Happy Accidents: Serendipity in Major Medical Breakthroughs in the Twentieth Century (17 page)

With the tenacity of a bloodhound, Marshall made intense efforts to enhance his data. Outbreaks of a condition known as acute epidemic gastritis had been reported in the previous several years in various places. With characteristic boldness, Marshall took it upon himself to contact these sources and obtain the microscopic sections from these cases. Failure to identify the presence of spiral bacteria would be a serious setback to his hypothesis, but he was enormously relieved and encouraged to find that most indeed harbored the bacteria.

By 1985 a leading textbook,
Bockus Gastroenterology,
could dismiss the psychosomatic hypothesis with the declaration “the philosophic and metaphysical jargon that plagues the psychologic analysis of ulcer disease is of no value in our understanding the disease, nor in predicting which individuals are at risk and when, nor in the therapy of ulcers.”
¹³
Stress and diet faded from the picture.

With the increasing recognition by microbiologists of Marshall and Warren's research, gastroenterologists and medical epidemiologists undertook further investigations of its clinical importance. The initial skepticism of clinicians was based on their bedrock beliefs regarding excess acidity. They had rejected the bacterial hypothesis of ulcers as inconsistent with what was already known.

But by the 1990s the focus was no longer on whether
H. pylori
causes ulcers but rather on how it does so and how it can be eradicated. Moreover, its mode of transmission, global prevalence, and role in causing gastric cancer and a form of gastric lymphoma were clarified. A torrent of research with the publication of thousands of articles ensued. Ulcers treated with the popular acid-inhibiting H2 blockers introduced back in the 1970s often recurred and therefore required repeated courses of the drugs, which provided a steady stream of profits to pharmaceutical firms. Marshall was convinced that this profit motive kept the drug companies, which funded much of the ulcer research at the time, from supporting the
Helicobacter
discovery.
¹⁴

In a 1988 report in the
Lancet,
Marshall and coworkers showed that combined bismuth and antibiotic therapy healed ulcers far better than one of the most commonly prescribed acid-blockers.
¹⁵
It was major proof that eradication of
H. pylori
cures ulcers. Both Austrian and Dutch researchers reported definitive clinical trials of ulcer cure with antibiotics, improved with the addition of an acid inhibitor. One American gastroenterologist who, a few years earlier, had challenged the validity of Marshall's work was now converted: “We scientists should have looked beyond Barry's evangelical patina and not dismissed him out of hand.”
¹⁶
A seven-year follow-up examination established the long-term benefits of
H. pylori
eradication.

Events rapidly unfolded. On the basis of these findings, expert panels convened by the National Institutes of Health and the American Digestive Health Foundation endorsed the conclusion that all patients with gastric or duodenal ulcers who are infected with
H. pylori
should be treated with antimicrobial and antisecretory agents. In 1995 Barry Marshall was awarded the prestigious Albert Lasker Clinical Medical Research Award. Marshall was finally vindicated after
years of being scorned as, in the words of one eminent gastroenterologist, a “crazy guy saying crazy things.”

“T
HE
U
NIMAGINABLE
H
AS
H
APPENED
”

Intensive epidemiologic studies showed in the early 1990s that
H. pylori
has a worldwide distribution and appears to be the most common chronic bacterial infection of humans, present in almost half of the world population, though usually without causing disease. Most carriers are without symptoms. A bacterium discovered only a few years earlier and greeted with disbelief was now proved to be globally endemic. Marshall was stunned: “I did not expect it to be the world's most common bacterial infection [in man].”
H. pylori
has been found in mummies thousands of years old. Today in the United States, it is found in 30 percent of adults and more than half of people over age sixty-five. Most people carrying it do not get ulcers, of course, so
H. pylori
is clearly not the sole cause of ulcers by itself. But there is no doubt that ulcers can be cured by attacking
H. pylori
with antibiotics and, more important, this cure is permanent!

H. pylori
is believed to be transmitted orally, by means of fecal matter, through the ingestion of waste-tainted food or water. Thus the bacterium is most widespread in places where clean water is lacking. (About 80 percent of the population in most developing countries have the bacteria.) But other modes of transmission are interesting. Researchers have found
H. pylori
in the dental plaque of Indians and in the prechewed food some African mothers feed their infants. It is also possible that it is transmitted from the stomach to the mouth through reflux (in which a small amount of the stomach's contents is involuntarily forced up the esophagus) or belching, common symptoms of gastritis. Although unlikely, the bacteria could then be transmitted through oral contact, as in kissing.

The serendipitous laboratory error in Perth less than a decade earlier next led to another major discovery. Through worldwide epidemiologic studies, a stunning revelation came to light:
H. pylori
was clearly shown to also be a major cause of cancer of the stomach. With
persistent
H. pylori
infection over the course of decades or years, the glands of the stomach lining are destroyed and the mucosal cells undergo a particular reactive transformation, changes that predispose them to cancer. Gastric cancer is second only to lung cancer as a cause of cancer death worldwide, killing hundreds of thousands of people each year. It is particularly prevalent in Asia and many developing countries. In the United States it is only the ninth most common.

