The Emperor of All Maladies: A Biography of Cancer (53 page)

The discovery of HBV was an embarrassment to the NCI. The institute’s highly targeted and heavily funded Special Virus Cancer Program, having inoculated thousands of monkeys with human cancer extracts, had yet to find a single cancer-associated virus. Yet a genetic anthropologist exploring aboriginal antigens had found a highly prevalent virus associated with a highly prevalent human cancer. Blumberg was acutely aware of the NCI’s embarrassment, and of the serendipity in his work. His departure from the NIH in 1964, although cordial, had been driven by precisely such conflicts; his interdisciplinary curiosity had chafed against the “
discipline-determined rigidity of the constituent institutes
,” among which the NCI, with its goal-directed cancer virus hunt, was the worst culprit. Worse still for the strongest enthusiasts of the cancer virus theory, it appeared as if Blumberg’s virus itself was not the proximal cause of the cancer. The
inflammation
induced by the virus in liver cells, and the associated cycle of death and repair, appeared to be responsible for the cancer—a blow to the notion that viruses directly cause cancer.

But Blumberg had little time to mull over these conflicts, and he certainly had no theoretical axes to grind about viruses and cancer. A pragmatist, he directed his team toward finding a vaccine for HBV.
By 1979, his group had devised one
. Like the blood-screening strategy, the vaccine did not, of course, alter the course of the cancer after its genesis, but it sharply reduced the susceptibility to HBV infection in uninfected men and women. Blumberg had thus made a critical link from cause to prevention. He had identified a viral carcinogen, found a method to detect it before transmission, then found a means to thwart transmission.

The strangest among the newly discovered “preventable” carcinogens, though, was not a virus or a chemical but a cellular organism—a bacterium. In 1979, the year that Blumberg’s hepatitis B vaccine was beginning its trial in America, a junior resident in medicine named Barry Marshall and a gastroenterologist, Robin Warren, both at the Royal Perth Hospital in Australia, set out to investigate the cause of stomach inflammation, gastritis, a condition known to predispose patients to peptic ulcers and to stomach cancer.

For centuries, gastritis had rather vaguely been attributed to stress and
neuroses. (In popular use, the term
dyspeptic
still refers to an irritable and fragile psychological state.) By extension, then, cancer of the stomach was cancer unleashed by neurotic stress, in essence a modern variant of the theory of clogged melancholia proposed by Galen.

But Warren had convinced himself that the true cause of gastritis was a yet unknown species of bacteria, an organism that, according to dogma, could not even exist in the inhospitable acidic lumen of the stomach. “
Since the early days of medical bacteriology
, over one hundred years ago,” Warren wrote, “it was taught that bacteria do not grow in the stomach. When I was a student, this was taken as so obvious as to barely rate a mention. It was a ‘known fact,’ like ‘everyone knows that the earth is flat.’”

But the flat-earth theory of stomach inflammation made little sense to Warren. When he examined biopsies of men and women with gastritis or gastric ulcers, he found a hazy, blue layer overlying the craterlike depressions of the ulcers in the stomach. When he looked even harder at that bluish layer, he inevitably saw spiral organisms teeming within it.

Or had he imagined it? Warren was convinced that these organisms represented a new species of bacterium that caused gastritis and peptic ulcers. But he could not isolate the bacteria in any form on a plate, dish, or culture. Others could not see the organism; Warren could not grow it; the whole theory, with its blue haze of alien organisms growing above craters in the stomach, smacked of science fiction.

Barry Marshall, in contrast, had no pet theory to test or disprove. The son of a Kalgoorlie boilermaker and a nurse, he had trained in medicine in Perth and was an unwhetted junior investigator looking for a project. Intrigued by Warren’s data (although skeptical of the link with an unknown, phantasmic bacteria), he started to collect brushings from patients with ulcers and spread out the material on petri dishes, hoping to grow a bacterium. But as with Warren, no bacteria grew out. Week after week, Marshall’s dishes piled up in the incubator and were discarded in large stacks after a few days of examination.

But then serendipity intervened: over an unexpectedly busy Easter weekend in 1982, with the hospital overflowing with medical admissions, Marshall forgot to examine his plates and left them in the incubator. When he remembered and returned to examine them, he found tiny, translucent pearls of bacterial colonies growing on the agar. The long incubation period had been critical. Under the microscope, the bacterium growing on the plate was a minuscule, slow-growing, fragile organism
with a helical tail, a species that had never been described by microbiologists. Warren and Marshall called it
Helicobacter pylori
—
helicobacter
for its appearance, and
pylorus
from the Latin for “gatekeeper,” for its location near the outlet valve of the stomach.

But the mere existence of the bacteria, or even its association with ulcers, was not proof enough that it caused gastritis. Koch’s third postulate stipulated that to be classified as a bona fide causal element for a disease, an organism needed to re-create the disease when introduced into a naive host. Marshall and Warren inoculated pigs with the bacteria and performed serial endoscopies. But the pigs—seventy pounds of porcine weight that did not take kindly to weekly endoscopies—did not sprout any ulcers. And testing the theory on humans was ethically impossible: how could one justify infecting a human with a new, uncharacterized species of bacteria to prove that it caused gastritis and predisposed to cancer?

