Happy Accidents: Serendipity in Major Medical Breakthroughs in the Twentieth Century (16 page)

Thus in subjects in which knowledge is still growing, or where the particular problem is a new one, or a new version of one already solved, all the advantage is with the expert, but where knowledge is no longer growing and the field has been worked out, a revolutionary new approach is required and this is more likely to come from the outsider. The skepticism with which the experts nearly always greet these revolutionary ideas confirms that the available knowledge has been a handicap.
⁵

—W. I. B. Beveridge, medical historian,
Cambridge University

Marshall's first indication that the bacteria were clinically relevant occurred in September 1981, when he treated a patient with severe abdominal discomfort caused by gastritis with tetracycline, an antibiotic. After fourteen days of treatment, the gastritis cleared up. Clearly, the next step was to culture the bacteria for identification and testing.

L
EFT
B
EHIND ON A
L
ONG
E
ASTER
W
EEKEND

Culturing a microorganism in a sterile medium with the proper nutrients is essential for its further investigation, including establishing its identification, characterization, and degree of susceptibility to antibiotics. This is generally accomplished by streaking a bacteria-laden site upon an agar plate or in nutrient broth.

Over the latter months of 1981, Marshall repeatedly tried to grow the bacteria in both oxygen-rich and oxygen-depleted environments but was unsuccessful. He thought the spiral bacteria were of the
Campylobacter
genus, bacteria that require only two days to grow in incubation, and on this reasoning the clinical laboratory discarded the agar plates after forty-eight hours if no growth was visible. In April 1982, after many months of failed attempts at culturing the bacteria, Marshall left for the four-day Easter weekend feeling dejected.

Marshall's agar plates were inadvertently left in the dark, humid incubator for five days. No one had ever thought to give the culture this much time to grow. But five days did the trick. Returning to the laboratory, Marshall was elated to find thriving colonies on some of the plates. Peering through a microscope at a culture smeared on a slide, Marshall saw dozens of corkscrew-shaped organisms. He and Warren had grown the bacteria! It was now evident that longer culture time was necessary. Within a few months, it became clear exactly what the fastidious organism required: an enriched culture medium, such as sheep blood or chocolate agar, incubated under humid, microaerobic conditions for five to seven days.

M
ARSHALL-ING THE
F
ACTS

Marshall then designed a clinical study in one hundred patients to look for the occurrence of the bacteria and the presence of stomach disorders. He found that bacteria were commonly associated with gastritis and were present in 80 percent of patients with gastric (stomach) ulcers and in 100 percent of patients with duodenal (intestinal) ulcers, in contrast to 50 percent of patients with a normal stomach.
⁶
The literature strongly indicated not only that chronic gastritis was associated with peptic ulcers but also that acid-reducing drugs, such as cimetidine, merely healed rather than cured duodenal ulcers. Clearly, stomach acid was not the sole cause.

Then Marshall had an idea. Early in the century, Paul Ehrlich had used arsenical compounds against the spirochete of syphilis. Bismuth, an element in the same chemical group, had long been used as a remedy for abdominal discomfort and peptic ulceration. As recently as 1980 it had been reported that duodenal ulcers treated with a bismuth compound—marketed over the counter as Pepto-Bismol—had a diminished relapse rate. “This suggested to me,” reasoned Marshall, “that bismuth compounds might inhibit the spiral bacteria” and thereby heal ulcers and gastritis.

The proper treatment regimen revealed itself in an unexpected circumstantial way. Marshall had earlier determined that, within a day of applying bismuth to a colony growing on an agar plate, all the bacteria died. In clinical trials, chewable bismuth tablets eradicated all signs of ulcers or gastritis, but to Marshall's disappointment, after discontinuing the treatment, nearly every patient suffered a relapse. Why, he wondered, would bismuth kill bacteria in a Petri dish but not in a patient's stomach? Then he noticed something strange. One patient, months after treatment with chewable bismuth tablets, continued to show no signs of recurrence. Reviewing the patient's record, Marshall saw that the man had suffered from a gum infection and, to treat it, had been given an antibiotic. Marshall hypothesized that bismuth alone did not reach all of the bacteria enshrouded in the stomach's thick mucus layer and had to be used in combination with an antibiotic.

The next development in the saga occurred due to another technological advance—the development of electron microscopy. A detailed morphology using the new equipment revealed that the stomach bacterium was not campylobacter. Clearly, this misidentification had been the cause of Marshall and Warren's earlier failures in growing the organism, as campylobacter required only a couple of days to get established. It would take another seven years, after RNA analysis and other studies, for these bacteria to be assigned to a new genus,
Helicobacter,
and receive a proper name,
H. pylori. Helicobacter
refers to its helical shape and
pylori
refers to the pylorus (“gateway”), the exit from the stomach to the duodenum.

The
H. pylori
Lifestyle

That
Helicobacter
flourishes in the human stomach is a testament to evolutionary ingenuity. Both its shape and its biochemistry favor the adaptation of the bacterium to its harsh acidic environment. The lining of the stomach is protected from the acid by a thick viscous layer of mucus, in which
H. pylori
can take refuge. Four whiplike flagella at one pole of each bacterium provide rapid motility through the gastric juice, and the helical structure of the bacteria facilitates a burrowing corkscrew path from the stomach cavity through the thick mucus to establish colonies next to the lining cells.

Once
H. pylori
is safely sheltered in the mucus, it is able to fight the stomach acid that does reach it with an enzyme it possesses called urease. Urease converts urea, which is abundantly present in the gastric juices, into bicarbonate (a natural Alka-Seltzer) and ammonia. These are both strong alkalis. In this fashion, the
Helicobacter
cocoons itself in a protective acid-neutralizing mist. Furthermore, the bacteria thrive best in 5 percent oxygen—exactly the level found in the stomach's mucus layer.

