that the cultures were being discarded too soon. It took longer than normal to get positive cultures, and when the samples were cultured longer, there was a 77-100 percent incidence of positive cultures. His colleagues still failed to believe the link hypothesized between the bacteria cultured and ulcer disease. He then went on to fulfill the rules of proof known as Koch's postulates — at which time his colleagues were virtually certain he was insane. But he persisted and eventually was able to show that he could take a patient with gastritis in which helicobacteria were cultured, successfully treat that patient with antibiotics, then re-create gastritis by inoculating that patient with helicobacteria.

Observations of the correlation between gastric inflammation and peptic ulcers go back to the time of Osler, so the disease was hardly a new phenomenon. And in 1966, an investigator named Ito, who was suffering from peptic ulcer disease, biopsied his own stomach and found it was colonized with a spiral-shaped organism (which we now know as helicobacterium pylori). Ito published an image of the specimen in a widely read textbook of physiology, so this observation had to have been noted by thousands of medical students, scientists and physicians. But still, no one had the courage to think of a plausible way to explain these observations.

In the speech given by Marshall on the awarding of the Nobel Prize, he quoted Daniel Boorstein, a noted historian:

"The greatest obstacle to knowledge is not ignorance; it is the illusion of knowledge."

Or to paraphrase using a quote that one might like to attribute to Yogi Berra:

"It's not what you don't know that will bite you; it's what you don't know that you don't know."

I often speak about the challenges our nation is facing from global competitiveness and the threats from emerging countries, especially in Asia, as they invest more in scientific research and education. At the same time, the one important trait that so far distinguishes and differentiates the United States from many other countries is the open environment in which we encourage our students to challenge the established dogma; probe our professors' assumptions, biases and beliefs; and work in an environment that fosters risk-taking and innovation.

Congratulations, Carol Greider, on a well-deserved honor! You join a distinguished line of Hopkins professors who have received the Lasker Prize, and my hope is that one of the young scientists you mentor will subsequently go on to win a Lasker Prize. This is the Hopkins tradition.


William R. Brody is president of The Johns Hopkins University.


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