In July 1984, with his experiments stalled and his grant applications in jeopardy, Marshall performed the ultimate experiment: “
On the morning of the experiment
, I omitted my breakfast. . . . Two hours later, Neil Noakes scraped a heavily inoculated 4 day culture plate of
Helicobacter
and dispersed the bacteria in alkaline peptone water (a kind of meat broth used to keep bacteria alive). I fasted until 10 am when Neil handed me a 200 ml beaker about one quarter full of the cloudy brown liquid. I drank it down in one gulp then fasted for the rest of the day. A few stomach gurgles occurred. Was it the bacteria or was I just hungry?”

Marshall was not “just hungry.” Within a few days of swallowing the turbid bacterial culture, he was violently ill, with nausea, vomiting, night sweats, and chills. He persuaded a colleague to perform serial biopsies to document the pathological changes, and he was diagnosed with highly active gastritis, with a dense overlay of bacteria in his stomach and ulcerating craters beneath—precisely what Warren had found in his patients. In late July, with Warren as coauthor, Marshall submitted his own case report to the
Medical Journal of Australia
for publication (“a normal volunteer [has] swallowed a pure culture of the organism,” he wrote). The critics had at last been silenced.
Helicobacter pylori
was indisputably the cause of gastric inflammation.

The link between
Helicobacter
and gastritis raised the possibility that
bacterial infection and chronic inflammation caused stomach cancer.
^*
Indeed, by the late 1980s, several epidemiological studies had linked
H. pylori
–induced gastritis with stomach cancer. Marshall and Warren had, meanwhile, tested antibiotic regimens (including the once-forsaken alchemical agent bismuth) to create a potent multidrug treatment for the
H. pylori
infection.
^*
Randomized trials run on the western coast of Japan, where stomach and
H. pylori
infection are endemic, showed that antibiotic treatment reduced gastric ulcers and gastritis.

The effect of antibiotic therapy on cancer
, though, was more complex. The eradication of
H. pylori
infection in young men and women reduced the incidence of gastric cancer. In older patients, in whom chronic gastritis had smoldered for several decades, eradication of the infection had little effect. In these elderly patients, presumably the chronic inflammation had already progressed to a point that its eradication made no difference. For cancer prevention to work, Auerbach’s march—the prodrome of cancer—had to be halted early.

Although unorthodox in the extreme, Barry Marshall’s “experiment”—swallowing a carcinogen to create a precancerous state in his own stomach—encapsulated a growing sense of impatience and frustration among cancer epidemiologists. Powerful strategies for cancer prevention arise, clearly, from a deep understanding of causes. The identification of a carcinogen is only the first step toward that understanding. To mount a successful strategy against cancer, one needs to know not only what the carcinogen
is
, but what the carcinogen
does
.

But the set of disparate observations—from Blumberg to Ames to Warren and Marshall—could not simply be stitched together into a coherent theory of carcinogenesis. How could DES, asbestos, radiation, hepatitis virus, and a stomach bacterium all converge on the same pathological state, although in different populations and in different organs? The list of cancer-causing agents seemed to get—as another swallower of unknown potions might have put it—“curiouser and curiouser.”

There was little precedent in other diseases for such an astonishing diversity of causes. Diabetes, a complex illness with complex mani
festations, is still fundamentally a disease of abnormal insulin signaling. Coronary heart disease occurs when a clot, arising from a ruptured and inflamed atherosclerotic plaque, occludes a blood vessel of the heart. But the search for a unifying mechanistic description of cancer seemed to be sorely missing. What, beyond abnormal, dysregulated cell division, was the common pathophysiological mechanism underlying cancer?

To answer this question, cancer biologists would need to return to the birth of cancer, to the very first steps of a cell’s journey toward malignant transformation—to carcino
genesis
.

*
H. pylori
infection is linked to several forms of cancer, including gastric adenocarcinoma and mucosa-associated lymphoma.

*
Marshall later treated himself with the regimen and eradicated his infection.

It is to earlier diagnosis that we must look
for any material improvement in our cancer cures.

—John Lockhart-Mummery, 1926

The greatest need we have today
in the human cancer problem, except for a universal cure, is a method of detecting the presence of cancer before there are any clinical signs of symptoms.

—Sidney Farber, letter to Etta Rosensohn,
November 1962

Lady, have you been “Paptized”
?

—
New York Amsterdam News,
on Pap smears, 1957

The long, slow march of carcinogenesis—the methodical, step-by-step progression of early-stage lesions of cancer into frankly malignant cells—inspired another strategy to prevent cancer. If cancer truly slouched to its birth, as Auerbach suspected, then perhaps one could still intervene on that progression in its earliest stages—by attacking
pre
cancer rather than cancer. Could one thwart the march of carcinogenesis in midstep?