People with
H. pylori
gastritis over decades have a risk of developing gastric cancer that is up to six times greater than among people without this infection, but the malignancy actually develops in only a tiny percentage. David Forman of the Imperial Cancer Research Fund in England had originally thought that Marshall's claim for various stomach diseases, including cancer, was a “totally crazy hypothesis.” Now, along with others, he is a convert to the fact that
H. pylori
infection is a major factor in gastric cancer and in ulcers. By 1993 a status report in
Gastroenterology
could proclaim: “It would have been unimaginable that such seemingly diverse diseases as gastritis, gastric ulcer, duodenal ulcer, and… gastric carcinoma would all be different manifestations of an infection with a bacterium. The unimaginable has happened.”
¹⁷

M
ARSHALL
's O
DYSSEY

Marshall's odyssey illustrates several characteristics that are typical of revolutions in medical science. Earlier observers had seen bacteria in the stomach but their importance was simply not recognized. The inability of these observers to connect the dots meant that opportunities for a major breakthrough were lost. After examination of random samples from limited segments of the stomach derived in a blind fashion, the bacteria were declared a mere contaminant in 1954 by a respected gastroenterologist and therefore of no particular interest. His premature conclusion slammed the door on further investigation. The development of the new technology known as fiberoptic endoscopy was necessary to allow Warren to inspect targeted samples for pathologic changes and thereby serendipitously observe the plentiful colonies
of spiral bacteria deep in the mucus layer. Yet gastroenterologists remained uninterested.

Marshall was a youthful maverick, not bound by traditional theory and not professionally invested in a widely held set of beliefs. There is such a thing as being too much of an insider. Marshall viewed the problem with fresh eyes and was not constrained by the requirement to obtain approval or funding for his pursuits. It is also noteworthy that his work was accomplished not at a high-powered academic ivory tower with teams of investigators but instead far from the prestigious research centers in the Western Hemisphere.

The delay in acceptance of Marshall's revolutionary hypothesis reflects the tenacity with which long-held concepts are maintained. Vested interests—intellectual, financial, commercial, status—keep these entrenched. Dogmatic believers find themselves under siege by a new set of explanations. The stage is set, in the scholarly phrase of the historian of science Thomas Kuhn, for “incommensurable competing paradigms where proponents live in different worlds.”
¹⁸

Given the confluence of multiple factors, are certain discoveries inevitable? Some think so. One investigator in the field was of this opinion: “Somebody was going to find the bacterium sooner or later. But the fact is he (Marshall) did find it. And he wrote it up and he pushed it.”
¹⁹

In 2005 Marshall and Warren were awarded the Nobel Prize for Physiology or Medicine. No further proof was needed to disclaim the tongue-in-cheek charge by some that Western Australia is “the wrong end of the wrong place.”

Part II

The Smell of Garlic
Launches the War on Cancer

It leaves the impression that all shots can be called from a national headquarters; that all, or nearly all, of the really important ideas are already in hand…. It fails to allow for the surprises which must surely lie ahead if we are really going to gain an understanding of cancer.

—A
COMMITTEE OF THE
I
NSTITUTE OF
M
EDICINE
,
N
ATIONAL
A
CADEMY OF
S
CIENCES,
ON THE
N
ATIONAL
C
ANCER
A
CT AND THE “WAR ON CANCER”

9

Tragedy at Bari

In late 1943 the Adriatic port of Bari on the southeastern coast of Italy was crowded with Allied tankers and munition ships to support the invasion of Italy following the victories in North Africa and Sicily. To supply these operations, convoys carrying thousands of tons of ammunition and aviation gasoline were rushed into the Bari harbor. By December 2, 1943, every dock was occupied, and additional ships were anchored along the entire length of the seawall waiting to be unloaded. The SS
John Harvey
was moored at the harbor's eastern jetty. The port was so crowded that the ships were tied up touching each other, and long lines of supply trucks extended to numerous storage depots.

Eastern Italy was then under British jurisdiction. In order to expedite the unloading of cargo at Bari, no blackout was in force in the harbor. Rather, the port was fully illuminated. The British were convinced that the German air force in Italy was so depleted that it posed no threat in the area. British Air Marshal Sir Arthur Coningham went so far as to proclaim, “I would regard it as a personal affront and insult if the Luftwaffe would attempt any significant action in this area.” He tragically underestimated the enemy.

Indeed, the Royal Air Force (RAF) had no fighter squadrons based in Bari. Yet the importance of the shipments at Bari to the Allied advance was obvious to German commanders. High-flying German reconnaissance planes documented the arrival of the convoys and the crowding in the harbor. A fleet of German bombers was rapidly
organized from scattered airfields in northern Italy and ordered to attack Bari at dusk from the east.

On the evening of December 2, 1943, in a raid lasting twenty minutes, 105 Junker 88s skimmed the water and destroyed the Bari harbor. Only a few ships needed to be hit; with their vast cargoes of ammunition and fuel, each ship's explosion ignited others. One after another, they detonated in a deadly series. The surface of the harbor became a sheet of flame as the oil from broken petroleum lines, gasoline, and other cargo burned.

Axis attack on Bari, Italy, December 1943.

Hundreds of men thrown into the Adriatic desperately tried to reach safety. As they struggled in the sea or on lifeboats, the oily water stirred up by the series of explosions continuously doused them. It coated their bodies and went into their eyes and nostrils and down their throats. Some had trouble breathing from the fumes carried by billowing clouds of smoke.

In the midst of this maelstrom, some noticed a curious smell. Several of the survivors from the harbor would later recall what they described as a “garlicky odor.” And across the harbor, as a very heavy cloud of smoke drifted over the town, a German prisoner of war turned to an American military policeman and said in perfect English, “I smell mustard gas.” The MP looked startled. He took a deep breath and coughed. “Hell, that's garlic.”
¹