Two Win Nobel Prize for Discovering Bacterium Tied to Stomach Ailments

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October 4, 2005

Two Win Nobel Prize for Discovering Bacterium Tied to Stomach Ailments

By LAWRENCE K. ALTMAN

Two Australian scientists who upset medical dogma by discovering a bacterium

that causes stomach inflammation, ulcers and cancer won the 2005 Nobel Prize

for Physiology or Medicine yesterday.

The winners were Dr. Barry J. Marshall, 54, a gastroenterologist from the

University of Western Australia in Nedlands, and Dr. J. Robin Warren, 68, a

retired pathologist from the Royal Perth Hospital.

The findings by the Australians in the early 1980's went so against medical

thinking, which held that psychological stress caused stomach and duodenal

ulcers, that it took many more years for an entrenched medical profession to

accept it.

In its citation, the Nobel committee from the Karolinska Institute in

Stockholm said that Dr. Marshall and Dr. Warren " made an irrefutable case that

the

bacterium Helicobacter pylori " causes ulcers and other diseases.

" It is now firmly established that H. pylori causes more than 90 percent of

duodenal ulcers and up to 80 percent of gastric ulcers, " the Nobel committee

said.

In the wake of the ulcer discovery, many scientists have been seeking unknown

infectious agents as the cause of many chronic diseases. Examples include

microbes that might produce atherosclerosis, the underlying basis of coronary

artery disease; ulcerative colitis; regional enteritis (Crohn's disease); and

rheumatoid arthritis.

A famous experiment Dr. Marshall conducted on himself was crucial in linking

the bacterium to inflammation of the stomach, or gastritis, and showing that

it resulted from an infection.

When the two began their research, doctors could heal ulcers with drugs that

blocked the production of gastric acid, believing stomach acid caused ulcers.

But the ulcers often relapsed because the bacteria remained to perpetuate the

inflammation that leads to ulcers and to certain cancers.

Ulcers at that time were often a chronic, debilitating disease that required

major surgery and that could cause life-threatening complications from

bleeding. Also, they would often erode through the stomach and lead to

peritonitis.

After Dr. Marshall and Dr. Warren discovered the role of the spiral-shaped H.

pylori bacterium, they and others conducted trials showing that antibiotics

and drugs inhibiting the production of stomach acid could cure gastritis and

most stomach and duodenal ulcers.

The inflammation produced by H. pylori can also lead to certain stomach

cancers that seem to be prevented by antibiotic treatment of the bacterium. In

the

early 1900's, stomach cancer was a leading cause of cancer deaths in the

United States. But its incidence fell significantly, for unknown reasons, before

the discovery of H. pylori's role. Stomach cancer remains the second leading

cause of cancer deaths worldwide.

H. pylori is also an important player in a type of lymphoma cancer of the

stomach known as MALT, for mucosa-associated lymphoid tissue. Such lymphomas

usually regress when antibiotics rid the stomach of H. pylori. Since the late

1800's, many doctors had noted the bacterium's presence in the stomachs of

patients with ulcers and gastritis, but they ignored the connection.

In the early 1980's, Dr. Warren noted the bacterium in the lower part of the

stomach in about half of the patients who had biopsies. He made a crucial

observation that signs of inflammation were always present in the surface lining

of the stomach near where he observed the bacterium.

Dr. Marshall joined Dr. Warren in studying biopsies from a series of

patients. After several attempts, Dr. Marshall succeeded in growing a bacterium

that

was unknown then; he named it Campylobacter pyloridis, believing that it was a

member of the Campylobacter family. (It was later found to be a member of the

Helicobacter family and renamed H. pylori.)

Still, many doctors were unconvinced by the findings, a point recognized by

the Nobel committee, which said the award went to Dr. Marshall and Dr. Warren

" who with tenacity and a prepared mind challenged prevailing dogmas. "

Dr. Marshall carried on a medical tradition in experimenting on himself to

test his and Dr. Warren's theory and to show that Helicobacter was the primary

cause of gastritis, not a secondary invader.

In earlier interviews, Dr. Marshall described how at age 32, he swallowed a

gastroscope tube to allow another doctor to look at his stomach and take

several biopsies. These procedures and examinations were needed to document that

Dr.

Marshall had no H. pylori in his stomach and did not suffer from gastritis or

another abnormality.

Dr. Marshall waited 10 days for the areas that had been biopsied to heal and

then swallowed a pure culture of H. pylori. A week later, he had an unusual

sensation of fullness after eating supper and felt ill. Friends told him that

his breath was " putrid. "

Ten days after the onset of symptoms, Dr. Marshall underwent the first of an

additional three gastroscopies. Biopsies obtained through them showed that he

had developed gastritis or inflammation of the stomach, but he did not

continue the experiment long enough to develop an ulcer. His symptoms quickly

disappeared after treatment.

Dr. Marshall said that working in a " weird " and academically obscure location

aided in the discovery because he and Dr. Warren could pursue their

observations without interference from the prevailing beliefs.

" If I had come up through the normal gastroenterology training schemes in the

United States, I would have been so indoctrinated on the acid theory that I

wouldn't have been considering anything else and might have skipped over

Helicobacter, as everyone else had done, " Dr. Marshall said in a telephone

interview

yesterday.

He continued: " Robin is quite obsessional. Once he sees something, he's

determined to see what it is. He would have found another Barry Marshall " to

work

with.

Dr. Marshall said that information he obtained from the National Library of

Medicine, a part of the National Institutes of Health in Bethesda, Md., aided

his discovery. While in training, Dr. Marshall worked in a hospital in Port

Hedland, in the Australian outback about 1,000 miles from Perth.

A librarian in Perth sent Dr. Marshall bundles of references. He said he

" pulled up a whole lot of literature showing that many patients with ulcers had

gastritis that the ulcer experts in the 1980's had forgotten about. "

One of those papers was published in 1940 by Dr. A. Stone Freedberg at

Harvard. He reported identifying similar bacteria in 40 percent of patients with

ulcers and stomach cancer. Then he went on to become a cardiologist, and other

scientists said they could not confirm his findings. In " Helicobacter Pioneers, "

a book edited by Dr. Marshall, Dr. Freedberg wrote that in 1990, he searched

for his old specimens and laboratory books at Beth Israel Hospital in Boston

to check them against Dr. Marshall's new findings. But Dr. Freedberg said

someone had discarded them.

When Dr. Marshall presented his first paper on the findings, he recalled

yesterday, an Australian mentor told him that he was wrong. But Dr. Marshall

persisted and showed the critic where he was wrong.

Researchers are trying to learn why only a small fraction of people who have

H. pylori in their stomachs develop gastritis and ulcers. One possible

explanation is that genetic differences among humans influence their

susceptibility

to stomach disease. Another theory is that differences in strains of H. pylori

may determine the bacterium's ability to produce inflammation.

Scientists recently discovered that the Mongolian gerbil is an animal model

for stomach ulcers, and the Nobel committee said studies on the gerbil could

provide more evidence of how H. pylori damages the stomach.

Dr. Marshall said that every day he reads material on the Internet that turns

up on a Google search of diseases that may be linked to H. pylori. " There's

always something new about H. pylori popping up every week, and I keep an open

mind on all the findings, " Dr. Marshall said.

Dr. Marshall and Dr. Warren will split the $1.3 million prize to be awarded

by the king of Sweden on Dec. 10, the anniversary of the death of Alfred Nobel,

the Swedish dynamite inventor who created the prizes in his will.

Copyright 2005 The New York Times Company