Discovery
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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