The Doctor Who Wouldn't Accept Noby Suzanne Chazin | ||
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| Painful Ulcers | As the hands of the wall clock edged toward midnight, Barry Marshall rubbed his eyes and laced a slide under the microscope at Western Australia's Royal Perth Hospital. The wary internal medicine resident had seen almost a dozen ulcer and gastritis patients that spring day in 1982. They came to the hospital grimacing in agony and feeling guilty for letting stress, alcohol, tobacco or spicy food turn their lives into a living hell. What frustrated the lanky, 30 year old internist was that there was no cure for their illness. For many, the pain became chronic. Marshall could temporarily reduce his patients' discomfort and inflammation with such prescription antacids as Zantac (ranitidine) and Tagamet (cimetidine). Within six months of stopping such drugs, however, half of all patients relapsed and within two years, as many as 95 percent would. |
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| Suspicious Bacteria |
Marshall hunched over the microscope and studied a biopsy taken from an ulcer patients' stomach. On the slide were dozens of corkscrew shaped organisms resembling Campy lobacter bacteria. They had first been identified by the hospital's pathologist, Dr. J. Robin Warren, who had shown Marshall the slide.For the past year, Marshall and Warren had studied 100 patients with ulcers of the stomach and duodenum (the upper end of the small intestine) and non ulcer stomach inflammation (gastritis). In 87 percent of the cases with ulcers, the mysterious bacteria appeared. Curiously, the bacteria were never present in biopsies taken from people without ulcers or gastritis. Was there a connection?Leading gastric specialists insisted the bacteria must have developed after the tissue was removed. It was considered impossible for the bacteria to survive in the stomach or adjoining duodenum. Hydrochloric acid and other digestive juices kept those regions sterile.Decades of clinical studies blamed ulcers on weak stomach linings and the stomach's inability to deal with gastric acid. Maybe, thought Marshall, the experts were wrong. |
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| Culture Shock | The eldest son of a welder and a nurse, Marshall grew up in a remote area of Western Australia where self sufficiency and common sense counted for more than bookish theories. He applied that same can do spirit to his work. When he needed a centrifuge to separate red blood cells for an experiment he substituted his kitchen ceiling fan, tying test tubes to the rotating blades.
Now he tried to make sense of what he was seeing under the microscope. He began with a computer search of articles on ulcer disease written over the past century. He was astounded that as far back as 1893, articles mentioned the presence of bacteria in the stomach. A paper in 1940 yielded another surprise: bismuth, an over the counter drug, seemed to help heal some ulcers. Marshall now had two links of a three link chain. If he could prove bismuth eradicated the bacteria, he'd be able to tie the presence of these bugs to ulcers and gastritis.To prove his theory, the bacteria had to be cultured for observation. By culturing them in a sterile medium with the proper nutrients, scientists can identify the microorganisms and learn how they function. For months Marshall and Warren had lab technicians try different mediums, with each petri dish left in the incubator two daysthe minimum time for culturing most bacteria. By April 1982 all attempts had failed. |
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| A Break |
Marshall left for the long Easter weekend feeling dejected. For six days some petri dishes languished in the dark, humid incubator.On Tuesday, Marshall found a patch of grayish white bumps on the dishes. After the culture had been smeared on a slide, he peered into the microscope, then hollered with delight. He could see dozens of grayish, corkscrew shaped organisms. He and Warren had grown the bacteria!
Later Marshall placed a quarter inch disc of colloidal bismuth on one of the culture dishes. After 24 hours, the area surrounding the disc previously marred by translucent bumps was smooth and clear. Bismuth had eradicated the bacteria.