Helicobacter
colonies may thrive for a long time before symptoms appear—indeed, for decades, as recent studies have shown. Eventually the bacteria cause injury to the stomach lining through their toxic waste products and release of destructive enzymes, causing chronic inflammation. Some
H. pylori
even use a structure similar to a hypodermic needle to inject a particularly potent toxin into the stomach lining, boosting the associated inflammatory response. On top of all this,
H. pylori
infection stimulates the secretion of gastric acid. At that point, the bacteria's human host experiences symptoms of gastritis, and a peptic ulcer may eventually result from the inflammation of the stomach lining.

The crafty invader gets its supplies from the unfortunate besieged victim itself—specifically, the stomach tissue—using the inflammatory response as a means of obtaining a constant and reliable source of nutrients. Thus, micronutrients from the body's bloodstream seep across to feed and sustain the
H. pylori
population for years or decades. The bacteria possess yet another survival mechanism: In unfavorable environments, such as nutrient deprivation and antibiotic exposure,
H. pylori
may ball itself up and assume a rounded (coccoid) form for survival in a dormant state.

The gastritis induced directly results in structural and functional changes in the stomach and intestinal lining that can cause ulcer disease. It is now known that
H. pylori
infection accounts for 80 to 90 percent of gastric ulcers (the remainder being the consequence of high doses of aspirin or other nonsteroidal anti-inflammatory agents) and more than 95 percent of duodenal ulcers. Of even greater significance, it is the leading cause of stomach cancer.

“T
HIS
G
UY
I
S A
M
ADMAN
”

Marshall's first formal sting of rejection by organized medicine's orthodoxy of belief in the causation and treatment of peptic ulcer disease was felt in January 1983 when he submitted a report for the meeting of the Australian Gastroenterology Society in which he contended that bacteria might be responsible for ulcers. Although fifty-nine of the sixty-seven submissions for this meeting were accepted, Marshall's was not. The society had neglected the wisdom of Claude Bernard, the nineteenth-century founder of experimental medicine, who famously said, “If an idea presents itself to us, we must not reject it simply because it does not agree with the logical deductions of a reigning theory.”
⁷
In a wry understatement Marshall noted, “It was clear I was thinking very differently from the gastroenterologists.”

He was encouraged by a colleague to present his findings to a meeting in September in Brussels of infectious disease specialists gathered
to focus on campylobacter infections. This paradigmatic shift in drawing the attention not of gastroenterologists but of infectious disease specialists at an international workshop was the stepping-stone to eventual acceptance. Marshall presented evidence that he had found a new bacterium in the stomach and that it resembled the campylobacter species. This part of his presentation was accepted by the audience as clear and appropriate.
⁸
However, to Martin Blaser, an American physician expert in infectious diseases, Marshall's claim regarding the bacterial causation of peptic ulcers without the presentation of any scientific evidence was “the most preposterous thing I'd ever heard. I thought, this guy is a madman.”
⁹
In time, Blaser became a dedicated researcher in the field.

Warren and Marshall's landmark study, “Unidentified curved bacilli on gastric epithelium in active chronic gastritis,” was published later that year in the
Lancet,
¹⁰
in an unusual format: two separate letters. Warren's letter described work on the bacteria that he had conducted alone before collaboration with Marshall. Marshall's described their joint work. The two men published a joint report the following year indicating the bacterial cause of gastritis and of gastric and duodenal ulcers.
¹¹
“I was certain,” Marshall said, “that it would immediately gain universal acceptance.” His confidence proved to be unduly optimistic. Indeed, most gastroenterologists viewed the hypothesis that peptic ulcers are caused by bacteria with incredulity. Nevertheless, growing interest was generated by reports published within the year by other investigators confirming the presence of gastric spiral bacteria and their association with gastritis.

P
HYSICIAN
, H
EAL
T
HYSELF
(B
UT
F
IRST
M
AKE
T
HYSELF
S
ICK
)

Marshall and Warren faced one especially big hurdle. They had not firmly established that the microorganism
H. pylori
was the cause of the disease in question. As declared by Robert Koch, the German scientist who established the bases of bacteriology in modern medicine in the latter part of the nineteenth century, three conditions are required in order to prove causation: the organism must be shown to be constantly present in characteristic form and arrangement in the diseased
tissue; pure cultures of the organism must be obtained; and the pure culture must be shown to induce the disease experimentally.

Marshall and Warren had satisfied postulates 1 and 2, correlating
H. pylori
infection with gastritis and peptic ulcer. Marshall tried to create an animal model to satisfy Koch's third postulate, but both the rats and the pigs that he tried to infect proved to be resistant to the bacteria. In desperation, in July 1984 he undertook a self-experiment that was reported in the
Medical Journal of Australia.
¹²
Self-experimentation is, in fact, a noble tradition in the history of medicine by means of which many advances and discoveries have been made. This maneuver was necessary, in Marshall's words, for “closing the circle.”

After gastroscopy found no bacteria or inflammation present in his stomach, Marshall swallowed a foul-tasting brew of
H. pylori
– laden broth after inhibition of gastric acidity. After a week, he suffered first vomiting and then, for about a week, headaches and putrid breath. Ten days after his symptoms began, follow-up gastroscopy with biopsy documented that he had acute gastritis and that the spiral bacteria had established themselves in his stomach. On the fourteenth day, Marshall began treating himself with an antibiotic and bismuth. His symptoms promptly cleared and another endoscopic biopsy documented resolution. This infection had induced an acute self-limited gastritis. Marshall had fulfilled Koch's third postulate, on himself!