By June Marshall and Warren had completed their 100 patient study linking ulcers with the Campylobacter like bacteria. They tried to have their results published in the British medical journal The Lancet but were initially rejected. Marshall knew what the experts were probably thinking: important work is done by important people. How could this young internist not even a gastrointerologist be right about something that flies in the face of decades of ulcer research? Marshall was now working at Fremantle Hospital, doing much of his research on his own time. Convinced that he was on the right track, he began treating patients with bismuth on an experimental basis. While some improved, most relapsed. It now looked to Marshall as if his therapy was no better than conventional prescription antacids. Why, he wondered, would bismuth kill bacteria in a petri dish but not in a patient's stomach? Then in a clinical trial, he noticed something strange. One patient continued to show no signs of relapse months after treatment with chewable bismuth tablets. Reviewing the patient's records, he recalled that the man had suffered a gum infection. To treat it, Marshall had given him a common antibiotic metronidazole. |
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| Night Call |
Marshall pieced together what was happening. Once a patient is infected with the bacteria, they burrow into the mucous lining of the stomach, where neither stomach acid nor most of the bismuth can reach the. Even if the bismuth kills 99 percent of the bacteria, the remaining one percent can multiply. For some patients, only a combination of bismuth and antibiotics is strong enough to destroy the bacteria.
With such a regimen, some patients experienced abdominal pain and diarrhea. But approximately seven out of ten had no ulcer or gastritis recurrences or signs of bacterial infection months after treatment. One night, after local television broadcast a story about Marshall's work, the doctor received a call from a man scheduled for ulcer surgery the next morning. The patient had just sold his business because doctors told him the stress of working was aggravating his condition. Marshall rushed to the hospital and performed an endoscopy of the man's stomach. Dozens of bacteria showed up in the biopsy. Over the next six months, Marshall gave him five treatments of antibiotics and bismuth, eradicating the bacteria and curing him of the disease. |
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| Desperate Gesture | When Marshall finally presented his and Warren's findings before an international conference of microbiologists in Brussels in September 1983, he was greeted with some skepticism. Unschooled at such presentations and filled with boyish eagerness, he refused to respond to questions in the measured, cautious manner of most researchers. Asked whether he though the bacteria were responsible for some ulcer disease, Marshall replied, No, I think they're responsible for all ulcer disease." Such blanket statements, backed only by small studies and anecdotal case histories alarmed many researchers. Microbiologist Martin Blaser, an infectious disease expert from Vanderbilt University who attended the conference, said, "At that time, I thought the guy was a madman." Months went by. Marshall received no invitations to speak or submit research papers to journals. His attempts to induce ulcers in laboratory animals failed. Over and over, he heard the same refrain: how could he be certain this bug which would later by called Helicobacter pylori, or H. pylori for short caused ulcers and gastritis? Every day Marshall saw patients being cured by his treatment. He knew millions more were suffering, but how could he reach them if their doctors wouldn't listen? So one evening in June 1984 he walked into the hospital lab, opened a test tube and added several eyedroppers of a light gray liquid to a glass beaker filled with broth. With a quick toss of the head, he swallowed the foul tasting concoction. Within 72 hours, he was doubled over in pain with a roaring case of clinical gastritis, a precursor to ulcers. Severe vomiting and stomach pain kept him awake for nights. He shuddered to think of what it was like for patients who had such symptoms on and off for years. But by the time he started the antibiotic/ bismuth treatment, his system had managed to eradicate the germ. While he wasn't able to show his treatment worked, Marshall had proved that the microbe could cause gastritis. Yet he knew his critics would remain unconvinced by his self experimentation. He'd have to persuade them with traditional scientific data. |
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| Grudging Friendship | Marshall researched outbreaks of gastritis to determine a possible link with infection. Soon he found what he was looking for: an outbreak in Texas that had occurred during tests, ironically, of new ulcer medications. Marshall figured H. Pylori in one subject had been passed to others during research. With characteristic boldness, Marshall wrote a letter to Dr. Walter Peterson, a noted American gastric expert and a member of the laboratory where the outbreak had occurred. In it, he told Peterson that he was certain if the team review the 1976 biopsies, they'd find H. pylori in the stomachs of those subjects who developed gastritis. Peterson, then chief of gastroenterology at the Veterans Affairs Medical Center in Dallas, later confirmed Marshall's findings. Impressed, he invited the young doctor to the United States to present his work to other researchers. Marshall arrived in late 1984 armed with a study he'd performed on 16 patients treated with a combination of bismuth and one of three common antibiotics. A year later after treatment, no patient had suffered a relapse. Marshall felt certain, the evidence would prompt clinical trials by others. Although the doctors questioned Marshall in detail, no trials were initiated. Peterson and others suggested Marshall embark upon a full scale, multiyear study of the effectiveness of his regimen. Marshall countered that his use of over the counter drugs and frequently prescribed generic antibiotics made a full scale study unnecessary. "If someone tries to prove me wrong, they might discover I'm right, he told them. One doctor who picked up the gauntlet was David Graham, chief of gastroenterology at Houston's Veterans Affairs Medical Center. Of Marshall's theory Graham said, If it's not true, it will be easy to disprove." Marshall later wrote: "Have you disproved me yet?" From there, the two men struck up a grudging friendship, and Graham began to examine Marshall's ideas more closely. |
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| Focus on Patients |
In 1985 Marshall took the advice of U.S. researchers and initiated a large scale, two year study of antibiotic/bismuth treatment of ulcer disease. His group split 100 patients into four units randomly selected to receive either bismuth or cimetidine, with either the antibiotic tinidazole or a placebo. After therapy, H. pylori was cleared in 70 percent of the patients taking the bismuth antibiotic combination. None of those relapsed after one year.
In 1988, little more than a year after accepting an assistant professorship in gastrointerology at the University of Virginia, Marshall submitted the findings to the New England Journal of Medicine. Reviewers rejected the study as inconclusive. Their harsh comments echoed through his head. Maybe I'm not the greatest researcher of all time, he thought. All he really wanted was to heal people and that was just what he was doing. Why focus on his methods? Couldn't they see people were being cured? He thought of Anna Lee Dunaways, a 58 year old patient from Waynesboro, Va. For ten years, she'd suffered severe heartburn and nausea because of ulcers. Twice she visited the emergency room with symptoms so acute the emergency room doctor suggested surgery. Other doctors prescribed drugs to alleviate stress; but nothing relieved her symptoms for more than a short period. Yet within two months of receiving a three-week regime of bismuth and antibiotics from Marshall, her ulcers vanished, never to return again. This was what his work was all about, Marshall decided If I can't persuade experts, he vowed, I'll just keep treating patients until the results are so overwhelming that no one will be able to ignore them. | |
| Cancer Link More Studies |
Gradually, noted researchers began paying attention to the brash Australian doctor. By 1986, more than 20 research groups had found H. pylori in the stomachs of patients with gastritis. Studies that followed found that adding a two week dose of generic antibiotics and bismuth to traditional ulcer medications can obliterate the bacteria and keep ulcers away in at least 75 percent of cases. Two more studies involving almost 135,000 people demonstrated the life saving possibilities of eradicating the bacteria. Researchers found that infection of H. pylori is strongly associated with the development of stomach cancer the second most common cancer. Treatments to kill H. pylori were refined in more scientifically conclusive studies, the first of importance performed by one time skeptic David Graham. In a two year study of 100 ulcer patients, published in 1992 in the Annals of Internal Medicine, Graham found that a combination of antibiotics, bismuth and ranitidine eradicated ulcers in 95 percent of patients with gastric ulcers. By contrast, ranitidine alone was effective for only 12 percent of gastric ulcer sufferers and 13 percent of duodenal patients. A second study by other researchers, published this year in the New England Journal of Medicine, confirmed Graham's findings. The data from around the world are consistent and unquestionable," says Graham. Ulcers associated with H. pylori infection are curable . " Even Walter Peterson, long a skeptic of Marshall's theories, has come around. He says now, We scientists should have looked beyond Barry's evangelical patina and not dismissed him out of hand." Agrees Vanderbilt's Blaser, Science needs solid research, but it also needs someone with great vision. Barry had vision." Yet despite overwhelming clinical evidence, Blaser estimates that at most ten percent of community based physicians currently treat chronic ulcer sufferers with antibiotic therapy. The majority of physicians are either unaware of the treatment or consider it still experimental. For Marshall, However, his greatest satisfaction comes not from proving the experts wrong, but from helping patients better their lives. We have the capability of wiping out ulcer disease in most people. There's no reason why that shouldn't be the standard of treatment for everyone today. | |